FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Jameson, ND Sheppard, BK Lateef, TM Vande Voort, JL He, JP Merikangas, KR AF Jameson, Nicole D. Sheppard, Brooke K. Lateef, Tarannum M. Vande Voort, Jennifer L. He, Jian-Ping Merikangas, Kathleen Ries TI Medical Comorbidity of Attention-Deficit/Hyperactivity Disorder in US Adolescents SO JOURNAL OF CHILD NEUROLOGY LA English DT Article DE ADHD; comorbidity; enuresis; National Comorbidity Replication Survey-Adolescent Supplement; Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition ID DEFICIT HYPERACTIVITY DISORDER; SUPPLEMENT NCS-A; HEALTH INTERVIEW SURVEY; NOCTURNAL ENURESIS; CHILDHOOD ADHD; MENTAL-HEALTH; PSYCHIATRIC COMORBIDITY; YOUNG-ADULTS; CARE USE; CHILDREN AB Understanding patterns of medical comorbidity in attention-deficit/hyperactivity disorder (ADHD) may lead to better treatment of affected individuals as well as aid in etiologic study of disease. This article provides the first systematic evaluation on the medical comorbidity of ADHD in a nationally representative sample (National Comorbidity Replication Survey-Adolescent Supplement; N = 6483) using formal diagnostic criteria. Survey-weighted odds ratios adjusted for demographics, additional medical, and mental disorders were calculated for associations between ADHD and medical conditions. Models adjusted for demographics revealed significantly increased odds of allergy, asthma, enuresis, headache/migraine, and serious stomach or bowel problems. After adjusting for comorbidity, across the medical conditions, enuresis and serious stomach problems were the strongest correlates of ADHD. These findings confirm the pervasive medical comorbidity of ADHD reported in previous clinical and community-based studies. The intriguing salience of enuresis and serious stomach or bowel conditions may also provide an important clue to multisystem involvement in ADHD. C1 [Jameson, Nicole D.; Sheppard, Brooke K.; Lateef, Tarannum M.; Vande Voort, Jennifer L.; He, Jian-Ping; Merikangas, Kathleen Ries] NIMH, 35 Convent Dr,MSC 3720, Bethesda, MD 20892 USA. RP Merikangas, KR (reprint author), NIMH, 35 Convent Dr,MSC 3720, Bethesda, MD 20892 USA. EM kathleen.merikangas@nih.gov FU Intramural Research Program of the National Institute of Mental Health [ZIAMH002808] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Intramural Research Program of the National Institute of Mental Health (ZIAMH002808). The views and opinions expressed in this article are those of the authors and should not be construed to represent the views of any of the sponsoring organizations, agencies, or US government. NR 81 TC 0 Z9 0 U1 8 U2 8 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0883-0738 EI 1708-8283 J9 J CHILD NEUROL JI J. Child Neurol. PD OCT PY 2016 VL 31 IS 11 BP 1282 EP 1289 DI 10.1177/0883073816653782 PG 8 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA DV9CR UT WOS:000383237700002 PM 27334310 ER PT J AU Feingold, PL Quadri, HS Steinberg, SM Malech, HL Gallin, JI Zerbe, CS Zarember, KA Marciano, BE Holland, SM Schrump, DS Ripley, RT AF Feingold, Paul L. Quadri, Humair S. Steinberg, Seth M. Malech, Harry L. Gallin, John I. Zerbe, Christa S. Zarember, Kol A. Marciano, Beatrice E. Holland, Steven M. Schrump, David S. Ripley, Robert T. TI Thoracic Surgery in Chronic Granulomatous Disease: a 25-Year Single-Institution Experience SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE Empyema; lung abscess; pulmonary resection; chronic granulomatous disease ID GENE-THERAPY; INFECTIONS; LUNG; MANAGEMENT; CHILDHOOD; FEATURES; REGISTRY AB Chronic granulomatous disease (CGD) is a genetic disorder in which phagocyte dysfunction leads to recurrent infection. Persistent pulmonary infections sometimes require thoracic surgical intervention. We reviewed our 25-year experience to identify outcomes and prognostic factors associated with thoracic surgery in these patients. A retrospective single-institution review of all patients with CGD from 1990 through 2015 was performed. Univariate analysis identified prognostic variables to include in a Cox model. Overall survival was estimated by the Kaplan-Meier method. We identified 258 patients who had 2221 admissions (both scheduled and emergent). During the period examined, 51 thoracic operations were performed in 13.6 % (35/258) of patients and 2.3 % (35/2221) of overall admissions. Patients undergoing surgery did not have statistically significant differences in disease genotype compared to those that did not require surgery. Pathogens were identified from 67 % (34/51) of specimens. Complications occurred in 27 % (14/51), including 10 % (5/51) with wound and 12 % (6/51) with pulmonary infections. Mortality at 30 and 90 days was 0 and 6 % (3/51), respectively. Overall survival probabilities were 75 and 62 % at 5- and 10-year follow-up (median potential follow-up: 16.5 years), respectively. Undergoing thoracic surgery was associated with an increased hazard ratio for death of 3.71 (p < 0.0001). Both chest wall resection and EBL > 500 mL were negative prognostic factors (p < 0.05). A minority of CGD patients required thoracic surgery for infections refractory to antibiotic or antifungal therapy. Patients who had these operations had significant morbidity and relatively poor long-term survival, particularly in the cases of chest wall resection or significant blood loss. C1 [Feingold, Paul L.; Quadri, Humair S.; Schrump, David S.; Ripley, Robert T.] NCI, Thorac & Gastrointestinal Oncol Branch, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Off Clin Director, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Malech, Harry L.; Gallin, John I.] NIAID, Lab Host Def, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Zerbe, Christa S.; Zarember, Kol A.; Marciano, Beatrice E.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Feingold, PL (reprint author), NCI, Thorac & Gastrointestinal Oncol Branch, NIH, Bethesda, MD 20892 USA. EM paul.feingold@nih.gov OI Feingold, Paul/0000-0002-3194-4309 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH FX The authors would like to thank the Laboratory of Clinical Infectious Disease at the National Institute of Allergy and Infectious Disease for their assistance and collaboration in this work. This work supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH. NR 23 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD OCT PY 2016 VL 36 IS 7 BP 677 EP 683 DI 10.1007/s10875-016-0319-9 PG 7 WC Immunology SC Immunology GA DV9FS UT WOS:000383246400010 PM 27497975 ER PT J AU John, T Walter, JE Schuetz, C Chen, K Abraham, RS Bonfim, C Boyce, TG Joshi, AY Kang, E Carvalho, BTC Mahajerin, A Nugent, D Puthenveetil, G Soni, A Su, HL Cowan, MJ Notarangelo, L Buchbinder, D AF John, Tami Walter, Jolan E. Schuetz, Catherina Chen, Karin Abraham, Roshini S. Bonfim, Carmem Boyce, Thomas G. Joshi, Avni Y. Kang, Elizabeth Costa Carvalho, Beatriz Tavares Mahajerin, Arash Nugent, Diane Puthenveetil, Geetha Soni, Amit Su, Helen Cowan, Morton J. Notarangelo, Luigi Buchbinder, David TI Unrelated Hematopoietic Cell Transplantation in a Patient with Combined Immunodeficiency with Granulomatous Disease and Autoimmunity Secondary to RAG Deficiency SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE RAG deficiency; primary immunodeficiency; immune dysregulation; autoimmunity; bone marrow transplantation ID POOR GRAFT FUNCTION; MUTATIONS AB The use of HLA-identical hematopoietic stem cell transplantation (HSCT) demonstrates overall survival rates greater than 75 % for T-B-NK+ severe combined immunodeficiency secondary to pathogenic mutation of recombinase activating genes 1 and 2 (RAG1/2). Limited data exist regarding the use of HSCT in patients with hypomorphic RAG variants marked by greater preservation of RAG activity and associated phenotypes such as granulomatous disease in combination with autoimmunity. We describe a 17-year-old with combined immunodeficiency and immune dysregulation characterized by granulomatous lung disease and autoimmunity secondary to compound heterozygous RAG mutations. A myeloablative reduced toxicity HSCT was completed using an unrelated bone marrow donor. With the increasing cases of immune dysregulation being discovered with hypomorphic RAG variants, the use of HSCT may advance to the forefront of treatment. This case serves to discuss indications of HSCT, approaches to preparative therapy, and the potential complications in this growing cohort of patients with immune dysregulation and RAG deficiency. C1 [John, Tami] CHOC Childrens Hosp, Div Hematol Oncol, 1201 W La Veta Ave, Orange, CA 92868 USA. [Walter, Jolan E.] MassGen Hosp Children, Div Immunol, 55 Fruit St, Boston, MA 02114 USA. [Schuetz, Catherina] Univ Med Ctr Ulm, Dept Pediat & Adolescent Med, Ulm, Germany. [Chen, Karin] Univ Utah, Sch Med, Dept Pediat, Div Allergy Immunol & Rheumatol, 81 Mario Capecchi Dr, Salt Lake City, UT USA. [Abraham, Roshini S.; Joshi, Avni Y.] Mayo Clin, Allergy & Immunol, 200 First St SW, Rochester, MN 55905 USA. [Bonfim, Carmem] Univ Fed Parana, Bone Marrow Transplantat Unit, Rua XV Novembro 1299, BR-80060000 Curitiba, Parana, Brazil. [Boyce, Thomas G.] Vanderbilt Univ, Dept Pediat, Sch Med, Nashville, TN 37232 USA. [Kang, Elizabeth; Su, Helen] NIAID, NIH, Bldg 10CRC,Room 5-3940,10 Ctr Dr,MSC 1456, Bethesda, MD 20892 USA. [Costa Carvalho, Beatriz Tavares] Univ Fed Sao Paulo, Disciplina Alergia Imunol Clin & Reumatol, Sao Paulo, Brazil. [Mahajerin, Arash; Nugent, Diane; Puthenveetil, Geetha; Soni, Amit; Buchbinder, David] CHOC Childrens Hosp, Div Hematol, 1201 W La Veta Ave, Orange, CA 92868 USA. [Cowan, Morton J.] Univ Calif San Francisco, Dept Pediat, Box 1278, San Francisco, CA 94143 USA. [Notarangelo, Luigi] Childrens Hosp Boston, Div Immunol, Karp Bldg,Room 10217,1 Blackfan Circle, Boston, MA 02115 USA. RP John, T (reprint author), CHOC Childrens Hosp, Div Hematol Oncol, 1201 W La Veta Ave, Orange, CA 92868 USA. EM tamidjohn@gmail.com; JEWALTER@partners.org; catharina.schuetz@uniklinik-ulm.de; karin.chen@hsc.utah.edu; Abraham.Roshini@mayo.edu; carmembonfim@gmail.com; Thomas.Boyce@mayo.edu; Joshi.Avni@mayo.edu; ekang@niaid.nih.gov; beacarvalho@terra.com.br; amaharein@choc.org; dnugent@choc.org; gputhenveetil@choc.org; asoni@choc.org; HSU@niaid.nih.gov; Mort.Cowan@ucsf.edu; Luigi.Notarangelo@childrens.harvard.edu; dbuchbinder@choc.org FU Intramural Research Program of the National Institute of Allergy and Infectious Disease (NIAID), National Institute of Health (NIH) FX This work was supported in part by funds from the Intramural Research Program of the National Institute of Allergy and Infectious Disease (NIAID), National Institute of Health (NIH). NR 26 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD OCT PY 2016 VL 36 IS 7 BP 725 EP 732 DI 10.1007/s10875-016-0326-x PG 8 WC Immunology SC Immunology GA DV9FS UT WOS:000383246400015 PM 27539235 ER PT J AU Devaiah, BN Gegonne, A Singer, DS AF Devaiah, Ballachanda N. Gegonne, Anne Singer, Dinah S. TI Bromodomain 4: a cellular Swiss army knife SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Review DE BRD4; kinase; Pol II; acetyltransferase; nucleosome eviction ID ACUTE MYELOID-LEUKEMIA; PROTEIN BRD4 BINDS; P-TEFB; TRANSCRIPTIONAL REGULATORS; ACETYLATED CHROMATIN; GENE-TRANSCRIPTION; SUPER-ENHANCERS; TERMINAL DOMAIN; BREAST-CANCER; S-PHASE AB Bromodomain protein 4 (BRD4) is a transcriptional and epigenetic regulator that plays a pivotal role in cancer and inflammatory diseases. BRD4 binds and stays associated with chromatin during mitosis, bookmarking early G1 genes and reactivating transcription after mitotic silencing. BRD4 plays an important role in transcription, both as a passive scaffold via its recruitment of vital transcription factors and as an active kinase that phosphorylates RNA polymerase II, directly and indirectly regulating transcription. Through its HAT activity, BRD4 contributes to the maintenance of chromatin structure and nucleosome clearance. This review summarizes the known functions of BRD4 and proposes a model in which BRD4 actively coordinates chromatin structure and transcription. C1 [Devaiah, Ballachanda N.; Gegonne, Anne; Singer, Dinah S.] NCI, Expt Immunol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Singer, DS (reprint author), NCI, Expt Immunol Branch, Ctr Canc Res, NIH, Bldg 10,Room 4B-36,9000 Rockville Pike, Bethesda, MD 20892 USA. EM dinah.singer@nih.gov FU U.S. National Institutes of Health, National Cancer Institute, Center for Cancer Research FX The authors are supported by the Intramural Research Program of the U.S. National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 69 TC 1 Z9 1 U1 12 U2 12 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 EI 1938-3673 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD OCT PY 2016 VL 100 IS 4 BP 679 EP 686 DI 10.1189/jlb.2RI0616-250R PG 8 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA DV3UO UT WOS:000382849500007 PM 27450555 ER PT J AU Munford, RS AF Munford, Robert S. TI Endotoxemia-menace, marker, or mistake? SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Review DE LPS; lipopolysaccharide; translocation; endotoxin; Limulus ID LIMULUS AMEBOCYTE LYSATE; INFLAMMATORY RESPONSE SYNDROME; GRAM-NEGATIVE BACTERIA; ESCHERICHIA-COLI LIPOPOLYSACCHARIDE; PERMEABILITY-INCREASING PROTEIN; TOLL-LIKE RECEPTORS; HUMAN SEPTIC SHOCK; CELL-BOUND LPS; HUMAN MONOCYTES; MICROBIAL TRANSLOCATION AB Endotoxemia is in its scientific ascendancy. Never has blood-borne, Gram-negative bacterial endotoxin (LPS) been invoked in the pathogenesis of so many diseases-not only as a trigger for septic shock, once its most cited role, but also as a contributor to atherosclerosis, obesity, chronic fatigue, metabolic syndrome, and many other conditions. Finding elevated plasma endotoxin levels has been essential supporting evidence for each of these links, yet the assays used to detect and quantitate endotoxin have important limitations. This article describes several assays for endotoxin in plasma, reviews what they do and do not measure, and discusses why LPS heterogeneity, LPS trafficking pathways, and host LPS inactivation mechanisms should be considered when interpreting endotoxin assay results. C1 [Munford, Robert S.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Munford, RS (reprint author), NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM munfordrs@niaid.nih.gov FU National Institute for Allergy and Infectious Diseases, U.S. National Institutes of Health FX This work was supported by the Division of Intramural Research, National Institute for Allergy and Infectious Diseases, U.S. National Institutes of Health. The author thanks Klaus Brandenburg, Anthony Suffredini, Jack Levin, Jason Brenchley, Clett Erridge, and Alan Cross for helpful suggestions. NR 152 TC 1 Z9 1 U1 4 U2 4 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 EI 1938-3673 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD OCT PY 2016 VL 100 IS 4 BP 687 EP 698 DI 10.1189/jlb.3RU0316-151R PG 12 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA DV3UO UT WOS:000382849500008 PM 27418356 ER PT J AU DeSouza-Vieira, T Guimaraes-Costa, A Rochael, NC Lira, MN Nascimento, MT Lima-Gomez, PD Mariante, RM Persechini, PM Saraiva, EM AF DeSouza-Vieira, Thiago Guimaraes-Costa, Anderson Rochael, Natalia C. Lira, Maria N. Nascimento, Michelle T. Lima-Gomez, Phillipe de Souza Mariante, Rafael M. Persechini, Pedro M. Saraiva, Elvira M. TI Neutrophil extracellular traps release induced by Leishmania: role of PI3K gamma, ERK, PI3K sigma, PKC, and [Ca2+] SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE parasitic protozoa; netosis; signaling ID NADPH OXIDASE; ACTIVATION; INFECTION; AMAZONENSIS; MACROPHAGES; APOPTOSIS; GRANULOCYTES; MECHANISMS; RECEPTORS; AUTOPHAGY AB Upon in vitro stimulation, neutrophils undergo a cell death named netosis. This process is characterized by extracellular release of chromatin scaffold associated with granular and cytoplasmic proteins, which together, ensnare and kill microbes. We have previously described that interaction of Leishmania amazonensis with human neutrophils leads to the release of neutrophil extracellular traps, which trap and kill the parasite. However, the signaling leading to Leishmania induced netosis is still unknown. Thus, we sought to evaluate signaling events that drive L. amazonensis induced neutrophil extracellular trap release from human neutrophils. Here, we found that PI3K, independently of protein kinase B, has a role in parasite-induced netosis. We also described that the main isoforms involved are PI3K gamma and PI3K delta, which work in reactive oxygen species-dependent and -independent ways, respectively. We demonstrated that activation of ERK downstream of PI3K gamma is important to trigger reactive oxygen species-dependent, parasite-induced netosis. Pharmacological inhibition of protein kinase C also significantly decreased parasite-induced neutrophil extracellular trap release. Intracellular calcium, regulated by PI3Kd, represents an alternative reactive oxygen species-independent pathway of netosis stimulated by L. amazonensis. Finally, intracellular calcium mobilization and reactive oxygen species generation are the major regulators of parasite-induced netosis. Our results contribute to a better understanding of the signaling behind netosis induced by interactions between Leishmania and neutrophils. C1 [DeSouza-Vieira, Thiago; Guimaraes-Costa, Anderson; Rochael, Natalia C.; Nascimento, Michelle T.; Lima-Gomez, Phillipe de Souza; Saraiva, Elvira M.] Univ Fed Rio de Janeiro, Inst Microbiol Paulo Goes, Dept Imunol, Lab Imunobiol Leishmanioses, Av Carlos Chagas Filho 373,Bloco D,Sala D-44, Rio De Janeiro, Brazil. [Lira, Maria N.; Persechini, Pedro M.] Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, Lab Imunobiofis, Rio De Janeiro, Brazil. [Mariante, Rafael M.] Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, Dept Neurobiol, Lab Neurogenese, Rio De Janeiro, Brazil. [Mariante, Rafael M.] Fiocruz MS, Inst Oswaldo Cruz, Lab Biol Estrutural, Rio De Janeiro, Brazil. [Guimaraes-Costa, Anderson] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Saraiva, EM (reprint author), Univ Fed Rio de Janeiro, Inst Microbiol Paulo Goes, Dept Imunol, Lab Imunobiol Leishmanioses, Av Carlos Chagas Filho 373,Bloco D,Sala D-44, Rio De Janeiro, Brazil. EM esaraiva@micro.ufrj.br FU Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ); Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES); Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) FX This study was supported by Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ), Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq). The authors thank Dr. Alessandra P. Granato (Instituto de Microbiologia Paulo de Goes, Universidade Federal do Rio de Janeiro, Brazil) for assistance on intracellular detection of phosphorylated protein assays and Dr. Flavio Lara (Lab. de Microbiologia Celular, Instituto Oswaldo Cruz, Rio de Janeiro, Brazil) for the video microscopy analysis. The authors are also grateful to the Hemotherapy Service Hospital Clementino Fraga Filho (Universidade Federal do Rio de Janeiro, Brazil) for the buffy coats. NR 43 TC 2 Z9 2 U1 6 U2 6 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 EI 1938-3673 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD OCT PY 2016 VL 100 IS 4 BP 801 EP 810 DI 10.1189/jlb.4A0615-261RR PG 10 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA DV3UO UT WOS:000382849500018 PM 27154356 ER PT J AU Cnops, L van Griensven, J Honko, AN Bausch, DG Sprecher, A Hill, CE Colebunders, R Johnson, JC Griffiths, A Palacios, GF Kraft, CS Kobinger, G Hewlett, A Norwood, DA Sabeti, P Jahrling, PB Formenty, P Kuhn, JH Arien, KK AF Cnops, Lieselotte van Griensven, Johan Honko, Anna N. Bausch, Daniel G. Sprecher, Armand Hill, Charles E. Colebunders, Robert Johnson, Joshua C. Griffiths, Anthony Palacios, Gustavo F. Kraft, Colleen S. Kobinger, Gary Hewlett, Angela Norwood, David A. Sabeti, Pardis Jahrling, Peter B. Formenty, Pierre Kuhn, Jens H. Arien, Kevin K. TI Overlooking the importance of immunoassays reply SO LANCET INFECTIOUS DISEASES LA English DT Letter C1 [Cnops, Lieselotte; van Griensven, Johan] Inst Trop Med, Dept Clin Sci, Antwerp, Belgium. [Honko, Anna N.; Johnson, Joshua C.; Jahrling, Peter B.; Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick, Div Clin Res, NIH, Frederick, MD USA. [Bausch, Daniel G.; Formenty, Pierre] WHO, Geneva, Switzerland. [Sprecher, Armand] Med Sans Frontieres Operat Ctr Brussels, Brussels, Belgium. [Hill, Charles E.] Emory Univ Hosp, Mol Diagnost Lab, 1364 Clifton Rd NE, Atlanta, GA 30322 USA. [Colebunders, Robert] Univ Antwerp, Int Hlth Unit, Global Hlth Inst, Fac Med & Hlth Sci, Antwerp, Belgium. [Griffiths, Anthony] Texas Biomed Res Inst, Dept Virol & Immunol, San Antonio, TX USA. [Palacios, Gustavo F.; Norwood, David A.] US Army, Med Res Inst Infect Dis, Frederick, MD USA. [Kraft, Colleen S.] Emory Univ, Sch Med, Pathol & Lab Med, Atlanta, GA USA. [Kobinger, Gary] Univ Manitoba, Natl Microbiol Lab, Publ Hlth Agcy Canada, Winnipeg, MB, Canada. [Hewlett, Angela] Univ Nebraska Med Ctr, Omaha, NE USA. [Sabeti, Pardis] Harvard Univ, Dept Organism & Evolutionary Biol, FAS Ctr Syst Biol, Cambridge, MA 02138 USA. [Arien, Kevin K.] Inst Trop Med, Dept Biomed Sci, Antwerp, Belgium. RP Arien, KK (reprint author), Inst Trop Med, Dept Biomed Sci, Antwerp, Belgium. EM karien@itg.be NR 5 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD OCT PY 2016 VL 16 IS 10 BP 1110 EP 1110 PG 1 WC Infectious Diseases SC Infectious Diseases GA DW2JP UT WOS:000383469000024 PM 27676345 ER PT J AU Sav, H Ozdemir, HG Altinbas, R Kiraz, N Ilkit, M Seyedmousavi, S AF Sav, Hafize Ozdemir, Havva Gul Altinbas, Rabiye Kiraz, Nuri Ilkit, Macit Seyedmousavi, Seyedmojtaba TI Virulence Attributes and Antifungal Susceptibility Profile of Opportunistic Fungi Isolated from Ophthalmic Infections SO MYCOPATHOLOGIA LA English DT Article DE Antifungal susceptibility testing; Ocular fungal isolates; Virulence factors ID IN-VITRO; FUSARIUM KERATITIS; PHOSPHOLIPASE-ACTIVITY; PROTEINASE PRODUCTION; MYCOTIC KERATITIS; AMPHOTERICIN-B; VORICONAZOLE; ENDOPHTHALMITIS; NATAMYCIN; ASPERGILLUS AB Investigations of both virulence factors and antifungal susceptibility profiles are crucial for understanding the pathogenesis and prognosis of ophthalmic mycoses. In this study, we investigated the in vitro antifungal susceptibility of amphotericin B (AMB), voriconazole (VRC), and natamycin (NAT) against a set of 50 fungal isolates obtained from patients with ocular mycoses using the Clinical and Laboratory Standards Institute broth microdilution method. In addition, putative virulence factor, such as secretory phospholipases and proteinases, and biofilm formation activity were analyzed. The geometric means (GMs) of the minimum inhibitory concentrations (MICs) of the antifungals across all isolates were the following (in increasing order): VRC (0.70 mu g/mL), AMB (0.81 mu g/mL), and NAT (1.05 mu g/mL). The highest activity against 14 Aspergillus strains was exhibited by VRC (GM MIC: 0.10 mu g/mL), followed by AMB and NAT (GM MICs: 0.21 and 0.27 mu g/mL), respectively. However, for 12 Fusarium spp., the GM MIC of VRC (2.66) was higher than those of NAT and AMB (GM MICs 1.3 and 0.8 mu g/mL, respectively). Proteinase and phospholipase activity were observed in 30 % and 42 % of the isolates, respectively, whereas only 8 % of the isolates were able to produce biofilms. Phospholipase activity was observed in all Fusarium isolates, but not in any of the Aspergillus isolates. In contrast, biofilm-forming capability was detected in 25 % of the Fusarium isolates, but none of the Aspergillus isolates. The differences in the MICs of AMB, VRC, and NAT, biofilm-forming ability and proteinase and phospholipase activities among the isolates were not significant (p > 0.05). Overall, our study suggests no significant correlation between the antifungal susceptibility profiles and virulence attributes of ocular fungal isolates. C1 [Sav, Hafize; Altinbas, Rabiye; Kiraz, Nuri] Istanbul Univ, Cerrahpasa Fac Med, Dept Microbiol, Div Mycol, TR-34098 Istanbul, Turkey. [Ozdemir, Havva Gul] Cukurova Univ, Medicosocial Hlth Ctr, Div Ophthalmol, Adana, Turkey. [Ilkit, Macit] Cukurova Univ, Fac Med, Div Mycol, Dept Microbiol, Adana, Turkey. [Seyedmousavi, Seyedmojtaba] Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands. [Seyedmousavi, Seyedmojtaba] Radboud UMC, Dept Med Microbiol, Nijmegen, Netherlands. [Seyedmousavi, Seyedmojtaba] Mazandaran Univ Med Sci, Invas Fungi Res Ctr, Sari, Iran. [Seyedmousavi, Seyedmojtaba] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Sav, H (reprint author), Istanbul Univ, Cerrahpasa Fac Med, Dept Microbiol, Div Mycol, TR-34098 Istanbul, Turkey. EM hafize.sav@hotmail.com; Seyedmousavi@nih.gov RI Seyedmousavi, Seyedmojtaba/O-9267-2016 OI Seyedmousavi, Seyedmojtaba/0000-0002-6194-7447 FU Astellas Pharma B.V.; Gilead Sciences FX S.S. has received research and travel grants from Astellas Pharma B.V. and a travel grant from Gilead Sciences. All other authors have no conflicts of interests. NR 34 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0301-486X EI 1573-0832 J9 MYCOPATHOLOGIA JI Mycopathologia PD OCT PY 2016 VL 181 IS 9-10 BP 653 EP 661 DI 10.1007/s11046-016-0018-3 PG 9 WC Mycology SC Mycology GA DV5AS UT WOS:000382938400005 PM 27193295 ER PT J AU Friel, KM Kuo, HC Fuller, J Ferre, CL Brandao, M Carmel, JB Bleyenheuft, Y Gowatsky, JL Stanford, AD Rowny, SB Luber, B Bassi, B Murphy, DLK Lisanby, SH Gordon, AM AF Friel, Kathleen M. Kuo, Hsing-Ching Fuller, Jason Ferre, Claudio L. Brandao, Marina Carmel, Jason B. Bleyenheuft, Yannick Gowatsky, Jaimie L. Stanford, Arielle D. Rowny, Stefan B. Luber, Bruce Bassi, Bruce Murphy, David L. K. Lisanby, Sarah H. Gordon, Andrew M. TI Skilled Bimanual Training Drives Motor Cortex Plasticity in Children With Unilateral Cerebral Palsy SO NEUROREHABILITATION AND NEURAL REPAIR LA English DT Article DE rehabilitation; pediatric; transcranial magnetic stimulation; neuroplasticity; hemiplegia ID INDUCED MOVEMENT THERAPY; ASSISTING HAND ASSESSMENT; RANDOMIZED CONTROL TRIAL; ADULT SQUIRREL-MONKEYS; STROKE PATIENTS; CORTICAL REORGANIZATION; CONGENITAL HEMIPARESIS; CORTICOSPINAL SYSTEM; FUNCTIONAL MRI; RECOVERY AB Background. Intensive bimanual therapy can improve hand function in children with unilateral spastic cerebral palsy (USCP). We compared the effects of structured bimanual skill training versus unstructured bimanual practice on motor outcomes and motor map plasticity in children with USCP. Objective. We hypothesized that structured skill training would produce greater motor map plasticity than unstructured practice. Methods. Twenty children with USCP (average age 9.5; 12 males) received therapy in a day camp setting, 6 h/day, 5 days/week, for 3 weeks. In structured skill training (n = 10), children performed progressively more difficult movements and practiced functional goals. In unstructured practice (n = 10), children engaged in bimanual activities but did not practice skillful movements or functional goals. We used the Assisting Hand Assessment (AHA), Jebsen-Taylor Test of Hand Function (JTTHF), and Canadian Occupational Performance Measure (COPM) to measure hand function. We used single-pulse transcranial magnetic stimulation to map the representation of first dorsal interosseous and flexor carpi radialis muscles bilaterally. Results. Both groups showed significant improvements in bimanual hand use (AHA; P < .05) and hand dexterity (JTTHF; P < .001). However, only the structured skill group showed increases in the size of the affected hand motor map and amplitudes of motor evoked potentials (P < .01). Most children who showed the most functional improvements (COPM) had the largest changes in map size. Conclusions. These findings uncover a dichotomy of plasticity: the unstructured practice group improved hand function but did not show changes in motor maps. Skill training is important for driving motor cortex plasticity in children with USCP. C1 [Friel, Kathleen M.; Fuller, Jason; Carmel, Jason B.] Burke Cornell Med Res Inst, 785 Mamaroneck Ave, White Plains, NY 10605 USA. [Friel, Kathleen M.; Kuo, Hsing-Ching; Ferre, Claudio L.; Gordon, Andrew M.] Columbia Univ, Teachers Coll, New York, NY 10027 USA. [Friel, Kathleen M.; Carmel, Jason B.] Weill Cornell Med Coll, New York, NY USA. [Fuller, Jason] NYU, New York, NY USA. [Brandao, Marina] Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil. [Bleyenheuft, Yannick] Catholic Univ Louvain, Brussels, Belgium. [Gowatsky, Jaimie L.; Rowny, Stefan B.; Bassi, Bruce; Murphy, David L. K.; Gordon, Andrew M.] Columbia Univ, Med Ctr, New York, NY USA. [Stanford, Arielle D.] Alkermes Inc, Waltham, MA USA. [Luber, Bruce] Duke Univ, Durham, NC USA. [Lisanby, Sarah H.] NIH, Div Translat Res, Bldg 10, Bethesda, MD 20892 USA. RP Friel, KM (reprint author), Burke Cornell Med Res Inst, 785 Mamaroneck Ave, White Plains, NY 10605 USA. EM kfriel@burke.org FU Columbia Professional Schools Diversity Award; NIH CTSA Award [KL2 RR024157, UL1 RR024156, TL1 RR024158]; [NS062116] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Funded by NS062116 (KMF), Columbia Professional Schools Diversity Award (KMF), and NIH CTSA Award (KMF) (KL2 RR024157, UL1 RR024156, TL1 RR024158). Each of these sponsors provided funding based on the design of the study. Funds were used to pay for equipment and personnel needed for data collection, management, analysis, and interpretation. NR 58 TC 4 Z9 5 U1 11 U2 15 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1545-9683 EI 1552-6844 J9 NEUROREHAB NEURAL RE JI Neurorehabil. Neural Repair PD OCT PY 2016 VL 30 IS 9 BP 834 EP 844 DI 10.1177/1545968315625838 PG 11 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA DV5UJ UT WOS:000382995300003 PM 26867559 ER PT J AU Ranjan, A Benjamin, CJ Negussie, AH Chokshi, S Chung, PH Volkin, D Yeram, N Linehan, WM Dreher, MR Pinto, PA Wood, BJ AF Ranjan, Ashish Benjamin, Compton J. Negussie, Ayele H. Chokshi, Saurin Chung, Paul H. Volkin, Dmitry Yeram, Nitin Linehan, W. Marston Dreher, Matthew R. Pinto, Peter A. Wood, Bradford J. TI Biodistribution and Efficacy of Low Temperature-Sensitive Liposome Encapsulated Docetaxel Combined with Mild Hyperthermia in a Mouse Model of Prostate Cancer SO PHARMACEUTICAL RESEARCH LA English DT Article DE cancer; docetaxel; HIFU; LTSL; prostate ID INTENSITY FOCUSED ULTRASOUND; TUMOR XENOGRAFT MODEL; THERMOSENSITIVE LIPOSOMES; RADICAL PROSTATECTOMY; THERMAL ENHANCEMENT; DISEASE RECURRENCE; DRUG-DELIVERY; RELEASE; CHEMOTHERAPY; FORMULATION AB Low temperature sensitive liposome (LTSL) encapsulated docetaxel were combined with mild hyperthermia (40-42A degrees C) to investigate in vivo biodistribution and efficacy against a castrate resistant prostate cancer. Female athymic nude mice with human prostate PC-3 M-luciferase cells grown subcutaneously into the right hind leg were randomized into six groups: saline (+/- heat), free docetaxel (+/- heat), and LTSL docetaxel (+/- heat). Treatment (15 mg docetaxel/kg) was administered via tail vein once tumors reached a size of 200-300 mm(3). Mice tumor volumes and body weights were recorded for up to 60 days. Docetaxel concentrations of harvested tumor and organ/tissue homogenates were determined by LC-MS. Histological evaluation (Mean vessel density, Ki67 proliferation, Caspase-3 apoptosis) of saline, free Docetaxel and LTSL docetaxel (+/- heat n = 3-5) was performed to determine molecular mechanism responsible for tumor cell killing. LTSL/heat resulted in significantly higher tumor docetaxel concentrations (4.7-fold greater compared to free docetaxel). Adding heat to LTSL Docetaxel or free docetaxel treatment resulted in significantly greater survival and growth delay compared to other treatments (p < 0.05). Differences in body weight between all Docetaxel treatments were not reduced by > 10% and were not statistically different from each other. Molecular markers such as caspase-3 were upregulated, and Ki67 expression was significantly decreased in the chemo-hyperthermia group. Vessel density was similar post treatment, but the heated group had reduced vessel area, suggesting thermal enhancement in efficacy by reduction in functional perfusion. This technique of hyperthermia sensitization and enhanced docetaxel delivery has potential for clinical translation for prostate cancer treatment. C1 [Ranjan, Ashish; Negussie, Ayele H.; Dreher, Matthew R.; Wood, Bradford J.] NIH, Ctr Intervent Oncol Radiol & Imaging Sci, Ctr Clin, MSC 1182,Bldg 10,Room 1c-341,10 Ctr Dr, Bethesda, MD 20892 USA. [Benjamin, Compton J.; Chokshi, Saurin; Chung, Paul H.; Volkin, Dmitry; Yeram, Nitin; Linehan, W. Marston; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Wood, BJ (reprint author), NIH, Ctr Intervent Oncol Radiol & Imaging Sci, Ctr Clin, MSC 1182,Bldg 10,Room 1c-341,10 Ctr Dr, Bethesda, MD 20892 USA. EM bwood@cc.nih.gov FU Center for Interventional Oncology in the Intramural Research Program of the National Institutes of Health (NIH); Apredica inc. FX This research was supported by the Center for Interventional Oncology in the Intramural Research Program of the National Institutes of Health (NIH). NIH and Celsion Corp. have a Cooperative Research and Development Agreement. We are grateful for NCI pathology/histotechnology laboratory for their advice and useful discussions. We also thank Apredica inc. for their support and technical expertise in LC/MS. NR 46 TC 0 Z9 0 U1 16 U2 16 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 EI 1573-904X J9 PHARM RES-DORDR JI Pharm. Res. PD OCT PY 2016 VL 33 IS 10 BP 2459 EP 2469 DI 10.1007/s11095-016-1971-8 PG 11 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA DV2NP UT WOS:000382757600012 PM 27343000 ER PT J AU Sylvetsky, AC Rother, KI AF Sylvetsky, Allison C. Rother, Kristina I. TI Trends in the consumption of low-calorie sweeteners SO PHYSIOLOGY & BEHAVIOR LA English DT Article DE Low-calorie sweeteners; Artificial or non-nutritive sweeteners; Diet soda; Consumption trends; Sweetened beverages ID UNITED-STATES; NONNUTRITIVE SWEETENERS; BEVERAGE CONSUMPTION; ARTIFICIAL SWEETENER; INTENSE SWEETENERS; PATTERNS; CHILDREN; ADULTS; SUCRALOSE; FUTURE AB Low-calorie sweeteners (LCS) offer a palatable alternative to caloric sugars such as sucrose (table sugar) and high fructose corn syrup and are commonly found in soft drinks, sweetener packets, grains, snack foods, dairy products, hygiene products, and medications. Consumption of LCS has increased significantly in recent years and while this trend is expected to continue, controversy exists surrounding their use. The purpose of this article is to review trends in the consumption of LCS, to summarize differences in LCS consumption across socio-demographic subgroups and subtypes of LCS-containing products, and to highlight important challenges in the accurate assessment of LCS consumption. (C) 2016 Elsevier Inc. All rights reserved. C1 [Sylvetsky, Allison C.] George Washington Univ, Dept Exercise & Nutr Sci, Milken Inst Sch Publ Hlth, Washington, DC 20052 USA. [Sylvetsky, Allison C.; Rother, Kristina I.] Natl Inst Diabet & Digest & Kidney Dis, Sect Pediat Diabet & Metab, NIH, Bethesda, MD USA. RP Sylvetsky, AC (reprint author), Milken Inst Sch Publ Hlth, 950 New Hampshire Ave NW,Room 204, Washington, DC 20037 USA. EM asylvets@gwu.edu NR 34 TC 4 Z9 4 U1 54 U2 54 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD OCT 1 PY 2016 VL 164 SI SI BP 446 EP 450 DI 10.1016/j.physbeh.2016.03.030 PN B PG 5 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA DV9YH UT WOS:000383297600006 PM 27039282 ER PT J AU Wang, XL Qian, MY Yu, HY Sun, Y Li, SW Yang, P Lin, MY Yao, NS Zhang, XL AF Wang, Xiaoling Qian, Mingyi Yu, Hongyu Sun, Yang Li, Songwei Yang, Peng Lin, Muyu Yao, Nishao Zhang, Xilin TI Social Anxiety and Interpretation Bias: Effect of Positive Priming SO PSYCHOLOGICAL REPORTS LA English DT Article DE Social anxiety; positive priming; interpretation bias ID FACIAL EXPRESSIONS; BRAIN POTENTIALS; PHOBIA; INFORMATION; DEPRESSION; DISORDER; EMOTION; BEHAVIORS; DISPLAYS; STIMULI AB This study examined how positive-scale assessment of ambiguous social stimuli affects interpretation bias in social anxiety. Participants with high and low social anxiety (N=60) performed a facial expression discrimination task to assess interpretation bias. Participants were then randomly assigned to assess the emotion of briefly presented faces either on a negative or on a positive scale. They subsequently repeated the facial expression discrimination task. Participants with high versus low social anxiety made more negative interpretations of ambiguous facial expressions. However, those in the positive-scale assessment condition subsequently showed reduced negative interpretations of ambiguous facial expressions. These results suggest that interpretation bias in social anxiety could be mediated by positive priming rather than an outright negative bias. C1 [Wang, Xiaoling] Tianjin Univ, Inst Appl Psychol, Tianjin, Peoples R China. [Wang, Xiaoling; Qian, Mingyi; Yu, Hongyu; Sun, Yang; Lin, Muyu; Yao, Nishao] Peking Univ, Dept Psychol, Room 221,Philosophy Bldg, Beijing, Peoples R China. [Wang, Xiaoling] Peking Univ, Beijing Key Lab Behav & Mental Hlth, Beijing, Peoples R China. [Li, Songwei] Tsinghua Univ, Mental Hlth Dev Ctr, Beijing, Peoples R China. [Yang, Peng] Guangdong Expt High Sch, Guangzhou, Guangdong, Peoples R China. [Zhang, Xilin] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Qian, MY (reprint author), Peking Univ, Dept Psychol, Room 221,Philosophy Bldg, Beijing, Peoples R China. EM qmy@pku.edu.cn OI Lin, Muyu/0000-0002-3803-5749 FU National Natural Science Foundation of China [31170991] 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 National Natural Science Foundation of China (Project 31170991). NR 48 TC 0 Z9 0 U1 11 U2 13 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0033-2941 EI 1558-691X J9 PSYCHOL REP JI Psychol. Rep. PD OCT PY 2016 VL 119 IS 2 BP 539 EP 556 DI 10.1177/0033294116658605 PG 18 WC Psychology, Multidisciplinary SC Psychology GA DV5DT UT WOS:000382947100012 PM 27431316 ER PT J AU Lipsky, LM Nansel, TR Haynie, DL Liu, D Eisenberg, MH Simons-Morton, B AF Lipsky, L. M. Nansel, T. R. Haynie, D. L. Liu, D. Eisenberg, M. H. Simons-Morton, B. TI Power of Food Scale in association with weight outcomes and dieting in a nationally representative cohort of US young adults SO APPETITE LA English DT Article DE Adolescent; Young adult; Body mass index; Obesity; Overweight; Cohort studies ID BODY-MASS INDEX; SEVERELY OBESE-PATIENTS; GASTRIC BYPASS-SURGERY; HEDONIC HUNGER; FUTURE INCREASES; HEALTH BEHAVIOR; RISK-FACTORS; ADOLESCENTS; GAIN; REWARD AB Food reward sensitivity may influence susceptibility to overeating in a permissive food environment, contributing to unintended weight gain and intentional weight loss behavior. This study examined associations of food reward sensitivity, assessed by the Power of Food Scale (PFS), with weight outcomes and dieting in a nationally representative cohort of U.S. emerging adults. Wave 5 (W5, 5th year of follow-up) respondents from the NEXT Generation Health Study were included (N = 2202, W5 age = 20.3 +/- 0.02 years). Baseline and W5 BMI, W5 weight status (normal weight = 18.5 <= BMI < 25, overweight = 25 <= BMI < 30, obese = BMI >= 30), BMI change (W5 -baseline BMI) and onset of overweight or obesity (OWOB) were calculated from self -reported height and weight. PFS (aggregate and 3 domain scores: food available, present, and tasted) and dieting for weight -loss were assessed at W5. Adjusted linear regressions estimated associations of PFS with W5 BMI and BMI change. Log -binomial regressions estimated associations of high W5 BMI (>= 25), OWOB onset and dieting with PFS. Post hoc analyses estimated associations of PFS with W5 perceived weight status (overweight vs. about right or under-weight). W5 BMI = 25.73 +/- 0.32 kg/m(2), and OWOB onset occurred in 27.7% of participants. The PFS-food available score was associated with BMI change, beta +/- SE = 0.41 +/- 0.19. Other PFS scores were not associated with weight outcomes. Dieting prevalence was higher in participants with high versus low W5 BMI (61% versus 32%), and was positively associated with all PFS scores except the PFS-food tasted score, e.g., relative risk (RR) of dieting for PFS-aggregate = 1.13, 95%CI [1.01-1.26]. Post -hoc analyses indicated perceived overweight was positively associated with PFS-food available, 1.12, [1.01-1.24], and PFS-food present, 1.13, [1.03-1.24]. PFS was positively related to dieting and perceived overweight, but not concurrent or change in weight status in a representative cohort of U.S. emerging adults. Published by Elsevier Ltd. C1 [Lipsky, L. M.; Nansel, T. R.; Haynie, D. L.; Eisenberg, M. H.; Simons-Morton, B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Hlth Behav Branch, North Bethesda, MD USA. [Liu, D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, North Bethesda, MD USA. RP Lipsky, LM (reprint author), 6710B Rockledge Dr,3rd Floor,Room 3139C,MSC 7004, Bethesda, MD 20817 USA. EM lipskylm@mail.nih.gov OI Eisenberg, Miriam/0000-0002-7133-8805; Nansel, Tonja/0000-0002-8298-7595; Simons-Morton, Bruce/0000-0003-1099-6617; Haynie, Denise/0000-0002-8270-6079; Lipsky, Leah/0000-0003-2645-4388 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HHSN275201200001I]; National Heart, Lung, and Blood Institute (NHLBI); National Institute on Alcohol Abuse and Alcoholism (NIAAA); Maternal and Child Health Bureau (MCHB) of the Health Resources and Services Administration (HRSA); National Institute on Drug Abuse (NIDA) FX This research (contract number HHSN275201200001I) was supported in part by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Heart, Lung, and Blood Institute (NHLBI), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and Maternal and Child Health Bureau (MCHB) of the Health Resources and Services Administration (HRSA), with supplemental support from the National Institute on Drug Abuse (NIDA). Intramural researchers were responsible for the design and conduct of the. study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The authors thank Ms. Katie Dempster for her contributions to this work. NR 61 TC 0 Z9 0 U1 9 U2 11 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0195-6663 EI 1095-8304 J9 APPETITE JI Appetite PD OCT 1 PY 2016 VL 105 BP 385 EP 391 DI 10.1016/j.appet.2016.06.012 PG 7 WC Behavioral Sciences; Nutrition & Dietetics SC Behavioral Sciences; Nutrition & Dietetics GA DU6SQ UT WOS:000382345300045 PM 27298083 ER PT J AU Chintrakarn, P Jiraporn, P Kim, YS Tong, SH AF Chintrakarn, Pandej Jiraporn, Pornsit Kim, Young S. Tong, Shenghui TI The causal effect of religious piety on shareholder wealth: evidence from acquirer returns and historical religious identification SO APPLIED ECONOMICS LETTERS LA English DT Article DE Mergers and acquisitions; M&A; religion; religiosity; religious piety; corporate restructuring; G34; Z12 ID STOCK RETURNS; CORPORATE; MATTER; RISK AB Prior research shows that religion promotes honesty. Honesty in turn motivates managers to view an expropriation from shareholders as self-serving, opportunistic and unethical, thereby alleviating the agency conflict. Religious piety is thus expected to discourage agency-driven acquisitions that reduce shareholder wealth. We exploit the variation in religious piety across US counties (and states) and show that firms located in a more religious environment are indeed less likely to make poor acquisitions, measured by the stock market reactions to the acquisition announcement. To draw a causal inference, we use historical religious piety as far back as 1952 as our instrument. The two-stage least squares (2SLS) analysis confirms that religious piety induces firms to make better acquisitions. Our analysis based on propensity score matching also corroborates the conclusion. C1 [Chintrakarn, Pandej] MUIC, Nakhon Pathom, Thailand. [Jiraporn, Pornsit] Penn State Univ, Sch Grad Profess Studies, Malvern, PA USA. [Jiraporn, Pornsit] NIDA, Bangkok, Thailand. [Kim, Young S.] Northern Kentucky Univ, Highland Hts, KY USA. [Tong, Shenghui] China Huarong Asset Management, Beijing, Peoples R China. [Jiraporn, Pornsit] Chulalongkorn Univ, NIDA, Bangkok, Thailand. [Jiraporn, Pornsit] Chulalongkorn Univ, SASIN Grad Inst Business Adm, Bangkok, Thailand. RP Jiraporn, P (reprint author), Penn State Univ, Sch Grad Profess Studies, Malvern, PA USA.; Jiraporn, P (reprint author), NIDA, Bangkok, Thailand. EM pxj11@psu.edu NR 14 TC 0 Z9 0 U1 7 U2 7 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1350-4851 EI 1466-4291 J9 APPL ECON LETT JI Appl. Econ. Lett. PD OCT PY 2016 VL 23 IS 15 BP 1110 EP 1116 DI 10.1080/13504851.2015.1137541 PG 7 WC Economics SC Business & Economics GA DU9OJ UT WOS:000382546900014 ER PT J AU Chen, D Sarkar, S Candia, J Florczyk, SJ Bodhak, S Driscoll, MK Simon, CG Dunkers, JP Losert, W AF Chen, Desu Sarkar, Sumona Candia, Julian Florczyk, Stephen J. Bodhak, Subhadip Driscoll, Meghan K. Simon, Carl G., Jr. Dunkers, Joy P. Losert, Wolfgang TI Machine learning based methodology to identify cell shape phenotypes associated with microenvironmental cues SO BIOMATERIALS LA English DT Article DE Cell morphology; Machine learning; Supercell; Fibrous substrates; Stem cell ID MESENCHYMAL STEM-CELLS; MARROW STROMAL CELLS; OSTEOGENIC DIFFERENTIATION; NANOFIBROUS SCAFFOLD; CYTOSKELETAL TENSION; PROLIFERATION; FATE; RHOA; HETEROGENEITY; ACTIVATION AB Cell morphology has been identified as a potential indicator of stem cell response to biomaterials. However, determination of cell shape phenotype in biomaterials is complicated by heterogeneous cell populations, microenvironment heterogeneity, and multi-parametric definitions of cell morphology. To associate cell morphology with cell-material interactions, we developed a shape phenotyping framework based on support vector machines. A feature selection procedure was implemented to select the most significant combination of cell shape metrics to build classifiers with both accuracy and stability to identify and predict microenvironment-driven morphological differences in heterogeneous cell populations. The analysis was conducted at a multi-cell level, where a "supercell" method used average shape measurements of small groups of single cells to account for heterogeneous populations and microenvironment. A subsampling validation algorithm revealed the range of supercell sizes and sample sizes needed for classifier stability and generalization capability. As an example, the responses of human bone marrow stromal cells (hBMSCs) to fibrous vs flat microenvironments were compared on day 1. Our analysis showed that 57 cells (grouped into supercells of size 4) are the minimum needed for phenotyping. The analysis identified that a combination of minor axis length, solidity, and mean negative curvature were the strongest early shape-based indicator of hBMSCs response to fibrous microenvironment. (C) 2016 Published by Elsevier Ltd. C1 [Chen, Desu] Univ Maryland, Biophys Program, College Pk, MD 20742 USA. [Candia, Julian; Driscoll, Meghan K.; Losert, Wolfgang] Univ Maryland, Dept Phys, College Pk, MD 20742 USA. [Sarkar, Sumona; Florczyk, Stephen J.; Bodhak, Subhadip; Simon, Carl G., Jr.; Dunkers, Joy P.] NIST, Biosyst & Biomat Div, Gaithersburg, MD 20899 USA. [Candia, Julian] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Candia, Julian] NIH, Ctr Human Immunol, Bldg 10, Bethesda, MD 20892 USA. RP Losert, W (reprint author), Univ Maryland, Dept Phys, College Pk, MD 20742 USA. EM wlosert@umd.edu FU NIST grant [70NANB14H282]; NSF [PHY120596] FX We would like to thank Hariharan K. Iyer (National Institute of Standards and Technology) for the discussion about canonical cell shapes. WL and DC acknowledge NIST grant [70NANB14H282] and WL, JC, and MD acknowledge NSF grant [PHY120596]. NR 57 TC 1 Z9 1 U1 10 U2 11 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 EI 1878-5905 J9 BIOMATERIALS JI Biomaterials PD OCT PY 2016 VL 104 BP 104 EP 118 DI 10.1016/j.biomaterials.2016.06.040 PG 15 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA DU6SN UT WOS:000382345000009 PM 27449947 ER PT J AU Jacobs, AS Schwartz, MD Valdimarsdottir, H Nusbaum, RH Hooker, GW DeMarco, TA Heinzmann, JE McKinnon, W McCormick, SR Davis, C Forman, AD Lebensohn, AP Dalton, E Tully, DM Graves, KD Similuk, M Kelly, S Peshkin, BN AF Jacobs, Aryana S. Schwartz, Marc D. Valdimarsdottir, Heiddis Nusbaum, Rachel H. Hooker, Gillian W. DeMarco, Tiffani A. Heinzmann, Jessica E. McKinnon, Wendy McCormick, Shelley R. Davis, Claire Forman, Andrea D. Lebensohn, Alexandra Perez Dalton, Emily Tully, Diana Moglia Graves, Kristi D. Similuk, Morgan Kelly, Scott Peshkin, Beth N. TI Patient and genetic counselor perceptions of in-person versus telephone genetic counseling for hereditary breast/ovarian cancer SO FAMILIAL CANCER LA English DT Article DE BRCA1/BRCA2; Genetic counseling; Patient satisfaction; Telephone counseling ID AFRICAN-AMERICAN WOMEN; RISK-ASSESSMENT; FAMILY PHYSICIANS; BREAST; COMMUNICATION; TRIAL; SUSCEPTIBILITY; VALIDATION; DELIVERY; STRESS AB Telephone genetic counseling (TC) for high-risk women interested in BRCA1/2 testing has been shown to yield positive outcomes comparable to usual care (UC; in-person) genetic counseling. However, little is known about how genetic counselors perceive the delivery of these alternate forms of genetic counseling. As part of a randomized trial of TC versus UC, genetic counselors completed a 5-item genetic counselor process questionnaire (GCQ) assessing key elements of pre-test sessions (information delivery, emotional support, addressing questions and concerns, tailoring of session, and facilitation of decision-making) with the 479 female participants (TC, N = 236; UC, N = 243). The GCQ scores did not differ for TC vs. UC sessions (t (477) = 0.11, p = 0.910). However, multivariate analysis showed that participant race/ethnicity significantly predicted genetic counselor perceptions (beta = 0.172, p < 0.001) in that the GCQ scores were lower for minorities in TC and UC. Exploratory analyses suggested that GCQ scores may be associated with patient preference for UC versus TC (t (79) = 2.21, p = 0.030). Additionally, we found that genetic counselor ratings of session effectiveness were generally concordant with patient perceptions of the session. These data indicate that genetic counselors perceive that key components of TC can be delivered as effectively as UC, and that these elements may contribute to specific aspects of patient satisfaction. However, undefined process differences may be present which account for lower counselor perceptions about the effectiveness of their sessions with minority women (i.e., those other than non-Hispanic Whites). We discuss other potential clinical and research implications of our findings. C1 [Jacobs, Aryana S.; Schwartz, Marc D.; Graves, Kristi D.; Peshkin, Beth N.] Georgetown Univ, Jess & Mildred Fisher Ctr Hereditary Canc & Clin, Lombardi Comprehens Canc Ctr, Dept Oncol,Med Ctr, 3300 Whitehaven St,NW,Suite 4100, Washington, DC 20007 USA. [Valdimarsdottir, Heiddis] Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA. [Valdimarsdottir, Heiddis] Reykjavik Univ, Dept Psychol, Reykjavik, Iceland. [Nusbaum, Rachel H.; Tully, Diana Moglia] GeneDx, Gaithersburg, MD USA. [Hooker, Gillian W.] NextGxDx Inc, Franklin, TN USA. [DeMarco, Tiffani A.] Inova Hlth Syst, Inova Translat Med Inst, Canc Genet Counseling Program, Falls Church, VA USA. [Heinzmann, Jessica E.] Atlant Hlth Syst, Carol G Simon Canc Ctr, Summit, NJ USA. [McKinnon, Wendy] Univ Vermont, Familial Canc Program, Ctr Canc, Burlington, VT USA. [McCormick, Shelley R.] Massachusetts Gen Hosp, Ctr Canc Risk Assessment, Boston, MA 02114 USA. [Davis, Claire] Sarah Lawrence Coll, Joan H Marks Grad Program Human Genet, Yonkers, NY USA. [Forman, Andrea D.] Fox Chase Canc Ctr, Dept Clin Genet, Risk Assessment Program, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Lebensohn, Alexandra Perez] Stanford Womens Canc Ctr, Stanford Healthcare, Stanford, CA USA. [Dalton, Emily] Ambry Genet, Aliso Viejo, CA USA. [Similuk, Morgan] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Kelly, Scott] George Washington Univ, Dept Epidemiol & Biostat, Washington, DC USA. RP Peshkin, BN (reprint author), Georgetown Univ, Jess & Mildred Fisher Ctr Hereditary Canc & Clin, Lombardi Comprehens Canc Ctr, Dept Oncol,Med Ctr, 3300 Whitehaven St,NW,Suite 4100, Washington, DC 20007 USA. EM peshkinb@georgetown.edu FU National Cancer Institute [R01 CA108933, P30 CA051008]; Jess and Mildred Fisher Center for Hereditary Cancer and Clinical Genomics Research FX The study was supported by Grants R01 CA108933 and P30 CA051008 from the National Cancer Institute and by the Jess and Mildred Fisher Center for Hereditary Cancer and Clinical Genomics Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. NR 41 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1389-9600 EI 1573-7292 J9 FAM CANCER JI Fam. Cancer PD OCT PY 2016 VL 15 IS 4 BP 529 EP 539 DI 10.1007/s10689-016-9900-x PG 11 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA DV1LB UT WOS:000382681500005 PM 26969308 ER PT J AU Thornton, E Kennedy, S Hayes-Watson, C Krouse, RZ Mitchell, H Cohn, RD Wildfire, J Mvula, MM Lichtveld, M Grimsley, F Martin, WJ Stephens, KU AF Thornton, Eleanor Kennedy, Suzanne Hayes-Watson, Claire Krouse, Rebecca Z. Mitchell, Herman Cohn, Richard D. Wildfire, Jeremy Mvula, Mosanda M. Lichtveld, Maureen Grimsley, Faye Martin, William J., II Stephens, Kevin U. TI Adapting and implementing an evidence-based asthma counseling intervention for resource-poor populations SO JOURNAL OF ASTHMA LA English DT Article DE Asthma counselors; post-disaster; case management; chronic disease counseling; environmental triggers ID OFF ENVIRONMENTAL ASTHMA; INNER-CITY CHILDREN; LOUISIANA HEAL; HOME; DESIGN AB Objective: To report implementation strategies and outcomes of an evidence-based asthma counseling intervention. The Head-off Environmental Asthma in Louisiana (HEAL) intervention integrated asthma counseling (AC) capacity and addressed challenges facing children with asthma in post-disaster New Orleans. Methods: The HEAL intervention enrolled 182 children (4-12years) with moderate-to-severe persistent asthma. Recruitment occurred from schools in the Greater New Orleans area for one year. Participants received home environmental assessments and tailored asthma counseling sessions during the study period based on the National Cooperative Inner City Asthma Study and the Inner City Asthma Study. Primary (i.e., asthma symptoms) and secondary outcomes (i.e., healthcare utilization) were captured. During the study, changes were made to meet the demands of a post-hurricane and resource-poor environment which included changes to staffing, training, AC tools, and AC sessions. Results: After study changes were made, the AC visit rate increased by 92.3%. Significant improvements were observed across several adherence measures (e.g., running out of medications (p = 0.009), financial/insurance problems for appointments (p = 0.006), worried about medication side-effects (p = 0.01), felt medications did not work (p < 0.001)). Additionally, an increasing number of AC visits was modestly associated with a greater reduction in symptoms (test-for-trend p = 0.059). Conclusion: By adapting to the needs of the study population and setting, investigators successfully implemented a counseling intervention that improved participant behaviors and clinical outcomes. The strategies for implementing the AC intervention may serve as a guide for managing asthma and other chronic conditions in resource-poor settings. C1 [Thornton, Eleanor; Hayes-Watson, Claire] Mason Enterprise Ctr Fairfax, Visionary Consulting Partners LLC, 4031 Univ Dr,Suite 100, Fairfax, VA 22030 USA. [Kennedy, Suzanne; Krouse, Rebecca Z.; Mitchell, Herman; Wildfire, Jeremy] Rho Fed Syst Div Inc, Chapel Hill, NC USA. [Cohn, Richard D.] Social & Sci Syst Inc, Durham, NC USA. [Mvula, Mosanda M.; Stephens, Kevin U.] New Orleans Hlth Dept, New Orleans, LA USA. [Lichtveld, Maureen; Grimsley, Faye] Tulane Univ, Sch Publ Hlth & Trop Med, New Orleans, LA USA. [Martin, William J., II] NICHD, NIH, US Dept HHS, Bethesda, MD USA. RP Hayes-Watson, C (reprint author), Mason Enterprise Ctr Fairfax, Visionary Consulting Partners LLC, 4031 Univ Dr,Suite 100, Fairfax, VA 22030 USA. EM chayes@vcp-llc.com FU NIMHD; National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health [NO1-ES-55553]; Merck Childhood Asthma Network, Inc.(MCAN); NIH; MCAN under Foundation for the National Institutes of Health; United States Congress; Merck Foundation, the philanthropic arm of Merck Co., Inc.; Louisiana Board of Regents RC/EEP FX This project was funded by the National Center of Minority Health and Health Disparities (NCMHD, now the NIMHD); the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health under Contract number NO1-ES-55553; and the Merck Childhood Asthma Network, Inc.(MCAN). Public-private funding provided by the NIH and MCAN was managed under the auspices of the Foundation for the National Institutes of Health. Established by the United States Congress to support the mission of the NIH-improving health through scientific discovery in the search for cures-the Foundation for the NIH is a leader in identifying and addressing complex scientific and health issues. The Foundation is a non-profit, 501(c) (3) charitable organization that raises private-sector funds for a broad portfolio of unique programs that complement and enhance the NIH priorities and activities. [Additional information about the Foundation for the NIH is available online (http://www.fnih.org/).] The Merck Childhood Asthma Network, Inc. is a separately incorporated, nonprofit, 501(c) (3) organization funded by the Merck Foundation, the philanthropic arm of Merck & Co., Inc. Other organizations that contributed include the National Toxicology Program (NIEHS), the U.S. Environmental Protection Agency (Cincinnati, OH), and the de Laski Family Foundation. The Clinical and Translational Research Center of Tulane and Louisiana State Universities Schools of Medicine was supported in whole or in part by funds provided through the Louisiana Board of Regents RC/EEP. The authors would also like to acknowledge the following funders of HEAL: The National Center of Minority Health and Health Disparities (NCMHD, now the NIMHD); the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health under Contract number NO1-ES-55553; and the Merck Childhood Asthma Network, Inc.(MCAN). Other organizations that contributed include the National Toxicology Program (NIEHS), the U.S. Environmental Protection Agency (Cincinnati, OH), and the de Laski Family Foundation. The Clinical and Translational Research Center of Tulane and Louisiana State Universities Schools of Medicine was supported in whole or in part by funds provided through the Louisiana Board of Regents RC/EEP. NR 18 TC 0 Z9 0 U1 1 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 0277-0903 EI 1532-4303 J9 J ASTHMA JI J. Asthma PD OCT PY 2016 VL 53 IS 8 BP 825 EP 834 DI 10.3109/02770903.2016.1155219 PG 10 WC Allergy; Respiratory System SC Allergy; Respiratory System GA DU9ZU UT WOS:000382577700007 PM 27049234 ER PT J AU Koopman, M Michels, H Dancy, BM Kamble, R Mouchiroud, L Auwerx, J Nollen, EAA Houtkooper, RH AF Koopman, Mandy Michels, Helen Dancy, Beverley M. Kamble, Rashmi Mouchiroud, Laurent Auwerx, Johan Nollen, Ellen A. A. Houtkooper, Riekelt H. TI A screening-based platform for the assessment of cellular respiration in Caenorhabditis elegans SO NATURE PROTOCOLS LA English DT Article ID C-ELEGANS; OXIDATIVE-PHOSPHORYLATION; MITOCHONDRIAL-FUNCTION; ENERGY-METABOLISM; LIFE-SPAN; CELLS; LONGEVITY; DISEASE; STRESS; RNAI AB Mitochondrial dysfunction is at the core of many diseases ranging from inherited metabolic diseases to common conditions that are associated with aging. Although associations between aging and mitochondrial function have been identified using mammalian models, much of the mechanistic insight has emerged from Caenorhabditis elegans. Mitochondrial respiration is recognized as an indicator of mitochondrial health. The Seahorse XF96 respirometer represents the state-of-the-art platform for assessing respiration in cells, and we adapted the technique for applications involving C. elegans. Here we provide a detailed protocol to optimize and measure respiration in C. elegans with the XF96 respirometer, including the interpretation of parameters and results. The protocol takes similar to 2 d to complete, excluding the time spent culturing C. elegans, and it includes (i) the preparation of C. elegans samples, (ii) selection and loading of compounds to be injected, (iii) preparation and execution of a run with the XF96 respirometer and (iv) postexperimental data analysis, including normalization. In addition, we compare our XF96 application with other existing techniques, including the eight-well Seahorse XFp. The main benefits of the XF96 include the limited number of worms required and the high throughput capacity due to the 96-well format. C1 [Koopman, Mandy; Michels, Helen; Nollen, Ellen A. A.] Univ Groningen, Univ Med Ctr Groningen, European Res Inst Biol Ageing, Lab Mol Neurobiol Ageing, Groningen, Netherlands. [Dancy, Beverley M.] NHLBI, Cardiac Energet Lab, Bethesda, MD 20892 USA. [Kamble, Rashmi; Houtkooper, Riekelt H.] Acad Med Ctr, Lab Genet Metab Dis, Amsterdam, Netherlands. [Mouchiroud, Laurent; Auwerx, Johan] Ecole Polytech Fed Lausanne, Lab Integrat & Syst Physiol, Lausanne, Switzerland. RP Koopman, M (reprint author), Univ Groningen, Univ Med Ctr Groningen, European Res Inst Biol Ageing, Lab Mol Neurobiol Ageing, Groningen, Netherlands.; Houtkooper, RH (reprint author), Acad Med Ctr, Lab Genet Metab Dis, Amsterdam, Netherlands. EM m.koopman@umcg.nl; r.h.houtkooper@amc.nl FU European Research Council (ERC) starting grant [281622]; ERC starting grant [638290]; VIDI grant from ZonMw [91715305]; NWO-Middelgroot [91112009] FX We thank T. Ackermann for advice and C.F. Calkhoven for allowing us to make use of the Seahorse XF96 machine. Work in the Nollen group is financially supported by an European Research Council (ERC) starting grant (no. 281622). Work in the Houtkooper group is financially supported by an ERC starting grant (no. 638290) and a VIDI grant from ZonMw (no. 91715305). The Seahorse XF96 at the Academic Medical Center, Amsterdam, the Netherlands, was supported by a grant from NWO-Middelgroot (no. 91112009). NR 73 TC 1 Z9 1 U1 17 U2 18 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1754-2189 EI 1750-2799 J9 NAT PROTOC JI Nat. Protoc. PD OCT PY 2016 VL 11 IS 10 BP 1798 EP 1816 DI 10.1038/nprot.2016.106 PG 19 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA DU8AP UT WOS:000382436000004 PM 27583642 ER PT J AU Trost, S Diekhof, EK Mohr, H Vieker, H Kramer, B Wolf', C Keil, M Dechent, P Binder, EB Gruber, O AF Trost, Sarah Diekhof, Esther K. Mohr, Holger Vieker, Henning Kraemer, Bernd Wolf', Claudia Keil, Maria Dechent, Peter Binder, Elisabeth B. Gruber, Oliver TI Investigating the Impact of a Genome-Wide Supported Bipolar Risk Variant of MAD1L1 on the Human Reward System SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID MAJOR DEPRESSIVE DISORDER; RESIST IMPULSIVE DESIRES; PREFRONTAL CORTEX; SCHIZOPHRENIA; TEMPERAMENT; CHARACTER; ANTICIPATION; DYSFUNCTION; PSYCHOSIS; NETWORK AB Recent genome-wide association studies have identified MAD1L1 (mitotic arrest deficient-like I) as a susceptibility gene for bipolar disorder and schizophrenia. The minor allele of the single-nucleotide polymorphism (SNP) rs11764590 in MAD1L1 was associated with bipolar disorder. Both diseases, bipolar disorder and schizophrenia, are linked to functional alterations in the reward system. We aimed at investigating possible effects of the MAD1L1 rs11764590 risk allele on reward systems functioning in healthy adults. A large homogenous sample of 224 young (aged 18-31 years) participants was genotyped and underwent functional magnetic resonance imaging (fMR1). All participants performed the 'Desire-Reason Dilemma' paradigm investigating the neural correlates that underlie reward processing and active reward dismissal in favor of a long-term goal. We found significant hypoactivations of the ventral tegmental area (VTA), the bilateral striatum and bilateral frontal and parietal cortices in response to conditioned reward stimuli in the risk allele carriers compared with major allele carriers. In the dilemma situation, functional connectivity between prefrontal brain regions and the ventral striatum was significantly diminished in the risk allele carriers. Healthy risk allele carriers showed a significant deficit of their bottom-up response to conditioned reward stimuli in the bilateral VTA and striatum. Furthermore, functional connectivity between the ventral striatum and prefrontal areas exerting top-down control on the mesolimbic reward system was reduced in this group. Similar alterations in reward processing and disturbances of prefrontal control mechanisms on mesolimbic brain circuits have also been reported in bipolar disorder and schizophrenia. Together, these findings suggest the existence of an intermediate phenotype associated with MAD1L1. C1 [Trost, Sarah; Diekhof, Esther K.; Mohr, Holger; Vieker, Henning; Kraemer, Bernd; Wolf', Claudia; Keil, Maria; Gruber, Oliver] Univ Gottingen, Ctr Translat Res Syst Neurosci & Clin Psychiat, Dept Psychiat & Psychotherapy, Von Siebold Str 5, D-37075 Gottingen, Germany. [Diekhof, Esther K.] Univ Hamburg, Bioctr Grindel, Hamburg, Germany. [Diekhof, Esther K.] Univ Hamburg, Inst Zool, Dept Human Biol, Hamburg, Germany. [Mohr, Holger] Tech Univ Dresden, Neuroimaging Ctr, Dept Psychol, Dresden, Germany. [Mohr, Holger] Tech Univ Dresden, Inst Gen Psychol Biopsychol & Methods Psychol, Dresden, Germany. [Vieker, Henning] Univ Med Ctr, Dept Psychiat & Psychotherapy, Hamburg, Germany. [Kraemer, Bernd; Gruber, Oliver] Heidelberg Univ, Univ Heidelberg Hosp, Dept Gen Psychiat, Sect Expt Psychopathol & Neuroimaging, Heidelberg, Germany. [Wolf', Claudia] NIA, Lab Behav Neurosci, Biomed Res Ctr, Baltimore, MD 21224 USA. [Dechent, Peter] Univ Gottingen, Dept Cognit Neurol, Gottingen, Germany. [Binder, Elisabeth B.] Max Planck Inst Psychiat, Dept Translat Psychiat, Munich, Germany. RP Trost, S (reprint author), Univ Gottingen, Ctr Translat Res Syst Neurosci & Clin Psychiat, Dept Psychiat & Psychotherapy, Von Siebold Str 5, D-37075 Gottingen, Germany. EM s.trost@med.uni-goettingen.de FU Servier FX OG was a honorary speaker for the following companies: Astra Zeneca, Bristol Myers Squibb, Janssen Cilag, Lilly, Servier, and Otsuka. He has been invited to scientific congresses by Astra Zeneca, Janssen Cilag, and Pfizer and has received a research grant from Servier. He reports that these potential conflicts have no relation to the subject of the present study. ST, EKD, HM, HV, BK, CW, MK, PD, and EBB declare that, except for income received from their primary employer, they have no biomedical financial interests or potential conflicts of interest. NR 58 TC 0 Z9 0 U1 6 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 OCT PY 2016 VL 41 IS 11 BP 2679 EP 2687 DI 10.1038/npp.2016.70 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DV4NI UT WOS:000382901900007 PM 27184339 ER PT J AU Tanda, G Mereu, M Hiranita, T Quarterman, JC Coggiano, M Katz, JL AF Tanda, Gianluigi Mereu, Maddalena Hiranita, Takato Quarterman, Juliana C. Coggiano, Mark Katz, Jonathan L. TI Lack of Specific Involvement of (+)-Naloxone and (+)-Naltrexone on the Reinforcing and Neurochemical Effects of Cocaine and Opioids SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID MESOLIMBIC DOPAMINE TRANSMISSION; RECEPTOR 4; NUCLEUS-ACCUMBENS; PHARMACOLOGICAL CHARACTERIZATION; EXTRACELLULAR DOPAMINE; NEUROPATHIC PAIN; CHRONIC MORPHINE; TOLL; ACTIVATION; MECHANISM AB Effective medications for drug abuse remain a largely unmet goal in biomedical science. Recently, the (+)-enantiomers of naloxone and naltrexone, TLR4 antagonists, have been reported to attenuate preclinical indicators of both opioid and stimulant abuse. To further examine the potential of these compounds as drug-abuse treatments, we extended the previous assessments to include a wider range of doses and procedures. We report the assessment of (+)-naloxone and (+)-naltrexone on the acute dopaminergic effects of cocaine and heroin determined by in vivo microdialysis, on the reinforcing effects of cocaine and the opioid agonist, remifentanil, tested under intravenous self-administration procedures, as well as the subjective effects of cocaine determined by discriminative-stimulus effects in rats. Pretreatments with (+)-naloxone or (+)-naltrexone did not attenuate, and under certain conditions enhanced the stimulation of dopamine levels produced by cocaine or heroin in the nucleus accumbens shell. Furthermore, although an attenuation of either cocaine or remifentanil self-administration was obtained at the highest doses of (+)-naloxone and (+)-naltrexone, those doses also attenuated rates of food-maintained behaviors, indicating a lack of selectivity of TLR4 antagonist effects for behaviors reinforced with drug injections. Drug discrimination studies failed to demonstrate a significant interaction of (+)-naloxone with subjective effects of cocaine. The present studies demonstrate that under a wide range of doses and experimental conditions, the TLR4 antagonists, (+)-naloxone and (+)-naltrexone, did not specifically block neurochemical or behavioral abuse-related effects of cocaine or opioid agonists. C1 [Tanda, Gianluigi; Mereu, Maddalena; Quarterman, Juliana C.; Coggiano, Mark] NIDA, Medicat Dev Program, Mol Targets & Medicat Discovery Branch, IRP,NIH,DHHS, Baltimore, MD USA. [Hiranita, Takato; Katz, Jonathan L.] NIDA, Psychobiol Sect, Mol Neuropsychiat Res Branch, IRP,NIH,DHHS, Baltimore, MD USA. RP Tanda, G (reprint author), Medicat Dev Program, TRIAD Bldg,NIDA Suite 3301,333 Cassell Dr, Baltimore, MD 21224 USA. EM Gtanda@mail.nih.gov RI Tanda, Gianluigi/B-3318-2009; OI Tanda, Gianluigi/0000-0001-9526-9878; Katz, Jonathan/0000-0002-1068-1159 FU Medication Development Program; NIDA-IRP; NIH/DHHS FX The animals in the present study were maintained in an AAALAC International accredited facility in accordance with NIH Policy Manual 3040-2, Animal Care and Use in the Intramural Program (releasedon 1 November 1999). Care of the subjects was in accordance with the guidelines of the National Institutes of Health and the National Institute on Drug Abuse Intramural Research Program Animal Care and Use Program, which is fully accredited by AAALAC International. We thank Dr Kenner Rice for providing us the (+)-enantiomers of the opioid antagonists. We also thank Dr Amy Newman for early discussion about the topic of this manuscript. The present study has been funded by the Medication Development Program, NIDA-IRP, and by NIDA-IRP, NIH/DHHS. NR 48 TC 2 Z9 2 U1 5 U2 7 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 OCT PY 2016 VL 41 IS 11 BP 2772 EP 2781 DI 10.1038/npp.2016.91 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DV4NI UT WOS:000382901900017 PM 27296151 ER PT J AU Gerig, G Fishbaugh, J Sadeghi, N AF Gerig, Guido Fishbaugh, James Sadeghi, Neda TI Longitudinal modeling of appearance and shape and its potential for clinical use SO MEDICAL IMAGE ANALYSIS LA English DT Editorial Material DE Longitudinal imaging; Shape analysis; Shape regression; Mixed-effects modeling ID DEVELOPING BRAIN; CHILDHOOD; MORPHOMETRY; REGRESSION; GROWTH; WHITE; MRI AB Clinical assessment routinely uses terms such as development, growth trajectory, degeneration, disease progression, recovery or prediction. This terminology inherently carries the aspect of dynamic processes, suggesting that single measurements in time and cross-sectional comparison may not sufficiently describe spatiotemporal changes. In view of medical imaging, such tasks encourage subject-specific longitudinal imaging. Whereas follow-up, monitoring and prediction are natural tasks in clinical diagnosis of disease progression and of assessment of therapeutic intervention, translation of methodologies for calculation of temporal profiles from longitudinal data to clinical routine still requires significant research and development efforts. Rapid advances in image acquisition technology with significantly reduced acquisition times and with increase of patient comfort favor repeated imaging over the observation period. In view of serial imaging ranging over multiple years, image acquisition faces the challenging issue of scanner standardization and calibration which is crucial for successful spatiotemporal analysis. Longitudinal 3D data, represented as 4D images, capture time-varying anatomy and function. Such data benefits from dedicated analysis methods and tools that make use of the inherent correlation and causality of repeated acquisitions of the same subject. Availability of such data spawned progress in the development of advanced 4D image analysis methodologies that carry the notion of linear and nonlinear regression, now applied to complex, high-dimensional data such as images, image-derived shapes and structures, or a combination thereof. This paper provides examples of recently developed analysis methodologies for 4D image data, primarily focusing on progress in areas of core expertise of the authors. These include spatiotemporal shape modeling and growth trajectories of white matter fiber tracts demonstrated with examples from ongoing longitudinal clinical neuroimaging studies such as analysis of early brain growth in subjects at risk for mental illness and neurodegeneration in Huntington's disease (HD). We will discuss broader aspects of current limitations and need for future research in view of data consistency and analysis methodologies. (C) 2016 Elsevier B.V. All rights reserved. C1 [Gerig, Guido; Fishbaugh, James] NYU, Dept Comp Sci & Engn, Tandon Sch Engn, MetroTech Ctr 2, Brooklyn, NY 11201 USA. [Sadeghi, Neda] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Quantitat Imaging & Tissue Sci, Bethesda, MD USA. RP Gerig, G (reprint author), NYU, Dept Comp Sci & Engn, Tandon Sch Engn, MetroTech Ctr 2, Brooklyn, NY 11201 USA. EM gerig@nyu.edu OI Gerig, Guido/0000-0002-9547-6233 FU NIBIB NIH HHS [U54 EB005149]; NICHD NIH HHS [R01 HD055741]; NIMH NIH HHS [P50 MH064065, R01 MH070890]; NINDS NIH HHS [U01 NS082086, R01 NS050568] NR 24 TC 0 Z9 0 U1 4 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1361-8415 EI 1361-8423 J9 MED IMAGE ANAL JI Med. Image Anal. PD OCT PY 2016 VL 33 SI SI BP 114 EP 121 DI 10.1016/j.media.2016.06.014 PG 8 WC Computer Science, Artificial Intelligence; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Radiology, Nuclear Medicine & Medical Imaging GA DU7TU UT WOS:000382418300021 PM 27344938 ER PT J AU Wegbreit, E Cushman, GK Weissman, AB Bojanek, E Kim, KL Leibenluft, E Dickstein, DP AF Wegbreit, Ezra Cushman, Grace K. Weissman, Alexandra B. Bojanek, Erin Kim, Kerri L. Leibenluft, Ellen Dickstein, Daniel P. TI Reversal-learning deficits in childhood-onset bipolar disorder across the transition from childhood to young adulthood SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Bipolar disorder; Cognitive flexibility; Development; Executive function; Reversal learning ID DEPRESSION RATING-SCALE; SPATIAL WORKING-MEMORY; I DISORDER; NEUROCOGNITIVE FUNCTION; PREFRONTAL CORTEX; GLOBAL ASSESSMENT; DECISION-MAKING; NEUROPSYCHOLOGICAL PERFORMANCE; COGNITIVE IMPAIRMENT; ANXIETY DISORDERS AB Background: Bipolar disorder (BD) is a severe mental illness that can have high costs for youths (< 18 years old) and adults. Relative to healthy controls (HC), individuals with BD often show impaired attention, working memory, executive function, and cognitive flexibility (the ability to adapt to changing reward/punishment contingencies). In our study of youths and young adults with BD, we investigated 1) how cognitive flexibility varies developmentally in BD, and 2) whether it is independent of other executive function deficits associated with BD. Methods: We measured errors on a reversal-learning task, as well as spatial working memory and other executive function, among participants with BD (N=75) and HC (N=130), 7-27 years old. Regression analyses focused on the effects of diagnosis on reversal-learning errors, controlling for age, gender, IQ, spatial span, and executive function. Similar analyses examined non-reversal errors to rule out general task impairment. Results: Participants with BD, regardless of age, gender, or cognitive ability, showed more errors than HC on the response reversal stages of the cognitive flexibility task. However, participants with BD did not show more errors on non-reversal stages, even when controlling for other variables. Limitations: Study limitations include the cross-sectional, rather than longitudinal, design; inability to measure non-linear age effects; and inclusion of medicated participants and those with psychiatric co-morbidity. Conclusions: Individuals with BD show a specific impairment in reversing a previously rewarded response, which persists across the transition from childhood to young adulthood. Tailored interventions targeting this deficit may be effective throughout this developmentally turbulent time. (C) 2016 Elsevier B.V. All rights reserved. C1 [Wegbreit, Ezra; Cushman, Grace K.; Weissman, Alexandra B.; Bojanek, Erin; Kim, Kerri L.; Dickstein, Daniel P.] Brown Univ, Pediat Mood Imaging & NeuroDev PediMIND Program, Dept Psychiat & Human Behav, Alpert Med Sch,Bradley Hosp, 1011 Vet Mem Pkwy, Riverside, RI 02915 USA. [Leibenluft, Ellen] NIMH, Intramural Res Program, Emot & Dev Branch, Sect Bipolar Spectrum Disorders, Bethesda, MD 20892 USA. RP Wegbreit, E (reprint author), Brown Univ, Pediat Mood Imaging & NeuroDev PediMIND Program, Dept Psychiat & Human Behav, Alpert Med Sch,Bradley Hosp, 1011 Vet Mem Pkwy, Riverside, RI 02915 USA. EM Ezra_Wegbreit@Brown.edu RI Dickstein, Daniel/L-3210-2016 OI Dickstein, Daniel/0000-0003-1647-5329 FU NIMH NIH HHS [K22 MH074945, R01 MH087513] NR 76 TC 1 Z9 1 U1 6 U2 13 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 OCT PY 2016 VL 203 BP 46 EP 54 DI 10.1016/j.jad.2016.05.046 PG 9 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DT9QA UT WOS:000381836200007 PM 27280962 ER PT J AU Geiger, JT Ding, JH Crain, B Pletnikova, O Letson, C Dawson, TM Rosenthal, LS Pantelyat, A Gibbs, JR Albert, MS Hernandez, DG Hillis, AE Stone, DJ Singleton, AB Hardy, JA Troncoso, JC Scholz, SW AF Geiger, Joshua T. Ding, Jinhui Crain, Barbara Pletnikova, Olga Letson, Christopher Dawson, Ted M. Rosenthal, Liana S. Pantelyat, Alexander Gibbs, J. Raphael Albert, Marilyn S. Hernandez, Dena G. Hillis, Argye E. Stone, David J. Singleton, Andrew B. Hardy, John A. Troncoso, Juan C. Scholz, Sonja W. CA North Amer Brain Expression Consor TI Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Dementia with Lewy bodies; Exome sequencing; Alzheimer dementia; Lewy body dementia; GBA; PSEN1; APP; APOE ID AMYLOID PRECURSOR PROTEIN; ONSET ALZHEIMERS-DISEASE; PARKINSONS-DISEASE; GAUCHER-DISEASE; GLUCOCEREBROSIDASE MUTATIONS; BODY DISEASE; ASSOCIATION; VARIANT; RISK; GBA AB Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer's disease. Although an increasing number of genetic factors have been connected to this debilitating condition, the proportion of cases that can be attributed to distinct genetic defects is unknown. To provide a comprehensive analysis of the frequency and spectrum of pathogenic missense mutations and coding risk variants in nine genes previously implicated in DLB, we performed exome sequencing in 111 pathologically confirmed DLB patients. All patients were Caucasian individuals from North America. Allele frequencies of identified missense mutations were compared to 222 control exomes. Remarkably, similar to 25% of cases were found to carry a pathogenic mutation or risk variant in APP, GBA or PSEN1, highlighting that genetic defects play a central role in the pathogenesis of this common neurodegenerative disorder. In total, 13% of our cohort carried a pathogenic mutation in GBA, 10% of cases carried a risk variant or mutation in PSEN1, and 2% were found to carry an APP mutation. The APOE 64 risk allele was significantly overrepresented in DLB patients (p-value <0.001). Our results conclusively show that mutations in GBA, PSEN1, and APP are common in DLB and consideration should be given to offer genetic testing to patients diagnosed with Lewy body dementia. Published by Elsevier Inc. C1 [Geiger, Joshua T.; Scholz, Sonja W.] NINDS, Neurodegenerat Dis Res Unit, NIH, 35 Convent Dr, Bethesda, MD 20892 USA. [Ding, Jinhui; Letson, Christopher; Gibbs, J. Raphael; Hernandez, Dena G.; Singleton, Andrew B.; Scholz, Sonja W.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Crain, Barbara; Pletnikova, Olga; Troncoso, Juan C.] Johns Hopkins Univ, Sch Med, Dept Pathol Neuropathol, Baltimore, MD USA. [Dawson, Ted M.; Rosenthal, Liana S.; Pantelyat, Alexander; Albert, Marilyn S.; Hillis, Argye E.; Troncoso, Juan C.; Scholz, Sonja W.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Dawson, Ted M.] Johns Hopkins Univ, Solomon H Synder Dept Neurosci, Baltimore, MD USA. [Dawson, Ted M.] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. [Dawson, Ted M.] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Neuroregenerat Program, Baltimore, MD USA. [Stone, David J.] Merck Res Labs, Genet & Pharmacogen, West Point, PA USA. [Hardy, John A.] UCL, Dept Mol Neurosci, London, England. RP Scholz, SW (reprint author), NINDS, Neurodegenerat Dis Res Unit, NIH, 35 Convent Dr, Bethesda, MD 20892 USA. EM sonja.scholz@nih.gov RI Hardy, John/C-2451-2009; OI Scholz, Sonja/0000-0002-6623-0429 FU Intramural Research Program of the National Institutes of Health (National Institute of Neurological Disorders and Stroke, National Institute on Aging) [Z01 AG000949]; Merck Research Laboratories; National Institute of Neurological Disorders and Stroke [R25 NS065729] FX This work was supported (in part) by the Intramural Research Program of the National Institutes of Health (National Institute of Neurological Disorders and Stroke, National Institute on Aging; project Z01 AG000949). This work was also supported by Merck Research Laboratories. S.W.S. received a R25 career development grant by the National Institute of Neurological Disorders and Stroke (grant number: R25 NS065729). NR 67 TC 1 Z9 1 U1 8 U2 15 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 EI 1095-953X J9 NEUROBIOL DIS JI Neurobiol. Dis. PD OCT PY 2016 VL 94 BP 55 EP 62 DI 10.1016/j.nbd.2016.06.004 PG 8 WC Neurosciences SC Neurosciences & Neurology GA DT9QF UT WOS:000381836700006 PM 27312774 ER PT J AU Zirkle, KW Nolan, BT Jones, RR Weyer, PJ Ward, MH Wheeler, DC AF Zirkle, Keith W. Nolan, Bernard T. Jones, Rena R. Weyer, Peter J. Ward, Mary H. Wheeler, David C. TI Assessing the relationship between groundwater nitrate and animal feeding operations in Iowa (USA) SO SCIENCE OF THE TOTAL ENVIRONMENT LA English DT Article DE Nitrate; Drinking water; Private wells; Animal feeding operations; Generalized additive models; Spatial cluster; Spatial clustering ID PUBLIC WATER-SUPPLIES; DRINKING-WATER; RISK; WELLS; CONTAMINATION; VULNERABILITY; DEFECTS; DISEASE; AQUIFER; QUALITY AB Nitrate-nitrogen is a common contaminant of drinking water in many agricultural areas of the United States of America (USA). Ingested nitrate from contaminated drinking water has been linked to an increased risk of several cancers, specific birth defects, and other diseases. In this research, we assessed the relationship between animal feeding operations (AFOs) and groundwater nitrate in private wells in Iowa. We characterized AFOs by swine and total animal units and type (open, confined, or mixed), and we evaluated the number and spatial intensities of AFOs in proximity to private wells. The types of AFO indicate the extent to which a facility is enclosed by a roof. Using linear regression models, we found significant positive associations between the total number of AFOs-within 2 km of a well (p trend < 0.001), number of open AFOs within 5 km of a well (p trend < 0.001), and number of mixed AFOs within 30 km of a well (p trend < 0.001) and the log nitrate concentration. Additionally, we found significant increases in log nitrate in the top quartiles for AFO spatial intensity, open AFO spatial intensity, and mixed AFO spatial intensity compared to the bottom quartile (0.171 log(mg/L), 0.319 log(mg/L), and 0.541 log(mg/L), respectively; all p < 0.001). We also explored the spatial distribution of nitrate-nitrogen in drinking wells and found significant spatial clustering of high-nitrate wells (>5 mg/L) compared with low-nitrate (<= 5 mg/L) wells (p = 0.001). A generalized additive model for high-nitrate status identified statistically significant areas of risk for high levels of nitrate. Adjustment for some AFO predictor variables explained a portion of the elevated nitrate risk. These results support a relationship between animal feeding operations and groundwater nitrate concentrations and differences in nitrate loss from confined AFOs vs. open or mixed types. (C) 2016 Elsevier B.V. All rights reserved. C1 [Zirkle, Keith W.; Wheeler, David C.] Virginia Commonwealth Univ, Dept Biostat, 830 East Main St, Richmond, VA 23298 USA. [Nolan, Bernard T.] US Geol Survey, Reston, VA USA. [Jones, Rena R.; Ward, Mary H.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Weyer, Peter J.] Univ Iowa, Ctr Hlth Effects Environm Contaminat, Iowa City, IA USA. RP Zirkle, KW (reprint author), Virginia Commonwealth Univ, Dept Biostat, 830 East Main St, Richmond, VA 23298 USA. FU National Institute of Environmental Health Sciences (NIEHS) [T32 ES007334]; Intramural Research Program of the National Cancer Institute FX The project described was supported by grant number T32 ES007334 from the National Institute of Environmental Health Sciences (NIEHS). This study was also supported by the Intramural Research Program of the National Cancer Institute. The publication contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIEHS or NIH. NR 42 TC 0 Z9 0 U1 19 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0048-9697 EI 1879-1026 J9 SCI TOTAL ENVIRON JI Sci. Total Environ. PD OCT 1 PY 2016 VL 566 BP 1062 EP 1068 DI 10.1016/j.scitotenv.2016.05.130 PG 7 WC Environmental Sciences SC Environmental Sciences & Ecology GA DS8VK UT WOS:000381060900101 PM 27277210 ER PT J AU Liu, Y Andersen, SW Wen, WQ Gao, YT Lan, Q Rothman, N Ji, BT Yang, G Xiang, YB Shu, XO Zheng, W AF Liu, Ying Andersen, Shaneda Warren Wen, Wanqing Gao, Yu-Tang Lan, Qing Rothman, Nathaniel Ji, Bu-Tian Yang, Gong Xiang, Yong-Bing Shu, Xiao-Ou Zheng, Wei TI Prospective cohort study of general and central obesity, weight change trajectory and risk of major cancers among Chinese women SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE body mass index; cancer; obesity; waist-hip ratio; weight change trajectory ID BODY-MASS-INDEX; POSTMENOPAUSAL BREAST-CANCER; COLORECTAL-CANCER; ABDOMINAL ADIPOSITY; WAIST CIRCUMFERENCE; ENDOMETRIAL CANCER; MORTALITY; HEALTH; MEN; ADULTS AB General obesity, typically measured using body mass index (BMI), has been associated with an increased risk of several cancers. However, few prospective studies have been conducted in Asian populations. Although central obesity, often measured using waist-hip ratio (WHR), is more predictive for type 2 diabetes and cardiovascular diseases (CVD) risk than BMI, knowledge of its association with cancer incidence is limited. In a cohort of 68,253 eligible Chinese women, we prospectively investigated the association of BMI, WHR and weight change during adulthood with risk of overall cancer and major site-specific cancers using multivariate Cox proportional hazard models. Compared to the BMI group of 18.5-22.9 kg/m(2), obese (BMI30 kg/m(2)) women were at an increased risk of developing overall cancer (hazard ratio=1.36, 95% confidence interval=1.21-1.52), postmenopausal breast cancer (HR: 2.43, 95% CI: 1.73-3.40), endometrial cancer (HR: 5.34, 95% CI: 3.48-8.18), liver cancer (HR: 1.93, 95% CI: 1.14-3.27) and epithelial ovarian cancer (HR: 2.44, 95% CI: 1.37-4.35). Weight gain during adulthood (per 5 kg gain) was associated with increased risk of all cancers combined (HR: 1.05, 95% CI: 1.03-1.08), postmenopausal breast cancer (HR: 1.17, 95% CI: 1.10-1.24) and endometrial cancer (HR: 1.37, 95% CI: 1.27-1.48). On the other hand, WHR was not associated with cancer risk after adjustment for baseline BMI. These findings suggest that obesity may be associated with cancer risk through different mechanisms from those for type 2 diabetes and CVD and support measures of maintaining health body weight to reduce cancer risk in Chinese women. What's new? Obesity rates have risen steeply in Asia, increasing the burden of obesity-related disease in many Asian populations. As a consequence, cancer risk may also be increasing. In populations of European descent, obesity is linked to an elevated cancer risk, and this analysis of data from the Shanghai Women's Health Study suggests that the same is true for Asian populations, revealing positive associations between overall cancer risk and overweight, obesity and high body mass index. These factors were further associated with increased risk of several site-specific cancers. General obesity and weight gain in adulthood were the greatest determinants of cancer risk. C1 [Liu, Ying; Andersen, Shaneda Warren; Wen, Wanqing; Yang, Gong; Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA. [Gao, Yu-Tang; Xiang, Yong-Bing] Shanghai Jiao Tong Univ, Shanghai Canc Inst, Dept Epidemiol, Renji Hosp,Sch Med, Shanghai, Peoples R China. [Lan, Qing; Rothman, Nathaniel; Ji, Bu-Tian] NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, Bethesda, MD 20892 USA. RP Zheng, W (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, 2525 West End Ave,8th Floor, Nashville, TN 37203 USA. EM wei.zheng@vanderbilt.edu RI Zheng, Wei/O-3351-2013 OI Zheng, Wei/0000-0003-1226-070X FU United States National Institutes of Health [R37 CA070867, UM1 CA182910] FX Grant sponsor: United States National Institutes of Health; Grant numbers: R37 CA070867, UM1 CA182910 NR 36 TC 2 Z9 2 U1 7 U2 28 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 OCT 1 PY 2016 VL 139 IS 7 BP 1461 EP 1470 DI 10.1002/ijc.30187 PG 10 WC Oncology SC Oncology GA DR5YB UT WOS:000379977200003 PM 27177094 ER PT J AU Petrick, JL Braunlin, M Laversanne, M Valery, PC Bray, F McGlynn, KA AF Petrick, Jessica L. Braunlin, Megan Laversanne, Mathieu Valery, Patricia C. Bray, Freddie McGlynn, Katherine A. TI International trends in liver cancer incidence, overall and by histologic subtype, 1978-2007 SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE liver cancer; incidence; trends; international ID B-VIRUS INFECTION; HEPATOCELLULAR-CARCINOMA; GLOBAL EPIDEMIOLOGY; TEMPORAL VARIATION; COHORT MODELS; AGE PERIOD; HEPATITIS; RATES; PATTERNS AB Primary liver cancer, the most common histologic types of which are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), is the second leading cause of cancer death worldwide. While rising incidence of liver cancer in low-risk areas and decreasing incidence in some high-risk areas has been reported, trends have not been thoroughly explored by country or by histologic type. We examined liver cancer incidence overall and by histology by calendar time and birth cohort for selected countries between 1978 and 2007. For each successive 5-year period, age-standardized incidence rates were calculated from volumes V-IX of the Cancer Incidence in Five Continents electronic database (CI5plus) and the newly released CI5X (volume X) database. Wide global variations persist in liver cancer incidence. Rates of liver cancer remain highest in Asian countries, specifically Eastern and South-Eastern Asian countries. While rates in most of these high-risk countries have been decreasing in recent years, rates in India and several low-risk countries of Africa, Europe, the Americas, and Oceania have been on the rise. Liver cancer rates by histologic type tend to convey a similar temporal profile. However, in Thailand, France, and Italy, ICC rates have increased while HCC rates have declined. We expect rates in high-risk countries to continue to decrease, as the population seroprevalence of hepatitis B virus (HBV) continues to decline. In low-risk countries, targeted screening and treatment of the hepatitis C virus (HCV), treatment of diabetes and primary prevention of obesity, will be key in reducing future liver cancer incidence. What's new? Liver cancer is the second leading cause of cancer death worldwide. In an analysis of liver cancer rates by country and by histologic type, the authors find that in many high-risk areas, liver cancer is declining. In contrast, in some low-risk areas rates are rising. However, in Thailand, France, and Italy, intrahepatic cholangiocarcinoma rates have increased while hepatocellular carcinoma rates have declined. C1 [Petrick, Jessica L.; Braunlin, Megan; McGlynn, Katherine A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Laversanne, Mathieu; Bray, Freddie] Int Agcy Res Canc, Canc Surveillance Sect, Lyon, France. [Valery, Patricia C.] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia. RP Petrick, JL (reprint author), 9609 Med Ctr Dr,7E-230, Bethesda, MD 20892 USA. EM jessica.petrick@nih.gov FU National Institutes of Health (NIH); National Cancer Institute; Australian National Health and Medical Research Council [1083090] FX Grant sponsors: National Institutes of Health (NIH; Intramural Research Program), National Cancer Institute and the Australian National Health and Medical Research Council (Career Development Fellowship #1083090) NR 35 TC 5 Z9 5 U1 7 U2 27 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 OCT 1 PY 2016 VL 139 IS 7 BP 1534 EP 1545 DI 10.1002/ijc.30211 PG 12 WC Oncology SC Oncology GA DR5YB UT WOS:000379977200010 PM 27244487 ER PT J AU Duffy, AG Makarova-Rusher, OV Ulahannan, SV Rahma, OE Fioravanti, S Walker, M Abdullah, S Raffeld, M Anderson, V Abi-Jaoudeh, N Levy, E Wood, BJ Lee, S Tomita, Y Trepel, JB Steinberg, SM Revenko, AS MacLeod, AR Peer, CJ Figg, WD Greten, TF AF Duffy, A. G. Makarova-Rusher, O. V. Ulahannan, S. V. Rahma, O. E. Fioravanti, S. Walker, M. Abdullah, S. Raffeld, M. Anderson, V. Abi-Jaoudeh, N. Levy, E. Wood, B. J. Lee, S. Tomita, Y. Trepel, J. B. Steinberg, S. M. Revenko, A. S. MacLeod, A. R. Peer, C. J. Figg, W. D. Greten, T. F. TI Modulation of tumor eIF4E by antisense inhibition: A phase I/II translational clinical trial of ISIS 183750an antisense oligonucleotide against eIF4Ein combination with irinotecan in solid tumors and irinotecan-refractory colorectal cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE antisense; colorectal cancer; eIF4E ID CAP-BINDING PROTEIN; PHARMACOKINETICS; PROGRESSION; METASTASIS; CETUXIMAB; EIF-4E; MODEL; COLON AB The eukaryotic translation initiation factor 4E (eIF4E) is a potent oncogene that is found to be dysregulated in 30% of human cancer, including colorectal carcinogenesis (CRC). ISIS 183750 is a second-generation antisense oligonucleotide (ASO) designed to inhibit the production of the eIF4E protein. In preclinical studies we found that EIF4e ASOs reduced expression of EIF4e mRNA and inhibited proliferation of colorectal carcinoma cells. An additive antiproliferative effect was observed in combination with irinotecan. We then performed a clinical trial evaluating this combination in patients with refractory cancer. No dose-limiting toxicities were seen but based on pharmacokinetic data and tolerability the dose of irinotecan was reduced to 160 mg/m(2) biweekly. Efficacy was evaluated in 15 patients with irinotecan-refractory colorectal cancer. The median time of disease control was 22.1 weeks. After ISIS 183750 treatment, peripheral blood levels of eIF4E mRNA were decreased in 13 of 19 patients. Matched pre- and posttreatment tumor biopsies showed decreased eIF4E mRNA levels in five of nine patients. In tumor tissue, the intracellular and stromal presence of ISIS 183750 was detected by IHC in all biopsied patients. Although there were no objective responses stable disease was seen in seven of 15 (47%) patients who were progressing before study entry, six of whom were stable at the time of the week 16 CT scan. We were also able to confirm through mandatory pre- and posttherapy tumor biopsies penetration of the ASO into the site of metastasis. What's new? Antisense technologies offer a number of potential advantages over more traditional therapeutic approaches, including improved specificity. Here the authors treated individuals afflicted with chemo-refractory colorectal cancer with an antisense oligonucleotide (ASO) against eIF4E, a critical translational factor often dysregulated in malignant tumors. Treatment was performed in combination with the chemotherapeutic irinotecan and halted disease progression in less than half of the treated individuals. The authors speculate based on detection of the ASO in tumor biopsies that stromal binding may reduce intracellular penetrance and lower effectiveness of the treatment. C1 [Duffy, A. G.; Makarova-Rusher, O. V.; Ulahannan, S. V.; Rahma, O. E.; Fioravanti, S.; Walker, M.; Greten, T. F.] NCI, Gastrointestinal Malignancies Sect, Thoracic GI Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Abdullah, S.; Raffeld, M.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Anderson, V.; Abi-Jaoudeh, N.; Levy, E.; Wood, B. J.] NCI, Radiol & Imaging Sci, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lee, S.; Tomita, Y.; Trepel, J. B.] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Steinberg, S. M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Revenko, A. S.; MacLeod, A. R.] ISIS Pharmaceut, Carlsbad, CA USA. [Peer, C. J.; Figg, W. D.] NCI, Clin Pharmacol Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Greten, TF (reprint author), NCI, 9000 Rockville Pike,10-12N224, Bethesda, MD 20892 USA. EM tim.greten@nih.gov RI Figg Sr, William/M-2411-2016; Ulahannan, Susanna/H-6525-2016 OI Ulahannan, Susanna/0000-0002-7234-2283 FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX Grant sponsor: Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research NR 24 TC 0 Z9 1 U1 4 U2 14 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 OCT 1 PY 2016 VL 139 IS 7 BP 1648 EP 1657 DI 10.1002/ijc.30199 PG 10 WC Oncology SC Oncology GA DR5YB UT WOS:000379977200021 PM 27194579 ER PT J AU Katki, HA Zhao, FH Hu, SY Zhang, Q Qiao, YL Schiffman, M AF Katki, Hormuzd A. Zhao, Fang-Hui Hu, Shang-Ying Zhang, Qian Qiao, You-Lin Schiffman, Mark TI Reply to Letter: Using novel risk stratification statistics to better understand the value of screening tests SO INTERNATIONAL JOURNAL OF CANCER LA English DT Letter ID POPULATION C1 [Katki, Hormuzd A.; Zhao, Fang-Hui; Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Zhao, Fang-Hui; Hu, Shang-Ying; Zhang, Qian; Qiao, You-Lin] Chinese Acad Med Sci, Canc Hosp, Beijing, Peoples R China. [Zhao, Fang-Hui; Hu, Shang-Ying; Zhang, Qian; Qiao, You-Lin] Peking Union Med Coll, Beijing, Peoples R China. RP Katki, HA (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr Room 7E606, Bethesda, MD 20892 USA. EM katkih@mail.nih.gov RI Qiao, You-Lin/B-4139-2012 OI Qiao, You-Lin/0000-0001-6380-0871 NR 3 TC 0 Z9 0 U1 0 U2 1 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 OCT 1 PY 2016 VL 139 IS 7 BP 1669 EP 1669 DI 10.1002/ijc.30192 PG 1 WC Oncology SC Oncology GA DR5YB UT WOS:000379977200024 PM 27184603 ER PT J AU Demchenko, Y Roschke, A Chen, WD Asmann, Y Bergsagel, PL Kuehl, WM AF Demchenko, Yulia Roschke, Anna Chen, Wei-Dong Asmann, Yan Bergsagel, Peter Leif Kuehl, Walter Michael TI Frequent occurrence of large duplications at reciprocal genomic rearrangement breakpoints in multiple myeloma and other tumors SO NUCLEIC ACIDS RESEARCH LA English DT Article ID CANCER GENOMES; DNA-DAMAGE; MYC; TRANSLOCATIONS; REREPLICATION; MECHANISMS; ABNORMALITIES; DYSREGULATION; PATHOGENESIS; DISRUPTION AB Using a combination of array comparative genomic hybridization, mate pair and cloned sequences, and FISH analyses, we have identified in multiple myeloma cell lines and tumors a novel and recurrent type of genomic rearrangement, i.e. interchromosomal rearrangements (translocations or insertions) and intrachromosomal inversions that contain long (1-4000 kb; median similar to 100 kb) identical sequences adjacent to both reciprocal breakpoint junctions. These duplicated sequences were generated from sequences immediately adjacent to the breakpoint from at least one-but sometimes both-chromosomal donor site(s). Tandem duplications had a similar size distribution suggesting the possibility of a shared mechanism for generating duplicated sequences at breakpoints. Although about 25% of apparent secondary rearrangements contained these duplications, primary IGH translocations rarely, if ever, had large duplications at breakpoint junctions. Significantly, these duplications often contain super-enhancers and/or oncogenes (e.g. MYC) that are dysregulated by rearrangements during tumor progression. We also found that long identical sequences often were identified at both reciprocal breakpoint junctions in six of eight other tumor types. Finally, we have been unable to find reports of similar kinds of rearrangements in wild-type or mutant prokaryotes or lower eukaryotes such as yeast. C1 [Demchenko, Yulia; Roschke, Anna; Chen, Wei-Dong; Kuehl, Walter Michael] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Asmann, Yan] Mayo Clin, Div Biomed Stat & Informat, 4500 San Pablo Rd South, Jacksonville, FL 32224 USA. [Bergsagel, Peter Leif] Mayo Clin Arizona, Comprehens Canc Ctr, 13400 E Shea Blvd, Scottsdale, AZ 85259 USA. RP Kuehl, WM (reprint author), NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM kuehlw@helix.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; National Institutes of Health [CA186781, CA195688]; Predolin Foundation; Intramural Research Funds of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (to W.M.K); National Institutes of Health Grants [CA186781, CA195688 to P.L.B.]; the Predolin Foundation (to P.L.B). Funding for open access charge: Intramural Research Funds of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 35 TC 0 Z9 0 U1 1 U2 1 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 SEP 30 PY 2016 VL 44 IS 17 BP 8189 EP 8198 DI 10.1093/nar/gkw527 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DZ8YL UT WOS:000386158800020 PM 27353332 ER PT J AU Godin, SK Zhang, ZY Herken, BW Westmoreland, JW Lee, AG Mihalevic, MJ Yu, ZX Sobol, RW Resnick, MA Bernstein, KA AF Godin, Stephen K. Zhang, Zhuying Herken, Benjamin W. Westmoreland, James W. Lee, Alison G. Mihalevic, Michael J. Yu, Zhongxun Sobol, Robert W. Resnick, Michael A. Bernstein, Kara A. TI The Shu complex promotes error-free tolerance of alkylation-induced base excision repair products SO NUCLEIC ACIDS RESEARCH LA English DT Article ID STRAND BREAK REPAIR; SACCHAROMYCES-CEREVISIAE; HOMOLOGOUS RECOMBINATION; ESCHERICHIA-COLI; DNA-REPLICATION; ABASIC SITES; IN-VIVO; RAD51-MEDIATED RECOMBINATION; RAD51 PARALOGUES; ENDONUCLEASE-IV AB Here, we investigate the role of the budding yeast Shu complex in promoting homologous recombination (HR) upon replication fork damage. We recently found that the Shu complex stimulates Rad51 filament formation during HR through its physical interactions with Rad55-Rad57. Unlike other HR factors, Shu complex mutants are primarily sensitive to replicative stress caused by MMS and not to more direct DNA breaks. Here, we uncover a novel role for the Shu complex in the repair of specific MMS-induced DNA lesions and elucidate the interplay between HR and translesion DNA synthesis. We find that the Shu complex promotes high-fidelity bypass of MMS-induced alkylation damage, such as N3-methyladenine, as well as bypassing the abasic sites generated after Mag1 removes N3-methyladenine lesions. Furthermore, we find that the Shu complex responds to ssDNA breaks generated in cells lacking the abasic site endonucleases. At each lesion, the Shu complex promotes Rad51-dependent HR as the primary repair/tolerance mechanism over error-prone translesion DNA polymerases. Together, our work demonstrates that the Shu complex's promotion of Rad51 pre-synaptic filaments is critical for high-fidelity bypass of multiple replication-blocking lesion. C1 [Godin, Stephen K.; Zhang, Zhuying; Herken, Benjamin W.; Lee, Alison G.; Mihalevic, Michael J.; Bernstein, Kara A.] Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, 5117 Ctr Ave, Pittsburgh, PA 15213 USA. [Zhang, Zhuying; Yu, Zhongxun] Tsinghua Univ, Sch Med, Beijing 100084, Peoples R China. [Westmoreland, James W.; Resnick, Michael A.] NIEHS, Chromosome Stabil Grp, Mol Genet Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Yu, Zhongxun; Sobol, Robert W.] Dept Pharmacol & Chem Biol, Pittsburgh, PA 15217 USA. [Sobol, Robert W.] Univ S Alabama, Mitchell Canc Inst, 1660 Springhill Ave, Mobile, AL 36604 USA. RP Bernstein, KA (reprint author), Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, 5117 Ctr Ave, Pittsburgh, PA 15213 USA. EM karab@pitt.edu RI Bernstein, Kara/S-4943-2016; OI Bernstein, Kara/0000-0003-2247-6459; Sobol, Robert/0000-0001-7385-3563 FU National Institutes of Health (NIH) [GM088413, ES024872, CA148629, GM087798]; V Foundation Scholar Award; China Scholarship Council; Intramural Research Program of the National Institute of Environmental Health Sciences, NIH [1 Z01 ES065073]; NIH [ES024872] FX National Institutes of Health (NIH) [GM088413, ES024872 to K.A.B. and CA148629, GM087798 to R.W.S.]; V Foundation Scholar Award (to K.A.B.); China Scholarship Council to (Z.Z.); Intramural Research Program of the National Institute of Environmental Health Sciences, NIH [project 1 Z01 ES065073 to M.A.R.]. Funding for open access charge: NIH [ES024872 to K.A.B]. NR 69 TC 0 Z9 0 U1 2 U2 2 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 SEP 30 PY 2016 VL 44 IS 17 BP 8199 EP 8215 DI 10.1093/nar/gkw535 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DZ8YL UT WOS:000386158800021 PM 27298254 ER PT J AU Ganji, M Docter, M Le Grice, SFJ Abbondanzieri, EA AF Ganji, Mahipal Docter, Margreet Le Grice, Stuart F. J. Abbondanzieri, Elio A. TI DNA binding proteins explore multiple local configurations during docking via rapid rebinding SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HIV-1 REVERSE-TRANSCRIPTASE; FRET-BASED ASSAY; SINGLE-MOLECULE; POLYMERASE-ACTIVITY; NUCLEIC-ACID; ACTIVE-SITE; IN-VIVO; MECHANISM; TRANSLOCATION; KINETICS AB Finding the target site and associating in a specific orientation are essential tasks for DNA-binding proteins. In order to make the target search process as efficient as possible, proteins should not only rapidly diffuse to the target site but also dynamically explore multiple local configurations before diffusing away. Protein flipping is an example of this second process that has been observed previously, but the underlying mechanism of flipping remains unclear. Here, we probed the mechanism of protein flipping at the single molecule level, using HIV-1 reverse transcriptase (RT) as a model system. In order to test the effects of long-range attractive forces on flipping efficiency, we varied the salt concentration and macromolecular crowding conditions. As expected, increased salt concentrations weaken the binding of RT to DNA while increased crowding strengthens the binding. Moreover, when we analyzed the flipping kinetics, i.e. the rate and probability of flipping, at each condition we found that flipping was more efficient when RT bound more strongly. Our data are consistent with a view that DNA bound proteins undergo multiple rapid re-binding events, or short hops, that allow the protein to explore other configurations without completely dissociating from the DNA. C1 [Ganji, Mahipal; Docter, Margreet; Abbondanzieri, Elio A.] Delft Univ Technol, Dept Bionanosci, Kavli Inst Nanosci, NL-2629 HZ Delft, Netherlands. [Le Grice, Stuart F. J.] NCI, Basic Res Lab, Frederick, MD 21702 USA. RP Abbondanzieri, EA (reprint author), Delft Univ Technol, Dept Bionanosci, Kavli Inst Nanosci, NL-2629 HZ Delft, Netherlands. EM e.a.abbondanzieri@tudelft.nl FU Marie Curie Career Integration Grant [304284]; Nanofront initiative of the Netherlands Organization for Scientific Research [NWO] [NF13BNS01]; Department of Bionanoscience of the Delft University of Technology; Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services FX Marie Curie Career Integration Grant [304284]; Nanofront initiative of the Netherlands Organization for Scientific Research [NWO, NF13BNS01]; Department of Bionanoscience of the Delft University of Technology; Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services [to S.F.J.L.G]. Funding for open access charge: Department of Bionanoscience of the Delft University of Technology. NR 54 TC 0 Z9 0 U1 2 U2 2 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 SEP 30 PY 2016 VL 44 IS 17 BP 8376 EP 8384 DI 10.1093/nar/gkw666 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DZ8YL UT WOS:000386158800034 PM 27471033 ER PT J AU Torres, CM Biran, A Burney, MJ Patel, H Henser-Brownhill, T Cohen, AHS Li, YL Ben-Hamo, R Nye, E Spencer-Dene, B Chakravarty, P Efroni, S Matthews, N Misteli, T Meshorer, E Scaffidi, P AF Torres, Cristina Morales Biran, Alva Burney, Matthew J. Patel, Harshil Henser-Brownhill, Tristan Cohen, Ayelet-Hashahar Shapira Li, Yilong Ben-Hamo, Rotem Nye, Emma Spencer-Dene, Bradley Chakravarty, Probir Efroni, Sol Matthews, Nik Misteli, Tom Meshorer, Eran Scaffidi, Paola TI The linker histone H1.0 generates epigenetic and functional intratumor heterogeneity SO SCIENCE LA English DT Article ID CANCER STEM-CELLS; TUMOR HETEROGENEITY; DIFFERENTIATION; GLIOBLASTOMA; EVOLUTION; CHROMATIN; ELEMENTS; RNA; DNA; DETERMINANTS AB Tumors comprise functionally diverse subpopulations of cells with distinct proliferative potential. Here, we show that dynamic epigenetic states defined by the linker histone H1.0 determine which cells within a tumor can sustain the long-term cancer growth. Numerous cancer types exhibit high inter-and intratumor heterogeneity of H1.0, with H1.0 levels correlating with tumor differentiation status, patient survival, and, at the single-cell level, cancer stem cell markers. Silencing of H1.0 promotes maintenance of self-renewing cells by inducing derepression of megabase-sized gene domains harboring downstream effectors of oncogenic pathways. Self-renewing epigenetic states are not stable, and reexpression of H1.0 in subsets of tumor cells establishes transcriptional programs that restrict cancer cells' long-term proliferative potential and drive their differentiation. Our results uncover epigenetic determinants of tumor-maintaining cells. C1 [Torres, Cristina Morales; Burney, Matthew J.; Henser-Brownhill, Tristan; Scaffidi, Paola] Francis Crick Inst, Lincolns Inn Fields Lab, Canc Epigenet Lab, London WC2A 3LY, England. [Biran, Alva; Cohen, Ayelet-Hashahar Shapira; Meshorer, Eran] Hebrew Univ Jerusalem, Dept Genet, Inst Life Sci, Edmond J Safra Campus, IL-91904 Jerusalem, Israel. [Biran, Alva; Cohen, Ayelet-Hashahar Shapira; Meshorer, Eran] Hebrew Univ Jerusalem, Edmond & Lily Safra Ctr Brain Sci ELSC, Edmond J Safra Campus, IL-91904 Jerusalem, Israel. [Patel, Harshil; Chakravarty, Probir] Francis Crick Inst, Lincolns Inn Fields Lab, Bioinformat, London WC2A 3LY, England. [Li, Yilong] Wellcome Trust Sanger Inst, Canc Genome Project, Wellcome Trust Genome Campus, Hinxton CB101SA, England. [Ben-Hamo, Rotem; Efroni, Sol] Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, IL-52900 Ramat Gan, Israel. [Nye, Emma; Spencer-Dene, Bradley] Francis Crick Inst, Lincolns Inn Fields Lab, Expt Histopathol, London WC2A 3LY, England. [Matthews, Nik] Francis Crick Inst, Lincolns Inn Fields Lab, Adv Sequencing, London WC2A 3LY, England. [Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. [Scaffidi, Paola] UCL, UCL Canc Inst, London WC1E 6DD, England. RP Scaffidi, P (reprint author), Francis Crick Inst, Lincolns Inn Fields Lab, Canc Epigenet Lab, London WC2A 3LY, England.; Scaffidi, P (reprint author), UCL, UCL Canc Inst, London WC1E 6DD, England. EM paola.scaffidi@crick.ac.uk FU Francis Crick Institute; Cancer Research UK [FC001152]; UK Medical Research Council [FC001152]; Wellcome Trust [FC001152]; Intramural Research Program of the NIH, NCI, Center for Cancer Research; Israel Science Foundation [ISF 1252/12, 657/12]; European Research Council [ERC-281781] FX We thank M. Salton and D. Donato for assistance; D. Bonnet and M. Bustin for sharing mice and reagents; I. Malanchi for help with transplantation assays; M. Becker, P. Van Loo, and I. Varela for useful discussions; and the Crick core facilities for technical support. pdCas9-DNMT3A- EGFP and pdCas9-DNMT3A-EGFP (ANV) plasmids are available from Addgene under a material transfer agreement with V. Zoldos. The results published here are in part based upon data generated by The Cancer Genome Atlas pilot project established by the National Cancer Institute and the National Human Genome Research Institute. This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001152), the UK Medical Research Council (FC001152), and the Wellcome Trust (FC001152), the Intramural Research Program of the NIH, NCI, Center for Cancer Research, the Israel Science Foundation (ISF 1252/12, 657/12), and the European Research Council (ERC-281781). Accompanying data sets are available through GEO (GSE65520, GSE66169, GSE73600, and GSE73580). Author contributions are in the supplementary text. NR 46 TC 2 Z9 2 U1 2 U2 2 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 SEP 30 PY 2016 VL 353 IS 6307 AR aaf1644 DI 10.1126/science.aaf1644 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB8YU UT WOS:000387678700038 ER PT J AU Eveland, M Brokamp, GA Lue, CH Harbison, ST Leips, J De Luca, M AF Eveland, Matthew Brokamp, Gabrielle A. Lue, Chia-Hua Harbison, Susan T. Leips, Jeff De Luca, Maria TI Knockdown expression of Syndecan in the fat body impacts nutrient metabolism and the organismal response to environmental stresses in Drosophila melanogaster (vol 477, pg 103, 2016) SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Correction C1 [Eveland, Matthew; Brokamp, Gabrielle A.; De Luca, Maria] Univ Alabama Birmingham, Dept Nutr Sci, Birmingham, AL 35294 USA. [Lue, Chia-Hua; Leips, Jeff] Univ Maryland Baltimore Cty, Dept Biol Sci, Baltimore, MD 21228 USA. [Harbison, Susan T.] NHLBI, Lab Syst Genet, Bldg 10, Bethesda, MD 20892 USA. [Eveland, Matthew] Columbia Univ, Med Ctr, Dept Biochem & Mol Biophys, New York, NY 10032 USA. RP De Luca, M (reprint author), Univ Alabama Birmingham, Dept Nutr Sci, Birmingham, AL 35294 USA. EM mdeluca2@uab.edu RI Harbison, Susan/P-2577-2016 OI Harbison, Susan/0000-0001-7233-0947 NR 1 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 30 PY 2016 VL 478 IS 4 BP 1798 EP 1798 DI 10.1016/j.bbrc.2016.09.031 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DX4ZS UT WOS:000384390200048 ER PT J AU Ali, SA Shi, V Maric, I Wang, M Stroncek, DF Rose, JJ Brudno, JN Stetler-Stevenson, M Feldman, SA Hansen, BG Fellowes, VS Hakim, FT Gress, RE Kochenderfer, JN AF Ali, Syed Abbas Shi, Victoria Maric, Irina Wang, Michael Stroncek, David F. Rose, Jeremy J. Brudno, Jennifer N. Stetler-Stevenson, Maryalice Feldman, Steven A. Hansen, Brenna G. Fellowes, Vicki S. Hakim, Frances T. Gress, Ronald E. Kochenderfer, James N. TI T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma SO BLOOD LA English DT Article ID THERAPY; MALIGNANCIES; LYMPHOCYTES; CD19; LYMPHOMA; DISEASE; BCMA; BAFF; TRANSPLANTATION; IMMUNOTHERAPY AB Therapies with novel mechanisms of action are needed for multiple myeloma (MM). B-cell maturation antigen (BCMA) is expressed in most cases of MM. We conducted the first-in-humans clinical trial of chimeric antigen receptor (CAR) T cells targeting BCMA. T cells expressing the CAR used in this work (CAR-BCMA) specifically recognized BCMA-expressing cells. Twelve patients received CAR-BCMA T cells in this dose-escalation trial. Among the 6 patients treated on the lowest 2 dose levels, limited antimyeloma activity and mild toxicity occurred. On the third dose level, 1 patient obtained a very good partial remission. Two patients were treated on the fourth dose level of 9 x 10(6) CAR(+) T cells/kg body weight. Before treatment, the first patient on the fourth dose level had chemotherapy-resistant MM, making up 90% of bone marrow cells. After treatment, bone marrow plasma cells became undetectable by flow cytometry, and the patient's MM entered a stringent complete remission that lasted for 17 weeks before relapse. The second patient on the fourth dose level had chemotherapy-resistant MM making up 80% of bone marrow cells before treatment. Twenty-eight weeks after this patient received CAR-BCMA T cells, bone marrow plasma cells were undetectable by flow cytometry, and the serum monoclonal protein had decreased by >95%. This patient is in an ongoing very good partial remission. Both patients treated on the fourth dose level had toxicity consistent with cytokine-release syndrome including fever, hypotension, and dyspnea. Both patients had prolonged cytopenias. Our findings demonstrate antimyeloma activity of CAR-BCMA T cells. This trial was registered to www.clinicaltrials.gov as #NCT02215967. C1 [Ali, Syed Abbas; Brudno, Jennifer N.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Shi, Victoria; Rose, Jeremy J.; Hansen, Brenna G.; Fellowes, Vicki S.; Hakim, Frances T.; Gress, Ronald E.; Kochenderfer, James N.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Maric, Irina] NIH, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Wang, Michael] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Stroncek, David F.] NIH, Dept Transfus Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Stetler-Stevenson, Maryalice] NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Feldman, Steven A.] NCI, Surg Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Ali, Syed Abbas] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. RP Kochenderfer, JN (reprint author), NIH, Bldg 10,Room 3E-3330, Bethesda, MD 20892 USA. EM kochendj@mail.nih.gov FU Center for Cancer Research, National Cancer Institute, NIH FX This work was supported by intramural funding of the Center for Cancer Research, National Cancer Institute, NIH. In addition, the NCI has a Cooperative Research and Development Agreement with bluebird bio, Inc, which supports development of anti-BCMA CAR T-cell therapies. J.N.K. is the NCI Principle Investigator of this Research Agreement. NR 46 TC 17 Z9 17 U1 13 U2 13 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 SEP 29 PY 2016 VL 128 IS 13 BP 1688 EP 1700 DI 10.1182/blood-2016-04-711903 PG 13 WC Hematology SC Hematology GA DZ3HN UT WOS:000385736300007 PM 27412889 ER PT J AU Bai, XM Zhang, YJ Huang, L Wang, JZ Li, WY Niu, LL Jiang, HY Dai, RX Zhou, LN Zhang, ZY Miller, H Song, WX Zhao, XD Liu, CH AF Bai, Xiaoming Zhang, Yongjie Huang, Lu Wang, Jinzhi Li, Wenyan Niu, Linlin Jiang, Hongyan Dai, Rongxin Zhou, Lina Zhang, Zhiyong Miller, Heather Song, Wenxia Zhao, Xiaodong Liu, Chaohong TI The early activation of memory B cells from Wiskott-Aldrich syndrome patients is suppressed by CD19 downregulation SO BLOOD LA English DT Article ID SYNDROME PROTEIN-DEFICIENCY; BRUTONS TYROSINE KINASE; MEMBRANE-BOUND ANTIGEN; SRC FAMILY KINASES; LYMPH-NODE; GENE-TRANSCRIPTION; DENDRITIC CELLS; GERMINAL CENTER; T-CELLS; RECEPTOR AB Wiskott-Aldrich syndrome (WAS) pediatric patients exhibit a deficiency in humoral immune memory. However, the mechanism by which Wiskott-Aldrich syndrome protein (WASP) regulates the differentiation and activation of memory B cells remains elusive. Here we examine the early activation events of memory B cells from the peripheral blood mononuclear cells of WAS patients and age-matched healthy controls (HCs) using total internal reflection fluorescence microscopy. In response to stimulation through the B-cell receptor (BCR), memory B cells from HCs showed significantly higher magnitudes of BCR clustering and cell spreading than naive B cells from the same individuals. This was associated with increases in CD19 recruitment to the BCR and the activation of its downstream signaling molecule Btk and decreases in Fc gamma RIIB recruitment and the activation of its downstream molecule Src homology 2-containing inositol 59 phosphatase (SHIP). However, these enhanced signaling activities mediated by CD19 and Btk are blocked in memory B cells from WAS patients, whereas the activation of FcgRIIB and SHIP was increased. Although the expression levels of CD19, Btk, and Fc gamma RIIB did not change between CD27(-) and CD27(+) B cells of HCs, the protein and mRNA levels of CD19 but not Btk and Fc gamma RIIB were significantly reduced in both CD27(-) and CD27(+) B cells of WAS patients, compared with those of HCs. Overall, our study suggests that WASP is required for memory B-cell activation, promoting the activation by positive regulating CD19 transcription and CD19 recruitment to the BCR. C1 [Bai, Xiaoming; Zhang, Yongjie; Huang, Lu; Wang, Jinzhi; Li, Wenyan; Niu, Linlin; Jiang, Hongyan; Dai, Rongxin; Zhou, Lina; Zhang, Zhiyong; Zhao, Xiaodong] Chongqing Med Univ, Chongqing Key Lab Child Infect & Immun, Childrens Hosp, 136 Zhongshan 2nd Rd, Chongqing 400014, Peoples R China. [Miller, Heather] NIAID, Dept Intracellular Pathogens, Hamilton, MT USA. [Song, Wenxia] Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. [Liu, Chaohong] Huazhong Univ Sci & Technol, Sch Basic Med, Dept Pathogen Biol, Wuhan 430030, Peoples R China. RP Zhao, XD (reprint author), Chongqing Med Univ, Chongqing Key Lab Child Infect & Immun, Childrens Hosp, 136 Zhongshan 2nd Rd, Chongqing 400014, Peoples R China.; Song, WX (reprint author), Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA.; Liu, CH (reprint author), Huazhong Univ Sci & Technol, Sch Basic Med, Dept Pathogen Biol, Wuhan 430030, Peoples R China. EM wenxsong@umd.edu; zhaoxd530@aliyun.com; chaohongliu80@126.com FU Natural Science Foundation of China [31500709]; Public Welfare Scientific Research Project of China [201402012] FX This work was supported by Natural Science Foundation of China (31500709) and Public Welfare Scientific Research Project of China (201402012). NR 48 TC 0 Z9 0 U1 6 U2 6 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 SEP 29 PY 2016 VL 128 IS 13 BP 1723 EP 1734 DI 10.1182/blood-2016-03-703579 PG 12 WC Hematology SC Hematology GA DZ3HN UT WOS:000385736300010 PM 27330000 ER PT J AU Curtis, KA Miller, D Millard, P Basu, S Horkay, F Chandran, PL AF Curtis, Kimberly A. Miller, Danielle Millard, Paul Basu, Saswati Horkay, Ferenc Chandran, Preethi L. TI Unusual Salt and pH Induced Changes in Polyethylenimine Solutions SO PLOS ONE LA English DT Article ID GENE DELIVERY; IN-VIVO; LINEAR POLYETHYLENIMINE; MOLECULAR-DYNAMICS; CELLS; DNA; POLY(ETHYLENIMINE); POLYELECTROLYTES; TRANSFECTION; MORPHOLOGY AB Linear PEI is a cationic polymer commonly used for complexing DNA into nanoparticles for cell-transfection and gene-therapy applications. The polymer has closely-spaced amines with weak-base protonation capacity, and a hydrophobic backbone that is kept unaggre-gated by intra-chain repulsion. As a result, in solution PEI exhibits multiple buffering mechanisms, and polyelectrolyte states that shift between aggregated and free forms. We studied the interplay between the aggregation and protonation behavior of 2.5 kDa linear PEI by pH probing, vapor pressure osmometry, dynamic light scattering, and ninhydrin assay. Our results indicate that: 1. At neutral pH, the PEI chains are associated and the addition of NaCl initially reduces and then increases the extent of association. 2. The aggregate form is uncollapsed and co-exists with the free chains. 3. PEI buffering occurs due to continuous or discontinuous charging between stalled states. 4. Ninhydrin assay tracks the number of unprotonated amines in PEI. 5. The size of PEI-DNA complexes is not significantly affected by the free vs. aggregated state of the PEI polymer. Despite its simple chemical structure, linear PEI displays intricate solution dynamics, which can be harnessed for environment-sensitive biomaterials and for overcoming current challenges with DNA delivery. C1 [Curtis, Kimberly A.; Miller, Danielle; Millard, Paul; Basu, Saswati; Chandran, Preethi L.] Howard Univ, Dept Chem Engn, Washington, DC 20059 USA. [Horkay, Ferenc] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Quantitat Imaging & Tissue Sci, NIH, Bethesda, MD 20892 USA. RP Chandran, PL (reprint author), Howard Univ, Dept Chem Engn, Washington, DC 20059 USA.; Horkay, F (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Quantitat Imaging & Tissue Sci, NIH, Bethesda, MD 20892 USA. EM horkayf@helix.nih.gov; preethi.chandran@howard.edu FU National Science Foundation [1407891]; NSF [1208880]; Intramural Research Program of the NICHD/NIH FX This material is based upon work supported by National Science Foundation under grant no. 1407891 awarded to Dr. Preethi Chandran and by a mini-grant awarded to Preethi Chandran under NSF grant no. 1208880 (PI: Dr. Sonya Smith). Dr. Ferenc Horkay acknowledges the support of the Intramural Research Program of the NICHD/NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; The authors are grateful to Howard University undergraduate students Ms. Tasneem Abdus-Shakur, Mr. Quentinn Roby, Ms. Mahtab Waseem, and Ms. Stacy Apugo for assistance in data collection and analysis. The authors are also grateful to Drs. Anna K. Allen (Howard University) and Richard W. Pastor (Membrane Biophysics Section, National Institutes of Health) for comments on the document. We are also extremely thankful to Dr. James Mitchell (Director, NSF-HU Crest Center for Nanomaterials Research, Howard University) and to Mr. Andy Hai-Ting (Lab Manager, NSF-HU Crest Center for Nanomaterials Research, Howard University) for access to instruments and facilities. Dr. Ferenc Horkay acknowledges the support of the Intramural Research Program of the NICHD/NIH. This material is also work supported by a mini-grant awarded to Preethi Chandran under NSF grant no. 1208880 (PI: Dr. Sonya Smith, Howard University) NR 35 TC 0 Z9 0 U1 5 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 SEP 29 PY 2016 VL 11 IS 9 AR e0158147 DI 10.1371/journal.pone.0158147 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX4CV UT WOS:000384328500002 PM 27685846 ER PT J AU Hartley, SW Mullikin, JC Klein, DC Park, M Coon, SL AF Hartley, Stephen W. Mullikin, James C. Klein, David C. Park, Morgan Coon, Steven L. CA NISC Comparative Sequencing Progr TI Alternative Isoform Analysis of Ttc8 Expression in the Rat Pineal Gland Using a Multi-Platform Sequencing Approach Reveals Neural Regulation SO PLOS ONE LA English DT Article ID NONSYNDROMIC RETINITIS-PIGMENTOSA; BARDET-BIEDL-SYNDROME; LONG NONCODING RNAS; S-ANTIGEN; CIRCADIAN EXPRESSION; MUSCLEBLIND PROTEINS; MORPHOLOGIC EVIDENCE; SIGNAL-TRANSDUCTION; CILIARY MEMBRANE; SEQ AB Alternative isoform regulation (AIR) vastly increases transcriptome diversity and plays an important role in numerous biological processes and pathologies. However, the detection and analysis of isoform-level differential regulation is difficult, particularly in the face of complex and incompletely-annotated transcriptomes. Here we have used Illumina short-read/high-throughput RNA-Seq to identify 55 genes that exhibit neurally-regulated AIR in the pineal gland, and then used two other complementary experimental platforms to further study and characterize the Ttc8 gene, which is involved in Bardet-Biedl syndrome and non-syndromic retinitis pigmentosa. Use of the JunctionSeq analysis tool led to the detection of several novel exons and splice junctions in this gene, including two novel alternative transcription start sites which were found to display disproportionately strong neurally-regulated differential expression in several independent experiments. These high-throughput sequencing results were validated and augmented via targeted qPCR and long-read Pacific Biosciences SMRT sequencing. We confirmed the existence of numerous novel splice junctions and the selective upregulation of the two novel start sites. In addition, we identified more than 20 novel isoforms of the Ttc8 gene that are co-expressed in this tissue. By using information from multiple independent platforms we not only greatly reduce the risk of errors, biases, and artifacts influencing our results, we also are able to characterize the regulation and splicing of the Ttc8 gene more deeply and more precisely than would be C1 [Hartley, Stephen W.; Mullikin, James C.] NHGRI, Comparat Genom Anal Unit, Canc Genet & Comparat Genom Branch, NIH, Bethesda, MD 20892 USA. [Klein, David C.; Coon, Steven L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Neuroendocrinol, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Park, Morgan] NHGRI, NIH, Intramural Sequencing Ctr, Rockville, MD 20852 USA. [Klein, David C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Coon, Steven L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. RP Hartley, SW (reprint author), NHGRI, Comparat Genom Anal Unit, Canc Genet & Comparat Genom Branch, NIH, Bethesda, MD 20892 USA. EM stephen.hartley@nih.gov FU Intramural Research Program, National Human Genome Research Institute, National Institutes of Health, Bethesda [MD20892]; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda [MD20892] FX This work was supported by the Intramural Research Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD20892; and, the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD20892.; This work was supported by the Intramural Research Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892; and, the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892. We greatly appreciate the animal management contributions of Mr. Daniel Abebe, Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892. Library preparation, sequencing, and data processing was performed by the NISC Comparative Sequencing Program: Betty Barnabas, PhD; Robert Blakesley, PhD; Gerry Bouffard, PhD; Shelise Brooks, BS; Holly Coleman, MSc; Mila Dekhtyar, MSc; Michael Gregory, MSc; Xiaobin Guan, PhD; Jyoti Gupta, MSc; Joel Han, BS; Shi-ling Ho, BS; Richelle Legaspi, MSc; Quino Maduro, BS; Cathy Masiello, MSc; Baishali Maskeri, PhD; Jenny McDowell, PhD; Casandra Montemayor, MSc; James Mullikin, PhD; Morgan Park, PhD; Nancy Riebow, BS; Karen Schandler, MSc; Brian Schmidt, BS; Christina Sison, BS; Mal Stantripop, BS; James Thomas, PhD; Pam Thomas, PhD; Meg Vemulapalli, MSc; Alice Young, BA. A complete list of the NISC Comparative Sequencing Program can be found in the supporting information. NR 62 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 SEP 29 PY 2016 VL 11 IS 9 AR e0163590 DI 10.1371/journal.pone.0163590 PG 24 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX4CV UT WOS:000384328500076 PM 27684375 ER PT J AU Kumari, V Dyba, MA Holland, RJ Liang, YH Singh, SV Ji, XH AF Kumari, Vandana Dyba, Marzena A. Holland, Ryan J. Liang, Yu-He Singh, Shivendra V. Ji, Xinhua TI Irreversible Inhibition of Glutathione S-Transferase by Phenethyl Isothiocyanate (PEITC), a Dietary Cancer Chemopreventive Phytochemical SO PLOS ONE LA English DT Article ID CHROMATOGRAPHY; VEGETABLES; P1-1; SITE AB Dietary isothiocyanates abundant as glucosinolate precursors in many edible cruciferous vegetables are effective for prevention of cancer in chemically-induced and transgenic rodent models. Some of these agents, including phenethyl isothiocyanate (PEITC), have already advanced to clinical investigations. The primary route of isothiocyanate metabolism is its conjugation with glutathione (GSH), a reaction catalyzed by glutathione S-transferase (GST). The pi class GST of subunit type 1 (hGSTP1) is much more effective than the alpha class GST of subunit type 1 (hGSTA1) in catalyzing the conjugation. Here, we report the crystal structures of hGSTP1 and hGSTA1 each in complex with the GSH adduct of PEITC. We find that PEITC also covalently modifies the cysteine side chains of GST, which irreversibly inhibits enzymatic activity. C1 [Kumari, Vandana; Dyba, Marzena A.; Holland, Ryan J.; Liang, Yu-He; Ji, Xinhua] NCI, Ctr Canc Res, Frederick, MD 21701 USA. [Dyba, Marzena A.] Leidos Biomed Res Inc, Basic Sci Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Singh, Shivendra V.] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA USA. [Singh, Shivendra V.] Univ Pittsburgh, Sch Med, Inst Canc, Pittsburgh, PA USA. [Holland, Ryan J.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Liang, Yu-He] Rutgers State Univ, Ctr Integrat Prote Res, Piscataway, NJ USA. RP Ji, XH (reprint author), NCI, Ctr Canc Res, Frederick, MD 21701 USA. EM jix@mail.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH); National Cancer Institute (NCI); Center for Cancer Research; Frederick National Laboratory for Cancer Research; NCI; NIH [HHSN261200800001E]; USPHS [R01 CA101753] FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research, and in part with Federal funds from the Frederick National Laboratory for Cancer Research, NCI, NIH, under contract HHSN261200800001E to Leidos Biomedical Research, Inc. that provided support in the form of salary for one author [MAD], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The research efforts of SVS were funded by the USPHS grant R01 CA101753 awarded by the NCI. The specific roles of MAD are articulated in the 'author contributions' section. NR 23 TC 0 Z9 0 U1 8 U2 8 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 SEP 29 PY 2016 VL 11 IS 9 AR e0163821 DI 10.1371/journal.pone.0163821 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX4CV UT WOS:000384328500119 PM 27684484 ER PT J AU Manzourolajdad, A Gonzalez, M Spouge, JL AF Manzourolajdad, Amirhossein Gonzalez, Mileidy Spouge, John L. TI Changes in the Plasticity of HIV-1 Nef RNA during the Evolution of the North American Epidemic SO PLOS ONE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; REV RESPONSE ELEMENT; FALSE DISCOVERY RATE; SECONDARY STRUCTURE; STRUCTURAL NEIGHBORS; STRUCTURE PREDICTION; INTERFERENCE; REPLICATION; GENE; EXPRESSION AB Because of a high mutation rate, HIV exists as a viral swarm of many sequence variants evolving under various selective pressures from the human immune system. Although the Nef gene codes for the most immunogenic of HIV accessory proteins, which alone makes it of great interest to HIV research, it also encodes an RNA structure, whose contribution to HIV virulence has been largely unexplored. Nef RNA helps HIV escape RNA interference (RNAi) through nucleotide changes and alternative folding. This study examines Historic and Modern Datasets of patient HIV-1 Nef sequences during the evolution of the North American epidemic for local changes in RNA plasticity. By definition, RNA plasticity refers to an RNA molecule's ability to take alternative folds (i.e., alternative conformations). Our most important finding is that an evolutionarily conserved region of the HIV-1 Nef gene, which we denote by R2, recently underwent a statistically significant increase in its RNA plasticity. Thus, our results indicate that Modern Nef R2 typically accommodates an alternative fold more readily than Historic Nef R2. Moreover, the increase in RNA plasticity resides mostly in synonymous nucleotide changes, which cannot be a response to selective pressures on the Nef protein. R2 may therefore be of interest in the development of antiviral RNAi therapies. C1 [Manzourolajdad, Amirhossein; Gonzalez, Mileidy; Spouge, John L.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Manzourolajdad, A (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM manzouro@ncbi.nlm.nih.gov FU Intramural Research Program of the National Institutes of Health, National Library of Medicine FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 81 TC 0 Z9 0 U1 2 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 SEP 29 PY 2016 VL 11 IS 9 AR e0163688 DI 10.1371/journal.pone.0163688 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX4CV UT WOS:000384328500097 PM 27685447 ER PT J AU Waters, AM Bagni, R Portugal, F Hartley, JL AF Waters, Andrew M. Bagni, Rachel Portugal, Franklin Hartley, James L. TI Single Synonymous Mutations in KRAS Cause Transformed Phenotypes in NIH3T3 Cells SO PLOS ONE LA English DT Article ID CODON-PAIR BIAS; GENE AMPLIFICATION; CANCER GENES; RAS; EXPRESSION; CARCINOMAS; PROTEIN; VIRUS; PROTOONCOGENES; POLYMORPHISM AB Synonymous mutations in the KRAS gene are clustered at G12, G13, and G60 in human cancers. We constructed 9 stable NIH3T3 cell lines expressing KRAS, each with one of these synonymous mutations. Compared to the negative control cell line expressing the wild type human KRAS gene, all the synonymous mutant lines expressed more KRAS protein, grew more rapidly and to higher densities, and were more invasive in multiple assays. Three of the cell lines showed dramatic loss of contact inhibition, were more refractile under phase contrast, and their refractility was greatly reduced by treatment with trametinib. Codon usage at these glycines is highly conserved in KRAS compared to HRAS, indicating selective pressure. These transformed phenotypes suggest that synonymous mutations found in driver genes such as KRAS may play a role in human cancers. C1 [Waters, Andrew M.; Bagni, Rachel; Hartley, James L.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Canc Res Technol Program, Frederick, MD 21701 USA. [Waters, Andrew M.; Portugal, Franklin] Catholic Univ Amer, Dept Biol, Washington, DC 20064 USA. [Waters, Andrew M.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. RP Hartley, JL (reprint author), Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Canc Res Technol Program, Frederick, MD 21701 USA. EM james.hartley@nih.gov OI Waters, Andrew/0000-0002-6058-5878 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; LBRI FX This work has been funded in whole or in part with federal funds from the National Cancer Institute, http://www.cancer.gov/, National Institutes of Health, under contract HHSN261200800001E. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Leidos Biomedical Research, Inc. operates the Frederick National Laboratory for Cancer Research for the National Cancer Institute under the above named contract. LBRI provided support in the form of salaries for authors AW, RB, and JH, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section.; We thank Yonggan Wu of the Bioinformatics Group in State Key Laboratory of Virology at Wuhan Institute of Virology in China for help with the microRNA prediction software, MiR-Para, which he developed; Jamie Almeida at the National Institute of Standards and Technology and Allison Meade at Memorial Sloan Kettering Cancer Center for technical assistance with cell line authentication; David Sun and Xiaolin Wu of the Frederick National Laboratory of Cancer Research for technical support and advice with interpretation of the digital droplet PCR experiments; and Ann Corsi and Pamela Tuma of the Catholic University of America for useful insights on data interpretation. This work has been funded in whole or in part 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 44 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 SEP 29 PY 2016 VL 11 IS 9 AR e0163272 DI 10.1371/journal.pone.0163272 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX4CV UT WOS:000384328500036 PM 27684555 ER PT J AU White, SH McDermott, MM Sufit, RL Kosmac, K Bugg, AW Gonzalez-Freire, M Ferrucci, L Tian, L Zhao, LH Gao, Y Kibbe, MR Criqui, MH Leeuwenburgh, C Peterson, CA AF White, Sarah H. McDermott, Mary M. Sufit, Robert L. Kosmac, Kate Bugg, Alex W. Gonzalez-Freire, Marta Ferrucci, Luigi Tian, Lu Zhao, Lihui Gao, Ying Kibbe, Melina R. Criqui, Michael H. Leeuwenburgh, Christiaan Peterson, Charlotte A. TI Walking performance is positively correlated to calf muscle fiber size in peripheral artery disease subjects, but fibers show aberrant mitophagy: an observational study SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE Mitochondria; Mitophagy; Fiber type; Calf muscle; Peripheral artery disease ID ANKLE-BRACHIAL INDEX; LOWER-EXTREMITY FUNCTION; SKELETAL-MUSCLE; OXIDATIVE DAMAGE; FUNCTIONAL PERFORMANCE; LEG SYMPTOMS; INTERMITTENT CLAUDICATION; MITOCHONDRIAL DYSFUNCTION; SUBSEQUENT DISABILITY; REPERFUSION INJURY AB Background: Patients with lower extremity peripheral artery disease (PAD) have decreased mobility, which is not fully explained by impaired blood supply to the lower limb. Additionally, reports are conflicted regarding fiber type distribution patterns in PAD, but agree that skeletal muscle mitochondrial respiration is impaired. Methods: To test the hypothesis that reduced muscle fiber oxidative activity and type I distribution are negatively associated with walking performance in PAD, calf muscle biopsies from non-PAD (n = 7) and PAD participants (n = 26) were analyzed immunohistochemically for fiber type and size, oxidative activity, markers of autophagy, and capillary density. Data were analyzed using analysis of covariance. Results: There was a wide range in fiber type distribution among subjects with PAD (9-81 % type I fibers) that did not correlate with walking performance. However, mean type I fiber size correlated with 4-min normal-and fastest-paced walk velocity (r = 0.4940, P = 0.010 and r = 0.4944, P = 0.010, respectively). Although intensity of succinate dehydrogenase activity staining was consistent with fiber type, up to 17 % of oxidative fibers were devoid of mitochondria in their cores, and the core showed accumulation of the autophagic marker, LC3, which did not completely co-localize with LAMP2, a lysosome marker. Conclusions: Calf muscle type I fiber size positively correlates with walking performance in PAD. Accumulation of LC3 and a lack of co-localization of LC3 with LAMP2 in the area depleted of mitochondria in PAD fibers suggests impaired clearance of damaged mitochondria, which may contribute to reduced muscle oxidative capacity. Further study is needed to determine whether defective mitophagy is associated with decline in function over time, and whether interventions aimed at preserving mitochondrial function and improving autophagy can improve walking performance in PAD. C1 [White, Sarah H.; Kosmac, Kate; Bugg, Alex W.; Peterson, Charlotte A.] Univ Kentucky, Coll Hlth Sci, 900 S Limestone CTW105, Lexington, KY 40536 USA. [White, Sarah H.; Kosmac, Kate; Bugg, Alex W.; Peterson, Charlotte A.] Univ Kentucky, Ctr Muscle Biol, 900 S Limestone CTW105, Lexington, KY 40536 USA. [McDermott, Mary M.] Northwestern Univ, Feinberg Sch Med, Dept Med, Div Gen Internal Med, 750 North Lake Shore Dr,10th Floor, Chicago, IL 60611 USA. [McDermott, Mary M.; Zhao, Lihui; Gao, Ying] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Sufit, Robert L.] Northwestern Univ, Feinberg Sch Med, Dept Neurol, Chicago, IL 60611 USA. [Gonzalez-Freire, Marta; Ferrucci, Luigi] NIA, Baltimore, MD 21224 USA. [Tian, Lu] Stanford Univ, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Kibbe, Melina R.] Northwestern Univ, Feinberg Sch Med, Dept Surg, Chicago, IL 60611 USA. [Kibbe, Melina R.] Jesse Brown Vet Affairs Med Ctr, Chicago, IL USA. [Criqui, Michael H.] Univ Calif San Diego, Dept Family Med & Publ Hlth, La Jolla, CA 92093 USA. [Leeuwenburgh, Christiaan] Univ Florida, Inst Aging, Dept Aging & Geriatr Res, Gainesville, FL USA. RP Peterson, CA (reprint author), Univ Kentucky, Coll Hlth Sci, 900 S Limestone CTW105, Lexington, KY 40536 USA.; Peterson, CA (reprint author), Univ Kentucky, Ctr Muscle Biol, 900 S Limestone CTW105, Lexington, KY 40536 USA.; McDermott, MM (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Med, Div Gen Internal Med, 750 North Lake Shore Dr,10th Floor, Chicago, IL 60611 USA.; McDermott, MM (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. EM mdm608@northwestern.edu; cpete4@uky.edu FU NIH [R01HL088589, R01HL083064, R01HL089619, R01HL107510, R21-AG047510, R01HL109244, R01AR60701-S1] FX The work was supported by NIH Grants R01HL088589, R01HL083064, R01HL089619, R01HL107510, R21-AG047510, and R01HL109244 (M.M.M.) and R01AR60701-S1 (C.A.P.). NR 55 TC 3 Z9 3 U1 5 U2 5 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 SEP 29 PY 2016 VL 14 AR 284 DI 10.1186/s12967-016-1030-6 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DX7WR UT WOS:000384600600004 PM 27687713 ER PT J AU Krashes, MJ AF Krashes, Michael J. TI PHYSIOLOGY Forecast for water balance SO NATURE LA English DT Editorial Material AB Disturbances in internal water equilibrium can be debilitating for mammals. Two studies pinpoint areas of the mouse brain that respond to and anticipate thirst, preserving systematic fluid regulation. See Letters p.680 & p.685 C1 [Krashes, Michael J.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Krashes, Michael J.] NIDA, NIH, Baltimore, MD USA. RP Krashes, MJ (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA.; Krashes, MJ (reprint author), NIDA, NIH, Baltimore, MD USA. EM michael.krashes@nih.gov NR 9 TC 0 Z9 0 U1 10 U2 10 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 SEP 29 PY 2016 VL 537 IS 7622 BP 626 EP 627 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX4DR UT WOS:000384331700037 PM 27680936 ER PT J AU Varadarajan, J McWilliams, MJ Mott, BT Thomas, CJ Smith, SJ Hughes, SH AF Varadarajan, Janani McWilliams, Mary Jane Mott, Bryan T. Thomas, Craig J. Smith, Steven J. Hughes, Stephen H. TI Drug resistant integrase mutants cause aberrant HIV integrations SO RETROVIROLOGY LA English DT Article DE Elvitegravir; Aberrant integration; Drug resistance; HIV ID TRANSFER-RNA CLEAVAGE; PRIMER BINDING-SITE; IN-VIVO; DNA-POLYMERASES; CA DINUCLEOTIDE; STRAND TRANSFER; B-CELL; RALTEGRAVIR; MUTATIONS; INHIBITORS AB Background: HIV-1 integrase is the target for three FDA-approved drugs, raltegravir, elvitegravir, and dolutegravir. All three drugs bind at the active site of integrase and block the strand transfer step of integration. We previously showed that sub-optimal doses of the anti-HIV drug raltegravir can cause aberrant HIV integrations that are accompanied by a variety of deletions, duplications, insertions and inversions of the adjacent host sequences. Results: We show here that a second drug, elvitegravir, also causes similar aberrant integrations. More importantly, we show that at least two of the three clinically relevant drug resistant integrase mutants we tested, N155H and G140S/Q148H, which reduce the enzymatic activity of integrase, can cause the same sorts of aberrant integrations, even in the absence of drugs. In addition, these drug resistant mutants have an elevated IC50 for anti-integrase drugs, and concentrations of the drugs that would be optimal against the WT virus are suboptimal for the mutants. Conclusions: We previously showed that suboptimal doses of a drug that binds to the HIV enzyme integrase and blocks the integration of a DNA copy of the viral genome into host DNA can cause aberrant integrations that involve rearrangements of the host DNA. We show here that suboptimal doses of a second anti-integrase drug can cause similar aberrant integrations. We also show that drug-resistance mutations in HIV integrase can also cause aberrant integrations, even in the absence of an anti-integrase drug. HIV DNA integrations in the oncogenes BACH2 and MKL2 that do not involve rearrangements of the viral or host DNA can stimulate the proliferation of infected cells. Based on what is known about the association of DNA rearrangements and the activation of oncogenes in human tumors, it is possible that some of the deletions, duplications, insertions, and inversions of the host DNA that accompany aberrant HIV DNA integrations could increase the chances that HIV integrations could lead to the development of a tumor. C1 [Varadarajan, Janani; McWilliams, Mary Jane; Smith, Steven J.; Hughes, Stephen H.] NCI, HIV Dynam & Replicat Program, Vector Design & Replicat Sect, 1050 Boyles St,Bldg 539,Room 130A, Frederick, MD 21702 USA. [Mott, Bryan T.; Thomas, Craig J.] NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Varadarajan, Janani] Vanderbilt Univ, Dept Pathol Microbiol & Immunol, Sch Med, Nashville, TN 37232 USA. RP Hughes, SH (reprint author), NCI, HIV Dynam & Replicat Program, Vector Design & Replicat Sect, 1050 Boyles St,Bldg 539,Room 130A, Frederick, MD 21702 USA. EM hughesst@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute. NR 40 TC 0 Z9 0 U1 5 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 29 PY 2016 VL 13 AR 71 DI 10.1186/s12977-016-0305-6 PG 10 WC Virology SC Virology GA DX4PJ UT WOS:000384363300001 PM 27682062 ER PT J AU Almawi, AW Matthews, LA Larasati Myrox, P Boulton, S Lai, C Moraes, T Melacini, G Ghirlando, R Duncker, BP Guarne, A AF Almawi, Ahmad W. Matthews, Lindsay A. Larasati Myrox, Polina Boulton, Stephen Lai, Christine Moraes, Trevor Melacini, Giuseppe Ghirlando, Rodolfo Duncker, Bernard P. Guarne, Alba TI 'AND' logic gates at work: Crystal structure of Rad53 bound to Dbf4 and Cdc7 SO SCIENTIFIC REPORTS LA English DT Article ID FORKHEAD-ASSOCIATED DOMAIN; CHK2 PROTEIN-KINASE; DNA-DAMAGE CHECKPOINT; FHA DOMAIN; SACCHAROMYCES-CEREVISIAE; SEDIMENTATION-VELOCITY; REPLICATION CHECKPOINT; S-PHASE; PHOSPHORYLATION; OLIGOMERIZATION AB Forkhead-associated (FHA) domains are phosphopeptide recognition modules found in many signaling proteins. The Saccharomyces cerevisiae protein kinase Rad53 is a key regulator of the DNA damage checkpoint and uses its two FHA domains to interact with multiple binding partners during the checkpoint response. One of these binding partners is the Dbf4-dependent kinase (DDK), a heterodimer composed of the Cdc7 kinase and its regulatory subunit Dbf4. Binding of Rad53 to DDK, through its N-terminal FHA (FHA1) domain, ultimately inhibits DDK kinase activity, thereby preventing firing of late origins. We have previously found that the FHA1 domain of Rad53 binds simultaneously to Dbf4 and a phosphoepitope, suggesting that this domain functions as an 'AND' logic gate. Here, we present the crystal structures of the FHA1 domain of Rad53 bound to Dbf4, in the presence and absence of a Cdc7 phosphorylated peptide. Our results reveal how the FHA1 uses a canonical binding interface to recognize the Cdc7 phosphopeptide and a non-canonical interface to bind Dbf4. Based on these data we propose a mechanism to explain how Rad53 enhances the specificity of FHA1-mediated transient interactions. C1 [Almawi, Ahmad W.; Matthews, Lindsay A.; Guarne, Alba] Dept Biochem & Biomed Sci, Hamilton, ON, Canada. [Larasati; Myrox, Polina; Duncker, Bernard P.] Univ Waterloo, Dept Biol, Waterloo, ON, Canada. [Boulton, Stephen; Melacini, Giuseppe] McMaster Univ, Dept Chem & Chem Biol, Hamilton, ON L8S 4L8, Canada. [Moraes, Trevor] Univ Toronto, Dept Biochem, Toronto, ON, Canada. [Ghirlando, Rodolfo] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Matthews, Lindsay A.] Univ Michigan, Dept Mol Cellular & Dev Biol, Ann Arbor, MI 48109 USA. RP Guarne, A (reprint author), Dept Biochem & Biomed Sci, Hamilton, ON, Canada. EM guarnea@mcmaster.ca FU Canadian Institutes of Health Research [MOP-67189]; Natural Sciences and Engineering Research Council [RGPIN 238392]; Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases; Ontario Graduate Scholarship FX We are grateful to Dr. Pawel Grochulski and Michel Fodje at the Canadian Light Source for assistance on data collection and processing of the ternary complex; as well as Aaron G. Robertson for assistance generating the Cdc7-T484A mutant. This work was funded by the Canadian Institutes of Health Research (MOP-67189 to AG); the Natural Sciences and Engineering Research Council (RGPIN 238392 to BPD); of and the Intramural Research Program of the NIH, the National Institute of Diabetes and Digestive and Kidney Diseases (to RG). A.W.A. was funded in part by an Ontario Graduate Scholarship. NR 51 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 SEP 29 PY 2016 VL 6 AR 34237 DI 10.1038/srep34237 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX2FM UT WOS:000384183100003 PM 27681475 ER PT J AU Killikelly, AM Kanekiyo, M Graham, BS AF Killikelly, April M. Kanekiyo, Masaru Graham, Barney S. TI Pre-fusion F is absent on the surface of formalin-inactivated respiratory syncytial virus SO SCIENTIFIC REPORTS LA English DT Article ID NEUTRALIZING EPITOPES; FIELD TRIAL; VACCINE; GLYCOPROTEIN; INFECTION; DISEASE; MECHANISM; CHILDREN; ANTIBODY; INFANTS AB The lack of a licensed vaccine for respiratory syncytial virus (RSV) can be partly attributed to regulatory hurdles resulting from vaccine enhanced respiratory disease (ERD) subsequent to natural RSV infection that was observed in clinical trials of formalin-inactivated RSV (FI-RSV) in antigen-naive infants. To develop an effective vaccine that does not enhance RSV illness, it is important to understand how formalin and heat inactivation affected the antigenicity and immunogenicity of FI-RSV compared to native virus. Informed by atomic structures of RSV fusion (F) glycoprotein in prefusion (pre-F) and postfusion (post-F) conformations, we demonstrate that FI-RSV predominately presents post-F on the virion surface, whereas infectious RSV presents both pre-F and post-F conformations. This significant antigenic distinction has not been previously appreciated. Thus, a stabilized pre-F antigen is more representative of live RSV than F in its post-F conformation, as displayed on the surface of FI-RSV. This finding has major implications for discriminating current pre-F-based immunogens from FI-RSV used in historical vaccine trials. C1 [Killikelly, April M.; Kanekiyo, Masaru; Graham, Barney S.] Natl Inst Infect Dis, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Graham, BS (reprint author), Natl Inst Infect Dis, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. EM bgraham@nih.gov FU Intramural Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank Alan Hoofring for assistance with graphic artwork, Jason McLellan (Dartmouth College), Tracy Ruckwardt, Kaitlyn Morabito, Joan Ngwuta and members of the Viral Pathogenesis Laboratory for advice and comments. This work was supported by the Intramural Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 26 TC 1 Z9 1 U1 10 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 SEP 29 PY 2016 VL 6 AR 34108 DI 10.1038/srep34108 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX2DB UT WOS:000384176200001 PM 27682426 ER PT J AU Marston, HD Lurie, N Borio, LL Fauci, AS AF Marston, Hilary D. Lurie, Nicole Borio, Luciana L. Fauci, Anthony S. TI Considerations for Developing a Zika Virus Vaccine SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID INFECTION C1 [Marston, Hilary D.; Fauci, Anthony S.] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Borio, Luciana L.] US FDA, Off Commissioner, Silver Spring, MD USA. [Lurie, Nicole] US Dept HHS, Off Assistant Secretary Preparedness & Response, Washington, DC 20201 USA. RP Marston, HD (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 4 TC 6 Z9 6 U1 25 U2 25 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 SEP 29 PY 2016 VL 375 IS 13 BP 1209 EP 1212 DI 10.1056/NEJMp1607762 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA DX3HU UT WOS:000384265000001 PM 27682031 ER PT J AU Taurog, JD Chhabra, A Colbert, RA AF Taurog, Joel D. Chhabra, Avneesh Colbert, Robert A. TI Viral Load Kinetics of MERS Coronavirus Infection Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Taurog, Joel D.; Chhabra, Avneesh] Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA. [Colbert, Robert A.] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Taurog, JD (reprint author), Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA. EM joel.taurog@utsouthwestern.edu NR 2 TC 0 Z9 0 U1 0 U2 0 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 SEP 29 PY 2016 VL 375 IS 13 BP 1303 EP 1303 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DX3HU UT WOS:000384265000029 PM 27682050 ER PT J AU Chu, CC Ge, SX Zhang, J Lin, HR Liu, G Chen, XY AF Chu, Chengchao Ge, Shengxiang Zhang, Jing Lin, Huirong Liu, Gang Chen, Xiaoyuan TI Enzyme-free colorimetric determination of EV71 virus using a 3D-MnO2-PEG nanoflower and 4-MBA-MA-AgNPs SO NANOSCALE LA English DT Article ID SILVER NANOPARTICLES; SENSITIVE DETECTION; GRAPHENE NANOSHEETS; MNO2 NANOSPHERES; FACILE SYNTHESIS; PATHOGENS; ACID; GLUCOSE; ASSAY; H2O2 AB We present a simple colorimetric assay for EV71 virus detection based on the aggregation of 4-mercaptobenzoic acid (4-MBA) and melamine (MA) modified silver nanoparticles (4-MBA-MA-AgNPs) in the presence of Mn2+. The EV71-Ab(1) was incubated on a 96-well plate and the EV71-Ab(2) was labeled on the surface of three-dimensional nanoflower-like MnO2-PEG (3D-MnO2-PEG). After layer-by-layer immunoreactions, the EV71 virus and the corresponding 3D-MnO2-PEG-Ab(2) were captured on the plate. With the addition of Vitamin C (Vc), Mn2+ was released from the 3D-MnO2-PEG and then the aggregation of the 4-MBA-MA-AgNPs was induced, allowing a naked-eye detection limit of EV71 virus to be as low as 5 x 104 particles per mL, which is about three orders of magnitude lower than the conventional enzyme-linked immunosorbent assay (ELISA). This enzyme-free immunoassay based on a hybrid 3D-MnO2 features signal amplification strategies via a simple reduction reaction. C1 [Chu, Chengchao; Ge, Shengxiang; Zhang, Jing; Lin, Huirong; Liu, Gang] Xiamen Univ, State Key Lab Mol Vaccinol & Mol Diagnost, Sch Publ Hlth, Xiamen 361102, Peoples R China. [Chu, Chengchao; Ge, Shengxiang; Zhang, Jing; Lin, Huirong; Liu, Gang] Xiamen Univ, Ctr Mol Imaging & Translat Med, Sch Publ Hlth, Xiamen 361102, Peoples R China. [Ge, Shengxiang; Zhang, Jing] Xiamen Univ, Sch Publ Hlth, Natl Inst Diagnost & Vaccine Dev Infect Dis, Xiamen 361102, Peoples R China. [Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. RP Liu, G (reprint author), Xiamen Univ, State Key Lab Mol Vaccinol & Mol Diagnost, Sch Publ Hlth, Xiamen 361102, Peoples R China.; Liu, G (reprint author), Xiamen Univ, Ctr Mol Imaging & Translat Med, Sch Publ Hlth, Xiamen 361102, Peoples R China. EM gangliu.cmitm@xmu.edu.cn FU Major State Basic Research Development Program of China (973 Program) [2013CB733802, 2014CB744503]; National Natural Science Foundation of China (NSFC) [81422023, 51273165, U1505221]; Fundamental Research Funds for the Central Universities [20720160065, 20720150141]; Science Foundation of Fujian Province [2014Y2004]; Program for New Century Excellent Talents in University, China [NCET-13-0502] FX This work was supported by the Major State Basic Research Development Program of China (973 Program) (Grant No. 2013CB733802 and 2014CB744503), the National Natural Science Foundation of China (NSFC) (Grant No. 81422023, 51273165, and U1505221), the Fundamental Research Funds for the Central Universities (Grant No. 20720160065 and 20720150141), the Science Foundation of Fujian Province (no. 2014Y2004), and the Program for New Century Excellent Talents in University, China (NCET-13-0502). NR 29 TC 0 Z9 0 U1 37 U2 37 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2040-3364 EI 2040-3372 J9 NANOSCALE JI Nanoscale PD SEP 28 PY 2016 VL 8 IS 36 BP 16168 EP 16171 DI 10.1039/c6nr06005f PG 4 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA DX6YI UT WOS:000384531600004 PM 27714132 ER PT J AU Singh, SR Rameshwar, P Siegel, P AF Singh, Shree Ram Rameshwar, Pranela Siegel, Peter TI Featuring the guest editors: Special issue tumor microenvironment SO CANCER LETTERS LA English DT Editorial Material C1 [Singh, Shree Ram] NCI, Stem Cell Regulat & Anim Aging Sect, Basic Res Lab, Frederick, MD 21702 USA. [Rameshwar, Pranela] New Jersey Med Sch NJMS Rutgers, Div Hematol & Oncol, Newark, NJ 07103 USA. [Siegel, Peter] McGill Univ, Rosalind & Morris Goodman Canc Res Ctr, Dept Med Biochem Anat & Cell Biol & Oncol, Montreal, PQ, Canada. RP Singh, SR (reprint author), NCI, Stem Cell Regulat & Anim Aging Sect, Basic Res Lab, Frederick, MD 21702 USA. EM singhshr@mail.nih.gov; rameshwa@njms.rutgers.edu; peter.siegel@mcgill.ca RI Singh, Shree Ram/B-7614-2008 OI Singh, Shree Ram/0000-0001-6545-583X NR 0 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 EI 1872-7980 J9 CANCER LETT JI Cancer Lett. PD SEP 28 PY 2016 VL 380 IS 1 BP 201 EP 202 DI 10.1016/j.canlet.2015.05.021 PG 2 WC Oncology SC Oncology GA DT5ON UT WOS:000381532600022 PM 26028171 ER PT J AU Singh, SR Rameshwar, P Siegel, P AF Singh, Shree Ram Rameshwar, Pranela Siegel, Peter TI Targeting tumor microenvironment in cancer therapy SO CANCER LETTERS LA English DT Editorial Material C1 [Singh, Shree Ram] NCI, Stem Cell Regulat & Anim Aging Sect, Basic Res Lab, Frederick, MD 21702 USA. [Rameshwar, Pranela] Rutgers, New Jersey Med Sch, Dept Med Hematol Oncol, Newark, NJ 07103 USA. [Siegel, Peter] McGill Univ, Dept Med Biochem & Anat & Cell Biol, Rosalind & Morris Goodman Canc Res Ctr, Montreal, PQ H3A 1A3, Canada. RP Singh, SR (reprint author), NCI, Stem Cell Regulat & Anim Aging Sect, Basic Res Lab, Frederick, MD 21702 USA. EM singhshr@mail.nih.gov RI Singh, Shree Ram/B-7614-2008 OI Singh, Shree Ram/0000-0001-6545-583X NR 0 TC 2 Z9 2 U1 8 U2 10 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 EI 1872-7980 J9 CANCER LETT JI Cancer Lett. PD SEP 28 PY 2016 VL 380 IS 1 BP 203 EP 204 DI 10.1016/j.canlet.2016.04.009 PG 2 WC Oncology SC Oncology GA DT5ON UT WOS:000381532600023 PM 27060765 ER PT J AU Qu, P Wang, LZ Lin, PC AF Qu, Peng Wang, Li-zhen Lin, P. Charles TI Expansion and functions of myeloid-derived suppressor cells in the tumor microenvironment SO CANCER LETTERS LA English DT Review DE Myeloid-derived suppressor cells; Tumor microenvironment; angiogenesis; immune suppression; M-MDSC; PMN-MDSC ID IMMUNE SUPPRESSION; TGF-BETA; DENDRITIC CELLS; CANCER-PATIENTS; BEARING HOST; INFLAMMATION; PROGRESSION; ANGIOGENESIS; METASTASIS; ACTIVATION AB Myeloid derived suppressor cells (MDSCs) are a group of immature myeloid cells accumulated in most cancer patients and mouse tumor models. MDSCs suppress host immune response and concurrently promote tumor angiogenesis, thereby promote tumor growth and progression. In this review, we discuss recent progresses in expansion and activity of tumor MDSCs, and describe new findings about immunosuppressive function of different subtypes of MDSCs in cancer. We also discussed tumor angiogenic activities and pro-tumor invasion/metastatic roles of MDSCs in tumor progression. Published by Elsevier Ireland Ltd. C1 [Qu, Peng; Wang, Li-zhen; Lin, P. Charles] NCI, NIH, Frederick, MD 21701 USA. RP Lin, PC (reprint author), NCI, NIH, Frederick, MD 21701 USA. EM p.lin@nih.gov FU Intramural Research Program at the NCI, NIH FX The work was supported by the Intramural Research Program at the NCI, NIH. NR 67 TC 2 Z9 2 U1 15 U2 15 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 EI 1872-7980 J9 CANCER LETT JI Cancer Lett. PD SEP 28 PY 2016 VL 380 IS 1 BP 253 EP 256 DI 10.1016/j.canlet.2015.10.022 PG 4 WC Oncology SC Oncology GA DT5ON UT WOS:000381532600029 PM 26519756 ER PT J AU Brozyna, AA Jozwicki, W Skobowiat, C Jetten, A Slominski, AT AF Brozyna, Anna A. Jozwicki, Wojciech Skobowiat, Cezary Jetten, Anton Slominski, Andrzej T. TI ROR alpha and ROR gamma expression inversely correlates with human melanoma progression SO ONCOTARGET LA English DT Article DE melanoma; ROR alpha; ROR gamma; melanocytic nevi; vitamin D ID ORPHAN RECEPTOR SUBFAMILY; IN-VIVO; NUCLEAR RECEPTORS; GENE-EXPRESSION; REV-ERB; TRANSCRIPTIONAL REGULATION; CELL-DIFFERENTIATION; CHOLESTEROL SULFATE; CIRCADIAN CLOCK; BREAST-CANCER AB The retinoic acid-related orphan receptors (RORs) regulate several physiological and pathological processes, including immune functions, development and cancer. To study the potential role of RORs in melanoma progression, we analysed ROR alpha and ROR gamma expression in nevi and primary melanomas and non-lesional skin and metastases in relation to melanoma clinico-pathomorphological features. The expression of ROR alpha and ROR gamma was lower in melanomas than in nevi and decreased during melanoma progression, with lowest levels found in primary melanomas at stages III and IV and in melanoma metastases. Their expression correlated with pathomorphological pTNM parameters being low in aggressive tumors and being high in tumors showing histological markers of good prognosis. Higher nuclear levels of ROR alpha and ROR gamma and of cytoplasmic ROR gamma correlated with significantly longer overall and disease free survival time. Highly pigmented melanomas showed significantly lower level of nuclear RORs. This study shows that human melanoma development and aggressiveness is associated with decreased expression of ROR alpha and ROR gamma, suggesting that RORs could be important in melanoma progression and host responses against the tumor. Furthermore, it suggests that ROR alpha and ROR gamma might constitute a novel druggable target in anti-melanoma management using tumor suppressor gene therapy restoring their normal functions. C1 [Brozyna, Anna A.; Jozwicki, Wojciech] Prof Franciszek Lukaszczyk Mem Hosp, Ctr Oncol, Dept Tumor Pathol & Pathomorphol, Bydgoszcz, Poland. [Brozyna, Anna A.; Jozwicki, Wojciech] Nicolaus Copernicus Univ, Coll Med Bydgoszcz, Fac Hlth Sci, Dept Tumor Pathol & Pathomorphol, Bydgoszcz, Poland. [Skobowiat, Cezary] Nicolaus Copernicus Univ, Coll Med Bydgoszcz, Fac Pharm, Dept Pharmacodynam & Mol Pharmacol, Bydgoszcz, Poland. [Jetten, Anton] NIEHS, Cell Biol Sect, Immun Inflammat & Dis Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Slominski, Andrzej T.] Univ Alabama Birmingham, Dept Dermatol, Canc Chemoprevent Program, Birmingham, AL 35294 USA. [Slominski, Andrzej T.] Univ Alabama Birmingham, Ctr Comprehens Canc, Canc Chemoprevent Program, Birmingham, AL 35294 USA. [Slominski, Andrzej T.] VA Med Ctr, Pathol & Lab Med Serv, Birmingham, AL 35233 USA. RP Brozyna, AA (reprint author), Prof Franciszek Lukaszczyk Mem Hosp, Ctr Oncol, Dept Tumor Pathol & Pathomorphol, Bydgoszcz, Poland.; Brozyna, AA (reprint author), Nicolaus Copernicus Univ, Coll Med Bydgoszcz, Fac Hlth Sci, Dept Tumor Pathol & Pathomorphol, Bydgoszcz, Poland.; Slominski, AT (reprint author), Univ Alabama Birmingham, Dept Dermatol, Canc Chemoprevent Program, Birmingham, AL 35294 USA.; Slominski, AT (reprint author), Univ Alabama Birmingham, Ctr Comprehens Canc, Canc Chemoprevent Program, Birmingham, AL 35294 USA.; Slominski, AT (reprint author), VA Med Ctr, Pathol & Lab Med Serv, Birmingham, AL 35233 USA. EM anna.brozyna@cm.umk.pl; aslominski@uabmc.edu RI Jozwicki, Wojciech/I-1948-2014 FU National Science Centre, Poland [2014/15/B/NZ4/00751]; Nicolaus Copernicus University [03/CM/2013]; Collegium Medicum Nicolaus Copernicus University; National Institutes of Health [2R01AR052190-A6, R21AR066505-01A1, 1R01AR056666-01A2]; Comprehensive Cancer Center, Cancer Chemoprevention Program; VA Merit Department of VA [1I01BX003395-01] FX The work was supported in part by grant 2014/15/B/NZ4/00751 from National Science Centre, Poland to AAB, 03/CM/2013 from Nicolaus Copernicus University to AAB, funds for statutory research from Collegium Medicum Nicolaus Copernicus University and grants from the National Institutes of Health (2R01AR052190-A6, R21AR066505-01A1 and 1R01AR056666-01A2) to ATS, and funding from Comprehensive Cancer Center, Cancer Chemoprevention Program to ATS and grant 1I01BX003395-01 VA Merit Department of VA. NR 81 TC 1 Z9 1 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 SEP 27 PY 2016 VL 7 IS 39 BP 63261 EP 63282 DI 10.18632/oncotarget.11211 PG 22 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB2DN UT WOS:000387167800035 PM 27542227 ER PT J AU van der Harst, P van Setten, J Verweij, N Vogler, G Franke, L Maurano, MT Wang, XC Leach, IM Eijgelsheim, M Sotoodehnia, N Hayward, C Sorice, R Meirelles, O Lyytikainen, LP Polasek, O Tanaka, T Arking, DE Ulivi, S Trompet, S Muller-Nurasyid, M Smith, AV Dorr, M Kerr, KF Magnani, JW Del Greco, F Zhang, WH Nolte, IM Silva, CT Padmanabhan, S Tragante, V Esko, T Abecasis, GR Adriaens, ME Andersen, K Barnett, P Bis, JC Bodmer, R Buckley, BM Campbell, H Cannon, MV Chakravarti, A Chen, LY Delitala, A Devereux, RB Doevendans, PA Dominiczak, AF Ferrucci, L Ford, I Gieger, C Harris, TB Haugen, E Heinig, M Hernandez, DG Hillege, HL Hirschhorn, JN Hofman, A Hubner, N Hwang, SJ Iorio, A Kahonen, M Kellis, M Kolcic, I Kooner, IK Kooner, JS Kors, JA Lakatta, EG Lage, K Launer, LJ Levy, D Lundby, A Macfarlane, PW May, D Meitinger, T Metspalu, A Nappo, S Naitza, S Neph, S Nord, AS Nutile, T Okin, PM Olsen, JV Oostra, B Penninger, JM Pennacchio, LA Pers, TH Perz, S Peters, A Pinto, YM Pfeufer, A Pilia, MG Pramstaller, PP Prins, BP Raitakari, OT Raychaudhuri, S Rice, KM Rossin, EJ Rotter, JI Schafer, S Schlessinger, D Schmidt, CO Sehmi, J Sillje, HHW Sinagra, G Sinner, MF Slowikowski, K Soliman, EZ Spector, TD Spiering, W Stamatoyannopoulos, JA Stolk, RP Strauch, K Tan, ST Tarasov, KV Trinh, B Uitterlinden, AG van den Boogaard, M van Duijn, CM van Gilst, WH Viikari, JS Visscher, PM Vitart, V Volker, U Waldenberger, M Weichenberger, CX Westra, HJ Wijmenga, C Wolffenbuttel, BH Yang, J Bezzina, CR Munroe, PB Snieder, H Wright, AF Rudan, I Boyer, LA Asselbergs, FW van Veldhuisen, DJ Stricker, BH Psaty, BM Ciullo, M Sanna, S Lehtimaki, T Wilson, JF Bandinelli, S Alonso, A Gasparini, P Jukema, JW Kaab, S Gudnason, V Felix, SB Heckbert, SR de Boer, RA Newton-Cheh, C Hicks, AA Chambers, JC Jamshidi, Y Visel, A Christoffels, VM Isaacs, A Samani, NJ de Bakker, PIW AF van der Harst, Pim van Setten, Jessica Verweij, Niek Vogler, Georg Franke, Lude Maurano, Matthew T. Wang, Xinchen Leach, Irene Mateo Eijgelsheim, Mark Sotoodehnia, Nona Hayward, Caroline Sorice, Rossella Meirelles, Osorio Lyytikainen, Leo-Pekka Polasek, Ozren Tanaka, Toshiko Arking, Dan E. Ulivi, Sheila Trompet, Stella Mueller-Nurasyid, Martina Smith, Albert V. Doerr, Marcus Kerr, Kathleen F. Magnani, Jared W. Del Greco, Fabiola Zhang, Weihua Nolte, Ilja M. Silva, Claudia T. Padmanabhan, Sandosh Tragante, Vinicius Esko, Tonu Abecasis, Gonclo R. Adriaens, Michiel E. Andersen, Karl Barnett, Phil Bis, Joshua C. Bodmer, Rolf Buckley, Brendan M. Campbell, Harry Cannon, Megan V. Chakravarti, Aravinda Chen, Lin Y. Delitala, Alessandro Devereux, Richard B. Doevendans, Pieter A. Dominiczak, Anna F. Ferrucci, Luigi Ford, Ian Gieger, Christian Harris, Tamara B. Haugen, Eric Heinig, Matthias Hernandez, Dena G. Hillege, Hans L. Hirschhorn, Joel N. Hofman, Albert Hubner, Norbert Hwang, Shih-Jen Iorio, Annamaria Kahonen, Mika Kellis, Manolis Kolcic, Ivana Kooner, Ishminder K. Kooner, Jaspal S. Kors, Jan A. Lakatta, Edward G. Lage, Kasper Launer, Lenore J. Levy, Daniel Lundby, Alicia Macfarlane, Peter W. May, Dalit Meitinger, Thomas Metspalu, Andres Nappo, Stefania Naitza, Silvia Neph, Shane Nord, Alex S. Nutile, Teresa Okin, Peter M. Olsen, Jesper V. Oostra, Ben A. Penninger, Josef M. Pennacchio, Len A. Pers, Tune H. Perz, Siegfried Peters, Annette Pinto, Yigal M. Pfeufer, Arne Pilia, Maria Grazia Pramstaller, Peter P. Prins, Bram P. Raitakari, Olli T. Raychaudhuri, Soumya Rice, Ken M. Rossin, Elizabeth J. Rotter, Jerome I. Schafer, Sebastian Schlessinger, David Schmidt, Carsten O. Sehmi, Jobanpreet Sillje, Herman H. W. Sinagra, Gianfranco Sinner, Moritz F. Slowikowski, Kamil Soliman, Elsayed Z. Spector, Timothy D. Spiering, Wilko Stamatoyannopoulos, John A. Stolk, Ronald P. Strauch, Konstantin Tan, Sian-Tsung Tarasov, Kirill V. Trinh, Bosco Uitterlinden, Andre G. van den Boogaard, Malou van Duijn, Cornelia M. van Gilst, Wiek H. Viikari, Jorma S. Visscher, Peter M. Vitart, Veronique Voelker, Uwe Waldenberger, Melanie Weichenberger, Christian X. Westra, Harm-Jan Wijmenga, Cisca Wolffenbuttel, Bruce H. Yang, Jian Bezzina, Connie R. Munroe, Patricia B. Snieder, Harold Wright, Alan F. Rudan, Igor Boyer, Laurie A. Asselbergs, Folkert W. van Veldhuisen, Dirk J. Stricker, Bruno H. Psaty, Bruce M. Ciullo, Marina Sanna, Serena Lehtimaki, Terho Wilson, James F. Bandinelli, Stefania Alonso, Alvaro Gasparini, Paolo Jukema, J. Wouter Kaeaeb, Stefan Gudnason, Vilmundur Felix, Stephan B. Heckbert, Susan R. de Boer, Rudolf A. Newton-Cheh, Christopher Hicks, Andrew A. Chambers, John C. Jamshidi, Yalda Visel, Axel Christoffels, Vincent M. Isaacs, Aaron Samani, Nilesh J. de Bakker, Paul I. W. TI 52 Genetic Loci Influencing Myocardial Mass SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE electrocardiogram; genetic association study; heart failure; left ventricular hypertrophy; QRS ID LEFT-VENTRICULAR HYPERTROPHY; CARDIAC-HYPERTROPHY; REGULATORY DNA; ELECTROCARDIOGRAM; MORTALITY; DISEASE; VOLTAGE; DYSFUNCTION; GENOME; HEART AB BACKGROUND Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. OBJECTIVES This meta-analysis sought to gain insights into the genetic determinants of myocardial mass. METHODS We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment. RESULTS We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 x 10(-8). These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo. CONCLUSIONS Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets. (C) 2016 by the American College of Cardiology Foundation. C1 [van der Harst, Pim; Verweij, Niek; Leach, Irene Mateo; Cannon, Megan V.; Hillege, Hans L.; Sillje, Herman H. W.; van Gilst, Wiek H.; van Veldhuisen, Dirk J.; de Boer, Rudolf A.] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Hanzepl 1, NL-9700 RB Groningen, Netherlands. [van der Harst, Pim; Franke, Lude] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Hanzepl 1, NL-9700 RB Groningen, Netherlands. [van der Harst, Pim; Asselbergs, Folkert W.] Netherlands Heart Inst, Durrer Ctr Cardiovasc Res, Utrecht, Netherlands. [van Setten, Jessica; Tragante, Vinicius; de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. [van Setten, Jessica; Tragante, Vinicius; Doevendans, Pieter A.; Asselbergs, Folkert W.] Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands. [Vogler, Georg; Bodmer, Rolf; Trinh, Bosco] Sanford Burnham Prebys Med Discovery Inst, Dev Aging & Regenerat, La Jolla, CA USA. [Maurano, Matthew T.; Haugen, Eric; Neph, Shane; Stamatoyannopoulos, John A.