FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Lu, TJ Lu, RB Hong, JS Yang, YK Yu, L AF Lu, Tsun-Jung Lu, Ru-Band Hong, Jau-Shyong Yang, Yen Kuang Yu, Lung TI Impairment of an Electroconvulsive Stimulus on Reconsolidation of Memories Established by Conditioning SO CHINESE JOURNAL OF PHYSIOLOGY LA English DT Article DE memory; reconsolidation; recall; ECT; cocaine; appetitive; passive avoidance ID BISPECTRAL INDEX; MOLECULAR-MECHANISMS; RETROGRADE-AMNESIA; THERAPY; CONSOLIDATION; ANTEROGRADE; AVOIDANCE; RETRIEVAL AB The deduced memory consolidation and reconsolidation phases are sensitive to similar amnesic and memory-enhancing treatment. Electroconvulsive stimulus has been well known to impair memory consolidation. Therefore, we hypothesized that electroconvulsive stimulus might disrupt reconsolidation for conditioning-established memories. Delivery of a 200-msec electroconvulsive stimulus (500 V, 25 mA) between mouse pinnas immediately after recall of the cocaine-induced conditioned place preference (CPP) impaired the reconsolidation and subsequent expression of this memory. In contrast, the electroconvulsive stimulus (500 V, 25 mA, lasting for 200 ms) did not affect subsequent cocaine-induced CPP performance when the recall procedure was omitted. Systemic pentobarbital injection immediately after the CPP test did not affect subsequent cocaine-induced CPP. Interestingly, several regimens of electroconvulsive stimulus given immediately after the recall of cocaine-induced CPP did not affect subsequent CPP performance when mice were anesthetized by pentobarbital throughout the ECS regimens. Finally, delivery of the ECS (500 V, 25 mA, lasting for 200 ms) immediately after the reactivation of passive avoidance (PA) and food-induced CPP impaired subsequent performance of these memories in the retest. Taken together, we conclude that a short-lasting electroconvulsive stimulus can deteriorate the reconsolidation of various forms of memory established by conditioning. C1 [Lu, Tsun-Jung; Yu, Lung] Natl Cheng Kung Univ, Coll Med, Inst Behav Med, Tainan 70101, Taiwan. [Lu, Ru-Band; Yang, Yen Kuang] Natl Cheng Kung Univ, Coll Med, Dept Psychiat, Tainan 70101, Taiwan. [Hong, Jau-Shyong] NIEHS, Labs Toxicol & Pharmacol, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Yu, L (reprint author), Natl Cheng Kung Univ, Coll Med, Inst Behav Med, Behav Neuropharmacol Lab, 1 Univ Rd, Tainan 70101, Taiwan. EM lungyu@mail.ncku.edu.tw FU ROC National Science Council [97-2321-B-006-010-, 97-2410-H-006-074-MY3] FX This research is supported, in part, by ROC National Science Council grants 97-2321-B-006-010- and 97-2410-H-006-074-MY3 to L.Y. NR 26 TC 1 Z9 1 U1 0 U2 8 PU CHINESE PHYSIOLOGICAL SOC PI TAIPEI PA NATL YANG-MING UNIV, TAIPEI, TAIWAN SN 0304-4920 J9 CHINESE J PHYSIOL JI Chin. J. Physiol. PD FEB 28 PY 2013 VL 56 IS 1 BP 44 EP 51 DI 10.4077/CJP.2013.BAA048 PG 8 WC Physiology SC Physiology GA 097MK UT WOS:000315478000006 PM 23347015 ER PT J AU Oka, Y Butnaru, M von Buchholtz, L Ryba, NJP Zuker, CS AF Oka, Yuki Butnaru, Matthew von Buchholtz, Lars Ryba, Nicholas J. P. Zuker, Charles S. TI High salt recruits aversive taste pathways SO NATURE LA English DT Article ID CARBONIC-ANHYDRASE-IV; BITTER TASTE; IN-VIVO; AMILORIDE; RECEPTOR; CELLS; MICE; NACL; DISCRIMINATION; TRANSDUCTION AB In the tongue, distinct classes of taste receptor cells detect the five basic tastes; sweet, sour, bitter, sodium salt and umami(1,2). Among these qualities, bitter and sour stimuli are innately aversive, whereas sweet and umami are appetitive and generally attractive to animals. By contrast, salty taste is unique in that increasing salt concentration fundamentally transforms an innately appetitive stimulus into a powerfully aversive one(3-7). This appetitive-aversive balance helps to maintain appropriate salt consumption(3,4,6,8), and represents an important part of fluid and electrolyte homeostasis. We have shown previously that the appetitive responses to NaCl are mediated by taste receptor cells expressing the epithelial sodium channel, ENaCs8, but the cellular substrate for salt aversion was unknown. Here we examine the cellular and molecular basis for the rejection of high concentrations of salts. We show that high salt recruits the two primary aversive taste pathways by activating the sour- and bitter-taste-sensing cells. We also demonstrate that genetic silencing of these pathways abolishes behavioural aversion to concentrated salt, without impairing salt attraction. Notably, mice devoid of salt-aversion pathways show unimpeded, continuous attraction even to very high concentrations of NaCl. We propose that the 'co-opting' of sour and bitter neural pathways evolved as a means to ensure that high levels of salt reliably trigger robust behavioural rejection, thus preventing its potentially detrimental effects on health. C1 [Oka, Yuki; Butnaru, Matthew; Zuker, Charles S.] Columbia Univ, Howard Hughes Med Inst, New York, NY 10032 USA. [Oka, Yuki; Butnaru, Matthew; Zuker, Charles S.] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. [Oka, Yuki; Butnaru, Matthew; Zuker, Charles S.] Columbia Univ, Dept Neurosci, Columbia Coll Phys & Surg, New York, NY 10032 USA. [von Buchholtz, Lars; Ryba, Nicholas J. P.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Zuker, CS (reprint author), Columbia Univ, Howard Hughes Med Inst, New York, NY 10032 USA. EM nick.ryba@nih.gov; cz2195@columbia.edu FU Japan Society for Promotion of Science; National Institutes of Health and National Institute of Dental and Craniofacial Research FX We thank E. Vitalis and N. Propp for the generation and maintenance of mouse lines, and K. Mueller for the construction of T2R-Sapphire lines. We also thank J. Chandrashekar, W. Sly and A. Waheed for advice and discussions, and K. Scott and members of our laboratories for comments. Y.O. was supported by the Japan Society for Promotion of Science. This research was supported in part by the intramural research program of the National Institutes of Health and National Institute of Dental and Craniofacial Research (to N.J.P.R.). C.S.Z. is an investigator of the Howard Hughes Medical Institute. NR 30 TC 63 Z9 64 U1 4 U2 108 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 28 PY 2013 VL 494 IS 7438 BP 472 EP 475 DI 10.1038/nature11905 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 099YI UT WOS:000315661500037 PM 23407495 ER PT J AU Kovalchik, SA Varadhan, R Fetterman, B Poitras, NE Wacholder, S Katki, HA AF Kovalchik, Stephanie A. Varadhan, Ravi Fetterman, Barbara Poitras, Nancy E. Wacholder, Sholom Katki, Hormuzd A. TI A general binomial regression model to estimate standardized risk differences from binary response data SO STATISTICS IN MEDICINE LA English DT Article DE absolute risk; binomial regression; constrained maximization; logistic regression; risk difference ID EPIDEMIOLOGIC ANALYSES; ODDS RATIO; CYTOLOGY AB Estimates of absolute risks and risk differences are necessary for evaluating the clinical and population impact of biomedical research findings. We have developed a linear-expit regression model (LEXPIT) to incorporate linear and nonlinear risk effects to estimate absolute risk from studies of a binary outcome. The LEXPIT is a generalization of both the binomial linear and logistic regression models. The coefficients of the LEXPIT linear terms estimate adjusted risk differences, whereas the exponentiated nonlinear terms estimate residual odds ratios. The LEXPIT could be particularly useful for epidemiological studies of risk association, where adjustment for multiple confounding variables is common. We present a constrained maximum likelihood estimation algorithm that ensures the feasibility of risk estimates of the LEXPIT model and describe procedures for defining the feasible region of the parameter space, judging convergence, and evaluating boundary cases. Simulations demonstrate that the methodology is computationally robust and yields feasible, consistent estimators. We applied the LEXPIT model to estimate the absolute 5-year risk of cervical precancer or cancer associated with different Pap and human papillomavirus test results in 167,171 women undergoing screening at Kaiser Permanente Northern California. The LEXPIT model found an increased risk due to abnormal Pap test in human papillomavirus-negative that was not detected with logistic regression. Our R package blm provides free and easy-to-use software for fitting the LEXPIT model. Published 2012. This article is a US Government work and is in the public domain in the USA. C1 [Kovalchik, Stephanie A.; Wacholder, Sholom; Katki, Hormuzd A.] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Varadhan, Ravi] Johns Hopkins Univ, Sch Med, Ctr Aging Hlth, Baltimore, MD USA. [Fetterman, Barbara; Poitras, Nancy E.] Kaiser Permanente No Calif, Berkeley, CA USA. RP Kovalchik, SA (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. EM kovalchiksa@nih.gov RI Katki, Hormuzd/B-4003-2015 FU NIH/NCI FX This research was supported by the intramural research program of the NIH/NCI. We thank Dr. Tom Lorey and Dr. Gene Pawlick (Regional Laboratory of the Northern California Kaiser Permanente Medical Care Program) for creating and supporting the data warehouse, and Kaiser Permanente Northern California for allowing use of the data. NR 32 TC 12 Z9 12 U1 1 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD FEB 28 PY 2013 VL 32 IS 5 BP 808 EP 821 DI 10.1002/sim.5553 PG 14 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 089PW UT WOS:000314923500006 PM 22865328 ER PT J AU Proschan, M Ford, CE Cutler, JA Graumlich, JF Pavlik, V Cushman, WC Davis, BR Alderman, MH Gordon, D Furberg, CD Franklin, SS Blumenthal, SS Castaldo, RS Preston, RA AF Proschan, Michael Ford, Charles E. Cutler, Jeffrey A. Graumlich, James F. Pavlik, Valory Cushman, William C. Davis, Barry R. Alderman, Michael H. Gordon, David Furberg, Curt D. Franklin, Stanley S. Blumenthal, Samuel S. Castaldo, Richard S. Preston, Richard A. CA ALLHAT Collaborative Res Grp TI How much effect of different antihypertensive medications on cardiovascular outcomes is attributable to their effects on blood pressure? SO STATISTICS IN MEDICINE LA English DT Article DE blood pressure; measurement error; meta-analysis; regression calibration; regression dilution bias; time-varying covariate analysis ID LIPID-LOWERING TREATMENT; ATTACK TRIAL ALLHAT; CORONARY HEART-DISEASE; HYPERTENSIVE PATIENTS; SURROGATE MARKER; CLINICAL-TRIALS; MAJOR OUTCOMES; STROKE; PROPORTION; ENDPOINTS AB The debate over whether certain antihypertensive medications have benefits beyond what would be expected from their blood pressure lowering spurred the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, which randomized 42,418 participants to chlorthalidone (15,255), amlodipine (9048), lisinopril (9054), or doxazosin (9061). We compared chlorthalidone, the active control, with each of the other three agents with respect to the primary outcome, fatal coronary heart disease or nonfatal myocardial infarction, and several other clinical endpoints. The arms were similar with respect to the primary endpoint, although some differences were found for other endpoints, most notably heart failure. Although the desire was to achieve similar blood pressure reductions in the four arms, we found some systolic blood pressure and diastolic blood pressure differences. A natural question is to what degree can observed treatment group differences in cardiovascular outcomes be attributed to these blood pressure differences. The purpose of this paper was to delineate the problems inherent in attempting to answer this question, and to present analyses intended to overcome these problems. Copyright (c) 2012 John Wiley & Sons, Ltd. C1 [Proschan, Michael] NIAID, Bethesda, MD 20892 USA. [Ford, Charles E.; Davis, Barry R.] Univ Texas Sch Publ Hlth, Houston, TX USA. [Cutler, Jeffrey A.; Gordon, David] NHLBI, Bethesda, MD 20892 USA. [Graumlich, James F.] Univ Illinois, Coll Med Peoria, Peoria, IL USA. [Pavlik, Valory] Baylor Coll Med, Houston, TX 77030 USA. [Cushman, William C.] Memphis Vet Affairs Med Ctr, Memphis, TN USA. [Alderman, Michael H.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Furberg, Curt D.] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Franklin, Stanley S.] Univ Calif Irvine, Los Angeles, CA USA. [Blumenthal, Samuel S.] Vet Affairs Med Ctr Milwaukee, Milwaukee, WI USA. [Preston, Richard A.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Preston, Richard A.] Vet Affairs Med Ctr, Miami, FL 33125 USA. RP Proschan, M (reprint author), NIAID, Biostat Res Branch, 6700A Rockledge Dr,Room 5140, Bethesda, MD 20892 USA. EM ProschaM@mail.nih.gov FU National Heart, Lung, and Blood Institute (NHLBI) [NO1-HC-35130]; Pfizer Inc.; Abbott Laboratories; Bristol-Myers Squibb; Merck; Pfizer; Roche; Wyeth; GlaxoSmithKline; King; Novartis; Bayer Corporation; Forest Laboratories; Schering Plough; Shionogi; Takeda FX The ALLHAT study was supported by contract NO1-HC-35130 with the National Heart, Lung, and Blood Institute (NHLBI). The ALLHAT investigators received contributions of study medications supplied by Pfizer (amlodipine besylate and doxazosin mesylate), AstraZeneca (atenolol and lisinopril), and Bristol-Myers Squibb (pravastatin), and financial support provided by Pfizer Inc.; Michael H. Alderman has received research support from Sankyo. Samuel S. Blumenthal has held a financial interest in Abbott Laboratories, Bristol-Myers Squibb, Merck, Pfizer, Roche, and Wyeth and has received honoraria from Boehringer Ingelheim. William C. Cushman has consulted for Calpis, Daiichi Sankyo, Gilead Colorado, Novartis, Noven, Pharmacopeia, Sanofi Aventis, Sciele, Takeda, Theravance; has received honoraria from Bristol-Myer Squibb, Forest Pharmaceuticals, King; and has received research support from GlaxoSmithKline, King, Novartis, and Merck. Barry R. Davis has consulted for Amgen, Forest Pharmaceuticals, and Takeda. Richard A. Preston has consulted for Gilead Colorado and has received research support from Abbott Laboratories, Bayer Corporation, Forest Laboratories, Merck, Novartis, Schering Plough, Shionogi, and Takeda. Richard S. Castaldo, Jeffrey A. Cutler, Charles E. Ford, Stanley S. Franklin, Curt D. Furberg, David Gordon, James F. Graumlich, Valory Pavlik, and Michael Proschan have no financial interests to report. NR 21 TC 2 Z9 2 U1 0 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD FEB 28 PY 2013 VL 32 IS 5 BP 884 EP 897 DI 10.1002/sim.5580 PG 14 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 089PW UT WOS:000314923500011 PM 22961832 ER PT J AU Pendse, J Ramachandran, PV Na, JB Narisu, N Fink, JL Cagan, RL Collins, FS Baranski, TJ AF Pendse, Jay Ramachandran, Prasanna V. Na, Jianbo Narisu, Narisu Fink, Jill L. Cagan, Ross L. Collins, Francis S. Baranski, Thomas J. TI A Drosophila functional evaluation of candidates from human genome-wide association studies of type 2 diabetes and related metabolic traits identifies tissue-specific roles for dHHEX SO BMC GENOMICS LA English DT Article DE Genome-wide association study; Drosophila melanogaster; Diabetes mellitus; type 2; Hyperglycemia; Dyslipidemias; Phylogeny; Reverse genetics; High-throughput screening assays; HHEX protein; human ID INSULIN-RECEPTOR; RISK LOCI; CELLS; GROWTH; FLIES; HEX; TRIGLYCERIDES; MUTATION; ENHANCER; HINDGUT AB Background: Genome-wide association studies (GWAS) identify regions of the genome that are associated with particular traits, but do not typically identify specific causative genetic elements. For example, while a large number of single nucleotide polymorphisms associated with type 2 diabetes (T2D) and related traits have been identified by human GWAS, only a few genes have functional evidence to support or to rule out a role in cellular metabolism or dietary interactions. Here, we use a recently developed Drosophila model in which high-sucrose feeding induces phenotypes similar to T2D to assess orthologs of human GWAS-identified candidate genes for risk of T2D and related traits. Results: Disrupting orthologs of certain T2D candidate genes (HHEX, THADA, PPARG, KCNJ11) led to sucrose-dependent toxicity. Tissue-specific knockdown of the HHEX ortholog dHHEX (CG7056) directed metabolic defects and enhanced lethality; for example, fat-body-specific loss of dHHEX led to increased hemolymph glucose and reduced insulin sensitivity. Conclusion: Candidate genes identified in human genetic studies of metabolic traits can be prioritized and functionally characterized using a simple Drosophila approach. To our knowledge, this is the first large-scale effort to study the functional interaction between GWAS-identified candidate genes and an environmental risk factor such as diet in a model organism system. C1 [Pendse, Jay; Na, Jianbo; Cagan, Ross L.] Mt Sinai Sch Med, Dept Dev & Regenerat Biol, New York, NY USA. [Ramachandran, Prasanna V.; Fink, Jill L.; Baranski, Thomas J.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Narisu, Narisu; Collins, Francis S.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Baranski, TJ (reprint author), Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. EM baranski@wustl.edu FU NIH [R21 DK069940, P60 DK20579, P20 RR020643]; NephCure Foundation; American Diabetes Association; NIGMS, NIH [T32 GM-62754]; NHGRI, NIH FX We thank Vivek A. Rudrapatna, Ruth I. Johnson, Susumu Hirabayashi, Erdem Bangi, Tirtha Kamal Das, Laura Palanker Musselman, Dac Anh Nguyen, Lori Bonnycastle, Michael Stitzel, Michael Erdos, and Laura Scott for advice and helpful discussions, and countless members of the free and open source software community for valuable guidance and code samples. This research was supported by NIH grants R21 DK069940 (RLC), P60 DK20579 (Washington University DRTC, TJB), and P20 RR020643 (TJB), as well as by grants from the NephCure Foundation (JN and RLC) and from the American Diabetes Association (JN and RLC). JP was supported in part by NIGMS Training Grant T32 GM-62754, NIH. NN and FSC were supported by the intramural program of NHGRI, NIH. NR 55 TC 9 Z9 9 U1 0 U2 9 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 FEB 27 PY 2013 VL 14 AR 136 DI 10.1186/1471-2164-14-136 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 113QB UT WOS:000316681500001 PM 23445342 ER PT J AU Chen, L Stuart, L Ohsumi, TK Burgess, S Varshney, GK Dastur, A Borowsky, M Benes, C Lacy-Hulbert, A Schmidt, EV AF Chen, Li Stuart, Lynda Ohsumi, Toshiro K. Burgess, Shawn Varshney, Gaurav K. Dastur, Anahita Borowsky, Mark Benes, Cyril Lacy-Hulbert, Adam Schmidt, Emmett V. TI Transposon activation mutagenesis as a screening tool for identifying resistance to cancer therapeutics SO BMC CANCER LA English DT Article DE Transposon mutagenesis; Chemotherapy; Resistance; Gene activation ID PDZ DOMAIN PROTEINS; INSERTIONAL MUTAGENESIS; STEM-CELLS; SIGNALING COMPLEXES; DRUG-SENSITIVITY; SLEEPING-BEAUTY; ION CHANNELS; GENOME; PIGGYBAC; EXPRESSION AB Background: The development of resistance to chemotherapies represents a significant barrier to successful cancer treatment. Resistance mechanisms are complex, can involve diverse and often unexpected cellular processes, and can vary with both the underlying genetic lesion and the origin or type of tumor. For these reasons developing experimental strategies that could be used to understand, identify and predict mechanisms of resistance in different malignant cells would be a major advance. Methods: Here we describe a gain-of-function forward genetic approach for identifying mechanisms of resistance. This approach uses a modified piggyBac transposon to generate libraries of mutagenized cells, each containing transposon insertions that randomly activate nearby gene expression. Genes of interest are identified using next-gen high-throughput sequencing and barcode multiplexing is used to reduce experimental cost. Results: Using this approach we successfully identify genes involved in paclitaxel resistance in a variety of cancer cell lines, including the multidrug transporter ABCB1, a previously identified major paclitaxel resistance gene. Analysis of co-occurring transposons integration sites in single cell clone allows for the identification of genes that might act cooperatively to produce drug resistance a level of information not accessible using RNAi or ORF expression screening approaches. Conclusion: We have developed a powerful pipeline to systematically discover drug resistance in mammalian cells in vitro. This cost-effective approach can be readily applied to different cell lines, to identify canonical or context specific resistance mechanisms. Its ability to probe complex genetic context and non-coding genomic elements as well as cooperative resistance events makes it a good complement to RNAi or ORF expression based screens. C1 [Chen, Li; Dastur, Anahita; Benes, Cyril] Massachusetts Gen Hosp, Ctr Canc Res, Ctr Mol Therapeut, Charlestown, MA 02129 USA. [Chen, Li; Dastur, Anahita; Benes, Cyril] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Chen, Li; Stuart, Lynda; Lacy-Hulbert, Adam; Schmidt, Emmett V.] Massachusetts Gen Hosp, Program Dev Immunol, Boston, MA 02115 USA. [Chen, Li; Stuart, Lynda; Lacy-Hulbert, Adam; Schmidt, Emmett V.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Ohsumi, Toshiro K.; Borowsky, Mark] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02115 USA. [Ohsumi, Toshiro K.; Borowsky, Mark] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Burgess, Shawn; Varshney, Gaurav K.] NHGRI, Dev Genom Sect, Genome Technol Branch, Bethesda, MD 20892 USA. RP Chen, L (reprint author), Massachusetts Gen Hosp, Ctr Canc Res, Ctr Mol Therapeut, CNY 149 Rm7308,13th St, Charlestown, MA 02129 USA. EM lchen13@partners.org RI Varshney, Gaurav/L-5261-2014; OI Burgess, Shawn/0000-0003-1147-0596; Lacy-Hulbert, Adam/0000-0003-2162-0156; Varshney, Gaurav K./0000-0002-0429-1904 FU National Institutes of Health [U01-AI070330]; Wellcome Trust [086357] FX This work was supported by National Institutes of Health grant (U01-AI070330). LC, AD, and CB received additional funding from the Wellcome Trust (086357). NR 50 TC 10 Z9 10 U1 0 U2 11 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 FEB 27 PY 2013 VL 13 AR 93 DI 10.1186/1471-2407-13-93 PG 15 WC Oncology SC Oncology GA 103NA UT WOS:000315922700001 PM 23442791 ER PT J AU Maltsev, AS Chen, J Levine, RL Bax, A AF Maltsev, Alexander S. Chen, Jue Levine, Rodney L. Bax, Ad TI Site-Specific Interaction between alpha-Synuclein and Membranes Probed by NMR-Observed Methionine Oxidation Rates SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; A-BETA COMPONENT; PARKINSONS-DISEASE; NEURODEGENERATIVE DISEASES; ALZHEIMERS-DISEASE; MASS-SPECTROMETRY; PRECURSOR PROTEIN; BINDING; STRESS; AGGREGATION AB alpha-Synuclein (alpha S) is an intrinsically disordered protein that is water-soluble but also can bind negatively charged lipid membranes while adopting an alpha-helical conformation. Membrane affinity is increased by post-translational N-terminal acetylation, a common modification in all eukaryotic cells. In the presence of lipid vesicles containing a small fraction of peroxidized lipids, the N-terminal Met residues in alpha S (Met1 and Met5) rapidly oxidize while reducing the toxic lipid hydroperoxide to a nonreactive lipid hydroxide, whereas C-terminal Met residues remain unaffected. Met oxidation can be probed conveniently and quantitatively by NMR spectroscopy. The results show that oxidation of Met1 reduces the rate of oxidation of Met5 and vice versa as a result of decreased membrane affinity of the partially oxidized protein. The effect of Met oxidation on the alpha S-membrane affinity extends over large distances, as in the V49M mutant, oxidation of Met1 and Met5 strongly impacts the oxidation rate of Met49 and vice versa. When not bound to membrane, oxidized Met1 and Met5 of alpha S are excellent substrates for methionine sulfoxide reductase (Msr), thereby providing an efficient vehicle for water-soluble Msr enzymes to protect the membrane against oxidative damage. C1 [Maltsev, Alexander S.; Bax, Ad] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Chen, Jue; Levine, Rodney L.] NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. EM bax@nih.gov RI Levine, Rodney/D-9885-2011 FU NIDDK; NHLBI; Office of the Director, NIH FX This work was supported by the Intramural Research Program of NIDDK and NHLBI and the Intramural Antiviral Target Program of the Office of the Director, NIH. We thank Nelson Cole for useful discussions and Barbara S. Berlett for accelerating lipid peroxidation by gamma irradiation. NR 36 TC 20 Z9 20 U1 2 U2 46 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 FEB 27 PY 2013 VL 135 IS 8 BP 2943 EP 2946 DI 10.1021/ja312415q PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA 099KC UT WOS:000315618900020 PM 23398174 ER PT J AU Reiner, JE Robertson, JWF Burden, DL Burden, LK Balijepalli, A Kasianowicz, JJ AF Reiner, Joseph E. Robertson, Joseph W. F. Burden, Daniel L. Burden, Lisa K. Balijepalli, Arvind Kasianowicz, John J. TI Temperature Sculpting in Yoctoliter Volumes SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID MOLECULE FLUORESCENCE SPECTROSCOPY; ALPHA-HEMOLYSIN CHANNELS; FLOW CIRCULAR-DICHROISM; BILAYER-LIPID MEMBRANES; NANOMETER-SCALE PORE; GOLD NANOPARTICLES; ION-CHANNEL; CONFORMATIONAL DYNAMICS; POLYETHYLENE-GLYCOL; MASS-SPECTROMETRY AB The ability to perturb large ensembles of molecules from equilibrium led to major advances in understanding reaction mechanisms in chemistry and biology. Here, we demonstrate the ability to control, measure, and make use of rapid temperature changes in fluid volumes that are commensurate with the size of single molecules. The method is based on attaching gold nanoparticles to a single nanometer-scale pore formed by a protein ion channel. Visible laser light incident on the nanoparticles causes a rapid and large increase of the adjacent solution temperature, which is estimated from the change in the nanopore ionic conductance. The temperature shift also affects the ability of individual molecules to enter into and interact with the nanopore. This technique could significantly improve sensor systems and force measurements based on single nanopores, thereby enabling a method for single molecule thermodynamics and kinetics. C1 [Reiner, Joseph E.] Virginia Commonwealth Univ, Dept Phys, Richmond, VA 23284 USA. [Robertson, Joseph W. F.; Balijepalli, Arvind; Kasianowicz, John J.] NIST, Semicond & Dimens Metrol Div, Phys Measurement Lab, Gaithersburg, MD 20899 USA. [Burden, Daniel L.] Wheaton Coll, Dept Chem, Wheaton, IL 60187 USA. [Burden, Lisa K.] Wheaton Coll, Dept Biol, Wheaton, IL 60187 USA. [Balijepalli, Arvind] NHLBI, Lab Computat Biol, NIH, Rockville, MD 20892 USA. RP Reiner, JE (reprint author), Virginia Commonwealth Univ, Dept Phys, Richmond, VA 23284 USA. EM jereiner@vcu.edu; joseph.robertson@nist.gov; john.kasianowicz@nist.gov OI Reiner, Joseph/0000-0002-1056-8703 FU NRC/NIST-NIH; NIST-ARRA; NIST Office of Law Enforcement Standards; NSF FX This work was supported in part by a NRC/NIST-NIH Research Fellowship (AB), NIST-ARRA Senior Fellowship (JER), and grants from the NIST Office of Law Enforcement Standards (J.J.K, J.W.F.R., J.E.R.) and the NSF (D.L.B.). We would like to thank Les Kirkegaard at BioAssay Works for helpful discussions regarding the characteristics of the gold nanoparticles, Arad Lajevardi-Khosh for sample preparation and SEM counting statistics, and Andras Vladar, Bin Ming, and Premsagar Kavuri for access to and assistance with SEM imaging. NR 107 TC 26 Z9 26 U1 2 U2 29 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 FEB 27 PY 2013 VL 135 IS 8 BP 3087 EP 3094 DI 10.1021/ja309892e PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA 099KC UT WOS:000315618900041 PM 23347384 ER PT J AU Davey, RT Lynfield, R Dwyer, DE Losso, MH Cozzi-Lepri, A Wentworth, D Lane, HC Dewar, R Rupert, A Metcalf, JA Pett, SL Uyeki, TM Bruguera, JM Angus, B Cummins, N Lundgren, J Neaton, JD AF Davey, Richard T., Jr. Lynfield, Ruth Dwyer, Dominic E. Losso, Marcello H. Cozzi-Lepri, Alessandro Wentworth, Deborah Lane, H. Clifford Dewar, Robin Rupert, Adam Metcalf, Julia A. Pett, Sarah L. Uyeki, Timothy M. Maria Bruguera, Jose Angus, Brian Cummins, Nathan Lundgren, Jens Neaton, James D. CA Insight FLU 002 Study Grp Insight FLU 003 Study Grp TI The Association between Serum Biomarkers and Disease Outcome in Influenza A(H1N1)pdm09 Virus Infection: Results of Two International Observational Cohort Studies SO PLOS ONE LA English DT Article ID PANDEMIC H1N1 2009; CYTOKINE RESPONSE; SEVERE PNEUMONIA; SURVEILLANCE; PATHOGENESIS; ILLNESS AB Background: Prospective studies establishing the temporal relationship between the degree of inflammation and human influenza disease progression are scarce. To assess predictors of disease progression among patients with influenza A(H1N1)pdm09 infection, 25 inflammatory biomarkers measured at enrollment were analyzed in two international observational cohort studies. Methods: Among patients with RT-PCR-confirmed influenza A(H1N1) pdm09 virus infection, odds ratios (ORs) estimated by logistic regression were used to summarize the associations of biomarkers measured at enrollment with worsened disease outcome or death after 14 days of follow-up for those seeking outpatient care (FLU 002) or after 60 days for those hospitalized with influenza complications (FLU 003). Biomarkers that were significantly associated with progression in both studies (p<0.05) or only in one (p<0.002 after Bonferroni correction) were identified. Results: In FLU 002 28/528 (5.3%) outpatients had influenza A(H1N1) pdm09 virus infection that progressed to a study endpoint of complications, hospitalization or death, whereas in FLU 003 28/170 (16.5%) inpatients enrolled from the general ward and 21/39 (53.8%) inpatients enrolled directly from the ICU experienced disease progression. Higher levels of 12 of the 25 markers were significantly associated with subsequent disease progression. Of these, 7 markers (IL-6, CD163, IL-10, LBP, IL-2, MCP-1, and IP-10), all with ORs for the 3rd versus 1st tertile of 2.5 or greater, were significant (p<0.05) in both outpatients and inpatients. In contrast, five markers (sICAM-1, IL-8, TNF-alpha, D-dimer, and sVCAM-1), all with ORs for the 3rd versus 1st tertile greater than 3.2, were significantly (p <=.002) associated with disease progression among hospitalized patients only. Conclusions: In patients presenting with varying severities of influenza A(H1N1)pdm09 virus infection, a baseline elevation in several biomarkers associated with inflammation, coagulation, or immune function strongly predicted a higher risk of disease progression. It is conceivable that interventions designed to abrogate these baseline elevations might affect disease outcome. C1 [Davey, Richard T., Jr.; Lane, H. Clifford; Metcalf, Julia A.] NIAID, NIH, Bethesda, MD 20892 USA. [Lynfield, Ruth] Minnesota Dept Hlth, Div Infect Dis, St Paul, MN USA. [Dwyer, Dominic E.] Westmead Hosp, Dept Virol, Ctr Infect Dis & Microbiol, Westmead, NSW 2145, Australia. [Dwyer, Dominic E.] Univ Sydney, Westmead, NSW 2145, Australia. [Losso, Marcello H.] Hosp Jose Maria Ramos Mejia, Dept Med, HIV Unit, Buenos Aires, DF, Argentina. [Cozzi-Lepri, Alessandro] UCL, Res Dept Infect & Populat Hlth, London, England. [Wentworth, Deborah; Neaton, James D.] Univ Minnesota, Div Biostat, Minneapolis, MN USA. [Dewar, Robin] SAIC Frederick Inc, Frederick Natl Lab, Virus Isolat & Serol Lab, Frederick, MD USA. [Rupert, Adam] SAIC Frederick Inc, AIDS Monitoring Lab, Frederick, MD USA. [Pett, Sarah L.] Univ New S Wales, Fac Med, Kirby Inst, Sydney, NSW, Australia. [Uyeki, Timothy M.] Ctr Dis Control & Prevent, Influenza Div, Atlanta, GA USA. [Maria Bruguera, Jose] Hosp Jose Maria Ramos Mejia, Serv Inmunocomprometidos, Buenos Aires, DF, Argentina. [Angus, Brian] Univ Oxford, Nuffield Dept Med, Oxford, England. [Cummins, Nathan] Mayo Clin, Div Infect Dis, Rochester, MN USA. [Lundgren, Jens] Rigshosp, Copenhagen Univ Hosp, Dept Infect Dis, DK-2100 Copenhagen, Denmark. [Lundgren, Jens] Univ Copenhagen, Copenhagen, Denmark. RP Davey, RT (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM rdavey@niaid.nih.gov RI Burgmann, Heinz/N-2409-2013; Emery, Sean/H-4920-2013; OI Emery, Sean/0000-0001-6072-8309; Lundgren, Jens/0000-0001-8901-7850; Angus, Brian/0000-0003-3598-7784 FU United States National Institutes of Health [UOI-AI068641]; SAIC-Frederick, Inc., NCI-Frederick, Maryland [HHSN261200800001E] FX INSIGHT is funded by United States National Institutes of Health Grant UOI-AI068641, and the FLU 002 and FLU 003 studies are partially funded by SAIC-Frederick, Inc., Prime Contract HHSN261200800001E, NCI-Frederick, Maryland 21702. Disclosure: The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 11 Z9 11 U1 0 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 FEB 27 PY 2013 VL 8 IS 2 AR e57121 DI 10.1371/journal.pone.0057121 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 098BN UT WOS:000315519000064 PM 23468921 ER PT J AU Gotea, V Petrykowska, HM Elnitski, L AF Gotea, Valer Petrykowska, Hanna M. Elnitski, Laura TI Bidirectional Promoters as Important Drivers for the Emergence of Species-Specific Transcripts SO PLOS ONE LA English DT Article ID LONG NONCODING RNAS; BIASED GENE CONVERSION; HUMAN GENOME; POSITIVE SELECTION; FACTOR-BINDING; ALU REPEATS; EVOLUTION; DNA; VARIABILITY; DROSOPHILA AB The diversification of gene functions has been largely attributed to the process of gene duplication. Novel examples of genes originating from previously untranscribed regions have been recently described without regard to a unifying functional mechanism for their emergence. Here we propose a model mechanism that could generate a large number of lineage-specific novel transcripts in vertebrates through the activation of bidirectional transcription from unidirectional promoters. We examined this model in silico using human transcriptomic and genomic data and identified evidence consistent with the emergence of more than 1,000 primate-specific transcripts. These are transcripts with low coding potential and virtually no functional annotation. They initiate at less than 1 kb upstream of an oppositely transcribed conserved protein coding gene, in agreement with the generally accepted definition of bidirectional promoters. We found that the genomic regions upstream of ancestral promoters, where the novel transcripts in our dataset reside, are characterized by preferential accumulation of transposable elements. This enhances the sequence diversity of regions located upstream of ancestral promoters, further highlighting their evolutionary importance for the emergence of transcriptional novelties. By applying a newly developed test for positive selection to transposable element-derived fragments in our set of novel transcripts, we found evidence of adaptive evolution in the human lineage in nearly 3% of the novel transcripts in our dataset. These findings indicate that at least some novel transcripts could become functionally relevant, and thus highlight the evolutionary importance of promoters, through their capacity for bidirectional transcription, for the emergence of novel genes. C1 [Gotea, Valer; Petrykowska, Hanna M.; Elnitski, Laura] NHGRI, DIR GTB Genom Funct Anal Sect, NIH, Bethesda, MD 20892 USA. RP Elnitski, L (reprint author), NHGRI, DIR GTB Genom Funct Anal Sect, NIH, Bethesda, MD 20892 USA. EM elnitski@mail.nih.gov OI Gotea, Valer/0000-0001-7857-3309 FU Intramural program of the National Human Genome Research Institute, National Institutes of Health FX This work was supported by the Intramural program of the National Human Genome Research Institute, 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 54 TC 14 Z9 14 U1 0 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 27 PY 2013 VL 8 IS 2 AR e57323 DI 10.1371/journal.pone.0057323 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 098BN UT WOS:000315519000092 PM 23460838 ER PT J AU James, MM Laeyendecker, O Sun, J Hoover, DR Mullis, CE Cousins, MM Coates, T Moore, RD Kelen, GD Fowler, MG Kumwenda, JJ Mofenson, LM Kumwenda, NI Taha, TE Eshleman, SH AF James, Maria M. Laeyendecker, Oliver Sun, Jin Hoover, Donald R. Mullis, Caroline E. Cousins, Matthew M. Coates, Thomas Moore, Richard D. Kelen, Gabor D. Fowler, Mary Glenn Kumwenda, Johnstone J. Mofenson, Lynne M. Kumwenda, Newton I. Taha, Taha E. Eshleman, Susan H. TI Antibody Maturation and Viral Diversification in HIV-Infected Women SO PLOS ONE LA English DT Article ID RESOLUTION MELTING ASSAY; ENZYME-IMMUNOASSAY; DRUG-RESISTANCE; SUBTYPE-C; DIVERSITY; TRANSMISSION; MUTATIONS; AFRICA; SEX AB Introduction: The Post-exposure Prophylaxis in Infants (PEPI)-Malawi trial evaluated infant antiretroviral regimens for prevention of post-natal HIV transmission. A multi-assay algorithm (MAA) that includes the BED capture immunoassay, an avidity assay, CD4 cell count, and viral load was used to identify women who were vs. were not recently infected at the time of enrollment (MAA recent, N = 73; MAA non-recent, N = 2,488); a subset of the women in the MAA non-recent group known to have been HIV infected for at least 2 years before enrollment (known non-recent, N = 54). Antibody maturation and viral diversification were examined in these women. Methods: Samples collected at enrollment (N = 2,561) and 12-24 months later (N = 1,306) were available for serologic analysis using the BED and avidity assays. A subset of those samples was used for analysis of viral diversity, which was performed using a high resolution melting (HRM) diversity assay. Viral diversity analysis was performed using all available samples from women in the MAA recent group (61 enrollment samples, 38 follow-up samples) and the known non-recent group (43 enrollment samples, 22 follow-up samples). Diversity data from PEPI-Malawi were also compared to similar data from 169 adults in the United States (US) with known recent infection (N = 102) and known non-recent infection (N = 67). Results: In PEPI-Malawi, results from the BED and avidity assays increased over time in the MAA recent group, but did not change significantly in the MAA non- recent group. At enrollment, HIV diversity was lower in the MAA recent group than in the known non- recent group. HRM diversity assay results from women in PEPI-Malawi were similar to those from adults in the US with known duration of HIV infection. Conclusions: Antibody maturation and HIV diversification patterns in African women provide additional support for use of the MAA to identify populations with recent HIV infection. C1 [James, Maria M.; Cousins, Matthew M.; Fowler, Mary Glenn; Eshleman, Susan H.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Laeyendecker, Oliver] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Laeyendecker, Oliver; Mullis, Caroline E.; Moore, Richard D.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Sun, Jin; Kumwenda, Newton I.; Taha, Taha E.] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Hoover, Donald R.] Rutgers State Univ, Dept Stat & Biostat, Piscataway, NJ USA. [Hoover, Donald R.] Rutgers State Univ, Inst Hlth Hlth Care Policy & Aging Res, Piscataway, NJ USA. [Coates, Thomas] Univ Calif Los Angeles, Program Global Hlth, Los Angeles, CA USA. [Kelen, Gabor D.] Johns Hopkins Univ, Sch Med, Dept Emergency Med, Baltimore, MD USA. [Kumwenda, Johnstone J.] Univ Malawi, Dept Med, Coll Med, Blantyre, Malawi. [Mofenson, Lynne M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, NIH, Rockville, MD USA. RP Eshleman, SH (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. EM seshlem@jhmi.edu RI Laeyendecker, Oliver/B-9331-2009; OI Mofenson, Lynne/0000-0002-2818-9808; Kelen, Gabor/0000-0002-3236-8286; Laeyendecker, Oliver/0000-0002-6429-4760 FU International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Group, American Recovery and Reinvestment Act (ARRA) award [3U01AI068632-05S3]; National Institute of Allergy and Infectious Diseases (NIAID); National Institute on Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Office of AIDS Research, of the National Institutes of Health (NIH), Dept. of Health and Human Services (DHHS) [U01AI068613, UM1AI068613]; Centers for Disease Control and Prevention [U50/CCU022061]; International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) Group [U01-AI068632] FX Funders for this work are as follows: (1) International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Group, American Recovery and Reinvestment Act (ARRA) award (Cooperative Agreement 3U01AI068632-05S3); (2) The HIV Prevention Trials Network (HPTN) sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and the Office of AIDS Research, of the National Institutes of Health (NIH), Dept. of Health and Human Services (DHHS) (U01AI068613, UM1AI068613); (3) The Centers for Disease Control and Prevention (Cooperative Agreement U50/CCU022061); and (4) The International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) Group (U01-AI068632). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 6 Z9 6 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 FEB 27 PY 2013 VL 8 IS 2 AR e57350 DI 10.1371/journal.pone.0057350 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 098BN UT WOS:000315519000096 PM 23460842 ER PT J AU Ma, LJ Murea, M Snipes, JA Marinelarena, A Kruger, J Hicks, PJ Langberg, KA Bostrom, MA Cooke, JN Suzuki, D Babazono, T Uzu, T Tang, SCW Mondal, AK Sharma, NK Kobes, S Antinozzi, PA Davis, M Das, SK Rasouli, N Kern, PA Shores, NJ Rudel, LL Bluuher, M Stumvoll, M Bowden, DW Maeda, S Parks, JS Kovacs, P Hanson, RL Baier, LJ Elbein, SC Freedman, BI AF Ma, Lijun Murea, Mariana Snipes, James A. Marinelarena, Alejandra Krueger, Jacqueline Hicks, Pamela J. Langberg, Kurt A. Bostrom, Meredith A. Cooke, Jessica N. Suzuki, Daisuke Babazono, Tetsuya Uzu, Takashi Tang, Sydney C. W. Mondal, Ashis K. Sharma, Neeraj K. Kobes, Sayuko Antinozzi, Peter A. Davis, Matthew Das, Swapan K. Rasouli, Neda Kern, Philip A. Shores, Nathan J. Rudel, Lawrence L. Blueher, Matthias Stumvoll, Michael Bowden, Donald W. Maeda, Shiro Parks, John S. Kovacs, Peter Hanson, Robert L. Baier, Leslie J. Elbein, Steven C. Freedman, Barry I. TI An ACACB Variant Implicated in Diabetic Nephropathy Associates with Body Mass Index and Gene Expression in Obese Subjects SO PLOS ONE LA English DT Article ID ACETYL-COA CARBOXYLASE-2; FATTY-ACID OXIDATION; ADIPOSE-TISSUE; MICE LACKING; MUTANT MICE; POLYMORPHISMS; METABOLISM; DIET; KNOCKOUT; GLUCOSE AB Acetyl coenzyme A carboxylase B gene (ACACB) single nucleotide polymorphism (SNP) rs2268388 is reproducibly associated with type 2 diabetes (T2DM)-associated nephropathy (DN). ACACB knock-out mice are also protected from obesity. This study assessed relationships between rs2268388, body mass index (BMI) and gene expression in multiple populations, with and without T2DM. Among subjects without T2DM, rs2268388 DN risk allele (T) associated with higher BMI in Pima Indian children (n = 2021; p-additive = 0.029) and African Americans (AAs) (n = 177; p-additive = 0.05), with a trend in European Americans (EAs) (n = 512; p-additive = 0.09), but not Germans (n = 858; p-additive = 0.765). Association with BMI was seen in a meta-analysis including all non-T2DM subjects (n = 3568; p-additive = 0.02). Among subjects with T2DM, rs2268388 was not associated with BMI in Japanese (n = 2912) or EAs (n = 1149); however, the T allele associated with higher BMI in the subset with BMI >= 30 kg/m(2) (n = 568 EAs; p-additive = 0.049, n = 196 Japanese; p-additive = 0.049). Association with BMI was strengthened in a T2DM meta-analysis that included an additional 756 AAs (p-additive = 0.080) and 48 Hong Kong Chinese (p-additive = 0.81) with BMI >= 30 kg/m(2) (n = 1575; p-additive = 0.0033). The effect of rs2268388 on gene expression revealed that the T risk allele associated with higher ACACB messenger levels in adipose tissue (41 EAs and 20 AAs with BMI > 30 kg/m(2); p-additive = 0.018) and ACACB protein levels in the liver tissue (mixed model p-additive = 0.03, in 25 EA bariatric surgery patients with BMI > 30 kg/m(2) for 75 exams). The T allele also associated with higher hepatic triglyceride levels. These data support a role for ACACB in obesity and potential roles for altered lipid metabolism in susceptibility to DN. C1 [Ma, Lijun; Murea, Mariana; Snipes, James A.; Hicks, Pamela J.; Langberg, Kurt A.; Bostrom, Meredith A.; Cooke, Jessica N.; Mondal, Ashis K.; Sharma, Neeraj K.; Antinozzi, Peter A.; Davis, Matthew; Das, Swapan K.; Shores, Nathan J.; Rudel, Lawrence L.; Bowden, Donald W.; Parks, John S.; Elbein, Steven C.; Freedman, Barry I.] Wake Forest Sch Med, Winston Salem, NC USA. [Marinelarena, Alejandra; Kobes, Sayuko; Hanson, Robert L.; Baier, Leslie J.] NIDDKD, PECRB, Phoenix, AZ USA. [Krueger, Jacqueline; Blueher, Matthias; Stumvoll, Michael; Kovacs, Peter] Univ Leipzig, Interdisciplinary Ctr Clin Res, D-04109 Leipzig, Germany. [Suzuki, Daisuke] Tokai Univ, Div Nephrol & Metab, Dept Internal Med, Tokyo 151, Japan. [Babazono, Tetsuya] Tokyo Womens Med Univ, Ctr Diabet, Tokyo, Japan. [Uzu, Takashi] Shiga Univ Med Sci, Dept Med, Otsu, Shiga 52021, Japan. [Tang, Sydney C. W.] Univ Hong Kong, Dept Internal Med, Queen Mary Hosp, Hong Kong, Hong Kong, Peoples R China. [Rasouli, Neda] Univ Colorado, Dept Internal Med, Sch Med, Aurora, CO USA. [Kern, Philip A.] Univ Kentucky, Coll Med, Dept Internal Med, Lexington, KY USA. [Shores, Nathan J.] Tulane Univ Med Ctr Hosp & Clin, Abdominal Transplant Inst, New Orleans, LA USA. [Maeda, Shiro] RIKEN, Ctr Genom Med, Lab Endocrinol & Metab, Yokohama, Kanagawa, Japan. RP Ma, LJ (reprint author), Wake Forest Sch Med, Winston Salem, NC USA. EM lima@wakehealth.edu RI Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 FU Wake Forest School of Medicine Translational Science Institute Synergy Grant [K99 DK081350]; National Institutes of Health [R01 DK071891, R01 HL67348, R01 DK53591, R01 DK039311]; Veterans Administration; NIDDK; Ministry of Education, Culture, Sports, Science and Technology, Japan; Boehringer Ingelheim Foundation; [R0171349] FX This study was supported by a Wake Forest School of Medicine Translational Science Institute Synergy Grant K99 DK081350, National Institutes of Health extramural grants R01 DK071891, R01 HL67348, R01 DK53591, R01 DK039311, and partially supported by R0171349, a Merit Grant from the Veterans Administration, and NIDDK intramural research program. The Japanese study was partly supported by a grant from the Ministry of Education, Culture, Sports, Science and Technology, Japan (S. M.). P. K. (Leipzig) was funded by Boehringer Ingelheim Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 3 Z9 4 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 27 PY 2013 VL 8 IS 2 AR e56193 DI 10.1371/journal.pone.0056193 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 098BN UT WOS:000315519000017 PM 23460794 ER PT J AU Moustafa, ME Carlson, BA Anver, MR Bobe, G Zhong, NX Ward, JM Perella, CM Hoffmann, VJ Rogers, K Combs, GF Schweizer, U Merlino, G Gladyshev, VN Hatfield, DL AF Moustafa, Mohamed E. Carlson, Bradley A. Anver, Miriam R. Bobe, Gerd Zhong, Nianxin Ward, Jerrold M. Perella, Christine M. Hoffmann, Victoria J. Rogers, Keith Combs, Gerald F., Jr. Schweizer, Ulrich Merlino, Glenn Gladyshev, Vadim N. Hatfield, Dolph L. TI Selenium and Selenoprotein Deficiencies Induce Widespread Pyogranuloma Formation in Mice, while High Levels of Dietary Selenium Decrease Liver Tumor Size Driven by TGF alpha SO PLOS ONE LA English DT Article ID SELENOCYSTEINE TRANSFER-RNA; TRANSGENIC MICE; MAMMALIAN-CELLS; EXPRESSION; MOUSE; CANCER; HEPATOCARCINOGENESIS; INFLAMMATION; POPULATION; DELETION AB Changes in dietary selenium and selenoprotein status may influence both anti- and pro-cancer pathways, making the outcome of interventions different from one study to another. To characterize such outcomes in a defined setting, we undertook a controlled hepatocarcinogenesis study involving varying levels of dietary selenium and altered selenoprotein status using mice carrying a mutant (A37G) selenocysteine tRNA transgene (Trsp(tG37)) and/or a cancer driver TGF alpha transgene. The use of Trsp(tG37) altered selenoprotein expression in a selenoprotein and tissue specific manner and, at sufficient dietary selenium levels, separate the effect of diet and selenoprotein status. Mice were maintained on diets deficient in selenium (0.02 ppm selenium) or supplemented with 0.1, 0.4 or 2.25 ppm selenium or 30 ppm triphenylselenonium chloride (TPSC), a non-metabolized selenium compound. Trsp(tG37) transgenic and TGF alpha/Trsp(tG37) bi-transgenic mice subjected to selenium-deficient or TPSC diets developed a neurological phenotype associated with early morbidity and mortality prior to hepatocarcinoma development. Pathology analyses revealed widespread disseminated pyogranulomatous inflammation. Pyogranulomas occurred in liver, lungs, heart, spleen, small and large intestine, and mesenteric lymph nodes in these transgenic and bi-transgenic mice. The incidence of liver tumors was significantly increased in mice carrying the TGF alpha transgene, while dietary selenium and selenoprotein status did not affect tumor number and multiplicity. However, adenoma and carcinoma size and area were smaller in TGF alpha transgenic mice that were fed 0.4 and 2.25 versus 0.1 ppm of selenium. Thus, selenium and selenoprotein deficiencies led to widespread pyogranuloma formation, while high selenium levels inhibited the size of TGF alpha-induced liver tumors. C1 [Moustafa, Mohamed E.; Carlson, Bradley A.; Zhong, Nianxin; Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, NIH, Bethesda, MD 20892 USA. [Anver, Miriam R.; Rogers, Keith] Sci Applicat Int Corp Frederick Inc, Pathol Histotechnol Lab, Frederick Natl Lab Canc Res, Frederick, MD USA. [Bobe, Gerd] Oregon State Univ, Dept Anim & Rangeland Sci, Coll Agr, Corvallis, OR 97331 USA. [Bobe, Gerd] Oregon State Univ, Linus Pauling Inst, Corvallis, OR 97331 USA. [Ward, Jerrold M.] NIAID, Immunopathol Sect, NIH, Bethesda, MD 20892 USA. [Perella, Christine M.] Sci Applicat Int Corp Frederick Inc, Lab Anim Sci Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Hoffmann, Victoria J.] NCI, Off Director, Diagnost & Res Serv Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Combs, Gerald F., Jr.] USDA ARS, Grand Forks Human Nutr Res Ctr, Grand Forks, ND 58202 USA. [Schweizer, Ulrich] Charite, Inst Expt Endokrinol, D-13353 Berlin, Germany. [Merlino, Glenn] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Gladyshev, Vadim N.] