FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Funderburk, SC Krashes, MJ AF Funderburk, Samuel C. Krashes, Michael J. TI Electromagnetic control of neural activity - prospective physics for physicians SO NATURE REVIEWS ENDOCRINOLOGY LA English DT Editorial Material ID GLUCOSE; NANOPARTICLES; HYPOTHALAMUS; BEHAVIOR; MICE AB Rapid, minimally invasive control of explicit neural activity would be a major advance for basic and clinical research in the neuroscience and neuroendocrinology fields, and could have applications for the potential treatment of neurological disorders. A new study by Stanley et al. brings us closer to this goal. C1 [Funderburk, Samuel C.; Krashes, Michael J.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. NIDA, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. RP Krashes, MJ (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM michael.krashes@nih.gov NR 10 TC 0 Z9 0 U1 5 U2 15 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5029 EI 1759-5037 J9 NAT REV ENDOCRINOL JI Nat. Rev. Endocrinol. PD JUN PY 2016 VL 12 IS 6 BP 317 EP 318 DI 10.1038/nrendo.2016.65 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DM2NU UT WOS:000376184300003 ER PT J AU Williams, JS Lujan, SA Kunkel, TA AF Williams, Jessica S. Lujan, Scott A. Kunkel, Thomas A. TI Processing ribonucleotides incorporated during eukaryotic DNA replication SO NATURE REVIEWS MOLECULAR CELL BIOLOGY LA English DT Review ID TRANSCRIPTION-ASSOCIATED MUTAGENESIS; AICARDI-GOUTIERES-SYNDROME; MAINTAIN GENOME INTEGRITY; IMBALANCED DNTP POOLS; RNASE H2 COMPLEX; SACCHAROMYCES-CEREVISIAE; POLYMERASE-EPSILON; TOPOISOMERASE-I; MISMATCH REPAIR; EXCISION-REPAIR AB The information encoded in DNA is influenced by the presence of non-canonical nucleotides, the most frequent of which are ribonucleotides. In this Review, we discuss recent discoveries about ribonucleotide incorporation into DNA during replication by the three major eukaryotic replicases, DNA polymerases alpha, delta and epsilon. The presence of ribonucleotides in DNA causes short deletion mutations and may result in the generation of single-and double-strand DNA breaks, leading to genome instability. We describe how these ribonucleotides are removed from DNA through ribonucleotide excision repair and by topoisomerase I. We discuss the biological consequences and the physiological roles of ribonucleotides in DNA, and consider how deficiencies in their removal from DNA may be important in the aetiology of disease. C1 [Williams, Jessica S.; Lujan, Scott A.; Kunkel, Thomas A.] NIEHS, Genome Integr & Struct Biol Lab, NIH, DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. RP Kunkel, TA (reprint author), NIEHS, Genome Integr & Struct Biol Lab, NIH, DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov FU Intramural Research Program of the US National Institutes of Health, National Institute of Environmental Health Sciences FX The authors thank Dmitry Gordenin and Scott Williams for critical reading of the manuscript. The laboratory is supported by the Intramural Research Program of the US National Institutes of Health, National Institute of Environmental Health Sciences. The authors apologize to colleagues whose primary research articles are not cited owing to space limitations. NR 148 TC 6 Z9 6 U1 7 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0072 EI 1471-0080 J9 NAT REV MOL CELL BIO JI Nat. Rev. Mol. Cell Biol. PD JUN PY 2016 VL 17 IS 6 BP 350 EP 363 DI 10.1038/nrm.2016.37 PG 14 WC Cell Biology SC Cell Biology GA DM7GU UT WOS:000376526400010 PM 27093943 ER PT J AU Armstrong, TS Grant, R Gilbert, MR Lee, JW Norden, AD AF Armstrong, Terri S. Grant, Robin Gilbert, Mark R. Lee, Jong Woo Norden, Andrew D. TI Epilepsy in glioma patients: mechanisms, management, and impact of anticonvulsant therapy SO NEURO-ONCOLOGY LA English DT Article DE anticonvulsant; epilepsy; glioma; seizure ID LOW-GRADE GLIOMAS; QUALITY STANDARDS SUBCOMMITTEE; MAJOR DEPRESSIVE DISORDER; TUMOR-ASSOCIATED EPILEPSY; ANTIEPILEPTIC DRUG-WITHDRAWAL; GAMMA-AMINOBUTYRIC-ACID; DIAGNOSED BRAIN-TUMORS; GLIOBLASTOMA-MULTIFORME; PRACTICE PARAMETER; AMERICAN-ACADEMY AB Seizures are a well-recognized symptom of primary brain tumors, and anticonvulsant use is common. This paper provides an overview of epilepsy and the use of anticonvulsants in glioma patients. Overall incidence and mechanisms of epileptogenesis are reviewed. Factors to consider with the use of antiepileptic drugs (AEDs) including incidence during the disease trajectory and prophylaxis along with considerations in the selection of anticonvulsant use (ie, potential side effects, drug interactions, adverse effects, and impact on survival) are also reviewed. Finally, areas for future research and exploring the pathophysiology and use of AEDs in this population are also discussed. C1 [Armstrong, Terri S.] Univ Texas Hlth Sci Ctr Houston, Dept Family Hlth, Houston, TX 77030 USA. [Grant, Robin] Edinburgh Ctr Neurooncol, Edinburgh, Midlothian, Scotland. [Gilbert, Mark R.] NCI, Neurooncol Branch, Bethesda, MD 20892 USA. [Gilbert, Mark R.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Lee, Jong Woo] Brigham & Womens Hosp, Div EEG & Epilepsy, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. [Norden, Andrew D.] Dana Farber Canc Inst, Ctr Neurooncol, Boston, MA 02115 USA. [Norden, Andrew D.] Brigham & Womens Hosp, Dept Neurol, Div Canc Neurol, 75 Francis St, Boston, MA 02115 USA. [Norden, Andrew D.] Harvard Univ, Sch Med, Boston, MA USA. RP Armstrong, TS (reprint author), Room 577,6901 Bertner Ave, Houston, TX 77030 USA. EM terri.s.armstrong@uth.tmc.edu RI Gilbert, Mark/J-7494-2016 OI Gilbert, Mark/0000-0003-2556-9722 FU UCB FX There was no funding support for the preparation of this manuscript. fee donated from UCB direct to UK Brain Tumour Charity. Terri Armstrong: consultant for ABBvie, Immunocellular Therapeutics, and Tocagen. NR 137 TC 5 Z9 5 U1 3 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2016 VL 18 IS 6 BP 779 EP 789 DI 10.1093/neuonc/nov269 PG 11 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DM2BO UT WOS:000376151200010 PM 26527735 ER PT J AU Lovallo, WR Enoch, MA Acheson, A Cohoon, AJ Sorocco, KH Hodgkinson, CA Vincent, AS Goldman, D AF Lovallo, William R. Enoch, Mary-Anne Acheson, Ashley Cohoon, Andrew J. Sorocco, Kristen H. Hodgkinson, Colin A. Vincent, Andrea S. Goldman, David TI Early-Life Adversity Interacts with FKBP5 Genotypes: Altered Working Memory and Cardiac Stress Reactivity in the Oklahoma Family Health Patterns Project SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID GLUCOCORTICOID-RECEPTOR GENE; MAJOR DEPRESSION; ENVIRONMENT INTERACTIONS; ADDISONS-DISEASE; HIPPOCAMPAL-FORMATION; PREFRONTAL CORTEX; LIMBIC STRUCTURES; DECISION-MAKING; PUBLIC SPEAKING; CORTISOL-LEVELS AB Exposure to stress during critical periods of development can have adverse effects on adult health behaviors, and genetic vulnerabilities may enhance these stress effects. We carried out an exploratory examination of psychological, physiological, and behavioral characteristics of 252 healthy young adults for the impact of early-life adversity (ELA) in relation to the G-to-A single nucleotide polymorphism (SNP), rs9296158, of the FKBP5 gene. FKBP5 is a molecular cochaperone that contributes to the functional status of the glucocorticoid receptor (GR) and to the quality of corticosteroid signaling. FKBP5 expression is upregulated by cortisol exposure during stressful episodes, with greater upregulation seen in A-allele carriers. As such, FKBP5 expression and GR function may be environmentally sensitive in A-allele carriers and therefore suitable for the study of gene-by-environment (G x E) interactions. Compared with FKBP5, GG homozygotes (N = 118), A-allele carriers (N = 132) without psychiatric morbidity had progressively worse performance on the Stroop color-word task with increasing levels of ELA exposure (Genotype x ELA, F=5.14, P=0.007), indicating a G x E interaction on working memory in early adulthood. In addition, heart rate response to mental stress was diminished overall in AA/AG-allele carriers (F=5.15, P=0.024). Diminished working memory and attenuated autonomic responses to stress are both associated with risk for alcoholism and other substance use disorders. The present data suggest that FKBP5 in the GR pathway may be a point of vulnerability to ELA, as seen in this group of non-traumatized young adults. FKBP5 is accordingly a potential target for more extensive studies of the impact of ELA on health and health behaviors in adulthood. C1 [Lovallo, William R.; Cohoon, Andrew J.; Sorocco, Kristen H.] VA Med Ctr, 755 Res Pkwy,Suite 586, Oklahoma City, OK 73104 USA. [Lovallo, William R.] Univ Oklahoma, Hlth Sci Ctr, Dept Psychiat & Behav Sci, Oklahoma City, OK 73190 USA. [Enoch, Mary-Anne; Hodgkinson, Colin A.; Goldman, David] NIAAA, Neurogenet Lab, NIH, Bethesda, MD USA. [Acheson, Ashley] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Acheson, Ashley] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, San Antonio, TX 78229 USA. [Sorocco, Kristen H.] Univ Oklahoma, Hlth Sci Ctr, Donald W Reynolds Dept Geriatr Med, Oklahoma City, OK USA. [Vincent, Andrea S.] Univ Oklahoma, Cognit Sci Res Ctr, Norman, OK 73019 USA. RP Lovallo, WR (reprint author), VA Med Ctr, Behav Sci Labs, 755 Res Pkwy,Suite 586, Oklahoma City, OK 73104 USA. EM bill@mindbody1.org RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU Department of Veterans Affairs Medical Research Service; NIH; NIAAA [R01AA019691, R01 AA012207]; NIAAA Intramural Research Program FX The content is solely the view of the authors and does not necessarily represent the official view of the National Institutes of Health or the Department of Veterans Affairs. Supported by the Department of Veterans Affairs Medical Research Service; NIH Grants, NIAAA R01AA019691 and R01 AA012207, and the NIAAA Intramural Research Program. NR 90 TC 0 Z9 0 U1 4 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUN PY 2016 VL 41 IS 7 BP 1724 EP 1732 DI 10.1038/npp.2015.347 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DL9MY UT WOS:000375968600004 PM 26632991 ER PT J AU Patton, MH Roberts, BM Lovinger, DM Mathur, BN AF Patton, Mary H. Roberts, Bradley M. Lovinger, David M. Mathur, Brian N. TI Ethanol Disinhibits Dorsolateral Striatal Medium Spiny Neurons Through Activation of A Presynaptic Delta Opioid Receptor SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID LONG-TERM DEPRESSION; GLOBUS-PALLIDUS; DORSAL STRIATUM; ALCOHOL SEEKING; IN-VIVO; INTERNEURONS; NEOSTRIATUM; EXPRESSION; OUTPUT; TRANSMISSION AB The dorsolateral striatum mediates habit formation, which is expedited by exposure to alcohol. Across species, alcohol exposure disinhibits the DLS by dampening GABAergic transmission onto this structure's principal medium spiny projection neurons (MSNs), providing a potential mechanistic basis for habitual alcohol drinking. However, the molecular and circuit components underlying this disinhibition remain unknown. To examine this, we used a combination of whole-cell patch-clamp recordings and optogenetics to demonstrate that ethanol potently depresses both MSN- and fast-spiking intemeuron (FSI)-MSN GABAergic synaptic transmission in the DLS. Concentrating on the powerfully inhibitory FSI-MSN synapse, we further show that acute exposure of ethanol (50 mM) to striatal slices activates delta opioid receptors that reside on FSI axon terminals and negatively couple to adenylyl cyclase to induce a long-term depression of GABA release onto both direct and indirect pathway MSNs. These findings elucidate a mechanism through which ethanol may globally disinhibit the DLS. C1 [Patton, Mary H.; Roberts, Bradley M.; Mathur, Brian N.] Univ Maryland, Sch Med, Dept Pharmacol, BRB RM 4011,655 West Baltimore St, Baltimore, MD 21201 USA. [Lovinger, David M.] NIAAA, Sect Synapt Pharmacol, Lab Integrat Neurosci, Div Intramural Clin & Biol Res,US Natl Inst Hlth, Bethesda, MD USA. RP Mathur, BN (reprint author), Univ Maryland, Sch Med, Dept Pharmacol, BRB RM 4011,655 West Baltimore St, Baltimore, MD 21201 USA. EM bmathur@som.umaryland.edu OI Roberts, Bradley/0000-0002-5192-2545 FU National Institute on Alcohol Abuse and Alcoholism of the US National Institutes of Health [K22 AA021414]; Division of Intramural Clinical and Biological Research of the NIAAA/NIH; Integrative Neuroscience Initiative on Alcoholism of the NIAAA/NIH FX For this work, MHP and BMR were supported by the National Institute on Alcohol Abuse and Alcoholism of the US National Institutes of Health (grant K22 AA021414 to BNM), the Division of Intramural Clinical and Biological Research of the NIAAA/NIH (DML) and the Integrative Neuroscience Initiative on Alcoholism of the NIAAA/NIH (DML). The authors declare no conflict of interest. NR 35 TC 2 Z9 2 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUN PY 2016 VL 41 IS 7 BP 1831 EP 1840 DI 10.1038/npp.2015.353 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DL9MY UT WOS:000375968600015 PM 26758662 ER PT J AU Lloyd, JT Alley, DE Hochberg, MC Waldstein, SR Harris, TB Kritchevsky, SB Schwartz, AV Strotmeyer, ES Womack, C Orwig, DL AF Lloyd, J. T. Alley, D. E. Hochberg, M. C. Waldstein, S. R. Harris, T. B. Kritchevsky, S. B. Schwartz, A. V. Strotmeyer, E. S. Womack, C. Orwig, D. L. CA Hlth ABC Study TI Changes in bone mineral density over time by body mass index in the health ABC study SO OSTEOPOROSIS INTERNATIONAL LA English DT Article DE Aging; Longitudinal; Obesity; Osteoporosis ID NORMAL POSTMENOPAUSAL WOMEN; VITAMIN-D SUPPLEMENTATION; OLDER US ADULTS; FOLLOW-UP; FEMORAL-NECK; NHANES-III; OBESITY; OSTEOPOROSIS; ASSOCIATION; WEIGHT AB Obesity appears protective against osteoporosis in cross-sectional studies. However, results from this longitudinal study found that obesity was associated with bone loss over time. Findings underscore the importance of looking at the longitudinal relationship, particularly given the increasing prevalence and duration of obesity among older adults. Cross-sectional studies have found a positive association between body mass index (BMI) and bone mineral density (BMD), but little is known about the longitudinal relationship in US older adults. We examined average annual rate of change in BMD by baseline BMI in the Health, Aging, and Body Composition Study. Repeated measurement of BMD was performed with dual-energy X-ray absorptiometry (DXA) at baseline and years 3, 5, 6, 8, and 10. Multivariate generalized estimating equations were used to predict mean BMD (femoral neck, total hip, and whole body) by baseline BMI (excluding underweight), adjusting for covariates. In the sample (n = 2570), 43 % were overweight and 24 % were obese with a mean baseline femoral neck BMD of 0.743 g/cm(2), hip BMD of 0.888 g/cm(2), and whole-body BMD of 1.09 g/cm(2). Change in total hip or whole-body BMD over time did not vary by BMI groups. However, obese older adults lost 0.003 g/cm(2) of femoral neck BMD per year more compared with normal weight older adults (p < 0.001). Femoral neck BMD change over time did not differ between the overweight and normal weight BMI groups (p = 0.74). In year 10, adjusted femoral neck BMD ranged from 0.696 g/cm(2) among obese, 0.709 g/cm(2) among normal weight, and 0.719 g/cm(2) among overweight older adults. Findings underscore the importance of looking at the longitudinal relationship between body composition and bone mineral density among older adults, indicating that high body mass may not be protective for bone loss over time. C1 [Lloyd, J. T.; Alley, D. E.] Ctr Medicare & Medicaid Serv, 7500 Security Blvd,WB-06-05, Baltimore, MD 21244 USA. [Alley, D. E.; Hochberg, M. C.; Orwig, D. L.] Univ Maryland, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Hochberg, M. C.; Orwig, D. L.] Univ Maryland, Doctoral Program Gerontol, Baltimore, MD 21201 USA. [Waldstein, S. R.] Univ Maryland, Dept Psychol, Baltimore, MD 21201 USA. [Harris, T. B.] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, Bethesda, MD 20892 USA. [Kritchevsky, S. B.] Wake Forest Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Schwartz, A. V.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Strotmeyer, E. S.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Womack, C.] Univ Tennessee, Hlth Sci Ctr, Memphis, TN USA. RP Lloyd, JT (reprint author), Ctr Medicare & Medicaid Serv, 7500 Security Blvd,WB-06-05, Baltimore, MD 21244 USA. EM Jennifer.Lloyd@cms.hhs.gov OI Strotmeyer, Elsa/0000-0002-4093-6036 NR 37 TC 2 Z9 2 U1 2 U2 5 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-941X EI 1433-2965 J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD JUN PY 2016 VL 27 IS 6 BP 2109 EP 2116 DI 10.1007/s00198-016-3506-x PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DM1JE UT WOS:000376100700017 PM 26856584 ER PT J AU Mosley, JD Shaffer, CM Van Driest, SL Weeke, PE Wells, QS Karnes, JH Edwards, DRV Wei, WQ Teixeira, PL Bastarache, L Crawford, DC Li, R Manolio, TA Bottinger, EP McCarty, CA Linneman, JG Brilliant, MH Pacheco, JA Thompson, W Chisholm, RL Jarvik, GP Crosslin, DR Carrell, DS Baldwin, E Ralston, J Larson, EB Grafton, J Scrol, A Jouni, H Kullo, IJ Tromp, G Borthwick, KM Kuivaniemi, H Carey, DJ Ritchie, MD Bradford, Y Verma, SS Chute, CG Veluchamy, A Siddiqui, MK Palmer, CNA Doney, A MahmoudPour, SH Maitland-van der Zee, AH Morris, AD Denny, JC Roden, DM AF Mosley, J. D. Shaffer, C. M. Van Driest, S. L. Weeke, P. E. Wells, Q. S. Karnes, J. H. Edwards, D. R. Velez Wei, W-Q Teixeira, P. L. Bastarache, L. Crawford, D. C. Li, R. Manolio, T. A. Bottinger, E. P. McCarty, C. A. Linneman, J. G. Brilliant, M. H. Pacheco, J. A. Thompson, W. Chisholm, R. L. Jarvik, G. P. Crosslin, D. R. Carrell, D. S. Baldwin, E. Ralston, J. Larson, E. B. Grafton, J. Scrol, A. Jouni, H. Kullo, I. J. Tromp, G. Borthwick, K. M. Kuivaniemi, H. Carey, D. J. Ritchie, M. D. Bradford, Y. Verma, S. S. Chute, C. G. Veluchamy, A. Siddiqui, M. K. Palmer, C. N. A. Doney, A. MahmoudPour, S. H. Maitland-van der Zee, A. H. Morris, A. D. Denny, J. C. Roden, D. M. TI A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough SO PHARMACOGENOMICS JOURNAL LA English DT Article ID ANGIOTENSIN-CONVERTING ENZYME; ELECTRONIC MEDICAL-RECORDS; BRADYKININ B2 RECEPTOR; GENE POLYMORPHISM; EMERGE NETWORK; EXPRESSION; CHINESE; ABO; SUSCEPTIBILITY; BRONCHOSPASM AB The most common side effect of angiotensin-converting enzyme inhibitor (ACEi) drugs is cough. We conducted a genome-wide association study (GWAS) of ACEi-induced cough among 7080 subjects of diverse ancestries in the Electronic Medical Records and Genomics (eMERGE) network. Cases were subjects diagnosed with ACEi-induced cough. Controls were subjects with at least 6 months of ACEi use and no cough. A GWAS (1595 cases and 5485 controls) identified associations on chromosome 4 in an intron of KCNIP4. The strongest association was at rs145489027 (minor allele frequency = 0.33, odds ratio (OR) = 1.3 (95% confidence interval (CI): 1.2-1.4), P = 1.0 x 10(-8)). Replication for six single-nucleotide polymorphisms (SNPs) in KCNIP4 was tested in a second eMERGE population (n = 926) and in the Genetics of Diabetes Audit and Research in Tayside, Scotland (GoDARTS) cohort (n = 4309). Replication was observed at rs7675300 (OR = 1.32 (1.01-1.70), P = 0.04) in eMERGE and at rs16870989 and rs1495509 (OR = 1.15 (1.01-1.30), P = 0.03 for both) in GoDARTS. The combined association at rs1495509 was significant (OR = 1.23 (1.15-1.32), P = 1.9 x 10(-9)). These results indicate that SNPs in KCNIP4 may modulate ACEi-induced cough risk. C1 [Mosley, J. D.; Shaffer, C. M.; Van Driest, S. L.; Weeke, P. E.; Wells, Q. S.; Karnes, J. H.; Denny, J. C.; Roden, D. M.] Vanderbilt Univ, Sch Med, Dept Med, 1285 Med Res Bldg 4, Nashville, TN 37212 USA. [Van Driest, S. L.] Vanderbilt Univ, Dept Pediat, Nashville, TN USA. [Weeke, P. E.] Univ Copenhagen, Dept Cardiol, Copenhagen, Denmark. [Edwards, D. R. Velez] Vanderbilt Univ, Dept Obstet & Gynecol, 221 Kirkland Hall, Nashville, TN 37235 USA. [Wei, W-Q; Teixeira, P. L.; Bastarache, L.; Denny, J. C.] Vanderbilt Univ, Biomed Informat, 221 Kirkland Hall, Nashville, TN 37235 USA. [Crawford, D. C.] Case Western Reserve Univ, Inst Computat Biol, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Li, R.; Manolio, T. A.] NHGRI, Div Genom Med, Bethesda, MD 20892 USA. [Bottinger, E. P.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [McCarty, C. A.] Essentia Inst Rural Hlth, Duluth, MN USA. [Linneman, J. G.; Brilliant, M. H.] Marshfield Clin Res Fdn, Marshfield, WI USA. [Pacheco, J. A.; Thompson, W.; Chisholm, R. L.] Northwestern Univ, Feinberg Sch Med, Ctr Genet Med, Chicago, IL 60611 USA. [Jarvik, G. P.; Crosslin, D. R.] Univ Washington, Dept Med Med Genet, Seattle, WA 98195 USA. [Jarvik, G. P.; Crosslin, D. R.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Carrell, D. S.; Baldwin, E.; Ralston, J.; Larson, E. B.; Grafton, J.; Scrol, A.] Grp Hlth Res Inst, Seattle, WA USA. [Jouni, H.; Kullo, I. J.] Mayo Clin, Div Cardiovasc Dis, Rochester, MN USA. [Tromp, G.; Borthwick, K. M.; Kuivaniemi, H.; Carey, D. J.] Geisinger Hlth Syst, Sigfried & Janet Weis Ctr Res, Danville, PA USA. [Ritchie, M. D.; Bradford, Y.; Verma, S. S.] Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. [Chute, C. G.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Chute, C. G.] Johns Hopkins Univ, Sch Publ Hlth, Baltimore, MD USA. [Chute, C. G.] Johns Hopkins Univ, Sch Nursing, Baltimore, MD USA. [Veluchamy, A.; Siddiqui, M. K.; Palmer, C. N. A.; Doney, A.] Univ Dundee, Med Res Inst, Dundee, Scotland. [MahmoudPour, S. H.; Maitland-van der Zee, A. H.] Univ Utrecht, UIPS, Utrecht, Netherlands. [Morris, A. D.] Univ Edinburgh, Sch Mol Genet & Populat Hlth Sci, Edinburgh, Midlothian, Scotland. RP Roden, DM (reprint author), Vanderbilt Univ, Sch Med, Dept Med, 1285 Med Res Bldg 4, Nashville, TN 37212 USA. EM dan.roden@vanderbilt.edu RI Palmer, Colin/C-7053-2008; Study, GoDARTS/K-9448-2016; OI Palmer, Colin/0000-0002-6415-6560; Kuivaniemi, Helena/0000-0001-5753-8766 FU VUMC Clinical Pharmacology Training grant [T32 GM07569]; electronic MEdical Records and GEnomics (eMERGE) Network [U01-HG-04603, 1U02HG004608-01, 1U01HG006389]; NCATS/NIH [UL1TR000427, U01HG006375, U01AG06781, U01-HG04599, U01-HG004609, U01HG006382]; ARRA grant from NCATS/NIH [RC2 GM092618, R01 LM 010685]; Vanderbilt PGRN grant from NCATS/NIH [U19 HL065962]; Vanderbilt CTSA grant from NCATS/NIH [UL1 TR000445]; NIH [P30DK072488, R01DK088231, R01DK091601]; Pennsylvania Commonwealth Universal Research Enhancement Program; Ben Franklin Technology Development Fund of PA; Geisinger Clinical Research Fund; American Heart Association; Wellcome Trust [084727/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z]; EU IMI-SUMMIT program FX This work was supported by the VUMC Clinical Pharmacology Training grant (T32 GM07569), the electronic MEdical Records and GEnomics (eMERGE) Network U01-HG-04603 (Vanderbilt), 1U02HG004608-01, 1U01HG006389 and NCATS/NIH grant UL1TR000427 (Marshfield/EIRH/Penn State), U01HG006375 and U01AG06781 (Group Health and University of Washington), U01-HG04599 (Mayo Clinic), U01-HG004609 (Northwestern University), U01HG006382 (Geisinger), an ARRA grant RC2 GM092618, R01 LM 010685, a Vanderbilt PGRN grant U19 HL065962 and the Vanderbilt CTSA grant UL1 TR000445 from NCATS/NIH. At Geisinger, the sample collection was supported by NIH (P30DK072488, R01DK088231 and R01DK091601), Pennsylvania Commonwealth Universal Research Enhancement Program, the Ben Franklin Technology Development Fund of PA, the Geisinger Clinical Research Fund and a Grant-In-Aid from the American Heart Association. GoDARTS was funded by the Wellcome Trust (084727/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z) and as part of the EU IMI-SUMMIT program. NR 54 TC 5 Z9 5 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1470-269X EI 1473-1150 J9 PHARMACOGENOMICS J JI Pharmacogenomics J. PD JUN PY 2016 VL 16 IS 3 BP 231 EP 237 DI 10.1038/tpj.2015.51 PG 7 WC Genetics & Heredity; Pharmacology & Pharmacy SC Genetics & Heredity; Pharmacology & Pharmacy GA DM2RQ UT WOS:000376195000003 PM 26169577 ER PT J AU Vamvaka, E Evans, A Ramessar, K Krumpe, LRH Shattock, RJ O'Keefe, BR Christou, P Capell, T AF Vamvaka, E. Evans, A. Ramessar, K. Krumpe, L. R. H. Shattock, R. J. O'Keefe, B. R. Christou, P. Capell, T. TI Cyanovirin-N produced in rice endosperm offers effective pre-exposure prophylaxis against HIV-1(BaL) infection in vitro SO PLANT CELL REPORTS LA English DT Article DE Cyanovirin-N; Rice crude extract; Endosperm; Anti-HIV; Microbicide ID HUMAN-IMMUNODEFICIENCY-VIRUS; SEED-DERIVED EXPLANTS; INACTIVATING PROTEIN; HIV MICROBICIDE; PARTICLE BOMBARDMENT; SEXUAL TRANSMISSION; TYPE-1 INFECTION; STORAGE PROTEINS; GP120; RESISTANCE AB Cyanovirin-N produced in rice endosperm provides efficient pre-exposure prophylaxis against HIV-1 (BaL) infection in vitro. Cyanovirin-N (CV-N) is a lectin with potent antiviral activity that has been proposed as a component of microbicides for the prevention of infection with Human immunodeficiency virus (HIV). The production of protein-based microbicide components requires a platform that is sufficiently economical and scalable to meet the demands of the large at-risk population, particularly in resource poor developing countries. We, therefore, expressed CV-N in rice endosperm, because the dried seed is ideal for storage and transport and crude extracts could be prepared locally and used as a microbicide component without further purification. We found that crude extracts from rice seeds expressing up to 10 A mu g CV-N per gram dry seed weight showed dose-dependent gp120 binding activity, confirming that the protein was soluble, correctly folded and active. The recombinant lectin ((CV)-C-OS-N) reduced the infectivity of HIV-1(BaL) (an R5 virus strain representing the majority of transmitted infections) by similar to 90 % but showed only weak neutralization activity against HIV-1(RF) (representative of X4 virus, rarely associated with transmission), suggesting it would be highly effective for pre-exposure prophylaxis against the vast majority of transmitted strains. Crude extracts expressing (CV)-C-OS-N showed no toxicity towards human cells at working dilutions indicating that microbicide components produced in rice endosperm are safe for direct application as topical microbicides in humans. C1 [Vamvaka, E.; Christou, P.; Capell, T.] Univ Lleida, Agrotecnio Ctr, Dept Plant Prod & Forestry Sci, Sch Agrifood & Forestry Sci & Engn ETSEA, Lleida, Spain. [Evans, A.; Shattock, R. J.] Univ London Imperial Coll Sci Technol & Med, Dept Med, Norfolk Pl, London, England. [Ramessar, K.; Krumpe, L. R. H.; O'Keefe, B. R.] NCI, Mol Targets Lab, Ctr Canc Res, NIH, Frederick, MD 21701 USA. [Krumpe, L. R. H.] Leidos Biomed Res Inc, Frederick Natl Lab, Frederick, MD USA. [O'Keefe, B. R.] NCI, Nat Prod Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21701 USA. [Christou, P.] Catalan Inst Res & Adv Studies ICREA, Barcelona, Spain. RP Capell, T (reprint author), Univ Lleida, Agrotecnio Ctr, Dept Plant Prod & Forestry Sci, Sch Agrifood & Forestry Sci & Engn ETSEA, Lleida, Spain. EM teresa.capell@pvcf.udl.cat FU Ministerio de Ciencia e Innovacion, Spain [BIO2012-35359]; Center CONSOLIDER on Agrigenomics - MICINN, Spain; COST Action [FA0804]; National Cancer Institute, National Institutes of Health [HHSN26120080001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX The authors are grateful to Dr. Maite Sabalza Gallues for cloning the CV-N gene in the pRP5 plasmid and Ms. Jennifer Wilson for technical assistance with live-virus anti-HIV assays. In addition, the authors would like to acknowledge funding from the Ministerio de Ciencia e Innovacion, Spain (BIO2012-35359), the Center CONSOLIDER on Agrigenomics funded by MICINN, Spain, and COST Action FA0804 (Molecular farming: plants as a production platform for high value proteins). This project was funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E, and supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 74 TC 1 Z9 1 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0721-7714 EI 1432-203X J9 PLANT CELL REP JI Plant Cell Reports PD JUN PY 2016 VL 35 IS 6 BP 1309 EP 1319 DI 10.1007/s00299-016-1963-5 PG 11 WC Plant Sciences SC Plant Sciences GA DM3LR UT WOS:000376248400009 PM 27007716 ER PT J AU Demirkan, A Lahti, J Direk, N Viktorin, A Lunetta, KL Terracciano, A Nalls, MA Tanaka, T Hek, K Fornage, M Wellmann, J Cornelis, MC Ollila, HM Yu, L Smith, JA Pilling, LC Isaacs, A Palotie, A Zhuang, WV Zonderman, A Faul, JD Sutin, A Meirelles, O Mulas, A Hofman, A Uitterlinden, A Rivadeneira, F Perola, M Zhao, W Salomaa, V Yaffe, K Luik, AI Liu, Y Ding, J Lichtenstein, P Landen, M Widen, E Weir, DR Llewellyn, DJ Murray, A Kardia, SLR Eriksson, JG Koenen, K Magnusson, PKE Ferrucci, L Mosley, TH Cucca, F Oostra, BA Bennett, DA Paunio, T Berger, K Harris, TB Pedersen, NL Murabito, JM Tiemeier, H van Duijn, CM Raikkonen, K AF Demirkan, A. Lahti, J. Direk, N. Viktorin, A. Lunetta, K. L. Terracciano, A. Nalls, M. A. Tanaka, T. Hek, K. Fornage, M. Wellmann, J. Cornelis, M. C. Ollila, H. M. Yu, L. Smith, J. A. Pilling, L. C. Isaacs, A. Palotie, A. Zhuang, W. V. Zonderman, A. Faul, J. D. Sutin, A. Meirelles, O. Mulas, A. Hofman, A. Uitterlinden, A. Rivadeneira, F. Perola, M. Zhao, W. Salomaa, V. Yaffe, K. Luik, A. I. Liu, Y. Ding, J. Lichtenstein, P. Landen, M. Widen, E. Weir, D. R. Llewellyn, D. J. Murray, A. Kardia, S. L. R. Eriksson, J. G. Koenen, K. Magnusson, P. K. E. Ferrucci, L. Mosley, T. H. Cucca, F. Oostra, B. A. Bennett, D. A. Paunio, T. Berger, K. Harris, T. B. Pedersen, N. L. Murabito, J. M. Tiemeier, H. van Duijn, C. M. Raeikkoenen, K. CA NABEC UKBEC TI Somatic, positive and negative domains of the Center for Epidemiological Studies Depression (CES-D) scale: a meta-analysis of genome-wide association studies SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Genome-wide association studies; major depressive disorder; meta-analyses ID CARDIOVASCULAR RISK-FACTORS; MAJOR DEPRESSION; GENETIC-FACTORS; AGING PROJECT; MELATONIN; POPULATION; SYMPTOMS; DESIGN; DISORDER; INDIVIDUALS AB Background. Major depressive disorder (MDD) is moderately heritable, however genome-wide association studies (GWAS) for MDD, as well as for related continuous outcomes, have not shown consistent results. Attempts to elucidate the genetic basis of MDD may be hindered by heterogeneity in diagnosis. The Center for Epidemiological Studies Depression (CES-D) scale provides a widely used tool for measuring depressive symptoms clustered in four different domains which can be combined together into a total score but also can be analysed as separate symptom domains. Method. We performed a meta-analysis of GWAS of the CES-D symptom clusters. We recruited 12 cohorts with the 20-or 10-item CES-D scale (32 528 persons). Results. One single nucleotide polymorphism (SNP), rs713224, located near the brain-expressed melatonin receptor (MTNR1A) gene, was associated with the somatic complaints domain of depression symptoms, with borderline genome-wide significance (p(discovery) = 3.82 x 10(-8)). The SNP was analysed in an additional five cohorts comprising the replication sample (6813 persons). However, the association was not consistent among the replication sample (p(discovery+replication) = 1.10 x 10(-6)) with evidence of heterogeneity. Conclusions. Despite the effort to harmonize the phenotypes across cohorts and participants, our study is still underpowered to detect consistent association for depression, even by means of symptom classification. On the contrary, the SNP-based heritability and co-heritability estimation results suggest that a very minor part of the variation could be captured by GWAS, explaining the reason of sparse findings. C1 Erasmus MC, Genet Epidemiol Unit, Dept Epidemiol, Rotterdam, Netherlands. [Demirkan, A.; Isaacs, A.; Oostra, B. A.; van Duijn, C. M.] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands. [Lahti, J.; Rivadeneira, F.; Raeikkoenen, K.] Univ Helsinki, Inst Behav Sci, Helsinki, Finland. [Direk, N.; Hek, K.; Hofman, A.; Uitterlinden, A.; Rivadeneira, F.; Luik, A. I.; Tiemeier, H.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Viktorin, A.; Lichtenstein, P.; Landen, M.; Magnusson, P. K. E.; Pedersen, N. L.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Lunetta, K. L.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Terracciano, A.; Tanaka, T.; Zonderman, A.; Sutin, A.; Meirelles, O.; Ferrucci, L.] NIA, NIH, Baltimore, MD 21224 USA. [Terracciano, A.] Florida State Univ, Coll Med, Tallahassee, FL 32306 USA. [Nalls, M. A.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Hek, K.] Erasmus MC, Dept Psychiat, Epidemiol & Social Psychiat Res Inst, Rotterdam, Netherlands. [Fornage, M.] Univ Texas Houston, Houston Inst Mol Med, Houston, TX USA. [Wellmann, J.; Berger, K.] Univ Munster, Inst Epidemiol & Social Med, D-48149 Munster, Germany. [Cornelis, M. C.] Harvard Univ, Brigham & Womens Hosp, Channing Div Network Med, Sch Med, Boston, MA 02115 USA. [Ollila, H. M.; Perola, M.; Paunio, T.] Natl Inst Hlth & Welf, Publ Hlth Genom Unit, Helsinki, Finland. [Ollila, H. M.; Perola, M.; Paunio, T.] Natl Inst Hlth & Welf, Inst Mol Med Finland FIMM, Helsinki, Finland. [Yu, L.; Bennett, D. A.] Rush Univ, Dept Neurol Sci, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. [Smith, J. A.] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Pilling, L. C.; Llewellyn, D. J.; Murray, A.] Univ Exeter, Sch Med, Exeter, Devon, England. [Palotie, A.] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge, England. [Palotie, A.; Widen, E.] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland. [Zhuang, W. V.] Creighton Univ, Sch Med, Dept Prevent Med & Publ Hlth, Omaha, NE USA. [Faul, J. D.; Zhao, W.; Weir, D. R.; Kardia, S. L. R.] Univ Michigan, Inst Social Res, Survey Res Ctr, Ann Arbor, MI USA. [Mulas, A.; Cucca, F.] CNR, Ist Ric Genet & Biomed, Cagliari, Italy. [Uitterlinden, A.; Rivadeneira, F.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Salomaa, V.] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Yaffe, K.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [NABEC] North Amer Brain Express Consortium, New York, NY USA. [UKBEC] UK Brain Express Consortium, London, England. [Liu, Y.] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Ctr Human Genom, Med Ctr Blvd, Winston Salem, NC USA. [Ding, J.] Wake Forest Univ, Geriatr & Gerontol, Sticht Ctr Aging, Primate Ctr,Epidemiol & Prevent, Winston Salem, NC 27109 USA. [Eriksson, J. G.] Natl Inst Hlth & Welf, Helsinki, Finland. [Eriksson, J. G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland. [Koenen, K.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Mosley, T. H.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Oostra, B. A.] Erasmus Univ, Dept Clin Genet, Med Ctr, NL-3000 DR Rotterdam, Netherlands. [Harris, T. B.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Murabito, J. M.] Boston Univ, Sch Med, Dept Med, Gen Internal Med Sect, Boston, MA 02118 USA. RP Lahti, J (reprint author), Univ Helsinki, Inst Behav Sci, Siltavuorenpenger 1A, Helsinki 00014, Finland. EM jari.lahti@helsinki.fi RI Magnusson, Patrik/C-4458-2017; OI Murray, Anna/0000-0002-2351-2522; Viktorin, Alexander/0000-0003-2141-2816; Zonderman, Alan B/0000-0002-6523-4778; Lahti, Jari/0000-0002-4310-5297 FU National Heart, Lung, and Blood Institute [N01-HC-55015, N01-HC-55016, N01-HC55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01-HL087641, R01-HL093029, R01-HL70825]; National Human Genome Research Institute [U01-HG004402]; National Institutes of Health (NIH) [HHSN268200625226C, DK U01-066134]; NIH Roadmap for Medical Research [UL1RR025005]; Intramural Research Program of the NIH, National Institute on Aging; Institute of Epidemiology and Social Medicine, University of Munster; German Migraine & Headache Society (DMKG); Almirall; Astra Zeneca; Berlin Chemie; Boehringer; Boots Health Care; Glaxo-Smith-Kline; Janssen Cilag; McNeil Pharma; MSD Sharp Dohme; Pfizer; EUROSPAN (European Special Populations Research Network); European Commission FP6 STRP grant [018947, LSHG-CT-2006-01947]; Netherlands Organization for Scientific Research; Erasmus MC; Centre for Medical Systems Biology (CMSB); Netherlands Brain Foundation (HersenStichting Nederland); National Heart, Lung, and Blood Institute's FHS [N01-HC-25195]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center; Sigrid Juselius Foundation; Jalmari and Rauha Ahokas Foundation; Biomedicum Helsinki Foundation; National Institute on Aging [N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1, RC2 AG036495, P30AG10161, R01AG17917, R01AG15819]; NIH [HHSN268200782096C]; Academy of Finland; Finnish Diabetes Research Society; Folkhalsan Research Foundation; Novo Nordisk Foundation; Finska Lakaresallskapet; Signe and Ane Gyllenberg Foundation; University of Helsinki; European Science Foundation (EUROSTRESS); Ministry of Education; Ahokas Foundation; Emil Aaltonen Foundation; Juho Vainio Foundation; Wellcome Trust [WT089062]; Italian Ministry of Health [ICS 110.1RS97.71]; US National Institute on Aging [N01-AG-916413, N01-AG-821336, 263 MD 916413, 263 MD 821336]; Intramural Research Program, National Institute on Aging, NIH, USA; Netherlands Organization of Scientific Research Investments [175.010.2005.011, 911-03-012]; Erasmus Medical Center; Erasmus University, Rotterdam; Netherlands Organization for Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Research Institute for Diseases in the Elderly (RIDE2); Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; Netherlands Genomics Initiative/Netherlands Organization for Scientific Research [050-060-810]; Illinois Department of Public Health; NARSAD Young Investigator Award; National Institute on Aging, NIH [NO1-AG-1-2109]; Ministry for Higher Education; Swedish Research Council [M-2005-1112]; GenomEUtwin [EU/QLRT-2001-01254, QLG2-CT-2002-01254]; Swedish Foundation for Strategic Research (SSF); Heart and Lung Foundation [20070481]; Intramural Research Program of the National Institute on Aging, NIH; US Department of Health and Human Services [ZIA AG000932-04]; Department of Defense [W81XWH-09-2-0128]; Medical Research Council (MRC) through MRC Sudden Death Brain Bank; King Faisal Specialist Hospital and Research Centre, Saudi Arabia; National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's; St Thomas' NHS Foundation Trust and King's College London; National Institute on Aging (NIA) [U01AG009740]; [R01-AG29451]; [G0901254]; [G0802462] FX ARIC study; The research is carried out as a collaborative study supported by: National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, and grants R01-HL087641, R01-HL093029 and R01-HL70825; National Human Genome Research Institute contract U01-HG004402; and National Institutes of Health (NIH) contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by grant number UL1RR025005, a component of the NIH Roadmap for Medical Research.; BLSA; BLSA research was supported by the Intramural Research Program of the NIH, National Institute on Aging.; Dortmund Health Study; Blood collection in the Dortmund Health Study was funded by the Institute of Epidemiology and Social Medicine, University of Munster and genotyping with the HumanOmni chip by the German Ministry of Research and Education (BMBF, 01ER0816). The collection of sociodemographic and clinical data in the Dortmund Health Study was supported by the German Migraine & Headache Society (DMKG) and by unrestricted grants of equal share from Almirall, Astra Zeneca, Berlin Chemie, Boehringer, Boots Health Care, Glaxo-Smith-Kline, Janssen Cilag, McNeil Pharma, MSD Sharp & Dohme and Pfizer to the University of Munster.; ERF study; The genotyping for the ERF study was supported by EUROSPAN (European Special Populations Research Network) and the European Commission FP6 STRP grant (018947; LSHG-CT-2006-01947). The ERF study was further supported by grants from the Netherlands Organization for Scientific Research, Erasmus MC, the Centre for Medical Systems Biology (CMSB) and the Netherlands Brain Foundation (HersenStichting Nederland). We are grateful to all participating individuals and their relatives, general practitioners and neurologists for their contributions and to P. Veraart for her help in genealogy, Jeannette Vergeer for the supervision of the laboratory work and P. Snijders for his help in data collection.; FHS; The phenotype-genotype association analyses in the FHS were supported by R01-AG29451. This research was conducted in part using data and resources from the FHS of the National Heart, Lung, and Blood Institute of the NIH and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the FHS investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung, and Blood Institute's FHS (contract no. N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (contract no. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center.; FINRISK; The FINRISK Study has been funded by the Sigrid Juselius Foundation, the Jalmari and Rauha Ahokas Foundation and the Biomedicum Helsinki Foundation.; HEALTH ABC-Eur; This research was supported by National Institute on Aging contracts N01AG62101, N01AG62103 and N01AG62106. The GWAS was funded by National Institute on Aging grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). The CIDR is fully funded through a federal contract from the NIH to The Johns Hopkins University (contract number HHSN268200782096C).; HBCS; We thank all study participants as well as everybody involved in the HBCS. The HBCS has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Folkhalsan Research Foundation, Novo Nordisk Foundation, Finska Lakaresallskapet, Signe and Ane Gyllenberg Foundation, University of Helsinki, European Science Foundation (EUROSTRESS), Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation, Juho Vainio Foundation and the Wellcome Trust (grant number WT089062).; HRS; The HRS is supported by the National Institute on Aging (NIA U01AG009740). The genotyping was funded as a separate award from the National Institute on Aging (RC2 AG036495). Our genotyping was conducted by the NIH CIDR at Johns Hopkins University. Genotyping quality control and final preparation of the data were performed by the Genetics Coordinating Center at the University of Washington.; InCHIANTI; The InCHIANTI Study was supported as a 'targeted project' (ICS 110.1RS97.71) by the Italian Ministry of Health, by the US National Institute on Aging (contracts N01-AG-916413, N01-AG-821336, 263 MD 916413 and 263 MD 821336) and in part by the Intramural Research Program, National Institute on Aging, NIH, USA.; RS; The generation and management of the genotype data for the RS are supported by the Netherlands Organization of Scientific Research Investments (no. 175.010.2005.011, 911-03-012). The RS is funded by: the Erasmus Medical Center and Erasmus University, Rotterdam; the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE and RIDE2); the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission (DG XII); the Municipality of Rotterdam; and the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research project number 050-060-810.; RUSH-ROS; The RUSH-ROS study was supported by National Institute on Aging grant P30AG10161 and the Illinois Department of Public Health.; RUSH-MAP; The RUSH-MAP study was supported by National Institute on Aging grants R01AG17917 and R01AG15819, and by the Illinois Department of Public Health.; SardiNIA; SardiNIA research was supported by the Intramural Research Program of the NIH, National Institute on Aging. M.C.C. is a recipient of a NARSAD Young Investigator Award. Funding was also provided through contract NO1-AG-1-2109 from the National Institute on Aging, NIH.; TWINGENE; The STR study was supported by The Ministry for Higher Education, the Swedish Research Council (M-2005-1112), GenomEUtwin (EU/QLRT-2001-01254; QLG2-CT-2002-01254), NIH DK U01-066134, the Swedish Foundation for Strategic Research (SSF) and the Heart and Lung Foundation (no. 20070481).; North American Brain Expression Consortium (NABEC) brain expression quantitative trait loci (eQTL) data; The work performed by the NABEC was supported in part by the Intramural Research Program of the National Institute on Aging, NIH, part of the US Department of Health and Human Services; project number ZIA AG000932-04. In addition this work was supported by a Research Grant from the Department of Defense, W81XWH-09-2-0128. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the NIH, Bethesda, MD (http://biowulf.nih.gov). NABEC scientists are Andrew B. Singleton, Mark R. Cookson, J. Raphael Gibbs, Dena G. Hernandez, Alissa Dilman, Michael A. Nalls, Alan B. Zonderman, Sampath Arepalli, Luigi Ferrucci, Robert Johnson, Dan L. Longo, Richard O'Brien, Bryan Traynor, Juan Troncoso and Marcel van der Brug.; UK Brain Expression Consortium (UKBEC) Brain eQTL data; UKBEC scientists are John Hardy, Michael E. Weale, Mina Ryten, Adaikalavan Ramasamy, Daniah Trabzuni, Colin Smith, H. Ronald Zielke and Robert Walker. These studies performed by the UKBEC were supported by the Medical Research Council (MRC) through the MRC Sudden Death Brain Bank (C.S.), by a project grant (G0901254 to J.H. and M.W.) and by a fellowship award (G0802462 to M.R.). D.T. was supported by the King Faisal Specialist Hospital and Research Centre, Saudi Arabia. Computing facilities used at King's College London were supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. We would like to thank AROS Applied Biotechnology AS company laboratories and Affymetrix for their valuable input (PMID: 20485568, PMID: 21848658 and PMID: 227230.18). NR 52 TC 4 Z9 4 U1 3 U2 7 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 EI 1469-8978 J9 PSYCHOL MED JI Psychol. Med. PD JUN PY 2016 VL 46 IS 8 BP 1613 EP 1623 DI 10.1017/S0033291715002081 PG 11 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA DL8XK UT WOS:000375925300004 PM 26997408 ER PT J AU Shen, ZJ Huang, PY Qian, W Wang, C Yu, HL Yang, YH Zhang, MM AF Shen, Zhujing Huang, Peiyu Qian, Wei Wang, Chao Yu, Hualiang Yang, Yihong Zhang, Minming TI Severity of dependence modulates smokers' functional connectivity in the reward circuit: a preliminary study SO PSYCHOPHARMACOLOGY LA English DT Article DE Nicotine-dependence severity; Resting-state functional connectivity; Reward circuit; Hippocampus ID VOXEL-BASED MORPHOMETRY; GRAY-MATTER VOLUMES; NICOTINE DEPENDENCE; SMOKING CUES; INDIVIDUAL-DIFFERENCES; WITHDRAWAL SYMPTOMS; VALUATION NETWORKS; MAJOR DEPRESSION; FAGERSTROM TEST; DRUG-ADDICTION AB Nicotine dependence is characterized as a neural circuit dysfunction, particularly with regard to the reward circuit. Although dependence severity moderates cue reactivity in the brain regions involved in reward processing, the direction of its influence remains controversial. Investigating the functional organization of the reward circuit may provide complementary information. Here, we used resting-state functional connectivity (rsFC) to evaluate the integrity of the reward circuit in smokers with different severities of nicotine dependence. Totals of 65 smokers and 37 non-smokers underwent resting-state functional magnetic resonance imaging (fMRI). The smokers were divided into low-dependent (FTND < 5, n = 26) and high-dependent smoker groups (FTND a parts per thousand yenaEuro parts per thousand 5, n = 39) based on their nicotine-dependence severity (as measured by the Fagerstrom test for nicotine dependence [FTND]). The region of interest (ROI)-wise rsFC within the reward circuit was compared between smokers and non-smokers as well as between low-dependent and high-dependent smokers and then correlated with smokers' FTND scores. Widespread rsFC attenuation was observed in the reward circuit of smokers compared with non-smokers. Compared with low-dependent smokers, high-dependent smokers showed greater rsFC between the right amygdala and the left nucleus accumbens (NAcc) as well as between the bilateral hippocampus. Furthermore, a positive correlation between the inter-hippocampus rsFC and the severity of nicotine dependence (FTND) was detected among all smokers (r = 0.416, p = 0.001). Our results indicate a dysfunction of the reward circuit in nicotine-dependent individuals. Moreover, our study improves the understanding of the neuroplastic changes that occur during the development of nicotine dependence. C1 [Shen, Zhujing; Huang, Peiyu; Qian, Wei; Wang, Chao; Zhang, Minming] Zhejiang Univ, Affiliated Hosp 2, Sch Med, Dept Radiol, 88 Jiefang Rd, Hangzhou 310009, Zhejiang, Peoples R China. [Yu, Hualiang] Zhejiang Univ, Affiliated Hosp 2, Sch Med, Dept Psychiat, 88 Jiefang Rd, Hangzhou 310009, Zhejiang, Peoples R China. [Yang, Yihong] NIDA, Neuroimaging Res Branch, NIH, Baltimore, MD USA. RP Zhang, MM (reprint author), Zhejiang Univ, Affiliated Hosp 2, Sch Med, Dept Radiol, 88 Jiefang Rd, Hangzhou 310009, Zhejiang, Peoples R China. EM zhangminming@zju.edu.cn FU National Natural Science Foundation of China [81171310]; Scientific Research Project of Zhejiang Province [2011C23094] FX Grants from the National Natural Science Foundation of China (No. 81171310) and the Scientific Research Project of Zhejiang Province (2011C23094) supported this research. NR 68 TC 1 Z9 1 U1 3 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUN PY 2016 VL 233 IS 11 BP 2129 EP 2137 DI 10.1007/s00213-016-4262-5 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DM1JS UT WOS:000376102100011 PM 26955839 ER PT J AU Gervasi, NM Scott, SS Aschrafi, A Gale, J Vohra, SN Macgibeny, MA Kar, AN Gioio, AE Kaplan, BB AF Gervasi, Noreen M. Scott, Shane S. Aschrafi, Armaz Gale, Jenna Vohra, Sanah N. Macgibeny, Margaret A. Kar, Amar N. Gioio, Anthony E. Kaplan, Barry B. TI The local expression and trafficking of tyrosine hydroxylase mRNA in the axons of sympathetic neurons SO RNA LA English DT Article DE catecholamine neurotransmitter; axonal mRNAs; axonal localization; intra-axonal translation; cis-acting regulatory element; superior cervical ganglion; dopamine ID PROTEIN-SYNTHESIS; SYNAPTOSOMAL FRACTION; ACTIVE POLYSOMES; SQUID BRAIN; TRANSPORT; IDENTIFICATION; TRANSLATION; LOCALIZATION; SYNAPSES; ENDINGS AB Synthesis and regulation of catecholamine neurotransmitters in the central nervous system are implicated in the pathogenesis of a number of neuropsychiatric disorders. To identify factors that regulate the presynaptic synthesis of catecholamines, we tested the hypothesis that the rate-limiting enzyme of the catecholamine biosynthetic pathway, tyrosine hydroxylase (TH), is locally synthesized in axons and presynaptic nerve terminals of noradrenergic neurons. To isolate pure axonal mRNA and protein, rat superior cervical ganglion sympathetic neurons were cultured in compartmentalized Campenot chambers. qRT-PCR and RNA in situ hybridization analyses showed that TH mRNA is present in distal axons. Colocalization experiments with nerve terminal marker proteins suggested that both TH mRNA and protein localize in regions of the axon that resemble nerve terminals (i.e., synaptic boutons). Analysis of polysome-bound RNA showed that TH mRNA is present in polysomes isolated from distal axons. Metabolic labeling of axonally synthesized proteins labeled with the methionine analog, L-azidohomoalanine, showed that TH is locally synthesized in axons. Moreover, the local transfection and translation of exogenous TH mRNA into distal axons facilitated axonal dopamine synthesis. Finally, using chimeric td-Tomato-tagged constructs, we identified a sequence element within the TH 3'UTR that is required for the axonal localization of the reporter mRNA. Taken together, our results provide the first direct evidence that TH mRNA is trafficked to the axon and that the mRNA is locally translated. These findings raise the interesting possibility that the biosynthesis of the catecholamine neurotransmitters is locally regulated in the axon and/or presynaptic nerve terminal. C1 [Gervasi, Noreen M.; Scott, Shane S.; Aschrafi, Armaz; Gale, Jenna; Vohra, Sanah N.; Macgibeny, Margaret A.; Kar, Amar N.; Gioio, Anthony E.; Kaplan, Barry B.] NIMH, Mol Biol Lab, Div Intramural Res Programs, NIH, Bethesda, MD 20892 USA. [Kar, Amar N.] Univ S Carolina, Dept Biol, Columbia, SC 29208 USA. RP Kaplan, BB (reprint author), NIMH, Mol Biol Lab, Div Intramural Res Programs, NIH, Bethesda, MD 20892 USA. EM barry.kaplan@mail.nih.gov OI Kar, Amar/0000-0003-2380-7504 FU Division of Intramural Research Programs of the National Institute of Mental Health [MH002768] FX We thank Ms. Cai Chen for invaluable technical assistance. We thank Dr. Lijin Dong (National Institutes of Health/National Eye Institute) for providing us with the pBLUE plasmid. This work was supported by the Division of Intramural Research Programs of the National Institute of Mental Health (MH002768). NR 36 TC 2 Z9 2 U1 1 U2 7 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1355-8382 EI 1469-9001 J9 RNA JI RNA PD JUN PY 2016 VL 22 IS 6 BP 883 EP 895 DI 10.1261/rna.053272.115 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DM2VG UT WOS:000376205600007 PM 27095027 ER PT J AU McNally, S Dsurney, J McGovern, J DeFilippis, N Chan, L AF McNally, Shannon Dsurney, John McGovern, Jessica DeFilippis, Nick Chan, Leighton TI Concurrent Validity of New Subscale Scores for the Booklet Category Test SO ASSESSMENT LA English DT Article DE Booklet Category Test; neuropsychology; psychometrics; traumatic brain injury; executive function; cognition; assessment ID CARD SORTING TEST; MULTIDIMENSIONAL INSTRUMENT; CONSTRUCT-VALIDITY; PERSEVERATION; DAMAGE AB The Booklet Category Test (BCT) is a neuropsychological test of cognitive dysfunction that provides only one overall error score indicative of global impairment. It does not, however, delineate specific domains that might be impaired. The aim of this study is to concurrently validate 13 new BCT subscales using legacy instruments in patients with nonpenetrating traumatic brain injury (TBI). Eighty-nine patients with mild, moderate, and severe TBI completed a battery of neuropsychology tests. Partial correlations controlling for age were performed and there were significant correlations between the a priori selected scores from legacy measures of major cognitive domains and both BCT total errors and subscale scores. Additional analysis showed that several subscales were able to differentiate between performance levels on the legacy measures. Overall, our results showed that the subscales measured cognitive skills beyond global impairment, supporting the use of the BCT subscales in a population with TBI. C1 [McNally, Shannon; Chan, Leighton] NIH, Bldg 10, Bethesda, MD 20892 USA. [Dsurney, John] Ctr Neurosci & Regenerat Med, Bethesda, MD USA. [McGovern, Jessica] Louisiana State Univ, Baton Rouge, LA 70803 USA. [DeFilippis, Nick] Georgia Sch Profess Psychol, Atlanta, GA USA. RP Dsurney, J (reprint author), NIH, Dept Rehabil Med, Ctr Clin, 10 Ctr Dr, Bethesda, MD 20892 USA. EM john.dsurney@nih.gov FU Department of Defense (Center for Neuroscience and Regenerative Medicine); National Institutes of Health Intramural Research Program FX The author( s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Department of Defense (Center for Neuroscience and Regenerative Medicine) and the National Institutes of Health Intramural Research Program. NR 29 TC 0 Z9 0 U1 1 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1073-1911 EI 1552-3489 J9 ASSESSMENT JI Assessment PD JUN PY 2016 VL 23 IS 3 BP 333 EP 341 DI 10.1177/1073191115588783 PG 9 WC Psychology, Clinical SC Psychology GA DL5XD UT WOS:000375709500006 PM 26033113 ER PT J AU Nuche-Berenguer, B Ramos-Alvarez, I Jensen, RT AF Nuche-Berenguer, Bernardo Ramos-Alvarez, Irene Jensen, R. T. TI The p21-activated kinase, PAK2, is important in the activation of numerous pancreatic acinar cell signaling cascades and in the onset of early pancreatitis events SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Article DE PAK2; Pancreatic acini; CCK; Signaling; IPA-3; FRAX597; PAK2-DN-advirus; Cell death; Pancreatitis ID NF-KAPPA-B; FOCAL ADHESION KINASE; SMOOTH-MUSCLE-CELLS; TYROSINE PHOSPHORYLATION; GASTROINTESTINAL HORMONES/NEUROTRANSMITTERS; GROWTH-FACTORS; GAMMA-PAK; INDUCED APOPTOSIS; PROTEIN-KINASES; DEATH PATHWAYS AB In a recent study we explored Group-1-p21-activated kinases (GP.1-PAKs) in rat pancreatic acini. Only PAK2 was present; it was activated by gastrointestinal-hormones/neurotransmitters and growth factors in a PKC-, Src- and small-GTPase-mediated manner. PAK2 was required for enzyme-secretion and ERK/1-2-activation. In the present study we examined PAK2's role in CCK and TPA-activation of important distal signaling cascades mediating their physiological/pathophysiological effects and analyzed its role in pathophysiological processes important in early pancreatitis. In rat pancreatic acini, PAK2-inhibition by the specific, GP.1.PAK-inhibitor, IPA-3-suppressed cholecystokinin (CCK)/TPA-stimulated activation of focal-adhesion kinases and mitogen-activated protein-kinases. PAK2-inhibition reversed the dual stimulatory/inhibitory effect of CCK/TPA on the PI3K/Akt/GSK-3 beta pathway. However, its inhibition did not affect PKC activation. PAK2-inhibition protected acini from CCK-induced ROS-generation; caspase/trypsin-activation, important in early pancreatitis; as well as from cell necrosis. Furthermore, PAK2-inhibition reduced proteolytic-activation of PAK-2p34, which is involved in programmed-cell-death. To ensure that the study did not only rely in the specificity of IPA-3 as a PAK inhibitor, we used two other approaches for PAK inhibition, FRAX597 a ATP-competitive-GP.1-PAKs-inhibitor and infection with a PAK2-dominant negative(DN)-Advirus. Those two approaches confirmed the results obtained with IPA-3. This study demonstrates that PAK2 is important in mediating CCK's effect on the activation of signaling-pathways known to mediate its physiological/pathophysiological responses including several cellular processes linked to the onset of pancreatitis. Our results suggest that PAK2 could be a new, important therapeutic target to consider for the treatment of diseases involving deregulation of pancreatic acinar cells. Published by Elsevier B.V. C1 [Nuche-Berenguer, Bernardo; Ramos-Alvarez, Irene; Jensen, R. T.] NIDDK, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Jensen, RT (reprint author), NIDDK, NIH, DDB, Bldg 10,Rm 9C-103,10 Ctr Dr,MSC 1804, Bethesda, MD 20892 USA. EM robertj@bdg10.niddk.nih.gov FU Intramural Research Program of the NIDDK, NIH [Z01-DK053100-20, Z01-DK53101-19] FX This work is partially supported by the Intramural Research Program of the NIDDK, NIH (Z01-DK053100-20, Z01-DK53101-19). NR 87 TC 0 Z9 0 U1 3 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 EI 0006-3002 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD JUN PY 2016 VL 1862 IS 6 BP 1122 EP 1136 DI 10.1016/j.bbadis.2016.02.008 PG 15 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DL7MW UT WOS:000375825800008 PM 26912410 ER PT J AU Ma, ZW Yao, WL Chan, CC Kannabiran, C Wawrousek, E Hejtmancik, JF AF Ma, Zhiwei Yao, Wenliang Chan, Chi-Chao Kannabiran, Chitra Wawrousek, Eric Hejtmancik, J. Fielding TI Human beta A3/A1-crystallin splicing mutation causes cataracts by activating the unfolded protein response and inducing apoptosis in differentiating lens fiber cells SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Article DE Splice mutation; Cataract; Crystallin gene; Unfolded protein response; Apoptosis ID ENDOPLASMIC-RETICULUM STRESS; AUTOSOMAL RECESSIVE CATARACT; SITE MUTATION; TRANSGENIC MICE; CRYSTALLIN GENE; CHINESE FAMILY; CONGENITAL CATARACT; PREMESSENGER RNA; EPITHELIAL-CELLS; INTRON REMOVAL AB beta gamma-Crystallins, having a uniquely stable two domain four Greek key structure, are crucial for transparency of the eye lens,. Mutations in lens crystallins have been proposed to cause cataract formation by a variety of mechanisms most of which involve destabilization of the protein fold. The underlying molecular mechanism for autosomal dominant zonular cataracts with sutural opacities in an Indian family caused by a c.215 + 1G > A splice mutation in the beta A3/Al-crystallin gene CRYBA1 was elucidated using three transgenic mice models. This mutation causes a splice defect in which the mutant mRNA escapes nonsense mediated decay by skipping both exons 3 and 4. Skipping these exons results in an in-frame deletion of the mRNA and synthesis of an unstable p.IIe33_Ala119del mutant beta A3/Al-crystallin protein. Transgenic expression of mutant beta A3/Al-crystallin but not the wild type protein results in toxicity and abnormalities in the maturation and orientation of differentiating lens fibers in c.97_357del CRYBA1 transgenic mice, leading to a small spherical lens, cataract, and often lens capsule rupture. On a cellular level, the lenses accumulated p.IIe33_Ala119del beta A3/Al-crystallin with resultant activation of the stress signaling pathway - unfolded protein response (UPR) and inhibition of normal protein synthesis, culminating in apoptosis. This highlights the mechanistic contrast between mild mutations that destabilize crystallins and other proteins, resulting in their being bound by the alpha-crystallins that buffer lens cells against damage by denatured proteins, and severely misfolded proteins that are not bound by alpha-crystallin but accumulate and have a direct toxic effect on lens cells, resulting in early onset cataracts. Published by Elsevier B.V. C1 [Ma, Zhiwei; Yao, Wenliang; Kannabiran, Chitra; Hejtmancik, J. Fielding] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. [Yao, Wenliang] Medimmune, Gaithersburg, MD USA. [Chan, Chi-Chao] NEI, Histol Core, NIH, Bethesda, MD 20892 USA. [Wawrousek, Eric] NEI, Lab Mol & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Hejtmancik, JF (reprint author), NEI, OGVFB, NIH, 5635 Fishers Lane,Room 1127, Rockville, MD 20852 USA. EM f3h@helix.nih.gov FU National Eye Institute [EY000281] FX This work was supported by the National Eye Institute: EY000281. NR 63 TC 1 Z9 1 U1 3 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 EI 0006-3002 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD JUN PY 2016 VL 1862 IS 6 BP 1214 EP 1227 DI 10.1016/j.bbadis.2016.02.003 PG 14 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DL7MW UT WOS:000375825800016 PM 26851658 ER PT J AU Green, DR Oguin, TH Martinez, J AF Green, D. R. Oguin, T. H. Martinez, J. TI The clearance of dying cells: table for two SO CELL DEATH AND DIFFERENTIATION LA English DT Review ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; ACTIVATED RECEPTOR-GAMMA; NADPH OXIDASE ACTIVATION; GENOME-WIDE ASSOCIATION; LIVER X RECEPTORS; FIND-ME SIGNAL; APOPTOTIC CELLS; RHEUMATOID-ARTHRITIS; DEAD CELLS AB Phagocytic cells of the immune system must constantly survey for, recognize, and efficiently clear the billions of cellular corpses that arise as a result of development, stress, infection, or normal homeostasis. This process, termed efferocytosis, is critical for the prevention of autoimmune and inflammatory disorders, and persistence of dead cells in tissue is characteristic of many human autoimmune diseases, notably systemic lupus erythematosus. The most notable characteristic of the efferocytosis of apoptotic cells is its 'immunologically silent' response. Although the mechanisms by which phagocytes facilitate engulfment of dead cells has been a well-studied area, the pathways that coordinate to process the ingested corpse and direct the subsequent immune response is an area of growing interest. The recently described pathway of LC3 (microtubule-associated protein 1A/1B-light chain 3)-associated phagocytosis (LAP) has shed some light on this issue. LAP is triggered when an extracellular particle, such as a dead cell, engages an extracellular receptor during phagocytosis, induces the translocation of autophagy machinery, and ultimately LC3 to the cargo-containing phagosome, termed the LAPosome. In this review, we will examine efferocytosis and the impact of LAP on efferocytosis, allowing us to reimagine the impact of the autophagy machinery on innate host defense mechanisms. C1 [Green, D. R.] St Jude Childrens Res Hosp, Dept Immunol, 332 N Lauderdale St, Memphis, TN 38105 USA. [Oguin, T. H.; Martinez, J.] NIEHS, Immun Inflammat & Dis Lab, NIH, 111 TW Alexander Dr,MD D2-01, Res Triangle Pk, NC 27709 USA. RP Martinez, J (reprint author), NIEHS, Immun Inflammat & Dis Lab, NIH, 111 TW Alexander Dr,MD D2-01, Res Triangle Pk, NC 27709 USA. EM jennifer.martinez3@nih.gov FU NIAID NIH HHS [R01 AI040646] NR 201 TC 13 Z9 13 U1 3 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 EI 1476-5403 J9 CELL DEATH DIFFER JI Cell Death Differ. PD JUN PY 2016 VL 23 IS 6 SI SI BP 915 EP 926 DI 10.1038/cdd.2015.172 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DL5XI UT WOS:000375710000002 PM 26990661 ER PT J AU Tian, L Choi, SC Lee, HN Murakami, Y Qi, CF Sengottuvelu, M Voss, O Krzewski, K Coligan, JE AF Tian, L. Choi, S-C Lee, H-N Murakami, Y. Qi, C-F Sengottuvelu, M. Voss, O. Krzewski, K. Coligan, J. E. TI Enhanced efferocytosis by dendritic cells underlies memory T-cell expansion and susceptibility to autoimmune disease in CD300f-deficient mice SO CELL DEATH AND DIFFERENTIATION LA English DT Article ID GENOME-WIDE ASSOCIATION; APOPTOTIC CELLS; NEGATIVE REGULATION; IMMUNE-SYSTEM; MARGINAL-ZONE; PHOSPHATIDYLSERINE RECOGNITION; CMRF-35-LIKE MOLECULE-1; MFG-E8-DEFICIENT MICE; INHIBITORY RECEPTOR; DYING CELLS AB Homeostasis requires the immunologically silent clearance of apoptotic cells before they become pro-inflammatory necrotic cells. CD300f (CLM-1) is a phosphatidylserine receptor known to positively regulate efferocytosis by macrophages, and CD300f gene-deficient mice are predisposed to develop a lupus-like disease. Here we show that, in contrast to CD300f function in macrophages, its expression inhibits efferocytosis by DC, and its deficiency leads to enhanced antigen processing and T-cell priming by these DC. The consequences are the expansion of memory T cells and increased ANA levels in aged CD300f-deficient mice, which predispose CD300f-deficient mice to develop an overt autoimmune disease when exposed to an overload of apoptotic cells, or an exacerbated autoimmunity when combined with Fc gamma RIIB deficiency. Thus, our data demonstrates that CD300f helps to maintain immune homeostasis by promoting macrophage clearance of self-antigens, while conversely inhibiting DC uptake and presentation of self-antigens. C1 [Tian, L.; Choi, S-C; Lee, H-N; Murakami, Y.; Sengottuvelu, M.; Voss, O.; Krzewski, K.; Coligan, J. E.] NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, 12441 Parklawn Dr,Twinbrook 2,Room 205, Rockville, MD 20852 USA. [Qi, C-F] NIAID, Pathol Core, Immunogenet Lab, NIH, Rockville, MD USA. [Choi, S-C] Univ Florida, Dept Pathol, Immunol, Gainesville, FL 32610 USA. [Choi, S-C] Univ Florida, Lab Med, Gainesville, FL 32610 USA. RP Coligan, JE (reprint author), NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, 12441 Parklawn Dr,Twinbrook 2,Room 205, Rockville, MD 20852 USA. EM jcoligan@niaid.nih.gov FU National Institutes of Health, National Institute of Allergy and Infectious Diseases FX The study was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. We thank Drs. Silvia Bolland, Francisco Borrego, Alexandra Gil-Krzewska, Herbert C. Morse III, Venkateswara Simhadri and Hongsheng Wang for critically reading our manuscript. We thank Dr. Joseph Brzostowski for the technical help with the microscopy. We thank Carol Henry and Calvin Eigsti for the cell sorting. We thank Mirna Pena for handling the animal colony and Mahnaz Minai for scanning histology images. NR 62 TC 2 Z9 2 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 EI 1476-5403 J9 CELL DEATH DIFFER JI Cell Death Differ. PD JUN PY 2016 VL 23 IS 6 SI SI BP 1086 EP 1096 DI 10.1038/cdd.2015.161 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DL5XI UT WOS:000375710000017 PM 26768664 ER PT J AU Stone, LB Silk, JS Siegle, GJ Lee, KH Stroud, LR Nelson, EE Dahl, RE Jones, NP AF Stone, Lindsey B. Silk, Jennifer S. Siegle, Greg J. Lee, Kyung Hwa Stroud, Laura R. Nelson, Eric E. Dahl, Ronald E. Jones, Neil P. TI Depressed Adolescents' Pupillary Response to Peer Acceptance and Rejection: The Role of Rumination SO CHILD PSYCHIATRY & HUMAN DEVELOPMENT LA English DT Article DE Peer relationships; Depression; Adolescence; Emotional reactivity; Pupil ID EMOTIONAL INFORMATION; COGNITIVE-THERAPY; NEURAL RESPONSE; IN-VIVO; REACTIVITY; CHILDREN; DILATION; CORTISOL; STYLES; AGE AB Heightened emotional reactivity to peer feedback is predictive of adolescents' depression risk. Examining variation in emotional reactivity within currently depressed adolescents may identify subgroups that struggle the most with these daily interactions. We tested whether trait rumination, which amplifies emotional reactions, explained variance in depressed adolescents' physiological reactivity to peer feedback, hypothesizing that rumination would be associated with greater pupillary response to peer rejection and diminished response to peer acceptance. Twenty currently depressed adolescents (12-17) completed a virtual peer interaction paradigm where they received fictitious rejection and acceptance feedback. Pupillary response provided a time-sensitive index of physiological arousal. Rumination was associated with greater initial pupil dilation to both peer rejection and acceptance, and diminished late pupillary response to peer acceptance trials only. Results indicate that depressed adolescents high on trait rumination are more reactive to social feedback regardless of valence, but fail to sustain cognitive-affective load on positive feedback. C1 [Stone, Lindsey B.; Silk, Jennifer S.; Siegle, Greg J.; Lee, Kyung Hwa; Jones, Neil P.] Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, Dept Psychiat, 3811 OHara St, Pittsburgh, PA 15213 USA. [Silk, Jennifer S.; Siegle, Greg J.] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15213 USA. [Stroud, Laura R.] Brown Med Sch, Dept Psychiat & Human Behav, Providence, RI USA. [Nelson, Eric E.] NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. [Dahl, Ronald E.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. RP Stone, LB (reprint author), Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, Dept Psychiat, 3811 OHara St, Pittsburgh, PA 15213 USA. EM lbs36@pitt.edu OI Nelson, Eric/0000-0002-3376-2453; Silk, Jennifer/0000-0002-8638-4337 FU National Institute of Drug Abuse Grant [R21DA024144]; Clinical and Translational Science Institute at the University of Pittsburgh (NIH/NCRR/CTSA Grant) [UL1 RR024153]; National Institute of Mental Health intramural research program; [MH086811] FX This research was supported by National Institute of Drug Abuse Grant R21DA024144 (J.S.S./R.E.D., PI's), the Clinical and Translational Science Institute at the University of Pittsburgh (NIH/NCRR/CTSA Grant UL1 RR024153) and the National Institute of Mental Health intramural research program. Dr. Jones is supported by MH086811. The authors are grateful to Daniel Pine, MD for his input and assistance on this project; Marcie Walker, Katie Burkhouse and Karen Garelik for their assistance in data acquisition; Harvey Iwamoto for task related computer programming; and Ruth Stroud and Jennifer Sears for their assistance with photography. We also thank the participants and their families. NR 49 TC 1 Z9 1 U1 9 U2 17 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-398X EI 1573-3327 J9 CHILD PSYCHIAT HUM D JI Child Psychiat. Hum. Dev. PD JUN PY 2016 VL 47 IS 3 BP 397 EP 406 DI 10.1007/s10578-015-0574-7 PG 10 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA DL3WP UT WOS:000375564500005 PM 26271345 ER PT J AU Cho, HJ Panyakaew, P Thirugnanasambandam, N Wu, TX Hallett, M AF Cho, Hyun Joo Panyakaew, Pattamon Thirugnanasambandam, Nivethida Wu, Tianxia Hallett, Mark TI Dynamic modulation of corticospinal excitability and short-latency afferent inhibition during onset and maintenance phase of selective finger movement SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE Surround inhibition; Short latency afferent inhibition (SAI); Transcranial magnetic stimulation; Tonic movement; Motor evoked potential ID DIRECT-CURRENT STIMULATION; SURROUND INHIBITION; MOTOR CORTEX; POTENTIALS; INITIATION; DYSTONIA; CIRCUITS; HUMANS; INPUT; HAND AB Objective: During highly selective finger movement, corticospinal excitability is reduced in surrounding muscles at the onset of movement but this phenomenon has not been demonstrated during maintenance of movement. Sensorimotor integration may play an important role in selective movement. We sought to investigate how corticospinal excitability and short-latency afferent inhibition changes in active and surrounding muscles during onset and maintenance of selective finger movement. Methods: Using transcranial magnetic stimulation (TMS) and paired peripheral stimulation, input-output recruitment curve and short-latency afferent inhibition (SAI) were measured in the first dorsal interosseus and abductor digiti minimi muscles during selective index finger flexion. Results: Motor surround inhibition was present only at the onset phase, but not at the maintenance phase of movement. SAI was reduced at onset but not at the maintenance phase of movement in both active and surrounding muscles. Conclusions: Our study showed dynamic changes in corticospinal excitability and sensorimotor modulation for active and surrounding muscles in different movement states. SAI does not appear to contribute to motor surround inhibition at the movement onset phase. Also, there seems to be different inhibitory circuit(s) other than SAI for the movement maintenance phase in order to delineate the motor output selectively when corticospinal excitability is increased in both active and surrounding muscles. Significance: This study enhances our knowledge of dynamic changes in corticospinal excitability and sensorimotor interaction in different movement states to understand normal and disordered movements. Published by Elsevier Ireland Ltd. on behalf of International Federation of Clinical Neurophysiology. C1 [Cho, Hyun Joo; Panyakaew, Pattamon; Thirugnanasambandam, Nivethida; Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Panyakaew, Pattamon] Chulalongkorn Univ, Dept Med, Fac Med, Chulalongkorn Ctr Excellence Parkinson Dis & Rela, Bangkok 10330, Thailand. [Panyakaew, Pattamon] King Chulalongkorn Mem Hosp, Thai Red Cross Soc, Bangkok 10330, Thailand. [Wu, Tianxia] NINDS, Clin Neurosci Program, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), 10 Ctr Dr MSC 1428,Bldg 10,Room 7D37, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov OI Hallett, Mark/0000-0002-3180-6811 FU NINDS Intramural Program; Dystonia Medical Research Foundation FX NINDS Intramural Program. Hyun Joo Cho is supported by a research grant from the Dystonia Medical Research Foundation. NR 23 TC 1 Z9 1 U1 2 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1388-2457 EI 1872-8952 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD JUN PY 2016 VL 127 IS 6 BP 2343 EP 2349 DI 10.1016/j.clinph.2016.02.020 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DL3YH UT WOS:000375569100007 PM 27178851 ER PT J AU Wendler, D Shah, NN Pulsipher, MA Fry, T Grady, C AF Wendler, David Shah, Nirali N. Pulsipher, Michael A. Fry, Terry Grady, Christine TI Research involving pediatric stem cell donors: A way forward SO CLINICAL TRIALS LA English DT Article DE Transplantation; donor; pediatric; regulations ID CHILDREN; BENEFIT AB The most suitable donor for younger patients who undergo hematopoietic stem cell transplantation in the research setting is frequently a minor sibling. These cases raise the question of whether minors who serve as stem cell donors for research subjects should be regarded as research subjects themselves. Regarding pediatric donors as research subjects ensures that an Institutional Review Boards reviews their involvement and determines whether it is appropriate. Yet, Institutional Review Boards must follow the US regulations for pediatric research, which were designed for patients and healthy volunteers, not for healthy donors. As a result, regarding pediatric donors as research subjects also can pose unnecessary obstacles to appropriate and potentially life-saving research. This article considers a new way to address this dilemma. The federal research regulations allow for waiver of some or all of the included requirements when they are unnecessary for a study or a class of studies. We argue that this option offers a way to ensure that the involvement of pediatric donors receives sufficient review and approval without inadvertently undermining valuable and potentially life-saving research. C1 [Wendler, David; Grady, Christine] NIH Clin Ctr, Dept Bioeth, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. [Shah, Nirali N.; Fry, Terry] Natl Canc Inst, Pediat Oncol Branch, Bethesda, MD USA. [Pulsipher, Michael A.] USC, Keck Sch Med, Los Angeles, CA USA. [Pulsipher, Michael A.] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. RP Wendler, D (reprint author), NIH Clin Ctr, Dept Bioeth, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM dwendler@nih.gov FU Department of Bioethics at the National Institutes of Health Clinical Center; intramural research program of the NIH FX This work was funded, in part, by the Department of Bioethics at the National Institutes of Health Clinical Center and the intramural research program of the NIH. NR 14 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD JUN PY 2016 VL 13 IS 3 BP 304 EP 310 DI 10.1177/1740774515627156 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DL5PP UT WOS:000375689500009 PM 26908544 ER PT J AU Ramsey, TM Snyder, JK Lovato, LC Roumie, CL Glasser, SP Cosgrove, NM Olney, CM Tang, RH Johnson, KC Still, CH Gren, LH Childs, JC Crago, OL Summerson, JH Walsh, SM Perdue, LH Bankowski, DM Goff, DC AF Ramsey, Thomas M. Snyder, Joni K. Lovato, Laura C. Roumie, Christianne L. Glasser, Steven P. Cosgrove, Nora M. Olney, Christine M. Tang, Rocky H. Johnson, Karen C. Still, Carolyn H. Gren, Lisa H. Childs, Jeffery C. Crago, Osa L. Summerson, John H. Walsh, Sandy M. Perdue, Letitia H. Bankowski, Denise M. Goff, David C. CA SPRINT Study Res Grp TI Recruitment strategies and challenges in a large intervention trial: Systolic Blood Pressure Intervention Trial SO CLINICAL TRIALS LA English DT Article DE Clinical Center Networks; hypertension; recruitment; SPRINT ID LIPID-LOWERING TREATMENT; CLINICAL-TRIAL; EXPERIENCE; ALLHAT AB Background: The Systolic Blood Pressure Intervention Trial is a multicenter, randomized clinical trial of 9361 participants with hypertension who are >= 50 years old. The trial is designed to evaluate the effect of intensive systolic blood pressure control (systolic blood pressure goal < 120 mm Hg) compared to standard control (systolic blood pressure goal < 140 mm Hg) on cardiovascular events using commonly prescribed antihypertensive medications and lifestyle modification. Objective: To describe the recruitment strategies and lessons learned during recruitment of the Systolic Blood Pressure Intervention Trial cohort and five targeted participant subgroups: pre-existing cardiovascular disease, preexisting chronic kidney disease, age >= 75 years, women, and minorities. Methods: In collaboration with the National Institutes of Health Project Office and Systolic Blood Pressure Intervention Trial Coordinating Center, five Clinical Center Networks oversaw clinical site selection, recruitment, and trial activities. Recruitment began on 8 November 2010 and ended on 15 March 2013 (about 28 months). Various recruitment strategies were used, including mass mailing, brochures, referrals from healthcare providers or friends, posters, newspaper ads, radio ads, and electronic medical record searches. Results: Recruitment was scheduled to last 24 months to enroll a target of 9250 participants; in just over 28 months, the trial enrolled 9361 participants. The trial screened 14,692 volunteers, with 33% of initial screens originating from the use of mass mailing lists. Screening results show that participants also responded to recruitment efforts through referral by Systolic Blood Pressure Intervention Trial staff, healthcare providers, or friends (45%); brochures or posters placed in clinic waiting areas (15%); and television, radio, newspaper, Internet ads, or toll-free numbers (8%). The overall recruitment yield (number randomized/number screened) was 64% (9361 randomized/14,692 screened), 77% for those with cardiovascular disease, 79% for those with chronic kidney disease, 70% for those aged >= 75 years, 55% for women, and 61% for minorities. As recruitment was observed to lag behind expectations, additional clinics were included and inclusion criteria were broadened, keeping event rates and trial power in mind. As overall recruitment improved, a greater focus on subgroup recruitment was implemented. Conclusion: Systolic Blood Pressure Intervention Trial met its overall projected recruitment goal using diverse, locally adapted enrollment strategies to specifically target persons with cardiovascular disease, chronic kidney disease, >= 75 years old, women, and minority subgroups. The trial exceeded its recruitment goal for minorities but found it a challenge to meet the competing demands of the targeted goals for recruiting into the remaining four subgroups. Important lessons include the imperative to monitor the recruitment process carefully, decide early to add new clinics or modify inclusion and exclusion criteria if recruitment lags, and consider limiting enrollment to subgroups only. We found benefit in using multiple recruitment sources simultaneously; mass mailing produced the largest number of participants, but referrals resulted in the greater randomization yield. C1 [Ramsey, Thomas M.; Glasser, Steven P.] Univ Alabama Birmingham, Sch Med, 1717 11th Ave South,Suite 401 S, Birmingham, AL 35294 USA. [Snyder, Joni K.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Lovato, Laura C.; Crago, Osa L.; Summerson, John H.; Perdue, Letitia H.] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Roumie, Christianne L.] Tennessee Valley Healthcare Syst, GRECC, Vet Hlth Adm, Nashville, TN USA. [Cosgrove, Nora M.; Bankowski, Denise M.] Rutgers State Univ, Cardiovasc Inst, New Brunswick, NJ 08903 USA. [Olney, Christine M.] Vet Hlth Adm, Minneapolis, MN USA. [Tang, Rocky H.] Columbia Univ, New York, NY USA. [Johnson, Karen C.] UTHSC, Memphis, TN USA. [Still, Carolyn H.] Case Western Reserve Univ, Sch Nursing, Cleveland, OH 44106 USA. [Gren, Lisa H.; Childs, Jeffery C.] Univ Utah, Salt Lake City, UT USA. [Walsh, Sandy M.] Vet Hlth Adm, Memphis, TN USA. [Goff, David C.] Univ Colorado, Colorado Sch Publ Hlth, Aurora, CO USA. RP Ramsey, TM (reprint author), Univ Alabama Birmingham, Sch Med, 1717 11th Ave South,Suite 401 S, Birmingham, AL 35294 USA. EM tramsey@uabmc.edu FU NCATS-CWRU [UL1TR000439]; OSU [UL1RR025755]; University of Pennsylvania [UL1RR024134, UL1TR000003]; University of Illinois [UL1TR000050]; University of Pittsburgh [UL1TR000005]; UT Southwestern [9U54TR000017-06]; University of Utah [UL1TR000105-05]; Vanderbilt University [UL1 TR000445]; George Washington University [UL1TR000075]; University of CA, Davis [UL1 TR000002]; University of Florida [UL1 TR000064]; University of Michigan [UL1TR000433]; National Institutes of Health (NIH), including the National Heart, Lung, and Blood Institute (NHLBI); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institute on Aging (NIA); National Institute of Neurological Disorders and Stroke (NINDS) [HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C, HHSN268200900049C, A-HL-13-002-001]; Tufts [UL1RR025752, UL1TR000073, UL1TR001064]; Stanford [UL1TR000093]; [UL1RR025771] FX This study was supported by the following CTSAs funded by NCATS-CWRU: UL1TR000439, OSU: UL1RR025755, University of Pennsylvania: UL1RR024134 and UL1TR000003, Boston: UL1RR025771, Stanford: UL1TR000093, Tufts: UL1RR025752, UL1TR000073 and UL1TR001064, University of Illinois: UL1TR000050, University of Pittsburgh: UL1TR000005, UT Southwestern: 9U54TR000017-06, University of Utah: UL1TR000105-05, Vanderbilt University: UL1 TR000445, George Washington University: UL1TR000075, University of CA, Davis: UL1 TR000002, University of Florida: UL1 TR000064, and University of Michigan: UL1TR000433. The SPRINT was funded with Federal funds from the National Institutes of Health (NIH), including the National Heart, Lung, and Blood Institute (NHLBI), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute on Aging (NIA), and the National Institute of Neurological Disorders and Stroke (NINDS), under Contract Numbers HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C, HHSN268200900049C, and Inter-Agency Agreement Number A-HL-13-002-001. It was also supported, in part, with resources and use of facilities through the Department of Veterans Affairs. NR 14 TC 0 Z9 0 U1 1 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD JUN PY 2016 VL 13 IS 3 BP 319 EP 330 DI 10.1177/1740774516631735 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DL5PP UT WOS:000375689500011 PM 26911833 ER PT J AU Montano, SM Mori, N Nelson, CA Ton, TGN Celis, V Ticona, E Sihuincha, M Tilley, DH Kochel, T Zunt, JR AF Montano, S. M. Mori, N. Nelson, C. A. Ton, T. G. N. Celis, V. Ticona, E. Sihuincha, M. Tilley, D. H. Kochel, T. Zunt, J. R. CA Meningoencephalitis Working Grp TI Herpes simplex virus encephalitis in Peru: a multicentre prospective study SO EPIDEMIOLOGY AND INFECTION LA English DT Article DE Central nervous system infections; encephalitis; epidemiology; herpes simplex virus; virology ID NERVOUS-SYSTEM; INFECTIONS; ETIOLOGIES; DIAGNOSIS; ADULTS AB Herpes simplex virus (HSV) is one of the most commonly identified infectious aetiologies of encephalitis in North America and Europe. The epidemiology of encephalitis beyond these regions, however, is poorly defined. During 2009-2012 we enrolled 313 patients in a multicentre prospective study of encephalitis in Peru, 45 (14.4%) of whom had confirmed HSV infection. Of 38 patients with known HSV type, 84% had HSV-1 and 16% had HSV-2. Patients with HSV infection were significantly more likely to present in the summer months (44.4% vs. 20.0%, P = 0.003) and have nausea (60.0% vs. 39.8%, P = 0.01) and rash (15.6% vs. 5.3%, P = 0.01) compared to patients without HSV infection. These findings highlight differences in the epidemiology and clinical presentation of HSV encephalitis outside of the Northern Hemisphere that warrant further investigation. Furthermore, there is an urgent need for improved HSV diagnostic capacity and availability of intravenous acyclovir in Peru. C1 [Montano, S. M.; Tilley, D. H.; Kochel, T.] US Naval Med Res Unit 6, Callao, Peru. [Mori, N.; Nelson, C. A.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Mori, N.] Hosp Daniel Alcides Carrion, Callao, Peru. [Ton, T. G. N.; Zunt, J. R.] Univ Washington, Sch Med, Dept Neurol, Seattle, WA USA. [Celis, V.] Hosp Belen, Trujillo, Peru. [Ticona, E.] Hosp Mayo, Lima, Peru. [Ticona, E.] Univ Nacl Mayor San Marcos, Lima 14, Peru. [Sihuincha, M.] Hosp Cesar Garayar Garcia, Loreto, Peru. [Zunt, J. R.] Univ Washington, Sch Med, Dept Global Hlth, Seattle, WA USA. [Zunt, J. R.] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. RP Nelson, CA (reprint author), Ctr Dis Control & Prevent, Div Vector Borne Dis, 3156 Rampart Rd,Mail Stop P-02, Ft Collins, CO 80521 USA. EM wje1@cdc.gov FU NIH Fogarty International Center grant [RO1NS55627]; National Institutes of Health Office of the Director; Fogarty International Center; Office of AIDS Research; National Cancer Center; National Eye Institute; National Heart, Blood, and Lung Institute; National Institute of Dental & Craniofacial Research; National Institute on Drug Abuse; National Institute of Mental Health; National Institute of Allergy and Infectious Diseases Health; NIH Office of Women's Health and Research through the International Clinical Research Fellows Program at Vanderbilt University [R24 TW007988] FX Funding for this study was provided by NIH Fogarty International Center grant RO1NS55627 to Joseph R. Zunt. This work was also supported by the National Institutes of Health Office of the Director, Fogarty International Center, Office of AIDS Research, National Cancer Center, National Eye Institute, National Heart, Blood, and Lung Institute, National Institute of Dental & Craniofacial Research, National Institute on Drug Abuse, National Institute of Mental Health, National Institute of Allergy and Infectious Diseases Health, and NIH Office of Women's Health and Research through the International Clinical Research Fellows Program at Vanderbilt University (R24 TW007988). NR 22 TC 0 Z9 0 U1 3 U2 3 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0950-2688 EI 1469-4409 J9 EPIDEMIOL INFECT JI Epidemiol. Infect. PD JUN PY 2016 VL 144 IS 8 BP 1673 EP 1678 DI 10.1017/S0950268815003222 PG 6 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA DL7EV UT WOS:000375804300011 PM 26733400 ER PT J AU Thevenon, J Souchay, C Seabold, GK Dygai-Cochet, I Callier, P Gay, S Corbin, L Duplomb, L Thauvin-Robinet, C Masurel-Paulet, A El Chehadeh, S Avila, M Minot, D Guedj, E Chancenotte, S Bonnet, M Lehalle, D Wang, YX Kuentz, P Huet, F Mosca-Boidron, AL Marle, N Petralia, RS Faivre, L AF Thevenon, Julien Souchay, Celine Seabold, Gail K. Dygai-Cochet, Inna Callier, Patrick Gay, Sebastien Corbin, Lucie Duplomb, Laurence Thauvin-Robinet, Christel Masurel-Paulet, Alice El Chehadeh, Salima Avila, Magali Minot, Delphine Guedj, Eric Chancenotte, Sophie Bonnet, Marlene Lehalle, Daphne Wang, Ya-Xian Kuentz, Paul Huet, Frederic Mosca-Boidron, Anne-Laure Marle, Nathalie Petralia, Ronald S. Faivre, Laurence TI Heterozygous deletion of the LRFN2 gene is associated with working memory deficits SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article ID ADHESION-LIKE MOLECULES; SHORT-TERM; NMDA RECEPTOR; DOWN-SYNDROME; LANGUAGE; SPEECH; EXPRESSION; DISORDERS; FAMILY; AUTISM AB Learning disabilities (LDs) are a clinically and genetically heterogeneous group of diseases. Array-CGH and high-throughput sequencing have dramatically expanded the number of genes implicated in isolated intellectual disabilities and LDs, highlighting the implication of neuron-specific post-mitotic transcription factors and synaptic proteins as candidate genes. We report a unique family diagnosed with autosomal dominant learning disability and a 6p21 microdeletion segregating in three patients. The 870 kb microdeletion encompassed the brain-expressed gene LRFN2, which encodes for a synaptic cell adhesion molecule. Neuropsychological assessment identified selective working memory deficits, with borderline intellectual functioning. Further investigations identified a defect in executive function, and auditory-verbal processes. These data were consistent with brain MRI and FDG-PET functional brain imaging, which, when compared with controls, revealed abnormal brain volume and hypometabolism of gray matter structures implicated in working memory. We performed electron microscopy immunogold labeling demonstrating the localization of LRFN2 at synapses of cerebellar and hippocampal rat neurons, often associated with the NR1 subunit of N-methyl-D-aspartate receptors (NMDARs). Altogether, the combined approaches imply a role for LRFN2 in LD, specifically for working memory processes and executive function. In conclusion, the identification of familial cases of clinically homogeneous endophenotypes of LD might help in both the management of patients and genetic counseling for families. C1 [Thevenon, Julien; Thauvin-Robinet, Christel; Masurel-Paulet, Alice; El Chehadeh, Salima; Minot, Delphine; Lehalle, Daphne; Faivre, Laurence] Hop Enfants, Ctr Genet, 14 Rue Gaffarel, F-21079 Dijon, France. [Thevenon, Julien; Thauvin-Robinet, Christel; Masurel-Paulet, Alice; El Chehadeh, Salima; Minot, Delphine; Lehalle, Daphne; Faivre, Laurence] Hop Enfants, Ctr Reference Anomalies Dev & Syndromes Malformat, 14 Rue Gaffarel, F-21079 Dijon, France. [Thevenon, Julien; Callier, Patrick; Duplomb, Laurence; Thauvin-Robinet, Christel; Lehalle, Daphne; Kuentz, Paul; Faivre, Laurence] Univ Bourgogne, Equipe GAD, EA 4271, Dijon, France. [Thevenon, Julien; Callier, Patrick; Duplomb, Laurence; Thauvin-Robinet, Christel; Lehalle, Daphne; Kuentz, Paul; Faivre, Laurence] Univ Bourgogne, FHU TRANSLAD, Dijon, France. [Souchay, Celine; Corbin, Lucie] Univ Bourgogne, LEAD CNRS UMR 5022, Lab Etud Apprentissage & Dev, Dijon, France. [Seabold, Gail K.] NIDCD, Neurochem Lab, NIH, Bethesda, MD USA. [Dygai-Cochet, Inna] CGFL, Dept Nucl Med, Dijon, France. [Callier, Patrick; Mosca-Boidron, Anne-Laure; Marle, Nathalie] CHU Dijon, Lab Cytogenet, Plateau Tech Biol, Dijon, France. [Gay, Sebastien] CH Wiliam Morey, Serv Pediat, Chalon Sur Saone, France. [Avila, Magali; Huet, Frederic] Hop Enfants, Serv Pediat, Dijon, France. [Guedj, Eric] Hop Enfants La Timone, AP HM, Dept Nucl Med, Marseille, France. [Chancenotte, Sophie; Bonnet, Marlene] CHU Dijon, Hop Enfants, Ctr Reference Troubles Langage & Apprentissages, Dijon, France. [Wang, Ya-Xian; Petralia, Ronald S.] NIDCD, Adv Imaging Core, NIH, Bethesda, MD USA. RP Faivre, L (reprint author), Hop Enfants, Ctr Genet, 14 Rue Gaffarel, F-21079 Dijon, France.; Faivre, L (reprint author), Hop Enfants, Ctr Reference Anomalies Dev & Syndromes Malformat, 14 Rue Gaffarel, F-21079 Dijon, France. EM laurence.faivre@chu-dijon.fr FU regional council of Burgundy; NIDCD/NIH FX We thank the family for their participation in this study. We also thank the regional council of Burgundy for the financial support of the project. GKS, YW, and RSP were supported by the NIDCD/NIH Intramural Research Program. NR 56 TC 0 Z9 0 U1 6 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD JUN PY 2016 VL 24 IS 6 BP 911 EP 918 DI 10.1038/ejhg.2015.221 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DL5WD UT WOS:000375706800019 PM 26486473 ER PT J AU Ambalavanan, A Girard, SL Ahn, K Zhou, SR Dionne-Laporte, A Spiegelman, D Bourassa, CV Gauthier, J Hamdan, FF Xiong, L Dion, PA Joober, R Rapoport, J Rouleau, GA AF Ambalavanan, Amirthagowri Girard, Simon L. Ahn, Kwangmi Zhou, Sirui Dionne-Laporte, Alexandre Spiegelman, Dan Bourassa, Cynthia V. Gauthier, Julie Hamdan, Fadi F. Xiong, Lan Dion, Patrick A. Joober, Ridha Rapoport, Judith Rouleau, Guy A. TI De novo variants in sporadic cases of childhood onset schizophrenia SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article ID AUTISM SPECTRUM DISORDERS; TUBULIN KINASE 1; INTELLECTUAL DISABILITY; SEQUENCING DATA; MUTATIONS; DISEASE; GENOME; EXPRESSION; RECEPTORS; BRAIN AB Childhood-onset schizophrenia (COS), defined by the onset of illness before age 13 years, is a rare severe neurodevelopmental disorder of unknown etiology. Recently, sequencing studies have identified rare, potentially causative de novo variants in sporadic cases of adult-onset schizophrenia and autism. In this study, we performed exome sequencing of 17 COS trios in order to test whether de novo variants could contribute to this disease. We identified 20 de novo variants in 17 COS probands, which is consistent with the de novo mutation rate reported in the adult form of the disease. Interestingly, the missense de novo variants in COS have a high likelihood for pathogenicity and were enriched for genes that are less tolerant to variants. Among the genes found disrupted in our study, SEZ6, RYR2, GPR153, GTF2IRD1, TTBK1 and ITGA6 have been previously linked to neuronal function or to psychiatric disorders, and thus may be considered as COS candidate genes. C1 [Ambalavanan, Amirthagowri; Girard, Simon L.; Joober, Ridha; Rouleau, Guy A.] McGill Univ, Dept Human Genet, Montreal, PQ, Canada. [Ahn, Kwangmi; Rapoport, Judith] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. [Zhou, Sirui; Gauthier, Julie; Hamdan, Fadi F.] Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada. [Dionne-Laporte, Alexandre; Spiegelman, Dan; Bourassa, Cynthia V.; Dion, Patrick A.; Rouleau, Guy A.] McGill Univ, Dept Neurol & Neurosurg, Montreal, PQ, Canada. [Xiong, Lan] Univ Montreal, Dept Psychiat, Montreal, PQ H3C 3J7, Canada. [Joober, Ridha] Douglas Mental Hlth Univ Inst, Dept Psychiat, Montreal, PQ, Canada. [Rouleau, Guy A.] Montreal Neurol Hosp & Inst, Montreal, PQ, Canada. RP Rouleau, GA (reprint author), Montreal Neurol Hosp & Inst, Dept Neurol & Neurosurg, 3801 Univ St, Montreal, PQ H3A 2B4, Canada. EM guy.rouleau@mcgill.ca FU Genome Canada; Genome Quebec [RMF_92086] FX The current study was supported by the Genome Canada and Genome Quebec (Grant No. RMF_92086). Bioinformatics analysis was supported by the Canadian Institutes of Health Research (CIHR). We thank the patients and the family members who agreed to participate in the study. We thank Daniel Rochefort and Sylvia Dobrezenicka for the technical support; also Edouard Henrion and Ousmane Diallo for their bioinformatics support. We also thank Claire Leblond, Pingxing Xie, Alanna Grant and Martine Therrien for their valuable suggestions and comments. NR 41 TC 3 Z9 3 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD JUN PY 2016 VL 24 IS 6 BP 944 EP 948 DI 10.1038/ejhg.2015.218 PG 5 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DL5WD UT WOS:000375706800024 PM 26508570 ER PT J AU Chen, C Zhang, XL Wang, YZ Zhou, TG Fang, F AF Chen, Cheng Zhang, Xilin Wang, Yizhou Zhou, Tiangang Fang, Fang TI Neural activities in V1 create the bottom-up saliency map of natural scenes SO EXPERIMENTAL BRAIN RESEARCH LA English DT Article DE Bottom-up saliency map; Visual attention; Natural scene; fMRI; Primary visual cortex ID LATERAL GENICULATE-NUCLEUS; STIMULUS-DRIVEN ATTENTION; VISUAL-ATTENTION; TOP-DOWN; CORTEX; FMRI; HUMANS; AREAS; MECHANISMS; CIRCUITRY AB A saliency map is the bottom-up contribution to the deployment of exogenous attention. It, as well as its underlying neural mechanism, is hard to identify because of the influence of top-down signals. A recent study showed that neural activities in V1 could create a bottom-up saliency map (Zhang et al. in Neuron 73(1):183-192, 2012). In this paper, we tested whether their conclusion can generalize to complex natural scenes. In order to avoid top-down influences, each image was presented with a low contrast for only 50 ms and was followed by a high contrast mask, which rendered the whole image invisible to participants (confirmed by a forced-choice test). The Posner cueing paradigm was adopted to measure the spatial cueing effect (i.e., saliency) by an orientation discrimination task. A positive cueing effect was found, and the magnitude of the cueing effect was consistent with the saliency prediction of a computational saliency model. In a following fMRI experiment, we used the same masked natural scenes as stimuli and measured BOLD signals responding to the predicted salient region (relative to the background). We found that the BOLD signal in V1, but not in other cortical areas, could well predict the cueing effect. These results suggest that the bottom-up saliency map of natural scenes could be created in V1, providing further evidence for the V1 saliency theory (Li in Trends Cogn Sci 6(1):9-16, 2002). C1 [Chen, Cheng; Wang, Yizhou] Peking Univ, Cooperat Medianet Innovat Ctr, Natl Engn Lab Video Technol, Beijing 100871, Peoples R China. [Chen, Cheng; Wang, Yizhou] Peking Univ, Sch Elect Engn & Comp Sci, Beijing 100871, Peoples R China. [Chen, Cheng; Wang, Yizhou; Fang, Fang] Peking Univ, Minist Educ, Key Lab Machine Percept, Beijing 100871, Peoples R China. [Zhang, Xilin] NIMH, Lab Brain & Cognit, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Zhou, Tiangang] Chinese Acad Sci, Inst Biophys, State Key Lab Brain & Cognit Sci, Beijing 100101, Peoples R China. [Fang, Fang] Peking Univ, Peking Tsinghua Ctr Life Sci, Dept Psychol, Beijing 100871, Peoples R China. [Fang, Fang] Peking Univ, Peking Tsinghua Ctr Life Sci, Beijing Key Lab Behav & Mental Hlth, Beijing 100871, Peoples R China. [Fang, Fang] Peking Univ, IDG McGovern Inst Brain Res, Beijing 100871, Peoples R China. RP Wang, YZ (reprint author), Peking Univ, Cooperat Medianet Innovat Ctr, Natl Engn Lab Video Technol, Beijing 100871, Peoples R China.; Wang, YZ (reprint author), Peking Univ, Sch Elect Engn & Comp Sci, Beijing 100871, Peoples R China.; Wang, YZ; Fang, F (reprint author), Peking Univ, Minist Educ, Key Lab Machine Percept, Beijing 100871, Peoples R China.; Fang, F (reprint author), Peking Univ, Peking Tsinghua Ctr Life Sci, Dept Psychol, Beijing 100871, Peoples R China.; Fang, F (reprint author), Peking Univ, Peking Tsinghua Ctr Life Sci, Beijing Key Lab Behav & Mental Hlth, Beijing 100871, Peoples R China.; Fang, F (reprint author), Peking Univ, IDG McGovern Inst Brain Res, Beijing 100871, Peoples R China. EM Yizhou.Wang@pku.edu.cn; ffang@pku.edu.cn FU MOST [2015CB351800]; NSFC [61272027, 31230029, 31421003, 61527804] FX This work was supported by MOST 2015CB351800, NSFC 61272027, NSFC 31230029, NSFC 31421003, and NSFC 61527804. NR 49 TC 1 Z9 1 U1 5 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0014-4819 EI 1432-1106 J9 EXP BRAIN RES JI Exp. Brain Res. PD JUN PY 2016 VL 234 IS 6 BP 1769 EP 1780 DI 10.1007/s00221-016-4583-y PG 12 WC Neurosciences SC Neurosciences & Neurology GA DL3RF UT WOS:000375550200039 PM 26879771 ER PT J AU Eitan, E Hutchison, ER Greig, NH Tweedie, D Celik, H Ghosh, S Fishbein, KW Spencer, RG Sasaki, CY Ghosh, P Das, S Chigurapati, S Raymick, J Sarkar, S Chigurupati, S Seal, S Mattson, MP AF Eitan, Erez Hutchison, Emmette R. Greig, Nigel H. Tweedie, David Celik, Hasan Ghosh, Soumita Fishbein, Kenneth W. Spencer, Richard G. Sasaki, Carl Y. Ghosh, Paritosh Das, Soumen Chigurapati, Susheela Raymick, James Sarkar, Sumit Chigurupati, Srinivasulu Seal, Sudipta Mattson, Mark P. TI Combination therapy with lenalidomide and nanoceria ameliorates CNS autoimmunity (vol 273, pg 151, 2015) SO EXPERIMENTAL NEUROLOGY LA English DT Correction C1 [Eitan, Erez; Hutchison, Emmette R.; Mattson, Mark P.] NIA, Lab Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. [Greig, Nigel H.; Tweedie, David] NIA, Translat Gerontol Branch, Intramural Res Program, Baltimore, MD 21224 USA. [Celik, Hasan; Ghosh, Soumita; Fishbein, Kenneth W.; Spencer, Richard G.] NIA, Lab Clin Invest, Intramural Res Program, Baltimore, MD 21224 USA. [Das, Soumen] Univ Cent Florida, Mat Sci & Engn Coll Med, Orlando, FL 32816 USA. [Sasaki, Carl Y.; Ghosh, Paritosh] NIA, Immunol Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Chigurapati, Susheela] US FDA, Arkansas Reg Lab, Off Regulatory Affairs, 3900 NCTR Rd,Bldg 26, Jefferson, AR 72079 USA. [Raymick, James; Sarkar, Sumit; Chigurupati, Srinivasulu] Natl Ctr Toxicol Res FDA, Div Neurotoxicol, Jefferson, AR 72079 USA. [Seal, Sudipta] Univ Cent Florida, Adv Mat Proc & Anal Ctr, Nanosci Technol Ctr, Mech Mat Aerosp Engn, Orlando, FL 32816 USA. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Lab Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. EM mark.mattson@nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 EI 1090-2430 J9 EXP NEUROL JI Exp. Neurol. PD JUN PY 2016 VL 280 BP 121 EP 121 DI 10.1016/j.expneurol.2016.02.015 PG 1 WC Neurosciences SC Neurosciences & Neurology GA DL7LK UT WOS:000375822000014 ER PT J AU Kamil, RJ Betz, J Powers, BB Pratt, S Kritchevsky, S Ayonayon, HN Harris, TB Helzner, E Deal, JA Martin, K Peterson, M Satterfield, S Simonsick, EM Lin, FR AF Kamil, Rebecca J. Betz, Joshua Powers, Becky Brott Pratt, Sheila Kritchevsky, Stephen Ayonayon, Hilsa N. Harris, Tammy B. Helzner, Elizabeth Deal, Jennifer A. Martin, Kathryn Peterson, Matthew Satterfield, Suzanne Simonsick, Eleanor M. Lin, Frank R. CA Hlth ABC study TI Association of Hearing Impairment With Incident Frailty and Falls in Older Adults SO JOURNAL OF AGING AND HEALTH LA English DT Article DE hearing impairment; frailty; falls; older adults; Health ABC ID RISK-FACTORS; COGNITIVE IMPAIRMENT; PHYSICAL-ACTIVITY; UNITED-STATES; OSTEOPOROTIC FRACTURES; CARDIOVASCULAR-DISEASE; FUNCTIONAL DECLINE; ELDERLY PERSONS; HEALTH; WOMEN AB Objective: We aimed to determine whether hearing impairment (HI) in older adults is associated with the development of frailty and falls. Method: Longitudinal analysis of observational data from the Health, Aging and Body Composition study of 2,000 participants aged 70 to 79 was conducted. Hearing was defined by the pure-tone-average of hearing thresholds at 0.5, 1, 2, and 4 kHz in the better hearing ear. Frailty was defined as a gait speed of <0.60 m/s and/or inability to rise from a chair without using arms. Falls were assessed annually by self-report. Results: Older adults with moderate-or-greater HI had a 63% increased risk of developing frailty (adjusted hazard ratio [HR] = 1.63, 95% confidence interval [CI] = [1.26, 2.12]) compared with normal-hearing individuals. Moderate-or-greater HI was significantly associated with a greater annual percent increase in odds of falling over time (9.7%, 95% CI = [7.0, 12.4] compared with normal hearing, 4.4%, 95% CI = [2.6, 6.2]). Discussion: HI is independently associated with the risk of frailty in older adults and with greater odds of falling over time. C1 [Kamil, Rebecca J.; Betz, Joshua; Deal, Jennifer A.; Simonsick, Eleanor M.; Lin, Frank R.] Johns Hopkins Univ, Baltimore, MD USA. [Powers, Becky Brott; Pratt, Sheila; Peterson, Matthew] US Dept Vet Affairs, Washington, DC USA. [Pratt, Sheila] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Kritchevsky, Stephen] Wake Forest Univ, Winston Salem, NC 27109 USA. [Ayonayon, Hilsa N.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Harris, Tammy B.; Simonsick, Eleanor M.] NIA, Bethesda, MD 20892 USA. [Helzner, Elizabeth] Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. [Martin, Kathryn] Univ Aberdeen, Aberdeen AB9 1FX, Scotland. [Peterson, Matthew] Duke Univ, Durham, NC USA. [Satterfield, Suzanne] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. RP Kamil, RJ (reprint author), Johns Hopkins Univ, Ctr Aging & Hlth, 2024 E Monument St,Suite 2-700, Baltimore, MD 21205 USA. EM rkamil1@jhmi.edu OI Betz, Joshua/0000-0003-4488-9799 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NIA [R01-AG028050]; NINR [R01-NR012459]; Intramural Research Program of the NIH, National Institute on Aging; National Institute of Deafness and Communication Disorders [K23DC011279]; Triological Society; American College of Surgeons Clinician Scientist Award; Eleanor Schwartz Charitable Foundation; Oticon Foundation; Geriatric Research Education and Clinical Center in the Veterans Administration Pittsburgh Healthcare System FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by National Institute on Aging (NIA) Contracts N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106; NIA Grant R01-AG028050; and NINR Grant R01-NR012459. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. Frank Lin is supported by the National Institute of Deafness and Communication Disorders K23DC011279 Grant, Triological Society and American College of Surgeons Clinician Scientist Award, and Eleanor Schwartz Charitable Foundation. Rebecca Kamil's coursework at Bloomberg School of Public Health is supported by the Oticon Foundation. Sheila Pratt and Becky Brott Powers were supported by the Geriatric Research Education and Clinical Center in the Veterans Administration Pittsburgh Healthcare System during the development of this article. NR 55 TC 1 Z9 1 U1 4 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0898-2643 EI 1552-6887 J9 J AGING HEALTH JI J. Aging Health PD JUN PY 2016 VL 28 IS 4 BP 644 EP 660 DI 10.1177/0898264315608730 PG 17 WC Gerontology; Health Policy & Services SC Geriatrics & Gerontology; Health Care Sciences & Services GA DL5ZC UT WOS:000375714700005 PM 26438083 ER PT J AU Zavala, B Tan, HL Little, S Ashkan, K Green, AL Aziz, T Foltynie, T Zrinzo, L Zaghloul, K Brown, P AF Zavala, Baltazar Tan, Huiling Little, Simon Ashkan, Keyoumars Green, Alexander L. Aziz, Tipu Foltynie, Thomas Zrinzo, Ludvic Zaghloul, Kareem Brown, Peter TI Decisions Made with Less Evidence Involve Higher Levels of Corticosubthalamic Nucleus Theta Band Synchrony SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Article ID ANTERIOR CINGULATE CORTEX; DEEP BRAIN-STIMULATION; HUMAN SUBTHALAMIC NUCLEUS; INCREASES RESPONSE-TIME; PARKINSONS-DISEASE; COGNITIVE CONTROL; TASK-DIFFICULTY; IMPULSE CONTROL; EEG-DATA; CONFLICT AB The switch between automatic action selection and more controlled forms of decision-making is a dynamic process thought to involve both cortical and subcortical structures. During sensory conflict, medial pFC oscillations in the theta band (<8 Hz) drive those of the subthalamic nucleus (STN), and this is thought to increase the threshold of evidence needed for one competing response to be selected over another. Here, we were interested in testing whether STN activity is also altered by the rate at which evidence is presented during a congruent dot motion task absent of any explicit sensory conflict. By having a series of randomly moving dots gradually transform to congruent motion at three different rates (slow, medium, fast), we were able to show that a slower rate increased the time it took participants to make a response but did not alter the total amount of evidence that was integrated before the response. Notably, this resulted in a decision being made with a lower amount of instantaneous evidence during the slow and medium trials. Consistent with the idea that medial pFC-STN activity is involved in executing cognitive control, the higher levels of ambiguity during these trials were associated with increased theta band synchrony between the cortex and the STN, with the cortical oscillations Granger-causal to those of the STN. These results further confirm the involvement of the STN in decision-making and suggest that the disruption of this network may underlie some of the unwanted cognitive deficits associated with STN deep brain stimulation. C1 [Zavala, Baltazar; Tan, Huiling; Green, Alexander L.; Aziz, Tipu; Brown, Peter] Univ Oxford, John Radcliffe Hosp, Oxford OX3 9DU, England. [Zavala, Baltazar; Zaghloul, Kareem] NIH, Bldg 10, Bethesda, MD 20892 USA. [Tan, Huiling; Green, Alexander L.; Aziz, Tipu; Brown, Peter] Univ Oxford, Brain Network Dynam Unit, Med Res Council, Oxford OX3 9DU, England. [Little, Simon; Foltynie, Thomas; Zrinzo, Ludvic] UCL, London WC1E 6BT, England. [Ashkan, Keyoumars] Kings Coll London, London WC2R 2LS, England. RP Brown, P (reprint author), Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Neurol, Level 6, Oxford OX3 9DU, England. EM peter.brown@ndcn.ox.ac.uk RI Brown, Peter/J-4307-2016; OI Brown, Peter/0000-0002-5201-3044; Tan, Huiling /0000-0001-8038-3029 FU Rhodes Trust; National Institutes of Health Oxford-Cambridge fellowship; Department of Health, National Institute for Health Research, University College London Biomedical Research Center; Monument Trust; Parkinson's Appeal for Deep Brain Stimulation; Medical Research Council; Department of Health, National Institute for Health Research, Oxford Biomedical Research Centre; Wellcome Trust FX B. Z. is supported by the Rhodes Trust and the National Institutes of Health Oxford-Cambridge fellowship. M. H., T. F., and L. Z. are funded by the Department of Health, National Institute for Health Research, University College London Biomedical Research Center; The Monument Trust; and Parkinson's Appeal for Deep Brain Stimulation. P. B. and H. T. are funded by the Medical Research Council, and P. B. is further funded by the Department of Health, National Institute for Health Research, Oxford Biomedical Research Centre. S. L. is funded by the Wellcome Trust. This work was partly carried out in the National Institute for Health Research cognitive health Clinical Research Facility, Oxford. NR 66 TC 1 Z9 1 U1 5 U2 8 PU MIT PRESS PI CAMBRIDGE PA ONE ROGERS ST, CAMBRIDGE, MA 02142-1209 USA SN 0898-929X EI 1530-8898 J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD JUN PY 2016 VL 28 IS 6 BP 811 EP 825 DI 10.1162/jocn_a_00934 PG 15 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA DL6WJ UT WOS:000375780300004 PM 26845109 ER PT J AU Racz, SJ O'Brennan, LM Bradshaw, CP Leaf, PJ AF Racz, Sarah J. O'Brennan, Lindsey M. Bradshaw, Catherine P. Leaf, Philip J. TI The Influence of Family and Teacher Factors on Early Disruptive School Behaviors: A Latent Profile Transition Analysis SO JOURNAL OF EMOTIONAL AND BEHAVIORAL DISORDERS LA English DT Article DE disruptive behaviors; early school behavior; family and teacher factors; latent profile transition analysis ID MENTAL-HEALTH PROBLEMS; ELEMENTARY-SCHOOL; CONDUCT PROBLEMS; CHILD-BEHAVIOR; AGGRESSIVE-BEHAVIOR; PRESCHOOL-CHILDREN; PREVENTION; CLASSROOM; INTERVENTIONS; OUTCOMES AB The kindergarten year plays an important role in establishing children's academic, social, and behavioral adjustment. Early identification of children who experience difficulties with the kindergarten transition is crucial to prevent continued behavioral and emotional problems. Family and school predictors of these early behavioral patterns can suggest important targets for preventive interventions. The current study examined heterogeneity in 2,814 children's disruptive behaviors over the course of the kindergarten school year using latent profile and transition analyses. We further investigated the degree to which changes in these behavioral patterns varied as a function of family and teacher factors. Results provided evidence of three distinct profiles of disruptive behavior exhibited by kindergarteners (well-adapted, concentration problems, and at-risk), which were relatively stable over the course of the kindergarten school year. These behavioral patterns were associated with family (i.e., family problems, family involvement) but not teacher (i.e., efficacy and burnout) factors. Findings have important implications for the early identification of children at-risk for behavioral problems. C1 [Racz, Sarah J.; O'Brennan, Lindsey M.; Leaf, Philip J.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Bradshaw, Catherine P.] Univ Virginia, Charlottesville, VA USA. RP Racz, SJ (reprint author), NICHHD, NIH, 6705 Rockledge Dr,Suite 8030, Bethesda, MD 20892 USA. EM sarah.racz@nih.gov FU National Institute of Mental Health (NIMH) [T32 MH19545-21]; Institute of Education Sciences [R324A07118, R305A090307, R324A110107]; Centers for Disease Control and Prevention [K01CE001333-01] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Support for this project comes from the National Institute of Mental Health (NIMH) Grant T32 MH19545-21, the Institute of Education Sciences (R324A07118, R305A090307, R324A110107), and the Centers for Disease Control and Prevention (K01CE001333-01). NR 69 TC 0 Z9 0 U1 9 U2 15 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1063-4266 EI 1538-4799 J9 J EMOT BEHAV DISORD JI J. Emot. Behav. Disord. PD JUN PY 2016 VL 24 IS 2 BP 67 EP 81 DI 10.1177/1063426615599541 PG 15 WC Education, Special; Psychology, Educational; Psychology, Multidisciplinary SC Education & Educational Research; Psychology GA DL6CU UT WOS:000375726700001 ER PT J AU Lu, DM Rauhauser, A Li, BH Ren, CY McEnery, K Zhu, JL Chaki, M Vadnagara, K Elhadi, S Jetten, AM Igarashi, P Attanasio, M AF Lu, Dongmei Rauhauser, Alysha Li, Binghua Ren, Chongyu McEnery, Kayla Zhu, Jili Chaki, Moumita Vadnagara, Komal Elhadi, Sarah Jetten, Anton M. Igarashi, Peter Attanasio, Massimo TI Loss of Glis2/NPHP7 causes kidney epithelial cell senescence and suppresses cyst growth in the Kif3a mouse model of cystic kidney disease SO KIDNEY INTERNATIONAL LA English DT Article DE cystic kidney disease; DNA damage; Kif3a; nephronophthisis; senescence ID DNA-DAMAGE RESPONSE; RENAL CILIOPATHIES; PRIMARY CILIA; CYCLIN B1; IN-VIVO; S-PHASE; NEPHRONOPHTHISIS; ACTIVATION; MECHANISMS; CHECKPOINT AB Enlargement of kidney tubules is a common feature of multiple cystic kidney diseases in humans and mice. However, while some of these pathologies are characterized by cyst expansion and organ enlargement, in others, progressive interstitial fibrosis and kidney atrophy prevail. The Kif3a knockout mouse is an established non-orthologous mouse model of cystic kidney disease. Conditional inactivation of Kif3a in kidney tubular cells results in loss of primary cilia and rapid cyst growth. Conversely, loss of function of the gene GLIS2/NPHP7 causes progressive kidney atrophy, interstitial inflammatory infiltration, and fibrosis. Kif3a null tubular cells have unrestrained proliferation and reduced stabilization of p53 resulting in a loss of cell cycle arrest in the presence of DNA damage. In contrast, loss of Glis2 is associated with activation of checkpoint kinase 1, stabilization of p53, and induction of cell senescence. Interestingly, the cystic phenotype of Kif3a knockout mice is partially rescued by genetic ablation of Glis2 and pharmacological stabilization of p53. Thus, Kif3a is required for cell cycle regulation and the DNA damage response, whereas cell senescence is significantly enhanced in Glis2 null cells. Hence, cell senescence is a central feature in nephronophthisis type 7 and Kif3a is unexpectedly required for efficient DNA damage response and cell cycle arrest. C1 [Lu, Dongmei; Rauhauser, Alysha; Li, Binghua; Ren, Chongyu; McEnery, Kayla; Zhu, Jili; Chaki, Moumita; Vadnagara, Komal; Attanasio, Massimo] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Zhu, Jili] Wuhan Univ, Renmin Hosp, Dept Nephrol, Wuhan 430072, Hubei, Peoples R China. [Elhadi, Sarah] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [Jetten, Anton M.] NIEHS, Cell Biol Sect, Div Intramural Res, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Igarashi, Peter] Univ Minnesota, Dept Internal Med, Minneapolis, MN USA. [Attanasio, Massimo] Univ Texas SW Med Ctr Dallas, Eugene McDermott Ctr Growth & Dev, Dallas, TX 75390 USA. RP Attanasio, M (reprint author), Univ Texas SW Med Ctr Dallas, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM massimo.attanasio@utsouthwestern.edu RI zhu, jili/L-5788-2013; OI zhu, jili/0000-0002-7285-6858; Igarashi, Peter/0000-0001-8698-1185 FU National Institutes of Health [1R01DK090326-01A1, P30DK079328-04]; American Society of Nephrology Norman Siegel award; Satellite Healthcare Norman Coplon extramural research award FX We would like to thank Patricia Cobo-Stark and Jessica Lucas for their technical support and Dr. Denise Marciano for editing the manuscript. MA was supported by the National Institutes of Health grants (1R01DK090326-01A1, P30DK079328-04), the American Society of Nephrology Norman Siegel award, and the Satellite Healthcare Norman Coplon extramural research award. NR 52 TC 1 Z9 1 U1 3 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD JUN PY 2016 VL 89 IS 6 BP 1307 EP 1323 DI 10.1016/j.kint.2016.03.006 PG 17 WC Urology & Nephrology SC Urology & Nephrology GA DL5QY UT WOS:000375693100018 PM 27181777 ER PT J AU Pacold, ME Brimacombe, KR Chan, SH Rohde, JM Lewis, CA Swier, LJYM Possemato, R Chen, WW Sullivan, LB Fiske, BP Cho, S Freinkman, E Birsoy, K Abu-Remaileh, M Shaul, YD Liu, CM Zhou, M Koh, MJ Chung, H Davidson, SM Luengo, A Wang, AQ Xu, X Yasgar, A Liu, L Rai, G Westover, KD Vander Heiden, MG Shen, M Gray, NS Boxer, MB Sabatini, DM AF Pacold, Michael E. Brimacombe, Kyle R. Chan, Sze Ham Rohde, Jason M. Lewis, Caroline A. Swier, Lotteke J. Y. M. Possemato, Richard Chen, Walter W. Sullivan, Lucas B. Fiske, Brian P. Cho, Steve Freinkman, Elizaveta Birsoy, Kivanc Abu-Remaileh, Monther Shaul, Yoav D. Liu, Chieh Min Zhou, Minerva Koh, Min Jung Chung, Haeyoon Davidson, Shawn M. Luengo, Alba Wang, Amy Q. Xu, Xin Yasgar, Adam Liu, Li Rai, Ganesha Westover, Kenneth D. Vander Heiden, Matthew G. Shen, Min Gray, Nathanael S. Boxer, Matthew B. Sabatini, David M. TI A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate SO NATURE CHEMICAL BIOLOGY LA English DT Article ID PYRUVATE-KINASE M2; CELL LUNG-CANCER; PHOSPHOGLYCERATE DEHYDROGENASE; METABOLISM; GLYCINE; BIOSYNTHESIS; PROLIFERATION; TUMORIGENESIS; IMBALANCE; PATHWAY AB Serine is both a proteinogenic amino acid and the source of one-carbon units essential for de novo purine and deoxythymidine synthesis. In the canonical pathway of glucose-derived serine synthesis, Homo sapiens phosphoglycerate dehydrogenase (PHGDH) catalyzes the first, rate-limiting step. Genetic loss of PHGDH is toxic toward PHGDH-overexpressing breast cancer cell lines even in the presence of exogenous serine. Here, we used a quantitative high-throughput screen to identify small-molecule PHGDH inhibitors. These compounds reduce the production of glucose-derived serine in cells and suppress the growth of PHGDH-dependent cancer cells in culture and in orthotopic xenograft tumors. Surprisingly, PHGDH inhibition reduced the incorporation into nucleotides of one-carbon units from glucose-derived and exogenous serine. We conclude that glycolytic serine synthesis coordinates the use of one-carbon units from endogenous and exogenous serine in nucleotide synthesis, and we suggest that one-carbon unit wasting thus may contribute to the efficacy of PHGDH inhibitors in vitro and in vivo. C1 [Pacold, Michael E.; Chan, Sze Ham; Swier, Lotteke J. Y. M.; Chen, Walter W.; Cho, Steve; Freinkman, Elizaveta; Abu-Remaileh, Monther; Liu, Chieh Min; Zhou, Minerva; Koh, Min Jung; Chung, Haeyoon; Sabatini, David M.] Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA. [Pacold, Michael E.; Chan, Sze Ham; Swier, Lotteke J. Y. M.; Chen, Walter W.; Cho, Steve; Abu-Remaileh, Monther; Liu, Chieh Min; Zhou, Minerva; Koh, Min Jung; Chung, Haeyoon; Sabatini, David M.] MIT, Howard Hughes Med Inst, Dept Biol, Cambridge, MA USA. [Pacold, Michael E.; Chan, Sze Ham; Lewis, Caroline A.; Swier, Lotteke J. Y. M.; Chen, Walter W.; Sullivan, Lucas B.; Fiske, Brian P.; Cho, Steve; Abu-Remaileh, Monther; Liu, Chieh Min; Zhou, Minerva; Koh, Min Jung; Chung, Haeyoon; Davidson, Shawn M.; Luengo, Alba; Vander Heiden, Matthew G.; Sabatini, David M.] Koch Inst Integrat Canc Res, Cambridge, MA USA. [Pacold, Michael E.; Chan, Sze Ham; Swier, Lotteke J. Y. M.; Chen, Walter W.; Cho, Steve; Abu-Remaileh, Monther; Liu, Chieh Min; Zhou, Minerva; Koh, Min Jung; Chung, Haeyoon; Sabatini, David M.] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA USA. [Pacold, Michael E.; Gray, Nathanael S.] Dana Farber Canc Inst, Longwood Ctr, Boston, MA 02115 USA. [Pacold, Michael E.; Chan, Sze Ham] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Brimacombe, Kyle R.; Rohde, Jason M.; Wang, Amy Q.; Xu, Xin; Yasgar, Adam; Liu, Li; Rai, Ganesha; Shen, Min; Boxer, Matthew B.] NIH, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Possemato, Richard] NYU, Langone Med Ctr, New York, NY USA. [Birsoy, Kivanc] Rockefeller Univ, Lab Metab Regulat & Genet, 1230 York Ave, New York, NY 10021 USA. [Shaul, Yoav D.] Hebrew Univ Jerusalem, Hadassah Med Sch, Inst Med Res Israel Canada, Dept Biochem & Mol Biol, IL-91010 Jerusalem, Israel. [Westover, Kenneth D.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. RP Sabatini, DM (reprint author), Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA.; Sabatini, DM (reprint author), MIT, Howard Hughes Med Inst, Dept Biol, Cambridge, MA USA.; Sabatini, DM (reprint author), Koch Inst Integrat Canc Res, Cambridge, MA USA.; Sabatini, DM (reprint author), Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA USA. EM sabatini@wi.mit.edu RI Abu-Remaileh, Monther/M-3747-2016; OI Possemato, Richard/0000-0002-2401-0030 FU Sally Gordon Fellowship of the Damon Runyon Cancer Research Foundation [DRG-112-12]; Department of Defense Breast Cancer Research Program Postdoctoral Fellowship [BC120208]; ASTRO Resident Seed Grant [RA-2011-1]; Susan G. Komen for the Cure; EMBO Long-Term Fellowship; NIH [1 R03 DA034602-01A1]; Stewart Trust FX We thank T. Wang and E. Edenberg for critical reading of the manuscript, S. Murphy for assistance with mouse experiments, and J. Pacold of the Lawrence Berkeley National Laboratory for assistance in interpreting Tm data. This research is supported by the Sally Gordon Fellowship of the Damon Runyon Cancer Research Foundation (DRG-112-12), a Department of Defense Breast Cancer Research Program Postdoctoral Fellowship (BC120208), and an ASTRO Resident Seed Grant (RA-2011-1) (all to M.E.P.)., by Susan G. Komen for the Cure (grant to R.L.P.), by an EMBO Long-Term Fellowship (to M.A.-R.), by the NIH (1 R03 DA034602-01A1 to D.M.S.) and by the Stewart Trust (to D.M.S.). D.M.S. is an investigator of the Howard Hughes Medical Institute. NR 36 TC 18 Z9 18 U1 8 U2 17 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 EI 1552-4469 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD JUN PY 2016 VL 12 IS 6 BP 452 EP U118 DI 10.1038/NCHEMBIO.2070 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DM2EW UT WOS:000376160600016 PM 27110680 ER PT J AU Xing, SJ Li, FY Zeng, ZH Zhao, YJ Yu, SY Shan, Q Li, YL Phillips, FC Maina, PK Qi, HH Liu, CY Zhu, J Pope, RM Musselman, CA Zeng, C Peng, WQ Xue, HH AF Xing, Shaojun Li, Fengyin Zeng, Zhouhao Zhao, Yunjie Yu, Shuyang Shan, Qiang Li, Yalan Phillips, Farrah C. Maina, Peterson K. Qi, Hank H. Liu, Chengyu Zhu, Jun Pope, R. Marshall Musselman, Catherine A. Zeng, Chen Peng, Weiqun Xue, Hai-Hui TI Tcf1 and Lef1 transcription factors establish CD8(+) T cell identity through intrinsic HDAC activity SO NATURE IMMUNOLOGY LA English DT Article ID HISTONE DEACETYLASES; CRYSTAL-STRUCTURE; LINEAGE CHOICE; SEQ DATA; DIFFERENTIATION; MODEL; SPECIFICATION; PROGENITORS; MECHANISMS; INHIBITORS AB The CD4(+) and CD8(+) T cell dichotomy is essential for effective cellular immunity. How individual T cell identity is established remains poorly understood. Here we show that the high-mobility group (HMG) transcription factors Tcf1 and Lef1 are essential for repressing CD4(+) lineage-associated genes including Cd4, Foxp3 and Rorc in CD8(+) T cells. Tcf1(-) and Lef1-deficient CD8(+) T cells exhibit histone hyperacetylation, which can be ascribed to intrinsic histone deacetylase (HDAC) activity in Tcf1 and Lef1. Mutation of five conserved amino acids in the Tcf1 HDAC domain diminishes HDAC activity and the ability to suppress CD4+ lineage genes in CD8(+) T cells. These findings reveal that sequence-specific transcription factors can utilize intrinsic HDAC activity to guard cell identity by repressing lineage-inappropriate genes. C1 [Xing, Shaojun; Li, Fengyin; Shan, Qiang; Phillips, Farrah C.; Xue, Hai-Hui] Univ Iowa, Dept Microbiol, Carver Coll Med, Iowa City, IA 52242 USA. [Zeng, Zhouhao; Zhao, Yunjie; Zeng, Chen; Peng, Weiqun] George Washington Univ, Dept Phys, Washington, DC 20052 USA. [Yu, Shuyang] China Agr Univ, Coll Biol Sci, State Key Lab Agrobiotechnol, Beijing 100094, Peoples R China. [Li, Yalan; Pope, R. Marshall] Univ Iowa, Prote Facil, Iowa City, IA USA. [Phillips, Farrah C.; Xue, Hai-Hui] Univ Iowa, Interdisciplinary Immunol Grad Program, Iowa City, IA USA. [Maina, Peterson K.; Qi, Hank H.] Univ Iowa, Dept Anat & Cell Biol, Carver Coll Med, Iowa City, IA USA. [Liu, Chengyu] NHLBI, Transgen Core Facil, NIH, Bldg 10, Bethesda, MD 20892 USA. [Zhu, Jun] NHLBI, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. [Musselman, Catherine A.] Univ Iowa, Dept Biochem, Carver Coll Med, Iowa City, IA 52242 USA. [Phillips, Farrah C.] St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA. RP Xue, HH (reprint author), Univ Iowa, Dept Microbiol, Carver Coll Med, Iowa City, IA 52242 USA.; Peng, WQ (reprint author), George Washington Univ, Dept Phys, Washington, DC 20052 USA.; Xue, HH (reprint author), Univ Iowa, Interdisciplinary Immunol Grad Program, Iowa City, IA USA. EM wpeng@gwu.edu; hai-hui-xue@uiowa.edu FU American Cancer Society [RSG-11-161-01-MPC]; NIH [AI112579, AI105351, AI115149, AI119160, AI113806]; US National Science Foundation (CAREER Award) [1452411]; Carver Trust Young Investigator Award [01-224]; Intramural Research Program of the NHLBI FX We thank A. Kalen (the Radiation Core facility, University of Iowa) for mouse irradiation and I. Antoshechkin (California Institute of Technology) for RNA-seq. We thank H. Kawamoto (Kyoto University) for Tcf1 antiserum, H. Habelhah for advice on purification of recombinant proteins, and J.T. Harty, J.D. Colgan and A. Bhandoola for critical reading and insightful discussion of the manuscript. We thank the Flow Cytometry Core Facility (J. Fishbaugh, H. Vignes and G. Rasmussen, University of Iowa) for cell sorting; the Flow Cytometry Core Facility is supported by the Carver College of Medicine/Holden Comprehensive Cancer Center (the University of Iowa), the Iowa City Veteran's Administration Medical Center, and the National Center for Research Resources of the NIH (1 S10 OD016199). The Proteomics Facility (University of Iowa) is supported by an endowment from the Carver Family trust. This study is supported by grants from the American Cancer Society (RSG-11-161-01-MPC to H.-H.X.), the NIH (AI112579, AI105351, AI115149 and AI119160 to H.-H.X. and AI113806 to W.P.), the US National Science Foundation (CAREER Award 1452411 to C.A.M.) and the Carver Trust Young Investigator Award (01-224) to H.H.Q.; J.Z. and C.L. are supported by the Intramural Research Program of the NHLBI. NR 52 TC 7 Z9 7 U1 2 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD JUN PY 2016 VL 17 IS 6 BP 695 EP + DI 10.1038/ni.3456 PG 12 WC Immunology SC Immunology GA DM2FK UT WOS:000376162200014 PM 27111144 ER PT J AU Pollizzi, KN Sun, IH Patel, CH Lo, YC Oh, MH Waickman, AT Tam, AJ Blosser, RL Wen, JY Delgoffe, GM Powell, JD AF Pollizzi, Kristen N. Sun, Im-Hong Patel, Chirag H. Lo, Ying-Chun Oh, Min-Hee Waickman, Adam T. Tam, Ada J. Blosser, Richard L. Wen, Jiayu Delgoffe, Greg M. Powell, Jonathan D. TI Asymmetric inheritance of mTORC1 kinase activity during division dictates CD8(+) T cell differentiation SO NATURE IMMUNOLOGY LA English DT Article ID AMINO-ACID-TRANSPORT; LYMPHOCYTE DIVISION; EARLY SPECIFICATION; MEMORY; EFFECTOR; ACTIVATION; METABOLISM; EXPRESSION; RAGULATOR; MECHANISM AB The asymmetric partitioning of fate-determining proteins has been shown to contribute to the generation of CD8(+) effector and memory T cell precursors. Here we demonstrate the asymmetric partitioning of mTORC1 activity after the activation of naive CD8(+) T cells. This results in the generation of two daughter T cells, one of which shows increased mTORC1 activity, increased glycolytic activity and increased expression of effector molecules. The other daughter T cell has relatively low mTORC1 activity and increased lipid metabolism, expresses increased amounts of anti-apoptotic molecules and subsequently displays enhanced long-term survival. Mechanistically, we demonstrate a link between T cell antigen receptor (TCR)-induced asymmetric expression of amino acid transporters and RagC-mediated translocation of mTOR to the lysosomes. Overall, our data provide important insight into how mTORC1-mediated metabolic reprogramming affects the fate decisions of T cells. C1 [Pollizzi, Kristen N.; Sun, Im-Hong; Patel, Chirag H.; Lo, Ying-Chun; Oh, Min-Hee; Waickman, Adam T.; Tam, Ada J.; Blosser, Richard L.; Wen, Jiayu; Delgoffe, Greg M.; Powell, Jonathan D.] Johns Hopkins Univ, Sch Med, Dept Oncol, Sidney Kimmel Comprehens Canc Res Ctr, Baltimore, MD 21205 USA. [Delgoffe, Greg M.] Univ Pittsburgh, Dept Immunol, Pittsburgh, PA USA. [Pollizzi, Kristen N.] MedImmune LLC, Dept Res Oncol, Gaithersburg, MD USA. [Lo, Ying-Chun] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. [Waickman, Adam T.] NCI, Expt Immunol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Powell, JD (reprint author), Johns Hopkins Univ, Sch Med, Dept Oncol, Sidney Kimmel Comprehens Canc Res Ctr, Baltimore, MD 21205 USA. EM poweljo@jhmi.edu FU NIH [AI072677, AI77610, AI091481, S10 OD016374, S10 RR024550] FX We thank members of the Powell lab and C. Gamper for critical discussion of the manuscript; B. Smith and T. Stephens for their technical support in microscopy studies; M. Gambello (Emory University, Atlanta, Georgia, USA) for Tsc2loxP mice; and P. Worley (Johns Hopkins University, Baltimore, Maryland, USA) for RhebloxP mice. This work was supported by the NIH (grants AI072677, AI77610 and AI091481 to J.D.P., and grants S10 OD016374 and S10 RR024550 to the JHUSOM Microscope Facility). NR 39 TC 15 Z9 16 U1 2 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD JUN PY 2016 VL 17 IS 6 BP 704 EP + DI 10.1038/ni.3438 PG 10 WC Immunology SC Immunology GA DM2FK UT WOS:000376162200015 PM 27064374 ER PT J AU Shah, NN Merchant, MS Cole, DE Jayaprakash, N Bernstein, D Delbrook, C Richards, K Widemann, BC Wayne, AS AF Shah, Nirali N. Merchant, Melinda S. Cole, Diane E. Jayaprakash, Nalini Bernstein, Donna Delbrook, Cindy Richards, Kelly Widemann, Brigitte C. Wayne, Alan S. TI Vincristine Sulfate Liposomes Injection (VSLI, Marqibo (R)): Results From a Phase I Study in Children, Adolescents, and Young Adults With Refractory Solid Tumors or Leukemias SO PEDIATRIC BLOOD & CANCER LA English DT Article DE acute lymphoblastic leukemia; Marqibo (R); pediatric; phase I ID ACUTE LYMPHOBLASTIC-LEUKEMIA; ACUTE LYMPHOCYTIC-LEUKEMIA; ONCOLOGY GROUP; RESPONSE CRITERIA; PHARMACOKINETICS; CANCER; IMPROVES; THERAPY; PHARMACODYNAMICS; CHEMOTHERAPY AB BackgroundVincristine sulfate liposome injection (VSLI; Marqibo (R)) is an encapsulated preparation of standard vincristine in sphingomyelin/cholesterol liposomes. Clinical trials in adults have demonstrated safety, tolerability, and activity, leading to Food and Drug Administration (FDA) approval for adults with relapsed acute lymphoblastic leukemia (ALL). Pediatric experience with VSLI is limited. ProcedureThis single center, phase I dose escalation study examined the safety, toxicity, maximum tolerated dose, and pharmacokinetics of VSLI administered weekly to pediatric patients age <21 years with relapsed or chemotherapy-refractory solid tumors or leukemia. ResultsTwenty-one subjects were treated in total. Median age was 13.3 years (range 2-19). Fourteen subjects completed one 28-day cycle of therapy and five subjects completed more than one cycle. No subject experienced dose-limiting toxicity (DLT) at the first dose level (1.75 mg/m(2)/dose, dose range: 2-3.7 mg). At the second dose level (2.25 mg/m(2)/dose, dose range: 1.3-4.5 mg), one subject had transient dose-limiting grade 4 transaminase elevation, and this dose level was expanded with no additional DLT observed. The second dose level then opened to an expansion phase to evaluate activity in ALL. Clinical activity included minimal residual disease negative complete remission in one subject with ALL and stable disease in nine subjects. Clearance of total vincristine was found to be approximately 100-fold lower in comparison to published data using standard vincristine. ConclusionsChildren tolerate 2.25 mg/m(2)/dose of weekly VSLI (the adult FDA-approved dose) with evidence for clinical activity without dose-limiting neurotoxicity. Future plans include studying VSLI as substitution for standard vincristine with combination chemotherapy in children with ALL. C1 [Shah, Nirali N.; Merchant, Melinda S.; Cole, Diane E.; Jayaprakash, Nalini; Bernstein, Donna; Delbrook, Cindy; Richards, Kelly; Widemann, Brigitte C.; Wayne, Alan S.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wayne, Alan S.] Univ So Calif, Keck Sch Med,Childrens Ctr Canc & Blood Dis, Childrens Hosp Los Angeles,Norris Comprehens Canc, Div Hematol Oncol & Blood & Marrow Transplantat, Los Angeles, CA USA. RP Shah, NN (reprint author), NCI, Pediat Oncol Branch, NIH, Bldg 10,Room 1W-3750,9000 Rockville Pike, Bethesda, MD 20892 USA. EM Nirali.Shah@nih.gov FU Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute FX We gratefully acknowledge the study participants and their families, referring medical care teams, the faculty and staff of the NIH, and Showri Kakumanu and Keith O'Neill. This research was supported by the Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute. This trial was conducted through a Clinical Trial Agreement between the Center for Cancer Research, National Cancer Institute, and Spectrum Pharmaceuticals, Inc., which provided study drug. NR 29 TC 1 Z9 1 U1 3 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2016 VL 63 IS 6 BP 997 EP 1005 DI 10.1002/pbc.25937 PG 9 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA DJ6FR UT WOS:000374306400007 PM 26891067 ER PT J AU Ordonez, AE Luscher, ZI Gogtay, N AF Ordonez, Anna E. Luscher, Zoe I. Gogtay, Nitin TI Neuroimaging findings from childhood onset schizophrenia patients and their non-psychotic siblings SO SCHIZOPHRENIA RESEARCH LA English DT Review DE Schizophrenia; Neuroimaging; Childhood; Endophenotype; Siblings ID NEUROLOGICAL SOFT SIGNS; CORPUS-CALLOSUM MORPHOLOGY; MAGNETIC-RESONANCE; BRAIN ABNORMALITIES; 1ST-EPISODE SCHIZOPHRENIA; SPECTRUM DISORDERS; HEALTHY SIBLINGS; CEREBELLAR VOLUME; METAANALYSIS; NETWORKS AB Childhood onset schizophrenia (COS), with onset of psychosis before age 13, is a rare form of schizophrenia that represents a more severe and chronic form of the adult onset illness. In this review we examine structural and functional magnetic resonance imaging (MRI) studies of COS and non-psychotic siblings of COS patients in the context of studies of schizophrenia as a whole. Studies of COS to date reveal progressive loss of gray matter volume and cortical thinning, ventricular enlargement, progressive decline in cerebellar volume and a significant but fixed deficit in hippocampal volume. COS is also associated with a slower rate of white matter growth and disrupted local connectivity strength. Sibling studies indicate that non-psychotic siblings of COS patients share many of these brain abnormalities, including decreased cortical thickness and disrupted white matter growth, yet these abnormalities normalize with age. Cross-sectional and longitudinal neuroimaging studies remain some of the few methods for assessing human brain function and play a pivotal role in the quest for understanding the neurobiology of schizophrenia as well as other psychiatric disorders. Parallel studies in non-psychotic siblings provide a unique opportunity to understand both risk and resilience in schizophrenia. Published by Elsevier B.V. C1 [Ordonez, Anna E.; Luscher, Zoe I.; Gogtay, Nitin] NIMH, Child Psychiat Branch, NIH, Bldg 10,Rm 3N202,10 Ctr Dr,MSC 1600, Bethesda, MD 20892 USA. RP Gogtay, N (reprint author), NIMH, Child Psychiat Branch, NIH, Bldg 10,Rm 3N202,10 Ctr Dr,MSC 1600, Bethesda, MD 20892 USA. EM gogtayn@mail.nih.gov FU NIMH Intramural Research Program FX The studies conducted at the National Institute of Mental Health Child Psychiatry Branch are funded by the NIMH Intramural Research Program. NR 86 TC 3 Z9 3 U1 5 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 EI 1573-2509 J9 SCHIZOPHR RES JI Schizophr. Res. PD JUN PY 2016 VL 173 IS 3 BP 124 EP 131 DI 10.1016/j.schres.2015.03.003 PG 8 WC Psychiatry SC Psychiatry GA DL7VE UT WOS:000375847400002 PM 25819937 ER PT J AU Liang, ZB Liu, RK Zhang, H Zhang, SZ Hu, XM Tan, J Liang, C Qiao, WT AF Liang, Zhibin Liu, Ruikang Zhang, Hui Zhang, Suzhen Hu, Xiaomei Tan, Juan Liang, Chen Qiao, Wentao TI GADD45 proteins inhibit HIV-1 replication through specific suppression of HIV-1 transcription SO VIROLOGY LA English DT Article DE GADD45; HIV-1; LTR; Transcription; Latency ID CELL NUCLEAR ANTIGEN; NF-KAPPA-B; ACTIVE DNA DEMETHYLATION; NEGATIVE GROWTH-CONTROL; INDUCED APOPTOSIS; TUMOR-SUPPRESSOR; GENE-EXPRESSION; DOWN-REGULATION; P38 ACTIVATION; CYCLE ARREST AB GADD45 proteins are a group of stress-induced proteins and participate in various cellular pathways including cell cycle regulation, cell survival and death, DNA repair and demethylation. It was recently shown that HIV-1 infection induces the expression of GADD45 proteins. However, the effect of GADD45 on HIV-1 replication has not been studied. Here, we report that overexpression of GADD45 proteins reduces HIV-1 production through suppressing transcription from the HIV-1 LTR promoter. This inhibitory effect is specific to HIV-1, since GADD45 proteins neither inhibit the LTR promoters from other retroviruses nor reduce the production of these viruses. Knockdown of endogenous GADD45 modestly activates HIV-1 in the J-Lat A72 latency cell line, which suggests GADD45 proteins might play a role in maintaining HIV-1 latency. (C) 2016 Elsevier Inc. All rights reserved. C1 [Liang, Zhibin; Liu, Ruikang; Zhang, Hui; Zhang, Suzhen; Hu, Xiaomei; Tan, Juan; Qiao, Wentao] Nankai Univ, Coll Life Sci, Minist Educ, Key Lab Mol Microbiol & Technol, Tianjin 300071, Peoples R China. [Liang, Chen] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Montreal, PQ H3T 1E2, Canada. [Liang, Chen] McGill Univ, Dept Med, Montreal, PQ, Canada. [Liang, Chen] McGill Univ, Dept Microbiol & Immunol, Montreal, PQ, Canada. [Liu, Ruikang] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Qiao, WT (reprint author), Nankai Univ, Coll Life Sci, Minist Educ, Key Lab Mol Microbiol & Technol, Tianjin 300071, Peoples R China.; Liang, C (reprint author), McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Montreal, PQ H3T 1E2, Canada. EM liangzhibin@mail.nankai.edu.cn; sunflower0430@gmail.com; zhanghui90111@126.com; zhangsuzhen819819@163.com; huxm189@163.com; juantan@nankai.edu.cn; chen.liang@mcgill.edu.ca; wentaoqiao@nankai.edu.cn FU Chinese Ministry of Health [2012ZX10001006]; National Natural Science Foundation of China [81271812, 81501747, 81571988]; 111 Project [B08011]; Tianjin Research Program of Application Foundation and Advanced Technology [15JCQNJC09600]; State Scholarship Fund from China Scholarship Council (CSC) FX This study was supported by funding from the Chinese Ministry of Health (2012ZX10001006), the National Natural Science Foundation of China (81271812, 81501747 and 81571988), 111 Project (B08011), Tianjin Research Program of Application Foundation and Advanced Technology (15JCQNJC09600), and the State Scholarship Fund from China Scholarship Council (CSC). NR 52 TC 0 Z9 0 U1 2 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JUN PY 2016 VL 493 BP 1 EP 11 DI 10.1016/j.virol.2016.02.014 PG 11 WC Virology SC Virology GA DL7MH UT WOS:000375824300001 PM 26994425 ER PT J AU Ayala, VI Trivett, MT Coren, LV Jain, S Bohn, PS Wiseman, RW O'Connor, DH Ohlen, C Ott, DE AF Ayala, Victor I. Trivett, Matthew T. Coren, Lori V. Jain, Sumiti Bohn, Patrick S. Wiseman, Roger W. O'Connor, David H. Ohlen, Claes Ott, David E. TI A novel SIV gag-specific CD4(+)7-cell clone suppresses SIVmac239 replication in CD4(+)T cells revealing the interplay between antiviral effector cells and their infected targets SO VIROLOGY LA English DT Article DE SIV; Cytolytic CD4(+)T cells; T-cell receptor; Virus-specific; TCR transduction; Virus suppression; T-cell effectors ID SIMIAN-IMMUNODEFICIENCY-VIRUS; MAJOR HISTOCOMPATIBILITY COMPLEX; CD4 T-CELLS; CLASS-II; SURFACE EXPRESSION; HIV-INFECTION; IN-VIVO; MACAQUES; RESPONSES; IMMUNIZATION AB To study CD4(+)T-cell suppression of AIDS virus replication, we isolated nine rhesus macaque SIVGag-specific CD4(+)T-cell clones. One responding clone, Gag68, produced a typical cytotoxic CD8(+)T-cell response: induction of intracellular IFN-gamma, MIP-1 alpha, MIP1-1 beta, and CD107a degranulation. Gag68 effectively suppressed the spread of SIVmac239 in CD4(+)T cells with a corresponding reduction of infected Gag68 effector cells, suggesting that CD4(+)effectors need to suppress their own infection in addition to their targets to be effective. Gag68 TCR cloning and gene transfer into CD4(+)T cells enabled additional experiments with this unique specificity after the original clone senesced. Our data supports the idea that CD4(+)T cells can directly limit AIDS virus spread in T cells. Furthermore, Gag68 TCR transfer into CD4(+)T-cell clones with differing properties holds promise to better understand the suppressive effector mechanisms used by this important component of the antiviral response using the rhesus macaque model. 2016 Elsevier Inc. All rights reserved. C1 [Ayala, Victor I.; Trivett, Matthew T.; Coren, Lori V.; Jain, Sumiti; Ohlen, Claes; Ott, David E.] Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Bohn, Patrick S.; Wiseman, Roger W.; O'Connor, David H.] Univ Wisconsin, Wisconsin Natl Primate Res Ctr, Madison, WI USA. [Ayala, Victor I.] ABL Inc, Rockville, MD 20850 USA. [Jain, Sumiti] Juno Therapeut, Seattle, WA 98109 USA. RP Ott, DE (reprint author), Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM ottde@mail.nih.gov FU WNPRC Base Grant from the National Center for Research Resources [P51 RR000167]; Office of Research Infrastructure Programs of the National Institutes of Health [P51 OD011106]; Federal funds from the National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX We thank the Kelli Oswald and Rebecca Shoemaker for PCR viral load analysis, Donald Johnson, Adam Wiles, Rodney Wiles, and Vicky Coalter for tissue processing and sample support and Cynthia Matthews and the Blood Services Section, Department of Transfusion Medicine, NIH for human leukopacks. The following reagents were obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: Human rIL-2 from Dr. Maurice Gately, Hoffmann-La Roche Inc; SlVmac p27 Hybridoma (55-2F12) from Dr Niels Pedersen; SIVmac239 Gag Peptide Pool. MHC genotyping efforts were supported by the WNPRC Base Grant from the National Center for Research Resources (P51 RR000167) and Office of Research Infrastructure Programs (P51 OD011106) of the National Institutes of Health. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 45 TC 2 Z9 2 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JUN PY 2016 VL 493 BP 100 EP 112 DI 10.1016/j.virol.2016.03.013 PG 13 WC Virology SC Virology GA DL7MH UT WOS:000375824300010 PM 27017056 ER PT J AU Davis, AS Chertow, DS Kindrachuk, J Qi, L Schwartzman, LM Suzich, J Alsaaty, S Logun, C Shelhamer, JH Taubenberger, JK AF Davis, A. Sally Chertow, Daniel S. Kindrachuk, Jason Qi, Li Schwartzman, Louis M. Suzich, Jon Alsaaty, Sara Logun, Carolea Shelhamer, James H. Taubenberger, Jeffery K. TI 1918 Influenza receptor binding domain variants bind and replicate in primary human airway cells regardless of receptor specificity SO VIROLOGY LA English DT Article DE Influenza A virus; Pandemic; Receptor binding; Hemagglutinin ID BRONCHIAL EPITHELIAL-CELLS; RESPIRATORY-TRACT; VIRUS ENTRY; A VIRUS; HEMAGGLUTININ; TROPISM; MICE; H5N1; PATHOGENESIS; INFECTION AB The 1918 influenza pandemic caused similar to 50 million deaths. Many questions remain regarding the origin, pathogenicity, and mechanisms of human adaptation of this virus. Avian-adapted influenza A viruses preferentially bind alpha 2,3-linked sialic acids (Sia) while human-adapted viruses preferentially bind alpha 2,6-linked Sia. A change in Sia preference from alpha 2,3 to alpha 2,6 is thought to be a requirement for human adaptation of avian influenza viruses. Autopsy data from 1918 cases, however, suggest that factors other than Sia preference played a role in viral binding and entry to human airway cells. Here, we evaluated binding and entry of five 1918 influenza receptor binding domain variants in a primary human airway cell model along with control avian and human influenza viruses. We observed that all five variants bound and entered cells efficiently and that Sia preference did not predict entry of influenza A virus to primary human airway cells evaluated in this model. Published by Elsevier Inc. C1 [Davis, A. Sally; Chertow, Daniel S.; Qi, Li; Schwartzman, Louis M.; Suzich, Jon; Taubenberger, Jeffery K.] NIAID, Viral Pathogenesis & Evolut Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Davis, A. Sally] Kansas State Univ, Diagnost Med & Pathobiol, Coll Vet Med, Manhattan, KS 66506 USA. [Chertow, Daniel S.; Kindrachuk, Jason; Suzich, Jon; Alsaaty, Sara; Logun, Carolea; Shelhamer, James H.] NIH, Dept Crit Care Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. RP Taubenberger, JK (reprint author), NIAID, 33 North Dr,MSC 3203, Bethesda, MD 20892 USA. EM taubenbergerj@niaid.nih.gov OI Kindrachuk, Jason/0000-0002-3305-7084 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases [1ZIAAI00098609, 1ZIAAI00099509]; National Institute of Health; NIH Comparative Molecular Pathology Research Training Program FX The authors would like to acknowledge the staff at the NIAID RTB Bioimaging Section for their assistance with confocal microscopy and image post-processing. We thank Sandra Horton and her staff at the North Carolina State University College of Veterinary Medicine Histopathology Laboratory for their preparation of tissue and embedded sections for immunofluorescence and histological analysis. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (1ZIAAI00098609, 1ZIAAI00099509) and National Institute of Health. ASD and JKT are further thankful for the support of the NIH Comparative Molecular Pathology Research Training Program. This work was done in partial fulfillment of A. Sally Davis' dissertation work towards a Ph.D. in Comparative Biomedical Sciences at the North Carolina State University College of Veterinary Medicine. NR 35 TC 0 Z9 0 U1 4 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JUN PY 2016 VL 493 BP 238 EP 246 DI 10.1016/j.virol.2016.03.025 PG 9 WC Virology SC Virology GA DL7MH UT WOS:000375824300023 PM 27062579 ER PT J AU Day, CR Kempson, SA AF Day, Christopher R. Kempson, Stephen A. TI Betaine chemistry, roles, and potential use in liver disease SO BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS LA English DT Review DE Alcohol; Hepatocyte; Fatty liver; Betaine/GABA transporter; Methionine cycle; Methyltransferase ID NONALCOHOLIC FATTY LIVER; HOMOCYSTEINE-S-METHYLTRANSFERASE; ACTIVATED PROTEIN-KINASE; ENDOPLASMIC-RETICULUM STRESS; POLARIZED EPITHELIAL-CELLS; ONE-CARBON METABOLISM; ALCOHOL-FED MICE; PLASMA HOMOCYSTEINE; OSMOTIC REGULATION; HYPERTONIC STRESS AB Background: Betaine is the trimethyl derivative of glycine and is normally present in human plasma due to dietary intake and endogenous synthesis in. liver and kidney. Betaine is utilized in the kidney primarily as an osmoprotectant, whereas in the liver its primary role is in metabolism as a methyl group donor. In both organs, a specific betaine transporter mediates cellular uptake of betaine from plasma. The abundance of both betaine and the betaine transporter in liver greatly exceeds that of other organs. Scope of review: The remarkable contributions of betaine to normal human and animal health are summarized together with a discussion of the mechanisms and potential beneficial effects of dietary betaine supplements on liver disease. Major conclusions: A significant amount of data from animal models of liver disease indicates that administration of betaine can halt and even reverse progression of the disruption of liver function. Betaine is well-tolerated, inexpensive, effective over a wide range of doses, and is already used in livestock feeding practices. General significance: The accumulated data indicate that carefully controlled additional investigations in humans are merited. The focus should be on the long-term use of betaine in large patient populations with liver diseases characterized by development of fatty liver, especially non-alcoholic fatty liver disease and alcoholic liver disease. (C) 2016 Elsevier B.V. All rights reserved. C1 [Day, Christopher R.] NCI, Lab Receptor Biol & Gene Express, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kempson, Stephen A.] Indiana Univ, Sch Med, Dept Cellular & Integrat Physiol, Indianapolis, IN 46202 USA. RP Kempson, SA (reprint author), MS 306,635 Barnhill Dr, Indianapolis, IN 46202 USA. EM skempson@iupui.edu NR 102 TC 5 Z9 5 U1 7 U2 26 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4165 EI 1872-8006 J9 BBA-GEN SUBJECTS JI Biochim. Biophys. Acta-Gen. Subj. PD JUN PY 2016 VL 1860 IS 6 BP 1098 EP 1106 DI 10.1016/j.bbagen.2016.02.001 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DK8GN UT WOS:000375165300006 PM 26850693 ER PT J AU Fash, DM Peer, CJ Li, ZW Talisman, IJ Hayavi, S Sulzmaier, FJ Ramos, JW Sourbier, C Neckers, L Figg, WD Beutler, JA Chain, WJ AF Fash, David M. Peer, Cody J. Li, Zhenwu Talisman, Ian J. Hayavi, Sima Sulzmaier, Florian J. Ramos, Joe W. Sourbier, Carole Neckers, Leonard Figg, W. Douglas Beutler, John A. Chain, William J. TI Synthesis of a stable and orally bioavailable englerin analogue SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Englerins; Cancer; Bioavailability; Sesquiterpenes ID 4+3 CYCLOADDITION REACTION; CANCER CELL-GROWTH; FORMAL SYNTHESIS; BIOLOGICAL EVALUATION; PKC-THETA; (-)-ENGLERIN AB Synthesis of analogues of englerin A with a reduced propensity for hydrolysis of the glycolate moiety led to a compound which possessed the renal cancer cell selectivity of the parent and was orally bioavailable in mice. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Fash, David M.; Li, Zhenwu; Talisman, Ian J.; Chain, William J.] Univ Hawaii Manoa, Dept Chem, 2545 McCarthy Mall, Honolulu, HI 96822 USA. [Sulzmaier, Florian J.; Ramos, Joe W.; Chain, William J.] Univ Hawaii, Ctr Canc, 701 Ilalo St, Honolulu, HI 96813 USA. [Peer, Cody J.; Figg, W. Douglas] NCI, Genitourinary Malignancies Branch, Frederick, MD 21702 USA. [Beutler, John A.] NCI, Mol Targets Lab, Frederick, MD 21702 USA. [Sourbier, Carole; Neckers, Leonard] NCI, Ctr Canc Res, Urol Oncol Branch, Frederick, MD 21702 USA. [Hayavi, Sima] NCI, Dev Therapeut Program, Frederick, MD 21702 USA. [Chain, William J.] Univ Delaware, Dept Chem & Biochem, 163 Green, Newark, DE 19716 USA. RP Chain, WJ (reprint author), Univ Hawaii Manoa, Dept Chem, 2545 McCarthy Mall, Honolulu, HI 96822 USA.; Chain, WJ (reprint author), Univ Hawaii, Ctr Canc, 701 Ilalo St, Honolulu, HI 96813 USA.; Beutler, JA (reprint author), NCI, Mol Targets Lab, Frederick, MD 21702 USA.; Chain, WJ (reprint author), Univ Delaware, Dept Chem & Biochem, 163 Green, Newark, DE 19716 USA. EM beutlerj@mail.nih.gov; wchain@udel.edu RI Figg Sr, William/M-2411-2016 FU Intramural Program of the National Cancer Institute [1ZIABC01147004, 1ZIABC01068311, 1ZICSC00653622]; National Institutes of Health [R01CA163287]; University of Hawaii; University of Hawaii Cancer Center; University of Delaware; NSF; NIS (NSF) [CHE0421224, CHE1229234, CHE0840401]; NIS (NIH) [P20GM103541, P20GM104316, P30GM110758, S10RR02692, S10OD016267] FX J.A.B., C.J.P., C.S., L.N., and W.D.F. are supported by the Intramural Program of the National Cancer Institute (1ZIABC01147004, 1ZIABC01068311, and 1ZICSC00653622). W.J. C. gratefully acknowledges financial support from the National Institutes of Health (R01CA163287), the University of Hawaii, the University of Hawaii Cancer Center, and the University of Delaware. Some data were acquired at UD on instruments obtained with the assistance of NSF and NIS funding (NSF CHE0421224, CHE1229234, and CHE0840401; NIH P20GM103541, P20GM104316, P30GM110758, S10RR02692, and S10OD016267). W.J.C. gratefully acknowledges the assistance of Michael F. Wisthoff and Senzhi Zhao in the preparation of the Supplemental Information and spectral data. NR 37 TC 2 Z9 2 U1 2 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD JUN 1 PY 2016 VL 26 IS 11 BP 2641 EP 2644 DI 10.1016/j.bmcl.2016.04.016 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA DK5VK UT WOS:000374988600015 PM 27107948 ER PT J AU Bodranghien, F Bastian, A Casali, C Hallett, M Louis, E Manto, M Marien, P Nowak, DA Schmahmann, JD Serrao, M Steiner, KM Strupp, M Tilikete, C Timmann, D van Dun, K AF Bodranghien, Florian Bastian, Amy Casali, Carlo Hallett, Mark Louis, Elan D. Manto, Mario Marien, Peter Nowak, Dennis A. Schmahmann, Jeremy D. Serrao, Mariano Steiner, Katharina Marie Strupp, Michael Tilikete, Caroline Timmann, Dagmar van Dun, Kim TI Consensus Paper: Revisiting the Symptoms and Signs of Cerebellar Syndrome SO CEREBELLUM LA English DT Article DE Cerebellum; Ataxia; Eye movements; Dysmetria; Tremor; A- or Dysdiadochokinesia; Hypotonia; Speech; Dysarthria; Language; Cognition; Affect; Loops; Functional topography; Cerebellar syndrome ID COGNITIVE-AFFECTIVE SYNDROME; ATAXIA RATING-SCALE; ESSENTIAL TREMOR; SPINOCEREBELLAR ATAXIA; SPEECH PRODUCTION; ARM MOVEMENTS; MOTOR CONTROL; FUNCTIONAL TOPOGRAPHY; DOWNBEAT NYSTAGMUS; ALZHEIMERS-DISEASE AB The cerebellum is involved in sensorimotor operations, cognitive tasks and affective processes. Here, we revisit the concept of the cerebellar syndrome in the light of recent advances in our understanding of cerebellar operations. The key symptoms and signs of cerebellar dysfunction, often grouped under the generic term of ataxia, are discussed. Vertigo, dizziness, and imbalance are associated with lesions of the vestibulo-cerebellar, vestibulo-spinal, or cerebellar ocular motor systems. The cerebellum plays a major role in the online to long-term control of eye movements (control of calibration, reduction of eye instability, maintenance of ocular alignment). Ocular instability, nystagmus, saccadic intrusions, impaired smooth pursuit, impaired vestibulo-ocular reflex (VOR), and ocular misalignment are at the core of oculomotor cerebellar deficits. As a motor speech disorder, ataxic dysarthria is highly suggestive of cerebellar pathology. Regarding motor control of limbs, hypotonia, a- or dysdiadochokinesia, dysmetria, grasping deficits and various tremor phenomenologies are observed in cerebellar disorders to varying degrees. There is clear evidence that the cerebellum participates in force perception and proprioceptive sense during active movements. Gait is staggering with a wide base, and tandem gait is very often impaired in cerebellar disorders. In terms of cognitive and affective operations, impairments are found in executive functions, visual-spatial processing, linguistic function, and affective regulation (Schmahmann's syndrome). Nonmotor linguistic deficits including disruption of articulatory and graphomotor planning, language dynamics, verbal fluency, phonological, and semantic word retrieval, expressive and receptive syntax, and various aspects of reading and writing may be impaired after cerebellar damage. The cerebellum is organized into (a) a primary sensorimotor region in the anterior lobe and adjacent part of lobule VI, (b) a second sensorimotor region in lobule VIII, and (c) cognitive and limbic regions located in the posterior lobe (lobule VI, lobule VIIA which includes crus I and crus II, and lobule VIIB). The limbic cerebellum is mainly represented in the posterior vermis. The cortico-ponto-cerebellar and cerebello-thalamo-cortical loops establish close functional connections between the cerebellum and the supratentorial motor, paralimbic and association cortices, and cerebellar symptoms are associated with a disruption of these loops. C1 [Bodranghien, Florian; Manto, Mario] FNRS ULB Erasme, Unite Etude Mouvement, 808 Route Lennik, B-1070 Brussels, Belgium. [Strupp, Michael] Univ Munich, Munich, Germany. [Tilikete, Caroline] Team ImpAct, CNRS UMR5292, CRNL INSERM U1028, F-69676 Bron, France. [Tilikete, Caroline] Univ Lyon 1, F-69373 Lyon, France. [Tilikete, Caroline] Hop Neurol Pierre Wertheimer, Hosp Civils Lyon, Neuroophthalmol & Neurol D, F-69677 Bron, France. [Hallett, Mark] NINDS, Human Motor Control Sect, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Timmann, Dagmar] Univ Clin Essen, Dept Neurol, Hufelandstr 55, D-45147 Essen, Germany. [Steiner, Katharina Marie; Timmann, Dagmar] Univ Duisburg Essen, Dept Neurol, Hufelandstr 55, D-45147 Essen, Germany. [Louis, Elan D.] Yale Univ, Sch Med, Dept Neurol, New Haven, CT USA. [Nowak, Dennis A.] Helios Klin Kipfenberg, Kindingerstr 13, D-85110 Kipfenberg, Germany. [Nowak, Dennis A.] Univ Marburg, Neurol Univ Klin, Baldingerstr, D-35043 Marburg, Germany. [Bastian, Amy] Kennedy Krieger Inst, 707 N Broadway, Baltimore, MD 21205 USA. [Casali, Carlo; Serrao, Mariano] Univ Rome La Sapienza, Dept Med & Surg Sci & Biotechnol, Rome, Italy. [Serrao, Mariano] Policlin Italia, Rehabil Ctr, Movement Anal LAB, Rome, Italy. [Schmahmann, Jeremy D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med,Cognit Behav Neurol Unit,Ataxia Unit, Dept Neurol,Lab Neuroanat & Cerebellar Neurobiol, Boston, MA 02114 USA. [Marien, Peter] Vrije Univ Brussel, CLIN, Clin & Expt Neurolinguist, Pleinlaan 2, B-1050 Brussels, Belgium. [van Dun, Kim] ZNA Middelheim Gen Hosp, Dept Neurol, Antwerp, Belgium. [van Dun, Kim] ZNA Middelheim Gen Hosp, Memory Clin, Antwerp, Belgium. RP Manto, M (reprint author), FNRS ULB Erasme, Unite Etude Mouvement, 808 Route Lennik, B-1070 Brussels, Belgium. EM fbodrang@ulb.ac.be; bastian@kennedykrieger.org; carlo.casali@uniroma1.it; hallettm@ninds.nih.gov; elan.louis@yale.edu; mmanto@ulb.ac.be; peter.marien5@telenet.be; dennis.nowak@neurologie-kipfenberg.de; JSCHMAHMANN@mgh.harvard.edu; mariano.serrao@uniroma1.it; KatharinaMarie.Steiner@uk-essen.de; Michael.Strupp@med.uni-muenchen.de; caroline.tilikete@inserm.fr; dagmar.timmann-braun@uni-duisburg-essen.de; kimvandun@gmail.com NR 185 TC 9 Z9 9 U1 9 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1473-4222 EI 1473-4230 J9 CEREBELLUM JI Cerebellum PD JUN PY 2016 VL 15 IS 3 SI SI BP 369 EP 391 DI 10.1007/s12311-015-0687-3 PG 23 WC Neurosciences SC Neurosciences & Neurology GA DK7EL UT WOS:000375087600015 PM 26105056 ER PT J AU Jourdan, T Godlewski, G Kunos, G AF Jourdan, T. Godlewski, G. Kunos, G. TI Endocannabinoid regulation of beta-cell functions: implications for glycaemic control and diabetes SO DIABETES OBESITY & METABOLISM LA English DT Review DE diabetes; endocannabinoids; inflammation; pancreas ID THIOREDOXIN-INTERACTING PROTEIN; STIMULATED INSULIN-SECRETION; CANNABINOID CB1 RECEPTOR; NLRP3 INFLAMMASOME; MOLECULAR CHARACTERIZATION; GLUCOSE-TOLERANCE; LEPTIN RESISTANCE; PANCREATIC-ISLETS; OXIDATIVE STRESS; BODY-WEIGHT AB Visceral obesity is a major risk factor for the development of insulin resistance which can progress to overt type 2 diabetes (T2D) with loss of beta-cell function and, ultimately, loss of beta-cells. Insulin secretion by beta-cells of the pancreatic islets is tightly coupled to blood glucose concentration and modulated by a large number of blood-borne or locally released mediators, including endocannabinoids. Obesity and its complications, including T2D, are associated with increased activity of the endocannabinoid/CB1 receptor (CB1R) system, as indicated by the therapeutic effects of CB1R antagonists. Similar beneficial effects of CB1R antagonists with limited brain penetrance indicate the important role of CB1R in peripheral tissues, including the endocrine pancreas. Pancreatic beta-cells express all of the components of the endocannabinoid system, and endocannabinoids modulate their function via both autocrine and paracrine mechanisms, which influence basal and glucose-induced insulin secretion and also affect beta-cell proliferation and survival. The present brief review will survey available information on the modulation of these processes by endocannabinoids and their receptors, with an attempt to assess the contribution of such effects to glycaemic control in T2D and insulin resistance. C1 [Jourdan, T.; Godlewski, G.; Kunos, G.] NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. RP Jourdan, T; Kunos, G (reprint author), NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. EM tony.jourdan@nih.gov; george.kunos@nih.gov FU National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA FX This work was supported by intramural funds from the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA. NR 100 TC 3 Z9 3 U1 11 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1462-8902 EI 1463-1326 J9 DIABETES OBES METAB JI Diabetes Obes. Metab. PD JUN PY 2016 VL 18 IS 6 BP 549 EP 557 DI 10.1111/dom.12646 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DK8AW UT WOS:000375150100001 PM 26880114 ER PT J AU Taieb, D Imperiale, A Pacak, K AF Taieb, David Imperiale, Alessio Pacak, Karel TI F-18-DOPA: the versatile radiopharmaceutical SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Letter ID DIGESTIVE ENDOCRINE TUMORS; NEUROENDOCRINE TUMORS; PARAGANGLIOMA; PET/CT; PHEOCHROMOCYTOMA; CANCER C1 [Taieb, David] Aix Marseille Univ, La Timone Univ Hosp, European Ctr Res Med Imaging, Biophys & Nucl Med, 264,Rue St Pierre 5, Marseille, France. [Imperiale, Alessio] Univ Strasbourg, CNRS, UMR 7357, ICube, Strasbourg, France. [Imperiale, Alessio] Univ Hosp Strasbourg, Hautepierre Hosp, Dept Biophys & Nucl Med, Strasbourg, France. [Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth Human, Sect Med Neuroendocrinol, NIH, Bethesda, MD 20892 USA. RP Taieb, D (reprint author), Aix Marseille Univ, La Timone Univ Hosp, European Ctr Res Med Imaging, Biophys & Nucl Med, 264,Rue St Pierre 5, Marseille, France. EM david.taieb@ap-hm.fr NR 13 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1619-7070 EI 1619-7089 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD JUN PY 2016 VL 43 IS 6 BP 1187 EP 1189 DI 10.1007/s00259-016-3354-0 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DK5PU UT WOS:000374972900023 PM 26966122 ER PT J AU Vihinen, M Hancock, JM Maglott, DR Landrum, MJ Schaafsma, GCP Taschner, P AF Vihinen, Mauno Hancock, John M. Maglott, Donna R. Landrum, Melissa J. Schaafsma, Gerard C. P. Taschner, Peter TI Human Variome Project Quality Assessment Criteria for Variation Databases SO HUMAN MUTATION LA English DT Article DE genetic variation; database quality; quality scheme; components of quality; Human Variome Project; locus-specific variation databases; LSDB; gene variant databases ID X-LINKED AGAMMAGLOBULINEMIA; LOCUS-SPECIFIC DATABASES; MUTATION DATABASES; VARIATION ONTOLOGY; SEQUENCE VARIATION; HUMAN PHENOTYPE; DISEASE; LSDBS; RECOMMENDATIONS; NOMENCLATURE AB Numerous databases containing information about DNA, RNA, and protein variations are available. Gene-specific variant databases (locus-specific variation databases, LSDBs) are typically curated and maintained for single genes or groups of genes for a certain disease(s). These databases are widely considered as the most reliable information source for a particular gene/protein/disease, but it should also be made clear they may have widely varying contents, infrastructure, and quality. Quality is very important to evaluate because these databases may affect health decision-making, research, and clinical practice. The Human Variome Project (HVP) established a Working Group for Variant Database Quality Assessment. The basic principle was to develop a simple system that nevertheless provides a good overview of the quality of a database. The HVP quality evaluation criteria that resulted are divided into four main components: data quality, technical quality, accessibility, and timeliness. This report elaborates on the developed quality criteria and how implementation of the quality scheme can be achieved. Examples are provided for the current status of the quality items in two different databases, BTKbase, an LSDB, and ClinVar, a central archive of submissions about variants and their clinical significance. C1 [Vihinen, Mauno; Schaafsma, Gerard C. P.] Lund Univ, Dept Expt Med Sci, BMC B13, SE-22184 Lund, Sweden. [Hancock, John M.] Genome Anal Ctr, Norwich Res Pk, Norwich NR4 7UH, Norfolk, England. [Maglott, Donna R.; Landrum, Melissa J.] NIH, Natl Ctr Biotechnol Informat, Bldg 10, Bethesda, MD 20892 USA. [Taschner, Peter] Generade Ctr Expertise Genom, Leiden, Netherlands. [Taschner, Peter] Univ Appl Sci Leiden, Leiden, Netherlands. [Taschner, Peter] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. RP Vihinen, M (reprint author), Lund Univ, Dept Expt Med Sci, BMC B13, SE-22184 Lund, Sweden. EM mauno.vihinen@med.lu.se RI Hancock, John/A-2442-2009; Schaafsma, Gerard/F-6138-2014; OI Hancock, John/0000-0003-2991-2217; Schaafsma, Gerard/0000-0001-6351-7486; Vihinen, Mauno/0000-0002-9614-7976; Taschner, Peter/0000-0001-9621-465X NR 43 TC 5 Z9 5 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 EI 1098-1004 J9 HUM MUTAT JI Hum. Mutat. PD JUN PY 2016 VL 37 IS 6 SI SI BP 549 EP 558 DI 10.1002/humu.22976 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA DK8DL UT WOS:000375157300008 PM 26919176 ER PT J AU den Dunnen, JT Dalgleish, R Maglott, DR Hart, RK Greenblatt, MS McGowan-Jordan, J Roux, AF Smith, T Antonarakis, SE Taschner, PEM AF den Dunnen, Johan T. Dalgleish, Raymond Maglott, Donna R. Hart, Reece K. Greenblatt, Marc S. McGowan-Jordan, Jean Roux, Anne-Francoise Smith, Timothy Antonarakis, Stylianos E. Taschner, Peter E. M. CA HGVS HVP Human Genome Org HUGO TI HGVS Recommendations for the Description of Sequence Variants: 2016 Update SO HUMAN MUTATION LA English DT Article DE standards; sequence variation; mutation; database; nomenclature ID HUMAN GENE-MUTATIONS; MOLECULAR PATHOLOGY; NOMENCLATURE; MEANINGS AB The consistent and unambiguous description of sequence variants is essential to report and exchange information on the analysis of a genome. In particular, DNA diagnostics critically depends on accurate and standardized description and sharing of the variants detected. The sequence variant nomenclature system proposed in 2000 by the Human Genome Variation Society has been widely adopted and has developed into an internationally accepted standard. The recommendations are currently commissioned through a Sequence Variant Description Working Group (SVD-WG) operating under the auspices of three international organizations: the Human Genome Variation Society (HGVS), the Human Variome Project (HVP), and the Human Genome Organization (HUGO). Requests for modifications and extensions go through the SVD-WG following a standard procedure including a community consultation step. Version numbers are assigned to the nomenclature system to allow users to specify the version used in their variant descriptions. Here, we present the current recommendations, HGVS version 15.11, and briefly summarize the changes that were made since the 2000 publication. Most focus has been on removing inconsistencies and tightening definitions allowing automatic data processing. An extensive version of the recommendations is available online, at . C1 [den Dunnen, Johan T.] Leiden Univ, Med Ctr, Human Genet & Clin Genet, NL-2300 RC Leiden, Netherlands. [Dalgleish, Raymond] Univ Leicester, Dept Genet, Univ Rd, Leicester LE1 7RH, Leics, England. [Maglott, Donna R.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. [Hart, Reece K.] Invitae Inc, San Francisco, CA USA. [Greenblatt, Marc S.] Univ Vermont, Coll Med, Burlington, VT USA. [McGowan-Jordan, Jean] Childrens Hosp Eastern Ontario, Ottawa, ON K1H 8L1, Canada. [McGowan-Jordan, Jean] Univ Ottawa, Ottawa, ON, Canada. [Roux, Anne-Francoise] CHRU Montpellier, Genet Mol Lab, Montpellier, France. [Smith, Timothy] Int Coordinating Off, Human Variome Project, Melbourne, Vic, Australia. [Antonarakis, Stylianos E.] Univ Geneva, Sch Med, Dept Genet Med, CH-1211 Geneva, Switzerland. [Taschner, Peter E. M.] Generade Ctr Expertise Genom, Leiden, Netherlands. [Taschner, Peter E. M.] Univ Appl Sci Leiden, Leiden, Netherlands. RP den Dunnen, JT (reprint author), Leiden Univ, Med Ctr, Human Genet S04 030, POB 9600, NL-2300 RC Leiden, Netherlands. EM varnomen@HGVS.org OI Hart, Reece/0000-0003-3463-0775; Taschner, Peter/0000-0001-9621-465X NR 18 TC 22 Z9 22 U1 3 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 EI 1098-1004 J9 HUM MUTAT JI Hum. Mutat. PD JUN PY 2016 VL 37 IS 6 SI SI BP 564 EP 569 DI 10.1002/humu.22981 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA DK8DL UT WOS:000375157300010 PM 26931183 ER PT J AU Santosh, KC Alam, N Roy, PP Wendling, L Antani, S Thoma, GR AF Santosh, K. C. Alam, Naved Roy, Partha Pratim Wendling, Laurent Antani, Sameer Thoma, George R. TI A Simple and Efficient Arrowhead Detection Technique in Biomedical Images SO INTERNATIONAL JOURNAL OF PATTERN RECOGNITION AND ARTIFICIAL INTELLIGENCE LA English DT Article DE Arrowhead detection; document images; biomedical publications; image region labeling; content-based image retrieval ID RECOGNITION; PERFORMANCE; DESCRIPTOR; ALGORITHM AB In biomedical documents/publications, medical images tend to be complex by nature and often contain several regions that are annotated using arrows. In this context, an automated arrowhead detection is a critical precursor to region-of-interest (ROI) labeling and image content analysis. To detect arrowheads, in this paper, images are first binarized using fuzzy binarization technique to segment a set of candidates based on connected component (CC) principle. To select arrow candidates, we use convexity defect-based filtering, which is followed by template matching via dynamic time warping (DTW). The DTW similarity score confirms the presence of arrows in the image. Our test results on biomedical images from imageCLEF 2010 collection shows the interest of the technique, and can be compared with previously reported state-of-the-art results. C1 [Santosh, K. C.] Univ S Dakota, Dept Comp Sci, 414 E Clark St, Vermillion, SD 57069 USA. [Alam, Naved; Roy, Partha Pratim] Indian Inst Technol, Dept Comp Sci, Roorkee 247667, Uttarakhand, India. [Wendling, Laurent] Univ Paris 05, LIPADE, F-75270 Paris 06, France. [Antani, Sameer; Thoma, George R.] NIH, Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. RP Santosh, KC (reprint author), Univ S Dakota, Dept Comp Sci, 414 E Clark St, Vermillion, SD 57069 USA. EM santosh.kc@usd.edu; navedalamalam@gmail.com; proy.fcs@iitr.ac.in; laurent.wendling@parisdescartes.fr; sameer.antani@nih.gov; george.thoma@nih.gov OI Santosh, K.C./0000-0003-4176-0236 FU Intramural Research Program of the National Institutes of Health (NIH); National Library of Medicine (NLM); Lister Hill National Center for Biomedical Communications (LHNCBC) FX This research was supported [in part] by the Intramural Research Program of the National Institutes of Health (NIH), National Library of Medicine (NLM) and Lister Hill National Center for Biomedical Communications (LHNCBC). NR 26 TC 0 Z9 0 U1 2 U2 11 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA 5 TOH TUCK LINK, SINGAPORE 596224, SINGAPORE SN 0218-0014 EI 1793-6381 J9 INT J PATTERN RECOGN JI Int. J. Pattern Recognit. Artif. Intell. PD JUN PY 2016 VL 30 IS 5 AR 1657002 DI 10.1142/S0218001416570020 PG 16 WC Computer Science, Artificial Intelligence SC Computer Science GA DK7FG UT WOS:000375089800007 ER PT J AU Thomas, HN Evans, GW Berlowitz, DR Chertow, GM Conroy, MB Foy, CG Glasser, SP Lewis, CE Riley, WT Russell, L Williams, O Hess, R AF Thomas, Holly N. Evans, Gregory W. Berlowitz, Dan R. Chertow, Glenn M. Conroy, Molly B. Foy, Capri G. Glasser, Stephen P. Lewis, Cora E. Riley, William T. Russell, Laurie Williams, Olubunmi Hess, Rachel CA SPRINT Study Grp TI Antihypertensive medications and sexual function in women: baseline data from the SBP intervention trial (SPRINT) SO JOURNAL OF HYPERTENSION LA English DT Article DE antihypertensive agents; female sexual function; hypertension; sexual activity ID QUALITY-OF-LIFE; CLITORAL CORPUS CAVERNOSUM; CORONARY-ARTERY-DISEASE; NITRIC-OXIDE; BLOOD-PRESSURE; RANDOMIZED-TRIAL; FUNCTION INDEX; ESSENTIAL-HYPERTENSION; MILD HYPERTENSION; OXIDATIVE STRESS AB Objectives: Hypertension is a risk factor for the development of cardiovascular and kidney disease, but treatment can substantially reduce risks. Many patients avoid antihypertensive medications because of fear of side-effects. Although associations between antihypertensives and sexual dysfunction in men have been documented, it remains unclear whether antihypertensives are associated with sexual dysfunction in women. We conducted a cross-sectional analysis of baseline data from women in the Systolic Blood Pressure Intervention Trial (SPRINT) to evaluate the relations among class of antihypertensive medication and the outcomes: sexual activity and sexual function. Methods: SPRINT enrolled individuals 50 and older with hypertension at high risk for cardiovascular disease. A subset of participants completed questionnaires regarding quality of life, including sexual function. Antihypertensive class was determined by medications taken at baseline. Results: Of 690 women in the quality of life subset of SPRINT, 183 (26.5%) were sexually active. There were no significant differences in sexual activity among women taking one or more antihypertensives and women not taking any. Women taking an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker had higher odds of sexual activity [odds ratio 1.66 (1.12-4.27), P = 0.011]. Among sexually active women, the prevalence of sexual dysfunction was high (52.5%). No class of medication was associated with sexual dysfunction in the multivariable model. Conclusion: Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use was associated with higher odds of sexual activity. Although prevalence of sexual dysfunction was high, no single class of antihypertensive medication was associated with sexual dysfunction. C1 [Thomas, Holly N.; Conroy, Molly B.] Univ Pittsburgh, 230 McKee Pl Suite 600, Pittsburgh, PA 15213 USA. [Evans, Gregory W.; Foy, Capri G.; Russell, Laurie] Wake Forest Sch Med, Winston Salem, NC USA. [Berlowitz, Dan R.] Bedford VA Hosp, Bedford, MA USA. [Chertow, Glenn M.] Stanford Univ, Stanford, CA 94305 USA. [Glasser, Stephen P.; Lewis, Cora E.] Univ Alabama Birmingham, Birmingham, AL USA. [Riley, William T.] NIMH, Bethesda, MD 20892 USA. [Williams, Olubunmi] Emory Univ, Atlanta, GA 30322 USA. [Hess, Rachel] Univ Utah, Salt Lake City, UT USA. RP Thomas, HN (reprint author), Univ Pittsburgh, 230 McKee Pl Suite 600, Pittsburgh, PA 15213 USA. EM thomashn@upmc.edu OI Glasser, Stephen/0000-0001-9620-6406 FU NIH; National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Aging; National Institute of Neurological Disorders and Stroke [HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN26820 0900048C, HHSN268200900049C]; Inter-Agency Agreement [A-HL-13-002-001]; Department of Veterans Affairs; Agency on Healthcare Research and Quality (AHRQ) [5K12HS022989]; AMGEN; CTSAs - NCATS: CWRU [UL1TR000439]; CTSAs - OSU [UL1RR025755]; CTSAs - U Penn [UL1RR0241 34, UL1TR000003]; CTSAs - U Boston [UL1RR025771]; CTSAs - U Stanford [UL1TR000093]; CTSAs - Tufts [UL1RR025752, UL1TR000073, UL1TR001064]; CTSAs - University of Illinois [UL1TR000050]; CTSAs - University of Pittsburgh [UL1TR000005]; CTSAs - UT Southwestern [9U54TR000017- 06]; CTSAs - University of Utah [UL1TR000105-05]; CTSAs - Vanderbilt University [UL1 TR000445]; CTSAs - George Washington University [UL1TR000075]; CTSAs - University of CA, Davis [UL1 TR000002]; CTSAs - University of Florida [UL1 TR000064]; CTSAs - University of Michigan [UL1TR000433]; CTSAs - Tulane University, COBRE Award NIGMS [P30GM 103337] FX The manuscript has not been published and is not being considered for publication elsewhere, in whole or in part, in any language, except as an abstract. We presented an abstract of this data as poster at the Society of General Internal Medicine national conference in San Diego, California in April 2014. The SPRINT is funded with Federal funds from the NIH, including the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke, under contract numbers HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN26820 0900048C, HHSN268200900049C, and Inter-Agency Agreement Number A-HL-13-002-001. It was also supported in part with resources and use of facilities through the Department of Veterans Affairs. The SPRINT investigators acknowledge the contribution of study medications (azilsartan and azilsartan combined with chlorthalidone) from Takeda Pharmaceuticals Inc. H. N. T. is supported by a grant from the Agency on Healthcare Research and Quality (AHRQ) (5K12HS022989). S. P. G. is partially supported by a grant from AMGEN. No other author has any conflicts of interest to report. All components of the SPRINT study protocol were designed and implemented by the investigators. The investigative team collected, analyzed, and interpreted the data. All aspects of manuscript writing and revision were carried out by the coauthors. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, the US Department of Veterans Affairs, or the United States Government. For a full list of contributors to SPRINT, please see the supplementary acknowledgement list: ClinicalTrials.gov Identifier: NCT01206062. We also acknowledge the support from the following CTSAs funded by NCATS: CWRU: UL1TR000439, OSU: UL1RR025755, U Penn: UL1RR0241 34& UL1TR000003, Boston: UL1RR025771, Stanford: UL1TR000093, Tufts: UL1RR025752, UL1TR000073 & UL1TR001064, University of Illinois: UL1TR000050, University of Pittsburgh: UL1TR000005, UT Southwestern: 9U54TR000017- 06, University of Utah: UL1TR000105-05, Vanderbilt University: UL1 TR000445, George Washington University: UL1TR000075, University of CA, Davis: UL1 TR000002, University of Florida: UL1 TR000064, University of Michigan: UL1TR000433, Tulane University: P30GM 103337 COBRE Award NIGMS. NR 59 TC 1 Z9 1 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0263-6352 EI 1473-5598 J9 J HYPERTENS JI J. Hypertens. PD JUN PY 2016 VL 34 IS 6 BP 1224 EP 1231 DI 10.1097/HJH.0000000000000911 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DK7ZM UT WOS:000375146000029 PM 27032074 ER PT J AU Han, B Kott, PS Hughes, A McKeon, R Blanco, C Compton, WM AF Han, Beth Kott, Phillip S. Hughes, Art McKeon, Richard Blanco, Carlos Compton, Wilson M. TI Estimating the rates of deaths by suicide among adults who attempt suicide in the United States SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Death by suicide; Suicide attempt; Suicide case fatality rates; Suicide prevention and intervention; Adults at high suicide risk; Variance estimation techniques ID CASE-FATALITY RATES; HEALTH; MORTALITY; PATTERNS; IMPACT AB Background: In 2012, over 1.3 million U.S. adults reported that they attempted suicide in the past year, and 39,426 adults died by suicide. This study estimated national suicide case fatality rates among adult suicide attempters (fatal and nonfatal cases) and examined how they varied by sociodemographic characteristics. Methods: We pooled data on deaths by suicide (n = 147,427, fatal cases in the U.S.) from the 2008-2011 U S. mortality files and data on suicide attempters who survived (n = 2000 nonfatal cases) from the 2008-2012 National Surveys on Drug Use and Health. Descriptive analyses and multivariable logistic regression models were applied. Results: Among adult suicide attempters in the U.S., the overall 12-month suicide case fatality rate was 3.2% (95% confidence interval (CI) = 2.9%-3.5%). It varied significantly by sociodemographic factors. For those aged 45 or older, the adjusted suicide case fatality rate was higher among men (7.6%) than among women (2.6%) (suicide case fatality rate ratio (SCFRR) = 3.0, 95% CI = 1.83-4.79), was higher among non Hispanic whites (7.9%) than among non-white minorities (0.8-2.5%) (SCFRRs = 3.2-9.9), and was higher among those with less than high school education (16.0%) than among college graduates (1.8%) (SCFRR = 8.8, 95% CI = 3.83-20.16). Across male and female attempters, being aged 45 or older and non Hispanic white and having less than secondary school were at a higher risk for death by suicide. Conclusions: Focusing on these demographic characteristics can help identify suicide attempters at higher risk for death by suicide, inform clinical assessments, and improve suicide prevention and intervention efforts by increasing high-risk suicide attempters' access to mental health treatment. Published by Elsevier Ltd. C1 [Han, Beth; Hughes, Art; McKeon, Richard] Subst Abuse & Mental Hlth Serv Adm, Washington, DC USA. [Kott, Phillip S.] RTI Int, Res Triangle Pk, NC USA. [Blanco, Carlos; Compton, Wilson M.] NIDA, NIH, Washington, DC USA. RP Han, B (reprint author), 5600 Fishers Lane,15E13B, Rockville, MD 20857 USA. EM Beth.Han@SAMHSA.HHS.GOV NR 37 TC 1 Z9 1 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD JUN PY 2016 VL 77 BP 125 EP 133 DI 10.1016/j.jpsychires.2016.03.002 PG 9 WC Psychiatry SC Psychiatry GA DK3GI UT WOS:000374804700016 PM 27032110 ER PT J AU Rastinehad, AR Abboud, SF George, AK Frye, TP Ho, R Chelluri, R Fascelli, M Shih, J Villani, R Ben-Levi, E Yaskiv, O Turkbey, B Choyke, PL Merino, MJ Wood, BJ Pinto, PA AF Rastinehad, Ardeshir R. Abboud, Steven F. George, Arvin K. Frye, Thomas P. Ho, Richard Chelluri, Raju Fascelli, Michele Shih, Joanna Villani, Robert Ben-Levi, Eran Yaskiv, Oksana Turkbey, Baris Choyke, Peter L. Merino, Maria J. Wood, Bradford J. Pinto, Peter A. TI Reproducibility of Multiparametric Magnetic Resonance Imaging and Fusion Guided Prostate Biopsy: Multi-Institutional External Validation by a Propensity Score Matched Cohort SO JOURNAL OF UROLOGY LA English DT Article DE prostate; adenocarcinoma; biopsy; magnetic resonance imaging; ultrasound, high-intensity focused, transrectal ID ULTRASOUND FUSION; TARGETED BIOPSY; CANCER; SYSTEM AB Purpose: As the adoption of magnetic resonance imaging/ultrasound fusion guided biopsy expands, the reproducibility of outcomes at expert centers becomes essential. We sought to validate the comprehensive NCI (National Cancer Institute) experience with multiparametric magnetic resonance imaging and fusion guided biopsy in an external, independent, matched cohort of patients. Materials and Methods: We compared 620 patients enrolled in a prospective trial comparing systematic biopsy to fusion guided biopsy at NCI to 310 who underwent a similar procedure at Long Island Jewish Medical Center. The propensity score, defined as the probability of being treated outside NCI, was calculated using the estimated logistic regression model. Patients from the hospital were matched 1:1 for age, prostate specific antigen, magnetic resonance imaging suspicion score and prior negative biopsies. Clinically significant disease was defined as Gleason 3 + 4 or greater. Results: Before matching we found differences between the cohorts in age, magnetic resonance imaging suspicion score (each p < 0.001), the number of patients with prior negative biopsies (p = 0.01), and the overall cancer detection rate and the cancer detection rate by fusion guided biopsy (each p < 0.001). No difference was found in the rates of upgrading by fusion guided biopsy (p = 0.28) or upgrading to clinically significant disease (p = 0.95). A statistically significant difference remained in the overall cancer detection rate and the rate by fusion guided biopsy after matching. On subgroup analysis we found a difference in the overall cancer detection rate and the rate by fusion guided biopsy (p < 0.001 and 0.003) in patients with prior negative systematic biopsy but no difference in the 2 rates (p = 0.39 and 0.51, respectively) in biopsy naive patients. Conclusions: Improved detection of clinically significant cancer by magnetic resonance imaging and fusion guided biopsy is reproducible by an experienced multidisciplinary team consisting of dedicated radiologists and urologists. C1 [Rastinehad, Ardeshir R.] Icahn Sch Med Mt Sinai, Dept Urol & Radiol, New York, NY 10029 USA. [Villani, Robert; Ben-Levi, Eran] North Shore Long Isl Jewish Hofstra Sch Med, Dept Radiol, New Hyde Pk, New York, NY USA. [Yaskiv, Oksana] North Shore Long Isl Jewish Hofstra Sch Med, Dept Pathol, New Hyde Pk, New York, NY USA. [Abboud, Steven F.; George, Arvin K.; Frye, Thomas P.; Ho, Richard; Chelluri, Raju; Fascelli, Michele; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, 10 Ctr Dr,MSC 1210,Bldg 10,CRC Room 2W-5940, Bethesda, MD 20892 USA. [Shih, Joanna] NCI, Biometr Res Branch, NIH, 10 Ctr Dr,MSC 1210,Bldg 10,CRC Room 2W-5940, Bethesda, MD 20892 USA. [Turkbey, Baris; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, 10 Ctr Dr,MSC 1210,Bldg 10,CRC Room 2W-5940, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, NIH, 10 Ctr Dr,MSC 1210,Bldg 10,CRC Room 2W-5940, Bethesda, MD 20892 USA. [Wood, Bradford J.] NCI, Ctr Intervent Oncol, NIH, 10 Ctr Dr,MSC 1210,Bldg 10,CRC Room 2W-5940, Bethesda, MD 20892 USA. RP Pinto, PA (reprint author), NCI, Urol Oncol Branch, NIH, 10 Ctr Dr,MSC 1210,Bldg 10,CRC Room 2W-5940, Bethesda, MD 20892 USA. EM pintop@mail.nih.gov FU Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research and Center for Interventional Oncology; NIH and Philips Healthcare cooperative research and development agreement; NIH Medical Research Scholars Program; NIH; Pfizer, Inc.; Doris Duke Charitable Foundation; Alexandria Real Estate Equities, Inc.; Mr. and Mrs. Joel S. Marcus, Howard Hughes Medical Institute FX Supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and Center for Interventional Oncology, a NIH and Philips Healthcare cooperative research and development agreement, the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and contributions to the Foundation for the NIH from Pfizer, Inc., The Doris Duke Charitable Foundation and The Alexandria Real Estate Equities, Inc., and Mr. and Mrs. Joel S. Marcus, Howard Hughes Medical Institute and other private donors (http://fnih.org/work/education-training-0/medical-research-scholars-pro gram). NR 30 TC 5 Z9 5 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD JUN PY 2016 VL 195 IS 6 BP 1737 EP 1742 DI 10.1016/j.juro.2015.12.102 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA DL1DZ UT WOS:000375373700035 PM 26812301 ER PT J AU Kaplan, SA Lee, JY Meehan, AG Kusek, JW AF Kaplan, Steven A. Lee, Jeannette Y. Meehan, Alan G. Kusek, John W. TI Time Course of Incident Adverse Experiences Associated with Doxazosin, Finasteride and Combination Therapy in Men with Benign Prostatic Hyperplasia: The MTOPS Trial SO JOURNAL OF UROLOGY LA English DT Article DE prostatic hyperplasia; doxazosin; finasteride; drug-related side effects and adverse reactions; sexual dysfunction; physiological ID TERAZOSIN AB Purpose: We examined first (incident) reports of selected adverse experiences associated with medical therapy in men with lower urinary tract symptoms secondary to benign prostatic hyperplasia. Materials and Methods: We studied the 6 most common adverse experiences, including nonsexual function related experiences (dizziness, orthostatic hypotension and weakness) and sexual function related experiences (impotence, decreased libido and abnormal ejaculation) reported in the MTOPS (Medical Therapy of Prostatic Symptoms) Study. A total of 3,047 men were randomized to placebo, doxazosin, finasteride or combination therapy and followed for a mean duration of 4.5 years. We compared the incidence rates of adverse experiences at year 1 to the rates thereafter. Results: For each assigned treatment group, the incidence rates were significantly higher for all 6 adverse experiences examined at year 1 compared with the rates thereafter. Men assigned to combination therapy experienced the highest rates at year 1 with rates 3.4-fold to 10.6-fold higher than rates after year 1. The incidence rates for orthostatic hypotension and dizziness were significantly higher in the doxazosin and combination therapy groups compared with the placebo group at year 1. The incidence rates of the 3 examined sexual function related adverse experiences were significantly higher in the finasteride and combination therapy groups than in the placebo group at year 1. Conclusions: Rates of the first report of sexual function related and other adverse experiences associated with doxazosin, finasteride and combination therapy were greatest during year 1 of treatment. These patterns should be considered by patients and physicians when treatment for lower urinary tract function is initiated with these drugs. C1 [Kaplan, Steven A.] Mt Sinai Hlth Syst, Icahn Sch Med Mt Sinai, Dept Urol, New York, NY 10065 USA. [Lee, Jeannette Y.] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Meehan, Alan G.] Merck & Co Inc, Kenilworth, NJ USA. [Kusek, John W.] NIDDK, Bethesda, MD 20892 USA. RP Kaplan, SA (reprint author), Mt Sinai Hlth Syst, Icahn Sch Med Mt Sinai, Dept Urol, New York, NY 10065 USA. EM steven.kaplan@mountsinai.org FU Merck Co., Inc.; Merck Sharp & Dohme Corp. of Merck Co., Inc.; NIDDK [U01 DK49977, U01 DK46416, U01 DK41418, U01 DK46429, U01 DK46431, U01 DK46437, U01 DK46468, U01 DK46472, U01 DK49880, U01 DK 49912, U01 DK49921, U01 DK49951, U01 DK49954, U01 DK49960, U01 DK49961, U01 DK49963, U01 DK49964, U01 DK49971, U01 DK49980]; National Institutes of Health National Center for Minority Health and Health Disparities; Pfizer FX Supported by Merck & Co., Inc., Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. MTOPS was supported by NIDDK cooperative agreements U01 DK49977, U01 DK46416, U01 DK41418, U01 DK46429, U01 DK46431, U01 DK46437, U01 DK46437, U01 DK46468, U01 DK46472, U01 DK49880, U01 DK 49912, U01 DK49921, U01 DK49951, U01 DK49954, U01 DK49960, U01 DK49961, U01 DK49963, U01 DK49964, U01 DK49971 and U01 DK49980, the National Institutes of Health National Center for Minority Health and Health Disparities, Merck & Co., Inc. and Pfizer. NR 15 TC 1 Z9 1 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD JUN PY 2016 VL 195 IS 6 BP 1825 EP 1829 DI 10.1016/j.juro.2015.11.065 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA DL1DZ UT WOS:000375373700070 PM 26678956 ER PT J AU Ishii, K Birmann, BM Zhang, XH Giovannucci, E Bertrand, KA AF Ishii, Kazusa Birmann, Brenda M. Zhang, Xuehong Giovannucci, Edward Bertrand, Kimberly A. TI A prospective analysis of blood donation history and risk of non-Hodgkin lymphoma SO LEUKEMIA & LYMPHOMA LA English DT Article DE Blood donation; non-Hodgkin lymphoma; epidemiology; risk ID KILLER-CELL ACTIVITY; EPIDEMIOLOGIC RESEARCH; DONORS; CANCER; NEOPLASMS; CYTOKINES; PLASMAPHERESIS; CLASSIFICATION; ASSOCIATION; INTERLYMPH AB Blood donation may influence subsequent NHL development via temporary immune system alterations. To test the hypothesis that frequent blood donation is associated with an increased risk of NHL and its most common histologic subtypes, this study followed 36 576 men in the Health Professionals Follow-up Study (HPFS), who provided information on frequency of blood donation in the past 30 years in 1992. This study confirmed 544 incident cases of NHL through 2010. Cox proportional hazards regression was used to calculate hazards ratios (HR) and 95% CI for the risk of all NHL and major NHL histologic subtypes associated with number of blood donations. In this prospective study, there was no significant evidence of an association between blood donation frequency and incidence of NHL (age-adjusted HR=1.26, 95% CI=0.94-1.68, comparing>20 donations vs 0 donations over 30 years, p for trend=0.18) or of any major NHL subtypes. C1 [Ishii, Kazusa] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Birmann, Brenda M.; Zhang, Xuehong; Giovannucci, Edward; Bertrand, Kimberly A.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 181 Longwood Ave, Boston, MA 02115 USA. [Birmann, Brenda M.; Zhang, Xuehong; Giovannucci, Edward; Bertrand, Kimberly A.] Harvard Univ, Sch Med, 181 Longwood Ave, Boston, MA 02115 USA. [Giovannucci, Edward] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Giovannucci, Edward] Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. RP Bertrand, KA (reprint author), Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 181 Longwood Ave, Boston, MA 02115 USA.; Bertrand, KA (reprint author), Harvard Univ, Sch Med, 181 Longwood Ave, Boston, MA 02115 USA. EM kbertran@hsph.harvard.edu FU NCI NIH HHS [CA055075, CA149445, CA167552, L30 CA162082, P01 CA055075, R01 CA149445, UM1 CA167552] NR 35 TC 0 Z9 0 U1 2 U2 4 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD JUN PY 2016 VL 57 IS 6 BP 1423 EP 1428 DI 10.3109/10428194.2015.1091928 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA DK7TS UT WOS:000375129200025 PM 26373836 ER PT J AU Andreotti, G Katz, M Hoering, A Van Ness, B Crowley, J Morgan, G Hoover, RN Baris, D Durie, B AF Andreotti, Gabriella Katz, Michael Hoering, Antje Van Ness, Brian Crowley, John Morgan, Gareth Hoover, Robert N. Baris, Dalsu Durie, Brian TI Risk of multiple myeloma in a case-spouse study SO LEUKEMIA & LYMPHOMA LA English DT Article DE Myeloma; epidemiology; case-spouse ID BODY-MASS INDEX; NON-HODGKINS-LYMPHOMA; PLASMA-CELL MYELOMA; CIGARETTE-SMOKING; UNDETERMINED SIGNIFICANCE; MONOCLONAL GAMMOPATHY; HEMATOPOIETIC CANCER; ALCOHOL-CONSUMPTION; UNITED-STATES; COHORT AB This study examined lifestyle, occupation, medical history and medication use with multiple myeloma risk in a case-spouse study (481 patients, 351 spouses). Odds ratios (ORs) and 95% confidence intervals (CI) were calculated using logistic regression. Compared to spouse controls, cases were more likely to have a family history of multiple myeloma (OR=2.8, 95% CI=1.2-6.4) and smoked cigarettes (OR=1.7, 95% CI=1.2-2.5), but less likely to have consumed alcohol (OR=0.6, 95% CI=0.4-0.9). Nurse/health practitioners (OR=2.8, 95% CI=1.3-6.2) and production workers (OR=3.7, 95% CI=1.0-13.7) had significantly increased risks; and some occupations linked to diesel exhaust had elevated, but non-significant, risks. History of herpes simplex (OR=1.7, 95% CI=1.2-2.4), shingles (OR=1.7, 95% CI=1.1-2.7), sexually transmitted diseases (OR=2.0, 95% CI=1.0-3.7) and medication allergies (OR=1.7, 95% CI=1.2-2.4) were associated with higher risks. Use of angiotensin-converting enzyme inhibitors, anti-convulsants, antidepressants, statins and diuretics were associated with reduced risks. The results are consistent with previous population-based studies and support the utility of patient databanks and spouse controls as a resource in epidemiologic research. C1 [Andreotti, Gabriella; Hoover, Robert N.; Baris, Dalsu] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD 20850 USA. [Katz, Michael; Durie, Brian] Int Myeloma Fdn, Hollywood, CA USA. [Hoering, Antje; Crowley, John] Canc Res & Biostat, Seattle, WA USA. [Van Ness, Brian] Univ Minnesota, Ctr Canc, Minneapolis, MN USA. [Morgan, Gareth] Inst Canc Res, Haematooncol, Sutton, Surrey, England. [Durie, Brian] Cedar Sinai Med Ctr, Los Angeles, CA USA. RP Andreotti, G (reprint author), NCI, NIH, DCEG, OEEB, 9609 Med Ctr Dr,Rm 6E622,MSC 9704, Rockville, MD 20850 USA. EM andreotg@mail.nih.gov FU Intramural NIH HHS NR 72 TC 1 Z9 1 U1 3 U2 6 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD JUN PY 2016 VL 57 IS 6 BP 1450 EP 1459 DI 10.3109/10428194.2015.1094693 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA DK7TS UT WOS:000375129200029 PM 26422532 ER PT J AU Ghani, M Sato, C Kakhki, EG Gibbs, JR Traynor, B St George-Hyslop, P Rogaeva, E AF Ghani, Mahdi Sato, Christine Kakhki, Erfan Ghani Gibbs, J. Raphael Traynor, Bryan St George-Hyslop, Peter Rogaeva, Ekaterina TI Mutation analysis of the MS4A and TREM gene clusters in a case-control Alzheimer's disease data set SO NEUROBIOLOGY OF AGING LA English DT Article DE TREM2; TREML2; MS4A6A; Targeted sequencing; Alzheimer's disease; Mutation ID GENOME-WIDE ASSOCIATION; APOLIPOPROTEIN-E; SEQUENCING DATA; VARIANTS; CELLS; SCLEROSIS; DISCOVERY; PROTECTS; FAMILY; BLOOD AB Genome wide association studies have identified an association between Alzheimer's disease (AD) and common polymorphisms in the MS4A and TREM loci (each containing a cluster of homologous genes) and should be thoroughly investigated for the presence of potentially functional variations. We conducted a mutation analysis by next generation sequencing of 15 genes within the MS4A and TREM gene clusters; and catalogued rare coding variants detected in a North American data set of 210 cases and 233 controls. Investigation of the 5 homologues genes in the TREM locus revealed potentially damaging rare variants in TREM2, TREML1, TREML2, and TREML4. In agreement with a previous report, we observed a significant enrichment of TREM2-damaging missense substitutions in cases (N = 9; 4.2%) compared with controls (N = 2; 0.9%; p = 0.010; after Yates' correction p = 0.022). Among known AD-associated TREM2 substitutions, we detected p.R47H, p.D87N, and p.H157Y affecting both TREM2 isoforms (NM_018965 and NM_001271821). In addition, we identified 2 cases with novel TREM2 variants (p.L205P and p.G219C), which mapped only to the isoform NM_001271821 at the C-terminus. Investigation of the MS4A gene cluster revealed that potentially damaging missense substitutions and loss-of-function variants were twice as frequent in controls (N = 19; 8.2%) than cases (N = 9; 4.3%), generating a nominally significant result (p = 0.047; after Yates' correction p = 0.07). Validation of our observation in large data sets might address the question whether such variants could contribute to the protective effect of the minor alleles of Genome wide association study-significant single nucleotide polymorphisms at the MS4A locus. (C) 2016 Elsevier Inc. All rights reserved. C1 [Ghani, Mahdi; Sato, Christine; Kakhki, Erfan Ghani; St George-Hyslop, Peter; Rogaeva, Ekaterina] Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Krembil Discovery Tower,60 Leonard Ave, Toronto, ON M5T 2S8, Canada. [Ghani, Mahdi; Sato, Christine; Kakhki, Erfan Ghani; St George-Hyslop, Peter; Rogaeva, Ekaterina] Univ Toronto, Dept Med, Toronto, ON M5T 2S8, Canada. [Gibbs, J. Raphael] NIA, Computat Biol Core, Neurogenet Lab, Bethesda, MD 20892 USA. [Traynor, Bryan] NIA, Neuromuscular Dis Res Sect, Neurogenet Lab, Bethesda, MD 20892 USA. [St George-Hyslop, Peter] Univ Cambridge, Dept Clin Neurosci, Cambridge Inst Med Res, Cambridge, England. RP St George-Hyslop, P; Rogaeva, E (reprint author), Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Krembil Discovery Tower,60 Leonard Ave, Toronto, ON M5T 2S8, Canada. EM p.hyslop@utoronto.ca; ekaterina.rogaeva@utoronto.ca FU Canadian Institutes of Health Research; Wellcome Trust; Medical Research Council; Ontario Research Fund Alzheimer Society of Ontario; Intramural Research Programs of the National Institutes of Health, National Institute on Aging [Z01-AG000949-02] FX This work was supported by grants from the Canadian Institutes of Health Research (Ekaterina Rogaeva, Peter St George-Hyslop), Wellcome Trust, Medical Research Council, Ontario Research Fund Alzheimer Society of Ontario (Peter St George-Hyslop), and the Intramural Research Programs (Z01-AG000949-02) of the National Institutes of Health, National Institute on Aging (Bryan Traynor). NR 40 TC 2 Z9 2 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUN PY 2016 VL 42 AR 217.e7 DI 10.1016/j.neurobiolaging.2016.03.009 PG 7 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA DK7TV UT WOS:000375129500026 PM 27084067 ER PT J AU Yao, Y Nisan, D Fujimoto, LM Antignani, A Barnes, A Tjandra, N Youle, RJ Marassi, FM AF Yao, Yong Nisan, Danielle Fujimoto, Lynn M. Antignani, Antonella Barnes, Ashley Tjandra, Nico Youle, Richard J. Marassi, Francesca M. TI Characterization of the membrane-inserted C-terminus of cytoprotective BCL-XL SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article DE BCL-2; Apoptosis; Membrane; Nanodisc; Structure; NMR ID MITOCHONDRIAL OUTER-MEMBRANE; CELL-DEATH; PRECURSOR PROTEINS; NMR-SPECTROSCOPY; IMPORT RECEPTOR; IN-VITRO; APOPTOSIS; MODULATION; BCL-X(L); COMPLEX AB BCL-XL is a dominant inhibitor of apoptosis and a significant anti-cancer drug target. Endogenous BCL-XL is integral to the mitochondrial outer membrane (MOM). BCL-XL reconstituted in detergent-free lipid bilayer nanodiscs is anchored to the nanodisc lipid bilayer membrane by tight association of its C-terminal tail, while the N-terminal head retains the canonical structure determined for water-soluble, tail truncated BCL-XL, with the surface groove solvent-exposed and available for BH3 ligand binding. To better understand the conformation and dynamics of this key region of BCL-XL we have developed methods for isolating the membrane-embedded C-terminal tail from its N-terminal head and for preparing protein suitable for structural and biochemical studies. Here, we outline the methods for sample preparation and characterization and describe previously unreported structural and dynamics features. We show that the C-terminal tail of BCL-XL forms a transmembrane a-helix that retains a significant degree of conformational dynamics. We also show that the presence of the intact C-terminus destabilizes the soluble state of the protein, and that the small fraction of soluble recombinant protein produced in Escherichia coli is susceptible to proteolytic degradation of C-terminal residues beyond M218. This finding impacts the numerous previous studies where recombinant soluble BCL-XL was presumed to be full-length. Nevertheless, the majority of recombinant BCL-XL produced in E. coli is insoluble and protected from proteolysis. This protein retains the complete C-terminal tail and can be reconstituted in lipid bilayers in a folded and active state. (C) 2016 Elsevier Inc. All rights reserved. C1 [Yao, Yong; Nisan, Danielle; Fujimoto, Lynn M.; Marassi, Francesca M.] Sanford Burnham Prebys Med Discovery Inst, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA. [Antignani, Antonella; Youle, Richard J.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Barnes, Ashley; Tjandra, Nico] NHLBI, Lab Mol Biophys, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Marassi, FM (reprint author), Sanford Burnham Prebys Med Discovery Inst, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM fmarassi@sbmri.org FU National Institutes of Health [R01CA179087, R01GM110658, P41EB002031, P30CA030199] FX This work was supported by grants (R01CA179087, R01GM110658, P41EB002031, P30CA030199) from the National Institutes of Health. NR 39 TC 3 Z9 3 U1 6 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-5928 EI 1096-0279 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD JUN PY 2016 VL 122 BP 56 EP 63 DI 10.1016/j.pep.2016.02.010 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA DK8JE UT WOS:000375172200008 PM 26923059 ER PT J AU Golding, J Steer, CD Gregory, S Lowery, T Hibbeln, JR Taylor, CM AF Golding, Jean Steer, Colin D. Gregory, Steven Lowery, Tony Hibbeln, Joseph R. Taylor, Caroline M. TI Dental associations with blood mercury in pregnant women SO COMMUNITY DENTISTRY AND ORAL EPIDEMIOLOGY LA English DT Article DE ALSPAC; blood mercury; dental amalgam; pregnancy; seafood ID SEYCHELLES CHILD-DEVELOPMENT; NEURODEVELOPMENTAL OUTCOMES; DEVELOPMENT NUTRITION; INORGANIC MERCURY; PRENATAL EXPOSURE; AMALGAM FILLINGS; UNITED-STATES; POPULATION; RESTORATIONS; METHYLMERCURY AB ObjectivesThere is curiosity concerning the source of mercury that is absorbed into the mother's blood and which may affect the developing fetus. This study therefore sets out to determine the extent to which dental amalgam (DA) may contribute to total blood mercury (TBHg) levels of pregnant women in the UK. MethodsWhole blood samples and information on diet and socio-demographic factors were collected from pregnant women (n=4484) enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC). The whole blood samples were assayed for total mercury levels using inductively coupled plasma dynamic reaction cell mass spectrometry (ICP-DRC-MS), and the women were retrospectively asked about features of their dental care during the pregnancy. Linear regression was used to estimate the relative contributions of DA to TBHg levels (log-transformed) based on R-2 values, compared to the results from dietary and socio-demographic variables. ResultsThe contribution to the variance of the mothers' TBHg levels by dental variables was 6.47%, a figure comparable to the 8.75% shown for seafood consumption in this population. Dietary and dental variables explained 20.16% of the variance, with socio-demographic variables contributing only a further 3.40%. The number of amalgams in the mouth at the start of pregnancy accounted for most of the variance in dental variables. ConclusionsDental amalgam contributes a comparable amount of variance in TBHg to seafood consumption in this population. However, because the measures of DA exposure were imprecise, these findings are likely to be an underestimate. There is no evidence to date in the literature that fetal exposures to mercury from maternal DAs have adverse effects on the developing child, but long-term studies are warranted. C1 [Golding, Jean; Steer, Colin D.; Gregory, Steven; Taylor, Caroline M.] Univ Bristol, Sch Social & Community Med, Ctr Child & Adolescent Hlth, Oakfield House,Oakfield Rd, Bristol BS8 2BN, Avon, England. [Lowery, Tony] NOAA, Natl Seafood Inspect Lab, Natl Marine Fisheries Serv, Pascagoula, MS USA. [Hibbeln, Joseph R.] NIAAA, NIH, Bethesda, MD USA. RP Golding, J (reprint author), Univ Bristol, Sch Social & Community Med, Ctr Child & Adolescent Hlth, Oakfield House,Oakfield Rd, Bristol BS8 2BN, Avon, England. EM jean.golding@bristol.ac.uk OI Golding, Jean/0000-0003-2826-3307 FU Wellcome Trust [102215/2/13/2, 104077/Z/14/Z]; NOAA FX We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. The UK Medical Research Council (MRC), the Wellcome Trust (Grant ref: 102215/2/13/2), and the University of Bristol currently provide core support for ALSPAC. CMT was supported by a Wellcome Trust Career Re-entry Fellowship (Grant ref: 104077/Z/14/Z). The assays of the maternal blood samples were carried out at the Centers for Disease Control and Prevention with funding from NOAA, and the statistical analyses were carried out in Bristol with funding from NOAA and support from the Intramural Research Program of NIAAA, NIH. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the CDC, NOAA or the NIH. NR 30 TC 2 Z9 2 U1 1 U2 25 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0301-5661 EI 1600-0528 J9 COMMUNITY DENT ORAL JI Community Dentist. Oral Epidemiol. PD JUN PY 2016 VL 44 IS 3 BP 216 EP 222 DI 10.1111/cdoe.12208 PG 7 WC Dentistry, Oral Surgery & Medicine; Public, Environmental & Occupational Health SC Dentistry, Oral Surgery & Medicine; Public, Environmental & Occupational Health GA DJ6LG UT WOS:000374323900004 PM 26688340 ER PT J AU Ni, MY Jiang, CQ Cheng, KK Zhang, WS Gilman, SE Lam, TH Leung, GM Schooling, CM AF Ni, Michael Y. Jiang, Chaoqiang Cheng, Kar Keung Zhang, Weisen Gilman, Stephen E. Lam, Tai Hing Leung, Gabriel M. Schooling, C. Mary TI Stress across the life course and depression in a rapidly developing population: the Guangzhou Biobank Cohort Study SO INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE depression; childhood adversity; life change events; life stress ID CHILDHOOD ADVERSITY; RETROSPECTIVE REPORTS; PSYCHIATRIC-DISORDER; MAJOR DEPRESSION; HONG-KONG; RISK; IDENTIFICATION; CHILDREN; EVENTS; ONSET AB ObjectiveThe objective of this study was to examine the role of stress across the life course in the development of depression among older adults in a non-Western developing setting. MethodsMultivariable linear and multinomial logistic regression were used in cross-sectional analyses of 9729 Chinese participants (mean age 60.2years) from phase 3 of the Guangzhou Biobank Cohort Study (2006-2008) to investigate the association of childhood adversities and adulthood stressors with depression. ResultsChildhood adversities were associated with mild depression (odds ratio (OR) 1.78, 95% confidence interval (CI) 1.58, 2.02) and moderate-to-severe depression (OR 2.30, 95% CI 1.68, 3.15), adjusted for age, sex, education and childhood socio-economic status. Past-year adulthood stressors were also associated with mild depression (OR 1.96, 95% CI 1.54, 2.02) and moderate-to-severe depression (OR 3.55, 95% CI 2.21, 5.68), adjusting additionally for occupation and income. Adulthood stressors were more strongly associated with depressive symptoms among individuals with a history of childhood adversities. ConclusionsChildhood adversities and adulthood stressors were independently associated with an increased risk of depression among older ambulatory adults, although adulthood stressors were more strongly associated with depression following exposure to childhood adversities. This is consistent with evidence from Western settings in which the social context of risk and protective factors for depression may differ and implies that the role of stress in the aetiology of depression is not context specific. Copyright (c) 2015 John Wiley & Sons, Ltd. C1 [Ni, Michael Y.; Lam, Tai Hing; Leung, Gabriel M.; Schooling, C. Mary] Univ Hong Kong, Li Ka Shing Fac Med, Sch Publ Hlth, Pokfulam, Hong Kong, Peoples R China. [Jiang, Chaoqiang; Zhang, Weisen] Guangzhou 12 Hosp, Guangzhou, Guangdong, Peoples R China. [Cheng, Kar Keung] Univ Birmingham, Dept Publ Hlth & Epidemiol, Birmingham, W Midlands, England. [Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Gilman, Stephen E.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Gilman, Stephen E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Hlth Behav Branch, Rockville, MD USA. [Schooling, C. Mary] CUNY Hunter Coll, Sch Publ Hlth, New York, NY 10021 USA. [Schooling, C. Mary] CUNY, New York, NY 10021 USA. RP Lam, TH (reprint author), Univ Hong Kong, Li Ka Shing Fac Med, Sch Publ Hlth, Pokfulam, Hong Kong, Peoples R China. EM hrmrlth@hku.hk OI Ni, Michael/0000-0002-1217-5858; Cheng, Kar/0000-0002-1516-1857; Gilman, Stephen/0000-0002-8331-6419 FU University of Hong Kong Foundation for Development and Research; University of Hong Kong University Research Committee Strategic Research Theme Public Health, Hong Kong; Guangzhou Public Health Bureau; Guangzhou Science and Technology Bureau, Guangzhou, China; University of Birmingham, UK; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, USA FX This work was supported by The University of Hong Kong Foundation for Development and Research and The University of Hong Kong University Research Committee Strategic Research Theme Public Health, Hong Kong; Guangzhou Public Health Bureau and Guangzhou Science and Technology Bureau, Guangzhou, China; and The University of Birmingham, UK; and in part by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, USA. The funding sources had no role in any of the following: study design; the collection, analysis and interpretation of data; the writing of the report; and the decision to submit the paper for publication. NR 61 TC 0 Z9 0 U1 5 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-6230 EI 1099-1166 J9 INT J GERIATR PSYCH JI Int. J. Geriatr. Psychiatr. PD JUN PY 2016 VL 31 IS 6 BP 629 EP 637 DI 10.1002/gps.4370 PG 9 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA DK1UM UT WOS:000374700000010 PM 26452069 ER PT J AU Waters, EA Janssen, E Kaufman, AR Peterson, LM Muscanell, NL Guadagno, RE Stock, ML AF Waters, Erika A. Janssen, Eva Kaufman, Annette R. Peterson, Laurel M. Muscanell, Nicole L. Guadagno, Rosanna E. Stock, Michelle L. TI The Relationship Between Young Adult Smokers' Beliefs About Nicotine Addiction and Smoking-Related Affect and Cognitions SO JOURNAL OF CANCER EDUCATION LA English DT Article DE Gene-environment interaction; Tobacco use; Risk perception; Health beliefs ID CANCER-RISK; PERCEPTIONS; CONSEQUENCES; FEELINGS; OPTIMISM AB Risk beliefs and self-efficacy play important roles in explaining smoking-related outcomes and are important to target in tobacco control interventions. However, information is lacking about the underlying beliefs that drive these constructs. The present study investigated the interrelationships among young adult smokers' beliefs about the nature of nicotine addiction and smoking-related affect and cognitions (i.e., feelings of risk, worry about experiencing the harms of smoking, self-efficacy of quitting, and intentions to quit). Smokers (n = 333) were recruited from two large universities. Results showed that quit intentions were associated with feelings of risk, but not with worry or self-efficacy. Furthermore, higher feelings of risk were associated with lower beliefs that addiction is an inevitable consequence of smoking and with lower beliefs that the harms of smoking are delayed. This suggests that it is important for health messages to counter the possible negative effects of messages that strongly emphasize the addictiveness of nicotine, possibly by emphasizing the importance of quitting earlier rather than later. The findings also add to the evidence base that feelings of risk are powerful predictors of behavioral intentions. Furthermore, our results suggest that in some circumstances, feelings of risk predict quit intentions beyond that predicted by worry and self-efficacy. Gaining additional understanding of the tobacco-related beliefs that can increase feelings of risk and incorporating those beliefs into educational campaigns may improve the quality of such campaigns and reduce tobacco use. C1 [Waters, Erika A.] Washington Univ, Sch Med, Div Publ Hlth Sci, 660 S Euclid Ave,Campus,Box 8100, St Louis, MO 63110 USA. [Janssen, Eva] Maastricht Univ, Sch Publ Hlth & Primary Care Caphri, Dept Hlth Promot, Fac Hlth Med & Life Sci, NL-6200 MD Maastricht, Netherlands. [Kaufman, Annette R.] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. [Peterson, Laurel M.] Bryn Mawr Coll, Dept Psychol, Bryn Mawr, PA 19010 USA. [Muscanell, Nicole L.] Knowledge Media Res Ctr, Tubingen, Germany. [Guadagno, Rosanna E.] Univ Texas Dallas, Emerging Media & Commun, Richardson, TX 75083 USA. [Guadagno, Rosanna E.] Univ Texas Dallas, Dept Psychol, Richardson, TX 75083 USA. [Stock, Michelle L.] George Washington Univ, Dept Psychol, Washington, DC 20052 USA. RP Waters, EA (reprint author), Washington Univ, Sch Med, Div Publ Hlth Sci, 660 S Euclid Ave,Campus,Box 8100, St Louis, MO 63110 USA. EM waterse@wudosis.wustl.edu OI Waters, Erika/0000-0001-7402-0133 FU Mentored Research Scholar Grant - American Cancer Society (ACS) [MRSG-11-214-01-CBBP]; Barnes Jewish Hospital Foundation (BJHF) FX The results presented in this paper were presented as a poster at the 34th Annual Meeting of the Society of Behavioral Medicine in 2013. This research was supported by a Mentored Research Scholar Grant awarded to EW by the American Cancer Society (ACS), MRSG-11-214-01-CBBP, and the Barnes Jewish Hospital Foundation (BJHF). The funding agreement ensured the authors' independence in designing the study, interpreting the data, writing, and publishing the report. The content is solely the responsibility of the authors and does not necessarily represent the official view of the ACS or BJHF. NR 25 TC 0 Z9 0 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-8195 EI 1543-0154 J9 J CANCER EDUC JI J. Cancer Educ. PD JUN PY 2016 VL 31 IS 2 BP 338 EP 347 DI 10.1007/s13187-015-0819-y PG 10 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA DJ5YD UT WOS:000374285800020 PM 25903051 ER PT J AU Rutten, LJF Agunwamba, AA Wilson, P Chawla, N Vieux, S Blanch-Hartigan, D Arora, NK Blake, K Hesse, BW AF Rutten, Lila J. Finney Agunwamba, Amenah A. Wilson, Patrick Chawla, Neetu Vieux, Sana Blanch-Hartigan, Danielle Arora, Neeraj K. Blake, Kelly Hesse, Bradford W. TI Cancer-Related Information Seeking Among Cancer Survivors: Trends Over a Decade (2003-2013) SO JOURNAL OF CANCER EDUCATION LA English DT Article DE Cancer information; Information seeking; Health information; Cancer survivors; Cancer communication ID HEALTH-CARE PROVIDERS; COMMUNICATIONS REVOLUTION; INTERNET; NEEDS AB The demonstrated benefits of information seeking for cancer patients, coupled with increases in information availability, underscore the importance of monitoring patient information seeking experiences over time. We compared information seeking among cancer survivors to those with a family history of cancer and those with no history of cancer. We identified characteristics associated with greater information seeking among cancer survivors, key sources of cancer-related information, and changes in information source use over time. Data from five iterations of the Health Information National Trends Survey (HINTS) spanning 2003 to 2013 were merged and analyzed. Frequencies, cross-tabulations, multivariate logistic regression, and multinomial regression analyses were conducted. All data were weighted to provide representative estimates of the adult US population. Cancer information seeking was reported most frequently by cancer survivors (69.8 %). The percentage of cancer survivors who reported information seeking increased from 66.8 % in 2003 to 80.8 % in 2013. Cancer information seeking was independently associated with age, education, and income; seeking was less likely among older adults, those with less education, and those with lower incomes. Compared to respondents in 2003, those in 2005 (odds ratio (OR) = 0.40, 95 % confidence interval (CI) = 0.24-0.65) and 2008 (OR = .43, 95 % CI = 0.26-0.70) were about half as likely to use the Internet as the first source of cancer information compared to a healthcare provider. Despite overall increases in cancer information seeking and access to health information from a variety of sources, healthcare providers remain a key source of health information for cancer survivors. C1 [Rutten, Lila J. Finney; Agunwamba, Amenah A.; Wilson, Patrick] Mayo Clin, Robert D & Patricia E Kern Ctr Sci Hlth Care Deli, 200 1st St SW, Rochester, MN 55905 USA. [Chawla, Neetu] Kaiser Permanente, Div Res, Oakland, CA USA. [Vieux, Sana] PCORI, Res Evaluat & Integrat, Washington, DC USA. [Blanch-Hartigan, Danielle] Bentley Univ, Dept Nat & Appl Sci, Waltham, MA USA. [Arora, Neeraj K.; Blake, Kelly; Hesse, Bradford W.] Natl Canc Inst, Div Canc Control & Populat Sci, Bethesda, MD USA. RP Rutten, LJF (reprint author), Mayo Clin, Robert D & Patricia E Kern Ctr Sci Hlth Care Deli, 200 1st St SW, Rochester, MN 55905 USA. EM rutten.lila@mayo.edu OI Hesse, Bradford/0000-0003-1142-1161 FU Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery FX This research was supported in part by the Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery. NR 26 TC 4 Z9 4 U1 3 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-8195 EI 1543-0154 J9 J CANCER EDUC JI J. Cancer Educ. PD JUN PY 2016 VL 31 IS 2 BP 348 EP 357 DI 10.1007/s13187-015-0802-7 PG 10 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA DJ5YD UT WOS:000374285800021 ER PT J AU Lippold, MA McHale, SM Davis, KD Almeida, DM King, RB AF Lippold, Melissa A. McHale, Susan M. Davis, Kelly D. Almeida, David M. King, Rosalind B. TI Experiences With Parents and Youth Physical Health Symptoms and Cortisol: A Daily Diary Investigation SO JOURNAL OF RESEARCH ON ADOLESCENCE LA English DT Article ID DAILY STRESSORS; GENDER DIFFERENCES; ALLOSTATIC LOAD; FAMILY CONTEXTS; CHILD; DEPRESSION; LIFE; VULNERABILITY; IMPACT; ASSOCIATIONS AB Using daily diary data, this study examined the associations between positive and negative parent-youth experiences and youth cortisol and physical health symptoms among a sample of adolescents (N = 132, mean age = 13.39). On days when girls reported more negative experiences than usual, they exhibited more physical health symptoms and flatter evening cortisol slopes than usual. Negative experiences with mothers were associated with higher dinner and bedtime youth cortisol levels (between-person). Daily positive experiences with fathers were linked with lower dinner cortisol levels. Youth with high levels of negative experiences, on average, were less sensitive to daily variation in negative experiences than youth who experienced lower parental negativity. We discuss the benefits of a daily diary approach. C1 [Lippold, Melissa A.] Univ N Carolina, Tate Turner Kuralt Bldg,325 Pittsboro St CB 3550, Chapel Hill, NC 27599 USA. [McHale, Susan M.; Davis, Kelly D.; Almeida, David M.] Penn State Univ, University Pk, PA 16802 USA. [King, Rosalind B.] Natl Inst Child Hlth & Human Dev NICHD, Bethesda, MD USA. RP Lippold, MA (reprint author), Univ N Carolina, Tate Turner Kuralt Bldg,325 Pittsboro St CB 3550, Chapel Hill, NC 27599 USA. EM mlippold@unc.edu FU National Institutes of Health and the Centers for Disease Control and Prevention: Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01HD051217, U01HD051218, U01HD051256, U01HD051276]; National Institute on Aging [U01AG027669]; Office of Behavioral and Science Sciences Research; National Institute for Occupational Safety and Health [U01OH008788, U01HD059773]; William T. Grant Foundation; Alfred P. Sloan Foundation; Administration for Children and Families FX This research was conducted as part of the Work, Family and Health Network (www.WorkFamilyHealthNetwork.org), which is funded by a cooperative agreement through the National Institutes of Health and the Centers for Disease Control and Prevention: Eunice Kennedy Shriver National Institute of Child Health and Human Development (Grant #U01HD051217, U01HD051218, U01HD051256, U01HD051276), National Institute on Aging (Grant # U01AG027669), Office of Behavioral and Science Sciences Research, and National Institute for Occupational Safety and Health (Grant # U01OH008788, U01HD059773). Grants from the William T. Grant Foundation, Alfred P. Sloan Foundation, and the Administration for Children and Families have provided additional funding. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of these institutes and offices. Special acknowledgment goes to Extramural Staff Science Collaborators Rosalind Berkowitz King, Ph.D. and Lynne Casper, Ph.D. for the design of the original Workplace, Family, Health and Well-Being Network Initiative. We also wish to express our gratitude to the worksites, employers, and employees who participated in this research. Full acknowledgments: http://www.kpchr.org/wfhn NR 56 TC 1 Z9 1 U1 6 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1050-8392 EI 1532-7795 J9 J RES ADOLESCENCE JI J. Res. Adolesc. PD JUN PY 2016 VL 26 IS 2 BP 226 EP 240 DI 10.1111/jora.12186 PG 15 WC Family Studies; Psychology, Developmental SC Family Studies; Psychology GA DK2VP UT WOS:000374772800001 PM 27231418 ER PT J AU Giri, N Reed, H Stratton, P Savage, S Alter, B AF Giri, Neelam Reed, Helen Stratton, Pamela Savage, Sharon Alter, Blanche TI PREGNANCY OUTCOMES AMONG MOTHERS OF PATIENTS WITH INHERITED BONE MARROW FAILURE SYNDROMES SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Giri, Neelam; Reed, Helen; Stratton, Pamela; Savage, Sharon; Alter, Blanche] NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2016 VL 63 SU 1 MA 681 BP S60 EP S60 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA DJ6FW UT WOS:000374306900209 ER PT J AU Gross, A Akshintala, S Dombi, E Baldwin, A Ukwuani, S Goodwin, A Liewehr, D Steinberg, S Widemann, B AF Gross, Andrea Akshintala, Srivandana Dombi, Eva Baldwin, Andrea Ukwuani, Somto Goodwin, Anne Liewehr, David Steinberg, Seth Widemann, Brigitte TI ASSOCIATION OF CLINICAL MORBIDITIES AND PLEXIFORM NEUROFIBROMA VOLUME CHANGES IN NEUROFIBROMATOSIS TYPE 1 SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Gross, Andrea; Akshintala, Srivandana; Dombi, Eva; Baldwin, Andrea; Ukwuani, Somto; Goodwin, Anne; Liewehr, David; Steinberg, Seth; Widemann, Brigitte] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2016 VL 63 SU 1 MA 680 BP S59 EP S59 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA DJ6FW UT WOS:000374306900208 ER PT J AU Khincha, P Savage, S Alter, B Bertuch, A Giri, N Kuo, C Artandi, S Boulad, F Agarwal, S Keel, S Shimamura, A Townsley, D Simoneau, T McCaslin, C Cox, D Chaffee, S AF Khincha, Payal Savage, Sharon Alter, Blanche Bertuch, Alison Giri, Neelam Kuo, Christin Artandi, Steven Boulad, Farid Agarwal, Suneet Keel, Sioban Shimamura, Akiko Townsley, Danielle Simoneau, Tregony McCaslin, Charles Cox, Des Chaffee, Sara TI PULMONARY ARTERIOVENOUS MALFORMATIONS: AN UNCHARACTERIZED PHENOTYPE OF DYSKERATOSIS CONGENITA SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Khincha, Payal; Savage, Sharon; Alter, Blanche; Bertuch, Alison; Giri, Neelam; Kuo, Christin; Artandi, Steven; Boulad, Farid; Agarwal, Suneet; Keel, Sioban; Shimamura, Akiko; Townsley, Danielle; Simoneau, Tregony; McCaslin, Charles; Cox, Des; Chaffee, Sara] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2016 VL 63 SU 1 MA 683 BP S60 EP S60 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA DJ6FW UT WOS:000374306900211 ER PT J AU Nomura, SJO Inoue-Choi, M Lazovich, D Robien, K AF Nomura, Sarah J. O. Inoue-Choi, Maki Lazovich, Deann Robien, Kim TI WCRF/AICR recommendation adherence and breast cancer incidence among postmenopausal women with and without non-modifiable risk factors SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE breast cancer; diet; body weight; physical activity; cancer prevention ID RESEARCH FUND/AMERICAN INSTITUTE; FOOD FREQUENCY QUESTIONNAIRE; MODERATE ALCOHOL-CONSUMPTION; PHYSICAL-ACTIVITY; PREVENTION GUIDELINES; PROSPECTIVE COHORT; RECEPTOR STATUS; FAMILY-HISTORY; LIFE-STYLE; MORTALITY AB Taller height, family history of breast cancer, greater number of years of potential fertility and nulliparity are established non-modifiable risk factors for postmenopausal breast cancer. Greater adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) diet, physical activity and body weight recommendations has previously been shown to be associated with lower breast cancer risk. However, no prior studies have evaluated whether women with non-modifiable risk factors receive similar benefits from recommendation adherence compared to women without these risk factors. In the Iowa Women's Health Study prospective cohort, we investigated whether associations of WCRF/AICR recommendation adherence differed by the presence/absence of non-modifiable breast cancer risk factors. Baseline (1986) questionnaire data from 36,626 postmenopausal women were used to create adherence scores for the WCRF/AICR recommendations (maximum score = 8.0). Overall and single recommendation adherence in relation to breast cancer risk (n = 3,189 cases) across levels of non-modifiable risk factors were evaluated using proportional hazards regression. Mean adherence score was 5.0 points (range: 0.5-8.0). Higher adherence scores (score >= 6.0 vs. <= 3.5, HR = 0.76, 95% CI = 0.67-0.87), and adherence to the individual recommendations for body weight and alcohol intake were associated with a lower breast cancer incidence. While not statistically significant among women with more non-modifiable risk factors (score >= 6.0 vs. <= 3.5, HR = 0.76, 95% CI = 0.36-1.63), hazard ratios were comparable to women with the no non-modifiable risk factors (score >= 6.0 vs. <= 3.5, HR 5 0.74, 95% CI = 0.49-0.93) (p-interaction = 0.57). WCRF/AICR recommendation adherence is associated with lower breast cancer risk, regardless of non-modifiable risk factor status. C1 [Nomura, Sarah J. O.] Georgetown Univ, Georgetown Lombardi Comprehens Canc Ctr, Off Minor Hlth & Hlth Dispar Res, Washington, DC 20003 USA. [Inoue-Choi, Maki] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Lazovich, Deann] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Lazovich, Deann] Masonic Canc Ctr, Prevent & Etiol Program, Minneapolis, MN USA. [Robien, Kim] George Washington Univ, Milken Inst Sch Publ Hlth, Dept Exercise & Nutr Sci, Washington, DC USA. RP Nomura, SJO (reprint author), Georgetown Univ, Lombardi Comprehens Canc Ctr, 1000 New Jersey Ave SE, Washington, DC 20003 USA. EM sjo36@georgetown.edu OI Robien, Kim/0000-0002-2120-2280 FU National Cancer Institute [R01 CA039742, T32 CA132670] FX Grant sponsor: National Cancer Institute; Grant number: R01 CA039742; Grant sponsor: National Cancer Institute; Grant number: T32 CA132670 NR 50 TC 7 Z9 7 U1 3 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD JUN 1 PY 2016 VL 138 IS 11 BP 2602 EP 2615 DI 10.1002/ijc.29994 PG 14 WC Oncology SC Oncology GA DH6PN UT WOS:000372913400006 PM 26756307 ER PT J AU Zhao, FH Hu, SY Zhang, Q Zhang, X Pan, QJ Zhang, WH Gage, JC Wentzensen, N Castle, PE Qiao, YL Katki, HA Schiffman, M AF Zhao, Fang-Hui Hu, Shang-Ying Zhang, Qian Zhang, Xun Pan, Qin-Jing Zhang, Wen-Hua Gage, Julia C. Wentzensen, Nicolas Castle, Philip E. Qiao, You-Lin Katki, Hormuzd A. Schiffman, Mark TI Risk assessment to guide cervical screening strategies in a large Chinese population SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE risk assessment; cervical screening; cytology; HPV DNA testing; VIA ID HUMAN-PAPILLOMAVIRUS; POOLED ANALYSIS; INTRAEPITHELIAL NEOPLASIA; CLINICAL MANAGEMENT; CANCER PREVENTION; POSITIVE WOMEN; FOLLOW-UP; HPV; CYTOLOGY; PAPANICOLAOU AB Three different cervical screening methods [cytology, human papillomavirus(HPV) testing and visual inspection with acetic acid(VIA)] are being considered in China for the national cervical screening program. Comparing risks of CIN3 and cervical cancer (CIN3+) for different results can inform test choice and management guidelines. We evaluated the immediate risk of CIN3+ for different screening results generated from individual and combined tests. We compared tests using a novel statistic designed for this purpose called Mean Risk Stratification (MRS), in a pooled analysis of 17 cross sectional population-based studies of 30,371Chinese women screened with all 3 methods and diagnosed by colposcopically-directed biopsies. The 3 tests combined powerfully distinguished CIN3+ risk; triple-negative screening conferred a risk of 0.01%, while HPV-positive HSIL+ that was VIA-positive yielded a risk of 57.8%. Among the three screening tests, HPV status most strongly stratified CIN3+ risk. Among HPV-positive women, cytology was the more useful second test. In HPV-negative women, the immediate risks of CIN3+ ranged from 0.01% (negative cytology), 0.00% (ASC-US), 1.1% (LSIL), to 6.6 (HSIL+). In HPV-positive women, the CIN3+ risks were 0.9% (negative cytology), 3.6% (ASC-US), 6.3% (LSIL) and 38.5% (HSIL+). VIA results did not meaningful stratify CIN3+ risk among HPV-negative women with negative or ASC-US cytology; however, positive VIA substantially elevated CIN3+ risk for all other, more positive combinations of HPV and cytology compared with a negative VIA. Because all 3 screening tests had independent value in defining risk of CIN3+, different combinations can be optimized as pragmatic strategies in different resource settings. C1 [Zhao, Fang-Hui; Hu, Shang-Ying; Zhang, Qian; Zhang, Xun; Pan, Qin-Jing; Zhang, Wen-Hua; Qiao, You-Lin] Chinese Acad Med Sci, Canc Hosp, Beijing 100021, Peoples R China. [Zhao, Fang-Hui; Hu, Shang-Ying; Zhang, Qian; Zhang, Xun; Pan, Qin-Jing; Zhang, Wen-Hua; Qiao, You-Lin] Peking Union Med Coll, 17 South Panjiayuan Lane,POB 2258, Beijing 100021, Peoples R China. [Zhao, Fang-Hui; Gage, Julia C.; Wentzensen, Nicolas; Katki, Hormuzd A.; Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Castle, Philip E.] Albert Einstein Coll Med, Bronx, NY 10467 USA. RP Zhao, FH; Qiao, YL (reprint author), Peking Union Med Coll, 17 South Panjiayuan Lane,POB 2258, Beijing 100021, Peoples R China.; Zhao, FH; Qiao, YL (reprint author), Chinese Acad Med Sci, Canc Hosp, Natl Canc Ctr, 17 South Panjiayuan Lane,POB 2258, Beijing 100021, Peoples R China. EM zhaofangh@cicams.ac.cn; qiaoy@cicams.ac.cn RI Qiao, You-Lin/B-4139-2012 OI Qiao, You-Lin/0000-0001-6380-0871 FU National Natural Science of Foundation of China [81322040] FX Grant sponsor: National Natural Science of Foundation of China; Grant number: 81322040 NR 35 TC 3 Z9 4 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD JUN 1 PY 2016 VL 138 IS 11 BP 2639 EP 2647 DI 10.1002/ijc.30012 PG 9 WC Oncology SC Oncology GA DH6PN UT WOS:000372913400010 PM 26800481 ER PT J AU Shirakawa, K Wang, L Man, N Maksimoska, J Sorum, AW Lim, HW Lee, IS Shimazu, T Newman, JC Schroder, S Ott, M Marmorstein, R Meier, J Nimer, S Verdin, E AF Shirakawa, Kotaro Wang, Lan Man, Na Maksimoska, Jasna Sorum, Alexander W. Lim, Hyung W. Lee, Intelly S. Shimazu, Tadahiro Newman, John C. Schroder, Sebastian Ott, Melanie Marmorstein, Ronen Meier, Jordan Nimer, Stephen Verdin, Eric TI Salicylate, diflunisal and their metabolites inhibit CBP/p300 and exhibit anticancer activity SO ELIFE LA English DT Article ID ACTIVATED PROTEIN-KINASE; NF-KAPPA-B; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; TRANSCRIPTIONAL COACTIVATOR P300; SODIUM-SALICYLATE; HISTONE ACETYLTRANSFERASE; INDUCIBLE CYCLOOXYGENASE; RANDOMIZED-TRIAL; TERMINAL KINASE; G1/S TRANSITION AB Salicylate and acetylsalicylic acid are potent and widely used anti-inflammatory drugs. They are thought to exert their therapeutic effects through multiple mechanisms, including the inhibition of cyclo-oxygenases, modulation of NF-kappa B activity, and direct activation of AMPK. However, the full spectrum of their activities is incompletely understood. Here we show that salicylate specifically inhibits CBP and p300 lysine acetyltransferase activity in vitro by direct competition with acetyl-Coenzyme A at the catalytic site. We used a chemical structure-similarity search to identify another anti-inflammatory drug, diflunisal, that inhibits p300 more potently than salicylate. At concentrations attainable in human plasma after oral administration, both salicylate and diflunisal blocked the acetylation of lysine residues on histone and non-histone proteins in cells. Finally, we found that diflunisal suppressed the growth of p300-dependent leukemia cell lines expressing AML1-ETO fusion protein in vitro and in vivo. These results highlight a novel epigenetic regulatory mechanism of action for salicylate and derivative drugs. C1 [Shirakawa, Kotaro; Lim, Hyung W.; Lee, Intelly S.; Shimazu, Tadahiro; Newman, John C.; Schroder, Sebastian; Ott, Melanie; Verdin, Eric] Univ Calif San Francisco, Gladstone Inst, San Francisco, CA 94143 USA. [Shirakawa, Kotaro; Lim, Hyung W.; Lee, Intelly S.; Shimazu, Tadahiro; Newman, John C.; Schroder, Sebastian; Ott, Melanie; Verdin, Eric] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Shirakawa, Kotaro] Kyoto Univ, Dept Hematol & Oncol, Kyoto, Japan. [Shirakawa, Kotaro] Kyoto Univ, Grad Sch Med, Kyoto, Japan. [Wang, Lan; Man, Na; Nimer, Stephen] Univ Miami, Gables, FL USA. [Wang, Lan; Man, Na; Nimer, Stephen] Sylvester Comprehens Canc Ctr, Miami, FL USA. [Maksimoska, Jasna; Marmorstein, Ronen] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Maksimoska, Jasna; Marmorstein, Ronen] Abramson Family Canc Res Inst, Dept Biochem & Biophys, Philadelphia, PA USA. [Sorum, Alexander W.; Meier, Jordan] NCI, Biol Chem Lab, Frederick, MD 21701 USA. RP Verdin, E (reprint author), Univ Calif San Francisco, Gladstone Inst, San Francisco, CA 94143 USA.; Verdin, E (reprint author), Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. EM everdin@gladstone.ucsf.edu FU National Institutes of Health [AI083139-02]; UCSF Gladstone Institute of Virology & Immunology Center for AIDS research [NIA 5T32AG000212-20]; University of California Berkeley Fogarty International AIDS Training Program; American Cancer Society; Larry L. Hillblom Foundation; Jonh A. Hartford Foundation; UCSF Geriatric Research Training Program FX National Institutes of Health AI083139-02 Melanie Ott Kotaro Shirakawa; UCSF Gladstone Institute of Virology & Immunology Center for AIDS research NIA 5T32AG000212-20 Kotaro Shirakawa; University of California Berkeley Fogarty International AIDS Training Program Kotaro Shirakawa; American Cancer Society Lan Wang; Larry L. Hillblom Foundation John C Newman; Jonh A. Hartford Foundation John C Newman; UCSF Geriatric Research Training Program John C Newman; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 48 TC 5 Z9 5 U1 3 U2 3 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD MAY 31 PY 2016 VL 5 AR e11156 DI 10.7554/eLife.11156 PG 17 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DS0IG UT WOS:000380278300001 ER PT J AU Derks, S Liao, XY Chiaravalli, AM Xu, XS Camargo, MC Solcia, E Sessa, F Fleitas, T Freeman, GJ Rodig, SJ Rabkin, CS Bass, AJ AF Derks, Sarah Liao, Xiaoyun Chiaravalli, Anna M. Xu, Xinsen Camargo, M. Constanza Solcia, Enrico Sessa, Fausto Fleitas, Tania Freeman, Gordon J. Rodig, Scott J. Rabkin, Charles S. Bass, Adam J. TI Abundant PD-L1 expression in Epstein-Barr Virus-infected gastric cancers SO ONCOTARGET LA English DT Article DE EBV-infected gastric cancers; MSI gastric cancer; PD-L1; PD-1 inhibitors ID T-CELLS; BLOCKADE; RECEPTOR; ACTIVATION; LYMPHOMAS; TUMORS; EBV AB Gastric cancer (GC) is a deadly disease with limited treatment options. Recent studies with PD-1 inhibition have shown promising results in GC, but key questions remain regarding which GC subclass may respond best. In other cancers, expression of the PD-1 ligand PD-L1 has been shown to identify cancers with greater likelihood of response to PD-1 blockade. We here show with immunohistochemistry that Epstein-Barr Virus (EBV) + GCs (n = 32) have robust PD-L1 expression not seen in other GCs. In EBV+ GC, we observed PD-L1 staining in tumor cells in 50% (16/32) and immune cells in 94% (30/32) of cases. Among EBV-negative GCs, PD-L1 expression within tumors cells was observed only in cases with microsatellite instability (MSI), although 35% of EBV-/MSS GCs possessed PD-L1 expression of inflammatory cells. Moreover, distinct classes of GC showed different patterns of PD-L1+ immune cell infiltrations. In both EBV+ and MSI tumors, PD-L1+ inflammatory cells were observed to infiltrate the tumor. By contrast, such cells remained at the tumor border of EBV-/MSS GCs. Consistent with these findings, we utilized gene expression profiling of GCs from The Cancer Genome Atlas study to demonstrate that an interferon-gamma driven gene signature, an additional proposed marker of sensitivity to PD-1 therapy, were enriched in EBV+ and MSI GC. These data suggest that patients with EBV+ and MSI GC may have greater likelihood of response to PD-1 blockade and that EBV and MSI status should be evaluated as variables in clinical trials of these emerging inhibitors. C1 [Derks, Sarah; Liao, Xiaoyun; Xu, Xinsen; Fleitas, Tania; Freeman, Gordon J.; Bass, Adam J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Derks, Sarah] Vrije Univ Amsterdam, Med Ctr, Dept Med Oncol, Amsterdam, Netherlands. [Liao, Xiaoyun; Rodig, Scott J.] Dana Farber Canc Inst, Ctr Immunooncol, Boston, MA 02115 USA. [Chiaravalli, Anna M.; Sessa, Fausto] Osped Circolo Varese, Dept Pathol, Varese, Italy. [Camargo, M. Constanza; Rabkin, Charles S.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Solcia, Enrico] Univ Pavia, Dept Mol Med, Via Palestro 3, I-27100 Pavia, Italy. [Solcia, Enrico] Policlin San Matteo, Pavia, Italy. [Fleitas, Tania] Hosp Clin Univ Valencia, Dept Med Oncol, Valencia, Spain. [Rodig, Scott J.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Bass, Adam J.] Broad Inst MIT & Harvard, Canc Program, Cambridge, MA USA. RP Bass, AJ (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.; Bass, AJ (reprint author), Broad Inst MIT & Harvard, Canc Program, Cambridge, MA USA. EM adam_bass@dfci.harvard.edu RI Camargo, M. Constanza/R-9891-2016 FU Dutch Cancer Society [VU 2012-535]; Center of Immune Oncology at Dana-Farber Cancer Institute [R01AI089955]; Target Cancer Foundation; Schottenstein Fund for Stomach Cancer Research FX The project described was supported by the Dutch Cancer Society (VU 2012-535) (SD), the Center of Immune Oncology at Dana-Farber Cancer Institute (XL and SJR), R01AI089955 (GJF) and Target Cancer Foundation and The Schottenstein Fund for Stomach Cancer Research (to AJB). NR 24 TC 5 Z9 5 U1 2 U2 6 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAY 31 PY 2016 VL 7 IS 22 BP 32925 EP 32932 DI 10.18632/oncotarget.9076 PG 8 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO4JP UT WOS:000377748500101 PM 27147580 ER PT J AU Beedie, SL Rore, HM Barnett, S Chau, CH Luo, WM Greig, NH Figg, WD Vargesson, N AF Beedie, Shaunna L. Rore, Holly M. Barnett, Shelby Chau, Cindy H. Luo, Weiming Greig, Nigel H. Figg, William D. Vargesson, Neil TI In vivo screening and discovery of novel candidate thalidomide analogs in the zebrafish embryo and chicken embryo model systems SO ONCOTARGET LA English DT Article DE angiogenesis; inflammation; thalidomide; cancer; teratogenesis ID NECROSIS-FACTOR-ALPHA; REFRACTORY MULTIPLE-MYELOMA; TNF-ALPHA; SYNTHESIS INHIBITOR; TRANSGENIC ZEBRAFISH; COGNITIVE DEFICITS; ALZHEIMERS-DISEASE; LIMB DEFECTS; ANGIOGENESIS; POMALIDOMIDE AB Thalidomide, a drug known for its teratogenic side-effects, is used successfully to treat a variety of clinical conditions including leprosy and multiple myeloma. Intense efforts are underway to synthesize and identify safer, clinically relevant analogs. Here, we conduct a preliminary in vivo screen of a library of new thalidomide analogs to determine which agents demonstrate activity, and describe a cohort of compounds with anti-angiogenic properties, anti-inflammatory properties and some compounds which exhibited both. The combination of the in vivo zebrafish and chicken embryo model systems allows for the accelerated discovery of new, potential therapies for cancerous and inflammatory conditions. C1 [Beedie, Shaunna L.; Rore, Holly M.; Barnett, Shelby; Vargesson, Neil] Univ Aberdeen, Inst Med Sci, Sch Med Med Sci & Nutr, Foresterhill, Aberdeen, Scotland. [Beedie, Shaunna L.; Chau, Cindy H.; Figg, William D.] NCI, Mol Pharmacol Sect, Genitourinary Malignancies Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Luo, Weiming; Greig, Nigel H.] NIA, Drug Design & Dev Sect, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Barnett, Shelby] Univ Manchester, Manchester Pharm Sch, Ctr Appl Pharmacokinet Res, Manchester, Lancs, England. RP Vargesson, N (reprint author), Univ Aberdeen, Inst Med Sci, Sch Med Med Sci & Nutr, Foresterhill, Aberdeen, Scotland.; Figg, WD (reprint author), NCI, Mol Pharmacol Sect, Genitourinary Malignancies Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM figgw@helix.nih.gov; n.vargesson@abdn.ac.uk RI Figg Sr, William/M-2411-2016; OI Vargesson, Neil/0000-0001-8027-114X FU Wellcome Trust-NIH [098252/Z/12/Z]; Intramural Research Program, NCI, NIH; Intramural Research Program, NIA, NIH FX This study was supported by a Wellcome Trust-NIH PhD Studentship to SB, WDF and NV. Grant number 098252/Z/12/Z. SB, CHC and WDF are supported by the Intramural Research Program, NCI, NIH. NHG and WL are supported by the Intramural Research Program, NIA, NIH. NR 52 TC 1 Z9 1 U1 0 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAY 31 PY 2016 VL 7 IS 22 BP 33237 EP 33245 DI 10.18632/oncotarget.8909 PG 9 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO4JP UT WOS:000377748500128 PM 27120781 ER PT J AU Byeon, IJL Byeon, CH Wu, TY Mitra, M Singer, D Levin, JG Gronenborn, AM AF Byeon, In-Ja L. Byeon, Chang-Hyeock Wu, Tiyun Mitra, Mithun Singer, Dustin Levin, Judith G. Gronenborn, Angela M. TI Nuclear Magnetic Resonance Structure of the APOBEC3B Catalytic Domain: Structural Basis for Substrate Binding and DNA Deaminase Activity SO BIOCHEMISTRY LA English DT Article ID SINGLE-STRANDED-DNA; INHIBIT LINE-1 RETROTRANSPOSITION; RESTRICTION FACTOR APOBEC3G; LEUKEMIA-VIRUS TYPE-1; HIV-1 VIF-BINDING; CYTIDINE DEAMINASE; CRYSTAL-STRUCTURE; CYTOSINE DEAMINASE; BREAST-CANCER; DELETION POLYMORPHISM AB Human APOBEC3B (A3B) is a member of the APOBEC3 (A3) family of cytidine deaminases, which function as DNA mutators and restrict viral pathogens and endogenous retrotransposons. Recently, A3B was identified as a major source of genetic heterogeneity in several human cancers. Here, we determined the solution nuclear magnetic resonance structure of the catalytically active C-terminal domain (CTD) of MB and performed detailed analyses of its deaminase activity. The core of the structure comprises a central five stranded beta-sheet with six surrounding helices, common to all A3 proteins. The structural fold is most similar to that of A3A and A3G-CTD, with the most prominent difference being found in loop 1. The catalytic activity of A3B-CTD is similar to 15-fold lower than that of A3A, although both exhibit a similar pH dependence. Interestingly, A3B-CTD with an A3A loop 1 substitution had significantly increased deaminase activity, while a single-residue change (H29R) in A3A loop 1 reduced MA activity to the level seen with A3B-CTD. This establishes that loop 1 plays an important role in A3-catalyzed deamination by precisely positioning the deamination-targeted C into the active site. Overall, our data provide important insights into the determinants of the activities of individual A3 proteins and facilitate understanding of their biological function. C1 [Byeon, In-Ja L.; Byeon, Chang-Hyeock; Gronenborn, Angela M.] Univ Pittsburgh, Sch Med, Dept Biol Struct, Pittsburgh, PA 15260 USA. [Byeon, In-Ja L.; Byeon, Chang-Hyeock; Gronenborn, Angela M.] Univ Pittsburgh, Sch Med, Pittsburgh Ctr HIV Prot Interact, Pittsburgh, PA 15260 USA. [Wu, Tiyun; Mitra, Mithun; Singer, Dustin; Levin, Judith G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Viral Gene Regulat, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Mitra, Mithun] Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA. RP Gronenborn, AM (reprint author), Univ Pittsburgh, Sch Med, Dept Biol Struct, Pittsburgh, PA 15260 USA.; Gronenborn, AM (reprint author), Univ Pittsburgh, Sch Med, Pittsburgh Ctr HIV Prot Interact, Pittsburgh, PA 15260 USA.; Levin, JG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Viral Gene Regulat, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. EM levinju@mail.nih.gov; amg100@pitt.edu FU National Institutes of Health [P50GM082251]; National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This work was supported by National Institutes of Health Grant P50GM082251 (to A.M.G.) and the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development (to J.G.L.). NR 139 TC 4 Z9 4 U1 2 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAY 31 PY 2016 VL 55 IS 21 BP 2944 EP 2959 DI 10.1021/acs.biochem.6b00382 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DN5ZT UT WOS:000377151100006 PM 27163633 ER PT J AU Hu, X Compton, JR Leary, DH Olson, MA Lee, MS Cheung, J Ye, W Ferrer, M Southall, N Jadhav, A Morazzani, EM Glass, PJ Marugan, J Legler, PM AF Hu, Xin Compton, Jaimee R. Leary, Dagmar H. Olson, Mark A. Lee, Michael S. Cheung, Jonah Ye, Wenjuan Ferrer, Mark Southall, Noel Jadhav, Ajit Morazzani, Elaine M. Glass, Pamela J. Marugan, Juan Legler, Patricia M. TI Kinetic, Mutational, and Structural Studies of the Venezuelan Equine Encephalitis Virus Nonstructural Protein 2 Cysteine Protease SO BIOCHEMISTRY LA English DT Article ID PAPAIN-LIKE PROTEASE; CRYSTAL-STRUCTURE; SINDBIS-VIRUS; CATHEPSIN-B; NONCYTOPATHIC REPLICATION; RECOMBINANT PROTEINS; ESCHERICHIA-COLI; TRANSITION-STATE; MAMMALIAN-CELLS; NSP2 PROTEASE AB The Venezuelan equine encephalitis virus (VEEV) nonstructural protein 2 (nsP2) cysteine protease (EC 3.4.22.-) is essential for viral replication and is involved in the cytopathic effects (CPE) of the virus. The VEEV nsP2 protease is a member of MEROPS Clan CN and characteristically contains a papain-like protease linked to an S-adenosyl-L-methionine-dependent RNA methyltransferase (SAM MTase) domain. The protease contains an alternative active site motif, (475)NVCWAK(480), which differs from papain's (CGS(25)CWAFS), and the enzyme lacks a transition state-stabilizing residue homologous to GIn-19 in papain. To understand the roles of conserved residues in catalysis, we determined the structure of the free enzyme and the first structure of an inhibitor-bound alphaviral protease. The peptide-like E64d inhibitor was found to bind beneath a beta-hairpin at the interface of the SAM MTase and protease domains. His-546 adopted a conformation that differed from that found in the free enzyme; one or both of the conformers may assist in leaving group departure of either the amine or Cys thiolate during the catalytic cycle. Interestingly, E64c (200 mu M), the carboxylic acid form of the E64d ester, did not inhibit the nsP2 protease. To identify key residues involved in substrate binding, a number of mutants were analyzed. Mutation of the motif residue, N475A, led to a 24 fold reduction in k(cat)/K-m, and the conformation of this residue did not change after inhibition. N475 forms a hydrogen bond with R662 in the SAM MTase domain, and the R662A and R662K mutations both led to 16-fold decreases in k(cat)/K-m. N475 forms the base of the P1 binding site and likely orients the substrate for nucleophilic attack or plays a role in product release. An Asn homologous to N475 is similarly found in coronaviral papain-like proteases (PLpro) of the Severe Acute Respiratory Syndrome (SARS) virus and Middle East Respiratory Syndrome (MERS) virus. Mutation of another motif residue, K480A, led to a 9-fold decrease in k(cat) and k(cat)/K-m. K480 likely enhances the nucleophilicity of the Cys. Consistent with our substrate-bound models, the SAM MTase domain K706A mutation increased K-m 4.5-fold to 500 mu M. Within the beta-hairpin, the N545A mutation slightly but not significantly increased k(cat) and K-m. The structures and identified active site residues may facilitate the discovery of protease inhibitors with antiviral activity. C1 [Hu, Xin; Ye, Wenjuan; Ferrer, Mark; Southall, Noel; Jadhav, Ajit; Marugan, Juan] NIH, Chem Genom Ctr, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Compton, Jaimee R.] Nova Res Inc, Alexandria, VA 22308 USA. [Cheung, Jonah] New York Struct Biol Ctr, New York, NY 10027 USA. [Olson, Mark A.; Lee, Michael S.; Morazzani, Elaine M.; Glass, Pamela J.] US Army, Med Res Inst Infect Dis, Frederick, MD 21702 USA. [Legler, Patricia M.] US Navy, Res Lab, Ctr Biomol Sci & Engn, Washington, DC 20375 USA. RP Legler, PM (reprint author), US Navy, Res Lab, Ctr Biomol Sci & Engn, Washington, DC 20375 USA. EM patricialegler@nrl.navy.mil FU DTRA [CB-SEED-SEED09-2-0061, CBCall4-CBM-05-2-0019] FX This work was supported by DTRA Projects CB-SEED-SEED09-2-0061 and CBCall4-CBM-05-2-0019. NR 75 TC 1 Z9 1 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAY 31 PY 2016 VL 55 IS 21 BP 3007 EP 3019 DI 10.1021/acs.biochem.5b00992 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DN5ZT UT WOS:000377151100011 PM 27030368 ER PT J AU Gilman, SE Cherkerzian, S Buka, SL Hahn, J Hornig, M Goldstein, JM AF Gilman, S. E. Cherkerzian, S. Buka, S. L. Hahn, J. Hornig, M. Goldstein, J. M. TI Prenatal immune programming of the sex-dependent risk for major depression SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID PITUITARY-ADRENAL AXIS; MULTIPLE-SCLEROSIS; MATERNAL INFECTION; INFLUENZA EPIDEMIC; BRAIN-DEVELOPMENT; FETAL-BRAIN; STRESS; PREGNANCY; EXPOSURE; ACTIVATION AB Maternal immune functioning during pregnancy contributes to sex-dependent deficits in neurodevelopment and to behaviors associated with affective traits in preclinical studies, and has been indirectly associated with offspring depression in epidemiologic studies. We therefore investigated the association between immune activity during pregnancy and the risk of depression among male and female offspring. We conducted a case-control study of depression (n=484 cases and n=774 controls) using data from the New England Family Study, a pregnancy cohort enrolled between 1959 and 1966 that assessed psychiatric outcomes in adult offspring (mean age = 39.7 years). We assayed concentrations of three pro-inflammatory cytokines, interleukin (IL)-1 beta, IL-6 and tumor necrosis factor (TNF)-alpha, and the anti-inflammatory cytokine, IL-10, in maternal serum collected at the end of the second and beginning of the third trimesters. High maternal TNF-alpha was associated with reduced odds of depression among both male and female offspring (odds ratio (OR) = 0.68; confidence interval (CI)=0.48, 0.98). However, when considering the TNF-alpha to IL-10 ratio, a measure of the ratio of pro-to anti-inflammatory loading, maternal immune effects on offspring depression differed significantly by sex (chi(2) = 13.9, degrees of freedom = 4, P=0.008). Among females, higher maternal TNF-alpha: IL-10 was associated with reduced odds of depression (OR = 0.51; CI=0.32, 0.81), whereas, among males, high maternal TNF-alpha: IL-10 was associated with elevated odds of depression (OR = 1.86; CI=1.02, 3.39). Thus, the balance between TNF-alpha and IL-10 in maternal prenatal serum was associated with depression in a sex-dependent manner. These findings are consistent with the role of TNF-alpha in the maturation of the sexually dimorphic fetal brain circuitry that regulates stress and affective responses, and support a prenatal stress-immune model of depression pathogenesis. C1 [Gilman, S. E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Hlth Behav Branch, Div Intramural Populat Hlth Res, 6100 Executive Blvd,Room 7B13M, Rockville, MD 20852 USA. [Gilman, S. E.; Hahn, J.] Harvard Univ, Dept Social & Behav Sci, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Gilman, S. E.] Harvard Univ, Dept Epidemiol, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Gilman, S. E.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Cherkerzian, S.; Goldstein, J. M.] Connors Ctr Womens Hlth & Gender Biol, Boston, MA USA. [Cherkerzian, S.; Goldstein, J. M.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Cherkerzian, S.; Goldstein, J. M.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Buka, S. L.] Brown Univ, Dept Epidemiol, Sch Publ Hlth, Providence, RI 02912 USA. [Hornig, M.] Columbia Univ, Ctr Infect & Immun, Mailman Sch Publ Hlth, New York, NY USA. [Hornig, M.] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA. [Goldstein, J. M.] Massachusetts Gen Hosp, Div Psychiat Neurosci, Boston, MA 02114 USA. RP Gilman, SE (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Hlth Behav Branch, Div Intramural Populat Hlth Res, 6100 Executive Blvd,Room 7B13M, Rockville, MD 20852 USA.; Gilman, SE (reprint author), Harvard Univ, Dept Social & Behav Sci, TH Chan Sch Publ Hlth, Boston, MA 02115 USA.; Gilman, SE (reprint author), Harvard Univ, Dept Epidemiol, TH Chan Sch Publ Hlth, Boston, MA 02115 USA.; Gilman, SE (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. EM stephen.gilman@nih.gov OI Gilman, Stephen/0000-0002-8331-6419 FU National Institute of Mental Health [P50MH082679, R01MH07467, R01MH090291, R01MH087544]; Office for Research on Women's Health; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX We appreciate the contributions of Stuart Tobet and Robert Handa (Co-Principal Investigators of P50 MH082679) for work on sexual differentiation; Anne Remington, JoAnn Donatelli, Harlyn Aizley and Jennifer Walch for data collection and study coordination; and Kathleen McGaffigan for her expertise in data management and statistical analysis. This work was supported in part by grants P50MH082679, R01MH07467 and R01MH090291 (JMG, Principal Investigator), and R01MH087544 (SEG, Principal Investigator) from the National Institute of Mental Health and Office for Research on Women's Health and by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 58 TC 3 Z9 3 U1 6 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD MAY 31 PY 2016 VL 6 AR e822 DI 10.1038/tp.2016.91 PG 8 WC Psychiatry SC Psychiatry GA DN8CK UT WOS:000377306600001 PM 27244231 ER PT J AU Tomasi, D Wang, GJ Volkow, ND AF Tomasi, D. Wang, G-J Volkow, N. D. TI Association between striatal dopamine D-2/D-3 receptors and brain activation during visual attention: effects of sleep deprivation SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID ANTERIOR CINGULATE CORTEX; DEFAULT MODE NETWORK; WORKING-MEMORY; RESPONSE-INHIBITION; PARKINSONS-DISEASE; VENTRAL STRIATUM; COCAINE ABUSERS; COGNITIVE IMPAIRMENT; SELECTIVE ATTENTION; EXECUTIVE FUNCTIONS AB Sleep deprivation (SD) disrupts dopamine (DA) signaling and impairs attention. However, the interpretation of these concomitant effects requires a better understanding of dopamine's role in attention processing. Here we test the hypotheses that D-2/D-3 receptors (D-2/D3R) in dorsal and ventral striatum would distinctly regulate the activation of attention regions and that, by decreasing D-2/D-3, SD would disrupt these associations. We measured striatal D-2/D3R using positron emission tomography with [C-11] raclopride and brain activation to a visual attention (VA) task using 4-Tesla functional magnetic resonance imaging. Fourteen healthy men were studied during rested wakefulness and also during SD. Increased D-2/D3R in striatum (caudate, putamen and ventral striatum) were linearly associated with higher thalamic activation. Subjects with higher D-2/D3R in caudate relative to ventral striatum had higher activation in superior parietal cortex and ventral precuneus, and those with higher D-2/D3R in putamen relative to ventral striatum had higher activation in anterior cingulate. SD impaired the association between striatal D-2/D3R and VA-induced thalamic activation, which is essential for alertness. Findings suggest a robust DAergic modulation of cortical activation during the VA task, such that D-2/D3R in dorsal striatum counterbalanced the stimulatory influence of D-2/D3R in ventral striatum, which was not significantly disrupted by SD. In contrast, SD disrupted thalamic activation, which did not show counterbalanced DAergic modulation but a positive association with D-2/D3R in both dorsal and ventral striatum. The counterbalanced dorsal versus ventral striatal DAergic modulation of VA activation mirrors similar findings during sensorimotor processing (Tomasi et al., 2015) suggesting a bidirectional influence in signaling between the dorsal caudate and putamen and the ventral striatum. C1 [Tomasi, D.; Wang, G-J; Volkow, N. D.] NIAAA, 10 Ctr Dr,Room B2L124, Bethesda, MD 20892 USA. [Volkow, N. D.] NIDA, Bethesda, MD 20892 USA. RP Tomasi, D (reprint author), NIAAA, 10 Ctr Dr,Room B2L124, Bethesda, MD 20892 USA. EM tomasidg@mail.nih.gov FU National Institute of Health's Intramural Research Program (National Institute on Alcohol Abuse and Alcoholism) [Y1AA-3009, DE-AC02-98CH10886] FX We thank Lisa Muench, Colleen Shea, Joanna Fowler and Youwen Xu for radiopharmaceutical preparation and quality control; Millard Jayne, Yana Studentsova, Frank Telang, Pauline Carter and Barbara Hubbard for subject care and protocol oversight; Karen Apelskog for protocol coordination; Michael Schueller for cyclotron operations; Dave Alexoff and Jean Logan for pharmacokinetic modeling and Ruiliang Wang for MRI data acquisition. We also thank the subjects who volunteered to participate in this study. The research was supported by the National Institute of Health's Intramural Research Program (National Institute on Alcohol Abuse and Alcoholism; Y1AA-3009) using infrastructure of Brookhaven National Laboratory under Contract DE-AC02-98CH10886. NR 119 TC 1 Z9 1 U1 3 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD MAY 31 PY 2016 VL 6 AR e828 DI 10.1038/tp.2016.93 PG 12 WC Psychiatry SC Psychiatry GA DN8CK UT WOS:000377306600007 PM 27244237 ER PT J AU Claps, G Cheli, Y Zhang, TW Scortegagna, M Lau, E Kim, H Qi, JF Li, JL James, B Dzung, A Levesque, MP Dummer, R Hayward, NK Bosenberg, M Brown, KM Ronai, ZA AF Claps, Giuseppina Cheli, Yann Zhang, Tongwu Scortegagna, Marzia Lau, Eric Kim, Hyungsoo Qi, Jianfei Li, Jian-Liang James, Brian Dzung, Andreas Levesque, Mitchell P. Dummer, Reinhard Hayward, Nicholas K. Bosenberg, Marcus Brown, Kevin M. Ronai, Ze'ev A. TI A Transcriptionally Inactive ATF2 Variant Drives Melanomagenesis SO CELL REPORTS LA English DT Article ID METASTASIS; GROWTH; INHIBITION; APOPTOSIS; SURVIVAL; FACTOR-2; CANCER; CELLS; PDK1 AB Melanoma is one of the most lethal cutaneous malignancies, characterized by chemoresistance and a striking propensity to metastasize. The transcription factor ATF2 elicits oncogenic activities in melanoma, and its inhibition attenuates melanoma development. Here, we show that expression of a transcriptionally inactive form of Atf2 (Atf2(Delta 8,9)) promotes development of melanoma in mouse models. Atf2(Delta 8,9)-driven tumors show enhanced pigmentation, immune infiltration, and metastatic propensity. Similar to mouse Atf2(Delta 8,9), we have identified a transcriptionally inactive human ATF2 splice variant 5 (ATF2(SV5)) that enhances the growth and migration capacity of cultured melanoma cells and immortalized melanocytes. ATF2(SV5) expression is elevated in human melanoma specimens and is associated with poor prognosis. These findings point to an oncogenic function for ATF2 in melanoma development that appears to be independent of its transcriptional activity. C1 [Claps, Giuseppina; Cheli, Yann; Scortegagna, Marzia; Lau, Eric; Kim, Hyungsoo; Qi, Jianfei; Li, Jian-Liang; James, Brian; Ronai, Ze'ev A.] Sanford Burnham Prebys Med Discovery Inst, Ctr Canc, Tumor Initiat & Maintenance Program, La Jolla, CA 92037 USA. [Zhang, Tongwu; Brown, Kevin M.] NCI, Div Canc Epidemiol & Genet, Lab Translat Gen, Bethesda, MD 20892 USA. [Dzung, Andreas; Levesque, Mitchell P.; Dummer, Reinhard] Univ Zurich, Univ Zurich Hosp, Dept Dermatol, CH-8091 Zurich, Switzerland. [Hayward, Nicholas K.] QIMR Berghofer Med Res Inst, Oncogen Lab, Brisbane, Qld 4006, Australia. [Bosenberg, Marcus] Yale Univ, Sch Med, Dept Dermatol, 333 Cedar St, New Haven, CT 06520 USA. [Bosenberg, Marcus] Yale Univ, Sch Med, Dept Pathol, 333 Cedar St, New Haven, CT 06520 USA. RP Ronai, ZA (reprint author), Sanford Burnham Prebys Med Discovery Inst, Ctr Canc, Tumor Initiat & Maintenance Program, La Jolla, CA 92037 USA. EM zeev@ronailab.net RI Cheli, Yann/O-5783-2016 FU NCI Cancer Center Support Grant [P30 CA30199]; Division of Cancer Epidemiology and Genetics at NCI; National Health and Medical Research Council of Australia; Joanna M. Nicolay Melanoma Foundation; NCI [CA99961, CA172017]; Melanoma Research Foundation; Hervey Family Non-endowment Fund at The San Diego Foundation FX We thank Drs. N. Jones and W. Breitweiser for sharing the ATF2 mutant mouse model; M. McMahon, M. Soengas, D. Bennet, and H. Yin for plasmids and cell lines; R. Newlin, G. Garcia, J. Morales, and V. Ylis for technical assistance in histology and animal work; and members of the Z.A.R. laboratory for helpful discussions. Core Services were supported by NCI Cancer Center Support Grant P30 CA30199. T.Z. and K.M.B. were supported by the Division of Cancer Epidemiology and Genetics at NCI. We thank the biobank of the University Research Priority Program (URPP) in translational cancer research for biopsy materials. This work utilized the computational resources of the NIH HPC Biowulf cluster (https://hpc.nih.gov). N.K.H. was supported by a fellowship from the National Health and Medical Research Council of Australia. G.C. was also supported by a Research Scholar Award from the Joanna M. Nicolay Melanoma Foundation. Support from NCI grants CA99961 and CA172017, the Melanoma Research Foundation, and the Hervey Family Non-endowment Fund at The San Diego Foundation to Z.A.R. is gratefully acknowledged. NR 20 TC 0 Z9 0 U1 3 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD MAY 31 PY 2016 VL 15 IS 9 BP 1884 EP 1892 DI 10.1016/j.celrep.2016.04.072 PG 9 WC Cell Biology SC Cell Biology GA DN2IO UT WOS:000376887500004 PM 27210757 ER PT J AU Mohle, L Mattei, D Heimesaat, MM Bereswill, S Fischer, A Alutis, M French, T Hambardzumyan, D Matzinger, P Dunay, IR Wolf, SA AF Moehle, Luisa Mattei, Daniele Heimesaat, Markus M. Bereswill, Stefan Fischer, Andre Alutis, Marie French, Timothy Hambardzumyan, Dolores Matzinger, Polly Dunay, Ildiko R. Wolf, Susanne A. TI Ly6C(hi) Monocytes Provide a Link between Antibiotic-Induced Changes in Gut Microbiota and Adult Hippocampal Neurogenesis SO CELL REPORTS LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; DENTATE GYRUS; PATTERN SEPARATION; BACTERIAL-INFECTION; RECOGNITION MEMORY; ALZHEIMERS-DISEASE; TOXOPLASMA-GONDII; IMMUNE-SYSTEM; GRANULE CELLS; MOUSE MODEL AB Antibiotics, though remarkably useful, can also cause certain adverse effects. We detected that treatment of adult mice with antibiotics decreases hippocampal neurogenesis and memory retention. Reconstitution with normal gut flora (SPF) did not completely reverse the deficits in neurogenesis unless the mice also had access to a running wheel or received probiotics. In parallel to an increase in neurogenesis and memory retention, both SPF-reconstituted mice that ran and mice supplemented with probiotics exhibited higher numbers of Ly6C(hi) monocytes in the brain than antibiotic-treated mice. Elimination of Ly6C(hi) monocytes by antibody depletion or the use of knockout mice resulted in decreased neurogenesis, whereas adoptive transfer of Ly6C(hi) monocytes rescued neurogenesis after antibiotic treatment. We propose that the rescue of neurogenesis and behavior deficits in antibiotic-treated mice by exercise and probiotics is partially mediated by Ly6C(hi) monocytes. C1 [Moehle, Luisa; French, Timothy; Dunay, Ildiko R.] Univ Magdeburg, Inst Med Microbiol, D-39106 Magdeburg, Germany. [Mattei, Daniele; Wolf, Susanne A.] Max Delbruck Ctr Mol Med, Dept Cellular Neurosci, D-13125 Berlin, Germany. [Heimesaat, Markus M.; Bereswill, Stefan; Fischer, Andre; Alutis, Marie] Charite, Dept Microbiol & Hyg, D-14195 Berlin, Germany. [Hambardzumyan, Dolores] Cleveland Clin, Lerner Res Inst, Dept Neurosci, Cleveland, OH 44195 USA. [Hambardzumyan, Dolores] Emory Univ, Sch Med, Aflac Canc & Blood Disorders Ctr, Childrens Healthcare Atlanta,Dept Pediat, Atlanta, GA 30322 USA. [Matzinger, Polly] NIAID, Ghost Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Wolf, SA (reprint author), Max Delbruck Ctr Mol Med, Dept Cellular Neurosci, D-13125 Berlin, Germany. EM susanne.wolf@mdc-berlin.de FU Deutsche Forschungsgemeinschaft (DFG) [DU1112/3-1, SFB 854/TP25, SFB 633, TP A07, B06]; [SFB TR43] FX We thank Gernot Reifenberger and Dana Zabler for technical assistance. This project was funded by the Deutsche Forschungsgemeinschaft (DFG; DU1112/3-1 and SFB 854/TP25 to I.R.D. and SFB 633, TP A07, and B06 to A.F., S.B., and M.M.H.). S.A.W. and D.M. were supported by the SFB TR43. NR 90 TC 20 Z9 20 U1 7 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD MAY 31 PY 2016 VL 15 IS 9 BP 1945 EP 1956 DI 10.1016/j.celrep.2016.04.074 PG 12 WC Cell Biology SC Cell Biology GA DN2IO UT WOS:000376887500010 PM 27210745 ER PT J AU Singhal, V Maffazioli, GD Ackerman, KE Lee, H Elia, EF Woolley, R Kolodny, G Cypess, AM Misra, M AF Singhal, Vibha Maffazioli, Giovana D. Ackerman, Kate E. Lee, Hang Elia, Elisa F. Woolley, Ryan Kolodny, Gerald Cypess, Aaron M. Misra, Madhusmita TI Effect of Chronic Athletic Activity on Brown Fat in Young Women SO PLOS ONE LA English DT Article ID ADIPOSE-TISSUE ACTIVITY; BODY-MASS INDEX; SECRETORY DYNAMICS; ENERGY-EXPENDITURE; ANOREXIA-NERVOSA; COLD; HUMANS; LEPTIN; WHITE; THERMOGENESIS AB Background The effect of chronic exercise activity on brown adipose tissue (BAT) is not clear, with some studies showing positive and others showing negative associations. Chronic exercise is associated with increased resting energy expenditure (REE) secondary to increased lean mass and a probable increase in BAT. Many athletes are in a state of relative energy deficit suggested by lower fat mass and hypothalamic amenorrhea. States of severe energy deficit such as anorexia nervosa are associated with reduced BAT. There are no data regarding the impact of chronic exercise activity on BAT volume or activity in young women and it is unclear whether relative energy deficiency modifies the effects of exercise on BAT. Purpose We assessed cold induced BAT volume and activity in young female athletes compared with non-athletes, and further evaluated associations of BAT with measures of REE, body composition and menstrual status. Methods The protocol was approved by our Institutional Review Board. Written informed consent was obtained from all participants prior to study initiation. This was a cross-sectional study of 24 women (16 athletes and8 non-athletes) between 18-25 years of age. Athletes were either oligo-amenorrheic (n = 8) or eumenorrheic (n = 8). We used PET/CT scans to determine cold induced BAT activity, VMAX Encore 29 metabolic cart to obtain measures of REE, and DXA for body composition. Results Athletes and non-athletes did not differ for age or BMI. Compared with non-athletes, athletes had lower percent body fat (p = 0.002), higher percent leanmass (p = 0.01) and trended higher in REE (p = 0.09). BAT volume and activity in athletes trended lower than in non-athletes (p = 0.06; p = 0.07, respectively). We found negative associations of BAT activity with duration of amenorrhea (r = -0.46, p = 0.02). BAT volume correlated inversely with leanmass (r = -0.46, p = 0.02), and positively with percent body fat, irisin and thyroid hormones. Conclusions Our study shows a trend for lower BAT in young female athletes compared with non-athletes, and shows associations of brown fat with menstrual status and body composition. Brown fat may undergo adaptive reductions with increasing energy deficit. C1 [Singhal, Vibha; Misra, Madhusmita] Massachusetts Gen Hosp, Pediat Endocrine Unit, Boston, MA 02114 USA. [Singhal, Vibha; Maffazioli, Giovana D.; Ackerman, Kate E.; Lee, Hang; Elia, Elisa F.; Woolley, Ryan; Kolodny, Gerald; Misra, Madhusmita] Harvard Univ, Sch Med, Boston, MA USA. [Singhal, Vibha; Maffazioli, Giovana D.; Ackerman, Kate E.; Woolley, Ryan; Misra, Madhusmita] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Ackerman, Kate E.] Boston Childrens Hosp, Div Sports Med, Boston, MA USA. [Lee, Hang] Massachusetts Gen Hosp, Dept Biostat, Boston, MA 02114 USA. [Elia, Elisa F.; Kolodny, Gerald] Beth Israel Deaconess Med Ctr, Dept Radiol, Div Nucl Med & Mol Imaging, 330 Brookline Ave, Boston, MA 02215 USA. [Cypess, Aaron M.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Singhal, V (reprint author), Massachusetts Gen Hosp, Pediat Endocrine Unit, Boston, MA 02114 USA.; Singhal, V (reprint author), Harvard Univ, Sch Med, Boston, MA USA.; Singhal, V (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. EM vsinghal1@partners.org FU National Institutes of Health [1 UL1 RR025758-01, 1UL1TR001102-01, 1 R01 HD 060827-01A1, K24 HD071843]; Fundacion Alfonso Martin Escudero FX This work was supported by National Institutes of Health Grants 1 UL1 RR025758-01, 1UL1TR001102-01, 1 R01 HD 060827-01A1, and K24 HD071843. E. Franquet was supported by Fundacion Alfonso Martin Escudero. NR 29 TC 3 Z9 3 U1 2 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 31 PY 2016 VL 11 IS 5 AR e0156353 DI 10.1371/journal.pone.0156353 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DN5XX UT WOS:000377146100031 PM 27243823 ER PT J AU Gunalan, K Lo, E Hostetler, JB Yewhalaw, D Mu, JB Neafsey, DE Yan, GY Miller, LH AF Gunalan, Karthigayan Lo, Eugenia Hostetler, Jessica B. Yewhalaw, Delenasaw Mu, Jianbing Neafsey, Daniel E. Yan, Guiyun Miller, Louis H. TI Role of Plasmodium vivax Duffy-binding protein 1 in invasion of Duffy-null Africans SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Plasmodium vivax; Duffy blood group antigen; Duffy-binding protein; DNA expansion ID BLOOD-GROUP; MALARIA PARASITE; NEGATIVE INDIVIDUALS; ERYTHROCYTE INVASION; CHEMOKINES DARC; NUTRIENT-UPTAKE; RESISTANCE; ANTIGEN; GENE; FALCIPARUM AB The ability of the malaria parasite Plasmodium vivax to invade erythrocytes is dependent on the expression of the Duffy blood group antigen on erythrocytes. Consequently, Africans who are null for the Duffy antigen are not susceptible to P. vivax infections. Recently, P. vivax infections in Duffy-null Africans have been documented, raising the possibility that P. vivax, a virulent pathogen in other parts of the world, may expand malarial disease in Africa. P. vivax binds the Duffy blood group antigen through its Duffy-binding protein 1 (DBP1). To determine if mutations in DBP1 resulted in the ability of P. vivax to bind Duffy-null erythrocytes, we analyzed P. vivax parasites obtained from two Duffy-null individuals living in Ethiopia where Duffy-null and - positive Africans live side-by-side. We determined that, although the DBP1s from these parasites contained unique sequences, they failed to bind Duffy-null erythrocytes, indicating that mutations in DBP1 did not account for the ability of P. vivax to infect Duffy-null Africans. However, an unusual DNA expansion of DBP1 (three and eight copies) in the two Duffy-null P. vivax infections suggests that an expansion of DBP1 may have been selected to allow low-affinity binding to another receptor on Duffy-null erythrocytes. Indeed, we show that Salvador (Sal) I P. vivax infects Squirrel monkeys independently of DBP1 binding to Squirrel monkey erythrocytes. We conclude that P. vivax Sal I and perhaps P. vivax in Duffy-null patients may have adapted to use new ligand-receptor pairs for invasion. C1 [Gunalan, Karthigayan; Hostetler, Jessica B.; Mu, Jianbing; Miller, Louis H.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Lo, Eugenia; Yan, Guiyun] Univ Calif Irvine, Coll Hlth Sci, Program Publ Hlth, Irvine, CA 92697 USA. [Hostetler, Jessica B.] Sanger Inst, Malaria Programme, Wellcome Trust, Wellcome Genome Campus, Cambridge CB10 1RQ, England. [Yewhalaw, Delenasaw] Jimma Univ, Coll Hlth Sci, Dept Med Lab Sci & Pathol, Jimma 5195, Ethiopia. [Yewhalaw, Delenasaw] Jimma Univ, Trop & Infect Dis Res Ctr, Jimma 5195, Ethiopia. [Neafsey, Daniel E.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. RP Miller, LH (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. EM lmiller@niaid.nih.gov FU Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; [R21 AI101802] FX We thank Dr. Susan K. Pierce (NIH) for valuable suggestions and critical reading of the manuscript; Mrs. Endalew Zemene, Estifanos Kebede, and Beka Raya (Tropical and Infectious Diseases Research Center, Jimma University) for sample collection; Drs. Gary Cohen and Roselyn Eisenberg (University of Pennsylvania) for the pRE4 vector and antibodies (ID3 and DL6); Drs. Thomas E. Wellems, Juliana Sa, and Roberto Moraes Barros for the erythrocytes from Aotus and Squirrel monkeys; Drs. Jose M. C. Ribeiro, (NIH), Julian C. Rayner (Wellcome Trust Sanger Institute), and Rick M. Fairhurst (NIH) for valuable suggestions; and Drs. Lubin Jiang (Institut Pasteur of Shanghai) and Yang Cheng (NIH) for help in cloning. This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health and Grant R21 AI101802 (to G.Y.). NR 53 TC 4 Z9 4 U1 1 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 31 PY 2016 VL 113 IS 22 BP 6271 EP 6276 DI 10.1073/pnas.1606113113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DN0VL UT WOS:000376784600055 PM 27190089 ER PT J AU Reber, SO Siebler, PH Donner, NC Morton, JT Smith, DG Kopelman, JM Lowe, KR Wheeler, KJ Fox, JH Hassell, JE Greenwood, BN Jansch, C Lechner, A Schmidt, D Uschold-Schmidt, N Fuchsl, AM Langgartner, D Walker, FR Hale, MW Perez, GL Van Treuren, W Gonzalez, A Halweg-Edwards, AL Fleshner, M Raison, CL Rook, GA Peddada, SD Knight, R Lowry, CA AF Reber, Stefan O. Siebler, Philip H. Donner, Nina C. Morton, James T. Smith, David G. Kopelman, Jared M. Lowe, Kenneth R. Wheeler, Kristen J. Fox, James H. Hassell, James E., Jr. Greenwood, Benjamin N. Jansch, Charline Lechner, Anja Schmidt, Dominic Uschold-Schmidt, Nicole Fuechsl, Andrea M. Langgartner, Dominik Walker, Frederick R. Hale, Matthew W. Perez, Gerardo Lopez Van Treuren, Will Gonzalez, Antonio Halweg-Edwards, Andrea L. Fleshner, Monika Raison, Charles L. Rook, Graham A. Peddada, Shyamal D. Knight, Rob Lowry, Christopher A. TI Immunization with a heat-killed preparation of the environmental bacterium Mycobacterium vaccae promotes stress resilience in mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE anxiety; chronic psychosocial stress; fear; microbiota; posttraumatic stress disorder ID CHRONIC PSYCHOSOCIAL STRESS; INFLAMMATORY-BOWEL-DISEASE; REGULATORY T-CELLS; MESSENGER-RNA EXPRESSION; DORSAL RAPHE NUCLEUS; EARLY-LIFE STRESS; SEROTONERGIC NEURONS; HELICOBACTER-PYLORI; SOCIAL STRESS; INTESTINAL MICROBIOTA AB The prevalence of inflammatory diseases is increasing in modern urban societies. Inflammation increases risk of stress-related pathology; consequently, immunoregulatory or antiinflammatory approaches may protect against negative stress-related outcomes. We show that stress disrupts the homeostatic relationship between the microbiota and the host, resulting in exaggerated inflammation. Repeated immunization with a heat-killed preparation of Mycobacterium vaccae, an immunoregulatory environmental microorganism, reduced subordinate, flight, and avoiding behavioral responses to a dominant aggressor in a murine model of chronic psychosocial stress when tested 1-2wk following the final immunization. Furthermore, immunization with M. vaccae prevented stress-induced spontaneous colitis and, in stressed mice, induced anxiolytic or fear-reducing effects as measured on the elevated plus-maze, despite stress-induced gut microbiota changes characteristic of gut infection and colitis. Immunization with M. vaccae also prevented stress-induced aggravation of colitis in a model of inflammatory bowel disease. Depletion of regulatory T cells negated protective effects of immunization with M. vaccae on stress-induced colitis and anxiety-like or fear behaviors. These data provide a framework for developing microbiome- and immunoregulation-based strategies for prevention of stress-related pathologies. C1 [Reber, Stefan O.] Univ Ulm, Clin Psychosomat Med & Psychotherapy, Lab Mol Psychosomat, D-89081 Ulm, Germany. [Reber, Stefan O.; Jansch, Charline; Uschold-Schmidt, Nicole; Fuechsl, Andrea M.; Langgartner, Dominik] Univ Regensburg, Dept Behav & Mol Neurobiol, D-93053 Regensburg, Germany. [Reber, Stefan O.; Donner, Nina C.; Morton, James T.; Smith, David G.; Kopelman, Jared M.; Lowe, Kenneth R.; Wheeler, Kristen J.; Fox, James H.; Hassell, James E., Jr.; Greenwood, Benjamin N.; Perez, Gerardo Lopez; Fleshner, Monika; Lowry, Christopher A.] Univ Colorado, Dept Integrat Physiol, Boulder, CO 80309 USA. [Siebler, Philip H.; Donner, Nina C.; Morton, James T.; Smith, David G.; Kopelman, Jared M.; Lowe, Kenneth R.; Wheeler, Kristen J.; Fox, James H.; Hassell, James E., Jr.; Greenwood, Benjamin N.; Perez, Gerardo Lopez; Fleshner, Monika; Lowry, Christopher A.] Univ Colorado, Ctr Neurosci, Boulder, CO 80309 USA. [Lechner, Anja; Schmidt, Dominic] Univ Regensburg, Inst Immunol, D-93042 Regensburg, Germany. [Walker, Frederick R.] Univ Newcastle, Sch Biomed Sci & Pharm, Callaghan, NSW 2308, Australia. [Hale, Matthew W.; Van Treuren, Will] La Trobe Univ, Sch Psychol Sci, Bundoora, Vic 3086, Australia. [Van Treuren, Will] Univ Colorado, Biofrontiers Inst, Boulder, CO 80309 USA. [Gonzalez, Antonio; Raison, Charles L.; Knight, Rob] Univ Calif San Diego, Dept Pediat, San Diego, CA 92093 USA. [Gonzalez, Antonio; Knight, Rob] Univ Calif San Diego, Comp Sci & Engn, San Diego 92093, CA USA. [Halweg-Edwards, Andrea L.] Univ Colorado, Dept Chem & Biol Engn, Boulder, CO 80309 USA. Univ Wisconsin, Sch Human Ecol, Madison, WI 53706 USA. [Raison, Charles L.] Univ Wisconsin Madison, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Rook, Graham A.] UCL, Ctr Clin Microbiol, Mortimer St, London WC1E 6BT, England. [Peddada, Shyamal D.] NIEHS, Biostat & Computat Biol Branch, Res Triangle Pk, NC 27709 USA. [Knight, Rob] Univ Calif San Diego, Ctr Microbiome Innovat, San Diego, CA 92093 USA. [Donner, Nina C.] Max Planck Inst Psychiat, Dept Stress Neurobiol & Neurogenet, D-80804 Munich, Germany. [Morton, James T.] Univ Calif San Diego, Dept Pediat & Comp Sci & Engn, San Diego, CA 92093 USA. [Kopelman, Jared M.] Univ Pittsburgh, Dept Psychiat, Translat Neurosci Program, Pittsburgh, PA 15213 USA. [Greenwood, Benjamin N.] Univ Colorado, Dept Psychol, Denver, CO 80217 USA. [Jansch, Charline] Univ Wurzburg, Dept Psychiat Psychosomat & Psychotherapy, D-97080 Wurzburg, Germany. [Lechner, Anja] Bionorica, Dept Preclin R&D, D-92318 Neumarkt, Germany. [Schmidt, Dominic] Univ Colorado Boulder, Dept Integrat Physiol, Boulder, CO 80309 USA. [Fuechsl, Andrea M.; Langgartner, Dominik] Univ Ulm, Clin Psychosomat Med & Psychotherapy, Lab Mol Psychosomat, D-89081 Ulm, Germany. [Van Treuren, Will] Stanford Univ, Dept Microbiol & Immunol, Stanford, CA 94305 USA. RP Lowry, CA (reprint author), Univ Colorado, Dept Integrat Physiol, Boulder, CO 80309 USA. EM christopher.lowry@colorado.edu FU NIEHS NIH HHS [Z01 ES101744] NR 134 TC 8 Z9 8 U1 5 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 31 PY 2016 VL 113 IS 22 BP E3130 EP E3139 DI 10.1073/pnas.1600324113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DN0VL UT WOS:000376784600013 PM 27185913 ER PT J AU Adebamowo, SN Adeyemo, AA Tekola-Ayele, F Doumatey, AP Bentley, AR Chen, GJ Zhou, J Shriner, D Fasanmade, OA Okafor, G Eghan, B Agyenim-Boateng, K Adeleye, J Balogun, W Amoah, AG Owusu, S Acheampong, J Johnson, T Oli, J Adebamowo, CA Rotimi, CN AF Adebamowo, Sally N. Adeyemo, Adebowale A. Tekola-Ayele, Fasil Doumatey, Ayo P. Bentley, Amy R. Chen, Guanjie Zhou, Jie Shriner, Daniel Fasanmade, Olufemi Adetola Okafor, Godfrey Eghan, Benjamin, Jr. Agyenim-Boateng, Kofi Adeleye, Jokotade Balogun, Williams Amoah, Albert G. Owusu, Samuel Acheampong, Joseph Johnson, Thomas Oli, Johnnie Adebamowo, Clement A. Rotimi, Charles N. TI Impact of Type 2 Diabetes on Impaired Kidney Function in Sub-Saharan African Populations SO FRONTIERS IN ENDOCRINOLOGY LA English DT Article DE impaired kidney function; type 2 diabetes; kidney disease; sub-Saharan Africa; diabetic kidney disease ID GLOMERULAR-FILTRATION-RATE; GLOBAL BURDEN; DISEASE; HYPERTENSION; MELLITUS; COMPLICATIONS; EPIDEMIOLOGY; NEPHROPATHY; PREVALENCE; EQUATION AB Background: Diabetes is a leading risk factor for impaired kidney function, an indicator of chronic kidney disease. The aim of this study was to examine the association between type 2 diabetes (T2D) and impaired kidney function among adults in sub-Saharan Africa (SSA). Methods: Participants were enrolled from Ghana, Kenya, and Nigeria. Impaired kidney function was based on an estimated glomerular filtration rate <60 ml/min/1.73 m(2). Using logistic regression models, we conducted case-control analyses to estimate the multivariate-adjusted association of T2D and kidney function. Results: We used data from 4815 participants for whom the mean (SD) age was 48 (15) years, 41% were male and 46% had T2D. Those with T2D were more likely to have impaired kidney function [13.4% (95% Cl: 11.9-14.7)] compared to those without T2D [4.8% (95% Cl: 4.0-5.6)], p-value <0.001. The multivariate odds ratio of impaired kidney function among those with type 2 diabetes was 1.50 (95% Cl: 1.17-1.91) p-value = 0.001, compared to those without T2D. Also, individuals with 120 who were at least 60 years old, obese, hypertensive or dyslipidemic were more likely to have impaired kidney function compared to those without T2D. Conclusion: T2D was associated with 50% increased risk of impaired kidney function in this sample of adults from SSA. Interventions targeted at prevention, early diagnosis, and management of T2D are likely to reduce the burden of kidney disease in SSA. C1 [Adebamowo, Sally N.; Adeyemo, Adebowale A.; Tekola-Ayele, Fasil; Doumatey, Ayo P.; Bentley, Amy R.; Chen, Guanjie; Zhou, Jie; Shriner, Daniel; Rotimi, Charles N.] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Fasanmade, Olufemi Adetola; Johnson, Thomas] Univ Lagos, Lagos, Nigeria. [Okafor, Godfrey; Oli, Johnnie] Univ Nigeria, Teaching Hosp, Enugu, Nigeria. [Eghan, Benjamin, Jr.; Agyenim-Boateng, Kofi; Acheampong, Joseph] Kwame Nkrumah Univ Sci & Technol, Kumasi, Ghana. [Adeleye, Jokotade; Balogun, Williams] Univ Ibadan, Ibadan, Nigeria. [Amoah, Albert G.; Owusu, Samuel] Univ Ghana, Sch Med, Accra, Ghana. [Adebamowo, Clement A.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Greenbaum Canc Ctr,Inst Human Virol, Baltimore, MD 21201 USA. RP Adebamowo, SN; Rotimi, CN (reprint author), NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. EM sally.adebamowo@nih.gov; rotimic@mail.nih.gov OI Tekola-Ayele, Fasil/0000-0003-4194-9370 FU Intramural Research Program of the National Human Genome Research Institute (NHGRI), National Institutes of Health; National Institutes of Health [NIH IRP 1ZIAHG200362, 3T37TW00041-03S2]; National Institutes of Health: National Center for Research Resources (NCRR); National Institutes of Health: NHGRI; National Institutes of Health: NIDDK grant [DK-54001] FX This research was supported, in part, by the Intramural Research Program of the National Human Genome Research Institute (NHGRI), National Institutes of Health. Funding for this research was provided by the following grants from the National Institutes of Health: NIH IRP 1ZIAHG200362, 3T37TW00041-03S2 (National Institute of Minority Health and Health Disparities), National Center for Research Resources (NCRR), NHGRI and NIDDK grant DK-54001. The Binders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding authors had full access to all data in the study and had final responsibility for the decision to submit for publication. NR 31 TC 0 Z9 0 U1 0 U2 2 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-2392 J9 FRONT ENDOCRINOL JI Front. Endocrinol. PD MAY 30 PY 2016 VL 7 AR 50 DI 10.3389/fendo.2016.00050 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DP5BL UT WOS:000378510900001 PM 27303364 ER PT J AU Berger, VW Agnor, R AF Berger, Vance W. Agnor, Rebecca TI Delayed unmasking and selection bias SO STATISTICS IN MEDICINE LA English DT Letter ID BLOCKED RANDOMIZATION C1 [Berger, Vance W.] Univ Maryland Baltimore Cty, Natl Canc Inst, 9609 Med Ctr Dr, Rockville, MD 20850 USA. [Berger, Vance W.] Univ Maryland Baltimore Cty, Biometry Res Grp, 9609 Med Ctr Dr, Rockville, MD 20850 USA. [Agnor, Rebecca] Univ N Carolina, Dept Biostat, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. RP Agnor, R (reprint author), Univ N Carolina, Dept Biostat, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. EM rcagnor@live.unc.edu NR 4 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD MAY 30 PY 2016 VL 35 IS 12 BP 2111 EP 2112 DI 10.1002/sim.6799 PG 2 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA DL0OJ UT WOS:000375332000012 PM 27118631 ER PT J AU Wang, JN Liu, MT Yang, C Wu, XG Wang, E Liu, P AF Wang, Jennie Liu, Mingtao Yang, Chun Wu, Xiaogang Wang, Euphemia Liu, Paul TI HPLC method development, validation, and impurity characterization of a potent antitumor indenoisoquinoline, LMP776 (NSC 725776) SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE LMP776; NSC 725776; Forced degradation; HPLC validation; Impurity and degradation product characterization; NMR ID TOPOISOMERASE-I INHIBITORS; NSC-725776 AB An HPLC method for the assay of a DNA topoisomerase inhibitor, LMP776 (NSC 725776), has been developed and validated. The stress testing of LMP776 was carried out in accordance with International Conference on Harmonization (ICH) guidelines Q1A (R2) under acidic, alkaline, oxidative, thermolytic, and photolytic conditions. The separation of LMP776 from its impurities and degradation products was achieved within 40 min on a Supelco Discovery HS F5 column (150 mm x 4.6 mm i.d., 5 mu m) with a gradient mobile phase comprising 38-80% acetonitrile in water, with 0.1% trifluoroacetic acid in both phases. LC/MS was used to obtain mass data for characterization of impurities and degradation products. One major impurity was isolated through chloroform extraction and identified by NMR. The proposed HPLC assay method was validated for specificity, linearity (concentration range 0.25-0.75 mg/mL, r = 0.9999), accuracy (recovery 98.6-100.4%), precision (RSD <= 1.4%), and sensitivity (LOD 0.13 mu g/mL). The validated method was used in the stability study of the LMP776 drug substance in conformance with the ICH Q1A (R2) guideline. (C) 2016 Elsevier B.V. All rights reserved. C1 [Wang, Jennie; Liu, Mingtao; Yang, Chun; Wu, Xiaogang; Wang, Euphemia] SRI Int, 333 Ravenswood Ave, Menlo Pk, CA 94025 USA. [Liu, Paul] NCI, Pharmaceut Resources Branch, DCTD, 6130 Execut Blvd, Bethesda, MD 20892 USA. RP Wang, JN (reprint author), SRI Int, 333 Ravenswood Ave, Menlo Pk, CA 94025 USA. EM jennie.wang@sri.com; liup@dtpepn.nci.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200722003C, HHSN261201200028C] FX This work has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200722003C and Contract No. HHSN261201200028C. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 9 TC 0 Z9 0 U1 5 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0731-7085 EI 1873-264X J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD MAY 30 PY 2016 VL 124 BP 267 EP 273 DI 10.1016/j.jpba.2016.02.036 PG 7 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA DJ4TX UT WOS:000374202000030 PM 26970596 ER PT J AU Berezhkovskii, AM Shvartsman, SY AF Berezhkovskii, Alexander M. Shvartsman, Stanislav Y. TI Diffusive flux in a model of stochastically gated oxygen transport in insect respiration SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID DISCONTINUOUS GAS-EXCHANGE; SLOW CONFORMATIONAL-CHANGES; FLUCTUATING BOTTLENECK; MOLECULAR-MOTION; LIMITED REACTIONS; HEME-PROTEINS; CO BINDING; DYNAMICS; KINETICS; LIGAND AB Oxygen delivery to insect tissues is controlled by transport through a branched tubular network that is connected to the atmosphere by valve-like gates, known as spiracles. In certain physiological regimes, the spiracles appear to be randomly switching between open and closed states. Quantitative analysis of this regime leads a reaction-diffusion problem with stochastically switching boundary condition. We derive an expression for the diffusive flux at long times in this problem. Our approach starts with the derivation of the passage probability for a single particle that diffuses between a stochastically gated boundary, which models the opening and closing spiracle, and the perfectly absorbing boundary, which models oxygen absorption by the tissue. This passage probability is then used to derive an expression giving the diffusive flux as a function of the geometric parameters of the tube and characteristic time scales of diffusion and gate dynamics. Published by AIP Publishing. C1 [Berezhkovskii, Alexander M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Bethesda, MD 20892 USA. [Shvartsman, Stanislav Y.] Princeton Univ, Dept Chem & Biol Engn, Princeton, NJ 08544 USA. [Shvartsman, Stanislav Y.] Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08544 USA. RP Berezhkovskii, AM (reprint author), NIH, Math & Stat Comp Lab, Div Computat Biosci, Bethesda, MD 20892 USA. FU Intramural Research Program of the NIH, Center for Information Technology; NIGMS [1R01GM107103] FX A.M.B. was supported by the Intramural Research Program of the NIH, Center for Information Technology. S.Y.S. acknowledges helpful discussions with Eran Gefen and funding through the No. 1R01GM107103 grant from the NIGMS. NR 33 TC 0 Z9 0 U1 4 U2 9 PU AMER INST PHYSICS PI MELVILLE PA 1305 WALT WHITMAN RD, STE 300, MELVILLE, NY 11747-4501 USA SN 0021-9606 EI 1089-7690 J9 J CHEM PHYS JI J. Chem. Phys. PD MAY 28 PY 2016 VL 144 IS 20 AR 204101 DI 10.1063/1.4950769 PG 5 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA DO3WI UT WOS:000377712700003 PM 27250273 ER PT J AU Dardik, R Livnat, T Halpert, G Jawad, S Nisgav, Y Azar-Avivi, S Liu, BY Nussenblatt, RB Weinberger, D Sredni, B AF Dardik, Rima Livnat, Tami Halpert, Gilad Jawad, Shayma Nisgav, Yael Azar-Avivi, Shirley Liu, Baoying Nussenblatt, Robert B. Weinberger, Dov Sredni, Benjamin TI The small tellurium-based compound SAS suppresses inflammation in human retinal pigment epithelium SO MOLECULAR VISION LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; NF-KAPPA-B; CHOROIDAL NEOVASCULAR MEMBRANES; DNA-BINDING ACTIVITY; MACULAR DEGENERATION; VEGF EXPRESSION; GENE-EXPRESSION; FACTOR PEDF; IN-VITRO; INTERLEUKIN-8 EXPRESSION AB Purpose: Pathological angiogenesis and chronic inflammation greatly contribute to the development of choroidal neovascularization (CNV) in chorioretinal diseases involving abnormal contact between retinal pigment epithelial (RPE) and endothelial cells (ECs), associated with Bruch's membrane rupture. We explored the ability of the small organotellurium compound octa-O-bis-(R,R)-tartarate ditellurane (SAS) to mitigate inflammatory processes in human RPE cells. Methods: Cell adhesion assays and analyses of gene and protein expression were used to examine the effect of SAS on ARPE-19 cells or primary human RPE cells that were grown alone or in an RPE-EC co-culture. Results: Adhesion assays showed that SAS inhibited av integrins expressed on RPE cells. Co-cultures of RPE cells with ECs significantly reduced the gene expression of PEDF, as compared to RPE cells cultured alone. Both SAS and the anti-alpha v beta 3 antibody LM609 significantly enhanced the production of PEDF at both mRNA and protein levels in RPE cells. RPE cells co-cultured with EC exhibited increased gene expression of CXCL5, COX1, MMP2, IGF1, and IL8, all of which are involved in both angiogenesis and inflammation. The enhanced expression of these genes was greatly suppressed by SAS, but interestingly, remained unaffected by LM609. Zymography assay showed that SAS reduced the level of MMP-2 activity in RPE cells. We also found that SAS significantly suppressed IL-1 beta-induced IL-6 expression and secretion from RPE cells by reducing the protein levels of phospho-IkappaBalpha (pI kappa B alpha). Conclusions: Our results suggest that SAS is a promising anti-inflammatory agent in RPE cells, and may be an effective therapeutic approach for controlling chorioretinal diseases. C1 [Dardik, Rima] Chaim Sheba Med Ctr, Inst Thrombosis & Hemostasis, IL-52621 Tel Hashomer, Israel. [Dardik, Rima; Livnat, Tami; Nisgav, Yael; Azar-Avivi, Shirley; Weinberger, Dov] Felsenstein Med Res Ctr, Lab Eye Res, Petah Tiqwa, Israel. [Weinberger, Dov] Rabin Med Ctr, Dept Ophthalmol, Beilinson Campus, Petah Tiqwa, Israel. [Weinberger, Dov] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Halpert, Gilad; Sredni, Benjamin] Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Safdie AIDS & Immunol Res Ctr, CAIR Inst, IL-52900 Ramat Gan, Israel. [Jawad, Shayma; Liu, Baoying; Nussenblatt, Robert B.] NEI, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Dardik, R (reprint author), Chaim Sheba Med Ctr, Inst Thrombosis & Hemostasis, IL-52621 Ramat Gan, Israel. EM rima.dardik@sheba.health.gov.il NR 83 TC 0 Z9 0 U1 2 U2 4 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD MAY 28 PY 2016 VL 22 BP 548 EP 562 PG 15 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA DN0WC UT WOS:000376786600003 PM 27293373 ER PT J AU Berrueta, M Hemingway-Foday, J Thorsten, VR Goldenberg, RL Carlo, WA Garces, A Patel, A Saleem, S Pasha, O Chomba, E Hibberd, PL Krebs, NF Goudar, S Derman, RJ Esamai, F Liechty, EA Moore, JL McClure, EM Koso-Thomas, M Buekens, PM Belizan, JM Althabe, F AF Berrueta, Mabel Hemingway-Foday, Jennifer Thorsten, Vanessa R. Goldenberg, Robert L. Carlo, Waldemar A. Garces, Ana Patel, Archana Saleem, Sarah Pasha, Omrana Chomba, Elwyn Hibberd, Patricia L. Krebs, Nancy F. Goudar, Shivaprasad Derman, Richard J. Esamai, Fabian Liechty, Edward A. Moore, Janet L. McClure, Elizabeth M. Koso-Thomas, Marion Buekens, Pierre M. Belizan, Jose M. Althabe, Fernando TI Use of antenatal corticosteroids at health facilities and communities in low-and-middle income countries SO REPRODUCTIVE HEALTH LA English DT Article ID PRETERM BIRTH; NEWBORN HEALTH; GESTATIONAL-AGE; SCALE-UP; DEATHS; MORTALITY; SURVIVAL; TRIAL; RISK AB Background: Antenatal corticosteroids (ACS) for women at high risk of preterm birth is an effective intervention to reduce neonatal mortality among preterm babies delivered in hospital settings, but has not been widely used in low-middle resource settings. We sought to assess the rates of ACS use at all levels of health care in low and middle income countries (LMIC). Methods: We assessed rates of ACS in 7 sites in 6 LMIC participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development's Global Network for Women and Children's Health Research Antenatal Corticosteroids Trial (ACT), a cluster-randomized trial to assess the feasibility, effectiveness, and safety of a multifaceted intervention designed to increase the use of ACS. We conducted this analysis using data from the control clusters, which did not receive any components of the intervention and intended to follow usual care. We included women who delivered an infant with a birth weight <5th percentile, a proxy for preterm birth, and were enrolled in the Maternal Newborn Health (MNH) Registry between October 2011 and March 2014 in all clusters. A survey of the site investigators regarding existing policies on ACS in health facilities and for health workers in the community was part of pre-trial activities. Results: Overall, of 51,523 women delivered in control clusters across all sites, the percentage of <5th percentile babies ranged from 3.5 % in Kenya to 10.7 % in Pakistan. There was variation among the sites in the use of ACS at all hospitals and among those hospitals having cesarean section and neonatal care capabilities (bag and mask and oxygen or mechanical ventilation). Rates of ACS use for <5th percentile babies in all hospitals ranged from 3. 8 % in the Kenya sites to 44.5 % in the Argentina site, and in hospitals with cesarean section and neonatal care capabilities from 0 % in Zambia to 43.5 % in Argentina. ACS were rarely used in clinic or home deliveries at any site. Guidelines for ACS use at all levels of the health system were available for most of the sites. Conclusion: Our study reports an overall low utilization of ACS among mothers of <5th percentile infants in hospital and clinic deliveries in LMIC. C1 [Berrueta, Mabel; Belizan, Jose M.; Althabe, Fernando] Inst Clin Effectiveness & Hlth Policy IECS, Buenos Aires, DF, Argentina. [Hemingway-Foday, Jennifer; Thorsten, Vanessa R.; Moore, Janet L.; McClure, Elizabeth M.] RTI Int, Durham, NC USA. [Goldenberg, Robert L.] Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. [Carlo, Waldemar A.] Univ Alabama Birmingham, Birmingham, AL USA. [Garces, Ana] Fdn Alimentac & Nutr Ctr Amer & Panama, Guatemala City, Guatemala. [Patel, Archana] Indira Gandhi Govt Med Coll, Lata Med Res Fdn, Nagpur, Maharashtra, India. [Saleem, Sarah; Pasha, Omrana] Aga Khan Univ, Dept Community Hlth Sci, Karachi, Pakistan. [Chomba, Elwyn] Univ Teaching Hosp, Lusaka, Zambia. [Hibberd, Patricia L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Krebs, Nancy F.] Univ Colorado, Sch Med, Denver, CO USA. [Goudar, Shivaprasad] KLE Univ, Jawaharlal Nehru Med Coll, Belgaum, Karnataka, India. [Derman, Richard J.] Christiana Hlth Care, Newark, DE USA. [Esamai, Fabian] Moi Univ, Sch Med, Eldoret, Kenya. [Liechty, Edward A.] Indiana Univ, Sch Med, Indianapolis, IN USA. [Koso-Thomas, Marion] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Buekens, Pierre M.] Tulane Sch Publ Hlth & Trop Med, New Orleans, LA USA. RP Berrueta, M (reprint author), Inst Clin Effectiveness & Hlth Policy IECS, Buenos Aires, DF, Argentina. EM mberrueta@iecs.org.ar FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01 HD058322, U01 HD040477, U01 HD043464, U01 HD040657, U01 HD042372, U01 HD040607, U01 HD058326, U01 HD040636]; Bill & Melinda Gates Foundation [OPP1132907] FX This study was funded by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant number U01 HD058322, U01 HD040477, U01 HD043464, U01 HD040657, U01 HD042372, U01 HD040607, U01 HD058326, U01 HD040636). Additional support was provided to FA and JB from Bill & Melinda Gates Foundation grant OPP1132907. NR 21 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4755 J9 REPROD HEALTH JI Reprod. Health PD MAY 27 PY 2016 VL 13 DI 10.1186/s12978-016-0176-2 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DP6NS UT WOS:000378614400001 PM 27228986 ER PT J AU Tesikova, M Dezitter, X Nenseth, HZ Klokk, TI Mueller, F Hager, GL Saatcioglu, F AF Tesikova, Martina Dezitter, Xavier Nenseth, Hatice Z. Klokk, Tove I. Mueller, Florian Hager, Gordon L. Saatcioglu, Fahri TI Divergent Binding and Transactivation by Two Related Steroid Receptors at the Same Response Element SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LIGAND-SPECIFIC DYNAMICS; TUMOR VIRUS PROMOTER; RNA-POLYMERASE-II; ANDROGEN RECEPTOR; GLUCOCORTICOID-RECEPTOR; LIVING CELLS; HISTONE DEACETYLASES; GENE-EXPRESSION; PROSTATE-CANCER; TRANSCRIPTION AB Transcription factor (TF) recruitment to chromatin is central to activation of transcription. TF-chromatin interactions are highly dynamic, which are evaluated by recovery half time (t(1/2)) in seconds, determined by fluorescence recovery experiments in living cells, and chromatin immunoprecipitation (ChIP) analysis, measured in minutes. These two states are related: the larger the t(1/2), the longer the ChIP occupancy resulting in increased transcription. Here we present data showing that this relationship does not always hold. We found that histone deacetylase inhibitors (HDACis) significantly increased t(1/2) of green fluorescent protein (GFP) fused androgen receptor (AR) on a tandem array of positive hormone response elements (HREs) in chromatin. This resulted in increased ChIP signal of GFP-AR. Unexpectedly, however, transcription was inhibited. In contrast, the GFP-fused glucocorticoid receptor (GR), acting through the same HREs, displayed a profile consistent with current models. We provide evidence that these differences are mediated, at least in part, by HDACs. Our results provide insight into TF action in living cells and show that very closely related TFs may trigger significantly divergent outcomes at the same REs. C1 [Tesikova, Martina; Dezitter, Xavier; Nenseth, Hatice Z.; Klokk, Tove I.; Saatcioglu, Fahri] Univ Oslo, Dept Biosci, N-0316 Oslo, Norway. [Mueller, Florian] Inst Pasteur, Computat Imaging & Modeling Unit, F-75015 Paris, France. [Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Saatcioglu, Fahri] Oslo Univ Hosp, Inst Canc Genet & Informat, Div Canc & Surg, N-0310 Oslo, Norway. [Dezitter, Xavier] Univ Lille Nord France, UDSL, ICPAL, Plateforme Binding, F-59000 Lille, France. [Klokk, Tove I.] Oslo Univ Hosp, Inst Canc Res, Dept Mol Cell Biol, Ctr Canc Biomed, N-0310 Oslo, Norway. RP Saatcioglu, F (reprint author), Univ Oslo, Dept Biosci, N-0316 Oslo, Norway.; Saatcioglu, F (reprint author), Oslo Univ Hosp, Inst Canc Genet & Informat, Div Canc & Surg, N-0310 Oslo, Norway. EM fahris@ibv.uio.no RI Mueller, Florian/C-9075-2012 OI Mueller, Florian/0000-0002-9622-4396 FU Norwegian Research Council [191733]; Norwegian Cancer Society [PR-2006-0335] FX This work was supported by the Norwegian Research Council (191733, to F. S.) and Norwegian Cancer Society (PR-2006-0335, to F. S.). The authors declare that they have no conflicts of interest with the contents of this article. NR 36 TC 0 Z9 0 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 27 PY 2016 VL 291 IS 22 BP 11899 EP 11910 DI 10.1074/jbc.M115.684480 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DN7NZ UT WOS:000377264800038 PM 27056330 ER PT J AU Lee, BC Kim, HS Shin, TH Kang, I Lee, JY Kim, JJ Kang, HK Seo, Y Lee, S Yu, KR Choi, SW Kang, KS AF Lee, Byung-Chul Kim, Hyung-Sik Shin, Tae-Hoon Kang, Insung Lee, Jin Young Kim, Jae-Jun Kang, Hyun Kyoung Seo, Yoojin Lee, Seunghee Yu, Kyung-Rok Choi, Soon Won Kang, Kyung-Sun TI PGE(2) maintains self-renewal of human adult stem cells via EP2-mediated autocrine signaling and its production is regulated by cell-to-cell contact SO SCIENTIFIC REPORTS LA English DT Article ID PROSTAGLANDIN E-2; CYCLOOXYGENASE-2 INHIBITION; ENDOTHELIAL-CELLS; CONDITIONED MEDIA; GAP-JUNCTIONS; STROMAL CELLS; CANCER CELLS; RECEPTOR; GROWTH; DIFFERENTIATION AB Mesenchymal stem cells (MSCs) possess unique immunomodulatory abilities. Many studies have elucidated the clinical efficacy and underlying mechanisms of MSCs in immune disorders. Although immunoregulatory factors, such as Prostaglandin E-2 (PGE(2)), and their mechanisms of action on immune cells have been revealed, their effects on MSCs and regulation of their production by the culture environment are less clear. Therefore, we investigated the autocrine effect of PGE(2) on human adult stem cells from cord blood or adipose tissue, and the regulation of its production by cell-to-cell contact, followed by the determination of its immunomodulatory properties. MSCs were treated with specific inhibitors to suppress PGE(2) secretion, and proliferation was assessed. PGE(2) exerted an autocrine regulatory function in MSCs by triggering E-Prostanoid (EP) 2 receptor. Inhibiting PGE(2) production led to growth arrest, whereas addition of MSC-derived PGE(2) restored proliferation. The level of PGE(2) production from an equivalent number of MSCs was down-regulated via gap junctional intercellular communication. This cell contact-mediated decrease in PGE(2) secretion down-regulated the suppressive effect of MSCs on immune cells. In conclusion, PGE(2) produced by MSCs contributes to maintenance of self-renewal capacity through EP2 in an autocrine manner, and PGE(2) secretion is down-regulated by cell-to-cell contact, attenuating its immunomodulatory potency. C1 [Lee, Byung-Chul; Kim, Hyung-Sik; Shin, Tae-Hoon; Kang, Insung; Lee, Jin Young; Kim, Jae-Jun; Kang, Hyun Kyoung; Seo, Yoojin; Yu, Kyung-Rok; Choi, Soon Won; Kang, Kyung-Sun] Seoul Natl Univ, Coll Vet Med, Adult Stem Cell Res Ctr, Seoul 08826, South Korea. [Kim, Hyung-Sik] Pusan Natl Univ, Sch Med, Busan 49241, South Korea. [Kim, Hyung-Sik] Pusan Natl Univ Hosp, Biomed Res Inst, Busan 49241, South Korea. [Lee, Seunghee; Choi, Soon Won; Kang, Kyung-Sun] Seoul Natl Univ, Vet Med Res Inst, Coll Vet Med, Seoul 08826, South Korea. [Yu, Kyung-Rok] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Kang, KS (reprint author), Seoul Natl Univ, Coll Vet Med, Adult Stem Cell Res Ctr, Seoul 08826, South Korea.; Kang, KS (reprint author), Seoul Natl Univ, Vet Med Res Inst, Coll Vet Med, Seoul 08826, South Korea. EM kangpub@snu.ac.kr RI Kang, Kyung-Sun/G-6205-2013 FU Materials and Components Technology Development Program of MOTIE/KEIT, Republic of Korea [10046508]; Research Institute for Veterinary Science, Seoul National University (SNU, Republic of Korea); National Research Foundation of Korea [2014073322] FX This work was supported by the Materials and Components Technology Development Program of MOTIE/KEIT, Republic of Korea (10046508, Development of immunomodulatory cell therapeutics through the development of culture media supplements for mesenchymal stem cells), and supported under the framework of international cooperation program managed by National Research Foundation of Korea (2014073322), and partially supported by the Research Institute for Veterinary Science, Seoul National University (SNU, Republic of Korea). NR 43 TC 1 Z9 2 U1 3 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAY 27 PY 2016 VL 6 AR 26298 DI 10.1038/srep26298 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM8WZ UT WOS:000376646500001 PM 27230257 ER PT J AU Davis, S Xu, R Gebeab, S Riestra, P Gaye, A Khan, R Wilson, J Bidulescu, A AF Davis, S. Xu, R. Gebeab, S. Riestra, P. Gaye, A. Khan, R. Wilson, J. Bidulescu, A. TI Association of adipoq gene with type 2 diabetes and related phenotypes in african american men and women: The jackson heart study SO HUMAN GENOMICS LA English DT Meeting Abstract C1 [Davis, S.; Xu, R.; Gebeab, S.; Riestra, P.; Gaye, A.; Khan, R.] NHGRI, Cardiovasc Sect, Metab Cardiovasc & Inflammatory Dis Genom Branch, NIH, Bethesda, MD USA. [Wilson, J.] Univ Mississippi, Med Ctr, University, MS 38677 USA. [Bidulescu, A.] Indiana Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Bloomington, IN USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1473-9542 EI 1479-7364 J9 HUM GENOMICS JI Hum. Genomics PD MAY 26 PY 2016 VL 10 SU 1 MA P48 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA DW5LM UT WOS:000383686700090 ER PT J AU Landrum, M Lee, J Rubinstein, W Maglott, D AF Landrum, M. Lee, J. Rubinstein, W. Maglott, D. TI ClinVar: a multi-source archive for variant interpretation SO HUMAN GENOMICS LA English DT Meeting Abstract C1 [Landrum, M.; Lee, J.; Rubinstein, W.; Maglott, D.] NCBI, NLM, NIH, Bethesda, MD 20894 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1473-9542 EI 1479-7364 J9 HUM GENOMICS JI Hum. Genomics PD MAY 26 PY 2016 VL 10 SU 1 MA P57 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA DW5LM UT WOS:000383686700098 ER PT J AU Moore, A Wang, Z Hofmann, J Purdue, M Stolzenberg-Solomon, R Weinstein, S Albanes, D Liu, CS Cheng, WL Lin, TT Lan, Q Rothman, N Berndt, S AF Moore, A. Wang, Z. Hofmann, J. Purdue, M. Stolzenberg-Solomon, R. Weinstein, S. Albanes, D. Liu, C. -S. Cheng, W. -L. Lin, T. -T. Lan, Q. Rothman, N. Berndt, S. TI A meta-analysis of genome-wide association studies of mitochondrial dna copy number SO HUMAN GENOMICS LA English DT Meeting Abstract C1 [Moore, A.; Purdue, M.; Stolzenberg-Solomon, R.; Weinstein, S.; Albanes, D.; Lan, Q.; Rothman, N.; Berndt, S.] NCI, Rockville, MD USA. [Wang, Z.] St Jude Childrens Res Hosp, Memphis, TN USA. [Hofmann, J.] NCI, DHHS, NIH, Rockville, MD USA. [Liu, C. -S.; Cheng, W. -L.; Lin, T. -T.] Changhua Christian Hosp, Changhua, Taiwan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1473-9542 EI 1479-7364 J9 HUM GENOMICS JI Hum. Genomics PD MAY 26 PY 2016 VL 10 SU 1 MA P1 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA DW5LM UT WOS:000383686700057 ER PT J AU Mulvihill, JJ Baynam, G Gahl, W Groft, SC Kosaki, K Lasko, P Melegh, B Taruscio, D AF Mulvihill, J. J. Baynam, G. Gahl, W. Groft, S. C. Kosaki, K. Lasko, P. Melegh, B. Taruscio, D. TI The undiagnosed diseases network international (UDNI): clinical and laboratory research to meet patient needs SO HUMAN GENOMICS LA English DT Meeting Abstract C1 [Mulvihill, J. J.] Natl Human Genome Res Inst, Div Genom Med, Bethesda, MD USA. [Baynam, G.] Office Populat Hlth, Dept Hlth, Perth, WA, Australia. [Gahl, W.] Natl Human Genome Res Inst, Undiagnosed Dis Program, Bethesda, MD USA. [Groft, S. C.] NatL Ctr Adv Translat Sci, Natl Inst Hlth, Bethesda, MD USA. [Kosaki, K.] Keio Univ, Ctr Med Genet, Sch Med, Tokyo, Japan. [Lasko, P.] McGill Univ, Dept Biol, Montreal, PQ, Canada. [Melegh, B.] Univ Pecs, Dept Med Genet, Pecs, Hungary. [Taruscio, D.] Natl Ctr Rare Dis, Ist Super Sanita, Rome, Italy. RP Mulvihill, JJ (reprint author), Natl Human Genome Res Inst, Div Genom Med, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1473-9542 EI 1479-7364 J9 HUM GENOMICS JI Hum. Genomics PD MAY 26 PY 2016 VL 10 SU 1 MA O34 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA DW5LM UT WOS:000383686700035 ER PT J AU Sherry, S Xiao, C Slotta, D Rodarmer, K Feolo, M Kimelman, M Godynskiy, G O'Sullivan, C Yaschenko, E AF Sherry, S. Xiao, C. Slotta, D. Rodarmer, K. Feolo, M. Kimelman, M. Godynskiy, G. O'Sullivan, C. Yaschenko, E. TI Accessing genomic evidence for clinical variants at NCBI SO HUMAN GENOMICS LA English DT Meeting Abstract C1 [Sherry, S.; Xiao, C.; Slotta, D.; Rodarmer, K.; Feolo, M.; Kimelman, M.; Godynskiy, G.; O'Sullivan, C.; Yaschenko, E.] NCBI, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1473-9542 EI 1479-7364 J9 HUM GENOMICS JI Hum. Genomics PD MAY 26 PY 2016 VL 10 SU 1 MA P36 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA DW5LM UT WOS:000383686700080 ER PT J AU Xiao, C Yaschenko, E Sherry, S AF Xiao, C. Yaschenko, E. Sherry, S. TI NGS-SWIFT: a cloud-based variant analysis framework using control-accessed sequencing data from DBGAP/SRA SO HUMAN GENOMICS LA English DT Meeting Abstract C1 [Xiao, C.; Yaschenko, E.; Sherry, S.] NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1473-9542 EI 1479-7364 J9 HUM GENOMICS JI Hum. Genomics PD MAY 26 PY 2016 VL 10 SU 1 MA P37 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA DW5LM UT WOS:000383686700081 ER PT J AU Somasundaram, V Hemalatha, SK Pal, K Sinha, S Nair, AS Mukhopadhyay, D Srinivas, P AF Somasundaram, Veena Hemalatha, Sreelatha K. Pal, Krishnendu Sinha, Sutapa Nair, Asha S. Mukhopadhyay, Debabrata Srinivas, Priya TI Selective mode of action of plumbagin through BRCA1 deficient breast cancer stem cells SO BMC CANCER LA English DT Article DE BRCA1; Cancer stem cells; Plumbagin; ALDH1 ID EPITHELIAL-MESENCHYMAL TRANSITION; ACUTE MYELOID-LEUKEMIA; CD44(+)/CD24(-) PHENOTYPE; DNA-DAMAGE; IN-VIVO; MAMMARY; APOPTOSIS; ALDH1; LINES; IDENTIFICATION AB Background: Studies over the past decade and half have identified cancer stem cells (CSCs) to be responsible for tumorigenesis, invasion, sustenance of metastatic disease, radio-and chemo-resistance and tumor relapse. Recent reports have described the plasticity of breast CSCs (BCSCs) to shift between the epithelial and mesenchymal phenotypes via Epithelial-Mesenchymal Transition (EMT) and Mesenchymal-Epithelial Transition (MET) states as the reason for their invasive capabilities. Additionally, BRCA1 has been found to be a mammary stem cell fate determinant. However, it is not clear what would be the best marker that can be used for identifying CSCs in BRCA1 mutated cancers. Also, anticancer agents that can reduce CSC population in a BRCA1 defective condition have not been addressed so far. Methods: Putative BCSCs were identified based on Hoechst exclusion, CD44(+)/24(-/low) expression and Aldehyde Dehydrogenase 1 (ALDH1) positivity using flow cytometry. The 'stemness' of the isolated ALDH1+ cells were analysed by immunofluorescence, western blotting for stem cell and EMT markers as well as in vitro mammosphere assays. Induction of Reactive Oxygen Species (ROS) by Plumbagin (PB) in BCSCs was assayed by Dichloro-dihydro-fluorescein diacetate (DCF-DA) staining. Ovarian cancer xenografts treated with PB were subjected to immunohistochemical analysis to study the ability of PB to target CSCs. Results: We have confirmed that ALDH1 positivity is the best marker for the identification of BCSCs in BRCA1-defective breast cancer cell lines when compared to the CD marker profile and Side Population (SP) analysis. BRCA1 status was observed to be a determinant of the abundance of epithelial-like (ALDH1+) or mesenchymal-like (CD44(+)/24(-/low)) BCSCs, and the reconstitution of a full length, wild type BRCA1 in HCC1937 breast cancer cells possessing a mutated BRCA1, transforms them from 'stem-like' to more 'mesenchymal'. For the first time we have shown that Plumbagin (PB), a naturally occurring naphthoquinone which is predominantly a ROS inducer, could reduce BCSCs specifically in BRCA1-defective, basal-like cancer cells. Conclusions: The best marker for identifying BCSCs in BRCA1 defective condition could be ALDH1 and that BRCA1 mutated BCSCs would be mostly 'stem like' than 'mesenchymal'. Also ROS inducers like PB could reduce BCSCs in BRCA1 defective cancers. C1 [Somasundaram, Veena; Hemalatha, Sreelatha K.; Nair, Asha S.; Srinivas, Priya] Rajiv Gandhi Ctr Biotechnol, Canc Res Program, Thiruvananthapuram 695014, Kerala, India. [Pal, Krishnendu; Mukhopadhyay, Debabrata] Mayo Clin, Dept Biochem & Mol Biol, Coll Med, Rochester, MN 55905 USA. [Sinha, Sutapa] Mayo Clin, Dept Hematol, Coll Med, Rochester, MN 55905 USA. [Somasundaram, Veena] NCI, Ctr Canc Res, Bldg 567,Room 254, Frederick, MD 21702 USA. RP Srinivas, P (reprint author), Rajiv Gandhi Ctr Biotechnol, Canc Res Program, Thiruvananthapuram 695014, Kerala, India. EM priyasrinivas@rgcb.res.in OI Pal, Krishnendu/0000-0002-4006-213X FU intramural grant from Rajiv Gandhi Centre for Biotechnology, Kerala State Council for Science Technology and Environment [016/SRSHS/2011/CSTE]; Board of Research in Nuclear Sciences [2009/37/5/BRNS/1620, 37(1)/14/16/2014]; Indian Council for Medical Research (ICMR) [53/20/2012-BMS]; National Institute of Health, USA [CA78383, CA148073]; Council for Scientific and Industrial Research, Govt. of India (C.S.I.R) [09/716(0105)/2008-EMR-I]; Indian Council for Medical Research, Govt. of India (ICMR) [3/1/3/JRF-2009/HRD-110(22150)] FX This work was supported by intramural grant from Rajiv Gandhi Centre for Biotechnology, Kerala State Council for Science Technology and Environment (No. 016/SRSHS/2011/CSTE), a grant-in-aid from the Board of Research in Nuclear Sciences (No. 2009/37/5/BRNS/1620 & No.37(1)/14/16/2014) and Indian Council for Medical Research (ICMR) (No. 53/20/2012-BMS) to PS. The work was partly supported by the grants CA78383 and CA148073 from National Institute of Health, USA to DM. The Senior Research Fellowships awarded by the Council for Scientific and Industrial Research, Govt. of India (C.S.I.R, Award No. 09/716(0105)/2008-EMR-I) (to VS) and the Indian Council for Medical Research, Govt. of India (ICMR, Award No. 3/1/3/JRF-2009/HRD-110(22150)) (to SKH) are duly acknowledged. NR 61 TC 0 Z9 0 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD MAY 26 PY 2016 VL 16 AR 336 DI 10.1186/s12885-016-2372-4 PG 16 WC Oncology SC Oncology GA DN3LH UT WOS:000376963000001 PM 27229859 ER PT J AU Lv, PC Elsayed, MSA Agama, K Marchand, C Pommier, Y Cushman, M AF Lv, Peng-Cheng Elsayed, Mohamed S. A. Agama, Keli Marchand, Christophe Pommier, Yves Cushman, Mark TI Design, Synthesis, and Biological Evaluation of Potential Prodrugs Related to the Experimental Anticancer Agent Indotecan (LMP400) SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID TOPOISOMERASE-I INHIBITORS; LACTAM SIDE-CHAIN; CANCER-CELLS; DNA TOPOISOMERASES; NITRATED INDENOISOQUINOLINES; STEREOSELECTIVE HYDROLYSIS; CAMPTOTHECIN DERIVATIVES; CLEAVAGE COMPLEXES; ANTITUMOR-ACTIVITY; NORMAL TISSUE AB Indenoisoquinoline topoisomerase I (Top1) inhibitors are a novel class of anticancer agents with two compounds in clinical trials. Recent metabolism studies of indotecan (LMP400) led to the discovery of the biologically active 2-hydroxylated analogue and 3-hydroxylated metabolite, thus providing strategically placed functional groups for the preparation of a variety of potential ester prodrugs of these two compounds. The current study details the design and synthesis of two series of indenoisoquinoline prodrugs, and it also reveals how substituents on the O-2 and O-3 positions of the A ring, which are next to the cleaved DNA strand in the drug-DNA-Top1 ternary cleavage complex, affect Top1 inhibitory activity and cytotoxicity. Many of the indenoisoquinoline prodrugs were very potent antiproliferative agents with GI(50) values below 10 nM in a variety of human cancer cell lines. C1 [Lv, Peng-Cheng; Elsayed, Mohamed S. A.; Cushman, Mark] Purdue Univ, Coll Pharm, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. [Lv, Peng-Cheng; Elsayed, Mohamed S. A.; Cushman, Mark] Purdue Univ, Purdue Ctr Canc Res, W Lafayette, IN 47907 USA. [Agama, Keli; Marchand, Christophe; Pommier, Yves] NCI, Dev Therapeut Branch, Bethesda, MD 20892 USA. [Agama, Keli; Marchand, Christophe; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Cushman, M (reprint author), Purdue Univ, Coll Pharm, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA.; Cushman, M (reprint author), Purdue Univ, Purdue Ctr Canc Res, W Lafayette, IN 47907 USA. EM cushman@purdue.edu FU National Institutes of Health (NIH) [UO1 CA89566, P30 CA023168]; NIH, National Cancer Institute, Center for Cancer Research; Developmental Therapeutics Program at the National Cancer Institute [NO1-CO-56000] FX This work was made possible by the National Institutes of Health (NIH) through support with Research Grants UO1 CA89566 and P30 CA023168. This research was also supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. In vitro cytotoxicity testing was performed by the Developmental Therapeutics Program at the National Cancer Institute, under contract NO1-CO-56000. The rat plasma stability testing of the acetate pro drug 16 was conducted by Cyprotex US, LLC, 313 Pleasant St., Watertown, MA 02472. NR 71 TC 4 Z9 4 U1 8 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD MAY 26 PY 2016 VL 59 IS 10 BP 4890 EP 4899 DI 10.1021/acs.jmedchem.6b00220 PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA DN1QN UT WOS:000376840600037 PM 27097152 ER PT J AU Ortiz, AM Carnathan, DG Yu, J Sheehan, KM Kim, P Reynaldi, A Vanderford, TH Klatt, NR Brenchley, JM Davenport, MP Silvestri, G AF Ortiz, Alexandra M. Carnathan, Diane G. Yu, Joana Sheehan, Katherine M. Kim, Peter Reynaldi, Arnold Vanderford, Thomas H. Klatt, Nichole R. Brenchley, Jason M. Davenport, Miles P. Silvestri, Guido TI Analysis of the In Vivo Turnover of CD4+T-Cell Subsets in Chronically SIV-Infected Sooty Mangabeys SO PLOS ONE LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; CD4(+) T-CELLS; LYMPHOCYTE TURNOVER; HIV-1 INFECTION; MACAQUES; SUBPOPULATIONS; DYNAMICS; RATES AB Aberrant turnover of memory CD4+ T-cells is central to Acquired Immunodeficiency Syndrome (AIDS) progression. Understanding the relationship between the turnover of CD4+ subsets and immunological homeostasis during simian immunodeficiency virus (SIV) infection in natural hosts may provide insight into mechanisms of immune regulation that may serve as models for therapeutic intervention in Human Immunodeficiency Virus (HIV)infected persons. Sooty mangabeys (SMs) have naturally evolved with SIV to avoid AIDS progression while maintaining healthy peripheral CD4+ T-cell counts and thus represent a model by which therapeutic interventions for AIDS progression might be elucidated. To assess the relationship between the turnover of CD4+ subsets and immunological homeostasis during SIV infection in non-progressive hosts, we treated 6 SIV-uninfected and 9 SIVinfected SMs with 2'-bromo-5'-deoxyuridine (BrdU) for 14 days and longitudinally assessed CD4+ T-cell subset turnover by polychromatic flow cytometry. We observed that, in SIVinfected SMs, turnover of CD4+ T-cell naive and central, transitional, and effector memory subsets is comparable to that in uninfected animals. Comparable turnover of CD4+ T-cell subsets irrespective of SIV-infection status likely contributes to the lack of aberrant immune activation and disease progression observed after infection in non-progressive hosts. C1 [Ortiz, Alexandra M.; Carnathan, Diane G.; Yu, Joana; Sheehan, Katherine M.; Vanderford, Thomas H.; Silvestri, Guido] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. [Ortiz, Alexandra M.; Carnathan, Diane G.; Yu, Joana; Sheehan, Katherine M.; Vanderford, Thomas H.; Silvestri, Guido] Emory Univ, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Kim, Peter; Reynaldi, Arnold; Davenport, Miles P.] Univ New S Wales, Ctr Vasc Res, Complex Syst Biol Grp, Sydney, NSW 2052, Australia. [Ortiz, Alexandra M.; Klatt, Nichole R.; Brenchley, Jason M.] NIH, Mol Microbiol Lab, Bldg 10, Bethesda, MD 20892 USA. [Klatt, Nichole R.] Univ Washington, Dept Pharmaceut, Seattle, WA 98195 USA. RP Silvestri, G (reprint author), Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA.; Silvestri, G (reprint author), Emory Univ, Emory Vaccine Ctr, Atlanta, GA 30322 USA. EM gsilves@emory.edu OI Reynaldi, Arnold/0000-0002-5529-5542 FU National Institutes of Health/National Center for Research Resources [P51RR000165]; Office of Research Infrastructure Programs / OD [P51OD011132]; [R37-AI066998] FX This work was supported primarily by R37-AI066998 to GS (URL: www.grants.nih.gov). In addition, it was supported by the National Institutes of Health/National Center for Research Resources (P51RR000165) and is currently supported by the Office of Research Infrastructure Programs / OD P51OD011132 to the Yerkes National Primate Research Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 15 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 26 PY 2016 VL 11 IS 5 AR e0156352 DI 10.1371/journal.pone.0156352 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DN2GQ UT WOS:000376882500121 PM 27227993 ER PT J AU Zanos, P Moaddel, R Morris, PJ Georgiou, P Fischell, J Elmer, GI Alkondon, M Yuan, PX Pribut, HJ Singh, NS Dossou, KSS Fang, YH Huang, XP Mayo, CL Wainer, IW Albuquerque, EX Thompson, SM Thomas, CJ Zarate, CA Gould, TD AF Zanos, Panos Moaddel, Ruin Morris, Patrick J. Georgiou, Polymnia Fischell, Jonathan Elmer, Greg I. Alkondon, Manickavasagom Yuan, Peixiong Pribut, Heather J. Singh, Nagendra S. Dossou, Katina S. S. Fang, Yuhong Huang, Xi-Ping Mayo, Cheryl L. Wainer, Irving W. Albuquerque, Edson X. Thompson, Scott M. Thomas, Craig J. Zarate, Carlos A., Jr. Gould, Todd D. TI NMDAR inhibition-independent antidepressant actions of ketamine metabolites SO NATURE LA English DT Article ID RESISTANT BIPOLAR DEPRESSION; D-ASPARTATE ANTAGONIST; STAR-ASTERISK-D; SUSTAINED ANTIDEPRESSANT; MAJOR DEPRESSION; RECEPTOR ANTAGONIST; SEX-DIFFERENCES; AMPA RECEPTOR; IN-VITRO; MICE AB Major depressive disorder affects around 16 per cent of the world population at some point in their lives. Despite the availability of numerous monoaminergic-based antidepressants, most patients require several weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive, glutamatergic NMDAR (N-methyl-D-aspartate receptor) antagonist(R,S)-ketamine exerts rapid and sustained antidepressant effects after a single dose in patients with depression, but its use is associated with undesirable side effects. Here we show that the metabolism of (R,S)-ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2R,6R)-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant-related actions in mice. These antidepressant actions are independent of NMDAR inhibition but involve early and sustained activation of AMPARs (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors). We also establish that (2R,6R)-HNK lacks ketamine-related side effects. Our data implicate a novel mechanism underlying the antidepressant properties of (R,S)-ketamine and have relevance for the development of next-generation, rapid-acting antidepressants. C1 [Zanos, Panos; Georgiou, Polymnia; Elmer, Greg I.; Pribut, Heather J.; Thompson, Scott M.; Gould, Todd D.] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. [Moaddel, Ruin; Singh, Nagendra S.; Dossou, Katina S. S.; Wainer, Irving W.] NIA, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. [Morris, Patrick J.; Fang, Yuhong; Thomas, Craig J.] NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Fischell, Jonathan; Thompson, Scott M.] Univ Maryland, Sch Med, Dept Physiol, Baltimore, MD 21201 USA. [Elmer, Greg I.; Albuquerque, Edson X.; Gould, Todd D.] Univ Maryland, Sch Med, Dept Pharmacol, Baltimore, MD 21201 USA. [Elmer, Greg I.; Mayo, Cheryl L.] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Catonsville, MD 21228 USA. [Alkondon, Manickavasagom; Albuquerque, Edson X.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Div Translat Toxicol, Baltimore, MD 21201 USA. [Yuan, Peixiong; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Huang, Xi-Ping] Univ N Carolina, Sch Med, Dept Pharmacol, NIMH Psychoact Drug Screening Program, Chapel Hill, NC 27516 USA. [Huang, Xi-Ping] Univ N Carolina, Sch Med, Div Chem Biol & Med Chem, Chapel Hill, NC 27516 USA. [Albuquerque, Edson X.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Gould, Todd D.] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Wainer, Irving W.] Mitchell Woods Pharmaceut, Shelton, CT 06484 USA. RP Gould, TD (reprint author), Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA.; Gould, TD (reprint author), Univ Maryland, Sch Med, Dept Pharmacol, Baltimore, MD 21201 USA.; Gould, TD (reprint author), Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. EM gouldlab@me.com OI Morris, Patrick/0000-0003-2380-4178 FU NIMH [MH099345, MH107615, MH086828, HHSN-271-2008-025C]; NIA, NIH; NIMH, NIH; NCATS, NIH; NIA [HHSN271201000008I] FX We thank A. Keller for his assistance with the qEEG experiments, M. K. Lobo for assistance with the social defeat experiments, B. Alkondon for the rat hippocampal slice preparation and biocytin processing, V. Meadows and S. Krimmel for assistance with behavioural experiments and manuscript review, E. Pereira for critical comments on the manuscript and figures, D. Luckenbaugh for assistance with statistical analysis, and C. Moore for the small molecule X-ray crystallography. Research was supported by NIMH grants MH099345 and MH107615 to T.D.G. and MH086828 to S.M.T., and the NIA (R.M., I.W.W.), NIMH (C.A.Z.), and NCATS (C.J.T.) NIH intramural research programs. Receptor binding profiles and Ki determinations were supported by the NIMH Psychoactive Drug Screening Program, Contract HHSN-271-2008-025C, to B. L. Roth in conjunction with J. Driscoll. Initial synthesis of the ketamine metabolites used in this study was supported by NIA Contract HHSN271201000008I to I.W.W. NR 39 TC 73 Z9 73 U1 27 U2 47 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAY 26 PY 2016 VL 533 IS 7604 BP 481 EP + DI 10.1038/nature17998 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM6EJ UT WOS:000376443100030 PM 27144355 ER PT J AU Okbay, A Beauchamp, JP Fontana, MA Lee, JJ Pers, TH Rietveld, CA Turley, P Chen, GB Emilsson, V Meddens, SFW Oskarsson, S Pickrell, JK Thom, K Timshel, P de Vlaming, R Abdellaoui, A Ahluwalia, TS Bacelis, J Baumbach, C Bjornsdottir, G Brandsma, JH Concas, MP Derringer, J Furlotte, NA Galesloot, TE Girotto, G Gupta, R Hall, LM Harris, SE Hofer, E Horikoshi, M Huffman, JE Kaasik, K Kalafati, IP Karlsson, R Kong, A Lahti, J van der Lee, SJ de Leeuw, C Lind, PA Lindgren, KO Liu, T Mangino, M Marten, J Mihailov, E Miller, MB van der Most, PJ Oldmeadow, C Payton, A Pervjakova, N Peyrot, WJ Qian, Y Raitakari, O Rueedi, R Salvi, E Schmidt, B Schraut, KE Shi, JX Smith, AV Poot, RA St Pourcain, B Teumer, A Thorleifsson, G Verweij, N Vuckovic, D Wellmann, J Westra, HJ Yang, JY Zhao, W Zhu, ZH Alizadeh, BZ Amin, N Bakshi, A Baumeister, SE Biino, G Bonnelykke, K Boyle, PA Campbell, H Cappuccio, FP Davies, G De Neve, JE Deloukas, P Demuth, I Ding, J Eibich, P Eisele, L Eklund, N Evans, DM Faul, JD Feitosa, MF Forstner, AJ Gandin, I Gunnarsson, B Halldorsson, BV Harris, TB Heath, AC Hocking, LJ Holliday, EG Homuth, G Horan, MA Hottenga, JJ de Jager, PL Joshi, PK Jugessur, A Kaakinen, MA Kahonen, M Kanoni, S Keltigangas-Jarvinen, L Kiemeney, LALM Kolcic, I Koskinen, S Kraja, AT Kroh, M Kutalik, Z Latvala, A Launer, LJ Lebreton, MP Levinson, DF Lichtenstein, P Lichtner, P Liewald, DCM Loukola, A Madden, PA Magi, R Maki-Opas, T Marioni, RE Marques-Vidal, P Meddens, GA McMahon, G Meisinger, C Meitinger, T Milaneschi, Y Milani, L Montgomery, GW Myhre, R Nelson, CP Nyholt, DR Ollier, WER Palotie, A Paternoster, L Pedersen, NL Petrovic, KE Porteous, DJ Raikkonen, K Ring, SM Robino, A Rostapshova, O Rudan, I Rustichini, A Salomaa, V Sanders, AR Sarin, AP Schmidt, H Scott, RJ Smith, BH Smith, JA Staessen, JA Steinhagen-Thiessen, E Strauch, K Terracciano, A Tobin, MD Ulivi, S Vaccargiu, S Quaye, L van Rooij, FJA Venturini, C Vinkhuyzen, AAE Volker, U Volzke, H Vonk, JM Vozzi, D Waage, J Ware, EB Willemsen, G Attia, JR Bennett, DA Berger, K Bertram, L Bisgaard, H Boomsma, DI Borecki, IB Bultmann, U Chabris, CF Cucca, F Cusi, D Deary, IJ Dedoussis, GV van Duijn, CM Eriksson, JG Franke, B Franke, L Gasparini, P Gejman, PV Gieger, C Grabe, HJ Gratten, J Groenen, PJF Gudnason, V van der Harst, P Hayward, C Hinds, DA Hoffmann, W Hyppnen, E Iacono, WG Jacobsson, B Jarvelin, MR Jockel, KH Kaprio, J Kardia, SLR Lehtimaki, T Lehrer, SF Magnusson, PKE Martin, NG McGue, M Metspalu, A Pendleton, N Penninx, BWJH Perola, M Pirastu, N Pirastu, M Polasek, O Posthuma, D Power, C Province, MA Samani, NJ Schlessinger, D Schmidt, R Sorensen, TIA Spector, TD Stefansson, K Thorsteinsdottir, U Thurik, AR Timpson, NJ Tiemeier, H Tung, JY Uitterlinden, AG Vitart, V Vollenweider, P Weir, DR Wilson, JF Wright, AF Conley, DC Krueger, RF Smith, GD Hofman, A Laibson, DI Medland, SE Meyer, MN Yang, J Johannesson, M Visscher, PM Esko, T Koellinger, PD Cesarini, D Benjamin, DJ AF Okbay, Aysu Beauchamp, Jonathan P. Fontana, Mark Alan Lee, James J. Pers, Tune H. Rietveld, Cornelius A. Turley, Patrick Chen, Guo-Bo Emilsson, Valur Meddens, S. Fleur W. Oskarsson, Sven Pickrell, Joseph K. Thom, Kevin Timshel, Pascal de Vlaming, Ronald Abdellaoui, Abdel Ahluwalia, Tarunveer S. Bacelis, Jonas Baumbach, Clemens Bjornsdottir, Gyda Brandsma, Johannes H. Concas, Maria Pina Derringer, Jaime Furlotte, Nicholas A. Galesloot, Tessel E. Girotto, Giorgia Gupta, Richa Hall, Leanne M. Harris, Sarah E. Hofer, Edith Horikoshi, Momoko Huffman, Jennifer E. Kaasik, Kadri Kalafati, Ioanna P. Karlsson, Robert Kong, Augustine Lahti, Jari van der Lee, Sven J. de Leeuw, Christiaan Lind, Penelope A. Lindgren, Karl-Oskar Liu, Tian Mangino, Massimo Marten, Jonathan Mihailov, Evelin Miller, Michael B. van der Most, Peter J. Oldmeadow, Christopher Payton, Antony Pervjakova, Natalia Peyrot, Wouter J. Qian, Yong Raitakari, Olli Rueedi, Rico Salvi, Erika Schmidt, Brge Schraut, Katharina E. Shi, Jianxin Smith, Albert V. Poot, Raymond A. St Pourcain, Beate Teumer, Alexander Thorleifsson, Gudmar Verweij, Niek Vuckovic, Dragana Wellmann, Juergen Westra, Harm-Jan Yang, Jingyun Zhao, Wei Zhu, Zhihong Alizadeh, Behrooz Z. Amin, Najaf Bakshi, Andrew Baumeister, Sebastian E. Biino, Ginevra Bonnelykke, Klaus Boyle, Patricia A. Campbell, Harry Cappuccio, Francesco P. Davies, Gail De Neve, Jan-Emmanuel Deloukas, Panos Demuth, Ilja Ding, Jun Eibich, Peter Eisele, Lewin Eklund, Niina Evans, David M. Faul, Jessica D. Feitosa, Mary F. Forstner, Andreas J. Gandin, Ilaria Gunnarsson, Bjarni Halldorsson, Bjarni V. Harris, Tamara B. Heath, Andrew C. Hocking, Lynne J. Holliday, Elizabeth G. Homuth, Georg Horan, Michael A. Hottenga, Jouke-Jan de Jager, Philip L. Joshi, Peter K. Jugessur, Astanand Kaakinen, Marika A. Kahonen, Mika Kanoni, Stavroula Keltigangas-Jarvinen, Liisa Kiemeney, Lambertus A. L. M. Kolcic, Ivana Koskinen, Seppo Kraja, Aldi T. Kroh, Martin Kutalik, Zoltan Latvala, Antti Launer, Lenore J. Lebreton, Mael P. Levinson, Douglas F. Lichtenstein, Paul Lichtner, Peter Liewald, David C. M. Loukola, Anu Madden, Pamela A. Magi, Reedik Maki-Opas, Tomi Marioni, Riccardo E. Marques-Vidal, Pedro Meddens, Gerardus A. McMahon, George Meisinger, Christa Meitinger, Thomas Milaneschi, Yusplitri Milani, Lili Montgomery, Grant W. Myhre, Ronny Nelson, Christopher P. Nyholt, Dale R. Ollier, William E. R. Palotie, Aarno Paternoster, Lavinia Pedersen, Nancy L. Petrovic, Katja E. Porteous, David J. Raikkonen, Katri Ring, Susan M. Robino, Antonietta Rostapshova, Olga Rudan, Igor Rustichini, Aldo Salomaa, Veikko Sanders, Alan R. Sarin, Antti-Pekka Schmidt, Helena Scott, Rodney J. Smith, Blair H. Smith, Jennifer A. Staessen, Jan A. Steinhagen-Thiessen, Elisabeth Strauch, Konstantin Terracciano, Antonio Tobin, Martin D. Ulivi, Sheila Vaccargiu, Simona Quaye, Lydia van Rooij, Frank J. A. Venturini, Cristina Vinkhuyzen, Anna A. E. Volker, Uwe Volzke, Henry Vonk, Judith M. Vozzi, Diego Waage, Johannes Ware, Erin B. Willemsen, Gonneke Attia, John R. Bennett, David A. Berger, Klaus Bertram, Lars Bisgaard, Hans Boomsma, Dorret I. Borecki, Ingrid B. Bultmann, Ute Chabris, Christopher F. Cucca, Francesco Cusi, Daniele Deary, Ian J. Dedoussis, George V. van Duijn, Cornelia M. Eriksson, Johan G. Franke, Barbara Franke, Lude Gasparini, Paolo Gejman, Pablo V. Gieger, Christian Grabe, Hans-Jorgen Gratten, Jacob Groenen, Patrick J. F. Gudnason, Vilmundur van der Harst, Pim Hayward, Caroline Hinds, David A. Hoffmann, Wolfgang Hyppnen, Elina Iacono, William G. Jacobsson, Bo Jarvelin, Marjo-Riitta Jockel, Karl-Heinz Kaprio, Jaakko Kardia, Sharon L. R. Lehtimaki, Terho Lehrer, Steven F. Magnusson, Patrik K. E. Martin, Nicholas G. McGue, Matt Metspalu, Andres Pendleton, Neil Penninx, Brenda W. J. H. Perola, Markus Pirastu, Nicola Pirastu, Mario Polasek, Ozren Posthuma, Danielle Power, Christine Province, Michael A. Samani, Nilesh J. Schlessinger, David Schmidt, Reinhold Sorensen, Thorkild I. A. Spector, Tim D. Stefansson, Kari Thorsteinsdottir, Unnur Thurik, A. Roy Timpson, Nicholas J. Tiemeier, Henning Tung, Joyce Y. Uitterlinden, Andre G. Vitart, Veronique Vollenweider, Peter Weir, David R. Wilson, James F. Wright, Alan F. Conley, Dalton C. Krueger, Robert F. Smith, George Davey Hofman, Albert Laibson, David I. Medland, Sarah E. Meyer, Michelle N. Yang, Jian Johannesson, Magnus Visscher, Peter M. Esko, Tonu Koellinger, Philipp D. Cesarini, David Benjamin, Daniel J. CA LifeLines Cohort Study TI Genome-wide association study identifies 74 loci associated with educational attainment SO NATURE LA English DT Article ID HERITABILITY; TRAITS; ACHIEVEMENT; IQ AB Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals(1). Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample(1,2) of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases. C1 [Okbay, Aysu; Rietveld, Cornelius A.; de Vlaming, Ronald; Thurik, A. Roy] Erasmus Univ, Erasmus Sch Econ, Dept Appl Econ, NL-3062 PA Rotterdam, Netherlands. [Okbay, Aysu; Rietveld, Cornelius A.; de Vlaming, Ronald; van der Lee, Sven J.; Amin, Najaf; van Rooij, Frank J. A.; van Duijn, Cornelia M.; Tiemeier, Henning; Uitterlinden, Andre G.] Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands. [Okbay, Aysu; Rietveld, Cornelius A.; Meddens, S. Fleur W.; de Vlaming, Ronald; Palotie, Aarno; Thurik, A. Roy; Koellinger, Philipp D.] Erasmus Univ, Inst Behav & Biol, NL-3062 PA Rotterdam, Netherlands. [Beauchamp, Jonathan P.; Turley, Patrick; Rostapshova, Olga; Laibson, David I.] Harvard Univ, Dept Econ, Cambridge, MA 02138 USA. [Fontana, Mark Alan; Benjamin, Daniel J.] Univ So Calif, Ctr Econ & Social Res, Los Angeles, CA 90089 USA. [Lee, James J.; Miller, Michael B.; Iacono, William G.; McGue, Matt; Krueger, Robert F.] Univ Minnesota Twin Cities, Dept Psychol, Minneapolis, MN 55455 USA. [Pers, Tune H.; Hofman, Albert; Esko, Tonu] Boston Childrens Hosp, Div Endocrinol, Boston, MA USA. [Pers, Tune H.; Hofman, Albert; Esko, Tonu] Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA USA. [Pers, Tune H.; Timshel, Pascal; Westra, Harm-Jan; de Jager, Philip L.; Esko, Tonu] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Pers, Tune H.; Ahluwalia, Tarunveer S.; Sorensen, Thorkild I. A.] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, DK-2100 Copenhagen, Denmark. [Pers, Tune H.] Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark. [Chen, Guo-Bo; Zhu, Zhihong; Bakshi, Andrew; Marioni, Riccardo E.; Vinkhuyzen, Anna A. E.; Gratten, Jacob; Yang, Jian; Visscher, Peter M.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia. [Emilsson, Valur; Gudnason, Vilmundur] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Emilsson, Valur] Univ Iceland, Fac Pharmaceut Sci, IS-107 Reykjavik, Iceland. [Meddens, S. Fleur W.; de Leeuw, Christiaan; Posthuma, Danielle; Koellinger, Philipp D.] Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Complex Trait Genet, NL-1081 HV Amsterdam, Netherlands. [Meddens, S. Fleur W.; Lebreton, Mael P.; Koellinger, Philipp D.] Univ Amsterdam, Amsterdam Business Sch, NL-1018 TV Amsterdam, Netherlands. [Oskarsson, Sven; Lindgren, Karl-Oskar] Uppsala Univ, Dept Govt, S-75120 Uppsala, Sweden. [Pickrell, Joseph K.] New York Genome Ctr, New York, NY 10013 USA. [Thom, Kevin; Cesarini, David] NYU, Dept Econ, New York, NY 10003 USA. [Timshel, Pascal] Tech Univ Denmark, Ctr Biol Sequence Anal, Dept Syst Biol, DK-2800 Lyngby, Denmark. [Abdellaoui, Abdel; Hottenga, Jouke-Jan; Willemsen, Gonneke; Boomsma, Dorret I.] Vrije Univ Amsterdam, Dept Biol Psychol, NL-1081 BT Amsterdam, Netherlands. [Ahluwalia, Tarunveer S.; Waage, Johannes; Bisgaard, Hans] Univ Copenhagen, Herlev & Gentofte Hosp, Copenhagen Prospect Studies Asthma Childhood, COPSAC, DK-2820 Copenhagen, Denmark. [Ahluwalia, Tarunveer S.; Waage, Johannes] Steno Diabet Ctr, DK-2820 Gentofte, Denmark. [Bacelis, Jonas; Jacobsson, Bo] Sahlgrens Acad, Inst Clin Sci, Dept Obstet & Gynecol, S-41685 Gothenburg, Sweden. [Baumbach, Clemens; Gieger, Christian] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany. [Baumbach, Clemens; Meisinger, Christa] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, D-85764 Neuherberg, Germany. [Brandsma, Johannes H.; Poot, Raymond A.] Erasmus MC, Dept Cell Biol, NL-3015 CN Rotterdam, Netherlands. [Concas, Maria Pina; Pirastu, Mario] Natl Res Council Italy, UOS Sassari, Ist Ric Genet & Biomed, I-07100 Sassari, Italy. [Derringer, Jaime] Univ Illinois, Psychol, Champaign, IL 61820 USA. [Furlotte, Nicholas A.; Hinds, David A.; Tung, Joyce Y.] 23andMe Inc, Mountain View, CA 94041 USA. [Galesloot, Tessel E.; Kiemeney, Lambertus A. L. M.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, NL-6500 HB Nijmegen, Netherlands. [Girotto, Giorgia; Vuckovic, Dragana; Gandin, Ilaria; Gasparini, Paolo; Pirastu, Nicola] Univ Trieste, Dept Med Surg & Hlth Sci, I-34100 Trieste, Italy. [Gupta, Richa; Latvala, Antti; Loukola, Anu; Kaprio, Jaakko] Univ Helsinki, Dept Publ Hlth, Helsinki 00014, Finland. [Hall, Leanne M.; Nelson, Christopher P.; Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England. 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RP Koellinger, PD (reprint author), Erasmus Univ, Inst Behav & Biol, NL-3062 PA Rotterdam, Netherlands.; Benjamin, DJ (reprint author), Univ So Calif, Ctr Econ & Social Res, Los Angeles, CA 90089 USA.; Visscher, PM (reprint author), Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia.; Koellinger, PD (reprint author), Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Complex Trait Genet, NL-1081 HV Amsterdam, Netherlands.; Koellinger, PD (reprint author), Univ Amsterdam, Amsterdam Business Sch, NL-1018 TV Amsterdam, Netherlands.; Cesarini, D (reprint author), NYU, Dept Econ, New York, NY 10003 USA.; Visscher, PM (reprint author), Univ Queensland, Diamantina Inst, Translat Res Inst, Brisbane, Qld 4102, Australia.; Cesarini, D (reprint author), Res Inst Ind Econ, S-10215 Stockholm, Sweden. EM peter.visscher@uq.edu.au; p.d.koellinger@vu.nl; dac12@nyu.edu; daniel.benjamin@gmail.com RI Verweij, Niek/A-4499-2017; Thurik, Roy/A-9386-2012; Davey Smith, George/A-7407-2013; Magnusson, Patrik/C-4458-2017; Gratten, Jake (Jacob)/G-1485-2011; Polasek, Ozren/B-6002-2011; Kolcic, Ivana/E-2713-2017; Feitosa, Mary/K-8044-2012; Staessen, Jan/A-1065-2011; Bisgaard, Hans/N-4761-2016; Yang, Jian/A-5852-2010; Bertram, Lars/K-3889-2015; Johannesson, Magnus/E-9680-2011; mangino, massimo/F-5134-2011; Franke, Barbara/D-4836-2009; Franke, Lude/P-7036-2016; Ormel, Johan/C-6094-2013; Wijmenga, Cisca/D-2173-2009; Fox, Laura /C-6249-2016; Deloukas, Panos/B-2922-2013; Colaus, PsyColaus/K-6607-2013 OI Vinkhuyzen, Anna/0000-0003-3352-0603; Bacelis, Jonas/0000-0002-2450-732X; Smith, Blair/0000-0002-5362-9430; Evans, David/0000-0003-0663-4621; Kaprio, Jaakko/0000-0002-3716-2455; Smith, Jennifer/0000-0002-3575-5468; Medland, Sarah/0000-0003-1382-380X; Timpson, Nicholas/0000-0002-7141-9189; Ware, Erin/0000-0003-4731-8158; Lahti, Jari/0000-0002-4310-5297; Halldorsson, Bjarni/0000-0003-0756-0767; Gupta, Richa/0000-0001-7700-5828; Maki-Opas, Tomi/0000-0002-0472-719X; Loukola, Anu-Maria/0000-0003-0542-5967; Meisinger, Christa/0000-0002-9026-6544; Bakshi, Andrew/0000-0001-5650-7036; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Salvi, Erika/0000-0002-2724-2291; vozzi, diego/0000-0002-2902-8184; Girotto, Giorgia/0000-0003-4507-6589; Thurik, Roy/0000-0002-0242-6908; Davey Smith, George/0000-0002-1407-8314; Gratten, Jake (Jacob)/0000-0003-1293-409X; Polasek, Ozren/0000-0002-5765-1862; Kolcic, Ivana/0000-0001-7918-6052; Feitosa, Mary/0000-0002-0933-2410; Cesarini, David/0000-0002-0043-009X; Verweij, Niek/0000-0002-4303-7685; Pendleton, Neil/0000-0003-0794-2386; Gieger, Christian/0000-0001-6986-9554; Hypponen, Elina/0000-0003-3670-9399; Chen, Guo-Bo/0000-0001-5475-8237; Payton, Antony/0000-0003-0335-152X; Staessen, Jan/0000-0002-3026-1637; Bisgaard, Hans/0000-0003-4131-7592; Yang, Jian/0000-0003-2001-2474; Bertram, Lars/0000-0002-0108-124X; Johannesson, Magnus/0000-0001-8759-6393; mangino, massimo/0000-0002-2167-7470; Franke, Barbara/0000-0003-4375-6572; Franke, Lude/0000-0002-5159-8802; Deloukas, Panos/0000-0001-9251-070X; FU Social Science Genetic Association Consortium (SSGAC); Ragnar Soderberg Foundation [E9/11]; Swedish Research Council [421-2013-1061]; Jan Wallander and Tom Hedelius Foundation; ERC [647648 EdGe]; Pershing Square Fund of the Foundations of Human Behavior; NIA/NIH [P01-AG005842, P01-AG005842-20S2, P30-AG012810, T32-AG000186-23, R01-AG042568] FX This research was carried out under the auspices of the Social Science Genetic Association Consortium (SSGAC). This research has also been conducted using the UK Biobank Resource. This study was supported by funding from the Ragnar Soderberg Foundation (E9/11), the Swedish Research Council (421-2013-1061), The Jan Wallander and Tom Hedelius Foundation, an ERC Consolidator Grant (647648 EdGe), the Pershing Square Fund of the Foundations of Human Behavior, and the NIA/NIH through grants P01-AG005842, P01-AG005842-20S2, P30-AG012810, and T32-AG000186-23 to NBER, and R01-AG042568 to USC. We thank S. Cunningham, N. Galla and J. Rashtian for research assistance. A full list of acknowledgments is provided in the Supplementary Information. NR 16 TC 36 Z9 36 U1 35 U2 71 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAY 26 PY 2016 VL 533 IS 7604 BP 539 EP + DI 10.1038/nature17671 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM6EJ UT WOS:000376443100042 PM 27225129 ER PT J AU Bonham, VL Callier, SL Royal, CD AF Bonham, Vence L. Callier, Shawneequa L. Royal, Charmaine D. TI Will Precision Medicine Move Us beyond Race? SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Bonham, Vence L.] NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. [Callier, Shawneequa L.] George Washington Univ, Dept Clin Res & Leadership, Washington, DC USA. [Royal, Charmaine D.] Duke Univ, Dept African & African Amer Studies, Durham, NC 27706 USA. [Royal, Charmaine D.] Duke Univ, Ctr Genom, Race, Ident,Difference, Durham, NC 27706 USA. RP Bonham, VL (reprint author), NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. NR 5 TC 5 Z9 5 U1 4 U2 7 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 26 PY 2016 VL 374 IS 21 BP 2003 EP 2005 DI 10.1056/NEJMp1511294 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DM6EN UT WOS:000376443500002 PM 27223144 ER PT J AU DiMichele, DM AF DiMichele, Donna M. TI Hemophilia Therapy - Navigating Speed Bumps on the Innovation Highway SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID FACTOR-VIII C1 [DiMichele, Donna M.] NHLBI, Div Blood Dis, NIH, Bldg 10, Bethesda, MD 20892 USA. RP DiMichele, DM (reprint author), NHLBI, Div Blood Dis, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 10 TC 1 Z9 1 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 26 PY 2016 VL 374 IS 21 BP 2087 EP 2089 DI 10.1056/NEJMe1603419 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DM6EN UT WOS:000376443500014 PM 27223151 ER PT J AU Joo, HS Fu, CI Otto, M AF Joo, Hwang-Soo Fu, Chih-Iung Otto, Michael TI Bacterial strategies of resistance to antimicrobial peptides SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Review DE bacterial resistance; antimicrobial peptides; Staphylococcus ID 2-COMPONENT REGULATORY SYSTEM; NONTYPABLE HAEMOPHILUS-INFLUENZAE; GRAM-NEGATIVE BACTERIA; PLATELET MICROBICIDAL PROTEIN; COMMON PATHOGENIC BACTERIA; PRECURSOR LIPID II; STAPHYLOCOCCUS-AUREUS; PSEUDOMONAS-AERUGINOSA; STREPTOCOCCUS-PYOGENES; SALMONELLA-TYPHIMURIUM AB Antimicrobial peptides (AMPs) are a key component of the host's innate immune system, targeting invasive and colonizing bacteria. For successful survival and colonization of the host, bacteria have a series of mechanisms to interfere with AMP activity, and AMP resistance is intimately connected with the virulence potential of bacterial pathogens. In particular, because AMPs are considered as potential novel antimicrobial drugs, it is vital to understand bacterial AMP resistance mechanisms. This review gives a comparative overview of Gram-positive and Gram-negative bacterial strategies of resistance to various AMPs, such as repulsion or sequestration by bacterial surface structures, alteration of membrane charge or fluidity, degradation and removal by efflux pumps. This article is part of the themed issue 'Evolutionary ecology of arthropod antimicrobial peptides'. C1 [Joo, Hwang-Soo; Fu, Chih-Iung; Otto, Michael] NIAID, Pathogen Mol Genet Sect, Bacteriol Lab, US Natl Inst Hlth NIH, 50 South Dr, Bethesda, MD 20892 USA. RP Otto, M (reprint author), NIAID, Pathogen Mol Genet Sect, Bacteriol Lab, US Natl Inst Hlth NIH, 50 South Dr, Bethesda, MD 20892 USA. EM motto@niaid.nih.gov OI Otto, Michael/0000-0002-2222-4115 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, US National Institutes of Health FX The authors are supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, US National Institutes of Health. NR 176 TC 5 Z9 5 U1 31 U2 60 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 EI 1471-2970 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD MAY 26 PY 2016 VL 371 IS 1695 AR 20150292 DI 10.1098/rstb.2015.0292 PG 11 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DM2EZ UT WOS:000376160900004 ER PT J AU Steenackers, A Olivier-Van Stichelen, S Baldini, SF Dehennaut, V Toillon, RA Le Bourhis, X El Yazidi-Belkoura, I Lefebvre, T AF Steenackers, Agata Olivier-Van Stichelen, Stephanie Baldini, Steffi F. Dehennaut, Vanessa Toillon, Robert-Alain Le Bourhis, Xuefen El Yazidi-Belkoura, Ikram Lefebvre, Tony TI Silencing the Nucleocytoplasmic O-GIcNAc Transferase Reduces Proliferation, Adhesion, and Migration of Cancer and Fetal Human Colon Cell Lines SO FRONTIERS IN ENDOCRINOLOGY LA English DT Article DE O-GIcNAcylation; O-linked N-acetylglucosamine transferase; colon cell lines; colorectal cancer; siRNA ID LINKED N-ACETYLGLUCOSAMINE; RAT SKELETAL-MUSCLE; BREAST-CANCER; COLORECTAL-CANCER; GLCNAC TRANSFERASE; GLCNACYLATION; PROTEINS; METABOLISM; EXPRESSION; PATHWAY AB The post-translational modification of proteins by O-linked beta-N-acetylglucosamine (O-GIcNAc) is regulated by a unique couple of enzymes. O-GIcNAc transferase (OGT) transfers the GIcNAc residue from UDP-GIcNAc, the final product of the hexosamine biosynthetic pathway (HBP), whereas O-GIcNAcase (OGA) removes it. This study and others show that OGT and O-GIcNAcylation levels are increased in cancer cell lines. In that context, we studied the effect of OGT silencing in the colon cancer cell lines HT29 and HCT116 and the primary colon cell line CCD841CoN. Herein, we report that OGT silencing diminished proliferation, in vitro cell survival and adhesion of primary and cancer cell lines. SiOGT dramatically decreased HT29 and CCD841CoN migration, CCD841CoN harboring high capabilities of migration in Boyden chamber system when compared to HT29 and HCT116. The expression levels of actin and tubulin were unaffected by OGT knockdown but siOGT seemed to disorganize microfilament, microtubule, and vinculin networks in CCD841CoN. While cancer cell lines harbor higher levels of OGT and O-GIcNAcylation to fulfill their proliferative and migratory properties, in agreement with their higher consumption of HBP main substrates glucose and glutamine, our data demonstrate that OGT expression is not only necessary for the biological properties of cancer cell lines but also for normal cells. C1 [Steenackers, Agata; Olivier-Van Stichelen, Stephanie; Baldini, Steffi F.; Dehennaut, Vanessa; El Yazidi-Belkoura, Ikram; Lefebvre, Tony] Univ Lille, FRABio FR 3688, CNRS, UGSF,UMR 8576, Lille, France. [Olivier-Van Stichelen, Stephanie] NIDDK, Lab Cellular & Mol Biol, NIH, Bethesda, MD USA. [Dehennaut, Vanessa] Univ Lille, FRABio FR 3688, Pasteur Inst Lille, CNRS,UMR 8161,M3T,Inst Biol Lille, Lille, France. [Toillon, Robert-Alain; Le Bourhis, Xuefen] Univ Lille, INSERM, U908, CPAC, Lille, France. RP Lefebvre, T (reprint author), Univ Lille, FRABio FR 3688, CNRS, UGSF,UMR 8576, Lille, France. EM tony.lefebvre@univ-lille1.fr FU Liguc Contrc le Cancer/Comite du Nord; Fondation ARC (Association pour la Recherche sur le Cancer); Region Nord-Pas de Calais (Cancer Regional Program); University of Lille; Centre National de la Recherche Scientifique FX The authors thank the "Liguc Contrc le Cancer/Comite du Nord," the "Fondation ARC (Association pour la Recherche sur le Cancer)," the Region Nord-Pas de Calais (Cancer Regional Program), the University of Lille and the "Centre National de la Recherche Scientifique," the "Institut National de la Sante et de la Recherche Medicale" for their financial support. The authors are also grateful to the "SIte de Recherche Integre sur le Cancer" (SIRIC) ONCOLille. The authors also appreciated the help of Dr. Christian Slomianny and Mrs. Elodic Richard of the CCMIC platform (BICeL Campus Lille 1). We thank Dr. Sophie Groux-Degroote (University Lille 1, UGSU), a fluent English speaker, for the final reading of our manuscript. NR 40 TC 1 Z9 1 U1 6 U2 7 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-2392 J9 FRONT ENDOCRINOL JI Front. Endocrinol. PD MAY 25 PY 2016 VL 7 AR 46 DI 10.3389/fendo.2016.00046 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DP5BC UT WOS:000378510000001 PM 27252680 ER PT J AU Mochizuki, Y Onaga, T Shimazaki, H Shimokawa, T Tsubo, Y Kimura, R Saiki, A Sakai, Y Isomura, Y Fujisawa, S Shibata, K Hirai, D Furuta, T Kaneko, T Takahashi, S Nakazono, T Ishino, S Sakurai, Y Kitsukawa, T Lee, JW Lee, H Jung, MW Babul, C Maldonado, PE Takahashi, K Arce-McShane, FI Ross, CF Sessle, BJ Hatsopoulos, NG Brochier, T Riehle, A Chorley, P Grun, S Nishijo, H Ichihara-Takeda, S Funahashi, S Shima, K Mushiake, H Yamane, Y Tamura, H Fujita, I Inaba, N Kawano, K Kurkin, S Fukushima, K Kurata, K Taira, M Tsutsui, KI Ogawa, T Komatsu, H Koida, K Toyama, K Richmond, BJ Shinomoto, S AF Mochizuki, Yasuhiro Onaga, Tomokatsu Shimazaki, Hideaki Shimokawa, Takeaki Tsubo, Yasuhiro Kimura, Rie Saiki, Akiko Sakai, Yutaka Isomura, Yoshikazu Fujisawa, Shigeyoshi Shibata, Ken-ichi Hirai, Daichi Furuta, Takahiro Kaneko, Takeshi Takahashi, Susumu Nakazono, Tomoaki Ishino, Seiya Sakurai, Yoshio Kitsukawa, Takashi Lee, Jong Won Lee, Hyunjung Jung, Min Whan Babul, Cecilia Maldonado, Pedro E. Takahashi, Kazutaka Arce-McShane, Fritzie I. Ross, Callum F. Sessle, Barry J. Hatsopoulos, Nicholas G. Brochier, Thomas Riehle, Alexa Chorley, Paul Gruen, Sonja Nishijo, Hisao Ichihara-Takeda, Satoe Funahashi, Shintaro Shima, Keisetsu Mushiake, Hajime Yamane, Yukako Tamura, Hiroshi Fujita, Ichiro Inaba, Naoko Kawano, Kenji Kurkin, Sergei Fukushima, Kikuro Kurata, Kiyoshi Taira, Masato Tsutsui, Ken-Ichiro Ogawa, Tadashi Komatsu, Hidehiko Koida, Kowa Toyama, Keisuke Richmond, Barry J. Shinomoto, Shigeru TI Similarity in Neuronal Firing Regimes across Mammalian Species SO JOURNAL OF NEUROSCIENCE LA English DT Article DE firing irregularity/regularity; interspecies similarity; neuronal firing pattern; neuronal firing regime ID MONKEY CEREBRAL-CORTEX; MACAQUE MONKEY; VISUAL-CORTEX; NEOCORTICAL NEURONS; PYRAMIDAL NEURONS; CORTICAL ACTIVITY; DIFFERENT AREAS; PATTERNS; SPIKING; CONNECTIVITY AB The architectonic subdivisions of the brain are believed to be functional modules, each processing parts of global functions. Previously, we showed that neurons in different regions operate in different firing regimes in monkeys. It is possible that firing regimes reflect differences in underlying information processing, and consequently the firing regimes in homologous regions across animal species might be similar. We analyzed neuronal spike trains recorded from behaving mice, rats, cats, and monkeys. The firing regularity differed systematically, with differences across regions in one species being greater than the differences in similar areas across species. Neuronal firing was consistently most regular in motor areas, nearly random in visual and prefrontal/medial prefrontal cortical areas, and bursting in the hippocampus in all animals examined. This suggests that firing regularity (or irregularity) plays a key role in neural computation in each functional subdivision, depending on the types of information being carried. C1 [Mochizuki, Yasuhiro; Onaga, Tomokatsu; Shibata, Ken-ichi; Hirai, Daichi; Furuta, Takahiro; Kaneko, Takeshi; Inaba, Naoko; Kawano, Kenji; Shinomoto, Shigeru] Kyoto Univ, Grad Sch Sci, Kyoto 6068502, Japan. [Shimazaki, Hideaki; Tsubo, Yasuhiro; Fujisawa, Shigeyoshi] RIKEN Brain Sci Inst, Wako, Saitama 3510198, Japan. [Shimokawa, Takeaki; Toyama, Keisuke] ATR Neural Informat Anal Labs, Kyoto 6190288, Japan. [Tsubo, Yasuhiro] Ritsumeikan Univ, Dept Human & Comp Intelligence, Shiga 5258577, Japan. [Kimura, Rie; Saiki, Akiko; Sakai, Yutaka; Isomura, Yoshikazu] Tamagawa Univ, Brain Sci Inst, Tokyo 1948610, Japan. [Funahashi, Shintaro] Kyoto Univ, Kokoro Res Ctr, Kyoto 6068501, Japan. [Takahashi, Susumu; Nakazono, Tomoaki; Sakurai, Yoshio] Doshisha Univ, Grad Sch Brain Sci, Kyoto 6100394, Japan. [Ishino, Seiya] Natl Inst Physiol Sci, Dept Dev Physiol, Okazaki, Aichi 4448585, Japan. [Ogawa, Tadashi; Komatsu, Hidehiko] Natl Inst Physiol Sci, Div Sensory & Cognit Informat, Okazaki, Aichi 4448585, Japan. [Kitsukawa, Takashi; Yamane, Yukako; Tamura, Hiroshi; Fujita, Ichiro] Osaka Univ, Grad Sch Frontier Biosci, 2-2 Yamadaoka, Suita, Osaka 5650871, Japan. [Lee, Jong Won; Jung, Min Whan] Inst for Basic Sci Korea, Ctr Synapt Brain Dysfunct, Taejon 305701, South Korea. [Lee, Hyunjung] Kyungpook Natl Univ, Sch Med, Daegu 700422, South Korea. [Jung, Min Whan] Korea Adv Inst Sci & Technol, Dept Biol Sci, Taejon 305701, South Korea. [Babul, Cecilia; Maldonado, Pedro E.] Univ Chile, Biomed Neurosci Inst, Santiago 8380453, Chile. [Takahashi, Kazutaka; Arce-McShane, Fritzie I.; Ross, Callum F.; Hatsopoulos, Nicholas G.] Univ Chicago, Dept Organismal Biol & Anat, 1025 E 57Th St, Chicago, IL 60637 USA. [Hatsopoulos, Nicholas G.] Univ Chicago, Comm Computat Neurosci, Chicago, IL 60637 USA. [Sessle, Barry J.] Univ Toronto, Fac Dent, 124 Edward St, Toronto, ON M5G 1G6, Canada. [Brochier, Thomas; Riehle, Alexa] CNRS AMU, Inst Neurosci Timone, F-13005 Marseille, France. [Riehle, Alexa; Chorley, Paul; Gruen, Sonja] INM 6, D-52425 Julich, Germany. [Riehle, Alexa; Chorley, Paul; Gruen, Sonja] IAS 6, D-52425 Julich, Germany. [Riehle, Alexa; Chorley, Paul; Gruen, Sonja] JARA Brain Inst I, D-52425 Julich, Germany. [Gruen, Sonja] Rhein Westfal TH Aachen, Theoret Syst Neurobiol, D-52056 Aachen, Germany. [Nishijo, Hisao] Toyama Univ, Grad Sch Med & Pharmaceut Sci, Toyama 9300194, Japan. [Ichihara-Takeda, Satoe] Sapporo Med Univ, Sch Hlth Sci, Sapporo, Hokkaido 0608556, Japan. [Shima, Keisetsu; Mushiake, Hajime] Tohoku Univ, Sch Med, Dept Physiol, Sendai, Miyagi 9808575, Japan. [Yamane, Yukako; Tamura, Hiroshi; Fujita, Ichiro] Osaka Univ, Ctr Informat & Neural Networks, 2-2 Yamadaoka, Suita, Osaka 5650871, Japan. [Yamane, Yukako; Tamura, Hiroshi; Fujita, Ichiro] Natl Inst Informat & Communicat Technol, Suita, Osaka 5650871, Japan. [Kurkin, Sergei; Fukushima, Kikuro] Hokkaido Univ, Sch Med, Dept Physiol, Sapporo, Hokkaido 0608638, Japan. [Kurata, Kiyoshi] Hirosaki Univ, Grad Sch Med, Dept Physiol, Hirosaki, Aomori 0368562, Japan. [Taira, Masato] Tokyo Med & Dent Univ, Grad Sch Med & Dent Sci, Tokyo 1138549, Japan. [Tsutsui, Ken-Ichiro] Tohoku Univ, Grad Sch Life Sci, Lab Syst Neurosci, Sendai, Miyagi 9808577, Japan. [Koida, Kowa] Toyohashi Univ Technol, Elect Inspired Interdisciplinary Res Inst, Toyohashi, Aichi 4418580, Japan. [Richmond, Barry J.] NIMH, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. RP Shinomoto, S (reprint author), Kyoto Univ, Grad Sch Sci, Sakyo Ku, Kyoto 6068502, Japan. EM shinomoto@scphys.kyoto-u.ac.jp OI Shimazaki, Hideaki/0000-0001-7794-3064; Inaba, Naoko/0000-0002-0073-275X; Onaga, Tomokatsu/0000-0002-2913-6193; Nakazono, Tomoaki/0000-0001-5816-4348; Grun, Sonja/0000-0003-2829-2220; Kimura, Rie/0000-0003-1798-5400; Arce-McShane, Fritzie/0000-0001-6616-3564 FU Ministry of Education, Culture, Sports, Science and Technology of Japan [25115718, 26280007, 24300148, 25560435]; Japan Science and Technology Agency (JST); JST Strategic International Research Cooperative Program (Japan-Germany); CREST; National Institute of Information and Communications Technology Contract "Development of network dynamics modeling methods for human brain data simulation systems"; Japan Society for the Promotion of Science KAKENHI Grant [26330288]; Strategic Information and Communications R&D Promotion Programme (SCOPE) from Ministry of Internal Affairs and Communications [152107008]; Research Center Program of the Institute for Basic Science, Korea [IBS-R002-G1]; FONDECYT Grant [1981184]; ICM Grant [P09-015F]; L'Agence nationale de la recherche-GRASP (France); RIKEN-CNRS Collaborative Research Agreement; German-Japanese Computational Neuroscience Project (BMBF) [01GQ1114]; Human Brain Project [604102]; Helmholtz Portfolio Theme "Supercomputing and Modeling for the Human Brain"; Deutsche Forschungsgemeinschaft Grant [GR 1753/3-1, Klinische Forschergruppe KF0219]; Naito Foundation Subsidy for Female Researchers after Maternity Leave; Intramural Research Program of the U.S. National Institute of Mental Health FX This work was supported by Grants-in-Aid for Scientific Research from Ministry of Education, Culture, Sports, Science and Technology of Japan (Contracts 25115718 and 26280007 to S.S.; Contracts 24300148 and 25560435 to S.T.); the Japan Science and Technology Agency (JST; S.S.); the JST Strategic International Research Cooperative Program (Japan-Germany) (H.T.); CREST (S.S.); National Institute of Information and Communications Technology Contract "Development of network dynamics modeling methods for human brain data simulation systems" (T.S.); Japan Society for the Promotion of Science KAKENHI Grant 26330288 (Y.T.); Strategic Information and Communications R&D Promotion Programme (SCOPE) from Ministry of Internal Affairs and Communications (Contract 152107008; S.T.); the Research Center Program of the Institute for Basic Science, Korea (Grant IBS-R002-G1; M.W.J.); FONDECYT Grant 1981184 (P.M., C.B.); ICM Grant P09-015F (P.M., C.B.); L'Agence nationale de la recherche-GRASP (France) (T.B., A.R.); the RIKEN-CNRS Collaborative Research Agreement (T.B., A.R.); the German-Japanese Computational Neuroscience Project (BMBF Grant 01GQ1114; S.G.); the Human Brain Project (Grant 604102; S.G.); Helmholtz Portfolio Theme "Supercomputing and Modeling for the Human Brain" (S.G.); Klinische Forschergruppe KF0219 (TP12, Deutsche Forschungsgemeinschaft Grant GR 1753/3-1; S.G.), the Naito Foundation Subsidy for Female Researchers after Maternity Leave (Y.Y.), and the Intramural Research Program of the U.S. National Institute of Mental Health (B.J.R.). We thank Kai Shinomoto for making pictures of animals for Figure 4. We thank Taro Toyoizumi, Okito Yamashita, and anonymous reviewers for thoughtful and constructive comments on this manuscript. NR 58 TC 5 Z9 5 U1 2 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 25 PY 2016 VL 36 IS 21 BP 5736 EP 5747 DI 10.1523/JNEUROSCI.0230-16.2016 PG 12 WC Neurosciences SC Neurosciences & Neurology GA DP2TG UT WOS:000378345000008 PM 27225764 ER PT J AU Case, LK Laubacher, CM Olausson, H Wang, BQ Spagnolo, PA Bushnell, MC AF Case, Laura K. Laubacher, Claire M. Olausson, Hakan Wang, Binquan Spagnolo, Primavera A. Bushnell, M. Catherine TI Encoding of Touch Intensity But Not Pleasantness in Human Primary Somatosensory Cortex SO JOURNAL OF NEUROSCIENCE LA English DT Article DE affect; c-tactile fibers; pleasantness; rTMS; somatosensory cortex; touch discrimination ID TRANSCRANIAL MAGNETIC STIMULATION; UNMYELINATED TACTILE AFFERENTS; POSTERIOR INSULAR CORTEX; HUMAN HAIRY SKIN; AFFECTIVE RESPONSES; CINGULATE CORTICES; ANTERIOR CINGULATE; SOCIAL TOUCH; PAIN; BRAIN AB Growing interest in affective touch has delineated a neural network that bypasses primary somatosensory cortex (S1). Several recent studies, however, have cast doubt on the segregation of touch discrimination and affect, suggesting that S1 also encodes affective qualities. We used functional magnetic resonance imaging (fMRI) and repetitive transcranial magnetic stimulation (rTMS) to examine the role of S1 in processing touch intensity and pleasantness. Twenty-six healthy human adults rated brushing on the hand during fMRI. Intensity ratings significantly predicted activation in S1, whereas pleasantness ratings predicted activation only in the anterior cingulate cortex. Nineteen subjects also received inhibitory rTMS over right hemisphere S1 and the vertex (control). After S1 rTMS, but not after vertex rTMS, sensory discrimination was reduced and subjects with reduced sensory discrimination rated touch as more intense. In contrast, rTMS did not alter ratings of touch pleasantness. Our findings support divergent neural processing of touch intensity and pleasantness, with affective touch encoded outside of S1. C1 [Case, Laura K.; Laubacher, Claire M.; Wang, Binquan; Bushnell, M. Catherine] NIH, Natl Ctr Complementary & Integrat Hlth, Bldg 10,CRC Room 4-1730,MSC 1302, Bethesda, MD 20892 USA. [Spagnolo, Primavera A.] NIAAA, NIH, Bethesda, MD 20892 USA. [Olausson, Hakan] Linkoping Univ, Dept Clin & Expt Med, S-58183 Linkoping, Sweden. RP Case, LK (reprint author), NIH, Natl Ctr Complementary & Integrat Hlth, Bldg 10,CRC Room 4-1730,MSC 1302, Bethesda, MD 20892 USA. EM laura.case@nih.gov FU National Center for Complementary and Integrative Health-National Institutes of Health FX This work was supported by the Intramural Research program of the National Center for Complementary and Integrative Health-National Institutes of Health. We thank John Gracely, Marta Ceko, and Mark Hallett for assistance with the experimental design and data analysis. NR 63 TC 1 Z9 1 U1 7 U2 7 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 25 PY 2016 VL 36 IS 21 BP 5850 EP 5860 DI 10.1523/JNEUROSCI.1130-15.2016 PG 11 WC Neurosciences SC Neurosciences & Neurology GA DP2TG UT WOS:000378345000017 PM 27225773 ER PT J AU Poleg-Polsky, A Diamond, JS AF Poleg-Polsky, Alon Diamond, Jeffrey S. TI Retinal Circuitry Balances Contrast Tuning of Excitation and Inhibition to Enable Reliable Computation of Direction Selectivity SO JOURNAL OF NEUROSCIENCE LA English DT Article DE calcium imaging; direction selectivity; feedforward; iGluSnFR; starburst amacrine; synaptic balance ID STARBURST AMACRINE CELLS; CORTICAL RECEPTIVE-FIELDS; GANGLION-CELLS; BIPOLAR CELLS; RABBIT RETINA; MOUSE RETINA; FEEDFORWARD INHIBITION; WIRING SPECIFICITY; MOTION DIRECTION; AUDITORY-CORTEX AB Feedforward (FF) inhibition is a common motif in many neural networks. Typically, excitatory inputs drive both principal neurons and interneurons; the interneurons then inhibit the principal neurons, thereby regulating the strength and timing of the FF signal. The interneurons introduce a likely nonlinear processing step that could distort the excitation/inhibition (E/I) ratio in the principal neuron, potentially degrading the reliability of computation in the circuit. In the retina, FF inhibition is an essential feature of the circuitry underlying direction selectivity (DS): glutamatergic bipolar cells (BCs) provide excitatory input to direction-selective ganglion cells (DSGCs) and GABAergic starburst amacrine cells (SACs), and the SACs then provide FF inhibition onto DSGCs. Robust DS computation requires a consistent synaptic E/I ratio in the DSGC in various visual conditions. Here, we show in mouse retina that the E/I ratio is maintained in DSGCs over a wide stimulus contrast range due to compensatory mechanisms in the diverse population of presynaptic BCs. BC inputs to SACs exhibit higher contrast sensitivity, so that the subsequent nonlinear transformation in SACs reduces the contrast sensitivity of FF inhibition to match the sensitivity of direct excitatory inputs onto DSGCs. Measurements of light-evoked responses from individual BC synaptic terminals suggest that the distinct sensitivity of BC inputs reflects different contrast sensitivity between BC subtypes. Numerical simulations suggest that this network arrangement is crucial for reliable DS computation. C1 [Poleg-Polsky, Alon; Diamond, Jeffrey S.] NINDS, Synapt Physiol Sect, NIH, Bethesda, MD 20892 USA. RP Poleg-Polsky, A (reprint author), NIH, 35 Convent Dr,Bldg 35,Room 3E-612, Bethesda, MD 20982 USA. EM polegpolskya@mail.nih.gov FU NINDS [NS003145] FX This work was supported by the NINDS Intramural Research Program (NS003145). We thank Hua Tian for mouse husbandry and genotyping support, and Huayu Ding and Dr Cole Graydon for discussions. NR 78 TC 3 Z9 3 U1 1 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 25 PY 2016 VL 36 IS 21 BP 5861 EP 5876 DI 10.1523/JNEUROSCI.4013-15.2016 PG 16 WC Neurosciences SC Neurosciences & Neurology GA DP2TG UT WOS:000378345000018 PM 27225774 ER PT J AU Montgomery, DC Garlick, JM Kulkarni, RA Kennedy, S Allali-Hassani, A Kuo, YM Andrews, AJ Wu, H Vedadi, M Meier, JL AF Montgomery, David C. Garlick, Julie M. Kulkarni, Rhushikesh A. Kennedy, Steven Allali-Hassani, Abdellah Kuo, Yin-Ming Andrews, Andrew J. Wu, Hong Vedadi, Masoud Meier, Jordan L. TI Global Profiling of Acetyltransferase Feedback Regulation SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID HISTONE ACETYLTRANSFERASES; LYSINE ACETYLTRANSFERASES; METABOLIC-REGULATION; ACETYLATION; CELL; P300; INHIBITION; COFACTORS; MECHANISM; BINDING AB Lysine acetyltransferases (KATs) are key mediators of cell signaling. Methods capable of providing new insights into their regulation thus constitute an important goal. Here we report an optimized platform for profiling KAT ligand interactions in complex proteomes using inhibitor-functionalized capture resins. This approach greatly expands the scope of KATs, KAT complexes, and CoA-dependent enzymes accessible to chemoproteomic methods. This enhanced profiling platform is then applied in the most comprehensive analysis to date of KAT inhibition by the feedback metabolite CoA. Our studies reveal that members of the KAT superfamily possess a spectrum of sensitivity to CoA and highlight NAT10 as a novel KAT that may be susceptible to metabolic feedback inhibition. This platform provides a powerful tool to define the potency and selectivity of reversible stimuli, such as small molecules and metabolites, that regulate KAT-dependent signaling. C1 [Montgomery, David C.; Garlick, Julie M.; Kulkarni, Rhushikesh A.; Meier, Jordan L.] NCI, Biol Chem Lab, Frederick, MD 21702 USA. [Kennedy, Steven; Allali-Hassani, Abdellah; Wu, Hong; Vedadi, Masoud] Univ Toronto, Struct Genom Consortium, Toronto, ON MG5 1L7, Canada. [Kuo, Yin-Ming; Andrews, Andrew J.