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Maurano, Matthew T.; Wijmenga, Cisca] Univ Washington, Dept Med, Div Oncol, Seattle, WA 98195 USA. [Maurano, Matthew T.] NYU, Dept Pathol, Langone Med Ctr, 550 1St Ave, New York, NY 10016 USA. [Maurano, Matthew T.] NYU, Inst Syst Genet, Langone Med Ctr, New York, NY USA. [Wang, Xinchen; Boyer, Laurie A.] MIT, Dept Biol, Cambridge, MA USA. [Eijgelsheim, Mark; Hofman, Albert; Uitterlinden, Andre G.; Stricker, Bruno H.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Eijgelsheim, Mark; Hofman, Albert; Uitterlinden, Andre G.; Stricker, Bruno H.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Sotoodehnia, Nona] Univ Washington, Div Cardiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Hayward, Caroline; Vitart, Veronique; Wright, Alan F.; Wilson, James F.] Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland. [Sorice, Rossella; Nappo, Stefania; Nutile, Teresa; Ciullo, Marina] Inst Genet & Biophys A Buzzati Traverso, Naples, Italy. [Meirelles, Osorio; Schlessinger, David] NIA, Genet Lab, Baltimore, MD 21224 USA. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Fimlab Labs, Dept Clin Chem, Tampere, Finland. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Univ Tampere, Sch Med, Dept Clin Chem, Tampere, Finland. [Polasek, Ozren; Campbell, Harry; Rudan, Igor; Wilson, James F.] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Edinburgh, Midlothian, Scotland. [Polasek, Ozren; Kolcic, Ivana] Univ Split, Dept Publ Hlth, Fac Med, Split, Croatia. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Arking, Dan E.; Chakravarti, Aravinda] Johns Hopkins Univ, Sch Med, Ctr Complex Dis Genom, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Ulivi, Sheila; Gasparini, Paolo] IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, Trieste, Italy. [Trompet, Stella; Jukema, J. Wouter] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands. [Trompet, Stella] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands. [Mueller-Nurasyid, Martina; Sinner, Moritz F.; Kaeaeb, Stefan] Univ Munich, Dept Med 1, Univ Hosp Munich, Campus Grosshadern, Munich, Germany. [Mueller-Nurasyid, Martina; Strauch, Konstantin] Univ Munich, Inst Med Informat Biometry & Epidemiol, Genet Epidemiol, Munich, Germany. [Mueller-Nurasyid, Martina; Strauch, Konstantin] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany. [Mueller-Nurasyid, Martina; Meitinger, Thomas; Peters, Annette; Kaeaeb, Stefan] Partner Site Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany. [Smith, Albert V.; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Andersen, Karl; Peters, Annette; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Doerr, Marcus; Felix, Stephan B.] Univ Med Greifswald, Dept Internal Med B, Greifswald, Germany. [Doerr, Marcus; Voelker, Uwe; Felix, Stephan B.] DZHK Partner Site, Greifswald, Germany. [Kerr, Kathleen F.; Padmanabhan, Sandosh; Rice, Ken M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Magnani, Jared W.] Boston Univ, Sch Med, Dept Med, Sect Cardiovasc Med, Boston, MA 02118 USA. [Del Greco, Fabiola; Pfeufer, Arne; Pramstaller, Peter P.; Weichenberger, Christian X.; Hicks, Andrew A.] Bolzano EURAC, European Acad Bozen, Ctr Biomed, Bolzano, Italy. [Del Greco, Fabiola; Pfeufer, Arne; Pramstaller, Peter P.; Weichenberger, Christian X.; Hicks, Andrew A.] Univ Lubeck, Lubeck, Germany. [Zhang, Weihua; Chambers, John C.] Imperial Coll London, Dept Epidemiol & Biostat, London, England. [Zhang, Weihua; Kooner, Ishminder K.; Kooner, Jaspal S.; Sehmi, Jobanpreet; Tan, Sian-Tsung; Chambers, John C.] Ealing Hosp NHS Trust, Southall, Middx, England. [Nolte, Ilja M.; Stolk, Ronald P.; Snieder, Harold] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands. [Silva, Claudia T.; Oostra, Ben A.; van Duijn, Cornelia M.; Isaacs, Aaron] Univ Med Ctr Rotterdam, Dept Epidemiol, Genet Epidemiol Unit, Erasmus MC, Rotterdam, Netherlands. [Silva, Claudia T.] Univ Rosario, Doctoral Program Biomed Sci, Bogota, Colombia. [Silva, Claudia T.] Univ Rosario, Dept Genet GENIUROS, Escuela Med & Ciencias Salud, Bogota, Colombia. [Dominiczak, Anna F.] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Esko, Tonu; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, Tartu, Estonia. [Esko, Tonu; Hirschhorn, Joel N.; Pers, Tune H.] Childrens Hosp Boston, Div Endocrinol, Boston, MA USA. [Esko, Tonu; Hirschhorn, Joel N.; Pers, Tune H.] Childrens Hosp Boston, Ctr Basic & Translat Obes Res, Boston, MA USA. [Abecasis, Gonclo R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Adriaens, Michiel E.; Pinto, Yigal M.; Bezzina, Connie R.] Univ Amsterdam, Acad Med Ctr, Dept Expt Cardiol, Amsterdam, Netherlands. [Adriaens, Michiel E.] Maastricht Univ, Maastricht Ctr Syst Biol, Maastricht, Netherlands. [Andersen, Karl] Landspitali Univ Hosp, Reykjavik, Iceland. [Barnett, Phil; van den Boogaard, Malou; Christoffels, Vincent M.] Univ Amsterdam, Acad Med Ctr, Dept Anat Embryol & Physiol, Amsterdam, Netherlands. [Bis, Joshua C.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Buckley, Brendan M.] Univ Coll Cork, Dept Pharmacol & Therapeut, Cork, Ireland. [Chen, Lin Y.] Univ Minnesota, Dept Med, Div Cardiovasc, Box 736 UMHC, Minneapolis, MN 55455 USA. [Delitala, Alessandro; Gieger, Christian; Naitza, Silvia; Pilia, Maria Grazia; Sanna, Serena] CNR, Ist Ric Genet & Biomed, Cagliari, Italy. [Devereux, Richard B.; Okin, Peter M.] Weill Cornell Med, Div Cardiol, Dept Med, New York, NY USA. [Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland. [Gieger, Christian; Perz, Siegfried; Waldenberger, Melanie] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany. [Gieger, Christian; Waldenberger, Melanie] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany. [Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA. [Heinig, Matthias; Hubner, Norbert; Schafer, Sebastian] Max Delbruck Ctr Mol Med MDC, Cardiovasc & Metab Dis, Berlin, Germany. [Heinig, Matthias] Max Planck Inst Mol Genet, Dept Computat Biol, Berlin, Germany. [Heinig, Matthias] Helmholtz Zentrum Munchen, Inst Computat Biol, Neuherberg, Germany. [Hernandez, Dena G.] NIA, Lab Neurogenet, Bethesda, MD 20892 USA. [Hirschhorn, Joel N.; Pers, Tune H.; Westra, Harm-Jan; Newton-Cheh, Christopher] Broad Inst, Med & Populat Genet Program, Cambridge, MA USA. [Hirschhorn, Joel N.] Harvard Med Sch, Dept Genet, Boston, MA USA. [Hubner, Norbert; Schafer, Sebastian] DZHK Partner Site, Berlin, Germany. [Hwang, Shih-Jen] NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Iorio, Annamaria; Sinagra, Gianfranco] Univ Trieste, Cardiovasc Dept, Trieste, Italy. [Iorio, Annamaria; Sinagra, Gianfranco] Univ Trieste, Postgrad Sch Cardiovasc Dis, Trieste, Italy. [Kahonen, Mika] Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland. [Kahonen, Mika] Univ Tampere, Sch Med, Dept Clin Physiol, Tampere, Finland. [Kellis, Manolis] MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Kellis, Manolis; Lage, Kasper] Broad Inst, Cambridge, MA USA. [Kooner, Jaspal S.; Sehmi, Jobanpreet; Tan, Sian-Tsung] Imperial Coll London, Natl Heart & Lung Inst, London, England. [Kors, Jan A.] Erasmus MC, Dept Med Informat, Rotterdam, Netherlands. [Lakatta, Edward G.; Tarasov, Kirill V.] NIA, Lab Cardiovasc Sci, Baltimore, MD 21224 USA. [Lage, Kasper] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Lage, Kasper; Rossin, Elizabeth J.] Harvard Univ, Harvard Med Sch, Boston, MA 02115 USA. [Levy, Daniel; Slowikowski, Kamil] NHLBI, Ctr Populat Studies, NIH, Bldg 10, Bethesda, MD 20892 USA. [Lundby, Alicia; Olsen, Jesper V.; Soliman, Elsayed Z.] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Prot Res, Copenhagen, Denmark. [Lundby, Alicia] Univ Copenhagen, Fac Hlth & Med Sci, Dept Biomed Sci, Copenhagen, Denmark. [Macfarlane, Peter W.] Univ Glasgow, Inst Cardiovasc & Med Sci, Electrocardiol Sect, Glasgow, Lanark, Scotland. [May, Dalit] Clalit Hlth Serv, Dept Family Med, Jerusalem, Israel. [May, Dalit] Hebrew Univ Jerusalem, Hadassah Med Sch, Jerusalem, Israel. [Meitinger, Thomas] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany. [Meitinger, Thomas] Tech Univ Munich, Inst Human Genet, Munich, Germany. [Nord, Alex S.; Pennacchio, Len A.; Visel, Axel] Lawrence Berkeley Natl Lab, Genom Div, Berkeley, CA USA. [Nord, Alex S.] Univ Calif Davis, Ctr Neurosci, Dept Neurobiol Physiol & Behav, Davis, CA 95616 USA. [Nord, Alex S.] Univ Calif Davis, Ctr Neurosci, Dept Psychiat & Behav Sci, Davis, CA 95616 USA. [Penninger, Josef M.] Austrian Acad Sci, Inst Mol Biotechnol, Vienna, Austria. [Pennacchio, Len A.; Visel, Axel] DOE Joint Genome Inst, Walnut Creek, CA USA. [Pers, Tune H.] Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark. [Pers, Tune H.] Statens Serum Inst, Dept Epidemiol Res, Copenhagen, Denmark. [Perz, Siegfried] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Biol & Med Imaging, Neuherberg, Germany. [Pfeufer, Arne] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Dept Bioinformat & Syst Biol IBIS, Neuherberg, Germany. [Pramstaller, Peter P.] Gen Cent Hosp, Dept Neurol, Bolzano, Italy. [Pramstaller, Peter P.] Univ Lubeck, Dept Neurol, Lubeck, Germany. [Prins, Bram P.; Jamshidi, Yalda] St Georges Univ London, Cardiogenet Lab, Human Genet Res Ctr, London, England. [Raitakari, Olli T.] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku, Finland. [Raitakari, Olli T.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Raychaudhuri, Soumya] Harvard Med Sch, Brigham & Womens Hosp, Div Genet, Boston, MA USA. [Raychaudhuri, Soumya] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Rossin, Elizabeth J.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat & Med, Torrance, CA 90509 USA. [Schafer, Sebastian] Natl Heart Ctr Singapore, Natl Heart Res Inst Singapore, Singapore, Singapore. [Schmidt, Carsten O.] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Slowikowski, Kamil] Harvard Univ, Bioinformat & Integrat Genom, Cambridge, MA 02138 USA. [Soliman, Elsayed Z.] Wake Forest Sch Med, Epidemiol Cardiol Res Ctr, Winston Salem, NC USA. [Spector, Timothy D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England. [Spiering, Wilko] Univ Med Ctr Utrecht, Dept Vasc Med, Utrecht, Netherlands. [Viikari, Jorma S.] Turku Univ Hosp, Div Med, Turku, Finland. [Viikari, Jorma S.] Univ Turku, Dept Med, Turku, Finland. [Viikari, Jorma S.] Univ Queensland, Queensland Brain Inst, St Lucia, Qld, Australia. [Visscher, Peter M.; Yang, Jian] Univ Queensland, Diamantina Inst, Translat Res Inst, Woolloongabba, Qld, Australia. [Voelker, Uwe] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Dept Funct Genom, Greifswald, Germany. [Westra, Harm-Jan] Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA. [Westra, Harm-Jan] Brigham & Womens Hosp, Dept Med, Div Rheumatol, 75 Francis St, Boston, MA 02115 USA. [Westra, Harm-Jan] Harvard Med Sch, Boston, MA USA. [Westra, Harm-Jan] Partners Ctr Personalized Genet Med, Boston, MA USA. [Wolffenbuttel, Bruce H.] Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol, Groningen, Netherlands. [Munroe, Patricia B.] Queen Mary Univ London, Clin Pharmacol, London, England. [Munroe, Patricia B.] Queen Mary Univ London, Barts & London Genome Ctr, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England. [Munroe, Patricia B.] Queen Mary Univ London, Natl Inst Hlth, Barts & London Sch Med, Res Biomed Res Unit, London, England. [Asselbergs, Folkert W.] UCL, Fac Populat Hlth Sci, Inst Cardiovasc Sci, London, England. [Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.; Heckbert, Susan R.] Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA USA. [Ciullo, Marina] IRCCS Neuromed, Isernia, Italy. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Unit, Florence, Italy. [Alonso, Alvaro] Emory Univ, Dept Epidemiol, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Gasparini, Paolo] Univ Trieste, Trieste, Italy. [Gasparini, Paolo] Sidra Med & Res Ctr, Doha, Qatar. [Jukema, J. Wouter] Netherlands Heart Inst, Utrecht, Netherlands. [Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Newton-Cheh, Christopher] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Newton-Cheh, Christopher] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Visel, Axel] Univ Calif, Sch Nat Sci, Merced, CA USA. [Isaacs, Aaron] Maastricht Univ, Dept Biochem, Maastricht Ctr Syst Biol, CARIM Sch Cardiovasc Dis, Maastricht, Netherlands. [Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, BHF Cardiovasc Res Ctr, Dept Cardiovasc Sci, Leicester, Leics, England. [Samani, Nilesh J.] Glenfield Hosp, Leicester Cardiovasc Biomed Res Unit, Natl Inst Hlth Res, Leicester, Leics, England. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Epidemiol, Utrecht, Netherlands. RP van der Harst, P (reprint author), Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Hanzepl 1, NL-9700 RB Groningen, Netherlands.; van der Harst, P (reprint author), Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Hanzepl 1, NL-9700 RB Groningen, Netherlands. EM p.van.der.harst@umcg.nl RI Lundby, Alicia/H-3322-2013; Naitza, Silvia/D-5620-2017; Polasek, Ozren/B-6002-2011; Kolcic, Ivana/E-2713-2017; Hicks, Andrew/E-9518-2017; Franke, Lude/P-7036-2016; Wijmenga, Cisca/D-2173-2009; Visel, Axel/A-9398-2009; Penninger, Josef/I-6860-2013; Yang, Jian/A-5852-2010; Padmanabhan, Sandosh/S-3963-2016; Alonso, Alvaro/A-4917-2010; Verweij, Niek/A-4499-2017; OI Polasek, Ozren/0000-0002-5765-1862; Kolcic, Ivana/0000-0001-7918-6052; Hicks, Andrew/0000-0001-6320-0411; Franke, Lude/0000-0002-5159-8802; Visel, Axel/0000-0002-4130-7784; Penninger, Josef/0000-0002-8194-3777; Yang, Jian/0000-0003-2001-2474; Alonso, Alvaro/0000-0002-2225-8323; Haugen, Eric/0000-0001-7444-8981; Adriaens, Michiel/0000-0002-4472-7119; Schafer, Sebastian/0000-0002-6909-8275; SINAGRA, GIANFRANCO/0000-0003-2700-8478; Peters, Annette/0000-0001-6645-0985 FU GlaxoSmithKline; Zoll LifeCor; Johnson Johnson; Metabiota FX Dr. Abecasis has served on the scientific advisory board for Regeneron Genetics Center. Dr. Haugen's current employer (Altius Institute) receives research funding from GlaxoSmithKline. Dr. Pennacchio is a salaried employee and ownsstock in Metabiota. Dr. Stamatoyannopoulos is the director of a nonprofit research institute. Dr. Psaty has served on the data and safety monitoring board for a clinical trial funded by Zoll LifeCor; and has served on the steering committee of the Yale Open Data Access project funded by Johnson & Johnson. Dr. de Bakker is currently an employee of and owns equity in Vertex Pharmaceuticals. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. van der Harst, van Setten, Verweij, Vogler, Franke, Maurano, Wang, Mateo Leach, Chambers, Jamshidi, Visel, Christoffels, Isaacs, Samani, and de Bakker contributed equally to this work. NR 26 TC 4 Z9 4 U1 13 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD SEP 27 PY 2016 VL 68 IS 13 BP 1435 EP 1448 DI 10.1016/j.jacc.2016.07.729 PG 14 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DZ5WX UT WOS:000385933800009 PM 27659466 ER PT J AU Mei, F Lehmann-Horn, K Shen, YAA Rankin, KA Stebbins, KJ Lorrain, DS Pekarek, K Sagan, SA Xiao, L Teuscher, C von Budingen, HC Wess, J Lawrence, JJ Green, AJ Fancy, SPJ Zamvil, SS Chan, JR AF Mei, Feng Lehmann-Horn, Klaus Shen, Yun-An A. Rankin, Kelsey A. Stebbins, Karin J. Lorrain, Daniel S. Pekarek, Kara Sagan, Sharon A. Xiao, Lan Teuscher, Cory von Budingen, H-Christian Wess, Jurgen Lawrence, J. Josh Green, Ari J. Fancy, Stephen P. J. Zamvil, Scott S. Chan, Jonah R. TI Accelerated remyelination during inflammatory demyelination prevents axonal loss and improves functional recovery SO ELIFE LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; MUSCARINIC RECEPTOR SUBTYPES; MULTIPLE-SCLEROSIS; THERAPEUTIC TARGET; STEM-CELLS; T-CELL; MYELIN; OLIGODENDROCYTES; MICE; DISEASE AB Demyelination in MS disrupts nerve signals and contributes to axon degeneration. While remyelination promises to restore lost function, it remains unclear whether remyelination will prevent axonal loss. Inflammatory demyelination is accompanied by significant neuronal loss in the experimental autoimmune encephalomyelitis (EAE) mouse model and evidence for remyelination in this model is complicated by ongoing inflammation, degeneration and possible remyelination. Demonstrating the functional significance of remyelination necessitates selectively altering the timing of remyelination relative to inflammation and degeneration. We demonstrate accelerated remyelination after EAE induction by direct lineage analysis and hypothesize that newly formed myelin remains stable at the height of inflammation due in part to the absence of MOG expression in immature myelin. Oligodendroglial-specific genetic ablation of the M1 muscarinic receptor, a potent negative regulator of oligodendrocyte differentiation and myelination, results in accelerated remyelination, preventing axonal loss and improving functional recovery. Together our findings demonstrate that accelerated remyelination supports axonal integrity and neuronal function after inflammatory demyelination. C1 [Mei, Feng; Lehmann-Horn, Klaus; Shen, Yun-An A.; Rankin, Kelsey A.; Pekarek, Kara; Sagan, Sharon A.; von Budingen, H-Christian; Green, Ari J.; Fancy, Stephen P. J.; Zamvil, Scott S.; Chan, Jonah R.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Mei, Feng; Xiao, Lan] Third Mil Med Univ, Dept Histol & Embryol, Chongqing Key Lab Neurobiol, Chongqing, Peoples R China. [Stebbins, Karin J.; Lorrain, Daniel S.] Incept Sci, San Diego, CA USA. [Teuscher, Cory] Univ Vermont, Dept Med, Immunobiol Program, Burlington, VT 05405 USA. [Wess, Jurgen] NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Lawrence, J. Josh] Texas Tech Univ, Hlth Sci Ctr, Sch Med, Dept Pharmacol & Neurosci, Lubbock, TX 79430 USA. [Fancy, Stephen P. J.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. RP Chan, JR (reprint author), Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. EM chan@ucsf.edu FU Third Military Medical University Overseas Youth Program Grant; National Natural Science Foundation of China [NSCF31471043, 81270017]; Deutsche Forschungsgemeinschaft Fellowship grants (DFG) [Le 3079/1-1]; National Multiple Sclerosis Society [FG 2067-A-1, RG5203A4]; Joint Research Fund [NSCF 31228011]; Chongqing Scientific and Technical Innovation Foundation of China [CSTCKJCXLJRC07]; Target ALS [A121679]; National Institutes of Health [R01NS062796]; Rachleff Endowment FX Third Military Medical University Overseas Youth Program Grant Feng Mei; National Natural Science Foundation of China NSCF31471043 Feng Mei; National Natural Science Foundation of China 81270017 Feng Mei; Deutsche Forschungsgemeinschaft Fellowship grants (DFG; Le 3079/1-1) Klaus Lehmann-Horn; National Multiple Sclerosis Society FG 2067-A-1 Klaus Lehmann-Horn; Joint Research Fund NSCF 31228011 Lan Xiao; Chongqing Scientific and Technical Innovation Foundation of China CSTCKJCXLJRC07 Lan Xiao; National Multiple Sclerosis Society RG5203A4 Jonah R Chan; Target ALS A121679 Jonah R Chan; National Institutes of Health R01NS062796 Jonah R Chan; Rachleff Endowment Jonah R Chan NR 61 TC 1 Z9 1 U1 2 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 SEP 27 PY 2016 VL 5 AR e18246 DI 10.7554/eLife.18246 PG 21 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DY8RZ UT WOS:000385399500001 ER PT J AU Rom, S Zuluaga-Ramirez, V Reichenbach, NL Dykstra, H Gajghate, S Pacher, P Persidsky, Y AF Rom, Slava Zuluaga-Ramirez, Viviana Reichenbach, Nancy L. Dykstra, Holly Gajghate, Sachin Pacher, Pal Persidsky, Yuri TI PARP inhibition in leukocytes diminishes inflammation via effects on integrins/cytoskeleton and protects the blood-brain barrier SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE Leukocyte-endothelial interaction; VLA-4; LFA-1; Actin cytoskeleton; PARP-1 ID NF-KAPPA-B; POLY(ADP-RIBOSE) POLYMERASE-1 INHIBITOR; MICROVASCULAR ENDOTHELIAL-CELLS; FOCAL CEREBRAL-ISCHEMIA; CANNABINOID RECEPTOR 2; TRANSENDOTHELIAL MIGRATION; MULTIPLE-SCLEROSIS; NEUROINFLAMMATORY CONDITIONS; VASCULAR-DISEASE; OXIDATIVE STRESS AB Background: Blood-brain barrier (BBB) dysfunction/disruption followed by leukocyte infiltration into the brain causes neuroinflammation and contributes to morbidity in multiple sclerosis, encephalitis, traumatic brain injury, and stroke. The identification of pathways that decreases the inflammatory potential of leukocytes would prevent such injury. Poly(ADP-ribose) polymerase 1 (PARP) controls various genes via its interaction with myriad transcription factors. Selective PARP inhibitors have appeared lately as potent anti-inflammatory tools. Their effects are outside the recognized PARP functions in DNA repair and transcriptional regulation. In this study, we explored the idea that selective inhibition of PARP in leukocytes would diminish their engagement of the brain endothelium. Methods: Cerebral vascular changes and leukocyte-endothelium interactions were surveyed by intravital videomicroscopy utilizing a novel in vivo model of localized aseptic meningitis when TNFa was introduced intracerebrally in wild-type (PARP(+/+)) and PARP-deficient (PARP(-/-)) mice. The effects of selective PARP inhibition on primary human monocytes ability to adhere to or migrate across the BBB were also tested in vitro, employing primary human brain microvascular endothelial cells (BMVEC) as an in vitro model of the BBB. Results: PARP suppression in monocytes diminished their adhesion to and migration across BBB in vitro models and prevented barrier injury. In monocytes, PARP inactivation decreased conformational activation of integrins that plays a key role in their tissue infiltration. Such changes were mediated by suppression of activation of small Rho GTPases and cytoskeletal rearrangements in monocytes. In vitro observations were confirmed in vivo showing diminished leukocyte-endothelial interaction after selective PARP suppression in leukocytes accompanied by BBB protection. PARP knockout animals demonstrated a substantial diminution of inflammatory responses in brain microvasculature and a decrease in BBB permeability. Conclusions: These results suggest PARP inhibition in leukocytes as a novel approach to BBB protection in the setting of endothelial dysfunction caused by inflammation-induced leukocyte engagement. C1 [Rom, Slava; Zuluaga-Ramirez, Viviana; Reichenbach, Nancy L.; Dykstra, Holly; Gajghate, Sachin; Persidsky, Yuri] Temple Univ, Dept Pathol & Lab Med, Philadelphia, PA 19140 USA. [Rom, Slava; Persidsky, Yuri] Temple Univ, Lewis Katz Sch Med, Ctr Subst Abuse Res, Philadelphia, PA 19140 USA. [Pacher, Pal] NIAAA, Lab Cardiovasc Physiol & Tissue Injury, NIH, Bethesda, MD 20852 USA. RP Rom, S; Persidsky, Y (reprint author), Temple Univ, Dept Pathol & Lab Med, Philadelphia, PA 19140 USA.; Rom, S; Persidsky, Y (reprint author), Temple Univ, Lewis Katz Sch Med, Ctr Subst Abuse Res, Philadelphia, PA 19140 USA. EM srom@temple.edu; yuri.persidsky@tuhs.temple.edu FU [MH65151]; [AA015913]; [DA013429]; [NS087385]; [ZIAAA000375] FX The work performed in the authors' laboratories is supported by grants from MH65151 (YP), AA015913 (YP), DA013429 (YP), NS087385 (SR), and ZIAAA000375 (PP). The fund agencies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 86 TC 0 Z9 0 U1 5 U2 5 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 SEP 27 PY 2016 VL 13 AR 254 DI 10.1186/s12974-016-0729-x PG 16 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA DX8EJ UT WOS:000384620600001 PM 27677851 ER PT J AU Minard, AY Tan, SX Yang, PY Fazakerley, DJ Domanova, W Parker, BL Humphrey, SJ Jothi, R Stockli, J James, DE AF Minard, Annabel Y. Tan, Shi-Xiong Yang, Pengyi Fazakerley, Daniel J. Domanova, Westa Parker, Benjamin L. Humphrey, Sean J. Jothi, Raja Stockli, Jacqueline James, David E. TI mTORC1 Is a Major Regulatory Node in the FGF21 Signaling Network in Adipocytes SO CELL REPORTS LA English DT Article ID INSULIN SENSITIVITY; IN-VIVO; PHOSPHOPROTEOMIC ANALYSIS; TUBEROUS SCLEROSIS; ENERGY-EXPENDITURE; CELL-CULTURE; BETA-KLOTHO; REVEALS; GROWTH; PHOSPHORYLATION AB FGF21 improves the metabolic profile of obese animals through its actions on adipocytes. To elucidate the signaling network responsible for mediating these effects, we quantified dynamic changes in the adipocyte phosphoproteome following acute exposure to FGF21. FGF21 regulated a network of 821 phosphosites on 542 proteins. A major FGF21-regulated signaling node was mTORC1/S6K. In contrast to insulin, FGF21 activated mTORC1 via MAPK rather than through the canonical PI3K/AKT pathway. Activation of mTORC1/S6K by FGF21 was surprising because this is thought to contribute to deleterious metabolic effects such as obesity and insulin resistance. Rather, mTORC1 mediated many of the beneficial actions of FGF21 in vitro, including UCP1 and FGF21 induction, increased adiponectin secretion, and enhanced glucose uptake without any adverse effects on insulin action. This study provides a global view of FGF21 signaling and suggests that mTORC1 may act to facilitate FGF21-mediated health benefits in vivo. C1 [Minard, Annabel Y.] Garvan Inst Med Res, Sydney, NSW 2010, Australia. [Minard, Annabel Y.; Yang, Pengyi; Fazakerley, Daniel J.; Domanova, Westa; Parker, Benjamin L.; Humphrey, Sean J.; Stockli, Jacqueline; James, David E.] Univ Sydney, Sch Life & Environm Sci, Charles Perkins Ctr, Sydney, NSW 2006, Australia. [Tan, Shi-Xiong] Inst Mol & Cell Biol, Singapore 138673, Singapore. [Yang, Pengyi] Univ Sydney, Sch Math & Stat, Sydney, NSW 2006, Australia. [Jothi, Raja] NIEHS, Syst Biol Sect, Epigenet & Stem Cell Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [James, David E.] Univ Sydney, Sch Med, Sydney, NSW 2006, Australia. [Tan, Shi-Xiong] Republ Polytech, Sch Appl Sci, Singapore 738964, Singapore. RP James, DE (reprint author), Univ Sydney, Sch Life & Environm Sci, Charles Perkins Ctr, Sydney, NSW 2006, Australia.; James, DE (reprint author), Univ Sydney, Sch Med, Sydney, NSW 2006, Australia. EM david.james@sydney.edu.au OI Yang, Pengyi/0000-0003-1098-3138 FU National Health and Medical Research Council (NHMRC) [GNT1047067, GNT1061122, GNT1068469]; Australian Postgraduate Award scholarship FX We thank Birgitte Andersen from Novo Nordisk for providing FGF21, Paul Cohen and Bruce Spiegleman for advice on culturing subcutaneous adipocytes, Aimin Xu for providing reagents, Yvonne Ng for assistance with experiments on subcutaneous adipocytes, and Kristen Thomas for help with mouse experiments. This study was supported by National Health and Medical Research Council (NHMRC) project grants GNT1047067 and GNT1061122 to D.E.J. and GNT1068469 to J.S. The contents of the published material are solely the responsibility of the individual authors and do not reflect the view of NHMRC. D.E.J. is an NHMRC senior principal research fellow, B.L.P. is an NHMRC early career fellow, and A.Y.M. is supported by an Australian Postgraduate Award scholarship. NR 46 TC 0 Z9 0 U1 13 U2 13 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 SEP 27 PY 2016 VL 17 IS 1 BP 29 EP 36 DI 10.1016/j.celrep.2016.08.086 PG 8 WC Cell Biology SC Cell Biology GA DX0CH UT WOS:000384028600004 PM 27681418 ER PT J AU Spira, A Disis, ML Schiller, JT Vilar, E Rebbeck, TR Bejar, R Ideker, T Arts, J Yurgelun, MB Mesirov, JP Rao, A Garber, J Jaffee, EM Lippman, SM AF Spira, Avrum Disis, Mary L. Schiller, John T. Vilar, Eduardo Rebbeck, Timothy R. Bejar, Rafael Ideker, Trey Arts, Janine Yurgelun, Matthew B. Mesirov, Jill P. Rao, Anjana Garber, Judy Jaffee, Elizabeth M. Lippman, Scott M. TI Leveraging premalignant biology for immune-based cancer prevention SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE premalignancy; biology; vaccines; cancer prevention; immune oncology ID MISMATCH REPAIR DEFICIENCY; CARCINOMA IN-SITU; ACUTE MYELOID-LEUKEMIA; COLORECTAL-CANCER; BREAST-CANCER; SOMATIC MUTATIONS; TUMOR-DEVELOPMENT; MYELOPROLIFERATIVE NEOPLASMS; CLONAL HEMATOPOIESIS; GENETIC ALTERATIONS AB Prevention is an essential component of cancer eradication. Next-generation sequencing of cancer genomes and epigenomes has defined large numbers of driver mutations and molecular subgroups, leading to therapeutic advances. By comparison, there is a relative paucity of such knowledge in premalignant neoplasia, which inherently limits the potential to develop precision prevention strategies. Studies on the interplay between germ-line and somatic events have elucidated genetic processes underlying premalignant progression and preventive targets. Emerging data hint at the immune system's ability to intercept premalignancy and prevent cancer. Genetically engineered mouse models have identified mechanisms by which genetic drivers and other somatic alterations recruit inflammatory cells and induce changes in normal cells to create and interact with the premalignant tumor microenvironment to promote oncogenesis and immune evasion. These studies are currently limited to only a few lesion types and patients. In this Perspective, we advocate a large-scale collaborative effort to systematically map the biology of premalignancy and the surrounding cellular response. By bringing together scientists from diverse disciplines (e.g., biochemistry, omics, and computational biology; microbiology, immunology, and medical genetics; engineering, imaging, and synthetic chemistry; and implementation science), we can drive a concerted effort focused on cancer vaccines to reprogram the immune response to prevent, detect, and reject premalignancy. Lynch syndrome, clonal hematopoiesis, and cervical intraepithelial neoplasia which also serve as models for inherited syndromes, blood, and viral premalignancies, are ideal scenarios in which to launch this initiative. C1 [Spira, Avrum] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Disis, Mary L.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Schiller, John T.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Vilar, Eduardo] Univ Texas MD Anderson Canc Ctr, Dept Clin Canc Prevent, Houston, TX 77030 USA. [Rebbeck, Timothy R.] Harvard TH Chan Sch Publ Hlth, Dana Farber Canc Inst, Boston, MA 02215 USA. [Bejar, Rafael; Ideker, Trey; Mesirov, Jill P.; Lippman, Scott M.] Univ Calif San Diego, Dept Med, Moores Canc Ctr, La Jolla, CA 92093 USA. [Arts, Janine] Pharmaceut Co Johnson & Johnson, Janssen Oncol Res & Dev, B-2300 Beerse, Belgium. [Yurgelun, Matthew B.; Garber, Judy] Dana Farber Canc Inst, Dept Med Oncol, Div Populat Sci, Boston, MA 02215 USA. [Rao, Anjana] La Jolla Inst Allergy & Immunol, Div Signaling & Gene Express, La Jolla, CA 92037 USA. [Jaffee, Elizabeth M.] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Dept Oncol, Baltimore, MD 21287 USA. RP Lippman, SM (reprint author), Univ Calif San Diego, Dept Med, Moores Canc Ctr, La Jolla, CA 92093 USA. EM slippman@ucsd.edu FU National Cancer Institute [P30-CA023100-29] FX The authors thank Nikki Lytle and Leona Flores for editorial assistance with this article. S.M.L. was supported for this work by National Cancer Institute Grant P30-CA023100-29. NR 147 TC 2 Z9 2 U1 13 U2 13 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 SEP 27 PY 2016 VL 113 IS 39 BP 10750 EP 10758 DI 10.1073/pnas.1608077113 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW9DD UT WOS:000383954700020 PM 27638202 ER PT J AU Choi, JM Kim, SS Choi, CI Cha, HL Oh, HH Ghil, S Lee, YD Birnbaumer, L Suh-Kim, H AF Choi, Jung-Mi Kim, Sung-Soo Choi, Chan-Il Cha, Hye Lim Oh, Huy-Hyen Ghil, Sungho Lee, Young-Don Birnbaumer, Lutz Suh-Kim, Haeyoung TI Development of the main olfactory system and main olfactory epithelium-dependent male mating behavior are altered in G(o)-deficient mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE heterotrimeric G(o) protein; olfactory mucosa; olfactory bulb interneuron; tyrosine monooxygenase; sexual behavior ID TYROSINE-HYDROXYLASE EXPRESSION; VOMERONASAL ORGAN REMOVAL; SENSORY NEURONS; MUTANT MICE; CHEMOSENSORY RECEPTORS; SEX-DISCRIMINATION; ADENYLYL-CYCLASE; TRANSGENIC MICE; MOUSE; BULB AB In mammals, initial detection of olfactory stimuli is mediated by sensory neurons in the main olfactory epithelium (MOE) and the vomeronasal organ (VNO). The heterotrimeric GTP-binding protein G(o) is widely expressed in the MOE and VNO of mice. Early studies indicated that G(o) expression in VNO sensory neurons is critical for directing social and sexual behaviors in female mice [Oboti L, et al. (2014) BMC Biol 12:31]. However, the physiological functions of G(o) in the MOE have remained poorly defined. Here, we examined the role of G(o) in the MOE using mice lacking the a subunit of G(o). Development of the olfactory bulb (OB) was perturbed in mutant mice as a result of reduced neurogenesis and increased cell death. The balance between cell types of OB interneurons was altered in mutant mice, with an increase in the number of tyrosine hydroxylase-positive interneurons at the expense of calbindin-positive interneurons. Sexual behavior toward female mice and preference for female urine odors by olfactory sensory neurons in the MOE were abolished in mutant male mice. Our data suggest that G(o) signaling is essential for the structural and functional integrity of the MOE and for specification of OB interneurons, which in turn are required for the transmission of pheromone signals and the initiation of mating behavior with the opposite sex. C1 [Choi, Jung-Mi; Kim, Sung-Soo; Choi, Chan-Il; Cha, Hye Lim; Oh, Huy-Hyen; Lee, Young-Don; Suh-Kim, Haeyoung] Ajou Univ, Sch Med, Dept Anat, Suwon 16499, South Korea. [Oh, Huy-Hyen; Lee, Young-Don; Suh-Kim, Haeyoung] Ajou Univ, Sch Med, Grad Sch, Dept Biomed Sci, Suwon 16499, South Korea. [Ghil, Sungho] Kyonggi Univ, Dept Life Sci, Suwon 16227, South Korea. [Birnbaumer, Lutz] NIEHS, Neurobiol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. [Birnbaumer, Lutz] Catholic Univ Argentina, Sch Med Sci, Inst Biomed Res, C1107AFF, Buenos Aires, DF, Argentina. RP Suh-Kim, H (reprint author), Ajou Univ, Sch Med, Dept Anat, Suwon 16499, South Korea.; Suh-Kim, H (reprint author), Ajou Univ, Sch Med, Grad Sch, Dept Biomed Sci, Suwon 16499, South Korea.; Birnbaumer, L (reprint author), NIEHS, Neurobiol Lab, POB 12233, Res Triangle Pk, NC 27709 USA.; Birnbaumer, L (reprint author), Catholic Univ Argentina, Sch Med Sci, Inst Biomed Res, C1107AFF, Buenos Aires, DF, Argentina. EM Birnbau1@gmail.com; hysuh@ajou.ac.kr FU Bio & Medical Technology Development Program of the Korean National Research Foundation [NRF-2013M3C7A1056565, NRF-2015M3A9B4067067]; NIH [Z01-ES101643] FX We thank Dr. Jaesang Kim (Ewha Womans University) and Dr. Joong-Jean Park (Korea University) for discussions and comments on the manuscript and Dr. Ronald Herbert (National Institute of Environmental Health Sciences) for help with histology. This study was supported by Bio & Medical Technology Development Program of the Korean National Research Foundation Grants NRF-2013M3C7A1056565 and NRF-2015M3A9B4067067 (to H.S.-K.) and by NIH Intramural Research Program Grant Z01-ES101643 (to L.B.). NR 42 TC 0 Z9 0 U1 2 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 SEP 27 PY 2016 VL 113 IS 39 BP 10974 EP 10979 DI 10.1073/pnas.1613026113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW9DD UT WOS:000383954700057 PM 27625425 ER PT J AU Lan, T Cheng, K Ren, TN Arce, SH Tseng, Y AF Lan, Tian Cheng, Kai Ren, Tina Arce, Stephen Hugo Tseng, Yiider TI Displacement correlations between a single mesenchymal-like cell and its nucleus effectively link subcellular activities and motility in cell migration analysis SO SCIENTIFIC REPORTS LA English DT Article ID PARTICLE TRACKING; 3T3 FIBROBLASTS; RANDOM-WALK; INVASION; RHO; MECHANISMS; ACCURACY; MOVEMENT; ADHESION; SYSTEMS AB Cell migration is an essential process in organism development and physiological maintenance. Although current methods permit accurate comparisons of the effects of molecular manipulations and drug applications on cell motility, effects of alterations in subcellular activities on motility cannot be fully elucidated from those methods. Here, we develop a strategy termed cell-nuclear (CN) correlation to parameterize represented dynamic subcellular activities and to quantify their contributions in mesenchymal-like migration. Based on the biophysical meaning of the CN correlation, we propose a cell migration potential index (CMPI) to measure cell motility. When the effectiveness of CMPI was evaluated with respect to one of the most popular cell migration analysis methods, Persistent Random Walk, we found that the cell motility estimates among six cell lines used in this study were highly consistent between these two approaches. Further evaluations indicated that CMPI can be determined using a shorter time period and smaller cell sample size, and it possesses excellent reliability and applicability, even in the presence of a wide range of noise, as might be generated from individual imaging acquisition systems. The novel approach outlined here introduces a robust strategy through an analysis of subcellular locomotion activities for single cell migration assessment. C1 [Lan, Tian; Cheng, Kai; Arce, Stephen Hugo; Tseng, Yiider] Dept Chem Engn, Gainesville, FL 32611 USA. [Ren, Tina] Harvard Sch Dent Med, Boston, MA 02115 USA. [Tseng, Yiider] J Crayton Pruitt Family Dept Biomed Engn, Gainesville, FL 32611 USA. [Tseng, Yiider] Univ Florida, Inst Cell Tissue Sci & Engn, Gainesville, FL 32611 USA. [Tseng, Yiider] Natl Canc Inst, Phys Sci Oncol Ctr, Gainesville, FL 32611 USA. RP Tseng, Y (reprint author), Dept Chem Engn, Gainesville, FL 32611 USA.; Tseng, Y (reprint author), J Crayton Pruitt Family Dept Biomed Engn, Gainesville, FL 32611 USA.; Tseng, Y (reprint author), Univ Florida, Inst Cell Tissue Sci & Engn, Gainesville, FL 32611 USA.; Tseng, Y (reprint author), Natl Canc Inst, Phys Sci Oncol Ctr, Gainesville, FL 32611 USA. EM ytseng@che.ufl.edu FU NIH/NCI [U54CA143868]; McKnight Doctoral Fellowship FX This study was supported in part by grants from NIH/NCI U54CA143868. Stephen Hugo Arce was partially supported by a McKnight Doctoral Fellowship. The authors thank Dr. Shen-hsiu Hung for his suggestion and assistant to collect the data. NR 39 TC 0 Z9 0 U1 0 U2 0 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 SEP 27 PY 2016 VL 6 AR 34047 DI 10.1038/srep34047 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX1BW UT WOS:000384101500001 PM 27670131 ER PT J AU Wang, MQ Xu, M Long, Y Fargue, S Southall, N Hu, X McKew, JC Danpure, CJ Zheng, W AF Wang, Mengqiao Xu, Miao Long, Yan Fargue, Sonia Southall, Noel Hu, Xin McKew, John C. Danpure, Christopher J. Zheng, Wei TI High throughput cell-based assay for identification of glycolate oxidase inhibitors as a potential treatment for Primary Hyperoxaluria Type 1 SO SCIENTIFIC REPORTS LA English DT Article ID ALANINE-GLYOXYLATE AMINOTRANSFERASE; MITOCHONDRIAL TARGETING SEQUENCE; ENZYME-TRAFFICKING DEFECT; GLYCOLLATE OXIDASE; PEA LEAVES; MUTATION; PURIFICATION; PATHWAYS; DISEASE; ACID AB Glycolate oxidase (GO) and alanine: glyoxylate aminotransferase (AGT) are both involved in the peroxisomal glyoxylate pathway. Deficiency in AGT function causes the accumulation of intracellular oxalate and the primary hyperoxaluria type 1 (PH1). AGT enhancers or GO inhibitors may restore the abnormal peroxisomal glyoxylate pathway in PH1 patients. With stably transformed cells which mimic the glyoxylate metabolic pathway, we developed an indirect glycolate cytotoxicity assay in a 1,536-well plate format for high throughput screening. This assay can be used to identify compounds that reduce indirect glycolate-induced cytotoxicity by either enhancing AGT activity or inhibiting GO. A pilot screen of 4,096 known compounds identified two membrane permeable GO inhibitors: dichromate salt and colistimethate. We also developed a GO enzyme assay using the hydrogen peroxide-Amplex red reporter system. The IC50 values of potassium dichromate, sodium dichromate, and colistimethate sodium were 0.096, 0.108, and 2.3 mu M in the GO enzyme assay, respectively. Further enzyme kinetic study revealed that both types of compounds inhibit GO activity by the mixed linear inhibition. Our results demonstrate that the cell-based assay and GO enzyme assay developed in this study are useful for further screening of large compound libraries for drug development to treat PH1. C1 [Wang, Mengqiao; Xu, Miao; Long, Yan; Southall, Noel; Hu, Xin; McKew, John C.; Zheng, Wei] NIH, Therapeut Rare & Neglected Dis, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. [Wang, Mengqiao] Sichuan Univ, West China Sch Publ Hlth, Chengdu 610041, Peoples R China. [Fargue, Sonia; Danpure, Christopher J.] UCL, Div Biosci, Dept Cell & Dev Biol, London WC1E 6BT, England. RP Zheng, W (reprint author), NIH, Therapeut Rare & Neglected Dis, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. EM wzheng@mail.nih.gov RI Zheng, Wei/J-8889-2014 OI Zheng, Wei/0000-0003-1034-0757 FU Intramural Research Programs of the National Center for Advancing Translational Sciences, National Institutes of Health; Oxalosis and Hyperoxaluria Foundation FX This work is funded by the Intramural Research Programs of the National Center for Advancing Translational Sciences, National Institutes of Health. The authors thank Paul Shinn and compound management team at NCATS for their assistance. The authors also thank Oxalosis and Hyperoxaluria Foundation for the support on this study. NR 41 TC 0 Z9 0 U1 3 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 SEP 27 PY 2016 VL 6 AR 34060 DI 10.1038/srep34060 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX0VN UT WOS:000384084200001 PM 27670739 ER PT J AU Bana, TM Lesosky, M Pepper, DJ van der Plas, H Schutz, C Goliath, R Morroni, C Mendelson, M Maartens, G Wilkinson, RJ Meintjes, G AF Bana, Tasnim M. Lesosky, Maia Pepper, Dominique J. van der Plas, Helen Schutz, Charlotte Goliath, Rene Morroni, Chelsea Mendelson, Marc Maartens, Gary Wilkinson, Robert J. Meintjes, Graeme TI Prolonged tuberculosis-associated immune reconstitution inflammatory syndrome: characteristics and risk factors SO BMC INFECTIOUS DISEASES LA English DT Article DE Tuberculosis; HIV; Immune reconstitution inflammatory syndrome; IRIS; Glucocorticoids ID HIV-INFECTED PATIENTS; ANTIRETROVIRAL THERAPY; INITIATION; SEVERITY; DISEASE; ADULTS; TRIAL; IRIS AB Background: In a proportion of patients with HIV-associated tuberculosis who develop paradoxical immune reconstitution inflammatory syndrome (IRIS), the clinical course of IRIS is prolonged necessitating substantial health care utilization for diagnostic and therapeutic interventions. Prolonged TB-IRIS has not been prospectively studied to date. We aimed to determine the proportion of patients with prolonged TB-IRIS, as well as the clinical characteristics and risk factors for prolonged TB-IRIS. Methods: We pooled data from two prospective observational studies and a randomized controlled trial conducted in Cape Town, South Africa, that enrolled patients with paradoxical TB-IRIS. We used the same diagnostic approach and clinical case definitions for TB-IRIS in the 3 studies. Prolonged TB-IRIS was defined as TB-IRIS symptoms lasting > 90 days. Risk factors for prolonged TB-IRIS were analysed using Wilcoxon rank sum test, Fisher's exact test, multivariate logistic regression and Cox proportional hazards models. Results: Two-hundred and sixteen patients with TB-IRIS were included. The median duration of TB-IRIS symptoms was 71.0 days (IQR 41.0-113.2). In 73/181 patients (40.3 %) with adequate follow-up data, IRIS duration was > 90 days. Six patients (3.3 %), mainly with lymph node involvement, had IRIS duration > 1 year. In univariate logistic regression analysis the following were significantly associated with IRIS duration > 90 days: lymph node involvement at initial TB diagnosis, drug-resistant TB, lymph node TB-IRIS, and not being hospitalised at time of TB-IRIS diagnosis. In our multivariate logistic regression model lymph node TB-IRIS (aOR 2.27, 95 % CI 1.13-4.59) and not being hospitalised at time of TB-IRIS diagnosis (aOR for being hospitalised 0.5, 95 % CI 0.25-0.99) remained significantly associated with prolonged TB-IRIS, and drug-resistant TB was of borderline significance (aOR 3.26, 95 % CI 0.97-12.99). The association of not being hospitalised with longer duration of IRIS might be related to 1 of the 3 cohorts in which all patients were hospitalised at ART initiation with close inpatient follow-up. This could have resulted in diagnosis of milder cases and earlier IRIS treatment potentially resulting in shorter TB-IRIS duration in these hospitalised patients. Conclusions: Around 40 % of patients with TB-IRIS have symptoms for more than 90 days. Involvement of lymph nodes at time of TB-IRIS is an independent risk factor for prolonged TB-IRIS. Future studies should address whether more prompt anti-inflammatory treatment of lymph node TB-IRIS reduces the risk of prolonged TB-IRIS. C1 [Bana, Tasnim M.; Lesosky, Maia; Schutz, Charlotte] Univ Cape Town, Dept Med, ZA-7925 Observatory, South Africa. [Pepper, Dominique J.] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [van der Plas, Helen; Mendelson, Marc; Wilkinson, Robert J.; Meintjes, Graeme] Univ Cape Town, Dept Med, Div Infect Dis & HIV Med, ZA-7925 Observatory, South Africa. [Schutz, Charlotte; Goliath, Rene; Wilkinson, Robert J.; Meintjes, Graeme] Univ Cape Town, Fac Hlth Sci, Inst Infect Dis & Mol Med, Clin Infect Dis Res Initiat, Anzio Rd, ZA-7925 Observatory, South Africa. [Morroni, Chelsea] UCL, Inst Womens Hlth, London, England. [Morroni, Chelsea] UCL, Inst Global Hlth, London, England. [Maartens, Gary] Univ Cape Town, Dept Med, Div Clin Pharmacol, ZA-7925 Observatory, South Africa. [Wilkinson, Robert J.] Francis Crick Inst, London NW7 1AA, England. [Wilkinson, Robert J.; Meintjes, Graeme] Imperial Coll London, Dept Med, London W2 1PG, England. RP Meintjes, G (reprint author), Univ Cape Town, Dept Med, Div Infect Dis & HIV Med, ZA-7925 Observatory, South Africa.; Meintjes, G (reprint author), Univ Cape Town, Fac Hlth Sci, Inst Infect Dis & Mol Med, Clin Infect Dis Res Initiat, Anzio Rd, ZA-7925 Observatory, South Africa.; Meintjes, G (reprint author), Imperial Coll London, Dept Med, London W2 1PG, England. EM Graeme.meintjes@uct.ac.za OI Wilkinson, Robert/0000-0002-2753-1800 FU University of Cape Town Department of Medicine; Wellcome Trust [098316, 084323, 104803]; South African Medical Research Council (TB and HIV Collaborating Centres Programme); South African Research Chairs Initiative of the Department of Science and Technology; National Research Foundation of South Africa [64787]; European Union [FP7-PEOPLE-2011-IRSES, FP7-HEALTH-F3-2012-305578]; UK MRC [U1175.02.002.00014.02]; South African National Research Foundation [96841] FX Tasnim M. Bana received funding from the University of Cape Town Department of Medicine. Graeme Meintjes was supported by the Wellcome Trust (098316), the South African Medical Research Council (TB and HIV Collaborating Centres Programme) and the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation of South Africa (Grant No. 64787). Robert J. Wilkinson was supported by the Wellcome Trust (084323, 104803), the European Union (FP7-PEOPLE-2011-IRSES, FP7-HEALTH-F3-2012-305578), the UK MRC (U1175.02.002.00014.02) and the South African National Research Foundation (96841). The funders had no role in the study design, data collection, data analysis, data interpretation, or writing of this report. The opinions, findings and conclusions expressed in this manuscript reflect those of the authors alone. NR 23 TC 1 Z9 1 U1 5 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD SEP 27 PY 2016 VL 16 AR 518 DI 10.1186/s12879-016-1850-2 PG 12 WC Infectious Diseases SC Infectious Diseases GA DX0CZ UT WOS:000384030400003 PM 27677424 ER PT J AU Barbieri, MM Kashinsky, L Rotstein, DS Colegrove, KM Haman, KH Magargal, SL Sweeny, AR Kaufman, AC Grigg, ME Littnan, CL AF Barbieri, Michelle M. Kashinsky, Lizabeth Rotstein, David S. Colegrove, Kathleen M. Haman, Katherine H. Magargal, Spencer L. Sweeny, Amy R. Kaufman, Angela C. Grigg, Michael E. Littnan, Charles L. TI Protozoal-related mortalities in endangered Hawaiian monk seals Neomonachus schauinslandi SO DISEASES OF AQUATIC ORGANISMS LA English DT Article DE Protozoa; Mortality; Pathology; Immunohistochemistry; Toxoplasma gondii; Sarcocystis; Pinniped ID ENHYDRA-LUTRIS-NEREIS; LIONS ZALOPHUS-CALIFORNIANUS; TOXOPLASMA-GONDII INFECTION; PHOCA-VITULINA-RICHARDSI; PACIFIC HARBOR SEAL; SARCOCYSTIS-NEURONA; MONACHUS-SCHAUINSLANDI; NEOSPORA-CANINUM; MARINE MAMMALS; LIFE-CYCLE AB Protozoal infections have been widely documented in marine mammals and may cause morbidity and mortality at levels that result in population level effects. The presence and potential impact on the recovery of endangered Hawaiian monk seals Neomonachus schauinslandi by protozoal pathogens was first identified in the carcass of a stranded adult male with disseminated toxoplasmosis and a captive monk seal with hepatitis. We report 7 additional cases and 2 suspect cases of protozoal-related mortality in Hawaiian monk seals between 2001 and 2015, including the first record of vertical transmission in this species. This study establishes case definitions for classification of protozoal infections in Hawaiian monk seals. Histopathology and immunohistochemistry were the primary diagnostic modalities used to define cases, given that these analyses establish a direct link between disease and pathogen presence. Findings were supported by serology and molecular data when available. Toxoplasma gondii was the predominant apicomplexan parasite identified and was associated with 100% of mortalities (n = 8) and 50% of suspect cases (n = 2). Incidental identification of sarcocysts in the skeletal muscle without tissue inflammation occurred in 4 seals, including one co-infected with T. gondii. In 2015, 2 cases of toxo-plasmosis were identified ante-mortem and shared similar clinical findings, including hematological abnormalities and histopathology. Protozoal-related mortalities, specifically due to toxoplasmosis, are emerging as a threat to the recovery of this endangered pinniped and other native Hawaiian taxa. By establishing case definitions, this study provides a foundation for measuring the impact of these diseases on Hawaiian monk seals. C1 [Barbieri, Michelle M.; Littnan, Charles L.] NOAA, Pacific Isl Fisheries Sci Ctr, Protected Species Div, Hawaiian Monk Seal Res Program, Honolulu, HI 96818 USA. [Kashinsky, Lizabeth; Kaufman, Angela C.] Univ Hawaii Manoa, Joint Inst Marine & Atmospher Res, 1000 Pope Rd,Marine Sci Bldg 312, Honolulu, HI 96822 USA. [Rotstein, David S.] Marine Mammal Pathol Serv, Olney, MD 20832 USA. [Colegrove, Kathleen M.] Univ Illinois, Coll Vet Med, Zool Pathol Program, Brookfield, IL 60513 USA. [Haman, Katherine H.] Washington Dept Fish & Wildlife, Hlth & Genet Program, Olympia, WA 98501 USA. [Haman, Katherine H.] Univ British Columbia, Inst Oceans & Fisheries, Marine Mammal Res Unit, Vancouver, BC V6T 1Z4, Canada. [Haman, Katherine H.; Magargal, Spencer L.; Sweeny, Amy R.; Grigg, Michael E.] NIAID, Mol Parasitol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Barbieri, MM (reprint author), NOAA, Pacific Isl Fisheries Sci Ctr, Protected Species Div, Hawaiian Monk Seal Res Program, Honolulu, HI 96818 USA. EM michelle.barbieri@noaa.gov FU Intramural Research Program of the NIH and NIAID FX This work was conducted under permits issued to the NMFS: 413, 657, 898, 848-1335, 848-1695, 10137, 16632, 932-1489, 932-1905, and 18786. The Hawaiian Monk Seal Research Program thanks the seasonal field staff, cooperating veterinarians (G. Levine, R. Braun) and volunteers for their assistance in emergency rescues and rehabilitation, data collection and organization, necropsies and sample archiving. This study was supported, in part, by the Intramural Research Program of the NIH and NIAID (M.E.G). M.E.G. is a scholar of the Canadian Institute for Advanced Research (CIFAR) program for Integrated Microbial Diversity. We also thank Jason Baker and Stacie Robinson for early reviews of this manuscript, Mr. LeRoy Brown of Histology Consultation Services for slide preparation, and S. Natarajan for his assistance with the molecular PCR analyses. NR 52 TC 0 Z9 0 U1 1 U2 1 PU INTER-RESEARCH PI OLDENDORF LUHE PA NORDBUNTE 23, D-21385 OLDENDORF LUHE, GERMANY SN 0177-5103 EI 1616-1580 J9 DIS AQUAT ORGAN JI Dis. Aquat. Org. PD SEP 26 PY 2016 VL 121 IS 2 BP 85 EP 95 DI 10.3354/dao03047 PG 11 WC Fisheries; Veterinary Sciences SC Fisheries; Veterinary Sciences GA EN0OW UT WOS:000395710300001 ER PT J AU Keenan, WT Rupp, AC Ross, RA Somasundaram, P Hiriyanna, S Wu, Z Badea, TC Robinson, PR Lowell, BB Hattar, SS AF Keenan, William Thomas Rupp, Alan C. Ross, Rachel A. Somasundaram, Preethi Hiriyanna, Suja Wu, Zhijian Badea, Tudor C. Robinson, Phyllis R. Lowell, Bradford B. Hattar, Samer S. TI A visual circuit uses complementary mechanisms to support transient and sustained pupil constriction SO ELIFE LA English DT Article ID RETINAL GANGLION-CELLS; CYCLASE-ACTIVATING POLYPEPTIDE; MELANOPSIN-KNOCKOUT MICE; CONE PHOTORECEPTORS; LIGHT RESPONSE; CIRCADIAN RESPONSES; ROD PHOTORECEPTORS; LACKING PACAP; REFLEX; VISION AB Rapid and stable control of pupil size in response to light is critical for vision, but the neural coding mechanisms remain unclear. Here, we investigated the neural basis of pupil control by monitoring pupil size across time while manipulating each photoreceptor input or neurotransmitter output of intrinsically photosensitive retinal ganglion cells (ipRGCs), a critical relay in the control of pupil size. We show that transient and sustained pupil responses are mediated by distinct photoreceptors and neurotransmitters. Transient responses utilize input from rod photoreceptors and output by the classical neurotransmitter glutamate, but adapt within minutes. In contrast, sustained responses are dominated by non-conventional signaling mechanisms: melanopsin phototransduction in ipRGCs and output by the neuropeptide PACAP, which provide stable pupil maintenance across the day. These results highlight a temporal switch in the coding mechanisms of a neural circuit to support proper behavioral dynamics. C1 [Keenan, William Thomas; Rupp, Alan C.; Hattar, Samer S.] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. [Ross, Rachel A.] Harvard Med Sch, Dept Psychiat, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Ross, Rachel A.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Somasundaram, Preethi; Robinson, Phyllis R.] Univ Marlyand, Dept Biol Sci, Baltimore, MD USA. [Hiriyanna, Suja; Wu, Zhijian; Badea, Tudor C.] NEI, NIH, Bethesda, MD 20892 USA. [Lowell, Bradford B.] Harvard Med Sch, Div Endocrinol Diabet & Metab, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Lowell, Bradford B.] Harvard Med Sch, Dept Med, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Lowell, Bradford B.] Harvard Med Sch, Program Neurosci, Boston, MA USA. [Hattar, Samer S.] Johns Hopkins Univ, Dept Neurosci, Baltimore, MD 21218 USA. RP Hattar, SS (reprint author), Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA.; Hattar, SS (reprint author), Johns Hopkins Univ, Dept Neurosci, Baltimore, MD 21218 USA. EM shattar@jhu.edu OI Rupp, Alan/0000-0001-5363-4494; Keenan, William/0000-0003-3381-744X FU National Eye Institute [R21 EY024452]; National Institute of General Medical Sciences [RO1 GM076430]; National Eye Institute Intramural research program [EY000504-06]; National Heart Lung and Blood Institute [5T32HL007374-36]; Harvard Medical School Department of Psychiatry FX National Eye Institute R21 EY024452 William Thomas Keenan Alan C Rupp Samer S Hattar; National Institute of General Medical Sciences RO1 GM076430 William Thomas Keenan Alan C Rupp Samer S Hattar; National Eye Institute Intramural research program EY000504-06 Tudor C Badea; National Heart Lung and Blood Institute 5T32HL007374-36 Rachel A Ross; Harvard Medical School Department of Psychiatry Dupont Warren Fellowship Rachel A Ross; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 75 TC 0 Z9 0 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 SEP 26 PY 2016 VL 5 AR e15392 DI 10.7554/eLife.15392 PG 23 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EB0LB UT WOS:000387034200001 ER PT J AU Xu, HY Cai, T Carmona, GN Abuhatzira, L Notkins, AL AF Xu, Huanyu Cai, Tao Carmona, Gilberto N. Abuhatzira, Liron Notkins, Abner L. TI Small cell lung cancer growth is inhibited by miR-342 through its effect of the target gene IA-2 SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE Small cell lung cancers (SCLC); Dense-core vesicle (DCV); microRNA; Autocrine; Therapeutic approach ID PROTEIN-TYROSINE-PHOSPHATASE; NONNEURONAL ACETYLCHOLINE; CARCINOMA GROWTH; IA-2-BETA; SECRETION; PROLIFERATION; EXPRESSION; NEUROENDOCRINE; AUTOANTIGEN; DISRUPTION AB Background: Small cell lung cancers (SCLC) are tumors of neuroendocrine origin. Previous in vitro studies from our laboratory showed that SCLC expresses high levels of the transmembrane dense core vesicle protein IA-2 (islet cell antigen-2) as compared to normal lung cells. IA-2, through its effect on dense core vesicles (DCVs), is known to be involved in the secretion of hormones and neurotransmitters. It is believed that the dysregulated release of the neurotransmitter Acetylcholine (ACh) by DCVs has an autocrine effect on SCLC cell growth. Recently, we found that IA-2 is a target of the microRNA miR-342 and that miR-342 mimics suppress the expression of IA-2. The present experiments were initiated to see whether IA-2 and/or miR-342 affect the growth of SCLC. Methods: SCLC cell growth was evaluated following the knockdown of endogenous IA-2 with RNAi or by overexpressing miR-342 with a mimic. The secretion and content of ACh in SCLC cells was analyzed using a human acetylcholine ELISA (enzyme-linked immunosorbent assay) kit. Results: The knockdown of endogenous IA-2 by RNAi reduced SCLC cell growth within 4 days by 40 % or more. Similar results were obtained when these cell lines were transfected with a miR-342 mimic. The knockdown of IA-2 by RNAi or miR-342 with a mimic also resulted in a significant decrease in the secretion of ACh, one of the autocrine hormones secreted by SCLC. Further studies revealed that the growth of SCLC cell lines that had been treated with the miR-342 mimic was restored to nearly normal levels by treatment with ACh. Conclusion: Our studies show for the first time that both miR-342 and its target gene IA-2 are involved in the growth process of SCLC cells and act by their effect on autocrine secretion. These findings point to possible new therapeutic approaches for the treatment of autocrine-induced tumor proliferation. C1 [Xu, Huanyu; Cai, Tao; Carmona, Gilberto N.; Abuhatzira, Liron; Notkins, Abner L.] Natl Inst Dent & Craniofacial Res, Expt Med Sect, Lab Sensory Biol, NIH, B30-Rm106, Bethesda, MD 20892 USA. RP Notkins, AL (reprint author), Natl Inst Dent & Craniofacial Res, Expt Med Sect, Lab Sensory Biol, NIH, B30-Rm106, Bethesda, MD 20892 USA. EM anotkins@dir.nidcr.nih.gov FU Intramural Research Program of the NIDCR, NIH FX This work was supported by the Intramural Research Program of the NIDCR, NIH. This work was supported by the Intramural Research Program of the NIDCR, NIH. No additional external funding was received for this study. The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 0 Z9 0 U1 7 U2 7 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 SEP 26 PY 2016 VL 14 AR 278 DI 10.1186/s12967-016-1036-0 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DX7WG UT WOS:000384599500001 PM 27670444 ER PT J AU Alzan, HF Lau, AOT Knowles, DP Herndon, DR Ueti, MW Scoles, GA Kappmeyer, LS Suarez, CE AF Alzan, Heba F. Lau, Audrey O. T. Knowles, Donald P. Herndon, David R. Ueti, Massaro W. Scoles, Glen A. Kappmeyer, Lowell S. Suarez, Carlos E. TI Expression of 6-Cys Gene Superfamily Defines Babesia bovis Sexual Stage Development within Rhipicephalus microplus SO PLOS ONE LA English DT Article ID TRANSMISSION-BLOCKING IMMUNITY; PLASMODIUM-FALCIPARUM; PHYLOGENETIC ANALYSIS; INVITRO CULTIVATION; SURFACE PROTEIN; IN-VITRO; PFS230; IDENTIFICATION; ATTENUATION; ANTIBODIES AB Babesia bovis, an intra-erythrocytic tick-borne apicomplexan protozoan, is one of the causative agents of bovine babesiosis. Its life cycle includes sexual reproduction within cattle fever ticks, Rhipicephalus spp. Six B. bovis 6-Cys gene superfamily members were previously identified (A, B, C, D, E, F) where their orthologues in Plasmodium parasite have been shown to encode for proteins required for the development of sexual stages. The current study identified four additional 6-Cys genes (G, H, I, J) in the B. bovis genome. These four genes are described in the context of the complete ten 6-Cys gene superfamily. The proteins expressed by this gene family are predicted to be secreted or surface membrane directed. Genetic analysis comparing the 6-Cys superfamily among five distinct B. bovis strains shows limited sequence variation. Additionally, A, B, E, H, I and J genes were transcribed in B. bovis infected tick midgut while genes A, B and E were also transcribed in the subsequent B. bovis kinete stage. Transcription of gene C was found exclusively in the kinete. In contrast, transcription of genes D, F and G in either B. bovis infected midguts or kinetes was not detected. None of the 6-Cys transcripts were detected in B. bovis blood stages. Subsequent protein analysis of 6-Cys A and B is concordant with their transcript profile. The collective data indicate as in Plasmodium parasite, certain B. bovis 6-Cys family members are uniquely expressed during sexual stages and therefore, they are likely required for parasite reproduction. Within B. bovis specifically, proteins encoded by 6-Cys genes A and B are markers for sexual stages and candidate antigens for developing novel vaccines able to interfere with the development of B. bovis within the tick vector. C1 [Alzan, Heba F.; Knowles, Donald P.; Ueti, Massaro W.; Scoles, Glen A.; Suarez, Carlos E.] Washington State Univ, Coll Vet Med, Dept Vet Microbiol & Pathol, Pullman, WA 99164 USA. [Alzan, Heba F.] Natl Res Ctr, Parasitol & Anim Dis Dept, Giza, Egypt. [Knowles, Donald P.; Herndon, David R.; Ueti, Massaro W.; Scoles, Glen A.; Kappmeyer, Lowell S.; Suarez, Carlos E.] USDA ARS, Anim Dis Res Unit, Pullman, WA USA. [Lau, Audrey O. T.] NIAID, 5601 Fishers Lane,MSC 9823, Bethesda, MD USA. RP Suarez, CE (reprint author), Washington State Univ, Coll Vet Med, Dept Vet Microbiol & Pathol, Pullman, WA 99164 USA.; Suarez, CE (reprint author), USDA ARS, Anim Dis Res Unit, Pullman, WA USA. EM ces@vetmed.wsu.edu FU Egyptian government, Ministry of High Education and Scientific Research scholarship; United States Department of Agriculture-Agriculture Research Service Current Research Information System [5348-32000-028-00D] FX This work was supported by the Egyptian government, Ministry of High Education and Scientific Research scholarship, and the United States Department of Agriculture-Agriculture Research Service Current Research Information System Project No. 5348-32000-028-00D. NR 48 TC 1 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 SEP 26 PY 2016 VL 11 IS 9 AR e0163791 DI 10.1371/journal.pone.0163791 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX1ZV UT WOS:000384167300071 PM 27668751 ER PT J AU Zhang, YF Ho, M AF Zhang, Yi-Fan Ho, Mitchell TI Humanization of high-affinity antibodies targeting glypican-3 in hepatocellular carcinoma SO SCIENTIFIC REPORTS LA English DT Article ID MONOCLONAL-ANTIBODIES; CANCER-THERAPY; LIGHT-CHAINS; IN-VITRO; COMPLEMENTARITY; FRAMEWORK; DESIGN; EXPRESSION; REGIONS; CELLS AB Glypican-3 (GPC3) is a cell-surface heparan sulfate proteoglycan highly expressed in hepatocellular carcinoma (HCC). We have generated a group of high-affinity mouse monoclonal antibodies targeting GPC3. Here, we report the humanization and testing of these antibodies for clinical development. We compared the affinity and cytotoxicity of recombinant immunotoxins containing mouse single-chain variable regions fused with a Pseudomonas toxin. To humanize the mouse Fvs, we grafted the combined KABAT/IMGT complementarity determining regions (CDR) into a human IgG germline framework. Interestingly, we found that the proline at position 41, a non-CDR residue in heavy chain variable regions (VH), is important for humanization of mouse antibodies. We also showed that two humanized anti-GPC3 antibodies (hYP7 and hYP9.1b) in the IgG format induced antibody-dependent cell-mediated cytotoxicity and complement-dependent-cytotoxicity in GPC3-positive cancer cells. The hYP7 antibody was tested and showed inhibition of HCC xenograft tumor growth in nude mice. This study successfully humanizes and validates high affinity anti-GPC3 antibodies and sets a foundation for future development of these antibodies in various clinical formats in the treatment of liver cancer. C1 [Zhang, Yi-Fan; Ho, Mitchell] NCI, Antibody Therapy Sect, Mol Biol Lab, Ctr Canc Res,NIT, Bethesda, MD 20892 USA. RP Ho, M (reprint author), NCI, Antibody Therapy Sect, Mol Biol Lab, Ctr Canc Res,NIT, Bethesda, MD 20892 USA. EM homi@mail.nih.gov RI Zhang, Yifan/O-9621-2015 OI Zhang, Yifan/0000-0002-0629-0200 FU Intramural Research Program of NIH, NCI, Center for Cancer Research [Z01 BC 010891, ZIA BC 010891]; NCI Technology Transfer Office FX This research was supported by the Intramural Research Program of NIH, NCI, Center for Cancer Research (Z01 BC 010891 and ZIA BC 010891 to MH). We thank the NCI Technology Transfer Office for providing the Invention Development Fund to support hYP7 antibody production for preclinical mouse testing. We thank Martin Skarzynski (NCI) and Hong Zhou (NCI) for technical assistance in CDC assay and preparation of PBMCs, respectively. We also thank Rimas Orentas and Dina Schneider (Lentigen Technology, Inc.) for providing the G1 and A431 lines that stably express luciferase in our ADCC and CDC assays. We thank Bryan Fleming (NCI), Yen Phung (NCI) and the NIH Fellows Editorial Board for editorial assistance. The National Cancer Institute (NCI) holds patent rights to YP7, YP9.1 and our other anti-GPC3 antibodies in many jurisdictions, including the United States[e.g., U.S. Patent 9,409,994, U.S Patent 9,304,364 and U.S. Patent 9,206,257], China, Japan, South Korea, Singapore and Europe. Claims cover the antibodies themselves, as well as conjugates that utilize the antibodies, such as recombinant immunotoxins (RITs), antibody drug conjugates (ADCs), bispecific antibodies and modified T cell receptors (TCRs)/chimeric antigen receptors (CARs). Anyone interested in licensing these antibodies can contact the authors directly for additional information. NR 63 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 SEP 26 PY 2016 VL 6 AR 33878 DI 10.1038/srep33878 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX6FI UT WOS:000384478500001 PM 27667400 ER PT J AU Fegert, JM Vitiello, B AF Fegert, Joerg M. Vitiello, Benedetto TI New journal structure of child and adolescent psychiatry and mental health SO CHILD AND ADOLESCENT PSYCHIATRY AND MENTAL HEALTH LA English DT Editorial Material C1 [Fegert, Joerg M.] Univ Hosp Ulm, Ulm, Germany. [Vitiello, Benedetto] NIMH, Bethesda, MD 20892 USA. RP Fegert, JM (reprint author), Univ Hosp Ulm, Ulm, Germany. EM Joerg.Fegert@uniklinik-ulm.de NR 3 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 1753-2000 J9 CHILD ADOL PSYCH MEN JI Child Adolesc. Psychiatry Ment. Health PD SEP 23 PY 2016 VL 10 AR 35 DI 10.1186/s13034-016-0123-6 PG 2 WC Pediatrics; Psychiatry SC Pediatrics; Psychiatry GA EF2PZ UT WOS:000390168100001 PM 27688800 ER PT J AU Kershaw, KN Liu, K Goff, DC Lloyd-Jones, DM Rasmussen-Torvik, LJ Reis, JP Schreiner, PJ Garside, DB Sidney, S AF Kershaw, Kiarri N. Liu, Kiang Goff, David C., Jr. Lloyd-Jones, Donald M. Rasmussen-Torvik, Laura J. Reis, Jared P. Schreiner, Pamela J. Garside, Daniel B. Sidney, Stephen TI Description and initial evaluation of incorporating electronic follow-up of study participants in a longstanding multisite cohort study SO BMC MEDICAL RESEARCH METHODOLOGY LA English DT Article DE Pilot projects; Cohort studies; Epidemiology ID RECRUITMENT; CARDIA AB Background: The objective of this study was to evaluate a pilot program that allowed Chicago field center participants of the Coronary Artery Risk Development in Young Adults (CARDIA) study to submit follow-up information electronically (eCARDIA). Methods: Chicago field center participants who provided email addresses were invited to complete contact information and follow-up questionnaires on medical conditions electronically in 2012-2013. Sociodemographic characteristics were compared between those who did and did not complete follow-up electronically. The number of participant contacts by CARDIA staff needed before follow-up was completed was also evaluated. Results: Blacks and low socioeconomic position individuals were less likely to complete follow-up using the electronic questionnaire. Participants who used the electronic questionnaire for follow-up needed fewer contacts (e.g., median 1 contact compared with 3 for contact information follow-up), but they also needed fewer contacts prior to eCARDIA (median 1 before and after eCARDIA). Conclusions: Findings suggest other approaches will be needed to maintain contact and elicit follow-up information from harder-to-reach individuals. C1 [Kershaw, Kiarri N.; Liu, Kiang; Lloyd-Jones, Donald M.; Rasmussen-Torvik, Laura J.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, 680 N Lake Shore,Suite 1400, Chicago, IL 60611 USA. [Goff, David C., Jr.] Colorado Sch Publ Hlth, Dept Epidemiol, 13001 E 17th Pl, Aurora, CO USA. [Reis, Jared P.] NHLBI, Div Cardiovasc Sci, 6701 Rockledge Dr,Suite 10197, Bethesda, MD 20892 USA. [Schreiner, Pamela J.] Univ Minnesota, Sch Publ Hlth, Dept Epidemiol & Community Hlth, 1300 S 2nd St,Suite 300, Minneapolis, MN USA. [Garside, Daniel B.] Univ Illinois, Dept Med, 1819 W Polk St,Suite 246, Chicago, IL USA. [Sidney, Stephen] Kaiser Permanente Northern Calif, Div Res, 2000 Broadway, Oakland, CA USA. RP Kershaw, KN (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, 680 N Lake Shore,Suite 1400, Chicago, IL 60611 USA. EM k-kershaw@northwestern.edu FU National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, HHSN268200900041C]; Intramural Research Program of the National Institute on Aging (NIA); NIA; NHLBI [AG0005] FX The Coronary Artery Risk Development in Young Adults Study (CARDIA) is supported by contracts HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, and HHSN268200900041C from the National Heart, Lung, and Blood Institute (NHLBI), the Intramural Research Program of the National Institute on Aging (NIA), and an intra-agency agreement between NIA and NHLBI (AG0005). These funding sources supported the collection of the data used in this study. NR 8 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 1471-2288 J9 BMC MED RES METHODOL JI BMC Med. Res. Methodol. PD SEP 23 PY 2016 VL 16 AR 125 DI 10.1186/s12874-016-0226-z PG 5 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DX9EL UT WOS:000384696300001 PM 27664124 ER PT J AU Koppenol-Raab, M Harwig, MC Posey, AE Egner, JM MacKenzie, KR Hill, RB AF Koppenol-Raab, Marijke Harwig, Megan Cleland Posey, Ammon E. Egner, John M. MacKenzie, Kevin R. Hill, R. Blake TI A Targeted Mutation Identified through pK(a) Measurements Indicates a Postrecruitment Role for Fis1 in Yeast Mitochondrial Fission SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE confocal microscopy; mitochondria; nuclear magnetic resonance (NMR); protein assembly; protein-protein interaction; structural model; macromolecular machine; mitochondrial dynamics; pKa measurements; tetratricopeptide repeat (TPR) domains ID PROTEIN-PROTEIN INTERACTIONS; WD REPEAT PROTEIN; SACCHAROMYCES-CEREVISIAE; MEMBRANE RECRUITMENT; RECOGNITION SITES; DRP1 RECRUITMENT; DIVISION; DYNAMICS; DNM1P; ADAPTER AB The tail-anchored protein Fis1 is implicated as a passive tether in yeast mitochondrial fission. We probed the functional role of Fis1 Glu-78, whose elevated side chain pK(a) suggests participation in protein interactions. Fis1 binds partners Mdv1 or Dnm1 tightly, but mutation E78A weakens Fis1 interaction with Mdv1, alters mitochondrial morphology, and abolishes fission in a growth assay. In fis1 rescue experiments, Fis1-E78A causes a novel localization pattern in which Dnm1 uniformly coats the mitochondria. By contrast, Fis1-E78A at lower expression levels recruits Dnm1 into mitochondrial punctate structures but fails to support normal fission. Thus, Fis1 makes multiple interactions that support Dnm1 puncta formation and may be essential after this step, supporting a revised model for assembly of the mitochondrial fission machinery. The insights gained by mutating a residue with a perturbed pK(a) suggest that side chain pK(a) values inferred from routine NMR sample pH optimization could provide useful leads for functional investigations. C1 [Koppenol-Raab, Marijke; Posey, Ammon E.] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. [Posey, Ammon E.] Johns Hopkins Univ, Program Mol Biophys, Baltimore, MD 21218 USA. [Harwig, Megan Cleland; Egner, John M.; Hill, R. Blake] Med Coll Wisconsin, Dept Biochem, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. [MacKenzie, Kevin R.] Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. [Koppenol-Raab, Marijke] NIAID, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Posey, Ammon E.] Washington Univ, Dept Biomed Engn, St Louis, MO 63130 USA. RP Hill, RB (reprint author), Med Coll Wisconsin, Dept Biochem, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM rbhill@mcw.edu FU National Institutes of Health [R01 GM067180] FX This work was supported by National Institutes of Health Grant R01 GM067180. 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 2 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 SEP 23 PY 2016 VL 291 IS 39 BP 20329 EP 20344 DI 10.1074/jbc.M116.724005 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DX7NN UT WOS:000384574800005 PM 27496949 ER PT J AU Desai, A Park, T Barnes, J Kevala, K Chen, HZ Kim, HY AF Desai, Abhishek Park, Taeyeop Barnes, Jaquel Kevala, Karl Chen, Huazhen Kim, Hee-Yong TI Reduced acute neuroinflammation and improved functional recovery after traumatic brain injury by alpha-linolenic acid supplementation in mice SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE Polyunsaturated fatty acids (PUFA); Docosahexaenoic acid (DHA); Alpha-linolenic acid (ALA); Traumatic brain injury (TBI); Inflammation; Diet; Nutrition ID SPINAL-CORD-INJURY; FATTY-ACIDS; HEAD-INJURY; RAT-BRAIN; ER STRESS; DHA; ACTIVATION; ASTROCYTES; NEUROPROTECTION; INFLAMMATION AB Background: Adequate consumption of polyunsaturated fatty acids (PUFA) is vital for normal development and functioning of the central nervous system. The long-chain n-3 PUFAs docosahexaenoic acid (DHA) and eicosapentaenoic acid are anti-inflammatory and neuroprotective in the models of central nervous system injury including traumatic brain injury (TBI). In the present study, we tested whether a higher brain DHA status in a mouse model on an adequate dietary alpha-linolenic acid (ALA) leads to reduced neuroinflammation and improved spontaneous recovery after TBI in comparison to a moderately lowered brain DHA status that can occur in humans. Methods: Mice reared on diets with differing ALA content were injured by a single cortical contusion impact. Change in the expression of inflammatory cytokines was measured, and cellular changes occurring after injury were analyzed by immunostaining for macrophage/microglia and astrocytes. Behavioral studies included rotarod and beam walk tests and contextual fear conditioning. Results: Marginal supply (0.04 %) of ALA as the sole dietary source of n-3 PUFA from early gestation produced reduction of brain DHA by 35 % in adult offspring mice in comparison to the mice on adequate ALA diet (3.1 %). The DHA-depleted group showed significantly increased TBI-induced expression of pro-inflammatory cytokines TNF-alpha, IL-1 beta, and IL-6 in the brain as well as slower functional recovery from motor deficits compared to the adequate ALA group. Despite the reduction of pro-inflammatory cytokine expression, adequate ALA diet did not significantly alter either microglia/macrophage density around the contusion site or the relative M1/M2 phenotype. However, the glial fibrillary acidic protein immunoreactivity was reduced in the injured cerebral cortex of the mice on adequate ALA diet, indicating that astrocyte activation may have contributed to the observed differences in cellular and behavioral responses to TBI. Conclusions: Increasing the brain DHA level even from a moderately DHA-depleted state can reduce neuroinflammation and improve functional recovery after TBI, suggesting possible improvement of functional outcome by increasing dietary n-3 PUFA in human TBI. C1 [Desai, Abhishek; Park, Taeyeop; Barnes, Jaquel; Kevala, Karl; Chen, Huazhen; Kim, Hee-Yong] NIAAA, Lab Mol Signaling, NIH, 5625 Fishers Lane,Rm 3N-07, Bethesda, MD 20892 USA. RP Kim, HY (reprint author), NIAAA, Lab Mol Signaling, NIH, 5625 Fishers Lane,Rm 3N-07, Bethesda, MD 20892 USA. EM hykim@nih.gov FU Henry M. Jackson Foundation; Intramural Research Program of the National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health FX This study was funded by the Henry M. Jackson Foundation and the Intramural Research Program of the National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health. The funding agencies did not participate in planning the experiments, data analysis, or preparing the manuscript. NR 36 TC 0 Z9 0 U1 6 U2 6 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 SEP 23 PY 2016 VL 13 AR 253 DI 10.1186/s12974-016-0714-4 PG 10 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA DX8ED UT WOS:000384620000003 ER PT J AU Yin, ZH Cui, ZG Li, H Ren, YW Qian, BY Rothman, N Lan, Q Zhou, BS AF Yin, Zhihua Cui, Zhigang Li, Hang Ren, Yangwu Qian, Biyun Rothman, Nathaniel Lan, Qing Zhou, Baosen TI Polymorphisms in miR-135a-2, miR-219-2 and miR-211 as well as their interaction with cooking oil fume exposure on the risk of lung cancer in Chinese nonsmoking females: a case-control study SO BMC CANCER LA English DT Article ID MICRORNA EXPRESSION; CELL-PROLIFERATION; WOMEN NONSMOKERS; ADENOCARCINOMA; METAANALYSIS; STATISTICS; BIOGENESIS; SMOKING; SITES AB Background: The associations between microRNAs and lung cancer have received increasing attention. This study assess the association between polymorphisms in miR-135a-2, miR-219-2 and miR-211 genes and the risk of lung cancer, as well as the gene-environment interaction between these polymorphisms and cooking oil fume exposure. Methods: A case-control study featuring 268 cases and 266 controls was conducted. The associations of miR-135a-2 rs10459194, miR-219-2 rs10988341 and miR-211 rs1514035 polymorphisms with the risk of lung cancer were analyzed. The gene-environment interactions were also reported on both additive and multiplicative scales. Results: There were no statistically significant associations between the single-nucleotide polymorphisms (SNPs) and lung cancer or lung adenocarcinoma. The individuals with both a risk genotype of miRNA SNPs and exposure to a risk factor (cooking oil fumes) were at higher risk of lung cancer than those with only one of these two risk factors (odd ratios of 2.208, 1.285 and 1.813 for miR-135a-2 rs10459194; 2.164, 1.209 and 1.806 for miR-219-2 rs10988341; and 2.122, 1.146 and 1.725 for miR-211 rs1514035, respectively). However, the measures of biological interaction indicate that there was no such interaction between the three SNPs and exposure to cooking oil fumes on an additive scale. Logistic regression models also suggested that the gene-environment interactions were not statistically significant on a multiplicative scale. Conclusions: There were no significant associations between the polymorphisms in miRNAs (miR-26a-1 rs7372209, miR-605 rs2043556 and miR-16-1 rs1022960) and the risk of lung cancer in the Chinese nonsmoking female population. The interactions between these polymorphisms in miRNAs and cooking oil fume exposure were also not statistically significant. C1 [Yin, Zhihua; Li, Hang; Ren, Yangwu; Zhou, Baosen] China Med Univ, Sch Publ Hlth, Dept Epidemiol, Shenyang North New Area, 77 Puhe Rd, Shenyang 110122, Peoples R China. [Yin, Zhihua; Li, Hang; Ren, Yangwu; Zhou, Baosen] Univ Liaoning Prov, Key Lab Canc Etiol & Intervent, Shenyang North New Area, 77 Puhe Rd, Shenyang 110122, Peoples R China. [Cui, Zhigang] China Med Univ, Sch Nursing, Shenyang North New Area, 77 Puhe Rd, Shenyang 110122, Peoples R China. [Qian, Biyun] Shanghai Jiao Tong Univ, Sch Publ Hlth, Dept Epidemiol, 800 Dongchuan Rd, Shanghai 200240, Peoples R China. [Rothman, Nathaniel; Lan, Qing] NCI, Div Canc Epidemiol & Genet, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Zhou, BS (reprint author), China Med Univ, Sch Publ Hlth, Dept Epidemiol, Shenyang North New Area, 77 Puhe Rd, Shenyang 110122, Peoples R China.; Zhou, BS (reprint author), Univ Liaoning Prov, Key Lab Canc Etiol & Intervent, Shenyang North New Area, 77 Puhe Rd, Shenyang 110122, Peoples R China. EM bszhou@mail.cmu.edu.cn FU National Natural Science Foundation of China [81102194] FX This study was supported by National Natural Science Foundation of China (No. 81102194). NR 36 TC 0 Z9 0 U1 6 U2 6 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 SEP 23 PY 2016 VL 16 AR 751 DI 10.1186/s12885-016-2784-1 PG 8 WC Oncology SC Oncology GA DX6LE UT WOS:000384494400001 ER PT J AU Sodt, AJ Venable, RM Lyman, E Pastor, RW AF Sodt, A. J. Venable, R. M. Lyman, E. Pastor, R. W. TI Nonadditive Compositional Curvature Energetics of Lipid Bilayers SO PHYSICAL REVIEW LETTERS LA English DT Article ID MOLECULAR-DYNAMICS SIMULATION; ADDITIVE FORCE-FIELD; PHOSPHOLIPID-MEMBRANES; BENDING ELASTICITY; CHAIN-LENGTH; PHASE; CHOLESTEROL; DOMAINS; TENSION; FUSION AB The unique properties of the individual lipids that compose biological membranes together determine the energetics of the surface. The energetics of the surface, in turn, govern the formation of membrane structures and membrane reshaping processes, and thus they will underlie cellular-scale models of viral fusion, vesicle-dependent transport, and lateral organization relevant to signaling. The spontaneous curvature, to the best of our knowledge, is always assumed to be additive. We describe observations from simulations of unexpected nonadditive compositional curvature energetics of two lipids essential to the plasma membrane: sphingomyelin and cholesterol. A model is developed that connects molecular interactions to curvature stress, and which explains the role of local composition. Cholesterol is shown to lower the number of effective Kuhn segments of saturated acyl chains, reducing lateral pressure below the neutral surface of bending and favoring positive curvature. The effect is not observed for unsaturated (flexible) acyl chains. Likewise, hydrogen bonding between sphingomyelin lipids leads to positive curvature, but only at sufficient concentration, below which the lipid prefers negative curvature. C1 [Sodt, A. J.; Venable, R. M.; Pastor, R. W.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Lyman, E.] Univ Delaware, Dept Phys & Astron, Newark, DE 19716 USA. [Lyman, E.] Univ Delaware, Dept Chem & Biochem, Newark, DE 19716 USA. [Sodt, A. J.] Kennedy Schriver Natl Inst Child Hlth & Human Dev, NIH, Bethesda, MD USA. RP Sodt, AJ (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA.; Sodt, AJ (reprint author), Kennedy Schriver Natl Inst Child Hlth & Human Dev, NIH, Bethesda, MD USA. EM alexander.sodt@nih.gov FU Intramural Research Program of the National Institutes of Health (NIH); National Heart, Lung, and Blood Institute (NHLBI); Eunice Kennedy Schriver National Institute of Child Health and Human Development; NIH [P20GM104316-01, P41GM103712-S1] FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), the National Heart, Lung, and Blood Institute (NHLBI), and the Eunice Kennedy Schriver National Institute of Child Health and Human Development. It used the NHLBI LoBoS cluster. E. L. was partially supported by NIH Grant No. P20GM104316-01. Anton computer time to construct the Lo and Ld ensembles was provided by the National Resource for Biomedical Supercomputing (NRBSC), the Pittsburgh Supercomputing Center (PSC), and the BTRC for Multiscale Modeling of Biological Systems (MMBioS) through Grant No. P41GM103712-S1 from the NIH. Feedback from anonymous reviewers of the work substantially enriched the interpretation of the data. NR 46 TC 1 Z9 1 U1 18 U2 20 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 0031-9007 EI 1079-7114 J9 PHYS REV LETT JI Phys. Rev. Lett. PD SEP 23 PY 2016 VL 117 IS 13 AR 138104 DI 10.1103/PhysRevLett.117.138104 PG 6 WC Physics, Multidisciplinary SC Physics GA DW7SO UT WOS:000383852100005 PM 27715135 ER PT J AU Bolnick, JM Kohan-Ghadr, HR Fritz, R Bolnick, AD Kilburn, BA Diamond, MP Armant, DR Drewlo, S AF Bolnick, Jay M. Kohan-Ghadr, Hamid-Reza Fritz, Rani Bolnick, Alan D. Kilburn, Brian A. Diamond, Michael P. Armant, D. Randall Drewlo, Sascha TI Altered Biomarkers in Trophoblast Cells Obtained Noninvasively Prior to Clinical Manifestation of Perinatal Disease SO SCIENTIFIC REPORTS LA English DT Article ID INTRAUTERINE GROWTH RESTRICTION; UTERINE ARTERY DOPPLER; GESTATIONAL-AGE INFANTS; SERUM ALPHA-FETOPROTEIN; EARLY-PREGNANCY; OXIDATIVE STRESS; PREECLAMPSIA; PREDICTION; CYTOBRUSH; RISK AB A contributing factor to poor placental perfusion, leading to intrauterine growth restriction and preeclampsia, is the failure of invading extravillous trophoblast (EVT) cells to remodel the maternal uterine arteries during the first and second trimesters of pregnancy. Noninvasive assessment of EVT cells in ongoing pregnancies is possible beginning three weeks after conception, using trophoblast retrieval and isolation from the cervix (TRIC). Seven proteins were semi-quantified by immunofluorescence microscopy in EVT cells obtained between gestational weeks 6 and 20 from pregnancies with normal outcomes (N = 29) and those with intrauterine growth restriction or preeclampsia (N = 12). Significant differences were measured in expression of PAPPA, FLT1, ENG, AFP, PGF, and LGALS14, but not LGALS13 or the lineage marker KRT7. These findings provide for the first time direct evidence of pathology-associated protein dysregulation in EVT cells during early placentation. The TRIC platform provides a novel approach to acquire molecular signatures of EVT cells that can be correlated with pregnancy outcome. C1 [Bolnick, Jay M.; Kohan-Ghadr, Hamid-Reza; Fritz, Rani; Bolnick, Alan D.; Kilburn, Brian A.; Armant, D. Randall; Drewlo, Sascha] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Diamond, Michael P.] Georgia Regents Univ, Dept Obstet & Gynecol, Augusta, GA USA. [Armant, D. Randall] NICHD, Program Reprod & Adult Endocrinol, NIH, DHHS, Bethesda, MD USA. RP Drewlo, S (reprint author), Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. EM sdrewlo@Med.Wayne.edu FU Intramural Research Program of the NICHD; NIH [HD071408, HL128628]; W.K. Kellogg Foundation; March of Dimes Foundation; PerkinElmer Health Sciences, Inc. FX This research was supported in part by the Intramural Research Program of the NICHD, NIH Grant HD071408 and HL128628, the W.K. Kellogg Foundation, the March of Dimes Foundation and PerkinElmer Health Sciences, Inc. NR 52 TC 2 Z9 2 U1 7 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 SEP 23 PY 2016 VL 6 AR 32382 DI 10.1038/srep32382 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW8OK UT WOS:000383915200001 PM 27660926 ER PT J AU Bram, Z Louiset, E Ragazzon, B Renouf, S Wils, J Duparc, C Boutelet, I Rizk-Rabin, M Libe, R Young, J Carson, D Vantyghem, MC Szarek, E Martinez, A Stratakis, CA Bertherat, J Lefebvre, H AF Bram, Zakariae Louiset, Estelle Ragazzon, Bruno Renouf, Sylvie Wils, Julien Duparc, Celine Boutelet, Isabelle Rizk-Rabin, Marthe Libe, Rossella Young, Jacques Carson, Dennis Vantyghem, Marie-Christine Szarek, Eva Martinez, Antoine Stratakis, Constantine A. Bertherat, Jerome Lefebvre, Herve TI PKA regulatory subunit 1A inactivating mutation induces serotonin signaling in primary pigmented nodular adrenal disease SO JCI INSIGHT LA English DT Article ID PROTEIN-KINASE-A; ALDOSTERONE-PRODUCING ADENOMAS; CARNEY COMPLEX; CUSHINGS-SYNDROME; ADRENOCORTICAL DISEASE; PRKAR1A MUTATION; CARCINOID-SYNDROME; MESSENGER-RNA; IN-VITRO; HYPERPLASIA AB Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent hypercortisolism. The disease is primarily caused by germline mutations of the protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene, which induces constitutive activation of PKA in adrenocortical cells. Hypercortisolism is thought to result from PKA hyperactivity, but PPNAD tissues exhibit features of neuroendocrine differentiation, which may lead to stimulation of steroidogenesis by abnormally expressed neurotransmitters. We hypothesized that serotonin (5-HT) may participate in the pathophysiology of PPNAD-associated hypercortisolism. We show that PPNAD tissues overexpress the 5-HT synthesizing enzyme tryptophan hydroxylase type 2 (Tph2) and the serotonin receptors types 4, 6, and 7, leading to formation of an illicit stimulatory serotonergic loop whose pharmacological inhibition in vitro decreases cortisol production. In the human PPNAD cell line CAR47, the PKA inhibitor H-89 decreases 5-HT4 and 5-HT7 receptor expression. Moreover, in the human adrenocortical cell line H295R, inhibition of PRKAR1A expression increases the expression of Tph2 and 5-HT4/6/7 receptors, an effect that is blocked by H-89. These findings show that the serotonergic process observed in PPNAD tissues results from PKA activation by PRKAR1A mutations. They also suggest that Tph inhibitors may represent efficient treatments of hypercortisolism in patients with PPNAD. C1 [Bram, Zakariae; Louiset, Estelle; Renouf, Sylvie; Wils, Julien; Duparc, Celine; Boutelet, Isabelle; Lefebvre, Herve] Normandie Univ, Lab Differenciat & Commun Neuronale & Neuroendocr, UNIROUEN, INSERM,U982, F-76000 Rouen, France. [Ragazzon, Bruno; Rizk-Rabin, Marthe; Libe, Rossella; Bertherat, Jerome] Univ Paris V, Cochin Inst, INSERM, U1016, Paris, France. [Young, Jacques] Univ Paris Sud, INSERM, Unite 693, Le Kremlin Bicetre, France. [Carson, Dennis] Royal Belfast Hosp Sick Children, Dept Paediat Endocrinol, Belfast, Antrim, North Ireland. [Vantyghem, Marie-Christine] CHU Lille, Endocrinol Diabetol & Metab, Lille, France. [Vantyghem, Marie-Christine] Univ Lille, INSERM, U1190, EGID, Lille, France. [Szarek, Eva; Stratakis, Constantine A.] NICHD, Sect Endocrinol & Genet, PDEGEN, Bethesda, MD USA. [Martinez, Antoine] Clermont Univ, CNRS, UMR6247, INSERM,U931,Gred, Aubiere, France. [Lefebvre, Herve] CHU Rouen, Dept Endocrinol, Rouen, France. RP Lefebvre, H (reprint author), Univ Hosp Rouen, INSERM, U982, Dept Endocrinol, F-76031 Rouen, France. EM herve.lefebvre@chu-rouen.fr RI Ragazzon, Bruno/E-6541-2017 OI Ragazzon, Bruno/0000-0001-9476-4973 NR 58 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD SEP 22 PY 2016 VL 1 IS 15 AR e87958 DI 10.1172/jci.insight.87958 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1OQ UT WOS:000387123200008 PM 27699247 ER PT J AU Sas, KM Kayampilly, P Byun, J Nair, V Hinder, LM Hur, J Zhang, HY Lin, CM Qi, NR Michailidis, G Groop, PH Nelson, RG Darshi, M Sharma, K Schelling, JR Sedor, JR Pop-Busui, R Weinberg, JM Soleimanpour, SA Abcouwer, SF Gardner, TW Burant, CF Feldman, EL Kretzler, M Brosius, FC Pennathur, S AF Sas, Kelli M. Kayampilly, Pradeep Byun, Jaeman Nair, Viji Hinder, Lucy M. Hur, Junguk Zhang, Hongyu Lin, Chengmao Qi, Nathan R. Michailidis, George Groop, Per-Henrik Nelson, Robert G. Darshi, Manjula Sharma, Kumar Schelling, Jeffrey R. Sedor, John R. Pop-Busui, Rodica Weinberg, Joel M. Soleimanpour, Scott A. Abcouwer, Steven F. Gardner, Thomas W. Burant, Charles F. Feldman, Eva L. Kretzler, Matthias Brosius, Frank C., III Pennathur, Subramaniam TI Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications SO JCI INSIGHT LA English DT Article ID FATTY-ACID OXIDATION; KIDNEY-DISEASE; SKELETAL-MUSCLE; HIGH GLUCOSE; MITOCHONDRIAL DYSFUNCTION; HYPERGLYCEMIC DAMAGE; CELLULAR-METABOLISM; LYSINE ACETYLATION; AMERICAN-INDIANS; RENAL-FUNCTION AB Diabetes is associated with altered cellular metabolism, but how altered metabolism contributes to the development of diabetic complications is unknown. We used the BKS db/db diabetic mouse model to investigate changes in carbohydrate and lipid metabolism in kidney cortex, peripheral nerve, and retina. A systems approach using transcriptomics, metabolomics, and metabolic flux analysis identified tissue-specific differences, with increased glucose and fatty acid metabolism in the kidney, a moderate increase in the retina, and a decrease in the nerve. In the kidney, increased metabolism was associated with enhanced protein acetylation and mitochondrial dysfunction. To confirm these findings in human disease, we analyzed diabetic kidney transcriptomic data and urinary metabolites from a cohort of Southwestern American Indians. The urinary findings were replicated in 2 independent patient cohorts, the Finnish Diabetic Nephropathy and the Family Investigation of Nephropathy and Diabetes studies. Increased concentrations of TCA cycle metabolites in urine, but not in plasma, predicted progression of diabetic kidney disease, and there was an enrichment of pathways involved in glycolysis and fatty acid and amino acid metabolism. Our findings highlight tissue-specific changes in metabolism in complication-prone tissues in diabetes and suggest that urinary TCA cycle intermediates are potential prognostic biomarkers of diabetic kidney disease progression. C1 [Sas, Kelli M.; Kayampilly, Pradeep; Byun, Jaeman; Nair, Viji; Zhang, Hongyu; Qi, Nathan R.; Pop-Busui, Rodica; Weinberg, Joel M.; Soleimanpour, Scott A.; Burant, Charles F.; Kretzler, Matthias; Brosius, Frank C., III; Pennathur, Subramaniam] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Nair, Viji; Kretzler, Matthias] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Hinder, Lucy M.; Feldman, Eva L.] Univ Michigan, Dept Neurol, Ann Arbor, MI USA. [Hur, Junguk] Univ North Dakota, Sch Med & Hlth Sci, Dept Biomed Sci, Grand Forks, ND USA. [Lin, Chengmao; Abcouwer, Steven F.; Gardner, Thomas W.] Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. [Michailidis, George] Univ Michigan, Dept Stat, Ann Arbor, MI 48109 USA. [Groop, Per-Henrik] Biomedicum Helsinki, Folkhalsan Inst Genet, Folkhalsan Res Ctr, Helsinki, Finland. [Groop, Per-Henrik] Univ Helsinki, Abdominal Ctr Nephrol, Helsinki, Finland. [Groop, Per-Henrik] Helsinki Univ Hosp, Helsinki, Finland. [Groop, Per-Henrik] Baker IDI Heart & Diabet Inst, Melbourne, Vic, Australia. [Nelson, Robert G.] NIDDK, Diabet Epidemiol & Clin Res Sect, NIH, Phoenix, AZ USA. [Darshi, Manjula; Sharma, Kumar] Univ Calif San Diego, Inst Metabol Med, La Jolla, CA 92093 USA. [Darshi, Manjula; Sharma, Kumar] Univ Calif San Diego, Dept Med, Ctr Renal Translat Med, La Jolla, CA 92093 USA. [Darshi, Manjula; Sharma, Kumar] Vet Adm San Diego Healthcare Syst, La Jolla, CA USA. [Schelling, Jeffrey R.; Sedor, John R.] Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. [Sedor, John R.] Case Western Reserve Univ, Dept Physiol & Biophys, Cleveland, OH 44106 USA. [Burant, Charles F.; Brosius, Frank C., III] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA. RP Pennathur, S (reprint author), Univ Michigan, 5309 Brehm Ctr,1000 Wall St, Ann Arbor, MI 48105 USA. EM spennath@umich.edu OI Hur, Junguk/0000-0002-0736-2149 FU NCATS NIH HHS [UL1 TR000433]; NCRR NIH HHS [M01 RR000080]; NEI NIH HHS [R01 EY020582]; NIDDK NIH HHS [R01 DK108921, DP3 DK094292, DP3 DK094352, K08 DK089117, P30 DK020572, P30 DK081943, P30 DK089503, R01 DK059997, R03 DK106304, R24 DK082841, R56 DK108921, U01 DK057329, U24 DK097153]; NIGMS NIH HHS [R01 GM114029] NR 67 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD SEP 22 PY 2016 VL 1 IS 15 AR e86976 DI 10.1172/jci.insight.86976 PG 19 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1OQ UT WOS:000387123200005 PM 27699244 ER PT J AU Captur, G Gatehouse, P Keenan, KE Heslinga, FG Bruehl, R Prothmann, M Graves, MJ Eames, RJ Torlasco, C Benedetti, G Donovan, J Ittermann, B Boubertakh, R Bathgate, A Royet, C Pang, WJ Nezafat, R Salerno, M Kellman, P Moon, JC AF Captur, Gabriella Gatehouse, Peter Keenan, Kathryn E. Heslinga, Friso G. Bruehl, Ruediger Prothmann, Marcel Graves, Martin J. Eames, Richard J. Torlasco, Camilla Benedetti, Giulia Donovan, Jacqueline Ittermann, Bernd Boubertakh, Redha Bathgate, Andrew Royet, Celine Pang, Wenjie Nezafat, Reza Salerno, Michael Kellman, Peter Moon, James C. TI A medical device-grade T1 and ECV phantom for global T1 mapping quality assurance-the T-1 Mapping and ECV Standardization in cardiovascular magnetic resonance (T1MES) program SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE T-1 mapping; Standardization; Phantom ID RELAXATION; HEART; FIELD; PRECISION; ACCURACY; WATER AB Background: T-1 mapping and extracellular volume (ECV) have the potential to guide patient care and serve as surrogate end-points in clinical trials, but measurements differ between cardiovascular magnetic resonance (CMR) scanners and pulse sequences. To help deliver T-1 mapping to global clinical care, we developed a phantom-based quality assurance (QA) system for verification of measurement stability over time at individual sites, with further aims of generalization of results across sites, vendor systems, software versions and imaging sequences. We thus created T1MES: The T1 Mapping and ECV Standardization Program. Methods: A design collaboration consisting of a specialist MRI small-medium enterprise, clinicians, physicists and national metrology institutes was formed. A phantom was designed covering clinically relevant ranges of T-1 and T-2 in blood and myocardium, pre and post-contrast, for 1.5 T and 3 T. Reproducible mass manufacture was established. The device received regulatory clearance by the Food and Drug Administration (FDA) and Conformite Europeene (CE) marking. Results: The T1MES phantom is an agarose gel-based phantom using nickel chloride as the paramagnetic relaxation modifier. It was reproducibly specified and mass-produced with a rigorously repeatable process. Each phantom contains nine differently-doped agarose gel tubes embedded in a gel/beads matrix. Phantoms were free of air bubbles and susceptibility artifacts at both field strengths and T-1 maps were free from off-resonance artifacts. The incorporation of high-density polyethylene beads in the main gel fill was effective at flattening the B-1 field. T-1 and T-2 values measured in T1MES showed coefficients of variation of 1 % or less between repeat scans indicating good short-term reproducibility. Temperature dependency experiments confirmed that over the range 15-30 degrees C the short-T-1 tubes were more stable with temperature than the long-T-1 tubes. A batch of 69 phantoms was mass-produced with random sampling of ten of these showing coefficients of variations for T-1 of 0.64 +/- 0.45 % and 0.49 +/- 0.34 % at 1.5 T and 3 T respectively. Conclusion: The T1MES program has developed a T-1 mapping phantom to CE/FDA manufacturing standards. An initial 69 phantoms with a multi-vendor user manual are now being scanned fortnightly in centers worldwide. Future results will explore T-1 mapping sequences, platform performance, stability and the potential for standardization. C1 [Captur, Gabriella] Inst Child Hlth, UCL Biol Mass Spectrometry Lab, 30 Guilford St, London, England. [Captur, Gabriella] Great Ormond St Hosp Sick Children, 30 Guilford St, London, England. [Captur, Gabriella; Moon, James C.] NIHR Univ Coll London Hosp Biomed Res Ctr, Maple House Suite,Tottenham Court Rd, London W1T 7DN, England. [Captur, Gabriella; Moon, James C.] St Bartholomews Hosp, Barts Heart Ctr, London EC1A 7BE, England. [Gatehouse, Peter] Royal Brompton Hosp, CMR Dept, Sydney St, London SW3 6NP, England. [Keenan, Kathryn E.] NIST, MS 818-03,325 Broadway, Boulder, CO 80305 USA. [Heslinga, Friso G.] Univ Western Australia, Sch Phys, Biomagnet Grp, 35 Stirling Hwy, Crawley, WA 6009, Australia. [Heslinga, Friso G.] Univ Twente, MIRA Inst Biomed Technol & Tech Med, NeuroImaging Grp, POB 217, NL-7500 AE Enschede, Netherlands. [Bruehl, Ruediger; Ittermann, Bernd] Phys Tech Bundesanstalt, Abbestr 2-12, D-10587 Berlin, Germany. [Prothmann, Marcel] Humboldt Univ, ECRC, Charite Med Fac, Cardiol, Berlin, Germany. [Prothmann, Marcel] HELIOS Clin, Berlin, Germany. [Graves, Martin J.] Cambridge Univ Hosp NHS Fdn Trust, Cambridge, England. [Eames, Richard J.] Imperial Coll London, Dept Phys, Prince Consort Rd, London SW7 2BB, England. [Torlasco, Camilla] Univ Milano Bicocca, Piazza Ateneo Nuovo 1, I-20100 Milan, Italy. [Benedetti, Giulia] Osped San Raffaele, Via Olgettina 60, I-20132 Milan, Italy. [Donovan, Jacqueline] Royal Brompton Hosp, Dept Clin Biochem, Sydney St, London SW3 6NP, England. [Boubertakh, Redha] Queen Mary Univ London, Barts & London Sch Med & Dent, Cardiovasc Biomed Res Unit, London, England. [Bathgate, Andrew; Royet, Celine; Pang, Wenjie] Resonance Hlth, 278 Stirling Highway, Claremont, WA 6010, Australia. [Nezafat, Reza] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Cardiovasc, Dept Med, Cardiol East Campus,Room E-SH455, Boston, MA 02215 USA. [Salerno, Michael] Univ Virginia Hlth Syst, 1215 Lee St,POB 800158, Charlottesville, VA 22908 USA. [Kellman, Peter] NHLBI, NIH, 10 Ctr Dr,Bldg 10,Room B1D416,MSC1061, Bethesda, MD 20892 USA. [Moon, James C.] UCL, UCL Inst Cardiovasc Sci, Gower St, London WC1E 6BT, England. RP Moon, JC (reprint author), NIHR Univ Coll London Hosp Biomed Res Ctr, Maple House Suite,Tottenham Court Rd, London W1T 7DN, England.; Moon, JC (reprint author), St Bartholomews Hosp, Barts Heart Ctr, London EC1A 7BE, England.; Moon, JC (reprint author), UCL, UCL Inst Cardiovasc Sci, Gower St, London WC1E 6BT, England. EM j.moon@ucl.ac.uk OI Heslinga, Friso/0000-0002-8383-307X FU European Association of Cardiovascular Imaging (EACVI part of the ESC) Imaging Research Grant; UK National Institute of Health Research (NIHR) Biomedical Research Center (BRC) Cardiometabolic Research Grant at University College London (UCL) [BRC/199/JM/101320]; Barts Charity Research Grant [1107/2356/MRC0140]; National Institute for Health Research Rare Diseases Translational Research Collaboration (NIHR RD-TRC); NIHR UCL Hospitals Biomedical Research Center; UCL Hospital NIHR BRC at Barts Hospital; UCL Hospital Biomedical Research Unit at Barts Hospital; NIHR BRC award; NIHR Cardiovascular Biomedical Research Unit support at Royal Brompton Hospital London UK FX This project has been funded by a European Association of Cardiovascular Imaging (EACVI part of the ESC) Imaging Research Grant, a UK National Institute of Health Research (NIHR) Biomedical Research Center (BRC) Cardiometabolic Research Grant at University College London (UCL, #BRC/199/JM/101320), and a Barts Charity Research Grant (#1107/2356/MRC0140). G.C. is supported by the National Institute for Health Research Rare Diseases Translational Research Collaboration (NIHR RD-TRC) and by the NIHR UCL Hospitals Biomedical Research Center. J.C.M. is directly and indirectly supported by the UCL Hospitals NIHR BRC and Biomedical Research Unit at Barts Hospital respectively. This work was in part supported by an NIHR BRC award to Cambridge University Hospitals NHS Foundation Trust and NIHR Cardiovascular Biomedical Research Unit support at Royal Brompton Hospital London UK. NR 25 TC 1 Z9 1 U1 2 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 SEP 22 PY 2016 VL 18 AR 58 DI 10.1186/s12968-016-0280-z PG 20 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA EA2ZK UT WOS:000386466400001 PM 27660042 ER PT J AU Liu, CH Wang, ZX Sun, Y SanGiovanni, JP Chen, J AF Liu, Chi-Hsiu Wang, Zhongxiao Sun, Ye SanGiovanni, John Paul Chen, Jing TI Retinal expression of small non-coding RNAs in a murine model of proliferative retinopathy SO SCIENTIFIC REPORTS LA English DT Article ID SMALL NUCLEOLAR RNAS; ENDOTHELIAL GROWTH-FACTOR; DIABETIC-RETINOPATHY; MICRORNA REGULATION; MOUSE RETINA; OCULAR NEOVASCULARIZATION; MICROARRAY ANALYSIS; PRERIBOSOMAL RNA; GENE-EXPRESSION; MESSENGER-RNAS AB Ocular neovascularization is a leading cause of blindness in proliferative retinopathy. Small non-coding RNAs (sncRNAs) play critical roles in both vascular and neuronal development of the retina through post-transcriptional regulation of target gene expression. To identify the function and therapeutic potential of sncRNAs in retinopathy, we assessed the expression profile of retinal sncRNAs in a mouse model of oxygen-induced retinopathy (OIR) with pathologic proliferation of neovessels. Approximately 2% of all analyzed sncRNAs were significantly altered in OIR retinas compared with normoxic controls. Twenty three microRNAs with substantial up-or down-regulation were identified, including miR-351, -762, -210, 145, -155, -129-5p, -150, -203, and -375, which were further analyzed for their potential target genes in angiogenic, hypoxic, and immune response-related pathways. In addition, nineteen small nucleolar RNAs also revealed differential expression in OIR retinas compared with control retinas. A decrease of overall microRNA expression in OIR retinas was consistent with reduced microRNA processing enzyme Dicer, and increased expression of Alu element in OIR. Together, our findings elucidated a group of differentially expressed sncRNAs in a murine model of proliferative retinopathy. These sncRNAs may exert critical post-transcriptional regulatory roles in regulating pathological neovascularization in eye diseases. C1 [Liu, Chi-Hsiu; Wang, Zhongxiao; Sun, Ye; Chen, Jing] Harvard Med Sch, Boston Childrens Hosp, Dept Ophthalmol, Boston, MA 02115 USA. [SanGiovanni, John Paul] NIAAA, Sect Nutr Neurosci, Bethesda, MD 20892 USA. RP Chen, J (reprint author), Harvard Med Sch, Boston Childrens Hosp, Dept Ophthalmol, Boston, MA 02115 USA. EM jing.chen@childrens.harvard.edu FU NIH/NEI [R01 EY024963]; Blind Childrens Center; Boston Children's Hospital Ophthalmology Foundation; Boston Children's Hospital Pilot Award; Massachusetts Lions Eye Research Fund Inc.; Taiwan Ministry of Science and Technology Postdoctoral Research Abroad Fellowship [104-2917-I-564-026] FX We thank Dr. Lois E. H. Smith for helpful discussion, and Aimee M. Juan and Ricky Z. Cui for their excellent technical assistance. This work was supported by NIH/NEI (R01 EY024963), Blind Childrens Center, Boston Children's Hospital Ophthalmology Foundation, Boston Children's Hospital Pilot Award, Massachusetts Lions Eye Research Fund Inc. (to JC), and Taiwan Ministry of Science and Technology Postdoctoral Research Abroad Fellowship (#104-2917-I-564-026, to CHL). NR 66 TC 0 Z9 0 U1 2 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 SEP 22 PY 2016 VL 6 AR 33947 DI 10.1038/srep33947 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW5XT UT WOS:000383721700001 PM 27653551 ER PT J AU Sedlyarova, N Shamovsky, I Bharati, BK Epshtein, V Chen, JD Gottesman, S Schroeder, R Nudler, E AF Sedlyarova, Nadezda Shamovsky, Ilya Bharati, Binod K. Epshtein, Vitaly Chen, Jiandong Gottesman, Susan Schroeder, Renee Nudler, Evgeny TI sRNA-Mediated Control of Transcription Termination in E-coli SO CELL LA English DT Article ID GENERAL STRESS-RESPONSE; RIBOSWITCH CONTROL; FACTOR-RHO; RPOS TRANSLATION; HFQ; BACTERIA; EXPRESSION; DNA; SALMONELLA; METABOLISM AB Bacterial small RNAs (sRNAs) have been implicated in various aspects of post-transcriptional gene regulation. Here, we demonstrate that sRNAs also act at the level of transcription termination. We use the rpoS gene, which encodes a general stress sigma factor sigma(S), as a model system, and show that sRNAs DsrA, ArcZ, and RprA bind the rpoS 5'UTR to suppress premature Rho-dependent transcription termination, both in vitro and in vivo. sRNA-mediated antitermination markedly stimulates transcription of rpoS during the transition to the stationary phase of growth, thereby facilitating a rapid adjustment of bacteria to global metabolic changes. Next generation RNA sequencing and bioinformatic analysis indicate that Rho functions as a global "attenuator'' of transcription, acting at the 5 ' UTR of hundreds of bacterial genes, and that its suppression by sRNAs is a widespread mode of bacterial gene regulation. C1 [Sedlyarova, Nadezda; Schroeder, Renee] Univ Vienna, Max F Perutz Labs, Dept Biochem & Cellbiol, Dr Bohrgasse 9-5, A-1030 Vienna, Austria. [Sedlyarova, Nadezda; Shamovsky, Ilya; Bharati, Binod K.; Epshtein, Vitaly; Nudler, Evgeny] NYU, Sch Med, Dept Mol Pharmacol & Biochem, New York, NY 10016 USA. [Chen, Jiandong; Gottesman, Susan] NCI, Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Nudler, Evgeny] NYU, Sch Med, Howard Hughes Med Inst, New York, NY 10016 USA. RP Nudler, E (reprint author), NYU, Sch Med, Dept Mol Pharmacol & Biochem, 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 NIH [R01 GM107329]; Howard Hughes Medical Institute; Austrian Science Fund FWF [I538-B12, F4301, F4308]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX We thank the Vienna BioCenter Core Facilities (VBCF) for NGS. This work was supported by the NIH grant R01 GM107329 and by the Howard Hughes Medical Institute (E.N.) and by the Austrian Science Fund FWF Grants I538-B12, F4301 and F4308 (R.S.). S.G. and J.C. were supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 58 TC 0 Z9 0 U1 13 U2 13 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 SEP 22 PY 2016 VL 167 IS 1 BP 111 EP + DI 10.1016/j.cell.2016.09.004 PG 24 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EA1GW UT WOS:000386341500018 PM 27662085 ER PT J AU Roberts, JN Graham, BS Karron, RA Munoz, FM Falsey, AR Anderson, LJ Marshall, V Kim, S Beeler, JA AF Roberts, Jeffrey N. Graham, Barney S. Karron, Ruth A. Munoz, Flor M. Falsey, Ann R. Anderson, Larry J. Marshall, V. Kim, Sonnie Beeler, Judy A. TI Challenges and opportunities in RSV vaccine development: Meeting report from FDA/NIH workshop SO VACCINE LA English DT Article DE RSV; Vaccination; Infants; Elderly; Maternal immunization; Vaccine-enhanced illness; Animal models; Subunit vaccine; Vaccine vector; Neutralization; Bronchitis; Wheezing; Human challenge; Clinical trials ID RESPIRATORY SYNCYTIAL VIRUS; IMMUNE GLOBULIN; UNITED-STATES; INFECTION; INFANTS; DISEASE; ADULTS; RISK; PREGNANCY; CHILDREN AB Respiratory syncytial virus (RSV) is the most common cause of serious acute lower respiratory illness in infants and young children and a significant cause of disease burden in the elderly and immunocompromised. There are no licensed RSV vaccines to address this significant public health need. While advances in vaccine technologies have led to a recent resurgence in RSV vaccine development, the immune correlates of protection against RSV and the immunology of vaccine-associated enhanced respiratory disease (ERD) remain poorly understood. FDA's Center for Biologics Evaluation and Research (CBER) and NIH's National Institute of Allergy and Infectious Diseases (NIAID) organized and co-sponsored an RSV Vaccines Workshop in Bethesda, Maryland on June 1 and 2, 2015. The goal of the conference was to convene scientists, regulators, and industry stakeholders to discuss approaches to RSV vaccine development within the context of three target populations - infants and children, pregnant women, and individuals >60 years of age. The agenda included topics related to RSV vaccine development in general, as well as considerations specific to each target population, such as clinical and serological endpoints. The meeting focused on vaccine development for high income countries (HIC), because issues relevant to vaccine development for low and middle income countries (LMIC) have been discussed in other forums. This manuscript summarizes the discussion of clinical, scientific, and regulatory perspectives, research gaps, and lessons learned. C1 [Roberts, Jeffrey N.; Marshall, V.; Beeler, Judy A.] FDA, CBER, OVRR, Silver Spring, MD 20993 USA. [Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Karron, Ruth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Ctr Immunizat Res, Baltimore, MD 21205 USA. [Munoz, Flor M.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Munoz, Flor M.] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. [Falsey, Ann R.] Univ Rochester, Rochester Gen Hosp, Dept Med, Div Infect Dis, Rochester, NY USA. [Anderson, Larry J.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA 30322 USA. [Anderson, Larry J.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Kim, Sonnie] NIAID, Div Microbiol & Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Roberts, JN (reprint author), FDA, CBER, OVRR, Silver Spring, MD 20993 USA. EM jeff.roberts@fda.hhs.gov FU Division of Microbiology and Infectious Diseases (DMID) at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH); DMID FX The Division of Microbiology and Infectious Diseases (DMID) at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH) is supporting a wide range of basic, preclinical and clinical research activities through grants and several contracts to develop RSV vaccines and therapeutics. In addition, DMID has developed reagent resources in the Biodefense and Emerging Infections (BEI) repository, preclinical contract services to allow researchers to perform gap analysis of their products, process development, cGMP production of compounds, animal model efficacy testing, assay development, and GLP toxicology testing.; DMID has awarded contracts for the Vaccine and Treatment Evaluation Units (VTEUs), the Respiratory Pathogens Research Centers (RPRC), and the Phase 1 Therapeutics Unit. The VTEUs perform phase 1, 2 safety and immunogenicity and phase 4 immunogenicity and efficacy trials as well as epidemiologic studies in a wide range of populations, including healthy adults, pregnant women, pediatric and the elderly. VTEU supports the evaluation of novel vaccines, therapeutics and delivery systems; it is also currently supporting the development of T cell and B cell assays for the detection of active and past RSV infection. NR 39 TC 3 Z9 3 U1 8 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD SEP 22 PY 2016 VL 34 IS 41 BP 4843 EP 4849 DI 10.1016/j.vaccine.2016.07.057 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DY1LY UT WOS:000384857700001 PM 27566900 ER PT J AU Connelly, CM Moon, MH Schneekloth, JS AF Connelly, Colleen M. Moon, Michelle H. Schneekloth, John S., Jr. TI The Emerging Role of RNA as a Therapeutic Target for Small Molecules SO CELL CHEMICAL BIOLOGY LA English DT Review ID HEPATITIS-C VIRUS; MYOTONIC-DYSTROPHY TYPE-1; RIBOSOME ENTRY SITE; BIOACTIVE SMALL MOLECULES; DESIGNED SMALL MOLECULES; MICRORNA MIR-21 FUNCTION; BINDING SMALL MOLECULES; PRE-MESSENGER-RNA; STEM-LOOP RNA; GENE-EXPRESSION AB Recent advances in understanding different RNAs and unique features of their biology have revealed a wealth of information. However, approaches to identify small molecules that target these newly discovered regulatory elements have been lacking. The application of new biochemical screening and design-based technologies, coupled with a resurgence of interest in phenotypic screening, has resulted in several compelling successes in targeting RNA. A number of recent advances suggest that achieving the long-standing goal of developing drug-like, biologically active small molecules that target RNA is possible. This review highlights advances and successes in approaches to targeting RNA with diverse small molecules, and the potential for these technologies to pave the way to new types of RNA-targeted therapeutics. C1 [Connelly, Colleen M.; Moon, Michelle H.; Schneekloth, John S., Jr.] NCI, Biol Chem Lab, Frederick, MD 21702 USA. RP Schneekloth, JS (reprint author), NCI, Biol Chem Lab, Frederick, MD 21702 USA. EM schneeklothjs@mail.nih.gov FU Intramural Research Program of the NIH; Center for Cancer Research; National Cancer Institute, NIH [1 ZIA BC011585 02] FX This work was supported by the Intramural Research Program of the NIH, the Center for Cancer Research, and the National Cancer Institute, NIH (1 ZIA BC011585 02). NR 105 TC 2 Z9 2 U1 12 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2451-9448 J9 CELL CHEM BIOL JI Cell Chem. Biol. PD SEP 22 PY 2016 VL 23 IS 9 BP 1077 EP 1090 DI 10.1016/j.chembiol.2016.05.021 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DX9RA UT WOS:000384731600009 PM 27593111 ER PT J AU Woo, HJ Yu, CG Kumar, K Gold, B Reifman, J AF Woo, Hyung Jun Yu, Chenggang Kumar, Kamal Gold, Bert Reifman, Jaques TI Genotype distribution-based inference of collective effects in genome-wide association studies: insights to age-related macular degeneration disease mechanism (vol 17, pg 695, 2016) SO BMC GENOMICS LA English DT Correction C1 [Woo, Hyung Jun; Yu, Chenggang; Kumar, Kamal; Reifman, Jaques] US Army Med Res & Mat Command, Telemed & Adv Technol Res Ctr, Biotechnol High Performance Comp Software Applica, Ft Detrick, MD USA. [Gold, Bert] NCI, Lab Genom Div, Frederick, MD 21701 USA. RP Reifman, J (reprint author), US Army Med Res & Mat Command, Telemed & Adv Technol Res Ctr, Biotechnol High Performance Comp Software Applica, Ft Detrick, MD USA. EM jaques.reifman.civ@mail.mil NR 1 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 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD SEP 22 PY 2016 VL 17 DI 10.1186/s12864-016-3095-2 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DX4OP UT WOS:000384361300001 ER PT J AU Lee, MK Hong, Y Kim, SY London, SJ Kim, WJ AF Lee, Mi Kyeong Hong, Yoonki Kim, Sun-Young London, Stephanie J. Kim, Woo Jin TI DNA methylation and smoking in Korean adults: epigenome-wide association study SO CLINICAL EPIGENETICS LA English DT Article DE DNA methylation; Smoking; Epigenome-wide association study; Cotinine; Duration of smoking cessation; Gene expression ID SELF-REPORTED SMOKING; HYDROCARBON RECEPTOR REPRESSOR; CIGARETTE-SMOKING; HUMAN GENOME; ANALYSIS PIPELINES; LUNG-CANCER; BIOMARKER; DISEASE; BLOOD; LOCI AB Background: Exposure to cigarette smoking can increase the risk of cancers and cardiovascular and pulmonary diseases. However, the underlying mechanisms of how smoking contributes to disease risks are not completely understood. Epigenome-wide association studies (EWASs), mostly in non-Asian populations, have been conducted to identify smoking-associated methylation alterations at individual probes. There are few data on regional methylation changes in relation to smoking. Few data link differential methylation in blood to differential gene expression in lung tissue. Results: We identified 108 significant (false discovery rate (FDR) < 0.05) differentially methylated probes (DMPs) and 87 significant differentially methylated regions (DMRs) (multiple-testing corrected p < 0.01) in current compared to never smokers from our EWAS of cotinine-validated smoking in blood DNA from a Korean chronic obstructive pulmonary disease cohort (n = 100 including 31 current, 30 former, and 39 never smokers) using Illumina HumanMethylation450 BeadChip. Of the 108 DMPs (FDR < 0.05), nine CpGs were statistically significant based on Bonferroni correction and 93 were novel including five that mapped to loci previously associated with smoking. Of the 87 DMRs, 66 were mapped to novel loci. Methylation correlated with urine cotinine levels in current smokers at six DMPs, with pack-years in current smokers at six DMPs, and with duration of smoking cessation in former smokers at eight DMPs. Of the 143 genes to which our significant DMPs or DMRs annotated, gene expression levels at 20 genes were associated with pack-years in lung tissue transcriptome data of smokers (Asan Biobank, n = 188). Conclusions: Our study of differential methylation in Koreans confirmed previous findings from non-Asian populations and revealed novel loci in relation to smoking. Smoking-related differential methylation in blood is associated with gene expression in lung tissue, an important target of adverse health effects of smoking, supporting the potential functional importance of methylation in smoking-related disease. C1 [Lee, Mi Kyeong; London, Stephanie J.] NIEHS, Epidemiol Branch, Dept Hlth & Human Serv, NIH, Durham, NC 27709 USA. [Lee, Mi Kyeong] Kangwon Natl Univ, Inst Med Sci, Chuncheon Si 24341, Gangwon Do, South Korea. [Lee, Mi Kyeong; Hong, Yoonki; Kim, Woo Jin] Kangwon Natl Univ, Sch Med, Kangwon Natl Univ Hosp, Dept Internal Med, Chuncheon Si 19300, Gangwon Do, South Korea. [Lee, Mi Kyeong; Hong, Yoonki; Kim, Woo Jin] Kangwon Natl Univ, Sch Med, Kangwon Natl Univ Hosp, Ctr Environm Hlth, Chuncheon Si 19300, Gangwon Do, South Korea. [Kim, Sun-Young] Seoul Natl Univ, Inst Hlth & Environm, Seoul 08826, South Korea. RP London, SJ (reprint author), NIEHS, Epidemiol Branch, Dept Hlth & Human Serv, NIH, Durham, NC 27709 USA.; Kim, WJ (reprint author), Kangwon Natl Univ, Sch Med, Kangwon Natl Univ Hosp, Dept Internal Med, Chuncheon Si 19300, Gangwon Do, South Korea.; Kim, WJ (reprint author), Kangwon Natl Univ, Sch Med, Kangwon Natl Univ Hosp, Ctr Environm Hlth, Chuncheon Si 19300, Gangwon Do, South Korea. EM london2@niehs.nih.gov; pulmo2@kangwon.ac.kr OI Lee, Mi Kyeong/0000-0002-3036-3684; London, Stephanie/0000-0003-4911-5290 FU Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Science, ICT and Future Planning [2013R1A1A1057961]; Ministry of Education, Science and Technology [NRF-355-2011-1-E00060, NRF-2012R1A6A3A01039450]; Ministry of Education [2013R1A6A3A04059017]; Environmental Health Center - Ministry of Environment, Republic of Korea; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (NIEHS) FX This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (2013R1A1A1057961), the Ministry of Education, Science and Technology (NRF-355-2011-1-E00060, NRF-2012R1A6A3A01039450), the Ministry of Education (2013R1A6A3A04059017), and grants from the Environmental Health Center funded by the Ministry of Environment, Republic of Korea. This study was also supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (NIEHS). NR 59 TC 0 Z9 0 U1 4 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1868-7083 J9 CLIN EPIGENETICS JI Clin. Epigenetics PD SEP 22 PY 2016 VL 8 AR 103 DI 10.1186/s13148-016-0266-6 PG 17 WC Oncology SC Oncology GA DX6CU UT WOS:000384471400002 PM 27688819 ER PT J AU Papanicolaou, A Schetelig, MF Arensburger, P Atkinson, PW Benoit, JB Bourtzis, K Castanera, P Cavanaugh, JP Chao, H Childers, C Curril, I Dinh, H Doddapaneni, H Dolan, A Dugan, S Friedrich, M Gasperi, G Geib, S Georgakilas, G Gibbs, RA Giers, SD Gomulski, LM Gonzalez-Guzman, M Guillem-Amat, A Han, Y Hatzigeorgiou, AG Hernandez-Crespo, P Hughes, DST Jones, JW Karagkouni, D Koskinioti, P Lee, SL Malacrida, AR Manni, M Mathiopoulos, K Meccariello, A Murali, SC Murphy, TD Muzny, DM Oberhofer, G Ortego, F Paraskevopoulou, MD Poelchau, M Qu, JX Reczko, M Robertson, HM Rosendale, AJ Rosselot, AE Saccone, G Salvemini, M Savini, G Schreiner, P Scolari, F Siciliano, P Sim, SB Tsiamis, G Urena, E Vlachos, IS Werren, JH Wimmer, EA Worley, KC Zacharopoulou, A Richards, S Handler, AM AF Papanicolaou, Alexie Schetelig, Marc F. Arensburger, Peter Atkinson, Peter W. Benoit, Joshua B. Bourtzis, Kostas Castanera, Pedro Cavanaugh, John P. Chao, Hsu Childers, Christopher Curril, Ingrid Huyen Dinh Doddapaneni, HarshaVardhan Dolan, Amanda Dugan, Shannon Friedrich, Markus Gasperi, Giuliano Geib, Scott Georgakilas, Georgios Gibbs, Richard A. Giers, Sarah D. Gomulski, Ludvik M. Gonzalez-Guzman, Miguel Guillem-Amat, Ana Han, Yi Hatzigeorgiou, Artemis G. Hernandez-Crespo, Pedro Hughes, Daniel S. T. Jones, Jeffery W. Karagkouni, Dimitra Koskinioti, Panagiota Lee, Sandra L. Malacrida, Anna R. Manni, Mose Mathiopoulos, Kostas Meccariello, Angela Murali, Shwetha C. Murphy, Terence D. Muzny, Donna M. Oberhofer, Georg Ortego, Felix Paraskevopoulou, Maria D. Poelchau, Monica Qu, Jiaxin Reczko, Martin Robertson, Hugh M. Rosendale, Andrew J. Rosselot, Andrew E. Saccone, Giuseppe Salvemini, Marco Savini, Grazia Schreiner, Patrick Scolari, Francesca Siciliano, Paolo Sim, Sheina B. Tsiamis, George Urena, Enric Vlachos, Ioannis S. Werren, John H. Wimmer, Ernst A. Worley, Kim C. Zacharopoulou, Antigone Richards, Stephen Handler, Alfred M. TI The whole genome sequence of the Mediterranean fruit fly, Ceratitis capitata (Wiedemann), reveals insights into the biology and adaptive evolution of a highly invasive pest species SO GENOME BIOLOGY LA English DT Article DE Medfly genome; Tephritid genomics; Insect orthology; Gene family evolution; Chromosomal synteny; Insect invasiveness; Insect adaptation; Medfly integrated pest management (IPM) ID GERM-LINE TRANSFORMATION; BACTERIA-BINDING PROTEIN; SEMINAL FLUID PROTEINS; PROGRAMMED CELL-DEATH; DROSOPHILA-MELANOGASTER; ANOPHELES-GAMBIAE; TRANSPOSABLE ELEMENT; DIPTERA TEPHRITIDAE; MOLECULAR EVOLUTION; ANASTREPHA-SUSPENSA AB Background: The Mediterranean fruit fly (medfly), Ceratitis capitata, is a major destructive insect pest due to its broad host range, which includes hundreds of fruits and vegetables. It exhibits a unique ability to invade and adapt to ecological niches throughout tropical and subtropical regions of the world, though medfly infestations have been prevented and controlled by the sterile insect technique (SIT) as part of integrated pest management programs (IPMs). The genetic analysis and manipulation of medfly has been subject to intensive study in an effort to improve SIT efficacy and other aspects of IPM control. Results: The 479 Mb medfly genome is sequenced from adult flies from lines inbred for 20 generations. A high-quality assembly is achieved having a contig N50 of 45.7 kb and scaffold N50 of 4.06 Mb. In-depth curation of more than 1800 messenger RNAs shows specific gene expansions that can be related to invasiveness and host adaptation, including gene families for chemoreception, toxin and insecticide metabolism, cuticle proteins, opsins, and aquaporins. We identify genes relevant to IPM control, including those required to improve SIT. Conclusions: The medfly genome sequence provides critical insights into the biology of one of the most serious and widespread agricultural pests. This knowledge should significantly advance the means of controlling the size and invasive potential of medfly populations. Its close relationship to Drosophila, and other insect species important to agriculture and human health, will further comparative functional and structural studies of insect genomes that should broaden our understanding of gene family evolution. C1 [Papanicolaou, Alexie] Univ Western Sydney, Hawkesbury Inst Environm, Sydney, NSW, Australia. [Schetelig, Marc F.] Univ Giessen, Inst Insect Biotechnol, D-35394 Giessen, Germany. [Arensburger, Peter] Cal Poly Pomona, Dept Biol Sci, Pomona, CA 91768 USA. [Atkinson, Peter W.] Univ Calif Riverside, Dept Entomol, Riverside, CA 92521 USA. [Atkinson, Peter W.] Univ Calif Riverside, Ctr Dis Vector Res, Riverside, CA 92521 USA. [Atkinson, Peter W.; Schreiner, Patrick] Univ Calif Riverside, Interdept Grad Program Genet Genom & Bioinformat, Riverside, CA 92521 USA. [Benoit, Joshua B.; Cavanaugh, John P.; Rosendale, Andrew J.; Rosselot, Andrew E.] Univ Cincinnati, Dept Biol Sci, Cincinnati, OH 45221 USA. [Bourtzis, Kostas] Joint FAO IAEA Programme Nucl Tech Food & Agr, Insect Pest Control Lab, Vienna, Austria. [Bourtzis, Kostas; Tsiamis, George] Univ Patras, Dept Environm & Nat Resources Management, Agrinion, Greece. [Castanera, Pedro; Gonzalez-Guzman, Miguel; Guillem-Amat, Ana; Hernandez-Crespo, Pedro; Ortego, Felix; Urena, Enric] CSIC, Ctr Invest Biol, Dept Environm Biol, Madrid 28040, Spain. [Chao, Hsu; Huyen Dinh; Doddapaneni, HarshaVardhan; Dugan, Shannon; Gibbs, Richard A.; Han, Yi; Hughes, Daniel S. T.; Lee, Sandra L.; Murali, Shwetha C.; Muzny, Donna M.; Qu, Jiaxin; Worley, Kim C.; Richards, Stephen] Baylor Coll Med, Human Genome Sequencing Ctr, Dept Human & Mol Genet, Houston, TX 77030 USA. [Childers, Christopher; Poelchau, Monica] USDA, Natl Agr Lib, Beltsville, MD 20705 USA. [Curril, Ingrid; Oberhofer, Georg; Wimmer, Ernst A.] Univ Gottingen, Johann Friedrich Blumenbach Inst Zool & Anthropol, D-37077 Gottingen, Germany. [Dolan, Amanda; Werren, John H.] Univ Rochester, Dept Biol, Rochester, NY 14627 USA. [Friedrich, Markus] Wayne State Univ, Dept Biol Sci, Detroit, MI 48202 USA. [Gasperi, Giuliano; Gomulski, Ludvik M.; Malacrida, Anna R.; Manni, Mose; Savini, Grazia; Scolari, Francesca; Siciliano, Paolo] Univ Pavia, Dept Biol & Biotechnol, I-27100 Pavia, Italy. [Geib, Scott; Sim, Sheina B.] ARS, USDA, Pacific Basin Agr Res Ctr, Hilo, HI 96720 USA. [Georgakilas, Georgios; Hatzigeorgiou, Artemis G.; Karagkouni, Dimitra; Paraskevopoulou, Maria D.; Vlachos, Ioannis S.] Univ Thessaly, Dept Elect & Comp Engn, DIANA Lab, Athens 11521, Greece. [Georgakilas, Georgios; Hatzigeorgiou, Artemis G.; Karagkouni, Dimitra; Paraskevopoulou, Maria D.; Vlachos, Ioannis S.] Hellenic Pasteur Inst, Athens 11521, Greece. [Giers, Sarah D.; Robertson, Hugh M.] Univ Illinois, Dept Entomol, Urbana, IL 61801 USA. [Jones, Jeffery W.] Oakland Univ, Dept Biol Sci, Rochester, MI 48309 USA. [Koskinioti, Panagiota; Mathiopoulos, Kostas] Univ Thessaly, Dept Biochem & Biotechnol, Larisa, Greece. [Meccariello, Angela; Saccone, Giuseppe; Salvemini, Marco] Univ Naples Federico II, Dept Biol, I-80126 Naples, Italy. [Murphy, Terence D.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. [Reczko, Martin] Biomed Sci Res Ctr Alexander Fleming, Inst Mol Biol & Genet, Vari, Greece. [Zacharopoulou, Antigone] Univ Patras, Dept Biol, Patras, Greece. [Handler, Alfred M.] ARS, USDA, Ctr Med Agr & Vet Entomol, 1700 SW 23rd Dr, Gainesville, FL 32608 USA. RP Handler, AM (reprint author), ARS, USDA, Ctr Med Agr & Vet Entomol, 1700 SW 23rd Dr, Gainesville, FL 32608 USA. EM al.handler@ars.usda.gov RI Pedro, Hernandez-Crespo/H-9937-2015; Papanicolaou, Alexie/A-1618-2011; Gonzalez-Guzman, Miguel/F-2318-2014; OI Pedro, Hernandez-Crespo/0000-0001-9350-3640; Papanicolaou, Alexie/0000-0002-3635-6848; Gonzalez-Guzman, Miguel/0000-0003-1000-9255; Schetelig, Marc F./0000-0002-9217-394X FU U.S. Department of Agriculture (USDA); Agricultural Research Service (ARS); Animal and Plant Health Inspection Service (APHIS); National Institute of Food and Agriculture (NIFA)-Biotechnology Risk Assessment Grants Program [2011-39211-30769]; National Institutes of Health (NIH)-National Human Genome Research Institute (NHGRI) [U54 HG003273]; NIH Intramural Research Program, National Library of Medicine; USDA-National Agricultural Library (NAL); MINECO, Spain [AGL2013-42632-R]; European Social Fund; National Strategic Reference Framework-THALES [MIS375869]; U.S. National Science Foundation [DEB 1257053]; USDA-NIFA [2016-67012-24652]; L.R. Campania [5/02]; FAO/IAEA [16966]; Cariplo IMPROVE; Emmy Noether program, DFG [SCHE 1833/1-1]; LOEWE Center for Insect Biotechnology & Bioresources grant of the Hessen State Ministry of Higher Education, Research and the Arts (HMWK), Germany; USDA-NIFA-Biotechnology Risk Assessment Grants Program [2015-33522-24094] FX Support of this project was provided by the U.S. Department of Agriculture (USDA), Agricultural Research Service (ARS), Animal and Plant Health Inspection Service (APHIS), and National Institute of Food and Agriculture (NIFA)-Biotechnology Risk Assessment Grants Program (grant no. 2011-39211-30769 to AMH) for funding the initial phase of this project, and to the National Institutes of Health (NIH)-National Human Genome Research Institute (NHGRI) for funding the medfly genome sequencing, assembly, and Maker 2.0 automated annotation as part of the i5K 30 genome pilot project (grant no. U54 HG003273 to RAG). The NIH Intramural Research Program, National Library of Medicine funded the NCBI Gnomon annotation and the USDA-National Agricultural Library (NAL) provided support for the WebApollo curation website. Support was provided for: toxin metabolism and insecticide resistance gene studies from MINECO, Spain (AGL2013-42632-R to FO and PH-C); microRNAs, horizontal gene transfer, and bacterial contaminant studies from the European Social Fund and National Strategic Reference Framework-THALES (MIS375869 to KB, GT, AGH, and KM) and the U.S. National Science Foundation (DEB 1257053 to JHW); cuticle protein gene studies from USDA-NIFA (grant no. 2016-67012-24652 to AJR); sex-determination studies from L.R. Campania (grant 5/02, 2008 to GS); male reproduction and sexual differentiation studies from the FAO/IAEA (Technical Contract No.: 16966 to GGa) and Cariplo IMPROVE (to FS); and programmed cell death gene studies and genomic data analysis (to MFS) from the Emmy Noether program, DFG (SCHE 1833/1-1) and the LOEWE Center for Insect Biotechnology & Bioresources grant of the Hessen State Ministry of Higher Education, Research and the Arts (HMWK), Germany and from the USDA-NIFA-Biotechnology Risk Assessment Grants Program (grant no. 2015-33522-24094 to AMH). NR 225 TC 5 Z9 5 U1 30 U2 30 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1474-760X J9 GENOME BIOL JI Genome Biol. PD SEP 22 PY 2016 VL 17 AR 192 DI 10.1186/s13059-016-1049-2 PG 31 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DX5ZR UT WOS:000384461900002 PM 27659211 ER PT J AU Albaugh, A Boateng, HA Bradshaw, RT Demerdash, ON Dziedzic, J Mao, YZ Margul, DT Swails, J Zeng, Q Case, DA Eastman, P Wang, LP Essex, JW Head-Gordon, M Pande, VS Ponder, JW Shao, YH Skylaris, CK Todorov, IT Tuckerman, ME Head-Gordon, T AF Albaugh, Alex Boateng, Henry A. Bradshaw, Richard T. Demerdash, Omar N. Dziedzic, Jacek Mao, Yuezhi Margul, Daniel T. Swails, Jason Zeng, Qiao Case, David A. Eastman, Peter Wang, Lee-Ping Essex, Jonathan W. Head-Gordon, Martin Pande, Vijay S. Ponder, Jay W. Shao, Yihan Skylaris, Chris-Kriton Todorov, Ilian T. Tuckerman, Mark E. Head-Gordon, Teresa TI Advanced Potential Energy Surfaces for Molecular Simulation SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID POLARIZABLE FORCE-FIELD; PARTICLE MESH EWALD; INITIO QUANTUM-CHEMISTRY; GENERALIZED GRADIENT APPROXIMATION; CLASSICAL DRUDE OSCILLATORS; DENSITY-FUNCTIONAL THEORY; MULTIPOLE WATER MODEL; BASIS-SET LIMIT; NONCOVALENT INTERACTIONS; DECOMPOSITION ANALYSIS AB Advanced potential energy surfaces are defined as theoretical models that explicitly include many-body effects that transcend the standard fixed-charge, pairwise-additive paradigm typically used in molecular simulation. However, several factors relating to their software implementation have precluded their widespread use in condensed-phase simulations: the computational cost of the theoretical models, a paucity of approximate Models and algorithmic improvements that can ameliorate their cost, underdeveloped interfaces and limited dissemination in computational code bases that are widely used in the computational chemistry community, and software implementations that have not kept pace with modern high-performance computing (HPC). architectures, such as multicore CPUs and modern graphics processing units (CPUs). In this Feature Article we review recent progress made in these areas, including well-defined polarization approximations and new multipole electrostatic formulations, novel methods for solving the mutual polarization equations and increasing the MD time step, combining linear-scaling electronic structure methods with new QM/MM methods that account for mutual polarization between the two regions, and the greatly improved software deployment of these models and methods onto GPU and CPU hardware-platforms. We have now approached an era where multipole-based polarizable force fields can be routinely used to obtain computational results comparable to state-of-the-art density functional theory-while reaching sampling statistics that are acceptable when compared to that obtained from simpler fixed partial charge force fields. C1 [Bradshaw, Richard T.; Dziedzic, Jacek; Essex, Jonathan W.; Skylaris, Chris-Kriton] Univ Southampton, Sch Chem, Southampton SO17 1BJ, Hants, England. [Demerdash, Omar N.; Mao, Yuezhi; Head-Gordon, Martin; Head-Gordon, Teresa] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA. [Albaugh, Alex; Head-Gordon, Teresa] Univ Calif Berkeley, Dept Chem & Biomol Engn, Berkeley, CA 94720 USA. [Head-Gordon, Teresa] Univ Calif Berkeley, Dept Bioengn, Berkeley, CA 94720 USA. [Dziedzic, Jacek] Gdansk Univ Technol, Fac Appl Phys & Math, PL-80223 Gdansk, Poland. [Margul, Daniel T.; Tuckerman, Mark E.] NYU, Dept Chem, New York, NY 10003 USA. [Tuckerman, Mark E.] NYU, Courant Inst Math Sci, New York, NY 10003 USA. [Zeng, Qiao] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Boateng, Henry A.] Bates Coll, Dept Math, 2 Andrews Rd, Lewiston, ME 04240 USA. [Swails, Jason; Case, David A.] Rutgers State Univ, Dept Chem & Chem Biol, Piscataway, NJ 08854 USA. [Eastman, Peter; Wang, Lee-Ping; Pande, Vijay S.] Stanford Univ, Dept Chem, Stanford, CA 94305 USA. [Ponder, Jay W.] Washington Univ, Dept Chem, St Louis, MO 63130 USA. [Shao, Yihan] Q Chem Inc, 6601 Owens Dr,Suite 105, Pleasanton, CA 94588 USA. [Todorov, Ilian T.] STFC Daresbury Lab, Keckwick Lane, Warrington WA4 4AD, Cheshire, England. [Tuckerman, Mark E.] NYU, Ctr Computat Chem, NYU ECNU, Shanghai 200062, Shanghai, Peoples R China. RP Head-Gordon, T (reprint author), Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA.; Head-Gordon, T (reprint author), Univ Calif Berkeley, Dept Chem & Biomol Engn, Berkeley, CA 94720 USA.; Head-Gordon, T (reprint author), Univ Calif Berkeley, Dept Bioengn, Berkeley, CA 94720 USA. EM thg@berkeley.edu RI Wang, Lee-Ping/P-8597-2016; Dziedzic, Jacek/F-3752-2012; OI Wang, Lee-Ping/0000-0003-3072-9946; Boateng, Henry/0000-0002-1066-149X FU National Science Foundation; National Institutes of Health [R01-GM106137]; Office of Science of the U.S. Department of Energy [DE-AC02-05CH11231]; Engineering and Physical Sciences Research Council (EPSRC) UK [EP/K039156/1, EP/ J015059/1, EP/K040529/1]; UKCP consortium (EPSRC) [EP/K013556/1]; [CHE-1265731]; [CHE-1363320]; [CHE-1363342]; [CHE-1265704]; [CHE-1265712] FX We thank the Edinburgh team, Weronika Filinger, Mario Antonioletti, Lorna Smith, Arno Proeme, and Neil Chue Hong, for their help during the last 3 years in regards to early improvements in OpenMP parallelization of TINKER and issues concerning software sustainability. We also thank Jean-Phillip Piquemal for early results on the new TINKER-HP distributed memory code. The U.S. researchers thank the National Science Foundation for support of this work: A.A., O.N.D., Y.M., M.H.-G., and T.H.-G. acknowledge Grant CHE-1265731 for the software developed in TINKER in this project. T.H.-G. acknowledges CHE-1363320 for the MBE work and the iEL/SCF method. M.H.-G. acknowledges CHE-1363342 for the EDA work. M.E.T. and D.T.M. acknowledge CHE-1265889 for software developed in TINKER D.A.C. and J.S. acknowledge CHE-1265704, and J.W.P. acknowledges Grant CHE-1265712 for support of work on TINKER J.W.P. also acknowledges National Institutes of Health Grant R01-GM106137 for funding of the SAMPL4 results. This research used resources of the National Energy Research Scientific Computing Center, a DOE Office of Science User Facility supported by the Office of Science of the U.S. Department of Energy under Contract DE-AC02-05CH11231. The UK investigators thank the Engineering and Physical Sciences Research Council (EPSRC) UK: J.W.E., C.-K.S., J.D., and R.T.B. (EP/K039156/1); C.-K.S. and J.D. (EP/ J015059/1); and H.A.B. and I.T.T. (EP/K040529/1). J.D. and C.-K.S. would like to acknowledge the UKCP consortium (EPSRC Grant EP/K013556/1) for access to the ARCHER national supercomputer, and for access to the IRIDIS High Performance Computing Facility of the University of Southampton. J.D. acknowledges the use of supercomputing resources at the TASK Computer Centre in Gdansk, Poland. NR 173 TC 5 Z9 5 U1 42 U2 42 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD SEP 22 PY 2016 VL 120 IS 37 BP 9811 EP 9832 DI 10.1021/acs.jpcb.6b06414 PG 22 WC Chemistry, Physical SC Chemistry GA DX0EH UT WOS:000384034100001 PM 27513316 ER PT J AU Flynn, JD Haas, BL Biteen, JS AF Flynn, Jessica D. Haas, Beth L. Biteen, Julie S. TI Plasmon-Enhanced Fluorescence from Single Proteins in Living Bacteria SO JOURNAL OF PHYSICAL CHEMISTRY C LA English DT Article ID VIRULENCE GENE-EXPRESSION; VIBRIO-CHOLERAE; NANOSPHERE LITHOGRAPHY; GOLD NANORODS; LOCALIZATION; MICROSCOPY; REVEALS; NANOPARTICLES; MEMBRANES; TRACKING AB The sensitivity and resolution of single molecule fluorescence imaging in biology are mainly limited by two known weaknesses of fluorescent proteins: label brightness and photostability. In this work, we use patterned gold substrates to achieve plasmon-enhanced emission from intrinsically fluorescent proteins in living pathogenic bacteria cells. By coupling membrane-bound single fluorescent protein fusions to the virulence regulator TcpP in living Vibrio cholerae bacteria to extracellular gold nanotriangle arrays, we use plasmonics to improve our measurements of this important question in pathogenesis: how does V. cholerae produce its deadly toxin? Based on a simple experimental geometry, we observe a 1.3X enhancement in the rate of emission and a 1.4X enhancement in the number of photons detected prior to photobleaching. Furthermore, by enhancing both the rate of emission and the total number of photons detected from single-molecule fluorescent probes in live cells, we show that plasmon-enhanced fluorescence is a biocompatible, generalizable path to directly improve the resolution and trajectory lengths of single molecules in live cells. C1 [Flynn, Jessica D.; Haas, Beth L.; Biteen, Julie S.] Univ Michigan, Dept Chem, Ann Arbor, MI 48109 USA. [Flynn, Jessica D.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Flynn, Jessica D.] NHLBI, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. [Haas, Beth L.] Misericordia Univ, Dallas, PA 18612 USA. RP Biteen, JS (reprint author), Univ Michigan, Dept Chem, Ann Arbor, MI 48109 USA. EM jsbiteen@umich.edu FU National Science Foundation CAREER award [CHE-1252322]; NSF Materials Research Science and Engineering Center (MRSEC) program [DMR-1120923] FX This work was funded in part through a National Science Foundation CAREER award (Grant CHE-1252322) to J.S.B. and by the NSF Materials Research Science and Engineering Center (MRSEC) program, Grant DMR-1120923. NR 29 TC 3 Z9 3 U1 30 U2 30 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1932-7447 J9 J PHYS CHEM C JI J. Phys. Chem. C PD SEP 22 PY 2016 VL 120 IS 37 SI SI BP 20512 EP 20517 DI 10.1021/acs.jpcc.5b08049 PG 6 WC Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA DX0EM UT WOS:000384034600003 ER PT J AU Tycko, R AF Tycko, Robert TI ALZHEIMER'S DISEASE Structure of aggregates revealed SO NATURE LA English DT Editorial Material ID ATOMIC-RESOLUTION STRUCTURE; A-BETA(42) AMYLOID FIBRILS; BETA; POLYMORPHISM; BRAIN C1 [Tycko, Robert] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov NR 10 TC 3 Z9 3 U1 48 U2 49 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 SEP 22 PY 2016 VL 537 IS 7621 BP 492 EP 493 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW3MO UT WOS:000383545900039 PM 27626376 ER PT J AU Eil, R Vodnala, SK Clever, D Klebanoff, CA Sukumar, M Pan, JH Palmer, DC Gros, A Yamamoto, TN Patel, SJ Guittard, GC Yu, ZY Carbonaro, V Okkenhaug, K Schrump, DS Linehan, WM Roychoudhuri, R Restifo, NP AF Eil, Robert Vodnala, Suman K. Clever, David Klebanoff, Christopher A. Sukumar, Madhusudhanan Pan, Jenny H. Palmer, Douglas C. Gros, Alena Yamamoto, Tori N. Patel, Shashank J. Guittard, Geoffrey C. Yu, Zhiya Carbonaro, Valentina Okkenhaug, Klaus Schrump, David S. Linehan, W. Marston Roychoudhuri, Rahul Restifo, Nicholas P. TI Ionic immune suppression within the tumour microenvironment limits T cell effector function SO NATURE LA English DT Article ID PHOSPHATASE 2A; CANCER-IMMUNOTHERAPY; CRITICAL REGULATOR; MODULATION; LYMPHOCYTES; POTASSIUM; CHANNELS; DIFFERENTIATION; QUANTIFICATION; PROLIFERATION AB Tumours progress despite being infiltrated by tumour-specific effector T cells(1). Tumours contain areas of cellular necrosis, which are associated with poor survival in a variety of cancers(2). Here, we show that necrosis releases intracellular potassium ions into the extracellular fluid of mouse and human tumours, causing profound suppression of T cell effector function. Elevation of the extracellular potassium concentration ([K+](e)) impairs T cell receptor (TCR)driven Akt-mTOR phosphorylation and effector programmes. Potassium-mediated suppression of Akt-mTOR signalling and T cell function is dependent upon the activity of the serine/threonine phosphatase PP2A(3,4). Although the suppressive effect mediated by elevated [K+](e) is independent of changes in plasma membrane potential (V-m), it requires an increase in intracellular potassium ([K+](i)). Accordingly, augmenting potassium efflux in tumour-specific T cells by overexpressing the potassium channel Kv(1.3) lowers [K+](i) and improves effector functions in vitro and in vivo and enhances tumour clearance and survival in melanoma-bearing mice. These results uncover an ionic checkpoint that blocks T cell function in tumours and identify potential new strategies for cancer immunotherapy. C1 [Eil, Robert; Vodnala, Suman K.; Clever, David; Klebanoff, Christopher A.; Sukumar, Madhusudhanan; Pan, Jenny H.; Palmer, Douglas C.; Gros, Alena; Yamamoto, Tori N.; Patel, Shashank J.; Guittard, Geoffrey C.; Yu, Zhiya; Schrump, David S.; Linehan, W. Marston; Restifo, Nicholas P.] NCI, NIH, Bethesda, MD 20892 USA. [Klebanoff, Christopher A.] Mem Sloan Kettering Canc Ctr, Ctr Cell Engn, New York, NY 10065 USA. [Klebanoff, Christopher A.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Carbonaro, Valentina; Okkenhaug, Klaus; Roychoudhuri, Rahul] Babraham Inst, Lab Lymphocyte Signalling & Dev, Cambridge CB22 3AT, England. [Eil, Robert] Oregon Hlth & Sci Univ, Dept Surg, Portland, OR 97239 USA. [Gros, Alena] Vall dHebron Univ Hosp, Vall dHebron Inst Oncol VHIO, C Natzaret 115-117, Barcelona 08035, Spain. RP Eil, R; Restifo, NP (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM eil@ohsu.edu; restifon@mail.nih.gov OI Gros, Alena/0000-0002-1207-1880; Guittard, Geoffrey/0000-0002-6061-8553; Okkenhaug, Klaus/0000-0002-9432-4051 FU NCI; Wellcome Trust/Royal Society [105663/Z/14/Z]; UK Biotechnology and Biological Sciences Research Council [BB/N007794/1] FX The research was supported by the Intramural Research Program of the NCI, Wellcome Trust/Royal Society grant 105663/Z/14/Z (R.R.) and UK Biotechnology and Biological Sciences Research Council grant BB/N007794/1 (R.R. and K.O.). We thank S. A. Rosenberg, K. Hanada and K. J. Swartz for their valuable discussions and intellectual input, A. Mixon and S. Farid for expertise with cell sorting and G. McMullen for expertise with mouse handling. NR 46 TC 11 Z9 11 U1 32 U2 35 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 SEP 22 PY 2016 VL 537 IS 7621 BP 539 EP + DI 10.1038/nature19364 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW3MO UT WOS:000383545900054 PM 27626381 ER PT J AU Meyerson, JR Chittori, S Merk, A Rao, P Han, TH Serpe, M Mayer, ML Subramaniam, S AF Meyerson, Joel R. Chittori, Sagar Merk, Alan Rao, Prashant Han, Tae Hee Serpe, Mihaela Mayer, Mark L. Subramaniam, Sriram TI Structural basis of kainate subtype glutamate receptor desensitization SO NATURE LA English DT Article ID LIGAND-BINDING DOMAIN; CRYO-EM; ELECTRON-MICROSCOPY; ATOMIC-RESOLUTION; CRYSTAL-STRUCTURES; AMPA; ACTIVATION; COMPLEXES; MUTATIONS; MECHANISM AB Glutamate receptors are ligand-gated tetrameric ion channels that mediate synaptic transmission in the central nervous system. They are instrumental in vertebrate cognition and their dysfunction underlies diverse diseases(1,2). In both the resting and desensitized states of AMPA and kainate receptor subtypes, the ion channels are closed, whereas the ligand-binding domains, which are physically coupled to the channels, adopt markedly different conformations(3-6). Without an atomic model for the desensitized state, it is not possible to address a central problem in receptor gating: how the resting and desensitized receptor states both display closed ion channels, although they have major differences in the quaternary structure of the ligand-binding domain. Here, by determining the structure of the kainate receptor GluK2 subtype in its desensitized state by cryo-electron microscopy (cryo-EM) at 3.8 angstrom resolution, we show that desensitization is characterized by the establishment of a ringlike structure in the ligand-binding domain layer of the receptor. Formation of this 'desensitization ring' is mediated by staggered helix contacts between adjacent subunits, which leads to a pseudo-four-fold symmetric arrangement of the ligand-binding domains, illustrating subtle changes in symmetry that are important for the gating mechanism. Disruption of the desensitization ring is probably the key switch that enables restoration of the receptor to its resting state, thereby completing the gating cycle. C1 [Meyerson, Joel R.; Chittori, Sagar; Merk, Alan; Rao, Prashant; Subramaniam, Sriram] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. [Chittori, Sagar; Mayer, Mark L.] NICHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. [Han, Tae Hee; Serpe, Mihaela] NICHD, Program Cellular Regulat & Metab, NIH, Bethesda, MD 20892 USA. [Meyerson, Joel R.] Brandeis Univ, Howard Hughes Med Inst, Dept Biochem, Waltham, MA 02454 USA. RP Meyerson, JR; Subramaniam, S (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA.; Mayer, ML (reprint author), NICHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA.; Meyerson, JR (reprint author), Brandeis Univ, Howard Hughes Med Inst, Dept Biochem, Waltham, MA 02454 USA. EM jmeyerson@brandeis.edu; mayerm@mail.nih.gov; ss1@nih.gov FU NCI; NICHD, NIH; IATAP program at NIH; NIH-FEI Living Laboratory for Structural Biology; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX This research was supported by the intramural programs of the NCI, and NICHD, NIH, the IATAP program at NIH, and the NIH-FEI Living Laboratory for Structural Biology. Synchrotron diffraction data was collected at Southeast Regional Collaborative Access Team (SER-CAT) 22-ID beamline at the Advanced Photon Source (APS), Argonne National Laboratory. Use of APS was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract number W-31-109-Eng-38. We thank D. Bleakman for the gift of LY466195, C. Glasser for preparing DNA constructs, and F. DiMaio and colleagues for assistance with use of the program Rosetta. We also thank V. Falconieri for preparing the schematic illustration panel. This study used the capabilities of the HPC Biowulf cluster at NIH, Bethesda, MD (http://hpc.nih.gov). NR 40 TC 3 Z9 3 U1 13 U2 13 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 SEP 22 PY 2016 VL 537 IS 7621 BP 567 EP + DI 10.1038/nature19352 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW3MO UT WOS:000383545900060 PM 27580033 ER PT J AU Grossman, RL Heath, AP Ferretti, V Varmus, HE Lowy, DR Kibbe, WA Staudt, LM AF Grossman, Robert L. Heath, Allison P. Ferretti, Vincent Varmus, Harold E. Lowy, Douglas R. Kibbe, Warren A. Staudt, Louis M. TI Toward a Shared Vision for Cancer Genomic Data SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Grossman, Robert L.; Heath, Allison P.] Univ Chicago, Ctr Data Intens Sci, Chicago, IL 60637 USA. [Ferretti, Vincent] Ontario Inst Canc Res, Toronto, ON, Canada. [Varmus, Harold E.] Cornell Univ, Weill Cornell Med, New York, NY 10021 USA. [Lowy, Douglas R.; Kibbe, Warren A.; Staudt, Louis M.] NCI, Bethesda, MD 20892 USA. RP Grossman, RL (reprint author), Univ Chicago, Ctr Data Intens Sci, Chicago, IL 60637 USA. NR 5 TC 7 Z9 7 U1 2 U2 2 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 SEP 22 PY 2016 VL 375 IS 12 BP 1109 EP 1112 DI 10.1056/NEJMp1607591 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA DW3JE UT WOS:000383537100002 PM 27653561 ER PT J AU Dong, SS Wang, CJ Xie, Y Hu, YZ Weng, J Chen, FY AF Dong, Shanshan Wang, Chunjie Xie, Ye Hu, Yuzheng Weng, Jian Chen, Feiyan TI THE IMPACT OF ABACUS TRAINING ON WORKING MEMORY AND UNDERLYING NEURAL CORRELATES IN YOUNG ADULTS SO NEUROSCIENCE LA English DT Article DE working memory; training; abacus-based mental calculation; functional MRI; frontoparietal circuitry; occipitotemporal junction ID MENTAL CALCULATION; FUNCTIONAL MRI; DIGIT MEMORY; CHILDREN; ACTIVATION; PLASTICITY; METAANALYSIS; EXPERTS; INTELLIGENCE; MAINTENANCE AB Abacus-based mental calculation (AMC) activates the frontoparietal areas largely overlapping with the working memory (WM) network. Given the critical role of WM in cognition, how to improve WM capability has attracted intensive attention in past years. However, it is still unclear whether WM could be enhanced by AMC training. The current research thus explored the impact of AMC training on verbal and visuospatial WM, as well as the underlying neural basis. Participants were randomly assigned to an abacus group and a control group. Their verbal WM was evaluated by digit/letter memory span (DMS/LMS) tests, and visuospatial WM was assessed by a visuospatial n-back task. Neural activity during the n-back task was examined using functional MRI. Our results showed reliable improvements of both verbal and visuospatial WM in the abacus group after 20-day AMC training but not in the control. In addition, the n-back task-induced activations in the right frontoparietal circuitry and left occipitotemporal junction (OTJ) declined as a result of training. Notably, the decreases in activity were positively correlated with performance gains across trained participants. These results suggest AMC training not only improves calculating skills but also have the potential to promote individuals' WM capabilities, which is associated with the functional plasticity of the common neural substrates. (C) 2016 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Dong, Shanshan; Wang, Chunjie; Xie, Ye; Hu, Yuzheng; Weng, Jian; Chen, Feiyan] Zhejiang Univ, Dept Phys, Bio X Lab, 38 Zheda Rd, Hangzhou 310027, Zhejiang, Peoples R China. [Hu, Yuzheng] NIDA, Neuroimage Res Branch, NIH, Baltimore, MD 21224 USA. RP Chen, FY (reprint author), Zhejiang Univ, Dept Phys, Bio X Lab, 38 Zheda Rd, Hangzhou 310027, Zhejiang, Peoples R China. EM chenfy@zju.edu.cn FU National Natural Science Foundation of China [30900389, 31270026] FX We thank all the participants for their cooperation in the study. This study was supported by grants from the National Natural Science Foundation of China (Nos. 30900389 and 31270026). S.D. contributed to the experiment design, collection and analysis of data as well as writing the manuscript. C.W. and Y.X. played a role in subject recruitment and data collection. Y.H. and J.W. contributed to the experiment design and manuscript revision. F.C. was the supervisor of the project, designed the study and revised the manuscript. NR 46 TC 0 Z9 0 U1 15 U2 15 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 EI 1873-7544 J9 NEUROSCIENCE JI Neuroscience PD SEP 22 PY 2016 VL 332 BP 181 EP 190 DI 10.1016/j.neuroscience.2016.06.051 PG 10 WC Neurosciences SC Neurosciences & Neurology GA DT2SD UT WOS:000381329800016 PM 27393250 ER PT J AU Riva, S Caminiti, C Iannelli, E Bryce, J Bagnalasta, M Arpinelli, F Bassi, M Betteto, P Del Mastro, L De Persis, D Nicelli, AL Passalacqua, R Porta, C Sparavigna, L Diodati, F Piparo, C Novello, S Castro, K Mitchell, SA Perrone, F AF Riva, S. Caminiti, C. Iannelli, E. Bryce, J. Bagnalasta, M. Arpinelli, F. Bassi, M. Betteto, P. Del Mastro, L. De Persis, D. Nicelli, A. L. Passalacqua, R. Porta, C. Sparavigna, L. Diodati, F. Piparo, C. Novello, S. Castro, K. Mitchell, S. A. Perrone, F. TI Cross-cultural adaptation of the US National Cancer Institute's PRO-CTCAE instrument into Italian for adult cancer patients SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract C1 [Riva, S.] Univ Milan, Dipartimento Oncol & Ematooncol, Milan, Italy. [Caminiti, C.; Diodati, F.] Azienda Osped Univ, SC Ric & Innovaz, Parma, Italy. [Iannelli, E.; Betteto, P.; De Persis, D.] Federaz Italiana Assoc Volontariato Oncol FAVO, Rome, Italy. [Bryce, J.; Sparavigna, L.; Perrone, F.] Fdn G Pascale IRCCS, Ist Nazl Studio & Cura Tumori, Naples, Italy. [Bagnalasta, M.; Arpinelli, F.; Bassi, M.; Nicelli, A. L.; Piparo, C.] Fdn Smith Kline, Verona, Italy. [Del Mastro, L.] Ist Nazl Ric Canc IST, IRCCS AOU San Martino, UO Sviluppo Terapie Innovat, Genoa, Italy. [Passalacqua, R.] Azienda Osped Ist Ospitalieri, Cremona, Italy. [Porta, C.] IRCCS Fdn Policlin San Matteo, Oncol Med, Pavia, Italy. [Novello, S.] Osped S Luigi Gonzaga, Orbassano, TO, Italy. [Castro, K.; Mitchell, S. A.] NCI, Outcomes Res Branch, Healthcare Delivery Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD SEP 21 PY 2016 VL 27 SU 4 MA S08 DI 10.1093/annonc/mdw345.8 PG 1 WC Oncology SC Oncology GA EK3LZ UT WOS:000393829200345 ER PT J AU Schramm, CA Sheng, ZZ Zhang, ZH Mascola, JR Kwong, PD Shapiro, L AF Schramm, Chaim A. Sheng, Zizhang Zhang, Zhenhai Mascola, John R. Kwong, Peter D. Shapiro, Lawrence TI SONAR: A High-Throughput Pipeline for Inferring Antibody Ontogenies from Longitudinal Sequencing of B Cell Transcripts SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE antibody repertoire; antibody lineage; antibody maturation; B cell ontogeny; longitudinal analysis; next-generation sequencing ID BROADLY NEUTRALIZING ANTIBODIES; HIV-1-NEUTRALIZING ANTIBODIES; REPERTOIRE ANALYSIS; HIV-1 ANTIBODY; GENERATION; MATURATION; LINEAGE; GERMLINE; VACCINATION; PROTECTION AB The rapid advance of massively parallel or next-generation sequencing technologies has made possible the characterization of B cell receptor repertoires in ever greater detail, and these developments have triggered a proliferation of software tools for processing and annotating these data. Of especial interest, however, is the capability to track the development of specific antibody lineages across time, which remains beyond the scope of most current programs. We have previously reported on the use of techniques such as inter-and intradonor analysis and CDR3 tracing to identify transcripts related to an antibody of interest. Here, we present Software for the Ontogenic aNalysis of Antibody Repertoires (SONAR), capable of automating both general repertoire analysis and specialized techniques for investigating specific lineages. SONAR annotates next-generation sequencing data, identifies transcripts in a lineage of interest, and tracks lineage development across multiple time points. SONAR also generates figures, such as identity-divergence plots and longitudinal phylogenetic "birthday" trees, and provides interfaces to other programs such as DNAML and BEAST. SONAR can be downloaded as a ready-to-run Docker image or manually installed on a local machine. In the latter case, it can also be configured to take advantage of a high-performance computing cluster for the most computationally intensive steps, if available. In summary, this software provides a useful new tool for the processing of large next-generation sequencing datasets and the ontogenic analysis of neutralizing antibody lineages. C1 [Schramm, Chaim A.; Sheng, Zizhang; Zhang, Zhenhai; Kwong, Peter D.; Shapiro, Lawrence] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY USA. [Schramm, Chaim A.; Sheng, Zizhang; Zhang, Zhenhai; Shapiro, Lawrence] Columbia Univ, Dept Syst Biol, New York, NY USA. [Schramm, Chaim A.; Mascola, John R.; Kwong, Peter D.; Shapiro, Lawrence] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Zhang, Zhenhai] Southern Med Univ, Nanfang Hosp, Natl Clin Res Ctr Kidney Dis, Minist Educ, Guangzhou, Guangdong, Peoples R China. [Zhang, Zhenhai] Southern Med Univ, Nanfang Hosp, Key Lab Organ Failure Res, Minist Educ, Guangzhou, Guangdong, Peoples R China. RP Schramm, CA; Kwong, PD; Shapiro, L (reprint author), Columbia Univ, Dept Biochem & Mol Biophys, New York, NY USA.; Schramm, CA; Shapiro, L (reprint author), Columbia Univ, Dept Syst Biol, New York, NY USA.; Schramm, CA; Kwong, PD; Shapiro, L (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM chaim.schramm@nih.gov; pdkwong@nih.gov; shapiro@convex.hhmi.columbia.edu FU intramural program of the Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health; HIVRAD grant [AI104722-3, U01 AI116086-01] FX We thank Batsirai Mabvakure and Dr. Cathrine Scheepers for help beta testing SONAR. Funding was provided in part by the intramural program of the Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health. Funding was also provided by HIVRAD grant AI104722-3 and U01 AI116086-01 to LS. NR 57 TC 1 Z9 1 U1 1 U2 1 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 SEP 21 PY 2016 VL 7 AR 372 DI 10.3389/fimmu.2016.00372 PG 10 WC Immunology SC Immunology GA DW5KD UT WOS:000383682500003 PM 27708645 ER PT J AU Gordon, EM Figueroa, DM Barochia, AV Yao, XL Levine, SJ AF Gordon, Elizabeth M. Figueroa, Debbie M. Barochia, Amisha V. Yao, Xianglan Levine, Stewart J. TI High-density Lipoproteins and Apolipoprotein A-I: Potential New Players in the Prevention and Treatment of Lung Disease SO FRONTIERS IN PHARMACOLOGY LA English DT Review DE high-density lipoprotein; Apolipoprotein A-I; lung diseases; apolipoprotein mimetic peptides ID NEUTROPHILIC AIRWAY INFLAMMATION; PULMONARY ARTERIAL-HYPERTENSION; RESPIRATORY-DISTRESS-SYNDROME; NUCLEAR-MAGNETIC-RESONANCE; MIMETIC PEPTIDE D-4F; CARDIOVASCULAR-DISEASE; APOA-I; SMOOTH-MUSCLE; MICE; HDL AB Apolipoprotein A-I (apoA-I) and high-density lipoproteins (HDL) mediate reverse cholesterol transport out of cells. Furthermore, HDL has additional protective functions, which include anti-oxidative, anti-inflammatory, anti-apoptotic, and vasoprotective effects. In contrast, HDL can become dysfunctional with a reduction in both cholesterol efflux and anti-inflammatory properties in the setting of disease or the acute phase response. These paradigms are increasingly being recognized to be active in the pulmonary system, where apoA-I and HDL have protective effects in normal lung health, as well as in a variety of disease states, including acute lung injury (ALI), asthma, chronic obstructive pulmonary disease, lung cancer, pulmonary arterial hypertension, pulmonary fibrosis, and viral pneumonia. Similar to observations in cardiovascular disease, however, HDL may become dysfunctional and contribute to disease pathogenesis in respiratory disorders. Furthermore, synthetic apoA-I mimetic peptides have been shown to have protective effects in animal models of ALI, asthma, pulmonary hypertension, and influenza pneumonia. These findings provide evidence to support the concept that apoA-I mimetic peptides might be developed into a new treatment that can either prevent or attenuate the manifestations of lung diseases, such as asthma. Thus, the lung is positioned to take a page from the cardiovascular disease playbook and utilize the protective properties of HDL and apoA-I as a novel therapeutic approach. C1 [Gordon, Elizabeth M.; Figueroa, Debbie M.; Barochia, Amisha V.; Yao, Xianglan; Levine, Stewart J.] NHLBI, Lab Asthma & Lung Inflammat, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Levine, SJ (reprint author), NHLBI, Lab Asthma & Lung Inflammat, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM levines@nhlbi.nih.gov FU Intramural Research Program of the National Heart, Lung, and Blood Institute, NIH Bethesda, Maryland FX This work was funded by the Intramural Research Program of the National Heart, Lung, and Blood Institute, NIH Bethesda, Maryland. NR 63 TC 2 Z9 2 U1 0 U2 0 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1663-9812 J9 FRONT PHARMACOL JI Front. Pharmacol. PD SEP 21 PY 2016 VL 7 AR 323 DI 10.3389/fphar.2016.00323 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DW3PG UT WOS:000383553500003 PM 27708582 ER PT J AU Foster, DJ Wilson, JM Remke, DH Mahmood, MS Uddin, MJ Wess, J Patel, S Marnett, LJ Niswender, CM Jones, CK Xiang, ZX Lindsley, CW Rook, JM Conn, PJ AF Foster, Daniel J. Wilson, Jermaine M. Remke, Daniel H. Mahmood, M. Suhaib Uddin, M. Jashim Wess, Jurgen Patel, Sachin Marnett, Lawrence J. Niswender, Colleen M. Jones, Carrie K. Xiang, Zixiu Lindsley, Craig W. Rook, Jerri M. Conn, P. Jeffrey TI Antipsychotic-like Effects of M-4 Positive Allosteric Modulators Are Mediated by CB2 Receptor-Dependent Inhibition of Dopamine Release SO NEURON LA English DT Article ID KNOCK-OUT MICE; MUSCARINIC ACETYLCHOLINE; CHOLINERGIC INTERNEURONS; MOLECULAR-MECHANISMS; AGONIST XANOMELINE; SCHIZOPHRENIA; TRANSMISSION; NEURONS; ACTIVATION; EXPRESSION AB Muscarinic receptors represent a promising therapeutic target for schizophrenia, but the mechanisms underlying the antipsychotic efficacy of muscarinic modulators are not well understood. Here, we report that activation of M-4 receptors on striatal spiny projection neurons results in a novel form of dopaminergic regulation resulting in a sustained depression of striatal dopamine release that is observed more than 30 min after removal of the muscarinic receptor agonist. Furthermore, both the M-4-mediated sustained inhibition of dopamine release and the antipsychotic- like efficacy of M-4 activators were found to require intact signaling through CB2 cannabinoid receptors. These findings highlight a novel mechanism by which striatal cholinergic and cannabinoid signaling leads to sustained reductions in dopaminergic transmission and concurrent behavioral effects predictive of antipsychotic efficacy. C1 [Foster, Daniel J.; Wilson, Jermaine M.; Remke, Daniel H.; Mahmood, M. Suhaib; Uddin, M. Jashim; Marnett, Lawrence J.; Niswender, Colleen M.; Jones, Carrie K.; Xiang, Zixiu; Lindsley, Craig W.; Rook, Jerri M.; Conn, P. Jeffrey] Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37232 USA. [Patel, Sachin] Vanderbilt Univ, Dept Psychiat & Behav Sci, Nashville, TN 37232 USA. [Patel, Sachin] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Uddin, M. Jashim; Marnett, Lawrence J.; Lindsley, Craig W.] Vanderbilt Univ, Dept Chem, Nashville, TN 37232 USA. [Uddin, M. Jashim; Marnett, Lawrence J.] Vanderbilt Univ, Dept Biochem, Nashville, TN 37232 USA. [Patel, Sachin; Conn, P. Jeffrey] Vanderbilt Univ, Vanderbilt Brain Inst, Nashville, TN 37232 USA. [Conn, P. Jeffrey] Vanderbilt Univ, Vanderbilt Kennedy Ctr, Nashville, TN 37232 USA. [Foster, Daniel J.; Wilson, Jermaine M.; Remke, Daniel H.; Mahmood, M. Suhaib; Niswender, Colleen M.; Jones, Carrie K.; Xiang, Zixiu; Lindsley, Craig W.; Rook, Jerri M.; Conn, P. Jeffrey] Vanderbilt Univ, Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37232 USA. [Wess, Jurgen] NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Conn, PJ (reprint author), Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37232 USA.; Conn, PJ (reprint author), Vanderbilt Univ, Vanderbilt Kennedy Ctr, Nashville, TN 37232 USA.; Conn, PJ (reprint author), Vanderbilt Univ, Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37232 USA. EM jeff.conn@vanderbilt.edu FU Brain & Behavior Research Foundation; NIH (NIMH); NIH (NINDS); Tourette Association of America; AstraZeneca FX We would like to thank Weimin Peng for her invaluable assistance. This work was supported by the Olga V. Tedeschi Young Investigator Award from the Brain & Behavior Research Foundation to D.J.F., as well as grants from the NIH (NIMH and NINDS) to D.J.F., P.J.C., C.K.J., and Z.X., and the Tourette Association of America to Z.X. P.J.C. and C.W.L. receive research support from AstraZeneca and are inventors on patents that protect multiple classes of M4R PAMs. NR 27 TC 3 Z9 3 U1 5 U2 5 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 SEP 21 PY 2016 VL 91 IS 6 BP 1244 EP 1252 DI 10.1016/j.neuron.2016.08.017 PG 9 WC Neurosciences SC Neurosciences & Neurology GA EA6SW UT WOS:000386760300010 PM 27618677 ER PT J AU Lu, SY Jang, H Gu, S Zhang, J Nussinov, R AF Lu, Shaoyong Jang, Hyunbum Gu, Shuo Zhang, Jian Nussinov, Ruth TI Drugging Ras GTPase: a comprehensive mechanistic and signaling structural view SO CHEMICAL SOCIETY REVIEWS LA English DT Review ID PROTEIN-PROTEIN INTERACTIONS; ONCOGENIC K-RAS; GUANINE-NUCLEOTIDE EXCHANGE; PANCREATIC-CARCINOMA CELLS; SMALL-MOLECULE INHIBITORS; EFFECTOR-BINDING SITE; TARGETING RAS; H-RAS; LUNG-CANCER; HYPERVARIABLE REGION AB Ras proteins are small GTPases, cycling between inactive GDP-bound and active GTP-bound states. Through these switches they regulate signaling that controls cell growth and proliferation. Activating Ras mutations are associated with approximately 30% of human cancers, which are frequently resistant to standard therapies. Over the past few years, structural biology and in silico drug design, coupled with improved screening technology, led to a handful of promising inhibitors, raising the possibility of drugging Ras proteins. At the same time, the invariable emergence of drug resistance argues for the critical importance of additionally honing in on signaling pathways which are likely to be involved. Here we overview current advances in Ras structural knowledge, including the conformational dynamic of full-length Ras in solution and at the membrane, therapeutic inhibition of Ras activity by targeting its active site, allosteric sites, and Ras-effector protein-protein interfaces, Ras dimers, the K-Ras4B/calmodulin/PI3K alpha trimer, and targeting Ras with siRNA. To mitigate drug resistance, we propose signaling pathways that can be co-targeted along with Ras and explain why. These include pathways leading to the expression (or activation) of YAP1 and c-Myc. We postulate that these and Ras signaling pathways, MAPK/ERK and PI3K/Akt/mTOR, act independently and in corresponding ways in cell cycle control. The structural data are instrumental in the discovery and development of Ras inhibitors for treating RAS-driven cancers. Together with the signaling blueprints through which drug resistance can evolve, this review provides a comprehensive and innovative master plan for tackling mutant Ras proteins. C1 [Lu, Shaoyong; Gu, Shuo; Zhang, Jian] Shanghai Jiao Tong Univ, Sch Med, Shanghai Childrens Med Ctr,Chinese Minist Educ, Dept Pathophysiol,Key Lab Cell Differentiat & Apo, Shanghai 200127, Peoples R China. [Jang, Hyunbum; Nussinov, Ruth] NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Inst Mol Med, Sackler Sch Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Zhang, J (reprint author), Shanghai Jiao Tong Univ, Sch Med, Shanghai Childrens Med Ctr,Chinese Minist Educ, Dept Pathophysiol,Key Lab Cell Differentiat & Apo, Shanghai 200127, Peoples R China.; Nussinov, R (reprint author), NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab, Frederick, MD 21702 USA.; Nussinov, R (reprint author), Tel Aviv Univ, Sackler Inst Mol Med, Sackler Sch Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. EM jian.zhang@sjtu.edu.cn; NussinoR@helix.nih.gov FU National Basic Research Program of China (973 Program) [2015CB910403]; National Natural Science Foundation of China [81322046, 81302698, 81473137]; Shanghai Rising-Star Program [13QA1402300]; Program for New Century Excellent Talents in University [NCET-12-0355]; Shanghai Health and Family Planning Commission [20154Y0058]; Collaborative Innovation Center of Systems Biomedicine; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of NIH, Frederick National Lab, Center for Cancer Research FX We thank Dr Chung-Jung Tsai for discussions. This work was supported by National Basic Research Program of China (973 Program) (2015CB910403); National Natural Science Foundation of China (81322046, 81302698, 81473137); Shanghai Rising-Star Program (13QA1402300); Program for New Century Excellent Talents in University (NCET-12-0355); Shanghai Health and Family Planning Commission (20154Y0058); Collaborative Innovation Center of Systems Biomedicine. This project has also been funded in whole or in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. This research was supported [in part] by the Intramural Research Program of NIH, Frederick National Lab, 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 241 TC 7 Z9 7 U1 30 U2 30 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 0306-0012 EI 1460-4744 J9 CHEM SOC REV JI Chem. Soc. Rev. PD SEP 21 PY 2016 VL 45 IS 18 BP 4929 EP 4952 DI 10.1039/c5cs00911a PG 24 WC Chemistry, Multidisciplinary SC Chemistry GA DX2OA UT WOS:000384208700004 PM 27396271 ER PT J AU Bayro, MJ Ganser-Pornillos, BK Zadrozny, KK Yeager, M Tycko, R AF Bayro, Marvin J. Ganser-Pornillos, Barbie K. Zadrozny, Kaneil K. Yeager, Mark Tycko, Robert TI Helical Conformation in the CA-SP1 Junction of the Immature HIV-1 Lattice Determined from Solid-State NMR of Virus-like Particles SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID CAPSID PROTEIN; TYPE-1 GAG; CRYOELECTRON MICROSCOPY; P2 DOMAIN; DIMERIZATION; ASSEMBLIES; DYNAMICS; SEQUENCE; MATURATION AB Maturation of HIV-1 requires disassembly of the Gag polyprotein lattice, which lines the viral membrane in the immature state, and subsequent assembly of the mature capsid protein lattice, which encloses viral RNA in the mature state. Metastability of the immature lattice has been proposed to depend on the existence of a structurally ordered, alpha-helical segment spanning the junction between capsid (CA) and spacer peptide 1 (SP1) subunits of Gag, a segment that is dynamically disordered in the mature capsid lattice. We report solid state nuclear magnetic resonance (ssNMR) measurements on the immature lattice in noncrystalline, spherical virus like particles (VLPs) derived from Gag. The ssNMR data provide definitive evidence for this critical alpha-helical segment in the VLPs. Differences in ssNMR chemical shifts and signal intensities between immature and mature lattice assemblies also support a major rearrangement of intermolecular interactions in the maturation process, consistent with recent models from electron cryomicroscopy and X-ray crystallography. C1 [Bayro, Marvin J.; Tycko, Robert] NIDDK, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. [Ganser-Pornillos, Barbie K.; Zadrozny, Kaneil K.; Yeager, Mark] Univ Virginia, Sch Med, Dept Mol Physiol & Biol Phys, Seridan G Snyder Translat Res Bldg, Charlottesville, VA 22908 USA. [Yeager, Mark] Univ Virginia Hlth Syst, Div Cardiovasc Med, Dept Med, Charlottesville, VA 22908 USA. [Yeager, Mark] Univ Virginia, Sch Med, Ctr Membrane & Cell Physiol, Charlottesville, VA 22908 USA. RP Tycko, R (reprint author), NIDDK, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov RI Bayro, Marvin/Q-4643-2016 OI Bayro, Marvin/0000-0003-1482-9381 FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; Intramural AIDS Targeted Antiviral Program of the National Institutes of Health; NIH [R01-GM066087, P50-GM082545] FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and by the Intramural AIDS Targeted Antiviral Program of the National Institutes of Health (R.T.). This work was also supported by NIH grants R01-GM066087 (M.Y. and B.K.G.