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. [Gladyshev, Vadim N.] Harvard Univ, Sch Med, Boston, MA USA. RP Hatfield, DL (reprint author), NCI, Mol Biol Selenium Sect, Lab Canc Prevent, NIH, Bethesda, MD 20892 USA. EM hatfield@dc37a.nci.nih.gov RI Gladyshev, Vadim/A-9894-2013; Schweizer, Ulrich/E-8105-2013 FU Intramural Research Program of the National Institutes of Health (NIH); National Cancer Institute; Center for Cancer Research; NIH; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research to DLH, NIH grants to VNG and the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The authors express their sincere appreciation to BAC, R. Irons and C. D. Davis who made the video shown in the Online Supplementary Information in DLH's laboratory. The content of this publication does not necessarily reflect the views of 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. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 11 Z9 11 U1 0 U2 17 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 FEB 27 PY 2013 VL 8 IS 2 AR e57389 DI 10.1371/journal.pone.0057389 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 098BN UT WOS:000315519000101 PM 23460847 ER PT J AU Waltz, JA Kasanova, Z Ross, TJ Salmeron, BJ McMahon, RP Gold, JM Stein, EA AF Waltz, James A. Kasanova, Zuzana Ross, Thomas J. Salmeron, Betty J. McMahon, Robert P. Gold, James M. Stein, Elliot A. TI The Roles of Reward, Default, and Executive Control Networks in Set-Shifting Impairments in Schizophrenia SO PLOS ONE LA English DT Article ID TEMPORAL DIFFERENCE MODELS; PREFRONTAL CORTEX; BRAIN NETWORKS; FUNCTIONAL CONNECTIVITY; CINGULATE CORTEX; DECISION-MAKING; RATING-SCALE; DYSFUNCTION; REPRESENTATION; COGNITION AB Patients with schizophrenia (SZ) show deficits on tasks of rapid reinforcement learning, like probabilistic reversal learning (PRL), but the neural bases for those impairments are not known. Recent evidence of relatively intact sensitivity to negative outcomes in the ventral striatum (VS) in many SZ patients suggests that PRL deficits may be largely attributable to processes downstream from feedback processing, involving both the activation of executive control task regions and deactivation of default mode network (DMN) components. We analyzed data from 29 chronic SZ patients and 21 matched normal controls (NCs) performing a PRL task in an MRI scanner. Subjects were presented with eight pairs of fractal stimuli, for 50 trials each. For each pair, subjects learned to choose the more frequently-rewarded (better) stimulus. Each time a criterion was reached, the better stimulus became the worse one, and the worse became the better. Responses to feedback events were assessed through whole-brain and regions-of-interest (ROI) analyses in DMN. We also assessed correlations between BOLD signal contrasts and clinical measures in SZs. Relative to NCs, SZ patients showed comparable deactivation of VS in response to negative feedback, but reduced deactivation of DMN components including medial prefrontal cortex (mPFC). The magnitudes of patients' punishment-evoked deactivations in VS and ventromedial PFC correlated significantly with clinical ratings for avolition/anhedonia. These findings suggest that schizophrenia is associated with a reduced ability to deactivate components of default mode networks, following the presentation of informative feedback and that motivational deficits in SZ relate closely to feedback-evoked activity in reward circuit components. These results also confirm a role for ventrolateral and dorsomedial PFC in the execution of response-set shifts. C1 [Waltz, James A.; Kasanova, Zuzana; McMahon, Robert P.; Gold, James M.] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat, Baltimore, MD 21201 USA. [Ross, Thomas J.; Salmeron, Betty J.; Stein, Elliot A.] NIDA, Neuroimaging Res Branch, Intramural Res Program, Baltimore, MD USA. RP Waltz, JA (reprint author), Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat, Baltimore, MD 21201 USA. EM jwaltz@mprc.umaryland.edu RI McMahon, Robert/C-5462-2009; Salmeron, Betty Jo/M-1793-2016; OI Salmeron, Betty Jo/0000-0003-1699-9333; Kasanova, Zuzana/0000-0002-8795-5373; Ross, Thomas/0000-0002-7745-3572 FU National Institutes of Health (NIH) [K12 RR023250, R01 MH080066]; National Institute on Drug Abuse - Intramural Research Program (NIDA-IRP); [HHSN271200599091C/ADB]; [N01DA-5-9909] FX This work supported by National Institutes of Health (NIH) grants K12 RR023250, R01 MH080066, a project grant from HHSN271200599091C/ADB Contract # N01DA-5-9909 and by the National Institute on Drug Abuse - Intramural Research Program (NIDA-IRP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 70 TC 28 Z9 28 U1 5 U2 20 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 FEB 27 PY 2013 VL 8 IS 2 AR e57257 DI 10.1371/journal.pone.0057257 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 098BN UT WOS:000315519000084 PM 23468948 ER PT J AU Evsen, L Sugahara, S Uchikawa, M Kondoh, H Wu, DK AF Evsen, Lale Sugahara, Satoko Uchikawa, Masanori Kondoh, Hisato Wu, Doris K. TI Progression of Neurogenesis in the Inner Ear Requires Inhibition of Sox2 Transcription by Neurogenin1 and Neurod1 SO JOURNAL OF NEUROSCIENCE LA English DT Article ID SENSORY ORGAN GENERATION; NEURAL STEM-CELLS; XENOPUS RETINA; CHICK-EMBRYO; HAIR-CELLS; GENE; DIFFERENTIATION; EXPRESSION; EPITHELIA; FATE AB Sox2 is required for proper neuronal formation in the CNS, but the molecular mechanisms involved are not well characterized. Here, we addressed the role of Sox2 in neurogenesis of the developing chicken inner ear. Overexpressing Sox2 from a constitutive (beta-actin) promoter induces the expression of the proneural gene, Neurogenin1 (Ngn1); however, the expression of a downstream target of Ngn1, Neurod1, is unchanged. As a result, there is a reduction of neural precursors to delaminate and populate the developing cochleovestibular ganglion. In contrast, overexpression of either Ngn1 or Neurod1 is sufficient to promote the neural fate in this system. These results suggest that high levels of Sox2 inhibit progression of neurogenesis in the developing inner ear. Furthermore, we provide evidence that Ngn1 and Neurod1 inhibit Sox2 transcription through a phylogenetically conserved Sox2 enhancer to mediate neurogenesis. We propose that Sox2 confers neural competency by promoting Ngn1 expression, and that negative feedback inhibition of Sox2 by Ngn1 is an essential step in the progression from neural precursor to nascent neuron. C1 [Evsen, Lale; Wu, Doris K.] Natl Inst Deafness & Other Commun Disorders, Rockville, MD 20850 USA. [Sugahara, Satoko; Uchikawa, Masanori; Kondoh, Hisato] Osaka Univ, Grad Sch Frontier Biosci, Suita, Osaka 5650871, Japan. [Evsen, Lale] Univ Maryland, Neurosci & Cognit Sci Program, College Pk, MD 20740 USA. RP Wu, DK (reprint author), NIDCD 5 Res Court,Room 2B34, Rockville, MD 20850 USA. EM wud@nidcd.nih.gov FU Intramural Program of NIDCD; MEXT Japan [22247035]; [23770248] FX This work was supported by the Intramural Program of NIDCD (to D.K.W.), Grants-in-Aid for Scientific Research 23770248 (to M.U.) and MEXT Japan 22247035 (to H.K.). We thank Michael Mulheisen, Nicole Huang, Nathan Hsieh, Eric Yi, and Andrew Yatteau for technical assistance. We thank Dr. Lisa Taneyhill at the University of Maryland at College Park for valuable advice throughout this project, Dr. Jonas Muhr for providing the Sox2 plasmid, Dr. Jean-Marc Matter for the Neurod1 plasmid, and Dr. Marianne Bronner-Fraser for the pCI-IRES-H2B-RFP plasmid. We also thank Drs. Lisa Cunningham, Tom Friedman, Matthew Kelley, James Keller, and Steven Raft for critical reading of this manuscript. NR 47 TC 21 Z9 24 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 27 PY 2013 VL 33 IS 9 BP 3879 EP 3890 DI 10.1523/JNEUROSCI.4030-12.2013 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 098ZO UT WOS:000315588000016 PM 23447599 ER PT J AU Izquierdo, A Darling, C Manos, N Pozos, H Kim, C Ostrander, S Cazares, V Stepp, H Rudebeck, PH AF Izquierdo, Alicia Darling, Chelsi Manos, Nic Pozos, Hilda Kim, Charissa Ostrander, Serena Cazares, Victor Stepp, Haley Rudebeck, Peter H. TI Basolateral Amygdala Lesions Facilitate Reward Choices after Negative Feedback in Rats SO JOURNAL OF NEUROSCIENCE LA English DT Article ID ORBITOFRONTAL CORTEX; PREFRONTAL CORTEX; FRONTAL-CORTEX; REVERSAL; MICE; MONKEYS; DISCRIMINATION; IMPAIRMENTS; STIMULI; MODELS AB The orbitofrontal cortex (OFC) and basolateral amygdala (BLA) constitute part of a neural circuit important for adaptive, goal-directed learning. One task measuring flexibility of response to changes in reward is discrimination reversal learning. Damage to OFC produces well documented impairments on various forms of reversal learning in rodents, monkeys, and humans. Recent reports show that BLA, though highly interconnected with OFC, may be differentially involved in reversal learning. In the present experiment, we compared the effects of bilateral, ibotenic acid lesions of OFC or BLA (or SHAM) on visual discrimination and reversal learning. Specifically, we used pairwise visual discrimination methods, as is commonly administered in non-human primate studies, and analyzed how animals use positive and negative trial-by-trial feedback, domains not previously explored in a rat study. As expected, OFC lesions displayed significantly slower reversal learning than SHAM and BLA rats across sessions. Rats with BLA lesions, conversely, showed facilitated reversal learning relative to SHAM and OFC groups. Furthermore, a trial-by-trial analysis of the errors committed showed the BLA group benefited more from incorrectly performed trials (or negative feedback) on future choices than either SHAM or OFC rats. This provides evidence that BLA and OFC are involved in updating responses to changes in reward contingency and that the roles are distinct. Our results are discussed in relation to a competitive framework model for OFC and BLA in reward processing. C1 [Izquierdo, Alicia; Darling, Chelsi; Manos, Nic; Pozos, Hilda; Kim, Charissa; Ostrander, Serena; Cazares, Victor; Stepp, Haley] Calif State Univ Los Angeles, Dept Psychol, Cognit Neurosci Lab, Los Angeles, CA 90032 USA. [Rudebeck, Peter H.] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. RP Izquierdo, A (reprint author), Calif State Univ Los Angeles, 5151 State Univ Dr, Los Angeles, CA 90032 USA. EM aizquie@calstatela.edu OI Rudebeck, Peter/0000-0002-1411-7555; Kim, Charissa/0000-0003-4899-5898 FU NIH Minority Biomedical Research Support program at California State University, Los Angeles (CSULA); NIMH [SC2MH087974-03] FX This work was supported by the NIH Minority Biomedical Research Support program at California State University, Los Angeles (CSULA). Partial support also came from NIMH (Grant SC2MH087974-03, to A.I.). We thank the CSULA Animal Care staff and the Russo-Neustadt and de Leon labs for technical support. NR 27 TC 20 Z9 20 U1 1 U2 9 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 FEB 27 PY 2013 VL 33 IS 9 BP 4105 EP + DI 10.1523/JNEUROSCI.4942-12.2013 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 098ZO UT WOS:000315588000035 PM 23447618 ER PT J AU Birdsong, WT Arttamangkul, S Clark, MJ Cheng, KJ Rice, KC Traynor, JR Williams, JT AF Birdsong, William T. Arttamangkul, Seksiri Clark, Mary J. Cheng, Kejun Rice, Kenner C. Traynor, John R. Williams, John T. TI Increased Agonist Affinity at the mu-Opioid Receptor Induced by Prolonged Agonist Exposure SO JOURNAL OF NEUROSCIENCE LA English DT Article ID BETA-ADRENERGIC-RECEPTOR; LOCUS-CERULEUS NEURONS; CONFORMATIONAL STATES; BINDING-PROPERTIES; KINETIC EVIDENCE; PERTUSSIS TOXIN; DESENSITIZATION; PROTEIN; MORPHINE; PHOSPHORYLATION AB Prolonged exposure to high-efficacy agonists results in desensitization of the mu-opioid receptor (MOR). Desensitized receptors are thought to be unable to couple to G-proteins, preventing downstream signaling; however, the changes to the receptor itself are not well characterized. In the current study, confocal imaging was used to determine whether desensitizing conditions cause a change in agonist-receptor interactions. Using rapid solution exchange, the binding kinetics of fluorescently labeled opioid agonist, dermorphin Alexa594 (derm A594), to MORs was measured in live cells. The affinity of derm A594 binding increased after prolonged treatment of cells with multiple agonists that are known to cause receptor desensitization. In contrast, binding of a fluorescent antagonist, naltrexamine Alexa594, was unaffected by similar agonist pretreatment. The increased affinity of derm A594 for the receptor was long-lived and partially reversed after a 45 min wash. Treatment of the cells with pertussis toxin did not alter the increase in affinity of the derm A594 for MOR. Likewise, the affinity of derm A594 for MORs expressed in mouse embryonic fibroblasts derived from arrestin 1 and 2 knock-out animals increased after treatment of the cells with the desensitization protocol. Thus, opioid receptors were "imprinted" with a memory of prior agonist exposure that was independent of G-protein activation or arrestin binding that altered subsequent agonist-receptor interactions. The increased affinity suggests that acute desensitization results in a long-lasting but reversible conformational change in the receptor. C1 [Birdsong, William T.; Arttamangkul, Seksiri; Williams, John T.] Oregon Hlth & Sci Univ, Vollum Inst, Portland, OR 97239 USA. [Clark, Mary J.; Traynor, John R.] Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA. [Cheng, Kejun; Rice, Kenner C.] NIDA, Chem Biol Res Branch, Bethesda, MD 20892 USA. [Cheng, Kejun; Rice, Kenner C.] NIAAA, NIH, Bethesda, MD 20892 USA. RP Williams, JT (reprint author), Oregon Hlth & Sci Univ, Vollum Inst, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM williamj@ohsu.edu FU National Institutes of Health [DA08136, MH083754]; Intramural Research Programs of National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism FX This work was supported by National Institutes of Health Grants DA08136 and MH083754 to J.R.T. and M.J.C., and in part by the Intramural Research Programs of National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism. We thank Dr. Shane Hentges for feedback during manuscript preparation, Dr. Erica Levitt for manuscript feedback and GraphPad expertise, and Dr. Dale Fortin for technical assistance. NR 42 TC 14 Z9 14 U1 0 U2 13 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 FEB 27 PY 2013 VL 33 IS 9 BP 4118 EP 4127 DI 10.1523/JNEUROSCI.4187-12.2013 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 098ZO UT WOS:000315588000037 PM 23447620 ER PT J AU Balaban, RS AF Balaban, Robert S. TI Allometry of brain metabolism SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID MITOCHONDRIAL; TISSUE C1 NHLBI, Cardiac Energet Lab, Bethesda, MD 20892 USA. RP Balaban, RS (reprint author), NHLBI, Cardiac Energet Lab, Bethesda, MD 20892 USA. EM balabanr@nhlbi.nih.gov NR 18 TC 4 Z9 4 U1 5 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 FEB 26 PY 2013 VL 110 IS 9 BP 3216 EP 3217 DI 10.1073/pnas.1221313110 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 102JW UT WOS:000315841900010 PM 23407170 ER PT J AU Sivan, G Martin, SE Myers, TG Buehler, E Szymczyk, KH Ormanoglu, P Moss, B AF Sivan, Gilad Martin, Scott E. Myers, Timothy G. Buehler, Eugen Szymczyk, Krysia H. Ormanoglu, Pinar Moss, Bernard TI Human genome-wide RNAi screen reveals a role for nuclear pore proteins in poxvirus morphogenesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE nucleoporin 62; poxvirus replication; poxvirus host interactions; syntaxin 5; vaccinia virus replication ID VACCINIA VIRUS-REPLICATION; BINDING PROTEIN; CELL-MEMBRANE; HOST-CELLS; INFECTION; TRANSPORT; COMPLEX; GENE; INTERMEDIATE; REQUIREMENT AB Poxviruses are considered less dependent on host functions than other DNA viruses because of their cytoplasmic site of replication and large genomes, which encode enzymes for DNA and mRNA synthesis. Nevertheless, RNAi screens with two independent human genome-scale libraries have identified more than 500 candidate genes that significantly inhibited and a similar number that enhanced replication and spread of infectious vaccinia virus.(VACV). Translational, ubiquitin-proteosome, and endoplasmic reticulum-to-Golgi transport functions, known to be important for VACV, were enriched in the siRNA-inhibiting group, and RNA polymerase II and associated functions were enriched in the siRNA-enhancing group. Additional findings, notably the inhibition of VACV spread by siRNAs to several nuclear pore genes, were unanticipated. Knockdown of nucleoporin 62 strongly inhibited viral morphogenesis, with only a modest effect on viral gene expression, recapitulating and providing insight into previous studies with enucleated cells. C1 [Sivan, Gilad; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Martin, Scott E.; Buehler, Eugen; Ormanoglu, Pinar] NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Myers, Timothy G.; Szymczyk, Krysia H.] NIAID, Genom Technol Sect, Res Technol Branch, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM bmoss@niaid.nih.gov OI Buehler, Eugen/0000-0001-7167-676X FU Division of Intramural Research, NIAID, National Institutes of Health FX We thank Elizabeth Fischer [National Institute of Allergy and Infectious Diseases (NIAID) Rocky Mountain Electron Microscopy Laboratory] for providing EM images and Catherine Cotter (MAID Laboratory of Viral Diseases) for assisting with tissue cultures. This research was supported by the Division of Intramural Research, NIAID, National Institutes of Health. NR 43 TC 27 Z9 27 U1 0 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 FEB 26 PY 2013 VL 110 IS 9 BP 3519 EP 3524 DI 10.1073/pnas.1300708110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 102JW UT WOS:000315841900065 PM 23401514 ER PT J AU Daszak, P Zambrana-Torrelio, C Bogich, TL Fernandez, M Epstein, JH Murray, KA Hamilton, H AF Daszak, Peter Zambrana-Torrelio, Carlos Bogich, Tiffany L. Fernandez, Miguel Epstein, Jonathan H. Murray, Kris A. Hamilton, Healy TI Interdisciplinary approaches to understanding disease emergence: The past, present, and future drivers of Nipah virus emergence SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID WEST NILE VIRUS; EMERGING INFECTIOUS-DISEASES; SPECIES DISTRIBUTION MODELS; ECOLOGICAL NICHE MODELS; AVIAN INFLUENZA H5N1; CLIMATE-CHANGE; FLYING-FOXES; UNITED-STATES; VECTOR-BORNE; FRUIT BATS AB Emerging infectious diseases (EIDs) pose a significant threat to human health, economic stability, and biodiversity. Despite this, the mechanisms underlying disease emergence are still not fully understood, and control measures rely heavily on mitigating the impact of EIDs after they have emerged. Here, we highlight the emergence of a zoonotic Henipavirus, Nipah virus, to demonstrate the interdisciplinary and macroecological approaches necessary to understand EID emergence. Previous work suggests that Nipah virus emerged due to the interaction of the wildlife reservoir (Pteropus spp. fruit bats) with intensively Managed livestock. The emergence of this and other henipaviruses involves interactions among a suite of anthropogenic environmental changes, socioeconomic factors, and changes in demography that overlay and interact with the distribution of these pathogens in their wildlife reservoirs. Here, we demonstrate how ecological niche modeling may be used to investigate the potential role of a changing climate on the future risk for Henipavirus emergence. We show that the distribution of Henipavirus reservoirs, and therefore henipaviruses, will likely change under climate change scenarios, a fundamental precondition for disease emergence in humans. We assess the variation among climate models to estimate where Henipavirus host distribution is most likely to expand, contract, or remain stable, presenting new risks for human health. We conclude that there is substantial potential to use this modeling framework to explore the distribution of wildlife hosts under a changing climate. These approaches may directly inform current and future management and surveillance strategies aiming to improve pathogen detection and, ultimately, reduce emergence risk. C1 [Daszak, Peter; Zambrana-Torrelio, Carlos; Bogich, Tiffany L.; Epstein, Jonathan H.; Murray, Kris A.] EcoHlth Alliance, New York, NY 10001 USA. [Bogich, Tiffany L.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Bogich, Tiffany L.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Fernandez, Miguel] Univ Calif, Environm Syst Grad Grp, Merced, CA 95344 USA. [Hamilton, Healy] Marine Conservat Inst, Glen Ellen, CA 95442 USA. RP Daszak, P (reprint author), EcoHlth Alliance, New York, NY 10001 USA. EM daszak@ecohealthalliance.org OI Bogich, Tiffany/0000-0002-8143-5289 FU National Institutes of Health/National Science Foundation "Ecology and Evolution of Infectious Diseases" award from the Fogarty International Center [2R01-TW005869]; National Institute of Allergy and Infectious Diseases [1 R01 AI079231]; National Science Foundation Human and Social Dynamics Agents of Change [BCS 0826779, BCS 0826840]; Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directorate; National Institutes of Health National Institute for Allergy and Infectious Diseases [K08AI067549]; US Department of Homeland Security; US Agency:for International Development [1272] FX This work was supported by a National Institutes of Health/National Science Foundation "Ecology and Evolution of Infectious Diseases" award from the Fogarty International Center (Grant 2R01-TW005869), National Institute of Allergy and Infectious Diseases Grant 1 R01 AI079231, a National Science Foundation Human and Social Dynamics Agents of Change award (BCS 0826779 and BCS 0826840), the Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directorate, the National Institutes of Health National Institute for Allergy and Infectious Diseases (Grant K08AI067549), and the US Department of Homeland Security, as well as by the generous support of the American people through the US Agency:for International Development (Grant 1272) "Emerging Pandemic Threats" (PREDICT). NR 111 TC 24 Z9 24 U1 7 U2 120 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 FEB 26 PY 2013 VL 110 SU 1 BP 3681 EP 3688 DI 10.1073/pnas.1201243109 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 102JY UT WOS:000315842100005 PM 22936052 ER PT J AU Harrington, WE Morrison, R Fried, M Duffy, PE AF Harrington, Whitney E. Morrison, Robert Fried, Michal Duffy, Patrick E. TI Intermittent Preventive Treatment in Pregnant Women Is Associated with Increased Risk of Severe Malaria in Their Offspring SO PLOS ONE LA English DT Article ID PLASMODIUM-FALCIPARUM MALARIA; PLACENTAL MALARIA; FACILITATION; INFECTIONS; RESISTANCE; MORBIDITY; PARASITES; EFFICACY; IMMUNITY; MODEL AB Background: In areas of widespread sulfadoxine-pyrimethamine resistance, intermittent treatment in pregnancy (IPTp) fails to prevent placental malaria (PM) and may exacerbate drug resistant infections. Because PM predicts increased susceptibility to parasitemia during infancy, we hypothesized that IPTp would also increase susceptibility to malaria infection and disease in the offspring. Methods: In a birth cohort from NE Tanzania, we evaluated the association between maternal IPTp use and risk of parasitemia and severe malaria in the offspring. Using Cox Proportional Hazards Models as well as Generalized Estimating Equations, we evaluated the effects of IPTp on the entire cohort and on subgroups stratified by PM status at delivery. Results and Conclusions: Offspring of PM+ women who received IPTp had a dose-dependent decrease in time to first parasitemia (AHR = 2.13, p = 0.04 [95%CI: 1.04, 4.38]). Among all offspring, IPTp was associated with earlier first severe malaria episode (AHR = 2.32, p = 0.02 [95%CI: 1.12, 4.78]) as well as increased overall odds of severe malaria (AOR = 2.31, p = 0.03 [95%CI: 1.09, 4.88]). Cost-benefit analyses of IPTp regimens should consider the long term effects on offspring in addition to pregnancy outcomes. C1 [Harrington, Whitney E.] Univ Washington, Sch Med, Dept Pediat, Seattle Childrens Hosp, Seattle, WA 98195 USA. [Morrison, Robert] Seattle Biomed Res Inst, Seattle, WA 98109 USA. [Fried, Michal; Duffy, Patrick E.] NIAID, NIH, Rockville, MD USA. RP Duffy, PE (reprint author), NIAID, NIH, Rockville, MD USA. EM patrick.duffy@nih.gov FU Bill & Melinda Gates Foundation [29202]; Foundation for the National Institutes of Health through the Grand Challenges in Global Health Initiative [1364]; U.S. National Institutes of Health Fogarty International Center (FIC) [D43 TW005509]; National Institute of Allergy and Infectious Diseases [R01AI52059]; National Heart, Lung, and Blood Institute (NIH Fellowship) [1F30HL096298] FX Funding was provided by the Bill & Melinda Gates Foundation (Grant 29202), the Foundation for the National Institutes of Health through the Grand Challenges in Global Health Initiative (Grant 1364), the U.S. National Institutes of Health Fogarty International Center (FIC) (Grant D43 TW005509), and the National Institute of Allergy and Infectious Diseases (R01AI52059) to PED, and by the National Heart, Lung, and Blood Institute (NIH Fellowship 1F30HL096298) to WEH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The content is solely the responsibility of the authors and does not represent the official views of the funding sources. NR 25 TC 14 Z9 14 U1 0 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 FEB 25 PY 2013 VL 8 IS 2 AR e56183 DI 10.1371/journal.pone.0056183 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 115ZB UT WOS:000316849500008 PM 23451036 ER PT J AU Kumar, NP Sridhar, R Banurekha, VV Nair, D Jawahar, MS Nutman, TB Babu, S AF Kumar, Nathella Pavan Sridhar, Rathinam Banurekha, Vaithilingam V. Nair, Dina Jawahar, Mohideen S. Nutman, Thomas B. Babu, Subash TI Expansion of Pathogen-Specific Mono- and Multifunctional Th1 and Th17 Cells in Multi-Focal Tuberculous Lymphadenitis SO PLOS ONE LA English DT Article ID REGULATORY T-CELLS; ACTIVE PULMONARY TUBERCULOSIS; MYCOBACTERIUM-TUBERCULOSIS; IFN-GAMMA; IMMUNE-RESPONSE; INTERFERON-GAMMA; INFECTION; DISEASE; MICE; EXPRESSION AB Background: Th1 and Th17 responses are known to play an important role in immunity to pulmonary tuberculosis (PTB), although little is known about their role in extrapulmonary forms of tuberculosis (TB). Methods: To identify the role of Th1, Th17, and Th22 cells in multi-focal TB lymphadenitis (TBL), we examined mycobacteria-specific immune responses in the whole blood of individuals with PTB (n = 20) and compared them with those with TBL (n = 25). Results: Elevated frequencies of CD4(+) T cells expressing IFN- gamma, TNF-alpha, and IL-2 were present in individuals with TBL compared with those with PTB at baseline and in response to ESAT-6 and CFP-10. Similarly, increased frequencies of CD4(+) T cells expressing IL-17A, IL-17F, and IFN-gamma were also present in individuals with TBL at baseline and following ESAT-6 and CFP-10 stimulation although no significant difference in frequency of Th22 cells was observed. Finally, frequencies of Th1 (but not Th17) cells exhibited a significantly negative correlation with natural regulatory T cell frequencies at baseline. Conclusions: Multi-focal TB lymphadenitis is therefore characterized by elevated frequencies of Th1 and Th17 cells, indicating that Th1 and Th17 responses in TB disease are probably correlates of disease severity rather than of protective immunity. C1 [Kumar, Nathella Pavan; Babu, Subash] Int Ctr Excellence Res, Natl Inst Hlth, Chennai, Tamil Nadu, India. [Sridhar, Rathinam] Govt Stanley Med Hosp, Chennai, Tamil Nadu, India. [Banurekha, Vaithilingam V.; Nair, Dina; Jawahar, Mohideen S.] Natl Inst Res TB, Chennai, Tamil Nadu, India. [Nutman, Thomas B.; Babu, Subash] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Babu, S (reprint author), Int Ctr Excellence Res, Natl Inst Hlth, Chennai, Tamil Nadu, India. EM sbabu@mail.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) FX This work was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 2 Z9 2 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 25 PY 2013 VL 8 IS 2 AR e57123 DI 10.1371/journal.pone.0057123 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 115ZB UT WOS:000316849500066 PM 23451159 ER PT J AU Lin, FR Yaffe, K Xia, J Xue, QL Harris, TB Purchase-Helzner, E Satterfield, S Ayonayon, HN Ferrucci, L Simonsick, EM AF Lin, Frank R. Yaffe, Kristine Xia, Jin Xue, Qian-Li Harris, Tamara B. Purchase-Helzner, Elizabeth Satterfield, Suzanne Ayonayon, Hilsa N. Ferrucci, Luigi Simonsick, Eleanor M. CA Hlth ABC Study Grp TI Hearing Loss and Cognitive Decline in Older Adults SO JAMA INTERNAL MEDICINE LA English DT Article ID OF-THE-SCIENCE; ALZHEIMERS-DISEASE; BODY-COMPOSITION; UNITED-STATES; RISK-FACTORS; HEALTH ABC; IMPAIRMENT; DEMENTIA; POPULATION; AGE AB Background: Whether hearing loss is independently associated with accelerated cognitive decline in older adults is unknown. Methods: We studied 1984 older adults (mean age, 77.4 years) enrolled in the Health ABC Study, a prospective observational study begun in 1997-1998. Our baseline cohort consisted of participants without prevalent cognitive impairment (Modified Mini-Mental State Examination [3MS] score, >= 80) who underwent audiometric testing in year 5. Participants were followed up for 6 years. Hearing was defined at baseline using a pure-tone average of thresholds at 0.5 to 4 kHz in the better-hearing ear. Cognitive testing was performed in years 5, 8, 10, and 11 and consisted of the 3MS (measuring global function) and the Digit Symbol Substitution test (measuring executive function). Incident cognitive impairment was defined as a 3MS score of less than 80 or a decline in 3MS score of more than 5 points from baseline. Mixed-effects regression and Cox proportional hazards regression models were adjusted for demographic and cardiovascular risk factors. Results: In total, 1162 individuals with baseline hearing loss (pure-tone average >25 dB) had annual rates of decline in 3MS and Digit Symbol Substitution test scores that were 41% and 32% greater, respectively, than those among individuals with normal hearing. On the 3MS, the annual score changes were -0.65 (95% CI, -0.73 to -0.56) vs -0.46 (95% CI, -0.55 to -0.36) points per year (P=.004). On the Digit Symbol Substitution test, the annual score changes were -0.83 (95% CI, -0.94 to -0.73) vs -0.63 (95% CI, -0.75 to -0.51) points per year (P=.02). Compared to those with normal hearing, individuals with hearing loss at baseline had a 24% (hazard ratio, 1.24; 95% CI, 1.05-1.48) increased risk for incident cognitive impairment. Rates of cognitive decline and the risk for incident cognitive impairment were linearly associated with the severity of an individual's baseline hearing loss. Conclusions: Hearing loss is independently associated with accelerated cognitive decline and incident cognitive impairment in community-dwelling older adults. Further studies are needed to investigate what the mechanistic basis of this association is and whether hearing rehabilitative interventions could affect cognitive decline. C1 [Lin, Frank R.] Johns Hopkins Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD USA. [Lin, Frank R.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Lin, Frank R.; Xia, Jin; Xue, Qian-Li] Johns Hopkins Ctr Aging & Hlth, Baltimore, MD USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Ferrucci, Luigi; Simonsick, Eleanor M.] NIA, Intramural Res Program, Bethesda, MD 20892 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat & Neurol, San Francisco, CA 94143 USA. [Yaffe, Kristine; Ayonayon, Hilsa N.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Purchase-Helzner, Elizabeth] Suny Downstate Med Ctr, Dept Epidemiol & Biostat, Brooklyn, NY 11203 USA. [Satterfield, Suzanne] Univ Tennessee, Dept Prevent Med, Memphis, TN USA. RP Lin, FR (reprint author), Johns Hopkins Ctr Aging & Hlth, 2024 E Monument St,Ste 2-700, Baltimore, MD 21205 USA. EM flin1@jhmi.edu RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU National Institute on Aging [R01-AG028050]; Johns Hopkins Older Americans Independence Center from the National Institute on Aging [P30-AG02133]; National Institute of Nursing Research [R01-NR012459]; National Institute on Deafness and Other Communication Disorders [K23DC011279]; Triological Society/American College of Surgeons Clinician Scientist Award; [N01-AG62101]; [N01-AG62103]; [N01-AG62106] FX This study was funded by contracts N01-AG62101, N01-AG62103, and N01-AG62106 and grant R01-AG028050 from the National Institute on Aging and The Johns Hopkins Older Americans Independence Center under contract P30-AG02133 from the National Institute on Aging (Dr Xue) and by grants R01-NR012459 from the National Institute of Nursing Research and K23DC011279 from the National Institute on Deafness and Other Communication Disorders and by a Triological Society/American College of Surgeons Clinician Scientist Award (Dr Lin). NR 50 TC 184 Z9 196 U1 7 U2 63 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6106 J9 JAMA INTERN MED JI JAMA Intern. Med. PD FEB 25 PY 2013 VL 173 IS 4 BP 293 EP 299 DI 10.1001/jamainternmed.2013.1868 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 153NZ UT WOS:000319610400009 PM 23337978 ER PT J AU Selvaraj, S Prasad, V AF Selvaraj, Senthil Prasad, Vinay TI Characteristics of Cluster Randomized Trials: Are They Living Up to the Randomized Trial? SO JAMA INTERNAL MEDICINE LA English DT Letter C1 [Selvaraj, Senthil] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Prasad, Vinay] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Prasad, V (reprint author), NCI, Med Oncol Branch, NIH, 10 Ctr Dr,Bldg 10,Room 12N226, Bethesda, MD 20892 USA. EM vinayak.prasad@nih.gov NR 5 TC 1 Z9 1 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6106 J9 JAMA INTERN MED JI JAMA Intern. Med. PD FEB 25 PY 2013 VL 173 IS 4 BP 313 EP 315 DI 10.1001/jamainternmed.2013.1638 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 153NZ UT WOS:000319610400015 PM 23337957 ER PT J AU Hakkinen, PJ AF Hakkinen, Pertti J. TI New Studies About Everyday Types of Chemical Exposures: What Readers Should Consider SO JAMA INTERNAL MEDICINE LA English DT Editorial Material ID MELAMINE; FORMALDEHYDE; MIGRATION C1 NIH, Off Clin Toxicol, Specialized Informat Serv, Natl Lib Med, Bethesda, MD 20892 USA. RP Hakkinen, PJ (reprint author), NIH, Off Clin Toxicol, Specialized Informat Serv, Natl Lib Med, 6707 Democracy Blvd,Ste 510, Bethesda, MD 20892 USA. EM pertti.hakkinen@nih.gov RI Hakkinen, Pertti/G-4803-2016 OI Hakkinen, Pertti/0000-0002-8295-9738 NR 9 TC 1 Z9 1 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6106 J9 JAMA INTERN MED JI JAMA Intern. Med. PD FEB 25 PY 2013 VL 173 IS 4 BP 319 EP 320 DI 10.1001/jamainternmed.2013.2133 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 153NZ UT WOS:000319610400019 PM 23338122 ER PT J AU Vinuelas, J Kaneko, G Coulon, A Vallin, E Morin, V Mejia-Pous, C Kupiec, JJ Beslon, G Gandrillon, O AF Vinuelas, Jose Kaneko, Gael Coulon, Antoine Vallin, Elodie Morin, Valerie Mejia-Pous, Camila Kupiec, Jean-Jacques Beslon, Guillaume Gandrillon, Olivier TI Quantifying the contribution of chromatin dynamics to stochastic gene expression reveals long, locus-dependent periods between transcriptional bursts SO BMC BIOLOGY LA English DT Article DE Chromatin dynamics; expression noise; gene regulation; stochastic model ID SINGLE-CELL; HISTONE DEACETYLATION; ESCHERICHIA-COLI; DNA METHYLATION; TRICHOSTATIN-A; HUMAN GENOME; NOISE; PROMOTER; DIFFERENTIATION; FLUCTUATIONS AB Background: A number of studies have established that stochasticity in gene expression may play an important role in many biological phenomena. This therefore calls for further investigations to identify the molecular mechanisms at stake, in order to understand and manipulate cell-to-cell variability. In this work, we explored the role played by chromatin dynamics in the regulation of stochastic gene expression in higher eukaryotic cells. Results: For this purpose, we generated isogenic chicken-cell populations expressing a fluorescent reporter integrated in one copy per clone. Although the clones differed only in the genetic locus at which the reporter was inserted, they showed markedly different fluorescence distributions, revealing different levels of stochastic gene expression. Use of chromatin-modifying agents showed that direct manipulation of chromatin dynamics had a marked effect on the extent of stochastic gene expression. To better understand the molecular mechanism involved in these phenomena, we fitted these data to a two-state model describing the opening/closing process of the chromatin. We found that the differences between clones seemed to be due mainly to the duration of the closed state, and that the agents we used mainly seem to act on the opening probability. Conclusions: In this study, we report biological experiments combined with computational modeling, highlighting the importance of chromatin dynamics in stochastic gene expression. This work sheds a new light on the mechanisms of gene expression in higher eukaryotic cells, and argues in favor of relatively slow dynamics with long (hours to days) periods of quiet state. C1 [Vinuelas, Jose; Kaneko, Gael; Vallin, Elodie; Morin, Valerie; Mejia-Pous, Camila; Gandrillon, Olivier] Univ Lyon 1, Univ Lyon, Ctr Genet & Physiol Mol & Cellulaire CGPhiMC, CNRS UMR5534, F-69622 Lyon, France. [Kaneko, Gael; Beslon, Guillaume] Univ Lyon, Lab InfoRmat Image & Systemes Informat LIRIS, INSA Lyon, INRIA,CNRS UMR5205, F-69621 Lyon, France. [Coulon, Antoine] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. [Kupiec, Jean-Jacques] Ecole Normale Super, Ctr Cavailles, INSERM, F-75005 Paris, France. RP Gandrillon, O (reprint author), Univ Lyon 1, Univ Lyon, Ctr Genet & Physiol Mol & Cellulaire CGPhiMC, CNRS UMR5534, F-69622 Lyon, France. EM olivier.gandrillon@univ-lyon1.fr RI Beslon, Guillaume/D-7369-2014; Coulon, Antoine/A-9006-2012 FU Institut Rhonalpin des Systemes Complexes (IXXI); Reseau National des Systemes Complexes (RNSC); ANR grant [ANR 2011 BSV6 014 01]; CNRS post-doctoral grant FX We thank Francois Chatelain, Alexandra Fuchs, and Manuel Thery for helpful discussions and support during the early stages of the project. We are grateful to Denis Ressnikoff of the platform Centre Commun de Quantimetrie de Lyon (CCQ) for flow-cytometry cell-sorting assistance. We thank the Centre de Calcul de l'Institut National de Physique Nucleaire et de Physique des Particules de Lyon (CC-IN2P3), and especially Pascal Calvat, for their computing resources. We also thank the interns who worked on this project: Mathieu Gineste, Yoann Meniere, Charles Rocabert. and Balthazar Rouberol. We thank the Andras Paldi group from the Genethon for the constructive and useful discussions on chromatin and stochasticity of gene expression. This work was supported by funding from the Institut Rhonalpin des Systemes Complexes (IXXI) and from the Reseau National des Systemes Complexes (RNSC). Part of the project was supported by an ANR grant (ANR 2011 BSV6 014 01). JV is supported by a CNRS post-doctoral grant and GK is a PhD Fellow from the Region Rhone Alpes and INRIA. NR 86 TC 22 Z9 22 U1 0 U2 19 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7007 J9 BMC BIOL JI BMC Biol. PD FEB 25 PY 2013 VL 11 AR 15 DI 10.1186/1741-7007-11-15 PG 19 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 138EE UT WOS:000318490700001 PM 23442824 ER PT J AU Vivar, C van Praag, H AF Vivar, Carmen van Praag, Henriette TI Functional circuits of new neurons in the dentate gyrus SO FRONTIERS IN NEURAL CIRCUITS LA English DT Review DE dentate gyrus; adult neurogenesis; rabies virus; retrograde trans-neuronal tracing; learning and memory; area CA3; lateral entorhinal cortex; pattern separation ID ADULT HIPPOCAMPAL NEUROGENESIS; GENERATED GRANULE CELLS; NEURAL STEM-CELLS; ENHANCED SYNAPTIC PLASTICITY; SPATIAL-PATTERN SEPARATION; SOURCE DENSITY ANALYSIS; CENTRAL-NERVOUS-SYSTEM; MEDIAL TEMPORAL-LOBE; RABIES VIRUS; IN-VIVO AB The hippocampus is crucial for memory formation. New neurons are added throughout life to the hippocampal dentate gyrus (DG), a brain area considered important for differential storage of similar experiences and contexts. To better understand the functional contribution of adult neurogenesis to pattern separation processes, we recently used a novel synapse specific trans-neuronal tracing approach to identify the (sub) cortical inputs to new dentate granule cells (GCs). It was observed that newly born neurons receive sequential innervation from structures important for memory function. Initially, septal-hippocampal cells provide input to new neurons, including transient innervation from mature GCs as well as direct feedback from area CA3 pyramidal neurons. After about 1 month perirhinal (PRH) and lateral entorhinal cortex (LEC), brain areas deemed relevant to integration of novel sensory and environmental information, become substantial input to new GCs. Here, we review the developmental time-course and proposed functional relevance of new neurons, within the context of their unique neural circuitry. C1 [Vivar, Carmen; van Praag, Henriette] NIA, Neuroplast & Behav Unit, Neurosci Lab, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP van Praag, H (reprint author), NIA, Neuroplast & Behav Unit, Neurosci Lab, Biomed Res Ctr,NIH, Suite 100,251 Bayview Blvd, Baltimore, MD 21224 USA. EM vanpraagh@mail.nih.gov RI van Praag, Henriette/F-3939-2015 OI van Praag, Henriette/0000-0002-5727-434X FU National Institute on Aging, Intramural Research Program FX This work was supported by the National Institute on Aging, Intramural Research Program. We thank Linda R. Kitabayashi for help with preparation of the photomicrographs. NR 193 TC 45 Z9 47 U1 1 U2 38 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5110 J9 FRONT NEURAL CIRCUIT JI Front. Neural Circuits PD FEB 25 PY 2013 VL 7 AR 15 DI 10.3389/fncir.2013.00015 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 125SC UT WOS:000317560600001 PM 23443839 ER PT J AU Yaniv, Y Spurgeon, HA Ziman, BD Lakatta, EG AF Yaniv, Yael Spurgeon, Harold A. Ziman, Bruce D. Lakatta, Edward G. TI Ca2+/Calmodulin-Dependent Protein Kinase II (CaMKII) Activity and Sinoatrial Nodal Pacemaker Cell Energetics SO PLOS ONE LA English DT Article ID CA2+ RELEASES; K+ CHANNELS; CALMODULIN; HEART; CALCIUM; CONTRACTION; MYOCYTES; PHOSPHORYLATION; AUTOMATICITY; ACTIVATION AB Ca2+-activated basal adenylate cyclase (AC) in rabbit sinoatrial node cells (SANC) guarantees, via basal cAMP/PKA-calmodulin/CaMKII-dependent protein phosphorylation, the occurrence of rhythmic, sarcoplasmic-reticulum generated, sub-membrane Ca2+ releases that prompt rhythmic, spontaneous action potentials (APs). This high-throughput signaling consumes ATP. Aims: We have previously demonstrated that basal AC-cAMP/PKA signaling directly, and Ca2+ indirectly, regulate mitochondrial ATP production. While, clearly, Ca2+-calmodulin-CaMKII activity regulates ATP consumption, whether it has a role in the control of ATP production is unknown. Methods and Results: We superfused single, isolated rabbit SANC at 37 degrees C with physiological saline containing CaMKII inhibitors, (KN-93 or autocamtide-2 Related Inhibitory Peptide (AIP)), or a calmodulin inhibitor (W-7) and measured cytosolic Ca2+, flavoprotein fluorescence and spontaneous AP firing rate. We measured cAMP, ATP and O-2 consumption in cell suspensions. Graded reductions in basal CaMKII activity by KN-93 (0.5-3 mu mol/L) or AIP (2-10 mu mol/L) markedly slow the kinetics of intracellular Ca2+ cycling, decrease the spontaneous AP firing rate, decrease cAMP, and reduce O-2 consumption and flavoprotein fluorescence. In this context of graded reductions in ATP demand, however, ATP also becomes depleted, indicating reduced ATP production. Conclusions: CaMKII signaling, a crucial element of normal automaticity in rabbit SANC, is also involved in SANC bioenergetics. C1 [Yaniv, Yael; Spurgeon, Harold A.; Ziman, Bruce D.; Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Lakatta, EG (reprint author), NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, Intramural Res Program,NIH, Baltimore, MD 21224 USA. EM LakattaE@mail.nih.gov RI Yaniv, Yael/B-3311-2015 OI Yaniv, Yael/0000-0002-5183-6284 FU Intramural Research Program of the National Institute on Aging, National Institutes of Health FX The work was supported entirely by the Intramural Research Program of the National Institute on Aging, 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 32 TC 14 Z9 14 U1 0 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 FEB 25 PY 2013 VL 8 IS 2 AR e57079 DI 10.1371/journal.pone.0057079 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 115ZB UT WOS:000316849500062 PM 23459256 ER PT J AU Li, Y Lee, C Lam, KH Shung, KK AF Li, Ying Lee, Changyang Lam, Kwok Ho Shung, K. Kirk TI A simple method for evaluating the trapping performance of acoustic tweezers SO APPLIED PHYSICS LETTERS LA English DT Article ID ULTRASONIC TRANSDUCERS; RADIATION PRESSURE; DIELECTRIC SPHERE; FORCES; FEASIBILITY; CALIBRATION; REGIME; TRAPS AB The purpose of this paper is to present a rapid and simple method to evaluate the trapping performance of high frequency focused ultrasonic transducers for acoustic tweezer applications. The method takes into consideration the friction between the particle to be trapped and the surface that it resides on. As a result it should be more reliable and accurate than the methods proposed previously. The trapping force produced by a 70-MHz press-focused transducer was measured to evaluate the performance of this approach. This method demonstrates its potential in optimizing the excitation conditions for acoustic tweezer applications and the design of acoustic tweezers. (C) 2013 American Institute of Physics. [http://dx.doi.org/10.1063/1.4793654] C1 [Li, Ying] Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. RP Li, Y (reprint author), Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. EM yli582@usc.edu RI Lam, K.H./B-7765-2014; OI Lam, K.H./0000-0003-1456-9049; Lee, Changyang/0000-0002-3746-7304 FU NIH [R01-EB12058, P41-EB02182] FX The authors would like to thank Dr. Qifa Zhou, Dr. Hyung Ham Kim and Dr. Jae Youn Hwang for their help in this work. This work has been supported by NIH Grant Nos. R01-EB12058 and P41-EB02182. NR 17 TC 6 Z9 6 U1 0 U2 27 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0003-6951 J9 APPL PHYS LETT JI Appl. Phys. Lett. PD FEB 25 PY 2013 VL 102 IS 8 AR 084102 DI 10.1063/1.4793654 PG 4 WC Physics, Applied SC Physics GA 099CN UT WOS:000315597000089 PM 23526834 ER PT J AU Prinz, WA AF Prinz, William A. TI A Bridge to Understanding Lipid Droplet Growth SO DEVELOPMENTAL CELL LA English DT Editorial Material AB Lipid droplets, storage sites of fatty acids and sterols, expand when excess lipids are converted to triacylglycerols. In this issue of Developmental Cell, Wilfling et al. (2013) show that this expansion relies on relocalization, via membrane bridges, of triacylglycerol-synthesizing enzymes from the ER to a subset of lipid droplets'. C1 NIDDKD, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Prinz, WA (reprint author), NIDDKD, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. EM prinzw@helix.nih.gov FU Intramural NIH HHS [ZIA DK060004-11] NR 4 TC 4 Z9 4 U1 0 U2 21 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD FEB 25 PY 2013 VL 24 IS 4 BP 335 EP 336 DI 10.1016/j.devcel.2013.02.004 PG 2 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 097KK UT WOS:000315472800001 PM 23449466 ER PT J AU Li, WL Kohara, H Uchida, Y James, JM Soneji, K Cronshaw, DG Zou, YR Nagasawa, T Mukouyama, YS AF Li, Wenling Kohara, Hiroshi Uchida, Yutaka James, Jennifer M. Soneji, Kosha Cronshaw, Darran G. Zou, Yong-Rui Nagasawa, Takashi Mukouyama, Yoh-suke TI Peripheral Nerve-Derived CXCL12 and VEGF-A Regulate the Patterning of Arterial Vessel Branching in Developing Limb Skin SO DEVELOPMENTAL CELL LA English DT Article ID ENDOTHELIAL-GROWTH-FACTOR; BONE-MARROW; IN-VIVO; RECEPTOR; MICE; DIFFERENTIATION; ANGIOGENESIS; DEFECTS; VASCULATURE; MECHANISMS AB In developing limb skin, peripheral nerves provide a spatial template that controls the branching pattern and differentiation of arteries. Our previous studies indicate that nerve-derived VEGF-A is required for arterial differentiation but not for nerve-vessel alignment. In this study, we demonstrate that nerve-vessel alignment depends on the activity of Cxcl12-Cxcr4 chemokine signaling. Genetic inactivation of Cxcl12-Cxcr4 signaling perturbs nerve-vessel alignment and abolishes arteriogenesis. Further in vitro assays allow us to uncouple nerve-vessel alignment and arteriogenesis, revealing that nerve-derived Cxcl12 stimulates endothelial cell migration, whereas nerve-derived VEGF-A is responsible for arterial differentiation. These findings suggest a coordinated sequential action in which nerve Cxcl12 functions over a distance to recruit vessels to align with nerves, and subsequent arterial differentiation presumably requires a local action of nerve VEGF-A in the nerve-associated vessels. C1 [Li, Wenling; Uchida, Yutaka; James, Jennifer M.; Soneji, Kosha; Mukouyama, Yoh-suke] NHLBI, Lab Stem Cell & Neurovasc Biol, Genet & Dev Biol Ctr, NIH, Bethesda, MD 20892 USA. [Kohara, Hiroshi; Nagasawa, Takashi] Kyoto Univ, Inst Frontier Med Sci, Dept Immunobiol & Hematol, Sakyo Ku, Shogoin, Kyoto 6068507, Japan. [Cronshaw, Darran G.; Zou, Yong-Rui] Feinstein Inst Med Res, Ctr Autoimmune & Musculoskeletal Dis, Manhasset, NY 11030 USA. RP Mukouyama, YS (reprint author), NHLBI, Lab Stem Cell & Neurovasc Biol, Genet & Dev Biol Ctr, NIH, Bldg 10-6C103,10 Ctr Dr, Bethesda, MD 20892 USA. EM mukoyamay@mail.nih.gov FU National Heart, Lung, and Blood Institute, National Institutes of Health FX We thank X. Chi and F. Costantini for breeding Cxcr7 mutants, A.L. Kolodkin for providing anti-Nrp1 antibody, T. Muller for providing anti-BFABP antibody, M. Taniguchi for providing Sema3A mutants, and N. Takakura for providing anti-ephrinB2 antibody. Thanks to L Samsel, P. Dagur, H. Sardon, and J.P. McCoy for FACS assistance, J. Hawkins and the staff of the National Institutes of Health Building 50 animal facility for assistance with mouse breeding and care, K. Gill for laboratory management and technical support, and Y. Carter and L. Oundo for administrative assistance. Thanks also to A.M. Michelson, R.S. Balaban, R.S. Adelstein, J.S. Gutkind, and H. Yagi for invaluable help and discussion, H. Zang and M.A. Conti for editorial advice on the manuscript, and other members of the Laboratory of Stem Cell and Neuro-Vascular Biology for technical help and thoughtful discussion. This work was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 32 TC 41 Z9 41 U1 0 U2 11 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 FEB 25 PY 2013 VL 24 IS 4 BP 359 EP 371 DI 10.1016/j.devcel.2013.01.009 PG 13 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 097KK UT WOS:000315472800007 PM 23395391 ER PT J AU Hasenour, CM Berglund, ED Wasserman, DH AF Hasenour, Clinton M. Berglund, Eric D. Wasserman, David H. TI Emerging role of AMP-activated protein kinase in endocrine control of metabolism in the liver SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Review DE AMPK; Endocrine; Glucagon; Adiponectin; Energy charge; Metabolism ID ACETYL-COA CARBOXYLASE; PERFUSED-RAT-LIVER; FATTY-ACID OXIDATION; INHIBITS HEPATIC GLUCONEOGENESIS; CREB COACTIVATOR TORC2; GLUCOSE-PRODUCTION; SKELETAL-MUSCLE; LIPID-METABOLISM; GENE-EXPRESSION; ENERGY-STATE AB This review summarizes the emerging role of AMP-activated protein kinase (AMPK) in mediating endocrine regulation of metabolic fluxes in the liver. There are a number of hormones which, when acting on the liver, alter AMPK activation. Here we describe those hormones associated with activation and de-activation of AMPK and the potential mechanisms for changes in AMPK activation state. The actions of these hormones, in many cases, are consistent with downstream effects of AMPK signaling thus strengthening the circumstantial case for AMPK-mediated hormone action. In recent years, genetic mouse models have also been used in an attempt to establish the role of AMPK in hormone-stimulated metabolism in the liver. Few experiments have, however, firmly established a causal relationship between hormone action at the liver and AMPK signaling. (C) 2012 Elsevier Ireland Ltd. All rights reserved. C1 Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. Vanderbilt Univ, Sch Med, Mouse Metab Phenotyping Ctr, Nashville, TN 37232 USA. RP Hasenour, CM (reprint author), Vanderbilt Univ, Sch Med, Light Hall,Room 702, Nashville, TN 37232 USA. EM clinton.m.hasenour@vanderbilt.edu FU NIH [R37 DK050277, U24 DK059637] FX This work was supported by Grants, NIH R37 DK050277 and U24 DK059637. NR 129 TC 28 Z9 29 U1 1 U2 22 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD FEB 25 PY 2013 VL 366 IS 2 SI SI BP 152 EP 162 DI 10.1016/j.mce.2012.06.018 PG 11 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 095AD UT WOS:000315306000004 PM 22796337 ER PT J AU Caughlin, TT Ruktanonchai, N Acevedo, MA Lopiano, KK Prosper, O Eagle, N Tatem, AJ AF Caughlin, T. Trevor Ruktanonchai, Nick Acevedo, Miguel A. Lopiano, Kenneth K. Prosper, Olivia Eagle, Nathan Tatem, Andrew J. TI Place-Based Attributes Predict Community Membership in a Mobile Phone Communication Network SO PLOS ONE LA English DT Article ID SOCIAL NETWORK; MODULARITY; SPREAD AB Social networks can be organized into communities of closely connected nodes, a property known as modularity. Because diseases, information, and behaviors spread faster within communities than between communities, understanding modularity has broad implications for public policy, epidemiology and the social sciences. Explanations for community formation in social networks often incorporate the attributes of individual people, such as gender, ethnicity or shared activities. High modularity is also a property of large-scale social networks, where each node represents a population of individuals at a location, such as call flow between mobile phone towers. However, whether or not place-based attributes, including land cover and economic activity, can predict community membership for network nodes in large-scale networks remains unknown. We describe the pattern of modularity in a mobile phone communication network in the Dominican Republic, and use a linear discriminant analysis (LDA) to determine whether geographic context can explain community membership. Our results demonstrate that place-based attributes, including sugar cane production, urbanization, distance to the nearest airport, and wealth, correctly predicted community membership for over 70% of mobile phone towers. We observed a strongly positive correlation (r = 0.97) between the modularity score and the predictive ability of the LDA, suggesting that place-based attributes can accurately represent the processes driving modularity. In the absence of social network data, the methods we present can be used to predict community membership over large scales using solely place-based attributes. C1 [Caughlin, T. Trevor; Ruktanonchai, Nick] Univ Florida, Dept Biol, Gainesville, FL 32611 USA. [Acevedo, Miguel A.] Univ Florida, Sch Nat Resources & Conservat, Dept Wildlife Ecol & Conservat, Gainesville, FL USA. [Lopiano, Kenneth K.] Univ Florida, Dept Stat, Gainesville, FL 32611 USA. [Prosper, Olivia] Univ Florida, Dept Math, Gainesville, FL 32611 USA. [Eagle, Nathan] MIT, Media Lab, Cambridge, MA 02139 USA. [Eagle, Nathan] Santa Fe Inst, Santa Fe, NM 87501 USA. [Tatem, Andrew J.] Univ Florida, Dept Geog, Gainesville, FL 32611 USA. [Tatem, Andrew J.] Univ Florida, Emerging Pathogens Inst, Gainesville, FL USA. [Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Caughlin, TT (reprint author), Univ Florida, Dept Biol, Gainesville, FL 32611 USA. EM trevor.caughlin@gmail.com FU National Science Foundation at the University of Florida [0801544]; Bill and Melinda Gates Foundation [49446, OPP1032350]; RAPIDD program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX TTC, NR, MAA, KL, and OP were supported by the National Science Foundation (http://www.nsf.gov/) under grant 0801544 at the University of Florida. AJT is supported by grants from the Bill and Melinda Gates Foundation (www.gatesfoundation.org/) under grants 49446 and OPP1032350). AJT also acknowledges funding support from the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security (www.dhs.gov), and the Fogarty International Center, National Institutes of Health (http://www.fic.nih.gov). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 3 Z9 3 U1 1 U2 10 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 FEB 22 PY 2013 VL 8 IS 2 AR e56057 DI 10.1371/journal.pone.0056057 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 113IC UT WOS:000316658800006 PM 23451034 ER PT J AU Meyer, J Gorbach, AM Liu, WM Medic, N Young, M Nelson, C Arceo, S Desai, A Metcalfe, DD Komarow, HD AF Meyer, Joseph Gorbach, Alexander M. Liu, Wei-Min Medic, Nevenka Young, Michael Nelson, Celeste Arceo, Sarah Desai, Avanti Metcalfe, Dean D. Komarow, Hirsh D. TI Mast Cell Dependent Vascular Changes Associated with an Acute Response to Cold Immersion in Primary Contact Urticaria SO PLOS ONE LA English DT Article ID ALLERGIC INFLAMMATION; CHOLINERGIC URTICARIA; HISTAMINE; ANAPHYLAXIS; BASOPHILS; TRYPTASE; RELEASE; MICROCIRCULATION; PATHOPHYSIOLOGY; DEGRANULATION AB Background: While a number of the consequences of mast cell degranulation within tissues have been documented including tissue-specific changes such as bronchospasm and the subsequent cellular infiltrate, there is little known about the immediate effects of mast cell degranulation on the associated vasculature, critical to understanding the evolution of mast cell dependent inflammation. Objective: To characterize the microcirculatory events that follow mast cell degranulation. Methodology/Principal Findings: Perturbations in dermal blood flow, temperature and skin color were analyzed using laser-speckle contrast imaging, infrared and polarized-light colorimetry following cold-hand immersion (CHI) challenge in patients with cold-induced urticaria compared to the response in healthy controls. Evidence for mast cell degranulation was established by documentation of serum histamine levels and the localized release of tryptase in post-challenge urticarial biopsies. Laser-speckle contrast imaging quantified the attenuated response to cold challenge in patients on cetirizine. We found that the histamine-associated vascular response accompanying mast cell degranulation is rapid and extensive. At the tissue level, it is characterized by a uniform pattern of increased blood flow, thermal warming, vasodilation, and recruitment of collateral circulation. These vascular responses are modified by the administration of an antihistamine. Conclusions/Significance: Monitoring the hemodynamic responses within tissues that are associated with mast cell degranulation provides additional insight into the evolution of the acute inflammatory response and offers a unique approach to assess the effectiveness of treatment intervention. C1 [Meyer, Joseph; Gorbach, Alexander M.; Liu, Wei-Min] Natl Inst Biomed Imaging & Bioengn, Infrared Imaging & Thermometry Unit, NIH, Bethesda, MD USA. [Medic, Nevenka; Nelson, Celeste; Arceo, Sarah; Desai, Avanti; Metcalfe, Dean D.; Komarow, Hirsh D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Young, Michael] NCI, Clin Res Directorate, CMRP, SAIC Frederick, Frederick, MD 21701 USA. RP Komarow, HD (reprint author), NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM komarowh@niaid.nih.gov FU Division of Intramural Research, NIAID, NIH; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported by the Division of Intramural Research, NIAID, NIH. Support by M.Y. for this project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 4 Z9 5 U1 0 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 FEB 22 PY 2013 VL 8 IS 2 AR e56773 DI 10.1371/journal.pone.0056773 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 113IC UT WOS:000316658800036 PM 23451084 ER PT J AU Sood, R Carrington, B Bishop, K Jones, M Rissone, A Candotti, F Chandrasekharappa, SC Liu, P AF Sood, Raman Carrington, Blake Bishop, Kevin Jones, MaryPat Rissone, Alberto Candotti, Fabio Chandrasekharappa, Settara C. Liu, Paul TI Efficient Methods for Targeted Mutagenesis in Zebrafish Using Zinc-Finger Nucleases: Data from Targeting of Nine Genes Using CompoZr or CoDA ZFNs SO PLOS ONE LA English DT Article ID POOL ENGINEERING OPEN; TAL EFFECTORS; GENOME; DNA; TRANSCRIPTION; INACTIVATION; SELECTION; PROTEINS; MUTATION; PROJECT AB Recently, it has been shown that targeted mutagenesis using zinc-finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) can be used to generate knockout zebrafish lines for analysis of their function and/or developing disease models. A number of different methods have been developed for the design and assembly of gene-specific ZFNs and TALENs, making them easily available to most zebrafish researchers. Regardless of the choice of targeting nuclease, the process of generating mutant fish is similar. It is a time-consuming and multi-step process that can benefit significantly from development of efficient high throughput methods. In this study, we used ZFNs assembled through either the CompoZr (Sigma-Aldrich) or the CoDA (context-dependent assembly) platforms to generate mutant zebrafish for nine genes. We report our improved high throughput methods for 1) evaluation of ZFNs activity by somatic lesion analysis using colony PCR, eliminating the need for plasmid DNA extractions from a large number of clones, and 2) a sensitive founder screening strategy using fluorescent PCR with PIG-tailed primers that eliminates the stutter bands and accurately identifies even single nucleotide insertions and deletions. Using these protocols, we have generated multiple mutant alleles for seven genes, five of which were targeted with CompoZr ZFNs and two with CoDA ZFNs. Our data also revealed that at least five-fold higher mRNA dose was required to achieve mutagenesis with CoDA ZFNs than with CompoZr ZFNs, and their somatic lesion frequency was lower (<5%) when compared to CopmoZr ZFNs (9-98%). This work provides high throughput protocols for efficient generation of zebrafish mutants using ZFNs and TALENs. C1 [Sood, Raman; Carrington, Blake; Bishop, Kevin] NHGRI, Zebrafish Core Facil, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. [Jones, MaryPat; Chandrasekharappa, Settara C.] NHGRI, Genom Core, Genome Technol Branch, Bethesda, MD 20892 USA. [Rissone, Alberto; Candotti, Fabio] NHGRI, Disorders Immun Sect, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. [Liu, Paul] NHGRI, Oncogenesis & Dev Sect, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. RP Sood, R (reprint author), NHGRI, Zebrafish Core Facil, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. EM rsood@mail.nih.gov RI Liu, Paul/A-7976-2012 OI Liu, Paul/0000-0002-6779-025X FU Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health FX This study was supported by the Intramural Research Program of the National Human Genome Research Institute, 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 45 TC 20 Z9 22 U1 0 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 22 PY 2013 VL 8 IS 2 AR e57239 DI 10.1371/journal.pone.0057239 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 113IC UT WOS:000316658800094 PM 23451191 ER PT J AU Pronk, A Nuckols, JR De Roos, AJ Airola, M Colt, JS Cerhan, JR Morton, L Cozen, W Severson, R Blair, A Cleverly, D Ward, MH AF Pronk, Anjoeka Nuckols, John R. De Roos, Anneclaire J. Airola, Matthew Colt, Joanne S. Cerhan, James R. Morton, Lindsay Cozen, Wendy Severson, Richard Blair, Aaron Cleverly, David Ward, Mary H. TI Residential proximity to industrial combustion facilities and risk of non-Hodgkin lymphoma: a case-control study SO ENVIRONMENTAL HEALTH LA English DT Article DE Non-Hodgkin lymphoma; Lymphomas; Dioxins; Air pollution; Geographic information systems; Case-control study ID SOLID-WASTE INCINERATOR; SOFT-TISSUE SARCOMA; DIBENZO-P-DIOXINS; PHENOXY HERBICIDES; CANCER-MORTALITY; FOLLOW-UP; WORKERS; VICINITY; SAMPLES; SOIL AB Background: Residence near municipal solid waste incinerators, a major historical source of dioxin emissions, has been associated with increased risk of non-Hodgkin lymphoma (NHL) in European studies. The aim of our study was to evaluate residence near industrial combustion facilities and estimates of dioxin emissions in relation to NHL risk in the United States. Methods: We conducted a population-based case-control study of NHL (1998-2000) in four National Cancer Institute-Surveillance Epidemiology and End Results centers (Detroit, Iowa, Los Angeles, Seattle). Residential histories 15 years before diagnosis (similar date for controls) were linked to an Environmental Protection Agency database of dioxin-emitting facilities for 969 cases and 749 controls. We evaluated proximity (3 and 5 km) to 10 facility types that accounted for >85% of U. S. emissions and a distance-weighted average emission index (AEI [ng toxic equivalency quotient (TEQ)/year]). Results: Proximity to any dioxin-emitting facility was not associated with NHL risk (3 km OR = 1.0, 95% CI 0.8-1.3). Risk was elevated for residence near cement kilns (5 km OR = 1.7, 95% CI 0.8-3.3; 3 km OR = 3.8, 95% CI 1.1-14.0) and reduced for residence near municipal solid waste incinerators (5 km OR = 0.5, 95% CI 0.3-0.9; 3 km OR = 0.3, 95% CI 0.1-1.4). The AEI was not associated with risk of NHL overall. Risk for marginal zone lymphoma was increased for the highest versus lowest quartile (5 km OR = 2.6, 95% CI 1.0-6.8; 3 km OR = 3.0, 95% CI 1.1-8.3). Conclusions: Overall, we found no association with residential exposure to dioxins and NHL risk. However, findings for high emissions and marginal zone lymphoma and for specific facility types and all NHL provide some evidence of an association and deserve future study. C1 [Pronk, Anjoeka; Colt, Joanne S.; Morton, Lindsay; Blair, Aaron; Ward, Mary H.] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Rockville, MD USA. [Pronk, Anjoeka] TNO, NL-3700 AJ Zeist, Netherlands. [Nuckols, John R.] Colorado State Univ, Dept Environm & Radiol Hlth Sci, Ft Collins, CO 80523 USA. [De Roos, Anneclaire J.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [De Roos, Anneclaire J.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Airola, Matthew] Westat Corp, Rockville, MD USA. [Cerhan, James R.] Mayo Clin, Coll Med, Rochester, MN USA. [Cozen, Wendy] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Cozen, Wendy] Univ So Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA 90033 USA. [Cozen, Wendy] Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Severson, Richard] Wayne State Univ, Dept Family Med, Detroit, MI USA. [Severson, Richard] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Cleverly, David] US EPA, Natl Ctr Environm Assessment, Off Res & Dev, Washington, DC 20460 USA. [Ward, Mary H.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Ward, MH (reprint author), NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Rockville, MD USA. EM wardm@mail.nih.gov OI Cerhan, James/0000-0002-7482-178X FU National Institutes of Health, NCI; NCI SEER [N01-PC-65064, N01-PC-67009, N01-CN-67008, N01-CN-67010]; NCI Occupational and Environmental Epidemiology Branch; Colorado State University FX We thank Lonn Tremblay and Nathan Appel of Information Management Systems, Inc for programming support. We also thank Laura Gold, Robert Mathes, Hozefa Divan, and Jim Giglierano and his staff at the Iowa Geologic Survey for their efforts in ground checking residential locations and Abigail Flory of Westat, Inc. for additional verification of GPS locations. This study was supported in part by the Intramural Research Program of the National Institutes of Health, NCI and by NCI SEER Contracts N01-PC-65064 (Detroit), N01-PC-67009 (Seattle), N01-CN-67008 (Iowa) and N01-CN-67010 (Los Angeles). John Nuckols was supported in part, through an intergovernmental personnel agreement between the NCI Occupational and Environmental Epidemiology Branch and Colorado State University. NR 36 TC 6 Z9 6 U1 1 U2 20 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-069X J9 ENVIRON HEALTH-GLOB JI Environ. Health PD FEB 22 PY 2013 VL 12 AR 20 DI 10.1186/1476-069X-12-20 PG 11 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 108JE UT WOS:000316288100001 PM 23433489 ER PT J AU Bidulescu, A Liu, JK Hickson, DA Hairston, KG Fox, ER Arnett, DK Sumner, AE Taylor, HA Gibbons, GH AF Bidulescu, Aurelian Liu, Jiankang Hickson, DeMarc A. Hairston, Kristen G. Fox, Ervin R. Arnett, Donna K. Sumner, Anne E. Taylor, Herman A. Gibbons, Gary H. TI Gender differences in the association of visceral and subcutaneous adiposity with adiponectin in African Americans: the Jackson Heart Study SO BMC CARDIOVASCULAR DISORDERS LA English DT Article ID BODY-FAT DISTRIBUTION; INSULIN-RESISTANCE; METABOLIC SYNDROME; RISK-FACTORS; SERUM ADIPONECTIN; PLASMA ADIPONECTIN; YOUNG-ADULTS; TISSUE; OBESITY; WOMEN AB Background: Adiponectin, paradoxically reduced in obesity and with lower levels in African Americans (AA), modulates several cardiometabolic risk factors. Because abdominal visceral adipose tissue (VAT), known to be reduced in AA, and subcutaneous adipose tissue (SAT) compartments may confer differential metabolic risk profiles, we investigated the associations of VAT and SAT with serum adiponectin, separately by gender, with the hypothesis that VAT is more strongly inversely associated with adiponectin than SAT. Methods: Participants from the Jackson Heart Study, an ongoing cohort of AA (n = 2,799; 64% women; mean age, 55 +/- 11 years) underwent computer tomography assessment of SAT and VAT volumes, and had stored serum specimens analyzed for adiponectin levels. These levels were examined by gender in relation to increments of VAT and SAT. Results: Compared to women, men had significantly lower mean levels of adiponectin (3.9 +/- 3.0 mu g/mL vs. 6.0 +/- 4.4 mu g/mL; p < 0.01) and mean volume of SAT (1,721 +/- 803 cm(3) vs. 2,668 +/- 968 cm(3); p < 0.01) but significantly higher mean volume of VAT (884 +/- 416 cm(3) vs. 801 +/- 363 cm(3); p < 0.01). Among women, a one standard deviation increment in VAT was inversely associated with adiponectin (beta = -0.13; p < 0.0001) after controlling for age, systolic blood pressure, fasting plasma glucose, high-density lipoprotein cholesterol, triglycerides, education, pack-years of smoking and daily intake of alcohol. The statistically significant inverse association of VAT and adiponectin persisted after additionally adjusting for SAT, body mass index (BMI) and waist circumference (WC), suggesting that VAT provides significant information above and beyond BMI and WC. Among men, after the same multivariable adjustment, there was a direct association of SAT and adiponectin (beta = 0.18; p = 0.002) that persisted when controlling for BMI and WC, supporting a beneficial effect of SAT. Insulin resistance mediated the association of SAT with adiponectin in women. Conclusion: In African Americans, abdominal visceral adipose tissue had an inverse association with serum adiponectin concentrations only among women. Abdominal subcutaneous adipose tissue appeared as a protective fat depot in men. C1 [Bidulescu, Aurelian] Morehouse Sch Med, Dept Community Hlth & Prevent Med, Cardiovasc Res Inst, Atlanta, GA 30310 USA. [Liu, Jiankang; Hickson, DeMarc A.; Fox, Ervin R.; Taylor, Herman A.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39213 USA. [Hairston, Kristen G.] Wake Forest Univ, Bowman Gray Sch Med, Dept Med, Sect Endocrinol & Metab, Winston Salem, NC 27157 USA. [Hickson, DeMarc A.; Taylor, Herman A.] Jackson State Univ, Jackson Heart Study, Jackson, MS 39217 USA. [Arnett, Donna K.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL 35294 USA. [Sumner, Anne E.] NIDDK, NIH, Bethesda, MD 20892 USA. [Gibbons, Gary H.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Bidulescu, A (reprint author), Morehouse Sch Med, Dept Community Hlth & Prevent Med, Cardiovasc Res Inst, Atlanta, GA 30310 USA. EM abidulescu@msm.edu RI Bidulescu, Aurelian/N-2617-2014 OI Bidulescu, Aurelian/0000-0001-8211-8309 FU Jackson State University [N01-HC-95170]; University of Mississippi Medical Center [N01-HC-95171]; Tougaloo College [N01-HC-95172]; NIH from the National Heart, Lung, and Blood Institute (NHLBI); National Center on Minority Health and Health Disparities (NCMHD); NHLBI [HL076784]; National Institute of Aging [AG028321]; PHS from the National Institutes of Health, National Center for Research Resources [UL1 RR025008]; NIH National Heart, Lung and Blood Institute [UH1 HL073461]; NIDDK/NIH FX The Jackson Heart Study is supported and conducted in collaboration with Jackson State University (N01-HC-95170), University of Mississippi Medical Center (N01-HC-95171), and Tougaloo College (N01-HC-95172) NIH contracts from the National Heart, Lung, and Blood Institute (NHLBI) and the National Center on Minority Health and Health Disparities (NCMHD) with additional support from NHLBI contract HL076784 and the National Institute of Aging (AG028321).; This study was partially supported by PHS Award UL1 RR025008 from the National Institutes of Health, National Center for Research Resources to the first author (A. B.) who was also supported by the NIH grant UH1 HL073461 provided by the National Heart, Lung and Blood Institute.; The intramural program of NIDDK/NIH supported one of the authors (A. E. S). The results described in this article have been presented in part during the American Heart Association Scientific Sessions Conference, November 2011 in Orlando, Florida. NR 50 TC 20 Z9 20 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2261 J9 BMC CARDIOVASC DISOR JI BMC Cardiovasc. Disord. PD FEB 22 PY 2013 VL 13 AR 9 DI 10.1186/1471-2261-13-9 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 101JR UT WOS:000315771800001 PM 23433085 ER PT J AU Nanda, JS Saini, AK Munoz, AM Hinnebusch, AG Lorsch, JR AF Nanda, Jagpreet S. Saini, Adesh K. Munoz, Antonio M. Hinnebusch, Alan G. Lorsch, Jon R. TI Coordinated Movements of Eukaryotic Translation Initiation Factors eIF1, eIF1A, and eIF5 Trigger Phosphate Release from eIF2 in Response to Start Codon Recognition by the Ribosomal Preinitiation Complex SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID C-TERMINAL DOMAIN; SELECTION IN-VIVO; SITE SELECTION; MULTIFACTOR COMPLEX; CRYSTAL-STRUCTURE; GTP HYDROLYSIS; AUG SELECTION; SUBUNIT; REVEALS; BINDING AB Accurate recognition of the start codon in an mRNA by the eukaryotic translation preinitiation complex (PIC) is essential for proper gene expression. The process is mediated by eukaryotic translation initiation factors (eIFs) in conjunction with the 40 S ribosomal subunit and (initiator) tRNA(i). Here, we provide evidence that the C-terminal tail (CTT) of eIF1A, which we previously implicated in start codon recognition, moves closer to the N-terminal domain of eIF5 when the PIC encounters an AUG codon. Importantly, this movement is coupled to dissociation of eIF1 from the PIC, a critical event in start codon recognition, and is dependent on the scanning enhancer elements in the eIF1A CTT. The data further indicate that eIF1 dissociation must be accompanied by the movement of the eIF1A CTT toward eIF5 in order to trigger release of phosphate from eIF2, which converts the latter to its GDP-bound state. Our results also suggest that release of eIF1 from the PIC and movement of the CTT of eIF1A are triggered by the same event, most likely accommodation of tRNA(i) in the P site of the 40 S subunit driven by base pairing between the start codon in the mRNA and the anticodon in tRNA(i). Finally, we show that the C-terminal domain of eIF5 is responsible for the factor's activity in antagonizing eIF1 binding to the PIC. Together, our data provide a more complete picture of the chain of molecular events that is triggered when the scanning PIC encounters an AUG start codon in the mRNA. C1 [Nanda, Jagpreet S.; Munoz, Antonio M.; Lorsch, Jon R.] Johns Hopkins Univ, Sch Med, Dept Biophys & Biophys Chem, Baltimore, MD 21205 USA. [Saini, Adesh K.; Hinnebusch, Alan G.] Eunice K Shriver NICHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Lorsch, JR (reprint author), Johns Hopkins Univ, Sch Med, Dept Biophys & Biophys Chem, 725 N Wolfe St, Baltimore, MD 21205 USA. EM jlorsch@jhmi.edu RI university, shoolini/K-9336-2015; OI Lorsch, Jon/0000-0002-4521-4999 FU National Institutes of Health [GM 62128]; National Institutes of Health Intramural Research Program FX This work was supported, in whole or in part, by National Institutes of Health Grants GM 62128 (to J.R.L.) and by the National Institutes of Health Intramural Research Program (to A.G.H.). NR 43 TC 28 Z9 29 U1 0 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 22 PY 2013 VL 288 IS 8 BP 5316 EP 5329 DI 10.1074/jbc.M112.440693 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 095NY UT WOS:000315342500006 PM 23293029 ER PT J AU Chen, PW Jian, XY Yoon, HY Randazzo, PA AF Chen, Pei-Wen Jian, Xiaoying Yoon, Hye-Young Randazzo, Paul A. TI ARAP2 Signals through Arf6 and Rac1 to Control Focal Adhesion Morphology SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ADP-RIBOSYLATION FACTOR; GTPASE-ACTIVATING-PROTEIN; CELL-MIGRATION; ACTIN CYTOSKELETON; DOWNSTREAM ACTIVATION; LEADING-EDGE; RHO GTPASES; COMPLEX; DYNAMICS; MICROTUBULE AB Focal adhesions (FAs) are dynamic structures that connect the actin cytoskeleton with the extracellular matrix. At least six ADP-ribosylation factor (Arf) GTPase-activating proteins (GAPs), including ARAP2 (an Arf6 GAP), are implicated in regulation of FAs but the mechanisms for most are not well defined. Although Rac1 has been reported to function downstream of Arf6 to control membrane ruffling and cell migration, this pathway has not been directly examined as a regulator of FAs. Here we test the hypothesis that ARAP2 promotes the growth of FAs by converting Arf6.GTP to Arf6.GDP thereby preventing the activation of the Rho family GTP-binding protein Rac1. Reduced expression of ARAP2 decreased the number and size of FAs in cells and increased cellular Arf6.GTP and Rac1.GTP levels. Overexpression of ARAP2 had the opposite effects. The effects of ARAP2 on FAs and Rac1 were dependent on a functional ArfGAP domain. Constitutively active Arf6 affected FAs in the same way as did reduced ARAP2 expression and dominant negative mutants of Arf6 and Rac1 reversed the effect of reduced ARAP2 expression. However, neither dominant negative Arf6 nor Rac1 had the same effect as ARAP2 overexpression. We conclude that changes in Arf6 and Rac1 activities are necessary but not sufficient for ARAP2 to promote the growth of FAs and we speculate that ARAP2 has additional functions that are effector in nature to promote or stabilize FAs. C1 [Chen, Pei-Wen; Jian, Xiaoying; Yoon, Hye-Young; Randazzo, Paul A.] NCI, Lab Cellular & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Randazzo, PA (reprint author), NCI, Lab Cellular & Mol Biol, Bldg 37 Room 2042, Bethesda, MD 20892 USA. EM randazzp@mail.nih.gov RI Chen, Pei-Wen/B-7142-2015 FU NCI, National Institutes of Health [BC 007365] FX This work was supported, in whole or in part, by the intramural program of the NCI, National Institutes of Health (Project BC 007365). NR 71 TC 9 Z9 9 U1 1 U2 18 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 22 PY 2013 VL 288 IS 8 BP 5849 EP 5860 DI 10.1074/jbc.M112.415778 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 095NY UT WOS:000315342500055 PM 23295182 ER PT J AU Hosokawa, H Dip, PV Merkulova, M Bakulina, A Zhuang, ZJ Khatri, A Jian, XY Keating, SM Bueler, SA Rubinstein, JL Randazzo, PA Ausiello, DA Gruber, G Marshansky, V AF Hosokawa, Hiroyuki Dip, Phat Vinh Merkulova, Maria Bakulina, Anastasia Zhuang, Zhenjie Khatri, Ashok Jian, Xiaoying Keating, Shawn M. Bueler, Stephanie A. Rubinstein, John L. Randazzo, Paul A. Ausiello, Dennis A. Grueber, Gerhard Marshansky, Vladimir TI The N Termini of a-Subunit Isoforms Are Involved in Signaling between Vacuolar H+-ATPase (V-ATPase) and Cytohesin-2 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NUCLEOTIDE EXCHANGE FACTOR; CIRCULAR-DICHROISM SPECTRA; PROTEIN SECONDARY STRUCTURE; VESICULAR TRAFFICKING; ARF ACTIVATION; PROTON PUMPS; FACTOR ARNO; PH-SENSOR; RECEPTOR; A2-SUBUNIT AB Previously, we reported an acidification-dependent interaction of the endosomal vacuolar H+-ATPase (V-ATPase) with cytohesin-2, a GDP/GTP exchange factor (GEF), suggesting that it functions as a pH-sensing receptor. Here, we have studied the molecular mechanism of signaling between the V-ATPase, cytohesin-2, and Arf GTP-binding proteins. We found that part of the N-terminal cytosolic tail of the V-ATPase a2-subunit (a2N), corresponding to its first 17 amino acids (a2N(1-17)), potently modulates the enzymatic GDP/GTP exchange activity of cytohesin-2. Moreover, this peptide strongly inhibits GEF activity via direct interaction with the Sec7 domain of cytohesin-2. The structure of a2N(1-17) and its amino acids Phe(5), Met(10), and Gln(14) involved in interaction with Sec7 domain were determined by NMR spectroscopy analysis. In silico docking experiments revealed that part of the V-ATPase formed by its a2N(1-17) epitope competes with the switch 2 region of Arf1 and Arf6 for binding to the Sec7 domain of cytohesin-2. The amino acid sequence alignment and GEF activity studies also uncovered the conserved character of signaling between all four (a1-a4) a-subunit isoforms of mammalian V-ATPase and cytohesin-2. Moreover, the conserved character of this phenomenon was also confirmed in experiments showing binding of mammalian cytohesin-2 to the intact yeast V-ATPase holo-complex. Thus, here we have uncovered an evolutionarily conserved function of the V-ATPase as a novel cytohesin-signaling receptor. C1 [Hosokawa, Hiroyuki; Merkulova, Maria; Zhuang, Zhenjie; Ausiello, Dennis A.; Marshansky, Vladimir] Massachusetts Gen Hosp, Simches Res Ctr, Ctr Syst Biol, Program Membrane Biol, Boston, MA 02114 USA. [Hosokawa, Hiroyuki; Merkulova, Maria; Zhuang, Zhenjie; Ausiello, Dennis A.; Marshansky, Vladimir] Massachusetts Gen Hosp, Simches Res Ctr, Div Nephrol, Boston, MA 02114 USA. [Ausiello, Dennis A.; Marshansky, Vladimir] Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. [Dip, Phat Vinh; Grueber, Gerhard] Nanyang Technol Univ, Sch Biol Sci, Div Struct Biol & Biochem, Singapore 637551, Singapore. [Bakulina, Anastasia] State Res Ctr Virol & Biotechnol VECTOR, Koltsov 630559, Novosibirsk Reg, Russia. [Khatri, Ashok] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Khatri, Ashok] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Jian, Xiaoying; Randazzo, Paul A.] NCI, Lab Cellular & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Keating, Shawn M.; Bueler, Stephanie A.; Rubinstein, John L.] Hosp Sick Children, Res Inst, Mol Struct & Funct Program, Toronto, ON M5G 1X8, Canada. [Keating, Shawn M.; Rubinstein, John L.] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 1X8, Canada. RP Marshansky, V (reprint author), Massachusetts Gen Hosp, Simches Res Ctr, Ctr Syst Biol, Program Membrane Biol, Boston, MA 02114 USA. EM Marshansky.Vladimir@mgh.harvard.edu RI Bakulina, Anastasia/A-6215-2014; OI Dip, Phat Vinh/0000-0002-1535-9644; Rubinstein, John/0000-0003-0566-2209 FU National Institutes of Health Grant [DK038452, DK57521]; Boston Area Diabetes Endocrinology Research Center Grant [DK057521-08]; National Institutes of Health Intramural Program of NCI; Canadian Institutes of Health Research Grant [MOP 81294]; A*STAR Biomedical Research Council Grant [09/1/22/19/609]; Center for the Study of Inflammatory Bowel Disease [DK43351]; Singapore International Graduate Award (SINGA) [20092010S10303] FX This work was supported, in whole or in part, by National Institutes of Health Grant DK038452. This work was also supported by Boston Area Diabetes Endocrinology Research Center Grant DK057521-08 (to V. M.).; Recipient of a Singapore International Graduate Award (SINGA, 20092010S10303).; Supported by the National Institutes of Health Intramural Program of NCI.; Supported by Canadian Institutes of Health Research Grant MOP 81294.; Supported by A*STAR Biomedical Research Council Grant 09/1/22/19/609.; We thank Dr. Dennis Brown for critical reading and constructive suggestions during the preparation of this manuscript. We are grateful to Dr. Masamitsu Futai and Dr. James Casanova for providing cDNA encoding V-ATPase a2-isoform and cytohesin-2, respectively. We are also grateful to Dr. Sylvain Bourgoin for the generous gift of SecinH3 inhibitor. The Microscopy Core Facility of the Program in Membrane Biology received additional support from National Institutes of Health Grant DK57521 to BADERC and Grant DK43351 to Center for the Study of Inflammatory Bowel Disease. NR 68 TC 21 Z9 21 U1 1 U2 15 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 22 PY 2013 VL 288 IS 8 BP 5896 EP 5913 DI 10.1074/jbc.M112.409169 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 095NY UT WOS:000315342500059 PM 23288846 ER PT J AU Van Duyne, R Guendel, I Jaworski, E Sampey, G Klase, Z Chen, H Zeng, C Kovalskyy, D el Kouni, MH Lepene, B Patanarut, A Nekhai, S Price, DH Kashanchi, F AF Van Duyne, Rachel Guendel, Irene Jaworski, Elizabeth Sampey, Gavin Klase, Zachary Chen, Hao Zeng, Chen Kovalskyy, Dmytro el Kouni, Mahmoud H. Lepene, Benjamin Patanarut, Alexis Nekhai, Sergei Price, David H. Kashanchi, Fatah TI Effect of Mimetic CDK9 Inhibitors on HIV-1-Activated Transcription SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE ATP analog; CDK9; cyclin T1; viral transactivator; inhibitors ID HUMAN-IMMUNODEFICIENCY-VIRUS; RNA-POLYMERASE-II; P-TEFB; HIV-1 TAT; CDK9/CYCLIN T1; BINDING; REPLICATION; COMPLEXES; CELLS; IDENTIFICATION AB Potent anti-retroviral therapy has transformed HIV-1 infection into a chronic manageable disease; however, drug resistance remains a common problem that limits the effectiveness and clinical benefits of this type of treatment. The discovery of viral reservoirs in the body, in which HIV-1 may persist, has helped to explain why therapeutic eradication of HIV-1 has proved so difficult. In the current study, we utilized a combination of structure-based analysis of cyclin/CDK complexes with our previously published Tat peptide derivatives. We modeled the Tat peptide inhibitors with CDKs and found a particular pocket that showed the most stable binding site (Cavity 1) using in silico analysis. Furthermore, we were able to find peptide mimetics that bound to similar regions using in silico searches of a chemical library, followed by cell-based biological assays. Using these methods, we obtained the first-generation mimetic drugs and tested these compounds on HIV-1 long terminal repeat-activated transcription. Using biological assays followed by similar in silico analysis to find second-generation drugs resembling the original mimetic, we found the new targets of Cavity 1 and Cavity 2 regions on CDK9. We examined the second-generation mimetic against various viral isolates and observed a generalized suppression of most HIV-1 isolates. Finally, the drug inhibited viral replication in humanized mouse models of Rag2(-/-)gamma c(-/-) with no toxicity to the animals at tested concentrations. Our results suggest that it may be possible to model peptide inhibitors into available crystal structures and further find drug mimetics using in silico analysis. (c) 2012 Elsevier Ltd. All rights reserved. C1 [Van Duyne, Rachel; Guendel, Irene; Jaworski, Elizabeth; Sampey, Gavin; Kashanchi, Fatah] George Mason Univ, Natl Ctr Biodef & Infect Dis, Manassas, VA 20110 USA. [Van Duyne, Rachel] George Washington Univ, Med Ctr, Dept Microbiol Immunol & Trop Med, Washington, DC 20037 USA. [Klase, Zachary] NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Chen, Hao; Zeng, Chen] George Washington Univ, Dept Phys, Washington, DC 20052 USA. [Zeng, Chen] Huazhong Univ Sci & Technol, Dept Phys, Wuhan 430074, Peoples R China. [Kovalskyy, Dmytro] Ukrainian Acad Sci, Inst Mol Biol & Genet, Dept Prot Engn, UA-252627 Kiev, Ukraine. [el Kouni, Mahmoud H.] Univ Alabama Birmingham, Ctr AIDS Res, Ctr Comprehens Canc, Dept Pharmacol & Toxicol, Birmingham, AL 35294 USA. [Lepene, Benjamin; Patanarut, Alexis] Ceres Nanosci Inc, Manassas, VA 20110 USA. [Nekhai, Sergei] Howard Univ, Ctr Sickle Cell Dis, Dept Med, Washington, DC 20060 USA. [Price, David H.] Univ Iowa, Interdisciplinary Mol Biol Program, Dept Biochem, Iowa City, IA 52242 USA. RP Kashanchi, F (reprint author), George Mason Univ, Natl Ctr Biodef & Infect Dis, Discovery Hall,Room 182,10900 Univ Blvd MS 1H8, Manassas, VA 20110 USA. EM fkashanc@gmu.edu FU GMU; NIH [AI043894, AI078859, AI074410] FX We would like to thank the members of the Kashanchi laboratory for experiments and assistance with the manuscript. Further support came from grants from the GMU funds to F.K. and NIH grants AI043894, AI078859, and AI074410. Rachel Van Duyne is a predoctoral student in the Microbiology and Immunology Program of the Institute for Biomedical Sciences at the George Washington University. This work is from a dissertation to be presented to the above program in partial fulfillment of the requirements for the Ph.D. degree. NR 29 TC 14 Z9 14 U1 0 U2 9 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD FEB 22 PY 2013 VL 425 IS 4 BP 812 EP 829 DI 10.1016/j.jmb.2012.12.005 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 098JV UT WOS:000315546500011 PM 23247501 ER PT J AU Singh, NS Paul, RK Torjman, MC Wainer, IW AF Singh, Nagendra S. Paul, Rajib K. Torjman, Marc C. Wainer, Irving W. TI Gabapentin and (S)-pregabalin decrease intracellular D-serine concentrations in PC-12 cells SO NEUROSCIENCE LETTERS LA English DT Article DE D-Serine; Serine racemase; Neuropathic pain; N-Methyl D-aspartate receptor; Gabapentin; (S)-pregabalin ID AMINO-ACID OXIDASE; RANDOMIZED CONTROLLED-TRIAL; SENSITIVE CA2+ CHANNELS; NEUROPATHIC PAIN; RAT-BRAIN; MESSENGER-RNAS; RACEMASE; CALCIUM; MECHANISMS; EXPRESSION AB The effects of gabapentin (GBP) and (S)-pregabalin (PGB) on the intracellular concentrations of D-serine and the expression of serine racemase (SR) in PC-12 cells were determined. Intracellular D-serine concentrations were determined using an enantioselective capillary electrophoresis assay with laser-induced fluorescence detection. Increasing concentrations of GBP, 0.1-20 mu M, produced a significant decrease in D-serine concentration relative to control, 22.9 +/- 6.7% at 20 mu M (*p < 0.05), with an IC50 value of 3.40 +/- 10.29 mu M. Increasing concentrations of PGB, 0.1-10 mu M, produced a significant decrease in D-serine concentration relative to control, 25.3 +/- 17.6% at 10 mu M (*p < 0.05), with an IC50 value of 3.38 +/- 10.21 mu M. The compounds had no effect on the expression of monomeric-SR or dimeric-SR as determined by Western blotting. The results suggest that incubation of PC-12 cells with GBP and PGB reduced the basal activity of SR, which is most likely a result of the decreased Ca2+ flux produced via interaction of the drugs with the alpha(2)-delta subunit of voltage-gated calcium channels. D-Serine is a co-agonist of the N-methyl D-aspartate receptor (NMDAR) and reduced D-serine concentrations have been associated with reduced NMDAR activity. Thus, GBP and PGB may act as indirect antagonists of NMDAR, a mechanism that may contribute to the clinical effects of the drugs in neuropathic pain. Published by Elsevier Ireland Ltd. C1 [Singh, Nagendra S.; Paul, Rajib K.; Wainer, Irving W.] NIA, Lab Clin Invest, NIH, Baltimore, MD 21224 USA. [Torjman, Marc C.] Rowan Univ, Cooper Med Sch, Biostat Grp, Camden, NJ 08103 USA. RP Wainer, IW (reprint author), NIA, Lab Clin Invest, NIH, Biomed Res Ctr, 251 Bayview Boul,Suite 100,Room 088133, Baltimore, MD 21224 USA. EM WainerIr@grc.nia.nih.gov RI Singh, Nagendra/K-8966-2015 FU Intramural Research Program of the National Institute on Aging/NIH FX This work was supported by funding from the Intramural Research Program of the National Institute on Aging/NIH. NR 31 TC 6 Z9 7 U1 0 U2 9 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD FEB 22 PY 2013 VL 535 BP 90 EP 94 DI 10.1016/j.neulet.2012.12.024 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 095XK UT WOS:000315368100017 PM 23274708 ER PT J AU Chiyaka, C Tatem, AJ Cohen, JM Gething, PW Johnston, G Gosling, R Laxminarayan, R Hay, SI Smith, DL AF Chiyaka, C. Tatem, A. J. Cohen, J. M. Gething, P. W. Johnston, G. Gosling, R. Laxminarayan, R. Hay, S. I. Smith, D. L. TI The Stability of Malaria Elimination SO SCIENCE LA English DT Editorial Material ID FEASIBILITY; POPULATION; STRATEGIES C1 [Chiyaka, C.; Tatem, A. J.] Univ Florida, Emerging Pathogens Inst, Gainesville, FL 32610 USA. [Tatem, A. J.] Univ Southampton, Dept Geog & Environm, Southampton SO17 1BJ, Hants, England. [Tatem, A. J.; Hay, S. I.; Smith, D. L.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Cohen, J. M.] Clinton Hlth Access Initiat, Boston, MA 02127 USA. [Gething, P. W.; Hay, S. I.] Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford OX1 3PS, England. [Johnston, G.; Smith, D. L.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Johnston, G.; Smith, D. L.] Johns Hopkins Bloomberg Sch Publ Hlth, Malaria Res Inst, Baltimore, MD 21205 USA. [Gosling, R.] Univ Calif San Francisco, Malaria Eliminat Initiat, Global Hlth Grp, San Francisco, CA 94105 USA. [Hay, S. I.; Smith, D. L.] Ctr Dis Dynam Econ & Policy, Washington, DC 20036 USA. RP Smith, DL (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM dlsmith@jhsph.edu RI Smith, David/L-8850-2013; Hay, Simon/F-8967-2015; OI Smith, David/0000-0003-4367-3849; Hay, Simon/0000-0002-0611-7272; Gething, Peter/0000-0001-6759-5449 FU Medical Research Council [MR/K00669X/1]; NIAID NIH HHS [U19AI089674]; Wellcome Trust [095066] NR 25 TC 26 Z9 26 U1 0 U2 18 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD FEB 22 PY 2013 VL 339 IS 6122 BP 909 EP 910 DI 10.1126/science.1229509 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 092UX UT WOS:000315149600032 PM 23430640 ER PT J AU Salaverria, I Royo, C Carvajal-Cuenca, A Clot, G Navarro, A Valera, A Song, JY Woroniecka, R Rymkiewicz, G Klapper, W Hartmann, EM Sujobert, P Wlodarska, I Ferry, JA Gaulard, P Ott, G Rosenwald, A Lopez-Guillermo, A Quintanilla-Martinez, L Harris, NL Jaffe, ES Siebert, R Campo, E Bea, S AF Salaverria, Itziar Royo, Cristina Carvajal-Cuenca, Alejandra Clot, Guillem Navarro, Alba Valera, Alejandra Song, Joo Y. Woroniecka, Renata Rymkiewicz, Grzegorz Klapper, Wolfram Hartmann, Elena M. Sujobert, Pierre Wlodarska, Iwona Ferry, Judith A. Gaulard, Philippe Ott, German Rosenwald, Andreas Lopez-Guillermo, Armando Quintanilla-Martinez, Leticia Harris, Nancy L. Jaffe, Elaine S. Siebert, Reiner Campo, Elias Bea, Silvia TI CCND2 rearrangements are the most frequent genetic events in cyclin D1(-) mantle cell lymphoma SO BLOOD LA English DT Article ID NUCLEAR EXPRESSION; SOX11 EXPRESSION; GENOME; TARGET; OVEREXPRESSION; AMPLIFICATIONS; TRANSLOCATION; PATHOGENESIS; NEOPLASMS; DIAGNOSIS AB Cyclin D1(-) mantle cell lymphomas (MCLs) are not well characterized, in part because of the difficulties in their recognition. SOX11 has been identified recently as a reliable biomarker of MCL that is also expressed in the cyclin D1(-) variant. We investigated 40 lymphomas with MCL morphology and immunophenotype that were negative for cyclin D1 expression/t(11;14)(q13;q32) but positive for SOX11. These tumors presented clinically with generalized lymphadenopathy, advanced stage, and poor outcome (5-year overall survival, 48%). Chromosomal rearrangements of the CCND2 locus were detected in 55% of the cases, with an IG gene as partner in 18 of 22, in particular with light chains (10 IGK@ and 5 IGL@). No mutations in the phosphorylation motifs of CCND1, CCND2, or CCND3 were detected. The global genomic profile and the high complexity of the 32 cyclin D1(-)SOX11(+) MCL patients analyzed by copy number arrays were similar to the conventional cyclin D1(+)/SOX11(+) MCL. 17p deletions and high Ki67 expression conferred a significantly worse outcome for the patients. This comprehensive characterization of a large series of cyclin D1(-) MCL patients indicates that these tumors are clinically and biologically similar to the conventional cyclin D1(+) MCL and provides a basis for the proper identification and clinical management of these patients. C1 [Salaverria, Itziar; Royo, Cristina; Carvajal-Cuenca, Alejandra; Clot, Guillem; Navarro, Alba; Valera, Alejandra; Campo, Elias; Bea, Silvia] Univ Barcelona, Inst Invest Biomed August Pi & Sunyer, Dept Pathol, Hematopathol Unit,Hosp Clin, Barcelona, Spain. [Salaverria, Itziar; Siebert, Reiner] Univ Kiel, Univ Hosp Schleswig Holstein Campus Kiel, Inst Human Genet, Kiel, Germany. [Song, Joo Y.; Jaffe, Elaine S.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Woroniecka, Renata] Maria Sklodowska Curie Mem Inst & Oncol Ctr, Cytogenet Lab, Warsaw, Poland. [Rymkiewicz, Grzegorz] Maria Sklodowska Curie Mem Inst & Oncol Ctr, Dept Pathol, Warsaw, Poland. [Klapper, Wolfram] Univ Kiel, Hematopathol Sect, Dept Pathol, Kiel, Germany. [Klapper, Wolfram] Univ Kiel, Lymph Node Registry, Kiel, Germany. [Hartmann, Elena M.; Rosenwald, Andreas] Univ Wurzburg, Inst Pathol, Wurzburg, Germany. [Sujobert, Pierre; Gaulard, Philippe] Hop Henri Mondor, F-94010 Creteil, France. [Wlodarska, Iwona] Katholieke Univ Leuven, Ctr Human Genet, Louvain, Belgium. [Ferry, Judith A.; Harris, Nancy L.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Ott, German] Robert Bosch Krankenhaus, Dept Clin Pathol, Stuttgart, Germany. [Ott, German] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. [Lopez-Guillermo, Armando] Hosp Clin Barcelona, Hematopathol Unit, Dept Hematol, Barcelona, Spain. [Quintanilla-Martinez, Leticia] Univ Tubingen, Inst Pathol, Tubingen, Germany. RP Bea, S (reprint author), Ctr Esther Koplowitz, 2nd Floor,Rossello 153, Barcelona 08036, Spain. EM sbea@clinic.cat RI Siebert, Reiner/A-8049-2010; Navarro, Alba/H-2611-2015; Royo, Cristina/H-3193-2015; SALAVERRIA, ITZIAR/L-2246-2015; Song, Joo/E-5356-2016; Jaffe, Elaine/G-8984-2014; Klapper, Wolfram/S-6314-2016; Bea, Silvia/K-7699-2014; OI Navarro, Alba/0000-0002-4041-0974; Royo, Cristina/0000-0002-1214-4656; SALAVERRIA, ITZIAR/0000-0002-2427-9822; Song, Joo/0000-0003-3497-2513; Jaffe, Elaine/0000-0003-4632-0301; Bea, Silvia/0000-0001-7192-2385; Campo, elias/0000-0001-9850-9793 FU Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias [PI08/0077, PI11/01177]; Alexander von Humboldt Foundation; Subprograma Juan de la Cierva Ministerio de Ciencia e Innovacion [JCI-2011-10232]; Instituto de Salud Carlos III, Beca Predoctoral de Formacion en Investigacion en Salud Comision Interministerial de Ciencia y Tecnologia Espanola [FI08/00347, SAF08/3630]; Red Tematica de Investigacion Cooperativa del Cancer [RD06/0020/0039 ISCIII]; Spanish Ministry of Science and Innovation; European Regional Development Fund (Unio Europea "Una manera de fer Europa") FX This study was supported by the Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias (PI08/0077; PI11/01177 to S. B.), Alexander von Humboldt Foundation (to I. S.) and Subprograma Juan de la Cierva Ministerio de Ciencia e Innovacion (JCI-2011-10232 to I. S.), Instituto de Salud Carlos III, Beca Predoctoral de Formacion en Investigacion en Salud (FI08/00347 to C. R.) Comision Interministerial de Ciencia y Tecnologia Espanola (SAF08/3630 to E. C.), Red Tematica de Investigacion Cooperativa del Cancer (RD06/0020/0039 ISCIII to E. C.), and the Spanish Ministry of Science and Innovation and European Regional Development Fund (Unio Europea "Una manera de fer Europa"). NR 33 TC 36 Z9 39 U1 1 U2 10 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 21 PY 2013 VL 121 IS 8 BP 1394 EP 1402 DI 10.1182/blood-2012-08-452284 PG 9 WC Hematology SC Hematology GA 182NK UT WOS:000321750000024 PM 23255553 ER PT J AU Li, ZJ Zhang, ZY Li, YY Arnovitz, S Chen, P Huang, H Jiang, X Hong, GM Kunjamma, RB Ren, HM He, CJ Wang, CZ Elkahloun, AG Valk, PJM Dohner, K Neilly, MB Bullinger, L Delwel, R Lowenberg, B Liu, PP Morgan, R Rowley, JD Yuan, CS Chen, JJ AF Li, Zejuan Zhang, Zhiyu Li, Yuanyuan Arnovitz, Stephen Chen, Ping Huang, Hao Jiang, Xi Hong, Gia-Ming Kunjamma, Rejani B. Ren, Haomin He, Chunjiang Wang, Chong-Zhi Elkahloun, Abdel G. Valk, Peter J. M. Doehner, Konstanze Neilly, Mary Beth Bullinger, Lars Delwel, Ruud Lowenberg, Bob Liu, Paul P. Morgan, Richard Rowley, Janet D. Yuan, Chun-Su Chen, Jianjun TI PBX3 is an important cofactor of HOXA9 in leukemogenesis SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; GENE-EXPRESSION PROFILE; REARRANGED ACUTE-LEUKEMIA; DNA-BINDING; TRANSCRIPTION FACTORS; HEMATOPOIETIC-CELLS; PROGNOSTIC IMPACT; DOWN-REGULATION; NPM1 MUTATIONS; HOMEOBOX GENES AB Although PBX proteins are known to increase DNA-binding/transcriptional activity of HOX proteins through their direct binding, the functional importance of their interaction in leukemogenesis is unclear. We recently reported that overexpression of a 4-homeoboxgene signature (ie, PBX3/HOXA7/HOXA9/HOXA11) is an independent predictor of poor survival in patients with cytogenetically abnormal acute myeloid leukemia (CA-AML). Here we show that it is PBX3, but not PBX1 or PBX2, that is consistently coexpressed with HOXA9 in various subtypes of CA-AML, particularly MLL-rearranged AML, and thus appears as a potential pathologic cofactor of HOXA9 in CA-AML. We then show that depletion of endogenous Pbx3 expression by shRNA significantly inhibits MLL-fusion-mediated cell transformation, and coexpressed PBX3 exhibits a significantly synergistic effect with HOXA9 in promoting cell transformation in vitro and leukemogenesis in vivo. Furthermore, as a proof of concept, we show that a small peptide, namely HXR9, which was developed to specifically disrupt the interactions between HOX and PBX proteins, can selectively kill leukemic cells with overexpression of HOXA/PBX3 genes. Collectively, our data suggest that PBX3 is a critical cofactor of HOXA9 in leukemogenesis, and targeting their interaction is a feasible strategy to treat presently therapy resistant CA-AML (eg, MLL-rearranged leukemia) in which HOXA/PBX3 genes are overexpressed. (Blood. 