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Meier, Jordan L.] Univ Toronto, Dept Pharmacol & Toxicol, 100 Coll St, Toronto, ON M5S 1A8, Canada. RP Meier, JL (reprint author), NCI, Biol Chem Lab, Frederick, MD 21702 USA.; Meier, JL (reprint author), Univ Toronto, Dept Pharmacol & Toxicol, 100 Coll St, Toronto, ON M5S 1A8, Canada. EM jordan.meier@nih.gov RI Meier, Jordan/N-2608-2014 FU AbbVie; Bayer Pharma AG; Boehringer Ingelheim; Canada Foundation for Innovation; Eshelman Institute for Innovation; Genome Canada; Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD] [115766]; Janssen; Merck Co.; Novartis Pharma AG; Ontario Ministry of Economic Development and Innovation; Pfizer; Sao Paulo Research Foundation-FAPESP; Takeda; Wellcome Trust; NIH, National Cancer Institute [ZIA BC011488-02] FX We thank the Laboratory of Proteomics and Analytical Technology for LC-MS/MS analyses. The SGC is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada, Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD grant no. 115766], Janssen, Merck & Co., Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, Sao Paulo Research Foundation-FAPESP, Takeda, and the Wellcome Trust. This work was supported by the Intramural Research Program of the NIH, National Cancer Institute (ZIA BC011488-02). NR 22 TC 1 Z9 1 U1 4 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD MAY 25 PY 2016 VL 138 IS 20 BP 6388 EP 6391 DI 10.1021/jacs.6b03036 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA DN1KY UT WOS:000376825900018 PM 27149119 ER PT J AU Nair, RS Kumar, JM Jose, J Somasundaram, V Hemalatha, SK Sengodan, SK Nadhan, R Anilkumar, TV Srinivas, P AF Nair, Rakesh Sathish Kumar, Jerald Mahesh Jose, Jedy Somasundaram, Veena Hemalatha, Sreelatha K. Sengodan, Satheesh Kumar Nadhan, Revathy Anilkumar, Thapasimuthu V. Srinivas, Priya TI Increased sensitivity of BRCA defective triple negative breast tumors to plumbagin through induction of DNA Double Strand Breaks (DSB) SO SCIENTIFIC REPORTS LA English DT Article ID CERVICAL-CANCER CELLS; NF-KAPPA-B; HOMOLOGOUS RECOMBINATION; APOPTOTIC PATHWAY; PROSTATE-CANCER; MAMMARY-TUMORS; CYCLE ARREST; IN-VITRO; INHIBITOR; DAMAGE AB We have earlier shown that Plumbagin (PB) can induce selective cytotoxicity to BRCA1 defective ovarian cancer cells; however, the effect of this molecule in BRCA1 mutated breast cancers has not been analyzed yet. Here, we report that reactive oxygen species (ROS) induced by PB resulted in DNA DSB and activates downstream signaling by ATR/ATM kinases and subsequent apoptosis. PB reduces DNA-dependent protein kinase (DNA-PK) expression and inhibits NHEJ (Non Homologous End Joining) activity in BRCA1 defective breast cancer cells. Also, PB induces apoptosis in two different BRCA1 conditional knock out murine models: MMTV-Cre; BRCA1(Co/Co) and WAP-Cre; BRCA1(Co/Co), at 2 mg/kg body weight, but 32 mg/kg of carboplatin (CN) was needed to induce apoptosis in them. This is the first study where two different tissue specific promoter driven transgenic mice models with BRCA1 exon 11 deletions are used for preclinical drug testing. The apoptosis induced by PB in HR (Homologous Recombination) defective triple negative BRCA1 mutant cell lines and in mouse models occur by inducing ROS mediated DNA DSB. The toxicity profile as compared with CN in transgenic mice provides evidence for PB's safer disposition as a therapeutic lead in breast cancer drug development. C1 [Nair, Rakesh Sathish; Somasundaram, Veena; Hemalatha, Sreelatha K.; Sengodan, Satheesh Kumar; Nadhan, Revathy; Srinivas, Priya] Rajiv Gandhi Ctr Biotechnol, Canc Res Program, Thiruvananthapuram, Kerala, India. [Kumar, Jerald Mahesh; Jose, Jedy] Ctr Cellular & Mol Biol, Hyderabad 500007, Andhra Pradesh, India. [Anilkumar, Thapasimuthu V.] Sree Chitra Tirunal Inst Med Sci & Technol, Expt Pathol, Thiruvananthapuram, Kerala, India. [Nair, Rakesh Sathish] Univ Illinois, Dept Surg, Div Surg Oncol, Oncol Res, Suit 601,840 South Wood St,Clin Sci Bldg,MC958, Chicago, IL 60612 USA. [Somasundaram, Veena] NCI, Canc & Inflammat Program, Ctr Canc Res, Ft Detrick, MD 21702 USA. RP Srinivas, P (reprint author), Rajiv Gandhi Ctr Biotechnol, Canc Res Program, Thiruvananthapuram, Kerala, India. EM priyasrinivas@rgcb.res.in FU Rajiv Gandhi Centre for Biotechnology, Department of Biotechnology [BT/RD/15/27/95-RGCB]; Kerala State Council for Science Technology and Environment [28/SRS/2005/CSTE, 016/SRSHS/2011/CSTE]; Board of Research in Nuclear Sciences [2009/37/5/BRNS/1620, 37(1)/14/16/2014]; Indian Council for Medical Research [53/20/2012-BMS]; Council for Scientific and Industrial Research; Indian Council for Medical Research, Govt. of India; University Grants Commission FX We acknowledge Professor. Chu Xia Deng, Faculty of Health Sciences, University of Macau, China, for providing the transgenic mice for this work. The authors thank Dr. Grant Mc Arthur, Peter MacCallum Cancer Centre, VIC, Australia, for the kind gift of HCC1937 and HCC1937 cell lines transfected with wild type BRCA1 and Dr. Cathrin Dressler, Laser- und Medizin-Technologie GmbH, Berlin, Germany, for MX1 cell line. This work was supported by intramural grant from Rajiv Gandhi Centre for Biotechnology, Department of Biotechnology (No. BT/R&D/15/27/95-RGCB), Kerala State Council for Science Technology and Environment (Nos [T] 28/SRS/2005/CSTE and 016/SRSHS/2011/CSTE), grant-in-aid from the Board of Research in Nuclear Sciences (No. 2009/37/5/BRNS/1620 and No. 37(1)/14/16/2014) and Indian Council for Medical Research (No. 53/20/2012-BMS) to PS. The Senior Research Fellowships awarded by the Council for Scientific and Industrial Research to RSN, VS and RN, the Indian Council for Medical Research, Govt. of India to SKH, University Grants Commission to SKS are duly acknowledged. NR 47 TC 0 Z9 0 U1 2 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAY 25 PY 2016 VL 6 AR 26631 DI 10.1038/srep26631 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM6XG UT WOS:000376495600003 PM 27220670 ER PT J AU Yabe-Wada, T Matsuba, S Takeda, K Sato, T Suyama, M Ohkawa, Y Takai, T Shi, HF Philpott, CC Nakamura, A AF Yabe-Wada, Toshiki Matsuba, Shintaro Takeda, Kazuya Sato, Tetsuya Suyama, Mikita Ohkawa, Yasuyuki Takai, Toshiyuki Shi, Haifeng Philpott, Caroline C. Nakamura, Akira TI TLR signals posttranscriptionally regulate the cytokine trafficking mediator sortilin SO SCIENTIFIC REPORTS LA English DT Article ID PLASMACYTOID DENDRITIC CELLS; IRON CHAPERONES PCBP1; MOTIF DISCOVERY; ZINC SIGNALS; DEGRADATION; SEQUENCE; PROTEIN; TRANSCRIPTION; INFLAMMATION; HYDROXYLASE AB Regulating the transcription, translation and secretion of cytokines is crucial for controlling the appropriate balance of inflammation. Here we report that the sorting receptor sortilin plays a key role in cytokine production. We observed interactions of sortilin with multiple cytokines including IFN-alpha, and sortilin depletion in plasmacytoid dendritic cells (pDCs) led to a reduction of IFN-alpha secretion, suggesting a pivotal role of sortilin in the exocytic trafficking of IFN-alpha in pDCs. Moreover, sortilin mRNA was degraded posttranscriptionally upon stimulation with various TLR ligands. Poly-rC-binding protein 1 (PCBP1) recognized the C-rich element (CRE) in the 3' UTR of sortilin mRNA, and depletion of PCBP1 enhanced the degradation of sortilin transcripts, suggesting that PCBP1 can act as a trans-acting factor to stabilize sortilin transcripts. The nucleotide-binding ability of PCBP1 was impaired by zinc ions and alterations of intracellular zinc affect sortilin expression. PCBP1 may therefore control the stability of sortilin transcripts by sensing intracellular zinc levels. Collectively, our findings provide insights into the posttranslational regulation of cytokine production through the posttranscriptional control of sortilin expression by TLR signals. C1 [Yabe-Wada, Toshiki; Matsuba, Shintaro; Takeda, Kazuya; Suyama, Mikita; Nakamura, Akira] Kanazawa Med Univ, Dept Immunol, Kahoku Uchinada, Ishikawa 9200293, Japan. [Yabe-Wada, Toshiki; Shi, Haifeng; Philpott, Caroline C.] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Sato, Tetsuya; Suyama, Mikita] Kyushu Univ, Med Inst Bioregulat, Div Bioinformat, Fukuoka 8128582, Japan. [Ohkawa, Yasuyuki] Kyushu Univ, Dept Adv Med Initiat, Fac Med, Fukuoka 8128582, Japan. [Takai, Toshiyuki] Tohoku Univ, Inst Dev Aging & Canc, Dept Expt Immunol, 4-1 Seiryo, Sendai, Miyagi 9808575, Japan. [Shi, Haifeng] Jiangsu Univ, Inst Life Sci, Zhenjiang 212013, Jiangsu, Peoples R China. RP Yabe-Wada, T; Nakamura, A (reprint author), Kanazawa Med Univ, Dept Immunol, Kahoku Uchinada, Ishikawa 9200293, Japan.; Yabe-Wada, T (reprint author), NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. EM tyw5510@kanazwa-med.ac.jp; aki-n@kanazwa-med.ac.jp RI Yabe-Wada, Toshiki/L-9942-2016 OI Yabe-Wada, Toshiki/0000-0002-6208-0590 FU Japan Society for the Promotion of Science [25870851, 16K18518, 22590431, 25460601]; Science Research Promotion Fund from the Promotion and Mutual Aid Corporation for Private Schools; Kanazawa Medical University [S2012-11]; Uehara Memorial Foundation; Cooperative Research Project Program of Joint Usage/Research Center at the Institute of Development, Aging and Cancer, Tohoku University; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, USA FX We thank H. Nakamura for technical support and E. Kiyokawa for Biacore instrument analysis. Research Institute for Information Technology Kyushu University for providing the high-performance computing resources. This work was supported in part by Grants-in-aid for Young Scientists 25870851 and 16K18518 (T.Y.-W.) and Grants-in-aid for Scientific Research 22590431 and 25460601 (A.N.) from the Japan Society for the Promotion of Science. This work was also supported in part by the Science Research Promotion Fund from the Promotion and Mutual Aid Corporation for Private Schools (T.Y.-W.), the Intramural Research Grant for Young Scientists S2012-11 from Kanazawa Medical University (T.Y.-W.), the Uehara Memorial Foundation (A.N.) and the Cooperative Research Project Program of Joint Usage/Research Center at the Institute of Development, Aging and Cancer, Tohoku University (A.N.). These studies were also supported in part by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, USA (T.Y.-W., H.S. and C.C.P.). NR 53 TC 0 Z9 0 U1 3 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAY 25 PY 2016 VL 6 AR 26566 DI 10.1038/srep26566 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM6WN UT WOS:000376493600001 PM 27220277 ER PT J AU Xia, D Tang, WK Ye, YH AF Xia, Di Tang, Wai Kwan Ye, Yihong TI Structure and function of the AAA + ATPase p97/Cdc48p SO GENE LA English DT Review DE p97/CDC48; AAA plus ATPase; Segregase; Unfoldase; Protein quality control; ER-associated degradation; Chromatin-associated degradation; Mitochondria-associated degradation; Ribosome-associated degradation; Membrane fusion; Ubiquitin; Proteasome ID RETICULUM-ASSOCIATED DEGRADATION; INCLUSION-BODY MYOPATHY; VALOSIN-CONTAINING PROTEIN; ENDOPLASMIC-RETICULUM; ATPASE ACTIVITY; QUALITY-CONTROL; FRONTOTEMPORAL DEMENTIA; CONFORMATIONAL-CHANGES; MEMBRANE-FUSION; PAGET-DISEASE AB p97 (also known as valosin-containing protein (VCP) in mammals or Cdc48p in Saccharomyces cerevisiae) is an evolutionarily conserved ATPase present in all eukaryotes and archaebacteria. In conjunction with a collection of cofactors and adaptors, p97/Cdc48p performs an array of biological functions mostly through modulating the stability of 'client' proteins. Using energy from ATP hydrolysis, p97/Cdc48p segregates these molecules from immobile cellular structures such as protein assemblies, membrane organelles, and chromatin. Consequently, the released polypeptides can be efficiently degraded by the ubiquitin proteasome system or recycled. This review summarizes our current understanding of the structure and function of this essential cellular chaperoning system. Published by Elsevier B.V. C1 [Xia, Di; Tang, Wai Kwan] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. [Ye, Yihong] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Ye, YH (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM xiad@mail.nih.gov; yihongy@mail.nih.gov FU National Institutes of Health [GM089820]; National Cancer Institute; National Institute of Diabetes, Digestive & Kidney Diseases at the National Institutes of Health FX This review and the corresponding Gene Wiki article are written as part of the Gene Wiki Review series-a series resulting from a collaboration between the journal GENE and the Gene Wild Initiative (https://en.wikipedia.org/wiki/Valosin-containing_protein). The Gene Wiki Initiative is supported by National Institutes of Health (GM089820). The research in the laboratories of D. Xia and Y. Ye is supported by the Intramural Research Program of the National Cancer Institute and of the National Institute of Diabetes, Digestive & Kidney Diseases at the National Institutes of Health. NR 153 TC 16 Z9 16 U1 2 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 EI 1879-0038 J9 GENE JI Gene PD MAY 25 PY 2016 VL 583 IS 1 BP 64 EP 77 DI 10.1016/j.gene.2016.02.042 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA DK0NI UT WOS:000374609100009 PM 26945625 ER PT J AU Klein, K McClure, EM Colaci, D Thorsten, V Hibberd, PL Esamai, F Garces, A Patel, A Saleem, S Pasha, O Chomba, E Carlo, WA Krebs, NF Goudar, S Derman, RJ Liechty, EA Koso-Thomas, M Buekens, PM Belizan, JM Goldenberg, RL Althabe, F AF Klein, Karen McClure, Elizabeth M. Colaci, Daniela Thorsten, Vanessa Hibberd, Patricia L. Esamai, Fabian Garces, Ana Patel, Archana Saleem, Sarah Pasha, Omrana Chomba, Elwyn Carlo, Waldemar A. Krebs, Nancy F. Goudar, Shivaprasad Derman, Richard J. Liechty, Edward A. Koso-Thomas, Marion Buekens, Pierre M. Belizan, Jose M. Goldenberg, Robert L. Althabe, Fernando TI The Antenatal Corticosteroids Trial (ACT): a secondary analysis to explore site differences in a multi-country trial SO REPRODUCTIVE HEALTH LA English DT Article ID RESPIRATORY-DISTRESS-SYNDROME; MIDDLE-INCOME COUNTRIES; NEWBORN HEALTH REGISTRY; PRETERM BIRTH; PREMATURE-INFANTS; GLOBAL-NETWORK; INTERVENTIONS; PREVENTION; MORTALITY; SURVIVAL AB Background: The Antenatal Corticosteroid Trial (ACT) assessed the feasibility, effectiveness, and safety of a multifaceted intervention to increase the use of antenatal corticosteroids (ACS) in mothers at risk of preterm birth at all levels of care in low and middle-income countries. The intervention effectively increased the use of ACS but had no overall impact on neonatal mortality in the targeted < 5th percentile birth weight infants. Being in the intervention clusters was also associated with an overall increase in neonatal deaths. We sought to explore plausible pathways through which this intervention increased neonatal mortality. Methods: We conducted secondary analyses to assess site differences in outcome and potential explanations for the differences in outcomes if found. By site, and in the intervention and control clusters, we evaluated characteristics of the mothers and care systems, the proportion of the < 5th percentile infants and the overall population that received ACS, the rates of possible severe bacterial infection (pSBI), determined from clinical signs, and neonatal mortality rates. Results: There were substantial differences between the sites in both participant and health system characteristics, with Guatemala and Argentina generally having the highest levels of care. In some sites there were substantial differences in the health system characteristics between the intervention and control clusters. The increase in ACS in the intervention clusters was similar among the sites. While overall, there was no difference in neonatal mortality among < 5th percentile births between the intervention and control clusters, Guatemala and Pakistan both had significant reductions in neonatal mortality in the < 5th percentile infants in the intervention clusters. The improvement in neonatal mortality in the Guatemalan site in the < 5th percentile infants was associated with a higher level of care at the site and an improvement in care in the intervention clusters. There was a significant increase overall in neonatal mortality in the intervention clusters compared to the control. Across sites, this increase in neonatal mortality was statistically significant and most apparent in the African sites. This increase in neonatal mortality was accompanied by a significant increase in pSBI in the African sites. Conclusions: The improvement in neonatal mortality in the Guatemalan site in the < 5th percentile infants was associated with a higher level of care and an improvement in care in the intervention clusters. The increase in neonatal mortality in the intervention clusters across all sites was largely driven by the poorer outcomes in the African sites, which also had an increase in pSBI in the intervention clusters. We emphasize that these results come from secondary analyses. Additional prospective studies are needed to assess the effectiveness and safety of ACS on neonatal health in low resource settings. C1 [Klein, Karen; Colaci, Daniela; Belizan, Jose M.; Althabe, Fernando] Inst Clin Effectiveness & Hlth Policy IECS, Buenos Aires, DF, Argentina. [McClure, Elizabeth M.; Thorsten, Vanessa] RTI Int, Durham, NC USA. [Hibberd, Patricia L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Esamai, Fabian] Moi Univ, Sch Med, Eldoret, Kenya. [Garces, Ana] Fdn Alimentac & Nut Ctr Amer & Panama, Guatemala City, Guatemala. [Patel, Archana] Indira Gandhi Govt Med Coll, Lata Med Res Fdn, Nagpur, Maharashtra, India. [Saleem, Sarah; Pasha, Omrana] Aga Khan Univ, Dept Community Hlth Sci, Karachi, Pakistan. [Chomba, Elwyn] Univ Teaching Hosp, Lusaka, Zambia. [Carlo, Waldemar A.] Univ Alabama Birmingham, Birmingham, AL USA. [Krebs, Nancy F.] Univ Colorado, Sch Med, Denver, CO USA. [Goudar, Shivaprasad] KLE Univ, Jawaharlal Nehru Med Coll, Belgaum, Karnataka, India. [Derman, Richard J.] Christiana Hlth Care, Newark, DE USA. [Liechty, Edward A.] Indiana Univ, Sch Med, Indianapolis, IN USA. [Koso-Thomas, Marion] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Buekens, Pierre M.] Tulane Sch Publ Hlth & Trop Med, New Orleans, LA USA. [Goldenberg, Robert L.] Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. RP Klein, K (reprint author), Inst Clin Effectiveness & Hlth Policy IECS, Buenos Aires, DF, Argentina. EM kklein@iecs.org.ar FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01 HD058322, U01 HD040477, U01 HD043464, U01 HD040657, U01 HD042372, U01 HD040607, U01 HD058326, U01 HD040636]; Bill & Melinda Gates Foundation; World Health Organization FX This study was funded by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant number U01 HD058322, U01 HD040477, U01 HD043464, U01 HD040657, U01 HD042372, U01 HD040607, U01 HD058326, U01 HD040636). FA, JB and KK also received funding from the Bill & Melinda Gates Foundation. Study support was also provided by the World Health Organization. Supplies were donated by Becton Dickson. NR 18 TC 1 Z9 1 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4755 J9 REPROD HEALTH JI Reprod. Health PD MAY 24 PY 2016 VL 13 AR 64 DI 10.1186/s12978-016-0179-z PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DP6NP UT WOS:000378614100001 PM 27221319 ER PT J AU McClure, EM Goldenberg, RL Jobe, AH Miodovnik, M Koso-Thomas, M Buekens, P Belizan, J Althabe, F AF McClure, Elizabeth M. Goldenberg, Robert L. Jobe, Alan H. Miodovnik, Menachem Koso-Thomas, Marion Buekens, Pierre Belizan, Jose Althabe, Fernando TI Reducing neonatal mortality associated with preterm birth: gaps in knowledge of the impact of antenatal corticosteroids on preterm birth outcomes in low-middle income countries SO REPRODUCTIVE HEALTH LA English DT Article ID TRIAL; MATURATION; PREVENTION; INFANTS; LABOR AB The Global Network's Antenatal Corticosteroids Trial (ACT), was a multi-country, cluster-randomized trial to improve appropriate use of antenatal corticosteroids (ACS) in low-resource settings in low-middle income countries (LMIC). ACT substantially increased ACS use in the intervention clusters, but the intervention failed to show benefit in the targeted < 5th percentile birth weight infants and was associated with increased neonatal mortality and stillbirth in the overall population. In this issue are six papers which are secondary analyses related to ACT that explore potential reasons for the increase in adverse outcomes overall, as well as site differences in outcomes. The African sites appeared to have increased neonatal mortality in the intervention clusters while the Guatemalan site had a significant reduction in neonatal mortality, perhaps related to a combination of ACS and improving obstetric care in the intervention clusters. Maternal and neonatal infections were increased in the intervention clusters across all sites and increased infections are a possible partial explanation for the increase in neonatal mortality and stillbirth in the intervention clusters, especially in the African sites. The analyses presented here provide guidance for future ACS trials in LMIC. These include having accurate gestational age dating of study subjects and having care givers who can diagnose conditions leading to preterm birth and predict which women likely will deliver in the next 7 days. All study subjects should be followed through delivery and the neonatal period, regardless of when they deliver. Clearly defined measures of maternal and neonatal infection should be utilized. Trials in low income country facilities including clinics and those without newborn intensive care seem to be of the highest priority. C1 [McClure, Elizabeth M.] RTI Int, Social Stat & Environm Hlth Sci, 3040 Cornwallis Rd, Durham, NC 27709 USA. [Goldenberg, Robert L.] Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. [Jobe, Alan H.] Cincinnati Childrens Hosp, Cincinnati, OH USA. [Miodovnik, Menachem; Koso-Thomas, Marion] Eunice Kennedy Shriver Natl Inst Child & Human De, Bethesda, MD USA. [Buekens, Pierre] Tulane Univ, Sch Trop Med & Hyg, New Orleans, LA 70118 USA. [Belizan, Jose; Althabe, Fernando] Inst Clin Effectiveness & Hlth Policy, Buenos Aires, DF, Argentina. RP McClure, EM (reprint author), RTI Int, Social Stat & Environm Hlth Sci, 3040 Cornwallis Rd, Durham, NC 27709 USA. EM mcclure@rti.org FU NICHD [U01 HD058322, U01 HD040477, U01 HD043464, U01 HD040657, U01 HD042372, U01 HD040607, U01 HD058326, U01 HD040636]; Bill & Melinda Gates Foundation FX This work was supported by grants from NICHD (grant number U01 HD058322, U01 HD040477, U01 HD043464, U01 HD040657, U01 HD042372, U01 HD040607, U01 HD058326, U01 HD040636). FA was also supported by the Bill & Melinda Gates Foundation. NR 25 TC 0 Z9 0 U1 2 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4755 J9 REPROD HEALTH JI Reprod. Health PD MAY 24 PY 2016 VL 13 AR 61 DI 10.1186/s12978-016-0180-6 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DP6NL UT WOS:000378613700002 PM 27221397 ER PT J AU Mazor, R Onda, M Park, D Addissie, S Xiang, LM Zhang, JL Hassan, R Pastan, I AF Mazor, Ronit Onda, Masanori Park, Dong Addissie, Selamawit Xiang, Laiman Zhang, Jingli Hassan, Raffit Pastan, Ira TI Dual B- and T-cell de-immunization of recombinant immunotoxin targeting mesothelin with high cytotoxic activity SO ONCOTARGET LA English DT Article DE epitope; immunogenicity; rational design; mesothelioma; pancreatic cancer ID LOW IMMUNOGENICITY; IMMUNE-RESPONSE; OVARIAN-CANCER; IN-VITRO; EPITOPE; IDENTIFICATION; PEPTIDES; RECOGNITION; ELIMINATION; BINDING AB Recombinant immunotoxins (RITs) are genetically engineered proteins being developed to treat cancer. They are composed of an Fv that targets a cancer antigen and a portion of a protein toxin. Their clinical success is limited by their immunogenicity. Our goal is to produce a new RIT that targets mesothelin and is non-immunogenic by combining mutations that decrease B-and T-cell epitopes. Starting with an immunotoxin that has B-cell epitopes suppressed, we added mutations step-wise that suppress T-cell epitopes. The final protein (LMB-T14) has greatly reduced antigenicity as assessed by binding to human anti-sera and a greatly decreased ability to activate helper T-cells evaluated in a T-cell activation assay. It is very cytotoxic to mesothelioma cells from patients, and to cancer cell lines. LMB-T14 produces complete remissions of a mesothelin expressing cancer (A431/H9) xenograft. The approach used here can be used to de-immunize other therapeutic foreign proteins. C1 [Mazor, Ronit; Onda, Masanori; Park, Dong; Addissie, Selamawit; Xiang, Laiman; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. [Zhang, Jingli; Hassan, Raffit] NCI, Thorac & GI Oncol Branch, NIH, Bethesda, MD 20892 USA. [Park, Dong] Medytox Inc, New Business Dev Dept, Songnam, Gyeonggi Do, South Korea. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 32 TC 2 Z9 2 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAY 24 PY 2016 VL 7 IS 21 BP 29916 EP 29926 DI 10.18632/oncotarget.9171 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO4IZ UT WOS:000377746600006 PM 27167198 ER PT J AU Selleri, S Bifsha, P Civini, S Pacelli, C Dieng, MM Lemieux, W Jin, P Bazin, R Patey, N Marincola, FM Moldovan, F Zaouter, C Trudeau, LE Benabdhalla, B Louis, I Beausejour, C Stroncek, D Le Deist, F Haddad, E AF Selleri, Silvia Bifsha, Panojot Civini, Sara Pacelli, Consiglia Dieng, Mame Massar Lemieux, William Jin, Ping Bazin, Renee Patey, Natacha Marincola, Francesco M. Moldovan, Florina Zaouter, Charlotte Trudeau, Louis-Eric Benabdhalla, Basma Louis, Isabelle Beausejour, Christian Stroncek, David Le Deist, Francoise Haddad, Elie TI Human mesenchymal stromal cell-secreted lactate induces M2-macrophage differentiation by metabolic reprogramming SO ONCOTARGET LA English DT Article DE mesenchymal stromal cells; dendritic cell differentiation; M2-macrophages; lactate; metabolism; Immunology and Microbiology Section; Immune response; Immunity ID VERSUS-HOST-DISEASE; LARGE GENE LISTS; STEM-CELLS; DENDRITIC CELLS; LACTIC-ACID; MACROPHAGE DIFFERENTIATION; MICROARRAY DATA; MSCS SCIENCE; MOUSE MODEL; POLARIZATION AB Human mesenchymal stromal cells (MSC) have been shown to dampen immune response and promote tissue repair, but the underlying mechanisms are still under investigation. Herein, we demonstrate that umbilical cord-derived MSC (UC-MSC) alter the phenotype and function of monocyte-derived dendritic cells (DC) through lactate-mediated metabolic reprogramming. UC-MSC can secrete large quantities of lactate and, when present during monocyte-to-DC differentiation, induce instead the acquisition of M2-macrophage features in terms of morphology, surface markers, migratory properties and antigen presentation capacity. Microarray expression profiling indicates that UC-MSC modify the expression of metabolic-related genes and induce a M2-macrophage expression signature. Importantly, monocyte-derived DC obtained in presence of UC-MSC, polarize naive allogeneic CD4(+) T-cells into Th2 cells. Treatment of UC-MSC with an inhibitor of lactate dehydrogenase strongly decreases lactate concentration in culture supernatant and abrogates the effect on monocyte-to-DC differentiation. Metabolic analysis further revealed that UC-MSC decrease oxidative phosphorylation in differentiating monocytes while strongly increasing the spare respiratory capacity proportional to the amount of secreted lactate. Because both MSC and monocytes are recruited in vivo at the site of tissue damage and inflammation, we propose the local increase of lactate concentration induced by UC-MSC and the consequent enrichment in M2-macrophage generation as a mechanism to achieve immunomodulation. C1 [Selleri, Silvia; Bifsha, Panojot; Dieng, Mame Massar; Lemieux, William; Moldovan, Florina; Zaouter, Charlotte; Benabdhalla, Basma; Louis, Isabelle; Beausejour, Christian; Le Deist, Francoise; Haddad, Elie] CHU St Justine, Res Ctr, Montreal, PQ, Canada. [Selleri, Silvia; Bifsha, Panojot; Lemieux, William; Le Deist, Francoise; Haddad, Elie] Univ Montreal, Dept Microbiol Infectiol & Immunol, Montreal, PQ, Canada. [Civini, Sara; Jin, Ping; Marincola, Francesco M.; Stroncek, David] NIH, Ctr Clin, Dept Transfus Med, Bldg 10, Bethesda, MD 20892 USA. [Pacelli, Consiglia; Trudeau, Louis-Eric; Beausejour, Christian] Univ Montreal, Dept Pharmacol, Montreal, PQ H3C 3J7, Canada. [Dieng, Mame Massar] NYU, Dept Biol, Abu Dhabi, U Arab Emirates. [Bazin, Renee] Hema Quebec, Dept Res & Dev, Quebec City, PQ, Canada. [Patey, Natacha] Univ Montreal, Dept Pathol, Montreal, PQ H3C 3J7, Canada. [Marincola, Francesco M.] Sidra Med & Res Ctr, Doha, Qatar. [Moldovan, Florina] Univ Montreal, Fac Dent, Montreal, PQ, Canada. [Louis, Isabelle; Le Deist, Francoise; Haddad, Elie] Univ Montreal, Dept Pediat, Montreal, PQ H3C 3J7, Canada. RP Haddad, E (reprint author), CHU St Justine, Res Ctr, Montreal, PQ, Canada.; Haddad, E (reprint author), Univ Montreal, Dept Microbiol Infectiol & Immunol, Montreal, PQ, Canada.; Haddad, E (reprint author), Univ Montreal, Dept Pediat, Montreal, PQ H3C 3J7, Canada. EM elie.haddad@umontreal.ca FU FRQS, Fonds de la Recherche en Sante du Quebec (Fonds de recherches en medecine transfusionnelle, en greffe et en biovigilance); La Fondation CHU Sainte-Justine; Pediatric Immunodeficiency Treatment Consortium (PIDTC) [U54AI082973] FX This work was funded by FRQS, Fonds de la Recherche en Sante du Quebec (Fonds de recherches en medecine transfusionnelle, en greffe et en biovigilance 2010-2013). SS received a scholarship from La Fondation CHU Sainte-Justine and from the Pediatric Immunodeficiency Treatment Consortium (PIDTC, grant number U54AI082973). EH was a scholar of the Fondation de la Recherche en Sante du Quebec (FRQS). NR 76 TC 2 Z9 2 U1 4 U2 7 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAY 24 PY 2016 VL 7 IS 21 BP 30193 EP 30210 DI 10.18632/oncotarget.8623 PG 18 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO4IZ UT WOS:000377746600028 PM 27070086 ER PT J AU Mark, DB Anstrom, KJ Sheng, SB Baloch, KN Daniels, MR Hoffmann, U Patel, MR Cooper, LS Lee, KL Douglas, PS AF Mark, Daniel B. Anstrom, Kevin J. Sheng, Shubin Baloch, Khaula N. Daniels, Melanie R. Hoffmann, Udo Patel, Manesh R. Cooper, Lawton S. Lee, Kerry L. Douglas, Pamela S. CA PROMISE Investigators TI Quality-of-Life Outcomes With Anatomic Versus Functional Diagnostic Testing Strategies in Symptomatic Patients With Suspected Coronary Artery Disease: Results From the PROMISE Randomized Trial SO CIRCULATION LA English DT Article DE chest pain; coronary artery disease; diagnosis; patient outcome assessment; quality of life ID COMPUTED-TOMOGRAPHY ANGIOGRAPHY; CHEST-PAIN; MYOCARDIAL-PERFUSION; COST-EFFECTIVENESS; CLINICAL-OUTCOMES; CT ANGIOGRAPHY; QUESTIONNAIRE; ANGINA AB Background The Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial found that initial use of 64 detector-row computed tomography angiography versus standard functional testing strategies (exercise ECG, stress nuclear methods, or stress echocardiography) did not improve clinical outcomes in 10003 stable symptomatic patients with suspected coronary artery disease requiring noninvasive testing. Symptom burden and quality of life (QOL) were major secondary outcomes. Methods and Results We prospectively collected a battery of QOL instruments in 5985 patients at baseline and 6, 12, and 24 months postrandomization. The prespecified primary QOL measures were the Duke Activity Status Index and the Seattle Angina Questionnaire frequency and QOL scales. All comparisons were made as randomized. Baseline variables were well balanced in the 2982 patients randomly assigned to computed tomography angiography testing and the 3003 patients randomly assigned to functional testing. The Duke Activity Status Index improved substantially in both groups over the first 6 months following testing, but we found no evidence for a strategy-related difference (mean difference [anatomic - functional] at 24 months of follow-up, 0.1 [95% confidence interval, -0.9 to 1.1]). Similar results were seen for the Seattle Angina Questionnaire frequency scale (mean difference at 24 months, -0.2; 95% confidence interval, -0.8 to 0.4) and QOL scale (mean difference at 24 months, -0.2; 95% confidence interval, -1.3 to 0.9). None of the secondary QOL measures showed a consistent strategy-related difference. Conclusions In symptomatic patients with suspected coronary artery disease who required noninvasive testing, symptoms and QOL improved significantly. However, a strategy of initial anatomic testing, in comparison with functional testing, did not provide an incremental benefit for QOL over 2 years of follow-up. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01174550. C1 [Mark, Daniel B.; Anstrom, Kevin J.; Sheng, Shubin; Baloch, Khaula N.; Daniels, Melanie R.] Duke Univ, Med Ctr, Outcomes Res Grp, Durham, NC USA. [Mark, Daniel B.; Anstrom, Kevin J.; Sheng, Shubin; Baloch, Khaula N.; Daniels, Melanie R.; Patel, Manesh R.; Lee, Kerry L.; Douglas, Pamela S.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Hoffmann, Udo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Cooper, Lawton S.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. RP Mark, DB (reprint author), Duke Clin Res Inst, Outcomes Res, 2400 Pratt St,Room 0311,POB 17969, Durham, NC 27715 USA. EM daniel.mark@duke.edu FU National Heart, Lung, and Blood Institute [R01HL098237, R01HL098236, R01HL98305, R01HL098235] FX This work was supported by grants R01HL098237, R01HL098236, R01HL98305, and R01HL098235 from the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health. NR 21 TC 5 Z9 5 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAY 24 PY 2016 VL 133 IS 21 BP 1995 EP 2007 DI 10.1161/CIRCULATIONAHA.115.020259 PG 13 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DN3DZ UT WOS:000376943900006 PM 27143676 ER PT J AU Li, CC Le, K Kato, J Moss, J Vaughan, M AF Li, Chun-Chun Le, Kang Kato, Jiro Moss, Joel Vaughan, Martha TI Enhancement of beta-catenin activity by BIG1 plus BIG2 via Arf activation and cAMP signals SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE ADP-ribosylation factor; cell migration; AKAP; phospholipase D ID ADP-RIBOSYLATION FACTORS; NUCLEOTIDE-EXCHANGE PROTEIN; TRANS-GOLGI NETWORK; SYNTHASE KINASE 3; TRANSCRIPTIONAL ACTIVITY; RECYCLING ENDOSOMES; LRP6 PHOSPHORYLATION; O-GLCNACYLATION; INTEGRIN BETA-1; ALPHA-CATENIN AB Multifunctional beta-catenin, with critical roles in both cell-cell adhesion and Wnt-signaling pathways, was among HeLa cell proteins coimmunoprecipitated by antibodies against brefeldin A-inhibited guanine nucleotide-exchange factors 1 and 2 (BIG1 or BIG2) that activate ADP-ribosylation factors (Arfs) by accelerating the replacement of bound GDP with GTP. BIG proteins also contain A-kinase anchoring protein (AKAP) sequences that can act as scaffolds for multimolecular assemblies that facilitate and limit cAMP signaling temporally and spatially. Direct interaction of BIG1 N-terminal sequence with beta-catenin was confirmed using yeast two-hybrid assays and in vitro synthesized proteins. Depletion of BIG1 and/or BIG2 or overexpression of guanine nucleotide-exchange factor inactive mutant, but not wild-type, proteins interfered with beta-catenin trafficking, leading to accumulation at perinuclear Golgi structures. Both phospholipase D activity and vesicular trafficking were required for effects of BIG1 and BIG2 on beta-catenin activation. Levels of PKA-phosphorylated beta-catenin S675 and beta-catenin association with PKA, BIG1, and BIG2 were also diminished after BIG1/BIG2 depletion. Inferring a requirement for BIG1 and/or BIG2 AKAP sequence in PKA modification of beta-catenin and its effect on transcription activation, we confirmed dependence of S675 phosphorylation and transcription coactivator function on BIG2 AKAP-C sequence. C1 [Li, Chun-Chun; Le, Kang; Kato, Jiro; Moss, Joel; Vaughan, Martha] NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Li, Chun-Chun] Natl Cheng Kung Univ, Coll Biosci & Biotechnol, Dept Life Sci, Tainan 701, Taiwan. RP Vaughan, M (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM vaughanm@nih.gov FU Intramural Research Program, NIH, NHLBI; Taiwan Ministry of Science and Technology [MOST 103-2320-B-006-039-MY3, MOST 104-2320-B-006-032-MY3] FX We thank Drs. Christian Combs and Daniela Malide [Light Microscopy Core Facility, National Heart, Lung, and Blood Institute (NHLBI)] for their much appreciated assistance with confocal microscopy and Dr. Michael A. Frohman for expert advice on PLD inhibitors. This work was supported by the Intramural Research Program, NIH, NHLBI, and in part by the Taiwan Ministry of Science and Technology (Grants MOST 103-2320-B-006-039-MY3 and MOST 104-2320-B-006-032-MY3) (to C.-C.L.). NR 69 TC 0 Z9 0 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 24 PY 2016 VL 113 IS 21 BP 5946 EP 5951 DI 10.1073/pnas.1601918113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DN0UD UT WOS:000376779900059 PM 27162341 ER PT J AU Motoike, T Long, JM Tanaka, H Sinton, CM Skach, A Williams, SC Hammer, RE Sakurai, T Yanagisawa, M AF Motoike, Toshiyuki Long, Jeffrey M. Tanaka, Hirokazu Sinton, Christopher M. Skach, Amber Williams, S. Clay Hammer, Robert E. Sakurai, Takeshi Yanagisawa, Masashi TI Mesolimbic neuropeptide W coordinates stress responses under novel environments SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE amygdala; fear; pain; dopaminergic; mouse ID PROTEIN-COUPLED RECEPTORS; CENTRAL EXTENDED AMYGDALA; STRIA TERMINALIS; BED NUCLEUS; CONDITIONED FEAR; RAT-BRAIN; TARGETED DISRUPTION; INHIBITORY CIRCUITS; ENDOGENOUS LIGAND; MESSENGER-RNA AB Neuropeptide B (NPB) and neuropeptide W(NPW) are endogenous neuropeptide ligands for the G protein-coupled receptors NPBWR1 and NPBWR2. Here we report that the majority of NPW neurons in the mesolimbic region possess tyrosine hydroxylase immunoreactivity, indicating that a small subset of dopaminergic neurons coexpress NPW. These NPW-containing neurons densely and exclusively innervate two limbic system nuclei in adult mouse brain: the lateral bed nucleus of the stria terminalis and the lateral part of the central amygdala nucleus (CeAL). In the CeAL of wild-type mice, restraint stress resulted in an inhibition of cellular activity, but this stress-induced inhibition was attenuated in the CeAL neurons of NPW-/- mice. Moreover, the response of NPW-/- mice to either formalin-induced pain stimuli or a live rat (i. e., a potential predator) was abnormal only when they were placed in a novel environment: The mice failed to show the normal species-specific self-protective and aversive reactions. In contrast, the behavior of NPW-/- mice in a habituated environment was indistinguishable from that of wildtype mice. These results indicate that the NPW/NPBWR1 system could play a critical role in the gating of stressful stimuli during exposure to novel environments. C1 [Motoike, Toshiyuki; Tanaka, Hirokazu; Skach, Amber; Williams, S. Clay; Yanagisawa, Masashi] Univ Texas SW Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA. [Motoike, Toshiyuki; Tanaka, Hirokazu; Skach, Amber; Williams, S. Clay; Yanagisawa, Masashi] Univ Texas SW Med Ctr Dallas, Dept Mol Genet, Dallas, TX 75390 USA. [Motoike, Toshiyuki; Tanaka, Hirokazu; Sakurai, Takeshi; Yanagisawa, Masashi] Japan Sci & Technol Agcy, Yanagisawa Orphan Receptor Project, Exploratory Res Adv Technol, Tokyo 1350064, Japan. [Long, Jeffrey M.; Hammer, Robert E.] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA. [Long, Jeffrey M.] NIA, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. [Sinton, Christopher M.] Univ Arizona, Dept Med, Arizona Resp Ctr, Tucson, AZ 85724 USA. [Sakurai, Takeshi] Kanazawa Univ, Inst Med Pharmacol & Hlth Sci, Fac Med, Dept Mol Neurosci & Integrat Physiol, Kanazawa, Ishikawa 9208640, Japan. [Yanagisawa, Masashi] Univ Tsukuba, Int Inst Integrat Sleep Med, Tsukuba, Ibaraki 3058575, Japan. [Tanaka, Hirokazu] Chiba Univ, Grad Sch Med, Dept Reprod Med, Chiba 2608670, Japan. RP Yanagisawa, M (reprint author), Univ Texas SW Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA.; Yanagisawa, M (reprint author), Univ Texas SW Med Ctr Dallas, Dept Mol Genet, Dallas, TX 75390 USA.; Yanagisawa, M (reprint author), Japan Sci & Technol Agcy, Yanagisawa Orphan Receptor Project, Exploratory Res Adv Technol, Tokyo 1350064, Japan.; Yanagisawa, M (reprint author), Univ Tsukuba, Int Inst Integrat Sleep Med, Tsukuba, Ibaraki 3058575, Japan. EM yanagisawa.masa.fu@u.tsukuba.ac.jp FU Keck Foundation; Perot Family Foundation; Exploratory Research for Advanced Technology of Japan Science and Technology Agency; World Premier International Research Center Initiative from the Ministry of Education, Culture, Sports, Science and Technology, Japan; Intramural Research Program of the NIH FX We thank Drs. Hiroshi Kuriyama, Shiori Ogawa, Kenji Shibata, Norimasa Miyamoto, and Yoji Kitamura for helpful advice and excellent technical assistance; Dr. David Hess for measuring serum corticosterone; Claudia Erbel-Sieler, Sandi Jo Estill, and Carol Dudley for technical assistance in behavioral studies; Elizabeth Lummus for the injection of ES cells for generating NPW-/- mice; and Shelley Dixon, Randal Floyd, and Marcus Thornton for technical support. This work was supported in part by research funds from the Keck Foundation; the Perot Family Foundation; the Exploratory Research for Advanced Technology of Japan Science and Technology Agency; the World Premier International Research Center Initiative from the Ministry of Education, Culture, Sports, Science and Technology, Japan; and the Intramural Research Program of the NIH (J.M.L.). M.Y. was an Investigator of the Howard Hughes Medical Institute during the period when this research was performed. NR 52 TC 0 Z9 0 U1 2 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 24 PY 2016 VL 113 IS 21 BP 6023 EP 6028 DI 10.1073/pnas.1518658113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DN0UD UT WOS:000376779900072 PM 27140610 ER PT J AU Madan, B Walker, MP Young, R Quick, L Orgel, KA Ryan, M Gupta, P Henrich, IC Ferrer, M Marine, S Roberts, BS Arthur, WT Berndt, JD Oliveira, AM Moon, RT Virshup, DM Chou, MM Major, MB AF Madan, Babita Walker, Matthew P. Young, Robert Quick, Laura Orgel, Kelly A. Ryan, Meagan Gupta, Priti Henrich, Ian C. Ferrer, Marc Marine, Shane Roberts, Brian S. Arthur, William T. Berndt, Jason D. Oliveira, Andre M. Moon, Randall T. Virshup, David M. Chou, Margaret M. Major, Michael B. TI USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Wnt signaling; ubiquitin-specific protease; USP6; Frizzled; ubiquitin ID ANEURYSMAL BONE-CYST; WNT/BETA-CATENIN PATHWAY; NF-KAPPA-B; NODULAR FASCIITIS; GROWTH; ENDOCYTOSIS; RECEPTORS; ACTIVATION; MAMMARY; PROTEIN AB The Wnt signaling pathways play pivotal roles in carcinogenesis. Modulation of the cell-surface abundance of Wnt receptors is emerging as an important mechanism for regulating sensitivity to Wnt ligands. Endocytosis and degradation of the Wnt receptors Frizzled (Fzd) and lipoprotein-related protein 6 (LRP6) are regulated by the E3 ubiquitin ligases zinc and ring finger 3 (ZNRF3) and ring finger protein 43 (RNF43), which are disrupted in cancer. In a genome-wide small interfering RNA screen, we identified the deubiquitylase ubiquitin-specific protease 6 (USP6) as a potent activator of Wnt signaling. USP6 enhances Wnt signaling by deubiquitylating Fzds, thereby increasing their cell-surface abundance. Chromosomal translocations in nodular fasciitis result in USP6 overexpression, leading to transcriptional activation of the Wnt/beta-catenin pathway. Inhibition of Wnt signaling using Dickkopf-1 (DKK1) or a Porcupine (PORCN) inhibitor significantly decreased the growth of USP6-driven xenograft tumors, indicating that Wnt signaling is a key target of USP6 during tumorigenesis. Our study defines an additional route to ectopic Wnt pathway activation in human disease, and identifies a potential approach to modulate Wnt signaling for therapeutic benefit. C1 [Madan, Babita; Gupta, Priti; Virshup, David M.] Duke NUS Med Sch, Program Canc & Stem Cell Biol, Singapore 169857, Singapore. [Walker, Matthew P.; Orgel, Kelly A.; Ryan, Meagan; Major, Michael B.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Cell Biol & Physiol, Chapel Hill, NC 27599 USA. [Young, Robert; Quick, Laura; Henrich, Ian C.; Chou, Margaret M.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Ferrer, Marc] Merck Res Labs, Dept Automated Biotechnol, N Wales, PA 19454 USA. [Ferrer, Marc] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Marine, Shane] Merck Res Labs, Dept Screening & Prot Sci, N Wales, PA 19454 USA. [Roberts, Brian S.; Arthur, William T.] Merck & Co Inc, Rosetta Inpharmat LLC, Seattle, WA 98109 USA. [Roberts, Brian S.] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA. [Arthur, William T.] Seattle Genet, Bothell, WA 98021 USA. [Berndt, Jason D.; Moon, Randall T.] Univ Washington, Howard Hughes Med Inst, Sch Med, Seattle, WA 98195 USA. [Berndt, Jason D.; Moon, Randall T.] Univ Washington, Sch Med, Dept Pharmacol, Seattle, WA 98195 USA. [Berndt, Jason D.; Moon, Randall T.] Univ Washington, Inst Stem Cell & Regenerat Med, Seattle, WA 98195 USA. [Oliveira, Andre M.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. RP Virshup, DM (reprint author), Duke NUS Med Sch, Program Canc & Stem Cell Biol, Singapore 169857, Singapore.; Major, MB (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Cell Biol & Physiol, Chapel Hill, NC 27599 USA.; Chou, MM (reprint author), Univ Penn, Childrens Hosp Philadelphia, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA.; Moon, RT (reprint author), Univ Washington, Howard Hughes Med Inst, Sch Med, Seattle, WA 98195 USA.; Moon, RT (reprint author), Univ Washington, Sch Med, Dept Pharmacol, Seattle, WA 98195 USA.; Moon, RT (reprint author), Univ Washington, Inst Stem Cell & Regenerat Med, Seattle, WA 98195 USA. EM rtmoon@uw.edu; david.virshup@duke-nus.edu.sg; mmc@mail.med.upenn.edu; ben_major@med.unc.edu OI Virshup, David M/0000-0001-6976-850X FU National Research Foundation Singapore; National Cancer Institute Center Core Support Grant [P30CA016086]; NIH [1-DP2-OD007149-01, T32-CA009156-35, RO1 CA168452, R21 CA178601]; Department of Laboratory Medicine and Pathology Mayo Clinic Award FX This research is supported, in part, by the National Research Foundation Singapore and administered by the Singapore Ministry of Health's National Medical Research Council under the Singapore Translational Research Investigator (STAR) Award Program (to D.M.V.). The University of North Carolina (UNC) Flow Cytometry Core Facility is supported, in part, by a National Cancer Institute Center Core Support Grant (P30CA016086) to the UNC Lineberger Comprehensive Cancer Center. M.B.M. is supported, in part, by the NIH (New Innovator Award 1-DP2-OD007149-01). M.P.W. received support from the NIH (Grant T32-CA009156-35). M.M.C. is supported, in part, by NIH Grants RO1 CA168452 and R21 CA178601. R.T.M. is an investigator of the Howard Hughes Medical Institute. A.M.O. is supported, in part, by Department of Laboratory Medicine and Pathology Mayo Clinic Award 2014. NR 44 TC 1 Z9 1 U1 4 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 24 PY 2016 VL 113 IS 21 BP E2945 EP E2954 DI 10.1073/pnas.1605691113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DN0UD UT WOS:000376779900012 PM 27162353 ER PT J AU Sun, X Park, JH Gumerson, J Wu, ZJ Swaroop, A Qian, HH Roll-Mecak, A Li, TS AF Sun, Xun Park, James H. Gumerson, Jessica Wu, Zhijian Swaroop, Anand Qian, Haohua Roll-Mecak, Antonina Li, Tiansen TI Loss of RPGR glutamylation underlies the pathogenic mechanism of retinal dystrophy caused by TTLL5 mutations SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cilia; polyglutamylation; retinitis pigmentosa; tubulin tyrosine ligase-like; RPGR ID LINKED RETINITIS-PIGMENTOSA; REGULATOR (RPGR)-INTERACTING PROTEIN; TUBULIN POLYGLUTAMYLATION; ALPHA-TUBULIN; POSTTRANSLATIONAL MODIFICATIONS; MICROTUBULE FUNCTIONS; MONOCLONAL-ANTIBODY; CONE DYSTROPHY; BETA-TUBULIN; EXON ORF15 AB Mutations in the X-linked retinitis pigmentosa GTPase regulator (RPGR) gene are a major cause of retinitis pigmentosa, a blinding retinal disease resulting from photoreceptor degeneration. A photoreceptor specific ORF15 variant of RPGR (RPGR(ORF15)), carrying multiple Glu-Gly tandem repeats and a C-terminal basic domain of unknown function, localizes to the connecting cilium where it is thought to regulate cargo trafficking. Here we show that tubulin tyrosine ligase like-5 (TTLL5) glutamylates RPGR(ORF15) in its Glu-Gly-rich repetitive region containing motifs homologous to the a-tubulin C-terminal tail. The RPGR(ORF15) C-terminal basic domain binds to the noncatalytic cofactor interaction domain unique to TTLL5 among TTLL family glutamylases and targets TTLL5 to glutamylate RPGR. Only TTLL5 and not other TTLL family glutamylases interacts with RPGR(ORF15) when expressed transiently in cells. Consistent with this, a Ttll5 mutant mouse displays a complete loss of RPGR glutamylation without marked changes in tubulin glutamylation levels. The Ttll5 mutant mouse develops slow photoreceptor degeneration with early mislocalization of cone opsins, features resembling those of Rpgr-null mice. Moreover TTLL5 disease mutants that cause human retinal dystrophy show impaired glutamylation of RPGR(ORF15). Thus, RPGR(ORF15) is a novel glutamylation substrate, and this posttranslational modification is critical for its function in photoreceptors. Our study uncovers the pathogenic mechanism whereby absence of RPGR(ORF15) glutamylation leads to retinal pathology in patients with TTLL5 gene mutations and connects these two genes into a common disease pathway. C1 [Sun, Xun; Gumerson, Jessica; Wu, Zhijian; Swaroop, Anand; Li, Tiansen] NEI, N NRL, Bethesda, MD 20892 USA. [Park, James H.; Roll-Mecak, Antonina] NINDS, Cell Biol & Biophys Unit, Bethesda, MD 20892 USA. [Qian, Haohua] NEI, Visual Funct Core, Bethesda, MD 20892 USA. RP Li, TS (reprint author), NEI, N NRL, Bethesda, MD 20892 USA.; Roll-Mecak, A (reprint author), NINDS, Cell Biol & Biophys Unit, Bethesda, MD 20892 USA. EM antonina@mail.nih.gov; tiansen.li@nih.gov OI Swaroop, Anand/0000-0002-1975-1141 FU NEI; NINDS FX We thank Dr. Stoney Simons, Jr. (National Institute of Diabetes and Digestive and Kidney Diseases) for transferring the Ttll5-/- mice to A. R.-M., Dr. Robert Fariss [National Eye Institute (NEI)] for help with confocal microscopy, Dr. Mones Abu-Asab (NEI) for help with TEM, Dr. Suresh Sharma (NEI) for advice on statistics, Suja Hiriyanna (NEI) and Dr. Wenhan Yu (NEI) for AAV vector production, Yide Mi (NEI) for colony management, Megan Kopera (NEI) and Hideko Takahashi (NEI) for rederivation of Ttll5 mice to the C57BL/6J background, Drs. Heather Narver and Brian Wilgenburg [National Institute of Neurological Disorders and Stroke (NINDS)] for veterinarian service and Ttll5 mouse colony management, and Arturo Rivera (NEI) for help with genotyping. This work was supported by the intramural programs of the NEI and NINDS (to T.L. and A.R.-M., respectively). NR 57 TC 7 Z9 7 U1 2 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 24 PY 2016 VL 113 IS 21 BP E2925 EP E2934 DI 10.1073/pnas.1523201113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DN0UD UT WOS:000376779900010 PM 27162334 ER PT J AU Madak-Erdogan, Z Kim, SH Gong, P Zhao, YC Zhang, H Chambliss, KL Carlson, KE Mayne, CG Shaul, PW Korach, KS Katzenellenbogen, JA Katzenellenbogen, BS AF Madak-Erdogan, Zeynep Kim, Sung Hoon Gong, Ping Zhao, Yiru C. Zhang, Hui Chambliss, Ken L. Carlson, Kathryn E. Mayne, Christopher G. Shaul, Philip W. Korach, Kenneth S. Katzenellenbogen, John A. Katzenellenbogen, Benita S. TI Design of pathway preferential estrogens that provide beneficial metabolic and vascular effects without stimulating reproductive tissues SO SCIENCE SIGNALING LA English DT Article ID BREAST-CANCER CELLS; ALPHA ER-ALPHA; RECEPTOR-ALPHA; ANDROGEN RECEPTOR; GENE-EXPRESSION; BETA; MEMBRANE; NUCLEAR; BINDING; ACTIVATION AB There is great medical need for estrogens with favorable pharmacological profiles that support desirable activities for menopausal women, such as metabolic and vascular protection, but that lack stimulatory activities on the breast and uterus. We report the development of structurally novel estrogens that preferentially activate a subset of estrogen receptor (ER) signaling pathways and result in favorable target tissue-selective activity. Through a process of structural alteration of estrogenic ligands that was designed to preserve their essential chemical and physical features but greatly reduced their binding affinity for ERs, we obtained "pathway preferential estrogens" (PaPEs), which interacted with ERs to activate the extranuclear-initiated signaling pathway preferentially over the nuclear-initiated pathway. PaPEs elicited a pattern of gene regulation and cellular and biological processes that did not stimulate reproductive and mammary tissues or breast cancer cells. However, in ovariectomized mice, PaPEs triggered beneficial responses both in metabolic tissues (adipose tissue and liver) that reduced body weight gain and fat accumulation and in the vasculature that accelerated repair of endothelial damage. This process of designed ligand structure alteration represents a novel approach to develop ligands that shift the balance in ER-mediated extranuclear and nuclear pathways to obtain tissue-selective, non-nuclear PaPEs, which may be beneficial for postmenopausal hormone replacement. The approach may also have broad applicability for other members of the nuclear hormone receptor superfamily. C1 [Madak-Erdogan, Zeynep; Gong, Ping; Zhao, Yiru C.; Katzenellenbogen, Benita S.] Univ Illinois, Dept Mol & Integrat Physiol, Urbana, IL 61801 USA. [Kim, Sung Hoon; Carlson, Kathryn E.; Katzenellenbogen, John A.] Univ Illinois, Dept Chem, 1209 W Calif St, Urbana, IL 61801 USA. [Zhang, Hui; Chambliss, Ken L.; Shaul, Philip W.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Ctr Pulm & Vasc Biol, Dallas, TX 75390 USA. [Mayne, Christopher G.] Univ Illinois, Beckman Inst Adv Sci & Technol, Urbana, IL 61801 USA. [Korach, Kenneth S.] NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. RP Katzenellenbogen, BS (reprint author), Univ Illinois, Dept Mol & Integrat Physiol, Urbana, IL 61801 USA. EM katzenel@illinois.edu OI Korach, Kenneth/0000-0002-7765-418X FU Breast Cancer Research Foundation; NIH from the National Center for Complementary and Integrative Health (NCCIH) [R37 DK015556, P50AT006268]; Office of Dietary Supplements (ODS); National Cancer Institute (NCI); National Institute of Food and Agriculture, U.S. Department of Agriculture [ILLU-698-909]; NIH [HL087564]; Associates First Capital Corporation Distinguished Chair in Pediatrics at University of Texas (UT) Southwestern; Sun Yat-sen University, China; Division of Intramural Research, National Institute of Environmental Health Sciences [1ZIAES070065] FX This work was supported by a grant from the Breast Cancer Research Foundation (to B.S.K.); NIH grants R37 DK015556 (to J.A.K.) and P50AT006268 (to B.S.K.) from the National Center for Complementary and Integrative Health (NCCIH), the Office of Dietary Supplements (ODS), and the National Cancer Institute (NCI); National Institute of Food and Agriculture, U.S. Department of Agriculture award ILLU-698-909 (to Z.M.-E.); NIH HL087564 (to P.W.S.); the Associates First Capital Corporation Distinguished Chair in Pediatrics at University of Texas (UT) Southwestern (to P.W.S.); a fellowship from Sun Yat-sen University, China (to H.Z.); and Division of Intramural Research, National Institute of Environmental Health Sciences 1ZIAES070065 (to K.S.K.). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH, NCCIH, ODS, NCI, or the U.S. Department of Agriculture. NR 65 TC 1 Z9 1 U1 4 U2 6 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1945-0877 EI 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD MAY 24 PY 2016 VL 9 IS 429 AR ra53 DI 10.1126/scisignal.aad8170 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DM6MV UT WOS:000376467800004 PM 27221711 ER PT J AU Tinaz, S Pillai, AS Hallett, M AF Tinaz, Sule Pillai, Ajay S. Hallett, Mark TI Sequence Effect in Parkinson's Disease Is Related to Motor Energetic Cost SO FRONTIERS IN NEUROLOGY LA English DT Article DE bradykinesia; decrement; dopamine; visual feedback; cost-benefit; motor control; fatigue ID BASAL GANGLIA; MENTAL FATIGUE; PATHOPHYSIOLOGY; DOPAMINE; LEVODOPA; GAIT; BRADYKINESIA; IMPAIRMENTS; PERFORMANCE; FESTINATION AB Bradykinesia is the most disabling motor symptom of Parkinson's disease (PD). The sequence effect (SE), a feature of bradykinesia, refers to the rapid decrement in amplitude and speed of repetitive movements (e.g., gait, handwriting) and is a major cause of morbidity in PD. Previous research has revealed mixed results regarding the role of dopaminergic treatment in the SE. However, external cueing has been shown to improve it. In this study, we aimed to characterize the SE systematically and relate this phenomenon to the energetic cost of movement within the context of cost-benefit framework of motor control. We used a dynamic isometric motor task with auditory pacing to assess the SE in motor output during a 15-s task segment in PD patients and matched controls. All participants performed the task with both hands, and without and with visual feedback (VF). Patients were also tested in "on" - and "off"-dopaminergic states. Patients in the "off" state did not show higher SE compared to controls, partly due to large variance in their performance. However, patients in the "on" state and in the absence of VF showed significantly higher SE compared to controls. Patients expended higher total motor energy compared to controls in all conditions and regardless of their medication status. In this experimental situation, the SE in PD is associated with the cumulative energetic cost of movement. Dopaminergic treatment, critical for internal triggering of movement, fails to maintain the motor vigor across responses. The high motor cost may be related to failure to incorporate limbic/motivational cues into the motor plan. VF may facilitate performance by shifting the driving of movement from internal to external or, alternatively, by functioning as a motivational cue. C1 [Tinaz, Sule] Yale Univ, Sch Med, Dept Neurol, Div Movement Disorders, New Haven, CT 06510 USA. [Tinaz, Sule; Pillai, Ajay S.; Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Tinaz, S (reprint author), Yale Univ, Sch Med, Dept Neurol, Div Movement Disorders, New Haven, CT 06510 USA.; Tinaz, S (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM sule.tinaz@yale.edu FU NINDS Intramural Research Program FX This work was supported by the NINDS Intramural Research Program. NR 46 TC 0 Z9 0 U1 3 U2 3 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-2295 J9 FRONT NEUROL JI Front. Neurol. PD MAY 24 PY 2016 VL 7 AR 83 DI 10.3389/fneur.2016.00083 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DM3JY UT WOS:000376243900001 PM 27252678 ER PT J AU Mills, KT Chen, J Yang, W Appel, LJ Kusek, JW Alper, A Delafontaine, P Keane, MG Mohler, E Ojo, A Rahman, M Ricardo, AC Soliman, EZ Steigerwalt, S Townsend, R He, J AF Mills, Katherine T. Chen, Jing Yang, Wei Appel, Lawrence J. Kusek, John W. Alper, Arnold Delafontaine, Patrice Keane, Martin G. Mohler, Emile Ojo, Akinlolu Rahman, Mahboob Ricardo, Ana C. Soliman, Elsayed Z. Steigerwalt, Susan Townsend, Raymond He, Jiang CA CRIC Study Investigators TI Sodium Excretion and the Risk of Cardiovascular Disease in Patients With Chronic Kidney Disease SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CHRONIC RENAL-INSUFFICIENCY; AMERICAN-HEART-ASSOCIATION; GLOMERULAR-FILTRATION-RATE; BLOOD-PRESSURE; URINARY SODIUM; REGRESSION-MODELS; POTASSIUM INTAKE; SALT INTAKE; HYPERTENSION; ADULTS AB IMPORTANCE Patients with chronic kidney disease (CKD) are at an increased risk of cardiovascular disease (CVD) compared with the general population. Prior studies have produced contradictory results on the association of dietary sodium intake with risk of CVD, and this relationship has not been investigated in patients with CKD. OBJECTIVE To evaluate the association between urinary sodium excretion and clinical CVD events among patients with CKD. DESIGN, SETTING, AND PARTICIPANTS A prospective cohort study of patients with CKD from 7 locations in the United States enrolled in the Chronic Renal Insufficiency Cohort Study and followed up from May 2003 to March 2013. EXPOSURES The cumulative mean of urinary sodium excretion from three 24-hour urinary measurements and calibrated to sex-specific mean 24-hour urinary creatinine excretion. MAIN OUTCOMES AND MEASURES A composite of CVD events defined as congestive heart failure, stroke, or myocardial infarction. Events were reported every 6 months and confirmed by medical record adjudication. RESULTS Among 3757 participants (mean age, 58 years; 45% women), 804 composite CVD events (575 heart failure, 305 myocardial infarction, and 148 stroke) occurred during a median 6.8 years of follow-up. From lowest (<2894 mg/24 hours) to highest (>= 4548 mg/24 hours) quartile of calibrated sodium excretion, 174, 159, 198, and 273 composite CVD events occurred, and the cumulative incidence was 18.4%, 16.5%, 20.6%, and 29.8% at median follow-up. In addition, the cumulative incidence of CVD events in the highest quartile of calibrated sodium excretion compared with the lowest was 23.2% vs 13.3% for heart failure, 10.9% vs 7.8% for myocardial infarction, and 6.4% vs 2.7% for stroke at median follow-up. Hazard ratios of the highest quartile compared with the lowest quartile were 1.36 (95% CI, 1.09-1.70; P = .007) for composite CVD events, 1.34 (95% CI, 1.03-1.74; P = .03) for heart failure, and 1.81 (95% CI, 1.08-3.02; P = .02) for stroke after multivariable adjustment. Restricted cubic spline analyses of the association between sodium excretion and composite CVD provided no evidence of a nonlinear association (P = .11) and indicated a significant linear association (P < .001). CONCLUSIONS AND RELEVANCE Among patients with CKD, higher urinary sodium excretion was associated with increased risk of CVD. C1 [Mills, Katherine T.; Chen, Jing; He, Jiang] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, 1440 Canal St,Ste 2000, New Orleans, LA 70112 USA. [Chen, Jing; Alper, Arnold; Delafontaine, Patrice; He, Jiang] Tulane Univ, Sch Med, Dept Med, New Orleans, LA 70112 USA. [Yang, Wei] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Appel, Lawrence J.] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Kusek, John W.; Townsend, Raymond] NIDDK, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. [Keane, Martin G.] Temple Univ, Sch Med, Dept Med, Philadelphia, PA 19122 USA. [Mohler, Emile] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Ojo, Akinlolu] Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. [Rahman, Mahboob] Case Western Reserve Univ, Univ Hosp Case Med Ctr, Div Nephrol & Hypertens, Cleveland, OH 44106 USA. [Rahman, Mahboob] Louis Stokes Cleveland VA Med Ctr, Cleveland, OH USA. [Ricardo, Ana C.] Univ Illinois, Dept Med, Chicago, IL USA. [Soliman, Elsayed Z.] Wake Forest Sch Med, Dept Internal Med Cardiol, Winston Salem, NC USA. [Steigerwalt, Susan] St Johns Hlth Syst, Dept Med, Detroit, MI USA. RP He, J (reprint author), Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, 1440 Canal St,Ste 2000, New Orleans, LA 70112 USA. EM jhe@tulane.edu OI Delafontaine, Patrice/0000-0003-3744-3617 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01DK074615]; NIDDK [U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, U01DK060902]; University of Pennsylvania Clinical and Translational Science Award [NIH/NCATS UL1TR000003]; Johns Hopkins University [UL1 TR-000424]; University of Maryland [GCRC M01 RR-16500]; Clinical and Translational Science Collaborative of Cleveland [UL1TR000439]; Michigan Institute for Clinical and Health Research [UL1TR000433]; University of Illinois at Chicago [CTSA UL1RR029879]; Tulane COBRE for Clinical and Translational Research in Cardiometabolic Diseases [P20 GM109036]; Kaiser [NIH/NCRR UCSF-CTSI UL1 RR-024131]; National Heart, Lung, and Blood Institute [T32HL007024] FX This study was funded by a research grant (R01DK074615) from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Funding for the CRIC Study was obtained under a cooperative agreement from the NIDDK (U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, and U01DK060902). In addition, this work was supported in part by the University of Pennsylvania Clinical and Translational Science Award (NIH/NCATS UL1TR000003), Johns Hopkins University (UL1 TR-000424), University of Maryland (GCRC M01 RR-16500), Clinical and Translational Science Collaborative of Cleveland (UL1TR000439), Michigan Institute for Clinical and Health Research (UL1TR000433), University of Illinois at Chicago (CTSA UL1RR029879), Tulane COBRE for Clinical and Translational Research in Cardiometabolic Diseases (P20 GM109036), and Kaiser (NIH/NCRR UCSF-CTSI UL1 RR-024131). Dr Mills is supported in part by the National Heart, Lung, and Blood Institute Cardiovascular Epidemiology training grant (T32HL007024, principal investigator: Coresh). NR 39 TC 12 Z9 12 U1 6 U2 11 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 24 PY 2016 VL 315 IS 20 BP 2200 EP 2210 DI 10.1001/jama.2016.4447 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA DM4US UT WOS:000376343000016 PM 27218629 ER PT J AU Romagnoli, R Baraldi, PG Prencipe, F Oliva, P Baraldi, S Tabrizi, MA Lopez-Cara, LC Ferla, S Brancale, A Hamel, E Ronca, R Bortolozzi, R Mariotto, E Basso, G Viola, G AF Romagnoli, Romeo Baraldi, Pier Giovanni Prencipe, Filippo Oliva, Paola Baraldi, Stefania Tabrizi, Mojgan Aghazadeh Carlota Lopez-Cara, Luisa Ferla, Salvatore Brancale, Andrea Hamel, Ernest Ronca, Roberto Bortolozzi, Roberta Mariotto, Elena Basso, Giuseppe Viola, Giampietro TI Design and Synthesis of Potent in Vitro and in Vivo Anticancer Agents Based on 1-(3 ',4 ',5 '-Trimethoxyphenyl)-2-Aryl-1H-Imidazole SO SCIENTIFIC REPORTS LA English DT Article ID COMBRETASTATIN A-4 ANALOGS; ANTITUMOR-ACTIVITY; BIOLOGICAL EVALUATION; MAMMALIAN-CELLS; DNA-DAMAGE; TUBULIN; PHOSPHORYLATION; COLCHICINE; BINDING; CANCER AB A novel series of tubulin polymerization inhibitors, based on the 1-(3',4',5'-trimethoxyphenyl)-2-aryl-1H-imidazole scaffold and designed as cis-restricted combretastatin A-4 analogues, was synthesized with the goal of evaluating the effects of various patterns of substitution on the phenyl at the 2-position of the imidazole ring on biological activity. A chloro and ethoxy group at the meta-and para-positions, respectively, produced the most active compound in the series (4o), with IC50 values of 0.4-3.8 nM against a panel of seven cancer cell lines. Except in HL-60 cells, 4o had greater antiproliferative than CA-4, indicating that the 3'-chloro-4'-ethoxyphenyl moiety was a good surrogate for the CA-4 B-ring. Experiments carried out in a mouse syngenic model demonstrated high antitumor activity of 4o, which significantly reduced the tumor mass at a dose thirty times lower than that required for CA-4P, which was used as a reference compound. Altogether, our findings suggest that 4o is a promising anticancer drug candidate that warrants further preclinical evaluation. C1 [Romagnoli, Romeo; Baraldi, Pier Giovanni; Prencipe, Filippo; Oliva, Paola; Baraldi, Stefania; Tabrizi, Mojgan Aghazadeh] Univ Ferrara, Dipartimento Sci Chim & Farmaceut, I-44121 Ferrara, Italy. [Carlota Lopez-Cara, Luisa] Fac Farm, Dept Quim Organ & Farmaceut, Campus Cartuja S-N, Granada 18071, Spain. [Ferla, Salvatore; Brancale, Andrea] Cardiff Univ, Sch Pharm & Pharmaceut Sci, King Edward VII Ave, Cardiff CF10 3NB, S Glam, Wales. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program,NIH, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Ft Detrick, MD 21702 USA. [Ronca, Roberto] Univ Brescia, Dipartimento Med Mol & Traslaz, Unita Oncol Sperimentale & Immunol, I-25123 Brescia, Italy. [Bortolozzi, Roberta; Mariotto, Elena; Basso, Giuseppe; Viola, Giampietro] Univ Padua, Dipartimento Salute Donna & Bambino, Lab Oncoematol, I-35131 Padua, Italy. RP Romagnoli, R (reprint author), Univ Ferrara, Dipartimento Sci Chim & Farmaceut, I-44121 Ferrara, Italy.; Lopez-Cara, LC (reprint author), Fac Farm, Dept Quim Organ & Farmaceut, Campus Cartuja S-N, Granada 18071, Spain.; Viola, G (reprint author), Univ Padua, Dipartimento Salute Donna & Bambino, Lab Oncoematol, I-35131 Padua, Italy. EM rmr@unife.it; lcarlotalopez@ugr.es; giampietro.viola1@unipd.it RI Mariotto, Elena/H-7449-2015; Viola, Giampietro/I-4095-2012; LOPEZ-CARA, LUISA CARLOTA/F-9686-2014; Baraldi, Stefania/B-7965-2017; Baraldi, Pier Giovanni/B-7933-2017; Ferla, Salvatore/F-7976-2016 OI Mariotto, Elena/0000-0002-3960-8561; Viola, Giampietro/0000-0001-9329-165X; LOPEZ-CARA, LUISA CARLOTA/0000-0003-1142-6448; Ferla, Salvatore/0000-0002-5918-9237 FU Proyecto de Excelencia de la Consejeria de Innovacion y Ciencia de la Junta de Andalucia, Spain [P12-CTS-696]; Life Science Research Net-work Wales [NRNPGSep14008]; Welsh Government's Ser Cymru program FX The authors would like to thank Dr. Alberto Casolari for excellent technical assistance. We acknowledge "Proyecto de Excelencia de la Consejeria de Innovacion y Ciencia de la Junta de Andalucia, Spain ref. P12-CTS-696" for its financial support. We also acknowledge the support of the Life Science Research Net-work Wales grant no. NRNPGSep14008, an initiative funded through the Welsh Government's Ser Cymru program. The content of this paper is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health. NR 46 TC 0 Z9 0 U1 7 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAY 24 PY 2016 VL 6 AR 26602 DI 10.1038/srep26602 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM5AO UT WOS:000376359000002 PM 27216165 ER PT J AU Gregory, MD Kippenhan, JS Dickinson, D Carrasco, J Mattay, VS Weinberger, DR Berman, KF AF Gregory, Michael D. Kippenhan, J. Shane Dickinson, Dwight Carrasco, Jessica Mattay, Venkata S. Weinberger, Daniel R. Berman, Karen F. TI Regional Variations in Brain Gyrification Are Associated with General Cognitive Ability in Humans SO CURRENT BIOLOGY LA English DT Article ID FRONTAL-INTEGRATION-THEORY; TEST BATTERIES; INTELLIGENCE; EVOLUTION; VOLUME; METAANALYSIS AB Searching for a neurobiological understanding of human intellectual capabilities has long occupied those very capabilities. Brain gyrification, or folding of the cortex, is as highly evolved and variable a characteristic in humans as is intelligence. Indeed, gyrification scales with brain size, and relationships between brain size and intelligence have been demonstrated in humans [1-3]. However, gyrification shows a large degree of variability that is independent from brain size [4-6], suggesting that the former may independently contribute to cognitive abilities and thus supporting a direct investigation of this parameter in the context of intelligence. Moreover, uncovering the regional pattern of such an association could offer insights into evolutionary and neural mechanisms. We tested for this brain-behavior relationship in two separate, independently collected, large cohorts-440 healthy adults and 662 healthy children-using high-resolution structural neuroimaging and comprehensive neuropsychometric batteries. In both samples, general cognitive ability was significantly associated (p(FDR) < 0.01) with increasing gyrification in a network of neocortical regions, including large portions of the prefrontal cortex, inferior parietal lobule, and temporoparietal junction, as well as the insula, cingulate cortex, and fusiformgyrus, a regional distribution that was nearly identical in both samples (Dice similarity coefficient = 0.80). This neuroanatomical pattern is consistent with an existing, well-known proposal, the Parieto-Frontal Integration Theory of intelligence [7], and is also consistent with research in comparative evolutionary biology showing rapid neocortical expansion of these regions in humans relative to other species. These data provide a framework for understanding the neurobiology of human cognitive abilities and suggest a potential neurocellular association. C1 [Gregory, Michael D.; Kippenhan, J. Shane; Carrasco, Jessica; Berman, Karen F.] NIMH, Sect Integrat Neuroimaging, Clin & Translat Neurosci Branch, NIH, Bethesda, MD 20892 USA. [Dickinson, Dwight; Berman, Karen F.] NIMH, Psychosis & Cognit Studies Sect, Clin & Translat Neurosci Branch, NIH, Bethesda, MD 20892 USA. [Mattay, Venkata S.; Weinberger, Daniel R.] Lieber Inst Brain Dev, Baltimore, MD 21205 USA. [Mattay, Venkata S.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. RP Gregory, MD; Berman, KF (reprint author), NIMH, Sect Integrat Neuroimaging, Clin & Translat Neurosci Branch, NIH, Bethesda, MD 20892 USA.; Berman, KF (reprint author), NIMH, Psychosis & Cognit Studies Sect, Clin & Translat Neurosci Branch, NIH, Bethesda, MD 20892 USA. EM gregorymd@mail.nih.gov; karen.berman@nih.gov FU Intramural Research Program, National Institute of Mental Health, NIH; [RC2MH089983]; [RC2MH089924] FX This work was supported by the Intramural Research Program, National Institute of Mental Health, NIH. The data for the NIMH cohort were obtained under protocol 00-M-0085/NCT00004571/ZIAMH002942-03. The data for the PNC cohort were obtained from dbGAP (accession number phs000607), and collection of the data was supported by grants RC2MH089983 awarded to Raquel Gur and RC2MH089924 awarded to Hakon Hakonarson. Some of this work utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). NR 28 TC 1 Z9 1 U1 2 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD MAY 23 PY 2016 VL 26 IS 10 BP 1301 EP 1305 DI 10.1016/j.cub.2016.03.021 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DM6ME UT WOS:000376466000025 PM 27133866 ER PT J AU Anand, A Sharma, K Sharma, SK Singh, R Sharma, NK Prasad, K AF Anand, Akshay Sharma, Kaushal Sharma, Suresh K. Singh, Ramandeep Sharma, Neel K. Prasad, Keshava TI AMD Genetics in India: The Missing Links SO FRONTIERS IN AGING NEUROSCIENCE LA English DT Review DE age related macular degeneration; SNP; biomarkers; longitudinal analysis; snSNPs; bio-informatics analysis; statistical modeling; Mendelian randomization ID RETINAL-PIGMENT EPITHELIUM; ENDOTHELIAL-GROWTH-FACTOR; TOLL-LIKE RECEPTOR-3; AMYOTROPHIC-LATERAL-SCLEROSIS; GENOME-WIDE ASSOCIATION; COMPLEMENT FACTOR-H; BODY-MASS INDEX; MACULAR DEGENERATION; MENDELIAN RANDOMIZATION; MESSENGER-RNA AB Age related macular degeneration is a disease which occurs in aged individuals. There are various changes that occur, at the cellular, molecular and physiological level with advancing age (Sarniec et al., 1988; Sharma K. et al., 2014). Drusen deposition between retinal pigment epithelium (RPE) and Bruch's membrane (BM) is one of the key features in AMD patients (Mullins et al., 2000: Hageman et al., 2001) similar to Artau aggregates in Alzheimer's disease (AD) patients. The primary goal of this review is to discuss whether the various candidate genes and associated biomarkers, that are known to play an independent role in progression of AMD, exert deleterious effect on phenotype, alone or in combination, in Indian AMD patients from the same ethnic group and the significance of such research. A statistical model for probable interaction between genes could be derived from such analysis. Therefore, one can use multiple modalities to identify and enrol AMD patients based on established clinical criteria and examine the risk factors to determine if these genes are associated with risk factors, biomarkers or disease by Mendelian randomization. Similarly, there are large numbers of single nucleotide polymorphisms (SNPs) identified in human population. Even non-synonymous SNPs (nsSNPs) are believed to induce deleterious effects on the functionality of various proteins. The study of such snSNPs could provide a better genetic insight for diverse phenotypes of AMD patients, predicting significant risk factors for the disease in Indian population. Therefore, the prediction of biological effect of nsSNPs in the candidate genes and the associated grant applications in the subject are highly solicited.Therefore, genotyping and levels of protein expression of various genes would provide wider canvas in genetic complexity of AMD pathology which should be evaluated by valid statistical and bioinformatics' tools. Longitudinal follow up of Indian AMD patients to evaluate the temporal effect of SNPs and biomarkers on progression of disease would provide a unique strategy in the field. C1 [Anand, Akshay; Sharma, Kaushal] Postgrad Inst Med Educ & Res, Neurosci Res Lab, Dept Neurol, Chandigarh 160012, India. [Sharma, Kaushal; Sharma, Suresh K.] Panjab Univ, Ctr Syst Biol & Bioinformat, Chandigarh 160014, India. [Sharma, Suresh K.] Panjab Univ, Dept Stat, Chandigarh 160014, India. [Singh, Ramandeep] Postgrad Inst Med Educ & Res, Adv Eye Ctr, Chandigarh 160012, India. [Sharma, Neel K.] NEI, Neurobiol Neurodegenerat & Repair Lab, Bethesda, MD 20892 USA. [Prasad, Keshava] Inst Bioinformat, Bangalore, Karnataka, India. [Prasad, Keshava] Yenepoya Univ, YU IOB Ctr Syst Biol & Mol Med, Mangalore, India. [Prasad, Keshava] Natl Inst Mental Hlth & Neurosci, NIMHANS IOB Prote & Bioinformat Lab, Neurobiol Res Ctr, Bangalore 560029, Karnataka, India. RP Anand, A (reprint author), Postgrad Inst Med Educ & Res, Neurosci Res Lab, Dept Neurol, Chandigarh 160012, India. EM akshay1anand@rediffmail.com NR 81 TC 0 Z9 0 U1 1 U2 10 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1663-4365 J9 FRONT AGING NEUROSCI JI Front. Aging Neurosci. PD MAY 23 PY 2016 VL 8 AR 115 DI 10.3389/fnagi.2016.00115 PG 14 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA DM6QP UT WOS:000376477800001 PM 27252648 ER PT J AU Galletta, BJ Jacobs, KC Fagerstrom, CJ Rusan, NM AF Galletta, Brian J. Jacobs, Katherine C. Fagerstrom, Carey J. Rusan, Nasser M. TI Asterless is required for centriole length control and sperm development SO JOURNAL OF CELL BIOLOGY LA English DT Article ID DROSOPHILA-MELANOGASTER; CAENORHABDITIS-ELEGANS; CENTROSOME BIOGENESIS; CELL DIVISION; PROTEIN; DUPLICATION; CEP152; PLK4; RECRUITMENT; ORGANIZATION AB Centrioles are the foundation of two organelles, centrosomes and cilia. Centriole numbers and functions are tightly controlled, and mutations in centriole proteins are linked to a variety of diseases, including microcephaly. Loss of the centriole protein Asterless (Asl), the Drosophila melanogaster orthologue of Cep152, prevents centriole duplication, which has limited the study of its nonduplication functions. Here, we identify populations of cells with Asl-free centrioles in developing Drosophila tissues, allowing us to assess its duplication-independent function. We show a role for Asl in controlling centriole length in germline and somatic tissue, functioning via the centriole protein Cep97. We also find that Asl is not essential for pericentriolar material recruitment or centrosome function in organizing mitotic spindles. Lastly, we show that AsI is required for proper basal body function and spermatid axoneme formation. Insights into the role of Asl/Cep152 beyond centriole duplication could help shed light on how Cep152 mutations lead to the development of microcephaly. C1 [Galletta, Brian J.; Jacobs, Katherine C.; Fagerstrom, Carey J.; Rusan, Nasser M.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Rusan, NM (reprint author), NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM nasser@nih.gov RI Rusan, Nasser/P-3511-2016 FU Division of Intramural Research at National Institutes of Health, National Heart, Lung, and Blood Institute [1ZIAHL006104] FX N.M. Rusan is supported by the Division of Intramural Research at National Institutes of Health, National Heart, Lung, and Blood Institute (1ZIAHL006104). NR 75 TC 3 Z9 3 U1 7 U2 10 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD MAY 23 PY 2016 VL 213 IS 4 BP 435 EP 450 DI 10.1083/jcb.201501120 PG 16 WC Cell Biology SC Cell Biology GA DN1GR UT WOS:000376814800007 PM 27185836 ER PT J AU Van Dyke, RB Chadwick, EG Hazra, R Williams, PL Seage, GR AF Van Dyke, Russell B. Chadwick, Ellen Gould Hazra, Rohan Williams, Paige L. Seage, George R., III TI The PHACS SMARTT Study: Assessment of the Safety of In Utero Exposure to Antiretroviral Drugs SO FRONTIERS IN IMMUNOLOGY LA English DT Review DE HIV exposure; in utero; children; safety; toxicity; antiretroviral drugs; infant; newborn ID HUMAN-IMMUNODEFICIENCY-VIRUS; TENOFOVIR DISOPROXIL FUMARATE; HIV-UNINFECTED CHILDREN; BONE-MINERAL DENSITY; TRIGGER-BASED DESIGN; INFECTED MOTHERS; MITOCHONDRIAL DYSFUNCTION; PERINATAL EXPOSURE; NUCLEOSIDE ANALOGS; INCREASED RISK AB The Surveillance Monitoring for ART Toxicities (SMARTT) cohort of the Pediatric HIV/AIDS Cohort Study includes over 3,500 HIV-exposed but uninfected infants and children at 22 sites in the US, including Puerto Rico. The goal of the study is to determine the safety of in utero exposure to antiretrovirals (ARVs) and to estimate the incidence of adverse events. Domains being assessed include metabolic, growth and development, cardiac, neurological, neurodevelopmental (ND), behavior, language, and hearing. SMARTTemploys an innovative trigger-based design as an efficient means to identify and evaluate adverse events. Participants who met a predefined clinical or laboratory threshold (trigger) undergo additional evaluations to define their case status. After adjusting for birth cohort and other factors, there was no significant increase in the likelihood of meeting overall case status (case in any domain) with exposure to combination ARVs (cARVs), any ARV class, or any specific ARV. However, several individual ARVs were significantly associated with case status in individual domains, including zidovudine for a metabolic case, first trimester stavudine for a language case, and didanosine plus stavudine for a ND case. We found an increased rate of preterm birth with first trimester exposure to protease inhibitor-based cARV. Although there was no overall increase in congenital anomalies with first trimester cARV, a significant increase was seen with exposure to atazanavir, ritonavir, and didanosine plus stavudine. Tenofovir exposure was associated with significantly lower mean whole-body bone mineral content in the newborn period and a lower length and head circumference at 1 year of age. With ND testing at 1 year of age, specific ARVs (atazanavir, ritonavir-boosted lopinavir, nelfinavir, and tenofovir) were associated with lower performance, although all groups were within the normal range. No ARVs or classes were associated with lower performance between 5 and13 years of age. Atazanavir and saquinavir exposure were associated with late language emergence at 1 year, but not at 2 years of age. The results of the SMARTT study are generally reassuring, with little evidence for serious adverse events resulting from in utero ARV exposure. However, several findings of concern warrant further evaluation, and new ARVs used in pregnancy need to be evaluated. C1 [Van Dyke, Russell B.] Tulane Univ, Sch Med, Dept Pediat, New Orleans, LA 70112 USA. [Chadwick, Ellen Gould] Northwestern Univ NUFSM, Feinberg Sch Med, Dept Pediat, Chicago, IL USA. [Hazra, Rohan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Williams, Paige L.] Harvard Univ, Dept Biostat, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Seage, George R., III] Harvard Univ, Dept Epidemiol, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. RP Van Dyke, RB (reprint author), Tulane Univ, Sch Med, Dept Pediat, New Orleans, LA 70112 USA. EM vandyke@tulane.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Drug Abuse; National Institute of Allergy and Infectious Diseases; Office of AIDS Research; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Institute on Deafness and Other Communication Disorders; National Heart Lung and Blood Institute; National Institute of Dental and Craniofacial Research; National Institute on Alcohol Abuse and Alcoholism; Harvard T.H. Chan School of Public Health [HD052102]; Tulane University School of Medicine [HD052104] FX The study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development with co-funding from the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the Office of AIDS Research, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication Disorders, the National Heart Lung and Blood Institute, the National Institute of Dental and Craniofacial Research, and the National Institute on Alcohol Abuse and Alcoholism, through cooperative agreements with the Harvard T.H. Chan School of Public Health (HD052102) (Principal Investigator: GS; Project Director: Julie Alperen) and the Tulane University School of Medicine (HD052104) (Principal Investigator: RD; Co-Principal Investigators: Kenneth Rich, EC; Project Director: Patrick Davis). Data management services were provided by Frontier Science and Technology Research Foundation (PI: Suzanne Siminski), and regulatory services and logistical support were provided by Westat, Inc. (PI: Julie Davidson). NR 44 TC 1 Z9 1 U1 2 U2 3 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD MAY 23 PY 2016 VL 7 AR 199 DI 10.3389/fimmu.2016.00199 PG 7 WC Immunology SC Immunology GA DM3JZ UT WOS:000376244000001 PM 27242802 ER PT J AU Jin, P Zhao, YL Liu, H Chen, JG Ren, JQ Jin, JJ Bedognetti, D Liu, ST Wang, EN Marincola, F Stroncek, D AF Jin, Ping Zhao, Yuanlong Liu, Hui Chen, Jinguo Ren, Jiaqiang Jin, Jianjian Bedognetti, Davide Liu, Shutong Wang, Ena Marincola, Francesco Stroncek, David TI Interferon-gamma and Tumor Necrosis Factor-alpha Polarize Bone Marrow Stromal Cells Uniformly to a Th1 Phenotype SO SCIENTIFIC REPORTS LA English DT Article ID METASTATIC MELANOMA PATIENTS; MESENCHYMAL STEM-CELLS; CANCER-IMMUNOTHERAPY; GENE SIGNATURES; EXPRESSION; THERAPY; ACTIVATION AB Activated T cells polarize mesenchymal stromal cells (MSCs) to a proinflammatory Th1 phenotype which likely has an important role in amplifying the immune response in the tumor microenvironment. We investigated the role of interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha), two factors produced by activated T cells, in MSC polarization. Gene expression and culture supernatant analysis showed that TNF-alpha and IFN-gamma stimulated MSCs expressed distinct sets of proinflammatory factors. The combination of IFN-gamma and TNF-alpha was synergistic and induced a transcriptome most similar to that found in MSCs stimulated with activated T cells and similar to that found in the inflamed tumor microenvironment; a Th1 phenotype with the expression of the immunosuppressive factors IL-4, IL-10, CD274/PD-L1 and indoleamine 2,3 dioxygenase (IDO). Single cell qRT-PCR analysis showed that the combination of IFN-gamma and TNF-alpha polarized uniformly to this phenotype. The combination of IFN-gamma and TNF-alpha results in the synergist uniform polarization of MSCs toward a primarily Th1 phenotype. The stimulation of MSCs by IFN-gamma and TNF-alpha released from activated tumor infiltrating T cells is likely responsible for the production of many factors that characterize the tumor microenvironment. C1 [Jin, Ping; Zhao, Yuanlong; Liu, Hui; Ren, Jiaqiang; Jin, Jianjian; Liu, Shutong; Stroncek, David] NIH, Ctr Clin, Dept Transfus Med, Cell Proc Sect, Bethesda, MD 20892 USA. [Chen, Jinguo] NIH, CHI, Bethesda, MD 20892 USA. [Bedognetti, Davide; Wang, Ena; Marincola, Francesco] Sidra Med & Res Ctr, Res Branch, Doha, Qatar. RP Stroncek, D (reprint author), NIH, Ctr Clin, Dept Transfus Med, Cell Proc Sect, Bethesda, MD 20892 USA. EM DStroncek@cc.nih.gov NR 27 TC 4 Z9 4 U1 3 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAY 23 PY 2016 VL 6 AR 26345 DI 10.1038/srep26345 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM3GD UT WOS:000376233900001 PM 27211104 ER PT J AU Shriner, D Tekola-Ayele, F Adeyemo, A Rotimi, CN AF Shriner, Daniel Tekola-Ayele, Fasil Adeyemo, Adebowale Rotimi, Charles N. TI Ancient Human Migration after Out-of-Africa SO SCIENTIFIC REPORTS LA English DT Article ID GENOME-WIDE PATTERNS; MITOCHONDRIAL-DNA; Y-CHROMOSOMES; HUMAN HISTORY; POPULATION; SELECTION; ANCESTRY AB The serial founder model of modern human origins predicts that the phylogeny of ancestries exhibits bifurcating, tree-like behavior. Here, we tested this prediction using three methods designed to investigate gene flow in autosome-wide genotype data from 3,528 unrelated individuals from 163 global samples. Specifically, we investigated whether Cushitic ancestry has an East African or Middle Eastern origin. We found evidence for non-tree-like behavior in the form of four migration events. First, we found that Cushitic ancestry is a mixture of ancestries closely related to Arabian ancestry and NiloSaharan or Omotic ancestry. We found evidence for additional migration events in the histories of: 1) Indian and Arabian ancestries, 2) Kalash ancestry, and 3) Native American and Northern European ancestries. These findings, based on analysis of ancestry of present-day humans, reveal migration in the distant past and provide new insights into human history. C1 [Shriner, Daniel; Tekola-Ayele, Fasil; Adeyemo, Adebowale; Rotimi, Charles N.] NHGRI, Ctr Res Genom & Global Hlth, Bldg 12A,Room 4047 12 South Dr, Bethesda, MD 20892 USA. RP Rotimi, CN (reprint author), NHGRI, Ctr Res Genom & Global Hlth, Bldg 12A,Room 4047 12 South Dr, Bethesda, MD 20892 USA. EM rotimic@mail.nih.gov OI Tekola-Ayele, Fasil/0000-0003-4194-9370 FU Intramural Research Program of the Center for Research on Genomics and Global Health (CRGGH); National Human Genome Research Institute; National Institute of Diabetes and Digestive and Kidney Diseases; Center for Information Technology; Office of the Director at the National Institutes of Health [Z01HG200362] FX The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of the National Institutes of Health. This research was supported by the Intramural Research Program of the Center for Research on Genomics and Global Health (CRGGH). The CRGGH is supported by the National Human Genome Research Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Center for Information Technology, and the Office of the Director at the National Institutes of Health (Z01HG200362). NR 28 TC 0 Z9 0 U1 8 U2 21 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAY 23 PY 2016 VL 6 AR 26565 DI 10.1038/srep26565 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM3JT UT WOS:000376243400001 PM 27212471 ER PT J AU Gelband, H Sankaranarayanan, R Gauvreau, CL Horton, S Anderson, BO Bray, F Cleary, J Dare, AJ Denny, L Gospodarowicz, MK Gupta, S Howard, SC Jaffray, DA Knaul, F Levin, C Rabeneck, L Rajaraman, P Sullivan, T Trimble, EL Jha, P AF Gelband, Hellen Sankaranarayanan, Rengaswamy Gauvreau, Cindy L. Horton, Susan Anderson, Benjamin O. Bray, Freddie Cleary, James Dare, Anna J. Denny, Lynette Gospodarowicz, Mary K. Gupta, Sumit Howard, Scott C. Jaffray, David A. Knaul, Felicia Levin, Carol Rabeneck, Linda Rajaraman, Preetha Sullivan, Terrence Trimble, Edward L. Jha, Prabhat CA Dis Control Priorities-Canc TI Costs, affordability, and feasibility of an essential package of cancer control interventions in low-income and middle-income countries: key messages from Disease Control Priorities, 3rd edition SO LANCET LA English DT Review ID UNIVERSAL HEALTH COVERAGE; BREAST-CANCER; CERVICAL-CANCER; ECONOMIC-EVALUATION; RANDOMIZED-TRIALS; MORTALITY; TOBACCO; DEATHS; INDIA; BEVACIZUMAB AB Investments in cancer control-prevention, detection, diagnosis, surgery, other treatment, and palliative care-are increasingly needed in low-income and particularly in middle-income countries, where most of the world's cancer deaths occur without treatment or palliation. To help countries expand locally appropriate services, Cancer (the third volume of nine in Disease Control Priorities, 3rd edition) developed an essential package of potentially cost-effective measures for countries to consider and adapt. Interventions included in the package are: prevention of tobacco-related cancer and virus-related liver and cervical cancers; diagnosis and treatment of early breast cancer, cervical cancer, and selected childhood cancers; and widespread availability of palliative care, including opioids. These interventions would cost an additional US$20 billion per year worldwide, constituting 3% of total public spending on health in low-income and middle-income countries. With implementation of an appropriately tailored package, most countries could substantially reduce suffering and premature death from cancer before 2030, with even greater improvements in later decades. C1 [Gelband, Hellen] Ctr Dis Dynam Econ & Policy, Washington, DC 20005 USA. [Sankaranarayanan, Rengaswamy; Bray, Freddie] Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon, France. [Gauvreau, Cindy L.; Dare, Anna J.; Jha, Prabhat] Univ Toronto, St Michaels Hosp, Ctr Global Hlth Res, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Sullivan, Terrence] Univ Toronto, Inst Hlth Policy Management & Evaluat, Toronto, ON, Canada. [Horton, Susan] Univ Waterloo, Waterloo, ON N2L 3G1, Canada. [Anderson, Benjamin O.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Cleary, James] Univ Wisconsin, Madison, WI USA. [Denny, Lynette] Univ Cape Town, ZA-7925 Cape Town, South Africa. [Gospodarowicz, Mary K.; Jaffray, David A.] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Gupta, Sumit] Hosp Sick Children, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Howard, Scott C.] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Knaul, Felicia] Harvard Univ, Cambridge, MA 02138 USA. [Levin, Carol] Univ Washington, Seattle, WA 98195 USA. [Rabeneck, Linda] Canc Care Ontario, Toronto, ON, Canada. [Rajaraman, Preetha; Trimble, Edward L.] NCI, Bethesda, MD 20892 USA. RP Gelband, H (reprint author), Ctr Dis Dynam Econ & Policy, Washington, DC 20005 USA.; Jha, P (reprint author), Univ Toronto, Toronto, ON M5B 2C5, Canada. EM gelband@cddep.org; prabhat.jha@utoronto.ca FU Bill & Melinda Gates Foundation; US National Cancer Institute; Canadian Institutes of Health Research [126347]; Centre for Global Health Research FX We thank George Alleyne for helpful comments on an earlier draft. The Bill & Melinda Gates Foundation provides financial support for the Disease Control Priorities Network project, of which this volume is a part. We received funding from the US National Cancer Institute, Canadian Institutes of Health Research (grant 126347), and Centre for Global Health Research. NR 88 TC 10 Z9 10 U1 10 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD MAY 21 PY 2016 VL 387 IS 10033 BP 2133 EP 2144 DI 10.1016/S0140-6736(15)00755-2 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA DM6HC UT WOS:000376450800037 PM 26578033 ER PT J AU Dagalakis, U Mallappa, A Elman, M Quezado, M Merke, DP AF Dagalakis, Urania Mallappa, Ashwini Elman, Meredith Quezado, Martha Merke, Deborah P. TI Positive fertility outcomes in a female with classic congenital adrenal hyperplasia following bilateral adrenalectomy SO INTERNATIONAL JOURNAL OF PEDIATRIC ENDOCRINOLOGY LA English DT Article DE Classic CAH; Fertility outcomes; Bilateral adrenalectomy; Adrenal hyperplasia; Hyperandrogenism ID 21-HYDROXYLASE DEFICIENCY; ADOLESCENTS; COHORT; ADULT AB Background: Classic congenital adrenal hyperplasia (CAH) requires lifetime steroid replacement and supraphysiologic glucocorticoid dose is often required for adequate adrenal androgen suppression. Patients often suffer from long-term co-morbidities and female infertility is common. Case presentation: We report the use of laparoscopic bilateral adrenalectomy as a treatment for a 21 year old female with classic simple virilizing CAH and infertility. She presented as an adolescent with increasing weight gain, amenorrhea and elevated adrenal androgens despite the use of dexamethasone (250 mcg given twice daily), and fludrocortisone (150 mcg daily). An anti-androgen (flutamide 250 mg given twice daily) and a combined oral contraceptive pill were added to her regimen and prevented progressive virilization, but she eventually desired fertility. A bilateral laparoscopic adrenalectomy was performed at age 21. The right adrenal gland weighed 41.8 grams and the left gland 45.5 grams. There were no complications during the surgery. Since the surgery, she has had a total of three pregnancies, resulting in 3 healthy full-term infants. Follow-up 7 years later at age 27 revealed overall excellent health with a BMI of 25.1 kg/m(2), no evidence of adrenal rest tissue based on hormonal testing, above average quality-of-life based on 36-item short-form health survey and she has not experienced an adrenal crisis. Conclusions: This case highlights the use of bilateral adrenalectomy as a treatment option for female infertility in a patient with classic CAH and difficult-to-control hyperandrogenism secondary to adrenal nodular hyperplasia. Outstanding quality-of-life, disease control and fertility were achieved. C1 [Dagalakis, Urania; Mallappa, Ashwini; Elman, Meredith; Merke, Deborah P.] NIH, Ctr Clin, 10 Ctr Dr Bldg 10,Rm 1-2740, Bethesda, MD 20892 USA. [Merke, Deborah P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Quezado, Martha] NCI, Bethesda, MD 20892 USA. [Dagalakis, Urania] Albany Med Coll, Albany, NY 12208 USA. RP Merke, DP (reprint author), NIH, Ctr Clin, 10 Ctr Dr Bldg 10,Rm 1-2740, Bethesda, MD 20892 USA.; Merke, DP (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. EM dmerke@cc.nih.gov NR 20 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1687-9848 EI 1687-9856 J9 INT J PEDIATR ENDOCR JI Int. J. Pediatr. Endocrinol. PD MAY 20 PY 2016 AR 10 DI 10.1186/s13633-016-0028-4 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DO1XP UT WOS:000377573700001 PM 27212956 ER PT J AU Czikora, A Lundberg, DJ Abramovitz, A Lewin, NE Kedei, N Peach, ML Zhou, XL Merritt, RC Craft, EA Braun, DC Blumberg, PM AF Czikora, Agnes Lundberg, Daniel J. Abramovitz, Adelle Lewin, Nancy E. Kedei, Noemi Peach, Megan L. Zhou, Xiaoling Merritt, Raymond C., Jr. Craft, Elizabeth A. Braun, Derek C. Blumberg, Peter M. TI Structural Basis for the Failure of the C1 Domain of Ras Guanine Nucleotide Releasing Protein 2 (RasGRP2) to Bind Phorbol Ester with High Affinity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE cloning; guanine nucleotide exchange factor (GEF); phorbol ester; protein kinase C (PKC); Ras-related protein 1 (Rap1); C1 domain; RasGRP2 ID KINASE-C; CALDAG-GEFI; EXCHANGE FACTOR; MOLECULAR-DYNAMICS; DIACYLGLYCEROL BINDING; MEMBRANE INTERACTIONS; CRYSTAL-STRUCTURE; SWISS-MODEL; ACTIVATION; LIGAND AB The C1 domain represents the recognition module for diacylglycerol and phorbol esters in protein kinase C, Ras guanine nucleotide releasing protein (RasGRP), and related proteins. RasGRP2 is exceptional in that its C1 domain has very weak binding affinity (K-d = 2890 +/- 240 nm for [H-3]phorbol 12,13-dibutyrate. We have identified four amino acid residues responsible for this lack of sensitivity. Replacing Asn(7), Ser(8), Ala(19), and Ile(21) with the corresponding residues from RasGRP1/3 (Thr(7), Tyr(8), Gly(19), and Leu(21), respectively) conferred potent binding affinity (K-d = 1.47 +/- 0.03 nm) in vitro and membrane translocation in response to phorbol 12-myristate 13-acetate in LNCaP cells. Mutant C1 domains incorporating one to three of the four residues showed intermediate behavior with S8Y making the greatest contribution. Binding activity for diacylglycerol was restored in parallel. The requirement for anionic phospholipid for [H-3]phorbol 12,13-dibutyrate binding was determined; it decreased in going from the single S8Y mutant to the quadruple mutant. The full-length RasGRP2 protein with the mutated C1 domains also showed strong phorbol ester binding, albeit modestly weaker than that of the C1 domain alone (K-d = 8.2 +/- 1.1 nm for the full-length protein containing all four mutations), and displayed translocation in response to phorbol ester. RasGRP2 is a guanyl exchange factor for Rap1. Consistent with the ability of phorbol ester to induce translocation of the full-length RasGRP2 with the mutated C1 domain, phorbol ester enhanced the ability of the mutated RasGRP2 to activate Rap1. Modeling confirmed that the four mutations helped the binding cleft maintain a stable conformation. C1 [Czikora, Agnes; Abramovitz, Adelle; Lewin, Nancy E.; Kedei, Noemi; Zhou, Xiaoling; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lundberg, Daniel J.; Merritt, Raymond C., Jr.; Craft, Elizabeth A.; Braun, Derek C.] Gallaudet Univ, Dept Sci Technol & Math, Washington, DC 20002 USA. [Peach, Megan L.] Frederick Natl Lab Canc Res, Basic Sci Program, Leidos Biomed Res Inc, Biol Chem Lab, Frederick, MD 21702 USA. RP Blumberg, PM (reprint author), NCI, Bldg 37,Rm 4048,37 Convent Dr MSC4255, Bethesda, MD 20892 USA. EM blumberp@dc37a.nci.nih.gov FU Intramural Research Program; Center for Cancer Research; NCI; National Institutes of Health [Z1A BC 005270]; NCI, National Institutes of Health [HHSN261200800001E] FX This work was supported in part by the Intramural Research Program, Center for Cancer Research, NCI, National Institutes of Health Project Z1A BC 005270 and in part with federal funds from the NCI, National Institutes of Health under Contract HHSN261200800001E. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 72 TC 1 Z9 1 U1 4 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 20 PY 2016 VL 291 IS 21 BP 11133 EP 11147 DI 10.1074/jbc.M116.725333 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DN4MT UT WOS:000377042100017 PM 27022025 ER PT J AU Rodriguez, Y Hinz, JM Laughery, MF Wyrick, JJ Smerdon, MJ AF Rodriguez, Yesenia Hinz, John M. Laughery, Marian F. Wyrick, John J. Smerdon, Michael J. TI Site-specific Acetylation of Histone H3 Decreases Polymerase Activity on Nucleosome Core Particles in Vitro SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE base excision repair (BER); DNA damage; DNA polymerase; histone acetylation; nucleosome; DNA glycosylase ID BASE EXCISION-REPAIR; DNA-DAMAGE RESPONSE; LYSINE 56; H3K56 ACETYLATION; APE1 ENDONUCLEASE; GENOME STABILITY; MAMMALIAN-CELLS; CHROMATIN; ACCESSIBILITY; GENE AB Histone posttranslational modifications have been associated with changes in chromatin structure necessary for transcription, replication, and DNA repair. Acetylation is one of the most studied and best characterized histone posttranslational modifications, but it is not known if histone acetylation modulates base excision repair of DNA lesions in chromatin. To address this question, we generated nucleosome core particles (NCPs) containing site-specifically acetylated H3K14 or H3K56 and measured repair of uracil and single-nucleotide gaps. We find that H3K56Ac and H3K14Ac do not significantly contribute to removal of uracils by uracil DNA glycosylase regardless of the translational or rotational position of the lesions within NCPs. In repair of single-nucleotide gaps, however, the presence of H3K56Ac or H3K14Ac in NCPs decreases the gap-filling activity of DNA polymerase near the dyad center, with H3K14Ac exhibiting stronger inhibition. To a lesser extent, H3K56Ac induces a similar effect near the DNA ends. Moreover, using restriction enzyme accessibility, we detect no changes in NCP structure or dynamics between H3K14Ac-NCPs and WT-NCPs containing single-nucleotide gaps. Thus, acetylation at H3K56 and H3K14 in nucleosomes may promote alternative gap-filling pathways by inhibiting DNA polymerase activity. C1 [Rodriguez, Yesenia; Hinz, John M.; Laughery, Marian F.; Wyrick, John J.; Smerdon, Michael J.] Washington State Univ, Sch Mol Biosci, Biochem & Biophys, Pullman, WA 99164 USA. [Rodriguez, Yesenia] NIEHS, Genorne Integr & Struct Biol Lab, NIH, POB 12233,Mail Drop F3-01, Res Triangle Pk, NC 27709 USA. RP Smerdon, MJ (reprint author), Washington State Univ, Sch Mol Biosci, Life Sci & Biotechnol Bldg, Pullman, WA 99164 USA. EM smerdon@wsu.edu FU National Institutes of Health [ES020955, ES002614, ES004106, T32GM008336] FX This work was supported by National Institutes of Health Grants ES020955 (to J M. H.), ES002614 and ES004106 (NIEHS; to M. J. S.), and Training Grant T32GM008336 (NIGMS; to Y. R.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 61 TC 1 Z9 1 U1 3 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 20 PY 2016 VL 291 IS 21 BP 11434 EP 11445 DI 10.1074/jbc.M116.725788 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DN4MT UT WOS:000377042100040 PM 27033702 ER PT J AU Pan, YM Lin, SY Xing, R Zhu, M Lin, BN Cui, JT Li, WM Gao, J Shen, L Zhao, YY Guo, MZ Wang, JM Huang, JQ Lu, YY AF Pan, Yuanming Lin, Shuye Xing, Rui Zhu, Min Lin, Bonan Cui, Jiantao Li, Wenmei Gao, Jing Shen, Lin Zhao, Yuanyuan Guo, Mingzhou Wang, Ji Ming Huang, Jiaqiang Lu, Youyong TI Epigenetic Upregulation of Metallothionein 2A by Diallyl Trisulfide Enhances Chemosensitivity of Human Gastric Cancer Cells to Docetaxel Through Attenuating NF-B Activation SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Article ID FACTOR-KAPPA-B; HUMAN HEPATOCELLULAR CARCINOMAS; REFRACTORY PROSTATE-CANCER; HELICOBACTER-PYLORI; HISTONE DEACETYLASE; INDUCED APOPTOSIS; OXIDATIVE STRESS; GENE-EXPRESSION; DOWN-REGULATION; BREAST-CANCER AB Aims: Metallothionein 2A (MT2A) and nuclear factor-kappaB (NF-B) are both involved in carcinogenesis and cancer chemosensitivity. We previously showed decreased expression of MT2A and IB- in human gastric cancer (GC) associated with poor prognosis of GC patients. The present study investigated the effect of diallyl trisulfide (DATS), a garlic-derived compound, and docetaxel (DOC) on regulation of MT2A in relation to NF-B in GC cells. Results: DATS attenuated NF-B signaling in GC cells, resulting in G2/M cell cycle arrest and apoptosis, culminating in the inhibition of cell proliferation and tumorigenesis in nude mice. The anti-GC effect of DATS was attributable to its capacity to epigenetically upregulate MT2A, which in turn enhanced transcription of IB- to suppress NF-B activation in GC cells. The combination of DATS with DOC exhibited a synergistic anti-GC activity accompanied by MT2A upregulation and NF-B inactivation. Histopathologic analysis of GC specimens from patients showed a significant increase in MT2A expression following DOC treatment. GC patients with high MT2A expression in tumor specimens showed significantly improved response to chemotherapy and prolonged survival compared with those with low MT2A expression in tumors. Innovation and Conclusion: We conclude that DATS exerts its anti-GC activity and enhances chemosensitivity of GC to DOC by epigenetic upregulation of MT2A to attenuate NF-B signaling. Our findings delineate a mechanistic basis of MT2A/NF-B signaling for DATS- and DOC-mediated anti-GC effects, suggesting that MT2A may be a chemosensitivity indicator in GC patients receiving DOC-based treatment and a promising target for more effective treatment of GC by combination of DATS and DOC. Antioxid. Redox Signal. 24, 839-854. C1 [Pan, Yuanming; Xing, Rui; Zhu, Min; Cui, Jiantao; Li, Wenmei; Lu, Youyong] Peking Univ, Mol Oncol Lab, Minist Educ, Key Lab Carcinogenesis & Translat Res,Canc Hosp I, 52 Fucheng Rd, Beijing 100142, Peoples R China. [Lin, Shuye; Lin, Bonan; Huang, Jiaqiang] Beijing Jiaotong Univ, Sch Sci, Coll Life Sci & Bioengn, 3 Shangyuancun, Beijing 100044, Peoples R China. [Lin, Shuye; Wang, Ji Ming; Huang, Jiaqiang] NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. [Gao, Jing; Shen, Lin] Peking Univ, Minist Educ, Key Lab Carcinogenesis & Translat Res, Dept GI Oncol,Sch Oncol,Peking Canc Hosp, Beijing 100871, Peoples R China. [Zhao, Yuanyuan] Natl Ctr Nanosci & Technol China, CAS Key Lab Biomed Effects Nanomat & Nanosafety, Beijing, Peoples R China. [Guo, Mingzhou] Chinese Peoples Liberat Army Gen Hosp, Dept Gastroenterol & Hepatol, Beijing 100853, Peoples R China. RP Lu, YY (reprint author), Peking Univ, Mol Oncol Lab, Minist Educ, Key Lab Carcinogenesis & Translat Res,Canc Hosp I, 52 Fucheng Rd, Beijing 100142, Peoples R China.; Huang, JQ (reprint author), Beijing Jiaotong Univ, Sch Sci, Coll Life Sci & Bioengn, 3 Shangyuancun, Beijing 100044, Peoples R China. EM jqhuang@bjtu.edu.cn; youyonglu@hsc.pku.edu.cn FU National Science Foundation of China [81272550]; National High-Tech Research and Development Program of China (863 Program) [2012AA02A504]; Open Project funded by the Key laboratory of Carcinogenesis and Translational Research, Ministry of Education (2014 Open Project-), Peking University Cancer Hospital/Institute, Beijing; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NCI, NIH; Intramural Research funding of Beijing Jiaotong University [S12RC00030] FX This work was supported by grants from the National Science Foundation of China (Grant No. 81272550), the National High-Tech Research and Development Program of China (863 Program, Grant No. 2012AA02A504), and the Open Project funded by the Key laboratory of Carcinogenesis and Translational Research, Ministry of Education (2014 Open Project-), Peking University Cancer Hospital/Institute, Beijing. J.H. and J.M.W. were also funded, in part, by Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E and were supported, in part, by the Intramural Research Program of the NCI, NIH. S.L. and J.H. were supported by the Intramural Research funding of Beijing Jiaotong University (S12RC00030). NR 61 TC 3 Z9 3 U1 4 U2 11 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD MAY 20 PY 2016 VL 24 IS 15 BP 839 EP 854 DI 10.1089/ars.2014.6128 PG 16 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA DN0SR UT WOS:000376775200001 PM 26801633 ER PT J AU Berg, JM Bhalla, N Bourne, PE Chalfie, M Drubin, DG Fraser, JS Greider, CW Hendricks, M Jones, C Kiley, R King, S Kirschner, MW Krumholz, HM Lehmann, R Leptin, M Pulverer, B Rosenzweig, B Spiro, JE Stebbins, M Strasser, C Swaminathan, S Turner, P Vale, RD VijayRaghavan, K Wolberger, C AF Berg, Jeremy M. Bhalla, Needhi Bourne, Philip E. Chalfie, Martin Drubin, David G. Fraser, James S. Greider, Carol W. Hendricks, Michael Jones, Chonnettia Kiley, Robert King, Susan Kirschner, Marc W. Krumholz, Harlan M. Lehmann, Ruth Leptin, Maria Pulverer, Bernd Rosenzweig, Brooke Spiro, John E. Stebbins, Michael Strasser, Carly Swaminathan, Sowmya Turner, Paul Vale, Ronald D. VijayRaghavan, K. Wolberger, Cynthia TI Preprints for the life sciences SO SCIENCE LA English DT Editorial Material C1 [Berg, Jeremy M.] Univ Pittsburgh, Sch Med, Inst Personalized Med, Pittsburgh, PA 15260 USA. [Bhalla, Needhi] Univ Calif Santa Cruz, Dept Mol Cell & Dev Biol, Santa Cruz, CA 95064 USA. [Bourne, Philip E.] NIH, Off Director, Bethesda, MD USA. [Chalfie, Martin] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA. [Drubin, David G.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Fraser, James S.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Greider, Carol W.] Johns Hopkins Univ, Dept Mol Biol & Genet, Sch Med, Baltimore, MD 21218 USA. [Hendricks, Michael] McGill Univ, Dept Biol, Montreal, PQ H3A 2T5, Canada. [Jones, Chonnettia; Kiley, Robert] Wellcome Trust Res Labs, London, England. [King, Susan] Rockefeller Univ Press, New York, NY 10065 USA. [Kirschner, Marc W.] Harvard Univ, Dept Syst Biol, Sch Med, Cambridge, MA 02138 USA. [Krumholz, Harlan M.] Yale Univ, Sch Med, New Haven, CT 06520 USA. [Lehmann, Ruth] NYU, Sch Med, Dept Cell Biol, Kimmel Ctr Biol & Med,Skirball Inst, New York, NY 10003 USA. [Leptin, Maria; Pulverer, Bernd] European Mol Biol Org, Heidelberg, Germany. [Rosenzweig, Brooke] Leona M & Harry B Helmsley Charitable Trust, New York, NY USA. [Spiro, John E.] Simons Fdn, New York, NY USA. [Stebbins, Michael] Laura & John Arnold Fdn, Houston, TX USA. [Strasser, Carly] Gordon & Betty Moore Fdn, Palo Alto, CA USA. [Swaminathan, Sowmya] Nat Res Grp, Banchory, Kincardine, Scotland. [Turner, Paul] Yale Univ, Dept Ecol & Evolutionary Biol, New Haven, CT 06520 USA. [Vale, Ronald D.] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA USA. [Vale, Ronald D.] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA USA. [VijayRaghavan, K.] Govt India, New Delhi, India. [Wolberger, Cynthia] Johns Hopkins Univ, Sch Med, Dept Biophys & Biophys Chem, Baltimore, MD 21218 USA. RP Vale, RD (reprint author), Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA USA.; Vale, RD (reprint author), Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA USA. EM ron.vale@ucsf.edu OI Hendricks, Michael/0000-0002-3408-3858; Berg, Jeremy/0000-0003-3022-0963; Strasser, Carly/0000-0001-9592-2339; Lehmann, Ruth/0000-0002-8454-5651 FU Howard Hughes Medical Institute NR 7 TC 7 Z9 7 U1 5 U2 16 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD MAY 20 PY 2016 VL 352 IS 6288 SI SI BP 899 EP 901 DI 10.1126/science.aaf9133 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM2AK UT WOS:000376147800021 PM 27199406 ER PT J AU Kamarthapu, V Epshtein, V Benjamin, B Proshkin, S Mironov, A Cashel, M Nudler, E AF Kamarthapu, Venu Epshtein, Vitaly Benjamin, Bradley Proshkin, Sergey Mironov, Alexander Cashel, Michael Nudler, Evgeny TI ppGpp couples transcription to DNA repair in E. coli SO SCIENCE LA English DT Article ID NUCLEOTIDE EXCISION-REPAIR; ESCHERICHIA-COLI; RNA-POLYMERASE; UVRD GENE; IN-VITRO; REPLICATION; MECHANISM; DAMAGE; INITIATION; HELICASE AB The small molecule alarmone (p) ppGpp mediates bacterial adaptation to nutrient deprivation by altering the initiation properties of RNA polymerase (RNAP). ppGpp is generated in Escherichia coli by two related enzymes, RelA and SpoT. We show that ppGpp is robustly, but transiently, induced in response to DNA damage and is required for efficient nucleotide excision DNA repair (NER). This explains why relA-spoT-deficient cells are sensitive to diverse genotoxic agents and ultraviolet radiation, whereas ppGpp induction renders them more resistant to such challenges. The mechanism of DNA protection by ppGpp involves promotion of UvrD-mediated RNAP backtracking. By rendering RNAP backtracking-prone, ppGpp couples transcription to DNA repair and prompts transitions between repair and recovery states. C1 [Kamarthapu, Venu; Epshtein, Vitaly; Benjamin, Bradley; Nudler, Evgeny] NYU, Sch Med, Dept Biochem & Mol Pharmacol, New York, NY 10016 USA. [Kamarthapu, Venu; Nudler, Evgeny] NYU, Sch Med, Howard Hughes Med Inst, New York, NY 10016 USA. [Proshkin, Sergey; Mironov, Alexander] Russian Acad Sci, Engelhardt Inst Mol Biol, Moscow 119991, Russia. [Cashel, Michael] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Dev Biol, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Nudler, E (reprint author), NYU, Sch Med, Dept Biochem & Mol Pharmacol, New York, NY 10016 USA.; Nudler, E (reprint author), NYU, Sch Med, Howard Hughes Med Inst, New York, NY 10016 USA. EM evgeny.nudler@nyumc.org OI Nudler, Evgeny/0000-0002-8811-3071 FU Russian Science Foundation [14-50-00060]; Ministry of Education and Science of the Russian Federation [14.Z50.31.0014]; National Institute of Child Health and Human Development, NIH; NIH [R01 GM107329]; Howard Hughes Medical Institute FX We thank R. Lloyd for N4849 and N4235 strains and T. Artemyev for his contribution. This work was supported by the Russian Science Foundation grant 14-50-00060 and the Ministry of Education and Science of the Russian Federation grant 14.Z50.31.0014 (S.P. and A.M.), the National Institute of Child Health and Human Development, NIH Intramural Program (M.C.), NIH grant R01 GM107329, and by the Howard Hughes Medical Institute (E.N.). NR 29 TC 8 Z9 8 U1 8 U2 20 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD MAY 20 PY 2016 VL 352 IS 6288 SI SI BP 993 EP 996 DI 10.1126/science.aad6945 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM2AK UT WOS:000376147800049 PM 27199428 ER PT J AU Petrick, JL Kelly, SP Altekruse, SF McGlynn, KA Rosenberg, PS AF Petrick, Jessica L. Kelly, Scott P. Altekruse, Sean F. McGlynn, Katherine A. Rosenberg, Philip S. TI Future of Hepatocellular Carcinoma Incidence in the United States Forecast Through 2030 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CANCER INCIDENCE; HEPATITIS-C; MORTALITY-RATES; RISK-FACTORS; SOFOSBUVIR; INFECTION; TRENDS; IMPACT; GENERATION; LEDIPASVIR AB Purpose Hepatocellular carcinoma (HCC) incidence rates have been increasing in the United States for the past 35 years. Because HCC has a poor prognosis, quantitative forecasts could help to inform prevention and treatment strategies to reduce the incidence and burden of HCC. Methods Single-year HCC incident case and population data for the years 2000 to 2012 and ages 35 to 84 years were obtained from the SEER 18 Registry Database. We forecast incident HCC cases through 2030, using novel age-period-cohort models and stratifying by sex, race/ethnicity, and age. Rates are presented because absolute numbers may be influenced by population increases. Results Rates of HCC increased with each successive birth cohort through 1959. However, rates began to decrease with the 1960 to 1969 birth cohorts. Asians/Pacific Islanders (APIs) have had the highest HCC rates in the United States for many years, but the rates have stabilized and begun to decline in recent years. Between 2013 and 2030, rates among APIs are forecast to decline further, with estimated annual percentage changes of -1.59% among men and -2.20% among women. Thus, by 2030, Asians are forecast to have the lowest incidence rates among men, and Hispanics are forecast to have the highest rates among men (age-standardized rate, 44.2). Blacks are forecast to have the highest rate among women (age-standardized rate, 12.82). Conclusion Although liver cancer has long had some of the most rapidly increasing incidence rates, the decreasing rates seen among APIs, individuals younger than 65 years, and cohorts born after 1960 suggest that there will be declines in incidence of HCC in future years. Prevention efforts should be focused on individuals in the 1950 to 1959 birth cohorts, Hispanics, and blacks. C1 [Petrick, Jessica L.; Kelly, Scott P.; Altekruse, Sean F.; McGlynn, Katherine A.; Rosenberg, Philip S.] NCI, Bethesda, MD 20892 USA. RP Petrick, JL (reprint author), 9609 Med Ctr Dr,7E-230, Bethesda, MD 20892 USA. EM jessica.petrick@nih.gov OI Kelly, Scott/0000-0002-0375-1040 NR 41 TC 5 Z9 5 U1 2 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2016 VL 34 IS 15 BP 1787 EP + DI 10.1200/JCO.2015.64.7412 PG 9 WC Oncology SC Oncology GA DL3NS UT WOS:000375541100016 PM 27044939 ER PT J AU Bachas, S Kohrs, B Wade, H AF Bachas, Sharrol Kohrs, Bryan Wade, Herschel TI Charge is Major Determinant of Activation of the Ligand-Responsive Multidrug Resistance Gene Regulator, BmrR SO CHEMMEDCHEM LA English DT Article DE allosterism; antibiotics; biosensors; molecular recognition; signal transduction ID EFFLUX PUMPS; RECOGNITION; SENSITIVITY; SELECTIVITY; MECHANISMS; BACTERIA; BINDING AB A medium-throughput approach (80+ compounds) to investigate allosteric transcriptional control in the multidrug resistance gene regulator BmrR, with cations, zwitterions, uncharged compounds and anions, is described. Even at the allosteric level, BmrR is quite promiscuous with regard to molecular shape and structure, but it is sensitive to molecular charge. A role for charge is further supported by differences in the activation properties of structurally similar ligands displaying variable charge properties as well as differences in activation by zwitterions and uncharged ligands, which show similar binding affinities. A comparison of allosteric selectivity with the distribution of differently charged ligands in bacterial cellular environments suggests that the selectivity of charge is a major factor in discrimination of xenobiotics, and native biological compounds and metabolites. Interestingly, in eukaryotic cells, the selectivity of cationic ligands might be a protective mechanism against chemical agents that act in a promiscuous fashion. C1 [Kohrs, Bryan; Wade, Herschel] Johns Hopkins Sch Med, Dept Biophys & Biophys Chem, 725 N Wolfe St, Baltimore, MD 21205 USA. [Bachas, Sharrol] NHLBI, Lab Biophys & Cellular Physiol, Biochem & Biophys Ctr, Bethesda, MD 20892 USA. RP Wade, H (reprint author), Johns Hopkins Sch Med, Dept Biophys & Biophys Chem, 725 N Wolfe St, Baltimore, MD 21205 USA. EM Herschel.wade@jhmi.edu OI Bachas, Sharrol/0000-0002-0662-1030 FU Arnold and Mabel Beckman Foundation; US National Science Foundation [MCB0953430, DGE0707427] FX The authors would like to acknowledge the Arnold and Mabel Beckman Foundation (H.W.) and the US National Science Foundation [MCB0953430 (H.W.) and DGE0707427 (S.B.)] for funding. The authors declare no competing financial interests. Author contributions to the work are as follows: S.B and B.K collected the data, S.B. and H.W. analyzed the data, and H.W wrote the paper. NR 20 TC 2 Z9 2 U1 1 U2 3 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1860-7179 EI 1860-7187 J9 CHEMMEDCHEM JI ChemMedChem PD MAY 19 PY 2016 VL 11 IS 10 BP 1038 EP 1041 DI 10.1002/cmdc.201600059 PG 4 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DR6PC UT WOS:000380022800002 PM 27010425 ER PT J AU Swerdlow, SH Campo, E Pileri, SA Harris, NL Stein, H Siebert, R Advani, R Ghielmini, M Salles, GA Zelenetz, AD Jaffe, ES AF Swerdlow, Steven H. Campo, Elias Pileri, Stefano A. Harris, Nancy Lee Stein, Harald Siebert, Reiner Advani, Ranjana Ghielmini, Michele Salles, Gilles A. Zelenetz, Andrew D. Jaffe, Elaine S. TI The 2016 revision of the World Health Organization classification of lymphoid neoplasms SO BLOOD LA English DT Review ID T-CELL LYMPHOMA; CHRONIC LYMPHOCYTIC-LEUKEMIA; GAMMA-DELTA-T; PREDOMINANT HODGKIN LYMPHOMA; IDENTIFIES RECURRENT MUTATIONS; POSITIVE MUCOCUTANEOUS ULCER; PARAFFIN-EMBEDDED TISSUE; FOLLICULAR-LYMPHOMA; BURKITT-LYMPHOMA; LYMPHOPROLIFERATIVE-DISORDER AB A revision of the nearly 8-year-old World Health Organization classification of the lymphoid neoplasms and the accompanying monograph is being published. It reflects a consensus among hematopathologists, geneticists, and clinicians regarding both updates to current entities as well as the addition of a limited number of new provisional entities. The revision clarifies the diagnosis and management of lesions at the very early stages of lymphomagenesis, refines the diagnostic criteria for some entities, details the expanding genetic/molecular landscape of numerous lymphoid neoplasms and their clinical correlates, and refers to investigations leading to more targeted therapeutic strategies. The major changes are reviewed with an emphasis on the most important advances in our understanding that impact our diagnostic approach, clinical expectations, and therapeutic strategies for the lymphoid neoplasms. C1 [Swerdlow, Steven H.] Univ Pittsburgh, Sch Med, Dept Pathol, Div Hematopathol, 200 Lothrop St, Pittsburgh, PA 15213 USA. [Campo, Elias] Univ Barcelona, Hosp Clin, Dept Pathol, August Pi & Sunyer Biomed Res Inst, Barcelona, Spain. [Pileri, Stefano A.] European Inst Oncol, Haematopathol Unit, Milan, Italy. [Pileri, Stefano A.] Univ Bologna, Sch Med, Dept Expt Diagnost & Specialty Med, Bologna, Italy. [Harris, Nancy Lee] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Harris, Nancy Lee] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Stein, Harald] Pathodiagnostik, Berlin, Germany. [Siebert, Reiner] Univ Kiel, Inst Human Genet, Kiel, Germany. [Advani, Ranjana] Stanford Univ, Dept Med, Div Oncol, Stanford, CA 94305 USA. [Ghielmini, Michele] Oncol Inst Southern Switzerland, Dept Med Oncol, Bellinzona, Switzerland. [Salles, Gilles A.] Hosp Civils Lyon, Dept Hematol, Lyon, France. [Salles, Gilles A.] Univ Lyon 1, F-69365 Lyon, France. [Zelenetz, Andrew D.] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Zelenetz, Andrew D.] Weill Cornell Med Coll, New York, NY USA. [Jaffe, Elaine S.] NCI, Hematopathol Sect, Pathol Lab, Bethesda, MD 20892 USA. RP Swerdlow, SH (reprint author), Univ Pittsburgh, Sch Med, Dept Pathol, Div Hematopathol, 200 Lothrop St, Pittsburgh, PA 15213 USA.; Campo, E (reprint author), Univ Barcelona, Hosp Clin, Dept Pathol, E-08036 Barcelona, Spain.; Jaffe, ES (reprint author), NCI, Hematopathol Sect, Pathol Lab, CCR, Bldg 10,Room 3s235, Bethesda, MD 20892 USA. EM swerdlowsh@upmc.edu; ecampo@clinic.cat; elainejaffe@nih.gov RI Campo, elias/O-7192-2016; Siebert, Reiner/A-8049-2010 OI Campo, elias/0000-0001-9850-9793; FU Italian Association for Cancer Research (AIRC, Milan) [10007]; National Institutes of Health (NIH)/National Cancer Institute (NCI) Cancer Center [P30 CA008748]; American Society of Hematology; Josep Carreras Foundation; Fondazione Italiana Linfomi (FIL); Leukemia Clinical Research Foundation; University of Chicago Comprehensive Cancer Center; Beckman Coulter Corporation; Celgene Corporation; Dako; Genentech Corporation; Incyte Corporation; Leica Corporation; Millennium Pharmaceuticals; Pharmacyclics; Seattle Genetics Corporation; Sysmex Corporation; Ventana Medical Systems, Inc of the Roche Group FX S.A.P. was supported in part through the Italian Association for Cancer Research (AIRC, Milan) grant 5x1000 number 10007. A.D.Z. was supported in part through the National Institutes of Health (NIH)/National Cancer Institute (NCI) Cancer Center Support Grant P30 CA008748. The authors acknowledge the unrestricted financial support of the Clinical Advisory Committee meeting held in Chicago, IL, March 31-April 1, 2014 from the following organizations: American Society of Hematology, Josep Carreras Foundation, Fondazione Italiana Linfomi (FIL), Leukemia Clinical Research Foundation, University of Chicago Comprehensive Cancer Center, Beckman Coulter Corporation, Celgene Corporation, Dako, Genentech Corporation, Incyte Corporation, Leica Corporation, Millennium Pharmaceuticals, Pharmacyclics, Seattle Genetics Corporation, Sysmex Corporation, and Ventana Medical Systems, Inc, a member of the Roche Group. NR 159 TC 140 Z9 151 U1 15 U2 26 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAY 19 PY 2016 VL 127 IS 20 BP 2375 EP 2390 DI 10.1182/blood-2016-01-643569 PG 16 WC Hematology SC Hematology GA DP2QH UT WOS:000378333900008 PM 26980727 ER PT J AU Teira, P Battiwalla, M Ramanathan, M Barrett, AJ Ahn, KW Chen, M Green, JS Saad, A Antin, JH Savani, BN Lazarus, HM Seftel, M Saber, W Marks, D Aljurf, M Norkin, M Wingard, JR Lindemans, CA Boeckh, M Riches, ML Auletta, JJ AF Teira, Pierre Battiwalla, Minoo Ramanathan, Muthalagu Barrett, A. John Ahn, Kwang Woo Chen, Min Green, Jaime S. Saad, Ayman Antin, Joseph H. Savani, Bipin N. Lazarus, Hillard M. Seftel, Matthew Saber, Wael Marks, David Aljurf, Mahmoud Norkin, Maxim Wingard, John R. Lindemans, Caroline A. Boeckh, Michael Riches, Marcie L. Auletta, Jeffery J. TI Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis SO BLOOD LA English DT Article ID HEMATOPOIETIC-CELL TRANSPLANTATION; ACUTE MYELOID-LEUKEMIA; BONE-MARROW-TRANSPLANTATION; RELAPSE RISK EVIDENCE; CMV REACTIVATION; T-CELLS; HEMATOLOGICAL MALIGNANCIES; REDUCED RISK; ALLO-SCT; DONOR AB Single-center studies have reported an association between early (before day 100) cytomegalovirus (CMV) reactivation and decreased incidence of relapse for acute myeloid leukemia (AML) following allogeneic hematopoietic cell transplantation. To substantiate these preliminary findings, the Center for International Blood and Marrow Transplant Research (CIBMTR) Database was interrogated to analyze the impact of CMV reactivation on hematologic disease relapse in the current era. Data from 9469 patients transplanted with bone marrow or peripheral blood between 2003 and 2010 were analyzed according to 4 disease categories: AML (n=5310); acute lymphoblastic leukemia (ALL, n=1883); chronic myeloid leukemia (CML, n= 1079); and myelodysplastic syndrome (MDS, n= 1197). Median time to initial CMV reactivation was 41 days (range, 1-362 days). CMV reactivation had no preventive effect on hematologic disease relapse irrespective of diagnosis. Moreover, CMV reactivation was associated with higher nonrelapse mortality [relative risk [RR] among disease categories ranged from 1.61 to 1.95 and P values from .0002 to <.0001; 95% confidence interval [CI], 1.14-2.61). As a result, CMV reactivation was associated with lower overall survival for AML (RR=1.27; 95% CI, 1.17-1.38; P <.0001), ALL (RR=1.46; 95% CI, 1.25-1.71; P <.0001), CML (RR=1.49; 95% CI, 1.19-1.88; P =.0005), and MDS (RR = 1.31; 95% CI, 1.09-1.57; P =.003). In conclusion, CMV reactivation continues to remain a risk factor for poor posttransplant outcomes and does not seem to confer protection against hematologic disease relapse. C1 [Teira, Pierre] Univ Montreal, Hop St Justine, Montreal, PQ H3T 1C5, Canada. [Battiwalla, Minoo; Barrett, A. John] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Ramanathan, Muthalagu] UMass Mem Med Ctr, Dept Med, Div Hematol & Oncol, Worcester, MA USA. [Ahn, Kwang Woo; Chen, Min; Saber, Wael] Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Ahn, Kwang Woo] Med Coll Wisconsin, Div Biostat, Inst Hlth & Soc, Milwaukee, WI 53226 USA. [Green, Jaime S.] Univ Minnesota, Dept Med, Div Infect Dis & Int Med, Box 736 UMHC, Minneapolis, MN 55455 USA. [Saad, Ayman] Univ Alabama Birmingham, Dept Med, Div Hematol Oncol, Birmingham, AL 35294 USA. [Antin, Joseph H.] Dana Farber Canc Inst, Ctr Hematol Oncol, Boston, MA 02115 USA. [Savani, Bipin N.] Vanderbilt Univ, Med Ctr, Dept Med, Div Hematol Oncol, Nashville, TN USA. [Lazarus, Hillard M.] Univ Hosp Case Med Ctr, Seidman Canc Ctr, Cleveland, OH USA. [Seftel, Matthew] Princess Margaret Canc Ctr, Dept Med Oncol & Hematol, Toronto, ON, Canada. [Marks, David] Univ Hosp Bristol Natl Hlth Serv Trust, Pediat Bone Marrow Transplant, Bristol, Avon, England. [Aljurf, Mahmoud] King Faisal Specialist Hosp Ctr & Res, Dept Oncol, Ridayh, Saudi Arabia. [Norkin, Maxim; Wingard, John R.] Univ Florida, Coll Med, Div Hematol Oncol, Gainesville, FL USA. [Lindemans, Caroline A.] Univ Med Ctr Utrecht, Pediat Blood & Marrow Transplantat Program, Utrecht, Netherlands. [Boeckh, Michael] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, 1124 Columbia St, Seattle, WA 98104 USA. [Riches, Marcie L.] Univ N Carolina, Div Hematol Oncol, Chapel Hill, NC USA. [Auletta, Jeffery J.] Nationwide Childrens Hosp, Host Def Program, Div Hematol Oncol Bone Marrow Transplant, Columbus, OH USA. [Auletta, Jeffery J.] Nationwide Childrens Hosp, Div Infect Dis, Columbus, OH USA. RP Teira, P (reprint author), Univ Montreal, Hop St Justine, Dept Hematol Oncol, 3175 Chemin Cote St Catherine, Montreal, PQ H3T 1C5, Canada. EM pierre.teira.hsj@ssss.gouv.qc.ca OI Saad, Ayman /0000-0003-0003-0130 FU Public Health Service from National Institutes of Health, National Cancer Institute (NCI), National Heart, Lung and Blood Institute (NHLBI) [5U24-CA076518]; National Institute of Allergy and Infectious Diseases (NIAID) [5U24-CA076518]; NHLBI [5U10HL069294]; NCI [5U10HL069294]; Health Resources and Services Administration (HRSA/DHHS) [HHSH250201200016C]; Office of Naval Research [N00014-13-1-0039, N00014-14-1-0028]; Alexion; Amgen, Inc; Be the Match Foundation; Bristol Myers Squibb Oncology; Celgene Corporation; Chimerix, Inc; Fred Hutchinson Cancer Research Center; Gamida Cell Ltd.; Genentech, Inc; Genzyme Corporation; Gilead Sciences, Inc; Health Research, Inc; Roswell Park Cancer Institute; HistoGenetics, Inc; Incyte Corporation; Jazz Pharmaceuticals, Inc; Jeff Gordon Children's Foundation; Leukemia & Lymphoma Society; Medical College of Wisconsin; Merck Co, Inc; Mesoblast; Millennium: The Takeda Oncology Co.; Miltenyi Biotec, Inc; National Marrow Donor Program; Neovii Biotech NA, Inc; Novartis Pharmaceuticals Corporation; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc; Otsuka America Pharmaceutical, Inc; Otsuka Pharmaceutical Co, Ltd.-Japan; Oxford Immunotec; Perkin Elmer, Inc; Pharmacyclics; Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Spectrum Pharmaceuticals, Inc; St. Baldrick's Foundation; Sunesis Pharmaceuticals, Inc; Swedish Orphan Biovitrum, Inc; Telomere Diagnostics, Inc; TerumoBCT; Therakos, Inc; University of Minnesota; Wellpoint, Inc. FX This study was conducted on behalf of the Infection and Immune Reconstitution Working Committee of the Center for International Blood and Marrow Transplant Research (CIBMTR) which includes more than 400 members. The CIBMTR is supported by Public Health Service grant/cooperative agreement 5U24-CA076518 from the National Institutes of Health, National Cancer Institute (NCI), National Heart, Lung and Blood Institute (NHLBI), and National Institute of Allergy and Infectious Diseases (NIAID); grant/cooperative agreement 5U10HL069294 from NHLBI and NCI; contract HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); grants N00014-13-1-0039 and N00014-14-1-0028 from the Office of Naval Research; and grants from Alexion; *Amgen, Inc; anonymous donation to the Medical College of Wisconsin; Be the Match Foundation; *Bristol Myers Squibb Oncology; *Celgene Corporation; *Chimerix, Inc; Fred Hutchinson Cancer Research Center; Gamida Cell Ltd.; Genentech, Inc; Genzyme Corporation; *Gilead Sciences, Inc; Health Research, Inc Roswell Park Cancer Institute; HistoGenetics, Inc; Incyte Corporation; *Jazz Pharmaceuticals, Inc; Jeff Gordon Children's Foundation; The Leukemia & Lymphoma Society; The Medical College of Wisconsin; Merck & Co, Inc; Mesoblast; *Millennium: The Takeda Oncology Co.; *Miltenyi Biotec, Inc; National Marrow Donor Program; Neovii Biotech NA, Inc; Novartis Pharmaceuticals Corporation; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc; Otsuka America Pharmaceutical, Inc; Otsuka Pharmaceutical Co, Ltd.-Japan; Oxford Immunotec; Perkin Elmer, Inc; Pharmacyclics; *Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; *Spectrum Pharmaceuticals, Inc; St. Baldrick's Foundation; *Sunesis Pharmaceuticals, Inc; Swedish Orphan Biovitrum, Inc; Telomere Diagnostics, Inc; TerumoBCT; Therakos, Inc; University of Minnesota; and *Wellpoint, Inc. *Corporate members. NR 41 TC 13 Z9 13 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAY 19 PY 2016 VL 127 IS 20 BP 2427 EP 2438 DI 10.1182/blood-2015-11-679639 PG 12 WC Hematology SC Hematology GA DP2QH UT WOS:000378333900013 PM 26884374 ER PT J AU Kim, T Freudenthal, BD Beard, WA Wilson, SH Schlick, T AF Kim, Taejin Freudenthal, Bret D. Beard, William A. Wilson, Samuel H. Schlick, Tamar TI Insertion of oxidized nucleotide triggers rapid DNA polymerase opening SO NUCLEIC ACIDS RESEARCH LA English DT Article ID BASE EXCISION-REPAIR; TEMPLATING 8-OXOGUANINE LESION; EMPIRICAL FORCE-FIELD; ACTIVE-SITE; MOLECULAR-DYNAMICS; OXIDATIVE STRESS; CONFORMATIONAL PATHWAYS; CRYSTAL-STRUCTURES; KINETIC MECHANISM; GASTRIC-CANCER AB A novel mechanism is unveiled to explain why a pro-mutagenic nucleotide lesion (oxidized guanine, 8-oxoG) causes the mammalian DNA repair polymerase-beta (pol-beta) to rapidly transition to an inactive open conformation. The mechanism involves unexpected features revealed recently in time-lapse crystallography. Specifically, a delicate water network associated with a lesion-stabilizing auxilliary product ion Mg(p) triggers a cascade of events that leads to poor active site geometry and the rupture of crucial molecular interactions between key residues in both the anti(8-oxoG:C) and syn(8-oxoG:A) systems. Once the base pairs in these lesioned systems are broken, dislocation of both Asp192 (a metal coordinating ligand) and the oxoG phosphate group (PO4) interfere with the hydrogen bonding between Asp192 and Arg258, whose rotation toward Asp192 is crucial to the closed-to-open enzyme transition. Energetically, the lesioned open states are similar in energy to those of the corresponding closed complexes after chemistry, in marked contrast to the unlesioned pol-beta anti(G:C) system, whose open state is energetically higher than the closed state. The delicate surveillance system offers a fundamental protective mechanism in the cell that triggers DNA repair events which help deter insertion of oxidized lesions. C1 [Kim, Taejin; Schlick, Tamar] NYU, Dept Chem, 10th Floor Silver Ctr,100 Washington Sq East, New York, NY 10031 USA. [Freudenthal, Bret D.; Beard, William A.; Wilson, Samuel H.] NIEHS, Genome Integr & Struct Biol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Schlick, Tamar] NYU, Courant Inst Math Sci, 251 Mercer St, New York, NY 10012 USA. [Freudenthal, Bret D.] Univ Kansas, Med Ctr, Dept Biochem & Mol Biol, 3901 Rainbow Blvd, Kansas City, KS 66160 USA. RP Schlick, T (reprint author), NYU, Dept Chem, 10th Floor Silver Ctr,100 Washington Sq East, New York, NY 10031 USA. EM Schlick@nyu.edu FU Philip Morris USA Inc; Intramural Research Program of the NIH; National Institute of Environmental Health Sciences [Z01-ES050158, Z01-ES050159]; NIH [1U19CA105010] FX Philip Morris USA Inc; Intramural Research Program of the NIH (in part); National Institute of Environmental Health Sciences [Z01-ES050158 and Z01-ES050159 to S.W. and was in association with NIH grant 1U19CA105010]. Funding for open access charge: NIH. NR 77 TC 0 Z9 0 U1 6 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAY 19 PY 2016 VL 44 IS 9 BP 4409 EP 4424 DI 10.1093/nar/gkw174 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DO0MD UT WOS:000377472100045 PM 27034465 ER PT J AU Bourgeois, FT Olson, KL Tse, T Ioannidis, JPA Mandl, KD AF Bourgeois, Florence T. Olson, Karen L. Tse, Tony Ioannidis, John P. A. Mandl, Kenneth D. TI Prevalence and Characteristics of Interventional Trials Conducted Exclusively in Elderly Persons: A Cross-Sectional Analysis of Registered Clinical Trials SO PLOS ONE LA English DT Article ID HEART-FAILURE; OLDER PATIENTS; DISEASE; BURDEN; AGE; CLINICALTRIALS.GOV; REGISTRATION; GUIDELINES; COMMITTEE; CRITERIA AB Background Elderly patients represent the greatest consumers of healthcare per capita but have historically been underrepresented in clinical trials. It is unknown how many trials are designed to focus exclusively on elderly patients. Objective To define the prevalence of interventional trials that study exclusively elderly persons and describe the characteristics of these trials, including their distribution across conditions most prevalent in the elderly. Design All interventional clinical trials enrolling exclusively elderly patients (>= 65 years), conducted primarily in high-income countries, and initiated between 2006 and 2014, identified through ClincialTrials.gov. Main Measures Trials were identified and characterized according to design features and disease categories studied. Across disease categories we examined the burden of disease in the elderly in high-income countries (measured in disability-adjusted life years [DALYs]) and compared to the number of trials conducted exclusively in the elderly. Results Among 80,965 interventional trials, 1,112 (1.4%) focused on elderly patients. Diverse types of interventions were studied in these trials (medications 33%, behavioral interventions 18%, and dietary supplements 10%) and the majority was funded by non-profit organizations (81%). Studies tended to be small (median sample size 122 participants [IQR 58, 305]), single-center studies (67%). Only 43% of 126 disease categories affecting elderly persons were studied in trials focused on the elderly. Among these disease categories, there was a 5162-fold range in the ratio of DALYs per trial. Across 5 conditions where over 80% of DALYs are in the elderly, there were a total of only 117 trials done exclusively in the elderly. Conclusions Very few and mostly small studies are conducted exclusively in elderly persons, even for conditions that affect almost exclusively the elderly. C1 [Bourgeois, Florence T.; Olson, Karen L.; Mandl, Kenneth D.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Bourgeois, Florence T.] Harvard Univ, Sch Med, Dept Emergency Med, Boston, MA USA. [Bourgeois, Florence T.; Olson, Karen L.; Mandl, Kenneth D.] Boston Childrens Hosp, Computat Hlth Informat Program, Boston, MA USA. [Tse, Tony] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Ioannidis, John P. A.] Stanford Univ, Dept Med, Sch Med, Stanford Prevent Res Ctr, Stanford, CA 94305 USA. [Ioannidis, John P. A.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. RP Bourgeois, FT (reprint author), Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA.; Bourgeois, FT (reprint author), Harvard Univ, Sch Med, Dept Emergency Med, Boston, MA USA.; Bourgeois, FT (reprint author), Boston Childrens Hosp, Computat Hlth Informat Program, Boston, MA USA. EM florence.bourgeois@childrens.harvard.edu FU National Institute of Aging, National Institutes of Health [1R21AG043715]; National Library of Medicine, National Institutes of Health FX Drs. Bourgeois, Olson, Ioannidis and Mandl were supported by a grant from the National Institute of Aging (1R21AG043715), National Institutes of Health. Dr. Tse received support from the Intramural Research Program of the National Library of Medicine, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 0 Z9 0 U1 1 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 19 PY 2016 VL 11 IS 5 AR e0155948 DI 10.1371/journal.pone.0155948 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM4BR UT WOS:000376291100140 PM 27196289 ER PT J AU Currier, JM Cheng, WY Menendez, D Conolly, R Chorley, BN AF Currier, Jenna M. Cheng, Wan-Yun Menendez, Daniel Conolly, Rory Chorley, Brian N. TI Developing a Gene Biomarker at the Tipping Point of Adaptive and Adverse Responses in Human Bronchial Epithelial Cells SO PLOS ONE LA English DT Article ID TOXCAST PROGRAM; IN-VITRO; ANTIOXIDANT RESPONSE; RISK-ASSESSMENT; BEAS-2B CELLS; CANCER-CELLS; ZINC; P53; TOXICITY; APOPTOSIS AB Determining mechanism-based biomarkers that distinguish adaptive and adverse cellular processes is critical to understanding the health effects of environmental exposures. Shifting from in vivo, low-throughput toxicity studies to high-throughput screening (HTS) paradigms and risk assessment based on in vitro and in silico testing requires utilizing toxicity pathway information to distinguish adverse outcomes from recoverable adaptive events. Little work has focused on oxidative stresses in human airway for the purposes of predicting adverse responses. We hypothesize that early gene expression-mediated molecular changes could be used to delineate adaptive and adverse responses to environmentally-based perturbations. Here, we examined cellular responses of the tracheobronchial airway to zinc (Zn) exposure, a model oxidant. Airway derived BEAS-2B cells exposed to 2-10 mu M Zn2+ elicited concentration-and time-dependent cytotoxicity. Normal, adaptive, and cytotoxic Zn2+ exposure conditions were determined with traditional apical endpoints, and differences in global gene expression around the tipping point of the responses were used to delineate underlying molecular mechanisms. Bioinformatic analyses of differentially expressed genes indicate early enrichment of stress signaling pathways, including those mediated by the transcription factors p53 and NRF2. After 4 h, 154 genes were differentially expressed (p < 0.01) between the adaptive and cytotoxic Zn2+ concentrations. Nearly 40% of the biomarker genes were related to the p53 signaling pathway with 30 genes identified as likely direct targets using a database of p53 ChIP-seq studies. Despite similar p53 activation profiles, these data revealed widespread dampening of p53 and NRF2-related genes as early as 4 h after exposure at higher, unrecoverable Zn2+ exposures. Thus, in our model early increased activation of stress response pathways indicated a recoverable adaptive event. Overall, this study highlights the importance of characterizing molecular mechanisms around the tipping point of adverse responses to better inform HTS paradigms. C1 [Currier, Jenna M.; Cheng, Wan-Yun] US EPA, Oak Ridge Inst Sci & Educ, Res Triangle Pk, NC 27711 USA. [Menendez, Daniel] NIEHS, Genome Integr & Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Conolly, Rory; Chorley, Brian N.] US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. RP Chorley, BN (reprint author), US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. EM chorley.brian@epa.gov FU United States Environmental Protection Agency, Office of Research and Development; Oak Ridge Institute for Science and Education Research/Participation Program at the US Environmental Protection Agency FX This work was supported by intramural funding by the United States Environmental Protection Agency, Office of Research and Development.; JMC and W-YC were supported by the Oak Ridge Institute for Science and Education Research/Participation Program at the US Environmental Protection Agency. This manuscript has been reviewed by the National Health and Environmental Effects Research Laboratory and approved for publication. The content does not necessarily reflect the views of the US EPA nor does mention of trade names or commercial products constitute endorsement or recommendation for use. NR 64 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 19 PY 2016 VL 11 IS 5 AR e0155875 DI 10.1371/journal.pone.0155875 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM4BR UT WOS:000376291100124 PM 27195669 ER PT J AU Lin, XP Steinberg, S Kandasamy, SK Afzal, J Mbiyangandu, B Liao, SSE Guan, YF Corona-Villalobos, CP Matkovich, SJ Epstein, N Tripodi, D Huo, ZX Cutting, G Abraham, TP Fukunaga, R Abraham, MR AF Lin, Xiaoping Steinberg, Steven Kandasamy, Suresh K. Afzal, Junaid Mbiyangandu, Blaid Liao, Susan E. Guan, Yufan Corona-Villalobos, Celia P. Matkovich, Scot J. Epstein, Neal Tripodi, Dotti Huo, Zhaoxia Cutting, Garry Abraham, Theodore P. Fukunaga, Ryuya Abraham, M. Roselle TI Common miR-590 Variant rs6971711 Present Only in African Americans Reduces miR-590 Biogenesis SO PLOS ONE LA English DT Article ID LEFT-VENTRICULAR DYSFUNCTION; GROWTH-FACTOR-BETA; HEART-FAILURE; CARDIAC-HYPERTROPHY; MYOCARDIAL-INFARCTION; MICROPROCESSOR COMPLEX; PRIMARY MICRORNAS; SEED REGION; CARDIOMYOPATHY; FIBROSIS AB MicroRNAs (miRNAs) are recognized as important regulators of cardiac development, hypertrophy and fibrosis. Recent studies have demonstrated that genetic variations which cause alterations in miRNA: target interactions can lead to disease. We hypothesized that genetic variations in miRNAs that regulate cardiac hypertrophy/fibrosis might be involved in generation of the cardiac phenotype in patients diagnosed with hypertrophic cardiomyopathy (HCM). To investigate this question, we Sanger sequenced 18 miRNA genes previously implicated in myocyte hypertrophy/fibrosis and apoptosis, using genomic DNA isolated from the leukocytes of 199 HCM patients. We identified a single nucleotide polymorphism (rs6971711, C57T SNP) at the 17th position of mature miR-590-3p (= 57th position of pre-miR-590) that is common in individuals of African ancestry. SNP frequency was higher in African American HCM patients (n = 55) than ethnically-matched controls (n = 100), but the difference was not statistically significant (8.2% vs. 6.5%; p = 0.5). Using a cell culture system, we discovered that presence of this SNP resulted in markedly lower levels of mature miR-590-5p (39 +/- 16%, p<0.003) and miR-590-3p (20 +/- 2%, p<0.003), when compared with wild-type (WT) miR-590, without affecting levels of pri-miR-590 and pre-miR-590. Consistent with this finding, the SNP resulted in reduced target suppression when compared to WT miR-590 (71% suppression by WT vs 60% suppression by SNP, p<0.03). Since miR-590 can regulate TGF-beta, Activin A and Akt signaling, SNP-induced reduction in miR-590 biogenesis could influence cardiac phenotype by de-repression of these signaling pathways. Since the SNP is only present in African Americans, population studies in this patient population would be valuable to investigate effects of this SNP on myocyte function and cardiac physiology. C1 [Lin, Xiaoping; Afzal, Junaid; Mbiyangandu, Blaid; Guan, Yufan; Corona-Villalobos, Celia P.; Abraham, Theodore P.; Abraham, M. Roselle] Johns Hopkins Univ, Sch Med, Dept Med, Hypertroph Cardiomyopathy Ctr Excellence, Baltimore, MD 21205 USA. [Lin, Xiaoping] Zhejiang Univ, Sch Med, Affiliated Hosp 2, Dept Cardiol, Hangzhou 310003, Zhejiang, Peoples R China. [Steinberg, Steven; Cutting, Garry] Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD USA. [Kandasamy, Suresh K.; Liao, Susan E.; Fukunaga, Ryuya] Johns Hopkins Sch Med, Dept Biol Chem, Baltimore, MD USA. [Matkovich, Scot J.] Washington Univ, Sch Med, Dept Internal Med, Ctr Pharmacogen, St Louis, MO 63110 USA. [Epstein, Neal; Tripodi, Dotti] NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. [Huo, Zhaoxia] Zhejiang Univ, Sch Med, Affiliated Hosp 1, Clin Res Ctr, Hangzhou 310003, Zhejiang, Peoples R China. RP Abraham, MR (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, Hypertroph Cardiomyopathy Ctr Excellence, Baltimore, MD 21205 USA.; Fukunaga, R (reprint author), Johns Hopkins Sch Med, Dept Biol Chem, Baltimore, MD USA. EM fukunaga@jhmi.edu; mabraha3@jhmi.edu OI Matkovich, Scot/0000-0002-7398-6857; Fukunaga, Ryuya/0000-0002-5814-8206 FU NIH [5UL1RR025005-05, RO1 HL098046]; John Taylor Babbit Foundation; WW Smith Charitable Trust [H1405]; American Heart Association [15SDG23220028]; National Natural Science Foundation of China [81500289]; Zhejiang Provincial Natural Science Foundation [LQ15H020003]; NIH; National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) [1UL1RR025005]; NIH Roadmap for Medical Research FX This work was supported by NIH 5UL1RR025005-05, RO1 HL098046, John Taylor Babbit Foundation, WW Smith Charitable Trust (H1405), the American Heart Association (15SDG23220028), National Natural Science Foundation of China (81500289), and Zhejiang Provincial Natural Science Foundation (LQ15H020003). Blaid Mbiyangandu was supported by an NIH Diversity supplement. DNA sequence analysis for this publication was made possible by Grant Number 1UL1RR025005 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. Information on NCRR is available at http://www.ncrr.nih.gov/. Information on Re-engineering the Clinical Research Enterprise can be obtained from http://nihroadmap.nih.gov/clinicalresearch/overview-translational.asp. NR 59 TC 1 Z9 1 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 19 PY 2016 VL 11 IS 5 AR e0156065 DI 10.1371/journal.pone.0156065 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM4BR UT WOS:000376291100155 PM 27196440 ER PT J AU Sano, O Tsujita, M Shimizu, Y Kato, R Kobayashi, A Kioka, N Remaley, AT Michikawa, M Ueda, K Matsuo, M AF Sano, Osamu Tsujita, Maki Shimizu, Yuji Kato, Reiko Kobayashi, Aya Kioka, Noriyuki Remaley, Alan T. Michikawa, Makoto Ueda, Kazumitsu Matsuo, Michinori TI ABCG1 and ABCG4 Suppress gamma-Secretase Activity and Amyloid beta Production SO PLOS ONE LA English DT Article ID CASSETTE TRANSPORTERS G1; TRANSGENIC MOUSE MODEL; CHOLESTEROL EFFLUX; PRECURSOR PROTEIN; ALZHEIMERS-DISEASE; APOLIPOPROTEIN-E; LIPID RAFTS; CELLULAR CHOLESTEROL; MEDIATE CHOLESTEROL; DENSITY-LIPOPROTEIN AB ATP-binding cassette G1 (ABCG1) and ABCG4, expressed in neurons and glia in the central nervous system, mediate cholesterol efflux to lipid acceptors. The relationship between cholesterol level in the central nervous system and Alzheimer's disease has been reported. In this study, we examined the effects of ABCG1 and ABCG4 on amyloid precursor protein (APP) processing, the product of which, amyloid beta (A beta), is involved in the pathogenesis of Alzheimer's disease. Expression of ABCG1 or ABCG4 in human embryonic kidney 293 cells that stably expressed Swedish-type mutant APP increased cellular and cell surface APP levels. Products of cleavage from APP by alpha-secretase and by beta-secretase also increased. The levels of secreted A beta, however, decreased in the presence of ABCG1 and ABCG4, but not ABCG4-KM, a nonfunctional Walker-A lysine mutant. In contrast, secreted A beta levels increased in differentiated SH-SY5Y neuron-like cells in which ABCG1 and ABCG4 were suppressed. Furthermore, A beta 42 peptide in the cerebrospinal fluid from Abcg1 null mice significantly increased compared to the wild type mice. To examine the underlying mechanism, we analyzed the activity and distribution of gamma-secretase. ABCG1 and ABCG4 suppressed gamma-secretase activity and disturbed gamma-secretase localization in the raft domains where gamma-secretase functions. These results suggest that ABCG1 and ABCG4 alter the distribution of -secretase on the plasma membrane, leading to the decreased -secretase activity and suppressed A beta secretion. ABCG1 and ABCG4 may inhibit the development of Alzheimer's disease and can be targets for the treatment of Alzheimer's disease. C1 [Sano, Osamu; Shimizu, Yuji; Kato, Reiko; Kobayashi, Aya; Kioka, Noriyuki; Ueda, Kazumitsu] Kyoto Univ, Grad Sch Agr, Div Appl Life Sci, Lab Cellular Biochem, Kyoto 6068502, Japan. [Tsujita, Maki; Michikawa, Makoto] Nagoya City Univ, Grad Sch Med Sci, Biochem, Nagoya, Aichi 4678601, Japan. [Remaley, Alan T.] NHLBI, Lipoprotein Metab Sect, NIH, Bldg 10, Bethesda, MD 20892 USA. [Ueda, Kazumitsu; Matsuo, Michinori] Kyoto Univ, iCeMS, Kyoto 6068502, Japan. [Matsuo, Michinori] Kyoto Womens Univ, Fac Home Econ, Dept Food & Nutr, Kyoto 6058501, Japan. RP Matsuo, M (reprint author), Kyoto Univ, iCeMS, Kyoto 6068502, Japan.; Matsuo, M (reprint author), Kyoto Womens Univ, Fac Home Econ, Dept Food & Nutr, Kyoto 6058501, Japan. EM matsuomi@kyoto-wu.ac.jp FU JSPS KAKENHI [21688007, 25221203, 24580139, 26660071]; MEXT (Ministry of Education, Culture, Sports, Science and Technology) KAKENHI [20056016]; World Premier International Research Center Initiative (WPI initiative) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; BRAIN (the Bio-oriented Technology Research Advancement Institution) FX This work was supported by a Grant-in-aid for Scientific Research for Young Scientists (A) (JSPS KAKENHI Grant Number 21688007), by a Grant-in-aid for Scientific Research (S) (JSPS KAKENHI Grant Number 25221203), by a Grant-in-aid for Scientific Research (C) (JSPS KAKENHI Grant Number 24580139), by a Grant-in-aid for Exploratory Research (JSPS KAKENHI Grant Number 26660071), by a Grant-in-aid for Scientific Research on Priority Areas (MEXT (Ministry of Education, Culture, Sports, Science and Technology) KAKENHI Grant Number 20056016), and by the World Premier International Research Center Initiative (WPI initiative) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and grants from BRAIN (the Bio-oriented Technology Research Advancement Institution). NR 58 TC 0 Z9 1 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 19 PY 2016 VL 11 IS 5 AR e0155400 DI 10.1371/journal.pone.0155400 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM4BR UT WOS:000376291100041 PM 27196068 ER PT J AU Shih, HY Sciume, G Mikami, Y Guo, LY Sun, HW Brooks, SR Urban, JF Davis, FP Kanno, Y O'Shea, JJ AF Shih, Han-Yu Sciume, Giuseppe Mikami, Yohei Guo, Liying Sun, Hong-Wei Brooks, Stephen R. Urban, Joseph F., Jr. Davis, Fred P. Kanno, Yuka O'Shea, John J. TI Developmental Acquisition of Regulomes Underlies Innate Lymphoid Cell Functionality SO CELL LA English DT Article ID IMMUNOLOGICAL GENOME PROJECT; MURINE BONE-MARROW; TRANSCRIPTION FACTOR; NATURAL-KILLER; T-BET; ADAPTIVE IMMUNITY; ENHANCERS; FATE; IDENTIFICATION; MACROPHAGE AB Innate lymphoid cells (ILCs) play key roles in host defense, barrier integrity, and homeostasis and mirror adaptive CD4(+) T helper (Th) cell subtypes in both usage of effector molecules and transcription factors. To better understand the relationship between ILC subsets and their Th cell counterparts, we measured genome-wide chromatin accessibility. We find that chromatin in proximity to effector genes is selectively accessible in ILCs prior to high-level transcription upon activation. Accessibility of these regions is acquired in a stepwise manner during development and changes little after in vitro or in vivo activation. Conversely, dramatic chromatin remodeling occurs in naive CD4(+) T cells during Th cell differentiation using a type-2-infection model. This alteration results in a substantial convergence of Th2 cells toward ILC2 regulomes. Our data indicate extensive sharing of regulatory circuitry across the innate and adaptive compartments of the immune system, in spite of their divergent developing pathways. C1 [Shih, Han-Yu; Sciume, Giuseppe; Mikami, Yohei; Davis, Fred P.; Kanno, Yuka; O'Shea, John J.] NIAMSD, Lymphocyte Cell Biol Sect, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. [Guo, Liying] NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Sun, Hong-Wei; Brooks, Stephen R.] NIAMSD, Biodata Min & Discovery Sect, NIH, Bethesda, MD 20892 USA. [Urban, Joseph F., Jr.] ARS, Diet Genom & Immunol Lab, Beltsville Human Nutr Res Ctr, USDA, Beltsville, MD 20705 USA. RP Shih, HY; O'Shea, JJ (reprint author), NIAMSD, Lymphocyte Cell Biol Sect, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. EM han-yu.shih@nih.gov; john.oshea@nih.gov RI Sciume, Giuseppe/K-8985-2016 OI Sciume, Giuseppe/0000-0003-0131-512X FU NIAMS FX We thank Drs. Y. Belkaid, K. Zhao, V. Sartorelli, J. Zhu, I. Fraser, and A. Poholek for critically reading this manuscript. We also thank G. Gutierrez-Cruz (Genome Analysis Core Facility, NIAMS) and J. Simone, J. Lay, and K. Tinsley (Flow Cytometry Section, NIAMS) for their technical support. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the NIH. This work was supported by the Intramural Research Programs of the NIAMS. NR 62 TC 13 Z9 13 U1 2 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD MAY 19 PY 2016 VL 165 IS 5 BP 1120 EP 1133 DI 10.1016/j.cell.2016.04.029 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DM6QT UT WOS:000376478200013 PM 27156451 ER PT J AU Xing, R Li, L Chen, L Gao, Z Wang, H Li, W Cui, J Tian, G Liang, Q Yu, J Sung, JJ Luo, G Gao, H Xu, X Yang, H Wang, J Zhang, X Wang, JM Huang, J Yu, Y Wang, J Lu, Y AF Xing, R. Li, L. Chen, L. Gao, Z. Wang, H. Li, W. Cui, J. Tian, G. Liang, Q. Yu, J. Sung, J. J. Luo, G. Gao, H. Xu, X. Yang, H. Wang, J. Zhang, X. Wang, J. M. Huang, J. Yu, Y. Wang, J. Lu, Y. TI Copy number variations of HLA-I and activation of NKp30 pathway determine the sensitivity of gastric cancer cells to the cytotoxicity of natural killer cells SO ONCOGENE LA English DT Article ID LUNG-CANCER; RECEPTORS NKP30; THERAPY; NKP44; GENE AB Nude mice are important in vivo model for characterization of cell malignancy behavior; however, many cancer cells fail to form tumors in it. Understanding this defective mechanism may provide novel insights into tumorigenesis and how tumor cells escape innate immunity. Whole-genome sequencing was conducted on two gastric cancer (GC) cells, BGC823 and AGS, which do and do not form tumors in nude mice, to identify their genomic differences relevant to natural killer (NK) cells. We found that the tumorigenic capacity of human GC cell lines was dependent on the recruitment and activation of NK cells in xenograft tumors. We used whole-genome sequence (WGS) on GC cell lines to identify potential genes controlling susceptibility to NK-mediated killing. The tumorigenic cell line BGC823 expressed high levels of HLA-I because of copy gain and was resistant to NK cell killing. In contrast, another cell line AGS expressing low levels of HLA-I with activated NKp30/MAPK/IL-12 (interleukin-12) or IL-2 (interleukin-2) pathway was susceptible to NK lysis. Treatment of tumor bearing mice with systemic administration of IL-12 in combination with intratumor injection of anti-HLA-I antibody significantly increased NK cell recruitment into xenograft tumors, which became sensitive to NK killing, resulting in reduced tumor progression. In human GC specimens, decreased HLA-I expression and increased NK cells surrounding tumor cells were correlated with decreased metastasis potential and better prognosis of patients. Our results provide a mechanistic basis for GC cells to escape NK lysis and a promising prospect of NK immunotherapy for GC cells. C1 [Xing, R.; Wang, H.; Li, W.; Cui, J.; Lu, Y.] Peking Univ, Canc Hosp & Inst, Key Lab Carcinogenesis & Translat Res, Lab Mol Oncol,Minist Educ, Fu Cheng Rd 52, Beijing 100142, Peoples R China. [Li, L.; Chen, L.; Gao, Z.; Tian, G.; Xu, X.; Yang, H.; Wang, J.; Zhang, X.; Wang, J.] Beijing Genom Inst Shenzhen, Shenzhen 518083, Peoples R China. [Liang, Q.; Yu, J.; Sung, J. J.] Chinese Univ Hong Kong, Shenzhen Res Inst, Inst Digest Dis, Hong Kong, Hong Kong, Peoples R China. [Liang, Q.; Yu, J.; Sung, J. J.] Chinese Univ Hong Kong, Shenzhen Res Inst, Li Ka Shing Inst Hlth Sci, Dept Med & Therapeut,State Key Lab Digest Dis, Hong Kong, Hong Kong, Peoples R China. [Luo, G.] Case Western Reserve Univ, Sch Med, Dept Genet & Genome Sci, Cleveland, OH USA. [Luo, G.] Beijing Univ Chinese Med, Beijing, Peoples R China. [Gao, H.] Shanghai Engn Ctr Mol Med, Shanghai, Peoples R China. [Wang, J. M.; Huang, J.] NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. [Yu, Y.] Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, Dept Surg, Shanghai 200030, Peoples R China. [Yu, Y.] Shanghai Jiao Tong Univ, Sch Med, Shanghai Inst Digest Surg, Shanghai 200030, Peoples R China. RP Lu, Y (reprint author), Peking Univ, Canc Hosp & Inst, Key Lab Carcinogenesis & Translat Res, Lab Mol Oncol,Minist Educ, Fu Cheng Rd 52, Beijing 100142, Peoples R China.; Wang, J (reprint author), Beijing Genom Inst Shenzhen, Shenzhen 518083, Peoples R China. EM wangj@genomics.org.cn; youyonglu@bjmu.edu.cn RI Yu, Jun /D-8569-2015 FU Ministry of Science and Technology of China (863 program) [2012AA02A203, 2012AA02A504]; Beijing Nova program [XXJH2015037, Z151100000315069] FX We thank Dr Richard Ascione (Department of Biochemistry and Molecular Biology, Medical School of Georgetown University USA) and Dr Laurie Goodman for critical reviewing and editing of the manuscript. This work was supported by the Ministry of Science and Technology of China (863 program, grants 2012AA02A203, 2012AA02A504) and Beijing Nova program (XXJH2015037, No.Z151100000315069). NR 19 TC 0 Z9 0 U1 4 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD MAY 19 PY 2016 VL 35 IS 20 BP 2584 EP 2591 DI 10.1038/onc.2015.324 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA DM2GS UT WOS:000376165700005 PM 26364607 ER PT J AU Lowy, DR Collins, FS AF Lowy, Douglas R. Collins, Francis S. TI Aiming High - Changing the Trajectory for Cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Lowy, Douglas R.] NCI, Bethesda, MD 20892 USA. [Collins, Francis S.] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Lowy, DR (reprint author), NCI, Bethesda, MD 20892 USA. NR 5 TC 10 Z9 10 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 19 PY 2016 VL 374 IS 20 BP 1901 EP 1904 DI 10.1056/NEJMp1600894 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA DM1OX UT WOS:000376116600001 PM 27043262 ER PT J AU Gillinov, AM Bagiella, E Moskowitz, AJ Raiten, JM Groh, MA Bowdish, ME Ailawadi, G Kirkwood, KA Perrault, LP Parides, MK Smith, RL Kern, JA Dussault, G Hackmann, AE Jeffries, NO Miller, MA Taddei-Peters, WC Rose, EA Weisel, RD Williams, DL Mangusan, RF Argenziano, M Moquete, EG O'Sullivan, KL Pellerin, M Shah, KJ Gammie, JS Mayer, ML Voisine, P Gelijns, AC O'Gara, PT Mack, MJ AF Gillinov, A. M. Bagiella, E. Moskowitz, A. J. Raiten, J. M. Groh, M. A. Bowdish, M. E. Ailawadi, G. Kirkwood, K. A. Perrault, L. P. Parides, M. K. Smith, R. L., II Kern, J. A. Dussault, G. Hackmann, A. E. Jeffries, N. O. Miller, M. A. Taddei-Peters, W. C. Rose, E. A. Weisel, R. D. Williams, D. L. Mangusan, R. F. Argenziano, M. Moquete, E. G. O'Sullivan, K. L. Pellerin, M. Shah, K. J. Gammie, J. S. Mayer, M. L. Voisine, P. Gelijns, A. C. O'Gara, P. T. Mack, M. J. CA CTSN TI Rate Control versus Rhythm Control for Atrial Fibrillation after Cardiac Surgery SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ACC/AHA/ESC 2006 GUIDELINES; HEART-ASSOCIATION; MANAGEMENT; MULTICENTER; PREVENTION; PREDICTORS; TRIAL AB BACKGROUND Atrial fibrillation after cardiac surgery is associated with increased rates of death, complications, and hospitalizations. In patients with postoperative atrial fibrillation who are in stable condition, the best initial treatment strategy - heart-rate control or rhythm control - remains controversial. METHODS Patients with new-onset postoperative atrial fibrillation were randomly assigned to undergo either rate control or rhythm control. The primary end point was the total number of days of hospitalization within 60 days after randomization, as assessed by the Wilcoxon rank-sum test. RESULTS Postoperative atrial fibrillation occurred in 695 of the 2109 patients (33.0%) who were enrolled preoperatively; of these patients, 523 underwent randomization. The total numbers of hospital days in the rate-control group and the rhythm-control group were similar (median, 5.1 days and 5.0 days, respectively; P = 0.76). There were no significant between-group differences in the rates of death (P = 0.64) or overall serious adverse events (24.8 per 100 patient-months in the rate-control group and 26.4 per 100 patient-months in the rhythm-control group, P = 0.61), including thromboembolic and bleeding events. About 25% of the patients in each group deviated from the assigned therapy, mainly because of drug ineffectiveness (in the rate-control group) or amiodarone side effects or adverse drug reactions (in the rhythm-control group). At 60 days, 93.8% of the patients in the rate-control group and 97.9% of those in the rhythm-control group had had a stable heart rhythm without atrial fibrillation for the previous 30 days (P = 0.02), and 84.2% and 86.9%, respectively, had been free from atrial fibrillation from discharge to 60 days (P = 0.41). CONCLUSIONS Strategies for rate control and rhythm control to treat postoperative atrial fibrillation were associated with equal numbers of days of hospitalization, similar complication rates, and similarly low rates of persistent atrial fibrillation 60 days after onset. Neither treatment strategy showed a net clinical advantage over the other. (Funded by the National Institutes of Health and the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT02132767.) C1 [Gillinov, A. M.] Cleveland Clin Fdn, Dept Thorac & Cardiovasc Surg, Cleveland, OH USA. [Bagiella, E.; Moskowitz, A. J.; Kirkwood, K. A.; Parides, M. K.; Williams, D. L.; Moquete, E. G.; O'Sullivan, K. L.; Shah, K. J.; Gelijns, A. C.] Icahn Sch Med Mt Sinai, Dept Populat Hlth Sci & Policy, Int Ctr Hlth Outcomes & Innovat Res, New York, NY 10029 USA. [Rose, E. A.] Mt Sinai Hlth Syst, Dept Cardiac Surg, New York, NY USA. [Argenziano, M.] Columbia Univ, Coll Phys & Surg, Dept Surg, Div Cardiothorac Surg, New York, NY USA. [Raiten, J. M.] Univ Penn, Dept Anesthesiol & Crit Care, Philadelphia, PA 19104 USA. [Mayer, M. L.] Univ Penn, Sch Med, Dept Surg, Div Cardiovasc Surg, Philadelphia, PA 19104 USA. [Groh, M. A.; Mangusan, R. F.] Mission Hlth & Hosp, Cardiovasc & Thorac Surg, Asheville, NC USA. [Bowdish, M. E.; Hackmann, A. E.] Univ So Calif, Keck Sch Med, Dept Surg, Los Angeles, CA 90033 USA. [Ailawadi, G.; Kern, J. A.] Univ Virginia, Sch Med, Div Thorac & Cardiovasc Surg, Charlottesville, VA 22908 USA. [Perrault, L. P.; Pellerin, M.] Univ Montreal, Montreal Heart Inst, Montreal, PQ, Canada. [Dussault, G.; Voisine, P.] Hop Laval, Inst Univ Cardiol & Pneumol Quebec, Quebec City, PQ, Canada. [Weisel, R. D.] Univ Toronto, Peter Munk Cardiac Ctr, Toronto, ON, Canada. [Weisel, R. D.] Univ Toronto, Toronto Gen Hosp, Univ Hlth Network, Div Cardiovasc Surg, Toronto, ON M5G 1L7, Canada. [Weisel, R. D.] Univ Toronto, Div Cardiac Surg, Toronto, ON, Canada. [Smith, R. L., II; Mack, M. J.] Baylor Hlth Care Syst, Heart Hosp Baylor Plano, Dept Cardiovasc Surg, Plano, TX USA. [Jeffries, N. O.] NHLBI, Off Biostat Res, Bldg 10, Bethesda, MD 20892 USA. [Miller, M. A.; Taddei-Peters, W. C.] NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. [Gammie, J. S.] Univ Maryland, Med Ctr, Dept Surg, Baltimore, MD 21201 USA. [O'Gara, P. T.] Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. RP Gelijns, AC (reprint author), Icahn Sch Med Mt Sinai, Dept Populat Hlth Sci & Policy, 1 Gustave L Levy Pl,Box 1077, New York, NY 10029 USA. EM annetine.gelijns@mountsinai.org OI Moskowitz, Alan/0000-0002-4412-9450; Browndyke, Jeffrey/0000-0002-8573-7073 FU National Institutes of Health; Canadian Institutes of Health Research FX Funded by the National Institutes of Health and the Canadian Institutes of Health Research; ClinicalTrials. gov number, NCT02132767. NR 20 TC 19 Z9 20 U1 1 U2 8 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 19 PY 2016 VL 374 IS 20 BP 1911 EP 1921 DI 10.1056/NEJMoa1602002 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA DM1OX UT WOS:000376116600004 PM 27043047 ER PT J AU Townsley, DM Dumitriu, B Liu, DL Biancotto, A Weinstein, B Chen, C Hardy, N Mihalek, AD Lingala, S Kim, YJ Yao, JH Jones, E Gochuico, BR Heller, T Wu, CO Calado, RT Scheinberg, P Young, NS AF Townsley, Danielle M. Dumitriu, Bogdan Liu, Delong Biancotto, Angelique Weinstein, Barbara Chen, Christina Hardy, Nathan Mihalek, Andrew D. Lingala, Shilpa Kim, Yun Ju Yao, Jianhua Jones, Elizabeth Gochuico, Bernadette R. Heller, Theo Wu, Colin O. Calado, Rodrigo T. Scheinberg, Phillip Young, Neal S. TI Danazol Treatment for Telomere Diseases SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SEVERE APLASTIC-ANEMIA; BONE-MARROW FAILURE; DYSKERATOSIS-CONGENITA; PULMONARY-FIBROSIS; ANDROGEN THERAPY; MUTATIONS; LENGTH; TRANSPLANTATION; CANCER; GENE AB BACKGROUND Genetic defects in telomere maintenance and repair cause bone marrow failure, liver cirrhosis, and pulmonary fibrosis, and they increase susceptibility to cancer. Historically, androgens have been useful as treatment for marrow failure syndromes. In tissue culture and animal models, sex hormones regulate expression of the telomerase gene. METHODS In a phase 1-2 prospective study involving patients with telomere diseases, we administered the synthetic sex hormone danazol orally at a dose of 800 mg per day for a total of 24 months. The goal of treatment was the attenuation of accelerated telomere attrition, and the primary efficacy end point was a 20% reduction in the annual rate of telomere attrition measured at 24 months. The occurrence of toxic effects of treatment was the primary safety end point. Hematologic response to treatment at various time points was the secondary efficacy end point. RESULTS After 27 patients were enrolled, the study was halted early, because telomere attrition was reduced in all 12 patients who could be evaluated for the primary end point; in the intention-to-treat analysis, 12 of 27 patients (44%; 95% confidence interval [CI], 26 to 64) met the primary efficacy end point. Unexpectedly, almost all the patients (11 of 12, 92%) had a gain in telomere length at 24 months as compared with baseline (mean increase, 386 bp [95% CI, 178 to 593]); in exploratory analyses, similar increases were observed at 6 months (16 of 21 patients; mean increase, 175 bp [95% CI, 79 to 271]) and 12 months (16 of 18 patients; mean increase, 360 bp [95% CI, 209 to 512]). Hematologic responses occurred in 19 of 24 patients (79%) who could be evaluated at 3 months and in 10 of 12 patients (83%) who could be evaluated at 24 months. Known adverse effects of danazol - elevated liver-enzyme levels and muscle cramps - of grade 2 or less occurred in 41% and 33% of the patients, respectively. CONCLUSIONS In our study, treatment with danazol led to telomere elongation in patients with telomere diseases. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01441037.) C1 [Townsley, Danielle M.; Dumitriu, Bogdan; Liu, Delong; Weinstein, Barbara; Chen, Christina; Hardy, Nathan; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Mihalek, Andrew D.] NHLBI, Cardiopulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Wu, Colin O.] NHLBI, Off Biostat Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Biancotto, Angelique] NIH, Ctr Human Immunol Autoimmun & Inflammat, Bldg 10, Bethesda, MD 20892 USA. [Lingala, Shilpa; Kim, Yun Ju; Heller, Theo] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Yao, Jianhua; Jones, Elizabeth] NIH, Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Gochuico, Bernadette R.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Calado, Rodrigo T.] Univ Sao Paulo, Dept Internal Med, Ribeirao Preto Medi Sch, BR-14049 Ribeirao Preto, Brazil. [Scheinberg, Phillip] Hosp Sao Jose & Beneficencia Portuguesa, Antonio Ermirio de Moraes Canc Ctr, Clin Hematol, Sao Paulo, Brazil. RP Townsley, DM (reprint author), NIH, Ctr Clin, Bldg 10 CRC,Rm 3-5216,10 Ctr Dr, Bethesda, MD 20892 USA. EM townsleydm@nhlbi.nih.gov RI Calado, Rodrigo/G-2619-2011; OI Hardy, Nathan/0000-0002-3833-6461 FU National Institutes of Health FX Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01441037. NR 40 TC 16 Z9 17 U1 2 U2 9 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 19 PY 2016 VL 374 IS 20 BP 1922 EP 1931 DI 10.1056/NEJMoa1515319 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DM1OX UT WOS:000376116600005 PM 27192671 ER PT J AU Michler, RE Smith, PK Parides, MK Ailawadi, G Thourani, V Moskowitz, AJ Acker, MA Hung, JW Chang, HL Perrault, LP Gillinov, AM Argenziano, M Bagiella, E Overbey, JR Moquete, EG Gupta, LN Miller, MA Taddei-Peters, WC Jeffries, N Weisel, RD Rose, EA Gammie, JS DeRose, JJ Puskas, JD Dagenais, F Burks, SG El-Hamamsy, I Milano, CA Atluri, P Voisine, P O'Gara, PT Gelijns, AC AF Michler, R. E. Smith, P. K. Parides, M. K. Ailawadi, G. Thourani, V. Moskowitz, A. J. Acker, M. A. Hung, J. W. Chang, H. L. Perrault, L. P. Gillinov, A. M. Argenziano, M. Bagiella, E. Overbey, J. R. Moquete, E. G. Gupta, L. N. Miller, M. A. Taddei-Peters, W. C. Jeffries, N. Weisel, R. D. Rose, E. A. Gammie, J. S. DeRose, J. J., Jr. Puskas, J. D. Dagenais, F. Burks, S. G. El-Hamamsy, I. Milano, C. A. Atluri, P. Voisine, P. O'Gara, P. T. Gelijns, A. C. CA CTSN TI Two-Year Outcomes of Surgical Treatment of Moderate Ischemic Mitral Regurgitation SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID LEFT-VENTRICULAR DYSFUNCTION; CHRONIC HEART-FAILURE; MYOCARDIAL-INFARCTION; PROGNOSTIC VALUE; BYPASS SURGERY; SURVIVAL; REVASCULARIZATION; TRIAL; ECHOCARDIOGRAPHY; VIABILITY AB BACKGROUND In a trial comparing coronary-artery bypass grafting (CABG) alone with CABG plus mitral-valve repair in patients with moderate ischemic mitral regurgitation, we found no significant difference in the left ventricular end-systolic volume index (LVESVI) or survival after 1 year. Concomitant mitral-valve repair was associated with a reduced prevalence of moderate or severe mitral regurgitation, but patients had more adverse events. We now report 2-year outcomes. METHODS We randomly assigned 301 patients to undergo either CABG alone or the combined procedure. Patients were followed for 2 years for clinical and echocardiographic outcomes. RESULTS At 2 years, the mean (+/- SD) LVESVI was 41.2 +/- 20.0 ml per square meter of body-surface area in the CABG-alone group and 43.2 +/- 20.6 ml per square meter in the combined-procedure group (mean improvement over baseline, -14.1 ml per square meter and -14.6 ml per square meter, respectively). The rate of death was 10.6% in the CABG-alone group and 10.0% in the combined-procedure group (hazard ratio in the combined-procedure group, 0.90; 95% confidence interval, 0.45 to 1.83; P = 0.78). There was no significant between-group difference in the rank-based assessment of the LVESVI (including death) at 2 years (z score, 0.38; P = 0.71). The 2-year rate of moderate or severe residual mitral regurgitation was higher in the CABG-alone group than in the combined-procedure group (32.3% vs. 11.2%, P< 0.001). Overall rates of hospital readmission and serious adverse events were similar in the two groups, but neurologic events and supraventricular arrhythmias remained more frequent in the combined-procedure group. CONCLUSIONS In patients with moderate ischemic mitral regurgitation undergoing CABG, the addition of mitral-valve repair did not lead to significant differences in left ventricular reverse remodeling at 2 years. Mitral-valve repair provided a more durable correction of mitral regurgitation but did not significantly improve survival or reduce overall adverse events or readmissions and was associated with an early hazard of increased neurologic events and supraventricular arrhythmias. (Funded by the National Institutes of Health and Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00806988.) C1 [Michler, R. E.; DeRose, J. J., Jr.] Albert Einstein Coll Med, Montefiore Med Ctr, Dept Cardiothorac & Vasc Surg, New York, NY USA. [Parides, M. K.; Moskowitz, A. J.; Chang, H. L.; Bagiella, E.; Overbey, J. R.; Moquete, E. G.; Gupta, L. N.; Gelijns, A. C.] Icahn Sch Med Mt Sinai, Dept Populat Hlth Sci & Policy, Int Ctr Hlth Outcomes & Innovat Res InCHOIR, New York, NY 10029 USA. [Argenziano, M.] Columbia Univ, Coll Phys & Surg, Dept Surg, Div Cardiothorac Surg, New York, NY USA. [Rose, E. A.; Puskas, J. D.] Mt Sinai Hlth Syst, Dept Cardiac Surg, New York, NY USA. [Smith, P. K.; Milano, C. A.] Duke Univ, Med Ctr, Dept Surg, Div Cardiovasc & Thorac Surg, Durham, NC 27710 USA. [Ailawadi, G.; Burks, S. G.] Univ Virginia, Sch Med, Div Thorac & Cardiovasc Surg, Charlottesville, VA 22908 USA. [Thourani, V.] Emory Univ, Sch Med, Div Cardiothorac Surg, Clin Res Unit, Atlanta, GA 30322 USA. [Acker, M. A.; Atluri, P.] Univ Penn, Sch Med, Dept Surg, Div Cardiovasc Surg, Philadelphia, PA 19104 USA. [Hung, J. W.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [O'Gara, P. T.] Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. [Perrault, L. P.; El-Hamamsy, I.] Univ Montreal, Montreal Heart Inst, Montreal, PQ, Canada. [Weisel, R. D.] Univ Toronto, Peter Munk Cardiac Ctr, Toronto, ON, Canada. [Weisel, R. D.] Univ Toronto, Toronto Gen Hosp, Div Cardiovasc Surg, Univ Hlth Network, Toronto, ON M5G 1L7, Canada. [Weisel, R. D.] Univ Toronto, Div Cardiac Surg, Toronto, ON, Canada. [Dagenais, F.; Voisine, P.] Hop Laval, Inst Univ Cardiol Quebec, Quebec City, PQ, Canada. [Gillinov, A. M.] Cleveland Clin Fdn, Dept Thorac & Cardiovasc Surg, Cleveland, OH 44195 USA. [Miller, M. A.; Taddei-Peters, W. C.] NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. [Jeffries, N.] NHLBI, Off Biostat Res, Bldg 10, Bethesda, MD 20892 USA. [Gammie, J. S.] Univ Maryland, Med Ctr, Dept Surg, Baltimore, MD 21201 USA. RP Gelijns, AC (reprint author), Icahn Sch Med Mt Sinai, Dept Populat Hlth Sci & Policy, 1Gustave L Levy Pl,Box 1077, New York, NY 10029 USA. EM annetine.gelijns@mountsinai.org OI Moskowitz, Alan/0000-0002-4412-9450; Browndyke, Jeffrey/0000-0002-8573-7073 FU National Institutes of Health; Canadian Institutes of Health Research FX Funded by the National Institutes of Health and Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00806988. NR 25 TC 16 Z9 16 U1 2 U2 6 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 19 PY 2016 VL 374 IS 20 BP 1932 EP 1941 DI 10.1056/NEJMoa1602003 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DM1OX UT WOS:000376116600006 PM 27040451 ER PT J AU Linehan, WM Merino, MJ Ricketts, CJ AF Linehan, W. Marston Merino, Maria J. Ricketts, Christopher J. TI Papillary Renal-Cell Carcinoma REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID PHENOTYPE C1 [Linehan, W. Marston; Merino, Maria J.; Ricketts, Christopher J.] NCI, Bethesda, MD 20892 USA. RP Linehan, WM (reprint author), NCI, Bethesda, MD 20892 USA. EM wml@nih.gov NR 4 TC 0 Z9 0 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 19 PY 2016 VL 374 IS 20 BP 1991 EP 1991 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DM1OX UT WOS:000376116600020 PM 27192682 ER PT J AU Merkel, PA Manion, M Gopal-Srivastava, R Groft, S Jinnah, HA Robertson, D Krischer, JP AF Merkel, Peter A. Manion, Michele Gopal-Srivastava, Rashmi Groft, Stephen Jinnah, H. A. Robertson, David Krischer, Jeffrey P. CA Rare Dis Clinical Res Network TI The partnership of patient advocacy groups and clinical investigators in the rare diseases clinical research network SO ORPHANET JOURNAL OF RARE DISEASES LA English DT Article DE Rare diseases; Patient engagement; Network ID CONTACT REGISTRY; ORGANIZATIONS; DESIGN AB Background: Among the unique features of the Rare Diseases Clinical Research Network (RDCRN) Program is the requirement for each Consortium to include patient advocacy groups (PAGs) as research partners. This development has transformed the work of the RDCRN and is a model for collaborative research. This article outlines the roles patients and PAGs play in the RDCRN and reports on the PAGs' impact on the Network's success. Methods: Principal Investigators from the 17 RDCRN Consortia and 28 representatives from 76 PAGs affiliated with these Consortia were contacted by email to provide feedback via an online RDCRN survey. Impact was measured in the key areas of 1) Research logistics; 2) Outreach and communication; and 3) Funding and in-kind support. Rating choices were: 1-very negative, 2-somewhat negative, 3-no impact, 4-somewhat positive, and 5-very positive. Results: Twenty-seven of the PAGs (96 %) disseminate information about the RDCRN within the patient community. The Consortium Principal Investigators also reported high levels of PAG involvement. Sixteen (94 %) Consortium Principal Investigators and 25 PAGs (89 %) reported PAGs participation in protocol review, study design, Consortium conference calls, attending Consortium meetings, or helping with patient recruitment. Conclusions: PAGs are actively involved in shaping Consortia's research agendas, help ensure the feasibility and success of research protocols by assisting with study design and patient recruitment, and support training programs. This extensive PAG-Investigator partnership in the RDCRN has had a strongly positive impact on the success of the Network. C1 [Merkel, Peter A.] Univ Penn, Div Rheumatol, Philadelphia, PA 19104 USA. [Merkel, Peter A.] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Manion, Michele] PCD Fdn, Minneapolis, MN USA. [Gopal-Srivastava, Rashmi] NIH, ORDR, NCATS, Bldg 10, Bethesda, MD 20892 USA. [Groft, Stephen] NIH, NCATS, Bldg 10, Bethesda, MD 20892 USA. [Jinnah, H. A.] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. [Jinnah, H. A.] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA USA. [Jinnah, H. A.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Robertson, David] Vanderbilt Univ, Dept Med, Clin Res Ctr, Nashville, TN USA. [Robertson, David] Vanderbilt Univ, Dept Pharmacol, Clin Res Ctr, Nashville, TN USA. [Robertson, David] Vanderbilt Univ, Dept Neurol, Clin Res Ctr, Nashville, TN USA. [Krischer, Jeffrey P.] Univ S Florida, Hlth Informat Inst, 3650 Spectrum Blvd, Tampa, FL 33612 USA. [Krischer, Jeffrey P.] Univ S Florida, Dept Pediat, 3650 Spectrum Blvd, Tampa, FL 33612 USA. RP Krischer, JP (reprint author), Univ S Florida, Hlth Informat Inst, 3650 Spectrum Blvd, Tampa, FL 33612 USA.; Krischer, JP (reprint author), Univ S Florida, Dept Pediat, 3650 Spectrum Blvd, Tampa, FL 33612 USA. EM Jeffrey.Krischer@epi.usf.edu FU NCATS; National Institute of Child Health and Human Development (NICHD); National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); National Institute of Neurological Disorders and Stroke (NINDS); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institute of Allergy and Infectious Diseases (NIAID); National Cancer Institute (NCI); National Heart, Lung and Blood Institute (NHLBI); National Institute of Dental and Craniofacial Research (NIDCR); National Institutes of Mental Health (NIMH); Office of Dietary Supplements (ODS) FX The RDCRN, an initiative of the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS), is funded and supported by NCATS, in collaboration with the National Institute of Child Health and Human Development (NICHD), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases (NIAID), the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), the National Institute of Dental and Craniofacial Research (NIDCR), the National Institutes of Mental Health (NIMH), and the Office of Dietary Supplements (ODS). The authors represent the Data Management and Coordinating Center (NS064808)7 and the following consortia of the RDCRN: Vasculitis Clinical Research Consortium (AR057319)1, Genetic Disorders of Mucociliary Clearance Consortium (HL096458)2, Dystonia Coalition (NS065701, TR001456)5, and Autonomic Rare Diseases Clinical Research Consortium (NS065736)6. NR 10 TC 3 Z9 3 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1172 J9 ORPHANET J RARE DIS JI Orphanet J. Rare Dis. PD MAY 18 PY 2016 VL 11 AR 66 DI 10.1186/s13023-016-0445-8 PG 10 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA DO0ZX UT WOS:000377508900002 PM 27194034 ER PT J AU Cortes-Puch, I Wesley, RA Carome, MA Danner, RL Wolfe, SM Natanson, C AF Cortes-Puch, Irene Wesley, Robert A. Carome, Michael A. Danner, Robert L. Wolfe, Sidney M. Natanson, Charles TI Usual Care and Informed Consent in Clinical Trials of Oxygen Management in Extremely Premature Infants SO PLOS ONE LA English DT Article ID BIRTH-WEIGHT INFANTS; EXTREMELY PRETERM INFANTS; RANDOMIZED CONTROLLED-TRIAL; PULSE OXIMETER SATURATION; INSPIRED OXYGEN; POSITIVE-PRESSURE; CROSSOVER TRIAL; ALARM LIMITS; TARGET RANGE; OUTCOMES AB Objective The adequacy of informed consent in the Surfactant, Positive Pressure, and Pulse Oximetry Randomized Trial (SUPPORT) has been questioned. SUPPORT investigators and publishing editors, heads of government study funding agencies, and many ethicists have argued that informed consent was adequate because the two oxygen saturation target ranges studied fell within a range commonly recommended in guidelines. We sought to determine whether each oxygen target as studied in SUPPORT and four similar randomized controlled trials (RCTs) was consistent with usual care. Design/Participants/Setting PubMed, EMBASE, Web of Science, and Scopus were searched for English articles back to 1990 providing information on usual care oxygen management in extremely premature infants. Data were extracted on intended and achieved oxygen saturation levels as determined by pulse oximetry. Twenty-two SUPPORT consent forms were examined for statements about oxygen interventions. Results While the high oxygen saturation target range (91 to 95%) was consistent with usual care, the low range (85 to 89%) was not used outside of the SUPPORT trial according to surveys and clinical studies of usual care. During usual care, similar lower limits (<88%) were universally paired with higher upper limits (>= 92%) and providers skewed achieved oxygen saturations toward the upper-end of these intended ranges. Blinded targeting of a low narrow range resulted in significantly lower achieved oxygen saturations and a doubling of time spent below the lower limit of the intended range compared to usual care practices. The SUPPORT consent forms suggested that the low oxygen saturation arm was a widely practiced subset of usual care. Conclusions SUPPORT does not exemplify comparative effectiveness research studying practices or therapies in common use. Descriptions of major differences between the interventions studied and commonly practiced usual care, as well as potential risks associated with these differences, are essential elements of adequate informed consent. C1 [Cortes-Puch, Irene; Danner, Robert L.; Natanson, Charles] NIH, Dept Crit Care Med, Ctr Clin, 9000 Rockville Pike,Bldg 10,Room 2C145, Bethesda, MD 20892 USA. [Wesley, Robert A.] NIH, Biostat & Clin Epidemiol Serv, Ctr Clin, 9000 Rockville Pike,Bldg 10,Room 2C145, Bethesda, MD 20892 USA. [Carome, Michael A.; Wolfe, Sidney M.] Publ Citizen, Hlth Res Grp, 1600 20th St NW, Washington, DC 20009 USA. RP Cortes-Puch, I; Natanson, C (reprint author), NIH, Dept Crit Care Med, Ctr Clin, 9000 Rockville Pike,Bldg 10,Room 2C145, Bethesda, MD 20892 USA. EM irene.cortes.es@gmail.com; CNatanson@cc.nih.gov FU Critical Care Medicine Department, Clinical Center at the NIH FX This study was funded by intramural sources at the Critical Care Medicine Department, Clinical Center at the NIH. NR 47 TC 0 Z9 0 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 18 PY 2016 VL 11 IS 5 AR e0155005 DI 10.1371/journal.pone.0155005 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM3ZU UT WOS:000376286100037 PM 27191961 ER PT J AU Dudek, J Faress, A Bornstein, MH Haley, DW AF Dudek, Joanna Faress, Ahmed Bornstein, Marc H. Haley, David W. TI Infant Cries Rattle Adult Cognition SO PLOS ONE LA English DT Article ID ANTERIOR CINGULATE CORTEX; EVENT-RELATED POTENTIALS; BASE SCRIPT KNOWLEDGE; EMOTIONAL STIMULI; TEMPORAL COURSE; ATTENTION; BRAIN; ERP; CONFLICT; MOTHERS AB The attention-grabbing quality of the infant cry is well recognized, but how the emotional valence of infant vocal signals affects adult cognition and cortical activity has heretofore been unknown. We examined the effects of two contrasting infant vocalizations (cries vs. laughs) on adult performance on a Stroop task using a cross-modal distraction paradigm in which infant distractors were vocal and targets were visual. Infant vocalizations were presented before (Experiment 1) or during each Stroop trial (Experiment 2). To evaluate the influence of infant vocalizations on cognitive control, neural responses to the Stroop task were obtained by measuring electroencephalography (EEG) and event-related potentials (ERPs) in Experiment 1. Based on the previously demonstrated existence of negative arousal bias, we hypothesized that cry vocalizations would be more distracting and invoke greater conflict processing than laugh vocalizations. Similarly, we expected participants to have greater difficulty shifting attention from the vocal distractors to the target task after hearing cries vs. after hearing laughs. Behavioral results from both experiments showed a cry interference effect, in which task performance was slower with cry than with laugh distractors. Electrophysiology data further revealed that cries more than laughs reduced attention to the task (smaller P200) and increased conflict processing (larger N450), albeit differently for incongruent and congruent trials. Results from a correlation analysis showed that the amplitudes of P200 and N450 were inversely related, suggesting a reciprocal relationship between attention and conflict processing. The findings suggest that cognitive control processes contribute to an attention bias to infant signals, which is modulated in part by the valence of the infant vocalization and the demands of the cognitive task. The findings thus support the notion that infant cries elicit a negative arousal bias that is distracting; they also identify, for the first time, the neural dynamics underlying the unique influence that infant cries and laughs have on cognitive control. C1 [Dudek, Joanna; Faress, Ahmed; Haley, David W.] Univ Toronto, Dept Psychol, Toronto, ON M5S 1A1, Canada. [Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Haley, DW (reprint author), Univ Toronto, Dept Psychol, Toronto, ON M5S 1A1, Canada. EM d.haley@utoronto.ca FU NSERC [482469]; NIH, NICHD FX This research was supported by the NSERC Discovery Program through grant 482469 to DH. This work was also supported by the NIH, NICHD to MB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 1 Z9 1 U1 4 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 18 PY 2016 VL 11 IS 5 AR e0154283 DI 10.1371/journal.pone.0154283 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM3ZU UT WOS:000376286100014 PM 27191845 ER PT J AU Saxena, D Spino, M Tricta, F Connelly, J Cracchiolo, BM Hanauske, AR Gandolfi, DD Mathews, MB Karn, J Holland, B Park, MH Pe'ery, T Palumbo, PE Hanauske-Abel, HM AF Saxena, Deepti Spino, Michael Tricta, Fernando Connelly, John Cracchiolo, Bernadette M. Hanauske, Axel-Rainer Gandolfi, Darlene D'Alliessi Mathews, Michael B. Karn, Jonathan Holland, Bart Park, Myung Hee Pe'ery, Tsafi Palumbo, Paul E. Hanauske-Abel, Hartmut M. TI Drug-Based Lead Discovery: The Novel Ablative Antiretroviral Profile of Deferiprone in HIV-1-Infected Cells and in HIV-Infected Treatment-Naive Subjects of a Double-Blind, Placebo-Controlled, Randomized Exploratory Trial SO PLOS ONE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; IRON CHELATOR DEFERIPRONE; CD4(+) T-CELLS; STRUCTURED TREATMENT INTERRUPTIONS; INITIATION-FACTOR 5A; P24 ANTIGEN LEVELS; IN-VITRO; THALASSEMIA MAJOR; GENE-EXPRESSION; DEOXYHYPUSINE HYDROXYLASE AB Antiretrovirals suppress HIV-1 production yet spare the sites of HIV-1 production, the HIV-1 DNA-harboring cells that evade immune detection and enable viral resistance on-drug and viral rebound off-drug. Therapeutic ablation of pathogenic cells markedly improves the outcome of many diseases. We extend this strategy to HIV-1 infection. Using drug-based lead discovery, we report the concentration threshold-dependent antiretroviral action of the medicinal chelator deferiprone and validate preclinical findings by a proof-of-concept double-blind trial. In isolate-infected primary cultures, supra-threshold concentrations during deferiprone monotherapy caused decline of HIV-1 RNA and HIV-1 DNA; did not allow viral breakthrough for up to 35 days on-drug, indicating resiliency against viral resistance; and prevented, for at least 87 days off-drug, viral rebound. Displaying a steep dose-effect curve, deferiprone produced infection-independent deficiency of hydroxylated hypusyl-eIF5A. However, unhydroxylated deoxyhypusyl-eIF5A accumulated particularly in HIV-infected cells; they preferentially underwent apoptotic DNA fragmentation. Since the threshold, ascertained at about 150 mu M, is achievable in deferiprone-treated patients, we proceeded from cell culture directly to an exploratory trial. HIV-1 RNA was measured after 7 days on-drug and after 28 and 56 days off-drug. Subjects who attained supra-threshold concentrations in serum and completed the protocol of 17 oral doses, experienced a zidovudine-like decline of HIV-1 RNA on-drug that was maintained off-drug without statistically significant rebound for 8 weeks, over 670 times the drug's half-life and thus clearance from circulation. The uniform deferiprone threshold is in agreement with mapping of, and crystallographic 3D-data on, the active site of deoxyhypusyl hydroxylase (DOHH), the eIF5A-hydroxylating enzyme. We propose that deficiency of hypusine-containing eIF5A impedes the translation of mRNAs encoding proline cluster ('polyproline')-containing proteins, exemplified by Gag/p24, and facilitated by the excess of deoxyhypusine-containing eIF5A, releases the innate apoptotic defense of HIV-infected cells from viral blockade, thus depleting the cellular reservoir of HIV-1 DNA that drives breakthrough and rebound. C1 [Saxena, Deepti; Palumbo, Paul E.; Hanauske-Abel, Hartmut M.] Rutgers State Univ, New Jersey Med Sch, Dept Pediat, Newark, NJ 07102 USA. [Spino, Michael] Univ Toronto, Leslie Dan Fac Pharm, Toronto, ON, Canada. [Spino, Michael; Tricta, Fernando; Connelly, John] ApoPharma Inc, Toronto, ON, Canada. [Cracchiolo, Bernadette M.; Hanauske-Abel, Hartmut M.] Rutgers State Univ, Dept Obstet Gynecol & Womens Hlth, New Jersey Med Sch, Newark, NJ 07102 USA. [Hanauske, Axel-Rainer] Asklepios Klin St Georg, Ctr Oncol, Hamburg, Germany. [Hanauske, Axel-Rainer] Asklepios Klin St Georg, Med Clin 3, Hamburg, Germany. [Gandolfi, Darlene D'Alliessi] Manhattanville Coll, Dept Chem, Purchase, NY USA. [Mathews, Michael B.; Holland, Bart; Pe'ery, Tsafi] Rutgers State Univ, Dept Med, New Jersey Med Sch, Newark, NJ 07102 USA. [Karn, Jonathan] Case Western Reserve Univ, Sch Med, Dept Mol Biol & Microbiol, Cleveland, OH 44106 USA. [Park, Myung Hee] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Hanauske-Abel, Hartmut M.] Rutgers State Univ, New Jersey Med Sch, Dept Microbiol Biochem & Mol Genet, Newark, NJ 07102 USA. [Saxena, Deepti; Palumbo, Paul E.] Geisel Sch Med Dartmouth, Sect Infect Dis & Int Hlth, Lebanon, NH USA. [Hanauske, Axel-Rainer] Eli Lilly & Co, Indianapolis, IN 46285 USA. RP Palumbo, PE; Hanauske-Abel, HM (reprint author), Rutgers State Univ, New Jersey Med Sch, Dept Pediat, Newark, NJ 07102 USA.; Hanauske-Abel, HM (reprint author), Rutgers State Univ, Dept Obstet Gynecol & Womens Hlth, New Jersey Med Sch, Newark, NJ 07102 USA.; Hanauske-Abel, HM (reprint author), Rutgers State Univ, New Jersey Med Sch, Dept Microbiol Biochem & Mol Genet, Newark, NJ 07102 USA.; Palumbo, PE (reprint author), Geisel Sch Med Dartmouth, Sect Infect Dis & Int Hlth, Lebanon, NH USA. EM Paul.E.Palumbo@dartmouth.edu; hanaushm@njms.rutgers.edu FU Foundation of UMDNJ; State of New Jersey, through its Commission on Cancer Research [05-2405-CCR-EO]; Pediatric AIDS Clinical Trials Group; National Institutes of Health [AI034552, AI060403]; National Institutes of Health, BIRCWH Program [HD-1457]; National Institutes of Health, Division of AIDS [202PVCL05]; Center for AIDS Research (CFAR) at Case Western Reserve University-University Hospitals [P30 AI036219]; ApoPharma Inc., Toronto, Canada FX The preclinical experiments were funded in part by the Foundation of UMDNJ; the State of New Jersey, through its Commission on Cancer Research (05-2405-CCR-EO); the Pediatric AIDS Clinical Trials Group; the National Institutes of Health (AI034552 and AI060403), its BIRCWH Program (HD-1457) and its Division of AIDS (202PVCL05); and the Center for AIDS Research (CFAR) at Case Western Reserve University-University Hospitals (P30 AI036219). The contributions of ARH to this work predate the current employment by Eli Lilly and Company, Indianapolis, USA; the latter did not play a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript; did not provide financial support; and has been listed solely to identify "Current Affiliation" as stated. The clinical trial was funded by ApoPharma Inc., Toronto, Canada, whose employees MS, FT, and JC received funding in the form of salary. MS, FT, and JC also collaborated with university-employed colleagues (PEP and HMHA) on the design of that trial and independently collected the trial data. The university-employed scientists HMHA, BH, PEP, ARH, and BMC lead the statistical analysis of these data, unconditionally provided by ApoPharma, and independently decided on their publication, without involvement of any financial instruments or support by ApoPharma in the form of authors' salaries, consultation fees, non-financial assistance, or research materials other than medicine-grade deferiprone. NR 221 TC 1 Z9 1 U1 5 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 18 PY 2016 VL 11 IS 5 AR e0154842 DI 10.1371/journal.pone.0154842 PG 45 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM3ZU UT WOS:000376286100032 PM 27191165 ER PT J AU Sliwiak, J Dauter, Z Jaskolski, M AF Sliwiak, Joanna Dauter, Zbigniew Jaskolski, Mariusz TI Crystal Structure of Hyp-1, a Hypericum perforatum PR-10 Protein, in Complex with Melatonin SO FRONTIERS IN PLANT SCIENCE LA English DT Article DE pathogenesis-related protein; PR-10; phytohormone; ligand binding; cytokinin ID PATHOGENESIS-RELATED PROTEINS; BET V 1; X-RAY; CYTOKININ; BINDING; BIOSYNTHESIS; PLANTS; L.; ALLERGEN; EXPRESSION AB Hyp-1, a PR-10-fold protein from Hypericum perforatum, was crystallized in complex with melatonin (MEL). The structure confirms the conserved protein fold and the presence of three unusual ligand binding sites, two of which are internal chambers (1,2), while the third one (3) is formed as an invagination of the protein surface. The MEL ligand in site 1 is well defined while that in site 3 seems to be rotating between the side chains of Lys33 and Tyr150 that act as a molecular vise. The patch of electron density in site 2 does not allow unambiguous modeling of a melatonin molecule but suggests a possible presence of its degradation product. This pattern of ligand occupation is reproducible in repeated crystallization/structure determination experiments. Although the binding of melatonin by Hyp-1 does not appear to be very strong (for example, MEL cannot displace the artificial fluorescence probe ANS), it is strong enough to suggest a physiological role of this interaction. For example, trans-zeatin, which is a common ligand of PR-10 proteins, does not overcompete melatonin for binding to Hyp-1 as it does not affect the crystallization process of the Hyp-1/MEL complex, and among a number of potential natural mediators tested, melatonin was the only one to form a crystalline complex with Hyp-1 with the use of standard crystallization screens. Hyp-1 is the second protein in the Protein Data Bank for which melatonin binding has been demonstrated crystallographically, the first one being human quinone reductase. C1 [Sliwiak, Joanna; Jaskolski, Mariusz] Polish Acad Sci, Inst Bioorgan Chem, Ctr Biocrystallog Res, Poznan, Poland. [Dauter, Zbigniew] Argonne Natl Lab, Synchrotron Radiat Res Sect, NCI, 9700 S Cass Ave, Argonne, IL 60439 USA. [Jaskolski, Mariusz] Adam Mickiewicz Univ, Fac Chem, Dept Crystallog, Grunwaldzka 6, PL-60780 Poznan, Poland. RP Jaskolski, M (reprint author), Polish Acad Sci, Inst Bioorgan Chem, Ctr Biocrystallog Res, Poznan, Poland.; Jaskolski, M (reprint author), Adam Mickiewicz Univ, Fac Chem, Dept Crystallog, Grunwaldzka 6, PL-60780 Poznan, Poland. EM mariuszj@amu.edu.pl FU US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; European Union within the European Regional Developmental Fund; Polish National Science Centre [2013/10/M/NZ1/00251]; Polish Ministry of Science and Higher Education under the KNOW program FX X-Ray diffraction data were collected at the Southeast Regional Collaborative Access Team (SER-CAT) beamline of the APS/ANL. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38. Financial support of the project was provided by the European Union within the European Regional Developmental Fund and by the Polish National Science Centre (grant No. 2013/10/M/NZ1/00251). This publication was supported by the Polish Ministry of Science and Higher Education under the KNOW program. NR 44 TC 0 Z9 0 U1 1 U2 8 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-462X J9 FRONT PLANT SCI JI Front. Plant Sci. PD MAY 18 PY 2016 VL 7 AR 668 DI 10.3389/fpls.2016.00668 PG 10 WC Plant Sciences SC Plant Sciences GA DL9QF UT WOS:000375977100003 PM 27242869 ER PT J AU Stempel, AV Stumpf, A Zhang, HY Ozdogan, T Pannasch, U Theis, AK Otte, DM Wojtalla, A Racz, I Ponomarenko, A Xi, ZX Zimmer, A Schmitz, D AF Stempel, A. Vanessa Stumpf, Alexander Zhang, Hai-Ying Oezdogan, Tugba Pannasch, Ulrike Theis, Anne-Kathrin Otte, David-Marian Wojtalla, Alexandra Racz, Ildiko Ponomarenko, Alexey Xi, Zheng-Xiong Zimmer, Andreas Schmitz, Dietmar TI Cannabinoid Type 2 Receptors Mediate a Cell Type-Specific Plasticity in the Hippocampus SO NEURON LA English DT Article ID LONG-TERM POTENTIATION; CB2 RECEPTORS; GAMMA OSCILLATIONS; SYNAPTIC-TRANSMISSION; PYRAMIDAL NEURONS; RAT-BRAIN; GROUP-I; GLUTAMATE RECEPTORS; INHIBITORY SYNAPSES; MEMBRANE-PROPERTIES AB Endocannabinoids (eCBs) exert major control over neuronal activity by activating cannabinoid receptors (CBRs). The functionality of the eCB system is primarily ascribed to the well-documented retrograde activation of presynaptic CB(1)Rs. We find that action potential-driven eCB release leads to a long-lasting membrane potential hyperpolarization in hippocampal principal cells that is independent of CB(1)Rs. The hyperpolarization, which is specific to CA3 and CA2 pyramidal cells (PCs), depends on the activation of neuronal CB(2)Rs, as shown by a combined pharmacogenetic and immunohistochemical approach. Upon activation, they modulate the activity of the sodium-bicarbonate co-transporter, leading to a hyperpolarization of the neuron. CB2R activation occurred in a purely self-regulatory manner, robustly altered the input/output function of CA3 PCs, and modulated gamma oscillations in vivo. To conclude, we describe a cell type-specific plasticity mechanism in the hippocampus that provides evidence for the neuronal expression of CB(2)Rs and emphasizes their importance in basic neuronal transmission. C1 [Stempel, A. Vanessa; Stumpf, Alexander; Oezdogan, Tugba; Pannasch, Ulrike; Theis, Anne-Kathrin; Schmitz, Dietmar] Neurosci Res Ctr NWFZ, D-10117 Berlin, Germany. [Zhang, Hai-Ying; Xi, Zheng-Xiong] NIDA, Intramural Res Program, Baltimore, MD 21224 USA. [Otte, David-Marian; Wojtalla, Alexandra; Racz, Ildiko; Zimmer, Andreas] Univ Bonn, Inst Mol Psychiat, D-53127 Bonn, Germany. [Ponomarenko, Alexey; Schmitz, Dietmar] NeuroCure Cluster Excellence, D-10117 Berlin, Germany. [Ponomarenko, Alexey] Leibniz Inst Mol Pharmakol FMP, D-13125 Berlin, Germany. [Schmitz, Dietmar] Bernstein Ctr Computat Neurosci BCCN, D-10115 Berlin, Germany. [Schmitz, Dietmar] Ctr Neurodegenerat Dis DZNE, D-10117 Berlin, Germany. [Schmitz, Dietmar] Einstein Ctr Neurosci, D-10117 Berlin, Germany. [Stempel, A. Vanessa] Med Res Council MRC, Mol Biol Lab, Cambridge CB2 0QH, England. RP Stempel, AV; Schmitz, D (reprint author), Neurosci Res Ctr NWFZ, D-10117 Berlin, Germany.; Schmitz, D (reprint author), NeuroCure Cluster Excellence, D-10117 Berlin, Germany.; Schmitz, D (reprint author), Bernstein Ctr Computat Neurosci BCCN, D-10115 Berlin, Germany.; Schmitz, D (reprint author), Ctr Neurodegenerat Dis DZNE, D-10117 Berlin, Germany.; Schmitz, D (reprint author), Einstein Ctr Neurosci, D-10117 Berlin, Germany.; Stempel, AV (reprint author), Med Res Council MRC, Mol Biol Lab, Cambridge CB2 0QH, England. EM vstempel@mrc-lmb.cam.ac.uk; dietmar.schmitz@charite.de OI Zhang, Haiying/0000-0003-0593-5940 FU NeuroCure; ImmunoSensation Clusters of Excellence; BCCN; DZNE; Einstein Foundation; Deutsche Forschungsgemeinschaft [FOR926, SFB665, SFB958, SPP1665, GRK1123] FX We thank S. Rieckmann and A. Schonherr for technical assistance; G. Buzsaki, K. Diba, and R. Schmidt for sharing their data; C. Bohm and F.W. Johenning for unpublished experiments; and I. Vida, I. Katona, and A. Kulik for their help. Also, we thank J.R. Geiger, U. Heinemann, and members of the D.S. lab for helpful discussions; N. Maier for critical comments on an early version of the manuscript; and D. Evans for proofreading the final version. This work was supported by the NeuroCure and the ImmunoSensation Clusters of Excellence, the BCCN, the DZNE, the Einstein Foundation, and the Deutsche Forschungsgemeinschaft (FOR926, SFB665, SFB958, SPP1665, and GRK1123). NR 74 TC 13 Z9 13 U1 5 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD MAY 18 PY 2016 VL 90 IS 4 BP 795 EP 809 DI 10.1016/j.neuron.2016.03.034 PG 15 WC Neurosciences SC Neurosciences & Neurology GA DM3OK UT WOS:000376255600013 PM 27133464 ER PT J AU Lemos, JC Friend, DM Kaplan, AR Shin, JH Rubinstein, M Kravitz, AV Alvarez, VA AF Lemos, Julia C. Friend, Danielle M. Kaplan, Alanna R. Shin, Jung Hoon Rubinstein, Marcelo Kravitz, Alexxai V. Alvarez, Veronica A. TI Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor Signaling SO NEURON LA English DT Article ID MEDIUM SPINY NEURONS; BASAL GANGLIA; PARKINSONS-DISEASE; STRIATAL NEURONS; DORSAL STRIATUM; STRIATOPALLIDAL NEURONS; DIFFERENTIAL REGULATION; MOTOR BEHAVIORS; DEFICIENT MICE; MESSENGER-RNA AB Bradykinesia is a prominent phenotype of Parkinson's disease, depression, and other neurological conditions. Disruption of dopamine (DA) transmission plays an important role, but progress in understanding the exact mechanisms driving slowness of movement has been impeded due to the heterogeneity of DA receptor distribution on multiple cell types within the striatum. Here we show that selective deletion of DA D2 receptors (D2Rs) from indirect-pathway medium spiny neurons (iMSNs) is sufficient to impair locomotor activity, phenocopying DA depletion models of Parkinson's disease, despite this mouse model having intact DA transmission. There was a robust enhancement of GABAergic transmission and a reduction of in vivo firing in striatal and pallidal neurons. Mimicking D2R signaling in iMSNs with Gi-DREADDs restored the level of tonic GABAergic transmission and rescued the motor deficit. These findings indicate that DA, through D2R activation in iMSNs, regulates motor output by constraining the strength of GABAergic transmission. C1 [Lemos, Julia C.; Kaplan, Alanna R.; Shin, Jung Hoon; Alvarez, Veronica A.] NIAAA, NIH, Bethesda, MD 20892 USA. [Friend, Danielle M.; Kravitz, Alexxai V.] NIDDK, NIH, Bethesda, MD 20892 USA. [Kravitz, Alexxai V.] NIDA, NIH, Bethesda, MD 20892 USA. [Rubinstein, Marcelo] Consejo Nacl Invest Cient & Tecn, Inst Invest Ingn Genet & Biol Mol, C1428ADN, RA-1033 Buenos Aires, DF, Argentina. [Rubinstein, Marcelo] Univ Buenos Aires, FCEN, C1428EGA, Buenos Aires, DF, Argentina. [Rubinstein, Marcelo] Univ Michigan, Sch Med, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA. RP Alvarez, VA (reprint author), NIAAA, NIH, Bethesda, MD 20892 USA. EM alvarezva@mail.nih.gov RI Alvarez, Veronica /E-9745-2015; OI Alvarez, Veronica /0000-0003-2611-8675; Kaplan, Alanna/0000-0002-2612-4736 FU Intramural Research Program of NIAAA; Intramural Research Program of NINDS [ZIA-AA000421]; NIDDK [ZIA-DK075096]; NIGMS and PRAT fellowship; ANPCYT-Mincyt; Universidad de Buenos Aires; Tourette Syndrome Association FX Funded by Intramural Research Programs of NIAAA, NINDS (ZIA-AA000421) to V.A.A.; NIDDK (ZIA-DK075096) to A.V.K.; NIGMS and PRAT fellowship to J.C.L.; ANPCYT-Mincyt, Universidad de Buenos Aires; and Tourette Syndrome Association to M.R. We are grateful to Roland Bock, who wrote the Igor procedures used for voltammetry and to Dr. Ono for sharing the confocal microscope. We thank Dr. Lovinger and members of the V.A.A. lab for helpful comments and Drs. Roth (UNC) and Deisseroth (Stanford) for generously providing hM4Di and ChR2 constructs. NR 59 TC 4 Z9 5 U1 5 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD MAY 18 PY 2016 VL 90 IS 4 BP 824 EP 838 DI 10.1016/j.neuron.2016.04.040 PG 15 WC Neurosciences SC Neurosciences & Neurology GA DM3OK UT WOS:000376255600015 PM 27196975 ER PT J AU Grillon, C Robinson, OJ Mathur, A Ernst, M AF Grillon, Christian Robinson, Oliver J. Mathur, Ambika Ernst, Monique TI Effect of attention control on sustained attention during induced anxiety SO COGNITION & EMOTION LA English DT Article DE Anxiety; SART; Threat of shock; Vigilance; Stress ID WORKING-MEMORY CAPACITY; RESPONSE-INHIBITION; EXECUTIVE-CONTROL; WANDERING MINDS; TRAIT ANXIETY; PERFORMANCE; TASK; TEMPERAMENT; VARIABILITY; THREAT AB Anxiety has wide-reaching and complex effects on cognitive performance. Although it can intrude on cognition and interfere with performance, it can also facilitate information processing and behavioural responses. In a previous study, we showed that anxiety induced by threat of shock facilitates performance on the Sustained Attention to Response Task, a vigilance test, which probes response inhibition to infrequent nogo stimuli. The present study sought to identify factors that may have contributed to such improved performance, including on- and off-task thinking (assessed with thought probes) and individual differences in attention control, as measured with the Attention Control Scale. Replicating our prior finding, we showed that shock threat significantly reduced errors of commission on the nogo trials. However, we extended this finding in demonstrating that this effect was driven by subjects with low attention control. We therefore confirm that anxiety increases inhibitory control of prepotent responses-a mechanism which is adaptive under threat-and show that this effect is greater in those who rely more upon such prepotent responding, i.e., those with low attentional control. C1 [Grillon, Christian; Robinson, Oliver J.; Mathur, Ambika; Ernst, Monique] NIMH, Sect Neurobiol Fear & Anxiety, NIH, 15K North Dr,Bldg 15K,Room 203,MSC 2670, Bethesda, MD 20892 USA. [Robinson, Oliver J.] UCL, Inst Cognit Neurosci, London, England. [Mathur, Ambika] Penn State Univ, Dept Biobehav Hlth, University Pk, PA 16802 USA. RP Grillon, C (reprint author), NIMH, Sect Neurobiol Fear & Anxiety, NIH, 15K North Dr,Bldg 15K,Room 203,MSC 2670, Bethesda, MD 20892 USA. EM Christian.grillon@nih.gov OI Robinson, Oliver/0000-0002-3100-1132 FU National Institutes of Mental Health [MH002798, 01-M-0185] FX This work was supported by the Intramural Research Program of the National Institutes of Mental Health [grant number MH002798] (Protocol 01-M-0185). NR 64 TC 3 Z9 3 U1 15 U2 55 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0269-9931 EI 1464-0600 J9 COGNITION EMOTION JI Cogn. Emot. PD MAY 18 PY 2016 VL 30 IS 4 BP 700 EP 712 DI 10.1080/02699931.2015.1024614 PG 13 WC Psychology, Experimental SC Psychology GA DG6OL UT WOS:000372205100008 PM 25899613 ER PT J AU Maass, T Marquardt, J Lee, JS Krupp, M Scholz-Kreisel, P Mogler, C Schirmacher, P Muller, M Westphal, H Galle, PR Teufel, A AF Maass, Thorsten Marquardt, Jens Lee, Ju-Seog Krupp, Markus Scholz-Kreisel, Peter Mogler, Carolin Schirmacher, Peter Mueller, Martina Westphal, Heiner Galle, Peter R. Teufel, Andreas TI Increased liver carcinogenesis and enrichment of stem cell properties in livers of Dickkopf 2 (Dkk2) deleted mice SO ONCOTARGET LA English DT Article DE transcriptomics profiling; prognostic signature; genetic signature; Dkk2; stem cells ID WNT ANTAGONIST DICKKOPF-1; HEPATOCELLULAR-CARCINOMA; HEPATOCYTE PROLIFERATION; CANCER DEVELOPMENT; SIGNALING PATHWAY; BETA-CATENIN; ADULT MICE; GENE; EXPRESSION; HCC AB Dkk2 a antagonist of the Wnt/beta-catenin-signaling pathway was shown to be silenced in diverse cancers. More recent data indicate that Dkk family members may also possess functions independent of Wnt-signaling during carcinogenesis. The detailed biological function of Dkks and its relevance for liver cancer is unknown. We analyzed the effects of a genetic deletion of Dkk2 (Dkk2(-/-)) in a hepatocarcinogenesis model using DEN/Phenobarbital. Untreated Dkk2(-/-) animals, showed considerable atypia with variation of hepatocyte size and chromatin density. In livers of Dkk2(-/-) mice nodule formation was seen at 9 months of age with focal loss of trabecular architecture and atypical hepatocytes and after DEN induction Dkk2(-/-) mice developed significantly more liver tumors compared to controls. Whole transcriptome analysis of untreated Dkk2(-/-) liver tissue revealed a Dkk2-dependent genetic network involving Wnt/beta-Catenin but also multiple additional oncogenic factors, such as e.g. Pdgf-b, Gdf-15 and Hnf4a. Dkk2(-/-) tumor cells showed a significant deregulation of stemness genes associated with enhanced colony forming properties. Integration of the Dkk2(-/-) signature into human data was strongly associated with patients survival. Dkk2 deletion results in alterations of liver morphology leading to an increased frequency of liver cancer. The associated genetic changes included factors not primarily related to Wnt/beta-Catenin-signaling and correlated with the clinical outcome of HCC-patients. C1 [Maass, Thorsten; Mueller, Martina; Teufel, Andreas] Univ Regensburg, Dept Internal Med 1, D-93053 Regensburg, Germany. [Marquardt, Jens; Scholz-Kreisel, Peter; Galle, Peter R.] Univ Med Ctr Mainz, Dept Med 1, Mainz, Germany. [Lee, Ju-Seog] Univ Texas MD Anderson Canc Ctr, Canc Biol Program, Houston, TX 77030 USA. [Krupp, Markus] Johannes Gutenberg Univ Mainz, Dept Informat, D-55122 Mainz, Germany. [Mogler, Carolin; Schirmacher, Peter] Heidelberg Univ, Inst Pathol, Neuenheimer Feld 220, Heidelberg, Germany. [Westphal, Heiner] NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. RP Teufel, A (reprint author), Univ Regensburg, Dept Internal Med 1, D-93053 Regensburg, Germany. EM andreas.teufel@ukr.de FU NCI NIH HHS [P30 CA016672] NR 39 TC 0 Z9 0 U1 4 U2 4 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAY 17 PY 2016 VL 7 IS 20 BP 28903 EP 28913 DI 10.18632/oncotarget.3293 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO4HO UT WOS:000377742600012 PM 25826080 ER PT J AU Boufraqech, M Wei, D Weyemi, U Zhang, LS Quezado, M Kalab, P Kebebew, E AF Boufraqech, Myriem Wei, Darmood Weyemi, Urbain Zhang, Lisa Quezado, Martha Kalab, Petr Kebebew, Electron TI LOX is a novel mitotic spindle-associated protein essential for mitosis SO ONCOTARGET LA English DT Article DE LOX; microtubules; cell cycle; mitosis; cancer ID LYSYL OXIDASE; HISTONE H3; AURORA-B; MICROTUBULE ATTACHMENT; CHROMOSOME ALIGNMENT; CELL; PHOSPHORYLATION; CHECKPOINT; KINETOCHORES; ACTIVATION AB LOX regulates cancer progression in a variety of human malignancies. It is overexpressed in aggressive cancers and higher expression of LOX is associated with higher cancer mortality. Here, we report a new function of LOX in mitosis. We show that LOX co-localizes to mitotic spindles from metaphase to telophase, and p-H3((Ser10))-positive cells harbor strong LOX staining. Further, purification of mitotic spindles from synchronized cells show that LOX fails to bind to microtubules in the presence of nocodazole, whereas paclitaxel treated samples showed enrichment in LOX expression, suggesting that LOX binds to stabilized microtubules. LOX knockdown leads to G2/M phase arrest; reduced p-H3((Ser10)), cyclin B1, CDK1, and Aurora B. Moreover, LOX knockdown significantly increased sensitivity of cancer cells to chemotherapeutic agents that target microtubules. Our findings suggest that LOX has a role in cancer cell mitosis and may be targeted to enhance the activity of microtubule inhibitors for cancer therapy. C1 [Boufraqech, Myriem; Zhang, Lisa; Kebebew, Electron] NCI, Endocrine Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wei, Darmood] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Weyemi, Urbain] NCI, Lab Mol Pharmacol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Quezado, Martha] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kalab, Petr] NCI, Lab Cellular & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kebebew, E (reprint author), NCI, Endocrine Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov FU intramural research program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This work was supported by the intramural research program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 32 TC 0 Z9 0 U1 2 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAY 17 PY 2016 VL 7 IS 20 BP 29023 EP 29035 DI 10.18632/oncotarget.8628 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO4HO UT WOS:000377742600022 PM 27296552 ER PT J AU An, R Wang, YS Voeller, D Gower, A Kim, IK Zhang, YW Giaccone, G AF An, Rong Wang, Yisong Voeller, Donna Gower, Arjan Kim, In-Kyu Zhang, Yu-Wen Giaccone, Giuseppe TI CRKL mediates EML4-ALK signaling and is a potential therapeutic target for ALK-rearranged lung adenocarcinoma SO ONCOTARGET LA English DT Article DE EML4-ALK; NSCLC; CRKL; ALK ID ACQUIRED-RESISTANCE; TYROSINE KINASE; BREAST-CANCER; OPEN-LABEL; BCR-ABL; INHIBITOR; CRIZOTINIB; CERITINIB; ONCOGENE; LYMPHOMA AB Anaplastic lymphoma kinase (ALK) gene rearrangements are oncogenic drivers in a small subset of patients with non-small-cell lung cancer (NSCLC). The ALK inhibitors are highly effective in NSCLC patients harboring ALK rearrangements; however, most patients acquire resistance to the therapy following an initial response. Mechanisms of acquired resistance are complex. We used LC-MS/MS-based phosphotyrosinepeptide profiling in the EML4-ALK rearranged H3122 and H2228 cells treated with ALK inhibitors, to identify downstream effectors of ALK. We then used Western blot, siRNA experiments, cell proliferation, viability and migration assays to validate our findings. We identified CRKL as a novel downstream effector of ALK signaling. We demonstrated that CRKL tyrosine phosphorylation was repressed by pharmacological inhibition or small interfering RNA (siRNA) knockdown of ALK in the ALK-rearranged cells. More importantly, CRKL knockdown attenuated their cell proliferation, viability, and migration, but it had no effect on ALK phosphorylation and expression in these cells. Furthermore, CRKL tyrosine phosphorylation was inhibited by dasatinib (an inhibitor of ABL and SRC kinases), which in combination with the ALK inhibitor crizotinib displayed a synergistic inhibitory effect in vitro. In conclusion, our study suggests that CRKL is a key downstream effector of ALK, and combined inhibition of ALK and CRKL may represent an effective strategy for treating ALK-rearranged NSCLC patients. C1 [An, Rong; Wang, Yisong; Voeller, Donna; Giaccone, Giuseppe] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Wang, Yisong; Gower, Arjan; Kim, In-Kyu; Zhang, Yu-Wen; Giaccone, Giuseppe] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. RP Giaccone, G (reprint author), NCI, Ctr Canc Res, Bethesda, MD 20892 USA.; Giaccone, G (reprint author), Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. EM gg496@georgetown.edu RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 FU NIH/NCI; Lombardi Comprehensive Cancer Center/Georgetown University FX We thank Marjan Gucek and Yutao Liu for mass spectrometry analysis. The work was supported by NIH/NCI intramural research program and Lombardi Comprehensive Cancer Center/Georgetown University research fund. NR 34 TC 0 Z9 0 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAY 17 PY 2016 VL 7 IS 20 BP 29199 EP 29210 DI 10.18632/oncotarget.8638 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO4HO UT WOS:000377742600036 PM 27078848 ER PT J AU Buch, ER Rizk, S Nicolo, P Cohen, LG Schnider, A Guggisberg, AG AF Buch, Ethan R. Rizk, Sviatlana Nicolo, Pierre Cohen, Leonardo G. Schnider, Armin Guggisberg, Adrian G. TI Predicting motor improvement after stroke with clinical assessment and diffusion tensor imaging SO NEUROLOGY LA English DT Editorial Material ID PROPORTIONAL RECOVERY; ISCHEMIC-STROKE; INTEGRITY; DEPENDS AB Reliable predictors of motor improvement in individual patients after stroke are scarce. Acute determination of upper limb Fugl-Meyer assessment (FMA) appears to have predictive value.(1,2) This approach predicts that patients will improve approximately 70% of the difference between the maximum upper extremity FMA score and the score first tested for a given individual (recovery-typical). However, a significant subset of patients improves much less than predicted (recovery-atypical). Alternative models using other techniques like diffusion tensor imaging (DTI)(3,4) also fail to predict recovery in some patients. Here, we show that a combination of FMA and DTI obtained in the first weeks after stroke accurately discriminate between recovery-typical and recovery-atypical patients. In addition, we identify an alternative set of model parameters required for predictions in the recovery-atypical subgroup. C1 [Buch, Ethan R.; Cohen, Leonardo G.] NINDS, Human Cort Physiol & Neurorehabil Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Rizk, Sviatlana; Nicolo, Pierre; Schnider, Armin; Guggisberg, Adrian G.] Univ Hosp, Basel, Switzerland. [Rizk, Sviatlana; Nicolo, Pierre; Schnider, Armin; Guggisberg, Adrian G.] Univ Geneva, CH-1211 Geneva 4, Switzerland. RP Guggisberg, AG (reprint author), Univ Hosp, Basel, Switzerland.; Guggisberg, AG (reprint author), Univ Geneva, CH-1211 Geneva 4, Switzerland. EM auggis@gmail.com OI Guggisberg, Adrian/0000-0001-7178-7793 NR 7 TC 2 Z9 2 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAY 17 PY 2016 VL 86 IS 20 BP 1924 EP 1925 DI 10.1212/WNL.0000000000002675 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA DN0US UT WOS:000376782000015 PM 27164664 ER PT J AU Liang, XY Schnaper, W Matsusaka, T Pastan, I Ledbetter, S Hayashida, T AF Liang, Xiaoyan Schnaper, William Matsusaka, Taiji Pastan, Ira Ledbetter, Steve Hayashida, Tomoko TI Anti-TGF-beta Antibody, 1D11, Ameliorates Glomerular Fibrosis in Mouse Models after the Onset of Proteinuria SO PLOS ONE LA English DT Article ID GROWTH-FACTOR-BETA; MATRIX GENE-EXPRESSION; PODOCYTE INJURY; EXTRACELLULAR-MATRIX; TRANSFORMING GROWTH-FACTOR-BETA-1; EXPERIMENTAL GLOMERULONEPHRITIS; MESENCHYMAL TRANSITION; ADRIAMYCIN NEPHROPATHY; DIABETIC-NEPHROPATHY; NEPHROTIC SYNDROME AB Fibrosis is a final common pathway leading to loss of kidney function, in which the fibrogenic cytokine, transforming growth factor beta (TGF-beta), plays a central role. While previous studies showed that TGF-beta antagonism by various means prevents fibrosis in mouse models, clinical approaches based on these findings remain elusive. 1D11 is a neutralizing antibody to all three isoforms of TGF-beta. In both adriamycin (ADR)-induced nephropathy and NEP25 podocyte ablation nephropathy, thrice-weekly intraperitoneal administration of 1D11 from the day of disease induction until the mice were sacrificed (day 14 for ADR and day 28 for NEP25), significantly reduced glomerular COL1A2 mRNA accumulation and histological changes. Consistent with our previous findings, proteinuria remained overt in the mice treated with 1D11, suggesting distinct mechanisms for proteinuria and fibrogenesis. Podocyte numbers determined by WT1 staining were significantly reduced in NEP25-model glomeruli as expected, while WT1-positive cells were preserved in mice receiving 1D11. Even when 1D11 was administered after the onset of proteinuria on day 3, 1D11 preserved WT1-positive cell numbers in glomeruli and significantly reduced glomerular scar score (2.5 +/- 0.2 [control IgG] vs. 1.8 +/- 0.2 [1D11], P < 0.05) and glomerular COL1A2 mRNA expression (19.3 +/- 4.4 [control IgG] vs. 8.4 +/- 2.4 [1D11] fold increase over the healthy control, P < 0.05). Transmission electron microscopy revealed loss of podocytes and denuded glomerular basement membrane in NEP25 mice with disease, whereas podocytes remained attached to the basement membrane, though effaced and swollen, in those receiving 1D11 from day 3. Together, these data suggest that TGF-beta neutralization by 1D11 prevents glomerular fibrosis even when started after the onset of proteinuria. While overt proteinuria and podocyte effacement persist, 1D11 prevents total podocytes detachment, which might be a key event activating fibrogenic events in glomeruli. C1 [Liang, Xiaoyan; Schnaper, William; Hayashida, Tomoko] Northwestern Univ, Dept Pediat, Feinberg Sch Med, Chicago, IL 60611 USA. [Matsusaka, Taiji] Tokai Univ, Sch Med, Dept Internal Med, Isehara, Kanagawa 25911, Japan. [Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, Bldg 37, Bethesda, MD 20892 USA. [Ledbetter, Steve] Sanofi Genzyme R&D Ctr, Framingham, MA USA. RP Hayashida, T (reprint author), Northwestern Univ, Dept Pediat, Feinberg Sch Med, Chicago, IL 60611 USA. EM hayashida@northwestern.edu OI Hayashida, Tomoko/0000-0002-4160-7859 FU National Institute of Diabetes and Digestive and Kidney Disease [R01-DK049362]; Intramural Research Program of the National Institute of Health, National Cancer Institute, Center for Cancer Research; National Cancer Institute [CCSG P30 CA060553] FX The present work was supported in part by Grant R01-DK049362 (HWS) from National Institute of Diabetes and Digestive and Kidney Disease and by the Intramural Research Program of the National Institute of Health, National Cancer Institute, Center for Cancer Research (IP). The Center for Advanced Microscopy and Mouse Histology and Phenotyping Laboratory of the Northwestern University are supported by National Cancer Institute CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. S Ledbetter was an employee of Sanofi/Genzyme. Sanofi/Genzyme provided support in the form of salaries for authors [SL], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 62 TC 2 Z9 2 U1 7 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 17 PY 2016 VL 11 IS 5 AR e0155534 DI 10.1371/journal.pone.0155534 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM3YJ UT WOS:000376282300042 PM 27187580 ER PT J AU Zvezdova, E Mikolajczak, J Garreau, A Marcellin, M Rigal, L Lee, J Choi, S Blaize, G Argenty, J Familiades, J Li, LQ de Peredo, AG Burlet-Schiltz, O Love, PE Lesourne, R AF Zvezdova, Ekaterina Mikolajczak, Judith Garreau, Anne Marcellin, Marlene Rigal, Lise Lee, Jan Choi, Seeyoung Blaize, Gaetan Argenty, Jeremy Familiades, Julien Li, Liqi de Peredo, Anne Gonzalez Burlet-Schiltz, Odile Love, Paul E. Lesourne, Renaud TI Themis1 enhances T cell receptor signaling during thymocyte development by promoting Vav1 activity and Grb2 stability SO SCIENCE SIGNALING LA English DT Article ID TRANSMEMBRANE ADAPTER PROTEIN; POSITIVE SELECTION; PHOSPHOLIPASE C-GAMMA-1; TYROSINE PHOSPHATASE; NEGATIVE SELECTION; ACTIVATION; TCR; SLP-76; SHP-1; LAT AB The T cell signaling protein Themis1 is essential for the positive and negative selection of thymocytes in the thymus. Although the developmental defect that results from the loss of Themis1 suggests that it enhances T cell receptor (TCR) signaling, Themis1 also recruits Src homology 2 domain-containing phosphatase-1 (SHP-1) to the vicinity of TCR signaling complexes, suggesting that it has an inhibitory role in TCR signaling. We used TCR signaling reporter mice and quantitative proteomics to explore the role of Themis1 in developing T cells. We found that Themis1 acted mostly as a positive regulator of TCR signaling in vivo when receptors were activated by positively selecting ligands. Proteomic analysis of the Themis1 interactome identified SHP-1, the TCR-associated adaptor protein Grb2, and the guanine nucleotide exchange factor Vav1 as the principal interacting partners of Themis1 in isolated mouse thymocytes. Analysis of TCR signaling in Themis1-deficient and Themis1-overexpressing mouse thymocytes demonstrated that Themis1 promoted Vav1 activity both in vitro and in vivo. The reduced activity of Vav1 and the impaired T cell development in Themis1(-/-) mice were due in part to increased degradation of Grb2, which suggests that Themis1 is required to maintain the steady-state abundance of Grb2 in thymocytes. Together, these data suggest that Themis1 acts as a positive regulator of TCR signaling in developing T cells, and identify a mechanism by which Themis1 regulates thymic selection. C1 [Zvezdova, Ekaterina; Lee, Jan; Choi, Seeyoung; Li, Liqi; Love, Paul E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular & Dev Biol, Bethesda, MD 20892 USA. [Mikolajczak, Judith; Garreau, Anne; Rigal, Lise; Blaize, Gaetan; Argenty, Jeremy; Familiades, Julien; Lesourne, Renaud] Ctr Physiopathol Toulouse Purpan, F-31300 Toulouse, France. [Mikolajczak, Judith; Garreau, Anne; Rigal, Lise; Blaize, Gaetan; Argenty, Jeremy; Familiades, Julien; Lesourne, Renaud] INSERM, U1043, F-31300 Toulouse, France. [Mikolajczak, Judith; Garreau, Anne; Rigal, Lise; Blaize, Gaetan; Argenty, Jeremy; Familiades, Julien; Lesourne, Renaud] CNRS, U5282, F-31300 Toulouse, France. [Mikolajczak, Judith; Garreau, Anne; Rigal, Lise; Blaize, Gaetan; Argenty, Jeremy; Familiades, Julien; Lesourne, Renaud] Univ Toulouse 3, Univ Toulouse, F-31300 Toulouse, France. [Marcellin, Marlene; de Peredo, Anne Gonzalez; Burlet-Schiltz, Odile] Univ Toulouse 3, Univ Toulouse, CNRS, Inst Pharmacol & Biol Struct, F-31077 Toulouse, France. RP Lesourne, R (reprint author), Ctr Physiopathol Toulouse Purpan, F-31300 Toulouse, France.; Lesourne, R (reprint author), INSERM, U1043, F-31300 Toulouse, France.; Lesourne, R (reprint author), CNRS, U5282, F-31300 Toulouse, France.; Lesourne, R (reprint author), Univ Toulouse 3, Univ Toulouse, F-31300 Toulouse, France. EM renaud.lesourne@inserm.fr RI Lesourne, Renaud/M-1855-2014 FU INSERM; Sanofi (Avenir grant); Intramural Research Program of the Eunice Kennedy Shriver, National Institute of Child Health and Human Development; Fondation pour la Recherche sur la Sclerose en Plaque (ARSEP); Marie Curie International Reintegration Grant; French Ministry of Higher Education and Research; Region Midi-Pyrenees; Fonds Europeens de Developpement Regional, FEDER; Toulouse metropole; French Ministry of Research; Investissement d'Avenir Infrastructures Nationales en Biologie et Sante program (ProFI); Investissement d'Avenir Infrastructures Nationales en Biologie et Sante program (Proteomics French Infrastructure project) [ANR-10-INBS-08] FX This work was supported by INSERM and Sanofi (Avenir grant to R.L.); the Intramural Research Program of the Eunice Kennedy Shriver, National Institute of Child Health and Human Development; the Fondation pour la Recherche sur la Sclerose en Plaque (ARSEP); a Marie Curie International Reintegration Grant (R.L.); the French Ministry of Higher Education and Research (PhD fellowships for A.G., G.B., and J.A.); the Region Midi-Pyrenees; the Fonds Europeens de Developpement Regional, FEDER; the Toulouse metropole; and the French Ministry of Research with the Investissement d'Avenir Infrastructures Nationales en Biologie et Sante program (ProFI, Proteomics French Infrastructure project, ANR-10-INBS-08). NR 47 TC 5 Z9 5 U1 1 U2 4 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1945-0877 EI 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD MAY 17 PY 2016 VL 9 IS 428 AR ra51 DI 10.1126/scisignal.aad1576 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DM6MQ UT WOS:000376467300003 PM 27188442 ER PT J AU Zhang, Y Chen, Y Gucek, M Xu, H AF Zhang, Yi Chen, Yong Gucek, Marjan Xu, Hong TI The mitochondrial outer membrane protein MDI promotes local protein synthesis and mtDNA replication SO EMBO JOURNAL LA English DT Article DE oogenesis; DNA replication; protein synthesis ID MESSENGER-RNA TRANSLATION; DNA COPY NUMBER; DROSOPHILA-MELANOGASTER; YEAST MITOCHONDRIA; IN-SITU; OOGENESIS; GENOME; KINASE; CELLS; PHOSPHORYLATION AB Early embryonic development features rapid nuclear DNA replication cycles, but lacks mtDNA replication. To meet the high-energy demands of embryogenesis, mature oocytes are furnished with vast amounts of mitochondria and mtDNA. However, the cellular machinery driving massive mtDNA replication in ovaries remains unknown. Here, we describe a Drosophila AKAP protein, MDI that recruits a translation stimulator, La-related protein (Larp), to the mitochondrial outer membrane in ovaries. The MDI-Larp complex promotes the synthesis of a subset of nuclear-encoded mitochondrial proteins by cytosolic ribosomes on the mitochondrial surface. MDI-Larp's targets include mtDNA replication factors, mitochondrial ribosomal proteins, and electron-transport chain subunits. Lack of MDI abolishes mtDNA replication in ovaries, which leads to mtDNA deficiency in mature eggs. Targeting Larp to the mitochondrial outer membrane independently of MDI restores local protein synthesis and rescues the phenotypes of mdi mutant flies. Our work suggests that a selective translational boost by the MDI-Larp complex on the outer mitochondrial membrane might be essential for mtDNA replication and mitochondrial biogenesis during oogenesis. C1 [Zhang, Yi; Xu, Hong] NHLBI, Mol Genet Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Chen, Yong; Gucek, Marjan] NHLBI, Prote Core, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Xu, H (reprint author), NHLBI, Mol Genet Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM hong.xu@nih.gov RI Xu, Hong/H-9997-2016 OI Xu, Hong/0000-0003-1049-1184 FU NHLBI FX We thank F Chanut and T Finkel for their comments and editing on the manuscript, R Balaban for the discussion on the work, Bloomington Drosophila Stock Center for various fly lines, B Tom and R Hogg for technical assistance on the polysomal analyses, E Matsuura for Drosophila TFAM antibody, D Glover for larp mutant and antibody, J Jia for PKA mutant fly, Developmental Hybridoma Bank for various antibodies, and Bestgene Inc. and Genetivision Inc. for the Drosophila embryo injection service. This work is supported by NHLBI Intramural Research Program. NR 58 TC 3 Z9 3 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0261-4189 EI 1460-2075 J9 EMBO J JI Embo J. PD MAY 17 PY 2016 VL 35 IS 10 BP 1045 EP 1057 DI 10.15252/embj.201592994 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DM2NW UT WOS:000376184500005 PM 27053724 ER PT J AU Doria-Rose, NA Mascola, JR AF Doria-Rose, Nicole A. Mascola, John R. TI HIV Immunology Goes Out On a Limb SO IMMUNITY LA English DT Editorial Material ID BROADLY NEUTRALIZING ANTIBODIES; HIGH-MANNOSE PATCH; MATURATION; LINEAGE AB Vaccines against HIV most likely need to elicit broadly neutralizing antibodies. In this issue of Immunity, Poignard and colleagues describe the co-evolution of a broadly neutralizing antibody and the virus that triggered it, providing a template for HIV vaccine design. C1 [Doria-Rose, Nicole A.; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Mascola, JR (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jmascola@mail.nih.gov NR 10 TC 1 Z9 1 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD MAY 17 PY 2016 VL 44 IS 5 BP 1088 EP 1090 DI 10.1016/j.immuni.2016.05.004 PG 3 WC Immunology SC Immunology GA DM6QW UT WOS:000376478500013 PM 27192575 ER PT J AU Gao, W Xu, YM Liu, J Ho, M AF Gao, Wei Xu, Yongmei Liu, Jian Ho, Mitchell TI Epitope mapping by a Wnt-blocking antibody: evidence of the Wnt binding domain in heparan sulfate SO SCIENTIFIC REPORTS LA English DT Article ID MOLECULAR-WEIGHT HEPARINS; HEPATOCELLULAR-CARCINOMA; LIVER-CANCER; PROTEOGLYCANS; GLYPICAN-3; RECEPTOR; BIOSYNTHESIS; DISEASE; GROWTH; COMMON AB Heparan sulfate (HS) is a polysaccharide known to modulate many important biological processes, including Wnt signaling. However, the biochemical interaction between HS and Wnt molecules is not well characterized largely due to the lack of suitable methods. To determine the Wnt binding domain in HS, we used a Wnt signaling-inhibitory antibody (HS20) and a panel of synthetic HS oligosaccharides with distinct lengths and sulfation modifications. We found that the binding of HS20 to heparan sulfate required sulfation at both the C2 position (2-O-sulfation) and C6 position (6-O-sulfation). The oligosaccharides with the greatest competitive effect for HS20 binding were between six and eight saccharide residues in length. Additionally, a four residue-long oligosaccharide could also be recognized by HS20 if an additional 3-O-sulfation modification was present. Furthermore, similar oligosaccharides with 2-O, 6-O and 3-O-sulfations showed inhibition for Wnt activation. These results have revealed that HS20 and Wnt recognize a HS structure containing IdoA2S and GlcNS6S, and that the 3-O-sulfation in GlcNS6S3S significantly enhances the binding of both HS20 and Wnt. This study provides the evidence for identifying the Wnt binding domain in HS and suggests a therapeutic approach to target the interaction of Wnt and HS in cancer and other diseases. C1 [Gao, Wei; Ho, Mitchell] NCI, Lab Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gao, Wei] Nanjing Med Univ, Sch Basic Med Sci, Dept Cell Biol, Key Lab Human Funct Genom Jiangsu Prov, Nanjing 210029, Jiangsu, Peoples R China. [Xu, Yongmei; Liu, Jian] Univ N Carolina, Eshelman Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA. RP Ho, M (reprint author), NCI, Lab Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM homi@mail.nih.gov FU Intramural Research Program of NIH; National Cancer Institute (NCI) [Z01 BC010891, ZIA BC010891]; NIH [HL094463-05, GM102137] FX This research was supported by the Intramural Research Program of NIH, National Cancer Institute (NCI) (Z01 BC010891 and ZIA BC010891) to M.H. and by NIH grants (HL094463-05 and GM102137) to J.L. We thank Dr. Jeffrey D. Esko, University of California, San Diego, for providing the pgsA-745 cell line; Dr. Robert J. Linhardt, Rensselaer Polytechnic Institute, for providing bikunin; Dr. Jeremy Nathans, Johns Hopkins School of Medicine, for providing the HEK293 Supertopflash stable cell line; and Dr. Yingzi Yang (Harvard University) for the kind gift of L-cell and L-Wnt3a cell lines. We thank the NIH Fellows Editorial Board and Dr. Bryan Fleming (NCI) for editorial assistance. We also thank Yvonne Ye (NCI) and Jessica Hong (FDA) for proofreading the final manuscript. NR 58 TC 1 Z9 1 U1 3 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAY 17 PY 2016 VL 6 AR 26245 DI 10.1038/srep26245 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DL9QL UT WOS:000375977700001 PM 27185050 ER PT J AU Berkowitz, ND Silverman, IM Childress, DM Kazan, H Wang, LS Gregory, BD AF Berkowitz, Nathan D. Silverman, Ian M. Childress, Daniel M. Kazan, Hilal Wang, Li-San Gregory, Brian D. TI A comprehensive database of high-throughput sequencing-based RNA secondary structure probing data (Structure Surfer) SO BMC BIOINFORMATICS LA English DT Article ID GLOBAL ANALYSIS; TRANSCRIPTOME AB Background: RNA molecules fold into complex three-dimensional shapes, guided by the pattern of hydrogen bonding between nucleotides. This pattern of base pairing, known as RNA secondary structure, is critical to their cellular function. Recently several diverse methods have been developed to assay RNA secondary structure on a transcriptome-wide scale using high-throughput sequencing. Each approach has its own strengths and caveats, however there is no widely available tool for visualizing and comparing the results from these varied methods. Methods: To address this, we have developed Structure Surfer, a database and visualization tool for inspecting RNA secondary structure in six transcriptome-wide data sets from human and mouse (http://tesla.pcbi.upenn.edu/strucuturesurfer/). The data sets were generated using four different high-throughput sequencing based methods. Each one was analyzed with a scoring pipeline specific to its experimental design. Users of Structure Surfer have the ability to query individual loci as well as detect trends across multiple sites. Results: Here, we describe the included data sets and their differences. We illustrate the database's function by examining known structural elements and we explore example use cases in which combined data is used to detect structural trends. Conclusions: In total, Structure Surfer provides an easy-to-use database and visualization interface for allowing users to interrogate the currently available transcriptome-wide RNA secondary structure information for mammals. C1 [Berkowitz, Nathan D.; Silverman, Ian M.; Gregory, Brian D.] Univ Penn, Dept Biol, 433 S Univ Ave, Philadelphia, PA 19104 USA. [Berkowitz, Nathan D.; Wang, Li-San; Gregory, Brian D.] Genom & Computat Biol Grad Grp, Philadelphia, PA USA. [Silverman, Ian M.; Gregory, Brian D.] Cell & Mol Biol Grad Grp, Philadelphia, PA USA. [Childress, Daniel M.; Wang, Li-San] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Kazan, Hilal] Antalya Int Univ, Dept Comp Engn, Antalya, Turkey. [Wang, Li-San] NIA, Baltimore, MD 21224 USA. [Wang, Li-San] Univ Penn, Perelman Sch Med, Penn Ctr Bioinformat, Philadelphia, PA 19104 USA. RP Gregory, BD (reprint author), Univ Penn, Dept Biol, 433 S Univ Ave, Philadelphia, PA 19104 USA.; Gregory, BD (reprint author), Genom & Computat Biol Grad Grp, Philadelphia, PA USA.; Gregory, BD (reprint author), Cell & Mol Biol Grad Grp, Philadelphia, PA USA. EM bdgregor@sas.upenn.edu FU NSF [MCB-1053846, MCB-1243947, IOS-1444490]; National Institute of General Medical Sciences [R01-GM099962]; EU FP7 Marie Curie CIG grant [631986]; NIGMS [5T32GM008216-26]; [U24-AG041689] FX This work was funded by the NSF (Career Award MCB-1053846, MCB-1243947, and IOS-1444490 to BDG) and the National Institute of General Medical Sciences (R01-GM099962 to LSW and BDG and NIGMS 5T32GM008216-26 to IMS). HK is supported by EU FP7 Marie Curie CIG grant (631986). U24-AG041689 funds DMC to develop web applications. NR 17 TC 1 Z9 1 U1 0 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD MAY 17 PY 2016 VL 17 AR 215 DI 10.1186/s12859-016-1071-0 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA DL8ND UT WOS:000375897800002 PM 27188311 ER PT J AU Corley, DA Haas, JS Kobrin, S AF Corley, Douglas A. Haas, Jennifer S. Kobrin, Sarah TI Reducing Variation in the "Standard of Care" for Cancer Screening Recommendations From the PROSPR Consortium SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Corley, Douglas A.] Kaiser Permanente No Calif, Div Res, 2000 Broadway, Oakland, CA 94612 USA. [Haas, Jennifer S.] Brigham & Womens Hosp, Div Gen Internal Med & Primary Care, 75 Francis St, Boston, MA 02115 USA. [Kobrin, Sarah] NCI, Hlth Syst & Intervent Res Branch, Bethesda, MD 20892 USA. RP Corley, DA (reprint author), Kaiser Permanente No Calif, Div Res, 2000 Broadway, Oakland, CA 94612 USA. EM douglas.corley@kp.org FU NCI NIH HHS [U54CA163307, 3U54CA163261-04S1, 3U54CA163262-04S1, 3U54CA163308-04S1, U01CA163304, U54 CA163262, U54CA163261, U54CA163262, U54CA163303, U54CA163308, U54CA163313, U54CA164336] NR 7 TC 0 Z9 0 U1 2 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 17 PY 2016 VL 315 IS 19 BP 2067 EP 2068 DI 10.1001/jama.2016.3067 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DL9PN UT WOS:000375975300012 PM 27089237 ER PT J AU Lai, ZN Yin, HG Cabrera-Perez, J Guimaro, MC Afione, S Michael, DG Glenton, P Patel, A Swaim, WD Zheng, CY Nguyen, CQ Nyberg, F Chiorini, JA AF Lai, Zhennan Yin, Hongen Cabrera-Perez, Javier Guimaro, Maria C. Afione, Sandra Michael, Drew G. Glenton, Patricia Patel, Ankur Swaim, William D. Zheng, Changyu Nguyen, Cuong Q. Nyberg, Fred Chiorini, John A. TI Aquaporin gene therapy corrects Sjogren's syndrome phenotype in mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE aquaporin; gene therapy; Sjogren's syndrome ID ADENOVIRAL-MEDIATED TRANSFER; SALIVARY-GLAND HYPOFUNCTION; TIGHT JUNCTION STRUCTURE; SYNDROME-LIKE DISEASE; AUTOIMMUNE-DISEASE; EPITHELIAL-CELLS; TRANSGENIC MICE; FACTOR-RECEPTOR; NEW-MODEL; PREVALENCE AB Primary Sjogren's syndrome (pSS) is a chronic autoimmune disease that is estimated to affect 35 million people worldwide. Currently, no effective treatments exist for Sjogren's syndrome, and there is a limited understanding of the physiological mechanisms associated with xerostomia and hyposalivation. The present work revealed that aquaporin 5 expression, a water channel critical for salivary gland fluid secretion, is regulated by bone morphogenetic protein 6. Increased expression of this cytokine is strongly associated with the most common symptom of primary Sjogren's syndrome, the loss of salivary gland function. This finding led us to develop a therapy in the treatment of Sjogren's syndrome by increasing the water permeability of the gland to restore saliva flow. Our study demonstrates that the targeted increase of gland permeability not only resulted in the restoration of secretory gland function but also resolved the hallmark salivary gland inflammation and systemic inflammation associated with disease. Secretory function also increased in the lacrimal gland, suggesting this local therapy could treat the systemic symptoms associated with primary Sjogren's syndrome. C1 [Lai, Zhennan; Yin, Hongen; Cabrera-Perez, Javier; Guimaro, Maria C.; Afione, Sandra; Michael, Drew G.; Patel, Ankur; Swaim, William D.; Zheng, Changyu; Chiorini, John A.] Natl Inst Dent & Craniofacial Res, Adenoassociated Virus Biol Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Lai, Zhennan; Nyberg, Fred] Uppsala Univ, Dept Pharmaceut Biosci, Div Biol Res Drug Dependence, S-75124 Uppsala, Sweden. [Glenton, Patricia; Nguyen, Cuong Q.] Univ Florida, Dept Pathol & Infect Dis, Gainesville, FL 32611 USA. RP Chiorini, JA (reprint author), Natl Inst Dent & Craniofacial Res, Adenoassociated Virus Biol Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. EM jchiorini@dir.nidcr.nih.gov FU Swedish Medical Research Grant [9549]; NIDCR, NIH intramural research grant; NIDCR, NIH extramural research Grant [DE023433, DE018958] FX We thank the staff of the Sjogren's syndrome clinic at the NIDCR, NIH for providing salivary gland tissue and patient diagnosis; members of the NIDCR animal facility for their ongoing assistance in the animal model maintenance; and patients with Sjogren's syndrome and HVs for contributing to this study. This study was supported by Swedish Medical Research Grant 9549 (to Z.L. and F.N.), an NIDCR, NIH intramural research grant (to J.A.C.), and NIDCR, NIH extramural research Grants DE023433 and DE018958 (to P.G. and to C.Q.N.). We thank Drs. James Melvin, Shmuel Muallem, Indu Ambudkar, and Sarah Knox for comments during review and discussion of this manuscript and the NIH Fellows Editorial Board for editorial assistance. NR 49 TC 3 Z9 3 U1 1 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 17 PY 2016 VL 113 IS 20 BP 5694 EP 5699 DI 10.1073/pnas.1601992113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DL9QK UT WOS:000375977600059 PM 27140635 ER PT J AU Rosenthal, ES Graham, CS AF Rosenthal, Elana S. Graham, Camilla S. TI Price and affordability of direct-acting antiviral regimens for hepatitis C virus in the United States SO INFECTIOUS AGENTS AND CANCER LA English DT Review DE Hepatitis C virus; Cost-effectiveness; Pharmaceutical pricing; Direct-acting antivirals ID HCV GENOTYPE 1; COST-EFFECTIVENESS; 3 INFECTION; SOFOSBUVIR; VELPATASVIR; LEDIPASVIR AB Hepatitis C virus is a serious infection causing cirrhosis, liver cancer, and death. The recent development of direct-acting antivirals has dramatically improved tolerability of treatment and rates of cure. However, the high price of these medications has often limited access to care and resulted in rationing of medications in the United States to those with advanced liver disease, access to specialist care, and without active substance use. This review assesses the way pharmaceutical prices are established and how pricing of directly acting antiviral regimens in the United States has impacted access to treatment for hepatitis C virus. C1 [Rosenthal, Elana S.] Frederick Natl Lab Canc Res, Clin Res Directorate, Clin Monitoring Res Program, Leidos Biomed Res, Frederick, MD USA. [Graham, Camilla S.] Beth Israel Deaconess Med Ctr, Div Infect Dis, Boston, MA 02215 USA. [Graham, Camilla S.] Harvard Univ, Sch Med, Boston, MA USA. [Graham, Camilla S.] Trek Therapeut PBC, Cambridge, MA USA. RP Rosenthal, ES (reprint author), Frederick Natl Lab Canc Res, Clin Res Directorate, Clin Monitoring Res Program, Leidos Biomed Res, Frederick, MD USA. EM elana.rosenthal@nih.gov OI Rosenthal, Elana/0000-0001-7234-4871 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Institutes of Allergy and Infectious Diseases FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This project was supported in part by the National Institutes of Allergy and Infectious Diseases. NR 32 TC 3 Z9 4 U1 4 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-9378 J9 INFECT AGENTS CANCER JI Infect. Agents Cancer PD MAY 16 PY 2016 VL 11 AR 24 DI 10.1186/s13027-016-0071-z PG 8 WC Oncology; Immunology SC Oncology; Immunology GA DO1EH UT WOS:000377520800001 PM 27186235 ER PT J AU Jiang, LL Wu, XF Wang, S Chen, SH Zhou, H Wilson, B Jin, CY Lu, RB Xie, KQ Wang, QS Hong, JS AF Jiang, Lulu Wu, Xuefei Wang, Shuo Chen, Shih-Heng Zhou, Hui Wilson, Belinda Jin, Chun-Yang Lu, Ru-Band Xie, Keqin Wang, Qingshan Hong, Jau-Shyong TI Clozapine metabolites protect dopaminergic neurons through inhibition of microglial NADPH oxidase SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE Neuroinflammation; NADPH oxidase; Clozapine metabolites; Parkinson's disease; Neuroprotection ID LIPOPOLYSACCHARIDE-INDUCED NEUROTOXICITY; PARKINSONS-DISEASE; INDUCED AGRANULOCYTOSIS; N-DESMETHYLCLOZAPINE; ALZHEIMERS-DISEASE; OXIDATIVE STRESS; DOUBLE-BLIND; NEURODEGENERATIVE DISEASES; REACTIVE MICROGLIOSIS; UNITED-STATES AB Background: Clozapine, an atypical antipsychotic medication, has been effectively used to treat refractory schizophrenia. However, the clinical usage of clozapine is limited due to a high incidence of neutropenia or agranulocytosis. We previously reported that clozapine protected dopaminergic neurons through inhibition of microglial activation. The purpose of this study was to explore the neuroprotective effects of clozapine metabolites clozapine N-oxide (CNO) and N-desmethylclozapine (NDC), as well as their propensity to cause neutropenia. Methods: The primary midbrain neuron-glia culture was applied to detect the neuroprotective and anti-inflammatory effect of clozapine and its metabolites in lipopolysaccharide (LPS) and MPP+-induced toxicity. And the subsequent mechanism was demonstrated by gp91(phox) mutant cell cultures as well as microgliosis cell lines. In vivo, to confirm the neuroprotective effect of clozapine and CNO, we measured the dopaminergic neuronal loss and rotarod motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-generated mouse Parkinson's disease (PD) model. The neutropenia or agranulocytosis of clozapine and its metabolites was illustrated by white blood cell count of the treated mice. Results: We found that, in midbrain neuron-glia cultures, CNO and NDC were more potent than clozapine in protecting dopaminergic neurons against LPS and MPP+-induced toxicity. CNO and NDC-afforded neuroprotection was linked to inhibition of microglia-mediated neuroinflammation, as demonstrated by abolished neuroprotection in microglia-depleted cultures and their capacity of inhibiting LPS-induced release of proinflammatory factors from activated microglia. NADPH oxidase (NOX2) was subsequently recognized as the main target of CNO and NDC since genetic ablation of gp91(phox), the catalytic subunit of NOX2, abolished their neuroprotective effects. CNO and NDC inhibited NOX2 activation through interfering with the membrane translocation of the NOX2 cytosolic subunit, p47(phox). The neuroprotective effects of CNO were further verified in vivo as shown by attenuation of dopaminergic neurodegeneration, motor deficits, and reactive microgliosis in MPTP-generated mouse PD model. More importantly, unlike clozapine, CNO did not lower the white blood cell count. Conclusions: Altogether, our results show that clozapine metabolites elicited neuroprotection through inactivation of microglia by inhibiting NOX2. The robust neuroprotective effects and lack of neutropenia suggest that clozapine metabolites may be promising candidates for potential therapy for neurodegenerative diseases. C1 [Jiang, Lulu; Chen, Shih-Heng; Wilson, Belinda; Hong, Jau-Shyong] NIEHS, Neuropharmacol Sect, Neurobiol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Jiang, Lulu; Wang, Shuo; Xie, Keqin] Shandong Univ, Sch Publ Hlth, Inst Toxicol, Jinan 250012, Shandong, Peoples R China. [Wu, Xuefei] Dalian Med Univ, Dept Physiol, Dalian 116044, Liaoning, Peoples R China. [Zhou, Hui] Peking Univ, Sch Publ Hlth, Dept Occupat & Environm Hlth, Beijing 100191, Peoples R China. [Jin, Chun-Yang] Res Triangle Inst, Ctr Drug Discovery, POB 12194, Res Triangle Pk, NC 27709 USA. [Lu, Ru-Band] Natl Cheng Kung Univ, Natl Cheng Kung Univ Hosp, Coll Med, Inst Allied Hlth Sci,Inst Behav Med,Dept Psychiat, Tainan 70101, Taiwan. [Lu, Ru-Band] Natl Cheng Kung Univ, Natl Cheng Kung Univ Hosp, Coll Med, Addict Res Ctr, Tainan 70101, Taiwan. [Lu, Ru-Band] Natl Hlth Res Inst, Ctr Neuropsychiat Res, Miaoli 35035, Taiwan. [Wang, Qingshan] Dalian Med Univ, Sch Publ Hlth, Dept Occupat & Environm Hlth, Dalian 116044, Liaoning, Peoples R China. RP Xie, KQ (reprint author), Shandong Univ, Sch Publ Hlth, Inst Toxicol, Jinan 250012, Shandong, Peoples R China.; Wang, QS (reprint author), Dalian Med Univ, Sch Publ Hlth, Dept Occupat & Environm Hlth, Dalian 116044, Liaoning, Peoples R China. EM keqinx@sdu.edu.cn; wangq4@126.com FU Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. We thank Anthony Lockhart for the assistance with the animal colony management and maintenance. NR 70 TC 1 Z9 1 U1 6 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD MAY 16 PY 2016 VL 13 AR 110 DI 10.1186/s12974-016-0573-z PG 14 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA DL8OT UT WOS:000375902000003 PM 27184631 ER PT J AU Mandal, A Mandal, S Park, MH AF Mandal, Ajeet Mandal, Swati Park, Myung Hee TI Global quantitative proteomics reveal up-regulation of endoplasmic reticulum stress response proteins upon depletion of eIF5A in HeLa cells SO SCIENTIFIC REPORTS LA English DT Article ID INITIATION-FACTOR 5A; PROMOTES TRANSLATION ELONGATION; FACTOR EF-P; CANCER-CELLS; AMINO-ACID; POLYPROLINE STRETCHES; PEPTIDE-BOND; HYPUSINE; RIBOSOME; YEAST AB The eukaryotic translation factor, eIF5A, is a translation factor essential for protein synthesis, cell growth and animal development. By use of a adenoviral eIF5A shRNA, we have achieved an effective depletion of eIF5A in HeLa cells and undertook in vivo comprehensive proteomic analyses to examine the effects of eIF5A depletion on the total proteome and to identify cellular pathways influenced by eIF5A. The proteome of HeLa cells transduced with eIF5A shRNA was compared with that of scramble shRNA-transduced counterpart by the iTRAQ method. We identified 972 proteins consistently detected in three iTRAQ experiments and 104 proteins with significantly altered levels (protein ratio >= 1.5 or <= 0.66, p-value <= 0.05) at 72 h and/or 96 h of Ad-eIF5A-shRNA transduction. The altered expression levels of key pathway proteins were validated by western blotting. Integration of functional ontology with expression data of the 104 proteins revealed specific biological processes that are prominently up-or down-regulated. Heatmap analysis and Cytoscape visualization of biological networks identified protein folding as the major cellular process affected by depletion of eIF5A. Our unbiased, quantitative, proteomic data demonstrate that the depletion of eIF5A leads to endoplasmic reticulum stress, an unfolded protein response and up-regulation of chaperone expression in HeLa cells. C1 [Mandal, Ajeet; Mandal, Swati; Park, Myung Hee] Natl Inst Dental & Craniofacial Res, Mol & Cellular Biochem Sect, Oral & Pharyngeal Canc Branch, NIH, Bldg 30 Rm 3A300, Bethesda, MD 20892 USA. RP Park, MH (reprint author), Natl Inst Dental & Craniofacial Res, Mol & Cellular Biochem Sect, Oral & Pharyngeal Canc Branch, NIH, Bldg 30 Rm 3A300, Bethesda, MD 20892 USA. EM mhpark@nih.gov FU Intramural Research Program of National Institute of Dental and Craniofacial Research (NIDCR), NIH FX The research was supported in part by the Intramural Research Program of National Institute of Dental and Craniofacial Research (NIDCR), NIH. We thank Dr. Edith C. Wolff (NIDCR, NIH) for helpful suggestions on the manuscript, Dr. Raghvendra Mirmira (School of Medicine, Indiana University) for a rabbit polyclonal antibody specific to the hypusine residue of eIF5A and Anne Stanley and Dr. Bruce Stanley (Pennsylvania State University, Mass Spectrometry and Proteomics facility) for technical assistance and helpful advice in iTRAQ analyses. NR 50 TC 0 Z9 0 U1 3 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAY 16 PY 2016 VL 6 AR 25795 DI 10.1038/srep25795 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DL8UT UT WOS:000375918000002 PM 27180817 ER PT J AU Niu, WB Wang, Y Wang, ZP Xin, QL Wang, YJ Feng, LZ Zhao, LH Wen, J Zhang, H Wang, C Xia, GL AF Niu, Wanbao Wang, Ye Wang, Zhengpin Xin, Qiliang Wang, Yijing Feng, Lizhao Zhao, Lihua Wen, Jia Zhang, Hua Wang, Chao Xia, Guoliang TI JNK signaling regulates E-cadherin junctions in germline cysts and determines primordial follicle formation in mice SO DEVELOPMENT LA English DT Article DE JNK; E-cadherin; Cadherin 1; MAPK; WNT4; Germline cyst; Primordial follicle ID N-TERMINAL KINASE; MOUSE OVARY; ADHERENS JUNCTIONS; EPITHELIAL-CELLS; STEM-CELLS; ACTIVATION; PATHWAY; DEGRADATION; EXPRESSION; DROSOPHILA AB Physiologically, the size of the primordial follicle pool determines the reproductive lifespan of female mammals, while its establishment largely depends on a process of germline cyst breakdown during the perinatal period. The mechanisms regulating this process are poorly understood. Here we demonstrate that c-Jun amino-terminal kinase (JNK) signaling is crucial for germline cyst breakdown and primordial follicle formation. JNK was specifically localized in oocytes and its activity increased as germline cyst breakdown progressed. Importantly, disruption of JNK signaling with a specific inhibitor (SP600125) or knockdown technology (Lenti-JNK-shRNAs) resulted in significantly suppressed cyst breakdown and primordial follicle formation in cultured mouse ovaries. Our results show that E-cadherin is intensely expressed in germline cysts, and that its decline is necessary for oocyte release from the cyst. However, inhibition of JNK signaling leads to aberrantly enhanced localization of E-cadherin at oocyte-oocyte contact sites. WNT4 expression is upregulated after SP600125 treatment. Additionally, similar to the effect of SP600125 treatment, WNT4 overexpression delays cyst breakdown and is accompanied by abnormal E-cadherin expression patterns. In conclusion, our results suggest that JNK signaling, which is inversely correlated with WNT4, plays an important role in perinatal germline cyst breakdown and primordial follicle formation by regulating E-cadherin junctions between oocytes in mouse ovaries. C1 [Niu, Wanbao; Wang, Ye; Xin, Qiliang; Feng, Lizhao; Zhao, Lihua; Wen, Jia; Zhang, Hua; Wang, Chao; Xia, Guoliang] China Agr Univ, Coll Biol Sci, State Key Lab Agrobiotechnol, Beijing 100193, Peoples R China. [Wang, Zhengpin] NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. [Wang, Yijing] Natl Inst Biol Sci, Zhongguancun Life Sci Pk, Beijing 102206, Peoples R China. RP Xia, GL (reprint author), China Agr Univ, Coll Biol Sci, State Key Lab Agrobiotechnol, Beijing 100193, Peoples R China. EM glxiachina@sohu.com FU National Basic Research Program of China (973) [2013CB945501, 2012CB944701]; National Natural Science Foundation of China [31371448]; Project for Extramural Scientists of the State Key Laboratory of Agrobiotechnology, China Agricultural University [2015SKLAB4-1] FX This work was funded by the National Basic Research Program of China (973) [2013CB945501, 2012CB944701]; National Natural Science Foundation of China [31371448]; and The Project for Extramural Scientists of the State Key Laboratory of Agrobiotechnology, China Agricultural University [2015SKLAB4-1]. NR 43 TC 1 Z9 1 U1 1 U2 1 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 EI 1477-9129 J9 DEVELOPMENT JI Development PD MAY 15 PY 2016 VL 143 IS 10 BP 1778 EP 1787 DI 10.1242/dev.132175 PG 10 WC Developmental Biology SC Developmental Biology GA EE4QD UT WOS:000389588300017 PM 27013242 ER PT J AU Hong, S Hu, P Marino, J Hufnagel, SB Hopkin, RJ Toromanovic, A Richieri-Costa, A Ribeiro-Bicudo, LA Kruszka, P Roessler, E Muenke, M AF Hong, Sungkook Hu, Ping Marino, Juliana Hufnagel, Sophia B. Hopkin, Robert J. Toromanovic, Alma Richieri-Costa, Antonio Ribeiro-Bicudo, Lucilene A. Kruszka, Paul Roessler, Erich Muenke, Maximilian TI Dominant-negative kinase domain mutations in FGFR1 can explain the clinical severity of Hartsfield syndrome SO HUMAN MOLECULAR GENETICS LA English DT Article ID GONADOTROPIN-RELEASING-HORMONE; FIBROBLAST GROWTH-FACTORS; HYPOGONADOTROPIC HYPOGONADISM; KALLMANN-SYNDROME; ZEBRAFISH; GENE; EXPRESSION; MUTANT; MORPHOGENESIS; DEFICIENCY AB Mutations in FGFR1 have recently been associated with Hartsfield syndrome, a clinically distinct syndromic form of holoprosencephaly (HPE) with ectrodactly, which frequently includes combinations of craniofacial, limb and brain abnormalities not typical for classical HPE. Unrelated clinical conditions generally without craniofacial or multi-system malformations include Kallmann syndrome and idiopathic hypogonadotropic hypogonadism. FGFR1 is a principal cause for these less severe diseases as well. Here we demonstrate that of the nine FGFR1 mutations recently detected in our screen of over 200 HPE probands by next generation sequencing, only five distinct mutations in the kinase domain behave as dominant-negative mutations in zebrafish over-expression assays. Three FGFR1 mutations seen in HPE probands behave identical to wild-type FGFR1 in rescue assays, including one apparent de novo variation. Interestingly, in one HPE family, a deleterious FGFR1 allele was transmitted from one parent and a loss-of-function allele in FGF8 from the other parent to both affected daughters. This family is one of the clearest examples to date of gene:gene synergistic interactions causing HPE in humans. C1 [Hong, Sungkook; Hu, Ping; Kruszka, Paul; Roessler, Erich; Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, 35 Convent Dr,MSC 3717,Bldg 35,Room 1B-203, Bethesda, MD 20892 USA. [Marino, Juliana; Richieri-Costa, Antonio; Ribeiro-Bicudo, Lucilene A.] Univ Sao Paulo, Bauru, Brazil. [Hufnagel, Sophia B.; Hopkin, Robert J.] Cincinnati Childrens Med Ctr, Dept Med Genet, Cincinnati, OH USA. [Toromanovic, Alma] Univ Clin Ctr Tuzla, Dept Pediat, Tuzla, Bosnia & Herceg. RP Muenke, M (reprint author), NHGRI, Med Genet Branch, NIH, 35 Convent Dr,MSC 3717,Bldg 35,Room 1B-203, Bethesda, MD 20892 USA. EM mmuenke@nhgri.nih.gov FU NIH Sequencing Center (NISC); Division of Intramural Support, NHGRI, National Institutes of Health, USA FX The NIH Sequencing Center (NISC) provided technical expertise and financial support through a Flagship award. This work was supported in part by the Division of Intramural Support, NHGRI, National Institutes of Health, USA. NR 42 TC 1 Z9 1 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAY 15 PY 2016 VL 25 IS 10 BP 1912 EP 1922 DI 10.1093/hmg/ddw064 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EA9JA UT WOS:000386958100003 PM 26931467 ER PT J AU Thirthagiri, E Klarmann, KD Shukla, AK Southon, E Biswas, K Martin, BK North, SL Magidson, V Burkett, S Haines, DC Noer, K Matthai, R Tessarollo, L Loncarek, J Keller, JR Sharan, SK AF Thirthagiri, Eswary Klarmann, Kimberly D. Shukla, Anil K. Southon, Eileen Biswas, Kajal Martin, Betty K. North, Susan Lynn Magidson, Valentin Burkett, Sandra Haines, Diana C. Noer, Kathleen Matthai, Roberta Tessarollo, Lino Loncarek, Jadranka Keller, Jonathan R. Sharan, Shyam K. TI BRCA2 minor transcript lacking exons 4-7 supports viability in mice and may account for survival of humans with a pathogenic biallelic mutation SO HUMAN MOLECULAR GENETICS LA English DT Article ID HEMATOPOIETIC STEM-CELLS; POLO-LIKE KINASE-1; FANCONI-ANEMIA; BREAST-CANCER; DNA-DAMAGE; HOMOLOGOUS RECOMBINATION; REGULATE CYTOKINESIS; PROTEIN BRCA2; MOUSE MODEL; REPAIR AB The breast cancer gene, BRCA2, is essential for viability, yet patients with Fanconi anemia-D1 subtype are born alive with biallelic mutations in this gene. The hypomorphic nature of the mutations is believed to support viability, but this is not always apparent. One such mutation is IVS7+2T > G, which causes premature protein truncation due to skipping of exon 7. We previously identified a transcript lacking exons 4-7, which restores the open-reading frame, encodes a DNA repair proficient protein and is expressed in IVS7+2T > G carriers. However, because the exons 4-7 encoded region contains several residues required for normal cell-cycle regulation and cytokinesis, this transcript's ability to support viability can be argued. To address this, we generated a Brca2 knock-in mouse model lacking exons 4-7 and demonstrated that these exons are dispensable for viability as well as tumor-free survival. This study provides the first in vivo evidence of the functional significance of a minor transcript of BRCA2 that can play a major role in the survival of humans who are homozygous for a clearly pathogenic mutation. Our results highlight the importance of assessing protein function restoration by premature truncating codon bypass by alternative splicing when evaluating the functional significance of variants such as nonsense and frame-shift mutations that are assumed to be clearly pathogenic. Our findings will impact not only the assessment of variants that map to this region, but also influence counseling paradigms and treatment options for such mutation carriers. C1 [Thirthagiri, Eswary; Klarmann, Kimberly D.; Southon, Eileen; Biswas, Kajal; Martin, Betty K.; North, Susan Lynn; Burkett, Sandra; Tessarollo, Lino; Keller, Jonathan R.; Sharan, Shyam K.] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. [Shukla, Anil K.; Loncarek, Jadranka] NCI, Lab Prot Dynam & Signaling, Frederick, MD 21702 USA. [Noer, Kathleen; Matthai, Roberta] NCI, Frederick CCR Flow Cytometry Core Canc & Inflamma, Frederick, MD 21702 USA. [Klarmann, Kimberly D.; Southon, Eileen; Martin, Betty K.; Keller, Jonathan R.] Frederick Natl Lab Canc Res, Basic Sci Program, Leidos Biomed Inc, Frederick, MD 21702 USA. [Magidson, Valentin] Frederick Natl Lab Canc Res, Basic Sci Program, Opt Microscopy & Anal Lab, Frederick, MD 21702 USA. [Haines, Diana C.] Frederick Natl Lab Canc Res, Basic Sci Program, Pathol Histotechnol Lab, Frederick, MD 21702 USA. RP Keller, JR; Sharan, SK (reprint author), NCI Frederick, Bldg 560,Room 32-33,1050 Boyles St, Frederick, MD USA. EM kellerjo@mail.nih.gov; sharans@mail.nih.gov OI Shukla, Anil/0000-0001-7797-7299 FU Federal funds from the National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program, Center for Cancer Research, U.S. National Cancer Institute FX This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E and the Intramural Research Program, Center for Cancer Research, U.S. National Cancer Institute. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 48 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAY 15 PY 2016 VL 25 IS 10 BP 1934 EP 1945 DI 10.1093/hmg/ddw066 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EA9JA UT WOS:000386958100005 PM 26920070 ER PT J AU Bott, LC Badders, NM Chen, KL Harmison, GG Bautista, E Shih, CCY Katsuno, M Sobue, G Taylor, JP Dantuma, NP Fischbeck, KH Rinaldi, C AF Bott, Laura C. Badders, Nisha M. Chen, Ke-lian Harmison, George G. Bautista, Elaine Shih, Charles C. -Y. Katsuno, Masahisa Sobue, Gen Taylor, J. Paul Dantuma, Nico P. Fischbeck, Kenneth H. Rinaldi, Carlo TI A small-molecule Nrf1 and Nrf2 activator mitigates polyglutamine toxicity in spinal and bulbar muscular atrophy SO HUMAN MOLECULAR GENETICS LA English DT Article ID HEAT-SHOCK RESPONSE; MOTOR-NEURON DEGENERATION; ANDROGEN RECEPTOR PROTEIN; BZIP TRANSCRIPTION FACTOR; TRANSGENIC MOUSE MODEL; HUNTINGTONS-DISEASE; DROSOPHILA MODEL; CELLULAR-MODEL; DEGRADATION; MICE AB Spinal and bulbar muscular atrophy (SBMA, also known as Kennedy's disease) is one of nine neurodegenerative disorders that are caused by expansion of polyglutamine-encoding CAG repeats. Intracellular accumulation of abnormal proteins in these diseases, a pathological hallmark, is associated with defects in protein homeostasis. Enhancement of the cellular proteostasis capacity with small molecules has therefore emerged as a promising approach to treatment. Here, we characterize a novel curcumin analog, ASC-JM17, as an activator of central pathways controlling protein folding, degradation and oxidative stress resistance. ASC-JM17 acts on Nrf1, Nrf2 and Hsf1 to increase the expression of proteasome subunits, antioxidant enzymes and molecular chaperones. We show that ASC-JM17 ameliorates toxicity of the mutant androgen receptor (AR) responsible for SBMA in cell, fly and mouse models. Knockdown of the Drosophila Nrf1 and Nrf2 ortholog cap 'n' collar isoform-C, but not Hsf1, blocks the protective effect of ASC-JM17 on mutant AR-induced eye degeneration in flies. Our observations indicate that activation of the Nrf1/Nrf2 pathway is a viable option for pharmacological intervention in SBMA and potentially other polyglutamine diseases. C1 [Bott, Laura C.; Chen, Ke-lian; Harmison, George G.; Bautista, Elaine; Fischbeck, Kenneth H.; Rinaldi, Carlo] NINDS, Neurogenet Branch, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Bott, Laura C.; Dantuma, Nico P.] Karolinska Inst, Dept Cell & Mol Biol, S-17177 Stockholm, Sweden. [Badders, Nisha M.; Taylor, J. Paul] St Jude Childrens Res Hosp, Dept Cell & Mol Biol, 332 N Lauderdale St, Memphis, TN 38105 USA. [Shih, Charles C. -Y.] AndroScience Corp, Solana Beach, CA 92075 USA. [Katsuno, Masahisa; Sobue, Gen] Nagoya Univ, Dept Neurol, Grad Sch Med, Nagoya, Aichi 4668550, Japan. [Bott, Laura C.] Northwestern Univ, Rice Inst Biomed Res, Dept Mol Biosci, 2205 Tech Dr,Hogan 2-100, Evanston, IL 60208 USA. [Rinaldi, Carlo] Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 3QX, England. RP Bott, LC (reprint author), Northwestern Univ, Rice Inst Biomed Res, Dept Mol Biosci, 2205 Tech Dr,Hogan 2-100, Evanston, IL 60208 USA. EM laura.bott@northwestern.edu FU Intramural Research Program of the NINDS, NIH [1ZIA NS003038]; NIH [U01NS069515, NS053825]; Swedish Research Council; KI-NIH Graduate Partnership Program in Neuroscience; Association Francaise contre les Myopathies (AFM) Telethon FX This work was supported by the Intramural Research Program of the NINDS, NIH (1ZIA NS003038); NIH grants U01NS069515 (C.C.-Y.S.) and NS053825 (J.P.T.) and the Swedish Research Council (N.P.D.). Further support comes from the KI-NIH Graduate Partnership Program in Neuroscience (L.C.B.) and the Association Francaise contre les Myopathies (AFM) Telethon (C.R.). NR 51 TC 1 Z9 1 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAY 15 PY 2016 VL 25 IS 10 BP 1979 EP 1989 DI 10.1093/hmg/ddw073 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EA9JA UT WOS:000386958100008 PM 26962150 ER PT J AU Tang, WL Robles, AI Beyer, RP Gray, LT Nguyen, GH Oshima, J Maizels, N Harris, CC Monnat, RJ AF Tang, Weiliang Robles, Ana I. Beyer, Richard P. Gray, Lucas T. Nguyen, Giang H. Oshima, Junko Maizels, Nancy Harris, Curtis C. Monnat, Raymond J., Jr. TI The Werner syndrome RECQ helicase targets G4 DNA in human cells to modulate transcription SO HUMAN MOLECULAR GENETICS LA English DT Article ID G-QUADRUPLEX DNA; GENE-EXPRESSION; CELLULAR SENESCENCE; HUMAN-FIBROBLASTS; STRAND SYNTHESIS; REPEAT SEQUENCE; WRN-DEFICIENT; TELOMERE; PROTEIN; REPLICATION AB The Werner syndrome (WS) is a prototypic adult Mendelian progeroid syndrome in which signs of premature aging are associated with genomic instability and an elevated risk of cancer. The WRN RECQ helicase protein binds and unwinds G-quadruplex (G4) DNA substrates in vitro, and we identified significant enrichment in G4 sequence motifs at the transcription start site and 5' ends of first introns (false discovery rate < 0.001) of genes down-regulated in WS patient fibroblasts. This finding provides strong evidence that WRN binds G4 DNA structures at many chromosomal sites to modulate gene expression. WRN appears to bind a distinct subpopulation of G4 motifs in human cells, when compared with the related Bloom syndrome RECQ helicase protein. Functional annotation of the genes and miRNAs altered in WS provided new insight into WS disease pathogenesis. WS patient fibroblasts displayed altered expression of multiple, mechanistically distinct, senescence-associated gene expression programs, with altered expression of disease-associated miRNAs, and dysregulation of canonical pathways that regulate cell signaling, genome stability and tumorigenesis. WS fibroblasts also displayed a highly statistically significant and distinct gene expression signature, with coordinate overexpression of nearly all of the cytoplasmic tRNA synthetases and associated ARS-interacting multifunctional protein genes. The 'non-canonical' functions of many of these upregulated tRNA charging proteins may together promote WS disease pathogenesis. Our results identify the human WRN RECQ protein as a G4 helicase that modulates gene expression in G4-dependent fashion at many chromosomal sites and provide several new and unexpected mechanistic insights into WS disease pathogenesis. C1 [Tang, Weiliang; Oshima, Junko; Maizels, Nancy; Monnat, Raymond J., Jr.] Univ Washington, Dept Pathol, Box 357705, Seattle, WA 98195 USA. [Beyer, Richard P.] Univ Washington, Ctr Ecogenet & Environm Hlth, Seattle, WA 98195 USA. [Gray, Lucas T.; Maizels, Nancy] Univ Washington, Dept Immunol, Seattle, WA 98195 USA. [Maizels, Nancy] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. [Monnat, Raymond J., Jr.] Univ Washington, Dept Genome Sci, Box 357705, Seattle, WA 98195 USA. [Robles, Ana I.; Nguyen, Giang H.; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. [Oshima, Junko] Chiba Univ, Dept Med, Chiba, Japan. [Gray, Lucas T.] Allen Inst Brain Sci, Seattle, WA USA. [Nguyen, Giang H.] Univ Colorado Anschutz Med Coll, Dept Dermatol, Aurora, CO 80020 USA. RP Monnat, RJ (reprint author), Univ Washington, Dept Pathol, Box 357705, Seattle, WA 98195 USA.; Monnat, RJ (reprint author), Univ Washington, Dept Genome Sci, Box 357705, Seattle, WA 98195 USA. EM monnat@u.washington.edu OI Gray, Lucas/0000-0002-8814-6818 FU National Cancer Institute of the National Institutes of Health (NIH) [P01CA77852]; Intramural Research Programof the National Cancer Institute, Center for Cancer Research, NIH; National Institute of Environmental Health Sciences of the NIH [5P30ES007033;]; International Registry of Werner Syndrome [R24AG042328]; NIH-Oxford MD/DPhil Fellowship Program FX This work was supported by National Cancer Institute of the National Institutes of Health (NIH) award P01CA77852 to R.J.M.; by the Intramural Research Programof the National Cancer Institute, Center for Cancer Research, NIH; by the National Institute of Environmental Health Sciences of the NIH under Award Number 5P30ES007033; by R24AG042328 (International Registry of Werner Syndrome) to J.O.; and by the NIH-Oxford MD/DPhil Fellowship Program (GHN). Research reported in this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. NR 71 TC 2 Z9 2 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAY 15 PY 2016 VL 25 IS 10 BP 2060 EP 2069 DI 10.1093/hmg/ddw079 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EA9JA UT WOS:000386958100014 PM 26984941 ER PT J AU Horikoshi, M Pasquali, L Wiltshire, S Huyghe, JR Mahajan, A Asimit, JL Ferreira, T Locke, AE Robertson, NR Wang, X Sim, XL Fujita, H Hara, K Young, R Zhang, WH Choi, S Chen, H Kaur, I Takeuchi, F Fontanillas, P Thuillier, D Yengo, L Below, JE Tam, CHT Wu, Y Abecasis, G Altshuler, D Bell, GI Blangero, J Burtt, NP Duggirala, R Florez, JC Hanis, CL Seielstad, M Atzmon, G Chan, JCN Ma, RCW Froguel, P Wilson, JG Bharadwaj, D Dupuis, J Meigs, JB Cho, YS Park, T Kooner, JS Chambers, JC Saleheen, D Kadowaki, T Tai, ES Mohlke, KL Cox, NJ Ferrer, J Zeggini, E Kato, N Teo, YY Boehnke, M McCarthy, MI Morris, AP AF Horikoshi, Momoko Pasquali, Lorenzo Wiltshire, Steven Huyghe, Jeroen R. Mahajan, Anubha Asimit, Jennifer L. Ferreira, Teresa Locke, Adam E. Robertson, Neil R. Wang, Xu Sim, Xueling Fujita, Hayato Hara, Kazuo Young, Robin Zhang, Weihua Choi, Sungkyoung Chen, Han Kaur, Ismeet Takeuchi, Fumihiko Fontanillas, Pierre Thuillier, Dorothee Yengo, Loic Below, Jennifer E. Tam, Claudia H. T. Wu, Ying Abecasis, Goncalo Altshuler, David Bell, Graeme I. Blangero, John Burtt, Noel P. Duggirala, Ravindranath Florez, Jose C. Hanis, Craig L. Seielstad, Mark Atzmon, Gil Chan, Juliana C. N. Ma, Ronald C. W. Froguel, Philippe Wilson, James G. Bharadwaj, Dwaipayan Dupuis, Josee Meigs, James B. Cho, Yoon Shin Park, Taesung Kooner, Jaspal S. Chambers, John C. Saleheen, Danish Kadowaki, Takashi Tai, E. Shyong Mohlke, Karen L. Cox, Nancy J. Ferrer, Jorge Zeggini, Eleftheria Kato, Norihiro Teo, Yik Ying Boehnke, Michael McCarthy, Mark I. Morris, Andrew P. CA T2D-GENES Consortium TI Transancestral fine-mapping of four type 2 diabetes susceptibility loci highlights potential causal regulatory mechanisms SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; GENETIC ARCHITECTURE; BETA-CELLS; METAANALYSIS; VARIANTS; KCNQ1; POPULATIONS; SNPS AB To gain insight into potential regulatory mechanisms through which the effects of variants at four established type 2 diabetes (T2D) susceptibility loci (CDKAL1, CDKN2A-B, IGF2BP2 and KCNQ1) are mediated, we undertook transancestral fine-mapping in 22 086 cases and 42 539 controls of East Asian, European, South Asian, African American and Mexican American descent. Through high-density imputation and conditional analyses, we identified seven distinct association signals at these four loci, each with allelic effects on T2D susceptibility that were homogenous across ancestry groups. By leveraging differences in the structure of linkage disequilibrium between diverse populations, and increased sample size, we localised the variants most likely to drive each distinct association signal. We demonstrated that integration of these genetic fine-mapping data with genomic annotation can highlight potential causal regulatory elements in T2D-relevant tissues. These analyses provide insight into the mechanisms through which T2D association signals are mediated, and suggest future routes to understanding the biology of specific disease susceptibility loci. C1 [Horikoshi, Momoko; Wiltshire, Steven; Mahajan, Anubha; Ferreira, Teresa; Robertson, Neil R.; McCarthy, Mark I.; Morris, Andrew P.] Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England. [Horikoshi, Momoko; Wiltshire, Steven; Robertson, Neil R.; McCarthy, Mark I.] Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Pasquali, Lorenzo] Germans Trias & Pujol Univ Hosp & Res Inst, PMPPC, Badalona, Spain. [Pasquali, Lorenzo] Josep Carreras Leukaemia Res Inst, Badalona, Spain. [Pasquali, Lorenzo; Ferrer, Jorge] CIBER Diabet & Enfermedades Metab Asociadas CIBER, Barcelona, Spain. [Huyghe, Jeroen R.; Locke, Adam E.; Sim, Xueling; Abecasis, Goncalo; Boehnke, Michael] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Huyghe, Jeroen R.; Locke, Adam E.; Sim, Xueling; Abecasis, Goncalo; Boehnke, Michael] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Asimit, Jennifer L.; Zeggini, Eleftheria] Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, Cambs, England. [Wang, Xu; Sim, Xueling; Tai, E. Shyong; Teo, Yik Ying] Natl Univ Singapore, Natl Univ Hlth Syst, Yong Loo Lin Sch Med, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore. [Tai, E. Shyong] Natl Univ Singapore, Natl Univ Hlth Syst, Yong Loo Lin Sch Med, Dept Med, Singapore, Singapore. [Fujita, Hayato] JR Tokyo Gen Hosp, Dept Diabet & Endocrinol, Tokyo, Japan. [Hara, Kazuo; Kadowaki, Takashi] Univ Tokyo, 22nd Century Med & Res Ctr, Dept Diabet & Metab Dis, Grad Sch Med, Tokyo, Japan. [Kadowaki, Takashi] Univ Tokyo, 22nd Century Med & Res Ctr, Dept Integrated Mol Sci Metab Dis, Tokyo, Japan. [Young, Robin] Univ Cambridge, Inst Publ Hlth, Dept Publ Hlth & Primary Care, Cambridge, England. [Zhang, Weihua; Kooner, Jaspal S.; Chambers, John C.] Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England. [Zhang, Weihua; Chambers, John C.] Imperial Coll London, Dept Epidemiol & Biostat, London, England. [Froguel, Philippe] Imperial Coll London, Dept Genom Common Dis, Sch Publ Hlth, London, England. [Kooner, Jaspal S.] Imperial Coll London, Natl Heart & Lung Inst, Cardiovasc Sci, Hammersmith Campus, London, England. [Kooner, Jaspal S.; Chambers, John C.] Imperial Coll London, Imperial Coll Healthcare NHS Trust, London, England. [Ferrer, Jorge] Imperial Coll London, Dept Med, London, England. [Choi, Sungkyoung; Park, Taesung] Seoul Natl Univ, Interdisciplinary Program Bioinformat, Seoul, South Korea. [Park, Taesung] Seoul Natl Univ, Dept Stat, Seoul, South Korea. [Chen, Han] Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Chen, Han; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Kaur, Ismeet; Bharadwaj, Dwaipayan] CSIR Inst Genom & Integrat Biol, Genom & Mol Med, New Delhi, India. [Takeuchi, Fumihiko; Kato, Norihiro] Natl Ctr Global Hlth & Med, Res Inst, Dept Gene Diagnost & Therapeut, Tokyo, Japan. [Fontanillas, Pierre; Altshuler, David; Burtt, Noel P.; Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Thuillier, Dorothee; Yengo, Loic; Froguel, Philippe] EGID FR3508 European Genom Inst Diabet, Lille Inst Biol, Integrat Genom & Modelizat Metab Dis CNRS UMR8199, Lille, France. [Below, Jennifer E.; Hanis, Craig L.] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA. [Tam, Claudia H. T.; Chan, Juliana C. N.; Ma, Ronald C. W.] Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China. [Chan, Juliana C. N.; Ma, Ronald C. W.] Chinese Univ Hong Kong, Hong Kong Inst Diabet & Obes, Hong Kong, Hong Kong, Peoples R China. [Chan, Juliana C. N.; Ma, Ronald C. W.] Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Hong Kong, Hong Kong, Peoples R China. [Wu, Ying; Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Altshuler, David] MIT, Dept Biol, Cambridge, MA USA. [Altshuler, David] Harvard Med Sch, Dept Genet, Boston, MA USA. [Altshuler, David; Florez, Jose C.; Meigs, James B.] Harvard Med Sch, Dept Med, Boston, MA USA. [Altshuler, David] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Altshuler, David; Florez, Jose C.] Massachusetts Gen Hosp, Dept Med, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Dept Med, Ctr Human Genet Res, Boston, MA 02114 USA. [Meigs, James B.] Massachusetts Gen Hosp, Gen Med Div, Boston, MA 02114 USA. [Bell, Graeme I.] Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Bell, Graeme I.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Blangero, John; Duggirala, Ravindranath] Texas Biomed Res Inst, Dept Genet, Houston, TX USA. [Seielstad, Mark] Blood Syst Res Inst, San Francisco, CA USA. [Seielstad, Mark] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. [Seielstad, Mark] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Atzmon, Gil] Univ Haifa, Dept Nat Sci, Haifa, Israel. [Atzmon, Gil] Albert Einstein Coll Med, Dept Med, New York, NY USA. [Atzmon, Gil] Albert Einstein Coll Med, Dept Genet, New York, NY USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Bharadwaj, Dwaipayan] Jawaharlal Nehru Univ, Sch Biotechnol, New Delhi, India. [Dupuis, Josee] NHLBI, Framingham Heart Study, Framingham, MA USA. [Cho, Yoon Shin] Hallym Univ, Dept Biomed Sci, Chunchon, South Korea. [Saleheen, Danish] Univ Penn, Dept Biostat & Epidemiol, Ctr Noncommunicable Dis, Philadelphia, PA 19104 USA. [Tai, E. Shyong] Duke NUS Grad Med Sch Singapore, Cardiovasc & Metab Disorders Program, Singapore, Singapore. [Cox, Nancy J.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Ferrer, Jorge] Inst Invest August Pi & Sunyer IDIBAPS, Gen Programming Beta Cells Lab, Barcelona, Spain. [Teo, Yik Ying] Natl Univ Singapore, Inst Life Sci, Singapore, Singapore. [Teo, Yik Ying] Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore, Singapore. [McCarthy, Mark I.] Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England. [Morris, Andrew P.] Univ Liverpool, Dept Biostat, Block F,Waterhouse Bldg,1-5 Brownlow St, Liverpool L69 3GL, Merseyside, England. RP Morris, AP (reprint author), Univ Liverpool, Dept Biostat, Block F,Waterhouse Bldg,1-5 Brownlow St, Liverpool L69 3GL, Merseyside, England. EM a.p.morris@liverpool.ac.uk RI Chan, Juliana /B-7918-2016; Ma, Ronald/C-2788-2009; Yengo, Loic/D-2692-2017; OI Chan, Juliana /0000-0003-1325-1194; Ma, Ronald/0000-0002-1227-803X; Yengo, Loic/0000-0002-4272-9305; Chen, Han/0000-0002-9510-4923; Tai, E Shyong/0000-0003-2929-8966 FU Action on Hearing Loss [G51]; American Federation for Aging; Einstein Glenn Center; Association Francaise des Diabetiques; British Heart Foundation [SP/04/002]; CARDIOMED-CSIR, India [BSC0122(6)]; Centre Hospitalier Universitaire Poitiers; CNAMTS; Endocrinology-Diabetology Department of the Corbeil-Essonnes Hospital; European Union (FP7 EpiMigrant) [279143]; Focused Investment Scheme of the Chinese University of Hong Kong; Fondation de France; Hong Kong Foundation for Research and Development in Diabetes; Genome Canada; Genome Quebec; Hong Kong Government Research Grant Committee Central Allocation Scheme [CUHK 1/04C]; Innovation and Technology Fund [ITS/487/09FP, ITS/130/11]; Research Grants Council Theme-based Research Scheme [T12-402/13N]; Japan Society for the Promotion of Science [KAKENHI 23710228]; Medical Research Council [G0601966, G0700931]; Ministerio de Economia y Competitividad [BFU2014-58150-R]; Ministry of Education, Culture, Sports, Science and Technology of Japan; National Center for Global Health and Medicine (NCGM); National Institute of Aging [PO1AG027734, R01AG046949, 1R01AG042188, P30AG038072, R014AG028872]; National Institutes of Health [K24-DK080140, U01-DK085526, R01-MH101820, P60-DK20595, U01-DK085501, R01-HL102830, U01-HG005773, R01-MH090937, R01-HG000376, R01-DK062370, R01-DK073541, U01-DK085524, U01-DK085545, U01-DK085584, U01-DK105535]; National Institute for Health Research [RP-PG-0407-10371]; National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre, Imperial College Healthcare NHS Trust; National Medical Research Program, Singapore; National Research Foundation of Korea [NRF-2012R1A2A1A03006155, 2012R1A3A2026438, 2013M3A9C4078158, 2015R1A5A6001906]; Program for Promotion of Fundamental Studies in Health Sciences, National Institute of Biomedical Innovation Organization (NIBIO); Wellcome Trust [WT084723, WT090532, WT098017, WT098051]; National Heart, Lung, and Blood Institute [HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C]; National Institute on Minority Health and Health Disparities; Wellcome Trust FX This work was supported by Action on Hearing Loss (G51); American Federation for Aging; Einstein Glenn Center; Association Francaise des Diabetiques; British Heart Foundation (SP/04/002); CARDIOMED BSC0122(6)-CSIR, India; Centre Hospitalier Universitaire Poitiers; CNAMTS; Endocrinology-Diabetology Department of the Corbeil-Essonnes Hospital; European Union (FP7 EpiMigrant, 279143); Focused Investment Scheme of the Chinese University of Hong Kong; Fondation de France; Hong Kong Foundation for Research and Development in Diabetes; Genome Canada; Genome Quebec; Hong Kong Government Research Grant Committee Central Allocation Scheme (CUHK 1/04C), Innovation and Technology Fund (ITS/487/09FP and ITS/130/11), and the Research Grants Council Theme-based Research Scheme (T12-402/13N); Japan Society for the Promotion of Science (KAKENHI 23710228); Medical Research Council (G0601966, G0700931); Ministerio de Economia y Competitividad (BFU2014-58150-R); Ministry of Education, Culture, Sports, Science and Technology of Japan; National Center for Global Health and Medicine (NCGM); National Institute of Aging (PO1AG027734, R01AG046949, 1R01AG042188, P30AG038072, R014AG028872); National Institutes of Health (K24-DK080140, U01-DK085526, R01-MH101820, P60-DK20595, U01-DK085501, R01-HL102830, U01-HG005773, R01-MH090937, R01-HL102830, R01-HG000376, R01-DK062370, R01-DK073541, U01-DK085524, U01-DK085545, U01-DK085584, U01-DK105535); National Institute for Health Research (RP-PG-0407-10371); National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre, Imperial College Healthcare NHS Trust; National Medical Research Program, Singapore; National Research Foundation of Korea (NRF-2012R1A2A1A03006155, 2012R1A3A2026438, 2013M3A9C4078158, 2015R1A5A6001906); Program for Promotion of Fundamental Studies in Health Sciences, National Institute of Biomedical Innovation Organization (NIBIO); Wellcome Trust (WT084723, WT090532, WT098017, WT098051). The Jackson Heart Study is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust. NR 45 TC 0 Z9 0 U1 3 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAY 15 PY 2016 VL 25 IS 10 BP 2070 EP 2081 DI 10.1093/hmg/ddw048 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EA9JA UT WOS:000386958100015 PM 26911676 ER PT J AU Chernomordikl, V Amyot, F Kenney, K Wassermann, E Diaz-Arrastia, R Gandjbakhche, A AF Chernomordikl, Victor Amyot, Franck Kenney, Kimbra Wassermann, Eric Diaz-Arrastia, Ramon Gandjbakhche, Amir TI Abnormality of low frequency cerebral hemodynamics oscillations in TBI population SO BRAIN RESEARCH LA English DT Article DE Cerebral autoregulation; Functional Near InfraRed; Spectroscopy; Low frequency oscillations; Parametric effect of the judgment of; complexity; Traumatic brain injury ID NEAR-INFRARED SPECTROSCOPY; HEAD-INJURY; COMPLEXITY; DYNAMICS; BRAIN; TASK AB Functional Near Infrared Spectroscopy (fNIRS) can non-invasively capture dynamic cognitive activation and underlying physiological processes by measuring changes in oxy- and deoxyhemoglobin levels, correlated to brain activation. It is a portable, inexpensive and user-friendly device which is easily adapted to the outpatient setting for the assessment of cognitive functions after Traumatic Brain Injury (TBI). Low frequency oscillations in hemodynamic signal, attributed in the literature to cerebral autoregulation, were assessed using recently introduced metrics, Oxygenation Variability (OV Index), obtained from oxy/deoxy-hemoglobin variations in response to mental tasks for a group of healthy control (HC, n=14) and TBI (n=29). Participants responded to an action complexity judgment task (evaluating the complexity of daily life activities by classifying the number of steps as "few" or "many") with a varying degree of cognitive load to produce brain activation. During the task, we measured blood variations with fNIRS and analyzed OV Index changes. Mean OV indices, corresponding to high complexity tasks, are higher than that of low complexity tasks in the HC group, revealing strong parametric effect (0.039 +/- 0.017 for low, 0.057 +/- 0.036 for high, p-value=0.069). However, no significant difference has been recorded for the OV indexes for two different loads in the TBI group (0.055 +/- 0.033 for low, 0.054 +/- 0.035 for high, p=0.9). OV index metrics proves to be sensitive to chronic TBI and can potentially be used to separate subpopulations TBI vs. HC. Noticeable differences in OV index spatial distributions between subpopulations have been observed. Published by Elsevier B.V. C1 [Chernomordikl, Victor; Amyot, Franck; Kenney, Kimbra; Wassermann, Eric; Diaz-Arrastia, Ramon; Gandjbakhche, Amir] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Gandjbakhche, A (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. EM amir@helix.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Neurological Disorders and Stroke; Center for Neuroscience and Regenerative Medicine FX We acknowledge the funding of the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Neurological Disorders and Stroke and Center for Neuroscience and Regenerative Medicine. We also thank Ross Passo, Leah Harburg, Carol Moore, Afrouz Anderson, Nader Shahni Karamzadeh and Fatima Chowdhry for their valuable help. NR 18 TC 2 Z9 2 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD MAY 15 PY 2016 VL 1639 BP 194 EP 199 DI 10.1016/j.brainres.2016.02.018 PG 6 WC Neurosciences SC Neurosciences & Neurology GA DP4DW UT WOS:000378447400017 PM 26996413 ER PT J AU Rouhani, S Yori, PP Olortegui, MP Salas, MS Trigoso, DR Mondal, D Bodhidatta, L Platts-Mills, J Samie, A Kabir, F Lima, A Babji, S Mason, CJ Kalam, A Bessong, P Ahmed, T Mduma, E Bhutta, ZA Lima, I Ramdass, R Lang, D George, A Zaidi, AKM Kang, G Houpt, E Kosek, MN AF Rouhani, Saba Yori, Pablo Penataro Olortegui, Maribel Paredes Salas, Mery Siguas Trigoso, Dixner Rengifo Mondal, Dinesh Bodhidatta, Ladaporn Platts-Mills, James Samie, Amidou Kabir, Furqan Lima, Aldo Babji, Sudhir Mason, Carl J. Kalam, Adil Bessong, Pascal Ahmed, Tahmeed Mduma, Estomih Bhutta, Zulfiqar A. Lima, Ila Ramdass, Rakhi Lang, Dennis George, Ajila Zaidi, Anita K. M. Kang, Gagandeep Houpt, Eric Kosek, Margaret N. CA Etiology Risk Factors Interactions TI Norovirus Infection and Acquired Immunity in 8 Countries: Results From the MAL-ED Study SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE norovirus; diarrhea; immunity ID BIRTH COHORT; GASTROENTERITIS; METAANALYSIS; COMMUNITY; CHILDREN AB Background. Norovirus is an important cause of childhood diarrhea. We present data from a longitudinal, multicountry study describing norovirus epidemiology during the first 2 years of life. Methods. A birth cohort of 1457 children across 8 countries contributed 7077 diarrheal stools for norovirus testing. A subset of 199 children contributed additional asymptomatic samples (2307) and diarrheal stools (770), which were used to derive incidence rates and evaluate evidence for acquired immunity. Results. Across sites, 89% of children experienced at least 1 norovirus infection before 24 months, and 22.7% of all diarrheal stools were norovirus positive. Severity of norovirus-positive diarrhea was comparable to other enteropathogens, with the exception of rotavirus. Incidence of genogroup II (GII) infection was higher than genogroup I and peaked at 6-11 months across sites. Undernutrition was a risk factor for symptomatic norovirus infection, with an increase in 1 standard deviation of length-for-age z score associated with a 17% reduction (odds ratio, 0.83 [95% confidence interval, .72-.97]; P = .011) in the odds of experiencing diarrhea when norovirus was present, after accounting for genogroup, rotavirus vaccine, and age. Evidence of acquired immunity was observed among GII infections only: Children with prior GII infection were found to have a 27% reduction in the hazard of subsequent infection (hazard ratio, 0.727; P = .010). Conclusions. The high prevalence of norovirus across 8 sites in highly variable epidemiologic settings and demonstration of protective immunity for GII infections provide support for investment in vaccine development. C1 [Rouhani, Saba; Kosek, Margaret N.] Johns Hopkins Sch Publ Hlth, Baltimore, MD USA. [Yori, Pablo Penataro] Johns Hopkins Univ, Baltimore, MD USA. [Olortegui, Maribel Paredes; Salas, Mery Siguas; Trigoso, Dixner Rengifo] AB PRISMA, Iquitos, Peru. [Mondal, Dinesh; Ahmed, Tahmeed] Icddr B, Dhaka, Bangladesh. [Bodhidatta, Ladaporn; Mason, Carl J.] Armed Forces Res Inst Med Sci, Bangkok 10400, Thailand. [Platts-Mills, James; Houpt, Eric] Univ Virginia, Charlottesville, VA USA. [Samie, Amidou] Univ Venda, Thohoyandou, South Africa. [Kabir, Furqan; Kalam, Adil; Bessong, Pascal; Bhutta, Zulfiqar A.; Zaidi, Anita K. M.] Aga Khan Univ, Naushahro Feroze, Pakistan. [Lima, Aldo; Lima, Ila] Univ Fed Ceara, Fortaleza, Ceara, Brazil. [Babji, Sudhir; Ramdass, Rakhi; George, Ajila; Kang, Gagandeep] Christian Med Coll & Hosp, Vellore, Tamil Nadu, India. [Mduma, Estomih] Haydom Lutheran Hosp, Haydom, Tanzania. [Lang, Dennis] Fdn Natl Inst Hlth, Bethesda, MD USA. RP Kosek, MN (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Rm E5608,615 N Wolfe St, Baltimore, MD 21205 USA. EM mkosek@jhu.edu RI Strand, Tor/D-9836-2016 OI Strand, Tor/0000-0002-4038-151X NR 15 TC 2 Z9 2 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAY 15 PY 2016 VL 62 IS 10 BP 1210 EP 1220 DI 10.1093/cid/ciw072 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DP3YM UT WOS:000378432100004 PM 27013692 ER PT J AU Siberry, GK Jacobson, DL AF Siberry, George K. Jacobson, Denise L. CA Pediat HIV AIDS Cohort Study TI Bone Mineral Content in Neonates Reply SO CLINICAL INFECTIOUS DISEASES LA English DT Letter C1 [Siberry, George K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, NIH, 6100 Executive Blvd, Bethesda, MD 20892 USA. [Jacobson, Denise L.] Harvard Univ, TH Chan Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA USA. RP Siberry, GK (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, NIH, 6100 Executive Blvd, Bethesda, MD 20892 USA. EM siberryg@mail.nih.gov NR 2 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAY 15 PY 2016 VL 62 IS 10 BP 1324 EP + DI 10.1093/cid/ciw116 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DP3YM UT WOS:000378432100024 PM 26936672 ER PT J AU Lim, JA Choi, SJ Moon, JY Kim, HS AF Lim, Jeong-A. Choi, Su Jin Moon, Jae Yun Kim, Hye Sun TI alpha-Syntrophin is involved in the survival signaling pathway in myoblasts under menadione-induced oxidative stress SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE alpha-Syntrophin; Menadione; Oxidative stress; Myoblast; Apoptosis; Calcium imaging ID NITRIC-OXIDE SYNTHASE; CYTOCHROME-C RELEASE; POLY(ADP-RIBOSE) POLYMERASE; MUSCULAR-DYSTROPHY; CULTURED MYOBLASTS; INDUCED APOPTOSIS; MUSCLE-CELLS; PROTEIN; ALPHA-1-SYNTROPHIN; CALCIUM AB Dystrophin-deficient muscle is known to be more vulnerable to oxidative stress, but not much is known about the signaling pathway(s) responsible for this phenomenon. alpha-Syntrophin, a component of the dystrophin-glycoprotein complex, can function as a scaffold protein because of its multiple protein interaction domains. In this study, we investigated the role of alpha-syntrophin in C2 myoblasts under menadione-induced oxidative stress. We found that the protein level of alpha-syntrophin was elevated when cells were exposed to menadione. To investigate the function of alpha-syntrophin during oxidative stress, we established alpha-syntrophin-overexpressing and knockdown cell lines. The alpha-syntrophin-overexpressing cells were resistant to the menadione-induced oxidative stress. In addition, survival signalings such as protein kinase B (Akt) phosphorylation and the Bcl-2/BAX ratio were increased in these cells. On the other hand, apoptotic signals such as cleavage of caspase-3 and poly ADP ribose polymerase (PARP) were increased in the alpha-syntrophin knockdown cells. Furthermore, Ca2+ influx, which is known to increase when cells are exposed to oxidative stress, decreased in the alpha-syntrophin-overexpressing cells, but increased in the knockdown cells. These results suggest that alpha-syntrophin plays a pivotal role in the survival pathway triggered by menadione-induced oxidative stress in cultured myoblasts. (C) 2016 Elsevier Inc. All rights reserved. C1 [Lim, Jeong-A.; Choi, Su Jin; Moon, Jae Yun; Kim, Hye Sun] Ajou Univ, Coll Nat Sci, Dept Biol Sci, Suwon 443749, South Korea. [Lim, Jeong-A.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Kim, HS (reprint author), Ajou Univ, Coll Nat Sci, Dept Biol Sci, Suwon 443749, South Korea. EM hsunkim@ajou.ac.kr FU Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology [NRF-2013R1A1A3011123] FX This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2013R1A1A3011123). We thank Dr. Marvin E. Adams (University of Washington, Seattle, WA, USA) for reading the manuscript and for his helpful comments. We also appreciate Prof. Hwan Myung Kim (Ajou University, Suwon, Korea) for the technical supports for the two-photon microscopy analysis. NR 49 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 EI 1090-2422 J9 EXP CELL RES JI Exp. Cell Res. PD MAY 15 PY 2016 VL 344 IS 1 BP 1 EP 10 DI 10.1016/j.yexcr.2016.04.001 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DN4SC UT WOS:000377056500001 PM 27086165 ER PT J AU Noh, JH Kim, KM Abdelmohsen, K Yoon, JH Panda, AC Munk, R Kim, J Curtis, J Moad, CA Wohler, CM Indig, FE de Paula, W Dudekula, DB De, S Piao, YL Yang, XL Martindale, JL de Cabo, R Gorospe, M AF Noh, Ji Heon Kim, Kyoung Mi Abdelmohsen, Kotb Yoon, Je-Hyun Panda, Amaresh C. Munk, Rachel Kim, Jiyoung Curtis, Jessica Moad, Christopher A. Wohler, Christina M. Indig, Fred E. de Paula, Wilson Dudekula, Dawood B. De, Supriyo Piao, Yulan Yang, Xiaoling Martindale, Jennifer L. de Cabo, Rafael Gorospe, Myriam TI HuR and GRSF1 modulate the nuclear export and mitochondrial localization of the lncRNA RMRP SO GENES & DEVELOPMENT LA English DT Article DE RNA-binding proteins; nuclear RNA export; ribonucleoprotein complex; mitochondrial RNA import; oxygen consumption rate ID RNA-BINDING-PROTEIN; MESSENGER-RNA; RIBOSOMAL-RNA; POSTTRANSLATIONAL MODIFICATION; RICH ELEMENT; IN-VIVO; EXPRESSION; SEQUENCE; MRP; PHOSPHORYLATION AB Some mitochondrial long noncoding RNAs (lncRNAs) are encoded by nuclear DNA, but the mechanisms that mediate their transport to mitochondria are poorly characterized. Using affinity RNA pull-down followed by mass spectrometry analysis, we found two RNA-binding proteins (RBPs), HuR (human antigen R) and GRSF1 (G-rich RNA sequence-binding factor 1), that associated with the nuclear DNA-encoded lncRNA RMRP and mobilized it to mitochondria. In cultured human cells, HuR bound RMRP in the nucleus and mediated its CRM1 (chromosome region maintenance 1)-dependent export to the cytosol. After RMRP was imported into mitochondria, GRSF1 bound RMRP and increased its abundance in the matrix. Loss of GRSF1 lowered the mitochondrial levels of RMRP, in turn suppressing oxygen consumption rates and modestly reducing mitochondrial DNA replication priming. Our findings indicate that RBPs HuR and GRSF1 govern the cytoplasmic and mitochondrial localization of the lncRNA RMRP, which is encoded by nuclear DNA but has key functions in mitochondria. C1 [Noh, Ji Heon; Kim, Kyoung Mi; Abdelmohsen, Kotb; Yoon, Je-Hyun; Panda, Amaresh C.; Munk, Rachel; Kim, Jiyoung; de Paula, Wilson; Dudekula, Dawood B.; De, Supriyo; Piao, Yulan; Yang, Xiaoling; Martindale, Jennifer L.; Gorospe, Myriam] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. [Curtis, Jessica; de Cabo, Rafael] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. [Moad, Christopher A.; Wohler, Christina M.; Indig, Fred E.] NIA, Confocal Imaging Facil, NIH, Baltimore, MD 21224 USA. RP Gorospe, M (reprint author), NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. EM myriam-gorospe@nih.gov RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; PANDA, AMARESH/0000-0003-3189-8995; De, Supriyo/0000-0002-2075-7655; , rafael/0000-0003-2830-5693 FU National Institute on Aging-Intramural Research Program, National Institutes of Health FX We thank P. Ghosh, E. Lehrmann, and W.H. Wood III (National Institute on Aging, National Institutes of Health) for their assistance. This work was funded in its entirety by the National Institute on Aging-Intramural Research Program, National Institutes of Health. NR 54 TC 2 Z9 3 U1 4 U2 5 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD MAY 15 PY 2016 VL 30 IS 10 BP 1224 EP 1239 DI 10.1101/gad.276022.115 PG 16 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA DN4RT UT WOS:000377055600008 PM 27198227 ER PT J AU Panagiotou, OA AF Panagiotou, Orestis A. TI Re: "Invited Commentary: How Big Is That Interaction (In My Community)-And in Which Direction?" Reply SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Letter C1 [Panagiotou, Orestis A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Panagiotou, OA (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM orestis.panagiotou@nih.gov NR 4 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAY 15 PY 2016 VL 183 IS 10 BP 958 EP 959 DI 10.1093/aje/kww036 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DM5HM UT WOS:000376378700011 PM 27076672 ER PT J AU Li, AJ Wiater, MF Wang, Q Wank, S Ritter, S AF Li, Ai-Jun Wiater, Michael F. Wang, Qing Wank, Stephen Ritter, Sue TI Deletion of GPR40 fatty acid receptor gene in mice blocks mercaptoacetate-induced feeding SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE mercaptoacetate; GPR40; fatty acid; lipoprivic feeding ID HEPATIC ENERGY STATUS; FOOD-INTAKE; INCRETIN SECRETION; RATS; OXIDATION; INSULIN; 2-DEOXY-D-GLUCOSE; 2-MERCAPTOACETATE; AGONIST; INHIBITION AB Both increased and decreased fatty acid (FA) availability contribute to control of food intake. For example, it is well documented that intestinal FA reduces feeding by triggering enterondocrine secretion of satietogenic peptides, such as cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1). In contrast, mechanisms by which decreased FA availability increase feeding are not well understood. Over the past three decades substantial research related to FA availability and increased feeding has involved use of the orexigenic compound mercaptoacetate (MA). Because MA reportedly inhibits FA oxidation, it has been assumed that reduced FA oxidation accounts for the orexigenic action of MA. Recently, however, we demonstrated that MA antagonizes G protein-coupled receptor 40 (GPR40), a membrane receptor for long and medium chain FA. We also demonstrated that, by antagonizing GPR40, MA inhibits GLP-1 secretion and attenuates vagal afferent activation by FA. Because both vagal afferent activation and GLP-1 inhibit food intake, we postulated that inhibition of GPR40 by MA might underlie the orexigenic action of MA. We tested this hypothesis using male and female GPR40 knockout (KO) and wild-type (WT) mice. Using several testing protocols, we found that MA increased feeding in WT, but not GPR40 KO mice, and that GPR40 KO mice gained more weight than WT on a high-fat diet. Metabolic monitoring after MA or saline injection in the absence of food did not reveal significant differences in respiratory quotient or energy expenditure between treatment groups or genotypes. These results support the hypothesis that MA stimulates food intake by blocking FA effects on GPR40. C1 [Li, Ai-Jun; Wiater, Michael F.; Wang, Qing; Ritter, Sue] Washington State Univ, Programs Neurosci, Pullman, WA 99164 USA. [Wank, Stephen] NIDDK, Digest Dis Branch, Bethesda, MD 20892 USA. RP Li, AJ (reprint author), Washington State Univ, Dept Integrat Physiol & Neurosci, Coll Vet Med, Pullman, WA 99164 USA. EM aijunli@vetmed.wsu.edu OI Li, Ai-Jun/0000-0003-3585-886X FU National Institute of Diabetes and Digestive and Kidney Diseases [DK040498, DK097437] FX This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK040498 and DK097437 to S. Ritter. NR 42 TC 1 Z9 1 U1 1 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 EI 1522-1490 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD MAY 15 PY 2016 VL 310 IS 10 BP R968 EP R974 DI 10.1152/ajpregu.00548.2015 PG 7 WC Physiology SC Physiology GA DM6ML UT WOS:000376466700011 PM 26984894 ER PT J AU Houser, KV Gretebeck, L Ying, TL Wang, YP Vogel, L Lamirande, EW Bock, KW Moore, IN Dimitrov, DS Subbarao, K AF Houser, Katherine V. Gretebeck, Lisa Ying, Tianlei Wang, Yanping Vogel, Leatrice Lamirande, Elaine W. Bock, Kevin W. Moore, Ian N. Dimitrov, Dimiter S. Subbarao, Kanta TI Prophylaxis With a Middle East Respiratory Syndrome Coronavirus (MERS-CoV)-Specific Human Monoclonal Antibody Protects Rabbits From MERS-CoV Infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE MERS-CoV; prophylaxis; m336; rabbits; human mAb ID SAUDI-ARABIA; NEUTRALIZATION; EFFICACY AB With >1600 documented human infections with Middle East respiratory syndrome coronavirus (MERS-CoV) and a case fatality rate of approximately 36%, medical countermeasures are needed to prevent and limit the disease. We examined the in vivo efficacy of the human monoclonal antibody m336, which has high neutralizing activity against MERS-CoV in vitro. m336 was administered to rabbits intravenously or intranasally before infection with MERS-CoV. Prophylaxis with m336 resulted in a reduction of pulmonary viral RNA titers by 40-9000-fold, compared with an irrelevant control antibody with little to no inflammation or viral antigen detected. This protection in rabbits supports further clinical development of m336. C1 [Houser, Katherine V.; Gretebeck, Lisa; Vogel, Leatrice; Lamirande, Elaine W.; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Bock, Kevin W.; Moore, Ian N.] NIAID, Comparat Med Branch, Infect Dis Pathogenesis Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Wang, Yanping; Dimitrov, Dimiter S.] NCI, Prot Interact Sect, Canc & Inflammat Program, Ctr Canc Res,NIH, Frederick, MD 21701 USA. [Ying, Tianlei] Fudan Univ, Key Lab Med Mol Virol, Shanghai Med Coll, Minist Educ, Shanghai, Peoples R China. [Ying, Tianlei] Fudan Univ, Key Lab Med Mol Virol, Shanghai Med Coll, Minist Hlth, Shanghai, Peoples R China. RP Subbarao, K (reprint author), Bldg 33,Rm 3E13C-1,33 North Dr,MSC 3203, Bethesda, MD 20892 USA. EM ksubbarao@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH); National Cancer Institute, NIH FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), and by the National Cancer Institute, NIH. NR 14 TC 5 Z9 5 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 15 PY 2016 VL 213 IS 10 BP 1557 EP 1561 DI 10.1093/infdis/jiw080 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DM8XX UT WOS:000376648900007 PM 26941283 ER PT J AU Kobayashi, SD Porter, AR Dorward, DW Brinkworth, AJ Chen, L Kreiswirth, BN DeLeo, FR AF Kobayashi, Scott D. Porter, Adeline R. Dorward, David W. Brinkworth, Amanda J. Chen, Liang Kreiswirth, Barry N. DeLeo, Frank R. TI Phagocytosis and Killing of Carbapenem-Resistant ST258 Klebsiella pneumoniae by Human Neutrophils SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Klebsiella pneumoniae; neutrophil; phagocytosis ID CAPSULAR POLYSACCHARIDE VACCINE; BLOOD-STREAM INFECTIONS; STAPHYLOCOCCUS-AUREUS; BACTERIAL PATHOGENS; HOST-DEFENSE; O-ANTIGEN; AEROGENES; MICE; APOPTOSIS; ENTEROBACTERIACEAE AB Carbapenem-resistant Klebsiella pneumoniae strains classified as multilocus sequence type 258 (ST258) are among the most widespread multidrug-resistant hospital-acquired pathogens. Treatment of infections caused by these organisms is difficult, and mortality is high. The basis for the success of ST258, outside of antibiotic resistance, remains incompletely determined. Here we tested the hypothesis that ST258 K. pneumoniae has enhanced capacity to circumvent killing by human neutrophils, the primary cellular defense against bacterial infections. There was limited binding and uptake of ST258 by human neutrophils, and correspondingly, there was limited killing of bacteria. On the other hand, transmission electron microscopy revealed that any ingested organisms were degraded readily within neutrophil phagosomes, thus indicating that survival in the neutrophil assays is due to limited phagocytosis, rather than to microbicide resistance after uptake. Our findings suggest that enhancing neutrophil phagocytosis is a potential therapeutic approach for treatment of infection caused by carbapenem-resistant ST258 K. pneumoniae. C1 [Kobayashi, Scott D.; Porter, Adeline R.; Brinkworth, Amanda J.; DeLeo, Frank R.] NIAID, Bacteriol Lab, NIH, Hamilton, MT 59840 USA. [Dorward, David W.] NIAID, Res Technol Branch, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Chen, Liang; Kreiswirth, Barry N.] Rutgers State Univ, Publ Hlth Res Inst, TB Ctr, New Jersey Med Sch, Newark, DE USA. [Brinkworth, Amanda J.] Washington State Univ, Sch Mol Biosci, Pullman, WA 99164 USA. RP DeLeo, FR (reprint author), NIAID, Rocky Mt Lab, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM fdeleo@niaid.nih.gov OI DeLeo, Frank/0000-0003-3150-2516 FU National Institutes of Health (NIH) [R01AI090155]; National Institute of Allergy and Infectious Diseases, NIH FX This work was supported by the National Institutes of Health (NIH; grant R01AI090155 to B. N. K.) and the Intramural Research Program, National Institute of Allergy and Infectious Diseases, NIH. NR 46 TC 5 Z9 5 U1 5 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 15 PY 2016 VL 213 IS 10 BP 1615 EP 1622 DI 10.1093/infdis/jiw001 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DM8XX UT WOS:000376648900014 PM 26768252 ER PT J AU Ventetuolo, CE Baird, GL Barr, RG Bluemke, DA Fritz, JS Hill, NS Klinger, JR Lima, JAC Ouyang, P Palevsky, HI Palmisciano, AJ Krishnan, I Pinder, D Preston, LR Roberts, KE Kawut, SM AF Ventetuolo, Corey E. Baird, Grayson L. Barr, R. Graham Bluemke, David A. Fritz, Jason S. Hill, Nicholas S. Klinger, James R. Lima, Joao A. C. Ouyang, Pamela Palevsky, Harold I. Palmisciano, Amy J. Krishnan, Ipsita Pinder, Diane Preston, Loana R. Roberts, Kari E. Kawut, Steven M. TI Higher Estradiol and Lower Dehydroepiandrosterone-Sulfate Levels Are Associated with Pulmonary Arterial Hypertension in Men SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE sex hormones; estradiol; DHEA; pulmonary hypertension ID HORMONE-BINDING GLOBULIN; RIGHT-VENTRICULAR STRUCTURE; VASCULAR ENDOTHELIAL-CELLS; LOW SERUM TESTOSTERONE; CARDIOVASCULAR-DISEASE; ESTROGEN-RECEPTOR; SEX-HORMONES; ELDERLY-MEN; RATS; SURVIVAL AB Rationale: Recent studies have focused on the role of female sex and estradiol (E2) in pulmonary arterial hypertension (PAH), but it is not known whether sex hormones are risk factors for PAH in men. Objectives: We performed a case-control study to determine whether hormone levels (E2, dehydroepiandrosterone-sulfate [DHEA-S], and testosterone) are associated with PAH in men. Methods: Plasma sex hormone levels in men with idiopathic, heritable, or connective tissue disease-associated PAH were compared with those from age- and body mass index-matched men without clinical cardiovascular disease. Measurements and Main Results: There were 23 cases with PAH (70% had idiopathic PAH, 65% were functional class III/IV) and 67 control subjects. Higher E2 and E2/testosterone levels were associated with the risk of PAH (odds ratio per 1 ln[E2:testosterone], 6.0; 95% confidence interval, 2.2-16.4; P = 0.001), whereas higher levels of DHEA-S were associated with a reduced risk (odds ratio per 1 ln[DHEA-S], 0.1; 95% confidence interval, 0.0-0.3; P = 0.001). E2 and DHEA-S levels were strong predictors of case status (C statistic for both, 0.82) but testosterone was not (C statistic, 0.53). Higher levels of E2 were associated with shorter 6-minute-walk distances (P = 0.03), whereas higher levels of DHEA-S were associated with lower right atrial pressure (P = 0.02) and pulmonary vascular resistance (P = 0.01) in men with PAH. Conclusions: Higher levels of E2 and lower levels of DHEA-S were associated with PAH in men. Sex-based differences in sex hormone processing and signaling may contribute to unique phenotypes in pulmonary vascular disease. C1 [Ventetuolo, Corey E.; Klinger, James R.] Brown Univ, Dept Med, Alpert Med Sch, Providence, RI 02912 USA. [Ventetuolo, Corey E.] Brown Univ, Alpert Med Sch, Dept Hlth Serv Policy & Practice, Providence, RI 02912 USA. [Ventetuolo, Corey E.; Baird, Grayson L.; Klinger, James R.; Palmisciano, Amy J.; Krishnan, Ipsita] Lifespan Hosp Syst, Providence, RI USA. [Barr, R. Graham] Columbia Univ Coll Phys & Surg, Dept Med, New York, NY USA. [Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, Radiol & Imaging Sci, NIH, Ctr Clin, Bethesda, MD USA. [Fritz, Jason S.; Palevsky, Harold I.; Pinder, Diane; Kawut, Steven M.] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Kawut, Steven M.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Kawut, Steven M.] Univ Penn, Perelman Sch Med, Penn Cardiovasc Inst, Philadelphia, PA 19104 USA. [Hill, Nicholas S.; Preston, Loana R.; Roberts, Kari E.] Tufts Univ, Sch Med, Dept Med, Tufts Med Ctr, Boston, MA 02111 USA. [Lima, Joao A. C.; Ouyang, Pamela] Johns Hopkins Sch Med, Dept Med, Baltimore, MD USA. RP Ventetuolo, CE (reprint author), Rhode Isl Hosp, Div Pulm Crit Care & Sleep, 593 Eddy St,APC 7, Providence, RI 02903 USA. EM corey_ventetuolo@brown.edu FU National Institutes of Health [P20 GM103652, K24 HL103844, R01-HL086719]; American Heart Association [11FTF7400032]; NHLBI [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169]; National Center for Research Resources [UL1-TR-000040, UL1-TR-001079] FX Supported by P20 GM103652, K24 HL103844, and R01-HL086719 from the National Institutes of Health and 11FTF7400032 from the American Heart Association. Support for MESA (Multi-Ethnic Study of Atherosclerosis) is provided by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from the NHLBI; and by grants UL1-TR-000040 and UL1-TR-001079 from the National Center for Research Resources. NR 49 TC 15 Z9 15 U1 2 U2 4 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD MAY 15 PY 2016 VL 193 IS 10 BP 1168 EP 1175 DI 10.1164/rccm.201509-1785OC PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DM0RR UT WOS:000376054000019 PM 26651504 ER PT J AU Caniglia, EC Patel, K Huo, YL Williams, PL Kapetanovic, S Rich, KC Sirois, PA Jacobson, DL Hernandez-Diaz, S Hernan, MA Seage, GR AF Caniglia, Ellen C. Patel, Kunjal Huo, Yanling Williams, Paige L. Kapetanovic, Suad Rich, Kenneth C. Sirois, Patricia A. Jacobson, Denise L. Hernandez-Diaz, Sonia Hernan, Miguel A. Seage, George R., III CA Pediatric HIV AIDS Cohort Study TI Atazanavir exposure in utero and neurodevelopment in infants: a comparative safety study SO AIDS LA English DT Article DE antiretrovirals; atazanavir; infant; neurodevelopment; observational study; pregnancy ID SERUM BILIRUBIN LEVELS; TO-CHILD TRANSMISSION; BLOOD-BRAIN-BARRIER; ANTIRETROVIRAL DRUGS; NEONATAL HYPERBILIRUBINEMIA; UNINFECTED CHILDREN; PREGNANT-WOMEN; HEALTHY TERM; BIRTH-WEIGHT; HIV AB Objective:To evaluate the safety of in-utero exposure to atazanavir and neurodevelopment in perinatally HIV-exposed but uninfected (PHEU) infants.Design:Prospective cohort study of mother-PHEU infant pairs in the Surveillance Monitoring for ART Toxicities protocol of the Pediatric HIV/AIDS Cohort Study.Methods:Pregnant women living with HIV who initiated an antiretroviral regimen during pregnancy were followed from the date of antiretroviral initiation. Women were classified according to whether the antiretroviral regimen contained atazanavir and the trimester of antiretroviral initiation. Neurodevelopment at 9-15 months was evaluated using the Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III). We estimated mean differences for the five Bayley-III domains for atazanavir-containing regimens versus all other regimens. Models included baseline covariates and adjustment for failure to complete the Bayley-III using inverse probability weighting.Results:PHEU infants were exposed in utero to atazanavir-containing (n=167) and nonatazanavir-containing (n=750) antiretroviral regimens. The adjusted mean differences (95% confidence interval) in Bayley-III domain scores for initiating an atazanavir-containing regimen in the first trimester were: cognitive, -1.5 (-6.2, 3.2); language, -3.3 (-7.6, 1.0); motor, -2.9 (-7.7, 1.9); social-emotional, 0.1 (-6.2, 6.4); and adaptive behavior, -0.1 (-4.3, 4.0). The mean differences for the second or third trimester were: cognitive, 0.4 (-3.2, 4.0); language, -3.4 (-6.2, -0.5); motor, 0.3 (-2.9, 3.4); social-emotional, -5.9 (-9.4, -2.3); and adaptive behavior, -2.5 (-5.9, 0.8).Conclusion:In-utero exposure to atazanavir-containing regimens compared with non-atazanavir-containing regimens may adversely affect language and social-emotional development in PHEU infants during the first year of life, but the absolute difference is small. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Caniglia, Ellen C.; Patel, Kunjal; Huo, Yanling; Williams, Paige L.; Jacobson, Denise L.; Hernandez-Diaz, Sonia; Hernan, Miguel A.; Seage, George R., III] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Kapetanovic, Suad] Univ So Calif, Keck Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90033 USA. [Kapetanovic, Suad] NIMH, NIH, Bethesda, MD 20892 USA. [Rich, Kenneth C.] Univ Illinois, Coll Med, Chicago, IL USA. [Sirois, Patricia A.] Tulane Univ, Sch Med, 1430 Tulane Ave, New Orleans, LA 70112 USA. [Hernan, Miguel A.] Harvard MIT Div Hlth Sci & Technol, Boston, MA USA. RP Caniglia, EC (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. EM ecanigli@hsph.harvard.edu FU National Institute of Allergy and Infectious Diseases [T32 AI007433]; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Drug Abuse; National Institute of Allergy and Infectious Diseases; Office of AIDS Research; National Institute of Mental Health (including the Intramural Research Program of the NIMH); National Institute of Neurological Disorders and Stroke; National Institute on Deafness and Other Communication Disorders; National Heart Lung and Blood Institute; National Institute of Dental and Craniofacial Research; National Institute on Alcohol Abuse and Alcoholism; Harvard T.H. Chan School of Public Health [HD052102]; Tulane University School of Medicine [HD052104] FX This research was made possible by Grant Number T32 AI007433 from the National Institute of Allergy and Infectious Diseases. The Pediatric HIV/AIDS Cohort Study (PHACS) was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development with cofunding from the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the Office of AIDS Research, the National Institute of Mental Health (including the Intramural Research Program of the NIMH), the National Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication Disorders, the National Heart Lung and Blood Institute, the National Institute of Dental and Craniofacial Research, and the National Institute on Alcohol Abuse and Alcoholism, through cooperative agreements with the Harvard T.H. Chan School of Public Health (HD052102) and the Tulane University School of Medicine (HD052104). NR 46 TC 2 Z9 2 U1 3 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD MAY 15 PY 2016 VL 30 IS 8 BP 1267 EP 1277 DI 10.1097/QAD.0000000000001052 PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DL6WR UT WOS:000375781200012 PM 26867136 ER PT J AU Sumner, T Houben, RMGJ Rangaka, MX Maartens, G Boulle, A Wilkinson, RJ White, RG AF Sumner, Tom Houben, Rein M. G. J. Rangaka, Molebogeng X. Maartens, Gary Boulle, Andrew Wilkinson, Robert J. White, Richard G. TI Post-treatment effect of isoniazid preventive therapy on tuberculosis incidence in HIV-infected individuals on antiretroviral therapy SO AIDS LA English DT Article DE HIV; isoniazid preventive therapy; preventive therapy; South Africa ID MULTIDRUG-RESISTANT TUBERCULOSIS; RANDOMIZED CONTROLLED-TRIAL; PLACEBO-CONTROLLED TRIAL; MYCOBACTERIUM-TUBERCULOSIS; LATENT TUBERCULOSIS; SOUTH-AFRICA; DOUBLE-BLIND; ADULTS; RISK; PREVALENCE AB Background:In HIV-uninfected individuals, isoniazid preventive therapy (IPT) has been associated with long-term protection against tuberculosis (TB). For HIV-infected/antiretroviral therapy (ART)-naive individuals, high TB rates have been observed following completion of IPT, consistent with a lack of cure' of infection. Recent trial data of IPT among HIV-infected individuals on ART in Khayelitsha, South Africa, have suggested that the effect of IPT persisted following completion of IPT.Methods:Using mathematical modelling, we explored if this increased duration of protection may be due to an increased curative ability of IPT when given in combination with ART. The model was used to estimate the annual risk of infection and proportion of individuals whose latent infection was cured' by IPT, defined such that they must be reinfected to be at risk of disease.Results:The estimated annual risk of infection was 4.0% (2.6-5.8) and the estimated proportion of individuals whose latent Mycobacterium tuberculosis infection was cured following IPT was 35.4% (2.4-76.4), higher than that previously estimated for HIV-infected/ART-naive individuals. Our results suggest that IPT can cure latent M. tuberculosis infection in approximately one-third of HIV-infected individuals on ART and therefore provide protection beyond the period of treatment.Conclusion:Among HIV-infected individuals on ART in low incidence settings, 12 months of IPT may provide additional long-term benefit. Among HIV-infected individuals on ART in high incidence settings, the durability of this protection will be limited because of continued risk of reinfection, and continuous preventive therapy together with improved infection control efforts will be required to provide long-term protection against TB. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Sumner, Tom; Houben, Rein M. G. J.; White, Richard G.] London Sch Hyg & Trop Med, Dept Infect Dis Epidemiol, TB Modelling Grp, TB Ctr,Ctr Math Modelling Infect Dis, London, England. [Rangaka, Molebogeng X.] UCL, Ctr Infect Dis Epidemiol, Dept Infect & Populat Hlth, London, England. [Rangaka, Molebogeng X.] Univ Cape Town, Inst Infect Dis & Mol Med, Dept Med, ZA-7925 Cape Town, South Africa. [Maartens, Gary] Univ Cape Town, Div Clin Pharmacol, ZA-7925 Cape Town, South Africa. [Maartens, Gary] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Boulle, Andrew] Univ Cape Town, Sch Publ Hlth & Family Med, Ctr Infect Dis Epidemiol & Res, ZA-7925 Cape Town, South Africa. [Wilkinson, Robert J.] Univ London Imperial Coll Sci Technol & Med, Dept Med, London SW7 2AZ, England. [Wilkinson, Robert J.] Francis Crick Inst, Mill Hill Lab, London, England. [Wilkinson, Robert J.] Univ Cape Town, Inst Infect Dis & Mol Med, ZA-7925 Cape Town, South Africa. RP Sumner, T (reprint author), London Sch Hyg & Trop Med, Dept Infect Dis Epidemiol, TB Modelling Grp, TB Ctr, London WC1E 7HT, England.; Sumner, T (reprint author), London Sch Hyg & Trop Med, Ctr Math Modelling Infect Dis, London WC1E 7HT, England. EM tom.sumner@lshtm.ac.uk RI White, Richard/D-5407-2009; Maartens, Gary/F-3836-2014; OI White, Richard/0000-0003-4410-6635; Maartens, Gary/0000-0003-3080-6606; Wilkinson, Robert/0000-0002-2753-1800 NR 38 TC 1 Z9 1 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD MAY 15 PY 2016 VL 30 IS 8 BP 1279 EP 1286 DI 10.1097/QAD.0000000000001078 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DL6WR UT WOS:000375781200013 PM 26950316 ER PT J AU Lewis, DR Chen, HS Cockburn, M Wu, XC Stroup, AM Midthune, DN Krapcho, MF Miller, DG Penberthy, L Feuer, EJ AF Lewis, Denise Riedel Chen, Huann-Sheng Cockburn, Myles Wu, Xiao-Cheng Stroup, Antoinette M. Midthune, Douglas N. Krapcho, Martin F. Miller, Daniel G. Penberthy, Lynne Feuer, Eric J. TI Preliminary estimates of SEER cancer incidence for 2013 SO CANCER LA English DT Article DE annual percent change; average annual percent change; delay adjustment; early estimates of cancer incidence rates; population-based registry data ID COLORECTAL-CANCER; MEAT CONSUMPTION; RISK AB BACKGROUNDThis article presents a first look at rates and trends for cases in the Surveillance, Epidemiology, and End Results (SEER) program diagnosed through 2013 using the February 2015 submission, and a validation of rates and trends from the February 2014 submission using the subsequent November 2014 submission. To the authors' knowledge, this is the second time SEER has published trends based on the early February submission. Three new cancer sites were added: cervix, thyroid, and liver/ intrahepatic bile duct. METHODSA reporting delay model adjusted for the undercount of cases, which is substantially larger for the February than the subsequent November submission, was used. Joinpoint regression methodology was used to assess trends. Delay-adjusted rates and trends were checked to assess validity between the February and November 2014 submissions. RESULTSThe validation of rates and trends from the February and November 2014 submissions demonstrated even better agreement than the previously reported comparison between the February and November 2013 submissions, thereby affording additional confidence that the delay-adjusted February submission data can be used to produce valid estimates of incidence trends. Trends for cases diagnosed through 2013 revealed more rapid declines in female colon and rectal cancer and prostate cancer. A plateau in female melanoma trends and a slowing of the increases in thyroid cancer and male liver/intrahepatic bile duct cancer trends were observed. CONCLUSIONSAnalysis of early cancer data submissions can provide a preliminary indication of differences in incidence trends with an additional year of data. Although the delay adjustment correction adjusts for underreporting of cases, caution should be exercised when interpreting the results in this early submission. (c) 2016 American Cancer Society. C1 [Lewis, Denise Riedel; Chen, Huann-Sheng; Penberthy, Lynne; Feuer, Eric J.] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Rm 4E538,MSC 9765, Bethesda, MD 20892 USA. [Cockburn, Myles] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Wu, Xiao-Cheng] Louisiana State Univ, Louisiana Tumor Registry, New Orleans, LA USA. [Stroup, Antoinette M.] Rutgers State Univ, New Jersey State Tumor Registry, New Brunswick, NJ 08903 USA. [Midthune, Douglas N.] NCI, Biometry Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Krapcho, Martin F.; Miller, Daniel G.] Informat Management Syst Inc, Calverton, MD USA. RP Lewis, DR (reprint author), NCI, Surveillance Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Rm 4E538,MSC 9765, Bethesda, MD 20892 USA. EM lewisde@mail.nih.gov NR 24 TC 0 Z9 0 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD MAY 15 PY 2016 VL 122 IS 10 BP 1579 EP 1587 DI 10.1002/cncr.29953 PG 9 WC Oncology SC Oncology GA DL8MW UT WOS:000375897100015 PM 26991915 ER PT J AU Greene, JM Levy, D Herrada, SP Gottesman, MM Lavi, O AF Greene, James M. Levy, Doron Herrada, Sylvia P. Gottesman, Michael M. Lavi, Orit TI Mathematical Modeling Reveals That Changes to Local Cell Density Dynamically Modulate Baseline Variations in Cell Growth and Drug Response SO CANCER RESEARCH LA English DT Article ID CANCER-CELLS; HETEROGENEITY; RESISTANCE; POPULATIONS; APOPTOSIS; THERAPY; SYSTEM; STATE AB Cell-to-cell variations contribute to drug resistance with consequent therapy failure in cancer. Experimental techniques have been developed to monitor tumor heterogeneity, but estimates of cell-to-cell variation typically fail to account for the expected spatiotemporal variations during the cell growth process. To fully capture the extent of such dynamic variations, we developed a mechanistic mathematical model supported by in vitro experiments with an ovarian cancer cell line. We introduce the notion of dynamic baseline cell-to-cell variation, showing how the emerging spatiotemporal heterogeneity of one cell population can be attributed to differences in local cell density and cell cycle. Manipulation of the geometric arrangement and spatial density of cancer cells revealed that given a fixed global cell density, significant differences in growth, proliferation, and paclitaxel-induced apoptosis rates were observed based solely on cell movement and local conditions. We conclude that any statistical estimate of changes in the level of heterogeneity should be integrated with the dynamics and spatial effects of the baseline system. This approach incorporates experimental and theoretical methods to systematically analyze biologic phenomena and merits consideration as an underlying reference model for cell biology studies that investigate dynamic processes affecting cancer cell behavior. (C) 2016 AACR. C1 [Greene, James M.] Rutgers State Univ, Dept Math, New Brunswick, NJ 08903 USA. [Levy, Doron] Univ Maryland, Dept Math, College Pk, MD 20742 USA. [Levy, Doron] Univ Maryland, Ctr Sci Computat & Math Modeling, College Pk, MD 20742 USA. [Herrada, Sylvia P.; Gottesman, Michael M.; Lavi, Orit] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. RP Lavi, O (reprint author), NCI, NIH, 37 Convent Dr,Room 2112, Bethesda, MD 20892 USA. EM orit.lavi@nih.gov NR 22 TC 0 Z9 0 U1 2 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD MAY 15 PY 2016 VL 76 IS 10 BP 2882 EP 2890 DI 10.1158/0008-5472.CAN-15-3232 PG 9 WC Oncology SC Oncology GA DL7SS UT WOS:000375841000007 PM 26933088 ER PT J AU Wahba, A Rath, BH Bisht, K Camphausen, K Tofilon, PJ AF Wahba, Amy Rath, Barbara H. Bisht, Kheem Camphausen, Kevin Tofilon, Philip J. TI Polysome Profiling Links Translational Control to the Radioresponse of Glioblastoma Stem-like Cells SO CANCER RESEARCH LA English DT Article ID MESSENGER-RNA TRANSLATION; TUMOR-INITIATING CELLS; GENE-EXPRESSION; IONIZING-RADIATION; CANCER; LINES; RADIOSENSITIVITY; GAMMA-H2AX; MECHANISMS; TARGET AB Changes in polysome-bound mRNA (translatome) are correlated closely with changes in the proteome in cells. Therefore, to better understand the processes mediating the response of glioblastoma to ionizing radiation (IR), we used polysome profiling to define the IR-induced translatomes of a set of human glioblastoma stem-like cell (GSC) lines. Although cell line specificity accounted for the largest proportion of genes within each translatome, there were also genes that were common to the GSC lines. In particular, analyses of the IR-induced common translatome identified components of the DNA damage response, consistent with a role for the translational control of gene expression in cellular radioresponse. Moreover, translatome analyses suggested that IR enhanced cap-dependent translation processes, an effect corroborated by the finding of increased eIF4F-cap complex formation detected after irradiation in all GSC lines. Translatome analyses also predicted that Golgi function was affected by IR. Accordingly, Golgi dispersal was detected after irradiation of each of the GSC lines. In addition to the common responses seen, translatome analyses predicted cell line-specific changes in mitochondria, as substantiated by changes in mitochondrial mass and DNA content. Together, these results suggest that analysis of radiation-induced translatomes can provide new molecular insights concerning the radiation response of cancer cells. More specifically, they suggest that the translational control of gene expression may provide a source of molecular targets for glioblastoma radiosensitization. (C) 2016 AACR. C1 [Wahba, Amy; Rath, Barbara H.; Bisht, Kheem; Camphausen, Kevin; Tofilon, Philip J.] NCI, Radiat Oncol Branch, Bldg 10, Bethesda, MD 20892 USA. RP Tofilon, PJ (reprint author), NCI, 10 Ctr Dr,MSC 1002,Bldg 10,B3B69B, Bethesda, MD 20892 USA. EM tofionp@mail.nih.gov FU Intramural NIH HHS [ZIA BC011372-04, ZIA BC011373-04] NR 45 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD MAY 15 PY 2016 VL 76 IS 10 BP 3078 EP 3087 DI 10.1158/0008-5472.CAN-15-3050 PG 10 WC Oncology SC Oncology GA DL7SS UT WOS:000375841000025 PM 27005284 ER PT J AU Kang, SA Rogers, JL Monteith, AJ Jiang, CC Schmitz, J Clarke, SH Tarrant, TK Truong, YK Diaz, M Fedoriw, Y Vilen, BJ AF Kang, SunAh Rogers, Jennifer L. Monteith, Andrew J. Jiang, Chuancang Schmitz, John Clarke, Stephen H. Tarrant, Teresa K. Truong, Young K. Diaz, Marilyn Fedoriw, Yuri Vilen, Barbara J. TI Apoptotic Debris Accumulates on Hematopoietic Cells and Promotes Disease in Murine and Human Systemic Lupus Erythematosus SO JOURNAL OF IMMUNOLOGY LA English DT Article ID C-REACTIVE PROTEIN; AUTOREACTIVE B-CELLS; FC-GAMMA-RIII; DEFICIENT MICE; MRL/LPR MICE; AUTOIMMUNE-DISEASE; ANTI-SM; RECEPTOR; NEPHRITIS; IGG AB Apoptotic debris, autoantibody, and IgG-immune complexes (ICs) have long been implicated in the inflammation associated with systemic lupus erythematosus (SLE); however, it remains unclear whether they initiate immune-mediated events that promote disease. In this study, we show that PBMCs from SLE patients experiencing active disease, and hematopoietic cells from lupus-prone MRL/lpr and NZM2410 mice accumulate markedly elevated levels of surface-bound nuclear self-antigens. On dendritic cells (DCs) and macrophages (MFs), the self-antigens are part of IgG-ICs that promote Fc gamma RI-mediated signal transduction. Accumulation of IgG-ICs is evident on ex vivo myeloid cells from MRL/lpr mice by 10 wk of age and steadily increases prior to lupus nephritis. IgG and Fc gamma RI play a critical role in disease pathology. Passive transfer of pathogenic IgG into IgG-deficient MRL/lpr mice promotes the accumulation of IgG-ICs prior to significant B cell expansion, BAFF secretion, and lupus nephritis. In contrast, diminishing the burden IgG-ICs in MRL/lpr mice through deficiency in Fc gamma RI markedly improves these lupus pathologies. Taken together, our findings reveal a previously unappreciated role for the cell surface accumulation of IgG-ICs in human and murine lupus. C1 [Kang, SunAh; Monteith, Andrew J.; Clarke, Stephen H.; Vilen, Barbara J.] Univ N Carolina, Dept Microbiol & Immunol, CB 7290,125 Mason Farm Rd, Chapel Hill, NC 27599 USA. [Rogers, Jennifer L.; Tarrant, Teresa K.] Univ N Carolina, Dept Med, Div Rheumatol Allergy & Immunol, Thurston Arthrit Res Ctr, Chapel Hill, NC 27599 USA. [Monteith, Andrew J.] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. [Jiang, Chuancang; Diaz, Marilyn] NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. [Schmitz, John; Fedoriw, Yuri] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. [Truong, Young K.] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. RP Vilen, BJ (reprint author), Univ N Carolina, Dept Microbiol & Immunol, CB 7290,125 Mason Farm Rd, Chapel Hill, NC 27599 USA. EM barb_vilen@med.unc.edu OI Schmitz, John/0000-0002-1425-236X; Kang, SunAh/0000-0002-6327-184X FU National Institutes of Health (NIH) [R01AI070984, R21AI105613]; Alliance for Lupus Research; National Center for Advancing Translational Sciences (NIH) [1UL1TR001111]; Flow Cytometry Core (NIH/National Cancer Institute) [P30CA016086]; Microscopy Services Laboratory (NIH) [CA 16086-26]; NIH [5T32AI07273-27] FX This work was supported by National Institutes of Health (NIH) Grants R01AI070984 and R21AI105613, Alliance for Lupus Research, the National Center for Advancing Translational Sciences (NIH) through Grant 1UL1TR001111, the Flow Cytometry Core (NIH/National Cancer Institute Grant P30CA016086), and the Microscopy Services Laboratory (NIH Grant CA 16086-26). A.J.M. was supported by NIH Grant 5T32AI07273-27. NR 59 TC 0 Z9 0 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2016 VL 196 IS 10 BP 4030 EP 4039 DI 10.4049/jimmunol.1500418 PG 10 WC Immunology SC Immunology GA DL7OY UT WOS:000375831200006 PM 27059595 ER PT J AU Wyatt, EV Diaz, K Griffin, AJ Rasmussen, JA Crane, DD Jones, BD Bosio, CM AF Wyatt, Elliott V. Diaz, Karina Griffin, Amanda J. Rasmussen, Jed A. Crane, Deborah D. Jones, Bradley D. Bosio, Catharine M. TI Metabolic Reprogramming of Host Cells by Virulent Francisella tularensis for Optimal Replication and Modulation of Inflammation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SCHU S4; ACTIVATED MACROPHAGES; O-ANTIGEN; HIF-1-ALPHA; SUPPRESSION; IL-1-BETA; TULAREMIA; INFECTION; AUTOPHAGY; PATHWAYS AB A shift in macrophage metabolism from oxidative phosphorylation to aerobic glycolysis is a requirement for activation to effectively combat invading pathogens. Francisella tularensis is a facultative intracellular bacterium that causes an acute, fatal disease called tularemia. Its primary mechanism of virulence is its ability to evade and suppress inflammatory responses while replicating in the cytosol of macrophages. The means by which F. tularensis modulates macrophage activation are not fully elucidated. In this study, we demonstrate that virulent F. tularensis impairs production of inflammatory cytokines in primary macrophages by preventing their shift to aerobic glycolysis, as evidenced by the downregulation of hypoxia inducible factor 1 alpha and failure to upregulate pfkfb3. We also show that Francisella capsule is required for this process. In addition to modulating inflammatory responses, inhibition of glycolysis in host cells is also required for early replication of virulent Francisella. Taken together, our data demonstrate that metabolic reprogramming of host cells by F. tularensis is a key component of both inhibition of host defense mechanisms and replication of the bacterium. C1 [Wyatt, Elliott V.; Diaz, Karina; Griffin, Amanda J.; Crane, Deborah D.; Bosio, Catharine M.] NIAID, Immun Pulm Pathogens Sect, Bacteriol Lab, Rocky Mt Labs,NIH, 903 S 4th St, Hamilton, MT 59840 USA. [Rasmussen, Jed A.] Univ Iowa, Carver Coll Med, Dept Microbiol, Iowa City, IA 52242 USA. [Jones, Bradley D.] Univ Iowa, Carver Coll Med, Genet Program, Iowa City, IA 52242 USA. [Jones, Bradley D.] Univ Iowa, Midwest Reg Ctr Excellence Biodef & Emerging Infe, Carver Coll Med, Iowa City, IA 52242 USA. [Diaz, Karina] Univ Washington, Sch Med, Seattle, WA USA. [Rasmussen, Jed A.] Snow Coll, Dept Biol, Ephraim, UT USA. RP Bosio, CM (reprint author), NIAID, Immun Pulm Pathogens Sect, Bacteriol Lab, Rocky Mt Labs,NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM bosioc@niaid.