-P.) and P50-GM082545 (M.Y.). NR 35 TC 1 Z9 1 U1 22 U2 23 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 SEP 21 PY 2016 VL 138 IS 37 BP 12029 EP 12032 DI 10.1021/jacs.6b07259 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA DX0FO UT WOS:000384037400007 PM 27593947 ER PT J AU Lam, J Sutton, P Kalkbrenner, A Windham, G Halladay, A Koustas, E Lawler, C Davidson, L Daniels, N Newschaffer, C Woodruff, T AF Lam, Juleen Sutton, Patrice Kalkbrenner, Amy Windham, Gayle Halladay, Alycia Koustas, Erica Lawler, Cindy Davidson, Lisette Daniels, Natalyn Newschaffer, Craig Woodruff, Tracey TI A Systematic Review and Meta-Analysis of Multiple Airborne Pollutants and Autism Spectrum Disorder SO PLOS ONE LA English DT Review ID HAZARDOUS AIR-POLLUTANTS; EVIDENCE-BASED MEDICINE; PARENTAL OCCUPATIONAL EXPOSURES; ENVIRONMENTAL-HEALTH SCIENCE; PARTICULATE MATTER; NEURODEVELOPMENTAL DISORDERS; RESIDENTIAL PROXIMITY; FETAL-GROWTH; AMBIENT AIR; POLLUTION AB Background Exposure to ambient air pollution is widespread and may be detrimental to human brain development and a potential risk factor for Autism Spectrum Disorder (ASD). We conducted a systematic review of the human evidence on the relationship between ASD and exposure to all airborne pollutants, including particulate matter air pollutants and others (e.g. pesticides and metals). Objective To answer the question: "is developmental exposure to air pollution associated with ASD?" Methods We conducted a comprehensive search of the literature, identified relevant studies using inclusion/exclusion criteria pre-specified in our protocol (registered in PROSPERO, CRD #42015017890), evaluated the potential risk of bias for each included study and identified an appropriate subset of studies to combine in a meta-analysis. We then rated the overall quality and strength of the evidence collectively across all air pollutants. Results Of 1,158 total references identified, 23 human studies met our inclusion criteria (17 case-control, 4 ecological, 2 cohort). Risk of bias was generally low across studies for most domains; study limitations were related to potential confounding and accuracy of exposure assessment methods. We rated the quality of the body of evidence across all air pollutants as "moderate." From our meta-analysis, we found statistically significant summary odds ratios (ORs) of 1.07 (95% CI: 1.06, 1.08) per 10-mu g/m(3) increase in PM10 exposure (n = 6 studies) and 2.32 (95% CI: 2.15, 2.51) per 10-mu g/m(3) increase in PM2.5 exposure (n = 3 studies). For pollutants not included in a meta-analysis, we collectively evaluated evidence from each study in rating the strength and quality of overall evidence considering factors such as inconsistency, imprecision, and evidence of dose-response. All included studies generally showed increased risk of ASD with increasing exposure to air pollution, although not consistently across all chemical components. Conclusion After considering strengths and limitations of the body of research, we concluded that there is "limited evidence of toxicity" for the association between early life exposure to air pollution as a whole and diagnosis of ASD. The strongest evidence was between prenatal exposure to particulate matter and ASD. However, the small number of studies in the meta-analysis and unexplained statistical heterogeneity across the individual study estimates means that the effect could be larger or smaller (including not significant) than these studies estimate. Our research supports the need for health protective public policy to reduce exposures to harmful airborne contaminants among pregnant women and children and suggests opportunities for optimizing future research. C1 [Lam, Juleen; Sutton, Patrice; Daniels, Natalyn; Woodruff, Tracey] Univ Calif San Francisco, Program Reprod Hlth & Environm, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA 94143 USA. [Kalkbrenner, Amy] Univ Wisconsin Milwaukee, Joseph J Zilber Sch Publ Hlth, Milkwaukee, WI USA. [Windham, Gayle] Calif Dept Publ Hlth, Div Environm & Occupat Dis Control, Richmond, CA USA. [Halladay, Alycia] Autism Sci Fdn, New York, NY USA. [Halladay, Alycia] Rutgers State Univ, Dept Pharmacol & Toxicol, New Brunswick, NJ USA. [Koustas, Erica] Univ Calif San Francisco, Sci Consultant, San Francisco, CA 94143 USA. [Lawler, Cindy] NIEHS, Div Extramural Res & Training, POB 12233, Res Triangle Pk, NC 27709 USA. [Davidson, Lisette] Kaiser Permanente, Dept Obstet & Gynecol, Oakland, CA USA. [Newschaffer, Craig] Drexel Univ, Dept Epidemiol & Biostat, Philadelphia, PA 19104 USA. RP Lam, J (reprint author), Univ Calif San Francisco, Program Reprod Hlth & Environm, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA 94143 USA. EM Juleen.Lam@ucsf.edu FU Autism Speaks; P01 grant from the US Environmental Protection Agency and National Institute of Environmental Health Sciences; NIEHS [P01ES022841]; USEPA [83543301] FX The work of JL, PS, ND, TW was supported in part by a grant from Autism Speaks (https://www.autismspeaks.org/) and by a P01 grant from the US Environmental Protection Agency and National Institute of Environmental Health Sciences (https://www3.epa.gov/; http://www.niehs.nih.gov/). NIEHS grant number: P01ES022841; USEPA grant number: 83543301. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 90 TC 2 Z9 2 U1 28 U2 28 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 SEP 21 PY 2016 VL 11 IS 9 AR e0161851 DI 10.1371/journal.pone.0161851 PG 27 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW8GK UT WOS:000383892700012 PM 27653281 ER PT J AU Peng, YQ Horwitz, N Lakatta, EG Lin, L AF Peng, Yunqian Horwitz, Naftali Lakatta, Edward G. Lin, Li TI Mouse RAGE Variant 4 Is a Dominant Membrane Receptor that Does Not Shed to Generate Soluble RAGE SO PLOS ONE LA English DT Article ID GLYCATION END-PRODUCTS; ATHEROSCLEROSIS RISK; NORTHERN MANHATTAN; ENDPRODUCTS RAGE; SPLICE VARIANTS; INFLAMMATION; EXPRESSION; SRAGE; MICE; COMMUNITIES AB The receptor for advanced glycation end products (RAGE) is a multi-ligand, immunoglobulin-like receptor that has been implicated in aging-associated diseases. Recent studies have demonstrated that both human and murine Ager genes undergo extensive alternative splicing that generatesmultiple putative transcripts encoding different receptor isoforms. Except for the soluble isoform(esRAGE), the majority of putative RAGE isoforms remain unstudied. Profiling of murine Ager transcripts showed that variant transcript 4 (mRAGE_v4), the second most abundant transcript in lungs and multiple other tissues, encodes a receptor that lacks nine residues located within the C2 extracellular section close to the trans-membrane domain. We therefore characterizedmRAGEV4 isoreceptor in comparison with the full-length mRAGE (mRAGEFL). Although differing in only nine residues, mRAGEFL and mRAGEV4 display very different cellular behaviors. While mRAGEFL undergoes constitutive, extensive shedding in the cell to generate sRAGE, mRAGEV4 hardly sheds. In addition, we found that while mRAGEFL can localize to both the plasma membrane and the endosome, mRAGEV4 is exclusively localized to the plasma membrane. These very different cellular localization patterns suggest that, in addition to their roles in sRAGE production, mRAGEFL and mRAGEV4 may play distinct, spatiotemporal roles in signaling and innate immune responses. Compared to mice, humans do not have the v4 transcript. Although hRAGE, like mRAGEFL, also localizes to the plasma membrane and the endosome, its rate of constitutive shedding is significantly lower. These observations provide valuable information regarding RAGE biology, and serve as a reference by which to create mouse models relating to human diseases. C1 [Peng, Yunqian; Horwitz, Naftali; Lakatta, Edward G.; Lin, Li] NIA, Lab Cardiovasc Sci, NIH, Baltimore, MD 21224 USA. RP Lin, L (reprint author), NIA, Lab Cardiovasc Sci, NIH, Baltimore, MD 21224 USA. EM linli@mail.nih.gov FU intramural research program of the National Institute on Aging, NIH FX This work was supported by the intramural research program of the National Institute on Aging, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 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 SEP 21 PY 2016 VL 11 IS 9 AR e0153657 DI 10.1371/journal.pone.0153657 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW8GK UT WOS:000383892700002 PM 27655067 ER PT J AU Diakite, SAS Ndour, PA Brousse, V Gay, F Roussel, C Biligui, S Dussiot, M Prendki, V Lopera-Mesa, TM Traore, K Konate, D Doumbia, S Cros, J Dokmak, S Fairhurst, RM Diakite, M Buffet, PA AF Diakite, Seidina A. S. Ndour, Papa Alioune Brousse, Valentine Gay, Frederick Roussel, Camille Biligui, Sylvestre Dussiot, Michael Prendki, Virginie Lopera-Mesa, Tatiana M. Traore, Karim Konate, Drissa Doumbia, Saibou Cros, Jerome Dokmak, Safi Fairhurst, Rick M. Diakite, Mahamadou Buffet, Pierre A. TI Stage-dependent fate of Plasmodium falciparum-infected red blood cells in the spleen and sickle-cell trait-related protection against malaria SO MALARIA JOURNAL LA English DT Article DE Malaria; Plasmodium falciparum; Sickle-cell trait; Red blood cell; Spleen; Retention ID IMMUNE-RESPONSES; ERYTHROCYTES; DISEASE; HEMOGLOBIN; RETENTION; MORBIDITY; MECHANISM; VARIANTS; ANTIGENS; GENE AB Background: Sickle-cell trait (HbAS) reduces falciparum malaria risk and suppresses parasitaemia. Although several candidate mechanisms have been proposed, their epidemiological, clinical and experimental correlates have not been adequately explained. To explore the basis for generally lower parasitaemias and delayed malaria episodes in children with HbAS, it is hypothesized here that their spleen-dependent removal of ring-infected red blood cells (RBCs) is more efficient than in children with normal haemoglobin A (HbAA). Methods: The mechanical splenic retention of Plasmodium falciparum-infected RBCs from subjects with HbAS or HbAA was investigated using two physiologically relevant methods: microsphiltration and ex vivo spleen perfusion. P. falciparum-infected RBCs obtained from in vitro cultures and from patients were used in either normoxic or hypoxic conditions. The effect of sickling in ring-infected HbAS RBCs was also investigated. Results: When a laboratory-adapted parasite strain was analysed, ring-infected HbAA RBCs were retained in microsphilters at similar or greater levels than ring-infected HbAS RBCs, under normoxic (retention rate 62.5 vs 43.8 %, P < 0.01) and hypoxic (54.0 vs 38.0 %, P = 0.11) conditions. When parasitized RBCs from Malian children were analysed, retention of ring-infected HbAA and HbAS RBCs was similar when tested either directly ex vivo (32.1 vs 28.7 %, P = 0.52) or after one re-invasion in vitro (55.9 vs 43.7 %, P = 0.30). In hypoxia, sickling of uninfected and ring-infected HbAS RBCs (8.6 vs 5.7 %, P = 0.51), and retention of ring-infected HbAA and HbAS RBCs in microsphilters (72.5 vs 68.8 %, P = 0.38) and spleens (41.2 vs 30.4 %, P = 0.11), also did not differ. Retention of HbAS and HbAA RBCs infected with mature P. falciparum stages was greater than 95 %. Conclusions: Sickle-cell trait is not associated with higher retention or sickling of ring-infected RBCs in experimental systems reflecting the mechanical sensing of RBCs by the human spleen. As observed with HbAA RBCs, HbAS RBCs infected with mature parasites are completely retained. Because the cytoadherence of HbAS RBCs infected with mature parasites is impaired, the very efficient splenic retention of such non-adherent infected RBCs is expected to result in a slower rise of P. falciparum parasitaemia in sickle-cell trait carriers. C1 [Diakite, Seidina A. S.; Ndour, Papa Alioune; Gay, Frederick; Roussel, Camille; Biligui, Sylvestre; Prendki, Virginie; Buffet, Pierre A.] Inst Natl Transfus Sanguine, INSERM U1134, Paris 5, Paris 7, F-75015 Paris, France. [Diakite, Seidina A. S.; Traore, Karim; Konate, Drissa; Doumbia, Saibou; Diakite, Mahamadou] Univ Bamako, Fac Med Pharm & Odontostomatol, Malaria Res & Training Ctr, BP 1805, Bamako, Mali. [Diakite, Seidina A. S.; Ndour, Papa Alioune; Dussiot, Michael; Buffet, Pierre A.] Lab Excellence Globule Rouge GR Ex, F-75115 Paris, France. [Brousse, Valentine] Hop Univ Necker Enfants Malad, Ctr Reference Drepanocytose, F-75012 Paris, France. [Dussiot, Michael] Univ Paris 05, Sorbonne Paris Cite, Inst Imagine, INSERM U1163,CNRS ERL 8254,Lab Cellular & Mol Mec, Paris, France. [Lopera-Mesa, Tatiana M.; Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Cros, Jerome; Dokmak, Safi] Hop Beaujon, AP HP, Dept Chirurg Digest & Viscerale, F-92110 Clichy, France. RP Buffet, PA (reprint author), Inst Natl Transfus Sanguine, INSERM U1134, Paris 5, Paris 7, F-75015 Paris, France.; Buffet, PA (reprint author), Lab Excellence Globule Rouge GR Ex, F-75115 Paris, France. EM pabuffet@gmail.com FU DIM Mal Inf Region Ile de France; Intramural Research Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bill and Melinda Gates Foundation; Laboratoire d'Excellence du Globule Rouge (Labex GR-Ex), Paris, France FX This work was supported by the DIM Mal Inf Region Ile de France; the Intramural Research Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health; the Bill and Melinda Gates Foundation (to PAN). SASD and PAN were additionally supported by the Laboratoire d'Excellence du Globule Rouge (Labex GR-Ex), Paris, France. NR 30 TC 0 Z9 0 U1 7 U2 7 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 SEP 21 PY 2016 VL 15 AR 482 DI 10.1186/s12936-016-1522-0 PG 10 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DW5ET UT WOS:000383666100001 PM 27655345 ER PT J AU Hu, GQ Zhao, KJ AF Hu, Gangqing Zhao, Keji TI Looping around Bcl6 in Germinal Center to Sharpen B Cell Immunity SO IMMUNITY LA English DT Editorial Material ID PROMOTER INTERACTIONS; ORGANIZATION; DOMAINS; GENOME; GENES AB We are beginning to understand the function of 3D genome architecture in the immune system. In this issue, Bunting et al. (2016) reported massive multi-layer genome reorganization from naive B cells to germinal center B cells, centered on a locus control region of Bcl6. C1 [Hu, Gangqing; Zhao, Keji] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. RP Zhao, KJ (reprint author), NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. EM zhaok@nhlbi.nih.gov NR 10 TC 0 Z9 0 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 SEP 20 PY 2016 VL 45 IS 3 BP 459 EP 461 DI 10.1016/j.immuni.2016.08.020 PG 3 WC Immunology SC Immunology GA EC9HD UT WOS:000388454300002 PM 27653595 ER PT J AU Beydoun, MA Beydoun, HA Dore, GA Canas, JA Fanelli-Kuczmarski, MT Evans, MK Zonderman, AB AF Beydoun, M. A. Beydoun, H. A. Dore, G. A. Canas, J-A Fanelli-Kuczmarski, M. T. Evans, M. K. Zonderman, A. B. TI White blood cell inflammatory markers are associated with depressive symptoms in a longitudinal study of urban adults SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID VITAMIN-E LEVELS; MAJOR DEPRESSION; PSYCHIATRIC-DISORDERS; SOCIOECONOMIC-STATUS; IMMUNE PARAMETERS; DIETARY-INTAKE; ELDERLY-WOMEN; FATTY-ACIDS; US ADULTS; FOLATE AB Total white blood cell count (TWBCC) and percentage (%) composition of lymphocytes (PL) or neutrophils (PN) are linked to mid-and late-life depression, though sex-specific temporal relationships between those inflammatory markers and depressive symptoms remain unclear. The association between inflammation and depressive symptoms in longitudinal data on ethnically and socioeconomically diverse urban adults was examined with two hypotheses. In hypothesis 1, we examined the relationship between TWBCC, PL and PN with change in level of depressive symptoms from baseline to follow-up, stratifying by sex. In hypothesis 2, we examined reverse causality, by testing the relationship of depressive symptoms with change in TWBCC, PL and PN. Multiple linear mixed-effects regression models were performed to examine both the hypotheses. The sample sizes of participants (n) and repeated observations (n') were: Hypothesis 1 (n = 2009; n' = 3501); Hypothesis 2 (n = 2081; n' = 3560). Among key findings (Hypothesis 1), in women, higher TWBCC was linked to a faster increase in depressive symptom total score (gamma(1112)+/- s.e.: +0.81 +/- 0.28, P = 0.003), with a slower increase over time in the positive affect subdomain coupled with faster increases in depressed affect and somatic complaints. Among women, baseline score on somatic complaints was positively associated with low PN (gamma(01a) = +1.61 +/- 0.48, P<0.001) and high PL (gamma(01a) = +1.16 +/- 0.45, P = 0.011), whereas baseline score on positive affect was inversely related to higher PL (gamma(01a) = -0.69 +/- 0.28, P = 0.017). Results among men indicated that there was a positive cross-sectional relationship between low TWBCC and depressive symptoms, depressed affect and an inverse cross-sectional relationship with positive affect. However, over time, a low TWBCC in men was linked to a higher score on positive affect. There was no evidence of a bi-directional relationship between WBC parameters and depressive symptoms (Hypothesis 2). In sum, TWBCC and related markers were linked to depressive symptoms, mostly among women. Further longitudinal studies are needed to replicate this sex-specific association. C1 [Beydoun, M. A.; Dore, G. A.; Evans, M. K.; Zonderman, A. B.] NIA, Lab Epidemiol & Populat Sci, NIH, Biomed Res Ctr,IRP, 251 Bayview Blvd,Suite 100,Room 04B118, Baltimore, MD 21224 USA. [Beydoun, H. A.] Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21205 USA. [Canas, J-A] Nemours Childrens Clin, Pediat Endocrinol Diabet & Metab, Jacksonville, FL USA. [Fanelli-Kuczmarski, M. T.] Univ Delaware, Dept Behav Hlth & Nutr, Newark, DE USA. RP Beydoun, MA (reprint author), NIA, Lab Epidemiol & Populat Sci, NIH, Biomed Res Ctr,IRP, 251 Bayview Blvd,Suite 100,Room 04B118, Baltimore, MD 21224 USA. EM baydounm@mail.nih.gov NR 70 TC 0 Z9 0 U1 5 U2 5 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 SEP 20 PY 2016 VL 6 AR e895 DI 10.1038/tp.2016.180 PG 11 WC Psychiatry SC Psychiatry GA DW1TU UT WOS:000383426300003 PM 27648917 ER PT J AU Underbayev, C Kasar, S Ruezinsky, W Degheidy, H Schneider, JS Marti, G Bauer, SR Fraidenraich, D Lightfoote, MM Parashar, V Raveche, E Batish, M AF Underbayev, Chingiz Kasar, Siddha Ruezinsky, William Degheidy, Heba Schneider, Joel Solomon Marti, Gerald Bauer, Steven R. Fraidenraich, Diego Lightfoote, Marilyn M. Parashar, Vijay Raveche, Elizabeth Batish, Mona TI Role of mir-15a/16-1 in early B cell development in a mouse model of chronic lymphocytic leukemia SO ONCOTARGET LA English DT Article DE chronic lymphocytic leukemia; microRNAs; B1 progenitors; induced pluripotent stem cells; cancer stem cells ID BONE-MARROW; STEM-CELLS; C-MYB; DIFFERENTIATION; ACTIVATION; LINEAGES; MIR-16-1; LYMPHOMA; PU.1; MICE AB In both human chronic lymphocytic leukemia (CLL) and the New Zealand Black (NZB) murine model of CLL, decreased levels of microRNAs miR-15a/16 play an important role in the disease. Here we investigate the effects of this microRNA on early steps of B cell development and the capacity of miR-15a-deficient hematopoietic stem cells (HSC) and B1 progenitor cells (B1P) to reproduce CLL-like phenotype both in vitro and in vivo. Our results demonstrate that both miR-15a deficient HSC and B1P cells are capable of repopulating irradiated recipients and produce higher numbers of B1 cells than sources with normal miR-15a/16 levels. Furthermore, induced pluripotent stem (iPS) cells derived for the first time from NZB mice, provided insights into the B cell differentiation roadblock inherent in this strain. In addition, exogenously delivered miR-15a into the NZB derived B cell line provided valuable clues into novel targets such as Mmp10 and Mt2. Our data supports the hypothesis that miR-15a/16 deficient stem cells and B1Ps experience a maturation blockage, which contributes to B1 cells bias in development. This work will help understand the role of miR-15a in early events of CLL and points to B1P cells as potential cells of origin for this incurable disease. C1 [Underbayev, Chingiz; Kasar, Siddha; Ruezinsky, William; Fraidenraich, Diego; Raveche, Elizabeth; Batish, Mona] Rutgers State Univ, New Jersey Med Sch, Newark, NJ 08901 USA. [Marti, Gerald] OSEL CDRH FDA, Silver Spring, MD USA. [Degheidy, Heba; Bauer, Steven R.; Lightfoote, Marilyn M.] CBER FDA Silver Spring, Silver Spring, MD USA. [Schneider, Joel Solomon] Solid Biosci LLC, Cambridge, MA USA. [Parashar, Vijay] Rutgers State Univ, Rutgers Sch Dent Med, Newark, NJ USA. [Underbayev, Chingiz] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Degheidy, Heba] Mansoura Univ, Fac Med, Mansoura, Egypt. RP Batish, M (reprint author), Rutgers State Univ, New Jersey Med Sch, Newark, NJ 08901 USA. EM batishmo@njms.rutgers.edu FU NIH [DP5OD012160, R01CA12926]; NSF [1238375] FX This work was supported by NIH Director's Early Independence Award DP5OD012160 (MB) and NIH R01CA12926 and NSF 1238375 grants (ER). NR 41 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 SEP 20 PY 2016 VL 7 IS 38 BP 60986 EP 60999 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB2CN UT WOS:000387164700016 PM 27533467 ER PT J AU Menendez, D Lowe, JM Snipe, J Resnick, MA AF Menendez, Daniel Lowe, Julie M. Snipe, Joyce Resnick, Michael A. TI Ligand dependent restoration of human TLR3 signaling and death in p53 mutant cells SO ONCOTARGET LA English DT Article DE apoptosis; poly (I:C); innate immunity; mutant p53; cancer therapy ID TOLL-LIKE RECEPTOR-3; PROSTATE-CANCER CELLS; NF-KAPPA-B; TUMOR SUPPRESSION; IN-VIVO; APOPTOSIS; IMMUNITY; REACTIVATION; EXPRESSION; MUTATIONS AB Diversity within the p53 transcriptional network can arise from a matrix of changes that include target response element sequences and p53 expression level variations. We previously found that wild type p53 (WT p53) can regulate expression of most innate immune-related Toll-like-receptor genes (TLRs) in human cells, thereby affecting immune responses. Since many tumor-associated p53 mutants exhibit change-of-spectrum transactivation from various p53 targets, we examined the ability of twenty-five p53 mutants to activate endogenous expression of the TLR gene family in p53 null human cancer cell lines following transfection with p53 mutant expression vectors. While many mutants retained the ability to drive TLR expression at WT levels, others exhibited null, limited, or change-of-spectrum transactivation of TLR genes. Using TLR3 signaling as a model, we show that some cancer-associated p53 mutants amplify cytokine, chemokine and apoptotic responses after stimulation by the cognate ligand poly(I:C). Furthermore, restoration of WT p53 activity for loss-of-function p53 mutants by the p53 reactivating drug RITA restored p53 regulation of TLR3 gene expression and enhanced DNA damage-induced apoptosis via TLR3 signaling. Overall, our findings have many implications for understanding the impact of WT and mutant p53 in immunological responses and cancer therapy. C1 [Menendez, Daniel; Lowe, Julie M.; Snipe, Joyce; Resnick, Michael A.] NIEHS, Genome Integr & Struct Biol Lab, Inflammat Dis Lab, NIH, Res Triangle Pk, NC 27709 USA. [Lowe, Julie M.] NIEHS, Immun, Inflammat Dis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Menendez, D; Resnick, MA (reprint author), NIEHS, Genome Integr & Struct Biol Lab, Inflammat Dis Lab, NIH, Res Triangle Pk, NC 27709 USA. EM menendez@niehs.nih.gov; resnick@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health, NIEHS [Z01-ES065079] FX This research was supported by the Intramural Research Program of the National Institutes of Health, NIEHS Z01-ES065079 [to MAR]. NR 51 TC 0 Z9 0 U1 2 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 SEP 20 PY 2016 VL 7 IS 38 BP 61630 EP 61642 DI 10.18632/oncotarget.11210 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB2CN UT WOS:000387164700062 PM 27533082 ER PT J AU Jung, J Lee, HC Seol, HS Choi, YS Kim, E Lee, EJ Rhee, JK Singh, SR Jun, ES Han, B Hong, SM Kim, SC Chang, S AF Jung, Jaeyun Lee, Hyun Cue Seol, Hyang Sook Choi, Yeon Sook Kim, Eunji Lee, Eun Ji Rhee, Je-Keun Singh, Shree Ram Jun, Eun Sung Han, Buhm Hong, Seung Mo Kim, Song Cheol Chang, Suhwan TI Generation and molecular characterization of pancreatic cancer patient-derived xenografts reveals their heterologous nature SO ONCOTARGET LA English DT Article DE pancreatic cancer; patient-derived xenograft; single nucleotide polymorphism; cancer panel; heterogeneity ID K-RAS; ESTABLISHMENT; MUTATIONS; GENES; MOUSE; MODEL AB Pancreatic ductal adenocarcinoma (PDAC) is the most challenging type of cancer to treat, with a 5-year survival rate of <10%. Furthermore, because of the large portion of the inoperable cases, it is difficult to obtain specimens to study the biology of the tumors. Therefore, a patient-derived xenograft (PDX) model is an attractive option for preserving and expanding these tumors for translational research. Here we report the generation and characterization of 20 PDX models of PDAC. The success rate of the initial graft was 74% and most tumors were re-transplantable. Histological analysis of the PDXs and primary tumors revealed a conserved expression pattern of p53 and SMAD4; an exome single nucleotide polymorphism (SNP) array and Comprehensive Cancer Panel showed that PDXs retained over 94% of cancer-associated variants. In addition, Polyphen2 and the Sorting Intolerant from Tolerant (SIFT) prediction identified 623 variants among the functional SNPs, highlighting the heterologous nature of pancreatic PDXs; an analysis of 409 tumor suppressor genes and oncogenes in Comprehensive Cancer Panel revealed heterologous cancer gene mutation profiles for each PDX-primary tumor pair. Altogether, we expect these PDX models are a promising platform for screening novel therapeutic agents and diagnostic markers for the detection and eradication of PDAC. C1 [Jung, Jaeyun; Lee, Eun Ji; Jun, Eun Sung; Chang, Suhwan] Univ Ulsan, Coll Med, Dept Biomed Sci, Seoul, South Korea. [Chang, Suhwan] Univ Ulsan, Coll Med, Dept Physiol, Seoul, South Korea. [Lee, Hyun Cue; Kim, Eunji; Han, Buhm] Univ Ulsan, Coll Med, Dept Convergence Med, Seoul, South Korea. [Seol, Hyang Sook; Choi, Yeon Sook] Asan Med Ctr, Asan Inst Life Sci, Seoul, South Korea. [Kim, Eunji] Seoul Natl Univ, Dept Chem, Seoul, South Korea. [Rhee, Je-Keun] Catholic Univ Korea, Coll Med, Dept Med Informat, Seoul, South Korea. [Singh, Shree Ram] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21701 USA. [Hong, Seung Mo] Asan Med Ctr, Dept Pathol, Seoul, South Korea. [Kim, Song Cheol] Asan Med Ctr, Dept Surg, Seoul, South Korea. RP Chang, S (reprint author), Univ Ulsan, Coll Med, Dept Biomed Sci, Seoul, South Korea.; Chang, S (reprint author), Univ Ulsan, Coll Med, Dept Physiol, Seoul, South Korea.; Kim, SC (reprint author), Asan Med Ctr, Dept Surg, Seoul, South Korea. EM drksc@amc.seoul.kr; suhwan.chang@amc.seoul.kr RI Singh, Shree Ram/B-7614-2008 OI Singh, Shree Ram/0000-0001-6545-583X FU Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea [HI14C2640] FX This study was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (Grant Number: HI14C2640). NR 30 TC 0 Z9 0 U1 2 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 SEP 20 PY 2016 VL 7 IS 38 BP 62533 EP 62546 DI 10.18632/oncotarget.11530 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB2CN UT WOS:000387164700128 PM 27613834 ER PT J AU Lungu, C Hirtz, D Damiano, D Gross, P Mink, JW AF Lungu, Codrin Hirtz, Deborah Damiano, Diane Gross, Paul Mink, Jonathan W. TI Report of a workshop on research gaps in the treatment of cerebral palsy SO NEUROLOGY LA English DT Review ID HYPOXIC-ISCHEMIC ENCEPHALOPATHY; COMMON DATA ELEMENTS; CLINICAL-RESEARCH; YOUNG-ADULTS; STEM-CELLS; CHILDREN; NEUROPLASTICITY; DISORDERS; INJURY; SAFETY AB Cerebral palsy (CP) is heterogeneous in etiology and manifestations, making research into relevant therapies difficult and limiting the generalizability of the results. We report here on the NIH CP symposium, where stakeholders from academic, clinical, regulatory, and advocacy backgrounds discussed the major challenges and needs for moving forward with clinical research in CP, and outlined priorities and action items. New information is constantly generated through research into pathogenesis and etiology. Clinical research and new therapeutic approaches need to keep pace, through large data registry integration and new research designs. Development of standardized data collection, increasing academic focus on CP research, and iterative approaches to treatment throughout the patients' lives, have all been identified as areas of focus. The workshop identified critical gaps and areas of focus to increase the evidence base for therapeutic approaches to determine which treatments work best for which patients in the near future. These include consolidation and optimization of databases and registries, updates to the research methodology, and better integration of resources and stakeholders. C1 [Lungu, Codrin] NINDS, Off Clin Director, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Hirtz, Deborah] NINDS, Off Clin Res, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Damiano, Diane] NIH, Funct & Appl Biomech Sect, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Gross, Paul] Cerebral Palsy Res Network, Woodinville, WA USA. [Mink, Jonathan W.] Univ Rochester, Dept Neurol, Rochester, NY 14627 USA. [Mink, Jonathan W.] Univ Rochester, Dept Neurosci, Rochester, NY 14627 USA. [Mink, Jonathan W.] Univ Rochester, Dept Pediat, Rochester, NY 14627 USA. RP Lungu, C (reprint author), NINDS, Off Clin Director, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM lunguci@ninds.nih.gov NR 37 TC 0 Z9 0 U1 3 U2 3 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 SEP 20 PY 2016 VL 87 IS 12 BP 1293 EP 1298 DI 10.1212/WNL.0000000000003116 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA DX5ZE UT WOS:000384460500021 PM 27558377 ER PT J AU Sen, ND Zhou, FJ Harris, MS Ingolia, NT Hinnebusch, AG AF Sen, Neelam Dabas Zhou, Fujun Harris, Michael S. Ingolia, Nicholas T. Hinnebusch, Alan G. TI eIF4B stimulates translation of long mRNAs with structured 5 ' UTRs and low closed-loop potential but weak dependence on eIF4G SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE eIF4B; eIF4A; eIF4G; Ded1; translation ID GENOME-WIDE ANALYSIS; DEAD-BOX HELICASE; SACCHAROMYCES-CEREVISIAE; EUKARYOTIC TRANSLATION; CONFORMATIONAL CYCLE; INITIATION-FACTORS; IN-VIVO; YEAST; SELECTION; PROTEIN AB DEAD-box RNA helicases eukaryotic translation initiation factor 4A (eIF4A) and Ded1 promote translation by resolving mRNA secondary structures that impede preinitiation complex (PIC) attachment to mRNA or scanning. Eukaryotic translation initiation factor 4B (eIF4B) is a cofactor for eIF4A but also might function independently of eIF4A. Ribosome profiling of mutants lacking eIF4B or with impaired eIF4A or Ded1 activity revealed that eliminating eIF4B reduces the relative translational efficiencies of many more genes than does inactivation of eIF4A, despite comparable reductions in bulk translation, and few genes display unusually strong requirements for both factors. However, either eliminating eIF4B or inactivating eIF4A preferentially impacts mRNAs with longer, more structured 5' untranslated regions (UTRs). These findings reveal an eIF4A-independent role for eIF4B in addition to its function as eIF4A cofactor in promoting PIC attachment or scanning on structured mRNAs. eIF4B, eIF4A, and Ded1 mutations also preferentially impair translation of longer mRNAs in a fashion mitigated by the ability to form closed-loop messenger ribonucleoprotein particles (mRNPs) via eIF4F-poly(A)-binding protein 1 (Pab1) association, suggesting cooperation between closed-loop assembly and eIF4B/helicase functions. Remarkably, depleting eukaryotic translation initiation factor 4G (eIF4G), the scaffold subunit of eukaryotic translation initiation factor 4F (eIF4F), preferentially impacts short mRNAs with strong closed-loop potential and unstructured 5' UTRs, exactly the opposite features associated with hyperdependence on the eIF4B/helicases. We propose that short, highly efficient mRNAs preferentially depend on the stimulatory effects of eIF4G-dependent closed-loop assembly. C1 [Sen, Neelam Dabas; Zhou, Fujun; Hinnebusch, Alan G.] Eunice K Shriver Natl Inst Child Hlth & Human Dev, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Harris, Michael S.; Ingolia, Nicholas T.] Univ Calif Berkeley, Dept Mol & Cell Biol, 229 Stanley Hall, Berkeley, CA 94720 USA. [Harris, Michael S.; Ingolia, Nicholas T.] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. RP Hinnebusch, AG (reprint author), Eunice K Shriver Natl Inst Child Hlth & Human Dev, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. EM ahinnebusch@nih.gov FU Searle Scholars Program Grant [11-SSP-229]; National Institute of Environment Health Sciences Grant [R21 ES22575-01]; Intramural Research Program of the National Institutes of Health FX We thank members of the A.G.H. laboratory and the Dever and Lorsch groups for many helpful suggestions; Wendy Gilbert and colleagues for critical insights about the closed-loop potential of short eIF4G-dependent genes; Sumit Sen, Razvan Chereji, and Tingfen Yan for help with bioinformatics; and Philip McQueen and Peter Munson for advice on statistical analysis. N.T.I. was supported by Searle Scholars Program Grant 11-SSP-229 and National Institute of Environment Health Sciences Grant R21 ES22575-01. This work was supported in part by the Intramural Research Program of the National Institutes of Health. NR 41 TC 3 Z9 3 U1 5 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 SEP 20 PY 2016 VL 113 IS 38 BP 10464 EP 10472 DI 10.1073/pnas.1612398113 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW4OL UT WOS:000383622600025 PM 27601676 ER PT J AU Liu, XF Xiang, LM Zhou, Q Carralot, JP Prunotto, M Niederfellner, G Pastan, I AF Liu, Xiu Fen Xiang, Laiman Zhou, Qi Carralot, Jean-Philippe Prunotto, Marco Niederfellner, Gerhard Pastan, Ira TI Actinomycin D enhances killing of cancer cells by immunotoxin RG7787 through activation of the extrinsic pathway of apoptosis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cancer therapy; apoptosis; immunotherapy; pancreatic cancer; mesothelioma ID NF-KAPPA-B; TUMOR-NECROSIS-FACTOR; ANTIMESOTHELIN IMMUNOTOXIN; PSEUDOMONAS EXOTOXIN; DEATH LIGAND; IN-VITRO; THERAPY; TOXIN; BAK; LEUKEMIA AB RG7787 is a mesothelin- targeted immunotoxin designed to have low- immunogenicity, high- cytotoxic activity and fewer side effects. RG7787 kills many types of mesothelin- expressing cancer cells lines and causes tumor regressions in mice. Safety and immunogenicity of RG7787 is now being assessed in a phase I trial. To enhance the antitumor activity of RG7787, we screened for clinically used drugs that can synergize with RG7787. Actinomycin D is a potent transcription inhibitor that is used for treating several cancers. We report here that actinomycin D and RG7787 act synergistically to kill many mesothelin- positive cancer cell lines and produce major regressions of pancreatic and stomach cancer xenografts. Analyses of RNA expression show that RG7787 or actinomycin D alone and together increase levels of TNF/ TNFR family members and NF-kappa B- regulated genes. Western blots revealed the combination changed apoptotic protein levels and enhanced cleavage of Caspases and PARP. C1 [Liu, Xiu Fen; Xiang, Laiman; Zhou, Qi; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. [Carralot, Jean-Philippe; Prunotto, Marco] Hoffmann La Roche AG, Off Innovat, CH-4070 Basel, Switzerland. [Niederfellner, Gerhard] Roche Diagnost GmbH, Roche Pharmaceut Res & Early Dev, Discovery Oncol, Innovat Ctr Penzberg, D-82377 Penzberg, Germany. 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 NIH; National Cancer Institute (NCI); Center for Cancer Research; NCI; Roche FX This work was supported by the Intramural Research Program of the NIH, National Cancer Institute (NCI), Center for Cancer Research, and a Cooperative Research and Development Agreement between NCI and Roche. NR 31 TC 1 Z9 1 U1 4 U2 4 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 SEP 20 PY 2016 VL 113 IS 38 BP 10666 EP 10671 DI 10.1073/pnas.1611481113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW4OL UT WOS:000383622600059 PM 27601652 ER PT J AU Dagnino, S Strynar, MJ McMahen, RL Lau, CS Ball, C Garantziotis, S Webster, TF McClean, MD Lindstrom, AB AF Dagnino, Sonia Strynar, Mark J. McMahen, Rebecca L. Lau, Christopher S. Ball, Carol Garantziotis, Stavros Webster, Thomas F. McClean, Michael D. Lindstrom, Andrew B. TI Identification of Biomarkers of Exposure to FTOHs and PAPs in Humans Using a Targeted and Nontargeted Analysis Approach SO ENVIRONMENTAL SCIENCE & TECHNOLOGY LA English DT Article ID PERFLUOROOCTANOIC ACID EXPOSURE; TANDEM MASS-SPECTROMETRY; POLYFLUOROALKYL SUBSTANCES; POLYFLUORINATED COMPOUNDS; CARBOXYLIC-ACIDS; OFFICE WORKERS; PERFLUOROALKYL; SAMPLES; URINE; AIR AB Although historic perfluorinated compounds are currently under scrutiny and growing regulatory control in the world, little is known about human exposure to other polyfluorinated compounds presently in use. Fluorotelomer alcohols (FTOHs) and polyfluoroalkyl phosphate esters (PAPs) are known to degrade to terminal perfluorinated acids and toxic reactive intermediates through metabolic pathways. Therefore, it is important to characterize their human exposure by the identification of unique biomarkers. With the use of liquid chromatography mass spectrometry-time-of-flight analysis (LC-MS-TOF), we developed a workflow for the identification of metabolites for the 8:2 FTOH and 8:2 diPAP. Analysis of serum and urine of dosed rats indicated the 8:2 FTOH sulfate and the 8:2 diPAP as potential biomarkers. These compounds, as well as 25 other fluorinated compounds and metabolites, were analyzed in human serum and urine samples from the general population (n = 100) and office workers (n = 30). The 8:2 FTOH sulfate was measured for the first time in human samples in 5 to 10% of the serum samples, ranging from 50 to 80 pg/mL. The 8:2 diPAP was measured in 58% of the samples, ranging from 100 to 800 pg/mL. This study indicates the FTOH sulfate conjugate as a biomarker of exposure to FTOHs and PAPs in humans. C1 [Dagnino, Sonia; Strynar, Mark J.; McMahen, Rebecca L.; Lindstrom, Andrew B.] US EPA, Natl Exposure Res Lab, Res Triangle Pk, NC 27711 USA. [Lau, Christopher S.] US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. [Dagnino, Sonia; McMahen, Rebecca L.] Oak Ridge Associated Univ, ORISE Program, Oak Ridge, TN 37831 USA. [Ball, Carol] Agilent Technol, 13000 Weston Pkwy, Cary, NC 27510 USA. [Garantziotis, Stavros] NIEHS, Clin Res Program, POB 12233, Res Triangle Pk, NC 27709 USA. [Garantziotis, Stavros] NIEHS, Lab Resp Biol, POB 12233, Res Triangle Pk, NC 27709 USA. [Webster, Thomas F.; McClean, Michael D.] Boston Univ, Sch Publ Hlth, Dept Environm Hlth, 715 Albany St,T4W, Boston, MA 02118 USA. RP Dagnino, S; Strynar, MJ (reprint author), US EPA, Natl Exposure Res Lab, Res Triangle Pk, NC 27711 USA.; Dagnino, S (reprint author), Oak Ridge Associated Univ, ORISE Program, Oak Ridge, TN 37831 USA. EM sonia.dagnino@ic.ac.uk; strynar.mark@epa.gov RI Garantziotis, Stavros/A-6903-2009 OI Garantziotis, Stavros/0000-0003-4007-375X FU Division of Intramural Research, National Institute of Environmental Health Sciences; [R01 ES015829] FX This research was partially supported by an appointment to the Research Participation Program at the National Exposure Research Laboratory administered by the Oak Ridge Institute for Science and Education. This research was also partially supported by funds from the Division of Intramural Research, National Institute of Environmental Health Sciences. We thank Agilent Technologies for their support of this effort through a TOFMS (U.S. EPA, CRADA 437-A-12) and in particular Joe Weitzel for his support of this work. We thank Imma Ferrer and Michael Thurman for training and advice on TOF MS. We also thank Matthew Stiegel for providing support on statistical analysis. M.D.M. and T.F.W. were supported in part by R01 ES015829. This article has been reviewed in accordance with the policy of the National Exposure Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. NR 46 TC 1 Z9 1 U1 17 U2 19 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0013-936X EI 1520-5851 J9 ENVIRON SCI TECHNOL JI Environ. Sci. Technol. PD SEP 20 PY 2016 VL 50 IS 18 BP 10216 EP 10225 DI 10.1021/acs.est.6b01170 PG 10 WC Engineering, Environmental; Environmental Sciences SC Engineering; Environmental Sciences & Ecology GA DX0FT UT WOS:000384037900049 PM 27477586 ER PT J AU Schwartz, LM Woloshin, S Zheng, E Tse, T Zarin, DA AF Schwartz, Lisa M. Woloshin, Steven Zheng, Eugene Tse, Tony Zarin, Deborah A. TI ClinicalTrials.gov and Drugs@FDA: A Comparison of Results Reporting for New Drug Approval Trials SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID RESULTS DATABASE; ANTIINFLAMMATORY DRUGS; PUBLICATIONS AB Background: Pharmaceutical companies and other trial sponsors must submit certain trial results to ClinicalTrials.gov. The validity of these results is unclear. Purpose: To validate results posted on ClinicalTrials.gov against publicly available U.S. Food and Drug Administration (FDA) reviews on Drugs@FDA. Data Sources: ClinicalTrials.gov (registry and results database) and Drugs@FDA (medical and statistical reviews). Study Selection: 100 parallel-group, randomized trials for new drug approvals (January 2013 to July 2014) with results posted on ClinicalTrials.gov (15 March 2015). Data Extraction: 2 assessors extracted, and another verified, the trial design, primary and secondary outcomes, adverse events, and deaths. Results: Most trials were phase 3 (90%), double-blind (92%), and placebo-controlled (73%) and involved 32 drugs from 24 companies. Of 137 primary outcomes identified from ClinicalTrials.gov, 134 (98%) had corresponding data at Drugs@FDA, 130 (95%) had concordant definitions, and 107 (78%) had concordant results. Most differences were nominal (that is, relative difference <10%). Primary outcome results in 14 trials could not be validated. Of 1927 secondary outcomes from ClinicalTrials.gov, Drugs@FDA mentioned 1061 (55%) and included results data for 367 (19%). Of 96 trials with 1 or more serious adverse events in either source, 14 could be compared and 7 had discordant numbers of persons experiencing the adverse events. Of 62 trials with 1 or more deaths in either source, 25 could be compared and 17 were discordant. Limitation: Unknown generalizability to uncontrolled or crossover trial results. Conclusion: Primary outcome definitions and results were largely concordant between ClinicalTrials. gov and Drugs@FDA. Half the secondary outcomes, as well as serious events and deaths, could not be validated because Drugs@FDA includes only "key outcomes" for regulatory decision making and frequently includes only adverse event results aggregated across multiple trials. C1 Dartmouth Inst Hlth Policy & Clin Practice, Dartmouth Hitchcock, NS, Canada. Informularly, Lebanon, NH USA. [Tse, Tony; Zarin, Deborah A.] Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. [Woloshin, Steven] Dartmouth Inst, WTRB, Level 5,1 Med Ctr Dr, Lebanon, NH 03756 USA. [Zheng, Eugene] 2900 Univ Ave Southeast,Apartment 306, Minneapolis, MN 55414 USA. RP Woloshin, S (reprint author), Dartmouth Inst, WTRB, Level 5,1 Med Ctr Dr, Lebanon, NH 03756 USA. EM steven.woloshin@dartmouth.edu OI Tse, Tony/0000-0002-9906-6864 FU National Library of Medicine FX Primary Funding Source: National Library of Medicine. NR 23 TC 3 Z9 3 U1 4 U2 4 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 SEP 20 PY 2016 VL 165 IS 6 BP 421 EP + DI 10.7326/M15-2658 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA DW9FR UT WOS:000383962000017 PM 27294570 ER PT J AU Perrin, BS Pastor, RW AF Perrin, B. Scott, Jr. Pastor, Richard W. TI Simulations of Membrane-Disrupting Peptides I: Alamethicin Pore Stability and Spontaneous Insertion SO BIOPHYSICAL JOURNAL LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; NUCLEAR-MAGNETIC-RESONANCE; STATE NMR-SPECTROSCOPY; ADDITIVE FORCE-FIELD; LIPID-BILAYERS; ANTIMICROBIAL PEPTIDES; PHOSPHOLIPID-BILAYERS; ORIENTATION; CHANNEL; CHARMM AB An all-atom molecular dynamics simulation of the archetype barrel-stave alamethicin (alm) pore in a 1,2-dioleoyl-sn-glycero-3-phosphocholine bilayer at 313 K indicates that similar to 7 mu s is required for equilibration of a preformed 6-peptide pore; the pore remains stable for the duration of the remaining 7 mu s of the trajectory, and the structure factors agree well with experiment. A 5 mu s simulation of 10 surface-bound alm peptides shows significant peptide unfolding and some unbinding, but no insertion. Simulations at 363 and 413 K with a -0.2 V electric field yield peptide insertion in 1 mu s. Insertion is initiated by the folding of residues 3-11 into an alpha-helix, and mediated by membrane water or by previously inserted peptides. The stability of five alm pore peptides at 413 K with a -0.2 V electric field demonstrates a significant preference for a transmembrane orientation. Hence, and in contrast to the cationic antimicrobial peptide described in the following article, alm shows a strong preference for the inserted over the surface-bound state. C1 [Perrin, B. Scott, Jr.; Pastor, Richard W.] NHLBI, Lab Computat Biol, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Pastor, RW (reprint author), NHLBI, Lab Computat Biol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM pastorr@nhlbi.nih.gov FU Intramural Research Program of the National Institutes of Health, National Heart, Lung and Blood Institute; National Institutes of Health [P41GM103712-S1] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Heart, Lung and Blood Institute, and utilized the high performance computational capabilities at the National Institutes of Health, Bethesda, MD (National Heart, Lung and Blood Institute LoBoS cluster). Anton computer time was provided by the National Center for Multiscale Modeling of Biological Systems through grant No. P41GM103712-S1 from the National Institutes of Health and the Pittsburgh Supercomputing Center. NR 57 TC 1 Z9 1 U1 21 U2 21 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD SEP 20 PY 2016 VL 111 IS 6 BP 1248 EP 1257 DI 10.1016/j.bpj.2016.08.014 PG 10 WC Biophysics SC Biophysics GA DW8SL UT WOS:000383925700017 PM 27653483 ER PT J AU Perrin, BS Fu, RQ Cotten, ML Pastor, RW AF Perrin, B. Scott, Jr. Fu, Riqiang Cotten, Myriam L. Pastor, Richard W. TI Simulations of Membrane-Disrupting Peptides II: AMP Piscidin 1 Favors Surface Defects over Pores SO BIOPHYSICAL JOURNAL LA English DT Article ID ADDITIVE FORCE-FIELD; ANTIMICROBIAL PEPTIDES; CROSS-POLARIZATION; CRYSTAL-STRUCTURE; TOROIDAL PORES; DYNAMICS; ALAMETHICIN; MECHANISM; CHARMM; MODEL AB Antimicrobial peptides (AMPs) that disrupt bacterial membranes are promising therapeutics against the growing number of antibiotic-resistant bacteria. The mechanism of membrane disruption by the AMP piscidin 1 was examined with multimicrosecond all-atom molecular dynamics simulations and solid-state NMR spectroscopy. The primary simulation was initialized with 20 peptides in four barrel-stave pores in a fully hydrated 1-palrnitoy1-2-oleoyl-sn-glycero-3-phosphocholine/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol bilayer. The four pores relaxed to toroidal by 200 ns, only one porelike structure containing two transmembrane helices remained at 26 his, and none of the 18 peptides released to the surface reinserted to form pores. The simulation was repeated at 413 K with an applied electric field and all peptides were surface-bound by 200 ns. Trajectories of surface-bound piscidin with and without applied fields at 313 and 413 K and totaling 6 mu s show transient distortions of the bilayer/water interface (consistent with P-31 NMR), but no insertion to trans membrane or pore states. N-15 chemical shifts confirm a fully surface-bound conformation. Taken together, the simulation and experimental results imply that transient defects rather than stable pores are responsible for membrane disruption by piscidin 1, and likely other AMPs. C1 [Perrin, B. Scott, Jr.; Pastor, Richard W.] NHLBI, Lab Computat Biol, NIH, Bldg 10, Bethesda, MD 20892 USA. [Fu, Riqiang] Natl Magnet Field Lab, Tallahassee, FL USA. [Cotten, Myriam L.] Coll William & Mary, Dept Appl Sci, Williamsburg, VA USA. RP Pastor, RW (reprint author), NHLBI, Lab Computat Biol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM pastorr@nhlbi.nih.gov FU Intramural Research Program of the National Institutes of Health, National Heart, Lung and Blood Institute; National Science Foundation [CHE 0832571, DMR-1157490]; Dreyfus Foundation; National Institutes of Health [P41GM103712-S1]; State of Florida FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Heart, Lung and Blood Institute, the National Science Foundation CAREER grant award (No. CHE 0832571), and a Dreyfus Foundation grant, and utilized the high performance computational capabilities at the National Institutes of Health, Bethesda, MD (National Heart, Lung and Blood Institute LoBoS cluster). Anton computer time was provided by the National Center for Multiscale Modeling of Biological Systems through grant No. P41GM103712-S1 from the National Institutes of Health and the Pittsburgh Supercomputing Center. The NMR experiments were performed at the National High Magnetic Field Lab supported by National Science Foundation Cooperative Agreement No. DMR-1157490 and the State of Florida. NR 54 TC 1 Z9 1 U1 15 U2 15 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD SEP 20 PY 2016 VL 111 IS 6 BP 1258 EP 1266 DI 10.1016/j.bpj.2016.08.015 PG 9 WC Biophysics SC Biophysics GA DW8SL UT WOS:000383925700018 PM 27653484 ER PT J AU Wanji, S Kengne-Ouafo, JA Datchoua-Poutcheu, FR Njouendou, AJ Tayong, DB Sofeu-Feugaing, DD Amvongo-Adjia, N Fovennso, BA Longang-Tchounkeu, YF Tekola-Ayele, F Enyong, PA Newport, MJ Davey, G AF Wanji, Samuel Kengne-Ouafo, Jonas A. Datchoua-Poutcheu, Fabrice R. Njouendou, Abdel Jelil Tayong, Dizzel Bita Sofeu-Feugaing, David D. Amvongo-Adjia, Nathalie Fovennso, Bridget A. Longang-Tchounkeu, Yolande F. Tekola-Ayele, Fasil Enyong, Peter A. Newport, Melanie J. Davey, Gail TI Detecting and staging podoconiosis cases in North West Cameroon: positive predictive value of clinical screening of patients by community health workers and researchers SO BMC PUBLIC HEALTH LA English DT Article DE Podoconiosis; Screening; Predictive value; Community Health Implementers; Cameroon ID ENDEMIC ELEPHANTIASIS; LOWER LEGS; ELIMINATION; MANAGEMENT; ETHIOPIA; DISEASE; CONSENT; AFRICA; STIGMA AB Background: The suitability of using clinical assessment to identify patients with podoconiosis in endemic communities has previously been demonstrated. In this study, we explored the feasibility and accuracy of using Community Health Implementers (CHIs) for the large scale clinical screening of the population for podoconiosis in North-west Cameroon. Methods: Before a regional podoconiosis mapping, 193 CHIs and 50 health personnel selected from 6 health districts were trained in the clinical diagnosis of the disease. After training, CHIs undertook community screening for podoconiosis patients under health personnel supervision. Identified cases were later re-examined by a research team with experience in the clinical identification of podoconiosis. Results: Cases were identified by CHIs with an overall positive predictive value (PPV) of 48.5% [34.1-70%]. They were more accurate in detecting advanced stages of the disease compared to early stages; OR 2.07, 95% CI = 1. 15-3.73, p = 0.015 for all advanced stages). Accuracy of detecting cases showed statistically significant differences among health districts (chi(2) = 25.30, p = 0.0001). Conclusion: Podoconiosis being a stigmatized disease, the use of CHIs who are familiar to the community appears appropriate for identifying cases through clinical diagnosis. However, to improve their effectiveness and accuracy, more training, supervision and support are required. More emphasis must be given in identifying early clinical stages and in health districts with relatively lower PPVs. C1 [Wanji, Samuel; Kengne-Ouafo, Jonas A.; Njouendou, Abdel Jelil; Tayong, Dizzel Bita; Fovennso, Bridget A.; Enyong, Peter A.] Univ Buea, Dept Microbiol & Parasitol, Parasites & Vector Biol Res Unit PAVBRU, Buea, Cameroon. [Wanji, Samuel; Kengne-Ouafo, Jonas A.; Datchoua-Poutcheu, Fabrice R.; Njouendou, Abdel Jelil; Tayong, Dizzel Bita; Sofeu-Feugaing, David D.; Amvongo-Adjia, Nathalie; Fovennso, Bridget A.; Longang-Tchounkeu, Yolande F.; Enyong, Peter A.] Res Fdn Trop Dis & Environm REFOTDE, Buea, Cameroon. [Sofeu-Feugaing, David D.] Univ Buea, Dept Biochem & Mol Biol, Buea, Cameroon. [Amvongo-Adjia, Nathalie] Univ Yaounde I, Dept Anim Biol & Physiol, Lab Parasitol & Ecol, Yaounde, Cameroon. [Tekola-Ayele, Fasil] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Newport, Melanie J.; Davey, Gail] Brighton & Sussex Med Sch, Wellcome Trust Ctr Global Hlth Res, Falmer Campus, Brighton BN1 9PX, E Sussex, England. RP Wanji, S (reprint author), Univ Buea, Dept Microbiol & Parasitol, Parasites & Vector Biol Res Unit PAVBRU, Buea, Cameroon.; Wanji, S (reprint author), Res Fdn Trop Dis & Environm REFOTDE, Buea, Cameroon. EM swanji@yahoo.fr OI Tekola-Ayele, Fasil/0000-0003-4194-9370 FU Wellcome Trust, UK [091956] FX This work was supported by the Wellcome Trust, UK [grant number 091956] to GD. The funding body had no direct role in the study design, the collection, analysis or interpretation of data, or the writing or submission of this manuscript for publication. NR 33 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 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD SEP 20 PY 2016 VL 16 AR 997 DI 10.1186/s12889-016-3669-6 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DW2BK UT WOS:000383447700004 PM 27650390 ER PT J AU Zhang, Z Christin, JR Wang, CH Ge, K Oktay, MH Guo, WJ AF Zhang, Zheng Christin, John R. Wang, Chunhui Ge, Kai Oktay, Maja H. Guo, Wenjun TI Mammary-Stem-Cell-Based Somatic Mouse Models Reveal Breast Cancer Drivers Causing Cell Fate Dysregulation SO CELL REPORTS LA English DT Article ID PI3 KINASE; GLAND; TUMORS; IDENTIFICATION; MULTIPOTENCY; PROGENITORS; METASTASIS; POPULATION; MECHANISMS; NEU AB Cancer genomics has provided an unprecedented opportunity for understanding genetic causes of human cancer. However, distinguishing which mutations are functionally relevant to cancer pathogenesis remains a major challenge. We describe here a mammary stem cell (MaSC) organoid-based approach for rapid generation of somatic genetically engineered mouse models (GEMMs). By using RNAi and CRISPR-mediated genome engineering in MaSC-GEMMs, we have discovered that inactivation of Ptpn22 or Mll3, two genes mutated in human breast cancer, greatly accelerated PI3K-driven mammary tumorigenesis. Using these tumor models, we have also identified genetic alterations promoting tumor metastasis and causing resistance to PI3Ktargeted therapy. Both Ptpn22 and Mll3 inactivation resulted in disruption of mammary gland differentiation and an increase in stem cell activity. Mechanistically, Mll3 deletion enhanced stem cell activity through activation of the HIF pathway. Thus, our study has established a robust in vivo platform for functional cancer genomics and has discovered functional breast cancer mutations. C1 [Zhang, Zheng; Christin, John R.; Wang, Chunhui; Guo, Wenjun] Albert Einstein Coll Med, Ruth L & David S Gottesman Inst Stem Cell & Regen, Bronx, NY 10461 USA. [Zhang, Zheng; Christin, John R.; Wang, Chunhui; Guo, Wenjun] Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA. [Ge, Kai] NIDDK, Adipocyte Biol & Gene Regulat Sect, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20814 USA. [Oktay, Maja H.] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10467 USA. [Oktay, Maja H.; Guo, Wenjun] Albert Einstein Coll Med, Albert Einstein Canc Ctr, Bronx, NY 10461 USA. [Oktay, Maja H.] Albert Einstein Coll Med, Dept Anat & Struct Biol, Bronx, NY 10461 USA. RP Guo, WJ (reprint author), Albert Einstein Coll Med, Ruth L & David S Gottesman Inst Stem Cell & Regen, Bronx, NY 10461 USA.; Guo, WJ (reprint author), Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA.; Guo, WJ (reprint author), Albert Einstein Coll Med, Albert Einstein Canc Ctr, Bronx, NY 10461 USA. EM wenjun.guo@einstein.yu.edu OI Ge, Kai/0000-0002-7442-5138 FU Einstein Cancer Center Support Grant [P30 CA013330]; New York State Department of Health (NYSTEM Program) [C029154]; NYSTEM [C028109, C029571]; Susan Komen for the Cure [CCR12224440]; V Foundation for Cancer Research; Training Program in Cellular and Molecular Biology and Genetics [2T32GM007491-36] FX We thank Dulguun Amgalan for screening shRNAs and Dr. Scott Lowe for generously providing Mll3 shRNA vectors. We are grateful to the shRNA, Flow Cytometry, Histopathology, Analytical Imaging, and Molecular Cytogenetic core facilities for technical assistance (supported by Einstein Cancer Center Support Grant P30 CA013330) and to the New York State Department of Health (NYSTEM Program) for shared facility grant support (C029154). This work is supported by grants from NYSTEM (C028109 and C029571), Susan Komen for the Cure (CCR12224440), and the V Foundation for Cancer Research. W.G. is a V Scholar. J.R.C. was supported by the 2T32GM007491-36 Training Program in Cellular and Molecular Biology and Genetics. NR 35 TC 4 Z9 4 U1 10 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 SEP 20 PY 2016 VL 16 IS 12 BP 3146 EP 3156 DI 10.1016/j.celrep.2016.08.048 PG 11 WC Cell Biology SC Cell Biology GA DW8DQ UT WOS:000383884200008 PM 27653681 ER PT J AU Yanik, EL Achenbach, CJ Gopal, S Coghill, AE Cole, SR Eron, JJ Moore, RD Mathews, WC Drozd, DR Hamdan, A Ballestas, ME Engels, EA AF Yanik, Elizabeth L. Achenbach, Chad J. Gopal, Satish Coghill, Anna E. Cole, Stephen R. Eron, Joseph J. Moore, Richard D. Mathews, W. Christopher Drozd, Daniel R. Hamdan, Ayad Ballestas, Mary E. Engels, Eric A. TI Changes in Clinical Context for Kaposi's Sarcoma and Non-Hodgkin Lymphoma Among People With HIV Infection in the United States SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT International Conference on Malignancies in AIDS and Other Acquired Immunodeficiencies CY OCT 26-27, 2015 CL Bethesda, MD ID ACTIVE ANTIRETROVIRAL THERAPY; CANCER-RISK; IMMUNE RECONSTITUTION; AIDS; HERPESVIRUS; VIREMIA; TRENDS; VIRUS; IMMUNODEFICIENCY; POPULATION AB Purpose The biology of HIV-associated cancers may differ depending on immunologic and virologic context during development. Therefore, an understanding of the burden of Kaposi's sarcoma (KS) and non-Hodgkin lymphoma (NHL) relative to antiretroviral therapy (ART), virologic suppression, and CD4 count is important. Patients and Methods KS and NHL diagnoses during 1996 to 2011 were identified among patients with HIV infection in eight clinical cohorts in the United States. Among patients in routine HIV clinical care, the proportion of cases in categories of ART use, HIV RNA, and CD4 count at diagnosis were described across calendar time. Person-time and incidence rates were calculated for each category. Results We identified 466 patients with KS and 258 with NHL. In recent years, KS was more frequently diagnosed after ART initiation (55% in 1996 to 2001 v 76% in 2007 to 2011; P-trend =.02). The proportion of patients with NHL who received ART was higher but stable over time (83% overall; P-trend =.81). An increasing proportion of KS and NHL occurred at higher CD4 counts (P<.05 for KS and NHL) and with undetectable HIV RNA (P<.05 for KS and NHL). In recent years, more person-time was contributed by patients who received ART, had high CD4 counts and had undetectable HIV RNA, whereas incidence rates in these same categories remained stable or declined. Conclusion Over time, KS and NHL occurred at higher CD4 counts and lower HIV RNA values, and KS occurred more frequently after ART initiation. These changes were driven by an increasing proportion of patients with HIV who received effective ART, had higher CD4 counts, and had suppressed HIV RNA and not by increases in cancer risk within these subgroups. An improved understanding of HIV-associated cancer pathogenesis and outcomes in the context of successful ART is therefore important. C1 [Yanik, Elizabeth L.; Coghill, Anna E.; Engels, Eric A.] NCI, Rockville, MD USA. [Moore, Richard D.] Johns Hopkins Univ, Baltimore, MD USA. [Achenbach, Chad J.] Northwestern Univ, Chicago, IL 60611 USA. [Gopal, Satish; Cole, Stephen R.; Eron, Joseph J.] Univ N Carolina, Chapel Hill, NC USA. [Mathews, W. Christopher] Univ Calif San Diego, San Diego, CA 92103 USA. [Drozd, Daniel R.] Univ Washington, Seattle, WA 98195 USA. [Hamdan, Ayad] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Ballestas, Mary E.] Univ Alabama Birmingham, Birmingham, AL USA. RP Yanik, EL (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 6E 216, Rockville, MD 20850 USA. EM elizabeth.yanik@nih.gov FU NIAID NIH HHS [R24 AI067039] NR 32 TC 1 Z9 1 U1 0 U2 0 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 SEP 20 PY 2016 VL 34 IS 27 BP 3276 EP + DI 10.1200/JCO.2016.67.6999 PG 10 WC Oncology SC Oncology GA DW9CN UT WOS:000383952600009 PM 27507879 ER PT J AU Minegishi, Y Sheng, XL Yoshitake, K Sergeev, Y Iejima, D Shibagaki, Y Monma, N Ikeo, K Furuno, M Zhuang, WJ Liu, YN Rong, WN Hattori, S Iwata, T AF Minegishi, Yuriko Sheng, XunLun Yoshitake, Kazutoshi Sergeev, Yuri Iejima, Daisuke Shibagaki, Yoshio Monma, Norikazu Ikeo, Kazuho Furuno, Masaaki Zhuang, Wenjun Liu, Yani Rong, Weining Hattori, Seisuke Iwata, Takeshi TI CCT2 Mutations Evoke Leber Congenital Amaurosis due to Chaperone Complex Instability SO SCIENTIFIC REPORTS LA English DT Article ID HEREDITARY SENSORY NEUROPATHY; CELL-CYCLE PROGRESSION; PHOSDUCIN-LIKE PROTEIN; CYTOSKELETAL ORGANIZATION; CYTOPLASMIC CHAPERONIN; EUKARYOTIC CHAPERONIN; DELTA-SUBUNIT; GENE; ACTIN; EXPRESSION AB Leber congenital amaurosis (LCA) is a hereditary early-onset retinal dystrophy that is accompanied by severe macular degeneration. In this study, novel compound heterozygous mutations were identified as LCA-causative in chaperonin-containing TCP-1, subunit 2 (CCT2), a gene that encodes the molecular chaperone protein, CCT beta. The zebrafish mutants of CCT beta are known to exhibit the eye phenotype while its mutation and association with human disease have been unknown. The CCT proteins (CCT alpha-theta) forms ring complex for its chaperon function. The LCA mutants of CCT beta, T400P and R516H, are biochemically instable and the affinity for the adjacent subunit, CCT gamma, was affected distinctly in both mutants. The patient-derived induced pluripotent stem cells (iPSCs), carrying these CCT beta mutants, were less proliferative than the control iPSCs. Decreased proliferation under Cct2 knockdown in 661W cells was significantly rescued by wild-type CCT beta expression. However, the expression of T400P and R516H didn't exhibit the significant effect. In mouse retina, both CCT beta and CCT gamma are expressed in the retinal ganglion cells and connecting cilium of photoreceptor cells. The Cct2 knockdown decreased its major client protein, transducing beta 1 (G beta 1). Here we report the novel LCA mutations in CCT beta and the impact of chaperon disability by these mutations in cellular biology. C1 [Minegishi, Yuriko; Iejima, Daisuke; Iwata, Takeshi] Natl Hosp Org, Tokyo Med Ctr, Natl Inst Sensory Organs, Div Mol & Cellular Biol, Tokyo, Japan. [Sheng, XunLun; Zhuang, Wenjun; Liu, Yani; Rong, Weining] Ningxia Peoples Hosp, Ningxia Eye Hosp, Ningxia, Peoples R China. [Yoshitake, Kazutoshi; Monma, Norikazu; Ikeo, Kazuho] Natl Inst Genet, Lab DNA Data Anal, Shizuoka, Japan. [Sergeev, Yuri] NEI, NIH, Bethesda, MD 20892 USA. [Shibagaki, Yoshio; Hattori, Seisuke] Kitasato Univ, Sch Pharmaceut Sci, Div Biochem, Tokyo, Japan. [Furuno, Masaaki] RIKEN Ctr Life Sci Technol, Div Genom Technol, Life Sci Accelerator Technol Grp, Transcriptome Technol Team, Yokohama, Kanagawa, Japan. RP Iwata, T (reprint author), Natl Hosp Org, Tokyo Med Ctr, Natl Inst Sensory Organs, Div Mol & Cellular Biol, Tokyo, Japan. EM takeshi.iwata@kankakuki.go.jp FU Japan Agency for Medical Research and Development, Practical Research Project for Rare/Intractable Diseases [15ek0109072h0002]; National Natural Science Foundation of China [81260154] FX This work was supported in part by a grant to T.I. from the Japan Agency for Medical Research and Development, Practical Research Project for Rare/Intractable Diseases, 15ek0109072h0002, and by grants to XunLun Sheng by the National Natural Science Foundation of China (81260154). NR 53 TC 1 Z9 1 U1 1 U2 1 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 SEP 20 PY 2016 VL 6 AR 33742 DI 10.1038/srep33742 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW3QX UT WOS:000383558700001 PM 27645772 ER PT J AU Wei, XB Yan, RH Chen, ZY Weng, RH Liu, X Gao, HM Xu, XF Kang, Z Liu, ZX Guo, Y Liu, ZH Larsen, JP Wang, J Tang, BS Hallett, M Wang, Q AF Wei, Xiaobo Yan, Ronghua Chen, Zhaoyu Weng, Ruihui Liu, Xu Gao, Huimin Xu, Xiaofeng Kang, Zhuang Liu, Zhexing Guo, Yan Liu, Zhenhua Larsen, Jan Petter Wang, Jin Tang, Beisha Hallett, Mark Wang, Qing TI Combined Diffusion Tensor Imaging and Arterial Spin Labeling as Markers of Early Parkinson's disease SO SCIENTIFIC REPORTS LA English DT Article ID DETERMINISTIC TRACTOGRAPHY; VASCULAR PARKINSONISM; COGNITIVE IMPAIRMENT; CEREBRAL PERFUSION; RATING-SCALE; BRAIN; MRI; PATHOLOGY; SEVERITY; PATTERN AB This study aimed to identify a PD-specific MRI pattern using combined diffusion tensor imaging (DTI) and arterial spin labeling (ASL) to discriminate patients with early PD from healthy subjects and evaluate disease status. Twenty-one early and 22 mid-late PD patients, and 22 healthy, age/gender-matched controls underwent 3-T MRI with apparent diffusion coefficient (ADC), fractional anisotropy (FA), fiber number (FN) and cerebral blood flow (CBF) measurements. We found that compared with healthy subjects, there was a profound reduction in FN passing through the SN in PD. FA in the SN and CBF in the caudate nucleus were inversely correlated with motor dysfunction. A negative correlation was observed between FA in the hippocampus (Hip) and the NMSS-Mood score, whereas CBF in the Hip and the prefrontal cortex(PFC) correlated with declined cognition. Stratified five-fold cross-validation identified FA in the SN(FA-SNAv), CBF in the PFC(CBF-PFCAv) and FA in the parietal white matter(FAPWM(Av)), and the combination of these measurements offered relatively high accuracy (AUC 0.975, 90% sensitivity and 100% specificity) in distinguishing those with early PD from healthy subjects. We demonstrate that the decreased FNs through SN in combination with changes in FA-SNAv, CBF-PFCAv and FA-PWMAv values might serve as potential markers of early-stage PD. C1 [Wei, Xiaobo; Chen, Zhaoyu; Weng, Ruihui; Liu, Xu; Gao, Huimin; Xu, Xiaofeng; Wang, Qing] Sun Yat Sen Univ, Dept Neurol, Affiliated Hosp 3, Tianhe Rd 600, Guangzhou 510630, Guangdong, Peoples R China. [Yan, Ronghua; Kang, Zhuang; Wang, Jin] Sun Yat Sen Univ, Dept Radiol, Affiliated Hosp 3, Tianhe Rd 600, Guangzhou 510630, Guangdong, Peoples R China. [Liu, Zhexing] Southern Med Univ, Sch Biomed Engn, Guangzhou 510515, Guangdong, Peoples R China. [Guo, Yan] Sun Yat Sen Univ, Sch Publ Hlth, Dept Med Stat & Epidemiol, 74 Zhongshan 2nd Rd, Guangzhou 510080, Guangdong, Peoples R China. [Liu, Zhenhua] Southern Med Univ, Zhujiang Hosp, Dept Neurol, Guangzhou 510282, Guangdong, Peoples R China. [Larsen, Jan Petter] Stavanger Univ Hosp, Norwegian Ctr Movement Disorders, Box 8100, N-4068 Stavanger, Norway. [Tang, Beisha] Cent S Univ, Dept Neurol, Changsha 410078, Hunan, Peoples R China. [Tang, Beisha] Cent S Univ, State Key Lab Med Genet, Changsha 410078, Hunan, Peoples R China. [Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Wang, Q (reprint author), Sun Yat Sen Univ, Dept Neurol, Affiliated Hosp 3, Tianhe Rd 600, Guangzhou 510630, Guangdong, Peoples R China.; Wang, J (reprint author), Sun Yat Sen Univ, Dept Radiol, Affiliated Hosp 3, Tianhe Rd 600, Guangzhou 510630, Guangdong, Peoples R China.; Tang, BS (reprint author), Cent S Univ, Dept Neurol, Changsha 410078, Hunan, Peoples R China.; Tang, BS (reprint author), Cent S Univ, State Key Lab Med Genet, Changsha 410078, Hunan, Peoples R China. EM wangjin21cn@163.com; bstang7398@163.com; denniswq@yahoo.com FU National Natural Science Foundation of China [81271427, 81471291, 81101097]; 973 Project [2011CB510000]; Scientific Research Foundation of Guangzhou [2014J4100210]; Science and Technology Program of Guangdong of China [2016A050502019]; National Natural Science Foundations of Guangdong of China [2014A020212068]; Doctoral Foundation of Ministry of Education of China [20110171120084]; NINDS Intramural Program FX This work was supported by the National Natural Science Foundation of China (Grant NO: 81271427, 81471291), 973 Project (2011CB510000), and Scientific Research Foundation of Guangzhou (Grant NO: 2014J4100210), Science and Technology Program of Guangdong of China (2016A050502019), National Natural Science Foundations of Guangdong of China (2014A020212068) to Q.W., National Natural Science Foundation of China (Grant NO: 81101097) and Doctoral Foundation of Ministry of Education of China (Grant NO: 20110171120084) to R.Y. MH is supported by the NINDS Intramural Program. We greatly thank Prof. Huston John III and Prof. Richard L. Ehman for their comments on the manuscript writing, and Dr. Silvina G. Horovitz for her methodological guidance. NR 52 TC 0 Z9 0 U1 7 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 SEP 20 PY 2016 VL 6 AR 33762 DI 10.1038/srep33762 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW3RF UT WOS:000383559500001 PM 27646647 ER PT J AU Doernberg, SN Wendler, D AF Doernberg, Samuel N. Wendler, David TI Ensuring Respect for Human Research Participants Institutional Review Boards and Sharing Results From Research SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID CLINICAL-TRIAL DATA C1 [Doernberg, Samuel N.; Wendler, David] NIH, Ctr Clin, Dept Bioeth, 10 Ctr Dr,MSC 1156,Bldg 10,Room 1C118, Bethesda, MD 20892 USA. RP Wendler, D (reprint author), NIH, Ctr Clin, Dept Bioeth, 10 Ctr Dr,MSC 1156,Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM dwendler@nih.gov NR 6 TC 0 Z9 0 U1 0 U2 0 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 SEP 20 PY 2016 VL 316 IS 11 BP 1149 EP 1150 DI 10.1001/jama.2016.7970 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DW2PK UT WOS:000383484100010 PM 27654597 ER PT J AU Marston, HD Dixon, DM Knisely, JM Palmore, TN Fauci, AS AF Marston, Hilary D. Dixon, Dennis M. Knisely, Jane M. Palmore, Tara N. Fauci, Anthony S. TI Antimicrobial Resistance SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CLOSTRIDIUM-DIFFICILE INFECTION; STAPHYLOCOCCUS-AUREUS INFECTIONS; CLINICAL-PRACTICE GUIDELINES; TRANSRECTAL PROSTATE BIOPSY; HEALTH-CARE EPIDEMIOLOGY; GRAM-NEGATIVE BACTERIA; FOOD-PRODUCING ANIMALS; UNITED-STATES; ANTIBIOTIC-RESISTANCE; KLEBSIELLA-PNEUMONIAE AB IMPORTANCE The development of antibiotics is considered among the most important advances of modern science. Antibiotics have saved millions of lives. However, antimicrobial resistance (AMR) threatens this progress and presents significant risks to human health. OBJECTIVE To identify factors associated with AMR, the current epidemiology of important resistant organisms, and possible solutions to the AMR problem. DATA SOURCES, STUDY SELECTION, AND DATA SYNTHESIS PubMed (2000-2016), NIH REPORTER, and ClinicalTrials.gov databases were searched for articles and entries related to AMR, focusing on epidemiology, clinical effects of AMR, discovery of novel agents to treat AMR bacterial infections, and nonpharmacological strategies to eliminate or modify AMR bacteria. In addition to articles and entries found in these databases, selected health policy reports and public health guidance documents were reviewed. Of 217 articles, databases, and reports identified, 103 were selected for review. RESULTS The increase in AMR has been driven by a diverse set of factors, including inappropriate antibiotic prescribing and sales, use of antibiotics outside of the health care sector, and genetic factors intrinsic to bacteria. The problem has been exacerbated by inadequate economic incentives for pharmaceutical development of new antimicrobial agents. A range of specific AMR concerns, including carbapenem-and colistin-resistant gram-negative organisms, pose a clinical challenge. Alternative approaches to address the AMR threat include new methods of antibacterial drug identification and strategies that neutralize virulence factors. CONCLUSIONS AND RELEVANCE Antimicrobial resistance poses significant challenges for current clinical care. Modified use of antimicrobial agents and public health interventions, coupled with novel antimicrobial strategies, may help mitigate the effect of multidrug-resistant organisms in the future. C1 [Marston, Hilary D.; Fauci, Anthony S.] NIAID, NIH, 31 Ctr Dr,Bldg 31A,Room 7A05C, Bethesda, MD 20892 USA. [Dixon, Dennis M.; Knisely, Jane M.] NIAID, Bacteriol & Mycol Branch, NIH, Rockville, MD USA. [Palmore, Tara N.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Marston, HD (reprint author), NIAID, NIH, 31 Ctr Dr,Bldg 31A,Room 7A05C, Bethesda, MD 20892 USA. EM hilary.marston@nih.gov NR 89 TC 4 Z9 4 U1 59 U2 65 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 SEP 20 PY 2016 VL 316 IS 11 BP 1193 EP 1204 DI 10.1001/jama.2016.11764 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA DW2PK UT WOS:000383484100019 PM 27654605 ER PT J AU Wang, YC Fang, JW Chen, SL AF Wang, Yongcui Fang, Jianwen Chen, Shilong TI Inferences of drug responses in cancer cells from cancer genomic features and compound chemical and therapeutic properties SO SCIENTIFIC REPORTS LA English DT Article ID ADVANCED PANCREATIC-CANCER; GENE-EXPRESSION LEVELS; LUNG-CANCER; PROTEIN FUNCTION; SENSITIVITY; PREDICTION; IRINOTECAN; IDENTIFICATION; TOPOTECAN; SEQUENCE AB Accurately predicting the response of a cancer patient to a therapeutic agent is a core goal of precision medicine. Existing approaches were mainly relied primarily on genomic alterations in cancer cells that have been treated with different drugs. Here we focus on predicting drug response based on integration of the heterogeneously pharmacogenomics data from both cell and drug sides. Through a systematical approach, named as PDRCC (Predict Drug Response in Cancer Cells), the cancer genomic alterations and compound chemical and therapeutic properties were incorporated to determine the chemotherapeutic response in cancer patients. Using the Cancer Cell Line Encyclopedia (CCLE) study as the benchmark dataset, all pharmacogenomics data exhibited their roles in inferring the relationships between cancer cells and drugs. When integrating both genomic resources and compound information, the prediction coverage was significantly increased. The validity of PDRCC was also supported by its effective in uncovering the unknown cell-drug associations with database and literature evidences. It set the stage for clinical testing of novel therapeutic strategies, such as the sensitive association between cancer cell 'A549_LUNG' and compound 'Topotecan'. In conclusion, PDRCC offers the possibility for faster, safer, and cheaper the development of novel anti-cancer therapeutics in the early-stage clinical trails. C1 [Wang, Yongcui; Chen, Shilong] Chinese Acad Sci, Northwest Inst Plateau Biol, Key Lab Adaptat & Evolut Plateau Biota, Xining 810001, Peoples R China. [Fang, Jianwen] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Rockville, MD 20850 USA. RP Wang, YC; Chen, SL (reprint author), Chinese Acad Sci, Northwest Inst Plateau Biol, Key Lab Adaptat & Evolut Plateau Biota, Xining 810001, Peoples R China. EM ycwang@nwipb.cas.cn; slchen@nwipb.cas.cn FU National Natural Science Foundation of China [11671396, 11371365, 31270270]; National Science Foundation of China for Basic Research Program [2015FY110500]; Qinghai Sciences and Technology Department for Basic Research Program [2016-ZJ-744] FX This work is supported by the National Natural Science Foundation of China (No. 11671396, No. 11371365, No. 31270270), a grant from the National Science Foundation of China for Basic Research Program (No. 2015FY110500), and a grant from Qinghai Sciences and Technology Department for Basic Research Program (No. 2016-ZJ-744). NR 50 TC 0 Z9 0 U1 8 U2 8 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 SEP 20 PY 2016 VL 6 AR 32679 DI 10.1038/srep32679 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW2RS UT WOS:000383490100001 PM 27645580 ER PT J AU Guo, LN Zaysteva, O Nie, ZQ Mitchell, NC Lee, JEA Ware, T Parsons, L Luwor, R Poortinga, G Hannan, RD Levens, DL Quinn, LM AF Guo, Linna Zaysteva, Olga Nie, Zuqin Mitchell, Naomi C. Lee, Jue Er Amanda Ware, Thomas Parsons, Linda Luwor, Rodney Poortinga, Gretchen Hannan, Ross D. Levens, David L. Quinn, Leonie M. TI Defining the essential function of FBP/KSRP proteins: Drosophila Psi interacts with the mediator complex to modulate MYC transcription and tissue growth SO NUCLEIC ACIDS RESEARCH LA English DT Article ID FUSE-BINDING-PROTEIN; SINGLE-STRANDED-DNA; C-MYC; GENE-EXPRESSION; TERMINAL DOMAIN; MOLECULAR-BASIS; KH DOMAINS; TFIIH; FBP; MELANOGASTER AB Despite two decades of research, the major function of FBP-family KH domain proteins during animal development remains controversial. The literature is divided between RNA processing and transcriptional functions for these single stranded nucleic acid binding proteins. Using Drosophila, where the three mammalian FBP proteins (FBP1-3) are represented by one ortholog, Psi, we demonstrate the primary developmental role is control of cell and tissue growth. Co-IP-mass spectrometry positioned Psi in an interactome predominantly comprised of RNA Polymerase II (RNA Pol II) transcriptional machinery and we demonstrate Psi is a potent transcriptional activator. The most striking interaction was between Psi and the transcriptional mediator (MED) complex, a known sensor of signaling inputs. Moreover, genetic manipulation of MED activity modified Psi-dependent growth, which suggests Psi interacts with MED to integrate developmental growth signals. Our data suggest the key target of the Psi/MED network in controlling developmentally regulated tissue growth is the transcription factor MYC. As FBP1 has been implicated in controlling expression of the MYC oncogene, we predict interaction between MED and FBP1 might also have implications for cancer initiation and progression. C1 [Guo, Linna; Zaysteva, Olga; Mitchell, Naomi C.; Lee, Jue Er Amanda; Parsons, Linda; Quinn, Leonie M.] Univ Melbourne, Sch Biomed Sci, Parkville, Vic 3010, Australia. [Nie, Zuqin; Levens, David L.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ware, Thomas; Luwor, Rodney] Univ Melbourne, Royal Melbourne Hosp, Dept Surg, Parkville, Vic 3010, Australia. [Poortinga, Gretchen] Peter MacCallum Canc Ctr, St Andrews Pl, East Melbourne, Vic 3002, Australia. [Hannan, Ross D.] Univ Melbourne, St Vincents Hosp, Dept Med, Parkville, Vic 3010, Australia. [Hannan, Ross D.] Australian Natl Univ, John Curtin Sch Med Res, Dept Canc Biol & Therapeut, Canberra, ACT 2600, Australia. RP Quinn, LM (reprint author), Univ Melbourne, Sch Biomed Sci, Parkville, Vic 3010, Australia. EM l.quinn@unimelb.edu.au FU National Health and Medical Research Council of Australia; NIH; Cancer Council of Victoria; Cancer Council Victoria FX Project Grants and a Senior Research Fellowship from the National Health and Medical Research Council of Australia (to L.Q and R.H.); NIH (to D.L.); Cancer Council of Victoria (to L.Q.). Funding for open access charge: Cancer Council Victoria. NR 54 TC 0 Z9 0 U1 10 U2 10 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 SEP 19 PY 2016 VL 44 IS 16 BP 7646 EP 7658 DI 10.1093/nar/gkw461 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DX9BC UT WOS:000384687000016 PM 27207882 ER PT J AU Cho, JE Huang, SYN Burgers, PM Shuman, S Pommier, Y Jinks-Robertson, S AF Cho, Jang-Eun Huang, Shar-yin N. Burgers, Peter M. Shuman, Stewart Pommier, Yves Jinks-Robertson, Sue TI Parallel analysis of ribonucleotide-dependent deletions produced by yeast Top1 in vitro and in vivo SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DNA TOPOISOMERASE-I; TRANSCRIPTION-ASSOCIATED MUTAGENESIS; SACCHAROMYCES-CEREVISIAE; REPLICATION; REPAIR; NICKS; CAMPTOTHECIN; CLEAVAGE; SYSTEM; STRAND AB Ribonucleotides are the most abundant non-canonical component of yeast genomic DNA and their persistence is associated with a distinctive mutation signature characterized by deletion of a single repeat unit from a short tandem repeat. These deletion events are dependent on DNA topoisomerase I (Top1) and are initiated by Top1 incision at the relevant ribonucleotide 3'-phosphodiester. A requirement for the re-ligation activity of Top1 led us to propose a sequential cleavage model for Top1-dependent mutagenesis at ribonucleotides. Here, we test key features of this model via parallel in vitro and in vivo analyses. We find that the distance between two Top1 cleavage sites determines the deletion size and that this distance is inversely related to the deletion frequency. Following the creation of a gap by two Top1 cleavage events, the tandem repeat provides complementarity that promotes realignment to a nick and subsequent Top1-mediated ligation. Complementarity downstream of the gap promotes deletion formation more effectively than does complementarity upstream of the gap, consistent with constraints to realignment of the strand to which Top1 is covalently bound. Our data fortify sequential Top1 cleavage as the mechanism for ribonucleotide-dependent deletions and provide new insight into the component steps of this process. C1 [Cho, Jang-Eun; Jinks-Robertson, Sue] Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC 27710 USA. [Huang, Shar-yin N.; Pommier, Yves] NCI, Dev Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Huang, Shar-yin N.] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Burgers, Peter M.] Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. [Shuman, Stewart] Sloan Kettering Inst, Mol Biol Program, New York, NY 10065 USA. RP Jinks-Robertson, S (reprint author), Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC 27710 USA. EM sue.robertson@duke.edu FU National Institutes of Health (NIH) [GM101690]; NIH [GM46330, GM32431]; NCI Intramural Program, Center for Cancer Research [BC006161] FX National Institutes of Health (NIH) [GM101690 to S.J.R.]; NIH [GM46330 to S.S.]; NIH [GM32431 to P.M.B.]; NCI Intramural Program, Center for Cancer Research [BC006161 to Y.P.]. Funding for open access charge: NIH [GM101690]. NR 31 TC 1 Z9 1 U1 3 U2 3 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 SEP 19 PY 2016 VL 44 IS 16 BP 7714 EP 7721 DI 10.1093/nar/gkw495 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DX9BC UT WOS:000384687000021 PM 27257064 ER PT J AU Desimmie, BA Burdick, RC Izumi, T Doi, H Shao, W Alvord, WG Sato, K Koyanagi, Y Jones, S Wilson, E Hill, S Maldarelli, F Hu, WS Pathak, VK AF Desimmie, Belete A. Burdick, Ryan C. Izumi, Taisuke Doi, Hibiki Shao, Wei Alvord, W. Gregory Sato, Kei Koyanagi, Yoshio Jones, Sara Wilson, Eleanor Hill, Shawn Maldarelli, Frank Hu, Wei-Shau Pathak, Vinay K. TI APOBEC3 proteins can copackage and comutate HIV-1 genomes SO NUCLEIC ACIDS RESEARCH LA English DT Article ID CD4(+) T-CELLS; REVERSE TRANSCRIPTION; 7SL RNA; IN-VIVO; RESTRICTION FACTORS; CYTIDINE DEAMINASE; ANTIVIRAL ACTIVITY; ANTIRETROVIRAL FACTOR; PERIPHERAL-BLOOD; VIRAL-RNA AB Although APOBEC3 cytidine deaminases A3G, A3F, A3D and A3H are packaged into virions and inhibit viral replication by inducing G-to-A hypermutation, it is not known whether they are copackaged and whether they can act additively or synergistically to inhibit HIV-1 replication. Here, we showed that APOBEC3 proteins can be copackaged by visualization of fluorescently-tagged APOBEC3 proteins using single-virion fluorescence microscopy. We further determined that viruses produced in the presence of A3G + A3F and A3G + A3H, exhibited extensive comutation of viral cDNA, as determined by the frequency of G-to-A mutations in the proviral genomes in the contexts of A3G (GG-to-AG) and A3D, A3F or A3H (GA-to-AA) edited sites. The copackaging of A3G + A3F and A3G + A3H resulted in an additive increase and a modest synergistic increase (1.8-fold) in the frequency of GA-to-AA mutations, respectively. We also identified distinct editing site trinucleotide sequence contexts for each APOBEC3 protein and used them to show that hypermutation of proviral DNAs from seven patients was induced by A3G, A3F (or A3H), A3D and A3G + A3F (or A3H). These results indicate that APOBEC3 proteins can be copackaged and can comutate the same genomes, and can cooperate to inhibit HIV replication. C1 [Desimmie, Belete A.; Burdick, Ryan C.; Izumi, Taisuke; Doi, Hibiki; Pathak, Vinay K.] NCI, Viral Mutat Sect, HIV Dynam & Replicat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Shao, Wei; Wilson, Eleanor; Hill, Shawn; Maldarelli, Frank] NCI, Clin Retrovirol Sect, HIV Dynam & Replicat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Alvord, W. Gregory] Data Management Serv Inc, Stat Consulting, Frederick, MD 21702 USA. [Sato, Kei; Koyanagi, Yoshio] Kyoto Univ, Inst Virus Res, Kyoto 6068057, Japan. [Sato, Kei] Japan Sci & Technol Agcy, CREST, Kawaguchi, Saitama 3320012, Japan. [Jones, Sara] Leidos Biomed Res Inc, Bethesda, MD 20892 USA. [Hu, Wei-Shau] NCI, Viral Recombinat Sect, HIV Dynam & Replicat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Wilson, Eleanor] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. RP Pathak, VK (reprint author), NCI, Viral Mutat Sect, HIV Dynam & Replicat Program, Ctr Canc Res, Frederick, MD 21702 USA. EM pathakv@mail.nih.gov OI Wilson, Eleanor/0000-0002-4855-514X FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; Intramural AIDS Targeted Antiviral Program; National Cancer Institute; National Institutes of Health, USA FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and by Intramural AIDS Targeted Antiviral Program grant funding to V.K.P. Funding for open access charge: National Cancer Institute; National Institutes of Health, USA. NR 95 TC 1 Z9 1 U1 2 U2 2 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 SEP 19 PY 2016 VL 44 IS 16 BP 7848 EP 7865 DI 10.1093/nar/gkw653 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DX9BC UT WOS:000384687000031 PM 27439715 ER PT J AU Lavatine, L He, SS Caumont-Sarcos, A Guynet, C Marty, B Chandler, M Bao, TH AF Lavatine, Laure He, Susu Caumont-Sarcos, Anne Guynet, Catherine Marty, Brigitte Chandler, Mick Bao Ton-Hoang TI Single strand transposition at the host replication fork SO NUCLEIC ACIDS RESEARCH LA English DT Article ID BACTERIAL RECA PROTEIN; DNA-BINDING PROTEIN; ESCHERICHIA-COLI; TRANSPOSABLE ELEMENTS; MECHANISM; REPAIR; TN7; RECOMBINATION; TRANSCRIPTION; IS608 AB Members of the IS200/IS605 insertion sequence family differ fundamentally from classical IS essentially by their specific single-strand (ss) transposition mechanism, orchestrated by the Y1 transposase, TnpA, a small HuH enzyme which recognizes and processes ss DNA substrates. Transposition occurs by the 'peel and paste' pathway composed of two steps: precise excision of the top strand as a circular ss DNA intermediate; and subsequent integration into a specific ssDNA target. Transposition of family members was experimentally shown or suggested by in silico high-throughput analysis to be intimately coupled to the lagging strand template of the replication fork. In this study, we investigated factors involved in replication fork targeting and analysed DNA-binding properties of the transposase which can assist localization of ss DNA substrates on the replication fork. We showed that TnpA interacts with the beta sliding clamp, DnaN and recognizes DNA which mimics replication fork structures. We also showed that dsDNA can facilitate TnpA targeting ssDNA substrates. We analysed the effect of Ssb and RecA proteins on TnpA activity in vitro and showed that while RecA does not show a notable effect, Ssb inhibits integration. Finally we discuss the way(s) in which integration may be directed into ssDNA at the replication fork. C1 [Lavatine, Laure; He, Susu; Caumont-Sarcos, Anne; Guynet, Catherine; Marty, Brigitte; Chandler, Mick; Bao Ton-Hoang] CNRS, CBI, Lab Microbiol & Genet Mol, 118 Route Narbonne, F-31062 Toulouse, France. [He, Susu] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Chandler, M; Bao, TH (reprint author), CNRS, CBI, Lab Microbiol & Genet Mol, 118 Route Narbonne, F-31062 Toulouse, France. EM mike@ibcg.biotoul.fr; tonhoang@ibcg.biotoul.fr FU Intramural CNRS; Agence National de la Recherche (France) Mobigen [ANR-08-BLAN-0336]; Mobising [ANR-12-BSV8-0009-01]; Paul Sabatier University; ARC Foundation FX Intramural CNRS (to M.C., B.T.H.); Agence National de la Recherche (France) Mobigen [ANR-08-BLAN-0336 to M.C.]; Mobising [ANR-12-BSV8-0009-01 to B.T.H.]; Paul Sabatier University (to L.L.); ARC Foundation (to L.L.). Funding for open access charge: Mobising [ANR-12-BSV8-0009-01]. NR 65 TC 1 Z9 1 U1 1 U2 1 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 SEP 19 PY 2016 VL 44 IS 16 BP 7866 EP 7883 DI 10.1093/nar/gkw661 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DX9BC UT WOS:000384687000032 PM 27466393 ER PT J AU James, TD Cardozo, T Abell, LE Hsieh, ML Jenkins, LMM Jha, SS Hinton, DM AF James, Tamara D. Cardozo, Timothy Abell, Lauren E. Hsieh, Meng-Lun Jenkins, Lisa M. Miller Jha, Saheli S. Hinton, Deborah M. TI Visualizing the phage T4 activated transcription complex of DNA and E. coli RNA polymerase SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SIGMA(70) BINDING-PROTEIN; C-TERMINAL REGION; STRUCTURAL BASIS; ASIA PROTEIN; PROMOTER DNA; BETA-FLAP; T4 ASIA; ANGSTROM RESOLUTION; CRYSTAL-STRUCTURE; MOTA INTERACTS AB The ability of RNA polymerase (RNAP) to select the right promoter sequence at the right time is fundamental to the control of gene expression in all organisms. However, there is only one crystallized structure of a complete activator/RNAP/DNA complex. In a process called sigma appropriation, bacteriophage T4 activates a class of phage promoters using an activator (MotA) and a co-activator (AsiA), which function through interactions with the sigma(70) subunit of RNAP. We have developed a holistic, structure-based model for sigma appropriation using multiple experimentally determined 3D structures (Escherichia coli RNAP, the Thermus aquaticus RNAP/DNA complex, AsiA /sigma(70) Region 4, the N-terminal domain of MotA [MotA(NTD)], and the C-terminal domain of MotA [MotA(CTD)]), molecular modeling, and extensive biochemical observations indicating the position of the proteins relative to each other and to the DNA. Our results visualize how AsiA/MotA redirects sigma, and therefore RNAP activity, to T4 promoter DNA, and demonstrate at a molecular level how the tactful interaction of transcriptional factors with even small segments of RNAP can alter promoter specificity. Furthermore, our model provides a rational basis for understanding how a mutation within the beta subunit of RNAP (G1249D), which is far removed from AsiA or MotA, impairs sigma appropriation. C1 [James, Tamara D.; Abell, Lauren E.; Hsieh, Meng-Lun; Jha, Saheli S.; Hinton, Deborah M.] NIDDK, Gene Express & Regulat Sect, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [James, Tamara D.; Cardozo, Timothy] NYU, NYU Langone Med Ctr, Sch Med, Dept Mol Pharmacol & Biochem, 180 Varick St,Room 637, New York, NY 10014 USA. [Jenkins, Lisa M. Miller] NCI, Collaborat Prot Technol Resource, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [James, Tamara D.] GeneCentrix Inc, 175 Varick St,4th Floor, New York, NY 10014 USA. [Hsieh, Meng-Lun] Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA. [Abell, Lauren E.] Univ Washington, Dept Pathol, Mitochondria & Metab Ctr, Seattle, WA 98109 USA. [Jha, Saheli S.] EpicentRx, Mountain View, CA 94040 USA. RP Hinton, DM (reprint author), NIDDK, Gene Express & Regulat Sect, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA.; Cardozo, T (reprint author), NYU, NYU Langone Med Ctr, Sch Med, Dept Mol Pharmacol & Biochem, 180 Varick St,Room 637, New York, NY 10014 USA. EM timothy.cardozo@med.nyu.edu; dhinton@helix.nih.gov FU Intramural Research Program of the National Institutes of Health; National Institutes of Health [DP2 OD004631] FX Intramural Research Program of the National Institutes of Health (to T.D.J., L.E.A., M.-L.H., L.M.M.J., S.S.J. and D.M.H.); National Institutes of Health [DP2 OD004631 to T.C.]. Funding for open access charge: The Intramural Research Program of the National Institutes of Health. NR 75 TC 0 Z9 0 U1 6 U2 6 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 SEP 19 PY 2016 VL 44 IS 16 BP 7974 EP 7988 DI 10.1093/nar/gkw656 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DX9BC UT WOS:000384687000041 PM 27458207 ER PT J AU Gonzalez-Mariscal, I Krzysik-Walker, SM Doyle, ME Liu, QR Cimbro, R Calvo, SSC Ghosh, S Ciesla, L Moaddel, R Carlson, OD Witek, RP O'Connell, JF Egan, JM AF Gonzalez-Mariscal, Isabel Krzysik-Walker, Susan M. Doyle, Maire E. Liu, Qing-Rong Cimbro, Raffaello Calvo, Sara Santa-Cruz Ghosh, Soumita Ciesla, Lukasz Moaddel, Ruin Carlson, Olga D. Witek, Rafal P. O'Connell, Jennifer F. Egan, Josephine M. TI Human CB1 Receptor Isoforms, present in Hepatocytes and beta-cells, are Involved in Regulating Metabolism SO SCIENTIFIC REPORTS LA English DT Article ID GLUCAGON-LIKE PEPTIDE-1; CANNABINOID RECEPTORS; INSULIN-SECRETION; ENDOCANNABINOID SYSTEM; OVERWEIGHT PATIENTS; LEPTIN RESISTANCE; ADIPOSE-TISSUE; HUMAN ISLETS; IN-VITRO; OBESITY AB Therapeutics aimed at blocking the cannabinoid 1 (CB1) receptor for treatment of obesity resulted in significant improvements in liver function, glucose uptake and pancreatic beta-cell function independent of weight loss or CB1 receptor blockade in the brain, suggesting that peripherally-acting only CB1 receptor blockers may be useful therapeutic agents. Neuropsychiatric side effects and lack of tissue specificity precluded clinical use of first-generation, centrally acting CB1 receptor blockers. In this study we specifically analyzed the potential relevance to diabetes of human CB1 receptor isoforms in extraneural tissues involved in glucose metabolism. We identified an isoform of the human CB1 receptor (CB1b) that is highly expressed in beta-cells and hepatocytes but not in the brain. Importantly, CB1b shows stronger affinity for the inverse agonist JD-5037 than for rimonabant compared to CB1 full length. Most relevant to the field, CB1b is a potent regulator of adenylyl cyclase activity in peripheral metabolic tissues. CB1b blockade by JD-5037 results in stronger adenylyl cyclase activation compared to rimonabant and it is a better enhancer of insulin secretion in beta-cells. We propose this isoform as a principal pharmacological target for the treatment of metabolic disorders involving glucose metabolism. C1 [Gonzalez-Mariscal, Isabel; Krzysik-Walker, Susan M.; Liu, Qing-Rong; Calvo, Sara Santa-Cruz; Ghosh, Soumita; Ciesla, Lukasz; Moaddel, Ruin; Carlson, Olga D.; O'Connell, Jennifer F.; Egan, Josephine M.] NIA, Lab Clin Invest, NIH, Baltimore, MD 21224 USA. [Doyle, Maire E.; Cimbro, Raffaello] Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21224 USA. [Witek, Rafal P.] Thermo Fisher Sci, 7300 Governors Way, Frederick, MD 21704 USA. RP Egan, JM (reprint author), NIA, Lab Clin Invest, NIH, Baltimore, MD 21224 USA. EM eganj@grc.nia.nih.gov FU Intramural Research Program of NIA in the National Institutes of Health; Juvenile Diabetes Research Foundation Grant; Sanford Project Funding [6-2013-2, 2-2010-727]; NIH/NIDDK FX Islet cell sorting was performed by Francis J. Chrest and RC (Johns Hopkins Bayview Medical Center). Human islets of Langerhans from cadaveric donors were obtained from the NIH/NIDDK-supported Integrated Islet Distribution Program (http://www.iidp.coh.org). Human hepatocytes were obtained from RW and Jessica Bonzo (Thermo Fisher Scientific). Vectors for CB1 receptor isoforms were kindly donated by Alex Straiker. We thank Drs. John McElroy and Robert Chorvat for compounds JD-5037 and rimonabant. This work was supported by the Intramural Research Program of NIA in the National Institutes of Health. MED was funded by the Juvenile Diabetes Research Foundation Grant and Sanford Project Funding (6-2013-2, 2-2010-727). NR 46 TC 1 Z9 1 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 SEP 19 PY 2016 VL 6 AR 33302 DI 10.1038/srep33302 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW0IQ UT WOS:000383324500001 PM 27641999 ER PT J AU Denniston, AK Sen, HN AF Denniston, Alastair K. Sen, H. Nida TI VISUALising a new framework for the treatment of uveitis SO LANCET LA English DT Editorial Material ID CHIMERIC MONOCLONAL-ANTIBODY; NECROSIS-FACTOR-ALPHA; INTERMEDIATE; PANUVEITIS; POSTERIOR; DISEASE; CA2 C1 [Denniston, Alastair K.] Univ Hosp Birmingham NHS Fdn Trust, Birmingham B15 2GW, W Midlands, England. [Denniston, Alastair K.] Univ Birmingham, Acad Unit Ophthalmol, Inst Inflammat & Ageing, Birmingham B15 2TT, W Midlands, England. [Sen, H. Nida] NEI, NIH, Bethesda, MD 20892 USA. RP Denniston, AK (reprint author), Univ Hosp Birmingham NHS Fdn Trust, Birmingham B15 2GW, W Midlands, England.; Denniston, AK (reprint author), Univ Birmingham, Acad Unit Ophthalmol, Inst Inflammat & Ageing, Birmingham B15 2TT, W Midlands, England. EM a.denniston@bham.ac.uk OI Denniston, Alastair/0000-0001-7849-0087 NR 11 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 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD SEP 17 PY 2016 VL 388 IS 10050 BP 1134 EP 1136 DI 10.1016/S0140-6736(16)31327-7 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DW5RA UT WOS:000383703100007 PM 27542304 ER PT J AU Chene, A Houard, S Nielsen, MA Hundt, S D'Alessio, F Sirima, SB Luty, AJF Duffy, P Leroy, O Gamain, B Viebig, NK AF Chene, Arnaud Houard, Sophie Nielsen, Morten A. Hundt, Sophia D'Alessio, Flavia Sirima, Sodiomon B. Luty, Adrian J. F. Duffy, Patrick Leroy, Odile Gamain, Benoit Viebig, Nicola K. TI Clinical development of placental malaria vaccines and immunoassays harmonization: a workshop report SO MALARIA JOURNAL LA English DT Article DE Placental malaria; Vaccine development; Clinical trial; Immunoassays; Harmonization ID CHONDROITIN SULFATE-A; FALCIPARUM-INFECTED ERYTHROCYTES; PREGNANCY-ASSOCIATED MALARIA; PLASMODIUM-FALCIPARUM; BINDING-INHIBITION; PARASITE ADHESION; BIRTH-WEIGHT; VAR2CSA; ANTIBODIES; WOMEN AB Placental malaria caused by Plasmodium falciparum infection constitutes a major health problem manifesting as severe disease and anaemia in the mother, impaired fetal development, low birth weight or spontaneous abortion. Prevention of placental malaria currently relies on two key strategies that are losing efficacy due to spread of resistance: long-lasting insecticide-treated nets and intermittent preventive treatment during pregnancy. A placental malaria vaccine would be an attractive, cost-effective complement to the existing control tools. Two placental malaria vaccine candidates are currently in Phase Ia/b clinical trials. During two workshops hosted by the European Vaccine Initiative, one in Paris in April 2014 and the other in Brussels in November 2014, the main actors in placental malaria vaccine research discussed the harmonization of clinical development plans and of the immunoassays with a goal to define standards that will allow comparative assessment of different placental malaria vaccine candidates. The recommendations of these workshops should guide researchers and clinicians in the further development of placental malaria vaccines. C1 [Chene, Arnaud; Gamain, Benoit] Univ Paris Diderot, Univ Paris Sorbonne Cite, Lab Excellence GR Ex,Inserm, Unite Biol Integree Globule Rouge,Inst Natl Trans, Paris, France. [Houard, Sophie; Hundt, Sophia; D'Alessio, Flavia; Leroy, Odile; Viebig, Nicola K.] Univ Klinikum Heidelberg, European Vaccine Initiat, Vossstr 2, D-69115 Heidelberg, Germany. [Nielsen, Morten A.] Univ Copenhagen, Fac Hlth & Med Sci, Dept Immunol & Microbiol, Ctr Med Parasitol, Copenhagen, Denmark. [Nielsen, Morten A.] Copenhagen Univ Hosp, Rigshosp, Dept Infect Dis, Copenhagen, Denmark. [Sirima, Sodiomon B.] Ctr Natl Rech & Format Paludisme, 01 BP 2208, Ouagadougou 01, Burkina Faso. [Luty, Adrian J. F.] IRD MERIT UMR 216, F-75006 Paris, France. [Luty, Adrian J. F.] Univ Paris 05, COMUE Sorbonne Paris Cite, Fac Sci Pharmaceut & Biol, F-75270 Paris, France. [Duffy, Patrick] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD USA. RP Viebig, NK (reprint author), Univ Klinikum Heidelberg, European Vaccine Initiat, Vossstr 2, D-69115 Heidelberg, Germany. EM nicola.viebig@euvaccine.eu OI Gamain, Benoit/0000-0002-8255-2145 FU German Federal Ministry of Education and Research (BMBF) through KfW; Irish Aid; EU Seventh Framework Programme (PlacMalVac) [304815]; Danish National Advanced Technology Foundation FX Main financial support for the workshop was provided by the German Federal Ministry of Education and Research (BMBF) through KfW and the Irish Aid.; Support was also provided by the EU Seventh Framework Programme under Grant Agreement No 304815 (PlacMalVac) and the Danish National Advanced Technology Foundation. NR 38 TC 0 Z9 0 U1 4 U2 4 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 SEP 17 PY 2016 VL 15 AR 476 DI 10.1186/s12936-016-1527-8 PG 11 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DW5EP UT WOS:000383665600002 PM 27639691 ER PT J AU Baldini, SF Steenackers, A Olivier-Van Stichelen, S Mir, AM Mortuaire, M Lefebvre, T Guinez, C AF Baldini, Steffi F. Steenackers, Agata Olivier-Van Stichelen, Stephanie Mir, Anne-Marie Mortuaire, Marlene Lefebvre, Tony Guinez, Celine TI Glucokinase expression is regulated by glucose through O-GlcNAc glycosylation SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Glucokinase; O-GIcNAcylation; Liver; Mouse; siOGT; Glucose metabolism ID MAMMALIAN GLUCOKINASE; N-ACETYLGLUCOSAMINE; HEXOKINASE I; TRANSCRIPTION; GLCNACYLATION; PROTEINS; INSULIN; HEPATOCYTES; LIVER; GENE AB Blood glucose fluctuates with the fasting-feeding cycle. One of the liver's functions is to maintain blood glucose concentrations within a physiological range. Glucokinase (GCK) or hexokinase IV, is the main enzyme that regulates the flux and the use of glucose in the liver leading to a compensation of hyperglycemia. In hepatocytes, GCK catalyzes the phosphorylation of glucose into glucose-6-phosphate. This critical enzymatic reaction is determinant for the metabolism of glucose in the liver which includes glycogen synthesis, glycolysis, lipogenesis and gluconeogenesis. In liver, simultaneous increase of glucose and insulin enhances GCK activity and gene expression, changes its subcellular location and interaction with regulatory proteins. The post-translational O-linked beta-N-acetylglucosaminylation (O-G1cNAcylation) acts as a glucose-sensitive modification and is believed to take part in hepatic glucose sensing by modifying key regulatory proteins. Therefore, we aimed to determine whether GCK is modified by O-GlcNAcylation in the liver of mice and investigated the role that this modification plays in regulating GCK protein expression. We demonstrated that endogenous GCK expression correlated with O-GIcNAc levels in the pathophysiological model ob/ob mice. More specifically, in response to the pharmacological inhibition of O-G1cNAcase (OGA) contents of GCK increased. Using the GlcNAc specific lectin succinylated-WGA and click chemistry labeling approaches, we demonstrated that GCK is modified by O-GIcNAcylation. Further, we demonstrated that siRNA-mediated Ogt knock-down not only decreases O-GlcNAc content but also GCK protein level. Altogether, our in vivo and in vitro results demonstrate that GCK expression is regulated by nutrient-sensing O-GlcNAc cycling in liver. (C) 2016 Elsevier Inc. All rights reserved. C1 [Baldini, Steffi F.; Steenackers, Agata; Olivier-Van Stichelen, Stephanie; Mir, Anne-Marie; Mortuaire, Marlene; Lefebvre, Tony; Guinez, Celine] Univ Lille, CNRS, UMR 8576, UGSF, F-59000 Lille, France. [Guinez, Celine] Univ Lille, EA4489, Equipe Malnutr Maternelle & Programmat Malad Meta, F-59000 Lille, France. [Olivier-Van Stichelen, Stephanie] NIDDK, Lab Cellular & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Guinez, C (reprint author), Univ Lille, CNRS, UMR 8576, UGSF, F-59000 Lille, France. EM celine.guinez@univ-lille1.fr FU gs2:Ministere de l'Enseignement Superieur et de la Recherche; Region Nord-Pas de Calais FX We are indebted to the Research Federation FRABio (Univ. Lille, CNRS, FR 3688, FRABio, Biochimie Structurale et Fonctionnelle des Assemblages Biomoleculaires) for providing the scientific and technical environment conducive to achieving this work. We would like to thank Pr. D. Vocadlo (Simon Fraser University) who provided us NButGT. SB is a recipient of a fellowship from the "gs2:Ministere de l'Enseignement Superieur et de la Recherche"and from the "Region Nord-Pas de Calais". NR 32 TC 0 Z9 0 U1 8 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 16 PY 2016 VL 478 IS 2 BP 942 EP 948 DI 10.1016/j.bbrc.2016.08.056 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DW3FX UT WOS:000383528600069 PM 27520373 ER PT J AU Khelashvili, G Schmidt, SG Shi, L Javitch, JA Gether, U Loland, CJ Weinstein, H AF Khelashvili, George Schmidt, Solveig Gaarde Shi, Lei Javitch, Jonathan A. Gether, Ulrik Loland, Claus J. Weinstein, Harel TI Conformational Dynamics on the Extracellular Side of LeuT Controlled by Na+ and K+ Ions and the Protonation State of Glu(290) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE conformational change; membrane protein; molecular dynamics; monoamine transporter; neurotransmitter transport ID NEUROTRANSMITTER SODIUM SYMPORTERS; X-RAY STRUCTURES; DOPAMINE TRANSPORTER; BINDING-SITE; MOLECULAR-DYNAMICS; BACTERIAL HOMOLOG; LEUCINE TRANSPORTER; MEMBRANE-TRANSPORT; SUBSTRATE-BINDING; OCCLUDED STATE AB Ions play key mechanistic roles in the gating dynamics of neurotransmitter:sodium symporters (NSSs). In recent microsecond scale molecular dynamics simulations of a complete model of the dopamine transporter, a NSS protein, we observed a partitioning of K+ ions from the intracellular side toward the unoccupied Na2 site of dopamine transporter following the release of the Na2-bound Na+. Here we evaluate with computational simulations and experimental measurements of ion affinities under corresponding conditions, the consequences of K+ binding in the Na2 site of LeuT, a bacterial homolog of NSS, when both Na+ ions and substrate have left, and the transporter prepares for a new cycle. We compare the results with the consequences of binding Na+ in the same apo system. Analysis of >50-s atomistic molecular dynamics and enhanced sampling trajectories of constructs with Glu(290), either charged or neutral, point to the Glu(290) protonation state as a main determinant in the structural reconfiguration of the extracellular vestibule of LeuT in which a water gate opens through coordinated motions of residues Leu(25), Tyr(108), and Phe(253). The resulting water channel enables the binding/dissociation of the Na+ and K+ ions that are prevalent, respectively, in the extracellular and intracellular environments. C1 [Khelashvili, George; Shi, Lei; Weinstein, Harel] Cornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA. [Schmidt, Solveig Gaarde; Gether, Ulrik; Loland, Claus J.] Univ Copenhagen, Fac Hlth & Med Sci, Dept Neurosci & Pharmacol, DK-2200 Copenhagen N, Denmark. [Shi, Lei] NIDA, Computat Chem & Mol Biophys Unit, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Javitch, Jonathan A.] Columbia Univ Coll Phys & Surg, Dept Psychiat, 722 W 168th St, New York, NY 10032 USA. [Javitch, Jonathan A.] Columbia Univ Coll Phys & Surg, Dept Pharmacol, 630 W 168th St, New York, NY 10032 USA. [Javitch, Jonathan A.] New York State Psychiat Inst & Hosp, Div Mol Therapeut, New York, NY 10032 USA. [Weinstein, Harel] Cornell Univ, Weill Med Coll, Inst Computat Biomed, New York, NY 10065 USA. RP Khelashvili, G (reprint author), Cornell Univ, Weill Med Coll, Dept Physiol & Biophys, 1300 York Ave,Rm LC 501A, New York, NY 10065 USA. EM gek2009@med.cornell.edu FU Texas Advanced Computing Center at the University of Texas at Austin [TG-MCB120008]; Office of Science of the U.S. Department of Energy [DE-AC05-00OR22725, PSCA14026P] FX The following computational resources are gratefully acknowledged: an XSEDE allocation at the Texas Advanced Computing Center at the University of Texas at Austin (Stampede supercomputer, project TG-MCB120008, used for initial studies); resources of the Oak Ridge Leadership Computing Facility (ALCC allocation BIP109) at the Oak Ridge National Laboratory, which is supported by the Office of Science of the U.S. Department of Energy under Contract DE-AC05-00OR22725; an allocation on the Anton supercomputer (Grant PSCA14026P); and the computational resources of the David A. Cofrin Center for Biomedical Information in the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine at Weill Cornell Medical College. His-tagged LeuT construct inserted in pET16b was a generous gift from Dr. Eric Gouaux (Vollum Institute, Oregon Health Science University). NR 73 TC 3 Z9 3 U1 5 U2 5 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 SEP 16 PY 2016 VL 291 IS 38 BP 19786 EP 19799 DI 10.1074/jbc.M116.731455 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV9EO UT WOS:000383243100006 PM 27474737 ER PT J AU Holdfeldt, A Skovbakke, SL Winther, M Gabl, M Nielsen, C Perez-Gassol, I Larsen, CJ Wang, JM Karlsson, A Dahlgren, C Forsman, H Franzyk, H AF Holdfeldt, Andre Skovbakke, Sarah Line Winther, Malene Gabl, Michael Nielsen, Christina Perez-Gassol, Iris Larsen, Camilla Josephine Wang, Ji Ming Karlsson, Anna Dahlgren, Claes Forsman, Huamei Franzyk, Henrik TI The Lipidated Peptidomimetic Lau-((S)-Aoc)-(Lys-Nphe)(6)-NH2 Is a Novel Formyl Peptide Receptor 2 Agonist That Activates Both Human and Mouse Neutrophil NADPH Oxidase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE G-protein-coupled receptor (GPCR); inflammation; NADPH oxidase; neutrophil; receptor structure-function; structure-function ID RESPIRATORY BURST PRODUCTS; N-FORMYLPEPTIDE RECEPTOR; CHEMOATTRACTANT RECEPTORS; HOST-DEFENSE; PROFESSIONAL PHAGOCYTES; LISTERIA-MONOCYTOGENES; ANTIMICROBIAL ACTIVITY; STAPHYLOCOCCUS-AUREUS; GRANULE MOBILIZATION; MURINE NEUTROPHILS AB Neutrophils expressing formyl peptide receptor 2 (FPR2) play key roles in host defense, immune regulation, and resolution of inflammation. Consequently, the search for FPR2-specific modulators has attracted much attention due to its therapeutic potential. Earlier described agonists for this receptor display potent activity for the human receptor (FPR2) but low activity for the mouse receptor orthologue (Fpr2), rendering them inapplicable in murine models of human disease. Here we describe a novel FPR2 agonist, the proteolytically stable -peptide/-peptoid hybrid Lau-((S)-Aoc)-(Lys-Nphe)(6)-NH2 (F2M2), showing comparable potency in activating human and mouse neutrophils by inducing a rise in intracellular Ca2+ concentration and assembly of the superoxide-generating NADPH oxidase. This FPR2/Fpr2 agonist contains a headgroup consisting of a 2-aminooctanoic acid (Aoc) residue acylated with lauric acid (C-12 fatty acid), which is linked to a peptide/peptoid repeat ((Lys-Nphe)(6)-NH2). Both the fatty acid moiety and the (S)-Aoc residue were required for FPR2/Fpr2 activation. This type of proteolytically stable FPR2-specific peptidomimetics may serve as valuable tools for future analysis of FPR2 signaling as well as for development of prophylactic immunomodulatory therapy. This novel class of cross-species FPR2/Fpr2 agonists should enable translation of results obtained with mouse neutrophils (and disease models) into enhanced understanding of human inflammatory and immune diseases. C1 [Holdfeldt, Andre; Winther, Malene; Gabl, Michael; Karlsson, Anna; Dahlgren, Claes; Forsman, Huamei] Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, S-40530 Gothenburg, Sweden. [Skovbakke, Sarah Line; Nielsen, Christina; Perez-Gassol, Iris; Larsen, Camilla Josephine; Franzyk, Henrik] Univ Copenhagen, Fac Hlth & Med Sci, Dept Drug Design & Pharmacol, Univ Pk 2, DK-2100 Copenhagen, Denmark. [Wang, Ji Ming] NCI Frederick, Canc & Inflammat Program, NIH, Frederick, MD 21702 USA. RP Forsman, H (reprint author), Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, S-40530 Gothenburg, Sweden. EM Huamei.forsman@rheuma.gu.se FU Swedish Research Council; King Gustaf V 80-Year Foundation; IngaBritt and Arne Lundbergs foundation; Sahlgrenska University Hospital through the national ALF agreement; Department of Drug Design and Pharmacology (Faculty of Health and Medical Sciences, University of Copenhagen); Aase and Ejnar Danielsens Foundation; King Christian 10th Foundation FX The Swedish research group was supported by grants from the Swedish Research Council, the King Gustaf V 80-Year Foundation, the IngaBritt and Arne Lundbergs foundation, and the Sahlgrenska University Hospital through the national ALF agreement. The authors declare that they have no conflicts of interest with the contents of this article.; Supported by grants from the Department of Drug Design and Pharmacology (Faculty of Health and Medical Sciences, University of Copenhagen), Aase and Ejnar Danielsens Foundation, and King Christian 10th Foundation. NR 51 TC 0 Z9 0 U1 3 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 SEP 16 PY 2016 VL 291 IS 38 BP 19888 EP 19899 DI 10.1074/jbc.M116.736850 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV9EO UT WOS:000383243100014 PM 27422818 ER PT J AU MacDonald, NJ Nguyen, V Shimp, R Reiter, K Herrera, R Burkhardt, M Muratova, O Kumar, K Aebig, J Rausch, K Lambert, L Dawson, N Sattabongkot, J Ambroggio, X Duffy, PE Wu, YM Narum, DL AF MacDonald, Nicholas J. Vu Nguyen Shimp, Richard Reiter, Karine Herrera, Raul Burkhardt, Martin Muratova, Olga Kumar, Krishan Aebig, Joan Rausch, Kelly Lambert, Lynn Dawson, Nikiah Sattabongkot, Jetsumon Ambroggio, Xavier Duffy, Patrick E. Wu, Yimin Narum, David L. TI Structural and Immunological Characterization of Recombinant 6-Cysteine Domains of the Plasmodium falciparum Sexual Stage Protein Pfs230 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE malaria; protein structure; recombinant protein expression; vaccine; yeast; Pfs230; Pichia pastoris; transmission blocking ID TRANSMISSION-BLOCKING VACCINE; RTS,S/AS01 MALARIA VACCINE; AERUGINOSA EXOPROTEIN-A; SURFACE-ANTIGEN PFS230; ANTIBODY-RESPONSES; ESCHERICHIA-COLI; CANDIDATE; PFS48/45; IMMUNITY; TARGET AB Development of a Plasmodium falciparum (Pf) transmission blocking vaccine (TBV) has the potential to significantly impact malaria control. Antibodies elicited against sexual stage proteins in the human bloodstream are taken up with the blood meal of the mosquitoes and inactivate parasite development in the mosquito. In a phase 1 trial, a leading TBV identified as Pfs25-EPA/Alhydrogel (R) appeared safe and immunogenic, however, the level of Pfs25-specific antibodies were likely too low for an effective vaccine. Pfs230, a 230-kDa sexual stage protein expressed in gametocytes is an alternative vaccine candidate. A unique 6-cysteine-rich domain structure within Pfs230 have thwarted its recombinant expression and characterization for clinical evaluation for nearly a quarter of a century. Here, we report on the identification, biochemical, biophysical, and immunological characterization of recombinant Pfs230 domains. Rabbit antibodies generated against recombinant Pfs230 domains blocked mosquito transmission of a laboratory strain and two field isolates using an ex vivo assay. A planned clinical trial of the Pfs230 vaccine is a significant step toward the potential development of a transmission blocking vaccine to eliminate malaria. C1 [MacDonald, Nicholas J.; Vu Nguyen; Shimp, Richard; Reiter, Karine; Herrera, Raul; Burkhardt, Martin; Muratova, Olga; Kumar, Krishan; Aebig, Joan; Rausch, Kelly; Lambert, Lynn; Dawson, Nikiah; Duffy, Patrick E.; Wu, Yimin; Narum, David L.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Twinbrook 1,Rm 1115, Rockville, MD 20852 USA. [Sattabongkot, Jetsumon] Mahidol Univ, Fac Trop Med, Mahidol Vivax Res Unit, Bangkok 10400, Thailand. [Ambroggio, Xavier] Rosetta Design Grp LLC, Burlington, VT 05401 USA. RP Narum, DL (reprint author), NIAID, Lab Malaria Immunol & Vaccinol, NIH, Twinbrook 1,Rm 1115, Rockville, MD 20852 USA. EM dnarum@niaid.nih.gov FU Wellcome Trust [098051, 090770] FX We thank Dr. Buddhadeb Mallik, Dr. Guan-Hong Song, Dr. Yanling Zhang, and Christopher Rowe for technical assistance within the Laboratory of Malaria Immunology and Vaccinology. Dr. Carl Hammer, Mark Garfield, from Research Technologies Branch, NIAID, for analytical support, and Dr. Michael Fay, from Biostatistics Research Branch, NIAID, for statistical support. Dr. Michael Nold from Waters Inc. for assistance with disulfide mapping studies, and Dr. Julian Rayner for the assistance with genotypic analysis of Pfs230 from the Wellcome Trust Sanger Institute. Finally we appreciate Dr. Louis Miller for his support and helpful discussion, This publication uses data from the MalariaGEN Pfalciparum Community Project as described in Ref. 28. Genome sequencing was performed by the Wellcome Trust Sanger Institute and the Community Projects is coordinated by the MalariaGENResource Centre with funding from the Wellcome Trust Grants 098051 and 090770. NR 45 TC 1 Z9 1 U1 8 U2 8 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 SEP 16 PY 2016 VL 291 IS 38 BP 19913 EP 19922 DI 10.1074/jbc.M116.732305 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV9EO UT WOS:000383243100016 PM 27432885 ER PT J AU Abeykoon, AH Noinaj, N Choi, BE Wise, L He, Y Chao, CC Wang, GH Gucek, M Ching, WM Chock, PB Buchanan, SK Yang, DCH AF Abeykoon, Amila H. Noinaj, Nicholas Choi, Bok-Eum Wise, Lindsay He, Yi Chao, Chien-Chung Wang, Guanghui Gucek, Marjan Ching, Wei-Mei Chock, P. Boon Buchanan, Susan K. Yang, David C. H. TI Structural Insights into Substrate Recognition and Catalysis in Outer Membrane Protein B (OmpB) by Protein-lysine Methyltransferases from Rickettsia SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE bacteria; cell surface protein; enzyme catalysis; enzyme structure; protein methylation; virulence factor ID HISTONE METHYLTRANSFERASE; PRODUCT SPECIFICITY; FUNCTIONAL-ANALYSIS; PROWAZEKII STRAINS; CHAPERONE DNAK; METHYLATION; DOMAIN; ROMPB; TYPHI; VIRULENCE AB Rickettsia belong to a family of Gram-negative obligate intracellular infectious bacteria that are the causative agents of typhus and spotted fever. Outer membrane protein B (OmpB) occurs in all rickettsial species, serves as a protective envelope, mediates host cell adhesion and invasion, and is a major immunodominant antigen. OmpBs from virulent strains contain multiple trimethylated lysine residues, whereas the avirulent strain contains mainly monomethyllysine. Two protein-lysine methyltransferases (PKMTs) that catalyze methylation of recombinant OmpB at multiple sites with varying sequences have been identified and overexpressed. PKMT1 catalyzes predominantly monomethylation, whereas PKMT2 catalyzes mainly trimethylation. Rickettsial PKMT1 and PKMT2 are unusual in that their primary substrate appears to be limited to OmpB, and both are capable of methylating multiple lysyl residues with broad sequence specificity. Here we report the crystal structures of PKMT1 from Rickettsia prowazekii and PKMT2 from Rickettsia typhi, both the apo form and in complex with its cofactor S-adenosylmethionine or S-adenosylhomocysteine. The structure of PKMT1 in complex with S-adenosylhomocysteine is solved to a resolution of 1.9 . Both enzymes are dimeric with each monomer containing an S-adenosylmethionine binding domain with a core Rossmann fold, a dimerization domain, a middle domain, a C-terminal domain, and a centrally located open cavity. Based on the crystal structures, residues involved in catalysis, cofactor binding, and substrate interactions were examined using site-directed mutagenesis followed by steady state kinetic analysis to ascertain their catalytic functions in solution. Together, our data reveal new structural and mechanistic insights into how rickettsial methyltransferases catalyze OmpB methylation. C1 [Abeykoon, Amila H.; Choi, Bok-Eum; Wise, Lindsay; Yang, David C. H.] Georgetown Univ, Dept Chem, Washington, DC 20057 USA. [Noinaj, Nicholas] Purdue Univ, Dept Biol Sci, Markey Ctr Struct Biol, W Lafayette, IN 47907 USA. [Wang, Guanghui; Gucek, Marjan] NHLBI, Prote Core Facil, NIH, Bethesda, MD 20892 USA. [Buchanan, Susan K.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Chao, Chien-Chung; Ching, Wei-Mei] Naval Med Res Ctr, Infect Dis Directorate, Viral & Rickettsial Dis Dept, Silver Spring, MD 20910 USA. RP Yang, DCH (reprint author), Georgetown Univ, Dept Chem, Washington, DC 20057 USA.; Noinaj, N (reprint author), Purdue Univ, Dept Biol Sci, Markey Ctr Struct Biol, W Lafayette, IN 47907 USA. EM nnoinaj@purdue.edu; yangdc@georgetown.edu FU United States Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX Data were collected at Southeast Regional Collaborative Access Team (SER-CAT) beamline 22-ID and the General Medicine Sciences and National Cancer Institute Collaborative Access Team (GM/CA-CAT) beamline 23-ID at the Advanced Photon Source, Argonne National Laboratory. Use of the Advanced Photon Source was supported by the United States Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract W-31-109-Eng-38. NR 49 TC 0 Z9 0 U1 5 U2 5 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 SEP 16 PY 2016 VL 291 IS 38 BP 19962 EP 19974 DI 10.1074/jbc.M116.723460 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV9EO UT WOS:000383243100020 PM 27474738 ER PT J AU Xu, Q Choksi, S Qu, JH Jang, J Choe, M Banfi, B Engelhardt, JF Liu, ZG AF Xu, Qing Choksi, Swati Qu, Jianhui Jang, Jonathan Choe, Moran Banfi, Botond Engelhardt, John F. Liu, Zheng-gang TI NADPH Oxidases Are Essential for Macrophage Differentiation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE cell biology; cell differentiation; macrophage; NADPH oxidase; reactive oxygen species (ROS) ID TUMOR-ASSOCIATED MACROPHAGES; ALTERNATIVELY ACTIVATED MACROPHAGES; CHRONIC GRANULOMATOUS-DISEASE; CRUCIAL ROLE; REPAIR; CELLS; POLARIZATION; INFLAMMATION; EXPRESSION; AUTOPHAGY AB NADPH oxidases (NOXs) are involved in inflammation, angiogenesis, tumor growth, and osteoclast differentiation. However, the role of NOX1 and NOX2 in macrophage differentiation and tumor progression is still elusive. Here we report that NOX1 and NOX2 are critical for the differentiation of monocytes to macrophages, the polarization of M2-type but not M1-type macrophages, and the occurrence of tumor-associated macrophages (TAMs). We found that deletion of both NOX1 and NOX2 led to a dramatic decrease in ROS production in macrophages and resulted in impaired efficiency in monocyte-to-macrophage differentiation and M2-type macrophage polarization. We further showed that NOX1 and NOX2 were critical for the activation of the MAPKs JNK and ERK during macrophage differentiation and that the deficiency of JNK and ERK activation was responsible for the failure of monocyte-to-macrophage differentiation, in turn affecting M2 macrophage polarization. Furthermore, we demonstrated that the decrease in M2 macrophages and TAMs, concomitant with the reduction of cytokine and chemokine secretion, contributed to the delay in wound healing and the inhibition of tumor growth and metastasis in NOX1/2 double knockout mice compared with WT mice. Collectively, these data provide direct evidence that NOX1 and NOX2 deficiency impairs macrophage differentiation and the occurrence of M2-type TAMs during tumor development. C1 [Xu, Qing; Choksi, Swati; Qu, Jianhui; Jang, Jonathan; Choe, Moran; Liu, Zheng-gang] NCI, Ctr Canc Res, NIH, Bldg 37,Rm 1130,37 Convent Dr, Bethesda, MD 20892 USA. [Banfi, Botond; Engelhardt, John F.] Univ Iowa, Dept Anat & Cell Biol, Iowa City, IA 52242 USA. RP Liu, ZG (reprint author), NCI, Ctr Canc Res, NIH, Bldg 37,Rm 1130,37 Convent Dr, Bethesda, MD 20892 USA. EM zgliu@helix.nih.gov FU Intramural Research Program of the Center for Cancer Research, NCI, National Institutes of Health FX This work was supported by the Intramural Research Program of the Center for Cancer Research, NCI, National Institutes of Health. 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 37 TC 1 Z9 1 U1 6 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 SEP 16 PY 2016 VL 291 IS 38 BP 20030 EP 20041 DI 10.1074/jbc.M116.731216 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV9EO UT WOS:000383243100026 PM 27489105 ER PT J AU Blondel, M Soubigou, F Evrard, J Nguyen, PH Hasin, N Chedin, S Gillet, R Contesse, MA Friocourt, G Stahl, G Jones, GW Voisset, C AF Blondel, Marc Soubigou, Flavie Evrard, Justine Phu Hai Nguyen Hasin, Naushaba Chedin, Stephane Gillet, Reynald Contesse, Marie-Astrid Friocourt, Gaelle Stahl, Guillaume Jones, Gary W. Voisset, Cecile TI Protein Folding Activity of the Ribosome is involved in Yeast Prion Propagation SO SCIENTIFIC REPORTS LA English DT Article ID SMALL NUCLEOLAR RNAS; SACCHAROMYCES-CEREVISIAE; IN-VIVO; ESCHERICHIA-COLI; MAMMALIAN PRIONS; NEURODEGENERATIVE DISEASES; HUNTINGTONS-DISEASE; INFECTIOUS PROTEIN; GENETIC-ANALYSIS; ANTIPRION DRUGS AB 6AP and GA are potent inhibitors of yeast and mammalian prions and also specific inhibitors of PFAR, the protein-folding activity borne by domain V of the large rRNA of the large subunit of the ribosome. We therefore explored the link between PFAR and yeast prion [PSI+] using both PFAR-enriched mutants and site-directed methylation. We demonstrate that PFAR is involved in propagation and de novo formation of [PSI+]. PFAR and the yeast heat-shock protein Hsp104 partially compensate each other for [PSI+] propagation. Our data also provide insight into new functions for the ribosome in basal thermotolerance and heat-shocked protein refolding. PFAR is thus an evolutionarily conserved cell component implicated in the prion life cycle, and we propose that it could be a potential therapeutic target for human protein misfolding diseases. C1 [Blondel, Marc; Soubigou, Flavie; Evrard, Justine; Phu Hai Nguyen; Contesse, Marie-Astrid; Friocourt, Gaelle; Voisset, Cecile] Univ Bretagne Occidentale, INSERM, UMR 1078, Fac Med & Sci Sante, Brest, France. [Blondel, Marc; Soubigou, Flavie; Evrard, Justine; Phu Hai Nguyen; Contesse, Marie-Astrid; Friocourt, Gaelle; Voisset, Cecile] Etab Francais Sang EFS Bretagne, Brest, France. [Blondel, Marc; Soubigou, Flavie; Evrard, Justine; Phu Hai Nguyen; Contesse, Marie-Astrid; Friocourt, Gaelle; Voisset, Cecile] CHRU Brest, Hop Morvan, Lab Genet Mol, Brest, France. [Hasin, Naushaba; Jones, Gary W.] Maynooth Univ, Dept Biol, Yeast Genet Lab, Maynooth, Kildare, Ireland. [Chedin, Stephane] Univ Paris 11, CEA Saclay, CNRS,SBIGeM, Inst Integrat Biol Cell I2BC,UMR 9198,CEA, Gif Sur Yvette, France. [Gillet, Reynald] Univ Rennes 1, CNRS, UMR IGDR 6290, Translat & Folding Team, Rennes, France. [Stahl, Guillaume] Univ Toulouse, CNRS, Lab Biol Mol Eucaryotes, Toulouse, France. [Phu Hai Nguyen] NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, NIH,Rocky Mt Labs, Hamilton, NJ USA. [Hasin, Naushaba] NICHHD, Sect Format RNA, NIH, Bethesda, MD 20814 USA. [Jones, Gary W.] Leeds Beckett Univ, Fac Hlth & Social Sci, Sch Clin & Appl Sci, Leeds LS1 3HE, W Yorkshire, England. RP Voisset, C (reprint author), Univ Bretagne Occidentale, INSERM, UMR 1078, Fac Med & Sci Sante, Brest, France.; Voisset, C (reprint author), Etab Francais Sang EFS Bretagne, Brest, France.; Voisset, C (reprint author), CHRU Brest, Hop Morvan, Lab Genet Mol, Brest, France. EM cecile.voisset@univ-brest.fr NR 80 TC 1 Z9 1 U1 7 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 SEP 16 PY 2016 VL 6 AR 32117 DI 10.1038/srep32117 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW0JU UT WOS:000383327500001 PM 27633137 ER PT J AU Crowell, TA Fletcher, JLK Sereti, I Pinyakorn, S Dewar, R Krebs, SJ Chomchey, N Rerknimitr, R Schuetz, A Michael, NL Phanuphak, N Chomont, N Ananworanich, J AF Crowell, Trevor A. Fletcher, James L. K. Sereti, Irini Pinyakorn, Suteeraporn Dewar, Robin Krebs, Shelly J. Chomchey, Nitiya Rerknimitr, Rungsun Schuetz, Alexandra Michael, Nelson L. Phanuphak, Nittaya Chomont, Nicolas Ananworanich, Jintanat CA RV254 SEAR010 Study Grp TI Initiation of antiretroviral therapy before detection of colonic infiltration by HIV reduces viral reservoirs, inflammation and immune activation SO JOURNAL OF THE INTERNATIONAL AIDS SOCIETY LA English DT Article DE HIV; inflammation; CD4 lymphocyte count; highly active antiretroviral therapy; virus latency; infectious disease reservoirs ID VIRUS TYPE-1 INFECTION; CD4(+) T-CELLS; GUT EPITHELIAL BARRIER; IMMUNODEFICIENCY-VIRUS; LYMPHOID-TISSUE; GASTROINTESTINAL-TRACT; POSITIVE PATIENTS; SIV INFECTION; PERSISTENCE; MUCOSA AB Introduction: Colonic infiltration by HIV occurs soon after infection, establishing a persistent viral reservoir and a barrier to cure. We investigated virologic and immunologic correlates of detectable colonic HIV RNA during acute HIV infection (AHI) and their response to antiretroviral treatment (ART). Methods: From 49,458 samples screened for HIV, 74 participants were enrolled during AHI and 41 consented to optional sigmoidoscopy, HIV RNA was categorized as detectable (>= 50 copies/mg) or undetectable in homogenized colon biopsy specimens. Biomarkers and HIV burden in blood, colon and cerebrospinal fluid were compared between groups and after 24 weeks of ART. Results: Colonic HIV RNA was detectable in 31 participants (76%) and was associated with longer duration since HIV exposure (median 16 vs. 11 days, p = 0.02), higher median plasma levels of cytokines and inflammatory markers (CXCL10 476 vs. 148 pg/mL, p = 0.02; TNF-RII 1036 vs. 649 pg/mL, p < 0.01; neopterin 2405 vs. 1368 pg/mL, p = 0.01) and higher levels of CD8 + T cell activation in the blood (human leukocyte antigen - antigen D related (HLA-DR)/CD38 expression 14.4% vs. 7.6%, p < 0.01) and colon (8.9% vs. 4.5%, p = 0.01). After 24 weeks of ART, participants with baseline detectable colonic HIV RNA demonstrated persistent elevations in total HIV DNA in colonic mucosal mononuclear cells (CMMCs) (median 61 vs. 0 copies/10(6) CMMCs, p = 0.03) and a trend towards higher total HIV DNA in peripheral blood mononuclear cells (PBMC) (41 vs. 1.5 copies/10(6) PBMCs, p = 0.06). There were no persistent differences in immune activation and inflammation. Conclusions: The presence of detectable colonic HIV RNA at the time of ART initiation during AHI is associated with higher levels of proviral DNA after 24 weeks of treatment. Seeding of HIV in the gut may have long-lasting effects on the size of persistent viral reservoirs and may represent an important therapeutic target in eradication strategies. C1 [Crowell, Trevor A.; Pinyakorn, Suteeraporn; Krebs, Shelly J.; Michael, Nelson L.; Ananworanich, Jintanat] Walter Reed Army Inst Res, US Mil HIV Res Program, 6720A Rockledge Dr,Suite 400, Bethesda, MD 20817 USA. [Crowell, Trevor A.; Pinyakorn, Suteeraporn; Krebs, Shelly J.; Schuetz, Alexandra; Ananworanich, Jintanat] Henry M Jackson Fdn Adv Mil Med, Bethesda, MD USA. [Fletcher, James L. K.; Chomchey, Nitiya; Phanuphak, Nittaya; Ananworanich, Jintanat] Thai Red Cross AIDS Res Ctr, SEARCH, Bangkok, Thailand. [Sereti, Irini] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Dewar, Robin] Natl Canc Inst Frederick, Virus Isolat & Serol Lab, Frederick, MD USA. [Rerknimitr, Rungsun] Chulalongkorn Univ, Fac Med, Dept Med, Bangkok, Thailand. [Schuetz, Alexandra] Armed Forces Res Inst Med Sci United States Compo, Dept Retrovirol, Bangkok, Thailand. [Chomont, Nicolas] Univ Montreal, Fac Med, Dept Microbiol Infectiol & Immunol, Montreal, PQ, Canada. [Chomont, Nicolas] CHUM, Ctr Rech, Montreal, PQ, Canada. RP Crowell, TA (reprint author), Walter Reed Army Inst Res, US Mil HIV Res Program, 6720A Rockledge Dr,Suite 400, Bethesda, MD 20817 USA. EM tcrowell@hivresearch.org FU Henry M Jackson Foundation for Advancement of Military Medicine, Inc. [W81XWH-07-2-0067, W81XWH-11-2-0174]; US Department of the Army; Thai Red Cross AIDS Research Center; Intramural Research Program of the National Institute of Allergy and Infectious Diseases (National Institutes of Health); Delaney AIDS Research Enterprise to find a cure (DARE) [1U19AI096109]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Thai Government Pharmaceutical Organization; Gilead; Merck and Pfizer FX We thank our study participants and staff from the Thai Red Cross AIDS Research Centre, Chulalongkorn University and AFRIMS for their valuable contributions to this study. We are grateful to the Thai Government Pharmaceutical Organization, ViiV Healthcare, Gilead and Merck for providing the antiretrovirals for this study. The RV254/SEARCH 010 Study Group includes from SEARCH/TRCARC/HIV-NAT: Nipat Teeratakulpisarn, Donn Colby, Duanghathai Sutthichom, Somprartthana Rattanamanee, Peeriya Prueksakaew, Sasiwimol Ubolyam, Pacharin Eamyoung, Suwanna Puttamaswin, Somporn Tipsuk and Putthachard Karnsomlap; from Chulalongkorn University: Wiriyaporn Ridtitid; from AFRIMS: Robert J O'Connell, Siriwat Akapirat, Yuwadee Phuang-Ngern, Suchada Sukhumvittaya, Chayada Sajjaweerawan, Surat Jongrakthaitae, Putita Saetun, Nipattra Tragonlugsana, Bessara Nuntapinit, Rapee Trichavaroj, Nantana Tantibul and Hathairat Savadsuk; from the US Military HIV Research Program: Merlin Robb, Michael Eller, Silvia-Ratto Kim, Bonnie Slike and Sodsai Tovanabutra; from VGTI Florida: Claire Vandergeeten, Wendy Bakeman, Amanda McNulty and Remi Fromentin; from Monogram Biosciences: Laura Napolitano, Molly Martell, Yolanda Lie, and the R&D and PDO groups. This work was supported by cooperative agreements (W81XWH-07-2-0067, W81XWH-11-2-0174) between the Henry M Jackson Foundation for the Advancement of Military Medicine, Inc., and the US Department of the Army and by an intramural grant from the Thai Red Cross AIDS Research Center. The US Army Medical Research Acquisition Activity (820 Chandler Street, Fort Detrick, MD 21702-5014, USA) is the awarding and administering acquisition office for the cooperative agreement. This research was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (National Institutes of Health) and the Delaney AIDS Research Enterprise to find a cure (DARE, 1U19AI096109). It has also been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. Antiretroviral therapy was supported by the Thai Government Pharmaceutical Organization, Gilead, Merck and Pfizer. NR 62 TC 0 Z9 0 U1 2 U2 2 PU INT AIDS SOCIETY PI GENEVA PA AVENUE DE FRANCE 23, GENEVA, 1202, SWITZERLAND SN 1758-2652 J9 J INT AIDS SOC JI J. Int. AIDS Soc. PD SEP 15 PY 2016 VL 19 AR 21163 DI 10.7448/IAS.19.1.21163 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA ED5FC UT WOS:000388876000001 PM 27637172 ER PT J AU Varshney, GK Burgess, SM AF Varshney, Gaurav K. Burgess, Shawn M. TI DNA-guided genome editing using structure-guided endonucleases SO GENOME BIOLOGY LA English DT Article ID ARGONAUTE AB The search for novel ways to target and alter the genomes of living organisms accelerated rapidly this decade with the discovery of CRISPR/Cas9. Since the initial discovery, efforts to find alternative methods for altering the genome have expanded. A new study presenting an alternative approach has been demonstrated that utilizes flap endonuclease 1 (FEN-1) fused to the Fok1 endonuclease, which shows potential for DNA-guided genome targeting in vivo. C1 [Varshney, Gaurav K.] Oklahoma Med Res Fdn, Funct & Chem Genom Program, 825 NE 13th St, Oklahoma City, OK 73104 USA. [Burgess, Shawn M.] NHGRI, Translat & Funct Genom Branch, NIH, Bethesda, MD 20892 USA. RP Burgess, SM (reprint author), NHGRI, Translat & Funct Genom Branch, NIH, Bethesda, MD 20892 USA. EM burgess@mail.nih.gov OI Varshney, Gaurav K./0000-0002-0429-1904 NR 9 TC 0 Z9 0 U1 9 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1474-760X J9 GENOME BIOL JI Genome Biol. PD SEP 15 PY 2016 VL 17 AR 187 DI 10.1186/s13059-016-1055-4 PG 4 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DW1UP UT WOS:000383428400003 PM 27640875 ER PT J AU Smarr, MM Kannan, K Louis, GMB AF Smarr, Melissa M. Kannan, Kurunthachalam Louis, Germaine M. Buck TI Endocrine disrupting chemicals and endometriosis SO FERTILITY AND STERILITY LA English DT Review DE Chemicals; endocrine disruptors; endometriosis; environment; pesticides ID FEMALE REPRODUCTIVE DISORDERS; DIOXIN-LIKE COMPOUNDS; IN-UTERO EXPOSURES; POLYCHLORINATED-BIPHENYLS; ENVIRONMENTAL CHEMICALS; ITALIAN WOMEN; BODY-SIZE; RISK; ENDO; ASSOCIATION AB Endometriosis is an estrogen dependent gynecologic disease with lasting implications for many women's fertility, somatic health, and overall quality of life. Growing evidence suggests that endocrine disrupting chemicals (EDCs) may be etiologically involved in the development and severity of disease. We weigh the available human evidence focusing on EDCs and endometriosis, restricting to research that has individually quantified chemical concentrations for women, included a comparison group of unaffected women, and used multivariable analytic techniques. Evidence supporting an environmental etiology for endometriosis includes metals/trace elements, dioxins, and other persistent organic pollutants, as well as nonpersistent chemicals, such as benzophenones and phthalates. To address the equivocal findings for various EDCs, future research directions for filling data gaps include [1] use of integrated clinical and population sampling frameworks allowing for incorporation of new diagnostic modalities; [2] the collection of various biologic media, including target tissues for quantifying exposures; [3] study designs that offer various comparison groups to assess potentially shared etiologies with other gynecologic disorders; and [4] novel laboratory and statistical approaches that fully explore all measured EDCs for the assessment of mixtures and low dose effects and the use of directed acyclic graphs and supporting causal analysis for empirically delineating relationships between EDCs and endometriosis. (C) 2016 by American Society for Reproductive Medicine. C1 [Smarr, Melissa M.; Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Off Director, 6710B Rockledge Dr, Bethesda, MD 20829 USA. [Kannan, Kurunthachalam] New York State Dept Hlth, Wadsworth Ctr, Albany, NY USA. RP Smarr, MM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Off Director, 6710B Rockledge Dr, Bethesda, MD 20829 USA. EM Melissa.smarr@nih.gov OI Smarr, Melissa/0000-0002-4347-405X; Buck Louis, Germaine/0000-0002-1774-4490 NR 70 TC 2 Z9 2 U1 17 U2 20 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP 15 PY 2016 VL 106 IS 4 BP 959 EP 966 DI 10.1016/j.fertnstert.2016.06.034 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA EA7QU UT WOS:000386827500014 PM 27424048 ER PT J AU Buchacz, K Lau, B Jing, YZ Bosch, R Abraham, AG Gill, MJ Silverberg, MJ Goedert, JJ Sterling, TR Althoff, KN Martin, JN Burkholder, G Gandhi, N Samji, H Patel, P Rachlis, A Thorne, JE Napravnik, S Henry, K Mayor, A Gebo, K Gange, SJ Moore, RD Brooks, JT AF Buchacz, Kate Lau, Bryan Jing, Yuezhou Bosch, Ronald Abraham, Alison G. Gill, M. John Silverberg, Michael J. Goedert, James J. Sterling, Timothy R. Althoff, Keri N. Martin, Jeffrey N. Burkholder, Greer Gandhi, Neel Samji, Hasina Patel, Pragna Rachlis, Anita Thorne, Jennifer E. Napravnik, Sonia Henry, Keith Mayor, Angel Gebo, Kelly Gange, Stephen J. Moore, Richard D. Brooks, John T. CA IeDEA TI Incidence of AIDS-Defining Opportunistic Infections in a Multicohort Analysis of HIV-infected Persons in the United States and Canada, 2000-2010 SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE AIDS-related opportunistic infections; HIV cohort studies; incidence; prophylaxis; combination antiretroviral therapy; CD4(+) T-lymphocyte count; epidemiology ID COMBINATION ANTIRETROVIRAL THERAPY; RECONSTITUTION INFLAMMATORY SYNDROME; CD4 CELL COUNT; COHORT COLLABORATION; NONFATAL AIDS; VIRAL LOAD; MORTALITY; ERA; ILLNESSES; EVENTS AB Background. There are few recent data on the rates of AIDS-defining opportunistic infections (OIs) among human immunodeficiency virus (HIV)-infected patients in care in the United States and Canada. Methods. We studiedHIV-infected participants in 16 cohorts in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) during 2000-2010. After excluding 16 737 (21%) with any AIDS-defining clinical events documented before NA-ACCORD enrollment, we analyzed incident OIs among the remaining 63 541 persons, most of whom received antiretroviral therapy during the observation. We calculated incidence rates per 100 person-years of observation (hereafter, "person-years") with 95% confidence intervals (CIs) for the first occurrence of any OI and select individual OIs during 2000-2003, 2004-2007, and 2008-2010. Results. A total of 63 541 persons contributed 261 573 person-years, of whom 5836 (9%) developed at least 1 OI. The incidence rate of any first OI decreased over the 3 observation periods, with 3.0 cases, 2.4 cases, and 1.5 cases per 100 person-years of observation during 2000-2003, 2004-2007, and 2008-2010, respectively (Ptrend<. 001); the rates of most individual OIs decreased as well. During 2008-2010, the leading OIs included Pneumocystis jiroveci pneumonia, esophageal candidiasis, and disseminated Mycobacterium avium complex or Mycobacterium kansasii infection. Conclusions. For HIV-infected persons in care during 2000-2010, rates of first OI were relatively low and generally declined over this time. C1 [Buchacz, Kate; Patel, Pragna; Brooks, John T.] Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Atlanta, GA USA. [Lau, Bryan; Jing, Yuezhou; Abraham, Alison G.; Althoff, Keri N.; Samji, Hasina; Thorne, Jennifer E.; Gebo, Kelly; Gange, Stephen J.; Moore, Richard D.] Johns Hopkins Univ, Baltimore, MD USA. [Bosch, Ronald] Harvard Univ, Boston, MA 02115 USA. [Gill, M. John] Univ Calgary, Calgary, AB T2N 1N4, Canada. [Silverberg, Michael J.] Kaiser Permanente Northern Calif, Oakland, CA USA. [Goedert, James J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Sterling, Timothy R.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Martin, Jeffrey N.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Burkholder, Greer] Univ Alabama Birmingham, Birmingham, AL USA. [Gandhi, Neel] Emory Univ, Atlanta, GA 30322 USA. [Samji, Hasina] British Columbia Ctr Excellence HIV AIDS, Vancouver, BC, Canada. [Rachlis, Anita] Univ Toronto, Toronto, ON M5S 1A1, Canada. [Napravnik, Sonia] Univ North Carolina Chapel Hill, Chapel Hill, NC USA. [Henry, Keith] Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. [Mayor, Angel] Univ Cent Caribe, Bayamon, PR USA. RP Buchacz, K (reprint author), Ctr Dis Control & Prevent, 1600 Clifton Rd NE,Mailstop E-45, Atlanta, GA 30329 USA. EM acu7@cdc.gov FU NIH [U01AI069918, F31DA037788, G12MD007583, K01AI093197, K23EY013707, K24DA000432, K24AI065298, KL2TR000421, M01RR000052, N02CP055504, P30AI027757, P30AI027763, P30AI027767, P30AI036219, P30AI050410, P30AI094189, P30AI110527, P30MH62246, 01AA016893]; CDC [CDC-200-2006-18797, CDC-200-2015-63931]; Agency for Healthcare Research and Quality [90047713]; Health Resources and Services Administration [90051652]; Canadian Institutes of Health Research [CBR-86906, CBR-94036, HCP-97105, TGF-96118]; Ontario Ministry of Health and Long Term Care; Government of Alberta, Canada; Intramural Research Program of the National Cancer Institute; THE NIH [R01CA165937, R01DA004334, R01DA011602, R01DA012568, R24AI067039, U01AA013566, U01AA020790, U01AI031834, U01AI034989, U01AI034993, U01AI034994, U01AI035004, U01AI035039, U01AI035040, U01AI035041, U01AI035042, U01AI037613, U01AI037984, U01AI038855, U01AI042590, U01AI068634]; A NIH [U01AI068636, U01AI069432, U01AI069434, U01AI103390, U01AI103397, U01AI103401, U01AI103408, U01DA036935, U01HD032632, U10EY008057, U10EY008052, U10EY008067, U24AA020794, U54MD007587, UL1RR024131, UL1TR000004, UL1TR000083, UL1TR000454, UM1AI035043, U01AI038858] FX This work was supported by NIH (grants U01AI069918, F31DA037788, G12MD007583, K01AI093197, K23EY013707, K24DA000432, K24AI065298, KL2TR000421, M01RR000052, N02CP055504, P30AI027757, P30AI027763, P30AI027767, P30AI036219, P30AI050410, P30AI094189, P30AI110527, P30MH62246, 01AA016893, R01CA165937, R01DA004334, R01DA011602, R01DA012568, R24AI067039, U01AA013566, U01AA020790, U01AI031834, U01AI034989, U01AI034993, U01AI034994, U01AI035004, U01AI035039, U01AI035040, U01AI035041, U01AI035042, U01AI037613, U01AI037984, U01AI038855, U01AI038858, U01AI042590, U01AI068634, U01AI068636, U01AI069432, U01AI069434, U01AI103390, U01AI103397, U01AI103401, U01AI103408, U01DA036935, U01HD032632, U10EY008057, U10EY008052, U10EY008067, U24AA020794, U54MD007587, UL1RR024131, UL1TR000004, UL1TR000083, UL1TR000454, UM1AI035043, Z01CP010214 and Z01CP010176); the CDC (contract CDC-200-2006-18797 and CDC-200-2015-63931); the Agency for Healthcare Research and Quality (contract 90047713); the Health Resources and Services Administration (contract 90051652); Canadian Institutes of Health Research (grants CBR-86906, CBR-94036, HCP-97105 and TGF-96118); Ontario Ministry of Health and Long Term Care; and the Government of Alberta, Canada. Additional support was provided by the Intramural Research Program of the National Cancer Institute. NR 41 TC 2 Z9 2 U1 5 U2 5 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 SEP 15 PY 2016 VL 214 IS 6 BP 862 EP 872 DI 10.1093/infdis/jiw085 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DZ8RB UT WOS:000386137400007 PM 27559122 ER PT J AU Jegaskanda, S Luke, C Hickman, HD Sangster, MY Wieland-Alter, WF McBride, JM Yewdell, JW Wright, PF Treanor, J Rosenberger, CM Subbarao, K AF Jegaskanda, Sinthujan Luke, Catherine Hickman, Heather D. Sangster, Mark Y. Wieland-Alter, Wendy F. McBride, Jacqueline M. Yewdell, Jon W. Wright, Peter F. Treanor, John Rosenberger, Carrie M. Subbarao, Kanta TI Generation and Protective Ability of Influenza Virus-Specific Antibody-Dependent Cellular Cytotoxicity in Humans Elicited by Vaccination, Natural Infection, and Experimental Challenge SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE ADCC; influenza; vaccine; immunity ID IN-VIVO; H1N1; CHILDREN; CELLS; IMMUNOGLOBULIN; VACCINES; ADULTS AB Background. Nonneutralizing antibodies (Abs) involved in antibody-dependent cellular cytotoxicity (ADCC) may provide some protection from influenza virus infection. The ability of influenza vaccines to induce ADCC-mediating Abs (ADCC-Abs) in adults and children is unclear. Methods. We quantified ADCC-Abs in serum samples from adults who received a dose of inactivated subunit vaccine (ISV) targeting monovalent 2009 pandemic influenza A(H1N1) virus or live-attenuated influenza vaccine (LAIV) or who had laboratory- confirmed influenza A(H1N1) virus infection. We also measured ADCC-Abs in children who either received a dose of trivalent seasonal ISV followed by trivalent seasonal LAIV or 2 doses of LAIV. Finally, we assessed the ability of low and high ADCC-Ab titers to protect adults from experimental challenge with influenza A/Wisconsin/67/131/2005(H3N2) virus. Results. Adults and children who received a dose of ISV had a robust increase in ADCC-Ab titers to both recombinant hemagglutinin (rHA) protein and homologous virus-infected cells. There was no detectable increase in titers of ADCC-Abs to rHA or virus-infected cells in adults and children who received LAIV. Higher titers (>= 320) of preexisting ADCC-Abs were associated with lower virus replication and a significant reduction in total symptom scores in experimentally infected adults. Conclusions. ADCC-Ab titers increased following experimental influenza virus infection in adults and after ISV administration in both children and adults. C1 [Jegaskanda, Sinthujan; Luke, Catherine; Subbarao, Kanta] NIAID, Lab Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Hickman, Heather D.; Yewdell, Jon W.] NIAID, Lab Viral Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Sangster, Mark Y.; Treanor, John] Univ Rochester, Med Ctr, Dept Med, New York, NY USA. [Wieland-Alter, Wendy F.; Wright, Peter F.] Geisel Sch Med Dartmouth, Dept Pediat, Hanover, NH USA. [McBride, Jacqueline M.] Genentech Inc, Biomarker Dev, San Francisco, CA USA. [Rosenberger, Carrie M.] Genentech Inc, Biomarker Discovery, San Francisco, CA USA. [Jegaskanda, Sinthujan] Peter Doherty Inst Infect & Immun, Dept Microbiol & Immunol, Melbourne, Vic, Australia. RP Jegaskanda, S (reprint author), Peter Doherty Inst Infect & Immun, Dept Microbiol & Immunol, Melbourne, Vic, Australia. EM sjeg@unimelb.edu.au FU Australian National Health and Medical Research Council; Australia Early Career Fellowship [APP1072127]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Australian National Health and Medical Research Council, an Australia Early Career Fellowship (APP1072127), and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 27 TC 3 Z9 3 U1 1 U2 2 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 SEP 15 PY 2016 VL 214 IS 6 BP 945 EP 952 DI 10.1093/infdis/jiw262 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DZ8RB UT WOS:000386137400015 PM 27354365 ER PT J AU Toepfer, CN West, TG Ferenczi, MA AF Toepfer, Christopher N. West, Timothy G. Ferenczi, Michael A. TI Revisiting Frank-Starling: regulatory light chain phosphorylation alters the rate of force redevelopment (k(tr)) in a length-dependent fashion SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article DE cardiac muscle; force redevelopment; muscle contraction; phosphorylation; regulatory light chain ID SKELETAL-MUSCLE FIBERS; CROSS-BRIDGE KINETICS; RABBIT PSOAS FIBERS; CARDIAC-MUSCLE; ACTIVATION DEPENDENCE; TENSION DEVELOPMENT; SARCOMERE-LENGTH; STRETCH ACTIVATION; CA2+ SENSITIVITY; MYOSIN KINETICS AB Key points Regulatory light chain (RLC) phosphorylation has been shown to alter the ability of muscle to produce force and power during shortening and to alter the rate of force redevelopment (k(tr)) at submaximal [Ca2+]. Increasing RLC phosphorylation approximate to 50% from the in vivo level in maximally [Ca2+]-activated cardiac trabecula accelerates k(tr). Decreasing RLC phosphorylation to approximate to 70% of the in vivo control level slows k(tr) and reduces force generation.k(tr) is dependent on sarcomere length in the physiological range 1.85-1.94m and RLC phosphorylation modulates this response. We demonstrate that Frank-Starling is evident at maximal [Ca2+] activation and therefore does not necessarily require length-dependent change in [Ca2+]-sensitivity of thin filament activation. The stretch response is modulated by changes in RLC phosphorylation, pinpointing RLC phosphorylation as a modulator of the Frank-Starling law in the heart. These data provide an explanation for slowed systolic function in the intact heart in response to RLC phosphorylation reduction. AbstractForce and power in cardiac muscle have a known dependence on phosphorylation of the myosin-associated regulatory light chain (RLC). We explore the effect of RLC phosphorylation on the ability of cardiac preparations to redevelop force (k(tr)) in maximally activating [Ca2+]. Activation was achieved by rapidly increasing the temperature (temperature-jump of 0.5-20oC) of permeabilized trabeculae over a physiological range of sarcomere lengths (1.85-1.94m). The trabeculae were subjected to shortening ramps over a range of velocities and the extent of RLC phosphorylation was varied. The latter was achieved using an RLC-exchange technique, which avoids changes in the phosphorylation level of other proteins. The results show that increasing RLC phosphorylation by 50% accelerates k(tr) by approximate to 50%, irrespective of the sarcomere length, whereas decreasing phosphorylation by 30% slows k(tr) by approximate to 50%, relative to the k(tr) obtained for in vivo phosphorylation. Clearly, phosphorylation affects the magnitude of k(tr) following step shortening or ramp shortening. Using a two-state model, we explore the effect of RLC phosphorylation on the kinetics of force development, which proposes that phosphorylation affects the kinetics of both attachment and detachment of cross-bridges. In summary, RLC phosphorylation affects the rate and extent of force redevelopment. These findings were obtained in maximally activated muscle at saturating [Ca2+] and are not explained by changes in the Ca2+-sensitivity of acto-myosin interactions. The length-dependence of the rate of force redevelopment, together with the modulation by the state of RLC phosphorylation, suggests that these effects play a role in the Frank-Starling law of the heart. C1 [Toepfer, Christopher N.; Ferenczi, Michael A.] Imperial Coll London, Natl Heart & Lung Inst, Mol Med Sect, London, England. [Toepfer, Christopher N.] NHLBI, Lab Mol Physiol, NIH, Bldg 10, Bethesda, MD 20892 USA. [West, Timothy G.] Royal Vet Coll London, Struct & Mot Lab, N Mymms, England. [Ferenczi, Michael A.] Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore, Singapore. RP Toepfer, CN (reprint author), Harvard Med Sch, Dept Genet, NRB Room 256,77 Ave Louis Pasteur, Boston, MA 02115 USA. EM christopher_toepfer@HMS.harvard.edu RI Ferenczi, Michael/F-9510-2015; OI Ferenczi, Michael/0000-0002-0349-331X; Toepfer, Christopher/0000-0003-4671-2030 FU Wellcome Trust [091460/Z/10/Z] FX The present study was supported by Wellcome Trust Grant 091460/Z/10/Z. NR 73 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3751 EI 1469-7793 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD SEP 15 PY 2016 VL 594 IS 18 BP 5237 EP 5254 DI 10.1113/JP272441 PG 18 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA DW3VO UT WOS:000383571400022 PM 27291932 ER PT J AU Guven, G Lohmann, E Bras, J Gibbs, JR Gurvit, H Bilgic, B Hanagasi, H Rizzu, P Heutink, P Emre, M Erginel-Unaltuna, N Just, W Hardy, J Singleton, A Guerreiro, R AF Guven, Gamze Lohmann, Ebba Bras, Jose Gibbs, J. Raphael Gurvit, Hakan Bilgic, Basar Hanagasi, Hasmet Rizzu, Patrizia Heutink, Peter Emre, Murat Erginel-Unaltuna, Nihan Just, Walter Hardy, John Singleton, Andrew Guerreiro, Rita TI Mutation Frequency of the Major Frontotemporal Dementia Genes, MAPT, GRN and C9ORF72 in a Turkish Cohort of Dementia Patients SO PLOS ONE LA English DT Article ID HEXANUCLEOTIDE REPEAT EXPANSION; LOBAR DEGENERATION; PROGRANULIN MUTATION; NULL MUTATIONS; TAU-MUTATIONS; DISEASE; RECOMMENDATIONS; ASSOCIATION; GUIDELINES; EPSILON-4 AB 'Microtubule-associated protein tau' (MAPT), 'granulin' (GRN) and 'chromosome 9 open reading frame72' (C9ORF72) genemutations are the major known genetic causes of frontotemporal dementia (FTD). Recent studies suggest that mutations in these genes may also be associated with other forms of dementia. Therefore we investigated whether MAPT, GRN and C9ORF72 genemutations are major contributors to dementia in a random, unselected Turkish cohort of dementia patients. A combination of whole-exome sequencing, Sanger sequencing and fragment analysis/Southern blot was performed in order to identify pathogenic mutations and novel variants in these genes as well as other FTD-related genes such as the 'charged multivesicular body protein 2B' (CHMP2B), the 'FUS RNA binding protein' (FUS),the 'TAR DNA binding protein' (TARDBP), the 'sequestosome1' (SQSTM1), and the 'valosin containing protein' (VCP). We determined one pathogenic MAPT mutation (c. 1906C> T, p. P636L) and one novel missense variant (c. 38A> G, p. D13G). In GRN we identified a probably pathogenic TGAG deletion in the splice donor site of exon 6. Three patients were found to carry the GGGGCC expansions in the non-coding region of the C9ORF72 gene. In summary, a complete screening for mutations in MAPT, GRN and C9ORF72 genes revealed a frequency of 5.4% of pathogenicmutations in a random cohort of 93 Turkish index patients with dementia. C1 [Guven, Gamze; Erginel-Unaltuna, Nihan] Istanbul Univ, Inst Expt Med, Dept Genet, Istanbul, Turkey. [Lohmann, Ebba; Gurvit, Hakan; Bilgic, Basar; Hanagasi, Hasmet; Emre, Murat] Istanbul Univ, Istanbul Fac Med, Dept Neurol, Behav Neurol & Movement Disorders Unit, Istanbul, Turkey. [Lohmann, Ebba; Heutink, Peter] Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany. [Lohmann, Ebba; Rizzu, Patrizia; Heutink, Peter] German Ctr Neurodegenerat Dis, DZNE, Tubingen, Germany. [Bras, Jose; Hardy, John] UCL, Inst Neurol, Dept Mol Neurosci, London, England. [Bras, Jose; Guerreiro, Rita] Univ Aveiro, Dept Med Sci, P-3810193 Aveiro, Portugal. [Bras, Jose; Guerreiro, Rita] Univ Aveiro, Inst Biomed iBiMED, P-3810193 Aveiro, Portugal. [Gibbs, J. Raphael; Singleton, Andrew] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Just, Walter] Univ Ulm, Inst Human Genet, Ulm, Germany. RP Lohmann, E (reprint author), Istanbul Univ, Istanbul Fac Med, Dept Neurol, Behav Neurol & Movement Disorders Unit, Istanbul, Turkey.; Lohmann, E (reprint author), Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany.; Lohmann, E (reprint author), German Ctr Neurodegenerat Dis, DZNE, Tubingen, Germany. EM ebbalohmann@gmx.net RI bilgic, basar/E-4821-2012; Hardy, John/C-2451-2009 FU Alzheimer's Research UK (ARUK); Wellcome Trust/MRC [WT089698]; National Institute on Aging; National Institute of Neurological Disease and Stroke, National Institutes of Health, Department Of Health and Human Services [ZO1 AG000950-10]; ARUK Alzheimer's Society; European Social Fund; Ministry of Science Research and the Arts Baden-Wurttemberg; Alzheimer's Society; Alzheimer's Research UK; National Institute on Aging, National Institutes of Health, Department of Health and Human Services FX This work was supported in part by the Alzheimer's Research UK (ARUK) by an anonymous donor, by the Wellcome Trust/MRC Joint Call in Neurodegeneration award (WT089698) to the UK Parkinson's Disease Consortium whose members are from the UCL/Institute of Neurology, the University of Sheffield and the MRC Protein Phosphorylation Unit at the University of Dundee; by the Intramural Research Programs of the National Institute on Aging and the National Institute of Neurological Disease and Stroke, National Institutes of Health, Department Of Health and Human Services, Project number ZO1 AG000950-10; and by Research Fellowships from ARUK Alzheimer's Society to Dr. Guerreiro and Dr Bras. This project was supported by the European Social Fund and by the Ministry of Science Research and the Arts Baden-Wurttemberg. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; The authors thank all patients and their families for taking part in this study. Ebru Ozer and Meltem Pak helped with obtaining the samples. Jose Bras and Rita Guerreiro are supported by Fellowships from the Alzheimer's Society. This work was partially funded by Alzheimer's Research UK, Alzheimer's Society and by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services and the European Social Fund and the Ministry of Science Research and the Arts Baden-Wurttemberg. NR 49 TC 0 Z9 0 U1 5 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 SEP 15 PY 2016 VL 11 IS 9 AR e0162592 DI 10.1371/journal.pone.0162592 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW5SJ UT WOS:000383706900056 PM 27632209 ER PT J AU Sun, XL Yang, LL Yan, XF Sun, YY Zhao, DL Ji, Y Wang, K Chen, XY Shen, BZ AF Sun, Xilin Yang, Lili Yan, Xuefeng Sun, Yingying Zhao, Dongliang Ji, Yang Wang, Kai Chen, Xiaoyuan Shen, Baozhong TI DCE-MRI-Derived Parameters in Evaluating Abraxane-Induced Early Vascular Response and the Effectiveness of Its Synergistic Interaction with Cisplatin SO PLOS ONE LA English DT Article ID ALBUMIN-BOUND PACLITAXEL; METASTATIC BREAST-CANCER; SQUAMOUS-CELL CARCINOMA; NAB-PACLITAXEL; ANTIANGIOGENIC THERAPY; LUNG-CANCER; CHEMOTHERAPY; EFFICACY; STAGE; ANTITUMOR AB Our previous studies revealed molecular alterations of tumor vessels, varying from immature to mature alterations, resulting from Abraxane, and demonstrated that the integrin-specific PET tracer F-18-FPPRGD2 can be used to noninvasively monitor such changes. However, changes in the tumor vasculature at functional levels such as perfusion and permeability are also important for monitoring Abraxane treatment outcomes in patients with cancer. The purpose of this study is to further investigate the vascular response during Abraxane therapy and the effectiveness of its synergistic interaction with cisplatin using Dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI). Thirty MDA-MB-435 tumor mice were randomized into three groups: PBS control (C group), Abraxane only (A group), and sequential treatment with Abraxane followed by cisplatin (A-P group). Tumor volume was monitored based on caliper measurements. A DCE-MRI protocol was performed at baseline and day 3. The K-trans, K-ep and V-e were calculated and compared with CD31, alpha-SMA, and Ki67 histology data. Sequential treatment with Abraxane followed by cis-platin produced a significantly greater inhibition of tumor growth during the three weeks of the observation period. Decreases in K-trans and K-ep for the A and A-P groups were observed on day 3. Immunohistological staining suggested vascular remodeling during the Abraxane therapy. The changes in K-trans and K-ep values were correlated with alterations in the permeability of the tumor vasculature induced by the Abraxane treatment. In conclusion, Abraxane- mediated permeability variations in tumor vasculature can be quantitatively visualized by DCE-MRI, making this a useful method for studying the effects of early cancer treatment, especially the early vascular response. Vascular remodeling by Abraxane improves the efficiency of cisplatin delivery and thus results in a favorable treatment outcome. C1 [Sun, Xilin; Yan, Xuefeng; Sun, Yingying; Zhao, Dongliang; Ji, Yang; Wang, Kai; Shen, Baozhong] Harbin Med Univ, Hosp 4, Dept Radiol, Harbin, Heilongjiang, Peoples R China. [Sun, Xilin; Yang, Lili; Yan, Xuefeng; Sun, Yingying; Zhao, Dongliang; Ji, Yang; Wang, Kai; Shen, Baozhong] Harbin Med Univ, Mol Imaging Res Ctr, Harbin, Heilongjiang, Peoples R China. [Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. RP Shen, BZ (reprint author), Harbin Med Univ, Hosp 4, Dept Radiol, Harbin, Heilongjiang, Peoples R China.; Shen, BZ (reprint author), Harbin Med Univ, Mol Imaging Res Ctr, Harbin, Heilongjiang, Peoples R China. EM shenbzh@vip.sina.com FU National Basic Research Program of China [2015CB931800]; National Natural Science Foundation of China [81101088, 81471724, 81130028, 31210103913]; Natural Science Foundation of Heilongjiang Province of China [LC2013C26]; Reserved Medical Imaging and Nuclear medicine Talent Team Foundation of Heilongjiang Province; Heilongjiang Province Department of Education Science and Technology Research Projects [12521184]; Innovation Talents Foundation of Harbin Science and Technology Bureau [2014RFQGJ011]; Youth Science WU LIANDE Foundation of Harbin Medical University [WLD-QN1119]; National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health FX This work was supported by the National Basic Research Program of China (2015CB931800), the National Natural Science Foundation of China (81101088, 81471724,81130028, 31210103913), Natural Science Foundation of Heilongjiang Province of China (LC2013C26), Reserved Medical Imaging and Nuclear medicine Talent Team Foundation of Heilongjiang Province, Heilongjiang Province Department of Education Science and Technology Research Projects (12521184), Innovation Talents Foundation of Harbin Science and Technology Bureau (2014RFQGJ011), The Youth Science WU LIANDE Foundation of Harbin Medical University (WLD-QN1119), and the Intramural Research Program, National Institute of Biomedical Imaging and Bioengineering, 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 21 TC 0 Z9 0 U1 8 U2 8 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 SEP 15 PY 2016 VL 11 IS 9 AR e0162601 DI 10.1371/journal.pone.0162601 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW5SJ UT WOS:000383706900058 PM 27632532 ER PT J AU Beydoun, HA Beydoun, MA Liang, HL Dore, GA Shaked, D Zonderman, AB Eid, SM AF Beydoun, Hind A. Beydoun, May A. Liang, Hailun Dore, Greg A. Shaked, Danielle Zonderman, Alan B. Eid, Shaker M. TI Sex, Race, and Socioeconomic Disparities in Patients With Aortic Stenosis (from a Nationwide Inpatient Sample) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID VALVE-REPLACEMENT; METABOLIC SYNDROME; TRANSCATHETER; PROGRESSION; ATHEROSCLEROSIS; GEOMETRY; OUTCOMES; WOMEN AB Aortic stenosis (AS) is the third most prevalent cardiovascular disease following hypertension and coronary artery disease. The primary objective of this cross-sectional study is to examine gender, racial, and socioeconomic disparities in AS-related health care utilization in patients aged >= 50 years using data from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample. AS was identified among inpatient discharges with International Classification of Diseases, Ninth Revision, Clinical Modification, code 424.1. Using stratum-specific weighted totals, means, proportions, and regression models, we examined time trends and disparities for inhospital AS prevalence according to gender,, race; and income over the 2002 to 2012 period, predictors of AS (gender, race, income, age, health insurance, co-morbidities, and hospital-level characteristics), and AS's role as a predictor of inhospital death, length of stay, and total charges. Inhospital AS prevalence increased from 2.10% in 2002 to 2.37% in 2012, with similar trends observed within gender, race, and income strata. Women were less likely to have AS compared with men (adjusted odds ratio [ORadj] 0.84; 95% confidence interval [CI] 0.83 to 0.86). Blacks (ORadj 0.68; 95% CI 0.66 to 0.71), Hispanics (ORadj 0.79; 95% CI 0.76 to 0.84), and Asians/Pacific Islanders (ORadj 0.68; 95% CI 0.64 to 0.74) were less likely than whites to have AS diagnosis that was directly associated with income. AS was inversely related to inhospital death but positively linked to total charges overall and longer hospital stays among men, whites, and middle-income patients. However, shorter stays with AS were observed among blacks. In conclusion, among older inpatients, AS prevalence was similar to 2% and was higher among males, whites, and higher income groups. Although inhospital death was lower and total charges were higher in AS, length of stay's association with AS varied by gender, race, and income. Published by Elsevier Inc. C1 [Beydoun, Hind A.] Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23501 USA. [Beydoun, Hind A.; Eid, Shaker M.] Johns Hopkins Univ, Sch Med, Dept Hosp Med, Baltimore, MD 21218 USA. [Beydoun, May A.; Dore, Greg A.; Zonderman, Alan B.] Natl Inst Aging Intramural Res Program, Lab Epidemiol & Populat Sci, Baltimore, MD USA. [Liang, Hailun] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD USA. [Shaked, Danielle] Univ Maryland, Dept Psychol, Baltimore, MD 21201 USA. RP Beydoun, HA (reprint author), Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23501 USA.; Beydoun, HA (reprint author), Johns Hopkins Univ, Sch Med, Dept Hosp Med, Baltimore, MD 21218 USA. EM hindb1972@gmail.com OI Zonderman, Alan B/0000-0002-6523-4778 FU National Institute on Aging/National Institutes of Health/Intramural Research Program; Johns Hopkins University School of Medicine FX This study was supported in part by the National Institute on Aging/National Institutes of Health/Intramural Research Program in collaboration with Johns Hopkins University School of Medicine. NR 20 TC 0 Z9 0 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD SEP 15 PY 2016 VL 118 IS 6 BP 860 EP 865 DI 10.1016/j.amjcard.2016.06.039 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DY4FB UT WOS:000385053300014 PM 27481471 ER PT J AU Kim, Y Bulea, TC Damiano, DL AF Kim, Yushin Bulea, Thomas C. Damiano, Diane L. TI Novel Methods to Enhance Precision and Reliability in Muscle Synergy Identification during Walking SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE muscle synergy; motor module; walking; motor complexity; coordination ID MOTOR MODULES; FACTORIZATION ALGORITHMS; MATRIX FACTORIZATION; ACTIVATION PATTERNS; SENSORY FEEDBACK; HUMAN LOCOMOTION; NUMBER; POSTSTROKE; COMPLEXITY; GAIT AB Muscle synergies are hypothesized to reflect modular control of muscle groups via descending commands sent through multiple neural pathways. Recently, the number of synergies has been reported as a functionally relevant indicator of motor control complexity in individuals with neurological movement disorders. Yet the number of synergies extracted during a given activity, e.g., gait, varies within and across studies, even for unimpaired individuals. With no standardized methods for precise determination, this variability remains unexplained making comparisons across studies and cohorts difficult. Here, we utilize k-means clustering and intra-class and between level correlation coefficients to precisely discriminate reliable from unreliable synergies. Electromyography (EMG) was recorded bilaterally from eight leg muscles during treadmill walking at self-selected speed. Muscle synergies were extracted from 20 consecutive gait cycles using non-negative matrix factorization. We demonstrate that the number of synergies is highly dependent on the threshold when using the variance accounted for by reconstructed EMG. Beyond use of threshold, our method utilized a quantitative metric to reliably identify four or five synergies underpinning walking in unimpaired adults and revealed synergies having poor reproducibility that should not be considered as true synergies. We show that robust and unreliable synergies emerge similarly, emphasizing the need for careful analysis in those with pathology. C1 [Kim, Yushin; Bulea, Thomas C.; Damiano, Diane L.] NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Bldg 10, Bethesda, MD 20892 USA. RP Damiano, DL (reprint author), NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Bldg 10, Bethesda, MD 20892 USA. EM damianod@cc.nih.gov FU Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI); Ministry of Health & Welfare, Republic of Korea [HI14C1155]; Intramural Research Program at the National Institutes of health (NIH) Clinical Center FX This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI14C1155) and by the Intramural Research Program at the National Institutes of health (NIH) Clinical Center. NR 36 TC 0 Z9 0 U1 10 U2 10 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 SEP 15 PY 2016 VL 10 AR 455 DI 10.3389/fnhum.2016.00455 PG 12 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA DW5GH UT WOS:000383670800001 PM 27695403 ER PT J AU Miyagawa, F Tagaya, Y Ozato, K Asada, H AF Miyagawa, Fumi Tagaya, Yutaka Ozato, Keiko Asada, Hideo TI Essential Requirement for IFN Regulatory Factor 7 in Autoantibody Production but Not Development of Nephritis in Murine Lupus SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PRISTANE-INDUCED LUPUS; NF-KAPPA-B; PLASMACYTOID DENDRITIC CELLS; HYDROCARBON OIL PRISTANE; SYSTEMIC-LUPUS; I INTERFERON; GENETIC SUSCEPTIBILITY; IMMUNE-COMPLEXES; VIRAL-INFECTION; ERYTHEMATOSUS AB Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by the production of autoantibodies against nuclear components. Recent genetic studies of SLE patients have revealed that IFN regulatory factor (IRF) 7 gene polymorphisms are associated with an increased risk of SLE, but the precise role of IRF7 in SLE development is not fully understood. We investigated the role of IRF7 in the pathogenesis of SLE using a mouse model and saw a curious dissociation of autoantibody production and development of glomerulonephritis. SLE was chemically induced into IRF7-deficient mice, and glomerulonephritis with deposits of IgG and lipogranulomas were observed after 10 mo. However, these mice failed to produce anti-dsDNA, ssDNA, ribonucleoprotein, and Sm autoantibodies. Following the chemical induction, IRF7-deficient mice expressed substantially lower levels of IFN-stimulated genes than did wild-type mice, but NF-kappa B target genes were equally upregulated in both strains. Therefore, the type I IFN pathway seems critical for the autoantibody production, but the NF-kappa B activation is sufficient for the development of glomerulonephritis in this model. Our study thus demonstrates a specific requirement for IRF7 in autoantibody production and uncovers a new layer of complexity in the pathogenesis of SLE. C1 [Miyagawa, Fumi; Asada, Hideo] Nara Med Univ, Dept Dermatol, Sch Med, 840 Shijo, Kashihara, Nara 6348522, Japan. [Tagaya, Yutaka] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. [Ozato, Keiko] NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. RP Miyagawa, F (reprint author), Nara Med Univ, Dept Dermatol, Sch Med, 840 Shijo, Kashihara, Nara 6348522, Japan. EM fumim@naramed-u.ac.jp OI Tagaya, Yutaka/0000-0002-1342-9282; Asada, Hideo/0000-0003-1971-9835 NR 52 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 SEP 15 PY 2016 VL 197 IS 6 BP 2167 EP 2176 DI 10.4049/jimmunol.1502445 PG 10 WC Immunology SC Immunology GA DY3ON UT WOS:000385003600013 PM 27527596 ER PT J AU Mohanram, V Demberg, T Musich, T Tuero, I Vargas-Inchaustegui, DA Miller-Novak, L Venzon, D Robert-Guroff, M AF Mohanram, Venkatramanan Demberg, Thorsten Musich, Thomas Tuero, Iskra Vargas-Inchaustegui, Diego A. Miller-Novak, Leia Venzon, David Robert-Guroff, Marjorie TI B Cell Responses Associated with Vaccine-Induced Delayed SIVmac251 Acquisition in Female Rhesus Macaques SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SIMIAN IMMUNODEFICIENCY; ANTIRETROVIRAL THERAPY; AUTOIMMUNE-DISEASES; NONHUMAN-PRIMATES; VIRUS-INFECTION; VIREMIA CONTROL; T-CELLS; MEMORY; PATHOGENESIS; POPULATIONS AB An established sex bias in HIV pathogenesis is linked to immune responses. Recently we reported a vaccine-induced sex bias: vaccinated female but not male rhesus macaques exhibited delayed SIV acquisition. This outcome was correlated with SIV Env-specific rectal IgA, rectal memory B cells, and total rectal plasma cells. To uncover additional contributing factors, using samples from the same study, we investigated memory B cell population dynamics in blood, bone marrow, and rectal tissue during immunization and postchallenge; IgG subtypes and Ab avidity; and regulatory B (B-reg) cell frequency and function. Few sex differences were seen in Env-specific memory B cell, plasmablast, or plasma cell frequencies in the three compartments. Males had higher IgG Ab titers and avidity indices than females. However, females had elevated levels of Env-specific IgG1, IgG2, and IgG3 Abs compared with males. gp140-specific IgG3 Abs of females but not males were correlated with Ab-dependent cell-mediated cytotoxicity activity against gp120 targets (p = 0.026) and with Ab-dependent phagocytic activity (p = 0.010). IgG3 Ab of females but not males also correlated with decreased peak viremia (p = 0.028). Peripheral blood CD19(+)CD25(+) B-reg cells suppressed T cell proliferation compared with CD19(+)CD25(-) cells (p = 0.031) and exhibited increased IL-10 mRNA expression (p = 0.031). Male macaques postvaccination (p = 0.018) and postinfection (p = 0.0048) exhibited higher B-reg frequencies than females. Moreover, male B-reg frequencies correlated with peak viremia (p = 0.0071). Our data suggest that vaccinated females developed better Ab quality, contributing to better functionality. The elevated Breg frequencies in males may have facilitated SIV acquisition. C1 [Mohanram, Venkatramanan; Demberg, Thorsten; Tuero, Iskra; Vargas-Inchaustegui, Diego A.; Miller-Novak, Leia; Robert-Guroff, Marjorie] NCI, Sect Immune Biol Retroviral Infect, Vaccine Branch, NIH, Bethesda, MD 20892 USA. [Venzon, David] NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. RP Robert-Guroff, M (reprint author), NCI, Vaccine Branch, Ctr Canc Res, NIH, 41 Medlars Dr,Bldg 41,Room D804, Bethesda, MD 20892 USA. EM guroffm@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 40 TC 2 Z9 2 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 SEP 15 PY 2016 VL 197 IS 6 BP 2316 EP 2324 DI 10.4049/jimmunol.1600544 PG 9 WC Immunology SC Immunology GA DY3ON UT WOS:000385003600028 PM 27534560 ER PT J AU Gershlick, DC Schindler, C Chen, Y Bonifacino, JS AF Gershlick, David C. Schindler, Christina Chen, Yu Bonifacino, Juan S. TI TSSC1 is novel component of the endosomal retrieval machinery SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID RETROGRADE PROTEIN COMPLEX; TRANS-GOLGI NETWORK; TO-TGN TRANSPORT; STRUCTURAL-ANALYSIS; HUMAN INTERACTOME; PLASMA-MEMBRANE; RETROMER; SNARE; CELLS; EXOCYTOSIS AB Endosomes function as a hub for multiple protein-sorting events, including retrograde transport to the trans-Golgi network (TGN) and recycling to the plasma membrane. These processes are mediated by tubular-vesicular carriers that bud from early endosomes and fuse with a corresponding acceptor compartment. Two tethering complexes named GARP (composed of ANG2, VPS52, VPS53, and VPS54 subunits) and EARP (composed of ANG2, VPS52, VPS53, and Syndetin subunits) were previously shown to participate in SNARE-dependent fusion of endosome-derived carriers with the TGN and recycling endosomes, respectively. Little is known, however, about other proteins that function with GARP and EARP in these processes. Here we identify a protein named TSSC1 as a specific interactor of both GARP and EARP and as a novel component of the endosomal retrieval machinery. TSSC1 is a predicted WD40/beta-propeller protein that coisolates with both GARP and EARP in affinity purification, immunoprecipitation, and gel filtration analyses. Confocal fluorescence microscopy shows co-localization of TSSC1 with both GARP and EARP. Silencing of TSSC1 impairs transport of internalized Shiga toxin B subunit to the TGN, as well as recycling of internalized transferrin to the plasma membrane. Fluorescence recovery after photobleaching shows that TSSC1 is required for efficient recruitment of GARP to the TGN. These studies thus demonstrate that TSSC1 plays a critical role in endosomal retrieval pathways as a regulator of both GARP and EARP function. C1 [Gershlick, David C.; Schindler, Christina; Chen, Yu; Bonifacino, Juan S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Neurobiol Branch, NIH, Bethesda, MD 20892 USA. [Schindler, Christina] MedImmune, Dept Antibody Discovery & Prot Engn, Cambridge CB21 6GH, England. RP Bonifacino, JS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Neurobiol Branch, NIH, Bethesda, MD 20892 USA. EM bonifacinoj@helix.nih.gov OI Gershlick, David/0000-0002-0602-210X; Bonifacino, Juan S./0000-0002-5673-6370 FU Intramural Program of the National Institute of Child Health and Human Development, National Institutes of Health [ZIA HD001607] FX We thank Yan Li at the National Institute of Neurological Disorders and Stroke Protein/Peptide Sequencing Facility for the mass-spectrometric analysis of VPS54-GFP isolates, Jing Pu for mouse tissues used in immunoblotting, Eric Balzer (Nikon Instruments) for assistance with photobleaching experiments, Matthew Gastinger (Imaris, Bitplane) for help with quantification of data, and Ludger Johannes for his generous gift of Cy3-STxB. This work was funded by the Intramural Program of the National Institute of Child Health and Human Development, National Institutes of Health (ZIA HD001607). NR 60 TC 0 Z9 0 U1 8 U2 8 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD SEP 15 PY 2016 VL 27 IS 18 BP 2867 EP 2878 DI 10.1091/mbc.E16-04-0209 PG 12 WC Cell Biology SC Cell Biology GA DX1JZ UT WOS:000384124700009 PM 27440922 ER PT J AU Eytan, DF Snow, GE Carlson, S Derakhshan, A Saleh, A Schiltz, S Cheng, H Mohan, S Cornelius, S Coupar, J Sowers, AL Hernandez, L Mitchell, JB Annunziata, CM Chen, Z Van Waes, C AF Eytan, Danielle F. Snow, Grace E. Carlson, Sophie Derakhshan, Adeeb Saleh, Anthony Schiltz, Stephen Cheng, Hui Mohan, Suresh Cornelius, Shaleeka Coupar, Jamie Sowers, Anastasia L. Hernandez, Lidia Mitchell, James B. Annunziata, Christina M. Chen, Zhong Van Waes, Carter TI SMAC Mimetic Birinapant plus Radiation Eradicates Human Head and Neck Cancers with Genomic Amplifications of Cell Death Genes FADD and BIRC2 SO CANCER RESEARCH LA English DT Article ID NF-KAPPA-B; LUNG-CANCER; IONIZING-RADIATION; CASPASE 8; CARCINOMA; APOPTOSIS; INFLAMMATION; ACTIVATION; PROLIFERATION; PROTEINS AB Comparison of tumors from The Cancer Genome Atlas (TCGA) reveals that head and neck squamous cell carcinomas (HNSCC) harbor the most frequent genomic amplifications of Fas-associated death domain (FADD), with or without Baculovirus inhibitor of apoptosis repeat containing BIRC2 (cIAP1), affecting about 30% of patients in association with worse prognosis. Here, we identified HNSCC cell lines harboring FADD/BIRC2 amplifications and overexpression by exome sequencing, RT-PCR, and Western blotting. In vitro, FADD or BIRC2 siRNA knockdown inhibited HNSCC displaying amplification and increased expression of these genes, supporting their functional importance in promoting proliferation. Birinapant, a novel SMAC mimetic, sensitized multiple HNSCC lines to cell death by agonists TNF alpha or TRAIL and inhibited cIAP1 > XIAP > IAP2. Combination of birinapant and TNF alpha induced sub-G(0) DNA fragmentation in sensitive lines and birinapant alone also induced significant G2-M cell-cycle arrest and cell death in UM-SCC-46 cells. Gene transfer and expression of FADD sensitized resistant UM-SCC-38 cells lacking FADD amplification to birinapant and TNF alpha, supporting a role for FADD in sensitization to IAP inhibitor and death ligands. HNSCC varied inmechanisms of cell death, as indicated by reversal by inhibitors or protein markers of caspase-dependent apoptosis and/or RIPK1/MLKL-mediated necroptosis. In vivo, birinapant inhibited tumor growth and enhanced radiation-induced TNF alpha, tumor responses, and host survival inUM-SCC-46 and -11B xenograft models displaying amplification and overexpression of FADD+/- BIRC2. These findings suggest that combination of SMAC mimetics such as birinapant plus radiation may be particularly active in HNSCC, which harbor frequent FADD/BIRC2 genomic alterations. (C) 2016 AACR. C1 [Eytan, Danielle F.; Snow, Grace E.; Carlson, Sophie; Derakhshan, Adeeb; Saleh, Anthony; Schiltz, Stephen; Cheng, Hui; Mohan, Suresh; Cornelius, Shaleeka; Coupar, Jamie; Chen, Zhong; Van Waes, Carter] Natl Inst Deafness & Other Commun Disorders, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bethesda, MD USA. [Eytan, Danielle F.; Snow, Grace E.; Derakhshan, Adeeb; Mohan, Suresh] HHMI NIH Scholars Res Program, NIH Med Res Scholars Program, Bethesda, MD USA. [Eytan, Danielle F.; Derakhshan, Adeeb] Cleveland Clin, Lerner Coll Med, Cleveland, OH 44106 USA. [Sowers, Anastasia L.; Mitchell, James B.] NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hernandez, Lidia; Annunziata, Christina M.] NCI, Womens Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Chen, Z (reprint author), Natl Inst Deafness & Other Commun Disorders, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bethesda, MD USA.; Van Waes, C (reprint author), Natl Inst Deafness & Other Commun Disorders, NIH, Bldg 10 Rm 7N240,10 Ctr Dr, Bethesda, MD 20891 USA. EM chenz@nidcd.nih.gov; vanwaesc@nidcd.nih.gov OI Eytan, Danielle/0000-0003-1032-2276; Derakhshan, Adeeb/0000-0003-4324-8113 FU Intramural NIH HHS [ZIA DC000074-08, ZIA DC000073-09]; NIDCD NIH HHS [ZIA DC000016] NR 38 TC 1 Z9 1 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 SEP 15 PY 2016 VL 76 IS 18 BP 5442 EP 5454 DI 10.1158/0008-5472.CAN-15-3317 PG 13 WC Oncology SC Oncology GA DW0UM UT WOS:000383358300026 PM 27469115 ER PT J AU Kassaye, SG Grossman, Z Balamane, M Johnston-White, B Liu, C Kumar, P Young, M Sneller, MC Sereti, I Dewar, R Rehm, C Meyer, W Shafer, R Katzenstein, D Maldarelli, F AF Kassaye, Seble G. Grossman, Zehava Balamane, Maya Johnston-White, Betsy Liu, Chenglong Kumar, Princy Young, Mary Sneller, Michael C. Sereti, Irini Dewar, Robin Rehm, Catherine Meyer, William, III Shafer, Robert Katzenstein, David Maldarelli, Frank TI Transmitted HIV Drug Resistance Is High and Longstanding in Metropolitan Washington, DC SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE HIV; transmitted drug resistance; transmission dynamics; HIV clusters; women ID PREEXPOSURE PROPHYLAXIS; INFECTION; PREVENTION; SURVEILLANCE; PERSISTENCE; COHORT; TRIAL; MEN; TRANSMISSION; MUTATIONS AB Background. Washington, DC, has 2.5% human immunodeficiency virus (HIV) prevalence, 3.9% among African Americans. Antiretrovirals (ARTs) are the cornerstone for treatment and prevention. Monitoring changes in transmitted drug resistance (TDR) is critical for effective HIV care. Methods. HIV genotype data for individuals enrolled in research studies in metropolitan Washington, D.C., were used to identify TDR using the World Health Organization mutation list [Bennett DE, Camacho RJ, Otelea D, et al. Drug resistance mutations for surveillance of transmitted HIV-1 drug-resistance: 2009 update. PloS One 2009; 4: e4724]. HIV phylogenies were reconstructed using maximum likelihood and Bayesian methods. HIV transmission clusters were supported by 1000 bootstrap values >0.70 and posterior probability > 0.95 of having a common ancestor. Results. Among 710 individuals enrolled in 1994-2013, the median age was 38.6 years, 46.2% were female, and 53.3% were African-American. TDR was 22.5% among 566 treatment-naive individuals; 15.8% had nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) resistance, 9.8% had nonnucleoside reverse-transcriptase inhibitor (NNRTI) resistance, and 4.2% had protease inhibitor (PI) resistance. Single class TDR was 10.0%, 5.1%, and 1.6% to NRTIs, NNRTIs, and PIs. Dual TDR to PI and NRTI was seen in 1.6%, NRTI and NNRTI in 3.4%, and triple class TDR in 0.9%. TDR frequency decreased from 1994-2006 (27.1%) to 2007-2013 (19.4%; P = .02). Only 6/79 (7.6%) individuals within transmission clusters had evidence of TDR. Discussions. We identified high prevalence of TDR among HIV-infected individuals in metropolitan Washington, DC, regardless of gender. Active surveillance for TDR is needed to guide ART usage and analyses of risk group contributions to HIV transmission and resistance. C1 [Kassaye, Seble G.; Balamane, Maya; Liu, Chenglong; Kumar, Princy; Young, Mary] Georgetown Univ, Dept Med, 2115 Wisconsin Ave NW,Ste 130, Washington, DC 20007 USA. [Grossman, Zehava] Tel Aviv Univ, Dept Epidemiol, IL-69978 Tel Aviv, Israel. [Grossman, Zehava; Maldarelli, Frank] NCI, HIV Dynam & Replicat Program, Frederick, MD 21701 USA. [Johnston-White, Betsy; Shafer, Robert; Katzenstein, David] Stanford Univ, Dept Med, Stanford, CA 94305 USA. [Sneller, Michael C.; Sereti, Irini; Rehm, Catherine] NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Dewar, Robin] Leidos Biomed Res, Frederick, MD USA. [Meyer, William, III] Quest Diagnost, Baltimore, MD USA. RP Kassaye, SG (reprint author), Georgetown Univ, Dept Med, 2115 Wisconsin Ave NW,Ste 130, Washington, DC 20007 USA. EM sgk23@georgetown.edu FU National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID) [U01AI034994]; National Cancer Institute; National Institute on Drug Abuse; Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIAID at the NIH [UO1 AI69503-03S2]; National Center for Research Resources [KL2TR000102, KL2RR031974]; National Center for Advancing Translational Sciences, a trademark of DHHS, part of the Re-Engineering the Clinical Research Enterprise; National Cancer Institute, NIH [HHSN261200800001E]; DC developmental Center for AIDS Research pilot grant [M0020R-PTA:32344-1-IXXs90297N]; AIDS Clinical Trials Group Minority HIV Investigator Mentoring Award [U01AI069494] FX Washington, DC, Metropolitan Site of the Women's Interagency Human immunodeficiency Virus (HIV) Study (WIHS) (multi-principal investigators, M. Y. and S. G. K.) is supported by the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID; U01AI034994) and co-funded by the National Cancer Institute, the National Institute on Drug Abuse, and Eunice Kennedy Shriver National Institute of Child Health and Human Development. The DC Cohort study is supported by NIAID at the NIH (grant UO1 AI69503-03S2). This project was funded in part with federal funds (grant KL2TR000102, previously KL2RR031974) from the National Center for Research Resources and the National Center for Advancing Translational Sciences, a trademark of DHHS, part of the Re-Engineering the Clinical Research Enterprise. This project was funded in whole or in part with federal funds from the National Cancer Institute, NIH, under contract HHSN261200800001E.; S. G. K. has received a DC developmental Center for AIDS Research pilot grant (2014-2015; M0020R-PTA:32344-1-IXXs90297N) and an AIDS Clinical Trials Group Minority HIV Investigator Mentoring Award (2013-2014) for this study (grant U01AI069494). NR 41 TC 0 Z9 0 U1 5 U2 5 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 SEP 15 PY 2016 VL 63 IS 6 BP 836 EP 843 DI 10.1093/cid/ciw382 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DW7UK UT WOS:000383857500022 PM 27307507 ER PT J AU Kraus, A Race, B Phillips, K Winkler, C Saturday, G Kurnellas, M Rothbard, JB Groveman, BR Steinman, L Caughey, B AF Kraus, Allison Race, Brent Phillips, Katie Winkler, Clayton Saturday, Greg Kurnellas, Michael Rothbard, Jonathan B. Groveman, Bradley R. Steinman, Lawrence Caughey, Byron TI Genetic background modulates outcome of therapeutic amyloid peptides in treatment of neuroinflammation SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE Experimental autoimmune encephalomyelitis; Amyloid; Prion protein ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; CELLULAR PRION PROTEIN; CENTRAL-NERVOUS-SYSTEM; KAINATE-INDUCED SEIZURES; INTERFERON-GAMMA; BETA OLIGOMERS; MICE; INDUCTION; DISEASE; EXPRESSION AB Amyloid hexapeptide molecules are effective in the treatment of the murine model of neuroinflammation, known as experimental autoimmune encephalomyelitis (EAE). Efficacy however differs between two inbred mouse strains, C57BL/6J (B6) and C57BL/10SnJ (B10). Amyloid hexapeptide treatments improved the clinical outcomes of B6, but not B10 mice, indicating that genetic background influences therapeutic efficacy. Moreover, although previous studies indicated that prion protein deficiency results in more severe EAE in B6 mice, we observed no such effect in B10 mice. In addition, we found that amyloid hexapeptide treatments of B10 and B6 mice elicited differential IL4 responses. Thus, the modulatory potential of prion protein and related treatments with other amyloid hexapeptides in EAE depends on mouse strain. Published by Elsevier B.V. C1 [Kraus, Allison; Race, Brent; Phillips, Katie; Winkler, Clayton; Groveman, Bradley R.; Caughey, Byron] NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. [Saturday, Greg] NIAID, Rocky Mt Labs, Rocky Mt Vet Branch, NIH, Hamilton, MT 59840 USA. [Kurnellas, Michael; Rothbard, Jonathan B.; Steinman, Lawrence] Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA. [Rothbard, Jonathan B.; Steinman, Lawrence] Stanford Univ, Sch Med, Div Immunol, Dept Med, Stanford, CA 94305 USA. RP Kraus, A (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. EM allison.kraus@nih.gov FU Intramural Research Program of the NIAID; National MS Society [RG 4240B12/2] FX We thank Drs. Kim J. Hasenkrug, James Carroll, and Karin Peterson for critical review of this manuscript, Dr. Katherine Taylor for help with splenocyte cultures, Anita Mora and Ryan Kissinger for graphics assistance, Jeffrey Severson for animal husbandry and Dan Long, Nancy Kurtz and Lori Lubke for histological technical support. This work was supported in part by the Intramural Research Program of the NIAID and the National MS Society (#RG 4240B12/2). NR 31 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 EI 1872-8421 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD SEP 15 PY 2016 VL 298 BP 42 EP 50 DI 10.1016/j.jneuroim.2016.06.010 PG 9 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA DW8WQ UT WOS:000383936600007 PM 27609274 ER PT J AU Gerrin, SJ Sowalsky, AG Balk, SP Ye, HH AF Gerrin, Sean J. Sowalsky, Adam G. Balk, Steven P. Ye, Huihui TI Mutation Profiling Indicates High Grade Prostatic Intraepithelial Neoplasia as Distant Precursors of Adjacent Invasive Prostatic Adenocarcinoma SO PROSTATE LA English DT Article DE carcinoma; prostate; high grade prostatic intraepithelial neoplasia; mutation; precursor ID ISUP CONSENSUS CONFERENCE; METHYLACYL-COA RACEMASE; IMMUNOHISTOCHEMICAL EXPRESSION; INTRADUCTAL CARCINOMA; INTERNATIONAL-SOCIETY; CANCER; PTEN; PATTERNS; BENIGN; GROWTH AB INTRODUCTION. High Grade Prostatic Intraepithelial Neoplasia (HGPIN) is the putative precursor lesion to prostatic adenocarcinoma (PCa), but the precise relationship between HGPIN and PCa remains unclear. METHODS. We performed a molecular case study in which we studied mutation profiles of six tumor-associated HGPIN lesions in a single case of TMPRSS2: ERG fusion positive Gleason score 7 PCa that we had previously mapped for somatic mutations in adjacent Gleason patterns 3 and 4 foci, using microdissection and targeted deep-sequencing. RESULTS. A total of 32 tumor-specific mutated sites were successfully amplified and sequenced, including 25 truncal mutations and 7 mutations that were specific to either the Gleason pattern 3 or pattern 4 foci. All six HGPIN foci shared the same tumor-specific TMPRSS2: ERG fusion breakpoint, establishing that they were all clonally related to the adjacent invasive tumor. Among the 32 gene targets mutated in the invasive tumor, only mutation of the OR2AP1 gene, a truncal mutation, was found in a single focus of HGPIN. The remaining gene targets that were successfully sequenced were wild-type in all other HGPIN foci. DISCUSSION. This study demonstrates the feasibility of targeted mutation profiling of HGPIN lesions, which will be important to understand PCa tumorigenesis. The results in this case, showing a remarkable absence of truncal mutations in HGPIN lesions bearing the tumor-specific ERG fusion, indicate HGPIN lesions may be relatively stable genetically and argue against a stepwise clonal evolution model of HGPIN to PCa. (C) 2016 Wiley Periodicals, Inc. C1 [Gerrin, Sean J.; Ye, Huihui] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA. [Sowalsky, Adam G.; Balk, Steven P.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Div Hematol Oncol, Boston, MA USA. [Sowalsky, Adam G.] NCI, Lab Genitourinary Canc Pathogenesis, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Ye, HH (reprint author), Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA. EM hye@bidmc.harvard.edu OI Sowalsky, Adam/0000-0003-2760-1853 FU Prostate Cancer Foundation (Young Investigator Awards and Challenge Award); Dana-Farber/Harvard Cancer Center; V Foundation for Cancer Research; Department of Defense Prostate Cancer Research Program Postdoctoral Training Award; Prostate and Breast Cancer Research Program; NIH [P50 CA090381] FX Grant sponsor: Prostate Cancer Foundation (Young Investigator Awards and Challenge Award); Grant sponsor: Dana-Farber/Harvard Cancer Center; Grant sponsor: V Foundation for Cancer Research; Grant sponsor: Department of Defense Prostate Cancer Research Program Postdoctoral Training Award; Grant sponsor: Prostate and Breast Cancer Research Program; Grant sponsor: NIH; Grant number: P50 CA090381. NR 30 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-4137 EI 1097-0045 J9 PROSTATE JI Prostate PD SEP 15 PY 2016 VL 76 IS 13 BP 1227 EP 1236 DI 10.1002/pros.23212 PG 10 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA DW2MO UT WOS:000383476700009 PM 27272561 ER PT J AU Geybels, MS Wright, JL Bibikova, M Klotzle, B Fan, JB Zhao, SS Feng, ZD Ostrander, EA Lin, DW Nelson, PS Stanford, JL AF Geybels, Milan S. Wright, Jonathan L. Bibikova, Marina Klotzle, Brandy Fan, Jian-Bing Zhao, Shanshan Feng, Ziding Ostrander, Elaine A. Lin, Daniel W. Nelson, Peter S. Stanford, Janet L. TI Epigenetic signature of Gleason score and prostate cancer recurrence after radical prostatectomy SO CLINICAL EPIGENETICS LA English DT Article DE Clinically localized prostate cancer; Tumor tissue; DNA methylation; Gene expression; Risk prediction for prognosis; Genome-wide profiling; Elastic net regularization ID DNA METHYLATION; CELL-CYCLE; BIOCHEMICAL RECURRENCE; EXPRESSION PROFILES; MARKERS; TUMORS; RISK; STATISTICS; PROGNOSIS; REVEALS AB Background: Identifying the subset of patients with clinically localized prostate cancer (PCa) at the highest risk of recurrence remains challenging, and better prognostic markers are needed. Gleason score is the best predictor of PCa aggressiveness and prognosis. In the present study, we generated an epigenetic signature based on high versus low Gleason score tumors and evaluated its ability to predict recurrence after radical prostatectomy. Methods: Genome-wide DNA methylation data from The Cancer Genome Atlas (TCGA; no. of patients = 333) and the elastic net method were used to generate an epigenetic signature by contrasting patients with high (8-10) versus low (= 6) Gleason score tumors. The signature was then tested in a cohort of 523 patients with clinically localized disease who had radical prostatectomy. Samples taken from the primary tumor were used for DNA methylation and mRNA expression profiling. Patients were followed for PCa recurrence on average for 8 years after diagnosis. Results: The epigenetic signature includes 52 differentially methylated CpG sites. In the testing cohort, the signature was associated with poorer recurrence-free survival (hazard ratio per 25 % increase = 1.78; 95 % confidence interval 1.48, 2.16). The signature significantly improved the area under the curve (AUC) for PCa recurrence compared to clinical-pathological parameters alone, particularly among patients diagnosed with Gleason score 7 tumors (0.64 vs. 0.76, P = 1.34E-4). Results were comparable for patients with Gleason 3 + 4 and those with 4 + 3 tumors. Gene Set Enrichment Analysis showed that higher levels of the signature were associated with increased expression of genes related to cell cycle proliferation and decreased expression of androgen-responsive genes. Conclusions: This report shows evidence that DNA methylation patterns measured in prostate tumor cells are predictive of PCa aggressiveness. The epigenetic signature may have clinical utility to improve prognostication particularly in patients with intermediate Gleason score 7 tumors. C1 [Geybels, Milan S.; Wright, Jonathan L.; Lin, Daniel W.; Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1100 Fairview Ave North, Seattle, WA 98109 USA. [Geybels, Milan S.] Maastricht Univ, GROW Sch Oncol & Dev Biol, Dept Epidemiol, Maastricht, Netherlands. [Wright, Jonathan L.; Lin, Daniel W.] Univ Washington, Sch Med, Dept Urol, Seattle, WA 98195 USA. [Bibikova, Marina; Klotzle, Brandy; Fan, Jian-Bing] Illumina Inc, San Diego, CA USA. [Zhao, Shanshan] NIEHS, Biostat & Computat Biol Branch, Durham, NC USA. [Feng, Ziding] MD Anderson Canc Ctr, Dept Biostat, Houston, TX USA. [Ostrander, Elaine A.] NHGRI, Canc Genet & Comparat Genom Branch, NIH, Bethesda, MD 20892 USA. [Nelson, Peter S.] Fred Hutchinson Canc Res Ctr, Div Human Biol, 1124 Columbia St, Seattle, WA 98104 USA. [Nelson, Peter S.] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [Nelson, Peter S.] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Stanford, Janet L.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Fan, Jian-Bing] AnchorDx Corp, Guangzhou 510300, Guangdong, Peoples R China. RP Geybels, MS (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1100 Fairview Ave North, Seattle, WA 98109 USA.; Geybels, MS (reprint author), Maastricht Univ, GROW Sch Oncol & Dev Biol, Dept Epidemiol, Maastricht, Netherlands. EM mgeybels@fredhutch.org OI Ostrander, Elaine/0000-0001-6075-9738 NR 42 TC 0 Z9 0 U1 3 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1868-7083 J9 CLIN EPIGENETICS JI Clin. Epigenetics PD SEP 15 PY 2016 VL 8 AR 97 DI 10.1186/s13148-016-0260-z PG 11 WC Oncology SC Oncology GA DV8CO UT WOS:000383165300001 PM 27651837 ER PT J AU de la Fuente, J Waterhouse, RM Sonenshine, DE Roe, RM Ribeiro, JM Sattelle, DB Hill, CA AF de la Fuente, Jose Waterhouse, Robert M. Sonenshine, Daniel E. Roe, R. Michael Ribeiro, Jose M. Sattelle, David B. Hill, Catherine A. TI Tick Genome Assembled: New Opportunities for Research on Tick-Host-Pathogen Interactions SO FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY LA English DT Article DE tick; Ixodes scapularis; genomics; proteomics; Borrelia; Anaplasma; evolution ID IXODES-SCAPULARIS; BORNE DISEASES; INFECTIOUS-DISEASES; SALIVARY-GLANDS; LYME-DISEASE; VECTOR; INSIGHTS; AMERICA; MIDGUT AB As tick-borne diseases are on the rise, an international effort resulted in the sequence and assembly of the first genome of a tick vector. This result promotes research on comparative, functional and evolutionary genomics and the study of tick-host-pathogen interactions to improve human, animal and ecosystem health on a global scale. C1 [de la Fuente, Jose] IREC CSIC UCLM JCCM, Inst Invest Recursos Cineget, SaBio, Ciudad Real, Spain. [de la Fuente, Jose] Oklahoma State Univ, Ctr Vet Hlth Sci, Dept Vet Pathobiol, Stillwater, OK 74078 USA. [Waterhouse, Robert M.] Univ Geneva, Sch Med, Dept Genet Med & Dev, Geneva, Switzerland. [Waterhouse, Robert M.] Swiss Inst Bioinformat, Geneva, Switzerland. [Waterhouse, Robert M.] MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Waterhouse, Robert M.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Sonenshine, Daniel E.] Old Dominion Univ, Dept Biol Sci, Norfolk, VA 23529 USA. [Roe, R. Michael] North Carolina State Univ, Dept Entomol, Raleigh, NC USA. [Ribeiro, Jose M.] NIAID, Lab Malaria & Vector Res, Rockville, MD USA. [Sattelle, David B.] UCL, Div Med, London, England. [Hill, Catherine A.] Purdue Univ, Dept Entomol, W Lafayette, IN 47907 USA. RP de la Fuente, J (reprint author), IREC CSIC UCLM JCCM, Inst Invest Recursos Cineget, SaBio, Ciudad Real, Spain.; de la Fuente, J (reprint author), Oklahoma State Univ, Ctr Vet Hlth Sci, Dept Vet Pathobiol, Stillwater, OK 74078 USA. EM jose_delafuente@yahoo.com OI Ribeiro, Jose/0000-0002-9107-0818; Waterhouse, Robert/0000-0003-4199-9052 FU National Institutes of Health, the National Institute of Allergy and Infectious Diseases; National Institutes of Health, U.S. Department of Health and Human Services FX The National Institutes of Health, the National Institute of Allergy and Infectious Diseases and the U.S. Department of Health and Human Services provided principle funding for the sequence and assembly of the I. scapularis genome. NR 37 TC 3 Z9 3 U1 13 U2 18 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2235-2988 J9 FRONT CELL INFECT MI JI Front. Cell. Infect. Microbiol. PD SEP 15 PY 2016 VL 6 AR 103 DI 10.3389/fcimb.2016.00103 PG 4 WC Immunology; Microbiology SC Immunology; Microbiology GA DV9QT UT WOS:000383276700001 PM 27695689 ER PT J AU Santisakultarm, TP Kersbergen, CJ Bandy, DK Ide, DC Choi, SH Silva, AC AF Santisakultarm, Thom P. Kersbergen, Calvin J. Bandy, Daryl K. Ide, David C. Choi, Sang-Ho Silva, Afonso C. TI Two-photon imaging of cerebral hemodynamics and neural activity in awake and anesthetized marmosets SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Non-human primates; Two-photon laser scanning microscopy; GCaMP; Neurovascular coupling; Vascular topology; Somatosensory activation ID BLOOD-FLOW; PROPOFOL ANESTHESIA; NONHUMAN-PRIMATES; INTRINSIC SIGNALS; NEURONAL-ACTIVITY; BEHAVING MONKEYS; BARREL CORTEX; RODENT BRAIN; ISOFLURANE; STROKE AB Background: Marmosets are a powerful, emerging model for human behavior and neurological disorders. However, longitudinal imaging modalities that visualize both cellular structure and function within the cortex are not available in this animal model. Hence, we implemented an approach to quantify vascular topology, hemodynamics, and neural activity in awake marmosets using two-photon microscopy (2PM). New method: Marmosets were acclimated to a custom stereotaxic system. AAV1-GCaMP5G was injected into somatosensory cortex to optically indicate neural activity, and a cranial chamber was implanted. Results: Longitudinal 2PM revealed vasculature and neurons 500 mu m below the cortical surface. Vascular response and neural activity during sensory stimulation were preserved over 5 and 3 months, respectively, before optical quality deteriorated. Vascular remodeling including increased tortuosity and branching was quantified. However, capillary connectivity from arterioles to venules remained unchanged. Further, behavioral assessment before and after surgery demonstrated no impact on cognitive and motor function. Immunohistochemistry confirmed minimal astrocyte activation with no focal damage. Over 6 months, total cortical depth visualized decreased. When under anesthesia, the most prominent isoflurane-induced vasodilation occurred in capillaries and smaller arterioles. Comparison with existing method(s): These results demonstrate the capability to repeatedly observe cortical physiology in awake marmosets over months. Conclusions: This work provides a novel and insightful technique to investigate critical mechanisms in neurological disorders in awake marmosets without introducing confounds from anesthesia. Published by Elsevier B.V. C1 [Santisakultarm, Thom P.; Kersbergen, Calvin J.; Choi, Sang-Ho; Silva, Afonso C.] Natl Inst Neurol Disorders & Stroke, Cerebral Microcirculat Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Bandy, Daryl K.] Natl Inst Neurol Disorders & Stroke, Sect Instrumentat, NIH, Bethesda, MD 20892 USA. [Ide, David C.] NIMH, Sect Instrumentat, NIH, Bethesda, MD 20892 USA. RP Silva, AC (reprint author), Natl Inst Neurol Disorders & Stroke, Cerebral Microcirculat Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. EM silvaa@ninds.nih.gov FU NIH; NINDS; NINDS Competitive Postdoctoral Fellowship FX This research was funded by the Intramural Research Program of the NIH and NINDS, and by the NINDS Competitive Postdoctoral Fellowship to Dr. Puifai Santisakultarm. We thank Drs. Chia-Chun Hung and Alan P. Koretsky for helpful discussions; Gabriel L. Otte for the 3D vasculature tracing tool and the algorithm to stitch 3D image stacks; Tianxia Wu for helpful discussion on statistics; and Xianfeng Zhang for assistance in handling animals. Lastly, we thank the NIH Fellows Editorial Board for editorial assistance. NR 54 TC 4 Z9 4 U1 18 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 EI 1872-678X J9 J NEUROSCI METH JI J. Neurosci. Methods PD SEP 15 PY 2016 VL 271 BP 55 EP 64 DI 10.1016/j.jneumeth.2016.07.003 PG 10 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DW0DU UT WOS:000383311900007 PM 27393311 ER PT J AU Im, SJ Hashimoto, M Gerner, MY Lee, J Kissick, HT Urger, MCB Shan, Q Hale, JS Lee, J Nasti, TH Sharpe, AH Freeman, GJ Germain, RN Nakaya, HI Xue, HH Ahmed, R AF Im, Se Jin Hashimoto, Masao Gerner, Michael Y. Lee, Junghwa Kissick, Haydn T. Urger, Matheus C. B. Shan, Qiang Hale, J. Scott Lee, Judong Nasti, Tahseen H. Sharpe, Arlene H. Freeman, Gordon J. Germain, Ronald N. Nakaya, Helder I. Xue, Hai-Hui Ahmed, Rafi TI Defining CD8(+) T cells that provide the proliferative burst after PD-1 therapy SO NATURE LA English DT Article ID CHRONIC VIRAL-INFECTION; LYMPHOCYTIC CHORIOMENINGITIS VIRUS; TRANSCRIPTION FACTOR; LYMPHOID ORGANS; MEMORY; PERSISTENCE; EFFECTOR; FH; DIFFERENTIATION; EXHAUSTION AB Chronic viral infections are characterized by a state of CD8(+) T-cell dysfunction that is associated with expression of the programmed cell death 1 (PD-1) inhibitory receptor(1-4). A better understanding of the mechanisms that regulate CD8(+) T-cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8(+) T cells. Here we identify a population of virus-specific CD8(+) T cells that proliferate after blockade of the PD-1 inhibitory pathway in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). These LCMV-specific CD8(+) T cells expressed the PD-1 inhibitory receptor, but also expressed several costimulatory molecules such as ICOS and CD28. This CD8(+) T-cell subset was characterized by a unique gene signature that was related to that of CD4(+) T follicular helper (T-FH) cells, CD8(+) T cell memory precursors and haematopoietic stem cell progenitors, but that was distinct from that of CD4(+) T(H)1 cells and CD8(+) terminal effectors. This CD8(+) T-cell population was found only in lymphoid tissues and resided predominantly in the T-cell zones along with naive CD8(+) T cells. These PD-1(+) CD8(+) T cells resembled stem cells during chronic LCMV infection, undergoing self-renewal and also differentiating into the terminally exhausted CD8(+) T cells that were present in both lymphoid and non-lymphoid tissues. The proliferative burst after PD-1 blockade came almost exclusively from this CD8(+) T-cell subset. Notably, the transcription factor TCF1 had a cell-intrinsic and essential role in the generation of this CD8(+) T-cell subset. These findings provide a better understanding of T-cell exhaustion and have implications in the optimization of PD-1-directed immunotherapy in chronic infections and cancer. C1 [Im, Se Jin; Hashimoto, Masao; Lee, Junghwa; Kissick, Haydn T.; Hale, J. Scott; Lee, Judong; Nasti, Tahseen H.; Ahmed, Rafi] Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Im, Se Jin; Hashimoto, Masao; Lee, Junghwa; Kissick, Haydn T.; Hale, J. Scott; Lee, Judong; Nasti, Tahseen H.; Ahmed, Rafi] Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. [Gerner, Michael Y.; Germain, Ronald N.] NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Gerner, Michael Y.] Univ Washington, Dept Immunol, Sch Med, Seattle, WA 98109 USA. [Kissick, Haydn T.] Emory Univ, Dept Urol, Sch Med, Atlanta, GA 30322 USA. [Urger, Matheus C. B.; Nakaya, Helder I.] Univ Sao Paulo, Sch Pharmaceut Sci, BR-05508 Sao Paulo, Brazil. [Shan, Qiang; Xue, Hai-Hui] Univ Iowa, Dept Microbiol, Carver Coll Med, Iowa City, IA 52242 USA. [Sharpe, Arlene H.] Harvard Med Sch, Dept Microbiol & Immunol, Boston, MA 02115 USA. [Sharpe, Arlene H.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Freeman, Gordon J.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Dept Med, Boston, MA 02115 USA. [Xue, Hai-Hui] Univ Iowa, Carver Coll Med, Interdisciplinary Immunol Grad Program, Iowa City, IA 52242 USA. RP Ahmed, R (reprint author), Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA.; Ahmed, R (reprint author), Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. EM rahmed@emory.edu RI Nakaya, Helder/A-1397-2010; CEPID, CRID/J-2644-2015 OI Nakaya, Helder/0000-0001-5297-9108; FU National Institutes of Health [R01 AI30048, P01 AI056299, R01 AI112579, R01 AI121080]; Intramural Research Program of NIAID, NIH; Prostate Cancer Foundation; Swim Across America; CNPq FX This work was supported by National Institutes of Health grants R01 AI30048 (R.A.), P01 AI056299 (R.A. and A.H.S.), R01 AI112579 (H.H.X.) and R01 AI121080 (H.-H.X.) and also by the Intramural Research Program of NIAID, NIH (R.N.G. and M.Y.G.). H.T.K. is supported by funding from the Prostate Cancer Foundation and Swim Across America. H.I.N. receives a CNPq research fellowship. The authors acknowledge technical support from R. Karaffa and S. Durham for cell sorting. NR 37 TC 23 Z9 23 U1 30 U2 30 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 SEP 15 PY 2016 VL 537 IS 7620 BP 417 EP + DI 10.1038/nature19330 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV7EC UT WOS:000383098000057 PM 27501248 ER PT J AU Qureshi, AI Palesch, YY Barsan, WG Hanley, DF Hsu, CY Martin, RL Moy, CS Silbergleit, R Steiner, T Suarez, JI Toyoda, K Wang, YJ Yamamoto, H Yoon, BW AF Qureshi, Adnan I. Palesch, Yuko Y. Barsan, William G. Hanley, Daniel F. Hsu, Chung Y. Martin, Renee L. Moy, Claudia S. Silbergleit, Robert Steiner, Thorsten Suarez, Jose I. Toyoda, Kazunori Wang, Yongjun Yamamoto, Haruko Yoon, Byung-Woo CA ATACH-2 Trial Investigators Neurological Emergency Treatment T TI Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ACUTE INTRACEREBRAL HEMORRHAGE; PERIHEMATOMAL EDEMA; REDUCTION; HEMATOMA; GROWTH; MANAGEMENT; STATES; TRIAL; CARE AB BACKGROUND Limited data are available to guide the choice of a target for the systolic blood-pressure level when treating acute hypertensive response in patients with intracerebral hemorrhage. METHODS We randomly assigned eligible participants with intracerebral hemorrhage (volume, <60 cm(3)) and a Glasgow Coma Scale (GCS) score of 5 or more (on a scale from 3 to 15, with lower scores indicating worse condition) to a systolic blood-pressure target of 110 to 139 mm Hg (intensive treatment) or a target of 140 to 179 mm Hg (standard treatment) in order to test the superiority of intensive reduction of systolic blood pressure to standard reduction; intravenous nicardipine to lower blood pressure was administered within 4.5 hours after symptom onset. The primary outcome was death or disability (modified Rankin scale score of 4 to 6, on a scale ranging from 0 [no symptoms] to 6 [death]) at 3 months after randomization, as ascertained by an investigator who was unaware of the treatment assignments. RESULTS Among 1000 participants with a mean (+/- SD) systolic blood pressure of 200.6 +/- 27.0 mm Hg at baseline, 500 were assigned to intensive treatment and 500 to standard treatment. The mean age of the patients was 61.9 years, and 56.2% were Asian. Enrollment was stopped because of futility after a prespecified interim analysis. The primary outcome of death or disability was observed in 38.7% of the participants (186 of 481) in the intensive-treatment group and in 37.7% (181 of 480) in the standard-treatment group (relative risk, 1.04; 95% confidence interval, 0.85 to 1.27; analysis was adjusted for age, initial GCS score, and presence or absence of intraventricular hemorrhage). Serious adverse events occurring within 72 hours after randomization that were considered by the site investigator to be related to treatment were reported in 1.6% of the patients in the intensive-treatment group and in 1.2% of those in the standard-treatment group. The rate of renal adverse events within 7 days after randomization was significantly higher in the intensive-treatment group than in the standard-treatment group (9.0% vs. 4.0%, P = 0.002). CONCLUSIONS The treatment of participants with intracerebral hemorrhage to achieve a target systolic blood pressure of 110 to 139 mm Hg did not result in a lower rate of death or disability than standard reduction to a target of 140 to 179 mm Hg. (Funded by the National Institute of Neurological Disorders and Stroke and the National Cerebral and Cardiovascular Center; ATACH-2 ClinicalTrials. gov number, NCT01176565.) C1 [Qureshi, Adnan I.] Univ Minnesota, Zeenat Qureshi Stroke Res Ctr, 925 Delaware St SE, Minneapolis, MN 55455 USA. [Palesch, Yuko Y.; Martin, Renee L.] Med Univ South Carolina, Dept Publ Hlth Sci, Charleston, SC USA. [Barsan, William G.; Silbergleit, Robert] Univ Michigan, Dept Emergency Med, Ann Arbor, MI 48109 USA. [Hanley, Daniel F.] Johns Hopkins Univ, Div Brain Injury Outcomes, Baltimore, MD USA. [Moy, Claudia S.] NINDS, Neurol Inst, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Hsu, Chung Y.] China Med Univ, Taichung, Taiwan. [Steiner, Thorsten] Klinikum Frankfurt Hochst, Dept Neurol, Frankfurt, Germany. [Steiner, Thorsten] Univ Heidelberg Hosp, Dept Neurol, Heidelberg, Germany. [Suarez, Jose I.] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. [Toyoda, Kazunori] Natl Cerebral & Cardiovasc Ctr, Dept Cerebrovasc Med, Suita, Osaka, Japan. [Yamamoto, Haruko] Natl Cerebral & Cardiovasc Ctr, Dept Data Sci, Suita, Osaka, Japan. [Wang, Yongjun] Beijing Tiantan Hosp, Beijing, Peoples R China. [Yoon, Byung-Woo] Seoul Natl Univ Hosp, Dept Neurol, Seoul, South Korea. RP Qureshi, AI (reprint author), Univ Minnesota, Zeenat Qureshi Stroke Res Ctr, 925 Delaware St SE, Minneapolis, MN 55455 USA. EM qureshai@gmail.com FU National Institute of Neurological Disorders and Stroke; National Cerebral and Cardiovascular Center [ATACH-2] FX Funded by the National Institute of Neurological Disorders and Stroke and the National Cerebral and Cardiovascular Center; ATACH-2 ClinicalTrials.gov number, NCT01176565. NR 23 TC 23 Z9 24 U1 13 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 SEP 15 PY 2016 VL 375 IS 11 BP 1033 EP 1043 DI 10.1056/NEJMoa1603460 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA DV6ZG UT WOS:000383085000006 PM 27276234 ER PT J AU Fagin, JA Wells, SA AF Fagin, James A. Wells, Samuel A., Jr. TI Biologic and Clinical Perspectives on Thyroid Cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID TERT PROMOTER MUTATIONS; ENDOCRINE NEOPLASIA TYPE-2; BRAF V600E MUTATION; RADIOACTIVE IODINE; CALCITONIN MEASUREMENTS; ACTIVE SURVEILLANCE; FEEDBACK INHIBITION; SERUM CALCITONIN; DOUBLE-BLIND; RET FUSION C1 [Fagin, James A.] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Fagin, James A.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA. [Wells, Samuel A., Jr.] NCI, Genet Branch, Bldg 37,Rm 6138,37 Convent Dr, Bethesda, MD 20892 USA. RP Wells, SA (reprint author), NCI, Genet Branch, Bldg 37,Rm 6138,37 Convent Dr, Bethesda, MD 20892 USA.; Fagin, JA (reprint author), Mem Sloan Kettering Canc Ctr, Serv Endocrinol, 1275 York Ave, New York, NY 10065 USA. EM faginj@mskcc.org; wellss@mail.nih.gov NR 88 TC 5 Z9 5 U1 10 U2 10 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 SEP 15 PY 2016 VL 375 IS 11 BP 1054 EP 1067 DI 10.1056/NEJMra1501993 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA DV6ZG UT WOS:000383085000008 PM 27626519 ER PT J AU Townsley, DM Dumitriu, B Young, NS AF Townsley, Danielle M. Dumitriu, Bogdan Young, Neal S. TI Danazol Treatment for Telomere Diseases Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID BINDING C1 [Townsley, Danielle M.; Dumitriu, Bogdan; Young, Neal S.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. RP Townsley, DM (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. EM townsleydm@nhlbi.nih.gov NR 5 TC 0 Z9 0 U1 0 U2 0 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 SEP 15 PY 2016 VL 375 IS 11 BP 1095 EP 1096 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DV6ZG UT WOS:000383085000021 PM 27626528 ER PT J AU Huang, XX Zhang, TF Tang, XG Jiang, YP Liu, QX Feng, ZY Zhou, QF AF Huang, Xian-Xiong Zhang, Tian-Fu Tang, Xin-Gui Jiang, Yan-Ping Liu, Qiu-Xiang Feng, Zu-Yong Zhou, Qi-Fa TI Dielectric relaxation and pinning phenomenon of (Sr,Pb)TiO3 ceramics for dielectric tunable device application SO SCIENTIFIC REPORTS LA English DT Article ID LEAD-ZIRCONATE-TITANATE; OXYGEN-VACANCY; THIN-FILMS; FERROELECTRIC CERAMICS; MOTION; SRTIO3; LOOP AB The behavior of ferroelectric domain under applied electric field is very sensitive to point defects, which can lead to high temperature dielectric relaxation behaviors. In this work, the phases, dielectric properties and ferroelectric switching behavior of strontium lead titanate ceramics were investigated. The structural characterization is confirmed by X-ray diffraction. The high dielectric tunability and high figure of merit of ceramics, especially Sr0.7Pb0.3TiO3 (SPT), imply that SPT ceramics are promising materials for tunable capacitor applications. Oxygen vacancies induced dielectric relaxation phenomenon is observed. Pinched shape hysteresis loops appeared in low temperature, low electric field or high frequency, whereas these pinched hysteresis loops also can become normal by rising temperature, enhancing electric field or lowering frequency. The pinning and depinning effect can be ascribed to the interaction between oxygen vacancies and domain switching. A qualitative model and a quantitative model are used to explain this phenomenon. Besides, polarization and oxygen treated experiment can exert an enormous influence on pinning effect and the machanisms are also discussed in this work. C1 [Huang, Xian-Xiong; Zhang, Tian-Fu; Tang, Xin-Gui; Jiang, Yan-Ping; Liu, Qiu-Xiang; Feng, Zu-Yong] Guangdong Univ Technol, Guangzhou Higher Educ Mega Ctr, Sch Phys & Optoelect Engn, Guangzhou 510006, Guangdong, Peoples R China. [Zhou, Qi-Fa] Univ Southern Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90015 USA. [Zhou, Qi-Fa] Univ Southern Calif, Dept Biomed Engn, Los Angeles, CA 90015 USA. RP Tang, XG (reprint author), Guangdong Univ Technol, Guangzhou Higher Educ Mega Ctr, Sch Phys & Optoelect Engn, Guangzhou 510006, Guangdong, Peoples R China. EM xgtang@gdut.edu.cn FU National Natural Science Foundation of China [11202054, 11574057]; Guangdong Provincial Natural Science Foundation of China [2016A030313718]; Science and Technology Program of Guangdong Province of China [2016A010104018] FX This work was supported by the National Natural Science Foundation of China (Grant Nos 11202054 and 11574057), the Guangdong Provincial Natural Science Foundation of China (Grant No. 2016A030313718) and the Science and Technology Program of Guangdong Province of China (Grant No. 2016A010104018). NR 42 TC 0 Z9 0 U1 21 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 SEP 15 PY 2016 VL 6 AR 31960 DI 10.1038/srep31960 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV8LK UT WOS:000383188300001 PM 27628266 ER PT J AU Zhang, MZ Zheng, J Nussinov, R Ma, BY AF Zhang, Mingzhen Zheng, Jie Nussinov, Ruth Ma, Buyong TI Oncogenic Mutations Differentially Affect Bax Monomer, Dimer, and Oligomeric Pore Formation in the Membrane SO SCIENTIFIC REPORTS LA English DT Article ID MITOCHONDRIAL OUTER-MEMBRANE; BCL-2 FAMILY PROTEINS; APOPTOTIC PORE; CELL-DEATH; PROAPOPTOTIC BAX; CYTOCHROME-C; BH3 DOMAINS; ACTIVATION; INSERTION; KINASE AB Dysfunction of Bax, a pro-apoptotic regulator of cellular metabolism is implicated in neurodegenerative diseases and cancer. We have constructed the first atomistic models of the Bax oligomeric pore consisting with experimental residue-residue distances. The models are stable, capturing well double electron-electron resonance (DEER) spectroscopy measurements and provide structural details in line with the DEER data. Comparison with the latest experimental results revealed that our models agree well with both Bax and Bak pores, pointed to a converged structural arrangement for Bax and Bak pore formation. Using multi-scale molecular dynamics simulations, we probed mutational effects on Bax transformation from monomer -> dimer -> membrane pore formation at atomic resolution. We observe that two cancer-related mutations, G40E and S118I, allosterically destabilize the monomer and stabilize an off-pathway swapped dimer, preventing productive pore formation. This observation suggests a mechanism whereby the mutations may work mainly by over-stabilizing the monomer -> dimer transformation toward an unproductive off-pathway swapped-dimer state. Our observations point to misfolded Bax states, shedding light on the molecular mechanism of Bax mutation-elicited cancer. Most importantly, the structure of the Bax pore facilitates future study of releases cytochrome C in atomic detail. C1 [Zhang, Mingzhen; Zheng, Jie] Univ Akron, Dept Chem & Biomol Engn, Akron, OH 44325 USA. [Nussinov, Ruth; Ma, Buyong] NCI, Basic Sci Program, Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Inst Mol Med, Sackler Sch Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R; Ma, BY (reprint author), NCI, Basic Sci Program, Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick, MD 21702 USA.; Nussinov, R (reprint author), Tel Aviv Univ, Sackler Inst Mol Med, Sackler Sch Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. EM nussinor@helix.nih.gov; mabuyong@mail.nih.gov RI Zheng, Jie/B-5057-2013; Ma, Buyong/F-9491-2011 OI Zheng, Jie/0000-0003-1547-3612; Ma, Buyong/0000-0002-7383-719X FU NSF grants (CAREER Award) [CBET-0952624, CBET-1510099]; Alzheimer Association - New Investigator Research Grant [2015-NIRG-341372]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX J.Z. thanks the financial support, in part, from NSF grants (CAREER Award CBET-0952624 and CBET-1510099) and Alzheimer Association - New Investigator Research Grant (2015-NIRG-341372). The high-performance computational facilities of the Biowulf PC/Linux cluster at the NIH were mainly used for the simulations. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number 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 research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 70 TC 0 Z9 0 U1 12 U2 12 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 SEP 15 PY 2016 VL 6 AR 33340 DI 10.1038/srep33340 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV8DF UT WOS:000383167000001 PM 27630059 ER PT J AU Scruggs, SB Wang, D Ping, PP AF Scruggs, Sarah B. Wang, Ding Ping, Peipei TI PRKCE gene encoding protein kinase C-epsilon-Dual roles at sarcomeres and mitochondria in cardiomyocytes SO GENE LA English DT Review DE Myocardial function; Phosphorylation; Cardiac hypertrophy; Cardioprotection; Drug target; Substrates ID CARDIAC TROPONIN-I; PERMEABILITY TRANSITION PORE; RAT VENTRICULAR MYOCYTES; FOCAL ADHESION KINASE; PKC-EPSILON; HEART-FAILURE; ATP SYNTHASE; CELL-DEATH; DIFFERENTIAL ACTIVATION; MYOFILAMENT PROPERTIES AB Protein kinase C-epsilon (PKCc) is an isoform of a large PKC family of enzymes that has a variety of functions in different cell types. Here we discuss two major roles of PKCe in cardiac muscle cells; specifically, its role in regulating cardiac muscle contraction via targeting the sarcomeric proteins, as well as modulating cardiac cell energy production and metabolism by targeting cardiac mitochondria. The importance of PKCE action is described within the context of intracellular localization, as substrate selectivity and specificity is achieved through spatiotemporal targeting of PKCc. Accordingly, the role of PKCe in regulating myocardial function in physiological and pathological states has been documented in both cardioprotection and cardiac hypertrophy. (C) 2016 Elsevier B.V. All rights reserved. C1 Univ Calif Los Angeles, Ctr Excellence Biomed Comp BD2K, Dept Physiol, NIH, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Ctr Excellence Biomed Comp BD2K, Dept Med Cardiol, NIH, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Ctr Excellence Biomed Comp BD2K, Dept Bioinformat, NIH, Los Angeles, CA 90095 USA. RP Ping, PP (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Physiol, Suite 1-609 MRL Bldg,675 Charles E Young Dr South, Los Angeles, CA 90095 USA.; Ping, PP (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Med Cardiol, Suite 1-609 MRL Bldg,675 Charles E Young Dr South, Los Angeles, CA 90095 USA.; Ping, PP (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Bioinformat, Suite 1-609 MRL Bldg,675 Charles E Young Dr South, Los Angeles, CA 90095 USA. EM sarahbscruggs@gmail.com; peipeiping@earthlink.net FU National Institutes of Health [R37 HL063901, R01 HL129723, U54 GM114833, R01 GM089820]; Elsevier, the publisher of GENE FX The authors are supported by the National Institutes of Health (R37 HL063901, R01 HL129723, and U54 GM114833).; This review and the corresponding Gene Wild article are written as part of the Cardiac Gene Wild Review series a series resulting from a collaboration between the journal GENE, the Gene Wiki Initiative, and the NIH BD2K Initiative. The Cardiac Gene Wiki Initiative is supported by National Institutes of Health (R01 GM089820 and U54 GM114833). Additional support for Gene Wiki Reviews is provided by Elsevier, the publisher of GENE. The corresponding Gene Wiki entry for this review can be found here: https://en.wikipedia.org/wiki/PRKCE. NR 100 TC 1 Z9 1 U1 7 U2 7 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 SEP 15 PY 2016 VL 590 IS 1 BP 90 EP 96 DI 10.1016/j.gene.2016.06.016 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA DT5RH UT WOS:000381539800012 PM 27312950 ER PT J AU Muthirulan, P Chandrasekaran, AR AF Muthirulan, Pushpanathan Chandrasekaran, Arun Richard TI Microbial flow cytometry: An ideal tool for prospective antimicrobial drug development SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE Flow cytometry; Antimicrobial peptides; Membrane acting; Cell translocating; Mode of action; Cytotoxicity ID ANTIFUNGAL PEPTIDE; CANDIDA-ALBICANS; IN-VIVO; FLUORESCENCE; PENETRATION; DATABASE; MMGP1; MODE AB Flow cytometry has tremendous applications in qualitative and quantitative analysis of characteristics of single microbial cells. Its ability to efficiently discriminate and quantify multiple parameters of microbial cells has made it a powerful tool to catalog the mechanism of action of antimicrobial peptides (AMPs) on target cells. Here, we provide a comprehensive overview and strategic design on how multi-parametric analysis of flow cytometry is unsurpassed in studying the antimicrobial process of AMPs in an accurate and rapid way. This strategy provides a conceptual framework for understanding distinct classes of AMPs and getting insights into antimicrobial mechanisms of novel AMPs. Published by Elsevier Inc. C1 [Muthirulan, Pushpanathan] NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Chandrasekaran, Arun Richard] SUNY Albany, RNA Inst, Albany, NY 12222 USA. RP Muthirulan, P (reprint author), NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. EM pushpanathan.muthuirulan@nih.gov OI Pushpanathan, Muthuirulan/0000-0001-6240-3073 NR 26 TC 0 Z9 0 U1 3 U2 3 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 SEP 15 PY 2016 VL 509 BP 89 EP 91 DI 10.1016/j.ab.2016.05.025 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA DS6BN UT WOS:000380866800014 PM 27288557 ER PT J AU Drevinge, C Dalen, KT Mannila, MN Tang, MS Stahlman, M Klevstig, M Lundqvist, A Mardani, I Haugen, F Fogelstrand, P Adiels, M Asin-Cayuela, J Ekestam, C Gadin, JR Lee, YK Nebb, H Svedlund, S Johansson, BR Hulten, LM Romeo, S Redfors, B Omerovic, E Levin, M Gan, LM Eriksson, P Andersson, L Ehrenborg, E Kimmel, AR Boren, J Levin, MC AF Drevinge, Christina Dalen, Knut T. Mannila, Maria Nastase Tang, Margareta Scharin Stahlman, Marcus Klevstig, Martina Lundqvist, Annika Mardani, Ismena Haugen, Fred Fogelstrand, Per Adiels, Martin Asin-Cayuela, Jorge Ekestam, Charlotte Gadin, Jesper R. Lee, Yun K. Nebb, Hilde Svedlund, Sara Johansson, Bengt R. Hulten, Lillemor Mattsson Romeo, Stefano Redfors, Bjorn Omerovic, Elmir Levin, Max Gan, Li-Ming Eriksson, Per Andersson, Linda Ehrenborg, Ewa Kimmel, Alan R. Boren, Jan Levin, Malin C. TI Perilipin 5 is protective in the ischemic heart SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Myocardial ischemia; Lipid droplets; Perilipin 5 ID FATTY-ACID; MYOCARDIAL-INFARCTION; INSULIN-RESISTANCE; LIPID-METABOLISM; PROTEIN; MECHANISMS; PROMOTES; DISEASE; MUSCLE; OVEREXPRESSION AB Background: Myocardial ischemia is associated with alterations in cardiac metabolism, resulting in decreased fatty acid oxidation and increased lipid accumulation. Here we investigate how myocardial lipid content and dynamics affect the function of the ischemic heart, and focus on the role of the lipid droplet protein perilipin 5 (Plin5) in the pathophysiology of myocardial ischemia. Methods and results: We generated Plin5(-/-) mice and found that Plin5 deficiency dramatically reduced the triglyceride content in the heart. Under normal conditions, Plin5(-/-) mice maintained a close to normal heart function by decreasing fatty acid uptake and increasing glucose uptake, thus preserving the energy balance. However, during stress or myocardial ischemia, Plin5 deficiency resulted in myocardial reduced substrate availability, severely reduced heart function and increased mortality. Importantly, analysis of a human cohort with suspected coronary artery disease showed that a common noncoding polymorphism, rs884164, decreases the cardiac expression of PLIN5 and is associated with reduced heart function following myocardial ischemia, indicating a role for Plin5 in cardiac dysfunction. Conclusion: Our findings indicate that Plin5 deficiency alters cardiac lipid metabolism and associates with reduced survival following myocardial ischemia, suggesting that Plin5 plays a beneficial role in the heart following ischemia. (C) 2016 The Authors. Published by Elsevier Ireland Ltd. C1 [Drevinge, Christina; Tang, Margareta Scharin; Stahlman, Marcus; Klevstig, Martina; Lundqvist, Annika; Mardani, Ismena; Fogelstrand, Per; Adiels, Martin; Svedlund, Sara; Hulten, Lillemor Mattsson; Romeo, Stefano; Redfors, Bjorn; Omerovic, Elmir; Levin, Max; Gan, Li-Ming; Andersson, Linda; Boren, Jan; Levin, Malin C.] Univ Gothenburg, Inst Med, Dept Mol & Clin Med, Gothenburg, Sweden. [Drevinge, Christina; Tang, Margareta Scharin; Stahlman, Marcus; Klevstig, Martina; Lundqvist, Annika; Mardani, Ismena; Fogelstrand, Per; Adiels, Martin; Svedlund, Sara; Hulten, Lillemor Mattsson; Romeo, Stefano; Redfors, Bjorn; Omerovic, Elmir; Levin, Max; Gan, Li-Ming; Andersson, Linda; Boren, Jan; Levin, Malin C.] Sahlgrens Univ Hosp, Gothenburg, Sweden. [Drevinge, Christina; Tang, Margareta Scharin; Stahlman, Marcus; Klevstig, Martina; Lundqvist, Annika; Mardani, Ismena; Fogelstrand, Per; Adiels, Martin; Svedlund, Sara; Hulten, Lillemor Mattsson; Romeo, Stefano; Redfors, Bjorn; Omerovic, Elmir; Levin, Max; Gan, Li-Ming; Andersson, Linda; Boren, Jan; Levin, Malin C.] Univ Gothenburg, Inst Med, Wallenberg Lab, Gothenburg, Sweden. [Dalen, Knut T.] Univ Oslo, Inst Basic Med Sci, Norwegian Transgen Ctr, Oslo, Norway. [Dalen, Knut T.; Nebb, Hilde] Univ Oslo, Inst Basic Med Sci, Dept Nutr, Oslo, Norway. [Mannila, Maria Nastase; Lee, Yun K.; Kimmel, Alan R.] NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. [Gan, Li-Ming] AstraZeneca R&D, Molndal, Sweden. [Johansson, Bengt R.] Univ Gothenburg, Inst Biomed, Dept Med Biochem & Cell Biol, Gothenburg, Sweden. [Mannila, Maria Nastase; Ekestam, Charlotte; Gadin, Jesper R.; Eriksson, Per; Ehrenborg, Ewa] Karolinska Univ Hosp, Ctr Mol Med, Atherosclerosis Res Unit, Stockholm, Sweden. [Haugen, Fred] Univ Oslo, Inst Basic Med Sci, Dept Physiol, Oslo, Norway. [Asin-Cayuela, Jorge] Univ Gothenburg, Dept Clin Chem, Gothenburg, Sweden. RP Levin, MC (reprint author), Sahlgrens Univ Hosp, Wallenberg Lab, S-41345 Gothenburg, Sweden. EM malin.levin@wlab.gu.se RI Dalen, Knut Tomas/C-4719-2016 OI Dalen, Knut Tomas/0000-0002-0270-5982 FU Swedish Research Council [C0166301]; Vinnova Foundation; Swedish Heart and Lung Foundation [20120399]; Novo Nordisk Foundation [10799]; Swedish Diabetes Foundation [DIA2012-095]; Diabetes Research Wellness Foundation [6648/2013SW]; Sahlgrenska University Hospital ALF research grants [ALFGBG-380231]; Intramural Research Program of the National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the Swedish Research Council (C0166301), the Vinnova Foundation, the Swedish Heart and Lung Foundation (20120399), Novo Nordisk Foundation (10799), Swedish Diabetes Foundation (DIA2012-095), Diabetes Research Wellness Foundation (6648/2013SW), the Sahlgrenska University Hospital ALF (ALFGBG-380231) research grants, the Intramural Research Program of the National Institutes of Health, and the National Institute of Diabetes and Digestive and Kidney Diseases. We thank Maria Heyden, Kristina Skalen, Elin Stenfeldt, Ylva Nyberg, Azra Miljanovic, and Josephine Kalm for technical assistance, Guro Valen for important conceptual advice, Bengt R Johansson for assistance with electron microscopy, and Rosie Perkins and Stephen Ordway for editing the manuscript. NR 37 TC 0 Z9 0 U1 6 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD SEP 15 PY 2016 VL 219 BP 446 EP 454 DI 10.1016/j.ijcard.2016.06.037 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DS5JG UT WOS:000380817400076 PM 27376234 ER PT J AU Shi, JJ Zhang, YF Zheng, W Michailidou, K Ghoussaini, M Bolla, MK Wang, Q Dennis, J Lush, M Milne, RL Shu, XO Beesley, J Kar, S Andrulis, IL Anton-Culver, H Arndt, V Beckmann, MW Zhao, ZG Guo, XY Benitez, J Beeghly-Fadiel, A Blot, W Bogdanova, NV Bojesen, SE Brauch, H Brenner, H Brinton, L Broeks, A Bruening, T Burwinkel, B Cai, H Canisius, S Chang-Claude, J Choi, JY Couch, FJ Cox, A Cross, SS Czene, K Darabi, H Devilee, P Droit, A Dork, T Fasching, PA Fletcher, O Flyger, H Fostira, F Gaborieau, V Garcia-Closas, M Giles, GG Grip, M Guenel, P Haiman, CA Hamann, U Hartman, M Miao, H Hollestelle, A Hopper, JL Hsiung, CN Investigators, K Ito, H Jakubowska, A Johnson, N Torres, D Kabisch, M Kang, D Khan, S Knight, JA Kosma, VM Lambrechts, D Li, JM Lindblom, A Lophatananon, A Lubinski, J Mannermaa, A Manoukian, S Le Marchand, L Margolin, S Marme, F Matsuo, K McLean, C Meindl, A Muir, K Neuhausen, SL Nevanlinna, H Nord, S Borresen-Dale, AL Olson, JE Orr, N van den Ouweland, AMW Peterlongo, P Putti, TC Rudolph, A Sangrajrang, S Sawyer, EJ Schmidt, MK Schmutzler, RK Shen, CY Hou, MF Shrubsole, MJ Southey, MC Swerdlow, A Teo, SH Thienpont, B Toland, AE Tollenaar, RAEM Tomlinson, I Truong, T Tseng, CC Wen, WQ Winqvist, R Wu, AH Yip, CH Zamora, PM Zheng, Y Floris, G Cheng, CY Hooning, MJ Martens, JWM Seynaeve, C Kristensen, VN Hall, P Pharoah, PDP Simard, J Chenevix-Trench, G Dunning, AM Antoniou, AC Easton, DF Cai, QY Long, JR AF Shi, Jiajun Zhang, Yanfeng Zheng, Wei Michailidou, Kyriaki Ghoussaini, Maya Bolla, Manjeet K. Wang, Qin Dennis, Joe Lush, Michael Milne, Roger L. Shu, Xiao-Ou Beesley, Jonathan Kar, Siddhartha Andrulis, Irene L. Anton-Culver, Hoda Arndt, Volker Beckmann, Matthias W. Zhao, Zhiguo Guo, Xingyi Benitez, Javier Beeghly-Fadiel, Alicia Blot, William Bogdanova, Natalia V. Bojesen, Stig E. Brauch, Hiltrud Brenner, Hermann Brinton, Louise Broeks, Annegien Bruening, Thomas Burwinkel, Barbara Cai, Hui Canisius, Sander Chang-Claude, Jenny Choi, Ji-Yeob Couch, Fergus J. Cox, Angela Cross, Simon S. Czene, Kamila Darabi, Hatef Devilee, Peter Droit, Arnaud Dork, Thilo Fasching, Peter A. Fletcher, Olivia Flyger, Henrik Fostira, Florentia Gaborieau, Valerie Garcia-Closas, Montserrat Giles, Graham G. Grip, Mervi Guenel, Pascal Haiman, Christopher A. Hamann, Ute Hartman, Mikael Miao, Hui Hollestelle, Antoinette Hopper, John L. Hsiung, Chia-Ni Investigators, KConFab Ito, Hidemi Jakubowska, Anna Johnson, Nichola Torres, Diana Kabisch, Maria Kang, Daehee Khan, Sofia Knight, Julia A. Kosma, Veli-Matti Lambrechts, Diether Li, Jingmei Lindblom, Annika Lophatananon, Artitaya Lubinski, Jan Mannermaa, Arto Manoukian, Siranoush Le Marchand, Loic Margolin, Sara Marme, Frederik Matsuo, Keitaro McLean, Catriona Meindl, Alfons Muir, Kenneth Neuhausen, Susan L. Nevanlinna, Heli Nord, Silje Borresen-Dale, Anne-Lise Olson, Janet E. Orr, Nick van den Ouweland, Ans M. W. Peterlongo, Paolo Putti, Thomas Choudary Rudolph, Anja Sangrajrang, Suleeporn Sawyer, Elinor J. Schmidt, Marjanka K. Schmutzler, Rita K. Shen, Chen-Yang Hou, Ming-Feng Shrubsole, Matha J. Southey, Melissa C. Swerdlow, Anthony Teo, Soo Hwang Thienpont, Bernard Toland, Amanda E. Tollenaar, Robert A. E. M. Tomlinson, Ian Truong, Therese Tseng, Chiu-Chen Wen, Wanqing Winqvist, Robert Wu, Anna H. Yip, Cheng Har Zamora, Pilar M. Zheng, Ying Floris, Giuseppe Cheng, Ching-Yu Hooning, Maartje J. Martens, John W. M. Seynaeve, Caroline Kristensen, Vessela N. Hall, Per Pharoah, Paul D. P. Simard, Jacques Chenevix-Trench, Georgia Dunning, Alison M. Antoniou, Antonis C. Easton, Douglas F. Cai, Qiuyin Long, Jirong TI Fine-scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE breast cancer; genetic susceptibility; 8q24; fine-mapping; single nucleotide polymorphism ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; COLORECTAL-CANCER; ANALYSES REVEAL; GENE DESERT; C-MYC; EXPRESSION; FOXA1; AMPLIFICATION; DETERMINANT AB Previous genome-wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. A fine-mapping study across 2.06 Mb (chr8: 127,561,724-129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium was conducted. Three additional independent association signals in women of European ancestry, represented by rs35961416 (OR=0.95, 95% CI=0.93-0.97, conditional p=5.8 x 10(-6)), rs7815245 (OR=0.94, 95% CI=0.91-0.96, conditional p=1.1 x 10(-6)) and rs2033101 (OR=1.05, 95% CI=1.02-1.07, conditional p=1.1 x 10(-4)) were found. Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r(2) = 0.77), were putatively functional variants for two of the five independent association signals. The results highlighted multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry. C1 [Shi, Jiajun; Zhang, Yanfeng; Zheng, Wei; Shu, Xiao-Ou; Zhao, Zhiguo; Guo, Xingyi; Beeghly-Fadiel, Alicia; Blot, William; Cai, Hui; Shrubsole, Matha J.; Wen, Wanqing; Cai, Qiuyin; Long, Jirong] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA. [Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Pharoah, Paul D. P.; Antoniou, Antonis C.; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Ghoussaini, Maya; Dennis, Joe; Lush, Michael; Kar, Siddhartha; Pharoah, Paul D. P.; Dunning, Alison M.; Easton, Douglas F.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Milne, Roger L.; Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Milne, Roger L.; Giles, Graham G.] Univ Melbourne, Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia. [Beesley, Jonathan; Anton-Culver, Hoda; Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Dept Genet, Brisbane, Qld, Australia. [Andrulis, Irene L.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Anton-Culver, Hoda] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Arndt, Volker; Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Beckmann, Matthias W.; Fasching, Peter A.] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Obstet & Gynaecol, Erlangen, Germany. [Benitez, Javier] Spanish Natl Canc Res Ctr, Human Canc Genet Program, Madrid, Spain. [Benitez, Javier] Ctr Invest Red Enfermedades Raras, Valencia, Spain. [Blot, William] Int Epidemiol Inst, Rockville, MD USA. [Bogdanova, Natalia V.] Hannover Med Sch, Dept Radiat Oncol, Hannover, Germany. [Bojesen, Stig E.] Herlev Hosp, Copenhagen Gen Populat Study, Herlev, Denmark. [Bojesen, Stig E.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev, Denmark. [Bojesen, Stig E.] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark. [Brauch, Hiltrud] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. [Brauch, Hiltrud] Univ Tubingen, Tubingen, Germany. [Brauch, Hiltrud; Brenner, Hermann] German Canc Consortium, German Canc Res Ctr DKFZ, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany. [Brinton, Louise] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Broeks, Annegien; Schmidt, Marjanka K.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands. [Bruening, Thomas] German Social Accid Insurance, Inst Prevent & Occupat Med, Bochum, Germany. [Burwinkel, Barbara] German Canc Res Ctr, Div Mol Genet Epidemiol, Heidelberg, Germany. [Burwinkel, Barbara] German Canc Res Ctr, Mol Epidemiol Grp, Heidelberg, Germany. [Canisius, Sander] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands. [Chang-Claude, Jenny; Rudolph, Anja] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Choi, Ji-Yeob; Kang, Daehee] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul, South Korea. [Choi, Ji-Yeob; Kang, Daehee] Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul, South Korea. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Cox, Angela] Univ Sheffield, Dept Oncol, Sheffield Canc Res Ctr, Sheffield, S Yorkshire, England. [Cross, Simon S.] Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield, S Yorkshire, England. [Czene, Kamila; Darabi, Hatef; Li, Jingmei; Hall, Per] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Devilee, Peter] Leiden Univ, Med Ctr, Separtment Pathol, Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. [Droit, Arnaud; Simard, Jacques] Univ Laval, Quebec Res Ctr, Ctr Hosp Univ, Quebec City, PQ, Canada. [Dork, Thilo] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Fletcher, Olivia; Garcia-Closas, Montserrat; Johnson, Nichola] Inst Canc Res, Breakthrough Breast Canc Res Ctr, Div Canc Studies, London, England. [Flyger, Henrik] Copenhagen Univ Hosp, Herlev Hosp, Dept Breast Surg, Herlev, Denmark. [Fostira, Florentia] Natl Ctr Sci Res Demokritos, IRRP, Mol Diagnost Lab, Athens, Greece. [Gaborieau, Valerie] Int Agcy Res Canc, Lyon, France. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, London, England. [Grip, Mervi] Oulu Univ Hosp, Dept Surg, Oulu, Finland. [Grip, Mervi] Univ Oulu, Oulu, Finland. [Guenel, Pascal; Truong, Therese] INSERM, Ctr Res Epidemiol & Populat Hlth, Environm Epidemiol Canc, Villejuif, France. [Guenel, Pascal; Truong, Therese] Univ Paris 11, Villejuif, France. [Haiman, Christopher A.; Tseng, Chiu-Chen; Wu, Anna H.] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. [Hamann, Ute; Torres, Diana; Kabisch, Maria] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany. [Hartman, Mikael; Miao, Hui] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore. [Hartman, Mikael] Natl Univ Hlth Syst, Dept Surg, Singapore, Singapore. [Hollestelle, Antoinette; Hooning, Maartje J.; Martens, John W. M.; Seynaeve, Caroline] Erasmus MC Canc Inst, Dept Med Oncol, Rotterdam, Netherlands. [Hopper, John L.; Meindl, Alfons] Tech Univ Munich, Div Gynaecol & Obstet, Munich, Germany. [Hsiung, Chia-Ni] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan. [Investigators, KConFab; Chenevix-Trench, Georgia] Univ Melbourne, Peter MacCallum Canc Ctr, East Melbourne, Vic, Australia. [Ito, Hidemi] Aichi Canc Ctr, Res Inst, Div Epidemiol & Prevent, Aichi, Japan. [Jakubowska, Anna; Lubinski, Jan] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. [Torres, Diana] Pontificia Univ Javeriana, Inst Human Genet, Bogota, Colombia. [Kang, Daehee] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. [Khan, Sofia; Nevanlinna, Heli] Univ Helsinki, Helsinki Univ Cent Hosp, Dept Obstet & Gynecol, Helsinki, Finland. [Knight, Julia A.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON, Canada. [Knight, Julia A.] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON, Canada. [Kosma, Veli-Matti; Mannermaa, Arto] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Sch Med, Kuopio 70210, Finland. [Kosma, Veli-Matti; Mannermaa, Arto] Univ Eastern Finland, Canc Ctr Eastern Finland, Kuopio 70210, Finland. [Kosma, Veli-Matti; Mannermaa, Arto] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, SF-70210 Kuopio, Finland. [Lambrechts, Diether; Thienpont, Bernard] Vesalius Res Ctr, Leuven, Belgium. [Lambrechts, Diether; Thienpont, Bernard] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium. [Lindblom, Annika] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Lophatananon, Artitaya; Muir, Kenneth] Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry, W Midlands, England. [Manoukian, Siranoush] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Med Genet, Milan, Italy. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Margolin, Sara] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Marme, Frederik] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany. [Marme, Frederik] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany. [Matsuo, Keitaro] Kyushu Univ, Fac Med Sci, Dept Prevent Med, Fukuoka, Japan. [McLean, Catriona] Alfred Hosp, Anat Pathol, Melbourne, Vic, Australia. [Muir, Kenneth] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England. [Neuhausen, Susan L.] City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA USA. [Nord, Silje; Borresen-Dale, Anne-Lise; Kristensen, Vessela N.] Oslo Univ Hosp, Inst Canc Res, Dept Genet, Oslo, Norway. [Nord, Silje; Borresen-Dale, Anne-Lise; Kristensen, Vessela N.] Univ Oslo, Fac Med, Inst Clin Med, KG Jebsen Ctr Breast Canc Res, Oslo, Norway. [Olson, Janet E.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Orr, Nick] Inst Canc Res, Div Breast Canc Res, London, England. [van den Ouweland, Ans M. W.] Erasmus Univ, Med Ctr, Dept Clin Genet, Rotterdam, Netherlands. [Peterlongo, Paolo] FIRC Inst Mol Oncol, IFOM, Milan, Italy. [Putti, Thomas Choudary] Natl Univ Hlth Syst, Dept Pathol, Singapore, Singapore. [Sangrajrang, Suleeporn] Natl Canc Inst, Bangkok, Thailand. [Sawyer, Elinor J.] Kings Coll London, Guys Hosp, Res Oncol, London, England. [Schmutzler, Rita K.] Univ Hosp Cologne, Dept Obstet & Gynaecol, Div Mol Gynecooncol, Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Ctr Integrated Oncol, Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Ctr Mol Med, Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Cologne, Germany. [Shen, Chen-Yang] China Med Univ, Sch Publ Hlth, Taichung, Taiwan. [Shen, Chen-Yang] Acad Sinica, Inst Biomed Sci, Taiwan Biobank, Taipei 115, Taiwan. [Hou, Ming-Feng] Kaohsiung Med Univ, Chung Ho Mem Hosp, Ctr Canc, Kaohsiung, Taiwan. [Hou, Ming-Feng] Kaohsiung Med Univ, Chung Ho Mem Hosp, Dept Surg, Kaohsiung, Taiwan. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia. [Swerdlow, Anthony] Inst Canc Res, Div Genet & Epidemiol, London, England. [Swerdlow, Anthony] Inst Canc Res, Div Breast Canc Res, London, England. [Teo, Soo Hwang] Canc Res Initiat Fdn, Subang Jaya, Selangor, Malaysia. [Teo, Soo Hwang; Yip, Cheng Har] Univ Malaya, Med Ctr, Canc Res Inst, Breast Canc Res Unit, Kuala Lumpur, Malaysia. [Toland, Amanda E.] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Tollenaar, Robert A. E. M.] Leiden Univ, Med Ctr, Dept Surg Oncol, Leiden, Netherlands. [Tomlinson, Ian] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Tomlinson, Ian] Univ Oxford, Oxford Biomed Res Ctr, Oxford, England. [Winqvist, Robert] Univ Oulu, Dept Clin Chem, Lab Canc Genet & Tumor Biol, Oulu, Finland. [Winqvist, Robert] Northern Finland Lab Ctr NordLab, Lab Canc Genet & Tumor Biol, Oulu, Finland. [Zamora, Pilar M.] Hosp Univ La Paz, Med Oncol Serv, Madrid, Spain. [Zheng, Ying] Shanghai Municipal Ctr Dis Control & Prevent, Shanghai, Peoples R China. [Floris, Giuseppe] Univ Hosp Gashuisberg, Leuven, Belgium. [Cheng, Ching-Yu] Natl Univ Singapore, Singapore Eye Res Inst, Singapore, Singapore. [Kristensen, Vessela N.] Univ Oslo UiO, Akershus Univ Hosp, Dept Clin Mol Biol EpiGen, Oslo, Norway. RP Long, JR (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, 2525 West End Ave,8th Floor, Nashville, TN 37203 USA.; Long, JR (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, 2525 West End Ave,8th Floor, Nashville, TN 37203 USA.; Cai, QY (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, 1161 21st Ave South, Nashville, TN 37232 USA.; Cai, QY (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, 1161 21st Ave South, Nashville, TN 37232 USA. EM qiuyin.cai@vanderbilt.edu; Jirong.Long@vander-bilt.edu RI Shrubsole, Martha/K-5052-2015; Dork, Thilo/J-8620-2012; Li, Jingmei/I-2904-2012; Yip, Cheng-Har/B-1909-2010; Teo, Soo-hwang/H-2353-2014; Rosczak, Agnieszka/K-2975-2012; Knight, Julia/A-6843-2012; Zheng, Wei/O-3351-2013; Nord, Silje/R-5212-2016; Brenner, Hermann/B-4627-2017; manoukian, siranoush/E-7132-2017 OI Dunning, Alison Margaret/0000-0001-6651-7166; Giles, Graham/0000-0003-4946-9099; Matsuo, Keitaro/0000-0003-1761-6314; Khan, Sofia/0000-0003-4185-8882; Shrubsole, Martha/0000-0002-5591-7575; Li, Jingmei/0000-0001-8587-7511; Zheng, Wei/0000-0003-1226-070X; Nord, Silje/0000-0002-3271-5356; Brenner, Hermann/0000-0002-6129-1572; manoukian, siranoush/0000-0002-6034-7562 FU Cancer Research UK [10118, 10119, 10124]; NCI NIH HHS [U19 CA148537, N01 CN025403, P30 CA068485, P50 CA116201, R01 CA054281, R01 CA063464, R01 CA064277, R01 CA077398, R01 CA092447, R01 CA100374, R01 CA122340, R01 CA128978, R01 CA132839, R01 CA148667, R37 CA054281, R37 CA070867, U01 CA063464, U01 CA098758, U19 CA148065, U19 CA148112, UM1 CA164920] NR 49 TC 1 Z9 1 U1 6 U2 21 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 SEP 15 PY 2016 VL 139 IS 6 BP 1303 EP 1317 DI 10.1002/ijc.30150 PG 15 WC Oncology SC Oncology GA DR5AO UT WOS:000379915600015 PM 27087578 ER PT J AU Zhao, AH Zhang, YB Yang, XW AF Zhao, Ai-Hong Zhang, You-Bo Yang, Xiu-Wei TI Simultaneous determination and pharmacokinetics of sixteen Angelicae dahurica coumarins in vivo by LC-ESI-MS/MS following oral delivery in rats SO PHYTOMEDICINE LA English DT Article DE LC-ESI-MS/MS; Traditional Chinese Medicine; Angelicae Dahuricae Radix; Coumarins; Pharmacokinetics ID CHROMATOGRAPHY-MASS SPECTROMETRY; ISOIMPERATORIN; FURANOCOUMARINS; BIOAVAILABILITY; OXYPEUCEDANIN; IMPERATORIN; PLASMA; CELLS; MICE AB Background: The roots of Angelica dahurica cv. Qibaizhi is frequently used in clinical practice as a traditional Chinese medicine. However, a comprehensive study of the pharmacokinetics of this medicine has not been carried out. Method: A sensitive and specific liquid chromatographic-tandem mass (LC-MS/MS) spectrometric method was established to investigate pharmacokinetics of sixteen coumarins of Angelicae dahuricae Radix (ADR) in rat plasma, including xanthotoxol (1), oxypeucedanin hydrate (2), 5-hydroxy-8-methoxypsoralen (3), (-)-marmesin (4), byakangelicin (5), columbianetin (6), psoralen (7), xanthotoxin (8), neobyakangelicol (9), isoimpinellin (10), bergapten (11), heraclenin (12), oxypeucedanin ethanolate (13), imperatorin (14), phellopterin (15), isoimperatorin (16). Detection was performed on a triple quadrupole mass spectrometer in multiple-reaction-mode (MRM). Results: The method established in this assay was successfully applied to the pharmacokinetic study of the selected coumarins in rat plasma after oral administration of the extract of ADR, and the pharmacokinetic characteristics of sixteen coumarins were clearly elucidated. Conclusion: This pharmacokinetic identification of multiple coumarins of ADR in rats provides a significant basis for better understanding the metabolic mechanism of the herb medicine. (C) 2016 Elsevier GmbH. All rights reserved. C1 [Zhao, Ai-Hong; Zhang, You-Bo; Yang, Xiu-Wei] Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China. [Zhao, Ai-Hong; Zhang, You-Bo; Yang, Xiu-Wei] Peking Univ, Sch Pharmaceut Sci, Dept Nat Med, Beijing 100191, Peoples R China. [Zhao, Ai-Hong] Lanzhou Univ Technol, Sch Life Sci & Engn, Lanzhou 730050, Peoples R China. [Zhang, You-Bo] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Yang, XW (reprint author), Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China.; Yang, XW (reprint author), Peking Univ, Sch Pharmaceut Sci, Dept Nat Med, Beijing 100191, Peoples R China. EM xwyang@bjmu.edu.cn FU National Key Technology R&D Program of China [2011BAI07B08, 2012BAI29B02]; National Natural Science Foundation of China [81473321]; Beijing Municipal Natural Science Foundation of China [7152086]; Beijing Municipal Special-purpose Science Foundation of China [Z0004105040311] FX The authors thank the NIH Fellows Editorial Board (NIH, Bethesda, USA) for editing this manuscript. This project was partly supported by the National Key Technology R&D Program of China (2011BAI07B08, 2012BAI29B02), the National Natural Science Foundation of China (81473321), Beijing Municipal Natural Science Foundation of China (7152086), Beijing Municipal Special-purpose Science Foundation of China (Z0004105040311). NR 28 TC 4 Z9 4 U1 25 U2 43 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 0944-7113 EI 1618-095X J9 PHYTOMEDICINE JI Phytomedicine PD SEP 15 PY 2016 VL 23 IS 10 BP 1029 EP 1036 DI 10.1016/j.phymed.2016.06.015 PG 8 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA DR3WX UT WOS:000379834500007 PM 27444348 ER PT J AU Chung, LK Park, YH Zheng, YT Brodsky, IE Hearing, P Kastner, DL Chae, JJ Bliska, JB AF Chung, Lawton K. Park, Yong Hwan Zheng, Yueting Brodsky, Igor E. Hearing, Patrick Kastner, Daniel L. Chae, Jae Jin Bliska, James B. TI The Yersinia Virulence Factor YopM Hijacks Host Kinases to Inhibit Type III Effector-Triggered Activation of the Pyrin Inflammasome SO CELL HOST & MICROBE LA English DT Article ID PROTEIN YOPM; RHO GTPASES; CASPASE-1; PESTIS; PSEUDOTUBERCULOSIS; PATHOGENESIS; INNATE; FAMILY; MACROPHAGES; RECOGNITION AB Pathogenic Yersinia, including Y. pestis, the agent of plague in humans, and Y. pseudotuberculosis, the related enteric pathogen, deliver virulence effectors into host cells via a prototypical type III secretion system to promote pathogenesis. These effectors, termed Yersinia outer proteins (Yops), modulate multiple host signaling responses. Studies in Y. pestis and Y. pseudotuberculosis have shown that YopM suppresses infection-induced inflammasome activation; however, the underlying molecular mechanism is largely unknown. Here we show that YopM specifically restricts the pyrin inflammasome, which is triggered by the RhoA-inactivating enzymatic activities of YopE and YopT, in Y. pseudotuberculosis-infected macrophages. The attenuation of a yopM mutant is fully reversed in pyrin knockout mice, demonstrating that YopM inhibits pyrin to promote virulence. Mechanistically, YopM recruits and activates the host kinases PRK1 and PRK2 to negatively regulate pyrin by phosphorylation. These results show how a virulence factor can hijack host kinases to inhibit effector-triggered pyrin inflammasome activation. C1 [Chung, Lawton K.; Zheng, Yueting; Hearing, Patrick; Bliska, James B.] SUNY Stony Brook, Sch Med, Dept Mol Genet & Microbiol, Stony Brook, NY 11794 USA. [Chung, Lawton K.; Bliska, James B.] SUNY Stony Brook, Sch Med, Ctr Infect Dis, Stony Brook, NY 11794 USA. [Park, Yong Hwan; Kastner, Daniel L.; Chae, Jae Jin] NHGRI, Inflammatory Dis Sect, Metab Cardiovasc & Inflammatory Dis Genom Branch, NIH, Bethesda, MD 20892 USA. [Brodsky, Igor E.] Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. RP Bliska, JB (reprint author), SUNY Stony Brook, Sch Med, Dept Mol Genet & Microbiol, Stony Brook, NY 11794 USA.; Bliska, JB (reprint author), SUNY Stony Brook, Sch Med, Ctr Infect Dis, Stony Brook, NY 11794 USA. EM james.bliska@stonybrook.edu FU NIH [R01AI099222, CA122677, T32AI007539, F31AI118220]; Sigma Xi, The Scientific Research Society [G201503151030819] FX We thank Carina Hall and David Wagner (Northern Arizona University) for DNA encoding YopMPestoidesA, Jean Rooney (Stony Brook University) for assistance with mouse infections, and Yuan He and Gabriel Nunez (University of Michigan) for caspase-1 and ASC antibodies. This research was supported by awards from the NIH to J.B.B. (R01AI099222), P.H. (CA122677), and L.K.C. (T32AI007539, F31AI118220), and by a Grant-In-Aid of Research (G201503151030819) from Sigma Xi, The Scientific Research Society, to L.K.C. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 50 TC 4 Z9 4 U1 2 U2 2 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 SEP 14 PY 2016 VL 20 IS 3 BP 296 EP 306 DI 10.1016/j.chom.2016.07.018 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DX1QW UT WOS:000384143100007 ER PT J AU Noh, JY Park, JK Lee, DH Yuk, SS Kwon, JH Lee, SW Lee, JB Park, SY Choi, IS Song, CS AF Noh, Jin-Yong Park, Jae-Keun Lee, Dong-Hun Yuk, Seong-Su Kwon, Jung-Hoon Lee, Sang-Won Lee, Joong-Bok Park, Seung-Yong Choi, In-Soo Song, Chang-Seon TI Chimeric Bivalent Virus-Like Particle Vaccine for H5N1 HPAI and ND Confers Protection against a Lethal Challenge in Chickens and Allows a Strategy of Differentiating Infected from Vaccinated Animals ( DIVA) SO PLOS ONE LA English DT Article ID NEWCASTLE-DISEASE VIRUS; AVIAN INFLUENZA-VIRUS; GP5 PROTEIN; IMMUNOGENICITY; ANTIBODIES; BIRDS; SERA; H7 AB Highly pathogenic avian influenza (HPAI) and Newcastle disease (ND) are considered as the most devastating poultry infections, owing to their worldwide distribution and economical threat. Vaccines have been widely used to control these diseases in the poultry industry in endemic countries. However, vaccination policy without differentiating infected animals from vaccinated animals (DIVA) makes the virus surveillance difficult. In this study, we developed a bivalent virus-like particle (VLP) vaccine that is composed of the hemagglutinin (HA) and matrix 1 (M1) proteins of the H5N1 HPAI virus (HPAIV) and a chimeric protein containing the ectodomain of the ND virus (NDV) fusion (F) protein fused with the cytoplasmic and transmembrane domains of the HPAIV HA protein. A single immunization of chickens with the chimeric VLP vaccine induced high levels of hemagglutination inhibition (HI) antibody titers against H5N1 HPAI virus and anti-NDV antibody detected in ELISA and protected chickens against subsequent lethal HPAIV and NDV infections. Furthermore, we could easily perform DIVA test using the commercial NP-cELISA tests against HPAIV and HI assay against NDV. These results strongly suggest that utilization of chimeric VLP vaccine in poultry species would be a promising strategy for the better control of HPAI and ND simultaneously. C1 [Noh, Jin-Yong; Park, Jae-Keun; Lee, Dong-Hun; Yuk, Seong-Su; Kwon, Jung-Hoon; Lee, Sang-Won; Lee, Joong-Bok; Park, Seung-Yong; Choi, In-Soo; Song, Chang-Seon] Konkuk Univ, Coll Vet Med, Avian Dis Lab, Seoul, South Korea. [Park, Jae-Keun] NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Lee, Dong-Hun] USDA ARS, Southeast Poultry Res Lab, Athens, GA 30613 USA. RP Song, CS (reprint author), Konkuk Univ, Coll Vet Med, Avian Dis Lab, Seoul, South Korea. EM songcs@konkuk.ac.kr FU Animal Disease Management Technology Development Program, Ministry of Agriculture, Food, and Rural Affairs, Republic of Korea [313013-3] FX This research was supported by the Animal Disease Management Technology Development Program (Grant No. 313013-3), Ministry of Agriculture, Food, and Rural Affairs, Republic of Korea. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 1 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 SEP 14 PY 2016 VL 11 IS 9 AR e0162946 DI 10.1371/journal.pone.0162946 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW5JO UT WOS:000383680600067 PM 27626934 ER PT J AU Wang, S Huang, P Chen, XY AF Wang, Sheng Huang, Peng Chen, Xiaoyuan TI Hierarchical Targeting Strategy for Enhanced Tumor Tissue Accumulation/Retention and Cellular Internalization SO ADVANCED MATERIALS LA English DT Review DE hierarchical targeting; stimuli-responsive nanoplatforms; changeable particle sizes; switchable surface charges; activatable surface ligands ID ANTICANCER DRUG-DELIVERY; MULTIFUNCTIONAL POLYMERIC MICELLE; MESOPOROUS SILICA NANOPARTICLES; SUPERPARAMAGNETIC IRON-OXIDE; GENERATING LIPOSOMAL SYSTEM; UP-CONVERSION NANOPARTICLES; PENETRATING PEPTIDE; GOLD NANOPARTICLES; CANCER-THERAPY; IN-VIVO AB Targeted delivery of therapeutic agents is an important way to improve the therapeutic index and reduce side effects. To design nanoparticles for targeted delivery, both enhanced tumor tissue accumulation/retention and enhanced cellular internalization should be considered simultaneously. So far, there have been very few nanoparticles with immutable structures that can achieve this goal efficiently. Hierarchical targeting, a novel targeting strategy based on stimuli responsiveness, shows good potential to enhance both tumor tissue accumulation/retention and cellular internalization. Here, the recent design and development of hierarchical targeting nanoplatforms, based on changeable particle sizes, switchable surface charges and activatable surface ligands, will be introduced. In general, the targeting moieties in these nanoplatforms are not activated during blood circulation for efficient tumor tissue accumulation, but re-activated by certain internal or external stimuli in the tumor microenvironment for enhanced cellular internalization. C1 [Wang, Sheng; Huang, Peng] Shenzhen Univ, Guangdong Key Lab Biomed Measurements & Ultrasoun, Sch Biomed Engn, Shenzhen 518060, Peoples R China. [Wang, Sheng] Shenzhen Univ, Minist Educ, Key Lab Optoelect Devices & Syst, Shenzhen 518060, Peoples R China. [Wang, Sheng] Shenzhen Univ, Coll Optoelect Engn, Shenzhen 518060, Peoples R China. [Wang, Sheng; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. RP Huang, P (reprint author), Shenzhen Univ, Guangdong Key Lab Biomed Measurements & Ultrasoun, Sch Biomed Engn, Shenzhen 518060, Peoples R China. 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 [81401465, 51573096, 81272987]; Intramural Research Program (IRP) of the NIBIB, NIH FX This work was supported by the National Science Foundation of China (81401465, 51573096, 81272987), and the Intramural Research Program (IRP) of the NIBIB, NIH. NR 131 TC 12 Z9 13 U1 141 U2 149 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 SEP 14 PY 2016 VL 28 IS 34 BP 7340 EP 7364 DI 10.1002/adma.201601498 PG 25 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 DW6RN UT WOS:000383778700002 PM 27255214 ER PT J AU Russ, BE Kaneko, T Saleem, KS Berman, RA Leopold, DA AF Russ, Brian E. Kaneko, Takaaki Saleem, Kadharbatcha S. Berman, Rebecca A. Leopold, David A. TI Distinct fMRI Responses to Self-Induced versus Stimulus Motion during Free Viewing in the Macaque SO JOURNAL OF NEUROSCIENCE LA English DT Article DE free viewing; macaque; MT; reafference; stimulus motion; V1 ID SACCADIC EYE-MOVEMENTS; PRIMARY VISUAL-CORTEX; LATERAL INTRAPARIETAL AREA; SUPERIOR TEMPORAL SULCUS; NATURAL VISION; VISUOTOPIC ORGANIZATION; NEURAL MECHANISMS; HUMAN BRAIN; NEURONS; MONKEY AB Visual motion responses in the brain are shaped by two distinct sources: the physical movement of objects in the environment and motion resulting from one's own actions. The latter source, termed visual reafference, stems from movements of the head and body, and in primates from the frequent saccadic eye movements that mark natural vision. To study the relative contribution of reafferent and stimulus motion during natural vision, we measured fMRI activity in the brains of two macaques as they freely viewed >50 hours of naturalistic video footage depicting dynamic social interactions. We used eye movements obtained during scanning to estimate the level of reafferent retinal motion at each moment in time. We also estimated the net stimulus motion by analyzing the video content during the same time periods. Mapping the responses to these distinct sources of retinal motion, we found a striking dissociation in the distribution of visual responses throughout the brain. Reafferent motion drove fMRI activity in the early retinotopic areas V1, V2, V3, and V4, particularly in their central visual field representations, as well as lateral aspects of the caudal inferotemporal cortex (area TE0. However, stimulus motion dominated fMRI responses in the superior temporal sulcus, including areas MT, MST, and FST as well as more rostral areas. We discuss this pronounced separation of motion processing in the context of natural vision, saccadic suppression, and the brain's utilization of corollary discharge signals. C1 [Russ, Brian E.; Saleem, Kadharbatcha S.; Berman, Rebecca A.; Leopold, David A.] NIMH, Neuropsychol Lab, NIH, Bldg 9, Bethesda, MD 20892 USA. [Kaneko, Takaaki] RIKEN Brain Sci Inst, Wako, Saitama 3510198, Japan. [Leopold, David A.] NEI, Neurophysiol Imaging Facil, NIMH, NINDS,NIH, Bethesda, MD 20892 USA. RP Russ, BE (reprint author), NIMH, Neuropsychol Lab, NIH, Bldg 9, Bethesda, MD 20892 USA. EM russbe@mail.nih.gov FU Intramural Research Program of the National Institute of Mental Health [ZIA-MH002898, ZIA-MH002838] FX This work was supported by the Intramural Research Program of the National Institute of Mental Health Grants ZIA-MH002898 and ZIA-MH002838. Functional and anatomical MRI scanning was performed in the Neurophysiology Imaging Facility Core (National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Eye Institute). We thank Dr. Daniel Glen for assistance with creating flat maps; George Dold and David Ide for design and machining related to data collection; and Dr. Frank Ye, Charles Zhu, David Yu, and Alex Clark for technical assistance. NR 76 TC 2 Z9 2 U1 5 U2 5 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 SEP 14 PY 2016 VL 36 IS 37 BP 9580 EP 9589 DI 10.1523/JNEUROSCI.1152-16.2016 PG 10 WC Neurosciences SC Neurosciences & Neurology GA DW9UM UT WOS:000384008200008 PM 27629710 ER PT J AU Zheng, WW Borgia, A Buholzer, K Grishaev, A Schuler, B Best, RB AF Zheng, Wenwei Borgia, Alessandro Buholzer, Karin Grishaev, Alexander Schuler, Benjamin Best, Robert B. TI Probing the Action of Chemical Denaturant on an Intrinsically Disordered Protein by Simulation and Experiment SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; X-RAY-SCATTERING; AQUEOUS UREA SOLUTIONS; RESONANCE ENERGY-TRANSFER; REDUCED RIBONUCLEASE-A; SMALL-ANGLE SCATTERING; SINGLE-MOLECULE; UNFOLDED PROTEINS; FORCE-FIELD; AMINO-ACIDS AB Chemical denaturants are the most commonly used agents for unfolding proteins and are thought to act by better solvating the unfolded state. Improved solvation is expected to lead to an expansion of unfolded chains with increasing denaturant concentration, providing a sensitive probe of the denaturant action. However, experiments have so far yielded qualitatively different results concerning the effects of chemical denaturation. Studies using Forster resonance energy transfer (FRET) and other methods found an increase in radius of gyration with denaturant concentration, but Most smalt-angle X-ray scattering (SAXS) studies found no change. This discrepancy therefore challenges our understanding of denaturation mechanism :and more generally the accuracy of these experiments as applied to unfolded or disordered proteins. Here, We use all-atom molecular simulations to investigate the effect of urea and guanidinium chloride on the structure of the intrinsically disordered protein ACTR, which can be studied by experiment over a wide range of denaturant concentration. Using unbiased molecular simulations with a carefully calibrated denaturant model, we find that the protein chain indeed swells with increasing denaturant concentration. This is due to the favorable association of urea or guanidinium chloride with the backbone of all residues and with the side-chains of almost all residues, with denaturant water transfer free energies inferred from this association in reasonable accord with experimental estimates. Interactions of the denaturants with the backbone are dominated by hydrogen bonding, while interactions with side chains include other contributions. By computing FRET efficiencies and SAXS intensities at each denaturant concentration, we show that the simulation trajectories are in accord with both experiments on thiS protein, demonstrating that there is no fundamental inconsistency between the two types of experiment. Agreement with experiment also supports the picture of chemical denaturation described in our simulations, driven by weak association of denaturant with the protein. Our simulations support some assumptions needed for each experiment to accurately reflect changes in protein size, namely, that the commonly used FRET chromophores do not qualitatively alter the results and that possible effects such as preferential Solvent partitioning into the interior of the chain do not interfere with the determination of radius of gyration from the SAXS experiments. C1 [Zheng, Wenwei; Best, Robert B.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Borgia, Alessandro; Buholzer, Karin; Schuler, Benjamin] Univ Zurich, Dept Biochem, Winterthurerstr 190, CH-8057 Zurich, Switzerland. [Grishaev, Alexander] NIST, Rockville, MD 20850 USA. [Grishaev, Alexander] Inst Biosci & Biotechnol Res, Rockville, MD 20850 USA. RP Zheng, WW; Best, RB (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM wenwei.zheng@nih.gov; robertbe@helix.nih.gov RI Schuler, Benjamin/E-7342-2011 OI Schuler, Benjamin/0000-0002-5970-4251 FU National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health; National Institute of Standards and Technology; Swiss National Science Foundation FX We would like to thank Jurgen Kofinger and Gerhard Hummer for providing their software package to perform the all-atom SAXS intensity calculation. R.B. and W.Z. were supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, and A.G. was supported by intramural funding from the National Institute of Standards and Technology. The work at the University of Zurich was supported by the Swiss National Science Foundation. This work utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). NR 112 TC 4 Z9 4 U1 39 U2 40 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 SEP 14 PY 2016 VL 138 IS 36 BP 11702 EP 11713 DI 10.1021/jacs.6b05443 PG 12 WC Chemistry, Multidisciplinary SC Chemistry GA DW1NU UT WOS:000383410700043 PM 27583687 ER PT J AU Borgia, A Zheng, WW Buholzer, K Borgia, MB Schuler, A Hofmann, H Soranno, A Nettels, D Gast, K Grishaev, A Best, RB Schuler, B AF Borgia, Alessandro Zheng, Wenwei Buholzer, Karin Borgia, Madeleine B. Schueler, Anja Hofmann, Hagen Soranno, Andrea Nettels, Daniel Gast, Klaus Grishaev, Alexander Best, Robert B. Schuler, Benjamin TI Consistent View of Polypeptide Chain Expansion in Chemical Denaturants from Multiple Experimental Methods SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID X-RAY-SCATTERING; INTRINSICALLY DISORDERED PROTEINS; SINGLE-MOLECULE FRET; FLUORESCENCE CORRELATION SPECTROSCOPY; END DISTANCE DISTRIBUTIONS; RESONANCE ENERGY-TRANSFER; COIL-GLOBULE TRANSITION; RIBONUCLEASE-A; UNFOLDED PROTEINS; FOLDING DYNAMICS AB There has been a long-standing controversy regarding the effect of chemical denaturants on the dimensions of unfolded and intrinsically disordered proteins: A wide range of experimental techniques suggest that polypeptide chains expand with increasing denaturant concentration, but several studies using small-angle X-ray scattering (SAXS) have reported no: such increase of the radius of gyration (R-g). This inconsistency challenges our current understanding of the mechanism of chemical denaturants, which are widely employed to investigate protein folding and stability. Here, we use a combination Of single-molecule Forster resonance energy transfer (FRET), SAXS, dynamic light scattering (DLS), and two-focus fluorescence correlation spectroscopy (2f-FCS) to characterize the denaturant dependence of the unfolded state of the spectrin domain R17 and the intrinsically disordered protein ACTR in two different denaturants. Standard analysis of the primary data clearly indicates an expansion of the unfolded state with increasing denaturant concentration irrespective of the protein, denaturant, or experimental method used. This is the first case in which SAXS and FRET have yielded even qualitatively consistent results regarding expansion in denaturant when applied to the same proteins. To more directly illustrate this self-consistency, we used both SAXS and FRET data in a Bayesian procedure to refine structural ensembles representative of the observed unfolded state. This analysis demonstrates that both of these experimental probes are compatible with a common ensemble of protein configurations for each denaturant concentration. Furthermore, the resulting ensembles reproduce the trend of increasing hydrodynamic radius, with denaturant concentration obtained by 2f-FCS,and DLS. We were thus able to reconcile the results from all four experimental techniques quantitatively, to obtain a comprehensive structural picture of denaturant;induced unfolded state expansion, and to identify the Most likely sources of earlier discrepancies. C1 [Borgia, Alessandro; Buholzer, Karin; Borgia, Madeleine B.; Hofmann, Hagen; Soranno, Andrea; Nettels, Daniel; Schuler, Benjamin] Univ Zurich, Dept Biochem, Winterthurerstr 190, CH-8057 Zurich, Switzerland. [Schuler, Benjamin] Univ Zurich, Dept Phys, Winterthurerstr 190, CH-8057 Zurich, Switzerland. [Zheng, Wenwei; Best, Robert B.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Schueler, Anja; Gast, Klaus] Univ Potsdam, Phys Biochem, D-14476 Potsdam, Germany. [Grishaev, Alexander] NIST, Rockville, MD 20850 USA. [Grishaev, Alexander] Univ Maryland, Inst Biosci & Biotechnol Res, Rockville, MD 20850 USA. [Hofmann, Hagen] Weizmann Inst Sci, Dept Biol Struct, Rehovot, Israel. RP Borgia, A; Schuler, B (reprint author), Univ Zurich, Dept Biochem, Winterthurerstr 190, CH-8057 Zurich, Switzerland.; Schuler, B (reprint author), Univ Zurich, Dept Phys, Winterthurerstr 190, CH-8057 Zurich, Switzerland.; Best, RB (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA.; Gast, K (reprint author), Univ Potsdam, Phys Biochem, D-14476 Potsdam, Germany.; Grishaev, A (reprint author), NIST, Rockville, MD 20850 USA.; Grishaev, A (reprint author), Univ Maryland, Inst Biosci & Biotechnol Res, Rockville, MD 20850 USA. EM a.borgia@bioc.uzh.ch; khpgast@uni-potsdam.de; alexander.grishaev@nist.gov; robertbe@helix.nih.gov; schuler@bioc.uzh.ch RI Schuler, Benjamin/E-7342-2011 OI Schuler, Benjamin/0000-0002-5970-4251 FU National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health; Swiss National Science foundation; European Research Council; DOE Office of Science by Argonne National Laboratory [DE-AC02-06CH11357] FX We thank Ad Bax, William Eaton, Gilad Haran, and Dave Thirumalai for helpful comments and suggestions, Jane Clarke for an expression plasmid for R17, Franziska Zosel for a high yield expression plasmid for ACTR, and Andrea Holla for help in identifying suitable alternative FRET pairs. R.B. and W.Z. were supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. This work utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). Work at the University of Zurich was supported by funding from the Swiss National Science foundation and the European Research Council. For the SAXS experiments, we gratefully acknowledge use of the SAXS Core Facility of Center for Cancer Research, National Cancer Institute (NCI). Scattering data were acquired using the shared scattering beamline 12-ID-B resource allocated under the PUP-24152 agreement between the National Cancer Institute and Argonne National Laboratory (ANL). We thank Dr. Lixin Fan (NCI) and Dr. Xiaobing Zuo (ANL) for their expert support. The Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility, is operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. NR 103 TC 4 Z9 4 U1 19 U2 22 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 SEP 14 PY 2016 VL 138 IS 36 BP 11714 EP 11726 DI 10.1021/jacs.6b05917 PG 13 WC Chemistry, Multidisciplinary SC Chemistry GA DW1NU UT WOS:000383410700044 PM 27583570 ER PT J AU Soumana, DI Yilmaz, NK Ali, A Prachanronarong, KL Schiffer, CA AF Soumana, Djade I. Yilmaz, Nese Kurt Ali, Akbar Prachanronarong, Kristina L. Schiffer, Celia A. TI Molecular and Dynamic Mechanism Underlying Drug Resistance in Genotype 3 Hepatitis C NS3/4A Protease SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID VIRUS-INFECTION; HIV-1 PROTEASE; SUBSTRATE RECOGNITION; STRUCTURAL-ANALYSIS; CRYSTAL-STRUCTURE; SERINE-PROTEASE; INHIBITOR; HCV; DISCOVERY; MK-5172 AB Hepatitis C virus (HCV), affecting an estimated 150 million people worldwide, is the leading cause of viral hepatitis, cirrhosis and hepatocellular carcinoma. HCV is genetically diverse with six genotypes (GTs) and multiple subtypes of different global distribution and prevalence. Recent development of direct-acting antivirals against HCV including NS3/4A protease inhibitors (PIs) has greatly improved treatment outcomes for GT-1. However, all current PIs exhibit significantly lower potency against GT-3. Lack of structural data on GT-3 protease has limited our ability to understand PI failure in GT-3. In this study the molecular basis for reduced potency of current inhibitors against GT-3 NS3/4A protease is elucidated with structure determination, molecular dynamics simulations and inhibition assays. A chimeric GT-1a3a NS3/4A protease amenable to crystallization was engineered to recapitulate decreased sensitivity of GT-3 protease to Pis. High-resolution crystal structures of this GT-1a3a bound to 3 PIs, asunaprevir, danoprevir and vaniprevir, had only subtle differences relative to GT-1 despite orders of magnitude loss in affinity. In contrast, hydrogen-bonding interactions within and with the protease active site and dynamic fluctuations of the PIs were drastically altered: The correlation:between loss of intermolecular dynamics and inhibitor potency suggests a mechanism where polymorphisms between genotypes (or selected mutations) in the drug target confer resistance through altering the intermolecular dynamics of the protein-inhibitor complex. C1 [Soumana, Djade I.; Yilmaz, Nese Kurt; Ali, Akbar; Prachanronarong, Kristina L.; Schiffer, Celia A.] Univ Massachusetts, Sch Med, Dept Biochem & Mol Pharmacol, Worcester, MA 01605 USA. [Soumana, Djade I.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Schiffer, CA (reprint author), Univ Massachusetts, Sch Med, Dept Biochem & Mol Pharmacol, Worcester, MA 01605 USA. EM celia.schiffer@umassmed.edu FU National Institute of Allergy and Infectious Disease [R01-AI085051]; National Institute of General Medical Sciences of the NIH [F31-GM103259]; HOPE scholarship - Biomedical Science Career Program (BSCP) FX The National Institute of Allergy and Infectious Disease (R01-AI085051) supported this work. DIS was also supported by National Institute of General Medical Sciences of the NIH (F31-GM103259) as well as the HOPE scholarship sponsored by the Biomedical Science Career Program (BSCP). We thank W. Royer, F. Massi and D. Lambright for helpful discussions. NR 65 TC 1 Z9 1 U1 11 U2 11 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 SEP 14 PY 2016 VL 138 IS 36 BP 11850 EP 11859 DI 10.1021/jacs.6b06454 PG 10 WC Chemistry, Multidisciplinary SC Chemistry GA DW1NU UT WOS:000383410700058 PM 27512818 ER PT J AU Helwa, R Gansmo, LB Romundstad, P Hveem, K Vatten, L Ryan, BM Harris, CC Lonning, PE Knappskog, S AF Helwa, Reham Gansmo, Liv B. Romundstad, Pal Hveem, Kristian Vatten, Lars Ryan, Brid M. Harris, Curtis C. Lonning, Per E. Knappskog, Stian TI MDM2 promoter SNP55 (rs2870820) affects risk of colon cancer but not breast-, lung-, or prostate cancer SO SCIENTIFIC REPORTS LA English DT Article ID NONPOLYPOSIS COLORECTAL-CANCER; SINGLE NUCLEOTIDE POLYMORPHISM; ACCELERATES TUMOR-FORMATION; SNP309; GENE; P53; SNP285; ASSOCIATION; AMPLIFICATION; MUTATION AB Two functional SNPs (SNP285G > C; rs117039649 and SNP309T > G; rs2279744) have previously been reported to modulate Sp1 transcription factor binding to the promoter of the proto-oncogene MDM2, and to influence cancer risk. Recently, a third SNP (SNP55C > T; rs2870820) was also reported to affect Sp1 binding and MDM2 transcription. In this large population based case-control study, we genotyped MDM2 SNP55 in 10,779 Caucasian individuals, previously genotyped for SNP309 and SNP285, including cases of colon (n = 1,524), lung (n = 1,323), breast (n = 1,709) and prostate cancer (n = 2,488) and 3,735 non-cancer controls, as well as 299 healthy African-Americans. Applying the dominant model, we found an elevated risk of colon cancer among individuals harbouring SNP55TT/CT genotypes compared to the SNP55CC genotype (OR = 1.15; 95% CI = 1.01-1.30). The risk was found to be highest for left-sided colon cancer (OR = 1.21; 95% CI = 1.00-1.45) and among females (OR = 1.32; 95% CI = 1.01-1.74). Assessing combined genotypes, we found the highest risk of colon cancer among individuals harbouring the SNP55TT or CT together with the SNP309TG genotype (OR = 1.21; 95% CI = 1.00-1.46). Supporting the conclusions from the risk estimates, we found colon cancer cases carrying the SNP55TT/CT genotypes to be diagnosed at younger age as compared to SNP55CC (p = 0.053), in particular among patients carrying the SNP309TG/TT genotypes (p = 0.009). C1 [Helwa, Reham; Gansmo, Liv B.; Lonning, Per E.; Knappskog, Stian] Univ Bergen, Sect Oncol, Dept Clin Sci, N-5020 Bergen, Norway. [Helwa, Reham; Gansmo, Liv B.; Lonning, Per E.; Knappskog, Stian] Haukeland Hosp, Dept Oncol, N-5021 Bergen, Norway. [Romundstad, Pal; Hveem, Kristian; Vatten, Lars] Norwegian Univ Sci & Technol, Dept Publ Hlth, Fac Med, N-7489 Trondheim, Norway. [Ryan, Brid M.; Harris, Curtis C.] NCI, Lab Human Carcinogenesis, Ctr Canc Res, Bethesda, MD 20892 USA. [Helwa, Reham] Ain Shams Univ, Dept Zool, Fac Sci, Mol Biol Lab, Cairo, Egypt. RP Knappskog, S (reprint author), Univ Bergen, Sect Oncol, Dept Clin Sci, N-5020 Bergen, Norway.; Knappskog, S (reprint author), Haukeland Hosp, Dept Oncol, N-5021 Bergen, Norway. EM stian.knappskog@uib.no OI Knappskog, Stian/0000-0002-4153-1655; Ryan, Brid/0000-0003-0038-131X FU Norwegian Cancer Society; Norwegian Research Council; Bergen Research Foundation FX Most of this work was performed in the Mohn Cancer Research Laboratory. This study was supported by grants from the Norwegian Cancer Society, the Norwegian Research Council and the Bergen Research Foundation. NR 36 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 SEP 14 PY 2016 VL 6 AR 33153 DI 10.1038/srep33153 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW2NM UT WOS:000383479100001 PM 27624283 ER PT J AU Singec, I Crain, AM Hou, J Tobe, BTD Talantova, M Winquist, AA Doctor, KS Choy, J Huang, X La Monaca, E Horn, DM Wolf, DA Lipton, SA Gutierrez, GJ Brill, LM Snyder, EY AF Singec, Ilyas Crain, Andrew M. Hou, Junjie Tobe, Brian T. D. Talantova, Maria Winquist, Alicia A. Doctor, Kutbuddin S. Choy, Jennifer Huang, Xiayu La Monaca, Esther Horn, David M. Wolf, Dieter A. Lipton, Stuart A. Gutierrez, Gustavo J. Brill, Laurence M. Snyder, Evan Y. TI Quantitative Analysis of Human Pluripotency and Neural Specification by In-Depth (Phospho) Proteomic Profiling SO STEM CELL REPORTS LA English DT Article AB Controlled differentiation of human embryonic stem cells (hESCs) can be utilized for precise analysis of cell type identities during early development. We established a highly efficient neural induction strategy and an improved analytical platform, and determined proteomic and phosphoproteomic profiles of hESCs and their specified multipotent neural stem cell derivatives (hNSCs). This quantitative dataset (nearly 13,000 proteins and 60,000 phosphorylation sites) provides unique molecular insights into pluripotency and neural lineage entry. Systems-level comparative analysis of proteins (e.g., transcription factors, epigenetic regulators, kinase families), phosphorylation sites, and numerous biological pathways allowed the identification of distinct signatures in pluripotent and multipotent cells. Furthermore, as predicted by the dataset, we functionally validated an autocrine/paracrine mechanism by demonstrating that the secreted protein midkine is a regulator of neural specification. This resource is freely available to the scientific community, including a searchable website, PluriProt. C1 [Singec, Ilyas; Crain, Andrew M.; Tobe, Brian T. D.; Talantova, Maria; Winquist, Alicia A.; Choy, Jennifer; Lipton, Stuart A.; Gutierrez, Gustavo J.; Snyder, Evan Y.] Sanford Burnham Prebys Med Discovery Inst, Ctr Stem Cells & Regenerat Med, La Jolla, CA 92037 USA. [Hou, Junjie; Wolf, Dieter A.; Brill, Laurence M.] Sanford Burnham Prebys Med Discovery Inst, Prote Facil, La Jolla, CA 92037 USA. [Doctor, Kutbuddin S.; Huang, Xiayu] Sanford Burnham Prebys Med Discovery Inst, Informat & Data Management, La Jolla, CA 92037 USA. [La Monaca, Esther; Gutierrez, Gustavo J.] Vrije Univ Brussel, Dept Biol, B-1050 Brussels, Belgium. [Horn, David M.] Thermo Fisher Sci Inc, San Jose, CA 95134 USA. [Singec, Ilyas] NIH, Regenerat Med Program, SCTL, NCATS, Bethesda, MD 20892 USA. [Hou, Junjie] Chinese Acad Sci, Inst Biophys, CAS Ctr Excellence Biomacromol, Natl Lab Biomacromol, Beijing 100101, Peoples R China. [Brill, Laurence M.] Bioanalyt & Prote LCMS, Intertek Pharmaceut Serv, San Diego, CA 92121 USA. RP Singec, I; Snyder, EY (reprint author), Sanford Burnham Prebys Med Discovery Inst, Ctr Stem Cells & Regenerat Med, La Jolla, CA 92037 USA.; Brill, LM (reprint author), Sanford Burnham Prebys Med Discovery Inst, Prote Facil, La Jolla, CA 92037 USA.; Singec, I (reprint author), NIH, Regenerat Med Program, SCTL, NCATS, Bethesda, MD 20892 USA.; Brill, LM (reprint author), Bioanalyt & Prote LCMS, Intertek Pharmaceut Serv, San Diego, CA 92121 USA. EM ilyas.singec@nih.gov; lbrill@san.rr.com; esnyder@sbpdiscovery.org FU International Bipolar Foundation; CIRM; Merck; German Research Council (DFG); Biomedical Sciences Graduate Program at UCSD; NIMH T32, UCSD Department of Psychiatry; BELSPO [IAP-VII/07]; Innoviris-Brussels [BB2B]; FWO; NIH [P20 GM075059, P01 ES016738-01]; CIRM [RC1-00125-1]; SBMRI NCI CCSG [5 P30 CA30199-28]; NINDS [5 P30 NS057096]; NIMH [RC2 MH090011, P50 GM 085764-03, P01 CA138390]; Sanford Children's Health Research Center FX We thank Toshio Kitamura for PLAT-A cells, and Gregg Duester and Daniel J. Donoghue for discussions. Yoav Altman, Joseph Russo, Edward Monosov, Frederick Lo, Maria Jose Martinez Lopez, Justin D. Blethrow, and Alexey Eroshkin kindly provided technical assistance. Several antibodies used in this study were obtained from the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH and maintained at The University of Iowa, Department of Biology. I.S. received support from the International Bipolar Foundation, CIRM, and Merck and the German Research Council (DFG). A.C. was supported by the Biomedical Sciences Graduate Program at UCSD. B.T. was funded by NIMH T32, UCSD Department of Psychiatry. G.J.G. is funded by BELSPO (IAP-VII/07), Innoviris-Brussels (BB2B), and the FWO. Additional support was provided by NIH P20 GM075059, P01 ES016738-01, CIRM RC1-00125-1, SBMRI NCI CCSG 5 P30 CA30199-28, NINDS 5 P30 NS057096, NIMH RC2 MH090011, P50 GM 085764-03, P01 CA138390, and the Sanford Children's Health Research Center. NR 5 TC 0 Z9 0 U1 0 U2 0 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 SEP 13 PY 2016 VL 7 IS 3 BP 527 EP 542 DI 10.1016/j.stemcr.2016.07.019 PG 16 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA EE3QD UT WOS:000389508300018 PM 27569059 ER PT J AU Nieto-Soler, M Morgado-Palacin, I Lafarga, V Lecona, E Murga, M Callen, E Azorin, D Alonso, J Lopez-Contreras, AJ Nussenzweig, A Fernandez-Capetillo, O AF Nieto-Soler, Maria Morgado-Palacin, Isabel Lafarga, Vanesa Lecona, Emilio Murga, Matilde Callen, Elsa Azorin, Daniel Alonso, Javier Lopez-Contreras, Andres J. Nussenzweig, Andre Fernandez-Capetillo, Oscar TI Efficacy of ATR inhibitors as single agents in Ewing sarcoma SO ONCOTARGET LA English DT Article DE ATR; Ewing sarcoma; replication stress; DNA repair; cancer ID INDUCED REPLICATIVE STRESS; DRUG-SENSITIVITY; CANCER-CELLS; MOUSE MODEL; GENE EWS; CHK1; SCREEN; POLY(ADP-RIBOSE); TRANSFORMATION; STRATEGY AB Ewing sarcomas (ES) are pediatric bone tumors that arise from a driver translocation, most frequently EWS/FLI1. Current ES treatment involves DNA damaging agents, yet the basis for the sensitivity to these therapies remains unknown. Oncogene-induced replication stress (RS) is a known source of endogenous DNA damage in cancer, which is suppressed by ATR and CHK1 kinases. We here show that ES suffer from high endogenous levels of RS, rendering them particularly dependent on the ATR pathway. Accordingly, two independent ATR inhibitors show in vitro toxicity in ES cell lines as well as in vivo efficacy in ES xenografts as single agents. Expression of EWS/FLI1 or EWS/ERG oncogenic translocations sensitizes non-ES cells to ATR inhibitors. Our data shed light onto the sensitivity of ES to genotoxic agents, and identify ATR inhibitors as a potential therapy for Ewing Sarcomas. C1 [Nieto-Soler, Maria; Morgado-Palacin, Isabel; Lafarga, Vanesa; Lecona, Emilio; Murga, Matilde; Fernandez-Capetillo, Oscar] Spanish Natl Canc Res Ctr CNIO, Genom Instabil Grp, Madrid, Spain. [Callen, Elsa; Nussenzweig, Andre] NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. [Azorin, Daniel] Hosp Univ Nino Jesus, Dept Pathol, Madrid, Spain. [Alonso, Javier] ISCIII, Inst Rare Dis Res, Pediat Solid Tumor Lab, Madrid, Spain. [Lopez-Contreras, Andres J.] Univ Copenhagen, Panum Inst, Dept Cellular & Mol Med, Ctr Chromosome Stabil, DK-1168 Copenhagen, Denmark. [Fernandez-Capetillo, Oscar] Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab, Stockholm, Sweden. RP Fernandez-Capetillo, O (reprint author), Spanish Natl Canc Res Ctr CNIO, Genom Instabil Grp, Madrid, Spain.; Fernandez-Capetillo, O (reprint author), Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab, Stockholm, Sweden. EM ofernandez@cnio.es RI Alonso, Javier/B-6012-2013 OI Alonso, Javier/0000-0002-6287-8391 FU Fundacion Botin; Banco Santander through its Santander Universities Global Division; MINECO [SAF2014-57791-REDC, SAF2014-59498-R]; Fundacio La Marato de TV3; Howard Hughes Medical Institute; European Research Council [ERC-617840]; Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research; Ellison Medical Foundation Senior Scholar in Aging; Alex Lemonade Stand Foundation Award; Asociacion Pablo Ugarte; ASION-La Hucha de Tomas; Fundacion La Sonrisa de Alex; Instituto de Salud Carlos III [PI12/00816]; Instituto de Salud Carlos III (Spanish Cancer Network RTICC) [RD12/0036/0027]; Danish National Research Foundation [DNRF115]; Danish Council for Independent Research (Sapere Aude, DFF-Starting Grant); Danish Cancer Society [KBVU-2014] FX We would want to thank Enrique de Alava for providing ES lines. Work in O.F. laboratory was supported by Fundacion Botin, by Banco Santander through its Santander Universities Global Division and by grants from MINECO (SAF2014-57791-REDC and SAF2014-59498-R), Fundacio La Marato de TV3, Howard Hughes Medical Institute and the European Research Council (ERC-617840). The A.N. laboratory was supported by the Intramural Research Program of the NIH, the National Cancer Institute, the Center for Cancer Research, an Ellison Medical Foundation Senior Scholar in Aging, and the Alex Lemonade Stand Foundation Award. J.A. laboratory is supported by Asociacion Pablo Ugarte, ASION-La Hucha de Tomas, Fundacion La Sonrisa de Alex and Instituto de Salud Carlos III (PI12/00816 and Spanish Cancer Network RTICC RD12/0036/0027). A.L. laboratory was supported by the Danish National Research Foundation (DNRF115), Danish Council for Independent Research (Sapere Aude, DFF-Starting Grant 2014) and Danish Cancer Society (KBVU-2014). NR 40 TC 0 Z9 0 U1 2 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 SEP 13 PY 2016 VL 7 IS 37 BP 58759 EP 58767 DI 10.18632/oncotarget.11643 PG 9 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB1YW UT WOS:000387153900004 PM 27577084 ER PT J AU Zhang, XY Lu, Y Cao, X Zhen, T Kovalovsky, D AF Zhang, Xianyu Lu, Ying Cao, Xin Zhen, Tao Kovalovsky, Damian TI Zbtb1 prevents default myeloid differentiation of lymphoid-primed multipotent progenitors SO ONCOTARGET LA English DT Article DE Zbtb1; lymphoid; development; myeloid; differentiation; Immunology and Microbiology Section; Immune response; Immunity ID HEMATOPOIETIC STEM-CELLS; DNA-DAMAGE; TRANSCRIPTION FACTORS; C/EBP-ALPHA; PU.1; EXPRESSION; CONVERSION; CYTOKINES; STRESS; FAMILY AB Zbtb1 is a transcription factor that prevents DNA damage and p53-mediated apoptosis in replicating immune progenitors, affecting lymphoid as well as myeloid development when hematopoietic progenitors are in competition in mixed bone marrow chimeras. However, Zbtb1-deficient mice do not have an apparent myeloid deficiency. We report here that Zbtb1-deficient lymphoid-primed multipotent progenitors ( LMPPs) are biased to develop towards the myeloid fate in detriment of lymphoid development, contributing to the apparent unaffected myeloid development. Zbtb1 expression was maintained during lymphoid development of LMPP cells but downregulated during myeloid development. Deficiency of Zbtb1 in LMPP cells was sufficient to direct a myeloid fate in lymphoid-inducing conditions and in the absence of myeloid cytokines as shown by upregulation of a myeloid gene signature and the generation of myeloid cells in vitro. Finally, biased myeloid differentiation of Zbtb1-deficient LMPP cells was not due to increased p53-dependent apoptosis as it was not reverted by transgenic Bcl2 expression or p53 deficiency. Altogether, our results show that Zbtb1 expression prevents activation of a default myeloid program in LMPP cells, ensuring the generation of lymphoid cells. C1 [Zhang, Xianyu; Lu, Ying; Kovalovsky, Damian] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Cao, Xin] Northwest Univ Nationalities, Gansu Engn Res Ctr Anim Cell, Coll Life Sci & Engn, Lanzhou, Peoples R China. [Zhen, Tao] NHGRI, Oncogenesis & Dev Sect, NIH, Bethesda, MD 20892 USA. RP Kovalovsky, D (reprint author), NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. EM kovalovskyd@mail.nih.gov FU NIH intramural funds [1ZIABC011429] FX This work was funded by NIH intramural funds (1ZIABC011429). NR 27 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 SEP 13 PY 2016 VL 7 IS 37 BP 58768 EP 58778 DI 10.18632/oncotarget.11356 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB1YW UT WOS:000387153900005 PM 27542215 ER PT J AU Morgado-Palacin, I Day, A Murga, M Lafarga, V Anton, ME Tubbs, A Chen, HT Ergen, AV Anderson, R Bhandoola, A Pike, KG Barlaam, B Cadogan, E Wang, X Pierce, AJ Hubbard, C Armstrong, SA Nussenzweig, A Fernandez-Capetillo, O AF Morgado-Palacin, Isabel Day, Amanda Murga, Matilde Lafarga, Vanesa Elena Anton, Marta Tubbs, Anthony Chen, Hua-Tang Ergen, Aysegul V. Anderson, Rhonda Bhandoola, Avinash Pike, Kurt G. Barlaam, Bernard Cadogan, Elaine Wang, Xi Pierce, Andrew J. Hubbard, Chad Armstrong, Scott A. Nussenzweig, Andre Fernandez-Capetillo, Oscar TI Targeting the kinase activities of ATR and ATM exhibits antitumoral activity in mouse models of MLL-rearranged AML SO SCIENCE SIGNALING LA English DT Article ID ACUTE MYELOID-LEUKEMIA; INDUCED REPLICATIVE STRESS; DNA-DAMAGE; STEM-CELLS; GENOMIC INSTABILITY; S-PHASE; SYNTHETIC LETHALITY; EMBRYONIC LETHALITY; THERAPEUTIC TARGET; GENE-EXPRESSION AB Among the various subtypes of acute myeloid leukemia (AML), those with chromosomal rearrangements of the MLL oncogene (AML-MLL) have a poor prognosis. AML-MLL tumor cells are resistant to current genotoxic therapies because of an attenuated response by p53, a protein that induces cell cycle arrest and apoptosis in response to DNA damage. In addition to chemicals that damage DNA, efforts have focused on targeting DNA repair enzymes as a general chemotherapeutic approach to cancer treatment. Here, we found that inhibition of the kinase ATR, which is the primary sensor of DNA replication stress, induced chromosomal breakage and death of mouse AML(MLL) cells (with an MLL-ENL fusion and a constitutively active N-RAS) independently of p53. Moreover, ATR inhibition as a single agent exhibited antitumoral activity, both reducing tumor burden after establishment and preventing tumors from growing, in an immunocompetent allograft mouse model of AML(MLL) and in xenografts of a human AML-MLL cell line. We also found that inhibition of ATM, a kinase that senses DNA double-strand breaks, also promoted the survival of the AML(MLL) mice. Collectively, these data indicated that ATR or ATM inhibition represent potential therapeutic strategies for the treatment of AML, especially MLL-driven leukemias. C1 [Morgado-Palacin, Isabel; Murga, Matilde; Lafarga, Vanesa; Elena Anton, Marta; Fernandez-Capetillo, Oscar] Spanish Natl Canc Res Ctr, Genom Instabil Grp, Madrid 28029, Spain. [Day, Amanda; Tubbs, Anthony; Chen, Hua-Tang; Ergen, Aysegul V.; Anderson, Rhonda; Bhandoola, Avinash; Hubbard, Chad; Nussenzweig, Andre] NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. [Pike, Kurt G.; Barlaam, Bernard; Cadogan, Elaine; Pierce, Andrew J.] AstraZeneca, Cambridge CB4 0WG, England. [Wang, Xi; Armstrong, Scott A.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Wang, Xi; Armstrong, Scott A.] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10065 USA. [Fernandez-Capetillo, Oscar] Karolinska Inst, Div Translat Med & Chem Biol, Dept Med Biochem & Biophys, Sci Life Lab, S-17165 Solna, Sweden. RP Fernandez-Capetillo, O (reprint author), Spanish Natl Canc Res Ctr, Genom Instabil Grp, Madrid 28029, Spain.; Nussenzweig, A (reprint author), NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA.; Fernandez-Capetillo, O (reprint author), Karolinska Inst, Div Translat Med & Chem Biol, Dept Med Biochem & Biophys, Sci Life Lab, S-17165 Solna, Sweden. EM nussenza@mail.nih.gov; ofernandez@cnio.es FU Fundacion Botin; Spanish Ministry of Economy and Competitiveness (MINECO) [SAF2014-57791-REDC, SVP-2013-068072]; Fundacio La Marato de TV3; Howard Hughes Medical Institute; European Research Council [ERC-617840]; Intramural Research Program of the NIH; National Cancer Institute (NCI); Center for Cancer Research; Ellison Medical Foundation Senior Scholar in Aging; Alex Lemonade Stand Foundation Award; Banco Santander through its Santander Universities Global Division FX Work in O.F.-C. laboratory was supported by Fundacion Botin, by Banco Santander through its Santander Universities Global Division, and by grants from the Spanish Ministry of Economy and Competitiveness (MINECO) (SAF2014-57791-REDC and SVP-2013-068072), Fundacio La Marato de TV3, the Howard Hughes Medical Institute, and the European Research Council (ERC-617840). The A.N. laboratory was supported by the Intramural Research Program of the NIH, the National Cancer Institute (NCI), the Center for Cancer Research, an Ellison Medical Foundation Senior Scholar in Aging, and the Alex Lemonade Stand Foundation Award. NR 52 TC 1 Z9 1 U1 2 U2 2 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 SEP 13 PY 2016 VL 9 IS 445 AR ra91 DI 10.1126/scisignal.aad8243 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EB0HY UT WOS:000387026100003 PM 27625305 ER PT J AU Vafai, SB Mevers, E Higgins, KW Fomina, Y Zhang, JM Mandinova, A Newman, D Shaw, SY Clardy, J Mootha, VK AF Vafai, Scott B. Mevers, Emily Higgins, Kathleen W. Fomina, Yevgenia Zhang, Jianming Mandinova, Anna Newman, David Shaw, Stanley Y. Clardy, Jon Mootha, Vamsi K. TI Natural Product Screening Reveals Naphthoquinone Complex I Bypass Factors SO PLOS ONE LA English DT Article ID MITOCHONDRIAL RESPIRATORY-CHAIN; APOPTOSIS; DISEASE; PINK1; CELLS; DEFICIENCY; IDEBENONE; OXIDATION; NDUFA9 AB Deficiency of mitochondrial complex I is encountered in both rare and common diseases, but we have limited therapeutic options to treat this lesion to the oxidative phosphorylation system (OXPHOS). Idebenone and menadione are redox-active molecules capable of rescuing OXPHOS activity by engaging complex I-independent pathways of entry, often referred to as "complex I bypass." In the present study, we created a cellular model of complex I deficiency by using CRISPR genome editing to knock out Ndufa9 in mousemyoblasts, and utilized this cell line to develop a high-throughput screening platform for novel complex I bypass factors. We screened a library of similar to 40,000 natural product extracts and performed bioassay-guided fractionation on a subset of the top scoring hits. We isolated four plant-derived 1,4-naphthoquinone complex I bypass factors with structural similarity to menadione: chimaphilin and 3-chloro-chimaphilin from Chimaphila umbellata and dehydro-alpha-lapachone and dehydroiso-alpha-lapachone from Stereospermum euphoroides. We also tested a small number of structurally related naphthoquinones from commercial sources and identified two additional compounds with complex I bypass activity: 2-methoxy-1,4-naphthoquinone and 2-methoxy-3-methyl-1,4,-naphthoquinone. The six novel complex I bypass factors reported here expand this class of molecules and will be useful as tool compounds for investigating complex I disease biology. C1 [Vafai, Scott B.; Higgins, Kathleen W.; Fomina, Yevgenia; Mootha, Vamsi K.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. [Vafai, Scott B.; Higgins, Kathleen W.; Fomina, Yevgenia; Mootha, Vamsi K.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Vafai, Scott B.; Higgins, Kathleen W.; Fomina, Yevgenia; Mootha, Vamsi K.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Mevers, Emily; Clardy, Jon] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA USA. [Zhang, Jianming; Mandinova, Anna] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Newman, David] NCI, Nat Prod Branch, Frederick, MD 21701 USA. [Shaw, Stanley Y.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Mootha, Vamsi K.] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA. RP Vafai, SB; Mootha, VK (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA.; Vafai, SB; Mootha, VK (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.; Vafai, SB; Mootha, VK (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.; Mootha, VK (reprint author), Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA. EM svafai@broadinstitute.org; vamsi@hms.harvard.edu FU NIH [R01GM099683]; KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Research Resources); KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health) [KL2 TR001100] FX This work was supported by a T-R01 grant R01GM099683 from NIH to VKM. VKM is an investigator of the Howard Hughes Medical Institute. SBV was supported by a KL2/Catalyst Medical Research Investigator Training award (an appointed KL2 award) from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award KL2 TR001100). The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic healthcare centers, or the National Institutes of Health. NR 28 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 SEP 13 PY 2016 VL 11 IS 9 AR e0162686 DI 10.1371/journal.pone.0162686 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW5JR UT WOS:000383681000046 PM 27622560 ER PT J AU Wilson, CJ de la Haye, K Coveney, J Hughes, DL Hutchinson, A Miller, C Prichard, I Ward, P Koehly, LM AF Wilson, Carlene J. de la Haye, Kayla Coveney, John Hughes, Donna L. Hutchinson, Amanda Miller, Caroline Prichard, Ivanka Ward, Paul Koehly, Laura M. TI Protocol for a randomized controlled trial testing the impact of feedback on familial risk of chronic diseases on family-level intentions to participate in preventive lifestyle behaviors SO BMC PUBLIC HEALTH LA English DT Article DE Intergeneration transmission; Eating behavior; Health behavior; Family health history; Randomised clinical trials; Culture ID PHYSICAL-ACTIVITY; SOCIOECONOMIC DIFFERENCES; ADOLESCENT FRIENDSHIPS; MEXICAN-AMERICAN; FOOD CHOICE; HEALTH; OBESITY; CHILDREN; ADULTS; COMMUNICATION AB Background: Common disease risk clusters in families due to shared genetics, exposure to environmental risk factors, and because many health behaviours are established and maintained in family environments. This randomised controlled trial will test whether the provision of a family health history (FHH) risk assessment tool increases intentions and engagement in health behaviors. Message distribution and collective behavior change within family networks will be mapped using social network analysis. The relative intervention impact will be compared between families from different ethnic backgrounds. Methods: One hundred and fifty mothers (50 Anglo-Australian, 50 Italian-Australian, 50 Vietnamese-Australian) will be recruited, with four or more other family members across three generations, including a child (aged 10-18 years). Each family is randomly assigned to intervention or control. At baseline and 6-month follow-up, all participants complete surveys to assess dietary and physical activity intentions and behaviors, attitudes towards food, and perceived disease risk. Intervention families receive a visual pedigree detailing their FHH of diabetes, heart disease, breast and bowel cancer, a health education workbook to ascertain members' disease risk (i. e. average or above average risk), and screening and primary prevention recommendations. After completion of follow-up assessments, controls will receive their pedigree and workbook. The primary hypothesis is that attitudes and lifestyle behaviors will improve more within families exposed to FHH feedback, although the extent of this improvement may vary between families from different ethnic backgrounds. Additionally, the extent of improvement in the treatment group will be moderated by the level of family disease risk, with above-average risk leading to greater improvement. A secondary aim will explore different family members' roles in message distribution and collective responses to risk using social network approaches and to compare network functioning between families with different ethnic backgrounds. Discussion: Results will guide future health promotion programs aimed at improving lifestyle factors. This research will assess whether FHH can motivate families to adopt family-level strategies to support health promoting behaviors. Secondary analyses aim to identify change agents within the family who are particularly effective in shifting normative behaviors. C1 [Wilson, Carlene J.; Hughes, Donna L.] Flinders Univ South Australia, Flinders Ctr Innovat Canc, Adelaide, SA, Australia. [Wilson, Carlene J.; Hughes, Donna L.] Canc Council South Australia, Adelaide, SA, Australia. [de la Haye, Kayla] Univ Southern Calif, Inst Hlth Promot & Dis Prevent Res, Los Angeles, CA USA. [Coveney, John; Prichard, Ivanka; Ward, Paul] Flinders Univ South Australia, Sch Hlth Sci, Adelaide, SA, Australia. [Hutchinson, Amanda] Univ South Australia, Sch Psychol Social Work & Social Policy, Adelaide, SA, Australia. [Miller, Caroline] South Australian Hlth & Med Res Inst, Adelaide, SA, Australia. [Koehly, Laura M.] NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. RP Koehly, LM (reprint author), NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. EM koehlyl@mail.nih.gov RI Hutchinson, Amanda/B-3629-2013; OI Hutchinson, Amanda/0000-0003-3983-8321; Prichard, Ivanka/0000-0001-8892-9129; Coveney, John/0000-0001-8237-0248; Ward, Paul/0000-0002-5559-9714 FU Australian Research Council [LP100200549]; Cancer Council SA [LP100200549]; Intramural Research Program of the National Human Genome Research Institute [ZIAHG20335] FX This trial is funded by a project linkage grant between the Australian Research Council and Cancer Council SA (Project ID: LP100200549). This research was supported, in part, by funding from the Intramural Research Program of the National Human Genome Research Institute (ZIAHG20335). NR 55 TC 0 Z9 0 U1 5 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD SEP 13 PY 2016 VL 16 AR 965 DI 10.1186/s12889-016-3623-7 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DX4NW UT WOS:000384359400001 PM 27618810 ER PT J AU Blackstone, C Prinz, WA AF Blackstone, Craig Prinz, William A. TI Keeping in shape SO ELIFE LA English DT Editorial Material ID ENDOPLASMIC-RETICULUM; 3-WAY JUNCTIONS; ER NETWORK; GENERATION; LUNAPARK C1 [Blackstone, Craig] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Prinz, William A.] NIDDKD, NIH, Bethesda, MD USA. RP Blackstone, C (reprint author), NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM BlackstC@ninds.nih.gov NR 11 TC 0 Z9 0 U1 2 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 SEP 13 PY 2016 VL 5 AR e20468 DI 10.7554/eLife.20468 PG 3 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DX2YX UT WOS:000384240900001 ER PT J AU McPhie, P Brown, P Chen, B Dayie, TK Minton, AP AF McPhie, Peter Brown, Patrick Chen, Bin Dayie, Theodore K. Minton, Allen P. TI Modulation of Conformational Equilibria in the S-Adenosylmethionine (SAM) II Riboswitch by SAM, Mg2+, and Trimethylamine N-Oxide SO BIOCHEMISTRY LA English DT Article ID BIOCHEMICAL REACTIONS; CIRCULAR-DICHROISM; RNA; LIGAND; PROTEINS; BINDING; ABSENCE; NMR; PREORGANIZATION; CONFINEMENT AB The dependence of the conformation of the S-adenosylmethionine (SAM) II riboswitch on the concentration of added Mg2+ ions and SAM, individually and in mixtures, was monitored by circular dichroism (CD) spectroscopy and by measurement of the diffusion coefficient. The results are analyzed in the context of two complementary quantitative models, both of which are consistent with a single underlying physical model. Magnesium binding sites in the open state have an affinity on average higher than the affinity of those in the compact state, but formation of the compact state is accompanied by an increase in the number of binding sites. Consequently, at low Mg2+ concentrations, Mg2+ binds preferentially to the open state, favoring its formation, but at high concentrations, Mg2+ binds preferentially to the compact state. The affinity of the riboswitch for SAM increases drastically with an increased level of binding of Mg2+ to the compact pseudoknot conformation. The effect of increasing concentrations of trimethylamine N-oxide (TMAO), a well-studied molecular crowding agent, on the conformation of the riboswitch and its affinity for SAM were also monitored by CD spectroscopy and measurement of diffusion. In the absence of added Mg2+, high concentrations of TMAO were found to induce a conformational change compatible with the formation of the pseudoknot form but have only a small effect on the affinity of the RNA for SAM. C1 [McPhie, Peter; Minton, Allen P.] NIDDKD, Sect Phys Biochem, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. [Brown, Patrick] Natl Inst Biomed Imaging & Bioengn, Sect Dynam Macromol Assembly, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. [Chen, Bin; Dayie, Theodore K.] Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. [Brown, Patrick] Watkins Mill High Sch, Dept Sci, Gaithersburg, MD 20879 USA. RP McPhie, P; Minton, AP (reprint author), NIDDKD, Sect Phys Biochem, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. EM pmcphie@helix.nih.gov; 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; Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering; Maryland Biotechnology Award FX This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (P.M. and A.P.M.), by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (P.B.), and by a Maryland Biotechnology Award (B.C. and T.K.D.). NR 40 TC 0 Z9 0 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 SEP 13 PY 2016 VL 55 IS 36 BP 5010 EP 5020 DI 10.1021/acs.biochem.6b00283 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DW0FJ UT WOS:000383316000004 PM 27552169 ER PT J AU Zhu, Y Gao, Y Tao, C Shao, ML Zhao, SG Huang, W Yao, T Johnson, JA Liu, TM Cypess, AM Gupta, O Holland, WL Gupta, RK Spray, DC Tanowitz, HB Cao, L Lynes, MD Tseng, YH Elmquist, JK Williams, KW Lin, HV Scherer, PE AF Zhu, Yi Gao, Yong Tao, Caroline Shao, Mengle Zhao, Shangang Huang, Wei Yao, Ting Johnson, Joshua A. Liu, Tiemin Cypess, Aaron M. Gupta, Olga Holland, William L. Gupta, Rana K. Spray, David C. Tanowitz, Herbert B. Cao, Lei Lynes, Matthew D. Tseng, Yu-Hua Elmquist, Joel K. Williams, Kevin W. Lin, Hua V. Scherer, Philipp E. TI Connexin 43 Mediates White Adipose Tissue Beiging by Facilitating the Propagation of Sympathetic Neuronal Signals SO CELL METABOLISM LA English DT Article ID GAP-JUNCTIONAL COMMUNICATION; ENERGY-BALANCE; INTERCELLULAR COMMUNICATION; GLUCOSE-HOMEOSTASIS; BROWN ADIPOCYTES; UP-REGULATION; POMC NEURONS; FAT; ADIPOGENESIS; EXPRESSION AB "Beige" adipocytes reside in white adipose tissue (WAT) and dissipate energy as heat. Several studies have shown that cold temperature can activate pro-opiomelanocortin-expressing (POMC) neurons and increase sympathetic neuronal tone to regulate WAT beiging. WAT, however, is traditionally known to be sparsely innervated. Details regarding the neuronal innervation and, more importantly, the propagation of the signal within the population of "beige" adipocytes are sparse. Here, we demonstrate that beige adipocytes display an increased cell-to-cell coupling via connexin 43 (Cx43) gap junction channels. Blocking of Cx43 channels by 18 alpha-glycyrrhetinic acid decreases POMC-activation-induced adipose tissue beiging. Adipocyte-specific deletion of Cx43 reduces WAT beiging to a level similar to that observed in denervated fat pads. In contrast, overexpression of Cx43 is sufficient to promote beiging even with mild cold stimuli. These data reveal the importance of cell-to-cell communication, effective in cold-induced WAT beiging, for the propagation of limited neuronal inputs in adipose tissue. C1 [Zhu, Yi; Tao, Caroline; Shao, Mengle; Zhao, Shangang; Johnson, Joshua A.; Gupta, Olga; Holland, William L.; Gupta, Rana K.; Scherer, Philipp E.] Univ Texas Southwestern Med Ctr, Touchstone Diabet Ctr, Dept Internal Med, Dallas, TX 75390 USA. [Zhu, Yi; Lin, Hua V.] Lilly Res Labs, Indianapolis, IN 46285 USA. [Gao, Yong; Yao, Ting; Liu, Tiemin; Elmquist, Joel K.; Williams, Kevin W.] Univ Texas Southwestern Med Ctr, Dept Internal Med, Div Hypothalam Res, Dallas, TX 75390 USA. [Gao, Yong] Chinese Acad Med Sci, Inst Basic Med Sci, Natl Lab Med Mol Biol, Beijing 100005, Peoples R China. [Gao, Yong] Peking Union Med Coll, Beijing 100005, Peoples R China. [Huang, Wei; Cao, Lei] Ohio State Univ, Coll Med, Dept Canc Biol & Genet, Columbus, OH 43210 USA. [Yao, Ting] Xi An Jiao Tong Univ, Sch Med, Dept Physiol & Pathophysiol, 76 West Yanta Rd, Xian 710061, Shaanxi, Peoples R China. [Cypess, Aaron M.] NIDDKD, Translat Physiol Sect, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Spray, David C.] Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10461 USA. [Spray, David C.] Albert Einstein Coll Med, Dept Med Cardiol, Bronx, NY 10461 USA. [Tanowitz, Herbert B.] Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10461 USA. [Tanowitz, Herbert B.] Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA. [Lynes, Matthew D.; Tseng, Yu-Hua] Harvard Med Sch, Joslin Diabet Ctr, Boston, MA 02215 USA. RP Scherer, PE (reprint author), Univ Texas Southwestern Med Ctr, Touchstone Diabet Ctr, Dept Internal Med, Dallas, TX 75390 USA. EM philipp.scherer@utsouthwestern.edu OI Shao, Mengle/0000-0002-5488-9904 FU NIH [R01-DK55758, R01-DK099110, P01-DK088761, R03-DK101865, R01-NS092466, R21-AI124000, R01-CA163640, R01-CA166590, R21-CA178227, R01-DK077097, R01-DK102898, R37-DK053301, R01-DK088423, R01-DK100659, R01-DK100699, R01-DK104789, R00-DK094973]; Cancer Prevention and Research Institute of Texas (CPRIT) [RP140412]; Lilly Innovation Fellowship Award (LIFA); China Scholarship Council [201406280111]; AHA [14SDG20370016] FX This study was supported by NIH grants R01-DK55758, R01-DK099110, and P01-DK088761; a grant from the Cancer Prevention and Research Institute of Texas (CPRIT RP140412) to P.E.S.; a Lilly Innovation Fellowship Award (LIFA) to Y.Z.; China Scholarship Council Scholarship number 201406280111 to T.Y.; AHA grant 14SDG20370016 to T.L.; NIH grant R03-DK101865 to O.G.; NIH grant R01-NS092466 to D.C.S.; NIH grant R21-AI124000 to H.B.T.; NIH grants R01-CA163640, R01-CA166590, and R21-CA178227 to L.C.; NIH grants R01-DK077097 and R01-DK102898 to Y.-H.T.; NIH grants R37-DK053301, R01-DK088423, R01-DK100659, and P01-DK088761 to J.K.E.; NIH grant R01-DK100699 to K.W.W.; NIH grant R01-DK104789 to R.K.G.; and NIH grant R00-DK094973 to W.L.H. NR 50 TC 1 Z9 1 U1 5 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD SEP 13 PY 2016 VL 24 IS 3 BP 420 EP 433 DI 10.1016/j.cmet.2016.08.005 PG 14 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA DW9XQ UT WOS:000384016500014 PM 27626200 ER PT J AU Kaneko, K Xu, PW Cordonier, EL Chen, SS Ng, A Xu, Y Morozov, A Fukuda, M AF Kaneko, Kentaro Xu, Pingwen Cordonier, Elizabeth L. Chen, Siyu S. Ng, Amy Xu, Yong Morozov, Alexei Fukuda, Makoto TI Neuronal Rap1 Regulates Energy Balance, Glucose Homeostasis, and Leptin Actions SO CELL REPORTS LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; DIET-INDUCED OBESITY; NERVOUS-SYSTEM CONTROL; CONNECTS ER STRESS; BODY-WEIGHT; CYCLIC-AMP; INSULIN-RESISTANCE; FOOD-INTAKE; MICE; CAMP AB The CNS contributes to obesity and metabolic disease; however, the underlying neurobiological pathways remain to be fully established. Here, we show that the small GTPase Rap1 is expressed in multiple hypothalamic nuclei that control whole-body metabolism and is activated in high-fat diet (HFD)-induced obesity. Genetic ablation of CNS Rap1 protects mice from dietary obesity, glucose imbalance, and insulin resistance in the periphery and from HFD-induced neuropathological changes in the hypothalamus, including diminished cellular leptin sensitivity and increased endoplasmic reticulum (ER) stress and inflammation. Furthermore, pharmacological inhibition of CNS Rap1 signaling normalizes hypothalamic ER stress and inflammation, improves cellular leptin sensitivity, and reduces body weight in mice with dietary obesity. We also demonstrate that Rap1 mediates leptin resistance via interplay with ER stress. Thus, neuronal Rap1 critically regulates leptin sensitivity and mediates HFD-induced obesity and hypothalamic pathology and may represent a potential therapeutic target for obesity treatment. C1 [Kaneko, Kentaro; Xu, Pingwen; Cordonier, Elizabeth L.; Chen, Siyu S.; Ng, Amy; Xu, Yong; Fukuda, Makoto] Baylor Coll Med, Dept Pediat, Childrens Nutr Res Ctr, Houston, TX 77030 USA. [Xu, Yong] Baylor Coll Med, Dept Mol & Cellular Biol, 1 Baylor Plaza, Houston, TX 77030 USA. [Morozov, Alexei] NIMH, Unit Behav Genet, Mol Pathophysiol Lab, NIH, Bethesda, MD 20892 USA. [Morozov, Alexei] Virginia Tech, Caril Res Inst, Roanoke, VA 24016 USA. RP Fukuda, M (reprint author), Baylor Coll Med, Dept Pediat, Childrens Nutr Res Ctr, Houston, TX 77030 USA. EM fukuda@bcm.edu OI Fukuda, Makoto/0000-0003-0112-9925 FU USDA [CRIS 6250-51000-055, AHA-14BGIA20460080, NIH-P30-DK079638, NIH R01DK104901]; NIH [R01DK093587, R01DK101379, AHA-15POST22500012, T32HD071839]; Uehara Memorial Foundation [201340214] FX The authors gratefully acknowledge Zainab Mabizari for technical assistance; Drs. Joel K. Elmquist and Takashi Kadowaki for helpful discussion during the course of this study; Qingchun Tong, Miao-Hsueh Chen, and Tuo Deng for comments on the manuscript; Mr. Mark Meyer for editing the manuscript; and Dr. Marta L. Fiorotto for interpretive assistance. This work was supported by USDA CRIS 6250-51000-055, AHA-14BGIA20460080, NIH-P30-DK079638, and NIH R01DK104901 (to M.F.); NIH Awards R01DK093587 and R01DK101379 (to Y.X.); AHA-15POST22500012 and Uehara Memorial Foundation 201340214 (to K.K.); and NIH T32HD071839 (to E.L.C.). NR 57 TC 1 Z9 1 U1 1 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 SEP 13 PY 2016 VL 16 IS 11 BP 3003 EP 3015 DI 10.1016/j.celrep.2016.08.039 PG 13 WC Cell Biology SC Cell Biology GA DW8CZ UT WOS:000383882300020 PM 27626668 ER PT J AU Savage, AM Hills, J Driscoll, K Fergus, DJ Grunden, AM Dunn, RR AF Savage, Amy M. Hills, Justin Driscoll, Kattherine Fergus, Daniel J. Grunden, Amy M. Dunn, Robert R. TI Microbial diversity of extreme habitats in human homes SO PEERJ LA English DT Article DE Community Ecology; Extreme environments; Human Homes; Interactive effects; Microbialdiversity; Temperature; pH; Chemical ID BACTERIAL COMMUNITY STRUCTURE; DRINKING-WATER; SP-NOV; HELCOCOCCUS-KUNZII; GENOME SEQUENCE; LIFE; ENVIRONMENTS; TEMPERATURE; EXTREMOPHILES; PATTERNS AB High-throughput sequencing techniques have opened up the world of microbial diversity to scientists, and a flurry of studies in the most remote and extreme habitats on earth have begun to elucidate the key roles of microbes in ecosystems with extreme conditions. These same environmental extremes can also be found closer to humans, even in our homes. Here, we used high-throughput sequencing techniques to assess bacterial and archaeal diversity in the extreme environments inside human homes (e.g., dishwashers, hot water heaters, washing machine bleach reservoirs, etc.). We focused on habitats in the home with extreme temperature, pH, and chemical environmental conditions. We found a lower diversity of microbes in these extreme home environments compared to less extreme habitats in the home. However, we were nonetheless able to detect sequences from a relatively diverse array of bacteria and archaea. Habitats with extreme temperatures alone appeared to be able to support a greater diversity of microbes than habitats with extreme pH or extreme chemical environments alone. Microbial diversity was lowest when habitats had both extreme temperature and one of these other extremes. In habitats with both extreme temperatures and extreme pH, taxa with known associations with extreme conditions dominated. Our findings highlight the importance of examining interactive effects of multiple environmental extremes on microbial communities. Inasmuch as taxa from extreme environments can be both beneficial and harmful to humans, our findings also suggest future work to understand both the threats and opportunities posed by the life in these habitats. C1 [Savage, Amy M.] Rutgers State Univ, Camden, NJ 08102 USA. [Hills, Justin] NIDDK, Lab Cellualr & Mol Biol, Bethesda, MD 20892 USA. [Driscoll, Kattherine] Wilds, Anim Management Dept, Cumberland, OH USA. [Fergus, Daniel J.] Noth Carolina Museum Nat Sci, Genom & Microbiol, Raleigh, NC USA. [Grunden, Amy M.] North Carolina State Univ, Dept Plant & Microbial Sci, Raleigh, NC 27695 USA. [Dunn, Robert R.] North Carolina State Univ, Dept Appl Ecol, Raleigh, NC 27695 USA. [Dunn, Robert R.] North Carolina State Univ, Keck Ctr Behav Biol, Raleigh, NC 27695 USA. RP Savage, AM (reprint author), Rutgers State Univ, Camden, NJ 08102 USA. EM amy.savage@rutgers.edu RI publicationpage, cmec/B-4405-2017 FU A.P. Sloan Microbiology of the Built Environment Program grant FX This work was funded by A.P. Sloan Microbiology of the Built Environment Program grant awarded to RRD. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 69 TC 0 Z9 0 U1 14 U2 14 PU PEERJ INC PI LONDON PA 341-345 OLD ST, THIRD FLR, LONDON, EC1V 9LL, ENGLAND SN 2167-8359 J9 PEERJ JI PeerJ PD SEP 13 PY 2016 VL 4 AR e2376 DI 10.7717/peerj.2376 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV9OC UT WOS:000383269600002 PM 27672493 ER PT J AU Ueda, T Nakata, Y Nagamachi, A Yamasaki, N Kanai, A Sera, Y Sasaki, M Matsui, H Honda, Z Oda, H Wolff, L Inaba, T Honda, H AF Ueda, Takeshi Nakata, Yuichiro Nagamachi, Akiko Yamasaki, Norimasa Kanai, Akinori Sera, Yasuyuki Sasaki, Masato Matsui, Hirotaka Honda, Zen-ichiro Oda, Hideaki Wolff, Linda Inaba, Toshiya Honda, Hiroaki TI Propagation of trimethylated H3K27 regulated by polycomb protein EED is required for embryogenesis, hematopoietic maintenance, and tumor suppression SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE histone methylation; repressive histone marks; hematologic malignancies ID REPRESSIVE COMPLEX 2; ACUTE MYELOID-LEUKEMIA; CANCER GENES; STEM-CELLS; EXPRESSION; DIFFERENTIATION; METHYLATION; GALECTIN-3; MUTATIONS; NEOPLASMS AB Polycomb repressive complex 2 (PRC2) catalyzes the monomethylation, dimethylation, and trimethylation of histone H3 Lys27 (H3K27) and acts as a central epigenetic regulator that marks the repressive chromatin domain. Embryonic ectoderm development (EED), an essential component of PRC2, interacts with trimethylated H3K27 (H3K27me3) through the aromatic cage structure composed of its three aromatic amino acids, Phe97, Trp364, and Tyr365. This interaction allosterically activates the histone methyltransferase activity of PRC2 and thereby propagates repressive histone marks. In this study, we report the analysis of knock-in mice harboring the myeloid disorder-associated EED Ile363Met (I363M) mutation, analogous to the EED aromatic cage mutants. The I363M homozygotes displayed a remarkable and preferential reduction of H3K27me3 and died at midgestation. The heterozygotes increased the clonogenic capacity and bone marrow repopulating activity of hematopoietic stem/progenitor cells (HSPCs) and were susceptible to leukemia. Lgals3, a PRC2 target gene encoding a multifunctional galactose-binding lectin, was derepressed in I363M heterozygotes, which enhanced the stemness of HSPCs. Thus, ourwork provides in vivo evidence that the structural integrity of EED to H3K27me3 propagation is critical, especially for embryonic development and hematopoietic homeostasis, and that its perturbation increases the predisposition to hematologic malignancies. C1 [Ueda, Takeshi; Nakata, Yuichiro; Yamasaki, Norimasa; Sera, Yasuyuki; Honda, Hiroaki] Hiroshima Univ, Res Inst Radiat Biol & Med, Dept Dis Model, Hiroshima 7348553, Japan. [Nagamachi, Akiko; Kanai, Akinori; Matsui, Hirotaka; Inaba, Toshiya] Hiroshima Univ, Res Inst Radiat Biol & Med, Dept Mol Oncol, Hiroshima 7348553, Japan. [Sasaki, Masato] Tohoku Med & Pharmaceut Univ, Fac Pharmaceut Sci, Div Infect & Host Def, Sendai, Miyagi 9818558, Japan. [Honda, Zen-ichiro] Ochanomizu Univ, Hlth Care Ctr, Tokyo 1128611, Japan. [Honda, Zen-ichiro] Ochanomizu Univ, Grad Sch Humanities & Sci, Inst Environm Sci Human Life, Tokyo 1128611, Japan. [Oda, Hideaki] Tokyo Womens Med Univ, Dept Pathol, Tokyo 1628666, Japan. [Wolff, Linda] NCI, Cellular Oncol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Ueda, Takeshi] Kindai Univ, Fac Med, Dept Biochem, Osakasayama 5898511, Japan. RP Ueda, T; Honda, H (reprint author), Hiroshima Univ, Res Inst Radiat Biol & Med, Dept Dis Model, Hiroshima 7348553, Japan.; Ueda, T (reprint author), Kindai Univ, Fac Med, Dept Biochem, Osakasayama 5898511, Japan. EM takeshiueda@med.kindai.ac.jp; hhonda@hiroshima-u.ac.jp FU Ministry of Education, Science and Culture of Japan; Takeda Science Foundation; Osaka Cancer Research Foundation; Japan Leukemia Research Fund FX We thank Yuki Sakai for animal care; Megumi Nakamura, Sawako Ogata, and Rika Tai for mouse genotyping and molecular experiments; and Dr. Tatsuo Miyamoto for technical assistance. We also thank the RIKEN BioResource Center for providing the B6.Cg-Tg(CAG-Cre)CZ-MO2Osb mice (RBRC01828). This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan; the Takeda Science Foundation; the Osaka Cancer Research Foundation; and the Japan Leukemia Research Fund. NR 33 TC 0 Z9 0 U1 2 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 SEP 13 PY 2016 VL 113 IS 37 BP 10370 EP 10375 DI 10.1073/pnas.1600070113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV7BW UT WOS:000383092000049 PM 27578866 ER PT J AU Pageon, SV Tabarin, T Yamamoto, Y Ma, YQ Bridgeman, JS Cohnen, A Benzing, C Gao, YJ Crowther, MD Tungatt, K Dolton, G Sewell, AK Price, DA Acuto, O Parton, RG Gooding, JJ Rossy, J Rossjohn, J Gaus, K AF Pageon, Sophie V. Tabarin, Thibault Yamamoto, Yui Ma, Yuanqing Bridgeman, John S. Cohnen, Andre Benzing, Carola Gao, Yijun Crowther, Michael D. Tungatt, Katie Dolton, Garry Sewell, Andrew K. Price, David A. Acuto, Oreste Parton, Robert G. Gooding, J. Justin Rossy, Jeremie Rossjohn, Jamie Gaus, Katharina TI Functional role of T-cell receptor nanoclusters in signal initiation and antigen discrimination SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE TCR triggering; signal transduction; single-molecule localization microscopy ID IMMUNOLOGICAL SYNAPSE; CD8 CORECEPTOR; ACTIVATION; TCR; COMPLEX; MOLECULES; MICROCLUSTERS; MECHANISMS; MICROSCOPY; CLUSTERS AB Antigen recognition by the T-cell receptor (TCR) is a hallmark of the adaptive immune system. When the TCR engages a peptide bound to the restricting major histocompatibility complex molecule (pMHC), it transmits a signal via the associated CD3 complex. How the extracellular antigen recognition event leads to intracellular phosphorylation remains unclear. Here, we used single-molecule localization microscopy to quantify the organization of TCR-CD3 complexes into nanoscale clusters and to distinguish between triggered and nontriggered TCR-CD3 complexes. We found that only TCR-CD3 complexes in dense clusters were phosphorylated and associated with downstream signaling proteins, demonstrating that the molecular density within clusters dictates signal initiation. Moreover, both pMHC dose and TCR-pMHC affinity determined the density of TCR-CD3 clusters, which scaled with overall phosphorylation levels. Thus, TCR-CD3 clustering translates antigen recognition by the TCR into signal initiation by the CD3 complex, and the formation of dense signaling-competent clusters is a process of antigen discrimination. C1 [Pageon, Sophie V.; Tabarin, Thibault; Yamamoto, Yui; Ma, Yuanqing; Benzing, Carola; Gao, Yijun; Rossy, Jeremie; Gaus, Katharina] Univ New South Wales, Sch Med Sci, European Mol Biol Lab, Australia Node Single Mol Sci, Sydney, NSW 2052, Australia. [Pageon, Sophie V.; Tabarin, Thibault; Yamamoto, Yui; Ma, Yuanqing; Benzing, Carola; Gao, Yijun; Rossy, Jeremie; Gaus, Katharina] Univ New South Wales, Australian Res Council, Ctr Excellence Adv Mol Imaging, Sydney, NSW 2052, Australia. [Bridgeman, John S.; Crowther, Michael D.; Tungatt, Katie; Dolton, Garry; Sewell, Andrew K.; Price, David A.; Rossjohn, Jamie] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff CF14 4XN, S Glam, Wales. [Bridgeman, John S.] Cellular Therapeut Ltd, Manchester M13 9XX, Lancs, England. [Cohnen, Andre; Acuto, Oreste] Univ Oxford, Sir William Dunn Sch Pathol, T Cell Signalling Lab, Oxford OX1 3RE, England. [Price, David A.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Parton, Robert G.] Univ Queensland, Inst Mol Biosci, St Lucia, Qld 4072, Australia. [Parton, Robert G.] Univ Queensland, Australia Ctr Microscopy & Microanal, St Lucia, Qld 4072, Australia. [Parton, Robert G.; Gooding, J. Justin] Univ Queensland, Australian Res Council, Ctr Excellence Convergent Bionano Sci & Technol, St Lucia, Qld 4072, Australia. [Gooding, J. Justin] Univ New South Wales, Sch Chem, Sydney, NSW 2052, Australia. [Gooding, J. Justin] Univ New South Wales, Australian Ctr NanoMed, Sydney, NSW 2052, Australia. [Rossjohn, Jamie] Monash Univ, Dept Biochem & Mol Biol Biomed Discovery, Infect & Immun Program, Clayton, Vic 3800, Australia. [Rossjohn, Jamie] Monash Univ, Australian Res Council, Ctr Excellence Adv Mol Imaging, Clayton, Vic 3800, Australia. RP Gaus, K (reprint author), Univ New South Wales, Sch Med Sci, European Mol Biol Lab, Australia Node Single Mol Sci, Sydney, NSW 2052, Australia.; Gaus, K (reprint author), Univ New South Wales, Australian Res Council, Ctr Excellence Adv Mol Imaging, Sydney, NSW 2052, Australia. EM k.gaus@unsw.edu.au RI Price, David/C-7876-2013; OI Price, David/0000-0001-9416-2737; Pageon, Sophie/0000-0003-1701-5551; Parton, Robert/0000-0002-7494-5248; Gooding, John Justin/0000-0002-5398-0597 FU National Health and Medical Research Council of Australia [1022182, 1037320, 1059278]; Australian Research Council [CE140100011] FX This work was supported by National Health and Medical Research Council of Australia Grants 1022182 (to K.G. and J. Rossy), 1037320 (to R.G.P. and K.G.), and 1059278 (to K.G.); and Australian Research Council Grant CE140100011 (to K.G. and J. Rossjohn). D.A.P. and A.K.S. are Wellcome Trust Senior Investigators. NR 70 TC 5 Z9 5 U1 9 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 SEP 13 PY 2016 VL 113 IS 37 BP E5454 EP E5463 DI 10.1073/pnas.1607436113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV7BW UT WOS:000383092000012 PM 27573839 ER PT J AU Tsetsarkin, KA Liu, GP Kenney, H Hermance, M Thangamani, S Pletnev, AG AF Tsetsarkin, Konstantin A. Liu, Guangping Kenney, Heather Hermance, Meghan Thangamani, Saravanan Pletnev, Alexander G. TI Concurrent micro-RNA mediated silencing of tick-borne flavivirus replication in tick vector and in the brain of vertebrate host SO SCIENTIFIC REPORTS LA English DT Article ID 3' NONCODING REGION; ENCEPHALITIS-VIRUS; TRANSOVARIAL TRANSMISSION; TARGET RECOGNITION; AEDES-ALBOPICTUS; VIRAL GENOME; INFECTION; NEUROINVASIVENESS; NEUROVIRULENCE; CONSTRUCTION AB Tick-borne viruses include medically important zoonotic pathogens that can cause life-threatening diseases. Unlike mosquito-borne viruses, whose impact can be restrained via mosquito population control programs, for tick-borne viruses only vaccination remains the reliable means of disease prevention. For live vaccine viruses a concern exists, that spillovers from viremic vaccinees could result in introduction of genetically modified viruses into sustainable tick-vertebrate host transmission cycle in nature. To restrict tick-borne flavivirus (Langat virus, LGTV) vector tropism, we inserted target sequences for tick-specific microRNAs (mir-1, mir-275 and mir-279) individually or in combination into several distant regions of LGTV genome. This caused selective attenuation of viral replication in tick-derived cells. LGTV expressing combinations of target sequences for tick-and vertebrate CNS-specific miRNAs were developed. The resulting viruses replicated efficiently and remained stable in simian Vero cells, which do not express these miRNAs, however were severely restricted to replicate in tick-derived cells. In addition, simultaneous dual miRNA targeting led to silencing of virus replication in live Ixodes ricinus ticks and abolished virus neurotropism in highly permissive newborn mice. The concurrent restriction of adverse replication events in vertebrate and invertebrate hosts will, therefore, ensure the environmental safety of live tick-borne virus vaccine candidates. C1 [Tsetsarkin, Konstantin A.; Liu, Guangping; Kenney, Heather; Pletnev, Alexander G.] NIAID, Lab Infect Dis, Bethesda, MD 20814 USA. [Hermance, Meghan] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA. [Thangamani, Saravanan] UTMB, Galveston Natl Lab, Dept Pathol, Galveston, TX USA. RP Pletnev, AG (reprint author), NIAID, Lab Infect Dis, Bethesda, MD 20814 USA. EM apletnev@niaid.nih.gov FU Division of Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank Dr. Ulrike Munderloh (University of Minnesota) and Marshall Bloom (Rocky Mountain Laboratories - NIAID) for providing ISE6 cells, as well as Evgeniya Volkova for critically reviewing the manuscript. This work was supported by the Division of Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 42 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 SEP 13 PY 2016 VL 6 AR 33088 DI 10.1038/srep33088 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV4YJ UT WOS:000382931400001 PM 27620807 ER PT J AU Wang, G Cao, LY Liu, XW Sieracki, NA Di, AK Wen, X Chen, Y Taylor, S Huang, XJ Tiruppathi, C Zhao, YY Song, YL Gao, XP Jin, T Bai, CX Malik, AB Xu, JS AF Wang, Gang Cao, Luyang Liu, Xiaowen Sieracki, Nathan A. Di, Anke Wen, Xi Chen, Yong Taylor, Shalina Huang, Xiaojia Tiruppathi, Chinnaswamy Zhao, You-yang Song, Yuanlin Gao, Xiaopei Jin, Tian Bai, Chunxue Malik, Asrar B. Xu, Jingsong TI Oxidant Sensing by TRPM2 Inhibits Neutrophil Migration and Mitigates Inflammation SO DEVELOPMENTAL CELL LA English DT Article ID ADP-RIBOSE; HYDROGEN-PEROXIDE; OXIDATIVE STRESS; CATION CHANNEL; NADPH OXIDASE; ACTIVATION; LTRPC2; GRANULOCYTES; CHEMOTAXIS; SEPSIS AB Blood neutrophils perform an essential host-defense function by directly migrating to bacterial invasion sites to kill bacteria. The mechanisms mediating the transition from the migratory to bactericidal phenotype remain elusive. Here, we demonstrate that TRPM2, a trp superfamily member, senses neutrophil-generated reactive oxygen species and restrains neutrophil migration. The inhibitory function of oxidant sensing by TRPM2 requires the oxidation of Cys549, which then induces TRMP2 binding to formyl peptide receptor 1 (FPR1) and subsequent FPR1 internalization and signaling inhibition. The oxidant sensing-induced termination of neutrophil migration at the site of infection permits a smooth transition to the subsequent microbial killing phase. C1 [Wang, Gang; Cao, Luyang; Liu, Xiaowen; Sieracki, Nathan A.; Di, Anke; Taylor, Shalina; Huang, Xiaojia; Tiruppathi, Chinnaswamy; Zhao, You-yang; Gao, Xiaopei; Malik, Asrar B.; Xu, Jingsong] Univ Illinois, Dept Pharmacol, Chicago, IL 60612 USA. [Wen, Xi; Jin, Tian] NIAID, Chemotaxis Signal Sect, Immunogenet Lab, NIH, Bethesda, MD 20892 USA. [Chen, Yong] NHLBI, Prote Core Facil, NIH, Bethesda, MD 20824 USA. [Song, Yuanlin; Bai, Chunxue] Fudan Univ, Dept Pulm Med, Zhongshan Hosp, Shanghai 200032, Peoples R China. [Xu, Jingsong] Sichuan Univ, West China Hosp, Dept Neurosurg, State Key Lab Biotherapy, Chengdu 610041, Peoples R China. [Wang, Gang] Xuzhou Med Coll, Ctr Collaborat & Innovat Canc Biotherapy, Xuzhou 221002, Jiangsu, Peoples R China. [Liu, Xiaowen] Boston Childrens Hosp, Howard Hughes Med Inst, Dept Cardiol, Boston, MA 02115 USA. [Sieracki, Nathan A.] Becton Dickinson, Vernon Hills, IL 60061 USA. [Taylor, Shalina] Stanford Univ, Dept Pediat, Sch Med, Stanford, CA 94305 USA. RP Xu, JS (reprint author), Univ Illinois, Dept Pharmacol, Chicago, IL 60612 USA.; Xu, JS (reprint author), Sichuan Univ, West China Hosp, Dept Neurosurg, State Key Lab Biotherapy, Chengdu 610041, Peoples R China. EM jingsong.xu@hotmail.com FU NHLBI NIH HHS [R01 HL122157] NR 47 TC 1 Z9 1 U1 8 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 EI 1878-1551 J9 DEV CELL JI Dev. Cell PD SEP 12 PY 2016 VL 38 IS 5 BP 453 EP 462 DI 10.1016/j.devcel.2016.07.014 PG 10 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA DW1OR UT WOS:000383413000005 PM 27569419 ER PT J AU Khan, JM Rogers, T Schenke, WH Mazal, JR Faranesh, AZ Greenbaum, AB Babaliaros, VC Chen, MY Lederman, RJ AF Khan, Jaffar M. Rogers, Toby Schenke, William H. Mazal, Jonathan R. Faranesh, Anthony Z. Greenbaum, Adam B. Babaliaros, Vasilis C. Chen, Marcus Y. Lederman, Robert J. TI Intentional Laceration of the Anterior Mitral Valve Leaflet to Prevent Left Ventricular Outflow Tract Obstruction During Transcatheter Mitral Valve Replacement SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Article DE left ventricular outflow tract obstruction; mitral valve; structural heart disease; subvalvular aortic stenosis; transcatheter mitral valve replacement; valvular heart disease ID ANNULAR CALCIFICATION; RING ANNULOPLASTY; AORTIC ACCESS; HEART-VALVES; INTERVENTIONS; IMPLANTATION; DISEASE; REPAIR AB OBJECTIVES The authors propose a novel transcatheter transection of the anterior mitral leaflet to prevent iatrogenic left ventricular outflow tract (LVOT) obstruction during transcatheter mitral valve replacement (TMVR). BACKGROUND LVOT obstruction is a life-threatening complication of TMVR caused by septal displacement of the anterior mitral leaflet. METHODS In vivo procedures in swine were guided by biplane x-ray fluoroscopy and intracardiac echocardiography. Retrograde transaortic 6-F guiding catheters straddled the anterior mitral leaflet. A stiff 0.014-inch guidewire with polymer jacket insulation was electrified and advanced from the LVOT, through the A2 leaflet base, into the left atrium. The wire was snared and externalized, forming a loop that was energized and withdrawn to lacerate the anterior mitral leaflet. RESULTS The anterior mitral leaflet was successfully lacerated in 7 live and 1 post-mortem swine under heparinization. Lacerations extended to 89 +/- 19% of leaflet length and were located within 0.5 +/- 0.4 mm of leaflet centerline. The chordae were preserved and retracted the leaflet halves away from the LVOT. LVOT narrowing after benchtop TMVR was significantly reduced with intentional laceration of the anterior mitral leaflet to prevent LVOT obstruction than without (65 +/- 10% vs. 31 +/- 18% of pre-implantation diameter, p < 0.01). The technique caused mean blood pressure to fall (from 54 +/- 6 mm Hg to 30 +/- 4 mm Hg, p < 0.01), but blood pressure remained steady until planned euthanasia. No collateral tissue injury was identified on necropsy. CONCLUSIONS Using simple catheter techniques, the anterior mitral valve leaflet was transected. Cautiously applied in patients, this strategy can prevent anterior mitral leaflet displacement and LVOT obstruction caused by TMVR. (C) 2016 by the American College of Cardiology Foundation. C1 [Khan, Jaffar M.; Rogers, Toby; Schenke, William H.; Mazal, Jonathan R.; Faranesh, Anthony Z.; Chen, Marcus Y.; Lederman, Robert J.] NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bldg 10,Room 2c713,MSC 1538, Bethesda, MD 20892 USA. [Greenbaum, Adam B.] Henry Ford Hlth Syst, Div Cardiol, Ctr Struct Heart Dis, Detroit, MI USA. [Babaliaros, Vasilis C.] Emory Univ Hosp, Struct Heart & Valve Ctr, 1364 Clifton Rd NE, Atlanta, GA 30322 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 NR 17 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 1936-8798 EI 1876-7605 J9 JACC-CARDIOVASC INTE JI JACC-Cardiovasc. Interv. PD SEP 12 PY 2016 VL 9 IS 17 BP 1835 EP 1843 DI 10.1016/j.jcin.2016.06.020 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DW0VM UT WOS:000383361100017 PM 27609260 ER PT J AU Ye, QH Zhu, WW Zhang, JB Qin, Y Lu, M Lin, GL Guo, L Zhang, B Lin, ZH Roessler, S Forgues, M Jia, HL Lu, L Zhang, XF Lian, BF Xie, L Dong, QZ Tang, ZY Wang, XW Qin, LX AF Ye, Qing-Hai Zhu, Wen-Wei Zhang, Ju-Bo Qin, Yi Lu, Ming Lin, Guo-Ling Guo, Lei Zhang, Bo Lin, Zhen-Hai Roessler, Stephanie Forgues, Marshonna Jia, Hu-Liang Lu, Lu Zhang, Xiao-Fei Lian, Bao-Feng Xie, Lu Dong, Qiong-Zhu Tang, Zhao-You Wang, Xin Wei Qin, Lun-Xiu TI GOLM1 Modulates EGFR/RTK Cell-Surface Recycling to Drive Hepatocellular Carcinoma Metastasis SO CANCER CELL LA English DT Article ID RECEPTOR TYROSINE KINASES; GOLGI-APPARATUS; CANCER; TRAFFICKING; INTEGRIN; ACTIVATION; GROWTH; FIBROBLASTS; ENDOCYTOSIS; INHIBITION AB The mechanism of cancer metastasis remains poorly understood. Using gene profiling of hepatocellular carcinoma (HCC) tissues, we have identified GOLM1 as a leading gene relating to HCC metastasis. GOLM1 expression is correlated with early recurrence, metastasis, and poor survival of HCC patients. Both gain and loss-of-function studies determine that GOLM1 acts as a key oncogene by promoting HCC growth and metastasis. It selectively interacts with epidermal growth factor receptor (EGFR) and serves as a specific cargo adaptor to assist EGFR/RTK anchoring on the trans-Golgi network (TGN) and recycling back to the plasma membrane, leading to prolonged activation of the downstream kinases. These findings reveal the functional role of GOLM1, a Golgi-related protein, in EGFR/RTK recycling and metastatic progression of HCC. C1 [Ye, Qing-Hai; Zhu, Wen-Wei; Zhang, Ju-Bo; Lin, Guo-Ling; Guo, Lei; Zhang, Bo; Lin, Zhen-Hai; Tang, Zhao-You; Qin, Lun-Xiu] Fudan Univ, Liver Canc Inst, Shanghai 200032, Peoples R China. [Zhu, Wen-Wei; Lu, Ming; Jia, Hu-Liang; Lu, Lu; Zhang, Xiao-Fei; Dong, Qiong-Zhu; Tang, Zhao-You; Qin, Lun-Xiu] Fudan Univ, Canc Metastasis Inst, Huashan Hosp, Dept Gen Surg, 12 Urumqi Rd M, Shanghai 200040, Peoples R China. [Qin, Yi; Dong, Qiong-Zhu; Qin, Lun-Xiu] Fudan Univ, Inst Biomed Sci, Shanghai 200032, Peoples R China. [Roessler, Stephanie; Forgues, Marshonna; Wang, Xin Wei] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. [Lian, Bao-Feng; Xie, Lu] Shanghai Ctr Bioinformat Technol, Shanghai 201203, Peoples R China. [Roessler, Stephanie] Univ Heidelberg Hosp, Inst Pathol, D-69120 Heidelberg, Germany. [Qin, Yi] Fudan Univ, Dept Pancreat & Hepatobiliary Surg, Shanghai Canc Ctr, Shanghai 200032, Peoples R China. [Zhang, Ju-Bo] Fudan Univ, Huashan Hosp, Dept Infect Dis, Shanghai 200040, Peoples R China. RP Qin, LX (reprint author), Fudan Univ, Liver Canc Inst, Shanghai 200032, Peoples R China.; Qin, LX (reprint author), Fudan Univ, Canc Metastasis Inst, Huashan Hosp, Dept Gen Surg, 12 Urumqi Rd M, Shanghai 200040, Peoples R China.; Qin, LX (reprint author), Fudan Univ, Inst Biomed Sci, Shanghai 200032, Peoples R China.; Wang, XW (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM xw3u@nih.gov; qinlx@fudan.edu.cn RI Wang, Xin/B-6162-2009 FU Intramural NIH HHS [ZIA BC010313-17, ZIA BC010877-08]; NCI NIH HHS [Z01 BC010313, Z01 BC010877] NR 43 TC 5 Z9 5 U1 26 U2 26 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 SEP 12 PY 2016 VL 30 IS 3 BP 444 EP 458 DI 10.1016/j.ccell.2016.07.017 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DW0ER UT WOS:000383314200010 PM 27569582 ER PT J AU Bell, AH Summerfield, C Morin, EL Malecek, NJ Ungerleider, LG AF Bell, Andrew H. Summerfield, Christopher Morin, Elyse L. Malecek, Nicholas J. Ungerleider, Leslie G. TI Encoding of Stimulus Probability in Macaque Inferior Temporal Cortex SO CURRENT BIOLOGY LA English DT Article ID MONKEY INFEROTEMPORAL CORTEX; PRIMARY VISUAL-CORTEX; REPETITION SUPPRESSION; PREDICTION ERRORS; EXPECTATION; PERCEPTION; RESPONSES; REPRESENTATIONS; TRANSITIONS; ADAPTATION AB Optimal perceptual decisions require sensory signals to be combined with prior information about stimulus probability. Although several theories propose that probabilistic information about stimulus occurrence is encoded in sensory cortex, evidence from neuronal recordings has not yet fully supported this view. We recorded activity from single neurons in inferior temporal cortex (IT) while monkeys performed a task that involved discriminating degraded images of faces and fruit. The relative probability of the cue being a face versus a fruit was manipulated by a latent variable that was not revealed to the monkeys and that changed unpredictably over the course of each recording session. In addition to responding to stimulus identity (face or fruit), population responses in IT encoded the long-term stimulus probability of whether a face or a fruit stimulus was more likely to occur. Face-responsive neurons showed reduced firing rates to expected faces, an effect consistent with "expectation suppression," but expected stimuli were decoded from multivariate population signals with greater accuracy. These findings support "predictive coding" theories, whereby neural signals in the mammalian visual system actively encode and update predictions about the local sensory environment. C1 [Bell, Andrew H.; Morin, Elyse L.; Malecek, Nicholas J.; Ungerleider, Leslie G.] NIMH, Lab Brain & Cognit, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Bell, Andrew H.; Summerfield, Christopher] Univ Oxford, Dept Expt Psychol, S Parks Rd, Oxford OX1 3UD, England. [Bell, Andrew H.] MRC Cognit & Brain Sci Unit, 15 Chaucer Rd, Cambridge CB2 7EF, England. RP Bell, AH (reprint author), NIMH, Lab Brain & Cognit, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Bell, AH (reprint author), Univ Oxford, Dept Expt Psychol, S Parks Rd, Oxford OX1 3UD, England.; Bell, AH (reprint author), MRC Cognit & Brain Sci Unit, 15 Chaucer Rd, Cambridge CB2 7EF, England. EM andrew.bell@psy.ox.ac.uk FU National Institute of Mental Health Intramural Research Program; European Research Council (ERC) [281628] FX This work was supported by the National Institute of Mental Health Intramural Research Program (to A.H.B., N.J.M., E.L.M., and L.G.U.) and by a European Research Council (ERC) Starter Grant (281628) to C.S. The authors would like to thank David Leopold and Mark Stokes for feedback on earlier drafts and Lucy Guillory and Jennifer Frihauf for their assistance with training the monkeys. NR 47 TC 2 Z9 2 U1 6 U2 6 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 SEP 12 PY 2016 VL 26 IS 17 BP 2280 EP 2290 DI 10.1016/j.cub.2016.07.007 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DW0EP UT WOS:000383314000021 PM 27524483 ER PT J AU Wang, JY Huang, YN Chiu, CC Tweedie, D Luo, WM Pick, CG Chou, SY Luo, Y Hoffer, BJ Greig, NH Wang, JY AF Wang, Jing-Ya Huang, Ya-Ni Chiu, Chong-Chi Tweedie, David Luo, Weiming Pick, Chaim G. Chou, Szu-Yi Luo, Yu Hoffer, Barry J. Greig, Nigel H. Wang, Jia-Yi TI Pomalidomide mitigates neuronal loss, neuroinflammation, and behavioral impairments induced by traumatic brain injury in rat (vol 13, pg 168, 2016) SO JOURNAL OF NEUROINFLAMMATION LA English DT Correction C1 [Wang, Jing-Ya; Huang, Ya-Ni; Wang, Jia-Yi] Taipei Med Univ, Coll Med, Grad Inst Med Sci, 250 Wu Hsing St, Taipei 110, Taiwan. [Huang, Ya-Ni] Hsin Sheng Jr Coll Med Care & Management, Dept Nursing, Taoyuan, Taiwan. [Chiu, Chong-Chi] Chi Mei Med Ctr, Dept Gen Surg, Tainan, Taiwan. [Chiu, Chong-Chi] Chi Mei Med Ctr, Dept Gen Surg, Liouying, Taiwan. [Tweedie, David; Luo, Weiming; Greig, Nigel H.] NIA, Drug Design & Dev Sect, Translat Gerontol Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Pick, Chaim G.] Tel Aviv Univ, Sackler Sch Med, Dept Anat & Anthropol, Tel Aviv, Israel. [Pick, Chaim G.] Tel Aviv Univ, Sagol Sch Neurosci, Tel Aviv, Israel. [Chou, Szu-Yi] Taipei Med Univ, Coll Med Sci & Technol, Grad Program Neuroregenerat, Taipei, Taiwan. [Luo, Yu; Hoffer, Barry J.] Case Western Reserve Univ, Sch Med, Dept Neurosurg, Cleveland, OH 44106 USA. [Wang, Jia-Yi] Taipei Med Univ, Coll Med, Dept Physiol, 250 Wu Hsing St, Taipei 110, Taiwan. RP Wang, JY (reprint author), Taipei Med Univ, Coll Med, Grad Inst Med Sci, 250 Wu Hsing St, Taipei 110, Taiwan.; Greig, NH (reprint author), NIA, Drug Design & Dev Sect, Translat Gerontol Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA.; Wang, JY (reprint author), Taipei Med Univ, Coll Med, Dept Physiol, 250 Wu Hsing St, Taipei 110, Taiwan. EM greign@mail.NIH.gov; jywang2010@tmu.edu.tw NR 1 TC 0 Z9 0 U1 4 U2 4 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 SEP 12 PY 2016 VL 13 AR 228 DI 10.1186/s12974-016-0668-6 PG 1 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA DV6GK UT WOS:000383030800001 ER PT J AU Melnikov, S Mailliot, J Shin, BS Rigger, L Yusupova, G Micura, R Dever, TE Yusupov, M AF Melnikov, Sergey Mailliot, Justine Shin, Byung-Sik Rigger, Lukas Yusupova, Gulnara Micura, Ronald Dever, Thomas E. Yusupov, Marat TI Crystal Structure of Hypusine-Containing Translation Factor eIF5A Bound to a Rotated Eukaryotic Ribosome SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article ID TRANSFER-RNA; EF-P; PROMOTES TRANSLATION; 70S RIBOSOME; ELONGATION; TRANSLOCATION; BINDING AB Eukaryotic translation initiation factor elF5A promotes protein synthesis by resolving polyproline-induced ribosomal stalling. Here, we report a 3.25-A resolution crystal structure of elF5A bound to the yeast 80S ribosome. The structure reveals a previously unseen conformation of an eIF5A ribosome complex and highlights a possible functional link between conformational changes of the ribosome during protein synthesis and the eIF5A ribosome association. (C) 2016 Published by Elsevier Ltd. C1 [Melnikov, Sergey; Mailliot, Justine; Yusupova, Gulnara; Yusupov, Marat] CNRS UMR7104, INSERM 0964, Inst Genet & Biol Mol & Cellulaire, 1 Rue Laurent Fries, F-67404 Illkirch Graffenstaden, France. [Melnikov, Sergey; Mailliot, Justine; Yusupova, Gulnara; Yusupov, Marat] Univ Strasbourg, 4 Rue Blaise Pascal, F-67081 Strasbourg, France. [Shin, Byung-Sik; Dever, Thomas E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD USA. [Rigger, Lukas; Micura, Ronald] Leopold Franzens Univ, Inst Organ Chem, Lnnrain 80-82, A-6020 Innsbruck, Austria. RP Yusupov, M (reprint author), CNRS UMR7104, INSERM 0964, Inst Genet & Biol Mol & Cellulaire, 1 Rue Laurent Fries, F-67404 Illkirch Graffenstaden, France.; Yusupov, M (reprint author), Univ Strasbourg, 4 Rue Blaise Pascal, F-67081 Strasbourg, France.; Dever, TE (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD USA.; Micura, R (reprint author), Leopold Franzens Univ, Inst Organ Chem, Lnnrain 80-82, A-6020 Innsbruck, Austria. EM ronald.micura@uibk.ac.at; tdever@nih.gov; marat@igbmc.fr RI Yusupov, Marat/I-6126-2013 OI Yusupov, Marat/0000-0001-5544-0597 FU Foundation pour la Recherche Medicale en France [SPF20111223404]; Austrian Science Fund FWF [P21641, I1040]; French National Research Agency [ANR-11-BSV8-006 01]; European Research Council [294312]; Human Frontier Science Program [RGP0062/2012]; Russian Government Program of Competitive Growth of Kazan Federal University; National Institutes of Health, NICHD FX We are grateful to the staff of PROXIMA 1 beamline at the synchrotron SOLEIL (France) and, in particular, to Andrew Thompson and Pierre Legrand for providing rapid access and assisting with data collection, Corwin Miller (Yale University) for critical reading of the manuscript, and to the members of R.M., T.D., and M.Y. teams for insightful and inspiring discussions! This work was supported by Foundation pour la Recherche Medicale en France SPF20111223404 (to S.M.), the Austrian Science Fund FWF (P21641 and I1040 to R.M.), the French National Research Agency ANR-11-BSV8-006 01 (to G.Y.), the European Research Council advanced grant 294312 and the Human Frontier Science Program grant RGP0062/2012 (both to M.Y.), the Russian Government Program of Competitive Growth of Kazan Federal University (both to M.Y. and G.Y.), and in part by the Intramural Research Program of the National Institutes of Health, NICHD (T.D.). NR 18 TC 3 Z9 3 U1 7 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 SEP 11 PY 2016 VL 428 IS 18 SI SI BP 3570 EP 3576 DI 10.1016/j.jmb.2016.05.011 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV9WU UT WOS:000383293700004 PM 27196944 ER PT J AU Holleran, JL Eiseman, JL Parise, RA Kummar, S Beumer, JH AF Holleran, Julianne L. Eiseman, Julie L. Parise, Robert A. Kummar, Shivaani Beumer, Jan H. TI LC-MS/MS assay for the quantitation of FdCyd and its metabolites FdUrd and FU in human plasma SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE FdCyd; Tandem mass spectrometry; Metabolites; Assay; Validation ID METHYLTRANSFERASE INHIBITOR 5-FLUORO-2'-DEOXYCYTIDINE; TETRAHYDROURIDINE; 5-FLUORO-2-DEOXYCYTIDINE; MICE; PHARMACOKINETICS; THU AB The hypomethylating agent 5-fluoro-2'-deoxycytidine (FdCyd, NSC 48006) is being evaluated clinically both via the intravenous route and via the oral route in combination with 3,4,5,6-tetrahydrouridine (THU), a potent inhibitor of FdCyd catabolism. To determine the pharmacokinetics of FdCyd and downstream metabolites, we developed and validated an LC-MS/MS assay for the quantitation of FdCyd, 5-fluoro-2'-deoxyuridine (FdUrd), and 5-fluorouracil (FU) in 0.2 mL human plasma. After acetonitrile protein precipitation, the sample was split and separate chromatography was achieved for FdCyd with a Synergi Polar-RP column and for FdUrd and FU with a Shodex Asahipak NH2P-50 2D column. Gradients of 0.1% acetic acid in acetonitrile and water were used. Detection with a Quattromicro quadrupole mass spectrometer with electrospray ionization in positive-ion (FdCyd) or negative-ion (FdUrd and FU) multiple reaction monitoring (MRM) mode. The assay was linear from 5 to 3000 ng/mL for all three analytes and proved to be accurate (96.7-105.5%) and precise (<8.1%CV), and fulfilled FDA criteria for bioanalytical method validation. We demonstrated the suitability of this assay for measuring FdCyd and metabolites FdUrd and FU in plasma from a patient who was administered 120 mg PO FdCyd 30 min after 3000 mg THU. Our LC-MS/MS assay will be an essential tool to further define the pharmacology of FdCyd in ongoing and future studies. (C) 2016 Elsevier B.V. All rights reserved. C1 [Holleran, Julianne L.; Eiseman, Julie L.; Parise, Robert A.; Beumer, Jan H.] Univ Pittsburgh, Inst Canc, Canc Therapeut Drug Discovery Program, Pittsburgh, PA USA. [Eiseman, Julie L.] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA USA. [Parise, Robert A.; Beumer, Jan H.] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. [Kummar, Shivaani] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Beumer, Jan H.] Univ Pittsburgh, Sch Med, Dept Med, Div Hematol Oncol, Pittsburgh, PA 15213 USA. RP Beumer, JH (reprint author), Univ Pittsburgh, Inst Canc, Room G27E,Hillman Res Pavill,5117 Ctr Ave, Pittsburgh, PA 15213 USA. EM beumerj@gmail.com OI Beumer, Jan/0000-0002-8978-9401 FU NCI [HHSN261201100015C]; NCl/CTEP (University of Pittsburgh) [UM1-CA186690]; [P30-CA47904] FX This project was supported by NCI contract HHSN261201100015C, NCl/CTEP grant UM1-CA186690 (University of Pittsburgh), and used the UPCI Cancer Pharmacokinetics and Pharmacodynamics Facility (CPPF) and was supported in part by award P30-CA47904. NR 12 TC 1 Z9 1 U1 1 U2 1 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 SEP 10 PY 2016 VL 129 BP 359 EP 366 DI 10.1016/j.jpba.2016.07.027 PG 8 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA EK3SL UT WOS:000393847600045 PM 27454087 ER PT J AU Maaske, A Devos, FC Niezold, T Lapuente, D Tannapfel, A Vanoirbeek, JA Uuml;berla, K Peters, M Tenbusch, M AF Maaske, A. Devos, F. C. Niezold, T. Lapuente, D. Tannapfel, A. Vanoirbeek, J. A. Ueberla, K. Peters, M. Tenbusch, M. TI Mucosal expression of DEC-205 targeted allergen alleviates an asthmatic phenotype in mice SO JOURNAL OF CONTROLLED RELEASE LA English DT Article DE Allergic asthma; DC-targeting; DEC-205; Adenoviral vectors; Immunotherapy; Mucosa ID INDUCED AIRWAY HYPERREACTIVITY; DENDRITIC CELLS; IN-VIVO; RECOMBINANT ADENOVIRUSES; TOLERANCE INDUCTION; IMMUNE REGULATION; TH2 CELLS; INFLAMMATION; IMMUNOTHERAPY; PROTEIN AB Considering the rising incidence of allergic asthma, the symptomatic treatments that are currently applied in most cases are less than ideal. Specific immunotherapy is currently the only treatment that is able to change the course of the disease, but suffers from a long treatment duration. A gene based immunization that elicits the targeting of allergens towards dendritic cells in a steady-state environment might have the potential to amend these difficulties. Here we used a replication deficient adenovirus to induce the mucosal expression of OVA coupled to a single-chain antibody against DEC-205. A single intranasal vaccination was sufficient to mitigate an OVA-dependent asthmatic phenotype in a murine model. Invasive airway measurements demonstrated improved lung function after Ad-Dec-OVA treatment, which was in line with a marked reduction of goblet cell hyperplasia and lung eosinophilia. Furthermore OVA-specific IgE titers and production of type 2 cytokines were significantly reduced. Together, the here presented data demonstrate the feasibility of mucosal expression of DEC-targeted allergens as a treatment of allergic asthma. (C) 2016 The Authors. Published by Elsevier B.V. C1 [Maaske, A.; Niezold, T.; Lapuente, D.; Ueberla, K.; Tenbusch, M.] Ruhr Univ Bochum, Dept Mol & Med Virol, Univ Str 150, D-44801 Bochum, Germany. [Devos, F. C.; Vanoirbeek, J. A.] Katholieke Univ Leuven, Ctr Environm & Hlth, Dept Publ Hlth & Primary Care, Leuven, Belgium. [Tannapfel, A.] Ruhr Univ Bochum, Inst Pathol, Bochum, Germany. [Peters, M.] Ruhr Univ Bochum, Dept Expt Pneumol, Bochum, Germany. [Niezold, T.] NIAID, Biodefense Res Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20814 USA. [Ueberla, K.] Univ Erlangen Nurnberg, Univ Klinikum Erlangen, Inst Clin & Mol Virol, Erlangen, Germany. RP Tenbusch, M (reprint author), Ruhr Univ Bochum, Dept Mol & Med Virol, Univ Str 150, D-44801 Bochum, Germany. EM Matthias.Tenbusch@rub.de OI Peters, Marcus/0000-0003-1850-2845 FU Mercator Research Centre Ruhr [St-2010-0004]; German Research Foundation [RTG1949/1]; Ruhr University Bochum [FoRUM F787R-2013] FX This work was supported by grants from the Mercator Research Centre Ruhr (St-2010-0004), German Research Foundation (RTG1949/1) and intramural research funding from Ruhr University Bochum (FoRUM F787R-2013). We thank Gertrud Muller and Sandra Busse for technical assistance and Rebecca Hess and Viktoria Stab for proofreading. Furthermore we are thankful to PARI for kindly providing the Turbo Boy SX. NR 52 TC 0 Z9 0 U1 7 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 EI 1873-4995 J9 J CONTROL RELEASE JI J. Control. Release PD SEP 10 PY 2016 VL 237 BP 14 EP 22 DI 10.1016/j.jconrel.2016.06.043 PG 9 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA DT3GF UT WOS:000381368300002 PM 27374625 ER PT J AU Cho, HJ Lee, SJ Park, SJ Paik, CH Lee, SM Kim, S Lee, YS AF Cho, Hong-Jun Lee, Sung-Jin Park, Sung-Jun Paik, Chang H. Lee, Sang-Myung Kim, Sehoon Lee, Yoon-Sik TI Activatable iRGD-based peptide monolith: Targeting, internalization, and fluorescence activation for precise tumor imaging SO JOURNAL OF CONTROLLED RELEASE LA English DT Article DE Internalizing RGD (iRGD); Activatable probe; Peptide monolith; Tumor imaging ID DRUG-DELIVERY; CANCER-CELLS; IN-VIVO; THERAPY; PROBES; NEUROPILIN-1; NANOPARTICLES; THERAPEUTICS; VASCULATURE; PENETRATION AB A disulfide-bridged cyclic RGD peptide, named iRGD (internalizing RGD, c(CRGDK/RGPD/EC)), is known to facilitate tumor targeting as well as tissue penetration. After the RGD motif-induced targeting on alpha v integrins expressed near tumor tissue, iRGD encounters proteolytic cleavage to expose the CendR motif that promotes penetration into cancer cells via the interaction with neuropilin-1. Based on these proteolytic cleavage and internalization mechanism, we designed an iRGD-based monolithic imaging probe that integrates multiple functions (cancer-specific targeting, internalization and fluorescence activation) within a small peptide framework. To provide the capability of activatable fluorescence signaling, we conjugated a fluorescent dye to the N-terminal of iRGD, which was linked to the internalizing sequence (CendR motif), and a quencher to the opposite C-terminal. It turned out that fluorescence activation of the dye/quencher-conjugated monolithic peptide probe requires dual (reductive and proteolytic) cleavages on both disulfide and amide bond of iRGD peptide. Furthermore, the cleavage of the iRGD peptide leading to fluorescence recovery was indeed operative depending on the tumor-related angiogenic receptors (alpha v beta 3 integrin and neuropilin-1) in vitro as well as in vivo. Compared to an 'always fluorescent' iRGD control probe without quencher conjugation, the dye/quencher-conjugated activatable monolithic peptide probe visualized tumor regions more precisely with lower background noise after intravenous injection, owing to the multifunctional responses specific to tumor microenvironment. All these results, along with minimal in vitro and in vivo toxicity profiles, suggest potential of the iRGD-based activatable monolithic peptide probe as a promising imaging agent for precise tumor diagnosis. (C) 2016 Elsevier B.V. All rights reserved. C1 [Cho, Hong-Jun; Park, Sung-Jun; Kim, Sehoon] Korea Inst Sci & Technol, Ctr Theragnosis, 39-1 Hawolgok Dong, Seoul 136791, South Korea. [Lee, Sung-Jin; Paik, Chang H.] NIH, Radiopharmaceut Lab, Div Nucl Med, Radiol & Imaging Sci,Clin Ctr, Bethesda, MD 20892 USA. [Park, Sung-Jun; Lee, Yoon-Sik] Seoul Natl Univ, Sch Chem & Biol Engn, Seoul 151744, South Korea. [Lee, Sang-Myung] Kangwon Natl Univ, Dept Chem Engn, Kangwon Do 200701, South Korea. RP Kim, S (reprint author), Korea Inst Sci & Technol, Ctr Theragnosis, 39-1 Hawolgok Dong, Seoul 136791, South Korea.; Lee, YS (reprint author), Seoul Natl Univ, Sch Chem & Biol Engn, Seoul 151744, South Korea.; Lee, SM (reprint author), Kangwon Natl Univ, Dept Chem Engn, Kangwon Do 200701, South Korea. EM sangmyung@kangwon.ac.kr; sehoonkim@kist.re.kr; yslee@snu.ac.kr FU National Research Foundation of Korea [2012K1A1A2A01055811, NRF-2014R1A1A1006711]; Korea Health Industry Development Institute [HI15C1540]; Development of Platform Technology for Innovative Medical Measurements Program from the Korea Research Institute of Standards and Science [GP2016-0022]; Basic Science Research Program - Ministry of Science, ICT & Future Planning; National Research Foundation of Korea (NRF) grant - Ministry of Science, ICT and Future Planning [NRF-2015M2B2A6028602]; Intramural Research Program of KIST FX This work was supported by grants from the National Research Foundation of Korea (2012K1A1A2A01055811), the Korea Health Industry Development Institute (HI15C1540), the Development of Platform Technology for Innovative Medical Measurements Program (GP2016-0022) from the Korea Research Institute of Standards and Science, the Intramural Research Program of KIST, Basic Science Research Program funded by the Ministry of Science, ICT & Future Planning and National Research Foundation of Korea (NRF-2014R1A1A1006711), and the National Research Foundation of Korea (NRF) grant funded by the Ministry of Science, ICT and Future Planning (NRF-2015M2B2A6028602). NR 46 TC 0 Z9 0 U1 33 U2 38 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 EI 1873-4995 J9 J CONTROL RELEASE JI J. Control. Release PD SEP 10 PY 2016 VL 237 BP 177 EP 184 DI 10.1016/j.jconrel.2016.06.032 PG 8 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA DT3GF UT WOS:000381368300018 PM 27349354 ER PT J AU Chen, HY Kaya, KD Dong, LJ Swaroop, A AF Chen, Holly Yu Kaya, Koray Dogan Dong, Lijin Swaroop, Anand TI Three-dimensional retinal organoids from mouse pluripotent stem cells mimic in vivo development with enhanced stratification and rod photoreceptor differentiation SO MOLECULAR VISION LA English DT Article ID GENE-THERAPY; PRECURSORS; CULTURE; TRANSPLANTATION; GENERATION; RETINOGENESIS; EXPRESSION; MICE; NRL; MORPHOGENESIS AB Purpose: The generation of three-dimensional (3D) organoids with optic cup-like structures from pluripotent stem cells has created opportunities for investigating mammalian retinal development in vitro. However, retinal organoids in culture do not completely reflect the developmental state and in vivo architecture of the rod-dominant mouse retina. The goals of this study were to develop an efficient protocol for generating retinal organoids from stem cells and examine the morphogenesis of rods in vitro. Methods: To assess rod photoreceptor differentiation in retinal organoids, we took advantage of Nrl-green fluorescent protein (GFP) mice that show rod-specific expression of GFP directed by the promoter of leucine zipper transcription factor NRL. Using embryonic and induced pluripotent stem cells (ESCs and iPSCs, respectively) derived from the Nrl-GFP mouse, we were successful in establishing long-term retinal organoid cultures using modified culture conditions (called High Efficiency Hypoxia Induced Generation of Photoreceptors in Retinal Organoids, or HIPRO). Results: We demonstrated efficient differentiation of pluripotent stem cells to retinal structures. More than 70% of embryoid bodies formed optic vesicles at day (D) 7, >50% produced optic cups by D10, and most of them survived until at least D35. The HIPRO organoids included distinct inner retina neurons in a somewhat stratified architecture and mature Muller glia spanning t entire retina. Almost 70% of the cells in the retinal organoids were rod photoreceptors that exhibited elongated cilia. Transcriptome profiles of GFP+ rod photoreceptors, purified from organoids at D25-35, demonstrated a high correlation with the gene profiles of purified rods from the mouse retina at P2 to P6, indicating their early state of differentiation. Conclusions: The 3D retinal organoids, generated by HIPRO method, closely mimic in vivo retinogenesis and provide an efficient in vitro model to investigate photoreceptor development and modeling disease pathology. C1 [Chen, Holly Yu; Kaya, Koray Dogan; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Dong, Lijin] NEI, Genet Engn Core, NIH, Bethesda, MD 20892 USA. RP Swaroop, A (reprint author), NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. EM swaroopa@nei.nih.gov FU intramural research program of the National Eye Institute [ZIAEY000450, ZIAEY000474] FX We are grateful to Pinghu Liu, Samantha Papal, Jung-woong Kim, Hiroko Shimada-Ishii, Jacklyn Mahgerefteh, Tyler DiStefano and Jacob Nellissery for insightful discussions and constructive comments. We thank Linn Gieser and Matthew Brooks for assistance with RNA-seq, and Julie Laux, Jessica Albrecht, and Rafael Villasmil for help with flow cytometry. This work was supported by intramural research program of the National Eye Institute (ZIAEY000450, ZIAEY000474). NR 65 TC 0 Z9 0 U1 6 U2 6 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 SEP 9 PY 2016 VL 22 BP 1077 EP 1094 PG 18 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA DX7NP UT WOS:000384575000001 PM 27667917 ER PT J AU Davison, M Treangen, TJ Koren, S Pop, M Bhaya, D AF Davison, Michelle Treangen, Todd J. Koren, Sergey Pop, Mihai Bhaya, Devaki TI Diversity in a Polymicrobial Community Revealed by Analysis of Viromes, Endolysins and CRISPR Spacers SO PLOS ONE LA English DT Article ID MULTIPLE SEQUENCE ALIGNMENT; SPRING MICROBIAL MATS; HIGH-THROUGHPUT; THERMOPHILIC CYANOBACTERIA; BACTERIOPHAGE ENDOLYSINS; PHYLOGENETIC ANALYSIS; COMPARATIVE GENOMICS; VIRAL DIVERSITY; METAGENOMES; POPULATION AB The polymicrobial biofilm communities in Mushroom and Octopus Spring in Yellowstone National Park (YNP) are well characterized, yet little is known about the phage populations. Dominant species, Synechococcus sp. JA-2-3B'a(2-13), Synechococcus sp. JA-3-3Ab, Chloroflexus sp. Y-400-fl, and Roseiflexus sp. RS-1, contain multiple CRISPR-Cas arrays, suggesting complex interactions with phage predators. To analyze phage populations from Octopus Spring biofilms, we sequenced a viral enriched fraction. To assemble and analyze phage metagenomic data, we developed a custom module, VIRITAS, implemented within the MetAMOS framework. This module bins contigs into groups based on tetranucleotide frequencies and CRISPR spacer-protospacer matching and ORF calling. Using this pipeline we were able to assemble phage sequences into contigs and bin them into three clusters that corroborated with their potential host range. The virome contained 52,348 predicted ORFs; some were clearly phage-like; 9319 ORFs had a recognizable Pfam domain while the rest were hypothetical. Of the recognized domains with CRISPR spacer matches, was the phage endolysin used by lytic phage to disrupt cells. Analysis of the endolysins present in the thermophilic cyanophage contigs revealed a subset of characterized endolysins as well as a Glyco_hydro_108 (PF05838) domain not previously associated with sequenced cyanophages. A search for CRISPR spacer matches to all identified phage endolysins demonstrated that a majority of endolysin domains were targets. This strategy provides a general way to link host and phage as endolysins are known to be widely distributed in bacteriophage. Endolysins can also provide information about host cell wall composition and have the additional potential to be used as targets for novel therapeutics. C1 [Davison, Michelle; Bhaya, Devaki] Carnegie Inst Sci, Dept Plant Biol, 290 Panama St, Stanford, CA 94305 USA. [Treangen, Todd J.; Koren, Sergey; Pop, Mihai] Ctr Bioinformat & Computat Biol, Biomol Sci Bldg, College Pk, MD 20742 USA. [Davison, Michelle; Bhaya, Devaki] Stanford Univ, Dept Biol, Stanford, CA 94305 USA. [Pop, Mihai] Univ Maryland, Dept Comp Sci, College Pk, MD 20742 USA. [Treangen, Todd J.] Natl Biodef Anal & Countermeasures Ctr, Ft Detrick, MD 21702 USA. [Koren, Sergey] NHGRI, Genome Informat Sect, Computat & Stat Genom Branch, NIH, Bethesda, MD 20892 USA. RP Davison, M; Bhaya, D (reprint author), Carnegie Inst Sci, Dept Plant Biol, 290 Panama St, Stanford, CA 94305 USA.; Davison, M; Bhaya, D (reprint author), Stanford Univ, Dept Biol, Stanford, CA 94305 USA. EM mdavison@carnegiescience.edu; dbhaya@carnegiescience.edu FU National Institutes of Health [R01HG004885]; National Science Foundation [IIS-0812111]; National Science Foundation Division of Molecular and Cellular Biosciences [1024755, 1331151]; Carnegie Institution for Science; Stanford Department of Biology FX Mihai Pop would like to acknowledge funding from National Institutes of Health grant # R01HG004885 and National Science Foundation grant # IIS-0812111. Devaki Bhaya would like to acknowledge funding from National Science Foundation Division of Molecular and Cellular Biosciences # 1024755 and National Science Foundation Division of Molecular and Cellular Biosciences # 1331151 and the Carnegie Institution for Science. Michelle Davison would like to acknowledge funding from the Stanford Department of Biology, as a portion of this work was done during her PhD. NR 96 TC 1 Z9 1 U1 11 U2 11 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 SEP 9 PY 2016 VL 11 IS 9 AR e0160574 DI 10.1371/journal.pone.0160574 PG 23 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV9JE UT WOS:000383255900008 PM 27611571 ER PT J AU Gu, FY Xiao, Q Chu, LW Yu, K Matthews, CE Hsing, AW Caporaso, NE AF Gu, Fangyi Xiao, Qian Chu, Lisa W. Yu, Kai Matthews, Charles E. Hsing, Ann W. Caporaso, Neil E. TI Sleep Duration and Cancer in the NIH-AARP Diet and Health Study Cohort SO PLOS ONE LA English DT Article ID HELICOBACTER-PYLORI INFECTION; RETIRED-PERSONS DIET; BREAST-CANCER; AMERICAN-ASSOCIATION; POSTMENOPAUSAL WOMEN; NATIONAL-INSTITUTES; OHSAKI COHORT; RISK; METAANALYSIS; DEPRESSION AB Background Very few studies have examined sleep duration in relation to cancer incidence with the exception of breast cancer. Methods We assessed the associations between sleep duration and incidences of total and 18 site-specific cancers in the NIH-AARP Health and Diet Study cohort, with 173,327 men and 123,858 women aged 51-72 years at baseline. Self-reportedsleep duration categories were assessed via questionnaire. We used multivariable Cox proportional hazards regression to estimate hazard ratios (HR) and 95% confidence intervals (CI), using 7-8 hours/night as the reference. Results We observed a significantly increased risk of stomach cancer among male short sleepers (multivariable HR5-6 vs. 7-8 hours = 1.29; 95% CI: 1.05, 1.59; P-trend = 0.03). We also observed suggestive associations in either short or long sleepers, which did not reach overall significance (P-trend > 0.05), including increased risks in male short sleepers for cancers of head and neck (HR<5vs. 7-8 hours = 1.39; 95% CI: 1.00-1.95), bladder (HR5-6vs. 7-8 hours = 1.10; 95% CI: 1.00-1.20), thyroid (HR<5 vs. 7-8 hours = 2.30; 95% CI: 1.06, 5.02), Non-Hodgkin Lymphoma (NHL) (HR5-6vs. 7-8 hours = 1.17; 95% CI: 1.02-1.33), and myeloma (HR<5vs. 7-8 hours = 2.06; 95% CI: 1.20-3.51). In women, the suggestive associations include a decreased total cancer risk (HR<5vs. 7-8 hours = 0.9; 95% CI: 0.83-0.99) and breast cancer risk (HR<5vs. 7-8 hours = 0.84; 95% CI: 0.71-0.98) among short sleepers. A decreased ovarian cancer risk (HR >= 9 vs. 7-8 hours = 0.50; 95% CI: 0.26-0.97) and an increased NHL risk (HR >= 9 vs. 7-8 hours = 1.45; 95% CI: 1.00-2.11) were observed among long sleepers. Conclusion In an older population, we observed an increased stomach cancer risk in male short sleepers and suggestive associations with short or long sleep duration for many cancer risks in both genders. C1 [Gu, Fangyi; Xiao, Qian; Yu, Kai; Matthews, Charles E.; Caporaso, Neil E.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Chu, Lisa W.; Hsing, Ann W.] Canc Prevent Inst Calif, Fremont, CA USA. [Chu, Lisa W.; Hsing, Ann W.] Stanford Canc Inst, Palo Alto, CA USA. [Hsing, Ann W.] Stanford Univ, Dept Hlth Res & Policy, Sch Med, Stanford, CA 94305 USA. RP Gu, FY (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM Guf@mail.nih.gov FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute FX Authors are supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute. The sponsor had no role in the design and conduct of the study; the collection, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript. NR 38 TC 0 Z9 0 U1 2 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 SEP 9 PY 2016 VL 11 IS 9 AR e0161561 DI 10.1371/journal.pone.0161561 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV9JE UT WOS:000383255900020 PM 27611440 ER PT J AU Kim, DK Beaven, MA Kulinski, JM Desai, A Bandara, G Bai, Y Prussin, C Schwartz, LB Komarow, H Metcalfe, DD Olivera, A AF Kim, Do-Kyun Beaven, Michael A. Kulinski, Joseph M. Desai, Avanti Bandara, Geethani Bai, Yun Prussin, Calman Schwartz, Lawrence B. Komarow, Hirsh Metcalfe, Dean D. Olivera, Ana TI Regulation of Reactive Oxygen Species and the Antioxidant Protein DJ-1 in Mastocytosis SO PLOS ONE LA English DT Article ID FC-EPSILON-RI; MAST-CELL DISORDERS; PARKINSONS-DISEASE; SYSTEMIC MASTOCYTOSIS; DIAGNOSTIC-CRITERIA; OXIDATIVE DAMAGE; CANCER-CELLS; ROS; ACTIVATION; MUTATION AB Neoplastic accumulation of mast cells in systemic mastocytosis (SM) associates with activating mutations in the receptor tyrosine kinase KIT. Constitutive activation of tyrosine kinase oncogenes has been linked to imbalances in oxidant/antioxidant mechanisms in other myeloproliferative disorders. However, the impact of KIT mutations on the redox status in SM and the potential therapeutic implications are not well understood. Here, we examined the regulation of reactive oxygen species (ROS) and of the antioxidant protein DJ-1 (PARK-7), which increases with cancer progression and acts to lessen oxidative damage to malignant cells, in relationship with SM severity. ROS levels were increased in both indolent (ISM) and aggressive variants of the disease (ASM). However, while DJ-1 levels were reduced in ISM with lower mast cell burden, they rose in ISM with higher mast cell burden and were significantly elevated in patients with ASM. Studies on mast cell lines revealed that activating KIT mutations induced constant ROS production and consequent DJ-1 oxidation and degradation that could explain the reduced levels of DJ-1 in the ISM population, while IL-6, a cytokine that increases with disease severity, caused a counteracting transcriptional induction of DJ-1 which would protect malignant mast cells from oxidative damage. A mouse model of mastocytosis recapitulated the biphasic changes in DJ-1 and the escalating IL-6, ROS and DJ-1 levels as mast cells accumulate, findings which were reversed with anti-IL-6 receptor blocking antibody. Our findings provide evidence of increased ROS and a biphasic regulation of the antioxidant DJ-1 in variants of SM and implicate IL-6 in DJ-1 induction and expansion of mast cells with KIT mutations. We propose consideration of IL-6 blockade as a potential adjunctive therapy in the treatment of patients with advanced mastocytosis, as it would reduce DJ-1 levels making mutation-positive mast cells vulnerable to oxidative damage. C1 [Kim, Do-Kyun; Kulinski, Joseph M.; Desai, Avanti; Bandara, Geethani; Bai, Yun; Prussin, Calman; Komarow, Hirsh; Metcalfe, Dean D.; Olivera, Ana] NIAID, Mast Cell Biol Sect, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Beaven, Michael A.] NHLBI, Lab Mol Immunol, Bldg 10, Bethesda, MD 20892 USA. [Schwartz, Lawrence B.] Virginia Commonwealth Univ, Dept Internal Med, Richmond, VA USA. RP Olivera, A (reprint author), NIAID, Mast Cell Biol Sect, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ana.olivera@nih.gov FU Division of Intramural Research Programs within NIAID, NIH [AI001206]; Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) - Ministry of Health & Welfare, Republic of Korea [HI14C1175] FX This work was supported by the Division of Intramural Research Programs within NIAID, NIH (AI001206). Dr. Do-Kyun Kim was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI14C1175). NR 63 TC 0 Z9 0 U1 2 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 SEP 9 PY 2016 VL 11 IS 9 AR e0162831 DI 10.1371/journal.pone.0162831 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV9JE UT WOS:000383255900175 PM 27611333 ER PT J AU Thompson, SM Callstrom, MR Jondal, DE Butters, KA Knudsen, BE Anderson, JL Lien, KR Sutor, SL Lee, JS Thorgeirsson, SS Grande, JP Roberts, LR Woodrum, DA AF Thompson, Scott M. Callstrom, Matthew R. Jondal, Danielle E. Butters, Kim A. Knudsen, Bruce E. Anderson, Jill L. Lien, Karen R. Sutor, Shari L. Lee, Ju-Seog Thorgeirsson, Snorri S. Grande, Joseph P. Roberts, Lewis R. Woodrum, David A. TI Heat Stress-Induced PI3K/mTORC2-Dependent AKT Signaling Is a Central Mediator of Hepatocellular Carcinoma Survival to Thermal Ablation Induced Heat Stress SO PLOS ONE LA English DT Article ID PERCUTANEOUS RADIOFREQUENCY ABLATION; PROTEIN-KINASE-B; IN-VIVO; CANCER-CELLS; DISEASE RECURRENCE; ANTITUMOR-ACTIVITY; RAPID PROGRESSION; TUMOR PROGRESSION; POOR-PROGNOSIS; RISK-FACTORS AB Thermal ablative therapies are important treatment options in the multidisciplinary care of patients with hepatocellular carcinoma (HCC), but lesions larger than 2-3 cm are plagued with high local recurrence rates and overall survival of these patients remains poor. Currently no adjuvant therapies exist to prevent local HCC recurrence in patients undergoing thermal ablation. The molecular mechanisms mediating HCC resistance to thermal ablation induced heat stress and local recurrence remain unclear. Here we demonstrate that the HCC cells with a poor prognostic hepatic stem cell subtype (Subtype HS) are more resistant to heat stress than HCC cells with a better prognostic hepatocyte subtype (Subtype HC). Moreover, sublethal heat stress rapidly induces phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dependent-protein kinase B (AKT) survival signaling in HCC cells in vitro and at the tumor ablation margin in vivo. Conversely, inhibition of PI3K/mTOR complex 2 (mTORC2)-dependent AKT phosphorylation or direct inhibition of AKT function both enhance HCC cell killing and decrease HCC cell survival to sublethal heat stress in both poor and better prognostic HCC subtypes while mTOR complex 1 (mTORC1)-inhibition has no impact. Finally, we showed that AKT isoforms 1, 2 and 3 are differentially upregulated in primaryhuman HCCs and that overexpression of AKT correlates with worse tumor biology and pathologic features (AKT3) and prognosis (AKT1). Together these findings define a novel molecular mechanism whereby heat stress induces PI3K/mTORC2-dependent AKT survival signaling in HCC cells and provide a mechanistic rationale for adjuvant AKT inhibition in combination with thermal ablation as a strategy to enhance HCC cell killing and prevent local recurrence, particularly at the ablation margin. C1 [Thompson, Scott M.; Callstrom, Matthew R.; Jondal, Danielle E.; Butters, Kim A.; Anderson, Jill L.; Woodrum, David A.] Mayo Clin, Coll Med, Dept Radiol, Rochester, MN 55902 USA. [Knudsen, Bruce E.; Lien, Karen R.; Grande, Joseph P.] Mayo Clin, Coll Med, Dept Lab Med & Pathol, Rochester, MN USA. [Sutor, Shari L.] Mayo Clin, Coll Med, Genom Res Ctr, Rochester, MN USA. [Lee, Ju-Seog] Univ Texas MD Anderson Canc Ctr, Div Canc Med, Houston, TX 77030 USA. [Thorgeirsson, Snorri S.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Roberts, Lewis R.] Mayo Clin, Coll Med, Div Gastroenterol & Hepatol, Rochester, MN USA. RP Thompson, SM; Woodrum, DA (reprint author), Mayo Clin, Coll Med, Dept Radiol, Rochester, MN 55902 USA. EM thompson.scott@mayo.edu; woodrum.david@mayo.edu FU National Institutes of Health (NIH) [NIH C06 RR018898]; Society of Interventional Radiology (SIR) Foundation Allied Scientist Training Grant; Mayo Clinic Center for Clinical and Translational Science (CCaTS) through National Center for Research Resources (NCRR), a component of the NIH [UL1 RR024150]; NIH from the National Cancer Institute (NCI) [R01 CA177686]; Mayo Clinic Center for Clinical and Translational Science (CCaTS) MD/PhD in Clinical and Translational Science [TL1 RR024152, TL1 TR000137] FX Infrastructure support provided by National Institutes of Health (NIH; https://www.nih.gov/) construction grant NIH C06 RR018898. Research support provided in part by the Society of Interventional Radiology (SIR) Foundation (http://www.sirfoundation.org/) Allied Scientist Training Grant (SMT), Mayo Clinic Center for Clinical and Translational Science (CCaTS; http://www.mayo.edu/ctsa) through grant number UL1 RR024150 from the National Center for Research Resources (NCRR), a component of the NIH (LRR, DAW) and NIH grant number R01 CA177686 from the National Cancer Institute (NCI) (DAW). The funding sources did not play any role in the study design, data collection or analysis, decision to publish or preparation of the manuscript. Dr. Thompson's MD, PhD training was supported by Mayo Clinic Center for Clinical and Translational Science (CCaTS) MD/PhD in Clinical and Translational Science TL1 RR024152 and TL1 TR000137. The contents herein are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. NR 75 TC 0 Z9 0 U1 2 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 SEP 9 PY 2016 VL 11 IS 9 AR e0162634 DI 10.1371/journal.pone.0162634 PG 29 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV9JE UT WOS:000383255900140 PM 27611696 ER PT J AU Sayedyahossein, S Li, ZG Hedman, AC Morgan, CJ Sacks, DB AF Sayedyahossein, Samar Li, Zhigang Hedman, Andrew C. Morgan, Chase J. Sacks, David B. TI IQGAP1 Binds to Yes-associated Protein (YAP) and Modulates Its Transcriptional Activity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE cell signaling; Hippo pathway; protein complex; transcription factor; yes-associated protein (YAP); IQGAP1 ID HIPPO PATHWAY; HEPATOCELLULAR-CARCINOMA; NEURITE OUTGROWTH; GROWTH-CONTROL; BETA-CATENIN; IQ MOTIFS; TAZ; CALMODULIN; COMPLEX; CANCER AB During development, the Hippo signaling pathway regulates key physiological processes, such as control of organ size, regeneration, and stem cell biology. Yes-associated protein (YAP) is a major transcriptional co-activator of the Hippo pathway. The scaffold protein IQGAP1 interacts with more than 100 binding partners to integrate diverse signaling pathways. In this study, we report that IQGAP1 binds to YAP and modulates its activity. IQGAP1 and YAP co-immunoprecipitated from cells. In vitro analysis with pure proteins demonstrated a direct interaction between IQGAP1 and YAP. Analysis with multiple fragments of each protein showed that the interaction occurs via the IQ domain of IQGAP1 and the TEAD-binding domain of YAP. The interaction between IQGAP1 and YAP has functional effects. Knock-out of endogenous IQGAP1 significantly increased the formation of nuclear YAP-TEAD complexes. Transcription assays were performed with IQGAP1-null mouse embryonic fibroblasts and HEK293 cells with IQGAP1 knockdown by CRISPR/Cas9. Quantification demonstrated that YAP-TEAD-mediated transcription in cells lacking IQGAP1 was significantly greater than in control cells. These data reveal that IQGAP1 binds to YAP and modulates its co-transcriptional function, suggesting that IQGAP1 participates in Hippo signaling. C1 [Sayedyahossein, Samar; Li, Zhigang; Hedman, Andrew C.; Morgan, Chase J.; Sacks, David B.] NIH, Dept Lab Med, 10 Ctr Dr,10-2C306, Bethesda, MD 20892 USA. RP Sacks, DB (reprint author), NIH, Dept Lab Med, 10 Ctr Dr,10-2C306, Bethesda, MD 20892 USA. EM david.sacks2@nih.gov OI Sacks, David/0000-0003-3100-0735 FU National Institutes of Health Intramural Research Program FX This work was supported by the National Institutes of Health Intramural Research Program. 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 47 TC 0 Z9 0 U1 7 U2 7 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 SEP 9 PY 2016 VL 291 IS 37 BP 19261 EP 19273 DI 10.1074/jbc.M116.732529 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV9EL UT WOS:000383242800008 PM 27440047 ER PT J AU Cruz-Topete, D He, B Xu, XJ Cidlowski, JA AF Cruz-Topete, Diana He, Bo Xu, Xiaojiang Cidlowski, John A. TI Kruppel-like Factor 13 Is a Major Mediator of Glucocorticoid Receptor Signaling in Cardiomyocytes and Protects These Cells from DNA Damage and Death SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE cardiomyocyte; gene regulation; glucocorticoid receptor; hypoxia; Kruppel-like factor (KLF) ID GENE-EXPRESSION; HEART-FAILURE; RAT-HEART; OXIDATIVE STRESS; APOPTOSIS; MECHANISMS; DOXORUBICIN; REGULATOR; DISEASE; HEALTH AB Glucocorticoid receptor (GR) signaling has recently been shown to play a direct role in the regulation of cardiomyocyte function. In this study, we investigated the potential role of KLF13 as a downstream effector of GR action utilizing both in vivo and in vitro approaches. Our data show that KLF13 mRNA and protein levels are significantly diminished in the hearts of mice lacking GR in cardiomyocytes. Glucocorticoid administration up-regulated Klf13 mRNA in the mouse heart, in isolated primary cardiomyocytes, and in immortal cardiomyocyte cell lines. Glucocorticoid Klf13 gene expression was abolished by treatment with a GR antagonist (RU486) or by knockdown of GR in cardiomyocytes. Moreover, glucocorticoid induction of Klf13 mRNA was resistant to de novo protein synthesis inhibition, demonstrating that Klf13 is a direct glucocorticoid receptor gene target. A glucocorticoid responsive element (GRE) was identified in the Klf13 gene and its function was verified by chromatin immunoprecipitation in HL-1 cells and mouse hearts. Functional studies showed that GR regulation of Klf13 is critical to protect cardiomyocytes from DNA damage and cell death induced by cobalt(II) chloride hexahydrate (CoCl(2)6H(2)O) and the antineoplastic drug doxorubicin. These results established a novel role for GR and KLF13 signaling in adult cardiomyocytes with potential clinical implications for the prevention of cardiotoxicity induced heart failure. C1 [Cruz-Topete, Diana; Cidlowski, John A.] NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. [He, Bo; Xu, Xiaojiang] NIEHS, Integrat Bioinformat, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, NIH, MD F3-07,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM cidlows1@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health, NIEHS FX This work was supported by the Intramural Research Program of the National Institutes of Health, NIEHS. 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 52 TC 0 Z9 0 U1 3 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 SEP 9 PY 2016 VL 291 IS 37 BP 19374 EP 19386 DI 10.1074/jbc.M116.725903 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV9EL UT WOS:000383242800017 PM 27451392 ER PT J AU Yariswamy, M Yoshida, T Valente, AJ Kandikattu, HK Sakamuri, SSVP Siddesha, JM Sukhanov, S Saifudeen, Z Ma, LX Siebenlist, U Gardner, JD Chandrasekar, B AF Yariswamy, Manjunath Yoshida, Tadashi Valente, Anthony J. Kandikattu, Hemanth Kumar Sakamuri, Siva S. V. P. Siddesha, Jalahalli M. Sukhanov, Sergiy Saifudeen, Zubaida Ma, Lixin Siebenlist, Ulrich Gardner, Jason D. Chandrasekar, Bysani TI Cardiac-restricted Overexpression of TRAF3 Interacting Protein 2 (TRAF3IP2) Results in Spontaneous Development of Myocardial Hypertrophy, Fibrosis, and Dysfunction SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE adaptor protein; cardiac hypertrophy; extracellular matrix; fibrosis; heart failure ID NF-KAPPA-B; HEART-FAILURE; DIASTOLIC DYSFUNCTION; SIGNALING PATHWAY; ACT1; INFLAMMATION; ACTIVATION; KINASE; CARDIOMYOPATHY; CONTRIBUTES AB TRAF3IP2 (TRAF3 interacting protein 2; previously known as CIKS or Act1) is a key intermediate in the normal inflammatory response and the pathogenesis of various autoimmune and inflammatory diseases. Induction of TRAF3IP2 activates IB kinase (IKK)/NF-B, JNK/AP-1, and c/EBP and stimulates the expression of various inflammatory mediators with negative myocardial inotropic effects. To investigate the role of TRAF3IP2 in heart disease, we generated a transgenic mouse model with cardiomyocyte-specific TRAF3IP2 overexpression (TRAF3IP2-Tg). Echocardiography, magnetic resonance imaging, and pressure-volume conductance catheterization revealed impaired cardiac function in 2-month-old male transgenic (Tg) mice as evidenced by decreased ejection fraction, stroke volume, cardiac output, and peak ejection rate. Moreover, the male Tg mice spontaneously developed myocardial hypertrophy (increased heart/body weight ratio, cardiomyocyte cross-sectional area, GATA4 induction, and fetal gene re-expression). Furthermore, TRAF3IP2 overexpression resulted in the activation of IKK/NF-B, JNK/AP-1, c/EBP, and p38 MAPK and induction of proinflammatory cytokines, chemokines, and extracellular matrix proteins in the heart. Although myocardial hypertrophy decreased with age, cardiac fibrosis (increased number of myofibroblasts and enhanced expression and deposition of fibrillar collagens) increased progressively. Despite these adverse changes, TRAF3IP2 overexpression did not result in cell death at any time period. Interestingly, despite increased mRNA expression, TRAF3IP2 protein levels and activation of its downstream signaling intermediates remained unchanged in the hearts of female Tg mice. The female Tg mice also failed to develop myocardial hypertrophy. In summary, these results demonstrate that overexpression of TRAF3IP2 in male mice is sufficient to induce myocardial hypertrophy, cardiac fibrosis, and contractile dysfunction. C1 [Yariswamy, Manjunath; Yoshida, Tadashi; Kandikattu, Hemanth Kumar; Sukhanov, Sergiy; Chandrasekar, Bysani] Univ Missouri, Dept Med, Columbia, MO 65211 USA. [Ma, Lixin] Univ Missouri, Dept Radiol, Columbia, MO 65211 USA. [Yariswamy, Manjunath; Ma, Lixin; Chandrasekar, Bysani] Harry S Truman Mem Vet Hosp, Columbia, MO 65201 USA. [Valente, Anthony J.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Sakamuri, Siva S. V. P.; Siddesha, Jalahalli M.] Tulane Univ, Sch Med, Dept Med, New Orleans, LA 70112 USA. [Saifudeen, Zubaida] Tulane Univ, Sch Med, Dept Pediat Nephrol, New Orleans, LA 70112 USA. [Siebenlist, Ulrich] NIAID, Lab Mol Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Gardner, Jason D.] Louisiana State Univ, Dept Physiol, Hlth Sci Ctr, New Orleans, LA 70112 USA. RP Chandrasekar, B (reprint author), Univ Missouri, Sch Med, Med Cardiol, 1 Hosp Dr, Columbia, MO 65212 USA. EM chandrasekarb@health.missouri.edu OI Sukhanov, Sergiy/0000-0002-9223-4263; Yoshida, Tadashi/0000-0002-4544-1497 FU Biomolecular Imaging Center at the Harry S. Truman Memorial Veterans' Hospital; University of Missouri-Columbia FX We thank Jiao Liu and Van Ninh for assistance with immunofluorescence and echocardiography, respectively. We gratefully acknowledge the support of the Biomolecular Imaging Center at the Harry S. Truman Memorial Veterans' Hospital and the University of Missouri-Columbia. NR 55 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 SEP 9 PY 2016 VL 291 IS 37 BP 19425 EP 19436 DI 10.1074/jbc.M116.724138 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV9EL UT WOS:000383242800021 PM 27466370 ER PT J AU Lai, LH Azzam, KM Lin, WC Rai, P Lowe, JM Gabor, KA Madenspacher, JH Aloor, JJ Parks, JS Naar, AM Fessler, MB AF Lai, Lihua Azzam, Kathleen M. Lin, Wan-Chi Rai, Prashant Lowe, Julie M. Gabor, Kristin A. Madenspacher, Jennifer H. Aloor, Jim J. Parks, John S. Naar, Anders M. Fessler, Michael B. TI MicroRNA-33 Regulates the Innate Immune Response via ATP Binding Cassette Transporter-mediated Remodeling of Membrane Microdomains SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE ABC transporter; cholesterol; lipid raft; macrophage; microRNA (miRNA); toll-like receptor (TLR) ID REVERSE CHOLESTEROL TRANSPORT; HIGH-DENSITY-LIPOPROTEIN; INFLAMMATORY RESPONSE; HOST-DEFENSE; LIPID RAFTS; ADAPTIVE IMMUNITY; DENDRITIC CELLS; X RECEPTOR; MACROPHAGES; EXPRESSION AB MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression by promoting degradation and/or repressing translation of specific target mRNAs. Several miRNAs have been identified that regulate the amplitude of the innate immune response by directly targeting Toll-like receptor (TLR) pathway members and/or cytokines. miR-33a and miR-33b (the latter present in primates but absent in rodents and lower species) are located in introns of the sterol regulatory element-binding protein (SREBP)-encoding genes and control cholesterol/lipid homeostasis in concert with their host gene products. These miRNAs regulate macrophage cholesterol by targeting the lipid efflux transporters ATP binding cassette (ABC)A1 and ABCG1. We and others have previously reported that Abca1(-/-) and Abcg1(-/-) macrophages have increased TLR proinflammatory responses due to augmented lipid raft cholesterol. Given this, we hypothesized that miR-33 would augment TLR signaling in macrophages via a raft cholesterol-dependent mechanism. Herein, we report that multiple TLR ligands down-regulate miR-33 in murine macrophages. In the case of lipopolysaccharide, this is a delayed, Toll/interleukin-1 receptor (TIR) domain-containing adapter-inducing interferon--dependent response that also down-regulates Srebf-2, the host gene for miR-33. miR-33 augments macrophage lipid rafts and enhances proinflammatory cytokine induction and NF-B activation by LPS. This occurs through an ABCA1- and ABCG1-dependent mechanism and is reversible by interventions upon raft cholesterol and by ABC transporter-inducing liver X receptor agonists. Taken together, these findings extend the purview of miR-33, identifying it as an indirect regulator of innate immunity that mediates bidirectional cross-talk between lipid homeostasis and inflammation. C1 [Lai, Lihua; Azzam, Kathleen M.; Lin, Wan-Chi; Rai, Prashant; Lowe, Julie M.; Gabor, Kristin A.; Madenspacher, Jennifer H.; Aloor, Jim J.; Fessler, Michael B.] NIEHS, Immun Inflammat & Dis Lab, NIH, Res Triangle Pk, NC 27709 USA. [Parks, John S.] Wake Forest Sch Med, Dept Internal Med, Sect Mol Med, Winston Salem, NC 27157 USA. [Naar, Anders M.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Naar, Anders M.] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA. RP Fessler, MB (reprint author), NIEHS, 111 TW Alexander Dr,POB 12233,D2-01, Res Triangle Pk, NC 27709 USA. EM fesslerm@niehs.nih.gov FU Intramural Research Program, NIEHS, National Institutes of Health Grant [Z01 ES102005]; China Scholarship Council; National Natural Science Foundation of China [81401283] FX This work was supported in part by Intramural Research Program, NIEHS, National Institutes of Health Grant Z01 ES102005. 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.; Supported in part by the China Scholarship Council and National Natural Science Foundation of China Grant 81401283. Present address: Inst. of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China. NR 59 TC 2 Z9 2 U1 8 U2 8 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 SEP 9 PY 2016 VL 291 IS 37 BP 19651 EP 19660 DI 10.1074/jbc.M116.723056 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV9EL UT WOS:000383242800038 PM 27471270 ER PT J AU Walseng, E Nelson, CG Qi, JP Nanna, AR Roush, WR Goswami, RK Sinha, SC Burke, TR Rader, C AF Walseng, Even Nelson, Christopher G. Qi, Junpeng Nanna, Alex R. Roush, William R. Goswami, Rajib K. Sinha, Subhash. C. Burke, Terrence R., Jr. Rader, Christoph TI Chemically Programmed Bispecific Antibodies in Diabody Format SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE antibody engineering; cancer therapy; chemical modification; folate; immunotherapy; ovarian cancer; T-cell ID CELL-ENGAGING ANTIBODY; T-CELLS; FOLATE-RECEPTOR; TUMOR-CELLS; ADAPTER IMMUNOTHERAPY; OVARIAN-CARCINOMA; MONOCLONAL-ANTIBODY; CANCER-THERAPY; SOLID TUMORS; PHASE-I AB Chemically programmed bispecific antibodies (biAbs) endow target cell-binding small molecules with the ability to recruit and activate effector cells of the immune system. Here we report a platform of chemically programmed biAbs aimed at redirecting cytotoxic T cells to eliminate cancer cells. Two different antibody technologies were merged together to make a novel chemically programmed biAb. This was achieved by combining the humanized anti-hapten monoclonal antibody (mAb) h38C2 with the humanized anti-human CD3 mAb v9 in a clinically investigated diabody format known as Dual-Affinity Re-Targeting (DART). We show that h38C2 x v9 DARTs can readily be equipped with tumor-targeting hapten-derivatized small molecules without causing a systemic response harming healthy tissues. As a proof of concept, we chemically programmed h38C2 x v9 with hapten-folate and demonstrated its selectivity and potency against folate receptor 1 (FOLR1)-expressing ovarian cancer cells in vitro and in vivo. Unlike conventional biAbs, chemically programmed biAbs in DART format are highly modular with broad utility in terms of both target and effector cell engagement. Most importantly, they provide tumor-targeting compounds access to the power of cancer immunotherapy. C1 [Walseng, Even; Qi, Junpeng; Nanna, Alex R.; Rader, Christoph] Scripps Res Inst, Dept Canc Biol, Jupiter, FL 33458 USA. [Nanna, Alex R.; Roush, William R.] Scripps Res Inst, Dept Chem, Jupiter, FL 33458 USA. [Rader, Christoph] Scripps Res Inst, Dept Mol Therapeut, Jupiter, FL 33458 USA. [Goswami, Rajib K.; Sinha, Subhash. C.] Scripps Res Inst, Dept Cell & Mol Biol, La Jolla, CA 92037 USA. [Nelson, Christopher G.; Burke, Terrence R., Jr.] NCI, Biol Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Walseng, Even] NCI, NIH, Bethesda, MD 20892 USA. [Nelson, Christopher G.] Bristol Myers Squibb Co, New York, NY 10154 USA. [Goswami, Rajib K.] Indian Assoc Cultivat Sci, Kolkata, India. [Sinha, Subhash. C.] Rockefeller Univ, New York, NY USA. RP Rader, C (reprint author), Scripps Res Inst, Dept Canc Biol, Jupiter, FL 33458 USA.; Rader, C (reprint author), Scripps Res Inst, Dept Mol Therapeut, Jupiter, FL 33458 USA. EM crader@scripps.edu FU National Institutes of Health [R01 CA181258]; Intramural Research Program, Center for Cancer Research, NCI, National Institutes of Health FX This work was supported by National Institutes of Health Grant R01 CA181258 (to C. R.) and the Intramural Research Program, Center for Cancer Research, NCI, National Institutes of Health (to T. R. B., Jr.). 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 58 TC 0 Z9 0 U1 7 U2 7 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 SEP 9 PY 2016 VL 291 IS 37 BP 19661 EP 19673 DI 10.1074/jbc.M116.745588 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV9EL UT WOS:000383242800039 PM 27445334 ER PT J AU Miura, K Stone, WJR Koolen, KM Deng, BB Zhou, LW van Gemert, GJ Locke, E Morin, M Bousema, T Sauerwein, RW Long, CA Dechering, KJ AF Miura, Kazutoyo Stone, Will J. R. Koolen, Karin M. Deng, Bingbing Zhou, Luwen van Gemert, Geert-Jan Locke, Emily Morin, Merribeth Bousema, Teun Sauerwein, Robert W. Long, Carole A. Dechering, Koen J. TI An inter-laboratory comparison of standard membrane-feeding assays for evaluation of malaria transmission-blocking vaccines SO MALARIA JOURNAL LA English DT Article DE Plasmodium falciparum; Gametocyte; Oocyst; Transmission; Anopheles; Mosquito; Vaccine; SSM-VIMT ID PLASMODIUM-FALCIPARUM TRANSMISSION; REDUCING ACTIVITY; CANDIDATES; PROTEIN; PARASITES; IMMUNITY; OOCYSTS; PFS25; SERA AB Background: An effective malaria transmission-blocking vaccine may play an important role in malaria elimination efforts, and a robust biological assay is essential for its development. The standard membrane-feeding assay (SMFA) for Plasmodium falciparum infection of mosquitoes is considered a "gold standard" assay to measure transmission-blocking activity of test antibodies, and has been utilized widely in both non-clinical and clinical studies. While several studies have discussed the inherent variability of SMFA within a study group, there has been no assessment of inter-laboratory variation. Therefore, there is currently no assurance that SMFA results are comparable between different studies. Methods: Mouse anti-Pfs25 monoclonal antibody (mAb, 4B7 mAb), rat anti-Pfs48/45 mAb (85RF45.1 mAb) and a human polyclonal antibody (pAb) collected from a malaria-exposed adult were tested at the same concentrations (6-94 mu g/mL for 4B7, 1.2-31.3 mu g/mL for 85RF45.1 and 23-630 mu g/mL for human pAb) in two laboratories following their own standardized SMFA protocols. The mAbs and pAb, previously shown to have strong inhibition activities in the SMFA, were tested at three or four concentrations in two or three independent assays in each laboratory, and percent inhibition in mean oocyst intensity relative to a control in the same feed was determined in each feeding experiment. Results: Both monoclonal and polyclonal antibodies dose-dependently reduced oocyst intensity in all experiments performed at the two test sites. In both laboratories, the inter-assay variability in percent inhibition in oocyst intensity decreased at higher levels of inhibition, regardless of which antibody was tested. At antibody concentrations that led to a >80 % reduction in oocyst numbers, the inter-laboratory variations were in the same range compared with the inter-assay variation observed within a single laboratory, and the differences in best estimates from multiple feeds between the two laboratories were <5 percentage points. Conclusions: This study confirms previous reports that the precision of the SMFA increases with increasing percent inhibition. Moreover, the variation between the two laboratories is not greater than the variation observed within a laboratory. The findings of this study provide guidance for comparison of SMFA data from different laboratories. C1 [Miura, Kazutoyo; Deng, Bingbing; Zhou, Luwen; Long, Carole A.] NIAID, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy, Rockville, MD 20852 USA. [Stone, Will J. R.; van Gemert, Geert-Jan; Bousema, Teun; Sauerwein, Robert W.] Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, NL-6500 HB Nijmegen, Netherlands. [Locke, Emily; Morin, Merribeth] PATH Malaria Vaccine Initiat, 455 Massachusetts Ave NW, Washington, DC 20001 USA. [Koolen, Karin M.; Dechering, Koen J.] TropIQ Hlth Sci, Transistorweg 5, NL-6534 AT Nijmegen, Netherlands. RP Miura, K (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy, Rockville, MD 20852 USA.; Dechering, KJ (reprint author), TropIQ Hlth Sci, Transistorweg 5, NL-6534 AT Nijmegen, Netherlands. EM kmiura@niaid.nih.gov; k.dechering@tropiq.nl FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH; PATH Malaria Vaccine Initiative; Marie Curie Career Integration Grant from the European Community's Seventh Framework Programme (SIGNAL) [PCIG12-GA-2012-333936]; VIDI fellowship from the Netherlands Organization for Scientific Research (NWO) [016.158.306] FX This study was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH and also by the PATH Malaria Vaccine Initiative. WS and TB were additionally supported by a Marie Curie Career Integration Grant from the European Community's Seventh Framework Programme (SIGNAL, PCIG12-GA-2012-333936) and a VIDI fellowship from the Netherlands Organization for Scientific Research (NWO; project number 016.158.306). NR 31 TC 1 Z9 1 U1 9 U2 9 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 SEP 9 PY 2016 VL 15 AR 463 DI 10.1186/s12936-016-1515-z PG 9 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DV4RX UT WOS:000382913900002 PM 27612458 ER PT J AU Selimovic, S AF Selimovic, Seila TI A Life Everlasting The Extraordinary Story of One Boy's Gift to Medical Science SO SCIENCE LA English DT Book Review C1 [Selimovic, Seila] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. RP Selimovic, S (reprint author), Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. EM seila.selimovic@nih.gov NR 1 TC 0 Z9 0 U1 1 U2 1 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 SEP 9 PY 2016 VL 353 IS 6304 BP 1093 EP 1093 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV0RN UT WOS:000382626800026 ER PT J AU Singer, DS Jacks, T Jaffee, E AF Singer, Dinah S. Jacks, Tyler Jaffee, Elizabeth TI A US "Cancer Moonshot" to accelerate cancer research SO SCIENCE LA English DT Editorial Material C1 [Singer, Dinah S.] NCI, Bethesda, MD 20892 USA. [Jacks, Tyler] MIT, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Jaffee, Elizabeth] Johns Hopkins Sch Med, Baltimore, MD 21231 USA. RP Singer, DS (reprint author), NCI, Bethesda, MD 20892 USA. EM singerd@mail.nih.gov NR 0 TC 1 Z9 1 U1 1 U2 4 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 SEP 9 PY 2016 VL 353 IS 6304 BP 1105 EP 1106 DI 10.1126/science.aai7862 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV0RN UT WOS:000382626800036 PM 27605537 ER PT J AU Barth, A Burkhalter, A Callaway, EM Connors, BW Cauli, B DeFelipe, J Feldmeyer, D Freund, T Kawaguchi, Y Kisvarday, Z Kubota, Y McBain, C Oberlaender, M Rossier, J Rudy, B Staiger, JF Somogyi, P Tamas, G Yuste, R AF Barth, Alison Burkhalter, Andreas Callaway, Edward M. Connors, Barry W. Cauli, Bruno DeFelipe, Javier Feldmeyer, Dirk Freund, Tamas Kawaguchi, Yasuo Kisvarday, Zoltan Kubota, Yoshiyuki McBain, Chris Oberlaender, Marcel Rossier, Jean Rudy, Bernardo Staiger, Jochen F. Somogyi, Peter Tamas, Gabor Yuste, Rafael TI Comment on "Principles of connectivity among morphologically defined cell types in adult neocortex" SO SCIENCE LA English DT Editorial Material ID NEURONS; CORTEX; LONG; CIRCUITS AB Jiang et al. (Research Article, 27 November 2015, aac9462) describe detailed experiments that substantially add to the knowledge of cortical microcircuitry and are unique in the number of connections reported and the quality of interneuron reconstruction. The work appeals to experts and laypersons because of the notion that it unveils new principles and provides a complete description of cortical circuits. We provide a counterbalance to the authors' claims to give those less familiar with the minutiae of cortical circuits a better sense of the contributions and the limitations of this study. C1 [Barth, Alison] Carnegie Mellon Univ, Dept Biol Sci, Mellon Inst 159C, 4400 Fifth Ave, Pittsburgh, PA 15213 USA. [Burkhalter, Andreas] Washington Univ, Sch Med, Dept Anat & Neurobiol, St Louis, MO 63110 USA. [Callaway, Edward M.] Salk Inst Biol Studies, Syst Neurobiol Lab, 10010 North Torrey Pines Rd, La Jolla, CA 92037 USA. [Connors, Barry W.] Brown Univ, Div Biol & Med, Dept Neurosci, Providence, RI 02912 USA. [Cauli, Bruno] UPMC, CNRS, INSERM, U1130,UM 119,NPS,CNNC,UMR 8246, 9 Quai St Bernard, F-75005 Paris, France. [DeFelipe, Javier] Univ Politecn Madrid, Ctr Tecnol Biomed, Lab Cajal Circuitos Cort, Campus Montegancedo S-N, Madrid 28223, Spain. [DeFelipe, Javier] Inst Cajal CSIC, Ave Doctor Arce 37, Madrid 28002, Spain. [Feldmeyer, Dirk] Forschungszentrum Julich, Inst Neurowissenschaft & Med INM 2, D-52425 Julich, Germany. [Freund, Tamas] Hungarian Acad Sci, Inst Expt Med, Lab Cerebral Cortex Res, Dept Cellular & Network Neurobiol, POB 67, H-1450 Budapest, Hungary. [Kawaguchi, Yasuo; Kubota, Yoshiyuki] Natl Inst Physiol Sci, Div Cerebral Circuitry, 5-1 Myodaiji Higashiyama, Okazaki, Aichi 4448787, Japan. [Kisvarday, Zoltan] Univ Debrecen, Dept Anat, Lab Cort Syst Neurosci, Histol,Embryol, Nagyerdei Krt 98, H-4012 Debrecen, Hungary. [McBain, Chris] NICHHD, Lab Cellular & Synapt Neurophysiol, 35 Convent Dr MSC3715, Bethesda, MD 20892 USA. [Oberlaender, Marcel] Computat Neuroanat Grp, Max Planck Inst Biol Cybernet, D-72076 Tubingen, Germany. [Rossier, Jean] Univ Paris 06, Neurosci Paris Seine, 7-9 Quai St Bernard, F-75005 Paris, France. [Rudy, Bernardo] NYU, Dept Anesthesiol Perioperat Care & Pain Med, Inst Neurosci, Sch Med,Smilow Res Ctr, 522 First Ave, New York, NY 10016 USA. [Staiger, Jochen F.] Univ Med Goettingen, Ctr Anat, Inst Neuroanat, Kreuzbergring 36, D-37075 Gottingen, Germany. [Somogyi, Peter] Univ Oxford, Dept Pharmacol, Brain Network Dynam Unit, MRC, Mansfield Rd, Oxford OX1 3TH, England. [Tamas, Gabor] Univ Szeged, Dept Physiol Anat & Neurosci, Hungarian Acad Sci, Res Grp Cort Microcircuits, Kozep Fasor 52, H-6726 Szeged, Hungary. [Yuste, Rafael] Columbia Univ, Dept Biol Sci, Kavli Inst Brain Sci, West 120 St, New York, NY 10027 USA. RP Callaway, EM (reprint author), Salk Inst Biol Studies, Syst Neurobiol Lab, 10010 North Torrey Pines Rd, La Jolla, CA 92037 USA.; Rudy, B (reprint author), NYU, Dept Anesthesiol Perioperat Care & Pain Med, Inst Neurosci, Sch Med,Smilow Res Ctr, 522 First Ave, New York, NY 10016 USA.; Staiger, JF (reprint author), Univ Med Goettingen, Ctr Anat, Inst Neuroanat, Kreuzbergring 36, D-37075 Gottingen, Germany. EM callaway@salk.edu; rudyb01@med.nyu.edu; jochen.staiger@med.uni-goettingen.de OI Connors, Barry/0000-0002-3739-3157; Rudy, Bernardo/0000-0001-5748-6900 NR 12 TC 1 Z9 1 U1 14 U2 14 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 SEP 9 PY 2016 VL 353 IS 6304 DI 10.1126/science.aaf5663 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV0RN UT WOS:000382626800039 ER PT J AU Ahidjo, BA Maiga, MC Ihms, EA Maiga, M Ordonez, AA Cheung, LS Beck, S Andrade, BB Jain, S Bishai, WR AF Ahidjo, Bintou A. Maiga, Mariama C. Ihms, Elizabeth A. Maiga, Mamoudou Ordonez, Alvaro A. Cheung, Laurene S. Beck, Sarah Andrade, Bruno B. Jain, Sanjay Bishai, William R. TI The antifibrotic drug pirfenidone promotes pulmonary cavitation and drug resistance in a mouse model of chronic tuberculosis SO JCI INSIGHT LA English DT Article ID HOST-DIRECTED THERAPIES; CONTROLLED-TRIAL; LUNG FIBROSIS; DOUBLE-BLIND; BLEOMYCIN; MICE; INHIBITOR; DISEASE; LESIONS AB Pirfenidone is a recently approved antifibrotic drug for the treatment of idiopathic pulmonary fibrosis (IPF). Because tuberculosis (TB) is characterized by granulomatous inflammation in conjunction with parenchymal destruction and replacement fibrosis, we sought to determine whether the addition of pirfenidone as an adjunctive, host-directed therapy provides a beneficial effect during antimicrobial treatment of TB. We hypothesized that pirfenidone's antiinflammatory and antifibrotic properties would reduce inflammatory lung damage and increase antimicrobial drug penetration in granulomas to accelerate treatment response. The effectiveness of adjunctive pirfenidone during TB drug therapy was evaluated using a murine model of chronic TB. Mice treated with standard therapy 2HRZ/4HR (H, isoniazid; R, rifampin; and Z, pyrazinamide) were compared with 2 alternative regimens containing pirfenidone (Pf) (2HRZPf/4HRPf and 2HRZPf/4HR). Contrary to our hypothesis, adjunctive pirfenidone use leads to reduced bacterial clearance and increased relapse rates. This treatment failure is closely associated with the emergence of isoniazid monoresistant bacilli, increased cavitation, and significant lung pathology. While antifibrotic agents may eventually be used as part of adjunctive host-directed therapy of TB, this study clearly demonstrates that caution must be exercised. Moreover, as pirfenidone becomes more widely used in clinical practice, increased patient monitoring would be required in endemic TB settings. C1 [Ahidjo, Bintou A.; Maiga, Mariama C.; Ihms, Elizabeth A.; Maiga, Mamoudou; Ordonez, Alvaro A.; Cheung, Laurene S.; Jain, Sanjay; Bishai, William R.] Johns Hopkins Univ, Sch Med, Ctr TB Res, Baltimore, MD USA. [Ahidjo, Bintou A.; Maiga, Mariama C.; Bishai, William R.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Maiga, Mamoudou] Univ Sci Tech & Technol Bamako, Bamako, Mali. [Ordonez, Alvaro A.; Jain, Sanjay] Johns Hopkins Univ, Sch Med, Ctr Infect & Inflammat Imaging Res, Baltimore, MD USA. [Ordonez, Alvaro A.; Jain, Sanjay] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. [Ihms, Elizabeth A.; Beck, Sarah] Johns Hopkins Univ, Sch Med, Mol & Comparat Pathobiol, Baltimore, MD USA. [Andrade, Bruno B.] Fundacao Oswaldo Cruz, Ctr Pesquisas Goncalo Moniz, Unidade Med Invest, Lab Integrado Microbiol & Imunorregulacao, Salvador, BA, Brazil. [Andrade, Bruno B.] Fundacao Jose Silveira, Inst Brasileiro Invest TB, Salvador, BA, Brazil. [Ahidjo, Bintou A.] Aurum Inst, Johannesburg, South Africa. [Maiga, Mariama C.] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Bishai, WR (reprint author), 1550 Orleans St,Room 103, Baltimore, MD 21231 USA. EM wbishai1@jhmi.edu FU NIAID NIH HHS [R01 AI036973, R01 AI037856, R01 AI079590]; NIGMS NIH HHS [T32 GM008752]; NIH HHS [T32 OD011089] NR 45 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD SEP 8 PY 2016 VL 1 IS 14 AR e86017 DI 10.1172/jci.insight.86017 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1OL UT WOS:000387122400001 PM 27699232 ER PT J AU Dasso, M Fontoura, BMA AF Dasso, Mary Fontoura, Beatriz M. A. TI Gating Immunity and Death at the Nuclear Pore Complex SO CELL LA English DT Editorial Material ID INNATE IMMUNITY; ARABIDOPSIS; DEFENSE AB The nuclear pore complex is the primary conduit for nuclear import and export of molecules. In this issue, Gu et al. uncover a novel mechanism in which immune signaling and programmed cell death require nuclear pore rearrangement and release of sequestered cyclin-dependent kinase inhibitors to elicit immunity and death. C1 [Dasso, Mary] NICHHD, Div Mol & Cellular Biol, NIH, Bethesda, MD 20892 USA. [Fontoura, Beatriz M. A.] Univ Texas Southwestern Med Ctr Dallas, Dept Cell Biol, Dallas, TX 75390 USA. RP Dasso, M (reprint author), NICHHD, Div Mol & Cellular Biol, NIH, Bethesda, MD 20892 USA.; Fontoura, BMA (reprint author), Univ Texas Southwestern Med Ctr Dallas, Dept Cell Biol, Dallas, TX 75390 USA. EM dassom@mail.nih.gov; beatriz.fontoura@utsouthwestern.edu OI Dasso, Mary/0000-0002-5410-1371 NR 10 TC 0 Z9 0 U1 5 U2 5 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 SEP 8 PY 2016 VL 166 IS 6 BP 1364 EP 1366 DI 10.1016/j.cell.2016.08.026 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EA1GG UT WOS:000386339900008 PM 27610561 ER PT J AU Tian, M Cheng, C Chen, XJ Duan, HY Cheng, HL Dao, M Sheng, ZZ Kimble, M Wang, LS Lin, S Schmidt, SD Du, Z Joyce, MG Chen, YW DeKosky, BJ Chen, YM Normandin, E Cantor, E Chen, RE Doria-Rose, NA Zhang, Y Shi, W Kong, WP Choe, M Henry, AR Laboune, F Georgiev, IS Huang, PY Jain, S McGuire, AT Georgeson, E Menis, S Douek, DC Schief, WR Stamatatos, L Kwong, PD Shapiro, L Haynes, BF Mascola, JR Alt, FW AF Tian, Ming Cheng, Cheng Chen, Xuejun Duan, Hongying Cheng, Hwei-Ling Dao, Mai Sheng, Zizhang Kimble, Michael Wang, Lingshu Lin, Sherry Schmidt, Stephen D. Du, Zhou Joyce, M. Gordon Chen, Yiwei DeKosky, Brandon J. Chen, Yimin Normandin, Erica Cantor, Elizabeth Chen, Rita E. Doria-Rose, Nicole A. Zhang, Yi Shi, Wei Kong, Wing-Pui Choe, Misook Henry, Amy R. Laboune, Farida Georgiev, Ivelin S. Huang, Pei-Yi Jain, Suvi McGuire, Andrew T. Georgeson, Eric Menis, Sergey Douek, Daniel C. Schief, William R. Stamatatos, Leonidas Kwong, Peter D. Shapiro, Lawrence Haynes, Barton F. Mascola, John R. Alt, Frederick W. TI Induction of HIV Neutralizing Antibody Lineages in Mice with Diverse Precursor Repertoires SO CELL LA English DT Article ID B-CELL RECEPTORS; VRC01-CLASS ANTIBODIES; MATURATION PATHWAY; SEQUENCE ALIGNMENT; IMMUNOGEN DESIGN; HIGH-THROUGHPUT; GERMLINE; BROAD; ENVELOPE; BINDING AB The design of immunogens that elicit broadly reactive neutralizing antibodies (bnAbs) has been a major obstacle to HIV-1 vaccine development. One approach to assess potential immunogens is to use mice expressing precursors of human bnAbs as vaccination models. The bnAbs of the VRC01-class derive from the IGHV1-2 immunoglobulin heavy chain and neutralize a wide spectrum of HIV-1 strains via targeting the CD4 binding site of the envelope glycoprotein gp120. Wenow describe a mouse vaccination model that allows a germline human IGHV1-2*02 segment to undergo normal V(D)J recombination and, thereby, leads to the generation of peripheral B cells that express a highly diverse repertoire of VRC01-related receptors. When sequentially immunized with modified gp120 glycoproteins designed to engage VRC01 germline and intermediate antibodies, IGHV1-2*02-rearranging mice, which also express a VRC01-antibody precursor light chain, can support the affinity maturation of VRC01 precursor antibodies into HIV-neutralizing antibody lineages. C1 [Tian, Ming; Cheng, Hwei-Ling; Dao, Mai; Kimble, Michael; Lin, Sherry; Du, Zhou; Chen, Yiwei; Chen, Yimin; Cantor, Elizabeth; Huang, Pei-Yi; Jain, Suvi; Alt, Frederick W.] Howard Hughes Med Inst, Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Tian, Ming; Cheng, Hwei-Ling; Dao, Mai; Kimble, Michael; Lin, Sherry; Du, Zhou; Chen, Yiwei; Chen, Yimin; Cantor, Elizabeth; Huang, Pei-Yi; Jain, Suvi; Alt, Frederick W.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Cheng, Cheng; Chen, Xuejun; Duan, Hongying; Wang, Lingshu; Schmidt, Stephen D.; Joyce, M. Gordon; DeKosky, Brandon J.; Normandin, Erica; Chen, Rita E.; Doria-Rose, Nicole A.; Zhang, Yi; Shi, Wei; Kong, Wing-Pui; Choe, Misook; Henry, Amy R.; Laboune, Farida; Douek, Daniel C.; Kwong, Peter D.; Shapiro, Lawrence; Mascola, John R.] NIAID, Vaccine Res Ctr, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Georgiev, Ivelin S.] Vanderbilt Univ, Vanderbilt Vaccine Ctr, Nashville, TN 37232 USA. [Sheng, Zizhang; Shapiro, Lawrence] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. [Sheng, Zizhang; Shapiro, Lawrence] Columbia Univ, Dept Syst Biol, New York, NY 10032 USA. [Georgeson, Eric; Menis, Sergey; Schief, William R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Georgeson, Eric; Menis, Sergey; Schief, William R.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Schief, William R.] MIT, Massachusetts Gen Hosp, Ragon Inst, Cambridge, MA 02129 USA. [Schief, William R.] Harvard Univ, Cambridge, MA 02129 USA. [McGuire, Andrew T.; Stamatatos, Leonidas] Fred Hutchinson Canc Res Ctr, Seattle, WA USA. [Haynes, Barton F.] Duke Univ, Duke Human Vaccine Inst, Sch Med, Durham, NC 27710 USA. RP Alt, FW (reprint author), Howard Hughes Med Inst, Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA.; Alt, FW (reprint author), Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.; Mascola, JR (reprint author), NIAID, Vaccine Res Ctr, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jmascola@mail.nih.gov; alt@enders.tch.harvard.edu FU NIH [R01AI077595, AI020047, P01 AI094419, U19AI109632, P01-AI104722]; NIAID, Division of AIDS, Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery (CHAVI-ID) [5UM1 AI100645]; NIH Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) [1UM1 AI100663]; intramural research program of the Vaccine Research Center, NIAID, NIH; International AIDS Vaccine Initiative Neutralizing Antibody Consortium; International AIDS Vaccine Initiative Neutralizing Antibody Center; CAVD funding for the IAVI NAC Center; Ragon Institute of MGH, MIT and Harvard; HHMI Medical Student Fellowship FX We thank Norman Letvin and Connie Gee for stimulating this collaborative study. We also thank Sam Darko for assistance with data analysis. This work was supported by NIH grants R01AI077595 and AI020047 (to F.W.A.); P01 AI094419 and U19AI109632 (to L.S., FHCRC); P01-AI104722 (to L.S., Columbia University); NIAID, Division of AIDS, Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery (CHAVI-ID) 5UM1 AI100645 (to B.F.H. and F.W.A.); and NIH Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) 1UM1 AI100663 (to W.R.S.). This work was also supported by the intramural research program of the Vaccine Research Center, NIAID, NIH and the International AIDS Vaccine Initiative Neutralizing Antibody Consortium and Center (to W.R.S.); CAVD funding for the IAVI NAC Center (W.R.S.); and the Ragon Institute of MGH, MIT and Harvard (W.R.S.). M.D. was supported by an HHMI Medical Student Fellowship. F.W.A. is an investigator and Z.D. is a postdoctoral fellow of the Howard Hughes Medical Institute. W.R.S. is a co-founder and stockholder in Compuvax, Inc., which has programs in non-HIV vaccine design that might benefit indirectly from this research. NR 38 TC 11 Z9 11 U1 9 U2 9 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 SEP 8 PY 2016 VL 166 IS 6 BP 1471 EP + DI 10.1016/j.cell.2016.07.029 PG 32 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EA1GG UT WOS:000386339900019 PM 27610571 ER PT J AU Udensi, UK Tchounwou, PB AF Udensi, Udensi K. Tchounwou, Paul B. TI Oxidative stress in prostate hyperplasia and carcinogenesis SO JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH LA English DT Review DE Prostate cancer; Oxidative stress; Antioxidants; Cancer treatment ID LONG NONCODING RNAS; LIPID-PEROXIDATION; CIRCULATING MICRORNAS; CANCER SUSCEPTIBILITY; 5-ALPHA-REDUCTASE INHIBITOR; INTRAEPITHELIAL NEOPLASIA; ANTIOXIDANT STATUS; MOLECULAR-BIOLOGY; BODY-COMPOSITION; GSTP1 GENE AB Prostatic hyperplasia (PH) is a common urologic disease that affects mostly elderly men. PH can be classified as benign prostatic hyperplasia (BPH), or prostate cancer (PCa) based on its severity. Oxidative stress (OS) is known to influence the activities of inflammatory mediators and other cellular processes involved in the initiation, promotion and progression of human neoplasms including prostate cancer. Scientific evidence also suggests that micronutrient supplementation may restore the antioxidant status and hence improve the clinical outcomes for patients with BPH and PCa. This review highlights the recent studies on prostate hyperplasia and carcinogenesis, and examines the role of OS on the molecular pathology of prostate cancer progression and treatment. C1 [Udensi, Udensi K.; Tchounwou, Paul B.] Jackson State Univ, Coll Sci Engn & Technol, NIMHD, NIH,RCMI Ctr Environm Hlth, Jackson, MS 39217 USA. RP Tchounwou, PB (reprint author), Jackson State Univ, Coll Sci Engn & Technol, NIMHD, NIH,RCMI Ctr Environm Hlth, Jackson, MS 39217 USA. EM paul.b.tchounwou@jsums.edu FU National Institutes of Health/National Institute on Minority Health and Health Disparities through the RCMI Center for Environmental Health at Jackson State University [G12MD007581] FX This research was supported by a grant from the National Institutes of Health/National Institute on Minority Health and Health Disparities (G12MD007581) through the RCMI Center for Environmental Health at Jackson State University. NR 153 TC 0 Z9 0 U1 3 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-9966 J9 J EXP CLIN CANC RES JI J. Exp. Clin. Cancer Res. PD SEP 8 PY 2016 VL 35 DI 10.1186/s13046-016-0418-8 PG 19 WC Oncology SC Oncology GA DY6YL UT WOS:000385275600001 PM 27609145 ER PT J AU Khaw, SL Suryani, S Evans, K Richmond, J Robbins, A Kurmasheva, RT Billups, CA Erickson, SW Guo, Y Houghton, PJ Smith, MA Carol, H Roberts, AW Huang, DCS Lock, RB AF Khaw, Seong Lin Suryani, Santi Evans, Kathryn Richmond, Jennifer Robbins, Alissa Kurmasheva, Raushan T. Billups, Catherine A. Erickson, Stephen W. Guo, Yuelong Houghton, Peter J. Smith, Malcolm A. Carol, Hernan Roberts, Andrew W. Huang, David C. S. Lock, Richard B. TI Venetoclax responses of pediatric ALL xenografts reveal sensitivity of MLL-rearranged leukemia SO BLOOD LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; CHRONIC LYMPHOCYTIC-LEUKEMIA; B-CELL PRECURSOR; PRECLINICAL TESTING PROGRAM; CHILDRENS-CANCER-GROUP; BH3 MIMETIC ABT-263; IN-VIVO EFFICACY; ONCOLOGY-GROUP; GENE-EXPRESSION; BCL-2 AB The clinical success of the BCL-2-selective BH3-mimetic venetoclax in patients with poor prognosis chronic lymphocytic leukemia (CLL) highlights the potential of targeting the BCL-2-regulated apoptotic pathway in previously untreatable lymphoid malignancies. By selectively inhibiting BCL-2, venetoclax circumvents the dose-limiting, BCL-X-L-mediated thrombocytopenia of its less selective predecessor navitoclax, while enhancing efficacy in CLL. We have previously reported the potent sensitivity of many high-risk childhood acute lymphoblastic leukemia (ALL) xenografts to navitoclax. Given the superior tolerability of venetoclax, here we have investigated its efficacy in childhood ALL. We demonstrate that in contrast to the clear dependence of CLL on BCL-2 alone, effective antileukemic activity in the majority of ALL xenografts requires concurrent inhibition of both BCL-2 and BCL-XL. We identify BCL-XL expression as a key predictor of poor response to venetoclax and demonstrate that concurrent inhibition of both BCL-2 and BCL-XL results in synergistic killing in the majority of ALL xenografts. A notable exception is mixed lineage leukemia rearranged infant ALL, where venetoclax largely recapitulates the activity of navitoclax, identifying this subgroup of patients as potential candidates for clinical trials of venetoclax in childhood ALL. Conversely, our findings provide a clear basis for progressing navitoclax into trials ahead of venetoclax in other subgroups. C1 [Khaw, Seong Lin; Roberts, Andrew W.; Huang, David C. S.] Walter Eliza Hall Inst Med Res, Melbourne, Vic, Australia. [Khaw, Seong Lin] Royal Childrens Hosp, Melbourne, Vic, Australia. [Suryani, Santi; Evans, Kathryn; Richmond, Jennifer; Robbins, Alissa; Carol, Hernan; Lock, Richard B.] Univ New South Wales Australia, Childrens Canc Inst, Lowy Canc Res Ctr, Sydney, NSW, Australia. [Kurmasheva, Raushan T.; Houghton, Peter J.] Univ Texas Hlth Sci Ctr San Antonio, Greehey Childrens Canc Res Inst, San Antonio, TX 78229 USA. [Billups, Catherine A.] St Jude Childrens Res Hosp, Dept Pathol, 332 N Lauderdale St, Memphis, TN 38105 USA. [Erickson, Stephen W.; Guo, Yuelong] Res Triangle Inst Int, Res Triangle Pk, NC USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Roberts, Andrew W.; Huang, David C. S.] Univ Melbourne, Fac Med Dent & Hlth Sci, Melbourne, Vic, Australia. RP Lock, RB (reprint author), UNSW, Childrens Canc Inst, Lowy Canc Res Ctr, POB 81, Randwick, NSW 2031, Australia. EM rlock@ccia.unsw.edu.au RI Lock, Richard/G-4253-2013; Roberts, Andrew/C-6736-2012 OI Roberts, Andrew/0000-0002-7341-5720 FU National Institutes of Health, National Cancer Institute [NOI-CM-42216, NOI-CM-91001-03]; Leukemia and Lymphoma Society [SCOR 7417-07, 7001-13]; National Health and Medical Research Council (NHMRC) of Australia [1016647, 1016701]; Leukaemia Foundation of Australia; Cure Cancer Australia Foundation; Cancer Institute New South Wales; NHMRC [1059804, 1079560, 1043149, 9000220]; Victorian State Government FX This research was funded by grants from the National Institutes of Health, National Cancer Institute (NOI-CM-42216 and NOI-CM-91001-03), the Leukemia and Lymphoma Society (SCOR 7417-07 and 7001-13), and the National Health and Medical Research Council (NHMRC) of Australia (1016647 and 1016701). S.S. was supported by Postdoctoral Fellowships from the Leukaemia Foundation of Australia and the Cure Cancer Australia Foundation, and an Early Career Fellowship from the Cancer Institute New South Wales. R.B.L., A.W.R., and D.C.S.H. are supported by Fellowships from the NHMRC (1059804, 1079560, 1043149). The authors thank AbbVie for providing navitoclax, venetoclax, A-1113567, and A-1155463. The Walter and Eliza Hall Institute of Medical Research is supported by an Independent Research Institutes Infrastructure Support Scheme grant 9000220 (NHMRC) and Victorian State Government Operational Infrastructure Support grant. NR 64 TC 8 Z9 8 U1 2 U2 2 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 SEP 8 PY 2016 VL 128 IS 10 BP 1382 EP 1395 DI 10.1182/blood-2016-03-707414 PG 14 WC Hematology SC Hematology GA DW8ZW UT WOS:000383945100010 PM 27343252 ER PT J AU Gardner, K Douiri, A Drasar, E Allman, M Mwirigi, A Awogbade, M Thein, SL AF Gardner, Kate Douiri, Abdel Drasar, Emma Allman, Marlene Mwirigi, Anne Awogbade, Moji Thein, Swee Lay TI Survival in adults with sickle cell disease in a high-income setting SO BLOOD LA English DT Letter ID CHILDREN; MORTALITY; COHORT; DEATH; POPULATION; OUTCOMES; US C1 [Gardner, Kate; Drasar, Emma; Thein, Swee Lay] Kings Coll London, Div Canc Studies, Mol Haematol, London, England. [Gardner, Kate; Drasar, Emma; Allman, Marlene; Mwirigi, Anne; Awogbade, Moji; Thein, Swee Lay] Kings Coll Hosp Natl Hlth Serv NHS Fdn Trust, Dept Haematol Med, London, England. [Douiri, Abdel] Kings Coll London, Div Hlth & Social Care, London, England. [Douiri, Abdel] Guys & St Thomas NHS Trust, Natl Inst Hlth Res NIHR Biomed Res Ctr, London, England. [Douiri, Abdel] Kings Coll London, London, England. [Douiri, Abdel] Kings Coll Hosp NHS Fdn Trust, NIHR Collaborat Leadership Appl Hlth Res & Care, London, England. RP Thein, SL (reprint author), NHLBI, Sickle Cell Branch, NIH, Bldg 10 CRC,Room 5E-5142,10 Ctr Dr, Bethesda, MD 20892 USA.; Gardner, K (reprint author), Kings Coll London, Mol Haematol, James Black Ctr, 125 Coldharbour Ln, London SE5 9NU, England. EM kate.gardner@doctors.org.uk; sl.thein@nih.gov NR 14 TC 3 Z9 3 U1 2 U2 2 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 SEP 8 PY 2016 VL 128 IS 10 BP 1436 EP 1438 DI 10.1182/blood-2016-05-716910 PG 3 WC Hematology SC Hematology GA DW8ZW UT WOS:000383945100015 PM 27439910 ER PT J AU Nick, JA Caceres, SM Kret, JE Poch, KR Strand, M Faino, AV Nichols, DP Saavedra, MT Taylor-Cousar, JL Geraci, MW Burnham, EL Fessler, MB Suratt, BT Abraham, E Moss, M Malcolm, KC AF Nick, Jerry A. Caceres, Silvia M. Kret, Jennifer E. Poch, Katie R. Strand, Matthew Faino, Anna V. Nichols, David P. Saavedra, Milene T. Taylor-Cousar, Jennifer L. Geraci, Mark W. Burnham, Ellen L. Fessler, Michael B. Suratt, Benjamin T. Abraham, Edward Moss, Marc Malcolm, Kenneth C. TI Extremes of Interferon-Stimulated Gene Expression Associate with Worse Outcomes in the Acute Respiratory Distress Syndrome SO PLOS ONE LA English DT Article ID ACUTE LUNG INJURY; HEPATITIS-C VIRUS; BRONCHOALVEOLAR LAVAGE FLUID; I INTERFERON; BLOOD NEUTROPHILS; CIGARETTE-SMOKING; CLINICAL-OUTCOMES; INFLUENZA-VIRUS; MICROARRAY DATA; INFECTION AB Acute Respiratory Distress Syndrome (ARDS) severity may be influenced by heterogeneity of neutrophil activation. Interferon-stimulated genes (ISG) are a broad gene family induced by Type I interferons, often as a response to viral infections, which evokes extensive immunomodulation. We tested the hypothesis that over-or under-expression of immunomodulatory ISG by neutrophils is associated with worse clinical outcomes in patients with ARDS. Genome-wide transcriptional profiles of circulating neutrophils isolated from patients with sepsis-induced ARDS (n = 31) and healthy controls (n = 19) were used to characterize ISG expression. Hierarchical clustering of expression identified 3 distinct subject groups with Low, Mid and High ISG expression. ISG accounting for the greatest variability in expression were identified (MX1, IFIT1, and ISG15) and used to analyze a prospective cohort at the Colorado ARDS Network site. One hundred twenty ARDS patients from four urban hospitals were enrolled within 72 hours of initiation of mechanical ventilation. Circulating neutrophils were isolated from patients and expression of ISG determined by PCR. Samples were stratified by standard deviation from the mean into High (n = 21), Mid, (n = 82) or Low (n = 17) ISG expression. Clinical outcomes were compared between patients with High or Low ISG expression to those with Mid-range expression. At enrollment, there were no differences in age, gender, co-existing medical conditions, or type of physiologic injury between cohorts. After adjusting for age, race, gender and BMI, patients with either High or Low ISG expression had significantly worse clinical outcomes than those in the Mid for number of 28-day ventilator-and ICU-free days (P = 0.0006 and 0.0004), as well as 90-day mortality and 90-day home with unassisted breathing (P = 0.02 and 0.004). These findings suggest extremes of ISG expression by circulating neutrophils from ARDS patients recovered early in the syndrome are associated with poorer clinical outcomes. C1 [Nick, Jerry A.; Caceres, Silvia M.; Poch, Katie R.; Saavedra, Milene T.; Taylor-Cousar, Jennifer L.; Malcolm, Kenneth C.] Natl Jewish Hlth, Dept Med, Denver, CO 80206 USA. [Nichols, David P.] Natl Jewish Hlth, Dept Pediat, Denver, CO USA. [Strand, Matthew; Faino, Anna V.] Natl Jewish Hlth, Div Biostat & Bioinformat, Denver, CO USA. [Nick, Jerry A.; Saavedra, Milene T.; Taylor-Cousar, Jennifer L.; Geraci, Mark W.; Burnham, Ellen L.; Moss, Marc; Malcolm, Kenneth C.] Univ Colorado, Denver Sch Med, Div Pulm Sci & Crit Care Med, Dept Med, Aurora, CO 80045 USA. [Kret, Jennifer E.] St Louis Cty Dept Publ Hlth, Berkeley, MO USA. [Fessler, Michael B.] NIEHS, Immun Inflammat & Dis Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Suratt, Benjamin T.] Univ Vermont, Coll Med, Dept Med, Burlington, VT 05405 USA. [Abraham, Edward] Wake Forest Sch Med, Off Dean, Winston Salem, NC USA. RP Malcolm, KC (reprint author), Natl Jewish Hlth, Dept Med, Denver, CO 80206 USA.; Malcolm, KC (reprint author), Univ Colorado, Denver Sch Med, Div Pulm Sci & Crit Care Med, Dept Med, Aurora, CO 80045 USA. EM malcolmk@njhealth.org FU NIH [R01HL090991, P01 HL068743, Z01 ES102005]; NIH NHLBI ARDS Network; Cystic Fibrosis Foundation [NICK14G0]; Rebecca Runyon Bryan Chair for Cystic Fibrosis FX Funding provided by NIH R01HL090991 JAN, NIH P01 HL068743 MBS, NIH Z01 ES102005 (Intramural Research Program, NIEHS) MBS, NIH NHLBI ARDS Network MM, Cystic Fibrosis Foundation (NICK14G0) JAN and Rebecca Runyon Bryan Chair for Cystic Fibrosis. NR 76 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 SEP 8 PY 2016 VL 11 IS 9 AR e0162490 DI 10.1371/journal.pone.0162490 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV9JB UT WOS:000383255600050 PM 27606687 ER PT J AU Kotzin, JJ Spencer, SP McCright, SJ Kumar, DBU Collet, MA Mowel, WK Elliott, EN Uyar, A Makiya, MA Dunagin, MC Harman, CCD Virtue, AT Zhu, S Bailis, W Stein, J Hughes, C Raj, A Wherry, EJ Goff, LA Klion, AD Rinn, JL Williams, A Flavell, RA Henao-Mejia, J AF Kotzin, Jonathan J. Spencer, Sean P. McCright, Sam J. Kumar, Dinesh B. Uthaya Collet, Magalie A. Mowel, Walter K. Elliott, Ellen N. Uyar, Asli Makiya, Michelle A. Dunagin, Margaret C. Harman, Christian C. D. Virtue, Anthony T. Zhu, Stella Bailis, Will Stein, Judith Hughes, Cynthia Raj, Arjun Wherry, E. John Goff, Loyal A. Klion, Amy D. Rinn, John L. Williams, Adam Flavell, Richard A. Henao-Mejia, Jorge TI The long non-coding RNA Morrbid regulates Bim and short-lived myeloid cell lifespan SO NATURE LA English DT Article ID CHROMATIN; MACROPHAGES; HOMEOSTASIS; MONOCYTES; BCL-2; DIFFERENTIATION; VERNALIZATION; EXPRESSION; SURVIVAL; PRC2 AB Neutrophils, eosinophils and 'classical' monocytes collectively account for about 70% of human blood leukocytes and are among the shortest-lived cells in the body(1,2). Precise regulation of the lifespan of these myeloid cells is critical to maintain protective immune responses and minimize the deleterious consequences of prolonged inflammation(1,2). However, how the lifespan of these cells is strictly controlled remains largely unknown. Here we identify a long non-coding RNA that we termed Morrbid, which tightly controls the survival of neutrophils, eosinophils and classical monocytes in response to pro-survival cytokines in mice. To control the lifespan of these cells, Morrbid regulates the transcription of the neighbouring pro-apoptotic gene, Bcl2l11 (also known as Bim), by promoting the enrichment of the PRC2 complex at the Bcl2l11 promoter to maintain this gene in a poised state. Notably, Morrbid regulates this process in cis, enabling allele-specific control of Bcl2l11 transcription. Thus, in these highly inflammatory cells, changes in Morrbid levels provide a locus-specific regulatory mechanism that allows rapid control of apoptosis in response to extracellular pro-survival signals. As MORRBID is present in humans and dysregulated in individuals with hypereosinophilic syndrome, this long non-coding RNA may represent a potential therapeutic target for inflammatory disorders characterized by aberrant short-lived myeloid cell lifespan. C1 [Kotzin, Jonathan J.; Spencer, Sean P.; McCright, Sam J.; Mowel, Walter K.; Virtue, Anthony T.; Henao-Mejia, Jorge] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Kotzin, Jonathan J.; Spencer, Sean P.; McCright, Sam J.; Mowel, Walter K.; Virtue, Anthony T.; Wherry, E. John; Henao-Mejia, Jorge] Univ Penn, Perelman Sch Med, Inst Immunol, Philadelphia, PA 19104 USA. [Kumar, Dinesh B. Uthaya; Collet, Magalie A.; Elliott, Ellen N.; Uyar, Asli; Zhu, Stella; Williams, Adam] Jackson Lab Genom Med, Farmington, CT 06032 USA. [Kumar, Dinesh B. Uthaya; Williams, Adam] Univ Connecticut, Ctr Hlth, Dept Genet & Genom Sci, Farmington, CT 06032 USA. [Makiya, Michelle A.; Klion, Amy D.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Dunagin, Margaret C.; Raj, Arjun] Univ Penn, Dept Bioengn, Philadelphia, PA 19104 USA. [Harman, Christian C. D.; Bailis, Will; Stein, Judith; Hughes, Cynthia; Flavell, Richard A.] Yale Univ, Sch Med, Dept Immunobiol, 333 Cedar St, New Haven, CT 06520 USA. [Harman, Christian C. D.; Stein, Judith; Hughes, Cynthia; Flavell, Richard A.] Yale Univ, Howard Hughes Med Inst, New Haven, CT 06510 USA. [Wherry, E. John] Univ Penn, Perelman Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA. [Goff, Loyal A.] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. [Goff, Loyal A.] Johns Hopkins Univ, Dept Neurosci, Baltimore, MD 21205 USA. [Rinn, John L.] Harvard Med Sch, Biol & Biomed Sci, Boston, MA 02115 USA. [Rinn, John L.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Henao-Mejia, Jorge] Childrens Hosp Philadelphia, Div Transplant Immunol, Philadelphia, PA 19104 USA. [Spencer, Sean P.] Massachusetts Gen Hosp, Dept Med, 55 Fruit St, Boston, MA 02114 USA. RP Henao-Mejia, J (reprint author), Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA.; Henao-Mejia, J (reprint author), Univ Penn, Perelman Sch Med, Inst Immunol, Philadelphia, PA 19104 USA.; Williams, A (reprint author), Jackson Lab Genom Med, Farmington, CT 06032 USA.; Williams, A (reprint author), Univ Connecticut, Ctr Hlth, Dept Genet & Genom Sci, Farmington, CT 06032 USA.; Flavell, RA (reprint author), Yale Univ, Sch Med, Dept Immunobiol, 333 Cedar St, New Haven, CT 06520 USA.; Flavell, RA (reprint author), Yale Univ, Howard Hughes Med Inst, New Haven, CT 06510 USA.; Henao-Mejia, J (reprint author), Childrens Hosp Philadelphia, Div Transplant Immunol, Philadelphia, PA 19104 USA. EM adam.williams@jax.org; richard.flavell@yale.edu; jhena@mail.med.upenn.edu OI Mowel, Walter/0000-0003-2393-4300 FU Children's Hospital of Philadelphia; IFI; IDOM; COE at the University of Pennsylvania; NIH NIAID [1R21AI110776-01]; Howard Hughes Medical Institute; NIH NIDDK [T32-DK00778017]; NIH NRSA [F30-DK094708]; NSF [1350601]; Division of Intramural Research, NIAID, NIH; [T32-AI05542803]; [1DP2OD008514]; [1R33EB019767] FX We thank several of our colleagues for critically reading our manuscript and their suggestions. J.H.-M. was supported by the Children's Hospital of Philadelphia, the IFI and IDOM pilot projects, and the COE at the University of Pennsylvania (J.H.-M.); A.W. and R.A.F. by NIH NIAID 1R21AI110776-01; C.C.D.H. and R.A.F by Howard Hughes Medical Institute; J.J.K. by NIH NIDDK T32-DK00778017; S.P.S. by NIH NRSA F30-DK094708; W.K.M. by T32-AI05542803; A.R. and M.C.D. by New Innovator 1DP2OD008514, 1R33EB019767, NSF CAREER 1350601. This work was funded in part by the Division of Intramural Research, NIAID, NIH (M.A.M. and A.D.K.) NR 26 TC 2 Z9 2 U1 15 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 SEP 8 PY 2016 VL 537 IS 7619 BP 239 EP + DI 10.1038/nature19346 PG 26 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DU9LQ UT WOS:000382539100049 PM 27525555 ER PT J AU Bender, E Hudson, K AF Bender, Eric Hudson, Kathy TI Q&A: Kathy Hudson Precision medicine goes megascale SO NATURE LA English DT Editorial Material C1 [Hudson, Kathy] US Natl Inst Hlth NIH, Sci Outreach & Policy, Bethesda, MD 20892 USA. RP Hudson, K (reprint author), US Natl Inst Hlth NIH, Sci Outreach & Policy, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 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 SEP 8 PY 2016 VL 537 IS 7619 BP S69 EP S69 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DU9LQ UT WOS:000382539100007 PM 27602746 ER PT J AU Kumar, SS Sun, YN Zou, SG Hong, JR AF Kumar, S. Santosh Sun, Yaning Zou, Sige Hong, Jiarong TI 3D Holographic Observatory for Long-term Monitoring of Complex Behaviors in Drosophila SO SCIENTIFIC REPORTS LA English DT Article ID IN-LINE HOLOGRAPHY; 3-DIMENSIONAL TRACKING; MICROSCOPY; DISEASE AB Drosophila is an excellent model organism towards understanding the cognitive function, aging and neurodegeneration in humans. The effects of aging and other long-term dynamics on the behavior serve as important biomarkers in identifying such changes to the brain. In this regard, we are presenting a new imaging technique for lifetime monitoring of Drosophila in 3D at spatial and temporal resolutions capable of resolving the motion of limbs and wings using holographic principles. The developed system is capable of monitoring and extracting various behavioral parameters, such as ethograms and spatial distributions, from a group of flies simultaneously. This technique can image complicated leg and wing motions of flies at a resolution, which allows capturing specific landing responses from the same data set. Overall, this system provides a unique opportunity for high throughput screenings of behavioral changes in 3D over a long term in Drosophila. C1 [Kumar, S. Santosh; Hong, Jiarong] Univ Minnesota, Dept Mech Engn, Minneapolis, MN 55455 USA. [Kumar, S. Santosh; Hong, Jiarong] Univ Minnesota, St Anthony Falls Lab, Minneapolis, MN 55414 USA. [Sun, Yaning; Zou, Sige] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. RP Hong, JR (reprint author), Univ Minnesota, Dept Mech Engn, Minneapolis, MN 55455 USA.; Hong, JR (reprint author), Univ Minnesota, St Anthony Falls Lab, Minneapolis, MN 55414 USA. EM jhong@umn.edu FU Jiarong Hong's Start-up package; NIH; Intramural Research Program at the National Institute on Aging, NIH FX This research was supported by Jiarong Hong's Start-up package as well as support from NIH. We would like to thank Dr. Michael B O'Conner for access to his lab and resources for making our fly food along with providing us with fly supplies and other relevant equipment. Additionally, we would like to acknowledge the work done by undergraduates of our group, Kishok Kumar and Samuel Hu, in maintaining the fly cultures, collection and sorting of flies and preparing the sugar-yeast food used in the experiment. This work was partially supported by the fund to S. Z. from the Intramural Research Program at the National Institute on Aging, NIH. NR 28 TC 0 Z9 0 U1 0 U2 0 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 SEP 8 PY 2016 VL 6 AR 33001 DI 10.1038/srep33001 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV1AL UT WOS:000382652200001 PM 27605243 ER PT J AU Panico, M Bouche, L Binet, D O'Connor, MJ Rahman, D Pang, PC Canis, K North, SJ Desrosiers, RC Chertova, E Keele, BF Bess, JW Lifson, JD Haslam, SM Dell, A Morris, HR AF Panico, Maria Bouche, Laura Binet, Daniel O'Connor, Michael-John Rahman, Dinah Pang, Poh-Choo Canis, Kevin North, Simon J. Desrosiers, Ronald C. Chertova, Elena Keele, Brandon F. Bess, Julian W., Jr. Lifson, Jeffrey D. Haslam, Stuart M. Dell, Anne Morris, Howard R. TI Mapping the complete glycoproteome of virion-derived HIV-1 gp120 provides insights into broadly neutralizing antibody binding SO SCIENTIFIC REPORTS LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; MASS-SPECTROMETRIC ANALYSIS; HAMSTER OVARY CELLS; ENVELOPE GLYCOPROTEIN; GLYCAN SHIELD; GLYCOSYLATION PROFILES; STRUCTURAL BASIS; 2G12 RECOGNIZES; PROTEINS; INFECTIVITY AB The surface envelope glycoprotein (SU) of Human immunodeficiency virus type 1 (HIV-1), gp120(SU) plays an essential role in virus binding to target CD4+ T-cells and is a major vaccine target. Gp120 has remarkably high levels of N-linked glycosylation and there is considerable evidence that this "glycan shield" can help protect the virus from antibody-mediated neutralization. In recent years, however, it has become clear that gp120 glycosylation can also be included in the targets of recognition by some of the most potent broadly neutralizing antibodies. Knowing the site-specific glycosylation of gp120 can facilitate the rational design of glycopeptide antigens for HIV vaccine development. While most prior studies have focused on glycan analysis of recombinant forms of gp120, here we report the first systematic glycosylation site analysis of gp120 derived from virions produced by infected T lymphoid cells and show that a single site is exclusively substituted with complex glycans. These results should help guide the design of vaccine immunogens. C1 [Panico, Maria; Bouche, Laura; Rahman, Dinah; Pang, Poh-Choo; Canis, Kevin; North, Simon J.; Haslam, Stuart M.; Dell, Anne; Morris, Howard R.] Imperial Coll London, Dept Life Sci, South Kensington Campus, London SW7 2AZ, England. [Binet, Daniel; O'Connor, Michael-John; Morris, Howard R.] BioPharmaSpec, Suite 3-1 Lido Med Ctr,St Saviours Rd, Jersey JE2 7LA, England. [Desrosiers, Ronald C.] Univ Miami, Dept Pathol, Miami, FL 33136 USA. [Chertova, Elena; Keele, Brandon F.; Bess, Julian W., Jr.; Lifson, Jeffrey D.] Leidos Biomedical Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Canis, Kevin] SGS M Scan SA, Geneva, Switzerland. RP Dell, A (reprint author), Imperial Coll London, Dept Life Sci, South Kensington Campus, London SW7 2AZ, England. EM a.dell@imperial.ac.uk FU Biotechnology and Biological Sciences Research Council [BB/K016164/1, BB/F008309/1]; National Cancer Institute; National Institutes of Health [HHSN261200800001E] FX This study was supported by grants BB/K016164/1 and BB/F008309/1 from the Biotechnology and Biological Sciences Research Council (to A.D., S.M.H. and H.R.M.). A.D. is a Wellcome Trust Senior Research Investigator. This work was supported 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. We thank Rodman Smith and Dave Westcott for the large scale production and purification of HIV, Terra Ireland for viral tropism and infectivity assays (all from the Biological Product Core) and Charles M. Trubey (from the Cellular Immunity Core) for flow cytometry analysis, all from the AIDS and Cancer Virus Program, Frederick National Laboratory. The TZM-bl cell line was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: TZM-bl from Dr. John C. Kappes, Dr. Xiaoyun Wu and Tranzyme Inc. NR 52 TC 3 Z9 3 U1 9 U2 9 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 SEP 8 PY 2016 VL 6 AR 32956 DI 10.1038/srep32956 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV0ZZ UT WOS:000382650800001 PM 27604319 ER PT J AU Van Doorslaer, K McBride, AA AF Van Doorslaer, Koenraad McBride, Alison A. TI Molecular archeological evidence in support of the repeated loss of a papillomavirus gene SO SCIENTIFIC REPORTS LA English DT Article ID PHYLOGENETIC ANALYSIS; CAPSID PROTEIN; E7 PROTEINS; E5 PROTEINS; EVOLUTION; SELECTION; E6; SUBSTITUTION; MAFFT; TIMESCALE AB It is becoming clear that, in addition to gene gain, the loss of genes may be an important evolutionary mechanism for many organisms. However, gene loss is often associated with an increased mutation rate, thus quickly erasing evidence from the genome. The analysis of evolutionarily related sequences can provide empirical evidence for gene loss events. This paper analyzes the sequences of over 300 genetically distinct papillomaviruses and provides evidence for a role of gene loss during the evolution of certain papillomavirus genomes. Phylogenetic analysis suggests that the viral E6 gene was lost at least twice. Despite belonging to distant papillomaviral genera, these viruses lacking a canonical E6 protein may potentially encode a highly hydrophobic protein from an overlapping open reading frame, which we designate E10. Evolutionary pressure working on this alternative frame, may explain why, despite having lost the E6 open reading frame between 20 and 60 million years ago, evidence of an E6-like protein is conserved. C1 [Van Doorslaer, Koenraad; McBride, Alison A.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Van Doorslaer, K (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM Koenraad.vandoorslaer@gmail.com OI Van Doorslaer, Koenraad/0000-0002-2985-0733 FU Intramural Research Program of the NIAID, NIH [ZIAAI000713] FX This research was supported by the Intramural Research Program of the NIAID, NIH (grant number ZIAAI000713). NR 53 TC 2 Z9 2 U1 2 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 SEP 8 PY 2016 VL 6 AR 33028 DI 10.1038/srep33028 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV1AS UT WOS:000382652900002 PM 27604338 ER PT J AU Yanpallewar, S Wang, T Koh, DCI Quarta, E Fulgenzi, G Tessarollo, L AF Yanpallewar, Sudhirkumar Wang, Ting Koh, Dawn C. I. Quarta, Eros Fulgenzi, Gianluca Tessarollo, Lino TI Nedd4-2 haploinsufficiency causes hyperactivity and increased sensitivity to inflammatory stimuli SO SCIENTIFIC REPORTS LA English DT Article ID GATED SODIUM-CHANNELS; UBIQUITIN LIGASE NEDD4-2; NGF-MEDIATED FUNCTIONS; BRAIN; GENE; MICE; TRKA; HYPERTENSION; EPILEPSY; HYPERPHAGIA AB Nedd4-2 (NEDD4L in humans) is a ubiquitin protein ligase best known for its role in regulating ion channel internalization and turnover. Nedd4-2 deletion in mice causes perinatal lethality associated with increased epithelial sodium channel (ENaC) expression in lung and kidney. Abundant data suggest that Nedd4-2 plays a role in neuronal functions and may be linked to epilepsy and dyslexia in humans. We used a mouse model of Nedd4-2 haploinsufficiency to investigate whether an alteration in Nedd4-2 levels of expression affects general nervous system functions. We found that Nedd4-2 heterozygous mice are hyperactive, have increased basal synaptic transmission and have enhanced sensitivity to inflammatory pain. Thus, Nedd4-2 heterozygous mice provide a new genetic model to study inflammatory pain. These data also suggest that in human, SNPs affecting NEDD4L levels may be involved in the development of neuropsychological deficits and peripheral neuropathies and may help unveil the genetic basis of comorbidities. C1 [Yanpallewar, Sudhirkumar; Wang, Ting; Koh, Dawn C. I.; Quarta, Eros; Fulgenzi, Gianluca; Tessarollo, Lino] NCI, Neural Dev Sect, Mouse Canc Genet Program, CCR, Frederick, MD 21702 USA. [Quarta, Eros] Univ Florence, Physiol Sci Sect, Dept Expt & Clin Med, I-50121 Florence, Italy. [Fulgenzi, Gianluca] Marche Polytech Univ, Dept Mol & Clin Sci, Ancona, Italy. [Koh, Dawn C. I.] Singapore Univ Technol & Design, Singapore 487372, Singapore. RP Tessarollo, L (reprint author), NCI, Neural Dev Sect, Mouse Canc Genet Program, CCR, Frederick, MD 21702 USA. EM tessarol@mail.nih.gov OI Fulgenzi, Gianluca/0000-0003-2646-7728 FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX We thank Eileen Southon, Colleen Barrick and Jodi Becker for excellent technical assistance with the generation and analysis of the Nedd4-2 mutant mouse. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 40 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 SEP 8 PY 2016 VL 6 AR 32957 DI 10.1038/srep32957 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV0ZZ UT WOS:000382650800002 PM 27604420 ER PT J AU Burnett, CJ Krashes, MJ AF Burnett, C. Joseph Krashes, Michael J. TI Resolving Behavioral Output via Chemogenetic Designer Receptors Exclusively Activated by Designer Drugs SO JOURNAL OF NEUROSCIENCE LA English DT Article DE behavior; cell-type specificity; chemogenetics; DREADD ID RAPHE SEROTONERGIC NEURONS; PROTEIN-COUPLED RECEPTORS; CHEMICAL-GENETIC APPROACH; VENTRAL TEGMENTAL AREA; AGOUTI-RELATED PROTEIN; BETA-CELL FUNCTION; CLOZAPINE-N-OXIDE; IN-VIVO; FOOD-INTAKE; PARAVENTRICULAR NUCLEUS AB Designer receptors exclusively activated by designer drugs (DREADDs) have proven to be highly effective neuromodulatory tools for the investigation of neural circuits underlying behavioral outputs. They exhibit a number of advantages: they rely on cell-specific manipulations through canonical intracellular signaling pathways, they are easy and cost-effective to implement in a laboratory setting, and they are easily scalable for single-region or full-brain manipulations. On the other hand, DREADDs rely on ligand-G-protein-coupled receptor interactions, leading to coarse temporal dynamics. In this review we will provide a brief overview of DREADDs, their implementation, and the advantages and disadvantages of their use in animal systems. We also will provide numerous examples of their use across a broad variety of biomedical research fields. C1 [Burnett, C. Joseph; Krashes, Michael J.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Burnett, C. Joseph; Krashes, Michael J.] NIDA, NIH, Baltimore, MD 21224 USA. [Burnett, C. Joseph] Brown Univ, NIH, Grad Partnerships Program, Providence, RI 02912 USA. RP Krashes, MJ (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA.; Krashes, MJ (reprint author), NIDA, NIH, Baltimore, MD 21224 USA. EM michael.krashes@nih.gov FU Intramural Research Program of the National Institutes of Health, The National Institutes of Diabetes and Digestive and Kidney Diseases [DK075087, DK075089] FX This work was supported by the Intramural Research Program of the National Institutes of Health, The National Institutes of Diabetes and Digestive and Kidney Diseases [DK075087 (M.J.K.), DK075089 (M.J.K.)]. We thank Bryan L. Roth for guidance. NR 142 TC 0 Z9 0 U1 11 U2 11 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 SEP 7 PY 2016 VL 36 IS 36 BP 9268 EP 9282 DI 10.1523/JNEUROSCI.1333-16.2016 PG 15 WC Neurosciences SC Neurosciences & Neurology GA DW9TT UT WOS:000384006300002 PM 27605603 ER PT J AU de Guglielmo, G Crawford, E Kim, S Vendruscolo, LF Hope, BT Brennan, M Cole, M Koob, GF George, O AF de Guglielmo, Giordano Crawford, Elena Kim, Sarah Vendruscolo, Leandro F. Hope, Bruce T. Brennan, Molly Cole, Maury Koob, George F. George, Olivier TI Recruitment of a Neuronal Ensemble in the Central Nucleus of the Amygdala Is Required for Alcohol Dependence SO JOURNAL OF NEUROSCIENCE LA English DT Article DE addiction; alcohol; CeA; Daun02; dependence; neuronal ensembles ID CONTEXT-SPECIFIC SENSITIZATION; ETHANOL-CONSUMPTION; RATS; DRINKING; SEEKING; CORTEX; ADDICTION; ACCUMBENS; RELAPSE; MODEL AB Abstinence from alcohol is associated with the recruitment of neurons in the central nucleus of the amygdala (CeA) in nondependent rats that binge drink alcohol and in alcohol-dependent rats. However, whether the recruitment of this neuronal ensemble in the CeAis causally related to excessive alcohol drinking or if it represents a consequence of excessive drinking remains unknown. We tested the hypothesis that the recruitment of a neuronal ensemble in the CeA during abstinence is required for excessive alcohol drinking in nondependent rats that binge drink alcohol and in alcohol-dependent rats. We found that inactivation of the CeA neuronal ensemble during abstinence significantly decreased alcohol drinking in both groups. In nondependent rats, the decrease in alcohol intake was transient and returned to normal the day after the injection. In dependent rats, inactivation of the neuronal ensemble with Daun02 produced a long-term decrease in alcohol drinking. Moreover, we observed a significant reduction of somatic withdrawal signs in dependent animals that were injected with Daun02 in the CeA. These results indicate that the recruitment of a neuronal ensemble in the CeA during abstinence from alcohol is causally related to excessive alcohol drinking in alcohol-dependent rats, whereas a similar neuronal ensemble only partially contributed to alcohol-binge-like drinking in nondependent rats. These results identify a critical neurobiological mechanism that may be required for the transition to alcohol dependence, suggesting that focusing on the neuronal ensemble in the CeA may lead to a better understanding of the etiology of alcohol use disorders and improve medication development. C1 [de Guglielmo, Giordano; Crawford, Elena; Kim, Sarah; Vendruscolo, Leandro F.; Brennan, Molly; Cole, Maury; Koob, George F.; George, Olivier] Scripps Res Inst, Committee Neurobiol Addict Disorders, 10550 North Torrey Pines Rd,SP30-2400, La Jolla, CA 92037 USA. [Hope, Bruce T.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP George, O (reprint author), Scripps Res Inst, Committee Neurobiol Addict Disorders, 10550 North Torrey Pines Rd,SP30-2400, La Jolla, CA 92037 USA. EM ogeorge@scripps.edu RI koob, george/P-8791-2016; Hope, Bruce/A-9223-2010 OI Hope, Bruce/0000-0001-5804-7061 FU National Institutes of Health [AA006420, AA020608, AA022977]; National Institute on Drug Abuse Intramural Research Program; Pearson Center for Alcohol and Addiction Research FX This work was supported by the National Institutes of Health (Grants AA006420, AA020608, and AA022977 to O.G.), the National Institute on Drug Abuse Intramural Research Program (B.T.H.), and the Pearson Center for Alcohol and Addiction Research. NR 34 TC 2 Z9 2 U1 3 U2 3 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 SEP 7 PY 2016 VL 36 IS 36 BP 9446 EP 9453 DI 10.1523/JNEUROSCI.1395-16.2016 PG 8 WC Neurosciences SC Neurosciences & Neurology GA DW9TT UT WOS:000384006300017 PM 27605618 ER PT J AU Smith, JB Klug, JR Ross, DL Howard, CD Hollon, NG Ko, VI Hoffman, H Callaway, EM Gerfen, CR Jin, X AF Smith, Jared B. Klug, Jason R. Ross, Danica L. Howard, Christopher D. Hollon, Nick G. Ko, Vivian I. Hoffman, Hilary Callaway, Edward M. Gerfen, Charles R. Jin, Xin TI Genetic-Based Dissection Unveils the Inputs and Outputs of Striatal Patch and Matrix Compartments SO NEURON LA English DT Article ID MU-OPIOID RECEPTOR; BASAL GANGLIA CIRCUITS; PROJECTION NEURONS; RAT STRIATUM; SUBSTANTIA NIGRA; CORTICAL INPUTS; RABIES VIRUS; BED NUCLEUS; MONKEY; ORGANIZATION AB The striatum contains neurochemically defined compartments termed patches and matrix. Previous studies suggest patches preferentially receive limbic inputs and project to dopamine neurons in substantia nigra pars compacta (SNc), whereas matrix neurons receive sensorimotor inputs and do not innervate SNc. Using BAC-Cre transgenic mice with viral tracing techniques, we mapped brain-wide differences in the input-output organization of the patch/matrix. Findings reveal a displaced population of striatal patch neurons termed "exo-patch,'' which reside in matrix zones but have neurochemistry, connectivity, and electrophysiological characteristics resembling patch neurons. Contrary to previous studies, results show patch/exo-patch and matrix neurons receive both limbic and sensorimotor information. A novel inhibitory projection from bed nucleus of the stria terminalis to patch/exo-patch neurons was revealed. Projections to SNc were found to originate from patch/exo-patch and matrix neurons. These findings redefine patch/matrix beyond traditional neurochemical topography and reveal new principles about their input-output connectivity, providing a foundation for future functional studies. C1 [Smith, Jared B.; Klug, Jason R.; Ross, Danica L.; Howard, Christopher D.; Hollon, Nick G.; Ko, Vivian I.; Hoffman, Hilary; Jin, Xin] Salk Inst Biol Studies, Mol Neurobiol Lab, La Jolla, CA 92037 USA. [Callaway, Edward M.] Salk Inst Biol Studies, Syst Neurobiol Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. [Gerfen, Charles R.] NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA. RP Jin, X (reprint author), Salk Inst Biol Studies, Mol Neurobiol Lab, La Jolla, CA 92037 USA. EM xjin@salk.edu FU NIH [R01NS083815, RF1AG047669]; Dana Foundation; Ellison Medical Foundation; Whitehall Foundation FX The authors thank Brian Mathur for comments on the manuscript and acknowledge the laboratory of Fred Gage for conversations regarding BrdU experiments. This work was supported by grants from the NIH (R01NS083815 and RF1AG047669), the Dana Foundation, the Ellison Medical Foundation, and the Whitehall Foundation to X.J. NR 58 TC 2 Z9 2 U1 6 U2 6 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 SEP 7 PY 2016 VL 91 IS 5 BP 1069 EP 1084 DI 10.1016/j.neuron.2016.07.046 PG 16 WC Neurosciences SC Neurosciences & Neurology GA DW2HH UT WOS:000383463000013 PM 27568516 ER PT J AU Bourret, TJ Lawrence, KA Shaw, JA Lin, T Norris, SJ Gherardini, FC AF Bourret, Travis J. Lawrence, Kevin A. Shaw, Jeff A. Lin, Tao Norris, Steven J. Gherardini, Frank C. TI The Nucleotide Excision Repair Pathway Protects Borrelia burgdorferi from Nitrosative Stress in Ixodes scapularis Ticks SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE Borrelia; Lyme disease; nitric oxide; oxidative stress; DNA repair ID PERITROPHIC MATRIX PROTEIN; BUG RHODNIUS-PROLIXUS; A DISULFIDE REDUCTASE; NITRIC-OXIDE SYNTHASE; LYME-DISEASE; ANOPHELES-GAMBIAE; DERMACENTOR-VARIABILIS; GENE-EXPRESSION; SALIVARY-GLANDS; MAMMALIAN HOST AB The Lyme disease spirochete Borrelia burgdorferi encounters a wide range of environmental conditions as it cycles between ticks of the genus lxodes and its various mammalian hosts. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are potent antimicrobial molecules generated during the innate immune response to infection, however, it is unclear whether ROS and RNS pose a significant challenge to B. burgdorferi in vivo. In this study, we screened a library of B. burgdorferi strains with mutations in DNA repair genes for increased susceptibility to ROS or RNS in vitro. Strains with mutations in the methyl-directed mismatch repair gene mutS1 are hypersensitive to killing by ROS, while strains lacking the nucleotide excision repair (N ER) gene uvrB show increased susceptibility to both ROS and RNS. Therefore, mutS1-deficient and uvrB-deficient strains were compared for their ability to complete their infectious cycle in Swiss Webster mice and I. scapularis ticks to help identify sites of oxidative and nitrosative stresses encountered by B. burgdorferi in vivo. Both mutS1 and uvrB were dispensable for infection of mice, while uvrB promoted the survival of spirochetes in I. scapularis ticks. The decreased survival of uvrB-deficient B. burgdorferi was associated with the generation of RNS in I. scapular's midguts and salivary glands during feeding. Collectively, these data suggest that B. burgdorferi must withstand cytotoxic levels of RNS produced during infection of I. scapular's ticks. C1 [Bourret, Travis J.; Shaw, Jeff A.] Creighton Univ, Dept Med Microbiol & Immunol, Omaha, NE 68178 USA. [Lawrence, Kevin A.; Gherardini, Frank C.] NIAID, Gene Regulat Sect, Lab Zoonot Pathogens, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. [Lin, Tao; Norris, Steven J.] Univ Texas Hlth Sci Ctr Houston, Dept Pathol & Lab Med, McGovern Med Sch, Houston, TX 77030 USA. RP Bourret, TJ (reprint author), Creighton Univ, Dept Med Microbiol & Immunol, Omaha, NE 68178 USA. EM travisbourret@creighton.edu OI Bourret, Travis/0000-0002-4154-929X FU National Center for Research Resources [5P20RR016469]; National Institute for General Medical Science (NIGMS) [5P20GM103427]; Intramural Research Program of the NIH, National Institute for Allergy and Infectious Diseases FX This work was supported in part by the National Center for Research Resources (5P20RR016469), the National Institute for General Medical Science (NIGMS; 5P20GM103427) and the Intramural Research Program of the NIH, National Institute for Allergy and Infectious Diseases. NR 48 TC 2 Z9 2 U1 5 U2 5 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 SEP 7 PY 2016 VL 7 AR 1397 DI 10.3389/fmicb.2016.01397 PG 13 WC Microbiology SC Microbiology GA DU9GO UT WOS:000382524700001 PM 27656169 ER PT J AU Seidman, JC Johnson, LB Levens, J Mkocha, H Munoz, B Silbergeld, EK West, SK Coles, CL AF Seidman, Jessica C. Johnson, Lashaunda B. Levens, Joshua Mkocha, Harran Munoz, Beatriz Silbergeld, Ellen K. West, Sheila K. Coles, Christian L. TI Longitudinal Comparison of Antibiotic Resistance in Diarrheagenic and Non-pathogenic Escherichia coli from Young Tanzanian Children SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE antibiotic resistance; diarrheagenic E. coli; Tanzania; non-pathogenic E. coli; children ID EARLY-CHILDHOOD DIARRHEA; ANTIMICROBIAL RESISTANCE; DEVELOPING-COUNTRIES; MASS-DISTRIBUTION; TRACHOMA CONTROL; STREPTOCOCCUS-PNEUMONIAE; AZITHROMYCIN; COMMUNITY; CARRIAGE; RISK AB Enteroaggregatiye, enteropathogenic, and enterotoxigenic Escherichia coli contribute significantly to the burden of diarrheal infections particularly in developing countries. Antibiotic resistance is increasingly common among bacterial pathogens including pathogenic E. coli. We assessed the relationship between pathogenic E. coli carriage and resistance to six antibiotics in E coli isolated from young children in rural Tanzania. We surveyed temporal stability in antibiotic resistance in 2492 E. coli isolated from fecal samples obtained from young children in rural Tanzania collected over a 6 months period. Approximately half of the 377 children sampled were exposed to an azithromycin mass treatment program for trachoma control and half resided in control villages. Children were sampled at baseline, 1-, 3-, and 6 months following azithromycin treatment. We compared resistance to six antibiotics in pathogenic and non-pathogenic strains at the population level, within fecal specimens, and within individuals over time using chi-square tests, paired odds ratios, and logistic regression, respectively. Resistance to ampicillin and trimethoprim/sulfamethoxazole was highly prevalent (>65%). Resistance to 5 of 6 antibiotics tested and multi drug resistance occurred more frequently in pathogenic isolates (p <= 0.001) within fecal specimens and overall. Azithromycin mass treatment exposure was significantly associated with increased odds of carriage of isolates resistant to erythromycin (OR 3.64, p < 0.001) and trimethoprim/sulfamethoxazole (OR 1.60, p < 0.05). Pathogenic isolates were approximately twice as likely to be resistant to erythromycin, ampicillin, or trimethoprim/sulfamethoxazole compared to non-pathogenic isolates from the same fecal specimen. The potential linkage between resistance and virulence in E. coli suggests hygiene and sanitation interventions aimed at reducing disease burden could play a role in controlling transmission of antibiotic resistance. C1 [Seidman, Jessica C.] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Johnson, Lashaunda B.] Morgan State Univ, Dept Biol, Baltimore, MD 21239 USA. [Levens, Joshua] CTS Global, Dar Es Salaam, Tanzania. [Mkocha, Harran] Kongwa Trachoma Project, Kongwa, Tanzania. [Munoz, Beatriz; West, Sheila K.] Johns Hopkins Univ, Wilmer Eye Inst, Dana Ctr Prevent Ophthalmol, Baltimore, MD 21218 USA. [Silbergeld, Ellen K.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth, Baltimore, MD USA. [Coles, Christian L.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. RP Seidman, JC (reprint author), NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM seidmanj@mail.nih.gov FU Johns Hopkins Global Water Program; Bill & Melinda Gates Foundation, Seattle, WA, USA [48027]; Research to Prevent Blindness FX This work was supported by a grant from the Johns Hopkins Global Water Program. The PRET+ study was funded by a grant from the Bill & Melinda Gates Foundation, Seattle, WA, USA (#48027) and an unrestricted grant from Research to Prevent Blindness. Pfizer, Inc. donated the azithromycin for the study. Dr. West has a Senior Scientific Award from Research to Prevent Blindness. NR 48 TC 0 Z9 0 U1 5 U2 5 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 SEP 7 PY 2016 VL 7 AR 1420 DI 10.3389/fmicb.2016.01420 PG 8 WC Microbiology SC Microbiology GA DU9GT UT WOS:000382525300003 PM 27656179 ER PT J AU Chen, X Nie, YJ Xiao, HT Bian, ZX Scarzello, AJ Song, NY Anna, TL Yang, D Oppenheim, JJ AF Chen, Xin Nie, Yingjie Xiao, Haitao Bian, Zhaoxiang Scarzello, Anthony J. Song, Na-Young Anna, Trivett L. Yang, De Oppenheim, Joost J. TI TNFR2 expression by CD4 effector T cells is required to induce full-fledged experimental colitis SO SCIENTIFIC REPORTS LA English DT Article ID TUMOR-NECROSIS-FACTOR; INFLAMMATORY-BOWEL-DISEASE; COMMON VARIABLE IMMUNODEFICIENCY; CHRONIC INTESTINAL INFLAMMATION; FACTOR RECEPTOR; CROHNS-DISEASE; IN-VIVO; REGULATORY-CELLS; MICE; ALPHA AB There is now compelling evidence that TNFR2 is constitutively expressed on CD4(+) Foxp3(+) regulatory T cells (Tregs) and TNF-TNFR2 interaction is critical for the activation, expansion and functional stability of Tregs. However, we showed that the expression of TNFR2 was also up-regulated on CD4+ Foxp3(-) effector T cells (Teffs) upon TCR stimulation. In order to define the role of TNFR2 in the pathogenic CD4 T cells, we compared the effect of transferred naive CD4 cells from WT mice and TNFR2(-/-) mice into Rag 1(-/-) recipients. Transfer of TNFR2-deficient Teff cells failed to induce full-fledged colitis, unlike WT Teffs. This was due to defective proliferative expansion of TNFR2-deficient Teff cells in the lymphopenic mice, as well as their reduced capacity to express proinflammatory Th1 cytokine on a per cell basis. In vitro, the proliferative response of TNFR2 deficient naive CD4 cells to anti-CD3 stimulation was markedly decreased as compared with that of WT naive CD4 cells. The hypoproliferative response of TNFR2-deficient Teff cells to TCR stimulation was associated with an increased ratio of p100/p52, providing a mechanistic basis for our findings. Therefore, this study clearly indicates that TNFR2 is important for the proliferative expansion of pathogenic Teff cells. C1 [Chen, Xin] Univ Macau, Inst Chinese Med Sci, State Key Lab Qual Res Chinese Med, Macau, Macau SAR, Peoples R China. [Chen, Xin; Nie, Yingjie; Xiao, Haitao; Scarzello, Anthony J.; Song, Na-Young; Anna, Trivett L.; Yang, De; Oppenheim, Joost J.] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Xiao, Haitao; Bian, Zhaoxiang] Hong Kong Baptist Univ, Sch Chinese Med, Kowloon, Hong Kong, Peoples R China. RP Chen, X (reprint author), Univ Macau, Inst Chinese Med Sci, State Key Lab Qual Res Chinese Med, Macau, Macau SAR, Peoples R China.; Chen, X; Oppenheim, JJ (reprint author), NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. EM xchen@umac.mo; oppenhej@mail.nih.gov RI Chen, Xin/I-6601-2015 OI Chen, Xin/0000-0002-2628-4027 FU federal funds from the National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; University of Macau [SRG2014-00024-ICMS-QRCM, MYRG2016-00023-ICMS-QRCM]; FDCT grant from Science and Technology Development Fund (FDCT), Macao S.A.R. [011/2015/A] 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 HHSN261200800001E. This Research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This project was also supported by grants SRG2014-00024-ICMS-QRCM, MYRG2016-00023-ICMS-QRCM from the University of Macau and FDCT grant 011/2015/A from the Science and Technology Development Fund (FDCT), Macao S.A.R. The authors thank Mses. O.M. Zack Howard, Qiong Zhou, Czarra T. Kelli and Julie Hixon for their help in this study. We thank NCI-Frederick Cancer and Inflammation Program Fluorescence Cytometry core (Mses. Kathleen B. Noer, Roberta M. Matthai and GuityMohammadi) for expert technical assistance with flow cytometry. NR 58 TC 1 Z9 1 U1 7 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 SEP 7 PY 2016 VL 6 AR 32834 DI 10.1038/srep32834 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV0MN UT WOS:000382611800001 PM 27601345 ER PT J AU Darabi, H Beesley, J Droit, A Kar, S Nord, S Marjaneh, MM Soucy, P Michailidou, K Ghoussaini, M Wahl, HF Bolla, MK Wang, Q Dennis, J Alonso, MR Andrulis, IL Anton-Culver, H Arndt, V Beckmann, MW Benitez, J Bogdanova, NV Bojesen, SE Brauch, H Brenner, H Broeks, A Bruning, T Burwinkel, B Chang-Claude, J Choi, JY Conroy, DM Couch, FJ Cox, A Cross, SS Czene, K Devilee, P Dork, T Easton, DF Fasching, PA Figueroa, J Fletcher, O Flyger, H Galle, E Garcia-Closas, M Giles, GG Goldberg, MS Gonzalez-Neira, A Guenel, P Haiman, CA Hallberg, E Hamann, U Hartman, M Hollestelle, A Hopper, JL Ito, H Jakubowska, A Johnson, N Kang, D Khan, S Kosma, VM Kriege, M Kristensen, V Lambrechts, D Le Marchand, L Lee, SC Lindblom, A Lophatananon, A Lubinski, J Mannermaa, A Manoukian, S Margolin, S Matsuo, K Mayes, R Mckay, J Meindl, A Milne, RL Muir, K Neuhausen, SL Nevanlinna, H Olswold, C Orr, N Peterlongo, P Pita, G Pylkas, K Rudolph, A Sangrajrang, S Sawyer, EJ Schmidt, MK Schmutzler, RK Seynaeve, C Shah, M Shen, CY Shu, XO Southey, MC Stram, DO Surowy, H Swerdlow, A Teo, SH Tessier, DC Tomlinson, I Torres, D Truong, T Vachon, CM Vincent, D Winqvist, R Wu, AH Wu, PE Yip, CH Zheng, W Pharoah, PDP Hall, P Edwards, SL Simard, J French, JD Chenevix-Trench, G Dunning, AM AF Darabi, Hatef Beesley, Jonathan Droit, Arnaud Kar, Siddhartha Nord, Silje Marjaneh, Mahdi Moradi Soucy, Penny Michailidou, Kyriaki Ghoussaini, Maya Wahl, Hanna Fues Bolla, Manjeet K. Wang, Qin Dennis, Joe Alonso, M. Rosario Andrulis, Irene L. Anton-Culver, Hoda Arndt, Volker Beckmann, Matthias W. Benitez, Javier Bogdanova, Natalia V. Bojesen, Stig E. Brauch, Hiltrud Brenner, Hermann Broeks, Annegien Bruening, Thomas Burwinkel, Barbara Chang-Claude, Jenny Choi, Ji-Yeob Conroy, Don M. Couch, Fergus J. Cox, Angela Cross, Simon S. Czene, Kamila Devilee, Peter Doerk, Thilo Easton, Douglas F. Fasching, Peter A. Figueroa, Jonine Fletcher, Olivia Flyger, Henrik Galle, Eva Garcia-Closas, Montserrat Giles, Graham G. Goldberg, Mark S. Gonzalez-Neira, Anna Guenel, Pascal Haiman, Christopher A. Hallberg, Emily Hamann, Ute Hartman, Mikael Hollestelle, Antoinette Hopper, John L. Ito, Hidemi Jakubowska, Anna Johnson, Nichola Kang, Daehee Khan, Sofia Kosma, Veli-Matti Kriege, Mieke Kristensen, Vessela Lambrechts, Diether Le Marchand, Loic Lee, Soo Chin Lindblom, Annika Lophatananon, Artitaya Lubinski, Jan Mannermaa, Arto Manoukian, Siranoush Margolin, Sara Matsuo, Keitaro Mayes, Rebecca Mckay, James Meindl, Alfons Milne, Roger L. Muir, Kenneth Neuhausen, Susan L. Nevanlinna, Heli Olswold, Curtis Orr, Nick Peterlongo, Paolo Pita, Guillermo Pylkaes, Katri Rudolph, Anja Sangrajrang, Suleeporn Sawyer, Elinor J. Schmidt, Marjanka K. Schmutzler, Rita K. Seynaeve, Caroline Shah, Mitul Shen, Chen-Yang Shu, Xiao-Ou Southey, Melissa C. Stram, Daniel O. Surowy, Harald Swerdlow, Anthony Teo, Soo H. Tessier, Daniel C. Tomlinson, Ian Torres, Diana Truong, Therese Vachon, Celine M. Vincent, Daniel Winqvist, Robert Wu, Anna H. Wu, Pei-Ei Yip, Cheng Har Zheng, Wei Pharoah, Paul D. P. Hall, Per Edwards, Stacey L. Simard, Jacques French, Juliet D. Chenevix-Trench, Georgia Dunning, Alison M. TI Fine scale mapping of the 17q22 breast cancer locus using dense SNPs, genotyped within the Collaborative Oncological Gene-Environment Study (COGs) SO SCIENTIFIC REPORTS LA English DT Article ID SUSCEPTIBILITY LOCI; FUNCTIONAL VARIANTS; HUMAN GENOME; RISK LOCUS; EXPRESSION; ASSOCIATION; CONSORTIUM; ENHANCERS; REVEALS; REGION AB Genome-wide association studies have found SNPs at 17q22 to be associated with breast cancer risk. To identify potential causal variants related to breast cancer risk, we performed a high resolution fine-mapping analysis that involved genotyping 517 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of genotypes for 3,134 SNPs in more than 89,000 participants of European ancestry from the Breast Cancer Association Consortium (BCAC). We identified 28 highly correlated common variants, in a 53 Kb region spanning two introns of the STXBP4 gene, that are strong candidates for driving breast cancer risk (lead SNP rs2787486 (OR = 0.92; CI 0.90-0.94; P = 8.96 x 10(-15))) and are correlated with two previously reported risk-associated variants at this locus, SNPs rs6504950 (OR = 0.94, P = 2.04 x 10-09, r(2) = 0.73 with lead SNP) and rs1156287 (OR = 0.93, P = 3.41 x 10(-11), r(2) = 0.83 with lead SNP). Analyses indicate only one causal SNP in the region and several enhancer elements targeting STXBP4 are located within the 53 kb association signal. Expression studies in breast tumor tissues found SNP rs2787486 to be associated with increased STXBP4 expression, suggesting this may be a target gene of this locus. C1 [Darabi, Hatef; Wahl, Hanna Fues; Czene, Kamila; Hall, Per] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Beesley, Jonathan; Marjaneh, Mahdi Moradi; Edwards, Stacey L.; French, Juliet D.; Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Dept Genet, Brisbane, Qld, Australia. [Droit, Arnaud] Univ Laval, Ctr Hosp Univ Quebec Res Ctr, Fac Med, Dept Mol Med, Quebec City, PQ, Canada. [Kar, Siddhartha; Ghoussaini, Maya; Conroy, Don M.; Easton, Douglas F.; Mayes, Rebecca; Shah, Mitul; Pharoah, Paul D. P.; Dunning, Alison M.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge, England. [Nord, Silje; Kristensen, Vessela] Oslo Univ Hosp Radiumhosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway. [Soucy, Penny; Simard, Jacques] Univ Laval, Ctr Hosp Univ Quebec Res Ctr, Genom Ctr, Quebec City, PQ, Canada. [Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Easton, Douglas F.; Pharoah, Paul D. P.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England. [Michailidou, Kyriaki] Cyprus Inst Neurol & Genet, Dept Elect Microscopy Mol Pathol, Nicosia, Cyprus. [Alonso, M. Rosario; Pita, Guillermo] Spanish Natl Canc Res Ctr, Human Canc Genet Program, Human Genotyping CEGEN Unit, Madrid, Spain. [Andrulis, Irene L.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Anton-Culver, Hoda] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Arndt, Volker; Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Beckmann, Matthias W.; Fasching, Peter A.] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Comprehens Canc Ctr Erlangen EMN, Dept Gynecol & Obstet, Erlangen, Germany. [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. [Bogdanova, Natalia V.] Hannover Med Sch, Dept Radiat Oncol, Hannover, Germany. [Bojesen, Stig E.] Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Copenhagen Gen Populat Study, Herlev, Denmark. [Bojesen, Stig E.] Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Clin Biochem, Herlev, Denmark. [Bojesen, Stig E.] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark. [Brauch, Hiltrud] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. [Brauch, Hiltrud] Univ Tubingen, Tubingen, Germany. [Brauch, Hiltrud; Brenner, Hermann] 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. [Broeks, Annegien; Schmidt, Marjanka K.] Antoni Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands. [Bruening, Thomas] Ruhr Univ Bochum, Inst Prevent & Occupat Med German Social Accident, Bochum, Germany. [Burwinkel, Barbara; Surowy, Harald] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany. [Burwinkel, Barbara; Surowy, Harald] German Canc Res Ctr, Mol Epidemiol Grp, Heidelberg, Germany. [Chang-Claude, Jenny; Rudolph, Anja] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Chang-Claude, Jenny] Univ Med Ctr Hamburg Eppendorf, UCCH, Hamburg, Germany. [Choi, Ji-Yeob; Kang, Daehee] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul, South Korea. [Choi, Ji-Yeob; Kang, Daehee] Seoul Natl Univ, Canc Res Inst, Seoul, South Korea. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Cox, Angela] Univ Sheffield, Dept Oncol & Metab, Sheffield Canc Res, Sheffield, S Yorkshire, England. [Cross, Simon S.] Univ Sheffield, Acad Unit Pathol, Dept Neurosci, Sheffield, S Yorkshire, England. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. [Doerk, Thilo] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Figueroa, Jonine] Univ Edinburgh, Sch Med, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland. [Figueroa, Jonine; Garcia-Closas, Montserrat] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Fletcher, Olivia; Johnson, Nichola; Orr, Nick] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London, England. [Fletcher, Olivia; Johnson, Nichola; Swerdlow, Anthony] Inst Canc Res, Div Breast Canc Res, London, England. [Flyger, Henrik] Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Breast Surg, Herlev, Denmark. [Galle, Eva; Lambrechts, Diether] Vesalius Res Ctr, Leuven, Belgium. [Galle, Eva; Lambrechts, Diether] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium. [Giles, Graham G.; Milne, Roger L.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Giles, Graham G.; Hopper, John L.; Milne, Roger L.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia. [Goldberg, Mark S.] McGill Univ, Dept Med, Montreal, PQ, Canada. [Goldberg, Mark S.] McGill Univ, Royal Victoria Hosp, Div Clin Epidemiol, Montreal, PQ, Canada. [Guenel, Pascal; Truong, Therese] Univ Paris Saclay, Univ Paris Sud, INSERM, Ctr Res Epidemiol & Populat Hlth CESP,Canc & Envi, Villejuif, France. [Haiman, Christopher A.; Stram, Daniel O.; Wu, Anna H.] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Hallberg, Emily; Olswold, Curtis; Vachon, Celine M.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Hamann, Ute; Torres, Diana] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany. [Hartman, Mikael] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore. [Hartman, Mikael] Natl Univ Hlth Syst, Dept Surg, Singapore, Singapore. [Hollestelle, Antoinette; Kriege, Mieke; Seynaeve, Caroline] Erasmus MC Canc Inst, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands. [Ito, Hidemi] Aichi Canc Ctr Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi, Japan. [Jakubowska, Anna; Lubinski, Jan] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. [Kang, Daehee] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. [Khan, Sofia; Nevanlinna, Heli] Univ Helsinki, Helsinki Univ Hosp, Dept Obstet & Gynecol, Helsinki, Finland. [Kosma, Veli-Matti; Mannermaa, Arto] Univ Eastern Finland, Canc Ctr Eastern Finland, Kuopio, Finland. [Kosma, Veli-Matti; Mannermaa, Arto] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Kuopio, Finland. [Kosma, Veli-Matti; Mannermaa, Arto] Kuopio Univ Hosp, Imaging Ctr, Dept Clin Pathol, Kuopio, Finland. [Kristensen, Vessela] 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. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Lee, Soo Chin] Natl Univ Hlth Syst, Dept Hematol Oncol, Singapore, Singapore. [Lee, Soo Chin] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore, Singapore. [Lindblom, Annika] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Lophatananon, Artitaya; Muir, Kenneth] Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry, W Midlands, England. [Manoukian, Siranoush] INT, Fdn IRCCS, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, Milan, Italy. [Margolin, Sara] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Matsuo, Keitaro] Aichi Canc Ctr Res Inst, Div Mol Med, Nagoya, Aichi, Japan. [Mckay, James] Int Agcy Res Canc, Lyon, France. [Meindl, Alfons] Tech Univ Munich, Div Gynaecol & Obstet, Munich, Germany. [Muir, Kenneth] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England. [Neuhausen, Susan L.] Beckman Res Inst City Hope, Dept Populat Sci, Duarte, CA USA. [Peterlongo, Paolo] Inst Mol Oncol, FIRC Italian Fdn Canc Res, IFOM, Milan, Italy. [Pylkaes, Katri; Winqvist, Robert] Univ Oulu, Bioctr Oulu, Canc & Translat Med Res Unit, Lab Canc Genet & Tumor Biol, Oulu, Finland. [Pylkaes, Katri; Winqvist, Robert] Northern Finland Lab Ctr Oulu, Lab Canc Genet & Tumor Biol, Oulu, Finland. [Sangrajrang, Suleeporn] Natl Canc Inst, Bangkok, Thailand. [Sawyer, Elinor J.] Kings Coll London, Guys Hosp, Res Oncol, London, England. [Schmutzler, Rita K.] Univ Hosp Cologne, Ctr Hereditary Breast & Ovarian Canc, Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, CIO, Cologne, Germany. [Schmutzler, Rita K.] Univ Cologne, CMMC, Cologne, Germany. [Shen, Chen-Yang] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan. [Shen, Chen-Yang; Wu, Pei-Ei] Acad Sinica, Inst Biomed Sci, Taiwan Biobank, Taipei, Taiwan. [Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Dept Med,Div Epidemiol, Nashville, TN 37235 USA. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia. [Swerdlow, Anthony] Inst Canc Res, Div Genet & Epidemiol, London, England. [Teo, Soo H.] Canc Res Initiat Fdn, Subang Jaya, Selangor, Malaysia. [Teo, Soo H.; Yip, Cheng Har] Univ Malaya, Med Ctr, Canc Res Inst, Breast Canc Res Unit, Kuala Lumpur, Malaysia. [Tessier, Daniel C.; Vincent, Daniel] McGill Univ, Montreal, PQ, Canada. [Tessier, Daniel C.; Vincent, Daniel] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. [Tomlinson, Ian] Wellcome Trust Ctr Human Genet, Oxford, England. [Tomlinson, Ian] Univ Oxford, Oxford NIHR Biomed Res Ctr, Oxford, England. [Torres, Diana] Pontificia Univ Javeriana, Inst Human Genet, Bogota, Colombia. RP Darabi, H (reprint author), Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. EM hatef.darabi@ki.se RI Yip, Cheng-Har/B-1909-2010; Teo, Soo-hwang/H-2353-2014; Zheng, Wei/O-3351-2013; Bruning, Thomas/G-8120-2015; Dork, Thilo/J-8620-2012; Nord, Silje/R-5212-2016; Brenner, Hermann/B-4627-2017; manoukian, siranoush/E-7132-2017; OI Zheng, Wei/0000-0003-1226-070X; Bruning, Thomas/0000-0001-9560-5464; Nord, Silje/0000-0002-3271-5356; Brenner, Hermann/0000-0002-6129-1572; manoukian, siranoush/0000-0002-6034-7562; Matsuo, Keitaro/0000-0003-1761-6314; Dunning, Alison Margaret/0000-0001-6651-7166 FU NHMRC; National Breast Cancer Foundation; Cancer Australia; National Institute of Health (USA); Breast Cancer Now; Institute of Cancer Research; NHS; Cancer Research UK [C1287/A10118, C1287/A12014, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565, C490/A10124]; European Community [223175, HEALTH-F2-2009-223175, 223175 (HEALTH-F2-2009-223175)]; National Institutes of Health [CA128978, R01 CA77398, R01 CA092447]; Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defence [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR); 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, RUL 1997-1505, DDHK 2004-3124, DDHK 2009-4318]; BBMRI-NL - Dutch government [NWO 184.021.007]; Dutch National Genomics Initiative; Breast Cancer Research Trust, UK; ELAN-Fond of the University Hospital of Erlangen; Cancer Research UK; 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]; California Breast Cancer Act; California Breast Cancer Research Fund [97-10500]; California Department of Public Health as part of the statewide cancer reporting program [103885]; Lon V Smith Foundation [LVS39420]; Baden Wurttemberg Ministry of Science, Research and Arts; German Cancer Aid (Deutsche Krebshilfe); German Cancer Aid [110837]; Federal Ministry of Education and Research (BMBF) Germany [01KW9975/5, 01KW9976/8, 1KW9977/0, 01KW0114, 01KH0402]; Robert Bosch Foundation, Stuttgart; Deutsches Krebsforschungszentrum (DKFZ), Heidelberg; Institute for Prevention and Occupational Medicine of the German Social Accident Insurance; Institute of the Ruhr University Bochum (IPA), Bochum; Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany; Helsinki University Central Hospital Research Fund; Academy of Finland [266528, 250083, 122715]; Finnish Cancer Society; Nordic Cancer Union; Sigrid Juselius Foundation; MEXT Kakenhi from the Ministry of Education, Science, Sports, Culture and Technology of Japan [170150181, 26253041]; Ministry Health, Labour and Welfare of Japan; National Cancer Center Research and Development Fund; Japan Agency for Medical Research and development, AMED [15ck0106177h0001]; Cancer Bio Bank Aichi; Friends of Hannover Medical School; Rudolf Bartling Foundation; Stockholm County Council; Karolinska Institutet; Swedish Cancer Society; Gustav V Jubilee foundation; Bert von Kantzows foundation; special Government Funding (EVO) of Kuopio University Hospital grants; Cancer Fund of North Savo; Finnish Cancer Organizations; University of Eastern Finland; Queensland Cancer Fund; Cancer Council of New South Wales; Cancer Council of Victoria; Cancer Council of Tasmania; Cancer Council of South Australia; Cancer Foundation of Western Australia; United States Army Medical Research and Materiel Command [DAMD17-01-1-0729]; Cancer Council Victoria; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; National Health and Medical Research Council of Australia (NHMRC) [400413, 400281, 199600]; California Breast Cancer Research Program [1RB-0287, 3PB-0102, 5PB-0018, 10PB-0098]; California Department of Health; National Cancer Institute's Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program [N01CN25403]; Stichting tegen Kanker [232-2008, 196-2010]; FWO; Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419]; Hamburg Cancer Society; Italian Association for Cancer Research (AIRC); Fondazione IRCCS Istituto Nazionale Tumori; NIH [CA128978, CA116167, CA176785, CA63464, CA54281, CA098758, CA132839, R01CA100374, R01CA64277, R01CA148667, R37CA70867]; NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; VicHealth; Australian NHMRC [209057, 251553, 504711]; Quebec Breast Cancer Foundation; Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program [CRN-87521]; Ministry of Economic Development, Innovation and Export Trade [PSR-SIIRI-701]; Malaysian Ministry of Science, Technology and Innovation (MOSTI); Malaysian Ministry of Higher Education [UM.C/HlR/MOHE/06]; Cancer Research Initiatives Foundation (CARIF); Biomedical Research Council, Singapore [BMRC08/1/35/19/550]; National medical Research Council, Singapore [NMRC/CG/SERI/2010]; K.G. Jebsen Centre for Breast Cancer Research; Research Council of Norway [193387/V50, 193387/H10]; South Eastern Norway Health Authority [39346]; Norwegian Cancer Society; Finnish Cancer Foundation; Finnish Cancer (Center of Excellence grant) [251314]; University of Oulu; University of Oulu Support Foundation; special Governmental EVO funds for Oulu University Hospital; Biobanking and Biomolecular Resources Research Infrastructure [BBMRI-NL CP16]; Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA; Marit and Hans Rausings Initiative Against Breast Cancer; Agency for Science, Technology and Research of Singapore (A*STAR); US National Institute of Health (NIH); Susan G. Komen Breast Cancer Foundation; Genetic Associations and Mechanisms in Oncology (GAME-ON) Network [U19 CA148065]; Yorkshire Cancer Research [S295, S299, S305PA]; Sheffield Experimental Cancer Medicine Centre; National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC); UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; BRL (Basic Research Laboratory) program through the National Research Foundation of Korea - Ministry of Education, Science and Technology [20120000347]; NUS start-up Grant; National University Cancer Institute Singapore (NCIS) Centre Grant; NMRC Clinician Scientist Award; Biomedical Research Council [05/1/21/19/425]; DKFZ; National Cancer Institute Thailand; Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; Hellenic Cooperative Oncology Group research grant [HR R_BG/04]; Greek General Secretary for Research and Technology (GSRT) Program, Research Excellence II; European Union (European Social Fund - ESF); Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF)-ARISTEIA; Taiwan Biobank project of the Institute of Biomedical Sciences, Academia Sinica, Taiwan; Institute of Cancer Research (ICR), London; [KULPFV/10/016-SymBioSysII]; [P30 CA68485]; [PBZ_KBN_122/P05/2004] FX The authors thank all the individuals who took part in these studies and all the researchers, study staff, clinicians, and other healthcare providers, technicians, and administrative staff who have enabled this work to be carried out. In particular, they thank: COGS: Andrew Berchuck (OCAC), Rosalind A. Eeles, Ali Amin Al Olama, Zsofia Kote-Jarai, Sara Benlloch (PRACTICAL), Antonis Antoniou, Lesley McGuffog and Ken Offit (CIMBA), Joe Dennis, Andrew Lee, and Ed Dicks, Craig Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory and the staff of the CNIO genotyping unit, Francois Bacot, Sylvie LaBoissiere and Frederic Robidoux and the staff of the McGill University and Genome Quebec Innovation Centre, Sune F. Nielsen, Borge G. Nordestgaard, and the staff of the Copenhagen DNA laboratory, and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer and the staff of Mayo Clinic Genotyping Core Facility; ABCFS: Maggie Angelakos, Judi Maskiell, Gillian Dite; ABCS: Sten Cornelissen, Richard van Hien, Linde Braaf, Frans Hogervorst, Senno Verhoef, Laura van 't Veer, Emiel Rutgers, C Ellen van der Schoot, Femke Atsma; ACP: The ACP study wishes to thank the participants in the Thai Breast Cancer study. Special Thanks also go to the Thai Ministry of Public Health (MOPH), doctors and nurses who helped with the data collection process. Finally, the study would like to thank Dr Prat Boonyawongviroj, the former Permanent Secretary of MOPH and Dr Pornthep Siriwanarungsan, the Department Director-General of Disease Control who have supported the study throughout; BBCS: Eileen Williams, Elaine Ryder-Mills, Kara Sargus; BIGGS: Niall McInerney, Gabrielle Colleran, Andrew Rowan, Angela Jones; BSUCH: Peter Bugert, Medical Faculty Mannheim; CGPS: Staff and participants of the Copenhagen General Population Study. For the excellent technical assistance: Dorthe Uldall Andersen, Maria Birna Arnadottir, Anne Bank, Dorthe Kjeldgard Hansen. The Danish Cancer Biobank is acknowledged for providing infrastructure for the collection of blood samples for the cases; CNIO-BCS: Charo Alonso, Daniel Herrero, Nuria aelvarez, Pilar Zamora, Primitiva Menendez, the Human Genotyping-CEGEN Unit (CNIO); CTS: The CTS Steering Committee includes Leslie Bernstein, James Lacey, Sophia Wang, Huiyan Ma, Yani Lu, and Jessica Clague DeHart at the Beckman Research Institute of City of Hope, Dennis Deapen, Rich Pinder, Eunjung Lee, and Fred Schumacher at the University of Southern California, Pam Horn-Ross, Peggy Reynolds, Christina Clarke Dur and David Nelson at the Cancer Prevention Institute of California, Argyrios Ziogas and Hannah Park at the University of California Irvine; ESTHER: Hartwig Ziegler, Sonja Wolf, Volker Hermann, Christa Stegmaier, Katja Butterbach; GC-HBOC: Stefanie Engert, Heide Hellebrand, Sandra Krober; GENICA: The GENICA Network: Dr.; Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of Tubingen, Germany [HB, Wing-Yee Lo, Christina Justenhoven], German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) [HB], Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany [Yon-Dschun Ko, Christian Baisch], Institute of Pathology, University of Bonn, Germany [Hans-Peter Fischer], Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany, Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany [TB, Beate Pesch, Sylvia Rabstein, Anne Lotz]; and Institute of Occupational Medicine and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Germany [Volker Harth]; HEBCS: Kirsimari Aaltonen, Karl von Smitten, Tuomas Heikkinen, Irja Erkkila; HMBCS: Peter Hillemanns, Hans Christiansen and Johann H. Karstens; KBCP: Eija Myohanen, Helena Kemilainen; kConFab/AOCS: We wish to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contribute to kConFab; LAABC: We thank all the study participants and the entire data collection team, especially Annie Fung and June Yashiki; LMBC: Gilian Peuteman, Dominiek Smeets, Thomas Van Brussel and Kathleen Corthouts; MARIE: Petra Seibold, Dieter Flesch-Janys, Judith Heinz, Nadia Obi, Alina Vrieling, Sabine Behrens, Ursula Eilber, Muhabbet Celik, Til Olchers and Stefan Nickels; MBCSG: Bernard Peissel and Jacopo Azzollini Daniela Zaffaroni of the Fondazione IRCCS Istituto Nazionale dei Tumori (INT); Bernardo Bonanni, Monica Barile and Irene Feroce of the Istituto Europeo di Oncologia (IEO) and the personnel of the Cogentech Cancer Genetic Test Laboratory; MTLGEBCS: We would like to thank Martine Tranchant (CHU de Quebec Research Center), Marie-France Valois, Annie Turgeon and Lea Heguy (McGill University Health Center, Royal Victoria Hospital; McGill University) for DNA extraction, sample management and skillful technical assistance. J.S. is Chairholder of the Canada Research Chair in Oncogenetics; MYBRCA: Phuah Sze Yee, Peter Kang, Kang In Nee, Kavitta Sivanandan, Shivaani Mariapun, Yoon Sook-Yee, Daphne Lee, Teh Yew Ching and Nur Aishah Mohd Taib for DNA Extraction and patient recruitment; NBCS: The following are NBCS Collaborators: Dr. Kristine K. Sahlberg, PhD (Department of Research, Vestre Viken Hospital, Drammen, Norway and Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway), Dr. Lars Ottestad, MD (Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway), Prof. Em. Rolf Karesen, MD (Institute of Clinical Medicine, University of Oslo, Oslo, Norway and Department of Breast-and Endocrine Surgery, Division of Surgery, Cancer and Transplantation, Oslo University Hospital, Oslo, Norway), Dr. Anita Langerod, PhD (Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway), Dr.; Ellen Schlichting, MD (Section for Breast-and Endocrine Surgery, Department of Cancer, Division of Surgery, Cancer and Transplantation Medicine, Oslo University Hospital, Oslo, Norway), Dr. Marit Muri Holmen, MD (Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway), Prof. Toril Sauer, MD (Department of Pathology at Akershus University hospital, Lorenskog, Norway and Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway), Dr. Vilde Haakensen, MD (Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway), Dr. Olav Engebraten, MD (Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway, Department of Oncology, Division of Surgery and Cancer and Transplantation Medicine, Oslo University Hospital, Oslo, Norway and Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway), Prof. Bjorn Naume, MD (Department of Oncology, Division of Surgery and Cancer and Transplantation Medicine, Oslo University Hospital-Radiumhospitalet, Oslo, Norway and K.G. Jebsen Centre for Breast Cancer, Institute for Clinical Medicine, University of Oslo, Oslo, Norway.), Dr. Cecile E. Kiserud, MD (National Advisory Unit on Late Effects after Cancer Treatment, Department of Oncology, Oslo University Hospital, Oslo, Norway and Department of Oncology, Oslo University Hospital, Oslo, Norway), Dr. Kristin V. Reinertsen, MD (National Advisory Unit on Late Effects after Cancer Treatment, Department of Oncology, Oslo University Hospital, Oslo, Norway and Department of Oncology, Oslo University Hospital, Oslo, Norway), Assoc. Prof. Aslaug Helland, MD (Department of Genetics, Institute for Cancer Research and Department of Oncology, Oslo University Hospital Radiumhospitalet, Oslo, Norway), Dr. Margit Riis, MD (Dept of Breast-and Endocrine Surgery, Oslo University Hospital, Ulleval, Oslo, Norway), Dr. Ida Bukholm, MD (Department of Breast-Endocrine Surgery, Akershus University Hospital, Oslo, Norway and Department of Oncology, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Oslo, Norway), Prof. Per Eystein Lonning, MD (Section of Oncology, Institute of Medicine, University of Bergen and Department of Oncology, Haukeland University Hospital, Bergen, Norway), OSBREAC (Oslo Breast Cancer Research Consortium), Prof. Anne-Lise Borresen-Dale, PhD (Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway and Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Norway) and Grethe I. Grenaker Alnaes, M.Sc. (Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway); NBHS: We thank study participants and research staff for their contributions and commitment to this study; OBCS: We thank Arja Jukkola-Vuorinen, Mervi Grip, Saila Kauppila, Meeri Otsukka and Kari Mononen for their contributions to this study; OFBCR: Teresa Selander, Nayana Weerasooriya; ORIGO: We thank E. Krol-Warmerdam, and J. Blom for patient accrual, administering questionnaires, and managing clinical information. The LUMC survival data were retrieved from the Leiden hospital-based cancer registry system (ONCDOC) with the help of Dr. J.; Molenaar; PBCS: Louise Brinton, Mark Sherman, Neonila Szeszenia-Dabrowska, Beata Peplonska, Witold Zatonski, Pei Chao, Michael Stagner; pKARMA: The Swedish Medical Research Counsel; RBCS: Petra Bos, Jannet Blom, Ellen Crepin, Elisabeth Huijskens, Annette Heemskerk, the Erasmus MC Family Cancer Clinic; SASBAC: The Swedish Medical Research Counsel; SBCGS: We thank study participants and research staff for their contributions and commitment to this study; SBCS: Sue Higham, Helen Cramp, Ian Brock, Sabapathy Balasubramanian and Dan Connley; SEARCH: The SEARCH and EPIC teams; SGBCC: We thank the participants and research coordinator Kimberley Chua; SKKDKFZS: We thank all study participants, clinicians, family doctors, researchers and technicians for their contributions and commitment to this study; TNBCC: Robert Pilarski and Charles Shapiro were instrumental in the formation of the OSU Breast Cancer Tissue Bank. We thank the Human Genetics Sample Bank for processing of samples and providing OSU Columbus area control samples. UKBGS: We thank Breast Cancer Now and the Institute of Cancer Research for support and funding of the Breakthrough Generations Study, and the study participants, study staff, and the doctors, nurses and other health care providers and health information sources who have contributed to the study. We acknowledge NHS funding to the Royal Marsden/ICR NIHR Biomedical Research Centre. The authors would also like to acknowledge Dr Katherine A. Hoadley for normalization and sharing of all of TCGA BRCA RNAseq gene expression data. The work conducted for this project is supported by 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 n' 223175 (HEALTH-F2-2009-223175) (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; ABCFS: 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) Senior Principal Research Fellow. M.C.S. is a NHMRC Senior Research Fellow; ABCS: The ABCS study was supported by the Dutch Cancer Society [grants NKI 2007-3839; 2009 4363]; BBMRI-NL, which is a Research Infrastructure financed by the Dutch government (NWO 184.021.; 007); and the Dutch National Genomics Initiative; ACP: The ACP study is funded by the Breast Cancer Research Trust, UK; BBCC: The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen; BBCS: The BBCS is funded by Cancer Research UK and Breast Cancer Now and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN); BIGGS: 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; BSUCH: The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ); CECILE: 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); CGPS: The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital; CNIO-BCS: he 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); CTS: 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); ESTHER: 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); GC-HBOC: 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); GENICA: 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; HEBCS: The HEBCS was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, The Nordic Cancer Union and the Sigrid Juselius Foundation; HERPACC: The HERPACC was supported by MEXT Kakenhi (No.; 170150181 and 26253041) from the Ministry of Education, Science, Sports, Culture and Technology of Japan, by a Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from Ministry Health, Labour and Welfare of Japan, by Health and Labour Sciences Research Grants for Research on Applying Health Technology from Ministry Health, Labour and Welfare of Japan, by National Cancer Center Research and Development Fund, and "Practical Research for Innovative Cancer Control (15ck0106177h0001)" from Japan Agency for Medical Research and development, AMED, and Cancer Bio Bank Aichi; HMBCS: The HMBCS was supported by a grant from the Friends of Hannover Medical School and by the Rudolf Bartling Foundation; KARBAC: 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; KBCP: 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/AOCS: 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; LAABC: LAABC is supported by grants (1RB-0287, 3PB-0102, 5PB-0018, 10PB-0098) from the California Breast Cancer Research Program. Incident breast cancer cases were collected by the USC Cancer Surveillance Program (CSP) which is supported under subcontract by the California Department of Health. The CSP is also part of the National Cancer Institute's Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program, under contract number N01CN25403; LMBC: LMBC is supported bysimilar tothe 'Stichting tegen Kanker' (232-2008 and 196-2010). Diether Lambrechts is supported by the FWO and the KULPFV/10/016-SymBioSysII; MARIE: 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: 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 "5 x 1000"); MCBCS: 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: 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) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database; MEC: The MEC was support by NIH grants CA63464, CA54281, CA098758 and CA132839; MTLGEBCS: 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; MYBRCA: MYBRCA is funded by research grants from the Malaysian Ministry of Science, Technology and Innovation (MOSTI), Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation (CARIF). Additional controls were recruited by the Singapore Eye Research Institute, which was supported by a grant from the Biomedical Research Council (BMRC08/1/35/19/550), Singapore and the National medical Research Council, Singapore (NMRC/CG/SERI/2010); NBCS: The NBCS has received funding from the K.G. Jebsen Centre for Breast Cancer Research; the Research Council of Norway grant 193387/V50 (to A-L 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); NBHS: 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; OBCS: 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; OFBCR: 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; ORIGO: The ORIGO study was supported by the Dutch Cancer Society (RUL 1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP16); PBCS: The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA; pKARMA: The pKARMA study was supported by Marit and Hans Rausings Initiative Against Breast Cancer; RBCS: The RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318); SASBAC: 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; SBCGS: The SBCGS was supported primarily by NIH grants R01CA64277, R01CA148667, and R37CA70867. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The scientific development and funding of this project were, in part, supported by the Genetic Associations and Mechanisms in Oncology (GAME-ON) Network U19 CA148065; SBCS: The SBCS was supported by Yorkshire Cancer Research S295, S299, S305PA and Sheffield Experimental Cancer Medicine Centre; SCCS: The SCCS is supported by a grant from the National Institutes of Health (R01 CA092447). Data on SCCS cancer cases used in this publication were provided by the Alabama Statewide Cancer Registry; Kentucky Cancer Registry, Lexington, KY; Tennessee Department of Health, Office of Cancer Surveillance; Florida Cancer Data System; North Carolina Central Cancer Registry, North Carolina Division of Public Health; Georgia Comprehensive Cancer Registry; Louisiana Tumor Registry; Mississippi Cancer Registry; South Carolina Central Cancer Registry; Virginia Department of Health, Virginia Cancer Registry; Arkansas Department of Health, Cancer Registry, 4815 W. Markham, Little Rock, AR 72205. The Arkansas Central Cancer Registry is fully funded by a grant from National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC). Data on SCCS cancer cases from Mississippi were collected by the Mississippi Cancer Registry which participates in the National Program of Cancer Registries (NPCR) of the Centers for Disease Control and Prevention (CDC). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Mississippi Cancer Registry; SEARCH: 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; SEBCS: SEBCS was supported by the BRL (Basic Research Laboratory) program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (20120000347); SGBCC: SGBCC is funded by the NUS start-up Grant, National University Cancer Institute Singapore (NCIS) Centre Grant and the NMRC Clinician Scientist Award. Additional controls were recruited by the Singapore Consortium of Cohort Studies-Multi-ethnic cohort (SCCS-MEC), which was funded by the Biomedical Research Council, grant number: 05/1/21/19/425; SKKDKFZS: SKKDKFZS is supported by the DKFZ; SZBCS: The SZBCS was supported by Grant PBZ_KBN_122/P05/2004; TBCS: The TBCS was funded by The National Cancer Institute Thailand; TNBCC: 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; TWBCS: The TWBCS is supported by the Taiwan Biobank project of the Institute of Biomedical Sciences, Academia Sinica, Taiwan; UKBGS: The UKBGS is funded by Breast Cancer Now and the Institute of Cancer Research (ICR), London. ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. NR 36 TC 0 Z9 0 U1 8 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 SEP 7 PY 2016 VL 6 AR 32512 DI 10.1038/srep32512 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV1RC UT WOS:000382697600001 PM 27600471 ER PT J AU Shi, JM Xie, C Liu, HB Krausz, KW Bewley, CA Zhang, SH Tang, LM Zhou, ZJ Gonzalez, FJ AF Shi, Jingmin Xie, Cen Liu, Hongbing Krausz, Kristopher W. Bewley, Carole A. Zhang, Suhui Tang, Liming Zhou, Zhijun Gonzalez, Frank J. TI Metabolism and Bioactivation of Fluorochloridone, a Novel Selective Herbicide, in Vivo and in Vitro SO ENVIRONMENTAL SCIENCE & TECHNOLOGY LA English DT Article ID GLUTATHIONE S-TRANSFERASES; TRAP MASS-SPECTROMETRY; LIVER-INJURY; FLUROCHLORIDONE; RECEPTOR; ALCOHOL; MECHANISMS; EXPRESSION; PESTICIDES; MICROSOMES AB Fluorochloridone (FLC) is a herbicide used worldwide that is thought to be safe. However, due to its potential genotoxicity, cytotoxicity, and even systematic toxicity, there are increasing concerns about human exposure to this compound. Thus, the metabolism and bioactivation of FLC was investigated. After oral administration to mice, 27 metabolites were identified by ultrahigh performance liquid chromatography-electrospray ionization-quadrupole time-of-flight-mass spectrometry and with further structural identification by nuclear magnetic resonance spectroscopy. Hydroxylation and oxidative dechlorination were the major phase I pathways, while glutathione (GSH) and N-acetylcysteine conjugations were two major phase II pathways, indicating the formation of a reactive intermediate. In vitro microsomal and cytosolic studies revealed that a GSH conjugate (M13) was the predominant metabolite of FLC formed through a nucleophilic S(N)2 substitution of 3-Cl by GSH; this pathway is NADPH independent and accelerated by glutathione S-transferase (GST). Further, a kinetic study showed that M13 formation in both human liver microsomes and cytosols obeyed typical Michaelis-Menten kinetics. The maximum clearance (V-max/K-m) of GSH conjugation in human liver microsomes was approximately 5.5-fold higher than human liver cytosol, thus implying that microsomal GST was mainly responsible for M13 formation. These findings are important for understanding the potential hazard of human exposure to FLC. C1 [Shi, Jingmin; Zhang, Suhui; Tang, Liming] Shanghai Inst Food & Drug Control, Dept Ctr Drug Safety Evaluat, Pharmacol & Toxicol, Shanghai 201203, Peoples R China. [Shi, Jingmin; Xie, Cen; Krausz, Kristopher W.; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. [Liu, Hongbing; Bewley, Carole A.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Zhou, Zhijun] Fudan Univ, Sch Publ Hlth, Shanghai 200032, Peoples R China. RP Tang, LM (reprint author), Shanghai Inst Food & Drug Control, Dept Ctr Drug Safety Evaluat, Pharmacol & Toxicol, Shanghai 201203, Peoples R China.; Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. EM tangliming@smda.gov.cn; gonzalef@mail.nih.gov FU National Natural Science Foundation of China [81373040]; NIH Intramural Research Program (NIDDK); NIH Intramural Research Program (NCI); Shanghai Institute for Food and Drug Control; Shanghai Food and Drug Administration FX This study was supported by the National Natural Science Foundation of China (Grant No. 81373040) and the NIH Intramural Research Program (NIDDK and NCI). J.S. was supported by the Shanghai Institute for Food and Drug Control, Shanghai Food and Drug Administration. NR 40 TC 0 Z9 0 U1 12 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0013-936X EI 1520-5851 J9 ENVIRON SCI TECHNOL JI Environ. Sci. Technol. PD SEP 6 PY 2016 VL 50 IS 17 BP 9652 EP 9660 DI 10.1021/acs.est.6b02113 PG 9 WC Engineering, Environmental; Environmental Sciences SC Engineering; Environmental Sciences & Ecology GA DV3FG UT WOS:000382805800083 PM 27443216 ER PT J AU Van Meter, M Simon, M Tombline, G May, A Morello, TD Hubbard, BP Bredbenner, K Park, R Sinclair, DA Bohr, VA Gorbunova, V Seluanov, A AF Van Meter, Michael Simon, Matthew Tombline, Gregory May, Alfred Morello, Timothy D. Hubbard, Basil P. Bredbenner, Katie Park, Rosa Sinclair, David A. Bohr, Vilhelm A. Gorbunova, Vera Seluanov, Andrei TI JNK Phosphorylates SIRT6 to Stimulate DNA Double-Strand Break Repair in Response to Oxidative Stress by Recruiting PARP1 to DNA Breaks SO CELL REPORTS LA English DT Article ID REGULATES LIFE-SPAN; REACTIVE OXYGEN; HOMOLOGOUS RECOMBINATION; GENOMIC INSTABILITY; CANCER-CELLS; PROMOTES; PROTEIN; DAMAGE; STABILITY; CHROMATIN AB The accumulation of damage caused by oxidative stress has been linked to aging and to the etiology of numerous age-related diseases. The longevity gene, sirtuin 6 (SIRT6), promotes genome stability by facilitating DNA repair, especially under oxidative stress conditions. Here we uncover the mechanism by which SIRT6 is activated by oxidative stress to promote DNA double-strand break (DSB) repair. We show that the stress-activated protein kinase, c-Jun N-terminal kinase (JNK), phosphorylates SIRT6 on serine 10 in response to oxidative stress. This post-translational modification facilitates the mobilization of SIRT6 to DNA damage sites and is required for efficient recruitment of poly (ADP-ribose) polymerase 1 (PARP1) to DNA break sites and for efficient repair of DSBs. Our results demonstrate a post-translational mechanism regulating SIRT6, and they provide the link between oxidative stress signaling and DNA repair pathways that may be critical for hormetic response and longevity assurance. C1 [Van Meter, Michael; Simon, Matthew; Tombline, Gregory; Morello, Timothy D.; Bredbenner, Katie; Park, Rosa; Gorbunova, Vera; Seluanov, Andrei] Univ Rochester, Dept Biol, Rochester, NY 14627 USA. [May, Alfred; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Baltimore, MD 21224 USA. [Hubbard, Basil P.; Sinclair, David A.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. RP Gorbunova, V; Seluanov, A (reprint author), Univ Rochester, Dept Biol, Rochester, NY 14627 USA. EM vera.gorbunova@rochester.edu; andrei.seluanov@rochester.edu FU Intramural program of the National Institute on Aging; National Institute on Aging; Life Extension Foundation FX This work was supported by the Intramural program of the National Institute on Aging to V.A.B.; grants from the National Institute on Aging to M.V.M., V.G., and A.S.; and Life Extension Foundation to V.G. and A.S. We thank Xiao Tian, Amita Vaidya, and Jorge Azpurua for helpful conversations. We also thank Juliya Ablaeva for technical assistance. NR 41 TC 1 Z9 1 U1 8 U2 8 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 SEP 6 PY 2016 VL 16 IS 10 BP 2641 EP 2650 DI 10.1016/j.celrep.2016.08.006 PG 10 WC Cell Biology SC Cell Biology GA DW8CH UT WOS:000383880400010 PM 27568560 ER PT J AU Yau, HJ Wang, DV Tsou, JH Chuang, YF Chen, BT Deisseroth, K Ikemoto, S Bonci, A AF Yau, Hau-Jie Wang, Dong V. Tsou, Jen-Hui Chuang, Yi-Fang Chen, Billy T. Deisseroth, Karl Ikemoto, Satoshi Bonci, Antonello TI Pontomesencephalic Tegmental Afferents to VTA Non-dopamine Neurons Are Necessary for Appetitive Pavlovian Learning SO CELL REPORTS LA English DT Article ID NICOTINIC ACETYLCHOLINE-RECEPTORS; CONDITIONED-RESPONSES; GLUTAMATERGIC NEURONS; SUPERIOR COLLICULUS; GABAERGIC NEURONS; PREDICTION ERRORS; SUBSTANTIA-NIGRA; VENTRAL PALLIDUM; MONKEY MIDBRAIN; NUCLEUS LESIONS AB The ventral tegmental area (VTA) receives phenotypically distinct innervations from the pedunculopontine tegmental nucleus (PPTg). While PPTg-to-VTA inputs are thought to play a critical role in stimulus-reward learning, direct evidence linking PPTg-to-VTA phenotypically distinct inputs in the learning process remains lacking. Here, we used optogenetic approaches to investigate the functional contribution of PPTg excitatory and inhibitory inputs to the VTA in appetitive Pavlovian conditioning. We show that photoinhibition of PPTg-to-VTA cholinergic or glutamatergic inputs during cue presentation dampens the development of anticipatory approach responding to the food receptacle during the cue. Furthermore, we employed in vivo optetrode recordings to show that photoinhibition of PPTg cholinergic or glutamatergic inputs significantly decreases VTA non-dopamine (non-DA) neural activity. Consistently, photoinhibition of VTA non-DA neurons disrupts the development of cueelicited anticipatory approach responding. Taken together, our study reveals a crucial regulatory mechanism by PPTg excitatory inputs onto VTA non-DA neurons during appetitive Pavlovian conditioning. C1 [Yau, Hau-Jie; Tsou, Jen-Hui; Chen, Billy T.; Bonci, Antonello] NIDA, Synapt Plast Sect, Intramural Res Program, NIH,US Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Wang, Dong V.; Ikemoto, Satoshi] NIDA, Neurocircuitry Motivat Sect, Intramural Res Program, NIH,US Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Chuang, Yi-Fang] Natl Yang Ming Univ, Inst Publ Hlth, Taipei 112, Taiwan. [Deisseroth, Karl] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA. [Deisseroth, Karl] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA. [Deisseroth, Karl] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Bonci, Antonello] Johns Hopkins Univ, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA. [Bonci, Antonello] Johns Hopkins Univ, Dept Psychiat, Baltimore, MD 21287 USA. [Yau, Hau-Jie] Natl Taiwan Univ, Grad Inst Brain & Mind Sci, Taipei 10051, Taiwan. [Chen, Billy T.] Ionis Pharmaceut Inc, Carlsbad, CA 92010 USA. RP Bonci, A (reprint author), NIDA, Synapt Plast Sect, Intramural Res Program, NIH,US Dept Hlth & Human Serv, Baltimore, MD 21224 USA.; Bonci, A (reprint author), Johns Hopkins Univ, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA. EM antonello.bonci@nih.gov FU Intramural Research Program at National Institute on Drug Abuse; Ministry of Science and Technology, Taiwan [MOST 103-2911-I-038-501] FX This work was supported by the Intramural Research Program at National Institute on Drug Abuse. J.