2013;121(8):1422-1431) C1 [Li, Zejuan; Li, Yuanyuan; Arnovitz, Stephen; Chen, Ping; Huang, Hao; Jiang, Xi; Hong, Gia-Ming; Kunjamma, Rejani B.; Ren, Haomin; He, Chunjiang; Neilly, Mary Beth; Rowley, Janet D.; Chen, Jianjun] Univ Chicago, Dept Med, Sect Hematol Oncol, Chicago, IL 60637 USA. [Zhang, Zhiyu; Wang, Chong-Zhi; Yuan, Chun-Su] Univ Chicago, Tang Ctr Herbal Med Res, Chicago, IL 60637 USA. [Elkahloun, Abdel G.; Liu, Paul P.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Valk, Peter J. M.; Delwel, Ruud; Lowenberg, Bob] Erasmus Univ, Med Ctr, Dept Hematol, Rotterdam, Netherlands. [Doehner, Konstanze; Bullinger, Lars] Univ Ulm, Dept Internal Med 3, D-89069 Ulm, Germany. [Morgan, Richard] Univ Surrey, Postgrad Med Sch, Fac Hlth & Med Sci, Guildford GU2 5XH, Surrey, England. RP Chen, JJ (reprint author), Univ Chicago, Dept Med, 900 E 57th St,KCBD Rm 7134, Chicago, IL 60637 USA. EM zjli@uchicago.edu; jchen@medicine.bsd.uchicago.edu RI Liu, Paul/A-7976-2012; OI Liu, Paul/0000-0002-6779-025X; He, Chunjiang/0000-0002-4868-331X FU Leukemia & Lymphoma Society; National Institutes of Health (NIH) [CA127277]; American Cancer Society (ACS); G. Harold and Leila Y. Mathers Charitable Foundation; LLS; Gabrielle's Angel Foundation for Cancer Research; The Spastic Paralysis Foundation of the Illinois; Eastern Iowa Branch of Kiwanis International; The Fidelity Foundation; The University of Chicago Committee on Cancer Biology (CCB) Fellowship Program; NIH/NCCAM [P01AT004418]; National Human Genome Research Institute, NIH; The Deutsche Jose Carreras Leukamie Stiftung (DJCLS) [R 06/41v]; The Deutsche Forschungsgemeinschaft (DFG) Heisenberg-Stipendium [BU 1339/3-1] FX This work was supported in part by the Leukemia & Lymphoma Society (L. L. S.) Translational Research Grant (J.D.R. and J.C.), the National Institutes of Health (NIH) R01 grant CA127277 (J.C.), American Cancer Society (ACS) Research Scholar grant (J.C.), the G. Harold and Leila Y. Mathers Charitable Foundation (J.C.), LLS Special Fellowship (Z.L.), Gabrielle's Angel Foundation for Cancer Research (J.C., Z.L., H. H., and X.J.), The Spastic Paralysis Foundation of the Illinois, Eastern Iowa Branch of Kiwanis International (J.D.R.), The Fidelity Foundation (J.D.R. and J.C.), The University of Chicago Committee on Cancer Biology (CCB) Fellowship Program (X.J.), NIH/NCCAM P01AT004418 (C. S. Y.), The Intramural Research Program of National Human Genome Research Institute, NIH (A. E. and P. P. L.), The Deutsche Jose Carreras Leukamie Stiftung (DJCLS) grant R 06/41v (L. B.), and The Deutsche Forschungsgemeinschaft (DFG) Heisenberg-Stipendium BU 1339/3-1 (L.B). NR 48 TC 35 Z9 36 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 21 PY 2013 VL 121 IS 8 BP 1422 EP 1431 DI 10.1182/blood-2012-07-442004 PG 10 WC Hematology SC Hematology GA 182NK UT WOS:000321750000027 PM 23264595 ER PT J AU Astermark, J Donfield, SM Gomperts, ED Schwarz, J Menius, ED Pavlova, A Oldenburg, J Kessing, B DiMichele, DM Shapiro, AD Winkler, CA Berntorp, E AF Astermark, Jan Donfield, Sharyne M. Gomperts, Edward D. Schwarz, John Menius, Erika D. Pavlova, Anna Oldenburg, Johannes Kessing, Bailey DiMichele, Donna M. Shapiro, Amy D. Winkler, Cheryl A. Berntorp, Erik CA Hemophilia Inhibitor Genetics TI The polygenic nature of inhibitors in hemophilia A: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort SO BLOOD LA English DT Article ID MALMO INTERNATIONAL BROTHER; GENOME-WIDE ASSOCIATION; FACTOR-VIII; INFLAMMATORY DISEASES; AUTOIMMUNE-DISEASE; CELL-ACTIVATION; RISK-FACTORS; FACTOR-XIII; POLYMORPHISMS; KINASES AB Studies of determinants of development of inhibitory Abs to factor VIII in people with hemophilia A indicate a complex process involving multiple factors. The Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort was formed to extend our understanding of the genetic background of risk. The study group contains 833 subjects from 3 independent cohorts: brother pairs and singletons with and without a history of inhibitors, as well as 104 brother pairs discordant for inhibitor status. Using an Illumina iSelect platform, 13 331 single-nucleotide polymorphisms from 1081 genes, primarily immune response and immune modifier genes, were typed. Each cohort was analyzed separately with results combined using a meta-analytic technique. After adjustment for potential confounders, 53 single-nucleotide polymorphisms were found to be significant predictors of inhibitor status using the criteria of odds ratios in the same direction in all cohorts or allowing for a 20% interval around an odds ratio = 1 in 1 of the 3 and significant in at least 2. Of the 53 markers, 13 had meta P < .001. Eight of the 53 were significant predictors among the discordant pairs. Results support the complexity of the immune response and encourage further research with the goal of understanding the pathways involved. (Blood. 2013;121(8):1446-1454) C1 [Astermark, Jan; Berntorp, Erik] Lund Univ, Ctr Thrombosis & Haemostasis, Skane Univ Hosp, SE-20502 Malmo, Sweden. [Donfield, Sharyne M.; Schwarz, John; Menius, Erika D.] Rho Inc, Dept Biostat, Chapel Hill, NC USA. [Gomperts, Edward D.] Childrens Hosp Los Angeles, Saban Res Inst, Los Angeles, CA 90027 USA. [Pavlova, Anna; Oldenburg, Johannes] Univ Clin, Inst Expt Haematol & Transfus Med, Bonn, Germany. [Kessing, Bailey; Winkler, Cheryl A.] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. [DiMichele, Donna M.] Weill Cornell Med Coll, Dept Pediat, New York, NY USA. [Shapiro, Amy D.] Indiana Hemophilia & Thrombosis Ctr, Indianapolis, IN USA. RP Astermark, J (reprint author), Lund Univ, Ctr Thrombosis & Haemostasis, Skane Univ Hosp, SE-20502 Malmo, Sweden. EM jan.astermark@med.lu.se FU Baxter BioScience; Frederick National Laboratory for Cancer Research, National Institutes of Health (NIH) [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research; Wyeth; Research Fund at Malmo University Hospital; NIH, National Institute of Child Health and Human Development [R01-HD-41224] FX This work was supported by an investigator-initiated grant from Baxter BioScience and by federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health (NIH; contract number HHSN261200800001E). This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The Malmo International Brother Study is funded through grants from Wyeth and the Research Fund at Malmo University Hospital. The Hemophilia Growth and Development Study is funded by the NIH, National Institute of Child Health and Human Development (grant R01-HD-41224). NR 51 TC 46 Z9 46 U1 1 U2 10 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 21 PY 2013 VL 121 IS 8 BP 1446 EP 1454 DI 10.1182/blood-2012-06-434803 PG 9 WC Hematology SC Hematology GA 182NK UT WOS:000321750000030 PM 23223434 ER PT J AU Cohen, KS Cheng, S Larson, MG Cupples, LA McCabe, EL Wang, YA Ngwa, JS Martin, RP Klein, RJ Hashmi, B Ge, Y O'Donnell, CJ Vasan, RS Shaw, SY Wang, TJ AF Cohen, Kenneth S. Cheng, Susan Larson, Martin G. Cupples, L. Adrienne McCabe, Elizabeth L. Wang, Ying A. Ngwa, Julius S. Martin, Roderick P. Klein, Rachael J. Hashmi, Basma Ge, Yin O'Donnell, Christopher J. Vasan, Ramachandran S. Shaw, Stanley Y. Wang, Thomas J. TI Circulating CD34(+) progenitor cell frequency is associated with clinical and genetic factors SO BLOOD LA English DT Article ID CORONARY-ARTERY-DISEASE; ACUTE MYOCARDIAL-INFARCTION; GENOME-WIDE ASSOCIATION; CARDIOVASCULAR RISK; ENDOTHELIAL-CELLS; STATIN THERAPY; HEART-DISEASE; DYSFUNCTION; MOBILIZATION; POPULATION AB Circulating blood CD34(+) cells consist of hematopoietic stem/progenitor cells, angiogenic cells, and endothelial cells. In addition to their clinical use in hematopoietic stem cell transplantation, CD34(+) cells may also promote therapeutic neovascularization. Therefore, understanding the factors that influence circulating CD34(+) cell frequency has wide implications for vascular biology in addition to stem cell transplantation. In the present study, we examined the clinical and genetic characteristics associated with circulating CD34(+) cell frequency in a large, community-based sample of 1786 Framingham Heart Study participants. Among subjects without cardiovascular disease (n = 1595), CD34(+) frequency was inversely related to older age, female sex, and smoking. CD34(+) frequency was positively related to weight, serum total cholesterol, and statin therapy. Clinical covariates accounted for 6.3% of CD34(+) variability. CD34(+) frequency was highly heritable (h(2) = 54%; P < .0001). Genome-wide association analysis of CD34(+) frequency identified suggestive associations at several loci, including OR4C12 (chromosome 11; P = 6.7 x 10(-7)) and ENO1 and RERE (chromosome 1; P = 8.8 x 10(-7)). CD34(+) cell frequency is reduced in older subjects and is influenced by environmental factors including smoking and statin use. CD34(+) frequency is highly heritable. The results of the present study have implications for therapies that use CD34+ cell populations and support efforts to better understand the genetic mechanisms that underlie CD34(+) frequency. C1 [Wang, Thomas J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Cohen, Kenneth S.; Martin, Roderick P.; Klein, Rachael J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Regenerat Med, Boston, MA USA. [Cohen, Kenneth S.] Univ Chicago, Med Ctr, Hematol Oncol Sect, Chicago, IL 60637 USA. [Cheng, Susan; McCabe, Elizabeth L.; O'Donnell, Christopher J.; Shaw, Stanley Y.; Wang, Thomas J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Cheng, Susan; Larson, Martin G.; O'Donnell, Christopher J.; Vasan, Ramachandran S.; Wang, Thomas J.] Framingham Heart Dis Epidemiol Study, Framingham, MA 90034 USA. [Cheng, Susan] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc Med, Boston, MA 02115 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Cupples, L. Adrienne; Wang, Ying A.; Ngwa, Julius S.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Martin, Roderick P.] Genzyme Corp, Cambridge, MA USA. [Hashmi, Basma] Harvard Univ, Dept Bioengn, Boston, MA 02115 USA. [Ge, Yin] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. [O'Donnell, Christopher J.] NHLBI, Ctr Populat Studies, NIH, Bethesda, MD 20892 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Prevent Med Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Div Cardiol, Boston, MA 02118 USA. [Shaw, Stanley Y.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA USA. RP Wang, TJ (reprint author), Massachusetts Gen Hosp, Div Cardiol, GRB 800,55 Fruit St, Boston, MA 02114 USA. EM kcohen@medicine.bsd.uchicago.edu; shaw.stanley@mgh.harvard.edu; tjwang@partners.org OI Larson, Martin/0000-0002-9631-1254; Cupples, L. Adrienne/0000-0003-0273-7965 FU National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195, R01-HL083197, R01-HL93328]; National Institutes of Health [K99HL107642]; Ellison Foundation FX This work was supported in part by the National Heart, Lung, and Blood Institute's Framingham Heart Study (contract number N01-HC-25195, grant R01-HL083197 to T.J.W., and grant R01-HL93328 to R. S. V.). S. C. is supported in part by National Institutes of Health grant K99HL107642 and the Ellison Foundation. NR 47 TC 23 Z9 23 U1 0 U2 3 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 FEB 21 PY 2013 VL 121 IS 8 BP E50 EP E56 DI 10.1182/blood-2012-05-424846 PG 7 WC Hematology SC Hematology GA 182NK UT WOS:000321750000002 PM 23287867 ER PT J AU Mendonca, VRR Queiroz, ATL Lopes, FM Andrade, BB Barral-Netto, M AF Mendonca, Vitor R. R. Queiroz, Artur T. L. Lopes, Fabricio M. Andrade, Bruno B. Barral-Netto, Manoel TI Networking the host immune response in Plasmodium vivax malaria SO MALARIA JOURNAL LA English DT Article DE Malaria; Plasmodium vivax; Biomarkers; Network analysis ID CD4(+) T-CELLS; FALCIPARUM-MALARIA; BRAZILIAN AMAZON; CEREBRAL MALARIA; LIVER STAGES; CHILDREN; SUSCEPTIBILITY; SEVERITY; INTERLEUKIN-10; CHEMOKINES AB Background: Plasmodium vivax malaria clinical outcomes are a consequence of the interaction of multiple parasite, environmental and host factors. The host molecular and genetic determinants driving susceptibility to disease severity in this infection are largely unknown. Here, a network analysis of large-scale data from a significant number of individuals with different clinical presentations of P. vivax malaria was performed in an attempt to identify patterns of association between various candidate biomarkers and the clinical outcomes. Methods: A retrospective analysis of 530 individuals from the Brazilian Amazon, including P. vivax-infected individuals who developed different clinical outcomes (148 asymptomatic malaria, 187 symptomatic malaria, 13 severe non-lethal malaria, and six severe lethal malaria) as well as 176 non-infected controls, was performed. Plasma levels of liver transaminases, bilirubins, creatinine, fibrinogen, C-reactive protein, superoxide dismutase (SOD)-1, haem oxygenase (HO)-1 and a panel composed by multiple cytokines and chemokines were measured and compared between the different clinical groups using network analysis. Results: Non-infected individuals displayed several statistically significant interactions in the networks, including associations between the levels of IL-10 and IL-4 with the chemokine CXCL9. Individuals with asymptomatic malaria displayed multiple significant interactions involving IL-4. Subjects with mild or severe non-lethal malaria displayed substantial loss of interactions in the networks and TNF had significant associations more frequently with other parameters. Cases of lethal P. vivax malaria infection were associated with significant interactions between TNF ALT, HO-1 and SOD-1. Conclusions: The findings imply that clinical immunity to P. vivax malaria is associated with multiple significant interactions in the network, mostly involving IL-4, while lethality is linked to a systematic reduction of complexity of these interactions and to an increase in connections between markers linked to haemolysis-induced damage. C1 [Mendonca, Vitor R. R.; Queiroz, Artur T. L.; Barral-Netto, Manoel] Fundacao Oswaldo Cruz, Ctr Pesquisas Goncalo Moniz, Salvador, BA, Brazil. [Mendonca, Vitor R. R.; Barral-Netto, Manoel] Univ Fed Bahia, Fac Med, Salvador, BA, Brazil. [Lopes, Fabricio M.] Univ Sao Paulo, Inst Matemat & Estat, Sao Paulo, Brazil. [Lopes, Fabricio M.] Univ Tecnol Fed Parana, Cornelio Procopio, Brazil. [Andrade, Bruno B.] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20893 USA. [Barral-Netto, Manoel] Inst Nacl Ciencia & Tecnol, Inst Invest Imunol, Sao Paulo, Brazil. RP Andrade, BB (reprint author), NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20893 USA. EM andradebd@niaid.nih.gov RI Barral Netto, Manoel/B-3904-2009; Andrade, Bruno/J-9111-2012; Queiroz, Artur/F-6083-2014; Lopes, Fabricio/F-6996-2010 OI Barral Netto, Manoel/0000-0002-5823-7903; Andrade, Bruno/0000-0001-6833-3811; Lopes, Fabricio/0000-0002-8786-3313 FU FINEP/FNDCT-CT Amazonia [010409605]; FIOCRUZ; CNPq; National Institute of Allergy and Infectious Diseases, National Institute of Health FX The authors thank David Kugler (NIAID, NIH, USA) for critical help with the data analysis and helpful discussions. A special thank to Joao Gambati (FUNASA, Brazil), Luis Marcelo Camargo (USP, Brazil) and the study team at FIOCRUZ-Bahia, Brazil, Daniela Andrade, Nivea Luz, Jorge Tolentino, Adorielze Leite, and Drs Aldina Barral and Jorge Clarencio for help in logistics of the field study and experiments involving cytokine measurements. This work was supported by FINEP/FNDCT-CT Amazonia [field work; grant # 010409605] and by FIOCRUZ. MB-N is a senior investigator from CNPq. VRRM is supported by CNPq. The work of BBA is supported by the intramural research programme of the National Institute of Allergy and Infectious Diseases, National Institute of Health. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 41 TC 21 Z9 22 U1 1 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 FEB 21 PY 2013 VL 12 AR 69 DI 10.1186/1475-2875-12-69 PG 10 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 119AM UT WOS:000317068900001 PM 23433077 ER PT J AU Jankovic, M Feldhahn, N Oliveira, TY Silva, IT Kieffer-Kwon, KR Yamane, A Resch, W Klein, I Robbiani, DF Casellas, R Nussenzweig, MC AF Jankovic, Mila Feldhahn, Niklas Oliveira, Thiago Y. Silva, Israel T. Kieffer-Kwon, Kyong-Rim Yamane, Arito Resch, Wolfgang Klein, Isaac Robbiani, Davide F. Casellas, Rafael Nussenzweig, Michel C. TI 53BP1 Alters the Landscape of DNA Rearrangements and Suppresses AID-Induced B Cell Lymphoma SO MOLECULAR CELL LA English DT Article ID INDUCED CYTIDINE DEAMINASE; CLASS SWITCH RECOMBINATION; DOUBLE-STRAND BREAKS; CHROMOSOMAL TRANSLOCATIONS; SOMATIC HYPERMUTATION; GENOMIC INSTABILITY; SEQUENCING REVEALS; TUMOR-SUPPRESSOR; C-MYC; DAMAGE AB Deficiencies in factors that regulate the DNA damage response enhance the incidence of malignancy by destabilizing the genome. However, the precise influence of the DNA damage response on regulation of cancer-associated rearrangements is not well defined. Here we examine the genome-wide impact of tumor protein P53-binding protein 1 (53BP1) deficiency in lymphoma and translocation. While both activation-induced cytidine deaminase (AID) and 53BP1 have been associated with cancer in humans, neither AID overexpression nor loss of 53BP1 is sufficient to produce malignancy. However, the combination of 53BP1 deficiency and AID deregulation results in B cell lymphoma. Deep sequencing of the genome of 53BP1(-/-) cancer cells and translocation capture sequencing (TC-Seq) of primary 53BP1(-/-) B cells revealed that their chromosomal rearrangements differ from those found in wildtype cells in that they show increased DNA end resection. Moreover, loss of 53BP1 alters the trans-locatome by increasing rearrangements to intergenic regions. C1 [Jankovic, Mila; Feldhahn, Niklas; Oliveira, Thiago Y.; Silva, Israel T.; Klein, Isaac; Robbiani, Davide F.; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Nussenzweig, Michel C.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA. [Kieffer-Kwon, Kyong-Rim; Yamane, Arito; Resch, Wolfgang; Casellas, Rafael] NIAMSD, NIH, Bethesda, MD 20892 USA. [Oliveira, Thiago Y.] Med Sch Ribeirao Preto USP, Dept Genet, BR-14051140 Sao Paulo, Brazil. [Oliveira, Thiago Y.; Silva, Israel T.] Natl Inst Sci & Technol Stem Cells & Cell Therapy, BR-14051140 Sao Paulo, Brazil. RP Casellas, R (reprint author), NIAMSD, NIH, Bethesda, MD 20892 USA. EM casellar@mail.nih.gov; nussen@rockefeller.edu RI Yamane, Arito/A-2959-2013; Silva, Israel/N-3858-2014; OI Silva, Israel/0000-0002-4687-1499; Oliveira, Thiago/0000-0002-2654-0879 FU NIH [AI037526] FX We thank all members of the Nussenzweig laboratory for discussions. We thank Dr F. Alt for helpful suggestions and discussions. We thank Klara Velinzon and Yelena Shatalina for cell sorting, and Thomas Eisenreich and David Bosque for help with mice. The work was supported by a NIH grant to M.C.N., number AI037526. N.F. was a Fellow of the Leukemia and Lymphoma Society. M.C.N. is a Howard Hughes Medical Institute Investigator. NR 61 TC 17 Z9 18 U1 2 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD FEB 21 PY 2013 VL 49 IS 4 BP 623 EP 631 DI 10.1016/j.molcel.2012.11.029 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 098NE UT WOS:000315555200007 PM 23290917 ER PT J AU Freeman, AK Ritt, DA Morrison, DK AF Freeman, Alyson K. Ritt, Daniel A. Morrison, Deborah K. TI Effects of Raf Dimerization and Its Inhibition on Normal and Disease-Associated Raf Signaling SO MOLECULAR CELL LA English DT Article ID FACIO-CUTANEOUS SYNDROME; B-RAF; ONCOGENIC RAS; MAPK PATHWAY; WILD-TYPE; A-RAF; BRAF; HETERODIMERIZATION; RESISTANCE; ACTIVATION AB Raf kinases are essential for normal Ras-Raf-MEK-ERK pathway signaling, and activating mutations in components of this pathway are associated with a variety of human cancers, as well as the related developmental disorders Noonan, LEOPARD, and cardiofaciocutaneous syndromes. Although the Raf kinases are known to dimerize during normal and disease-associated Raf signaling, the functional significance of Raf dimerization has not been fully elucidated. Here, using mutational analysis and a peptide inhibitor, we show that dimerization is required for normal Ras-dependent Raf activation and for the biological function of disease-associated Raf mutants with moderate, low, or impaired kinase activity. However, dimerization is not needed for the function of B-Raf mutants with high catalytic activity, such as V600E-B-Raf. Importantly, we find that a dimer interface peptide can effectively block Raf dimerization and inhibit Raf signaling when dimerization is required for Raf function, thus identifying the Raf dimer interface as a therapeutic target. C1 [Freeman, Alyson K.; Ritt, Daniel A.; Morrison, Deborah K.] NCI, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. RP Morrison, DK (reprint author), NCI, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. EM morrisod@mail.nih.gov FU National Cancer Institute FX We would like to thank Dr. Ming Zhou at SAIC-Frederick for assistance with the mass spectrometry analysis. This project was funded by federal funds from the National Cancer Institute. NR 22 TC 61 Z9 62 U1 0 U2 16 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD FEB 21 PY 2013 VL 49 IS 4 BP 751 EP 758 DI 10.1016/j.molcel.2012.12.018 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 098NE UT WOS:000315555200018 PM 23352452 ER PT J AU Modjarrad, K Mohraz, M Madani, N AF Modjarrad, Kayvon Mohraz, Minoo Madani, Navid TI Iran needs global support to fight HIV SO NATURE LA English DT Letter C1 [Modjarrad, Kayvon] NIAID, Bethesda, MD 20892 USA. [Mohraz, Minoo] Univ Tehran Med Sci, Tehran, Iran. [Madani, Navid] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Modjarrad, K (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM kayvon.modjarrad@nih.gov NR 1 TC 1 Z9 1 U1 0 U2 6 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 FEB 21 PY 2013 VL 494 IS 7437 BP 314 EP 314 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 095CS UT WOS:000315312900022 PM 23426315 ER PT J AU Burns, MB Lackey, L Carpenter, MA Rathore, A Land, AM Leonard, B Refsland, EW Kotandeniya, D Tretyakova, N Nikas, JB Yee, D Temiz, NIA Donohue, DE McDougle, RM Brown, WL Law, EK Harris, RS AF Burns, Michael B. Lackey, Lela Carpenter, Michael A. Rathore, Anurag Land, Allison M. Leonard, Brandon Refsland, Eric W. Kotandeniya, Delshanee Tretyakova, Natalia Nikas, Jason B. Yee, Douglas Temiz, Nuri I. A. Donohue, Duncan E. McDougle, Rebecca M. Brown, William L. Law, Emily K. Harris, Reuben S. TI APOBEC3B is an enzymatic source of mutation in breast cancer SO NATURE LA English DT Article ID SOMATIC HYPERMUTATION; CELL CARCINOMA; FOREIGN DNA; RESTRICTION; LANDSCAPE; DEAMINATION; MECHANISMS; GENOMES; AID AB Several mutations are required for cancer development, and genome sequencing has revealed that many cancers, including breast cancer, have somatic mutation spectra dominated by C-to-T transitions(1-9). Most of these mutations occur at hydrolytically disfavoured(10) non-methylated cytosines throughout the genome, and are sometimes clustered(8). Here we show that the DNA cytosine deaminase APOBEC3B is a probable source of these mutations. APOBEC3B messenger RNA is upregulated in most primary breast tumours and breast cancer cell lines. Tumours that express high levels of APOBEC3B have twice as many mutations as those that express low levels and are more likely to have mutations in TP53. Endogenous APOBEC3B protein is predominantly nuclear and the only detectable source of DNA C-to-U editing activity in breast cancer cell-line extracts. Knockdown experiments show that endogenous APOBEC3B correlates with increased levels of genomic uracil, increased mutation frequencies, and C-to-T transitions. Furthermore, induced APOBEC3B overexpression causes cell cycle deviations, cell death, DNA fragmentation, gamma-H2AX accumulation and C-to-T mutations. Our data suggest a model in which APOBEC3B-catalysed deamination provides a chronic source of DNA damage in breast cancers that could select TP53 inactivation and explain how some tumours evolve rapidly and manifest heterogeneity. C1 [Burns, Michael B.; Lackey, Lela; Carpenter, Michael A.; Rathore, Anurag; Land, Allison M.; Refsland, Eric W.; McDougle, Rebecca M.; Brown, William L.; Law, Emily K.; Harris, Reuben S.] Univ Minnesota, Biochem Mol Biol & Biophys Dept, Minneapolis, MN 55455 USA. [Burns, Michael B.; Lackey, Lela; Carpenter, Michael A.; Rathore, Anurag; Land, Allison M.; Leonard, Brandon; Refsland, Eric W.; Kotandeniya, Delshanee; Tretyakova, Natalia; Nikas, Jason B.; Yee, Douglas; McDougle, Rebecca M.; Brown, William L.; Law, Emily K.; Harris, Reuben S.] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA. [Burns, Michael B.; Lackey, Lela; Carpenter, Michael A.; Rathore, Anurag; Land, Allison M.; Leonard, Brandon; Refsland, Eric W.; McDougle, Rebecca M.; Brown, William L.; Law, Emily K.; Harris, Reuben S.] Univ Minnesota, Inst Mol Virol, Minneapolis, MN 55455 USA. [Burns, Michael B.; Lackey, Lela; Carpenter, Michael A.; Rathore, Anurag; Land, Allison M.; Leonard, Brandon; Refsland, Eric W.; McDougle, Rebecca M.; Brown, William L.; Law, Emily K.; Harris, Reuben S.] Univ Minnesota, Ctr Genome Engn, Minneapolis, MN 55455 USA. [Leonard, Brandon; Harris, Reuben S.] Univ Minnesota, Microbiol Canc Biol & Immunol Grad Program, Minneapolis, MN 55455 USA. [Kotandeniya, Delshanee; Tretyakova, Natalia] Univ Minnesota, Dept Med Chem, Minneapolis, MN 55455 USA. [Temiz, Nuri I. A.; Donohue, Duncan E.] SAIC Frederick Inc, In Silico Res Ctr Excellence, Adv Biomed Comp Ctr, Informat Syst Program,Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Harris, RS (reprint author), Univ Minnesota, Biochem Mol Biol & Biophys Dept, Minneapolis, MN 55455 USA. EM rsh@umn.edu OI Lackey, Lela/0000-0003-2163-4005; Burns, Michael/0000-0001-9791-4359 FU Academic Health Center; National Institutes of Health (NIH) [P30 CA77598, P50 CA101955, KL2 RR033182]; Cancer Biology Training Grant [NIH NCI T32 CA009138]; Department of Defense Breast Cancer Research Program Predoctoral Fellowship [BC101124]; National Science Foundation Predoctoral Fellowship; Institute for Molecular Virology Training Grant NIH [T32 AI083196]; NIH [F32 GM095219, F31 DA033186, R01 AI064046, NIH P01 GM091743, 1UL1RR033183]; CIHR; National Cancer Institute, NIH, CBIIT/caBIG ISRCE [09-260]; Children's Cancer Research Fund FX We thank J. Hultquist and R. Vogel for statistics, T. Hwang for bioinformatic assistance, V. Polunovsky for hTERT-HMECs, V. Simon for shRNA, S. Kaufmann, C. Lange and D. Largaespada for consultation, and the Masonic Cancer Center Breast Cancer Research Fund for purchasing the ATCC breast cancer panel. Tissues were obtained from the Masonic Cancer Center Tissue Procurement Facility, which is part of BioNet, supported by the Academic Health Center and National Institutes of Health (NIH) grants P30 CA77598 (D.Y.), P50 CA101955 (D. Buchsbaum) and KL2 RR033182 (B. Blazar). M.B.B. was supported in part by a Cancer Biology Training Grant (NIH NCI T32 CA009138) and a Department of Defense Breast Cancer Research Program Predoctoral Fellowship (BC101124). L.L. was supported in part by a National Science Foundation Predoctoral Fellowship and by a position on the Institute for Molecular Virology Training Grant NIH T32 AI083196. MAC. was supported by an NIH postdoctoral fellowship (F32 GM095219). A.M.L. was supported by a CIHR postdoctoral fellowship. E.W.R. was supported by a position on the Institute for Molecular Virology Training Grant NIH T32 AI083196 and subsequently by an NIH predoctoral fellowship (F31 DA033186). Computational analyses (N.A.T. and D.E.D.) were supported by federal funds from the National Cancer Institute, NIH, CBIIT/caBIG ISRCE yellow task 09-260. The Harris laboratory was supported in part by NIH R01 AI064046, NIH P01 GM091743, the Children's Cancer Research Fund, and a seed grant from the University of Minnesota Clinical and Translational Science Institute (supported by NIH 1UL1RR033183). NR 27 TC 235 Z9 238 U1 4 U2 64 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 FEB 21 PY 2013 VL 494 IS 7437 BP 366 EP 370 DI 10.1038/nature11881 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 095CS UT WOS:000315312900041 PM 23389445 ER PT J AU Rappaport, SM Berezhkovskii, AM Zimmerberg, J Bezrukov, SM AF Rappaport, Shay M. Berezhkovskii, Alexander M. Zimmerberg, Joshua Bezrukov, Sergey M. TI Thermodynamics of interleaflet cavitation in lipid bilayer membranes SO PHYSICAL REVIEW E LA English DT Article ID ELASTIC PROPERTIES; DRUG-DELIVERY; ULTRASOUND; LIPOSOMES; RELEASE AB Interleaflet cavitation in lipid bilayer membranes, or, shortly, intramembrane cavitation (IMC), is the formation of gas bubbles between the two leaflets of the membrane. The present paper focuses on the thermodynamics of IMC, namely, on the minimum work required to form an intramembrane cavity. The minimum work can be separated into two parts, one that depends on the volume and number of gas molecules in the bubble and another that depends on the bubble geometry. Minimization of the second part at a fixed bubble volume determines the optimized bubble shape. In homogeneous cavitation this part is proportional to the bubble surface area and therefore the bubble is spherical. In contrast, in IMC the second part is no longer a simple function of the bubble area and the optimized cavity is not spherical because of the finite elasticity of the membrane. Using a simplified assumption about the cavity shape, the geometry-dependent term is derived and minimized at a fixed cavity volume. It is found that the optimized cavity is almost spherical at large bubble volumes, while at small volumes the cavity has a lenslike shape. The optimized shape is used to analyze the minimum work of IMC. DOI: 10.1103/PhysRevE.87.022715 C1 [Rappaport, Shay M.; Berezhkovskii, Alexander M.; Zimmerberg, Joshua; Bezrukov, Sergey M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Rappaport, Shay M.; Zimmerberg, Joshua; Bezrukov, Sergey M.] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Berezhkovskii, Alexander M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Rappaport, SM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. FU Department of Defense through the Center for Neuroscience and Regenerative Medicine; Intramural Research Program of the NIH, Center for Information Technology; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX We are grateful to Valdimir Zitserman for helpful and illuminating discussions. This study was supported by the Department of Defense through the Center for Neuroscience and Regenerative Medicine and the Intramural Research Program of the NIH, Center for Information Technology, and Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 19 TC 1 Z9 1 U1 0 U2 16 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1539-3755 J9 PHYS REV E JI Phys. Rev. E PD FEB 21 PY 2013 VL 87 IS 2 AR 022715 DI 10.1103/PhysRevE.87.022715 PG 8 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 094RY UT WOS:000315282700009 PM 23496556 ER PT J AU Mertins, SD Scudiero, DA Hollingshead, MG Divelbiss, RD Alley, MC Monks, A Covell, DG Hite, KM Salomon, DS Niederhuber, JE AF Mertins, Susan D. Scudiero, Dominic A. Hollingshead, Melinda G. Divelbiss, Raymond D., Jr. Alley, Michael C. Monks, Anne Covell, David G. Hite, Karen M. Salomon, David S. Niederhuber, John E. TI A Small Molecule (Pluripotin) as a Tool for Studying Cancer Stem Cell Biology: Proof of Concept SO PLOS ONE LA English DT Article ID STEM/PROGENITOR CELLS; PROSPECTIVE IDENTIFICATION; GENE-EXPRESSION; TUMOR; DIFFERENTIATION; PROLIFERATION; INHIBITORS; CARCINOMA; REVEALS; PATHWAY AB Background: Cancer stem cells (CSC) are thought to be responsible for tumor maintenance and heterogeneity. Bona fide CSC purified from tumor biopsies are limited in supply and this hampers study of CSC biology. Furthermore, purified stem-like CSC subpopulations from existing tumor lines are unstable in culture. Finding a means to overcome these technical challenges would be a useful goal. In a first effort towards this, we examined whether a chemical probe that promotes survival of murine embryonic stem cells without added exogenous factors can alter functional characteristics in extant tumor lines in a fashion consistent with a CSC phenotype. Methodology/Principal Findings: The seven tumor lines of the NCI60 colon subpanel were exposed to SC-1 (pluripotin), a dual kinase and GTPase inhibitor that promotes self-renewal, and then examined for tumorigenicity under limiting dilution conditions and clonogenic activity in soft agar. A statistically significant increase in tumor formation following SC-1 treatment was observed (p<0.04). Cloning efficiencies and expression of putative CSC surface antigens (CD133 and CD44) were also increased. SC-1 treatment led to sphere formation in some colon tumor lines. Finally, SC-1 inhibited in vitro kinase activity of RSK2, and another RSK2 inhibitor increased colony formation implicating a role for this kinase in eliciting a CSC phenotype. Conclusions/Significance: These findings validate a proof of concept study exposure of extant tumor lines to a small molecule may provide a tractable in vitro model for understanding CSC biology. C1 [Mertins, Susan D.; Alley, Michael C.; Covell, David G.] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21701 USA. [Scudiero, Dominic A.; Monks, Anne; Hite, Karen M.] NCI, SAIC Frederick, Frederick, MD 21701 USA. [Hollingshead, Melinda G.; Divelbiss, Raymond D., Jr.] NCI, Biol Testing Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21701 USA. [Salomon, David S.] NCI, Mammary Biol & Tumorigenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Niederhuber, John E.] NCI, Cell & Canc Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Mertins, SD (reprint author), NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21701 USA. EM smertins@mail.nih.gov FU Division for Cancer Diagnosis and Treatment; Center for Cancer Research at the National Cancer Institute; NCI Contract [HHSN261200800001E] FX This study was supported by the Division for Cancer Diagnosis and Treatment and Center for Cancer Research at the National Cancer Institute and partially funded by NCI Contract HHSN261200800001E. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 2 Z9 2 U1 0 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 21 PY 2013 VL 8 IS 2 AR e57099 DI 10.1371/journal.pone.0057099 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 093IT UT WOS:000315186000076 PM 23437320 ER PT J AU Tammemagi, MC Katki, HA Hocking, WG Church, TR Caporaso, N Kvale, PA Chaturvedi, AK Silvestri, GA Riley, TL Commins, J Berg, CD AF Tammemaegi, Martin C. Katki, Hormuzd A. Hocking, William G. Church, Timothy R. Caporaso, Neil Kvale, Paul A. Chaturvedi, Anil K. Silvestri, Gerard A. Riley, Tom L. Commins, John Berg, Christine D. TI Selection Criteria for Lung-Cancer Screening SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RISK PREDICTION MODEL; RANDOMIZED PROSTATE; INCREMENTAL VALUE; CHEST RADIOGRAPH; TRIAL; VALIDATION; MORTALITY; SMOKERS AB BACKGROUND The National Lung Screening Trial (NLST) used risk factors for lung cancer (e. g., >= 30 pack-years of smoking and <15 years since quitting) as selection criteria for lung-cancer screening. Use of an accurate model that incorporates additional risk factors to select persons for screening may identify more persons who have lung cancer or in whom lung cancer will develop. METHODS We modified the 2011 lung-cancer risk-prediction model from our Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial to ensure applicability to NLST data; risk was the probability of a diagnosis of lung cancer during the 6-year study period. We developed and validated the model (PLCOM2012) with data from the 80,375 persons in the PLCO control and intervention groups who had ever smoked. Discrimination (area under the receiver-operating-characteristic curve [AUC]) and calibration were assessed. In the validation data set, 14,144 of 37,332 persons (37.9%) met NLST criteria. For comparison, 14,144 highest-risk persons were considered positive (eligible for screening) according to PLCOM2012 criteria. We compared the accuracy of PLCOM2012 criteria with NLST criteria to detect lung cancer. Cox models were used to evaluate whether the reduction in mortality among 53,202 persons undergoing low-dose computed tomographic screening in the NLST differed according to risk. RESULTS The AUC was 0.803 in the development data set and 0.797 in the validation data set. As compared with NLST criteria, PLCOM2012 criteria had improved sensitivity (83.0% vs. 71.1%, P<0.001) and positive predictive value (4.0% vs. 3.4%, P = 0.01), without loss of specificity (62.9% and. 62.7%, respectively; P = 0.54); 41.3% fewer lung cancers were missed. The NLST screening effect did not vary according to PLCOM2012 risk (P = 0.61 for interaction). CONCLUSIONS The use of the PLCOM2012 model was more sensitive than the NLST criteria for lung-cancer detection. C1 [Tammemaegi, Martin C.] Brock Univ, Dept Community Hlth Sci, St Catharines, ON L2S 3A1, Canada. [Katki, Hormuzd A.; Caporaso, Neil; Chaturvedi, Anil K.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Berg, Christine D.] NCI, Early Detect Res Grp, Canc Prevent Div, NIH, Rockville, MD USA. [Riley, Tom L.; Commins, John] Informat Management Serv Inc, Rockville, MD USA. [Hocking, William G.] Marshfield Clin Res Fdn, Marshfield, WI USA. [Church, Timothy R.] Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. [Kvale, Paul A.] Henry Ford Hlth Syst, Detroit, MI USA. [Silvestri, Gerard A.] Med Univ S Carolina, Charleston, SC USA. RP Tammemagi, MC (reprint author), Brock Univ, Dept Community Hlth Sci, Walker Complex S,Rm 306,500 Glenridge Ave, St Catharines, ON L2S 3A1, Canada. EM martin.tammemagi@brocku.ca RI Berg , Christine/K-1047-2014; Katki, Hormuzd/B-4003-2015; Chaturvedi, Anil/J-2024-2015; OI Chaturvedi, Anil/0000-0003-2696-8899; Hocking, William/0000-0002-0690-3759; Church, Timothy R./0000-0003-3292-5035 FU National Cancer Institute (NCI); Division of Cancer Prevention; Intramural Research Program of the Division of Cancer Epidemiology and Genetics; Cancer Imaging Program, Division of Cancer Treatment and Diagnosis [U01-CA-80098, U01-CA-79778] FX The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was supported by the National Cancer Institute (NCI), in part by contracts with the Division of Cancer Prevention and by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics. The American College of Radiology Imaging Network component of the National Lung Screening Trial (NLST) was supported by grants provided under a cooperative agreement with the Cancer Imaging Program, Division of Cancer Treatment and Diagnosis (U01-CA-80098 and U01-CA-79778). The Lung Screening Study sites of the NLST were supported by contracts with the Early Detection Research Group and Biometry Research Group, Division of Cancer Prevention (N01-CN-25514, to the University of Colorado-Denver; N01-CN-25522, to Georgetown University; N01-CN-25515, to the Pacific Health Research and Education Institute; N01-CN-25512, to the Henry Ford Health System; N01-CN-25513, to the University of Minnesota; N01-CN-25516, to Washington University in St. Louis; N01-CN-25511, to the University of Pittsburgh; N01-CN-25524, to the University of Utah; N01-CN-25518, to the Marshfield Clinic Research Foundation; N01-CN-75022, to the University of Alabama at Birmingham; N01-CN-25476, to Westat; and N02-CN-63300, to Information Management Services). NR 28 TC 154 Z9 166 U1 2 U2 30 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 21 PY 2013 VL 368 IS 8 BP 728 EP 736 DI 10.1056/NEJMoa1211776 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 092CG UT WOS:000315095800007 PM 23425165 ER PT J AU Zumla, A Raviglione, M Hafner, R von Reyn, CF AF Zumla, Alimuddin Raviglione, Mario Hafner, Richard von Reyn, C. Fordham TI CURRENT CONCEPTS Tuberculosis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID MULTIDRUG-RESISTANT TUBERCULOSIS; HIV-INFECTED ADULTS; ANTIRETROVIRAL THERAPY; PULMONARY TUBERCULOSIS; MYCOBACTERIUM-TUBERCULOSIS; ACTIVE TUBERCULOSIS; UNITED-STATES; TRIAL; PREVENTION; DIAGNOSIS C1 [Zumla, Alimuddin] UCL, Sch Med, Dept Infect, Div Infect & Immun, London W1N 8AA, England. [Raviglione, Mario] WHO, STOP TB Dept, Geneva, Switzerland. [Hafner, Richard] NIAID, TB Clin Res Branch, Div Aids, NIH, Bethesda, MD 20892 USA. [von Reyn, C. Fordham] Geisel Sch Med Dartmouth, Sect Infect Dis & Int Hlth, Hanover, NH USA. RP Zumla, A (reprint author), Ctr Clin Microbiol, Div Infect & Immun, 2nd Fl,UCL Royal Free Campus,Rowland Hill St, London NW3 OPE, England. EM a.zumla@ucl.ac.uk RI Rivet, Catherine/M-7978-2014; OI Zumla, Alimuddin/0000-0002-5111-5735 FU Oxford Immunotec FX Dr. von Reyn reports receiving consulting fees from Oxford Immunotec. No other potential conflict of interest relevant to this article was reported. NR 71 TC 259 Z9 273 U1 7 U2 105 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 21 PY 2013 VL 368 IS 8 BP 745 EP 755 DI 10.1056/NEJMra1200894 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 092CG UT WOS:000315095800009 PM 23425167 ER PT J AU Murphy, MP Siegel, RM AF Murphy, Michael P. Siegel, Richard M. TI Mitochondrial ROS Fire Up T Cell Activation SO IMMUNITY LA English DT Editorial Material ID SIGNAL-TRANSDUCTION AB Metabolic reprogramming has emerged as an important feature of immune cell activation. Two new studies, including Sena et al. (2013) in this issue of Immunity, identify mitochondrial reactive oxygen species (ROS) arising from metabolic reprogramming as signaling molecules in T cell activation. C1 [Murphy, Michael P.] MRC, Mitochondrial Biol Unit, Cambridge CB2 0XY, England. [Siegel, Richard M.] NIAMSD, Immunoregulat Sect, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. RP Siegel, RM (reprint author), NIAMSD, Immunoregulat Sect, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. EM rsiegel@nih.gov RI Murphy, Michael/C-2120-2009 OI Murphy, Michael/0000-0003-1115-9618 NR 9 TC 12 Z9 14 U1 1 U2 4 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 FEB 21 PY 2013 VL 38 IS 2 BP 201 EP 202 DI 10.1016/j.immuni.2013.02.005 PG 2 WC Immunology SC Immunology GA AA2RC UT WOS:000330940800001 PM 23438817 ER PT J AU Mandl, JN Monteiro, JP Vrisekoop, N Germain, RN AF Mandl, Judith N. Monteiro, Joao P. Vrisekoop, Nienke Germain, Ronald N. TI T Cell-Positive Selection Uses Self-Ligand Binding Strength to Optimize Repertoire Recognition of Foreign Antigens SO IMMUNITY LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; MHC CLASS-II; SENSORY ADAPTATION; NAIVE CD4(+); RECEPTOR; PEPTIDE; TCR; SPECIFICITY; AFFINITY; AVIDITY AB Developing T cells express diverse antigen receptors whose specificities are not prematched to the foreign antigens they eventually encounter. Past experiments have revealed that thymocytes must productively signal in response to self antigens to mature and enter the peripheral T cell pool (positive selection), but how this process enhances effective mature T cell responses to foreign antigen is not fully understood. Here we have documented an unsuspected connection between thymic recognition events and foreign antigen-driven T cell responses. We find that the strength of self-reactivity is a clone-specific property unexpectedly directly related to the strength of T cell receptor (TCR) binding to presented foreign antigen. T cells with receptors showing stronger interaction with self dominate in responses to infections and accumulate in aging individuals, revealing that positive selection contributes to effective immunity by skewing the mature TCR repertoire toward highly effective recognition of pathogens that pose a danger to the host. C1 [Mandl, Judith N.; Monteiro, Joao P.; Vrisekoop, Nienke; Germain, Ronald N.] NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. RP Germain, RN (reprint author), NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM rgermain@nih.gov FU NIAID, NIH, DHHS; Netherlands Organization for Scientific Research; NIH Office of AIDS Research FX The authors would like to thank J. Edwards for performing the CD5 sorts; N. Subramanian for assistance with immunoblots; M. Levy and A. Yates for statistical advice; Y. Belkaid for providing germ-free mice; P. Love for providing AND Cd5-/- mice; M. K. Jenkins and M. Pepper for providing L. monocytogenes Delta ActA, tetramer reagents, and assistance with the tetramer bead enrichment methodology; the NIH Tetramer Facility for providing pMHC tetramer reagents; G. Punkosdy and R. Ahmed for providing LCMV-Armstrong; P. Thomas and P. Doherty for providing the initial stock of influenza A virus; D. van Baarle for providing human blood samples and reagents; and N. Nanlohy for providing assistance with human experiments. We are grateful to I. Stefanova and M. Jenkins for discussion and technical advice, J.D. Ashwell, G. I. Germain, M.J. Lenardo, A. Poholek, and C. Reis e Sousa for their critical review of the manuscript, and members of the Lymphocyte Biology Section for intellectual support and critical discussions. This work was supported by the Intramural Research Program of NIAID, NIH, DHHS, and also by the Netherlands Organization for Scientific Research (N. V.) and by the NIH Office of AIDS Research (J.N.M.). J.P.M. is a Pew Latin American Fellow in the Biomedical Sciences. J.P.M., J.N.M., N. V., and R. N. G. designed the study. J.N.M., J.P.M., and N. V. conducted all experiments. All authors contributed to interpreting the data and writing the paper. NR 51 TC 74 Z9 75 U1 0 U2 6 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 FEB 21 PY 2013 VL 38 IS 2 BP 263 EP 274 DI 10.1016/j.immuni.2012.09.011 PG 12 WC Immunology SC Immunology GA AA2RC UT WOS:000330940800009 PM 23290521 ER PT J AU Cokic, VP Smith, RD Biancotto, A Noguchi, CT Puri, RK Schechter, AN AF Cokic, Vladan P. Smith, Reginald D. Biancotto, Angelique Noguchi, Constance T. Puri, Raj K. Schechter, Alan N. TI Globin gene expression in correlation with G protein-related genes during erythroid differentiation SO BMC GENOMICS LA English DT Article DE G protein; G protein-coupled receptors; Erythroid progenitors; Ontogeny; Globins ID SOLUBLE GUANYLYL CYCLASE; NITRIC-OXIDE-SYNTHASE; COUPLED RECEPTOR; FETAL-HEMOGLOBIN; K562 CELLS; BETA(2)-ADRENERGIC RECEPTOR; DEPENDENT ACTIVATION; HEMATOPOIETIC-CELLS; BINDING PROTEIN; CD34(+) CELLS AB Background: The guanine nucleotide binding protein (G protein)-coupled receptors (GPCRs) regulate cell growth, proliferation and differentiation. G proteins are also implicated in erythroid differentiation, and some of them are expressed principally in hematopoietic cells. GPCRs-linked NO/cGMP and p38 MAPK signaling pathways already demonstrated potency for globin gene stimulation. By analyzing erythroid progenitors, derived from hematopoietic cells through in vitro ontogeny, our study intends to determine early markers and signaling pathways of globin gene regulation and their relation to GPCR expression. Results: Human hematopoietic CD34(+) progenitors are isolated from fetal liver (FL), cord blood (CB), adult bone marrow (BM), peripheral blood (PB) and G-CSF stimulated mobilized PB (mPB), and then differentiated in vitro into erythroid progenitors. We find that growth capacity is most abundant in FL- and CB-derived erythroid cells. The erythroid progenitor cells are sorted as 100% CD71(+), but we did not find statistical significance in the variations of CD34, CD36 and GlyA antigens and that confirms similarity in maturation of studied ontogenic periods. During ontogeny, beta-globin gene expression reaches maximum levels in cells of adult blood origin (176 fmol/mu g), while gamma-globin gene expression is consistently up-regulated in CB-derived cells (60 fmol/mu g). During gamma-globin induction by hydroxycarbamide, we identify stimulated GPCRs (PTGDR, PTGER1) and GPCRs-coupled genes known to be activated via the cAMP/PKA (ADIPOQ), MAPK pathway (JUN) and NO/cGMP (PRPF18) signaling pathways. During ontogeny, GPR45 and ARRDC1 genes have the most prominent expression in FL-derived erythroid progenitor cells, GNL3 and GRP65 genes in CB-derived cells (high gamma-globin gene expression), GPR110 and GNG10 in BM-derived cells, GPR89C and GPR172A in PB-derived cells, and GPR44 and GNAQ genes in mPB-derived cells (high beta-globin gene expression). Conclusions: These results demonstrate the concomitant activity of GPCR-coupled genes and related signaling pathways during erythropoietic stimulation of globin genes. In accordance with previous reports, the stimulation of GPCRs supports the postulated connection between cAMP/PKA and NO/cGMP pathways in activation of.