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 37 TC 0 Z9 0 U1 3 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2016 VL 196 IS 10 BP 4227 EP 4236 DI 10.4049/jimmunol.1502456 PG 10 WC Immunology SC Immunology GA DL7OY UT WOS:000375831200025 PM 27029588 ER PT J AU Ilinskaya, AN Dobrovolskaia, MA AF Ilinskaya, Anna N. Dobrovolskaia, Marina A. TI Understanding the immunogenicity and antigenicity of nanomaterials: Past, present and future SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Nanoparticles; Preclinical; Immunogenicity; Cytokines; Anaphylaxis; Phagocytosis; Antibody; Antigenicity ID ACCELERATED BLOOD CLEARANCE; GLYCOL-MODIFIED PROTEINS; ANTI-PEG ANTIBODIES; PEGYLATED LIPOSOMES; POLYETHYLENE-GLYCOL; ABC PHENOMENON; IMMUNOLOGICAL-PROPERTIES; COMPLEMENT ACTIVATION; MONOCLONAL-ANTIBODY; REPEATED INJECTIONS AB Nanoparticle immunogenicity and antigenicity have been under investigation for many years. During the past decade, significant progress has been made in understanding what makes a nanoparticle immunogenic, how immune cells respond to nanoparticles, what consequences of nanoparticle-specific antibody formation exist and how they challenge the application of nanoparticles for drug delivery. Moreover, it has been recognized that accidental contamination of therapeutic protein formulations with nanosized particulate materials may contribute to the immunogenicity of this type of biotechnology products. While the immunological properties of engineered nanomaterials and their application as vaccine carriers and adjuvants have been given substantial consideration in the current literature, little attention has been paid to nanoparticle immuno- and antigenicity. To fill in this gap, we herein provide an overview of this subject to highlight the current state of the field, review past and present research, and discuss future research directions. (C) 2016 Elsevier Inc. All rights reserved. C1 [Ilinskaya, Anna N.; Dobrovolskaia, Marina A.] NCI, Nanotechnol Characterizat Lab, Canc Res Technol Program, Leidos Biomed Res Inc,Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Dobrovolskaia, MA (reprint author), NCI, Nanotechnol Characterizat Lab, Canc Res Technol Program, Leidos Biomed Res Inc,Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM marina@mail.nih.gov RI Nanotechnology Characterization Lab, NCL/K-8454-2012 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work has been funded with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. NR 113 TC 4 Z9 4 U1 13 U2 36 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD MAY 15 PY 2016 VL 299 SI SI BP 70 EP 77 DI 10.1016/j.taap.2016.01.005 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA DJ8BA UT WOS:000374435900010 PM 26773813 ER PT J AU Dobrovolskaia, MA Shurin, M Shvedova, AA AF Dobrovolskaia, Marina A. Shurin, Michael Shvedova, Anna A. TI Current understanding of interactions between nanoparticles and the immune system SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Nanoparticles; Preclinical; Immunotoxicity; Immunology; Drug delivery ID WALLED CARBON NANOTUBES; CHALLENGING CLINICAL TRANSLATION; LEUKOCYTE PROCOAGULANT ACTIVITY; COLLOIDAL GOLD NANOPARTICLES; ALBUMIN-BOUND PACLITAXEL; ACID-BASED THERAPEUTICS; POTENT DELIVERY-SYSTEM; HUMAN DENDRITIC CELLS; ACUTE LUNG INJURY; IN-VITRO AB The delivery of drugs, antigens, and imaging agents benefits from using nanotechnology-based carriers. The successful translation of nanoformulations to the clinic involves thorough assessment of their safety profiles, which, among other end-points, includes evaluation of immunotoxicity. The past decade of research focusing on nano particle interaction with the immune system has been fruitful in terms of understanding the basics of nanoparticle immunocompatibility, developing a bioanalytical infrastructure to screen for nanoparticle-mediated immune reactions, beginning to uncover the mechanisms of nanoparticle immunotoxicity, and utilizing current knowledge about the structure-activity relationship between nanoparticles' physicochemical properties and their effects on the immune system to guide safe drug delivery. In the present review, we focus on the most prominent pieces of the nanoparticle-immune system puzzle and discuss the achievements, disappointments, and lessons learned over the past 15 years of research on the immunotoxicity of engineered nanomaterials. (C) 2016 Elsevier Inc. All rights reserved. C1 [Dobrovolskaia, Marina A.] NCI, Nanotechnol Characterizat Lab, Canc Res Technol Program, Leidos Biomed Res Inc,Frederick Natl Lab Canc Res, Ft Detrick, MD 21702 USA. [Shurin, Michael] Univ Pittsburgh, Med Ctr, Dept Pathol, Pittsburgh, PA 15213 USA. [Shurin, Michael] Univ Pittsburgh, Med Ctr, Dept Immunol, Pittsburgh, PA 15213 USA. [Shvedova, Anna A.] NIOSH, Hlth Effects Lab Div, Ctr Dis Control & Prevent, Morgantown, WV 26505 USA. [Shvedova, Anna A.] W Virginia Univ, Dept Physiol & Pharmacol, Morgantown, WV 26506 USA. RP Dobrovolskaia, MA (reprint author), NCI, Nanotechnol Characterizat Lab, Canc Res Technol Program, Leidos Biomed Res Inc,Frederick Natl Lab Canc Res, Ft Detrick, MD 21702 USA.; Shvedova, AA (reprint author), NIOSH, Hlth Effects Lab Div, Ctr Dis Control & Prevent, Morgantown, WV 26505 USA.; Shvedova, AA (reprint author), W Virginia Univ, Dept Physiol & Pharmacol, Morgantown, WV 26506 USA. EM marina@mail.nih.gov; ats1@cdc.gov RI Nanotechnology Characterization Lab, NCL/K-8454-2012 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX M.D.'s work has been funded with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. NR 174 TC 9 Z9 9 U1 15 U2 52 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD MAY 15 PY 2016 VL 299 SI SI BP 78 EP 89 DI 10.1016/j.taap.2015.12.022 PG 12 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA DJ8BA UT WOS:000374435900011 PM 26739622 ER PT J AU Colloca, L Pine, DS Ernst, M Miller, FG Grillon, C AF Colloca, Luana Pine, Daniel S. Ernst, Monique Miller, Franklin G. Grillon, Christian TI Vasopressin Boosts Placebo Analgesic Effects in Women: A Randomized Trial SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Anxiety; Expectancy; Pain; Sexual dimorphism; Stress; Verbal suggestions ID SOCIAL BRAIN; INTERMALE AGGRESSION; INTRANASAL OXYTOCIN; NEURAL CIRCUITRY; OPIOID ACTIVITY; OUT-GROUP; BEHAVIOR; PAIN; HUMANS; RESPONSES AB BACKGROUND: Social cues and interpersonal interactions strongly contribute to evoke placebo effects that are pervasive in medicine and depend upon the activation of endogenous modulatory systems. Here, we explore the possibility to boost placebo effects by targeting pharmacologically the vasopressin system, characterized by a sexually dimorphic response and involved in the regulation of human and nonhuman social behaviors. METHODS: We enrolled 109 healthy participants and studied the effects of intranasal administration of an arginine vasopressin 1A and 1B receptor agonist against 1) no treatment, 2) oxytocin, and 3) saline in a randomized, placebo-controlled, double-blind, parallel design trial using a well-established model of placebo analgesia while controlling for sex differences. RESULTS: Vasopressin agonists boosted placebo effects in women but had no effect in men. The effects of vasopressin on expectancy-induced analgesia were significantly larger than those observed in the no-treatment (p < .004), oxytocin (p < .001), and saline (p < .015) groups. Moreover, women with lower dispositional anxiety and cortisol levels showed the largest vasopressin-induced modulation of placebo effects, suggesting a moderating interplay between pre-existing psychological factors and treatment cortisol changes. CONCLUSIONS: This is the first study that demonstrates that arginine vasopressin boosts placebo effects and that the effect of vasopressin depends upon a significant sex by treatment interaction. These findings are novel and might open up new avenues for clinically relevant research due to the therapeutic potentials of vasopressin as well as the possibility to systematically control for influences of placebo responses in clinical trials. C1 [Colloca, Luana] Univ Maryland, Baltimore, MD 21201 USA. [Pine, Daniel S.; Ernst, Monique; Grillon, Christian] NIMH, Bethesda, MD 20892 USA. [Miller, Franklin G.] Weill Cornell Med Coll, New York, NY USA. RP Colloca, L (reprint author), Univ Maryland, Sch Nursing, 655 W Lombard St,Room 729A, Baltimore, MD 21201 USA. EM colloca@son.umaryland.edu OI Colloca, Luana/0000-0002-6503-4709 FU Intramural Program of the National Institute of Mental Health; University of Maryland Baltimore; International Association for Study of Pain; International Association for Study of Pain (IASP); Georgetown University (United States); National Center for Complementary and Integrative Health FX This project was partially supported by the Intramural Program of the National Institute of Mental Health, the National Center for Complementary and Integrative Health (LC), University of Maryland Baltimore (LC), and International Association for Study of Pain (Early Research Grant [LC]).; Dr. Colloca reports having received research funding from the International Association for Study of Pain (IASP) and University of Maryland Baltimore; travel reimbursements from different institutions, including the German Research Foundation Research Program (Germany), French Chapter of IASP, Scuola Internazionale Superiore di Studi Avanzati (Italy), Center of Biomedical Research Excellence (United States), Center for Pain Research and Innovation (North Carolina, United States), Brocher Foundation (Switzerland), University of Sydney (Australia), and IASP (United States); and lecture fees from Georgetown University (United States). All other authors reported no biomedical financial interests or potential conflicts of interest. NR 68 TC 2 Z9 2 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 15 PY 2016 VL 79 IS 10 BP 794 EP 802 DI 10.1016/j.biopsych.2015.07.019 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DK6ZJ UT WOS:000375074200008 PM 26321018 ER PT J AU Whitmore, NW Lin, SC AF Whitmore, Nathan W. Lin, Shih-Chieh TI Unmasking local activity within local field potentials (LFPs) by removing distal electrical signals using independent component analysis SO NEUROIMAGE LA English DT Article DE Movement artifact; Gamma oscillation; Basal forebrain; Event-related potential; 1/f power spectrum; Functional connectivity ID GAMMA-OSCILLATIONS; BLIND SEPARATION; CEREBRAL-CORTEX; EEG; BRAIN; ARTIFACTS; EMG; ELECTROCORTICOGRAPHY; STATISTICS; RECORDINGS AB Local field potentials (LFPs) are commonly thought to reflect the aggregate dynamics in local neural circuits around recording electrodes. However, we show that when LFPs are recorded in awake behaving animals against a distal reference on the skull as commonly practiced, LFPs are significantly contaminated by non-local and non-neural sources arising from the reference electrode and from movement-related noise. In a data set with simultaneously recorded LFPs and electroencephalograms (EEGs) across multiple brain regions while rats perform an auditory oddball task, we used independent component analysis (ICA) to identify signals arising from electrical reference and from volume-conducted noise based on their distributed spatial pattern across multiple electrodes and distinct power spectral features. These sources of distal electrical signals collectively accounted for 23-77% of total variance in unprocessed LFPs, as well as most of the gamma oscillation responses to the target stimulus in EEGs. Gamma oscillation power was concentrated in volume-conducted noise and was tightly coupled with the onset of licking behavior, suggesting a likely origin of muscle activity associated with body movement or orofacial movement. The removal of distal signal contamination also selectively reduced correlations of LFP/EEG signals between distant brain regions but not within the same region. Finally, the removal of contamination from distal electrical signals preserved an event-related potential (ERP) response to auditory stimuli in the frontal cortex and also increased the coupling between the frontal ERP amplitude and neuronal activity in the basal forebrain, supporting the conclusion that removing distal electrical signals unmasked local activity within LFPs. Together, these results highlight the significant contamination of LFPs by distal electrical signals and caution against the straightforward interpretation of unprocessed LFPs. Our results provide a principled approach to identify and remove such contamination to unmask local LFPs. Published by Elsevier Inc. C1 [Whitmore, Nathan W.; Lin, Shih-Chieh] NIA, Neural Circuits & Cognit Unit, Lab Behav Neurosci, NIH, 251 Bayview Blvd,Suite 100,9C220, Baltimore, MD 21224 USA. RP Lin, SC (reprint author), NIA, Neural Circuits & Cognit Unit, Lab Behav Neurosci, NIH, 251 Bayview Blvd,Suite 100,9C220, Baltimore, MD 21224 USA. EM shih-chieh.lin@nih.gov OI Lin, Shih-Chieh/0000-0003-3693-5476 FU intramural research program of the National Institute on Aging, NIH; NARSAD Young Investigator Award FX This research is funded by the intramural research program of the National Institute on Aging, NIH and by a NARSAD Young Investigator Award to SL. We thank D.P. Nguyen for collecting the original data set; H.M.V. Manzur, S.M. Raver, and P.R. Rapp for critical discussions and reading of the manuscript; H.M.V. Manzur and B. Brock for technical help. The authors declare no competing financial interests. NR 59 TC 2 Z9 2 U1 5 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD MAY 15 PY 2016 VL 132 BP 79 EP 92 DI 10.1016/j.neuroimage.2016.02.032 PG 14 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DK3QK UT WOS:000374832200010 PM 26899209 ER PT J AU Steele, VR Anderson, NE Claus, ED Bernat, EM Rao, V Assaf, M Pearlson, GD Calhoun, VD Kiehl, KA AF Steele, Vaughn R. Anderson, Nathaniel E. Claus, Eric D. Bernat, Edward M. Rao, Vikram Assaf, Michal Pearlson, Godfrey D. Calhoun, Vince D. Kiehl, Kent A. TI Neuroimaging measures of error-processing: Extracting reliable signals from event-related potentials and functional magnetic resonance imaging SO NEUROIMAGE LA English DT Article DE ERP; fMRI; Error-processing; Reliability; Time-frequency analysis; Principal component analysis; Independent component analysis ID ANTERIOR CINGULATE CORTEX; INDEPENDENT COMPONENT ANALYSIS; BRAIN ACTIVITY; GO/NOGO TASK; EXTERNALIZING PSYCHOPATHOLOGY; ANTISACCADE TASK; FMRI; ERP; NEGATIVITY; NUMBER AB Error-related brain activity has become an increasingly important focus of cognitive neuroscience research utilizing both event-related potentials (ERPs) and functional magnetic resonance imaging (fMRI). Given the significant time and resources required to collect these data, it is important for researchers to plan their experiments such that stable estimates of error-related processes can be achieved efficiently. Reliability of error-related brain measures will vary as a function of the number of error trials and the number of participants included in the averages. Unfortunately, systematic investigations of the number of events and participants required to achieve stability in error-related processing are sparse, and none have addressed variability in sample size. Our goal here is to provide data compiled from a large sample of healthy participants (n = 180) performing a Go/NoGo task, resampled iteratively to demonstrate the relative stability of measures of error-related brain activity given a range of sample sizes and event numbers included in the averages. We examine ERP measures of error-related negativity (ERN/Ne) and error positivity (Pe), as well as event-related fMRI measures locked to False Alarms. We find that achieving stable estimates of ERP measures required four to six error trials and approximately 30 participants; fMRI measures required six to eight trials and approximately 40 participants. Fewer trials and participants were required for measures where additional data reduction techniques (i.e., principal component analysis and independent component analysis) were implemented. Ranges of reliability statistics for various sample sizes and numbers of trials are provided. We intend this to be a useful resource for those planning or evaluating ERP or fMRI investigations with tasks designed to measure error-processing. (C) 2016 Elsevier Inc. All rights reserved. C1 [Steele, Vaughn R.] NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Steele, Vaughn R.; Anderson, Nathaniel E.; Claus, Eric D.; Rao, Vikram; Calhoun, Vince D.; Kiehl, Kent A.] Nonprofit Mind Res Network MRN, Albuquerque, NM USA. [Steele, Vaughn R.; Anderson, Nathaniel E.; Claus, Eric D.; Rao, Vikram; Calhoun, Vince D.; Kiehl, Kent A.] LBERI, Albuquerque, NM USA. [Steele, Vaughn R.; Calhoun, Vince D.; Kiehl, Kent A.] Univ New Mexico, Albuquerque, NM 87131 USA. [Bernat, Edward M.] Univ Maryland, College Pk, MD 20742 USA. [Assaf, Michal; Pearlson, Godfrey D.; Calhoun, Vince D.] Yale Univ, Sch Med, New Haven, CT USA. [Assaf, Michal; Pearlson, Godfrey D.] Inst Living, Olin Neuropsychiat Res Ctr, Hartford, CT USA. RP Steele, VR (reprint author), NIDA, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM vaughn.r.steele@gmail.com RI Rao, Vikram/J-6931-2016 FU National Institute of Mental Health [R01 MH070539-01, R01 MH071896-01, RO1 DA020709, P50-AA12870-05, F32MH098532]; National Institute of Biomedical Imaging and Bioengineering [1R01EB020407, 1R01EB006841]; National Institute of General Medical Sciences [P20GM103472]; Donaghue Foundation; Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland USA FX The authors thank Craig Bennett, Matthew Shane, J. Michael Maurer, Lora Cope, members of the Olin Neuropsychiatry Research Center, and the Mind Research Network. This research was supported in part by grants from the National Institute of Mental Health: R01 MH070539-01 (PI: Kiehl), R01 MH071896-01 (PI: Kiehl), RO1 DA020709 (PI: Pearlson), P50-AA12870-05 (PI for Project 4: Pearlson), and F32MH098532 (PI: Anderson), the National Institute of Biomedical Imaging and Bioengineering: 1R01EB020407 (PI: Calhoun) and 1R01EB006841 (PI: Calhoun), the National Institute of General Medical Sciences: P20GM103472 (PI: Calhoun), and The Donaghue Foundation (PI: Assaf). This work was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland USA. NR 70 TC 4 Z9 4 U1 5 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD MAY 15 PY 2016 VL 132 BP 247 EP 260 DI 10.1016/j.neuroimage.2016.02.046 PG 14 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DK3QK UT WOS:000374832200026 PM 26908319 ER PT J AU Irfanoglu, MO Nayak, A Jenkins, J Hutchinson, EB Sadeghi, N Thomas, CP Pierpaoli, C AF Irfanoglu, M. Okan Nayak, Amritha Jenkins, Jeffrey Hutchinson, Elizabeth B. Sadeghi, Neda Thomas, Cibu P. Pierpaoli, Carlo TI DR-TAMAS: Diffeomorphic Registration for Tensor Accurate Alignment of Anatomical Structures SO NEUROIMAGE LA English DT Article DE Diffusion tensor imaging; Diffeomorphic image registration; Fiber tractography ID DIFFUSION IMAGING METHOD; HUMAN BRAIN; SPATIAL NORMALIZATION; NONRIGID REGISTRATION; DTI REGISTRATION; SPIN-ECHO; MRI; IMAGES; ORIENTATION; DISEASE AB In this work, we propose DR-TAMAS (Diffeomorphic Registration for Tensor Accurate alignMent of Anatomical Structures), a novel framework for intersubject registration of Diffusion Tensor Imaging (DTI) data sets. This framework is optimized for brain data and its main goal is to achieve an accurate alignment of all brain structures, including white matter (WM), gray matter (GM), and spaces containing cerebrospinal fluid (CSF). Currently most DTI-based spatial normalization algorithms emphasize alignment of anisotropic structures. While some diffusion-derived metrics, such as diffusion anisotropy and tensor eigenvector orientation, are highly informative for proper alignment of WM, other tensor metrics such as the trace or mean diffusivity (MD) are fundamental for a proper alignment of GM and CSF boundaries. Moreover, it is desirable to include information from structural MRI data, e.g., T-1-weighted or T-2-weighted images, which are usually available together with the diffusion data. The fundamental property of DR-TAMAS is to achieve global anatomical accuracy by incorporating in its cost function the most informative metrics locally. Another important feature of DR-TAMAS is a symmetric time-varying velocity-based transformation model, which enables it to account for potentially large anatomical variability in healthy subjects and patients. The performance of DR-TAMAS is evaluated with several data sets and compared with other widely-used diffeomorphic image registration techniques employing both full tensor information and/or DTI-derived scalar maps. Our results show that the proposed method has excellent overall performance in the entire brain, while being equivalent to the best existing methods in WM. (C) 2016 Elsevier Inc. All rights reserved. C1 [Irfanoglu, M. Okan; Nayak, Amritha; Jenkins, Jeffrey; Hutchinson, Elizabeth B.; Sadeghi, Neda; Thomas, Cibu P.; Pierpaoli, Carlo] NICHHD, Sect Quantitat Imaging & Tissue Sci, NIH, Bethesda, MD 20892 USA. [Thomas, Cibu P.] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Irfanoglu, M. Okan; Nayak, Amritha; Jenkins, Jeffrey; Hutchinson, Elizabeth B.] Henry Jackson Fdn, Bethesda, MD 20814 USA. RP Irfanoglu, MO (reprint author), NICHHD, Sect Quantitat Imaging & Tissue Sci, NIH, Bethesda, MD 20892 USA. EM irfanoglumo@helix.nih.gov FU Intramural Research Program of the National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH); Department of Defense through the Henry Jackson Foundation (HJF Award) [W81XWH-13-2-0019]; U.S. Army Medical Research Acquisition Activity, Chandler Street, Fort Detrick, Maryland [21702-5014] FX This research was supported by the Intramural Research Program of the National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH). Support included funding from the Department of Defense through the Henry Jackson Foundation (HJF Award#: W81XWH-13-2-0019) with the U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick, Maryland, 21702-5014, being the awarding office. The contents of this work do not necessarily reflect the position or the policy of the government, and no official endorsement should be inferred. Special thanks go to Dr. Alex Martin, Section on Cognitive Neuropsychology, NIMH, for providing the MRI data used for the Atlas Set, Dr. Filippo Arrigoni of the Eugenio Medea Institute in Bosisio Parini, Italy, for providing the diffusion tensor data acquired on the HSP SPG11 subject, and Drs. Susan Schwerin and Sharon Juliano who are partner investigators in the Ferret study from which a sample dataset was used in this work. We also thank Liz Salak for editing this manuscript. NR 61 TC 3 Z9 3 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD MAY 15 PY 2016 VL 132 BP 439 EP 454 DI 10.1016/j.neuroimage.2016.02.066 PG 16 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DK3QK UT WOS:000374832200043 PM 26931817 ER PT J AU Vadnie, CA Ayers-Ringler, J Oliveros, A Abulseoud, OA Choi, S Hitschfeld, MJ Choi, DS AF Vadnie, Chelsea A. Ayers-Ringler, Jennifer Oliveros, Alfredo Abulseoud, Osama A. Choi, Sun Hitschfeld, Mario J. Choi, Doo-Sup TI Antipsychotic-like effects of a neurotensin receptor type 1 agonist SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Amphetamine; Prepulse inhibition; Locomotion; Neurotensin type 1 receptor; Glycogen synthase kinase 3 ID GLYCOGEN-SYNTHASE KINASE-3; SENSORIMOTOR GATING DEFICITS; PREPULSE INHIBITION; BIPOLAR DISORDER; ANIMAL-MODELS; LOCOMOTOR-ACTIVITY; ENTORHINAL CORTEX; MOOD STABILIZERS; BRATTLEBORO RATS; SCHIZOPHRENIA AB Although neurotensin (NT) analogs are known to produce antipsychotic-like effects, the therapeutic possibility of a brain penetrant NTS1 agonist in treating psychiatric disorders has not been well studied. Here, we examined whether PD149163, a brain-penetrant NTS1-specific agonist, displays antipsychotic-like effects in C57BL/6J mice by investigating the effect of PD149163 on amphetamine-mediated hyperactivity and amphetamine-induced disruption of prepulse inhibition. In addition, we assessed the effect of PD149163 on glycogen synthase kinase-3 (GSK-3) activity, a downstream molecular target of antipsychotics and mood stabilizers, using phospho-specific antibodies. PD149163 (0.1 and 0.5 mg/kg) inhibited amphetamine-induced hyperactivity in mice, indicating that NTS1 activation inhibits psychomotor agitation. PD149163 (0.5 mg/kg) also increased prepulse inhibition, suggesting that NTS1 activation reduces prepulse inhibition deficits which often co-occur with psychosis in humans. Interestingly, PD149163 increased the inhibitory serine phosphorylation on both GSK-3 alpha and GSK-3 beta in a dose- and time dependent manner in the nucleus accumbens and medial prefrontal cortex of the mice. Moreover, PD149163 inhibited GSK-3 activity in the nucleus accumbens and medial prefrontal cortex in the presence of amphetamine. Thus, like most current antipsychotics and mood stabilizers, PD149163 inhibited GSK-3 activity in cortico-striatal circuitry. Together, our findings indicate that PD149163 may be a novel antipsychotic. (C) 2016 Elsevier B.V. All rights reserved. C1 [Vadnie, Chelsea A.; Ayers-Ringler, Jennifer; Choi, Doo-Sup] Mayo Grad Sch, Neurobiol Dis Program, Rochester, MN USA. [Vadnie, Chelsea A.; Ayers-Ringler, Jennifer; Oliveros, Alfredo; Choi, Sun; Choi, Doo-Sup] Mayo Clin, Coll Med, Dept Mol Pharmacol & Expt Therapeut, 200 First St SW, Rochester, MN 55905 USA. [Abulseoud, Osama A.; Hitschfeld, Mario J.; Choi, Doo-Sup] Mayo Clin, Coll Med, Dept Psychiat & Psychol, Rochester, MN USA. [Vadnie, Chelsea A.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Abulseoud, Osama A.] NIDA, Baltimore, MD USA. [Hitschfeld, Mario J.] Hosp Dr Sotero del Rio, Psychiat & Mental Hlth Serv, Santiago, Chile. RP Choi, DS (reprint author), Mayo Clin, Coll Med, Dept Mol Pharmacol & Expt Therapeut, 200 First St SW, Rochester, MN 55905 USA. EM choids@mayo.edu RI Choi, Doo-Sup/G-9474-2012 FU Samuel C. Johnson Genomics of Addiction Program; Ulm Foundation; American Society for Pharmacology and Experimental Therapeutics; National Institutes of Health [AA018779]; Mayo Graduate School FX This project was funded by the Samuel C. Johnson Genomics of Addiction Program, the Ulm Foundation, the David Lehr Research Award from American Society for Pharmacology and Experimental Therapeutics, and by a grant from the National Institutes of Health (AA018779). The funding sources had no involvement in the study design or preparation of the manuscript. CAV was supported by fellowship funding from Mayo Graduate School. NR 68 TC 1 Z9 1 U1 3 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 EI 1872-7549 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD MAY 15 PY 2016 VL 305 BP 8 EP 17 DI 10.1016/j.bbr.2016.02.019 PG 10 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA DK0OZ UT WOS:000374613400002 PM 26909848 ER PT J AU Fraser, KM Haight, JL Gardner, EL Flagel, SB AF Fraser, Kurt M. Haight, Joshua L. Gardner, Eliot L. Flagel, Shelly B. TI Examining the role of dopamine D-2 and D-3 receptors in Pavlovian conditioned approach behaviors SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Motivation; Sign-tracking; Goal-tracking; Dopamine; D-2 receptor; D-3 receptor ID INCENTIVE SALIENCE; ACCUMBENS CORE; INDIVIDUAL-DIFFERENCES; GOAL-TRACKING; REWARD; RATS; CUE; PREDICTION; NUCLEUS; NEURONS AB Elucidating the neurobiological mechanisms underlying individual differences in the extent to which reward cues acquire the ability to act as incentive stimuli may contribute to the development of successful treatments for addiction and related disorders. We used the sign-tracker/goal-tracker animal model to examine the role of dopamine D-2 and D-3 receptors in the propensity to attribute incentive salience to reward cues. Following Pavlovian training, wherein a discrete lever-cue was paired with food reward, rats were classified as sign- or goal-trackers based on the resultant conditioned response. We examined the effects of D-2/D-3 agonists, 7-OH-DPAT (0.01-0.32 mg/kg) or pramipexole (0.032-0.32 mg/kg), the D-2/D-3 antagonist raclopride (0.1 mg/kg), and the selective D-3 antagonist, SB-277011A (6 or 24 mg/kg), on the expression of sign- and goal-tracking conditioned responses. The lever-cue acquired predictive value and elicited a conditioned response for sign- and goal-trackers, but only for sign-trackers did it also acquire incentive value. Following administration of either 7-OH-DPAT, pramipexole, or raclopride, the performance of the previously acquired conditioned response was attenuated for both sign- and goal-trackers. For sign-trackers, the D-2/D-3 agonist, 7-OH-DPAT, also attenuated the conditioned reinforcing properties of the lever-cue. The selective D-3 antagonist did not affect either conditioned response. Alterations in D-2/D-3 receptor signaling, but not D-3 signaling alone, transiently attenuate a previously acquired Pavlovian conditioned response, regardless of whether the response is a result of incentive motivational processes. These findings suggest activity at the dopamine D-2 receptor is critical for a reward cue to maintain either its incentive or predictive qualities. (C) 2016 Elsevier B.V. All rights reserved. C1 [Fraser, Kurt M.; Flagel, Shelly B.] Univ Michigan, Undergrad Program Neurosci, Ann Arbor, MI 48109 USA. [Fraser, Kurt M.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Haight, Joshua L.; Flagel, Shelly B.] Univ Michigan, Neurosci Grad Program, Ann Arbor, MI 48109 USA. [Gardner, Eliot L.] NIDA, Intramural Res Program, Baltimore, MD USA. [Flagel, Shelly B.] Univ Michigan, Mol & Behav Neurosci Inst, 205 Zina Pitcher Pl, Ann Arbor, MI 48109 USA. RP Flagel, SB (reprint author), Univ Michigan, Mol & Behav Neurosci Inst, 205 Zina Pitcher Pl, Ann Arbor, MI 48109 USA. EM sflagel@umich.edu OI Fraser, Kurt/0000-0002-2988-7683; Haight, Joshua/0000-0003-1508-4123 FU National Institute on Drug Abuse [T32 DA007281, F31 DA037680, P01 DA031656]; Intramural Research Program, National Institute on Drug Abuse FX This work was supported by grants from the National Institute on Drug Abuse to J.L.H (T32 DA007281; F31 DA037680) and S.B.F (P01 DA031656) and by funding from the Intramural Research Program, National Institute on Drug Abuse to E.L.G. NR 59 TC 6 Z9 6 U1 3 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 EI 1872-7549 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD MAY 15 PY 2016 VL 305 BP 87 EP 99 DI 10.1016/j.bbr.2016.02.022 PG 13 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA DK0OZ UT WOS:000374613400011 PM 26909847 ER PT J AU Minton, AP AF Minton, Allen P. TI Recent applications of light scattering measurement in the biological and biopharmaceutical sciences SO ANALYTICAL BIOCHEMISTRY LA English DT Review ID PROTEIN-PROTEIN INTERACTIONS; BOVINE SERUM-ALBUMIN; OSMOTIC VIRIAL-COEFFICIENTS; REVERSIBLE SELF-ASSOCIATION; MONOCLONAL-ANTIBODY ROLE; QUANTITATIVE CHARACTERIZATION; CONCENTRATED-SOLUTIONS; INTERMOLECULAR INTERACTIONS; ELECTROPHORETIC MOBILITY; GUANIDINE-HYDROCHLORIDE C1 [Minton, Allen P.] NIDDK, Lab Biochem & Genet, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Minton, AP (reprint author), NIDDK, Lab Biochem & Genet, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM minton@helix.nih.gov OI Minton, Allen/0000-0001-8459-1247 FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases FX The author thanks Patricia Fausset for assistance in the literature search and Dan Some for Figs. 1, 2, 4 and 5 and for constructive comments on the initial draft. This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 96 TC 3 Z9 3 U1 17 U2 37 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 EI 1096-0309 J9 ANAL BIOCHEM JI Anal. Biochem. PD MAY 15 PY 2016 VL 501 BP 4 EP 22 DI 10.1016/j.ab.2016.02.007 PG 19 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA DJ4UT UT WOS:000374204300002 PM 26896682 ER PT J AU Vazquez, L Blood, JD Wu, J Chaplin, TM Hommer, RE Rutherford, HJV Potenza, MN Mayes, LC Crowley, MJ AF Vazquez, Lauren Blood, Julia D. Wu, Jia Chaplin, Tara M. Hommer, Rebecca E. Rutherford, Helena J. V. Potenza, Marc N. Mayes, Linda C. Crowley, Michael J. TI High frequency heart-rate variability predicts adolescent depressive symptoms, particularly anhedonia, across one year SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Adolescence; Depression; Anhedonia; Heart rate variability; Time-frequency analysis ID RESPIRATORY SINUS ARRHYTHMIA; CARDIOVASCULAR CHANGES; STRESS; MODEL; CHILDREN; DYSREGULATION; DISORDER; DISEASE; ANXIETY; ASSOCIATION AB Background: Few prospective studies examine the link between lower heart rate variability (HRV) and depression symptoms in adolescents. A recent animal model specifically links HRV to anhedonia, suggesting a potential translational model for human research. Method: We investigated the association between spectral measures of resting HRV and depressive symptoms measured one year later, among 73 adolescents, aged 11-18 years. We evaluated (1) the predictive power of relative high frequency (HF) HRV, relative low frequency (LF) and relative very low frequency (VLF) HRV for depressive symptoms; and (2) the relative strength of association between HF HRV and depressive symptomatology (anhedonia, negative mood, interpersonal problems, ineffectiveness, negative self-esteem). Results: HF HRV significantly predicted self-reported depressive symptoms across one year, controlling for age, puberty and sex. HF HRV was most strongly associated with anhedonia one year later, after considering other facets of depressive symptomatology. Conclusions: Results provide support for the prospective relationship between relative HF HRV and depressive symptoms among adolescents across one year. Findings concur with rodent models that suggest a specific link between HF HRV and anhedonia. Limitations: We investigated relative spectral power HF HRV and depressive symptom dimensions. We cannot make strong claims about these associations in clinical depression. Physical activity levels could be controlled in future work. (C) 2016 Elsevier B.V. All rights reserved. C1 [Vazquez, Lauren; Wu, Jia; Rutherford, Helena J. V.; Potenza, Marc N.; Mayes, Linda C.; Crowley, Michael J.] Yale Univ, Sch Med, Yale Child Study Ctr, New Haven, CT USA. [Blood, Julia D.] Univ Texas Hlth Sci Ctr San Antonio, Sch Med, San Antonio, TX 78229 USA. [Chaplin, Tara M.] George Mason Univ, Dept Psychol, Fairfax, VA 22030 USA. [Hommer, Rebecca E.] NIMH, Emot & Dev Branch, NIH, Bethesda, MD 20892 USA. [Crowley, Michael J.] Yale Child Study Ctr, Program Anxiety Disorders, New Haven, CT 06520 USA. [Wu, Jia; Rutherford, Helena J. V.; Mayes, Linda C.; Crowley, Michael J.] Yale Child Study Ctr, Dev Electrophysiol Lab, New Haven, CT 06520 USA. [Potenza, Marc N.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Potenza, Marc N.] Yale Univ, Sch Med, Dept Neurosci, New Haven, CT USA. [Potenza, Marc N.] Yale Univ, Sch Med, CASAColumbia, New Haven, CT USA. [Potenza, Marc N.] Yale Univ, Sch Med, Connecticut Mental Hlth Ctr, New Haven, CT 06508 USA. RP Crowley, MJ (reprint author), Yale Child Study Ctr, 230 South Frontage Rd, New Haven, CT 06520 USA. EM michael.crowley@yale.edu FU NARSAD Young Investigator Award; Yale Interdisciplinary Research Consortium on Stress, Self-Control and Addiction Pilot Project [UL1RR024925-01]; NIDA [K01 DA034125, RO1-DA-06025, DA-017863, KO5]; Gustavus and Louise Pfeiffer Research Foundation; CTSA from the National Center for Research Resources (NCRR) a component of the National Institutes of Health (NIH) [UL1 RR024139]; NIH Roadmap for Medical Research FX This research was supported by NARSAD Young Investigator Award (MJC), Yale Interdisciplinary Research Consortium on Stress, Self-Control and Addiction Pilot Project funding (MJC) through UL1RR024925-01 (R. Sinha); NIDA Grants K01 DA034125 (MJC), RO1-DA-06025 (LCM), DA-017863 (LCM) and KO5 (LCM), and a Grant from the Gustavus and Louise Pfeiffer Research Foundation (LCM). This publication was also made possible by CTSA Grant Number UL1 RR024139 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. NR 38 TC 2 Z9 2 U1 4 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD MAY 15 PY 2016 VL 196 BP 243 EP 247 DI 10.1016/j.jad.2016.02.040 PG 5 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DH3WF UT WOS:000372716800029 PM 26943940 ER PT J AU Wu, K Spiegelman, D Hou, T Albanes, D Allen, NE Berndt, SI van den Brandt, PA Giles, GG Giovannucci, E Goldbohm, RA Goodman, GG Goodman, PJ Hakansson, N Inoue, M Key, TJ Kolonel, LN Mannisto, S McCullough, ML Neuhouser, ML Park, Y Platz, EA Schenk, JM Sinha, R Stampfer, MJ Stevens, VL Tsugane, S Visvanathan, K Wilkens, LR Wolk, A Ziegler, RG Smith-Warner, SA AF Wu, Kana Spiegelman, Donna Hou, Tao Albanes, Demetrius Allen, Naomi E. Berndt, Sonja I. van den Brandt, Piet A. Giles, Graham G. Giovannucci, Edward Goldbohm, R. Alexandra Goodman, Gary G. Goodman, Phyllis J. Hakansson, Niclas Inoue, Manami Key, Timothy J. Kolonel, Laurence N. Mannisto, Satu McCullough, Marjorie L. Neuhouser, Marian L. Park, Yikyung Platz, Elizabeth A. Schenk, Jeannette M. Sinha, Rashmi Stampfer, Meir J. Stevens, Victoria L. Tsugane, Shoichiro Visvanathan, Kala Wilkens, Lynne R. Wolk, Alicja Ziegler, Regina G. Smith-Warner, Stephanie A. TI Associations between unprocessed red and processed meat, poultry, seafood and egg intake and the risk of prostate cancer: A pooled analysis of 15 prospective cohort studies SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE prostate cancer; diet; unprocessed red meat; processed meat; poultry; seafood; egg ID FOOD-FREQUENCY QUESTIONNAIRE; MULTIETHNIC COHORT; FISH CONSUMPTION; HETEROCYCLIC AMINES; PROPENSITY SCORES; ANIMAL PRODUCTS; SUPPLEMENT USE; SWEDISH MEN; DIET; PREVENTION AB Reports relating meat intake to prostate cancer risk are inconsistent. Associations between these dietary factors and prostate cancer were examined in a consortium of 15 cohort studies. During follow-up, 52,683 incident prostate cancer cases, including 4,924 advanced cases, were identified among 842,149 men. Cox proportional hazard models were used to calculate study-specific relative risks (RR) and then pooled using random effects models. Results do not support a substantial effect of total red, unprocessed red and processed meat for all prostate cancer outcomes, except for a modest positive association for tumors identified as advanced stage at diagnosis (advanced(r)). For seafood, no substantial effect was observed for prostate cancer regardless of stage or grade. Poultry intake was inversely associated with risk of advanced and fatal cancers (pooled multivariable RR [MVRR], 95% confidence interval, comparing 45 vs. <5 g/day: advanced 0.83, 0.70-0.99; trend test p value 0.29), fatal, 0.69, 0.59-0.82, trend test p value 0.16). Participants who ate 25 versus <5 g/day of eggs (1 egg approximate to 50 g) had a significant 14% increased risk of advanced and fatal cancers (advanced 1.14, 1.01-1.28, trend test p value 0.01; fatal 1.14, 1.00-1.30, trend test p value 0.01). When associations were analyzed separately by geographical region (North America vs. other continents), positive associations between unprocessed red meat and egg intake, and inverse associations between poultry intake and advanced, advanced(r) and fatal cancers were limited to North American studies. However, differences were only statistically significant for eggs. Observed differences in associations by geographical region warrant further investigation. What's New? The debate over red meat consumption and cancer risk is longstanding. In this consortium of 15 cohorts from North America, Europe, Australia and Asia, the authors examined over 50,000 cases of prostate cancer and the associated intake of unprocessed red and processed meat, seafood, eggs and poultry. Overall no substantial risk for unprocessed red and processed meat intake and prostate cancer was found. Interestingly, positive associations between intake of unprocessed red meat as well as eggs and advanced or fatal prostate cancers were detected only in participants living in North America, a finding which warrants further investigation into meat and egg composition, consumption and potential differences in lifestyle and screening practices between continents. C1 [Wu, Kana; Hou, Tao; Giovannucci, Edward; Stampfer, Meir J.; Smith-Warner, Stephanie A.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Spiegelman, Donna; Giovannucci, Edward; Stampfer, Meir J.; Smith-Warner, Stephanie A.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Spiegelman, Donna] Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Albanes, Demetrius; Berndt, Sonja I.; Sinha, Rashmi; Ziegler, Regina G.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Allen, Naomi E.] Univ Oxford, Clin Trial Serv Unit, Nuffield Dept Populat Hlth, Oxford, England. [Allen, Naomi E.] Univ Oxford, Epidemiol Studies Unit, Oxford, England. [van den Brandt, Piet A.] Maastricht Univ, GROW Sch Oncol & Dev Biol, Dept Epidemiol, NL-6200 MD Maastricht, Netherlands. [Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Giles, Graham G.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic, Australia. [Giovannucci, Edward; Stampfer, Meir J.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Giovannucci, Edward; Stampfer, Meir J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Goldbohm, R. Alexandra] TNO Qual Life, Dept Food & Chem Risk Anal, Zeist, Netherlands. [Goodman, Gary G.; Neuhouser, Marian L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Goodman, Phyllis J.] SWOG Stat Ctr, Seattle, WA USA. [Hakansson, Niclas; Wolk, Alicja] Karolinska Inst, Inst Environm Med, Div Nutr Epidemiol, S-10401 Stockholm, Sweden. [Inoue, Manami; Tsugane, Shoichiro] Natl Canc Ctr, Res Ctr Canc Prevent & Screening, Epidemiol & Prevent Grp, Tokyo 104, Japan. [Key, Timothy J.] Univ Oxford, Canc Epidemiol Unit, Nuffield Dept Populat Hlth, Oxford, England. [Kolonel, Laurence N.; Wilkens, Lynne R.] Univ Hawaii, Canc Res Ctr, Dept Epidemiol, Honolulu, HI 96813 USA. [Mannisto, Satu] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [McCullough, Marjorie L.; Stevens, Victoria L.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Park, Yikyung] Washington Univ, Sch Med, Div Publ Hlth Sci, St Louis, MO USA. [Platz, Elizabeth A.; Visvanathan, Kala] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Schenk, Jeannette M.] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, 1124 Columbia St, Seattle, WA 98104 USA. RP Wu, K (reprint author), 665 Huntington Ave, Boston, MA 02115 USA. EM kana.wu@channing.harvard.edu OI Mannisto, Satu/0000-0002-8668-3046 FU National Cancer Institute, National Institutes of Health, USA [P01 CA55075]; World Cancer Research Fund (WCRF UK), as part of the WCRF International grant programme [2009/89] FX Grant sponsor: National Cancer Institute, National Institutes of Health, USA; Grant number: P01 CA55075; Grant sponsor: World Cancer Research Fund (WCRF UK), as part of the WCRF International grant programme; Grant number: 2009/89 NR 68 TC 4 Z9 4 U1 5 U2 25 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD MAY 15 PY 2016 VL 138 IS 10 BP 2368 EP 2382 DI 10.1002/ijc.29973 PG 15 WC Oncology SC Oncology GA DG7IF UT WOS:000372257300007 PM 26685908 ER PT J AU Pongpiachan, S Wiriwutikorn, T Rungruang, C Yodden, K Duangdee, N Sbrilli, A Gobbi, M Centeno, C AF Pongpiachan, S. Wiriwutikorn, T. Rungruang, C. Yodden, K. Duangdee, N. Sbrilli, A. Gobbi, M. Centeno, C. TI Impacts of micro-emulsion system on polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) reduction from industrial boilers SO FUEL LA English DT Article DE Best available techniques (BAT); Best environmental practices (BEP); PCDDs/PCDFs; Micro-emulsion; Industrial boiler ID POLYCYCLIC AROMATIC-HYDROCARBONS; PERSISTENT ORGANIC POLLUTANTS; WATER-OIL EMULSION; COMBUSTION; EMISSION; BIOACCUMULATION; THAILAND; PAHS; INCINERATOR; FUEL AB Previous studies have raised public concerns regarding issues of adverse health impacts on human exposure to PCDDs/PCDFs. Industrial boilers have been criticized as one of the main contributors of PCDDs/PCDFs emissions. To minimize dioxin releases from unintentional production, a study on the best available techniques (BAT) and best environmental practices (BEP) was conducted using a micro-emulsion technology, which was developed for enhancing the combustion efficiency of industrial boilers. In this study, the performance of micro-emulsion technology on reducing PCDDs/PCDFs emissions from an industrial boiler using three types of fuels, 100% heavy fuel oil (100% HFO), 90% HFO coupled with 10% ethanol (90% HFO-10% ethanol), and 90% HFO coupled with 10% water (90% HFO-10% water), were carefully evaluated and statistically analyzed. The use of the ANOVA statistical method for the analysis of variance showed that there were no significant differences associated with the trace gaseous concentrations (e.g., CO, NOx, and SO2) among the three types of fuels. Furthermore, an industrial boiler using 90% HFO-10% ethanol tends to show the minimum PCDDs/PCDFs emissions in comparison with other two types of fuels. In addition, significant reductions of TCDDs, PeCDDs, HxCDDs, HpCDDs, TCDFs, PeCDFs, and total PCDDs were observed in an industrial boiler using the combination of HFO and ethanol. Overall, micro-emulsion can be considered a promising clean technology in term of PCDDs/PCDFs reduction. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Pongpiachan, S.] NIDA, Ctr Res & Dev Disaster Prevent & Management, Sch Social & Environm Dev, 118 Moo 3,Serithai Rd, Bangkok 10240, Thailand. [Wiriwutikorn, T.; Rungruang, C.; Yodden, K.] PCD, Waste & Hazardous Substance Management Bur, Hazardous Substance Div, 92 Soi Phahonyothin 7,Phahonyothin Rd, Bangkok, Thailand. [Duangdee, N.] Red Bull Distillery Co Ltd, 15 Moo 14,Vibhavadi Rangsit Rd, Bangkok, Thailand. [Sbrilli, A.; Gobbi, M.; Centeno, C.] Environm Management Branch, Stockholm Convent Unit, A-1400 Vienna, Austria. RP Pongpiachan, S (reprint author), NIDA, Ctr Res & Dev Disaster Prevent & Management, Sch Social & Environm Dev, 118 Moo 3,Serithai Rd, Bangkok 10240, Thailand. EM pongpiajun@gmail.com FU GEF (Global Environment Fund) FX The authors acknowledge GEF (Global Environment Fund) for financial support of this project. NR 30 TC 0 Z9 0 U1 10 U2 45 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0016-2361 EI 1873-7153 J9 FUEL JI Fuel PD MAY 15 PY 2016 VL 172 BP 58 EP 64 DI 10.1016/j.fuel.2016.01.003 PG 7 WC Energy & Fuels; Engineering, Chemical SC Energy & Fuels; Engineering GA DC0BI UT WOS:000368881200007 ER PT J AU Broce, S Hensley, L Sato, T Lehrer-Graiwer, J Essrich, C Edwards, KJ Pajda, J Davis, CJ Bhadresh, R Hurt, CR Freeman, B Lingappa, VR Kelleher, CA Karpuj, MV AF Broce, Sean Hensley, Lisa Sato, Tomoharu Lehrer-Graiwer, Joshua Essrich, Christian Edwards, Katie J. Pajda, Jacqueline Davis, Christopher J. Bhadresh, Rami Hurt, Clarence R. Freeman, Beverly Lingappa, Vishwanath R. Kelleher, Colm A. Karpuj, Marcela V. TI Biochemical and biophysical characterization of cell-free synthesized Rift Valley fever virus nucleoprotein capsids enables in vitro screening to identify novel antivirals SO BIOLOGY DIRECT LA English DT Article DE Cell-free protein synthesis; Rift Valley fever virus; Antivirals; Capsid nucleoprotein oligomerization; Wheat germ extracts ID FREE SYSTEM; HEPATITIS; PROTEIN; RNA; PATHWAY; CATTLE AB Background: Viral capsid assembly involves the oligomerization of the capsid nucleoprotein (NP), which is an essential step in viral replication and may represent a potential antiviral target. An in vitro transcription-translation reaction using a wheat germ (WG) extract in combination with a sandwich ELISA assay has recently been used to identify small molecules with antiviral activity against the rabies virus. Results: Here, we examined the application of this system to viruses with capsids with a different structure, such as the Rift Valley fever virus (RVFV), the etiological agent of a severe emerging infectious disease. The biochemical and immunological characterization of the in vitro-generated RVFV NP assembly products enabled the distinction between intermediately and highly ordered capsid structures. This distinction was used to establish a screening method for the identification of potential antiviral drugs for RVFV countermeasures. Conclusions: These results indicated that this unique analytical system, which combines nucleoprotein oligomerization with the specific immune recognition of a highly ordered capsid structure, can be extended to various viral families and used both to study the early stages of NP assembly and to assist in the identification of potential antiviral drugs in a cost-efficient manner. C1 [Broce, Sean; Sato, Tomoharu; Lehrer-Graiwer, Joshua; Essrich, Christian; Bhadresh, Rami; Hurt, Clarence R.; Freeman, Beverly; Lingappa, Vishwanath R.; Kelleher, Colm A.; Karpuj, Marcela V.] Prosetta Antiviral Inc, San Francisco, CA USA. [Hensley, Lisa] NIAID, Ft Detrick, MD USA. [Sato, Tomoharu] DuPont Ind Biosci, Palo Alto, CA USA. [Lehrer-Graiwer, Joshua] Global Blood Therapeut Inc, Palo Alto, CA USA. [Edwards, Katie J.; Karpuj, Marcela V.] CUBRC Inc, Buffalo, NY USA. [Pajda, Jacqueline] Life Technol Inc, Grand Isl, NY USA. [Davis, Christopher J.] US Dept HHS, Biomed Adv Res & Dev Author, Off Assistant Secretary Preparedness & Response, Washington, DC 20201 USA. [Bhadresh, Rami] Syngene Int Ltd, Biocon Bristol Myers Squibb, Bangalore, Karnataka, India. [Kelleher, Colm A.] Bigelow Aerosp Adv Space Studies, Las Vegas, NV USA. [Karpuj, Marcela V.] Bar Ilan Univ, Fac Med, 8 Henrietta Szold, IL-1311502 Safed, Israel. RP Karpuj, MV (reprint author), Prosetta Antiviral Inc, San Francisco, CA USA.; Karpuj, MV (reprint author), CUBRC Inc, Buffalo, NY USA. EM mvkarpuj@bioa2z.com FU United States Defense Threat Reduction Agency [HDTRA1-06-C-0028] FX This study was supported in part by the United States Defense Threat Reduction Agency under Contract No. HDTRA1-06-C-0028. Any opinions, findings and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the Defense Threat Reduction Agency. The authors would like to thank Dr. Theodor Chitlaru and Dr. Edith Chitlaru for the critical review of the manuscript. We thank Scott Fujawa, Dr. Shuly Cooper, and Dr. Soen for their continous support. NR 27 TC 0 Z9 0 U1 2 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD MAY 14 PY 2016 VL 11 AR 25 DI 10.1186/s13062-016-0126-5 PG 14 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DN7JJ UT WOS:000377251100001 PM 27179769 ER PT J AU Maduro, V Pusey, BN Cherukuri, PF Atkins, P du Souich, C Rupps, R Limbos, M Adams, DR Bhatt, SS Eydoux, P Links, AE Lehman, A Malicdan, MC Mason, CE Morimoto, M Mullikin, JC Sear, A Van Karnebeek, C Stankiewicz, P Gahl, WA Toro, C Boerkoel, CF AF Maduro, Valerie Pusey, Barbara N. Cherukuri, Praveen F. Atkins, Paul du Souich, ChristSle Rupps, Rosemarie Limbos, Marjolaine Adams, David R. Bhatt, Samarth S. Eydoux, Patrice Links, Amanda E. Lehman, Anna Malicdan, May C. Mason, Christopher E. Morimoto, Marie Mullikin, James C. Sear, Andrew Van Karnebeek, Clara Stankiewicz, Pawel Gahl, William A. Toro, Camilo Boerkoel, Cornelius F. TI Complex translocation disrupting TCF4 and altering TCF4 isoform expression segregates as mild autosomal dominant intellectual disability SO ORPHANET JOURNAL OF RARE DISEASES LA English DT Article DE Intellectual disability; Promoter utilization; Pitt-Hopkins syndrome; TCF4; Gene expression; Translocation; Transcriptome; RNAseq ID PITT-HOPKINS-SYNDROME; LINKED MENTAL-RETARDATION; TRANSCRIPTION FACTOR; EPIGENETIC MECHANISMS; CLINICAL SCORE; RNA-SEQ; GENE; MUTATIONS; PHENOTYPE; DELETION AB Background: Mutations of TCF4, which encodes a basic helix-loop-helix transcription factor, cause Pitt-Hopkins syndrome (PTHS) via multiple genetic mechanisms. TCF4 is a complex locus expressing multiple transcripts by alternative splicing and use of multiple promoters. To address the relationship between mutation of these transcripts and phenotype, we report a three-generation family segregating mild intellectual disability with a chromosomal translocation disrupting TCF4. Results: Using whole genome sequencing, we detected a complex unbalanced karyotype disrupting TCF4 (46,XY,del(14)(q23.3q23.3)del(18)(q21.2q21.2)del(18)(q21.2q21.2)inv(18)(q21.2q21.2)t(14; 18)(q23.3; q21.2)(14pter (R) 14q23.3::18q21.2 (R) 18q21.2::18q21.1 (R) 18qter;18pter (R) 18q21.2::14q23.3 (R) 14qter). Subsequent transcriptome sequencing, qRT-PCR and nCounter analyses revealed that cultured skin fibroblasts and peripheral blood had normal expression of genes along chromosomes 14 or 18 and no marked changes in expression of genes other than TCF4. Affected individuals had 12-33 fold higher mRNA levels of TCF4 than did unaffected controls or individuals with PTHS. Although the derivative chromosome generated a PLEKHG3-TCF4 fusion transcript, the increased levels of TCF4 mRNA arose from transcript variants originating distal to the translocation breakpoint, not from the fusion transcript. Conclusions: Although validation in additional patients is required, our findings suggest that the dysmorphic features and severe intellectual disability characteristic of PTHS are partially rescued by overexpression of those short TCF4 transcripts encoding a nuclear localization signal, a transcription activation domain, and the basic helix-loop-helix domain. C1 [Maduro, Valerie; Pusey, Barbara N.; Cherukuri, Praveen F.; Adams, David R.; Links, Amanda E.; Malicdan, May C.; Gahl, William A.; Toro, Camilo; Boerkoel, Cornelius F.] NIH, NIH Undiag Dis Program, Common Fund, Off Director, Bldg 10, Bethesda, MD 20892 USA. [Atkins, Paul; du Souich, ChristSle; Rupps, Rosemarie; Lehman, Anna; Morimoto, Marie; Boerkoel, Cornelius F.] Univ British Columbia, Dept Med Genet, Childrens & Womens Hlth Ctr BC, Vancouver, BC, Canada. [Atkins, Paul; du Souich, ChristSle; Rupps, Rosemarie; Lehman, Anna; Morimoto, Marie; Van Karnebeek, Clara; Boerkoel, Cornelius F.] Univ British Columbia, Child & Family Res Inst, Vancouver, BC V5Z 1M9, Canada. [Limbos, Marjolaine] Sunny Hill Hlth Ctr Children, Vancouver, BC, Canada. [Bhatt, Samarth S.; Stankiewicz, Pawel] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Eydoux, Patrice] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada. [Mason, Christopher E.] Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY USA. [Mason, Christopher E.] HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsau, New York, NY USA. [Mason, Christopher E.] Feil Family Brain & Mind Res Inst BMRI, New York, NY USA. [Mullikin, James C.] NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. [Sear, Andrew] Univ British Columbia, Fac Med, Dept Gen Practice, Vancouver, BC, Canada. [Gahl, William A.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Boerkoel, CF (reprint author), NIH, NIH Undiag Dis Program, Common Fund, Off Director, Bldg 10, Bethesda, MD 20892 USA.; Boerkoel, CF (reprint author), Univ British Columbia, Dept Med Genet, Childrens & Womens Hlth Ctr BC, Vancouver, BC, Canada.; Boerkoel, CF (reprint author), Univ British Columbia, Child & Family Res Inst, Vancouver, BC V5Z 1M9, Canada. EM cboerkoel@gmail.com OI BHATT, SAMARTH/0000-0001-5706-4572; Lehman, Anna/0000-0003-0636-123X FU Intramural Research Program of National Human Genome Research Institute; Common, Fund, Office of Director (NIH, Bethesda, Maryland); Scottish Rite Foundation; Child and Family Research Institute Establishment Award; Clinical Genomics Platform of the Michael Smith Foundation for Health Research; National Institutes of Health [R01NS076465] FX The authors thank Dr. Jan Friedman for critical review of this manuscript. This work was supported in part by the Intramural Research Program of the National Human Genome Research Institute and the Common, Fund, Office of the Director (NIH, Bethesda, Maryland). This work was supported in part by the Scottish Rite Foundation (C.D.S.), a Child and Family Research Institute Establishment Award (C.F.B.), and the Clinical Genomics Platform of the Michael Smith Foundation for Health Research (P.A.). For C.E.M. we would to like to thank the Bert L. and N. Kuggie Vallee Foundation, the Irma T. Hirschl and Monique Weill-Caulier Charitable Trusts, the WorldQuant Foundation, the Pershing Square Sohn Prize, the STARR Consortium (I7-A765, I9-A9-071), and support from the National Institutes of Health (R01NS076465). NR 61 TC 0 Z9 0 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1172 J9 ORPHANET J RARE DIS JI Orphanet J. Rare Dis. PD MAY 14 PY 2016 VL 11 DI 10.1186/s13023-016-0439-6 PG 15 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA DL7FM UT WOS:000375806000001 PM 27179618 ER PT J AU Zhang, F Hanson, SM Jara-Oseguera, A Krepkiy, D Bae, C Pearce, LV Blumberg, PM Newstead, S Swartz, KJ AF Zhang, Feng Hanson, Sonya M. Jara-Oseguera, Andres Krepkiy, Dmitriy Bae, Chanyung Pearce, Larry V. Blumberg, Peter M. Newstead, Simon Swartz, Kenton J. TI Engineering vanilloid-sensitivity into the rat TRPV2 channel SO ELIFE LA English DT Article ID DEPENDENT K+ CHANNEL; ION-CHANNEL; CAPSAICIN-RECEPTOR; 2-AMINOETHOXYDIPHENYL BORATE; SACCHAROMYCES-CEREVISIAE; ELECTRON CRYOMICROSCOPY; MOLECULAR DETERMINANTS; ACTIVATION; VOLTAGE; BINDING AB The TRPV1 channel is a detector of noxious stimuli, including heat, acidosis, vanilloid compounds and lipids. The gating mechanisms of the related TRPV2 channel are poorly understood because selective high affinity ligands are not available, and the threshold for heat activation is extremely high (>50 degrees C). Cryo-EM structures of TRPV1 and TRPV2 reveal that they adopt similar structures, and identify a putative vanilloid binding pocket near the internal side of TRPV1. Here we use biochemical and electrophysiological approaches to investigate the resiniferatoxin(RTx) binding site in TRPV1 and to explore the functional relationships between TRPV1 and TRPV2. Collectively, our results support the interaction of vanilloids with the proposed RTx binding pocket, and demonstrate an allosteric influence of a tarantula toxin on vanilloid binding. Moreover, we show that sensitivity to RTx can be engineered into TRPV2, demonstrating that the gating and permeation properties of this channel are similar to TRPV1. C1 [Zhang, Feng; Hanson, Sonya M.; Jara-Oseguera, Andres; Krepkiy, Dmitriy; Bae, Chanyung; Swartz, Kenton J.] NINDS, Mol Physiol & Biophys Sect, Porter Neurosci Res Ctr, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Hanson, Sonya M.; Newstead, Simon] Univ Oxford, Dept Biochem, Oxford OX1 3QU, England. [Pearce, Larry V.; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. [Hanson, Sonya M.] Mem Sloan Kettering Canc Ctr, Computat Biol Program, 1275 York Ave, New York, NY 10021 USA. RP Swartz, KJ (reprint author), NINDS, Mol Physiol & Biophys Sect, Porter Neurosci Res Ctr, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM swartzk@ninds.nih.gov OI Newstead, Simon/0000-0001-7432-2270; Hanson, Sonya/0000-0001-8960-5353 FU National Institute of Neurological Disorders and Stroke [NS002945]; National Cancer Institute [BC005270]; Wellcome Trust [102890]; Korea Research Institute of Bioscience and Biotechnology FX National Institute of Neurological Disorders and Stroke NS002945 Kenton J Swartz; National Cancer Institute BC005270 Peter M Blumberg; Wellcome Trust 102890 Simon Newstead; Korea Research Institute of Bioscience and Biotechnology Chanhyung Bae; National Institute of Neurological Disorders and Stroke Andres Jara-Oseguera; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 58 TC 1 Z9 1 U1 4 U2 4 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD MAY 13 PY 2016 VL 5 AR e16409 DI 10.7554/eLife.16409 PG 18 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DP7AZ UT WOS:000378652700001 ER PT J AU Sato, S Jung, HM Nakagawa, T Pawlosky, R Takeshima, T Lee, WR Sakiyama, H Laxman, S Wynn, RM Tu, BP MacMillan, JB De Brabander, JK Veech, RL Uyeda, K AF Sato, Shogo Jung, Hunmin Nakagawa, Tsutomu Pawlosky, Robert Takeshima, Tomomi Lee, Wan-Ru Sakiyama, Haruhiko Laxman, Sunil Wynn, R. Max Tu, Benjamin P. MacMillan, John B. De Brabander, Jef K. Veech, Richard L. Uyeda, Kosaku TI Metabolite Regulation of Nuclear Localization of Carbohydrate-response Element-binding Protein (ChREBP) ROLE OF AMP AS AN ALLOSTERIC INHIBITOR SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BETA-HYDROXYBUTYRATE; TRANSCRIPTION FACTOR; RAT-TISSUES; FATTY-ACID; FREE MG2+; GLUCOSE; LIVER; PHOSPHORYLATION; KINASE; LIPOGENESIS AB The carbohydrate-response element-binding protein (ChREBP) is a glucose-responsive transcription factor that plays an essential role in converting excess carbohydrate to fat storage in the liver. In response to glucose levels, ChREBP is regulated by nuclear/cytosol trafficking via interaction with 14-3-3 proteins, CRM-1 (exportin-1 or XPO-1), or importins. Nuclear localization of ChREBP was rapidly inhibited when incubated in branched-chain alpha-ketoacids, saturated and unsaturated fatty acids, or 5-aminoimidazole-4-carboxamide ribonucleotide. Here, we discovered that protein-free extracts of high fat-fed livers contained, in addition to ketone bodies, a new metabolite, identified as AMP, which specifically activates the interaction between ChREBP and 14-3-3. The crystal structure showed that AMP binds directly to the N terminus of ChREBP-alpha 2 helix. Our results suggest that AMP inhibits the nuclear localization of ChREBP through an allosteric activation of ChREBP/14-3-3 interactions and not by activation of AMPK. AMP and ketone bodies together can therefore inhibit lipogenesis by restricting localization of ChREBP to the cytoplasm during periods of ketosis. C1 [Sakiyama, Haruhiko; Laxman, Sunil; Wynn, R. Max; Tu, Benjamin P.; MacMillan, John B.; De Brabander, Jef K.; Uyeda, Kosaku] Univ Texas SW Med Ctr Dallas, Dept Biochem, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. [Pawlosky, Robert; Veech, Richard L.] NIAAA, Bethesda, MD 20892 USA. [Uyeda, Kosaku] Dallas Vet Affairs Med Ctr, Dallas, TX 75216 USA. RP Uyeda, K (reprint author), Univ Texas SW Med Ctr Dallas, Dept Biochem, 5323 Harry Hines Blvd, Dallas, TX 75390 USA.; Uyeda, K (reprint author), Vet Affairs Med Ctr, 4500 S Lancaster Rd, Dallas, TX USA. EM kuyeda@utsouthwestern.edu OI Laxman, Sunil/0000-0002-0861-5080; Sato, Shogo/0000-0002-2874-7072; MacMillan, John/0000-0003-1430-1077 FU United States Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357] FX We thank Dr. Hong Zhang, the Biochemistry and Biophysics Department, University of Texas Southwestern Medical Center for use of the crystallization chamber, and Dr. Jay Horton, Internal Medicine, University of Texas Southwestern Medical Center, for acetylCoA carboxylase. We also thank Dr Martin Kemper, the National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, for assistance in calculation of phosphorylation potentials. Results shown in this report are derived from work performed at Argonne National Laboratory, Structural Biology Center at the Advanced Photon Source. Argonne is operated by University of Chicago Argonne, LLC, for the United States Department of Energy, Office of Biological and Environmental Research under Contract DE-AC02-06CH11357. NR 32 TC 3 Z9 3 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 13 PY 2016 VL 291 IS 20 BP 10515 EP 10527 DI 10.1074/jbc.M115.708982 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DN4MY UT WOS:000377042600007 PM 26984404 ER PT J AU He, L Chang, E Peng, J An, H McMillin, SM Radovick, S Stratakis, CA Wondisford, FE AF He, Ling Chang, Evan Peng, Jinghua An, Hongying McMillin, Sara M. Radovick, Sally Stratakis, Constantine A. Wondisford, Fredric E. TI Activation of the cAMP-PKA pathway Antagonizes Metformin Suppression of Hepatic Glucose Production SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE; GENETIC-VARIATION; COACTIVATOR P300; AMPK ACTIVATION; GLUCAGON; ALPHA; PHOSPHORYLATION; HYPERGLYCEMIA; HYPERGLUCAGONEMIA; GLUCONEOGENESIS AB Metformin is the most commonly prescribed oral anti-diabetic agent worldwide. Surprisingly, about 35% of diabetic patients either lack or have a delayed response to metformin treatment, and many patients become less responsive to metformin over time. It remains unknown how metformin resistance or insensitivity occurs. Recently, we found that therapeutic metformin concentrations suppressed glucose production in primary hepatocytes through AMPK; activation of the cAMP-PKA pathway negatively regulates AMPK activity by phosphorylating AMPK alpha subunit at Ser-485, which in turn reduces AMPK activity. In this study, we find that metformin failed to suppress glucose production in primary hepatocytes with constitutively activated PKA and did not improve hyperglycemia in mice with hyperglucagonemia. Expression of the AMPK alpha 1(S485A) mutant, which is unable to be phosphorylated by PKA, increased both AMPK alpha activation and the suppression of glucose production in primary hepatocytes treated with metformin. Intriguingly, salicylate/aspirin prevents the phosphorylation of AMPK alpha at Ser-485, blocks cAMP-PKA negative regulation of AMPK, and improves metformin resistance. We propose that aspirin/salicylate may augment metformin's hepatic action to suppress glucose production. C1 [He, Ling; Chang, Evan; Peng, Jinghua; An, Hongying] Johns Hopkins Univ, Sch Med, Dept Pediat, Div Metab, Baltimore, MD 21287 USA. [McMillin, Sara M.; Wondisford, Fredric E.] Rutgers Robert Wood Johnson Med Sch, Dept Med, New Brunswick, NJ 08901 USA. [Radovick, Sally] Rutgers Robert Wood Johnson Med Sch, Dept Pediat, New Brunswick, NJ 08901 USA. [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Bethesda, MD 20892 USA. RP He, L (reprint author), Div Metab, 600 N Wolfe St,CMSC10-113, Baltimore, MD 21287 USA. EM heling@jhmi.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health [R00DK085142, R01DK107641, R01DK063349] FX This work was supported in part by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health: R00DK085142 (to L. H.), R01DK107641 (to L. H.), and R01DK063349 (to F. E. W.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 35 TC 2 Z9 2 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 13 PY 2016 VL 291 IS 20 BP 10562 EP 10570 DI 10.1074/jbc.M116.719666 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DN4MY UT WOS:000377042600011 PM 27002150 ER PT J AU Babinsky, VN Hannan, FM Gorvin, CM Howles, SA Nesbit, MA Rust, N Hanyaloglu, AC Hu, JX Spiegel, AM Thakker, RV AF Babinsky, Valerie N. Hannan, Fadil M. Gorvin, Caroline M. Howles, Sarah A. Nesbit, M. Andrew Rust, Nigel Hanyaloglu, Aylin C. Hu, Jianxin Spiegel, Allen M. Thakker, Rajesh V. TI Allosteric Modulation of the Calcium-sensing Receptor Rectifies Signaling Abnormalities Associated with G-protein alpha-11 Mutations Causing Hypercalcemic and Hypocalcemic Disorders SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FAMILIAL HYPOCALCIURIC HYPERCALCEMIA; ACTIVATING MUTATIONS; MUTANT RECEPTORS; CINACALCET; DOMAIN; CELLS; HYPOPARATHYROIDISM; IDENTIFICATION; TRANSDUCTION; KIDNEY AB Germline loss- and gain-of-function mutations of G-protein alpha-11 (G alpha(11)), which couples the calcium-sensing receptor (CaSR) to intracellular calcium (Ca-i(2+)) signaling, lead to familial hypocalciuric hypercalcemia type 2 (FHH2) and autosomal dominant hypocalcemia type 2 (ADH2), respectively, whereas somatic Gall mutations mediate uveal melanoma development by constitutively up-regulating MAPK signaling. Cinacalcet and NPS-2143 are allosteric CaSR activators and inactivators, respectively, that ameliorate signaling disturbances associated with CaSR mutations, but their potential to modulate abnormalities of the downstream Gall protein is unknown. This study investigated whether cinacalcet and NPS-2143 may rectify Ca-i(2+) alterations associated with FHH2- and ADH2-causing Got, mutations, and evaluated the influence of germline gain of-function Gall mutations on MAPK signaling by measuring ERK phosphorylation, and assessed the effect of NPS-2143 on a uveal melanoma Gall mutant. WT and mutant G alpha(11) proteins causing FHH2, ADH2 or uveal melanoma were transfected in CaSR-expressing HEK293 cells, and Ca-i(2+) and ERK phosphorylation responses measured by flow-cytometry and Alphascreen immunoassay following exposure to extracellular Ca2+ (Ca-0(2+)) and allosteric modulators. Cinacalcet and NPS-2143 rectified the Ca-i(2+) responses of FHH2- and ADH2-associated G alpha(11) loss and gain-of-function mutations, respectively. ADH2-causing C1 [Babinsky, Valerie N.; Hannan, Fadil M.; Gorvin, Caroline M.; Howles, Sarah A.; Nesbit, M. Andrew; Thakker, Rajesh V.] Univ Oxford, Radcliffe Dept Med, S Parks Rd, Oxford OX3 7LJ, England. [Hannan, Fadil M.] Univ Liverpool, Dept Musculoskeletal Biol, Liverpool L69 3GA, Merseyside, England. [Nesbit, M. Andrew] Univ Ulster, Biomed Sci Res Inst, Coleraine BT52 1SA, Londonderry, North Ireland. [Rust, Nigel] Univ Oxford, Sir William Dunn Sch Pathol, S Parks Rd, Oxford OX1 3RE, England. [Hanyaloglu, Aylin C.] Univ London Imperial Coll Sci Technol & Med, Dept Surg & Canc, Inst Reprod Biol & Dev, London W12 0NN, England. [Hu, Jianxin] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Spiegel, Allen M.] Albert Einstein Coll Med, Bronx, NY 10461 USA. RP Thakker, RV (reprint author), Churchill Hosp, Acad Endocrine Unit, Radcliffe Dept Med, OCDEM, Oxford OX3 7LJ, England. EM rajesh.thakker@ndm.ox.ac.uk FU United Kingdom Medical Research Council (MRC) [G9825289, G1000467]; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Programme; European Commission [FP7-264663] FX This work was supported by the United Kingdom Medical Research Council (MRC) Programme Grants G9825289 and G1000467 (to M. A. N., F. M. H., C. M. G., and R. V. T), and National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Programme (to M. A. N. and R. V. T.); European Commission Seventh Framework Programme (FP7-264663) (to V. N. B.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or NIHR (UK). NR 35 TC 6 Z9 6 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 13 PY 2016 VL 291 IS 20 BP 10876 EP 10885 DI 10.1074/jbc.M115.696401 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DN4MY UT WOS:000377042600037 PM 26994139 ER PT J AU Oh, YS Robinson, V Stanley, DV Tolunay, E Kim, DY Galis, ZS AF Oh, Young S. Robinson, Valerie Stanley, Dennis V. Tolunay, Eser Kim, Dong-Yun Galis, Zorina S. TI "The Good Old R01" Challenging Downward Funding Success Trends at the National Heart, Lung, and Blood Institute SO CIRCULATION RESEARCH LA English DT Editorial Material DE biomedical research; cardiovascular disease; financial support; government; hypertension ID US AB The National Institutes of Health (NIH) remains the largest source of funding for biomedical research in the United States. However, the current tight fiscal climate is creating concerns related to the success in obtaining NIH funding. In this report, we focused on analyzing the trend of new and renewal competing R01 applications, as a measure of the most prevalent NIH funding mechanism that supports many US laboratories, and the new science being proposed in the field. We analyzed data on R01 applications submitted to the NIH, the National Heart, Lung, and Blood Institute (NHLBI), the Division of Cardiovascular Sciences, and the Vascular Biology and Hypertension Branch for fiscal years 2010 through 2014. This comparative analysis at multiple levels allowed us to position the situation of cardiovascular research R01s, from within the big picture of NIH funding to looking at specific trends at the level of particular areas of investigation within Vascular Biology and Hypertension Branch. We found that the success rates of competing R01s decreased at all levels: NIH, NHLBI, Division of Cardiovascular Sciences, and Vascular Biology and Hypertension Branch. Interestingly, we found that competitive renewal R01 applications remained more successful (approximate to 2x) than new R01 applications at all levels during this period. By identifying and analyzing some variances to the general trends, we found that some successes may be attributed to effectively using the specific R01 structure that supports team science (ie, Multiple Principal Investigator awards), which enables the active collaborations among investigators with different expertise to pursue together a novel scientific hypothesis. C1 [Oh, Young S.; Robinson, Valerie; Stanley, Dennis V.; Tolunay, Eser; Galis, Zorina S.] NHLBI, Vasc Biol & Hypertens Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Kim, Dong-Yun] NHLBI, Div Cardiovasc Sci, Off Biostat Res, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Oh, YS (reprint author), NHLBI, Vasc Biol & Hypertens Branch, 6701 Rockledge Dr,Room 8106, Bethesda, MD 20892 USA. EM yoh@mail.nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 14 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD MAY 13 PY 2016 VL 118 IS 10 BP 1475 EP U48 DI 10.1161/CIRCRESAHA.115.308241 PG 14 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA DM6ND UT WOS:000376468700008 PM 27174948 ER PT J AU Alfaras, I Di Germanio, C Bernier, M Csiszar, A Ungvari, Z Lakatta, EG de Cabo, R AF Alfaras, Irene Di Germanio, Clara Bernier, Michel Csiszar, Anna Ungvari, Zoltan Lakatta, Edward G. de Cabo, Rafael TI Pharmacological Strategies to Retard Cardiovascular Aging SO CIRCULATION RESEARCH LA English DT Review DE aging; calorie restriction; cardiovascular diseases; pharmacological strategies; prevention ID NF-KAPPA-B; CEREBROMICROVASCULAR ENDOTHELIAL-CELLS; VASCULAR OXIDATIVE STRESS; PRESERVED EJECTION FRACTION; IMPAIRS ANGIOGENIC CAPACITY; ACTIVATED PROTEIN-KINASE; CARDIAC MYOSIN ACTIVATOR; PRIMATE MACACA-MULATTA; EXTENDS LIFE-SPAN; E-DEFICIENT MICE AB Aging is the major risk factor for cardiovascular diseases, which are the leading cause of death in the United States. Traditionally, the effort to prevent cardiovascular disease has been focused on addressing the conventional risk factors, including hypertension, hyperglycemia, hypercholesterolemia, and high circulating levels of triglycerides. However, recent preclinical studies have identified new approaches to combat cardiovascular disease. Calorie restriction has been reproducibly shown to prolong lifespan in various experimental model animals. This has led to the development of calorie restriction mimetics and other pharmacological interventions capable to delay age-related diseases. In this review, we will address the mechanistic effects of aging per se on the cardiovascular system and focus on the prolongevity benefits of various therapeutic strategies that support cardiovascular health. C1 [Alfaras, Irene; Di Germanio, Clara; Bernier, Michel; de Cabo, Rafael] NIA, Expt Gerontol Sect, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Lakatta, Edward G.] NIA, Lab Cardiovasc Sci, NIH, Baltimore, MD 21224 USA. [Di Germanio, Clara] Univ Teramo, Fac Vet Med, Teramo, Italy. [Csiszar, Anna; Ungvari, Zoltan] Univ Oklahoma, Hlth Sci Ctr, Dept Geriatr Med, Reynolds Oklahoma Ctr Aging, Oklahoma City, OK USA. RP de Cabo, R (reprint author), NIA, NIH, Biomed Res Ctr, 251 Bayview Blvd,Suite 100,Room 09C216, Baltimore, MD 21224 USA. EM deCaboRa@grc.nia.nih.gov RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU Intramural NIH HHS [ZIA AG000368-11]; NCCIH NIH HHS [R01 AT006526]; NIA NIH HHS [R01 AG047879, P30 AG028718] NR 257 TC 2 Z9 2 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD MAY 13 PY 2016 VL 118 IS 10 BP 1626 EP 1642 DI 10.1161/CIRCRESAHA.116.307475 PG 17 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA DM6ND UT WOS:000376468700019 PM 27174954 ER PT J AU Torrey, HL Keren, I Via, LE Lee, JS Lewis, K AF Torrey, Heather L. Keren, Iris Via, Laura E. Lee, Jong Seok Lewis, Kim TI High Persister Mutants in Mycobacterium tuberculosis SO PLOS ONE LA English DT Article ID ESCHERICHIA-COLI; MULTIDRUG TOLERANCE; BACTERIAL PERSISTENCE; GENE-EXPRESSION; PSEUDOMONAS-AERUGINOSA; ANTIBIOTIC TOLERANCE; TOXIN; CELLS; HIPA; VIRULENCE AB Mycobacterium tuberculosis forms drug-tolerant persister cells that are the probable cause of its recalcitrance to antibiotic therapy. While genetically identical to the rest of the population, persisters are dormant, which protects them from killing by bactericidal antibiotics. The mechanism of persister formation in M. tuberculosis is not well understood. In this study, we selected for high persister (hip) mutants and characterized them by whole genome sequencing and transcriptome analysis. In parallel, we identified and characterized clinical isolates that naturally produce high levels of persisters. We compared the hip mutants obtained in vitro with clinical isolates to identify candidate persister genes. Genes involved in lipid biosynthesis, carbon metabolism, toxin-antitoxin systems, and transcriptional regulators were among those identified. We also found that clinical hip isolates exhibited greater ex vivo survival than the low persister isolates. Our data suggest that M. tuberculosis persister formation involves multiple pathways, and hip mutants may contribute to the recalcitrance of the infection. C1 [Torrey, Heather L.; Keren, Iris; Lewis, Kim] Northeastern Univ, Dept Biol, Boston, MA 02115 USA. [Via, Laura E.] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Lee, Jong Seok] Int TB Res Ctr, Chang Won, South Korea. RP Lewis, K (reprint author), Northeastern Univ, Dept Biol, Boston, MA 02115 USA. EM k.lewis@neu.edu FU National Institutes of Health (NIH) Transformative Award [T-R01AI085585]; Bill & Melinda Gates Foundation; National Institute of Allergy and Infectious Diseases (NIAID), NIH, Department of Health and Human Services [HHSN272200900018C]; Intramural Research Program of NIAID; Korean Centers for Disease Control of the Korean Ministry of Health and Welfare FX This study was supported by the National Institutes of Health (NIH) Transformative Award T-R01AI085585 and Bill & Melinda Gates Foundation Grand Challenges award to KL; by National Institute of Allergy and Infectious Diseases (NIAID), NIH, Department of Health and Human Services, under Contract No.: HHSN272200900018C. The clinical study and sample collection and analysis was jointly funded by Intramural Research Program of NIAID and the Korean Centers for Disease Control of the Korean Ministry of Health and Welfare including support of LEV and JSL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 TC 6 Z9 6 U1 6 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 13 PY 2016 VL 11 IS 5 AR e0155127 DI 10.1371/journal.pone.0155127 PG 28 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM8CX UT WOS:000376589400043 PM 27176494 ER PT J AU Chang, C Raven, EP Duyn, JH AF Chang, Catie Raven, Erika P. Duyn, Jeff H. TI Brain-heart interactions: challenges and opportunities with functional magnetic resonance imaging at ultra-high field SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY A-MATHEMATICAL PHYSICAL AND ENGINEERING SCIENCES LA English DT Review DE functional magnetic resonance imaging; high-field imaging; high resolution; brain-heart ID HIGH-RESOLUTION FMRI; INDEPENDENT COMPONENT ANALYSIS; AUTONOMIC NERVOUS-SYSTEM; PHYSIOLOGICAL NOISE CORRECTION; BLOOD OXYGENATION CHANGES; HUMAN CONNECTOME PROJECT; MULTI-ECHO EPI; RESTING-STATE; RATE-VARIABILITY; BOLD SIGNAL AB Magnetic resonance imaging (MRI) at ultra-high field (UHF) strengths (7 T and above) offers unique opportunities for studying the human brain with increased spatial resolution, contrast and sensitivity. However, its reliability can be compromised by factors such as head motion, image distortion and non-neural fluctuations of the functional MRI signal. The objective of this review is to provide a critical discussion of the advantages and trade-offs associated with UHF imaging, focusing on the application to studying brain-heart interactions. We describe how UHF MRI may provide contrast and resolution benefits for measuring neural activity of regions involved in the control and mediation of autonomic processes, and in delineating such regions based on anatomical MRI contrast. Limitations arising from confounding signals are discussed, including challenges with distinguishing non-neural physiological effects from the neural signals of interest that reflect cardiorespiratory function. We also consider how recently developed data analysis techniques may be applied to high-field imaging data to uncover novel information about brain-heart interactions. C1 [Chang, Catie; Raven, Erika P.; Duyn, Jeff H.] NINDS, Adv Magnet Resonance Imaging Sect, Lab Funct & Mol Imaging, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Raven, Erika P.] Georgetown Univ, Med Ctr, Ctr Funct & Mol Imaging, Washington, DC 20007 USA. RP Chang, C (reprint author), NINDS, Adv Magnet Resonance Imaging Sect, Lab Funct & Mol Imaging, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM catie.chang@nih.gov FU National Science Foundation Graduate Research Fellowship [DGE-1444316]; Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke. This material is based in part upon work supported by the National Science Foundation Graduate Research Fellowship under grant no. DGE-1444316. NR 174 TC 1 Z9 1 U1 7 U2 11 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1364-503X EI 1471-2962 J9 PHILOS T R SOC A JI Philos. Trans. R. Soc. A-Math. Phys. Eng. Sci. PD MAY 13 PY 2016 VL 374 IS 2067 AR 20150188 DI 10.1098/rsta.2015.0188 PG 23 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM2EM UT WOS:000376159500013 ER PT J AU Demers, L Ben Mortenson, W Fuhrer, MJ Jutai, JW Plante, M Mah, J DeRuyter, F AF Demers, Louise Ben Mortenson, W. Fuhrer, Marcus J. Jutai, Jeffrey W. Plante, Michelle Mah, Jasmine DeRuyter, Frank TI Effect of a tailored assistive technology intervention on older adults and their family caregiver: a pragmatic study protocol SO BMC GERIATRICS LA English DT Article DE Randomized control trial; Older adults; Assistive technology; Informal caregiving ID LONG-TERM-CARE; CHRONIC PAIN; DEVICE USE; HOME-CARE; RELIABILITY; DISABILITY; MOBILITY; REHABILITATION; REINTEGRATION; INDEPENDENCE AB Background: Many older adults with mobility limitations use assistive technology to help them perform daily activities. However, little attention has been paid to the impact on their family caregivers. This neglect produces an incomplete portrayal of the outcomes of assistive technology provision. This paper describes the protocol for a study that examines the impact of a tailored assistive technology intervention that is inclusive of assistance users and their family caregivers. Methods/design: This research will use a combination of quantitative and qualitative methods. The quantitative portion will be an experimental, single-blinded study in which participants are randomly assigned to either an experimental assistive technology intervention or a standard care group. We will enroll 240 participants (120 dyads) into the study from three Canadian sites. Participants will include older adults (>55) and family caregivers who provide >= 4 h per week of assistance with daily activities and social participation. The primary outcome measure for the older adults will be the Functional Autonomy Measurement System, and the primary outcome measure for the caregivers will be the Caregiver Assistive Technology Outcomes Measure. Qualitative data will be collected through detailed records of the therapists' interventions, as well as through interviews with dyads and therapists following the interventions. Data collection will occur at baseline (T-0) with follow-ups at 6 weeks (T-1), 22 weeks (T-2), and 58 weeks (T-3) after baseline evaluation. Discussion: The findings from this study will help service providers and clinicians to move forward with assistive technology recommendations that are more attuned to the needs of both older adults with mobility limitations and their family caregivers. Additionally, the study's findings will enhance our conceptual understanding of the spectrum of assistive technology outcomes and set the stage for econometric studies assessing cost-effectiveness. C1 [Demers, Louise; Plante, Michelle] Ctr Sud de Ile de Montreal, Ctr Integre Univ Sante & Serv Soc, Inst Univ Geriatrie Montreal, Ctr Rech, Montreal, PQ, Canada. [Demers, Louise] Univ Montreal, Ecole Readaptat, Montreal, PQ, Canada. [Ben Mortenson, W.] Univ British Columbia, Dept Occupat Sci & Occupat Therapy, Vancouver, BC V5Z 1M9, Canada. [Ben Mortenson, W.] GF Strong Rehabil Res Program, Vancouver, BC, Canada. [Ben Mortenson, W.] Int Collaborat Repair Discovery, Vancouver, BC, Canada. [Fuhrer, Marcus J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Jutai, Jeffrey W.; Mah, Jasmine] Univ Ottawa, Interdisciplinary Sch Hlth Sci, Ottawa, ON, Canada. [Jutai, Jeffrey W.] Bruyere Res Inst, Ottawa, ON, Canada. [DeRuyter, Frank] Duke Univ, Dept Surg Speech Pathol & Audiol, Durham, NC USA. RP Demers, L (reprint author), Ctr Sud de Ile de Montreal, Ctr Integre Univ Sante & Serv Soc, Inst Univ Geriatrie Montreal, Ctr Rech, Montreal, PQ, Canada.; Demers, L (reprint author), Univ Montreal, Ecole Readaptat, Montreal, PQ, Canada. EM louise.demers@umontreal.ca RI Mortenson, William/L-7441-2013; OI Mortenson, William/0000-0002-0183-6163; Jutai, Jeffrey/0000-0002-7294-1323 FU Canadian Institutes of Health Research (CIHR, Ottawa, Ontario, Canada) [NRF-111147, K1A 0 W9] FX The study was peer reviewed by and is funded by the Canadian Institutes of Health Research (CIHR, 160 Elgin Street, 9th Floor, Address Locator 4809A, Ottawa, Ontario, Canada, K1A 0 W9), grant no NRF-111147. This funding source will play no role in study design, data collection, management, analysis, or the reporting and publication of results. NR 55 TC 0 Z9 0 U1 4 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2318 J9 BMC GERIATR JI BMC Geriatr. PD MAY 13 PY 2016 VL 16 AR 103 DI 10.1186/s12877-016-0269-3 PG 11 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DL7FW UT WOS:000375807000001 PM 27177609 ER PT J AU Swortwood, MJ Scheidweiler, KB Barnes, AJ Jansson, LM Huestis, MA AF Swortwood, Madeleine J. Scheidweiler, Karl B. Barnes, Allan J. Jansson, Lauren M. Huestis, Marilyn A. TI Simultaneous quantification of buprenorphine, naloxone and phase I and II metabolites in plasma and breastmilk by liquid chromatography-tandem mass spectrometry SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE Buprenorphine; Naloxone; Prenatal drug exposure; Plasma; Breastmilk; Liquid chromatography-tandem mass spectrometry ID NEONATAL ABSTINENCE SYNDROME; DEPENDENT PREGNANT-WOMEN; NORBUPRENORPHINE; PHARMACOKINETICS; OPIOIDS; TABLET; VIVO AB Opioid abuse during pregnancy is associated with fetal growth restriction, placental abruption, preterm labor, fetal death, and Neonatal Abstinence Syndrome. Current guidelines for medication-assisted opioid addiction treatment during pregnancy are methadone or buprenorphine monotherapy. Buprenorphine/naloxone combination therapy (Suboxone (R)) has not been thoroughly evaluated during pregnancy and insufficient naloxone safety data exist. While methadone- and buprenorphine-treated mothers are encouraged to breastfeed, no studies to date investigated naloxone concentrations during breastfeeding following Suboxone administration. For this reason, we developed and fully validated a liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of buprenorphine, buprenorphine-glucuronide, norbuprenorphine, norbuprenorphine-glucuronide, naloxone, naloxone-glucuronide and naloxone-N-oxide in 100 mu L human plasma and breastmilk in a single injection following protein precipitation and solid-phase extraction. Lowest limits of quantification were 0.1-2 mu g/L with 20-100 mu g/L, upper limits of linearity. Bias and imprecision were < +/-16%. Matrix effects ranged from -57.9 to 11.2 and -84.6 to 29.3% in plasma and breastmilk, respectively, All analytes were stable (within +/-20% change from baseline) under all tested conditions (24 h room temperature, 72 h at 4 degrees C, 3 freeze thaw cycles at -20 degrees C, and in the autosampler for 72 hat 4 degrees C). For proof of concept, buprenorphine and its metabolites were successfully quantified in authentic positive maternal and infant plasma and paired breastmilk specimens. This comprehensive, highly sensitive and specific method detects multiple buprenorphine markers in a small specimen volume. Published by Elsevier B.V. C1 [Swortwood, Madeleine J.; Scheidweiler, Karl B.; Barnes, Allan J.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Jansson, Lauren M.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab, Intramural Res Program, 251 Bayview Blvd,Suite 200 Room 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU National Institute on Drug Abuse, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. NR 29 TC 1 Z9 1 U1 4 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 EI 1873-3778 J9 J CHROMATOGR A JI J. Chromatogr. A PD MAY 13 PY 2016 VL 1446 BP 70 EP 77 DI 10.1016/j.chroma.2016.03.076 PG 8 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA DL3AN UT WOS:000375506700018 PM 27083254 ER PT J AU Fan, Q Guo, X Tideman, JWL Williams, KM Yazar, S Hosseini, SM Howe, LD St Pourcain, B Evans, DM Timpson, NJ McMahon, G Hysi, PG Krapohl, E Wang, YX Jonas, JB Baird, PN Wang, JJ Cheng, CY Teo, YY Wong, TY Ding, X Wojciechowski, R Young, TL Parssinen, O Oexle, K Pfeiffer, N Bailey-Wilson, JE Paterson, AD Klaver, CCW Plomin, R Hammond, CJ Mackey, DA He, MG Saw, SM Williams, C Guggenheim, JA AF Fan, Qiao Guo, Xiaobo Tideman, J. Willem L. Williams, Katie M. Yazar, Seyhan Hosseini, S. Mohsen Howe, Laura D. St Pourcain, Beate Evans, David M. Timpson, Nicholas J. McMahon, George Hysi, Pirro G. Krapohl, Eva Wang, Ya Xing Jonas, Jost B. Baird, Paul Nigel Wang, Jie Jin Cheng, Ching-Yu Teo, Yik-Ying Wong, Tien-Yin Ding, Xiaohu Wojciechowski, Robert Young, Terri L. Parssinen, Olavi Oexle, Konrad Pfeiffer, Norbert Bailey-Wilson, Joan E. Paterson, Andrew D. Klaver, Caroline C. W. Plomin, Robert Hammond, Christopher J. Mackey, David A. He, Mingguang Saw, Seang-Mei Williams, Cathy Guggenheim, Jeremy A. CA CREAM Consortium TI Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia: The CREAM Consortium SO SCIENTIFIC REPORTS LA English DT Article ID GENOME-WIDE ASSOCIATION; HIGH-GRADE MYOPIA; TIME OUTDOORS; EDUCATION INFLUENCES; CHINESE CHILDREN; COMMON VARIANTS; METAANALYSIS; PREVALENCE; REVEALS; SUSCEPTIBILITY AB Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7-15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E-08) and 2.3% (P = 6.9E-21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry samples (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4; P = 6.3E-04). C1 [Fan, Qiao] Duke NUS Medial Sch, Ctr Quantitat Med, Singapore, Singapore. [Guo, Xiaobo] Sun Yat Sen Univ, Sch Math & Computat Sci, Dept Stat Sci, Guangzhou, Peoples R China. [Guo, Xiaobo; Ding, Xiaohu; He, Mingguang] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, State Key Lab Ophthalmol, Guangzhou, Peoples R China. [Tideman, J. Willem L.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Tideman, J. Willem L.; Klaver, Caroline C. W.] Erasmus MC, Dept Ophthalmol, Rotterdam, Netherlands. [Williams, Katie M.] Kings Coll London, Dept Ophthalmol, St Thomas Hosp Campus, London WC2R 2LS, England. [Williams, Katie M.; Hysi, Pirro G.; Hammond, Christopher J.] Kings Coll London, Sch Med, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Yazar, Seyhan; Mackey, David A.] Univ Western Australia, Lions Eye Inst, Ctr Ophthalmol & Visual Sci, Perth, WA 6009, Australia. [Hosseini, S. Mohsen; Paterson, Andrew D.] Univ Toronto, Hosp Sick Children, Genet & Genome Biol Program, Toronto, ON M5G 1X8, Canada. [Howe, Laura D.; St Pourcain, Beate; Evans, David M.; Timpson, Nicholas J.; McMahon, George] Univ Bristol, MRC Integrat Epidemiol Unit IEU, Bristol, Avon, England. [Howe, Laura D.; Williams, Cathy] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [St Pourcain, Beate] Max Planck Inst Psycholinguist, Wundtlaan 1, NL-6525 XD Nijmegen, Netherlands. [Evans, David M.] Univ Queensland, Diamantina Inst, Translat Res Inst, Brisbane, Qld, Australia. [Krapohl, Eva; Plomin, Robert] Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC Social Genet & Dev Psychiat Ctr, London WC2R 2LS, England. [Wang, Ya Xing; Jonas, Jost B.] Capital Med Univ, Beijing Tongren Hosp, Beijing Inst Ophthalmol, Beijing, Peoples R China. [Wang, Ya Xing; Jonas, Jost B.] Beijing Ophthalmol & Visual Sci Key Lab, Beijing, Peoples R China. [Jonas, Jost B.] Heidelberg Univ, Med Fac Mannheim, Dept Ophthalmol, Mannheim, Germany. [Baird, Paul Nigel; Wang, Jie Jin; Mackey, David A.; He, Mingguang] Univ Melbourne, Royal Victorian Eye & Ear Hosp, CERA, Melbourne, Vic, Australia. [Wang, Jie Jin] Univ Sydney, Dept Ophthalmol, Ctr Vis Res, Sydney, NSW 2006, Australia. [Wang, Jie Jin] Univ Sydney, Westmead Inst Med Res, Sydney, NSW 2006, Australia. [Cheng, Ching-Yu; Wong, Tien-Yin] Natl Univ Singapore, Natl Univ Hlth Syst, Dept Ophthalmol, Singapore 117548, Singapore. [Cheng, Ching-Yu; Wong, Tien-Yin; Saw, Seang-Mei] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore. [Teo, Yik-Ying] Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore 117548, Singapore. [Teo, Yik-Ying; Saw, Seang-Mei] Natl Univ Singapore, Natl Univ Hlth Syst, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore. [Wojciechowski, Robert; Bailey-Wilson, Joan E.] NHGRI, Computat & Stat Genom Branch, NIH, Baltimore, MD USA. [Wojciechowski, Robert] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Wojciechowski, Robert] Johns Hopkins Sch Med, Wilmer Eye Inst, Baltimore, MD USA. [Young, Terri L.] Univ Wisconsin, Ophthalmol & Visual Sci, Madison, WI USA. [Young, Terri L.] Duke Natl Univ Singapore, Grad Sch Med, Singapore, Singapore. [Parssinen, Olavi] Univ Jyvaskyla, Dept Hlth Sci, Jyvaskyla, Finland. [Parssinen, Olavi] Univ Jyvaskyla, Gerontol Res Ctr, Jyvaskyla, Finland. [Parssinen, Olavi] Cent Hosp Cent Finland, Dept Ophthalmol, Jyvaskyla, Finland. [Oexle, Konrad] Tech Univ Munich, Inst Human Genet, D-80290 Munich, Germany. [Pfeiffer, Norbert] Univ Med Ctr Mainz, Dept Ophthalmol, Mainz, Germany. [Guggenheim, Jeremy A.] Cardiff Univ, Sch Optometry & Vis Sci, Cardiff CF10 3AX, S Glam, Wales. RP Guggenheim, JA (reprint author), Cardiff Univ, Sch Optometry & Vis Sci, Cardiff CF10 3AX, S Glam, Wales. EM GuggenheimJ1@cardiff.ac.uk RI wang, YA XING/K-9671-2016; Delcourt, Cecile/I-2627-2013; Fox, Laura /C-6249-2016; Wang, Jie Jin/P-1499-2014; Davey Smith, George/A-7407-2013; Polasek, Ozren/B-6002-2011; Mackey, David/H-5340-2014; Paterson, Andrew/A-4088-2011 OI Hammond, Christopher/0000-0002-3227-2620; Kemp, John/0000-0002-9105-2249; Ikram, Mohammad Kamran/0000-0003-0173-9571; Evans, David/0000-0003-0663-4621; Williams, Katie M/0000-0003-4596-3938; Tai, E Shyong/0000-0003-2929-8966; wang, YA XING/0000-0003-2749-7793; Krapohl, Eva/0000-0002-6809-7908; Rantanen, Taina/0000-0002-1604-1945; Delcourt, Cecile/0000-0002-2099-0481; Wang, Jie Jin/0000-0001-9491-4898; Gharahkhani, Puya/0000-0002-4203-5952; Hohn, Rene /0000-0003-2870-1469; Fossarello, Maurizio/0000-0003-1520-7760; Davey Smith, George/0000-0002-1407-8314; Polasek, Ozren/0000-0002-5765-1862; Mackey, David/0000-0001-7914-4709; Paterson, Andrew/0000-0002-9169-118X FU Wellcome Trust [102215/2/13/2]; UK Medical Research Council [MC_UU_12013/3, MC_UU_12013/4, G0901245, G0500079]; Hong Kong Polytechnic University [Z0GM]; Australian National Health and Medical Research Council (NHMRC); NHMRC Medical Genomics Grant; National Institutes of Health (NIH)/National Eye Institute (NEI) [RO1EY018246]; Clifford Craig Medical Research Trust; Ophthalmic Research Institute of Australia (ORIA); American Health Assistance Foundation (AHAF); Peggy and Leslie Cranbourne Foundation; Foundation for Children; NHMRC [350415]; Center for Inherited Diseases Research (CIDR); National Science Foundation [81125007]; Fundamental Research Funds for the State Key Laboratory, NSFC [11401600]; Fundamental Research Funds for the Central Universities [15lgpy07]; SYSU-CMU Shunde International Joint Research Institute; University of Western Australia (UWA); Telethon Institute for Child Health Research; Raine Medical Research Foundation; UWA Faculty of Medicine; Dentistry and Health Sciences; Women's and Infant's Research Foundation; Curtin University; Australian National Health and Medical Research Council (NHMRC) [1021105]; LEI; Australian Foundation for the Prevention of Blindness; Singapore BioMedical Research Council (BMRC); Singapore Tissue Network; NMRC [1176/2008]; US National Institutes of Health [HD044454, HD059215]; Medical Research Council Research Professorship award [G19/2]; European Research Council Advanced Investigator award [295366]; Medical Research Council Clinical Research Training Fellowship; Institute of Psychiatry, Psychology and Neuroscience Excellence Studentship; National Eye Institute, National Institutes of Health [R01-EY016379]; Research to Prevent Blindness, New York, NY; Intramural Research Program of the National Human Genome Research Institute, NIH; Research to Prevent Blindness, Inc.; NIH [NEI R01EY014685]; Jack Brockhoff Foundation; Pfizer Australia Senior Research Fellowship FX ALSPAC. We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council and the Wellcome Trust (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and JAG and CW will serve as guarantors for the contents of this paper. This research was specifically funded by grant MC_UU_12013/3&4 from the UK Medical Research Council and grant Z0GM from the Hong Kong Polytechnic University. GWAS data were generated by Sample Logistics and Genotyping Facilities at the Wellcome Trust Sanger Institute and LabCorp (Laboratory Corportation of America) using support from 23andMe.; BATS and TEST. The Australian Twin Registry is supported by an Australian National Health and Medical Research Council (NHMRC) Enabling Grant (2004-2009). Part of the genotyping was funded by an NHMRC Medical Genomics Grant. Genotyping for the remainder was performed by the National Institutes of Health (NIH)/National Eye Institute (NEI) grant RO1EY018246 and a Center for Inherited Diseases Research (CIDR) genotyping project grant both awarded to Terri L. Young (PI), and we are grateful to Dr Camilla Day and staff. Ophthalmic examination of the Twin cohorts was funded by the Clifford Craig Medical Research Trust, Ophthalmic Research Institute of Australia (ORIA), American Health Assistance Foundation (AHAF), Peggy and Leslie Cranbourne Foundation, Foundation for Children, NHMRC Project Grant 350415 (2005-2007), Jack Brockhoff Foundation and the Pfizer Australia Senior Research Fellowship (DAM). We also would like to acknowledge that CERA receives Operational Infrastructure Support from the Victorian Government. The Berghofer QIMR authors thank the twins eye study investigators; Nicholas G Martin, Scott D. Gordon, Anjali K. Henders, Sarah E. Medland, Brian McEvoy, Dale R. Nyholt, Margaret J. Wright, Megan J. Campbell, and Anthony Caracella for their assistance in processing the Australian genotyping data. We are also grateful for Jane MacKinnon, Shayne Brown, Sandra Staffieri, Olivia Bigault, Colleen Wilkinson, Julie Barbour, Byoung Sung Chu, Jonathan Ruddle Paul Sanfilippo, Cong Sun, Justin Sherwin, Robert Macmillan, Rachael Adams, Robyn Troutbeck, Ya Ling Ma, Christine Chen and Amy Cohn In addition, we appreciate the assistance in recruiting twins from Thanuja Gunasekera, Allison McKenzie, Anne-Louise Ponsonby, Terry Dwyer, James Dilger, Palma Ragno, Jenny Boadle, Kim Dorrell, Shyamali Dharmage, John Hopper; GZT. We are extremely grateful to all the twins and their parents, and the whole Guangzhou Twins team which includes research scientists, interviewers, statistician, laboratory technicians, clerical workers, volunteers, managers, receptionists, nurses and graduate students. The Guangzhou Twin Eye study is supported by National Science Foundation for Distinguished Young Scholars (81125007), Fundamental Research Funds for the Central Universities, Fundamental Research Funds for the State Key Laboratory, NSFC(11401600), the Fundamental Research Funds for the Central Universities (15lgpy07) and the free application projects from the SYSU-CMU Shunde International Joint Research Institute.; RAINE. We are grateful to all the study participants. We also thank the Raine Study and Lions Eye Institute (LEI) research staff for cohort coordination and data collection. The core management of the Raine Study is funded by The University of Western Australia (UWA), The Telethon Institute for Child Health Research, Raine Medical Research Foundation, UWA Faculty of Medicine, Dentistry and Health Sciences, Women's and Infant's Research Foundation and Curtin University. Genotyping was funded by Australian National Health and Medical Research Council (NHMRC) project grant 1021105. Support for the REHS was provided by LEI, the Australian Foundation for the Prevention of Blindness and Ophthalmic Research Institute of Australia (ORIA).; SCORM: We wish to express our gratitude to all the participants and patients who volunteered to take part in this study. The SCORM GWAS study was supported by the Singapore BioMedical Research Council (BMRC). Additional support was provided by the Singapore Tissue Network. We acknowledge the Genome Institute of Singapore for genotyping all the samples collected from SCORM.; STARS: The Strabismus, Amblyopia, and Refractive Error Study of Preschool Children (STARS) was supported by a NMRC grant (1176/2008). We acknowledge the Genome Institute of Singapore for genotyping all the samples collected from STARS.; TEDS. We gratefully acknowledge the ongoing contribution of the participants in the Twins Early Development Study (TEDS) and their families. TEDS is supported by a program grant to Robert Plomin from the UK Medical Research Council [G0901245; previously G0500079], with additional support from the US National Institutes of Health [HD044454 and HD059215]. RP is supported by a Medical Research Council Research Professorship award [G19/2] and a European Research Council Advanced Investigator award [295366]. KMW is supported by a Medical Research Council Clinical Research Training Fellowship. EK is supported by an Institute of Psychiatry, Psychology and Neuroscience Excellence Studentship.; WESDR. The WESDR was supported by grant R01-EY016379 from the National Eye Institute, National Institutes of Health and an unrestricted grant from Research to Prevent Blindness, New York, NY.; JEBW is supported by the Intramural Research Program of the National Human Genome Research Institute, NIH. TLY is supported by Research to Prevent Blindness, Inc., and NIH NEI R01EY014685. NR 43 TC 3 Z9 3 U1 6 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAY 13 PY 2016 VL 6 AR 25853 DI 10.1038/srep25853 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DL6RW UT WOS:000375767300001 PM 27174397 ER PT J AU Kong, R Xu, K Zhou, TQ Acharya, P Lemmin, T Liu, K Ozorowski, G Soto, C Taft, JD Bailer, RT Cale, EM Chen, L Choi, CW Chuang, GY Doria-Rose, NA Druz, A Georgiev, IS Gorman, J Huang, JH Joyce, MG Louder, MK Ma, XC Mckee, K O'Dell, S Pancera, M Yang, YP Blanchard, SC Mothes, W Burton, DR Koff, WC Connors, M Ward, AB Kwong, PD Mascola, JR AF Kong, Rui Xu, Kai Zhou, Tongqing Acharya, Priyamvada Lemmin, Thomas Liu, Kevin Ozorowski, Gabriel Soto, Cinque Taft, Justin D. Bailer, Robert T. Cale, Evan M. Chen, Lei Choi, Chang W. Chuang, Gwo-Yu Doria-Rose, Nicole A. Druz, Aliaksandr Georgiev, Ivelin S. Gorman, Jason Huang, Jinghe Joyce, M. Gordon Louder, Mark K. Ma, Xiaochu Mckee, Krisha O'Dell, Sijy Pancera, Marie Yang, Yongping Blanchard, Scott C. Mothes, Walther Burton, Dennis R. Koff, Wayne C. Connors, Mark Ward, Andrew B. Kwong, Peter D. Mascola, John R. TI Fusion peptide of HIV-1 as a site of vulnerability to neutralizing antibody SO SCIENCE LA English DT Article ID VIRAL MEMBRANE-FUSION; CRYO-EM STRUCTURE; ENVELOPE TRIMER; GP41-GP120 INTERFACE; DEPENDENT EPITOPE; CRYSTAL-STRUCTURE; ENV; RECOGNITION; QUATERNARY; DYNAMICS AB The HIV-1 fusion peptide, comprising 15 to 20 hydrophobic residues at the N terminus of the Env-gp41 subunit, is a critical component of the virus-cell entry machinery. Here, we report the identification of a neutralizing antibody, N123-VRC34.01, which targets the fusion peptide and blocks viral entry by inhibiting conformational changes in gp120 and gp41 subunits of Env required for entry. Crystal structures of N123-VRC34.01 liganded to the fusion peptide, and to the full Env trimer, revealed an epitope consisting of the N-terminal eight residues of the gp41 fusion peptide and glycan N88 of gp120, and molecular dynamics showed that the N-terminal portion of the fusion peptide can be solvent-exposed. These results reveal the fusion peptide to be a neutralizing antibody epitope and thus a target for vaccine design. C1 [Kong, Rui; Xu, Kai; Zhou, Tongqing; Acharya, Priyamvada; Liu, Kevin; Soto, Cinque; Taft, Justin D.; Bailer, Robert T.; Cale, Evan M.; Chen, Lei; Choi, Chang W.; Chuang, Gwo-Yu; Doria-Rose, Nicole A.; Druz, Aliaksandr; Georgiev, Ivelin S.; Gorman, Jason; Joyce, M. Gordon; Louder, Mark K.; Mckee, Krisha; O'Dell, Sijy; Pancera, Marie; Yang, Yongping; Kwong, Peter D.; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Lemmin, Thomas] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA USA. [Ozorowski, Gabriel; Ward, Andrew B.] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA. [Ozorowski, Gabriel; Ward, Andrew B.] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Disc, La Jolla, CA 92037 USA. [Ozorowski, Gabriel; Ward, Andrew B.] Scripps Res Inst, Int AIDS Vaccine Initiat, Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Huang, Jinghe; Connors, Mark] NIAID, HIV Specif Immun Sect, Immunoregulat Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Ma, Xiaochu; Mothes, Walther] Yale Univ, Sch Med, Dept Microbial Pathogenesis, 333 Cedar St, New Haven, CT 06536 USA. [Blanchard, Scott C.] Cornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10021 USA. [Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, Int AIDS Vaccine Initiat Neutralizing Antibody Ct, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. [Burton, Dennis R.] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Boston, MA 02142 USA. [Koff, Wayne C.] Int AIDS Vaccine Initiat, New York, NY 10038 USA. RP Kwong, PD; Mascola, JR (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM pdkwong@nih.gov; jmascola@nih.gov RI Blanchard, Scott/A-5804-2009; Ward, Andrew/F-9203-2014; Zhou, Tongqing/A-6880-2010 OI Ward, Andrew/0000-0001-7153-3769; Zhou, Tongqing/0000-0002-3935-4637 FU Intramural Research Programs of the Vaccine Research Center and Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health; International AIDS Vaccine Initiative's (IAVI's) Neutralizing Antibody Consortium; Bill & Melinda Gates Foundation; Ministry of Foreign Affairs of Denmark, Irish Aid; Ministry of Finance of Japan; Ministry of Foreign Affairs of the Netherlands; Norwegian Agency for Development Cooperation (NORAD); UK Department for International Development (DFID); U.S. Agency for International Development (USAID); NIH [R01GM079238, P01GM56550, R01GM116654]; U.S. Department of Energy, Basic Energy Sciences, Office of Science, [W-31-109-Eng-38] FX We thank the members of the Flow Cytometry Core, Vaccine Research Center, and especially R. Nguyen for his assistance in cell sorting. We thank members of the Structural Biology Section, Structural Bioinformatics Core Section, and Human Immunology Section, Vaccine Research Center, for discussions and comments on the manuscript. We thank J. Baalwa, D. Ellenberger, F. Gao, B. Hahn, K. Hong, J. Kim, F. McCutchan, D. Montefiori, L. Morris, J. Overbaugh, E. Sanders-Buell, G. Shaw, R. Swanstrom, M. Thomson, S. Tovanabutra, C. Williamson, and L. Zhang for contributing the HIV-1 Envelope plasmids used in our neutralization panel. The data presented in this manuscript are tabulated in the main paper and in the supplementary materials. Nucleotide sequences of VRC34.01-VRC34.07 variable regions are available under GenBank accession numbers KU711816 to KU711829. Atomic coordinates and structure factors of the reported crystal structures have been deposited with the Protein Data Bank (PDB) under accession codes 5I8C, 5I8E, and 5I8H. EM data have been deposited with the Electron Microscopy Data Bank under accession code EMD-8125. Support for this work was provided by the Intramural Research Programs of the Vaccine Research Center and Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, and from the International AIDS Vaccine Initiative's (IAVI's) Neutralizing Antibody Consortium. IAVI's work is made possible by support from many donors, including the Bill & Melinda Gates Foundation, the Ministry of Foreign Affairs of Denmark, Irish Aid, the Ministry of Finance of Japan, the Ministry of Foreign Affairs of the Netherlands, the Norwegian Agency for Development Cooperation (NORAD), the UK Department for International Development (DFID), and the U.S. Agency for International Development (USAID). The full list of IAVI donors is available at www.iavi.org. S.C.B. was supported by NIH grants R01GM079238 and P01GM56550. W.M. was supported by NIH grants R01GM116654 and P01GM56550. Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under contract number W-31-109-Eng-38. The following patent applications are pending: U.S. Patent Application 13/202,351, Methods and Compositions for Altering Photopysical Properties of Fluorophores via Proximal Quenching (S.C.B.); U.S. Patent Application 14/373,402 Dye Compositions, Methods of Preparation, Conjugates Thereof, and Methods of Use (S.C.B.); and International and U.S. Patent Application PCT/US13/42249 Reagents and Methods for Identifying Anti-HIV Compounds (S.C.B. and W.M.). S.C.B. holds an equity interest in Lumidyne Technologies Corporation. NR 24 TC 26 Z9 26 U1 8 U2 25 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD MAY 13 PY 2016 VL 352 IS 6287 BP 828 EP 833 DI 10.1126/science.aae0474 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DL5FP UT WOS:000375663000042 PM 27174988 ER PT J AU Atlas, LY Doll, BB Li, J Daw, ND Phelps, EA AF Atlas, Lauren Y. Doll, Bradley B. Li, Jian Daw, Nataniel D. Phelps, Elizabeth A. TI Instructed knowledge shapes feedback-driven aversive learning in striatum and orbitofrontal cortex, but not the amygdala SO ELIFE LA English DT Article ID UNILATERAL TEMPORAL LOBECTOMY; PREFRONTAL CORTEX; BRAIN MEDIATORS; NEURAL SYSTEMS; FEAR; REVERSAL; PAIN; EXTINCTION; NEURONS; REWARD AB Socially-conveyed rules and instructions strongly shape expectations and emotions. Yet most neuroscientific studies of learning consider reinforcement history alone, irrespective of knowledge acquired through other means. We examined fear conditioning and reversal in humans to test whether instructed knowledge modulates the neural mechanisms of feedback-driven learning. One group was informed about contingencies and reversals. A second group learned only from reinforcement. We combined quantitative models with functional magnetic resonance imaging and found that instructions induced dissociations in the neural systems of aversive learning. Responses in striatum and orbitofrontal cortex updated with instructions and correlated with prefrontal responses to instructions. Amygdala responses were influenced by reinforcement similarly in both groups and did not update with instructions. Results extend work on instructed reward learning and reveal novel dissociations that have not been observed with punishments or rewards. Findings support theories of specialized threat-detection and may have implications for fear maintenance in anxiety. C1 [Atlas, Lauren Y.] NIH, Natl Ctr Complementary & Integrat Hlth, Bldg 10, Bethesda, MD 20892 USA. [Atlas, Lauren Y.] NIDA, NIH, Bayview, MD USA. [Doll, Bradley B.; Phelps, Elizabeth A.] NYU, Ctr Neural Sci, New York, NY 10003 USA. [Doll, Bradley B.] Columbia Univ, Dept Psychol, New York, NY 10027 USA. [Li, Jian] Peking Univ, Dept Psychol, Beijing Key Lab Behav & Mental Hlth, Beijing 100871, Peoples R China. [Li, Jian] Peking Univ, PKU IDG McGovern Inst Brain Res, Beijing 100871, Peoples R China. [Daw, Nataniel D.] Princeton Univ, Dept Psychol, Princeton Neurosci Inst, Princeton, NJ 08544 USA. [Phelps, Elizabeth A.] NYU, Dept Psychol, 6 Washington Pl, New York, NY 10003 USA. [Phelps, Elizabeth A.] Nathan S Kline Inst Psychiat Res, Orangeburg, NY 10962 USA. RP Atlas, LY (reprint author), NIH, Natl Ctr Complementary & Integrat Hlth, Bldg 10, Bethesda, MD 20892 USA.; Atlas, LY (reprint author), NIDA, NIH, Bayview, MD USA.; Phelps, EA (reprint author), NYU, Ctr Neural Sci, New York, NY 10003 USA.; Phelps, EA (reprint author), NYU, Dept Psychol, 6 Washington Pl, New York, NY 10003 USA.; Phelps, EA (reprint author), Nathan S Kline Inst Psychiat Res, Orangeburg, NY 10962 USA. EM lauren.atlas@nih.gov; liz.phelps@nyu.edu FU National Center for Complementary and Integrative Health; National Institute of Mental Health [RO1MH097085] FX National Center for Complementary and Integrative Health Lauren Y Atlas; National Institute of Mental Health RO1MH097085 Elizabeth A Phelps; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 67 TC 2 Z9 2 U1 1 U2 4 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD MAY 12 PY 2016 VL 5 AR e15192 DI 10.7554/eLife.15192 PG 26 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DP7AP UT WOS:000378651700001 ER PT J AU Aprelikova, O Tomlinson, CC Hoenerhoff, M Hixon, JA Durum, SK Qiu, TH He, SP Burkett, S Liu, ZY Swanson, SM Green, JE AF Aprelikova, Olga Tomlinson, Christine C. Hoenerhoff, Mark Hixon, Julie A. Durum, Scott K. Qiu, Ting-hu He, Siping Burkett, Sandra Liu, Zi-Yao Swanson, Steven M. Green, Jeffrey E. TI Development and Preclinical Application of an Immunocompetent Transplant Model of Basal Breast Cancer with Lung, Liver and Brain Metastases SO PLOS ONE LA English DT Article ID MAMMARY-TUMOR PROGRESSION; ANTIGEN TRANSGENIC MICE; PROSTATE-CANCER; MOUSE MODEL; IN-VITRO; C-MYC; CARCINOMA; ADENOCARCINOMA; GENE; IDENTIFICATION AB Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is associated with a poor prognosis and for which no targeted therapies currently exist. In order to improve preclinical testing for TNBC that relies primarily on using human xenografts in immunodeficient mice, we have developed a novel immunocompetent syngeneic murine tumor transplant model for basal-like triple-negative breast cancer. The C3(1)/SV40-T/t-antigen (C3(1)/Tag) mouse mammary tumor model in the FVB/N background shares important similarities with human basal-like TNBC. However, these tumors or derived cell lines are rejected when transplanted into wt FVB/N mice, likely due to the expression of SV40 T-antigen. We have developed a sub-line of mice (designated REAR mice) that carry only one copy of the C3(1)/Tag-antigen transgene resulting from a spontaneous transgene rearrangement in the original founder line. Unlike the original C3(1)/Tag mice, REAR mice do not develop mammary tumors or other phenotypes observed in the original C3(1)/Tag transgenic mice. REAR mice are more immunologically tolerant to SV40 T-antigen driven tumors and cell lines in an FVB/N background (including prostate tumors from TRAMP mice), but are otherwise immunologically intact. This transplant model system offers the ability to synchronously implant the C3(1)/Tag tumor-derived M6 cell line or individual C3(1)/Tag tumors from various stages of tumor development into the mammary fat pads or tail veins of REAR mice. C3(1)/Tag tumors or M6 cells implanted into the mammary fat pads spontaneously metastasize at a high frequency to the lung and liver. M6 cells injected by tail vein can form brain metastases. We demonstrate that irradiated M6 tumor cells or the same cells expressing GM-CSF can act as a vaccine to retard tumor growth of implanted tumor cells in the REAR model. Preclinical studies performed in animals with an intact immune system should more authentically replicate treatment responses in human patients. C1 [Aprelikova, Olga; Tomlinson, Christine C.; Hoenerhoff, Mark; Qiu, Ting-hu; He, Siping; Liu, Zi-Yao; Green, Jeffrey E.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Hixon, Julie A.; Durum, Scott K.] NCI, Mol Immunoregulat Lab, NIH, Frederick, MD 21701 USA. [Burkett, Sandra] NCI, Comparat Mol Cytogenet Core, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. [Swanson, Steven M.] Univ Wisconsin, Sch Pharm, 425 N Charter St, Madison, WI 53706 USA. [Hoenerhoff, Mark] Univ Michigan, Sch Med, Unit Lab Anim Med, In Vivo Anim Core, Ann Arbor, MI USA. RP Green, JE (reprint author), NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. EM jegreen@nih.gov FU Intramural Research Program of the NIH; NCI; CCR FX This work was supported by the Intramural Research Program of the NIH, CCR, and NCI. NR 37 TC 0 Z9 0 U1 4 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 12 PY 2016 VL 11 IS 5 AR e0155262 DI 10.1371/journal.pone.0155262 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM8CQ UT WOS:000376588600037 PM 27171183 ER PT J AU Mode, NA Evans, MK Zonderman, AB AF Mode, Nicolle A. Evans, Michele K. Zonderman, Alan B. TI Race, Neighborhood Economic Status, Income Inequality and Mortality SO PLOS ONE LA English DT Article ID DISPARITIES GEOCODING PROJECT; US METROPOLITAN-AREAS; SOCIOECONOMIC-STATUS; UNITED-STATES; HEALTHY FOODS; DEPRIVATION; MULTILEVEL; CHOICE; URBAN; RISK AB Mortality rates in the United States vary based on race, individual economic status and neighborhood. Correlations among these variables in most urban areas have limited what conclusions can be drawn from existing research. Our study employs a unique factorial design of race, sex, age and individual poverty status, measuring time to death as an objective measure of health, and including both neighborhood economic status and income inequality for a sample of middle-aged urban-dwelling adults (N = 3675). At enrollment, African American and White participants lived in 46 unique census tracts in Baltimore, Maryland, which varied in neighborhood economic status and degree of income inequality. A Cox regression model for 9-year mortality identified a three-way interaction among sex, race and individual poverty status (p = 0.03), with African American men living below poverty having the highest mortality. Neighborhood economic status, whether measured by a composite index or simply median household income, was negatively associated with overall mortality (p<0.001). Neighborhood income inequality was associated with mortality through an interaction with individual poverty status (p = 0.04). While racial and economic disparities in mortality are well known, this study suggests that several social conditions associated with health may unequally affect African American men in poverty in the United States. Beyond these individual factors are the influences of neighborhood economic status and income inequality, which may be affected by a history of residential segregation. The significant association of neighborhood economic status and income inequality with mortality beyond the synergistic combination of sex, race and individual poverty status suggests the long-term importance of small area influence on overall mortality. C1 [Mode, Nicolle A.; Evans, Michele K.; Zonderman, Alan B.] NIA, NIH, Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Mode, NA (reprint author), NIA, NIH, Dept Hlth & Human Serv, Baltimore, MD 21224 USA. EM nicolle.mode@nih.gov OI Zonderman, Alan B/0000-0002-6523-4778 FU National Institute on Aging, National Institutes of Health [Z01-AG000513]; National Institute on Minority Health and Health Disparities, National Institutes of Health FX The Healthy Aging in Neighborhoods of Diversity across the Life Span study is supported by the Intramural Research Program (Z01-AG000513) of the National Institute on Aging, National Institutes of Health (MKE, ABZ). Support was also provided by the National Institute on Minority Health and Health Disparities, National Institutes of Health (MKE). The funders had no role in the study design, data collection and analysis, or preparation of the manuscript. NR 68 TC 1 Z9 1 U1 7 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 12 PY 2016 VL 11 IS 5 AR e0154535 DI 10.1371/journal.pone.0154535 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM8CQ UT WOS:000376588600113 PM 27171406 ER PT J AU Sun, L St Leger, AJ Yu, CR He, C Mahdi, RM Chan, CC Wang, HS Morse, HC Egwuagu, CE AF Sun, Lin St Leger, Anthony J. Yu, Cheng-Rong He, Chang Mahdi, Rashid M. Chan, Chi-Chao Wang, Hongsheng Morse, Herbert C., III Egwuagu, Charles E. TI Interferon Regulator Factor 8 (IRF8) Limits Ocular Pathology during HSV-1 Infection by Restraining the Activation and Expansion of CD8(+) T Cells SO PLOS ONE LA English DT Article ID SIMPLEX-VIRUS TYPE-1; SEQUENCE BINDING-PROTEIN; TRANSCRIPTION FACTOR; CONFERS PROTECTION; GAMMA-INTERFERON; GENE-EXPRESSION; ICSBP GENE; DIFFERENTIATION; MEMORY; UVEITIS AB Interferon Regulatory Factor-8 (IRF8) is constitutively expressed in monocytes and B cell lineages and plays important roles in immunity to pathogens and cancer. Although IRF8 expression is induced in activated T cells, the functional relevance of IRF8 in T cell-mediated immunity is not well understood. In this study, we used mice with targeted deletion of Irf8 in T-cells (IRF8KO) to investigate the role of IRF8 in T cell-mediated responses during herpes simplex virus 1 (HSV-1) infection of the eye. In contrast to wild type mice, HSV-1-infected IRF8KO mice mounted a more robust anti-HSV-1 immune response, which included marked expansion of HSV-1-specific CD8(+) T cells, increased infiltration of inflammatory cells into the cornea and trigeminal ganglia (TG) and enhanced elimination of virus within the trigeminal ganglion. However, the consequence of the enhanced immunological response was the development of ocular inflammation, limbitis, and neutrophilic infiltration into the cornea of HSV-1-infected IRF8KO mice. Surprisingly, we observed a marked increase in virus-specific memory precursor effector cells (MPEC) in IRF8KO mice, suggesting that IRF8 might play a role in regulating the differentiation of effector CD8(+) T cells to the memory phenotype. Together, our data suggest that IRF8 might play a role in restraining excess lymphocyte proliferation. Thus, modulating IRF8 levels in T cells can be exploited therapeutically to prevent immune-mediated ocular pathology during autoimmune and infectious diseases of the eye. C1 [Sun, Lin; Yu, Cheng-Rong; He, Chang; Mahdi, Rashid M.; Egwuagu, Charles E.] NEI, Mol Immunol Sect, NIH, Bethesda, MD 20892 USA. [St Leger, Anthony J.] NEI, Immunoregulat Sect, NIH, Bethesda, MD 20892 USA. [Chan, Chi-Chao] NEI, Immunopathol Sect, NIH, Bethesda, MD 20892 USA. [Wang, Hongsheng; Morse, Herbert C., III] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [He, Chang] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, State Key Lab Ophthalmol, Guangzhou 510275, Guangdong, Peoples R China. RP Egwuagu, CE (reprint author), NEI, Mol Immunol Sect, NIH, Bethesda, MD 20892 USA. EM egwuaguc@nei.nih.gov FU National Eye Institute [EY000350-15, EY000372-14] FX This work was supported by: (i) EY000350-15: National Eye Institute CEE; (ii) EY000372-14: National Eye Institute CEE. NR 45 TC 1 Z9 1 U1 1 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 12 PY 2016 VL 11 IS 5 AR e0155420 DI 10.1371/journal.pone.0155420 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM8CQ UT WOS:000376588600076 PM 27171004 ER PT J AU Vogtmann, E Hua, X Zeller, G Sunagawa, S Voigt, AY Hercog, R Goedert, JJ Shi, JX Bork, P Sinha, R AF Vogtmann, Emily Hua, Xing Zeller, Georg Sunagawa, Shinichi Voigt, Anita Y. Hercog, Rajna Goedert, James J. Shi, Jianxin Bork, Peer Sinha, Rashmi TI Colorectal Cancer and the Human Gut Microbiome: Reproducibility with Whole-Genome Shotgun Sequencing SO PLOS ONE LA English DT Article ID FECAL MICROBIOTA; METAGENOME; BACTERIAL; COLLECTION AB Accumulating evidence indicates that the gut microbiota affects colorectal cancer development, but previous studies have varied in population, technical methods, and associations with cancer. Understanding these variations is needed for comparisons and for potential pooling across studies. Therefore, we performed whole-genome shotgun sequencing on fecal samples from 52 pre-treatment colorectal cancer cases and 52 matched controls from Washington, DC. We compared findings from a previously published 16S rRNA study to the metagenomics-derived taxonomy within the same population. In addition, metagenome-predicted genes, modules, and pathways in the Washington, DC cases and controls were compared to cases and controls recruited in France whose specimens were processed using the same platform. Associations between the presence of fecal Fusobacteria, Fusobacterium, and Porphyromonas with colorectal cancer detected by 16S rRNA were reproduced by metagenomics, whereas higher relative abundance of Clostridia in cancer cases based on 16S rRNA was merely borderline based on metagenomics. This demonstrated that within the same sample set, most, but not all taxonomic associations were seen with both methods. Considering significant cancer associations with the relative abundance of genes, modules, and pathways in a recently published French metagenomics dataset, statistically significant associations in the Washington, DC population were detected for four out of 10 genes, three out of nine modules, and seven out of 17 pathways. In total, colorectal cancer status in the Washington, DC study was associated with 39% of the metagenome-predicted genes, modules, and pathways identified in the French study. More within and between population comparisons are needed to identify sources of variation and disease associations that can be reproduced despite these variations. Future studies should have larger sample sizes or pool data across studies to have sufficient power to detect associations that are reproducible and significant after correction for multiple testing. C1 [Vogtmann, Emily; Hua, Xing; Goedert, James J.; Shi, Jianxin; Sinha, Rashmi] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Vogtmann, Emily] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Zeller, Georg; Sunagawa, Shinichi; Voigt, Anita Y.; Bork, Peer] European Mol Biol Lab, Struct & Computat Biol Unit, Heidelberg, Germany. [Voigt, Anita Y.] Univ Heidelberg Hosp, Inst Pathol, Dept Appl Tumor Biol, Heidelberg, Germany. [Voigt, Anita Y.] German Canc Res Ctr, Clin Cooperat Unit Appl Tumor Biol, Heidelberg, Germany. [Voigt, Anita Y.; Bork, Peer] Univ Heidelberg Hosp, MMPU, Heidelberg, Germany. [Voigt, Anita Y.; Bork, Peer] European Mol Biol Lab, Heidelberg, Germany. [Hercog, Rajna] European Mol Biol Lab, Genom Core Facil, Heidelberg, Germany. [Bork, Peer] Max Delbruck Ctr Mol Med, Berlin, Germany. [Bork, Peer] Univ Wurzburg, Bioctr, Dept Bioinformat, D-97070 Wurzburg, Germany. RP Vogtmann, E (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.; Vogtmann, E (reprint author), NCI, Canc Prevent Div, Bethesda, MD 20892 USA. EM emily.vogtmann@nih.gov RI Sunagawa, Shinichi/D-9715-2011; Bork, Peer/F-1813-2013 OI Sunagawa, Shinichi/0000-0003-3065-0314; Bork, Peer/0000-0002-2627-833X FU Intramural Research Program of the National Cancer Institute; CancerBiome project (European Research Council) [268985] FX This project was supported by the Intramural Research Program of the National Cancer Institute. GZ, SS, AYV, RH, and PB received funding through the CancerBiome project (European Research Council project reference 268985).; This project was supported by the Intramural Research Program of the National Cancer Institute. A portion of the data analysis was conducting using the computational resources of the National Institutes of Health HPC Biowulf cluster (http://hpc.nih.gov). GZ, SS, AYV, RH, and PB received funding through the CancerBiome project (European Research Council project reference 268985). NR 32 TC 3 Z9 3 U1 6 U2 19 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 12 PY 2016 VL 11 IS 5 AR e0155362 DI 10.1371/journal.pone.0155362 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM8CQ UT WOS:000376588600028 PM 27171425 ER PT J AU Zhao, Z Xie, L Xie, L Bourne, PE AF Zhao, Zheng Xie, Li Xie, Lei Bourne, Philip E. TI Delineation of Polypharmacology across the Human Structural Kinome Using a Functional Site Interaction Fingerprint Approach SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID LIGAND-BINDING-SITES; PROTEIN DATA-BANK; MOLECULE KINASE INHIBITORS; CHRONIC MYELOID-LEUKEMIA; IRREVERSIBLE INHIBITORS; COMPREHENSIVE ANALYSIS; TYROSINE KINASE; DRUG DISCOVERY; LUNG-CANCER; MUTANT AB Targeted polypharmacology of kinases has emerged as a promising strategy to design efficient and safe therapeutics. Here, we perform a systematic study of kinase ligand binding modes for the human structural kinome at scale (208 kinases, 1777 unique ligands, and their complexes) by integrating chemical genomics and structural genomics data and by introducing a functional site interaction fingerprint (Fs-IFP) method. New insights into kinase ligand binding modes were obtained. We establish relationships between the features of binding modes, the ligands, and the binding pockets, respectively. We also drive the intrinsic binding specificity and which correlation with amino acid conservation. Third, we explore the landscape of the binding modes and highlight the regions of "selectivity pocket" and "selectivity entrance". Finally, we demonstrate that Fs-IFP similarity is directly correlated to the experimentally determined profile. These improve our understanding of kinase-ligand interactions and contribute to the design of novel polypharmacological therapies targeting kinases. C1 [Zhao, Zheng] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Xie, Li] Scripps Ranch, San Diego, CA 92131 USA. [Xie, Lei] CUNY Hunter Coll, Dept Comp Sci, New York, NY 10065 USA. [Xie, Lei] CUNY, Grad Ctr, New York, NY 10016 USA. [Bourne, Philip E.] NIH, Off Director, Bldg 10, Bethesda, MD 20892 USA. RP Xie, L (reprint author), CUNY Hunter Coll, Dept Comp Sci, New York, NY 10065 USA.; Xie, L (reprint author), CUNY, Grad Ctr, New York, NY 10016 USA.; Bourne, PE (reprint author), NIH, Off Director, Bldg 10, Bethesda, MD 20892 USA. EM lei.xie@hunter.cuny.edu; philip.bourne@nih.gov FU Intramural Research Program of the National Library of Medicine, National Institutes of Health; National Library of Medicine, National Institutes of Health [R01LM011986]; National Institute on Minority Health and Health Disparities, National Institutes of Health [G12MD007599] FX This research was supported by the Intramural Research Program of the National Library of Medicine, National Institutes of Health (Z.Z. and P.E.B.), the National Library of Medicine, National Institutes of Health under Award R01LM011986 (L.X.), and the National Institute on Minority Health and Health Disparities, National Institutes of Health, under Award G12MD007599 (L.X.). We also appreciate Dr. Enade Perdana Istyastono et al. for providing the IFP software, Pyplif and Dr. T. Exner et al. for providing the docking program PLANTS. NR 102 TC 3 Z9 3 U1 2 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD MAY 12 PY 2016 VL 59 IS 9 SI SI BP 4326 EP 4341 DI 10.1021/acs.jmedchem.5b02041 PG 16 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA DL9NE UT WOS:000375969200022 PM 26929980 ER PT J AU Leaman, R Wei, CH Zou, C Lu, ZY AF Leaman, Robert Wei, Chih-Hsuan Zou, Cherry Lu, Zhiyong TI Mining chemical patents with an ensemble of open systems SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION LA English DT Article ID GENE NORMALIZATION; BIOMEDICAL TEXT AB The significant amount of medicinal chemistry information contained in patents makes them an attractive target for text mining. In this manuscript, we describe systems for named entity recognition (NER) of chemicals and genes/proteins in patents, using the CEMP (for chemicals) and GPRO (for genes/proteins) corpora provided by the CHEMDNER task at BioCreative V. Our chemical NER system is an ensemble of five open systems, including both versions of tmChem, our previous work on chemical NER. Their output is combined using a machine learning classification approach. Our chemical NER system obtained 0.8752 precision and 0.9129 recall, for 0.8937 f-score on the CEMP task. Our gene/protein NER system is an extension of our previous work for gene and protein NER, GNormPlus. This system obtained a performance of 0.8143 precision and 0.8141 recall, for 0.8137 f-score on the GPRO task. Both systems achieved the highest performance in their respective tasks at BioCreative V. We conclude that an ensemble of independently-created open systems is sufficiently diverse to significantly improve performance over any individual system, even when they use a similar approach. C1 [Leaman, Robert; Wei, Chih-Hsuan; Zou, Cherry; Lu, Zhiyong] Natl Lib Med, Natl Ctr Biotechnol Informat, 8600 Rockville Pike, Bethesda, MD 20894 USA. [Zou, Cherry] Poolesville High Sch, 17501 W Wilard Rd, Poolesville, MD USA. RP Lu, ZY (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM zhiyong.lu@nih.gov FU National Institutes of Health Intramural Research Program, National Library of Medicine; NIH Intramural Research Training Award FX This research is funded by the National Institutes of Health Intramural Research Program, National Library of Medicine (R.L., C.H., Z.L.). C.Z. was a summer intern at the NCBI/NIH and supported by an NIH Intramural Research Training Award. NR 28 TC 0 Z9 0 U1 4 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1758-0463 J9 DATABASE-OXFORD JI Database PD MAY 12 PY 2016 AR baw065 DI 10.1093/database/baw065 PG 7 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA DL6VI UT WOS:000375777300002 ER PT J AU Vitner, EB Farfel-Becker, T Ferreira, NS Leshkowitz, D Sharma, P Lang, KS Futerman, AH AF Vitner, Einat B. Farfel-Becker, Tamar Ferreira, Natalia Santos Leshkowitz, Dena Sharma, Piyush Lang, Karl S. Futerman, Anthony H. TI Induction of the type I interferon response in neurological forms of Gaucher disease SO JOURNAL OF NEUROINFLAMMATION LA English DT Article ID INNATE IMMUNE-RESPONSES; CENTRAL-NERVOUS-SYSTEM; LYSOSOMAL STORAGE DISEASES; PROGRAMMED NECROSIS; MOUSE MODEL; NEURONOPATHIC FORMS; PARKINSONS-DISEASE; SANDHOFF-DISEASE; CELL-DEATH; ACTIVATION AB Background: Neuroinflammation is a key phenomenon in the pathogenesis of many neurodegenerative diseases. Understanding the mechanisms by which brain inflammation is engaged and delineating the key players in the immune response and their contribution to brain pathology is of great importance for the identification of novel therapeutic targets for these devastating diseases. Gaucher disease, the most common lysosomal storage disease, is caused by mutations in the GBA1 gene and is a significant risk factor for Parkinson's disease; in some forms of Gaucher disease, neuroinflammation is observed. Methods: An unbiased gene profile analysis was performed on a severely affected brain area of a neurological form of a Gaucher disease mouse at a pre-symptomatic stage; the mouse used for this study, the Gba(flox/flox); nestin-Cre mouse, was engineered such that GBA1 deficiency is restricted to cells of neuronal lineage, i.e., neurons and macroglia. Results: The 10 most up-regulated genes in the ventral posteromedial/posterolateral region of the thalamus were inflammatory genes, with the gene expression signature significantly enriched in interferon signaling genes. Interferon beta levels were elevated in neurons, and interferon-stimulated genes were elevated mainly in microglia. Interferon signaling pathways were elevated to a small extent in the brain of another lysosomal storage disease mouse model, Krabbe disease, but not in Niemann-Pick C or Sandhoff mouse brain. Ablation of the type I interferon receptor attenuated neuroinflammation but had no effect on GD mouse viability. Conclusions: Our results imply that the type I interferon response is involved in the development of nGD pathology, and possibly in other lysosomal storage diseases in which simple glycosphingolipids accumulate, and support the notion that interferon signaling pathways play a vital role in the sterile inflammation that often occurs during chronic neurodegenerative diseases in which neuroinflammation is present. C1 [Vitner, Einat B.; Farfel-Becker, Tamar; Ferreira, Natalia Santos; Futerman, Anthony H.] Weizmann Inst Sci, Dept Biomol Sci, IL-76100 Rehovot, Israel. [Leshkowitz, Dena] Weizmann Inst Sci, Biol Serv Dept, Bioinformat Unit, IL-76100 Rehovot, Israel. [Sharma, Piyush; Lang, Karl S.] Univ Duisburg Essen, Fac Med, Inst Immunol, Essen, Germany. [Lang, Karl S.] Univ Dusseldorf, Dept Gastroenterol Hepatol & Infect Dis, Dusseldorf, Germany. [Vitner, Einat B.] Israel Inst Biol Res, Dept Infect Dis, IL-74100 Ness Ziona, Israel. [Farfel-Becker, Tamar] NINDS, Synapt Funct Sect, Porter Neurosci Res Ctr, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Futerman, AH (reprint author), Weizmann Inst Sci, Dept Biomol Sci, IL-76100 Rehovot, Israel. EM tony.futerman@weizmann.ac.il RI Lang, Karl/R-2505-2016; OI Sharma, Piyush/0000-0003-1185-9534 FU Children's Gaucher Research Fund; Minerva Foundation FX This work was generously supported by the Children's Gaucher Research Fund and by the Minerva Foundation. NR 70 TC 3 Z9 3 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD MAY 12 PY 2016 VL 13 AR 104 DI 10.1186/s12974-016-0570-2 PG 15 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA DL8OL UT WOS:000375901200001 PM 27175482 ER PT J AU Ceccon, A Tugarinov, V Box, A Clore, GM AF Ceccon, Alberto Tugarinov, Vitali Box, Ad Clore, G. Marius TI Global Dynamics and Exchange Kinetics of a Protein on the Surface of Nanoparticles Revealed by Relaxation-Based Solution NMR Spectroscopy SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID UBIQUITIN; MACROMOLECULES; RESOLUTION; DIFFUSION; GROEL AB The global motions and exchange kinetics of a model protein, ubiquitin, bound to the surface of negatively charged lipid-based nanoparticles (liposomes) are derived from combined analysis of exchange lifetime broadening arising from binding to nanoparticles of differing size. The relative contributions of residence time and rotational tumbling to the total effective correlation time of the bound protein are modulated by nanoparticle size, thereby permitting the various motional and exchange parameters to be determined. The residence time of ubiquitin bound to the surface of both large and small unilamellar liposomes is similar to 20 mu s. Bound ubiquitin undergoes internal rotation about an axis approximately perpendicular to the lipid surface on a low microsecond time scale (similar to 2 mu s), while simultaneously wobbling in a cone of semiangle 30-55 degrees centered about the internal rotation axis on the nanosecond time scale. The binding, interface of ubiquitin with liposomes is mapped by intermolecular paramagnetic relaxation enhancement using Gd3+-tagged vesicles, to a predominantly positively charged surface orthogonal to the internal rotation axis. C1 [Ceccon, Alberto; Tugarinov, Vitali; Box, Ad; Clore, G. Marius] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tugarinov, V; Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM vitali.tugarinov@nih.gov; mariusc@mail.nih.gov FU NIDDK, NIH; AIDS Targeted Antiviral Program of the Office of the Director of the NIH FX We thank Attila Szabo for useful discussions. This work was supported by the Intramural Program of NIDDK, NIH, and by the AIDS Targeted Antiviral Program of the Office of the Director of the NIH (to G.M.C. and A.B.). NR 21 TC 5 Z9 5 U1 6 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD MAY 11 PY 2016 VL 138 IS 18 BP 5789 EP 5792 DI 10.1021/jacs.6b02654 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA DL8JU UT WOS:000375889100013 PM 27111298 ER PT J AU Zerhouni, E Hamburg, M AF Zerhouni, Elias Hamburg, Margaret TI The need for global regulatory harmonization: A public health imperative SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Editorial Material C1 [Zerhouni, Elias] Sanofi, Global R&D, Paris, France. [Zerhouni, Elias] US Natl Inst Hlth, Bethesda, MD 20892 USA. [Hamburg, Margaret] US Natl Acad Med, Washington, DC 20001 USA. [Hamburg, Margaret] US Food & Drug Adm FDA, Silver Spring, MD 20993 USA. [Hamburg, Margaret] New York City Dept Hlth & Mental Hyg, New York, NY 10013 USA. RP Zerhouni, E (reprint author), Sanofi, Global R&D, Paris, France.; Hamburg, M (reprint author), US Natl Acad Med, Washington, DC 20001 USA. EM Elias.Zerhouni@sanofi.com; Mhamburg@nas.edu NR 3 TC 2 Z9 2 U1 1 U2 1 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD MAY 11 PY 2016 VL 8 IS 338 AR 338ed6 DI 10.1126/scitranslmed.aaf1396 PG 2 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA DL7PN UT WOS:000375832700001 PM 27169801 ER PT J AU Hughes, SH Coffin, JM AF Hughes, Stephen H. Coffin, John M. TI What Integration Sites Tell Us about HIV Persistence SO CELL HOST & MICROBE LA English DT Review ID MURINE LEUKEMIA-VIRUS; CD4(+) T-CELLS; ACTIVE ANTIRETROVIRAL THERAPY; RETROVIRAL DNA INTEGRATION; TRANSCRIPTION START SITES; GENE-THERAPY; HUMAN GENOME; PREINTEGRATION COMPLEXES; ENDOGENOUS RETROVIRUSES; INFECTED INDIVIDUALS AB Advances in technology have made it possible to analyze integration sites in cells from HIV-infected patients. A significant fraction of infected cells in patients on long-term therapy are clonally expanded; in some cases the integrated viral DNA contributes to the clonal expansion of the infected cells. Although the large majority (> 95%) of the HIV proviruses in treated patients are defective, expanded clones can carry replication-competent proviruses, and cells from these clones can release infectious virus. As discussed in this Perspective, it is likely that cells that produce virus are strongly selected against in vivo, and cells with replication competent proviruses expand and survive because only a small fraction of the cells produce virus. These findings have implications for strategies that are intended to eliminate the reservoir of infected cells that has made it almost impossible to cure HIV-infected patients. C1 [Hughes, Stephen H.] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Coffin, John M.] Tufts Univ, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. RP Hughes, SH (reprint author), NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM hughesst@mail.nih.gov FU Leidos Biomedical Inc. [13XS110]; Intramural Research Program of the NIH, National Cancer Institute, National Institutes of Health FX We thank Joseph Meyer for help with the figures; John Mellors, Frank Maldarelli, Xiaolin Wu, and Mary Kearney for helpful and stimulating discussions; and Terri Burdette for help in preparing the manuscript. J.M.C. was supported by contract 13XS110 through Leidos Biomedical Inc. and was a Research Professor of the American Cancer Society. This work was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, National Institutes of Health. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 107 TC 4 Z9 4 U1 2 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 EI 1934-6069 J9 CELL HOST MICROBE JI Cell Host Microbe PD MAY 11 PY 2016 VL 19 IS 5 BP 588 EP 598 DI 10.1016/j.chom.2016.04.010 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DL4HR UT WOS:000375595500009 PM 27173927 ER PT J AU Ruktanonchai, NW Bhavnani, D Sorichetta, A Bengtsson, L Carter, KH Cordoba, RC Le Menach, A Lu, X Wetter, E Erbach-Schoenberg, EZ Tatem, AJ AF Ruktanonchai, Nick W. Bhavnani, Darlene Sorichetta, Alessandro Bengtsson, Linus Carter, Keith H. Cordoba, Roberto C. Le Menach, Arnaud Lu, Xin Wetter, Erik Erbach-Schoenberg, Elisabeth Zu Tatem, Andrew J. TI Census-derived migration data as a tool for informing malaria elimination policy SO MALARIA JOURNAL LA English DT Article DE Malaria elimination; Human mobility; Census data; Migration; Mobile phone data ID MOBILE PHONE DATA; PLASMODIUM-FALCIPARUM; HUMAN MOVEMENT; POPULATION; TRANSMISSION; STRATEGIES; AMERICA; RISK AB Background: Numerous countries around the world are approaching malaria elimination. Until global eradication is achieved, countries that successfully eliminate the disease will contend with parasite reintroduction through international movement of infected people. Human-mediated parasite mobility is also important within countries near elimination, as it drives parasite flows that affect disease transmission on a subnational scale. Methods: Movement patterns exhibited in census-based migration data are compared with patterns exhibited in a mobile phone data set from Haiti to quantify how well migration data predict short-term movement patterns. Because short-term movement data were unavailable for Mesoamerica, a logistic regression model fit to migration data from three countries in Mesoamerica is used to predict flows of infected people between subnational administrative units throughout the region. Results: Population flows predicted using census-based migration data correlated strongly with mobile phone-derived movements when used as a measure of relative connectivity. Relative population flows are therefore predicted using census data across Mesoamerica, informing the areas that are likely exporters and importers of infected people. Relative population flows are used to identify community structure, useful for coordinating interventions and elimination efforts to minimize importation risk. Finally, the ability of census microdata inform future intervention planning is discussed in a country-specific setting using Costa Rica as an example. Conclusions: These results show long-term migration data can effectively predict the relative flows of infected people to direct malaria elimination policy, a particularly relevant result because migration data are generally easier to obtain than short-term movement data such as mobile phone records. Further, predicted relative flows highlight policy-relevant population dynamics, such as major exporters across the region, and Nicaragua and Costa Rica's strong connection by movement of infected people, suggesting close coordination of their elimination efforts. Country-specific applications are discussed as well, such as predicting areas at relatively high risk of importation, which could inform surveillance and treatment strategies. C1 [Ruktanonchai, Nick W.; Sorichetta, Alessandro; Bengtsson, Linus; Lu, Xin; Wetter, Erik; Erbach-Schoenberg, Elisabeth Zu; Tatem, Andrew J.] Flowminder Fdn, Stockholm, Sweden. [Ruktanonchai, Nick W.; Sorichetta, Alessandro; Erbach-Schoenberg, Elisabeth Zu; Tatem, Andrew J.] Univ Southampton, Geog & Environm, WorldPop, Southampton SO17 1BJ, Hants, England. [Bhavnani, Darlene; Le Menach, Arnaud] Clinton Hlth Access Initiat, Boston, MA USA. [Bengtsson, Linus; Lu, Xin] Karolinska Inst, Stockholm, Sweden. [Carter, Keith H.] World Hlth Org, Pan Amer Hlth Org, Washington, DC USA. [Cordoba, Roberto C.] Costa Rica Minist Hlth, Dept Hlth Surveillance, San Jose, Costa Rica. [Wetter, Erik] Stockholm Sch Econ, S-11383 Stockholm, Sweden. [Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. RP Ruktanonchai, NW (reprint author), Flowminder Fdn, Stockholm, Sweden. EM nick.ruktanonchai@flowminder.org FU World Health Organization [001] NR 40 TC 2 Z9 2 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD MAY 11 PY 2016 VL 15 AR 273 DI 10.1186/s12936-016-1315-5 PG 13 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DL3LP UT WOS:000375535600001 PM 27169470 ER PT J AU Hage, TA Sun, YJ Khaliq, ZM AF Hage, Travis A. Sun, Yujie Khaliq, Zayd M. TI Electrical and Ca2+ signaling in dendritic spines of substantia nigra dopaminergic neurons SO ELIFE LA English DT Article ID VENTRAL TEGMENTAL AREA; LONG-TERM POTENTIATION; CALCIUM SIGNALS; SQUIRREL-MONKEY; SODIUM CURRENT; NECK; SYNAPSES; RAT; COMPARTMENTALIZATION; MORPHOLOGY AB Little is known about the density and function of dendritic spines on midbrain dopamine neurons, or the relative contribution of spine and shaft synapses to excitability. Using Ca2+ imaging, glutamate uncaging, fluorescence recovery after photobleaching and transgenic mice expressing labeled PSD-95, we comparatively analyzed electrical and Ca2+ signaling in spines and shaft synapses of dopamine neurons. Dendritic spines were present on dopaminergic neurons at low densities in live and fixed tissue. Uncaging-evoked potential amplitudes correlated inversely with spine length but positively with the presence of PSD-95. Spine Ca2+ signals were less sensitive to hyperpolarization than shaft synapses, suggesting amplification of spine head voltages. Lastly, activating spines during pacemaking, we observed an unexpected enhancement of spine Ca2+ midway throughout the spike cycle, likely involving recruitment of NMDA receptors and voltage gated conductances. These results demonstrate functionality of spines in dopamine neurons and reveal a novel modulation of spine Ca2+ signaling during pacemaking. C1 [Hage, Travis A.; Sun, Yujie; Khaliq, Zayd M.] NINDS, Cellular Neurophysiol Unit, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Khaliq, ZM (reprint author), NINDS, Cellular Neurophysiol Unit, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM zayd.khaliq@nih.gov FU National Institutes of Health [NS003135] FX National Institutes of Health NS003135 Travis A Hage Yujie Sun Zayd M Khaliq; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 74 TC 1 Z9 1 U1 6 U2 6 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD MAY 10 PY 2016 VL 5 AR e13905 DI 10.7554/eLife.13905 PG 26 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EB5ZT UT WOS:000387460600001 ER PT J AU Simpson, DM Hallett, M Ashman, EJ Comella, CL Green, MW Gronseth, GS Armstrong, MJ Gloss, D Potrebic, S Jankovic, J Karp, BP Naumann, M So, YT Yablon, SA AF Simpson, David M. Hallett, Mark Ashman, Eric J. Comella, Cynthia L. Green, Mark W. Gronseth, Gary S. Armstrong, Melissa J. Gloss, David Potrebic, Sonja Jankovic, Joseph Karp, Barbara P. Naumann, Markus So, Yuen T. Yablon, Stuart A. CA Amer Acad Neurology TI Practice guideline update summary: Botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache Report of the Guideline Development Subcommittee of the American Academy of Neurology SO NEUROLOGY LA English DT Article ID UPPER-LIMB SPASTICITY; TOXIN TYPE-A; TECHNOLOGY-ASSESSMENT SUBCOMMITTEE; BENIGN ESSENTIAL BLEPHAROSPASM; RANDOMIZED CONTROLLED-TRIAL; INCOBOTULINUMTOXINA NT 201; PLACEBO-CONTROLLED TRIAL; LONG-TERM TREATMENT; DOUBLE-BLIND; OF-NEUROLOGY AB Objective: To update the 2008 American Academy of Neurology (AAN) guidelines regarding botulinum neurotoxin for blepharospasm, cervical dystonia (CD), headache, and adult spasticity. Methods: We searched the literature for relevant articles and classified them using 2004 AAN criteria. Results and recommendations: Blepharospasm: OnabotulinumtoxinA (onaBoNT-A) and incobotulinumtoxinA (incoBoNT-A) are probably effective and should be considered (Level B). AbobotulinumtoxinA (aboBoNT-A) is possibly effective and may be considered (Level C). CD: AboBoNT-A and rimabotulinumtoxinB (rimaBoNT-B) are established as effective and should be offered (Level A), and onaBoNT-A and incoBoNT-A are probably effective and should be considered (Level B). Adult spasticity: AboBoNT-A, incoBoNT-A, and onaBoNT-A are established as effective and should be offered (Level A), and rimaBoNT-B is probably effective and should be considered (Level B), for upper limb spasticity. AboBoNT-A and onaBoNT-A are established as effective and should be offered (Level A) for lower-limb spasticity. Headache: OnaBoNT-A is established as effective and should be offered to increase headache-free days (Level A) and is probably effective and should be considered to improve health-related quality of life (Level B) in chronic migraine. OnaBoNT-A is established as ineffective and should not be offered for episodicmigraine (Level A) and is probably ineffective for chronic tension-type headaches (Level B). C1 [Simpson, David M.; Green, Mark W.] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA. [Hallett, Mark] NIH, Human Motor Control Sect, Bldg 10, Bethesda, MD 20892 USA. [Karp, Barbara P.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Ashman, Eric J.] Bronson Methodist Hosp, Bronson Neurosci Ctr, Dept Neurol, Kalamazoo, MI USA. [Comella, Cynthia L.] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Gronseth, Gary S.] Univ Kansas, Sch Med, Dept Neurol, Kansas City, KS USA. [Armstrong, Melissa J.] Univ Maryland, Dept Neurol, Baltimore, MD 21201 USA. [Gloss, David] Geisinger Hlth Syst, Dept Neurol, Danville, PA USA. [Potrebic, Sonja] Kaiser Permanente Los Angeles Med Ctr, Dept Neurol, Los Angeles, CA USA. [Jankovic, Joseph] Baylor Coll Med, Dept Neurol, Parkinsons Dis Ctr & Movement Disorders Clin, Houston, TX USA. [Naumann, Markus] Klinikum Augsburg, Dept Neurol & Clin Neurophysiol, Munich, Germany. [So, Yuen T.] Stanford Univ, Dept Neurol & Neurol Sci, Palo Alto, CA 94304 USA. [Yablon, Stuart A.] Univ Alberta, Div Phys Med & Rehabil, Edmonton, AB, Canada. RP Simpson, DM (reprint author), Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA. FU American Academy of Neurology FX This guideline was developed with financial support from the American Academy of Neurology. Authors who serve as AAN subcommittee members or methodologists (E.J.A., G.S.G., M.J.A., D.G., S.P.) were reimbursed by the AAN for expenses related to travel to subcommittee meetings where drafts of manuscripts were reviewed. NR 40 TC 9 Z9 10 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAY 10 PY 2016 VL 86 IS 19 BP 1818 EP 1826 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA DU1WD UT WOS:000382000000014 PM 27164716 ER PT J AU Lynch, J AF Lynch, John TI Comment: Telemedicine training during stroke fellowship SO NEUROLOGY LA English DT Editorial Material C1 [Lynch, John] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Lynch, J (reprint author), NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAY 10 PY 2016 VL 86 IS 19 BP 1832 EP 1832 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA DU1WD UT WOS:000382000000016 PM 27016524 ER PT J AU Jia, JT Shi, Y Yan, B Xiao, DS Lai, WW Pan, Y Jiang, YQ Chen, L Mao, C Zhou, J Xi, SC Cao, Y Liu, S Tao, YG AF Jia, Jiantao Shi, Ying Yan, Bin Xiao, Deshen Lai, Weiwei Pan, Yu Jiang, Yiqun Chen, Ling Mao, Chao Zhou, Jian Xi, Sichuan Cao, Ya Liu, Shuang Tao, Yongguang TI LGR5 expression is controled by IKK alpha in basal cell carcinoma through activating STAT3 signaling pathway SO ONCOTARGET LA English DT Article DE LGR5; IKK alpha; STAT3; BCC; EGF ID NF-KAPPA-B; HAIR FOLLICLE STEM; TUMOR-INITIATING CELLS; GENE-EXPRESSION; CANCER METASTASIS; PROSTATE-CANCER; SKIN-CANCER; T-CELLS; INFLAMMATION; PROMOTES AB Basal cell carcinomas (BCC) of the skin are the most common of human cancers. The noncanonical NF-kappa B pathway is dependent on IKK alpha. However, the role of IKK alpha in BCC has not been elucidated. We show here that IKK alpha is expressed in the nucleus in BCC and non-malignant diseases. Nuclear IKK alpha could directly bind to the promoters of inflammation factors and LGR5, a stem cell marker, in turn, upregulating LGR5 expression through activation of STAT3 signaling pathway during cancer progression. Activation of STAT3 signaling pathway contributes LGR5 expression in dependent of IKK alpha after the interplay between STAT3 and IKK alpha. Meanwhile knockdown of IKK alpha inhibits tumor growth and transition of epithelial stage to mescheme stage. Taken together, we demonstrate that IKK alpha functions as a bone fide chromatin regulator in BCC, whose promoted expression contributes to oncogenic transformation via promoting expression stemness- and inflammatory-related genes. Our finding reveals a novel viewpoint for how IKK alpha may involve in BCCs tumor progression in the inflammatory microenvironment. C1 [Jia, Jiantao; Liu, Shuang; Tao, Yongguang] Cent S Univ, Xiangya Hosp, Med Res Ctr, Changsha, Hunan, Peoples R China. [Jia, Jiantao; Shi, Ying; Yan, Bin; Lai, Weiwei; Jiang, Yiqun; Chen, Ling; Mao, Chao; Cao, Ya; Tao, Yongguang] Cent S Univ, Canc Res Inst, Changsha, Hunan, Peoples R China. [Jia, Jiantao] Changzhi Med Coll, Dept Pathophysiol, Changzhi, Shanxi, Peoples R China. [Shi, Ying; Yan, Bin; Lai, Weiwei; Jiang, Yiqun; Chen, Ling; Mao, Chao; Cao, Ya; Tao, Yongguang] Minist Educ, Key Lab Carcinogenesis & Canc Invas, Beijing, Hunan, Peoples R China. [Shi, Ying; Yan, Bin; Lai, Weiwei; Jiang, Yiqun; Chen, Ling; Mao, Chao; Cao, Ya; Tao, Yongguang] Minist Hlth, Key Lab Carcinogenesis, Beijing, Hunan, Peoples R China. [Xiao, Deshen; Pan, Yu] Cent S Univ, Xiangya Hosp, Dept Pathol, Changsha, Hunan, Peoples R China. [Zhou, Jian] Fudan Univ, Liver Surg Dept, Liver Canc Inst,Minist Educ, Zhongshan Hosp,Key Lab Carcinogenesis & Canc Inva, Shanghai 200433, Peoples R China. [Zhou, Jian] Fudan Univ, Inst Biomed Sci, Shanghai 200433, Peoples R China. [Xi, Sichuan] NCI, Thorac Surg Sect, Thorac & GI Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Liu, S; Tao, YG (reprint author), Cent S Univ, Xiangya Hosp, Med Res Ctr, Changsha, Hunan, Peoples R China.; Tao, YG (reprint author), Cent S Univ, Canc Res Inst, Changsha, Hunan, Peoples R China.; Tao, YG (reprint author), Minist Educ, Key Lab Carcinogenesis & Canc Invas, Beijing, Hunan, Peoples R China.; Tao, YG (reprint author), Minist Hlth, Key Lab Carcinogenesis, Beijing, Hunan, Peoples R China. EM liushuang1999@yahoo.com; taoyong@csu.edu.cn RI Shi, Ying-Hong/B-7063-2017 FU National Basic Research Program of China [2015CB553903, 2011CB504300]; National Natural Science Foundation of China [81171881, 81372427, 81271763, 81302354]; Hunan Natural Science Foundation of China [12JJ1013]; Fundamental Research Funds for the Central Universities [2011JQ019, 2013ZZTS074] FX This work was supported by the National Basic Research Program of China [2015CB553903(Y.T.); 2011CB504300 (Y.T.)]; the National Natural Science Foundation of China [81171881 and 81372427(Y.T.), 81271763(S.L.), 81302354(Y.S.)]; the Hunan Natural Science Foundation of China [12JJ1013(Y.T.)]; and the Fundamental Research Funds for the Central Universities [2011JQ019(Y.T.), 2013ZZTS074(B.Y.)]. NR 57 TC 0 Z9 0 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAY 10 PY 2016 VL 7 IS 19 BP 27280 EP 27294 DI 10.18632/oncotarget.8465 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO4HF UT WOS:000377741700028 PM 27049829 ER PT J AU Huang, BH Yin, MZ Li, X Cao, GS Qi, J Lou, G Sheng, SJ Kou, JP Chen, K Yu, BY AF Huang, Bihui Yin, Mingzhu Li, Xia Cao, Guosheng Qi, Jin Lou, Ge Sheng, Shijie Kou, Junping Chen, Kang Yu, Boyang TI Migration-Inducing Gene 7 promotes tumorigenesis and angiogenesis and independently predicts poor prognosis of epithelial ovarian cancer SO ONCOTARGET LA English DT Article DE epithelial ovarian cancer; biomarker; prognosis; Migration-Inducting Gene 7; angiogenesis ID ENDOTHELIAL GROWTH-FACTOR; CELL-SPECIFIC MIG-7; PHASE-II; CARCINOMA; SURVIVAL; HYPOXIA; PROTEIN; OVEREXPRESSION; BEVACIZUMAB; METASTASIS AB Epithelial ovarian carcinomas (EOC) cause more mortality than any other cancer of the female reproductive system. New therapeutic approaches to reduce EOC mortality have been largely unsuccessful due to the poor understanding of the mechanisms underlying EOC proliferation and metastasis. Progress in EOC treatment is further hampered by a lack of reliable prognostic biomarkers for early risk assessment. In this study, we identify that Migration-Inducting Gene 7 (MIG-7) is specifically induced in human EOC tissues but not normal ovaries or ovarian cyst. Ovarian MIG-7 expression strongly correlated with EOC progression. Elevated MIG-7 level at the time of primary cytoreductive surgery was a strong and independent predictor of poor survival of EOC patients. Cell and murine xenograft models showed that MIG-7 was required for EOC proliferation and invasion, and MIG-7 enhanced EOC-associated angiogenesis by promoting the expression of vascular endothelial growth factor. Inhibiting MIG-7 by RNA interference in grafted EOC cells retarded tumor growth, angiogenesis and improved host survival, and suppressing MIG-7 expression with a small molecule inhibitor D-39 identified from the medicinal plant Liriope muscari mitigated EOC growth and invasion and specifically abrogated the expression of vascular endothelial growth factor. Our data not only reveal a critical function of MIG-7 in EOC growth and metastasis and support MIG-7 as an independent prognostic biomarker for EOC, but also demonstrate that therapeutic targeting of MIG-7 is likely beneficial in the treatment of EOC. C1 [Huang, Bihui] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06510 USA. [Huang, Bihui; Chen, Kang] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Huang, Bihui; Chen, Kang] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Detroit, MI USA. [Yin, Mingzhu; Cao, Guosheng; Qi, Jin; Kou, Junping; Yu, Boyang] China Pharmaceut Univ, State Key Lab Nat Prod, Dept Complex Prescript TCM, Nanjing, Jiangsu, Peoples R China. [Yin, Mingzhu; Cao, Guosheng; Qi, Jin; Kou, Junping; Yu, Boyang] China Pharmaceut Univ, Jiangsu Key Lab Tradit Chinese Med TCM Evaluat &, Dept Complex Prescript TCM, Nanjing, Jiangsu, Peoples R China. [Yin, Mingzhu] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. [Li, Xia] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Li, Xia] Yale Univ, Yale Stem Cell Ctr, New Haven, CT USA. [Lou, Ge] Harbin Med Univ, Dept Gynecol Oncol, Affiliated Canc Hosp, Harbin, Peoples R China. [Sheng, Shijie] Wayne State Univ, Dept Pathol, Detroit, MI 48202 USA. [Sheng, Shijie; Chen, Kang] Wayne State Univ, Tumor Biol & Microenvironm Program, Barbara Ann Karmanos Canc Ctr, Detroit, MI USA. [Sheng, Shijie; Chen, Kang] Wayne State Univ, Dept Oncol, Detroit, MI USA. [Chen, Kang] Wayne State Univ, Dept Immunol & Microbiol, Detroit, MI USA. [Chen, Kang] NIAID, Mucosal Immunol Studies Team, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Chen, K (reprint author), Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA.; Chen, K (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Detroit, MI USA.; Kou, JP (reprint author), China Pharmaceut Univ, State Key Lab Nat Prod, Dept Complex Prescript TCM, Nanjing, Jiangsu, Peoples R China.; Kou, JP (reprint author), China Pharmaceut Univ, Jiangsu Key Lab Tradit Chinese Med TCM Evaluat &, Dept Complex Prescript TCM, Nanjing, Jiangsu, Peoples R China.; Chen, K (reprint author), Wayne State Univ, Tumor Biol & Microenvironm Program, Barbara Ann Karmanos Canc Ctr, Detroit, MI USA.; Chen, K (reprint author), Wayne State Univ, Dept Oncol, Detroit, MI USA.; Chen, K (reprint author), Wayne State Univ, Dept Immunol & Microbiol, Detroit, MI USA.; Chen, K (reprint author), NIAID, Mucosal Immunol Studies Team, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM junpingkou@cpu.edu.cn; kchen@med.wayne.edu FU Major National Science and Technology Project of China [2012ZX09102201-015]; National Natural Science Foundation of China [81274131]; Project Program of the State Key Laboratory of Natural Medicines of China Pharmaceutical University [JKGZ201107]; US National Institutes of Health [U01AI95776, P30CA22453]; Burroughs Wellcome Fund; American Congress of Obstetricians and Gynecologists; Wayne State University Maternal; Perinatal and Child Health Initiative; Wayne State University Office of the Vice President for Research; Jiangsu Province Plan for Collaborative Innovation FX The authors thank Dr. Wei-Zen Wei (Barbara Ann Karmanos Cancer Institute) for helpful discussion of the manuscript and the core facilities of Harbin Medical University, China Pharmaceutical University and Barbara Ann Karmanos Cancer Institute for technical assistance. This work was supported by grants from the Major National Science and Technology Project of China for Significant New Drugs Development (2012ZX09102201-015), National Natural Science Foundation of China (81274131), Jiangsu Province 2011 Plan for Collaborative Innovation, Project Program of the State Key Laboratory of Natural Medicines of China Pharmaceutical University (JKGZ201107) to J.K., US National Institutes of Health (U01AI95776 Young Investigator Award, Cancer Center Support Grant P30CA22453), Burroughs Wellcome Fund, American Congress of Obstetricians and Gynecologists, Wayne State University Maternal, Perinatal and Child Health Initiative, and Wayne State University Office of the Vice President for Research to K.C. NR 37 TC 0 Z9 1 U1 5 U2 7 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAY 10 PY 2016 VL 7 IS 19 BP 27552 EP 27566 DI 10.18632/oncotarget.8487 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO4HF UT WOS:000377741700050 PM 27050277 ER PT J AU Fadlullah, MZH Chiang, IKN Dionne, KR Yee, PS Gan, CP Sam, KK Tiong, KH Ng, AKW Martin, D Lim, KP Kallarakkal, TG Mustafa, WMW Lau, SH Abraham, MT Zain, RB Rahman, ZAA Molinolo, A Patel, V Gutkind, JS Tan, AC Cheong, SC AF Fadlullah, Muhammad Zaki Hidayatullah Chiang, Ivy Kim-Ni Dionne, Kalen R. Yee, Pei San Gan, Chai Phei Sam, Kin Kit Tiong, Kai Hung Ng, Adrian Kwok Wen Martin, Daniel Lim, Kue Peng Kallarakkal, Thomas George Mustafa, Wan Mahadzir Wan Lau, Shin Hin Abraham, Mannil Thomas Zain, Rosnah Binti Rahman, Zainal Ariff Abdul Molinolo, Alfredo Patel, Vyomesh Gutkind, J. Silvio Tan, Aik Choon Cheong, Sok Ching TI Genetically-defined novel oral squamous cell carcinoma cell lines for the development of molecular therapies SO ONCOTARGET LA English DT Article DE oral squamous cell carcinoma; gene expression; mutation; copy number alteration; cell lines ID TOPOISOMERASE-I INHIBITORS; COLORECTAL-CANCER; INACTIVATING MUTATIONS; DRUG-SENSITIVITY; PARP INHIBITION; S-PHASE; HEAD; EXPRESSION; CDK1; GENE AB Emerging biological and translational insights from large sequencing efforts underscore the need for genetically-relevant cell lines to study the relationships between genomic alterations of tumors, and therapeutic dependencies. Here, we report a detailed characterization of a novel panel of clinically annotated oral squamous cell carcinoma (OSCC) cell lines, derived from patients with diverse ethnicity and risk habits. Molecular analysis by RNAseq and copy number alterations (CNA) identified that the cell lines harbour CNA that have been previously reported in OSCC, for example focal amplications in 3q, 7p, 8q, 11q, 20q and deletions in 3p, 5q, 8p, 18q. Similarly, our analysis identified the same cohort of frequently mutated genes previously reported in OSCC including TP53, CDKN2A, EPHA2, FAT1, NOTCH1, CASP8 and PIK3CA. Notably, we identified mutations (MLL4, USP9X, ARID2) in cell lines derived from betel quid users that may be associated with this specific risk factor. Gene expression profiles of the ORL lines also aligned with those reported for OSCC. By focusing on those gene expression signatures that are predictive of chemotherapeutic response, we observed that the ORL lines broadly clustered into three groups (cell cycle, xenobiotic metabolism, others). The ORL lines noted to be enriched in cell cycle genes responded preferentially to the CDK1 inhibitor RO3306, by MTT cell viability assay. Overall, our in-depth characterization of clinically annotated ORL lines provides new insight into the molecular alterations synonymous with OSCC, which can facilitate in the identification of biomarkers that can be used to guide diagnosis, prognosis, and treatment of OSCC. C1 [Fadlullah, Muhammad Zaki Hidayatullah; Chiang, Ivy Kim-Ni; Dionne, Kalen R.; Yee, Pei San; Gan, Chai Phei; Sam, Kin Kit; Tiong, Kai Hung; Ng, Adrian Kwok Wen; Lim, Kue Peng; Patel, Vyomesh; Cheong, Sok Ching] Canc Res Malaysia, Subang Jaya, Selangor, Malaysia. [Chiang, Ivy Kim-Ni; Dionne, Kalen R.; Tiong, Kai Hung; Kallarakkal, Thomas George; Zain, Rosnah Binti] Univ Malaya, Fac Dent, Oral Canc Res & Coordinating Ctr, Kuala Lumpur, Malaysia. [Dionne, Kalen R.] Univ Colorado Denver, Med Scientist Training Program, Anschutz Med Campus, Aurora, CO USA. [Martin, Daniel; Molinolo, Alfredo; Gutkind, J. Silvio] NIH, Oral & Pharyngeal Canc Branch, Bldg 10, Bethesda, MD 20892 USA. [Kallarakkal, Thomas George; Zain, Rosnah Binti; Rahman, Zainal Ariff Abdul; Cheong, Sok Ching] Univ Malaya, Fac Dent, Dept Oromaxillofacial Surg & Med Sci, Kuala Lumpur, Malaysia. [Mustafa, Wan Mahadzir Wan] Hosp Kuala Lumpur, Dept Oral & Maxillofacial Surg, Kuala Lumpur, Malaysia. [Lau, Shin Hin] Inst Med Res, Stomatol Unit, Kuala Lumpur 50588, Malaysia. [Abraham, Mannil Thomas] Tengku Ampuan Rahimah Hosp, Dept Oral & Maxillofacial Surg, Klang, Selangor, Malaysia. [Tan, Aik Choon] Univ Colorado, Div Med Oncol, Sch Med, Anschutz Med Campus, Aurora, CO USA. RP Cheong, SC (reprint author), Canc Res Malaysia, Subang Jaya, Selangor, Malaysia.; Cheong, SC (reprint author), Univ Malaya, Fac Dent, Dept Oromaxillofacial Surg & Med Sci, Kuala Lumpur, Malaysia. EM sokching.cheong@cancerresearch.my RI KALLARAKKAL, THOMAS GEORGE/B-7774-2010; Management Center, Dental Research/C-2478-2013 FU High Impact Research, Ministry of Higher Education (HIR-MOHE) from University of Malaya [UM.C/625/1/HIR/MOHE/DENT-03]; Cancer Research Malaysia FX This study was funded by High Impact Research, Ministry of Higher Education (HIR-MOHE) from University of Malaya (UM.C/625/1/HIR/MOHE/DENT-03) and other sponsors of the Cancer Research Malaysia (formerly known as Cancer Research Initiatives Foundation; CARIF). NR 67 TC 2 Z9 2 U1 0 U2 5 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAY 10 PY 2016 VL 7 IS 19 BP 27802 EP 27818 DI 10.18632/oncotarget.8533 PG 17 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO4HF UT WOS:000377741700068 PM 27050151 ER PT J AU Yang, XJ Guo, XC Chen, Y Chen, GR Ma, Y Huang, K Zhang, YN Zhao, QY Winkler, CA An, P Lyu, JX AF Yang, Xunjun Guo, Xiuchan Chen, Yao Chen, Guorong Ma, Yin Huang, Kate Zhang, Yuning Zhao, Qiongya Winkler, Cheryl A. An, Ping Lyu, Jianxin TI Telomerase reverse transcriptase promoter mutations in hepatitis B virus-associated hepatocellular carcinoma SO ONCOTARGET LA English DT Article DE hepatocellular carcinoma; TERT; mutation; telomerase reverse transcriptase ID CELL CARCINOMAS; THYROID-CANCER; BRAF V600E; TUMORS; INFECTION; CARCINOGENESIS; CLASSIFICATION; RECURRENCE; EXPRESSION; PROGNOSIS AB Telomerase reverse transcriptase (TERT) promoter mutations are among the most frequent noncoding somatic mutations in multiple cancers, including hepatocellular carcinoma (HCC). The clinical and pathological implications of TERT promoter mutations in hepatitis B virus (HBV)-associated HCC have not been resolved. To investigate TERT promoter mutations, protein expression, and their clinical-pathological implications, we sequenced the TERT promoter region for hotspot mutations in HCC tissues and performed immunostaining for TERT protein expression from HBV-associated HCC in Chinese patients. Of 276 HCC tumor DNA samples sequenced, 85 (31%) carried TERT promoter mutations. TERT promoter mutations were more frequent in those with low a-fetoprotein (AFP) serum levels (p = 0.03), advanced age (p = 0.04), and in those lacking HCC family history (p = 0.02), but were not correlated with HCC stages and grades. TERT protein levels were higher in HCC (n = 28) compared to normal liver tissues (n = 8) (p = 0.001), but did not differ between mutated and non-mutated tumor tissues. In conclusion, TERT promoter mutations are common somatic mutations in HCC of Han Chinese with HBV infection. Detection of TERT promoter mutations in those with low levels of AFP may aid diagnosis of HCC with atypical presentation. C1 [Yang, Xunjun; Guo, Xiuchan; Ma, Yin; Zhang, Yuning; Zhao, Qiongya; Lyu, Jianxin] Wenzhou Med Univ, Zhejiang Prov Key Lab Med Genet, Key Lab Lab Med, Minist Educ, Wenzhou, Zhejiang, Peoples R China. [Yang, Xunjun] Wenzhou Med Univ, Affiliated Hosp 2, Dept Lab Med, Wenzhou, Zhejiang, Peoples R China. [Yang, Xunjun] Wenzhou Med Univ, Yuying Childrens Hosp, Wenzhou, Zhejiang, Peoples R China. [Guo, Xiuchan] ICF Int, Atlanta, GA USA. [Chen, Yao; Chen, Guorong; Huang, Kate] Wenzhou Med Univ, Affiliated Hosp 1, Dept Pathol, Wenzhou, Zhejiang, Peoples R China. [Winkler, Cheryl A.; An, Ping] Leidos Biomed Res Inc, Basic Res Lab, Ctr Canc Res, NCI,Frederick Natl Lab Canc Res, Frederick, MD USA. RP Lyu, JX (reprint author), Wenzhou Med Univ, Zhejiang Prov Key Lab Med Genet, Key Lab Lab Med, Minist Educ, Wenzhou, Zhejiang, Peoples R China.; An, P (reprint author), Leidos Biomed Res Inc, Basic Res Lab, Ctr Canc Res, NCI,Frederick Natl Lab Canc Res, Frederick, MD USA. EM anp@mail.nih.gov; ljx@wmu.edu.cn FU Opening Project of Zhejiang Provincial Top Key Discipline of Clinical Medicine; National Cancer Institute, National Institutes of health [HHSN26120080001E]; NIH, National Cancer Institute, Center for Cancer Research FX This project has been supported by the Opening Project of Zhejiang Provincial Top Key Discipline of Clinical Medicine. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of health, under contract HHSN26120080001E. This Research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 42 TC 2 Z9 2 U1 1 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAY 10 PY 2016 VL 7 IS 19 BP 27838 EP 27847 DI 10.18632/oncotarget.8539 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO4HF UT WOS:000377741700070 PM 27056898 ER PT J AU Gansmo, LB Vatten, L Romundstad, P Hveem, K Ryan, BM Harris, CC Knappskog, S Lonning, PE AF Gansmo, Liv B. Vatten, Lars Romundstad, Pal Hveem, Kristian Ryan, Brid M. Harris, Curtis C. Knappskog, Stian Lonning, Per E. TI Associations between the MDM2 promoter P1 polymorphism del1518 (rs3730485) and incidence of cancer of the breast, lung, colon and prostate SO ONCOTARGET LA English DT Article DE MDM2; polymorphism; del1518; SNP309; cancer risk ID NONPOLYPOSIS COLORECTAL-CANCER; SINGLE NUCLEOTIDE POLYMORPHISM; TRANSCRIPTION FACTOR-BINDING; ACCELERATES TUMOR-FORMATION; SNP309 POLYMORPHISM; CHINESE POPULATION; CONSTITUTIVE PROMOTER; OVARIAN-CANCER; P53 PROTEIN; RISK AB The MDM2 promoter region contains several polymorphisms, some of which have been associated with MDM2 expression, cancer risk and age at cancer onset. del1518 (rs3730485) is an indel polymorphism residing in the MDM2 promoter P1 and is in almost complete linkage disequilibrium with the MDM2 promoter P2 polymorphism SNP309T>G (rs2279744). Cancer risk assessments of del1518 have previously been conducted in relatively small Chinese populations only. In this study we assessed the genotype distribution of del1518 among healthy Caucasians, African Americans and Chinese, and we estimated the Odds Ratios (OR) for incident cancer of the breast, colon, lung and prostate (n=7,081) as compared to controls (n=3,749) in a large Caucasian (Norwegian) cohort. We found the genotypes of the del1518 to vary significantly between healthy Caucasians, African-Americans and Chinese (p<1x10(-5)). Further, we found a positive association of the del1518 del-allele with risk of colon cancer (dominant model: OR = 1.15; 95 % CI = 1.01 - 1.31). Stratifying according to SNP309 status, this association remained among carriers of the SNP309TG genotype (OR = 1.21; 95 % CI = 1.01 - 1.46), but with no clear association among carriers of the SNP309TT genotype. In conclusion, our findings suggest del1518 to be associated with increased risk of colon cancer. C1 [Gansmo, Liv B.; Knappskog, Stian; Lonning, Per E.] Univ Bergen, Sect Oncol, Dept Clin Sci, Bergen, Norway. [Gansmo, Liv B.; Knappskog, Stian; Lonning, Per E.] Haukeland Hosp, Dept Oncol, N-5021 Bergen, Norway. [Vatten, Lars; Romundstad, Pal; Hveem, Kristian] Norwegian Univ Sci & Technol, Fac Med, Dept Publ Hlth, N-7034 Trondheim, Norway. [Ryan, Brid M.; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bldg 37, Bethesda, MD 20892 USA. RP Lonning, PE (reprint author), Univ Bergen, Sect Oncol, Dept Clin Sci, Bergen, Norway.; Lonning, PE (reprint author), Haukeland Hosp, Dept Oncol, N-5021 Bergen, Norway. EM per.lonning@helse-bergen.no OI Knappskog, Stian/0000-0002-4153-1655; Ryan, Brid/0000-0003-0038-131X FU Norwegian Cancer Society; Norwegian Health Region West funding body; Norwegian Research Council; Bergen Research Foundation FX This study was supported by grants from the Norwegian Cancer Society, the Norwegian Health Region West funding body, the Norwegian Research Council and the Bergen Research Foundation. NR 39 TC 1 Z9 1 U1 0 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAY 10 PY 2016 VL 7 IS 19 BP 28637 EP 28646 DI 10.18632/oncotarget.8705 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO4HF UT WOS:000377741700131 PM 27081698 ER PT J AU Iqbal, J Nussenzweig, A Lubinski, J Byrski, T Eisen, A Bordeleau, L Tung, NM Manoukian, S Phelan, CM Sun, P Narod, SA AF Iqbal, Javaid Nussenzweig, Andre Lubinski, Jan Byrski, Tomasz Eisen, Andrea Bordeleau, Louise Tung, Nadine M. Manoukian, Siranoush Phelan, Catherine M. Sun, Ping Narod, Steven A. CA Hereditary Breast Canc Res Grp TI The incidence of leukaemia in women with BRCA1 and BRCA2 mutations: an International Prospective Cohort Study SO BRITISH JOURNAL OF CANCER LA English DT Article ID OVARIAN-CANCER; BREAST; CARRIERS; RISK; PENETRANCE AB Background: Germline mutations in BRCA1 and BRCA2 increase the susceptibility to develop breast and ovarian cancers as well as increase the risk of some other cancers. Primary objective was to estimate the risk of leukaemia in BRCA1 and BRCA2 mutation carriers. Methods: We followed 7243 women with a BRCA1 or a BRCA2 mutation for incident cases of leukaemia. We used the standardised incidence ratio (SIR) to estimate the relative risk of leukaemia, according to mutation and history of breast cancer. Results: We identified five incident cases of leukaemia (two BRCA1, three BRCA2). All five women had a prior history of breast cancer and four had received chemotherapy. The mean time from breast cancer diagnosis to the development of leukaemia was 10.2 years (range 3-18 years). The SIR for BRCA1 carriers was 0.66 (95% CI: 0.11-2.19, P = 0.61) and the SIR for BRCA2 carriers was 2.42 (95% CI: 0.61-6.58, P = 0.17). The SIR was significantly higher than expected for women with a BRCA2 mutation and breast cancer (SIR = 4.76, 95% CI: 1.21-12.96, P = 0.03), in particular for women who received chemotherapy (SIR = 8.11, 2.06-22.07, P = 0.007). Conclusions: We observed an increased risk of leukaemia in women with a BRCA2 mutation who receive chemotherapy for breast cancer. C1 [Iqbal, Javaid; Sun, Ping; Narod, Steven A.] Womens Coll Res Inst, Familial Breast Canc Res, Toronto, ON M5G 1N8, Canada. [Nussenzweig, Andre] NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. [Lubinski, Jan; Byrski, Tomasz] Pomeranian Med Univ, Int Hereditary Canc Ctr, PL-70111 Szczecin, Poland. [Eisen, Andrea] Sunnybrook Reg Canc Ctr, Toronto, ON M4N 3M5, Canada. [Bordeleau, Louise] Juravinksi Canc Ctr, Hamilton, ON L8V 5C2, Canada. [Tung, Nadine M.] Beth Israel Deaconess Med Ctr, Canc Risk & Prevent Program, Boston, MA 02215 USA. [Manoukian, Siranoush] Fdn IRCSS Ist Nazl Tumori, Dept Prevent & Predict Med, I-20133 Milan, Italy. [Phelan, Catherine M.] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL 33647 USA. RP Narod, SA (reprint author), Womens Coll Res Inst, Familial Breast Canc Res, Toronto, ON M5G 1N8, Canada. EM steven.narod@wchospital.ca RI BYRSKI, Tomasz/I-2844-2014; Gronwald, Jacek/A-4576-2017; manoukian, siranoush/E-7132-2017; OI Gronwald, Jacek/0000-0002-3643-2871; manoukian, siranoush/0000-0002-6034-7562; Evans, Gareth/0000-0002-8482-5784 NR 21 TC 3 Z9 3 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD MAY 10 PY 2016 VL 114 IS 10 BP 1160 EP 1164 DI 10.1038/bjc.2016.58 PG 5 WC Oncology SC Oncology GA DM6AA UT WOS:000376430800020 PM 26986251 ER PT J AU Gamble-George, JC Baldi, R Halladay, L Kocharian, A Hartley, N Silva, CG Roberts, H Haymer, A Marnett, LJ Holmes, A Patel, S AF Gamble-George, Joyonna Carrie Baldi, Rita Halladay, Lindsay Kocharian, Adrina Hartley, Nolan Silva, Carolyn Grace Roberts, Holly Haymer, Andre Marnett, Lawrence J. Holmes, Andrew Patel, Sachin TI Cyclooxygenase-2 inhibition reduces stress-induced affective pathology SO ELIFE LA English DT Article ID SELECTIVE COX-2 INHIBITION; MAJOR DEPRESSIVE DISORDER; PLACEBO-CONTROLLED TRIAL; INDUCED HYPOPHAGIA TEST; DOUBLE-BLIND; ENDOCANNABINOID AUGMENTATION; BIOCHEMICAL-ALTERATIONS; CANNABINOID RECEPTORS; MOOD DISORDERS; FEAR MEMORY AB Mood and anxiety disorders are the most prevalent psychiatric conditions and are exacerbated by stress. Recent studies have suggested cyclooxygenase-2 (COX-2) inhibition could represent a novel treatment approach or augmentation strategy for affective disorders including anxiety disorders and major depression. We show that traditional COX-2 inhibitors and a newly developed substrate-selective COX-2 inhibitor (SSCI) reduce a variety of stress-induced behavioral pathologies in mice. We found that these behavioral effects were associated with a dampening of neuronal excitability in the basolateral amygdala (BLA) ex vivo and in vivo, and were mediated by small-conductance calcium-activated potassium (SK) channel and CBI cannabinoid receptor activation. Taken together, these data provide further support for the potential utility of SSCIs, as well as traditional COX-2 inhibitors, as novel treatment approaches for stress-related psychiatric disorders. C1 [Gamble-George, Joyonna Carrie; Baldi, Rita; Hartley, Nolan; Silva, Carolyn Grace; Roberts, Holly; Haymer, Andre; Patel, Sachin] Vanderbilt Univ, Med Ctr, Dept Psychiat & Behav Sci, Nashville, TN USA. [Gamble-George, Joyonna Carrie; Hartley, Nolan; Patel, Sachin] Vanderbilt Univ, Vanderbilt Brain Inst, 221 Kirkland Hall, Nashville, TN 37235 USA. [Halladay, Lindsay; Kocharian, Adrina; Holmes, Andrew] NIAAA, Lab Behav & Genom Neurosci, Bethesda, MD USA. [Marnett, Lawrence J.] Vanderbilt Inst of Chem Biol, Ctr Mol Toxicol, AB Hancock Jr Mem Lab Canc Res, Dept Biochem, Nashville, TN USA. [Marnett, Lawrence J.] Vanderbilt Inst of Chem Biol, Ctr Mol Toxicol, Dept Chem, Nashville, TN USA. [Marnett, Lawrence J.] Vanderbilt Inst of Chem Biol, Ctr Mol Toxicol, Dept Pharmacol, Nashville, TN USA. Vanderbilt-Ingram Canc Ctr, Nashville, TN USA. [Patel, Sachin] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37212 USA. [Patel, Sachin] Vanderbilt Univ, Med Ctr, Vanderbilt Kennedy Ctr Human Dev, Nashville, TN USA. RP Patel, S (reprint author), Vanderbilt Univ, Med Ctr, Dept Psychiat & Behav Sci, Nashville, TN USA.; Patel, S (reprint author), Vanderbilt Univ, Vanderbilt Brain Inst, 221 Kirkland Hall, Nashville, TN 37235 USA.; Patel, S (reprint author), Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37212 USA.; Patel, S (reprint author), Vanderbilt Univ, Med Ctr, Vanderbilt Kennedy Ctr Human Dev, Nashville, TN USA. EM patel@vanderbilt.edu FU National Institute of Mental Health [MH100096]; National Institute of General Medical Sciences [GM15431] FX National Institute of Mental Health MH100096 Sachin Patel; National Institute of General Medical Sciences GM15431 Lawrence Marnett; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 63 TC 1 Z9 1 U1 3 U2 7 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD MAY 10 PY 2016 VL 5 AR e14137 DI 10.7754/eLife.14137 PG 20 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DM8IJ UT WOS:000376605300001 ER PT J AU Smith, OK Kim, R Fu, HQ Martin, MM Lin, CM Utani, K Zhang, Y Marks, AB Lalande, M Chamberlain, S Libbrecht, MW Bouhassira, EE Ryan, MC Noble, WS Aladjem, MI AF Smith, Owen K. Kim, RyanGuk Fu, Haiqing Martin, Melvenia M. Lin, Chii Mei Utani, Koichi Zhang, Ya Marks, Anna B. Lalande, Marc Chamberlain, Stormy Libbrecht, Maxwell W. Bouhassira, Eric E. Ryan, Michael C. Noble, William S. Aladjem, Mirit I. TI Distinct epigenetic features of differentiation-regulated replication origins SO EPIGENETICS & CHROMATIN LA English DT Article DE Origin of replication; Chromatin; Histone modification; Cellular differentiation; CpG islands; H3K4me3; H3K9Ac; H3K9me3; Cell cycle; Proliferation ID EUKARYOTIC DNA-REPLICATION; BETA-GLOBIN LOCUS; PLURIPOTENT STEM-CELLS; CHROMATIN-STRUCTURE; CHROMOSOME-REPLICATION; HISTONE MODIFICATION; GENE-EXPRESSION; GENOME-WIDE; INITIATION; SEQUENCE AB Background: Eukaryotic genome duplication starts at discrete sequences (replication origins) that coordinate cell cycle progression, ensure genomic stability and modulate gene expression. Origins share some sequence features, but their activity also responds to changes in transcription and cellular differentiation status. Results: To identify chromatin states and histone modifications that locally mark replication origins, we profiled origin distributions in eight human cell lines representing embryonic and differentiated cell types. Consistent with a role of chromatin structure in determining origin activity, we found that cancer and non-cancer cells of similar lineages exhibited highly similar replication origin distributions. Surprisingly, our study revealed that DNase hypersensitivity, which often correlates with early replication at large-scale chromatin domains, did not emerge as a strong local determinant of origin activity. Instead, we found that two distinct sets of chromatin modifications exhibited strong local associations with two discrete groups of replication origins. The first origin group consisted of about 40,000 regions that actively initiated replication in all cell types and preferentially colocalized with unmethylated CpGs and with the euchromatin markers, H3K4me3 and H3K9Ac. The second group included origins that were consistently active in cells of a single type or lineage and preferentially colocalized with the heterochromatin marker, H3K9me3. Shared origins replicated throughout the S-phase of the cell cycle, whereas cell-type-specific origins preferentially replicated during late S-phase. Conclusions: These observations are in line with the hypothesis that differentiation-associated changes in chromatin and gene expression affect the activation of specific replication origins. C1 [Smith, Owen K.; Fu, Haiqing; Martin, Melvenia M.; Lin, Chii Mei; Utani, Koichi; Zhang, Ya; Marks, Anna B.; Aladjem, Mirit I.] NCI, DNA Replicat Grp, Dev Therapeut Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Kim, RyanGuk; Ryan, Michael C.] In Silico Solut, Fairfax, VA 22033 USA. [Lalande, Marc; Chamberlain, Stormy] Univ Connecticut, Ctr Hlth, Dept Genet & Dev Biol, Farmington, CT 06032 USA. [Libbrecht, Maxwell W.; Noble, William S.] Univ Washington, Dept Comp Sci & Engn, Seattle, WA 98195 USA. [Bouhassira, Eric E.] Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA. [Noble, William S.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. RP Aladjem, MI (reprint author), NCI, DNA Replicat Grp, Dev Therapeut Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM aladjemm@mail.nih.gov FU National Institutes of Health Intramural Research Program, National Cancer Institute, Center for Cancer Research [ZIA BC010411 15] FX This work was supported by the National Institutes of Health Intramural Research Program, National Cancer Institute, Center for Cancer Research [ZIA BC010411 15]. NR 69 TC 4 Z9 4 U1 2 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-8935 J9 EPIGENET CHROMATIN JI Epigenetics Chromatin PD MAY 10 PY 2016 VL 9 AR 18 DI 10.1186/s13072-016-0067-3 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA DN1YO UT WOS:000376861500001 PM 27168766 ER PT J AU Vishwasrao, HM Master, AM Seo, YG Liu, XMM Pothayee, N Zhou, ZY Yuan, DF Boska, MD Bronich, TK Davis, RM Riffle, JS Sokolsky-Papkov, M Kabanov, AV AF Vishwasrao, Hemant M. Master, Alyssa M. Seo, Youn Gee Liu, Xinming M. Pothayee, Nikorn Zhou, Zhengyuan Yuan, Dongfen Boska, Michael D. Bronich, Tatiana K. Davis, Richey M. Riffle, Judy S. Sokolsky-Papkov, Marina Kabanov, Alexander V. TI Luteinizing Hormone Releasing Hormone-Targeted Cisplatin-Loaded Magnetite Nanoclusters for Simultaneous MR Imaging and Chemotherapy of Ovarian Cancer SO CHEMISTRY OF MATERIALS LA English DT Article ID IRON-OXIDE NANOPARTICLES; DRUG-DELIVERY-SYSTEM; CONTRAST AGENTS; IN-VIVO; SUPERPARAMAGNETIC NANOPARTICLES; POLYMERIC NANOPARTICLES; DIBLOCK COPOLYMERS; LHRH PEPTIDE; THERAPY; DESIGN AB Given the superior soft tissue contrasts obtained by MRI and the long residence times of magnetic nanoparticles (MNPs) in soft tissues, MNP-based theranostic systems are being developed for simultaneous imaging and treatment. However, development of such theranostic nanoformulations presents significant challenges of balancing the therapeutic and diagnostic functionalities in order to achieve optimum effect from both. Here we developed a simple theranostic nanoformulation based on magnetic nanoclusters (MNCs) stabilized by a bisphosphonate-modified poly(glutamic acid)-b-(ethylene glycol) block copolymer and complexed with cisplatin. The MNCs were decorated with luteinizing hormone releasing hormone (LHRH) to target LHRH receptors (LHRHr) overexpressed in ovarian cancer cells. The targeted MNCs significantly improved the uptake of the drug in cancer cells and decreased its IC50 compared to the nontargeted formulations. Also, the enhanced LHRHr-mediated uptake of the targeted MNCs resulted in enhancement in the T-2-weighted negative contrast in cellular phantom gels. Taken together, the LHRH-conjugated MNCs show good potential as ovarian cancer theranostics. C1 [Vishwasrao, Hemant M.; Liu, Xinming M.; Zhou, Zhengyuan; Bronich, Tatiana K.] Univ Nebraska Med Ctr, Coll Pharm, Dept Pharmaceut Sci, Ctr Drug Delivery & Nanomed, Omaha, NE 68198 USA. [Vishwasrao, Hemant M.; Master, Alyssa M.; Seo, Youn Gee; Yuan, Dongfen; Sokolsky-Papkov, Marina; Kabanov, Alexander V.] Univ N Carolina, Ctr Nanotechnol Drug Delivery, Mol Pharmaceut Div, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA. [Liu, Xinming M.] Univ Nebraska Med Ctr, Dept Pharmacol & Expt Neurosci, Omaha, NE 68198 USA. [Pothayee, Nikorn] NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Boska, Michael D.] Univ Nebraska Med Ctr, Coll Med, Dept Radiol, Omaha, NE 68198 USA. [Davis, Richey M.; Riffle, Judy S.] Virginia Tech, Macromol & Interfaces Inst, Blacksburg, VA 24061 USA. [Riffle, Judy S.] Virginia Tech, Dept Chem, Blacksburg, VA 24061 USA. [Davis, Richey M.] Virginia Tech, Dept Chem Engn, Blacksburg, VA 24061 USA. [Kabanov, Alexander V.] Moscow MV Lomonosov State Univ, Fac Chem, Moscow 119899, Russia. RP Sokolsky-Papkov, M; Kabanov, AV (reprint author), Univ N Carolina, Ctr Nanotechnol Drug Delivery, UNC Eshelman Sch Pharm, Marsico Hall,Room 2012,Campus Box 7362, Chapel Hill, NC 27599 USA. EM msokolsk@email.unc.edu; kabanov@email.unc.edu FU innovative Research in Cancer Nanotechnology (IRCN) Grant of the National Cancer Institute Alliance for Nanotechnology in Cancer [U01CA198910-01]; UNC Eshelman School of Pharmacy; University Cancer Research Fund through the Lineberger Comprehensive Cancer Center FX This work was supported in part by the innovative Research in Cancer Nanotechnology (IRCN) Grant (U01CA198910-01) of the National Cancer Institute Alliance for Nanotechnology in Cancer and the Carolina Partnership, a strategic partnership between the UNC Eshelman School of Pharmacy and The University Cancer Research Fund through the Lineberger Comprehensive Cancer Center. NR 93 TC 2 Z9 2 U1 8 U2 23 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0897-4756 EI 1520-5002 J9 CHEM MATER JI Chem. Mat. PD MAY 10 PY 2016 VL 28 IS 9 BP 3024 EP 3040 DI 10.1021/acs.chemmater.6b00197 PG 17 WC Chemistry, Physical; Materials Science, Multidisciplinary SC Chemistry; Materials Science GA DL7HA UT WOS:000375810400018 ER PT J AU Graham, B Marcais, A Dharmalingam, G Carroll, T Kanellopoulou, C Graumann, J Nesterova, TB Bermange, A Brazauskas, P Xella, B Kriaucionis, S Higgs, DR Brockdorff, N Mann, M Fisher, AG Merkenschlager, M AF Graham, Bryony Marcais, Antoine Dharmalingam, Gopuraja Carroll, Thomas Kanellopoulou, Chryssa Graumann, Johannes Nesterova, Tatyana B. Bermange, Anna Brazauskas, Pijus Xella, Barbara Kriaucionis, Skirmantas Higgs, Douglas R. Brockdorff, Neil Mann, Matthias Fisher, Amanda G. Merkenschlager, Matthias TI MicroRNAs of the miR-290-295 Family Maintain Bivalency in Mouse Embryonic Stem Cells SO STEM CELL REPORTS LA English DT Article ID GENOME-WIDE; SELF-RENEWAL; MATURE MICRORNAS; DNA METHYLATION; GROUND-STATE; POLYCOMB; PLURIPOTENCY; RNA; DICER; GENES AB Numerous developmentally regulated genes in mouse embryonic stem cells (ESCs) are marked by both active (H3K4me3)- and polycomb group (PcG)-mediated repressive (H3K27me3) histone modifications. This bivalent state is thought to be important for transcriptional poising, but the mechanisms that regulate bivalent genes and the bivalent state remain incompletely understood. Examining the contribution of microRNAs (miRNAs) to the regulation of bivalent genes, we found that the miRNA biogenesis enzyme DICER was required for the binding of the PRC2 core components EZH2 and SUZ12, and for the presence of the PRC2-mediated histone modification H3K27me3 at many bivalent genes. Genes that lost bivalency were preferentially upregulated at the mRNA and protein levels. Finally, reconstituting Dicer-deficient ESCs with ESC miRNAs restored bivalent gene repression and PRC2 binding at formerly bivalent genes. Therefore, miRNAs regulate bivalent genes and the bivalent state itself. C1 [Graham, Bryony; Marcais, Antoine; Bermange, Anna; Fisher, Amanda G.; Merkenschlager, Matthias] Univ London Imperial Coll Sci Technol & Med, Fac Med, MRC Clin Sci Ctr, Lymphocyte Dev Grp, Du Cane Rd, London W12 0NN, England. [Graham, Bryony; Marcais, Antoine; Dharmalingam, Gopuraja; Carroll, Thomas; Bermange, Anna; Fisher, Amanda G.; Merkenschlager, Matthias] Univ London Imperial Coll Sci Technol & Med, Fac Med, MRC Clin Sci Ctr, Epigenet Sect, Du Cane Rd, London W12 0NN, England. [Graham, Bryony; Xella, Barbara; Higgs, Douglas R.] Univ Oxford, MRC Weatherall Inst Mol Med, MRC Mol Haematol Unit, Oxford OX3 9DS, England. [Kanellopoulou, Chryssa] NIH, Immunol Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Graumann, Johannes; Mann, Matthias] Max Planck Inst Biochem, Dept Prote & Signal Transduct, Klopferspitz 18A, D-82152 Martinsried, Germany. [Nesterova, Tatyana B.; Brockdorff, Neil] Univ Oxford, Dept Biochem, Oxford OX1 3QU, England. [Brazauskas, Pijus; Kriaucionis, Skirmantas] Univ Oxford, Nuffield Dept Clin Med, Ludwig Inst Canc Res, Oxford OX3 7DQ, England. [Marcais, Antoine] Univ Lyon, INSERM U1111, Lyon, France. [Graumann, Johannes] Weill Cornell Med Coll Qatar, Doha, Qatar. [Bermange, Anna] Univ London, London E1 4NS, England. RP Merkenschlager, M (reprint author), Univ London Imperial Coll Sci Technol & Med, Fac Med, MRC Clin Sci Ctr, Lymphocyte Dev Grp, Du Cane Rd, London W12 0NN, England.; Merkenschlager, M (reprint author), Univ London Imperial Coll Sci Technol & Med, Fac Med, MRC Clin Sci Ctr, Epigenet Sect, Du Cane Rd, London W12 0NN, England. EM matthias.merkenschlager@csc.mrc.ac.uk RI Graumann, Johannes/C-5241-2008; Marcais, Antoine/F-4341-2017; OI Graumann, Johannes/0000-0002-3015-5850; Nesterova, Tatyana/0000-0001-7740-4386; Graham, Bryony/0000-0002-4464-5770; Merkenschlager, Matthias/0000-0003-2889-3288; Marcais, Antoine/0000-0002-3591-6268; Terry, Anna/0000-0002-1946-8223 FU Medical Research Council [MC_U120027516] NR 44 TC 0 Z9 0 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2213-6711 J9 STEM CELL REP JI Stem Cell Rep. PD MAY 10 PY 2016 VL 6 IS 5 BP 635 EP 642 DI 10.1016/j.stemcr.2016.03.005 PG 8 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA DL4LC UT WOS:000375606400001 PM 27150236 ER PT J AU Borkent, M Bennett, BD Lackford, B Bar-Nur, O Brumbaugh, J Wang, L Du, Y Fargo, DC Apostolou, E Cheloufi, S Maherali, N Elledge, SJ Hu, G Hochedlinger, K AF Borkent, Marti Bennett, Brian D. Lackford, Brad Bar-Nur, Ori Brumbaugh, Justin Wang, Li Du, Ying Fargo, David C. Apostolou, Effie Cheloufi, Sihem Maherali, Nimet Elledge, Stephen J. Hu, Guang Hochedlinger, Konrad TI A Serial shRNA Screen for Roadblocks to Reprogramming Identifies the Protein Modifier SUMO2 SO STEM CELL REPORTS LA English DT Article ID SYSTEMATIC IDENTIFICATION; DEPENDENT MANNER; IPSC GENERATION; SOMATIC-CELLS; STEM-CELLS; PLURIPOTENCY; SUMOYLATION; MOUSE; PROLIFERATION; SAFEGUARDS AB The generation of induced pluripotent stem cells (iPSCs) from differentiated cells following forced expression of OCT4, KLF4, SOX2, and C-MYC (OKSM) is slow and inefficient, suggesting that transcription factors have to overcome somatic barriers that resist cell fate change. Here, we performed an unbiased serial shRNA enrichment screen to identify potent repressors of somatic cell reprogramming into iPSCs. This effort uncovered the protein modifier SUMO2 as one of the strongest roadblocks to iPSC formation. Depletion of SUMO2 both enhances and accelerates reprogramming, yielding transgene-independent, chimera-competent iPSCs after as little as 38 hr of OKSM expression. We further show that the SUMO2 pathway acts independently of exogenous C-MYC expression and in parallel with small-molecule enhancers of reprogramming. Importantly, suppression of SUMO2 also promotes the generation of human iPSCs. Together, our results reveal sumoylation as a crucial post-transcriptional mechanism that resists the acquisition of pluripotency from fibroblasts using defined factors. C1 [Borkent, Marti; Bar-Nur, Ori; Brumbaugh, Justin; Apostolou, Effie; Cheloufi, Sihem; Maherali, Nimet; Hochedlinger, Konrad] Massachusetts Gen Hosp, Dept Mol Biol, Ctr Regenerat Med, Boston, MA 02114 USA. [Borkent, Marti; Bar-Nur, Ori; Brumbaugh, Justin; Apostolou, Effie; Cheloufi, Sihem; Maherali, Nimet; Hochedlinger, Konrad] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Borkent, Marti; Bar-Nur, Ori; Brumbaugh, Justin; Apostolou, Effie; Cheloufi, Sihem; Maherali, Nimet; Hochedlinger, Konrad] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Borkent, Marti; Bar-Nur, Ori; Brumbaugh, Justin; Apostolou, Effie; Cheloufi, Sihem; Maherali, Nimet; Hochedlinger, Konrad] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Borkent, Marti; Bar-Nur, Ori; Brumbaugh, Justin; Apostolou, Effie; Cheloufi, Sihem; Maherali, Nimet; Elledge, Stephen J.; Hochedlinger, Konrad] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Bennett, Brian D.; Du, Ying; Fargo, David C.] NIEHS, Integrat Bioinformat, POB 12233, Res Triangle Pk, NC 27709 USA. [Lackford, Brad; Wang, Li; Hu, Guang] NIEHS, Epigenet & Stem Cell Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. [Elledge, Stephen J.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Hochedlinger, K (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Ctr Regenerat Med, Boston, MA 02114 USA.; Hochedlinger, K (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA.; Hochedlinger, K (reprint author), Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA.; Hochedlinger, K (reprint author), Harvard Stem Cell Inst, Cambridge, MA 02138 USA.; Hochedlinger, K (reprint author), Howard Hughes Med Inst, Chevy Chase, MD 20815 USA.; Hu, G (reprint author), NIEHS, Epigenet & Stem Cell Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM hug4@niehs.nih.gov; khochedlinger@mgh.harvard.edu FU Boehringer Ingelheim Fonds predoctoral fellowship; MGH Tosteson fellowship; NIH [1F32HD078029-01A1, GM44664, AG011085, HD058013]; PRCRP at the Department of Defense [CA 120212]; Intramural Research Program at the National Institute of Environmental Health Sciences [Z01ES102745]; Gerald and Darlene Jordan Endowment; Early Career Award from Howard Hughes Medical Institute FX We thank Laura Prickett, Kat Folz-Donahue, and Meredith Weglarz of the CRM Flow Cytometry core facility and all K.H. and G.H. lab members for advice and discussions. We are grateful to Dr. Peter Brown for providing the DOT1L inhibitor, and Dr. Jianping Jin for providing the SUMO2 entry vector. We thank Dr. Mehrnaz Ghazvini for help with human reprogramming experiments. We thank our animal facility for the care of mice; all mouse experiments have been approved by the Institutional Animal Care and Use Committee. M.B. was supported by a Boehringer Ingelheim Fonds predoctoral fellowship, O.B.N. by a MGH Tosteson fellowship, J.B. by the NIH (1F32HD078029-01A1) and S.C. by the PRCRP at the Department of Defense (CA 120212). This work was supported by grants from the NIH (GM44664 and AG011085) to S.J.E.; S.J.E. is an Investigator with the Howard Hughes Medical Institute. G.H. was supported by the Intramural Research Program at the National Institute of Environmental Health Sciences (Z01ES102745). Support to K.H. was from the Gerald and Darlene Jordan Endowment, the NIH (HD058013), and an Early Career Award from the Howard Hughes Medical Institute. NR 32 TC 3 Z9 3 U1 1 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2213-6711 J9 STEM CELL REP JI Stem Cell Rep. PD MAY 10 PY 2016 VL 6 IS 5 BP 704 EP 716 DI 10.1016/j.stemcr.2016.02.004 PG 13 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA DL4LC UT WOS:000375606400008 PM 26947976 ER PT J AU Chambers, DA Feero, WG Khoury, MJ AF Chambers, David A. Feero, W. Gregory Khoury, Muin J. TI Convergence of Implementation Science, Precision Medicine, and the Learning Health Care System A New Model for Biomedical Research SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Chambers, David A.; Khoury, Muin J.] NCI, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Room 3E414, Rockville, MD 20850 USA. [Feero, W. Gregory] Maine Dartmouth Family Med Residency, Augusta, GA USA. [Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Gen, Atlanta, GA USA. RP Chambers, DA (reprint author), NCI, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Room 3E414, Rockville, MD 20850 USA. EM dchamber@mail.nih.gov NR 7 TC 10 Z9 10 U1 1 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 10 PY 2016 VL 315 IS 18 BP 1941 EP 1942 DI 10.1001/jama.2016.3867 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DL2JP UT WOS:000375461100006 PM 27163980 ER PT J AU Shaw, P AF Shaw, Philip TI Quantifying the Benefits and Risks of Methylphenidate as Treatment for Childhood Attention-Deficit/Hyperactivity Disorder SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID CHILDREN; ADHD; ADOLESCENTS; METAANALYSES; EFFICACY; TRIALS C1 [Shaw, Philip] NHGRI, Sect Neurobehav Clin Res, Social & Behav Res Branch, Bethesda, MD 20892 USA. [Shaw, Philip] NIMH, Bethesda, MD 20892 USA. RP Shaw, P (reprint author), NHGRI, Bldg 31, Bethesda, MD 20852 USA. EM shawp@mail.nih.gov FU Intramural NIH HHS NR 15 TC 1 Z9 1 U1 2 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 10 PY 2016 VL 315 IS 18 BP 1953 EP 1955 DI 10.1001/jama.2016.3427 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DL2JP UT WOS:000375461100012 PM 27163984 ER PT J AU Gilbert, MR AF Gilbert, Mark R. TI Antiangiogenic Therapy for Glioblastoma: Complex Biology and Complicated Results SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID NEWLY-DIAGNOSED GLIOBLASTOMA; MALIGNANT GLIOMA; BEVACIZUMAB; TRIAL; RADIOTHERAPY; TEMOZOLOMIDE; IRINOTECAN; BENEFIT C1 [Gilbert, Mark R.] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Gilbert, MR (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. RI Gilbert, Mark/J-7494-2016 OI Gilbert, Mark/0000-0003-2556-9722 NR 19 TC 1 Z9 1 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 10 PY 2016 VL 34 IS 14 BP 1567 EP U44 DI 10.1200/JCO.2016.66.5364 PG 4 WC Oncology SC Oncology GA DL0FZ UT WOS:000375309100004 PM 27001588 ER PT J AU Blakeley, JO Ye, XB Duda, DG Halpin, CF Bergner, AL Muzikansky, A Merker, VL Gerstner, ER Fayad, LM Ahlawat, S Jacobs, MA Jain, RK Zalewski, C Dombi, E Widemann, BC Plotkin, SR AF Blakeley, Jaishri O. Ye, Xiaobu Duda, Dan G. Halpin, Chris F. Bergner, Amanda L. Muzikansky, Alona Merker, Vanessa L. Gerstner, Elizabeth R. Fayad, Laura M. Ahlawat, Shivani Jacobs, Michael A. Jain, Rakesh K. Zalewski, Christopher Dombi, Eva Widemann, Brigitte C. Plotkin, Scott R. TI Efficacy and Biomarker Study of Bevacizumab for Hearing Loss Resulting From Neurofibromatosis Type 2-Associated Vestibular Schwannomas SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; ANTIANGIOGENIC THERAPY; NATURAL-HISTORY; CLINICAL-TRIALS; MANAGEMENT; TUMORS; CRITERIA AB Purpose Neurofibromatosis type 2 (NF2) is a tumor predisposition syndrome characterized by bilateral vestibular schwannomas (VSs) resulting in deafness and brainstem compression. This study evaluated efficacy and biomarkers of bevacizumab activity for NF2-associated progressive and symptomatic VSs. Patients and Methods Bevacizumab 7.5 mg/ kg was administered every 3 weeks for 46 weeks, followed by 24 weeks of surveillance after treatment with the drug. The primary end point was hearing response defined by word recognition score (WRS). Secondary end points included toxicity, tolerability, imaging response using volumetric magnetic resonance imaging analysis, durability of response, and imaging and blood biomarkers. Results Fourteen patients (estimated to yield >90% power to detect an alternative response rate of 50% at alpha level of 0.05) with NF2, with a median age of 30 years (range, 14 to 79 years) and progressive hearing loss in the target ear (median baseline WRS, 60%; range 13% to 82%), were enrolled. The primary end point, confirmed hearing response (improvement maintained >3 months), occurred in five (36%) of 14 patients (95% CI, 13% to 65%; P < .001). Eight (57%) of 14 patients had transient hearing improvement above the 95% CI for WRS. No patients experienced hearing decline. Radiographic response was seen in six (43%) of 14 target VSs. Three grade 3 adverse events, hypertension (n = 2) and immune-mediated thrombocytopenic purpura (n = 1), were possibly related to bevacizumab. Bevacizumab treatment was associated with decreased free vascular endothelial growth factor (not bound to bevacizumab) and increased placental growth factor in plasma. Hearing responses were inversely associated with baseline plasma hepatocyte growth factor (P =.019). Imaging responses were associated with high baseline tumor vessel permeability and elevated blood levels of vascular endothelial growth factor D and stromal cell-derived factor 1 alpha (P = .037 and .025, respectively). Conclusion Bevacizumab treatment resulted in durable hearing response in 36% of patients with NF2 and confirmed progressive VS-associated hearing loss. Imaging and plasma biomarkers showed promising associations with response that should be validated in larger studies. (C) 2016 by American Society of Clinical Oncology C1 [Blakeley, Jaishri O.; Ye, Xiaobu; Bergner, Amanda L.; Fayad, Laura M.; Ahlawat, Shivani; Jacobs, Michael A.] Johns Hopkins Univ, Baltimore, MD USA. [Dombi, Eva; Widemann, Brigitte C.] NCI, Bethesda, MD 20892 USA. [Duda, Dan G.; Muzikansky, Alona; Merker, Vanessa L.; Jain, Rakesh K.; Plotkin, Scott R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Halpin, Chris F.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Blakeley, JO (reprint author), Johns Hopkins Univ, Johns Hopkins Comprehens Neurofibromatosis Ctr, Baltimore, MD USA. EM jblakel3@jhmi.edu OI Merker, Vanessa/0000-0002-4542-5227 FU Cancer Therapy Evaluation Program; Galloway Family Foundation; National Cancer Institute Center for Cancer Research Intramural Research Program; National Institute on Deafness; Other Communication Disorders Intramural Research Program, National Institutes of Health (Bethesda, MD) FX Supported by the Cancer Therapy Evaluation Program, Galloway Family Foundation, and National Cancer Institute Center for Cancer Research Intramural Research Program and National Institute on Deafness and Other Communication Disorders Intramural Research Program, National Institutes of Health (Bethesda, MD). NR 39 TC 4 Z9 4 U1 1 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 10 PY 2016 VL 34 IS 14 BP 1669 EP U220 DI 10.1200/JCO.2015.64.3817 PG 16 WC Oncology SC Oncology GA DL0FZ UT WOS:000375309100018 PM 26976425 ER PT J AU Molina-Cruz, A Barillas-Mury, C AF Molina-Cruz, Alvaro Barillas-Mury, Carolina TI Mosquito vectors of apemalarias: Another piece of the puzzle SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID PLASMODIUM-FALCIPARUM; HUMAN MALARIA; GREAT APES; VIVAX; DIVERSITY; ORIGIN C1 [Molina-Cruz, Alvaro; Barillas-Mury, Carolina] NIAID, Lab Malaria & Vector Res, Mosquito Immun & Vector Competence Sect, NIH, Rockville, MD 20852 USA. RP Barillas-Mury, C (reprint author), NIAID, Lab Malaria & Vector Res, Mosquito Immun & Vector Competence Sect, NIH, Rockville, MD 20852 USA. EM cbarillas@niaid.nih.gov NR 15 TC 2 Z9 2 U1 2 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 10 PY 2016 VL 113 IS 19 BP 5153 EP 5154 DI 10.1073/pnas.1604913113 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DL2QA UT WOS:000375478800033 PM 27118843 ER PT J AU Tolun, G Vijayasarathy, C Huang, R Zeng, Y Li, Y Steven, AC Sieving, PA Heymann, JB AF Tolun, Gokhan Vijayasarathy, Camasamudram Huang, Rick Zeng, Yong Li, Yan Steven, Alasdair C. Sieving, Paul A. Heymann, J. Bernard TI Paired octamer rings of retinoschisin suggest a junctional model for cell-cell adhesion in the retina SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE retinoschisin; X-linked retinoschisis; discoidin domain; cryo-electron microscopy; single particle analysis ID X-LINKED RETINOSCHISIS; EM STRUCTURE DETERMINATION; JUVENILE RETINOSCHISIS; ELECTRON-MICROSCOPY; C2 DOMAIN; RS1 GENE; CRYO-EM; MOLECULAR-MECHANISMS; CHINESE FAMILIES; FACTOR-VIII AB Retinoschisin (RS1) is involved in cell-cell junctions in the retina, but is unique among known cell-adhesion proteins in that it is a soluble secreted protein. Loss-of-function mutations in RS1 lead to early vision impairment in young males, called X-linked retinoschisis. The disease is characterized by separation of inner retinal layers and disruption of synaptic signaling. Using cryo-electron microscopy, we report the structure at 4.1 angstrom, revealing double octamer rings not observed before. Each subunit is composed of a discoidin domain and a small N-terminal (RS1) domain. The RS1 domains occupy the centers of the rings, but are not required for ring formation and are less clearly defined, suggesting mobility. We determined the structure of the discoidin rings, consistent with known intramolecular and intermolecular disulfides. The interfaces internal to and between rings feature residues implicated in X-linked retinoschisis, indicating the importance of correct assembly. Based on this structure, we propose that RS1 couples neighboring membranes together through octamer-octamer contacts, perhaps modulated by interactions with other membrane components. C1 [Tolun, Gokhan; Huang, Rick; Steven, Alasdair C.; Heymann, J. Bernard] NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. [Tolun, Gokhan] NCI, Mol Control & Genet Sect, Gene Regulat & Chromosome Biol Lab, Ctr Canc Res,NIH, Frederick, MD 21702 USA. [Vijayasarathy, Camasamudram; Zeng, Yong; Sieving, Paul A.] NIDCD, Sect Translat Res Retinal & Macular Degenerat, NIH, Bethesda, MD 20892 USA. [Huang, Rick] Howard Hughes Med Inst, Cryoelectron Microscopy Facil, Janelia Res Campus, Ashburn, VA 20147 USA. [Li, Yan] NINDS, Prot Peptide Sequencing Facil, NIH, Bethesda, MD 20892 USA. [Sieving, Paul A.] NEI, NIH, Bethesda, MD 20892 USA. RP Heymann, JB (reprint author), NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA.; Sieving, PA (reprint author), NIDCD, Sect Translat Res Retinal & Macular Degenerat, NIH, Bethesda, MD 20892 USA.; Sieving, PA (reprint author), NEI, NIH, Bethesda, MD 20892 USA. EM pas@nei.nih.gov; heymannb@mail.nih.gov OI Heymann, Bernard/0000-0002-8872-5326 FU National Eye Institute; National Institute on Deafness and Other Communication Disorders; National Institute of Arthritis and Musculoskeletal and Skin Diseases FX We thank Dr. Emilios Dimitriadis (National Institute of Biomedical Imaging and Bioengineering) for assistance in assessing the initial protein preparations; Dr. Dennis Winkler (National Institute of Arthritis and Musculoskeletal and Skin Diseases) for assistance in installing and using SerialEM; and Dr. R. E. Anderson (University of Oklahoma) for helpful discussions. This work was supported by the Intramural Research Programs of the National Eye Institute, National Institute on Deafness and Other Communication Disorders, and National Institute of Arthritis and Musculoskeletal and Skin Diseases. NR 50 TC 2 Z9 2 U1 3 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 10 PY 2016 VL 113 IS 19 BP 5287 EP 5292 DI 10.1073/pnas.1519048113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DL2QA UT WOS:000375478800056 PM 27114531 ER PT J AU Ravin, R Blank, PS Busse, B Ravin, N Vira, S Bezrukov, L Waters, H Guerrero-Cazares, H Quinones-Hinojosa, A Lee, PR Fields, RD Bezrukov, SM Zimmerberg, J AF Ravin, Rea Blank, Paul S. Busse, Brad Ravin, Nitay Vira, Shaleen Bezrukov, Ludmila Waters, Hang Guerrero-Cazares, Hugo Quinones-Hinojosa, Alfredo Lee, Philip R. Fields, R. Douglas Bezrukov, Sergey M. Zimmerberg, Joshua TI Blast shockwaves propagate Ca2+ activity via purinergic astrocyte networks in human central nervous system cells SO SCIENTIFIC REPORTS LA English DT Article ID TRAUMATIC BRAIN-INJURY; STRETCH-INDUCED INJURY; RT-QPCR DATA; EXTRACELLULAR ATP; RECEPTORS; MODEL; GLIA; RATS; ANTAGONIST; ACTIVATION AB In a recent study of the pathophysiology of mild, blast-induced traumatic brain injury (bTBI) the exposure of dissociated, central nervous system (CNS) cells to simulated blast resulted in propagating waves of elevated intracellular Ca2+. Here we show, in dissociated human CNS cultures, that these calcium waves primarily propagate through astrocyte-dependent, purinergic signaling pathways that are blocked by P2 antagonists. Human, compared to rat, astrocytes had an increased calcium response and prolonged calcium wave propagation kinetics, suggesting that in our model system rat CNS cells are less responsive to simulated blast. Furthermore, in response to simulated blast, human CNS cells have increased expressions of a reactive astrocyte marker, glial fibrillary acidic protein (GFAP) and a protease, matrix metallopeptidase 9 (MMP-9). The conjoint increased expression of GFAP and MMP-9 and a purinergic ATP (P2) receptor antagonist reduction in calcium response identifies both potential mechanisms for sustained changes in brain function following primary bTBI and therapeutic strategies targeting abnormal astrocyte activity. C1 [Ravin, Rea; Blank, Paul S.; Busse, Brad; Ravin, Nitay; Vira, Shaleen; Bezrukov, Ludmila; Waters, Hang; Zimmerberg, Joshua] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Integrat Biophys, NIH, Bethesda, MD 20892 USA. [Ravin, Rea; Ravin, Nitay] Celoptics Inc, Rockville, MD 20852 USA. [Guerrero-Cazares, Hugo; Quinones-Hinojosa, Alfredo] Johns Hopkins Univ, Dept Neurosurg, Baltimore, MD 21287 USA. [Lee, Philip R.; Fields, R. Douglas] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Nervous Syst Dev & Plast, NIH, Bethesda, MD 20892 USA. [Bezrukov, Sergey M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Transport, NIH, Bethesda, MD 20892 USA. RP Zimmerberg, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Integrat Biophys, NIH, Bethesda, MD 20892 USA. EM zimmerbj@mail.nih.gov FU Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) of the National Institutes of Health (NIH); NIH [R01NS070024] FX We thank Dr. Sachiko Murase NINDS, NIH, for a generous gift of rat CNS cortex tissue. This work was supported by the Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) of the National Institutes of Health (NIH) and under NIH award number R01NS070024 (A.Q.H.). NR 55 TC 0 Z9 0 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAY 10 PY 2016 VL 6 AR 25713 DI 10.1038/srep25713 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DL2UD UT WOS:000375489800003 PM 27162174 ER PT J AU Li, F Lokhnygina, Y Murray, DM Heagerty, PJ DeLong, ER AF Li, Fan Lokhnygina, Yuliya Murray, David M. Heagerty, Patrick J. DeLong, Elizabeth R. TI An evaluation of constrained randomization for the design and analysis of group-randomized trials SO STATISTICS IN MEDICINE LA English DT Article DE constrained randomization; group-randomized trial; permutation test; model-based F-test; candidate set size; balance metric ID CLINICAL-TRIALS; MIXED-MODEL; BALANCE; INTERVENTION; CARE AB In group-randomized trials, a frequent practical limitation to adopting rigorous research designs is that only a small number of groups may be available, and therefore, simple randomization cannot be relied upon to balance key group-level prognostic factors across the comparison arms. Constrained randomization is an allocation technique proposed for ensuring balance and can be used together with a permutation test for randomization-based inference. However, several statistical issues have not been thoroughly studied when constrained randomization is considered. Therefore, we used simulations to evaluate key issues including the following: the impact of the choice of the candidate set size and the balance metric used to guide randomization; the choice of adjusted versus unadjusted analysis; and the use of model-based versus randomization-based tests. We conducted a simulation study to compare the type I error and power of the F-test and the permutation test in the presence of group-level potential confounders. Our results indicate that the adjusted F-test and the permutation test perform similarly and slightly better for constrained randomization relative to simple randomization in terms of power, and the candidate set size does not substantially affect their power. Under constrained randomization, however, the unadjusted F-test is conservative, while the unadjusted permutation test carries the desired type I error rate as long as the candidate set size is not too small; the unadjusted permutation test is consistently more powerful than the unadjusted F-test and gains power as candidate set size changes. Finally, we caution against the inappropriate specification of permutation distribution under constrained randomization. An ongoing group-randomized trial is used as an illustrative example for the constrained randomization design. Copyright (C) 2015 John Wiley & Sons, Ltd. C1 [Li, Fan; Lokhnygina, Yuliya; DeLong, Elizabeth R.] Duke Univ, Sch Med, Dept Biostat & Bioinformat, Durham, NC 27710 USA. [Lokhnygina, Yuliya; DeLong, Elizabeth R.] Duke Clin Res Inst, Durham, NC 27705 USA. [Murray, David M.] NIH, Off Dis Prevent, Rockville, MD 20892 USA. [Heagerty, Patrick J.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. RP DeLong, ER (reprint author), Duke Univ, Sch Med, Dept Biostat & Bioinformat, Durham, NC 27710 USA. EM elizabeth.delong@dm.duke.edu OI Murray, David/0000-0003-0797-9269 FU Office of The Director, National Institutes of Health; NIH Common Fund [U54 AT007748]; NIH Health Care Systems Research Collaboratory FX This work is funded by the Office of The Director, National Institutes of Health, and supported by the NIH Common Fund through a cooperative agreement (U54 AT007748) with the NIH Health Care Systems Research Collaboratory. The views presented here are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. We thank Dr. Allison Kempe and Dr. Miriam Dickinson in the Collaboratory group for kindly sharing the data set from the reminder-recall for vaccination trial. We are grateful to the associate editor and the two anonymous referees for their helpful comments. NR 28 TC 1 Z9 1 U1 2 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD MAY 10 PY 2016 VL 35 IS 10 BP 1565 EP 1579 DI 10.1002/sim.6813 PG 15 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA DJ1AL UT WOS:000373935400001 PM 26598212 ER PT J AU Murray, J Savva, CG Shin, BS Dever, TE Ramakrishnan, V Fernandez, IS AF Murray, Jason Savva, Christos G. Shin, Byung-Sik Dever, Thomas E. Ramakrishnan, V. Fernandez, Israel S. TI Structural characterization of ribosome recruitment and translocation by type IV IRES SO ELIFE LA English DT Article ID ELONGATION-FACTOR-G; CRICKET PARALYSIS VIRUS; EUKARYOTIC TRANSLATION INITIATION; TRANSFER-RNA TRANSLOCATION; CRYO-EM STRUCTURE; ENTRY SITE IRES; INTERNAL RIBOSOME; GTP HYDROLYSIS; SACCHAROMYCES-CEREVISIAE; DIPHTHAMIDE MODIFICATION AB Viral mRNA sequences with a type IV IRES are able to initiate translation without any host initiation factors. Initial recruitment of the small ribosomal subunit as well as two translocation steps before the first peptidyl transfer are essential for the initiation of translation by these mRNAs. Using electron cryomicroscopy (cryo-EM) we have structurally characterized at high resolution how the Cricket Paralysis Virus Internal Ribosomal Entry Site (CrPV-IRES) binds the small ribosomal subunit (40S) and the translocation intermediate stabilized by elongation factor 2 (eEF2). The CrPV-IRES restricts tvhe otherwise flexible 40S head to a conformation compatible with binding the large ribosomal subunit (60S). Once the 60S is recruited, the binary CrPV-IRES/80S complex oscillates between canonical and rotated states (Fernandez et al., 2014; Koh et al., 2014), as seen for pre-translocation complexes with tRNAs. Elongation factor eEF2 with a GTP analog stabilizes the ribosome-IRES complex in a rotated state with an extra similar to 3 degrees of rotation. Key residues in domain IV of eEF2 interact with pseudoknot I (PKI) of the CrPV-IRES stabilizing it in a conformation reminiscent of a hybrid tRNA state. The structure explains how diphthamide, a eukaryotic and archaeal specific post-translational modification of a histidine residue of eEF2, is involved in translocation. C1 [Murray, Jason; Savva, Christos G.; Ramakrishnan, V.; Fernandez, Israel S.] MRC, Mol Biol Lab, Hills Rd, Cambridge CB2 2QH, England. [Murray, Jason; Shin, Byung-Sik; Dever, Thomas E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD USA. [Fernandez, Israel S.] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY USA. RP Ramakrishnan, V; Fernandez, IS (reprint author), MRC, Mol Biol Lab, Hills Rd, Cambridge CB2 2QH, England.; Fernandez, IS (reprint author), Columbia Univ, Dept Biochem & Mol Biophys, New York, NY USA. EM ramak@mrc-lmb.cam.ac.uk; isf2106@cumc.columbia.edu OI Dever, Thomas/0000-0001-7120-9678; Ramakrishnan, V/0000-0002-4699-2194 FU Medical Research Council [MC_U105184332]; Wellcome Trust [WT096570]; Agouron Institute; National Institutes of Health FX Medical Research Council MC_U105184332 Jason Murray Christos G Savva Venki Ramakrishnan Israel S Fernandez; Wellcome Trust WT096570 Venki Ramakrishnan Israel S Fernandez; Agouron Institute Venki Ramakrishnan; National Institutes of Health Jason Murray Thomas E Dever; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 87 TC 6 Z9 6 U1 4 U2 5 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD MAY 9 PY 2016 VL 5 AR e13567 DI 10.7554/eLife.13567 PG 24 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DM3PF UT WOS:000376257800001 ER PT J AU Temkin, SM Tanner, EJ Dewdney, SB Minasian, LM AF Temkin, Sarah M. Tanner, Edward J. Dewdney, Summer B. Minasian, Lori M. TI Reducing Overtreatment in Gynecologic Oncology: The Case for Less in endometrial and Ovarian Cancer SO FRONTIERS IN ONCOLOGY LA English DT Article DE gynecologic cancer; ovarian cancer; endometrial cancer; overtreatment; cancer care delivery ID RANDOMIZED-TRIAL; SURVEILLANCE PROCEDURES; PELVIC RADIATION; CORPUS CANCER; LYMPHADENECTOMY; RADIOTHERAPY; CARCINOMA; SURVIVAL; ADENOCARCINOMA; BRACHYTHERAPY AB A growing awareness of the harms of overtreatment in cancer care has reached physicians, patients, health policy makers, and medical researchers. Overtreatment exposes patients to the risk of adverse events from procedures or medications that were not necessary. This review examines common practices in gynecologic malignancies that are unlikely to produce direct benefit to patients with these malignancies, but are likely to produce harms. Specifically, we will explore the utility of lymphadenectomy and adjuvant radiation for women with early-stage endometrial cancer; and screening for recurrence and continuous chemotherapy for advanced-stage ovarian cancer patients. C1 [Temkin, Sarah M.; Minasian, Lori M.] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Tanner, Edward J.] Johns Hopkins Sch Med, Kelly Gynecol Oncol Serv, Baltimore, MD USA. [Dewdney, Summer B.] Rush Univ, Sch Med, Div Gynecol Oncol, Chicago, IL 60612 USA. RP Temkin, SM (reprint author), NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. EM stemkin1@jhmi.edu NR 44 TC 0 Z9 0 U1 4 U2 4 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2234-943X J9 FRONT ONCOL JI Front. Oncol. PD MAY 9 PY 2016 VL 6 AR 118 DI 10.3389/fonc.2016.00118 PG 6 WC Oncology SC Oncology GA DL3IC UT WOS:000375526500002 PM 27242958 ER PT J AU Ratnayaka, K Rogers, T Schenke, WH Mazal, JR Chen, MY Sonmez, M Hansen, MS Kocaturk, O Faranesh, AZ Lederman, RJ AF Ratnayaka, Kanishka Rogers, Toby Schenke, William H. Mazal, Jonathan R. Chen, Marcus Y. Sonmez, Merdim Hansen, Michael S. Kocaturk, Ozgur Faranesh, Anthony Z. Lederman, Robert J. TI Magnetic Resonance Imaging-Guided Transcatheter Cavopulmonary Shunt SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Article DE congenital heart disease; image-guided intervention; interventional MRI; real-time MRI; sutureless anastomosis; vascular ID PULMONARY-ARTERY; CREATION; SWINE; AORTOPULMONARY; HYPERTENSION; FEASIBILITY; COARCTATION; CATHETERS; DEVICES; FONTAN AB OBJECTIVES The aim of this study was to test the hypothesis that real-time magnetic resonance imaging (MRI) would enable closed-chest percutaneous cavopulmonary anastomosis and shunt by facilitating needle guidance along a curvilinear trajectory, around critical structures, and between a superior vena cava "donor" vessel and a pulmonary artery "target." BACKGROUND Children with single-ventricle physiology require multiple open heart operations for palliation, including sternotomies and cardiopulmonary bypass. The reduced morbidity of a catheter-based approach would be attractive. METHODS Fifteen naive swine underwent transcatheter cavopulmonary anastomosis and shunt creation under 1.5-T MRI guidance. An MRI antenna-needle was advanced from the superior vena cava into the target pulmonary artery bifurcation using real-time MRI guidance. In 10 animals, balloon-expanded off-the-shelf endografts secured a proximal end-to-end caval anastomosis and a distal end-to-side pulmonary anastomosis that preserved blood flow to both branch pulmonary arteries. In 5 animals, this was achieved with a novel, purpose-built, self-expanding device. RESULTS Real-time MRI needle access of target vessels (pulmonary artery), endograft delivery, and superior vena cava shunt to pulmonary arteries were successful in all animals. All survived the procedure without complications. Intraprocedural real-time MRI, post-procedural MRI, x-ray angiography, computed tomography, and necropsy showed patent shunts with bidirectional pulmonary artery blood flow. CONCLUSIONS MRI guidance enabled a complex, closed-chest, beating-heart, pediatric, transcatheter structural heart procedure. In this study, MRI guided trajectory planning and reproducible, reliable bidirectional cavopulmonary shunt creation. (C) 2016 by the American College of Cardiology Foundation. C1 [Ratnayaka, Kanishka; Rogers, Toby; Schenke, William H.; Mazal, Jonathan R.; Chen, Marcus Y.; Sonmez, Merdim; Hansen, Michael S.; Kocaturk, Ozgur; Faranesh, Anthony Z.; Lederman, Robert J.] NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA. [Ratnayaka, Kanishka] Childrens Natl Med Ctr, Div Cardiol, Washington, DC 20010 USA. RP Lederman, RJ (reprint author), NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bldg 10,Room 2c713,MSC 1538, Bethesda, MD 20892 USA. EM lederman@nih.gov RI Hansen, Michael/J-5391-2015; OI Hansen, Michael/0000-0002-8087-8731; Rogers, Toby/0000-0002-6043-3137 FU Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health [Z01-HL005062, Z01-HL006041] FX This work was supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health (grants Z01-HL005062 and Z01-HL006041 to Dr. Lederman). The National Institutes of Health and Children's National Medical Center have collaborative research and development agreements for interventional cardiovascular magnetic resonance imaging with Siemens Medical Systems. NUMED, Inc., supplied mounted covered CP Stents. Transmural Systems supplied purpose-built cavopulmonary anastomosis devices. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 16 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-8798 EI 1876-7605 J9 JACC-CARDIOVASC INTE JI JACC-Cardiovasc. Interv. PD MAY 9 PY 2016 VL 9 IS 9 BP 959 EP 970 DI 10.1016/j.jcin.2016.01.032 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DL4IC UT WOS:000375596600017 PM 27085581 ER PT J AU Zheng, SY Cherniack, AD Dewal, N Moffitt, RA Danilova, L Murray, BA Lerario, AM Else, T Knijnenburg, TA Ciriello, G Kim, S Assie, G Morozova, O Akbani, R Shih, J Hoadley, KA Choueiri, TK Waldmann, J Mete, O Robertson, AG Wu, HT Raphael, BJ Shao, LN Meyerson, M Demeure, MJ Beuschlein, F Gill, AJ Sidhu, SB Almeida, MQ Fragoso, MCBV Cope, LM Kebebew, E Habra, MA Whitsett, TG Bussey, KJ Rainey, WE Asa, SL Bertherat, J Fassnacht, M Wheeler, DA Hammer, GD Giordano, TJ Verhaak, RGW AF Zheng, Siyuan Cherniack, Andrew D. Dewal, Ninad Moffitt, Richard A. Danilova, Ludmila Murray, Bradley A. Lerario, Antonio M. Else, Tobias Knijnenburg, Theo A. Ciriello, Giovanni Kim, Seungchan Assie, Guillaume Morozova, Olena Akbani, Rehan Shih, Juliann Hoadley, Katherine A. Choueiri, Toni K. Waldmann, Jens Mete, Ozgur Robertson, A. Gordon Wu, Hsin-Ta Raphael, Benjamin J. Shao, Lina Meyerson, Matthew Demeure, Michael J. Beuschlein, Felix Gill, Anthony J. Sidhu, Stan B. Almeida, Madson Q. Fragoso, Maria C. B. V. Cope, Leslie M. Kebebew, Electron Habra, Mouhammed A. Whitsett, Timothy G. Bussey, Kimberly J. Rainey, William E. Asa, Sylvia L. Bertherat, Jerome Fassnacht, Martin Wheeler, David A. Hammer, Gary D. Giordano, Thomas J. Verhaak, Roel G. W. CA Canc Genome Atlas Res Network TI Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma SO CANCER CELL LA English DT Article ID COPY-NUMBER ALTERATION; PKA CATALYTIC SUBUNIT; SOMATIC MUTATIONS; HUMAN CANCER; TELOMERE LENGTH; ADRENAL-TUMORS; CARNEY COMPLEX; EXPRESSION; LANDSCAPE; GENES AB We describe a comprehensive genomic characterization of adrenocortical carcinoma (ACC). Using this dataset, we expand the catalogue of known ACC driver genes to include PRKAR1A, RPL22, TERF2, CCNE1, and NF1. Genome wide DNA copy-number analysis revealed frequent occurrence of massive DNA loss followed by whole-genome doubling (WGD), which was associated with aggressive clinical course, suggesting WGD is a hallmark of disease progression. Corroborating this hypothesis were increased TERT expression, decreased telomere length, and activation of cell-cycle programs. Integrated subtype analysis identified three ACC subtypes with distinct clinical outcome and molecular alterations which could be captured by a 68-CpG probe DNA-methylation signature, proposing a strategy for clinical stratification of patients based on molecular markers. C1 [Zheng, Siyuan; Akbani, Rehan; Habra, Mouhammed A.; Verhaak, Roel G. W.] Univ Texas MD Anderson Canc Ctr, Endocrine Neoplasia & Hormonal Disorders, Dept Genom Med, Houston, TX 77030 USA. [Zheng, Siyuan; Akbani, Rehan; Habra, Mouhammed A.; Verhaak, Roel G. W.] Univ Texas MD Anderson Canc Ctr, Endocrine Neoplasia & Hormonal Disorders, Dept Bioinformat, Houston, TX 77030 USA. [Zheng, Siyuan; Akbani, Rehan; Habra, Mouhammed A.; Verhaak, Roel G. W.] Univ Texas MD Anderson Canc Ctr, Endocrine Neoplasia & Hormonal Disorders, Dept Computat Biol, Houston, TX 77030 USA. [Cherniack, Andrew D.; Murray, Bradley A.; Shih, Juliann; Meyerson, Matthew] MIT, Eli & Edythe L Broad Inst, Cambridge, MA 02142 USA. [Cherniack, Andrew D.; Murray, Bradley A.; Shih, Juliann; Meyerson, Matthew] Harvard Univ, Cambridge, MA 02142 USA. [Cherniack, Andrew D.; Murray, Bradley A.; Shih, Juliann; Choueiri, Toni K.; Meyerson, Matthew] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Dewal, Ninad; Wheeler, David A.] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Moffitt, Richard A.; Hoadley, Katherine A.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Danilova, Ludmila; Cope, Leslie M.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21287 USA. [Lerario, Antonio M.; Almeida, Madson Q.; Fragoso, Maria C. B. V.] Univ Sao Paulo, Fac Med, Serv Endocrinol & Metabol,Hosp Clin, Unidade Suprarrenal,Lab Hormonios & Genet Mol LIM, BR-05403900 Sao Paulo, Brazil. [Lerario, Antonio M.; Else, Tobias; Shao, Lina; Rainey, William E.; Hammer, Gary D.; Giordano, Thomas J.] Univ Michigan, Dept Cell & Dev Biol, Ann Arbor, MI 48109 USA. [Lerario, Antonio M.; Else, Tobias; Shao, Lina; Rainey, William E.; Hammer, Gary D.; Giordano, Thomas J.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Lerario, Antonio M.; Else, Tobias; Shao, Lina; Rainey, William E.; Hammer, Gary D.; Giordano, Thomas J.] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA. [Lerario, Antonio M.; Else, Tobias; Shao, Lina; Rainey, William E.; Hammer, Gary D.; Giordano, Thomas J.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Lerario, Antonio M.; Else, Tobias; Rainey, William E.; Hammer, Gary D.; Giordano, Thomas J.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Knijnenburg, Theo A.] Inst Syst Biol, Seattle, WA 98109 USA. [Ciriello, Giovanni] Univ Lausanne, Dept Computat Biol, Rue Bugnon 27, CH-1005 Lausanne, Switzerland. [Ciriello, Giovanni] Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10065 USA. [Kim, Seungchan; Demeure, Michael J.; Whitsett, Timothy G.; Bussey, Kimberly J.] Translat Genom Res Inst, Phoenix, AZ 85004 USA. [Assie, Guillaume; Bertherat, Jerome] Inst Cochin, Inserm, U1016, CNRS UMR 8104, F-75014 Paris, France. [Assie, Guillaume; Bertherat, Jerome] Univ Paris 05, Sorbonne Paris Cite, Fac Med Paris Descartes, F-75006 Paris, France. [Assie, Guillaume; Bertherat, Jerome] Hop Cochin, AP HP, Dept Endocrinol, Referral Ctr Rare Adrenal Dis, F-75014 Paris, France. [Assie, Guillaume; Waldmann, Jens; Beuschlein, Felix; Bertherat, Jerome; Fassnacht, Martin] European Network Study Adrenal Tumors, F-75014 Paris, France. [Morozova, Olena] Univ Calif Santa Cruz, Genom Inst, Santa Cruz, CA 95064 USA. [Choueiri, Toni K.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Waldmann, Jens] Univ Hosp Giessen & Marburg, Dept Visceral Thorac & Vasc Surg, Endocrine Ctr, Gen Surg, Campus Marburg, D-34501 Marburg, Germany. [Mete, Ozgur; Asa, Sylvia L.] Univ Hlth Network, Dept Lab Med & Pathobiol, Toronto, ON M5G 2C4, Canada. [Robertson, A. Gordon] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4S6, Canada. [Wu, Hsin-Ta; Raphael, Benjamin J.] Brown Univ, Dept Comp Sci, Providence, RI 02906 USA. [Meyerson, Matthew] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02215 USA. Klinikum Univ Munchen, Endocrine Res Unit, Med Klin, D-80336 Munich, Germany. [Beuschlein, Felix] Klinikum Univ Munchen, Poliklin 4, D-80336 Munich, Germany. Univ Sydney, Canc Diag & Pathol Grp, Kolling Inst Med Res, Sydney, NSW 2006, Australia. [Gill, Anthony J.; Sidhu, Stan B.] Univ Sydney, Canc Genet Lab, Kolling Inst Med Res, Sydney, NSW 2006, Australia. [Gill, Anthony J.] Royal N Shore Hosp, Dept Anat Pathol, St Leonards, NSW 2065, Australia. [Sidhu, Stan B.] Royal N Shore Hosp, Endocrine Surg Unit, St Leonards, NSW 2065, Australia. [Almeida, Madson Q.; Fragoso, Maria C. B. V.] Univ Sao Paulo, Fac Med, ICESP, BR-05403900 Sao Paulo, Brazil. [Kebebew, Electron] NCI, Endocrine Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Bussey, Kimberly J.] Arizona State Univ, NantOm LLC, Biodesign Inst, Tempe, AZ 85287 USA. [Fassnacht, Martin] Univ Hosp Wurzburg, Endocrine & Diabet Unit, Dept Internal Med 1, D-97080 Wurzburg, Germany. [Fassnacht, Martin] Univ Wurzburg, Comprehens Canc Ctr Mainfranken, D-97080 Wurzburg, Germany. [Murray, Bradley A.] Intellia Therapeut, Cambridge, MA 02139 USA. [Demeure, Michael J.] Ash Analyt, Phoenix, AZ 85004 USA. RP Verhaak, RGW (reprint author), Univ Texas MD Anderson Canc Ctr, Endocrine Neoplasia & Hormonal Disorders, Dept Genom Med, Houston, TX 77030 USA.; Verhaak, RGW (reprint author), Univ Texas MD Anderson Canc Ctr, Endocrine Neoplasia & Hormonal Disorders, Dept Bioinformat, Houston, TX 77030 USA.; Verhaak, RGW (reprint author), Univ Texas MD Anderson Canc Ctr, Endocrine Neoplasia & Hormonal Disorders, Dept Computat Biol, Houston, TX 77030 USA.; Giordano, TJ (reprint author), Univ Michigan, Dept Cell & Dev Biol, Ann Arbor, MI 48109 USA.; Giordano, TJ (reprint author), Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA.; Giordano, TJ (reprint author), Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA.; Giordano, TJ (reprint author), Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA.; Giordano, TJ (reprint author), Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. EM giordano@med.umich.edu; rverhaak@mdanderson.org RI Fragoso, Maria Candida/I-4572-2013; Marra, Marco/B-5987-2008 FU United States NIH [5U24CA143799, 5U24CA143835, 5U24CA143840, 5U24CA143843, 5U24CA143845, 5U24CA143848, 5U24CA143858, 5U24CA143866, 5U24CA143867, 5U24CA143882, 5U24CA143883, 5U24CA144025, U54HG003067, U54HG003079, U54HG003273, P30CA16672]; Novartis; Bayer FX We are grateful to all the patients and families who contributed to this study, to Ina Felau, Margi Sheth, and Jiashan (Julia) Zhang for project management. Supported by the following grants from the United States NIH: 5U24CA143799, 5U24CA143835, 5U24CA143840, 5U24CA143843, 5U24CA143845, 5U24CA143848, 5U24CA143858, 5U24CA143866, 5U24CA143867, 5U24CA143882, 5U24CA143883, 5U24CA144025, U54HG003067, U54HG003079, and U54HG003273, P30CA16672. G.D.H. has equity interest in, is a consultant for, and scientific advisory board director of Millendo Therapeutics. R.B. is a consultant for and received grant funding from Novartis. J.S., B.A.M., A.D.C., and M.M. received grant support from Bayer. S.L.A. is a member of the Medical Advisory Board of Leica Aperio. D.J.W. is a consultant for Zymo Research Corporation. NR 58 TC 20 Z9 20 U1 4 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD MAY 9 PY 2016 VL 29 IS 5 BP 723 EP 736 DI 10.1016/j.ccell.2016.04.002 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL4AD UT WOS:000375573900013 PM 27165744 ER PT J AU Martin, A Berger, JM Sellers, JR Ostankovitch, M AF Martin, Andreas Berger, James M. Sellers, James R. Ostankovitch, Marina TI Mechanisms and Functional Diversity of Macromolecular Remodeling by ATP-Dependent Motors SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Editorial Material C1 [Martin, Andreas] Univ Calif Berkeley, Berkeley, CA 94720 USA. [Berger, James M.] Johns Hopkins Sch Med, Baltimore, MD 21205 USA. [Sellers, James R.] NHLBI, Bethesda, MD 20814 USA. [Ostankovitch, Marina] Journal Mol Biol, Cambridge, MA 02139 USA. RP Martin, A (reprint author), Univ Calif Berkeley, Berkeley, CA 94720 USA.; Berger, JM (reprint author), Johns Hopkins Sch Med, Baltimore, MD 21205 USA.; Sellers, JR (reprint author), NHLBI, Bethesda, MD 20814 USA.; Ostankovitch, M (reprint author), Journal Mol Biol, Cambridge, MA 02139 USA. EM a.martin@berkeley.edu; jberge29@jhmi.edu; sellersj@nhlbi.nih.gov; m.ostankovitch@elsevier.com NR 9 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 EI 1089-8638 J9 J MOL BIOL JI J. Mol. Biol. PD MAY 8 PY 2016 VL 428 IS 9 BP 1819 EP 1821 PN B PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DM9OH UT WOS:000376695100001 PM 27113061 ER PT J AU Heissler, SM Sellers, JR AF Heissler, Sarah M. Sellers, James R. TI Various Themes of Myosin Regulation SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Review ID SMOOTH-MUSCLE MYOSIN; HEAVY-CHAIN PHOSPHORYLATION; PROTEIN-KINASE-C; ACTIN-ACTIVATED ATPASE; CLASS-V MYOSIN; CLASS-I MYOSIN; RABBIT SKELETAL-MUSCLE; GLOBULAR TAIL DOMAIN; LIGHT-CHAIN; MOTOR-ACTIVITY AB Members of the myosin superfamily are actin-based molecular motors that are indispensable for cellular homeostasis. The vast functional and structural diversity of myosins accounts for the variety and complexity of the underlying allosteric regulatory mechanisms that determine the activation or inhibition of myosin motor activity and enable precise timing and spatial aspects of myosin function at the cellular level. This review focuses on the molecular basis of posttranslational regulation of eukaryotic myosins from different classes across species by allosteric intrinsic and extrinsic effectors. First, we highlight the impact of heavy and light chain phosphorylation. Second, we outline intramolecular regulatory mechanisms such as autoinhibition and subsequent activation. Third, we discuss diverse extramolecular allosteric mechanisms ranging from actin-linked regulatory mechanisms to myosin:cargo interactions. At last, we briefly outline the allosteric regulation of myosins with synthetic compounds. Published by Elsevier Ltd. C1 [Heissler, Sarah M.; Sellers, James R.] NHLBI, Lab Mol Physiol, NIH, 50 South Dr,B50-3529, Bethesda, MD 20892 USA. RP Heissler, SM (reprint author), NHLBI, Lab Mol Physiol, NIH, 50 South Dr,B50-3529, Bethesda, MD 20892 USA. EM sarah.heissler@nih.gov FU National Heart, Lung, and Blood Institute FX We apologize in advance to all authors whose work was not cited due to length considerations of the manuscript. This work was funded by the Intramural Program of the National Heart, Lung, and Blood Institute. NR 210 TC 5 Z9 5 U1 4 U2 7 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 EI 1089-8638 J9 J MOL BIOL JI J. Mol. Biol. PD MAY 8 PY 2016 VL 428 IS 9 BP 1927 EP 1946 DI 10.1016/j.jmb.2016.01.022 PN B PG 20 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DM9OH UT WOS:000376695100010 PM 26827725 ER PT J AU Abdel-Gadir, A Berber, R Porter, JB Quinn, PD Suri, D Kellman, P Hart, AJ Moon, JC Manisty, C Skinner, JA AF Abdel-Gadir, Amna Berber, Reshid Porter, John B. Quinn, Paul D. Suri, Deepak Kellman, Peter Hart, Alister J. Moon, James C. Manisty, Charlotte Skinner, John A. TI Detection of metallic cobalt and chromium liver deposition following failed hip replacement using T2*and R2 magnetic resonance SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE MRI; T2*; Metal-on-metal hip; Cobalt; Chromium; Metal loading ID IRON OVERLOAD; RESURFACING ARTHROPLASTY; DIAGNOSIS AB Background: Failed hip prostheses can cause elevated circulating cobalt and chromium levels, with rare reports of fatal systemic organ deposition, including cobalt cardiomyopathy. Although blood cobalt and chromium levels are easily measured, organ deposition is difficult to detect without invasive biopsy. The T2* magnetic resonance (MR) method is used to quantify tissue iron deposition, and plays an important role in the management of iron-loading conditions. Cobalt and chromium, like iron, also affect magnetism and are proposed MR contrast agents. Case Presentation: We describe a case of a 44-year-old male with a failed hip implant and very elevated blood cobalt and chromium levels. Despite normal cardiac MR findings, liver T2* and R2 values were abnormal, triggering tissue biopsy. Liver tissue analysis, including X-ray fluorescence, demonstrated heavy elemental cobalt and chromium deposition in macrophages, and no detectable iron. Conclusions: Our case demonstrates T2* and R2 quantification of liver metal deposition in a patient with a failed hip implant. Further work is needed to investigate the role of T2* and R2 MR in the detection of metal deposition from metal on metal hip prostheses. C1 [Abdel-Gadir, Amna; Moon, James C.; Manisty, Charlotte] UCL, Inst Cardiovasc Sci, London, England. [Abdel-Gadir, Amna; Moon, James C.; Manisty, Charlotte] St Bartholomews Hosp, Barts Heart Ctr, London, England. [Berber, Reshid; Hart, Alister J.; Skinner, John A.] Royal Natl Orthoped Hosp, Stanmore, Middx, England. [Porter, John B.] UCL, Dept Hematol, London, England. [Quinn, Paul D.] Diamond Light Source, Harwell Sci & Innovat Campus, Harwell, Berks, England. [Suri, Deepak] Whittington Hosp, Dept Gastroenterol, London N19 5NF, England. [Kellman, Peter] NHLBI, Med Signal & Image Proc Program, Bldg 10, Bethesda, MD 20892 USA. RP Manisty, C (reprint author), UCL, Inst Cardiovasc Sci, London, England.; Manisty, C (reprint author), St Bartholomews Hosp, Barts Heart Ctr, London, England. EM c.manisty@ucl.ac.uk RI Hart, Alister/I-2948-2014; OI Hart, Alister/0000-0003-1281-6886; Porter, John/0000-0003-3000-9359; moon, james/0000-0001-8071-1491 FU Rosetrees Trust; UK National Institute for Health Research Biomedical Research Centre funding scheme; Zimmer; Stryker; Smith Nephew; Biomet; Corin; JRI; Mathys; Depuy; Finsbury FX AAG is supported by the Rosetrees Trust. JM and CM are supported by the UK National Institute for Health Research Biomedical Research Centre funding scheme.; JS and AH receive institutional funding from 9 implant manufacturers (Zimmer, Stryker, Smith & Nephew, Biomet, Corin, JRI, Mathys, Depuy, Finsbury) for retrieval analysis and freedom to publish all results and consultancy contracts from Depuy ASR Retrieval Program and Stryker retrieval program for modular neck hips. The authors declare that they have no competing interests. NR 19 TC 0 Z9 0 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 EI 1532-429X J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD MAY 6 PY 2016 VL 18 AR 29 DI 10.1186/s12968-016-0248-z PG 5 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA DO0YB UT WOS:000377503900001 PM 27153940 ER PT J AU Lopez-Suarez, L Riesgo, L Bravo, F Ransom, TT Beutler, JA Echavarren, AM AF Lopez-Suarez, Laura Riesgo, Lorena Bravo, Fernando Ransom, Tanya T. Beutler, John A. Echavarren, Antonio M. TI Synthesis and Biological Evaluation of New (-)-Englerin Analogues SO CHEMMEDCHEM LA English DT Article DE enantioselective synthesis; englerin A; gold catalysis; natural products; renal cancer; tumor growth inhibition ID 4+3 CYCLOADDITION REACTION; CANCER CELL-GROWTH; FORMAL SYNTHESIS; RING-SYSTEM; ENGLERIN AB We report the synthesis and biological evaluation of a series of (-)-englerin A analogues obtained along our previously reported synthetic route based on a stereoselective gold(I) cycloaddition process. This synthetic route is a convenient platform to access analogues with broad structural diversity and has led us to the discovery of unprecedented and easier-to-synthesize derivatives with an unsaturation in the cyclopentyl ring between C4 and C5. We also introduce novel analogues in which the original isopropyl motif has been substituted with cyclohexyl, phenyl, and cyclopropyl moieties. The high selectivity and growth-inhibitory activity shown by these new derivatives in renal cancer cell lines opens new ways toward the final goal of finding effective drugs for the treatment of renal cell carcinoma (RCC). C1 [Lopez-Suarez, Laura; Riesgo, Lorena; Bravo, Fernando; Echavarren, Antonio M.] Inst Chem Res Catalonia ICIQ, Av Paisos Catalans 16, Tarragona 43007, Spain. [Echavarren, Antonio M.] Univ Rovira & Virgili, Dept Quim Analit & Quim Organ, C Marcel Li Domingo S-N, E-43007 Tarragona, Spain. [Ransom, Tanya T.; Beutler, John A.] NCI, Mol Targets Lab, Mol Discovery Program, Ctr Canc Res, Frederick, MD 21702 USA. [Riesgo, Lorena] ICTP CSIC, Inst Polymer Sci & Technol, Juan Cierva 3, Madrid 28006, Spain. RP Echavarren, AM (reprint author), Inst Chem Res Catalonia ICIQ, Av Paisos Catalans 16, Tarragona 43007, Spain.; Echavarren, AM (reprint author), Univ Rovira & Virgili, Dept Quim Analit & Quim Organ, C Marcel Li Domingo S-N, E-43007 Tarragona, Spain.; Beutler, JA (reprint author), NCI, Mol Targets Lab, Mol Discovery Program, Ctr Canc Res, Frederick, MD 21702 USA. EM beutlerj@mail.nih.gov; aechavarren@iciq.es RI Echavarren, Antonio /A-2116-2010 OI Echavarren, Antonio /0000-0001-6808-3007 FU MINECO Severo Ochoa Excellence Accreditation [SEV-2013-0319, CTQ2013-42106-P]; European Research Council [321066]; AGAUR [2014 SGR 818, 2010 VALOR 00015]; ICIQ Foundation; Intramural Research Program, National Cancer Institute [1 ZIA BC01147 003] FX We thank MINECO Severo Ochoa Excellence Accreditation 2014-2018 (SEV-2013-0319), project (CTQ2013-42106-P), the European Research Council (Advanced Grant No. 321066), the AGAUR (projects 2014 SGR 818 and 2010 VALOR 00015), and the ICIQ Foundation. We also thank Imma Escofet and the Chiraltech and Cromatography unit ICIQ for technical support. This research was supported in part with funds from the Intramural Research Program, National Cancer Institute (project 1 ZIA BC01147 003, to J.A.B. and T.T.R.). We thank the Developmental Therapeutics Program of NCI for NCI 60 testing, and E. Goncharova, J. Evans, and T. Bostaph for their implementation of the COMPARE algorithm. NR 48 TC 3 Z9 3 U1 5 U2 7 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1860-7179 EI 1860-7187 J9 CHEMMEDCHEM JI ChemMedChem PD MAY 6 PY 2016 VL 11 IS 9 BP 1003 EP 1007 DI 10.1002/cmdc.201600040 PG 5 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DL9EG UT WOS:000375943700007 PM 27005578 ER PT J AU Curtis, C Landis, GN Folk, D Wehr, NB Hoe, N Waskar, M Abdueva, D Skvortsov, D Ford, D Luu, A Badrinath, A Levine, RL Bradley, TJ Tavare, S Tower, J AF Curtis, Christina Landis, Gary N. Folk, Donna Wehr, Nancy B. Hoe, Nicholas Waskar, Morris Abdueva, Diana Skvortsov, Dmitriy Ford, Daniel Luu, Allan Badrinath, Ananth Levine, Rodney L. Bradley, Timothy J. Tavare, Simon Tower, John TI Transcriptional profiling of MnSOD-mediated lifespan extension in Drosophila reveals a species-general network of aging and metabolic genes (vol 8, R262, 2007) SO GENOME BIOLOGY LA English DT Correction C1 [Curtis, Christina; Landis, Gary N.; Hoe, Nicholas; Waskar, Morris; Abdueva, Diana; Skvortsov, Dmitriy; Ford, Daniel; Luu, Allan; Badrinath, Ananth; Tavare, Simon; Tower, John] Univ So Calif, Dept Biol Sci, Mol & Computat Biol Program, Los Angeles, CA 90089 USA. [Folk, Donna; Bradley, Timothy J.] Univ Calif Irvine, Dept Ecol & Evolutionary Biol, Irvine, CA 92717 USA. [Wehr, Nancy B.; Levine, Rodney L.] NHLBI, Biochem Lab, Bethesda, MD USA. [Abdueva, Diana] Univ So Calif, Childrens Hosp Los Angeles, Dept Pathol & Lab Med, Keck Sch Med, Los Angeles, CA 90089 USA. [Tavare, Simon] Univ Cambridge, Dept Oncol, Cambridge CB2 2XZ, England. RP Tower, J (reprint author), Univ So Calif, Dept Biol Sci, Mol & Computat Biol Program, Los Angeles, CA 90089 USA. EM jtower@usc.edu RI Levine, Rodney/D-9885-2011 NR 1 TC 0 Z9 0 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-6906 EI 1474-760X J9 GENOME BIOL JI Genome Biol. PD MAY 6 PY 2016 VL 17 AR 93 DI 10.1186/s13059-016-0959-3 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DL9KY UT WOS:000375962700003 ER PT J AU Akan, I Love, DC Harwood, KR Bond, MR Hanover, JA AF Akan, Ilhan Love, Dona C. Harwood, Katryn R. Bond, Michelle R. Hanover, John A. TI Drosophila O-GlcNAcase Deletion Globally Perturbs Chromatin O-GlcNAcylation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BETA-N-ACETYLGLUCOSAMINE; GROUP PROTEINS; TRANSCRIPTION FACTORS; INSULIN-RESISTANCE; TRANSFERASE OGT; GENE ENCODES; POLYCOMB; GLYCOSYLATION; REPRESSION; PHOSPHORYLATION AB Gene expression during Drosophila development is subject to regulation by the Polycomb (Pc), Trithorax (Trx), and Compass chromatin modifier complexes. O-GlcNAc transferase (OGT/SXC) is essential for Pc repression suggesting that the O-GlcNAcylation of proteins plays a key role in regulating development. OGT transfers O-GlcNAc onto serine and threonine residues in intrinsically disordered domains of key transcriptional regulators; O-GlcNAcase (OGA) removes the modification. To pinpoint genomic regions that are regulated by O-GlcNAc levels, we performed ChIP-chip and microarray analysis after OGT or OGA RNAi knockdown in S2 cells. After OGA RNAi, we observed a genome-wide increase in the intensity of most O-GlcNAc-occupied regions including genes linked to cell cycle, ubiquitin, and steroid response. In contrast, O-GlcNAc levels were strikingly insensitive to OGA RNAi at sites of polycomb repression such as the Hox and NK homeobox gene clusters. Microarray analysis suggested that altered O-GlcNAc cycling perturbed the expression of genes associated with morphogenesis and cell cycle regulation. We then produced a viable null allele of oga (oga(del.1)) in Drosophila allowing visualization of altered O-GlcNAc cycling on polytene chromosomes. We found that trithorax (TRX), absent small or homeotic discs 1 (ASH1), and Compass member SET1 histone methyltransferases were O-GlcNAc-modified in oga(del.1) mutants. The oga(del.1) mutants displayed altered expression of a distinct set of cell cycle-related genes. Our results show that the loss of OGA in Drosophila globally impacts the epigenetic machinery allowing O-GlcNAc accumulation on RNA polymerase II and numerous chromatin factors including TRX, ASH1, and SET1. C1 [Akan, Ilhan; Harwood, Katryn R.; Bond, Michelle R.; Hanover, John A.] NIDDK, Bethesda, MD 20892 USA. [Love, Dona C.] NCI, NIH, Bethesda, MD 20892 USA. RP Hanover, JA (reprint author), NIDDK, LCBB, NIH, 8 Ctr Dr, Bethesda, MD 20892 USA. EM jah@helix.nih.gov FU NIDDK, National Institutes of Health Intramural Grant FX This work was supported, in whole or in part, by an NIDDK, National Institutes of Health Intramural Grant. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors declare that they have no conflicts of interest with the contents of this article NR 56 TC 2 Z9 2 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 6 PY 2016 VL 291 IS 19 BP 9906 EP + DI 10.1074/jbc.M115.704783 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DL4KB UT WOS:000375602800005 PM 26957542 ER PT J AU Ruszkowski, M Dauter, Z AF Ruszkowski, Milosz Dauter, Zbigniew TI Structural Studies of Medicago truncatula Histidinol Phosphate Phosphatase from Inositol Monophosphatase Superfamily Reveal Details of Penultimate Step of Histidine Biosynthesis in Plants SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SITE-DIRECTED MUTAGENESIS; AMINO-ACID USAGE; MYOINOSITOL MONOPHOSPHATASE; ARABIDOPSIS-THALIANA; PUTATIVE TARGET; LITHIUM-THERAPY; NICOTIANA-TABACUM; MOLECULAR-CLONING; BACILLUS-SUBTILIS; ESCHERICHIA-COLI AB The penultimate enzyme in the histidine biosynthetic pathway catalyzes dephosphorylation of L-histidinol 1-phosphate (HOLP) into L-histidinol. The recently discovered in Arabidopsis thaliana plant-type histidinol phosphate phosphatase (HPP) shares no homology with the two other HPP superfamilies known previously in prokaryotes and resembles myo-inositol monophosphatases (IMPases). In this work, identification of an HPP enzyme from a model legume, Medicago truncatula (MtHPP) was based on the highest sequence identity to A. thaliana enzyme. Biochemical assays confirmed that MtHPP was able to cleave inorganic phosphate from HOLP but not from D-myo-inositol-1-phosphate, the main substrate of IMPases. Dimers of MtHPP, determined by size exclusion chromatography, in the presence of CO2 or formaldehyde form mutual, methylene-bridged cross-links between Lys(158) and Cys(245) residues. Four high resolution crystal structures, namely complexes with HOLP (substrate), L-histidinol (product), and PO43- (by-product) as well as the structure showing the cross-linking between two MtHPP molecules, provide detailed structural information on the enzyme. Based on the crystal structures, the enzymatic reaction mechanism of IMPases is accustomed to fit the data for MtHPP. The enzymatic reaction, which requires Mg2+ cations, is catalyzed mainly by amino acid residues from the N-terminal domain. The C-terminal domain, sharing little identity with IMPases, is responsible for the substrate specificity (i.e. allows the enzyme to distinguish between HOLP and D-myo-inositol-1-phosphate). Structural features, mainly the presence of a conserved Asp(246), allow MtHPP to bind HOLP specifically. C1 [Ruszkowski, Milosz; Dauter, Zbigniew] NCI, Synchrotron Radiat Res Sect, MCL, NIH, Argonne, IL 60439 USA. RP Ruszkowski, M (reprint author), NCI, Synchrotron Radiat Res Sect, MCL, S Cass Ave 9700,Bldg 202,Rm Q-141, Argonne, IL 60439 USA. EM mruszkowski@anl.gov FU United States Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; United States Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357] FX We gratefully acknowledge Dr. Joanna Banasiak for assistance with identification of the MTHPP gene. We are also thankful to Dr. Jerry Alexandratos, who performed LC-MS studies at the Biophysics Resource in the Structural Biophysics Laboratory, National Cancer Institute at Frederick. Diffraction data were collected at the (i) SER-CAT beamline 22-ID at the Advanced Photon Source, Argonne National Laboratory, supported by the United States Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract W-31-109-Eng-38 and (ii) Structural Biology Center at the Advanced Photon Source, operated by UChicago Argonne, LLC, for the United States Department of Energy, Office of Biological and Environmental Research under Contract DE-AC02-06CH11357. NR 85 TC 2 Z9 2 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 6 PY 2016 VL 291 IS 19 BP 9960 EP + DI 10.1074/jbc.M115.708727 PG 22 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DL4KB UT WOS:000375602800011 PM 26994138 ER PT J AU Caropreso, V Darvishi, E Turbyville, TJ Ratnayake, R Grohar, PJ McMahon, JB Woldemichael, GM AF Caropreso, Vittorio Darvishi, Emad Turbyville, Thomas J. Ratnayake, Ranjala Grohar, Patrick J. McMahon, James B. Woldemichael, Girma M. TI Englerin A Inhibits EWS-FLI1 DNA Binding in Ewing Sarcoma Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CHILDRENS ONCOLOGY GROUP; PROTEIN-KINASE-C; TRANSCRIPTION FACTOR; GENE-EXPRESSION; FUSION PROTEINS; GROWTH-FACTOR; TARGET GENE; IQ DOMAIN; CALCIUM; CANCER AB High-throughput screening of extracts from plants, marine, and micro-organisms led to the identification of the extract from the plant Phyttanthus engieri as the most potent inhibitor of EWS-FI.I1 induced luciferase reporter expression. Testing of compounds isolated from this extract in turn led to the identification of Englerin A (EA) as the active constituent of the extract. EA induced both necrosis and apoptosis in Ewing cells subsequent to a G2M accumulation of cells in the cell cycle. It also impacted clonogenic survival and anchorage-independent proliferation while also decreasing the proportion of chemotherapy-resistant cells identified by high ALDH activity. EA also caused a sustained increase in cytosolic calcium levels. EA appears to exert its effect on Ewing cells through a decrease in phosphorylation of EWS-FLI1 and its ability to bind DNA. This effect is mediated, at least in part, through a decrease in the levels of the calcium-dependent protein kinase PKC-13I after a transient up-regulation. C1 [Caropreso, Vittorio; Darvishi, Emad; Ratnayake, Ranjala; McMahon, James B.] NCI, Mol Targets Lab, NIH, Frederick, MD 21702 USA. [Turbyville, Thomas J.] Leidos Biomed Res Inc, Opt Microscopy & Anal Lab, Frederick, MD 21702 USA. [Woldemichael, Girma M.] Leidos Biomed Res Inc, Basic Sci Program, Mol Targets Lab, Frederick Natl Lab, Frederick, MD 21702 USA. [Grohar, Patrick J.] Van Andel Inst, Ctr Canc & Cell Biol, Grand Rapids, MI 49503 USA. [Grohar, Patrick J.] Helen DeVos Childrens Hosp, Div Hematol Oncol, Grand Rapids, MI 49503 USA. RP Woldemichael, GM (reprint author), Frederick Natl Lab, Mol Targets Lab, Bldg 538,Rm 131,1050 Boyles St, Frederick, MD 21702 USA. EM woldemichaelg@mail.nih.gov FU National Institutes of Health, Frederick National Lab, Center for Cancer Research; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E] FX This research was supported in part by the Intramural Research Program of National Institutes of Health, Frederick National Lab, Center for Cancer Research. It has also been funded in part with federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Dept. of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. The authors declare that they have no conflicts of interest with the contents of this article. NR 46 TC 4 Z9 4 U1 2 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 6 PY 2016 VL 291 IS 19 BP 10058 EP 10066 DI 10.1074/jbc.M115.701375 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DL4KB UT WOS:000375602800018 PM 26961871 ER PT J AU Leroy, C Belkina, NV Long, T Deruy, E Dissous, C Shaw, S Tulasne, D AF Leroy, Catherine Belkina, Natalya V. Long, Thavy Deruy, Emeric Dissous, Colette Shaw, Stephen Tulasne, David TI Caspase Cleavages of the Lymphocyte-oriented Kinase Prevent Ezrin, Radixin, and Moesin Phosphorylation during Apoptosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID STE20-RELATED KINASE; PROTEIN-KINASE; ROCK-I; ACTIVATION; FAMILY; STK10; CELLS; LOK; SLK; POLARIZATION AB The lymphocyte-oriented kinase (LOK), also called serine threonine kinase 10 (SiK10), is synthesized mainly in lymphocytes. It is involved in lymphocyte migration and polarization and can phosphorylate ezrin, radixin, and moesin (the ERM proteins). In a T lymphocyte cell line and in purified human lymphocytes, we found LOK to be cleaved by caspases during apoptosis. The first cleavage occurs at aspartic residue 332, located between the kinase domain and the coiled-coil regulation domain. This cleavage generates an N-terminal fragment, p50 N-LOK, containing the kinase domain and a C-terminal fragment, which is further cleaved during apoptosis. Although these cleavages preserve the entire kinase domain, p50 N-LOK displays no kinase activity. In apoptotic lymphocytes, caspase cleavages of LOK are concomitant with a decrease in ERN phosphorylation. When non-apoptotic lymphocytes from mice with homozygous and heterozygous LOK knockout were compared, the latter showed a higher level of ERM phosphorylation, but when apoptosis was induced, LOK-/- and LOK+/- lymphocytes showed the same low level, confirming in vivo that LOK-induced ERM phosphorylation is prevented during lymphocyte apoptosis. Our results demonstrate that cleavage of LOK during apoptosis abolishes its kinase activity, causing a decrease in ERM phosphorylation, crucial to the role of the ERM proteins in linking the plasma membrane to actin filaments. C1 [Leroy, Catherine; Tulasne, David] Univ Lille, CNRS, Inst Pasteur Lille, UMR 8161,Mech Tumorigenesis & Target Therapies, 1 Rue Pr Calmette, F-59000 Lille, France. [Belkina, Natalya V.] NCI, Thorac & Gastrointestinal Oncol, NIH, Bethesda, MD 20892 USA. [Shaw, Stephen] NCI, Expt Immunol Branch Branches, NIH, Bethesda, MD 20892 USA. [Long, Thavy; Deruy, Emeric; Dissous, Colette] Univ Lille, Ctr Hosp Reg, Inst Pasteur Lille, CNRS,INSERM,U1019 UMR 8204,Ctr Infect & Immun Lil, F-59000 Lille, France. RP Tulasne, D (reprint author), Univ Lille, CNRS, Inst Pasteur Lille, UMR 8161,Mech Tumorigenesis & Target Therapies, 1 Rue Pr Calmette, F-59000 Lille, France. FU CNRS; Institut Pasteur de Lille; INSERM; Ligue contre le Cancer, Comite Nord; Association pour la Recherche sur le Cancer; Institut National du Cancer; Canceropole Nord-Ouest; Site de Recherche Integree sur le Cancer SIRIC ONCOLiIIe FX This work was supported by the CNRS, the Institut Pasteur de Lille, and INSERM, and by grants from the Ligue contre le Cancer, Comite Nord, the Association pour la Recherche sur le Cancer, the Institut National du Cancer, the Canceropole Nord-Ouest, and the Site de Recherche Integree sur le Cancer SIRIC ONCOLiIIe. The authors declare that they have no conflicts of interest with the contents of this article. NR 28 TC 1 Z9 1 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 6 PY 2016 VL 291 IS 19 BP 10148 EP 10161 DI 10.1074/jbc.M116.721365 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DL4KB UT WOS:000375602800025 PM 26945071 ER PT J AU Siqueira, CC Valiengo, LL Carvalho, AF Santos-Silva, PR Missio, G de Sousa, RT Di Natale, G Gattaz, WF Moreno, RA Machado-Vieira, R AF Siqueira, Cristiana Carvalho Valiengo, Leandro L. Carvalho, Andre F. Santos-Silva, Paulo Roberto Missio, Giovani de Sousa, Rafael T. Di Natale, Georgia Gattaz, Wagner F. Moreno, Ricardo Alberto Machado-Vieira, Rodrigo TI Antidepressant Efficacy of Adjunctive Aerobic Activity and Associated Biomarkers in Major Depression: A 4-Week, Randomized, Single-Blind, Controlled Clinical Trial SO PLOS ONE LA English DT Article ID PHYSICAL-EXERCISE; DISORDERS; SYMPTOMS; FITNESS; MEN AB Background Major depressive disorder (MDD) is a highly prevalent, heterogeneous and systemic medical condition. Treatment options are limited, and recent studies have suggested that physical exercise can play an important role in the therapeutics of MDD. The aim of this study was to evaluate the antidepressant efficacy of adjunctive aerobic activity in association with pharmacotherapy (selective serotonin reuptake inhibitor) in symptomatic MDD as well as its association with physiological biomarkers. Methods In this randomized, single-blind, add-on, controlled clinical trial, 57 patients (18-55 years of age) were followed-up for 28 days. All patients were drug-free, had been diagnosed with symptomatic MDD and received flexible dose of sertraline during the trial. Patients were randomized to either a 4-week program (4x/week) of add-on aerobic exercise (exercise group, N = 29) or no activity (control group, N = 28). Depression severity was assessed using the Hamilton Rating Scale for Depression (HAM-D) as the primary outcome. At baseline and endpoint, all patients underwent a comprehensive metabolic/cardiopulmonary exercise testing-including determination of maximal oxygen uptake (VO(2)max), VO2 at the second ventilatory threshold (VO2-VT2), and oxygen pulse (O-2 pulse). Results Depression scores significantly decreased in both groups after intervention. Importantly, patients in the aerobic exercise group required lower sertraline dose compared to the control group (sertraline monotherapy). The VO(2)max and O-2 pulse parameters increased over time only in the exercise group and remained unchanged in the control group. Conclusions The present findings suggest that a 4-week training of aerobic exercise significantly improves functional capacity in patients with MDD and may be associated with antidepressant efficacy. This approach may also decrease the need for higher doses of antidepressants to achieve response. Further studies in unmedicated and treatment-resistant MDD patients are needed in order to confirm the utility of short-term aerobic exercise as an alternative therapeutic approach in MDD. C1 [Siqueira, Cristiana Carvalho; Valiengo, Leandro L.; de Sousa, Rafael T.; Di Natale, Georgia; Gattaz, Wagner F.; Machado-Vieira, Rodrigo] Univ Sao Paulo, Inst & Dept Psychiat, Lab Neurosci LIM 27, Sao Paulo, SP, Brazil. [de Sousa, Rafael T.; Machado-Vieira, Rodrigo] NIMH, Expt Therapeut & Pathophysiol Branch, Bethesda, MD 20892 USA. [Santos-Silva, Paulo Roberto] Univ Sao Paulo, Sch Med, Hosp Clin, Lab Movement Studies, Sao Paulo, SP, Brazil. [Gattaz, Wagner F.; Machado-Vieira, Rodrigo] Univ Sao Paulo, Ctr Interdisciplinary Res Appl Neurosci NAPNA, Sao Paulo, SP, Brazil. [Missio, Giovani; Moreno, Ricardo Alberto] Univ Sao Paulo, Inst & Dept Psychiat, Mood Disorders Unit GRUDA, Sao Paulo, SP, Brazil. [Carvalho, Andre F.] Univ Fed Ceara, Fac Med, Dept Clin Med, Fortaleza, Ceara, Brazil. [Carvalho, Andre F.] Univ Fed Ceara, Fac Med, Translat Psychiat Res Grp, Fortaleza, Ceara, Brazil. RP Machado-Vieira, R (reprint author), Univ Sao Paulo, Inst & Dept Psychiat, Lab Neurosci LIM 27, Sao Paulo, SP, Brazil.; Machado-Vieira, R (reprint author), NIMH, Expt Therapeut & Pathophysiol Branch, Bethesda, MD 20892 USA.; Machado-Vieira, R (reprint author), Univ Sao Paulo, Ctr Interdisciplinary Res Appl Neurosci NAPNA, Sao Paulo, SP, Brazil. EM machadovieirar@gmail.com RI MACHADO-VIEIRA, RODRIGO/D-8293-2012; OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190; Gattaz, Wagner/0000-0001-5215-4077 FU Sao Paulo Research Foundation (FAPESP) [2012/20002-5] FX Support for this work was provided by grant 2012/20002-5, Sao Paulo Research Foundation (FAPESP). The grant was used to create the Physical Training Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 1 Z9 1 U1 3 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 6 PY 2016 VL 11 IS 5 AR e0154195 DI 10.1371/journal.pone.0154195 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DL5KX UT WOS:000375677000012 PM 27152523 ER PT J AU Chander, BS Witkowski, M Braun, C Robinson, SE Born, J Cohen, LG Birbaumer, N Soekadar, SR AF Chander, Bankim S. Witkowski, Matthias Braun, Christoph Robinson, Stephen E. Born, Jan Cohen, Leonardo G. Birbaumer, Niels Soekadar, Surjo R. TI tACS Phase Locking of Frontal Midline Theta Oscillations Disrupts Working Memory Performance SO FRONTIERS IN CELLULAR NEUROSCIENCE LA English DT Article DE frontal midline theta (FMT); entrainment; transcranial alternating current stimulation (tACS); magnetoencephalography (MEG); working memory performance ID CURRENT STIMULATION; BRAIN OSCILLATIONS; NETWORK ACTIVITY; CINGULATE CORTEX; TASK; RETRIEVAL; RESONANCE; DISEASE; TOOLS; MODEL AB Background: Frontal midline theta (FMT) oscillations (4-8 Hz) are strongly related to cognitive and executive control during mental tasks such as memory processing, arithmetic problem solving or sustained attention. While maintenance of temporal order information during a working memory (WM) task was recently linked to FMT phase, a positive correlation between FMT power, WM demand and WM performance was shown. However, the relationship between these measures is not well understood, and it is unknown whether purposeful FMT phase manipulation during a WM task impacts FMT power and WM performance. Here we present evidence that FMT phase manipulation mediated by transcranial alternating current stimulation (tACS) can block WM demand-related FMT power increase (FMT Delta power) and disrupt normal WM performance. Methods: Twenty healthy volunteers were assigned to one of two groups (group A, group B) and performed a 2-back task across a baseline block (block 1) and an intervention block (block 2) while 275-sensor magnetoencephalography (MEG) was recorded. After no stimulation was applied during block 1, participants in group A received tACS oscillating at their individual FMT frequency over the prefrontal cortex (PFC) while group B received sham stimulation during block 2. After assessing and mapping phase locking values (PLV) between the tACS signal and brain oscillatory activity across the whole brain, FMT power and WM performance were assessed and compared between blocks and groups. Results: During block 2 of group A but not B, FMT oscillations showed increased PLV across task-related cortical areas underneath the frontal tACS electrode. While WM task-related FMT Delta power and WM performance were comparable across groups in block 1, tACS resulted in lower FMT Delta power and WM performance compared to sham stimulation in block 2. Conclusion: tACS-related manipulation of FMT phase can disrupt WM performance and influence WM task-related FMT Delta power. This finding may have important implications for the treatment of brain disorders such as depression and attention deficit disorder associated with abnormal regulation of FMT activity or disorders characterized by dysfunctional coupling of brain activity, e.g., epilepsy, Alzheimer's or Parkinson's disease (AD/PD). C1 [Chander, Bankim S.; Witkowski, Matthias; Soekadar, Surjo R.] Univ Tubingen Hosp, Dept Psychiat & Psychotherapy, Appl Neurotechnol Lab, Tubingen, Germany. [Braun, Christoph; Soekadar, Surjo R.] Univ Tubingen Hosp, MEG Ctr, Tubingen, Germany. [Braun, Christoph] Univ Trento, CIMeC, Ctr Mind Brain Sci, Trento, Italy. [Robinson, Stephen E.] NIMH, MEG Core Facil, Bethesda, MD 20892 USA. [Born, Jan; Birbaumer, Niels] Univ Tubingen, Inst Med Psychol & Behav Neurobiol, Tubingen, Germany. [Cohen, Leonardo G.] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Soekadar, SR (reprint author), Univ Tubingen Hosp, Dept Psychiat & Psychotherapy, Appl Neurotechnol Lab, Tubingen, Germany.; Soekadar, SR (reprint author), Univ Tubingen Hosp, MEG Ctr, Tubingen, Germany. EM surjo.soekadar@uni-tuebingen.de RI Braun, Christoph/J-4160-2014; Born, Jan/K-2596-2016; OI Braun, Christoph/0000-0002-7836-4010; Born, Jan/0000-0002-1847-6248 FU Deutsche Forschungsgemeinschaft (DFG) [SO932-2]; University of Tiibingen's fortune program; German Federal Ministry of Research and Education (BMBF) [01GQ0831, 16SV5838K]; European Commission [645322]; Open Access Publishing Fund of the University of Tubingen FX We thank Birgit Teufel for her assistance in organizing the experiments and preparing the manuscript. This study was funded by the Deutsche Forschungsgemeinschaft (DFG, SO932-2) and the University of Tiibingen's fortune program, as well as the German Federal Ministry of Research and Education (BMBF, 01GQ0831 and 16SV5838K) and European Commission under the project AIDE (645322), and supported by the Open Access Publishing Fund of the University of Tubingen. NR 47 TC 1 Z9 1 U1 11 U2 20 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5102 J9 FRONT CELL NEUROSCI JI Front. Cell. Neurosci. PD MAY 6 PY 2016 VL 10 AR 120 DI 10.3389/fncel.2016.00120 PG 10 WC Neurosciences SC Neurosciences & Neurology GA DL1HG UT WOS:000375382600001 PM 27199669 ER PT J AU Ewen, JB Lakshmanan, BM Pillai, AS McAuliffe, D Nettles, C Hallett, M Crone, NE Mostofsky, SH AF Ewen, Joshua B. Lakshmanan, Balaji M. Pillai, Ajay S. McAuliffe, Danielle Nettles, Carrie Hallett, Mark Crone, Nathan E. Mostofsky, Stewart H. TI Decreased Modulation of EEG Oscillations in High-Functioning Autism during a Motor Control Task SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE dyspraxia; motor planning; event-related desynchronization; autism; praxis ID PRAXIS HAND MOVEMENTS; SPECTRUM DISORDERS; PREMOTOR AREAS; ALPHA-BAND; CHILDREN; DYSPRAXIA; CONNECTIVITY; SUPPRESSION; ACTIVATION; SYNCHRONY AB Autism spectrum disorders (ASD) are thought to result in part from altered cortical excitatory-inhibitory balance; this pathophysiology may impact the generation of oscillations on electroencephalogram (EEG). We investigated premotor-parietal cortical physiology associated with praxis, which has strong theoretical and empirical associations with ASD symptomatology. Twenty five children with high-functioning ASD (HFA) and 33 controls performed a praxis task involving the pantomiming of tool use, while EEG was recorded. We assessed task-related modulation of signal power in alpha and beta frequency bands. Compared with controls, subjects with HFA showed 27% less left central (motor/premotor) beta (18-22 Hz) event-related desynchronization (ERD; p = 0.030), as well as 24% less left parietal alpha (7-13 Hz) ERD (p = 0.046). Within the HFA group, blunting of central ERD attenuation was associated with impairments in clinical measures of praxis imitation (r = 0.4; p = 0.04) and increased autism severity (r = 0.48; p = 0.016). The modulation of central beta activity is associated, among other things, with motor imagery, which may be necessary for imitation. Impaired imitation has been associated with core features of ASD. Altered modulation of oscillatory activity may be mechanistically involved in those aspects of motor network function that relate to the core symptoms of ASD. C1 [Ewen, Joshua B.; Lakshmanan, Balaji M.; Pillai, Ajay S.; McAuliffe, Danielle] Kennedy Krieger Inst, Dept Neurol & Dev Med, Baltimore, MD USA. [Ewen, Joshua B.; Pillai, Ajay S.; Crone, Nathan E.; Mostofsky, Stewart H.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Ewen, Joshua B.] Johns Hopkins Univ, Dept Psychol & Brain Sci, Baltimore, MD USA. [Pillai, Ajay S.; Hallett, Mark] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Nettles, Carrie; Mostofsky, Stewart H.] Kennedy Krieger Inst, Ctr Neurodev & Imaging Res, Baltimore, MD USA. [Mostofsky, Stewart H.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. RP Ewen, JB (reprint author), Kennedy Krieger Inst, Dept Neurol & Dev Med, Baltimore, MD USA.; Ewen, JB (reprint author), Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA.; Ewen, JB (reprint author), Johns Hopkins Univ, Dept Psychol & Brain Sci, Baltimore, MD USA. EM ewen@kennedykrieger.org FU National Institute of Neurological Disorders and Stroke/National Institutes of Health [K23NS073626, R01NS048527]; Autism Speaks FX This work was funded by the National Institute of Neurological Disorders and Stroke/National Institutes of Health (Intramural Program-MH; K23NS073626 to JBE; and R01NS048527 to SHM) and Autism Speaks (to SEIM). NR 69 TC 1 Z9 1 U1 8 U2 12 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD MAY 6 PY 2016 VL 10 AR 198 DI 10.3389/fnhum.2016.00198 PG 11 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA DL1FI UT WOS:000375377400002 PM 27199719 ER PT J AU Makarova, KS Koonin, EV Albers, SV AF Makarova, Kira S. Koonin, Eugene V. Albers, Sonja-Verena TI Diversity and Evolution of Type IV pili Systems in Archaea SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE type IV pili; archaea; evolution; comparative genomics; secretion ATPase ID PSEUDOMONAS-AERUGINOSA; SIGNAL PEPTIDES; METHANOCOCCUS-MARIPALUDIS; SULFOLOBUS-ACIDOCALDARIUS; SURFACE-STRUCTURES; SECRETION SYSTEMS; BIOFILM FORMATION; CELL-ENVELOPE; II SECRETION; PROTEIN AB Many surface structures in archaea including various types of pili and the archaellum (archaeal flagellum) are homologous to bacterial type IV pili systems (T4P). The T4P consist of multiple proteins, often with poorly conserved sequences, complicating their identification in sequenced genomes. Here we report a comprehensive census of T4P encoded in archaeal genomes using sensitive methods for protein sequence comparison. This analysis confidently identifies as T4P components about 5000 archaeal gene products, 56% of which are currently annotated as hypothetical in public databases. Combining results of this analysis with a comprehensive comparison of genomic neighborhoods of the T4P, we present models of organization of 10 most abundant variants of archaeal T4P. In addition to the differentiation between major and minor pilins, these models include extra components, such as Slayer proteins, adhesins and other membrane and intracellular proteins. For most of these systems, dedicated major pilin families are identified including numerous stand alone major pilin genes of the PilA family. Evidence is presented that secretion ATPases of the T4P and cognate TadC proteins can interact with different pilin sets. Modular evolution of T4P results in combinatorial variability of these systems. Potential regulatory or modulating proteins for the T4P are identified including KaiC family ATPases, vWA domain-containing proteins and the associated MoxR/GvpN ATPase, TFIIB homologs and multiple unrelated transcription regulators some of which are associated specific T4P. Phylogenomic analysis suggests that at least one T4P system was present in the last common ancestor of the extant archaea. Multiple cases of horizontal transfer and lineage-specific duplication of T4P loci were detected. Generally, the T4P of the archaeal TACK superphylum are more diverse and evolve notably faster than those of euryarchaea. The abundance and enormous diversity of T4P in hyperthermophilic archaea present a major enigma. Apparently, fundamental aspects of the biology of hyperthermophiles remain to be elucidated. C1 [Makarova, Kira S.; Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Albers, Sonja-Verena] Univ Freiburg, Inst Biol 2, Mol Biol Archaea, Schanzlestr 1, Freiburg, Germany. RP Makarova, KS (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM makarova@ncbi.nlm.nih.gov FU US Department of Health and Human Services; ERC starting grant (ARCHAELLUM) [311523] FX EK and KM are supported by intramural funds of the US Department of Health and Human Services (to the National Library of Medicine). S-VA was supported by an ERC starting grant (ARCHAELLUM, 311523). NR 63 TC 3 Z9 3 U1 5 U2 11 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-302X J9 FRONT MICROBIOL JI Front. Microbiol. PD MAY 6 PY 2016 VL 7 AR 667 DI 10.3389/fmicb.2016.00667 PG 16 WC Microbiology SC Microbiology GA DL1OD UT WOS:000375400700001 PM 27199977 ER PT J AU Choi, CH Chung, JY Kim, JH Kim, BG Hewitt, SM AF Choi, Chel Hun Chung, Joon-Yong Kim, Jae-Hoon Kim, Byoung-Gie Hewitt, Stephen M. TI Expression of fibroblast growth factor receptor family members is associated with prognosis in early stage cervical cancer patients SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE Fibroblast growth factor receptor; Image analysis; Immunohistochemistry; Prognosis; Survival analysis; Uterine cervical neoplasm ID SQUAMOUS-CELL CARCINOMAS; FREQUENT FGFR3 MUTATIONS; BLADDER-TUMORS; ACTIVATING MUTATIONS; PHOSPHO-MTOR; BREAST; GENES; HEAD; HPV; PROLIFERATION AB Background: The oncogenic role of the fibroblast growth factor receptor (FGFR) has been recognized in a number of different cancer types. However, the prognostic significance of FGFRs has not been elucidated yet in cervical cancer. In the present study, we investigate the expression of FGFRs and their prognostic value in cervical cancer patients. Methods: FGFR1, FGFR2, FGFR3, and FGFR4 expression was determined by immunohistochemistry in conjunction with quantitative digital image analysis of 336 formalin-fixed, paraffin-embedded cervical cancer tissues and 61 normal cervical tissues, as well as NCI60 cell microarray. Subsequently, the association between clinicopathological characteristics and patient survival was assessed. Results: FGFRs proteins were differentially expressed in the NCI60 cell line panel and showed considerable correlation between protein and mRNA expression. The expression of FGFR1, FGFR2, and FGFR4 were higher in cancer tissues than in normal tissues, whereas the expression of FGFR3 was higher in normal tissues. FGFR1 was highly expressed in adeno-/adenosquamous carcinoma (P = 0.020), while FGFR2, FGFR3, and FGFR4 expression were more prominent in squamous cell carcinoma (P < 0.001, P < 0.001, and P = 0.020, respectively). FGFR2 expression was significantly higher in small sized tumors (P = 0.020). Additionally, high FGFR2 and FGFR4 were correlated with negative lymph node metastasis (P = 0.048 and P = 0.040, respectively). FGFR1, FGFR2, and FGFR3 were highly expressed in tumors without parametrial involvement (P = 0.030, P = 0.005, and P = 0.010, respectively). In survival analysis, high expressions of FGFR2, FGFR3, and FGFR4 was associated with longer disease-free survival (P = 0.006, P = 0.035, P = 0.001, respectively) and overall survival (P = 0.003, P = 0.002, P = 0.003, respectively). Notably, the co-expression of all three FGFRs was significantly associated with favorable disease-free survival (P < 0.001) and overall survival (P < 0.001), compared to the negative expressions of the three FGFRs. The prognostic significance persisted in the cox regression analysis. Conclusions: The frequent expression of members of the FGFR family in cervical cancer suggests they may have prognostic and therapeutic relevance. C1 [Choi, Chel Hun; Chung, Joon-Yong; Hewitt, Stephen M.] NCI, Expt Pathol Lab, Pathol Lab, Ctr Canc Res,NIH, MSC 1500, Bethesda, MD 20892 USA. [Choi, Chel Hun; Kim, Byoung-Gie] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Obstet & Gynecol, 50 Irwon Dong, Seoul 135710, South Korea. [Kim, Jae-Hoon] Yonsei Univ, Coll Med, Gangnam Severance Hosp, Dept Obstet & Gynecol, Seoul 135720, South Korea. RP Hewitt, SM (reprint author), NCI, Expt Pathol Lab, Pathol Lab, Ctr Canc Res,NIH, MSC 1500, Bethesda, MD 20892 USA.; Kim, BG (reprint author), Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Obstet & Gynecol, 50 Irwon Dong, Seoul 135710, South Korea. EM bksong.kim@samsung.com; genejock@helix.nih.gov OI Hewitt, Stephen/0000-0001-8283-1788; Chung, Joon-Yong/0000-0001-5041-5982 FU Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education, Republic of Korea [2013R1A1A2013629]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This study was supported in part by a Grant from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Republic of Korea (2013R1A1A2013629) and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 55 TC 4 Z9 4 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD MAY 6 PY 2016 VL 14 AR 124 DI 10.1186/s12967-016-0874-0 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DL2OR UT WOS:000375475200002 PM 27154171 ER PT J AU Bustin, M Misteli, T AF Bustin, Michael Misteli, Tom TI Nongenetic functions of the genome SO SCIENCE LA English DT Review ID XENOPUS EGG EXTRACTS; EMBRYONIC STEM-CELLS; NUCLEAR-ENVELOPE; INTERPHASE CHROMOSOMES; CHROMATIN CONDENSATION; HISTONE MODIFICATIONS; LINKER HISTONES; IN-VIVO; DNA; MIGRATION AB The primary function of the genome is to store, propagate, and express the genetic information that gives rise to a cell's architectural and functional machinery. However, the genome is also a major structural component of the cell. Besides its genetic roles, the genome affects cellular functions by nongenetic means through its physical and structural properties, particularly by exerting mechanical forces and by serving as a scaffold for binding of cellular components. Major cellular processes affected by nongenetic functions of the genome include establishment of nuclear structure, signal transduction, mechanoresponses, cell migration, and vision in nocturnal animals. We discuss the concept, mechanisms, and implications of nongenetic functions of the genome. C1 [Bustin, Michael; Misteli, Tom] NCI, Bethesda, MD 20892 USA. RP Bustin, M; Misteli, T (reprint author), NCI, Bethesda, MD 20892 USA. EM bustinm@mail.nih.gov; mistelit@mail.nih.gov RI Bustin, Michael/G-6155-2015 FU NIH Intramural Research Program, National Cancer Institute, Center for Cancer Research FX We thank members of the Misteli lab and P. Oberdoerffer for comments on the manuscript; G. Gerlitz (Ariel University, Israel) and members of the Bustin laboratory for informative discussions on various topics of this review; and T. Ried and R. Lefcoe for illustrations. Work in the authors' laboratories is supported by the NIH Intramural Research Program, National Cancer Institute, Center for Cancer Research. NR 78 TC 2 Z9 2 U1 5 U2 20 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD MAY 6 PY 2016 VL 352 IS 6286 AR aad6933 DI 10.1126/science.aad6933 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DL1UC UT WOS:000375417100027 ER PT J AU Yamamizu, K Sharov, AA Piao, YL Amano, M Yu, H Nishiyama, A Dudekula, DB Schlessinger, D Ko, MSH AF Yamamizu, Kohei Sharov, Alexei A. Piao, Yulan Amano, Misa Yu, Hong Nishiyama, Akira Dudekula, Dawood B. Schlessinger, David Ko, Minoru S. H. TI Generation and gene expression profiling of 48 transcription-factor-inducible mouse embryonic stem cell lines SO SCIENTIFIC REPORTS LA English DT Article ID IDENTIFICATION; MICROARRAY; INDUCTION; ENHANCERS; NETWORKS; BINDING; SYSTEM; PITX2 AB Mouse embryonic stem cells (ESCs) can differentiate into a wide range - and possibly all cell types in vitro, and thus provide an ideal platform to study systematically the action of transcription factors (TFs) in cell differentiation. Previously, we have generated and analyzed 137 TF-inducible mouse ESC lines. As an extension of this "NIA Mouse ESC Bank," we generated and characterized 48 additional mouse ESC lines, in which single TFs in each line could be induced in a doxycycline-controllable manner. Together, with the previous ESC lines, the bank now comprises 185 TF-manipulable ESC lines (>10% of all mouse TFs). Global gene expression (transcriptome) profiling revealed that the induction of individual TFs in mouse ESCs for 48 hours shifts their transcriptomes toward specific differentiation fates (e.g., neural lineages by Myt1 Isl1, and St18; mesodermal lineages by Pitx1, Pitx2, Barhl2, and Lmx1a; white blood cells by Myb, Etv2, and Tbx6, and ovary by Pitx1, Pitx2, and Dmrtc2). These data also provide and lists of inferred target genes of each TF and possible functions of these TFs. The results demonstrate the utility of mouse ESC lines and their transcriptome data for understanding the mechanism of cell differentiation and the function of TFs. C1 [Yamamizu, Kohei; Sharov, Alexei A.; Piao, Yulan; Amano, Misa; Yu, Hong; Nishiyama, Akira; Dudekula, Dawood B.; Schlessinger, David; Ko, Minoru S. H.] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. [Ko, Minoru S. H.] Keio Univ, Sch Med, Dept Syst Med, Tokyo 1608582, Japan. RP Ko, MSH (reprint author), NIA, Genet Lab, NIH, Baltimore, MD 21224 USA.; Ko, MSH (reprint author), Keio Univ, Sch Med, Dept Syst Med, Tokyo 1608582, Japan. EM ko.minoru@keio.jp FU Intramural Research Program of the NIH, National Institute on Aging [ZIA AG000656-13]; Keio University Medical Science Fund - The Mitsunada Sakaguchi Laboratory; CREST program from the Japan Science and Technology Agency (JST); Research Center Network for Realization of Regenerative Medicine, Japan Agency for Medical Research and Development (AMED) FX This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (ZIA AG000656-13). This work was also in part supported by the Keio University Medical Science Fund - The Mitsunada Sakaguchi Laboratory, the CREST program from the Japan Science and Technology Agency (JST), and the Research Center Network for Realization of Regenerative Medicine, Japan Agency for Medical Research and Development (AMED). NR 32 TC 1 Z9 1 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAY 6 PY 2016 VL 6 AR 25667 DI 10.1038/srep25667 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DL2BH UT WOS:000375437100001 PM 27150017 ER PT J AU Lorberbaum, DS Ramos, AI Peterson, KA Carpenter, BS Parker, DS De, S Hillers, LE Blake, VM Nishi, Y McFarlane, MR Chiang, ACY Kassis, JA Allen, BL McMahon, AP Barolo, S AF Lorberbaum, David S. Ramos, Andrea I. Peterson, Kevin A. Carpenter, Brandon S. Parker, David S. De, Sandip Hillers, Lauren E. Blake, Victoria M. Nishi, Yuichi McFarlane, Matthew R. Chiang, Ason C. Y. Kassis, Judith A. Allen, Benjamin L. McMahon, Andrew P. Barolo, Scott TI An ancient yet flexible cis-regulatory architecture allows localized Hedgehog tuning by patched/Ptch1 SO ELIFE LA English DT Article ID GLI-BINDING-AFFINITY; TRANSCRIPTION-FACTOR; DROSOPHILA EMBRYO; DEVELOPMENTAL ENHANCERS; EYE ENHANCER; TARGET GENES; GENOME; MECHANISMS; CHROMATIN; PATHWAY AB The Hedgehog signaling pathway is part of the ancient developmental-evolutionary animal toolkit. Frequently co-opted to pattern new structures, the pathway is conserved among eumetazoans yet flexible and pleiotropic in its effects. The Hedgehog receptor, Patched, is transcriptionally activated by Hedgehog, providing essential negative feedback in all tissues. Our locus-wide dissections of the cis-regulatory landscapes of fly patched and mouse Ptchl reveal abundant, diverse enhancers with stage- and tissue-specific expression patterns. The seemingly simple, constitutive Hedgehog response of patched/Ptchl is driven by a complex regulatory architecture, with batteries of context-specific enhancers engaged in promoter-specific interactions to tune signaling individually in each tissue, without disturbing patterning elsewhere. This structure one of the oldest cis-regulatory features discovered in animal genomes explains how patched/Ptchl can drive dramatic adaptations in animal morphology while maintaining its essential core function. It may also suggest a general model for the evolutionary flexibility of conserved regulators and pathways. C1 [Lorberbaum, David S.; Ramos, Andrea I.; Carpenter, Brandon S.; Parker, David S.; Hillers, Lauren E.; Blake, Victoria M.; Chiang, Ason C. Y.; Allen, Benjamin L.; Barolo, Scott] Univ Michigan, Sch Med, Dept Cell & Dev Biol, Ann Arbor, MI 48109 USA. [Lorberbaum, David S.; Ramos, Andrea I.] Univ Michigan, Sch Med, Program Cellular & Mol Biol, Ann Arbor, MI USA. [Peterson, Kevin A.; McFarlane, Matthew R.; McMahon, Andrew P.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Peterson, Kevin A.] Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. [De, Sandip; Blake, Victoria M.; Kassis, Judith A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD USA. [Nishi, Yuichi; McMahon, Andrew P.] Univ Southern Calif, Keck Sch Med, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, Dept Stem Cell Biol & Regenerat Med, Los Angeles, CA USA. [Parker, David S.] Elon Univ, Dept Biol, Elon, NC USA. [Hillers, Lauren E.] Univ Wisconsin, Grad Program Cellular & Mol Biol, Madison, WI 53706 USA. [McFarlane, Matthew R.] Univ Texas Southwestern Med Ctr, Dept Mol Genet, Dallas, TX USA. RP Barolo, S (reprint author), Univ Michigan, Sch Med, Dept Cell & Dev Biol, Ann Arbor, MI 48109 USA. EM sbarolo@umich.edu FU National Institute of General Medical Sciences [T32-GM007315, R01 GM076509]; Eunice Kennedy Shriver National Institute of Child Health and Human Development; American Heart Association [11SDG638000]; National Science Foundation [MCB-1157800]; National Institute on Deafness and Other Communication Disorders [R01 DC014428]; National Institute of Neurological Disorders and Stroke [R01 NS033642] FX National Institute of General Medical Sciences T32-GM007315 David S Lorberbaum Andrea I Ramos; Eunice Kennedy Shriver National Institute of Child Health and Human Development Intramural Research Program Sandip De Judith A Kassis; American Heart Association 11SDG638000 Benjamin L Allen; National Science Foundation MCB-1157800 Scott Barolo; National Institute on Deafness and Other Communication Disorders R01 DC014428 Benjamin L Allen; National Institute of General Medical Sciences R01 GM076509 Scott Barolo; National Institute of Neurological Disorders and Stroke R01 NS033642 Andrew P McMahon NR 65 TC 3 Z9 3 U1 1 U2 2 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD MAY 5 PY 2016 VL 5 AR e13550 DI 10.7554/eLife.13550 PG 22 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DS0KO UT WOS:000380284500001 ER PT J AU Zhang, DP Burroughs, AM Vidal, ND Iyer, LM Aravind, L AF Zhang, Dapeng Burroughs, A. Maxwell Vidal, Newton D. Iyer, Lakshminarayan M. Aravind, L. TI Transposons to toxins: the provenance, architecture and diversification of a widespread class of eukaryotic effectors SO NUCLEIC ACIDS RESEARCH LA English DT Article ID MULTIPLE SEQUENCE ALIGNMENT; DNA STRAND TRANSFER; TN7 TRANSPOSITION; TARGET IMMUNITY; PLASMODIOPHORA-BRASSICAE; PATHOGEN PHYTOPHTHORA; TN7-ENCODED PROTEINS; STRUCTURE PREDICTION; MAXIMUM-LIKELIHOOD; BACTERIOPHAGE-MU AB Enzymatic effectors targeting nucleic acids, proteins and other cellular components are the mainstay of conflicts across life forms. Using comparative genomics we identify a large class of eukaryotic proteins, which include effectors from oomycetes, fungi and other parasites. The majority of these proteins have a characteristic domain architecture with one of several N-terminal 'Header' domains, which are predicted to play a role in trafficking of these effectors, including a novel version of the Ubiquitin fold. The Headers are followed by one or more diverse C-terminal domains, such as restriction endonuclease (REase), protein kinase, HNH endonuclease, LK-nuclease (a RNase) and multiple distinct peptidase domains, which are predicted to carry their toxicity determinants. The most common types of these proteins appear to have originated from prokaryotic transposases (e.g. TN7 and Mu) and combine a CDC6/ORC1-STAND clade NTPase domain with a C-terminal REase domain. Other than the so-called Crinkler effectors of oomycetes and fungi, these effectors are encoded by other eukaryotic parasites such as trypanosomatids (the RHS proteins) and the rhizarian Plasmodiophora, and symbionts like Capsaspora. Remarkably, we also find these proteins in free-living eukaryotes, including several viridiplantae, fungi, amoebozoans and animals. These versions might either still be transposons or function in other poorly understood eukaryote-specific inter-organismal and inter-genomic conflicts. These include the Medea1 selfish element of Tribolium that spreads via post-zygotic killing. We present a unified mechanism for the recombination-dependent diversification and action of this widespread class of molecular weaponry deployed across diverse conflicts ranging from parasitic to free-living forms. C1 [Zhang, Dapeng; Burroughs, A. Maxwell; Vidal, Newton D.; Iyer, Lakshminarayan M.; Aravind, L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM aravind@ncbi.nlm.nih.gov FU Intramural Research Program of National Library of Medicine at the National Institutes of Health, USA; CNPq (Brazil); National Institutes of Health (USA) FX Intramural Research Program of National Library of Medicine at the National Institutes of Health, USA. NMV's postdoctoral fellowship is funded by a partnership between CNPq (Brazil) and the National Institutes of Health (USA). NR 121 TC 3 Z9 3 U1 4 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAY 5 PY 2016 VL 44 IS 8 BP 3513 EP 3533 DI 10.1093/nar/gkw221 PG 21 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DM5KX UT WOS:000376389000014 PM 27060143 ER PT J AU Schellenberg, MJ Perera, L Strom, CN Waters, CA Monian, B Appel, CD Vilas, CK Williams, JG Ramsden, DA Williams, RS AF Schellenberg, Matthew J. Perera, Lalith Strom, Christina N. Waters, Crystal A. Monian, Brinda Appel, C. Denise Vilas, Caroline K. Williams, Jason G. Ramsden, Dale A. Williams, R. Scott TI Reversal of DNA damage induced Topoisomerase 2 DNA-protein crosslinks by Tdp2 SO NUCLEIC ACIDS RESEARCH LA English DT Article ID II POISONS; EXONUCLEASE-III; REPAIR ENZYME; PHOSPHODIESTERASE; CLEAVAGE; LIGATION; LESIONS; ALPHA; ENDS; RECOGNITION AB Mammalian Tyrosyl-DNA phosphodiesterase 2 (Tdp2) reverses Topoisomerase 2 (Top2) DNA-protein crosslinks triggered by Top2 engagement of DNA damage or poisoning by anticancer drugs. Tdp2 deficiencies are linked to neurological disease and cellular sensitivity to Top2 poisons. Herein, we report X-ray crystal structures of ligand-free Tdp2 and Tdp2-DNA complexes with alkylated and abasic DNA that unveil a dynamic Tdp2 active site lid and deep substrate binding trench well-suited for engaging the diverse DNA damage triggers of abortive Top2 reactions. Modeling of a proposed Tdp2 reaction coordinate, combined with mutagenesis and biochemical studies support a single Mg2+-ion mechanism assisted by a phosphotyrosyl-arginine cation-pi interface. We further identify a Tdp2 active site SNP that ablates Tdp2 Mg2+ binding and catalytic activity, impairs Tdp2 mediated NHEJ of tyrosine blocked termini, and renders cells sensitive to the anticancer agent etoposide. Collectively, our results provide a structural mechanism for Tdp2 engagement of heterogeneous DNA damage that causes Top2 poisoning, and indicate that evaluation of Tdp2 status may be an important personalized medicine biomarker informing on individual sensitivities to chemotherapeutic Top2 poisons. C1 [Schellenberg, Matthew J.; Perera, Lalith; Monian, Brinda; Appel, C. Denise; Vilas, Caroline K.; Williams, R. Scott] NIEHS, Genome Integr & Struct Biol Lab, US Natl Inst Hlth, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. [Strom, Christina N.; Waters, Crystal A.; Ramsden, Dale A.] Univ N Carolina, Lineberger Comprehens Canc, Chapel Hill, NC 27599 USA. [Williams, Jason G.] NIEHS, Epigenet & Stem Cell Biol Lab, US Natl Inst Hlth, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. RP Williams, RS (reprint author), NIEHS, Genome Integr & Struct Biol Lab, US Natl Inst Hlth, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM williamsrs@niehs.nih.gov FU US National Institute of Health Intramural Program; US National Institute of Environmental Health Sciences (NIEHS) [1Z01ES102765]; National Cancer Institute (NCI) [R01 CA084442]; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; NIEHS [1Z01ES102765] FX US National Institute of Health Intramural Program; US National Institute of Environmental Health Sciences (NIEHS) [1Z01ES102765 to R.S.W.]; National Cancer Institute (NCI) [R01 CA084442 to D.A.R]. Use of the APS was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38. Funding for open access publication: NIEHS [1Z01ES102765 to R.S.W]. NR 44 TC 0 Z9 0 U1 10 U2 19 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAY 5 PY 2016 VL 44 IS 8 BP 3829 EP 3844 DI 10.1093/nar/gkw228 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DM5KX UT WOS:000376389000037 PM 27060144 ER PT J AU Moon, AF Krahn, JM Lu, X Cuneo, MJ Pedersen, LC AF Moon, Andrea F. Krahn, Juno M. Lu, Xun Cuneo, Matthew J. Pedersen, Lars C. TI Structural characterization of the virulence factor Sda1 nuclease from Streptococcus pyogenes SO NUCLEIC ACIDS RESEARCH LA English DT Article ID GROUP-A STREPTOCOCCUS; NEUTROPHIL EXTRACELLULAR TRAPS; ACTIVE-SITE; M1T1 CLONE; CHEMICAL RESCUE; PNEUMONIAE; DNASE; ENDA; SUPERANTIGENS; INFECTIONS AB Infection by Group A Streptococcus pyogenes (GAS) is a leading cause of severe invasive disease in humans, including streptococcal toxic shock syndrome and necrotizing fasciitis. GAS infections lead to nearly 163,000 annual deaths worldwide. Hypervirulent strains of S. pyogenes have evolved a plethora of virulence factors that aid in disease-by promoting bacterial adhesion to host cells, subsequent invasion of deeper tissues and blocking the immune system's attempts to eradicate the infection. Expression and secretion of the extracellular nuclease Sda1 is advantageous for promoting bacterial dissemination throughout the host organism, and evasion of the host's innate immune response. Here we present two crystal structures of Sda1, as well as biochemical studies to address key structural features and surface residues involved in DNA binding and catalysis. In the active site, Asn211 is observed to directly chelate a hydrated divalent metal ion and Arg124, on the putative substrate binding loop, likely stabilizes the transition state during phosphodiester bond cleavage. These structures provide a foundation for rational drug design of small molecule inhibitors to be used in prevention of invasive streptococcal disease. C1 [Moon, Andrea F.; Krahn, Juno M.; Pedersen, Lars C.] NIEHS, Genome Integr & Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Lu, Xun; Cuneo, Matthew J.] Oak Ridge Natl Lab, Spallat Neutron Source, Oak Ridge, TN 37831 USA. RP Moon, AF (reprint author), NIEHS, Genome Integr & Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM moon@niehs.nih.gov FU Division of Intramural Research of the National Institute of Environmental Health Sciences; National Institutes of Health [1ZIA ES102645-03]; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; Scientific User Facilities Division, Office of Basic Energy Sciences, US Department of Energy; Office of Biological and Environmental Research FX Division of Intramural Research of the National Institute of Environmental Health Sciences; National Institutes of Health Grant 1ZIA ES102645-03 (to L.C.P.); US Department of Energy, Office of Science, Office of Basic Energy Sciences Contract W-31-109-Eng-38. The research at the Spallation Neutron Source at Oak Ridge National Laboratory was sponsored by the Scientific User Facilities Division, Office of Basic Energy Sciences, US Department of Energy; Office of Biological and Environmental Research supported the research at Oak Ridge National Laboratory's Center for Structural Molecular Biology (CSMB) using facilities supported by the Scientific User Facilities Division, Office of Basic Energy Sciences, US Department of Energy. NR 35 TC 0 Z9 0 U1 10 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAY 5 PY 2016 VL 44 IS 8 BP 3946 EP 3957 DI 10.1093/nar/gkw143 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DM5KX UT WOS:000376389000045 PM 26969731 ER PT J AU Juan, AH Sartorelli, V AF Juan, Aster H. Sartorelli, Vittorio TI S6K1ing to ResTOR Adipogenesis with Polycomb SO MOLECULAR CELL LA English DT Editorial Material ID ACTIVATION; OBESITY AB Signal-directed chromatin recruitment of mammalian Polycomb complexes is a fundamental component of epigenetic regulation. In this issue, Yi et al. (2016) reveal how mTORC1 activation deploys the ribosomal serine/threonine kinase S6K1 and Polycomb proteins at genomic regulatory regions to repress expression of anti-adipogenic developmental regulators. C1 [Juan, Aster H.; Sartorelli, Vittorio] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIAMS, NIH, Bethesda, MD 20892 USA. RP Sartorelli, V (reprint author), NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIAMS, NIH, Bethesda, MD 20892 USA. EM sartorev@mail.nih.gov NR 11 TC 1 Z9 1 U1 1 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD MAY 5 PY 2016 VL 62 IS 3 BP 325 EP 326 DI 10.1016/j.molcel.2016.04.018 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DM6EZ UT WOS:000376444700002 PM 27153531 ER PT J AU Kuehn, MH Lipsett, KA Menotti-Raymond, M Whitmore, SS Scheetz, TE David, VA O'Brien, SJ Zhao, ZY Jens, JK Snella, EM Ellinwood, NM McLellan, GJ AF Kuehn, Markus H. Lipsett, Koren A. Menotti-Raymond, Marilyn Whitmore, S. Scott Scheetz, Todd E. David, Victor A. O'Brien, Stephen J. Zhao, Zhongyuan Jens, Jackie K. Snella, Elizabeth M. Ellinwood, N. Matthew McLellan, Gillian J. TI A Mutation in LTBP2 Causes Congenital Glaucoma in Domestic Cats (Felis catus) SO PLOS ONE LA English DT Article ID OPEN-ANGLE GLAUCOMA; GROWTH-FACTOR-BETA; LATENT TGF-BETA; BINDING-PROTEIN 2; SECONDARY GLAUCOMA; GENE; IDENTIFICATION; TYROSINASE; PHENOTYPES; SEQUENCE AB The glaucomas are a group of diseases characterized by optic nerve damage that together represent a leading cause of blindness in the human population and in domestic animals. Here we report a mutation in LTBP2 that causes primary congenital glaucoma (PCG) in domestic cats. We identified a spontaneous form of PCG in cats and established a breeding colony segregating for PCG consistent with fully penetrant, autosomal recessive inheritance of the trait. Elevated intraocular pressure, globe enlargement and elongated ciliary processes were consistently observed in all affected cats by 8 weeks of age. Varying degrees of optic nerve damage resulted by 6 months of age. Although subtle lens zonular instability was a common feature in this cohort, pronounced ectopia lentis was identified in less than 10% of cats examined. Thus, glaucoma in this pedigree is attributed to histologically confirmed arrest in the early post-natal development of the aqueous humor outflow pathways in the anterior segment of the eyes of affected animals. Using a candidate gene approach, significant linkage was established on cat chromosome B3 (LOD 18.38, theta = 0.00) using tightly linked short tandem repeat (STR) loci to the candidate gene, LTBP2. A 4 base-pair insertion was identified in exon 8 of LTBP2 in affected individuals that generates a frame shift that completely alters the downstream open reading frame and eliminates functional domains. Thus, we describe the first spontaneous and highly penetrant non-rodent model of PCG identifying a valuable animal model for primary glaucoma that closely resembles the human disease, providing valuable insights into mechanisms underlying the disease and a valuable animal model for testing therapies. C1 [Kuehn, Markus H.; Whitmore, S. Scott; Scheetz, Todd E.] Univ Iowa, Dept Ophthalmol & Visual Sci, Carver Coll Med, Iowa City, IA USA. [Lipsett, Koren A.; Menotti-Raymond, Marilyn; David, Victor A.; O'Brien, Stephen J.] NCI, Lab Genom Div, Frederick, MD 21701 USA. [David, Victor A.] NCI, Basic Res Lab, Frederick, MD 21701 USA. [Lipsett, Koren A.; Zhao, Zhongyuan] Gettysburg Coll, Dept Chem, Gettysburg, PA 17325 USA. [O'Brien, Stephen J.] St Petersburg State Univ, Theodosius Dobzhansky Ctr Genome Bioinformat, St Petersburg 199034, Russia. [O'Brien, Stephen J.] Nova SE Univ, Oceanog Ctr, Ft Lauderdale, FL 33314 USA. [Jens, Jackie K.; Snella, Elizabeth M.; Ellinwood, N. Matthew] Iowa State Univ, Dept Anim Sci, Ames, IA USA. [Ellinwood, N. Matthew] Iowa State Univ, Dept Vet Clin Sci, Ames, IA USA. [McLellan, Gillian J.] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Madison, WI USA. [McLellan, Gillian J.] Univ Wisconsin, Dept Surg Sci, Madison, WI USA. [McLellan, Gillian J.] McPherson Eye Res Inst, Madison, WI USA. RP McLellan, GJ (reprint author), Univ Wisconsin, Dept Ophthalmol & Visual Sci, Madison, WI USA.; McLellan, GJ (reprint author), Univ Wisconsin, Dept Surg Sci, Madison, WI USA.; McLellan, GJ (reprint author), McPherson Eye Res Inst, Madison, WI USA. EM gillian.mclellan@wisc.edu OI Whitmore, S. Scott/0000-0003-0161-9625 FU Glaucoma Research Foundation; National Institutes of Health [K08 EY018609, P30 EY0016665]; Center for Integrated Animal Genomics, Iowa State University; Battelle General Platform and Infrastructure Awards; Foundation Fighting Blindness; Research to Prevent Blindness; Russian Ministry of Science Mega-grant [11.G34.31.0068]; Intramural Research Program of the NIH, Frederick National Laboratory, Center for Cancer Research, National Cancer Institute FX The studies were supported by The Glaucoma Research Foundation (MHK), the National Institutes of Health Grants K08 EY018609 (GJM) and P30 EY0016665 (GJM); the Center for Integrated Animal Genomics, Iowa State University (NME and GJM), a Battelle General Platform and Infrastructure Awards (NME), and unrestricted grants to the University of Iowa Department of Ophthalmology and Visual Sciences from the Foundation Fighting Blindness and to the University of Wisconsin-Madison Department of Ophthalmology and Visual Sciences from Research to Prevent Blindness; and in part by Russian Ministry of Science Mega-grant no. 11.G34.31.0068 (SJO). This research was supported (in part) by the Intramural Research Program of the NIH, Frederick National Laboratory, Center for Cancer Research, National Cancer Institute. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the United States government. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 71 TC 1 Z9 1 U1 3 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 5 PY 2016 VL 11 IS 5 AR e0154412 DI 10.1371/journal.pone.0154412 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DL5KV UT WOS:000375676800029 PM 27149523 ER PT J AU Low, LA Bauer, LC Klaunberg, BA AF Low, Lucie A. Bauer, Lucy C. Klaunberg, Brenda A. TI Comparing the Effects of Isoflurane and Alpha Chloralose upon Mouse Physiology SO PLOS ONE LA English DT Article ID RESTING-STATE FMRI; FUNCTIONAL CONNECTIVITY; ANESTHETIZED RAT; BOLD FMRI; SOMATOSENSORY CORTEX; PHARMACOLOGICAL MRI; FOREPAW STIMULATION; BLOOD-FLOW; AWAKE RATS; BRAIN AB Functional magnetic resonance imaging of mice requires that the physiology of the mouse (body temperature, respiration and heart rates, blood pH level) be maintained in order to prevent changes affecting the outcomes of functional scanning, namely blood oxygenation level dependent (BOLD) measures and cerebral blood flow (CBF). The anesthetic used to sedate mice for scanning can have major effects on physiology. While alpha chloralose has been commonly used for functional imaging of rats, its effects on physiology are not well characterized in the literature for any species. In this study, we anesthetized or sedated mice with isoflurane or alpha chloralose for up to two hours, and monitored physiological parameters and arterial blood gasses. We found that, when normal body temperature is maintained, breathing rates for both drugs decrease over the course of two hours. In addition, alpha chloralose causes a substantial drop in heart rate and blood pH with severe hypercapnia (elevated blood CO2) that is not seen in isoflurane-treated animals. We suggest that alpha chloralose does not maintain normal mouse physiology adequately for functional brain imaging outcome measures. C1 [Low, Lucie A.; Bauer, Lucy C.] NIH, Natl Ctr Complementary & Integrat Hlth, Bldg 10, Bethesda, MD 20892 USA. [Klaunberg, Brenda A.] NINDS, NIH Mouse Imaging Facil, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Low, LA (reprint author), NIH, Natl Ctr Complementary & Integrat Hlth, Bldg 10, Bethesda, MD 20892 USA. EM lucie.low@nih.gov OI Low, Lucie/0000-0001-6082-8625 FU Division of Intramural Research at the National Center for Complementary and Integrative Health (NCCIH); NIH Mouse Imaging Facility at the National Institute for Neurological Disorders and Stroke (NINDS) FX This research was funded by the Division of Intramural Research at the National Center for Complementary and Integrative Health (NCCIH), and the NIH Mouse Imaging Facility at the National Institute for Neurological Disorders and Stroke (NINDS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 1 Z9 1 U1 4 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 5 PY 2016 VL 11 IS 5 AR e0154936 DI 10.1371/journal.pone.0154936 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DL5KV UT WOS:000375676800094 PM 27148970 ER PT J AU Pelttari, LM Khan, S Vuorela, M Kiiski, JI Vilske, S Nevanlinna, V Ranta, S Schleutker, J Winqvist, R Kallioniemi, A Dork, T Bogdanova, NV Figueroa, J Pharoah, PDP Schmidt, MK Dunning, AM Garcia-Closas, M Bolla, MK Dennis, J Michailidou, K Wang, Q Hopper, JL Southey, MC Rosenberg, EH Fasching, PA Beckmann, MW Peto, J dos-Santos-Silva, I Sawyer, EJ Tomlinson, I Burwinkel, B Surowy, H Guenel, P Truong, T Bojesen, SE Nordestgaard, BG Benitez, J Gonzalez-Neira, A Neuhausen, SL Anton-Culver, H Brenner, H Arndt, V Meindl, A Schmutzler, RK Brauch, H Bruning, T Lindblom, A Margolin, S Mannermaa, A Hartikainen, JM Chenevix-Trench, G Van Dyck, L Janssen, H Chang-Claude, J Rudolph, A Radice, P Peterlongo, P Hallberg, E Olson, JE Giles, GG Milne, RL Haiman, CA Schumacher, F Simard, J Dumont, M Kristensen, V Borresen-Dale, AL Zheng, W Beeghly-Fadiel, A Grip, M Andrulis, IL Glendon, G Devilee, P Seynaeve, C Hooning, MJ Collee, M Cox, A Cross, SS Shah, M Luben, RN Hamann, U Torres, D Jakubowska, A Lubinski, J Couch, FJ Yannoukakos, D Orr, N Swerdlow, A Darabi, H Li, JM Czene, K Hall, P Easton, DF Mattson, J Blomqvist, C Aittomaki, K Nevanlinna, H AF Pelttari, Liisa M. Khan, Sofia Vuorela, Mikko Kiiski, Johanna I. Vilske, Sara Nevanlinna, Viivi Ranta, Salla Schleutker, Johanna Winqvist, Robert Kallioniemi, Anne Doerk, Thilo Bogdanova, Natalia V. Figueroa, Jonine Pharoah, Paul D. P. Schmidt, Marjanka K. Dunning, Alison M. Garcia-Closas, Montserrat Bolla, Manjeet K. Dennis, Joe Michailidou, Kyriaki Wang, Qin Hopper, John L. Southey, Melissa C. Rosenberg, Efraim H. Fasching, Peter A. Beckmann, Matthias W. Peto, Julian dos-Santos-Silva, Isabel Sawyer, Elinor J. Tomlinson, Ian Burwinkel, Barbara Surowy, Harald Guenel, Pascal Truong, Therese Bojesen, Stig E. Nordestgaard, Borge G. Benitez, Javier Gonzalez-Neira, Anna Neuhausen, Susan L. Anton-Culver, Hoda Brenner, Hermann Arndt, Volker Meindl, Alfons Schmutzler, Rita K. Brauch, Hiltrud Bruening, Thomas Lindblom, Annika Margolin, Sara Mannermaa, Arto Hartikainen, Jaana M. Chenevix-Trench, Georgia Van Dyck, Laurien Janssen, Hilde Chang-Claude, Jenny Rudolph, Anja Radice, Paolo Peterlongo, Paolo Hallberg, Emily Olson, Janet E. Giles, Graham G. Milne, Roger L. Haiman, Christopher A. Schumacher, Fredrick Simard, Jacques Dumont, Martine Kristensen, Vessela Borresen-Dale, Anne-Lise Zheng, Wei Beeghly-Fadiel, Alicia Grip, Mervi Andrulis, Irene L. Glendon, Gord Devilee, Peter Seynaeve, Caroline Hooning, Maartje J. Collee, Margriet Cox, Angela Cross, Simon S. Shah, Mitul Luben, Robert N. Hamann, Ute Torres, Diana Jakubowska, Anna Lubinski, Jan Couch, Fergus J. Yannoukakos, Drakoulis Orr, Nick Swerdlow, Anthony Darabi, Hatef Li, Jingmei Czene, Kamila Hall, Per Easton, Douglas F. Mattson, Johanna Blomqvist, Carl Aittomaki, Kristiina Nevanlinna, Heli CA kConFab AOCS Investigators TI RAD51B in Familial Breast Cancer SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; OVARIAN-CANCER; CONFER SUSCEPTIBILITY; GERMLINE MUTATIONS; 14Q24.1 RAD51L1; FANCONI-ANEMIA; RISK; GENE; VARIANTS; XRCC2 AB Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 x 10(-16)) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 x 10(-11)), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk. C1 [Pelttari, Liisa M.; Khan, Sofia; Kiiski, Johanna I.; Vilske, Sara; Nevanlinna, Viivi; Ranta, Salla; Nevanlinna, Heli] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland. [Pelttari, Liisa M.; Khan, Sofia; Kiiski, Johanna I.; Vilske, Sara; Nevanlinna, Viivi; Ranta, Salla; Mattson, Johanna; Blomqvist, Carl; Aittomaki, Kristiina; Nevanlinna, Heli] Helsinki Univ Hosp, Helsinki, Finland. [Vuorela, Mikko; Winqvist, Robert] Univ Oulu, Bioctr Oulu, Lab Canc Genet & Tumor Biol, Canc Res & Translat Med, Oulu, Finland. [Schleutker, Johanna; Kallioniemi, Anne] Univ Tampere, BioMediTech, FIN-33101 Tampere, Finland. [Schleutker, Johanna] Univ Turku, Dept Med Biochem & Genet, Turku, Finland. [Schleutker, Johanna] Turku Univ Hosp, Dept Med Genet, Tyks Microbiol & Genet, FIN-20520 Turku, Finland. [Winqvist, Robert] Northern Finland Lab Ctr NordLab, Lab Canc Genet & Tumor Biol, Oulu, Finland. [Kallioniemi, Anne] Fimlab Labs, Tampere, Finland. [Doerk, Thilo] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany. [Bogdanova, Natalia V.] Hannover Med Sch, Radiat Oncol Res Unit, Hannover, Germany. [Figueroa, Jonine; Garcia-Closas, Montserrat] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Pharoah, Paul D. P.; Dunning, Alison M.; Shah, Mitul; Easton, Douglas F.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Pharoah, Paul D. P.; Bolla, Manjeet K.; Dennis, Joe; Michailidou, Kyriaki; Wang, Qin; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Schmidt, Marjanka K.; Rosenberg, Efraim H.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands. [Garcia-Closas, Montserrat; Swerdlow, Anthony] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England. [Hopper, John L.; Giles, Graham G.; Milne, Roger L.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic, Australia. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia. [Fasching, Peter A.; Beckmann, Matthias W.] Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen EMN, Univ Hosp Erlangen, Dept Obstet & Gynaecol, D-91054 Erlangen, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, Dept Med, Div Hematol & Oncol, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Peto, Julian; dos-Santos-Silva, Isabel] London Sch Hyg & Trop Med, Dept Noncommun Dis Epidemiol, London WC1, England. [Sawyer, Elinor J.] Kings Coll London, Guys Hosp, Res Oncol, London WC2R 2LS, England. [Tomlinson, Ian] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Tomlinson, Ian] Univ Oxford, Oxford NIHR Biomed Res Ctr, Oxford, England. [Burwinkel, Barbara; Surowy, Harald] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany. [Burwinkel, Barbara; Surowy, Harald] German Canc Res Ctr, Mol Epidemiol Grp, Heidelberg, Germany. [Guenel, Pascal; Truong, Therese] INSERM, Ctr Res Epidemiol & Populat Hlth, Environm Epidemiol Canc, Villejuif, France. [Guenel, Pascal; Truong, Therese] Univ Paris 11, Villejuif, France. [Bojesen, Stig E.] Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, Herlev, Denmark. [Bojesen, Stig E.; Nordestgaard, Borge G.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev, Denmark. [Bojesen, Stig E.; Nordestgaard, Borge G.] Univ Copenhagen, Fac Med & Hlth Sci, Copenhagen, Denmark. [Benitez, Javier; Gonzalez-Neira, Anna] Spanish Natl Canc Res Ctr, Human Canc Genet Program, Madrid, Spain. [Benitez, Javier] Ctr Invest Red Enfermedades Raras, Valencia, Spain. [Neuhausen, Susan L.] Beckman Res Inst City Hope, Duarte, CA USA. [Anton-Culver, Hoda] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Brenner, Hermann; Arndt, Volker] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann; Brauch, Hiltrud] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany. [Brenner, Hermann] Natl Ctr Tumor Dis NCT, Heidelberg, Germany. [Meindl, Alfons] Tech Univ Munich, Div Gynaecol & Obstet, D-80290 Munich, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Ctr Hereditary Breast & Ovarian Canc, Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Ctr Integrated Oncol, Cologne, Germany. [Schmutzler, Rita K.] Univ Cologne, Ctr Mol Med Cologne, D-50931 Cologne, Germany. [Brauch, Hiltrud] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. [Brauch, Hiltrud] Univ Tubingen, Tubingen, Germany. [Bruening, Thomas] Ruhr Univ Bochum, German Social Accid Insurance Inst, Inst Prevent & Occupat Med, Univ Str 150, Bochum, Germany. [Lindblom, Annika] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Margolin, Sara] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Mannermaa, Arto; Hartikainen, Jaana M.] Kuopio Univ Hosp, Ctr Canc, SF-70210 Kuopio, Finland. [Mannermaa, Arto; Hartikainen, Jaana M.] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Kuopio, Finland. [Mannermaa, Arto; Hartikainen, Jaana M.] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, SF-70210 Kuopio, Finland. [Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Dept Genet, Brisbane, Qld, Australia. [kConFab AOCS Investigators] Univ Melbourne, Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Van Dyck, Laurien] VIB, Vesalius Res Ctr, Leuven, Belgium. [Van Dyck, Laurien] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium. [Janssen, Hilde] Univ Hosp Leuven, Leuven Canc Inst, Leuven Multidisciplinary Breast Ctr, Leuven, Belgium. [Chang-Claude, Jenny; Rudolph, Anja] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Chang-Claude, Jenny] Univ Med Ctr Hamburg Eppendorf, Univ Canc Ctr Hamburg UCCH, Hamburg, Germany. [Radice, Paolo] Ist Nazl Tumori, Fdn IRCCS Ist Di Ricovero & Cura Carattere Sci, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, Via Venezian 1, I-20133 Milan, Italy. [Peterlongo, Paolo] Italian Fdn Canc Res Oncol Mol, Fdn Ist FIRC, IFOM, Milan, Italy. [Hallberg, Emily; Olson, Janet E.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Giles, Graham G.; Milne, Roger L.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Haiman, Christopher A.; Schumacher, Fredrick] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Simard, Jacques; Dumont, Martine] Univ Laval, Ctr Hosp Univ Quebec Res Ctr, Genom Ctr, Quebec City, PQ, Canada. [Kristensen, Vessela; Borresen-Dale, Anne-Lise] Oslo Univ Hosp, Radiumhosp, Inst Canc Res, Dept Genet, N-0450 Oslo, Norway. [Kristensen, Vessela; Borresen-Dale, Anne-Lise] Univ Oslo, Fac Med, Inst Clin Med, KG Jebsen Ctr Breast Canc Res, Oslo, Norway. [Kristensen, Vessela] Univ Oslo, Oslo Univ Hosp, Dept Clin Mol Biol, Oslo, Norway. [Zheng, Wei; Beeghly-Fadiel, Alicia] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, Nashville, TN 37212 USA. [Grip, Mervi] Univ Oulu, Oulu Univ Hosp, Dept Surg, Oulu, Finland. [Andrulis, Irene L.; Glendon, Gord] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. [Seynaeve, Caroline; Hooning, Maartje J.] Erasmus MC Canc Inst, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands. [Collee, Margriet] Erasmus Univ, Med Ctr, Dept Clin Genet, Rotterdam, Netherlands. [Cox, Angela] Univ Sheffield, Dept Oncol, Sheffield Canc Res, Sheffield, S Yorkshire, England. [Cross, Simon S.] Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield, S Yorkshire, England. [Luben, Robert N.] Univ Cambridge, Dept Publ Hlth & Primary Care, Clin Gerontol, Cambridge, England. [Hamann, Ute; Torres, Diana] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany. [Torres, Diana] Pontificia Univ Javeriana, Inst Human Genet, Bogota, Colombia. [Jakubowska, Anna; Lubinski, Jan] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Yannoukakos, Drakoulis] Natl Ctr Sci Res Demokritos, IRRP, Mol Diagnost Lab, Athens, Greece. [Orr, Nick] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Swerdlow, Anthony] Inst Canc Res, Div Breast Canc Res, London SW3 6JB, England. [Darabi, Hatef; Li, Jingmei; Czene, Kamila; Hall, Per] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Mattson, Johanna; Blomqvist, Carl] Univ Helsinki, Dept Oncol, Helsinki, Finland. [Aittomaki, Kristiina] Univ Helsinki, Dept Clin Genet, Helsinki, Finland. RP Nevanlinna, H (reprint author), Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland.; Nevanlinna, H (reprint author), Helsinki Univ Hosp, Helsinki, Finland. EM heli.nevanlinna@hus.fi RI Hartikainen, Jaana/E-6256-2015; Bruning, Thomas/G-8120-2015; Van Dyck, Laurien/I-4018-2016; Dork, Thilo/J-8620-2012; Li, Jingmei/I-2904-2012; Zheng, Wei/O-3351-2013; Brenner, Hermann/B-4627-2017; OI Dunning, Alison Margaret/0000-0001-6651-7166; Bruning, Thomas/0000-0001-9560-5464; Van Dyck, Laurien/0000-0002-1373-7656; Li, Jingmei/0000-0001-8587-7511; Zheng, Wei/0000-0003-1226-070X; Brenner, Hermann/0000-0002-6129-1572; Khan, Sofia/0000-0003-4185-8882; Yannoukakos, Drakoulis/0000-0001-7509-3510 FU Helsinki University Hospital Research Fund; Academy of Finland [266528]; Finnish Cancer Society; Nordic Cancer Union; Sigrid Juselius Foundation; Orion-Farmos Research Foundation; Maud Kuistila Memorial Foundation; Biomedicum Helsinki Foundation; Alfred Kordelin Foundation; Paulo Foundation; Finnish Cultural Foundation; Cancer Research UK [C1287/A12014, C1287/A10118, C1287/A 10710, C12292/A11174, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565]; European Community [223175, HEALTH-F2-2009-223175]; European Community's Seventh Framework Programme [223175 (HEALTH-F2-2009223175)]; National Institutes of Health [CA128978]; Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defence [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer; Komen Foundation for the Cure; Breast Cancer Research Foundation; Ovarian Cancer Research Fund; National Cancer Institute (USA) [UM1 CA164920]; National Health and Medical Research Council of Australia; New South Wales Cancer Council; Victorian Health Promotion Foundation (Australia); Victorian Breast Cancer Research Consortium; Dutch Cancer Society [NKI 2007-3839, 2009 4363]; ELAN-Fond of the University Hospital of Erlangen; Breakthrough Breast Cancer; NHS; National Cancer Research Network (NCRN); NIHR Comprehensive Biomedical Research Centre; Guy's & St. Thomas' NHS Foundation Trust; King's College London, United Kingdom; Oxford Biomedical Research Centre; Dietmar-Hopp Foundation; Helmholtz Society; German Cancer Research Center (DKFZ); Fondation de France; Institut National du Cancer (INCa); Ligue Nationale contre le Cancer; Ligue contre le Cancer Grand Ouest; Agence Nationale de Securite Sanitaire (ANSES); Agence Nationale de la Recherche (ANR); Chief Physician Johan Boserup and Lise Boserup Fund; Danish Medical Research Council; Herlev Hospital; Instituto de Salud Carlos III; Red Tematica de Investigacion Cooperativa en Cancer; Asociacion Espanola Contra el Cancer; Fondo de Investigacion Sanitario [PI11/00923, PI12/00070] FX The HEBCS was financially supported by the Helsinki University Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, The Nordic Cancer Union and the Sigrid Juselius Foundation. LMP received funding from Orion-Farmos Research Foundation, Maud Kuistila Memorial Foundation, Biomedicum Helsinki Foundation, Alfred Kordelin Foundation, Paulo Foundation and the Finnish Cultural Foundation. BCAC is funded by Cancer Research UK [C1287/A10118, C1287/A12014] and by the European Community's Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 -the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The Australian Breast Cancer Family Study (ABCFS) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and the Victorian Breast Cancer Research Consortium. J.L.H. is a National Health and Medical Research Council (NHMRC) Australia Fellow and a Victorian Breast Cancer Research Consortium Group Leader. M.C.S. is a NHMRC Senior Research Fellow and a Victorian Breast Cancer Research Consortium Group Leader. The ABCS study was supported by the Dutch Cancer Society [grants NKI 2007-3839; 2009 4363]. The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen. The BBCS is funded by Cancer Research UK and Breakthrough Breast Cancer and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). ES is supported by NIHR Comprehensive Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London, United Kingdom. IT is supported by the Oxford Biomedical Research Centre. The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ). The CECILE study was funded by Fondation de France, Institut National du Cancer (INCa), Ligue Nationale contre le Cancer, Ligue contre le Cancer Grand Ouest, Agence Nationale de Securite Sanitaire (ANSES), Agence Nationale de la Recherche (ANR). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital.; The CNIO-BCS was supported by the Instituto de Salud Carlos III, the Red Tematica de Investigacion Cooperativa en Cancer and grants from the Asociacion Espanola Contra el Cancer and the Fondo de Investigacion Sanitario (PI11/00923 and PI12/00070). The CTS was initially supported by the California Breast Cancer Act of 1993 and the California Breast Cancer Research Fund (contract 97-10500) and is currently funded through the National Institutes of Health (R01 CA77398). Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. HAC receives support from the Lon V Smith Foundation (LVS39420). The ESTHER study was supported by a grant from the Baden Wurttemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). The GC-HBOC (German Consortium of Hereditary Breast and Ovarian Cancer) is supported by the German Cancer Aid (grant no 110837, coordinator: Rita K. Schmutzler). The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114, the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, the Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany. The HMBCS was supported by a grant from the Friends of Hannover Medical School and by the Rudolf Bartling Foundation. Financial support for KARBAC was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, the Swedish Cancer Society, The Gustav V Jubilee foundation and Bert von Kantzows foundation. The KBCP was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, and by the strategic funding of the University of Eastern Finland. kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command [DAMD17-01-1-0729], Cancer Council Victoria, Queensland Cancer Fund, Cancer Council New South Wales, Cancer Council South Australia, The Cancer Foundation of Western Australia, Cancer Council Tasmania and the National Health and Medical Research Council of Australia (NHMRC; 400413, 400281, 199600). G.C.T. and P.W. are supported by the NHMRC. RB was a Cancer Institute NSW Clinical Research Fellow. LMBC is supported by the "Stichting tegen Kanker" (232-2008 and 196-2010). Diether Lambrechts is supported by the FWO and the KULPFV/10/016-SymBioSysII. The MARIE study was supported by the Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419], the Hamburg Cancer Society, the German Cancer Research Center (DKFZ) and the Federal Ministry of Education and Research (BMBF) Germany [01KH0402].; MBCSG is supported by grants from the Italian Association for Cancer Research (AIRC) and by funds from the Italian citizens who allocated the 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects "5x1000"). The MCBCS was supported by the NIH grants CA128978, CA116167, CA176785 an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201], and the Breast Cancer Research Foundation and a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR). The MEC was support by NIH grants CA63464, CA54281, CA098758 and CA132839. The work of MTLGEBCS was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research for the " CIHR Team in Familial Risks of Breast Cancer" program - grant #CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade -grant #PSR-SIIRI-701. The NBCS has received funding from the K.G. Jebsen Centre for Breast Cancer Research; the Research Council of Norway grant 193387/V50 (to AL Borresen-Dale and V.N. Kristensen) and grant 193387/H10 (to A-L Borresen-Dale and V.N. Kristensen), South Eastern Norway Health Authority (grant 39346 to A-L Borresen-Dale) and the Norwegian Cancer Society (to A-L Borresen-Dale and V.N. Kristensen). The NBHS was supported by NIH grant R01CA100374. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The OBCS was supported by research grants from the Finnish Cancer Foundation, the Academy of Finland (grant number 250083, 122715 and Center of Excellence grant number 251314), the Finnish Cancer Foundation, the Sigrid Juselius Foundation, the University of Oulu, the University of Oulu Support Foundation and the special Governmental EVO funds for Oulu University Hospital-based research activities. The Ontario Familial Breast Cancer Registry (OFBCR) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The ORIGO study was supported by the Dutch Cancer Society (RUL 1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP16). The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The pKARMA study was supported by Marit and Hans Rausings Initiative Against Breast Cancer. The RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318). The SASBAC study was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation. The SBCS was supported by Yorkshire Cancer Research S295, S299, S305PA and Sheffield Experimental Cancer Medicine Centre.; SEARCH is funded by a programme grant from Cancer Research UK [C490/A10124] and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. SKKDKFZS is supported by the DKFZ. The SZBCS was supported by Grant PBZ_KBN_122/P05/2004. The TNBCC was supported by: a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a grant from the Breast Cancer Research Foundation, a generous gift from the David F. and Margaret T. Grohne Family Foundation, the Stefanie Spielman Breast Cancer fund and the OSU Comprehensive Cancer Center, the Hellenic Cooperative Oncology Group research grant (HR R_BG/04) and the Greek General Secretary for Research and Technology (GSRT) Program, Research Excellence II, the European Union (European Social Fund - ESF), and Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) - ARISTEIA. The UKBGS is funded by BreakthroughBreast Cancer and the Institute of Cancer Research (ICR), London. ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 0 Z9 0 U1 6 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 5 PY 2016 VL 11 IS 5 AR e0153788 DI 10.1371/journal.pone.0153788 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DL5KV UT WOS:000375676800015 PM 27149063 ER PT J AU Maxwell, KN Hart, SN Vijai, J Schrader, KA Slavin, TP Thomas, T Wubbenhorst, B Ravichandran, V Moore, RM Hu, CL Guidugli, L Wenz, B Domchek, SM Robson, ME Szabo, C Neuhausen, SL Weitzel, JN Offit, K Couch, FJ Nathanson, KL AF Maxwell, Kara N. Hart, Steven N. Vijai, Joseph Schrader, Kasmintan A. Slavin, Thomas P. Thomas, Tinu Wubbenhorst, Bradley Ravichandran, Vignesh Moore, Raymond M. Hu, Chunling Guidugli, Lucia Wenz, Brandon Domchek, Susan M. Robson, Mark E. Szabo, Csilla Neuhausen, Susan L. Weitzel, Jeffrey N. Offit, Kenneth Couch, Fergus J. Nathanson, Katherine L. TI Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID INCIDENTAL FINDINGS; NEXT-GENERATION; SECONDARY FINDINGS; COLORECTAL-CANCER; SEQUENCE VARIANTS; RISK ASSESSMENT; CLINICAL EXOME; RARE MUTATIONS; OVARIAN-CANCER; GENOMICS AB Sequencing tests assaying panels of genes or whole exomes are widely available for cancer risk evaluation. However, methods for classification of variants resulting from this testing are not well studied. We evaluated the ability of a variant-classification methodology based on American College of Medical Genetics and Genomics (ACMG) guidelines to define the rate of mutations and variants of uncertain significance (VUS) in 180 medically relevant genes, including all ACMG-designated reportable cancer and non-cancer-associated genes, in individuals who met guidelines for hereditary cancer risk evaluation. We performed whole-exome sequencing in 404 individuals in 253 families and classified 1,640 variants. Potentially clinically actionable (likely pathogenic [LP] or pathogenic [P]) versus non-actionable (VUS, likely benign, or benign) calls were 95% concordant with locus-specific databases and Clinvar. LP or P mutations were identified in 12 of 25 breast cancer susceptibility genes in 26 families without identified BRCA1/2 mutations (11%). Evaluation of 84 additional genes associated with autosomal-dominant cancer susceptibility identified LP or P mutations in only two additional families (0.8%). However, individuals from 10 of 253 families (3.9%) had incidental LP or P mutations in 32 non-cancer-associated genes, and 9% of individuals were monoallelic carriers of a rare LP or P mutation in 39 genes associated with autosomal-recessive cancer susceptibility. Furthermore, 95% of individuals had at least one VUS. In summary, these data support the clinical utility of ACMG variant-classification guidelines. Additionally, evaluation of extended panels of cancer-associated genes in breast/ovarian cancer families leads to only an incremental clinical benefit but substantially increases the complexity of the results. C1 [Maxwell, Kara N.] Univ Penn, Dept Med, Div Hematol Oncol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Hart, Steven N.; Moore, Raymond M.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Vijai, Joseph; Thomas, Tinu; Ravichandran, Vignesh; Robson, Mark E.; Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Res Lab, New York, NY 10065 USA. [Vijai, Joseph; Thomas, Tinu; Ravichandran, Vignesh; Robson, Mark E.; Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Clin Genet Serv, New York, NY 10065 USA. [Schrader, Kasmintan A.] Univ British Columbia, Dept Med Genet, Vancouver, BC V6T 1Z4, Canada. [Slavin, Thomas P.; Weitzel, Jeffrey N.] City Hope Natl Med Ctr, Div Clin Canc Genet, Dept Med Oncol, Duarte, CA 91010 USA. [Slavin, Thomas P.; Neuhausen, Susan L.; Weitzel, Jeffrey N.] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA 91010 USA. [Wubbenhorst, Bradley; Wenz, Brandon; Nathanson, Katherine L.] Univ Penn, Perelman Sch Med, Dept Med, Div Translat Med & Genet, Philadelphia, PA 19104 USA. [Hu, Chunling; Guidugli, Lucia] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. [Domchek, Susan M.; Nathanson, Katherine L.] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Robson, Mark E.; Offit, Kenneth] Weill Cornell Med Coll, New York, NY 10065 USA. [Szabo, Csilla] NHGRI, NIH, Bethesda, MD 20892 USA. RP Nathanson, KL (reprint author), Univ Penn, Perelman Sch Med, Dept Med, Div Translat Med & Genet, Philadelphia, PA 19104 USA.; Nathanson, KL (reprint author), Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA. EM knathans@exchange.upenn.edu FU National Institutes of Health [T32-GM008638, CA192393, CA176785, CA116167]; City of Hope Clinical Cancer Genomics Community Research Network [RC4 CA153828]; Mayo Clinic Breast Specialized Program of Research Excellence (SPORE) [P50 CA116201]; Abramson Cancer Center [CA016520]; Memorial Sloan Kettering Cancer Center [CA008748]; U.S. Department of Defense [W81XWH-13-1-0338]; American Society of Clinical Oncology [10048914]; Avon Foundation [02-2013-044]; Breast Cancer Research Foundation; Canadian Institutes of Health Research; Michael Smith Foundation for Health Research; BC Cancer Foundation; Rooney Family Foundation; Komen Foundation for the Cure; Commonwealth of Pennsylvania; Sharon Levine Corzine Cancer Research Fund; Robert and Kate Niehaus Clinical Cancer Initiative; Filomen M. D'Agostino Foundation; Andrew Sabin Family Fund; American Cancer Society; Morris Family Endowed Professorship; Horowitz Family Endowed Professorship FX This work is supported by National Institutes of Health grants (T32-GM008638 to K.N.M.; CA192393 to F.J.C. and K.L.N.; CA176785 to K.O., F.J.C., and K.L.N.; and CA116167 to F.J.C.); City of Hope Clinical Cancer Genomics Community Research Network grant RC4 CA153828 to J.N.W.; Mayo Clinic Breast Specialized Program of Research Excellence (SPORE) grant P50 CA116201; Abramson Cancer Center Core grant CA016520; Memorial Sloan Kettering Cancer Center Core grant CA008748; the U.S. Department of Defense (W81XWH-13-1-0338 to K.N.M.), the American Society of Clinical Oncology (PD# 10048914 to K.N.M.); the Avon Foundation (02-2013-044 to J.N.W.); the Breast Cancer Research Foundation (K.N.M., S.M.D., M.E.R., J.N.W., K.O., F.J.C., and K.L.N.); the Canadian Institutes of Health Research (K.A.S.); the Michael Smith Foundation for Health Research (K.A.S.); the BC Cancer Foundation (K.A.S.); the Rooney Family Foundation (K.L.N. and S.M.D.); Komen Foundation for the Cure (S.M.D.); the Commonwealth of Pennsylvania (K.L.N.); the Sharon Levine Corzine Cancer Research Fund (K.O.); the Robert and Kate Niehaus Clinical Cancer Initiative (K.O.); Filomen M. D'Agostino Foundation (K.O.); the Andrew Sabin Family Fund (K.O.); the American Cancer Society (J.N.W.); and the Morris and Horowitz Families Endowed Professorship (S.L.N.). All work contained in this manuscript is original. K.O. is co-Chair of the ClinGen Hereditary Cancer Working Group, of which F.J.C. and K.L.N. are members; the views expressed in this article are those of the authors and not of this Working Group. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Views and opinions of and endorsements by the authors do not reflect those of the US Army or the Department of Defense. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations, or conclusions. NR 52 TC 9 Z9 9 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAY 5 PY 2016 VL 98 IS 5 BP 801 EP 817 DI 10.1016/j.ajhg.2016.02.024 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA DL8DF UT WOS:000375869300001 PM 27153395 ER PT J AU Decker, B Karyadi, DM Davis, BW Karlins, E Tillmans, LS Stanford, JL Thibodeau, SN Ostrander, EA AF Decker, Brennan Karyadi, Danielle M. Davis, Brian W. Karlins, Eric Tillmans, Lori S. Stanford, Janet L. Thibodeau, Stephen N. Ostrander, Elaine A. TI Biallelic BRCA2 Mutations Shape the Somatic Mutational Landscape of Aggressive Prostate Tumors SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID DNA-SEQUENCING DATA; BREAST CANCERS; OVARIAN-CANCER; GENE; REPAIR; PHENOTYPE; FRAMEWORK; GENOMES; PTEN; END AB To identify clinically important molecular subtypes of prostate cancer (PCa), we characterized the somatic landscape of aggressive tumors via deep, whole-genome sequencing. In our discovery set of ten tumor/normal subject pairs with Gleason scores of 8-10 at diagnosis, coordinated analysis of germline and somatic variants, including single-nucleotide variants, indels, and structural variants, revealed biallelic BRCA2 disruptions in a subset of samples. Compared to the other samples, the PCa BRCA2-deficient tumors exhibited a complex and highly specific mutation signature, featuring a 2.88-fold increased somatic mutation rate, depletion of context-specific C>T substitutions, and an enrichment for deletions, especially those longer than 10 bp. We next performed a BRCA2 deficiency-targeted reanalysis of 150 metastatic PCa tumors, and each of the 18 BRCA2-mutated samples recapitulated the BRCA2 deficiency-associated mutation signature, underscoring the potent influence of these lesions on somatic mutagenesis and tumor evolution. Among all 21 individuals with BRCA2-deficient tumors, only about half carried deleterious germline alleles. Importantly, the somatic mutation signature in tumors with one germline and one somatic risk allele was indistinguishable from those with purely somatic mutations. Our observations clearly demonstrate that BRCA2-disrupted tumors represent a unique and clinically relevant molecular subtype of aggressive PCa, highlighting both the promise and utility of this mutation signature as a prognostic and treatment-selection biomarker. Further, any test designed to leverage BRCA2 status as a biomarker for PCa must consider both germline and somatic mutations and all types of deleterious mutations. C1 [Decker, Brennan; Karyadi, Danielle M.; Davis, Brian W.; Karlins, Eric; Ostrander, Elaine A.] NHGRI, NIH, Canc Genet Branch, Bethesda, MD 20892 USA. [Decker, Brennan] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England. [Tillmans, Lori S.; Thibodeau, Stephen N.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. [Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. RP Ostrander, EA (reprint author), NHGRI, NIH, Canc Genet Branch, Bethesda, MD 20892 USA. EM eostrand@mail.nih.gov OI Ostrander, Elaine/0000-0001-6075-9738 FU National Human Genome Research Institute; Prostate Cancer SPORE Grant [CA17205]; NIH-Cambridge Scholars Program FX This work was supported by Intramural Research Program of the National Human Genome Research Institute (E.A.O., B.D., D.M.K., B.W.D., E.K.), Prostate Cancer SPORE Grant # CA17205 (S.N.T., L.S.T.), and the NIH-Cambridge Scholars Program (B.D.). We thank the Mayo Clinic Pathology Core for sample processing. This work utilized the NIH Biowulf high-performance computing cluster. Finally, we thank the many men who provided samples for this study. NR 50 TC 2 Z9 2 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAY 5 PY 2016 VL 98 IS 5 BP 818 EP 829 DI 10.1016/j.ajhg.2016.03.003 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA DL8DF UT WOS:000375869300002 PM 27087322 ER PT J AU Li, J Woods, SL Healey, S Beesley, J Chen, XQ Lee, JS Sivakumaran, H Wayte, N Nones, K Waterfall, JJ Pearson, J Patch, AM Senz, J Ferreira, MA Kaurah, P Mackenzie, R Heravi-Moussavi, A Hansford, S Lannagan, TRM Spurdle, AB Simpson, PT da Silva, L Lakhani, SR Clouston, AD Bettington, M Grimpen, F Busuttil, RA Di Costanzo, N Boussioutas, A Jeanjean, M Chong, G Fabre, A Olschwang, S Faulkner, GJ Bellos, E Coin, L Rioux, K Bathe, OF Wen, XG Martin, HC Neklason, DW Davis, SR Walker, RL Calzone, KA Avital, I Heller, T Koh, C Pineda, M Rudloff, U Quezado, M Pichurin, PN Hulick, PJ Weissman, SM Newlin, A Rubinstein, WS Sampson, JE Hamman, K Goldgar, D Poplawski, N Phillips, K Schofield, L Armstrong, J Kiraly-Borri, C Suthers, GK Huntsman, DG Foulkes, WD Carneiro, F Lindor, NM Edwards, SL French, JD Waddell, N Meltzer, PS Worthley, DL Schrader, KA Chenevix-Trench, G AF Li, Jun Woods, Susan L. Healey, Sue Beesley, Jonathan Chen, Xiaoqing Lee, Jason S. Sivakumaran, Haran Wayte, Nicci Nones, Katia Waterfall, Joshua J. Pearson, John Patch, Anne-Marie Senz, Janine Ferreira, Manuel A. Kaurah, Pardeep Mackenzie, Robertson Heravi-Moussavi, Alireza Hansford, Samantha Lannagan, Tamsin R. M. Spurdle, Amanda B. Simpson, Peter T. da Silva, Leonard Lakhani, Sunil R. Clouston, Andrew D. Bettington, Mark Grimpen, Florian Busuttil, Rita A. Di Costanzo, Natasha Boussioutas, Alex Jeanjean, Marie Chong, George Fabre, Aurelie Olschwang, Sylviane Faulkner, Geoffrey J. Bellos, Evangelos Coin, Lachlan Rioux, Kevin Bathe, Oliver F. Wen, Xiaogang Martin, Hilary C. Neklason, Deborah W. Davis, Sean R. Walker, Robert L. Calzone, Kathleen A. Avital, Itzhak Heller, Theo Koh, Christopher Pineda, Marbin Rudloff, Udo Quezado, Martha Pichurin, Pavel N. Hulick, Peter J. Weissman, Scott M. Newlin, Anna Rubinstein, Wendy S. Sampson, Jone E. Hamman, Kelly Goldgar, David Poplawski, Nicola Phillips, Kerry Schofield, Lyn Armstrong, Jacqueline Kiraly-Borri, Cathy Suthers, Graeme K. Huntsman, David G. Foulkes, William D. Carneiro, Fatima Lindor, Noralane M. Edwards, Stacey L. French, Juliet D. Waddell, Nicola Meltzer, Paul S. Worthley, Daniel L. Schrader, Kasmintan A. Chenevix-Trench, Georgia TI Point Mutations in Exon 1B of APC Reveal Gastric Adenocarcinoma and Proximal Polyposis of the Stomach as a Familial Adenomatous Polyposis Variant SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID FUNDIC GLAND POLYPS; HIGH-GRADE DYSPLASIA; PROMOTER 1B; SEQUENCING DATA; HUMAN GENOME; COLI GENE; CANCER; PATIENT; FAP; RETROTRANSPOSITION AB Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is an autosomal-dominant cancer-predisposition syndrome with a significant risk of gastric, but not colorectal, adenocarcinoma. We mapped the gene to 5q22 and found loss of the wild-type allele on 5q in fundic gland polyps from affected individuals. Whole-exome and -genome sequencing failed to find causal mutations but, through Sanger sequencing, we identified point mutations in APC promoter 1B that co-segregated with disease in all six families. The mutations reduced binding of the YY1 transcription factor and impaired activity of the APC promoter 1B in luciferase assays. Analysis of blood and saliva from carriers showed allelic imbalance of APC, suggesting that these mutations lead to decreased allele-specific expression in vivo. Similar mutations in APC promoter 1B occur in rare families with familial adenomatous polyposis (FAP). Promoter 1A is methylated in GAPPS and sporadic FGPs and in normal stomach, which suggests that 1B transcripts are more important than 1A in gastric mucosa. This might explain why all known GAPPS-affected families carry promoter 1B point mutations but only rare FAP-affected families carry similar mutations, the colonic cells usually being protected by the expression of the 1A isoform. Gastric polyposis and cancer have been previously described in some FAP-affected individuals with large deletions around promoter 1B. Our finding that GAPPS is caused by point mutations in the same promoter suggests that families with mutations affecting the promoter 1B are at risk of gastric adenocarcinoma, regardless of whether or not colorectal polyps are present. C1 [Li, Jun; Healey, Sue; Beesley, Jonathan; Chen, Xiaoqing; Lee, Jason S.; Sivakumaran, Haran; Wayte, Nicci; Nones, Katia; Pearson, John; Patch, Anne-Marie; Ferreira, Manuel A.; Spurdle, Amanda B.; Edwards, Stacey L.; French, Juliet D.; Waddell, Nicola; Chenevix-Trench, Georgia] QIMR Berghofer, Dept Genet & Computat Biol, Herston, Qld 4029, Australia. [Woods, Susan L.; Lannagan, Tamsin R. M.; Worthley, Daniel L.] Univ Adelaide & Canc Theme, Sch Med, SAHMRI, Adelaide, SA 5000, Australia. [Waterfall, Joshua J.; Davis, Sean R.; Walker, Robert L.; Calzone, Kathleen A.; Pineda, Marbin; Meltzer, Paul S.] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Pearson, John; Bellos, Evangelos; Coin, Lachlan; Waddell, Nicola] Univ Queensland, Inst Mol Biosci, St Lucia, Qld 4072, Australia. [Senz, Janine; Hansford, Samantha] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V6T 2B5, Canada. [Kaurah, Pardeep; Schrader, Kasmintan A.] Univ British Columbia, Dept Med Genet, Vancouver, BC V6H 3N1, Canada. [Mackenzie, Robertson; Huntsman, David G.; Schrader, Kasmintan A.] British Columbia Canc Res Ctr, Dept Mol Oncol, Vancouver, BC V5Z 1L3, Canada. [Heravi-Moussavi, Alireza] Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4S6, Canada. [Simpson, Peter T.; da Silva, Leonard; Lakhani, Sunil R.] Univ Queensland, UQ Ctr Clin Res, Brisbane, Qld 4029, Australia. [Simpson, Peter T.; da Silva, Leonard; Lakhani, Sunil R.; Bettington, Mark] Univ Queensland, Sch Med, Brisbane, Qld 4006, Australia. [Lakhani, Sunil R.] Royal Brisbane & Womens Hosp, Anat Pathol, Pathol Queensland, Brisbane, Qld 4029, Australia. [Clouston, Andrew D.] Univ Queensland, Ctr Liver Dis Res, TRI Bldg, Woolloongabba, Qld 4102, Australia. [Clouston, Andrew D.; Bettington, Mark] Envoi Specialist Pathologists, Bishop St, Kelvin Grove, Qld 4059, Australia. [Bettington, Mark] QIMR Berghofer, Conjoint Gastroenterol Lab, Herston, Qld 4029, Australia. [Grimpen, Florian] Royal Brisbane & Womens Hosp, Dept Gastroenterol, Brisbane, Qld 4006, Australia. [Grimpen, Florian] Royal Brisbane & Womens Hosp, Dept Hepatol, Brisbane, Qld 4006, Australia. [Busuttil, Rita A.; Di Costanzo, Natasha; Boussioutas, Alex] Peter MacCallum Canc Ctr, Canc Genet & Genom Lab, Locked Bag 1, Melbourne, Vic 8006, Australia. [Busuttil, Rita A.; Boussioutas, Alex] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3010, Australia. [Busuttil, Rita A.; Boussioutas, Alex] Univ Melbourne, Dept Med, Royal Melbourne Hosp, Parkville, Vic 3010, Australia. [Boussioutas, Alex] Royal Melbourne Hosp, Dept Gastroenterol, Parkville, Vic 3010, Australia. [Jeanjean, Marie; Foulkes, William D.] Jewish Gen Hosp, Segal Canc Ctr, Lady Davis Inst, Montreal, PQ H3T 1E2, Canada. [Chong, George] McGill Univ, Jewish Gen Hosp, Dept Pathol, Mol Pathol Ctr, Montreal, PQ H3T 1E2, Canada. [Fabre, Aurelie; Olschwang, Sylviane] AP HM Timone, Dept Med Genet, F-13385 Marseille, France. [Fabre, Aurelie; Olschwang, Sylviane] Aix Marseille Univ, INSERM, GMGF UMR S 910, F-13385 Marseille, France. [Fabre, Aurelie; Olschwang, Sylviane] Clairval Hosp, Gen Sante, Oncol Unit, F-13009 Marseille, France. [Faulkner, Geoffrey J.] Univ Queensland, Mater Res Inst, TRI Bldg, Woolloongabba, Qld 4102, Australia. [Bellos, Evangelos] Univ London Imperial Coll Sci Technol & Med, Dept Genom Common Dis, London W12 0NN, England. [Rioux, Kevin] Univ Calgary, Dept Med, Dept Microbiol & Infect Dis, Div Gastroenterol,Gastrointestinal Res Grp, Calgary, AB T2N 4N1, Canada. [Bathe, Oliver F.] Univ Calgary, Dept Surg, Calgary, AB T2N 4N1, Canada. [Bathe, Oliver F.] Univ Calgary, Dept Oncol, Calgary, AB T2N 4N1, Canada. [Bathe, Oliver F.] Tom Baker Canc Clin, Div Surg Oncol, 1331 29th St NW, Calgary, AB T2N 4N1, Canada. [Wen, Xiaogang; Carneiro, Fatima] Univ Porto, Inst Mol Pathol & Immunol, IPATIMUP Inst Invest & Inovacao Saude, P-4200135 Oporto, Portugal. [Wen, Xiaogang] Ctr Hosp Vila Nova Gaia Espinho, P-4430027 Oporto, Portugal. [Martin, Hilary C.] Ctr Human Genet, Wellcome Trust, Oxford OX3 7BN, England. [Neklason, Deborah W.] Univ Utah, Huntsman Canc Inst, Dept Internal Med, Salt Lake City, UT 84112 USA. [Avital, Itzhak] Rutgers State Univ, St Peters Univ Hosp, Dept Surg, New Brunswick, NJ 08901 USA. [Heller, Theo; Koh, Christopher] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Rudloff, Udo] NCI, Thorac & Gastrointestinal Oncol Branch, CCR, NIH, Bethesda, MD 20892 USA. [Quezado, Martha] NCI, Pathol Lab, CCR, NIH, Bethesda, MD 20892 USA. [Pichurin, Pavel N.] Mayo Clin, Dept Med Genet, Rochester, MN 55905 USA. [Hulick, Peter J.; Newlin, Anna] NorthShore Univ HealthSyst, Ctr Med Genet, Evanston, IL 60201 USA. [Weissman, Scott M.] GeneDx, 207 Perry Pkwy, Gaithersburg, MD 20877 USA. [Rubinstein, Wendy S.] NIH, NCBI, Natl Lib Med, Bethesda, MD 20892 USA. [Sampson, Jone E.; Hamman, Kelly] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97239 USA. [Goldgar, David] Univ Utah, Sch Med, Dept Dermatol, Salt Lake City, UT 84112 USA. [Goldgar, David] Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [Poplawski, Nicola; Phillips, Kerry; Armstrong, Jacqueline] Womens & Childrens Hosp, Adult Genet Unit, SA Pathol, Adelaide, SA 5006, Australia. [Poplawski, Nicola; Phillips, Kerry; Suthers, Graeme K.] Univ Adelaide, Univ Dept Paediat, Adelaide, SA 5005, Australia. [Schofield, Lyn; Kiraly-Borri, Cathy] King Edward Mem Hosp Women, Genet Serv Western Australia, Subiaco, WA 6008, Australia. [Huntsman, David G.] Univ British Columbia, Dept Pathol & Obstet & Gynaecol, Vancouver, BC V6Z 2K5, Canada. [Foulkes, William D.] McGill Univ, Program Canc Genet, Dept Oncol, Montreal, PQ H3A 1B1, Canada. [Foulkes, William D.] McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada. [Carneiro, Fatima] Univ Porto, Fac Med, Ctr Hosp Sao Joao, P-4200319 Oporto, Portugal. [Lindor, Noralane M.] Mayo Clin, Dept Hlth Sci Res, Scottsdale, AZ 85259 USA. RP Chenevix-Trench, G (reprint author), QIMR Berghofer, Dept Genet & Computat Biol, Herston, Qld 4029, Australia. EM georgia.trench@qimrberghofer.edu.au RI Edwards, Stacey/A-4980-2011; Simpson, Peter/F-1225-2010; Carneiro, Fatima/J-6432-2013; Olschwang, Sylviane/G-2716-2013; Fabre, Aurelie/M-1660-2016; Lee, Jason/M-7522-2016; OI Simpson, Peter/0000-0002-4816-8289; Carneiro, Fatima/0000-0002-1964-1006; Lee, Jason/0000-0003-0879-934X; Coin, Lachlan/0000-0002-4300-455X; Clouston, Andrew/0000-0002-9601-7952; Sivakumaran, Haran/0000-0002-4691-4989; Boussioutas, Alex/0000-0002-8109-6897 FU NHMRC; NIH [PO1-CA073992]; Canadian Institutes of Health Research [MOP-123517]; Ride to Conquer Cancer; NHMRC [GNT1045237]; Cancer Council South Australia; Canadian Institutes of Health Research; Michael Smith Foundation for Health Research; BC Cancer Foundation; NIH; Amgen; Sanofi Canada; pathology lab: Perth Pathology; pathology lab: St John of God Pathology; pathology lab: Western Diagnostics; pathology lab: PathWest (Royal Perth Hospital); pathology lab: PathWest (Fremantle Hospital); pathology lab: PathWest (King Edward Memorial Hospital); pathology lab: PathWest (Sir Charles Gairdner Hospital) FX We thank all the individuals from the GAPPS-affected families who took part in this study, Andrew Giraud for providing the AGS and MKN74 cell lines, and Vicki Whitehall for HCT116 and RKO. The work was funded by the NHMRC, NIH (PO1-CA073992), and grant MOP-123517 from the Canadian Institutes of Health Research and the Ride to Conquer Cancer. G.J.F. acknowledges the support of an NHMRC Career Development Fellowship (GNT1045237); D.L.W., T.R.M.L., and S.L.W. are funded by Cancer Council South Australia Beat Cancer Project; G.C.-T. and A.B.S. by NHMRC Research Fellowships; and K.A.S. by the Canadian Institutes of Health Research, Michael Smith Foundation for Health Research, and BC Cancer Foundation. W.D.F. thanks Ms. N. Wong for clinical contributions. We acknowledge the support provided by the following pathology labs: Perth Pathology, St John of God Pathology, Western Diagnostics, and PathWest (Royal Perth Hospital, Fremantle Hospital, King Edward Memorial Hospital, and Sir Charles Gairdner Hospital). The authors are very grateful to staff at the Australian Red Cross Blood Services for their assistance with the collection of risk factor information and blood samples of healthy donor control subjects and thank members of the QIMR Molecular Cancer Epidemiology Laboratory for their assistance with recruitment and biospecimen processing. This study was in part (P.S.M., U.R.) supported by the Intramural Research Program of the NIH. O.F.B. has been paid consultancy fees by Amgen and Sanofi Canada. NR 69 TC 7 Z9 7 U1 4 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAY 5 PY 2016 VL 98 IS 5 BP 830 EP 842 DI 10.1016/j.ajhg.2016.03.001 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA DL8DF UT WOS:000375869300003 PM 27087319 ER PT J AU Molloy, AM Pangilinan, F Mills, JL Shane, B O'Neill, MB McGaughey, DM Velkova, A Abaan, HO Ueland, PM McNulty, H Ward, M Strain, JJ Cunningham, C Casey, M Cropp, CD Kim, Y Bailey-Wilson, JE Wilson, AF Brody, LC AF Molloy, Anne M. Pangilinan, Faith Mills, James L. Shane, Barry O'Neill, Mary B. McGaughey, David M. Velkova, Aneliya Abaan, Hatice Ozel Ueland, Per M. McNulty, Helene Ward, Mary Strain, J. J. Cunningham, Conal Casey, Miriam Cropp, Cheryl D. Kim, Yoonhee Bailey-Wilson, Joan E. Wilson, Alexander F. Brody, Lawrence C. TI A Common Polymorphism in HIBCH Influences Methylmalonic Acid Concentrations in Blood Independently of Cobalamin SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; VITAMIN-B-12 STATUS; TOTAL HOMOCYSTEINE; SERUM VITAMIN-B-12; VALINE METABOLISM; AUTOMATED-ASSAY; AXSYM ANALYZER; DEFICIENCY; PLASMA; FOLATE AB Methylmalonic acid (MMA) is a by-product of propionic acid metabolism through the vitamin B-12 (cobalamin)-dependent enzyme methylmalonyl CoA mutase. Elevated MMA concentrations are a hallmark of several inborn errors of metabolism and indicators of cobalamin deficiency in older persons. In a genome-wide analysis of 2,210 healthy young Irish adults (median age 22 years) we identified a strong association of plasma MMA with SNPs in 3-hydroxyisobutyryl-CoA hydrolase (HIBCH, p = 8.42 x 10(-89)) and acyl-CoA synthetase family member 3 (ACSF3, p = 3.48x10(-19)). These loci accounted for 12% of the variance in MMA concentration. The most strongly associated SNP (HIBCH rs291466; c:2T>C) causes a missense change of the initiator methionine codon (minor-allele frequency = 0.43) to threonine. Surprisingly, the resulting variant, p.Met1?, is associated with increased expression of HIBCH mRNA and encoded protein. These homozygotes had, on average, 46% higher MMA concentrations than methionine-encoding homozygotes in young adults with generally low MMA concentrations (0.17 [0.14-0.21] mu mol/L; median [25th-75th quartile]). The association between MMA levels and HIBCH rs291466 was highly significant in a replication cohort of 1,481 older individuals (median age 79 years) with elevated plasma MMA concentrations (0.34 [0.24-0.51] mu mol/L; p = 4.0 x 10(-26)). In a longitudinal study of 185 pregnant women and their newborns, the association of this SNP remained significant across the gestational trimesters and in newborns. HIBCH is unique to valine catabolism. Studies evaluating flux through the valine catabolic pathway in humans should account for these variants. Furthermore, this SNP could help resolve equivocal clinical tests where plasma MMA values have been used to diagnose cobalamin deficiency. C1 [Molloy, Anne M.] Univ Dublin, Trinity Coll Dublin, Sch Med, Dept Clin Med, Dublin 2, Ireland. [Pangilinan, Faith; O'Neill, Mary B.; McGaughey, David M.; Velkova, Aneliya; Abaan, Hatice Ozel; Brody, Lawrence C.] NHGRI, Med Genom & Metab Genet Branch, Bethesda, MD 20892 USA. [Mills, James L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Bethesda, MD 20892 USA. [Shane, Barry] Univ Calif Berkeley, Dept Nutr Sci & Toxicol, Berkeley, CA 94720 USA. [Ueland, Per M.] Univ Bergen, Inst Med, Pharmacol Sect, N-5021 Bergen, Norway. [Ueland, Per M.] Haukeland Hosp, N-5021 Bergen, Norway. [McNulty, Helene; Ward, Mary; Strain, J. J.] Univ Ulster, Northern Ireland Ctr Food & Hlth, Coleraine BT52 1SA, Londonderry, North Ireland. [Cunningham, Conal; Casey, Miriam] St James Hosp, Dublin 8, Ireland. [Cropp, Cheryl D.; Kim, Yoonhee; Bailey-Wilson, Joan E.; Wilson, Alexander F.] NHGRI, Computat & Stat Genom Branch, Bethesda, MD 20892 USA. [Cropp, Cheryl D.] Translat Genom Res Inst TGen, Phoenix, AZ 85004 USA. [Kim, Yoonhee] Macrogen, Rockville, MD 20850 USA. RP Molloy, AM (reprint author), Univ Dublin, Trinity Coll Dublin, Sch Med, Dept Clin Med, Dublin 2, Ireland.; Brody, LC (reprint author), NHGRI, Med Genom & Metab Genet Branch, Bethesda, MD 20892 USA. EM amolloy@tcd.ie; lbrody@mail.nih.gov FU National Human Genome Research Institute (NHGRI); Eunice Kennedy Shriver National Institute of Child Health and Human Development of the NIH; Health Research Board, Dublin; NHGRI; Irish Department of Agriculture, Food and the Marine's Food Institutional Research Measure initiative; Northern Ireland Department for Employment and Learning under the Cross-Border Research and Development Programme "Strengthening the all-Island Research Base"; Axis-Shield Diagnostics FX The authors acknowledge the contributions made by the participants in the Trinity Student Study, the Trinity Ulster Department of Agriculture study, and the longitudinal pregnancy study. The TSS GWAS work was supported in part by the Intramural Research Programs of the National Human Genome Research Institute (NHGRI), the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the NIH, and the Health Research Board, Dublin. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the NIH (https://hpc.nih.gov/systems). C.D.C. is the recipient of an NHGRI Health Disparities Research Fellowship. The TUDA study was funded by the Irish Department of Agriculture, Food and the Marine's Food Institutional Research Measure initiative and the Northern Ireland Department for Employment and Learning under the Cross-Border Research and Development Programme "Strengthening the all-Island Research Base." Holotranscobalamin and methylmalonic acid measurements in the TUDA cohort were sponsored by Axis-Shield Diagnostics. NR 63 TC 0 Z9 0 U1 1 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAY 5 PY 2016 VL 98 IS 5 BP 869 EP 882 DI 10.1016/j.ajhg.2016.03.005 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA DL8DF UT WOS:000375869300006 PM 27132595 ER PT J AU Vetter, P Dayer, JA Schibler, M Allegranzi, B Brown, D Calmy, A Christie, D Eremin, S Hagon, O Henderson, D Iten, A Kelley, E Marais, F Ndoye, B Pugin, J Robert-Nicoud, H Sterk, E Tapper, M Siegrist, CA Kaiser, L Pittet, D AF Vetter, Pauline Dayer, Julie-Anne Schibler, Manuel Allegranzi, Benedetta Brown, Donal Calmy, Alexandra Christie, Derek Eremin, Sergey Hagon, Olivier Henderson, David Iten, Anne Kelley, Edward Marais, Frederick Ndoye, Babacar Pugin, Jerome Robert-Nicoud, Hugues Sterk, Esther Tapper, Michael Siegrist, Claire-Anne Kaiser, Laurent Pittet, Didier TI The 2014-2015 Ebola outbreak in West Africa: Hands On SO ANTIMICROBIAL RESISTANCE AND INFECTION CONTROL LA English DT Editorial Material ID HEALTH-CARE WORKERS; VIRUS DISEASE; HEMORRHAGIC-FEVER; CONVALESCENT PLASMA; POSTEXPOSURE PROTECTION; NONHUMAN-PRIMATES; SIERRA-LEONE; SEXUAL TRANSMISSION; RNA INTERFERENCE; VIRAL LOAD AB The International Consortium for Prevention and Infection Control (ICPIC) organises a biannual conference ( ICPIC) on various subjects related to infection prevention, treatment and control. During ICPIC 2015, held in Geneva in June 2015, a full one-day session focused on the 2014-2015 Ebola virus disease (EVD) outbreak in West Africa. This article is a non-exhaustive compilation of these discussions. It concentrates on lessons learned and imagining a way forward for the communities most affected by the epidemic. The reader can access video recordings of all lectures delivered during this one-day session, as referenced. Topics include the timeline of the international response, linkages between the dynamics of the epidemic and infection prevention and control, the importance of community engagement, and updates on virology, diagnosis, treatment and vaccination issues. The paper also includes discussions from public health, infectious diseases, critical care and infection control experts who cared for patients with EVD in Africa, in Europe, and in the United Sates and were involved in Ebola preparedness in both high- and low-resource settings and countries. This review concludes that too little is known about the pathogenesis and treatment of EVD, therefore basic and applied research in this area are urgently required. Furthermore, it is clear that epidemic preparedness needs to improve globally, in particular through the strengthening of health systems at local and national levels. There is a strong need for culturally sensitive approaches to public health which could be designed and delivered by social scientists and medical professionals working together. As of December 2015, this epidemic killed more than 11,000 people and infected more than 28,000; it has also generated more than 17,000 survivors and orphans, many of whom face somatic and psychological complications. The continued treatment and rehabilitation of these people is a public health priority, which also requires an integration of specific medical and social science approaches, not always available in West Africa. C1 [Vetter, Pauline; Iten, Anne; Pittet, Didier] Univ Hosp Geneva, Infect Control Programme, Geneva, Switzerland. [Vetter, Pauline; Iten, Anne; Pittet, Didier] Univ Hosp Geneva, WHO Collaborating Ctr Patient Safety, Geneva, Switzerland. [Vetter, Pauline; Iten, Anne; Pittet, Didier] Univ Geneva, Sch Med, CH-1211 Geneva, Switzerland. [Vetter, Pauline; Dayer, Julie-Anne; Schibler, Manuel; Kaiser, Laurent] Univ Hosp Geneva, Virol Lab, Div Infect Dis, Geneva, Switzerland. [Vetter, Pauline; Dayer, Julie-Anne; Schibler, Manuel; Kaiser, Laurent] Univ Hosp Geneva, Swiss Reference Ctr Emerging Viral Dis, Geneva, Switzerland. [Allegranzi, Benedetta; Eremin, Sergey; Kelley, Edward] WHO, CH-1211 Geneva, Switzerland. [Brown, Donal] UK Dept Int Dev, London, England. [Calmy, Alexandra] Univ Hosp Geneva, Div Infect Dis, HIV Unit, Geneva, Switzerland. [Christie, Derek] Univ Geneva, Inst Global Hlth, Geneva, Switzerland. [Christie, Derek] Ecole Polytech Fed Lausanne, Lab Urban Sociol, CH-1015 Lausanne, Switzerland. [Hagon, Olivier] Univ Hosp Geneva, Div Trop & Humanitarian Med, Geneva, Switzerland. [Henderson, David] NIH, Ctr Clin, Washington, DC USA. [Marais, Frederick] Western Cape Govt, Cape Town, South Africa. [Marais, Frederick] Univ Stellenbosch, Cape Town, South Africa. [Ndoye, Babacar] Hosp Hyg Infect Control & Patient Safety WHO & UN, Dakar, Senegal. [Pugin, Jerome] Univ Hosp Geneva, Intens Care Unit, Geneva, Switzerland. [Robert-Nicoud, Hugues; Sterk, Esther] Med sans Frontieres, Geneva, Switzerland. [Tapper, Michael] Lenox Hill Hosp, Div Infect Dis, New York, NY 10021 USA. [Siegrist, Claire-Anne] Univ Hosp Geneva, WHO Collaborating Ctr Vaccine Immunol, Dept Pathol, Geneva, Switzerland. [Siegrist, Claire-Anne] Univ Hosp Geneva, WHO Collaborating Ctr Vaccine Immunol, Dept Immunol, Geneva, Switzerland. [Siegrist, Claire-Anne] Univ Hosp Geneva, WHO Collaborating Ctr Vaccine Immunol, Dept Paediat, Geneva, Switzerland. RP Pittet, D (reprint author), Univ Hosp Geneva, Infect Control Programme, Geneva, Switzerland.; Pittet, D (reprint author), Univ Hosp Geneva, WHO Collaborating Ctr Patient Safety, Geneva, Switzerland.; Pittet, D (reprint author), Univ Geneva, Sch Med, CH-1211 Geneva, Switzerland. EM didier.pittet@hcuge.ch RI Christie, Derek/A-3273-2016 OI Christie, Derek/0000-0001-7642-0245 NR 81 TC 0 Z9 0 U1 6 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2047-2994 J9 ANTIMICROB RESIST IN JI Antimicrob. Resist. Infect. Control PD MAY 5 PY 2016 VL 5 AR 17 DI 10.1186/s13756-016-0112-9 PG 17 WC Public, Environmental & Occupational Health; Infectious Diseases; Microbiology SC Public, Environmental & Occupational Health; Infectious Diseases; Microbiology GA DL5LY UT WOS:000375679800001 ER PT J AU Stewart-Jones, GBE Soto, C Lemmin, T Chuang, GY Druz, A Kong, R Thomas, PV Wagh, K Zhou, TQ Behrens, AJ Bylund, T Choi, CW Davison, JR Georgiev, IS Joyce, MG Do Kwon, Y Pancera, M Taft, J Yang, YP Zhang, BS Shivatare, SS Shivatare, VS Lee, CCD Wu, CY Bewley, CA Burton, DR Koff, WC Connors, M Crispin, M Baxa, U Korber, BT Wong, CH Mascola, JR Kwong, PD AF Stewart-Jones, Guillaume B. E. Soto, Cinque Lemmin, Thomas Chuang, Gwo-Yu Druz, Aliaksandr Kong, Rui Thomas, Paul V. Wagh, Kshitij Zhou, Tongqing Behrens, Anna-Janina Bylund, Tatsiana Choi, Chang W. Davison, Jack R. Georgiev, Ivelin S. Joyce, M. Gordon Do Kwon, Young Pancera, Marie Taft, Justin Yang, Yongping Zhang, Baoshan Shivatare, Sachin S. Shivatare, Vidya S. Lee, Chang-Chun D. Wu, Chung-Yi Bewley, Carole A. Burton, Dennis R. Koff, Wayne C. Connors, Mark Crispin, Max Baxa, Ulrich Korber, Bette T. Wong, Chi-Huey Mascola, John R. Kwong, Peter D. TI Trimeric HIV-1-Env Structures Define Glycan Shields from Clades A, B, and G SO CELL LA English DT Article ID BROADLY NEUTRALIZING ANTIBODIES; CRYO-EM STRUCTURE; HIV-ANTIBODIES; ENVELOPE TRIMER; CRYSTAL-STRUCTURE; VACCINE DESIGN; ENV; GLYCOPROTEIN; RECOGNITION; POTENT AB The HIV-1-envelope (Env) trimer is covered by a glycan shield of similar to 90 N-linked oligosaccharides, which comprises roughly half its mass and is a key component of HIV evasion from humoral immunity. To understand how antibodies can overcome the barriers imposed by the glycan shield, we crystallized fully glycosylated Env trimers from clades A, B, and G, visualizing the shield at 3.4-3.7 angstrom resolution. These structures reveal the HIV-1-glycan shield to comprise a network of interlocking oligosaccharides, substantially ordered by glycan crowding, that encase the protein component of Env and enable HIV-1 to avoid most antibody-mediated neutralization. The revealed features delineate a taxonomy of N-linked glycan-glycan interactions. Crowded and dispersed glycans are differently ordered, conserved, processed, and recognized by antibody. The structures, along with glycan-array binding and molecular dynamics, reveal a diversity in oligosaccharide affinity and a requirement for accommodating glycans among known broadly neutralizing antibodies that target the glycan-shielded trimer. C1 [Stewart-Jones, Guillaume B. E.; Soto, Cinque; Lemmin, Thomas; Chuang, Gwo-Yu; Druz, Aliaksandr; Kong, Rui; Thomas, Paul V.; Zhou, Tongqing; Bylund, Tatsiana; Choi, Chang W.; Georgiev, Ivelin S.; Joyce, M. Gordon; Do Kwon, Young; Pancera, Marie; Taft, Justin; Yang, Yongping; Zhang, Baoshan; Mascola, John R.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Lemmin, Thomas] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA. [Wagh, Kshitij; Korber, Bette T.] Los Alamos Natl Lab, Theoret Biol & Biophys Grp, POB 1663, Los Alamos, NM 87544 USA. [Behrens, Anna-Janina; Crispin, Max] Univ Oxford, Dept Biochem, Oxford Glycobiol Inst, S Parks Rd, Oxford OX1 3QU, England. [Davison, Jack R.; Bewley, Carole A.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Shivatare, Sachin S.; Shivatare, Vidya S.; Lee, Chang-Chun D.; Wu, Chung-Yi; Wong, Chi-Huey] Acad Sinica, Genom Res Ctr, 128 Acad Rd,Sect 2, Taipei 115, Taiwan. [Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, Int AIDS Vaccine Initiat Neutralizing Antibody Ct, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. [Burton, Dennis R.] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Boston, MA 02142 USA. [Koff, Wayne C.] Int AIDS Vaccine Initiat, New York, NY 10038 USA. [Connors, Mark] NIAID, HIV Specif Immun Sect, Immunoregulat Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Baxa, Ulrich] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Canc Res Technol Program, Electron Microscopy Lab, Ft Detrick, MD 21702 USA. [Wong, Chi-Huey] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA. RP Kwong, PD (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM pdkwong@nih.gov RI Kwon, Young Do/A-6957-2010; Zhou, Tongqing/A-6880-2010; OI Zhou, Tongqing/0000-0002-3935-4637; Korber, Bette/0000-0002-2026-5757; Davison, Jack/0000-0002-6803-304X FU Intramural Research Program of the Vaccine Research Center; National Institute of Allergy and Infectious Diseases; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH); International AIDS Vaccine Initiative's (IAVI's) Neutralizing Antibody Consortium; Bill & Melinda Gates Foundation; Ministry of Foreign Affairs of Denmark; Irish Aid; Ministry of Finance of Japan; Ministry of Foreign Affairs of the Netherlands; Norwegian Agency for Development Cooperation; UK Department for International Development; United States Agency for International Development (USAID); International AIDS Vaccine Initiative Neutralizing Antibody Center CAVD grant; Scripps Center For HIV/AIDS Vaccine Immunology-Immunogen Discovery (CHAVI-ID) grant [1UM1AI100663]; Duke CHAVI-ID grant [UM1 AI100645]; Swiss National Foundation of Science Fellowship [148914]; Academia Sinica; Ministry of Science and Technology [MOST 104-0210-01-09-02, 103-2321-B-001-004]; NIH [R01 AI072155]; US Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38]; [HHSN261200800001E] FX We thank R. O'Connor for NMR support, J. Stuckey for assistance with graphics, and members of the Structural Biology Section and Structural Bioinformatics Core, Vaccine Research Center for discussions and comments on the manuscript. We thank Acellera for assistance with molecular dynamics simulations. Support for this work was provided by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), and from the International AIDS Vaccine Initiative's (IAVI's) Neutralizing Antibody Consortium. IAVI's work is made possible by support from many donors, including the Bill & Melinda Gates Foundation; the Ministry of Foreign Affairs of Denmark; Irish Aid; the Ministry of Finance of Japan; the Ministry of Foreign Affairs of the Netherlands; the Norwegian Agency for Development Cooperation; the UK Department for International Development; and the United States Agency for International Development (USAID). The contents of this manuscript do not necessarily reflect the views of USAID or the US Government. The full list of IAVI donors is available at http://www.iavi.org. A.-J.B. and M. Crispin were supported by the International AIDS Vaccine Initiative Neutralizing Antibody Center CAVD grant (Glycan characterization and Outer Domain glycoform design) and the Scripps Center For HIV/AIDS Vaccine Immunology-Immunogen Discovery (CHAVI-ID) grant 1UM1AI100663. K.W. and B.K. were supported by the Duke CHAVI-ID grant UM1 AI100645. T.L. was supported by the Swiss National Foundation of Science Fellowship 148914. V.S.S., C.-C.D.L., C.-Y.W., and C.-H.W. were supported by Academia Sinica and Ministry of Science and Technology grants MOST 104-0210-01-09-02 and 103-2321-B-001-004. C.-H.W. was supported by NIH grant R01 AI072155. The Frederick National Laboratory for Cancer Research, National Institutes of Health, is supported under contract HHSN261200800001E. Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract number W-31-109-Eng-38. NR 46 TC 37 Z9 37 U1 12 U2 20 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD MAY 5 PY 2016 VL 165 IS 4 BP 813 EP 826 DI 10.1016/j.cell.2016.04.010 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DL7DN UT WOS:000375800300011 PM 27114034 ER PT J AU Oh, J Byrd, AL Park, M Kong, HH Segre, JA AF Oh, Julia Byrd, Allyson L. Park, Morgan Kong, Heidi H. Segre, Julia A. CA NISC Comparative Sequencing TI Temporal Stability of the Human Skin Microbiome SO CELL LA English DT Article ID SEQUENCING DATA; DIVERSITY; FRAMEWORK; IMMUNITY; FUNGAL AB Biogeography and individuality shape the structural and functional composition of the human skin microbiome. To explore these factors' contribution to skin microbial community stability, we generated metagenomic sequence data from longitudinal samples collected over months and years. Analyzing these samples using a multi-kingdom, reference-based approach, we found that despite the skin's exposure to the external environment, its bacterial, fungal, and viral communities were largely stable over time. Site, individuality, and phylogeny were all determinants of stability. Foot sites exhibited the most variability; individuals differed in stability; and transience was a particular characteristic of eukaryotic viruses, which showed little site-specificity in colonization. Strain and single-nucleotide variant-level analysis showed that individuals maintain, rather than reacquire, prevalent microbes from the environment. Longitudinal stability of skin microbial communities generates hypotheses about colonization resistance and empowers clinical studies exploring alterations observed in disease states. C1 [Oh, Julia; Byrd, Allyson L.; Segre, Julia A.] NHGRI, Translat & Funct Genom Branch, NIH, Bethesda, MD 20892 USA. [Byrd, Allyson L.] Boston Univ, Dept Bioinformat, Boston, MA 02215 USA. [Park, Morgan; NISC Comparative Sequencing] NHGRI, NIH, Intramural Sequencing Ctr, Bethesda, MD 20892 USA. [Kong, Heidi H.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Oh, Julia] Jackson Lab Genom Med, Farmington, CT 06030 USA. RP Segre, JA (reprint author), NHGRI, Translat & Funct Genom Branch, NIH, Bethesda, MD 20892 USA.; Kong, HH (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM konghe@mail.nih.gov; jsegre@mail.nih.gov OI Kong, Heidi/0000-0003-4424-064X FU NHGRI; NCI Intramural Research Programs; Chanel/CE.R.I.E.S. research award; NIH [4UH3AR057504-02] FX Amynah Pradhan, Sharon Osgood, Clay Deming, Cynthia Ng, Brian Schmidt, Pamela Thomas, and Sean Conlan provided underlying efforts; the J.A.S. lab and Mark Udey engaged in helpful discussions. Work was supported by NHGRI and NCI Intramural Research Programs and a Chanel/CE.R.I.E.S. research award (to J.A.S.). This study utilized the high-performance computational capabilities of the NIH Biowulf Linux cluster. Sequencing was funded by grants from the NIH (4UH3AR057504-02). IGS Analysis Engine at University of Maryland School of Medicine provided structural and functional annotation of genomes. NR 34 TC 23 Z9 23 U1 29 U2 44 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD MAY 5 PY 2016 VL 165 IS 4 BP 854 EP 866 DI 10.1016/j.cell.2016.04.008 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DL7DN UT WOS:000375800300014 PM 27153496 ER PT J AU Yamano, T Nishimasu, H Zetsche, B Hirano, H Slaymaker, IM Li, YQ Fedorova, I Nakane, T Makarova, KS Koonin, EV Ishitani, R Zhang, F Nureki, O AF Yamano, Takashi Nishimasu, Hiroshi Zetsche, Bernd Hirano, Hisato Slaymaker, Ian M. Li, Yinqing Fedorova, Iana Nakane, Takanori Makarova, Kira S. Koonin, Eugene V. Ishitani, Ryuichiro Zhang, Feng Nureki, Osamu TI Crystal Structure of Cpf1 in Complex with Guide RNA and Target DNA SO CELL LA English DT Article ID CRISPR-CAS SYSTEMS; DUAL-RNA; RECOGNITION; NUCLEASES; ENDONUCLEASE; IMMUNITY; SPECIFICITY; PROKARYOTES; ACTIVATION; ENHANCERS AB Cpf1 is an RNA-guided endonuclease of a type V CRISPR-Cas system that has been recently harnessed for genome editing. Here, we report the crystal structure of Acidaminococcus sp. Cpf1 (AsCpf1) in complex with the guide RNA and its target DNA at 2.8 angstrom resolution. AsCpf1 adopts a bilobed architecture, with the RNA-DNA heteroduplex bound inside the central channel. The structural comparison of AsCpf1 with Cas9, a type II CRISPR-Cas nuclease, reveals both striking similarity and major differences, thereby explaining their distinct functionalities. AsCpf1 contains the RuvC domain and a putative novel nuclease domain, which are responsible for cleaving the non-target and target strands, respectively, and for jointly generating staggered DNA double-strand breaks. AsCpf1 recognizes the 50-TTTN-30 protospacer adjacent motif by base and shape readout mechanisms. Our findings provide mechanistic insights into RNA-guided DNA cleavage by Cpf1 and establish a framework for rational engineering of the CRISPR-Cpf1 toolbox. C1 [Yamano, Takashi; Nishimasu, Hiroshi; Hirano, Hisato; Nakane, Takanori; Ishitani, Ryuichiro; Nureki, Osamu] Univ Tokyo, Grad Sch Sci, Dept Biol Sci, Tokyo 1130032, Japan. [Nishimasu, Hiroshi] JST, PRESTO, Tokyo 1130032, Japan. [Zetsche, Bernd; Slaymaker, Ian M.; Li, Yinqing; Fedorova, Iana; Zhang, Feng] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Zetsche, Bernd; Slaymaker, Ian M.; Li, Yinqing; Fedorova, Iana; Zhang, Feng] MIT, McGovern Inst Brain Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Zetsche, Bernd; Slaymaker, Ian M.; Li, Yinqing; Fedorova, Iana; Zhang, Feng] MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA. [Zetsche, Bernd; Slaymaker, Ian M.; Li, Yinqing; Fedorova, Iana; Zhang, Feng] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Zetsche, Bernd] Bonn Med Sch, Inst Pathol, Dept Dev Pathol, D-53127 Bonn, Germany. [Fedorova, Iana] Peter Great St Petersburg Polytech Univ, St Petersburg 195251, Russia. [Fedorova, Iana] Skolkovo Inst Sci & Technol, Skolkovo 143026, Russia. [Makarova, Kira S.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Nureki, O (reprint author), Univ Tokyo, Grad Sch Sci, Dept Biol Sci, Tokyo 1130032, Japan.; Zhang, F (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.; Zhang, F (reprint author), MIT, McGovern Inst Brain Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Zhang, F (reprint author), MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA.; Zhang, F (reprint author), MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM zhang@broadinstitute.org; nureki@bs.s.u-tokyo.ac.jp FU JST; PRESTO; JSPS KAKENHI [26291010, 15H01463]; Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology; US Department of Health and Human Services; NIH through the NIMH [5DP1-MH100706, 1R01-MH110049]; Waterman Award from the National Science Foundation; New York Stem Cell Foundation; Simons Foundation; Paul G. Allen Family Foundation; Vallee Foundation; Basic Science and Platform Technology Program for Innovative Biological Medicine from the Japan Agency for Medical Research and Development, AMED; Council for Science FX We thank Arisa Kurabayashi for assistance with vector construction. We thank the beamline scientists at PXI X06SA at the Swiss Light Source and BL41XU at SPring-8 for assistance with data collection. H.N. is supported by JST, PRESTO, JSPS KAKENHI (26291010 and 15H01463), and the Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology. K.S.M. and E.V.K. are supported by intramural funds of the US Department of Health and Human Services (to the National Library of Medicine). F.Z. is supported by the NIH through the NIMH (5DP1-MH100706 and 1R01-MH110049); a Waterman Award from the National Science Foundation; the New York Stem Cell, Simons, Paul G. Allen Family, and Vallee Foundations; and B. Metcalfe. F.Z. is a New York Stem Cell Foundation Robertson Investigator. F.Z. is a founder of Editas Medicine and a scientific advisor for Editas Medicine and Horizon Discovery. O.N. is supported by the Basic Science and Platform Technology Program for Innovative Biological Medicine from the Japan Agency for Medical Research and Development, AMED, the Council for Science, and the Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the NIH. NR 42 TC 26 Z9 28 U1 40 U2 78 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD MAY 5 PY 2016 VL 165 IS 4 BP 949 EP 962 DI 10.1016/j.cell.2016.04.003 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DL7DN UT WOS:000375800300021 PM 27114038 ER PT J AU O'Brien, SJ Koepfli, KP Eizirik, E Johnson, W Driscoll, C Antunes, A Schmidt-Kuntzel, A Marker, L Dobrynin, P AF O'Brien, Stephen J. Koepfli, Klaus Peter Eizirik, Eduardo Johnson, Warren Driscoll, Carlos Antunes, Agostinho Schmidt-Kuntzel, Anne Marker, Laurie Dobrynin, Pavel TI Response to Comment by Faurby, Werdelin and Svenning SO GENOME BIOLOGY LA English DT Article ID PUMA PUMA-CONCOLOR; CHEETAH-LIKE CAT; AMERICAN; FELIDAE; EVOLUTION C1 [O'Brien, Stephen J.; Koepfli, Klaus Peter; Dobrynin, Pavel] St Petersburg State Univ, Theodosius Dobzhansky Ctr Genome Bioinformat, 41A Sredniy Ave, St Petersburg 199004, Russia. [O'Brien, Stephen J.] Nova SE Univ, Oceanog Ctr, 8000 N Ocean Dr, Ft Lauderdale, FL 33004 USA. [Koepfli, Klaus Peter] Smithsonian Conservat Biol Inst, Natl Zool Pk, Washington, DC 20008 USA. [Eizirik, Eduardo] Pontificia Univ Catolica Rio Grande do Sul, Fac Biociencias, Lab Biol Genom & Mol, Inst Procarivoros, BR-90619900 Porto Alegre, RS, Brazil. [Driscoll, Carlos] NIAAA, Neurogenet Lab, 5625 Fishers Lane, Rockville, MD 20852 USA. [Antunes, Agostinho] Univ Porto, Fac Sci, Dept Biol, Rua Campo, P-4169007 Oporto, Portugal. [Schmidt-Kuntzel, Anne] Cheetah Conservat Fund, Life Technol Conservat Genet Lab, Otjiwarongo 9000, Namibia. [Schmidt-Kuntzel, Anne; Marker, Laurie] Cheetah Conservat Fund, Otjiwarongo 9000, Namibia. RP O'Brien, SJ (reprint author), St Petersburg State Univ, Theodosius Dobzhansky Ctr Genome Bioinformat, 41A Sredniy Ave, St Petersburg 199004, Russia.; O'Brien, SJ (reprint author), Nova SE Univ, Oceanog Ctr, 8000 N Ocean Dr, Ft Lauderdale, FL 33004 USA. EM lgdchief@gmail.com RI Eizirik, Eduardo/K-8034-2012; OI Eizirik, Eduardo/0000-0002-9658-0999; Driscoll, Carlos/0000-0003-2392-505X NR 14 TC 0 Z9 0 U1 3 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-6906 EI 1474-760X J9 GENOME BIOL JI Genome Biol. PD MAY 5 PY 2016 VL 17 AR 90 DI 10.1186/s13059-016-0942-z PG 3 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DL9KX UT WOS:000375962600003 PM 27150130 ER PT J AU Yamada, T Ogawa, A Freire, M AF Yamada, Tadataka Ogawa, Ayano Freire, Maria TI Security spending must cover disease outbreaks SO NATURE LA English DT Editorial Material C1 [Yamada, Tadataka] Global Hlth Risk Framework Commiss, Seattle, WA USA. [Yamada, Tadataka] Frazier Healthcare Partners, Seattle, WA USA. [Ogawa, Ayano] US Natl Acad Med, Global Hlth Risk Framework Commiss, Washington, DC USA. [Freire, Maria] Global Hlth Risk Framework Commiss, Bethesda, MD USA. [Freire, Maria] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Yamada, T (reprint author), Global Hlth Risk Framework Commiss, Seattle, WA USA.; Yamada, T (reprint author), Frazier Healthcare Partners, Seattle, WA USA. EM tachi.yamada@gmail.com NR 8 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAY 5 PY 2016 VL 533 IS 7601 BP 29 EP 31 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DL2OE UT WOS:000375473900023 PM 27147017 ER PT J AU Ruibal, P Oestereich, L Ludtke, A Becker-Ziaja, B Wozniak, DM Kerber, R Korva, M Cabeza-Cabrerizo, M Bore, JA Koundouno, FR Duraffour, S Weller, R Thorenz, A Cimini, E Viola, D Agrati, C Repits, J Afrough, B Cowley, LA Ngabo, D Hinzmann, J Mertens, M Vitoriano, I Logue, CH Boettcher, JP Pallasch, E Sachse, A Bah, A Nitzsche, K Kuisma, E Michel, J Holm, T Zekeng, EG Garcia-Dorival, I Wolfel, R Stoecker, K Fleischmann, E Strecker, T Di Caro, A Avsic-Zupanc, T Kurth, A Meschi, S Mely, S Newman, E Bocquin, A Kis, Z Kelterbaum, A Molkenthin, P Carletti, F Portmann, J Wolff, S Castilletti, C Schudt, G Fizet, A Ottowell, LJ Herker, E Jacobs, T Kretschmer, B Severi, E Ouedraogo, N Lago, M Negredo, A Franco, L Anda, P Schmiedel, S Kreuels, B Wichmann, D Addo, MM Lohse, AW De Clerck, H Nanclares, C Jonckheere, S Van Herp, M Sprecher, A Gao, XJ Carrington, M Miranda, O Castro, CM Gabriel, M Drury, P Formenty, P Diallo, B Koivogui, L Magassouba, N Carroll, MW Gunther, S Munoz-Fontela, C AF Ruibal, Paula Oestereich, Lisa Luedtke, Anja Becker-Ziaja, Beate Wozniak, David M. Kerber, Romy Korva, Misa Cabeza-Cabrerizo, Mar Bore, Joseph A. Koundouno, Fara Raymond Duraffour, Sophie Weller, Romy Thorenz, Anja Cimini, Eleonora Viola, Domenico Agrati, Chiara Repits, Johanna Afrough, Babak Cowley, Lauren A. Ngabo, Didier Hinzmann, Julia Mertens, Marc Vitoriano, Ines Logue, Christopher H. Boettcher, Jan Peter Pallasch, Elisa Sachse, Andreas Bah, Amadou Nitzsche, Katja Kuisma, Eeva Michel, Janine Holm, Tobias Zekeng, Elsa-Gayle Garcia-Dorival, Isabel Woelfel, Roman Stoecker, Kilian Fleischmann, Erna Strecker, Thomas Di Caro, Antonino Avsic-Zupanc, Tatjana Kurth, Andreas Meschi, Silvia Mely, Stephane Newman, Edmund Bocquin, Anne Kis, Zoltan Kelterbaum, Anne Molkenthin, Peter Carletti, Fabrizio Portmann, Jasmine Wolff, Svenja Castilletti, Concetta Schudt, Gordian Fizet, Alexandra Ottowell, Lisa J. Herker, Eva Jacobs, Thomas Kretschmer, Birte Severi, Ettore Ouedraogo, Nobila Lago, Mar Negredo, Anabel Franco, Leticia Anda, Pedro Schmiedel, Stefan Kreuels, Benno Wichmann, Dominic Addo, Marylyn M. Lohse, Ansgar W. De Clerck, Hilde Nanclares, Carolina Jonckheere, Sylvie Van Herp, Michel Sprecher, Armand Gao Xiaojiang Carrington, Mary Miranda, Osvaldo Castro, Carlos M. Gabriel, Martin Drury, Patrick Formenty, Pierre Diallo, Boubacar Koivogui, Lamine Magassouba, N'Faly Carroll, Miles W. Guenther, Stephan Munoz-Fontela, Cesar TI Unique human immune signature of Ebola virus disease in Guinea SO NATURE LA English DT Article ID T-CELL RESPONSES; INFECTION; CTLA-4; IDENTIFICATION; PROGRESSION; ACTIVATION; EXPRESSION; EFFECTOR; EPITOPES; INSIGHTS AB Despite the magnitude of the Ebola virus disease (EVD) outbreak in West Africa, there is still a fundamental lack of knowledge about the pathophysiology of EVD1. In particular, very little is known about human immune responses to Ebola virus(2,3). Here we evaluate the physiology of the human T cell immune response in EVD patients at the time of admission to the Ebola Treatment Center in Guinea, and longitudinally until discharge or death. Through the use of multiparametric flow cytometry established by the European Mobile Laboratory in the field, we identify an immune signature that is unique in EVD fatalities. Fatal EVD was characterized by a high percentage of CD4(+) and CD8(+) T cells expressing the inhibitory molecules CTLA-4 and PD-1, which correlated with elevated inflammatory markers and high virus load. Conversely, surviving individuals showed significantly lower expression of CTLA-4 and PD-1 as well as lower inflammation, despite comparable overall T cell activation. Concomitant with virus clearance, survivors mounted a robust Ebola-virus-specific T cell response. Our findings suggest that dysregulation of the T cell response is a key component of EVD pathophysiology. C1 [Ruibal, Paula; Luedtke, Anja; Herker, Eva; Munoz-Fontela, Cesar] Leibniz Inst Expt Virol, Heinrich Pette Inst, D-20251 Hamburg, Germany. [Ruibal, Paula; Oestereich, Lisa; Luedtke, Anja; Becker-Ziaja, Beate; Wozniak, David M.; Kerber, Romy; Cabeza-Cabrerizo, Mar; Duraffour, Sophie; Pallasch, Elisa; Holm, Tobias; Jacobs, Thomas; Kreuels, Benno; Gabriel, Martin; Guenther, Stephan; Munoz-Fontela, Cesar] WHO, Bernhard Nocht Inst Trop Med, Collaborating Ctr Arbovirus & Hemorrhag Fever Ref, D-20359 Hamburg, Germany. [Ruibal, Paula; Oestereich, Lisa; Luedtke, Anja; Becker-Ziaja, Beate; Wozniak, David M.; Kerber, Romy; Pallasch, Elisa; Nitzsche, Katja; Holm, Tobias; Woelfel, Roman; Stoecker, Kilian; Fleischmann, Erna; Strecker, Thomas; Kelterbaum, Anne; Molkenthin, Peter; Wolff, Svenja; Schudt, Gordian; Kreuels, Benno; Wichmann, Dominic; Addo, Marylyn M.; Lohse, Ansgar W.; Gabriel, Martin; Guenther, Stephan; Munoz-Fontela, Cesar] German Ctr Infect Res DZIF, Partner Sites Hamburg, Munich, Germany. [Ruibal, Paula; Oestereich, Lisa; Luedtke, Anja; Becker-Ziaja, Beate; Wozniak, David M.; Kerber, Romy; Korva, Misa; Cabeza-Cabrerizo, Mar; Bore, Joseph A.; Koundouno, Fara Raymond; Duraffour, Sophie; Weller, Romy; Thorenz, Anja; Cimini, Eleonora; Viola, Domenico; Agrati, Chiara; Repits, Johanna; Afrough, Babak; Cowley, Lauren A.; Ngabo, Didier; Hinzmann, Julia; Mertens, Marc; Vitoriano, Ines; Logue, Christopher H.; Boettcher, Jan Peter; Pallasch, Elisa; Sachse, Andreas; Bah, Amadou; Nitzsche, Katja; Kuisma, Eeva; Michel, Janine; Holm, Tobias; Zekeng, Elsa-Gayle; Garcia-Dorival, Isabel; Woelfel, Roman; Stoecker, Kilian; Fleischmann, Erna; Strecker, Thomas; Di Caro, Antonino; Avsic-Zupanc, Tatjana; Kurth, Andreas; Meschi, Silvia; Mely, Stephane; Newman, Edmund; Bocquin, Anne; Kis, Zoltan; Kelterbaum, Anne; Molkenthin, Peter; Carletti, Fabrizio; Portmann, Jasmine; Wolff, Svenja; Castilletti, Concetta; Schudt, Gordian; Fizet, Alexandra; Ottowell, Lisa J.; Negredo, Anabel; Lohse, Ansgar W.; Gabriel, Martin; Carroll, Miles W.; Guenther, Stephan; Munoz-Fontela, Cesar] European Mobile Lab Consortium, Bernhard Nocht Inst Trop Med, D-20359 Hamburg, Germany. [Korva, Misa; Avsic-Zupanc, Tatjana] Univ Ljubljana, Fac Med, Inst Microbiol & Immunol, Ljubljana 1000, Slovenia. [Weller, Romy] Twincore, Ctr Expt & Clin Infect Res, Inst Expt Virol, D-30625 Hannover, Germany. [Thorenz, Anja] Hannover Med Sch, D-30625 Hannover, Germany. [Cimini, Eleonora; Viola, Domenico; Agrati, Chiara; Di Caro, Antonino; Meschi, Silvia; Carletti, Fabrizio; Castilletti, Concetta] Natl Inst Infect Dis Lazzaro Spallanzani, I-00149 Rome, Italy. [Afrough, Babak; Ngabo, Didier; Vitoriano, Ines; Logue, Christopher H.; Kuisma, Eeva; Newman, Edmund; Ottowell, Lisa J.; Carroll, Miles W.] Publ Hlth England, Porton Down, Salisbury SP4 0JG, Wilts, England. [Cowley, Lauren A.] Publ Hlth England, Colindale Ave, London NW9 5EQ, England. [Hinzmann, Julia; Boettcher, Jan Peter; Sachse, Andreas; Michel, Janine; Kurth, Andreas; Ouedraogo, Nobila] Robert Koch Inst, D-13353 Berlin, Germany. [Mertens, Marc] Friedrich Loeffler Inst, D-17493 Greifswald, Germany. [Bah, Amadou] Swiss Trop & Publ Hlth Inst, CH-4051 Basel, Switzerland. [Garcia-Dorival, Isabel] Univ Liverpool, Inst Infect & Global Hlth, Liverpool L69 7BE, Merseyside, England. [Woelfel, Roman; Stoecker, Kilian; Fleischmann, Erna; Molkenthin, Peter] Bundeswehr Inst Microbiol, D-80937 Munich, Germany. [Strecker, Thomas; Kelterbaum, Anne; Wolff, Svenja; Schudt, Gordian] Univ Marburg, Inst Virol, D-35043 Marburg, Germany. [Mely, Stephane; Bocquin, Anne] INSERM, Lab P4 Jean Merieux, F-69365 Lyon, France. [Kis, Zoltan] Hungarian Natl Biosafety Lab, Natl Ctr Epidemiol, H-1097 Budapest, Hungary. [Kis, Zoltan; Severi, Ettore] European Ctr Dis Prevent & Control, S-17165 Solna, Sweden. [Portmann, Jasmine] Fed Off Civil Protect, CH-3700 Spiez, Switzerland. [Fizet, Alexandra] Inst Pasteur, Unite Biol Infect Virales Emergentes, F-69365 Lyon, France. [Kretschmer, Birte] European Res & Project Off, Eurice, D-10115 Berlin, Germany. [Lago, Mar] Hosp La Paz, Infect Dis Unit, Internal Med Serv, Madrid 28046, Spain. [Negredo, Anabel; Franco, Leticia; Anda, Pedro] Inst Hlth Carlos III, Natl Ctr Microbiol, Madrid 28220, Spain. [Schmiedel, Stefan; Kreuels, Benno; Wichmann, Dominic; Addo, Marylyn M.; Lohse, Ansgar W.] Univ Med Ctr Hamburg Eppendorf, D-20246 Hamburg, Germany. [De Clerck, Hilde; Nanclares, Carolina; Jonckheere, Sylvie; Van Herp, Michel; Sprecher, Armand] Med Sans Frontieres, B-1050 Brussels, Belgium. [Gao Xiaojiang; Carrington, Mary] Leidos Biomed Res, Canc & Inflammat Program, Expt Immunol Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Gao Xiaojiang; Carrington, Mary] Ragon Inst MGH MIT & Harvard, Cambridge, MA 02139 USA. [Miranda, Osvaldo; Castro, Carlos M.] Hosp Militar Cent Dr Carlos J Finlay, Havana 11400, Cuba. [Drury, Patrick; Formenty, Pierre; Diallo, Boubacar] WHO, CH-1211 Geneva 27, Switzerland. [Koivogui, Lamine] Inst Natl Sante Publ, Conakry 2101, Guinea. [Magassouba, N'Faly] Univ Gamal Abdel Nasser Conakry, CHU Donka, Conakry 2101, Guinea. RP Munoz-Fontela, C (reprint author), Leibniz Inst Expt Virol, Heinrich Pette Inst, D-20251 Hamburg, Germany.; Gunther, S; Munoz-Fontela, C (reprint author), WHO, Bernhard Nocht Inst Trop Med, Collaborating Ctr Arbovirus & Hemorrhag Fever Ref, D-20359 Hamburg, Germany.; Gunther, S; Munoz-Fontela, C (reprint author), German Ctr Infect Res DZIF, Partner Sites Hamburg, Munich, Germany.; Gunther, S; Munoz-Fontela, C (reprint author), European Mobile Lab Consortium, Bernhard Nocht Inst Trop Med, D-20359 Hamburg, Germany. EM guenther@bni.uni-hamburg.de; cesar.munoz-fontela@hpi.uni-hamburg.de RI Di Caro, Antonino/K-6854-2016; Herker, Eva/B-9699-2014; Castilletti, Concetta/B-6545-2016; OI Ngabo, Didier/0000-0003-1818-1439; Di Caro, Antonino/0000-0001-6027-3009; Herker, Eva/0000-0001-9644-2484; Castilletti, Concetta/0000-0001-9819-236X; meschi, silvia/0000-0003-0924-993X FU European Union [666100]; Directorate-General for International Cooperation and Development [IFS/2011/272-372]; German Research Foundation [GU 883/4-1]; Spanish National Plan for Research and Development ISCIII; FEDER [RD12/0018/006]; Frederick National Laboratory for Cancer Research [HHSN261200800001E]; Intramural Research Program of the NIH, Frederick National Laboratory, Center for Cancer Research; Leibniz Center of Infection; European Program for Public Health Microbiology Training (EUPHEM) FX We thank the African Union, MSF and WHO field teams and the Guinean health authorities in Gueckedou, Coyah and Conakry for their commitment and cooperation. We also thank J. Snyder-Cappione (Boston University) and M. Altfeld (Heinrich Pette Institute) for technical support. The EMLab is a technical partner of the WHO Emerging and Dangerous Pathogens Laboratory Network (EDPLN), and the Global Outbreak Alert and Response Network (GOARN) and the deployments in West Africa have been coordinated and supported by the GOARN Operational Support Team at WHO/HQ. This work was carried out in the context of the project EVIDENT (Ebola virus disease: correlates of protection, determinants of outcome, and clinical management) that received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No. 666100 and in the context of service contract IFS/2011/272-372 funded by Directorate-General for International Cooperation and Development. The project was further supported by grant GU 883/4-1 from the German Research Foundation. This project has been funded in in part with funds from the Spanish National Plan for Research and Development ISCIII and FEDER RD12/0018/006 as well as federal funds from the Frederick National Laboratory for Cancer Research, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Program of the NIH, Frederick National Laboratory, Center for Cancer Research. A.L. is a recipient of a pre-doctoral fellowship from the Leibniz Center of Infection. Z.K. is a recipient of a fellowship from the European Program for Public Health Microbiology Training (EUPHEM). NR 30 TC 12 Z9 12 U1 8 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAY 5 PY 2016 VL 533 IS 7601 BP 100 EP + DI 10.1038/nature17949 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DL2OE UT WOS:000375473900047 PM 27147028 ER PT J AU Gautam, R Nishimura, Y Pegu, A Nason, MC Klein, F Gazumyan, A Golijanin, J Buckler-White, A Sadjadpour, R Wang, KY Mankoff, Z Schmidt, SD Lifson, JD Mascola, JR Nussenzweig, MC Martin, MA AF Gautam, Rajeev Nishimura, Yoshiaki Pegu, Amarendra Nason, Martha C. Klein, Florian Gazumyan, Anna Golijanin, Jovana Buckler-White, Alicia Sadjadpour, Reza Wang, Keyun Mankoff, Zachary Schmidt, Stephen D. Lifson, Jeffrey D. Mascola, John R. Nussenzweig, Michel C. Martin, Malcolm A. TI A single injection of anti-HIV-1 antibodies protects against repeated SHIV challenges SO NATURE LA English DT Article ID SIMIAN/HUMAN IMMUNODEFICIENCY VIRUS; BROADLY NEUTRALIZING ANTIBODY; HIV-1/SIV CHIMERIC VIRUS; MONOCLONAL-ANTIBODIES; IN-VITRO; IMPROVES PROTECTION; PASSIVE TRANSFER; HIV-ANTIBODIES; RHESUS-MONKEYS; MACAQUES AB Despite the success of potent anti-retroviral drugs in controlling human immunodeficiency virus type 1 (HIV-1) infection, little progress has been made in generating an effective HIV-1 vaccine. Although passive transfer of anti-HIV-1 broadly neutralizing antibodies can protect mice or macaques against a single high-dose challenge with HIV or simian/human (SIV/HIV) chimaeric viruses (SHIVs) respectively(1-8), the long-term efficacy of a passive antibody transfer approach for HIV-1 has not been examined. Here we show, on the basis of the relatively long-term protection conferred by hepatitis A immune globulin, the efficacy of a single injection (20 mg kg(-1)) of four anti-HIV-1-neutralizing monoclonal antibodies (VRC01, VRC01-LS, 3BNC117, and 10-1074 (refs 9-12)) in blocking repeated weekly low-dose virus challenges of the clade B SHIVAD8. Compared with control animals, which required two to six challenges (median = 3) for infection, a single broadly neutralizing antibody infusion prevented virus acquisition for up to 23 weekly challenges. This effect depended on antibody potency and half-life. The highest levels of plasma-neutralizing activity and, correspondingly, the longest protection were found in monkeys administered the more potent antibodies 3BNC117 and 10-1074 (median = 13 and 12.5 weeks, respectively). VRC01, which showed lower plasma-neutralizing activity, protected for a shorter time (median = 8 weeks). The introduction of a mutation that extends antibody half-life into the crystallizable fragment (Fc) domain of VRC01 increased median protection from 8 to 14.5 weeks. If administered to populations at high risk of HIV-1 transmission, such an immunoprophylaxis regimen could have a major impact on virus transmission. C1 [Gautam, Rajeev; Nishimura, Yoshiaki; Buckler-White, Alicia; Sadjadpour, Reza; Martin, Malcolm A.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Pegu, Amarendra; Wang, Keyun; Mankoff, Zachary; Schmidt, Stephen D.; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Nason, Martha C.] NIAID, Biostat Res Branch, Div Clin Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Klein, Florian; Gazumyan, Anna; Golijanin, Jovana; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Klein, Florian] Univ Cologne, Lab Expt Immunol, CMMC, D-50931 Cologne, Germany. [Klein, Florian] Univ Hosp Cologne, Ctr Integrated Oncol Cologne Bonn, Dept Internal Med 1, D-50937 Cologne, Germany. [Lifson, Jeffrey D.] Frederick Natl Lab Canc Res, Leidos Biomed Res, AIDS & Canc Virus Program, Frederick, MD 21702 USA. [Nussenzweig, Michel C.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Martin, MA (reprint author), NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. EM malm@nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH; National Cancer Institute, NIH [HHSN261200800001E]; Bill and Melinda Gates Foundation [OPP1033115, OPP1092074]; NIH [AI-100148, UM1 AI100663-01]; Robertson Foundation; Howard Hughes Medical Institute FX We thank R. Plishka, A. Peach, and T. Lewis for determining plasma viral RNA loads, and K. Rice, R. Engel, R. Petros, and S. Fong for assisting in the maintenance of animals and assisting with procedures. We also thank R. Schwartz for clinical-grade VRC01 and VRC01-LS, and X. Chen for protein reagents for ELISA. We thank the National Institutes of Health (NIH) AIDS Research and Reference Reagent Program for TZM-bl cells. We thank R. Fast for ultrasensitive plasma SIV RNA assays and W. Bosche and M Hull for ultrasensitive peripheral blood mononuclear cell SIV RNA/DNA assays. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH and, in part, with federal funds from the National Cancer Institute, NIH, under contract number HHSN261200800001E (to J.D.L.). The research was also funded in part by the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery Grants OPP1033115 and OPP1092074 (to M.C.Nu.), by the NIH under award numbers AI-100148, UM1 AI100663-01. M.C.Nu. is supported by the Robertson Foundation and the The Howard Hughes Medical Institute. NR 33 TC 34 Z9 34 U1 7 U2 18 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAY 5 PY 2016 VL 533 IS 7601 BP 105 EP + DI 10.1038/nature17677 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DL2OE UT WOS:000375473900048 PM 27120156 ER PT J AU Martinez, J Cunha, LD Park, S Yang, M Lu, Q Orchard, R Li, QZ Yan, M Janke, L Guy, C Linkermann, A Virgin, HW Green, DR AF Martinez, Jennifer Cunha, Larissa D. Park, Sunmin Yang, Mao Lu, Qun Orchard, Robert Li, Quan-Zhen Yan, Mei Janke, Laura Guy, Cliff Linkermann, Andreas Virgin, Herbert W. Green, Douglas R. TI Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells SO NATURE LA English DT Article ID AUTOIMMUNE-DISEASE; ERYTHEMATOSUS; PHAGOCYTOSIS; CLEARANCE; IL-10; MICE; SUSCEPTIBILITY; ASSOCIATION; MACROPHAGES; PROTEINS AB Defects in clearance of dying cells have been proposed to underlie the pathogenesis of systemic lupus erythematosus (SLE)(1). Mice lacking molecules associated with dying cell clearance develop SLE-like disease(2), and phagocytes from patients with SLE often display defective clearance and increased inflammatory cytokine production when exposed to dying cells in vitro. Previously, we(3-6) and others(7) described a form of noncanonical autophagy known as LC3-associated phagocytosis (LAP), in which phagosomes containing engulfed particles, including dying cells(3,4,7), recruit elements of the autophagy pathway to facilitate maturation of phagosomes and digestion of their contents. Genome-wide association studies have identified polymorphisms in the Atg5 (ref. 8) and possibly Atg7 (ref. 9) genes, involved in both canonical autophagy and LAP(3-7), as markers of a predisposition for SLE. Here we describe the consequences of defective LAP in vivo. Mice lacking any of several components of the LAP pathway show increased serum levels of inflammatory cytokines and autoantibodies, glomerular immune complex deposition, and evidence of kidney damage. When dying cells are injected into LAP-deficient mice, they are engulfed but not efficiently degraded and trigger acute elevation of pro-inflammatory cytokines but not anti-inflammatory interleukin (IL)-10. Repeated injection of dying cells into LAP-deficient, but not LAP-sufficient, mice accelerated the development of SLE-like disease, including increased serum levels of autoantibodies. By contrast, mice deficient in genes required for canonical autophagy but not LAP do not display defective dying cell clearance, inflammatory cytokine production, or SLE-like disease, and, like wild-type mice, produce IL-10 in response to dying cells. Therefore, defects in LAP, rather than canonical autophagy, can cause SLE-like phenomena, and may contribute to the pathogenesis of SLE. C1 [Martinez, Jennifer; Cunha, Larissa D.; Yang, Mao; Janke, Laura; Guy, Cliff; Green, Douglas R.] St Jude Childrens Res Hosp, Dept Immunol, 332 N Lauderdale St, Memphis, TN 38105 USA. [Martinez, Jennifer] NIEHS, Immun Inflammat & Dis Lab, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. [Park, Sunmin; Lu, Qun; Orchard, Robert; Virgin, Herbert W.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Li, Quan-Zhen; Yan, Mei] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Linkermann, Andreas] Univ Kiel, Div Nephrol & Hypertens, D-24105 Kiel, Germany. RP Martinez, J; Green, DR (reprint author), St Jude Childrens Res Hosp, Dept Immunol, 332 N Lauderdale St, Memphis, TN 38105 USA.; Martinez, J (reprint author), NIEHS, Immun Inflammat & Dis Lab, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM jennifer.martinez3@nih.gov; douglas.green@stjude.org RI Cunha, Larissa/I-4204-2012; OI Linkermann, Andreas/0000-0001-6287-9725 FU Intramural Research Program of the National Institutes of Health, NIEHS [1ZIAES10328601]; US National Institutes of Health [RO1 AI40646, U19 AI109725]; Lupus Research Institute; German Research Foundation [EXC306]; ALSAC FX The authors thank T. Brewer, P. Fitzgerald, M. Henderson, J. Kolb and T. Oguin for technical assistance. We also thank K. Gerrish and R. Fannin for their work and analysis of the Nanostring data. This work was supported by the Intramural Research Program of the National Institutes of Health, NIEHS (1ZIAES10328601), as well as grants from the US National Institutes of Health (RO1 AI40646, U19 AI109725), the Lupus Research Institute, the German Research Foundation (EXC306), and ALSAC. NR 29 TC 28 Z9 28 U1 19 U2 27 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAY 5 PY 2016 VL 533 IS 7601 BP 115 EP + DI 10.1038/nature17950 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DL2OE UT WOS:000375473900050 PM 27096368 ER PT J AU Eastman, RT Khine, P Huang, RL Thomas, CJ Su, XZ AF Eastman, Richard T. Khine, Pwint Huang, Ruili Thomas, Craig J. Su, Xin-zhuan TI PfCRT and PfMDR1 modulate interactions of artemisinin derivatives and ion channel blockers SO SCIENTIFIC REPORTS LA English DT Article ID PLASMODIUM-FALCIPARUM MALARIA; ANTIMALARIAL-DRUG RESISTANCE; TRANSMEMBRANE PROTEIN PFCRT; IN-VIVO SELECTION; CHLOROQUINE RESISTANCE; ARTEMETHER-LUMEFANTRINE; QUININE RESISTANCE; DIGESTIVE VACUOLE; WESTERN CAMBODIA; SOUTHEAST-ASIA AB Treatment of the symptomatic asexual stage of Plasmodium falciparum relies almost exclusively on artemisinin (ART) combination therapies (ACTs) in endemic regions. ACTs combine ART or its derivative with a long-acting partner drug to maximize efficacy during the typical three-day regimen. Both laboratory and clinical studies have previously demonstrated that the common drug resistance determinants P. falciparum chloroquine resistance transporter (PfCRT) and multidrug resistance transporter (PfMDR1) can modulate the susceptibility to many current antimalarial drugs and chemical compounds. Here we investigated the parasite responses to dihydroartemisinin (DHA) and various Ca2+ and Na+ channel blockers and showed positively correlated responses between DHA and several channel blockers, suggesting potential shared transport pathways or mode of action. Additionally, we demonstrated that PfCRT and PfMDR1 could also significantly modulate the pharmacodynamic interactions of the compounds and that the interactions were influenced by the parasite genetic backgrounds. These results provide important information for better understanding of drug resistance and for assessing the overall impact of drug resistance markers on parasite response to ACTs. C1 [Eastman, Richard T.; Khine, Pwint; Su, Xin-zhuan] NIAID, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Eastman, Richard T.; Huang, Ruili; Thomas, Craig J.] Natl Ctr Adv Translat Sci, Div Preclin Dev, NIH, Bethesda, MD USA. RP Eastman, RT; Su, XZ (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Eastman, RT (reprint author), Natl Ctr Adv Translat Sci, Div Preclin Dev, NIH, Bethesda, MD USA. EM richard.eastman@nih.gov; xsu@niaid.nih.gov OI Su, Xinzhuan/0000-0003-3246-3248 FU Division of Intramural Research at National Institute of Allergy and Infectious Diseases (NIAID); Division of Preclinical Innovation, National Center for Advancing Translational Sciences; Molecular Libraries Initiative of National Institutes of Health Roadmap for Medical Research, NIH FX This work was supported by the Division of Intramural Research at the National Institute of Allergy and Infectious Diseases (NIAID), the Division of Preclinical Innovation, National Center for Advancing Translational Sciences, and the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research, NIH. We thank Cindy Clark, NIH Library, for editing. NR 66 TC 2 Z9 2 U1 2 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAY 5 PY 2016 VL 6 AR 25379 DI 10.1038/srep25379 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DL2PX UT WOS:000375478500001 PM 27147113 ER PT J AU Kudenchuk, PJ Brown, SP Daya, M Rea, T Nichol, G Morrison, LJ Leroux, B Vaillancourt, C Wittwer, L Callaway, CW Christenson, J Egan, D Ornato, JP Weisfeldt, ML Stiell, IG Idris, AH Aufderheide, TP Dunford, JV Colella, MR Vilke, GM Brienza, AM Desvigne-Nickens, P Gray, PC Gray, R Seals, N Straight, R Dorian, P AF Kudenchuk, P. J. Brown, S. P. Daya, M. Rea, T. Nichol, G. Morrison, L. J. Leroux, B. Vaillancourt, C. Wittwer, L. Callaway, C. W. Christenson, J. Egan, D. Ornato, J. P. Weisfeldt, M. L. Stiell, I. G. Idris, A. H. Aufderheide, T. P. Dunford, J. V. Colella, M. R. Vilke, G. M. Brienza, A. M. Desvigne-Nickens, P. Gray, P. C. Gray, R. Seals, N. Straight, R. Dorian, P. CA Resuscitation Outcomes Consortium TI Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RESUSCITATION OUTCOMES CONSORTIUM; AMERICAN-HEART-ASSOCIATION; EMERGENCY CARDIOVASCULAR CARE; VENTRICULAR-FIBRILLATION; CARDIOPULMONARY-RESUSCITATION; ANTIARRHYTHMIC-DRUG; TRIAL; DURATION; RHYTHM; TIME AB BACKGROUND Antiarrhythmic drugs are used commonly in out-of-hospital cardiac arrest for shock-refractory ventricular fibrillation or pulseless ventricular tachycardia, but without proven survival benefit. METHODS In this randomized, double-blind trial, we compared parenteral amiodarone, lidocaine, and saline placebo, along with standard care, in adults who had nontraumatic out-of-hospital cardiac arrest, shock-refractory ventricular fibrillation or pulseless ventricular tachycardia after at least one shock, and vascular access. Paramedics enrolled patients at 10 North American sites. The primary outcome was survival to hospital discharge; the secondary outcome was favorable neurologic function at discharge. The per-protocol (primary analysis) population included all randomly assigned participants who met eligibility criteria and received any dose of a trial drug and whose initial cardiac-arrest rhythm of ventricular fibrillation or pulseless ventricular tachycardia was refractory to shock. RESULTS In the per-protocol population, 3026 patients were randomly assigned to amiodarone (974), lidocaine (993), or placebo (1059); of those, 24.4%, 23.7%, and 21.0%, respectively, survived to hospital discharge. The difference in survival rate for amiodarone versus placebo was 3.2 percentage points (95% confidence interval [CI], -0.4 to 7.0; P = 0.08); for lidocaine versus placebo, 2.6 percentage points (95% CI, -1.0 to 6.3; P = 0.16); and for amiodarone versus lidocaine, 0.7 percentage points (95% CI, -3.2 to 4.7; P = 0.70). Neurologic outcome at discharge was similar in the three groups. There was heterogeneity of treatment effect with respect to whether the arrest was witnessed (P = 0.05); active drugs were associated with a survival rate that was significantly higher than the rate with placebo among patients with bystander-witnessed arrest but not among those with unwitnessed arrest. More amiodarone recipients required temporary cardiac pacing than did recipients of lidocaine or placebo. CONCLUSIONS Overall, neither amiodarone nor lidocaine resulted in a significantly higher rate of survival or favorable neurologic outcome than the rate with placebo among patients with out-of-hospital cardiac arrest due to initial shock-refractory ventricular fibrillation or pulseless ventricular tachycardia. C1 [Kudenchuk, P. J.] Univ Washington, Div Cardiol, 1959 N E Pacific St,Box 356422, Seattle, WA 98166 USA. [Kudenchuk, P. J.] Univ Washington, Dept Med, Seattle, WA 98166 USA. [Kudenchuk, P. J.; Rea, T.] King Cty Emergency Med Serv, Seattle, WA USA. [Brown, S. P.; Nichol, G.; Leroux, B.] Univ Washington, Dept Biostat, Clin Trial Ctr, Seattle, WA 98195 USA. [Nichol, G.] Univ Washington, Harborview Ctr Prehosp Emergency Care, Seattle, WA 98195 USA. [Wittwer, L.] Clark Cty Emergency Med Serv, Vancouver, WA USA. [Daya, M.] Oregon Hlth & Sci Univ, Dept Emergency Med, Portland, OR 97201 USA. [Morrison, L. J.; Dorian, P.] St Michaels Hosp, Li Ka Shing Knowledge Inst, Rescu, 30 Bond St, Toronto, ON M5B 1W8, Canada. [Morrison, L. J.] Univ Toronto, Div Emergency Med, Dept Med, Toronto, ON, Canada. [Dorian, P.] Univ Toronto, Dept Med, Div Cardiol, Toronto, ON, Canada. [Vaillancourt, C.; Stiell, I. G.] Univ Ottawa, Ottawa Hosp Res Inst, Dept Emergency Med, Ottawa, ON, Canada. [Christenson, J.] Univ British Columbia, Providence Hlth Care Res Inst, Fac Med, Dept Emergency Med, Vancouver, BC V5Z 1M9, Canada. [Straight, R.] Providence Hlth Care Res Inst, Vancouver, BC, Canada. [Straight, R.] British Columbia Emergency Hlth Serv, Vancouver, BC, Canada. [Callaway, C. W.; Brienza, A. M.] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Egan, D.; Desvigne-Nickens, P.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Weisfeldt, M. L.] Johns Hopkins Univ, Baltimore, MD USA. [Ornato, J. P.] Virginia Commonwealth Univ, Dept Emergency Med, Richmond, VA 23284 USA. [Idris, A. H.] Univ Texas SW Med Ctr Dallas, Dept Emergency Med, Dallas, TX 75390 USA. [Idris, A. H.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Seals, N.] Dallas Fire Rescue Dept, Dallas, TX USA. [Aufderheide, T. P.] Med Coll Wisconsin, Dept Emergency Med, Milwaukee, WI 53226 USA. [Colella, M. R.] Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA. [Dunford, J. V.; Vilke, G. M.] Univ Calif San Diego, Dept Emergency Med, San Diego, CA 92103 USA. [Dunford, J. V.] San Diego Fire Rescue Dept, San Diego, CA USA. Univ Alabama Birmingham, Birmingham, AL USA. RP Kudenchuk, PJ (reprint author), Univ Washington, Div Cardiol, 1959 N E Pacific St,Box 356422, Seattle, WA 98166 USA. RI morrison, laurie/A-6325-2012; OI morrison, laurie/0000-0001-8369-9774; Ferguson, Niall/0000-0002-6213-5264 FU National Heart, Lung, and Blood Institute FX Funded by the National Heart, Lung, and Blood Institute and others NR 25 TC 28 Z9 31 U1 3 U2 13 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 5 PY 2016 VL 374 IS 18 BP 1711 EP 1722 DI 10.1056/NEJMoa1514204 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA DL0RY UT WOS:000375341500004 PM 27043165 ER PT J AU Kulinski, JM Munoz-Cano, R Olivera, A AF Kulinski, Joseph M. Munoz-Cano, Rosa Olivera, Ana TI Sphingosine-1-phosphate and other lipid mediators generated by mast cells as critical players in allergy and mast cell function SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE Mast cells; Sphingosine-l-phosphate; Eicosanoids; Platelet activating factor; Lipid mediators; Allergy ID PLATELET-ACTIVATING-FACTOR; PROSTAGLANDIN D-2 GENERATION; FC-EPSILON-RI; SPHINGOSINE 1-PHOSPHATE RECEPTORS; LEUKOTRIENE B-4 RECEPTORS; PROTEIN-COUPLED RECEPTOR; CYSTEINYL LEUKOTRIENES; IN-VIVO; ENDOPEROXIDE SYNTHASE-1; PULMONARY INFLAMMATION AB Sphingosine-l-phosphate (SIP), platelet activating factor (PAF) and eicosanoids are bioactive lipid mediators abundantly produced by antigen-stimulated mast cells that exert their function mostly through specific cell surface receptors. Although it has long been recognized that some of these bioactive lipids are potent regulators of allergic diseases, their exact contributions to disease pathology have been obscured by the complexity of their mode of action and the regulation of their metabolism. Indeed, the effects of such lipids are usually mediated by multiple receptor subtypes that may differ in their signaling mechanisms and functions. In addition, their actions may be elicited by cell surface receptor independent mechanisms. Furthermore, these lipids may be converted into metabolites that exhibit different functionalities, adding another layer of complexity to their overall biological responses. In some instances, a second wave of lipid mediator synthesis by both mast cell and non-mast cell sources may occur late during inflammation, bringing about additional roles in the altered environment. New evidence also suggests that bioactive lipids in the local environment can fine-tune mast cell maturation and phenotype, and thus their responsiveness. A better understanding of the subtleties of the spatiotemporal regulation of these lipid mediators, their receptors and functions may aid in the pursuit of pharmacological applications for allergy treatments. Published by Elsevier B.V. C1 [Kulinski, Joseph M.; Munoz-Cano, Rosa; Olivera, Ana] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Olivera, A (reprint author), NIAID, Mast Cell Biol Sect, Lab Allerg Dis, NIH, Bldg 10,Rm 11C205,10 Ctr Drive, Bethesda, MD 20892 USA. EM joseph.kulinski@nih.gov; munozcanorm@niaid.nih.gov; ana.olivera@nih.gov OI Munoz Cano, Rosa/0000-0001-8566-8285 FU Division of Intramural Research Program within NIAID; NIAMS, NIH FX This work was supported by the Division of Intramural Research Program within NIAID and NIAMS, NIH. NR 139 TC 3 Z9 3 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 EI 1879-0712 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD MAY 5 PY 2016 VL 778 BP 56 EP 67 DI 10.1016/j.ejphar.2015.02.058 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DI5TB UT WOS:000373561300007 PM 25941085 ER PT J AU Cruse, G Bradding, P AF Cruse, Glenn Bradding, Peter TI Mast cells in airway diseases and interstitial lung disease SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Review DE Mast cell; Asthma; Airway diseases; Interstitial lung disease ID FC-EPSILON-RI; TUMOR-NECROSIS-FACTOR; BRONCHOALVEOLAR LAVAGE FLUID; FIBROBLAST-GROWTH-FACTOR; SMOOTH-MUSCLE-CELLS; OBSTRUCTIVE PULMONARY-DISEASE; C-KIT RECEPTOR; BRONCHIAL EPITHELIAL-CELLS; LOCAL ALLERGEN CHALLENGE; HUMAN-ENDOTHELIAL-CELLS AB Mast cells are major effector cells of inflammation and there is strong evidence that mast cells play a significant role in asthma pathophysiology. There is also a growing body of evidence that mast cells contribute to other inflammatory and fibrotic lung diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. This review discusses the role that mast cells play in airway diseases and highlights how mast cell microlocalisation within specific lung compartments and their cellular interactions are likely to be critical for their effector function in disease. Published by Elsevier B.V. C1 [Cruse, Glenn] NIAID, Lab Allerg Dis, NIH, Bldg 10,Rm 11C213,10 Ctr Dr MSC 1881, Bethesda, MD 20892 USA. [Bradding, Peter] Univ Leicester, Glenfield Hosp, Dept Infect Immun & Inflammat, Inst Lung Hlth, Leicester LE3 9QP, Leics, England. RP Cruse, G (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Rm 11C213,10 Ctr Dr MSC 1881, Bethesda, MD 20892 USA. EM glenn.cruse@nih.gov FU Division of Intramural Research of NIAID; National Institutes of Health, United States; National Institute for Health Research Leicester Respiratory Biomedical Research Unit, United Kingdom FX Financial support was provided by the Division of Intramural Research of NIAID and National Institutes of Health, United States, and by the National Institute for Health Research Leicester Respiratory Biomedical Research Unit, United Kingdom. NR 259 TC 5 Z9 6 U1 5 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 EI 1879-0712 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD MAY 5 PY 2016 VL 778 BP 125 EP 138 DI 10.1016/j.ejphar.2015.04.046 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DI5TB UT WOS:000373561300015 PM 25959386 ER PT J AU Laucis, NC Chowdhury, M Dasgupta, A Bhattacharyya, T AF Laucis, Nicholas C. Chowdhury, Mohammed Dasgupta, Abhijit Bhattacharyya, Timothy TI Trend Toward High-Volume Hospitals and the Influence on Complications in Knee and Hip Arthroplasty SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID SURGEON PROCEDURE VOLUME; STATES MEDICARE POPULATION; UNITED-STATES; PATIENT OUTCOMES; REVISION HIP; REPLACEMENT; ASSOCIATION; IMPACT; OLDER; CARE AB Background: Hospitals in which a high volume of arthroplasty procedures are performed have been observed to have better outcomes. As the number of arthroplasties has increased, it is not known whether surgical cases have shifted to high-volume hospitals. In this study, we examined the change in the volume of arthroplasties to provide a contemporary definition of "high-volume" centers, quantified surgical volume that shifted to high-volume centers, and investigated the resulting effect on complications. Methods: Data from the National (Nationwide) Inpatient Sample (2000 to 2012) were used to quantify trends in total hip arthroplasty (THA) and total knee arthroplasty (TKA) volume. Elective primary THAs and TKAs were identified and grouped by hospital by utilizing the hospital identifier, which indicates the geographic location of the hospital. County geographic and population data were obtained from the U.S. Census, and the distances between hospitals and the centroids of counties were calculated. Risk-standardized surgical complication rates for hospitals (2009 to 2012) were obtained from Medicare Hospital Compare and grouped by hospital volume. Results: From 2000 to 2012, there was a marked increase in the number of hospitals that performed a combined volume of >= 400 elective primary THAs and TKAs. The number of elective primary TKAs and THAs performed annually increased from 343,000 to 851,000. In 2012, 65.5% of the arthroplasties were performed in high-volume hospitals (>= 400 arthroplasties annually), and 26.6% of the arthroplasties were performed in very high-volume hospitals (>= 1,000 procedures annually). The proportion of arthroplasties performed in low-volume hospitals (<100 arthroplasties annually) shrank from 17.9% to 5.4%. Very high-volume hospitals had the lowest complication rates (2.745 per 100; 95% confidence interval [CI], 2.56 to 2.93), and lowvolume hospitals had the highest complication rates (3.610 per 100; 95% CI, 3.58 to 3.64; p < 0.0001) (odds ratio, 1.327; 95% CI, 1.26 to 1.40). Our analysis showed that 81.9% of the U.S. population lived within 50 miles of a high-volume hospital. Conclusions: Arthroplasty patients are electing to have their procedures at higher-volume hospitals in the United States. Each successively higher hospital volume category manifested a lower complication rate. C1 [Laucis, Nicholas C.; Chowdhury, Mohammed; Dasgupta, Abhijit; Bhattacharyya, Timothy] NIAMSD, Clin & Invest Orthoped Surg Unit, NIH, Bethesda, MD 20892 USA. RP Bhattacharyya, T (reprint author), NIAMSD, Clin & Invest Orthoped Surg Unit, NIH, Bethesda, MD 20892 USA. EM timothy.bhattacharyya@nih.gov FU Intramural Research Program at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health FX This study was funded by the Intramural Research Program at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health. NR 26 TC 2 Z9 2 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0021-9355 EI 1535-1386 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD MAY 4 PY 2016 VL 98 IS 9 BP 707 EP 712 DI 10.2106/JBJS.15.00399 PG 6 WC Orthopedics; Surgery SC Orthopedics; Surgery GA DP6WX UT WOS:000378641400005 PM 27147682 ER PT J AU Williams, RC Elston, RC Kumar, P Knowler, WC Abboud, HE Adler, S Bowden, DW Divers, J Freedman, BI Igo, RP Ipp, E Iyengar, SK Kimmel, PL Klag, MJ Kohn, O Langefeld, CD Leehey, DJ Nelson, RG Nicholas, SB Pahl, MV Parekh, RS Rotter, JI Schelling, JR Sedor, JR Shah, VO Smith, MW Taylor, KD Thameem, F Thornley-Brown, D Winkler, CA Guo, XQ Zager, P Hanson, RL AF Williams, Robert C. Elston, Robert C. Kumar, Pankaj Knowler, William C. Abboud, Hanna E. Adler, Sharon Bowden, Donald W. Divers, Jasmin Freedman, Barry I. Igo, Robert P., Jr. Ipp, Eli Iyengar, Sudha K. Kimmel, Paul L. Klag, Michael J. Kohn, Orly Langefeld, Carl D. Leehey, David J. Nelson, Robert G. Nicholas, Susanne B. Pahl, Madeleine V. Parekh, Rulan S. Rotter, Jerome I. Schelling, Jeffrey R. Sedor, John R. Shah, Vallabh O. Smith, Michael W. Taylor, Kent D. Thameem, Farook Thornley-Brown, Denyse Winkler, Cheryl A. Guo, Xiuqing Zager, Phillip Hanson, Robert L. CA FIND Res Grp TI Selecting SNPs informative for African, American Indian and European Ancestry: application to the Family Investigation of Nephropathy and Diabetes (FIND) SO BMC GENOMICS LA English DT Article DE Individual genetic ancestry; Population structure; SNP; Diabetic nephropathy ID GENOME-WIDE ASSOCIATION; ADMIXTURE PROPORTIONS; ADMIXED POPULATIONS; GENETIC ANCESTRY; MEXICAN-AMERICANS; BREAST-CANCER; PIMA-INDIANS; RISK-FACTORS; INFERENCE; ARIZONA AB Background: The presence of population structure in a sample may confound the search for important genetic loci associated with disease. Our four samples in the Family Investigation of Nephropathy and Diabetes (FIND), European Americans, Mexican Americans, African Americans, and American Indians are part of a genome-wide association study in which population structure might be particularly important. We therefore decided to study in detail one component of this, individual genetic ancestry (IGA). From SNPs present on the Affymetrix 6.0 Human SNP array, we identified 3 sets of ancestry informative markers (AIMs), each maximized for the information in one the three contrasts among ancestral populations: Europeans (HAPMAP, CEU), Africans (HAPMAP, YRI and LWK), and Native Americans (full heritage Pima Indians). We estimate IGA and present an algorithm for their standard errors, compare IGA to principal components, emphasize the importance of balancing information in the ancestry informative markers (AIMs), and test the association of IGA with diabetic nephropathy in the combined sample. Results: A fixed parental allele maximum likelihood algorithm was applied to the FIND to estimate IGA in four samples: 869 American Indians; 1385 African Americans; 1451 Mexican Americans; and 826 European Americans. When the information in the AIMs is unbalanced, the estimates are incorrect with large error. Individual genetic admixture is highly correlated with principle components for capturing population structure. It takes similar to 700 SNPs to reduce the average standard error of individual admixture below 0.01. When the samples are combined, the resulting population structure creates associations between IGA and diabetic nephropathy. Conclusions: The identified set of AIMs, which include American Indian parental allele frequencies, may be particularly useful for estimating genetic admixture in populations from the Americas. Failure to balance information in maximum likelihood, poly-ancestry models creates biased estimates of individual admixture with large error. This also occurs when estimating IGA using the Bayesian clustering method as implemented in the program STRUCTURE. Odds ratios for the associations of IGA with disease are consistent with what is known about the incidence and prevalence of diabetic nephropathy in these populations. C1 [Williams, Robert C.; Kumar, Pankaj; Knowler, William C.; Nelson, Robert G.; Hanson, Robert L.] NIDDKD, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85014 USA. [Elston, Robert C.; Igo, Robert P., Jr.; Iyengar, Sudha K.] Case Western Reserve Univ, Genet Anal & Data Coordinating Ctr, Cleveland, OH 44104 USA. [Abboud, Hanna E.; Thameem, Farook] Univ Texas Hlth Sci Ctr San Antonio, Div Nephrol, San Antonio, TX 78229 USA. [Adler, Sharon; Ipp, Eli] Harbor UCLA Med Ctr, Dept Nephrol, Torrance, CA 90502 USA. [Bowden, Donald W.; Divers, Jasmin; Freedman, Barry I.; Langefeld, Carl D.] Wake Forest Sch Med, Winston Salem, NC 27157 USA. [Kimmel, Paul L.] NIDDKD, Bethesda, MD 20892 USA. [Klag, Michael J.] Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. [Kohn, Orly] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Leehey, David J.] Loyola Univ, Med Ctr, Chicago, IL 60611 USA. [Nicholas, Susanne B.] Univ Calif Los Angeles, David Geffen Sch Med, Div Nephrol, Los Angeles, CA 90095 USA. [Nicholas, Susanne B.] Univ Calif Los Angeles, David Geffen Sch Med, Div Endocrinol, Los Angeles, CA 90095 USA. [Pahl, Madeleine V.] Univ Calif, UC Irvine Sch Med, Dept Med, Div Nephrol & Hypertens, Orange, CA 92868 USA. [Parekh, Rulan S.] Hosp Sick Children, Univ Hlth Network, Toronto, ON M5G 1X8, Canada. [Parekh, Rulan S.] Univ Toronto, Toronto, ON M5G 1X8, Canada. [Rotter, Jerome I.; Taylor, Kent D.; Guo, Xiuqing] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst, Torrance, CA 90502 USA. [Rotter, Jerome I.; Taylor, Kent D.; Guo, Xiuqing] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90502 USA. [Schelling, Jeffrey R.; Sedor, John R.] Case Western Reserve Univ, Dept Med, Cleveland, OH 44104 USA. [Schelling, Jeffrey R.; Sedor, John R.] Case Western Reserve Univ, Dept Physiol & Biophys, Cleveland, OH 44104 USA. [Shah, Vallabh O.; Zager, Phillip] Univ New Mexico, Albuquerque, NM 87131 USA. [Smith, Michael W.] NHGRI, NIH, Bethesda, MD 20892 USA. [Thameem, Farook] Kuwait Univ, Fac Med, Dept Biochem, Kuwait, Kuwait. [Thornley-Brown, Denyse] Univ Alabama Birmingham, Birmingham, AL 35233 USA. [Winkler, Cheryl A.] NCI, Ctr Canc Res, NIH, Leidos Biomed Inc,Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Williams, RC (reprint author), NIDDKD, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85014 USA. EM williamsr@mail.nih.gov OI Rasooly, Rebekah/0000-0002-6357-5528 FU National Institutes of Health (NIH) [R01 DK 070941, R01 DK 084149, R01 DK53591]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [F32 DK080617]; NIDDK [U01DK57292, U01DK57329, U01DK057300, U01DK057298, U01DK057249, U01DK57295, U01DK070657, U01DK057303, U01DK57304, DK07024]; Intramural Research Program of the NIDDK; NIH National Cancer Institute (NCI) [HHSN26120080001E]; Intramural Research Program of the NIH-NCI Center for Cancer Research; National Center for Research Resources [M01-RR-000080, M01-RR-07122, M01-RR-00425, M01-RR-00827-29, HSC M01-RR-00997, M01-RR-01346]; Agency for Healthcare Research and Quality, Rockville, MD [HS08365]; National Heart, Lung, and Blood Institute, Bethesda, MD [HL62985]; NIH [N01-HG-65403] FX This study was supported in part by National Institutes of Health (NIH) grants R01 DK 070941 and R01 DK 084149 (Dr. Freedman) and R01 DK53591 (Dr. Bowden). Dr. Bostrom was supported by F32 DK080617 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Computing resources were provided by the Wake Forest University Health Sciences Center for Public Health Genomics. This study was also supported by FIND grants U01DK57292, U01DK57329, U01DK057300, U01DK057298, U01DK057249, U01DK57295, U01DK070657, U01DK057303, U01DK070657, U01DK57304 and CHOICE study DK07024 from the NIDDK and in part by the Intramural Research Program of the NIDDK. This project has been funded in whole or in part with federal funds from the NIH National Cancer Institute (NCI) under contract HHSN26120080001E and the Intramural Research Program of the NIH-NCI Center for Cancer Research. This work also was supported by the National Center for Research Resources for the General Clinical Research Center grants: Case Western Reserve University, M01-RR-000080; Wake Forest University, M01-RR-07122; Harbor-University of California, Los Angeles Medical Center, M01-RR-00425; College of Medicine, University of California, Irvine, M01-RR-00827-29; University of New Mexico, HSC M01-RR-00997; and Frederic C. Bartter, M01-RR-01346. The CHOICE Study was supported in part by HS08365 from the Agency for Healthcare Research and Quality, Rockville, MD, and HL62985 from the National Heart, Lung, and Blood Institute, Bethesda, MD. Genotyping was performed by the Center for Inherited Disease Research, which is fully funded through a federal contract from the NIH to Johns Hopkins University (N01-HG-65403). NR 33 TC 2 Z9 2 U1 5 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD MAY 4 PY 2016 VL 17 AR 325 DI 10.1186/s12864-016-2654-x PG 17 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DL9RF UT WOS:000375979700001 PM 27142425 ER PT J AU Jiang, J Zhu, Q Gendron, TF Saberi, S McAlonis-Downes, M Seelman, A Stauffer, JE Jafar-Nejad, P Drenner, K Schulte, D Chun, S Sun, SY Ling, SC Myers, B Engelhardt, J Katz, M Baughn, M Platoshyn, O Marsala, M Watt, A Heyser, CJ Ard, MC De Muynck, L Daughrity, LM Swing, DA Tessarollo, L Jung, CJ Delpoux, A Utzschneider, DT Hedrick, SM de Jong, PJ Edbauer, D Van Damme, P Petrucelli, L Shaw, CE Bennett, CF Da Cruz, S Ravits, J Rigo, F Cleveland, DW Lagier-Tourenne, C AF Jiang, Jie Zhu, Qiang Gendron, Tania F. Saberi, Shahram McAlonis-Downes, Melissa Seelman, Amanda Stauffer, Jennifer E. Jafar-nejad, Paymaan Drenner, Kevin Schulte, Derek Chun, Seung Sun, Shuying Ling, Shuo-Chien Myers, Brian Engelhardt, Jeffery Katz, Melanie Baughn, Michael Platoshyn, Oleksandr Marsala, Martin Watt, Andy Heyser, Charles J. Ard, M. Colin De Muynck, Louis Daughrity, Lillian M. Swing, Deborah A. Tessarollo, Lino Jung, Chris J. Delpoux, Arnaud Utzschneider, Daniel T. Hedrick, Stephen M. de Jong, Pieter J. Edbauer, Dieter Van Damme, Philip Petrucelli, Leonard Shaw, Christopher E. Bennett, C. Frank Da Cruz, Sandrine Ravits, John Rigo, Frank Cleveland, Don W. Lagier-Tourenne, Clotilde TI Gain of Toxicity from ALS/FTD-Linked Repeat Expansions in C9ORF72 Is Alleviated by Antisense Oligonucleotides Targeting GGGGCC-Containing RNAs SO NEURON LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; FRONTOTEMPORAL LOBAR DEGENERATION; HEXANUCLEOTIDE REPEAT; NUCLEOCYTOPLASMIC TRANSPORT; EXPANDED C9ORF72; NUCLEAR-RNA; PROTEINS; ALS; FOCI; MICE AB Hexanucleotide expansions in C9ORF72 are the most frequent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Disease mechanisms were evaluated in mice expressing C9ORF72 RNAs with up to 450 GGGGCC repeats or with one or both C9orf72 alleles inactivated. Chronic 50% reduction of C9ORF72 did not provoke disease, while its absence produced splenomegaly, enlarged lymph nodes, and mild social interaction deficits, but not motor dysfunction. Hexanucleotide expansions caused age-, repeat-length-, and expression-level-dependent accumulation of RNA foci and dipeptide-repeat proteins synthesized by AUG-independent translation, accompanied by loss of hippocampal neurons, increased anxiety, and impaired cognitive function. Single-dose injection of antisense oligonucleotides (ASOs) that target repeat-containing RNAs but preserve levels of mRNAs encoding C9ORF72 produced sustained reductions in RNA foci and dipeptide-repeat proteins, and ameliorated behavioral deficits. These efforts identify gain of toxicity as a central disease mechanism caused by repeat-expanded C9ORF72 and establish the feasibility of ASO-mediated therapy. C1 [Jiang, Jie; Zhu, Qiang; McAlonis-Downes, Melissa; Seelman, Amanda; Drenner, Kevin; Sun, Shuying; Ling, Shuo-Chien; Myers, Brian; Baughn, Michael; Da Cruz, Sandrine; Cleveland, Don W.; Lagier-Tourenne, Clotilde] Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA. [Baughn, Michael; Delpoux, Arnaud; Utzschneider, Daniel T.; Hedrick, Stephen M.; Cleveland, Don W.] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. [Jiang, Jie; Saberi, Shahram; Stauffer, Jennifer E.; Schulte, Derek; Baughn, Michael; Heyser, Charles J.; Ard, M. Colin; Ravits, John; Cleveland, Don W.; Lagier-Tourenne, Clotilde] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Gendron, Tania F.; Daughrity, Lillian M.; Petrucelli, Leonard] Mayo Clin, Dept Neurosci, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. [Jafar-nejad, Paymaan; Chun, Seung; Engelhardt, Jeffery; Katz, Melanie; Watt, Andy; Bennett, C. Frank; Rigo, Frank] Ionis Pharmaceut, 2855 Gazelle Court, Carlsbad, CA 92010 USA. [Ling, Shuo-Chien] Natl Univ Singapore, Dept Physiol, 12 Sci Dr 2, Singapore 117549, Singapore. [Platoshyn, Oleksandr; Marsala, Martin] Univ Calif San Diego, Dept Anesthesiol, La Jolla, CA 92093 USA. [Platoshyn, Oleksandr; Marsala, Martin] Sanford Consortium Regenerat Med, Neuroregenerat Lab, 2880 Torrey Pines Scen Dr, La Jolla, CA 92037 USA. [Marsala, Martin] Slovak Acad Sci, Inst Neurobiol, Soltesovej 9, Kosice 04001, Slovakia. [De Muynck, Louis; Van Damme, Philip] KU Leuven VIB, Dept Neurosci, Expt Neurol, Lab Neurobiol,Vesalius Res Ctr, B-3000 Leuven, Belgium. [De Muynck, Louis; Van Damme, Philip] Univ Hosp Leuven, Dept Neurol, B-3000 Leuven, Belgium. [Swing, Deborah A.; Tessarollo, Lino] NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. [Jung, Chris J.; de Jong, Pieter J.] Childrens Hosp Oakland, Res Inst, 5700 Martin Luther King Jr Way, Oakland, CA 94609 USA. [Delpoux, Arnaud; Utzschneider, Daniel T.; Hedrick, Stephen M.] Univ Calif San Diego, Div Biol Sci, Mol Biol Sect, La Jolla, CA 92093 USA. [Edbauer, Dieter] Univ Munich, German Ctr Neurodegenerat Dis DZNE, Feodor Lynen Str 17, D-81377 Munich, Germany. [Edbauer, Dieter] Munich Cluster Syst Neurol SyNergy, Feodor Lynen Str 17, D-81377 Munich, Germany. [Shaw, Christopher E.] Kings Coll London, Inst Psychiat, London WC2R 2LS, England. [Lagier-Tourenne, Clotilde] Harvard Univ, Sch Med, Massachusetts Gen Hosp, MassGeneral Inst Neurodegenerat Dis,Dept Neurol, Charlestown, MA 02129 USA. RP Cleveland, DW; Lagier-Tourenne, C (reprint author), Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA.; Cleveland, DW (reprint author), Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA.; Cleveland, DW; Lagier-Tourenne, C (reprint author), Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA.; Lagier-Tourenne, C (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, MassGeneral Inst Neurodegenerat Dis,Dept Neurol, Charlestown, MA 02129 USA. EM dcleveland@ucsd.edu; clagier-tourenne@mgh.harvard.edu RI Utzschneider, Daniel/D-5855-2016; Van Damme, Philip/A-6464-2009; OI Van Damme, Philip/0000-0001-6384-0611; Delpoux, Arnaud/0000-0003-4963-9676 FU ALS Association; NIH [R01-NS088578, R01-NS087227, R21-NS089979, R21-NS084528, R01-NS088689, R01-NS063964, R01-NS077402, P01-NS084974, T32 AG00216, F32 NS087842, K99 NS091538]; UCSD Alzheimer's Disease Research Center; Target ALS [13-04827, 13-44792]; Robert Packard Center for ALS Research at Johns Hopkins; Mayo Clinic Foundation; FWO-Vlaanderen; Belgian Alzheimer Disease Association (SAO); European Union's Seventh Framework Programme FP7 [617198]; University of California, San Diego; Ludwig Institute for Cancer Research FX We thank Patrick King, Clement Ng, Cheyenne Schloffman, Marcus Maldonado, Anh Bui, and Drs. Ricardos Tabet, Kent Osborn, and Nissi Varki for their advice and technical assistance. We thank all members of D.W.C., C.L.-T., and J.R. groups and the teamat Ionis Pharmaceuticals for critical suggestions on this project. This work was supported by the ALS Association (a Neurocollaborative grant to D.W.C., grants to T.F.G. and L.P., and a Milton Safenowitz postdoctoral fellowship to Q.Z.); grants from the NIH (R01-NS088578 to J.R. and D.W.C., R01-NS087227 to C.L.-T., R21-NS089979 to T.F.G., as well as R21-NS084528, R01-NS088689, R01-NS063964, R01-NS077402, and P01-NS084974 to L.P.); the UCSD Alzheimer's Disease Research Center (to C.L.-T.); research project funding from Target ALS to C.L.-T. (13-04827), J.R. (13-44792), and L.P.; the Robert Packard Center for ALS Research at Johns Hopkins (to L.P.); the Mayo Clinic Foundation (to L.P.); a senior clinical investigatorship and a grant from FWO-Vlaanderen to P.V.D.; the Belgian Alzheimer Disease Association (SAO; to P.V.D.); and the European Union's Seventh Framework Programme FP7/2014-2019 under grant agreement no 617198 [DPR-MODELS] (to D.E.). J. J. was supported by NIH postdoctoral fellowships (T32 AG00216 and F32 NS087842). S. Sun is the recipient of career development grants from the NIH (K99 NS091538) and Target ALS. L.D.M. is employed by Janssen Pharmaceutical Companies of Johnson & Johnson. P.J., S.C., J.E., A.W., C.F.B., and F.R. are employees and D.W.C. is a consultant for Ionis Pharmaceuticals. J.R. received salary support from the University of California, San Diego. C.L.-T. and D.W.C. received salary support from the Ludwig Institute for Cancer Research. NR 64 TC 19 Z9 19 U1 5 U2 23 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD MAY 4 PY 2016 VL 90 IS 3 BP 535 EP 550 DI 10.1016/j.neuron.2016.04.006 PG 16 WC Neurosciences SC Neurosciences & Neurology GA DM3NZ UT WOS:000376254500014 PM 27112497 ER PT J AU Oettl, LL Ravi, N Schneider, M Scheller, MF Schneider, P Mitre, M Gouveia, MD Froemke, RC Chao, MV Young, WS Meyer-Lindenberg, A Grinevich, V Shusterman, R Kelsch, W AF Oettl, Lars-Lennart Ravi, Namasivayam Schneider, Miriam Scheller, Max F. Schneider, Peggy Mitre, Mariela Gouveia, Miriam da Silva Froemke, Robert C. Chao, Moses V. Young, W. Scott Meyer-Lindenberg, Andreas Grinevich, Valery Shusterman, Roman Kelsch, Wolfgang TI Oxytocin Enhances Social Recognition by Modulating Cortical Control of Early Olfactory Processing SO NEURON LA English DT Article ID BULB GRANULE CELLS; CENTRAL AMYGDALA; RAT-BRAIN; NEUROANATOMICAL DISTRIBUTION; ADULT NEUROGENESIS; MATERNAL-BEHAVIOR; MEDIAL AMYGDALA; BINDING-SITES; MITRAL CELLS; SYSTEM AB Oxytocin promotes social interactions and recognition of conspecifics that rely on olfaction in most species. The circuit mechanisms through which oxytocin modifies olfactory processing are incompletely understood. Here, we observed that optogenetically induced oxytocin release enhanced olfactory exploration and same-sex recognition of adult rats. Consistent with oxytocin's function in the anterior olfactory cortex, particularly in social cue processing, region-selective receptor deletion impaired social recognition but left odor discrimination and recognition intact outside a social context. Oxytocin transiently increased the drive of the anterior olfactory cortex projecting to olfactory bulb interneurons. Cortical top-down recruitment of interneurons dynamically enhanced the inhibitory input to olfactory bulb projection neurons and increased the signal-to-noise of their output. In summary, oxytocin generates states for optimized information extraction in an early cortical top-down network that is required for social interactions with potential implications for sensory processing deficits in autism spectrum disorders. C1 [Oettl, Lars-Lennart; Ravi, Namasivayam; Schneider, Miriam; Scheller, Max F.; Schneider, Peggy; Meyer-Lindenberg, Andreas; Grinevich, Valery; Kelsch, Wolfgang] Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, D-68159 Mannheim, Germany. [Mitre, Mariela; Froemke, Robert C.; Chao, Moses V.] NYU, Sch Med, Skirball Inst Biomol Med, New York, NY 10016 USA. [Gouveia, Miriam da Silva; Grinevich, Valery] German Canc Res Ctr, Schaller Res Grp Neuropeptides, D-69120 Heidelberg, Germany. [Young, W. Scott] NIMH, Sect Neural Gene Express, NIH, Bethesda, MD 20892 USA. [Shusterman, Roman] Univ Haifa, Sagol Dept Neurobiol, IL-3498838 Haifa, Israel. [Shusterman, Roman] Univ Oregon, Inst Neurosci, Eugene, OR 97403 USA. RP Kelsch, W (reprint author), Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, D-68159 Mannheim, Germany. EM wolfgang.kelsch@zi-mannheim.de RI Young, W Scott/A-9333-2009; Meyer-Lindenberg, Andreas/H-1076-2011; OI Young, W Scott/0000-0001-6614-5112; Meyer-Lindenberg, Andreas/0000-0001-5619-1123; Chao, Moses/0000-0002-6969-3744; Froemke, Robert/0000-0002-1230-6811 FU DFG [KE1661/1-1, SFB 1134]; DFG Collaborative Research Center [(SFB) 636]; Schaller Research Foundation; NIMH [ZIA-MH-002498-24] FX We thank Patrick Jendritza for help with recordings, Drs. Heike Tost and Georg Kohr for discussions, Dr. Marina Eliava for histology, Cathrin Huber and Christian Gluch for technical assistance, and Dr. Wolfgang Weber-Fahr and Felix Hoerner for structural MRI imaging. The project was funded by DFG KE1661/1-1 and DFG Collaborative Research Center (SFB) 636 to W.K. and the Schaller Research Foundation and DFG SFB 1134 to V.G. and to W.K. W.S.Y. was supported by the intramural research program of the NIMH (ZIA-MH-002498-24). NR 88 TC 11 Z9 11 U1 4 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD MAY 4 PY 2016 VL 90 IS 3 BP 609 EP 621 DI 10.1016/j.neuron.2016.03.033 PG 13 WC Neurosciences SC Neurosciences & Neurology GA DM3NZ UT WOS:000376254500019 PM 27112498 ER PT J AU Fava, A Cimbro, R Wigley, FM Liu, QR Rosen, A Boin, F AF Fava, Andrea Cimbro, Raffaello Wigley, Fredrick M. Liu, Qing-Rong Rosen, Antony Boin, Francesco TI Frequency of circulating topoisomerase-I-specific CD4 T cells predicts presence and progression of interstitial lung disease in scleroderma SO ARTHRITIS RESEARCH & THERAPY LA English DT Article DE Systemic sclerosis; Interstitial lung disease; T lymphocytes; Th17; Autoantigen ID SYSTEMIC-SCLEROSIS; BRONCHOALVEOLAR LAVAGE; CYTOKINE PROFILES; SKIN INVOLVEMENT; ANTIBODY-LEVELS; IFN-GAMMA; INTERLEUKIN-17; MANIFESTATIONS; ASSOCIATION; EXPRESSION AB Background: Scleroderma is an antigen-driven T cell-mediated autoimmune disease. Presence of anti-topoisomerase-I antibodies is associated with pulmonary fibrosis and predicts increased mortality. Characterization of autoreactive T lymphocytes may shed light on disease pathogenesis and serve as a biomarker for disease activity. Here, we aimed to quantify and functionally characterize circulating topoisomerase I (topo-I)-specific CD4+ T cells and to define their association with presence and progression of interstitial lung disease (ILD) in patients with scleroderma. Methods: Using flow cytometry, circulating topo-I-reactive CD4+ T cells were identified by the expression of specific activation markers (CD154 and CD69) upon stimulation with purified topo-I and quantified in 27 SSc patients and 4 healthy donors (HD). Polarization of autoreactive T cells (Th1, Th2, Th17, Th1-17) was defined using surface expression of specific chemokine receptors. Presence and progression of ILD were determined using high-resolution chest CT and pulmonary function tests. Results: Topo-I-reactive CD4+ T cells were found in all topo-I-positive patients compared to one topo-I-negative subject and no HD. Topo-I-specific CD4+ T cells exhibited a distinct Th17 polarized phenotype. Autoreactive T cells were significantly increased in subjects with evidence of ILD and were quantitatively associated with the decline of lung volumes. Conclusions: Topo-I-specific T cells can be reliably quantified in the peripheral blood of patients with scleroderma, exhibit a pro-inflammatory Th17 phenotype, and predict progression of ILD. C1 [Boin, Francesco] Univ Calif San Francisco, Div Rheumatol, Dept Med, 513 Parnassus Ave,Med Sci,S-847, San Francisco, CA 94143 USA. [Fava, Andrea; Cimbro, Raffaello; Wigley, Fredrick M.; Rosen, Antony] Johns Hopkins Univ, Div Rheumatol, Dept Med, Sch Med, 5200 Eastern Ave,MFL Bldg,Ctr Tower,Suite 4100, Baltimore, MD 21224 USA. [Liu, Qing-Rong] NIDA, Behav Neurosci Res Branch, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. RP Boin, F (reprint author), Univ Calif San Francisco, Div Rheumatol, Dept Med, 513 Parnassus Ave,Med Sci,S-847, San Francisco, CA 94143 USA. EM francesco.boin@ucsf.edu RI Liu, Qing-Rong/A-3059-2012; OI Liu, Qing-Rong/0000-0001-8477-6452; Cimbro, Raffaello/0000-0002-6251-5160 FU Scleroderma Research Foundation; Jerome L. Greene Foundation; Donald B. and Dorothy L. Stabler Foundation; National Institute of Arthritis and Musculoskeletal and Skin Diseases of National Institute of Health [P30AR053503] FX Research reported in this publication was supported by the Scleroderma Research Foundation (FB, FW), the Jerome L. Greene Foundation (FB), the Donald B. and Dorothy L. Stabler Foundation (FB), and the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institute of Health under Award Number P30AR053503 (AR, FB). NR 48 TC 2 Z9 2 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 EI 1478-6362 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PD MAY 4 PY 2016 VL 18 AR 99 DI 10.1186/s13075-016-0993-2 PG 12 WC Rheumatology SC Rheumatology GA DL4WY UT WOS:000375639700004 PM 27145754 ER PT J AU Tao-Cheng, JH Toy, D Winters, CA Reese, TS Dosemeci, A AF Tao-Cheng, Jung-Hwa Toy, Dana Winters, Christine A. Reese, Thomas S. Dosemeci, Ayse TI Zinc Stabilizes Shank3 at the Postsynaptic Density of Hippocampal Synapses SO PLOS ONE LA English DT Article ID AUTISM SPECTRUM DISORDERS; DIFFERENTIAL EXPRESSION; AMPA RECEPTORS; NEURONS; PROTEIN; PROSAP/SHANK; FAMILY; SCAFFOLD; BRAIN; NMDA AB Shank3 is a postsynaptic density (PSD) scaffold protein of the Shank family. Here we use pre-embedding immunogold electron microscopy to investigate factors influencing the distribution of Shank3 at the PSD. In dissociated rat hippocampal cultures under basal conditions, label for Shank3 was concentrated in a broad layer of the PSD, similar to 20-80 nm from the postsynaptic membrane. Upon depolarization with high K+ (90 mM, 2 min), or application of NMDA (50 mu M, 2 min), both the labeling intensity at the PSD and the median distance of label from the postsynaptic membrane increased significantly, indicating that Shank3 molecules are preferentially recruited to the distal layer of the PSD. Incubation in medium supplemented with zinc (50 mu M ZnCl2, 1 hr) also significantly increased labeling intensity for Shank3 at the PSD, but this addition of Shank3 was not preferential to the distal layer. When cells were incubated with zinc and then treated with NMDA, labeling intensity of Shank3 became higher than with either treatment alone and manifested a preference for the distal layer of the PSD. Without zinc supplementation, NMDA-induced accumulation of Shank3 at the PSD was transient, reversing within 30 min after return to control medium. However, when zinc was included in culture media throughout the experiment, the NMDA-induced accumulation of Shank3 was largely retained, including Shank3 molecules recruited to the distal layer of the PSD. These results demonstrate that activity induces accumulation of Shank3 at the PSD and that zinc stabilizes PSD-associated Shank3, possibly through strengthening of Shank-Shank association. C1 [Tao-Cheng, Jung-Hwa] NINDS, NINDS EM Facil, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Toy, Dana; Winters, Christine A.; Reese, Thomas S.; Dosemeci, Ayse] NINDS, Neurobiol Lab, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Tao-Cheng, JH (reprint author), NINDS, NINDS EM Facil, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM chengs@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke FX This study was supported by National Institute of Neurological Disorders and Stroke intramural funds. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 1 Z9 1 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 4 PY 2016 VL 11 IS 5 AR e0153979 DI 10.1371/journal.pone.0153979 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DL5KR UT WOS:000375676400035 PM 27144302 ER PT J AU Jiang, XT Sidhu, R Mydock-McGrane, L Hsu, FF Covey, DF Scherrer, DE Earley, B Gale, SE Farhat, NY Porter, FD Dietzen, DJ Orsini, JJ Berry-Kravis, E Zhang, XK Reunert, J Marquardt, T Runz, H Giugliani, R Schaffer, JE Ory, DS AF Jiang, Xuntian Sidhu, Rohini Mydock-McGrane, Laurel Hsu, Fong-Fu Covey, Douglas F. Scherrer, David E. Earley, Brian Gale, Sarah E. Farhat, Nicole Y. Porter, Forbes D. Dietzen, Dennis J. Orsini, Joseph J. Berry-Kravis, Elizabeth Zhang, Xiaokui Reunert, Janice Marquardt, Thorsten Runz, Heiko Giugliani, Roberto Schaffer, Jean E. Ory, Daniel S. TI Development of a bile acid-based newborn screen for Niemann-Pick disease type C SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID CEREBROTENDINOUS XANTHOMATOSIS; CHOLESTEROL; MICE; STORAGE; PLASMA; NPC1; IDENTIFICATION; DIAGNOSIS; TRANSPORT; MOUSE AB Niemann-Pick disease type C (NPC) is a fatal, neurodegenerative, cholesterol storage disorder. With new therapeutics in clinical trials, it is imperative to improve diagnostics and facilitate early intervention. We used metabolomic profiling to identify potential markers and discovered three unknown bile acids that were increased in plasma from NPC but not control subjects. The bile acids most elevated in the NPC subjects were identified as 3 beta, 5 alpha, 6 beta-trihydroxycholanic acid and its glycine conjugate, which were shown to be metabolites of cholestane-3 beta, 5 alpha, 6 beta-triol, an oxysterol elevated in NPC. A high-throughput mass spectrometry-based method was developed and validated to measure the glycine-conjugated bile acid in dried blood spots. Analysis of dried blood spots from 4992 controls, 134 NPC carriers, and 44 NPC subjects provided 100% sensitivity and specificity in the study samples. Quantification of the bile acid in dried blood spots, therefore, provides the basis for a newborn screen for NPC that is ready for piloting in newborn screening programs. C1 [Jiang, Xuntian; Sidhu, Rohini; Scherrer, David E.; Earley, Brian; Gale, Sarah E.; Schaffer, Jean E.; Ory, Daniel S.] Washington Univ, Sch Med, Diabet Cardiovasc Dis Ctr, St Louis, MO 63110 USA. [Mydock-McGrane, Laurel; Covey, Douglas F.] Washington Univ, Sch Med, Dept Dev Biol, St Louis, MO 63110 USA. [Hsu, Fong-Fu] Washington Univ, Sch Med, Dept Internal Med, St Louis, MO 63110 USA. [Farhat, Nicole Y.; Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Dysmorphol, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Dietzen, Dennis J.] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. [Orsini, Joseph J.] New York State Dept Hlth, Wadsworth Ctr, Albany, NY 12201 USA. [Berry-Kravis, Elizabeth] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Zhang, Xiaokui] Genzyme, 500 Kendall St, Cambridge, MA 02142 USA. [Reunert, Janice; Marquardt, Thorsten] Univ Klinikum Munster, Klin & Poliklin Kinder & Jugendmed Allgemeine Pad, Albert Schweitzer Campus 1,Gebaude A1, D-48149 Munster, Germany. [Runz, Heiko] Heidelberg Univ, Inst Human Genet, Neuenheimer Feld 366, D-69120 Heidelberg, Germany. [Runz, Heiko] Merck Res Labs, Dept Genet & Pharmacogen, 33 Ave Louis Pasteur, Boston, MA 02115 USA. [Giugliani, Roberto] Hosp Clin Porto Alegre, Serv Genet Med, Rua Ramiro Barcelos 2350, BR-90035003 Porto Alegre, RS, Brazil. RP Ory, DS (reprint author), Washington Univ, Sch Med, Diabet Cardiovasc Dis Ctr, St Louis, MO 63110 USA. EM dory@wustl.edu RI Sidhu, Rohini/G-3547-2012; OI Earley, Brian/0000-0002-6707-6785 FU National Niemann-Pick Disease Foundation; Dana's Angels Research Trust; Ara Parseghian Medical Research Foundation; Accelerated Research for NPC Disease; NIH [T32 HL07275, R01 NS081985]; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; Office of Rare Diseases FX This work was supported by grants from the National Niemann-Pick Disease Foundation (X.J.), Dana's Angels Research Trust (D.S.O. and N.Y.F.), Ara Parseghian Medical Research Foundation (D.S.O. and N.Y.F.), Support of Accelerated Research for NPC Disease (D.S.O.), and NIH (T32 HL07275 to L.M.-M. and R01 NS081985 to D.S.O. and J.E.S.). This study was also supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (F.D.P.) and a Bench to Bedside award from the Office of Rare Diseases (F.D.P. and D.S.O.). This work was performed in the Metabolomics Facility at Washington University (NIH, P30 DK020579). NR 41 TC 4 Z9 4 U1 6 U2 6 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD MAY 4 PY 2016 VL 8 IS 337 AR 337ra63 DI 10.1126/scitranslmed.aaf2326 PG 10 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA DL7EF UT WOS:000375802500001 PM 27147587 ER PT J AU Vannella, KM Ramalingam, TR Borthwick, LA Barron, L Hart, KM Thompson, RW Kindrachuk, KN Cheever, AW White, S Budelsky, AL Comeau, MR Smith, DE Wynn, TA AF Vannella, Kevin M. Ramalingam, Thirumalai R. Borthwick, Lee A. Barron, Luke Hart, Kevin M. Thompson, Robert W. Kindrachuk, Kristen N. Cheever, Allen W. White, Sandra Budelsky, Alison L. Comeau, Michael R. Smith, Dirk E. Wynn, Thomas A. TI Combinatorial targeting of TSLP, IL-25, and IL-33 in type 2 cytokine-driven inflammation and fibrosis SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID INNATE LYMPHOID-CELLS; THYMIC STROMAL LYMPHOPOIETIN; TH2 IMMUNE-RESPONSES; HOUSE-DUST MITE; T-CELLS; ADAPTIVE IMMUNITY; IN-VIVO; AIRWAY INFLAMMATION; SCHISTOSOMA-MANSONI; HEPATIC-FIBROSIS AB Thymic stromal lymphopoietin (TSLP), interleukin-25 (IL-25), and IL-33 are important initiators of type 2-associated mucosal inflammation and immunity. However, their role in the maintenance of progressive type 2 inflammation and fibrosis is much less clear. Using chronic models of helminth infection and allergic lung inflammation, we show that collective disruption of TSLP, IL-25, and IL-33 signaling suppresses chronic and progressive type 2 cytokine-driven inflammation and fibrosis. In a schistosome lung granuloma model or during chronic Schistosoma mansoni infection in the liver, individual ablation of TSLP, IL-25, or IL-33/ST2 had no impact on the development of IL-4/IL-13-dependent inflammation or fibrosis. However, significant reductions in granuloma-associated eosinophils, hepatic fibrosis, and IL-13-producing type 2 innate lymphoid cells (ILC2s) were observed when signaling of all three mediators was simultaneously disrupted. Combined blockade through monoclonal antibody (mAb) treatment also reduced IL-5 and IL-13 expression during primary and secondary granuloma formation in the lungs. In a model of chronic house dust mite-induced allergic lung inflammation, combined mAb treatment did not decrease established inflammation or fibrosis. TSLP/IL-33 double-knockout mice treated with anti-IL-25 mAb during priming, however, displayed decreased inflammation, mucus production, and lung remodeling in the chronic phase. Together, these studies reveal partially redundant roles for TSLP, IL-25, and IL-33 in the maintenance of type 2 pathology and suggest that in some settings, early combined targeting of these mediators is necessary to ameliorate progressive type 2-driven disease. C1 [Vannella, Kevin M.; Ramalingam, Thirumalai R.; Borthwick, Lee A.; Barron, Luke; Hart, Kevin M.; Thompson, Robert W.; Kindrachuk, Kristen N.; Cheever, Allen W.; White, Sandra; Wynn, Thomas A.] NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Borthwick, Lee A.] Newcastle Univ, Inst Cellular Med, Tissue Fibrosis & Repair Grp, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. [Cheever, Allen W.] Biomed Res Inst, Rockville, MD 20852 USA. [Budelsky, Alison L.; Comeau, Michael R.; Smith, Dirk E.] Amgen Inc, Dept Inflammat Res, 1201 Amgen Court West, Seattle, WA 98119 USA. RP Wynn, TA (reprint author), NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM twynn@niaid.nih.gov FU Intramural Research Program of NIH, National Institute of Allergy and Infectious Diseases FX This research was supported by the Intramural Research Program of NIH, National Institute of Allergy and Infectious Diseases. NR 63 TC 4 Z9 4 U1 3 U2 9 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD MAY 4 PY 2016 VL 8 IS 337 AR 337ra65 DI 10.1126/scitranslmed.aaf1938 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA DL7EF UT WOS:000375802500003 PM 27147589 ER PT J AU Lin, J Wang, M Hu, H Yang, XY Wen, B Wang, ZT Jacobson, O Song, JB Zhang, GF Niu, G Huang, P Chen, XY AF Lin, Jing Wang, Min Hu, Hao Yang, Xiangyu Wen, Bronte Wang, Zhantong Jacobson, Orit Song, Jibin Zhang, Guofeng Niu, Gang Huang, Peng Chen, Xiaoyuan TI Multimodal-Imaging-Guided Cancer Phototherapy by Versatile Biomimetic Theranostics with UV and gamma-Irradiation Protection SO ADVANCED MATERIALS LA English DT Article ID IRON-OXIDE NANOPARTICLES; RADIOPROTECTIVE AGENTS; MAGNETIC NANOPARTICLES; MELANIN NANOPARTICLES; IONIZING-RADIATION; CONTRAST AGENTS; THERAPY; CONVERSION; PLATFORM; NANOVESICLES AB A versatile biomimetic theranostic agent based on magnetic melanin nanoparticles is developed for positron-emission tomography/magnetic resonance/photoacoustic/photothermal multimodal-imaging-guided cancer photothermal therapy and UV and gamma-irradiation protection. C1 [Lin, Jing; Huang, Peng] Shenzhen Univ, Sch Med, Dept Biomed Engn, Guangdong Key Lab Biomed Measurements & Ultrasoun, Shenzhen 518060, Peoples R China. [Wang, Min; Hu, Hao] Fourth Mil Med Univ, Xijing Hosp Digest Dis, State Key Lab Canc Biol, Xian 710032, Peoples R China. [Hu, Hao; Yang, Xiangyu; Wen, Bronte; Wang, Zhantong; Jacobson, Orit; Song, Jibin; Niu, Gang; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Zhang, Guofeng] NIBIB, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. RP Huang, P (reprint author), Shenzhen Univ, Sch Med, Dept Biomed Engn, Guangdong Key Lab Biomed Measurements & Ultrasoun, Shenzhen 518060, Peoples R China.; Chen, XY (reprint author), NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. EM peng.huang@szu.edu.cn; shawn.chen@nih.gov RI Huang, Peng/R-2480-2016 OI Huang, Peng/0000-0003-3651-7813 FU National Science Foundation of China [51573096, 81401465]; Intramural Research Program (IRP) of the NIBIB, NIH FX J.L., M.W., and H.H. contributed equally to this work. This work was supported by the National Science Foundation of China (51573096, 81401465), and the Intramural Research Program (IRP) of the NIBIB, NIH. The animal work on cancer theranostics was performed following a protocol approved by the National Institutes of Health Clinical Center Animal Care and Use Committee (NIH CC/ACUC). NR 44 TC 16 Z9 16 U1 50 U2 115 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 0935-9648 EI 1521-4095 J9 ADV MATER JI Adv. Mater. PD MAY 4 PY 2016 VL 28 IS 17 BP 3273 EP 3279 DI 10.1002/adma.201505700 PG 7 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA DK6TV UT WOS:000375059200002 PM 26928972 ER PT J AU Hewitt, WM Lountos, GT Zlotkowski, K Dahlhauser, SD Saunders, LB Needle, D Tropea, JE Zhan, CD Wei, GH Ma, BY Nussinov, R Waugh, DS Schneekloth, JS AF Hewitt, William M. Lountos, George T. Zlotkowski, Katherine Dahlhauser, Samuel D. Saunders, Lindsey B. Needle, Danielle Tropea, Joseph E. Zhan, Chendi Wei, Guanghong Ma, Buyong Nussinov, Ruth Waugh, David S. Schneekloth, John S., Jr. TI Insights Into the Allosteric Inhibition of the SUMO E2 Enzyme Ubc9 SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE allostery; inhibitors; SUMOylation; Ubc9; X-ray crystallography ID UBIQUITIN-CONJUGATING ENZYME; DRUG DISCOVERY; SUMOYLATION; TUMORIGENESIS; PATHWAY; COMPLEX; DESIGN; DRIVEN AB Conjugation of the small ubiquitin-like modifier (SUMO) to protein substrates is an important disease-associated posttranslational modification, although few inhibitors of this process are known. Herein, we report the discovery of an allosteric small-molecule binding site on Ubc9, the sole SUMO E2 enzyme. An X-ray crystallographic screen was used to identify two distinct small-molecule fragments that bind to Ubc9 at a site distal to its catalytic cysteine. These fragments and related compounds inhibit SUMO conjugation in biochemical assays with potencies of 1.9-5.8mm. Mechanistic and biophysical analyses, coupled with molecular dynamics simulations, point toward ligand-induced rigidification of Ubc9 as a mechanism of inhibition. C1 [Hewitt, William M.; Zlotkowski, Katherine; Dahlhauser, Samuel D.; Saunders, Lindsey B.; Schneekloth, John S., Jr.] NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Lountos, George T.; Needle, Danielle; Tropea, Joseph E.; Waugh, David S.] NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Lountos, George T.] Leidos Biomed Res Inc, Basic Sci Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Zhan, Chendi; Wei, Guanghong] Fudan Univ, State Key Lab Surface Phys, Key Lab Computat Phys Sci MOE, Shanghai 200433, Peoples R China. [Zhan, Chendi; Wei, Guanghong] Fudan Univ, Dept Phys, Shanghai 200433, Peoples R China. [Ma, Buyong; Nussinov, Ruth] Leidos Biomed Res Inc, Basic Sci Program, Canc & Inflammat Program, NCI, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Schneekloth, JS (reprint author), NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. EM schneeklothjs@mail.nih.gov RI Ma, Buyong/F-9491-2011; OI Ma, Buyong/0000-0002-7383-719X; Hewitt, William/0000-0002-2881-7704 FU Federal funds from the Frederick National Laboratory for Cancer Research; National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX This project was funded in whole or in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We thank Dr. T. Andresson and Dr. M. O'Neill (Protein Characterization Lab, CRTP, NCI at Frederick) for help with SPR experiments, and Dr. S. Tarasov and M. Dyba (Biophysics Resource, SBL, NCI at Frederick) for assistance with HRMS studies. X-ray diffraction data were collected at the Southeast Regional Collaborative Access Team (SER-CAT) beamlines 22-ID and 22-BM of the Advanced Photon Source, Argonne National Laboratory. Supporting institutions may be found at http://www.ser-cat.org/members.html. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract no. W-31-109-Eng-38. NR 33 TC 2 Z9 2 U1 4 U2 9 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1433-7851 EI 1521-3773 J9 ANGEW CHEM INT EDIT JI Angew. Chem.-Int. Edit. PD MAY 4 PY 2016 VL 55 IS 19 BP 5703 EP 5707 DI 10.1002/anie.201511351 PG 5 WC Chemistry, Multidisciplinary SC Chemistry GA DK7PP UT WOS:000375118500005 PM 27038327 ER PT J AU Heikkinen, MSA Khalaf, A Beard, B Viet, SM Dellarco, M AF Heikkinen, Maire S. A. Khalaf, Abdisalam Beard, Barbara Viet, Susan M. Dellarco, Michael TI Evaluation of Environmental Sample Analysis Methods and Results Reporting in the National Children's Study Vanguard Study SO ANALYTICAL CHEMISTRY LA English DT Article AB During the initial Vanguard phase of the U.S. National Children's Study (NCS), about 2000 tap water, surface wipe, and air samples were collected and analyzed immediately. The shipping conditions, analysis methods, results, and laboratory performance were evaluated to determine the best approaches for use in the NCS Main Study. The main conclusions were (1) to employ established sample analysis methods, when possible, and alternate methodologies only after careful consideration with method validation studies; (2) lot control and prescreening sample collection materials are important quality assurance procedures; (3) packing samples correctly requires careful training and adjustment of shipping conditions to local conditions; (4) trip blanks and spiked samples should be considered for samplers with short expiration times and labile analytes; (5) two study-specific results reports should be required: laboratory electronic data deliverables (EDD) of sample results in a useable electronic format (CSV or SEDD XML/CSV) and a data package with sample results and supporting information in PDF format. These experiences and lessons learned can be applied to any long-term study. C1 [Heikkinen, Maire S. A.; Khalaf, Abdisalam; Beard, Barbara; Viet, Susan M.] WESTAT Corp, 1600 Res Blvd, Rockville, MD 20850 USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, 6100 Execut Blvd,MSC 7510, Bethesda, MD 20852 USA. [Heikkinen, Maire S. A.] Icahn Sch Med Mt Sinai, Dept Prevent Med, One Gustave L Levy Pl,Box 1057, New York, NY 10029 USA. [Dellarco, Michael] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, 6100 Execut Blvd,MSC 7510, Bethesda, MD 20852 USA. RP Heikkinen, MSA (reprint author), WESTAT Corp, 1600 Res Blvd, Rockville, MD 20850 USA.; Heikkinen, MSA (reprint author), Icahn Sch Med Mt Sinai, Dept Prevent Med, One Gustave L Levy Pl,Box 1057, New York, NY 10029 USA. EM maire.heikkinen@mssm.edu FU Eunice Kennedy Shriver National Institute of Child Health [HHSN275201300092U] FX This work was conducted as part of the National Children's Study and supported by Eunice Kennedy Shriver National Institute of Child Health Contract No. HHSN275201300092U. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention, National Children's Study, National Institutes of Health, or U.S. Department of Health and Human Services. The authors wish to thank Asia Khan for her assistance with data analysis, the laboratories for performing the NCS sample analysis and developing the results reports, and the NCS participants. NR 15 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 EI 1520-6882 J9 ANAL CHEM JI Anal. Chem. PD MAY 3 PY 2016 VL 88 IS 9 BP 4692 EP 4700 DI 10.1021/acs.analchem.5b04599 PG 9 WC Chemistry, Analytical SC Chemistry GA DR0ZV UT WOS:000379636600017 PM 27049443 ER PT J AU Siu, MK Chen, WY Tsai, HY Yeh, HL Yin, JJ Liu, SY Liu, YN AF Siu, Man Kit Chen, Wei-Yu Tsai, Hong-Yuan Yeh, Hsiu-Lien Yin, Juan Juan Liu, Shih-Yang Liu, Yen-Nien TI Androgen receptor regulates SRC expression through microRNA-203 SO ONCOTARGET LA English DT Article DE androgen receptor (AR); microRNA (miR)-203; prostate cancer (PCa); SRC ID CANCER BONE METASTASIS; INDEPENDENT PROSTATE-CANCER; TYROSINE PHOSPHORYLATION; SIGNALING PATHWAYS; GENE-EXPRESSION; INHIBITS BONE; CELL-GROWTH; DIFFERENTIATION; PROGRESSION; BIOGENESIS AB The SRC kinase has pivotal roles in multiple developmental processes and in tumor progression. An inverse relationship has been observed between androgen receptor (AR) activity and SRC signaling in advanced prostate cancer (PCa); however, the modulation of AR/SRC crosstalk that leads to metastatic PCa is unclear. Here, we showed that patients with high SRC levels displayed correspondingly low canonical AR gene signatures. Our results demonstrated that activated AR induced miR-203 and reduced SRC levels in PCa model systems. miR-203 directly binds to the 3' UTR of SRC and regulates the stability of SRC mRNA upon AR activation. Moreover, we found that progressive PCa cell migration and growth were associated with a decrease in AR-regulated miR-203 and an increase in SRC. Relationships among AR, miR-203, and SRC were also confirmed in clinical datasets and specimens. We suggest that the induction of SRC results in increased PCa metastasis that is linked to the dysregulation of the AR signaling pathway through the inactivation of miR-203. C1 [Siu, Man Kit; Liu, Yen-Nien] Taipei Med Univ, Coll Med Sci & Technol, PhD Program Canc Biol & Drug Discovery, Taipei, Taiwan. [Siu, Man Kit; Liu, Yen-Nien] Acad Sinica, Taipei 115, Taiwan. [Siu, Man Kit; Tsai, Hong-Yuan; Liu, Yen-Nien] Taipei Med Univ, Coll Med Sci & Technol, Grad Inst Canc Biol & Drug Discovery, Taipei, Taiwan. [Siu, Man Kit] Taipei Med Univ, Wan Fang Hosp, Dept Anesthesiol, Taipei, Taiwan. [Chen, Wei-Yu] Taipei Med Univ, Wan Fang Hosp, Dept Pathol, Taipei, Taiwan. [Chen, Wei-Yu] Taipei Med Univ, Coll Med, Sch Med, Dept Pathol, Taipei, Taiwan. [Yeh, Hsiu-Lien] Natl Tsing Hua Univ, Inst Informat Syst & Applicat, Hsinchu, Taiwan. [Yin, Juan Juan] NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. [Liu, Shih-Yang] Pingtan Hosp Tradit Chinese Med, Dept Androl, Fuzhou, Fujian, Peoples R China. RP Liu, YN (reprint author), Taipei Med Univ, Coll Med Sci & Technol, PhD Program Canc Biol & Drug Discovery, Taipei, Taiwan.; Liu, YN (reprint author), Acad Sinica, Taipei 115, Taiwan.; Liu, YN (reprint author), Taipei Med Univ, Coll Med Sci & Technol, Grad Inst Canc Biol & Drug Discovery, Taipei, Taiwan. EM liuy@tmu.edu.tw FU Ministry of Science and Technology of Taiwan [MOST 104-2314-B-038-045-MY3, MOST 104-2320-B-038-038]; National Health Research Institutes of Taiwan [NHRI-EX105-10308BC]; Wan Fang Hospital [105-wf-phd-02] FX This work was jointly supported by grants from the Ministry of Science and Technology of Taiwan (MOST 104-2314-B-038-045-MY3) to YNL and (MOST 104-2320-B-038-038) to MKS and the National Health Research Institutes of Taiwan (NHRI-EX105-10308BC) to YNL and the Wan Fang Hospital (105-wf-phd-02) to MKS. NR 64 TC 0 Z9 0 U1 0 U2 0 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAY 3 PY 2016 VL 7 IS 18 BP 25726 EP 25741 DI 10.18632/oncotarget.8366 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO3ZW UT WOS:000377722300063 PM 27028864 ER PT J AU Koppen, H Palm-Meinders, IH Mess, WH Keunen, RW Terwindt, GM Launer, LJ van Buchem, MA Kruit, MC Ferrari, MD AF Koppen, Hille Palm-Meinders, Inge H. Mess, Werner H. Keunen, Ruud W. Terwindt, Gisela M. Launer, Lenore J. van Buchem, Mark A. Kruit, Mark C. Ferrari, Michel D. TI Systemic right-to-left shunts, ischemic brain lesions, and persistent migraine activity SO NEUROLOGY LA English DT Article ID PATENT FORAMEN OVALE; TRANSCRANIAL DOPPLER; TRANSESOPHAGEAL ECHOCARDIOGRAPHY; TRANSCATHETER CLOSURE; CRYPTOGENIC STROKE; PREVALENCE; HEADACHE; RISK; DIAGNOSIS; THERAPY AB Objective: To assess whether migraine in the general population is associated with increased risk of systemic right-to-left shunts (RLS) and whether RLS are associated with increased prevalence of brain infarcts and persistent recurrence of migraine attacks at older age. Methods: Brain MRI and transcranial Doppler with air contrast in 166 unselected migraineurs (mean age +/- SD 56 +/- 7.7 years; 70% women; n = 96 migraine with aura) and 69 controls (mean age +/- SD 55 +/- 7.6 years; 65% women) from the general population. Results: Participants with migraine with aura more frequently had Valsalva-induced RLS (60%), in particular large-sized, compared to controls (42%; odds ratio [OR] 2.1; 95% confidence interval [ CI] 1.1-3.9; p = 0.02) and participants with migraine without aura (40%; OR 2.3; 95% CI 1.2-4.3; p = 0.01). They also more frequently had spontaneous RLS (35%) than participants with migraine without aura (17%; OR 2.6; 95% CI 1.3-5.6; p = 0.01) but not compared to controls (26%; OR 1.6; 95% CI 0.8-3.1; p = 0.2). Participants with migraine with aura and spontaneous RLS more frequently had persistent migraine activity (85%) than participants with migraine without spontaneous RLS (63%; OR 3.4; 95% CI 1.2-10.1; p = 0.03). Nine percent of participants with RLS had silent posterior circulation infarcts compared to 3% of participants without RLS (OR 2.8; 95% CI 0.9-9.3; p = 0.08), independent of migraine status. RLS were not associated with white matter lesions. Conclusions: RLS are more prevalent in migraineurs with aura but do not explain the increased prevalence of silent posterior circulation infarcts or white matter lesions in migraineurs. Spontaneous RLS are associated with persistent migraine. C1 [Koppen, Hille; Keunen, Ruud W.] Haga Hosp, Dept Neurol, The Hague, Netherlands. [Koppen, Hille; Terwindt, Gisela M.; Ferrari, Michel D.] Leiden Univ, Med Ctr, Dept Neurol, NL-2300 RA Leiden, Netherlands. [Palm-Meinders, Inge H.; van Buchem, Mark A.; Kruit, Mark C.] Leiden Univ, Med Ctr, Dept Radiol, NL-2300 RA Leiden, Netherlands. [Mess, Werner H.] Maastricht Univ, Med Ctr, Clin Neurophysiol, NL-6200 MD Maastricht, Netherlands. [Launer, Lenore J.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. RP Koppen, H (reprint author), Haga Hosp, Dept Neurol, The Hague, Netherlands.; Koppen, H (reprint author), Leiden Univ, Med Ctr, Dept Neurol, NL-2300 RA Leiden, Netherlands. EM h.koppen@hagaziekenhuis.nl RI Kruit, Mark/K-2431-2012 OI Kruit, Mark/0000-0002-4319-834X FU NIH [1R01NS061382-01]; Netherlands Heart Foundation [2007B016]; Spinoza 2009 Premium; Netherlands Organisation of Science (NWO) [90700217f, 91711319]; Intramural Research Program, National Institute on Aging, NIH FX Supported by grants from the NIH (1R01NS061382-01 to M.D.F. and M.C.K.), the Netherlands Heart Foundation (2007B016 to M.A.v.B., M.C.K., and M.D.F.), and the Spinoza 2009 Premium (to M.D.F.), the Clinical Fellowship (90700217f to G.M.T.) and the VIDI 2011 grant (91711319 to G.M.T.) of the Netherlands Organisation of Science (NWO), and the Intramural Research Program, National Institute on Aging, NIH (L.J.L.). The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the Netherlands Heart Foundation. NR 37 TC 1 Z9 1 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAY 3 PY 2016 VL 86 IS 18 BP 1668 EP 1675 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA DN6QZ UT WOS:000377202100009 PM 26968513 ER PT J AU Grammatikakis, I Zhang, PS Panda, AC Kim, J Maudsley, S Abdelmohsen, K Yang, XL Martindale, JL Motino, O Hutchison, ER Mattson, MP Gorospe, M AF Grammatikakis, Ioannis Zhang, Peisu Panda, Amaresh C. Kim, Jiyoung Maudsley, Stuart Abdelmohsen, Kotb Yang, Xiaoling Martindale, Jennifer L. Motino, Omar Hutchison, Emmette R. Mattson, Mark P. Gorospe, Myriam TI Alternative Splicing of Neuronal Differentiation Factor TRF2 Regulated by HNRNPH1/H2 SO CELL REPORTS LA English DT Article ID PRE-MESSENGER-RNA; STEM-CELLS; PROTEINS; COMPLEX; REPRESSOR; INSIGHTS; ELEMENTS; NETWORK; DESIGN; GROWTH AB During neuronal differentiation, use of an alternative splice site on the rat telomere repeat-binding factor 2 (TRF2) mRNA generates a short TRF2 protein isoform (TRF2-S) capable of derepressing neuronal genes. However, the RNA-binding proteins (RBPs) controlling this splicing event are unknown. Here, using affinity pull-down analysis, we identified heterogeneous nuclear ribonucleoproteins H1 and H2(HNRNPH) as RBPs specifically capable of interacting with the spliced RNA segment (exon 7) of Trf2 pre-mRNA. HNRNPH proteins prevent the production of the short isoform of Trf2 mRNA, as HNRNPH silencing selectively elevates TRF2-S levels. Accordingly, HNRNPH levels decline while TRF2-S levels increase during neuronal differentiation. In addition, CRISPR/Cas9-mediated deletion of hnRNPH2 selectively accelerates the NGF-triggered differentiation of rat pheochromocytoma cells into neurons. In sum, HNRNPH is a splicing regulator of Trf2 pre-mRNA that prevents the expression of TRF2-S, a factor implicated in neuronal differentiation. C1 [Grammatikakis, Ioannis; Panda, Amaresh C.; Kim, Jiyoung; Abdelmohsen, Kotb; Yang, Xiaoling; Martindale, Jennifer L.; Motino, Omar; Gorospe, Myriam] NIA, Intramural Res Program, NIH, Genet Lab, Baltimore, MD 21224 USA. [Zhang, Peisu; Hutchison, Emmette R.; Mattson, Mark P.] NIA, Intramural Res Program, NIH, Neurosci Lab, Baltimore, MD 21224 USA. [Maudsley, Stuart] Univ Antwerp VIB, Dept Mol Genet, Translat Neurobiol Grp, B-2610 Antwerp, Belgium. RP Gorospe, M (reprint author), NIA, Intramural Res Program, NIH, Genet Lab, Baltimore, MD 21224 USA. EM myriam-gorospe@nih.gov OI PANDA, AMARESH/0000-0003-3189-8995 FU NIA-IRP, NIH FX This work was supported in its entirety by the NIA-IRP, NIH. NR 39 TC 1 Z9 1 U1 4 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD MAY 3 PY 2016 VL 15 IS 5 BP 926 EP 934 DI 10.1016/j.celrep.2016.03.080 PG 9 WC Cell Biology SC Cell Biology GA DM2GH UT WOS:000376164600003 PM 27117401 ER PT J AU Ebrahim, S Ingham, NJ Lewis, MA Rogers, MJC Cui, RJ Kachar, B Pass, JC Steel, KP AF Ebrahim, Seham Ingham, Neil J. Lewis, Morag A. Rogers, Michael J. C. Cui, Runjia Kachar, Bechara Pass, Johanna C. Steel, Karen P. TI Alternative Splice Forms Influence Functions of Whirlin in Mechanosensory Hair Cell Stereocilia SO CELL REPORTS LA English DT Article ID SENSORINEURAL HEARING-LOSS; USHER-SYNDROME TYPE-2; MOUSE MUTANT WHIRLER; KNOCKOUT MICE; MYOSIN-XVA; DFNB31; GENE; ELONGATION; MUTATIONS; DYNAMICS AB WHRN (DFNB31) mutations cause diverse hearing disorders: profound deafness (DFNB31) or variable hearing loss in Usher syndrome type II. The known role of WHRN in stereocilia elongation does not explain these different pathophysiologies. Using spontaneous and targeted Whrn mutants, we show that the major long (WHRN-L) and short (WHRN-S) isoforms of WHRN have distinct localizations within stereocilia and also across hair cell types. Lack of both isoforms causes abnormally short stereocilia and profound deafness and vestibular dysfunction. WHRN-S expression, however, is sufficient to maintain stereocilia bundle morphology and function in a subset of hair cells, resulting in some auditory response and no overt vestibular dysfunction. WHRN-S interacts with EPS8, and both are required at stereocilia tips for normal length regulation. WHRN-L localizes midway along the shorter stereocilia, at the level of inter-stereociliary links. We propose that differential isoform expression underlies the variable auditory and vestibular phenotypes associated with WHRN mutations. C1 [Ebrahim, Seham; Ingham, Neil J.; Lewis, Morag A.; Pass, Johanna C.; Steel, Karen P.] Kings Coll London, Wolfson Ctr Age Related Dis, Guys Campus, London SE1 1UL, England. [Ingham, Neil J.; Pass, Johanna C.; Steel, Karen P.] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. [Rogers, Michael J. C.; Steel, Karen P.] MRC, Inst Hearing Res, Nottingham NG7 2RD, England. [Cui, Runjia; Kachar, Bechara] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. RP Steel, KP (reprint author), Kings Coll London, Wolfson Ctr Age Related Dis, Guys Campus, London SE1 1UL, England.; Steel, KP (reprint author), Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England.; Steel, KP (reprint author), MRC, Inst Hearing Res, Nottingham NG7 2RD, England. EM karen.steel@kcl.ac.uk FU Wellcome Trust [100669, 098051]; MRC; Action on Hearing Loss; NIH [Z01-DC000002] FX We thank the Wellcome Trust Sanger Institute's Mouse Genetics Project for generating the Whrntm1a mouse allele, Jonathan Gale for the FM1-43 dye, Victoria Rook for genotyping, colony management, and LacZ staining, Lorenzo Preite for genotyping, Roz Lacey for contact righting tests, Selina Pearson for initial ABR screening of the tm1a allele, and Allan Bradley and Haydn Prosser for providing the HprtTg(CMV-Cre)Brd mouse line. The work was supported by the Wellcome Trust (100669 and 098051 to K.P.S.), the MRC (K.P.S. and M.J.C.R.), Action on Hearing Loss (S.E. and K.P.S.) and by NIH intramural research funds Z01-DC000002 (to B.K.). NR 27 TC 2 Z9 2 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD MAY 3 PY 2016 VL 15 IS 5 BP 935 EP 943 DI 10.1016/j.celrep.2016.03.081 PG 9 WC Cell Biology SC Cell Biology GA DM2GH UT WOS:000376164600004 PM 27117407 ER PT J AU Topol, A Zhu, SJ Hartley, BJ English, J Hauberg, ME Tran, N Rittenhouse, CA Simone, A Ruderfer, DM Johnson, J Readhead, B Hadas, Y Gochman, PA Wang, YC Shah, H Cagney, G Rapoport, J Gage, FH Dudley, JT Sklar, P Mattheisen, M Cotter, D Fang, G Brennand, KJ AF Topol, Aaron Zhu, Shijia Hartley, Brigham J. English, Jane Hauberg, Mads E. Tran, Ngoc Rittenhouse, Chelsea Ann Simone, Anthony Ruderfer, Douglas M. Johnson, Jessica Readhead, Ben Hadas, Yoav Gochman, Peter A. Wang, Ying-Chih Shah, Hardik Cagney, Gerard Rapoport, Judith Gage, Fred H. Dudley, Joel T. Sklar, Pamela Mattheisen, Manuel Cotter, David Fang, Gang Brennand, Kristen J. TI Dysregulation of miRNA-9 in a Subset of Schizophrenia Patient-Derived Neural Progenitor Cells SO CELL REPORTS LA English DT Article ID PLURIPOTENT STEM-CELLS; NUCLEAR RECEPTOR TLX; MESSENGER-RNA; EXPRESSION ANALYSIS; BRAIN-DEVELOPMENT; REGULATORY LOOP; MICRORNA-9; NETWORK; NEUROGENESIS; PROFILES AB Converging evidence indicates that microRNAs (miRNAs) may contribute to disease risk for schizophrenia (SZ). We show that microRNA-9 (miR-9) is abundantly expressed in control neural progenitor cells (NPCs) but also significantly downregulated in a subset of SZ NPCs. We observed a strong correlation between miR-9 expression and miR-9 regulatory activity in NPCs as well as between miR-9 levels/activity, neural migration, and diagnosis. Overexpression of miR-9 was sufficient to ameliorate a previously reported neural migration deficit in SZ NPCs, whereas knockdown partially phenocopied aberrant migration in control NPCs. Unexpectedly, proteomic- and RNA sequencing (RNA-seq)-based analysis revealed that these effects were mediated primarily by small changes in expression of indirect miR-9 targets rather than large changes in direct miR-9 targets; these indirect targets are enriched for migration-associated genes. Together, these data indicate that aberrant levels and activity of miR-9 may be one of the many factors that contribute to SZ risk, at least in a subset of patients. C1 [Topol, Aaron; Hartley, Brigham J.; Tran, Ngoc; Rittenhouse, Chelsea Ann; Ruderfer, Douglas M.; Johnson, Jessica; Hadas, Yoav; Sklar, Pamela; Brennand, Kristen J.] Icahn Sch Med Mt Sinai, Dept Psychiat, 1425 Madison Ave, New York, NY 10029 USA. [Zhu, Shijia; Readhead, Ben; Wang, Ying-Chih; Shah, Hardik; Dudley, Joel T.; Fang, Gang] Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, 1425 Madison Ave, New York, NY 10029 USA. [Hartley, Brigham J.; Brennand, Kristen J.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, 1425 Madison Ave, New York, NY 10029 USA. [English, Jane; Cotter, David] Royal Coll Surgeons Ireland, Beaumont Hosp, Dept Psychiat, Dublin 9, Ireland. [Hauberg, Mads E.; Mattheisen, Manuel] Aarhus Univ, Dept Biomed, Wilhelm Meyers Alle 4, DK-8000 Aarhus C, Denmark. [Hauberg, Mads E.; Mattheisen, Manuel] Aarhus Univ, Ctr Integrat Sequencing iSEQ, Wilhelm Meyers Alle 4, DK-8000 Aarhus C, Denmark. [Hauberg, Mads E.; Mattheisen, Manuel] Aarhus Univ, Lundbeck Fdn Initiat Integrat Psychiat Res iPSYCH, Wilhelm Meyers Alle 4, DK-8000 Aarhus, Denmark. [Simone, Anthony; Gage, Fred H.] Salk Inst Biol Studies, Genet Lab, 10010 North Torrey Pines Rd, La Jolla, CA 92037 USA. [Cagney, Gerard] Natl Univ Ireland Univ Coll Dublin, Conway Inst, Sch Biomol & Biomed Sci, Dublin 4, Ireland. [Rapoport, Judith] NIMH, Childhood Psychiat Branch, NIH, Bethesda, MD 20892 USA. RP Brennand, KJ (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, 1425 Madison Ave, New York, NY 10029 USA.; Fang, G (reprint author), Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, 1425 Madison Ave, New York, NY 10029 USA.; Brennand, KJ (reprint author), Icahn Sch Med Mt Sinai, Friedman Brain Inst, 1425 Madison Ave, New York, NY 10029 USA. EM gang.fang@mssm.edu; kristen.brennand@mssm.edu RI Ruderfer, Douglas/M-5795-2016; Brennand, Kristen/J-8704-2012 OI Ruderfer, Douglas/0000-0002-2365-386X; Brennand, Kristen/0000-0003-0993-5956 FU Brain and Behavior Research Foundation; NIH [R01 MH101454, R01 MH106056, R01 MH097276, R01 GM114472]; New York Stem Cell Foundation; Health Research Board Clinical Scientist Award FX K.J.B. is a New York Stem Cell Foundation-Robertson Investigator. The K.J.B. lab is supported by the Brain and Behavior Research Foundation, NIH grants R01 MH101454 and R01 MH106056, and the New York Stem Cell Foundation. The G.F. lab is supported by NIH grants R01 MH097276 and R01 GM114472. The D.C. lab is supported by Health Research Board Clinical Scientist Award. FACS purification was conducted at the ISMMS Flow Cytometry Center of Research Excellence, and RNA-seq was conducted at the ISMMS Genomics Core Facility. This work was supported in part through the computational resources and staff expertise provided by the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai. As per our agreement with Coriell Cell Repository, some hiPSC lines generated from control and SZ fibroblasts will be available from Coriell. Additionally, all control, SZ, and COS hiPSCs are currently being deposited with the NIMH Center for Collaborative Studies of Mental Disorders at RUCDR. NR 40 TC 8 Z9 8 U1 1 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD MAY 3 PY 2016 VL 15 IS 5 BP 1024 EP 1036 DI 10.1016/j.celrep.2016.03.090 PG 13 WC Cell Biology SC Cell Biology GA DM2GH UT WOS:000376164600013 PM 27117414 ER PT J AU Psaila, B Barkas, N Iskander, D Roy, A Anderson, S Ashley, N Caputo, VS Lichtenberg, J Loaiza, S Bodine, DM Karadimitris, A Mead, AJ Roberts, I AF Psaila, Bethan Barkas, Nikolaos Iskander, Deena Roy, Anindita Anderson, Stacie Ashley, Neil Caputo, Valentina S. Lichtenberg, Jens Loaiza, Sandra Bodine, David M. Karadimitris, Anastasios Mead, Adam J. Roberts, Irene TI Single-cell profiling of human megakaryocyte-erythroid progenitors identifies distinct megakaryocyte and erythroid differentiation pathways SO GENOME BIOLOGY LA English DT Article DE Hematopoiesis; megakaryopoiesis; erythropoiesis; thrombopoiesis; myelopoiesis; hematopoietic stem cell ID HEMATOPOIETIC STEM-CELLS; GENE-EXPRESSION ANALYSIS; MYELOID PROGENITORS; COMMITTED PROGENITORS; BONE-MARROW; CORD BLOOD; IN-VIVO; T-SNE; HIERARCHY; HETEROGENEITY AB Background: Recent advances in single-cell techniques have provided the opportunity to finely dissect cellular heterogeneity within populations previously defined by "bulk" assays and to uncover rare cell types. In human hematopoiesis, megakaryocytes and erythroid cells differentiate from a shared precursor, the megakaryocyte-erythroid progenitor (MEP), which remains poorly defined. Results: To clarify the cellular pathway in erythro-megakaryocyte differentiation, we correlate the surface immunophenotype, transcriptional profile, and differentiation potential of individual MEP cells. Highly purified, single MEP cells were analyzed using index fluorescence-activated cell sorting and parallel targeted transcriptional profiling of the same cells was performed using a specifically designed panel of genes. Differentiation potential was tested in novel, single-cell differentiation assays. Our results demonstrate that immunophenotypic MEP comprise three distinct subpopulations: "Pre-MEP," enriched for erythroid/megakaryocyte progenitors but with residual myeloid differentiation capacity; "E-MEP," strongly biased towards erythroid differentiation; and "MK-MEP," a previously undescribed, rare population of cells that are bipotent but primarily generate megakaryocytic progeny. Therefore, conventionally defined MEP are a mixed population, as a minority give rise to mixed-lineage colonies while the majority of cells are transcriptionally primed to generate exclusively single-lineage output. Conclusions: Our study clarifies the cellular hierarchy in human megakaryocyte/erythroid lineage commitment and highlights the importance of using a combination of single-cell approaches to dissect cellular heterogeneity and identify rare cell types within a population. We present a novel immunophenotyping strategy that enables the prospective identification of specific intermediate progenitor populations in erythro-megakaryopoiesis, allowing for in-depth study of disorders including inherited cytopenias, myeloproliferative disorders, and erythromegakaryocytic leukemias. C1 [Psaila, Bethan; Barkas, Nikolaos; Roy, Anindita; Ashley, Neil; Mead, Adam J.; Roberts, Irene] Univ Oxford, MRC, Mol Haematol Unit, Weatherall Inst Mol Med, Oxford, England. [Psaila, Bethan; Barkas, Nikolaos; Roy, Anindita; Ashley, Neil; Mead, Adam J.; Roberts, Irene] NIHR Oxford Biomed Ctr, BRC Blood Theme, Oxford OX3 9DU, England. [Psaila, Bethan; Iskander, Deena; Caputo, Valentina S.; Loaiza, Sandra; Karadimitris, Anastasios] Univ London Imperial Coll Sci Technol & Med, Dept Med, Hammersmith Hosp, Ctr Haematol, London, England. [Psaila, Bethan; Lichtenberg, Jens; Bodine, David M.] NHGRI, Hematopoiesis Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Roy, Anindita; Roberts, Irene] Univ Oxford, Dept Paediat, Weatherall Inst Mol Med, Oxford OX3 9DU, England. [Anderson, Stacie] NHGRI, Flow Cytometry Core, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Mead, AJ; Roberts, I (reprint author), Univ Oxford, MRC, Mol Haematol Unit, Weatherall Inst Mol Med, Oxford, England.; Mead, AJ; Roberts, I (reprint author), NIHR Oxford Biomed Ctr, BRC Blood Theme, Oxford OX3 9DU, England. EM adam.mead@imm.ox.ac.uk; irene.roberts@paediatrics.ox.ac.uk RI Mead, Adam/A-8796-2012 FU NIHR; Academy of Medical Sciences - Wellcome Trust; Academy of Medical Sciences - Medical Research Council; Academy of Medical Sciences - British Heart Foundation; Academy of Medical Sciences - Arthritis Research UK; Academy of Medical Sciences - Prostate Cancer UK; British Society of Haematology; ASH-EHA Translational Research Training in Hematology Fellowship; Bloodwise Clinical Research Fellowship; Bloodwise Clinician Scientist Fellowship; Medical Research Council; MRC; NHGRI; Oxford NIHR Biomedical Centre based at Oxford University Hospitals NHS Trust; University of Oxford; London NIHR Biomedical Centre based at Imperial College London FX BP is supported by an NIHR Academic Clinical Lectureship; the Academy of Medical Sciences (a scheme funded by the Wellcome Trust, the Medical Research Council, the British Heart Foundation, Arthritis Research UK, and Prostate Cancer UK); the British Society of Haematology; and an ASH-EHA Translational Research Training in Hematology Fellowship. DI is supported by a Bloodwise Clinical Research Fellowship. AR is supported by a Bloodwise Clinician Scientist Fellowship and an ASH-EHA Translational Research Training in Hematology Fellowship. AJM is funded by a Medical Research Council Senior Clinical Fellowship. This work was supported by The MRC funded Oxford Consortium for Single Cell Biology; NHGRI Intramural Funds; Oxford NIHR Biomedical Centre based at Oxford University Hospitals NHS Trust and University of Oxford and London NIHR Biomedical Centre based at Imperial College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health, or the NIH. NR 49 TC 5 Z9 5 U1 1 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-6906 EI 1474-760X J9 GENOME BIOL JI Genome Biol. PD MAY 3 PY 2016 VL 17 AR 83 DI 10.1186/s13059-016-0939-7 PG 19 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DL9KU UT WOS:000375962300001 PM 27142433 ER PT J AU Wager, TD Atlas, LY Botvinick, MM Chang, LJ Coghill, RC Davis, KD Iannetti, GD Poldrack, RA Shackman, AJ Yarkoni, T AF Wager, Tor D. Atlas, Lauren Y. Botvinick, Matthew M. Chang, Luke J. Coghill, Robert C. Davis, Karen Deborah Iannetti, Gian Domenico Poldrack, Russell A. Shackman, Alexander J. Yarkoni, Tal TI Pain in the ACC? SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Letter ID ANTERIOR CINGULATE CORTEX; FMRI C1 [Wager, Tor D.] Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80305 USA. [Wager, Tor D.] Univ Colorado, Inst Cognit Sci, Boulder, CO 80305 USA. [Atlas, Lauren Y.] NIH, Natl Ctr Complementary & Integrat Hlth, Bldg 10, Bethesda, MD 20892 USA. [Atlas, Lauren Y.] NIDA, NIH, Bethesda, MD 20892 USA. [Botvinick, Matthew M.] Princeton Univ, Princeton, NJ 08544 USA. [Chang, Luke J.] Dartmouth Coll, Dept Psychol & Brain Sci, Hanover, NH 03755 USA. [Coghill, Robert C.] Cincinnati Childrens Hosp, Dept Anesthesiol, Cincinnati, OH 45229 USA. [Davis, Karen Deborah] Univ Hlth Network, Toronto Western Hosp, Krembil Res Inst, Toronto, ON M5G 2C4, Canada. [Davis, Karen Deborah] Univ Toronto, Dept Surg, Toronto, ON M5G 1V7, Canada. [Davis, Karen Deborah] Univ Toronto, Inst Med Sci, Toronto, ON M5G 1V7, Canada. [Iannetti, Gian Domenico] UCL, Mortimer St, London WC1E 6BT, England. [Poldrack, Russell A.] Stanford Univ, Stanford, CA 94305 USA. [Shackman, Alexander J.] Univ Maryland, Dept Psychol, College Pk, MD 20742 USA. [Shackman, Alexander J.] Univ Maryland, Neurosci & Cognit Sci Program, College Pk, MD 20742 USA. [Shackman, Alexander J.] Univ Maryland, Maryland Neuroimaging Ctr, College Pk, MD 20742 USA. [Yarkoni, Tal] Univ Texas Austin, Austin, TX 78712 USA. RP Wager, TD (reprint author), Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80305 USA.; Wager, TD (reprint author), Univ Colorado, Inst Cognit Sci, Boulder, CO 80305 USA. EM tor.wager@colorado.edu OI Yarkoni, Tal/0000-0002-6558-5113; Chang, Luke/0000-0002-6621-8120 NR 10 TC 12 Z9 12 U1 2 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 3 PY 2016 VL 113 IS 18 BP E2474 EP E2475 DI 10.1073/pnas.1600282113 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DL1MH UT WOS:000375395700003 PM 27095849 ER PT J AU Lauer, MS AF Lauer, Michael S. TI PCSK9 Inhibitors: Lots of Work Done, Lots More to Do SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID CARDIOVASCULAR EVENTS; REDUCING LIPIDS; HYPERCHOLESTEROLEMIA; EFFICACY; DISEASE; SAFETY; LDL C1 [Lauer, Michael S.] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Lauer, MS (reprint author), NIH, Off Extramural Res, Bldg 1,1 Ctr Dr, Bethesda, MD 20892 USA. EM michael.lauer@nih.gov NR 10 TC 0 Z9 0 U1 3 U2 3 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD MAY 3 PY 2016 VL 164 IS 9 BP 624 EP 625 DI 10.7326/M16-0422 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DL6IX UT WOS:000375744000026 PM 26999561 ER PT J AU Flood, BE Fliss, P Jones, DS Dick, GJ Jain, S Kaster, AK Winkel, M Mussmann, M Bailey, J AF Flood, Beverly E. Fliss, Palmer Jones, Daniel S. Dick, Gregory J. Jain, Sunit Kaster, Anne-Kristin Winkel, Matthias Mussmann, Marc Bailey, Jake TI Single-Cell (Meta-)Genomics of a Dimorphic Candidatus Thiomargarita nelsonii Reveals Genomic Plasticity SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE Thiomargarita; single-cell genomics; arsenite oxidation; intron; mobile genetic elements; genome instability; miniature inverted-repeat transposable elements; metacaspase ID GROUP-I INTRONS; GIANT SULFUR BACTERIA; SELF-SPLICING INTRONS; 16S RIBOSOMAL-RNA; RIBONUCLEOTIDE REDUCTASE; CLOSTRIDIUM-DIFFICILE; PHYLOGENETIC ANALYSES; INSERTION SEQUENCES; PHOSPHATE RELEASE; DRAFT GENOME AB The genus Thiomargarita includes the world's largest bacteria. But as uncultured organisms, their physiology, metabolism, and basis for their gigantism are not well understood. Thus, a genomics approach, applied to a single Candidatus Thiomargarita nelsonii cell was employed to explore the genetic potential of one of these enigmatic giant bacteria. The Thiomargarita cell was obtained from an assemblage of budding Ca. T. nelsonii attached to a provannid gastropod shell from Hydrate Ridge, a methane seep offshore of Oregon, USA. Here we present a manually curated genome of Bud S10 resulting from a hybrid assembly of long Pacific Biosciences and short Illumina sequencing reads. With respect to inorganic carbon fixation and sulfur oxidation pathways, the Ca. T nelsonii Hydrate Ridge Bud S10 genome was similar to marine sister taxa within the family Beggiatoaceae. However, the Bud S10 genome contains genes suggestive of the genetic potential for lithotrophic growth on arsenite and perhaps hydrogen. The genome also revealed that Bud 510 likely respires nitrate via two pathways: a complete denitrification pathway and a dissimilatory nitrate reduction to ammonia pathway. Both pathways have been predicted, but not previously fully elucidated, in the genomes of other large, vacuolated, sulfur-oxidizing bacteria. Surprisingly, the genome also had a high number of unusual features for a bacterium to include the largest number of metacaspases and introns ever reported in a bacterium. Also present, are a large number of other mobile genetic elements, such as insertion sequence (IS) transposable elements and miniature inverted-repeat transposable elements (MITEs). In some cases, mobile genetic elements disrupted key genes in metabolic pathways. For example, a MITE interrupts hupL, which encodes the large subunit of the hydrogenase in hydrogen oxidation. Moreover, we detected a group I intron in one of the most critical genes in the sulfur oxidation pathway, dsrA. The dsrA group I intron also carried a MITE sequence that, like the hupL MITE family, occurs broadly across the genome. The presence of a high degree of mobile elements in genes central to Thiomargarita's core metabolism has not been previously reported in free-living bacteria and suggests a highly mutable genome. C1 [Flood, Beverly E.; Fliss, Palmer; Jones, Daniel S.; Bailey, Jake] Univ Minnesota, Dept Earth Sci, Minneapolis, MN USA. [Jones, Daniel S.] Univ Minnesota, Inst Biotechnol, St Paul, MN 55108 USA. [Dick, Gregory J.; Jain, Sunit] Univ Michigan, Dept Earth & Environm Sci, Ann Arbor, MI 48109 USA. [Kaster, Anne-Kristin] German Collect Microorganisms & Cell Cultures, Leibniz Inst DSMZ, Braunschweig, Germany. [Winkel, Matthias] GFZ German Res Ctr Geosci, Helmholtz Ctr Potsdam, Potsdam, Germany. [Mussmann, Marc] Max Planck Inst Marine Microbiol, Bremen, Germany. [Fliss, Palmer] Leidos Biomed Res Inc, Mol Characterizat & Clin Assay Dev Lab, Frederick, MD USA. [Fliss, Palmer] Frederick Natl Lab Canc Res, Frederick, MD USA. RP Flood, BE (reprint author), Univ Minnesota, Dept Earth Sci, Minneapolis, MN USA. EM beflood@umn.edu RI Mussmann, Marc/A-8649-2017 FU University of Minnesota Office of the Vice President for Research [22025]; Alfred P. Sloan Foundation research fellowship; Simons Foundation; U.S. National Science Foundation (NSF) [EAR-1057119]; NSF grant [OCE-0826254] FX Portions of this research was supported by a Grant-in-Aid from the University of Minnesota Office of the Vice President for Research (#22025), and Alfred P. Sloan Foundation research fellowship, an Early Career Investigator in Marine Microbial Ecology and Evolution Award from the Simons Foundation and the U.S. National Science Foundation (NSF) grant EAR-1057119. The research cruise was funded by NSF grant OCE-0826254. NR 116 TC 3 Z9 3 U1 7 U2 14 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-302X J9 FRONT MICROBIOL JI Front. Microbiol. PD MAY 3 PY 2016 VL 7 AR 603 DI 10.3389/fmicb.2016.00603 PG 17 WC Microbiology SC Microbiology GA DL1MB UT WOS:000375395100001 PM 27199933 ER PT J AU Gahl, WA Wise, AL Ashley, EA AF Gahl, William A. Wise, Anastasia L. Ashley, Euan A. TI The Undiagnosed Diseases Program Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Gahl, William A.; Wise, Anastasia L.] NHGRI, NIH, Bethesda, MD 20892 USA. [Ashley, Euan A.] Stanford Univ, Dept Med, Stanford, CA 94305 USA. RP Ashley, EA (reprint author), Stanford Univ, Dept Med, Falk CVRB, 870 Quarry Rd, Stanford, CA 94305 USA.; Ashley, EA (reprint author), Stanford Univ, Dept Genet, Falk CVRB, 870 Quarry Rd, Stanford, CA 94305 USA. EM euan@stanford.edu FU NHGRI NIH HHS [U01 HG007708] NR 5 TC 0 Z9 0 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 3 PY 2016 VL 315 IS 17 BP 1904 EP 1904 DI 10.1001/jama.2016.0454 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DK9XF UT WOS:000375284400025 PM 27139070 ER PT J AU Risso, DS Mezzavilla, M Pagani, L Robino, A Morini, G Tofanelli, S Carrai, M Campa, D Barale, R Caradonna, F Gasparini, P Luiselli, D Wooding, S Drayna, D AF Risso, Davide S. Mezzavilla, Massimo Pagani, Luca Robino, Antonietta Morini, Gabriella Tofanelli, Sergio Carrai, Maura Campa, Daniele Barale, Roberto Caradonna, Fabio Gasparini, Paolo Luiselli, Donata Wooding, Stephen Drayna, Dennis TI Global diversity in the TAS2R38 bitter taste receptor: revisiting a classic evolutionary PROPosal SO SCIENTIFIC REPORTS LA English DT Article ID HUMAN GENETIC DIVERSITY; SENSITIVITY; POPULATION; AFRICA; PTC; PHENYLTHIOCARBAMIDE; VEGETABLES; SELECTION; HUMANS; LOCUS AB The ability to taste phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP) is a polymorphic trait mediated by the TAS2R38 bitter taste receptor gene. It has long been hypothesized that global genetic diversity at this locus evolved under pervasive pressures from balancing natural selection. However, recent high-resolution population genetic studies of TAS2Rs suggest that demographic events have played a critical role in the evolution of these genes. We here utilized the largest TAS2R38 database yet analyzed, consisting of 5,589 individuals from 105 populations, to examine natural selection, haplotype frequencies and linkage disequilibrium to estimate the effects of both selection and demography on contemporary patterns of variation at this locus. We found signs of an ancient balancing selection acting on this gene but no post Out-Of-Africa departures from neutrality, implying that the current observed patterns of variation can be predominantly explained by demographic, rather than selective events. In addition, we found signatures of ancient selective forces acting on different African TAS2R38 haplotypes. Collectively our results provide evidence for a relaxation of recent selective forces acting on this gene and a revised hypothesis for the origins of the present-day worldwide distribution of TAS2R38 haplotypes. C1 [Risso, Davide S.; Drayna, Dennis] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. [Risso, Davide S.; Pagani, Luca; Luiselli, Donata] Univ Bologna, Dept Biol Geol & Environm Sci BiGeA, Lab Mol Anthropol, Via Selmi 3, I-40126 Bologna, Italy. [Risso, Davide S.; Pagani, Luca; Luiselli, Donata] Univ Bologna, Ctr Genome Biol, Via Selmi 3, I-40126 Bologna, Italy. [Mezzavilla, Massimo; Robino, Antonietta; Gasparini, Paolo] Univ Trieste, IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, I-34137 Trieste, Italy. [Mezzavilla, Massimo] Sidra Med & Res Ctr, Div Expt Genet, Doha, Qatar. [Pagani, Luca] Univ Cambridge, Div Biol Anthropol, Cambridge CB2 1QH, England. [Morini, Gabriella] Univ Gastron Sci, Piazza Vittorio Emanuele 9, I-12042 Pollenzo, CN, Italy. [Tofanelli, Sergio; Carrai, Maura; Campa, Daniele; Barale, Roberto] Univ Pisa, Dept Biol, Via Ghini 13, I-56126 Pisa, Italy. [Caradonna, Fabio] Univ Palermo, STEBICEF, Biol Chem & Pharmaceut Sci & Technol Dept, Vle Sci,Edificio 16, I-90128 Palermo, Italy. [Wooding, Stephen] Univ Calif Merced, Hlth Sci Res Inst, 5200 North Lake Rd, Merced, CA 95343 USA. RP Risso, DS (reprint author), Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA.; Risso, DS (reprint author), Univ Bologna, Dept Biol Geol & Environm Sci BiGeA, Lab Mol Anthropol, Via Selmi 3, I-40126 Bologna, Italy.; Risso, DS (reprint author), Univ Bologna, Ctr Genome Biol, Via Selmi 3, I-40126 Bologna, Italy. EM davide.risso@nih.gov RI Campa, Daniele/K-1617-2016; Caradonna, Fabio/D-7785-2017; OI Campa, Daniele/0000-0003-3220-9944; Caradonna, Fabio/0000-0002-7659-7312; Risso, Davide/0000-0001-9848-8996; Pagani, Luca/0000-0002-6639-524X FU National Institute on Deafness and Other Communication Disorders Intramural grant [Z1A-000046-14]; ERC [FP7 - 261213]; Ministry of Health (IRCCS-Burlo Garofolo - Ricerca Corrente); Italian Ministry of Health [RC 35/09]; PRIN [2010EL8TXP_006]; European Research Council [ERC-2011-AdG 295733]; University of Pisa PRA Grant FX DR and DD were supported by the National Institute on Deafness and Other Communication Disorders Intramural grant number Z1A-000046-14. LP was funded by the ERC Grant FP7 - 261213. MM, AR and PG were funded by the sponsors of the scientific expedition Marcopolo 2010, by Ministry of Health (IRCCS-Burlo Garofolo - Ricerca Corrente) and by Italian Ministry of Health RC 35/09. DL was supported by the PRIN 2010EL8TXP_006 grant and, by the European Research Council [ERC-2011-AdG 295733 (Langelin). ST, DC and RB were supported by a University of Pisa PRA 2016 Grant. NR 56 TC 2 Z9 2 U1 17 U2 36 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAY 3 PY 2016 VL 6 AR 25506 DI 10.1038/srep25506 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK9ML UT WOS:000375254400001 PM 27138342 ER PT J AU Bermejo, GA Clore, GM Schwieters, CD AF Bermejo, Guillermo A. Clore, G. Marius Schwieters, Charles D. TI Improving NMR Structures of RNA SO STRUCTURE LA English DT Article ID MOLECULAR-STRUCTURE DETERMINATION; THEOPHYLLINE-BINDING RNA; NUCLEIC-ACID STRUCTURES; CONFORMATIONAL DATABASE; MEAN-FORCE; STRUCTURE VALIDATION; PROTEIN STRUCTURES; CROSS-VALIDATION; ATOM CONTACTS; XPLOR-NIH AB Here, we show that modern solution nuclear magnetic resonance (NMR) structures of RNA exhibit more steric clashes and conformational ambiguities than their crystallographic X-ray counterparts. To tackle these issues, we developed RNA-ff1, a new force field for structure calculation with Xplor-NIH. Using seven published NMR datasets, RNA-ff1 improves covalent geometry and MolProbity validation criteria for clashes and backbone conformation in most cases, relative to both the previous Xplor-NIH force field and the original structures associated with the experimental data. In addition, with smaller base-pair step rises in helical stems, RNA-ff1 structures enjoy more favorable base stacking. Finally, structural accuracy improves in the majority of cases, as supported by complete residual dipolar coupling cross-validation. Thus, the reported advances show great promise in bridging the quality gap that separates NMR and X-ray structures of RNA. C1 [Bermejo, Guillermo A.; Schwieters, Charles D.] Natl Inst Hlth, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Clore, G. Marius] NIDDK, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Schwieters, CD (reprint author), Natl Inst Hlth, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. EM charles.schwieters@nih.gov FU NIH Intramural Research Program of CIT; NIH Intramural Research Program of NIDDK; NIH Intramural Research Program of NHLBI; NIH Intramural Research Program of NCI; AIDS Targeted Antiviral Program of the Office of the Director of the NIH FX We thank Mijeong Kang and Juli Feigon for kindly providing the Xplor-NIH topology and parameter files associated with the PreQ1 small-molecule ligand in PDB: 2L1V, and Nico Tjandra's group for useful discussions. This work was supported by the NIH Intramural Research Programs of CIT (to G.A.B and C.D.S.), NIDDK (to G.M.C.), NHLBI (through Nico Tjandra) and NCI (through R. Andrew Byrd), and by the AIDS Targeted Antiviral Program of the Office of the Director of the NIH (to G.M.C.). NR 43 TC 3 Z9 3 U1 3 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD MAY 3 PY 2016 VL 24 IS 5 BP 806 EP 815 DI 10.1016/j.str.2016.03.007 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DL1VG UT WOS:000375420100017 PM 27066747 ER PT J AU Gaines, TL Caldwell, JT Ford, CL Mulatu, MS Godette, DC AF Gaines, Tommi L. Caldwell, Julia T. Ford, Chandra L. Mulatu, Mesfin S. Godette, Dionne C. TI Relationship between a Centers for Disease Control and Prevention expanded HIV testing initiative and past-year testing by race/ethnicity: a multilevel analysis of the Behavioral Risk Factor Surveillance System SO AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV LA English DT Article DE testing initiative; screening; multilevel; HIV/AIDS; race/ethnic differences ID HEALTH INTERVIEW SURVEY; SEXUALLY-TRANSMITTED-DISEASES; UNITED-STATES; CARE; ADOLESCENTS; DISPARITIES; SERVICES; ACCESS; LATINO; ADULTS AB The Centers for Disease Control and Prevention's (CDC) expanded testing initiative (ETI) aims to bolster HIV testing among populations disproportionately affected by the HIV epidemic by providing additional funding to health departments serving these communities. ETI prioritizes testing in clinical settings; therefore, we examined the relationship between state-level ETI participation and past-year HIV testing among a racially/ethnically diverse sample of adult respondents to the 2012 Behavioral Risk Factor Surveillance System who accessed health services within the 12 months prior to being interviewed. Controlling for individual- and state-level characteristics in a multilevel logistic regression model, ETI participation was independently and positively associated with past-year testing, but this association varied by race/ethnicity. Hispanics had higher odds (adjusted odds ratio [AOR]: 1.49; 95% CI: 1.11-2.02) and American Indian/Alaska Natives had lower odds (AOR: 0.66; 95% CI: 0.43-0.99) of testing if they resided in states with (vs. without) ETI participation. State-level ETI participation did not significantly alter past-year testing among other racial/ethnic groups. Prioritizing public health resources in states most affected by HIV can improve testing patterns, but other mechanisms likely influence which racial/ethnic groups undergo testing. C1 [Gaines, Tommi L.] Univ Calif San Diego, Dept Med, Div Global Publ Hlth, La Jolla, CA 92093 USA. [Caldwell, Julia T.; Ford, Chandra L.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Community Hlth Sci, Los Angeles, CA USA. [Godette, Dionne C.] NIAAA, Div Epidemiol & Prevent Res, NIH, Rockville, MD 20852 USA. RP Gaines, TL (reprint author), Univ Calif San Diego, Dept Med, Div Global Publ Hlth, La Jolla, CA 92093 USA. EM togaines@ucsd.edu FU National Institute on Drug Abuse [K01DA034523]; Eunice Kennedy Schriver National Institute of Child Health and Human Development via the California Center for Population Research at the University of California Los Angeles [5R24HD041022]; Agency for Healthcare Research and Quality [R36HS022811-01] FX This research was supported by the National Institute on Drug Abuse [grant number K01DA034523]; the Eunice Kennedy Schriver National Institute of Child Health and Human Development via the California Center for Population Research at the University of California Los Angeles [grant number 5R24HD041022]; and the Agency for Healthcare Research and Quality [grant number R36HS022811-01]. NR 29 TC 0 Z9 0 U1 5 U2 16 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0954-0121 EI 1360-0451 J9 AIDS CARE JI Aids Care-Psychol. Socio-Med. Asp. Aids-Hiv PD MAY 3 PY 2016 VL 28 IS 5 BP 554 EP 560 DI 10.1080/09540121.2015.1131968 PG 7 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Respiratory System; Social Sciences, Biomedical SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychology; Respiratory System; Biomedical Social Sciences GA DI3JR UT WOS:000373395400002 PM 27045327 ER PT J AU Hughes, MF Ross, DG Edwards, BC DeVito, MJ Starr, JM AF Hughes, Michael F. Ross, David G. Edwards, Brenda C. DeVito, Michael J. Starr, James M. TI Tissue time course and bioavailability of the pyrethroid insecticide bifenthrin in the Long-Evans rat SO XENOBIOTICA LA English DT Article DE disposition; pharmacokinetics; pyrethroids; Bifenthrin ID P-GLYCOPROTEIN; PHARMACOKINETIC MODEL; ACUTE NEUROTOXICITY; TRANS-PERMETHRIN; MOTOR FUNCTION; BRAIN LEVELS; HUMAN MDR1; IN-VITRO; DELTAMETHRIN; METABOLISM AB 1. Pyrethroids are neurotoxic and parent pyrethroid appears to be toxic entity. This study evaluated the oral disposition and bioavailability of bifenthrin in the adult male Long-Evans rat. 2. In the disposition study, rats were administered bifenthrin (0.3 or 3 mg/kg) by oral gavage and serially sacrificed (0.25 h to 21 days). Blood, liver, brain and adipose tissue were removed. In the bioavailability study, blood was collected serially from jugular vein cannulated rats (0.25 to 24 h) following oral (0.3 or 3 mg/kg) or intravenous (0.3 mg/kg) administration of bifenthrin. Tissues were extracted and analyzed for bifenthrin by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). 3. Bifenthrin concentration in blood and liver peaked 1-2-h postoral administration and were approximately 90 ng/ml (or g) and 1000 ng/ml (or g) for both tissues at 0.3 and 3 mg/kg, respectively. Bifenthrin was rapidly cleared from both blood and liver. Brain concentrations peaked at 4-6 h and were lower than in blood at both doses (12 and 143 ng/g). Bifenthrin in adipose tissue peaked at the collected time points of 8 (157 ng/g) and 24 (1145 ng/g) h for the 0.3 and 3 mg/kg doses, respectively and was retained 21 days postoral administration. Following intravenous administration, the blood bifenthrin concentration decreased bi-exponentially, with a distribution half-life of 0.2 h and an elimination half-life of 8 h. Bifenthrin bioavailability was approximately 30%. These disposition and kinetic bifenthrin data may decrease uncertainties in the risk assessment for this pyrethroid insecticide. C1 [Hughes, Michael F.; Ross, David G.; Edwards, Brenda C.] US EPA, Off Res & Dev, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. [DeVito, Michael J.] NIEHS, Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. [Starr, James M.] US EPA, Off Res & Dev, Natl Exposure Res Lab, Res Triangle Pk, NC 27711 USA. RP Hughes, MF (reprint author), US EPA, Off Res & Dev, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. EM hughes.michaelf@epa.gov FU U.S. Environmental Protection Agency FX The authors gratefully acknowledge Drs. E. Kenyon, J.E. Simmons and M. Tornero-Velez for their comments on a previous version of this manuscript. The authors thank Ms. J. Hutchison for her technical assistance in this study. All research was funded internally by the U.S. Environmental Protection Agency. NR 47 TC 0 Z9 0 U1 3 U2 16 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0049-8254 EI 1366-5928 J9 XENOBIOTICA JI Xenobiotica PD MAY 3 PY 2016 VL 46 IS 5 BP 430 EP 438 DI 10.3109/00498254.2015.1081710 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA DE4SU UT WOS:000370621300006 PM 26367082 ER PT J AU Saunders, PM Pymm, P Pietra, G Hughes, VA Hitchen, C O'Connor, GM Loiacono, F Widjaja, J Price, DA Falco, M Mingari, MC Moretta, L McVicar, DW Rossjohn, J Brooks, AG Vivian, JP AF Saunders, Philippa M. Pymm, Phillip Pietra, Gabriella Hughes, Victoria A. Hitchen, Corinne O'Connor, Geraldine M. Loiacono, Fabrizio Widjaja, Jacqueline Price, David A. Falco, Michela Mingari, Maria Cristina Moretta, Lorenzo McVicar, Daniel W. Rossjohn, Jamie Brooks, Andrew G. Vivian, Julian P. TI Killer cell immunoglobulin-like receptor 3DL1 polymorphism defines distinct hierarchies of HLA class I recognition SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID NK CELLS; INHIBITORY RECEPTOR; CONFERS PROTECTION; B MOLECULES; BW4 EPITOPE; KIR3DL1; HAPLOTYPES; SELECTION; ALLELES; CLONES AB Natural killer ( NK) cells play a key role in immunity, but how HLA class I ( HLA-I) and killer cell immunoglobulin-like receptor 3DL1 ( KIR3DL1) polymorphism impacts disease outcome remains unclear. KIR3DL1 (*001/*005/*015) tetramers were screened for reactivity against a panel of HLA-I molecules. This revealed different and distinct hierarchies of specificity for each KIR3DL1 allotype, with KIR3DL1*005 recognizing the widest array of HLA-I ligands. These differences were further reflected in functional studies using NK clones expressing these specific KIR3DL1 allotypes. Unexpectedly, the Ile/Thr80 dimorphism in the Bw4-motif did not categorically define strong/weak KIR3DL1 recognition. Although the KIR3DL1*001, *005, and *015 polymorphisms are remote from the KIR3DL1-HLA-I interface, the structures of these three KIR3DL1-HLA-I complexes showed that the broader HLA-I specificity of KIR3DL1*005 correlated with an altered KIR3DL1*005 interdomain positioning and increased mobility within its ligand-binding site. Collectively, we provide a generic framework for understanding the impact of KIR3DL1 polymorphism on the recognition of HLA-I allomorphs. C1 [Saunders, Philippa M.; O'Connor, Geraldine M.; Widjaja, Jacqueline; Brooks, Andrew G.] Univ Melbourne, Peter Doherty Inst Infect & Immun, Dept Microbiol & Immunol, Parkville, Vic 3010, Australia. [Pymm, Phillip; Hughes, Victoria A.; Hitchen, Corinne; Rossjohn, Jamie; Vivian, Julian P.] Monash Univ, Biomed Discovery Inst, Infect & Immun Program, Clayton, Vic 3800, Australia. [Pymm, Phillip; Hughes, Victoria A.; Rossjohn, Jamie; Vivian, Julian P.] Monash Univ, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia. [Pymm, Phillip; Hughes, Victoria A.; Rossjohn, Jamie; Vivian, Julian P.] Monash Univ, Australian Res Council, Ctr Excellence Adv Mol Imaging, Clayton, Vic 3800, Australia. [Pietra, Gabriella; Mingari, Maria Cristina] Univ Genoa, Dept Expt Med, I-16132 Genoa, Italy. [Pietra, Gabriella; Mingari, Maria Cristina] IRCCS AOU San Martino IST Natl Inst Canc Res, I-16132 Genoa, Italy. [Loiacono, Fabrizio; Falco, Michela] IRCCS Ist Giannina Gaslini, I-16148 Genoa, Italy. [Price, David A.; Rossjohn, Jamie] Cardiff Univ, Inst Infect & Immun, Sch Med, Heath Pk, Cardiff CF14 4XN, S Glam, Wales. [Price, David A.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Moretta, Lorenzo] IRCCS Osped Pediat Bambino Gesu, I-00146 Rome, Italy. [McVicar, Daniel W.] NCI, Canc & Inflammat Program, Frederick, MD 21701 USA. RP Brooks, AG (reprint author), Univ Melbourne, Peter Doherty Inst Infect & Immun, Dept Microbiol & Immunol, Parkville, Vic 3010, Australia.; Rossjohn, J; Vivian, JP (reprint author), Monash Univ, Biomed Discovery Inst, Infect & Immun Program, Clayton, Vic 3800, Australia.; Rossjohn, J; Vivian, JP (reprint author), Monash Univ, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia.; Rossjohn, J; Vivian, JP (reprint author), Monash Univ, Australian Res Council, Ctr Excellence Adv Mol Imaging, Clayton, Vic 3800, Australia.; Rossjohn, J (reprint author), Cardiff Univ, Inst Infect & Immun, Sch Med, Heath Pk, Cardiff CF14 4XN, S Glam, Wales. EM jamie.rossjohn@monash.edu; agbrooks@unimelb.edu.au; julian.vivian@monash.edu RI Price, David/C-7876-2013; Falco, Michela/K-1574-2016; pietra, gabriella/J-7204-2016; OI Price, David/0000-0001-9416-2737; pietra, gabriella/0000-0002-7080-531X; Rossjohn, Jamie/0000-0002-2020-7522 FU National Health and Medical Research Council (NHMRC) [1016629, 1046685, 1062267]; Worldwide Cancer Research organization [12-1076]; National Cancer Institute [ZIA BC010747]; National Institutes of Health Intramural AIDS Targeted Antiviral Program; Associazione Italiana per la Ricerca sul Cancro [9962]; Wellcome Trust [100326/Z/12/Z]; NHMRC [AF50]; Australian Research Council DECRA Fellowship [130101504] FX This work was funded by grants from the National Health and Medical Research Council (NHMRC; 1016629, 1046685, 1062267) and the Worldwide Cancer Research organization (12-1076). This work was funded in part by the National Cancer Institute (ZIA BC010747) and the National Institutes of Health Intramural AIDS Targeted Antiviral Program. L. Moretta is supported by the Associazione Italiana per la Ricerca sul Cancro (9962). D.A. Price is supported by a Wellcome Trust Senior Investigator Award (100326/Z/12/Z). J. Rossjohn is supported by an Australia Fellowship from the NHMRC (AF50). J.P. Vivian is supported by an Australian Research Council DECRA Fellowship (130101504). NR 47 TC 3 Z9 4 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD MAY 2 PY 2016 VL 213 IS 5 BP 791 EP 807 DI 10.1084/jem.20152023 PG 17 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DS5TP UT WOS:000380845500012 PM 27045007 ER PT J AU Ghitza, UE AF Ghitza, Udi E. TI Overlapping Mechanisms of Stress-Induced Relapse to Opioid Use Disorder and Chronic Pain: Clinical Implications SO FRONTIERS IN PSYCHIATRY LA English DT Article DE chronic pain; addiction; opiate addiction; addiction treatment; opiate dependence; opioid dependence; substance use disorders; substance use disorder ID NEUROPATHIC PAIN; UNITED-STATES; INDUCED REINSTATEMENT; 5-HT1A RECEPTORS; CONTROLLED-TRIAL; HEROIN SEEKING; DOUBLE-BLIND; CANNABIDIOL; ADDICTION; ABUSE AB Over the past two decades, a steeply growing number of persons with chronic non-cancer pain have been using opioid analgesics chronically to treat it, accompanied by a markedly increased prevalence of individuals with opioid-related misuse, opioid use disorders, emergency department visits, hospitalizations, admissions to drug treatment programs, and drug overdose deaths. This opioid misuse and overdose epidemic calls for well-designed randomized-controlled clinical trials into more skillful and appropriate pain management and for developing effective analgesics that have lower abuse liability and are protective against stress induced by chronic non-cancer pain. However, incomplete knowledge regarding effective approaches to treat various types of pain has been worsened by an under-appreciation of overlapping neurobiological mechanisms of stress, stress-induced relapse to opioid use, and chronic non-cancer pain in patients presenting for care for these conditions. This insufficient knowledge base has unfortunately encouraged common prescription of conveniently available opioid pain-relieving drugs with abuse liability, as opposed to treating underlying problems using team-based multidisciplinary, patient-centered, collaborative-care approaches for addressing pain and co-occurring stress and risk for opioid use disorder. This paper reviews recent neurobiological findings regarding overlapping mechanisms of stress-induced relapse to opioid misuse and chronic non-cancer pain, and then discusses these in the context of key outstanding evidence gaps and clinical-treatment research directions that may be pursued to fill these gaps. Such research directions, if conducted through well-designed randomized-controlled trials, may substantively inform clinical practice in general medical settings on how to effectively care for patients presenting with pain-related distress and these common co-occurring conditions. C1 [Ghitza, Udi E.] NIDA, US Dept HHS, Ctr Clin Trials Network, NIH, Bethesda, MD 20892 USA. RP Ghitza, UE (reprint author), NIDA, US Dept HHS, Ctr Clin Trials Network, NIH, Bethesda, MD 20892 USA. EM ghitzau@nida.nih.gov NR 54 TC 0 Z9 0 U1 5 U2 7 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-0640 J9 FRONT PSYCHIATRY JI Front. Psychiatry PD MAY 2 PY 2016 VL 7 AR 80 DI 10.3389/fpsyt.2016.00080 PG 6 WC Psychiatry SC Psychiatry GA DK8MA UT WOS:000375179600002 PM 27199787 ER PT J AU Horsley, W Coughlan, D Baqir, W Williamson, S AF Horsley, W. Coughlan, D. Baqir, W. Williamson, S. TI COST AND SERVICE IMPACT OF FORTNIGHTLY VERSUS WEEKLY CETUXIMAB DOSING REGIMENS SO VALUE IN HEALTH LA English DT Meeting Abstract C1 [Horsley, W.] North England Specialised Commissioning Team, NHS England, Newcastle, England. [Coughlan, D.] NCI, Rockville, MD USA. [Baqir, W.; Williamson, S.] Northumbria Healthcare NHS Trust, North Tyneside, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-3015 EI 1524-4733 J9 VALUE HEALTH JI Value Health PD MAY PY 2016 VL 19 IS 3 MA PCN122 BP A155 EP A155 PG 1 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA EL9HJ UT WOS:000394931000295 ER PT J AU Tsai, H Pfeiffer, R Philips, G Barac, A Fu, AZ Zhou, Y Potosky, A AF Tsai, H. Pfeiffer, R. Philips, G. Barac, A. Fu, A. Z. Zhou, Y. Potosky, A. TI POPULATION-BASED COMPARISON OF THE RISKS OF SERIOUS ADVERSE EVENTS FROM INTERMITTENT VERSUS CONTINUOUS ANDROGEN DEPRIVATION THERAPY IN ADVANCED PROSTATE CANCER PATIENTS SO VALUE IN HEALTH LA English DT Meeting Abstract C1 [Tsai, H.; Fu, A. Z.; Zhou, Y.; Potosky, A.] Georgetown Univ, Washington, DC USA. [Pfeiffer, R.] NCI, Rockville, MD USA. [Philips, G.] Georgetown Univ Hosp, Washington, DC 20007 USA. [Barac, A.] MedStar Washington Hosp Ctr, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-3015 EI 1524-4733 J9 VALUE HEALTH JI Value Health PD MAY PY 2016 VL 19 IS 3 MA PCN5 BP A134 EP A134 PG 1 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA EL9HJ UT WOS:000394931000179 ER PT J AU Estrada-Veras, JI Cabrera-Pena, GA de Ferran, CPE AF Estrada-Veras, Juvianee I. Cabrera-Pena, Giselle A. Perez-Estrella de Ferran, Ceila TI Medical genetics and genomic medicine in the Dominican Republic: challenges and opportunities SO MOLECULAR GENETICS & GENOMIC MEDICINE LA English DT Article ID CANDIDATE GENES; ALZHEIMER-DISEASE; LATIN-AMERICA; SANTO-DOMINGO; FAMILIES; ASSOCIATION; DEFICIENCY; MUTATIONS; SPECTRUM C1 [Estrada-Veras, Juvianee I.] NHGRI, Med Genet Branch, Sect Human Biochem Genet, NIH, Bethesda, MD 20892 USA. [Cabrera-Pena, Giselle A.] Carol Morgan Sch Santo Domingo, Primary Care Unit, Santo Domingo, Dominican Rep. [Perez-Estrella de Ferran, Ceila] Robert Reid Cabral Childrens Hosp, Dept Pediat, Santo Domingo, Dominican Rep. RP Estrada-Veras, JI (reprint author), 10 Ctr Dr,Bldg 10,Room 3-2551, Bethesda, MD 20892 USA. EM estradaverasji@mail.nih.gov NR 44 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2324-9269 J9 MOL GENET GENOM MED JI Mol. Genet. Genom. Med. PD MAY PY 2016 VL 4 IS 3 BP 243 EP 256 DI 10.1002/mgg3.224 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA EL2HW UT WOS:000394441700002 PM 27247952 ER PT J AU Freund, PR Sergeev, YV MacDonald, IM AF Freund, Paul R. Sergeev, Yuri V. MacDonald, Ian M. TI Analysis of a large choroideremia dataset does not suggest a preference for inclusion of certain genotypes in future trials of gene therapy SO MOLECULAR GENETICS & GENOMIC MEDICINE LA English DT Article DE Choroideremia; natural history; Rab escort protein-1; retinal dystrophy; visual acuity; visual fields ID RAB ESCORT PROTEIN-1; RETINITIS-PIGMENTOSA; MUTATION ANALYSIS; CANDIDATE GENE; CHM MUTATION; FORCE-FIELD; REP-1 GENE; FAMILIES; CLONING AB Background Choroideremia (CHM) is an X-linked degeneration of the retinal pigment epithelium, photoreceptors, and choroid, which causes nyctalopia and progressive constriction of visual fields leading to blindness. The CHM gene encodes Rab escort protein 1 (REP-1). In this work, we reviewed the phenotypes and genotypes of affected males with the purpose of understanding the functional effects of CHM mutations and their relationship with the phenotypes. Methods A retrospective review of 128 affected males was performed analyzing the onset of symptoms, visual acuity, and visual fields with respect to their mutations in the CHM gene. Results In rank order, reflecting data from this report, the most common mutations found in the CHM gene were nonsense mutations (41%), exon deletions (37%), and splice sites (14%) associated with a loss of functional protein. In the pool of 106 CHM mutations, we discovered four novel missense mutations (c.238C>T; p.L80F, c.819G>T; p.Q273H, c.1327A>G; p.M443V, and c.1370C>T; p.L457P) predicted to be severe changes affecting protein stability and folding with the effect similar to that of other types of mutations. No significant genotype-phenotype correlation was found with respect to the onset of nyctalopia, the onset of other visual symptoms, visual acuity, or width of visual fields. Conclusion There is no evidence to support exclusion of CHM patients from clinical trials based on their genotypes or any potential genotype-phenotype correlations. C1 [Freund, Paul R.; MacDonald, Ian M.] Univ Alberta, Dept Ophthalmol & Visual Sci, Edmonton, AB, Canada. [Sergeev, Yuri V.] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. RP MacDonald, IM (reprint author), Royal Alexandra Hosp, Dept Ophthalmol & Visual Sci, Off 2319, 10240 Kingsway Ave, Edmonton, AB T5H 3V9, Canada. EM macdonal@ualberta.ca FU Canadian Institutes of Health Research Emerging Team Grant; Foundation Fighting Blindness; Choroideremia Research Foundation Canada, Inc.; Alberta Innovate-Health Solutions; Intramural Program National Eye Institute/National Institutes of Health FX IM: Canadian Institutes of Health Research Emerging Team Grant, Foundation Fighting Blindness and the Choroideremia Research Foundation Canada, Inc., Alberta Innovate-Health Solutions; YS: Intramural Program National Eye Institute/National Institutes of Health. NR 39 TC 1 Z9 1 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2324-9269 J9 MOL GENET GENOM MED JI Mol. Genet. Genom. Med. PD MAY PY 2016 VL 4 IS 3 BP 344 EP 358 DI 10.1002/mgg3.208 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA EL2HW UT WOS:000394441700011 PM 27247961 ER PT J AU Berger, Z Zuo, SW Bowen, ME Yeh, JS Burke, HB Kormos, W Nandiwada, DR Correa, RR Carter, JA Elliott, DJ Sateia, H Beyth, R Smith, B AF Berger, Zackary Zuo, Stephanie W. Bowen, Michael E. Yeh, James S. Burke, Harry B. Kormos, William Nandiwada, Deepa R. Correa, Ricardo R. Carter, Jocelyn A. Elliott, Daniel J. Sateia, Heather Beyth, Rebecca Smith, Beth TI QUALITY MEASURES OF ACCOUNTABLE CARE ORGANIZATIONS: TRANSPARENCY OF THE EVIDENCE BASE SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract CT Meeting of the Society-of-General-Internal-Medicine (SGIM) CY MAY 11-14, 2015-2016 CL Hollywood, FL SP Soc Gen Internal Med C1 [Yeh, James S.] Brigham & Women, Boston, MA USA. [Elliott, Daniel J.] Christiana Care Hlth Syst, Newark, DE USA. [Berger, Zackary; Zuo, Stephanie W.] Johns Hopkins Sch Med, Baltimore, MD USA. [Sateia, Heather] Johns Hopkins Univ, Lutherville Timonium, MD USA. [Kormos, William] Mass Gen Hosp, Boston, MA USA. [Carter, Jocelyn A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Correa, Ricardo R.] NIH, Rockville, MD USA. [Smith, Beth] OHSU, Portland, OR USA. [Bowen, Michael E.] UT Southwestern Med Ctr, Dallas, TX USA. [Burke, Harry B.] Uniformed Serv Univ Hlth Sci, Bethesda, MD USA. [Beyth, Rebecca] Univ Florida, Gainesville, FL USA. [Beyth, Rebecca] Malcom Randall VAMC, Gainesville, FL USA. [Nandiwada, Deepa R.] Univ Pittsburgh, Pittsburgh, PA USA. [Berger, Zackary] Johns Hopkins Berman Inst Bioeth, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD MAY PY 2016 VL 31 SU 2 BP S379 EP S379 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EI0YL UT WOS:000392201601146 ER PT J AU Blackstock, OJ Moore, BA Berkenblit, G Calabrese, SK Cunningham, C Fiellin, DA Patel, VV Phillips, KA Shah, M Tetrault, J Edelman, EJ AF Blackstock, Oni J. Moore, Brent A. Berkenblit, Gail Calabrese, Sarah K. Cunningham, Chinazo Fiellin, David A. Patel, Viraj V. Phillips, Karran A. Shah, Minesh Tetrault, JeanetteM. Edelman, E. J. TI PRIMARY CARE PROVIDER AND PRACTICE CHARACTERISTICS ASSOCIATED WITH HIV PRE-EXPOSURE PROPHYLAXIS (PREP) UPTAKE SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract CT Meeting of the Society-of-General-Internal-Medicine (SGIM) CY MAY 11-14, 2015-2016 CL Hollywood, FL SP Soc Gen Internal Med C1 [Blackstock, Oni J.; Cunningham, Chinazo; Patel, Viraj V.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Blackstock, Oni J.; Cunningham, Chinazo; Patel, Viraj V.] Montefiore Med Ctr, 111 E 210th St, Bronx, NY 10467 USA. [Berkenblit, Gail] Johns Hopkins, Baltimore, MD USA. [Phillips, Karran A.] NIDA, NIH, Baltimore, MD USA. [Shah, Minesh] Univ Illinois, Chicago, IL USA. [Calabrese, Sarah K.] Yale Univ, New Haven, CT USA. [Moore, Brent A.; Fiellin, David A.; Tetrault, JeanetteM.; Edelman, E. J.] Yale Univ, Sch Med, New Haven, CT USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD MAY PY 2016 VL 31 SU 2 BP S362 EP S363 PG 2 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EI0YL UT WOS:000392201601117 ER PT J AU Edelman, EJ Moore, BA Berkenblit, G Calabrese, SK Cunningham, C Fiellin, DA Katz, T Patel, VV Phillips, KA Tetrault, JM Shah, M Blackstock, OJ AF Edelman, E. J. Moore, Brent A. Berkenblit, Gail Calabrese, Sarah K. Cunningham, Chinazo Fiellin, David A. Katz, Theresa Patel, Viraj V. Phillips, Karran A. Tetrault, Jeanette M. Shah, Minesh Blackstock, Oni J. TI GETTING HIV PRE-EXPOSURE PROPHYLAXIS (PREP) INTO PRIMARY CARE PRACTICE: TRAIN ALL PROVIDERS, DESIGNATE AN ON-SITE PREP SPECIALIST, OR REFER OUT? SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract CT Meeting of the Society-of-General-Internal-Medicine (SGIM) CY MAY 11-14, 2015-2016 CL Hollywood, FL SP Soc Gen Internal Med C1 [Edelman, E. J.; Moore, Brent A.; Fiellin, David A.; Katz, Theresa; Tetrault, Jeanette M.] Yale Univ, Sch Med, New Haven, CT USA. [Berkenblit, Gail] Johns Hopkins, Baltimore, MD USA. [Calabrese, Sarah K.] Yale Univ, New Haven, CT USA. [Cunningham, Chinazo; Patel, Viraj V.; Blackstock, Oni J.] Montefiore Med Ctr, AECOM, New York, NY USA. [Phillips, Karran A.] NIDA, NIH, Baltimore, MD USA. [Shah, Minesh] Univ Illinois, Chicago, IL USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD MAY PY 2016 VL 31 SU 2 BP S232 EP S233 PG 2 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EI0YL UT WOS:000392201600258 ER PT J AU Goold, SD Myers, CD Szymecko, L Calhoun, K Hammad, A Bridgeforth, J Ledon, C Rowe, Z Kim, M Danis, M Abelson, J AF Goold, Susan D. Myers, C. D. Szymecko, Lisa Calhoun, Karen Hammad, Adnan Bridgeforth, James Ledon, Charo Rowe, Zachary Kim, Myra Danis, Marion Abelson, Julia TI PRIORITIES OF MINORITY AND UNDERSERVED COMMUNITIES FOR HEALTH RESEARCH: THE EFFECT OF DELIBERATION SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract CT Meeting of the Society-of-General-Internal-Medicine (SGIM) CY MAY 11-14, 2015-2016 CL Hollywood, FL SP Soc Gen Internal Med C1 [Danis, Marion] NIH, Bldg 10, Bethesda, MD 20892 USA. [Goold, Susan D.; Szymecko, Lisa; Kim, Myra] Univ Michigan, Ann Arbor, MI 48109 USA. [Myers, C. D.] Univ Minnesota, Minneapolis, MN USA. [Calhoun, Karen] Michigan Inst Clin & Hlth Res, Ann Arbor, MI USA. [Hammad, Adnan] Arab Amer Med Assoc, Dearborn, MI USA. [Bridgeforth, James] Michigan Ctr Urban African Amer Aging Res, Detroit, MI USA. [Ledon, Charo] Acc Buenos Vecinos, Ann Arbor, MI USA. [Rowe, Zachary] Friends Parkside, Detroit, MI USA. [Abelson, Julia] McMaster Univ, Hamilton, ON, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD MAY PY 2016 VL 31 SU 2 BP S369 EP S369 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EI0YL UT WOS:000392201601129 ER PT J AU Goold, SD Myers, CD Szymecko, L Cunningham, C Martinez, S Ledon, C Campbell, T Danis, M Cargill, SS Kim, M Rowe, Z AF Goold, Susan D. Myers, C. D. Szymecko, Lisa Cunningham, Carla Martinez, Sal Ledon, Charo Campbell, Terrance Danis, Marion Cargill, Stephanie Solomon Kim, Myra Rowe, Zachary TI PRIORITIES FOR PATIENT CENTERED OUTCOMES RESEARCH: THE VIEWS OF MINORITY AND UNDERSERVED COMMUNITIES SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract CT Meeting of the Society-of-General-Internal-Medicine (SGIM) CY MAY 11-14, 2015-2016 CL Hollywood, FL SP Soc Gen Internal Med C1 [Danis, Marion] NIH, Bldg 10, Bethesda, MD 20892 USA. [Goold, Susan D.; Szymecko, Lisa; Ledon, Charo; Kim, Myra] Univ Michigan, Ann Arbor, MI 48109 USA. [Myers, C. D.] Univ Minnesota, Minneapolis, MN USA. [Cunningham, Carla] Reynolds Cty Hlth Dept, Centerville, MO USA. [Martinez, Sal] Community Renewal & Dev Inc, St Louis, MO USA. [Campbell, Terrance] YOUR Ctr, Flint, MI USA. [Cargill, Stephanie Solomon] St Louis Univ, St Louis, MO 63103 USA. [Rowe, Zachary] Friends Parkside, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD MAY PY 2016 VL 31 SU 2 BP S368 EP S369 PG 2 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EI0YL UT WOS:000392201601128 ER PT J AU Karliner, LS Perez-Stable, EJ Gregorich, S AF Karliner, Leah S. Perez-Stable, Eliseo J. Gregorich, Steven TI EASY ACCESS TO PROFESSIONAL INTERPRETERS IN THE HOSPITAL DECREASES READMISSION RATES AND HEALTHCARE EXPENDITURES FOR LIMITED ENGLISH PROFICIENT PATIENTS SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract CT Meeting of the Society-of-General-Internal-Medicine (SGIM) CY MAY 11-14, 2015-2016 CL Hollywood, FL SP Soc Gen Internal Med C1 [Karliner, Leah S.; Perez-Stable, Eliseo J.; Gregorich, Steven] UCSF, San Francisco, CA USA. [Perez-Stable, Eliseo J.] NIH, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD MAY PY 2016 VL 31 SU 2 BP S202 EP S203 PG 2 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EI0YL UT WOS:000392201600203 ER PT J AU Lee, JS Gregorich, S Mutha, S Napoles, AM Perez-Stable, EJ Livaudais-Toman, J Karliner, LS AF Lee, Jonathan S. Gregorich, Steven Mutha, Sunita Napoles, Anna M. Perez-Stable, Eliseo J. Livaudais-Toman, Jennifer Karliner, Leah S. TI DO BEDSIDE INTERPRETER PHONES IMPROVE HOSPITAL DISCHARGE PREPAREDNESS FOR LIMITED ENGLISH PROFICIENT PATIENTS? A NATURAL EXPERIMENT SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract CT Meeting of the Society-of-General-Internal-Medicine (SGIM) CY MAY 11-14, 2015-2016 CL Hollywood, FL SP Soc Gen Internal Med C1 [Perez-Stable, Eliseo J.] Natl Inst Minor Hlth & Hlth Dispar, Bethesda, MD USA. [Lee, Jonathan S.; Gregorich, Steven; Mutha, Sunita; Napoles, Anna M.; Livaudais-Toman, Jennifer; Karliner, Leah S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD MAY PY 2016 VL 31 SU 2 BP S196 EP S197 PG 2 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EI0YL UT WOS:000392201600195 ER PT J AU Mundkur, M McDonald, CJ AF Mundkur, Mallika McDonald, Clement J. TI UTILIZING MEDICARE CLAIMS FOR THE ASSESSMENT OF INFLUENZA VACCINATION COVERAGE IN THE US ELDERLY SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract CT Meeting of the Society-of-General-Internal-Medicine (SGIM) CY MAY 11-14, 2015-2016 CL Hollywood, FL SP Soc Gen Internal Med C1 [Mundkur, Mallika] Brigham & Womens Hosp, Lexington, MA USA. [McDonald, Clement J.] Natl Lib Med, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD MAY PY 2016 VL 31 SU 2 BP S463 EP S463 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EI0YL UT WOS:000392201601305 ER PT J AU Rendle, K Quaife, S Suls, J Edwards, H Moser, RP Blake, KD Kobrin, S AF Rendle, Katharine Quaife, Samantha Suls, Jerry Edwards, Heather Moser, Richard P. Blake, Kelly D. Kobrin, Sarah TI CANCER SYMPTOM RECOGNITION AND ANTICIPATED DELAY IN HELP-SEEKING IN A POPULATION SAMPLE OF US ADULTS SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract CT Meeting of the Society-of-General-Internal-Medicine (SGIM) CY MAY 11-14, 2015-2016 CL Hollywood, FL SP Soc Gen Internal Med C1 [Rendle, Katharine; Suls, Jerry; Edwards, Heather; Moser, Richard P.; Blake, Kelly D.; Kobrin, Sarah] NCI, Bethesda, MD USA. [Quaife, Samantha] UCL, London, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD MAY PY 2016 VL 31 SU 2 MA 2469113 BP S145 EP S145 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EI0YL UT WOS:000392201600108 ER PT J AU Howard, K Clifford, S Saretsky, T Cho, M Hoffmann, SC Talbot, GH Powers, JH AF Howard, K. Clifford, S. Saretsky, T. Cho, M. Hoffmann, S. C. Talbot, G. H. Powers, J. H. TI HOSPITAL-ACQUIRED BACTERIAL PNEUMONIA: DEVELOPMENT OF A NEW PATIENT-REPORTED OUTCOME INSTRUMENT SO VALUE IN HEALTH LA English DT Meeting Abstract C1 [Howard, K.; Clifford, S.; Saretsky, T.; Cho, M.] ICON Clin Res LLC, San Francisco, CA USA. [Hoffmann, S. C.] Fdn Natl Inst Hlth, Bethesda, MD USA. [Talbot, G. H.] Talbot Advisors LLC, Anna Maria, FL USA. [Powers, J. H.] George Washington Univ, Sch Med, Leidos Biomed Res, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-3015 EI 1524-4733 J9 VALUE HEALTH JI Value Health PD MAY PY 2016 VL 19 IS 3 MA PIN53 BP A221 EP A221 PG 1 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA EL9HP UT WOS:000394931600064 ER PT J AU Lynch, J Chun, DS Berse, B Venne, V Efimova, O DuVall, S Filipski, KK Kelley, MJ AF Lynch, J. Chun, D. S. Berse, B. Venne, V. Efimova, O. DuVall, S. Filipski, K. K. Kelley, M. J. TI CLINICAL IMPACT OF THE 21-GENE RS TEST WITHIN THE VETERANS HEALTH CARE ADMINISTRATION SO VALUE IN HEALTH LA English DT Meeting Abstract C1 [Lynch, J.] RTI Int, Waltham, MA USA. [Chun, D. S.] Univ Utah, Salt Lake City, UT USA. [Berse, B.] Boston Univ, Boston, MA 02215 USA. [Venne, V.; Efimova, O.] VA Salt Lake City, Salt Lake City, UT USA. [DuVall, S.] VA Salt Lake City Hlth Care Syst, Salt Lake City, UT USA. [Filipski, K. K.] NCI, Bethesda, MD 20892 USA. [Kelley, M. J.] Duke Univ, Durham, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-3015 EI 1524-4733 J9 VALUE HEALTH JI Value Health PD MAY PY 2016 VL 19 IS 3 MA PMD86 BP A312 EP A312 PG 1 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA EL9HP UT WOS:000394931600570 ER PT J AU Powers, JH Bacci, ED Leidy, NK Stringer, S Kim, K Memoli, MJ Han, A Fairchok, MP Chen, W Arnold, JC Danaher, PJ Lalani, T Hansen, EA Ridore, M Burgess, TH Millar, EV Hernandez, A Rodriguez-Zulueta, P Ortega-Gallegos, H Galindo-Fraga, A Ruiz-Palacios, GM Pett, S Fischer, W Gillor, D Macias, LM DuVal, A Rothman, R Dugas, A Guerrero, ML AF Powers, J. H. Bacci, E. D. Leidy, N. K. Stringer, S. Kim, K. Memoli, M. J. Han, A. Fairchok, M. P. Chen, W. Arnold, J. C. Danaher, P. J. Lalani, T. Hansen, E. A. Ridore, M. Burgess, T. H. Millar, E., V Hernandez, A. Rodriguez-Zulueta, P. Ortega-Gallegos, H. Galindo-Fraga, A. Ruiz-Palacios, G. M. Pett, S. Fischer, W. Gillor, D. Macias, L. M. DuVal, A. Rothman, R. Dugas, A. Guerrero, M. L. TI EVALUATION OF THE PERFORMANCE PROPERTIES OF THE INFLUENZA PATIENT-REPORTED OUTCOMES INSTRUMENT (FLU-PRO) SO VALUE IN HEALTH LA English DT Meeting Abstract C1 [Powers, J. H.] George Washington Univ, Sch Med, Leidos Biomed Res, Rockville, MD USA. [Bacci, E. D.] Evidera, Seattle, WA USA. [Leidy, N. K.; Stringer, S.; Kim, K.] Evidera, Bethesda, MD USA. [Memoli, M. J.; Han, A.] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Fairchok, M. P.; Millar, E., V] Uniformed Serv Univ Hlth Sci, Infect Dis Clin Res Program, Madigan Army Med Ctr, Tacoma, WA USA. [Chen, W.; Burgess, T. H.] Uniformed Serv Univ Hlth Sci, Infect Dis Clin Res Program, Rockville, MD USA. [Arnold, J. C.] Naval Med Ctr, San Diego, CA USA. [Danaher, P. J.] AFMOA, Lackland AFB, TX USA. [Lalani, T.] Naval Med Ctr, Portsmouth, VA USA. [Hansen, E. A.] Naval Hlth Res Ctr, Operat Infect Dis, San Diego, CA USA. [Ridore, M.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Hernandez, A.] Inst Nacl Enfermedades Resp, Mexico City, DF, Mexico. [Rodriguez-Zulueta, P.] Hosp Gen Dr Manuel Gea Gonzalez, Mexico City, DF, Mexico. [Ortega-Gallegos, H.; Galindo-Fraga, A.; Ruiz-Palacios, G. M.; Guerrero, M. L.] Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Mexico City, DF, Mexico. [Pett, S.] UCL, London, England. [Fischer, W.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Gillor, D.] Univ Hosp Cologne, Cologne, Germany. [Macias, L. M.] Hosp Gen Agudos JM Ramos Mejia, Servicio Inmunocomprometidos, Buenos Aires, DF, Argentina. [DuVal, A.; Rothman, R.; Dugas, A.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-3015 EI 1524-4733 J9 VALUE HEALTH JI Value Health PD MAY PY 2016 VL 19 IS 3 MA PIN52 BP A220 EP A221 PG 2 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA EL9HP UT WOS:000394931600063 ER PT J AU Koizumi, H Mosher, B Tariq, MF Zhang, RL Koshiya, N Smith, JC AF Koizumi, Hidehiko Mosher, Bryan Tariq, Mohammad F. Zhang, Ruli Koshiya, Naohiro Smith, Jeffrey C. TI Voltage-Dependent Rhythmogenic Property of Respiratory Pre-Botzinger Complex Glutamatergic, Dbx1-Derived, and Somatostatin-Expressing Neuron Populations Revealed by Graded Optogenetic Inhibition SO ENEURO LA English DT Article DE brainstem microcircuit; breathing; optogenetics; rhythmogenesis ID PREBOTZINGER COMPLEX; PACEMAKER NEURONS; IN-VITRO; GENERATION; MOUSE; INTERNEURONS; NETWORK; RAT; PATTERN; MODELS AB The rhythm of breathing in mammals, originating within the brainstem pre-Botzinger complex (pre-BotC), is presumed to be generated by glutamatergic neurons, but this has not been directly demonstrated. Additionally, developmental expression of the transcription factor Dbx1 or expression of the neuropeptide somatostatin (Sst), has been proposed as a marker for the rhythmogenic pre-BotC glutamatergic neurons, but it is unknown whether these other two phenotypically defined neuronal populations are functionally equivalent to glutamatergic neurons with regard to rhythm generation. To address these problems, we comparatively investigated, by optogenetic approaches, the roles of pre-BotC glutamatergic, Dbx1-derived, and Sst-expressing neurons in respiratory rhythm generation in neonatal transgenic mouse medullary slices in vitro and also more intact adult perfused brainstem-spinal cord preparations in situ. We established three different triple-transgenic mouse lines with Cre-driven Archaerhodopsin-3 (Arch) expression selectively in glutamatergic, Dbx1-derived, or Sst-expressing neurons for targeted photoinhibition. In each line, we identified subpopulations of rhythmically active, Arch-expressing pre-BotC inspiratory neurons by whole-cell recordings in medullary slice preparations in vitro, and established that Arch-mediated hyperpolarization of these inspiratory neurons was laser power dependent with equal efficacy. By site-and population-specific graded photoinhibition, we then demonstrated that inspiratory frequency was reduced by each population with the same neuronal voltage-dependent frequency control mechanism in each state of the respiratory network examined. We infer that enough of the rhythmogenic pre-BotC glutamatergic neurons also have the Dbx1 and Sst expression phenotypes, and thus all three phenotypes share the same voltage-dependent frequency control property. C1 [Koizumi, Hidehiko; Mosher, Bryan; Tariq, Mohammad F.; Zhang, Ruli; Koshiya, Naohiro; Smith, Jeffrey C.] NINDS, Cellular & Syst Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Smith, JC (reprint author), NINDS, NIH, 49 Convent Dr,Room 2A10, Bethesda, MD 20892 USA.; Koizumi, H (reprint author), NINDS, NIH, 49 Convent Dr,Room 2A22, Bethesda, MD 20892 USA. EM koizumih@mail.nih.gov; smithj2@helix.nih.gov FU Intramural Research Program of National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke; NIH Undergraduate Scholarship Program FX This research was supported by the Intramural Research Program of National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke. M.F.T. was supported, in part, by the NIH Undergraduate Scholarship Program. NR 45 TC 0 Z9 0 U1 2 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 2373-2822 J9 ENEURO JI eNeuro PD MAY-JUN PY 2016 VL 3 IS 3 DI 10.1523/ENEURO.0081-16.2016 PG 23 WC Neurosciences SC Neurosciences & Neurology GA EH7BH UT WOS:000391927300012 ER PT J AU Pujala, A Blivis, D O'Donovan, MJ AF Pujala, Avinash Blivis, Dvir O'Donovan, Michael J. TI Interactions between Dorsal and Ventral Root Stimulation on the Generation of Locomotor-Like Activity in the Neonatal Mouse Spinal Cord SO ENEURO LA English DT Article DE central pattern generator; dorsal root; locomotion; spinal cord; ventral root ID PATTERN GENERATORS; FICTIVE LOCOMOTION; SACROCAUDAL AFFERENTS; SUPRASPINAL CONTROL; EXCITATORY ACTIONS; NEURONAL-ACTIVITY; V2A INTERNEURONS; INSIGHTS; ORGANIZATION; ACTIVATION AB We investigated whether dorsal (DR) and ventral root (VR) stimulus trains engage common postsynaptic components to activate the central pattern generator (CPG) for locomotion in the neonatal mouse spinal cord. VR stimulation did not activate the first order interneurons mediating the activation of the locomotor CPG by sacrocaudal afferent stimulation. Simultaneous stimulation of adjacent dorsal or ventral root pairs, subthreshold for evoking locomotor-like activity, did not summate to activate the CPG. This suggests that locomotor-like activity is triggered when a critical class of efferent or afferent axons is stimulated and does not depend on the number of stimulated axons or activated postsynaptic neurons. DR- and VR-evoked episodes exhibited differences in the coupling between VR pairs. In DR-evoked episodes, the coupling between the ipsilateral and contralateral flexor/extensor roots was similar and stronger than the bilateral extensor roots. In VR-evoked episodes, ipsilateral flexor/extensor coupling was stronger than both the contralateral flexor/extensor and the bilateral extensor coupling. For both types of stimulation, the coupling was greatest between the bilateral L1/L2 flexor-dominated roots. This indicates that the recruitment and/or the firing pattern of motoneurons differed in DR and VR-evoked episodes. However, the DR and VR trains do not appear to activate distinct CPGs because trains of DR and VR stimuli at frequencies too low to evoke locomotor-like activity did so when they were interleaved. These results indicate that the excitatory actions of VR stimulation converge onto the CPG through an unknown pathway that is not captured by current models of the locomotor CPG. C1 [Pujala, Avinash] Janelia Farms Res Campus, Ashburn, VA 20147 USA. [Blivis, Dvir; O'Donovan, Michael J.] NINDS, Sect Dev Neurobiol, NIH, Room 3C-1014,Bldg 35, Bethesda, MD 20892 USA. RP O'Donovan, MJ (reprint author), NINDS, Sect Dev Neurobiol, NIH, Room 3C-1014,Bldg 35, Bethesda, MD 20892 USA. EM odonovm@ninds.nih.gov OI Blivis, Dvir/0000-0001-6203-7325 FU National Institute of Neurological Disorders and Stroke FX This work was supported by the intramural program of the National Institute of Neurological Disorders and Stroke. We thank Melanie Falgairolle for critical comments, David Ide for construction of equipment, and Aharon Lev-Tov for a copy of the software program "Spinalcore". NR 36 TC 1 Z9 1 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 2373-2822 J9 ENEURO JI eNeuro PD MAY-JUN PY 2016 VL 3 IS 3 DI 10.1523/ENEURO.0101-16.2016 PG 16 WC Neurosciences SC Neurosciences & Neurology GA EH7BH UT WOS:000391927300017 ER PT J AU Snyder, JS Grigereit, L Russo, A Seib, DR Brewer, M Pickel, J Cameron, HA AF Snyder, Jason S. Grigereit, Laura Russo, Alexandra Seib, Desiree R. Brewer, Michelle Pickel, James Cameron, Heather A. TI A Transgenic Rat for Specifically Inhibiting Adult Neurogenesis SO ENEURO LA English DT Article DE adult neurogenesis; hippocampus; olfactory bulb; plasticity ID NEURAL STEM-CELLS; BORN HIPPOCAMPAL-NEURONS; DENTATE GRANULE CELLS; CONDITIONAL ABLATION; CORTICAL GLIOGENESIS; SUBVENTRICULAR ZONE; REACTIVE ASTROCYTES; BRAIN IRRADIATION; THYMIDINE KINASE; MAMMALIAN BRAIN AB The growth of research on adult neurogenesis and the development of new models and tools have greatly advanced our understanding of the function of newborn neurons in recent years. However, there are still significant limitations in the ability to identify the functions of adult neurogenesis in available models. Here we report a transgenic rat (TK rat) that expresses herpes simplex virus thymidine kinase in GFAP+ cells. Upon treating TK rats with the antiviral drug valganciclovir, granule cell neurogenesis can be completely inhibited in adulthood, in both the hippocampus and olfactory bulb. Interestingly, neurogenesis in the glomerular and external plexiform layers of the olfactory bulb was only partially inhibited, suggesting that some adult-born neurons in these regions derive from a distinct precursor population that does not express GFAP. Within the hippocampus, blockade of neurogenesis was rapid and nearly complete within 1 week of starting treatment. Preliminary behavioral analyses indicate that general anxiety levels and patterns of exploration are generally unaffected in neurogenesis-deficient rats. However, neurogenesis-deficient TK rats showed reduced sucrose preference, suggesting deficits in reward-related behaviors. We expect that TK rats will facilitate structural, physiological, and behavioral studies that complement those possible in existing models, broadly enhancing understanding of the function of adult neurogenesis. C1 [Snyder, Jason S.; Grigereit, Laura; Russo, Alexandra; Brewer, Michelle; Cameron, Heather A.] NIMH, Sect Neuroplast, NIH, Bethesda, MD 20892 USA. [Pickel, James] NIMH, Transgen Core Facil, NIH, Bethesda, MD 20892 USA. [Snyder, Jason S.; Seib, Desiree R.] Univ British Columbia, Djavad Mowafaghian Ctr Brain Hlth, Dept Psychol, Vancouver, BC V6T 1Z4, Canada. RP Cameron, HA (reprint author), NIMH, NIH, Bldg 35-3C915,35 Lincoln Dr MSC3718, Bethesda, MD 20892 USA. EM heathercameron@mail.nih.gov OI Snyder, Jason/0000-0002-5509-0272 FU NSERC; Intramural Program of the NIH, National Institute of Mental Health [ZIAMH002784] FX This work was supported by the Intramural Program of the NIH, National Institute of Mental Health, ZIAMH002784 (H.A.C) and NSERC (J.S.S). We thank Dr Lauren Brinster and Rachel Fleishmann, from the Division of Veterinary Resources, NIH, for assistance with pathology. NR 80 TC 2 Z9 2 U1 1 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 2373-2822 J9 ENEURO JI eNeuro PD MAY-JUN PY 2016 VL 3 IS 3 DI 10.1523/ENEURO.0064-16.2016 PG 13 WC Neurosciences SC Neurosciences & Neurology GA EH7BH UT WOS:000391927300009 ER PT J AU Orru, CD Hughson, AG Groveman, BR Campbell, KJ Anson, KJ Manca, M Kraus, A Caughey, B AF Orru, Christina D. Hughson, Andrew G. Groveman, Bradley R. Campbell, Katrina J. Anson, Kelsie J. Manca, Matteo Kraus, Allison Caughey, Byron TI Factors That Improve RT-QuIC Detection of Prion Seeding Activity SO VIRUSES-BASEL LA English DT Article DE prion; CJD; olfactory mucosa; RT-QuIC; scrapie; CWD; BSE ID QUAKING-INDUCED CONVERSION; CREUTZFELDT-JAKOB-DISEASE; BOVINE SPONGIFORM ENCEPHALOPATHY; NASAL BRUSHINGS; CEREBROSPINAL-FLUID; LYSINE CLUSTER; PRP AMYLOIDS; DISCRIMINATION; TISSUES AB Rapid and sensitive detection of prions is important in managing prion diseases. The real-time quaking-induced conversion (RT-QuIC) assay for prion seeding activity has been applied to many prion diseases and provides for specific antemortem diagnostic testing. We evaluated RT-QuIC's long-term consistency and varied multiple reaction parameters. Repeated assays of a single scrapie sample using multiple plate readers and recombinant prion protein (rPrP(Sen)) substrates gave comparable results. N-terminal truncated hamster rPrP(Sen) (residues 90-231) hastened both prion-seeded and prion-independent reactions but maintained a clear kinetic distinction between the two. Raising temperatures or shaking speeds accelerated RT-QuIC reactions without compromising specificity. When applied to nasal brushings from Creutzfeldt-Jakob disease patients, higher temperatures accelerated RT-QuIC kinetics, and the use of hamster rPrP(Sen) (90-231) strengthened RT-QuIC responses. Elongation of shaking periods reduced scrapie-seeded reaction times, but continuous shaking promoted false-positive reactions. Furthermore, pH 7.4 provided for more rapid RT-QuIC reactions than more acidic pHs. Additionally, we show that small variations in the amount of sodium dodecyl sulfate (SDS) significantly impacted the assay. Finally, RT-QuIC performed in multiplate thermoshakers followed by fluorescence readings in separate plate readers enhanced assay throughput economically. Collectively, these results demonstrate improved speed, efficacy and practicality of RT-QuIC assays and highlight variables to be optimized for future applications. C1 [Orru, Christina D.; Hughson, Andrew G.; Groveman, Bradley R.; Campbell, Katrina J.; Anson, Kelsie J.; Manca, Matteo; Kraus, Allison; Caughey, Byron] NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. RP Caughey, B (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. EM christina.orru@nih.gov; ahughson@niaid.nih.gov; bradley.groveman@nih.gov; katrina.campbell@nih.gov; kelsiejaness@gmail.com; matteo.manca@nih.gov; allison.kraus@nih.gov; bcaughey@nih.gov FU NIAID, a Foundation Alliance Biosecure grant FX We thank Roger Moore, James Carrol and Kentaro Masujin for critical review of this manuscript; and Anita Mora and Austin Athman for graphics assistance. We are thankful to Gianluigi Zanusso for providing us with human olfactory mucosa samples. This work was supported by the Intramural Research Program of the NIAID, a Foundation Alliance Biosecure grant to C.D.O. NR 29 TC 1 Z9 1 U1 2 U2 2 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD MAY PY 2016 VL 8 IS 5 AR 140 DI 10.3390/v8050140 PG 17 WC Virology SC Virology GA DN9VU UT WOS:000377429600023 ER PT J AU Hingorani, P Janeway, K Crompton, BD Kadoch, C Mackall, CL Khan, J Shern, JF Schiffman, J Mirabello, L Savage, SA Ladanyi, M Meltzer, P Bult, CJ Adamson, PC Lupo, PJ Mody, R DuBois, SG Parsons, DW Khanna, C Lau, C Hawkins, DS Randall, RL Smith, M Sorensen, PH Plon, SE Skapek, SX Lessnick, S Gorlick, R Reed, DR AF Hingorani, Pooja Janeway, Katherine Crompton, Brian D. Kadoch, Cigall Mackall, Crystal L. Khan, Javed Shern, Jack F. Schiffman, Joshua Mirabello, Lisa Savage, Sharon A. Ladanyi, Marc Meltzer, Paul Bult, Carol J. Adamson, Peter C. Lupo, Philip J. Mody, Rajen DuBois, Steven G. Parsons, D. Williams Khanna, Chand Lau, Ching Hawkins, Douglas S. Randall, R. Lor Smith, Malcolm Sorensen, Poul H. Plon, Sharon E. Skapek, Stephen X. Lessnick, Stephen Gorlick, Richard Reed, Damon R. TI Current state of pediatric sarcoma biology and opportunities for future discovery: A report from the sarcoma translational research workshop SO Cancer Genetics LA English DT Review DE Pediatric sarcoma; genomics; precision medicine; molecular profiling; patient derived xenografts; sarcoma biology ID CHILDRENS ONCOLOGY GROUP; LOCALIZED EWING SARCOMA; EMBRYONAL RHABDOMYOSARCOMA; CHILDHOOD RHABDOMYOSARCOMA; GENOMIC LANDSCAPE; CANCER-PATIENTS; GENE FUSION; OSTEOSARCOMA; TUMORS; FAMILY AB Sarcomas are a rare subgroup of pediatric cancers comprised of a variety of bone and soft tissue tumors. While significant advances have been made in improving outcomes of patients with localized pediatric sarcomas since the addition of systemic chemotherapy to local control many decades ago, outcomes for patients with metastatic and relapsed sarcoma remain poor with few novel therapeutics identified to date. With the advent of new technologies to study cancer genomes, transcriptomes and epigenomes, our understanding of sarcoma biology has improved tremendously in a relatively short period of time. However, much remains to be accomplished in this arena especially with regard to translating all of this new knowledge to the bedside. To this end, a meeting was convened in Philadelphia, PA, on April 18, 2015 sponsored by the QuadW foundation, Children's Oncology Group and CureSearch for Children's Cancer that brought to-gether sarcoma clinicians and scientists from North America to review the current state of pediatric sarcoma biology and ongoing/planned genomics based clinical trials in an effort to identify and bridge knowledge gaps that continue to exist at present. At the conclusion of the workshop, three key objectives that would significantly further our understanding of sarcoma were identified and a proposal was put forward to develop an all-encompassing pediatric sarcoma biology protocol that would address these specific needs. This review summarizes the proceedings of the workshop. C1 [Hingorani, Pooja] Phoenix Childrens Hosp, Ctr Canc & Blood Disorders, Phoenix, AZ 85016 USA. [Janeway, Katherine; Crompton, Brian D.; Kadoch, Cigall; DuBois, Steven G.] Dana Farber Canc Inst, Dept Pediat Hematol Oncol, Boston, MA 02115 USA. [Janeway, Katherine; Crompton, Brian D.; Kadoch, Cigall; DuBois, Steven G.] Boston Childrens Hosp, Boston, MA USA. [Mackall, Crystal L.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Khan, Javed; Shern, Jack F.; Meltzer, Paul] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Schiffman, Joshua; Randall, R. Lor] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. [Schiffman, Joshua; Randall, R. Lor] Univ Utah, Primary Childrens Med Ctr, Salt Lake City, UT USA. [Mirabello, Lisa; Savage, Sharon A.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Ladanyi, Marc] Mem Sloan Kettering Canc Ctr, Dept Pathol, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA. [Bult, Carol J.] Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. [Adamson, Peter C.] Childrens Hosp Philadelphia, Div Clin Pharmacol & Therapeut, Philadelphia, PA 19104 USA. [Lupo, Philip J.; Lau, Ching] Baylor Coll Med, Dept Pediat, Hematol Oncol Sect, Houston, TX 77030 USA. [Mody, Rajen] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Parsons, D. Williams; Plon, Sharon E.] Baylor Coll Med, Texas Childrens Canc Ctr, Houston, TX 77030 USA. [Khanna, Chand] NCI, Mol Oncol Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hawkins, Douglas S.] Univ Washington, Seattle Childrens Hosp, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. [Smith, Malcolm] NCI, NIH, Bethesda, MD 20892 USA. [Sorensen, Poul H.] Univ British Columbia, Dept Pathol, Vancouver, BC, Canada. [Sorensen, Poul H.] BC Canc Res Ctr, Dept Mol Oncol, Vancouver, BC, Canada. [Skapek, Stephen X.] Univ Texas Southwestern Med Ctr Dallas, Div Hematol Oncol, Dallas, TX 75390 USA. [Lessnick, Stephen] Nationwide Childrens Hosp, Div Hematol Oncol, Columbus, OH USA. [Gorlick, Richard] Albert Einstein Coll Med, Childrens Hosp Montefiore, Div Pediat Hematol Oncol, Bronx, NY 10467 USA. [Reed, Damon R.] H Lee Moffitt Canc Ctr & Res Inst, Sarcoma Dept, Adolescent & Young Adult Program, Tampa, FL USA. RP Hingorani, P (reprint author), Phoenix Childrens Hosp, Ctr Canc & Blood Disorders, Phoenix, AZ 85016 USA. EM phingorani@phoenixchildrens.com RI Khan, Javed/P-9157-2014 OI Khan, Javed/0000-0002-5858-0488 FU NCI NIH HHS [P30 CA008748] NR 61 TC 2 Z9 2 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2210-7762 EI 2210-7770 J9 CANCER GENET-NY JI Cancer Genet. PD MAY PY 2016 VL 209 IS 5 BP 182 EP 194 DI 10.1016/j.cancergen.2016.03.004 PG 13 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA ED8ZT UT WOS:000389160300002 PM 27132463 ER PT J AU Yadav, SP Sharma, NK Liu, CQ Dong, LJ Li, TS Swaroop, A AF Yadav, Sharda Prasad Sharma, Neel Kamal Liu, Chunqiao Dong, Lijin Li, Tiansen Swaroop, Anand TI Centrosomal protein CP110 controls maturation of the mother centriole during cilia biogenesis SO DEVELOPMENT LA English DT Article DE Centrosome; Ciliopathies; Microtubule; Primary cilia; Organogenesis; Membrane anchoring; Ccp110; Mouse ID MICROTUBULE ORGANIZATION; CELLS ANTENNA; CILIOGENESIS; DISEASE; MOUSE; CILIOPATHIES; DUPLICATION; APPENDAGES; CEP290; INACTIVATION AB Defects in cilia centrosomal genes cause pleiotropic clinical phenotypes, collectively called ciliopathies. Cilia biogenesis is initiated by the interaction of positive and negative regulators. Centriolar coiled coil protein 110 (CP110) caps the distal end of the mother centriole and is known to act as a suppressor to control the timing of ciliogenesis. Here, we demonstrate that CP110 promotes cilia formation in vivo, in contrast to findings in cultured cells. Cp110(-/-) mice die shortly after birth owing to organogenesis defects as in ciliopathies. Shh signaling is impaired in null embryos and primary cilia are reduced in multiple tissues. We show that CP110 is required for anchoring of basal bodies to the membrane during cilia formation. CP110 loss resulted in an abnormal distribution of core components of subdistal appendages (SDAs) and of recycling endosomes, which may be associated with premature extension of axonemal microtubules. Our data implicate CP110 in SDA assembly and ciliary vesicle docking, two requisite early steps in cilia formation. We suggest that CP110 has unique context-dependent functions, acting as both a suppressor and a promoter of ciliogenesis. C1 [Yadav, Sharda Prasad; Sharma, Neel Kamal; Liu, Chunqiao; Li, Tiansen; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Dong, Lijin] NEI, Genet Engn Core, NIH, Bethesda, MD 20892 USA. [Liu, Chunqiao] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, Guangzhou 510060, Guangdong, Peoples R China. RP Yadav, SP; Li, TS; Swaroop, A (reprint author), NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. EM yadavsh@mail.nih.gov; tiansen.li@nih.gov; swaroopa@nei.nih.gov FU National Eye Institute, National Institutes of Health [EY000450, EY000473] FX This research was supported by the Intramural Research Program of the National Eye Institute, National Institutes of Health [EY000450 and EY000473]. Deposited in PMC for immediate release. NR 58 TC 3 Z9 4 U1 0 U2 0 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 EI 1477-9129 J9 DEVELOPMENT JI Development PD MAY 1 PY 2016 VL 143 IS 9 BP 1491 EP 1501 DI 10.1242/dev.130120 PG 11 WC Developmental Biology SC Developmental Biology GA EE4QC UT WOS:000389588100007 PM 26965371 ER PT J AU Range, RC Wei, Z AF Range, Ryan C. Wei, Zheng TI An anterior signaling center patterns and sizes the anterior neuroectoderm of the sea urchin embryo SO DEVELOPMENT LA English DT Article DE Neuroectoderm patterning; Wnt signal transduction; Anterior-posterior; Deuterostome evolution; Gene regulatory networks; Dkk3; sFRP1/5; Strongylocentrotus purpuratus ID FRIZZLED-RELATED PROTEIN-1; HEMICHORDATE SACCOGLOSSUS-KOWALEVSKII; WNT/BETA-CATENIN; NEMATOSTELLA-VECTENSIS; NEURAL DEVELOPMENT; VERTEBRATE BRAIN; BETA-CATENIN; WNT; AMPHIOXUS; GENE AB Anterior signaling centers help specify and pattern the early anterior neuroectoderm (ANE) in many deuterostomes. In sea urchin the ANE is restricted to the anterior of the late blastula stage embryo, where it forms a simple neural territory comprising several types of neurons as well as the apical tuft. Here, we show that during early development, the sea urchin ANE territory separates into inner and outer regulatory domains that express the cardinal ANE transcriptional regulators FoxQ2 and Six3, respectively. FoxQ2 drives this patterning process, which is required to eliminate six3 expression from the inner domain and activate the expression of Dkk3 and sFRP1/5, two secreted Wnt modulators. Dkk3 and low expression levels of sFRP1/5 act additively to potentiate the Wnt/JNK signaling pathway governing the positioning of the ANE territory around the anterior pole, whereas high expression levels of sFRP1/5 antagonize Wnt/JNK signaling. sFRP1/5 and Dkk3 levels are rigidly maintained via autorepressive and cross-repressive interactions with Wnt signaling components and additional ANE transcription factors. Together, these data support a model in which FoxQ2 initiates an anterior patterning center that implements correct size and positions of ANE structures. Comparisons of functional and expression studies in sea urchin, hemichordate and chordate embryos reveal striking similarities among deuterostome ANE regulatory networks and the molecular mechanism that positions and defines ANE borders. These data strongly support the idea that the sea urchin embryo uses an ancient anterior patterning system that was present in the common ambulacrarian/chordate ancestor. C1 [Range, Ryan C.; Wei, Zheng] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. [Range, Ryan C.] Mississippi State Univ, Dept Biol Sci, Mississippi State, MS 39762 USA. RP Range, RC (reprint author), Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA.; Range, RC (reprint author), Mississippi State Univ, Dept Biol Sci, Mississippi State, MS 39762 USA. EM range@biology.msstate.edu FU National Institutes of Health (NIDCR) [ZO1DE000712]; Mississippi State University FX This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIDCR) [grant number ZO1DE000712], as well as startup funding from Mississippi State University. Deposited in PMC for release after 12 months. NR 59 TC 2 Z9 2 U1 2 U2 2 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 EI 1477-9129 J9 DEVELOPMENT JI Development PD MAY 1 PY 2016 VL 143 IS 9 BP 1523 EP 1533 DI 10.1242/dev.128165 PG 11 WC Developmental Biology SC Developmental Biology GA EE4QC UT WOS:000389588100010 PM 26952978 ER PT J AU El-Maouche, D Welch, J Agarwal, SK Weinstein, LS Simonds, WF Marx, SJ AF El-Maouche, Diala Welch, James Agarwal, Sunita K. Weinstein, Lee S. Simonds, William F. Marx, Stephen J. TI A patient with MEN1 typical features and MEN2-like features SO INTERNATIONAL JOURNAL OF ENDOCRINE ONCOLOGY LA English DT Article DE 1132delG; G691S; MEN1; MEN2; MEN4; MENX; multiple endocrine neoplasias; R982C ID MULTIPLE-ENDOCRINE-NEOPLASIA; MEDULLARY-THYROID CARCINOMA; FUNCTIONAL-CHARACTERIZATION; G691S POLYMORPHISM; RET PROTOONCOGENE; CORNEAL NERVES; TYPE-1; MUTATIONS; ASSOCIATION; PENETRANCE AB Multiple endocrine neoplasia (MEN) type 1 (MEN1) and 2 (MEN2) rarely co-exist in one case. Here we report a patient with features of both syndromes. The patient presented with typical MEN1 features plus pheochromocytoma and thickened corneal nerves. She had a germline 1132delG frameshift mutation in MEN1, no mutation in CDKN1B (p27) and no RET mutation, but had both RET polymorphisms Gly691Ser and Arg982Cys. This is the first case report of a combination of typical clinical findings of MEN1 harboring a germline MEN1 mutation and the MEN2-like phenotype with negative full RET gene analysis of pathogenic variants. Possible explanations include a previously unrecognized phenotype-genotype association or the influence of potential phenotypic modifying RET variants. Furthermore, the combination observed in this patient may point to a single molecular pathway, and supports the possibility of as yet unrecognized connections between the molecular pathways for MEN1 / menin protein and MEN2 / RET protein. C1 [El-Maouche, Diala] Univ Miami, Miller Sch Med, Div Endocrinol Diabet & Metab, Miami, FL 33136 USA. [El-Maouche, Diala] NIDCR, NIH, Bethesda, MD 20892 USA. [Welch, James; Agarwal, Sunita K.; Weinstein, Lee S.; Simonds, William F.; Marx, Stephen J.] NIDDK, NIH, Bethesda, MD 20892 USA. RP El-Maouche, D (reprint author), Univ Miami, Miller Sch Med, Div Endocrinol Diabet & Metab, Miami, FL 33136 USA.; El-Maouche, D (reprint author), NIDCR, NIH, Bethesda, MD 20892 USA. EM dxe90@miami.edu RI Agarwal, Sunita/D-1428-2016 OI Agarwal, Sunita/0000-0002-7557-3191 FU Intramural NIH HHS [Z99 HD999999, Z01 DK043009-21, Z01 DK043322-01, Z99 DE999999, Z99 DK999999] NR 34 TC 0 Z9 0 U1 0 U2 0 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 2045-0869 EI 2045-0877 J9 INT J ENDOCR ONCOL JI Int. J. Endocr. Oncol. PD MAY PY 2016 VL 3 IS 2 BP 89 EP 95 DI 10.2217/ije-2015-0008 PG 7 WC Oncology SC Oncology GA EB6NL UT WOS:000387500800002 PM 27594983 ER PT J AU McDuffie, LA Aufforth, RD AF McDuffie, Lucas A. Aufforth, Rachel D. TI Adrenocortical carcinoma: modern management and evolving treatment strategies SO INTERNATIONAL JOURNAL OF ENDOCRINE ONCOLOGY LA English DT Review DE ACC; adrenal cancer; adrenal surgery; adrenocortical carcinoma; Ki-67; Mitotane; Weisse score ID LONG-TERM SURVIVAL; ADRENAL-TUMORS; LAPAROSCOPIC ADRENALECTOMY; SURGICAL-MANAGEMENT; COMPLETE RESECTION; PROGNOSTIC-FACTORS; RADIATION-THERAPY; ADJUVANT MITOTANE; LOCAL RECURRENCE; ADULT PATIENTS AB Adrenocortical carcinoma (ACC) is a rare cancer with a poor prognosis. Unlike many other cancers, there has been little improvement in patient outcome over the past several decades. However, as scientific advancements are made and our understanding of the molecular genetics involved in ACC improve then progress may be achieved in this devastating disease. This review focuses on recent literature published in the field of ACC from 2010 to 2015 with an emphasis on improving diagnosis, staging and treatment for ACC. C1 [McDuffie, Lucas A.] NCI, Thorac & Gastrointestinal Oncol Branch, NIH, Bethesda, MD 20892 USA. [Aufforth, Rachel D.] St Agnes Hosp, Dept Surg, Baltimore, MD 21229 USA. RP Aufforth, RD (reprint author), St Agnes Hosp, Dept Surg, Baltimore, MD 21229 USA. EM rachel.aufforth@stagnes.org FU Intramural NIH HHS [Z99 CA999999] NR 99 TC 1 Z9 1 U1 3 U2 3 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 2045-0869 EI 2045-0877 J9 INT J ENDOCR ONCOL JI Int. J. Endocr. Oncol. PD MAY PY 2016 VL 3 IS 2 BP 161 EP 174 DI 10.2217/ije-2015-0003 PG 14 WC Oncology SC Oncology GA EB6NL UT WOS:000387500800008 PM 27213037 ER PT J AU Khan, J Helman, LJ AF Khan, Javed Helman, Lee J. TI Precision Therapy for Pediatric Cancers SO JAMA ONCOLOGY LA English DT Editorial Material ID NEUROBLASTOMAS; LANDSCAPE C1 [Khan, Javed] NCI, Oncogen Sect, Genet Branch, Bldg 37,37 Convent Dr, Bethesda, MD 20892 USA. [Helman, Lee J.] NCI, Ctr Canc Res, Mol Oncol Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Khan, J (reprint author), NCI, Oncogen Sect, Genet Branch, Bldg 37,37 Convent Dr, Bethesda, MD 20892 USA. EM khanjav@mail.nih.gov RI Khan, Javed/P-9157-2014 OI Khan, Javed/0000-0002-5858-0488 NR 11 TC 2 Z9 2 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD MAY PY 2016 VL 2 IS 5 BP 575 EP 577 DI 10.1001/jamaoncol.2015.5685 PG 3 WC Oncology SC Oncology GA DW5KS UT WOS:000383684300005 ER PT J AU Lee, JJ Britton, KA Pedley, A Massaro, JM Speliotes, EK Murabito, JM Hoffmann, U Ingram, C Keaney, JF Vasan, RS Fox, CS AF Lee, Jane J. Britton, Kathryn A. Pedley, Alison Massaro, Joseph M. Speliotes, Elizabeth K. Murabito, Joanne M. Hoffmann, Udo Ingram, Cheryl Keaney, John F., Jr. Vasan, Ramachandran S. Fox, Caroline S. TI Adipose Tissue Depots and Their Cross-Sectional Associations With Circulating Biomarkers of Metabolic Regulation SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE adipokines; adipose tissue; biomarkers; epidemiology; obesity ID NONALCOHOLIC FATTY LIVER; SOLUBLE LEPTIN RECEPTOR; NECROSIS-FACTOR-ALPHA; II DIABETES-MELLITUS; ACID-BINDING PROTEIN; INSULIN-RESISTANCE; RISK-FACTORS; CARDIOVASCULAR-DISEASE; VISCERAL FAT; FETUIN-A AB Background-Visceral adipose tissue (VAT) and fatty liver differ in their associations with cardiovascular risk compared with subcutaneous adipose tissue (SAT). Several biomarkers have been linked to metabolic derangements and may contribute to the pathogenicity of fat depots. We examined the association between fat depots on multidetector computed tomography and metabolic regulatory biomarkers. Methods and Results-Participants from the Framingham Heart Study (n= 1583, 47% women) underwent assessment of SAT, VAT, and liver attenuation. We measured circulating biomarkers secreted by adipose tissue or liver (adiponectin, leptin, leptin receptor, fatty acid binding protein 4, fetuin-A, and retinol binding protein 4). Using multivariable linear regression models, we examined relations of fat depots with biomarkers. Higher levels of fat depots were positively associated with leptin and fatty acid binding protein 4 but negatively associated with adiponectin (all P< 0.001). Associations with leptin receptor, fetuin-A, and retinol binding protein 4 varied according to fat depot type or sex. When comparing the associations of SAT and VAT with biomarkers, VAT was the stronger correlate of adiponectin (beta = -0.28 [women]; beta= -0.30 [men]; both P< 0.001), whereas SAT was the stronger correlate of leptin (b= 0.62 [women]; b= 0.49 [men]; both P< 0.001; P< 0.001 for comparing VAT versus SAT). Although fetuin-A and retinol binding protein 4 are secreted by the liver in addition to adipose tissue, associations of liver attenuation with these biomarkers was not stronger than that of SAT or VAT. Conclusions-SAT, VAT, and liver attenuation are associated with metabolic regulatory biomarkers with differences in the associations by fat depot type and sex. These findings support the possibility of biological differences between fat depots. C1 [Lee, Jane J.; Britton, Kathryn A.; Pedley, Alison; Massaro, Joseph M.; Vasan, Ramachandran S.; Fox, Caroline S.] NHLBI, Framingham, MA USA. [Lee, Jane J.; Britton, Kathryn A.; Pedley, Alison; Massaro, Joseph M.; Vasan, Ramachandran S.; Fox, Caroline S.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Britton, Kathryn A.] Brigham & Womens Hosp, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, 75 Francis St, Boston, MA 02115 USA. [Britton, Kathryn A.] Harvard Med Sch, Boston, MA USA. [Massaro, Joseph M.] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Speliotes, Elizabeth K.] Univ Michigan, Dept Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Evans Dept Med,Sect Cardiol, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Evans Dept Med,Sect Prevent Med, Boston, MA 02118 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Ingram, Cheryl; Keaney, John F., Jr.] Univ Massachusetts, Sch Med, Div Cardiovasc Med, Worcester, MA USA. [Vasan, Ramachandran S.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov FU National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]; National Institutes of Health [K23DK080145]; Doris Duke Medical Foundation; University of Michigan Internal Medicine Department, Division of Gastroenterology, and Biological Sciences Scholars Program; [R01DK080739]; [K12 HL083786] FX This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (contract N01-HC-25195) and by R01DK080739. Dr Britton was supported by Research Career Development Award K12 HL083786 and Dr Speliotes was supported by National Institutes of Health grant K23DK080145, the Doris Duke Medical Foundation, and the University of Michigan Internal Medicine Department, Division of Gastroenterology, and Biological Sciences Scholars Program. NR 68 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD MAY PY 2016 VL 5 IS 5 AR e002936 DI 10.1161/JAHA.115.002936 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA6BY UT WOS:000386711200015 ER PT J AU Li, WY Wilker, EH Dorans, KS Rice, MB Schwartz, J Coull, BA Koutrakis, P Gold, DR Keaney, JF Lin, HH Vasan, RS Benjamin, EJ Mittleman, MA AF Li, Wenyuan Wilker, Elissa H. Dorans, Kirsten S. Rice, Mary B. Schwartz, Joel Coull, Brent A. Koutrakis, Petros Gold, Diane R. Keaney, John F., Jr. Lin, Honghuang Vasan, Ramachandran S. Benjamin, Emelia J. Mittleman, Murray A. TI Short-Term Exposure to Air Pollution and Biomarkers of Oxidative Stress: The Framingham Heart Study SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE air pollution; isoprostanes; myeloperoxidase ID ACUTE ISCHEMIC-STROKE; HEALTHY-YOUNG ADULTS; NEW-YORK-CITY; LIPID-PEROXIDATION; PARTICULATE MATTER; CARDIOVASCULAR-DISEASE; SYSTEMIC INFLAMMATION; MYOCARDIAL-INFARCTION; AIRBORNE PARTICLES; DIESEL EXHAUST AB Background-Short-term exposure to elevated air pollution has been associated with higher risk of acute cardiovascular diseases, with systemic oxidative stress induced by air pollution hypothesized as an important underlying mechanism. However, few community-based studies have assessed this association. Methods and Results-Two thousand thirty-five Framingham Offspring Cohort participants living within 50 km of the Harvard Boston Supersite who were not current smokers were included. We assessed circulating biomarkers of oxidative stress including blood myeloperoxidase at the seventh examination (1998-2001) and urinary creatinine-indexed 8-epi-prostaglandin F-2 alpha (8-epi-PGF(2 alpha)) at the seventh and eighth (2005-2008) examinations. We measured fine particulate matter (PM2.5), black carbon, sulfate, nitrogen oxides, and ozone at the Supersite and calculated 1-, 2-, 3-, 5-, and 7-day moving averages of each pollutant. Measured myeloperoxidase and 8-epi-PGF(2 alpha) were loge transformed. We used linear regression models and linear mixed-effects models with random intercepts for myeloperoxidase and indexed 8-epi-PGF(2 alpha), respectively. Models were adjusted for demographic variables, individual-and area-level measures of socioeconomic position, clinical and lifestyle factors, weather, and temporal trend. We found positive associations of PM2.5 and black carbon with myeloperoxidase across multiple moving averages. Additionally, 2-to 7-day moving averages of PM2.5 and sulfate were consistently positively associated with 8-epi-PGF(2 alpha). Stronger positive associations of black carbon and sulfate with myeloperoxidase were observed among participants with diabetes than in those without. Conclusions-Our community-based investigation supports an association of select markers of ambient air pollution with circulating biomarkers of oxidative stress. C1 [Li, Wenyuan; Dorans, Kirsten S.; Schwartz, Joel; Mittleman, Murray A.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Wilker, Elissa H.; Schwartz, Joel; Koutrakis, Petros; Gold, Diane R.] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Coull, Brent A.] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Li, Wenyuan; Wilker, Elissa H.; Dorans, Kirsten S.; Rice, Mary B.; Mittleman, Murray A.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Cardiol, Cardiovasc Epidemiol Res Unit, Boston, MA USA. [Rice, Mary B.] Beth Israel Deaconess Med Ctr, Div Pulm Crit Care & Sleep Med, Boston, MA 02215 USA. [Keaney, John F., Jr.] Univ Massachusetts, Sch Med, Div Cardiovasc Med, Worcester, MA USA. [Lin, Honghuang; Vasan, Ramachandran S.; Benjamin, Emelia J.] NHLBI, Framingham, MA USA. [Lin, Honghuang; Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ Framingham Heart Study, Framingham, MA USA. [Lin, Honghuang; Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Prevent Med Sect, Boston, MA 02118 USA. [Lin, Honghuang; Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Cardiovasc Med Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Mittleman, MA (reprint author), Harvard TH Chan Sch Publ Hlth, 677 Huntington Ave,Suite 505, Boston, MA 02215 USA. EM mmittlem@hsph.harvard.edu OI Li, Wenyuan/0000-0001-6196-9964; Dorans, Kirsten/0000-0002-3182-5633 FU USEPA [RD-83479801]; National Heart, Lung, and Blood Institute of the National Institutes of Health [HHSN268201500001I, N01-HC 25195, 1RO1HL64753, R01HL076784, 1R01AG028321, T32HL007575]; National Institutes of Environmental Health Sciences [1F32ES023352-01, P30ES000002] FX This publication was made possible by USEPA grant RD-83479801. Its contents are solely the responsibility of the grantee and do not necessarily represent the official views of the USEPA. Further, USEPA does not endorse the purchase of any commercial products or services mentioned in the publication. This work was further supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health contracts and grants HHSN268201500001I, N01-HC 25195, 1RO1HL64753, R01HL076784, 1R01AG028321, and T32HL007575 and National Institutes of Environmental Health Sciences grants 1F32ES023352-01 and P30ES000002. NR 48 TC 0 Z9 0 U1 6 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD MAY PY 2016 VL 5 IS 5 AR e002742 DI 10.1161/JAHA.115.002742 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA6BY UT WOS:000386711200008 ER PT J AU Khan, I Arany, PR AF Khan, Imran Arany, Praveen R. TI Dosimetry for photobiomodulation therapy: response to Sommers et al. SO ANNALS OF TRANSLATIONAL MEDICINE LA English DT Letter ID STRESS C1 [Khan, Imran; Arany, Praveen R.] NIDCR, Cell Regulat & Control Unit, NIH, Bethesda, MD USA. [Arany, Praveen R.] Univ Buffalo, Sch Dent Med, Oral Biol, Buffalo, NY USA. RP Arany, PR (reprint author), 3435 Main St,B36A,Foster Hall, Buffalo, NY 14214 USA. EM prarany@buffalo.edu NR 9 TC 0 Z9 0 U1 0 U2 0 PU AME PUBL CO PI SHEUNG WAN PA ROOM 604 6-F HOLLYWOOD CENTER, 77-91, QUEENS ROAD, SHEUNG WAN, HONG KONG 00000, PEOPLES R CHINA SN 2305-5839 EI 2305-5847 J9 ANN TRANSL MED JI ANN. TRANSL. MED. PD MAY PY 2016 VL 4 IS 10 AR 208 DI 10.21037/atm.2016.05.34 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DY0NF UT WOS:000384792800022 PM 27294101 ER PT J AU Cho, HJ Hallett, M AF Cho, Hyun Joo Hallett, Mark TI Non-Invasive Brain Stimulation for Treatment of Focal Hand Dystonia: Update and Future Direction SO JOURNAL OF MOVEMENT DISORDERS LA English DT Review DE Focal hand dystonia; Non-invasive brain stimulation; Transcranial magnetic stimulation; Transcranial direct current stimulation ID TRANSCRANIAL MAGNETIC STIMULATION; HUMAN MOTOR CORTEX; WRITERS CRAMP; MUSICIANS DYSTONIA; SOMATOSENSORY CORTEX; PREMOTOR CORTEX; REPETITIVE TMS; EXCITABILITY; INHIBITION; NEUROREHABILITATION AB Focal hand dystonia (FHD) is characterized by excessive and unwanted muscle activation in both the hand and arm resulting in impaired performance in particular tasks. Understanding the pathophysiology of FHD has progressed significantly for several decades and this has led to consideration of other potential therapies such as non-invasive brain stimulation (NIBS). A number of studies have been conducted to develop new therapy for FHD using transcranial magnetic stimulation and transcranial direct current stimulation. In this paper, we review previous studies and describe the potential therapeutic use of NIBS for FHD. We also discuss the future direction of NIBS to treat FHD. C1 [Cho, Hyun Joo; Hallett, Mark] NINDS, Human Motor Control Sect, NIH, 10 Ctr Dr,MSC 1428,Bldg 10,Room 7D37, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, NIH, 10 Ctr Dr,MSC 1428,Bldg 10,Room 7D37, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov NR 39 TC 1 Z9 1 U1 2 U2 2 PU KOREAN MOVEMENT DISORDERS SOC PI SEOUL PA 2011 MAPO HANWHA OBELISK, 555, DOHWA-DONG, MAPO-GU, SEOUL, 04167, SOUTH KOREA SN 2005-940X EI 2093-4939 J9 J MOV DISORD JI J. Mov. Disord. PD MAY PY 2016 VL 9 IS 2 BP 55 EP 62 DI 10.14802/jmd.16014 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA DX8MJ UT WOS:000384642600001 PM 27240806 ER PT J AU Park, JE Ramos, VFML Hallett, M AF Park, Jung E. Ramos, Vesper Fe Marie L. Hallett, Mark TI Tremor in a Bassoonist: Tremor in Dystonia or Essential Tremor? SO JOURNAL OF MOVEMENT DISORDERS LA English DT Letter ID TEMPORAL DISCRIMINATION C1 [Park, Jung E.; Ramos, Vesper Fe Marie L.; Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bldg 10,Room 7D42,10 Ctr Dr, Bethesda, MD 20892 USA. [Park, Jung E.] Dongguk Univ, Dept Neurol, Ilsan Hosp, Goyang, South Korea. [Ramos, Vesper Fe Marie L.] US FDA, Ctr Devices & Radiol Hlth, Off Device Evaluat, Div Neurol & Phys Med,Neurodiagnost & Neurosurg D, White Oak, MD USA. RP Park, JE (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 10,Room 7D42,10 Ctr Dr, Bethesda, MD 20892 USA. EM junge.park@nih.gov NR 7 TC 0 Z9 0 U1 0 U2 0 PU KOREAN MOVEMENT DISORDERS SOC PI SEOUL PA 2011 MAPO HANWHA OBELISK, 555, DOHWA-DONG, MAPO-GU, SEOUL, 04167, SOUTH KOREA SN 2005-940X EI 2093-4939 J9 J MOV DISORD JI J. Mov. Disord. PD MAY PY 2016 VL 9 IS 2 BP 124 EP 125 DI 10.14802/jmd.15054 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA DX8MJ UT WOS:000384642600010 ER PT J AU Qian, H Ruan, Y Liu, Y Spiegel, H Yin, L Li, D Shepherd, B Shao, Y Vermund, S Milam, D AF Qian, H. Ruan, Y. Liu, Y. Spiegel, H. Yin, L. Li, D. Shepherd, B. Shao, Y. Vermund, S. Milam, D. TI IMPACT OF ANAL SEX ROLE ON THE HIV PROTECTIVE EFFECT OF CIRCUMCISION IN MSM SO JOURNAL OF SEXUAL MEDICINE LA English DT Meeting Abstract C1 [Qian, H.; Liu, Y.; Yin, L.; Shepherd, B.; Vermund, S.; Milam, D.] Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA. [Ruan, Y.] Collaborat Inov Ctr, Beijing, Peoples R China. [Spiegel, H.] NIH, Jackson Fdn, Bldg 10, Bethesda, MD 20892 USA. [Li, D.] Chaoyang CDC, Chaoyang, Peoples R China. [Shao, Y.] Chinese CDC, Beijing, Peoples R China. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1743-6095 EI 1743-6109 J9 J SEX MED JI J. Sex. Med. PD MAY PY 2016 VL 13 IS 5 SU 1 MA 051 BP S25 EP S25 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA DX9RN UT WOS:000384732900052 ER PT J AU Conlan, S Park, M Deming, C Thomas, PJ Young, AC Coleman, H Sison, C Weingarten, RA Lau, AF Dekker, JP Palmore, TN Frank, KM Segre, JA AF Conlan, Sean Park, Morgan Deming, Clayton Thomas, Pamela J. Young, Alice C. Coleman, Holly Sison, Christina Weingarten, Rebecca A. Lau, Anna F. Dekker, John P. Palmore, Tara N. Frank, Karen M. Segre, Julia A. CA NISC Comparative Sequencing TI Plasmid Dynamics in KPC-Positive Klebsiella pneumoniae during Long-Term Patient Colonization SO MBIO LA English DT Article ID COMPARATIVE GENOMICS; ESCHERICHIA-COLI; ENTEROBACTERIACEAE; IDENTIFICATION; EPIDEMIOLOGY; HOSPITALS; CARRIAGE; SEQUENCE AB Carbapenem-resistant Klebsiella pneumoniae strains are formidable hospital pathogens that pose a serious threat to patients around the globe due to a rising incidence in health care facilities, high mortality rates associated with infection, and potential to spread antibiotic resistance to other bacterial species, such as Escherichia coli. Over 6 months in 2011, 17 patients at the National Institutes of Health (NIH) Clinical Center became colonized with a highly virulent, transmissible carbapenem-resistant strain of K. pneumoniae. Our real-time genomic sequencing tracked patient-to-patient routes of transmission and informed epidemiologists' actions to monitor and control this outbreak. Two of these patients remained colonized with carbapenemase-producing organisms for at least 2 to 4 years, providing the opportunity to undertake a focused genomic study of long-term colonization with antibiotic-resistant bacteria. Whole-genome sequencing studies shed light on the underlying complex microbial colonization, including mixed or evolving bacterial populations and gain or loss of plasmids. Isolates from NIH patient 15 showed complex plasmid rearrangements, leaving the chromosome and the bla(KPC)-carrying plasmid intact but rearranging the two other plasmids of this outbreak strain. NIH patient 16 has shown continuous colonization with bla(KPC)-positive organisms across multiple time points spanning 2011 to 2015. Genomic studies defined a complex pattern of succession and plasmid transmission across two different K. pneumoniae sequence types and an E. coli isolate. These findings demonstrate the utility of genomic methods for understanding strain succession, genome plasticity, and long-term carriage of antibiotic-resistant organisms. IMPORTANCE In 2011, the NIH Clinical Center had a nosocomial outbreak involving 19 patients who became colonized or infected with bla(KPC)-positive Klebsiella pneumoniae. Patients who have intestinal colonization with bla(KPC)-positive K. pneumoniae are at risk for developing infections that are difficult or nearly impossible to treat with existing antibiotic options. Two of those patients remained colonized with bla(KPC)-positive Klebsiella pneumoniae for over a year, leading to the initiation of a detailed genomic analysis exploring mixed colonization, plasmid recombination, and plasmid diversification. Whole-genome sequence analysis identified a variety of changes, both subtle and large, in the bla(KPC)-positive organisms. Long-term colonization of patients with bla(KPC)-positive Klebsiella pneumoniae creates new opportunities for horizontal gene transfer of plasmids encoding antibiotic resistance genes and poses complications for the delivery of health care. C1 [Conlan, Sean; Deming, Clayton; Segre, Julia A.] NHGRI, Bethesda, MD 20892 USA. [Park, Morgan; Thomas, Pamela J.; Young, Alice C.; Coleman, Holly; Sison, Christina; NISC Comparative Sequencing] NIH, Intramural Sequencing Ctr NISC, Rockville, MD USA. [Weingarten, Rebecca A.; Lau, Anna F.; Dekker, John P.; Palmore, Tara N.; Frank, Karen M.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Segre, JA (reprint author), NHGRI, Bethesda, MD 20892 USA. EM jsegre@nhgri.nih.gov FU DH \ National Institute for Health Research (NIHR) [1ZIAHG200382-04]; HHS \ NIH \ NIH Clinical Center (Clinical Center) FX This work, including the efforts of Julia A Segre, was funded by DH vertical bar National Institute for Health Research (NIHR) (1ZIAHG200382-04). This work, including the efforts of Karen M Frank, was funded by HHS vertical bar NIH vertical bar NIH Clinical Center (Clinical Center). NR 26 TC 2 Z9 2 U1 3 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD MAY-JUN PY 2016 VL 7 IS 3 AR e00742-16 DI 10.1128/mBio.00742-16 PG 9 WC Microbiology SC Microbiology GA DW1YP UT WOS:000383440300057 ER PT J AU Mlera, L Lam, J Offerdahl, DK Martens, C Sturdevant, D Turner, CV Porcella, SF Bloom, ME AF Mlera, Luwanika Lam, Jennifer Offerdahl, Danielle K. Martens, Craig Sturdevant, Daniel Turner, Charles V. Porcella, Stephen F. Bloom, Marshall E. TI Transcriptome Analysis Reveals a Signature Profile for Tick-Borne Flavivirus Persistence in HEK 293T Cells SO MBIO LA English DT Article ID JAPANESE ENCEPHALITIS-VIRUS; ENDOPLASMIC-RETICULUM STRESS; UNFOLDED PROTEIN RESPONSE; WEST-NILE-VIRUS; PHOSPHATIDYLINOSITOL 3-KINASE; INFECTION; APOPTOSIS; PATHWAY; DEATH; PANTHER AB Tick-borne flaviviruses (TBFVs) cause febrile illnesses, which may progress to severe encephalitis and/or death in humans globally. Most people who recover from severe acute disease suffer from debilitating neurological sequelae, which may be due to viral persistence, infection-induced neurological cell damage, host response, or some combination of these. Acute TBFV infection of human embryonic kidney (HEK) 293T cells in vitro results in the death of >95% of infected cells by day 5. However, replacing cell growth medium allows surviving cells to repopulate and become persistently infected for extended periods of time. The mechanisms responsible for initiation and maintenance of viral persistence remain vague. We subjected the HEK 293T cell transcriptome to deep sequencing to identify genes differentially expressed during acute infection and persistent infection. A total of 451 genes showed unique significant differential expression levels in persistently infected cells relative to the acute phase of infection. Ingenuity Pathway Analysis results suggested that the expression of prosurvival oncogenes AKT2 and ERBB2 was upregulated in persistently infected cells, whereas proapoptotic genes, such as Bad and the beta interferon 1 (IFN-beta 1) gene, were downregulated. Genes encoding antiviral cytokines such as the CCL5, tumor necrosis factor alpha (TNF-alpha), and CXCL10 genes were upregulated during the acute phase, but the same genes were relatively quiescent in persistently infected cells. Exogenous induction of apoptosis demonstrated that persistently infected cells were resistant to apoptosis in a dose-dependent manner. In summary, the differential transcriptome profiles of acute-phase compared to persistently infected HEK 293T cells demonstrated an evasion of apoptosis, which may be critical for a chronic TBFV infection state. These results provide a basis for further study of the mechanisms of TBFV persistence. IMPORTANCE Tick-borne flaviviruses (TBFVs) cause life-threatening encephalitic disease in humans worldwide. Some people who recover from severe disease may suffer prolonged neurological symptoms due to either virus-or host response-induced cell damage or a combination of the two that are linked to viral persistence. By examining the genes that are significantly differentially expressed in acute TBFV infection versus persistent TBFV infection, we may be able to find the molecular basis of viral persistence. Here we used deep sequencing of the host cell transcriptome to discover that the expression levels of prosurvival genes were upregulated in persistently infected cells relative to acute TBFV infections whereas the expression levels of genes that promote programmed cell death were downregulated. In addition, persistently infected cells were also resistant to exogenous chemical induction of cell death, in a dose-dependent manner, compared to uninfected cells. Our results pave the way for further studies aimed at understanding the precise mechanisms of TBFV persistence. C1 [Mlera, Luwanika; Lam, Jennifer; Offerdahl, Danielle K.; Bloom, Marshall E.] NIAID, Virol Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Martens, Craig; Sturdevant, Daniel; Turner, Charles V.; Porcella, Stephen F.] NIAID, Genom Unit, Res Technol Sect, Rocky Mt Labs, Hamilton, MT USA. RP Mlera, L (reprint author), NIAID, Virol Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM Luwanika.Mlera@nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases (DIR, NIAID) FX This work, including the efforts of Luwanika Mlera and Marshall E. Bloom, was funded by Division of Intramural Research, National Institute of Allergy and Infectious Diseases (DIR, NIAID). NR 66 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD MAY-JUN PY 2016 VL 7 IS 3 AR e00314-16 DI 10.1128/mBio.00314-16 PG 11 WC Microbiology SC Microbiology GA DW1YP UT WOS:000383440300012 ER PT J AU Stone, LA Cutter, GR Fisher, E Richert, N McCartin, J Ohayon, J Bash, C McFarland, H AF Stone, Lael Anne Cutter, Gary Raymond Fisher, Elizabeth Richert, Nancy McCartin, Jennifer Ohayon, Joan Bash, Craig McFarland, Henry TI Relapse May Serve as a Mediator Variable in Longitudinal Outcomes in Multiple Sclerosis SO JOURNAL OF NEUROIMAGING LA English DT Article DE Contrast-enhancing lesions; disability; mediator variable; MRI; multiple sclerosis; relapses ID REMITTING MS; METAANALYTIC APPROACH; PREDICTIVE-VALUE; BRAIN ATROPHY; MRI LESIONS; FOLLOW-UP; DISABILITY; SURROGATE; IMPAIRMENT; EDSS AB BACKGROUND/PURPOSE: Contrast-enhancing lesions (CEL) on magnetic resonance imaging (MRI) are believed to represent inflammatory disease activity in multiple sclerosis (MS), but their relationship to subsequent long-term disability and progression is unclear, particularly at longer time periods such as 8-10 years. METHODS: Between 1989 and 1994, 111 MS patients were seen at the National Institutes of Health for clinical evaluations and 3 monthly contrast-enhanced MRI scans. Of these, 94 patients were re-evaluated a mean of 8 years later (range 6.1-10.5 years) with a single MRI scan and clinical evaluation. CEL number and volume were determined at baseline and follow-up. The number of relapses was ascertained over the follow-up period and annualized relapse rates were calculated. Other MRI parameters, such as T2 hyperintensity volume, T1 volume, and brain parenchymal fraction, were also calculated. RESULTS: While there was no direct correlation between CEL number or volume at baseline and disability status at follow-up, CEL measures at baseline did correlate with number of relapses observed in the subsequent years, and the number of relapses in turn correlated with subsequent disability as well as transition to progressive MS. CONCLUSION: While number and volume of CEL at baseline do not directly correlate with disability in the longer term in MS, our data suggest that 1 route to disability involves relapses as a mediator variable in the causal sequence of MS progression from CEL to disability. Further studies using relapse as a mediator variable in a larger data set may be warranted. C1 [Stone, Lael Anne] Cleveland Clin Fdn, Mellen Ctr Treatment & Res, 9500 Euclid Ave,U-10, Cleveland, OH 44195 USA. [Cutter, Gary Raymond] UAB Sch Publ Hlth, Dept Biostat, Birmingham, AL USA. [Fisher, Elizabeth; Richert, Nancy] Biogen Inc, 14 Cambridge Ctr, Cambridge, MA 02142 USA. [McCartin, Jennifer; Ohayon, Joan] NINDS, Neuroimmunol Branch, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Bash, Craig] Uniformed Serv Sch Med, Dept Neuroradiol, Bethesda, MD USA. [McFarland, Henry] Cumming Fdn, Salt Lake City, UT USA. RP Stone, LA (reprint author), Cleveland Clin Fdn, Mellen Ctr Treatment & Res, 9500 Euclid Ave,U-10, Cleveland, OH 44195 USA. EM stonel@ccf.org FU National MS Society FX This study was funded from a grant from the National MS Society. NR 23 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1051-2284 EI 1552-6569 J9 J NEUROIMAGING JI J. Neuroimaging PD MAY-JUN PY 2016 VL 26 IS 3 BP 296 EP 302 DI 10.1111/jon.12321 PG 7 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DV4BG UT WOS:000382869200008 PM 26686343 ER PT J AU Ramos, VFML Considine, E Karp, BI Lungu, C Alter, K Hallett, M AF Ramos, Vesper Fe Marie Llaneza Considine, Elaine Karp, Barbara I. Lungu, Codrin Alter, Katharine Hallett, Mark TI Ultrasound as Diagnostic Tool for Diaphragmatic Myoclonus SO MOVEMENT DISORDERS CLINICAL PRACTICE LA English DT Article DE ultrasound; myoclonus; motor control; conversion ID RESPIRATORY MYOCLONUS; FLUTTER AB Background: Diaphragmatic myoclonus is a rare disorder of repetitive diaphragmatic contractions, acknowledged to be a spectrum that includes psychogenic features. Electromyography has been the diagnostic tool most commonly used in the literature. Methods: To test whether we could perform a noninvasive technique to delineate the diaphragm as the source of abnormal movements and demonstrate distractibility and entrainability, we used B-mode ultrasound in a patient with diaphragmatic myoclonus. Results: Ultrasound imaging clearly delineated the diaphragm as the source of her abdominal movements. We were able to demonstrate entrainability of the diaphragm to hand tapping to a prescribed rhythm set by the examiner. Conclusions: We recommend the use of ultrasound as a noninvasive, convenient diagnostic tool for further studies of diaphragmatic myoclonus. We agree with previous findings that diaphragmatic myoclonus may be a functional movement disorder, as evidenced by distractibility and entrainability demonstrated on real-time video with ultrasonography. C1 [Ramos, Vesper Fe Marie Llaneza; Considine, Elaine; Hallett, Mark] NIH, Human Motor Control Sect, Bldg 10,Room 7D42,10 Ctr Dr, Bethesda, MD 20814 USA. [Karp, Barbara I.] NIH, CNS, IRB, Bldg 10, Bethesda, MD 20892 USA. [Lungu, Codrin] NINDS, Off Clin Director, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Alter, Katharine] NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Bldg 10, Bethesda, MD 20892 USA. [Alter, Katharine] Mt Washington Pediat Hosp, Washington, DC USA. RP Ramos, VFML (reprint author), NIH, Human Motor Control Sect, Bldg 10,Room 7D42,10 Ctr Dr, Bethesda, MD 20814 USA. EM vesper.ramos@yahoo.com NR 10 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2330-1619 J9 MOV DISORD CLIN PRAC JI MOV. DISORD. CLIN. PRACT. PD MAY-JUN PY 2016 VL 3 IS 3 BP 282 EP 284 DI 10.1002/mdc3.12295 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA DV9GM UT WOS:000383248600008 ER PT J AU Cho, HJ Panyakaew, P Srivanitchapoom, P Hallett, M AF Cho, Hyun Joo Panyakaew, Pattamon Srivanitchapoom, Prachaya Hallett, Mark TI A Case of Functional Belly Dancer's Dyskinesia SO MOVEMENT DISORDERS CLINICAL PRACTICE LA English DT Article DE belly dancer's dyskinesia; functional movement disorders ID MYOCLONUS C1 [Cho, Hyun Joo; Hallett, Mark] NINDS, Human Motor Control Sect, NIH, 10 Ctr Dr,MSC 1428,Bldg 10,Room 7D37, Bethesda, MD 20892 USA. [Panyakaew, Pattamon] Chulalongkorn Unibers, King Chulalongkorn Mem Hosp, Fac Med, Dept Med, Bangkok, Thailand. [Srivanitchapoom, Prachaya] Mahidol Univ, Siriraj Hosp, Fac Med, Dept Med, Bangkok, Thailand. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, NIH, 10 Ctr Dr,MSC 1428,Bldg 10,Room 7D37, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov NR 10 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2330-1619 J9 MOV DISORD CLIN PRAC JI MOV. DISORD. CLIN. PRACT. PD MAY-JUN PY 2016 VL 3 IS 3 BP 306 EP 308 DI 10.1002/mdc3.12276 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA DV9GM UT WOS:000383248600015 ER PT J AU Cimino, L Coassin, M Chan, CC Marchi, S Belpoliti, M Fanti, A Iovieno, A Fontana, L AF Cimino, Luca Coassin, Marco Chan, Chi-Chao Marchi, Sylvia Belpoliti, Matteo Fanti, Andrea Iovieno, Alfonso Fontana, Luigi TI Vitreoretinal lymphomas misdiagnosed as uveitis: Lessons learned from a case series SO INDIAN JOURNAL OF OPHTHALMOLOGY LA English DT Article DE Diagnostic vitrectomy; intraocular inflammation; intraocular lymphoma; subretinal infiltrates; uveitis; vitreoretinal lymphoma ID PRIMARY INTRAOCULAR LYMPHOMA; NEOPLASTIC MASQUERADE SYNDROMES; CLINICAL-FEATURES; DIAGNOSIS AB Purpose: To present challenging cases of vitreoretinal lymphoma (VRL) that was misdiagnosed as uveitis because of the apparent intraocular inflammation. At the light of the new classification of intraocular lymphomas, we detail the characteristics that masqueraded the tumors and the clinical aspects that guided us to the correct diagnosis. Materials and Methods: We retrospectively reviewed the patients referred to our uveitis service between January 2006 and December 2014. Results: Seven patients referred with a presumptive diagnosis of idiopathic uveitis received a final diagnosis of VRL. The median time between the onset of symptoms and definitive diagnosis was 25 months for these complex cases. The median time from presentation at our clinic to final diagnosis was 1 month. The described clinical features including dense vitreous cells and subretinal infiltrates were characteristic and tend to be present in all these chronically ill patients. Vitreous samples were collected, and all demonstrated the pathognomonic tumor cells, the specific immunoglobulin heavy chain gene rearrangements, and an interleukin (IL)-10 to IL-6 ratio > 1. Conclusion: VRLs are severe diseases with a poor prognosis that may be misdiagnosed as idiopathic inflammatory conditions of the eye. Treatment with steroids may occult the tumors and delay the correct diagnosis. Appropriate evaluation may prompt to a timely vitreous sampling and therefore to a faster diagnosis in these peculiar cases where the correct diagnosis was delayed by several months. C1 [Cimino, Luca; Marchi, Sylvia] Santa Maria Nuova Hosp IRCCS, Uveitis Serv, Dept Ophthalmol, Viale Risorgimento 80, I-42123 Reggio Emilia, Italy. [Coassin, Marco; Belpoliti, Matteo; Fanti, Andrea; Iovieno, Alfonso; Fontana, Luigi] Santa Maria Nuova Hosp IRCCS, Dept Ophthalmol, Reggio Emilia, Italy. [Chan, Chi-Chao] NEI, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Cimino, L (reprint author), Santa Maria Nuova Hosp IRCCS, Uveitis Serv, Dept Ophthalmol, Viale Risorgimento 80, I-42123 Reggio Emilia, Italy. EM cimino.luca@asmn.re.it OI Cimino, Luca/0000-0001-7956-9950 NR 24 TC 0 Z9 0 U1 2 U2 2 PU MEDKNOW PUBLICATIONS & MEDIA PVT LTD PI MUMBAI PA B-9, KANARA BUSINESS CENTRE, OFF LINK RD, GHAKTOPAR-E, MUMBAI, 400075, INDIA SN 0301-4738 EI 1998-3689 J9 INDIAN J OPHTHALMOL JI Indian J. Ophthalmol. PD MAY PY 2016 VL 64 IS 5 BP 369 EP 375 DI 10.4103/0301-4738.185600 PG 7 WC Ophthalmology SC Ophthalmology GA DT2BZ UT WOS:000381287100007 PM 27380976 ER PT J AU Yeo, L Romero, R AF Yeo, Lami Romero, Roberto TI How to Acquire Cardiac Volumes for Sonographic Examination of the Fetal Heart Part 1 SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article DE fetal echocardiography; fetus; 4-dimensional; spatiotemporal image correlation; ultrasound ID SPATIOTEMPORAL IMAGE CORRELATION; VENTRICULAR SEPTAL-DEFECT; COMPUTER-AIDED ANALYSIS; 4-DIMENSIONAL ULTRASOUND; PRENATAL-DIAGNOSIS; WEEKS GESTATION; INVERSION MODE; GREAT-ARTERIES; TOMOGRAPHIC ULTRASOUND; B-FLOW AB Four-dimensional sonography with spatiotemporal image correlation (STIC) technology allows acquisition of a fetal cardiac volume data set and displays a cine loop of a complete single cardiac cycle in motion. Part 1 of this 2-part article reviews STIC technology and its features, the importance of operator training/experience, and acquisition of high-quality STIC volumes, as well as factors that affect STIC volume acquisition rates. We also propose a detailed and practical stepwise approach to performing 4-dimensional sonography with STIC and begin herein by providing general recommendations. Part 2 will discuss specifics of the approach, along with how to determine whether such volumes are appropriate for analysis. C1 [Yeo, Lami; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Bethesda, MD USA. [Yeo, Lami; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Detroit, MI 48201 USA. [Yeo, Lami] Hutzel Womens Hosp, Detroit Med Ctr, Detroit, MI USA. [Yeo, Lami] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. RP Yeo, L (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Dept Hlth & Human Serv,Hutzel Womens Hosp, 3990 John R,4 Brush, Detroit, MI 48201 USA. EM lyeo@med.wayne.edu FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Department of Health and Human Services; NICHD, NIH [HHSN275201300006C] FX Dr Romero has contributed to this work as part of his official duties as an employee of the United States Federal Government. This article is a US Government work and is in the public domain in the United States. This research was supported in part by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Department of Health and Human Services; and in part with federal funds from the NICHD, NIH, under contract No. HHSN275201300006C. NR 142 TC 3 Z9 3 U1 0 U2 0 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 EI 1550-9613 J9 J ULTRAS MED JI J. Ultrasound Med. PD MAY 1 PY 2016 VL 35 IS 5 BP 1021 EP 1042 DI 10.7863/ultra.16.01081 PG 22 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA DU8YN UT WOS:000382502700022 PM 27091914 ER PT J AU Yeo, L Romero, R AF Yeo, Lami Romero, Roberto TI How to Acquire Cardiac Volumes for Sonographic Examination of the Fetal Heart Part 2 SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article DE fetal echocardiography; fetus; 4-dimensional; spatiotemporal image correlation; STICLoop; ultrasound ID SPATIOTEMPORAL IMAGE CORRELATION; 4-DIMENSIONAL ULTRASOUND; PRENATAL-DIAGNOSIS; INVERSION MODE; WEEKS GESTATION; OUTFLOW TRACTS; GREAT-ARTERIES; 4-CHAMBER VIEW; 4D ULTRASOUND; 3-DIMENSIONAL ECHOCARDIOGRAPHY AB The effective performance of fetal cardiac examination using spatiotemporal image correlation (STIC) technology requires 2 essential steps: volume acquisition and post-processing. An important prerequisite is training sonologists to acquire high-quality volume data sets so that when analyzed, such volumes are informative. This article is part 2 of a series on 4-dimensional sonography with STIC. Part 1 focused on STIC technology and its features, the importance of operator training/experience and acquisition of high-quality STIC volumes, factors that affect STIC volume acquisition rates, and general recommendations on performing 4D sonography with STIC. In part 2, we discuss a detailed and practical stepwise approach for STIC volume acquisition, along with methods to determine whether such volumes are appropriate for analysis. C1 [Yeo, Lami; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Bethesda, MD USA. [Yeo, Lami; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Detroit, MI 48201 USA. [Yeo, Lami] Hutzel Womens Hosp, Detroit Med Ctr, Detroit, MI USA. [Yeo, Lami] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. RP Yeo, L (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Dept Hlth & Human Serv,Hutzel Womens Hosp, 3990 John R,4 Brush, Detroit, MI 48201 USA. EM lyeo@med.wayne.edu FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Department of Health and Human Services; NICHD, NIH [HHSN275201300006C] FX Dr Romero has contributed to this work as part of his official duties as an employee of the United States Federal Government. This article is a US Government work and is in the public domain in the United States. This research was supported in part by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Department of Health and Human Services; and in part with federal funds from the NICHD, NIH, under contract No. HHSN275201300006C. NR 113 TC 3 Z9 3 U1 0 U2 0 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 EI 1550-9613 J9 J ULTRAS MED JI J. Ultrasound Med. PD MAY 1 PY 2016 VL 35 IS 5 BP 1043 EP 1066 DI 10.7863/ultra.16.01082 PG 24 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA DU8YN UT WOS:000382502700023 PM 27091912 ER PT J AU Cowen, EW Pichard, DC Garabedian, E Miettinen, M AF Cowen, Edward W. Pichard, Dominique C. Garabedian, Elizabeth Miettinen, Markku TI MEDALLION-LIKE DERMAL DENDROCYTIC HAMARTOMA, DERMATOFIBROSARCOMA PROTUBERANS, AND ADENOSINE DEAMINASE-DEFICIENT SEVERE COMBINED IMMUNODEFICIENCY SO PEDIATRIC DERMATOLOGY LA English DT Editorial Material C1 [Cowen, Edward W.; Pichard, Dominique C.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Garabedian, Elizabeth] NHGRI, NIH, Bethesda, MD 20892 USA. [Miettinen, Markku] NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Cowen, EW (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM cowene@mail.nih.gov OI Miettinen, Markku/0000-0002-3282-8107 FU Intramural NIH HHS [Z99 CA999999] NR 3 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0736-8046 EI 1525-1470 J9 PEDIATR DERMATOL JI Pediatr. Dermatol. PD MAY-JUN PY 2016 VL 33 IS 3 BP 359 EP 360 DI 10.1111/pde.12847 PG 2 WC Dermatology; Pediatrics SC Dermatology; Pediatrics GA DV2YW UT WOS:000382789200042 PM 27176810 ER PT J AU Ngoh, A Bras, J Guerreiro, R Meyer, E McTague, A Dawson, E Mankad, K Gunny, R Clayton, P Mills, PB Thornton, R Lai, M Forsyth, R Kurian, MA AF Ngoh, Adeline Bras, Jose Guerreiro, Rita Meyer, Esther McTague, Amy Dawson, Eleanor Mankad, Kshitij Gunny, Roxana Clayton, Peter Mills, Philippa B. Thornton, Rachel Lai, Ming Forsyth, Robert Kurian, Manju A. TI RARS2 mutations in a sibship with infantile spasms SO EPILEPSIA LA English DT Article DE RARS2; Infantile spasms; Whole exome sequencing; Pontocerebellar hypoplasia type 6 ID HYPOPLASIA TYPE 6; DNA-SEQUENCING DATA; PONTOCEREBELLAR HYPOPLASIA; FRAMEWORK; SIBLINGS; FEATURES AB Pontocerebellar hypoplasia is a group of heterogeneous neurodevelopmental disorders characterized by reduced volume of the brainstem and cerebellum. We report two male siblings who presented with early infantile clonic seizures, and then developed infantile spasms associated with prominent isolated cerebellar hypoplasia/ atrophy on magnetic resonance imaging (MRI). Using whole exome sequencing techniques, both were found to be compound heterozygotes for one previously reported and one novel mutation in the gene encoding mitochondrial arginyl-tRNA synthetase 2 (RARS2). Mutations in this gene have been classically described in pontocerebellar hypoplasia type six (PCH6), a phenotype characterized by early (often intractable) seizures, profound developmental delay, and progressive pontocerebellar atrophy. The electroclinical spectrum of PCH6 is broad and includes a number of seizure types: myoclonic, generalized tonic-clonic, and focal clonic seizures. Our report expands the characterization of the PCH6 disease spectrum and presents infantile spasms as an associated electroclinical phenotype. C1 [Ngoh, Adeline; Meyer, Esther; McTague, Amy; Kurian, Manju A.] UCL Inst Child Hlth, Mol Neurosci, Dev Neurosci Programme, London, England. [Ngoh, Adeline; McTague, Amy; Kurian, Manju A.] Great Ormond St Hosp Children NHS Fdn Trust, Dept Neurol, London, England. [Bras, Jose; Guerreiro, Rita] UCL Inst Neurol, Dept Mol Neurosci, London, England. [Guerreiro, Rita] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Dawson, Eleanor] Great North Childrens Hosp, Royal Victoria Infirm, Dept Paediat Neurol, Newcastle Upon Tyne, Tyne & Wear, England. [Mankad, Kshitij; Gunny, Roxana] Great Ormond St Hosp Children NHS Fdn Trust, Dept Radiol, London, England. [Clayton, Peter; Mills, Philippa B.] UCL Inst Child Hlth, Genet & Genom Med Programme, London, England. [Clayton, Peter] Great Ormond St Hosp Children NHS Fdn Trust, Metab Med Unit, London, England. [Thornton, Rachel] Great Ormond St Hosp Children NHS Fdn Trust, Dept Neurophysiol, London, England. [Lai, Ming] Royal Victoria Infirm, Dept Neurophysiol, Newcastle Upon Tyne, Tyne & Wear, England. Newcastle Univ, Inst Neurosci, Newcastle Upon Tyne, Tyne & Wear, England. RP Kurian, MA (reprint author), Inst Child Hlth, Dev Neurosci, Room 111,Level 1 CMGU,30 Guilford St, London WC1N 1EH, England. EM manju.kurian@ucl.ac.uk FU Guarantors of Brain Entry Fellowship; Action Medical Research Training Fellowship; Alzheimer's Society; Alzheimer's Research UK Fellowship; Medical Research Council; Medical Research Foundation; Child Brain Research; Young Epilepsy; Great Ormond Street Children's Charity; Wellcome Trust Intermediate Clinical Fellowship; Rosetrees Trust; Gracious Heart Charity Foundation; Rachel Marie Trafford Trust FX AN is funded by a Guarantors of Brain Entry Fellowship and an Action Medical Research Training Fellowship. JB's work is supported by a Fellowship from the Alzheimer's Society. RG is funded by an Alzheimer's Research UK Fellowship. AMT is funded by the Medical Research Council and has also received support from the Medical Research Foundation, Child Brain Research, and Young Epilepsy. PTC is funded by Great Ormond Street Children's Charity. MAK is funded by a Wellcome Trust Intermediate Clinical Fellowship and receives funding from the Rosetrees Trust, Gracious Heart Charity Foundation, Rachel Marie Trafford Trust, and Child Brain Research. Dr Stewart Boyd, Department of Neurophysiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom. NR 13 TC 2 Z9 2 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0013-9580 EI 1528-1167 J9 EPILEPSIA JI Epilepsia PD MAY PY 2016 VL 57 IS 5 BP E97 EP E102 DI 10.1111/epi.13358 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA DR8ID UT WOS:000380140700003 PM 27061686 ER PT J AU Cawley, NX Li, ZJ Loh, YP AF Cawley, Niamh X. Li, Zhaojin Loh, Y. Peng TI 60 YEARS OF POMC Biosynthesis, trafficking, and secretion of pro-opiomelanocortin-derived peptides SO JOURNAL OF MOLECULAR ENDOCRINOLOGY LA English DT Review DE hypothalamus-pituitary-adrenal axis; POMC sorting; POMC-derived peptide secretion; vesicle trafficking; prohormone processing enzymes ID PITUITARY-TUMOR-CELLS; PROHORMONE CONVERTASES PC1; PATHWAY-SORTING RECEPTOR; BETA-ENDORPHIN RELEASE; RAT PARS-INTERMEDIA; EARLY-ONSET OBESITY; PROOPIOMELANOCORTIN GENE-EXPRESSION; CARBOXYPEPTIDASE-PROCESSING ENZYME; ACTIVITY-DEPENDENT SECRETION; GRANULE CONTENT PROTEINS AB Pro-opiomelanocortin (POMC) is a prohormone that encodes multiple smaller peptide hormones within its structure. These peptide hormones can be generated by cleavage of POMC at basic residue cleavage sites by prohormone-converting enzymes in the regulated secretory pathway (RSP) of POMC-synthesizing endocrine cells and neurons. The peptides are stored inside the cells in dense-core secretory granules until released in a stimulus-dependent manner. The complexity of the regulation of the biosynthesis, trafficking, and secretion of POMC and its peptides reflects an impressive level of control over many factors involved in the ultimate role of POMC-expressing cells, that is, to produce a range of different biologically active peptide hormones ready for action when signaled by the body. From the discovery of POMC as the precursor to adrenocorticotropic hormone (ACTH) and beta-lipotropin in the late 1970s to our current knowledge, the understanding of POMC physiology remains a monumental body of work that has provided insight into many aspects of molecular endocrinology. In this article, we describe the intracellular trafficking of POMC in endocrine cells, its sorting into dense-core secretory granules and transport of these granules to the RSP. Additionally, we review the enzymes involved in the maturation of POMC to its various peptides and the mechanisms involved in the differential processing of POMC in different cell types. Finally, we highlight studies pertaining to the regulation of ACTH secretion in the anterior and intermediate pituitary and POMC neurons of the hypothalamus. C1 [Cawley, Niamh X.; Li, Zhaojin; Loh, Y. Peng] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cellular Neurobiol Sect, NIH, Bethesda, MD USA. RP Loh, YP (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cellular Neurobiol Sect, NIH, Bethesda, MD USA. EM lohp@mail.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA [HD000056] FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA (Grant #HD000056). NR 177 TC 6 Z9 6 U1 4 U2 5 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0952-5041 EI 1479-6813 J9 J MOL ENDOCRINOL JI J. Mol. Endocrinol. PD MAY PY 2016 VL 56 IS 4 BP T77 EP T97 DI 10.1530/JME-15-0323 PG 21 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DS3XX UT WOS:000380717100008 PM 26880796 ER PT J AU Wahome, N Sully, E Singer, C Thomas, JC Hu, L Joshi, SB Volkin, DB Fang, JW Karanicolas, J Jacobs, DJ Mantis, NJ Middaugh, CR AF Wahome, Newton Sully, Erin Singer, Christopher Thomas, Justin C. Hu, Lei Joshi, Sangeeta B. Volkin, David B. Fang, Jianwen Karanicolas, John Jacobs, Donald J. Mantis, Nicholas J. Middaugh, C. Russell TI Novel Ricin Subunit Antigens With Enhanced Capacity to Elicit Toxin-Neutralizing Antibody Responses in Mice SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE ricin; computational biology; immunology; vaccines; protein structure; physical stability ID QUANTITATIVE STABILITY/FLEXIBILITY RELATIONSHIPS; PROTECTS MICE; CONFORMATIONAL VARIABILITY; CLINICAL-TRIAL; A-CHAIN; VACCINE; STABILITY; RIVAX; MODEL; INTOXICATION AB RiVax is a candidate ricin toxin subunit vaccine antigen that has proven to be safe in human phase I clinical trials. In this study, we introduced double and triple cavity-filling point mutations into the RiVax antigen with the expectation that stability-enhancing modifications would have a beneficial effect on overall immunogenicity of the recombinant proteins. We demonstrate that 2 RiVax triple mutant derivatives, RB (V81L/C171L/V204I) and RC (V81I/C171L/V204I), when adsorbed to aluminum salts adjuvant and tested in a mouse prime-boost-boost regimen were 5- to 10-fold more effective than RiVax at eliciting toxin-neutralizing serum IgG antibody titers. Increased toxin neutralizing antibody values and seroconversion rates were evident at different antigen dosages and within 7 days after the first booster. Quantitative stability/flexibility relationships analysis revealed that the RB and RC mutations affect rigidification of regions spanning residues 98-103, which constitutes a known immunodominant neutralizing B-cell epitope. A more detailed understanding of the immunogenic nature of RB and RC may provide insight into the fundamental relationship between local protein stability and antibody reactivity. (C) 2016 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved. C1 [Wahome, Newton; Thomas, Justin C.; Hu, Lei; Joshi, Sangeeta B.; Volkin, David B.; Middaugh, C. Russell] Univ Kansas, Dept Pharmaceut Chem, Macromol & Vaccine Stabilizat Ctr, Lawrence, KS 66047 USA. [Sully, Erin; Mantis, Nicholas J.] New York State Dept Hlth, Wadsworth Ctr, Div Infect Dis, Albany, NY 12208 USA. [Singer, Christopher; Jacobs, Donald J.] Univ North Carolina Charlotte, Dept Phys & Opt Sci, Charlotte, NC 28223 USA. [Fang, Jianwen] Univ Kansas, Dept Med Chem, Appl Bioinformat Lab, Lawrence, KS 66047 USA. [Karanicolas, John] Univ Kansas, Dept Mol Biosci, Ctr Computat Biol, Lawrence, KS 66045 USA. [Mantis, Nicholas J.] SUNY Albany, Sch Publ Hlth, Dept Biomed Sci, Albany, NY 12201 USA. [Thomas, Justin C.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Hu, Lei] Pfizer, Pearl River, NY 10965 USA. [Fang, Jianwen] NCI, Bethesda, MD 20892 USA. RP Middaugh, CR (reprint author), Univ Kansas, Dept Pharmaceut Chem, Macromol & Vaccine Stabilizat Ctr, Lawrence, KS 66047 USA.; Mantis, NJ (reprint author), New York State Dept Hlth, Wadsworth Ctr, Div Infect Dis, Albany, NY 12208 USA.; Jacobs, DJ (reprint author), Univ North Carolina Charlotte, Dept Phys & Opt Sci, Charlotte, NC 28223 USA.; Mantis, NJ (reprint author), SUNY Albany, Sch Publ Hlth, Dept Biomed Sci, Albany, NY 12201 USA. EM djacobs1@uncc.edu; nicholas.mantis@health.ny.gov; middaugh@ku.edu OI Mantis, Nicholas/0000-0002-5083-8640 FU NIH [U01AI082210, 8P20GM103420, 5P20RR017708, T32 GM008359, T32 AI055429]; Kauffman Foundation, Kansas City, MO; PhRMA Foundation, Washington, DC FX This work was supported by NIH grants U01AI082210, 8P20GM103420, and 5P20RR017708 as well as a research grant from the Kauffman Foundation, Kansas City, MO. Justin C. Thomas acknowledges financial support from NIH T32 GM008359 and a pre-doctoral fellowship from the PhRMA Foundation, Washington, DC. Erin Sully acknowledges financial support from NIH T32 AI055429 (PI: McDonough). NR 53 TC 1 Z9 1 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3549 EI 1520-6017 J9 J PHARM SCI-US JI J. Pharm. Sci. PD MAY PY 2016 VL 105 IS 5 BP 1603 EP 1613 DI 10.1016/j.xphs.2016.02.009 PG 11 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA DT8TZ UT WOS:000381769800004 PM 26987947 ER PT J AU Ellefsen, KN Concheiro, M Huestis, MA AF Ellefsen, Kayla N. Concheiro, Marta Huestis, Marilyn A. TI Synthetic cathinone pharmacokinetics, analytical methods, and toxicological findings from human performance and postmortem cases SO DRUG METABOLISM REVIEWS LA English DT Review DE Analytical methods; GC-MS; LC-MS; MS; metabolism; novel psychoactive substances; pharmacokinetics; synthetic cathinones ID CHROMATOGRAPHY-MASS-SPECTROMETRY; HUMAN LIVER-MICROSOMES; IN-VITRO METABOLISM; ENCOUNTERED DESIGNER DRUG; PSYCHOACTIVE BATH SALTS; LC-HR-MS/MS; ALPHA-PYRROLIDINOVALEROPHENONE; 3,4-METHYLENEDIOXYPYROVALERONE MDPV; RAT URINE; GC-MS AB Synthetic cathinones are commonly abused novel psychoactive substances (NPS). We present a comprehensive systematic review addressing in vitro and in vivo synthetic cathinone pharmacokinetics, analytical methods for detection and quantification in biological matrices, and toxicological findings from human performance and postmortem toxicology cases. Few preclinical administration studies examined synthetic cathinone pharmacokinetic profiles (absorption, distribution, metabolism, and excretion), and only one investigated metabolite pharmacokinetics. Synthetic cathinone metabolic profiling studies, primarily with human liver microsomes, elucidated metabolite structures and identified suitable biomarkers to extend detection windows beyond those provided by parent compounds. Generally, cathinone derivatives underwent ketone reduction, carbonylation of the pyrrolidine ring, and oxidative reactions, with phase II metabolites also detected. Reliable analytical methods are necessary for cathinone identification in biological matrices to document intake and link adverse events to specific compounds and concentrations. NPS analytical methods are constrained in their ability to detect new emerging synthetic cathinones due to limited commercially available reference standards and continuous development of new analogs. Immunoassay screening methods are especially affected, but also gas-chromatography and liquid-chromatography mass spectrometry confirmation methods. Non-targeted high-resolution-mass spectrometry screening methods are advantageous, as they allow for retrospective data analysis and easier addition of new synthetic cathinones to existing methods. Lack of controlled administration studies in humans complicate interpretation of synthetic cathinones in biological matrices, as dosing information is typically unknown. Furthermore, antemortem and postmortem concentrations often overlap and the presence of other psychoactive substances are typically found in combination with cathinones derivatives, further confounding result interpretation. C1 [Ellefsen, Kayla N.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab, IRP, NIH, Baltimore, MD USA. [Ellefsen, Kayla N.] Univ Maryland, Program Toxicol, Baltimore, MD 21201 USA. [Concheiro, Marta] CUNY John Jay Coll Criminal Justice, Dept Sci, New York, NY 10019 USA. RP Huestis, MA (reprint author), Univ Baltimore, Maryland Sch Med, Baltimore, MD 21201 USA. EM marilyn.huestis@gmail.com FU Intramural Research Program, National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH) FX This work was supported by the Intramural Research Program, National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH). NR 150 TC 1 Z9 1 U1 10 U2 20 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 0360-2532 EI 1097-9883 J9 DRUG METAB REV JI Drug Metab. Rev. PD MAY PY 2016 VL 48 IS 2 BP 237 EP 265 DI 10.1080/03602532.2016.1188937 PG 29 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DR8GG UT WOS:000380135800005 PM 27249313 ER PT J AU Kawabe, T Suzuki, N Yamaki, S Sun, SL Asao, A Okuyama, Y So, T Iwakura, Y Ishii, N AF Kawabe, Takeshi Suzuki, Nobu Yamaki, Satoshi Sun, Shu-lan Asao, Atsuko Okuyama, Yuko So, Takanori Iwakura, Yoichiro Ishii, Naoto TI Mesenteric lymph nodes contribute to proinflammatory Th17-cell generation during inflammation of the small intestine in mice SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Effector memory CD4(+) T cells; Mesenteric lymph nodes; Small intestinal inflammation; Th17 cells ID CD4(+) T-CELLS; GROWTH-FACTOR-BETA; DENDRITIC CELLS; LAMINA PROPRIA; HOMEOSTATIC PROLIFERATION; DIFFERENTIAL ROLES; T(H)17 CELLS; HOST-DEFENSE; TH17 CELLS; IN-VIVO AB T cells of the small intestine, including Th17 cells, are critically involved in host protection from microbial infection, and also contribute to the pathogenesis of small bowel inflammatory disorders. Accumulating evidence suggests that mesenteric lymph nodes (MLNs) play important roles in gut-tropic T-cell generation, although it is still unclear if MLNs are involved in the pathogenesis of small intestine inflammation. To address this issue, we analyzed the roles of both MLNs and Peyer's patches (PPs) by evaluating MLN- or PP-deficient mice in an experimental model of small intestine inflammation, induced by CD3-specific mAb injection. Interestingly, MLNs, but not PPs, were essential for the pathogenesis of intestinal inflammation, in particular the accumulation and infiltration of CD4(+) T-cell populations, including Th17 cells, from the blood. In addition, CD4+ T-cell accumulation was dependent on the function of the alpha(4)beta(7) integrin. Furthermore, MLN removal led to a significantly reduced number of peripheral alpha(4)beta(+)(7) CD4(+) effector memory T cells under normal conditions, suggesting that MLNs may play a role in maintaining the number of gut-tropic CD4(+) effector memory T cells circulating in the blood. Taken together, the present study highlights the important role of MLNs in contributing to the pathogenesis of small intestine inflammation. C1 [Kawabe, Takeshi; Suzuki, Nobu; Yamaki, Satoshi; Sun, Shu-lan; Asao, Atsuko; Okuyama, Yuko; So, Takanori; Ishii, Naoto] Tohoku Univ, Grad Sch Med, Dept Microbiol & Immunol, Sendai, Miyagi 9808575, Japan. [Kawabe, Takeshi] Tohoku Univ, Tohoku Med Megabank Org, Dept Community Med Supports, Sendai, Miyagi 9808575, Japan. [Iwakura, Yoichiro] Tokyo Univ Sci, Div Expt Anim Immunol, Res Inst Biol Sci, Chiba, Japan. [Kawabe, Takeshi] NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Ishii, N (reprint author), Tohoku Univ, Grad Sch Med, Dept Microbiol & Immunol, Aoba Ku, 2-1 Seiryo Machi, Sendai, Miyagi 9808575, Japan. EM ishiin@med.tohoku.ac.jp RI Iwakura, Yoichiro/E-5457-2011; OI Iwakura, Yoichiro/0000-0002-9934-5775; So, Takanori/0000-0003-3004-8526 FU Ministry of Education, Science, Sports and Culture of Japan; Japan Society for the Promotion of Science; Japan Science and Technology Agency; Sumitomo Foundation; Uehara Memorial Foundation; Novartis Foundation for the Promotion of Science; Yakult Bio-Science Foundation FX This work was supported in part by a grant-in-aid for scientific research on priority areas from the Ministry of Education, Science, Sports and Culture of Japan, a grant-in-aid for scientific research on priority areas from the Japan Society for the Promotion of Science, and grants from the Japan Science and Technology Agency, the Sumitomo Foundation, the Uehara Memorial Foundation, the Novartis Foundation for the Promotion of Science, and the Yakult Bio-Science Foundation. NR 55 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD MAY PY 2016 VL 46 IS 5 BP 1119 EP 1131 DI 10.1002/eji.201545907 PG 13 WC Immunology SC Immunology GA DS4LD UT WOS:000380751700007 PM 26887964 ER PT J AU Dougherty, JP Springer, DA Gershengorn, MC AF Dougherty, John P. Springer, Danielle A. Gershengorn, Marvin C. TI The Treadmill Fatigue Test: A Simple, High-throughput Assay of Fatigue-like Behavior for the Mouse SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Behavior; Issue 111; Mouse; Treadmill; Fatigue; Chemotherapy; Cancer-related fatigue; Chemotherapy-induced fatigue ID CANCER-RELATED FATIGUE; DOUBLE-BLIND; BREAST-CANCER; RECEIVING CHEMOTHERAPY; CLINICAL-TRIAL; PHASE-III; MICE; EXERCISE; METHYLPHENIDATE; WOMEN AB Fatigue is a prominent symptom in many diseases and disorders and reduces quality of life for many people. The lack of clear pathogenesis and failure of current interventions to adequately treat fatigue in all patients leaves a need for new treatment options. Despite the therapeutic need and importance of preclinical research in helping identify promising novel treatments, few preclinical assays of fatigue are available. Moreover, the most common preclinical assay used to assess fatigue-like behavior, voluntary wheel running, is not suitable for use with some strains of mice, may not be sensitive to drugs that reduce fatigue, and has relatively low throughput. The current protocol describes a novel, non-voluntary preclinical assay of fatigue-like behavior, the treadmill fatigue test, and provides evidence of its efficacy in detecting fatigue-like behavior in mice treated with a chemotherapy drug known to cause fatigue in humans and fatigue-like behavior in animals. This assay may be a beneficial alternative to wheel running, as fatigue-like behavior and potential interventions can be assessed in a greater number of mice over a shorter time frame, thus permitting faster discovery of new therapeutic options. C1 [Dougherty, John P.; Gershengorn, Marvin C.] NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. [Springer, Danielle A.] NHLBI, Murine Phenotyping Core, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Gershengorn, MC (reprint author), NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. EM marving@mail.nih.gov FU Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [1Z01 DK011006] FX This research was supported by the Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Grant 1Z01 DK011006. We wish to thank Michele Allen for providing technical assistance, Eleni Solomos for editorial assistance, and the NIH veterinary and animal care staff for providing care for the mice used in developing this method. NR 30 TC 0 Z9 0 U1 2 U2 2 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD MAY PY 2016 IS 111 AR e54052 DI 10.3791/54052 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DS0BJ UT WOS:000380259900079 ER PT J AU Adkins, EB Wang, XL Sproule, TJ Christianson, GG Park, G Lane-Reiticker, SK Jain, S Carter, GW Morse, HC Roopenian, DC AF Adkins, Elisabeth B. Wang, Xulong Sproule, Thomas J. Christianson, Gregory G. Park, Giljun Lane-Reiticker, Sarah-Kate Jain, Shweta Carter, Gregory W. Morse, Herbert C. Roopenian, Derry C. TI Natural T-FH arise in the thymus and periphery of young naive mice SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Adkins, Elisabeth B.; Wang, Xulong; Sproule, Thomas J.; Christianson, Gregory G.; Park, Giljun; Lane-Reiticker, Sarah-Kate; Carter, Gregory W.; Roopenian, Derry C.] Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. [Adkins, Elisabeth B.; Carter, Gregory W.; Roopenian, Derry C.] Tufts Univ, Sackler Sch Grad Biomed Sci, Medford, MA 02155 USA. [Jain, Shweta; Morse, Herbert C.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288302107 ER PT J AU Akkaya, B Akkaya, M Holstein, AH Kamenyeva, O Kabat, J Shevach, EM AF Akkaya, Billur Akkaya, Munir Holstein, Amanda H. Kamenyeva, Olena Kabat, Juraj Shevach, Ethan M. TI Antigen-specific induced T regulatory cells (iTregs) inhibit dendritic cell (DC) function by capturing peptide-MHCII complexes from the DC surface SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Akkaya, Billur; Akkaya, Munir; Holstein, Amanda H.; Kamenyeva, Olena; Kabat, Juraj; Shevach, Ethan M.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 MA 125.4 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288302451 ER PT J AU Akkaya, B Holstein, AH Kamenyeva, O Akkaya, M Shevach, EM AF Akkaya, Billur Holstein, Amanda H. Kamenyeva, Olena Akkaya, Munir Shevach, Ethan M. TI Dynamic imaging of a Tbet-Foxp3 double reporter in the course of Thl mediated immune response SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Akkaya, Billur; Holstein, Amanda H.; Kamenyeva, Olena; Akkaya, Munir; Shevach, Ethan M.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301438 ER PT J AU Akkaya, M Rawat, M Akkaya, B Chaturvedi, A Pena, M Miozzo, P Kim, AS Pierce, SK AF Akkaya, Munir Rawat, Mukul Akkaya, Billur Chaturvedi, Akanksha Pena, Mirna Miozzo, Pietro Kim, Ann S. Pierce, Susan K. TI B cells have bifurcated Toll-like receptor signaling allowing both inflammatory cytokine and type 1 interferon responses. SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Akkaya, Munir; Akkaya, Billur; Chaturvedi, Akanksha; Pena, Mirna; Miozzo, Pietro; Kim, Ann S.; Pierce, Susan K.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Rawat, Mukul] Indian Inst Sci, Bengaluru, Karnataka, India. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288302342 ER PT J AU Akkaya, M Kim, AS Miozzo, P Sohn, HW Akkaya, B Pena, M Pierce, SK AF Akkaya, Munir Kim, Ann S. Miozzo, Pietro Sohn, Hae-Won Akkaya, Billur Pena, Mirna Pierce, Susan K. TI Toll-like receptor 9 signaling antagonizes the B cell receptor-dependent ability of B cells to process and present antigen to helper T cells SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Akkaya, Munir; Kim, Ann S.; Miozzo, Pietro; Sohn, Hae-Won; Akkaya, Billur; Pena, Mirna; Pierce, Susan K.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300197 ER PT J AU Anderson, S McCullen, MV Sen, S McVicar, DW AF Anderson, Stephen McCullen, Matthew V. Sen, Shurjo McVicar, Daniel W. TI Ly49 Pro1 activity is associated with gene activation, not gene expression: Pro1 transcripts are not present in mature Ly49-expressing NK cells. SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Anderson, Stephen] Leidos Biomed Res Inc, Frederick, MD USA. [McCullen, Matthew V.; McVicar, Daniel W.] NCI, NIH, Bethesda, MD 20892 USA. [Sen, Shurjo] NHGRI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 MA 202.3 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288302453 ER PT J AU Andrews, OE Van Ryk, D Ansari, A Cicala, C Fauci, A Arthos, J AF Andrews, Omozusi E. Van Ryk, Donald Ansari, Aftab Cicala, Claudia Fauci, Anthony Arthos, James TI MAdCAM as a potential biomarker of HIV-induced inflammation SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Andrews, Omozusi E.; Van Ryk, Donald; Cicala, Claudia; Fauci, Anthony; Arthos, James] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Ansari, Aftab] Emory Univ, Atlanta, GA 30322 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 MA 208.15 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301219 ER PT J AU Arora, G Hart, GT Desail, SA Long, EO AF Arora, Gunjan Hart, Geoffrey T. Desail, Sanjay A. Long, Eric O. TI Natural Killer cell-mediated antibody-dependent cellular cytotoxicity towards red blood cells infected by Plasmodium falciparum SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Arora, Gunjan; Hart, Geoffrey T.; Desail, Sanjay A.; Long, Eric O.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288302156 ER PT J AU Bally, A Austin, JW Lu, PY Boss, J AF Bally, Alexander Austin, James W. Lu, Peiyuan Boss, Jeremy TI The histone demethylase LSD1 inhibits PD-1 expression in acute viral infections SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Bally, Alexander; Boss, Jeremy] Emory Univ, Atlanta, GA 30322 USA. [Austin, James W.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Lu, Peiyuan] Albert Einstein Coll Med, New York, NY USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288302321 ER PT J AU Biragyn, A Lee-Chang, C Bodogai, M AF Biragyn, Arya Lee-Chang, Catalina Bodogai, Monica TI Aging converts innate B1a cells into potentially pathogenic 4BL cells that induce cytolytic CD8(+)T cells. SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Biragyn, Arya; Lee-Chang, Catalina; Bodogai, Monica] NIA, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288302087 ER PT J AU Bosio, CM Nardone, G Broeckling, C Chiramel, A Best, S Ireland, R AF Bosio, Catharine M. Nardone, Glenn Broeckling, Corey Chiramel, Abilash Best, Sonja Ireland, Robin TI Identification of a unique lipid from Francisella tularensis as an effective therapeutic for viral mediated inflammation SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Bosio, Catharine M.; Chiramel, Abilash; Best, Sonja; Ireland, Robin] Rocky Mt Labs, Hamilton, MT USA. [Nardone, Glenn] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Broeckling, Corey] Colorado State Univ, Ft Collins, CO 80523 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288302371 ER PT J AU Bouladoux, N Naik, S Linehan, JL Han, SJ Harrison, OJ Tussiwand, R Murphy, KM Merad, M Segre, JA Belkaid, Y AF Bouladoux, Nicolas Naik, Shruti Linehan, Jonathan L. Han, Seong-Ji Harrison, Oliver J. Tussiwand, Roxanne Murphy, Kenneth M. Merad, Miriam Segre, Julia A. Belkaid, Yasmine TI Commensal-dendritic-cell interaction specifies a unique protective skin immune signature SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Bouladoux, Nicolas; Naik, Shruti; Linehan, Jonathan L.; Han, Seong-Ji; Harrison, Oliver J.; Belkaid, Yasmine] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Naik, Shruti] Rockefeller Univ, 1230 York Ave, New York, NY 10021 USA. [Tussiwand, Roxanne; Murphy, Kenneth M.] Washington Univ, Sch Med St Louis, St Louis, MO 63130 USA. [Murphy, Kenneth M.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Merad, Miriam] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Segre, Julia A.] NHGRI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288303224 ER PT J AU Carneiro, MB Lopes, MED Romano, A Campos, AC Sacks, D Vieira, LQ Peters, NC AF Carneiro, Matheus Batista de Moura Lopes, Mateus Eustaquio Romano, Audrey Campos, Alexandre Camargo Sacks, David Vieira, Leda Q. Peters, Nathan Colin TI IFN-gamma mediated inflammatory monocyte recruitment neutralizes iNOS-dependent parasite killing by expanding the permissive host cell reservoir during early Leishmania amazonensis infection SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Carneiro, Matheus Batista; Peters, Nathan Colin] Univ Calgary, Calgary, AB T2N 1N4, Canada. [Carneiro, Matheus Batista; de Moura Lopes, Mateus Eustaquio; Campos, Alexandre Camargo; Vieira, Leda Q.] Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil. [Romano, Audrey; Sacks, David] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300355 ER PT J AU Cascio, S Faylo, J Sciurba, J Xue, J Finn, OJ AF Cascio, Sandra Faylo, Jacque Sciurba, Joshua Xue, Jia Finn, Olivera J. TI MUC1 promotes an inflammatory microenvironment aggravating colitis associated tumorigenesis in mice through up-regulation of pro-inflammatory cytokines SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Cascio, Sandra; Xue, Jia; Finn, Olivera J.] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15260 USA. [Faylo, Jacque] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Sciurba, Joshua] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 MA 73.7 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301250 ER PT J AU Caspi, RR Drummond, R Desai, J Silver, PB Lionakis, MS St Leger, AJ AF Caspi, Rachel R. Drummond, Rebecca Desai, Jigarkumar Silver, Phyllis B. Lionakis, Michail S. St Leger, Anthony J. TI Microbiome-dependent modulation of mucosal immunity at the ocular surface SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Caspi, Rachel R.; Silver, Phyllis B.; St Leger, Anthony J.] NEI, NIH, Bethesda, MD 20892 USA. [Drummond, Rebecca; Desai, Jigarkumar; Lionakis, Michail S.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 2 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288303226 ER PT J AU Catalfamo, M Cecile, L Luckey, MA Villarino, A Smith, M Myers, TG Hasley, RB Park, JH O'Shea, JJ Lane, HC AF Catalfamo, Marta Cecile, Le Saout Luckey, Megan A. Villarino, Alejandro Smith, Mindy Myers, Timothy G. Hasley, Rebecca B. Park, Jung-Hyun O'Shea, J. J. Lane, H. Clifford TI Overexpression of total STAT1 during lymphopenia-induced proliferation leads to decrease CD4 T cell survival SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Catalfamo, Marta; Cecile, Le Saout; Smith, Mindy; Myers, Timothy G.; Hasley, Rebecca B.; Lane, H. Clifford] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Luckey, Megan A.; Villarino, Alejandro; Park, Jung-Hyun] NCI, NIH, Bethesda, MD 20892 USA. [O'Shea, J. J.] NIAMS, NIH, Bethesda, MD USA. RI Park, Jung Hyun /B-5712-2015 OI Park, Jung Hyun /0000-0002-9547-9055 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301433 ER PT J AU Chen, GB Yang, XB Ko, A Ga, MM Zhang, YQ Shi, A Sun, XP Mariuzza, RA Weng, NP AF Chen, Guobing Yang, Xinbo Ko, Annette Ga, Mingming Zhang, Yongqing Shi, Alvin Sun, Xiaoping Mariuzza, Roy A. Weng, Nan-Ping TI Distinct features of human CD8 T cell TCR repertoire specific to influenza A virus matrix protein M1 SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Chen, Guobing; Ko, Annette; Zhang, Yongqing; Shi, Alvin; Sun, Xiaoping; Weng, Nan-Ping] NIA, NIH, Bethesda, MD 20892 USA. [Yang, Xinbo; Ga, Mingming; Mariuzza, Roy A.] Univ Maryland, College Pk, MD USA. RI Chen, Guobing/D-9572-2012 OI Chen, Guobing/0000-0002-2401-6168 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301423 ER PT J AU Chen, X Oppenheim, JJ AF Chen, Xin Oppenheim, Joost J. TI Tetrandrine (TET), an immunosuppressive component of Chinese herb, induces tolerogenic dendritic cells and consequently expands regulatory T cells SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Chen, Xin] Univ Macau, Inst Chinese Med Sci, Taipa, Macau, Peoples R China. [Chen, Xin; Oppenheim, Joost J.] NCI, NIH, Bethesda, MD 20892 USA. RI Chen, Xin/I-6601-2015 OI Chen, Xin/0000-0002-2628-4027 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288303253 ER PT J AU Chiang, J Hodes, RJ AF Chiang, Jeffrey Hodes, Richard J. TI Long-range transcriptional effects and specific epigenetic marks in regulation of transcription from Lck proximal and distal promoters SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Chiang, Jeffrey; Hodes, Richard J.] NCI, NIH, Bethesda, MD 20892 USA. [Hodes, Richard J.] NIA, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288303218 ER PT J AU Constantinides, MG Ridaura, VK Belkaid, Y AF Constantinides, Michael G. Ridaura, Vanessa K. Belkaid, Yasmine TI Cutaneous microbiota drive the accumulation of IL-17A-producing T cells within the lungs SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Constantinides, Michael G.; Ridaura, Vanessa K.; Belkaid, Yasmine] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288303232 ER PT J AU Corbel, AF Kemp, TJ Pinto, LA Koshiol, J AF Corbel, Amanda Faith Kemp, Troy J. Pinto, Ligia A. Koshiol, Jill TI High sensitivity multiplex cytokine panel used to identify unique signatures in serum associated with gallbladder cancer SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Corbel, Amanda Faith; Koshiol, Jill] NCI, NIH, Bethesda, MD 20892 USA. [Kemp, Troy J.; Pinto, Ligia A.] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300374 ER PT J AU Costa, DL Mayer-Barber, KD Andrade, BB Amaral, EP Maiga, M Namasivayam, S Mittereder, L Orland, S Barber, DL Sher, A AF Costa, Diego L. Mayer-Barber, Katrin D. Andrade, Bruno B. Amaral, Eduardo P. Maiga, Mamoudou Namasivayam, Sivaranjani Mittereder, Lara Orland, Sandra Barber, Daniel L. Sher, Alan TI Enhancing CD4+T cell function as a strategy for improving antibiotic therapy of Mycobacterium tuberculosis infection SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Costa, Diego L.; Mayer-Barber, Katrin D.; Maiga, Mamoudou; Namasivayam, Sivaranjani; Mittereder, Lara; Orland, Sandra; Barber, Daniel L.; Sher, Alan] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Andrade, Bruno B.] Fiocruz MS, Oswaldo Cruz Fdn, Rio De Janeiro, Brazil. [Amaral, Eduardo P.] Univ Sao Paulo, BR-05508 Sao Paulo, Brazil. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288302021 ER PT J AU Davis, MJ Sionov, E Mayer-Barber, KD Barber, DL Chang, YC Kwon-Chung, KJ AF Davis, Michael J. Sionov, Edward Mayer-Barber, Katrin D. Barber, Daniel L. Chang, Yun C. Kwon-Chung, Kyung J. TI Exogenous induction of type I IFN protects mice from Cryptococcus neoformans and Cryptococcus gattii infections by distinct CD4+T cell and CD8+T cell-mediated mechanisms SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Davis, Michael J.; Mayer-Barber, Katrin D.; Barber, Daniel L.; Chang, Yun C.; Kwon-Chung, Kyung J.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Sionov, Edward] Agr Res Org, Volcani Ctr, Bet Dagan, Israel. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300368 ER PT J AU DeVault, VL Dienz, O Lilley, GWJ Benoit, PJ Schwartzberg, PL Boyson, JE AF DeVault, Victoria L. Dienz, Oliver Lilley, Graham W. J. Benoit, Patrick J. Schwartzberg, Pamela L. Boyson, Jonathan E. TI Slamf6 acts as a negative regulator of NKT cell expansion in the presence of a strong agonist SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [DeVault, Victoria L.; Dienz, Oliver; Lilley, Graham W. J.; Benoit, Patrick J.; Boyson, Jonathan E.] Univ Vermont, Burlington, VT 05405 USA. [Schwartzberg, Pamela L.] NHGRI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288302080 ER PT J AU Doyle, A Cicala, C Jelicic, K Van Ryk, D Ansari, AA Fauci, AS Arthos, J AF Doyle, Allison Cicala, Claudia Jelicic, Katija Van Ryk, Donald Ansari, Aftab Ahmed Fauci, Anthony S. Arthos, James TI Evaluation of a newly developed assay designed to assess the interaction between alpha(4)beta(7) and MAdCAM SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Doyle, Allison; Cicala, Claudia; Jelicic, Katija; Van Ryk, Donald; Fauci, Anthony S.; Arthos, James] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Ansari, Aftab Ahmed] Emory Univ, Sch Med, Atlanta, GA 30322 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 MA 207.14 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301068 ER PT J AU Drumheller, LB Wehrly, T Case, ED Celli, J Bosio, CM AF Drumheller, L. Brock Wehrly, Tara Case, Elizabeth Di Russo Celli, Jean Bosio, Catharine M. TI yidC is required for virulent Francisella tularensis to modulate IRF1 and resist killing by host cells SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Drumheller, L. Brock; Wehrly, Tara; Bosio, Catharine M.] NIAID, NIH, Bethesda, MD USA. [Case, Elizabeth Di Russo] Texas A&M Hlth Sci Ctr, Round Rock, TX USA. [Celli, Jean] Washington State Univ, Pullman, WA 99164 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288302243 ER PT J AU Gabor, K Madenspacher, JH Wassif, CA Bushel, PR Porter, FD Fessler, MB AF Gabor, Kristin Madenspacher, Jennifer H. Wassif, Christopher A. Bushel, Pierre R. Porter, Forbes D. Fessler, Michael B. TI Smith-Lemli-Opitz syndrome reveals requirement for sterol biosynthesis in the innate immune response SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Gabor, Kristin; Madenspacher, Jennifer H.; Bushel, Pierre R.; Fessler, Michael B.] NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Wassif, Christopher A.; Porter, Forbes D.] NICHD, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300455 ER PT J AU Gemer, M Kastenmuller, W Germain, RN AF Gemer, Michael Kastenmuller, Wolfgang Germain, Ronald N. TI Dendritic cell subset positioning governs clonal diversity and magnitude of the CD8 T cell response SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Gemer, Michael] Univ Washington, Seattle, WA 98195 USA. [Kastenmuller, Wolfgang] Univ Bonn, Bonn, Germany. [Germain, Ronald N.] NIAID, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 MA 126.28 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301301 ER PT J AU Gerner, MY Li, WZ Germain, RN AF Gerner, Michael Y. Li, Weizhe Germain, Ronald N. TI Novel tissue clearing method for preservation of morphology, fluorescence and epitope integrity permits quantitative cellular analysis in intact organs SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Gerner, Michael Y.] Univ Washington, Seattle, WA 98195 USA. [Li, Weizhe; Germain, Ronald N.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288303164 ER PT J AU Gokhale, AS Gangaplara, A Rieder, S Shevach, EM AF Gokhale, Ameya Sanjeev Gangaplara, Arunakumar Rieder, Sadiye Shevach, Ethan M. TI Functional Characterization of the role of Eos (Ikzf4) in CD4(+) and CD8(+) T cells SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Gokhale, Ameya Sanjeev; Gangaplara, Arunakumar; Shevach, Ethan M.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Rieder, Sadiye] MedImmune, Gaithersburg, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288303057 ER PT J AU Gomez-Rodriguez, JW Meylan, F Handon, R Hayes, E Anderson, S Kirby, M Siegel, RM Schwartzberg, PL AF Gomez-Rodriguez, Julio Washington Meylan, Francoise Handon, Robin Hayes, Erika Anderson, Stacie Kirby, Martha Siegel, Richard M. Schwartzberg, Pamela L. TI An essential role for Itk in Th9 differentiation via TCR-mediated induction of IL-2 and IRF4 SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Gomez-Rodriguez, Julio Washington; Handon, Robin; Anderson, Stacie; Kirby, Martha; Schwartzberg, Pamela L.] NHGRI, NIH, Bethesda, MD 20892 USA. [Meylan, Francoise; Hayes, Erika; Siegel, Richard M.] NIAMS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288302083 ER PT J AU Gonzalez-Espinosa, C Ibarra-Sanchez, A Avila, AM Medina-Tamayo, J Vazquez-Victorio, G Castillo-Arellano, JI Hernandez-Mondragon, AC Rivera, J Madera-Salcedo, IK Blank, U Macias-Silva, M AF Gonzalez-Espinosa, Claudia Ibarra-Sanchez, Alfredo Martin Avila, Alejandro Medina-Tamayo, Jaciel Vazquez-Victorio, Genaro Ivan Castillo-Arellano, Jorge Cristal Hernandez-Mondragon, Alma Rivera, Juan Madera-Salcedo, Iris Karina Blank, Ulrich Macias-Silva, Marina TI Protein tyrosine kinase Fyn regulates TLR4-elicited responses on mast cells controlling the function of a PP2A-PKC a/b signaling node leading to TNF secretion SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Gonzalez-Espinosa, Claudia; Ibarra-Sanchez, Alfredo; Martin Avila, Alejandro; Medina-Tamayo, Jaciel; Ivan Castillo-Arellano, Jorge; Cristal Hernandez-Mondragon, Alma] CINVESTAV, Sede Sur, Mexico. [Vazquez-Victorio, Genaro; Macias-Silva, Marina] Univ Nacl Autonoma Mexico, Mexico City, DF, Mexico. [Rivera, Juan] NIAMS, NIH, Bethesda, MD USA. [Madera-Salcedo, Iris Karina; Blank, Ulrich] Natl Inst Hlth & Med Res, Paris, France. [Madera-Salcedo, Iris Karina; Blank, Ulrich] INSERM, Paris, France. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 MA 203.20 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301345 ER PT J AU Graham, AC Obeng-Adjei, N Guthmiller, JJ Zander, RA Wohlfert, EA Crompton, PD Butler, NS AF Graham, Amy C. Obeng-Adjei, Nyamekye Guthmiller, Jenna J. Zander, Ryan A. Wohlfert, Elizabeth A. Crompton, Peter D. Butler, Noah S. TI Targeting TIGIT to modulate immunity and disease during experimental malaria SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Graham, Amy C.; Guthmiller, Jenna J.; Zander, Ryan A.; Butler, Noah S.] Univ Oklahoma, Hlth Sci Ctr, Norman, OK 73019 USA. [Obeng-Adjei, Nyamekye; Crompton, Peter D.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Wohlfert, Elizabeth A.] SUNY Buffalo, Univ Buffalo, Buffalo, NY USA. RI Crompton, Peter/N-1130-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300442 ER PT J AU Guimaraes, A Wen, X Carvalho, AM Brzostowski, J Valenzuela, J Oliveira, F AF Guimaraes, Anderson Wen, Xi Carvalho, Augusto Marcelino Brzostowski, Joseph Valenzuela, Jesus Oliveira, Fabiano TI Neutrophil recruitment during Leishmania infection: The role of sand fly salivary proteins SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Guimaraes, Anderson; Wen, Xi; Carvalho, Augusto Marcelino; Brzostowski, Joseph; Valenzuela, Jesus; Oliveira, Fabiano] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300367 ER PT J AU Hakeem, RM Druey, K Xie, ZH AF Hakeem, Reem M. Druey, Kirk Xie Zhihui TI The role of monoclonal paraproteins in Systemic Capillary Leak Syndrome (SCLS) SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Hakeem, Reem M.; Druey, Kirk; Xie Zhihui] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 MA 124.58 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300072 ER PT J AU Hessell, AJ Sacha, JB Kahl, C Graham, B Mascola, JR Haigwood, NL AF Hessell, Ann Jones Sacha, Jonah B. Kahl, Christoph Graham, Barney Mascola, John R. Haigwood, Nancy L. TI Early prophylaxis impact for newborns at risk for HIV-1 transmission at birth: viral clearance and attenuation with neutralizing monoclonal antibodies in infant rhesus macaques SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Hessell, Ann Jones; Sacha, Jonah B.; Kahl, Christoph; Haigwood, Nancy L.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Sacha, Jonah B.] Vaccine & Gene Therapy Inst, Portland, OR USA. [Graham, Barney; Mascola, John R.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 MA 146.18 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301121 ER PT J AU Hudspeth, KL Shu, W Wang, JY Rahman, S Smith, MA Casey, KA Stephens, GL Sanjuan, MA Hasni, SA Ettinger, R Siegel, RM AF Hudspeth, Kelly L. Shu, Wang Wang, Jingya Rahman, Saifur Smith, Michael A. Casey, Kerry Anne Stephens, Geoffrey L. Sanjuan, Miguel A. Hasni, Sarfaraz A. Ettinger, Rachel Siegel, Richard M. CA Autoimmunity Mol Team TI NK cell phenotype and proliferation in Systemic Lupus Erythematosus SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Hudspeth, Kelly L.; Hasni, Sarfaraz A.; Siegel, Richard M.] NIAMS, NIH, Bethesda, MD USA. [Shu, Wang; Wang, Jingya; Rahman, Saifur; Smith, Michael A.; Casey, Kerry Anne; Stephens, Geoffrey L.; Sanjuan, Miguel A.; Ettinger, Rachel; Autoimmunity Mol Team] MedImmune LLC, Gaithersburg, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301427 ER PT J AU Hurwitz, JL Jones, BG Sealy, RE Xu, BS Fan, YP Partridge, JF Maul, RW Gearhart, PJ Penkert, R AF Hurwitz, Julia L. Jones, Bart G. Sealy, Robert E. Xu, Beisi Fan, Yiping Partridge, Janet F. Maul, Robert W. Gearhart, Patricia J. Penkert, Rhiannon TI Hotspots for hormone response elements in So switch regions of immunoglobulin heavy chain loci; how estrogen may influence class switch recombination (CSR) and IgA/IgG isotype expression by activated B cells SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Hurwitz, Julia L.; Jones, Bart G.; Sealy, Robert E.; Xu, Beisi; Fan, Yiping; Partridge, Janet F.; Penkert, Rhiannon] St Jude Childrens Res Hosp, Memphis, TN USA. [Maul, Robert W.; Gearhart, Patricia J.] NIA, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300187 ER PT J AU Iwamura, C Jankoyic, D Bouladoux, N Belkaid, Y Sher, A AF Iwamura, Chiaki Jankoyic, Dragana Bouladoux, Nicolas Belkaid, Yasmine Sher, Alan TI NOD1 ligand administration restores optimal steady-state hematopoiesis in germ-free mice SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Iwamura, Chiaki; Jankoyic, Dragana; Bouladoux, Nicolas; Belkaid, Yasmine; Sher, Alan] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300471 ER PT J AU Jain, P Ginwala, R Charlins, P Akkina, R Loonawat, R Caruso, B Jacobson, S Sreedhar, S Khan, Z AF Jain, Pooja Ginwala, Rashida Charlins, Paige Akkina, Ramesh Loonawat, Ronak Caruso, Breanna Jacobson, Steven Sreedhar, Sreesha Khan, Zafar TI HTLV-1 infection and neuropathogenesis in the context of Rag1(-/-)gamma c(-/-) (RAG1) and BLT mice SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Jain, Pooja; Ginwala, Rashida; Loonawat, Ronak; Sreedhar, Sreesha; Khan, Zafar] Drexel Univ, Coll Med, Philadelphia, PA 19104 USA. [Charlins, Paige; Akkina, Ramesh] Colorado State Univ, Ft Collins, CO 80523 USA. [Caruso, Breanna; Jacobson, Steven] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301373 ER PT J AU Jankovic, D Kugler, DG Flomerfelt, FA Costa, DL Laky, K Kamenyeva, O Mittelstadt, PF Gress, RE Ashwell, JD Sher, A AF Jankovic, Dragana Kugler, David G. Flomerfelt, Francis A. Costa, Diego L. Laky, Karen Kamenyeva, Olena Mittelstadt, Paul Ft Gress, Ronald E. Ashwell, Jonathan D. Sher, Alan TI Toxoplasma gondii infection triggers a long-term defect in the generation and function of naive CD4(+) T lymphocytes SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Jankovic, Dragana; Kugler, David G.; Costa, Diego L.; Laky, Karen; Kamenyeva, Olena; Sher, Alan] NIAID, NIH, Bethesda, MD USA. [Flomerfelt, Francis A.; Mittelstadt, Paul Ft; Gress, Ronald E.; Ashwell, Jonathan D.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288302274 ER PT J AU Jiang, JS Boyd, LF Natarajan, K Margulies, DH AF Jiang, Jiansheng Boyd, Lisa F. Natarajan, Kannan Margulies, David H. TI MHC-I molecules disulfide -linked to antigenic peptides offer a simple approach to stable MHC-I/peptide complexes SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Jiang, Jiansheng; Boyd, Lisa F.; Natarajan, Kannan; Margulies, David H.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300125 ER PT J AU Jun, HS Kim, GY Kwon, JH Chou, J AF Jun, Hyun Sik Kim, Goo-Young Kwon, Joon Hyun Chou, Janice TI Aberrant expression of CD11b and CD11a underlies impaired neutrophil adhesion in glucose-6-phosphate transporter-deficient mice SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Jun, Hyun Sik] Korea Univ, Coll Med, Seoul, South Korea. [Kim, Goo-Young; Kwon, Joon Hyun; Chou, Janice] NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301407 ER PT J AU Karauzum, H Haudenschild, C Mahmoudieh, M Moore, IN Datta, SK AF Karauzum, Hatice Haudenschild, Christian Mahmoudieh, Mahta Moore, Ian N. Datta, Sandip K. TI CD4 T cell-mediated immunopathology of a Staphylococcus aureus whole cell vaccine during systemic infection SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Karauzum, Hatice; Haudenschild, Christian; Mahmoudieh, Mahta; Moore, Ian N.; Datta, Sandip K.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 MA 146.2 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301123 ER PT J AU Kenyon, EA Nayak, D McGavern, DB AF Kenyon, Elizabeth A. Nayak, Debasis McGavern, Dorian B. TI Tetherin controls T cell proliferation and exhaustion by shaping the early distribution of a persistent viral infection SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Kenyon, Elizabeth A.; Nayak, Debasis; McGavern, Dorian B.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288303343 ER PT J AU Kim, YC Kim, KK Yoon, JH Shevach, EM Scott, DW AF Kim, Yong Chan Kim, Kee Kwang Yoon, Jeong Heon Shevach, Ethan M. Scott, David W. TI Stability of Foxp3 mRNA is controlled by SAMHD1 in human T regulatory cells SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Kim, Yong Chan; Yoon, Jeong Heon; Scott, David W.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Kim, Kee Kwang] Chungnam Natl Univ, Daejeon, South Korea. [Shevach, Ethan M.] NIAID, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288302255 ER PT J AU Kotzin, JJ Spencer, SP McCright, SJ Kumar, DBU Mowel, WK Makiya, M Klion, AD Williams, A Flavell, RA Henao-Mejia, J AF Kotzin, Jonathan J. Spencer, Sean P. McCright, Sam J. Kumar, Dinesh B. Uthaya Mowel, Walter K. Makiya, Michelle Klion, Amy D. Williams, Adam Flavell, Richard A. Henao-Mejia, Jorge TI Short-lived myeloid cell lifespan is regulated by a long non-coding RNA SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Kotzin, Jonathan J.; Spencer, Sean P.; McCright, Sam J.; Mowel, Walter K.; Henao-Mejia, Jorge] Univ Penn, Philadelphia, PA 19104 USA. [Kumar, Dinesh B. Uthaya; Williams, Adam] Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. [Makiya, Michelle; Klion, Amy D.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Flavell, Richard A.] Yale Univ, New Haven, CT 06520 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 MA 202.28 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288302457 ER PT J AU Krishnamurty, AT Thouvenel, C Hondowicz, B Keitany, G Crompton, P Rawlings, DJ Pepper, M AF Krishnamurty, Akshay T. Thouvenel, Chris Hondowicz, Brian Keitany, Gladys Crompton, Peter Rawlings, David J. Pepper, Marion TI Germinal-center derived, somatically hypermutated Plasmodium-specific IgM plus memory B cells are optimally responsive to a secondary blood stage malaria infection SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Krishnamurty, Akshay T.; Hondowicz, Brian; Keitany, Gladys; Pepper, Marion] Univ Washington, Seattle, WA 98195 USA. [Thouvenel, Chris; Rawlings, David J.] Seattle Childrens Res Inst, Seattle, WA USA. [Crompton, Peter] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300436 ER PT J AU Krogsgaard, M Moogk, D Zhong, S Rittase, W Fang, V Dougherty, J Perez-Garcia, A Osman, I Zhu, C Varadarajan, N Restifo, NP Frey, AB AF Krogsgaard, Michelle Moogk, Duane Zhong, Shi Rittase, William Fang, Victoria Dougherty, Janna Perez-Garcia, Arianne Osman, Iman Zhu, Cheng Varadarajan, Navin Restifo, Nicholas P. Frey, Alan B. TI Constitutive LcK activity drives sensitivity differences between CD8+memory T cell subsets SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Krogsgaard, Michelle; Moogk, Duane; Fang, Victoria; Dougherty, Janna; Osman, Iman; Frey, Alan B.] NYU, Sch Med, New York, NY 10003 USA. [Zhong, Shi] Xiangue Pharmaceut Ltd, Xian, Peoples R China. [Rittase, William; Zhu, Cheng] Georgia Inst Technol, Atlanta, GA 30332 USA. [Perez-Garcia, Arianne] Kite Pharma, Santa Monica, CA USA. [Varadarajan, Navin] Univ Houston, Houston, TX 77004 USA. [Restifo, Nicholas P.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288302078 ER PT J AU Kwak, K Sohn, H Brzostowski, J Manzella-Lapeira, J Pierce, SK AF Kwak, Kihyuck Sohn, Haewon Brzostowski, Joseph Manzella-Lapeira, Javier Pierce, Susan K. TI Human tonsil naive B cells and germinal center B cells show distinct behaviors upon contact of antigen in lipid bilayers SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Kwak, Kihyuck; Sohn, Haewon; Brzostowski, Joseph; Manzella-Lapeira, Javier; Pierce, Susan K.] NIAID, NIH, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300225 ER PT J AU Kwong, B Flickinger, J Lazarevic, V AF Kwong, Brandon Flickinger, John Lazarevic, Vanja TI T-bet expression in NK cells is critical in the pathogenicity of Th17-induced neuroinflammation SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Kwong, Brandon; Flickinger, John; Lazarevic, Vanja] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 MA 117.6 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301264 ER PT J AU Lacerda-Queiroz, N Riteau, N Eastman, R Moore, I Sher, A Jankovic, D Su, XZ AF Lacerda-Queiroz, Norinne Riteau, Nicolas Eastman, Richard Moore, Ian Sher, Alan Jankovic, Dragana Su, Xin-zhuan TI Deciphering the IFN-gamma-mediated immunopathology during Plasmodium yoelii N67C infection SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Lacerda-Queiroz, Norinne; Riteau, Nicolas; Eastman, Richard; Moore, Ian; Sher, Alan; Jankovic, Dragana; Su, Xin-zhuan] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300267 ER PT J AU Laky, K Guerrerio, A Weissler, KA Frischmeyer-Guerrerio, P AF Laky, Karen Guerrerio, Anthony Weissler, Katherine A. Frischmeyer-Guerrerio, Pamela TI TGFBR1M318R(+/-) Knock-In mice recapitulate the immune phenotypes of Loeys-Dietz syndrome SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Laky, Karen; Weissler, Katherine A.; Frischmeyer-Guerrerio, Pamela] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Guerrerio, Anthony] Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300458 ER PT J AU Lee, E Brown, B Snow, P Vance, E Silver, P Wells, C Caspi, RR Rosenzweig, HL AF Lee, Ellen Brown, Brieanna Snow, Paige Vance, Emily Silver, Phyllis Wells, Christine Caspi, Rachel R. Rosenzweig, Holly L. TI Mincle activation and the Syk/Card9 signaling axis are central to development of autoimmune disease of the eye SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Lee, Ellen; Vance, Emily; Rosenzweig, Holly L.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Lee, Ellen; Brown, Brieanna; Snow, Paige; Vance, Emily; Rosenzweig, Holly L.] VA Portland Hlth Care Syst, Portland, OR USA. [Silver, Phyllis; Caspi, Rachel R.] NEI, NIH, Bethesda, MD USA. [Wells, Christine] Univ Queensland, Brisbane, Qld 4072, Australia. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288302249 ER PT J AU Lee, PH Germain, RN Paul, WE AF Lee, Ping-Hsien Germain, Ronald N. Paul, William E. TI IL-1 uses distinct mechanisms to enhance CD8(+) T cell expansion and differentiation SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Lee, Ping-Hsien; Germain, Ronald N.; Paul, William E.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300341 ER PT J AU Li, H Bradbury, A Edin, ML Gruzdev, A Sparks, M Hoopes, SL DeGraff, LM Bortner, CD Coffman, T Zeldin, DC AF Li, Hong Bradbury, Alyce Edin, Matthew L. Gruzdev, Artiom Sparks, Matthew Hoopes, Samantha L. DeGraff, Laura M. Bortner, Carl D. Coffman, Thomas Zeldin, Darryl C. TI Thromboxane (TXA2) Attenuates Lung Inflammatory Responses and Th9 Cell Differentiation and Function During Allergic Lung Inflammation SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Li, Hong; Bradbury, Alyce; Edin, Matthew L.; Gruzdev, Artiom; Hoopes, Samantha L.; DeGraff, Laura M.; Bortner, Carl D.; Zeldin, Darryl C.] NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Sparks, Matthew; Coffman, Thomas] Duke Univ, Durham, NC 27706 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300139 ER PT J AU Li, WQ Hixon, JA Tritapoe, J Barata, JT Durum, SK AF Li, Wenqing Hixon, Julie A. Tritapoe, Julia Barata, Joao T. Durum, Scott K. TI IL-7 receptor polymorphisms is related to signaling strength which is associated with autoimmune T cells activation in multiple sclerosis SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Li, Wenqing; Hixon, Julie A.; Tritapoe, Julia; Durum, Scott K.] NCI, Bethesda, MD 20892 USA. [Barata, Joao T.] Univ Lisbon, Sch Med, P-1699 Lisbon, Portugal. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288302336 ER PT J AU Lin, WHW Yen, B Nish, SA Kratchmarov, R Bhandoola, A Xue, HH Reiner, SL AF Lin, Wen-Hsuan Wendy Yen, Bonnie Nish, Simone A. Kratchmarov, Radomir Bhandoola, Avinash Xue, Hai-Hui (Howard) Reiner, Steven L. TI Irreversible effector CD8+T cell differentiation is linked to asymmetric, intra-divisional TCF1 silencing SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Lin, Wen-Hsuan Wendy; Yen, Bonnie; Nish, Simone A.; Kratchmarov, Radomir; Reiner, Steven L.] Columbia Univ, Med Ctr, New York, NY 10027 USA. [Bhandoola, Avinash] NCI, NIH, Bethesda, MD 20892 USA. [Xue, Hai-Hui (Howard)] Univ Iowa, Iowa City, IA 52242 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288302084 ER PT J AU Liu, S Xin, HY Nie, YJ Trivett, A Oppenheim, JJ Yang, D AF Liu, Shuo Xin, Haiyun Nie, Yingjie Trivett, Anna Oppenheim, Joost J. Yang, De TI Crytotanshinone Induces the Maturation of Human Dendritic Cells through Activation of NF-kB, p38 and JNK MAPKs SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Liu, Shuo; Xin, Haiyun; Nie, Yingjie; Trivett, Anna; Oppenheim, Joost J.; Yang, De] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 MA 142.20 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301284 ER PT J AU Lowe, JM Menendez, D Resnick, MA Fessler, MB AF Lowe, Julie Marie Menendez, Daniel Resnick, Michael A. Fessler, Michael B. TI TNFAIP8 variant 2 has an anti-inflammatory role in Toll like Receptor 4 signaling SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Lowe, Julie Marie; Menendez, Daniel; Resnick, Michael A.; Fessler, Michael B.] NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 MA 203.12 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301341 ER PT J AU Lu, Y Zhang, XY Bouladoux, N Belkaid, Y Kovalovsky, D AF Lu, Ying Zhang, Xianyu Bouladoux, Nicolas Belkaid, Yasmine Kovalovsky, Damian TI Zbtb-1 controls NKp46(+)RORgammat(+) innate lymphoid cell (ILC3) development SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Lu, Ying; Zhang, Xianyu; Kovalovsky, Damian] NCI, NIH, Bethesda, MD 20892 USA. [Bouladoux, Nicolas; Belkaid, Yasmine] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300316 ER PT J AU Luo, ZW Martin, L Kilby, M Liu, H Jin, P Stroncek, D Jiang, W AF Luo, Zhenwu Martin, Lisa Kilby, Michael Liu, Hui Jin, Ping Stroncek, David Jiang, Wei TI Influenza vaccine induces anti-nuclear and anti-double strand DNA IgG antibodies and their relates to levels of microbial translocation in antiretroviral-treated aviremic HIV-infected patients but not in healthy controls SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Luo, Zhenwu; Martin, Lisa; Kilby, Michael; Jiang, Wei] Med Univ South Carolina, Charleston, SC USA. [Liu, Hui; Jin, Ping; Stroncek, David] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300424 ER PT J AU Lyons-Cohen, MR Nakano, H Whitehead, GS Cook, DN AF Lyons-Cohen, Miranda R. Nakano, Hideki Whitehead, Gregory S. Cook, Donald N. TI Localization and trafficking of pulmonary dendritic cells during early stages of airway inflammation SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Lyons-Cohen, Miranda R.; Nakano, Hideki; Whitehead, Gregory S.; Cook, Donald N.] NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 MA 188.8 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301181 ER PT J AU Macapagal, D Connor, J Ramalingam, TR Wynn, TA Mustelin, TM Davidson, TS AF Macapagal, Daphne Connor, Jane Ramalingam, Thirumalai R. Wynn, Thomas A. Mustelin, Tomas Mikael Davidson, Todd S. TI Necrotic liver induces pyroptosis through Caspase-1 in eosinophils SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Macapagal, Daphne; Connor, Jane; Mustelin, Tomas Mikael; Davidson, Todd S.] MedImmune, Gaithersburg, MD USA. [Ramalingam, Thirumalai R.; Wynn, Thomas A.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301430 ER PT J AU Madigan, L Gordon, E Ganesan, S Levine, S Druey, KM AF Madigan, Laura Gordon, Elizabeth Ganesan, Sundar Levine, Stewart Druey, Kirk M. TI The Role of Regulator of G-Protein-Signaling 4 (RGS4) in Control of Airway Hyper responsiveness in Asthma SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Madigan, Laura; Ganesan, Sundar; Druey, Kirk M.] NIAID, NIH, Bethesda, MD USA. [Gordon, Elizabeth; Levine, Stewart] NHLBI, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300148 ER PT J AU Malhotra, D Linehan, JL Dileepan, T Lee, YJ Purtha, WE Lu, JV Nelson, RW Fife, BT Orr, HT Anderson, MS Hogquist, KA Jenkins, MK AF Malhotra, Deepali Linehan, Jonathan L. Dileepan, Thamotharampillai Lee, You Jeong Purtha, Whitney E. Lu, Jennifer V. Nelson, Ryan W. Fife, Brian T. Orr, Harry T. Anderson, Mark S. Hogquist, Kristin A. Jenkins, Marc K. TI Specific patterns of self-antigen expression determine the mechanisms by which polyclonal self-reactive CD4(+) T cells are tolerized SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Malhotra, Deepali; Linehan, Jonathan L.; Dileepan, Thamotharampillai; Lee, You Jeong; Nelson, Ryan W.; Fife, Brian T.; Orr, Harry T.; Hogquist, Kristin A.; Jenkins, Marc K.] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Linehan, Jonathan L.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Purtha, Whitney E.; Lu, Jennifer V.; Anderson, Mark S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288303074 ER PT J AU Marrero, B Liu, Y Biancotto, A Calvo, KR Huang, Y De Jesus, AA Goldbach-Mansky, R AF Marrero, Bernadette Liu, Yin Biancotto, Angelique Calvo, Katherine R. Huang, Yan De Jesus, Adriana A. Goldbach-Mansky, Raphaela TI Differences in Innate immune cell production of IFN alpha and IFN I3 to cell activation in the Autoinflammatory Diseases CANDLE (Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature) and SAVI (STING Associated Vasculopathy with Onset in Infancy) SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Marrero, Bernadette; Liu, Yin; Biancotto, Angelique; Calvo, Katherine R.; Huang, Yan; De Jesus, Adriana A.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Goldbach-Mansky, Raphaela] NIAMS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300459 ER PT J AU McCarthy, MK Hawman, DW Elmore, SA Morrison, TE AF McCarthy, Mary K. Hawman, David W. Elmore, Susan A. Morrison, Thomas E. TI Chronic chikungunya virus infection disrupts the architecture and function of draining lymphoid tissue SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [McCarthy, Mary K.; Hawman, David W.; Morrison, Thomas E.] Univ Colorado, Sch Med, Boulder, CO 80309 USA. [Elmore, Susan A.] NIEHS, NIH, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301383 ER PT J AU Meylan, F Hayes, E Ferdinand, J Farley, T Richoz, N Gabay, O Siegel, RM AF Meylan, Francoise Hayes, Erika Ferdinand, John Farley, Taylor Richoz, Nathan Gabay, Odile Siegel, Richard M. TI Role of the TNF-family cytokine TL1A and its receptor DR3 in systemic autoimmunity and glomerulonephritis SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Meylan, Francoise; Hayes, Erika; Ferdinand, John; Farley, Taylor; Richoz, Nathan; Gabay, Odile; Siegel, Richard M.] NIAMS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300420 ER PT J AU Morawski, PA Qi, CF Bolland, S AF Morawski, Peter A. Qi, Chen-Feng Bolland, Silvia TI Brain infiltrating CD8+T lymphocytes in lupus-prone mice SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Morawski, Peter A.; Qi, Chen-Feng; Bolland, Silvia] NIAID, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288303018 ER PT J AU Mu, QH Zhang, HS Luo, XM AF Mu, Qinghui Zhang, Husen Luo, Xin M. TI Disease stage-dependent response of lupus-prone mice to antibiotics SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Mu, Qinghui; Luo, Xin M.] Virginia Polytech Inst & State Univ, Blacksburg, VA 24061 USA. [Zhang, Husen] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300163 ER PT J AU Narasimhan, PB Akabas, L Huda, N Sabzevari, H Hofmeister, R Nutman, TB Semnani, RT AF Narasimhan, Prakash Babu Akabas, Leor Huda, Naureen Sabzevari, Helen Hofmeister, Robert Nutman, Thomas B. Semnani, Roshanak Tolouei TI Helminth parasites and cancer-causing tumors condition human monocytes similarly: insights into parallel mechanisms of immune evasion SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Narasimhan, Prakash Babu; Akabas, Leor; Huda, Naureen; Nutman, Thomas B.; Semnani, Roshanak Tolouei] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Sabzevari, Helen; Hofmeister, Robert] EMD Serono Res & Dev Inst Inc, Billerica, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300271 ER PT J AU Natarajan, K Morozov, G Jiang, JS Boyd, LF Mage, MG Margulies, DH AF Natarajan, Kannan Morozov, Giora Jiang, Jiansheng Boyd, Lisa F. Mage, Michael G. Margulies, David H. TI TAPBPR, a Peptide Editor - interactions with MHC complexes and SAXS structural studies SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Natarajan, Kannan; Morozov, Giora; Jiang, Jiansheng; Boyd, Lisa F.; Mage, Michael G.; Margulies, David H.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300126 ER PT J AU Nie, YJ Oppenheim, JJ Yang, D Trivett, A Xin, HY AF Nie, Yingjie Oppenheim, Joost J. Yang, De Trivett, Anna Xin, Haiyun TI Development of a Curative Immunotherapeutic Strategy for the Treatment of Big Established CT26 Tumors SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Nie, Yingjie; Oppenheim, Joost J.; Yang, De; Trivett, Anna; Xin, Haiyun] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288303117 ER PT J AU ONeill, R Leigh, N Du, W Kumar, S Chen, C Qiu, JX Chen, G Borst, J Ashwell, JD McCarthy, P Cao, XF AF ONeill, Rachel Leigh, Nicholas Du, Wei Kumar, Sandeep Chen, Chuan Qiu, Jingxin Chen, George Borst, Jannie Ashwell, Jonathan D. McCarthy, Philip Cao, Xuefang TI CD27/CD70 mediated negative regulation of inflammatory T cell response SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [ONeill, Rachel; Leigh, Nicholas; Du, Wei; Kumar, Sandeep; Chen, Chuan; Qiu, Jingxin; Chen, George; McCarthy, Philip; Cao, Xuefang] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Borst, Jannie] Netherlands Canc Inst, Amsterdam, Netherlands. [Ashwell, Jonathan D.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288303260 ER PT J AU Paulos, CM Bowers, JS Bailey, SR Diven, MA Fugle, CW Kaiser, AD Wrzesinski, C Liu, B Restifo, NP Nelson, M AF Paulos, Chrystal M. Bowers, Jacob S. Bailey, Stefanie R. Diven, Marshall A. Fugle, Caroline W. Kaiser, Andrew D. Wrzesinski, Claudia Liu, Bei Restifo, Nicholas P. Nelson, Michelle TI Toll-like receptor agonist therapy augments the antitumor activity of adoptively transferred CD8(+) T cells without host preconditioning SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Paulos, Chrystal M.; Bowers, Jacob S.; Bailey, Stefanie R.; Diven, Marshall A.; Fugle, Caroline W.; Liu, Bei; Nelson, Michelle] Med Univ South Carolina, Charleston, SC USA. [Paulos, Chrystal M.; Kaiser, Andrew D.; Wrzesinski, Claudia; Restifo, Nicholas P.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 MA 213.7 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301078 ER PT J AU Pavlakis, GN Ng, SM Dimas, K Valentin, A Nagy, B Alicea, C Felber, BK Bergamaschi, C AF Pavlakis, George N. Ng, Sin Man Dimas, Konstantinos Valentin, Antonio Nagy, Bethany Alicea, Candido Felber, Barbara K. Bergamaschi, Cristina TI hetIL-15 therapy results in tumor control by promoting tumor infiltration of CD8(+) T cells with increased cytotoxic potential and decreased PD-1 expression SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Pavlakis, George N.; Ng, Sin Man; Dimas, Konstantinos; Valentin, Antonio; Nagy, Bethany; Alicea, Candido; Felber, Barbara K.; Bergamaschi, Cristina] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300320 ER PT J AU Perrone, I Cicala, C Nawaz, F Ray, J Olowojesiku, R Waliszewski, M Jelicic, K Wei, D Van Ryk, D Ansari, AA Fauci, AS Arthos, J AF Perrone, Ian Cicala, Claudia Nawaz, Fatima Ray, Jocelyn Olowojesiku, Ronke Waliszewski, Mia Jelicic, Katija Wei, Danlan Van Ryk, Donald Ansari, Aftab Ahmed Fauci, Anthony S. Arthos, James TI MAdCAM signaling through integrin alpha(4)beta(7) modulates surface expression of CCR5 and markers of CD4(+) cell activation. SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Perrone, Ian; Cicala, Claudia; Nawaz, Fatima; Ray, Jocelyn; Olowojesiku, Ronke; Waliszewski, Mia; Jelicic, Katija; Wei, Danlan; Van Ryk, Donald; Fauci, Anthony S.; Arthos, James] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Ansari, Aftab Ahmed] Emory Univ, Sch Med, Atlanta, GA 30322 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 MA 207.13 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301070 ER PT J AU Ploch, M Pelletier, M Billingham, L Siegel, RM AF Ploch, Michelle Pelletier, Martin Billingham, Leah Siegel, Richard M. TI Potential interaction of WT and Mutant TNF-Receptor 1 and Pyruvate Kinase M2 in TNF-Receptor-Associated Periodic Fever Syndrome (TRAPS) SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Ploch, Michelle; Pelletier, Martin; Billingham, Leah; Siegel, Richard M.] NIAMS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 MA 117.12 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301254 ER PT J AU Roberts, LM Crane, DD Wehrly, TD Fletcher, JR Jones, BD Bosio, CM AF Roberts, Lydia M. Crane, Deborah D. Wehrly, Tara D. Fletcher, Joshua R. Jones, Bradley D. Bosio, Catharine M. TI Inclusion of non-Francisella epitopes promotes expansion of high avidity, antigen-specific CD4(+) T cells for improvement of existing Francisella vaccines SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Roberts, Lydia M.; Crane, Deborah D.; Wehrly, Tara D.; Bosio, Catharine M.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Fletcher, Joshua R.; Jones, Bradley D.] Univ Iowa, Carver Coll Med, Iowa City, IA 52242 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 MA 66.6 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301012 ER PT J AU Rua, R McGavern, DB AF Rua, Rejane McGavern, Dorian B. TI Alternatively activated brain-resident macrophages acquire and retain inflammatory properties following CNS infection while interacting with effector and memory T cells SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Rua, Rejane; McGavern, Dorian B.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301100 ER PT J AU Sato, N Asiedu, KO Choyke, PL AF Sato, Noriko Asiedu, Kingsley O. Choyke, Peter L. TI Zr-89 positron emission tomography detects migration of donor cells to the ileum in a mouse bone marrow transplantation model SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Sato, Noriko; Asiedu, Kingsley O.; Choyke, Peter L.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288303176 ER PT J AU Shalaby, KH Whitehead, GS Thomas, SY Cook, DN AF Shalaby, Karim H. Whitehead, Gregory S. Thomas, Seddon Y. Cook, Donald N. TI Chronic antigen-specific T helper 17 inflammatory responses in the lungs require persistent adjuvant exposure to be sustained SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Shalaby, Karim H.; Whitehead, Gregory S.; Thomas, Seddon Y.; Cook, Donald N.] NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288302076 ER PT J AU Siebenlist, U Ha, HL Wang, HS Claudio, E Tang, WH AF Siebenlist, Ulrich Ha, Hye-lin Wang, Hongshan Claudio, Estefania Tang, Wanhu TI IL-17 drives but can also restrain psoriatic inflammation via distinct, target cell-specific mechanisms SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Siebenlist, Ulrich; Ha, Hye-lin; Wang, Hongshan; Claudio, Estefania; Tang, Wanhu] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300376 ER PT J AU Smith, CE Jalbert, E de Almeida, V Mussi-Pinhata, M Cohen, RA Yu, QL Amaral, F Pinto, J Alarcon, J Siberry, G Weinberg, A AF Smith, Christiana E. Jalbert, Emilie de Almeida, Volia Mussi-Pinhata, Marisa Cohen, Rachel A. Yu, Qilu Amaral, Fabiana Pinto, Jorge Alarcon, Jorge Siberry, George Weinberg, Adriana TI Natural killer cell dysfunction in HIV-exposed uninfected infants correlates with acquisition of lower respiratory tract infection SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Smith, Christiana E.; Jalbert, Emilie; Weinberg, Adriana] Univ Colorado, Sch Med, Boulder, CO 80309 USA. [de Almeida, Volia] Univ Fed Sao Carlos, BR-13560 Sao Carlos, SP, Brazil. [Mussi-Pinhata, Marisa; Amaral, Fabiana] Univ Sao Paulo, Ribeirao Preto Fac Med, BR-05508 Sao Paulo, Brazil. [Cohen, Rachel A.; Yu, Qilu] WESTAT Corp, Rockville, MD 20850 USA. [Pinto, Jorge] Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil. [Alarcon, Jorge] DA Carr Inst Trop Med, Lima, Peru. [Siberry, George] NICHD, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301106 ER PT J AU Spolski, R West, EE Li, P Kazemian, M Leonard, W AF Spolski, Rosanne West, Erin E. Li, Peng Kazemian, Majid Leonard, Warren TI IL-21 regulates the innate immune response to Staphylococcus aureus pulmonary infection SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Spolski, Rosanne; West, Erin E.; Li, Peng; Kazemian, Majid; Leonard, Warren] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300343 ER PT J AU Sun, J Li, N Oh, KS Dutta, B Vayttaden, SJ Lin, B Ebert, TS De Nardo, D Davis, J Bagirzadeh, R Lounsbury, NW Pasare, C Latz, E Hornung, V Fraser, I AF Sun, Jing Li, Ning Oh, Kyu-Seon Dutta, Bhaskar Vayttaden, Sharat J. Lin, Bin Ebert, Thomas S. De Nardo, Dominic Davis, Joie Bagirzadeh, Rustam Lounsbury, Nicolas W. Pasare, Chandrashekhar Latz, Eicke Hornung, Veit Fraser, Iain TI Comprehensive RNAi-based screening of human and mouse TLR pathways identifies species-specific preferences in signaling protein use SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Sun, Jing; Li, Ning; Oh, Kyu-Seon; Dutta, Bhaskar; Vayttaden, Sharat J.; Lin, Bin; Davis, Joie; Lounsbury, Nicolas W.; Fraser, Iain] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Ebert, Thomas S.; De Nardo, Dominic; Latz, Eicke; Hornung, Veit] Univ Bonn, Bonn, Germany. [Bagirzadeh, Rustam; Pasare, Chandrashekhar] Univ Texas Southwestern Med Ctr, Dallas, TX USA. [Latz, Eicke] German Ctr Neurodegenerat Dis, Gottingen, Germany. [Latz, Eicke] Univ Massachusetts, Sch Med, Amherst, MA 01003 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 MA 203.22 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301332 ER PT J AU Swanson, PA Hart, GT Russo, MV Pierce, SK McGavern, DB AF Swanson, Phillip A. Hart, Geoffrey T. Russo, Matthew V. Pierce, Susan K. McGavern, Dorian B. TI Antigen-dependent engagement of brain endothelium by CD8 T cells leads to fatal brainstem pathology during cerebral malaria SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Swanson, Phillip A.; McGavern, Dorian B.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Hart, Geoffrey T.; Pierce, Susan K.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Russo, Matthew V.] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300440 ER PT J AU Tariq, Z McGavern, DB O'Shea, JJ Canna, S AF Tariq, Zeshan McGavern, Dorian B. O'Shea, John J. Canna, Scott TI An NIrc4 mutation associated with systemic hyperinflammation drives spontaneous non-hematopoietic IL-18 hyperproduction SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Tariq, Zeshan; O'Shea, John J.; Canna, Scott] NIAMS, NIH, Bethesda, MD USA. [McGavern, Dorian B.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 MA 62.10 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301168 ER PT J AU Tatomir, A Tegla, CA Cudrici, CD Boodhoo, D Martin, A Mekala, A Rus, V Badea, TC Rus, H AF Tatomir, Alexandru Tegla, Cosmin A. Cudrici, Cornelia D. Boodhoo, Dallas Martin, Alvaro Mekala, Armugam Rus, Violeta Badea, Tudor C. Rus, Horea TI RGC-32 regulates TGF-beta extracellular matrix production in multiple sclerosis. SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Tatomir, Alexandru; Tegla, Cosmin A.; Boodhoo, Dallas; Martin, Alvaro; Mekala, Armugam; Rus, Violeta; Rus, Horea] Univ Maryland, Sch Med, College Pk, MD 20742 USA. [Cudrici, Cornelia D.] NIAMS, NIH, Bethesda, MD USA. [Badea, Tudor C.] NEI, NIH, Bethesda, MD USA. [Rus, Horea] VA Maryland Hlth Care Syst, Perry Point, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288302326 ER PT J AU Thomas, SK Ouyang, C Cruz, AC Klebanoff, CA Yamamoto, TN Chan, FK Mocarski, ES Roback, L Restifo, NP Siegei, RM AF Thomas, Stacy K. Ouyang, Claudia Cruz, Anthony C. Klebanoff, Christopher A. Yamamoto, Tori N. Chan, Francis K. Mocarski, Edward S. Roback, Linda Restifo, Nicholas P. Siegei, Richard M. TI Identifying Fas/CD95 non-apoptotic signaling pathways associated with T cell differentiation SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Thomas, Stacy K.; Ouyang, Claudia; Cruz, Anthony C.; Siegei, Richard M.] NIAMS, NIH, Bethesda, MD USA. [Klebanoff, Christopher A.; Yamamoto, Tori N.; Restifo, Nicholas P.] NCI, NIH, Bethesda, MD 20892 USA. [Chan, Francis K.] Univ Massachusetts, Sch Med, Amherst, MA 01003 USA. [Mocarski, Edward S.; Roback, Linda] Emory Univ, Sch Med, Atlanta, GA 30322 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288303080 ER PT J AU Thornton, AM Kilaru, G Burr, P Rieder, S Muljo, SA Shevach, EM AF Thornton, Angela M. Kilaru, Gokhul Burr, Patrick Rieder, Sadiye Muljo, Stefan Adi Shevach, Ethan M. TI Helios expression defines two distinct populations of Foxp3(+) regulatory T cells SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Thornton, Angela M.; Kilaru, Gokhul; Burr, Patrick; Rieder, Sadiye; Muljo, Stefan Adi; Shevach, Ethan M.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288302438 ER PT J AU Tran, TM Gul, T Hong, S Bennett, J Colbert, RA AF Tran, Tri M. Gul, Tejpal Hong, Sohee Bennett, Joshua Colbert, Robert A. TI ERAP1 deficiency protects HLA-B27 transgenic rats from arthritis SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Tran, Tri M.; Gul, Tejpal; Hong, Sohee; Bennett, Joshua; Colbert, Robert A.] NIAMS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300127 ER PT J AU Uehling, M Hillyer, P Shepard, R Sheik, F Luongo, C Buchholz, U Collins, PL Donnelly, RP Rabin, RL AF Uehling, Megan Hillyer, Philippa Shepard, Rachel Sheik, Faruk Luongo, Cindy Buchholz, Ursula Collins, Peter L. Donnelly, Raymond P. Rabin, Ronald L. TI Innate IFNs and pro-inflammatory cytokines in local control of Respiratory Syncytial Virus infection of respiratory epithelial cells SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Uehling, Megan; Hillyer, Philippa; Shepard, Rachel; Rabin, Ronald L.] US FDA, CBER, Rockville, MD 20857 USA. [Sheik, Faruk; Donnelly, Raymond P.] US FDA, CDER, Rockville, MD 20857 USA. [Luongo, Cindy; Buchholz, Ursula; Collins, Peter L.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301112 ER PT J AU van Panhuys, NJ Palmer, D AF van Panhuys, Nicholas J. Palmer, Douglas TI CD4+T Cell Differentiation is Determined During an Initial Priming Phase and Occurs Independently of Effects due to Division or Survival. SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [van Panhuys, Nicholas J.] Sidra Med & Res Ctr, Doha, Qatar. [Palmer, Douglas] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288302072 ER PT J AU Veres, TZ Kopcsanyi, T van Panhuys, N Gerner, MY Liu, ZD Rantakari, P Dunkel, J Miyasaka, M Jalkanen, S Germain, RN AF Veres, Tibor Z. Kopcsanyi, Tarnas van Panhuys, Nicholas Gerner, Michael Y. Liu, Zhiduo Rantakari, Pia Dunkel, Johannes Miyasaka, Masayuki Jalkanen, Sirpa Germain, Ronald N. TI CD4(+) T-cell cytokine production within a ay mucosal DC-T-cell clusters drives the local recruitment of myeloid effector cells in response to house dust mite allergen SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Veres, Tibor Z.; Kopcsanyi, Tarnas; Rantakari, Pia; Dunkel, Johannes; Miyasaka, Masayuki; Jalkanen, Sirpa] Univ Turku, SF-20500 Turku, Finland. [Veres, Tibor Z.; van Panhuys, Nicholas; Gerner, Michael Y.; Liu, Zhiduo; Germain, Ronald N.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [van Panhuys, Nicholas] Sidra Med & Res Ctr, Doha, Qatar. [Gerner, Michael Y.] Univ Washington, Seattle, WA 98195 USA. [Miyasaka, Masayuki] Osaka Univ, Suita, Osaka 565, Japan. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300161 ER PT J AU Voss, OH Coligan, JE AF Voss, Oliver H. Coligan, John E. TI LPS-induced interaction between Cd300b/DAP12 and TLR4/CD14 results in the amplification of inflammation and increased mortality from sepsis. SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Voss, Oliver H.; Coligan, John E.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 MA 202.11 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288302479 ER PT J AU Waliszewski, M Nawaz, F Cicala, C Ray, J Olowojesiku, R Perrone, I Wei, DL Jelicic, K van Ryk, D Ansari, AA Fauci, AS Arthos, J AF Waliszewski, Mia Nawaz, Fatima Cicala, Claudia Ray, Jocelyn Olowojesiku, Ronke Perrone, Ian Wei, Danlan Jelicic, Katija van Ryk, Donald Ansari, Aftab Ahmed Fauci, Anthony S. Arthos, James TI Anti-alpha(4)beta(7) mAb prevents MAdCAM-1-mediated activation and HIV replication in CD4(+) T cells SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Waliszewski, Mia; Nawaz, Fatima; Cicala, Claudia; Ray, Jocelyn; Olowojesiku, Ronke; Perrone, Ian; Wei, Danlan; Jelicic, Katija; van Ryk, Donald; Fauci, Anthony S.; Arthos, James] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Ansari, Aftab Ahmed] Emory Univ, Sch Med, Atlanta, GA 30322 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 MA 208.11 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301214 ER PT J AU Watanabe, M Fujihara, C Jeffrey, CY Bhatia, S Hodes, RJ AF Watanabe, Masashi Fujihara, Chiharu Jeffrey, Chiang Y. Bhatia, Sumeena Hodes, Richard J. TI Costimulatory pathways mediating T-dependent germinal center responses: distinct cellular requirements for CD40 and B7 costimulation SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Watanabe, Masashi; Fujihara, Chiharu; Jeffrey, Chiang Y.; Bhatia, Sumeena; Hodes, Richard J.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288303075 ER PT J AU West, EE Arbore, G Robertson, AAB Klos, A Woodruff, TM O'Neill, LA Coll, RC Sher, A Leonard, WJ Kohl, J Monk, P Cooper, MA Afzali, B Lachmann, HJ Cope, AP Mayer-Barber, K Kemper, C AF West, Erin E. Arbore, Giuseppina Robertson, Avril A. B. Klos, Andreas Woodruff, Trent M. O'Neill, Luke A. Coll, Rebecca C. Sher, Alan Leonard, Warren J. Koehl, Joerg Monk, Pete Cooper, Matthew A. Afzali, Behdad Lachmann, Helen J. Cope, Andrew P. Mayer-Barber, Katrin Kemper, Claudia TI Autocrine NLPR3 inflammasome activity is critical to normal adaptive immunity via regulation of IFN-gamma in CD4(+) T cells SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [West, Erin E.; Leonard, Warren J.; Kemper, Claudia] NHLBI, NIH, Bethesda, MD USA. [Arbore, Giuseppina; Afzali, Behdad; Cope, Andrew P.; Kemper, Claudia] Kings Coll London, London WC2R 2LS, England. [Robertson, Avril A. B.; Woodruff, Trent M.; Coll, Rebecca C.; Cooper, Matthew A.] Univ Queensland, Brisbane, Qld 4072, Australia. [Klos, Andreas] Hannover Med Sch, Hannover, Germany. [O'Neill, Luke A.] Trinity Coll Dublin, Dublin, Ireland. [Sher, Alan; Mayer-Barber, Katrin] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Koehl, Joerg] Univ Lubeck, Lubeck, Germany. [Monk, Pete] Univ Sheffield, Sheffield S10 2TN, S Yorkshire, England. [Afzali, Behdad] NIAMS, NIH, Bethesda, MD USA. [Lachmann, Helen J.] UCL, London WC1E 6BT, England. RI Monk, Peter/C-6155-2008; Robertson, Avril/A-4043-2012 OI Monk, Peter/0000-0003-4637-3059; Robertson, Avril/0000-0002-9652-8357 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288302413 ER PT J AU West, EE Spolski, R Kazemian, M Kemper, C Leonard, WJ AF West, Erin E. Spolski, Rosanne Kazemian, Majid Kemper, Claudia Leonard, Warren J. TI TSLP acts on neutrophils to drive complement-mediated killing of methicillin-resistant Staphylococcus aureus SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [West, Erin E.; Spolski, Rosanne; Kazemian, Majid; Kemper, Claudia; Leonard, Warren J.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Kemper, Claudia] Kings Coll London, London, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300493 ER PT J AU Wu, TQ Shin, HM Moseman, EA Ji, Y Huang, BN Harly, C Sen, JM Berg, LJ Gattinoni, L McGavern, DB Schwartzberg, PL AF Wu, Tuoqi Shin, HyunMu Moseman, E. Ashley Ji, Yun Huang, Bonnie Harly, Christelle Sen, Jyoti M. Berg, Leslie J. Gattinoni, Luca McGavern, Dorian B. Schwartzberg, Pamela L. TI TCF1 regulates antiviral T follicular helper (Tfh) cell responses through a negative feedback loop with IL-2 and Blimp1 SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Wu, Tuoqi; Huang, Bonnie; Schwartzberg, Pamela L.] NHGRI, NIH, Los Angeles, CA USA. [Shin, HyunMu; Berg, Leslie J.] Univ Massachusetts, Sch Med, Amherst, MA 01003 USA. [Moseman, E. Ashley; McGavern, Dorian B.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Ji, Yun; Harly, Christelle; Gattinoni, Luca] NCI, NIH, Bethesda, MD 20892 USA. [Sen, Jyoti M.] NIA, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300237 ER PT J AU Wyatt, EV Diaz, K Griffin, A Rasmussen, J Crane, D Jones, B Bosio, CM AF Wyatt, Elliott V. Diaz, Karina Griffin, Amanda Rasmussen, Jed Crane, Deborah Jones, Bradley Bosio, Catharine M. TI Optimal replication and suppression of inflammation by virulent Francisella tularensis is achieved through reprogramming of host glycolysis. SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Wyatt, Elliott V.; Griffin, Amanda; Crane, Deborah; Bosio, Catharine M.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Diaz, Karina] Univ Washington, Seattle, WA 98195 USA. [Rasmussen, Jed] Snow Coll, Ephraim, UT USA. [Jones, Bradley] Univ Iowa, Iowa City, IA 52242 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 MA 66.7 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301034 ER PT J AU Yang, D Li, YN Nie, YJ Trivett, A Oppenheim, JJ AF Yang, De Li, Yana Nie, Yingjie Trivett, Anna Oppenheim, Joost J. TI Keratinocyte Release of Alarm in HMGN1 Is triggered by Elevation of Intracellular Calcium SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Yang, De; Li, Yana; Nie, Yingjie; Trivett, Anna; Oppenheim, Joost J.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 MA 203.19 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301336 ER PT J AU Ye, J AF Ye, Jian TI An update on IgBLAST, a tool for Ig and TCR sequence analysis SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Ye, Jian] NIH, NCBI, NLM, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301490 ER PT J AU Young, HA Leung, P Tsuneyama, K Valencia, J Hodge, DL Kim, S Back, T Karwan, M Merchant, A Feng, DC Gao, B Park, O Gershwin, ME Bae, R AF Young, Howard A. Leung, Patrick Tsuneyama, Koichi Valencia, Julio Hodge, Deborah L. Kim, Seohyun Back, Tim Karwan, Megan Merchant, Anand Feng, Dechun Gao, Bin Park, Ogyi Gershwin, M. Eric Bae, Rachel TI Chronic Interferon-gamma expression triggers a female bias in the development of primary biliary cholangitis SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Young, Howard A.; Valencia, Julio; Kim, Seohyun; Back, Tim; Karwan, Megan; Merchant, Anand; Bae, Rachel] NCI, NIH, Bethesda, MD 20892 USA. [Leung, Patrick; Gershwin, M. Eric] Univ Calif Davis, Sch Med, Davis, CA 95616 USA. [Tsuneyama, Koichi] Univ Tokushima, Tokushima, Japan. [Hodge, Deborah L.] NIH, CSR, Bethesda, MD USA. [Feng, Dechun; Gao, Bin] NIAAA, NIH, Bethesda, MD USA. [Park, Ogyi] Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300435 ER PT J AU Yuan, WM Wen, XS Li, M Xiong, R Bosselut, R Rao, P AF Yuan, Weiming Wen, Xiangshu Li, Michelle Xiong, Ran Bosselut, Remy Rao, Ping TI Transcriptional regulation in the development of CD8ab+iNKT cells in a humanized mouse model SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Yuan, Weiming; Wen, Xiangshu; Li, Michelle; Xiong, Ran; Rao, Ping] Univ Southern Calif, Los Angeles, CA USA. [Bosselut, Remy] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288300116 ER PT J AU Zhong, C Cui, KR Wilhelm, C Hu, GQ Mao, KR Belkaid, Y Zhao, KJ Zhu, JF AF Zhong, Chao Cui, Kairong Wilhelm, Christoph Hu, Gangqing Mao, Kairui Belkaid, Yasmine Zhao, Keji Zhu, Jinfang TI Group 3 innate lymphoid cells continuously require the transcription factor GATA-3 after commitment SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Zhong, Chao; Mao, Kairui; Belkaid, Yasmine; Zhu, Jinfang] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Cui, Kairong; Hu, Gangqing; Zhao, Keji] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Wilhelm, Christoph] Univ Bonn, Bonn, Germany. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288302094 ER PT J AU Aziz, A Sharova, T Klimova, A Ryu, B Muegge, K Botchkarev, V Sharov, A AF Aziz, A. Sharova, T. Klimova, A. Ryu, B. Muegge, K. Botchkarev, V. Sharov, A. TI Chromatin remodeler Lymphoid-specific helicase (Lsh) is a critical determinant controlling postnatal epidermal growth, differentiation and response to injury SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Investigative-Dermatology (SID) CY MAY 11-14, 2016 CL Scottsdale, AZ SP Soc Investigat Dermatol C1 [Aziz, A.; Sharova, T.; Klimova, A.; Ryu, B.; Botchkarev, V.; Sharov, A.] Boston Univ, Dermatol, Boston, MA 02215 USA. [Muegge, K.] NCI, Ctr Canc Res, Frederick, MD 21701 USA. [Botchkarev, V.] Univ Bradford, Ctr Skin Sci, Bradford, W Yorkshire, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2016 VL 136 IS 5 SU 1 MA 707 BP S125 EP S125 PG 1 WC Dermatology SC Dermatology GA DR6RK UT WOS:000380028800707 ER PT J AU Baysac, K Bible, P Smith, J Kellett, M Jenkins, L Morasso, MI AF Baysac, K. Bible, P. Smith, J. Kellett, M. Jenkins, L. Morasso, M. I. TI Elucidating the DLX3 interactome to identify the mechanisms through which it regulates skin differentiation SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Investigative-Dermatology (SID) CY MAY 11-14, 2016 CL Scottsdale, AZ SP Soc Investigat Dermatol C1 [Baysac, K.; Bible, P.; Smith, J.; Kellett, M.; Morasso, M. I.] NIAMS, Bethesda, MD USA. [Jenkins, L.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2016 VL 136 IS 5 SU 1 MA 354 BP S62 EP S62 PG 1 WC Dermatology SC Dermatology GA DR6RK UT WOS:000380028800354 ER PT J AU Bhattacharya, S Kim, J Nakato, G Ogawa, Y Udey, M Morasso, MI AF Bhattacharya, S. Kim, J. Nakato, G. Ogawa, Y. Udey, M. Morasso, M. I. TI Ablation of DLX3 in adult murine keratinocytes lead to deregulation of cell cycle and infiltration of IL-17 producing leukocytes SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Investigative-Dermatology (SID) CY MAY 11-14, 2016 CL Scottsdale, AZ SP Soc Investigat Dermatol C1 [Bhattacharya, S.; Kim, J.; Morasso, M. I.] NIAMSD, Skin Biol Lab, NIH, Bethesda, MD USA. [Nakato, G.; Ogawa, Y.; Udey, M.] NCI, Dermatol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2016 VL 136 IS 5 SU 1 MA 477 BP S84 EP S84 PG 1 WC Dermatology SC Dermatology GA DR6RK UT WOS:000380028800477 ER PT J AU Cui, C Michel, M Piao, Y Kume, T Schlessinger, D AF Cui, C. Michel, M. Piao, Y. Kume, T. Schlessinger, D. TI A common acute myeloid leukemia-associated DNMT3A mutation, when expressed ubiquitously in mice, causes reversible alopecia SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Investigative-Dermatology (SID) CY MAY 11-14, 2016 CL Scottsdale, AZ SP Soc Investigat Dermatol C1 [Cui, C.; Michel, M.; Piao, Y.; Schlessinger, D.] NIA, Genet Lab, Baltimore, MD 21224 USA. [Kume, T.] Northwestern Univ, Feinberg Cardiovasc Res Inst, Feinberg Sch Med, Chicago, IL 60611 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2016 VL 136 IS 5 SU 1 MA 682 BP S121 EP S121 PG 1 WC Dermatology SC Dermatology GA DR6RK UT WOS:000380028800682 ER PT J AU Iglesias-Bartolome, R Edwards, D Molinolo, AA Brooks, S Doci, C Abusleme, L Moutsopoulos, N Gutkind, JS Morasso, MI AF Iglesias-Bartolome, R. Edwards, D. Molinolo, A. A. Brooks, S. Doci, C. Abusleme, L. Moutsopoulos, N. Gutkind, J. S. Morasso, M. I. TI The molecular anatomy of human oral and cutaneous wound healing SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Investigative-Dermatology (SID) CY MAY 11-14, 2016 CL Scottsdale, AZ SP Soc Investigat Dermatol C1 [Edwards, D.; Molinolo, A. A.; Doci, C.; Abusleme, L.; Moutsopoulos, N.; Gutkind, J. S.] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, Bethesda, MD USA. [Iglesias-Bartolome, R.; Brooks, S.; Morasso, M. I.] NIAMSD, Skin Biol Lab, Bethesda, MD USA. [Molinolo, A. A.; Gutkind, J. S.] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2016 VL 136 IS 5 SU 1 MA 711 BP S126 EP S126 PG 1 WC Dermatology SC Dermatology GA DR6RK UT WOS:000380028800711 ER PT J AU Kaunitz, G Topalian, SL Yanik, EL Cottrell, T Esandrio, J Engels, EA Taube, JM AF Kaunitz, G. Topalian, S. L. Yanik, E. L. Cottrell, T. Esandrio, J. Engels, E. A. Taube, J. M. TI Characterization of the tumor immune microenvironment in anal squamous cell carcinomas from HIV(+) versus HIV(-) patients SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Investigative-Dermatology (SID) CY MAY 11-14, 2016 CL Scottsdale, AZ SP Soc Investigat Dermatol C1 [Kaunitz, G.; Topalian, S. L.; Cottrell, T.; Esandrio, J.; Taube, J. M.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Kaunitz, G.; Topalian, S. L.; Cottrell, T.; Esandrio, J.; Taube, J. M.] Sidney Kimmel Canc Ctr, Baltimore, MD USA. [Yanik, E. L.; Engels, E. A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2016 VL 136 IS 5 SU 1 MA 241 BP S43 EP S43 PG 1 WC Dermatology SC Dermatology GA DR6RK UT WOS:000380028800241 ER PT J AU Kellett, M Palazzo, E Cataisson, C Bible, P Gormley, A Lessard, J Yuspa, S Morasso, MI AF Kellett, M. Palazzo, E. Cataisson, C. Bible, P. Gormley, A. Lessard, J. Yuspa, S. Morasso, M. I. TI Homeostatic balance of DLX3-PKC interplay controls keratinocyte cell cycle, differentiation, and inflammation-related pathways SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Investigative-Dermatology (SID) CY MAY 11-14, 2016 CL Scottsdale, AZ SP Soc Investigat Dermatol C1 [Kellett, M.; Palazzo, E.; Bible, P.; Gormley, A.; Lessard, J.; Morasso, M. I.] NIAMS, Skin Biol Lab, NIH, Bethesda, MD USA. [Cataisson, C.; Yuspa, S.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2016 VL 136 IS 5 SU 1 MA 318 BP S56 EP S56 PG 1 WC Dermatology SC Dermatology GA DR6RK UT WOS:000380028800318 ER PT J AU Kennedy, EA Gallagher, A Hourihane, JO Fallon, P Murray, D Segre, JA Kong, HH Irvine, AD AF Kennedy, E. A. Gallagher, A. Hourihane, J. O. Fallon, P. Murray, D. Segre, J. A. Kong, H. H. Irvine, A. D. TI Skin microbiome alterations in infants before clinical atopic dermatitis SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Investigative-Dermatology (SID) CY MAY 11-14, 2016 CL Scottsdale, AZ SP Soc Investigat Dermatol C1 [Kennedy, E. A.; Kong, H. H.] NCI, Dermatol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Gallagher, A.; Hourihane, J. O.; Murray, D.] Univ Coll, Cork, Ireland. [Fallon, P.] Trinity Coll Dublin, Dublin, Ireland. [Segre, J. A.] NHGRI, NIH, Bethesda, MD 20892 USA. [Irvine, A. D.] Our Ladys Childrens Hosp Crumlin, Natl Childrens Res Ctr, Dublin, Ireland. [Irvine, A. D.] Trinity Coll Dublin, Med Clin, Dublin, Ireland. [Irvine, A. D.] Our Ladys Childrens Hosp Crumlin, Paediat Dermatol, Dublin, Ireland. NR 0 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2016 VL 136 IS 5 SU 1 MA 476 BP S84 EP S84 PG 1 WC Dermatology SC Dermatology GA DR6RK UT WOS:000380028800476 ER PT J AU Kiss, A Koppel, AC Cataisson, C Anders, J Yuspa, S Bible, P Kellett, M Morasso, MI Efimova, T AF Kiss, A. Koppel, A. C. Cataisson, C. Anders, J. Yuspa, S. Bible, P. Kellett, M. Morasso, M. I. Efimova, T. TI Keratinocyte p38 alpha loss results in increased tumor initiation, decreased malignant progression, and altered tumor type specification during two-stage chemical carcinogenesis in murine skin SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Investigative-Dermatology (SID) CY MAY 11-14, 2016 CL Scottsdale, AZ SP Soc Investigat Dermatol C1 [Kiss, A.; Koppel, A. C.; Efimova, T.] George Washington Univ, Sch Med & Hlth Sci, Anat & Regenerat Biol, Washington, DC 20052 USA. [Cataisson, C.; Anders, J.; Yuspa, S.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Bible, P.; Kellett, M.; Morasso, M. I.] NIAMSD, Lab Skin Biol, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2016 VL 136 IS 5 SU 1 MA 105 BP S19 EP S19 PG 1 WC Dermatology SC Dermatology GA DR6RK UT WOS:000380028800105 ER PT J AU Klover, P Thangapazham, R Kato, J Wang, J Li, S Dalgard, C Wilkerson, M Mccart, E Moss, J Darling, T AF Klover, P. Thangapazham, R. Kato, J. Wang, J. Li, S. Dalgard, C. Wilkerson, M. Mccart, E. Moss, J. Darling, T. TI Dermal fibroblasts with loss of TSC2 express increased galectin-3, a potential biomarker for tuberous sclerosis complex SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Investigative-Dermatology (SID) CY MAY 11-14, 2016 CL Scottsdale, AZ SP Soc Investigat Dermatol C1 [Klover, P.; Thangapazham, R.; Wang, J.; Li, S.; Mccart, E.; Darling, T.] Uniformed Serv Univ Hlth Sci, Dermatol, Bethesda, MD 20814 USA. [Kato, J.; Moss, J.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Dalgard, C.; Wilkerson, M.] Uniformed Serv Univ Hlth Sci, Anat Physiol & Genet, Bethesda, MD 20814 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2016 VL 136 IS 5 SU 1 MA 401 BP S71 EP S71 PG 1 WC Dermatology SC Dermatology GA DR6RK UT WOS:000380028800401 ER PT J AU Merrill, ED Askenase, M Harrison, O Nakijama, S Ridaura, V Belkaid, Y AF Merrill, E. D. Askenase, M. Harrison, O. Nakijama, S. Ridaura, V. Belkaid, Y. TI Murine intestinal commensal bacteria modulate the cutaneous inflammatory response to imiquimod SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Investigative-Dermatology (SID) CY MAY 11-14, 2016 CL Scottsdale, AZ SP Soc Investigat Dermatol C1 [Merrill, E. D.] Univ Missouri, Sch Med, Kansas City, MO 64108 USA. [Merrill, E. D.; Askenase, M.; Harrison, O.; Nakijama, S.; Ridaura, V.; Belkaid, Y.] NIAID, Mucosal Immunol Sect, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Askenase, M.] Yale Sch Med, New Haven, CT USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2016 VL 136 IS 5 SU 1 MA 462 BP S82 EP S82 PG 1 WC Dermatology SC Dermatology GA DR6RK UT WOS:000380028800462 ER PT J AU Morimura, S Ouchi, T Udey, M AF Morimura, S. Ouchi, T. Udey, M. TI Epithelial Cell Adhesion Molecule (EpCAM) regulates epithelial homeostasis via Rho-associated protein kinase (ROCK) SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Investigative-Dermatology (SID) CY MAY 11-14, 2016 CL Scottsdale, AZ SP Soc Investigat Dermatol C1 [Morimura, S.; Ouchi, T.; Udey, M.] NCI, Dermatol Branch, CCR, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2016 VL 136 IS 5 SU 1 MA 426 BP S75 EP S75 PG 1 WC Dermatology SC Dermatology GA DR6RK UT WOS:000380028800426 ER PT J AU Nathan, N Patel, R Crenshaw, M Lindhurst, M Olsen, C Biesecker, L Keppler-Noreuil, K Darling, T AF Nathan, N. Patel, R. Crenshaw, M. Lindhurst, M. Olsen, C. Biesecker, L. Keppler-Noreuil, K. Darling, T. TI Growth of the cerebriform connective tissue nevus in individuals with Proteus syndrome SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Investigative-Dermatology (SID) CY MAY 11-14, 2016 CL Scottsdale, AZ SP Soc Investigat Dermatol C1 [Nathan, N.; Darling, T.] Uniformed Serv Univ Hlth Sci, Dermatol, Bethesda, MD 20814 USA. [Patel, R.; Crenshaw, M.; Lindhurst, M.; Biesecker, L.; Keppler-Noreuil, K.] NHGRI, Med Genom & Metab Genet Branch, Bethesda, MD 20892 USA. [Olsen, C.] Uniformed Serv Univ Hlth Sci, Preventat Med & Biometr, Bethesda, MD 20814 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2016 VL 136 IS 5 SU 1 MA 266 BP S47 EP S47 PG 1 WC Dermatology SC Dermatology GA DR6RK UT WOS:000380028800266 ER PT J AU Ono, R Khan, SG Masaki, T Kuschal, C Nishigori, C Chu, M Tamura, D DiGiovanna, J Kraemer, KH AF Ono, R. Khan, S. G. Masaki, T. Kuschal, C. Nishigori, C. Chu, M. Tamura, D. DiGiovanna, J. Kraemer, K. H. TI Precision medicine intervention in xeroderma pigmentosum SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Investigative-Dermatology (SID) CY MAY 11-14, 2016 CL Scottsdale, AZ SP Soc Investigat Dermatol C1 [Ono, R.; Masaki, T.; Nishigori, C.] Kobe Univ, Derm, Kobe, Hyogo, Japan. [Ono, R.; Khan, S. G.; Kuschal, C.; Chu, M.; Tamura, D.; DiGiovanna, J.; Kraemer, K. H.] NCI, Derm, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2016 VL 136 IS 5 SU 1 MA 402 BP S71 EP S71 PG 1 WC Dermatology SC Dermatology GA DR6RK UT WOS:000380028800402 ER PT J AU Pichard, DC van Doorslaer, K McBride, AA Zerbe, CS Stratton, P Holland, SM Kong, HH Cowen, EW AF Pichard, D. C. van Doorslaer, K. McBride, A. A. Zerbe, C. S. Stratton, P. Holland, S. M. Kong, H. H. Cowen, E. W. TI HPV genotypes in genital dysplasia and carcinoma in GATA2 deficiency SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Investigative-Dermatology (SID) CY MAY 11-14, 2016 CL Scottsdale, AZ SP Soc Investigat Dermatol C1 [Pichard, D. C.; Kong, H. H.; Cowen, E. W.] NCI, Dermatol, NIH, Bethesda, MD 20892 USA. [van Doorslaer, K.; McBride, A. A.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Zerbe, C. S.; Holland, S. M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Stratton, P.] NICHD, Off Clin Director, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2016 VL 136 IS 5 SU 1 MA 072 BP S13 EP S13 PG 1 WC Dermatology SC Dermatology GA DR6RK UT WOS:000380028800072 ER PT J AU Pichard, DC Haun, PL Navarro, AL Lopez-Terrada, D Brownell, I Chu, EY Miettinen, M Cowen, EW AF Pichard, D. C. Haun, P. L. Navarro, A. L. Lopez-Terrada, D. Brownell, I. Chu, E. Y. Miettinen, M. Cowen, E. W. TI Characteristics of DFSP tumors in adenosine deaminase deficient-severe combined immunodeficiency (ADA-SCID) SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Investigative-Dermatology (SID) CY MAY 11-14, 2016 CL Scottsdale, AZ SP Soc Investigat Dermatol C1 [Pichard, D. C.; Brownell, I.; Cowen, E. W.] NCI, Dermatol, NIH, CCR, Bethesda, MD 20892 USA. [Haun, P. L.; Chu, E. Y.] Univ Penn, Dermatol, Philadelphia, PA 19104 USA. [Miettinen, M.] NCI, Pathol Lab, NIH, CCR, Bldg 10, Bethesda, MD 20892 USA. [Navarro, A. L.; Lopez-Terrada, D.] Texas Childrens Hosp, Pathol, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2016 VL 136 IS 5 SU 1 MA 073 BP S13 EP S13 PG 1 WC Dermatology SC Dermatology GA DR6RK UT WOS:000380028800073 ER PT J AU Pugh, J Khan, SG Tamura, D Merideth, M Heller, E DiGiovanna, J Kraemer, KH AF Pugh, J. Khan, S. G. Tamura, D. Merideth, M. Heller, E. DiGiovanna, J. Kraemer, K. H. TI Influence of paternal alleles on clinical outcome in trichothiodsytrophy SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Investigative-Dermatology (SID) CY MAY 11-14, 2016 CL Scottsdale, AZ SP Soc Investigat Dermatol C1 [Pugh, J.; Khan, S. G.; Tamura, D.; Heller, E.; DiGiovanna, J.; Kraemer, K. H.] NCI, Derm, Bethesda, MD 20892 USA. [Merideth, M.] NHGRI, Med Gen Br, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2016 VL 136 IS 5 SU 1 MA 368 BP S65 EP S65 PG 1 WC Dermatology SC Dermatology GA DR6RK UT WOS:000380028800368 ER PT J AU Sato, E Takahashi, T Usdin, TB Gallo, RL AF Sato, E. Takahashi, T. Usdin, T. B. Gallo, R. L. TI A parathyroid hormone family member TIP39 increases intracellular calcium via the IP3 pathway SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Investigative-Dermatology (SID) CY MAY 11-14, 2016 CL Scottsdale, AZ SP Soc Investigat Dermatol C1 [Sato, E.; Takahashi, T.; Gallo, R. L.] Univ Calif San Diego, Dermatol, San Diego, CA 92103 USA. [Usdin, T. B.] NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2016 VL 136 IS 5 SU 1 MA 323 BP S57 EP S57 PG 1 WC Dermatology SC Dermatology GA DR6RK UT WOS:000380028800323 ER PT J AU Slominski, AT Kim, T Hobrath, J Janjetovic, Z Oak, AS Postlethwaite, A Li, W Jetten, A Tuckey, R AF Slominski, A. T. Kim, T. Hobrath, J. Janjetovic, Z. Oak, A. S. Postlethwaite, A. Li, W. Jetten, A. Tuckey, R. TI Discovery of new pathway activating lumisterol in vivo to biologically active molecules SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Investigative-Dermatology (SID) CY MAY 11-14, 2016 CL Scottsdale, AZ SP Soc Investigat Dermatol C1 [Slominski, A. T.; Kim, T.; Janjetovic, Z.; Oak, A. S.] UAB, Dermatol, Birmingham, AL USA. [Slominski, A. T.] VA Med Ctr, Birmingham, AL USA. [Hobrath, J.] UAB, Chem, Birmingham, AL USA. [Postlethwaite, A.] UTHSC, Med, Memphis, TN USA. [Li, W.] UTHSC, Pharmaceut Sci, Memphis, TN USA. [Jetten, A.] NIEHS, Cell Biol Sect, POB 12233, Res Triangle Pk, NC 27709 USA. [Tuckey, R.] UWA, Sch Chem & Biochem, Crawley, WA, Australia. NR 0 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2016 VL 136 IS 5 SU 1 MA 596 BP S105 EP S105 PG 1 WC Dermatology SC Dermatology GA DR6RK UT WOS:000380028800596 ER PT J AU Smith, J Bible, P Baysac, K Shih, H Duverger, O Kellett, M Morasso, MI AF Smith, J. Bible, P. Baysac, K. Shih, H. Duverger, O. Kellett, M. Morasso, M. I. TI The application of ATAC-seq to murine keratinocytes in the elucidation of the role of DLX3 in epidermal differentiation SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Investigative-Dermatology (SID) CY MAY 11-14, 2016 CL Scottsdale, AZ SP Soc Investigat Dermatol C1 [Smith, J.; Bible, P.; Baysac, K.; Duverger, O.; Kellett, M.; Morasso, M. I.] NIAMS, Skin Biol Lab, Bethesda, MD USA. [Shih, H.] NIAMS, Lymphocyte Cell Biol Sect, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2016 VL 136 IS 5 SU 1 MA 410 BP S72 EP S72 PG 1 WC Dermatology SC Dermatology GA DR6RK UT WOS:000380028800410 ER EF