-H.T was supported by MOST 103-2911-I-038-501 from the Ministry of Science and Technology, Taiwan. The authors thank Stephanie Goddard and Christina Hatch for technical assistance and Roy Wise, Ross McDevitt, and Hugo Tejeda for critical reading of the manuscript. NR 63 TC 1 Z9 1 U1 2 U2 2 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 SEP 6 PY 2016 VL 16 IS 10 BP 2699 EP 2710 DI 10.1016/j.celrep.2016.08.007 PG 12 WC Cell Biology SC Cell Biology GA DW8CH UT WOS:000383880400014 PM 27568569 ER PT J AU LeCour, L Boyapati, VK Liu, J Li, ZG Sacks, DB Worthylake, DK AF LeCour, Louis, Jr. Boyapati, Vamsi. K. Liu, Jing Li, Zhigang Sacks, David B. Worthylake, David K. TI The Structural Basis for Cdc42-Induced Dimerization of IQGAPs SO STRUCTURE LA English DT Article ID GTPASE-ACTIVATING PROTEIN; CRYSTAL-STRUCTURE; SECONDARY STRUCTURE; CELL-PROLIFERATION; RHO GTPASES; CDC42; DOMAIN; BINDING; RASGAP; COMPLEX AB In signaling, Rho-family GTPases bind effector proteins and alter their behavior. Here we present the crystal structure of Cdc42.GTP bound to the GTPase-activating protein (GAP)-related domain (GRD) of IQGAP2. Four molecules of Cdc42 are bound to two GRD molecules, which bind each other in a parallel dimer. Two Cdc42s bind very similarly to the Ras/RasGAP interaction, while the other two bind primarily to "extra domain" sequences from both GRDs, tying the GRDs together. Calorimetry confirms two-site binding of Cdc42.GTP for the GRDs of both IQGAP2 and IQGAP1. Mutation of important extra domain residues reduces binding to single-site and abrogates Cdc42 binding to a much larger IQGAP1 fragment. Importantly, Rac1.GTP displays only single-site binding to the GRDs, indicating that only Cdc42 promotes IQGAP dimerization. The structure identifies an unexpected role for Cdc42 in protein dimerization, thus expanding the repertoire of interactions of Ras family proteins with their targets. C1 [LeCour, Louis, Jr.; Boyapati, Vamsi. K.; Liu, Jing; Worthylake, David K.] Louisiana State Univ, Dept Biochem & Mol Biol, Hlth Sci Ctr, New Orleans, LA 70112 USA. [Li, Zhigang; Sacks, David B.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Worthylake, DK (reprint author), Louisiana State Univ, Dept Biochem & Mol Biol, Hlth Sci Ctr, New Orleans, LA 70112 USA. EM dworth@lsuhsc.edu FU NIH [RO1 GM084072]; Intramural Research Program of the NIH FX We thank Kent Rossman, John Sondek, Fareed Aboul-Ela, Francis Whitby, and Arthur Haas for critical reading of the manuscript. We thank Verna Frasca for help with ITC data fitting. This research was supported by the NIH RO1 GM084072 (to D.K.W.) and by the Intramural Research Program of the NIH (to D.B.S.). The authors declare that they have no financial or personal relationships with other people or organizations that might influence the content of this manuscript. NR 49 TC 2 Z9 2 U1 2 U2 2 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 SEP 6 PY 2016 VL 24 IS 9 BP 1499 EP 1508 DI 10.1016/j.str.2016.06.016 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DV9FI UT WOS:000383245300009 PM 27524202 ER PT J AU Brisbois, CA Lee, JC AF Brisbois, Chase A. Lee, Jennifer C. TI Apolipoprotein C-III Nanodiscs Studied by Site-Specific Tryptophan Fluorescence SO BIOCHEMISTRY LA English DT Article ID HIGH-DENSITY-LIPOPROTEINS; APOC-III; A-I; DIMYRISTOYLPHOSPHATIDYLCHOLINE VESICLE; CHOLESTEROL ACYLTRANSFERASE; LIPID-BINDING; PHOSPHATIDYLCHOLINES; SPECTROSCOPY; ORIENTATION; PHOSPHORUS AB Apolipoprotein C-III (ApoC-III) is found on high density lipoproteins (HDLs) and remodels 1,2-dimyristoyl-sn-glycero-3-phosphocholine vesicles into HDL-like particles known as nanodiscs. Using single-Trp-containing ApoC-III mutants, we have studied local side chain environments and interactions in nanodiscs at positions W42, W54, and W65. Using transmission electron microscopy and circular dichroism spectroscopy, nano discs were characterized at the ultrastructural and secondary conformational levels, respectively. Nearly identical particles (15 +/- 2 nm) were produced from all proteins containing approximately 25 +/- 4 proteins per particle with an average helicity of 45-51% per protein. Distinct residue-specific fluorescence properties were observed with W54 residing in the most hydrophobic environment followed by W42 and W65. Interestingly, time-resolved anisotropy measurements revealed that Trp side chain mobility is uncorrelated to the polarity of its surroundings. W54 is the most mobile compared to W65 and W42, which are more immobile in a nanodisc-bound state. On the basis of Trp spectral comparisons of ApoC-III in micellar and vesicle environments, ApoC-III binding within nanodiscs more closely resembles a bilayer-bound state. Despite the nanodiscs being structurally similar, we found marked differences during nanodisc formation by the Tip variants as a function of temperature, with W42 behaving the most like the wild-type protein. Our data suggest that despite the modest mutations of Trp to Phe at two of the three native sites, the interfacial location of W42 is important for lipid binding and nanodisc assembly, which may be biologically meaningful as of the three Trp residues, only W42 is invariant among mammals. C1 [Brisbois, Chase A.; Lee, Jennifer C.] NHLBI, Lab Prot Conformat & Dynam, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Lee, JC (reprint author), NHLBI, Lab Prot Conformat & Dynam, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM leej4@mail.nih.gov FU Intramural Research Program at the National Heart, Lung, and Blood Institute of the National Institutes of Health FX This work is supported by the Intramural Research Program at the National Heart, Lung, and Blood Institute of the National Institutes of Health. NR 40 TC 1 Z9 1 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 SEP 6 PY 2016 VL 55 IS 35 BP 4939 EP 4948 DI 10.1021/acs.biochem.6b00599 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV3FD UT WOS:000382805500006 PM 27529357 ER PT J AU Lee, JH Ying, JF Bax, A AF Lee, Jung Ho Ying, Jinfa Bax, Ad TI Nuclear Magnetic Resonance Observation of alpha-Synuclein Membrane Interaction by Monitoring the Acetylation Reactivity of Its Lysine Side Chains SO BIOCHEMISTRY LA English DT Article ID NMR-SPECTROSCOPY; CROSS-LINKING; PARKINSONS-DISEASE; RANDOM COIL; IN-VIVO; BINDING; PROTEINS; CELLS; HELIX; PHOSPHORYLATION AB The interaction between alpha-synuclein (alpha S) protein and lipid membranes is key to its role in synaptic vesicle homeostasis and plays a role in initiating fibril formation, which is implicated in Parkinson's disease. The natural state of alpha S inside the cell is generally believed to be intrinsically disordered, but chemical cross-linking experiments provided evidence of a tetrameric arrangement, which was reported to be rich in alpha-helical secondary structure based on circular dichroism (CD). Cross-linking relies on chemical modification of the protein's Lys C-epsilon amino groups, commonly by glutaraldehyde, or by disuccinimidyl glutarate (DSG), with the latter agent preferred for cellular assays. We used ultra-high resolution homonuclear decoupled nuclear magnetic resonance experiments to probe the reactivity of the 15 alpha S Lys residues toward N-succinimidyl acetate, effectively half the DSG cross-linker, which results in acetylation of Lys. The intensities of both side chain and backbone amide signals of acetylated Lys residues provide direct information about the reactivity, showing a difference of a factor of 2.5 between the most reactive (K6) and the least reactive (K102) residue. The presence of phospholipid vesicles decreases reactivity of most Lys residues by up to an order of magnitude at high lipid:protein stoichiometries (500:1), but only weakly at low ratios. The decrease in Lys reactivity is found to be impacted by lipid composition, even for vesicles that yield similar alpha S CD signatures. Our data provide new insight into the alpha S-bilayer interaction, including the pivotal state in which the available lipid surface is limited. Protection of Lys C-epsilon amino groups by alpha S-bilayer interaction will strongly impact quantitative interpretation of DSG cross-linking experiments. C1 [Lee, Jung Ho; Ying, Jinfa; Bax, Ad] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM bax@nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; Intramural Antiviral Target Program of the Office of the Director, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and by the Intramural Antiviral Target Program of the Office of the Director, National Institutes of Health. NR 42 TC 1 Z9 1 U1 15 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 6 PY 2016 VL 55 IS 35 BP 4949 EP 4959 DI 10.1021/acs.biochem.6b00637 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV3FD UT WOS:000382805500007 PM 27455358 ER PT J AU Patti, M Fenollar-Ferrer, C Werner, A Forrest, LR Forster, IC AF Patti, Monica Fenollar-Ferrer, Cristina Werner, Andreas Forrest, Lucy R. Forster, Ian C. TI Cation Interactions and Membrane Potential Induce Conformational Changes in NaPi-IIb SO BIOPHYSICAL JOURNAL LA English DT Article ID NA+/P-I COTRANSPORTER; PHOSPHATE COTRANSPORTER; DICARBOXYLATE TRANSPORTER; SUBSTRATE INTERACTIONS; BINDING-SITES; MECHANISM; PROTEINS; ELECTROGENICITY; IDENTIFICATION; KINETICS AB Voltage-dependence of Na+-coupled phosphate cotransporters of the SLC34 family arises from displacement of charges intrinsic to the protein and the binding/release of one Na+ ion in response to changes in the transmembrane electric field. Candidate coordination residues for the cation at the Na1 site were previously predicted by structural modeling using the x-ray structure of dicarboxylate transporter VcINDY as template and confirmed by functional studies. Mutations at Na1 resulted in altered steady-state and presteady-state characteristics that should be mirrored in the conformational changes induced by membrane potential changes. To test this hypothesis by functional analysis, double mutants of the flounder SLC34A2 protein were constructed that contain one of the Na1-site perturbing mutations together with a substituted cysteine for fluorophore labeling, as expressed in Xenopus oocytes. The locations of the mutations were mapped onto a homology model of the flounder protein. The effects of the mutagenesis were characterized by steady-state, presteady-state, and fluorometric assays. Changes in fluorescence intensity (Delta F) in response to membrane potential steps were resolved at three previously identified positions. These fluorescence data corroborated the altered presteady-state kinetics upon perturbation of Na1, and furthermore indicated concomitant changes in the microenvironment of the respective fluorophores, as evidenced by changes in the voltage dependence and time course of Delta F. Moreover, iodide quenching experiments indicated that the aqueous nature of the fluorophore microenvironment depended on the membrane potential. These findings provide compelling evidence that membrane potential and cation interactions induce significant large-scale structural rearrangements of the protein. C1 [Fenollar-Ferrer, Cristina; Forrest, Lucy R.] NINDS, Computat Struct Biol Sect, Porter Neurosci Res Ctr, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Patti, Monica; Forster, Ian C.] Univ Zurich, Inst Physiol, Zurich, Switzerland. [Patti, Monica; Forster, Ian C.] Univ Zurich, Zurich Ctr Integrat Human Physiol, Zurich, Switzerland. [Werner, Andreas] Univ Newcastle Tyne, Epithelial Res Grp, Inst Cell & Mol Biosci, Newcastle Upon Tyne, Tyne & Wear, England. RP Forster, IC (reprint author), Univ Zurich, Inst Physiol, Zurich, Switzerland.; Forster, IC (reprint author), Univ Zurich, Zurich Ctr Integrat Human Physiol, Zurich, Switzerland. EM ian.forster@florey.edu.au FU Swiss National Science Foundation; Hartmann Muller Foundation; Northern Counties Kidney Research Fund, UK; Division of Intramural Research of the National Institutes of Health, National Institute of Neurological Disorders and Stroke FX Financial support was provided by the Swiss National Science Foundation (to I.C.F.) and the Hartmann Muller Foundation (to I.C.F.), the Northern Counties Kidney Research Fund, UK (to A.W.), and the Division of Intramural Research of the National Institutes of Health, National Institute of Neurological Disorders and Stroke (to L.R.F. and C.F.-F.). NR 28 TC 2 Z9 2 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD SEP 6 PY 2016 VL 111 IS 5 BP 973 EP 988 DI 10.1016/j.bpj.2016.07.025 PG 16 WC Biophysics SC Biophysics GA DV3DN UT WOS:000382801300013 PM 27602725 ER PT J AU Chen, J Liu, J AF Chen, Jing Liu, Jian TI Spindle Size Scaling Contributes to Robust Silencing of Mitotic Spindle Assembly Checkpoint SO BIOPHYSICAL JOURNAL LA English DT Article ID AURORA-B KINASE; CYTOPLASMIC DYNEIN; MEIOTIC SPINDLES; PROTEIN DYNAMICS; ELEGANS EMBRYOS; CENTROSOME SIZE; CELL-DIVISION; MICROTUBULE; KINETOCHORES; MITOSIS AB Chromosome segregation during mitosis hinges on proper assembly of the microtubule spindle that establishes bipolar attachment to each chromosome. Experiments demonstrate allometry of mitotic spindles and a universal scaling relationship between spindle size and cell size across metazoans, which indicates a conserved principle of spindle assembly at play during evolution. However, the nature of this principle is currently unknown. Researchers have focused on deriving the mechanistic underpinning of the size scaling from the mechanical aspects of the spindle assembly process. In this work we take a different standpoint and ask: What is the size scaling for? We address this question from the functional perspectives of spindle assembly checkpoint (SAC). SAC is the critical surveillance mechanism that prevents premature chromosome segregation in the presence of unattached or misattached chromosomes. The SAC signal gets silenced after and only after the last chromosome-spindle attachment in mitosis. We previously established a model that explains the robustness of SAC silencing based on spindle-mediated spatiotemporal regulation of SAC proteins. Here, we refine the previous model, and find that robust and timely SAC silencing entails proper size scaling of mitotic spindle. This finding provides, to our knowledge, a novel, function-oriented angle toward understanding the observed spindle allometry, and the universal scaling relationship between spindle size and cell size in metazoans. In a broad sense, the functional requirement of robust SAC silencing could have helped shape the spindle assembly mechanism in evolution. C1 [Chen, Jing] Virginia Polytech Inst & State Univ, Dept Biol Sci, Blacksburg, VA 24061 USA. [Liu, Jian] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Liu, J (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM jian.liu@nih.gov RI Chen, Jing/D-4845-2016 OI Chen, Jing/0000-0001-6321-0505 FU intramural research program at the National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD FX This work is supported by the intramural research program at the National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD. NR 58 TC 1 Z9 1 U1 3 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD SEP 6 PY 2016 VL 111 IS 5 BP 1064 EP 1077 DI 10.1016/j.bpj.2016.07.039 PG 14 WC Biophysics SC Biophysics GA DV3DN UT WOS:000382801300022 PM 27602734 ER PT J AU Torok, A Schiffer, PH Schnitzler, CE Ford, K Mullikin, JC Baxevanis, AD Bacic, A Frank, U Gornik, SG AF Torok, Anna Schiffer, Philipp H. Schnitzler, Christine E. Ford, Kris Mullikin, James C. Baxevanis, Andreas D. Bacic, Antony Frank, Uri Gornik, Sebastian G. TI The cnidarian Hydractinia echinata employs canonical and highly adapted histones to pack its DNA SO EPIGENETICS & CHROMATIN LA English DT Article DE Histone; Chromatin; Cnidaria; Histone variants; Sperm-specific histones ID NUCLEAR BASIC-PROTEINS; VARIANT H3.3; SEA-URCHIN; NUCLEOSOMAL DNA; MESSENGER-RNAS; CHROMATIN; SEQUENCE; SPERM; ORIGIN; GENE AB Background: Cnidarians are a group of early branching animals including corals, jellyfish and hydroids that are renowned for their high regenerative ability, growth plasticity and longevity. Because cnidarian genomes are conventional in terms of protein-coding genes, their remarkable features are likely a consequence of epigenetic regulation. To facilitate epigenetics research in cnidarians, we analysed the histone complement of the cnidarian model organism Hydractinia echinata using phylogenomics, proteomics, transcriptomics and mRNA in situ hybridisations. Results: We find that the Hydractinia genome encodes 19 histones and analyse their spatial expression patterns, genomic loci and replication-dependency. Alongside core and other replication-independent histone variants, we find several histone replication-dependent variants, including a rare replication-dependent H3.3, a female germ cell-specific H2A. X and an unusual set of five H2B variants, four of which are male germ cell-specific. We further confirm the absence of protamines in Hydractinia. Conclusions: Since no protamines are found in hydroids, we suggest that the novel H2B variants are pivotal for sperm DNA packaging in this class of Cnidaria. This study adds to the limited number of full histone gene complements available in animals and sets a comprehensive framework for future studies on the role of histones and their post-translational modifications in cnidarian epigenetics. Finally, it provides insight into the evolution of spermatogenesis. C1 [Torok, Anna; Frank, Uri; Gornik, Sebastian G.] Natl Univ Ireland, Sch Nat Sci, Ctr Chromosome Biol, Galway, Ireland. [Schiffer, Philipp H.] UCL, Genet Environm & Evolut, London, England. [Schnitzler, Christine E.; Mullikin, James C.; Baxevanis, Andreas D.] NHGRI, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Schnitzler, Christine E.; Ford, Kris] Univ Florida, Whitney Lab Marine Biosci, St Augustine, FL 32080 USA. [Ford, Kris; Bacic, Antony] Univ Melbourne, Sch Biosci, Australian Res Council, Ctr Excellence Plant Cell Walls, Parkville, Vic 3010, Australia. [Mullikin, James C.] NHGRI, NIH, Intramural Sequencing Ctr, Rockville, MD 20852 USA. RP Frank, U; Gornik, SG (reprint author), Natl Univ Ireland, Sch Nat Sci, Ctr Chromosome Biol, Galway, Ireland. EM uri.frank@nuigalway.ie; sebastian.gornik@nuigalway.ie OI Frank, Uri/0000-0003-2094-6381; Bacic, Tony/0000-0001-7483-8605 FU Science Foundation Ireland [13/SIRG/2125, 11-PI-1020]; European Commission [PIIF-GA-2013-623748]; Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health; Australian Research Council [CE1101007]; Volkswagen Foundation as part of their initiative for Evolutionary Biology FX This work was funded by Science Foundation Ireland [13/SIRG/2125 to SGG, 11-PI-1020 to UF], by the European Commission Marie Curie Actions [PIIF-GA-2013-623748 to SGG], by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health [to ADB], by the Australian Research Council [CE1101007 to AB] and by the Volkswagen Foundation as part of their initiative for Evolutionary Biology [to PHS]. NR 67 TC 0 Z9 0 U1 6 U2 6 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 SEP 6 PY 2016 VL 9 AR 36 DI 10.1186/s13072-016-0085-1 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA DV8CS UT WOS:000383165700001 PM 27602058 ER PT J AU Shee, K Lucas, A Flashman, LA Nho, K Tsongalis, GJ McDonald, BC Saykin, AJ McAllister, TW Rhodes, CH AF Shee, Kevin Lucas, Alexandra Flashman, Laura A. Nho, Kwangsik Tsongalis, Gregory J. McDonald, Brenna C. Saykin, Andrew J. McAllister, Thomas W. Rhodes, C. Harker TI Alpha-synuclein (SNCA) polymorphisms exert protective effects on memory after mild traumatic brain injury SO NEUROSCIENCE LETTERS LA English DT Article DE Traumatic brain injury; Parkinson's disease; Alpha-synuclein; Memory; Neuropsychiatry ID WORKING-MEMORY; DOPAMINE; EXPRESSION; DEPRESSION; DEPLETION; DEFICITS; CORTEX AB Problems with attention and short-term learning and memory are commonly reported after mild traumatic brain injury (mTBI). Due to the known relationships between alpha-synuclein (SNCA), dopaminergic transmission, and neurologic deficits, we hypothesized that SNCA polymorphisms might be associated with cognitive outcome after mTBI. A cohort of 91 mTBI patients one month after injury and 86 healthy controls completed a series of cognitive tests assessing baseline intellectual function, attentional function, and memory, and was genotyped at 13 common single nucleotide polymorphisms (SNPs) in the SNCA gene. Significant differences in two memory measures (p = 0.001 and 0.002), but not baseline intellectual function or attentional function tasks, were found between the mTBI group and controls. A highly significant protective association between memory performance and SNCA promoter SNP rs1372525 was observed in the mTBI patients (p = 0.006 and 0.029 for the long and short delay conditions of the California Verbal Learning Tests, respectively), where the presence of at least one copy of the A (minor) allele was protective after mTBI. These results may help elucidate the pathophysiology of cognitive alterations after mTBI, and thus warrant further investigation. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Shee, Kevin; Lucas, Alexandra] Geisel Sch Med, Hanover, NH USA. [Flashman, Laura A.] Geisel Sch Med, Dept Psychiat, Hanover, NH USA. [McAllister, Thomas W.] Indiana Univ Sch Med, Dept Psychiat, Indianapolis, IN 46202 USA. [Nho, Kwangsik; McDonald, Brenna C.; Saykin, Andrew J.] Indiana Univ Sch Med, Dept Radiol, Indianapolis, IN 46202 USA. [Nho, Kwangsik; McDonald, Brenna C.; Saykin, Andrew J.] Indiana Univ Sch Med, Dept Imaging Sci, Indianapolis, IN 46202 USA. [Tsongalis, Gregory J.; Rhodes, C. Harker] NIMH, Human Brain Collect Core, Bethesda, MD 20892 USA. RP Shee, K (reprint author), Geisel Sch Med Dartmouth, 1 Rope Ferry Rd, Hanover, NH 03755 USA. EM Kevin.Shee.MED@dartmouth.edu FU NICHD [R01 HD048176]; NCI [R01 CA101318]; NLM [R00 LM011384]; NIA [R01 AG019771, P30 AG010133] FX This research was supported in part by R01 HD048176 (NICHD), R01 CA101318 (NCI), R00 LM011384 (NLM), R01 AG019771 (NIA) and P30 AG010133 (NIA). NR 33 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 EI 1872-7972 J9 NEUROSCI LETT JI Neurosci. Lett. PD SEP 6 PY 2016 VL 630 BP 241 EP 246 DI 10.1016/j.neulet.2016.07.057 PG 6 WC Neurosciences SC Neurosciences & Neurology GA DV5ZG UT WOS:000383008600039 PM 27478013 ER PT J AU Zhang, SF Zhu, I Deng, T Furusawa, T Rochman, M Vacchio, MS Bosselut, R Yamane, A Casellas, R Landsman, D Bustin, M AF Zhang, Shaofei Zhu, Iris Deng, Tao Furusawa, Takashi Rochman, Mark Vacchio, Melanie S. Bosselut, Remy Yamane, Arito Casellas, Rafael Landsman, David Bustin, Michael TI HMGN proteins modulate chromatin regulatory sites and gene expression during activation of naive B cells SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HISTONE H1; CHROMOSOMAL-PROTEINS; LINKER HISTONE; LIVING CELLS; HUMAN GENOME; MOBILITY; BINDING; TRANSCRIPTION; LYMPHOCYTES; NUCLEOSOMES AB The activation of naive B lymphocyte involves rapid and major changes in chromatin organization and gene expression; however, the complete repertoire of nuclear factors affecting these genomic changes is not known. We report that HMGN proteins, which bind to nucleosomes and affect chromatin structure and function, co-localize with, and maintain the intensity of DNase I hypersensitive sites genome wide, in resting but not in activated B cells. Transcription analyses of resting and activated B cells from wildtype and Hmgn(-/-) mice, show that loss of HMGNs dampens the magnitude of the transcriptional response and alters the pattern of gene expression during the course of B-cell activation; defense response genes are most affected at the onset of activation. Our study provides insights into the biological function of the ubiquitous HMGN chromatin binding proteins and into epigenetic processes that affect the fidelity of the transcriptional response during the activation of B cell lymphocytes. C1 [Zhang, Shaofei; Deng, Tao; Furusawa, Takashi; Rochman, Mark; Bustin, Michael] NCI, Prot Sect, Lab Metab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Zhu, Iris; Landsman, David] Natl Lib Med, Computat Biol Branch, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. [Vacchio, Melanie S.; Bosselut, Remy] NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Yamane, Arito; Casellas, Rafael] NIAMS, Genom & Immun, NIH, Bethesda, MD 20892 USA. [Rochman, Mark] Cincinnati Childrens Hosp, Div Allergy & Immunol, Cincinnati, OH 45229 USA. RP Bustin, M (reprint author), NCI, Prot Sect, Lab Metab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA.; Landsman, D (reprint author), Natl Lib Med, Computat Biol Branch, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. EM landsman@ncbi.nlm.nih.gov; bustin@helix.nih.gov RI Bustin, Michael/G-6155-2015; OI Landsman, David/0000-0002-9819-6675 FU Center for Cancer Research; Intramural Research Programs of the National Cancer Institute, NIH; National Center for Biotechnology Information; National Library of Medicine, NIH; NIH FX Center for Cancer Research; Intramural Research Programs of the National Cancer Institute, NIH; National Center for Biotechnology Information; National Library of Medicine, NIH. Funding for open access charge: NIH. NR 46 TC 0 Z9 0 U1 3 U2 3 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 SEP 6 PY 2016 VL 44 IS 15 BP 7144 EP 7158 DI 10.1093/nar/gkw323 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV5WJ UT WOS:000383001100013 PM 27112571 ER PT J AU Li, Y Schulz, VP Deng, CW Li, GY Shen, Y Tusi, BK Ma, GN Stees, J Qiu, Y Steiner, LA Zhou, L Zhao, KJ Bungert, J Gallagher, PG Huang, SM AF Li, Ying Schulz, Vincent P. Deng, Changwang Li, Guangyao Shen, Yong Tusi, Betsabeh K. Ma, Gina Stees, Jared Qiu, Yi Steiner, Laurie A. Zhou, Lei Zhao, Keji Bungert, Jorg Gallagher, Patrick G. Huang, Suming TI Setd1a and NURF mediate chromatin dynamics and gene regulation during erythroid lineage commitment and differentiation SO NUCLEIC ACIDS RESEARCH LA English DT Article ID BETA-GLOBIN LOCUS; INTEGRATIVE GENOMICS VIEWER; CHIP-SEQ; METHYLTRANSFERASE ACTIVITY; MOLECULAR REGULATION; CONTROL REGION; STEM-CELLS; TRANSCRIPTION; ERYTHROPOIESIS; COMPLEXES AB The modulation of chromatin structure is a key step in transcription regulation in mammalian cells and eventually determines lineage commitment and differentiation. USF1/2, Setd1a and NURF complexes interact to regulate chromatin architecture in erythropoiesis, but the mechanistic basis for this regulation is hitherto unknown. Here we showed that Setd1a and NURF complexes bind to promoters to control chromatin structural alterations and gene activation in a cell context dependent manner. In human primary erythroid cells USF1/2, H3K4me3 and the NURF complex were significantly co-enriched at transcription start sites of erythroid genes, and their binding was associated with promoter/enhancer accessibility that resulted from nucleosome repositioning. Mice deficient for Setd1a, an H3K4 trimethylase, in the erythroid compartment exhibited reduced Ter119/CD71 positive erythroblasts, peripheral blood RBCs and hemoglobin levels. Loss of Setd1a led to a reduction of promoter-associated H3K4 methylation, inhibition of gene transcription and blockade of erythroid differentiation. This was associated with alterations in NURF complex occupancy at erythroid gene promoters and reduced chromatin accessibility. Setd1a deficiency caused decreased associations between enhancer and promoter looped interactions as well as reduced expression of erythroid genes such as the adult beta-globin gene. These data indicate that Setd1a and NURF complexes are specifically targeted to and coordinately regulate erythroid promoter chromatin dynamics during erythroid lineage differentiation. C1 [Li, Ying; Deng, Changwang; Shen, Yong; Tusi, Betsabeh K.; Stees, Jared; Bungert, Jorg; Huang, Suming] Univ Florida, Coll Med, Dept Biochem & Mol Biol, Gainesville, FL 32610 USA. [Li, Ying; Huang, Suming] Macau Univ Sci & Technol, State Key Lab Qual Res Chinese Med, Macau Inst Appl Res Med & Hlth, Ave Wai Long, Taipa 519020, Macau, Peoples R China. [Schulz, Vincent P.; Gallagher, Patrick G.] Yale Univ, Sch Med, Dept Pediat Pathol & Genet, 333 Cedar St, New Haven, CT 06520 USA. [Li, Guangyao; Zhou, Lei] Univ Florida, Coll Med, Dept Mol Genet & Microbiol, Gainesville, FL 32610 USA. [Ma, Gina] Johns Hopkins Univ, Publ Hlth Studies, Baltimore, MD 21218 USA. [Qiu, Yi] Univ Florida, Coll Med, Dept Anat & Cell Biol, Gainesville, FL 32610 USA. [Qiu, Yi; Zhou, Lei; Bungert, Jorg; Huang, Suming] Univ Florida, Genet Inst, Gainesville, FL 32610 USA. [Qiu, Yi; Zhou, Lei; Huang, Suming] Univ Florida, Coll Med, UF Hlth Canc Ctr, Gainesville, FL 32610 USA. [Steiner, Laurie A.] Univ Rochester, Dept Pediat, Rochester, NY 14642 USA. [Zhao, Keji] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20814 USA. RP Huang, SM (reprint author), Univ Florida, Coll Med, Dept Biochem & Mol Biol, Gainesville, FL 32610 USA.; Huang, SM (reprint author), Macau Univ Sci & Technol, State Key Lab Qual Res Chinese Med, Macau Inst Appl Res Med & Hlth, Ave Wai Long, Taipa 519020, Macau, Peoples R China.; Gallagher, PG (reprint author), Yale Univ, Sch Med, Dept Pediat Pathol & Genet, 333 Cedar St, New Haven, CT 06520 USA.; Huang, SM (reprint author), Univ Florida, Genet Inst, Gainesville, FL 32610 USA.; Huang, SM (reprint author), Univ Florida, Coll Med, UF Hlth Canc Ctr, Gainesville, FL 32610 USA. EM Patrick.gallagher@yale.edu; sumingh@ufl.edu FU National Institute of Health [R56DK101994, R01HL106184, R01HL095674, R01DK052356, R01GM106174]; National Heart Lung and Blood Institute FX National Institute of Health [R56DK101994 to S.H; R01HL106184 to P.G.G.; R01HL095674 to Y.Q.; R01DK052356 to J.B.; R01GM106174 to L.Z.]; Intramural research programs (to K.Z.); National Heart Lung and Blood Institute; National Institute of Health. Funding for open access charge: National Institute of Health [R56DK101994, R01HL106184]. NR 61 TC 1 Z9 1 U1 4 U2 4 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 SEP 6 PY 2016 VL 44 IS 15 BP 7173 EP 7188 DI 10.1093/nar/gkw327 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV5WJ UT WOS:000383001100015 PM 27141965 ER PT J AU Roy, U Mukherjee, S Sharma, A Frank, EG Scharer, OD AF Roy, Upasana Mukherjee, Shivam Sharma, Anjali Frank, Ekaterina G. Scharer, Orlando D. TI The structure and duplex context of DNA interstrand crosslinks affects the activity of DNA polymerase eta SO NUCLEIC ACIDS RESEARCH LA English DT Article ID YEAST REV1 PROTEIN; TRANSLESION SYNTHESIS; INDEPENDENT REPAIR; CATALYTIC SUBUNIT; FANCONI-ANEMIA; THYMINE DIMER; REPLICATION; MECHANISM; BYPASS; CISPLATIN AB Several important anti-tumor agents form DNA interstrand crosslinks (ICLs), but their clinical efficiency is counteracted by multiple complex DNA repair pathways. All of these pathways require unhooking of the ICL from one strand of a DNA duplex by nucleases, followed by bypass of the unhooked ICL by translesion synthesis (TLS) polymerases. The structures of the unhooked ICLs remain unknown, yet the position of incisions and processing of the unhooked ICLs significantly influence the efficiency and fidelity of bypass by TLS polymerases. We have synthesized a panel of model unhooked nitrogen mustard ICLs to systematically investigate how the state of an unhooked ICL affects pol eta activity. We find that duplex distortion induced by a crosslink plays a crucial role in translesion synthesis, and length of the duplex surrounding an unhooked ICL critically affects polymerase efficiency. We report the synthesis of a putative ICL repair intermediate that mimics the complete processing of an unhooked ICL to a single crosslinked nucleotide, and find that it provides only aminimal obstacle for DNA polymerases. Our results raise the possibility that, depending on the structure and extent of processing of an ICL, its bypass may not absolutely require TLS polymerases. C1 [Roy, Upasana; Mukherjee, Shivam; Scharer, Orlando D.] SUNY Stony Brook, Dept Chem, Stony Brook, NY 11794 USA. [Sharma, Anjali; Scharer, Orlando D.] SUNY Stony Brook, Dept Pharmacol Sci, Stony Brook, NY 11794 USA. [Frank, Ekaterina G.] NICHHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. RP Scharer, OD (reprint author), SUNY Stony Brook, Dept Chem, Stony Brook, NY 11794 USA.; Scharer, OD (reprint author), SUNY Stony Brook, Dept Pharmacol Sci, Stony Brook, NY 11794 USA. EM orlando.scharer@stonybrook.edu RI Scharer, Orlando/B-8908-2008 OI Scharer, Orlando/0000-0003-2425-2715 FU NCI [R01 CA165911]; NICHD Intramural Research Program FX NCI [R01 CA165911 to O.D.S]; NICHD Intramural Research Program (to E.G.F). Funding for open access charge: NCI [R01 CA165911]. NR 58 TC 1 Z9 1 U1 5 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 SEP 6 PY 2016 VL 44 IS 15 BP 7281 EP 7291 DI 10.1093/nar/gkw485 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV5WJ UT WOS:000383001100023 PM 27257072 ER PT J AU Tiedje, C Diaz-Munoz, MD Trulley, P Ahlfors, H Laass, K Blackshear, PJ Turner, M Gaestel, M AF Tiedje, Christopher Diaz-Munoz, Manuel D. Trulley, Philipp Ahlfors, Helena Laass, Kathrin Blackshear, Perry J. Turner, Martin Gaestel, Matthias TI The RNA-binding protein TTP is a global post-transcriptional regulator of feedback control in inflammation SO NUCLEIC ACIDS RESEARCH LA English DT Article ID TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; INNATE IMMUNE-RESPONSES; TRISTETRAPROLIN MESSENGER-RNA; AU-RICH ELEMENTS; CELL-SURVIVAL; KINASE P38; TNF-ALPHA; STABILITY; EXPRESSION AB RNA-binding proteins (RBPs) facilitate post-transcriptional control of eukaryotic gene expression at multiple levels. The RBP tristetraprolin (TTP/Zfp36) is a signal-induced phosphorylated anti-inflammatory protein guiding unstable mRNAs of pro-inflammatory proteins for degradation and preventing translation. Using iCLIP, we have identified numerous mRNA targets bound by wild-type TTP and by a non-MK2-phosphorylatable TTP mutant (TTP-AA) in 1 h LPS-stimulated macrophages and correlated their interaction with TTP to changes at the level of mRNA abundance and translation in a transcriptome-wide manner. The close similarity of the transcriptomes of TTP-deficient and TTP-expressing macrophages upon short LPS stimulation suggested an effective inactivation of TTP by MK2, whereas retained RNA-binding capacity of TTP-AA to 3'UTRs caused profound changes in the transcriptome and translatome, altered NF-kappa B-activation and induced cell death. Increased TTP binding to the 3'UTR of feedback inhibitor mRNAs, such as Ier3, Dusp1 or Tnfaip3, in the absence of MK2-dependent TTP neutralization resulted in a strong reduction of their protein synthesis contributing to the deregulation of the NF-kappa B-signaling pathway. Taken together, our study uncovers a role of TTP as a suppressor of feedback inhibitors of inflammation and highlights the importance of fine-tuned TTP activity-regulation by MK2 in order to control the pro-inflammatory response. C1 [Tiedje, Christopher; Trulley, Philipp; Laass, Kathrin; Gaestel, Matthias] Med Sch Hannover MHH, Inst Physiol Chem, D-30625 Hannover, Germany. [Diaz-Munoz, Manuel D.; Ahlfors, Helena; Turner, Martin] Babraham Inst, Lymphocyte Signalling & Dev, Cambridge CB22 3AT, England. [Blackshear, Perry J.] NIEHS, Lab Signal Transduct, POB 12233, Res Triangle Pk, NC 27709 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. RP Tiedje, C (reprint author), Med Sch Hannover MHH, Inst Physiol Chem, D-30625 Hannover, Germany.; Diaz-Munoz, MD (reprint author), Babraham Inst, Lymphocyte Signalling & Dev, Cambridge CB22 3AT, England. EM Tiedje.Christopher@mh-hannover.de; manuel.diaz-munoz@babraham.ac.uk FU European Molecular Biology Organization (EMBO) short-term fellowship [EMBO-ASTF-69-2013]; Zytokinpreis der Freunde der MHH e.V.; Deutsche Forschungsgemeinschaft [Ga 453/13-1]; Biotechnology and Biological Sciences Research Council (BBRSC) [BB/J00152X/1]; National Institutes of Health (NIH); National Institute of Environmental Health Sciences (NIEHS); DFG [Ga 453/13-1]; Hannover Medical School 'Young Academy'; [BBS/E/B/000C0409] FX European Molecular Biology Organization (EMBO) short-term fellowship [EMBO-ASTF-69-2013]; 'Zytokinpreis der Freunde der MHH e.V.' (to C.T.); Deutsche Forschungsgemeinschaft [Ga 453/13-1 to C.T. and M.G.]; Biotechnology and Biological Sciences Research Council (BBRSC) strategic Lola [BB/J00152X/1 to M.D.D.-M., H.A. and M.T.]; programme funding [BBS/E/B/000C0409]; National Institutes of Health (NIH) (to P.J.B.); National Institute of Environmental Health Sciences (NIEHS). Funding for open access charge: DFG grant [Ga 453/13-1]; Hannover Medical School 'Young Academy'. NR 84 TC 6 Z9 6 U1 4 U2 4 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 SEP 6 PY 2016 VL 44 IS 15 BP 7418 EP 7440 DI 10.1093/nar/gkw474 PG 23 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV5WJ UT WOS:000383001100034 PM 27220464 ER PT J AU Hartley, SW Mullikin, JC AF Hartley, Stephen W. Mullikin, James C. TI Detection and visualization of differential splicing in RNA-Seq data with JunctionSeq SO NUCLEIC ACIDS RESEARCH LA English DT Article ID RAT PINEAL-GLAND; TRANSCRIPTION FACTOR; SEQUENCING EXPERIMENTS; N-ACETYLTRANSFERASE; SIGNAL-TRANSDUCTION; MELATONIN SYNTHESIS; EXPRESSION; GENE; PHOSPHORYLATION; GENOME AB Although RNA-Seq data provide unprecedented isoform-level expression information, detection of alternative isoform regulation (AIR) remains difficult, particularly when working with an incomplete transcript annotation. We introduce JunctionSeq, a new method that builds on the statistical techniques used by the well-established DEXSeq package to detect differential usage of both exonic regions and splice junctions. In particular, JunctionSeq is capable of detecting differential usage of novel splice junctions without the need for an additional isoform assembly step, greatly improving performance when the available transcript annotation is flawed or incomplete. JunctionSeq also provides a powerful and streamlined visualization toolset that allows bioinformaticians to quickly and intuitively interpret their results. We tested our method on publicly available data from several experiments performed on the rat pineal gland and Toxoplasma gondii, successfully detecting known and previously validated AIR genes in 19 out of 19 gene-level hypothesis tests. Due to its ability to query novel splice sites, JunctionSeq is still able to detect these differences even when all alternative isoforms for these genes were not included in the transcript annotation. JunctionSeq thus provides a powerful method for detecting alternative isoform regulation even with low-quality annotations. An implementation of JunctionSeq is available as an R/Bioconductor package. C1 [Hartley, Stephen W.; Mullikin, James C.] NHGRI, Comparat Genom Anal Unit, Canc Genet & Comparat Genom Branch, NIH, Bethesda, MD 20892 USA. RP Hartley, SW (reprint author), NHGRI, Comparat Genom Anal Unit, Canc Genet & Comparat Genom Branch, NIH, Bethesda, MD 20892 USA. EM stephen.hartley@nih.gov FU Intramural Research Program of the National Human Genome Research Institute; National Institutes of Health; Comparative Genomics Analysis Unit, Cancer Genomics and Comarative Genomics Branch, National Human Genome Research Institute, National Institutes of Health FX Intramural Research Program of the National Human Genome Research Institute; National Institutes of Health. Funding for open access charge: Comparative Genomics Analysis Unit, Cancer Genomics and Comarative Genomics Branch, National Human Genome Research Institute, National Institutes of Health. NR 62 TC 3 Z9 3 U1 8 U2 8 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 SEP 6 PY 2016 VL 44 IS 15 AR e127 DI 10.1093/nar/gkw501 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV5WJ UT WOS:000383001100002 PM 27257077 ER PT J AU Duffy, S Fam, HK Wang, YK Styles, EB Kim, JH Ang, JS Singh, T Larionov, V Shah, SP Andrews, B Boerkoel, CF Hieter, P AF Duffy, Supipi Fam, Hok Khim Wang, Yi Kan Styles, Erin B. Kim, Jung-Hyun Ang, J. Sidney Singh, Tejomayee Larionov, Vladimir Shah, Sohrab P. Andrews, Brenda Boerkoel, Cornelius F. Hieter, Philip TI Overexpression screens identify conserved dosage chromosome instability genes in yeast and human cancer SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE dosage chromosome instability; overexpression; synthetic dosage lethality; TDP1; rhabdomyosarcoma ID HISTONE DEACETYLASE INHIBITOR; PHOSPHOLIPASE-D SUPERFAMILY; DNA PHOSPHODIESTERASE TDP1; CHILDRENS ONCOLOGY GROUP; COPY-NUMBER ALTERATION; I COVALENT COMPLEXES; SACCHAROMYCES-CEREVISIAE; TRANSMISSION FIDELITY; SYNTHETIC LETHAL; SPINOCEREBELLAR ATAXIA AB Somatic copy number amplification and gene overexpression are common features of many cancers. To determine the role of gene overexpression on chromosome instability (CIN), we performed genome-wide screens in the budding yeast for yeast genes that cause CIN when overexpressed, a phenotype we refer to as dosage CIN (dCIN), and identified 245 dCIN genes. This catalog of genes reveals human orthologs known to be recurrently overexpressed and/or amplified in tumors. We show that two genes, TDP1, a tyrosyl-DNA-phosphdiesterase, and TAF12, an RNA polymerase II TATA-box binding factor, cause CIN when overexpressed in human cells. Rhabdomyosarcoma lines with elevated human Tdp1 levels also exhibit CIN that can be partially rescued by siRNA-mediated knockdown of TDP1. Overexpression of dCIN genes represents a genetic vulnerability that could be leveraged for selective killing of cancer cells through targeting of an unlinked synthetic dosage lethal (SDL) partner. Using SDL screens in yeast, we identified a set of genes that when deleted specifically kill cells with high levels of Tdp1. One gene was the histone deacetylase RPD3, for which there are known inhibitors. Both HT1080 cells overexpressing hTDP1 and rhabdomyosarcoma cells with elevated levels of hTdp1 were more sensitive to histone deacetylase inhibitors valproic acid (VPA) and trichostatin A (TSA), recapitulating the SDL interaction in human cells and suggesting VPA and TSA as potential therapeutic agents for tumors with elevated levels of hTdp1. The catalog of dCIN genes presented here provides a candidate list to identify genes that cause CIN when overexpressed in cancer, which can then be leveraged through SDL to selectively target tumors. C1 [Duffy, Supipi; Ang, J. Sidney; Singh, Tejomayee; Hieter, Philip] Univ British Columbia, Michael Smith Labs, Vancouver, BC V6T 1Z4, Canada. [Fam, Hok Khim; Boerkoel, Cornelius F.] Univ British Columbia, Child & Family Res Inst, Vancouver, BC V5Z 4H4, Canada. [Fam, Hok Khim; Boerkoel, Cornelius F.; Hieter, Philip] Univ British Columbia, Dept Med Genet, Vancouver, BC V6T 1Z3, Canada. [Wang, Yi Kan; Shah, Sohrab P.] BC Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Styles, Erin B.; Andrews, Brenda] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada. [Styles, Erin B.; Andrews, Brenda] Univ Toronto, Donnelly Ctr Cellular & Biomol Res, Toronto, ON M5S 3E1, Canada. [Kim, Jung-Hyun; Larionov, Vladimir] Natl Canc Inst, Ctr Canc Res, Bethesda, MD 20892 USA. RP Hieter, P (reprint author), Univ British Columbia, Michael Smith Labs, Vancouver, BC V6T 1Z4, Canada.; Hieter, P (reprint author), Univ British Columbia, Dept Med Genet, Vancouver, BC V6T 1Z3, Canada. EM hieter@msl.ubc.ca FU Canadian Institute of Health Research [MOP 38096]; National Institute of Health [RO1CA158162]; Canadian Institute for Advance Research Global Fellowship FX We thank Dr. Nigel O'Neil, Dr. Melanie Bailey, and Dr. Peter C. Stirling for their helpful discussion and comments. This work was supported by Canadian Institute of Health Research Grant MOP 38096 and National Institute of Health Grant RO1CA158162 (to P.H.). S.D. was supported by a Canadian Institute for Advance Research Global Fellowship and a Canadian Institute for Health Research Banting Postdoctoral Fellowship. P.H. and B.A. are senior fellows in the Genetics Networks Program at the Canadian Institute for Advanced Research. C.F.B. is a scholar of the Michael Smith Foundation for Health Research (Vancouver, Canada) and a Clinical Investigator of the Child & Family Research Institute (Vancouver, Canada). NR 114 TC 3 Z9 3 U1 5 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 SEP 6 PY 2016 VL 113 IS 36 BP 9967 EP 9976 DI 10.1073/pnas.1611839113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV7CU UT WOS:000383094500024 PM 27551064 ER PT J AU Zhou, Q Yu, XM Demirkaya, E Deuitch, N Stone, D Tsai, WXL Kuehn, HS Wang, HY Yang, D Park, YH Ombrello, AK Blake, M Romeo, T Remmers, EF Chae, JJ Mullikin, JC Guzel, F Milner, JD Boehm, M Rosenzweig, SD Gadina, M Welch, SB Ozeni, S Topaloglu, R Abinun, M Kastner, DL Aksentijevich, I AF Zhou, Qing Yu, Xiaomin Demirkaya, Erkan Deuitch, Natalie Stone, Deborah Tsai, Wanxia Li Kuehn, Hye Sun Wang, Hongying Yang, Dan Park, Yong Hwan Ombrello, Amanda K. Blake, Mary Romeo, Tina Remmers, Elaine F. Chae, Jae Jin Mullikin, James C. Guzel, Ferhat Milner, Joshua D. Boehm, Manfred Rosenzweig, Sergio D. Gadina, Massimo Welch, Steven B. Ozeni, Seza Topaloglu, Rezan Abinun, Mario Kastner, Daniel L. Aksentijevich, Ivona TI Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE OTULIN; linear deubiquitinase; NF-kappa B pathway; autoinflammatory disease; cytokines ID ASSEMBLY COMPLEX; LUBAC DEFICIENCY; CELL-DEATH; UBIQUITIN; HOIP; IMMUNODEFICIENCY; AMYLOPECTINOSIS; INFLAMMATION; ACTIVATION; SHARPIN AB Systemic autoinflammatory diseases are caused by mutations in genes that function in innate immunity. Here, we report an autoinflammatory disease caused by loss-of-function mutations in OTULIN (FAM105B), encoding a deubiquitinase with linear linkage specificity. We identified two missense and one frameshift mutations in one Pakistani and two Turkish families with four affected patients. Patients presented with neonatal-onset fever, neutrophilic dermatitis/panniculitis, and failure to thrive, but without obvious primary immunodeficiency. HEK293 cells transfected with mutated OTULIN had decreased enzyme activity relative to cells transfected with WT OTULIN, and showed a substantial defect in the linear deubiquitination of target molecules. Stimulated patients' fibroblasts and peripheral blood mononuclear cells showed evidence for increased signaling in the canonical NF-kappa B pathway and accumulated linear ubiquitin aggregates. Levels of proinflammatory cytokines were significantly increased in the supernatants of stimulated primary cells and serum samples. This discovery adds to the emerging spectrum of human diseases caused by defects in the ubiquitin pathway and suggests a role for targeted cytokine therapies. C1 [Zhou, Qing; Deuitch, Natalie; Stone, Deborah; Wang, Hongying; Park, Yong Hwan; Ombrello, Amanda K.; Romeo, Tina; Remmers, Elaine F.; Chae, Jae Jin; Kastner, Daniel L.; Aksentijevich, Ivona] NHGRI, Inflammatory Dis Sect, Bethesda, MD 20892 USA. [Yu, Xiaomin; Milner, Joshua D.] NIAID, Genet & Pathogenesis Allergy Sect, Lab Allerg Dis, Bethesda, MD 20892 USA. [Demirkaya, Erkan; Guzel, Ferhat] Gulhane Mil Med Acad, Inst Hlth Sci, Familial Mediterranean Fever Arthrit Vasculitis &, R&D Ctr, TR-06018 Ankara, Turkey. [Tsai, Wanxia Li; Blake, Mary; Gadina, Massimo] NIAMSD, Translat Immunol Sect, Bethesda, MD 20892 USA. [Kuehn, Hye Sun; Rosenzweig, Sergio D.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Yang, Dan; Boehm, Manfred] NHLBI, Lab Cardiovasc Regenerat Med, Bethesda, MD 20892 USA. [Mullikin, James C.] NHGRI, NIH, Intramural Sequencing Ctr, Rockville, MD 20852 USA. [Welch, Steven B.] Heart England Natl Hlth Serv Fdn Trust, Birmingham B9 5ST, W Midlands, England. [Ozeni, Seza; Topaloglu, Rezan] Hacettepe Univ, Dept Pediat Nephrol & Rheumatol, Fac Med, TR-06100 Ankara, Turkey. [Abinun, Mario] Newcastle Univ, Inst Cellular Med, Newcastle NE2 4HH, England. RP Kastner, DL; Aksentijevich, I (reprint author), NHGRI, Inflammatory Dis Sect, Bethesda, MD 20892 USA. EM kastnerd@mail.nih.gov; aksentii@mail.nih.gov FU Intramural Research Programs of the National Human Genome Research Institute; NIAMS; NHLBI; National Institute of Allergy and Infectious Diseases; NIH Clinical Center; Tubitak 1003, Primary Subjects R&D Funding Program - Scientific and Technological Research Council of Turkey [315S122] FX We thank all the patients and their families, and the healthy controls, for their enthusiastic support during this research study. We thank Drs. Alejandra Negro and Xiaodong Fu from National Heart, Lung, and Blood Institute (NHLBI) for technical support, and Dr. Eric P. Hanson from National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) for helpful suggestions. This research was supported by the Intramural Research Programs of the National Human Genome Research Institute, NIAMS, NHLBI, National Institute of Allergy and Infectious Diseases, and the NIH Clinical Center. E.D. received grant support from Tubitak 1003, Primary Subjects R&D Funding Program (Project 315S122), which is supported by the Scientific and Technological Research Council of Turkey. NR 19 TC 7 Z9 7 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 SEP 6 PY 2016 VL 113 IS 36 BP 10127 EP 10132 DI 10.1073/pnas.1612594113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV7CU UT WOS:000383094500050 PM 27559085 ER PT J AU Loh, L Wang, ZF Sant, S Koutsakos, M Jegaskanda, S Corbett, AJ Liu, LG Fairlie, DP Crowe, J Rossjohn, J Xu, JQ Doherty, PC McCluskey, J Kedzierska, K AF Loh, Liyen Wang, Zhongfang Sant, Sneha Koutsakos, Marios Jegaskanda, Sinthujan Corbett, Alexandra J. Liu, Ligong Fairlie, David P. Crowe, Jane Rossjohn, Jamie Xu, Jianqing Doherty, Peter C. McCluskey, James Kedzierska, Katherine TI Human mucosal-associated invariant T cells contribute to antiviral influenza immunity via IL-18-dependent activation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE MAIT cells; influenza virus; H7N9; IL-18; monocytes ID VITAMIN-B METABOLITES; MAIT CELLS; RECEPTOR HETEROGENEITY; RAPID DIFFERENTIATION; DENDRITIC CELLS; VIRUS-INFECTION; HIV-INFECTION; IL-18; MR1; HYPERCYTOKINEMIA AB Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes known to elicit potent immunity to a broad range of bacteria, mainly via the rapid production of inflammatory cytokines. Whether MAIT cells contribute to antiviral immunity is less clear. Here we asked whether MAIT cells produce cytokines/chemokines during severe human influenza virus infection. Our analysis in patients hospitalized with avian H7N9 influenza pneumonia showed that individuals who recovered had higher numbers of CD161(+)V alpha 7.2(+) MAIT cells in peripheral blood compared with those who succumbed, suggesting a possible protective role for this lymphocyte population. To understand the mechanism underlying MAIT cell activation during influenza, we cocultured influenza A virus (IAV)-infected human lung epithelial cells (A549) and human peripheral blood mononuclear cells in vitro, then assayed them by intracellular cytokine staining. Comparison of influenza-induced MAIT cell activation with the profile for natural killer cells (CD56(+)CD3(-)) showed robust up-regulation of IFN gamma for both cell populations and granzyme B in MAIT cells, although the individual responses varied among healthy donors. However, in contrast to the requirement for cell-associated factors to promote NK cell activation, the induction of MAIT cell cytokine production was dependent on IL-18 (but not IL-12) production by IAV-exposed CD14(+) monocytes. Overall, this evidence for IAV activation via an indirect, IL-18-dependent mechanism indicates that MAIT cells are protective in influenza, and also possibly in any human disease process in which inflammation and IL-18 production occur. C1 [Loh, Liyen; Wang, Zhongfang; Sant, Sneha; Koutsakos, Marios; Jegaskanda, Sinthujan; Corbett, Alexandra J.; Doherty, Peter C.; McCluskey, James; Kedzierska, Katherine] Univ Melbourne, Dept Microbiol & Immunol, Peter Doherty Inst Infect & Immun, Melbourne, Vic 3000, Australia. [Jegaskanda, Sinthujan] NIAID, Bethesda, MD 20852 USA. [Liu, Ligong; Fairlie, David P.] Univ Queensland, Ctr Inflammat Dis Res, Brisbane, Qld 4072, Australia. [Liu, Ligong; Fairlie, David P.] Univ Queensland, ARC Ctr Excellence Adv Mol Imaging, Inst Mol Biosci, Brisbane, Qld 4072, Australia. [Crowe, Jane] Deepdene Surg, Deepdene, Vic 3103, Australia. [Rossjohn, Jamie] Monash Univ, Infect & Immun Program, Biomed Discovery Inst, Clayton, Vic 3800, Australia. [Rossjohn, Jamie] Monash Univ, Dept Biochem & Mol Biol, Biomed Discovery Inst, Clayton, Vic 3800, Australia. [Rossjohn, Jamie] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff CF14 4XN, S Glam, Wales. [Rossjohn, Jamie] Monash Univ, Australian Res Council, Ctr Excellence Adv Mol Imaging, Clayton, Vic 3800, Australia. [Xu, Jianqing] Fudan Univ, Shanghai Med Coll, Shanghai Publ Hlth Clin Ctr, Shanghai 201508, Peoples R China. [Xu, Jianqing] Fudan Univ, Shanghai Med Coll, Minist Educ Hlth, Inst Biomed Sci,Key Lab Med Mol Virol, Shanghai 201508, Peoples R China. [Doherty, Peter C.] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA. RP Doherty, PC; Kedzierska, K (reprint author), Univ Melbourne, Dept Microbiol & Immunol, Peter Doherty Inst Infect & Immun, Melbourne, Vic 3000, Australia.; Doherty, PC (reprint author), St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA. EM pcd@unimelb.edu.au; kkedz@unimelb.edu.au RI McCluskey, James/A-1291-2007; liu, ligong/B-1690-2010; OI McCluskey, James/0000-0002-8597-815X; liu, ligong/0000-0002-2693-1896; Rossjohn, Jamie/0000-0002-2020-7522; Fairlie, David/0000-0002-7856-8566; Corbett, Alexandra/0000-0003-1618-4337 FU National Health and Medical Research Council Program (NHMRC) [1071916]; NHMRC C. J. Martin fellowship; NHMRC Australia-China exchange fellowship; Victoria-India Doctoral Scholarship; Melbourne International Fee Remission Scholarship (MIFRS); Melbourne International Research Scholarship; MIFRS FX We thank Andrew Brooks for insightful discussions; Ted Hansen for the alpha-MR1-26.5 blocking reagent; and Thakshila Amarasena, Sheilajen Alcantara, and Bernie McCudden for collecting blood. We thank all donors for donating blood for this study. This work was supported by National Health and Medical Research Council Program (NHMRC) Grant 1071916 (to P.C.D. and K.K.). L. Loh and S.J. were supported by an NHMRC C. J. Martin fellowship. Z.W. was supported by an NHMRC Australia-China exchange fellowship. K.K. is an NHMRC Senior Research Fellow. J.R. is an NHMRC Australia Fellow (AF50). D.P.F. is an NHMRC Senior Principal Research Fellow (1027369). S.S. is supported by a Victoria-India Doctoral Scholarship and a Melbourne International Fee Remission Scholarship (MIFRS). M.K. is supported by a Melbourne International Research Scholarship and an MIFRS. NR 36 TC 1 Z9 1 U1 11 U2 12 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 SEP 6 PY 2016 VL 113 IS 36 BP 10133 EP 10138 DI 10.1073/pnas.1610750113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV7CU UT WOS:000383094500051 PM 27543331 ER PT J AU Guo, XL Farias, GG Mattera, R Bonifacino, JS AF Guo, Xiaoli Farias, Ginny G. Mattera, Rafael Bonifacino, Juan S. TI Rab5 and its effector FHF contribute to neuronal polarity through dynein-dependent retrieval of somatodendritic proteins from the axon SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Rab5; FHF complex; dynein; neuronal polarity; retrograde transport ID SMALL GTPASE RAB5; KINESIN SUPERFAMILY MOTOR; HIPPOCAMPAL-NEURONS; EARLY ENDOSOMES; INITIAL SEGMENT; RETROGRADE TRANSPORT; DENDRITIC TRANSPORT; CYTOPLASMIC DYNEIN; MEMBRANE-PROTEINS; ENDOCYTIC PATHWAYS AB An open question in cell biology is how the general intracellular transport machinery is adapted to perform specialized functions in polarized cells such as neurons. Here we illustrate this adaptation by elucidating a role for the ubiquitous small GTPase Ras-related protein in brain 5 (Rab5) in neuronal polarity. We show that inactivation or depletion of Rab5 in rat hippocampal neurons abrogates the somatodendritic polarity of the transferrin receptor and several glutamate receptor types, resulting in their appearance in the axon. This loss of polarity is not caused primarily by increased transport from the soma to the axon but rather by decreased retrieval from the axon to the soma. Retrieval is also dependent on the Rab5 effector Fused Toes (FTS)-Hook-FTS and Hook-interacting protein (FHIP) (FHF) complex, which interacts with the minus-end-directed microtubule motor dynein and its activator dynactin to drive a population of axonal retrograde carriers containing somatodendritic proteins toward the soma. These findings emphasize the importance of both biosynthetic sorting and axonal retrieval for the polarized distribution of somatodendritic receptors at steady state. C1 [Guo, Xiaoli; Farias, Ginny G.; Mattera, Rafael; Bonifacino, Juan S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Neurobiol Branch, NIH, Bethesda, MD 20892 USA. RP Bonifacino, JS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Neurobiol Branch, NIH, Bethesda, MD 20892 USA. EM bonifacinoj@helix.nih.gov OI Bonifacino, Juan S./0000-0002-5673-6370 FU Intramural Program of the National Institute of Child Health and Human Development, NIH Grant [ZIA HD001607] FX We thank X. Zhu for expert technical assistance; J. W. Harper, H. Kramer, C. Schindler, and M. Zerial for generous gifts of reagents; and X. Xiang, D. Gershlick, and C. Guardia for helpful discussions and critical review of the manuscript. This work was funded by the Intramural Program of the National Institute of Child Health and Human Development, NIH Grant ZIA HD001607. NR 88 TC 0 Z9 0 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 SEP 6 PY 2016 VL 113 IS 36 BP E5318 EP E5327 DI 10.1073/pnas.1601844113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV7CU UT WOS:000383094500011 PM 27559088 ER PT J AU Yang, W Weng, PJ Gao, Y AF Yang, Wei Weng, Peter J. Gao, Yang TI A new paradigm of DNA synthesis: three-metal-ion catalysis SO CELL AND BIOSCIENCE LA English DT Review ID POLYMERASE-ETA; NUCLEOTIDE INCORPORATION; COMPUTATIONAL DESIGN; CRYSTAL-STRUCTURE; INDUCED-FIT; MECHANISM; FIDELITY; REPLICATION; BETA; COMPLEX AB Enzyme catalysis has been studied for over a century. How it actually occurs has not been visualized until recently. By combining in crystallo reaction and X-ray diffraction analysis of reaction intermediates, we have obtained unprecedented atomic details of the DNA synthesis process. Contrary to the established theory that enzyme-substrate complexes and transition states have identical atomic composition and catalysis occurs by the two-metal-ion mechanism, we have discovered that an additional divalent cation has to be captured en route to product formation. Unlike the canonical two metal ions, which are coordinated by DNA polymerases, this third metal ion is free of enzyme coordination. Its location between the alpha- and beta-phosphates of dNTP suggests that the third metal ion may drive the phosphoryltransfer from the leaving group opposite to the 3'-OH nucleophile. Experimental data indicate that binding of the third metal ion may be the rate-limiting step in DNA synthesis and the free energy associated with the metal-ion binding can overcome the activation barrier to the DNA synthesis reaction. C1 [Yang, Wei; Weng, Peter J.; Gao, Yang] NIDDK, Mol Biol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Yang, W (reprint author), NIDDK, Mol Biol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM wei.yang@nih.gov RI Gao, Yang/O-3445-2016 FU NIH intramural program [DK036146-08] FX This work is funded by NIH intramural program (DK036146-08, W.Y.). NR 46 TC 0 Z9 0 U1 14 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD SEP 6 PY 2016 VL 6 AR 51 DI 10.1186/s13578-016-0118-2 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV1XK UT WOS:000382715200001 PM 27602203 ER PT J AU Page, J Constantino, JN Zambrana, K Martin, E Tunc, I Zhang, Y Abbacchi, A Messinger, D AF Page, Joshua Constantino, John Nicholas Zambrana, Katherine Martin, Eden Tunc, Ilker Zhang, Yi Abbacchi, Anna Messinger, Daniel TI Quantitative autistic trait measurements index background genetic risk for ASD in Hispanic families SO MOLECULAR AUTISM LA English DT Article DE Measurement; Social Responsiveness Scale; Hispanic; Ancestry; Assortative mating ID SOCIAL RESPONSIVENESS SCALE; CLINICAL VARIABILITY; GENERAL-POPULATION; TRANSMISSION; INDIVIDUALS; DISORDERS; ANCESTRY; TWIN AB Background: Recent studies have indicated that quantitative autistic traits (QATs) of parents reflect inherited liabilities that may index background genetic risk for clinical autism spectrum disorder (ASD) in their offspring. Moreover, preferential mating for QATs has been observed as a potential factor in concentrating autistic liabilities in some families across generations. Heretofore, intergenerational studies of QATs have focused almost exclusively on Caucasian populations-the present study explored these phenomena in a well-characterized Hispanic population. Methods: The present study examined QAT scores in siblings and parents of 83 Hispanic probands meeting research diagnostic criteria for ASD, and 64 non-ASD controls, using the Social Responsiveness Scale-2 (SRS-2). Ancestry of the probands was characterized by genotype, using information from 541,929 single nucleotide polymorphic markers. Results: In families of Hispanic children with an ASD diagnosis, the pattern of quantitative trait correlations observed between ASD-affected children and their first-degree relatives (ICCs on the order of 0.20), between unaffected first-degree relatives in ASD-affected families (sibling/mother ICC = 0.36; sibling/father ICC = 0.53), and between spouses (mother/father ICC = 0.48) were in keeping with the influence of transmitted background genetic risk and strong preferential mating for variation in quantitative autistic trait burden. Results from analysis of ancestry-informative genetic markers among probands in this sample were consistent with that from other Hispanic populations. Conclusions: Quantitative autistic traits represent measurable indices of inherited liability to ASD in Hispanic families. The accumulation of autistic traits occurs within generations, between spouses, and across generations, among Hispanic families affected by ASD. The occurrence of preferential mating for QATs-the magnitude of which may vary across cultures-constitutes a mechanism by which background genetic liability for ASD can accumulate in a given family in successive generations. C1 [Page, Joshua; Constantino, John Nicholas; Zhang, Yi; Abbacchi, Anna] Washington Univ, Sch Med, Dept Psychiat & Pediat, 4444 Forest Pk Ave, St Louis, MO 63130 USA. [Zambrana, Katherine; Messinger, Daniel] Univ Miami, Dept Psychol, POB 248185-0751, Coral Gables, FL 33124 USA. [Martin, Eden] Univ Miami, Sch Med, Ctr Genet Epidemiol & Stat Genet, 1501 NW 10th Ave, Miami, FL USA. [Tunc, Ilker] NHLBI, Div Intramural Res, NIH, 31 Ctr Dr, Bethesda, MD USA. RP Constantino, JN (reprint author), Washington Univ, Sch Med, Dept Psychiat & Pediat, 4444 Forest Pk Ave, St Louis, MO 63130 USA. EM constantino@wustl.edu FU U.S. NIH [R01 HD 042541, U54 HD 087011]; NIH [1R01GM090087] FX This work was supported by U.S. NIH grants R01 HD 042541, and U54 HD 087011 (The Washington University Intellectual and Developmental Disabilities Research Center) to Dr. Constantino. Collection and genotyping of samples from the Genomic Origins and Admixture in Latinos (GOAL) study were supported by NIH grant 1R01GM090087 to Dr. Martin. NR 40 TC 0 Z9 0 U1 5 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2040-2392 J9 MOL AUTISM JI Mol. Autism PD SEP 6 PY 2016 VL 7 AR 39 DI 10.1186/s13229-016-0100-1 PG 10 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA DV1UB UT WOS:000382705600002 PM 27606047 ER PT J AU Solca, MS Andrade, BB Abbehusen, MMC Teixeira, CR Khouri, R Valenzuela, JG Kamhawi, S Bozza, PT Fraga, DBM Borges, VM Veras, PST Brodskyn, CI AF Solca, Manuela S. Andrade, Bruno B. Abbehusen, Melissa Moura Costa Teixeira, Clarissa R. Khouri, Ricardo Valenzuela, Jesus G. Kamhawi, Shaden Bozza, Patricia Torres Mothe Fraga, Deborah Bittencourt Borges, Valeria Matos Tavares Veras, Patricia Sampaio Brodskyn, Claudia Ida TI Circulating Biomarkers of Immune Activation, Oxidative Stress and Inflammation Characterize Severe Canine Visceral Leishmaniasis SO SCIENTIFIC REPORTS LA English DT Article ID LUTZOMYIA-LONGIPALPIS SALIVA; PLASMODIUM-VIVAX MALARIA; CUTANEOUS LEISHMANIASIS; AMAZONENSIS INFECTION; INFANTUM; DOGS; EXPRESSION; SUSCEPTIBILITY; CONTRIBUTE; EXPOSURE AB Clinical manifestations in canine visceral leishmaniasis (CVL) have not been clearly associated with immunological status or disease progression. We simultaneously assessed biomarkers of inflammation, immune activation, oxidative stress, and anti-sand fly saliva IgG concentrations in dog sera with different clinical manifestations to characterize a biosignature associated with CVL severity. In a cross-sectional exploratory study, a random population of 70 dogs from an endemic area in Brazil was classified according to CVL clinical severity and parasitological evaluation. A panel of biomarkers and anti-sand fly saliva IgG were measured in canine sera. Assessment of protein expression of profile biomarkers identified a distinct biosignature that could cluster separately animal groups with different clinical scores. Increasing severity scores were associated with a gradual decrease of LTB4 and PGE2, and a gradual increase in CXCL1 and CCL2. Discriminant analyses revealed that combined assessment of LTB4, PGE2 and CXCL1 was able to distinguish dogs with different clinical scores. Dogs with the highest clinical score values also exhibited high parasite loads and higher concentrations of anti-saliva antibodies. Our findings suggest CVL clinical severity is tightly associated with a distinct inflammatory profile hallmarked by a differential expression of circulating eicosanoids and chemokines. C1 [Solca, Manuela S.; Mothe Fraga, Deborah Bittencourt; Tavares Veras, Patricia Sampaio] Fiocruz MS, Inst Pesquisas Goncalo Moniz, Lab Patol & Biointervencao, BR-40296710 Salvador, BA, Brazil. [Andrade, Bruno B.; Abbehusen, Melissa Moura Costa; Khouri, Ricardo; Borges, Valeria Matos; Brodskyn, Claudia Ida] Fiocruz MS, Inst Pesquisas Goncalo Moniz, Lab Integrado Microbiol & Imunoregulacao, BR-40296710 Salvador, BA, Brazil. [Andrade, Bruno B.] Fundacao Jose Silveira, MONSTER Initiat, BR-40070080 Salvador, BA, Brazil. [Teixeira, Clarissa R.] Fundacao Oswaldo Cruz, Fiocruz Piaui, BR-64128 Teresina, Brazil. [Valenzuela, Jesus G.; Kamhawi, Shaden] NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy, Rockville, MD 20852 USA. [Bozza, Patricia Torres] Fiocruz MS, BioManguinhos, Inst Oswaldo Cruz, Lab Imunofarmacol, BR-21040900 Rio De Janeiro, Brazil. [Mothe Fraga, Deborah Bittencourt] Univ Fed Bahia, Escola Med Vet & Zootecnia, Dept Med Vet Prevent & Prod Anim, BR-40170110 Salvador, BA, Brazil. [Mothe Fraga, Deborah Bittencourt; Tavares Veras, Patricia Sampaio] INCT DT, BR-40110160 Salvador, BA, Brazil. [Brodskyn, Claudia Ida] Inst Nacl Ciencia & Tecnol Invest Imunol III INCT, BR-05403900 Sao Paulo, Brazil. RP Brodskyn, CI (reprint author), Fiocruz MS, Inst Pesquisas Goncalo Moniz, Lab Integrado Microbiol & Imunoregulacao, BR-40296710 Salvador, BA, Brazil.; Brodskyn, CI (reprint author), Inst Nacl Ciencia & Tecnol Invest Imunol III INCT, BR-05403900 Sao Paulo, Brazil. EM brodskyn@bahia.fiocruz.br OI Borges, Valeria/0000-0002-2775-5409 FU Fundacao de Amparo a Pesquisa do Estado da Bahia-FAPESB [SUS0036/2013, PET0024/2013]; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico [402670/2012-4, 400898/2013-6]; Instituto Nacional de Ciencia e Tecnologia em Doencas Tropicais (INCT-DT); Intramural Research Programs at the NIAID, NIH, USA; Instituto Nacional de Ciencia e Tecnologia de Investigacao em Imunologia (III-INCT) FX The authors thank Andrezza Souza for technical and logistics support. This work was supported by grants from Fundacao de Amparo a Pesquisa do Estado da Bahia-FAPESB (No SUS0036/2013 and PET0024/2013 to C.I.B.); grant from Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (402670/2012-4 to C.I.B. and 400898/2013-6 to P.S.T.V.); grants from Instituto Nacional de Ciencia e Tecnologia em Doencas Tropicais (INCT-DT) (to D.B.M.F. and P.S.T.V.), from the Intramural Research Programs at the NIAID, NIH, USA (SK, JGV) and Instituto Nacional de Ciencia e Tecnologia de Investigacao em Imunologia (III-INCT) (to C.I.B.). C.I.B., P.S.T.V., V.M.B., P.T.B., are senior investigators of CNPq. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 0 Z9 0 U1 0 U2 0 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 SEP 6 PY 2016 VL 6 AR 32619 DI 10.1038/srep32619 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DU8KW UT WOS:000382463000001 PM 27595802 ER PT J AU Caballero, IS Honko, AN Gire, SK Winnicki, SM Mele, M Gerhardinger, C Lin, AE Rinn, JL Sabeti, PC Hensley, LE Connor, JH AF Caballero, Ignacio S. Honko, Anna N. Gire, Stephen K. Winnicki, Sarah M. Mele, Marta Gerhardinger, Chiara Lin, Aaron E. Rinn, John L. Sabeti, Pardis C. Hensley, Lisa E. Connor, John H. TI In vivo Ebola virus infection leads to a strong innate response in circulating immune cells SO BMC GENOMICS LA English DT Article DE Ebola virus; Transcriptional response; Transcriptomics; Interferon-stimulated genes ID HEMORRHAGIC-FEVER; GENE-EXPRESSION; NONHUMAN-PRIMATES; CYNOMOLGUS MACAQUES; ZAIRE-EBOLAVIRUS; RHESUS MACAQUES; MARBURG VIRUSES; RNA; CHALLENGE; REVEALS AB Background: Ebola virus is the causative agent of a severe syndrome in humans with a fatality rate that can approach 90 %. During infection, the host immune response is thought to become dysregulated, but the mechanisms through which this happens are not entirely understood. In this study, we analyze RNA sequencing data to determine the host response to Ebola virus infection in circulating immune cells. Results: Approximately half of the 100 genes with the strongest early increases in expression were interferon-stimulated genes, such as ISG15, OAS1, IFIT2, HERC5, MX1 and DHX58. Other highly upregulated genes included cytokines CXCL11, CCL7, IL2RA, IL2R1, IL15RA, and CSF2RB, which have not been previously reported to change during Ebola virus infection. Comparing this response in two different models of exposure (intramuscular and aerosol) revealed a similar signature of infection. The strong innate response in the aerosol model was seen not only in circulating cells, but also in primary and secondary target tissues. Conversely, the innate immune response of vaccinated macaques was almost non-existent. This suggests that the innate response is a major aspect of the cellular response to Ebola virus infection in multiple tissues. Conclusions: Ebola virus causes a severe infection in humans that is associated with high mortality. The host immune response to virus infection is thought to be an important aspect leading to severe pathology, but the components of this overactive response are not well characterized. Here, we analyzed how circulating immune cells respond to the virus and found that there is a strong innate response dependent on active virus replication. This finding is in stark contrast to in vitro evidence showing a suppression of innate immune signaling, and it suggests that the strong innate response we observe in infected animals may be an important contributor to pathogenesis. C1 [Caballero, Ignacio S.] Boston Univ, Bioinformat Grad Program, Boston, MA 02215 USA. [Honko, Anna N.; Hensley, Lisa E.] US Army, Med Res Inst Infect Dis, Virol Div, Ft Detrick, MD 21702 USA. [Honko, Anna N.; Hensley, Lisa E.] NIAID, Integrated Res Facil, NIH, Ft Detrick, MD USA. [Gire, Stephen K.; Winnicki, Sarah M.; Mele, Marta; Gerhardinger, Chiara; Lin, Aaron E.; Rinn, John L.; Sabeti, Pardis C.] Harvard Univ, Dept Organism & Evolutionary Biol, Ctr Syst Biol, Cambridge, MA 02138 USA. [Gire, Stephen K.; Winnicki, Sarah M.; Lin, Aaron E.; Sabeti, Pardis C.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Mele, Marta; Gerhardinger, Chiara; Rinn, John L.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Connor, John H.] Boston Univ, Sch Med, Dept Microbiol, Boston, MA 02118 USA. RP Connor, JH (reprint author), Boston Univ, Sch Med, Dept Microbiol, Boston, MA 02118 USA. EM jhconnor@bu.edu OI Honko, Anna/0000-0001-9165-148X FU USAMRAA Biomarkers [W81XWH-11-1-0141]; National Science Foundation [DGE 1144152]; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [U19AI110818]; [W81XWH 100-02-0008]; [11-02-0130] FX This work was supported by contracts W81XWH 100-02-0008, 11-02-0130, and USAMRAA Biomarkers W81XWH-11-1-0141, and by a grant from the National Science Foundation No. DGE 1144152 (AEL). This project has been funded in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Grant Number U19AI110818 to the Broad Institute. Marta Mele Messeguer is a Gilead Fellow of the Life Sciences Research Foundation. NR 53 TC 1 Z9 1 U1 2 U2 2 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 SEP 5 PY 2016 VL 17 AR 707 DI 10.1186/s12864-016-3060-0 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DW2JR UT WOS:000383469200003 PM 27595844 ER PT J AU Springborn, M Chowell, G MacLachlan, M Fenichel, EP AF Springborn, Michael Chowell, Gerardo MacLachlan, Matthew Fenichel, Eli P. TI Accounting for Behavioral Responses during a Flu Epidemic Using Home Television Viewing (vol 15, 21, 2015) SO BMC INFECTIOUS DISEASES LA English DT Correction C1 [Springborn, Michael] Univ Calif Davis, Dept Environm Sci & Policy, 2104 Wickson Hall,One Shields Ave, Davis, CA 95616 USA. [Chowell, Gerardo] Georgia State Univ, Sch Publ Hlth, POB 3965, Atlanta, GA 30302 USA. [Chowell, Gerardo] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, 31 Ctr Dr,MSC 2220, Bethesda, MD 20892 USA. [Chowell, Gerardo] Arizona State Univ, Sch Human Evolut & Social Change, Math Computat & Modeling Sci Ctr, 900 S Cady Mall, Tempe, AZ 85287 USA. [MacLachlan, Matthew] Univ Calif Davis, Dept Agr & Resource Econ, Social Sci & Humanities 2116, One Shields Ave,Davis,CA 95616, Davis, CA 95616 USA. [Fenichel, Eli P.] Yale Sch Forestry & Environm Studies, 195 Prospect St, New Haven, CT 06511 USA. RP Springborn, M (reprint author), Univ Calif Davis, Dept Environm Sci & Policy, 2104 Wickson Hall,One Shields Ave, Davis, CA 95616 USA. EM mspringborn@ucdavis.edu 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 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD SEP 5 PY 2016 VL 16 AR 474 DI 10.1186/s12879-016-1795-5 PG 2 WC Infectious Diseases SC Infectious Diseases GA DV2IZ UT WOS:000382745400006 ER PT J AU Yahr, R Schoch, CL Dentinger, BTM AF Yahr, Rebecca Schoch, Conrad L. Dentinger, Bryn T. M. TI Scaling up discovery of hidden diversity in fungi: impacts of barcoding approaches SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Review DE internal transcribed spacer; fungi; barcoding; diversity; metabarcoding; taxonomy ID INTERNAL TRANSCRIBED SPACER; ARBUSCULAR MYCORRHIZAL FUNGI; PHYLOGENETIC SPECIES RECOGNITION; SEQUENCE-BASED IDENTIFICATION; OPERATIONAL TAXONOMIC UNITS; LICHEN-FORMING FUNGI; ECTOMYCORRHIZAL FUNGI; MONOTROPOIDEAE ERICACEAE; GEOGRAPHICAL STRUCTURE; DISTRIBUTION PATTERNS AB The fungal kingdom is a hyperdiverse group of multicellular eukaryotes with profound impacts on human society and ecosystem function. The challenge of documenting and describing fungal diversity is exacerbated by their typically cryptic nature, their ability to produce seemingly unrelated morphologies from a single individual and their similarity in appearance to distantly related taxa. This multiplicity of hurdles resulted in the early adoption of DNA-based comparisons to study fungal diversity, including linking curated DNA sequence data to expertly identified voucher specimens. DNA-barcoding approaches in fungi were first applied in specimen-based studies for identification and discovery of taxonomic diversity, but are now widely deployed for community characterization based on sequencing of environmental samples. Collectively, fungal barcoding approaches have yielded important advances across biological scales and research applications, from taxonomic, ecological, industrial and health perspectives. A major outstanding issue is the growing problem of 'sequences without names' that are somewhat uncoupled from the traditional framework of fungal classification based on morphology and preserved specimens. This review summarizes some of the most significant impacts of fungal barcoding, its limitations, and progress towards the challenge of effective utilization of the exponentially growing volume of data gathered from high-throughput sequencing technologies. This article is part of the themed issue 'From DNA barcodes to biomes'. C1 [Yahr, Rebecca] Royal Bot Garden Edinburgh, 20A Inverleith Row, Edinburgh, Midlothian, Scotland. [Schoch, Conrad L.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Dentinger, Bryn T. M.] Royal Bot Gardens Kew, Richmond, Surrey, England. [Dentinger, Bryn T. M.] Aberystwyth Univ, Inst Biol Environm & Rural Sci, Cledwyn Bldg, Aberystwyth SY23 3DD, Dyfed, Wales. RP Yahr, R (reprint author), Royal Bot Garden Edinburgh, 20A Inverleith Row, Edinburgh, Midlothian, Scotland. EM r.yahr@rbge.ac.uk FU Intramural Research Program of the US National Institutes of Health, National Library of Medicine; Scottish Government's Rural and Environment Science and Analytical Services FX C.L.S. acknowledges support from the Intramural Research Program of the US National Institutes of Health, National Library of Medicine. R.Y. was supported by the Scottish Government's Rural and Environment Science and Analytical Services. NR 158 TC 2 Z9 2 U1 43 U2 55 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 SEP 5 PY 2016 VL 371 IS 1702 AR 20150336 DI 10.1098/rstb.2015.0336 PG 11 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DT8XT UT WOS:000381779700008 ER PT J AU Pasetto, A Gros, A Robbins, PF Deniger, DC Prickett, TD Matus-Nicodemos, R Douek, DC Howie, B Robins, H Parkhurst, MR Gartner, J Trebska-McGowan, K Crystal, JS Rosenberg, SA AF Pasetto, Anna Gros, Alena Robbins, Paul F. Deniger, Drew C. Prickett, Todd D. Matus-Nicodemos, Rodrigo Douek, Daniel C. Howie, Bryan Robins, Harlan Parkhurst, Maria R. Gartner, Jared Trebska-McGowan, Katarzyna Crystal, Jessica S. Rosenberg, Steven A. TI Tumor- and Neoantigen-Reactive T-cell Receptors Can Be Identified Based on Their Frequency in Fresh Tumor SO CANCER IMMUNOLOGY RESEARCH LA English DT Article ID INFILTRATING LYMPHOCYTES; HUMAN-MELANOMA; BLOOD-LYMPHOCYTES; OVARIAN-CANCER; EXPRESSION; ANTIGEN; REPERTOIRE; REGRESSION; PATIENT; VECTOR AB Adoptive transfer of T cells with engineered T-cell receptor (TCR) genes that target tumor-specific antigens can mediate cancer regression. Accumulating evidence suggests that the clinical success of many immunotherapies is mediated by T cells targeting mutated neoantigens unique to the patient. We hypothesized that the most frequent TCR clonotypes infiltrating the tumor were reactive against tumor antigens. To test this hypothesis, we developed a multistep strategy that involved TCRB deep sequencing of the CD8(+)PD-1+ T-cell subset, matching of TCRA-TCRB pairs by pair SEQ and single-cell RT-PCR, followed by testing of the TCRs for tumor-antigen specificity. Analysis of 12 fresh metastatic melanomas revealed that in 11 samples, up to 5 tumor-reactive TCRs were present in the 5 most frequently occurring clonotypes, which included reactivity against neoantigens. These data show the feasibility of developing a rapid, personalized TCR-gene therapy approach that targets the unique set of antigens presented by the autologous tumor without the need to identify their immunologic reactivity. (C) 2016 AACR. C1 [Pasetto, Anna; Gros, Alena; Robbins, Paul F.; Deniger, Drew C.; Prickett, Todd D.; Parkhurst, Maria R.; Gartner, Jared; Trebska-McGowan, Katarzyna; Crystal, Jessica S.; Rosenberg, Steven A.] NCI, Surg Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Matus-Nicodemos, Rodrigo] NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. [Matus-Nicodemos, Rodrigo; Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Howie, Bryan; Robins, Harlan] Adapt Biotechnol, Seattle, WA USA. [Robins, Harlan] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. RP Rosenberg, SA (reprint author), NCI, Ctr Canc Res, Bldg 10 CRC,Room 3W-3940,10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM sar@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 43 TC 2 Z9 2 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2326-6066 EI 2326-6074 J9 CANCER IMMUNOL RES JI Cancer Immunol. Res. PD SEP 2 PY 2016 VL 4 IS 9 BP 734 EP 743 DI 10.1158/2326-6066.CIR-16-0001 PG 10 WC Oncology; Immunology SC Oncology; Immunology GA DV6OE UT WOS:000383055500004 PM 27354337 ER PT J AU Farsaci, B Donahue, RN Grenga, I Lepone, LM Kim, PS Dempsey, B Siebert, JC Ibrahim, NK Madan, RA Heery, CR Gulley, JL Schlom, J AF Farsaci, Benedetto Donahue, Renee N. Grenga, Italia Lepone, Lauren M. Kim, Peter S. Dempsey, Brendan Siebert, Janet C. Ibrahim, Nuhad K. Madan, Ravi A. Heery, Christopher R. Gulley, James L. Schlom, Jeffrey TI Analyses of Pretherapy Peripheral Immunoscore and Response to Vaccine Therapy SO CANCER IMMUNOLOGY RESEARCH LA English DT Article ID CELL LUNG-CANCER; RESISTANT PROSTATE-CANCER; RANDOMIZED PHASE-II; COLORECTAL-CANCER; MELANOMA PATIENTS; IMMUNE CELLS; T-CELLS; PD-L1 EXPRESSION; DENDRITIC CELLS; COMBINATION AB Tumor immunoscore analyses, especially for primary colorectal cancer and melanoma lesions, provide valuable prognostic information. Metastatic lesions of many carcinoma types, however, are often not easily accessible. We hypothesized that immune cells in peripheral blood may differ among individual patients with metastatic disease, which, in turn, may influence their response to immunotherapy. We thus analyzed immune cell subsets within peripheral blood mononuclear cells to determine if a "peripheral immunoscore" could have any prognostic significance for patients before receiving immunotherapy. Patients with metastatic breast cancer were randomly assigned to receive docetaxel +/- PANVAC vaccine. In another trial, prostate cancer patients with metastatic bone lesions were randomly assigned to receive a bone-seeking radionuclide +/- PROSTVAC vaccine. Predefined analyses of "classic" immune cell types (CD4, CD8, natural killer cells, regulatory T cells, myeloid-derived suppressor cells, and ratios) revealed no differences in progression-free survival (PFS) for either arm in both trials. Predefined analyses of refined immune cell subsets for which a biologic function had been previously reported also showed no significant prognostic value in PFS for patients receiving either docetaxel or radionuclide alone; however, in patients receiving these agents in combination with vaccine, the peripheral immunoscore of refined subsets revealed statistically significant differences in PFS (P < 0.001) for breast cancer patients receiving docetaxel plus vaccine, and in prostate cancer patients receiving radionuclide plus vaccine (P = 0.004). Larger randomized studies will be required to validate these findings. These studies, however, provide the rationale for the evaluation of refined immune cell subsets to help determine which patients may benefit most from immunotherapy. (C) 2016 AACR. C1 [Farsaci, Benedetto; Donahue, Renee N.; Grenga, Italia; Lepone, Lauren M.; Kim, Peter S.; Dempsey, Brendan; Heery, Christopher R.; Schlom, Jeffrey] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Siebert, Janet C.] Cytoanalytics, Denver, CO USA. [Ibrahim, Nuhad K.] Univ Texas MD Anderson Canc Ctr, Div Canc Med, Dept Breast Med Oncol, Houston, TX 77030 USA. [Madan, Ravi A.; Gulley, James L.] NCI, Genitourinary Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, 10 Ctr Dr,Bldg 10,Room 8B09, Bethesda, MD 20892 USA. EM js141c@nih.gov FU Intramural NIH HHS [ZIA BC010425-15] NR 55 TC 3 Z9 3 U1 8 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2326-6066 EI 2326-6074 J9 CANCER IMMUNOL RES JI Cancer Immunol. Res. PD SEP 2 PY 2016 VL 4 IS 9 BP 755 EP 765 DI 10.1158/2326-6066.CIR-16-0037 PG 11 WC Oncology; Immunology SC Oncology; Immunology GA DV6OE UT WOS:000383055500006 PM 27485137 ER PT J AU Eto, M Naruse, N Morimoto, K Yamaoka, K Sato, K Tsuji, K Inokuma, T Shigenaga, A Otaka, A AF Eto, Mitsuhiro Naruse, Naoto Morimoto, Kyohei Yamaoka, Kosuke Sato, Kohei Tsuji, Kohei Inokuma, Tsubasa Shigenaga, Akira Otaka, Akira TI Development of an Anilide-Type Scaffold for the Thioester Precursor N-Sulfanylethylcoumarinyl Amide SO ORGANIC LETTERS LA English DT Article ID NATIVE CHEMICAL LIGATION; INTRAMOLECULAR N,S-ACYL SHIFT; SOLID-PHASE SYNTHESIS; S ACYL TRANSFER; PEPTIDE THIOESTERS; SULFANYLETHYLANILIDE PEPTIDE; CRYPTO-THIOESTER; PROTEINS; CYSTEINE; CHEMISTRY AB N-Sulfanylethylcoumarinyl amide (SECmide) peptide, which was initially developed for use in the fluorescence-guided detection of promoters of N-S acyl transfer, was successfully applied to a facile and side reaction-free protocol for N-S acyl-transfer-mediated synthesis of peptide thioesters. Additionally, 4-mercaptobenzylphosphonic acid (MBPA) was proven to be a useful catalyst for the SECmide or N-sulfanylethylanilide (SEAlide)-mediated NCL reaction. C1 [Eto, Mitsuhiro; Naruse, Naoto; Morimoto, Kyohei; Yamaoka, Kosuke; Sato, Kohei; Tsuji, Kohei; Inokuma, Tsubasa; Shigenaga, Akira; Otaka, Akira] Univ Tokushima, Inst Biomed Sci, Tokushima 7708505, Japan. [Eto, Mitsuhiro; Naruse, Naoto; Morimoto, Kyohei; Yamaoka, Kosuke; Sato, Kohei; Tsuji, Kohei; Inokuma, Tsubasa; Shigenaga, Akira; Otaka, Akira] Univ Tokushima, Grad Sch Pharmaceut Sci, Tokushima 7708505, Japan. [Shigenaga, Akira] Japan Sci & Technol Agcy JST, RESTO, Kawaguchi, Saitama 3320012, Japan. [Sato, Kohei] Shizuoka Univ, Dept Appl Chem & Biochem Engn, Hamamatsu, Shizuoka 4328561, Japan. [Sato, Kohei] Shizuoka Univ, Green Energy Res Div, Hamamatsu, Shizuoka 4328561, Japan. [Tsuji, Kohei] NCI, Biol Chem Lab, NIH, Frederick, MD 21702 USA. RP Shigenaga, A; Otaka, A (reprint author), Univ Tokushima, Inst Biomed Sci, Tokushima 7708505, Japan.; Shigenaga, A; Otaka, A (reprint author), Univ Tokushima, Grad Sch Pharmaceut Sci, Tokushima 7708505, Japan.; Shigenaga, A (reprint author), Japan Sci & Technol Agcy JST, RESTO, Kawaguchi, Saitama 3320012, Japan. EM shigenaga.akira@tokushima-u.ac.jp; aotaka@tokushima-u.ac.jp FU KAKENHI; PRESTO, JST FX This research was supported in part by a Grant-in-Aid for Scientific Research (KAKENHI) and PRESTO, JST. NR 34 TC 2 Z9 2 U1 2 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1523-7060 EI 1523-7052 J9 ORG LETT JI Org. Lett. PD SEP 2 PY 2016 VL 18 IS 17 BP 4416 EP 4419 DI 10.1021/acs.orglett.6b02207 PG 4 WC Chemistry, Organic SC Chemistry GA DV1VW UT WOS:000382711200068 PM 27529363 ER PT J AU Baumann, DO McGowan, KM Kedei, N Peach, ML Blumberg, PM Keck, GE AF Baumann, David O. McGowan, Kevin M. Kedei, Noemi Peach, Megan L. Blumberg, Peter M. Keck, Gary E. TI Synthesis and Biological Evaluation of Several Bryostatin Analogues Bearing a Diacylglycerol Lactone C-Ring SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID PROTEIN-KINASE-C; CONFORMATIONALLY CONSTRAINED ANALOGS; ALPHA-PHOSPHONO LACTONES; PHORBOL ESTER; SELECTIVE DEPROTECTION; ANTITUMOR MACROLIDES; ASYMMETRIC-SYNTHESIS; PYRAN ANNULATION; FORMAL SYNTHESIS; TUMOR PROMOTION AB As an initial step in designing a simplified bryostatin hybrid molecule, three bryostatin analogues bearing a diacylglycerol lactone-based C-ring, which possessed the requisite pharmacophores for binding to protein kinase C (PKC) together with a modified bryostatin-like A- and B-ring region, were synthesized and evaluated. Merle 46 and Merle 47 exhibited binding affinity to PKC alpha with K-i values of 7000 +/- 990 and 4940 +/- 470 nM, respectively. Reinstallation of the trans-olefin and gem-dimethyl group present in bryostatin 1 in Merle 48 resulted in improved binding affinity, 363 +/- 42 nM. While Merle 46 and 47 were only marginally active biologically, Merle 48 showed sufficient activity on the U937 cells to confirm that it was PMA-like for growth and attachment, as predicted by the substitution pattern of its A- and B-rings. C1 [Baumann, David O.; McGowan, Kevin M.; Keck, Gary E.] Univ Utah, Dept Chem, 315 S 1300 E,RM 2020, Salt Lake City, UT 84112 USA. [Kedei, Noemi; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. [Peach, Megan L.] Leidos Biomed Res Inc, Basic Sci Program, Biol Chem Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Keck, GE (reprint author), Univ Utah, Dept Chem, 315 S 1300 E,RM 2020, Salt Lake City, UT 84112 USA. EM keck@chem.utah.edu FU National Institutes of Health [GM28961]; Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute [Z1A BC 005270]; Federal funds from the National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX Financial support was provided by the National Institutes of Health through Grant No. GM28961 and was supported in part by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute (Project Z1A BC 005270). The project was also funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract HHSN261200800001E. NR 59 TC 1 Z9 1 U1 2 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD SEP 2 PY 2016 VL 81 IS 17 BP 7862 EP 7883 DI 10.1021/acs.joc.6b01516 PG 22 WC Chemistry, Organic SC Chemistry GA DV1WW UT WOS:000382713800058 PM 27494208 ER PT J AU Muenke, M AF Muenke, Maximilian TI Mentors without Borders SO MOLECULAR GENETICS & GENOMIC MEDICINE LA English DT Editorial Material ID ACADEMIC MEDICINE C1 [Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20814 USA. RP Muenke, M (reprint author), NHGRI, NIH, 35 Convent Dr,35-1B-203, Bethesda, MD 20814 USA. EM muenke@nih.gov FU Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health FX I am indebted to my mentors (you know who you are) and my trainees alike for benefiting from their wisdom. I want to thank my fellow founding members of Mentors without Borders for their input. Lastly, many friends and colleagues contributed to the discussion of this topic, too many to individually mention by name. This manuscript has undergone major revisions based on the input of Carlos Ferreira, Donald Hadley, Suzanne Hart, Robert Lembo, Carter Owen, and Benjamin D. Solomon who helped in the process of thinking about and writing this manuscript. I am grateful to all of them. M.M. is supported by the Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health. NR 10 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 SEP PY 2016 VL 4 IS 5 BP 489 EP 493 DI 10.1002/mgg3.246 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA EL2LF UT WOS:000394450500001 PM 27652276 ER PT J AU Acosta, MT Swanson, J Stehli, A Molina, BSG Martinez, AF Arcos-Burgos, M Muenke, M AF Acosta, Maria T. Swanson, James Stehli, Annamarie Molina, Brooke S. G. Martinez, Ariel F. Arcos-Burgos, Mauricio Muenke, Maximilian CA MTA Team TI ADGRL3 (LPHN3) variants are associated with a refined phenotype of ADHD in the MTA study SO MOLECULAR GENETICS & GENOMIC MEDICINE LA English DT Article DE ADGRL3; ADHD; genetics; LPHN3; MTA ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; ADOLESCENT SUBSTANCE USE; FOLLOW-UP; SUSCEPTIBILITY; REPLICATION; CHILDREN; GENE; MEDICATION; LOCI AB Background ADHD is the most common neuropsychiatric condition affecting individuals of all ages. Long-term outcomes of affected individuals and association with severe comorbidities as SUD or conduct disorders are the main concern. Genetic associations have been extensively described. Multiple studies show that intronic variants harbored in the ADGRL3 (LPHN3) gene are associated with ADHD, especially associated with poor outcomes. Methods In this study, we evaluated this association in the Multimodal Treatment Study of children with ADHD (MTA), initiated as a 14-month randomized clinical trial of 579 children diagnosed with DSM-IV ADHD-Combined Type (ADHD-C), that transitioned to a 16-year prospective observational follow-up, and 289 classmates added at the 2-year assessment to serve as a local normative comparison group (LNCG). Diagnostic evaluations at entry were based on the Diagnostic Interview Schedule for Children-Parent (DISC-P), which was repeated at several points over the years. For an add-on genetic study, blood samples were collected from 232 in the MTA group and 139 in the LNCG. Results For the 205 MTA participants, 14.6% retained the DISC-P diagnosis of ADHD-C in adolescence. For 127 LNCG participants, 88.2% remained undiagnosed by the DISC-P. We genotyped 15 polymorphic SNP markers harbored in the ADGRL3 gene, and compared allele frequencies for the 30 cases with continued diagnosis of ADHD-C in adolescence to the other participants. Replication of the association of rs2345039 ADGRL3 variant was observed (P value = 0.004, FDR corrected = 0.03; Odds ratio = 2.25, upper CI 1.28-3.97). Conclusion The detection of susceptibility conferred by ADGRL3 variants in the extreme phenotype of continued diagnosis of ADHD-C from childhood to adolescence provides additional support that the association of ADGRL3 and ADHD is not spurious. Exploring genetic effects in longitudinal cohorts, in which refined, age-dependent phenotypes are documented, is crucial to understand the natural history of ADHD. C1 [Acosta, Maria T.; Martinez, Ariel F.; Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, 35 Convent Dr,MSC 3717,Bldg 35,Room 1B203, Bethesda, MD 20892 USA. [Acosta, Maria T.] George Washington Univ, Childrens Natl Med Ctr, Dept Pediat & Neurol, Washington, DC USA. [Swanson, James] Florida Int Univ, Dept Psychiat, Miami, FL 33199 USA. [Swanson, James; Stehli, Annamarie] Univ Calif Irvine, Dept Pediat, Irvine, CA 92717 USA. [Molina, Brooke S. G.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Molina, Brooke S. G.] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. [Arcos-Burgos, Mauricio] Australian Natl Univ, Genom & Predict Med, Genome Biol Dept, John Curtin Sch Med Res,ANU Coll Med Biol & Envir, Bldg 131 Garran Rd, Canberra, ACT 2600, Australia. RP Muenke, M (reprint author), NHGRI, Med Genet Branch, NIH, 35 Convent Dr,MSC 3717,Bldg 35,Room 1B203, Bethesda, MD 20892 USA.; Arcos-Burgos, M (reprint author), Australian Natl Univ, Genom & Predict Med, Genome Biol Dept, John Curtin Sch Med Res,ANU Coll Med Biol & Envir, Bldg 131 Garran Rd, Canberra, ACT 2600, Australia. EM Mauricio.Arcos-Burgos@anu.edu.au; mamuenke@mail.nih.gov NR 31 TC 0 Z9 0 U1 1 U2 1 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 SEP PY 2016 VL 4 IS 5 BP 540 EP 547 DI 10.1002/mgg3.230 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA EL2LF UT WOS:000394450500007 PM 27652281 ER PT J AU Husain, MJ Virk-Baker, M Parascandola, M Khondker, BH Ahluwalia, IB AF Husain, Muhammad Jami Virk-Baker, Mandeep Parascandola, Mark Khondker, Bazlul Haque Ahluwalia, Indu B. TI Money Gone Up in Smoke: The Tobacco Use and Malnutrition Nexus in Bangladesh SO ANNALS OF GLOBAL HEALTH LA English DT Article DE tobacco use; malnutrition; Bangladesh; opportunity costs of tobacco expenditures; household income and expenditure survey ID HOUSEHOLD RESOURCE-ALLOCATION; CONSUMPTION PATTERNS; CHILD MALNUTRITION; EXPENDITURE; HEALTH; IMPACT; INDIA AB B A C K G R O U N D The tobacco epidemic in Bangladesh is pervasive. Expenditures on tobacco may reduce money available for food in a country with a high malnutrition rate. O B J E C T I V E S The aims of the study are to quantify the opportunity costs of tobacco expenditure in terms of nutrition (ie, food energy) forgone and the potential improvements in the household level food-energy status if the money spent on tobacco were diverted for food consumption. M E T H O D We analyzed data from the 2010 Bangladesh Household Income and Expenditure Survey, a nationally representative survey conducted among 12,240 households. We present 2 analytical scenarios: (1) the lower-bound gain scenario entailing money spent on tobacco partially diverted to acquiring food according to households' food consumption share in total expenditures; and (2) the upper-bound gain scenario entailing money spent on tobacco diverted to acquiring food only. Age-and gender-based energy norms were used to identify food-energy deficient households. Data were analyzed by mutually exclusive smoking-only, smokeless-only, and dualtobacco user households. F I N D I N G S On average, a smoking-only household could gain 269-497 kilocalories (kcal) daily under the lower-bound and upper-bound scenarios, respectively. The potential energy gains for smokeless-only and dual-tobacco user households ranged from 148-268 kcal and 508-924 kcal, respectively. Under these lower-and upper-bound estimates, the percentage of smoking-only user households that are malnourished declined significantly from the baseline rate of 38% to 33% and 29%, respectively. For the smokeless-only and dual-tobacco user households, there were 2-3 and 69 percentage point drops in the malnutrition prevalence rates. The tobacco expenditure shift could translate to an additional 4.6-7.7 million food-energy malnourished persons meeting their caloric requirements. C O N C L U S I O N S The findings suggest that tobacco use reduction could facilitate concomitant improvements in population-level nutrition status and may inform the development and refinement of tobacco prevention and control efforts in Bangladesh. C1 [Husain, Muhammad Jami; Ahluwalia, Indu B.] Centers Dis Control & Prevent, Atlanta, GA USA. [Khondker, Bazlul Haque] Natl Canc Inst, Natl Inst Hlth, Rockville, MD USA. [Husain, Muhammad Jami] Univ Dhaka, Dept Econ, Dhaka, Bangladesh. RP Husain, MJ (reprint author), Univ Dhaka, Dept Econ, Dhaka, Bangladesh. EM MHusain@cdc.gov NR 33 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2214-9996 J9 ANN GLOB HEALTH JI Ann. Glob. Health PD SEP-OCT PY 2016 VL 82 IS 5 BP 749 EP + DI 10.1016/j.aogh.2016.07.005 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EO4UP UT WOS:000396690100010 PM 28283125 ER PT J AU Hussein, H Mtoroki, M Gerendasy, DD Detlefsen, EG AF Haruna, Hussein Mtoroki, Majaliwa Gerendasy, Dan D. Detlefsen, Ellen G. TI Health Libraries and Information Services in Tanzania: A Strategic Assessment SO ANNALS OF GLOBAL HEALTH LA English DT Article DE health information; health information needs; health information specialist; health sciences libraries; Tanzania ID PUBLIC-HEALTH; SEEKING BEHAVIOR; CARE; NEEDS; PRACTITIONERS; PROFESSIONALS; LIBRARIANSHIP; COMPETENCES; LITERACY; SCIENCES AB B A C K G R O U N D The intention of the Government of Tanzania is to establish more health information resource canters in all health facilities. With this regard, health information science personnel are needed to provide adequate and accurate health information services. However, availability of these personnel remains to be a challenge because of their non-existence. O B J E C T I V E To identify the current status and local impact of health sciences libraries and user perception of these libraries, as a prerequisite to the development of a competence-based curriculum for health information science training in Tanzania. M E T H O D S A needs assessment was carried out using a convenience sample of local respondents, including librarians, trainers, academicians, students, health care providers, and patients and families, drawn from national, referral, regional, district hospitals, health training institutions, and universities from both government and nongovernment entities in Tanzania. A focus group approach was used to gather data from respondents. R E S U L T S Results from this assessment revealed that health science libraries in Tanzania are faced with the challenges of insufficient infrastructure, old technology, limited facilities and furniture, inadequate and incompetent library staff, lack of health sciences librarians, outdated and insufficient resources, and low knowledge and use of information technologies by library clients. Most respondents would prefer to have both physical and electronic libraries, as well as librarians with specialized health information science skills, to cope with changing nature of the medical field. C O N C L U S I O N S The findings obtained from this assessment are strong enough to guide the development of a curriculum and training strategy and an operational plan and training packages for health information professionals. The development of a training curriculum for health information science professionals will mean better health information service delivery for Tanzania. C1 [Haruna, Hussein] Minist Hlth & Social Welf, Dept Human Resource Dev, Dar Es Salaam, Tanzania. [Mtoroki, Majaliwa] Minist Hlth & Social Welf, Dept Qual Assurance, Dar Es Salaam, Tanzania. [Gerendasy, Dan D.] Natl Lib Med, Bethesda, MD USA. [Detlefsen, Ellen G.] Univ Pittsburgh, Pittsburgh, PA USA. RP Hussein, H (reprint author), Minist Hlth & Social Welf, Dept Human Resource Dev, Dar Es Salaam, Tanzania. EM harunahussein@gmail.com FU Intramural Research Program of the National Institutes of Health, National Library of Medicine FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 37 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2214-9996 J9 ANN GLOB HEALTH JI Ann. Glob. Health PD SEP-OCT PY 2016 VL 82 IS 5 BP 912 EP + DI 10.1016/j.aogh.2016.10.003 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EO4UP UT WOS:000396690100031 ER PT J AU Amaral, J Campos, MM Maminishkis, A Khristov, V Zhou, R Charles, ST Stanzel, B Jha, B Bunea, I Miller, SS Bharti, K AF Amaral, Juan Campos, Maria Mercedes Maminishkis, Arvydas Khristov, Vladimir Zhou, Raymond Charles, Steve T. Stanzel, Boris Jha, Balendu Bunea, Irina Miller, Sheldon S. Bharti, Kapil TI A Porcine Model of Retinal Pigment Epithelium (RPE) Injury to Test the Efficacy of Human Induced Pluripotent Stem Cell-derived RPE (hiPSC-RPE) Transplants SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Amaral, Juan; Campos, Maria Mercedes; Maminishkis, Arvydas; Khristov, Vladimir; Zhou, Raymond; Charles, Steve T.; Stanzel, Boris; Jha, Balendu; Bunea, Irina; Miller, Sheldon S.; Bharti, Kapil] NEI, Bethesda, MD 20892 USA. [Campos, Maria Mercedes] NEI, Histol Core, Bethesda, MD 20892 USA. [Khristov, Vladimir; Zhou, Raymond; Miller, Sheldon S.] Sect Epithelial & Retinal Phisiol & Dis, Bethesda, MD USA. [Charles, Steve T.] Charles Retina Inst, Memphis, TN USA. [Stanzel, Boris] Univ Bonn, Ophthalmol, Bonn, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 258 PG 3 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174001099 ER PT J AU Armbrust, KR Fox, AR Jeffrey, BG Sherry, P Nussenblatt, RB Sen, HN AF Armbrust, Karen R. Fox, Austin Roy Jeffrey, Brett G. Sherry, Patti Nussenblatt, Robert B. Sen, H. Nida TI Rituximab for Autoimmune Retinopathy SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Armbrust, Karen R.; Fox, Austin Roy; Jeffrey, Brett G.; Sherry, Patti; Nussenblatt, Robert B.; Sen, H. Nida] NEI, NIH, Bethesda, MD 20892 USA. FU NEI Intramural Research Program FX NEI Intramural Research Program NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 1858 PG 2 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174004185 ER PT J AU Balraj, A Yoshimatsu, T Nelson, RF AF Balraj, Annika Yoshimatsu, Takeshi Nelson, Ralph F. TI Thyroxin b2 receptor (trb2) overexpression alters cone spectra in zebrafish SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Balraj, Annika; Nelson, Ralph F.] NINDS, NIH, Washington, DC USA. [Yoshimatsu, Takeshi] Univ Washington, Biol Struct, Seattle, WA 98195 USA. FU Basic Neurosciences Program, NINDS NIH FX Supported by Basic Neurosciences Program, NINDS NIH NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 586 PG 2 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174002007 ER PT J AU Becerra, SP Michelis, G German, L Rotstein, NP Politi, L AF Becerra, S. Patricia Michelis, German German, Lorena Patricia Rotstein, Nora Politi, Luis TI Pigment epithelium-derived factor (PEDF) prevents apoptosis and promotes apical localization of opsin in retina photoreceptors SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Becerra, S. Patricia] NEI, NIH, Bethesda, MD 20892 USA. [Michelis, German; German, Lorena; Patricia Rotstein, Nora; Politi, Luis] UNS, CONICET, Inst Invest Bioquim INIBIBB, Bahia Blanca, Buenos Aires, Argentina. FU Intramural Research Program of the NEI-NIH; ANPCYT; CONICET; Universidad Nacional del Sur FX The Intramural Research Program of the NEI-NIH; and ANPCYT, CONICET and Universidad Nacional del Sur (to LEP) NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 188 PG 2 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174001033 ER PT J AU Benedicto, I Lehmann-Mantaras, G Ginsberg, M Nolan, DJ Elemento, O Alam, NM Prusky, GT Maminishkis, A Miller, SS Rafii, S Rodriguez-Boulan, EJ AF Benedicto, Ignacio Lehmann-Mantaras, Guillermo Ginsberg, Michael Nolan, Daniel J. Elemento, Olivier Alam, Nazia M. Prusky, Glen T. Maminishkis, Arvydas Miller, Sheldon S. Rafii, Shahin Rodriguez-Boulan, Enrique J. TI Choroid endothelial cells regulate RPE tight junctions through modulation of Bruch's membrane assembly SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Benedicto, Ignacio; Lehmann-Mantaras, Guillermo; Rodriguez-Boulan, Enrique J.] Weill Cornell Med Coll, Ophthalmol, New York, NY USA. [Ginsberg, Michael; Nolan, Daniel J.; Rafii, Shahin] Angiocrine Biosci, New York, NY USA. [Elemento, Olivier; Alam, Nazia M.; Prusky, Glen T.] Weill Cornell Med Coll, Physiol & Biophys, New York, NY USA. [Alam, Nazia M.; Prusky, Glen T.] Burke Med Res Inst, White Plains, NY USA. [Maminishkis, Arvydas; Miller, Sheldon S.] NEI, NIH, Bethesda, MD 20892 USA. [Rafii, Shahin] Weill Cornell Med Coll, Genet Med, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 241 PG 3 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174001083 ER PT J AU Brown, B Lee, EJ Snow, P Vance, E Caspi, RR Rosenzweig, HL AF Brown, Brieanna Lee, Ellen J. Snow, Paige Vance, Emily Caspi, Rachel R. Rosenzweig, Holly Lallman TI Fungal components trigger induction of EAU through a Card9-dependent mechanism SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Brown, Brieanna; Lee, Ellen J.; Snow, Paige; Vance, Emily; Rosenzweig, Holly Lallman] VA Portland Hlth Care Syst, Portland, OR USA. [Lee, Ellen J.; Vance, Emily; Rosenzweig, Holly Lallman] Oregon Hlth & Sci Univ, Mol Microbiol & Immunol, Portland, OR 97201 USA. [Caspi, Rachel R.] NEI, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. FU NIH/NEI [EY019020]; Department of Veterans Affairs Biomedical Laboratory; NEI [EY000184] FX NIH/NEI (grant EY019020), the Department of Veterans Affairs Biomedical Laboratory, and NEI intramural support (project # EY000184) NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 502 PG 3 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174001334 ER PT J AU Chang, JR Ha, BS Lal, M Sharma, R Ferrer, M Bharti, K AF Chang, Justin R. Ha, Balendu Shekhar Lal, Madhu Sharma, Ruchi Ferrer, Marc Bharti, Kapil TI Discovering Novel Genes and Pathways Involved in Maintenance of Epithelial Phenotype in Retinal Pigment Epithelium Cells SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Chang, Justin R.; Ha, Balendu Shekhar; Sharma, Ruchi; Bharti, Kapil] NEI, NIH, Bethesda, MD 20892 USA. [Lal, Madhu; Ferrer, Marc] NIH, Natl Ctr Adv Translat Sci, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 238 PG 3 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174001080 ER PT J AU Clemons, TE Chew, EV Peto, T Sallo, FB Leung, I AF Clemons, Traci E. Chew, Emily V. Peto, Tunde Sallo, Ferenc B. Leung, Irene TI Ciliary Neurotrophic Factor for Macular Telangiectasia Type 2: 48 Month Results from the Phase 1 Safety Trial SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Clemons, Traci E.] Emmes Corp, Ophthalmol, Rockville, MD USA. [Chew, Emily V.] NEI, NIH, Bethesda, MD 20892 USA. [Peto, Tunde; Sallo, Ferenc B.; Leung, Irene] Moorfields Eye Hosp, NIHR BMRC, London, England. [Peto, Tunde; Sallo, Ferenc B.; Leung, Irene] UCL, London, England. FU Lowy Medical Research Institute Limited FX Funding provided by The Lowy Medical Research Institute Limited NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 2038 PG 2 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174004362 ER PT J AU Diaz-Lezama, N Wu, ZJ Adan-Castro, E Moreno-Carranza, B de la Escalera, GM Clapp, C AF Diaz-Lezama, Nundehui Wu, Zhijian Adan-Castro, Elva Moreno-Carranza, Bibiana Martinez de la Escalera, Gonzalo Clapp, Carmen TI An AAV2 vector encoding prolactin reverses blood retinal barrier pathology when administered intravitreally to diabetic rats SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Diaz-Lezama, Nundehui; Adan-Castro, Elva; Moreno-Carranza, Bibiana; Martinez de la Escalera, Gonzalo; Clapp, Carmen] Univ Nacl Autonoma Mexico, Inst Neurobiol, Queretaro, Queretaro, Mexico. [Wu, Zhijian] NIH, Ocular Gene Therapy Lab, Bldg 10, Bethesda, MD 20892 USA. FU National Council of Science and Technology of Mexico (CONACYT) [247164] FX Support National Council of Science and Technology of Mexico (CONACYT) grant 247164 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 758 PG 2 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174002178 ER PT J AU Eghrari, AO Bishop, RJ Brady, CJ Ray, V Fallah, M Cunningham, D Reilly, CS Ferris, FL Larbelee, J AF Eghrari, Allen O. Bishop, Rachel Jessica Brady, Christopher J. Ray, Vincent Fallah, Mosoka Cunningham, Denise Reilly, Cavan S. Ferris, Frederick L. Larbelee, Jemma TI Clinical characterization of Ebola-associated eye disease with spectral domain optical coherence tomography SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Eghrari, Allen O.; Brady, Christopher J.] Johns Hopkins Univ, Sch Med, Ophthalmol, Baltimore, MD USA. [Bishop, Rachel Jessica; Cunningham, Denise; Ferris, Frederick L.] NEI, Ophthalmol, Bethesda, MD 20892 USA. [Ray, Vincent] Calif Pacific Med Ctr, Ophthalmol, San Francisco, CA USA. [Fallah, Mosoka] PREVAIL III, Monrovia, Liberia. [Reilly, Cavan S.] Univ Minnesota, Biostat, Minneapolis, MN USA. [Larbelee, Jemma] Redempt Hosp, Ophthalmol, Monrovia, Liberia. FU NIH [K12 EY015025-10] FX NIH K12 EY015025-10 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 1668 PG 3 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174004062 ER PT J AU Fairless, E Kooragayala, K Karakulah, G Kim, JW Boleda, A Cogliati, T Swaroop, A AF Fairless, Elizabeth Kooragayala, Keshav Karakulah, Gokhan Kim, Jung-Woong Boleda, Alexis Cogliati, Tiziana Swaroop, Anand TI Distinct Expression of Heat Shock Proteins in Mouse Models of Retinal Degeneration SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Fairless, Elizabeth; Kooragayala, Keshav; Karakulah, Gokhan; Kim, Jung-Woong; Boleda, Alexis; Cogliati, Tiziana; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, Bethesda, MD USA. FU NIH FX Support NIH Intramural Program NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 2258 PG 3 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174005160 ER PT J AU Farney, K Dolinska, MB Sergeev, YV AF Farney, Katie Dolinska, Monika B. Sergeev, Yuri V. TI A Computational Analysis of Human Tyrosinase to Further Understanding of Oculocutaneous Albinism Type 1 SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Farney, Katie; Dolinska, Monika B.; Sergeev, Yuri V.] NEI, Ophthalm Genet & Visual Funct Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 670 PG 2 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174002090 ER PT J AU Gnana-Prakasam, JP Chaudhary, K Promsote, W Smith, SB Ganapathy, V Martin, PM Saul, A AF Gnana-Prakasam, Jaya P. Chaudhary, Kapil Promsote, Wanwisa Smith, Sylvia B. Ganapathy, Vadivel Martin, Pamela M. Saul, Alan TI Retinal Iron Overload during Diabetic Retinopathy Accelerates Ganglion Cell Death SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Gnana-Prakasam, Jaya P.; Martin, Pamela M.] Augusta Univ, Biochem & Mol Biol, Augusta, GA USA. [Gnana-Prakasam, Jaya P.; Smith, Sylvia B.; Martin, Pamela M.; Saul, Alan] Augusta Univ, Vis Discovery Inst, Augusta, GA USA. [Chaudhary, Kapil] Augusta Univ, Dept Med, Augusta, GA USA. [Promsote, Wanwisa] NIH, Baltimore, MD USA. [Ganapathy, Vadivel] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. FU AHA [14SDG20510062] FX Support AHA 14SDG20510062 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 751 PG 3 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174002171 ER PT J AU Hacibekiroglu, S Michael, JP Westenskow, PD Ballios, B Mitrousis, N Tuo, JS Chan, CC van der Kooy, D Shoichet, M Friedlander, M Nagy, A AF Hacibekiroglu, Sabiha Michael, Jacovos P. Westenskow, Peter D. Ballios, Brian Mitrousis, Nikolaos Tuo, Jingsheng Chan, Chi-Chao van der Kooy, Derek Shoichet, Molly Friedlander, Martin Nagy, Andras TI Combined Cell and Gene Therapy towards the Treatment of Age-Related Macular Degeneration and Diabetic Retinopathy SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Hacibekiroglu, Sabiha; Michael, Jacovos P.; Nagy, Andras] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. [Hacibekiroglu, Sabiha; Ballios, Brian; Nagy, Andras] Univ Toronto, Inst Med Sci, Toronto, ON, Canada. [Westenskow, Peter D.; Friedlander, Martin] Scripps Res Inst, San Diego, CA USA. [Ballios, Brian; Mitrousis, Nikolaos; van der Kooy, Derek; Shoichet, Molly] Donnelly Ctr Cellular & Biomol Res, Toronto, ON, Canada. [Tuo, Jingsheng; Chan, Chi-Chao] NEI, NIH, Bethesda, MD 20892 USA. FU Foundation Fighting Blindness Grant FX Foundation Fighting Blindness Grant NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 525 PG 4 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174001356 ER PT J AU Hotaling, NA Schaub, N Ferrari, J Jha, B Simon, C Bharti, K AF Hotaling, Nathan A. Schaub, Nicholas Ferrari, Jorge Jha, Balendu Simon, Carl, Jr. Bharti, Kapil TI Computational Analysis of iPSC-Derived RPE Shape and Primary Cilium Location to Create Predictive Models of Cell Function SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Hotaling, Nathan A.; Ferrari, Jorge; Jha, Balendu; Bharti, Kapil] NEI, Unit Ocular & Stem Cell Translat Res, Washington, DC USA. [Hotaling, Nathan A.; Schaub, Nicholas; Simon, Carl, Jr.] NIST, Biosyst & Biomat Div, Gaithersburg, MD 20899 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 250 PG 3 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174001092 ER PT J AU Huryn, L Jeffrey, BG Hinduja, A Cukras, CA Zein, WM Hufnagel, RB Sergeev, YV Falsini, B Turriff, A Cunningham, D Brooks, BP AF Huryn, Laryssa Jeffrey, Brett G. Hinduja, Aarti Cukras, Catherine A. Zein, Wadih M. Hufnagel, Robert B. Sergeev, Yuri V. Falsini, Benedetto Turriff, Amy Cunningham, Denise Brooks, Brian Patrick TI The National Eye Institute Prospective ABCA4 Retinopathy Natural History Study: Autofluorescence Imaging Analysis SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Huryn, Laryssa; Jeffrey, Brett G.; Hinduja, Aarti; Cukras, Catherine A.; Zein, Wadih M.; Hufnagel, Robert B.; Sergeev, Yuri V.; Turriff, Amy; Cunningham, Denise; Brooks, Brian Patrick] NEI, Ophthalm Genet, Bethesda, MD 20892 USA. [Falsini, Benedetto] Univ Cattolica, Rome, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 3 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174000128 ER PT J AU Insinna, C Lu, QL Ott, C Lippincott-Schwartz, J Jackson, P Westlake, C AF Insinna, Christine Lu, Quanlong Ott, Carolyn Lippincott-Schwartz, Jennifer Jackson, Peter Westlake, Christopher TI Membrane trafficking regulation of intracellular ciliogenesis initiation and progression in RPE-1 cells and photoreceptors SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Insinna, Christine; Lu, Quanlong; Westlake, Christopher] NCI, Frederick Natl Lab, LCDS, Frederick, MD 21701 USA. [Ott, Carolyn; Lippincott-Schwartz, Jennifer] NICHD, NIH, Bethesda, MD USA. [Jackson, Peter] Standford Univ, Stanford, CA USA. FU NIH FX NIH intramural funding NR 0 TC 0 Z9 0 U1 1 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 567 PG 2 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174001397 ER PT J AU Jeffrey, BG Nimmagadda, M Hinduja, A Turriff, A Huryn, L Hufnagel, RB Cukras, CA Zein, WM Brooks, BP AF Jeffrey, Brett G. Nimmagadda, Malika Hinduja, Aarti Turriff, Amy Huryn, Laryssa Hufnagel, Robert B. Cukras, Catherine A. Zein, Wadih M. Brooks, Brian Patrick TI The National Eye Institute Prospective ABCA4 Retinopathy Natural History Study: Fundus Guided Retinal Sensitivity Over Year SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Jeffrey, Brett G.; Nimmagadda, Malika; Hinduja, Aarti; Turriff, Amy; Huryn, Laryssa; Hufnagel, Robert B.; Cukras, Catherine A.; Zein, Wadih M.; Brooks, Brian Patrick] NEI, Ophthalm Genet & Visual Fundt Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 3 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174000129 ER PT J AU Killingsworth, L Shimada-Ishii, H English, M Mahgerefteh, L Wolfe, S Cogliati, T Brooks, B Lacobson, SG Swaroop, A AF Killingsworth, Lauren Shimada-Ishii, Hiroko English, Milton Mahgerefteh, Lacklyn Wolfe, Sharon Cogliati, Tiziana Brooks, Brian Lacobson, Samuel G. Swaroop, Anand TI Modeling ciliogenesis in Leber congenital amaurosis using fibroblasts from patients with CEP290 mutations SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Killingsworth, Lauren; Shimada-Ishii, Hiroko; English, Milton; Mahgerefteh, Lacklyn; Cogliati, Tiziana; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Killingsworth, Lauren] Stanford Univ, Stanford, CA 94305 USA. [Wolfe, Sharon; Lacobson, Samuel G.] Univ Penn, Ctr Hereditary Retinal Degenerat, Philadelphia, PA 19104 USA. [Wolfe, Sharon; Lacobson, Samuel G.] Univ Penn, Scheie Eye Inst, Retinal Funct Dept, Philadelphia, PA 19104 USA. [Brooks, Brian] NEI, Pediat Dev & Genet Ophthalmol Unit, NIH, Bethesda, MD 20892 USA. FU NIH Intramural Research Program FX NIH Intramural Research Program NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 176 PG 3 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174001022 ER PT J AU Kus, NJ Dolinska, MB Sergeev, YV AF Kus, Nicole Joanne Dolinska, Monika B. Sergeev, Yuri V. TI Purification and biochemical characterization of full-length human tyrosinase SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Kus, Nicole Joanne; Dolinska, Monika B.; Sergeev, Yuri V.] NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 1723 PG 2 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174004117 ER PT J AU Valiente-Soriano, FL Garcia-Ayuso, D Ortin-Martinez, A Jimenez-Lopez, M Caja-Matas, Y Canovas-Leon, A Bernal-Garro, JM Becerra, SP Villegas-Perez, MP Vidal-Sanz, M AF Lavier Valiente-Soriano, F. Garcia-Ayuso, Diego Ortin-Martinez, Arturo Jimenez-Lopez, Manuel Caja-Matas, Yolanda Canovas-Leon, Antonio Manuel Bernal-Garro, Jose Patricia Becerra, S. Paz Villegas-Perez, Maria Vidal-Sanz, Manuel TI Study of the neuroprotective effects of BDNF, bFGF, CNTF or several doses of PEDF in a focal Light-emission-diode (LED) - induced phototoxicity model in adult albino mice SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Lavier Valiente-Soriano, F.; Garcia-Ayuso, Diego; Ortin-Martinez, Arturo; Jimenez-Lopez, Manuel; Caja-Matas, Yolanda; Canovas-Leon, Antonio; Manuel Bernal-Garro, Jose; Paz Villegas-Perez, Maria; Vidal-Sanz, Manuel] Hosp Virgen de la Arrixaca IMIB Virgen de la Arri, Inst Murciano Invest Biosanitaria, Murcia, Spain. [Lavier Valiente-Soriano, F.; Garcia-Ayuso, Diego; Ortin-Martinez, Arturo; Jimenez-Lopez, Manuel; Caja-Matas, Yolanda; Canovas-Leon, Antonio; Manuel Bernal-Garro, Jose; Paz Villegas-Perez, Maria; Vidal-Sanz, Manuel] Univ Murcia, Fac Med, Dept Oftalmol, Murcia, Spain. [Patricia Becerra, S.] NEI, Sect Prot Struct & Funct, NIH, Bethesda, MD 20892 USA. FU Fundacion Seneca [19881/GERM/15]; Spanish Ministry of Education and Science [SAF2015-67643]; ISCIII-FEDER RETICS [RD12/0034/0014]; ISCIII-FEDER [P113/00643, P113/01266] FX Fundacion Seneca 19881/GERM/15; Spanish Ministry of Education and Science SAF2015-67643; ISCIII-FEDER RETICS RD12/0034/0014; ISCIII-FEDER P113/00643, P113/01266 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 186 PG 3 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174001032 ER PT J AU Li, Q Peng, XY Li, Y Zhu, XQ AF Li, Qian Peng, Xiaoyan Li, Yang Zhu, Xiaoqing TI Angiogenic Complications Exhibited in Patients with Inherited Retinal Degenerations SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Li, Qian; Peng, Xiaoyan; Zhu, Xiaoqing] Beijing Tongren Eye Ctr, Ophthalmol, Beijing, Peoples R China. [Li, Qian] NEI, Bethesda, MD 20892 USA. [Peng, Xiaoyan; Li, Yang] Beijing Inst Ophthalmol, Beijing, Peoples R China. FU Beijing Municipal Administration of Hospitals' Youth Programm [QML20150205] FX Beijing Municipal Administration of Hospitals' Youth Programm (QML20150205) NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 162 PG 3 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174001008 ER PT J AU Liu, TT Poliakov, E Gentleman, S Redmond, TM AF Liu, Tingting Poliakov, Eugenia Gentleman, Susan Redmond, T. Michael TI Probing RPE65 palmitoylation by acyl-exchange labeling SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Liu, Tingting; Poliakov, Eugenia; Gentleman, Susan; Redmond, T. Michael] NEI, NIH, Bethesda, MD 20892 USA. FU Intramural Research Program of the National Eye Institute, National Institutes of Health FX Intramural Research Program of the National Eye Institute, National Institutes of Health NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 1733 PG 2 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174004127 ER PT J AU Ma, WX Gao, C Fariss, RN Wong, WT AF Ma, Wenxin Gao, Chun Fariss, Robert N. Wong, Wai T. TI Mobilization of endogenous microglia is coordinated with systemic monocyte infiltration in a model of RPE cell injury SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Ma, Wenxin; Wong, Wai T.] NEI, UNGIRD, Bethesda, MD 20892 USA. [Gao, Chun; Fariss, Robert N.] NEI, Biol Imaging Core, Bethesda, MD 20892 USA. FU NEI FX Support NEI Intramural Research Program NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 2229 PG 2 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174005131 ER PT J AU Patterson, S Yoshimatsu, T Suresh, T Nelson, RF AF Patterson, Sara Yoshimatsu, Takeshi Suresh, Tara Nelson, Ralph F. TI The Role of Thyroid Hormone Receptor B2 (tr beta 2) in Photoreceptor Opsin Development SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Patterson, Sara; Yoshimatsu, Takeshi] Univ Washington, Neurosci, Seattle, WA 98195 USA. [Patterson, Sara; Suresh, Tara; Nelson, Ralph F.] NINDS, Neural Circuits Unit, NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 587 PG 2 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174002008 ER PT J AU Ruchi, F Khristov, V Jha, B Patel, D Wan, Q Hotaling, N Zhang, CX Bharti, K AF Ruchi, Fnu Khristov, Vladimir Jha, Balendu Patel, Dishita Wan, Qin Hotaling, Nathan Zhang, Congxiao Bharti, Kapil TI Functional Validation of GLP-grade Induced Pluripotent Stem Cell Derived Retinal Pigment Epithelium: developing a Cell Therapy for AMD. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Ruchi, Fnu; Khristov, Vladimir; Jha, Balendu; Patel, Dishita; Wan, Qin; Hotaling, Nathan; Zhang, Congxiao; Bharti, Kapil] NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 2127 PG 2 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174005034 ER PT J AU Sharma, A Sunshine, SB Tisdale, A Chew, EY Wong, WT AF Sharma, Aman Sunshine, Sarah B. Tisdale, Alanna Chew, Emily Y. Wong, Wai T. TI Changes in Clinical Appearance and Fundus Autofluorescence Associated with Drusen Regression in Intermediate Age-Related Macular Degeneration SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Sharma, Aman; Sunshine, Sarah B.; Tisdale, Alanna; Chew, Emily Y.; Wong, Wai T.] NEI, NIH, Bethesda, MD 20892 USA. FU NEI Intramural Research Program FX NEI Intramural Research Program NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 1612 PG 3 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174004009 ER PT J AU Singaravelu, J Zhao, L Fariss, RN Nork, TM Wong, WT AF Singaravelu, Janani Zhao, Lian Fariss, Robert N. Nork, T. Michael Wong, Wai T. TI Microglia specialization in the primate macula: Changes in distribution and morphology with retinal position and aging SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Singaravelu, Janani; Zhao, Lian; Wong, Wai T.] NEI, Unit Neuron Glia Interact Retinal Dis, Bethesda, MD 20892 USA. [Fariss, Robert N.] NEI, Bethesda, MD 20892 USA. [Nork, T. Michael] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Madison, WI USA. FU NIH MRSP FX Support NIH MRSP NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 2230 PG 2 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174005132 ER PT J AU Smith, A Daly, C Collery, RF Chaitankar, V Brooks, M Cogliati, T Swaroop, A Kennedy, BN AF Smith, Andrew Daly, Conor Collery, Ross F. Chaitankar, Vijender Brooks, Matthew Cogliati, Tiziana Swaroop, Anand Kennedy, Breandan N. TI Identification and Characterisation of Novel Cone Photoreceptor-Enriched Factors Conserved in Zebrafish, Mouse and Human SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Smith, Andrew; Daly, Conor; Kennedy, Breandan N.] UCD Conway Inst, UCD Sch Biomol & Biomed Sci, Dublin, Ireland. [Collery, Ross F.] Med Coll Wisconsin, Dept Cell Biol Neurobiol & Anat, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. [Chaitankar, Vijender; Brooks, Matthew; Cogliati, Tiziana; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, 6 Ctr Dr, Bethesda, MD 20892 USA. FU Wellcome Trust - National Institutes of Health PhD Studentship FX Wellcome Trust - National Institutes of Health PhD Studentship NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 572 PG 3 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174001402 ER PT J AU Snow, PE Lee, EJ Furtado, JM Brown, B Vance, E Dugan, J Silver, P Smith, JR Caspi, RR Rosenzweig, HL AF Snow, Paige E. Lee, Ellen J. Furtado, Joao M. Brown, Brieanna Vance, Emily Dugan, Jae Silver, Phyllis Smith, Justine R. Caspi, Rachel R. Rosenzweig, Holly Lallman TI Nod2 controls susceptibility to autoimmune uveitis through control of a Th17-driven response SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Snow, Paige E.; Lee, Ellen J.; Brown, Brieanna; Vance, Emily; Dugan, Jae; Rosenzweig, Holly Lallman] VA Portland Hlth Care Syst, Portland, OR USA. [Lee, Ellen J.; Vance, Emily; Rosenzweig, Holly Lallman] Oregon Hlth & Sci Univ, Mol Microbiol & Immunol, Portland, OR 97201 USA. [Furtado, Joao M.] Univ Sao Paulo, Ribeirao Preto Med Sch, Sao Paulo, Brazil. [Silver, Phyllis; Caspi, Rachel R.] NEI, NIH, Immunol Lab, Bethesda, MD 20892 USA. [Smith, Justine R.] Flinders Univ S Australia, Adelaide, SA, Australia. FU NIH/NEI [EY025250]; Department of Veterans Affairs Biomedical Laboratory [I01 BX002180, IK2 BX001295]; NEI [EY00184]; ARC [FT130101648] FX NIH/NEI (grant EY025250), the Department of Veterans Affairs Biomedical Laboratory (I01 BX002180; IK2 BX001295); NEI intramural support (Project # EY00184), and ARC (FT130101648). NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 507 PG 3 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174001338 ER PT J AU Suarez, MJ Levi, J Rivera-Michlig, R Rosenberg, A Rodriguez, F AF Suarez B, Maria Jose Levi, Jonathan Rivera-Michlig, Roxana Rosenberg, Avi Rodriguez, Fausto TI Clinicopathologic and Proteomic Analysis of Amyloid Deposition in Ocular Surface and Adnexa SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Suarez B, Maria Jose; Rodriguez, Fausto] Johns Hopkins Univ, Pathol, Baltimore, MD USA. [Levi, Jonathan] NIDDK, Bethesda, MD 20892 USA. [Rivera-Michlig, Roxana] Wilmer Eye Inst, Ophthalmol, Baltimore, MD 21287 USA. [Rosenberg, Avi] Childrens Natl Hlth Syst, Washington, DC USA. FU Research to prevent blindness FX Research to prevent blindness NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 2429 PG 2 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174005267 ER PT J AU Subramanian, P Bullock, J Winokur, P Arocas, V Becerra, SP AF Subramanian, Preeti Bullock, Jeanee Winokur, Paige Arocas, Veronique Becerra, S. Patricia TI Protease Nexin-1 (PN-1): A Novel Survival Factor for Retina Cells SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Subramanian, Preeti; Bullock, Jeanee; Winokur, Paige; Becerra, S. Patricia] NEI, Bethesda, MD 20892 USA. [Bullock, Jeanee] Georgetown Univ, Med Ctr, Biochem & Mol & Cellular Biol, Washington, DC 20007 USA. [Arocas, Veronique] Hop Bichat Claude Bernard, Sect Claude Bernard, INSERM, U1148, Batiment Inserm, Paris, France. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 1738 PG 2 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174004132 ER PT J AU Takeuchi, M Karasawa, Y Harimoto, K Sakurai, Y Sato, T Caspi, RR Ito, M AF Takeuchi, Masaru Karasawa, Yoko Harimoto, Kohzou Sakurai, Yutaka Sato, Tomohito Caspi, Rachel R. Ito, Masataka TI Immune responses of Behcet's disease patients with or without recurrent uveitis after infliximab treatment SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Takeuchi, Masaru; Karasawa, Yoko; Harimoto, Kohzou; Sakurai, Yutaka; Sato, Tomohito] Natl Def Med Coll, Ophthalmol, Tokorozawa, Saitama, Japan. [Caspi, Rachel R.] NEI, Immunol, Bethesda, MD 20892 USA. [Ito, Masataka] Natl Def Med Coll, Dev Anat & Regenerat Biol, Tokorozawa, Saitama, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 1891 PG 3 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174004217 ER PT J AU Tisdale, AK Agron, E Sunshine, SB Clemons, TE Ferris, F Chew, EY AF Tisdale, Alanna Kira Agron, Elvira Sunshine, Sarah B. Clemons, Traci E. Ferris, Frederick Chew, Emily Y. TI The Association of Calcium Intake with Incidence of Age-Related Macular Degeneration in the Age-Related Eye Disease Study (AREDS) SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Tisdale, Alanna Kira; Agron, Elvira; Sunshine, Sarah B.; Clemons, Traci E.; Ferris, Frederick; Chew, Emily Y.] NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 2 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174000010 ER PT J AU Tumminia, SJ Abhyankar, S Hendrickson, B Hufnagel, R Hutter, D McDonald, C Goetz, K AF Tumminia, Santa J. Abhyankar, Swapna Hendrickson, Bryan Hufnagel, Robert Hutter, Daniel McDonald, Clement Goetz, Kerry TI A Set of Ophthalmologic Logical Observation Identifiers Names and Codes (LOINC (R)) for Standardizing Data Collection in eyeGENE (R) and in Other Ocular Clinical Studies SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Tumminia, Santa J.] NEI, Off Director, NIH, Bethesda, MD 20892 USA. [Abhyankar, Swapna] Regenstrief Inst Inc, Indianapolis, IN USA. [Hendrickson, Bryan; Hutter, Daniel; McDonald, Clement] Natl Lib Med, Bethesda, MD USA. [Hufnagel, Robert; Goetz, Kerry] NEI, OGVFB, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 669 PG 3 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174002089 ER PT J AU Valent, D Nussenblatt, RB Sen, HN AF Valent, David Nussenblatt, Robert B. Sen, H. Nida TI CD4+and CD8+T Lymphocyte Levels in Uveitis Patients Treated with Cellcept SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Valent, David; Nussenblatt, Robert B.; Sen, H. Nida] NIH, Retina Uveitis, Portland, OR USA. [Valent, David] Retina Care Ctr, Medford, OR USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 1898 PG 2 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174004224 ER PT J AU Vance, EE Lee, EJ Brown, B Snow, PE Truax, A Ting, JP Caspi, RR Rosenzweig, HL AF Vance, Emily E. Lee, Ellen J. Brown, Brieanna Snow, Paige E. Truax, Agna Ting, Jenny P. Caspi, Rachel R. Rosenzweig, Holy Lallman TI The innate immune receptor Nlrp12 participates in protection against experimental autoimmune uveitis SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Vance, Emily E.; Lee, Ellen J.; Rosenzweig, Holy Lallman] Oregon Hlth & Sci Univ, Mol Microbiol & Immunol, Portland, OR 97201 USA. [Vance, Emily E.; Lee, Ellen J.; Brown, Brieanna; Snow, Paige E.; Rosenzweig, Holy Lallman] VA Portland Hlth Care Syst, Portland, OR USA. [Truax, Agna; Ting, Jenny P.] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC USA. [Caspi, Rachel R.] NEI, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. FU NIH/NEI [R21 EY025039]; Department of Veterans Affairs Biomedical Laboratory Research and Development Service; NEI [EY000184] FX NIH/NEI (R21 EY025039), the Department of Veterans Affairs Biomedical Laboratory Research and Development Service, and NEI intramural support (Project # EY000184). NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 490 PG 3 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174001323 ER PT J AU Wan, Q Jha, B May-Simera, H Sharma, R Hartford, J Khristov, V Miyagishima, K Lotfi, MR Miller, SS Bharti, K AF Wan, Qin Jha, Balendu May-Simera, Helen Sharma, Ruchi Hartford, Juliet Khristov, Vladimir Miyagishima, Kiyoharu Lotfi, Mostafa Reza Miller, Sheldon S. Bharti, Kapil TI Primary Cilia Regulates Human iPSC-RPE Maturation via Regulation of WNT Signaling SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Wan, Qin; Khristov, Vladimir; Miyagishima, Kiyoharu; Lotfi, Mostafa Reza; Miller, Sheldon S.] NEI, SERPD, NIH, Bethesda, MD 20892 USA. [Jha, Balendu; Sharma, Ruchi; Hartford, Juliet; Bharti, Kapil] NEI, OSCTR, NIH, Bethesda, MD 20892 USA. [May-Simera, Helen] Johannes Gutenberg Univ Mainz, Inst Zool, Mainz, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 252 PG 3 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174001093 ER PT J AU Wetherby, K Cukras, C Turriff, A Wang, XJ AF Wetherby, Keith Cukras, Catherine Turriff, Amy Wang, Xinjing TI Intronic screening of the RS1 gene in an affected retinoschisis patient suggests a potential cryptic acceptor splice site variation SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Wetherby, Keith; Cukras, Catherine; Turriff, Amy; Wang, Xinjing] NEI, Bethesda, MD 20892 USA. FU NEI FX NEI intramural programs NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 656 PG 2 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174002076 ER PT J AU Willis, JR Vitale, S Morse, LS Parke, DW Rich, WL Lum, F Cantrell, R AF Willis, Jeffrey Ryuta Vitale, Susan Morse, Lawrence S. Parke, David W. Rich, William L. Lum, Flora Cantrell, Ronald TI The Burden of High Myopia and Pathological Myopia in the United States SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Willis, Jeffrey Ryuta; Cantrell, Ronald] Genentech Inc, San Francisco, CA 94080 USA. [Willis, Jeffrey Ryuta; Morse, Lawrence S.] Univ Calif Davis, Dept Ophthalmol, Sacramento, CA USA. [Vitale, Susan] NEI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. [Parke, David W.; Rich, William L.; Lum, Flora] Amer Acad Ophthalmol, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 2467 PG 2 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174005305 ER PT J AU Yng, F Ma, HW Belcher, J Redmond, M Ding, XQ AF Yng, Fan Ma, Hongwei Belcher, Josh Redmond, Michael Ding, Xi-Qin TI Inhibition of Type II Iodothyronine Deiodinase Preserves Cones in Mouse Models of Retinal Degeneration SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Yng, Fan; Ma, Hongwei; Belcher, Josh; Ding, Xi-Qin] Univ Oklahoma, Hlth Sci Ctr, Cell Biol, Oklahoma City, OK USA. [Redmond, Michael] NEI, Lab Retinal Cell & Mol Biol, Bethesda, MD 20892 USA. FU National Eye Institute [P30EY12190, R01EY019490, R21EY024583, T32EY023202]; Foundation Fighting Blindness FX This work was supported by grants from the National Eye Institute (P30EY12190, R01EY019490, R21EY024583, and T32EY023202) and the Foundation Fighting Blindness. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 181 PG 2 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174001027 ER PT J AU Yu, CR Mahdi, RM Egwuagu, CE AF Yu, Chengrong Mahdi, Rashid M. Egwuagu, Charles E. TI IL-10-and IL-35-expressing cells are highly enriched among peripheral blood B cells during experimental autoimmune uveitis SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Yu, Chengrong; Mahdi, Rashid M.; Egwuagu, Charles E.] NEI, Immunol Lab, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 495 PG 2 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174001327 ER PT J AU Zhao, L Zabel, M Zhang, YK Gonzalez, S Ma, WX Wang, X Fariss, RN Wong, WT AF Zhao, Lian Zabel, Matthew Zhang, Yikui Gonzalez, Shaimar Ma, Wenxin Wang, Xu Fariss, Robert N. Wong, Wai T. TI CX3CR1 deficiency affects microglial phagocytosis in rd10 retinal degeneration SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Zhao, Lian; Zabel, Matthew; Zhang, Yikui; Gonzalez, Shaimar; Ma, Wenxin; Wang, Xu; Wong, Wai T.] NEI, Unit Neuron Glia Interact Retinal Dis, Bethesda, MD 20892 USA. [Fariss, Robert N.] NEI, Biol Imaging Core, Bethesda, MD 20892 USA. FU National Eye Institute Intramural Research Program FX National Eye Institute Intramural Research Program NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 2267 PG 3 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174005169 ER PT J AU Zhao, TT Ou, JX Chen, S Li, W AF Zhao, Tantai Ou, Jingxing Chen, Shan Li, Wei TI Microglia cells in cone-dominant ground squirrel retina SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Zhao, Tantai] Cent S Univ, Xiangya Hosp 2, Ophthalmol, Changsha, Hunan, Peoples R China. [Zhao, Tantai; Ou, Jingxing; Chen, Shan; Li, Wei] NEI, NIH, Bethesda, MD 20892 USA. FU NEI FX Support NEI intramural research program NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 2233 PG 2 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174005135 ER PT J AU Zhou, R Li, YC Qian, HH Maminishkis, A Jha, B Campos, MM Amaral, J Stanzel, B Bharti, K AF Zhou, Raymond Li, Yichao Qian, Haohua Maminishkis, Arvydas Jha, Balendu Campos, Maria Mercedes Amaral, Juan Stanzel, Boris Bharti, Kapil TI Sodium iodate-induced retina and choroid damage model in rabbits to test efficacy of RPE auto-transplants SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Zhou, Raymond; Maminishkis, Arvydas] NEI, SERPD, North Potomac, MD USA. [Li, Yichao; Qian, Haohua] NEI, Visual Funct Core, Bethesda, MD 20892 USA. [Jha, Balendu; Bharti, Kapil] NEI, OSCTRU, Bethesda, MD 20892 USA. [Campos, Maria Mercedes] NEI, Histol Core, Bethesda, MD 20892 USA. [Amaral, Juan] NEI, Off Sci Director, Bethesda, MD 20892 USA. [Stanzel, Boris] Univ Bonn, Ophthalmol, Bonn, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 2253 PG 3 WC Ophthalmology SC Ophthalmology GA EK8LA UT WOS:000394174005155 ER PT J AU Abbott, A Valent, D Wei, M Ricks, M Mabundo, L Chung, ST Sumner, A Chew, EY AF Abbott, Akshar Valent, David Wei, Maggie Ricks, Madia Mabundo, Lilian Chung, Stephanie T. Sumner, Anne Chew, Emily Y. TI Glucose Tolerance Status as a marker of diabetic retinopathy in Africans: The Africans in America cohort SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Abbott, Akshar; Valent, David; Wei, Maggie; Chew, Emily Y.] NEI, NIH, Bethesda, MD 20892 USA. [Ricks, Madia; Mabundo, Lilian; Chung, Stephanie T.; Sumner, Anne] NIDDK, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 6331 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210603065 ER PT J AU Abu-Asab, MS Ardeljan, CP Campos, MM AF Abu-Asab, Mones S. Ardeljan, Christopher P. Campos, Maria Mercedes TI Bruch's Membrane is Leaky and RPE lacks Apoptosis, Autophagy and Lysosomes in AMD SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Abu-Asab, Mones S.; Ardeljan, Christopher P.; Campos, Maria Mercedes] NEI, Histol Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 6033 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210602258 ER PT J AU Agrawal, S Eblimit, A Wang, F Xu, MC Goetz, K Li, YM Chen, R AF Agrawal, Smriti Eblimit, Aiden Wang, Feng Xu, Mingchu Goetz, Kerry Li, Yumei Chen, Rui TI Mutations in Receptor Expression Enhancing Protein 6 (REEP6) Cause Early Onset RP in Humans SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Agrawal, Smriti; Eblimit, Aiden; Wang, Feng; Xu, Mingchu; Li, Yumei; Chen, Rui] Baylor Coll Med, Mol & Human Genet, Houston, TX 77030 USA. [Agrawal, Smriti; Eblimit, Aiden; Wang, Feng; Xu, Mingchu; Li, Yumei; Chen, Rui] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Goetz, Kerry] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. FU NEI [R01EY022356, R01EY018571]; Foundation Fighting Blindness Grant [BR-GE-0613-0618-BCM] FX NEI Grant R01EY022356 and R01EY018571, Foundation Fighting Blindness Grant BR-GE-0613-0618-BCM NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 6586 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210603312 ER PT J AU Agron, E Clemons, TE Chew, EY AF Agron, Elvira Clemons, Traci E. Chew, Emily Y. TI Charles Bonnet Syndrome in Participants of the Age-Related Eye Disease Study 2 (AREDS2) SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Agron, Elvira; Chew, Emily Y.] NEI, Bethesda, MD 20892 USA. [Clemons, Traci E.] EMMES Corp, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 2662 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210201037 ER PT J AU Allahdina, AM Stetson, PF Wong, WT Chew, EY Cukras, CA AF Allahdina, Ali M. Stetson, Paul F. Wong, Wai T. Chew, Emily Y. Cukras, Catherine A. TI Optical Coherence Tomography Minimum Intensity as an objective measure for the detection of hydroxychloroquine toxicity SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Allahdina, Ali M.; Wong, Wai T.; Chew, Emily Y.; Cukras, Catherine A.] NEI, NIH, Bethesda, MD 20892 USA. [Stetson, Paul F.] Carl Zeiss Meditec, Res & Dev, Dublin, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 3408 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210202284 ER PT J AU Alvarez, JA Yazdanie, M Wong, WT Thompson, D Lipson, R Wiley, H Chew, EY Ferris, F Cukras, C AF Alvarez, Jason Andrew Yazdanie, Mohammad Wong, Wai T. Thompson, Darby Lipson, Rachel Wiley, Henry Chew, Emily Y. Ferris, Frederick Cukras, Catherine TI Longitudinal Study of Dark Adaptation as a Functional Outcome Measure for Age-Related Macular Degeneration SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Alvarez, Jason Andrew; Yazdanie, Mohammad; Wong, Wai T.; Wiley, Henry; Chew, Emily Y.; Ferris, Frederick; Cukras, Catherine] NEI, NIH, Bethesda, MD 20892 USA. [Thompson, Darby; Lipson, Rachel] EMMES Canada, Barnaby, BC, Canada. FU NIH Medical Research Scholars Program FX NIH Medical Research Scholars Program NR 0 TC 0 Z9 0 U1 1 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 2654 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210201029 ER PT J AU Ardeljan, CP Abu-Asab, MS Campos, MM AF Ardeljan, Christopher P. Abu-Asab, Mones S. Campos, Maria Mercedes TI Choriocapillaris Loss of Endothelial Polarity and Fenestration May Be Contributing Factors in AMD SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Ardeljan, Christopher P.; Abu-Asab, Mones S.; Campos, Maria Mercedes] NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 4997 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210205265 ER PT J AU Bailey-Wilson, JE Musolf, AM Simpson, CL Portas, L Murgia, F Li, Q Stambolian, D AF Bailey-Wilson, Joan Ellen Musolf, Anthony M. Simpson, Claire L. Portas, Laura Murgia, Federico Li, Qing Stambolian, Dwight TI Replication of known loci and suggestive linkage for Familial Myopia on three chromosomes in African-Americans SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Bailey-Wilson, Joan Ellen; Musolf, Anthony M.; Simpson, Claire L.; Portas, Laura; Murgia, Federico; Li, Qing] NHGRI, Computat & Stat Genom Branch, NIH, Baltimore, MD USA. [Portas, Laura; Murgia, Federico] Inst Populat Genet, Sassari, Italy. [Stambolian, Dwight] Univ Penn, Ophthalmol, Philadelphia, PA 19104 USA. FU NIH [5-R01-EY-020483-05] FX Support NIH Grant 5-R01-EY-020483-05 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 3607 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210202404 ER PT J AU Bharti, K Khristov, V Jha, B Campos, MM Raymond, Z Li, YC Qian, HH Maminishkis, A Charles, ST Amaral, J Miller, SS AF Bharti, Kapil Khristov, Vladimir Jha, Balendu Campos, Maria Mercedes Raymond, Zhu Li, Yichao Qian, Haohua Maminishkis, Arvydas Charles, Steve T. Amaral, Juan Miller, Sheldon S. TI Developing Autologous Cell Therapy for Age-related Macular Degeneration using Patient-specific Induced Pluripotent Stem Cell derived Retinal Pigment Epithelium SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Bharti, Kapil; Khristov, Vladimir; Jha, Balendu; Campos, Maria Mercedes; Raymond, Zhu; Li, Yichao; Qian, Haohua; Maminishkis, Arvydas; Charles, Steve T.; Amaral, Juan; Miller, Sheldon S.] NEI, NIH, Potomac, MD USA. FU NEI IRP grants; Common Fund Therapeutic Challenge Award FX NEI IRP grants and Common Fund Therapeutic Challenge Award NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210605215 ER PT J AU Bishop, RJ Eghrari, AO Brady, C Ray, V Reilly, CS Ferris, F Cunningham, D Guizie, E Fallah, M AF Bishop, Rachel Jessica Eghrari, Allen O. Brady, Christopher Ray, Vincent Reilly, Cavan S. Ferris, Frederick Cunningham, Denise Guizie, Edward Fallah, Mosoka TI Expanding the spectrum of Ebola-associated eye disease: a summary of ocular findings in a large cohort of Ebola survivors SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Bishop, Rachel Jessica; Ferris, Frederick; Cunningham, Denise] NEI, Rockville, MD USA. [Eghrari, Allen O.; Brady, Christopher] Johns Hopkins Univ, Sch Med, Ophthalmol, Baltimore, MD USA. [Ray, Vincent] Calif Pacific Med Ctr, Ophthalmol, San Francisco, CA USA. [Reilly, Cavan S.] Univ Minnesota, Div Biostat, Minneapolis, MN USA. [Guizie, Edward] John F Kennedy Med Ctr, Ophthalmol, Monrovia, Liberia. [Fallah, Mosoka] PREVAIL III, Monrovia, Liberia. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210605246 ER PT J AU Biswas, P Chavali, VRM Khan, NW Suk, J Homsher, M Riazuddin, S Hejtmancik, JF Riazuddin, SA Ayyagari, R AF Biswas, Pooja Chavali, Venkata R. M. Khan, Naheed W. Suk, John Homsher, Melissa Riazuddin, Sheikh Hejtmancik, J. Fielding Riazuddin, S. Amer Ayyagari, Radha TI Zebrafish and Mouse Models with Mutations in the Novel Gene ASRGL1 Develop Retinal Degeneration (RD) Recapitulating the Human Phenotype SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Biswas, Pooja; Suk, John; Ayyagari, Radha] Univ Calif San Diego, Shiley Eye Inst, La Jolla, CA 92093 USA. [Chavali, Venkata R. M.; Homsher, Melissa] Univ Penn, Ophthalmol, Philadelphia, PA 19104 USA. [Khan, Naheed W.] Univ Michigan, WK Kellogg Eye Ctr, Ann Arbor, MI 48109 USA. [Riazuddin, Sheikh] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore, Pakistan. [Riazuddin, Sheikh] Univ Hlth Sci, Allama Iqbal Med Coll, Lahore, Pakistan. [Hejtmancik, J. Fielding] NEI, OMGS OGVFB, NIH, Bethesda, MD 20892 USA. [Riazuddin, S. Amer] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. FU Foundation Fighting Blindness; Research to Prevent Blindness; [NIH-EY13198]; [NIH-EY21237]; [P30-EY22589] FX The Foundation Fighting Blindness, Research to Prevent Blindness, NIH-EY13198, NIH-EY21237, P30-EY22589. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 3149 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210202035 ER PT J AU Bonilha, VL Bell, BA Rayborn, ME Hollyfield, JG Samuels, IS Xie, CS Cai, HB AF Bonilha, Vera L. Bell, Brent A. Rayborn, Mary E. Hollyfield, Joe G. Samuels, Ivy S. Xie, Chengsong Cai, Huaibin TI Age-related degeneration of the retinal pigment epithelium (RPE) of DJ-1 mice. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Bonilha, Vera L.; Bell, Brent A.; Rayborn, Mary E.; Hollyfield, Joe G.; Samuels, Ivy S.] Cleveland Clin, Ophthalm Res, Cleveland, OH 44106 USA. [Bonilha, Vera L.; Hollyfield, Joe G.] CCLCM, Ophthalmol, Cole Eye Inst, Cleveland, OH USA. [Samuels, Ivy S.] Louis Stokes Cleveland Vet Affairs Med Ctr, Res Serv, Cleveland, OH USA. [Xie, Chengsong; Cai, Huaibin] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. FU Research to Prevent Blindness; Wolf Family Foundation; National Eye Institute [EY014240-08]; VA Merit Award from Biomedical Laboratory Research and Development (ISS) [I01-BX002754] FX Research to Prevent Blindness, Wolf Family Foundation,National Eye Institute (EY014240-08) and a VA Merit Award I01-BX002754 from Biomedical Laboratory Research and Development (ISS). NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 6038 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210602263 ER PT J AU Bullock, L Subramanian, P Becerra, SP AF Bullock, Leanee Subramanian, Preeti Becerra, S. Patricia TI Expression, purification and characterization of a membrane-bound receptor for PEDF SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Bullock, Leanee; Subramanian, Preeti; Becerra, S. Patricia] NEI, Bethesda, MD 20892 USA. [Bullock, Leanee] Georgetown Univ, Biochem & Mol & Cellular Biol, Washington, DC USA. FU NEI-NIH [ZIA EY000306] FX Intramural Research Program of the NEI-NIH Project # ZIA EY000306 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 4806 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210205083 ER PT J AU Chew, EY Agron, E Clemons, TE Domalpally, A Danis, RP AF Chew, Emily Y. Agron, Elvira Clemons, Traci E. Domalpally, Amitha Danis, Ronald P. TI Progression of Geographic Atrophy in the Age-Related Eye Disease Study 2 (AREDS2) SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Chew, Emily Y.; Agron, Elvira] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Clemons, Traci E.] EMMES Corp, Rockville, MD USA. [Domalpally, Amitha; Danis, Ronald P.] Univ Wisconsin, Madison, WI USA. FU ADB [NO1-EY-5-0007]; [HHS-N-260-2005-00007-C] FX contract HHS-N-260-2005-00007-C; ADB contract NO1-EY-5-0007 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210605164 ER PT J AU Chew, EY AF Chew, Emily Y. TI Retina diseases in pregnancy SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Chew, Emily Y.] NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210604298 ER PT J AU Chong, WP Horai, R Silver, P Jittayasothorn, Y Chan, CC Caspi, RR AF Chong, Wai Po Horai, Reiko Silver, Phyllis Jittayasothorn, Yingyos Chan, Chi-Chao Caspi, Rachel R. TI IL-17A is dispensable for spontaneous autoimmune uveitis and negatively regulates the Th17 cytokine program SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Chong, Wai Po; Horai, Reiko; Silver, Phyllis; Jittayasothorn, Yingyos; Chan, Chi-Chao; Caspi, Rachel R.] NEI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210605302 ER PT J AU Cvekl, A Xie, Q McGreal, R Harris, R Limi, S Gao, C Liu, W Reneker, LW Musil, L AF Cvekl, Ales Xie, Qing McGreal, Rebecca Harris, Raven Limi, Saima Gao, Chun Liu, Wei Reneker, Lixing W. Musil, Linda TI The molecular basis of crystallin gene expresssion in lens: Role of FGF signaling and c-MAF SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Cvekl, Ales; Xie, Qing; McGreal, Rebecca; Harris, Raven; Limi, Saima; Liu, Wei] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Gao, Chun] NEI, Bethesda, MD 20892 USA. [Reneker, Lixing W.] Univ Missouri, Columbia, MO USA. [Musil, Linda] Oregon Hlth & Sci Univ, Portland, OR USA. FU RPB [R01 EY014237] FX R01 EY014237, RPB NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210605098 ER PT J AU Daniel, E Grunwald, JE Kim, BJ Maguire, MG Shaffer, JA Jaffe, GJ Toth, CA Martin, DF Ferris, FL Ying, GS AF Daniel, Ebenezer Grunwald, Juan E. Kim, Benjamin J. Maguire, Maureen G. Shaffer, James A. Jaffe, Glenn J. Toth, Cynthia A. Martin, Daniel F. Ferris, Frederick L. Ying, Gui-Shuang TI Hard Exudates and Treatment Outcomes in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Daniel, Ebenezer; Grunwald, Juan E.; Kim, Benjamin J.; Maguire, Maureen G.; Shaffer, James A.; Ying, Gui-Shuang] Univ Penn, Ophthalmol, Philadelphia, PA 19104 USA. [Jaffe, Glenn J.; Toth, Cynthia A.] Duke Univ, Durham, NC USA. [Martin, Daniel F.] Cleveland Clin, Cleveland, OH 44106 USA. [Ferris, Frederick L.] NEI, Bethesda, MD 20892 USA. FU National Eye Institute, National Institutes of Health, Department of Health and Human Services [U10EY023530, U10 EY017823, U10 EY017825, U10 EY017826, U10 EY017828, R21EY02369, R21EY023689] FX Coooperative agreements U10EY023530, U10 EY017823, U10 EY017825, U10 EY017826, U10 EY017828, R21EY02369 and R21EY023689 from the National Eye Institute, National Institutes of Health, Department of Health and Human Services NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 2653 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210201028 ER PT J AU Domalpally, A Danis, RP Chew, EY Clemons, TE AF Domalpally, Amitha Danis, Ronald P. Chew, Emily Y. Clemons, Traci E. TI Fundus Autofluorescence Imaging and Macular Atrophy in Eyes with Neovascular Age Related Macular Degeneration in AREDS2 SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Domalpally, Amitha; Danis, Ronald P.] Univ Wisconsin, Fundus Photograph Reading Ctr, Madison, WI USA. [Chew, Emily Y.] NEI, NIH, Bethesda, MD 20892 USA. [Clemons, Traci E.] EMMES Corp, Rockville, MD USA. FU Research to Prevent Blindness FX Research to Prevent Blindness NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210603328 ER PT J AU Economopoulou, M Troulinaki, M Garcia-Martin, R Pillunat, LE Nussenzweig, A Chavakis, T AF Economopoulou, Matina Troulinaki, Maria Garcia-Martin, Ruben Pillunat, Lutz E. Nussenzweig, Andre Chavakis, Triantafyllos TI The role of DNA repair in the choice between sprouting or proliferating angiogenesis in the context of proliferative retinopathies SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Economopoulou, Matina; Pillunat, Lutz E.] Tech Univ Dresden, Univ Clin, Ophthalmol, Dresden, Germany. [Troulinaki, Maria; Garcia-Martin, Ruben; Chavakis, Triantafyllos] Tech Univ Dresden, Univ Clin, IKL, Dresden, Germany. [Nussenzweig, Andre] NCI, NIH, Bethesda, MD 20892 USA. FU EKFS foundation FX Support EKFS foundation NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 3656 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210203045 ER PT J AU Fadda, A Falsini, B Jeffrey, BG Zein, WM Sieving, PA AF Fadda, Antonello Falsini, Benedetto Jeffrey, Brett G. Zein, Wadih M. Sieving, Paul A. TI A Novel Algorithm for Recording Low-Amplitude ERGs by Cycle-by-Cycle Analysis in Advanced Retinal Degeneration SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Fadda, Antonello] Ist Super Sanita, Technol & Hlth, Rome, Italy. [Falsini, Benedetto] Catholic Univ, Ophthalmol, Rome, Italy. [Jeffrey, Brett G.; Zein, Wadih M.] NEI, Ophthalm Genet & Visual Funct Branch, Bethesda, MD 20892 USA. [Sieving, Paul A.] NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 5764 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210602007 ER PT J AU Frederiksen, R Pahlberg, J Pollock, G Miyagishima, K Nymark, S Sampath, AP Cornwall, MC AF Frederiksen, Rikard Pahlberg, Johan Pollock, Gabriel Miyagishima, Kiyoharu Nymark, Soile Sampath, Alapakkam P. Cornwall, M. Carter TI Voltage-gated conductances increase the sensitivity of mouse rod photoresponses following pigment bleaching SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Frederiksen, Rikard; Cornwall, M. Carter] Boston Univ, Sch Med, Dept Physiol & Biophys, Boston, MA 02118 USA. [Pahlberg, Johan; Pollock, Gabriel; Sampath, Alapakkam P.] Univ Calif Los Angeles, David Geffen Sch Med, Jules Stein Eye Inst, Dept Ophthalmol, Los Angeles, CA 90095 USA. [Miyagishima, Kiyoharu] NEI, NIH, Bethesda, MD 20892 USA. [Nymark, Soile] Tampere Univ Technol, BioMediTech, Dept Elect & Commun Engn, Tampere, Finland. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210604377 ER PT J AU Friberg, TR Domalpally, A Danis, R Clemons, TE Sadda, SR Toth, CA Chew, EY AF Friberg, Thomas R. Domalpally, Amitha Danis, Ron Clemons, Traci E. Sadda, Srinivas R. Toth, Cynthia A. Chew, Emily Y. TI Peripheral Retinal Abnormalities Associated with Age-Related Macular Degeneration in the Age-Related Eye Diseases Study 2 (AREDS2) SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Friberg, Thomas R.] Univ Pittsburgh, Ophthalmol & BioEngn, Pittsburgh, PA USA. [Domalpally, Amitha; Danis, Ron] Univ Wisconsin, Reading Ctr, Madison, WI USA. [Clemons, Traci E.] Emmes Corp, Bethesda, MD USA. [Sadda, Srinivas R.] Doheny, Los Angeles, CA USA. [Toth, Cynthia A.] Duke Eye Ctr, Durham, NC USA. [Chew, Emily Y.] NEI, Bethesda, MD 20892 USA. FU Optos, NEI FX Optos, NEI NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210605081 ER PT J AU George, A Lee, J Dutta, S Brooks, BP AF George, Aman Lee, Jerry Dutta, Sunit Brooks, Brian Patrick TI Zebrafish atr2 gene is required for optic fissure closure SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [George, Aman; Lee, Jerry; Dutta, Sunit; Brooks, Brian Patrick] NEI, OGVFB, NIH, Bethesda, MD 20892 USA. FU NEI intramural FX NEI intramural NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 6577 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210603304 ER PT J AU Gong, Y Fu, ZJ Edin, M Saba, N Fredrick, T Morss, P Burnim, S Meng, S Zeldin, D Smith, LEH AF Gong, Yan Fu, Zhongjie Edin, Matthew Saba, Nicholas Fredrick, Thomas Morss, Peyton Burnim, Samuel Meng, Steven Zeldin, Darryl Smith, Lois E. H. TI Fenofibrate Suppresses Retinal Pathologic Neovascularization via Inhibiting Cytochrome P450 Epoxygenase 2C Activity SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Gong, Yan; Fu, Zhongjie; Saba, Nicholas; Fredrick, Thomas; Morss, Peyton; Burnim, Samuel; Meng, Steven; Smith, Lois E. H.] Harvard Med Sch, Boston Childrens Hosp, Ophthalmol, Boston, MA USA. [Edin, Matthew; Zeldin, Darryl] NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. FU NIH/NEI [R01 EY022275, R01 EY017017, P01 HD18655, R01 EY024963]; Lowy Medical Foundation; European Commission FP7 [305485] FX NIH/NEI (R01 EY022275, R01 EY017017, P01 HD18655), Lowy Medical Foundation, European Commission FP7 (305485) (LEHS), NIH/NEI (R01 EY024963) (JC) NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 4529 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210204301 ER PT J AU Guedez, L Popp, N Chan, CC AF Guedez, Liliana Popp, Nicholas Chan, Chi-Chao TI The role of chemokine CCL-2 and CX3CRI in inflammatory-related retinal degeneration SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Guedez, Liliana; Popp, Nicholas; Chan, Chi-Chao] NEI, Immunol Lab, Bldg 10, Bethesda, MD 20892 USA. FU NIH Intramural Program FX NIH Intramural Program NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 4507 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210204281 ER PT J AU Guru, AA Biswas, P Suk, J Kishaba, K Ullah, I Naeem, MA Riazuddin, S Riazuddin, SA Ayyagari, R Hejtmancik, JF AF Guru, Aditya A. Biswas, Pooga Suk, John Kishaba, Kameron Ullah, Inayat Naeem, Muhammad Asif Riazuddin, Sheikh Riazuddin, S. Amer Ayyagari, Radha Hejtmancik, J. Fielding TI Identification of a novel frame-shift deletion in the CHM gene in a consanguineous family SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Guru, Aditya A.; Biswas, Pooga; Suk, John; Kishaba, Kameron; Ayyagari, Radha] Univ Calif San Diego, Shiley Eye Inst, San Diego, CA USA. [Ullah, Inayat; Naeem, Muhammad Asif; Riazuddin, Sheikh] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore, Pakistan. [Riazuddin, Sheikh] Univ Hlth Sci, Allama Iqbal Med Coll, Lahore, Pakistan. [Riazuddin, S. Amer] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Hejtmancik, J. Fielding] NEI, OMGS OGVFB, NIH, Bethesda, MD 20892 USA. FU FFB; RPB FX FFB, RPB NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 3144 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210202030 ER PT J AU Hanke-Gogokhia, C Wu, ZJ Frederick, JM Zhang, HB Baehr, W AF Hanke-Gogokhia, Christin Wu, Zhijian Frederick, Jeanne M. Zhang, Houbin Baehr, Wolfgang TI The function of ARL3 in mouse photoreceptors SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Hanke-Gogokhia, Christin; Frederick, Jeanne M.; Baehr, Wolfgang] Univ Utah, Ophthalmol, Salt Lake City, UT USA. [Hanke-Gogokhia, Christin] Univ Potsdam, Biochem & Biol, Potsdam, Germany. [Wu, Zhijian] NEI, NIH, Bethesda, MD 20892 USA. [Zhang, Houbin] Univ Elect Sci & Technol China, Sch Med, Chengdu, Sichuan, Peoples R China. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210604379 ER PT J AU Hufnagel, RB Hull, S Pedroso, JL Dai, S Nemeth, A Dollfus, H Brooks, BP Sisk, R Michaelides, M Moore, AT Ahmed, Z AF Hufnagel, Robert B. Hull, Sarah Pedroso, Jose Luiz Dai, Shuan Nemeth, Andrea Dollfus, Helene Brooks, Brian Patrick Sisk, Robert Michaelides, Michel Moore, Anthony T. Ahmed, Zubair TI Survey of ophthalmic and systemic features in patients with PNPLA6-related disorders SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Hufnagel, Robert B.; Brooks, Brian Patrick] NEI, Ophthalm Genet Branch, NIH, Washington, DC USA. [Hufnagel, Robert B.; Sisk, Robert] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Hull, Sarah; Michaelides, Michel; Moore, Anthony T.] Moorfields Eye Hosp, London, England. [Pedroso, Jose Luiz] Univ Fed Sao Paulo, Sao Paulo, Brazil. [Dai, Shuan] Univ Auckland, Auckland, New Zealand. [Nemeth, Andrea] Univ Oxford, Oxford, England. [Dollfus, Helene] Univ Strasbourg, Strasbourg, France. [Moore, Anthony T.] Univ San Francisco, San Francisco, CA 94117 USA. [Ahmed, Zubair] Univ Maryland, Baltimore, MD 21201 USA. FU National Eye Institute FX National Eye Institute, Intramural NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 6564 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210603292 ER PT J AU Jeon, J Hotaling, N Zamani, M Dejene, R Ingber, D Bharti, K AF Jeon, Jun Hotaling, Nathan Zamani, Marion Dejene, Roba Ingber, Donald Bharti, Kapil TI Tissue Engineered Human Blood-Retinal Barrier-on-a-Chip SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Jeon, Jun; Hotaling, Nathan; Zamani, Marion; Bharti, Kapil] NEI, Unit Ocular Stem Cell & Translat Res, NIH, Bethesda, MD 20892 USA. [Hotaling, Nathan] NIST, Biosyst & Biomat Div, Gaithersburg, MD 20899 USA. [Zamani, Marion; Ingber, Donald] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. [Dejene, Roba; Bharti, Kapil] NEI, Sect Epithelial & Retinal Physiol & Dis, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 5325 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210601006 ER PT J AU Kabir, F Khan, SY Riazuddin, S Akram, J Hejtmancik, JF Riazuddin, SA AF Kabir, Firoz Khan, Shahid Yar Riazuddin, Sheikh Akram, Javed Hejtmancik, J. Fielding Riazuddin, S. Amer TI Functional Assessment of FYC11 Underlines the Association with Autophagy and Confirms the Indispensable Role in Lens Development SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Kabir, Firoz; Khan, Shahid Yar; Riazuddin, S. Amer] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Riazuddin, Sheikh] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore, Pakistan. [Riazuddin, Sheikh; Akram, Javed] Shaheed Zulficiar Ali Bhutto Med Univ, Natl Ctr Genet Dis, Islamabad, Pakistan. [Akram, Javed] Univ Hlth Sci, Allama Iqbal Med Coll, Lahore, Pakistan. [Hejtmancik, J. Fielding] NEI, Ophthalm Genet & Visual Funct Branch, Bethesda, MD 20892 USA. FU [R01EY022714] FX R01EY022714 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210604283 ER PT J AU Khan, SY Vasanth, S Kabir, F Khan, AO Ma, ZW Riazuddin, S Pourmand, N Zaghloul, NA Hejtmancik, JF Riazuddin, SA AF Khan, Shahid Yar Vasanth, Shivakumar Kabir, Firoz Khan, Arif O. Ma, Zhiwei Riazuddin, Sheikh Pourmand, Nader Zaghloul, Norann A. Hejtmancik, J. Fielding Riazuddin, S. Amer TI Functional Dissection Shows FOXE3 Contributes to Peters Anomaly through the Transcriptional Regulation of an Autophagy Associated Co-Chaperone, DNAJB1 SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Khan, Shahid Yar; Vasanth, Shivakumar; Kabir, Firoz; Riazuddin, S. Amer] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Khan, Arif O.] King Khalid Eye Specialist Hosp, Pediat Ophthalmol, Riyadh, Saudi Arabia. [Ma, Zhiwei; Hejtmancik, J. Fielding] NEI, Ophthalm Genet & Visual Funct Branch, Bethesda, MD 20892 USA. [Riazuddin, Sheikh] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore, Pakistan. [Riazuddin, Sheikh] Shaheed Zulficiar Ali Bhutto Med Univ, Natl Ctr Genet Dis, Islamabad, Pakistan. [Pourmand, Nader] Univ Calif Santa Cruz, Biomol Engn, Santa Cruz, CA 95064 USA. [Zaghloul, Norann A.] Univ Maryland, Dept Med, Baltimore, MD 21201 USA. FU [R01EY022714] FX R01EY022714 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210604281 ER PT J AU Khristov, V Hotaling, N Li, YC Qian, HH Wan, Q Sharma, R Maminishkis, A Amaral, J Miller, SS Davis, J Bharti, K AF Khristov, Vladimir Hotaling, Nathan Li, Yichao Qian, Haohua Wan, Qin Sharma, Ruchi Maminishkis, Arvydas Amaral, Juan Miller, Sheldon S. Davis, Janine Bharti, Kapil TI Optimizing a Biodegradable Scaffold for Clinical Applications of iPS Cell Derived RPE Tissue SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Khristov, Vladimir; Hotaling, Nathan; Li, Yichao; Qian, Haohua; Wan, Qin; Sharma, Ruchi; Maminishkis, Arvydas; Amaral, Juan; Miller, Sheldon S.; Davis, Janine; Bharti, Kapil] NEI, Bethesda, MD 20892 USA. FU NIH/NEI; NIH/NIA Intramural Research Program and Common Fund Therapeutic Challenge Award FX NIH/NEI, NIH/NIA Intramural Research Program and Common Fund Therapeutic Challenge Award NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 3739 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210203121 ER PT J AU Kielczewski, JL Horai, R Caspi, RR AF Kielczewski, Jennifer Lee Horai, Reiko Caspi, Rachel R. TI Naive retina-specific T cells provide neuroprotection to retinal ganglion cells in mouse models of glaucoma SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Kielczewski, Jennifer Lee] NEI, Lab Immunol & Imaging Core, NIH, Bethesda, MD 20892 USA. [Horai, Reiko; Caspi, Rachel R.] NEI, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. FU National Eye Institute [EY000184] FX National Eye Institute, Project# EY000184 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 3298 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210202177 ER PT J AU Kishaba, K Biswas, P Suk, J Ullah, I Naeem, MA Riazuddin, S Akram, J Hejtmancik, JF Riazuddin, SA Ayyagari, R AF Kishaba, Kameron Biswas, Pooja Suk, John Ullah, Inayat Naeem, Muhammad Asif Riazuddin, Sheikh Akram, Javed Hejtmancik, J. Fielding Riazuddin, S. Amer Ayyagari, Radha TI Exome Analysis Detected a Novel 7.4 kb Deletion in the PRPH2 Gene as the Underlying Cause of Recessive Retinal Degeneration in a Consanguineous Family SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Kishaba, Kameron; Biswas, Pooja; Suk, John; Ayyagari, Radha] Univ Calif San Diego, Shiley Eye Inst, La Jolla, CA 92093 USA. [Ullah, Inayat; Naeem, Muhammad Asif; Riazuddin, Sheikh] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore, Pakistan. [Riazuddin, Sheikh] Univ Hlth Sci, Allama Iqbal Med Coll, Lahore, Pakistan. [Akram, Javed] Shaheed Zulfiqar Ali Bhutto Med Univ, Natl Ctr Genet Dis, Islamabad, Pakistan. [Hejtmancik, J. Fielding] NEI, OMGS OGVFB, NIH, Bethesda, MD 20892 USA. [Riazuddin, S. Amer] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. FU Foundation Fighting Blindness; Research to Prevent Blindness [P30EY022589]; [NIH-EY13198]; [NIH-EY21237] FX Foundation Fighting Blindness, Research to Prevent Blindness, P30EY022589, NIH-EY13198, NIH-EY21237 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 3137 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210202023 ER PT J AU Knickelbein, JE Wei, M Jeffrey, BG Nussenblatt, RB Sen, HN AF Knickelbein, Jared E. Wei, Maggie Jeffrey, Brett G. Nussenblatt, Robert B. Sen, H. Nida TI Variability in full-field electoretinogram measurements in patients with birdshot chorioretinopathy SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Knickelbein, Jared E.; Wei, Maggie; Jeffrey, Brett G.; Nussenblatt, Robert B.; Sen, H. Nida] NEI, Bethesda, MD 20892 USA. FU National Eye Institute FX National Eye Institute Intramural Funding NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 3310 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210202189 ER PT J AU Kuo, D Wei, MM Armbrust, KR Yeung, I Chan, CC Nussenblatt, RB Sen, HN AF Kuo, David Wei, Maggie M. Armbrust, Karen R. Yeung, Ian Chan, Chi-Chao Nussenblatt, Robert B. Sen, H. Nida TI Differentiating Endophthalmitis from Uveitis and Vitreoretinal Lymphoma by Aqueous and Vitreous IL-6 and IL-10 SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Kuo, David; Wei, Maggie M.; Armbrust, Karen R.; Yeung, Ian; Chan, Chi-Chao; Nussenblatt, Robert B.; Sen, H. Nida] NEI, NIH, Bethesda, MD 20892 USA. FU NIH; Pfizer Inc; Doris Duke Charitable Foundation; Newport Foundation; American Association for Dental Research; Howard Hughes Medical Institute; Colgate-Palmolive Company FX This research was made possible through the National Institutes of Health (NIH) Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer Inc, The Doris Duke Charitable Foundation, The Newport Foundation, The American Association for Dental Research, The Howard Hughes Medical Institute, and the Colgate-Palmolive Company, as well as other private donors. For a complete list, please visit the Foundation website at: http://fnih.org/work/education-training-0/medical-research-scholars-prog ram. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 3307 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210202186 ER PT J AU Kutty, RK Samuel, W Jaworski, C Duncan, T Nagineni, CN Redmond, TM AF Kutty, R. Krishnan Samuel, William Jaworski, Cynthia Duncan, Todd Nagineni, Chandrasekharam N. Redmond, T. Michael TI Altered expression of long non-Coding RNAs is associated with retinal pigment epithelial dysfunction induced by proinflammatory cytokines SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Kutty, R. Krishnan; Samuel, William; Jaworski, Cynthia; Duncan, Todd; Redmond, T. Michael] NEI, Lab Retinal Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Nagineni, Chandrasekharam N.] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 5788 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210602030 ER PT J AU Lad, EM Mukherjee, D Vann, RR Clemons, TE Chew, EY Jaffe, GJ Farsiu, S AF Lad, Eleonora M. Mukherjee, Dibyendu Vann, Ryan R. Clemons, Traci E. Chew, Emily Y. Jaffe, Glenn J. Farsiu, Sina TI Novel software to assess correlation between MAIA microperimetry and OCT imaging of ellipsoid zone in type 2 idiopathic macular telangiectasia SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Lad, Eleonora M.; Mukherjee, Dibyendu; Jaffe, Glenn J.] Duke Eye Ctr, Ophthalmol, Durham, NC USA. [Vann, Ryan R.] Res Triangle High Sch, Durham, NC USA. [Clemons, Traci E.] EMMES, Ophthalmol, Rockville, MD USA. [Chew, Emily Y.] NEI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. [Farsiu, Sina] Duke Univ, Med Ctr, Biomed Engn, Durham, NC USA. FU Lowy Medical Foundation Research Institute FX Lowy Medical Foundation Research Institute NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210604270 ER PT J AU Lee, J Sisk, R Linne, C Krueger, L Schoenberger, S Fritsche, L Chew, EY Brooks, BP Agarwal, A Ahmed, Z Hufnagel, RB AF Lee, Jerry Sisk, Robert Linne, Courtney Krueger, Laura Schoenberger, Scott Fritsche, Lars Chew, Emily Y. Brooks, Brian Patrick Agarwal, Anita Ahmed, Zubair Hufnagel, Robert B. TI Variable expression of TIMP3-related maculopathy due to an atypical mutation in a large family SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Lee, Jerry; Brooks, Brian Patrick; Hufnagel, Robert B.] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. [Sisk, Robert] Cincinnati Eye Inst, Cincinnati, OH USA. [Linne, Courtney] Washington Univ, St Louis, MO USA. [Krueger, Laura] Univ Kentucky, Lexington, KY USA. [Schoenberger, Scott] Retina Phys & Surg, Dayton, OH USA. [Fritsche, Lars] Univ Michigan, Ann Arbor, MI 48109 USA. [Chew, Emily Y.] NEI, NIH, Bethesda, MD 20892 USA. [Agarwal, Anita] Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA. [Ahmed, Zubair] Univ Maryland, Baltimore, MD 21201 USA. FU National Eye Institute FX National Eye Institute, Intramural NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 3145 PG 4 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210202031 ER PT J AU Lenis, TL Jiang, ZC Sarfare, S Le, A Eddington, S Bok, D Molday, RS Nusinowitz, S Redmond, M Travis, GH Radu, RA AF Lenis, Tamara Lee Jiang, Zhichun Sarfare, Shanta Le, Andrew Eddington, Shannan Bok, Dean Molday, Robert S. Nusinowitz, Steven Redmond, Michael Travis, Gabriel H. Radu, Roxana A. TI Elucidating the role of Retinal Pigment Epithelium (RPE)-specific ABCA4 in Stargardt disease SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Lenis, Tamara Lee; Jiang, Zhichun; Le, Andrew; Eddington, Shannan; Bok, Dean; Nusinowitz, Steven; Travis, Gabriel H.; Radu, Roxana A.] Univ Calif Los Angeles, Stein Eye Inst, Los Angeles, CA USA. [Sarfare, Shanta] Ora Inc, Andover, MA USA. [Molday, Robert S.] Univ British Columbia, Vancouver, BC, Canada. [Redmond, Michael] NEI, Bethesda, MD 20892 USA. FU NIH [R01 EY025002]; JSEI NIH Core Grant [EY00031-48]; Macula Vision Research Foundation Sponsor Award [20142217]; Gerald Oppenheimer Family Foundation FX Support NIH-R01 EY025002, JSEI NIH Core Grant EY00031-48, Macula Vision Research Foundation Sponsor Award 20142217, Gerald Oppenheimer Family Foundation NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 3177 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210202062 ER PT J AU Li, YC Amaral, J Zhou, R Maminishkis, A Miller, SS Qian, HH Bharti, K AF Li, Yichao Amaral, Juan Zhou, Raymond Maminishkis, Arvydas Miller, Sheldon S. Qian, Haohua Bharti, Kapil TI Functional Evaluation of Subretinal Space iPSC-RPE Implant In a Laser-Induced RPE Injury Model In Pig SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Li, Yichao; Amaral, Juan; Zhou, Raymond; Maminishkis, Arvydas; Miller, Sheldon S.; Qian, Haohua; Bharti, Kapil] NEI, Rockville, MD USA. FU NIH FX NIH Common Fund Therapeutic Challenge Award NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 3754 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210203135 ER PT J AU Liu, CH Sun, Y SanGiovanni, JP Evans, L Tian, K Stahl, A Kamenecka, T Solt, L Chen, J AF Liu, Chi-Hsiu Sun, Ye SanGiovanni, John Paul Evans, Lucy Tian, Katherine Stahl, Andreas Kamenecka, Theodore Solt, Laura Chen, Jing TI Nuclear receptor RORa regulates retinal inflammation and neovascularization in retinopathy through SOCS3 SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Liu, Chi-Hsiu; Sun, Ye; Evans, Lucy; Tian, Katherine; Chen, Jing] Boston Childrens Hosp, Dept Ophthalmol, Boston, MA USA. [SanGiovanni, John Paul] NIH, Bldg 10, Bethesda, MD 20892 USA. [Stahl, Andreas] Univ Freiburg, Freiburg, Germany. [Kamenecka, Theodore; Solt, Laura] Scripps Res Inst, Jupiter, FL USA. FU NIH/NEI Grant [R01 EY024963]; Boston Children's Hospital (BCH) Career Development Award; BrightFocus Foundation; BCH Ophthalmology Foundation FX NIH/NEI Grant R01 EY024963, Boston Children's Hospital (BCH) Career Development Award, BrightFocus Foundation and BCH Ophthalmology Foundation NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 3630 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210203019 ER PT J AU Liu, JF Cukras, CA Tam, J AF Liu, Jianfei Cukras, Catherine A. Tam, Johnny TI Quantitative Analysis of Photoreceptor Swelling in Late-Onset Retinal Degeneration Using Adaptive Optics SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Liu, Jianfei; Cukras, Catherine A.; Tam, Johnny] NEI, NIH, Bethesda, MD 20892 USA. FU Intramural Research Program of the National Eye Institute, National Institutes of Health FX Support Intramural Research Program of the National Eye Institute, National Institutes of Health NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 3168 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210202053 ER PT J AU Lujan, BJ Chew, EY Duncan, JL Antony, BJ Makhijani, V Roorda, A AF Lujan, Brandon J. Chew, Emily Y. Duncan, Jacque L. Antony, Bhavna J. Makhijani, Vikram Roorda, Austin TI Altered Photoreceptor Bands Surrounding Areas of Loss in MacTel Cause En Face OCT Endpoint Variability SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Lujan, Brandon J.; Antony, Bhavna J.; Makhijani, Vikram; Roorda, Austin] Univ Calif Berkeley, Sch Optometry, Berkeley, CA 94720 USA. [Lujan, Brandon J.; Antony, Bhavna J.; Makhijani, Vikram; Roorda, Austin] Univ Calif Berkeley, Vis Sci Grad Program, Berkeley, CA 94720 USA. [Lujan, Brandon J.] OHSU, Casey Eye Inst, Ophthalmol, Portland, OR USA. [Chew, Emily Y.] NEI, Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Duncan, Jacque L.] Univ Calif San Francisco, Ophthalmol, San Francisco, CA 94143 USA. [Antony, Bhavna J.] Johns Hopkins Univ, Elect & Comp Engn, Baltimore, MD USA. [Makhijani, Vikram] Bronx Lebanon Hosp Ctr, Ophthlalmol, Bronx, NY USA. FU Lowy Medical Research Institute; Beckman Initiative for Macular Research; Macula Vision Research Foundation; [EY023591] FX Lowy Medical Research Institute, Beckman Initiative for Macular Research, EY023591, Macula Vision Research Foundation NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 4250 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210204099 ER PT J AU Ma, HW Yang, F Belcher, J Butler, M Redmond, TM Scanlan, TS Boye, SL Hauswirth, WW Ding, XQ AF Ma, Hongwei Yang, Fan Belcher, Josh Butler, Michael Redmond, T. Michael Scanlan, Thomas S. Boye, Sanford L. Hauswirth, William W. Ding, Xi-Qin TI Ocular Inhibition of Thyroid Hormone Signaling Protects Cone Photoreceptors in Mouse Models of Retinal Degeneration SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Ma, Hongwei; Yang, Fan; Belcher, Josh; Butler, Michael; Ding, Xi-Qin] Univ Oklahoma, Hlth Sci Ctr, Dept Cell Biol, Oklahoma City, OK USA. [Redmond, T. Michael] NEI, Lab Retinal Cell & Mol Biol, Bethesda, MD 20892 USA. [Scanlan, Thomas S.] Oregon Hlth & Sci Univ, Dept Physiol & Pharmacol, Portland, OR 97201 USA. [Boye, Sanford L.; Hauswirth, William W.] Univ Florida, Dept Ophthalmol, Gainesville, FL USA. [Boye, Sanford L.; Hauswirth, William W.] Univ Florida, Dept Mol Genet & Microbiol, Gainesville, FL USA. FU National Eye Institute [P30EY12190, R01EY019490, R21 EY024583, T32EY023202, P30EY021721]; National Institute of Diabetes and Digestive and Kidney Diseases [DK52798]; Research to Prevent Blindness; Foundation Fighting Blindness FX This work was supported by grants from the National Eye Institute (P30EY12190, R01EY019490, R21 EY024583, T32EY023202, and P30EY021721), the National Institute of Diabetes and Digestive and Kidney Diseases (DK52798), Research to Prevent Blindness, and the Foundation Fighting Blindness. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210604172 ER PT J AU Maminishkis, A Amaral, J Charles, ST Bharti, K Miller, SS AF Maminishkis, Arvydas Amaral, Juan Charles, Steve T. Bharti, Kapil Miller, Sheldon S. TI Surgical tool for subretinal delivery of RPE implants SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Maminishkis, Arvydas; Amaral, Juan; Charles, Steve T.; Bharti, Kapil; Miller, Sheldon S.] NEI, NIH, Bethesda, MD 20892 USA. FU NEI IRP, NIH Common Fund FX NEI IRP, NIH Common Fund NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 5003 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210205270 ER PT J AU May-Simera, H Patnaik, S Kretschmer, V Bharti, K AF May-Simera, Helen Patnaik, Sarita Kretschmer, Viola Bharti, Kapil TI Primary Cilia Temporally Regulate RPE Maturation via Regulation of WNT Signaling SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [May-Simera, Helen; Patnaik, Sarita; Kretschmer, Viola] Johannes Gutenberg Univ Mainz, Zool, Mainz, Germany. [Bharti, Kapil] NEI, Unit Ocular & Stem Cell Translat Res, Bethesda, MD 20892 USA. FU Alexander Von Humboldt Foundation FX Alexander Von Humboldt Foundation NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 5416 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210601093 ER PT J AU McCafferty, C Sergeev, YV AF McCafferty, Caitlyn Sergeev, Yuri V. TI Unfolding mutation screen for inherited eye disease SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [McCafferty, Caitlyn; Sergeev, Yuri V.] NEI, NIH, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 3162 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210202047 ER PT J AU Meguro, A Yamane, T Takeuchi, M Ohno, S Mizuki, N AF Meguro, Akira Yamane, Takahiro Takeuchi, Masaki Ohno, Shigeaki Mizuki, Nobuhisa TI Screening of susceptibility loci for ocular Behcet's disease using a genome-wide association study: preliminary report SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Meguro, Akira; Yamane, Takahiro; Takeuchi, Masaki; Mizuki, Nobuhisa] Yokohama City Univ, Sch Med, Dept Ophthalmol, Yokohama, Kanagawa, Japan. [Takeuchi, Masaki] NHGRI, Inflammatory Dis Sect, NIH, Bethesda, MD 20892 USA. [Ohno, Shigeaki] Hokkaido Univ, Grad Sch Med, Dept Ophthalmol, Sapporo, Hokkaido, Japan. FU JSPS KAKENHI [22390065] FX JSPS KAKENHI grant 22390065 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 6572 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210603299 ER PT J AU Musof, AM Simpson, CL Murgia, F Portas, L Li, Q Stambolian, D Bailey-Wilson, JE AF Musof, Anthony M. Simpson, Claire L. Murgia, Federico Portas, Laura Li, Qing Stambolian, Dwight Bailey-Wilson, Joan E. TI Strong Evidence for Myopia Linkage on Chromosomes 1, 3, and 15 in Pennsylvania Amish Families SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Musof, Anthony M.; Simpson, Claire L.; Li, Qing; Bailey-Wilson, Joan E.] NHGRI, NIH, Baltimore, MD USA. [Murgia, Federico; Portas, Laura] Inst Populat Genet, Sassari, Italy. [Stambolian, Dwight] Univ Penn, Dept Ophthalmol, Philadelphia, PA 19104 USA. FU [5-R01-EY-020483-05] FX 5-R01-EY-020483-05 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 2495 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210200025 ER PT J AU O'Brien, L Lin, YP Kothmann, W Moore, KB Mitchell, CK Diamond, JS AF O'Brien, Lohn Lin, Ya-Ping Kothmann, Wade Moore, Keith B. Mitchell, Cheryl K. Diamond, Jeffrey S. TI Calcium signaling at Cx36 gap junctions in the mouse retina SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [O'Brien, Lohn; Lin, Ya-Ping; Moore, Keith B.; Mitchell, Cheryl K.] Univ Texas Houston Med Sch, Ophthalmol, Houston, TX USA. [Kothmann, Wade; Diamond, Jeffrey S.] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Kothmann, Wade] Amer Univ, Washington, DC 20016 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210605071 ER PT J AU Patel, R Zaffer, A Ramic, A Preston, K Gaynes, B Stefonowicz, C AF Patel, Rima Zaffer, Adnaan Ramic, Alma Preston, Kenzie Gaynes, Bruce Stefonowicz, Christopher TI Functional Correlates of Intrinsically Photosensitive Retinal Ganglion Cells among Individuals Exposed to Cocaine. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Patel, Rima; Stefonowicz, Christopher] Loyola Univ, Med Ctr, Ophthalmol & Visual Sci, 2160 S 1st Ave, Maywood, IL 60153 USA. [Zaffer, Adnaan; Ramic, Alma; Gaynes, Bruce] Edward Hines Jr VA Hosp, Ophthalmol, Hines, IL USA. [Preston, Kenzie] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 4655 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210205013 ER PT J AU Pavletic, S AF Pavletic, Steven TI Ocular chronic GVHD in clinical transplant practice luid dynamics and ocular perfusion pressure? SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Pavletic, Steven] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. FU Intramural program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland FX Intramural program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 1 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210604095 ER PT J AU Qureshy, Z Miyagishima, K Clore-Gronenborn, K Zhang, CX Sharma, R Rajan, V Khristov, V Cukras, C Miller, SS Bharti, K AF Qureshy, Zoya Miyagishima, Kiyoharu Clore-Gronenborn, Katharina Zhang, Congxiao Sharma, Ruchi Rajan, Vaishakh Khristov, Vladimir Cukras, Catherine Miller, Sheldon S. Bharti, Kapil TI Investigating the molecular mechanisms of Late-Onset Retinal Degeneration using patient-specific induced pluripotent stem cells SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Qureshy, Zoya; Clore-Gronenborn, Katharina; Sharma, Ruchi; Rajan, Vaishakh; Bharti, Kapil] NEI, Unit Ocular Stem Cell & Translat Res, NIH, Bethesda, MD 20892 USA. [Miyagishima, Kiyoharu; Zhang, Congxiao; Khristov, Vladimir; Miller, Sheldon S.] NEI, Sect Epithelial & Retinal Physiol & Dis, NIH, Bethesda, MD 20892 USA. [Cukras, Catherine] NEI, Clin Trials Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210604307 ER PT J AU Ratnapriya, R Walton, A Starostik, M Montezuma, SR Ferrington, DA Swaroop, A AF Ratnapriya, Rinki Walton, Ashley Starostik, Margaret Montezuma, Sandra Rocio Ferrington, Deborah A. Swaroop, Anand TI Retinal transcriptome signatures associated with age-related macular degeneration SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Ratnapriya, Rinki; Walton, Ashley; Starostik, Margaret; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, Bethesda, MD 20892 USA. [Montezuma, Sandra Rocio; Ferrington, Deborah A.] Univ Minnesota, Dept Ophthalmol & Visual Neurosci, Minneapolis, MN USA. FU NIH intramural research program FX NIH intramural research program NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210605006 ER PT J AU Roger, JE Gieser, L Barnes, M Hamon, A Masson-Garcia, C Perron, M AF Roger, Jerome E. Gieser, Linn Barnes, Megan Hamon, Annaig Masson-Garcia, Christel Perron, Muriel TI Whole transcriptome sequencing in rd10 revealed new factors and pathways involved in stem cells biology and neuroprotection in the inner retina and ciliary body. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Roger, Jerome E.; Barnes, Megan; Hamon, Annaig; Masson-Garcia, Christel; Perron, Muriel] CERTO, NeuroPSI, Orsay, France. [Gieser, Linn] NEI, NIH, Bethesda, MD 20892 USA. [Perron, Muriel] CNRS, Orsay, France. FU Retina France [129655]; FRM; Idex Paris-Saclay FX Support Retina France - 129655; FRM; Idex Paris-Saclay NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 3194 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210202078 ER PT J AU Rosenzweig, HL Brown, B Snow, P Vance, E Silver, P Caspi, RR Lee, EJ AF Rosenzweig, Holly Lallman Brown, Brieanna Snow, Paige Vance, Emily Silver, Phyllis Caspi, Rachel R. Lee, Ellen J. TI Mincle activation and Syk/Card9 signaling axis are central to development of autoimmune disease of the eye SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Rosenzweig, Holly Lallman; Brown, Brieanna; Snow, Paige; Vance, Emily; Lee, Ellen J.] Portland VA Med Ctr, Portland, OR USA. [Rosenzweig, Holly Lallman; Vance, Emily; Lee, Ellen J.] Oregon Hlth & Sci Univ, Mol Microbiol & Immunol, Portland, OR 97201 USA. [Silver, Phyllis; Caspi, Rachel R.] NEI, Immunol Lab, Bldg 10, Bethesda, MD 20892 USA. FU NIH/NEI [EY025250]; Department of Veterans Affairs Biomedical Laboratory [I01 BX002180]; NEI [EY00184] FX NIH/NEI (grant EY025250), the Department of Veterans Affairs Biomedical Laboratory (I01 BX002180), and NEI intramural support (Project # EY00184). NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210605301 ER PT J AU Sabbah, S Kim, MT Manoff, G Bhatia-Lin, A Papendorp, C Briggman, K Berson, DM AF Sabbah, Shai Kim, Min Tae Manoff, Gabrielle Bhatia-Lin, Ananya Papendorp, Carin Briggman, Kevin Berson, David M. TI Connectomics of irradiance-encoding ON bipolar-cell inputs to ipRGCs SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Sabbah, Shai; Kim, Min Tae; Manoff, Gabrielle; Bhatia-Lin, Ananya; Papendorp, Carin; Berson, David M.] Brown Univ, Neurosci, Providence, RI 02912 USA. [Briggman, Kevin] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210605072 ER PT J AU Sallo, FB Leung, I Esposti, S Clemons, TE Pauleikhoff, D Chew, EY Bird, AC Peto, T AF Sallo, Ferenc B. Leung, Irene Esposti, Simona Clemons, Traci E. Pauleikhoff, Daniel Chew, Emily Y. Bird, Alan C. Peto, Tunde TI Functional and structural measures of disease severity from a Phase 1 clinical trial in type 2 idiopathic macular telangiectasia. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Sallo, Ferenc B.; Leung, Irene; Esposti, Simona] Moorfields Eye Hosp NHS Fdn Trust, Res & Dev, London, England. [Sallo, Ferenc B.] UCL Inst Ophthalmol, Cell Biol, London, England. [Clemons, Traci E.] EMMES Corp, Rockville, MD USA. [Pauleikhoff, Daniel] St Franziskus Hosp, Ophthalmol, Munster, Germany. [Chew, Emily Y.] NEI, Bethesda, MD 20892 USA. [Bird, Alan C.] Moorfields Eye Hosp, Inherited Eye Dis, London, England. [Peto, Tunde] Moorfields Eye Hosp NHS Fdn Trust, NIHR Biomed Res Ctr Ophthalmol, London, England. [Peto, Tunde] UCL Inst Ophthalmol, London, England. FU Lowy Medical Research Institute FX Lowy Medical Research Institute NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 4955 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210205225 ER PT J AU Sergeev, YV McCafferty, C Fujinami, K Falsini, B Zein, WM Jayasundera, KT Michaelides, M Brooks, BP Sieving, PA AF Sergeev, Yuri V. McCafferty, Caitlyn Fujinami, Kaoru Falsini, Benedetto Zein, Wadih M. Jayasundera, Kanishka Thiran Michaelides, Michel Brooks, Brian Patrick Sieving, Paul A. TI In-silico unfolding: a role of missense changes in Stargardt's disease. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Sergeev, Yuri V.; McCafferty, Caitlyn; Falsini, Benedetto; Zein, Wadih M.; Brooks, Brian Patrick; Sieving, Paul A.] NEI, OGVFB, Bethesda, MD 20892 USA. [Fujinami, Kaoru] Natl Inst Sensory Organs, Tokyo, Japan. [Falsini, Benedetto] Catholic Med Univ, Rome, Italy. [Jayasundera, Kanishka Thiran] Univ Michigan, Ann Arbor, MI 48109 USA. [Michaelides, Michel] Moorfields Eye Hosp, London, England. FU NIH Intramural ZIA [EY000476-07] FX Support NIH Intramural ZIA EY000476-07 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 3163 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210202048 ER PT J AU Sessa, R Padmanaban, P Wan, S Shen, S Smith, A Yamaguchi, T Lang, RA Chen, L AF Sessa, Roberto Padmanaban, Preethi Wan, Stephanie Shen, Steve Smith, April Yamaguchi, Terry Lang, Richard A. Chen, Lu TI Overexpression of monocyte-derived Wnt5a promotes corneal lymphangiogenesis SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Sessa, Roberto; Padmanaban, Preethi; Wan, Stephanie; Shen, Steve; Chen, Lu] Univ Calif Berkeley, Optometry, Berkekely, CA USA. [Smith, April; Lang, Richard A.] Cincinnati Childrens Hosp Med Ctr, Visual Syst Grp, Cincinnati, OH 45229 USA. [Yamaguchi, Terry] NIH, Ctr Canc Res, Frederick, MD USA. FU NIH; University of California at Berkeley FX Support NIH and University of California at Berkeley (LC) NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 3535 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210202334 ER PT J AU Sharon, D Namburi, P Ratnapriya, R Lazar, C Obolensky, A Ben-Yosef, T Pras, E Gross, M Banin, E Swaroop, A AF Sharon, Dror Namburi, Prasanthi Ratnapriya, Rinki Lazar, Csilla Obolensky, Alexey Ben-Yosef, Tamar Pras, Eran Gross, Menachem Banin, Eyal Swaroop, Anand TI Whole exome sequencing reveals a homozygous splicing mutation in CEP78 as the cause of atypical Usher syndrome in Eastern Jewish patients SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Sharon, Dror; Namburi, Prasanthi; Obolensky, Alexey; Banin, Eyal] Hadassah Hebrew Univ Med Ctr, Ophthalmol, Jerusalem, Israel. [Ratnapriya, Rinki; Lazar, Csilla; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Ben-Yosef, Tamar] Technion Israel Inst Technol, Rappaport Fac Med, Haifa, Israel. [Pras, Eran] Assaf Harofeh Med Ctr, Ophthalmol, Zerifin, Israel. [Gross, Menachem] Hadassah Hebrew Univ Med Ctr, Dept Otolaryngol Head & Neck Surg, Jerusalem, Israel. FU FFB [BR-GE-0214-0639-TECH]; United States - Israel Binational Science Foundation [2011202]; Yedidut Research Grant; National Eye Institute, National Institutes of Health [EY000473] FX FFB grant No. BR-GE-0214-0639-TECH, United States - Israel Binational Science Foundation grant number 2011202, Yedidut Research Grant, and Intramural Research Program (# EY000473) of the National Eye Institute, National Institutes of Health. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 3153 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210202039 ER PT J AU Simpson, CL Musolf, AM Portas, L Murgia, F QingLi Bailey-Wilson, JE Stambolian, D AF Simpson, Claire L. Musolf, Anthony M. Portas, Laura Murgia, Federico QingLi Bailey-Wilson, Joan E. Stambolian, Dwight TI Linkage Analysis of Common Myopia using Whole Exome Genotyping in Highly Aggregated Ashkenazi Families Replicates Loci on Chromosomes 1 and 7. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Simpson, Claire L.; Musolf, Anthony M.; Portas, Laura; Murgia, Federico; QingLi; Bailey-Wilson, Joan E.] NHGRI, Computat & Stat Genom Branch, NIH, Baltimore, MD USA. [Simpson, Claire L.] Univ Tennessee, Ctr Hlth Sci, Genet Genom & Informat, Memphis, TN 38163 USA. [Stambolian, Dwight] Univ Penn, Perelman Sch Med, Ophthalmol, Philadelphia, PA 19104 USA. FU [5-R01-EY-020483-05] FX 5-R01-EY-020483-05 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 4839 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210205115 ER PT J AU Sleiman, AKE Veerappan, M Winter, K McCall, M Farsiu, S Chew, EY Clemons, TE Toth, CA AF Sleiman, Abdul Karim El Hage Veerappan, Malini Winter, Katrina McCall, Michelle Farsiu, Sina Chew, Emily Y. Clemons, Traci E. Toth, Cynthia A. TI Optical Coherence Tomography Predictors of 5-Year Progression to Non-Neovascular Late Age-Related Macular Degeneration SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Sleiman, Abdul Karim El Hage; Veerappan, Malini; Winter, Katrina; McCall, Michelle; Farsiu, Sina; Toth, Cynthia A.] Duke Univ, Med Ctr, Dept Ophthalmol, Durham, NC 27710 USA. [Farsiu, Sina; Toth, Cynthia A.] Duke Univ, Dept Biomed Engn, Durham, NC 27706 USA. [Chew, Emily Y.] NEI, NIH, Bethesda, MD 20892 USA. [Clemons, Traci E.] Emmes Corp, Rockville, MD USA. FU [FVFs4400] FX FVFs4400 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210603347 ER PT J AU Stasheff, SF Shankar, M AF Stasheff, Steven F. Shankar, Malini TI Dark rearing slows deterioration of retinal ganglion cell light-evoked responses in rd10 mice and extends a period of immature retinal ganglion cell physiology SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Stasheff, Steven F.; Shankar, Malini] NEI, Retinal Physiol sect, Bethesda, MD 20892 USA. [Stasheff, Steven F.] NEI, Ctr Neurosci & Behav Med, Bethesda, MD 20892 USA. [Stasheff, Steven F.] Childrens Natl Hlth Syst, Bethesda, MD USA. FU March of Dimes Research Grant [12-FY11-200] FX March of Dimes Research Grant # 12-FY11-200 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210605320 ER PT J AU Stetson, PF Allahdina, AM Vitale, S Cukras, C AF Stetson, Paul F. Allahdina, Ali M. Vitale, Susan Cukras, Catherine TI Optical Coherence Tomography Minimum Intensity Abnormalities in Hydroxychloroquine Toxicity SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Stetson, Paul F.] Carl Zeiss Meditec, Res & Dev, Dublin, CA USA. [Allahdina, Ali M.; Vitale, Susan; Cukras, Catherine] NEI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 4246 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210204095 ER PT J AU Sunshine, SB Agron, E Hartford, J Ferris, F Chew, EY AF Sunshine, Sarah B. Agron, Elvira Hartford, Juliet Ferris, Frederick Chew, Emily Y. TI An Improved Method for Measuring Geographic Atrophy (GA) in patients with Age-related Macular Degeneration (AMD) SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Sunshine, Sarah B.; Agron, Elvira; Hartford, Juliet; Ferris, Frederick; Chew, Emily Y.] NEI, NIH, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 1612a PG 2 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210604207 ER PT J AU Swaroop, A AF Swaroop, Anand TI Revisiting the Mendelian disease paradigm: Lessons from next-generation sequencing for retinal and macular degenerative diseases SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Swaroop, Anand] NEI, Bethesda, MD 20892 USA. FU National Eye Institute Intramural Research program FX National Eye Institute Intramural Research program NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210604318 ER PT J AU Takeuchi, M Mizuki, N Meguro, A Ombrello, M Tugal-tutkun, I Ozyazgan, Y Ohno, S Gul, A Kastner, DL Remmers, EF AF Takeuchi, Masaki Mizuki, Nobuhisa Meguro, Akira Ombrello, Michael Tugal-tutkun, Ilknur Ozyazgan, Yilmaz Ohno, Shigeaki Gul, Ahmet Kastner, Daniel L. Remmers, Elaine F. TI Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behcet's disease susceptibility SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Takeuchi, Masaki; Kastner, Daniel L.; Remmers, Elaine F.] NHGRI, NIH, Bethesda, MD 20892 USA. [Takeuchi, Masaki; Mizuki, Nobuhisa; Meguro, Akira] Yokohama City Univ, Yokohama, Kanagawa, Japan. [Ombrello, Michael] NIAMS, NIH, Bethesda, MD USA. [Tugal-tutkun, Ilknur; Ozyazgan, Yilmaz; Gul, Ahmet] Istanbul Univ, Insatnbul, Turkey. [Ohno, Shigeaki] Hokkaido Univ, Sapporo, Hokkaido, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 6573 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210603300 ER PT J AU Tam, J Liu, JF Dubra, A Fariss, RN AF Tam, Johnny Liu, Jianfei Dubra, Alfredo Fariss, Robert N. TI Visualization of retinal pigment epithelial cells using adaptive optics enhanced indocyanine green imaging SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Tam, Johnny; Liu, Jianfei; Fariss, Robert N.] NEI, NIH, Bethesda, MD 20892 USA. [Dubra, Alfredo] Med Coll Wisconsin, Ophthalmol, Milwaukee, WI 53226 USA. [Dubra, Alfredo] Med Coll Wisconsin, Biophys, Milwaukee, WI 53226 USA. FU Intramural Research Program of the National Eye Institute, National Institutes of Health; Glaucoma Research Foundation Catalyst for a Cure Initiative; NIH [U01-EY025477] FX Support Intramural Research Program of the National Eye Institute, National Institutes of Health; Glaucoma Research Foundation Catalyst for a Cure Initiative; NIH Grant U01-EY025477. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 4634 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210204405 ER PT J AU Tomarev, SI Joe, MK AF Tomarev, Stanislav I. Joe, Myung Kuk TI Myocilin is a modulator of TIMP3 activity SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Tomarev, Stanislav I.; Joe, Myung Kuk] NEI, Sect Retinal Gangl Cell Biol, LRCMB, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210605317 ER PT J AU Townley, B Krevosky, MK Bowen, J AF Townley, Brittany Krevosky, Merideth Kamradt Bowen, Jeffery TI A PAR-ting Gift: 3-Aminobenzamide attenuates PARP-1-dependent cell death induced by Melphalan in a Retinoblastoma cell line SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Townley, Brittany] NCI, NIH, Bethesda, MD 20892 USA. [Townley, Brittany; Krevosky, Merideth Kamradt; Bowen, Jeffery] Bridgewater State Univ, Biol, Bridgewater, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 3196 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210202080 ER PT J AU Vahedi, S Eghrari, AO Bishop, RJ Brady, CJ Reilly, CS Ferris, FL Larbelee, J Fallah, M AF Vahedi, Sina Eghrari, Allen O. Bishop, Rachel Jessica Brady, Christopher J. Reilly, Cavan S. Ferris, Frederick L. Larbelee, Jemma Fallah, Mosoka TI Implementation and assessment of visual acuity screening of Ebola Virus Disease survivors utilizing the Peek Vision smartphone platform SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Vahedi, Sina] Jefferson Med Coll, Philadelphia, PA USA. [Eghrari, Allen O.; Brady, Christopher J.] Wilmer Eye Inst, Baltimore, MD USA. [Bishop, Rachel Jessica; Ferris, Frederick L.] NEI, Bethesda, MD 20892 USA. [Reilly, Cavan S.] Univ Minnesota, Minneapolis, MN USA. [Larbelee, Jemma] Minist Hlth, Redempt Hosp, Monrovia, Liberia. [Fallah, Mosoka] PREVAIL III, Monrovia, Liberia. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 5537 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210601209 ER PT J AU Veerappan, M Tai, V Chiu, S Winter, K EI-Hage-Sleiman, AK Lad, E Harrington, C Gunther, R Wong, WT Chew, EY Toth, CA AF Veerappan, Malini Tai, Vincent Chiu, Stephanie Winter, Katrina EI-Hage-Sleiman, Abdul-Karim Lad, Eleonora Harrington, Christopher Gunther, Randall Wong, Wai T. Chew, Emily Y. Toth, Cynthia A. TI Spectral Domain Optical Coherence Tomography 2-Year Localized Precursors to New Onset Geographic Atrophy in Age-Related Macular Degeneration SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Veerappan, Malini; Tai, Vincent; Chiu, Stephanie; Winter, Katrina; EI-Hage-Sleiman, Abdul-Karim; Lad, Eleonora; Harrington, Christopher; Gunther, Randall; Toth, Cynthia A.] Duke Univ, Med Ctr, Duke Eye Ctr, Durham, NC USA. [Wong, Wai T.; Chew, Emily Y.] NEI, NIH, Bethesda, MD 20892 USA. [Toth, Cynthia A.] Duke Univ, Dept Biomed Engn, Durham, NC 27706 USA. FU Genentech; NIH [1 R01 EY023039]; Alcon; Bioptigen FX Genentech (unrestricted research grant), NIH (1 R01 EY023039 grant), Alcon (research grant) and Bioptigen (research equipment) NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 3711 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210203095 ER PT J AU Vitale, S Willis, JR AF Vitale, Susan Willis, Jeffrey Ryuta TI Feasibility of assessing population prevalence of pathological consequences of myopia in NHANES 2005-2008 data SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Vitale, Susan] NEI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. [Willis, Jeffrey Ryuta] Univ Calif Davis, Dept Ophthalmol, Sacramento, CA 95817 USA. FU NCHS/CDC; National Eye Institute, NIH [Z01EY000402] FX The NHANES is sponsored by the NCHS/CDC. Additional funding for the NHANES Vision Component was provided by the National Eye Institute, NIH (Intramural Research Program Z01EY000402). NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 2480 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210200010 ER PT J AU Wallace, GR Candia, J Morton, LM Biancotto, A Murray, PI Nussenblatt, RB Situnayake, D AF Wallace, Graham R. Candia, Julian Morton, Laura M. Biancotto, Angelique Murray, Philip Ian Nussenblatt, Robert B. Situnayake, Deva TI Ocular disease phenotyping from multiparameter cell analysis by machine learning algorithms SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Wallace, Graham R.; Morton, Laura M.; Murray, Philip Ian; Situnayake, Deva] Univ Birmingham, Neurol & Ophthalmol, Birmingham, W Midlands, England. [Candia, Julian; Nussenblatt, Robert B.] NIH, Ctr Human Immunol, Bldg 10, Bethesda, MD 20892 USA. [Biancotto, Angelique] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. FU Fight For Sight FX Fight For Sight NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210604115 ER PT J AU Wang, JJ Huang, CX Jin, CJ Tuo, JS Yu, Q Chan, CC Zhang, SX AF Wang, Joshua Jianxin Huang, Chuangxin Jin, Chen-Jin Tuo, Jingsheng Yu, Qiang Chan, Chi-Chao Zhang, Sarah Xin TI Differential Influences of CCL2/CX3CR1 Axis on Vascular and Retinal Degeneration in Diabetic Retinopathy SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Wang, Joshua Jianxin; Huang, Chuangxin; Zhang, Sarah Xin] SUNY Buffalo, Dept Ophthalmol, Buffalo, NY USA. [Wang, Joshua Jianxin; Huang, Chuangxin; Zhang, Sarah Xin] SUNY Buffalo, Ross Eye Inst, Buffalo, NY USA. [Wang, Joshua Jianxin; Zhang, Sarah Xin] SUNY Buffalo, SUNY Eye Inst, New York, NY USA. [Huang, Chuangxin; Jin, Chen-Jin; Yu, Qiang] Sun Yat Sen Univ, State Key Lab Ophthalmol, Zhongshan Ophthalm Ctr, Guangzhou, Guangdong, Peoples R China. [Tuo, Jingsheng; Chan, Chi-Chao] NEI, Immunopathol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. FU NIH [EY019949, EY025061]; ADA Research Award [7-11-BS-182]; Research to Prevent Blindness FX NIH grants EY019949 and EY025061, ADA Research Award 7-11-BS-182, and Unrestricted Grants from Research to Prevent Blindness to the Department of Ophthalmology of University at Buffalo. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 5436 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210601113 ER PT J AU Wang, XJ Gao, J Wetherby, K Roberson, C Reeves, M Garafalo, A Parrish, R Yim, A AF Wang, Xinjing Gao, Jackson Wetherby, Keith Roberson, Chimere Reeves, Melissa Garafalo, Alexandra Parrish, Rebecca Yim, Annette TI Segregation analysis revealed causative mutations in an Oculocutaneous Albinism (OCA) patient SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Wang, Xinjing; Gao, Jackson; Wetherby, Keith; Roberson, Chimere; Reeves, Melissa; Garafalo, Alexandra; Parrish, Rebecca; Yim, Annette] NEI, Bethesda, MD 20892 USA. FU NEI FX NEI intramural programs NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 6581 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210603307 ER PT J AU Wang, X Zhao, L Zhang, J Fariss, RN Ma, WX Kretschmer, F Wang, MH Qian, HH Badea, TC Roger, JE Wong, WT AF Wang, Xu Zhao, Lian Zhang, Jun Fariss, Robert N. Ma, Wenxin Kretschmer, Friedrich Wang, Minhua Qian, Haohua Badea, Tudor C. Roger, Jerome E. Wong, Wai T. TI Requirement for Microglia for the Maintenance of Synaptic Function and Integrity in the Mature Retina SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Wang, Xu; Zhao, Lian; Ma, Wenxin; Wang, Minhua; Wong, Wai T.] NEI, Unit Neuron Glia Interact Retinal Dis, Bethesda, MD 20892 USA. [Zhang, Jun] NINDS, Synapt Physiol Sect, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Fariss, Robert N.] NEI, Biol Imaging Core, Bethesda, MD 20892 USA. [Kretschmer, Friedrich; Badea, Tudor C.] NEI, Retinal Circuit Dev & Genet Unit, Bethesda, MD 20892 USA. [Qian, Haohua] NEI, Visual Funct Core, Bethesda, MD 20892 USA. [Roger, Jerome E.] CERTO, Inst Neurosci Paris Saclay, Orsay, France. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210604123 ER PT J AU Wei, MM Knickelbein, JE Armbrust, KR Cunningham, D Vitale, S Nussenblatt, RB Sen, HN AF Wei, Maggie M. Knickelbein, Jared E. Armbrust, Karen R. Cunningham, Denise Vitale, Susan Nussenblatt, Robert B. Sen, H. Nida TI Validation study for an image-based standardized grading system for scleritis SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Wei, Maggie M.; Knickelbein, Jared E.; Armbrust, Karen R.; Cunningham, Denise; Vitale, Susan; Nussenblatt, Robert B.; Sen, H. Nida] NIH, Dept Ophthalmol, Bldg 10, Bethesda, MD 20892 USA. FU NIH; Pfizer Inc; Doris Duke Charitable Foundation; Newport Foundation; American Association for Dental Research; Howard Hughes Medical Institute; Colgate-Palmolive Company FX This research was made possible through the National Institutes of Health (NIH) Medical Research Scholars Program, a public private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer Inc, The Doris Duke Charitable Foundation, The Newport Foundation, The American Association for Dental Research, The Howard Hughes Medical Institute, and the Colgate-Palmolive Company, as well as other private donors. For a complete list, please visit the Foundation website at: http://fnih.org/work/education-training-0/medicalresearch-scholars-progr am. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 3305 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210202184 ER PT J AU Wojciechowski, R Fan, Q Hysi, PG Verhoeven, VJM Guggenheim, JA Cheng, CY Klaver, CCW Hammond, CJ Saw, SM AF Wojciechowski, Robert Fan, Qiao Hysi, Pirro G. Verhoeven, Virginie J. M. Guggenheim, Jeremy A. Cheng, Ching-Yu Klaver, Caroline C. W. Hammond, Christopher J. Saw, Seang-Mei TI Gene-based analyses of whole-genome interaction studies of refractive error: results from the Consortium for Refractive Error and Myopia SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Wojciechowski, Robert] Johns Hopkins Bloomberg Sch Publ Hlth, Epidemiol, Baltimore, MD USA. [Wojciechowski, Robert] NHGRI, Computat & Stat Genom Branch, Baltimore, MD USA. [Fan, Qiao; Cheng, Ching-Yu; Saw, Seang-Mei] Singapore Eye Res Inst, Singapore, Singapore. [Hysi, Pirro G.; Hammond, Christopher J.] Kings Coll London, London, England. [Verhoeven, Virginie J. M.; Klaver, Caroline C. W.] Erasmus Univ, Rotterdam, Netherlands. [Guggenheim, Jeremy A.] Cardiff Univ, Cardiff, S Glam, Wales. [Cheng, Ching-Yu] Natl Univ Singapore, Ophthalmol, Singapore, Singapore. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210604390 ER PT J AU Wong, WT AF Wong, Wai T. TI Parainflammation in retinal microglia: Mechanisms in photoreceptor degeneration SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Wong, Wai T.] NEI, Bethesda, MD 20892 USA. FU NEI Intramural Research Program FX NEI Intramural Research Program NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 1 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210604179 ER PT J AU Yazdanie, MS Alvarez, JA Agron, E Chew, EY Wong, WT Wiley, H Ferris, F Cukras, CA AF Yazdanie, Mohammad Saad Alvarez, Jason Andrew Agron, Elvira Chew, Emily Y. Wong, Wai T. Wiley, Henry Ferris, Frederick Cukras, Catherine A. TI y Association of Focal Dark Adaptation Testing with Low Luminance Questionnaire Responses SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Yazdanie, Mohammad Saad; Alvarez, Jason Andrew; Agron, Elvira; Chew, Emily Y.; Wong, Wai T.; Wiley, Henry; Ferris, Frederick; Cukras, Catherine A.] NEI, NIH, Bethesda, MD 20892 USA. FU NIH Summer Internship Program FX NIH Summer Internship Program NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 2659 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210201034 ER PT J AU Yu, WH Mookherjee, S Kim, JW Hiriyanna, S Ataeijannati, Y Sun, X Dong, LJ Li, TS Swaroop, A Wu, ZJ AF Yu, Wenhan Mookherjee, Suddhasil Kim, Jung-Woong Hiriyanna, Suja Ataeijannati, Yasaman Sun, Xun Dong, Lijin Li, Tiansen Swaroop, Anand Wu, Zhijian TI In vivo reprogramming of rods to cone-like cells by Nrl-knockdown using AAV-delivered CRISPR-Cas9 rescues retinal degeneration SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Yu, Wenhan; Mookherjee, Suddhasil; Hiriyanna, Suja; Ataeijannati, Yasaman; Wu, Zhijian] NEI, Ocular Gene Therapy Core, NIH, Bethesda, MD 20892 USA. [Kim, Jung-Woong; Sun, Xun; 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. FU National Eye Institute FX This work was supported by the intramural research program of the National Eye Institute NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210604245 ER PT J AU Zein, WM Bharucha-Goebel, DX Mohassel, P Foley, AR Lehky, TJ Waite, M Mina, JS Jeffrey, BG Brooks, BP Bonnemann, C AF Zein, Wadih M. Bharucha-Goebel, Diana X. Mohassel, Payam Foley, Aileen Reghan Lehky, Tanya J. Waite, Melissa Mina, Jain S. Jeffrey, Brett G. Brooks, Brian Patrick Bonnemann, Carsten TI Ophthalmic Manifestations of Giant Axonal Neuropathy (GAN): Towards Establishing Visual Function / Optic Atrophy Assessments as a Secondary Outcome Measure in an Ongoing Intrathecal Gene Transfer Trial SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Zein, Wadih M.; Jeffrey, Brett G.; Brooks, Brian Patrick] NEI, OGVFB, NIH, Bethesda, MD 20892 USA. [Bharucha-Goebel, Diana X.; Mohassel, Payam; Foley, Aileen Reghan; Lehky, Tanya J.; Bonnemann, Carsten] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Waite, Melissa; Mina, Jain S.] NIH, Ctr Clin, Bethesda, MD 20892 USA. FU National Institutes of Health (NIH) FX Support This work was supported by the Intramural Research Program of the National Institutes of Health (NIH). NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 5995 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210602222 ER PT J AU Zhang, LJ Bell, BA Li, Y Zhang, XM Fung, J Caspi, RR Lin, F AF Zhang, Lingjun Bell, Brent A. Li, Yan Zhang, Xiaomin Fung, John Caspi, Rachel R. Lin, Feng TI The lectin but not classical pathway of activation is important for complement to regulate the development of experimental autoimmune uveitis SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Zhang, Lingjun; Li, Yan; Lin, Feng] Cleveland Clin, Immunol, Cleveland, OH 44106 USA. [Bell, Brent A.] Cleveland Clin, Cole Eye Inst, Cleveland, OH 44106 USA. [Zhang, Xiaomin] Tianjin Med Univ, Hosp Eye, Inst Eye, Tianjin, Peoples R China. [Fung, John] Cleveland Clin, Inst Digest Dis, Cleveland, OH 44106 USA. [Caspi, Rachel R.] NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210605303 ER PT J AU Zhang, YK Zhao, L Wang, X Fariss, RN Wong, WT AF Zhang, Yikui Zhao, Lian Wang, Xu Fariss, Robert N. Wong, Wai T. TI Repopulation of the retina by myeloid cells following depletion of endogenous retinal microglia in adult mice SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Zhang, Yikui; Zhao, Lian; Wang, Xu; Fariss, Robert N.; Wong, Wai T.] NEI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 12 MA 4185 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210204034 ER PT J AU Rothman, AM Button, J Balcer, LJ Frohman, EM Frohman, TC Reich, DS Saidha, S Calabresi, PA AF Rothman, A. M. Button, J. Balcer, L. J. Frohman, E. M. Frohman, T. C. Reich, D. S. Saidha, S. Calabresi, P. A. TI Retinal measurements predict 10-year disability in multiple sclerosis. SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 32nd Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) CY SEP 14-17, 2016 CL London, ENGLAND SP European Comm Treatment & Res Multiple Sclerosis C1 [Rothman, A. M.; Button, J.; Saidha, S.; Calabresi, P. A.] Johns Hopkins Sch Med, Neurol, Baltimore, MD USA. [Balcer, L. J.] NYU Langone Med Ctr, Neurol, New York, NY USA. [Frohman, E. M.; Frohman, T. C.] UT Southwestern Med Ctr, Neurol & Ophthalmol, Dallas, TX USA. [Reich, D. S.] NIH, Translat Neuroradiol, Bldg 10, Bethesda, MD 20892 USA. FU Biogen; Genzyme; Novartis; Acorda; TEVA; Medical Logix; Axon Advisors LLC; Novartis & Teva Neurosciences; Race to Erase MS; Genentech Corporation; Vertex; Abbvie; Merck; MedImmune FX Laura Balcer has received consulting fees from Biogen and Genzyme and has received research funding from Biogen.; Elliot Frohman has received speaker and consulting fees from Novartis, Genzyme, Acorda and TEVA.; Teresa Frohman has received speaker and consultant fees from Novartis, Genzyme, and Acorda.; Shiv Saidha has received consulting fees from Medical Logix for the development of CME programs in neurology, consulting fees from Axon Advisors LLC, Educational Grant Support from Novartis & Teva Neurosciences, speaking honoraria from the National Association of Managed Care Physicians, Advanced Studies in Medicine and the Family Medicine Foundation of West Virginia, and served on scientific advisory boards for Biogen-Idec, Genzyme & Novartis. He is a researcher in the OCTIMS study. He receives research funding from the Race to Erase MS and Genentech Corporation.; Peter A Calabresi has received consulting fees from Vertex, Abbvie, and Merck and has received research funding from Biogen, Novartis and MedImmune. He is co-chairman of the scientific advisory board of the OCTIMS study. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2016 VL 22 SU 3 MA 100 BP 20 EP 21 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DV9NJ UT WOS:000383267200027 ER PT J AU Sethi, VV Nair, G Ha, SK Popescu, B Schindler, MK Smith, BR Absinta, M Sati, P Wuthrich, C Webb, SM Kumar, S Ohayon, J Lucchinetti, C Koralnik, I Major, E Nath, A Cortese, I Reich, DS AF Sethi, V. V. Nair, G. Ha, S. K. Popescu, B. Schindler, M. K. Smith, B. R. Absinta, M. Sati, P. Wuthrich, C. Webb, S. M. Kumar, S. Ohayon, J. Lucchinetti, C. Koralnik, I. Major, E. Nath, A. Cortese, I. Reich, D. S. TI Evolving dark band on T2*-weighted images is characteristic of PML and indicates iron deposition - a combined MRI, XRF & histopathology study. SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 32nd Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) CY SEP 14-17, 2016 CL London, ENGLAND SP European Comm Treatment & Res Multiple Sclerosis C1 [Sethi, V. V.; Nair, G.; Ha, S. K.; Schindler, M. K.; Smith, B. R.; Absinta, M.; Sati, P.; Ohayon, J.; Major, E.; Nath, A.; Cortese, I.; Reich, D. S.] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Popescu, B.; Kumar, S.] Univ Saskatchewan, Saskatoon, SK, Canada. [Wuthrich, C.; Koralnik, I.] Beth Israel Deaconess Med Ctr, Boston, MD USA. [Webb, S. M.] SLAC Natl Accelerator Lab, Stanford Synchrotron Radiat Lightsource, Menlo Pk, CA USA. [Lucchinetti, C.] Mayo Clin, Rochester, MN USA. FU Canada Research Chairs program, University of Saskatchewan, Government of Saskatchewan; Saskatchewan Health Research Foundation; Biogen; Novartis; NIH [R01 NS047029, NS 074995] FX B Popescu: Dr Popescu served as a speaker for Teva Innovation Canada, received an honorarium for publishing in Continuum: Lifelong Learning in Neurology and presenting at the 67th American Academy of Neurology Annual Meeting, Washington, and receives research support from the Canada Research Chairs program, University of Saskatchewan, Government of Saskatchewan and Saskatchewan Health Research Foundation.; C Lucchinetti: receives funding support from Biogen and Novartis but neither is directly related to this work.; I J Koralnik: is funded by NIH grants R01 NS047029 and NS 074995 and a research grant from Biogen. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2016 VL 22 SU 3 MA 171 BP 53 EP 54 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DV9NJ UT WOS:000383267200085 ER PT J AU Kosa, P Barbour, C Komori, M Tanigawa, M Wu, T Johnson, K Herbst, R Wang, Y Tan, K Greenwood, M Bielekova, B AF Kosa, P. Barbour, C. Komori, M. Tanigawa, M. Wu, T. Johnson, K. Herbst, R. Wang, Y. Tan, K. Greenwood, M. Bielekova, B. TI Molecular-based diagnosis of multiple sclerosis and its progressive stage. SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 32nd Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) CY SEP 14-17, 2016 CL London, ENGLAND SP European Comm Treatment & Res Multiple Sclerosis C1 [Kosa, P.; Komori, M.; Tanigawa, M.; Bielekova, B.] NINDS, Neuroimmunol Dis Unit, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Barbour, C.; Greenwood, M.] Montana State Univ, Dept Math Sci, Bozeman, MT 59717 USA. [Wu, T.] NINDS, Clin Trials Unit, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Johnson, K.] NINDS, Bioinformat Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Herbst, R.; Wang, Y.] MedImmune LLC, Dept Resp Inflammat & Autoimmun Res, Gaithersburg, MD USA. [Tan, K.] MedImmune Ltd, Translat Med, Neurosci Innovat Med, Cambridge, England. FU National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH); NINDS; Medimmune, LLC (A member of the AstraZeneca Group) FX The study was supported by the intramural research program of the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH) and the Material Transfer Agreement (MTA) between NINDS and Medimmune, LLC (A member of the AstraZeneca Group) that funded the SOMAscan assay performed in the validation cohort. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2016 VL 22 SU 3 MA 219 BP 79 EP 79 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DV9NJ UT WOS:000383267200128 ER PT J AU Christensen, JR Komori, M von Essen, MR Ratzer, R Bornsen, L Bielekova, B Sellebjerg, F AF Christensen, J. Romme Komori, M. von Essen, M. R. Ratzer, R. Bornsen, L. Bielekova, B. Sellebjerg, F. TI Residual intrathecal inflammation after natalizumab and methylprednisolone treatment in progressive multiple sclerosis correlates with axonal damage SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 32nd Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) CY SEP 14-17, 2016 CL London, ENGLAND SP European Comm Treatment & Res Multiple Sclerosis C1 [Christensen, J. Romme; von Essen, M. R.; Ratzer, R.; Bornsen, L.; Sellebjerg, F.] Univ Copenhagen, Dept Neurol, Danish Multiple Sclerosis Ctr, Copenhagen, Denmark. [Komori, M.; Bielekova, B.] NINDS, Neuroimmunol Dis Unit, Neuroimmunol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. FU Danish Multiple Sclerosis Society; NIH; Biogen; EMD Serono; Genzyme; Lundbeck; Merck Serono; Novartis; Teva FX LB has received support for conference participation from Genzyme and Novartis and has received research grants from the Danish Multiple Sclerosis Society.; BB is a co-inventor on several NIH patents related to daclizumab and as such has received patent royalty payments from NIH.; FS has served on scientific advisory boards, been on the steering committees of clinical trials, served as a consultant, received support for congress participation, received speaker honoraria, or received research support for his laboratory from Biogen, EMD Serono, Genzyme, Lundbeck, Merck Serono, Novartis and Teva. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2016 VL 22 SU 3 MA P469 BP 200 EP 200 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DV9NJ UT WOS:000383267201208 ER PT J AU Dworkin, JD Sweeney, EM Schindler, MK Chahin, S Reich, DS Shinohara, RT AF Dworkin, J. D. Sweeney, E. M. Schindler, M. K. Chahin, S. Reich, D. S. Shinohara, R. T. TI PREVAIL: predicting pecovery through estimation and visualization of active and incident lesions SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 32nd Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) CY SEP 14-17, 2016 CL London, ENGLAND SP European Comm Treatment & Res Multiple Sclerosis C1 [Dworkin, J. D.; Shinohara, R. T.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Sweeney, E. M.] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Schindler, M. K.; Reich, D. S.] NINDS, Translat Neuroradiol Unit, Div Neuroimmunol & Neurovirol, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Chahin, S.] Univ Penn, Dept Neurol, Perelman Sch Med, Multiple Sclerosis Div, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2016 VL 22 SU 3 MA P487 BP 210 EP 210 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DV9NJ UT WOS:000383267201226 ER PT J AU Xia, Z Steele, S Bakshi, A Clarkson, S Schindler, M Dewey, B Ohayon, J Chibnik, L Cortese, I De Jager, P Reich, D AF Xia, Z. Steele, S. Bakshi, A. Clarkson, S. Schindler, M. Dewey, B. Ohayon, J. Chibnik, L. Cortese, I. De Jager, P. Reich, D. TI Investigating early evidence of multiple sclerosis in a prospective study of asymptomatic high-risk first-degree family members SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 32nd Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) CY SEP 14-17, 2016 CL London, ENGLAND SP European Comm Treatment & Res Multiple Sclerosis C1 [Xia, Z.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. [Xia, Z.; Clarkson, S.; Chibnik, L.; De Jager, P.] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA. [Steele, S.; Bakshi, A.; Schindler, M.; Dewey, B.; Ohayon, J.; Cortese, I.; Reich, D.] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. FU Clinician Scientist Development Award from the National Multiple Sclerosis Society; American Academy of Neurology; NINDS [K08NS079493]; DNAGenotek; National Multiple Sclerosis Society [RG5003A2]; Biogen; Sanofi/Genzyme; Intramural Research Program of NINDS; Myelin Repair Foundation; Vertex Pharmaceuticals FX Zongqi Xia: a recipient of the Clinician Scientist Development Award from the National Multiple Sclerosis Society and the American Academy of Neurology, research funding from NINDS (K08NS079493), research grant from DNAGenotek (not relevant to this abstract); Philip De Jager: a Harry Weaver Neuroscience Scholar of the National Multiple Sclerosis Society, research funding from the National Multiple Sclerosis Society (RG5003A2), research grant from Biogen, Sanofi/Genzyme (none relevant to this abstract); Daniel Reich: research funding from Intramural Research Program of NINDS, Myelin Repair Foundation, and Vertex Pharmaceuticals (none relevant to this abstract) NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2016 VL 22 SU 3 MA P537 BP 241 EP 241 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DV9NJ UT WOS:000383267201276 ER PT J AU Ryerson, LZ Monaco, MC Kister, I Zuniga-Estrada, G Jacob, A Major, E AF Ryerson, L. Zhovtis Monaco, M. C. Kister, I. Zuniga-Estrada, G. Jacob, A. Major, E. TI Effect of extended interval dose natalizumab therapy on CD19+and CD34+cell mobilization from bone marrow and JC Viremia SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 32nd Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) CY SEP 14-17, 2016 CL London, ENGLAND SP European Comm Treatment & Res Multiple Sclerosis C1 [Ryerson, L. Zhovtis; Kister, I.; Zuniga-Estrada, G.; Jacob, A.] NYU Langone Med Ctr, New York, NY USA. [Monaco, M. C.; Major, E.] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. FU Biogen Idec; Guthy-Jackson Charitable Foundation; National Multiple Sclerosis Society; Biogen-Idec; Serono; Novartis; PML Consortium; Takeda/Millennium Pharma; Glaxo Smith Klein; Genentech Roche; Sanofi Genzyme FX Lana Zhovtis Ryerson has received research support from Biogen Idec. She has received compensation for advisory board and speaker activities from Biogen Idec and Teva.; Ilya Kister has served on scientific advisory board for Biogen Idec and received research support from Guthy-Jackson Charitable Foundation, National Multiple Sclerosis Society, Biogen-Idec, Serono, and Novartis.; Eugene Major reports personal fees from PML Consortium, Takeda/Millennium Pharma, Glaxo Smith Klein, Genentech Roche, and Sanofi Genzyme. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2016 VL 22 SU 3 MA P711 BP 346 EP 346 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DV9NJ UT WOS:000383267201450 ER PT J AU Kosa, P Ghazali, D Tanigawa, M Barbour, C Cortese, I Kelly, W Snyder, B Ohayon, J Fenton, K Lehky, T Wu, T Greenwood, M Nair, G Bielekova, B AF Kosa, P. Ghazali, D. Tanigawa, M. Barbour, C. Cortese, I. Kelly, W. Snyder, B. Ohayon, J. Fenton, K. Lehky, T. Wu, T. Greenwood, M. Nair, G. Bielekova, B. TI Development of a sensitive outcome for economical drug screening for progressive multiple sclerosis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 32nd Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) CY SEP 14-17, 2016 CL London, ENGLAND SP European Comm Treatment & Res Multiple Sclerosis C1 [Kosa, P.; Ghazali, D.; Tanigawa, M.; Kelly, W.; Snyder, B.; Bielekova, B.] NINDS, Neuroimmunol Dis Unit, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Barbour, C.; Greenwood, M.] Montana State Univ, Dept Math Sci, Bozeman, MT 59717 USA. [Cortese, I.; Ohayon, J.; Fenton, K.; Nair, G.] NINDS, Neuroimmunol Clin, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Lehky, T.] NINDS, EMG Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Wu, T.] NINDS, Clin Trials Unit, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. FU National Institute of Neurological Disorders and Stroke FX Intramural Research Program of National Institute of Neurological Disorders and Stroke. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2016 VL 22 SU 3 MA P737 BP 364 EP 365 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DV9NJ UT WOS:000383267201476 ER PT J AU Vuolo, L Emmi, G Carlucci, G Repice, A Magnani, E Spagni, G Prisco, D Silvestri, E Barilaro, A Sati, P Reich, D Massacesi, L AF Vuolo, L. Emmi, G. Carlucci, G. Repice, A. Magnani, E. Spagni, G. Prisco, D. Silvestri, E. Barilaro, A. Sati, P. Reich, D. Massacesi, L. TI MRI evaluation of the "central vein sign" in brain white matter lesions of multiple sclerosis and systemic autoimmune diseases SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 32nd Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) CY SEP 14-17, 2016 CL London, ENGLAND SP European Comm Treatment & Res Multiple Sclerosis C1 [Vuolo, L.] Univ Florence, Dept Biomed Sci, Florence, Italy. [Emmi, G.; Silvestri, E.] Careggi Univ Hosp, Dept Internal Med, Florence, Italy. [Carlucci, G.; Magnani, E.; Massacesi, L.] Univ Florence, Dept Neurosci, Florence, Italy. [Repice, A.; Barilaro, A.] Careggi Univ Hosp, Dept Neurol 2, Florence, Italy. [Spagni, G.] Univ Florence, Dept Neurosci, Florence, Italy. [Prisco, D.] Univ Florence, Dept Clin & Expt Med, Florence, Italy. [Sati, P.; Reich, D.] NINDS, Translat Neuroradiol Unit, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2016 VL 22 SU 3 MA P806 BP 403 EP 404 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DV9NJ UT WOS:000383267202008 ER PT J AU Bove, R Xia, Z Clarkson, S Cortese, I Reich, D Chibnik, L De Jager, PL AF Bove, R. Xia, Z. Clarkson, S. Cortese, I. Reich, D. Chibnik, L. De Jager, P. L. TI Leveraging patient-reported outcomes to assess new neurological symptoms in a prospective cohort study of individuals at risk for multiple sclerosis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 32nd Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) CY SEP 14-17, 2016 CL London, ENGLAND SP European Comm Treatment & Res Multiple Sclerosis C1 [Bove, R.; Xia, Z.; Chibnik, L.; De Jager, P. L.] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA. [Bove, R.] Univ Calif San Francisco, Neurol, San Francisco, CA 94143 USA. [Xia, Z.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Clarkson, S.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Cortese, I.; Reich, D.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. FU Clinician Scientist Development Award from the National Multiple Sclerosis Society; American Academy of Neurology; NMSS Career Transition Award; NINDS [K08NS079493]; DNAGenotek; Intramural Research Program of NINDS; Myelin Repair Foundation; Vertex Pharmaceuticals; National Multiple Sclerosis Society [RG5003A2]; Biogen; Sanofi/Genzyme FX R. Bove: a recipient of the Clinician Scientist Development Award from the National Multiple Sclerosis Society and the American Academy of Neurology and the NMSS Career Transition Award. Nothing to disclose.; Zongqi Xia: a recipient of the Clinician Scientist Development Award from the National Multiple Sclerosis Society and the American Academy of Neurology, research funding from NINDS (K08NS079493), research grant from DNAGenotek (not relevant to this abstract); Daniel S. Reich, MD, PhD: research funding from Intramural Research Program of NINDS, Myelin Repair Foundation, and Vertex Pharmaceuticals (none relevant to this abstract); Philip L. De Jager, MD, PhD: Harry Weaver Neuroscience Scholar of the National Multiple Sclerosis Society, research funding from the National Multiple Sclerosis Society (RG5003A2), research grant from Biogen, Sanofi/Genzyme (none relevant to this abstract) NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2016 VL 22 SU 3 MA P842 BP 425 EP 425 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DV9NJ UT WOS:000383267202044 ER PT J AU Casaccia, P Castro, K Petracca, M Zhu, Y Gacias, M Watson, CT Kosa, P Sikder, T Zhang, J Naik, P Bencosme, Y Phelps, S Kiebisch, M Sharp, A Bielekova, B Inglese, M Sand, IK AF Casaccia, P. Castro, K. Petracca, M. Zhu, Y. Gacias, M. Watson, C. T. Kosa, P. Sikder, T. Zhang, J. Naik, P. Bencosme, Y. Phelps, S. Kiebisch, M. Sharp, A. Bielekova, B. Inglese, M. Sand, I. Katz TI Epigenomic changes in monocytes from RRMS patients with high body mass index and related preclinical animal models SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 32nd Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) CY SEP 14-17, 2016 CL London, ENGLAND SP European Comm Treatment & Res Multiple Sclerosis C1 [Casaccia, P.; Castro, K.; Petracca, M.; Zhu, Y.; Gacias, M.; Watson, C. T.; Sikder, T.; Zhang, J.; Naik, P.; Bencosme, Y.; Phelps, S.; Sharp, A.; Inglese, M.; Sand, I. Katz] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Kosa, P.; Bielekova, B.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Kiebisch, M.] Berg Hlth Inc, Framingham, MA USA. FU NIH NINDS FX Funded in part by NIH NINDS NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2016 VL 22 SU 3 MA P990 BP 502 EP 502 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DV9NJ UT WOS:000383267202191 ER PT J AU Tagge, I Schwartz, D Powers, K Bakshi, R Calabresi, P Constable, T Grinstead, J Henry, R Nair, G Oh, J Papinutto, N Pelletier, D Reich, DS Sicotte, N Simon, J Stern, W Rooney, W AF Tagge, I. Schwartz, D. Powers, K. Bakshi, R. Calabresi, P. Constable, T. Grinstead, J. Henry, R. Nair, G. Oh, J. Papinutto, N. Pelletier, D. Reich, D. S. Sicotte, N. Simon, J. Stern, W. Rooney, W. TI Toward a standardized quantitative imaging protocol for multiple sclerosis: a NAIMS multisite study of magnetization transfer and quantitative T1 imaging techniques SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 32nd Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) CY SEP 14-17, 2016 CL London, ENGLAND SP European Comm Treatment & Res Multiple Sclerosis C1 [Tagge, I.; Schwartz, D.; Powers, K.; Grinstead, J.; Simon, J.; Rooney, W.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Bakshi, R.] Harvard Med Sch, Brigham & Womens Hosp, Brookline, MA USA. [Calabresi, P.; Oh, J.] Johns Hopkins, Baltimore, MD USA. [Constable, T.] Yale, New Haven, CT USA. [Grinstead, J.] USA, Siemens Med Solut, Portland, OR USA. [Henry, R.; Papinutto, N.; Stern, W.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Nair, G.; Reich, D. S.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Oh, J.] Univ Toronto, Toronto, ON, Canada. [Pelletier, D.; Sicotte, N.] Univ Southern Calif, Keck Sch Med, Los Angeles, CA USA. FU Race to Erase MS Fund; NINDS; AbbVie; EMD Serono; Genentech; Novartis; Biogen; EMD-Serono; Sanofi-Genzyme; NIH [R01 NS082347]; MedImmune; Multiple Sclerosis Society of Canada; Biogen-Idec; Genzyme; Teva; Roche; Myelin Repair Foundation; Vertex Pharmaceuticals; National MS Society; Guthy-Jackson Charitable Foundation FX Ian Tagge is funded by the Race to Erase MS Fund and NINDS and has nothing to disclose.; Rohit Bakshi is funded by the Race to Erase MS Fund and has received consulting fees from AbbVie, EMD Serono, Genentech, and Novartis, received research support from Biogen, EMD-Serono, Novartis, and Sanofi-Genzyme, and serves as Editor-in-Chief of the Journal of Neuroimaging.; Peter Calabresi is funded by NIH R01 NS082347 - Imaging neurodegeneration in multiple sclerosis, and has received grants to Johns Hopkins from Biogen, Novartis, and MedImmune, and has received honoraria for consulting from Vertex.; Roland Henry recieves funding from NIH, DOD, and Roche/Genentech, and nothing to disclose.; Jiwon Oh has received research funding from Multiple Sclerosis Society of Canada, Sanofi-Genzyme, and Biogen-Idec, and has received fees for consulting or speaking from EMD-Serono, Genzyme, Biogen-Idec, Novartis, Teva, and Roche.; Daniel S. Reich recieves research funding from Intramural Research Program of NINDS, Myelin Repair Foundation, and Vertex Pharmaceuticals and has nothing to disclose.; Nancy Sicotte recieves funding from National MS Society and Guthy-Jackson Charitable Foundation and has nothing to disclose. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2016 VL 22 SU 3 MA P1036 BP 530 EP 531 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DV9NJ UT WOS:000383267202237 ER PT J AU Shinohara, RC Calabresi, PA Davatzikos, C Doshi, J Henry, RG Kim, G Linn, KA Nair, G Oh, J Papinutto, N Pham, DL Reich, DS Rooney, W Roy, S Sicotte, NL Stern, W Tummala, S Yousuf, F Zhu, A Bakshi, R AF Shinohara, R. C. Calabresi, P. A. Davatzikos, C. Doshi, J. Henry, R. G. Kim, G. Linn, K. A. Nair, G. Oh, J. Papinutto, N. Pham, D. L. Reich, D. S. Rooney, W. Roy, S. Sicotte, N. L. Stern, W. Tummala, S. Yousuf, F. Zhu, A. Bakshi, R. CA NAIMS Cooperative TI Inter-scanner MRI variability of multiple sclerosis lesion and tissue volumes in the NAIMS cooperative SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 32nd Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) CY SEP 14-17, 2016 CL London, ENGLAND SP European Comm Treatment & Res Multiple Sclerosis C1 [Shinohara, R. C.] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Calabresi, P. A.] Johns Hopkins Univ, Baltimore, MD USA. [Davatzikos, C.; Doshi, J.; Linn, K. A.] Univ Penn, Philadelphia, PA 19104 USA. [Henry, R. G.; Papinutto, N.; Stern, W.; Zhu, A.] UCSF, San Francisco, CA USA. [Kim, G.; Tummala, S.; Yousuf, F.; Bakshi, R.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Nair, G.; Pham, D. L.; Reich, D. S.; Roy, S.] NIH, Washington, DC USA. [Oh, J.] Univ Toronto, Toronto, ON, Canada. [Rooney, W.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Sicotte, N. L.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. FU Race to Erase MS FX Study supported by: The Race to Erase MS NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2016 VL 22 SU 3 MA P1049 BP 538 EP 539 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DV9NJ UT WOS:000383267202250 ER PT J AU Schwartz, DL Tagge, I Bakshi, R Nair, G Calabresi, P Constable, T Grinstead, J Henry, R Oh, J Papinutto, N Pelletier, D Reich, DS Sicotte, N Stern, W Simon, J Rooney, W AF Schwartz, D. L. Tagge, I. Bakshi, R. Nair, G. Calabresi, P. Constable, T. Grinstead, J. Henry, R. Oh, J. Papinutto, N. Pelletier, D. Reich, D. S. Sicotte, N. Stern, W. Simon, J. Rooney, W. TI Toward a standardized advanced imaging protocol for multiple sclerosis: inter- and intra-site variability in multiband diffusion measurements acquired by NAIMS SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 32nd Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) CY SEP 14-17, 2016 CL London, ENGLAND SP European Comm Treatment & Res Multiple Sclerosis C1 [Schwartz, D. L.; Tagge, I.; Simon, J.; Rooney, W.] OHSU, Portland, OR USA. [Bakshi, R.] Harvard Med Sch, Boston, MA USA. [Nair, G.; Reich, D. S.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Calabresi, P.] Johns Hopkins Univ, Baltimore, MD USA. [Constable, T.] Yale, New Haven, CT USA. [Grinstead, J.] Siemens Med Solut, Portland, OR USA. [Henry, R.; Papinutto, N.; Stern, W.] UCSF, San Francisco, CA USA. [Oh, J.] Univ Toronto, Toronto, ON, Canada. [Pelletier, D.; Sicotte, N.] Univ Southern Calif, Keck Sch Med, Los Angeles, CA USA. FU Race to Erase MS Fund; AbbVie; EMD Serono; Genentech; Novartis; Biogen; EMD-Serono; Sanofi-Genzyme; NINDS; NIH [R01 NS082347]; MedImmune; NIH; DOD; Roche/Genentech; Multiple Sclerosis Society of Canada; Biogen-Idec; Genzyme; Teva; Roche; Myelin Repair Foundation; Vertex Pharmaceuticals; National MS Society; Guthy-Jackson Charitable Foundation FX Daniel Schwartz is funded by Race to Erase MS Fund and has nothing to disclose.; Rohit Bakshi is funded by the Race to Erase MS Fund and has received consulting fees from AbbVie, EMD Serono, Genentech, and Novartis, received research support from Biogen, EMD-Serono, Novartis, and Sanofi-Genzyme, and serves as Editor-in-Chief of the Journal of Neuroimaging.; Govind Nair is funded by Intramural Research Program, NINDS and has nothing to disclose.; Peter Calabresi is funded by NIH R01 NS082347 - Imaging neurodegeneration in multiple sclerosis, and has received grants to Johns Hopkins from Biogen, Novartis, and MedImmune, and has received honoraria for consulting from Vertex.; Roland Henry receives funding from NIH, DOD, and Roche/Genentech, and nothing to disclose.; Jiwon Oh has received research funding from Multiple Sclerosis Society of Canada, Sanofi-Genzyme, and Biogen-Idec, and has received fees for consulting or speaking from EMD-Serono, Genzyme, Biogen-Idec, Novartis, Teva, and Roche.; Daniel S. Reich receives research funding from Intramural Research Program of NINDS, Myelin Repair Foundation, and Vertex Pharmaceuticals and has nothing to disclose.; Nancy Sicotte receives funding from National MS Society and Guthy-Jackson Charitable Foundation and has nothing to disclose. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2016 VL 22 SU 3 MA P1053 BP 541 EP 542 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DV9NJ UT WOS:000383267202254 ER PT J AU Schwartz, DL Tagge, I Bakshi, R Nair, G Calabresi, P Grinstead, J Henry, R Oh, J Papinutto, N Constable, T Stern, W Simon, J Pelletier, D Reich, DS Sicotte, N Rooney, W AF Schwartz, D. L. Tagge, I. Bakshi, R. Nair, G. Calabresi, P. Grinstead, J. Henry, R. Oh, J. Papinutto, N. Constable, T. Stern, W. Simon, J. Pelletier, D. Reich, D. S. Sicotte, N. Rooney, W. TI Toward a standardized quantitative imaging protocol for multiple sclerosis: inter- and intra-site variability in multiband rsfMRI measurements acquired by NAIMS SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 32nd Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) CY SEP 14-17, 2016 CL London, ENGLAND SP European Comm Treatment & Res Multiple Sclerosis C1 [Schwartz, D. L.; Tagge, I.; Simon, J.; Rooney, W.] OHSU, Portland, OR USA. [Bakshi, R.] Harvard Med Sch, Boston, MA USA. [Nair, G.; Reich, D. S.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Calabresi, P.] Johns Hopkins Univ, Baltimore, MD USA. [Grinstead, J.] USA, Siemens Med Solut, Portland, OR USA. [Henry, R.; Papinutto, N.] UCSF, San Francisco, CA USA. [Oh, J.] Univ Toronto, Toronto, ON, Canada. [Constable, T.] Yale, New Haven, CT USA. [Pelletier, D.; Sicotte, N.] Univ Southern Calif, Keck Sch Med, Los Angeles, CA USA. FU Race to Erase MS Fund; AbbVie; EMD Serono; Genentech; Novartis; Biogen; EMD-Serono; Sanofi-Genzyme; NINDS; NIH [R01 NS082347]; MedImmune; NIH; DOD; Roche/Genentech; Multiple Sclerosis Society of Canada; Biogen-Idec; Genzyme; Teva; Roche; Myelin Repair Foundation; Vertex Pharmaceuticals; National MS Society; Guthy-Jackson Charitable Foundation FX Daniel Schwartz is funded by Race to Erase MS Fund and has nothing to disclose.; Rohit Bakshi is funded by the Race to Erase MS Fund and has received consulting fees from AbbVie, EMD Serono, Genentech, and Novartis, received research support from Biogen, EMD-Serono, Novartis, and Sanofi-Genzyme, and serves as Editor-in-Chief of the Journal of Neuroimaging.; Govind Nair is funded by Intramural Research Program, NINDS and has nothing to disclose.; Peter Calabresi is funded by NIH R01 NS082347 - Imaging neurodegeneration in multiple sclerosis, and has received grants to Johns Hopkins from Biogen, Novartis, and MedImmune, and has received honoraria for consulting from Vertex.; Roland Henry receives funding from NIH, DOD, and Roche/Genentech, and nothing to disclose.; Jiwon Oh has received research funding from Multiple Sclerosis Society of Canada, Sanofi-Genzyme, and Biogen-Idec, and has received fees for consulting or speaking from EMD-Serono, Genzyme, Biogen-Idec, Novartis, Teva, and Roche.; Daniel S. Reich receives research funding from Intramural Research Program of NINDS, Myelin Repair Foundation, and Vertex Pharmaceuticals and has nothing to disclose.; Nancy Sicotte receives funding from National MS Society and Guthy-Jackson Charitable Foundation and has nothing to disclose. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2016 VL 22 SU 3 MA P1061 BP 546 EP 547 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DV9NJ UT WOS:000383267202262 ER PT J AU Tatomir, A Rus, V Nguyen, V Boodhoo, D Mekala, AP Cudrici, C Badea, TC Rus, H AF Tatomir, A. Rus, V. Nguyen, V. Boodhoo, D. Mekala, A. P. Cudrici, C. Badea, T. C. Rus, H. TI RGC-32 promotes Th17 cell differentiation and enhances experimental autoimmune encephalomyelitis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 32nd Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) CY SEP 14-17, 2016 CL London, ENGLAND SP European Comm Treatment & Res Multiple Sclerosis C1 [Tatomir, A.; Boodhoo, D.; Mekala, A. P.; Rus, H.] Univ Maryland, Sch Med, Neurol, Baltimore, MD 21201 USA. [Rus, V.; Nguyen, V.] Univ Maryland, Sch Med, Med, Baltimore, MD 21201 USA. [Cudrici, C.; Badea, T. C.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Rus, H.] Vet Adm Multiple Sclerosis Ctr Excellence East, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2016 VL 22 SU 3 MA P1613 BP 851 EP 852 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DV9NJ UT WOS:000383267203286 ER PT J AU Chauhan, S Diril, MK Lee, JHS Bisteau, X Manoharan, V Adhikari, D Ratnacaram, CK Janela, B Noffke, J Ginhoux, F Coppola, V Liu, K Tessarollo, L Kaldis, P AF Chauhan, Sangeeta Diril, M. Kasim Lee, Joanna H. S. Bisteau, Xavier Manoharan, Vanessa Adhikari, Deepak Ratnacaram, Chandrahas Koumar Janela, Baptiste Noffke, Juliane Ginhoux, Florent Coppola, Vincenzo Liu, Kui Tessarollo, Lino Kaldis, Philipp TI Cdk2 catalytic activity is essential for meiotic cell division in vivo SO BIOCHEMICAL JOURNAL LA English DT Article ID CYCLIN-DEPENDENT KINASES; ACTIVATING KINASE; CENTROSOME AMPLIFICATION; INDEPENDENT FUNCTION; NUCLEAR-ENVELOPE; DENDRITIC CELLS; PHOSPHORYLATION; MEIOSIS; PROTEIN; MICE AB Cyclin-dependent kinases (Cdks) control the eukaryotic cell cycle by phosphorylating serine and threonine residues in key regulatory proteins, but some Cdk family members may exert kinase-independent functions that cannot easily be assessed using gene knockout approaches. While Cdk2-deficient mice display near-normal mitotic cell proliferation due to the compensatory activities of Cdk1 and Cdk4, they are unable to undergo meiotic generation of gametes and are consequently sterile. To investigate whether Cdk2 regulates meiosis via protein phosphorylation or by alternative kinase-independent mechanisms, we generated two different knockin mouse strains in which Cdk2 point mutations ablated enzyme activity without altering protein expression levels. Mice homozygous for the mutations Cdk2(D145N/D145N) or Cdk2(T160A/T160A) expressed only 'kinase-dead' variants of Cdk2 under the control of the endogenous promoter, and despite exhibiting normal expression of cell cycle regulatory proteins and complexes, both mutations rendered mice sterile. Mouse cells that expressed only 'kinase-dead' variants of Cdk2 displayed normal mitotic cell cycle progression and proliferation both in vitro and in vivo, indicating that loss of Cdk2 kinase activity exerted little effect on this mode of cell division. In contrast, the reproductive organs of Cdk2 mutant mice exhibited abnormal morphology and impaired function associated with defective meiotic cell division and inability to produce gametes. Cdk2 mutant animals were therefore comparable to gene knockout mice, which completely lack the Cdk2 protein. Together, our data indicate that the essential meiotic functions of Cdk2 depend on its kinase activity, without which the generation of haploid cells is disrupted, resulting in sterility of otherwise healthy animals. C1 [Chauhan, Sangeeta; Diril, M. Kasim; Lee, Joanna H. S.; Bisteau, Xavier; Manoharan, Vanessa; Ratnacaram, Chandrahas Koumar; Noffke, Juliane; Kaldis, Philipp] ASTAR, IMCB, 61 Biopolis Dr,Proteos 3-09, Singapore 138673, Singapore. [Adhikari, Deepak; Liu, Kui] Univ Gothenburg, Dept Chem & Mol Biol, SE-40530 Gothenburg, Sweden. [Janela, Baptiste; Ginhoux, Florent] ASTAR, Singapore Immunol Network SIgN, 8A Biomed Grove, Singapore 138648, Singapore. [Coppola, Vincenzo; Tessarollo, Lino] NCI Frederick, NCI, Mouse Canc Genet Program, Bldg 560,1050 Boyles St, Frederick, MA 21702 USA. [Kaldis, Philipp] Natl Univ Singapore NUS, Dept Biochem, Singapore 117597, Singapore. [Diril, M. Kasim] Dokuz Eylul Univ, Izmir Biomed & Genome Inst, TR-35340 Izmir, Turkey. [Adhikari, Deepak] Monash Univ, Sch Biomed Sci Nursing & Hlth Sci, Clayton, Vic 3800, Australia. [Coppola, Vincenzo] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, 988 Biomed Res Tower,460 West 12th Ave, Columbus, OH 43210 USA. RP Kaldis, P (reprint author), ASTAR, IMCB, 61 Biopolis Dr,Proteos 3-09, Singapore 138673, Singapore.; Kaldis, P (reprint author), Natl Univ Singapore NUS, Dept Biochem, Singapore 117597, Singapore. EM kaldis@imcb.a-star.edu.sg FU Biomedical Research Council of A*STAR (Agency for Science, Technology and Research), Singapore; Jane and Dan Olssons Foundation; LUA/ALF-medel Vastra Gotalandsregionen; AFA Insurance; Swedish Research Council; the Swedish Cancer Foundation; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX P.K., S.C., M.K.D., J.H.S.L., X.B., V.M., C.K.R., B.J., J.N., and F.G. acknowledge the support by the Biomedical Research Council of A*STAR (Agency for Science, Technology and Research), Singapore. D.A. and K.L. were supported by grants (to K.L.) from the Jane and Dan Olssons Foundation, the LUA/ALF-medel Vastra Gotalandsregionen, AFA Insurance, the Swedish Research Council, and the Swedish Cancer Foundation. V.C. and L.T. were supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 55 TC 0 Z9 0 U1 1 U2 1 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0264-6021 EI 1470-8728 J9 BIOCHEM J JI Biochem. J. PD SEP PY 2016 VL 473 BP 2783 EP 2798 DI 10.1042/BCJ20160607 PN 18 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EK2JP UT WOS:000393753900006 PM 27371320 ER PT J AU Matsuda, M Rand, K Palardy, G Shimizu, N Ikeda, H Nogare, DD Itoh, M Chitnis, AB AF Matsuda, Miho Rand, Kinneret Palardy, Greg Shimizu, Nobuyuki Ikeda, Hiromi Nogare, Damian Dalle Itoh, Motoyuki Chitnis, Ajay B. TI Epb41l5 competes with Delta as a substrate for Mib1 to coordinate specification and differentiation of neurons SO DEVELOPMENT LA English DT Article DE Notch signaling; Mind bomb; Zebrafish; Epb41l5; Neurogenesis; Neuronal differentiation; Epithelial morphogenesis ID EPITHELIAL-MESENCHYMAL TRANSITION; GLASS-ONION LOCUS; N-CADHERIN; UBIQUITIN LIGASE; MIND BOMB; RETINAL LAMINATION; NERVOUS-SYSTEM; MOSAIC EYES; PRECURSOR CELLS; CRUMBS COMPLEX AB We identified Erythrocyte membrane protein band 4.1-like 5 (Epb41l5) as a substrate for the E3 ubiquitin ligase Mind bomb 1 (Mib1), which is essential for activation of Notch signaling. Although loss of Epb41l5 does not significantly alter the pattern of neural progenitor cells (NPCs) specified as neurons at the neural plate stage, it delays their delamination and differentiation after neurulation when NPCs normally acquire organized apical junctional complexes (AJCs) in the zebrafish hindbrain. Delays in differentiation are reduced by knocking down N-cadherin, a manipulation expected to help destabilize adherens junctions (AJs). This suggested that delays in neuronal differentiation in epb41l5-deficient embryos are related to a previously described role for Epb41l5 in facilitating disassembly of cadherin-dependent AJCs. Mib1 ubiquitylates Epb41l5 to promote its degradation. DeltaD can compete with Epb41l5 to reduce Mib1-dependent Epb41l5 degradation. In this context, increasing the number of NPCs specified to become neurons, i.e. cells expressing high levels of DeltaD, stabilizes Epb41l5 in the embryo. Together, these observations suggest that relatively high levels of Delta stabilize Epb41l5 in NPCs specified as neurons. This, we suggest, helps coordinate NPC specification with Epb41l5-dependent delamination and differentiation as neurons. C1 [Matsuda, Miho; Shimizu, Nobuyuki] Rutgers State Univ, New Jersey Med Sch, Dept Cell Biol & Mol Med, Newark, NJ 07103 USA. [Matsuda, Miho; Rand, Kinneret; Palardy, Greg; Ikeda, Hiromi; Nogare, Damian Dalle; Itoh, Motoyuki; Chitnis, Ajay B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Neural Dev Dynam, Div Dev Biol, NIH, Bethesda, MD 20892 USA. [Itoh, Motoyuki] Chiba Univ, Dept Pharmacol, Chiba 2608675, Japan. RP Matsuda, M (reprint author), Rutgers State Univ, New Jersey Med Sch, Dept Cell Biol & Mol Med, Newark, NJ 07103 USA.; Matsuda, M; Chitnis, AB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Neural Dev Dynam, Div Dev Biol, NIH, Bethesda, MD 20892 USA. EM matsudmi@njms.rutgers.edu; chitnisa@mail.nih.gov OI Matsuda, Miho/0000-0002-7495-5905 FU National Institute of Child Health and Human Development (NICHD, NIH) [HD062561]; NICHD [HD001012] FX This research was supported by the National Institute of Child Health and Human Development (NICHD, NIH) [HD062561 to M.M] and NICHD intramural program [HD001012 to A.B.C.]. Deposited in PMC for release after 12 months. NR 67 TC 0 Z9 0 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 SEP 1 PY 2016 VL 143 IS 17 BP 3085 EP 3096 DI 10.1242/dev.138743 PG 12 WC Developmental Biology SC Developmental Biology GA EJ8BY UT WOS:000393450600007 PM 27510968 ER PT J AU Stepanik, V Dunipace, L Bae, YK Macabenta, F Sun, JJ Trisnadi, N Stathopoulos, A AF Stepanik, Vincent Dunipace, Leslie Bae, Young-Kyung Macabenta, Frank Sun, Jingjing Trisnadi, Nathanie Stathopoulos, Angelike TI The migrations of Drosophila muscle founders and primordial germ cells are interdependent SO DEVELOPMENT LA English DT Article DE Caudal visceral mesoderm; Longitudinal visceral muscle founder; Cell migration; Primordial germ cells; Wunen; Lipid phosphate phosphatase; Tre1; Drosophila melanogaster ID LIPID PHOSPHATE PHOSPHATASES; SPHINGOSINE 1-PHOSPHATE; POSTERIOR DETERMINANT; LYSOPHOSPHATIDIC ACID; VISCERAL MUSCULATURE; GENE-EXPRESSION; IN-VIVO; MESODERM; LOCALIZATION; RECEPTOR AB Caudal visceral mesoderm (CVM) cells migrate from posterior to anterior of the Drosophila embryo as two bilateral streams of cells to support the specification of longitudinal muscles along the midgut. To accomplish this long-distance migration, CVM cells receive input from their environment, but little is known about how this collective cell migration is regulated. In a screen we found that wunen mutants exhibit CVM cell migration defects. Wunens are lipid phosphate phosphatases known to regulate the directional migration of primordial germ cells (PGCs). PGC and CVM cell types interact while PGCs are en route to the somatic gonadal mesoderm, and previous studies have shown that CVM impacts PGC migration. In turn, we found here that CVM cells exhibit an affinity for PGCs, localizing to the position of PGCs whether mislocalized or trapped in the endoderm. In the absence of PGCs, CVM cells exhibit subtle changes, including more cohesive movement of the migrating collective, and an increased number of longitudinal muscles is found at anterior sections of the larval midgut. These data demonstrate that PGC and CVM cell migrations are interdependent and suggest that distinct migrating cell types can coordinately influence each other to promote effective cell migration during development. C1 [Stepanik, Vincent; Dunipace, Leslie; Bae, Young-Kyung; Macabenta, Frank; Sun, Jingjing; Trisnadi, Nathanie; Stathopoulos, Angelike] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA. [Bae, Young-Kyung] Korea Inst Stand & Sci, KRISS, Ctr Bioanal, 267 Gajeong Ro, Daejeon 305340, South Korea. [Trisnadi, Nathanie] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Stathopoulos, A (reprint author), CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA. EM angelike@caltech.edu OI Macabenta, Frank/0000-0002-6583-3244 FU National Institutes of Health [R21HD073860, R01GM104838]; American Heart Association [11POST7600181]; American Cancer Society [PF-15-202-01-DDC] FX This work was funded by the National Institutes of Health [R21HD073860 and R01GM104838 to A.S.]; the American Heart Association [11POST7600181 to Y.-K.B.]; and the American Cancer Society [PF-15-202-01-DDC to V.S.]. Deposited in PMC for release after 12 months. NR 57 TC 0 Z9 0 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 SEP 1 PY 2016 VL 143 IS 17 BP 3206 EP 3215 DI 10.1242/dev.134346 PG 10 WC Developmental Biology SC Developmental Biology GA EJ8BY UT WOS:000393450600017 PM 27578182 ER PT J AU Kaczkurkin, A Moore, T Ruparel, K Shinohara, R Calkins, M Elliott, M Hopson, R Roalf, D Ciric, R Vandekar, S Gennatas, E Wolf, D Scott, JC Pine, D Leibenluft, E Detre, J Foa, E Gur, R Gur, R Satterwaite, T AF Kaczkurkin, Antonia Moore, Tyler Ruparel, Kosha Shinohara, Russell Calkins, Monica Elliott, Mark Hopson, Ryan Roalf, David Ciric, Rastko Vandekar, Simon Gennatas, Efstathios Wolf, Daniel Scott, J. Cobb Pine, Daniel Leibenluft, Ellen Detre, John Foa, Edna Gur, Raquel Gur, Ruben Satterwaite, Theodore TI SEX DIFFERENCES IN TRAIT ANXIETY DURING ADOLESCENCE IS MEDIATED BY ELEVATED AMYGDALA PERFUSION SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract C1 [Kaczkurkin, Antonia; Moore, Tyler; Ruparel, Kosha; Shinohara, Russell; Calkins, Monica; Elliott, Mark; Hopson, Ryan; Roalf, David; Ciric, Rastko; Vandekar, Simon; Gennatas, Efstathios; Wolf, Daniel; Scott, J. Cobb; Detre, John; Foa, Edna; Gur, Raquel; Gur, Ruben; Satterwaite, Theodore] Univ Penn, Philadelphia, PA 19104 USA. [Pine, Daniel; Leibenluft, Ellen] NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0048-5772 EI 1469-8986 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2016 VL 53 SU 1 SI SI BP S11 EP S11 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA EK1FX UT WOS:000393672300040 ER PT J AU Kuntzelman, K Costa, V Miskovic, V AF Kuntzelman, Karl Costa, Vincent Miskovic, Vladimir TI EMOTIONAL MODULATION OF PERCEPTUAL DECISION MAKING SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract DE decision making; affect; perception C1 [Kuntzelman, Karl; Costa, Vincent; Miskovic, Vladimir] NIMH, 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 0048-5772 EI 1469-8986 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2016 VL 53 SU 1 SI SI MA 2-2 BP S38 EP S38 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA EK1FX UT WOS:000393672300143 ER PT J AU Pedersen, W Balderston, N Miskovich, TA Belleau, EL Helmstetter, F Larson, CL AF Pedersen, Walker Balderston, Nicholas Miskovich, Tara A. Belleau, Emily L. Helmstetter, Fred Larson, Christine L. TI DISENTANGLING THE EFFECTS OF STIMULUS NOVELTY AND AFFECTIVE VALENCE IN THE AMYGDALA, HIPPOCAMPUS, AND BED NUCLEUS OF THE STRIA TERMINALIS SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract DE bed nucleus of the stria terminalis; amygdala; novelty C1 [Pedersen, Walker; Miskovich, Tara A.; Belleau, Emily L.; Helmstetter, Fred; Larson, Christine L.] Univ Wisconsin Milwaukee, Milwaukee, WI USA. [Balderston, Nicholas] NIMH, Bethesda, MD 20892 USA. FU NIH K01 award [MH086809] FX This study was funded by an NIH K01 awarded to Dr. Christine Larson (MH086809). 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 0048-5772 EI 1469-8986 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2016 VL 53 SU 1 SI SI MA 1-79 BP S36 EP S36 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA EK1FX UT WOS:000393672300135 ER PT J AU Smith, E Mash, C Thurm, A Bornstein, M AF Smith, Elizabeth Mash, Clay Thurm, Audrey Bornstein, Marc TI EEG GAMMA POWER CORRELATES OF DEVELOPMENTAL CHANGE IN AUDIOVISUAL SYNCHRONY DETECTION SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract DE audiovisual; synchrony; children C1 [Smith, Elizabeth; Mash, Clay; Bornstein, Marc] NICHHD, Bethesda, MD 20892 USA. [Thurm, Audrey] NIMH, Bethesda, MD 20892 USA. FU Division of Intramural Research, NICHD/NIH FX This work was supported by the Division of Intramural Research, NICHD/NIH. 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 0048-5772 EI 1469-8986 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2016 VL 53 SU 1 SI SI MA 2-4 BP S38 EP S38 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA EK1FX UT WOS:000393672300145 ER PT J AU Thornton, LC Penner, E Nolan, Z Adalio, C Hwang, S Meffert, H Blair, J White, S AF Thornton, Laura C. Penner, Elizabeth Nolan, Zachary Adalio, Christopher Hwang, Soonjo Meffert, Harma Blair, James White, Stuart TI DYSFUNCTION IN ANIMACY INFORMATION PROCESSING IN ADOLESCENTS WITH DISRUPTIVE BEHAVIOR DISORDERS AND CALLOUS-UNEMOTIONAL TRAITS SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract DE amygdala dysfunction; animacy information processing; disruptive behavior disorders; callous-unemotional traits C1 [Thornton, Laura C.; Penner, Elizabeth; Meffert, Harma; White, Stuart] Boys Town Natl Res Hosp, Omaha, NE 68131 USA. [Nolan, Zachary] Penn State Coll Med, Hershey, PA USA. [Adalio, Christopher] Univ Calif Berkeley, Berkeley, CA 94720 USA. [Hwang, Soonjo] Univ Nebraska Med Ctr, Omaha, NE USA. [Blair, James] NIMH, Bethesda, MD 20892 USA. FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health [1-ZIA-MH002860] FX This work was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (1-ZIA-MH002860), J.R.B principle investigator. 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 0048-5772 EI 1469-8986 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2016 VL 53 SU 1 SI SI MA 2-25 BP S43 EP S43 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA EK1FX UT WOS:000393672300162 ER PT J AU Thorpe, RJ Simonsick, E Zonderman, A Evans, MK AF Thorpe, Roland J., Jr. Simonsick, Eleanor Zonderman, Alan Evans, Michelle K. TI ASSOCIATION BETWEEN RACE, HOUSEHOLD INCOME AND GRIP STRENGTH IN MIDDLE- AND OLDER-AGED ADULTS SO ETHNICITY & DISEASE LA English DT Article DE Physical Function; Race; Aging; Health Disparities ID LOWER-EXTREMITY FUNCTION; SOCIOECONOMIC-STATUS; WOMENS HEALTH; PHYSICAL PERFORMANCE; MUSCLE STRENGTH; RACIAL-DIFFERENCES; WALKING SPEED; DISPARITIES; PREDICTORS; DISABILITY AB Background: Poor grip strength is an indicator of frailty and a precursor to functional limitations. Although poor grip strength is more prevalent in older disabled African American women, little is known about the association between race and poverty-related disparities and grip strength in middle-aged men and women. Methods: We examined the cross-sectional relationship between race, socioeconomic status as assessed by household income, and hand grip strength in men and women in the Healthy Aging in Neighborhoods of Diversity across the Life Span study. General linear models examined grip strength (maximum of two trials on both sides) by race and household income adjusted for age, weight, height, hand pain, education, insurance status, family income, and two or more chronic conditions. Results: Of 2,091 adults, 422(45.4%) were male, 509(54.8%) were African American, and 320 (34.5%) were living in households with incomes below 125% of the federal poverty level (low SES). In adjusted models, African American women had greater grip strength than White women independent of SES (low income household: 29.3 vs 26.9 kg and high income household: 30.5 vs. 28.3kg; P<.05 for both); whereas in men, only African Americans in the high income household group had better grip strength than Whites (46.3 vs. 43.2; P<.05). Conclusions: The relationship between grip strength, race and SES as assessed by household income varied in this cohort. Efforts to develop grip strength norms and cut points that indicate frailty and sarcopenia may need to be race- and income-specific. C1 [Thorpe, Roland J., Jr.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Hlth Behav & Soc, 624 N Broadway,Ste 708, Baltimore, MD 21205 USA. [Simonsick, Eleanor; Zonderman, Alan] NIA, Intramural Res Program, Bethesda, MD 20892 USA. [Evans, Michelle K.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. RP Thorpe, RJ (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Hlth Behav & Soc, 624 N Broadway,Ste 708, Baltimore, MD 21205 USA. EM rthorpe@jhu.edu OI Zonderman, Alan B/0000-0002-6523-4778 FU Intramural Research Program of the NIH, National Institute on Aging [ZIA AG000513]; National Institute on Minority Health and Health Disparities (NIMHD) of NIH [P60MD000214] FX This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (project ZIA AG000513). Research conducted by the first author was funded by grant P60MD000214 from the National Institute on Minority Health and Health Disparities (NIMHD) of NIH. NR 29 TC 0 Z9 0 U1 0 U2 0 PU INT SOC HYPERTENSION BLACKS-ISHIB PI ATLANTA PA 100 AUBURN AVE NE STE 401, ATLANTA, GA 30303-2527 USA SN 1049-510X EI 1945-0826 J9 ETHNIC DIS JI Ethn. Dis. PD FAL PY 2016 VL 26 IS 4 BP 493 EP 500 DI 10.18865/ed.26.4.493 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EJ4PW UT WOS:000393200300004 PM 27773976 ER PT J AU Zhao, JL Kodippili, K Yue, YP Hakim, CH Wasala, L Pan, XF Zhang, KQ Yang, NN Duan, DS Lai, Y AF Zhao, Junling Kodippili, Kasun Yue, Yongping Hakim, Chady H. Wasala, Lakmini Pan, Xiufang Zhang, Keqing Yang, Nora N. Duan, Dongsheng Lai, Yi TI Dystrophin contains multiple independent membrane-binding domains SO HUMAN MOLECULAR GENETICS LA English DT Article ID DUCHENNE MUSCULAR-DYSTROPHY; C-TERMINAL DOMAINS; GLYCOPROTEIN COMPLEX; ROD DOMAIN; STABILITY PROPERTIES; BETA-DYSTROGLYCAN; CYSTEINE-RICH; LIPID-BINDING; F-ACTIN; MUSCLE AB Dystrophin is a large sub-sarcolemmal protein. Its absence leads to Duchenne muscular dystrophy (DMD). Binding to the sarcolemmais essential for dystrophin to protect muscle from contraction-induced injury. It has long been thought that membrane binding of dystrophin depends on its cysteine-rich (CR) domain. Here, we provide in vivo evidence suggesting that dystrophin contains three additional membrane-binding domains including spectrin-like repeats (R) 1-3, R10-12 and C-terminus (CT). To systematically study dystrophin membrane binding, we split full-length dystrophin into ten fragments and examined subcellular localizations of each fragment by adeno-associated virus-mediated gene transfer. In skeletal muscle, R1-3, CR domain and CT were exclusively localized at the sarcolemma. R10-12 showed both cytosolic and sarcolemmal localization. Importantly, the CR-independent membrane binding was conserved in murine and canine muscles. A critical function of the CR-mediated membrane interaction is the assembly of the dystrophin-associated glycoprotein complex (DGC). While R1-3 and R10-12 did not restore the DGC, surprisingly, CT alone was sufficient to establish the DGC at the sarcolemma. Additional studies suggest that R1-3 and CT also bind to the sarcolemmain the heart, though relatively weak. Taken together, our study provides the first conclusive in vivo evidence that dystrophin contains multiple independent membrane-binding domains. These structurally and functionally distinctive membrane-binding domains provide a molecular framework for dystrophin to function as a shock absorber and signaling hub. Our results not only shed critical light on dystrophin biology and DMD pathogenesis, but also provide a foundation for rationally engineering minimized dystrophins for DMD gene therapy. C1 [Zhao, Junling; Kodippili, Kasun; Yue, Yongping; Hakim, Chady H.; Wasala, Lakmini; Pan, Xiufang; Zhang, Keqing; Duan, Dongsheng; Lai, Yi] NIH, Sch Med, Dept Mol Microbiol & Immunol, Rockville, MD USA. [Hakim, Chady H.; Yang, Nora N.] NIH, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Duan, Dongsheng] Univ Missouri, Sch Med, Dept Neurol, Columbia, MO USA. [Duan, Dongsheng] Univ Missouri, Coll Vet Med, Dept Bioengn, Columbia, MO USA. [Duan, Dongsheng] Univ Missouri, Coll Vet Med, Dept Biomed Engn, Columbia, MO USA. RP Duan, DS; Lai, Y (reprint author), Dept Mol Microbiol & Immunol, One Hosp Dr, Columbia, MO 65212 USA. EM duand@health.missouri.edu; laiy@health.missouri.edu FU Duchenne Parent Project, the Netherlands; National Institutes of Health [NS90634, AR67985]; Department of Defense [MD130014]; Jesse's Journey-The Foundation for Gene and Cell Therapy FX This work was supported by the grants from Duchenne Parent Project, the Netherlands [to Y.L.]; the National Institutes of Health [NS90634 to D.D., AR67985 to D.D. and Y.L.]; Department of Defense [MD130014 to D.D.]; and Jesse's Journey-The Foundation for Gene and Cell Therapy [to D.D.]. NR 44 TC 0 Z9 0 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 SEP 1 PY 2016 VL 25 IS 17 BP 3647 EP 3653 DI 10.1093/hmg/ddw210 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EJ4IW UT WOS:000393181300001 PM 27378693 ER PT J AU Kumari, D Usdin, K AF Kumari, Daman Usdin, Karen TI Sustained expression of FMR1 mRNA from reactivated fragile X syndrome alleles after treatment with small molecules that prevent trimethylation of H3K27 SO HUMAN MOLECULAR GENETICS LA English DT Article ID TREMOR ATAXIA SYNDROME; REPRESSIVE COMPLEX 2; CGG-REPEAT; TRINUCLEOTIDE REPEAT; PREMUTATION ALLELES; HUMAN FIBROBLASTS; NONCODING RNAS; HUMAN-CELLS; STEM-CELLS; TRANSCRIPTION AB Expansion of a CGG-repeat tract in the 5'-untranslated region of the FMR1 gene to >200 repeats results in epigenetic silencing of the gene by a mechanism that is still unknown. FMR1 gene silencing results in fragile X syndrome (FXS), the most common heritable cause of intellectual disability. We have previously shown that reactivation of the FMR1 gene in FXS cells with 5-azadeoxycytidine (AZA) leads to the transient recruitment of EZH2, the polycomb repressive complex 2 (PRC2) component responsible for H3K27 trimethylation, and that this recruitment depends on the presence of the FMR1 transcript. However, whether H3K27 trimethylation was essential for FMR1 re-silencing was not known. We show here that EZH2 inhibitors increased FMR1 expression and significantly delayed re-silencing of the FMR1 gene in AZA-treated FXS cells. This delay occurred despite the fact that EZH2 inhibition did not prevent the return of DNA methylation. Treatment with compound 1a, a small molecule that targets CGG-repeats in the FMR1 mRNA, also resulted in sustained expression of the FMR1 gene in AZA-treated cells. This effect of 1a was also associated with a decrease in the levels of H3K27 trimethylation but not DNA methylation. Thus, our data show that EZH2 plays a critical role in the FMR1 gene silencing process and that its inhibition can prolong expression of the FMR1 gene even in the presence of its transcript. C1 [Kumari, Daman; Usdin, Karen] NIDDK, Sect Genom Struct & Funct, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Kumari, D (reprint author), NIH, Bldg 8,Room 2A19,8 Ctr Dr MSC 0830, Bethesda, MD 20892 USA. EM damank@helix.nih.gov FU National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health [DK05760218] FX This work was supported by the intramural funds of National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health (DK05760218 to K.U.) NR 52 TC 0 Z9 0 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 SEP 1 PY 2016 VL 25 IS 17 BP 3689 EP 3698 DI 10.1093/hmg/ddw215 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EJ4IW UT WOS:000393181300004 PM 27378697 ER PT J AU Wyszynski, A Hong, CC Lam, K Michailidou, K Lytle, C Yao, S Zhang, Y Bolla, MK Wang, Q Dennis, J Hopper, JL Southey, MC Schmidt, MK Broeks, A Muir, K Lophatananon, A Fasching, PA Beckmann, MW Peto, J dos-Santos-Silva, I Sawyer, EJ Tomlinson, I Burwinkel, B Marme, F Guenel, P Truong, T Bojesen, SE Nordestgaard, BG Gonzalez-Neira, A Benitez, J Neuhausen, SL Brenner, H Dieffenbach, AK Meindl, A Schmutzler, RK Brauch, H Nevanlinna, H Khan, S Matsuo, K Ito, H Dork, T Bogdanova, NV Lindblom, A Margolin, S Mannermaa, A Kosma, VM Wu, AH Van den Berg, D Lambrechts, D Wildiers, H Chang-Claude, J Rudolph, A Radice, P Peterlongo, P Couch, FJ Olson, JE Giles, GG Milne, RL Haiman, CA Henderson, BE Dumont, M Teo, SH Wong, TY Kristensen, V Zheng, W Long, JR Winqvist, R Pylkas, K Andrulis, IL Knight, JA Devilee, P Seynaeve, C Garcia-Closas, M Figueroa, J Klevebring, D Czene, K Hooning, MJ van den Ouweland, AMW Darabi, H Shu, XO Gao, YT Cox, A Blot, W Signorello, LB Shah, M Kang, D Choi, JY Hartman, M Miao, H Hamann, U Jakubowska, A Lubinski, J Sangrajrang, S McKay, J Toland, AE Yannoukakos, D Shen, CY Wu, PE Swerdlow, A Orr, N Simard, J Pharoah, PDP Dunning, AM Chenevix-Trench, G Hall, P Bandera, E Amos, C Ambrosone, C Easton, DF Cole, MD AF Wyszynski, Asaf Hong, Chi-Chen Lam, Kristin Michailidou, Kyriaki Lytle, Christian Yao, Song Zhang, Yali Bolla, Manjeet K. Wang, Qin Dennis, Joe Hopper, John L. Southey, Melissa C. Schmidt, Marjanka K. Broeks, Annegien Muir, Kenneth Lophatananon, Artitaya Fasching, Peter A. Beckmann, Matthias W. Peto, Julian dos-Santos-Silva, Isabel Sawyer, Elinor J. Tomlinson, Ian Burwinkel, Barbara Marme, Frederik Guenel, Pascal Truong, Therese Bojesen, Stig E. Nordestgaard, Borge G. Gonzalez-Neira, Anna Benitez, Javier Neuhausen, Susan L. Brenner, Hermann Dieffenbach, Aida Karina Meindl, Alfons Schmutzler, Rita K. Brauch, Hiltrud Nevanlinna, Heli Khan, Sofia Matsuo, Keitaro Ito, Hidemi Doerk, Thilo Bogdanova, Natalia V. Lindblom, Annika Margolin, Sara Mannermaa, Arto Kosma, Veli-Matti Wu, Anna H. Van den Berg, David Lambrechts, Diether Wildiers, Hans Chang-Claude, Jenny Rudolph, Anja Radice, Paolo Peterlongo, Paolo Couch, Fergus J. Olson, Janet E. Giles, Graham G. Milne, Roger L. Haiman, Christopher A. Henderson, Brian E. Dumont, Martine Teo, Soo Hwang Wong, Tien Y. Kristensen, Vessela Zheng, Wei Long, Jirong Winqvist, Robert Pylkas, Katri Andrulis, Irene L. Knight, Julia A. Devilee, Peter Seynaeve, Caroline Garcia-Closas, Montserrat Figueroa, Jonine Klevebring, Daniel Czene, Kamila Hooning, Maartje J. van den Ouweland, Ans M. W. Darabi, Hatef Shu, Xiao-Ou Gao, Yu-Tang Cox, Angela Blot, William Signorello, Lisa B. Shah, Mitul Kang, Daehee Choi, Ji-Yeob Hartman, Mikael Miao, Hui Hamann, Ute Jakubowska, Anna Lubinski, Jan Sangrajrang, Suleeporn McKay, James Toland, Amanda E. Yannoukakos, Drakoulis Shen, Chen-Yang Wu, Pei-Ei Swerdlow, Anthony Orr, Nick Simard, Jacques Pharoah, Paul D. P. Dunning, Alison M. Chenevix-Trench, Georgia Hall, Per Bandera, Elisa Amos, Chris Ambrosone, Christine Easton, Douglas F. Cole, Michael D. CA GENICA Network KConFab Investigators Australian Ovarian Canc Study Grp TI An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; GENOTYPE IMPUTATION; GROWTH; CELLS; SUSCEPTIBILITY; ACTIVATION; INVOLUTION; MUTATION; GENE; MICE AB Breast cancer is the most diagnosed malignancy and the second leading cause of cancer mortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression. We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ER alpha-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated with modified ER alpha binding and monoallelic-repression of IGFBP5 following oestrogen treatment. We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from 41 case control studies and 11 GWAS. We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR = 0.68 95% CI 0.55-0.83, P = 0.0002; replication OR = 0.77 95% CI 0.73-0.82, P = 2.1 x 10 (-19)) and identify 13 additional linked variants (r(2) > 0.8) in the 20Kb linkage block containing the enCNV (P = 3.2 x 10 (-15) - 5.6 x 10 (-17)). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk loci may be mediating their effect through IGFBP5. C1 [Wyszynski, Asaf; Amos, Chris] Dartmouth, Dept Biomed Data Sci, Geisel Sch Med, Hanover, NH 03755 USA. [Hong, Chi-Chen; Yao, Song; Zhang, Yali; Ambrosone, Christine] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Lam, Kristin] Dartmouth Coll, Hanover, NH 03755 USA. [Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Pharoah, Paul D. P.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England. [Lytle, Christian] Dartmouth Coll, Mol Biol Core Facil, Hanover, NH 03755 USA. [Hopper, John L.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic 3010, Australia. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia. [Schmidt, Marjanka K.; Broeks, Annegien] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, NL-1066 CX Amsterdam, Netherlands. [Muir, Kenneth; Lophatananon, Artitaya] Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry CV4 7AL, W Midlands, England. [Muir, Kenneth] Univ Manchester, Inst Populat Hlth, Manchester M13 9PL, Lancs, England. [Fasching, Peter A.; Beckmann, Matthias W.] Friedrich Alexander Univ Erlangen Nuremberg, Comprehens Canc Ctr Erlangen EMN, Univ Hosp Erlangen, Univ Breast Ctr Franconia,Dept Gynecol & Obstet, D-91054 Erlangen, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, Div Hematol & Oncol, Dept Med, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Peto, Julian; dos-Santos-Silva, Isabel] London Sch Hyg & Trop Med, Dept Noncommun Dis Epidemiol, London WC1E 7HT, England. [Sawyer, Elinor J.] Kings Coll London, Guys Hosp, Div Canc Studies, Res Oncol, London SE1 9RT, England. [Tomlinson, Ian] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Tomlinson, Ian] Univ Oxford, Oxford Biomed Res Ctr, Oxford OX3 7BN, England. [Burwinkel, Barbara; Marme, Frederik] Heidelberg Univ, Dept Obstet & Gynecol, D-69120 Heidelberg, Germany. [Burwinkel, Barbara] German Canc Res Ctr, Mol Epidemiol Grp, D-69120 Heidelberg, Germany. [Marme, Frederik] Heidelberg Univ, Natl Ctr Tumor Dis, D-69120 Heidelberg, Germany. [Guenel, Pascal; Truong, Therese] CESP, INSERM, Environm Epidemiol Canc, U1018, F-94807 Villejuif, France. [Guenel, Pascal; Truong, Therese] Univ Paris Sud, UMRS 1018, F-94807 Villejuif, France. [Bojesen, Stig E.; Nordestgaard, Borge G.] Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, DK-2730 Herlev, Denmark. [Bojesen, Stig E.; Nordestgaard, Borge G.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, DK-2730 Herlev, Denmark. [Gonzalez-Neira, Anna] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Human Genotyping CEGEN Unit, Madrid 28029, Spain. [Benitez, Javier] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Human Genet Grp, Madrid 28029, Spain. [Benitez, Javier] CIBERER, Valencia 46010, Spain. [Neuhausen, Susan L.] City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA 91010 USA. [Brenner, Hermann; Dieffenbach, Aida Karina] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, D-69120 Heidelberg, Germany. [Brenner, Hermann; Dieffenbach, Aida Karina] German Canc Consortium DKTK, D-69120 Heidelberg, Germany. [Meindl, Alfons] Tech Univ Munich, Div Gynaecol & Obstet, D-81675 Munich, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Dept Obstet & Gynaecol, Div Mol Gynecooncol, D-50931 Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, D-50931 Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, CIO, D-50931 Cologne, Germany. [Schmutzler, Rita K.] Univ Cologne, CMMC, D-50931 Cologne, Germany. [Brauch, Hiltrud] Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-70376 Stuttgart, Germany. [Brauch, Hiltrud] Univ Tubingen, D-72074 Tubingen, Germany. Inst Ruhr Univ Bochum IPA, German Social Accid Insurance, Inst Prevent & Occupat Med, D-44789 Bochum, Germany. Johanniter Krankenhaus, Evangel Kliniken Bonn gGmbH, Dept Internal Med, D-53113 Bonn, Germany. Deutsch Krebsforschungszentrum DKFZ, Mol Genet Breast Canc, D-69120 Heidelberg, Germany. Univ Bonn, Fac Med, Inst Pathol, D-53127 Bonn, Germany. [GENICA Network] Univ Med Ctr Hamburg Eppendorf, Inst Occupat Med & Maritime Med, D-20246 Hamburg, Germany. [Nevanlinna, Heli; Khan, Sofia] Univ Helsinki, Dept Obstet & Gynecol, FI-00029 Helsinki, Finland. [Nevanlinna, Heli; Khan, Sofia] Univ Helsinki, Cent Hosp, FI-00029 Helsinki, Finland. [Matsuo, Keitaro] Kyushu Univ, Fac Med Sci, Dept Prevent Med, Fukuoka, Japan. [Ito, Hidemi] Aichi Canc Ctr, Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi 4648681, Japan. [Doerk, Thilo] Hannover Med Sch, Dept Obstet & Gynaecol, D-30625 Hannover, Germany. [Bogdanova, Natalia V.] Hannover Med Sch, Dept Radiat Oncol, D-30625 Hannover, Germany. [Lindblom, Annika] Karolinska Inst, Dept Mol Med & Surg, SE-17177 Stockholm, Sweden. [Margolin, Sara] Karolinska Inst, Dept Oncol Pathol, SE-17177 Stockholm, Sweden. [Mannermaa, Arto; Kosma, Veli-Matti] Univ Eastern Finland, Sch Med, Inst Clin Med Pathol & Forens Med, FI-70211 Kuopio, Finland. [Mannermaa, Arto; Kosma, Veli-Matti] Univ Eastern Finland, Canc Ctr Eastern Finland, FI-70211 Kuopio, Finland. [Mannermaa, Arto; Kosma, Veli-Matti] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, Kuopio 70210, Finland. [KConFab Investigators] Peter MacCallum Canc Ctr, Melbourne, Vic 3002, Australia. [Australian Ovarian Canc Study Grp] QIMR Berghofer Med Res Inst, Brisbane, Qld 4006, Australia. [Wu, Anna H.; Van den Berg, David; Haiman, Christopher A.; Henderson, Brian E.] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Lambrechts, Diether] VIB, VRC, B-3000 Leuven, Belgium. [Lambrechts, Diether] Univ Leuven, Dept Oncol, Lab Translat Genet, B-3000 Leuven, Belgium. [Wildiers, Hans] Univ Hosp Leuven, Dept Gen Med Oncol, Multidisciplinary Breast Ctr, B-3000 Leuven, Belgium. [Chang-Claude, Jenny; Rudolph, Anja] German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany. [Chang-Claude, Jenny] Univ Med Ctr Hamburg Eppendorf, UCCH, D-20246 Hamburg, Germany. [Radice, Paolo] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, I-20133 Milan, Italy. [Peterlongo, Paolo] Fdn Ist FIRC Oncol Mol, IFOM, I-20139 Milan, Italy. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. [Olson, Janet E.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Giles, Graham G.; Milne, Roger L.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic 3004, Australia. [Giles, Graham G.; Milne, Roger L.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic 3010, Australia. [Dumont, Martine; Simard, Jacques] Ctr Hosp Univ Quebec, Res Ctr, Quebec City, PQ G1V 4G2, Canada. [Dumont, Martine; Simard, Jacques] Univ Laval, Quebec City, PQ G1V 4G2, Canada. [Teo, Soo Hwang] Sime Darby Med Ctr, Canc Res Initiat Fdn, Subang Jaya 47500, Selangor, Malaysia. [Teo, Soo Hwang] UMMC, Univ Malaya Canc Res Inst, Breast Canc Res Unit, Kuala Lumpur 59100, Malaysia. [Wong, Tien Y.] Natl Univ Singapore, Singapore Eye Res Inst, Singapore 168751, Singapore. [Kristensen, Vessela] Radiumhospitalet, Oslo Univ Hosp, Inst Canc Res, Dept Genet, N-0310 Oslo, Norway. [Kristensen, Vessela] Univ Oslo UiO, Inst Clin Med, N-0450 Oslo, Norway. [Kristensen, Vessela] Univ Oslo UiO, Dept Clin Mol Biol EpiGen, N-0450 Oslo, Norway. [Zheng, Wei; Long, Jirong] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37203 USA. [Winqvist, Robert; Pylkas, Katri] Univ Oulu, NordLab Oulu, Oulu Univ Hosp, Lab Canc Genet & Tumor Biol,Dept Clin Chem, FI-90220 Oulu, Finland. [Winqvist, Robert; Pylkas, Katri] Univ Oulu, NordLab Oulu, Oulu Univ Hosp, Bioctr Oulu, FI-90220 Oulu, Finland. [Andrulis, Irene L.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada. [Knight, Julia A.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada. [Knight, Julia A.] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON M5S 1A8, Canada. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Human Genet, NL-2333 ZC Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Pathol, NL-2333 ZC Leiden, Netherlands. [Seynaeve, Caroline] Daniel Denhoed Canc Ctr, Erasmus MC, Dept Med Oncol, Family Canc Clin, NL-3075 EA Rotterdam, Netherlands. [Garcia-Closas, Montserrat; Swerdlow, Anthony] Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England. [Garcia-Closas, Montserrat] Inst Canc Res, Div Breast Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Figueroa, Jonine] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. [Klevebring, Daniel; Czene, Kamila; Darabi, Hatef; Hall, Per] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. [Hooning, Maartje J.] Erasmus Univ, Med Ctr, Dept Med Oncol, NL-3075 EA Rotterdam, Netherlands. [van den Ouweland, Ans M. W.] Erasmus Univ, Med Ctr, Dept Clin Genet, NL-3075 EA Rotterdam, Netherlands. [Shu, Xiao-Ou; Blot, William] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37203 USA. [Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Cox, Angela] Univ Sheffield, Dept Oncol, CRUK YCR Sheffield Canc Res Ctr, Sheffield S10 2RX, S Yorkshire, England. [Blot, William] Int Epidemiol Inst, Rockville, MD 20850 USA. [Signorello, Lisa B.] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Shah, Mitul; Pharoah, Paul D. P.; Dunning, Alison M.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England. [Kang, Daehee] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul 110799, South Korea. [Kang, Daehee; Choi, Ji-Yeob] Seoul Natl Univ, Grad Sch, Dept Biomed Sci, Seoul 151742, South Korea. [Kang, Daehee; Choi, Ji-Yeob] Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul 110799, South Korea. [Hartman, Mikael; Miao, Hui] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117597, Singapore. [Hartman, Mikael; Miao, Hui] Natl Univ Hlth Syst, Singapore 117597, Singapore. [Hartman, Mikael] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Surg, Singapore 117597, Singapore. [Hamann, Ute] German Canc Res Ctr, Mol Genet Breast Canc, D-69120 Heidelberg, Germany. [Jakubowska, Anna; Lubinski, Jan] Pomeranian Med Univ, Dept Genet & Pathol, PL-70115 Szczecin, Poland. [Sangrajrang, Suleeporn] Natl Canc Inst, Bangkok 10400, Thailand. [McKay, James] Int Agcy Res Canc, F-69372 Lyon 08, France. [Toland, Amanda E.] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Yannoukakos, Drakoulis] Natl Ctr Sci Res Demokritos, IRRP, Mol Diagnost Lab, Athens 15310, Greece. [Shen, Chen-Yang; Wu, Pei-Ei] Acad Sinica, Inst Biomed Sci, Taiwan Biobank, Taipei 115, Taiwan. [Shen, Chen-Yang; Wu, Pei-Ei] Acad Sinica, Inst Biomed Sci, Taipei 115, Taiwan. [Shen, Chen-Yang] China Med Univ, Sch Publ Hlth, Taichung 404, Taiwan. [Swerdlow, Anthony] Inst Canc Res, Div Breast Canc Res, Sutton SM2 5NG, Surrey, England. [Orr, Nick] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Dept Genet, Brisbane, Qld 4006, Australia. [Bandera, Elisa] Rutgers Canc Inst New Jersey, New Brunswick, NJ 08901 USA. [Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Easton, Douglas F.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Cole, Michael D.] Dartmouth, Geisel Sch Med, Dept Mol & Syst Biol, Hanover, NH 03755 USA. RP Cole, MD (reprint author), Dartmouth, Geisel Sch Med, Hanover, NH 03755 USA. EM Michael.D.Cole@dartmouth.edu OI Matsuo, Keitaro/0000-0003-1761-6314; Yannoukakos, Drakoulis/0000-0001-7509-3510; Dunning, Alison Margaret/0000-0001-6651-7166 FU National Cancer Institute [CA080320]; Cancer Research UK [C1287/A10118, C1287/A12014, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565, C8620/A8372, C8620/A8857, C490/A10124]; European Community's Seventh Framework Programme [223175, HEALTH-F2-2009-223175]; National Institutes of Health [CA128978, R01 CA77398, R01 CA092447]; 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, RUL 1997-1505, DDHK 2004-3124, DDHK 2009-4318]; Dutch government [NWO 184.021.007]; Dutch National Genomics Initiative; Cancer Institute NSW; National Breast Cancer Foundation; Breast Cancer Research Trust, UK; ELAN-Fond of the University Hospital of Erlangen; Cancer Research UK; Breakthrough Breast Cancer; NHS; NIHR Comprehensive Biomedical Research Centre; Guy's & St. Thomas' NHS Foundation Trust; King's College London, United Kingdom; Oxford Biomedical Research Centre; US Military Acquisition (ACQ) Activity, Era of Hope Award [W81XWH-05-1-0204]; Institute of Cancer Research (UK); Medical Research Council (UK) Clinical Research Fellowship; 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]; California Breast Cancer; California Breast Cancer Research Fund [97-10500]; California Department of Public Health [103885]; Lon V Smith Foundation [LVS39420]; Against Breast Cancer Registered Charity [1121258]; Baden Wurttemberg Ministry of Science, Research and Arts; German Cancer Aid (Deutsche Krebshilfe); German Cancer Aid [110837]; Federal Ministry of Education and Research (BMBF) Germany [01KW9975/5, 01KW9976/8, 01KW9977/0, 01KW0114, 01KH0402]; Robert Bosch Foundation, Stuttgart; Deutsches Krebsforschungszentrum (DKFZ), Heidelberg; Institute for Prevention and Occupational Medicine of the German Social Accident Insurance; Institute of the Ruhr University Bochum (IPA), Bochum; Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany; Deutsche Krebshilfe e.V. [70492, 70-2892-BR I, 106332, 108253, 108419]; Hannover Medical School; Helsinki University Central Hospital Research Fund; Academy of Finland [266528, 250083, 122715, 251314]; Finnish Cancer Society; Nordic Cancer Union; Sigrid Juselius Foundation; Ministry of Education, Science, Sports, Culture and Technology of Japan; Ministry Health, Labour and Welfare of Japan; Health and Labour Sciences Research Grants for Research on Applying Health Technology from Ministry Health, Labour and Welfare of Japan; National Cancer Center Research and Development Fund; Takeda Health Foundation; Friends of Hannover Medical School; Rudolf Bartling Foundation; German Federal Ministry of Research and Education [RUS08/017]; Stockholm County Council; Karolinska Institutet; Swedish Cancer Society; Gustav V Jubilee foundation; Bert von Kantzows foundation; special Government Funding (EVO) of Kuopio University Hospital grants; Cancer Fund of North Savo; Finnish Cancer Organizations; University of Eastern Finland; Queensland Cancer Fund; Cancer Council of New South Wales; Cancer Council of Victoria; Cancer Council of Tasmania; Cancer Council of South Australia; Cancer Foundation of Western Australia; United States Army Medical Research and Materiel Command [DAMD17-01-1-0729]; Cancer Council Victoria; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; National Health and Medical Research Council of Australia (NHMRC) [400413, 400281, 199600]; NHMRC; California Breast Cancer Research Program [1RB-0287, 3PB-0102, 5PB-0018, 10PB-0098]; California Department of Health; National Cancer Institute's Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program [N01CN25403]; Stichting tegen Kanker [232-2008, 196-2010]; FWO; Hamburg Cancer Society; Italian Association for Cancer Research (AIRC); Fondazione IRCCS Istituto Nazionale Tumori; NIH [CA128978, CA116167, CA176785, CA116201, CA63464, CA54281, CA098758, CA132839, R01CA100374, CA87969, R01CA64277, R01CA148667, R37CA70867, CA58860, CA92044]; VicHealth and Cancer Council Victoria; Australian NHMRC [209057, 251553, 504711]; Robert and Kate Niehaus Clinical Cancer Genetics Initiative; Quebec Breast Cancer Foundation; Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program [CRN-87521]; Ministry of Economic Development, Innovation and Export Trade [PSR-SIIRI-701]; Malaysian Ministry of Science, Technology and Innovation (MOSTI); Malaysian Ministry of Higher Education [UM.C/HlR/MOHE/06]; Cancer Research Initiatives Foundation (CARIF); Biomedical Research Council, Singapore [BMRC08/1/35/19/550]; National medical Research Council, Singapore [NMRC/CG/SERI/2010]; K.G. Jebsen Centre for Breast Cancer Research; Research Council of Norway [193387/V50, 193387/H10]; South Eastern Norway Health Authority [39346]; Norwegian Cancer Society; Finnish Cancer Foundation; University of Oulu; University of Oulu Support Foundation; special Governmental EVO funds; Biobanking and Biomolecular Resources Research Infrastructure [BBMRI-NL CP16]; Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA; Marit and Hans Rausings Initiative Against Breast Cancer; Agency for Science, Technology and Research of Singapore (A*STAR); US National Institute of Health (NIH); Susan G. Komen Breast Cancer Foundation; Genetic Associations and Mechanisms in Oncology (GAME-ON) Network [U19 CA148065]; Yorkshire Cancer Research [S295, S299, S305PA]; Sheffield Experimental Cancer Medicine Centre; National Program of Cancer Registries; Centers for Disease Control and Prevention (CDC); UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; BRL (Basic Research Laboratory) program through the National Research Foundation of Korea - Ministry of Education, Science and Technology [2012-0000347]; NUS start-up Grant; National University Cancer Institute Singapore (NCIS) Centre Grant; NMRC Clinician Scientist Award; Biomedical Research Council [05/1/21/19/425]; DKFZ; National Cancer Institute Thailand; Breast Cancer Research Foundation [CA116201]; Stefanie Spielman Breast Cancer fund; OSU Comprehensive Cancer Center; Hellenic Cooperative Oncology Group research grant [HR R_BG/04]; Greek General Secretary for Research and Technology (GSRT) Program; Research Excellence II; European Union (European Social Fund - ESF); Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) - ARISTEIA; Taiwan Biobank project of the Institute of Biomedical Sciences, Academia Sinica, Taiwan; Institute of Cancer Research (ICR), London; Massachusetts [R01CA47305]; Wisconsin [R01 CA47147]; New Hampshire [R01CA69664]; Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services; [KULPFV/10/016-SymBioSysII]; [P30 CA68485]; [PBZ_KBN_122/P05/2004] FX This work was funded primarily by the National Cancer Institute (CA080320). The 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-F2-2009-223175) (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]; BBMRI-NL, which is a Research Infrastructure financed by the Dutch government (NWO 184.021.007); and the Dutch National Genomics Initiative. The Australian Breast Cancer Tissue Bank is generously supported by the National Health and Medical Research Council of Australia, The Cancer Institute NSW and the National Breast Cancer Foundation. The ACP study is funded by the Breast Cancer Research Trust, UK. 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. BOCS is supported by funds from Cancer Research UK (C8620/A8372 and C8620/A8857), a US Military Acquisition (ACQ) Activity, Era of Hope Award (W81XWH-05-1-0204) and the Institute of Cancer Research (UK). C.T. is funded by a Medical Research Council (UK) Clinical Research Fellowship. BOCS acknowledges NHS funding to the Royal Marsden/Institute of Cancer Research NIHR Specialist Cancer 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 University of Westminster curates the DietCompLyf database created by and funded by Against Breast Cancer Registered Charity No. 1121258.; The ESTHER study was supportd 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 GESBC was supported by the Deutsche Krebshilfe e.V. [70492] and the German Cancer Research Center (DKFZ).; The HABCS study was supported by an intramural grant from Hannover Medical School.; The HEBCS was financilly supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, The Nordic Cancer Union and the Sigrid Juselius Foundation. The HERPACC was supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports, Culture and Technology of Japan, by a Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from Ministry Health, Labour and Welfare of Japan, by Health and Labour Sciences Research Grants for Research on Applying Health Technology from Ministry Health, Labour and Welfare of Japan, National Cancer Center Research and Development Fund and Grant from Takeda Health Foundation. The HMBCS was supported by a grant from the Friends of Hannover Medical School and by the Rudolf Bartling Foundation. The HUBCS was supported by a grant from the German Federal Ministry of Research and Education (RUS08/017).; "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. LAABC is supported by grants (1RB-0287, 3PB-0102, 5PB-0018, 10PB-0098) from the California Breast Cancer Research Program. Incident breast cancer cases were collected by the USC Cancer Surveillance Program (CSP) which is supported under subcontract by the California Department of Health. The CSP is also part of the National Cancer Institute's Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program, under contract number N01CN25403. 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. MSKCC is supported by grants from the Breast Cancer Research Foundation and Robert and Kate Niehaus Clinical Cancer Genetics Initiative. 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. MYBRCA is funded by research grants from the Malaysian Ministry of Science, Technology and Innovation (MOSTI), Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation (CARIF). Additional controls were recruited by the Singapore Eye Research Institute, which was supported by a grant from the Biomedical Research Council (BMRC08/1/35/19/550), Singapore and the National medical Research Council, Singapore (NMRC/CG/SERI/2010). The NBCS has received funding from the K.G. Jebsen Centre for Breast Cancer Research; the Research Council of Norway grant 193387/V50 (to A-L 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 Northern California Breast Cancer Family Registry (NC-BCFR) 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 NHS was funded by NIH grant CA87969. 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 SBCGS was supported primarily by NIH grants R01CA64277, R01CA148667, and R37CA70867. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The scientific development and funding of this project were, in part, supported by the Genetic Associations and Mechanisms in Oncology (GAME-ON) Network U19 CA148065. The SBCS was supported by Yorkshire Cancer Research S295, S299, S305PA and Sheffield Experimental Cancer Medicine Centre. The SCCS is supported by a grant from the National Institutes of Health (R01 CA092447). Data on SCCS cancer cases used in this publication were provided by the Alabama Statewide Cancer Registry; Kentucky Cancer Registry, Lexington, KY; Tennessee Department of Health, Office of Cancer Surveillance; Florida Cancer Data System; North Carolina Central Cancer Registry, North Carolina Division of Public Health; Georgia Comprehensive Cancer Registry; Louisiana Tumor Registry; Mississippi Cancer Registry; South Carolina Central Cancer Registry; Virginia Department of Health, Virginia Cancer Registry; Arkansas Department of Health, Cancer Registry, 4815 W. Markham, Little Rock, AR 72205. The Arkansas Central Cancer Registry is fully funded by a grant from National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC). Data on SCCS cancer cases from Mississippi were collected by the Mississippi Cancer Registry which participates in the National Program of Cancer Registries (NPCR) of the Centers for Disease Control and Prevention (CDC). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Mississippi Cancer Registry. 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. SEBCS was supported by the BRL (Basic Research Laboratory) program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2012-0000347). SGBCC is funded by the NUS start-up Grant, National University Cancer Institute Singapore (NCIS) Centre Grant and the NMRC Clinician Scientist Award. Additional controls were recruited by the Singapore Consortium of Cohort Studies-Multi-ethnic cohort (SCCS-MEC), which was funded by the Biomedical Research Council, grant number: 05/1/21/19/425. SKKDKFZS is supported by the DKFZ. The SZBCS was supported by Grant PBZ_KBN_122/P05/2004.; The TBCS was funded by The National Cancer Institute Thailand. 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 TWBCS is supported by the Taiwan Biobank project of the Institute of Biomedical Sciences, Academia Sinica, Taiwan. The UCIBCS component of this research was supported by the NIH [CA58860, CA92044] and the Lon V Smith Foundation [LVS39420]. The UKBGS is funded by Breakthrough Breast Cancer and the Institute of Cancer Research (ICR), London. ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. The US3SS study was supported by Massachusetts (K.M.E., R01CA47305), Wisconsin (P.A.N., R01 CA47147) and New Hampshire (L.T.-E., R01CA69664) centers, and Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The USRT Study was funded by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services. NR 39 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 SEP 1 PY 2016 VL 25 IS 17 BP 3863 EP 3876 DI 10.1093/hmg/ddw223 PG 14 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EJ4IW UT WOS:000393181300017 PM 27402876 ER PT J AU Balbus, J Berry, P Brettle, M Jagnarine-Azan, S Soares, A Ugarte, C Varangu, L Prats, EV AF Balbus, John Berry, Peter Brettle, Meagan Jagnarine-Azan, Shalini Soares, Agnes Ugarte, Ciro Varangu, Linda Prats, Elena Villalobos TI Enhancing the sustainability and climate resiliency of health care facilities: a comparison of initiatives and toolkits SO REVISTA PANAMERICANA DE SALUD PUBLICA-PAN AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article DE Climate change; climate effects; prevention and mitigation; disaster preparedness; health care facilities; sustainable development; Americas AB Extreme weather events have revealed the vulnerability of health care facilities and the extent of devastation to the community when they fail. With climate change anticipated to increase extreme weather and its impacts worldwide-severe droughts, floods, heat waves, and related vector-borne diseases-health care officials need to understand and address the vulnerabilities of their health care systems and take action to improve resiliency in ways that also meet sustainability goals. Generally, the health sector is among a country's largest consumers of energy and a significant source of greenhouse gas emissions. Now it has the opportunity lead climate mitigation, while reducing energy, water, and other costs. This Special Report summarizes several initiatives and compares three toolkits for implementing sustainability and resiliency measures for health care facilities: the Canadian Health Care Facility Climate Change Resiliency Toolkit, the U. S. Sustainable and Climate Resilient Health Care Facilities Toolkit, and the PAHO SMART Hospitals Toolkit of the World Health Organization/Pan American Health Organization. These tools and the lessons learned can provide a critical starting point for any health system in the Americas. C1 [Balbus, John] Natl Inst Environm Hlth Sci, Bethesda, MD USA. [Berry, Peter] Hlth Canada, Climate Change & Hlth Off, Ottawa, ON, Canada. [Brettle, Meagan] Hlth Canada, Ottawa, ON, Canada. [Jagnarine-Azan, Shalini] Pan Amer Hlth Org, Washington, DC USA. [Soares, Agnes] PAHO, Special Program Sustainable Dev & Hlth Equ, Washington, DC USA. [Ugarte, Ciro] PAHO, Dept Emergency Preparedness & Disaster Relief, Washington, DC USA. [Varangu, Linda] Canadian Coalit Green Hlth Care, Branchton, ON, Canada. [Prats, Elena Villalobos] WHO, Geneva, Switzerland. RP Balbus, J (reprint author), Natl Inst Environm Hlth Sci, Bethesda, MD USA. EM john.balbus@nih.gov NR 15 TC 0 Z9 0 U1 1 U2 1 PU PAN AMER HEALTH ORGANIZATION PI WASHINGTON PA 525 23RD ST NW, WASHINGTON, DC 20037 USA SN 1020-4989 J9 REV PANAM SALUD PUBL JI Rev. Panam. Salud Publica PD SEP PY 2016 VL 40 IS 3 BP 174 EP 180 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EJ4UD UT WOS:000393211500005 PM 27991975 ER PT J AU Tijjani, A Kim, J Kim, H Mrode, R Hanotte, O AF Tijjani, A. Kim, J. Kim, H. Mrode, R. Hanotte, O. TI Comparative genomics reveal common diversity and signature of positive selection in West African taurine cattle populations. SO JOURNAL OF ANIMAL SCIENCE LA English DT Meeting Abstract DE African taurine; re-sequencing; SNPs C1 [Tijjani, A.; Hanotte, O.] Univ Nottingham, Sch Life Sci, Nottingham, England. [Tijjani, A.] Natl Biotechnol Dev Agcy NABDA, Abuja, Nigeria. [Kim, J.] NHGRI, NIH, Bethesda, MD 20892 USA. [Kim, H.] Seoul Natl Univ, Seoul, South Korea. [Mrode, R.; Hanotte, O.] Int Livestock Res Inst, Nairobi, Kenya. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC ANIMAL SCIENCE PI CHAMPAIGN PA PO BOX 7410, CHAMPAIGN, IL 61826-7410 USA SN 0021-8812 EI 1525-3163 J9 J ANIM SCI JI J. Anim. Sci. PD SEP PY 2016 VL 94 SU 4 MA P5062 BP 145 EP 145 DI 10.2134/jas2016.94supplement4145a PG 1 WC Agriculture, Dairy & Animal Science SC Agriculture GA EI7GM UT WOS:000392665800285 ER PT J AU Pruitt, KD Murphy, TD Thibaud-Nissen, F Kitts, PA AF Pruitt, K. D. Murphy, T. D. Thibaud-Nissen, F. Kitts, P. A. TI RefSeq and Gene-NCBI resources to support comparative genomics. SO JOURNAL OF ANIMAL SCIENCE LA English DT Meeting Abstract DE RefSeq; Gene; orthologs; genome annotation; biocuration C1 [Pruitt, K. D.; Murphy, T. D.; Thibaud-Nissen, F.; Kitts, P. A.] NIH, NCBI, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC ANIMAL SCIENCE PI CHAMPAIGN PA PO BOX 7410, CHAMPAIGN, IL 61826-7410 USA SN 0021-8812 EI 1525-3163 J9 J ANIM SCI JI J. Anim. Sci. PD SEP PY 2016 VL 94 SU 4 MA P8007 BP 183 EP 184 DI 10.2134/jas2016.94supplement4183b PG 2 WC Agriculture, Dairy & Animal Science SC Agriculture GA EI7GM UT WOS:000392665800362 ER PT J AU Thibaud-Nissen, F DiCuccio, M Hlavina, W Kimchi, A Kitts, PA Murphy, TD Pruitt, KD Souvorov, A AF Thibaud-Nissen, F. DiCuccio, M. Hlavina, W. Kimchi, A. Kitts, P. A. Murphy, T. D. Pruitt, K. D. Souvorov, A. TI The NCBI Eukaryotic Genome Annotation Pipeline SO JOURNAL OF ANIMAL SCIENCE LA English DT Meeting Abstract DE annotation; whole-genome; gene prediction; RNA-Seq; curation; genome; assembly C1 [Thibaud-Nissen, F.; DiCuccio, M.; Hlavina, W.; Kimchi, A.; Kitts, P. A.; Murphy, T. D.; Pruitt, K. D.; Souvorov, A.] NIH, NCBI, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC ANIMAL SCIENCE PI CHAMPAIGN PA PO BOX 7410, CHAMPAIGN, IL 61826-7410 USA SN 0021-8812 EI 1525-3163 J9 J ANIM SCI JI J. Anim. Sci. PD SEP PY 2016 VL 94 SU 4 MA P8008 BP 184 EP 184 DI 10.2134/jas2016.94supplement4184x PG 1 WC Agriculture, Dairy & Animal Science SC Agriculture GA EI7GM UT WOS:000392665800363 ER PT J AU Harel, A Groen, IIA Kravitz, DJ Deouell, LY Baker, CI AF Harel, Assaf Groen, Iris I. A. Kravitz, Dwight J. Deouell, Leon Y. Baker, Chris I. TI The Temporal Dynamics of Scene Processing: A Multifaceted EEG Investigation SO ENEURO LA English DT Article DE EEG; ERP; scene recognition; visual perception ID HUMAN OCCIPITOTEMPORAL CORTEX; PARAHIPPOCAMPAL PLACE AREA; FUSIFORM FACE AREA; REAL-WORLD SCENES; TIME-COURSE; VISUAL-CORTEX; PERCEPTION; OBJECT; LEVEL; CATEGORIZATION AB Our remarkable ability to process complex visual scenes is supported by a network of scene-selective cortical regions. Despite growing knowledge about the scene representation in these regions, much less is known about the temporal dynamics with which these representations emerge. We conducted two experiments aimed at identifying and characterizing the earliest markers of scene-specific processing. In the first experiment, human participants viewed images of scenes, faces, and everyday objects while event-related potentials (ERPs) were recorded. We found that the first ERP component to evince a significantly stronger response to scenes than the other categories was the P2, peaking similar to 220 ms after stimulus onset. To establish that the P2 component reflects scene-specific processing, in the second experiment, we recorded ERPs while the participants viewed diverse real-world scenes spanning the following three global scene properties: spatial expanse (open/closed), relative distance (near/far), and naturalness (man-made/natural). We found that P2 amplitude was sensitive to these scene properties at both the categorical level, distinguishing between open and closed natural scenes, as well as at the single-image level, reflecting both computationally derived scene statistics and behavioral ratings of naturalness and spatial expanse. Together, these results establish the P2 as an ERP marker for scene processing, and demonstrate that scene-specific global information is available in the neural response as early as 220 ms. C1 [Harel, Assaf; Groen, Iris I. A.; Baker, Chris I.] NIMH, Sect Learning & Plast, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Kravitz, Dwight J.] George Washington Univ, Dept Psychol, Washington, DC 20052 USA. [Deouell, Leon Y.] Hebrew Univ Jerusalem, Dept Psychol, IL-91905 Jerusalem, Israel. [Deouell, Leon Y.] Hebrew Univ Jerusalem, Edmond & Lily Safra Ctr Brain Sci, IL-9190401 Jerusalem, Israel. RP Harel, A (reprint author), Wright State Univ, Dept Psychol, Dayton, OH 45435 USA. EM assaf.harel@wright.edu OI Groen, Iris/0000-0002-5536-6128 FU National Institute of Mental Health [ZIA-MH-002909]; Rubicon Fellowship from Netherlands Organization of Scientific Research (NWO) FX This work was supported by the Intramural Program of the National Institute of Mental Health (Grant ZIA-MH-002909). IIAG is supported by a Rubicon Fellowship from the Netherlands Organization of Scientific Research (NWO). NR 60 TC 1 Z9 1 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 SEP-OCT PY 2016 VL 3 IS 5 DI 10.1523/ENEURO.0139-16.2016 PG 18 WC Neurosciences SC Neurosciences & Neurology GA EH7CL UT WOS:000391930400016 ER PT J AU Lin, A Maniscalco, B He, BJ AF Lin, Amy Maniscalco, Brian He, Biyu J. TI Scale-Free Neural and Physiological Dynamics in Naturalistic Stimuli Processing SO ENEURO LA English DT Article DE alpha oscillations; arrhythmic brain activity; heart rate variability; natural stimuli; scale-free dynamics; slow cortical potentials ID RANGE TEMPORAL CORRELATIONS; FREE BRAIN ACTIVITY; NEURONAL OSCILLATIONS; THETA-OSCILLATIONS; 1/F NOISE; NETWORKS; BEHAVIOR; PREDICT; ALPHA; EEG AB Neural activity recorded at multiple spatiotemporal scales is dominated by arrhythmic fluctuations without a characteristic temporal periodicity. Such activity often exhibits a 1/f-type power spectrum, in which power falls off with increasing frequency following a power-law function: P(f) proportional to 1/f(beta), which is indicative of scale-free dynamics. Two extensively studied forms of scale-free neural dynamics in the human brain are slow cortical potentials (SCPs)-the low-frequency (<5 Hz) component of brain field potentials-and the amplitude fluctuations of alpha-oscillations, both of which have been shown to carry important functional roles. In addition, scale-free dynamics characterize normal human physiology such as heartbeat dynamics. However, the exact relationships among these scale-free neural and physiological dynamics remain unclear. We recorded simultaneous magnetoencephalography and electrocardiography in healthy subjects in the resting state and while performing a discrimination task on scale-free dynamical auditory stimuli that followed different scale-free statistics. We observed that long-range temporal correlation (captured by the power-law exponent beta) in SCPs positively correlated with that of heartbeat dynamics across time within an individual and negatively correlated with that of alpha-amplitude fluctuations across individuals. In addition, across individuals, long-range temporal correlation of both SCP and alpha-oscillation amplitude predicted subjects' discrimination performance in the auditory task, albeit through antagonistic relationships. These findings reveal interrelations among different scale-free neural and physiological dynamics and initial evidence for the involvement of scale-free neural dynamics in the processing of natural stimuli, which often exhibit scale-free dynamics. C1 [Lin, Amy; Maniscalco, Brian; He, Biyu J.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Lin, Amy] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA. [Maniscalco, Brian; He, Biyu J.] NYU, Langone Med Ctr, Neurosci Inst, New York, NY 10016 USA. [He, Biyu J.] NYU, Langone Med Ctr, Dept Neurol, New York, NY 10016 USA. [He, Biyu J.] NYU, Langone Med Ctr, Dept Neurosci, New York, NY 10016 USA. [He, Biyu J.] NYU, Langone Med Ctr, Dept Physiol, New York, NY 10016 USA. RP He, BJ (reprint author), 550 1st Ave,MSB 460, New York, NY 10016 USA. EM biyu.jade.he@gmail.com OI He, Biyu/0000-0003-1549-1351 FU Intramural Research Program of the National Institutes of Health/National Institute of Neurological Disorders and Stroke; Leon Levy Foundation FX This research was supported by the Intramural Research Program of the National Institutes of Health/National Institute of Neurological Disorders and Stroke. B.J.H. also acknowledges support by Leon Levy Foundation. NR 45 TC 0 Z9 0 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 SEP-OCT PY 2016 VL 3 IS 5 DI 10.1523/ENEURO.0191-16.2016 PG 13 WC Neurosciences SC Neurosciences & Neurology GA EH7CL UT WOS:000391930400027 ER PT J AU Antropova, IP Yushkov, BG Kobrinsky, E Varaksin, AN AF Antropova, Irina P. Yushkov, Boris G. Kobrinsky, Evgeny Varaksin, Anatoliy N. TI Soluble Thrombomodulin and Major Orthopedic Surgery SO INTERNATIONAL JOURNAL OF BIOMEDICINE LA English DT Article DE thrombomodulin; coagulation; bleeding; total hip and knee replacement ID PLASMA THROMBOMODULIN; VENOUS THROMBOSIS; PROTEIN-C; TOTAL HIP; REPLACEMENT; PREVENTION; DISORDER; MUTATION; MICE AB Background: A high level of soluble thrombomodulin (sTM) is associated with a lower risk of thrombosis but can cause severe bleeding after operations. Deep vein thrombosis (DVT) and blood loss are serious threats after orthopedic surgery. The aim of our pilot study was to evaluate the effect of the preoperative level of sTM on coagulation and inflammation as well as the blood loss and the development of symptomatic DVT after total large joint replacement. Methods and Results: In all patients (n=50) who underwent total hip or knee replacement, sTM, PrC, D-dimer, vWF, CRP, and platelets were determined before and after the operation. According to the preoperative sTM level, patients were divided into 2 groups: the thrombomodulin low (TML) group (n=25) and thrombomodulin high (TMH) group (n=25). The concentration of sTM was 4.4 [3.4, 4.7] ng/ml in the TML-group and 8.7[7.3, 10.6] ng/ml in the TMH-group. After surgery, D-dimer, vWF, platelet count and CRP were higher and total blood loss was lower in the TML group. In the TML-group, a symptomatic DVT was detected in 3(12%) patients; in the TMH-group, a symptomatic DVT was identified only in 1(4%) case. Conclusion: These findings support the important role of sTM in coagulation, inflammation, bleeding, and presumably in venous thrombosis after major orthopedic surgery. C1 [Antropova, Irina P.] Ural State Med Univ, Ekaterinburg, Russia. [Antropova, Irina P.] Ural Inst Traumatol & Orthoped, Ekaterinburg, Russia. [Yushkov, Boris G.] RAS, Urals Branch, Inst Immunol & Physiol, Ekaterinburg, Russia. [Yushkov, Boris G.] Ural Fed Univ, Ekaterinburg, Russia. [Kobrinsky, Evgeny] NIA, NIH, Baltimore, MD 21224 USA. [Varaksin, Anatoliy N.] RAS, Urals Branch, Inst Ind Ecol, Ekaterinburg, Russia. RP Antropova, IP (reprint author), Ural State Med Univ, Ural Inst Traumatol & Orthoped, Ekaterinburg, Russia. EM aip.hemolab@mail.ru FU research program of the Russian Federation [215063040014]; Intramural research Program of the NIH, National Institute on Aging (USA) FX This study was supported by the research program of the Russian Federation No 215063040014 and in part by the Intramural research Program of the NIH, National Institute on Aging (USA). NR 22 TC 0 Z9 0 U1 0 U2 0 PU INT MEDICAL RESEARCH & DEVELOPMENT CORP PI NEW YORK PA 6308 12TH AVE, NEW YORK, NY 11219 USA SN 2158-0510 EI 2158-0529 J9 INT J BIOMED JI Int. J. Biomed. PD SEP PY 2016 VL 6 IS 3 BP 213 EP 217 DI 10.21103/Article6(3)_OA11 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EG6HW UT WOS:000391146500012 ER PT J AU Kumari, R John, T AF Kumari, Rajesh John, Tom TI BIOCIDAL EFFICACY OF SYNTHETIC COPOLYESTERS HAVING CHALCONE MOIETY SO INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES AND RESEARCH LA English DT Article DE Polycondensation; Copolyesters; Antibacterial; Antifungal ID DERIVATIVES; INHIBITORS; ALPHA AB Two chalcone diols (2E)-1-(4-hydroxyphenyl)-3(4-hydroxy, 3-ethoxy phenyl) prop-en-1-one and (2E)-1-(4-hydroxy-3-methoxy phenyl)-3(4-hydroxy, 3-ethoxy phenyl) prop-en-1-one were synthesized by acid catalyzed ClaisenSchmidt reaction. The synthesized chalcones were made to undergo polymerization using three aliphatic dichlorides namely glutaryl, succinyl and oxalyl chlorides. The polymers were random copolyesters and characterized by solubility and viscosity measurement. The structure of the copolyester was established by FTIR, H-1-NMR and C-13-NMR. The biocidal efficacy was done by Disc diffusion method and found to be nominal against the standards used. Thus these copolyesters may be considered as drug carriers. C1 [Kumari, Rajesh] Shiv Shakti Ayurved Coll, Dept Dravyaguna Vigyan, Mansa, Punjab, India. [John, Tom] NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. RP John, T (reprint author), NIEHS, Neuropharmacol Sect, POB 12233, Res Triangle Pk, NC 27709 USA. EM tom0318@outlook.com NR 20 TC 0 Z9 0 U1 0 U2 0 PU INT JOURNAL PHARMACEUTICAL SCIENCES & RESEARCH PI HARYANA PA 1117, SECTOR 12 A, PANCHKULA, HARYANA, 00000, INDIA SN 0975-8232 J9 INT J PHARM SCI RES JI Int. J. Pharm.l Sci. Res. PD SEP PY 2016 VL 7 IS 9 BP 3611 EP 3616 DI 10.13040/IJPSR.0975-8232.7(9).3611-16 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EG6YL UT WOS:000391192100007 ER PT J AU Rosenkrantz, AB Ginocchio, LA Cornfeld, D Froemming, AT Gupta, RT Turkbey, B Westphalen, AC Babb, JS Margolis, DJ AF Rosenkrantz, Andrew B. Ginocchio, Luke A. Cornfeld, Daniel Froemming, Adam T. Gupta, Rajan T. Turkbey, Baris Westphalen, Antonio C. Babb, James S. Margolis, Daniel J. TI Interobserver Reproducibility of the PI-RADS Version 2 Lexicon: A Multicenter Study of Six Experienced Prostate Radiologists SO RADIOLOGY LA English DT Article ID DATA SYSTEM; MULTIPARAMETRIC MRI; SCORING SYSTEMS; IMAGE QUALITY; AGREEMENT; BIOPSY; FUSION; ULTRASOUND; PARADOXES; IMPACT AB Purpose: To determine the interobserver reproducibility of the Prostate Imaging Reporting and Data System (PI-RADS) version 2 lexicon. Materials and Methods: This retrospective HIPAA-compliant study was institutional review board-approved. Six radiologists from six separate institutions, all experienced in prostate magnetic resonance (MR) imaging, assessed prostate MR imaging examinations performed at a single center by using the PI-RADS lexicon. Readers were provided screen captures that denoted the location of one specific lesion per case. Analysis entailed two sessions (40 and 80 examinations per session) and an intersession training period for individualized feedback and group discussion. Percent agreement (fraction of pairwise reader combinations with concordant readings) was compared between sessions. k coefficients were computed. Results: No substantial difference in interobserver agreement was observed between sessions, and the sessions were subsequently pooled. Agreement for PI-RADS score of 4 or greater was 0.593 in peripheral zone (PZ) and 0.509 in transition zone (TZ). In PZ, reproducibility was moderate to substantial for features related to diffusion-weighted imaging (k = 0.535-0.619); fair to moderate for features related to dynamic contrast material-enhanced (DCE) imaging (k = 0.266-0.439); and fair for definite extraprostatic extension on T2-weighted images (k = 0.289). In TZ, reproducibility for features related to lesion texture and margins on T2-weighted images ranged from 0.136 (moderately hypointense) to 0.529 (encapsulation). Among 63 lesions that underwent targeted biopsy, classification as PI-RADS score of 4 or greater by a majority of readers yielded tumor with a Gleason score of 3+4 or greater in 45.9% (17 of 37), without missing any tumor with a Gleason score of 3+4 or greater. Conclusion: Experienced radiologists achieved moderate reproducibility for PI-RADS version 2, and neither required nor benefitted from a training session. Agreement tended to be better in PZ than TZ, although was weak for DCE in PZ. The findings may help guide future PI-RADS lexicon updates. (C) RSNA, 2016 C1 [Rosenkrantz, Andrew B.; Ginocchio, Luke A.; Babb, James S.] NYU, Langone Med Ctr, Dept Radiol, Sch Med, 660 1st Ave,Third Floor, New York, NY 10016 USA. [Cornfeld, Daniel] Yale Sch Med, Dept Radiol, New Haven, CT USA. [Froemming, Adam T.] Mayo Clin, Dept Radiol, Rochester, MN USA. [Gupta, Rajan T.] Duke Univ, Med Ctr, Dept Radiol, Duke Canc Inst, Durham, NC 27710 USA. [Turkbey, Baris] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Westphalen, Antonio C.] Univ Calif San Francisco, Dept Radiol, San Francisco, CA USA. [Westphalen, Antonio C.] Univ Calif San Francisco, Dept Biomed Imaging, San Francisco, CA USA. [Westphalen, Antonio C.] Univ Calif San Francisco, Dept Urol, San Francisco, CA USA. [Margolis, Daniel J.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Radiol, Los Angeles, CA 90095 USA. RP Rosenkrantz, AB (reprint author), NYU, Langone Med Ctr, Dept Radiol, Sch Med, 660 1st Ave,Third Floor, New York, NY 10016 USA. EM Andrew.Rosenkrantz@nyumc.org RI Gupta, Rajan/M-1571-2015 OI Gupta, Rajan/0000-0002-2984-5010 FU Siemens Medical Systems; 3D Biopsy FX A.B.R. disclosed no relevant relationships. L.A.G. disclosed no relevant relationships. D.C. disclosed no relevant relationships. A.T.F. disclosed no relevant relationships. R.T.G. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: disclosed a consultancy for Invivo. Other relationships: disclosed no relevant relationships. B.T. disclosed no relevant relationships. A.C.W. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: disclosed money paid by 3D Biopsy for membership on a scientific advisory board. Other relationships: disclosed no relevant relationships. J.S.B. disclosed no relevant relationships. D.J.M. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: disclosed an institutional grant without salary support from Siemens Medical Systems. Other relationships: disclosed no relevant relationships. NR 37 TC 9 Z9 9 U1 1 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD SEP PY 2016 VL 280 IS 3 BP 793 EP 804 DI 10.1148/radiol.2016152542 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EG8MM UT WOS:000391311200016 PM 27035179 ER PT J AU Mumford, SL Legro, RS Diamond, MP Coutifaris, C Steiner, AZ Schlaff, WD Alvero, R Christman, GM Casson, PR Huang, H Santoro, N Eisenberg, E Zhang, HP Cedars, MI AF Mumford, Sunni L. Legro, Richard S. Diamond, Michael P. Coutifaris, Christos Steiner, Anne Z. Schlaff, William D. Alvero, Ruben Christman, Gregory M. Casson, Peter R. Huang, Hao Santoro, Nanette Eisenberg, Esther Zhang, Heping Cedars, Marcelle I. TI Baseline AMH Level Associated With Ovulation Following Ovulation Induction in Women With Polycystic Ovary Syndrome SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ANTI-MULLERIAN HORMONE; ANTRAL FOLLICLE COUNT; ANTIMULLERIAN HORMONE; STIMULATING-HORMONE; MOUSE OVARY; ANTAGONIST PROTOCOL; PREDICTIVE-VALUE; ASSAY; DEFINITION; DIAGNOSIS AB Context: Anti-Mullerian hormone (AMH) reduces aromatase activity and sensitivity of follicles to FSH stimulation. Therefore, elevated serum AMH may indicate a higher threshold for response to ovulation induction in women with polycystic ovary syndrome (PCOS). Objective: This study sought to determine the association between AMH levels and ovulatory response to treatment among the women enrolled into the Pregnancy in PCOS II (PPCOS II) trial. Design and setting: This was a secondary analysis of data from a randomized clinical trial in academic health centers throughout the United States Participants: A total of 748 women age 18-40 years, with PCOS and measured AMH levels at baseline, were included in this study. Main Outcome Measures: Couples were followed for up to five treatment cycles to determine ovulation (midluteal serum progesterone >5 ng/mL) and the dose required to achieve ovulation. Results: A lower mean AMH and AMH per follicle was observed among women who ovulated compared with women who never achieved ovulation during the study (geometric mean AMH, 5.54 vs 7.35 ng/mL; P = .0001; geometric mean AMH per follicle, 0.14 vs 0.18; P = .01) after adjustment for age, body mass index, T, and insulin level. As AMH levels increased, the dose of ovulation induction medication needed to achieve ovulation also increased. No associations were observed between antral follicle count and ovulation. Conclusions: These results suggest that high serum AMH is associated with a reduced response to ovulation induction among women with PCOS. Women with higher AMH levels may require higher doses of medication to achieve ovulation. C1 [Mumford, Sunni L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Epidemiol Branch, Rockville, MD USA. [Legro, Richard S.] Penn State Univ, Dept Obstet & Gynecol, Hershey, PA 17033 USA. [Diamond, Michael P.] Augusta Univ, Dept Obstet & Gynecol, Augusta, GA USA. [Coutifaris, Christos] Univ Penn, Sch Med, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Steiner, Anne Z.] Univ N Carolina, Dept Obstet & Gynecol, Chapel Hill, NC USA. [Alvero, Ruben; Santoro, Nanette] Univ Colorado Anschutz Med Campus, Dept Obstet & Gynecol, Aurora, CO USA. [Christman, Gregory M.] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Casson, Peter R.] Univ Vermont, Dept Obstet & Gynecol, Burlington, VT USA. [Huang, Hao; Zhang, Heping] Yale Univ, Sch Publ Hlth, Dept Biostat, New Haven, CT USA. Yale Univ, Sch Publ Hlth, Dept Biostat, Fertil & Infertil Branch, New Haven, CT USA. [Eisenberg, Esther] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Fertil & Infertil Branch, Rockville, MD USA. [Cedars, Marcelle I.] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, 1635 Div St,Suite 601, San Francisco, CA 94115 USA. RP Cedars, MI (reprint author), Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, 1635 Div St,Suite 601, San Francisco, CA 94115 USA. EM cedarsm@obgyn.ucsf.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institutes of Health (NIH), Bethesda, MD; NICHD [U10 HD27049, U10 HD38992, U10HD055925, U10 HD39005, U10 HD38998, U10 HD055936, U10 HD055942, U10 HD055944, U54-HD29834]; National Center for Research Resources; National Center for Advancing Translational Sciences through an NIH [UL1 TR000127] FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institutes of Health (NIH), Bethesda, MD; and by grants from NICHD (U10 HD27049, to C.C.; U10 HD38992, to R.S.L.; U10HD055925, to H.Z.; U10 HD39005, to M.P.D.; U10 HD38998, to W.D.S.; U10 HD055936, to G.M.C.; U10 HD055942, to C.C.; U10 HD055944, to P.R.C.; and U54-HD29834, to the University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core of the Specialized Cooperative Centers Program in Reproduction and Infertility Research); and by the National Center for Research Resources and the National Center for Advancing Translational Sciences through an NIH grant (UL1 TR000127) to Pennsylvania State University. NR 64 TC 1 Z9 1 U1 1 U2 1 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD SEP PY 2016 VL 101 IS 9 BP 3288 EP 3296 DI 10.1210/jc.2016-1340 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG2CB UT WOS:000390849100012 PM 27228369 ER PT J AU Liu-Chittenden, Y Patel, D Gaskins, K Giordano, TJ Assie, G Bertherat, J Kebebew, E AF Liu-Chittenden, Yi Patel, Dhaval Gaskins, Kelli Giordano, Thomas J. Assie, Guillaume Bertherat, Jerome Kebebew, Electron TI Serum RARRES2 Is a Prognostic Marker in Patients With Adrenocortical Carcinoma SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID DENDRITIC CELLS; GASTRIC-CANCER; CHEMERIN; EXPRESSION; MANAGEMENT; TUMORS; CLASSIFICATION; MALIGNANCY; ADIPOKINE; SURVIVAL AB Context: Retinoic acid receptor responder protein 2 (RARRES2) is a small secreted protein involved in multiple cancers, including adrenocortical carcinoma (ACC). However, discordant tumor and serum RARRES2 levels have been reported in various cancers. The etiology of this discordance is unknown and has not been studied in pair-matched tumor and serum samples. Objective: To determine tissue and serum RARRES2 levels in patients with adrenocortical neoplasm and to elucidate the prognostic implications of RARRES2 levels. Design, Settings, and Patients: Tissue and serum RARRES2 levels were analyzed. A pair-matched analysis was performed to examine tissue and serum RARRES2 from 51 patients with benign adrenocortical tumors and 18 patients with ACC. Overall survival was analyzed based on RARRES2 expression. A mouse xenograft model was used to determine the source of serum RARRES2. Results: Patients with ACC had decreased tumor RARRES2 gene expression (P = .0001) and increased serum RARRES2 levels (P = .005) as compared with patients with benign adrenocortical tumors. Higher serum RARRES2 levels were associated with improved overall survival (P = .0227). A mouse xenograft model demonstrated that higher tissue RARRES2 expression was associated with higher RARRES2 secretion in the serum and that there was an intrinsic mechanism in maintaining serum RARRES2 homeostasis. Conclusions: Serum and tissue RARRES2 expression levels are paradoxical in patients with ACC. The elevated RARRES2 in patient serum is unlikely to be secreted from tumor cells. Serum RARRES2 may be used as a novel prognostic marker for ACC. C1 [Liu-Chittenden, Yi; Patel, Dhaval; Gaskins, Kelli; Kebebew, Electron] NCI, NIH, Endocrine Oncol Branch, Bethesda, MD 20892 USA. [Giordano, Thomas J.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Assie, Guillaume; Bertherat, Jerome] Descartes Univ, CNRS, Inserm Unit 1016, UMR 8104, F-75014 Paris, France. [Assie, Guillaume; Bertherat, Jerome] Hosp Cochin, AP HP, Reference Ctr Rare Adrenal Dis, Dept Endocrinol, F-75014 Paris, France. RP Kebebew, E (reprint author), NCI, NIH, Endocrine Oncol Branch, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov OI Patel, Dhaval/0000-0002-5744-568X FU Center for Cancer Research, National Cancer Institute, National Institutes of Health [1ZIABC01127506] FX This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (1ZIABC01127506). NR 32 TC 0 Z9 0 U1 0 U2 0 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD SEP PY 2016 VL 101 IS 9 BP 3345 EP 3352 DI 10.1210/jc.2016-1781 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG2CB UT WOS:000390849100018 PM 27336360 ER PT J AU Gourgari, E Lodish, M Keil, M Sinaii, N Turkbey, E Lyssikatos, C Nesterova, M Sierra, M Xekouki, P Khurana, D Ten, S Dobs, A Stratakis, CA AF Gourgari, E. Lodish, M. Keil, M. Sinaii, N. Turkbey, E. Lyssikatos, C. Nesterova, M. Sierra, M. Xekouki, P. Khurana, D. Ten, S. Dobs, A. Stratakis, C. A. TI Bilateral Adrenal Hyperplasia as a Possible Mechanism for Hyperandrogenism in Women With Polycystic Ovary Syndrome SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID NODULAR ADRENOCORTICAL-DISEASE; DEHYDROEPIANDROSTERONE-SULFATE LEVELS; DEXAMETHASONE-SUPPRESSION TEST; ANDROGEN EXCESS; GLUCOCORTICOID-RECEPTOR; CORTISOL SECRETION; DIAGNOSIS; AXIS; CATHETERIZATION; OVERPRODUCTION AB Context: Androgen excess may be adrenal and/or ovarian in origin; we hypothesized that a subgroup of patients with polycystic ovarian syndrome (PCOS) may have some degree of abnormal adrenocortical function. Objective: The objective of the study was to evaluate the pituitary adrenal axis with an oral lowand high-dose dexamethasone-suppression test (Liddle's test) in women with PCOS. Design: This was a case-control study. Setting: The study was conducted at the National Institutes of Health Clinical Center. Participants: A total of 38 women with PCOS and 20 healthy volunteers (HV) aged 16-29 years participated in the study. Main Outcome Measures: Urinary free cortisol (UFC) and 17-hydroxysteroids (17OHS) before and after low-and high-dose dexamethasone and assessment of adrenal volume by computed tomography scan were measured. Results: Twenty-four-hour urinary 17OHS and UFC were measured during day 1 to day 6 of the Liddle's test. Baseline UFC levels were not different between PCOS and HVs; on the day after the completion of high-dose dexamethasone administration (d 6), UFC was higher in the PCOS group (2.0 +/- 0.7 mu g/m(2).d) than the HV group(1.5 +/- 0.5) (P = .038). On day 5,17OHS and UFC were negatively correlated with adrenal volumes(left side, r(p) = -0.47, P = .009, and r(p) = -0.61, P = .001, respectively). PCOS patients above the 75th percentile for UFC and/or 17OHS after high-dose dexamethasone (n = 15) had a significantly smaller total adrenal volume (6.9 +/- 1.9 cm(3) vs 9.2 +/- 1.8 cm(3), P = .003) when compared with the remaining PCOS patients (n = 22), but they did not have worse insulin resistance or hyperandrogenism. Conclusions: In a subset of young women with PCOS, we detected a pattern of glucocorticoid secretion that mimicked that of patients with micronodular adrenocortical hyperplasia: they had smaller adrenal volumes and higher steroid hormone secretion after dexamethasone compared with the group of PCOS with appropriate response to dexamethasone. C1 [Gourgari, E.; Lodish, M.; Keil, M.; Lyssikatos, C.; Nesterova, M.; Sierra, M.; Xekouki, P.; Stratakis, C. A.] NIH, Sect Endocrinol & Genet, Bethesda, MD 20892 USA. NIH, Pediat Endocrinol Inter Inst Training Program, Bethesda, MD 20892 USA. [Turkbey, E.] NIH, Ctr Clin, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Radiol, Bethesda, MD 20892 USA. [Gourgari, E.] Georgetown Univ, Med Ctr, Div Pediat Endocrinol, Washington, DC 20007 USA. [Sinaii, N.] NIH, Ctr Clin, Biostat & Clin Epidemiol Serv, Bldg 10, Bethesda, MD 20892 USA. [Khurana, D.; Ten, S.] CUNY, Infants & Childrens Hosp Brooklyn Maimonides & Ch, Div Pediat Endocrinol, Brooklyn, NY 11219 USA. [Dobs, A.] Johns Hopkins Med Univ, Sch Med, Dept Endocrinol, Baltimore, MD 21205 USA. RP Gourgari, E (reprint author), Georgetown Univ Hosp, Div Pediat Endocrinol, 4200 Wisconsin Ave,NW,Fourth Floor, Washington, DC 20016 USA. EM evgenia.gourgari@gunet.georgetown.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland; National Institutes of Health (NIH) Clinical Center, Bethesda, Maryland; Bench to Bedside Award Program of the NIH Clinical Research Center, Bethesda, Maryland; Office of Women's Health at the NIH, Bethesda, Maryland FX This work was supported by the Intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health (NIH) Clinical Center, the Bench to Bedside Award Program of the NIH Clinical Research Center, and the Office of Women's Health, also at the NIH, all in Bethesda, Maryland (2010). NR 30 TC 0 Z9 0 U1 0 U2 0 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD SEP PY 2016 VL 101 IS 9 BP 3353 EP 3360 DI 10.1210/jc.2015-4019 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG2CB UT WOS:000390849100019 PM 27336356 ER PT J AU Harmon, QE Umbach, DM Baird, DD AF Harmon, Quaker E. Umbach, David M. Baird, Donna D. TI Use of Estrogen-Containing Contraception Is Associated With Increased Concentrations of 25-Hydroxy Vitamin D SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID POSTMENOPAUSAL WOMEN; HORMONAL CONTRACEPTIVES; ORAL-CONTRACEPTIVES; BINDING-PROTEIN; D INSUFFICIENCY; D METABOLITES; SERUM; CALCIUM; VARIABILITY; POPULATION AB Context: Small studies suggest exogenous estrogen may improve vitamin D status, but the etiology is unclear because women who use hormones may make lifestyle choices that differentially affect vitamin D status. Objective: Our objective was to investigate the association between use of hormonal contraception and 25-hydroxy-vitamin D (25(OH) D). Design: We used linear regression modeling of cross-sectional data to estimate percent change in season-adjusted serum 25(OH) D with estrogen use after adjustment for other factors. Setting: At the enrollment clinic visit (2010-2012) into a cohort study of uterine fibroids, each subject provided a blood sample, had anthropomorphic variables and skin reflectance measured, and answered questionnaires on demographics, dietary and supplement intake, contraceptive use, reproductive and medical history, and behaviors. Participants: A total of 1662 African American women, community volunteers, 23-34 years old, living in the Detroit, Michigan, area were included. Interventions: None. Main Outcomes and Measures: Serum 25(OH) D was measured. Results: Serum 25(OH) D concentrations were low (70% <20 ng/ml). Current use of an estrogen-containing contraceptive was associated with a 20% (95% confidence interval: 14-27) increase in 25(OH) D after adjustment. There was no increase in 25(OH) D among participants who had used estrogen in the past, but were not current users, indicating that results were unlikely to be due to unmeasured confounding by factors related to contraceptive choice. Conclusions: The increase in 25(OH) D with use of estrogen-containing contraceptives raise mechanistic questions regarding the biological pathways involved, and highlights the need for studies that examine possible endogenous estrogen effects on vitamin D. C1 [Harmon, Quaker E.; Baird, Donna D.] NIEHS, Epidemiol Branch, POB 12233,MD A3-05,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. [Umbach, David M.] NIEHS, Biostat & Computat Biol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. RP Harmon, QE (reprint author), NIEHS, Epidemiol Branch, POB 12233,MD A3-05,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM quaker.harmon@nih.gov RI Baird, Donna/D-5214-2017 OI Baird, Donna/0000-0002-5544-2653 FU NIH, National Institute of Environmental Health Sciences FX This work was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 38 TC 1 Z9 1 U1 1 U2 1 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD SEP PY 2016 VL 101 IS 9 BP 3370 EP 3377 DI 10.1210/jc.2016-1658 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG2CB UT WOS:000390849100021 PM 27490916 ER PT J AU Fratzl-Zelman, N Barnes, AM Weis, M Carter, E Hefferan, TE Perino, G Chang, WZ Smith, PA Roschger, P Klaushofer, K Glorieux, FH Eyre, DR Raggio, C Rauch, F Marini, JC AF Fratzl-Zelman, Nadja Barnes, Aileen M. Weis, MaryAnn Carter, Erin Hefferan, Theresa E. Perino, Giorgio Chang, Weizhong Smith, Peter A. Roschger, Paul Klaushofer, Klaus Glorieux, Francis H. Eyre, David R. Raggio, Cathleen Rauch, Frank Marini, Joan C. TI Non-Lethal Type VIII Osteogenesis Imperfecta Has Elevated Bone Matrix Mineralization SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID COLLAGEN PROLYL 3-HYDROXYLATION; INTRAVENOUS PAMIDRONATE; DENSITY DISTRIBUTION; BISPHOSPHONATE TREATMENT; HEALTHY-CHILDREN; GROWING CHILDREN; NORMATIVE DATA; MUTATIONS; CRTAP; HISTOMORPHOMETRY AB Context: Type VIII osteogenesis imperfecta (OI; OMIM601915) is a recessive form of lethal or severe OI caused by null mutations in P3H1, which encodes prolyl 3-hydroxylase 1. Objectives: Clinical and bone material description of non-lethal type VIII OI. Design: Natural history study of type VIII OI. Setting: Pediatric academic research centers. Patients: Five patients with non-lethal type VIII OI, and one patient with lethal type VIII OI. Interventions: None. Main Outcome Measures: Clinical examinations included bone mineral density, radiographs, and serum and urinary metabolites. Bone biopsy samples were analyzed for histomorphometry and bone mineral density distribution by quantitative backscattered electron imaging microscopy. Collagen biochemistry was examined by mass spectrometry, and collagen fibrils were examined by transmission electron microscopy. Results: Type VIII OI patients have extreme growth deficiency, an L1-L4 areal bone mineral density Z-score of -5 to -6, and normal bone formation markers. Collagen from bone and skin tissue and cultured osteoblasts and fibroblasts have nearly absent 3-hydroxylation (1-4%). Collagen fibrils showed abnormal diameters and irregular borders. Bone histomorphometry revealed decreased cortical width and very thin trabeculae with patches of increased osteoid, although the overall osteoid surface was normal. Quantitative backscattered electron imaging showed increased matrix mineralization of cortical and trabecular bone, typical of other OI types. However, the proportion of bone with low mineralization was increased in type VIII OI bone, compared to type VII OI. Conclusions: P3H1 is the unique enzyme responsible for collagen 3-hydroxylation in skin and bone. Bone from non-lethal type VIII OI children is similar to type VII, especially bone matrix hypermineralization, but it has distinctive features including extremely thin trabeculae, focal osteoid accumulation, and an increased proportion of low mineralized bone. C1 [Fratzl-Zelman, Nadja; Roschger, Paul; Klaushofer, Klaus] Hanusch Hosp Wiener Gebietskrankenkasse, Ludwig Boltzmann Inst Osteol, A-1140 Vienna, Austria. [Fratzl-Zelman, Nadja; Roschger, Paul; Klaushofer, Klaus] Hanusch Hosp, Dept Med 1, Allgemeine Unfallversicherungsanstalt Trauma Ctr, A-1140 Vienna, Austria. [Barnes, Aileen M.; Chang, Weizhong; Marini, Joan C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Heritable Disorders Bone, NIH, Bethesda, MD 20892 USA. [Weis, MaryAnn; Eyre, David R.] Univ Washington, Orthopaed Res Labs, Seattle, WA 98195 USA. [Carter, Erin; Perino, Giorgio; Raggio, Cathleen] Hosp Special Surg, New York, NY 10021 USA. [Hefferan, Theresa E.] Mayo Clin, Coll Med, Dept Orthoped, Rochester, MN 55905 USA. [Smith, Peter A.] Shriners Hosp Children, Chicago, IL 60707 USA. [Glorieux, Francis H.; Rauch, Frank] Shriners Hosp Children, Montreal, PQ H4A 0A9, Canada. [Glorieux, Francis H.; Rauch, Frank] McGill Univ, Montreal, PQ H4A 0A9, Canada. [Chang, Weizhong] OpGen Inc, Gaithersburg, MD 20878 USA. RP Marini, JC (reprint author), NICHD, SHDB, NIH, Bldg 10,Room 10D39,9000 Rockville Pike, Bethesda, MD 20892 USA. EM oidoc@helix.nih.gov FU Allgemeine Unfallversicherungsanstalt (Austrian workers compensation board); Wiener Gebietskrankenkasse (Viennese sickness insurance funds); National Institute of Arthritis and Musculoskeletal and Skin Diseases [AR037318]; Shriners of North America; National Institute of Child Health and Human Development; Chercheur-Boursier Clinicien program of the Fonds de Recherche du Quebec-Sante FX This study was supported by the Allgemeine Unfallversicherungsanstalt (research funds of the Austrian workers compensation board) and the Wiener Gebietskrankenkasse (Viennese sickness insurance funds) (to N.F.-Z., P.R., K.K.), National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant AR037318 (to D.R.E.), the Shriners of North America (to P.A.S., F.R., and F.H.G.), and National Institute of Child Health and Human Development intramural funds (to J.C.M.). F.R. received support from the Chercheur-Boursier Clinicien program of the Fonds de Recherche du Quebec-Sante. NR 44 TC 1 Z9 1 U1 0 U2 0 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD SEP PY 2016 VL 101 IS 9 BP 3516 EP 3525 DI 10.1210/jc.2016-1334 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG2CB UT WOS:000390849100038 PM 27383115 ER PT J AU Cortes-Martins, H Matos, R Moura, S Almeida, L Ferreira, S Manita, C Santos, J Pinto, S Nunes, B Roquette, R Cardoso, C Brum, L Palminha, P AF Cortes-Martins, H. Matos, R. Moura, S. Almeida, L. Ferreira, S. Manita, C. Santos, J. Pinto, S. Nunes, B. Roquette, R. Cardoso, C. Brum, L. Palminha, P. TI Anti-HAV IgG seroprevalence in Lisbon region residents: Preliminary results from the National Serological Survey 2015-2016 SO JOURNAL OF CLINICAL VIROLOGY LA English DT Meeting Abstract CT 19th Annual Meeting of the European-Society-for-Clinical-Virology CY SEP 14-17, 2016 CL Lisbon, PORTUGAL SP European Soc Clin Virol C1 [Cortes-Martins, H.; Matos, R.; Moura, S.; Almeida, L.; Ferreira, S.; Manita, C.; Santos, J.; Palminha, P.] NIH, Dept Infect Dis, Bethesda, MD USA. [Pinto, S.; Nunes, B.; Roquette, R.] NIH, Dept Epidemiol, Bethesda, MD USA. [Cardoso, C.] Dr Joaquim Chaves Clin Lab, Lisbon, Portugal. [Brum, L.] Labco Grp, New Delhi, India. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1386-6532 EI 1873-5967 J9 J CLIN VIROL JI J. Clin. Virol. PD SEP PY 2016 VL 82 SU S MA 317 BP S79 EP S80 DI 10.1016/j.jcv.2016.08.158 PG 3 WC Virology SC Virology GA EF8NC UT WOS:000390584800158 ER PT J AU Chen, BH Marioni, RE Colicino, E Peters, MJ Ward-Caviness, CK Tsai, PC Roetker, NS Just, AC Demerath, EW Guan, WH Bressler, J Fornage, M Studenski, S Vandiver, AR Moore, AZ Tanaka, T Kiel, DP Liang, LM Vokonas, P Schwartz, J Lunetta, KL Murabito, JM Bandinelli, S Hernandez, DG Melzer, D Nalls, M Pilling, LC Price, TR Singleton, AB Gieger, C Holle, R Kretschmer, A Kronenberg, F Kunze, S Linseisen, J Meisinger, C Rathmann, W Waldenberger, M Visscher, PM Shah, S Wray, NR McRae, AF Franco, OH Hofman, A Uitterlinden, AG Absher, D Assimes, T Levine, ME Lu, AT Tsao, PS Hou, LF Manson, JE Carty, CL LaCroix, AZ Reiner, AP Spector, TD Feinberg, AP Levy, D Baccarelli, A van Meurs, J Bell, JT Peters, A Deary, IJ Pankow, JS Ferrucci, L Horvath, S AF Chen, Brian H. Marioni, Riccardo E. Colicino, Elena Peters, Marjolein J. Ward-Caviness, Cavin K. Tsai, Pei-Chien Roetker, Nicholas S. Just, Allan C. Demerath, Ellen W. Guan, Weihua Bressler, Jan Fornage, Myriam Studenski, Stephanie Vandiver, Amy R. Moore, Ann Zenobia Tanaka, Toshiko Kiel, Douglas P. Liang, Liming Vokonas, Pantel Schwartz, Joel Lunetta, Kathryn L. Murabito, Joanne M. Bandinelli, Stefania Hernandez, Dena G. Melzer, David Nalls, Michael Pilling, Luke C. Price, Timothy R. Singleton, Andrew B. Gieger, Christian Holle, Rolf Kretschmer, Anja Kronenberg, Florian Kunze, Sonja Linseisen, Jakob Meisinger, Christine Rathmann, Wolfgang Waldenberger, Melanie Visscher, Peter M. Shah, Sonia Wray, Naomi R. McRae, Allan F. Franco, Oscar H. Hofman, Albert Uitterlinden, Andre G. Absher, Devin Assimes, Themistocles Levine, Morgan E. Lu, Ake T. Tsao, Philip S. Hou, Lifang Manson, JoAnn E. Carty, Cara L. LaCroix, Andrea Z. Reiner, Alexander P. Spector, Tim D. Feinberg, Andrew P. Levy, Daniel Baccarelli, Andrea van Meurs, Joyce Bell, Jordana T. Peters, Annette Deary, Ian J. Pankow, James S. Ferrucci, Luigi Horvath, Steve TI DNA methylation-based measures of biological age: meta-analysis predicting time to death SO AGING-US LA English DT Article DE all-cause mortality; lifespan; epigenetics; epigenetic clock; DNA methylation; mortality ID ALL-CAUSE MORTALITY; EPIGENETIC CLOCK; DISEASE; BLOOD; COHORT; EPIDEMIOLOGY; CANCER; BRAIN; LIFE AB Estimates of biological age based on DNA methylation patterns, often referred to as "epigenetic age", "DNAm age", have been shown to be robust biomarkers of age in humans. We previously demonstrated that independent of chronological age, epigenetic age assessed in blood predicted all-cause mortality in four human cohorts. Here, we expanded our original observation to 13 different cohorts for a total sample size of 13,089 individuals, including three racial/ethnic groups. In addition, we examined whether incorporating information on blood cell composition into the epigenetic age metrics improves their predictive power for mortality. All considered measures of epigenetic age acceleration were predictive of mortality (p <= 8.2x10(-9)), independent of chronological age, even after adjusting for additional risk factors (p<5.4x10(-4)), and within the racial/ethnic groups that we examined (non-Hispanic whites, Hispanics, African Americans). Epigenetic age estimates that incorporated information on blood cell composition led to the smallest p-values for time to death (p=7.5x10(-43)). Overall, this study a) strengthens the evidence that epigenetic age predicts all-cause mortality above and beyond chronological age and traditional risk factors, and b) demonstrates that epigenetic age estimates that incorporate information on blood cell counts lead to highly significant associations with all-cause mortality. C1 [Chen, Brian H.; Studenski, Stephanie; Moore, Ann Zenobia; Tanaka, Toshiko; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Chen, Brian H.; Lunetta, Kathryn L.; Murabito, Joanne M.; Levy, Daniel] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Chen, Brian H.] NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Bethesda, MD 01702 USA. [Marioni, Riccardo E.; Visscher, Peter M.; Deary, Ian J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, 7 George Sq, Edinburgh EH8 9JZ, Midlothian, Scotland. [Marioni, Riccardo E.] Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Med Genet Sect, Edinburgh EH4 2XU, Midlothian, Scotland. [Marioni, Riccardo E.; Visscher, Peter M.; Shah, Sonia; Wray, Naomi R.; McRae, Allan F.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. [Colicino, Elena; Just, Allan C.; Baccarelli, Andrea] Columbia Univ, Mailman Sch Publ Hlth, Dept Environm Hlth Sci, Lab Environm Epigenet, New York, NY 10032 USA. [Colicino, Elena; Just, Allan C.; Baccarelli, Andrea] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, Lab Environm Epigenet, New York, NY 10032 USA. [Peters, Marjolein J.; Uitterlinden, Andre G.; van Meurs, Joyce] Erasmus Univ, Med Ctr, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands. [Ward-Caviness, Cavin K.; Gieger, Christian; Kretschmer, Anja; Kunze, Sonja; Linseisen, Jakob; Meisinger, Christine; Waldenberger, Melanie; Peters, Annette] Helmholtz Zentrum Munchen, Inst Epidemiol 2, D-85764 Neuherberg, Germany. [Tsai, Pei-Chien; Spector, Tim D.; Bell, Jordana T.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England. [Roetker, Nicholas S.; Demerath, Ellen W.; Pankow, James S.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA. [Guan, Weihua] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. [Bressler, Jan; Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Human Genet Ctr, Houston, TX 77030 USA. [Fornage, Myriam] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Vandiver, Amy R.; Feinberg, Andrew P.] Johns Hopkins Univ, Ctr Epigenet, Baltimore, MD 21205 USA. [Kiel, Douglas P.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Kiel, Douglas P.] Harvard Med Sch, Boston, MA USA. [Kiel, Douglas P.] Hebrew Senior Life, Inst Aging Res, Boston, MA 02215 USA. [Liang, Liming; Vokonas, Pantel; Schwartz, Joel; Hofman, Albert] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Liang, Liming] Harvard Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Lunetta, Kathryn L.