-globin expression, via JUN and p38 MAPK signaling. C1 [Cokic, Vladan P.] Univ Belgrade, Inst Med Res, Lab Expt Hematol, Belgrade 11129, Serbia. [Smith, Reginald D.] GE Global Res Ctr, Niskayuna, NY USA. [Biancotto, Angelique] NHLBI, Ctr Human Immunol, NIH, Bethesda, MD 20892 USA. [Noguchi, Constance T.; Schechter, Alan N.] NIDDKD, Mol Med Branch, NIH, Bethesda, MD 20892 USA. [Puri, Raj K.] US FDA, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. RP Cokic, VP (reprint author), Univ Belgrade, Inst Med Res, Lab Expt Hematol, Dr Subotica 4, Belgrade 11129, Serbia. EM vl@imi.bg.ac.rs OI Schechter, Alan N/0000-0002-5235-9408 FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; Serbian Ministry of Education and Science [175053] FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and by grant from the Serbian Ministry of Education and Science [175053]. NR 46 TC 6 Z9 6 U1 0 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 FEB 20 PY 2013 VL 14 AR 116 DI 10.1186/1471-2164-14-116 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 109WV UT WOS:000316401900001 PM 23425329 ER PT J AU Yamazaki, Y Schonherr, C Varshney, GK Dogru, M Hallberg, B Palmer, RH AF Yamazaki, Yasuo Schoenherr, Christina Varshney, Gaurav K. Dogru, Murat Hallberg, Bengt Palmer, Ruth H. TI Goliath family E3 ligases regulate the recycling endosome pathway via VAMP3 ubiquitylation SO EMBO JOURNAL LA English DT Article DE E3 ubiquitin ligase; goliath; RING domain; SNARE; VAMP3 ID MEMBRANE-FUSION; SNARE COMPLEX; UBIQUITIN LIGASES; MEDIATED CLEAVAGE; CRYSTAL-STRUCTURE; CELL-MIGRATION; ZINC-FINGER; GENOME-WIDE; DROSOPHILA; PROTEIN AB Diverse cellular processes depend on endocytosis, intracellular vesicle trafficking, sorting and exocytosis, processes regulated post-transcriptionally by modifications such as phosphorylation and ubiquitylation. In addition to sorting to the lysosome, cargo is recycled to the plasma membrane via recycling endosomes. Here, we describe a role of the goliath gene family of protease-associated (PA) domain E3 ligases in regulating recycling endosome trafficking. The two Drosophila members of this family-Goliath and Godzilla(CG10277) - are located on endosomes, and both ectopic expression and loss-of-function lead to the accumulation of Rab5-positive giant endosomes. Furthermore, the human homologue RNF167 exhibits similar behaviour. We show that the soluble N-ethylmaleimide-sensitive fusion attachment protein receptor (SNARE) protein VAMP3 is a target of these ubiquitin ligases, and that recycling endosome trafficking is abrogated in response to their activity. Furthermore, mutation of the Godzilla ubiquitylation target lysines on VAMP3 abrogates the formation of enlarged endosomes induced by either Godzilla or RNF167. Thus, Goliath ubiquitin ligases play a novel role in regulating recycling endosome trafficking via ubiquitylation of the VAMP3 SNARE protein. The EMBO Journal (2013) 32, 524-537. doi: 10.1038/emboj.2013.1; Published online 25 January 2013 C1 [Yamazaki, Yasuo; Schoenherr, Christina; Dogru, Murat; Hallberg, Bengt; Palmer, Ruth H.] Umea Univ, Dept Mol Biol, S-90187 Umea, Sweden. [Varshney, Gaurav K.] NHGRI, Dev Genom Sect, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Palmer, RH (reprint author), Umea Univ, Dept Mol Biol, S-90187 Umea, Sweden. EM ruth.palmer@ucmp.umu.se RI Varshney, Gaurav/L-5261-2014; OI Varshney, Gaurav K./0000-0002-0429-1904 FU Swedish Cancer Society [11-0336]; Children's Cancer Foundation [10/065]; Swedish Research Council [621-2011-5181]; Lions Cancer Society, Umea; Association for International Cancer Research [08-0177] FX This work has been supported by grants from the Swedish Cancer Society (RHP 11-0336), the Children's Cancer Foundation (RHP 10/065), the Swedish Research Council (RHP 621-2011-5181), Lions Cancer Society, Umea, Association for International Cancer Research (RHP 08-0177). RHP is a Swedish Cancer Foundation Research Fellow. NR 57 TC 8 Z9 9 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD FEB 20 PY 2013 VL 32 IS 4 BP 524 EP 537 DI 10.1038/emboj.2013.1 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 110SX UT WOS:000316467200006 PM 23353890 ER PT J AU Keren-Kaplan, T Attali, I Estrin, M Kuo, LS Farkash, E Jerabek-Willemsen, M Blutraich, N Artzi, S Peri, A Freed, EO Wolfson, HJ Prag, G AF Keren-Kaplan, Tal Attali, Ilan Estrin, Michael Kuo, Lillian S. Farkash, Efrat Jerabek-Willemsen, Moran Blutraich, Noa Artzi, Shay Peri, Aviyah Freed, Eric O. Wolfson, Haim J. Prag, Gali TI Structure-based in silico identification of ubiquitin-binding domains provides insights into the ALIX-V: ubiquitin complex and retrovirus budding SO EMBO JOURNAL LA English DT Article DE computational analyses; in silico scan; protein trafficking; ubiquitin; virus budding ID FIT BACKBONE REFINEMENT; MOLECULAR DOCKING; FUNCTIONAL REPLACEMENT; CUE DOMAIN; ESCRT-III; PROTEIN; RECOGNITION; HIV-1; ENDOCYTOSIS; PERMEASE AB The ubiquitylation signal promotes trafficking of endogenous and retroviral transmembrane proteins. The signal is decoded by a large set of ubiquitin (Ub) receptors that tether Ub-binding domains (UBDs) to the trafficking machinery. We developed a structure-based procedure to scan the protein data bank for hidden UBDs. The screen retrieved many of the known UBDs. Intriguingly, new potential UBDs were identified, including the ALIX-V domain. Pull-down, cross-linking and E3-independent ubiquitylation assays biochemically corroborated the in silico findings. Guided by the output model, we designed mutations at the postulated ALIX-V: Ub interface. Biophysical affinity measurements using microscale-thermophoresis of wild-type and mutant proteins revealed some of the interacting residues of the complex. ALIX-V binds mono-Ub with a K-d of 119 mu M. We show that ALIX-V oligomerizes with a Hill coefficient of 5.4 and IC50 of 27.6 mu M and that mono-Ub induces ALIX-V oligomerization. Moreover, we show that ALIX-V preferentially binds K63 di-Ub compared with mono-Ub and K48 di-Ub. Finally, an in vivo functionality assay demonstrates the significance of ALIX-V: Ub interaction in equine infectious anaemia virus budding. These results not only validate the new procedure, but also demonstrate that ALIX-V directly interacts with Ub in vivo and that this interaction can influence retroviral budding. The EMBO Journal (2013) 32, 538-551. doi: 10.1038/emboj.2013.4; Published online 29 January 2013 C1 [Keren-Kaplan, Tal; Attali, Ilan; Blutraich, Noa; Artzi, Shay; Prag, Gali] Tel Aviv Univ, Dept Biochem & Mol Biol, IL-69978 Tel Aviv, Israel. [Keren-Kaplan, Tal; Attali, Ilan; Blutraich, Noa; Artzi, Shay; Prag, Gali] Tel Aviv Univ, George S Wise Fac Life Sci, Rich Inst Struct Biol, IL-69978 Tel Aviv, Israel. [Estrin, Michael; Farkash, Efrat; Peri, Aviyah; Wolfson, Haim J.] Tel Aviv Univ, Raymond & Beverly Sackler Fac Exact Sci, Blavatnik Sch Comp Sci, IL-69978 Tel Aviv, Israel. [Kuo, Lillian S.; Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Natl Lab Canc Res, Frederick, MD 21701 USA. [Jerabek-Willemsen, Moran] NanoTemper Technol GmbH, Munich, Germany. RP Prag, G (reprint author), Tel Aviv Univ, Dept Biochem & Mol Biol, IL-69978 Tel Aviv, Israel. EM prag@tau.ac.il FU Israeli Science Foundation [1695/08, 464/11]; EC FP7 Marie Curie International Reintegration Grant [PIRG03-GA-2008-231079]; Israeli Ministry of Health [5108]; Marianna and Jorge Saia Fund for HIV and Parkinson Diseases; Center for Cancer Research, National Cancer Institute, NIH; Intramural AIDS Targeted Antiviral Programme; Israel Science Foundation (ISF) [1403/09]; Minerva-Minkowski Center for Geometry; Adams Fellowship Fund FX We wish to thank Neta Tanner and Bella Zion for technical help and James Hurley for kindly providing the pGST-ALIX-V vector. This research was supported by grants from the Israeli Science Foundation (grants numbers 1695/08 and 464/11), from the EC FP7 Marie Curie International Reintegration Grant (PIRG03-GA-2008-231079), from the Israeli Ministry of Health (5108), and the Marianna and Jorge Saia Fund for HIV and Parkinson Diseases to GP. The Constantiner Institute for Molecular Genetics for travel support to TKK Research in the EOF laboratory is supported by the Intramural Research Programme of the Center for Cancer Research, National Cancer Institute, NIH, and by the Intramural AIDS Targeted Antiviral Programme. The Research of HJW was partially supported by Israel Science Foundation (ISF grant no. 1403/09) and the Minerva-Minkowski Center for Geometry. EF was supported by the Adams Fellowship Fund. NR 59 TC 26 Z9 27 U1 1 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0261-4189 EI 1460-2075 J9 EMBO J JI Embo J. PD FEB 20 PY 2013 VL 32 IS 4 BP 538 EP 551 DI 10.1038/emboj.2013.4 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 110SX UT WOS:000316467200007 PM 23361315 ER PT J AU Wendel, SK Mullis, CE Eshleman, SH Blankson, JN Moore, RD Keruly, JC Brookmeyer, R Quinn, TC Laeyendecker, O AF Wendel, Sarah K. Mullis, Caroline E. Eshleman, Susan H. Blankson, Joel N. Moore, Richard D. Keruly, Jeanne C. Brookmeyer, Ron Quinn, Thomas C. Laeyendecker, Oliver TI Effect of Natural and ARV-Induced Viral Suppression and Viral Breakthrough on Anti-HIV Antibody Proportion and Avidity in Patients with HIV-1 Subtype B Infection SO PLOS ONE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; BED-ENZYME IMMUNOASSAY; ANTIRETROVIRAL THERAPY; ELITE SUPPRESSORS; SEROCONVERSION; INDIVIDUALS; CHALLENGES; PREVENTION; MARYLAND; ASSAYS AB Background: Viral suppression and viral breakthrough impact the humoral immune response to HIV infection. We evaluated the impact of viral suppression and viral breakthrough on results obtained with two cross-sectional HIV incidence assays. Methods: All samples were collected from adults in the US who were HIV infected for >2 years. Samples were tested with the BED capture enzyme immunoassay (BED-CEIA) which measures the proportion of IgG that is HIV-specific, and with an antibody avidity assay based on the Genetic Systems 1/2+ O ELISA. We tested 281 samples: (1) 30 samples from 18 patients with natural control of HIV-1 infection known as elite controllers or suppressors (2) 72 samples from 18 adults on antiretroviral therapy (ART), with 1 sample before and 2-6 samples after ART initiation, and (3) 179 samples from 20 virally-suppressed adults who had evidence of viral breakthrough receiving ART (>400 copies/ml HIV RNA) and with subsequent viral suppression. Results: For elite suppressors, 10/18 had BED-CEIA values <0.8 normalized optical density units (OD-n) and these values did not change significantly over time. For patients receiving ART, 14/18 had BED-CEIA values that decreased over time, with a median decrease of 0.42 OD-n (range 0.10 to 0.63)/time point receiving ART. Three patterns of BED-CEIA values were observed during viral breakthrough: (1) values that increased then returned to pre-breakthrough values when viral suppression was re-established, (2) values that increased after viral breakthrough, and (3) values that did not change with viral breakthrough. Conclusions: Viral suppression and viral breakthrough were associated with changes in BED-CEIA values, reflecting changes in the proportion of HIV-specific IgG. These changes can result in misclassification of patients with long-term HIV infection as recently infected using the BED-CEIA, thereby influencing a falsely high value for cross-sectional incidence estimates. C1 [Wendel, Sarah K.; Quinn, Thomas C.; Laeyendecker, Oliver] NIAID, Div Intramural Res, NIH, Baltimore, MD USA. [Mullis, Caroline E.; Blankson, Joel N.; Moore, Richard D.; Keruly, Jeanne C.; Quinn, Thomas C.; Laeyendecker, Oliver] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Eshleman, Susan H.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Brookmeyer, Ron] Univ Calif Los Angeles, Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90024 USA. RP Laeyendecker, O (reprint author), NIAID, Div Intramural Res, NIH, Baltimore, MD USA. EM olaeyen1@jhmi.edu RI Laeyendecker, Oliver/B-9331-2009; OI Laeyendecker, Oliver/0000-0002-6429-4760 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH); HIV Prevention Trials Network; NIAID [R01-AI-80328, R24-AI-067039]; National Institutes of Child Health and Human Development; National Institute on Drug Abuse (NIDA) [R01-DA-11602]; National Institute of Mental Health; Office of AIDS Research, of the NIH, Department of Health and Human Services [UM1-AI068613]; National Institute on Alcohol Abuse and Alcoholism [R01-AA16893] FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). Additional support was provided by the HIV Prevention Trials Network sponsored by NIAID, National Institutes of Child Health and Human Development, National Institute on Drug Abuse (NIDA), National Institute of Mental Health, and Office of AIDS Research, of the NIH, Department of Health and Human Services (UM1-AI068613). The Johns Hopkins HIV Clinical Practice Cohort was supported by NIDA (R01-DA-11602), National Institute on Alcohol Abuse and Alcoholism (R01-AA16893), NIAID (R01-AI-80328) and NIAID (R24-AI-067039). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 17 Z9 17 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 20 PY 2013 VL 8 IS 2 AR e55525 DI 10.1371/journal.pone.0055525 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 093IE UT WOS:000315184200020 PM 23437058 ER PT J AU Morse, CG Dodd, LE Nghiem, K Costello, R Csako, G Lane, HC Lozier, JN Kovacs, JA AF Morse, Caryn G. Dodd, Lori E. Nghiem, Khanh Costello, Rene Csako, Gyorgy Lane, H. Clifford Lozier, Jay N. Kovacs, Joseph A. TI Elevations in D-dimer and C-reactive protein are associated with the development of osteonecrosis of the hip in HIV-infected adults SO AIDS LA English DT Article DE C-reactive protein; D-dimer; HIV; osteonecrosis ID HUMAN-IMMUNODEFICIENCY-VIRUS; FEMORAL-HEAD; COAGULATION BIOMARKERS; ANTIRETROVIRAL THERAPY; DISEASE; BONE; HYPOFIBRINOLYSIS; SENSITIVITY; INHIBITOR; MORTALITY AB Background: A high incidence of nontraumatic osteonecrosis has been reported in HIV-infected patients. We investigated the levels of D-dimer and C-reactive protein (CRP) in a cohort of HIV-infected adults with and without osteonecrosis of the femoral head. Methods: Forty-three HIV-infected patients with osteonecrosis of the femoral head and a comparison group of 50 HIV-infected patients with negative MRI of the hips and for whom serial plasma samples were available were included. D-dimer and CRP levels were measured prior to and at the time of diagnosis for osteonecrosis patients, at the time of negative MRI of the hips for controls, and at least 6 months later for both groups. Results: Biomarker levels were elevated at the time of diagnosis in the osteonecrosis cohort compared with controls. Median D-dimer value was 0.32 mu g/ml in the osteonecrosis group compared with less than 0.22 mu g/ml in the control group (P = 0.016). For CRP, the corresponding values were 2.52 mg/l and 1.23 mg/l (P = 0.003). Postdiagnosis, D-dimer and CRP levels were also elevated in the osteonecrosis patients compared with controls. Linear regression demonstrated a rise in D-dimer levels from prediagnosis to diagnosis in the osteonecrosis patients whereas CRP levels did not change significantly over time. Conclusion: Compared to controls, patients who developed osteonecrosis had elevated levels of D-dimer and CRP at diagnosis. D-dimer levels increased whereas CRP levels did not change significantly from prediagnosis to diagnosis. These data suggest that patients with higher levels of inflammation are at an increased risk of osteonecrosis. (C) 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins AIDS 2013, 27: 591-595 C1 [Morse, Caryn G.; Kovacs, Joseph A.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Dodd, Lori E.] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. [Nghiem, Khanh; Costello, Rene; Csako, Gyorgy; Lozier, Jay N.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Lane, H. Clifford] NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. RP Morse, CG (reprint author), Bldg 10,Room 5A06,MSC 1403, Bethesda, MD 20892 USA. EM cmorse@mail.nih.gov OI Morse, Caryn/0000-0002-1177-4365 FU NIH Clinical Center; National Institute of Allergy and Infectious Diseases FX This research was supported by the Intramural Research Programs of the NIH Clinical Center and the National Institute of Allergy and Infectious Diseases. NR 23 TC 6 Z9 6 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD FEB 20 PY 2013 VL 27 IS 4 BP 591 EP 595 DI 10.1097/QAD.0b013e32835c206a PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 094SM UT WOS:000315284100011 PM 23169328 ER PT J AU Lacombe, JM Boue, F Grabar, S Viget, N Gazaignes, S Lascaux-Cametz, AS Pacanowski, J Partisani, M Launay, O Matheron, S Rosenthal, E Rouveix, E Tattevin, P de Truchis, P Costagliola, D Goedert, JJ AF Lacombe, Jean-Marc Boue, Francois Grabar, Sophie Viget, Nathalie Gazaignes, Sandrine Lascaux-Cametz, Anne-Sophie Pacanowski, Jerome Partisani, Marialuisa Launay, Odile Matheron, Sophie Rosenthal, Eric Rouveix, Elisabeth Tattevin, Pierre de Truchis, Pierre Costagliola, Dominique Goedert, James J. TI Risk of Kaposi sarcoma during the first months on combination antiretroviral therapy SO AIDS LA English DT Article DE combination antiretroviral therapy; immune reconstitution; inflammatory syndrome; Kaposi sarcoma; Pneumocystis jiroveci pneumonia; prospective cohort study ID RECONSTITUTION INFLAMMATORY SYNDROME; CD4(+) T-CELLS; IMMUNE RECONSTITUTION; HOMOSEXUAL-MEN; HIV; HERPESVIRUS; PREDICTORS; INFECTION; LYMPHOMA; SURVIVAL AB Objective: To determine whether incident AIDS-defining Kaposi sarcoma or Pneumocystis jiroveci pneumonia (PJP) is associated with combination antiretroviral therapy (cART) initiation. Design: Compare risk for Kaposi sarcoma and PJP by time on cART and CD4 reconstitution. Methods: In the FHDH-ANRS CO4 cohort (N = 66 369), Kaposi sarcoma (N = 1811) and PJP (N = 1718) incidence rates were computed by demographic and HIV strata. Crude and adjusted relative risk (RR) with 95% confidence intervals (CIs) following cART initiation were calculated by Poisson regression with untreated patients during 1996-2009 as reference. CD4 cell counts were compared by Wilcoxon rank sum tests. Results: The risk of Kaposi sarcoma was very high during months 1-3 on cART (N = 160, RRCrude 3.94, 95% Cl 3.26-4.76), which was incompletely attenuated by adjustment for demographics and contemporaneous CD4 cell count (RRAdj 1.25, 95% Cl 1.02-1.53). Corresponding PJP risk was minimally elevated (N = 84, RRCrude 1.80, 95% Cl 1.42-2.30) and markedly reduced with adjustment on the same variables and PJP prophylaxis (RRAdj 0.52, Cl 0.41-0.67). HIV load had no added effect. Median CD4 cell count at cART initiation was much lower in patients with incident Kaposi sarcoma (82 cells/mu l) or PJP (61 cells/mu l) within 3 months than in those who did not develop these conditions (> 250 cells/mu l). Notably, median CD4 cell count change was +44 cells/mu l per month with incident Kaposi sarcoma within 3 months of cART initiation versus 0 cells/mu l per month with incident PJP (P = 0.0003). Conclusion: Failure of CD4 cell count reconstitution during months 1-3 on cART fully accounted for incident PJP. In contrast, there were 1.6 additional Kaposi sarcoma cases per 1000 person-years during months 1-3 on cART, suggesting that immune reconstitution may contribute to the risk for AIDS-defining Kaposi sarcoma. (C) 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins AIDS 2013, 27:635-643 C1 [Lacombe, Jean-Marc] Univ Paris 06, INSERM, UMR S 943, INSERM TRANSFERT, Paris, France. [Boue, Francois] Univ Paris Sud, Serv Med Interne & Immunol Clin, Hop Antoine Beclere, AP HP, Clamart, France. [Grabar, Sophie] Univ Paris 05, Grp Hosp Cochin Hotel Dieu, AP HP, Unite Biostat & Epidemiol,INSERM UMR S 943, Paris, France. [Viget, Nathalie] Ctr Hosp Tourcoing, Serv Univ Malad Infect & Voyage, Tourcoing, France. [Gazaignes, Sandrine] Hop St Louis, AP HP, Serv Malad Infect & Trop, Paris, France. [Lascaux-Cametz, Anne-Sophie] Hop Henri Mondor, AP HP, Serv Immunol Clin, F-94010 Creteil, France. [Pacanowski, Jerome] Hop St Antoine, AP HP, Serv Malad Infect & Trop, F-75571 Paris, France. [Partisani, Marialuisa] Hop Univ Strasbourg, Le Trait Union Ctr Soins Infect VIH, Strasbourg, France. [Launay, Odile] Univ Paris 05, Hop Cochin, AP HP, Paris, France. [Matheron, Sophie] Univ Paris 07, Hop Bichat Claude Bernard, AP HP, Serv Malad Infect & Trop, Paris, France. [Rosenthal, Eric] Univ Nice Sophia Antipolis, Dept Med Interne, Hop Archet, Nice, France. [Rouveix, Elisabeth] Hop Ambroise Pare, Serv Med Interne, Boulogne, France. [Tattevin, Pierre] CHU Pontchaillou, Serv Malad Infect & Reanimat Med, Rennes, France. [de Truchis, Pierre] Hop Raymond Poincare, AP HP, Serv Med Aigue Specialisee, Garches, France. [Costagliola, Dominique] Univ Paris 06, INSERM, UMR S 943, Paris, France. RP Goedert, JJ (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 7068, Rockville, MD 20852 USA. EM goedertj@mail.nih.gov RI Costagliola, Dominique/H-5849-2011; Matheron, Sophie/D-7420-2017 OI Costagliola, Dominique/0000-0003-0765-0869; Matheron, Sophie/0000-0001-7879-6553 FU Agence Nationale de Recherches sur le SIDA et les hepatites (ANRS); INSERM; INSERM and the French Ministry of Health; ANRS; National Cancer Institute; National Institutes of Health FX The French Hospital Database on HIV is supported by Agence Nationale de Recherches sur le SIDA et les hepatites (ANRS), INSERM and the French Ministry of Health.; This work, specifically the French Hospital Database on HIV, was supported by ANRS, INSERM and the French Ministry of Health, and the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 32 TC 12 Z9 13 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD FEB 20 PY 2013 VL 27 IS 4 BP 635 EP 643 DI 10.1097/QAD.0b013e32835cba6c PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 094SM UT WOS:000315284100016 PM 23196937 ER PT J AU Schonfeld, SJ de Gonzalez, AB Visvanathan, K Pfeiffer, RM Anderson, WF AF Schonfeld, Sara J. de Gonzalez, Amy Berrington Visvanathan, Kala Pfeiffer, Ruth M. Anderson, William F. TI Declining Second Primary Ovarian Cancer After First Primary Breast Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID UNITED-STATES; RANDOMIZED-TRIALS; WOMEN; RISK; SURVIVORS; SUBSEQUENT; TRENDS AB Purpose Although ovarian cancer incidence rates have declined in the United States, less is known of ovarian cancer trends among survivors of breast cancer. Therefore, we examined second primary ovarian cancers after first primary breast cancer. Methods Data were obtained from the Surveillance, Epidemiology, and End Results program (1973 to 2008). Standardized incidence ratios (SIRs) were calculated as the observed numbers of ovarian cancers among survivors of breast cancer compared with the expected numbers in the general population. Absolute rates were measured as the incidence rates for second primary ovarian cancer by year of diagnosis of the first primary breast cancer adjusted for age of breast cancer diagnosis and years since diagnosis. Results SIRs for second primary ovarian cancer were elevated over the entire study period (SIR, 1.24; 95% CI, 1.2 to 1.3), whereas the absolute rates declined with an estimated annual percentage change near 1% (-1.34% to -0.09% per year). Secular trends for second ovarian cancers were similar after estrogen receptor (ER) -positive and ER-negative breast cancers, whereas the age-specific patterns varied significantly by ER expression (P for interaction < .001). The largest SIR was among women age less than 50 years with ER-negative breast cancer (SIR, 4.35; 95% CI, 3.5 to 5.4). Conclusion Persistently elevated SIRs along with decreasing absolute rates over the entire study period suggest that ovarian cancers in both the general population and survivors of breast cancer are declining in parallel, possibly because of common risk factor exposures. Analytic studies are needed to further assess the parallel overall trends and the age-specific interaction by ER expression. J Clin Oncol 31:738-743. (C) 2013 by American Society of Clinical Oncology C1 [Schonfeld, Sara J.; de Gonzalez, Amy Berrington; Pfeiffer, Ruth M.; Anderson, William F.] NCI, DHHS, NIH, Bethesda, MD 20892 USA. [Visvanathan, Kala] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Anderson, WF (reprint author), NCI, Dept Hlth & Human Serv, NIH, Execut Plaza S,Room 8036,6120 Execut Blvd, Rockville, MD 20852 USA. EM wanderso@mail.nih.gov FU National Institutes of Health, National Cancer Institute FX Supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 30 TC 3 Z9 4 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 20 PY 2013 VL 31 IS 6 BP 738 EP 743 DI 10.1200/JCO.2012.43.2757 PG 6 WC Oncology SC Oncology GA 091YT UT WOS:000315086400023 PM 23284037 ER PT J AU Davidson-Moncada, JK McDuffee, E Roschewski, M AF Davidson-Moncada, Jan K. McDuffee, Emily Roschewski, Mark TI CD5(+) Diffuse Large B-Cell Lymphoma With Hemophagocytosis SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CLINICOPATHOLOGICAL CHARACTERISTICS; EXPRESSION; LYMPHOHISTIOCYTOSIS; CHEMOTHERAPY; RITUXIMAB C1 [Davidson-Moncada, Jan K.] NCI, Bethesda, MD 20892 USA. [McDuffee, Emily; Roschewski, Mark] Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. RP Davidson-Moncada, JK (reprint author), NCI, Bethesda, MD 20892 USA. OI Roschewski, Mark/0000-0003-0278-2635 NR 30 TC 3 Z9 3 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 20 PY 2013 VL 31 IS 6 BP E76 EP E79 DI 10.1200/JCO.2012.44.2301 PG 4 WC Oncology SC Oncology GA 091YT UT WOS:000315086400003 PM 23182983 ER PT J AU Baydyuk, M Xie, YX Tessarollo, L Xu, BJ AF Baydyuk, Maryna Xie, Yuxiang Tessarollo, Lino Xu, Baoji TI Midbrain-Derived Neurotrophins Support Survival of Immature Striatal Projection Neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article ID CRE RECOMBINASE; BASAL GANGLIA; CELL-DEATH; BRAIN; MICE; RECEPTOR; TRKB; HIPPOCAMPAL; INNERVATION; EXPRESSION AB Neuronal death occurs at several stages during embryogenesis and early postnatal development; however, it is unknown how the survival of immature neurons at their origin is regulated before these cells migrate to their final destination. Striatal projection neurons, known as medium-sized spiny neurons (MSNs), in both the direct and indirect pathways are generated in the lateral ganglionic eminence (LGE). Here we report that brain-derived neurotrophic factor and neurotrophin-3 are anterogradely transported from midbrain dopaminergic neurons and support the survival of immature MSNs of the indirect and direct pathways, respectively, in the developing mouse striatum and LGE. These results reveal a novel mode of neurotrophic action in the nervous system by linking neurotrophins to the survival of immature neurons at their origin, while also suggesting that innervating neurons may control the size of their targeting neuronal population in the brain. C1 [Baydyuk, Maryna; Xie, Yuxiang; Xu, Baoji] Georgetown Univ, Dept Physiol & Pharmacol, Med Ctr, Washington, DC 20057 USA. [Tessarollo, Lino] NCI, Neural Dev Sect, Ctr Canc Res, Frederick, MD 21702 USA. RP Xu, BJ (reprint author), Georgetown Univ, Dept Physiol & Pharmacol, Med Ctr, 3900 Reservoir Rd NW, Washington, DC 20057 USA. EM bx3@georgetown.edu FU US National Institutes of Health [R01 NS050596] FX This work was supported by a grant from the US National Institutes of Health to B. X. (R01 NS050596). We thank Nicole Calakos for Drd1a-tdTomato mice, Stefano Vicini for Drd2-EGFP mice, and Eric Huang for Th-Cre mice. NR 24 TC 9 Z9 10 U1 0 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 FEB 20 PY 2013 VL 33 IS 8 BP 3363 EP 3369 DI 10.1523/JNEUROSCI.3687-12.2013 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 093MJ UT WOS:000315195700012 PM 23426664 ER PT J AU Rhodes, SEV Murray, EA AF Rhodes, Sarah E. V. Murray, Elisabeth A. TI Differential Effects of Amygdala, Orbital Prefrontal Cortex, and Prelimbic Cortex Lesions on Goal-Directed Behavior in Rhesus Macaques SO JOURNAL OF NEUROSCIENCE LA English DT Article ID ANTERIOR CINGULATE CORTEX; REWARD-GUIDED BEHAVIOR; ORBITOFRONTAL CORTEX; BASOLATERAL AMYGDALA; REINFORCER DEVALUATION; ACTION SELECTION; DOUBLE DISSOCIATION; INSTRUMENTAL ACTION; DECISION-MAKING; FRONTAL-CORTEX AB We assessed the involvement of the orbital prefrontal cortex (PFo), the prelimbic region of the medial prefrontal cortex (PL), and the amygdala in goal-directed behavior. Rhesus monkeys were trained on a task in which two different instrumental responses were linked to two different outcomes. One response, called "tap," required the monkeys to repeatedly touch a colored square on a video monitor to produce one kind of food reward. The other response, called " hold," required persistent contact of an identical stimulus, and it produced a different kind of food reward. After training, we assessed the effects of sensory-specific reinforcer devaluation as a way to probe each monkey's use of goal-directed behavior. In this procedure, monkeys were allowed to consume one of the two foods to satiety and were then tested for tap/hold preference under extinction. Unoperated control monkeys showed a reduction in the response associated with obtaining the devalued food, called the "devaluation effect," a hallmark of goal-directed behavior. Monkeys with bilateral lesions of PFo or the amygdala exhibited significantly reduced devaluation effects. Results from monkeys with PL lesions were equivocal. We conclude that both PFo and the amygdala play a significant role in goal-directed behavior in monkeys. Notably, the findings for PFo challenge the idea that orbital and medial prefrontal regions are exclusively dedicated to object-and action-based processes, respectively. C1 [Rhodes, Sarah E. V.; Murray, Elisabeth A.] NIMH, Sect Neurobiol Learning & Memory, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. RP Rhodes, SEV (reprint author), NIMH, Neuropsychol Lab, NIH, Bldg 49,Room 1B-80,49 Convent Dr, Bethesda, MD 20892 USA. EM sarah.rhodes@mail.nih.gov OI Murray, Elisabeth/0000-0003-1450-1642 FU National Institute of Mental Health FX This research was supported by the Intramural Research Program of the National Institute of Mental Health. We thank Steven Wise and Janine Simmons for their comments on a previous version of this manuscript. We are grateful to Yogita Chudasama, Emily Howland, Alicia Izquierdo, Peter Kaskan, Anna Prescott, Rachel Reoli, and Richard Saunders for help during surgery. We also thank Renee Hill and the staff of the Nuclear Magnetic Resonance Imaging Facility of the National Institute of Neurological Disorders and Stroke for assistance obtaining MR scans. Finally, we thank Ping-Yu Chen for help preparing figures and Yogita Chudasama, Alicia Izquierdo, Peter Rudebeck, and Katherine Wright for help with brain lesion reconstructions. NR 56 TC 20 Z9 21 U1 1 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 FEB 20 PY 2013 VL 33 IS 8 BP 3380 EP U570 DI 10.1523/JNEUROSCI.4374-12.2013 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 093MJ UT WOS:000315195700014 PM 23426666 ER PT J AU Quaia, C Sheliga, BM Optican, LM Cumming, BG AF Quaia, Christian Sheliga, Boris M. Optican, Lance M. Cumming, Bruce G. TI Temporal Evolution of Pattern Disparity Processing in Humans SO JOURNAL OF NEUROSCIENCE LA English DT Article ID VERGENCE EYE-MOVEMENTS; MACAQUE AREA MT; VISUAL-CORTEX; STEREOSCOPIC DEPTH; 2-DIMENSIONAL PATTERNS; HUMAN STEREOPSIS; SIMPLE CELLS; MOTION; DYNAMICS; RESPONSES AB Stereo matching, i.e., the matching by the visual system of corresponding parts of the images seen by the two eyes, is inherently a 2D problem. To gain insights into how this operation is carried out by the visual system, we measured, in human subjects, the reflexive vergence eye movements elicited by the sudden presentation of stereo plaids. We found compelling evidence that the 2D pattern disparity is computed by combining disparities first extracted within orientation selective channels. This neural computation takes 10 - 15 ms, and is carried out even when subjects perceive not a single plaid but rather two gratings in different depth planes (transparency). However, we found that 1D disparities are not always effectively combined: When spatial frequency and contrast of the gratings are sufficiently different pattern disparity is not computed, a result that cannot be simply attributed to the transparency of such stimuli. Based on our results, we propose that a narrow-band implementation of the IOC (Intersection of Constraints) rule (Fennema and Thompson, 1979; Adelson and Movshon, 1982), preceded by cross-orientation suppression, underlies the extraction of pattern disparity. C1 [Quaia, Christian; Sheliga, Boris M.; Optican, Lance M.; Cumming, Bruce G.] NEI, Sensorimotor Res Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Quaia, C (reprint author), NEI, Sensorimotor Res Lab, NIH, Dept Hlth & Human Serv, 49 Convent Dr,Room 2A50, Bethesda, MD 20892 USA. EM quaiac@nei.nih.gov FU National Eye Institute, NIH, Department of Health and Human Services FX This research was supported by the Intramural Research Program of the National Eye Institute, NIH, Department of Health and Human Services. NR 55 TC 3 Z9 3 U1 0 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 FEB 20 PY 2013 VL 33 IS 8 BP 3465 EP 3476 DI 10.1523/JNEUROSCI.4318-12.2013 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 093MJ UT WOS:000315195700022 PM 23426674 ER PT J AU Inaba, K Mizuhiki, T Setogawa, T Toda, K Richmond, BJ Shidara, M AF Inaba, Kiyonori Mizuhiki, Takashi Setogawa, Tsuyoshi Toda, Koji Richmond, Barry J. Shidara, Munetaka TI Neurons in Monkey Dorsal Raphe Nucleus Code Beginning and Progress of Step-by-Step Schedule, Reward Expectation, and Amount of Reward Outcome in the Reward Schedule Task SO JOURNAL OF NEUROSCIENCE LA English DT Article ID ORBITOFRONTAL CORTEX; SEROTONERGIC SYSTEM; DELAYED REWARDS; SIGNALS; RAT; IDENTIFICATION; INFORMATION; PROJECTIONS; MODULATION; ACTIVATION AB The dorsal raphe nucleus is the major source of serotonin in the brain. It is connected to brain regions related to reward processing, and the neurons show activity related to predicted reward outcome. Clinical observations also suggest that it is important in maintaining alertness and its apparent role in addiction seems to be related to reward processing. Here, we examined whether the neurons in dorsal raphe carry signals about reward outcome and task progress during multitrial schedules. We recorded from 98 single neurons in dorsal raphe of two monkeys. The monkeys perform one, two, or three visual discrimination trials (schedule), obtaining one, two, or three drops of liquid. In the valid cue condition, the length and brightness of a visual cue indicated schedule progress and reward amount, respectively. In the random cue condition, the visual cue was randomly presented with respect to schedule length and reward amount. We found information encoded about (1) schedule onset, (2) reward expectation, (3) reward outcome, and (4) reward amount in the mean firing rates. Information theoretic analysis showed that the temporal variation of the neuronal responses contained additional information related to the progress of the schedule toward the reward rather than only discriminating schedule onset or reward/no reward. When considered in light of all that is known about the raphe in anatomy, physiology, and behavior, the rich encoding about both task progress and predicted reward outcome makes the raphe a strong candidate for providing signals throughout the brain to coordinate persistent goal-seeking behavior. C1 [Inaba, Kiyonori; Mizuhiki, Takashi; Setogawa, Tsuyoshi; Toda, Koji; Shidara, Munetaka] Univ Tsukuba, Grad Sch Comprehens Human Sci, Doctoral Program Kansei Behav & Brain Sci, Tsukuba, Ibaraki 3058577, Japan. [Inaba, Kiyonori; Setogawa, Tsuyoshi] Japan Soc Promot Sci, Tsukuba, Ibaraki 3058577, Japan. [Mizuhiki, Takashi; Shidara, Munetaka] Univ Tsukuba, Fac Med, Tsukuba, Ibaraki 3058577, Japan. [Richmond, Barry J.] NIMH, Neuropsychol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Shidara, M (reprint author), Univ Tsukuba, Fac Med, 1-1-1 Tennoudai, Tsukuba, Ibaraki 3058577, Japan. EM mshidara@md.tsukuba.ac.jp FU MEXT of Japan [21119006, 17022052]; KAKENHI [22300138]; U.S. National Institute of Mental Health FX This work was supported by Grant-in-Aid for JSPS Fellows (21119006; K. I.); Grant-in-Aid for Scientific Research on Priority Areas-System study on higher order brain functions from MEXT of Japan (17022052; M. S.); and KAKENHI (22300138; M. S.), the U.S. National Institute of Mental Health intramural program (B. J. R.). We thank Dr. Noriyuki Higo at the National Institute of Advanced Industrial Science and Technology (AIST) for histological technique and Dr. Shigeru Ozaki at the University of Tsukuba for comments. We also received generous support for MRI examination from Dr. Keiji Matsuda in AIST. NR 43 TC 17 Z9 18 U1 1 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 FEB 20 PY 2013 VL 33 IS 8 BP 3477 EP 3491 DI 10.1523/JNEUROSCI.4388-12.2013 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 093MJ UT WOS:000315195700023 PM 23426675 ER PT J AU Fadlallah, B Chen, BD Keil, A Principe, J AF Fadlallah, Bilal Chen, Badong Keil, Andreas Principe, Jose TI Weighted-permutation entropy: A complexity measure for time series incorporating amplitude information SO PHYSICAL REVIEW E LA English DT Article ID APPROXIMATE ENTROPY; SEIZURES; EEG AB Permutation entropy (PE) has been recently suggested as a novel measure to characterize the complexity of nonlinear time series. In this paper, we propose a simple method to address some of PE's limitations, mainly its inability to differentiate between distinct patterns of a certain motif and the sensitivity of patterns close to the noise floor. The method relies on the fact that patterns may be too disparate in amplitudes and variances and proceeds by assigning weights for each extracted vector when computing the relative frequencies associated with every motif. Simulations were conducted over synthetic and real data for a weighting scheme inspired by the variance of each pattern. Results show better robustness and stability in the presence of higher levels of noise, in addition to a distinctive ability to extract complexity information from data with spiky features or having abrupt changes in magnitude. DOI: 10.1103/PhysRevE.87.022911 C1 [Fadlallah, Bilal; Principe, Jose] Univ Florida, Dept Elect & Comp Engn, Computat NeuroEngn Lab, Gainesville, FL 32611 USA. [Chen, Badong] Xi An Jiao Tong Univ, Inst Artificial Intelligence & Robot, Xian 710049, Peoples R China. [Keil, Andreas] Univ Florida, NIMH, Ctr Study Emot & Attent, Dept Psychol, Gainesville, FL 32611 USA. RP Fadlallah, B (reprint author), Univ Florida, Dept Elect & Comp Engn, Computat NeuroEngn Lab, Gainesville, FL 32611 USA. EM bhf@cnel.ufl.edu; chenbd@mail.xjtu.edu.cn; principe@cnel.ufl.edu RI Keil, Andreas/F-9427-2011; Chen, Badong/F-4211-2015 OI Keil, Andreas/0000-0002-4064-1924; Chen, Badong/0000-0003-1710-3818 FU U.S. National Science Foundation [IIS-0964197]; Lebanese Center for Scientific Research (CNRS) FX This work was supported by the U.S. National Science Foundation under Grant No. IIS-0964197 and the Lebanese Center for Scientific Research (CNRS). The authors thank Austin Brockmeier for useful discussion and the anonymous reviewers for their constructive suggestions. NR 20 TC 42 Z9 42 U1 3 U2 26 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1539-3755 J9 PHYS REV E JI Phys. Rev. E PD FEB 20 PY 2013 VL 87 IS 2 AR 022911 DI 10.1103/PhysRevE.87.022911 PG 7 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 092VL UT WOS:000315151000010 PM 23496595 ER PT J AU Thomason, ME Dassanayake, MT Shen, S Katkuri, Y Alexis, M Anderson, AL Yeo, LM Mody, S Hernandez-Andrade, E Hassan, SS Studholme, C Jeong, JW Romero, R AF Thomason, Moriah E. Dassanayake, Maya T. Shen, Stephen Katkuri, Yashwanth Alexis, Mitchell Anderson, Amy L. Yeo, Lami Mody, Swati Hernandez-Andrade, Edgar Hassan, Sonia S. Studholme, Colin Jeong, Jeong-Won Romero, Roberto TI Cross-Hemispheric Functional Connectivity in the Human Fetal Brain SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID RESTING-STATE NETWORKS; DEFICIT HYPERACTIVITY DISORDER; LOW-FREQUENCY FLUCTUATIONS; DEFAULT NETWORK; INFANT BRAIN; COMPONENT ANALYSIS; CINGULATE CORTEX; IN-UTERO; EXPOSURE; FETUS AB Compelling evidence indicates that psychiatric and developmental disorders are generally caused by disruptions in the functional connectivity (FC) of brain networks. Events occurring during development, and in particular during fetal life, have been implicated in the genesis of such disorders. However, the developmental timetable for the emergence of neural FC during human fetal life is unknown. We present the results of resting-state functional magnetic resonance imaging performed in 25 healthy human fetuses in the second and third trimesters of pregnancy (24 to 38 weeks of gestation). We report the presence of bilateral fetal brain FC and regional and age-related variation in FC. Significant bilateral connectivity was evident in half of the 42 areas tested, and the strength of FC between homologous cortical brain regions increased with advancing gestational age. We also observed medial to lateral gradients in fetal functional brain connectivity. These findings improve understanding of human fetal central nervous system development and provide a basis for examining the role of insults during fetal life in the subsequent development of disorders in neural FC. C1 [Thomason, Moriah E.; Anderson, Amy L.] Wayne State Univ, Merrill Palmer Skillman Inst Child & Family Dev, Detroit, MI 48202 USA. [Thomason, Moriah E.; Jeong, Jeong-Won] Wayne State Univ, Dept Pediat, Sch Med, Detroit, MI 48202 USA. [Thomason, Moriah E.; Anderson, Amy L.; Yeo, Lami; Hernandez-Andrade, Edgar; Hassan, Sonia S.; Romero, Roberto] Natl Inst Child Hlth & Human Dev NICHD, Perinatol Res Branch, NIH, US Dept HHS, Detroit, MI 48202 USA. [Dassanayake, Maya T.; Alexis, Mitchell] Wayne State Univ, Basic Med Sci Program, Sch Med, Detroit, MI 48202 USA. [Shen, Stephen] Wayne State Univ, Sch Med, Detroit, MI 48202 USA. [Katkuri, Yashwanth; Mody, Swati] Wayne State Univ, Dept Radiol, Sch Med, Detroit, MI 48202 USA. [Yeo, Lami; Hernandez-Andrade, Edgar; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Sch Med, Detroit, MI 48202 USA. [Studholme, Colin] Univ Washington, Dept Pediat & Neonatol, Seattle, WA 98105 USA. [Studholme, Colin] Univ Washington, Dept Bioengn, Seattle, WA 98105 USA. [Jeong, Jeong-Won] Wayne State Univ, Dept Neurol, Sch Med, Detroit, MI 48202 USA. [Romero, Roberto] NICHD, Perinatol Res Branch, NIH, US Dept HHS, Bethesda, MD 20814 USA. RP Thomason, ME (reprint author), Wayne State Univ, Merrill Palmer Skillman Inst Child & Family Dev, Detroit, MI 48202 USA. EM moriah@wayne.edu FU Merrill Palmer Skillman Institute for Child and Family Development; Department of Pediatrics, Wayne State University (WSU) School of Medicine; WSU Perinatal Initiative; Intramural Research Program of the Eunice Kennedy Shriver NICHD, NIH, Department of Health and Human Services [N01-HD-2-3342]; NIH/NINDS [NS 055064]; WSU's Perinatology Virtual Discovery Grant [P3018205]; WSU's Research Grant Program awards FX This research was supported, in part, by the Merrill Palmer Skillman Institute for Child and Family Development; the Department of Pediatrics, Wayne State University (WSU) School of Medicine; the WSU Perinatal Initiative; and the Intramural Research Program of the Eunice Kennedy Shriver NICHD, NIH, Department of Health and Human Services through contract N01-HD-2-3342. This project was also supported by NIH/NINDS R01 grant NS 055064 (to C. S.), WSU's Perinatology Virtual Discovery Grant (made possible by W. K. Kellogg Foundation award P3018205), and WSU's Research Grant Program awards (to M. E. T.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NICHD or the NIH. NR 82 TC 23 Z9 23 U1 1 U2 10 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD FEB 20 PY 2013 VL 5 IS 173 AR 173ra24 DI 10.1126/scitranslmed.3004978 PG 10 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 094KQ UT WOS:000315262000003 PM 23427244 ER PT J AU Duan, JB Shi, JX Ge, XJ Dolken, L Moy, W He, DL Shi, S Sanders, AR Ross, J Gejman, PV AF Duan, Jubao Shi, Jianxin Ge, Xijin Doelken, Lars Moy, Winton He, Deli Shi, Sandra Sanders, Alan R. Ross, Jeff Gejman, Pablo V. TI Genome-wide survey of interindividual differences of RNA stability in human lymphoblastoid cell lines SO SCIENTIFIC REPORTS LA English DT Article ID HUMAN GENE-EXPRESSION; NEWLY SYNTHESIZED RNA; MESSENGER-RNA; MICROARRAY ANALYSIS; MAMMALIAN-CELLS; NORMALIZATION METHODS; MENTAL-RETARDATION; DECAY-RATES; ASSOCIATION; POPULATION AB The extent to which RNA stability differs between individuals and its contribution to the interindividual expression variation remain unknown. We conducted a genome-wide analysis of RNA stability in seven human HapMap lymphoblastoid cell lines (LCLs) and analyzed the effect of DNA sequence variation on RNA half-life differences. Twenty-six percent of the expressed genes exhibited RNA half-life differences between LCLs at a false discovery rate (FDR) < 0.05, which accounted for similar to 37% of the gene expression differences between individuals. Nonsense polymorphisms were associated with reduced RNA half-lives. In genes presenting interindividual RNA half-life differences, higher coding GC3 contents (G and C percentages at the third-codon positions) were correlated with increased RNA half-life. Consistently, G and C alleles of single nucleotide polymorphisms (SNPs) in protein coding sequences were associated with enhanced RNA stability. These results suggest widespread interindividual differences in RNA stability related to DNA sequence and composition variation. C1 [Duan, Jubao; Moy, Winton; He, Deli; Shi, Sandra; Sanders, Alan R.; Gejman, Pablo V.] NorthShore Univ HealthSyst Res Inst, Ctr Psychiat Genet, Evanston, IL 60201 USA. [Duan, Jubao; Sanders, Alan R.; Gejman, Pablo V.] Univ Chicago, Dept Psychiat & Behav Sci, Chicago, IL 60637 USA. [Shi, Jianxin] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Ge, Xijin] S Dakota State Univ, Dept Math & Stat, Brookings, SD 57007 USA. [Doelken, Lars] Univ Cambridge, Dept Med, Addenbrookes Hosp, Cambridge CB2 0QQ, England. [Ross, Jeff] Univ Wisconsin, McArdle Lab Canc Res, Madison, WI 53706 USA. RP Duan, JB (reprint author), NorthShore Univ HealthSyst Res Inst, Ctr Psychiat Genet, Evanston, IL 60201 USA. EM jduan@uchicago.edu OI Ge, Steven/0000-0001-7406-3782 FU NorthShore University HealthSystem Research Career Development Award; MRC [G1002523]; National Institute of Health [RC2MH090030, R01MH94091] FX This work was supported by NorthShore University HealthSystem (formally Evanston Northwestern Healthcare) Research Career Development Award to J.D.; MRC Fellowship grant G1002523 to L.D.' and grants from National Institute of Health (RC2MH090030 to A. R. S. and R01MH94091 to P. V. G.). We thank Dr. Kai Wang (Zilkha Neurogenetic Institute, CA) for bioinformatic assistance on gene annotation by ANOVAR. NR 84 TC 19 Z9 19 U1 1 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 FEB 20 PY 2013 VL 3 AR 1318 DI 10.1038/srep01318 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 092WI UT WOS:000315153300001 PM 23422947 ER PT J AU Baker, SG AF Baker, Stuart G. TI Remarks on 'A simple decision analytic solution to the comparison of two binary diagnostic tests' by Vickers et al. SO STATISTICS IN MEDICINE LA English DT Letter C1 NCI, Biometry Res Grp, Bethesda, MD 20892 USA. RP Baker, SG (reprint author), NCI, Biometry Res Grp, Bethesda, MD 20892 USA. EM sb16i@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 4 TC 0 Z9 0 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD FEB 20 PY 2013 VL 32 IS 4 BP 718 EP 718 DI 10.1002/sim.5663 PG 1 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 076TK UT WOS:000313980700017 PM 23341085 ER PT J AU Apolo, AB Lee, YH Cecchi, F Agarwal, PK Parnes, HL Khadar, K Summerell, A Gulley, JL Compton, K Figg, WD Dahut, WL Bottaro, DP AF Apolo, Andrea Borghese Lee, Young H. Cecchi, Fabiola Agarwal, Piyush K. Parnes, Howard L. Khadar, Kattie Summerell, Amelia Gulley, James L. Compton, Kathryn Figg, William Douglas Dahut, William L. Bottaro, Donald P. TI Preclinical and correlative studies of cabozantinib (XL184) in urothelial cancer (UC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium of the Conquer-Cancer-Foundation of American-Society-of-Clinical-Oncology (ASCO) CY FEB 14-16, 2013 CL Orlando, FL SP Amer Soc Clin Oncol, Conquer Canc Fdn C1 NCI, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. NCI, Canc Prevent Div, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016; Figg Sr, William/M-2411-2016 OI Gulley, James/0000-0002-6569-2912; NR 0 TC 2 Z9 2 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 FEB 20 PY 2013 VL 31 IS 6 SU S MA 314 PG 1 WC Oncology SC Oncology GA AE0TR UT WOS:000333679600314 ER PT J AU Couvillon, A Beatson, MA Harold, N Karzai, FH Madan, RA Gulley, JL Dahut, WL AF Couvillon, Anna Beatson, Melony A. Harold, Nancy Karzai, Fatima H. Madan, Ravi Amrit Gulley, James L. Dahut, William L. TI Feasibility of continuing docetaxel-based therapy in patients with metastatic castrate-resistant prostate cancer (mCRPC) that experience hypersensitivity reactions (HSR) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium of the Conquer-Cancer-Foundation of American-Society-of-Clinical-Oncology (ASCO) CY FEB 14-16, 2013 CL Orlando, FL SP Amer Soc Clin Oncol, Conquer Canc Fdn C1 NCI, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NCI, Lab Tumor Immunol & Biol, Med Oncol Branch, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 20 PY 2013 VL 31 IS 6 SU S MA 132 PG 1 WC Oncology SC Oncology GA AE0TR UT WOS:000333679600133 ER PT J AU Goodman, PJ Thompson, IM Tangen, CM Parnes, HL Godley, PA Ford, LG AF Goodman, Phyllis J. Thompson, Ian Murchie Tangen, Catherine M. Parnes, Howard L. Godley, Paul Alphonso Ford, Leslie G. TI Long-term survival of subjects in the prostate cancer prevention trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium of the Conquer-Cancer-Foundation of American-Society-of-Clinical-Oncology (ASCO) CY FEB 14-16, 2013 CL Orlando, FL SP Amer Soc Clin Oncol, Conquer Canc Fdn C1 SWOG Stat Ctr, Seattle, WA USA. Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. NCI, Canc Prevent Div, Bethesda, MD 20892 USA. Univ N Carolina, Chapel Hill, NC USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 FEB 20 PY 2013 VL 31 IS 6 SU S MA 10 PG 1 WC Oncology SC Oncology GA AE0TR UT WOS:000333679600013 ER PT J AU Gulley, JL Madan, RA Stein, WD Wilkerson, J Dahut, WL Heery, CR Schlom, J Wilding, G DiPaola, RS AF Gulley, James L. Madan, Ravi Amrit Stein, Wilfred Donald Wilkerson, Julia Dahut, William L. Heery, Christopher Ryan Schlom, Jeffrey Wilding, George DiPaola, Robert S. TI Effect of PSA-tricom, a pox-viral vaccine in prostate cancer (PCa), on tumor growth rates within 80 days after initiation in nonmetastatic PCa SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium of the Conquer-Cancer-Foundation of American-Society-of-Clinical-Oncology (ASCO) CY FEB 14-16, 2013 CL Orlando, FL SP Amer Soc Clin Oncol, Conquer Canc Fdn C1 NCI, Tumor Immunol & Biol Lab, Med Oncol Branch, Bethesda, MD 20892 USA. Hebrew Univ Jerusalem, Jerusalem, Israel. NCI, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, New Brunswick, NJ USA. RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 0 TC 0 Z9 0 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 FEB 20 PY 2013 VL 31 IS 6 SU S MA 57 PG 1 WC Oncology SC Oncology GA AE0TR UT WOS:000333679600058 ER PT J AU Heath, EI Mannuel, HD Liu, G Lara, P Monk, JP Flaig, TW Zurita, AJ Vaishampayan, UN Stella, PJ Smith, DW Dobson, K Hussain, A Al-Janadi, A Ivy, SP Heilbrun, LK AF Heath, Elisabeth I. Mannuel, Heather Dorothy Liu, Glenn Lara, Primo Monk, J. P. Flaig, Thomas W. Zurita, Amado J. Vaishampayan, Ulka N. Stella, Philip J. Smith, Daryn W. Dobson, Kimberlee Hussain, Arif Al-Janadi, Anas Ivy, S. Percy Heilbrun, Lance K. TI Randomized phase II trial of docetaxel (Doc) and prednisone (Pred) with or without AZD2171 (cediranib), in chemotherapy-naive, metastatic castrate-resistant prostate cancer (mCRPC) (NCI 7451) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium of the Conquer-Cancer-Foundation of American-Society-of-Clinical-Oncology (ASCO) CY FEB 14-16, 2013 CL Orlando, FL SP Amer Soc Clin Oncol, Conquer Canc Fdn C1 Karmanos Canc Inst, Detroit, MI USA. Univ Maryland, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA. Univ Calif Davis, Sacramento, CA 95817 USA. Ohio State Univ, Columbus, OH 43210 USA. Univ Colorado Denver, Aurora, CO USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. Natl Surg Adjuvant Breast & Bowel Project, Ann Arbor, MI USA. St Joseph Mercy Hlth Syst, Ann Arbor, MI USA. Michigan State Univ, Dept Med, Lansing, MI USA. NCI, Div Canc Treatment, Canc Therapy Evaluat Program, Invest Drug Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 20 PY 2013 VL 31 IS 6 SU S MA 38 PG 1 WC Oncology SC Oncology GA AE0TR UT WOS:000333679600040 ER PT J AU Heery, CR Madan, RA Bilusic, M Kim, JW Singh, NK Rauckhorst, M Steinberg, SM Dahut, WL Chen, C DiPaola, RS Stein, MN Panicali, D Hodge, JW Schlom, J Gulley, JL AF Heery, Christopher Ryan Madan, Ravi Amrit Bilusic, Marijo Kim, Joseph W. Singh, Nishith K. Rauckhorst, Myrna Steinberg, Seth M. Dahut, William L. Chen, Clara DiPaola, Robert S. Stein, Mark N. Panicali, Dennis Hodge, James W. Schlom, Jeffrey Gulley, James L. TI A phase II randomized clinical trial of samarium-153 EDTMP (Sm-153) with or without PSA-TRICOM vaccine in metastatic castration-resistant prostate cancer (mCRPC) after docetaxel SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium of the Conquer-Cancer-Foundation of American-Society-of-Clinical-Oncology (ASCO) CY FEB 14-16, 2013 CL Orlando, FL SP Amer Soc Clin Oncol, Conquer Canc Fdn C1 NCI, Lab Tumor Immunol & Biol, Med Oncol Branch, Bethesda, MD 20892 USA. NHLBI, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, CCR, NIH, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NIH, Dept Nucl Med, Ctr Clin, Bethesda, MD USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, New Brunswick, NJ USA. Canc Inst New Jersey, New Brunswick, NJ USA. Bavarian Nord ImmunoTherapeut, Mountain View, CA USA. RI Hodge, James/D-5518-2015; Gulley, James/K-4139-2016 OI Hodge, James/0000-0001-5282-3154; Gulley, James/0000-0002-6569-2912 NR 0 TC 0 Z9 0 U1 1 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 20 PY 2013 VL 31 IS 6 SU S MA 102 PG 1 WC Oncology SC Oncology GA AE0TR UT WOS:000333679600103 ER PT J AU Truong, H Nix, J Smith, K Mittal, A Agarwal, P AF Hong Truong Nix, Jeffrey Smith, Kamal Mittal, Aayush Agarwal, Piyush TI Perioperative management of radical cystectomy patients: A questionnaire survey of the American Urological Association members SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium of the Conquer-Cancer-Foundation of American-Society-of-Clinical-Oncology (ASCO) CY FEB 14-16, 2013 CL Orlando, FL SP Amer Soc Clin Oncol, Conquer Canc Fdn C1 [Hong Truong; Nix, Jeffrey; Smith, Kamal; Mittal, Aayush; Agarwal, Piyush] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 20 PY 2013 VL 31 IS 6 SU S MA 316 PG 1 WC Oncology SC Oncology GA AE0TR UT WOS:000333679600316 ER PT J AU Karzai, FH Adesunloye, B Ning, YMM Madan, RA Gulley, JL Apolo, AB Beatson, MA Couvillon, A Harold, N Parnes, HL Arlen, PM Wright, JJ Chen, C Dawson, NA Figg, WD Dahut, WL AF Karzai, Fatima H. Adesunloye, Bamidele Ning, Yangmin M. Madan, Ravi Amrit Gulley, James L. Apolo, Andrea Borghese Beatson, Melony A. Couvillon, Anna Harold, Nancy Parnes, Howard L. Arlen, Philip M. Wright, John Joseph Chen, Clara Dawson, Nancy Ann Figg, William Douglas Dahut, William L. TI Use of supportive measures to improve outcome and decrease toxicity in docetaxel-based antiangiogenesis combinations SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium of the Conquer-Cancer-Foundation of American-Society-of-Clinical-Oncology (ASCO) CY FEB 14-16, 2013 CL Orlando, FL SP Amer Soc Clin Oncol, Conquer Canc Fdn C1 NCI, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, US FDA, Silver Spring, MD USA. NCI, Lab Tumor Immunol & Biol, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NCI, Canc Prevent Div, Bethesda, MD 20892 USA. Neogenix Oncol, Rockville, MD USA. NCI, Rockville, MD USA. NCI, Dept Nucl Med, Ctr Clin, Bethesda, MD 20892 USA. Georgetown Lombardi Comprehens Canc Ctr, Washington, DC USA. RI Gulley, James/K-4139-2016; Figg Sr, William/M-2411-2016 OI Gulley, James/0000-0002-6569-2912; NR 0 TC 0 Z9 0 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 FEB 20 PY 2013 VL 31 IS 6 SU S MA 128 PG 1 WC Oncology SC Oncology GA AE0TR UT WOS:000333679600129 ER PT J AU Kim, JW Marte, JL Bilusic, M Singh, NK Heery, CR Madan, RA Pazdur, M McMahon, S Rauckhorst, M Schlom, J Gulley, JL AF Kim, Joseph W. Marte, Jennifer L. Bilusic, Marijo Singh, Nishith K. Heery, Christopher Ryan Madan, Ravi Amrit Pazdur, Mary McMahon, Sheri Rauckhorst, Myrna Schlom, Jeffrey Gulley, James L. TI Safety profile of poxviral vaccines: NCI experience SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium of the Conquer-Cancer-Foundation of American-Society-of-Clinical-Oncology (ASCO) CY FEB 14-16, 2013 CL Orlando, FL SP Amer Soc Clin Oncol, Conquer Canc Fdn C1 NCI, Lab Tumor Immunol & Biol, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 0 TC 0 Z9 0 U1 0 U2 2 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 FEB 20 PY 2013 VL 31 IS 6 SU S MA 85 PG 1 WC Oncology SC Oncology GA AE0TR UT WOS:000333679600086 ER PT J AU Park, JC Kurdziel, KA Lindenberg, L Gulley, JL Madan, RA Wood, LV McKinney, Y Choyke, PL Dahut, WL Apolo, AB AF Park, Jong Chul Kurdziel, Karen A. Lindenberg, Liza Gulley, James L. Madan, Ravi Amrit Wood, Lauren V. McKinney, Yolanda Choyke, Peter L. Dahut, William L. Apolo, Andrea Borghese TI Preliminary results of a prospective study of 18F-NAF PET/CT in prostate cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium of the Conquer-Cancer-Foundation of American-Society-of-Clinical-Oncology (ASCO) CY FEB 14-16, 2013 CL Orlando, FL SP Amer Soc Clin Oncol, Conquer Canc Fdn C1 NCI, Bethesda, MD 20892 USA. Ctr Canc Res, Mol Imaging Program, Bethesda, MD USA. NIC, CCR, Bethesda, MD USA. NCI, Lab Tumor Immunol & Biol, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 0 TC 0 Z9 0 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 FEB 20 PY 2013 VL 31 IS 6 SU S MA 103 PG 1 WC Oncology SC Oncology GA AE0TR UT WOS:000333679600104 ER PT J AU Shuch, B Asher, KP Chen, C Lin, K Bratslavsky, G Linehan, WM Srinivasan, R AF Shuch, Brian Asher, Kevin P. Chen, Clara Lin, Kelly Bratslavsky, Gennady Linehan, W. Marston Srinivasan, Ramaprasad TI Clinical evaluation of 2-(F-18) fluoro-2 deoxy-D-glucose PET/CT in hereditary leiomyomatosis and renal cell carcinoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium of the Conquer-Cancer-Foundation of American-Society-of-Clinical-Oncology (ASCO) CY FEB 14-16, 2013 CL Orlando, FL SP Amer Soc Clin Oncol, Conquer Canc Fdn C1 NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. NIH, Dept Nucl Med, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 FEB 20 PY 2013 VL 31 IS 6 SU S MA 383 PG 1 WC Oncology SC Oncology GA AE0TR UT WOS:000333679600380 ER PT J AU Shuch, B Hanley, J Lai, J Setodji, CM Vourganti, S Chow, WH Saigal, C AF Shuch, Brian Hanley, Janet Lai, Julie Setodji, Claude Messan Vourganti, Srinivas Chow, Wong Ho Saigal, Christopher TI Association of adverse health outcomes with partial and radical nephrectomy: Is it time to reassess the "gold standard" for the small renal mass? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium of the Conquer-Cancer-Foundation of American-Society-of-Clinical-Oncology (ASCO) CY FEB 14-16, 2013 CL Orlando, FL SP Amer Soc Clin Oncol, Conquer Canc Fdn C1 NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. RAND Corp, Santa Monica, CA USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Dept Urol, Los Angeles, CA USA. NR 0 TC 0 Z9 0 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 FEB 20 PY 2013 VL 31 IS 6 SU S MA 363 PG 1 WC Oncology SC Oncology GA AE0TR UT WOS:000333679600361 ER PT J AU Shuch, B Vourganti, S Middleton, L Linehan, WM AF Shuch, Brian Vourganti, Srinivas Middleton, Lindsay Linehan, W. Marston TI Defining early-onset kidney cancer: Implications for genetic counseling SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium of the Conquer-Cancer-Foundation of American-Society-of-Clinical-Oncology (ASCO) CY FEB 14-16, 2013 CL Orlando, FL SP Amer Soc Clin Oncol, Conquer Canc Fdn C1 [Shuch, Brian; Vourganti, Srinivas; Middleton, Lindsay; Linehan, W. Marston] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 FEB 20 PY 2013 VL 31 IS 6 SU S MA 342 PG 1 WC Oncology SC Oncology GA AE0TR UT WOS:000333679600342 ER PT J AU Vourganti, S Harbin, A Singer, EA Shuch, B Metwalli, AR Agarwal, PK AF Vourganti, Srinivas Harbin, Andrew Singer, Eric A. Shuch, Brian Metwalli, Adam R. Agarwal, Piyush K. TI Low-grade micropapillary urothelial carcinoma: Does it exist? A SEER analysis of management and outcomes SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium of the Conquer-Cancer-Foundation of American-Society-of-Clinical-Oncology (ASCO) CY FEB 14-16, 2013 CL Orlando, FL SP Amer Soc Clin Oncol, Conquer Canc Fdn C1 NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. Georgetown Univ, Dept Urol, Washington, DC USA. Canc Inst New Jersey, Urol Oncol Program, New Brunswick, NJ USA. NR 0 TC 0 Z9 0 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 FEB 20 PY 2013 VL 31 IS 6 SU S MA 315 PG 1 WC Oncology SC Oncology GA AE0TR UT WOS:000333679600315 ER PT J AU Weintraub, M Siddiqui, M Vourganti, S Shuch, B Agarwal, P Linehan, WM AF Weintraub, Michael Siddiqui, Minhaj Vourganti, Srinivas Shuch, Brian Agarwal, Piyush Linehan, W. Marston TI Paragangliomas of the urinary bladder: Experience at the National Cancer Institute SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium of the Conquer-Cancer-Foundation of American-Society-of-Clinical-Oncology (ASCO) CY FEB 14-16, 2013 CL Orlando, FL SP Amer Soc Clin Oncol, Conquer Canc Fdn C1 [Weintraub, Michael; Siddiqui, Minhaj; Vourganti, Srinivas; Shuch, Brian; Agarwal, Piyush; Linehan, W. Marston] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 FEB 20 PY 2013 VL 31 IS 6 SU S MA 307 PG 1 WC Oncology SC Oncology GA AE0TR UT WOS:000333679600307 ER PT J AU Gangarossa, G Espallergues, J d'Exaerde, AD El Mestikawy, S Gerfen, CR Herve, D Girault, JA Valjent, E AF Gangarossa, Giuseppe Espallergues, Julie d'Exaerde, Alban de Kerchove El Mestikawy, Salah Gerfen, Charles R. Herve, Denis Girault, Jean-Antoine Valjent, Emmanuel TI Distribution and compartmental organization of GABAergic medium-sized spiny neurons in the mouse nucleus accumbens SO FRONTIERS IN NEURAL CIRCUITS LA English DT Article DE medium-sized spiny neurons; BAC transgenic; nucleus accumbens; dopamine; psychostimulant; ERK signaling; neural circuits ID SIGNAL-REGULATED KINASE; SITU HYBRIDIZATION HISTOCHEMISTRY; VENTRAL STRIATUM; DOPAMINE-RECEPTOR; RAT-BRAIN; STRIATOPALLIDAL NEURONS; TYROSINE-HYDROXYLASE; GENE-EXPRESSION; SUBSTANCE-P; ADENOSINE-A2 RECEPTOR AB The nucleus accumbens (NAc) is a critical brain region involved in many reward-related behaviors. The NAc comprises major compartments the core and the shell, which encompass several subterritories. GABAergic medium-sized spiny neurons (MSNs) constitute the output neurons of the NAc core and shell. While the functional organization of the NAc core outputs resembles the one described for the dorsal striatum, a simple classification of the NAc shell neurons has been difficult to define due to the complexity of the compartmental segregation of cells. We used a variety of BAC transgenic mice expressing enhanced green fluorescence (EGFP) or the Cre-recombinase (Cre) under the control of the promoter of dopamine D1, D2, and D3 receptors and of adenosine A2a receptor to dissect the microanatomy of the NAc. Moreover, using various immunological markers we characterized in detail the distribution of MSNs in the mouse NAc. In addition, cell-type specific extracellular signal-regulated kinase (ERK) phosphorylation in the NAc subterritories was analyzed following acute administration of SKF81297 (a D1R-like agonist), quinpirole (a D2 receptors (D2R)-like agonist), apomorphine (a non-selective DA receptor agonist), raclopride (a D2R-like antagonist), and psychostimulant drugs, including cocaine and d-amphetamine. Each drug generated a unique topography and cell-type specific activation of ERK in the NAc. Our results show the existence of marked differences in the receptor expression pattern and functional activation of MSNs within the shell subterritories. This study emphasizes the anatomical and functional heterogeneity of the NAc, which will have to be considered in its further study. C1 [Gangarossa, Giuseppe; Espallergues, Julie; Valjent, Emmanuel] CNRS, UMR 5203, Inst Genom Fonct, Montpellier, France. [Gangarossa, Giuseppe; Espallergues, Julie; Valjent, Emmanuel] INSERM, U661, Montpellier, France. [Gangarossa, Giuseppe; Espallergues, Julie; Valjent, Emmanuel] Univ Montpellier I, UMR 5203, F-34094 Montpellier, France. [Gangarossa, Giuseppe; Espallergues, Julie; Valjent, Emmanuel] Univ Montpellier 2, UMR 5203, F-34094 Montpellier, France. [d'Exaerde, Alban de Kerchove] Univ Libre Brussels, Sch Med, Neurophysiol Lab, ULB Neurosci Inst, Brussels, Belgium. [El Mestikawy, Salah] CNRS, UMR 7224, Paris, France. [El Mestikawy, Salah] INSERM, U952, Paris, France. [El Mestikawy, Salah] Univ Paris 06, UMR 7224, Paris, France. [Gerfen, Charles R.] NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA. [Herve, Denis; Girault, Jean-Antoine] INSERM, UMR S 839, Paris, France. [Herve, Denis; Girault, Jean-Antoine] Univ Paris 06, UMR S 839, Paris, France. [Herve, Denis; Girault, Jean-Antoine] Inst Fer Moulin, Paris, France. RP Valjent, E (reprint author), Univ Montpellier I, INSERM, U661, F-34094 Montpellier, France. EM emmanuel.valjent@igf.cnrs.fr RI Girault, Jean-Antoine/F-7518-2013; HERVE, Denis/E-2929-2017; OI Girault, Jean-Antoine/0000-0002-7900-1705; HERVE, Denis/0000-0003-1376-1522; Gangarossa, Giuseppe/0000-0001-9045-2139 FU Inserm; ATIP-Avenir (Inserm); Sanofi-Aventis RD; Agence Nationale de la Recherche [ANR-2010-JCJC-1412, ANR-BLAN08-1_346422]; Fondation pour la recherche medicale (FRM); European Union; European research council (ERC); FRS-FNRS (Belgium); ULB; Action de Recherche Concertee from the CFWB; UM1 FX This work was supported by Inserm and grants from ATIP-Avenir (Inserm), Sanofi-Aventis R&D, and from the Agence Nationale de la Recherche (ANR-2010-JCJC-1412) to Emmanuel Valjent. Research in Jean-Antoine Girault and Denis Herve lab was supported by grants from the Fondation pour la recherche medicale (FRM), the Agence nationale de la recherche (ANR-BLAN08-1_346422), European Union Framework program 7 (FP7, SynSys), and the European research council (ERC). AdKdE is a Research Associate of the FRS-FNRS (Belgium) and is supported by FRS-FNRS (Belgium), FER from ULB, Action de Recherche Concertee from the CFWB. Julie Espallergues was a recipient of a postdoctoral fellowship from UM1. We are grateful to Laurent Fagni and Julie Perroy (Institut de Genomique Fonctionnelle) for providing some transgenic mice used in this study. We thank Frederic Gallardo (IGF) and Natacha Roblot, Rachida Boukhari, and Yohann Bertelle (IFM) for animal care, breeding and genotyping. NR 68 TC 36 Z9 36 U1 3 U2 31 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5110 J9 FRONT NEURAL CIRCUIT JI Front. Neural Circuits PD FEB 19 PY 2013 VL 7 AR 22 DI 10.3389/fncir.2013.00022 PG 20 WC Neurosciences SC Neurosciences & Neurology GA 125SM UT WOS:000317561600001 PM 23423476 ER PT J AU Felix, AS Cook, LS Gaudet, MM Rohan, TE Schouten, LJ Setiawan, VW Wise, LA Anderson, KE Bernstein, L De Vivo, I Friedenreich, CM Gapstur, SM Goldbohm, RA Henderson, B Horn-Ross, PL Kolonel, L Lacey, JV Liang, X Lissowska, J Magliocco, A McCullough, ML Miller, AB Olson, SH Palmer, JR Park, Y Patel, AV Prescott, J Rastogi, R Robien, K Rosenberg, L Schairer, C Shu, XO van den Brandt, PA Virkus, RA Wentzensen, N Xiang, YB Xu, WH Yang, HP Brinton, LA AF Felix, A. S. Cook, L. S. Gaudet, M. M. Rohan, T. E. Schouten, L. J. Setiawan, V. W. Wise, L. A. Anderson, K. E. Bernstein, L. De Vivo, I. Friedenreich, C. M. Gapstur, S. M. Goldbohm, R. A. Henderson, B. Horn-Ross, P. L. Kolonel, L. Lacey, J. V. Liang, X. Lissowska, J. Magliocco, A. McCullough, M. L. Miller, A. B. Olson, S. H. Palmer, J. R. Park, Y. Patel, A. V. Prescott, J. Rastogi, R. Robien, K. Rosenberg, L. Schairer, C. Shu, X. Ou van den Brandt, P. A. Virkus, R. A. Wentzensen, N. Xiang, Y-B Xu, W-H Yang, H. P. Brinton, L. A. TI The etiology of uterine sarcomas: a pooled analysis of the epidemiology of endometrial cancer consortium SO BRITISH JOURNAL OF CANCER LA English DT Article DE risk factors; uterine sarcoma; pooled analysis; obesity; diabetes ID HISTOLOGIC TYPES; STROMAL SARCOMA; RISK; TUMORS; UTERUS; MARKERS; OBESITY; OVARIAN; CORPUS AB Background: Uterine sarcomas are characterised by early age at diagnosis, poor prognosis, and higher incidence among Black compared with White women, but their aetiology is poorly understood. Therefore, we performed a pooled analysis of data collected in the Epidemiology of Endometrial Cancer Consortium. We also examined risk factor associations for malignant mixed mullerian tumours (MMMTs) and endometrioid endometrial carcinomas (EECs) for comparison purposes. Methods: We pooled data on 229 uterine sarcomas, 244 MMMTs, 7623 EEC cases, and 28 829 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) for risk factors associated with uterine sarcoma, MMMT, and EEC were estimated with polytomous logistic regression. We also examined associations between epidemiological factors and histological subtypes of uterine sarcoma. Results: Significant risk factors for uterine sarcoma included obesity (body mass index (BMI) >= 30 vs BMI < 25 kg m(-2) (OR: 1.73, 95% CI: 1.22-2.46), P-trend = 0.008) and history of diabetes (OR: 2.33, 95% CI: 1.41-3.83). Older age at menarche was inversely associated with uterine sarcoma risk (>= 15 years vs < 11 years (OR: 0.70, 95% CI: 0.34-1.44), P-trend: 0.04). BMI was significantly, but less strongly related to uterine sarcomas compared with EECs (OR: 3.03, 95% CI: 2.82-3.26) or MMMTs (OR: 2.25, 95% Cl: 1.60-3.15, P-heterogeneity = 0.01). Conclusion: In the largest aetiological study of uterine sarcomas, associations between menstrual, hormonal, and anthropometric risk factors and uterine sarcoma were similar to those identified for EEC. Further exploration of factors that might explain patterns of age- and race-specific incidence rates for uterine sarcoma are needed. C1 [Felix, A. S.] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, NIH, Rockville, MD USA. [Felix, A. S.; Park, Y.; Schairer, C.; Wentzensen, N.; Yang, H. P.; Brinton, L. A.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Cook, L. S.] Univ New Mexico, Dept Internal Med, Div Epidemiol & Biostat, Albuquerque, NM 87131 USA. [Gaudet, M. M.; Gapstur, S. M.; McCullough, M. L.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Rohan, T. E.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Schouten, L. J.; van den Brandt, P. A.] Maastricht Univ, GROW Sch Oncol & Dev Biol, Maastricht, Netherlands. [Setiawan, V. W.; Henderson, B.] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. [Wise, L. A.; Palmer, J. R.; Rosenberg, L.; Virkus, R. A.] Boston Univ, Slone Epidemiol Ctr, Boston, MA 02215 USA. [Anderson, K. E.; Robien, K.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Bernstein, L.; Lacey, J. V.] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA 91010 USA. [De Vivo, I.; Prescott, J.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [De Vivo, I.; Prescott, J.] Harvard Univ, Sch Med, Boston, MA USA. [De Vivo, I.; Prescott, J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Friedenreich, C. M.] Alberta Hlth Serv Canc Care, Div Canc Care, Edmonton, AB, Canada. [Goldbohm, R. A.] Netherlands Org Appl Sci Res TNO, Dept Prevent & Hlth, Leiden, Netherlands. [Horn-Ross, P. L.] Canc Prevent Inst Calif, Fremont, CA USA. [Kolonel, L.] Univ Hawaii, Ctr Canc, Epidemiol Program, Honolulu, HI 96822 USA. [Liang, X.; Olson, S. H.; Rastogi, R.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Lissowska, J.] M Sklodowska Curie Mem Canc Ctr & Inst Oncol, Warsaw, Poland. [Magliocco, A.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Anat Pathol, Tampa, FL 33682 USA. [Miller, A. B.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Shu, X. Ou] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. [Xiang, Y-B; Xu, W-H] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. RP Felix, AS (reprint author), NCI, Canc Prevent Fellowship Program, Canc Prevent Div, NIH, Rockville, MD USA. EM ashley.felix@nih.gov RI Schouten, Leo/G-3713-2012; Brinton, Louise/G-7486-2015; Felix, Ashley/A-3240-2016; OI Brinton, Louise/0000-0003-3853-8562; Palmer, Julie/0000-0002-6534-335X; Lissowska, Jolanta/0000-0003-2695-5799; Wise, Lauren/0000-0003-2138-3752; Robien, Kim/0000-0002-2120-2280; Park, Yikyung/0000-0002-6281-489X FU Intramural Research Program of the National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 28 TC 11 Z9 14 U1 0 U2 21 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD FEB 19 PY 2013 VL 108 IS 3 BP 727 EP 734 DI 10.1038/bjc.2013.2 PG 8 WC Oncology SC Oncology GA 111LS UT WOS:000316523400035 PM 23348519 ER PT J AU Zarelli, VE Dawid, IB AF Zarelli, Valeria E. Dawid, Igor B. TI Inhibition of neural crest formation by Kctd15 involves regulation of transcription factor AP-2 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE neural plate border; Tfap2; FoxD3; transcriptional regulation ID CRANIOFACIAL DEVELOPMENT; SIGNALING PATHWAYS; XENOPUS EMBRYOS; BINDING-SITES; PLATE BORDER; BTB DOMAIN; EXPRESSION; GENE; INDUCTION; ZEBRAFISH AB The neural crest develops in vertebrate embryos within a discrete domain at the neural plate boundary and eventually gives rise to a migrating population of cells that differentiate into a multitude of derivatives. We have shown that the broad-complex, tramtrack and bric a brac (BTB) domain-containing factor potassium channel tetramerization domain containing 15 (Kctd15) inhibits neural crest formation, and we proposed that its function is to delimit the neural crest domain. Here we report that Kctd15 is a highly effective inhibitor of transcription factor activating enhancer binding protein 2 (AP-2) in zebrafish embryos and in human cells; AP-2 is known to be critical for several steps of neural crest development. Kctd15 interacts with AP-2 alpha but does not interfere with its nuclear localization or binding to cognate sites in the genome. Kctd15 binds specifically to the activation domain of AP-2 alpha and efficiently inhibits transcriptional activation by a hybrid protein composed of the regulatory protein Gal4 DNA binding and AP-2 alpha activation domains. Mutation of one proline residue in the activation domain to an alanine (P59A) yields a protein that is highly active but largely insensitive to Kctd15. These results indicate that Kctd15 acts in the embryo at least in part by specifically binding to the activation domain of AP-2 alpha, thereby blocking the function of this critical factor in the neural crest induction hierarchy. C1 [Zarelli, Valeria E.; Dawid, Igor B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. RP Dawid, IB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. EM idawid@nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX We thank Martha Rebbert for assistance with Xenopus experiments, and Sunit Dutta, Ramanujan Hegde, Helen Hurst, Javier Magadan, Hyunju Ro, Tom Sargent, Trevor Williams, and Minho Won for advice and reagents. This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 63 TC 17 Z9 24 U1 0 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 FEB 19 PY 2013 VL 110 IS 8 BP 2870 EP 2875 DI 10.1073/pnas.1300203110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 103YC UT WOS:000315954400058 PM 23382213 ER PT J AU Gostissa, M Bianco, JM Malkin, DJ Kutok, JL Rodig, SJ Morse, HC Bassing, CH Alt, FW AF Gostissa, Monica Bianco, Julia M. Malkin, Daniel J. Kutok, Jeffery L. Rodig, Scott J. Morse, Herbert C., III Bassing, Craig H. Alt, Frederick W. TI Conditional inactivation of p53 in mature B cells promotes generation of nongerminal center-derived B-cell lymphomas SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MARGINAL ZONE LYMPHOMA; CHROMOSOMAL TRANSLOCATIONS; SOMATIC HYPERMUTATION; ONCOGENIC TRANSLOCATIONS; GENOMIC INSTABILITY; P53-DEFICIENT MICE; BREAST-CANCER; HISTONE H2AX; MOUSE MODEL; DNA BREAKS AB The p53 tumor suppressor exerts a central role in protecting cells from oncogenic transformation. Accordingly, the p53 gene is mutated in a large number of human cancers. In mice, germ-line inactivation of p53 confers strong predisposition to development of different types of malignancies, but the early onset of thymic lymphomas in the majority of the animals prevents detailed studies of tumorigenesis in other tissues. Here, we use the Cre/Lox approach to inactivate p53 in mature B cells in mice (referred to as "CP" B cells) and find that such p53 inactivation results in the routine development of IgM-positive CP peripheral B-cell lymphomas. The CP lymphomas generally appear to arise, even in mice subjected to immunization protocols to activate germinal center reaction, from naive B cells that had not undergone immunoglobulin (Ig) heavy chain gene class switching or somatic hypermutation. In contrast to thymic lymphomas that arise in p53-deficient mice, which generally lack clonal translocations, nearly all analyzed CP B-cell tumors carried clonal translocations. However, in contrast to spontaneous translocations in other mouse B-cell tumor models, CP B-cell tumor translocations were not recurrent and did not involve Ig loci. Therefore, CP tumors might provide models for human lymphomas lacking Ig translocations, such as splenic marginal zone B-cell lymphoma or Waldenstrom macroglobulinemia. Our studies indicate that deletion of p53 is sufficient to trigger transformation of mature B cells and support the notion that p53 deficiency may allow accumulation of oncogenic translocations in B cells. C1 [Gostissa, Monica; Bianco, Julia M.; Malkin, Daniel J.; Alt, Frederick W.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston Childrens Hosp, Boston, MA 02115 USA. [Gostissa, Monica; Bianco, Julia M.; Malkin, Daniel J.; Alt, Frederick W.] Harvard Univ, Sch Med, Program Cellular & Mol Med, Boston Childrens Hosp, Boston, MA 02115 USA. [Gostissa, Monica; Bianco, Julia M.; Malkin, Daniel J.; Alt, Frederick W.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Kutok, Jeffery L.; Rodig, Scott J.] Harvard Univ, Sch Med, Dept Pathol, Brigham & Womens Hosp, Boston, MA 02115 USA. [Morse, Herbert C., III] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Bassing, Craig H.] Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. RP Alt, FW (reprint author), Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston Childrens Hosp, Boston, MA 02115 USA. EM alt@enders.tch.harvard.edu OI Morse, Herbert/0000-0002-9331-3705 FU National Institutes of Health [5P01CA92625, CA098285]; Leukemia and Lymphoma Society of America (LLS) Specialized Center of Research grant; Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases FX We thank Roberto Chiarle for helpful suggestions. This work was supported by National Institutes of Health Grants 5P01CA92625 and CA098285 and a Leukemia and Lymphoma Society of America (LLS) Specialized Center of Research grant (to F. W. A.). This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases (to H. C. M.). M. G. was an LLS senior fellow. C. H. B. is an LLS Scholar. F. W. A. is an investigator of the Howard Hughes Medical Institute. NR 48 TC 11 Z9 11 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 19 PY 2013 VL 110 IS 8 BP 2934 EP 2939 DI 10.1073/pnas.1222570110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 103YC UT WOS:000315954400069 PM 23382223 ER PT J AU Baccala, R Gonzalez-Quintial, R Blasius, AL Rimann, I Ozato, K Kono, DH Beutler, B Theofilopoulos, AN AF Baccala, Roberto Gonzalez-Quintial, Rosana Blasius, Amanda L. Rimann, Ivo Ozato, Keiko Kono, Dwight H. Beutler, Bruce Theofilopoulos, Argyrios N. TI Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID I INTERFERON INDUCTION; APOPTOTIC U937 CELLS; TOLL-LIKE RECEPTORS; ACTIVATE B-CELLS; NUCLEIC-ACID; SYSTEMIC AUTOIMMUNITY; RHEUMATOID-ARTHRITIS; SUSCEPTIBILITY LOCI; IMMUNE-COMPLEXES; ALPHA PRODUCTION AB In vitro evidence suggests that plasmacytoid dendritic cells (pDCs) are intimately involved in the pathogenesis of lupus. However, it remains to be determined whether these cells are required in vivo for disease development, and whether their contribution is restricted to hyperproduction of type I IFNs. To address these issues, we created lupus-predisposed mice lacking the IFN regulatory factor 8 (IRF8) or carrying a mutation that impairs the peptide/histidine transporter solute carrier family 15, member 4 (SLC15A4). IRF8-deficient NZB mice, lacking pDCs, showed almost complete absence of anti-nuclear, anti-chromatin, and anti-erythrocyte autoantibodies, along with reduced kidney disease. These effects were observed despite normal B-cell responses to Toll-like receptor (TLR) 7 and TLR9 stimuli and intact humoral responses to conventional T-dependent and -independent antigens. Moreover, Slc15a4 mutant C57BL/6-Fas(lpr) mice, in which pDCs are present but unable to produce type I IFNs in response to endosomal TLR ligands, also showed an absence of autoantibodies, reduced lymphadenopathy and splenomegaly, and extended survival. Taken together, our results demonstrate that pDCs and the production of type I IFNs by these cells are critical contributors to the pathogenesis of lupus-like autoimmunity in these models. Thus, IRF8 and SLC15A4 may provide important targets for therapeutic intervention in human lupus. C1 [Baccala, Roberto; Gonzalez-Quintial, Rosana; Rimann, Ivo; Kono, Dwight H.; Theofilopoulos, Argyrios N.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Blasius, Amanda L.; Beutler, Bruce] Scripps Res Inst, Dept Genet, La Jolla, CA 92037 USA. [Ozato, Keiko] NICHHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Beutler, Bruce] Univ Texas SW Med Ctr Dallas, Ctr Genet Host Def, Dallas, TX 75390 USA. RP Baccala, R (reprint author), Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. EM rbaccala@scripps.edu; Bruce.Beutler@UTSouthwestern.edu; argyrio@scripps.edu FU National Institutes of Health [AR53228, AR31203, AR39555, 1U19-AI100627-01, 2P01-AI070167-06A1]; Irvington Institute Fellowship Program of the Cancer Research Institute FX We thank Carrie N. Arnold for assistance with the B cell proliferation assays and Anthony Nguyen for excellent technical support. This work was supported by National Institutes of Health Grants AR53228, AR31203, AR39555, 1U19-AI100627-01, and 2P01-AI070167-06A1. A. L. B. was supported by The Irvington Institute Fellowship Program of the Cancer Research Institute. This is article number 22092 from The Scripps Research Institute, Department of Immunology and Microbial Sciences. NR 68 TC 37 Z9 37 U1 0 U2 16 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 FEB 19 PY 2013 VL 110 IS 8 BP 2940 EP 2945 DI 10.1073/pnas.1222798110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 103YC UT WOS:000315954400070 PM 23382217 ER PT J AU Patel, V Jalah, R Kulkarni, V Valentin, A Rosati, M Alicea, C von Gegerfelt, A Huang, WS Guan, YJ Keele, BF Bess, JW Piatak, M Lifson, JD Williams, WT Shen, XY Tomaras, GD Amara, RR Robinson, HL Johnson, W Broderick, KE Sardesai, NY Venzon, DJ Hirsch, VM Felber, BK Pavlakis, GN AF Patel, Vainav Jalah, Rashmi Kulkarni, Viraj Valentin, Antonio Rosati, Margherita Alicea, Candido von Gegerfelt, Agneta Huang, Wensheng Guan, Yongjun Keele, Brandon F. Bess, Julian W., Jr. Piatak, Michael, Jr. Lifson, Jeffrey D. Williams, William T. Shen, Xiaoying Tomaras, Georgia D. Amara, Rama R. Robinson, Harriet L. Johnson, Welkin Broderick, Kate E. Sardesai, Niranjan Y. Venzon, David J. Hirsch, Vanessa M. Felber, Barbara K. Pavlakis, George N. TI DNA and virus particle vaccination protects against acquisition and confers control of viremia upon heterologous simian immunodeficiency virus challenge SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE virus acquisition; HIV-1 vaccine; viral vaccines/immunology; humoral immunity; HIV-1/immunology ID RHESUS MACAQUES; IMMUNE-RESPONSES; HIV-1 INFECTION; SIVMAC251 CHALLENGE; T-CELLS; SIV; SIVSME660; EFFICACY; VACCINES; MONKEYS AB We have previously shown that macaques vaccinated with DNA vectors expressing SIVmac239 antigens developed potent immune responses able to reduce viremia upon high-dose SIVmac251 challenge. To further improve vaccine-induced immunity and protection, we combined the SIVmac239 DNA vaccine with protein immunization using inactivated SIVmac239 viral particles as protein source. Twenty-six weeks after the last vaccination, the animals were challenged intrarectally at weekly intervals with a titrated dose of the heterologous SIVsmE660. Two of DNA-protein coimmunized macaques did not become infected after 14 challenges, but all controls were infected by 11 challenges. Vaccinated macaques showed modest protection from SIVsmE660 acquisition compared with naive controls (P = 0.050; stratified for TRIM5 alpha genotype). Vaccinees had significantly lower peak (1.6 log, P = 0.0048) and chronic phase viremia (P = 0.044), with 73% of the vaccinees suppressing viral replication to levels below assay detection during the 40-wk follow-up. Vaccine-induced immune responses associated significantly with virus control: binding antibody titers and the presence of rectal IgG to SIVsmE660 Env correlated with delayed SIVsmE660 acquisition; SIV-specific cytotoxic T cells, prechallenge CD4(+) effector memory, and postchallenge CD8(+) transitional memory cells correlated with control of viremia. Thus, SIVmac239 DNA and protein-based vaccine protocols were able to achieve high, persistent, broad, and effective cellular and humoral immune responses able to delay heterologous SIVsmE660 infection and to provide long-term control of viremia. These studies support a role of DNA and protein-based vaccines for development of an efficacious HIV/AIDS vaccine. C1 [Patel, Vainav; Valentin, Antonio; Rosati, Margherita; von Gegerfelt, Agneta; Pavlakis, George N.] Frederick Natl Lab Canc Res, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21702 USA. [Jalah, Rashmi; Kulkarni, Viraj; Alicea, Candido; Felber, Barbara K.] Frederick Natl Lab Canc Res, Human Retrovirus Pathogenesis Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21702 USA. [Huang, Wensheng; Guan, Yongjun] Univ Maryland, Sch Med, Inst Human Virol, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Keele, Brandon F.; Bess, Julian W., Jr.; Piatak, Michael, Jr.; Lifson, Jeffrey D.] Sci Applicat Int Corp Frederick Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Williams, William T.; Shen, Xiaoying; Tomaras, Georgia D.] Duke Human Vaccine Inst, Durham, NC 27710 USA. [Amara, Rama R.] Emory Univ, Yerkes Natl Primate Ctr, Atlanta, GA 30329 USA. [Robinson, Harriet L.] GeoVax Inc, Smyrna, GA 30080 USA. [Johnson, Welkin] Boston Coll, Dept Biol, Boston, MA 02467 USA. [Broderick, Kate E.; Sardesai, Niranjan Y.] Inovio Pharmaceut Inc, Blue Bell, PA 19422 USA. [Venzon, David J.] NCI, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20852 USA. [Hirsch, Vanessa M.] NIAID, Nonhuman Primate Virol Sect, Mol Microbiol Lab, Bethesda, MD 20814 USA. RP Felber, BK (reprint author), Frederick Natl Lab Canc Res, Human Retrovirus Pathogenesis Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21702 USA. EM felberb@mail.nih.gov; pavlakig@mail.nih.gov RI Tomaras, Georgia/J-5041-2016; bebarta, vikhyat/K-3476-2015 FU National Cancer Institute, National Institutes of Health (NCI/NIH) [HHSN261200800001E]; NIH [AI083118]; National Institute of Allergy and Infectious Diseases-NIH [HHSN27201100016C] FX We thank D. Weiss, J. Treece, E. M. Lee, I. Kalisz, and the staff at Advanced BioScience Laboratory; C. LaBranche and D. C. Montefiori for the Nab assay; Glenn Overman for the mucosal binding antibody assays; B. Chowdhury, T. Ireland, B. Bohn, and J. Miller for technical assistance; and T. Jones for editorial assistance. This work was supported in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health (NCI/NIH) (B. K. F. and G. N. P.); federal funds from the NCI/NIH under Contract HHSN261200800001E (to J. D. L.); NIH Grant AI083118 (to W. J.); and National Institute of Allergy and Infectious Diseases-NIH Contract HHSN27201100016C (to G. D. T., X. S., C. LaBranche, and D. C. Montefiori). NR 31 TC 40 Z9 40 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 19 PY 2013 VL 110 IS 8 BP 2975 EP 2980 DI 10.1073/pnas.1215393110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 103YC UT WOS:000315954400076 PM 23359688 ER PT J AU Wang, DR El-Amouri, SS Dai, M Kuan, CY Hui, DY Brady, RO Pan, D AF Wang, Daren El-Amouri, Salim S. Dai, Mei Kuan, Chia-Yi Hui, David Y. Brady, Roscoe O. Pan, Dao TI Engineering a lysosomal enzyme with a derivative of receptor-binding domain of apoE enables delivery across the blood-brain barrier SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE in vivo evaluation; LDL receptor-related protein 1; lysosomal storage diseases; neurological disorders; CNS protein delivery ID MUCOPOLYSACCHARIDOSIS TYPE-I; APOLIPOPROTEIN-E; HURLER-SYNDROME; GENE-THERAPY; REPLACEMENT THERAPY; ALZHEIMERS-DISEASE; TARGETED DELIVERY; FUSION PROTEIN; DRUG-DELIVERY; BONE-MARROW AB To realize the potential of large molecular weight substances to treat neurological disorders, novel approaches are required to surmount the blood-brain barrier (BBB). We investigated whether fusion of a receptor-binding peptide from apolipoprotein E (apoE) with a potentially therapeutic protein can bind to LDL receptors on the BBB and be transcytosed into the CNS. A lysosomal enzyme, alpha-L-iduronidase (IDUA), was used for biological and therapeutic evaluation in a mouse model of mucopolysaccharidosis (MPS) type I, one of the most common lysosomal storage disorders with CNS deficits. We identified two fusion candidates, IDUAe1 and IDUAe2, by in vitro screening, that exhibited desirable receptor-mediated binding, endocytosis, and transendothelial transport as well as appropriate lysosomal enzyme trafficking and biological function. Robust peripheral IDUAe1 or IDUAe2 generated by transient hepatic expression led to elevated enzyme levels in capillary-depleted, enzyme-deficient brain tissues and protein delivery into nonendothelium perivascular cells, neurons, and astrocytes within 2 d of treatment. Moreover, 5 mo after long-term delivery of moderate levels of IDUAe1 derived from maturing red blood cells, 2% to 3% of normal brain IDUA activities were obtained in MPS I mice, and IDUAe1 protein was detected in neurons and astrocytes throughout the brain. The therapeutic potential was demonstrated by normalization of brain glycosaminoglycan and beta-hexosaminidase in MPS I mice 5 mo after moderate yet sustained delivery of IDUAe1. These findings provide a noninvasive and BBB-targeted procedure for the delivery of large-molecule therapeutic agents to treat neurological lysosomal storage disorders and potentially other diseases that involve the brain. C1 [Wang, Daren; El-Amouri, Salim S.; Dai, Mei; Pan, Dao] Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA. [Kuan, Chia-Yi] Cincinnati Childrens Hosp Med Ctr, Div Dev Biol, Cincinnati, OH 45229 USA. [Hui, David Y.] Univ Cincinnati, Dept Pathol, Cincinnati, OH 45267 USA. [Pan, Dao] Univ Cincinnati, Dept Pediat, Cincinnati, OH 45267 USA. [Brady, Roscoe O.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. RP Brady, RO (reprint author), Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. EM bradyr@ninds.nih.gov; dao.pan@cchmc.org FU National Institutes of Health [NS064330, DK074932, U54 HL06-008] FX We thank Meghan Bromwell and the Comprehensive Mouse Core for technical assistance. We thank Dr. C. Miao (Seattle Children's Research Institute) for the pBS-HCRHPI-A plasmid and Dr. M. Krieger (Massachusetts Institute of Technology) for the CHOLDLRneg cell line. This work was supported by the National Institutes of Health Grants NS064330, DK074932, and U54 HL06-008. NR 37 TC 27 Z9 27 U1 0 U2 17 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 FEB 19 PY 2013 VL 110 IS 8 BP 2999 EP 3004 DI 10.1073/pnas.1222742110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 103YC UT WOS:000315954400080 PM 23382178 ER PT J AU Arnold, ES Ling, SC Huelga, SC Lagier-Tourenne, C Polymenidou, M Ditsworth, D Kordasiewicz, HB McAlonis-Downes, M Platoshyn, O Parone, PA Da Cruz, S Clutario, KM Swing, D Tessarollo, L Marsala, M Shaw, CE Yeo, GW Cleveland, DW AF Arnold, Eveline S. Ling, Shuo-Chien Huelga, Stephanie C. Lagier-Tourenne, Clotilde Polymenidou, Magdalini Ditsworth, Dara Kordasiewicz, Holly B. McAlonis-Downes, Melissa Platoshyn, Oleksandr Parone, Philippe A. Da Cruz, Sandrine Clutario, Kevin M. Swing, Debbie Tessarollo, Lino Marsala, Martin Shaw, Christopher E. Yeo, Gene W. Cleveland, Don W. TI ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE neurodegeneration; RNA binding proteins; frontotemporal dementia ID AMYOTROPHIC-LATERAL-SCLEROSIS; FRONTOTEMPORAL LOBAR DEGENERATION; DNA-BINDING PROTEIN-43; TRANSGENIC MICE; SPINAL-CORD; PROCESSING PROTEIN; CELLULAR TOXICITY; TARDBP MUTATIONS; ALPHA-SYNUCLEIN; MUTANT TDP-43 AB Transactivating response region DNA binding protein (TDP-43) is the major protein component of ubiquitinated inclusions found in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitinated inclusions. Two ALS-causing mutants (TDP-43(Q331K) and TDP-43(M337V)), but not wild-type human TDP-43, are shown here to provoke age-dependent, mutant-dependent, progressive motor axon degeneration and motor neuron death when expressed in mice at levels and in a cell type-selective pattern similar to endogenous TDP-43. Mutant TDP-43-dependent degeneration of lower motor neurons occurs without: (i) loss of TDP-43 from the corresponding nuclei, (ii) accumulation of TDP-43 aggregates, and (iii) accumulation of insoluble TDP-43. Computational analysis using splicing-sensitive microarrays demonstrates alterations of endogenous TDP-43-dependent alternative splicing events conferred by both human wild-type and mutant TDP-43(Q331K), but with high levels of mutant TDP-43 preferentially enhancing exon exclusion of some target pre-mRNAs affecting genes involved in neurological transmission and function. Comparison with splicing alterations following TDP-43 depletion demonstrates that TDP-43(Q331K) enhances normal TDP-43 splicing function for some RNA targets but loss-of-function for others. Thus, adult-onset motor neuron disease does not require aggregation or loss of nuclear TDP-43, with ALS-linked mutants producing loss and gain of splicing function of selected RNA targets at an early disease stage. C1 [Ling, Shuo-Chien; Cleveland, Don W.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Arnold, Eveline S.; Ling, Shuo-Chien; Huelga, Stephanie C.; Lagier-Tourenne, Clotilde; Polymenidou, Magdalini; Ditsworth, Dara; Kordasiewicz, Holly B.; McAlonis-Downes, Melissa; Parone, Philippe A.; Da Cruz, Sandrine; Clutario, Kevin M.; Yeo, Gene W.; Cleveland, Don W.] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. [Platoshyn, Oleksandr; Marsala, Martin] Univ Calif San Diego, Dept Anesthesiol, La Jolla, CA 92093 USA. [Arnold, Eveline S.; Ling, Shuo-Chien; Lagier-Tourenne, Clotilde; Polymenidou, Magdalini; Ditsworth, Dara; Kordasiewicz, Holly B.; McAlonis-Downes, Melissa; Parone, Philippe A.; Da Cruz, Sandrine; Clutario, Kevin M.; Cleveland, Don W.] Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA. [Huelga, Stephanie C.; Platoshyn, Oleksandr; Marsala, Martin; Yeo, Gene W.] Univ Calif San Diego, Stem Cell Program, La Jolla, CA 92093 USA. [Huelga, Stephanie C.; Platoshyn, Oleksandr; Marsala, Martin; Yeo, Gene W.] Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA. [Swing, Debbie; Tessarollo, Lino] NCI, Neural Dev Sect, Mouse Canc Genet Program, Frederick, MD 21702 USA. [Shaw, Christopher E.] Kings Coll London, Inst Psychiat, MRC, Ctr Neurodegenerat Res, London SE5 8AF, England. RP Cleveland, DW (reprint author), Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA. EM dcleveland@ucsd.edu FU Wellcome Trust; Ludwig Institute for Cancer Research; University of California San Diego Genetics Training Grant National Institute of General Medical Sciences [T32 GM008666]; National Institutes of Health Neuroplasticity of Aging Training Grant [T32 AG 000216]; National Science Foundation Graduate Research Fellowship; Amyotrophic Lateral Sclerosis Association; Muscular Dystrophy Association Career Development Award; National Institutes of Health [NS075449, HG004659, NS075216]; [NS069144] FX The authors thank Timothy Meerloo and Ying Jones (University of California at San Diego) and Janet Folmer (The Johns Hopkins University) for technical assistance in plastic thin sectioning and staining; Seiya Tokunaga, Sandra Lee, Anne Vetto, and Han Jin Park for technical assistance; and all members of the D. W. C. laboratory for helpful suggestions and discussion regarding the work. This work was supported by a Wellcome Trust grant (to D. W. C. and C. E. S.) and Grant NS069144 (to D. W. C.); salary support from the Ludwig Institute for Cancer Research (D. W. C.); University of California San Diego Genetics Training Grant National Institute of General Medical Sciences T32 GM008666 (to E. S. A.); National Institutes of Health Neuroplasticity of Aging Training Grant T32 AG 000216 (to S.-C. L.); a National Science Foundation Graduate Research Fellowship (to S. C. H.); a Milton Safenowitz Postdoctoral Fellowship from the Amyotrophic Lateral Sclerosis Association (to D. D.); a Muscular Dystrophy Association Career Development Award (to C. L.