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Sect Gen Internal Med, Boston, MA 02118 USA. [Bandinelli, Stefania] Usl Ctr Toscana, Geriatr Unit, Florence, Italy. [Hernandez, Dena G.; Nalls, Michael; Price, Timothy R.; Singleton, Andrew B.] NIA, Lab Neurogenet, Intramural Res Program, NIH, Bethesda, MD 20814 USA. [Melzer, David; Pilling, Luke C.] Univ Exeter, Sch Med, Epidemiol & Publ Hlth, Exeter EX2 5DW, Devon, England. [Gieger, Christian; Kretschmer, Anja; Kunze, Sonja; Waldenberger, Melanie] Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany. [Holle, Rolf] Helmholtz Zentrum Munchen, Inst Hlth Econ & Hlth Care Management, D-85764 Neuherberg, Germany. [Kronenberg, Florian] Med Univ Innsbruck, Dept Med Genet Mol & Clin Pharmacol, Div Genet Epidemiol, A-6020 Innsbruck, Austria. [Rathmann, Wolfgang] Heinrich Heine Univ, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Biometr & Epidemiol, D-40225 Dusseldorf, Germany. [Visscher, Peter M.; Shah, Sonia; McRae, Allan F.] Univ Queensland, Diamantina Inst, Brisbane, Qld, Australia. [Franco, Oscar H.; Hofman, Albert; Uitterlinden, Andre G.] Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3015 CN Rotterdam, Netherlands. [Absher, Devin] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA. [Assimes, Themistocles; Tsao, Philip S.] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. [Levine, Morgan E.; Lu, Ake T.; Horvath, Steve] Univ Calif Los Angeles, David Geffen Sch Med, Human Genet, Los Angeles, CA 90095 USA. [Tsao, Philip S.] VA Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USA. [Hou, Lifang] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Hou, Lifang] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Manson, JoAnn E.] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA. [Manson, JoAnn E.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. [Carty, Cara L.] George Washington Univ, Childrens Natl Med Ctr, Ctr Translat Sci, Washington, DC 20010 USA. [LaCroix, Andrea Z.] Univ Calif San Diego, Dept Family Med & Publ Hlth, La Jolla, CA 92093 USA. [Reiner, Alexander P.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Reiner, Alexander P.] Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98109 USA. [Feinberg, Andrew P.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Feinberg, Andrew P.] Johns Hopkins Univ, Sch Med, Dept Mol Biol Genet, Baltimore, MD 21205 USA. [Feinberg, Andrew P.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Feinberg, Andrew P.] Johns Hopkins Univ, Sch Med, Dept Biostat, Baltimore, MD 21205 USA. [Levy, Daniel] NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Bethesda, MD USA. [Baccarelli, Andrea] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Deary, Ian J.] Univ Edinburgh, Dept Psychol, 7 George Sq, Edinburgh EH8 9JZ, Midlothian, Scotland. [Horvath, Steve] Univ Calif Los Angeles, Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90095 USA. RP Horvath, S (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Human Genet, Los Angeles, CA 90095 USA.; Horvath, S (reprint author), Univ Calif Los Angeles, Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90095 USA. EM shorvath@mednet.ucla.edu RI Kronenberg, Florian/B-1736-2008; Shah, Sonia/N-7547-2013; OI Kronenberg, Florian/0000-0003-2229-1120; Shah, Sonia/0000-0001-5860-4526; Colicino, Elena/0000-0002-1875-8448; Assimes, Themistocles/0000-0003-2349-0009; Just, Allan/0000-0003-4312-5957; Peters, Annette/0000-0001-6645-0985 FU NIH/NIA [1U34AG051425-01]; Cooperative Studies Program/ERIC FX This work was supported by NIH/NIA 1U34AG051425-01 and by grants mentioned in the acknowledgement section. The United States Department of Veterans Affairs (VA) Normative Aging Study (NAS) is supported by the Cooperative Studies Program/ERIC and is a research component of the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), Boston Massachusetts. NR 37 TC 3 Z9 3 U1 4 U2 4 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD SEP PY 2016 VL 8 IS 9 BP 1844 EP 1865 DI 10.18632/aging.101020 PG 22 WC Cell Biology SC Cell Biology GA EF4OY UT WOS:000390311600006 PM 27690265 ER PT J AU Dizdaroglu, M Jacobs, AC Donley, N Calkins, MJ Jadhav, A Dorjsuren, D Maloney, D Simeonov, A Jaruga, P Coskun, E McCullough, AK Lloyd, RS AF Dizdaroglu, M. Jacobs, A. C. Donley, N. Calkins, M. J. Jadhav, A. Dorjsuren, D. Maloney, D. Simeonov, A. Jaruga, P. Coskun, E. McCullough, A. K. Lloyd, R. S. TI Inhibition of DNA repair proteins via small molecule compounds as potential drugs in cancer therapy SO FEBS JOURNAL LA English DT Meeting Abstract CT 41st FEBS Congress on Molecular and Systems Biology for a Better Life CY SEP 03-08, 2016 CL Kusadasi, TURKEY SP FEBS C1 [Dizdaroglu, M.; Jaruga, P.; Coskun, E.] NIST, Gaithersburg, MD 20899 USA. [Jacobs, A. C.; Donley, N.; Calkins, M. J.; McCullough, A. K.; Lloyd, R. S.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Jadhav, A.; Dorjsuren, D.; Maloney, D.; Simeonov, A.] NIH, 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 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD SEP PY 2016 VL 283 SU 1 SI SI MA S05.011002 BP 17 EP 17 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DW4MJ UT WOS:000383616900044 ER PT J AU Wilson, D AF Wilson, D. TI Repair mechanisms for endogenous DNA damage SO FEBS JOURNAL LA English DT Meeting Abstract CT 41st FEBS Congress on Molecular and Systems Biology for a Better Life CY SEP 03-08, 2016 CL Kusadasi, TURKEY SP FEBS C1 [Wilson, D.] NIA, NIH, Baltimore, MD 21224 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 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD SEP PY 2016 VL 283 SU 1 SI SI MA S05.011003 BP 17 EP 17 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DW4MJ UT WOS:000383616900042 ER PT J AU Subramanian, P Mendez, EF Becerra, SP AF Subramanian, Preeti Mendez, Emily F. Becerra, S. Patricia TI A Novel Inhibitor of 5-Lipoxygenase (5-LOX) Prevents Oxidative Stress-Induced Cell Death of Retinal Pigment Epithelium (RPE) Cells SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE 5-Lipoxygenase; RPE; oxidative stress; PNPLA2; LTB4 ID RECEPTOR PEDF-R; MACULAR DEGENERATION; FAMILY-MEMBERS; ARPE-19 CELLS; MOUSE MODEL; IDENTIFICATION; EXPRESSION; LIPASE; DAMAGE; PHOSPHOLIPASE AB PURPOSE. 5-Lipoxygenase (5-LOX) oxygenates arachidonic acid to form 5-hydroperoxyeicosatetraenoic acid, which is further converted into biologically detrimental leukotrienes, such as leukotriene B4 (LTB4). The RPE and retina express the PNPLA2 gene for pigment epithelium-derived factor receptor (PEDF-R), a lipase involved in cell survival. The purpose here was to investigate the role of PEDF-R on the 5-LOX pathway in oxidative stress of RPE. METHODS. Lipoxygenase activity assays were performed with soybean and potato lipoxygenase. Binding was evaluated by peptide-affinity chromatography and pull-down assays with PEDF-R-derived synthetic peptides or recombinant protein. Oxidative stress was induced in human ARPE-19 and primary pig RPE cells with indicated concentrations of H2O2/TNF-alpha. Reverse transcription-PCR of ALOX5 and PNPLA2 genes was performed. Cell viability and death rates were determined using respective biomarkers. Leukotriene B4 levels were measured by ELISA. RESULTS. Among five peptides spanning between positions Leu(159) and Met(325) of human PEDF-R polypeptide, only two overlapping peptides, E5b and P1, bound and inhibited lipoxygenase activity. Human recombinant 5-LOX bound specifically to peptide P1 and to His6/Xpress-tagged PEDF-R via ionic interactions. The two inhibitor peptides E5b and P1 promoted cell viability and decreased cell death of RPE cells undergoing oxidative stress. Oxidative stress decreased the levels of PNPLA2 transcripts with no effect on ALOX5 expression. Exogenous additions of P1 peptide or overexpression of the PNPLA2 gene decreased both LTB4 levels and death of RPE cells undergoing oxidative stress. CONCLUSIONS. A novel peptide region of PEDF-R inhibits 5-LOX, which intersects with RPE cell death pathways induced by oxidative stress. C1 [Subramanian, Preeti; Mendez, Emily F.; Becerra, S. Patricia] NEI, Sect Prot Struct & Funct, Lab Retinal Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Subramanian, P (reprint author), NEI, LRCMB, NIH, Bldg 6 Room 131F,6 Ctr Dr,MSC 0608, Bethesda, MD 20892 USA.; Becerra, SP (reprint author), NEI, LRCMB, NIH, Bldg 6 Room 134,6 Ctr Dr,MSC 0608, Bethesda, MD 20892 USA. EM subramanianp@nei.nih.gov; becerrap@nei.nih.gov FU Intramural Research Program of the National Institutes of Health, National Eye Institute FX Supported by the Intramural Research Program of the National Institutes of Health, National Eye Institute. NR 33 TC 0 Z9 0 U1 3 U2 3 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 11 BP 4581 EP 4588 DI 10.1167/iovs.15-19039 PG 8 WC Ophthalmology SC Ophthalmology GA EF2LP UT WOS:000390156400009 PM 27635633 ER PT J AU Luna, G Lewis, GP Linberg, KA Chang, B Hu, QR Munson, PJ Maminishkis, A Miller, SS Fisher, SK AF Luna, Gabriel Lewis, Geoffrey P. Linberg, Kenneth A. Chang, Bo Hu, Quiri Munson, Peter J. Maminishkis, Arvydas Miller, Sheldon S. Fisher, Steven K. TI Anatomical and Gene Expression Changes in the Retinal Pigmented Epithelium Atrophy 1 (rpea1) Mouse: A Potential Model of Serous Retinal Detachment SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE retinal pigment epithelium; cell adhesion; retinal detachment; photoreceptors; extracellular matrix ID PROTEIN-KINASE-C; PKC-THETA; INTESTINAL EPITHELIUM; MACULAR DEGENERATION; BARRIER PERMEABILITY; ENDOTHELIAL-CELLS; MATRIX; ADHESION; DISEASE; CHORIORETINOPATHY AB PURPOSE. The purpose of this study was to examine the rpea1 mouse whose retina spontaneously detaches from the underlying RPE as a potential model for studying the cellular effects of serous retinal detachment (SRD). METHODS. Optical coherence tomography (OCT) was performed immediately prior to euthanasia; retinal tissue was subsequently prepared for Western blotting, microarray analysis, immunocytochemistry, and light and electron microscopy (LM, EM). RESULTS. By postnatal day (P) 30, OCT, LM, and EM revealed the presence of small shallow detachments that increased in number and size over time. By P60 in regions of detachment, there was a dramatic loss of PNA binding around cones in the interphotoreceptor matrix and a concomitant increase in labeling of the outer nuclear layer and rod synaptic terminals. Retinal pigment epithelium wholemounts revealed a patchy loss in immunolabeling for both ezrin and aquaporin 1. Anti-ezrin labeling was lost from small regions of the RPE apical surface underlying detachments at P30. Labeling for tight-junction proteins provided a regular array of profiles outlining the periphery of RPE cells in wild-type tissue, however, this pattern was disrupted in the mutant as early as P30. Microarray analysis revealed a broad range of changes in genes involved in metabolism, signaling, cell polarity, and tight-junction organization. CONCLUSIONS. These data indicate changes in this mutant mouse that may provide clues to the underlying mechanisms of SRD in humans. Importantly, these changes include the production of multiple spontaneous detachments without the presence of a retinal tear or significant degeneration of outer segments, changes in the expression of proteins involved in adhesion and fluid transport, and a disrupted organization of RPE tight junctions that may contribute to the formation of focal detachments. C1 [Luna, Gabriel; Lewis, Geoffrey P.; Linberg, Kenneth A.; Hu, Quiri; Fisher, Steven K.] Univ Calif Santa Barbara, Neurosci Res Inst, Santa Barbara, CA 93106 USA. [Luna, Gabriel; Lewis, Geoffrey P.; Fisher, Steven K.] Univ Calif Santa Barbara, Ctr Bioimage Informat, Santa Barbara, CA 93106 USA. [Chang, Bo] Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. [Munson, Peter J.] NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. [Maminishkis, Arvydas; Miller, Sheldon S.] NEI, NIH, Bethesda, MD 20892 USA. [Fisher, Steven K.] Univ Calif Santa Barbara, Dept Mol Cellular & Dev Biol, Santa Barbara, CA 93106 USA. RP Fisher, SK (reprint author), Univ Calif Santa Barbara, Neurosci Res Inst, Santa Barbara, CA 93106 USA. EM fisher@lifesci.ucsb.edu FU Macula Vision Research Foundation; Santa Barbara Cottage Hospital; National Science Foundation [IIS-0808772, ITR-0331697] FX Supported by Macula Vision Research Foundation, Santa Barbara Cottage Hospital, National Science Foundation (IIS-0808772, ITR-0331697). NR 56 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2016 VL 57 IS 11 BP 4641 EP 4654 DI 10.1167/iovs.15-19044 PG 14 WC Ophthalmology SC Ophthalmology GA EF2LP UT WOS:000390156400016 PM 27603725 ER PT J AU Costa, DL Namasivayam, S Amaral, EP Arora, K Chao, A Mittereder, LR Maiga, M Boshoff, HI Barry, CE Goulding, CW Andrade, BB Sher, A AF Costa, Diego L. Namasivayam, Sivaranjani Amaral, Eduardo P. Arora, Kriti Chao, Alex Mittereder, Lara R. Maiga, Mamoudou Boshoff, Helena I. Barry, Clifton E., III Goulding, Celia W. Andrade, Bruno B. Sher, Alan TI Pharmacological Inhibition of Host Heme Oxygenase-1 Suppresses Mycobacterium tuberculosis Infection In Vivo by a Mechanism Dependent on T Lymphocytes SO MBIO LA English DT Article ID CARBON-MONOXIDE; MICE; INFLAMMATION; MACROPHAGES; EXPRESSION; RESISTANCE AB Heme oxygenase-1 (HO-1) is a stress response antioxidant enzyme which catalyzes the degradation of heme released during inflammation. HO-1 expression is upregulated in both experimental and human Mycobacterium tuberculosis infection, and in patients it is a biomarker of active disease. Whether the enzyme plays a protective versus pathogenic role in tuberculosis has been the subject of debate. To address this controversy, we administered tin protoporphyrin IX (SnPPIX), a well-characterized HO-1 enzymatic inhibitor, to mice during acute M. tuberculosis infection. These SnPPIX-treated animals displayed a substantial reduction in pulmonary bacterial loads comparable to that achieved following conventional antibiotic therapy. Moreover, when administered adjunctively with antimycobacterial drugs, the HO-1 inhibitor markedly enhanced and accelerated pathogen clearance. Interestingly, both the pulmonary induction of HO-1 expression and the efficacy of SnPPIX treatment in reducing bacterial burden were dependent on the presence of host T lymphocytes. Although M. tuberculosis expresses its own heme-degrading enzyme, SnPPIX failed to inhibit its enzymatic activity or significantly restrict bacterial growth in liquid culture. Together, the above findings reveal mammalian HO-1 as a potential target for host-directed monotherapy and adjunctive therapy of tuberculosis and identify the immune response as a critical regulator of this function. IMPORTANCE There is no reliable vaccine against tuberculosis (TB), and conventional antibiotic therapy is administered over at least 6 months. This prolonged treatment period can lead to noncompliance resulting in relapsed infection as well as the emergence of multidrug resistance. Thus, there is an urgent need for improved therapeutic regimens that can more rapidly and efficiently control M. tuberculosis in infected patients. Here, we describe a potential strategy for treating TB based on pharmacological inhibition of the host heme-degrading enzyme HO-1. This approach results in significantly reduced bacterial burdens in mice, and when administered in conjunction with conventional antibiotic therapy, leads to faster, more effective pathogen clearance without detectable direct effects on the mycobacteria themselves. Interestingly, the effects of HO-1 inhibition on M. tuberculosis infection in vivo are dependent on the presence of an intact host immune system. These observations establish mammalian HO-1 as a potential target for host-directed therapy of TB. C1 [Costa, Diego L.; Namasivayam, Sivaranjani; Amaral, Eduardo P.; Mittereder, Lara R.; Maiga, Mamoudou; Andrade, Bruno B.; Sher, Alan] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Arora, Kriti; Boshoff, Helena I.; Barry, Clifton E., III] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Chao, Alex; Goulding, Celia W.] Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92717 USA. [Goulding, Celia W.] Univ Calif Irvine, Dept Pharmaceut Sci, Irvine, CA USA. [Andrade, Bruno B.] Fiocruz MS, Inst Pesquisas Goncalo Moniz, Unidade Med Invest, Lab Integrado Microbiol & Imunorregulacao, Salvador, BA, Brazil. [Andrade, Bruno B.] Fundacao Jose Silveira, Multinatl Org Network Sponsoring Translat & Epide, Inst Brasileiro Invest TB, Salvador, BA, Brazil. RP Sher, A (reprint author), NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM asher@niaid.nih.gov FU Brazilian National Council of Scientific and Technological Development (CNPq) [237267/2012-8]; HHS \ National Institutes of Health (NIH) [AI095208]; HHS \ NIH \ National Institute of Allergy and Infectious Diseases (NIAID); National Science Foundation (NSF) [NSF-GRFP DGE-1321846] FX This work, including the efforts of Diego Luis Costa, was funded by Brazilian National Council of Scientific and Technological Development (CNPq) (237267/2012-8). This work, including the efforts of Celia Goulding, was funded by HHS vertical bar National Institutes of Health (NIH) (AI095208). This work, including the efforts of Diego Luis Costa, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (Intramural Research Program). This work, including the efforts of Alex Chao, was funded by National Science Foundation (NSF) (NSF-GRFP DGE-1321846). NR 25 TC 0 Z9 0 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 SEP-OCT PY 2016 VL 7 IS 5 AR e01675-16 DI 10.1128/mBio.01675-16 PG 6 WC Microbiology SC Microbiology GA EF2CU UT WOS:000390132900009 ER PT J AU Dooley, KE Warburton, A McBride, AA AF Dooley, Katharine E. Warburton, Alix McBride, Alison A. TI Tandemly Integrated HPV16 Can Form a Brd4-Dependent Super-Enhancer-Like Element That Drives Transcription of Viral Oncogenes SO MBIO LA English DT Article ID HUMAN-PAPILLOMAVIRUS TYPE-16; CERVICAL-CARCINOMA CELLS; BROMODOMAIN PROTEIN BRD4; DNA-DAMAGE RESPONSE; E2 PROTEIN; SELECTIVE-INHIBITION; E6/E7 PROMOTER; CANCER CELLS; ACTIVATION; REPRESSION AB In cancer cells associated with human papillomavirus (HPV) infections, the viral genome is very often found integrated into the cellular genome. The viral oncogenes E6 and E7 are transcribed from the viral promoter, and integration events that alter transcriptional regulation of this promoter contribute to carcinogenic progression. In this study, we detected highly enriched binding of the super-enhancer markers Brd4, MED1, and H3K27ac, visible as a prominent nuclear focus by immunofluorescence, at the tandemly integrated copies of HPV16 in cells of the cervical neoplasia cell line W12 subclone 20861. Tumor cells are often addicted to super-enhancer-driven oncogenes and are particularly sensitive to disruption of transcription factor binding to the enhancers. Treatment of 20861 cells with bromodomain inhibitors displaced Brd4 from the HPV integration site, greatly decreased E6/E7 transcription, and inhibited cellular proliferation. Thus, Brd4 activates viral transcription at this integration site, and strong selection for E6/E7 expression can drive the formation of a super-enhancer-like element to promote oncogenesis. IMPORTANCE Oncogenic human papillomaviruses play an essential role in the development of cervical cancer, and growth of these cancer cells requires continued expression of the viral E6 and E7 oncogenes. Integration of the virus into the host genome often results in deregulation of E6 and E7 expression, which provides a selective growth advantage and increases genetic instability of infected cells. We show here that tandemly integrated copies of the viral genome can form a super-enhancer-like element that drives E6/E7 transcription. Targeted disruption of factors binding to this element decreases viral transcription and causes cell death. Thus, cancer cells that harbor integrated HPV could be targeted by therapeutics that disrupt super-enhancer function. C1 [Dooley, Katharine E.; Warburton, Alix; McBride, Alison A.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP McBride, AA (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM amcbride@nih.gov FU HHS \ National Institutes of Health (NIH) [ZIA AI001073]; NIAID, NIH FX This work, including the efforts of Alison A. McBride, was funded by HHS vertical bar National Institutes of Health (NIH) (ZIA AI001073).; This research was supported by the Intramural Research Program of the NIAID, NIH. NR 46 TC 0 Z9 0 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 SEP-OCT PY 2016 VL 7 IS 5 AR e01446-16 DI 10.1128/mBio.01446-16 PG 10 WC Microbiology SC Microbiology GA EF2CU UT WOS:000390132900011 ER PT J AU Goo, L Dowd, KA Smith, ARY Pelc, RS DeMaso, CR Pierson, TC AF Goo, Leslie Dowd, Kimberly A. Smith, Alexander R. Y. Pelc, Rebecca S. DeMaso, Christina R. Pierson, Theodore C. TI Zika Virus Is Not Uniquely Stable at Physiological Temperatures Compared to Other Flaviviruses SO MBIO LA English DT Article ID TRANSMISSION; OUTBREAK; BRAZIL AB Zika virus (ZIKV) is a flavivirus that has emerged as a global health threat due in part to its association with congenital abnormalities. Other globally relevant flaviviruses include dengue virus (DENV) and West Nile virus (WNV). High-resolution structures of ZIKV reveal many similarities to DENV and suggest some differences, including an extended glycan loop (D. Sirohi, Z. Chen, L. Sun, T. Klose, T. C. Pierson, et al., 352:467-470, 2016, http://dx.doi.org/10.1126/science.aaf5316) and unique interactions among envelope (E) protein residues that were proposed to confer increased virion stability and contribute mechanistically to the distinctive pathobiology of ZIKV (V. A. Kostyuchenko, E. X. Lim, S. Zhang, G. Fibriansah, T. S. Ng, et al., Nature 533: 425-428, 2016, http://dx.doi.org/10.1038/nature17994). However, in the latter study, virus stability was inferred by measuring the loss of infectivity following a short incubation period. Here, we rigorously assessed the relative stability of ZIKV, DENV, and WNV by measuring changes in infectivity following prolonged incubation at physiological temperatures. At 37 degrees C, the half-life of ZIKV was approximately twice as long as the half-life of DENV (11.8 and 5.2 h, respectively) but shorter than that of WNV (17.7 h). Incubation at 40 degrees C accelerated the loss of ZIKV infectivity. Increasing virion maturation efficiency modestly increased ZIKV stability, as observed previously with WNV and DENV. Finally, mutations at E residues predicted to confer increased stability to ZIKV did not affect virion half-life. Our results demonstrate that ZIKV is not uniquely stable relative to other flaviviruses, suggesting that its unique pathobiology is explained by an alternative mechanism. IMPORTANCE Zika virus (ZIKV) belongs to the Flavivirus genus, which includes other clinically relevant mosquito-borne pathogens such as dengue virus (DENV) and West Nile virus (WNV). Historically, ZIKV infection was characterized by a self-limiting, mild disease, but recent outbreaks have been associated with severe clinical complications, including Guillain-Barre syndrome and microcephaly, which are atypical of other flavivirus infections. Moreover, ZIKV has been detected in saliva, urine, and semen, and it may be sexually transmitted. Analysis of a high-resolution cryo-electron microscopic reconstruction of ZIKV hypothesized that the unusual stability of this virus contributes to its distinctive pathobiology. Here, we directly compared the stability of ZIKV to that of other flaviviruses following prolonged incubation in solution at physiological temperatures. We found that the stability of multiple ZIKV strains, including those from recent outbreaks, is intermediate between that of DENV and WNV, suggesting an alternative explanation for the unique clinical manifestations of ZIKV infection. C1 [Goo, Leslie; Dowd, Kimberly A.; Smith, Alexander R. Y.; Pelc, Rebecca S.; DeMaso, Christina R.; Pierson, Theodore C.] NIAID, Viral Pathogenesis Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Pierson, TC (reprint author), NIAID, Viral Pathogenesis Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM piersontc@mail.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases (DIR, NIAID) FX This work, including the efforts of Leslie Goo, Kimberly A Dowd, Alexander R.Y. Smith, Rebecca S. Pelc, Christina R DeMaso, and Theodore C. Pierson, was funded by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (DIR, NIAID). NR 25 TC 4 Z9 4 U1 4 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD SEP-OCT PY 2016 VL 7 IS 5 AR e01396-16 DI 10.1128/mBio.01396-16 PG 4 WC Microbiology SC Microbiology GA EF2CU UT WOS:000390132900022 ER PT J AU Joo, HS Chatterjee, SS Villaruz, AE Dickey, SW Tan, VY Chen, Y Sturdevant, DE Ricklefs, SM Otto, M AF Joo, Hwang-Soo Chatterjee, Som S. Villaruz, Amer E. Dickey, Seth W. Tan, Vee Y. Chen, Yan Sturdevant, Daniel E. Ricklefs, Stacy M. Otto, Michael TI Mechanism of Gene Regulation by a Staphylococcus aureus Toxin SO MBIO LA English DT Article ID PHENOL-SOLUBLE MODULINS; VIRULENCE DETERMINANTS; AGR; SYSTEM; INFECTION; PATHOGENESIS; EXPRESSION; PNEUMONIA; SKIN; DNA AB The virulence of many bacterial pathogens, including the important human pathogen Staphylococcus aureus, depends on the secretion of frequently large amounts of toxins. Toxin production involves the need for the bacteria to make physiological adjustments for energy conservation. While toxins are primarily targets of gene regulation, such changes may be accomplished by regulatory functions of the toxins themselves. However, mechanisms by which toxins regulate gene expression have remained poorly understood. We show here that the staphylococcal phenol-soluble modulin (PSM) toxins have gene regulatory functions that, in particular, include inducing expression of their own transport system by direct interference with a GntR-type repressor protein. This capacity was most pronounced in PSMs with low cytolytic capacity, demonstrating functional specification among closely related members of that toxin family during evolution. Our study presents a molecular mechanism of gene regulation by a bacterial toxin that adapts bacterial physiology to enhanced toxin production. IMPORTANCE Toxins play a major role in many bacterial diseases. When toxins are produced during infection, the bacteria need to balance this energy-consuming task with other physiological processes. However, it has remained poorly understood how toxins can impact gene expression to trigger such adaptations. We found that specific members of a toxin family in the major human pathogen Staphylococcus aureus have evolved for gene regulatory purposes. These specific toxins interact with a DNA-binding regulator protein to enable production of the toxin export machinery and ascertain that the machinery is not expressed when toxins are not made and it is not needed. Our study gives mechanistic insight into how toxins may directly adjust bacterial physiology to times of toxin production during infection. C1 [Joo, Hwang-Soo; Chatterjee, Som S.; Villaruz, Amer E.; Dickey, Seth W.; Tan, Vee Y.; Chen, Yan; Otto, Michael] NIAID, Pathogen Mol Genet Sect, Bacteriol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Sturdevant, Daniel E.; Ricklefs, Stacy M.] NIAID, Genom Unit, Res Technol Branch, Rocky Mt Labs,NIH, Hamilton, MT USA. [Chatterjee, Som S.] Univ Calif San Francisco, San Francisco Gen Hosp, San Francisco, CA USA. [Chen, Yan] Zhejiang Univ, Coll Med, Sir Run Run Shaw Hosp, Dept Infect Dis, Hangzhou, Zhejiang, Peoples R China. RP Otto, M (reprint author), NIAID, Pathogen Mol Genet Sect, Bacteriol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM motto@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases (DIR, NIAID) [ZIA AI000904-15] FX This work, including the efforts of Michael Otto, was funded by Division of Intramural Research, National Institute of Allergy and Infectious Diseases (DIR, NIAID) (ZIA AI000904-15). NR 33 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD SEP-OCT PY 2016 VL 7 IS 5 AR e01579-16 DI 10.1128/mBio.01579-16 PG 10 WC Microbiology SC Microbiology GA EF2CU UT WOS:000390132900030 ER PT J AU Kohler, LJ Reed, SCO Sarraf, SA Arteaga, DD Newton, HJ Roy, CR AF Kohler, Lara J. Reed, Shawna C. O. Sarraf, Shireen A. Arteaga, David D. Newton, Hayley J. Roy, Craig R. TI Effector Protein Cig2 Decreases Host Tolerance of Infection by Directing Constitutive Fusion of Autophagosomes with the Coxiella-Containing Vacuole (vol 7, e01327, 2016) SO MBIO LA English DT Correction C1 [Kohler, Lara J.; Reed, Shawna C. O.; Arteaga, David D.; Roy, Craig R.] Yale Univ, Sch Med, Boyer Ctr Mol Med, Dept Microbial Pathogenesis, New Haven, CT 06520 USA. [Sarraf, Shireen A.] NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Newton, Hayley J.] Univ Melbourne, Dept Microbiol & Immunol, Peter Doherty Inst Infect & Immun, Melbourne, Vic, Australia. RP Roy, CR (reprint author), Yale Univ, Sch Med, Boyer Ctr Mol Med, Dept Microbial Pathogenesis, New Haven, CT 06520 USA. EM craig.roy@yale.edu NR 1 TC 0 Z9 0 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 SEP-OCT PY 2016 VL 7 IS 5 AR e01327-16 DI 10.1128/mBio.01127-16 PG 1 WC Microbiology SC Microbiology GA EF2CU UT WOS:000390132900038 ER PT J AU Patton, MJ McCorrister, S Grant, C Westmacott, G Fariss, R Hu, PZ Zhao, KQ Blake, M Whitmire, B Yang, CF Caldwell, HD McClarty, G AF Patton, Michael John McCorrister, Stuart Grant, Chris Westmacott, Garrett Fariss, Robert Hu, Pingzhao Zhao, Kaiqiong Blake, Mary Whitmire, Bill Yang, Chunfu Caldwell, Harlan D. McClarty, Grant TI Chlamydial Protease-Like Activity Factor and Type III Secreted Effectors Cooperate in Inhibition of p65 Nuclear Translocation SO MBIO LA English DT Article ID INTERFERON-STIMULATED GENES; TRACHOMATIS INFECTION; STRUCTURAL BASIS; GENITAL-TRACT; CPAF; HOST; CELLS; ACTIVATION; INDUCTION; VIRULENCE AB The chlamydial protease-like activity factor (CPAF) is hypothesized to be an important secreted virulence factor; however, challenges in denaturing its proteolytic activity have hampered attempts to identify its legitimate targets. Here, we use a genetic and proteomic approach to identify authentic CPAF targets. Human epithelial cells infected with CPAF-sufficient and CPAF-deficient chlamydiae were lysed using known CPAF-denaturing conditions. Their protein profiles were analyzed using isobaric mass tags and liquid chromatography-tandem mass spectrometry. Comparative analysis of CPAF-sufficient and CPAF-deficient infections identified a limited number of CPAF host and chlamydial protein targets. Host targets were primarily interferon-stimulated gene products, whereas chlamydial targets were type III secreted proteins. We provide evidence supporting a cooperative role for CPAF and type III secreted effectors in blocking NF-kappa B p65 nuclear translocation, resulting in decreased beta interferon and proinflammatory cytokine synthesis. Genetic complementation of null organisms with CPAF restored p65 nuclear translocation inhibition and proteolysis of chlamydial type III secreted effector proteins (T3SEs). We propose that CPAF and T3SEs cooperate in the inhibition of host innate immunity. IMPORTANCE Chlamydia trachomatis is an important human pathogen responsible for over 100 million infections each year worldwide. Its success as an intracellular pathogen revolves around its ability to evade host immunity. The chlamydial protease-like activity factor (CPAF) is a conserved serine protease secreted into the host cytosol of infected cells that is thought to play an important role in immune evasion. Currently, CPAF's authentic in situ target(s) and mechanism of action in immune evasion are poorly characterized. Using a CPAF-deficient strain and high-throughput proteomics, we report novel CPAF host and chlamydial targets. Host targets were primarily interferon-stimulated genes, whereas chlamydial targets were exclusively type III secreted proteins. We propose a novel mechanism for CPAF and type III secreted proteins in the evasion of host innate immune responses. These findings provide new insights into CPAF's function as a virulence factor and a better understanding of how chlamydiae evade host immunity. C1 [Patton, Michael John; Whitmire, Bill; Yang, Chunfu; Caldwell, Harlan D.] NIH, Lab Clin Infect Dis, Bldg 10, Bethesda, MD 20892 USA. [McCorrister, Stuart; Grant, Chris; Westmacott, Garrett; McClarty, Grant] Natl Microbiol Labs, Winnipeg, MB, Canada. [Fariss, Robert] NEI, NIH, Bethesda, MD 20892 USA. [Hu, Pingzhao; Zhao, Kaiqiong] Univ Manitoba, Dept Biochem & Med Genet, Winnipeg, MB, Canada. [Blake, Mary] NIH, Natl Inst Arthrit & Musculoskeletal & Skin Dis, Bldg 10, Bethesda, MD 20892 USA. RP Caldwell, HD (reprint author), NIH, Lab Clin Infect Dis, Bldg 10, Bethesda, MD 20892 USA.; McClarty, G (reprint author), Natl Microbiol Labs, Winnipeg, MB, Canada. EM hcaldwell@niaid.nih.gov; Grant.McClarty@umanitoba.ca FU HHS \ National Institutes of Health (NIH) FX This work, including the efforts of Harlan D Caldwell, was funded by HHS vertical bar National Institutes of Health (NIH). NR 36 TC 0 Z9 0 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 SEP-OCT PY 2016 VL 7 IS 5 AR e01427-16 DI 10.1128/mBio.01427-16 PG 9 WC Microbiology SC Microbiology GA EF2CU UT WOS:000390132900053 ER PT J AU Quemin, ERJ Chlanda, P Sachse, M Forterre, P Prangishvili, D Krupovic, M AF Quemin, Emmanuelle R. J. Chlanda, Petr Sachse, Martin Forterre, Patrick Prangishvili, David Krupovic, Mart TI Eukaryotic-Like Virus Budding in Archaea SO MBIO LA English DT Article ID PARTICLE SSV1; CELL-DIVISION; SULFOLOBUS; PROTEINS; SCISSION; DNA AB Similar to many eukaryotic viruses (and unlike bacteriophages), viruses infecting archaea are often encased in lipid-containing envelopes. However, the mechanisms of their morphogenesis and egress remain unexplored. Here, we used dual-axis electron tomography (ET) to characterize the morphogenesis of Sulfolobus spindle-shaped virus 1 (SSV1), the prototype of the family Fuselloviridae and representative of the most abundant archaea-specific group of viruses. Our results show that SSV1 assembly and egress are concomitant and occur at the cellular cytoplasmic membrane via a process highly reminiscent of the budding of enveloped viruses that infect eukaryotes. The viral nucleoprotein complexes are extruded in the form of previously unknown rod-shaped intermediate structures which have an envelope continuous with the host membrane. Further maturation into characteristic spindle-shaped virions takes place while virions remain attached to the cell surface. Our data also revealed the formation of constricted ring-like structures which resemble the budding necks observed prior to the ESCRT machinery-mediated membrane scission during egress of various enveloped viruses of eukaryotes. Collectively, we provide evidence that archaeal spindle-shaped viruses contain a lipid envelope acquired upon budding of the viral nucleoprotein complex through the host cytoplasmic membrane. The proposed model bears a clear resemblance to the egress strategy employed by enveloped eukaryotic viruses and raises important questions as to how the archaeal single-layered membrane composed of tetraether lipids can undergo scission. IMPORTANCE The replication of enveloped viruses has been extensively studied in eukaryotes but has remained unexplored for enveloped viruses infecting bacteria and archaea. Here, we provide a sequential view on the assembly and egress of SSV1, a prototypic archaeal virus. The observed process is highly similar to the budding of eukaryotic enveloped viruses, including human immunodeficiency virus, influenza virus, and Ebola virus. The present study is the first to characterize such a phenomenon in archaeal cells, showing that membrane budding is not an exclusive feature of eukaryotic viruses. Our results provide significant insights into the biogenesis and architecture of unique, spindle-shaped virions that infect archaea. Furthermore, our findings open doors for future inquiries into (i) the evolution of the virus budding process, (ii) mechanistic details of virus-mediated membrane scission in Archaea, and (iii) elucidation of virus-and host-encoded molecular players responsible for archaeal membrane and surface remodeling. C1 [Quemin, Emmanuelle R. J.; Forterre, Patrick; Prangishvili, David; Krupovic, Mart] Inst Pasteur, Dept Microbiol, Unite Biol Mol Gene Chez Extremophiles, Paris, France. [Chlanda, Petr] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Integrat Biophys, NIH, Bethesda, MD USA. [Quemin, Emmanuelle R. J.; Sachse, Martin] Inst Pasteur, Ultrapole, Paris, France. RP Prangishvili, D; Krupovic, M (reprint author), Inst Pasteur, Dept Microbiol, Unite Biol Mol Gene Chez Extremophiles, Paris, France. EM david.prangishvili@pasteur.fr; krupovic@pasteur.fr OI Krupovic, Mart/0000-0001-5486-0098 FU HHS \ National Institutes of Health (NIH) (Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development); EC \ European Research Council (ERC) [340440]; Agence Nationale de la Recherche (ANR) FX This work was funded by HHS vertical bar National Institutes of Health (NIH) (Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development); EC vertical bar European Research Council (ERC) (Project EVOMOBIL - ERC Grant Agreement no. 340440); Agence Nationale de la Recherche (ANR) (program BLANC project EXAVIR). NR 19 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD SEP-OCT PY 2016 VL 7 IS 5 AR e01439-16 DI 10.1128/mBio.01439-16 PG 5 WC Microbiology SC Microbiology GA EF2CU UT WOS:000390132900058 ER PT J AU Thomason, LC Costantino, N Court, DL AF Thomason, Lynn C. Costantino, Nina Court, Donald L. TI Examining a DNA Replication Requirement for Bacteriophage lambda Red- and Rac Prophage RecET-Promoted Recombination in Escherichia coli SO MBIO LA English DT Article ID PHAGE-LAMBDA; HOMOLOGOUS RECOMBINATION; BETA-PROTEIN; GENETIC-RECOMBINATION; EXONUCLEASE-VIII; MISMATCH REPAIR; INTRAMOLECULAR RECOMBINATION; STIMULATED RECOMBINATION; PLASMID RECOMBINATION; STRAND EXCHANGE AB Recombineering, in vivo genetic engineering with bacteriophage homologous recombination systems, is a powerful technique for making genetic modifications in bacteria. Two systems widely used in Escherichia coli are the Red system from phage lambda and RecET from the defective Rac prophage. We investigated the in vivo dependence of recombineering on DNA replication of the recombining substrate using plasmid targets. For lambda Red recombination, when DNA replication of a circular target plasmid is prevented, recombination with single-stranded DNA oligonucleotides is greatly reduced compared to that under replicating conditions. For RecET recombination, when DNA replication of the targeted plasmid is prevented, the recombination frequency is also reduced, to a level identical to that seen for the Red system in the absence of replication. The very low level of oligonucleotide recombination observed in the absence of any phage recombination functions is the same in the presence or absence of DNA replication. In contrast, both the Red and RecET systems recombine a nonreplicating linear dimer plasmid with high efficiency to yield a circular monomer. Therefore, the DNA replication requirement is substrate dependent. Our data are consistent with recombination by both the Red and RecET systems occurring predominately by single-strand annealing rather than by strand invasion. IMPORTANCE Bacteriophage homologous recombination systems are widely used for in vivo genetic engineering in bacteria. Single-or double-stranded linear DNA substrates containing short flanking homologies to chromosome targets are used to generate precise and accurate genetic modifications when introduced into bacteria expressing phage recombinases. Understanding the molecular mechanism of these recombination systems will facilitate improvements in the technology. Here, two phage-specific systems are shown to require exposure of complementary single-strand homologous targets for efficient recombination; these single-strand regions may be created during DNA replication or by single-strand exonuclease digestion of linear duplex DNA. Previously, in vitro studies reported that these recombinases promote the single-strand annealing of two complementary DNAs and also strand invasion of a single DNA strand into duplex DNA to create a three-stranded region. Here, in vivo experiments show that recombinase-mediated annealing of complementary single-stranded DNA is the predominant recombination pathway in E. coli. C1 [Thomason, Lynn C.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Basic Sci Program, GRCBL Mol Control & Genet Sect, Frederick, MD USA. [Thomason, Lynn C.; Costantino, Nina; Court, Donald L.] NCI, Chromosome Biol Lab, Frederick, MD 21701 USA. RP Court, DL (reprint author), NCI, Chromosome Biol Lab, Frederick, MD 21701 USA. EM courtd@mail.nih.gov FU HHS \ NIH \ National Cancer Institute (NCI) [HHSN261200800001E] FX This work, including the efforts of Lynn Clarice Thomason, was funded by HHS vertical bar NIH vertical bar National Cancer Institute (NCI) (HHSN261200800001E). This work, including the efforts of Nina Costantino, was funded by HHS vertical bar NIH vertical bar National Cancer Institute (NCI) (HHSN261200800001E). This work, including the efforts of Donald L Court, was funded by HHS vertical bar NIH vertical bar National Cancer Institute (NCI) (HHSN261200800001E). NR 57 TC 0 Z9 0 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 SEP-OCT PY 2016 VL 7 IS 5 AR e01443-16 DI 10.1128/mBio.01443-16 PG 10 WC Microbiology SC Microbiology GA EF2CU UT WOS:000390132900071 ER PT J AU Zouboulis, CC Stratakis, CA Chrousos, GP Koch, CA AF Zouboulis, Christos C. Stratakis, Constantine A. Chrousos, George P. Koch, Christian A. TI Metabolism and skin diseases SO REVIEWS IN ENDOCRINE & METABOLIC DISORDERS LA English DT Article C1 [Zouboulis, Christos C.] Dessau Med Ctr, Dept Dermatol, Auenweg 38, D-06847 Dessau, Germany. [Zouboulis, Christos C.] Dessau Med Ctr, Dept Venereol, Auenweg 38, D-06847 Dessau, Germany. [Zouboulis, Christos C.] Dessau Med Ctr, Dept Allergol, Auenweg 38, D-06847 Dessau, Germany. [Zouboulis, Christos C.] Dessau Med Ctr, Dept Immunol, Auenweg 38, D-06847 Dessau, Germany. [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet SEGEN, NIH, Bethesda, MD USA. [Chrousos, George P.] Univ Athens, Dept Pediat 1, Aghia Sophia Childrens Hosp, Sch Med, Athens, Greece. [Koch, Christian A.] Univ Mississippi, Med Ctr, Div Endocrinol, Diabet,Metab, Jackson, MS 39216 USA. [Koch, Christian A.] GV Sonny Montgomery VA Med Ctr, Jackson, MS USA. [Koch, Christian A.] Univ Mississippi, Med Ctr, Inst Canc, Jackson, MS 39216 USA. RP Zouboulis, CC (reprint author), Dessau Med Ctr, Dept Dermatol, Auenweg 38, D-06847 Dessau, Germany.; Zouboulis, CC (reprint author), Dessau Med Ctr, Dept Venereol, Auenweg 38, D-06847 Dessau, Germany.; Zouboulis, CC (reprint author), Dessau Med Ctr, Dept Allergol, Auenweg 38, D-06847 Dessau, Germany.; Zouboulis, CC (reprint author), Dessau Med Ctr, Dept Immunol, Auenweg 38, D-06847 Dessau, Germany. EM christos.zouboulis@klinikum-dessau.de FU Intramural Research Program, NICHD, NIH, USA FX The contribution of Dr. C.A. Stratakis to this work was supported by the Intramural Research Program, NICHD, NIH, USA. NR 22 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1389-9155 EI 1573-2606 J9 REV ENDOCR METAB DIS JI Rev. Endocr. Metab. Disord. PD SEP PY 2016 VL 17 IS 3 BP 241 EP 246 DI 10.1007/s11154-016-9396-6 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EF1EX UT WOS:000390069000001 PM 27924431 ER PT J AU Nikolakis, G Stratakis, CA Kanaki, T Slominski, A Zouboulis, CC AF Nikolakis, Georgios Stratakis, Constantine A. Kanaki, Theodora Slominski, Andrej Zouboulis, Christos C. TI Skin steroidogenesis in health and disease SO REVIEWS IN ENDOCRINE & METABOLIC DISORDERS LA English DT Article DE Steroids; Steroidogenesis; Testosterone; Androgens; Estrogens; Androgen receptor; Rosacea; Acne; Aromatase; 5a-reductase; DHEA; Dermatoendocrinology; Glucocorticoids ID ACUTE REGULATORY PROTEIN; CORTICOTROPIN-RELEASING HORMONE; HUMAN SEBACEOUS GLANDS; ELEMENT BINDING-PROTEIN; SEX STEROID-SYNTHESIS; ACNE-VULGARIS; HPA AXIS; ANDROGENETIC ALOPECIA; DERMAL FIBROBLASTS; HUMAN SEBOCYTES AB The skin is an important extra-gonadal steroidogenic organ, capable of metabolizing various hormones from their precursors, as well as of synthesizing de novo a broad palette of sex steroids and glucocorticoids from cholesterol. In this manuscript, we review the major steroidogenic properties of human skin and we suggest steroidogenesis' impairment as a cardinal factor for various pathological conditions such as acne, rosacea, atopic dermatitis, and androgenic alopecia. C1 [Nikolakis, Georgios; Kanaki, Theodora; Zouboulis, Christos C.] Dessau Med Ctr, Dept Dermatol, Auenweg 38, D-06847 Dessau, Germany. [Nikolakis, Georgios; Kanaki, Theodora; Zouboulis, Christos C.] Dessau Med Ctr, Dept Venereol, Auenweg 38, D-06847 Dessau, Germany. [Nikolakis, Georgios; Kanaki, Theodora; Zouboulis, Christos C.] Dessau Med Ctr, Dept Allergol, Auenweg 38, D-06847 Dessau, Germany. [Nikolakis, Georgios; Kanaki, Theodora; Zouboulis, Christos C.] Dessau Med Ctr, Dept Immunol, Auenweg 38, D-06847 Dessau, Germany. [Stratakis, Constantine A.] NICHD, Sect Endocrinol & Genet, NIH, Bethesda, MD USA. [Slominski, Andrej] Univ Alabama Birmingham, Dept Dermatol, Birmingham, AL 35294 USA. RP Nikolakis, G (reprint author), Dessau Med Ctr, Dept Dermatol, Auenweg 38, D-06847 Dessau, Germany.; Nikolakis, G (reprint author), Dessau Med Ctr, Dept Venereol, Auenweg 38, D-06847 Dessau, Germany.; Nikolakis, G (reprint author), Dessau Med Ctr, Dept Allergol, Auenweg 38, D-06847 Dessau, Germany.; Nikolakis, G (reprint author), Dessau Med Ctr, Dept Immunol, Auenweg 38, D-06847 Dessau, Germany. EM georgios.nikolakis@klinikum-dessau.de NR 163 TC 1 Z9 1 U1 2 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1389-9155 EI 1573-2606 J9 REV ENDOCR METAB DIS JI Rev. Endocr. Metab. Disord. PD SEP PY 2016 VL 17 IS 3 BP 247 EP 258 DI 10.1007/s11154-016-9390-z PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EF1EX UT WOS:000390069000002 PM 27761789 ER PT J AU Stratakis, CA AF Stratakis, Constantine A. TI Skin manifestations of Cushing's syndrome SO REVIEWS IN ENDOCRINE & METABOLIC DISORDERS LA English DT Article DE Cushing's syndrome; Glucocorticoids; Skin; Acne; Plethora; Hyperpigmentation; Bruise; Striae; Hirsutism; Acanthosis ID PITUITARY-ADRENAL AXIS; SURGICAL CURE; GLUCOCORTICOID-RECEPTOR; CHILDREN; DISEASE; GROWTH; ADOLESCENTS; EXPRESSION; DISORDERS; RECOVERY AB Among the most common diagnostic manifestations of Cushing's syndrome (CS) are those involving the skin; they include violaceous striae, facial acne, hirsutism, acanthosis nigricans (AN), fungal infections, hyperpigmentation (Hp) and easy bruisability. Fortunately, most resolve within a year or two after cure of CS, although light-colored striae can persist for years depending on the age of the patients. AN, Hp, and bruisability usually resolve within months after cure in almost all ages. Facial plethora (along with acne and other facial skin changes) is a typical sign of CS that is due to increased perfusion. It resolves immediately after curative therapy of CS. Typically, the severity of the manifestations does not correlate with the biochemical indices of the disease, pointing to age, gender, genetic and skin-type differences that determine the cutaneous manifestations of CS. C1 [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, CRC, Bldg 10,Room East 1330,10 Ctr Dr MSC1862, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, CRC, Bldg 10,Room East 1330,10 Ctr Dr MSC1862, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA [Z01-HD008920] FX This review was supported by the research project Z01-HD008920 (Principal Investigator: Dr. Constantine A Stratakis) of the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA. NR 32 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1389-9155 EI 1573-2606 J9 REV ENDOCR METAB DIS JI Rev. Endocr. Metab. Disord. PD SEP PY 2016 VL 17 IS 3 BP 283 EP 286 DI 10.1007/s11154-016-9399-3 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EF1EX UT WOS:000390069000005 PM 27943005 ER PT J AU Stratakis, CA AF Stratakis, Constantine A. TI Carney complex: A familial lentiginosis predisposing to a variety of tumors SO REVIEWS IN ENDOCRINE & METABOLIC DISORDERS LA English DT Article DE Carney complex; Primary pigmented nodular adrenocortical disease; Myxomas; Schwannomas; Acromegaly ID PROTEIN-KINASE-A; SUBUNIT TYPE 1A; REGULATORY SUBUNIT; I-ALPHA; PRKAR1A; ENDOCRINE; DISEASE; NEOPLASIA; MUTATIONS; GENETICS AB Carney complex is a familial lentiginosis syndrome; these disorders cover a wide phenotypic spectrum ranging from a benign inherited predisposition to develop cutaneous spots not associated with systemic disease to associations with several syndromes. Carney complex is caused by PRKAR1A mutations and perturbations of the cyclic AMP-dependent protein kinase (PKA) signaling pathway. In addition to the cutaneous findings, the main tumors associated with Carney complex are endocrine: 1) primary pigmented nodular adrenocortical disease, a bilateral adrenal hyperplasia leading to Cushing syndrome; 2) growth-hormone secreting pituitary adenoma or pituitary somatotropic hyperplasia leading to acromegaly; 3) thyroid and gonadal tumors, including a predisposition to thyroid cancer. Other tumors associated with Carney complex include: 1) myxomas of the heart, breast and other sites; 2) psamommatous melanotic schwannomas which can become malignant; 4) a predisposition to a variety of cancers. C1 [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, CRC, Bldg 10,Room East 1330,10 Ctr Dr MSC1862, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, CRC, Bldg 10,Room East 1330,10 Ctr Dr MSC1862, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU Intramural Research Program NICHD, NIH FX This work was supported by the Intramural Research Program NICHD, NIH. NR 22 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1389-9155 EI 1573-2606 J9 REV ENDOCR METAB DIS JI Rev. Endocr. Metab. Disord. PD SEP PY 2016 VL 17 IS 3 BP 367 EP 371 DI 10.1007/s11154-016-9400-1 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EF1EX UT WOS:000390069000013 PM 27943004 ER PT J AU Hannah-Shmouni, F Stratakis, CA Koch, CA AF Hannah-Shmouni, Fady Stratakis, Constantine A. Koch, Christian A. TI Flushing in (neuro)endocrinology SO REVIEWS IN ENDOCRINE & METABOLIC DISORDERS LA English DT Article DE Flushing; Neuroendocrine tumor; Carcinoid; Pheochromocytoma; Histamine; Substance P ID NEUROENDOCRINE-TUMORS; CARCINOID-SYNDROME; ENDOCRINE TUMORS; CONSENSUS GUIDELINES; CUSHINGS-SYNDROME; PEMBERTONS SIGN; MANAGEMENT; DIAGNOSIS; PHEOCHROMOCYTOMA; PROGNOSIS AB Cutaneous flushing is a common presenting complaint in endocrine disorders. The pathophysiology of flushing involves changes in cutaneous blood flow triggered by multiple intrinsic factors that are either related to physiology or disease. Flushing can be divided into episodic or persistent causes. Episodic flushing is mediated by the release of endogenous vasoactive mediators or medications, while persistent flushing results in a fixed facial erythema with telangiectasia and cyanosis due to slow-flowing deoxygenated blood in large cutaneous blood vessels. The differential diagnosis of cutaneous flushing in neuroendocrine disorders is limited, yet encompasses a broad spectrum of benign and malignant entities, including carcinoid syndrome, pheochromocytoma, Cushing syndrome, medullary thyroid cancer, and pancreatic neuroendocrine tumors. In this review, we provide a concise and up-to-date discussion on the differential diagnosis and approach of flushing in neuroendocrinology. C1 [Hannah-Shmouni, Fady; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Sect Endocrinol Genet SEGEN, Bethesda, MD 20892 USA. [Koch, Christian A.] Univ Mississippi, Med Ctr, Div Endocrinol, Jackson, MS 39216 USA. [Koch, Christian A.] GV Sonny Montgomery VA Med Ctr, Jackson, MS 39216 USA. RP Hannah-Shmouni, F (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Sect Endocrinol Genet SEGEN, Bethesda, MD 20892 USA.; Koch, CA (reprint author), Univ Mississippi, Med Ctr, Div Endocrinol, Jackson, MS 39216 USA.; Koch, CA (reprint author), GV Sonny Montgomery VA Med Ctr, Jackson, MS 39216 USA. EM fady.hannah-shmouni@nih.gov; Christian_albert_koch@yahoo.com FU Intramural NIH HHS [Z99 HD999999] NR 65 TC 1 Z9 1 U1 2 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1389-9155 EI 1573-2606 J9 REV ENDOCR METAB DIS JI Rev. Endocr. Metab. Disord. PD SEP PY 2016 VL 17 IS 3 BP 373 EP 380 DI 10.1007/s11154-016-9394-8 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EF1EX UT WOS:000390069000014 PM 27873108 ER PT J AU Stratakis, CA AF Stratakis, Constantine A. TI Hereditary syndromes predisposing to endocrine tumors and their skin manifestations SO REVIEWS IN ENDOCRINE & METABOLIC DISORDERS LA English DT Article DE Multiple endocrine neoplasia; Hereditary tumor syndrome; Peutz-Jeghers syndrome; Cowden disease; Neurofibromatosis type 1; Tuberous sclerosis ID PEUTZ-JEGHERS-SYNDROME; CUTANEOUS LICHEN AMYLOIDOSIS; RET PROTOONCOGENE MUTATIONS; MEDULLARY-THYROID CARCINOMA; TUBEROUS SCLEROSIS COMPLEX; SERTOLI-CELL TUMORS; NEOPLASIA TYPE-1; HIRSCHSPRUNG-DISEASE; COWDEN SYNDROME; FACIAL ANGIOFIBROMAS AB We often think of the lentiginoses, phacomatoses and other neurocutaneous syndromes as conditions that affect the skin and also predispose to a variety of tumors. However, we rarely think of Peutz-Jeghers syndrome (PJS), Carney complex (CNC), Cowden disease (CD), neurofibromatosis type-1 (NF-1) or tuberous sclerosis (TSC) as conditions that are multiple endocrine neoplasias (MEN). Indeed, all of these conditions predispose to a variety of endocrine tumors, in addition to many other neoplasms. On the other hand, the classic MENs, type 1 and 2 (MEN-1 and MEN-2, respectively) are almost never thought in terms of their skin manifestations. In this review, we present extensively the MEN-1, MEN-2 and PJS syndromes, and briefly refer to CD, NF-1, and TSC. CNC is discussed in another article in this journal issue. C1 [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, CRC, Bldg 10,Room East 1330,10 Ctr Dr MSC1862, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, CRC, Bldg 10,Room East 1330,10 Ctr Dr MSC1862, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA [Z01-HD008920] FX This review was supported by the research project Z01-HD008920 (Principal Investigator: Dr. Constantine A Stratakis) of the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA. NR 61 TC 1 Z9 1 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1389-9155 EI 1573-2606 J9 REV ENDOCR METAB DIS JI Rev. Endocr. Metab. Disord. PD SEP PY 2016 VL 17 IS 3 BP 381 EP 388 DI 10.1007/s11154-016-9401-0 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EF1EX UT WOS:000390069000015 PM 27943006 ER PT J AU Ebiasah, RP Sise, TK Wildman, M AF Ebiasah, Ruth P. Sise, Thucuma K. Wildman, Michelle TI Zika Virus and Its Effects in Pregnancy SO US PHARMACIST LA English DT Article AB Recently, a major outbreak of Zika virus occurred in several countries in South and Central America and the Caribbean. The World Health Organization estimated that more than 3 million cases of Zika infection would occur in the Americas in 2016, spurring the global community to develop preventive and supportive strategies. Recognizing the signs and symptoms of Zika infection, performing diagnostic tests based on current knowledge, successfully implementing preventive measures, and further evaluating the effects of Zika virus in pregnancy are of chief importance in response to the outbreak. The pharmacist's role in patient counseling and education and the pharmacy technician's role in symptom identification are essential for successfully managing the current outbreak and curbing further spread to the most vulnerable populations, including pregnant women. C1 [Ebiasah, Ruth P.; Sise, Thucuma K.; Wildman, Michelle] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Ebiasah, RP (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU JOBSON PUBLISHING LLC PI NEW YORK PA 100 AVE OF THE AMERICAS, NEW YORK, NY 10013-1678 USA SN 0148-4818 EI 2331-3501 J9 US PHARM JI US Pharm. PD SEP PY 2016 VL 41 IS 9 BP 48 EP 56 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EF1XF UT WOS:000390117700020 ER PT J AU Gudmundsson, G Margretardottir, OB Sigurdsson, MI Harris, TB Launer, LJ Sigurdsson, S Olafsson, O Aspelund, T Gudnason, V AF Gudmundsson, Gunnar Margretardottir, Olof Birna Sigurdsson, Martin Ingi Harris, Tamara B. Launer, Lenore J. Sigurdsson, Sigurdur Olafsson, Orn Aspelund, Thor Gudnason, Vilmundur TI Airflow obstruction, atherosclerosis and cardiovascular risk factors in the AGES Reykjavik study SO ATHEROSCLEROSIS LA English DT Article DE Chronic obstructive pulmonary disease; Systemic inflammation; Atherosclerosis; Cardiovascular risk factors ID CORONARY-ARTERY-DISEASE; C-REACTIVE PROTEIN; PULMONARY-DISEASE; SYSTEMIC INFLAMMATION; CAROTID ATHEROSCLEROSIS; LIMITATION; LUNG; ASSOCIATION; CALCIUM; BURDEN AB Background and aims: Airflow limitation, i. e. reduced forced expiratory volume in 1-s (FEV1), is associated with increased prevalence of atherosclerosis, however, causal mechanisms remain elusive. The objective of the study was to determine if the association between airflow obstruction and markers of atherosclerosis is mediated by systemic inflammation. Methods: 1154 subjects from the longitudinal AGES Reykjavik study were included. Population characteristics, systemic inflammation markers from blood (white blood cell counts (WBC) and level of Creactive protein (CRP)) were compared between patients with and without airflow limitation defined by reduced FEV1 on spirometry. Atherosclerosis burden was quantified by measurements of coronary artery calcium, aortic arch and distal aortic calcification in addition to carotid intimal media thickness (CIMT). Results: Subjects were split into four groups according to smoking status and whether airflow limitation was present. There was a higher overall burden of atherosclerosis in ever-smokers compared to neversmokers, and in individuals with airflow obstruction compared to individuals without airflow obstruction. After adjusting for population characteristics, Framingham cardiovascular risk factors and markers of systemic inflammation (WBC and CRP), there was a significantly increased aortic arch and distal aorta calcification and higher CIMT measurement in individuals with airflow obstruction compared to individuals without airflow obstruction. After adjusting for population characteristics, Framingham cardiovascular risk factors and markers of systemic inflammation (WBC and CRP), there was a significantly increased aortic arch and distal aorta calcification and higher CIMT measurement in individuals with airflow obstruction compared to individuals without airflow obstruction. Conclusions: Systemic inflammation (WBC and CRP) does not appear to mediate the association between airflow limitation and atherosclerosis. Only airflow limitation and not systemic inflammation (WBC and CRP) appears to be an independent predictor of atherosclerosis. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Gudmundsson, Gunnar; Margretardottir, Olof Birna; Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Gudmundsson, Gunnar] Landspitali Natl Univ Hosp, Dept Resp Med & Sleep, Reykjavik, Iceland. [Margretardottir, Olof Birna] Sahlgrens Univ Hosp, Dept Surg, Gothenburg, Sweden. [Sigurdsson, Martin Ingi] Harvard Med Sch, Brigham & Womens Hosp, Dept Anesthesia Perioperat & Pain Med, Boston, MA USA. [Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Sigurdsson, Sigurdur; Olafsson, Orn; Aspelund, Thor; Gudnason, Vilmundur] Icelandic Heart Assoc, Kopavogur, Iceland. RP Gudmundsson, G (reprint author), Landspitali Univ Hosp, Dept Resp Med, E-7 Fossvogur, IS-108 Reykjavik, Iceland. EM ggudmund@landspitali.is; ggudmund@landspitali.is FU National Institute on Aging Intramural Research Program, Hjartavernd (Icelandic Heart Association); Althingi (the Icelandic Parliament); Landspitali Scientific Fund; Icelandic Research Fund [90414021, 90414022]; National Institute on Aging, US National Institutes of Health [N01-AG012100] FX This work was supported by the National Institute on Aging, US National Institutes of Health (grant N01-AG012100), the National Institute on Aging Intramural Research Program, Hjartavernd (Icelandic Heart Association), and the Althingi (the Icelandic Parliament). Gunnar Gudmundsson was funded by Landspitali Scientific Fund and by the Icelandic Research Fund, Project Grant 90414021 and 90414022. NR 27 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD SEP PY 2016 VL 252 BP 122 EP 127 DI 10.1016/j.atherosclerosis.2016.07.919 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EE3IF UT WOS:000389480300017 PM 27522264 ER PT J AU Sakamuri, SSVP Higashi, Y Sukhanov, S Siddesha, JM Delafontaine, P Siebenlist, U Chandrasekar, B AF Sakamuri, Siva Sankara Vara Prasad Higashi, Yusuke Sukhanov, Sergiy Siddesha, Jalahalli M. Delafontaine, Patrice Siebenlist, Ulrich Chandrasekar, Bysani TI TRAF3IP2 mediates atherosclerotic plaque development and vulnerability in ApoE(-/-) mice SO ATHEROSCLEROSIS LA English DT Article DE TRAF3IP2; CIKS; Act1; Atherosclerosis; Plaque stability; Collagen ID SMOOTH-MUSCLE-CELLS; FACTOR-KAPPA-B; ACTIVATED PROTEIN-KINASE; ANGIOTENSIN-II; ENDOTHELIAL DYSFUNCTION; FIBROBLAST MIGRATION; SIGNALING CASCADE; ADAPTER PROTEIN; MESSENGER-RNA; CIKS ACT1 AB Background and aims: Atherosclerosis is a major cause of heart attack and stroke. Inflammation plays a critical role in the development of atherosclerosis. Since the cytoplasmic adaptor molecule TRAF3IP2 (TRAF3-Interacting Protein 2) plays a causal role in various autoimmune and inflammatory diseases, we hypothesized that TRAF3IP2 mediates atherosclerotic plaque development. Methods: TRAF3IP2/ApoE double knockout (DKO) mice were generated by crossing TRAF3IP2(-/-) and ApoE(-/-) mice. ApoE(-/-) mice served as controls. Both DKO and control mice were fed a high-fat diet for 12 weeks. Plasma lipids were measured by ELISA, atherosclerosis by en face analysis of aorta and plaque cross-section measurements at the aortic valve region, plaque necrotic core area, collagen and smooth muscle cell (SMC) content by histomorphometry, and aortic gene expression by RT-qPCR. Results: The plasma lipoprotein profile was not altered by TRAF3IP2 gene deletion in ApoE(-/-) mice. While total aortic plaque area was decreased in DKO female, but not male mice, the plaque necrotic area was significantly decreased in DKO mice of both genders. Plaque collagen and SMC contents were increased significantly in both female and male DKO mice compared to respective controls. Aortic expression of proinflammatory cytokine (Tumor necrosis factor alpha, TNF alpha), chemokine (Chemokine (C-X-C motif) Ligand 1, CXCL1) and adhesion molecule (Vascular cell adhesion molecule 1, VCAM1; and Intercellular adhesion molecule 1, ICAM1) gene expression were decreased in both male and female DKO mice. In addition, the male DKO mice expressed markedly reduced levels of extracellular matrix (ECM)-related genes, including TIMP1 (Tissue inhibitor of metalloproteinase 1), RECK (Reversion-Inducing-Cysteine-Rich Protein with Kazal Motifs) and ADAM17 (A Disintegrin And Metalloproteinase 17). Conclusions: TRAF3IP2 plays a causal role in atherosclerotic plaque development and vulnerability, possibly by inducing the expression of multiple proinflammatory mediators. TRAF3IP2 could be a potential therapeutic target in atherosclerotic vascular diseases. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Sakamuri, Siva Sankara Vara Prasad; Higashi, Yusuke; Sukhanov, Sergiy; Siddesha, Jalahalli M.; Delafontaine, Patrice; Chandrasekar, Bysani] Tulane Univ, Sch Med, Inst Heart & Vasc, New Orleans, LA 70112 USA. [Siebenlist, Ulrich] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Chandrasekar, Bysani] HS Truman Mem Vet Hosp, 800 Hosp Dr, Columbia, MO 75201 USA. [Higashi, Yusuke; Sukhanov, Sergiy; Delafontaine, Patrice; Chandrasekar, Bysani] Univ Missouri, Sch Med, Med Cardiol, 1 Hosp Dr, Columbia, MO 65211 USA. [Siddesha, Jalahalli M.] Univ Vermont, Lab Pathol & Med, Burlington, VT 05405 USA. [Sakamuri, Siva Sankara Vara Prasad] Univ Alberta, Dept Physiol, Edmonton, AB T6G 2H7, Canada. RP Chandrasekar, B (reprint author), Univ Missouri, Sch Med, Med Cardiol, 1 Hosp Dr, Columbia, MO 65211 USA. EM chandrasekarb@health.missouri.edu OI Sukhanov, Sergiy/0000-0002-9223-4263 FU Department of Veterans Affairs Research Career Scientist award; VA Office of Research and Development Biomedical Laboratory Research and Development Service Award [I01-BX002255]; NIH/NHLBI [HL-86787]; NHLBI [HL-70241, HL-80682]; Intramural Research Program of the NIH/NIAID FX BC is a recipient of the Department of Veterans Affairs Research Career Scientist award and is supported by VA Office of Research and Development Biomedical Laboratory Research and Development Service Award I01-BX002255 and the NIH/NHLBI grant HL-86787. PD is supported by NHLBI grants HL-70241 and HL-80682. US is supported by the Intramural Research Program of the NIH/NIAID. The contents of this report do not represent the views of the Department of Veterans Affairs or the United States government. NR 46 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD SEP PY 2016 VL 252 BP 153 EP 160 DI 10.1016/j.atherosclerosis.2016.05.029 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EE3IF UT WOS:000389480300021 PM 27237075 ER PT J AU Williams, KW Ware, J Abiodun, A Holland-Thomas, NC Khoury, P Klion, AD AF Williams, Kelli W. Ware, JeanAnne Abiodun, Annalise Holland-Thomas, Nicole C. Khoury, Paneez Klion, Amy D. TI Hypereosinophilia in Children and Adults: A Retrospective Comparison SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE LA English DT Article DE Eosinophil; Hypereosinophilic syndrome; Pediatric; Children ID IDIOPATHIC EOSINOPHILIA; LYMPHOBLASTIC-LEUKEMIA; EPISODIC ANGIOEDEMA; PREVALENCE; RESPONSIVENESS; CHROMOSOME; IMATINIB; VARIANT AB BACKGROUND: The differential diagnosis of hypereosinophilia is broad and includes asthma, atopic disease, drug hypersensitivity, parasitic infection, connective tissue disorders, malignancy, and rare hypereosinophilic disorders. Hypereosinophilia in children has not been well characterized to date. OBJECTIVE: The objective of this study was to identify the common causes of marked eosinophilia in children and to characterize and compare the clinical symptoms at presentation, laboratory findings, final diagnosis, and therapeutic responses between children and adults with hypereosinophilic syndromes. METHODS: A retrospective analysis of consecutive subjects evaluated for unexplained eosinophilia >= 1.5 3 10(9)/L was conducted. All subjects underwent standardized clinical and laboratory evaluations with yearly follow-up. Clinical and laboratory parameters, final diagnoses, treatment responses, and outcomes were assessed. Medians and proportions were compared using Mann-Whitney U and Fisher Exact tests, respectively. RESULTS: Of the 291 subjects evaluated, 37 (13%) were children and 254 were adults (87%). Whereas the frequencies of clinical hypereosinophilic syndrome (HES) variants were similar between children and adults, primary immunodeficiency was a more common secondary cause of HES in children (5% vs 0.4% in adults). Excluding subjects with treatable secondary causes, the median peak absolute eosinophil count was increased in pediatric subjects (9376 vs 5543/mu L; P = .002), and children had more gastrointestinal complaints (62% vs 34%; P = .003) and less pulmonary involvement (34% vs 59%; P = .01) than adults. Despite these differences, corticosteroid responsiveness and overall prognosis were similar between the 2 groups. CONCLUSIONS: Although children with HES often present with higher peak eosinophil counts than adults, the differential diagnosis, clinical characteristics, and prognosis of HES are similar in the 2 groups. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology C1 [Williams, Kelli W.] Med Univ South Carolina, Dept Pediat, Charleston, SC 29425 USA. [Ware, JeanAnne; Abiodun, Annalise; Khoury, Paneez; Klion, Amy D.] NIAID, Lab Parasit Dis, NIH, Bldg 4,Room B1-28,4 Mem Dr, Bethesda, MD 20892 USA. [Abiodun, Annalise] GBMC Healthcare, Dept Internal Med, Baltimore, MD USA. [Holland-Thomas, Nicole C.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Clin Res Directorate, Clin Monitoring Res Program, Frederick, MD USA. RP Klion, AD (reprint author), NIAID, Lab Parasit Dis, NIH, Bldg 4,Room B1-28,4 Mem Dr, Bethesda, MD 20892 USA. EM aklion@nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH); National Cancer Institute, NIH [HHSN2610080001E]; National Institute of Allergy and Infectious Diseases FX The work was funded by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH). This project has been funded in whole or in part with federal funds from the National Cancer Institute, NIH under Contract No. HHSN2610080001E. 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 National Institute of Allergy and Infectious Diseases. NR 27 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2198 EI 2213-2201 J9 J ALLER CL IMM-PRACT JI J. Allergy Clin. Immunol.-Pract. PD SEP-OCT PY 2016 VL 4 IS 5 BP 941 EP + DI 10.1016/j.jaip.2016.03.020 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA EE4YW UT WOS:000389612800020 PM 27130711 ER PT J AU Zhang, XY Guo, L Zeng, HY White, SL Furniss, M Balasubramanian, B Lis, E Lagrutta, A Sannajust, F Zhao, LL Xi, B Wang, XB Davis, M Abassi, YA AF Zhang, Xiaoyu Guo, Liang Zeng, Haoyu White, Stephen L. Furniss, Michael Balasubramanian, Bharathi Lis, Edward Lagrutta, Armando Sannajust, Frederick Zhao, Li Leyna Xi, Biao Wang, Xiaobo Davis, Myrtle Abassi, Yama A. TI Multi-parametric assessment of cardiomyocyte excitation-contraction coupling using impedance and field potential recording: A tool for cardiac safety assessment SO JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS LA English DT Article DE Cardiomyocytes; CardioECR; Contractility; Arrhythmia; iPSC ID LONG QT SYNDROME; INTERVAL PROLONGATION; POTASSIUM CHANNELS; RISK-ASSESSMENT; THOROUGH QT; RANOLAZINE; INHIBITION; ASSAYS; REPOLARIZATION; PROARRHYTHMIA AB Introduction: The ICH S7B guidelines recommend that all new chemical entities should be subjected to hERG repolarization screening due to its association with life-threatening "Torsades de Pointes" (TdP) arrhythmia. However, it has become evident that not all hERG channel inhibitors result in TdP and not all compounds that induce QT prolongation and TdP necessarily inhibit hERG. In order to address the limitations of the S7B/E14 guidelines, the FDA through a public/private partnership initiated the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative to examine the possible modification and refinement of the ICH E14/S7B guidelines. One of the main components of the CiPA initiative is to utilize a predictive assay system together with human cardiomyocytes for risk assessment of arrhythmia. Method: In this manuscript we utilize the xCELLigence (R) CardioECR system which simultaneously measures excitation-contraction coupling together with human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) to assess the effect of 8 reference compounds across 3 different independent sites. These 8 compounds were part of Phase I CiPA validation study. Results: Our data demonstrate that hERG channel blockers, such as E4031 and moxifloxacin, prolonged field potential duration (FPD) at lowconcentration and induced arrhythmic beating activity as measured by field potential (FP) recording and impedance (IMP) recordings at higher concentrations. On the contrary, nifedipine, an inhibitor of calcium channel, didn't disrupt the periodicity of cell beating and weakened cell contractile activity and shortened FPD. Multichannel inhibitors, such as flecainide, quinidine and mexiletine, not only increased FPD and induced arrhythmia but also significantly reduced the amplitude of FP spike. JNJ303, an IKs inhibitor, only affected FPD. Comparison of the compound effect on FPD across the 3 different sites is consistent in terms of trend of the effect with observed 3-10 fold differences in minimal effective concentration at which a minimum of 10% response is detected. In addition, pentamidine, a hERG trafficking inhibitor which induced irregular beating activity over a more prolonged duration of time was readily flagged in this assay system. Taken together, this multi-parameter assay using hiPSC-CMs in conjunction with simultaneous measurement of ion channel activity and contractility can be a reliable approach for risk assessment of proarrhythmic compounds. (C) 2016 Elsevier Inc. All rights reserved. C1 [Zhang, Xiaoyu; Zhao, Li Leyna; Xi, Biao; Wang, Xiaobo; Abassi, Yama A.] ACEA Biosci Inc, San Diego, CA 92121 USA. [Guo, Liang; Furniss, Michael] Leidos Biomed Res Inc, Lab Invest Toxicol, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Zeng, Haoyu; Balasubramanian, Bharathi; Lis, Edward; Lagrutta, Armando; Sannajust, Frederick] Merck Res Labs, SALAR, Safety & Exploratory Pharmacol Dept, West Point, PA 19486 USA. [White, Stephen L.] NCI, Drug Synth & Chem Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Bethesda, MD 20892 USA. [Davis, Myrtle] NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Bethesda, MD 20892 USA. RP Abassi, YA (reprint author), ACEA Biosci Inc, San Diego, CA 92121 USA. EM yabassi@aceabio.com NR 39 TC 2 Z9 3 U1 4 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1056-8719 EI 1873-488X J9 J PHARMACOL TOX MET JI J. Pharmacol. Toxicol. Methods PD SEP-OCT PY 2016 VL 81 BP 201 EP 216 DI 10.1016/j.vascn.2016.06.004 PG 16 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA EE3YB UT WOS:000389537100022 PM 27282640 ER PT J AU Ferris, FL Nathan, DM AF Ferris, Frederick L. Nathan, David M. TI Preventing Diabetic Retinopathy Progression SO OPHTHALMOLOGY LA English DT Editorial Material ID FOLLOW-UP; COMPLICATIONS; TRIAL; RISK C1 [Ferris, Frederick L.] NEI, Div Epidemiol & Clin Applicat, Bldg 10 CRC,Room 3-2531,31 Ctr Dr, Bethesda, MD 20892 USA. RP Ferris, FL (reprint author), NEI, Div Epidemiol & Clin Applicat, Bldg 10 CRC,Room 3-2531,31 Ctr Dr, Bethesda, MD 20892 USA. EM rickferris3@gmail.com NR 15 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 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD SEP PY 2016 VL 123 IS 9 BP 1840 EP 1842 DI 10.1016/j.ophtha.2016.05.039 PG 3 WC Ophthalmology SC Ophthalmology GA EE3QE UT WOS:000389508500011 PM 27549874 ER PT J AU Yeetong, P Vilboux, T Ciccone, C Boulier, K Schnur, RE Gahl, WA Huizing, M Laje, G Smith, ACM AF Yeetong, Patra Vilboux, Thierry Ciccone, Carla Boulier, Kristin Schnur, Rhonda E. Gahl, William A. Huizing, Marjan Laje, Gonzalo Smith, Ann C. M. TI Delayed Diagnosis in a House of Correction: Smith-Magenis Syndrome Due to a De Novo Nonsense RAI1 Variant SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE aggressive behavior; incarceration; legal discussion; psychiatric comorbidity; RAI1; Smith-Magenis syndrome ID 17P11.2; GENE; (17)(P11.2P11.2); GENOTYPE; SPECTRUM; DELETION AB We report a 25-year-old female confirmed to have Smith-Magenis syndrome (SMS) due to a de novo RAI1 variant. Her past history is significant for developmental and intellectual delay, early and escalating maladaptive behaviors, and features consistent with significant sleep disturbance, the etiology of which was not confirmed for over two decades. The diagnosis of SMS was initially suspected in 1998 (at age 12 years), but that was 5 years before the initial report of RAI1 variants as causative of the SMS phenotype; cytogenetic fluorescence in situ hybridization studies failed to confirm an interstitial deletion of 17p11.2. Re-evaluation for suspected SMS was pursued with RAI1 sequencing analysis in response to urgent parental concerns of escalating behaviors and aggression with subsequent incarceration of the subject for assault of a health professional. Genetic analysis revealed a de novo RAI1 (NM_030665.3) nonsense variant, c.5536C>T; p.Q1846X. This case illustrates the importance of confirming the SMS diagnosis, which is associated with cognitive and functional impairment, as well as significant psychiatric comorbidities and behavioral problems. The diagnosis was particularly relevant to the legal discussion and determination of her competence to stand trial. As other similar cases may exist, this report will help to increase awareness of the possibility of a very late diagnosis of SMS, with the need for re-evaluation of individuals suspected to have SMS who were initially evaluated prior to the identification of the RAI1 gene. (C) 2016 Wiley Periodicals, Inc. C1 [Yeetong, Patra; Vilboux, Thierry; Ciccone, Carla; Boulier, Kristin; Gahl, William A.; Huizing, Marjan] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Yeetong, Patra] Chulalongkorn Univ, Div Human Genet, Dept Bot, Fac Sci, Bangkok, Thailand. [Vilboux, Thierry] Inova Translat Med Inst, Div Med Genom, Falls Church, VA USA. [Schnur, Rhonda E.] Rowan Univ, Cooper Univ Hlth Care, Cooper Med Sch, Div Genet,Dept Pediat, Camden, NJ USA. [Gahl, William A.; Smith, Ann C. M.] NHGRI, Off Clin Director, NIH, 10 Ctr Dr,MSC 1851,Bld 10,Rm 10C103, Bethesda, MD 20895 USA. [Laje, Gonzalo] Autism Spectrum Partners LLC, Washington Behav Med Associates LLC, MIND, Chevy Chase, MD USA. RP Smith, ACM (reprint author), NHGRI, Off Clin Director, NIH, 10 Ctr Dr,MSC 1851,Bld 10,Rm 10C103, Bethesda, MD 20895 USA. EM acmsmith@mail.nih.gov FU Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health; Intramural Research Program of the National Institute of Mental Health, National Institutes of Health; Jerome Lejeune Foundation FX Grant sponsor: Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health; Grant sponsor: Intramural Research Program of the National Institute of Mental Health, National Institutes of Health; Grant sponsor: Jerome Lejeune Foundation. NR 18 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD SEP PY 2016 VL 170 IS 9 BP 2383 EP 2388 DI 10.1002/ajmg.a.37602 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA DW4JJ UT WOS:000383608700021 PM 27311559 ER PT J AU Cohen, BE AF Cohen, B. Eleazar TI The Role of Signaling via Aqueous Pore Formation in Resistance Responses to Amphotericin B SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Review ID SPHINGOLIPID BIOSYNTHETIC-PATHWAY; LIPID BILAYER-MEMBRANES; PLASMA-MEMBRANE; ASPERGILLUS-TERREUS; POLYENE ANTIBIOTICS; CANDIDA-ALBICANS; MULTIDRUG-RESISTANCE; LEISHMANIA-DONOVANI; CRYSTAL-STRUCTURE; RAS NANOCLUSTERS AB Drug resistance studies have played an important role in the validation of antibiotic targets. In the case of the polyene antibiotic amphotericin B (AmB), such studies have demonstrated the essential role that depletion of ergosterol plays in the development of AmB-resistant (AmB-R) organisms. However, AmB-R strains also occur in fungi and parasitic protozoa that maintain a normal level of ergosterol at the plasma membrane. Here, I review evidence that shows not only that there is increased protection against the deleterious consequences of AmB-induced ion leakage across the membrane in these resistant pathogens but also that a set of events are activated that block the cell signaling responses that trigger the oxidative damage produced by the antibiotic. Such signaling events appear to be the consequence of a membrane-thinning effect that is exerted upon lipid-anchored Ras proteins by the aqueous pores formed by AmB. A similar membrane disturbance effect may also explain the activity of AmB on mammalian cells containing Toll-like receptors. These resistance mechanisms expand our current understanding of the role that the formation of AmB aqueous pores plays in triggering signal transduction responses in both pathogens and host immune cells. C1 [Cohen, B. Eleazar] NIAID, Div Extramural Act, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Cohen, BE (reprint author), NIAID, Div Extramural Act, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ecohen@niaid.nih.gov NR 97 TC 1 Z9 1 U1 2 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD SEP PY 2016 VL 60 IS 9 BP 5122 EP 5129 DI 10.1128/AAC.00878-16 PG 8 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA ED7OH UT WOS:000389055400003 PM 27381391 ER PT J AU Noguchi, LM Montgomery, ET Biggio, JR Hendrix, CW Bogen, DL Hillier, SL Dai, JY Piper, JM Marzinke, MA Dezzutti, CS Isaacs, SK Schwartz, JL Watts, DH Beigi, RH AF Noguchi, Lisa M. Montgomery, Elizabeth T. Biggio, Joseph R. Hendrix, Craig W. Bogen, Debra L. Hillier, Sharon L. Dai, James Y. Piper, Jeanna M. Marzinke, Mark A. Dezzutti, Charlene S. Isaacs, S. Karen Schwartz, Jill L. Watts, D. Heather Beigi, Richard H. TI Detectable Tenofovir Levels in Breast-Feeding Infants of Mothers Exposed to Topical Tenofovir SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID LACTATING WOMEN; HIV-INFECTION; PHARMACOKINETICS; GEL; PROPHYLAXIS; MILK AB Lactation studies are necessary evaluations of medications for reproductive-age women. We evaluated pharmacokinetics (PK), pharmacodynamics, safety, and adherence profiles associated with 7 days of 1% tenofovir (TFV) vaginal gel use during lactation. Tenofovir levels (maternal/infant serum, milk) and anti-HIV activity (milk), adverse events (AEs), and adherence were measured for 17 HIV-1-seronegative breast-feeding mother-infant pairs. Tenofovir use was well-tolerated and detected at low levels in maternal serum, milk, and infant serum but demonstrated no anti-HIV activity in milk. C1 [Noguchi, Lisa M.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Montgomery, Elizabeth T.] RTI Int, Womens Global Hlth Imperat, San Francisco, CA USA. [Biggio, Joseph R.] Univ Alabama Birmingham, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. [Hendrix, Craig W.] Johns Hopkins Univ, Dept Med Clin Pharmacol, Baltimore, MD USA. [Bogen, Debra L.] Univ Pittsburgh, Dept Pediat, Pittsburgh, PA 15260 USA. [Hillier, Sharon L.; Dezzutti, Charlene S.; Beigi, Richard H.] Univ Pittsburgh, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Dai, James Y.] Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res, 1124 Columbia St, Seattle, WA 98104 USA. [Piper, Jeanna M.] NIAID, Div Aids, US Natl Inst Hlth, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Marzinke, Mark A.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Isaacs, S. Karen] FHI 360, Sci Facilitat, Durham, NC USA. [Schwartz, Jill L.] CONRAD Eastern Virginia Med Sch, Arlington, VA USA. [Watts, D. Heather] NICHD, Maternal & Pediat Infect Dis Branch, US Natl Inst Hlth, Bethesda, MD USA. [Isaacs, S. Karen] Parexel Int, Durham, NC USA. [Watts, D. Heather] US Dept State, Washington, DC 20520 USA. RP Noguchi, LM (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. EM lnoguch1@jhu.edu RI Hendrix, Craig/G-4182-2014 OI Hendrix, Craig/0000-0002-5696-8665 FU HHS \ National Institutes of Health (NIH) [UM1AI068633, UM1AI068615, UM1AI106707, P30AI042855]; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Development; National Institute of Mental Health [UM1AI068633, UM1AI068615, UM1AI106707]; USAID; Johns Hopkins Center for AIDS Research [P30AI042855] FX This work, including the efforts of Lisa M. Noguchi, Elizabeth T. Montgomery, Joseph R. Biggio, Craig W. Hendrix, Debra L. Bogen, Sharon L. Hillier, James Y. Dai, Jeanna M. Piper, Mark A. Marzinke, Charlene S. Dezzutti, S. Karen Isaacs, Jill Schwartz, D. Heather Watts, and Richard H. Beigi, was funded by HHS vertical bar National Institutes of Health (NIH) (UM1AI068633, UM1AI068615, UM1AI106707, and P30AI042855).; This work was conducted by the Microbicide Trials Network, which is funded by the National Institute of Allergy and Infectious Diseases, with cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Development and the National Institute of Mental Health (UM1AI068633, UM1AI068615, and UM1AI106707), all components of the National Institutes of Health. Tenofovir gel was provided by CONRAD (Arlington, VA) using funding from USAID. TFV assays were supported, in part, by the Johns Hopkins Center for AIDS Research (P30AI042855). NR 19 TC 1 Z9 1 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD SEP PY 2016 VL 60 IS 9 BP 5616 EP 5619 DI 10.1128/AAC.00645-16 PG 4 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA ED7OH UT WOS:000389055400065 PM 27401570 ER PT J AU Lebedeva, A Nikitskaya, E Ivanova, O Grivel, JC Maryukhnich, E Shpektor, A Vasilieva, E Margolis, L AF Lebedeva, A. Nikitskaya, E. Ivanova, O. Grivel, J. C. Maryukhnich, E. Shpektor, A. Vasilieva, E. Margolis, L. TI CYTOMEGALOVIRUS DNA LOAD AND T-LYMPHOCYTES ACTIVATION IN ATHEROSCLEROTIC PLAQUES SO ATHEROSCLEROSIS LA English DT Meeting Abstract CT Congress of the European-Atherosclerosis-Society (EAS) CY MAY 29-JUN 01, 2016 CL Innsbruck, AUSTRIA SP European Atherosclerosis Soc C1 [Lebedeva, A.; Nikitskaya, E.; Ivanova, O.; Maryukhnich, E.; Shpektor, A.; Vasilieva, E.] Moscow State Univ Med & Dent, Lab Atherothrombosis, Moscow, Russia. [Grivel, J. C.; Margolis, L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Sect Intercellular Interact, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD SEP PY 2016 VL 252 MA EAS16-0760 BP E177 EP E178 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA ED6PR UT WOS:000388978400601 ER PT J AU Nikitskaya, E Ivanova, O Elena, M Jean-Charles, G Lebedeva, A Shpektor, A Margolis, L Vasilieva, E AF Nikitskaya, E. Ivanova, O. Elena, M. Jean-Charles, G. Lebedeva, A. Shpektor, A. Margolis, L. Vasilieva, E. TI HUMAN HERPESVIRUS ACTIVATION IN PATIENTS WITH ACUTE CORONARY SYNDROME SO ATHEROSCLEROSIS LA English DT Meeting Abstract CT Congress of the European-Atherosclerosis-Society (EAS) CY MAY 29-JUN 01, 2016 CL Innsbruck, AUSTRIA SP European Atherosclerosis Soc C1 [Ivanova, O.; Elena, M.; Lebedeva, A.; Shpektor, A.; Vasilieva, E.] Moscow State Univ Med & Dent, Lab Atherothrombosis, Moscow, Russia. [Jean-Charles, G.; Margolis, L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Sect Intercellular Interact, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD SEP PY 2016 VL 252 MA EAS16-0763 BP E180 EP E180 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA ED6PR UT WOS:000388978400608 ER PT J AU Ryazankina, N Vagida, M Manchurov, V Lebedeva, A Arakelyan, A Grivel, C Margolis, L Vasilieva, E Shpektor, A AF Ryazankina, N. Vagida, M. Manchurov, V. Lebedeva, A. Arakelyan, A. Grivel, C. Margolis, L. Vasilieva, E. Shpektor, A. TI REMOTE ISCHEMIC PRECONDITIONING AND ENDOTHELIAL FUNCTION IN HEALTHY VOLUNTEERS SO ATHEROSCLEROSIS LA English DT Meeting Abstract CT Congress of the European-Atherosclerosis-Society (EAS) CY MAY 29-JUN 01, 2016 CL Innsbruck, AUSTRIA SP European Atherosclerosis Soc C1 [Ryazankina, N.; Vagida, M.; Manchurov, V.; Lebedeva, A.; Vasilieva, E.; Shpektor, A.] Moscow State Univ Med & Dent, Cardiol, Moscow, Russia. [Arakelyan, A.; Grivel, C.; Margolis, L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Program Phys Biol, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD SEP PY 2016 VL 252 MA EAS16-0714 BP E52 EP E52 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA ED6PR UT WOS:000388978400171 ER PT J AU Tsujita, M Yokota, T Akita, N Gonzalez, FJ Yokoyama, S AF Tsujita, M. Yokota, T. Akita, N. Gonzalez, F. J. Yokoyama, S. TI SR-BI INVOLVED ON PLASMA HDL2-APOA-I RECIRCULATION TO PRE beta-HDL IN MICE SO ATHEROSCLEROSIS LA English DT Meeting Abstract CT Congress of the European-Atherosclerosis-Society (EAS) CY MAY 29-JUN 01, 2016 CL Innsbruck, AUSTRIA SP European Atherosclerosis Soc C1 [Tsujita, M.; Yokota, T.] Nagoya City Univ, Grad Sch Med Sci, Biochem, Nagoya, Aichi, Japan. [Akita, N.] Gifu Prefectural Tajimi Hosp, Cardiol, Tajimi, Japan. [Gonzalez, F. J.] NCI, CCR, NIH, Lab Metab, Bethesda, MD 20892 USA. [Yokoyama, S.] Chubu Univ, Nutr Hlth Sci Res Ctr, Kasugai, Aichi, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD SEP PY 2016 VL 252 MA EAS16-0249 BP E207 EP E207 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA ED6PR UT WOS:000388978400701 ER PT J AU Olson, JL Bild, DE Kronmal, RA Burke, GL AF Olson, Jean L. Bild, Diane E. Kronmal, Richard A. Burke, Gregory L. TI Legacy of MESA SO Global Heart LA English DT Article ID CORONARY-ARTERY CALCIUM; POPULATION-BASED COHORT; CARDIOVASCULAR EVENTS; ATHEROSCLEROSIS MESA; HEART-DISEASE; RISK; DECLINE AB The MESA (Multi-Ethnic Study of Atherosclerosis) was initiated to address unresolved questions about subclinical cardiovascular disease and its progression to clinically overt cardiovascular disease in a diverse population-based sample, incorporating emerging imaging technologies for better evaluation of subclinical disease and creating a population laboratory for future research. MESA's recruited (from 2000 to 2002) cohort comprised >6,000 adults from 4 racial/ethnic groups, ages 45 to 84 years, who were free of cardiovascular disease at baseline. Extensive cohort data have been collected over 5 exams (through 2011) with additional exam components added through extramurally funded ancillary study grants, and through regular phone follow-up contacts. Over 1,000 MESA papers have been published to date. Exam 6 will incorporate components that use novel wearable, imaging, and other technologies to address new research questions. MESA investigators have and continue to seek opportunities for collaboration with other researchers on a wide variety of topics to further expand the science of MESA. C1 [Olson, Jean L.] NHLBI, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. [Bild, Diane E.] Patient Ctr Outcomes Res Inst, Clin Effectiveness Res Dept, Washington, DC USA. [Kronmal, Richard A.] Collaborat Hlth Studies Coordinating Ctr, Dept Biostat, Seattle, WA USA. [Burke, Gregory L.] Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC USA. RP Burke, GL (reprint author), Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC USA. EM gburke@wakehealth.edu FU NCATS NIH HHS [UL1 TR001420]; NHLBI NIH HHS [N01 HC095165, R01 HL071258, N01 HC095159] NR 21 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 2211-8160 EI 2211-8179 J9 GLOB HEART JI Glob. Heart PD SEP PY 2016 VL 11 IS 3 BP 269 EP 274 DI 10.1016/j.gheart.2016.08.004 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA ED9WY UT WOS:000389225400002 PM 27741974 ER PT J AU Mensah, GA AF Mensah, George A. TI Charting the Future for Ethnicity and Health Research Clinical and Population Science Insights From the MESA SO Global Heart LA English DT Article ID INTIMA-MEDIA THICKNESS; AMBIENT AIR-POLLUTION; CORONARY-HEART-DISEASE; ATHEROSCLEROSIS MESA; SUBCLINICAL ATHEROSCLEROSIS; CARDIOVASCULAR EVENTS; CALCIUM; RISK; INDIVIDUALS; ASSOCIATION AB The MESA (Multi-Ethnic Study of Atherosclerosis) has been highly successful in investigating the prevalence, characteristics, and progression of subclinical cardiovascular disease (CVD) in a multiethnic American cohort of adult men and women free of CVD at baseline. MESA has also championed the use of novel biomarkers and emerging imaging techniques for the assessment of subclinical CVD and has created an extensive set of data that continues to fuel dozens of ongoing analyses. Insights from MESA include the first demonstration of ethnic differences in coronary artery calcification and its association with subclinical disease progression and incident CVD. Other findings include ethnic differences in the prevalence of pharmacological, behavioral, and lifestyle interventions for the primary prevention of CVD. MESA has also shown the association between residential neighborhood characteristics and behavioral and biomedical risk factors for CVD. This vast amount of data documenting ethnic differences in progression of subclinical CVD, diabetes, kidney disease, and pulmonary disease contrasts sharply with the relative scarcity of specific information that can pave the way for the elimination of racial and ethnic disparities. Intervention research, however, goes beyond the original objectives of MESA and other observational studies. The time has now come to build on the legacy of MESA by supporting rigorous intervention research that informs clinical and public health strategies as well as policy and environmental changes for eliminating racial and ethnic disparities in CVD and other chronic diseases and advancing the health of multiethnic communities. C1 [Mensah, George A.] NHLBI, Ctr Translat Res & Implementat Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. [Mensah, George A.] NHLBI, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Mensah, GA (reprint author), NHLBI, Ctr Translat Res & Implementat Sci, NIH, Bldg 10, Bethesda, MD 20892 USA.; Mensah, GA (reprint author), NHLBI, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. EM George.Mensah@nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 36 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 2211-8160 EI 2211-8179 J9 GLOB HEART JI Glob. Heart PD SEP PY 2016 VL 11 IS 3 BP 365 EP 367 DI 10.1016/j.gheart.2016.09.002 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA ED9WY UT WOS:000389225400011 PM 27741983 ER PT J AU Emukule, GO Mott, JA Spreeuwenberg, P Viboud, C Commanday, A Muthoka, P Munywoki, PK Nokes, DJ van Der Velden, K Paget, JW AF Emukule, Gideon O. Mott, Joshua A. Spreeuwenberg, Peter Viboud, Cecile Commanday, Alexander Muthoka, Philip Munywoki, Patrick K. Nokes, David J. van der Velden, Koos Paget, John W. TI Influenza activity in Kenya, 2007-2013: timing, association with climatic factors, and implications for vaccination campaigns SO INFLUENZA AND OTHER RESPIRATORY VIRUSES LA English DT Article DE Humidity; influenza; Kenya; respiratory; seasonality; vaccination ID SEASONALITY; CHILDREN; TROPICS; VIRUS AB Background Information on the timing of influenza circulation remains scarce in Tropical regions of Africa. Objectives We assessed the relationship between influenza activity and several meteorological factors (temperature, specific humidity, precipitation) and characterized the timing of influenza circulation and its implications to vaccination strategies in Kenya. Methods We analyzed virologically confirmed influenza data for outpatient influenza-like illness (ILI), hospitalized for severe acute respiratory infections (SARI), and cases of severe pneumonia over the period 2007-2013. Using logistic and negative binomial regression methods, we assessed the independent association between climatic variables (lagged up to 4 weeks) and influenza activity. Results There were multiple influenza epidemics occurring each year and lasting a median duration of 2-4 months. On average, there were two epidemics occurring each year in most of the regions in Kenya, with the first epidemic occurring between the months of February and March and the second one between July and November. Specific humidity was independently and negatively associated with influenza activity. Combinations of low temperature (<18 degrees C) and low specific humidity (<11 g/kg) were significantly associated with increased influenza activity. Conclusions Our study broadens understanding of the relationships between seasonal influenza activity and meteorological factors in the Kenyan context. While rainfall is frequently thought to be associated with influenza circulation in the tropics, the present findings suggest low humidity is more important in Kenya. If annual vaccination were a component of a vaccination strategy in Kenya, the months of April to June are proposed as optimal for associated campaigns. C1 [Emukule, Gideon O.; Mott, Joshua A.] Ctr Dis Control & Prevent, Kenya Country Off, Nairobi, Kenya. [Emukule, Gideon O.; van der Velden, Koos; Paget, John W.] Radboud Univ Nijmegen, Med Ctr, Dept Primary & Community Care, Nijmegen, Netherlands. [Mott, Joshua A.; Commanday, Alexander] US Ctr Dis Control & Prevent, Influenza Div, Natl Ctr Immunizat & Resp Dis, Atlanta, GA USA. [Mott, Joshua A.] US PHS, Rockville, MD USA. [Spreeuwenberg, Peter; Paget, John W.] Netherlands Inst Hlth Serv Res NIVEL, Utrecht, Netherlands. [Viboud, Cecile] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Muthoka, Philip] Govt Kenya, Minist Hlth, Nairobi, Kenya. [Munywoki, Patrick K.; Nokes, David J.] Kenya Govt Med Res Ctr, Ctr Geog Med Res Coast, Kilifi, Kenya. [Nokes, David J.] Univ Warwick, Sch Life Sci, Coventry, W Midlands, England. RP Emukule, GO (reprint author), Mbagathi Rd,Off Mbagathi Way,POB 606, Nairobi, Kenya. EM uyr9@cdc.gov FU KEMRI; U.S. CDC research collaboration; Wellcome Trust, UK FX This study was supported through The KEMRI and U.S. CDC research collaboration and The Wellcome Trust, UK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 24 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1750-2640 EI 1750-2659 J9 INFLUENZA OTHER RESP JI Influenza Other Respir. Viruses PD SEP PY 2016 VL 10 IS 5 BP 375 EP 385 DI 10.1111/irv.12393 PG 11 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA ED3MV UT WOS:000388754100004 PM 27100128 ER PT J AU Umar, A Richmond, E AF Umar, Asad Richmond, Ellen TI NSAIDs and EGFR Inhibitors for Duodenal Polyp Prevention SO JAMA ONCOLOGY LA English DT Editorial Material ID FAMILIAL ADENOMATOUS POLYPOSIS; SULINDAC; TRIAL; DIFLUOROMETHYLORNITHINE; CELECOXIB; PLACEBO AB IMPORTANCE Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for duodenal polyps and cancer. Surgical and endoscopic management of duodenal neoplasia is difficult and chemoprevention has not been successful. OBJECTIVE To evaluate the effect of a combination of sulindac and erlotinib on duodenal adenoma regression in patients with FAP. DESIGN, SETTING, AND PARTICIPANTS Double-blind, randomized, placebo-controlled trial, enrolling 92 participants with FAP, conducted from July 2010 through June 2014 at Huntsman Cancer Institute in Salt Lake City, Utah. INTERVENTIONS Participants with FAP were randomized to sulindac (150mg) twice daily and erlotinib (75mg) daily (n = 46) vs placebo (n = 46) for 6 months. MAIN OUTCOMES AND MEASURES The total number and diameter of polyps in the proximal duodenum were mapped at baseline and 6 months. The primary outcome was change in total polyp burden at 6 months. Polyp burden was calculated as the sum of the diameters of polyps. The secondary outcomes were change in total duodenal polyp count, change in duodenal polyp burden or count stratified by genotype and initial polyp burden, and percentage of change from baseline in duodenal polyp burden. RESULTS Ninety-two participants (mean age, 41 years [range, 24-55]; women, 56 [61%]) were randomized when the trial was stopped prematurely by recommendation of the external data and safety monitoring board because the second preplanned interim analysis met the prespecified stopping rule for superiority. Over 6 months, the median duodenal polyp burden in the sulindac-erlotinib group decreased from 29.0mmto 19.5mm(median change, -8.5 mm), and in the placebo group increased from 23.0mmto 31.0mm(median change, 8.0 mm), for a net difference of -19.0mm(95% CI, -32.0 to -10.9; P <.001) between the groups. The median duodenal polyp count in the sulindac-erlotinib group decreased from 13.5 to 10.0 (median change, -2.8), and in the placebo group increased from 10.5 to 17.0 (median change, 4.3), for a net difference between treatment and placebo groups of -8.0 polyps (95% CI, -12.2 to -4.7; P <.001). Grade 1 and 2 adverse events were more common in the sulindac-erlotinib group, with an acne-like rash observed in 87% of participants receiving treatment and 20% of participants receiving placebo (P <.001). Only 2 participants experienced grade 3 adverse events: 1 in the treatment group experienced oral mucositis and 1 receiving placebo experienced abdominal pain. CONCLUSIONS AND RELEVANCE Among participants with FAP, the use of sulindac and erlotinib compared with placebo resulted in a lower duodenal polyp burden after 6 months. Adverse events may limit the use of these medications at the doses used in this study. Further research is necessary to evaluate these preliminary findings in a larger study population with longer follow-up to determine whether the observed effects will result in improved clinical outcomes. C1 [Umar, Asad; Richmond, Ellen] NCI, Canc Prevent Div, Gastrointestinal & Other Canc Res Grp, 9609 Med Ctr Dr,5E226, Bethesda, MD 20892 USA. RP Umar, A (reprint author), NCI, Canc Prevent Div, Gastrointestinal & Other Canc Res Grp, 9609 Med Ctr Dr,5E226, Bethesda, MD 20892 USA. EM asad.umar@nih.gov NR 8 TC 0 Z9 0 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 SEP PY 2016 VL 2 IS 9 BP 1223 EP 1225 DI 10.1001/jamaoncol.2016.1227 PG 3 WC Oncology SC Oncology GA DW5RS UT WOS:000383705200020 PM 27367234 ER PT J AU Sherwin, LB Leary, E Henderson, WA AF Sherwin, LeeAnne B. Leary, Emily Henderson, Wendy A. TI Effect of Illness Representations and Catastrophizing on Quality of Life in Adults With Irritable Bowel Syndrome SO JOURNAL OF PSYCHOSOCIAL NURSING AND MENTAL HEALTH SERVICES LA English DT Article ID PSYCHOSOCIAL VITAL SIGNS; COPING STRATEGIES; SYMPTOM SEVERITY; IBS PATIENTS; SYNDROME-CONSTIPATION; RHEUMATOID-ARTHRITIS; ABDOMINAL-PAIN; DISEASE; PERCEPTIONS; ADJUSTMENT AB There is limited understanding of the influence of psychosocial factors on irritable bowel syndrome (IBS), which contributes to management difficulties and ineffective long-term treatment. The goal of the current study was to assess the effect illness representations and coping had on health-related quality of life (HRQOL) in adults with IBS. Self-report data were collected from 101 adults with IBS. Illness representations were measured with the Revised Illness Perception Questionnaire; catastrophizing was measured with the catastrophizing subscale of the Coping Strategies Questionnaire; and HRQOL was measured using the IBS-Quality of Life Measure. Participants perceived their IBS to be a chronic, cyclical condition with negative consequences, moderate symptomatology, and strong negative emotional impact. Their quality of life was poor and catastrophic thinking was noted to be used. Therefore, integrating illness beliefs and coping style into the management of IBS may improve well-being and minimize suffering. C1 [Sherwin, LeeAnne B.] Univ Missouri, Sinclair Sch Nursing, S 430, Columbia, MO 65211 USA. [Leary, Emily] Natl Inst Nursing Res, NIH, Biobehav Branch, Bethesda, MD USA. [Henderson, Wendy A.] Univ Missouri, Sch Med, Biostat & Res Design Unit, Columbia, MO 65211 USA. RP Sherwin, LB (reprint author), Univ Missouri, Sinclair Sch Nursing, S 430, Columbia, MO 65211 USA. EM sherwinl@missouri.edu OI Leary, Emily /0000-0003-0836-7440 FU Grand Teton Gastroenterology, Idaho; Gastroenterology Center of Connecticut FX The authors have disclosed no potential conflicts of interest, financial or otherwise. This study was financially supported by Grand Teton Gastroenterology, Idaho, and The Gastroenterology Center of Connecticut. The authors acknowledge the editorial support and guidance provided by Vicki Conn, PhD, RN, FAAN, and Todd Ruppar, PhD, RN, for manuscript preparation. NR 62 TC 0 Z9 0 U1 1 U2 2 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0279-3695 EI 1938-2413 J9 J PSYCHOSOC NURS MEN JI J. Psychosoc. Nurs. Ment. Health Serv. PD SEP PY 2016 VL 54 IS 9 BP 44 EP 56 PG 13 WC Nursing SC Nursing GA ED8TJ UT WOS:000389143500012 PM 27576228 ER PT J AU Drozdovitch, V Chumak, V Kesminiene, A Ostroumova, E Bouville, A AF Drozdovitch, Vladimir Chumak, Vadim Kesminiene, Ausrele Ostroumova, Evgenia Bouville, Andre TI Doses for post-Chernobyl epidemiological studies: are they reliable? SO JOURNAL OF RADIOLOGICAL PROTECTION LA English DT Review DE Chernobyl; dosimetry; uncertainty; reliability; epidemiological study ID US RADIOLOGIC TECHNOLOGISTS; NUCLEAR-REACTOR ACCIDENT; CHILDHOOD THYROID-CANCER; SHORT-LIVED RADIOIODINES; EXPOSED IN-UTERO; CLEANUP WORKERS; UKRAINIAN-AMERICAN; MONTE-CARLO; BELARUSIAN CHILDREN; RADIATION-EXPOSURE AB On 26 April 2016, thirty years will have elapsed since the occurrence of the Chernobyl accident, which has so far been the most severe in the history of the nuclear reactor industry. Numerous epidemiological studies were conducted to evaluate the possible health consequences of the accident. Since the credibility of the association between the radiation exposure and health outcome is highly dependent on the adequacy of the dosimetric quantities used in these studies, this paper makes an effort to overview the methods used to estimate individual doses and the associated uncertainties in the main analytical epidemiological studies (i. e. cohort or case-control) related to the Chernobyl accident. Based on the thorough analysis and comparison with other radiation studies, the authors conclude that individual doses for the Chernobyl analytical epidemiological studies have been calculated with a relatively high degree of reliability and well-characterized uncertainties, and that they compare favorably with many other non-Chernobyl studies. The major strengths of the Chernobyl studies are: (1) they are grounded on a large number of measurements, either performed on humans or made in the environment; and (2) extensive effort has been invested to evaluate the uncertainties associated with the dose estimates. Nevertheless, gaps in the methodology are identified and suggestions for the possible improvement of the current dose estimates are made. C1 [Drozdovitch, Vladimir; Bouville, Andre] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Chumak, Vadim] Natl Res Ctr Radiat Med, Kiev, Ukraine. [Kesminiene, Ausrele; Ostroumova, Evgenia] Int Agcy Res Canc, Lyon, France. RP Drozdovitch, V (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM drozdovv@mail.nih.gov FU European Commission Euratom FP7 [605302] FX This paper was prepared within the framework of the European Commission Euratom FP7 grant No. 605302 'Cooperation on Chernobyl Health Research (CO-CHER)' coordinated by the International Agency for Research on Cancer (Lyon, France). NR 98 TC 1 Z9 1 U1 3 U2 3 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0952-4746 EI 1361-6498 J9 J RADIOL PROT JI J. Radiol. Prot. PD SEP PY 2016 VL 36 IS 3 BP R36 EP R73 DI 10.1088/0952-4746/36/3/R36 PG 38 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA EE6IB UT WOS:000389712100001 PM 27355439 ER PT J AU Song, XL Schenk, JM Diep, P Murphy, RA Harris, TB Eiriksdottir, G Gudnason, V Casper, C Lampe, JW Neuhouser, ML AF Song, Xiaoling Schenk, Jeannette M. Diep, Pho Murphy, Rachel A. Harris, Tamara B. Eiriksdottir, Gudny Gudnason, Vilmundur Casper, Corey Lampe, Johanna W. Neuhouser, Marian L. TI Measurement of Circulating Phospholipid Fatty Acids: Association between Relative Weight Percentage and Absolute Concentrations SO JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION LA English DT Article DE absolute concentration; correlation; partial correlation; phospholipid fatty acid; relative concentration; semipartial correlation ID DE-NOVO LIPOGENESIS; CORONARY-HEART-DISEASE; CARDIOVASCULAR-DISEASE; PROSTATE-CANCER; DIETARY-INTAKE; PLASMA PHOSPHOLIPIDS; RISK; METAANALYSIS; LIPIDS; BLOOD AB Objective: Most epidemiologic studies of circulating phospholipid fatty acids (PLFAs) and disease risk have used the relative concentration (percentage of total) of each fatty acid as the measure of exposure. Using relative concentrations, the total of all fatty acids is summed to 100% and thus the values of individual fatty acid are not independent. This has led to debate, along with the suggestion to use absolute concentrations of fatty acids. We aimed to examine the relationship between relative (weight percentage) and absolute (mg/L) concentrations of individual circulating PLFAs.Methods: Relative and absolute concentrations of 41 circulating PLFAs were measured by gas chromatography in samples from 3 diverse populations. Correlations between the relative and absolute concentrations for each fatty acid were used to measure agreement. Unadjusted correlations and correlations adjusting absolute PLFA concentrations for total cholesterol were calculated.Results: Unadjusted correlations between relative and absolute concentrations, as well as correlations adjusting absolute PLFA concentrations for total cholesterol, were high for most PLFAs in all 3 studies. Across the 3 studies, 28 of the 41 analyzed PLFAs had unadjusted correlations > 0.6 and 39 had adjusted correlations > 0.6.Conclusions: Choice of relative vs absolute concentration may not affect interpretation of results for most circulating PLFAs in studies of association between individual PLFAs and disease outcomes, especially if a covariate reflecting total lipids, such as total circulating cholesterol, is included in the model. However, for fatty acids, such as 16:0 (palmitic acid), with low correlation between the 2 metrics, using relative vs absolute concentration may lead to different inferences regarding their association with the outcome. Because both concentrations could be obtained simultaneously from the same laboratory assay, use of both metrics is warranted to better understand PLFA-disease relationships. C1 [Song, Xiaoling; Schenk, Jeannette M.; Diep, Pho; Casper, Corey; Lampe, Johanna W.; Neuhouser, Marian L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Murphy, Rachel A.; Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. RP Song, XL (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave N,Mail Box M5-A864, Seattle, WA 98109 USA. EM xsong2@fredhutch.org FU Fred Hutchinson Cancer Research Center; Office of Dietary Supplements, NIH [N01-AG012100]; NIA; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); NIH [U54 CA116847, P30 CA015704, R01 CA138165, P30 AI027757] FX This work was supported by the Fred Hutchinson Cancer Research Center; Office of Dietary Supplements, NIH contract N01-AG012100, the NIA Intramural Research Program; Hjartavernd (the Icelandic Heart Association); the Althingi (the Icelandic Parliament); and NIH grants U54 CA116847, P30 CA015704, R01 CA138165, and P30 AI027757. NR 32 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0731-5724 EI 1541-1087 J9 J AM COLL NUTR JI J. Am. Coll. Nutr. PD SEP-OCT PY 2016 VL 35 IS 7 BP 647 EP 656 DI 10.1080/07315724.2015.1116417 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EC0LH UT WOS:000387792000008 PM 27314836 ER PT J AU Naifeh, JA Colpe, LJ Aliaga, PA Sampson, NA Heeringa, SG Stein, MB Ursano, RJ Fullerton, CS Nock, MK Schoenbaum, M Zaslavsky, AM Kessler, RC AF Naifeh, James A. Colpe, Lisa J. Aliaga, Pablo A. Sampson, Nancy A. Heeringa, Steven G. Stein, Murray B. Ursano, Robert J. Fullerton, Carol S. Nock, Matthew K. Schoenbaum, Michael Zaslavsky, Alan M. Kessler, Ronald C. CA Army STARRS Collaborators TI Barriers to Initiating and Continuing Mental Health Treatment Among Soldiers in the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) SO MILITARY MEDICINE LA English DT Article ID NATIONAL-GUARD SOLDIERS; COMBAT TEAM STRUCTURE; MILITARY PERSONNEL; PEACEKEEPING OPERATIONS; PERCEIVED NEED; ACTIVE-DUTY; CARE; DISORDERS; DEPLOYMENT; SEEKING AB U.S. Army soldiers with mental disorders report a variety of barriers to initiating and continuing treatment. Improved understanding of these barriers can help direct mental health services to soldiers in need. A representative sample of 5,428 nondeployed Regular Army soldiers participating in the Army Study to Assess Risk and Resilience in Servicemembers completed a self-administered questionnaire and consented to linking self-administered questionnaire data with administrative records. We examined reported treatment barriers (perceived need, structural reasons, attitudinal reasons) among respondents with current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, mental disorders who either did not seek treatment in the past year (n = 744) or discontinued treatment (n = 145). About 82.4% of soldiers who did not initiate treatment and 69.5% of those who discontinued treatment endorsed at least two barriers; 69.8% of never-treated soldiers reported no perceived need. Attitudinal reasons were cited more frequently than structural reasons among never-treated soldiers with perceived need (80.7% vs. 62.7%) and those who discontinued treatment (71.0% vs. 37.8%). Multivariate associations with sociodemographic, Army career, and mental health predictors varied across barrier categories. These findings suggest most soldiers with mental disorders do not believe they need treatment and those who do typically face multiple attitudinal and, to a lesser extent, structural barriers. C1 [Naifeh, James A.; Aliaga, Pablo A.; Ursano, Robert J.; Fullerton, Carol S.] Uniformed Serv Univ Hlth Sci, Dept Psychiat, Ctr Study Traumat Stress, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. [Colpe, Lisa J.; Schoenbaum, Michael] NIMH, Off Clin & Populat Epidemiol Res, Div Serv & Intervent Res, 6001 Execut Blvd,Room 7137,MSC 9635, Bethesda, MD 20892 USA. [Sampson, Nancy A.; Zaslavsky, Alan M.; Kessler, Ronald C.] Harvard Med Sch, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. [Heeringa, Steven G.] Univ Michigan, Inst Social Res, 426 Thompson St, Ann Arbor, MI 48106 USA. [Stein, Murray B.] Univ Calif San Diego, Dept Psychiat, 8939 Villa La Jolla Dr,Suite 200, La Jolla, CA 92037 USA. [Stein, Murray B.] Univ Calif San Diego, Dept Family Med & Publ Hlth, 8939 Villa La Jolla Dr,Suite 200, La Jolla, CA 92037 USA. [Stein, Murray B.] VA San Diego Healthcare Syst, 8810 Rio San Diego Dr, San Diego, CA 92108 USA. [Nock, Matthew K.] Harvard Univ, Dept Psychol, William James Hall 1220,33 Kirkland St, Cambridge, MA 02138 USA. RP Naifeh, JA (reprint author), Uniformed Serv Univ Hlth Sci, Dept Psychiat, Ctr Study Traumat Stress, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. FU U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health [U01MH087981]; Department of the Army FX Army STARRS was sponsored by the Department of the Army and funded under cooperative agreement number U01MH087981 with the U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health. NR 39 TC 0 Z9 0 U1 6 U2 7 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 EI 1930-613X J9 MIL MED JI Milit. Med. PD SEP PY 2016 VL 181 IS 9 BP 1021 EP 1032 DI 10.7205/MILMED-D-15-00211 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA DW5MV UT WOS:000383690500021 PM 27612348 ER PT J AU Kim, J Fann, DYW Seet, RCS Jo, DG Mattson, MP Arumugam, TV AF Kim, Joonki Fann, David Yang-Wei Seet, Raymond Chee Seong Jo, Dong-Gyu Mattson, Mark P. Arumugam, Thiruma V. TI Phytochemicals in Ischemic Stroke SO NEUROMOLECULAR MEDICINE LA English DT Review DE Stroke; Inflammation; Neuronal cell death; Ischemia; Natural products; Phytochemical ID FOCAL CEREBRAL-ISCHEMIA; NF-KAPPA-B; INTERCELLULAR-ADHESION MOLECULE-1; CULTURED HIPPOCAMPAL-NEURONS; OXYGEN-GLUCOSE DEPRIVATION; TRANSCRIPTION FACTOR FOXO1; CELLULAR STRESS RESPONSES; ACTIVATED PROTEIN-KINASE; ATTENUATES BRAIN-DAMAGE; SENSING ION CHANNELS AB Stroke is the second foremost cause of mortality worldwide and a major cause of long-term disability. Due to changes in lifestyle and an aging population, the incidence of stroke continues to increase and stroke mortality predicted to exceed 12 % by the year 2030. However, the development of pharmacological treatments for stroke has failed to progress much in over 20 years since the introduction of the thrombolytic drug, recombinant tissue plasminogen activator. These alarming circumstances caused many research groups to search for alternative treatments in the form of neuroprotectants. Here, we consider the potential use of phytochemicals in the treatment of stroke. Their historical use in traditional medicine and their excellent safety profile make phytochemicals attractive for the development of therapeutics in human diseases. Emerging findings suggest that some phytochemicals have the ability to target multiple pathophysiological processes involved in stroke including oxidative stress, inflammation and apoptotic cell death. Furthermore, epidemiological studies suggest that the consumption of plant sources rich in phytochemicals may reduce stroke risk, and so reinforce the possibility of developing preventative or neuroprotectant therapies for stroke. In this review, we describe results of preclinical studies that demonstrate beneficial effects of phytochemicals in experimental models relevant to stroke pathogenesis, and we consider their possible mechanisms of action. C1 [Kim, Joonki; Fann, David Yang-Wei; Arumugam, Thiruma V.] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Singapore 117597, Singapore. [Kim, Joonki] Korea Inst Sci & Technol, Nat Prod Res Ctr, Kangnung, South Korea. [Seet, Raymond Chee Seong] Natl Univ Hlth Syst, Yong Loo Lin Sch Med, Dept Med, Singapore, Singapore. [Jo, Dong-Gyu; Arumugam, Thiruma V.] Sungkyunkwan Univ, Sch Pharm, Suwon, South Korea. [Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Arumugam, TV (reprint author), Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Singapore 117597, Singapore.; Arumugam, TV (reprint author), Sungkyunkwan Univ, Sch Pharm, Suwon, South Korea. EM phstva@nus.edu.sg FU NUHS Seed Fund for Basic Science Research [R-185-000-255-112]; Singapore Ministry of Education [R-185-000-285-112]; National University of Singapore; Intramural Research Program of the National Institute on Aging, NIH FX This work was supported NUHS Seed Fund for Basic Science Research (R-185-000-255-112), Singapore Ministry of Education Tier 1 grant (R-185-000-285-112), the start-up fund provided by the National University of Singapore, and in part, by the Intramural Research Program of the National Institute on Aging, NIH. NR 313 TC 1 Z9 1 U1 2 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1535-1084 EI 1559-1174 J9 NEUROMOL MED JI Neuromol. Med. PD SEP PY 2016 VL 18 IS 3 BP 283 EP 305 DI 10.1007/s12017-016-8403-0 PG 23 WC Neurosciences SC Neurosciences & Neurology GA EC1GA UT WOS:000387851700006 PM 27193940 ER PT J AU Froehlich, RJ Sandoval, G Bailit, JL Grobman, WA Reddy, UM Wapner, RJ Varner, MW Thorp, JM Prasad, M Tita, ATN Saade, G Sorokin, Y Blackwell, SC Tolosa, JE AF Froehlich, Rosemary J. Sandoval, Grecio Bailit, Jennifer L. Grobman, William A. Reddy, Uma M. Wapner, Ronald J. Varner, Michael W. Thorp, John M., Jr. Prasad, Mona Tita, Alan T. N. Saade, George Sorokin, Yoram Blackwell, Sean C. Tolosa, Jorge E. CA Eunice Kennedy Shriver Natl Inst Maternal-Fetal Med Units MFMU TI Association of Recorded Estimated Fetal Weight and Cesarean Delivery in Attempted Vaginal Delivery at Term SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID MACROSOMIA; PREDICTION AB OBJECTIVE: To evaluate the association between documentation of estimated fetal weight, and its value, with cesarean delivery. METHODS: This was a secondary analysis of a multicenter observational cohort of 115,502 deliveries from 2008 to 2011. Data were abstracted by trained and certified study personnel. We included women at 37 weeks of gestation or greater attempting vaginal delivery with live, nonanomalous, singleton, vertex fetuses and no history of cesarean delivery. Rates and odds ratios (ORs) were calculated for women with ultrasonography or clinical estimated fetal weight compared with women without documentation of estimated fetal weight. Further subgroup analyses were performed for estimated fetal weight categories (less than 3,500, 3,500-3,999, and 4,000 g or greater) stratified by diabetic status. Multivariable analyses were performed to adjust for important potential confounding variables. RESULTS: We included 64,030 women. Cesarean delivery rates were 18.5% in the ultrasound estimated fetal weight group, 13.4% in the clinical estimated fetal weight group, and 11.7% in the no documented estimated fetal weight group (P<.001). After adjustment (including for birth weight), the adjusted OR of cesarean delivery was 1.44 (95% confidence interval [CI] 1.31-1.58, P<.001) for women with ultrasound estimated fetal weight and 1.08 for clinical estimated fetal weight (95% CI 1.01-1.15, P=.017) compared with women with no documented estimated fetal weight (referent). The highest estimates of fetal weight conveyed the greatest odds of cesarean delivery. When ultrasound estimated fetal weight was 4,000 g or greater, the adjusted OR was 2.15 (95% CI 1.55-2.98, P<.001) in women without diabetes and 9.00 (95% CI 3.65-22.17, P<.001) in women with diabetes compared to those with estimated fetal weight less than 3,500 g. CONCLUSION: In this contemporary cohort of women attempting vaginal delivery at term, documentation of estimated fetal weight (obtained clinically or, particularly, by ultrasonography) was associated with increased odds of cesarean delivery. This relationship was strongest at higher fetal weight estimates, even after controlling for the effects of birth weight and other factors associated with increased cesarean delivery risk. C1 Brown Univ, Women & Infants Hosp, Dept Obstet, Providence, RI USA. Brown Univ, Women & Infants Hosp, Dept Gynecol, Providence, RI USA. Case Western Reserve Univ, MetroHlth Med Ctr, Cleveland, OH 44106 USA. Columbia Univ, New York, NY USA. Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. Univ N Carolina, Chapel Hill, NC USA. Ohio State Univ, Columbus, OH 43210 USA. Univ Alabama Birmingham, Birmingham, AL USA. Wayne State Univ, Detroit, MI USA. Brown Univ, Providence, RI 02912 USA. Univ Texas Hlth Sci Ctr Houston, Childrens Mem Hermann Hosp, Houston, TX 77030 USA. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. George Washington Univ, Biostat Ctr, Washington, DC USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Froehlich, RJ (reprint author), Brown Univ, Women & Infants Hosp, Warren Alpert Med Sch, Dept Obstet & Gynecol, 101 Pl St,7th Floor, Providence, RI 02903 USA. EM rfroehlich@wihri.org FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD21410, HD27869, HD27915, HD27917, HD34116, HD34208, HD36801, HD40500, HD40512, HD40544, HD40545, HD40560, HD40485, HD53097, HD53118]; National Center for Research Resources [UL1 RR024989, 5UL1 RR025764] FX Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD21410, HD27869, HD27915, HD27917, HD34116, HD34208, HD36801, HD40500, HD40512, HD40544, HD40545, HD40560, HD40485, HD53097, HD53118) and the National Center for Research Resources (UL1 RR024989; 5UL1 RR025764) and its contents do not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Center for Research Resources, or the National Institutes of Health. NR 12 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD SEP PY 2016 VL 128 IS 3 BP 487 EP 494 DI 10.1097/AOG.0000000000001571 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DX6VQ UT WOS:000384523200016 PM 27500344 ER PT J AU Romero, R Nicolaides, KH Conde-Agudelo, A O'Brien, JM Cetingoz, E Da Fonseca, E Creasy, GW Hassan, SS AF Romero, R. Nicolaides, K. H. Conde-Agudelo, A. O'Brien, J. M. Cetingoz, E. Da Fonseca, E. Creasy, G. W. Hassan, S. S. TI Vaginal progesterone decreases preterm birth <= 34 weeks of gestation in women with a singleton pregnancy and a short cervix: an updated meta-analysis including data from the OPPTIMUM study SO ULTRASOUND IN OBSTETRICS & GYNECOLOGY LA English DT Article DE cervical length; neonatal morbidity; neonatal mortality; prematurity; preterm delivery; progestins; progestogens; transvaginal ultrasound ID PLACEBO-CONTROLLED TRIAL; SONOGRAPHIC SHORT CERVIX; DOUBLE-BLIND; COST-EFFECTIVENESS; MICRONIZED PROGESTERONE; SUBGROUP ANALYSIS; RANDOMIZED-TRIAL; INCREASED RISK; BIRTH; LENGTH AB Objective To evaluate the efficacy of vaginal progesterone administration for preventing preterm birth and perinatal morbidity and mortality in asymptomatic women with a singleton gestation and a mid-trimester sonographic cervical length (CL)<= 25 mm. Methods This was an updated systematic review and meta-analysis of randomized controlled trials comparing the use of vaginal progesterone to placebo/no treatment in women with a singleton gestation and a mid-trimester sonographic CL <= 25 mm. Electronic databases, from their inception to May 2016, bibliographies and conference proceedings were searched. The primary outcome measure was preterm birth <= 34 weeks of gestation or fetal death. Two reviewers independently selected studies, assessed the risk of bias and extracted the data. Pooled relative risks (RRs) with 95% confidence intervals (CI) were calculated. Results Five trials involving 974 women were included. A meta-analysis, including data from the OPPTIMUM study, showed that vaginal progesterone significantly decreased the risk of preterm birth <= 34 weeks of gestation or fetal death compared to placebo (18.1% vs 27.5%; RR, 0.66 (95% CI, 0.52-0.83); P=0.0005; five studies; 974 women). Meta-analyses of data from four trials (723 women) showed that vaginal progesterone administration was associated with a statistically significant reduction in the risk of preterm birth occurring at <28 to <36 gestational weeks (RRs from 0.51 to 0.79), respiratory distress syndrome (RR, 0.47 (95% CI, 0.27-0.81)), composite neonatal morbidity and mortality (RR, 0.59 (95% CI, 0.38-0.91)), birth weight <1500 g (RR, 0.52 (95% CI, 0.34-0.81)) and admission to the neonatal intensive care unit (RR, 0.67 (95% CI, 0.50-0.91)). There were no significant differences in neurodevelopmental outcomes at 2 years of age between the vaginal progesterone and placebo groups. Conclusion This updated systematic review and meta-analysis reaffirms that vaginal progesterone reduces the risk of preterm birth and neonatalmorbidity and mortality in women with a singleton gestation and a mid-trimester CL <= 25 mm, without any deleterious effects on neurodevelopmental outcome. Clinicians should continue to perform universal transvaginal CL screening at 18-24 weeks of gestation in women with a singleton gestation and to offer vaginal progesterone to those with a CL <= 25 mm. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. C1 [Romero, R.; Conde-Agudelo, A.; Hassan, S. S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH,Dept Hlth & Human Serv, Bethesda, MD USA. [Romero, R.; Conde-Agudelo, A.; Hassan, S. S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH,Dept Hlth & Human Serv, Detroit, MI USA. [Romero, R.] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, R.] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Romero, R.] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Nicolaides, K. H.] Kings Coll Hosp London, Harris Birthright Res Ctr Fetal Med, London, England. [O'Brien, J. M.] Univ Kentucky, Dept Obstet & Gynecol, Lexington, KY USA. [Cetingoz, E.] Zeynep Kamil Women & Children Dis Educ & Res Hosp, Dept Obstet & Gynecol, Istanbul, Turkey. [Da Fonseca, E.] Univ Sao Paulo, Hosp Servidor Publ Estadual Francisco Morato de O, Dept Obstet & Ginecol, Sao Paulo, Brazil. [Da Fonseca, E.] Univ Sao Paulo, Sch Med, Sao Paulo, Brazil. [Creasy, G. W.] Populat Council, Ctr Biomed Res, 1230 York Ave, New York, NY 10021 USA. [Hassan, S. S.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. RP Romero, R (reprint author), NICHD, Perinatol Res Branch, Perinatal Res & Obstet, Div Intramural Res,NIH,DHHS,Hutzel Womens Hosp, Box 4,3990 John R, Detroit, MI 48201 USA. EM romeror@mail.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services. NR 74 TC 6 Z9 6 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0960-7692 EI 1469-0705 J9 ULTRASOUND OBST GYN JI Ultrasound Obstet. Gynecol. PD SEP PY 2016 VL 48 IS 3 BP 308 EP 317 DI 10.1002/uog.15953 PG 10 WC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging GA DW5QF UT WOS:000383700700009 PM 27444208 ER PT J AU Sissung, TM Venzon, DJ Figg, WD AF Sissung, Tristan M. Venzon, David J. Figg, William D. TI Association of a CYP17 Polymorphism With Overall Survival in Caucasian Patients With Androgen-independent Prostate Cancer (vol 70, pg 217, 2007) SO UROLOGY LA English DT Correction C1 [Figg, William D.] NCI, Clin Pharmacol Program, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Clin Pharmacol Program, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov NR 2 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 EI 1527-9995 J9 UROLOGY JI Urology PD SEP PY 2016 VL 95 BP 225 EP 225 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA DW5PK UT WOS:000383698300060 ER PT J AU Sierra, F AF Sierra, F. TI Translational Gerocience - from bench to bedside SO ZEITSCHRIFT FUR GERONTOLOGIE UND GERIATRIE LA English DT Meeting Abstract C1 [Sierra, F.] NIA, DAB, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0948-6704 EI 1435-1269 J9 Z GERONTOL GERIATR JI Z. Gerontol. Geriatr. PD SEP PY 2016 VL 49 SU 1 MA S134-01 BP S27 EP S27 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DV2RV UT WOS:000382769600080 ER PT J AU Jiang, LL Hu, J He, SF Zhang, L Zhang, Y AF Jiang, Lingling Hu, Jun He, Shufang Zhang, Li Zhang, Ye TI Spinal Neuronal NOS Signaling Contributes to Morphine Cardioprotection in Ischemia Reperfusion Injury in Rats SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID PRECONDITIONING CONFERS CARDIOPROTECTION; INTRATHECALLY INJECTED MORPHINE; NITRIC-OXIDE SYNTHASE; OPIOID RECEPTORS; REMOTE CARDIOPROTECTION; POTASSIUM CHANNELS; DORSAL-HORN; SUBSTANCE-P; ACTIVATION; PAIN AB Morphine has been widely used as rescue treatment for heart attack and failure in humans for many decades. Relatively little has been known about the role of spinal opioid receptors in morphine cardioprotection. Recent studies have shown that intrathecal injection of morphine can reduce the heart injury caused by ischemia (I)/reperfusion (R) in rats. However, the molecular and cellular mechanisms underlying intrathecal morphine cardioprotection has not been determined. Here, we report that intrathecal morphine postconditioning (IMPOC) rescued mean artery pressure (MAP) and reduced myocardial injury in I/R. Pretreatment with either naloxone (NAL), a selective muopioid receptor antagonist, or nitric oxide synthase (NOS) inhibitors via intrathecal delivery completely abolished IMPOC cardioprotection, suggesting that the spinal mu-opioid receptor and its downstream NOS signaling pathway are involved in the mechanism of the morphine-induced effect. Consistent with this, IMPOC significantly enhanced spinal neural NOS phosphorylation, nitric oxide, and cGMP content in a similar time course. Intrathecal application of 1H-[1,2,4] oxadiazolo[4,3-a] quinoxalin1-one, a specific inhibitor of guanylate cyclase, completely ablated IMPOC-induced enhancement of cardioprotection and spinal cGMP content. IMPOC rescue of MAP and ischemic injury is correlated with IMPOC enhancement of NOS signaling. Collectively, these findings strengthen the concept of spinal mu-opioid receptors as a therapeutic target that mediates morphine-induced cardioprotection. We also provide evidence suggesting that the activation of spinal NOS signaling is essential for morphine cardioprotection. C1 [Jiang, Lingling; Hu, Jun; He, Shufang; Zhang, Ye] Anhui Med Univ, Dept Anesthesiol, Affiliated Hosp 2, Hefei, Anhui, Peoples R China. [Jiang, Lingling; Zhang, Li] NIAAA, Lab Integrat Neurosci, NIA, Bethesda, MD USA. RP Zhang, Y (reprint author), Anhui Med Univ, Dept Anesthesiol, Affiliated Hosp 2, Hefei, Anhui, Peoples R China. EM zhangye_hassan@sina.com NR 40 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD SEP 1 PY 2016 VL 358 IS 3 BP 450 EP 456 DI 10.1124/jpet.116.234021 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ED7RA UT WOS:000389065700009 PM 27358482 ER PT J AU Zhang, Y Shen, J AF Zhang, Yan Shen, Jun TI Simultaneous Quantification of Glutamate and Glutamine by J-modulated Spectroscopy at 3 Tesla SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE glutamate; glutamine; quantification; J-resolved spectroscopy; one-dimensional cross-section; TE-averaged spectroscopy; human brain ID MAGNETIC-RESONANCE-SPECTROSCOPY; REGULARIZED LINESHAPE DECONVOLUTION; METABOLITE RELAXATION-TIMES; TE-AVERAGED PRESS; HUMAN BRAIN; IN-VIVO; T-2 RELAXATION; WATER; MRS; SPECTRA AB Purpose: The echo time (TE) averaged spectrum is the one-dimensional (1D) cross-section of the J-resolved spectrum at J = 0. In multiecho TE-averaged spectroscopy, glutamate (Glu) is differentiated from glutamine (Gln) at 3 Tesla (T). This method, however, almost entirely suppresses Gln resonance lines around 2.35 ppm, leaving Gln undetermined. This study presents a novel method for quantifying both Glu and Gln using multi-echo spectral data. Methods: A 1D cross-section of J-resolved spectroscopy at J = 7.5 Hz-referred to as J-modulated spectroscopy-was developed to simultaneously quantify Glu and Gln levels in the human brain. The transverse relaxation times (T(2)s) of metabolites were first determined using conventional TE-averaged spectroscopy with different starting echo time and then incorporated into the spectral model for fitting J-modulated data. Results: Simulation and in vivo data showed that the resonance signals of Glu and Gln were clearly separated around 2.35 ppm in J-modulated spectroscopy. In the anterior cingulate cortex, both Glu and Gln levels were found to be significantly higher in gray matter than in white matter in healthy subjects (P < 10(-10) and< 10(-5), respectively). Conclusion: Gln resonances can be clearly separated from Glu and N-acetyl-aspartate around 2.35 ppm using J-modulated spectroscopy. This method can be used to quantitatively measure Glu and Gln simultaneously at 3T. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. C1 [Zhang, Yan; Shen, Jun] NIMH, MR Spect Core Facil, NIH, Bethesda, MD 20892 USA. [Shen, Jun] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Zhang, Y (reprint author), NIMH, MR Spect Core Facil, Bldg 10,Room 2D50 9000, Bethesda, MD 20892 USA. EM zhangya@mail.nih.gov FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) FX Grant sponsor: Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH). NR 38 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD SEP PY 2016 VL 76 IS 3 BP 725 EP 732 DI 10.1002/mrm.25922 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA ED1PK UT WOS:000388617200001 PM 26361892 ER PT J AU Reiter, DA Magin, RL Li, WG Trujillo, JJ Velasco, MP Spencer, RG AF Reiter, David A. Magin, Richard L. Li, Weiguo Trujillo, Juan J. Pilar Velasco, M. Spencer, Richard G. TI Anomalous T-2 Relaxation in Normal and Degraded Cartilage SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE spin-spin relaxation; fractional calculus; cartilage; magnetic resonance; multiexponential T-2; proteoglycan ID UNDERLYING DISTRIBUTIONS; MATHEMATICAL FUNCTIONS; BICOMPONENT ANALYSIS; LUMINESCENCE DECAYS; T2 AB Purpose: To compare the ordinary monoexponential model with three anomalous relaxation models-the stretched Mittag-Leffler, stretched exponential, and biexponential functions - using both simulated and experimental cartilage relaxation data. Methods: Monte Carlo simulations were used to examine both the ability of identifying a given model under high signal-to-noise ratio (SNR) conditions and the accuracy and precision of parameter estimates under more modest SNR as would be encountered clinically. Experimental transverse relaxation data were analyzed from normal and enzymatically degraded cartilage samples under high SNR and rapid echo sampling to compare each model. Results: Both simulation and experimental results showed improvement in signal representation with the anomalous relaxation models. The stretched exponential model consistently showed the lowest mean squared error in experimental data and closely represents the signal decay over multiple decades of the decay time (e.g., 1-10 ms, 10-100 ms, and > 100 ms). The stretched exponential parameter alpha(se) showed an inverse correlation with biochemically derived cartilage proteoglycan content. Conclusion: Experimental results obtained at high field suggest potential application of ase as a measure of matrix integrity. Simulation reflecting more clinical imaging conditions, indicate the ability to robustly estimate ase and distinguish between normal and degraded tissue, highlighting its potential as a biomarker for human studies. (C) 2015 Wiley Periodicals, Inc. C1 [Reiter, David A.; Spencer, Richard G.] NIA, Lab Clin Invest, NIH, 3001 S Hanover St,GNM 39, Baltimore, MD 21225 USA. [Magin, Richard L.; Li, Weiguo] Univ Illinois, Dept Bioengn, Chicago, IL USA. [Trujillo, Juan J.] Univ La Laguna, Dept Anal Matemat, San Cristobal la Laguna, Tenerife, Spain. [Pilar Velasco, M.] Def Univ Zaragoza, Ctr Univ, Dept Matemat Estadist & Invest Operat, Zaragoza, Spain. RP Reiter, DA (reprint author), NIA, Lab Clin Invest, NIH, 3001 S Hanover St,GNM 39, Baltimore, MD 21225 USA. EM reiterda@mail.nih.gov RI Velasco, M. Pilar/G-6747-2015; OI Velasco, M. Pilar/0000-0002-0988-2527; Trujillo, Juan J./0000-0001-8700-6410 FU National Institutes of Health, Intramural Research Program of the National Institute on Aging and the National Institutes of Health extramural program [R01 EB 007537]; Government of Spain [MTM2013-41704-P] FX Grant sponsor: National Institutes of Health, Intramural Research Program of the National Institute on Aging and the National Institutes of Health extramural program; Grant number: R01 EB 007537; Grant sponsor: the Government of Spain; Grant number: MTM2013-41704-P. NR 28 TC 1 Z9 1 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD SEP PY 2016 VL 76 IS 3 BP 953 EP 962 DI 10.1002/mrm.25913 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA ED1PK UT WOS:000388617200025 PM 26336966 ER PT J AU Ley, SH Korat, AVA Sun, Q Tobias, DK Zhang, CL Qi, L Willett, WC Manson, JE Hu, FB AF Ley, Sylvia H. Korat, Andres V. Ardisson Sun, Qi Tobias, Deirdre K. Zhang, Cuilin Qi, Lu Willett, Walter C. Manson, JoAnn E. Hu, Frank B. TI Contribution of the Nurses' Health Studies to Uncovering Risk Factors for Type 2 Diabetes: Diet, Lifestyle, Biomarkers, and Genetics SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID SUGAR-SWEETENED BEVERAGES; MIDDLE-AGED WOMEN; PROSPECTIVE COHORT; PHYSICAL-ACTIVITY; SEDENTARY BEHAVIORS; US WOMEN; MELLITUS; CONSUMPTION; PATTERNS; YOUNGER AB Objectives. To review the contribution of the Nurses' Health Study (NHS) and the NHS II to addressing hypotheses regarding risk factors for type 2 diabetes. Methods. We carried out a narrative review of 1976 to 2016 NHS and NHS II publications. Results. The NHS and NHS II have uncovered important roles in type 2 diabetes for individual nutrients, foods, dietary patterns, and physical activity independent of excess body weight. Up to 90% of type 2 diabetes cases are potentially preventable if individuals follow a healthy diet and lifestyle. The NHS investigations have also identified novel biomarkers for diabetes, including adipokines, inflammatory cytokines, nutrition metabolites, and environmental pollutants, offering new insights into the pathophysiology of the disease. Global collaborative efforts have uncovered many common genetic variants associated with type 2 diabetes and improved our understanding of gene-environment interactions. Continued efforts to identify epigenetic, metagenomic, and metabolomic risk factors for type 2 diabetes have the potential to reveal new pathways and improve prediction and prevention. Conclusions. Over the past several decades, the NHS and NHS II have made major contributions to public health recommendations and strategies designed to reduce the global burden of diabetes. C1 [Ley, Sylvia H.; Korat, Andres V. Ardisson; Sun, Qi; Qi, Lu; Willett, Walter C.; Hu, Frank B.] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Tobias, Deirdre K.; Manson, JoAnn E.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Tobias, Deirdre K.; Manson, JoAnn E.] Harvard Med Sch, Boston, MA USA. [Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD USA. RP Hu, FB (reprint author), Harvard TH Chan Sch Publ Hlth, 665 Huntington Ave, Boston, MA 02115 USA. EM frank.hu@channing.harvard.edu FU National Institutes of Health [P01 CA87969, UM1 CA186107, UM1 CA176726, DK58845] FX Nurses' Health Study (NHS) cohort research is supported by grants from the National Institutes of Health (P01 CA87969, UM1 CA186107, UM1 CA176726, and DK58845). NR 45 TC 2 Z9 2 U1 5 U2 5 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD SEP PY 2016 VL 106 IS 9 BP 1624 EP 1630 DI 10.2105/AJPH.2016.303314 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EC4CB UT WOS:000388072300027 PM 27459454 ER PT J AU Chavarro, JE Rich-Edwards, JW Gaskins, AJ Farland, LV Terry, KL Zhang, CL Missmer, SA AF Chavarro, Jorge E. Rich-Edwards, Janet W. Gaskins, Audrey J. Farland, Leslie V. Terry, Kathryn L. Zhang, Cuilin Missmer, Stacey A. TI Contributions of the Nurses' Health Studies to Reproductive Health Research SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID GESTATIONAL DIABETES-MELLITUS; BODY-MASS INDEX; PRENATAL DIETHYLSTILBESTROL EXPOSURE; OVULATORY DISORDER INFERTILITY; CORONARY-HEART-DISEASE; LIFE-STYLE FACTORS; LONG-TERM RISK; PROSPECTIVE COHORT; BIRTH-WEIGHT; PREMENOPAUSAL WOMEN AB Objectives. To review the Nurses' Health Study's (NHS's) contribution to identifying risk factors and long-term health consequences of reproductive events. Methods. We performed a narrative review of the NHS I, NHS II, NHS3, and Growing Up Today Study (GUTS) publications between 1976 and 2016. Results. Collection of detailed reproductive history to identify breast cancer risk factors allowed the NHS to document an association between menstrual irregularities, a proxy for polycystic ovary syndrome (PCOS), and increased risk of diabetes and cardiovascular disease. The NHS II found that infertility associated with ovulation problems and gestational diabetes are largely preventable through diet and lifestyle modification. It also identified developmental and nutritional risk factors for pregnancy loss, endometriosis, and uterine leiomyomata. As women in NHS II age, it has become possible to address questions regarding long-term health consequences of pregnancy complications and benign gynecologic conditions on chronic disease risk. Furthermore, the NHS3 and GUTS are allowing new lines of research into human fertility, PCOS, and transgenerational effects of environmental exposures. Conclusions. The multigenerational resources of the NHSs and GUTS, including linkages of related individuals across cohorts, can improve women's health from preconception through late adulthood and onto the next generation. C1 [Chavarro, Jorge E.; Rich-Edwards, Janet W.; Gaskins, Audrey J.; Farland, Leslie V.; Terry, Kathryn L.; Missmer, Stacey A.] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Chavarro, Jorge E.; Rich-Edwards, Janet W.; Gaskins, Audrey J.; Farland, Leslie V.; Terry, Kathryn L.; Missmer, Stacey A.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Chavarro, Jorge E.; Rich-Edwards, Janet W.; Gaskins, Audrey J.; Farland, Leslie V.; Terry, Kathryn L.; Missmer, Stacey A.] Harvard Med Sch, Boston, MA USA. [Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, Rockville, MD USA. RP Chavarro, JE (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Nutr, 655 Huntington Ave, Boston, MA 02115 USA. EM jchavarr@hsph.harvard.edu FU National Institutes of Health (NIH) [UM1 CA186107, P01 CA87969, R01 CA49449, R01 HL034594, R01 HL088521]; NIH [UM1 CA176726, R01 CA67262, 3R25CA057711, T32HD060454, P30 DK046200, R03 HD081064, R21 HD059955, R03 HD48544, R01 HD52473, R01 HD57210, HHSN275201000020C]; Breast Cancer Research Foundation; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH FX The Nurses' Health Study (NHS) is supported by National Institutes of Health (NIH) grants UM1 CA186107, P01 CA87969, R01 CA49449, R01 HL034594, and R01 HL088521. The NHS II is supported by NIH grants UM1 CA176726 and R01 CA67262. The NHS3 and the Growing Up Today Study have also been supported by grants from the Breast Cancer Research Foundation. Specific work presented in this article was additionally supported by NIH grants 3R25CA057711, T32HD060454, P30 DK046200, R03 HD081064, R21 HD059955, R03 HD48544, R01 HD52473, and R01 HD57210, and NIH contract HHSN275201000020C. C. Zhang is supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. NR 45 TC 0 Z9 0 U1 2 U2 2 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD SEP PY 2016 VL 106 IS 9 BP 1669 EP 1676 DI 10.2105/AJPH.2016.303350 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EC4CB UT WOS:000388072300034 PM 27459445 ER PT J AU Gibbs, KD Marsteller, P AF Gibbs, Kenneth D., Jr. Marsteller, Pat TI Broadening Participation in the Life Sciences: Current Landscape and Future Directions SO CBE-LIFE SCIENCES EDUCATION LA English DT Editorial Material ID BIOMEDICAL SCIENCE; VALUES; DIVERSITY; STUDENTS C1 [Gibbs, Kenneth D., Jr.] NIGMS, Off Program Planning Anal & Evaluat, Bethesda, MD 20892 USA. [Marsteller, Pat] Emory Univ, Dept Biol, Atlanta, GA 30322 USA. RP Gibbs, KD (reprint author), NIGMS, Off Program Planning Anal & Evaluat, Bethesda, MD 20892 USA. EM kenneth.gibbs@nih.gov NR 24 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1931-7913 J9 CBE-LIFE SCI EDUC JI CBE-Life Sci. Educ. PD SEP 1 PY 2016 VL 15 IS 3 AR ed1 DI 10.1187/cbe.16-06-0198 PG 3 WC Education, Scientific Disciplines SC Education & Educational Research GA EC4KC UT WOS:000388096500027 ER PT J AU Valantine, HA Lund, PK Gammie, AE AF Valantine, Hannah A. Lund, P. Kay Gammie, Alison E. TI From the NIH: A Systems Approach to Increasing the Diversity of the Biomedical Research Workforce SO CBE-LIFE SCIENCES EDUCATION LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; FACULTY; MENTORS; SCIENCE AB The National Institutes of Health (NIH) is committed to attracting, developing, and supporting the best scientists from all groups as an integral part of excellence in training. Biomedical research workforce diversity, capitalizing on the full spectrum of skills, talents, and viewpoints, is essential for solving complex human health challenges. Over the past few decades, the biomedical research workforce has benefited from NIH programs aimed at enhancing diversity. However, there is considerable room for improvement, particularly at the level of independent scientists and within scientific leadership. We provide a rationale and specific opportunities to develop and sustain a diverse biomedical research workforce through interventions that promote the successful transitions to different stages on the path toward completion of training and entry into the biomedical workforce. C1 [Valantine, Hannah A.; Lund, P. Kay] NIH, Off Director, Bldg 10, Bethesda, MD 20892 USA. [Gammie, Alison E.] NIGMS, NIH, Bethesda, MD 20892 USA. RP Valantine, HA (reprint author), NIH, Off Director, Bldg 10, Bethesda, MD 20892 USA. EM hannah.valantine@nih.gov NR 19 TC 1 Z9 1 U1 1 U2 1 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1931-7913 J9 CBE-LIFE SCI EDUC JI CBE-Life Sci. Educ. PD SEP 1 PY 2016 VL 15 IS 3 AR fe4 DI 10.1187/cbe.16-03-0138 PG 5 WC Education, Scientific Disciplines SC Education & Educational Research GA EC4KC UT WOS:000388096500031 ER PT J AU Robles, AI Jen, J Harris, CC AF Robles, Ana I. Jen, Jin Harris, Curtis C. TI Clinical Outcomes of TP53 Mutations in Cancers SO COLD SPRING HARBOR PERSPECTIVES IN MEDICINE LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; LI-FRAUMENI SYNDROME; SQUAMOUS-CELL CARCINOMA; CIRCULATING TUMOR DNA; BREAST-CANCER; P53 MUTATIONS; GENOMIC LANDSCAPE; LUNG-CANCER; STEM-CELLS; HEPATOCELLULAR CARCINOMAS AB High-throughput sequencing of cancer genomes is increasingly becoming an essential tool of clinical oncology that facilitates target identification and targeted therapy within the context of precision medicine. The cumulative profiles of somatic mutations in cancer yielded by comprehensive molecular studies also constitute a fingerprint of historical exposures to exogenous and endogenous mutagens, providing insight into cancer evolution and etiology. Mutational signatures that were first established by inspection of the TP53 gene somatic landscape have now been confirmed and expanded by comprehensive sequencing studies. Further, the degree of granularity achieved by deep sequencing allows detection of low-abundance mutations with clinical relevance. In tumors, they represent the emergence of small aggressive clones; in normal tissues, they signal a mutagenic exposure related to cancer risk; and, in blood, they may soon become effective surveillance tools for diagnostic purposes and for monitoring of cancer prognosis and recurrence. C1 [Robles, Ana I.; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. [Jen, Jin] Mayo Clin, Dept Lab Med & Pathol, Div Expt Pathol, Rochester, MN 55905 USA. [Jen, Jin] Mayo Clin, Div Pulm & Crit Care Med, Dept Med, Rochester, MN 55905 USA. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM curtis_harris@nih.gov FU Mayo Clinic Center for Individualized Medicine, Biomarker Discovery Program FX We thank Mr. Mohammed Khan for graphic design support. J.J. is supported in part by the Mayo Clinic Center for Individualized Medicine, Biomarker Discovery Program. NR 137 TC 0 Z9 0 U1 1 U2 1 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 2157-1422 J9 CSH PERSPECT MED JI Cold Spring Harb. Perspect. Med. PD SEP PY 2016 VL 6 IS 9 AR a026294 DI 10.1101/cshperspect.a026294 PG 16 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EC7KQ UT WOS:000388317500001 ER PT J AU Ohyama, Y Teixido-Tura, G Ambale-Venkatesh, B Noda, C Chugh, AR Liu, CY Redheuil, A Stacey, RB Dietz, H Gomes, AS Prince, MR Evangelista, A Wu, CO Hundley, WG Bluemke, DA Lima, JAC AF Ohyama, Yoshiaki Teixido-Tura, Gisela Ambale-Venkatesh, Bharath Noda, Chikara Chugh, Atul R. Liu, Chia-Ying Redheuil, Alban Stacey, R. Brandon Dietz, Harry Gomes, Antoinette S. Prince, Martin R. Evangelista, Arturo Wu, Colin O. Hundley, W. Gregory Bluemke, David A. Lima, Joao A. C. TI Ten-year longitudinal change in aortic stiffness assessed by cardiac MRI in the second half of the human lifespan: the multi-ethnic study of atherosclerosis SO EUROPEAN HEART JOURNAL-CARDIOVASCULAR IMAGING LA English DT Article DE aortic stiffness; magnetic resonance imaging; aortic distensibility; pulse-wave velocity; cardiovascular risk ID PULSE-WAVE VELOCITY; ARTERIAL STIFFNESS; BLOOD-PRESSURE; CARDIOVASCULAR EVENTS; ALL-CAUSE; MORTALITY; REPRODUCIBILITY; DISTENSIBILITY; HYPERTENSION; PROGRESSION AB Aims Longitudinal determinants of aortic stiffness (AS) measured by magnetic resonance imaging (MRI) have not been assessed in a large community-based population. Our aim was to examine the determinants of change in thoracic AS over 10 years of follow-up in a multi-ethnic population of individuals 45 years of age and older measured by MRI. Methods and results We studied 1160 participants (mean age = 60 +/- 9 years at baseline, 45% male) with aortic MRI at both the MESA Year 0 and Year 10 examinations. Ascending and descending aorta distensibility (AAD/DAD) and aortic arch pulse-wave velocity (PWV) were measured usingMRI. Determinants of the change in AS parameters over 10 years were assessed using linear regression adjusted for baseline values, demographic variables, baseline risk factors and change in risk factors, and chronic risk exposure. AADandDADdecreased slightly (5% decrease in median for AAD: 1.33-1.26 mmHg(-1).10(-3), P = 0.008; 5% decrease in median forDAD: 1.73-1.64 mmHg(-1).10(-3), P<0.001), andPWV increased over 10 years (18% increase in median: 6.8-8.0 m/s P<0.001). Baseline age was related to a reduction in AAD and DAD and an increase in PWV throughout the follow-up period. Baseline and change in mean blood pressure and continued smoking were associated with a reduction in AADand an increase in PWV. Furthermore, baseline heart ratewas also related to a reduction in AAD and DAD. Blood pressure normalization was related to less aortic stiffening throughout the follow-up period. Conclusions In our longitudinal, community-based cohort study of adult individuals aged 45 years or greater, greater mean blood pressure and a history of smoking history were associated with increased aortic stiffening over 10 years as assessed by MRI. C1 [Ohyama, Yoshiaki; Teixido-Tura, Gisela; Noda, Chikara; Chugh, Atul R.; Lima, Joao A. C.] Johns Hopkins Univ, Dept Cardiol, 600 N Wolf St Blalock 524, Baltimore, MD 21287 USA. [Teixido-Tura, Gisela; Prince, Martin R.] Cornell Univ, Weil Med Coll, Dept Radiol, New York, NY 10021 USA. [Ambale-Venkatesh, Bharath] Johns Hopkins Univ, Dept Radiol, Baltimore, MD USA. [Liu, Chia-Ying] NIH, Ctr Clin, Bethesda, MD USA. [Redheuil, Alban] Sorbonne Univ, UPMC, La Pitie Salpetriere, Cardiol Inst,ICAN,LIB INSERM UMRS 1146, Paris, France. [Redheuil, Alban] Sorbonne Univ, UPMC, La Pitie Salpetriere, Cardiol Inst,ICAN,Cardiovasc Imaging Dept DICVRI, Paris, France. [Stacey, R. Brandon; Hundley, W. Gregory] Wake Forest Sch Med, Dept Cardiol, Winston Salem, NC USA. [Dietz, Harry] Johns Hopkins Univ, Dept Pediat Cardiol, Baltimore, MD USA. [Gomes, Antoinette S.] Univ Calif Los Angeles, Dept Radiol, Los Angeles, CA USA. [Evangelista, Arturo] Hosp Gen Univ Vall Herbron, Dept Cardiol, Barcelona, Spain. [Wu, Colin O.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. RP Lima, JAC (reprint author), Johns Hopkins Univ, Dept Cardiol, 600 N Wolf St Blalock 524, Baltimore, MD 21287 USA. EM jlima@jhmi.edu OI Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute [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-95168] FX This research was supported 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, and N01-HC-95168 from the National Heart, Lung, and Blood Institute. NR 29 TC 2 Z9 2 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 2047-2404 EI 2047-2412 J9 EUR HEART J-CARD IMG JI Eur. Heart J.-Cardiovasc. Imaging PD SEP 1 PY 2016 VL 17 IS 9 BP 1044 EP 1053 DI 10.1093/ehjci/jev332 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EC8CE UT WOS:000388367000016 PM 26758407 ER PT J AU Grady, C AF Grady, Christine TI Cultivating Synergy in Nursing, Bioethics, and Policy SO HASTINGS CENTER REPORT LA English DT Article ID PRESIDENTIAL-ADDRESS C1 [Grady, Christine] NIH, Dept Bioeth, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Grady, Christine] Presidential Commiss Study Bioeth Issues, Washington, DC 20201 USA. RP Grady, C (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA.; Grady, C (reprint author), Presidential Commiss Study Bioeth Issues, Washington, DC 20201 USA. NR 30 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0093-0334 EI 1552-146X J9 HASTINGS CENT REP JI Hastings Cent. Rep. PD SEP-OCT PY 2016 VL 46 SU 1 SI SI BP S5 EP S8 DI 10.1002/hast.623 PG 4 WC Ethics; Health Care Sciences & Services; Medical Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Health Care Sciences & Services; Medical Ethics; Biomedical Social Sciences GA EC7KM UT WOS:000388317000002 PM 27649922 ER PT J AU Wolf, L Ulrich, CM Grady, C AF Wolf, Lisa Ulrich, Connie M. Grady, Christine TI Emergency Nursing, Ebola, and Public Policy: The Contributions of Nursing to the Public Policy Conversation SO HASTINGS CENTER REPORT LA English DT Article C1 [Wolf, Lisa] Emergency Nurses Assoc, Inst Emergency Nursing Res, Des Plaines, IL 60016 USA. [Ulrich, Connie M.] Univ Penn, Sch Nursing, Bioeth & Nursing, Philadelphia, PA 19104 USA. [Ulrich, Connie M.] Univ Penn, Dept Med Eth & Hlth Policy, Perelman Sch Med, Philadelphia, PA 19104 USA. [Ulrich, Connie M.] Univ Penn, NewCourtland Ctr Transit & Hlth, Philadelphia, PA 19104 USA. [Ulrich, Connie M.] Univ Penn, Hillman Scholars Program Nursing Innovat, Philadelphia, PA 19104 USA. [Grady, Christine] NIH, Dept Bioeth, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Grady, Christine] Presidential Commiss Study Bioeth Issues, Washington, DC USA. RP Wolf, L (reprint author), Emergency Nurses Assoc, Inst Emergency Nursing Res, Des Plaines, IL 60016 USA. NR 12 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0093-0334 EI 1552-146X J9 HASTINGS CENT REP JI Hastings Cent. Rep. PD SEP-OCT PY 2016 VL 46 SU 1 SI SI BP S35 EP S38 DI 10.1002/hast.630 PG 4 WC Ethics; Health Care Sciences & Services; Medical Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Health Care Sciences & Services; Medical Ethics; Biomedical Social Sciences GA EC7KM UT WOS:000388317000009 PM 27649918 ER PT J AU Boukari, F Makrogiannis, S Nossal, R Boukari, H AF Boukari, Fatima Makrogiannis, Sokratis Nossal, Ralph Boukari, Hacene TI Imaging and tracking HIV viruses in human cervical mucus SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE fluorescence confocal imaging; particle tracking; cervical mucus; HIV virus; constrained random walk ID SIMIAN IMMUNODEFICIENCY VIRUS; RHESUS-MONKEYS; PARTICLE TRACKING; SHIV CHALLENGES; TRANSMISSION; INFECTION; DIFFUSION; CELL; GLYCOPROTEINS; TISSUE AB We describe a systematic approach to image, track, and quantify the movements of HIV viruses embedded in human cervical mucus. The underlying motivation for this study is that, in HIV-infected adults, women account for more than half of all new cases and most of these women acquire the infection through heterosexual contact. The endocervix is believed to be a susceptible site for HIV entry. Cervical mucus, which coats the endocervix, should play a protective role against the viruses. Thus, we developed a methodology to apply time-resolved confocal microscopy to examine the motion of HIV viruses that were added to samples of untreated cervical mucus. From the images, we identified the viruses, tracked them over time, and calculated changes of the statistical mean-squared displacement (MSD) of each virus. Approximately half of tracked viruses appear constrained while the others show mobility with MSDs that are proportional to tau(alpha) + upsilon(2) tau(2), over time range tau, depicting a combination of anomalous diffusion (0 < alpha < 0.4) and flow-like behavior. The MSD data also reveal plateaus attributable to possible stalling of the viruses. Although a more extensive study is warranted, these results support the assumption of mucus being a barrier against the motion of these viruses. (C) 2016 Society of Photo-Optical Instrumentation Engineers (SPIE) C1 [Boukari, Fatima] Delaware State Univ, Dept Math, 1200 North Dupont Highway, Delaware, OH 19901 USA. [Boukari, Fatima; Makrogiannis, Sokratis; Boukari, Hacene] Delaware State Univ, Dept Phys & Engn, 1200 North Dupont Highway, Delaware, OH 19901 USA. [Makrogiannis, Sokratis; Boukari, Hacene] Delaware State Univ, Delaware Inst Sci & Technol, 1200 North Dupont Highway, Delaware, OH 19901 USA. [Nossal, Ralph] Eunice Kennedy Shriver Natl Inst Child & Human De, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Boukari, H (reprint author), Delaware State Univ, Dept Phys & Engn, 1200 North Dupont Highway, Delaware, OH 19901 USA.; Boukari, H (reprint author), Delaware State Univ, Delaware Inst Sci & Technol, 1200 North Dupont Highway, Delaware, OH 19901 USA. EM hboukari@desu.edu FU Center for Research and Education in Optical Sciences and Applications (CREOSA) at Delaware State University - NSF [HRD-1242067]; NASA [NNX09AU90A]; NIH Delaware INBRE [P20 RR016472]; National Institute of General Medical Sciences [SC3GM113754]; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX F. Boukari, S. Makrogiannis, and H. Boukari received support from the Center for Research and Education in Optical Sciences and Applications (CREOSA) at Delaware State University funded by NSF (HRD-1242067), from NASA Grant #NNX09AU90A, and from NIH Delaware INBRE (P20 RR016472). Research reported in this publication was also supported by the National Institute of General Medical Sciences under Award Number SC3GM113754. R. Nossal was supported by intramural funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. We thank our NIH colleagues, Dr. Beda Brichacek, Dr. Jeffrey Lifson, Dr. Leonid Margolis, Dr. Sheila Mahoney, and Dr. Pamela Stratton for their earlier participation in this project. NR 39 TC 0 Z9 0 U1 3 U2 3 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 EI 1560-2281 J9 J BIOMED OPT JI J. Biomed. Opt. PD SEP PY 2016 VL 21 IS 9 AR 096001 DI 10.1117/1.JBO.21.9.096001 PG 7 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA EC5YH UT WOS:000388212700032 PM 27598560 ER PT J AU Tan, Z Luo, M Yang, JL Cheng, YQ Huang, J Lu, CD Song, DJ Ye, ML Dai, MY Gonzalez, FJ Liu, AM Guo, B AF Tan, Zhen Luo, Min Yang, Julin Cheng, Yuqing Huang, Jing Lu, Caide Song, Danjun Ye, Meiling Dai, Manyun Gonzalez, Frank J. Liu, Aiming Guo, Bin TI Chlorogenic acid inhibits cholestatic liver injury induced by alpha-naphthylisothiocyanate: involvement of STAT3 and NF kappa B signalling regulation SO JOURNAL OF PHARMACY AND PHARMACOLOGY LA English DT Article DE chlorogenic acid; cholestasis; NF kappa B; STAT3; alpha-naphthylisothiocyanate ID PROTECTS AB Objectives Chlorogenic acid (CGA) is one of the most widely consumed polyphenols in diets and is recognized to be a natural hepatoprotective agent. Here, we evaluated the protective effect and the potential mechanism of CGA against alpha-naphthylisothiocyanate (ANIT)-induced cholestasis and liver injury. Methods Twenty-five male 129/Sv mice were administered with CGA, and ANIT challenge was performed at 75 mg/kg on the 4th day. Blood was collected and subjected to biochemical analysis; the liver tissues were examined using histopathological analysis and signalling pathways. Key findings Chlorogenic acid almost totally attenuated the ANIT-induced liver damage and cholestasis, compared with the ANIT group. Dose of 50 mg/kg of CGA significantly prevented ANIT-induced changes in serum levels of alanine aminotransferase, alkaline phosphatases, total bile acid, direct bilirubin, indirect bilirubin (5.3-, 6.3-, 18.8-, 158-, 41.4-fold, P< 0.001) and aspartate aminotransferase (4.6-fold, P< 0.01). Expressions of the altered bile acid metabolism and transport-related genes were normalized by cotreatment with CGA. The expressions of interleukin 6, tumour necrosis factor-alpha and suppressor of cytokine signalling 3 were found to be significantly decreased (1.2-fold, ns; 11.0-fold, P< 0.01; 4.4-fold, P< 0.05) in the CGA/ANIT group. Western blot revealed that CGA inhibited the activation and expression of signal transducer and activator of transcription 3 and NF kappa B. Conclusions These data suggest that CGA inhibits both ANIT-induced intrahepatic cholestasis and the liver injury. This protective effect involves downregulation of STAT3 and NF kappa B signalling. C1 [Tan, Zhen; Cheng, Yuqing; Ye, Meiling; Guo, Bin] Hunan Normal Univ, Key Lab Phytochem R&D Hunan Prov, Changsha, Hunan, Peoples R China. [Luo, Min; Huang, Jing; Lu, Caide; Song, Danjun; Dai, Manyun; Liu, Aiming] Ningbo Univ, Sch Med, Ningbo 315211, Zhejiang, Peoples R China. [Yang, Julin] Ningbo Coll Hlth Sci, Ningbo, Zhejiang, Peoples R China. [Gonzalez, Frank J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Liu, AM (reprint author), Ningbo Univ, Sch Med, Ningbo 315211, Zhejiang, Peoples R China.; Guo, B (reprint author), Hunan Normal Univ, Changsha 410081, Hunan, Peoples R China. EM liuaiming@nbu.edu.cn; binguo@hunnu.edu.cn FU National Natural Science Foundation of China [81274178, 81273582, 81302848]; Zhejiang Provincial Education Department [Y201329949]; Foundation for University Young Key Teacher by the Education Department of Hunan Province; Construct Program of the Key Discipline in Hunan Province FX This work was financially supported by the National Natural Science Foundation of China (Grant No. 81274178, 81273582 and 81302848), Zhejiang Provincial Education Department (No. Y201329949), Foundation for University Young Key Teacher by the Education Department of Hunan Province and the Construct Program of the Key Discipline in Hunan Province. We greatly thank the technical support by Key Laboratory of Phytochemical R&D of Hunan Province and Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research (Ministry of Education of China). NR 46 TC 1 Z9 1 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3573 EI 2042-7158 J9 J PHARM PHARMACOL JI J. Pharm. Pharmacol. PD SEP PY 2016 VL 68 IS 9 BP 1203 EP 1213 DI 10.1111/jphp.12592 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EC7JJ UT WOS:000388313100011 PM 27367057 ER PT J AU Smith-Gagen, J Loux, T Drake, C Perez-Stable, EJ AF Smith-Gagen, Julie Loux, Travis Drake, Chris Perez-Stable, Eliseo J. TI How Does Managed Care Improve the Quality of Breast Cancer Care Among Medicare-Insured Minority Women? SO JOURNAL OF RACIAL AND ETHNIC HEALTH DISPARITIES LA English DT Article DE Breast cancer; Disparities; Medicare managed care ID PROPENSITY SCORE METHODS; HORMONE-RECEPTOR STATUS; HEALTH-CARE; PERCEIVED DISCRIMINATION; LOGISTIC-REGRESSION; CLINICAL-ONCOLOGY; AMERICAN-SOCIETY; MAMMOGRAPHY USE; DIAGNOSIS; STAGE AB Purpose The aim of this study is to investigate if evidence-based clinical guidelines are implemented equitability among ethnic minority breast cancer patients using Medicare Advantage and investigate if presumed advantages of managed care over fee-for-service are greater for minorities than for Whites. Methods Data from the Surveillance, Epidemiology, and End Results and Medicare were used to examine 70,755 women over age 65 diagnosed with early stage breast cancer between 2005 and 2009. Implementation of two clinical guidelines was assessed: receipt of radiation therapy after breast conserving surgery and estrogen receptor status documentation. Multilevel logistic regression and inverse propensity weighting controlled for confounding. Results African Americans are still less likely than Whites to receive radiation therapy after breast-conserving surgery, whether they use Medicare fee-for-service (OR 95 % CI) = 0.90 (0.83, 0.98) or managed care (OR 95 % CI) = 0.87 (0.76, 1.00). Differences between receipt of radiation therapy by insurance plan type was nonexistent. Relative to FFS, the use of managed care improved the odds of having estrogen receptor status documented by 44 % in African Americans, (OR 95 % CI) = 1.44 (1.15, 1.83) and by 42 % in Latina patients (OR 95 % CI) = 1.42 (1.17, 1.78). Conclusions Compared to Medicare fee-for-service, ethnic and racial disparities among Medicare Advantage users were reduced. We observed fewer disparities, but not an elimination of disparities, among Medicare Advantage enrollees receiving breast cancer care with an organizational and patient component of care. This suggests managed care may still need to focus on minority patient empowerment and involvement in care. C1 [Smith-Gagen, Julie] Univ Nevada, Sch Community Hlth Sci, 1664 North Virginia St MS 274, Reno, NV 89557 USA. [Loux, Travis] St Louis Univ, Coll Publ Hlth & Social Justice, St Louis, MO 63103 USA. [Drake, Chris] Univ Calif Davis, Div Stat, Davis, CA 95616 USA. [Perez-Stable, Eliseo J.] Univ Calif San Francisco, Div Gen Internal Med, Dept Med, Med Effectiveness Res Ctr Div Populat,Sch Med, San Francisco, CA 94143 USA. [Perez-Stable, Eliseo J.] Natl Inst Minor Hlth & Hlth Dispar, NIH, Bethesda, MD USA. RP Smith-Gagen, J (reprint author), Univ Nevada, Sch Community Hlth Sci, 1664 North Virginia St MS 274, Reno, NV 89557 USA. EM jsmithgagen@unr.edu OI Loux, Travis/0000-0002-9215-0617 NR 71 TC 0 Z9 0 U1 5 U2 5 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 2197-3792 EI 2196-8837 J9 J RACIAL ETHN HEALTH JI J. Racial Ethn. Health Disparities PD SEP PY 2016 VL 3 IS 3 BP 496 EP 507 DI 10.1007/s40615-015-0167-y PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EC5TJ UT WOS:000388198900013 PM 27294748 ER PT J AU Catenacci, VA Pan, ZX Ostendorf, D Brannon, S Gozansky, WS Mattson, MP Martin, B MacLean, PS Melanson, EL Donahoo, WT AF Catenacci, Victoria A. Pan, Zhaoxing Ostendorf, Danielle Brannon, Sarah Gozansky, Wendolyn S. Mattson, Mark P. Martin, Bronwen MacLean, Paul S. Melanson, Edward L. Donahoo, William Troy TI A Randomized Pilot Study Comparing Zero-Calorie Alternate-Day Fasting to Daily Caloric Restriction in Adults with Obesity SO OBESITY LA English DT Article ID RESTING METABOLIC-RATE; BINGE-EATING DISORDER; BODY-WEIGHT; ENERGY-EXPENDITURE; MEAL FREQUENCY; DISEASE; HEALTH; BDNF; METAANALYSIS; ASSOCIATION AB Objective: To evaluate the safety and tolerability of alternate-day fasting (ADF) and to compare changes in weight, body composition, lipids, and insulin sensitivity index (Si) with those produced by a standard weight loss diet, moderate daily caloric restriction (CR). Methods: Adults with obesity (BMI >= 30 kg/m(2), age 18-55) were randomized to either zero-calorie ADF (n=14) or CR (2400 kcal/day, n=12) for 8 weeks. Outcomes were measured at the end of the 8-week intervention and after 24 weeks of unsupervised follow-up. Results: No adverse effects were attributed to ADF, and 93% completed the 8-week ADF protocol. At 8 weeks, ADF achieved a 376 kcal/day greater energy deficit; however, there were no significant betweengroup differences in change in weight (mean +/- SE; ADF -8.2 +/- 0.9 kg, CR -7.1 +/- 1.0 kg), body composition, lipids, or Si. After 24 weeks of unsupervised follow-up, there were no significant differences in weight regain; however, changes from baseline in % fat mass and lean mass were more favorable in ADF. Conclusions: ADF is a safe and tolerable approach to weight loss. ADF produced similar changes in weight, body composition, lipids, and Si at 8 weeks and did not appear to increase risk for weight regain 24 weeks after completing the intervention. C1 [Catenacci, Victoria A.; MacLean, Paul S.; Melanson, Edward L.; Donahoo, William Troy] Univ Colorado, Div Endocrinol Metab & Diabet, Dept Med, Anschutz Med Campus, Aurora, CO 80045 USA. [Catenacci, Victoria A.; Ostendorf, Danielle; MacLean, Paul S.] Univ Colorado, Anschutz Hlth & Wellness Ctr, Colorado Sch Publ Hlth, Dept Biostat & Informat, Anschutz Med Campus, Aurora, CO 80045 USA. [Pan, Zhaoxing] Univ Colorado, Dept Pediat, Childrens Hosp Colorado Res Inst, Anschutz Med Campus, Aurora, CO USA. [Ostendorf, Danielle] Univ Colorado, Colorado Sch Publ Hlth, Dept Epidemiol, Anschutz Med Campus, Aurora, CO USA. [Brannon, Sarah] Univ Colorado, Colorado Sch Publ Hlth, Dept Community & Behav Hlth, Anschutz Med Campus, Aurora, CO USA. [Gozansky, Wendolyn S.; Donahoo, William Troy] Kaiser Permanente, Denver, CO USA. [Mattson, Mark P.] NIA, Neurosci Lab, NIH, Baltimore, MD 21224 USA. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Martin, Bronwen] NIA, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. [Melanson, Edward L.] Univ Colorado, Div Geriatr, Dept Med, Anschutz Med Campus, Aurora, CO USA. RP Catenacci, VA (reprint author), Univ Colorado, Div Endocrinol Metab & Diabet, Dept Med, Anschutz Med Campus, Aurora, CO 80045 USA.; Catenacci, VA (reprint author), Univ Colorado, Anschutz Hlth & Wellness Ctr, Colorado Sch Publ Hlth, Dept Biostat & Informat, Anschutz Med Campus, Aurora, CO 80045 USA. EM vicki.catenacci@ucdenver.edu RI MacLean, Paul/A-7887-2008 OI MacLean, Paul/0000-0002-1123-6612 FU NIH [R21 AT002617-02, UL1 TR001082, DK 048520]; Colorado Obesity Research Institute (CORI); Intramural Research Program of the National Institute on Aging FX NIH R21 AT002617-02, NIH UL1 TR001082, NIH DK 048520, the Colorado Obesity Research Institute (CORI), and the Intramural Research Program of the National Institute on Aging. Dr. Melanson is supported with resources and the use of facilities at the Denver VA Medical Center. NR 35 TC 1 Z9 1 U1 9 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD SEP PY 2016 VL 24 IS 9 BP 1874 EP 1883 DI 10.1002/oby.21581 PG 10 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA EC6VW UT WOS:000388275800010 PM 27569118 ER PT J AU Dutton, GR Kim, Y Jacobs, DR Li, XL Loria, CM Reis, JP Carnethon, M Durant, NH Gordon-Larsen, P Shikany, JM Sidney, S Lewis, CE AF Dutton, Gareth R. Kim, Yongin Jacobs, David R., Jr. Li, Xuelin Loria, Catherine M. Reis, Jared P. Carnethon, Mercedes Durant, Nefertiti H. Gordon-Larsen, Penny Shikany, James M. Sidney, Stephen Lewis, Cora E. TI 25-Year Weight Gain in a Racially Balanced Sample of US Adults: The CARDIA Study SO OBESITY LA English DT Article ID BODY-MASS INDEX; UNITED-STATES; YOUNG-ADULTS; PREVALENCE; TRENDS; WOMEN; OBESITY; COHORT; MEN; RECRUITMENT AB Objective: To examine 25-year trends in weight gain, partitioned by time-related and aging-related changes, during early and middle adulthood. Methods: Coronary Artery Risk Development in Young Adults (CARDIA), a prospective, non-nationally representative cohort study conducted at four urban field centers that began in 1985 to 1986 with 5,109 Black (B) and White (W) men (M) and women (W) aged 18 to 30 years, has followed participants for 25 years (aged 43-55 years in 2010-2011). Time-related and aging-related components of weight change were estimated to construct longitudinal models of linear and nonlinear trends. Results: There were nonlinear trends in time-related weight gain in W, with larger weight gains early that attenuated at subsequent exams. Time-related trends were linear in M. There were nonlinear trends in aging-related weight gain in BM, BW, and WM, with the greatest weight gains at younger ages. Aging-related trends were linear in WW. Participants with overweight or obesity in early adulthood had greater attenuation of aging-related weight gain during middle adulthood. Conclusions: These findings partially support recent surveys indicating slower increases in obesity prevalence in recent years. Findings further suggest that aging-related weight gain is greatest in the 20s and may begin attenuating as early as the mid-30s among some groups. C1 [Dutton, Gareth R.; Kim, Yongin; Li, Xuelin; Durant, Nefertiti H.; Shikany, James M.; Lewis, Cora E.] Univ Alabama Birmingham, Dept Med, Div Prevent Med, Birmingham, AL 35294 USA. [Jacobs, David R., Jr.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Loria, Catherine M.; Reis, Jared P.] NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. [Carnethon, Mercedes] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Gordon-Larsen, Penny] Univ North Carolina Chapel Hill, Gillings Sch Global Publ Hlth, Dept Nutr, Chapel Hill, NC USA. [Sidney, Stephen] Kaiser Permanente Northern Calif, Div Res, Oakland, CA USA. RP Dutton, GR (reprint author), Univ Alabama Birmingham, Dept Med, Div Prevent Med, Birmingham, AL 35294 USA. EM gdutton@uabmc.edu FU National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, HHSN268200900041C]; Intramural Research Program of the National Institute on Aging (NIA); NIA [AG0005]; NHLBI [AG0005] FX The Coronary Artery Risk Development in Young Adults Study (CARDIA) is supported by contracts HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, and HHSN268200900041C from the National Heart, Lung, and Blood Institute (NHLBI), the Intramural Research Program of the National Institute on Aging (NIA), and an intra-agency agreement between NIA and NHLBI (AG0005). NR 21 TC 1 Z9 1 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD SEP PY 2016 VL 24 IS 9 BP 1962 EP 1968 DI 10.1002/oby.21573 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA EC6VW UT WOS:000388275800021 PM 27569121 ER EF