-T.); and National Institutes of Health Grants NS075449 and HG004659 (to G. W. Y.) and NS075216 (to M. P.). G. W. Y. is an Alfred P. Sloan Research Fellow. NR 63 TC 80 Z9 83 U1 3 U2 33 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 FEB 19 PY 2013 VL 110 IS 8 BP E736 EP E745 DI 10.1073/pnas.1222809110 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 103YC UT WOS:000315954400016 PM 23382207 ER PT J AU Frisz, JF Lou, KY Klitzing, HA Hanafin, WP Lizunov, V Wilson, RL Carpenter, KJ Kim, R Hutcheon, ID Zimmerberg, J Weber, PK Kraft, ML AF Frisz, Jessica F. Lou, Kaiyan Klitzing, Haley A. Hanafin, William P. Lizunov, Vladimir Wilson, Robert L. Carpenter, Kevin J. Kim, Raehyun Hutcheon, Ian D. Zimmerberg, Joshua Weber, Peter K. Kraft, Mary L. TI Direct chemical evidence for sphingolipid domains in the plasma membranes of fibroblasts SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE SIMS; stable isotope ID ION MASS-SPECTROMETRY; GPI-ANCHORED PROTEINS; CELL-MEMBRANE; LIPID RAFTS; INFLUENZA-VIRUS; CHOLESTEROL; SURFACE; ACTIN; ORGANIZATION; MOLECULES AB Sphingolipids play important roles in plasma membrane structure and cell signaling. However, their lateral distribution in the plasma membrane is poorly understood. Here we quantitatively analyzed the sphingolipid organization on the entire dorsal surface of intact cells by mapping the distribution of N-15-enriched ions from metabolically labeled N-15-sphingolipids in the plasma membrane, using high-resolution imaging mass spectrometry. Many types of control experiments (internal, positive, negative, and fixation temperature), along with parallel experiments involving the imaging of fluorescent sphingolipids-both in living cells and during fixation of living cells-exclude potential artifacts. Micrometer-scale sphingolipid patches consisting of numerous N-15-sphingolipid microdomains with mean diameters of similar to 200 nm are always present in the plasma membrane. Depletion of 30% of the cellular cholesterol did not eliminate the sphingolipid domains, but did reduce their abundance and long-range organization in the plasma membrane. In contrast, disruption of the cytoskeleton eliminated the sphingolipid domains. These results indicate that these sphingolipid assemblages are not lipid rafts and are instead a distinctly different type of sphingolipid-enriched plasma membrane domain that depends upon cortical actin. C1 [Frisz, Jessica F.; Lou, Kaiyan; Klitzing, Haley A.; Hanafin, William P.; Wilson, Robert L.; Kim, Raehyun; Kraft, Mary L.] Univ Illinois, Sch Chem Sci, Urbana, IL 61801 USA. [Lizunov, Vladimir; Zimmerberg, Joshua] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Carpenter, Kevin J.; Hutcheon, Ian D.; Weber, Peter K.] Lawrence Livermore Natl Lab, Glenn T Seaborg Inst, Livermore, CA 94551 USA. RP Kraft, ML (reprint author), Univ Illinois, Sch Chem Sci, Urbana, IL 61801 USA. EM mlkraft@illinois.edu RI Lou, Kaiyan/D-4199-2012; Wunder, Stephanie/B-5066-2012; Zdilla, Michael/B-4145-2011 OI Lou, Kaiyan/0000-0003-3443-0343; FU US Department of Energy [DE-FG02-07ER46471]; Burroughs Wellcome Fund; National Institutes of Health [T32 GM070421]; Laboratory Directed Research and Development funding; National Institute of Child Health and Human Development; National Institutes of Health; National Science Foundation [CHE-1058809] FX We thank C. Ramon for technical assistance and L. R. Nittler for software development. Portions of this work were carried out in the Metabolomics Center in the Roy J. Carver Biotechnology Center, University of Illinois and the Frederick Seitz Materials Research Laboratory Central Facilities, University of Illinois, which is partially supported by the US Department of Energy under Grant DE-FG02-07ER46471. M. L. K. holds a Career Award at the Scientific Interface from the Burroughs Wellcome Fund. J. F. F. was supported by the National Institutes of Health Training Program in the Chemistry-Biology Interface (T32 GM070421). Work at Lawrence Livermore National Laboratory was supported by Laboratory Directed Research and Development funding and performed under the auspices of the US Department of Energy under Contract DE-AC52-07NA27344. This work was partially supported by the Intramural Program of the National Institute of Child Health and Human Development; National Institutes of Health; and by the National Science Foundation under Grant CHE-1058809. NR 52 TC 60 Z9 60 U1 3 U2 59 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 FEB 19 PY 2013 VL 110 IS 8 BP E613 EP E622 DI 10.1073/pnas.1216585110 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 103YC UT WOS:000315954400003 PM 23359681 ER PT J AU Ng, KY Chew, KK Kaur, P Kwan, JY Khong, WX Lin, L Chua, A Tan, MT Quinn, TC Laeyendecker, O Leo, YS Ng, OT AF Ng, Kah Ying Chew, Kuan Kiat Kaur, Palvinder Kwan, Joe Yap Khong, Wei Xin Lin, Li Chua, Arlene Tan, Mei Ting Quinn, Thomas C. Laeyendecker, Oliver Leo, Yee Sin Ng, Oon Tek TI High prevalence of CXCR4 usage among treatment-naive CRF01_AE and CRF51_01B-infected HIV-1 subjects in Singapore SO BMC INFECTIOUS DISEASES LA English DT Article DE CXCR4 usage; HIV-1; treatment-naive ID SYNCYTIUM-INDUCING PHENOTYPE; CORECEPTOR USAGE; VIRAL TROPISM; PREDICTION; SUBTYPES; TOOLS AB Background: Recent studies suggest HIV-1 inter-subtype differences in co-receptor usage. We examined the correlation between HIV-1 subtype and co-receptor usage among treatment-naive HIV-1 subjects in Singapore. Additionally, we investigated whether the subtype co-receptor association was influenced by stage of infection. Methods: V3 sequences of HIV-1 envelope protein gp120 were obtained from 110 HIV treatment-naive patients and genotypic co-receptor tropism determination was performed using Geno2pheno. Two false-positive rate (FPR) cut-offs, 10% and 5.75% were selected for tropism testing. Results: Subtype assignment of viral strains from 110 HIV-infected individuals based on partial sequencing of HIV-1 pol, gp120 and gp41 were as follows: 27 subtype B, 64 CRF01_AE, 10 CRF51_01B, and 9 other subtypes. At FPR=10%, 10 (100%) CRF51_01B-infected subjects and 26 (40.6%) CRF01_AE-infected subjects had CXCR4-using virus, compared to 7 (25.9%) subtype B subjects and 1 (11.1%) CRF33_01B-infected subject (P < 0.001). At FPR=5.75%, 10 (100%) CRF51_01B-infected subjects and 20 (31.3%) CRF01_AE-infected subjects had CXCR4-using virus, compared to 4 (14.8%) subtype B and 1 (11.1%) CRF33_01B-infected subjects (P < 0.001). Among those with evidence of seroconversion within 2 years prior to study enrolment, 100% of CRF51_01B-infected subjects had CXCR4-using virus, independent of Geno2pheno FPR. Conclusion: CRF51_01B and CRF01_AE-infected individuals have higher prevalence of CXCR4-usage compared to subtype B infected individuals. Further studies examining these differences could help optimise the use of CCR5-antagonist in populations with these subtypes, and increase our understanding of HIV-1 biology. C1 [Ng, Kah Ying; Chew, Kuan Kiat; Kaur, Palvinder; Kwan, Joe Yap; Khong, Wei Xin; Chua, Arlene; Tan, Mei Ting; Leo, Yee Sin; Ng, Oon Tek] Tan Tock Seng Hosp, Inst Infect Dis & Epidemiol, Communicable Dis Ctr, Singapore 308433, Singapore. [Lin, Li] Jurong Gen Hosp, Dept Infect Dis, Singapore 159964, Singapore. [Quinn, Thomas C.; Laeyendecker, Oliver] Johns Hopkins Sch Med, Baltimore, MD USA. [Quinn, Thomas C.; Laeyendecker, Oliver] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Baltimore, MD USA. RP Ng, OT (reprint author), Tan Tock Seng Hosp, Inst Infect Dis & Epidemiol, Communicable Dis Ctr, Singapore 308433, Singapore. EM oon_tek_NG@ttsh.com.sg RI Laeyendecker, Oliver/B-9331-2009; OI Laeyendecker, Oliver/0000-0002-6429-4760; Chua, Arlene/0000-0001-6428-9083 FU A Singapore National Medical Research Training Fellowship; Division of Intramural Research, NIAID, NIH FX A Singapore National Medical Research Training Fellowship grant provided salary support for O.T. Ng. We acknowledge the physicians, staff, and patients of the outpatient service at the Communicable Disease Centre, Singapore who made this study possible. Additional support was provided by the Division of Intramural Research, NIAID, NIH. NR 19 TC 8 Z9 8 U1 0 U2 3 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 FEB 19 PY 2013 VL 13 AR 90 DI 10.1186/1471-2334-13-90 PG 6 WC Infectious Diseases SC Infectious Diseases GA 099OA UT WOS:000315629900001 PM 23421710 ER PT J AU Hall, B Nakashima, H Sun, ZJ Sato, Y Bian, YS Husain, SR Puri, RK Kulkarni, AB AF Hall, Bradford Nakashima, Hideyuki Sun, Zhi-Jun Sato, Yuki Bian, Yansong Husain, Syed R. Puri, Raj K. Kulkarni, Ashok B. TI Targeting of interleukin-13 receptor alpha 2 for treatment of head and neck squamous cell carcinoma induced by conditional deletion of TGF-beta and PTEN signaling SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE IL-13 receptor; Immunotoxin; TGF-beta; PTEN; HNSCC ID POTENT ANTITUMOR-ACTIVITY; CHIMERIC FUSION PROTEINS; MURINE TUMOR-MODELS; PSEUDOMONAS EXOTOXIN; IL-13 CYTOTOXIN; MOUSE MODEL; EXPRESSION; CANCER; THERAPY; CHAIN AB Background: The sixth leading class of cancer worldwide is head and neck cancer, which typically arise within the squamous epithelium of the oral mucosa. Human head and neck squamous cell carcinoma (HNSCC) is known to be difficult to treat and has only a 50% five-year survival rate. With HNSCC, novel therapeutics are needed along with a means of rapidly screening anti-cancer agents in vivo, such as mouse models. Methods: In order to develop new animal models of cancer to test safety and efficacy of novel therapeutic agents for human HNSCC, tumors resembling clinical cases of human HNSCC were induced in the head and neck epithelium of a genetically engineered mouse model. This mouse model was generated by conditional deletion of two tumor suppressors, Transforming Growth Factor-beta Receptor 1 (TGF beta RI) and Phosphatase and Tensin homolog (PTEN), in the oral epithelium. We discovered that the tumors derived from these Tgfbr1/Pten double conditional knockout (2cKO) mice over-expressed IL-13R alpha 2, a high affinity receptor for IL-13 that can function as a tumor antigen. To demonstrate a proof-of-concept that targeted therapy against IL-13R alpha 2 expression would have any antitumor efficacy in this spontaneous tumor model, these mice were treated systemically with IL-13-PE, a recombinant immunotoxin consisting of IL-13 fused to the Pseudomonas exotoxin A. Results: Tgfbr1/Pten 2cKO mice when treated with IL-13-PE displayed significantly increased survival when compared to the untreated control mice. The untreated mice exhibited weight loss, particularly with the rapid onset of tongue tumors, but the treated mice gained weight while on IL-13-PE therapy and showed no clinical signs of toxicity due to the immunotoxin. Expression of IL-13Ra2 in tumors was significantly decreased with IL-13-PE treatment as compared to the controls and the number of myeloid-derived suppressor cells (MDSC) was also significantly reduced in the spleens of the IL-13-PE treated mice. Conclusions: Our study demonstrates that the Tgfbr1/Pten 2cKO mouse model of human HNSCC is a useful model for assessing antitumor activity of new cancer therapeutic agents, and that IL-13-PE has therapeutic potential to treat human head and neck cancer. C1 [Hall, Bradford; Sun, Zhi-Jun; Bian, Yansong; Kulkarni, Ashok B.] Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. [Nakashima, Hideyuki; Sato, Yuki; Husain, Syed R.; Puri, Raj K.] US FDA, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. [Bian, Yansong] Natl Inst Deafness & Other Commun Disorders, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bethesda, MD USA. RP Kulkarni, AB (reprint author), Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Lab Cell & Dev Biol, NIH, 30 Convent Dr,Bldg 30,Room 130, Bethesda, MD USA. EM ak40m@nih.gov FU Division of Intramural Research of the National Institute of Dental and Craniofacial Research, NIH [ZIA-DE-000698]; Center for Biologics Evaluation and Research, U.S. Food and Drug Administration; National Institute of Dental and Craniofacial Research; National Institute on Deafness and Other Communication Disorders, NIH FX We thank Riddhi Patel for help with the biochemical analysis of tumors, Alfredo Molinolo for the analysis of the tumor sections, and Shelagh Johnson for expert editorial assistance. We are grateful to Drs. Jing Han and Shyh-Ching Lo, CBER, FDA for internal review of the manuscript. These studies were supported by the Division of Intramural Research of the National Institute of Dental and Craniofacial Research, NIH to ABK (ZIA-DE-000698), and the Center for Biologics Evaluation and Research, U.S. Food and Drug Administration.; Intramural Research Programs of the National Institute of Dental and Craniofacial Research and National Institute on Deafness and Other Communication Disorders, NIH, and the Center for Biologics Evaluation and Research, U.S. Food and Drug Administration. NR 31 TC 5 Z9 8 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD FEB 19 PY 2013 VL 11 AR 45 DI 10.1186/1479-5876-11-45 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 099PL UT WOS:000315633600002 PM 23421960 ER PT J AU Duggal, P Thio, CL Wojcik, GL Goedert, JJ Mangia, A Latanich, R Kim, AY Lauer, GM Chung, RT Peters, MG Kirk, GD Mehta, SH Cox, AL Khakoo, SI Alric, L Cramp, ME Donfield, SM Edlin, BR Tobler, LH Busch, MP Alexander, G Rosen, HR Gao, XJ Abdel-Hamid, M Apps, R Carrington, M Thomas, DL AF Duggal, Priya Thio, Chloe L. Wojcik, Genevieve L. Goedert, James J. Mangia, Alessandra Latanich, Rachel Kim, Arthur Y. Lauer, Georg M. Chung, Raymond T. Peters, Marion G. Kirk, Gregory D. Mehta, Shruti H. Cox, Andrea L. Khakoo, Salim I. Alric, Laurent Cramp, Matthew E. Donfield, Sharyne M. Edlin, Brian R. Tobler, Leslie H. Busch, Michael P. Alexander, Graeme Rosen, Hugo R. Gao, Xiaojiang Abdel-Hamid, Mohamed Apps, Richard Carrington, Mary Thomas, David L. TI Genome-Wide Association Study of Spontaneous Resolution of Hepatitis C Virus Infection: Data From Multiple Cohorts SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID SPONTANEOUS CLEARANCE; GENETIC-VARIATION; HCV INFECTION; VIRAL LOAD; HLA; VIREMIA; GENOTYPE; PERSISTENCE; POPULATION; VARIANTS AB Background: Hepatitis C virus (HCV) infections occur worldwide and either spontaneously resolve or persist and markedly increase the person's lifetime risk for cirrhosis and hepatocellular carcinoma. Although HCV persistence occurs more often in persons of African ancestry and persons with genetic variants near interleukin-28B (IL-28B), the genetic basis is not well-understood. Objective: To evaluate the host genetic basis for spontaneous resolution of HCV infection. Design: 2-stage, genome-wide association study. Setting: 13 international multicenter study sites. Patients: 919 persons with serum HCV antibodies but no HCV RNA (spontaneous resolution) and 1482 persons with serum HCV antibodies and HCV RNA (persistence). Measurements: Frequencies of 792 721 single nucleotide polymorphisms (SNPs). Results: Differences in allele frequencies between persons with spontaneous resolution and persistence were identified on chromosomes 19q13.13 and 6p21.32. On chromosome 19, allele frequency differences localized near IL-28B and included rs12979860 (overall per-allele OR, 0.45; P = 2.17 x 10(-30)) and 10 additional SNPs spanning 55 000 base pairs. On chromosome 6, allele frequency differences localized near genes for HLA class II and included rs4273729 (overall per-allele OR, 0.59; P = 1.71 x 10(-16)) near DQB1*03:01 and an additional 116 SNPs spanning 1 090 000 base pairs. The associations in chromosomes 19 and 6 were independent and additive and explain an estimated 14.9% (95% CI, 8.5% to 22.6%) and 15.8% (CI, 4.4% to 31.0%) of the variation in HCV resolution in persons of European and African ancestry, respectively. Replication of the chromosome 6 SNP, rs4272729, in an additional 745 persons confirmed the findings (P = 0.015). Limitation: Epigenetic effects were not studied. Conclusion: IL-28B and HLA class II are independently associated with spontaneous resolution of HCV infection, and SNPs marking IL-28B and DQB1*03:01 may explain approximately 15% of spontaneous resolution of HCV infection. C1 Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. NCI, Rockville, MD 20852 USA. IRCCS Casa Sollievo Sofferenza, San Giovanni Rotondo, Italy. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. Ragon Inst Harvard, Boston, MA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Blood Syst Res Inst, Viral Reference Lab, San Francisco, CA 94118 USA. Blood Syst Res Inst, Repository Core, San Francisco, CA 94118 USA. Univ Southampton, Southampton, Hants, England. Southampton Gen Hosp, Southampton SO9 4XY, Hants, England. Univ Toulouse 3, F-31062 Toulouse, France. Plymouth Hosp NHS Trust, SW Liver Unit, Plymouth, Devon, England. Rho, Chapel Hill, NC USA. State Univ New York Downstate Coll Med, Brooklyn, NY USA. Cambridge Univ Hosp NHS Fdn Trust, Cambridge, England. Addenbrookes Hosp, Cambridge, England. Univ Colorado, Denver, CO 80045 USA. Menia Univ, Al Minya, Egypt. Natl Hepatol & Trop Dis Res Inst, Viral Hepatitis Res Lab, Cairo, Egypt. Frederick Natl Lab Canc Res, Canc & Inflammat Program, Expt Immunol Lab, Sci Applicat Int Corp Frederick, Frederick, MD USA. RP Thomas, DL (reprint author), Johns Hopkins Sch Med, 1830 E Monument St,Suite 437, Baltimore, MD 21287 USA. EM pduggal@jhsph.edu; dthomas@jhmi.edu OI Edlin, Brian/0000-0001-8172-8797; Khakoo, Salim/0000-0002-4057-9091 FU Office of AIDS Research, National Institutes of Health; Frederick National Laboratory for Cancer Research; Office of AIDS Research through the Center for Inherited Diseases at Johns Hopkins University; National Institute on Drug Abuse [R01013324, DA033541, DA12568, DA04334]; National Institute of Allergy and Infectious Diseases [U19AI088791, AI082630]; Frederick National Laboratory for Cancer Research [HHSN261200800001E]; National Institutes of Health; National Institute of Allergy and Infectious Diseases; National Cancer Institute [UO1-AI-35042, UL1-RR025005, UO1-AI-35043, UO1-AI-35039, UO1-AI-35040, UO1-AI-35041]; National Institute of Allery and Infectious Diseases [UO1-AI35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI34993, UO1-AI-42590]; National Institute of Child Health and Human Development [UO1-HD-32632]; [R01HL076902]; [R01-DA16159]; [R01-DA21550]; [UL1-RR024996] FX Office of AIDS Research, National Institutes of Health, and Frederick National Laboratory for Cancer Research.; This project was funded in whole or in part by the Office of AIDS Research through the Center for Inherited Diseases at Johns Hopkins University, the National Institute on Drug Abuse (R01013324, DA033541, DA12568, and DA04334), the National Institute of Allergy and Infectious Diseases (U19AI088791 and AI082630), and the Frederick National Laboratory for Cancer Research (contract HHSN261200800001E). This research was supported in part by the Intramural Research Programs of the National Institutes of Health and the Frederick National Laboratory for Cancer Research. The MACS is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute (UO1-AI-35042, UL1-RR025005, UO1-AI-35043, UO1-AI-35039, UO1-AI-35040, and UO1-AI-35041). The WIHS is funded by the National Institute of Allery and Infectious Diseases (UO1-AI35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI34993, and UO1-AI-42590) and by the National Institute of Child Health and Human Development (UO1-HD-32632). The REVELL cohort was funded by R01HL076902. Swann cohort was funded by R01-DA16159, R01-DA21550, and UL1-RR024996. NR 38 TC 82 Z9 82 U1 0 U2 8 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 FEB 19 PY 2013 VL 158 IS 4 BP 235 EP 245 DI 10.7326/0003-4819-158-4-201302190-00003 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 098WR UT WOS:000315580300014 PM 23420232 ER PT J AU Johnson, AD Hwang, SJ Voorman, A Morrison, A Peloso, GM Hsu, YH Thanassoulis, G Newton-Cheh, C Rogers, IS Hoffmann, U Freedman, JE Fox, CS Psaty, BM Boerwinkle, E Cupples, LA O'Donnell, CJ AF Johnson, Andrew D. Hwang, Shih-Jen Voorman, Arend Morrison, Alanna Peloso, Gina M. Hsu, Yi-Hsiang Thanassoulis, George Newton-Cheh, Christopher Rogers, Ian S. Hoffmann, Udo Freedman, Jane E. Fox, Caroline S. Psaty, Bruce M. Boerwinkle, Eric Cupples, L. Adrienne O'Donnell, Christopher J. TI Resequencing and Clinical Associations of the 9p21.3 Region A Comprehensive Investigation in the Framingham Heart Study SO CIRCULATION LA English DT Article DE atherosclerosis; calcium; genetics; myocardial infarction; risk factors ID GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; SINGLE NUCLEOTIDE POLYMORPHISMS; ABDOMINAL AORTIC-ANEURYSM; CHROMOSOME 9P21; MYOCARDIAL-INFARCTION; COMMON SNPS; VARIANTS; LOCUS; ANRIL AB Background-9p21.3 is among the most strongly replicated regions for cardiovascular disease. There are few reports of sequencing the associated 9p21.3 interval. We set out to sequence the 9p21.3 region followed by a comprehensive study of genetic associations with clinical and subclinical cardiovascular disease and its risk factors, as well as with copy number variation and gene expression, in the Framingham Heart Study (FHS). Methods and Results-We sequenced 281 individuals (94 with myocardial infarction, 94 with high coronary artery calcium levels, and 93 control subjects free of elevated coronary artery calcium or myocardial infarction), followed by genotyping and association in >7000 additional FHS individuals. We assessed genetic associations with clinical and subclinical cardiovascular disease, risk factor phenotypes, and gene expression levels of the protein-coding genes CDKN2A and CDKN2B and the noncoding gene ANRIL in freshly harvested leukocytes and platelets. Within this large sample, we found strong associations of 9p21.3 variants with increased risk for myocardial infarction, higher coronary artery calcium levels, and larger abdominal aorta diameters and no evidence for association with traditional cardiovascular disease risk factors. No common protein-coding variation, variants in splice donor or acceptor sites, or copy number variation events were observed. By contrast, strong associations were observed between genetic variants and gene expression, particularly for a short isoform of ANRIL and for CDKN2B. Conclusions-Our thorough genomic characterization of 9p21.3 suggests common variants likely account for observed disease associations and provides further support for the hypothesis that complex regulatory variation affecting ANRIL and CDKN2B gene expression may contribute to increased risk for clinically apparent and subclinical coronary artery disease and aortic disease. (Circulation. 2013;127:799-810.) C1 [Johnson, Andrew D.; Hwang, Shih-Jen; Peloso, Gina M.; Thanassoulis, George; Fox, Caroline S.; Cupples, L. Adrienne; O'Donnell, Christopher J.] NHLBI, NIH, Framingham Heart Study, Framingham, MA USA. [Johnson, Andrew D.; Hwang, Shih-Jen; Fox, Caroline S.; O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [Voorman, Arend] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [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. [Morrison, Alanna; Boerwinkle, Eric] Baylor Coll Med, Texas Med Ctr, Program Human Genet, Houston, TX 77030 USA. [Peloso, Gina M.; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Hsu, Yi-Hsiang] Harvard Univ, Sch Med, Hebrew SeniorLife Inst Aging Res, Boston, MA USA. [Thanassoulis, George] McGill Univ, Ctr Hlth, Montreal, PQ, Canada. [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. [Rogers, Ian S.; Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Newton-Cheh, Christopher] Broad Inst Harvard & MIT, Program Med & Populat Genet, Boston, MA USA. [Rogers, Ian S.] Stanford Univ, Div Cardiovasc Med, Stanford, CA 94305 USA. [Freedman, Jane E.] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Hlth Res Inst, Seattle, WA USA. [O'Donnell, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. RP O'Donnell, CJ (reprint author), 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM odonnellc@nhlbi.nih.gov RI Johnson, Andrew/G-6520-2013; OI Cupples, L. Adrienne/0000-0003-0273-7965 FU National Heart, Lung, and Blood Institute (NHLBI) DNA Resequencing and Genotyping Program [N01-HV-48194]; NHLBI's FHS [N01-HC-25195]; Affymetrix, Inc [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center; National Institute of Arthritis and Musculoskeletal and Skin Diseases [R21-AR056405]; NHLBI [RC2-HL02419, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01-HL-087641, R01-HL-59367, R01-HL-086694, N01-HC-85239, N01-HC-85079, N01-HC-85080]; National Human Genome Research Institute [U01-HG-004402]; National Institutes of Health [HHSN268200625226C, UL1-RR-025005]; NIH Roadmap for Medical Research; National Institute on Aging [AG-023629, AG-15928, AG-20098, AG-027058]; National Center of Advancing Translational Technologies Clinical & Translational Science Institute [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; NHLBI. [N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HHSN268201200036C, HL080295, HL087652, HL105756, 1T32 HL076136] FX Resequencing provided via the National Heart, Lung, and Blood Institute (NHLBI) DNA Resequencing and Genotyping Program by N01-HV-48194. Work on CNV calling and the FHS LD map was supported by the NHLBI's FHS (contract No. N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (contract No. N02-HL-6-4278). A portion of this research used the Linux Cluster for Genetic Analysis (LinGA-II), funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. CNV calling was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases grant R21-AR056405. Whole genome sequencing in CHS and ARIC was conducted as part of the CHARGE-S (Cohorts for Heart and Aging Research in Genome Epidemiology Consortium) sequencing programming supported by NHLBI Grand Opportunity grant RC2-HL02419. The ARIC Study is supported by NHLBI contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022 and grants R01-HL-087641, R01-HL-59367, and R01-HL-086694; National Human Genome Research Institute contract U01-HG-004402; and National Institutes of Health contract HHSN268200625226C. The infrastructure was supported in part by grant No. UL1-RR-025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. The CHS research was supported by NHLBI contracts N01-HC-85239, N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, and HHSN268201200036C and NHLBI grants HL080295, HL087652, and HL105756, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the National Institute on Aging. See also the CHS Web site (http://www.chsnhlbi.org/pi.htm). DNA handling and genotyping was supported in part by National Center of Advancing Translational Technologies Clinical & Translational Science Institute grant UL1TR000124 and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. We thank Daniel Levy and Dr O'Donnell for genotyping funding. Dr Rogers was supported by NHLBI 1T32 HL076136. Dr Johnson was supported by an NHLBI Intramural Research Training Award fellowship. NR 41 TC 31 Z9 33 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 19 PY 2013 VL 127 IS 7 BP 799 EP 810 DI 10.1161/CIRCULATIONAHA.112.111559 PG 12 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 094YS UT WOS:000315302200017 PM 23315372 ER PT J AU Magnuson, EA Farkouh, ME Fuster, V Wang, KJ Vilain, K Li, HY Appelwick, J Muratov, V Sleeper, LA Boineau, R Abdallah, M Cohen, DJ AF Magnuson, Elizabeth A. Farkouh, Michael E. Fuster, Valentin Wang, Kaijun Vilain, Katherine Li, Haiyan Appelwick, Jaime Muratov, Victoria Sleeper, Lynn A. Boineau, Robin Abdallah, Mouin Cohen, David J. CA FREEDOM Trial Investigators TI Cost-Effectiveness of Percutaneous Coronary Intervention With Drug Eluting Stents Versus Bypass Surgery for Patients With Diabetes Mellitus and Multivessel Coronary Artery Disease Results From the FREEDOM Trial SO CIRCULATION LA English DT Article DE coronary artery bypass grafting; cost-benefit analysis; diabetes mellitus; drug-eluting stents; percutaneous coronary intervention ID QUALITY-OF-LIFE; MEDICAL COSTS; REVASCULARIZATION; ANGIOPLASTY; METAANALYSIS; ARTS; RANDOMIZATION; STANDARD; EFFICACY; OUTCOMES AB Background-Studies from the balloon angioplasty and bare metal stent eras have demonstrated that coronary artery bypass grafting (CABG) is cost-effective compared with percutaneous coronary intervention (PCI) for patients undergoing multivessel coronary revascularization-particularly among patients with complex coronary artery disease or diabetes mellitus. Whether these results apply in the drug-eluting stent (DES) era is unknown. Methods and Results-Between 2005 and 2010, 1900 patients with diabetes mellitus and multivessel coronary artery disease were randomized to PCI with DES (DES-PCI; n=953) or CABG (n=947). Costs were assessed from the perspective of the U. S. health care system. Health state utilities were assessed using the EuroQOL 5 dimension 3 level questionnaire. A patient-level microsimulation model based on U. S. life-tables and in-trial results was used to estimate lifetime cost-effectiveness. Although initial procedural costs were lower for CABG, total costs for the index hospitalization were $8622 higher per patient. Over the next 5 years, follow-up costs were higher with PCI, owing to more frequent repeat revascularization and higher outpatient medication costs. Nonetheless, cumulative 5-year costs remained $3641 higher per patient with CABG. Although there were only modest gains in survival with CABG during the trial period, when the in-trial results were extended to a lifetime horizon, CABG was projected to be economically attractive relative to DES-PCI, with substantial gains in both life expectancy and quality-adjusted life expectancy and incremental cost-effectiveness ratios <$10 000 per life-year or quality-adjusted life-year gained across a broad range of assumptions regarding the effect of CABG on post-trial survival and costs. Conclusions-Despite higher initial costs, CABG is a highly cost-effective revascularization strategy compared with DES-PCI for patients with diabetes mellitus and multivessel coronary artery disease. C1 [Magnuson, Elizabeth A.; Wang, Kaijun; Vilain, Katherine; Li, Haiyan; Appelwick, Jaime; Abdallah, Mouin; Cohen, David J.] St Lukes Mid Amer Heart Inst, Kansas City, MO USA. [Farkouh, Michael E.; Fuster, Valentin] Mt Sinai Sch Med, Dept Cardiol, New York, NY USA. [Farkouh, Michael E.] Univ Toronto, Peter Munk Cardiac Ctr, Toronto, ON, Canada. [Farkouh, Michael E.] Univ Toronto, Li Ka Shing Knowledge Inst, Toronto, ON, Canada. [Muratov, Victoria; Sleeper, Lynn A.] New England Res Inst, Watertown, MA 02172 USA. [Boineau, Robin] NHLBI, NIH, Bethesda, MD 20892 USA. RP Cohen, DJ (reprint author), Univ Missouri, Kansas City Sch Med, St Lukes Mid Amer Heart Inst, 4401 Wornall Rd, Kansas City, MO 64111 USA. EM dcohen@saint-lukes.org RI Caramori, Paulo/I-1370-2012; Fuster, Valentin/H-4319-2015 OI Fuster, Valentin/0000-0002-9043-9986 FU National Heart, Lung, and Blood Institute (NHLBI) [01HL071988, 01HL092989]; Eli Lilly; Abbott Vascular; Astra Zeneca; Boston Scientific; Daiichi Sankyo; Edwards Lifesciences; Medtronic; Bristol-Myers Squibb; Cordis; Sanofi-Aventis; Biomet; Jannsen Pharmaceuticals FX The FREEDOM Trial was supported by U01 grants #01HL071988 and #01HL092989 from the National Heart, Lung, and Blood Institute (NHLBI) with provision of stents from Cordis, Johnson and Johnson, and Boston Scientific, provision of abciximab and an unrestricted research grant from Eli Lilly, and provision of clopidogrel from Sanofi-Aventis and Bristol Myers Squibb. The views expressed are not necessarily the views of NHLBI, but of the individual authors.; Dr Magnuson has received grant support from Abbott Vascular, Astra Zeneca, Boston Scientific, Daiichi Sankyo, Edwards Lifesciences, Eli Lilly, and Medtronic. Dr Farkouh has received grant support from Eli Lilly and other research support from Boston Scientific, Bristol-Myers Squibb, Cordis, Eli Lilly, and Sanofi-Aventis. Dr Cohen has received grant support from Abbott Vascular, Astra Zeneca, Biomet, Boston Scientific, Edwards Lifesciences, Eli Lilly, Jannsen Pharmaceuticals, and Medtronic and consulting fees from Abbott Vascular, Astra Zeneca, Eli Lilly and Medtronic. The other authors report no conflicts. NR 36 TC 39 Z9 40 U1 2 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 19 PY 2013 VL 127 IS 7 BP 820 EP 831 DI 10.1161/CIRCULATIONAHA.112.147488 PG 12 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 094YS UT WOS:000315302200019 PM 23277307 ER PT J AU Bagci, U Yao, JH Miller-Jaster, K Chen, XJ Mollura, DJ AF Bagci, Ulas Yao, Jianhua Miller-Jaster, Kirsten Chen, Xinjian Mollura, Daniel J. TI Predicting Future Morphological Changes of Lesions from Radiotracer Uptake in 18F-FDG-PET Images SO PLOS ONE LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; F-18-FDG PET; SEGMENTATION; TEXTURE; HETEROGENEITY; VARIANCE; VOLUMES AB We introduce a novel computational framework to enable automated identification of texture and shape features of lesions on F-18-FDG-PET images through a graph-based image segmentation method. The proposed framework predicts future morphological changes of lesions with high accuracy. The presented methodology has several benefits over conventional qualitative and semi-quantitative methods, due to its fully quantitative nature and high accuracy in each step of (i) detection, (ii) segmentation, and (iii) feature extraction. To evaluate our proposed computational framework, thirty patients received 2 F-18-FDG-PET scans (60 scans total), at two different time points. Metastatic papillary renal cell carcinoma, cerebellar hemongioblastoma, non-small cell lung cancer, neurofibroma, lymphomatoid granulomatosis, lung neoplasm, neuroendocrine tumor, soft tissue thoracic mass, nonnecrotizing granulomatous inflammation, renal cell carcinoma with papillary and cystic features, diffuse large B-cell lymphoma, metastatic alveolar soft part sarcoma, and small cell lung cancer were included in this analysis. The radiotracer accumulation in patients' scans was automatically detected and segmented by the proposed segmentation algorithm. Delineated regions were used to extract shape and textural features, with the proposed adaptive feature extraction framework, as well as standardized uptake values (SUV) of uptake regions, to conduct a broad quantitative analysis. Evaluation of segmentation results indicates that our proposed segmentation algorithm has a mean dice similarity coefficient of 85.75 +/- 1.75%. We found that 28 of 68 extracted imaging features were correlated well with SUVmax (p<0.05), and some of the textural features (such as entropy and maximum probability) were superior in predicting morphological changes of radiotracer uptake regions longitudinally, compared to single intensity feature such as SUVmax. We also found that integrating textural features with SUV measurements significantly improves the prediction accuracy of morphological changes (Spearman correlation coefficient = 0.8715, p= 1.0) underwent colposcopy and biopsy, as did a sample of double-negative women with an abnormal cervix at visual inspection or with risk factors for cervical lesions. Crude and verification bias-corrected sensitivities and specificities were estimated. In total, 8,265 women (98.8% of eligible) had complete screening results. Of these, 10.7% were HPV positive, 1.7% were Pap positive and 1.1% were positive by both tests. In all, 931 (11.3%) women were screen-positive, of whom 94.3% attended colposcopy. Additionally, 295 control women were invited for colposcopy, of whom 78% attended. In all, 42 CIN2, 45 CIN3 and 9 cancers were identified. Verification bias-corrected sensitivity for CIN2+ (95% confidence interval) was 92.7% (84.4-96.8) for HPV and 22.1% (16.4-29.2) for Pap; corresponding specificities were 92.0% (91.4-92.6) and 98.9% (98.7-99.0). In conclusion, in routine clinical practice in a developing country, HPV testing was four times more sensitive for CIN2+ than Pap testing, identifying three times more CIN2+ lesions; HPV testing was easily implemented in our established cervical cancer prevention program. C1 [Ferreccio, Catterina] Pontificia Univ Catolica Chile, Sch Med, Dept Publ Hlth, Santiago 8330073, Chile. [Isabel Barriga, Maria; Nunez, Felipe; Cartagena, Jaime; Branes, Jorge] Pontificia Univ Catolica Chile, Dept Ginecol & Obstet, Santiago 8330073, Chile. [Lagos, Marcela; Poggi, Helena] Pontificia Univ Catolica Chile, Dept Lab Clin, Santiago 8330073, Chile. [Katki, Hormuzd A.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Vinales, Daysi] Serv Salud Metropolitano S Oriente, Santiago, Chile. RP Ferreccio, C (reprint author), Pontificia Univ Catolica Chile, Sch Med, Dept Publ Hlth, Marcoleta 434, Santiago 8330073, Chile. EM cferrec@med.puc.cl RI Katki, Hormuzd/B-4003-2015 FU Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT), a Chilean State fund for research [1090597] FX Grant sponsor: Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT), a Chilean State fund for research; Grant number: 1090597 NR 38 TC 15 Z9 18 U1 0 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD FEB 15 PY 2013 VL 132 IS 4 BP 916 EP 923 DI 10.1002/ijc.27662 PG 8 WC Oncology SC Oncology GA 078AB UT WOS:000314069400019 PM 22684726 ER PT J AU Mattoo, AR Fitzgerald, DJ AF Mattoo, Abid R. Fitzgerald, David J. TI Combination treatments with ABT-263 and an immunotoxin produce synergistic killing of ABT-263-resistant small cell lung cancer cell lines SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE SCLC; ABT-263; ABT-737; immunotoxin and Mcl-1 ID BCL-2 FAMILY INHIBITOR; PSEUDOMONAS EXOTOXIN; RECOMBINANT IMMUNOTOXINS; PHASE-I; APOPTOSIS; IMMUNOTHERAPY; LEUKEMIA; ABT-737; PROTEINS; TOXINS AB Synergistic killing was achieved when Small Cell Lung Cancer (SCLC) cell lines were incubated with ABT-263 and an immunotoxin directed to the transferrin receptor. SCLC lines are variably sensitive to the BH-3 only peptide mimetic, ABT-263. To determine their sensitivity to toxin-based reagents, we incubated four representative SCLC lines with a model Pseudomonas exotoxin-based immunotoxin directed to the transferrin receptor. Remarkably in 4-of-4 lines, there was little evidence of immunotoxin-mediated cytotoxicity despite near complete inhibition of protein synthesis. However, when combinations of ABT-263 and immunotoxin were added to the ABT-263-resistant cell lines (H196 and H69AR), there was synergistic killing as evidenced by increased activation of caspase 3/7, annexin V staining, and loss of cell integrity. Synergistic killing was evident at 6 hr and correlated with loss of Mcl-1. This synergy was also noted when the closely related compound ABT-737 was combined with the same immunotoxin. To establish that the synergy seen in tissue culture could be achieved in vivo, H69AR cells were grown as tumors in nude mice and shown to be susceptible to the killing action of an immunotoxin-ABT-737 combination but not to either agent alone. When immunotoxin-ABT combinations were added to ABT-263-sensitive lines (H146 and H1417), killing was additive. Our data support combination approaches for treating ABT-263-resistant SCLC with ABT-263 and a second agent that provides synergistic killing action. C1 [Mattoo, Abid R.; Fitzgerald, David J.] NCI, Biotherapy Sect, Mol Biol Lab, Ctr Canc Res,NIH,HHS, Bethesda, MD 20819 USA. RP Fitzgerald, DJ (reprint author), NCI, Biotherapy Sect, Mol Biol Lab, Ctr Canc Res,NIH,HHS, Bldg 37,Room 5124, Bethesda, MD 20819 USA. EM djpf@helix.nih.gov OI MATTOO, ABID/0000-0002-4947-0113 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX Grant sponsors: Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research NR 31 TC 16 Z9 16 U1 1 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD FEB 15 PY 2013 VL 132 IS 4 BP 978 EP 987 DI 10.1002/ijc.27732 PG 10 WC Oncology SC Oncology GA 078AB UT WOS:000314069400026 PM 22821746 ER PT J AU Brinas, RP Maetani, M Barchi, JJ AF Brinas, Raymond P. Maetani, Micah Barchi, Joseph J., Jr. TI A survey of place-exchange reaction for the preparation of water-soluble gold nanoparticles SO JOURNAL OF COLLOID AND INTERFACE SCIENCE LA English DT Article DE Gold nanoparticles; Place-exchange reaction; Water-soluble ligands; Peptides; Carbohydrates; Amino acids; Ligands; Glycopeptides; Water soluble ID THOMSEN-FRIEDENREICH DISACCHARIDE; CLUSTER MOLECULES; AU NANOPARTICLES; CONTRAST AGENT; LIGANDS; CHARGE; IDENTIFICATION; NANOCRYSTALS; DYNAMICS; ANTIGEN AB Water-soluble gold nanoparticles (AuNPs) have gained considerable attention because they offer a myriad of potential applications, especially in the fields of biology and medicine. One method to prepare such gold nanoparticles is through the well-known Murray place-exchange reaction. In this method, precursor gold nanoparticles, bearing labile ligands and with very good size distribution, are synthesized first, and then reacted with a large excess of the desired ligand. We report a comparison of the reactivity of several known precursor gold nanoparticles (citrate-stabilized, pentanethiol-stabilized, tetraoctylammonium bromide-stabilized, and 4-dimethylaminopyridine-stabilized) to several biologically relevant ligands, including amino acids, peptides, and carbohydrates. We found that citrate-stabilized and 4-dimethylaminopyridine-stabilized gold nanoparticles have broader reactivities than the other precursors studied. Citrate-stabilized gold nanoparticles are more versatile precursors because they can be prepared in a wide range of sizes and are very stable. The hydrophobic pentane-stabilized gold nanoparticles made them "inert" toward highly water-soluble ligands. Tetraoctylammonium bromide-stabilized gold nanoparticles exhibited selective reactivity, especially for small, unhindered and amphiphilic ligands. Depending on the desired ligand and size of AuNPs, a judicious selection of the available precursors can be made for use in place-exchange reactions. In preparing water-soluble AuNPs with biologically relevant ligands, the nature of the incoming ligand and the size of the AuNP should be taken into account in order to choose the most suitable place-exchange procedure. Published by Elsevier Inc. C1 [Brinas, Raymond P.; Maetani, Micah; Barchi, Joseph J., Jr.] NCI, Biol Chem Lab, Mol Discovery Program, Ctr Canc Res, Ft Detrick, MD 21702 USA. RP Barchi, JJ (reprint author), NCI, Biol Chem Lab, Mol Discovery Program, Ctr Canc Res, 376 Boyles St,POB B, Ft Detrick, MD 21702 USA. EM Barchi@helix.nih.gov RI Barchi Jr., Joseph/N-3784-2014 FU Intramural program of the National Cancer Institute at the National Institutes of Health FX We are grateful to Dr. Kunio Nagashima for performing the TEM analyses. We also appreciate the assistance of Dr. Sergei Tarasov and Ms. Marzena Dyba with the UV-vis spectrophotometer and Souvik Biswas for help with the high pH exchange reactions. This work was supported by funds from the Intramural program of the National Cancer Institute at the National Institutes of Health. We gratefully thank the Biophysics Resource of the Structural Biophysics Laboratory, CCR, NCI for help with nanoparticle characterization. NR 51 TC 13 Z9 13 U1 0 U2 76 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0021-9797 J9 J COLLOID INTERF SCI JI J. Colloid Interface Sci. PD FEB 15 PY 2013 VL 392 BP 415 EP 421 DI 10.1016/j.jcis.2012.06.042 PG 7 WC Chemistry, Physical SC Chemistry GA 078YK UT WOS:000314136800055 PM 23149107 ER PT J AU Watts, DH Williams, PL Kacanek, D Griner, R Rich, K Hazra, R Mofenson, LM Mendez, HA AF Watts, D. Heather Williams, Paige L. Kacanek, Deborah Griner, Raymond Rich, Kenneth Hazra, Rohan Mofenson, Lynne M. Mendez, Hermann A. CA Pediat HIV-AIDS Cohort Study TI Combination Antiretroviral Use and Preterm Birth SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE preterm birth; antiretrovirals; pregnancy; small for gestational age ID HIV-INFECTED WOMEN; PREGNANT-WOMEN; PREMATURE DELIVERY; INCREASED RISK; IN-UTERO; PROTEASE INHIBITORS; UNITED-KINGDOM; THERAPY; EXPOSURE; OUTCOMES AB Background. Use of antiretroviral drugs (ARVs) during pregnancy has been associated with higher risk of preterm birth. Methods. The Pediatric HIV/AIDS Cohort Study network's Surveillance Monitoring for ART Toxicities study is a US-based cohort of human immunodeficiency virus (HIV)-exposed uninfected children. We evaluated maternal ARV use during pregnancy and the risk of any type of preterm birth (ie, birth before 37 completed weeks of gestation), the risk of spontaneous preterm birth (ie, preterm birth that occurred after preterm labor or membrane rupture, without other complications), and the risk of small for gestational age (SGA; ie, a birth weight of <10th percentile for gestational age). Multivariable logistic regression models were used to evaluate the association of ARVs and timing of exposure, while adjusting for maternal characteristics. Results. Among 1869 singleton births, 18.6% were preterm, 10.2% were spontaneous preterm, and 7.3% were SGA. A total of 89% used 3-drug combination ARV regimens during pregnancy. In adjusted models, the odds of preterm birth and spontaneous preterm birth were significantly greater among mothers who used protease inhibitors during the first trimester (adjusted odds ratios, 1.55 and 1.59, respectively) but not among mothers who used nonnucleoside reverse-transcriptase inhibitor or triple-nucleoside regimens during the first trimester. Combination ARV exposure starting later in pregnancy was not associated with increased risk. No associations were observed between SGA and exposure to combination ARV regimens. Conclusions. Protease inhibitor use early in pregnancy may be associated with increased risk for prematurity. C1 [Watts, D. Heather; Hazra, Rohan; Mofenson, Lynne M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, Bethesda, MD USA. [Williams, Paige L.; Kacanek, Deborah; Griner, Raymond] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Rich, Kenneth] Univ Illinois, Chicago, IL USA. [Mendez, Hermann A.] Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. RP Watts, DH (reprint author), 6100 Execut Blvd,Rm 4B11, Bethesda, MD USA. EM hw59i@nih.gov OI Mofenson, Lynne/0000-0002-2818-9808 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Allergy and Infectious Diseases; National Institute on Drug Abuse; National Institute of Mental Health; National Institute of Deafness and Other Communication Disorders; National Heart Lung and Blood Institute; National Institute of Neurological Disorders and Stroke; National Institute on Alcohol Abuse and Alcoholism through the Harvard University School of Public Health [U01 HD052102-04]; National Institute on Alcohol Abuse and Alcoholism through the Tulane University School of Medicine [U01 HD052104-01] FX This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, with cofunding from the National Institute of Allergy and Infectious Diseases, the National Institute on Drug Abuse, the National Institute of Mental Health, the National Institute of Deafness and Other Communication Disorders, the National Heart Lung and Blood Institute, the National Institute of Neurological Disorders and Stroke, and the National Institute on Alcohol Abuse and Alcoholism, through cooperative agreements with the Harvard University School of Public Health (U01 HD052102-04) and the Tulane University School of Medicine (U01 HD052104-01). NR 30 TC 39 Z9 39 U1 0 U2 13 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD FEB 15 PY 2013 VL 207 IS 4 BP 612 EP 621 DI 10.1093/infdis/jis728 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 078TG UT WOS:000314121800010 PM 23204173 ER PT J AU Hurley, A Smith, M Karpova, T Hasley, RB Belkina, N Shaw, S Balenga, N Druey, KM Nickel, E Packard, B Imamichi, H Hu, ZH Follmann, D McNally, J Higgins, J Sneller, M Lane, HC Catalfamo, M AF Hurley, Amanda Smith, Mindy Karpova, Tatiana Hasley, Rebecca B. Belkina, Natalya Shaw, Stephen Balenga, Nariman Druey, Kirk M. Nickel, Erin Packard, Beverly Imamichi, Hiromi Hu, Zonghui Follmann, Dean McNally, James Higgins, Jeanette Sneller, Michael Lane, H. Clifford Catalfamo, Marta TI Enhanced Effector Function of CD8(+) T Cells From Healthy Controls and HIV-Infected Patients Occurs Through Thrombin Activation of Protease-Activated Receptor 1 SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE PAR-1; T cells; thrombin; HIV pathogenesis; coagulation; inflammation ID ANTIGEN-PRESENTING CELLS; CARDIOVASCULAR-DISEASE; ANTIRETROVIRAL THERAPY; DANGER MODEL; COAGULATION; INFLAMMATION; SEPSIS; POLARIZATION; EXPRESSION; ERM AB Disruption of vascular integrity by trauma and other tissue insults leads to inflammation and activation of the coagulation cascade. The serine protease thrombin links these 2 processes. The proinflammatory function of thrombin is mediated by activation of protease-activated receptor 1 (PAR-1). We found that peripheral blood effector memory CD4(+) and CD8(+) T lymphocytes expressed PAR-1 and that expression was increased in CD8(+) T cells from human immunodeficiency virus (HIV)-infected patients. Thrombin enhanced cytokine secretion in CD8(+) T cells from healthy controls and HIV-infected patients. In addition, thrombin induced chemokinesis, but not chemotaxis, of CD8(+) T cells, which led to structural changes, including cell polarization and formation of a structure rich in F-actin and phosphorylated ezrin-radexin-moesin proteins. These findings suggest that thrombin mediates cross-talk between the coagulation system and the adaptive immune system at sites of vascular injury through increased T-cell motility and production of proinflammatory cytokines. C1 [Hurley, Amanda; Smith, Mindy; Hasley, Rebecca B.; Nickel, Erin; Imamichi, Hiromi; Sneller, Michael; Lane, H. Clifford; Catalfamo, Marta] NIAID, Immunoregulat Lab, NIH, CMRS, Bethesda, MD 20892 USA. [Balenga, Nariman; Druey, Kirk M.] NIAID, Lab Allerg Dis, Bethesda, MD 20892 USA. [Hu, Zonghui; Follmann, Dean] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. [Karpova, Tatiana; McNally, James] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Belkina, Natalya; Shaw, Stephen] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Packard, Beverly] OncoImmunin, Gaithersburg, MD USA. [Higgins, Jeanette] SAIC, AIDS Monitoring Labs, Frederick, MD USA. RP Catalfamo, M (reprint author), NIAID, Immunoregulat Lab, NIH, CMRS, Bldg 10,Room 11B07,9000 Rockville Pike, Bethesda, MD 20892 USA. EM catalfam@mail.nih.gov RI Aghaei Balenga, Nariman/A-5895-2011 OI Aghaei Balenga, Nariman/0000-0002-2741-9595 FU National Institute of Allergy and Infectious Diseases, National Institute of Health (NIH); National Cancer Institute, NIH [HHSN261200800001E] FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institute of Health (NIH; intramural research program) and the National Cancer Institute, NIH (contract HHSN261200800001E). NR 50 TC 9 Z9 9 U1 0 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD FEB 15 PY 2013 VL 207 IS 4 BP 638 EP 650 DI 10.1093/infdis/jis730 PG 13 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 078TG UT WOS:000314121800013 PM 23204166 ER PT J AU Gonzalez-Castillo, J Duthie, KN Saad, ZS Chu, C Bandettini, PA Luh, WM AF Gonzalez-Castillo, Javier Duthie, Kristen N. Saad, Ziad S. Chu, Carlton Bandettini, Peter A. Luh, Wen-Ming TI Effects of image contrast on functional MRI image registration SO NEUROIMAGE LA English DT Article ID MAGNETIC-RESONANCE; MOTION CORRECTION; ENHANCED MRI; BRAIN; GADOLINIUM; FMRI; ROBUST; ACTIVATIONS; SOFTWARE; ACCURATE AB Lack of tissue contrast and existing inhomogeneous bias fields from multi-channel coils have the potential to degrade the output of registration algorithms; and consequently degrade group analysis and any attempt to accurately localize brain function. Non-invasive ways to improve tissue contrast in fMRI images include the use of low flip angles (FAs) well below the Ernst angle and longer repetition times (TR). Techniques to correct intensity inhomogeneity are also available in most mainstream fMRI data analysis packages; but are not used as part of the pre-processing pipeline in many studies. In this work, we use a combination of real data and simulations to show that simple-to-implement acquisition/pre-processing techniques can significantly improve the outcome of both functional-to-functional and anatomical-to-functional image registrations. We also emphasize the need of tissue contrast on EPI images to be able to appropriately evaluate the quality of the alignment. In particular, we show that the use of low FAs (e.g., 0 40), when physiological noise considerations permit such an approach, significantly improves accuracy, consistency and stability of registration for data acquired at relatively short TRs (TR <= 2 s). Moreover, we also show that the application of bias correction techniques significantly improves alignment both for array-coil data (known to contain high intensity inhomogeneity) as well as birdcage-coil data. Finally, improvements in alignment derived from the use of the first infinite-TR volumes (ITVs) as targets for registration are also demonstrated. For the purpose of quantitatively evaluating the different scenarios, two novel metrics were developed: Mean Voxel Distance (MVD) to evaluate registration consistency, and Deviation of Mean Voxel Distance (dMVD) to evaluate registration stability across successive alignment attempts. Published by Elsevier Inc. C1 [Gonzalez-Castillo, Javier; Duthie, Kristen N.; Chu, Carlton; Bandettini, Peter A.] NIMH, Sect Funct Imaging Methods, NIH, Bethesda, MD 20892 USA. [Bandettini, Peter A.; Luh, Wen-Ming] NIMH, Funct MRI Facil, NIH, Bethesda, MD 20892 USA. RP Gonzalez-Castillo, J (reprint author), NIMH, Sect Funct Imaging Methods, NIH, Bethesda, MD 20892 USA. EM javier.gonzalez-castillo@nih.gov OI Gonzalez-Castillo, Javier/0000-0002-6520-5125 FU Intramural Research Program of the National Institute of Mental Health FX The authors would also like to thank Dr. Gang Chen and Daniel Glen from the Scientific and Statistical Computing Core at the National Institute of Mental Health for their invaluable help during the preparation of this manuscript. This research was supported by the Intramural Research Program of the National Institute of Mental Health. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Md. (http://biowulf.nih.gov). NR 38 TC 5 Z9 5 U1 0 U2 23 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2013 VL 67 BP 163 EP 174 DI 10.1016/j.neuroimage.2012.10.076 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 079BG UT WOS:000314144600016 PM 23128074 ER PT J AU Kong, XF Vogt, G Itan, Y Macura-Biegun, A Szaflarska, A Kowalczyk, D Chapgier, A Abhyankar, A Furthner, D Khayat, CD Okada, S Bryant, VL Bogunovic, D Kreins, A Moncada-Velez, M Migaud, M Al-Ajaji, S Al-Muhsen, S Holland, SM Abel, L Picard, C Chaussabel, D Bustamante, J Casanova, JL Boisson-Dupuis, S AF Kong, Xiao-Fei Vogt, Guillaume Itan, Yuval Macura-Biegun, Anna Szaflarska, Anna Kowalczyk, Danuta Chapgier, Ariane Abhyankar, Avinash Furthner, Dieter Khayat, Claudia Djambas Okada, Satoshi Bryant, Vanessa L. Bogunovic, Dusan Kreins, Alexandra Moncada-Velez, Marcela Migaud, Melanie Al-Ajaji, Sulaiman Al-Muhsen, Saleh Holland, Steven M. Abel, Laurent Picard, Capucine Chaussabel, Damien Bustamante, Jacinta Casanova, Jean-Laurent Boisson-Dupuis, Stephanie TI Haploinsufficiency at the human IFNGR2 locus contributes to mycobacterial disease SO HUMAN MOLECULAR GENETICS LA English DT Article ID INTERFERON-GAMMA-RECEPTOR; SEQUENCING-BASED DISCOVERY; CALMETTE-GUERIN INFECTION; GENETIC DISSECTION; CLINICAL-FEATURES; MEDIATED IMMUNITY; STAT1 DEFICIENCY; HUMAN-MODEL; BETA CHAIN; CELL AB Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare syndrome, the known genetic etiologies of which impair the production of, or the response to interferon-gamma (IFN-). We report here a patient (P1) with MSMD whose cells display mildly impaired responses to IFN-, at levels, however, similar to those from MSMD patients with autosomal recessive (AR) partial IFN-R2 or STAT1 deficiency. Whole-exome sequencing (WES) and Sanger sequencing revealed only one candidate variation for both MSMD-causing and IFN--related genes. P1 carried a heterozygous frame-shift IFNGR2 mutation inherited from her father. We show that the mutant allele is intrinsically loss-of-function and not dominant-negative, suggesting haploinsufficiency at the IFNGR2 locus. We also show that Epstein-Barr virus transformed B lymphocyte cells from 10 heterozygous relatives of patients with AR complete IFN-R2 deficiency respond poorly to IFN-, in some cases as poorly as the cells of P1. Naive CD4 T cells and memory IL-4-producing T cells from these individuals also responded poorly to IFN-, whereas monocytes and monocyte-derived macrophages (MDMs) did not. This is consistent with the lower levels of expression of IFN-R2 in lymphoid than in myeloid cells. Overall, MSMD in this patient is probably due to autosomal dominant (AD) IFN-R2 deficiency, resulting from haploinsufficiency, at least in lymphoid cells. The clinical penetrance of AD IFN-R2 deficiency is incomplete, possibly due, at least partly, to the variability of cellular responses to IFN- in these individuals. C1 [Kong, Xiao-Fei; Vogt, Guillaume; Itan, Yuval; Abhyankar, Avinash; Okada, Satoshi; Bryant, Vanessa L.; Bogunovic, Dusan; Kreins, Alexandra; Moncada-Velez, Marcela; Casanova, Jean-Laurent; Boisson-Dupuis, Stephanie] Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, New York, NY 10065 USA. [Vogt, Guillaume; Chapgier, Ariane; Migaud, Melanie; Abel, Laurent; Picard, Capucine; Bustamante, Jacinta; Casanova, Jean-Laurent; Boisson-Dupuis, Stephanie] INSERM, Lab Human Genet Infect Dis, Necker Branch, U980, F-75015 Paris, France. [Vogt, Guillaume; Chapgier, Ariane; Abel, Laurent; Picard, Capucine; Bustamante, Jacinta; Casanova, Jean-Laurent; Boisson-Dupuis, Stephanie] Univ Paris 05, Paris Cite Sorbonne, Necker Med Sch, F-75015 Paris, France. [Macura-Biegun, Anna; Szaflarska, Anna; Kowalczyk, Danuta] Jagiellonian Univ, Coll Med, Dept Clin Immunol, PL-30663 Krakow, Poland. [Furthner, Dieter] Women & Childrens Hosp Linz, Landes Frauen & Kinderklin Linz, A-4020 Linz, Austria. [Khayat, Claudia Djambas] Hotel Dieu France Hosp, Dept Pediat, Beirut, Lebanon. [Moncada-Velez, Marcela] Univ Antioquia, Sch Med, Grp Primary Immunodeficiencies, Medellin, Colombia. [Al-Ajaji, Sulaiman] King Abdul Aziz Med City, Dept Pediat, Riyadh 11426, Saudi Arabia. [Al-Muhsen, Saleh] King Saud Univ, Dept Pediat, Coll Med, Novel Primary Immunodeficiency & Infect Dis Progr, Riyadh 11451, Saudi Arabia. [Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Chaussabel, Damien] Benaroya Res Inst, Seattle, WA 98101 USA. [Picard, Capucine; Casanova, Jean-Laurent] Hop Necker Enfants Malad, AP HP, Pediat Immunol Hematol Unit, F-75015 Paris, France. [Picard, Capucine; Bustamante, Jacinta] Hop Necker Enfants Malad, AP HP, Ctr Primary Immunodeficiencies, F-75015 Paris, France. RP Casanova, JL (reprint author), Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, 1230 York Ave,POB 163, New York, NY 10065 USA. EM jean-laurent.casanova@rockefeller.edu RI Vogt, Guillaume/L-6046-2015; Okada, Satoshi/B-8901-2011; OI Vogt, Guillaume/0000-0001-8192-1247; Okada, Satoshi/0000-0002-4622-5657; Picard, Capucine/0000-0001-8788-5056; Chaussabel, Damien/0000-0002-6131-7242 FU Stony Wold-Herbert Fund; Choh-Hao Li Memorial Fund Scholar award; Shanghai Educational Development Foundation; AXA Research Fund; Fondation Medicale Medische Stichting Mathilde E. Horlait-Dapens; St Giles Foundation; Jeffrey Modell Foundation; Rockefeller University Center for Clinical and Translational Science from the National Center for Research Resources [8UL1TR000043]; National Center for Advancing Sciences (NCATS), National Institutes of Health; National Institute of Allergy and Infectious Diseases [5R01AI089970-02]; Rockefeller University; European Research Council (ERC); Talecris BioTherapeutics FX X.F.K. was supported by the Stony Wold-Herbert Fund, Choh-Hao Li Memorial Fund Scholar award and the Shanghai Educational Development Foundation, Y.I. is supported by the AXA Research Fund, V. L. B. is supported by the Stony Wold-Herbert Fund and A. K. is supported by the Fondation Medicale Medische Stichting Mathilde E. Horlait-Dapens. The Laboratory of Human Genetics of Infectious Diseases is supported in part by grants from the St Giles Foundation, the Jeffrey Modell Foundation, The Rockefeller University Center for Clinical and Translational Science grant number 8UL1TR000043 from the National Center for Research Resources and the National Center for Advancing Sciences (NCATS), National Institutes of Health, the National Institute of Allergy and Infectious Diseases grant number 5R01AI089970-02, The Rockefeller University and the European Research Council (ERC). J.L.C. received a research grant from the Jeffrey Modell Foundation in collaboration with Talecris BioTherapeutics. The funder was not involved in the study design; collection, analysis and interpretation of data; writing of the paper or decision to submit for publication. NR 52 TC 16 Z9 17 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD FEB 15 PY 2013 VL 22 IS 4 BP 769 EP 781 DI 10.1093/hmg/dds484 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 078RI UT WOS:000314116600013 PM 23161749 ER PT J AU Henrion, M Frampton, M Scelo, G Purdue, M Ye, YQ Broderick, P Ritchie, A Kaplan, R Meade, A McKay, J Johansson, M Lathrop, M Larkin, J Rothman, N Wang, ZM Chow, WH Stevens, VL Diver, WR Gapstur, SM Albanes, D Virtamo, J Wu, XF Brennan, P Chanock, S Eisen, T Houlston, RS AF Henrion, Marc Frampton, Matthew Scelo, Ghislaine Purdue, Mark Ye, Yuanqing Broderick, Peter Ritchie, Alastair Kaplan, Richard Meade, Angela McKay, James Johansson, Mattias Lathrop, Mark Larkin, James Rothman, Nathaniel Wang, Zhaoming Chow, Wong-Ho Stevens, Victoria L. Diver, W. Ryan Gapstur, Susan M. Albanes, Demetrius Virtamo, Jarmo Wu, Xifeng Brennan, Paul Chanock, Stephen Eisen, Timothy Houlston, Richard S. TI Common variation at 2q22.3 (ZEB2) influences the risk of renal cancer SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CELL CARCINOMA; SUSCEPTIBILITY LOCI; KIDNEY CANCER; DISEASE; COMPLEX; 2P21 AB Genome-wide association studies (GWASs) of renal cell cancer (RCC) have identified four susceptibility loci thus far. To identify an additional RCC common susceptibility locus, we conducted a GWAS and performed a meta-analysis with published GWASs (totalling 2215 cases and 8566 controls of European background) and followed up the most significant association signals [nine single nucleotide polymorphisms (SNPs) in eight genomic regions] in 3739 cases and 8786 controls. A combined analysis identified a novel susceptibility locus mapping to 2q22.3 marked by rs12105918 (P 1.80 10(8); odds ratio 1.29, 95 CI: 1.181.41). The signal localizes to intron 2 of the ZEB2 gene (zinc finger E box-binding homeobox 2). Our findings suggest that genetic variation in ZEB2 influences the risk of RCC. This finding provides further insights into the genetic and biological basis of inherited genetic susceptibility to RCC. C1 [Henrion, Marc; Frampton, Matthew; Broderick, Peter; Houlston, Richard S.] Inst Canc Res, Sect Canc Genet, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England. [Scelo, Ghislaine; McKay, James; Johansson, Mattias; Brennan, Paul] Int Agcy Res Canc, F-69372 Lyon, France. [Purdue, Mark; Rothman, Nathaniel; Wang, Zhaoming; Chow, Wong-Ho; Albanes, Demetrius; Chanock, Stephen] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Ye, Yuanqing; Chow, Wong-Ho; Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Div Canc Prevent & Populat Sci, Dept Epidemiol, Houston, TX 77030 USA. [Ritchie, Alastair; Kaplan, Richard; Meade, Angela] MRC Clin Trials Unit, London WC2B 6NH, England. [Lathrop, Mark] Commissariat Energie Atom, Inst Genom, Ctr Natl Genotypage, F-91000 Evry, France. [Larkin, James] Royal Marsden NHS Fdn Trust, London, England. [Wang, Zhaoming] NCI, Core Genotyping Facil, SAIC Frederick Inc, Frederick, MD 21701 USA. [Stevens, Victoria L.; Diver, W. Ryan; Gapstur, Susan M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, FIN-00300 Helsinki, Finland. [Eisen, Timothy] Cambridge Univ Hlth Partners, Cambridge, England. RP Houlston, RS (reprint author), Inst Canc Res, Sect Canc Genet, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England. EM richard.houlston@icr.ac.uk RI Albanes, Demetrius/B-9749-2015; OI Henrion, Marc/0000-0003-1242-839X; Houlston, Richard/0000-0002-5268-0242; Broderick, Peter/0000-0002-8348-5829 FU MRC; Cancer Research UK; Bayer; Cancer Research UK [C1298/A8362, C490/A10124]; Bobby Moore Fund; Leukaemia Lymphoma Research; NHS; Intramural Research Program of the National Cancer Institute, NIH FX SORCE is coordinated by the Medical Research Council (MRC) and funded principally by the MRC and Cancer Research UK with an educational grant from Bayer. Additional funding was provided by Cancer Research UK (C1298/A8362 supported by the Bobby Moore Fund). Marc Henrion was supported by Leukaemia Lymphoma Research. NHS funding for the Royal Marsden Biomedical Research Centre and Cambridge University Health Partners is acknowledged. Funding for the SEARCH team was provided by Cancer Research UK (C490/A10124). The US kidney GWAS was funded by the Intramural Research Program of the National Cancer Institute, NIH. NR 24 TC 21 Z9 22 U1 0 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD FEB 15 PY 2013 VL 22 IS 4 BP 825 EP 831 DI 10.1093/hmg/dds489 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 078RI UT WOS:000314116600018 PM 23184150 ER PT J AU Algotar, AM Stratton, MS Ahmann, FR Ranger-Moore, J Nagle, RB Thompson, PA Slate, E Hsu, CH Dalkin, BL Sindhwani, P Holmes, MA Tuckey, JA Graham, DL Parnes, HL Clark, LC Stratton, SP AF Algotar, Amit M. Stratton, M. Suzanne Ahmann, Frederick. R. Ranger-Moore, James Nagle, Raymond B. Thompson, Patricia A. Slate, Elizabeth Hsu, Chiu H. Dalkin, Bruce L. Sindhwani, Puneet Holmes, Michael A. Tuckey, John A. Graham, David. L. Parnes, Howard L. Clark, Lawrence C. Stratton, Steven P. TI Phase 3 clinical trial investigating the effect of selenium supplementation in men at high-risk for prostate cancer SO PROSTATE LA English DT Article DE prostate cancer; incidence; selenium supplementation ID PREVENTION TRIAL; NUTRITIONAL PREVENTION; VITAMIN-E; BIOPSIES; SELECT AB PURPOSE This study was conducted to investigate the effect of Se supplementation on prostate cancer incidence in men at high risk for prostate cancer. METHODS A Phase 3 randomized, double-blind, placebo-controlled clinical trial was conducted in 699 men at high risk for prostate cancer (prostate specific antigen (PSA) >4?ng/ml and/or suspicious digital rectal examination and/or PSA velocity >0.75?ng/ml/year), but with a negative prostate biopsy. Participants were randomized to receive daily oral placebo (N?=?232), 200?mu g selenium (N?=?234), or 400?mu g selenium (N?=?233) as selenized yeast. They were followed every 6 months for up to 5 years. The time to diagnosis of prostate cancer was compared between treatment groups using the Cox proportional hazards model. RESULT Compared to placebo, the hazard ratios [95% confidence intervals] for risk of developing prostate cancer in the selenium 200?mu g/day or the selenium 400?mu g/day group were 0.94 [0.52, 1.7] and 0.90 [0.48, 1.7], respectively. PSA velocity in the selenium arms was not significantly different from that observed in the placebo group (P?=?0.18 and P?=?0.17, respectively). CONCLUSION Selenium supplementation appeared to have no effect on the incidence of prostate cancer in men at high risk. In conjunction with results of other studies, these data indicate that selenium supplementation may not have a role in prostate cancer chemoprevention. Prostate 73: 328335, 2013. (c) 2012 Wiley Periodicals, Inc. C1 [Algotar, Amit M.; Stratton, M. Suzanne; Ahmann, Frederick. R.; Ranger-Moore, James; Nagle, Raymond B.; Thompson, Patricia A.; Hsu, Chiu H.; Clark, Lawrence C.; Stratton, Steven P.] Univ Arizona, Ctr Canc, Tucson, AZ 85724 USA. [Ahmann, Frederick. R.; Hsu, Chiu H.] Univ Arizona, Coll Med, Dept Med, Tucson, AZ 85724 USA. [Ranger-Moore, James; Stratton, Steven P.] Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth, Tucson, AZ 85724 USA. [Nagle, Raymond B.] Univ Arizona, Coll Med, Dept Pathol, Tucson, AZ 85724 USA. [Thompson, Patricia A.] Univ Arizona, Coll Med, Dept Anat & Cell Biol, Tucson, AZ 85724 USA. [Slate, Elizabeth] Med Univ S Carolina, Charleston, SC 29425 USA. [Dalkin, Bruce L.] Univ Washington, Sch Med, Dept Urol, Seattle, WA 98195 USA. [Sindhwani, Puneet] Univ Oklahoma, Dept Urol, Oklahoma City, OK USA. [Holmes, Michael A.] Waikato Hosp, Urol Clin, Hamilton, New Zealand. [Tuckey, John A.] Auckland Hosp, Auckland, New Zealand. [Graham, David. L.] Carle Canc Ctr, Urbana, IL USA. [Parnes, Howard L.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Stratton, SP (reprint author), Univ Arizona, Ctr Canc, POB 245024,1515 N Campbell Ave, Tucson, AZ 85724 USA. EM sstratton@azcc.arizona.edu FU National Cancer Institute [PHS CA077789, PHS 023074] FX Grant sponsor: National Cancer Institute; Grant numbers: PHS CA077789. PHS 023074. NR 22 TC 25 Z9 29 U1 1 U2 26 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-4137 J9 PROSTATE JI Prostate PD FEB 15 PY 2013 VL 73 IS 3 BP 328 EP 335 DI 10.1002/pros.22573 PG 8 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 075OH UT WOS:000313895900012 PM 22887343 ER PT J AU Hudson, RS Yi, M Volfovsky, N Prueitt, RL Esposito, D Volinia, S Liu, CG Schetter, AJ Van Roosbroeck, K Stephens, RM Calin, GA Croce, CM Ambs, S AF Hudson, Robert S. Yi, Ming Volfovsky, Natalia Prueitt, Robyn L. Esposito, Dominic Volinia, Stefano Liu, Chang-Gong Schetter, Aaron J. Van Roosbroeck, Katrien Stephens, Robert M. Calin, George A. Croce, Carlo M. Ambs, Stefan TI Transcription signatures encoded by ultraconserved genomic regions in human prostate cancer SO MOLECULAR CANCER LA English DT Article DE Ultraconserved region; Gene expression; Prostate cancer ID MICRORNA EXPRESSION; DNA METHYLATION; NONCODING RNAS; GENE-EXPRESSION; ELEMENTS; IDENTIFICATION; NEUROBLASTOMA; REGULATORS; CARCINOMA; TARGETS AB Background: Ultraconserved regions (UCR) are genomic segments of more than 200 base pairs that are evolutionarily conserved among mammalian species. They are thought to have functions as transcriptional enhancers and regulators of alternative splicing. Recently, it was shown that numerous RNAs are transcribed from these regions. These UCR-encoded transcripts (ucRNAs) were found to be expressed in a tissue- and disease-specific manner and may interfere with the function of other RNAs through RNA: RNA interactions. We hypothesized that ucRNAs have unidentified roles in the pathogenesis of human prostate cancer. In a pilot study, we examined ucRNA expression profiles in human prostate tumors. Methods: Using a custom microarray with 962 probesets representing sense and antisense sequences for the 481 human UCRs, we examined ucRNA expression in resected, fresh-frozen human prostate tissues (57 tumors, 7 non-cancerous prostate tissues) and in cultured prostate cancer cells treated with either epigenetic drugs (the hypomethylating agent, 5-Aza 2 ' deoxycytidine, and the histone deacetylase inhibitor, trichostatin A) or a synthetic androgen, R1881. Expression of selected ucRNAs was also assessed by qRT-PCR and NanoString (R)-based assays. Because ucRNAs may function as RNAs that target protein-coding genes through direct and inhibitory RNA: RNA interactions, computational analyses were applied to identify candidate ucRNA: mRNA binding pairs. Results: We observed altered ucRNA expression in prostate cancer (e.g., uc.106+, uc.477+, uc.363 + A, uc.454 + A) and found that these ucRNAs were associated with cancer development, Gleason score, and extraprostatic extension after controlling for false discovery (false discovery rate < 5% for many of the transcripts). We also identified several ucRNAs that were responsive to treatment with either epigenetic drugs or androgen (R1881). For example, experiments with LNCaP human prostate cancer cells showed that uc.287+ is induced by R1881 (P < 0.05) whereas uc.283 + A was up-regulated following treatment with combined 5-Aza 2 ' deoxycytidine and trichostatin A (P < 0.05). Additional computational analyses predicted RNA loop-loop interactions of 302 different sense and antisense ucRNAs with 1058 different mRNAs, inferring possible functions of ucRNAs via direct interactions with mRNAs. Conclusions: This first study of ucRNA expression in human prostate cancer indicates an altered transcript expression in the disease. C1 [Hudson, Robert S.; Prueitt, Robyn L.; Schetter, Aaron J.; Ambs, Stefan] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Yi, Ming; Volfovsky, Natalia; Stephens, Robert M.] NCI, Adv Biomed Comp Ctr, SAIC Frederick Inc, Frederick, MD 21701 USA. [Esposito, Dominic] NCI, Prot Express Lab, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Volinia, Stefano; Croce, Carlo M.] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Liu, Chang-Gong; Van Roosbroeck, Katrien; Calin, George A.] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA. RP Ambs, S (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM ambss@mail.nih.gov OI Volinia, Stefano/0000-0003-0910-3893 FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; National Institutes of Health [CA081534, CA128609]; DPR grant from the Prostate SPORE at the MD Anderson Cancer Center FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and by National Institutes of Health grants CA081534 and CA128609 (C. M. Croce). G.A. Calin is supported by a DPR grant from the Prostate SPORE at the MD Anderson Cancer Center. The authors thank the Cooperative Prostate Cancer Tissue Resource for providing tissue specimens and supporting data. NR 41 TC 19 Z9 19 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-4598 J9 MOL CANCER JI Mol. Cancer PD FEB 14 PY 2013 VL 12 AR 13 DI 10.1186/1476-4598-12-13 PG 13 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 123RG UT WOS:000317407500001 PM 23409773 ER PT J AU Bloom-Feshbach, K Alonso, WJ Charu, V Tamerius, J Simonsen, L Miller, MA Viboud, C AF Bloom-Feshbach, Kimberly Alonso, Wladimir J. Charu, Vivek Tamerius, James Simonsen, Lone Miller, Mark A. Viboud, Cecile TI Latitudinal Variations in Seasonal Activity of Influenza and Respiratory Syncytial Virus (RSV): A Global Comparative Review SO PLOS ONE LA English DT Review ID TRACT INFECTIONS; CLINICAL CHARACTERISTICS; EPIDEMIC INFLUENZA; ABSOLUTE-HUMIDITY; HONG-KONG; A VIRUS; GROUP-B; CHILDREN; TRANSMISSION; MORTALITY AB Background: There is limited information on influenza and respiratory syncytial virus (RSV) seasonal patterns in tropical areas, although there is renewed interest in understanding the seasonal drivers of respiratory viruses. Methods: We review geographic variations in seasonality of laboratory-confirmed influenza and RSV epidemics in 137 global locations based on literature review and electronic sources. We assessed peak timing and epidemic duration and explored their association with geography and study settings. We fitted time series model to weekly national data available from the WHO influenza surveillance system (FluNet) to further characterize seasonal parameters. Results: Influenza and RSV activity consistently peaked during winter months in temperate locales, while there was greater diversity in the tropics. Several temperate locations experienced semi-annual influenza activity with peaks occurring in winter and summer. Semi-annual activity was relatively common in tropical areas of Southeast Asia for both viruses. Biennial cycles of RSV activity were identified in Northern Europe. Both viruses exhibited weak latitudinal gradients in the timing of epidemics by hemisphere, with peak timing occurring later in the calendar year with increasing latitude (P < 0.03). Time series model applied to influenza data from 85 countries confirmed the presence of latitudinal gradients in timing, duration, seasonal amplitude, and between-year variability of epidemics. Overall, 80% of tropical locations experienced distinct RSV seasons lasting 6 months or less, while the percentage was 50% for influenza. Conclusion: Our review combining literature and electronic data sources suggests that a large fraction of tropical locations experience focused seasons of respiratory virus activity in individual years. Information on seasonal patterns remains limited in large undersampled regions, included Africa and Central America. Future studies should attempt to link the observed latitudinal gradients in seasonality of viral epidemics with climatic and population factors, and explore regional differences in disease transmission dynamics and attack rates. C1 [Bloom-Feshbach, Kimberly; Alonso, Wladimir J.; Charu, Vivek; Simonsen, Lone; Miller, Mark A.; Viboud, Cecile] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Bloom-Feshbach, Kimberly] Mt Sinai Sch Med, New York, NY USA. [Charu, Vivek] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Tamerius, James] Columbia Univ, Dept Environm Hlth Sci, New York, NY USA. [Simonsen, Lone] George Washington Univ, Sch Publ Hlth & Hlth Serv, Dept Global Hlth, Washington, DC USA. RP Viboud, C (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM viboudc@mail.nih.gov OI Simonsen, Lone/0000-0003-1535-8526 FU in-house Influenza Research Program of the Division of International Epidemiology and Population Studies, Fogarty International Center, National Institutes of Health; International Influenza Unit, Office of Global Affairs, Department of Health and Human Services; RAPIDD program of the Science and Technology Directorate, Department of Homeland Security FX This work was supported by the in-house Influenza Research Program of the Division of International Epidemiology and Population Studies, Fogarty International Center, National Institutes of Health, which is funded by the International Influenza Unit, Office of Global Affairs, Department of Health and Human Services, and by the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security (to L.S.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 68 TC 64 Z9 66 U1 2 U2 24 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 FEB 14 PY 2013 VL 8 IS 2 AR e54445 DI 10.1371/journal.pone.0054445 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 099EJ UT WOS:000315602700007 PM 23457451 ER PT J AU Chen, B Yi, B Mao, R Liu, HT Wang, JH Sharma, A Peiper, S Leonard, WJ She, JX AF Chen, Bo Yi, Bing Mao, Rui Liu, Haitao Wang, Jinhua Sharma, Ashok Peiper, Stephen Leonard, Warren J. She, Jin-Xiong TI Enhanced T Cell Lymphoma in NOD.Stat5b Transgenic Mice Is Caused by Hyperactivation of Stat5b in CD8(+) Thymocytes SO PLOS ONE LA English DT Article ID NONOBESE DIABETIC MICE; CONSTITUTIVE ACTIVATION; LYMPHOBLASTIC LYMPHOMA; UP-REGULATION; JANUS KINASE; DNA-BINDING; NOD MICE; EXPRESSION; LEUKEMIA; CANCER AB Activation of signal transducers and activators of transcription (STAT) proteins may be critical to their oncogenic functions as demonstrated by the development of B-cell lymphoma/leukemia in transgenic (TG) mice overexpressing a constitutively activated form of Stat5b. However, low incidence of CD8(+) T cell lymphoma was observed in B6 transgenic mice overexpressing a wild-type Stat5b (B6.Stat5b(Tg)) despite of undetectable Stat5b phosphorylation and the rate of lymphomagenesis was markedly enhanced by immunization or the introduction of TCR transgenes [1]. Here, we report that the wild-type Stat5b transgene leads to the acceleration and high incidence (74%) of CD8(+) T cell lymphoblastic lymphomas in the non-obese-diabetic (NOD) background. In contrast to the B6.Stat5b(Tg) mice, Stat5b in transgenic NOD (NOD.Stat5b(Tg)) mice is selectively and progressively phosphorylated in CD8(+) thymocytes. Stat5 phosphorylation also leads to up-regulation of many genes putatively relevant to tumorigenesis. Treatment of NOD.Stat5b(Tg) mice with cancer chemopreventive agents Apigenin and Xanthohumol efficiently blocked lymphomagenesis through reduction of Stat5 phosphorylation and genes up-regulated in the NOD.Stat5b(Tg) mice. These results suggest that NOD genetic background is critical to the Stat5b-mediated lymphomagenesis through regulation of Stat5 hyperactivation. NOD.Stat5b(Tg) mouse is an excellent model for studying the molecular mechanisms underlying lymphomagenesis and testing novel chemoprevention strategies. C1 [Chen, Bo; Yi, Bing; Mao, Rui; Liu, Haitao; Wang, Jinhua; Sharma, Ashok; She, Jin-Xiong] Georgia Regents Univ, Med Coll Georgia, Ctr Biotechnol & Genom Med, Augusta, GA USA. [Chen, Bo; Wang, Jinhua; She, Jin-Xiong] Nanjing Univ Technol, Sinoamer Inst Translat Med, Nanjing, Jiangsu, Peoples R China. [Wang, Jinhua] Jiangsu Canc Hosp, Nanjing, Jiangsu, Peoples R China. [Peiper, Stephen] Jefferson Univ, Dept Pathol, Philadelphia, PA USA. [Leonard, Warren J.] NHLBI, NIH, Bethesda, MD 20892 USA. RP She, JX (reprint author), Georgia Regents Univ, Med Coll Georgia, Ctr Biotechnol & Genom Med, Augusta, GA USA. EM jshe@georgiahealth.edu RI chen, bo/G-4522-2014 FU Georgia Health Sciences University; National Natural Science Foundation of China [81272244]; GRA endowment FX This study was supported by funds from the Georgia Health Sciences University and National Natural Science Foundation of China(81272244). J.X.S. is a Georgia Research Alliance (GRA) Eminent Scholar and supported by a GRA endowment. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 4 Z9 4 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 14 PY 2013 VL 8 IS 2 AR e56600 DI 10.1371/journal.pone.0056600 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 099EJ UT WOS:000315602700084 PM 23457589 ER PT J AU Giubellino, A Sourbier, C Lee, MJ Scroggins, B Bullova, P Landau, M Ying, WW Neckers, L Trepel, JB Pacak, K AF Giubellino, Alessio Sourbier, Carole Lee, Min-Jung Scroggins, Brad Bullova, Petra Landau, Michael Ying, Weiwen Neckers, Len Trepel, Jane B. Pacak, Karel TI Targeting Heat Shock Protein 90 for the Treatment of Malignant Pheochromocytoma SO PLOS ONE LA English DT Article ID MOLECULAR CHAPERONE; HSP90 INHIBITORS; SIGNALING PATHWAYS; TUMOR-SUPPRESSOR; CANCER-THERAPY; GROWTH-FACTOR; PHASE-I; COMPLEX; PARAGANGLIOMAS; EXPRESSION AB Metastatic pheochromocytoma represents one of the major clinical challenges in the field of neuroendocrine oncology. Recent molecular characterization of pheochromocytoma suggests new treatment options with targeted therapies. In this study we investigated the 90 kDa heat shock protein (Hsp90) as a potential therapeutic target for advanced pheochromocytoma. Both the first generation, natural product Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin), and the second-generation synthetic Hsp90 inhibitor STA-9090 (ganetespib) demonstrated potent inhibition of proliferation and migration of pheochromocytoma cell lines and induced degradation of key Hsp90 clients. Furthermore, ganetespib induced dose-dependent cytotoxicity in primary pheochromocytoma cells. Using metastatic models of pheochromocytoma, we demonstrate the efficacy of 17-AAG and ganetespib in reducing metastatic burden and increasing survival. Levels of Hsp70 in plasma from the xenograft studies served as a proximal biomarker of drug treatment. Our study suggests that targeting Hsp90 may benefit patients with advanced pheochromocytoma. C1 [Giubellino, Alessio; Bullova, Petra; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Sourbier, Carole; Scroggins, Brad; Neckers, Len] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Lee, Min-Jung; Landau, Michael; Trepel, Jane B.] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Ying, Weiwen] Synta Pharmaceut, Lexington, MA USA. RP Giubellino, A (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. EM giubella@mail.nih.gov; karel@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; Center for Cancer Research, National Cancer Institute of the National Institutes of Health FX This work was supported by intramural research funding of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Center for Cancer Research, National Cancer Institute of the 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 51 TC 8 Z9 10 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 14 PY 2013 VL 8 IS 2 AR e56083 DI 10.1371/journal.pone.0056083 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 099EJ UT WOS:000315602700042 PM 23457505 ER PT J AU Himes, BE Sheppard, K Berndt, A Leme, AS Myers, RA Gignoux, CR Levin, AM Gauderman, WJ Yang, JJ Mathias, RA Romieu, I Torgerson, DG Roth, LA Huntsman, S Eng, C Klanderman, B Ziniti, J Senter-Sylvia, J Szefler, SJ Lemanske, RF Zeiger, RS Strunk, RC Martinez, FD Boushey, H Chinchilli, VM Israel, E Mauger, D Koppelman, GH Postma, DS Nieuwenhuis, MAE Vonk, JM Lima, JJ Irvin, CG Peters, SP Kubo, M Tamari, M Nakamura, Y Litonjua, AA Tantisira, KG Raby, BA Bleecker, ER Meyers, DA London, SJ Barnes, KC Gilliland, FD Williams, LK Burchard, EG Nicolae, DL Ober, C DeMeo, DL Silverman, EK Paigen, B Churchill, G Shapiro, SD Weiss, ST AF Himes, Blanca E. Sheppard, Keith Berndt, Annerose Leme, Adriana S. Myers, Rachel A. Gignoux, Christopher R. Levin, Albert M. Gauderman, W. James Yang, James J. Mathias, Rasika A. Romieu, Isabelle Torgerson, Dara G. Roth, Lindsey A. Huntsman, Scott Eng, Celeste Klanderman, Barbara Ziniti, John Senter-Sylvia, Jody Szefler, Stanley J. Lemanske, Robert F., Jr. Zeiger, Robert S. Strunk, Robert C. Martinez, Fernando D. Boushey, Homer Chinchilli, Vernon M. Israel, Elliot Mauger, David Koppelman, Gerard H. Postma, Dirkje S. Nieuwenhuis, Maartje A. E. Vonk, Judith M. Lima, John J. Irvin, Charles G. Peters, Stephen P. Kubo, Michiaki Tamari, Mayumi Nakamura, Yusuke Litonjua, Augusto A. Tantisira, Kelan G. Raby, Benjamin A. Bleecker, Eugene R. Meyers, Deborah A. London, Stephanie J. Barnes, Kathleen C. Gilliland, Frank D. Williams, L. Keoki Burchard, Esteban G. Nicolae, Dan L. Ober, Carole DeMeo, Dawn L. Silverman, Edwin K. Paigen, Beverly Churchill, Gary Shapiro, Steve D. Weiss, Scott T. TI Integration of Mouse and Human Genome-Wide Association Data Identifies KCNIP4 as an Asthma Gene SO PLOS ONE LA English DT Article ID QUANTITATIVE-TRAIT LOCI; INDUCED AIRWAY HYPERRESPONSIVENESS; CHILDHOOD ASTHMA; SUBSPECIFIC ORIGIN; UNDERLYING ASTHMA; LABORATORY MOUSE; INBRED MICE; MODEL; SEARCH; POPULATION AB Asthma is a common chronic respiratory disease characterized by airway hyperresponsiveness (AHR). The genetics of asthma have been widely studied in mouse and human, and homologous genomic regions have been associated with mouse AHR and human asthma-related phenotypes. Our goal was to identify asthma-related genes by integrating AHR associations in mouse with human genome-wide association study (GWAS) data. We used Efficient Mixed Model Association (EMMA) analysis to conduct a GWAS of baseline AHR measures from males and females of 31 mouse strains. Genes near or containing SNPs with EMMA p-values <0.001 were selected for further study in human GWAS. The results of the previously reported EVE consortium asthma GWAS meta-analysis consisting of 12,958 diverse North American subjects from 9 study centers were used to select a subset of homologous genes with evidence of association with asthma in humans. Following validation attempts in three human asthma GWAS (i.e., Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG) and two human AHR GWAS (i.e., SHARP, DAG), the Kv channel interacting protein 4 (KCNIP4) gene was identified as nominally associated with both asthma and AHR at a gene- and SNP-level. In EVE, the smallest KCNIP4 association was at rs6833065 (P-value 2.9e-04), while the strongest associations for Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG were 1.5e-03, 1.0e-03, 3.1e-03 at rs7664617, rs4697177, rs4696975, respectively. At a SNP level, the strongest association across all asthma GWAS was at rs4697177 (P-value 1.1e-04). The smallest P-values for association with AHR were 2.3e-03 at rs11947661 in SHARP and 2.1e-03 at rs402802 in DAG. Functional studies are required to validate the potential involvement of KCNIP4 in modulating asthma susceptibility and/or AHR. Our results suggest that a useful approach to identify genes associated with human asthma is to leverage mouse AHR association data. C1 [Himes, Blanca E.; Ziniti, John; Senter-Sylvia, Jody; Litonjua, Augusto A.; Tantisira, Kelan G.; Raby, Benjamin A.; DeMeo, Dawn L.; Silverman, Edwin K.; Weiss, Scott T.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Himes, Blanca E.; Ziniti, John; Senter-Sylvia, Jody; Litonjua, Augusto A.; Tantisira, Kelan G.; Raby, Benjamin A.; DeMeo, Dawn L.; Silverman, Edwin K.; Weiss, Scott T.] Harvard Univ, Sch Med, Boston, MA USA. [Himes, Blanca E.] Childrens Hosp Informat Program, Boston, MA USA. [Himes, Blanca E.; Klanderman, Barbara; Weiss, Scott T.] Partners HealthCare Ctr Personalized Genet Med, Boston, MA USA. [Sheppard, Keith; Paigen, Beverly; Churchill, Gary] Jackson Lab, Bar Harbor, ME 04609 USA. [Berndt, Annerose; Leme, Adriana S.; Shapiro, Steve D.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA. [Myers, Rachel A.; Nicolae, Dan L.; Ober, Carole] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Gignoux, Christopher R.; Torgerson, Dara G.; Roth, Lindsey A.; Huntsman, Scott; Eng, Celeste; Burchard, Esteban G.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Levin, Albert M.; Yang, James J.] Henry Ford Hlth Syst, Dept Publ Hlth Sci, Detroit, MI USA. [Gauderman, W. James; Gilliland, Frank D.] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. [Mathias, Rasika A.; Barnes, Kathleen C.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Romieu, Isabelle] Int Agcy Res Canc, F-69372 Lyon, France. [Szefler, Stanley J.] Natl Jewish Hlth, Denver, CO USA. [Szefler, Stanley J.] Univ Colorado, Denver Sch Med, Denver, CO 80202 USA. [Lemanske, Robert F., Jr.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. [Zeiger, Robert S.] Kaiser Permanente Southern Calif Reg, San Diego, CA USA. [Zeiger, Robert S.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Strunk, Robert C.] Washington Univ, Sch Med, St Louis, MO USA. [Martinez, Fernando D.] Univ Arizona, Coll Med, Arizona Resp Ctr, Tucson, AZ USA. [Boushey, Homer] Univ Calif San Francisco, Dept Med, Div Pulm Crit Care & Allergy Immunol, San Francisco, CA USA. [Chinchilli, Vernon M.; Mauger, David] Penn State Coll Med, Dept Publ Hlth Sci, Hershey, PA USA. [Israel, Elliot] Brigham & Womens Hosp, Dept Med, Div Pulm & Crit Care Med, Boston, MA 02115 USA. [Koppelman, Gerard H.] Univ Groningen, Univ Med Ctr Groningen, Dept Pediat Pulmonol & Pediat Allergol, Beatrix Childrens Hosp,GRIAC Res Inst, Groningen, Netherlands. [Postma, Dirkje S.; Nieuwenhuis, Maartje A. E.] Univ Groningen, Univ Med Ctr Groningen, Dept Pulmonol & TB, GRIAC Res Inst, Groningen, Netherlands. [Vonk, Judith M.] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, GRIAC Res Inst, Groningen, Netherlands. [Lima, John J.] Ctr Pharmacogen & Translat Res, Nemours Childrens Clin, Jacksonville, FL USA. [Irvin, Charles G.] Univ Vermont, Dept Physiol & Med, Vermont Lung Ctr, Burlington, VT USA. [Peters, Stephen P.; Bleecker, Eugene R.; Meyers, Deborah A.] Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA. [Kubo, Michiaki; Tamari, Mayumi] RIKEN, Ctr Genom Med, Kanagawa, Japan. [Nakamura, Yusuke] Univ Tokyo, Inst Med Sci, Mol Med Lab, Tokyo, Japan. [London, Stephanie J.] NIEHS, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Williams, L. Keoki] Henry Ford Hlth Syst, Ctr Hlth Policy & Hlth Serv Res, Dept Internal Med, Detroit, MI USA. RP Himes, BE (reprint author), Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. EM blanca.himes@channing.harvard.edu RI Kubo, Michiaki/N-7947-2015; Tamari, Mayumi/N-5378-2015; OI Litonjua, Augusto/0000-0003-0422-5875; London, Stephanie/0000-0003-4911-5290 FU NHLBI, National Institutes of Health (NIH) [U01 HL075419, U01 HL65899, P01 HL083069, R01 HL086601, T32 HL07427]; NIH [U01 HL65899, U10 HL064287, U10 HL064288, U10 HL064295, U10 HL064305, U10 HL064307, U01 HL064313, RC2 HL101487, R01 HL087699, K99 HL105663]; NIH Pharmacogenomics Research Network (PGRN) - RIKEN Center for Genomic Medicine (CGM) Global Alliance; BioBank Japan project; Ministry of Education, Culture, Sports, Sciences and Technology of the Japanese government; American Asthma Foundation; Fund for Henry Ford Hospital; NIH from the National Institute of Allergy and Infectious Diseases (NIAID) [R01AI079139, R01AI061774]; Mary Beryl Patch Turnbull Scholar Program; Division of Intramural Research, National Institute of Environmental Health Sciences; Netherlands Asthma Foundation grant AF [AF 95.09, AF 98.48, AF 3.2.02.51, AF 3.2.07.015]; University Medical Center Groningen; Ter Meulen Fund grant from the Royal Netherlands Academy of Arts and Sciences; Royal Netherlands Academy of Arts and Sciences Honorary Professorship; National Heart, Lung and Blood Institute (NHLBI) FX The CAMP Genetics Ancillary Study is supported by U01 HL075419, U01 HL65899, P01 HL083069, R01 HL086601, and T32 HL07427 from the NHLBI, National Institutes of Health (NIH). Additional support was provided by NIH U10 HL064287, U10 HL064288, U10 HL064295, U10 HL064305, U10 HL064307, U01 HL064313, RC2 HL101487, R01 HL087699 and U01 HL65899, an NIH Pharmacogenomics Research Network (PGRN) - RIKEN Center for Genomic Medicine (CGM) Global Alliance and by funding from the BioBank Japan project that was supported by the Ministry of Education, Culture, Sports, Sciences and Technology of the Japanese government. We thank the American Lung Association Asthma Clinical Research Centers (ALA-ACRC) for use of LOCCS and LODO study samples. B.E.H. was supported by NIH K99 HL105663. L.K.W. is funded by the American Asthma Foundation, the Fund for Henry Ford Hospital, and by NIH R01AI079139 and R01AI061774 from the National Institute of Allergy and Infectious Diseases (NIAID). K.C.B. was supported in part by the Mary Beryl Patch Turnbull Scholar Program. S.J.L. is supported by the Division of Intramural Research, National Institute of Environmental Health Sciences. D.A.G. was supported by the Netherlands Asthma Foundation grant AF (AF 95.09, AF 98.48, AF 3.2.02.51 and AF 3.2.07.015) and a grant from the University Medical Center Groningen. GHK was supported by a Ter Meulen Fund grant from the Royal Netherlands Academy of Arts and Sciences. D.S.P. was supported by a Royal Netherlands Academy of Arts and Sciences Honorary Professorship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; We thank all CAMP subjects for their ongoing participation in this study. We acknowledge the CAMP investigators and research team, supported by the National Heart, Lung and Blood Institute (NHLBI), for collection of CAMP Genetic Ancillary Study data. All work on data collected from the CAMP Genetic Ancillary Study was conducted at the Channing Laboratory of the Brigham and Women's Hospital under appropriate CAMP policies and human subject's protections. We acknowledge the following GALA 1 investigators: Michael A. LeNoir, MD (Bay Area Pediatrics, Oakland, CA, USA), Harold J. Farber, MD (Section of Pulmonology, Baylor College of Medicine, Houston, TX, USA), Rajesh Kumar, MD, MPH (Division of Allergy and Immunology, Children's Memorial Hospital, Chicago, IL, USA), Pedro C. Avila, MD (Department of Medicine, Northwestern University, Chicago, IL, USA), Kelley Meade, MD (Children's Hospital of Oakland, Oakland, CA, USA), Denise Serebrisky, MD (Jacobi Medical Center and Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA), Shannon Thyne, MD (Department of Medicine, University of California, San Francisco, San Francisco, CA, USA), William Rodriguez-Cintron, MD (Veterans Affairs Medical Center, San Juan, Puerto Rico), Jose R. Rodriguez-Santana, MD (Centro de Neumologia Pediatrica, San Juan, Puerto Rico), Luisa N. Borrell, DDS, PhD (Department of Health Sciences, Lehman College, City University of New York, New York, NY, USA). NR 57 TC 16 Z9 18 U1 0 U2 10 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 FEB 14 PY 2013 VL 8 IS 2 AR e56179 DI 10.1371/journal.pone.0056179 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 099EJ UT WOS:000315602700056 PM 23457522 ER PT J AU Wongtrakoongate, P Jones, M Gokhale, PJ Andrews, PW AF Wongtrakoongate, Patompon Jones, Mark Gokhale, Paul J. Andrews, Peter W. TI STELLA Facilitates Differentiation of Germ Cell and Endodermal Lineages of Human Embryonic Stem Cells SO PLOS ONE LA English DT Article ID DNA DEMETHYLATION; IN-VITRO; EXPRESSION PATTERNS; LINES; CULTURE; TUMORS; SPECIFICATION; ADAPTATION; DERIVATION; DEAMINASE AB Stella is a developmentally regulated gene highly expressed in mouse embryonic stem (ES) cells and in primordial germ cells (PGCs). In human, the gene encoding the STELLA homologue lies on chromosome 12p, which is frequently amplified in long-term cultured human ES cells. However, the role played by STELLA in human ES cells has not been reported. In the present study, we show that during retinoic acid (RA)-induced differentiation of human ES cells, expression of STELLA follows that of VASA, a marker of germline differentiation. By contrast, human embryonal carcinoma cells express STELLA at a higher level compared with both karyotypically normal and abnormal human ES cell lines. We found that over-expression of STELLA does not interfere with maintenance of the stem cell state of human ES cells, but following retinoic acid induction it leads to up-regulation of germline- and endodermal-associated genes, whereas neural markers PAX6 and NEUROD1 are down-regulated. Further, STELLA over-expression facilitates the differentiation of human ES cells into BE12-positive cells, in which the expression of germline- and endodermal-associated genes is enriched, and suppresses differentiation of the neural lineage. Taken together, this finding suggests a role for STELLA in facilitating germline and endodermal differentiation of human ES cells. C1 [Wongtrakoongate, Patompon; Jones, Mark; Gokhale, Paul J.; Andrews, Peter W.] Univ Sheffield, Dept Biomed Sci, Ctr Stem Cell Biol, Sheffield S10 2TN, S Yorkshire, England. RP Wongtrakoongate, P (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM p.wongtrakoongate@gmail.com; p.w.andrews@sheffield.ac.uk OI Gokhale, Paul/0000-0001-7225-4403 FU Thai government; Royal Thai Government; Medical Research Council FX PW is a PhD student supported by the Thai government. This work was supported by the Royal Thai Government. PWA is supported by a grant from the Medical Research Council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 16 Z9 19 U1 0 U2 13 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 FEB 14 PY 2013 VL 8 IS 2 AR e56893 DI 10.1371/journal.pone.0056893 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 099EJ UT WOS:000315602700101 PM 23457636 ER PT J AU Kumar, TS Yang, T Mishra, S Cronin, C Chakraborty, S Shen, JB Liang, BT Jacobson, KA AF Kumar, T. Santhosh Yang, Tiehong Mishra, Shilpi Cronin, Chunxia Chakraborty, Saibal Shen, Jian-Bing Liang, Bruce T. Jacobson, Kenneth A. TI 5 '-Phosphate and 5 '-Phosphonate Ester Derivatives of (N)-Methanocarba Adenosine with in Vivo Cardioprotective Activity SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID HEART-FAILURE; P2X RECEPTOR; STABILITY; PRODRUGS; ANALOGS; CARDIOMYOPATHY; CONFORMATION; ACTIVATION; MYOCYTES; RESCUE AB Activation of a cardiac myocyte P2X4 receptor protects against heart failure. 5'-Phosphonate and 5'-phosphate analogues of AMP containing a (N)-methanocarba (bicyclo[3.1.0]hexane) system could protect from heart failure by potentially activating this cardioprotective channel. Phosphoesters and phosphonodiesters were synthesized and administered in vivo via a miniosmotic pump in a mouse ischemic heart failure model and most significantly increased intact heart contractile function (echocardiography) compared to vehicle were protective in a calsequestrin (CSQ) overexpressing heart infusion. Several new thio and deuterated phosphate derivatives failure model. Diethyl (7, MRS4084) and diisopropyl (8, MRS4074) phosphotriesters were highly protective in the ischemic model. Substitution of 2-Cl with iodo reduced protection in the CSQ model. Diisopropyl ester 16 (MRS2978) of (1'S,2'R,3'S,4'R,5'S)-4'-(6-amino-2-chloropurin-9-yl)-2',3'-(dihydroxy)-1'-(phosphonoethylene)bicyclo[3.1.0]hexane was highly efficacious (CSQ), while lower homologue 1'-phosphonomethylene derivative 14 was inactive. Thus, we identified undiarged carbocyclic nucleotide analogues that represent potential candidates for the treatment of heart failure, suggesting this as a viable and structurally broad approach. C1 [Kumar, T. Santhosh; Mishra, Shilpi; Chakraborty, Saibal; Jacobson, Kenneth A.] NIDDKD, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. [Yang, Tiehong; Cronin, Chunxia; Shen, Jian-Bing; Liang, Bruce T.] Univ Connecticut, Ctr Hlth, Pat & Jim Calhoun Cardiol Ctr, Farmington, CT 06030 USA. RP Jacobson, KA (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Bldg 8A,Rm B1A-19, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases; Ray Neag Distinguished Professorship; [RO1-HL48225] FX Mass spectral measurements were carried out by Dr. John Lloyd and Dr. Noel Whittaker (NIDDK). This research was supported in part by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. This work was supported in part by Grant RO1-HL48225 and Ray Neag Distinguished Professorship to Bruce T. Liang. NR 23 TC 13 Z9 13 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD FEB 14 PY 2013 VL 56 IS 3 BP 902 EP 914 DI 10.1021/jm301372c PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 093HK UT WOS:000315182100024 PM 23286881 ER PT J AU Cui, GH Jun, SB Jin, X Pham, MD Vogel, SS Lovinger, DM Costa, RM AF Cui, Guohong Jun, Sang Beom Jin, Xin Pham, Michael D. Vogel, Steven S. Lovinger, David M. Costa, Rui M. TI Concurrent activation of striatal direct and indirect pathways during action initiation SO NATURE LA English DT Article ID IMAGING IN-VIVO; BASAL GANGLIA; STRIATOPALLIDAL NEURONS; MOTOR BEHAVIORS; POPULATIONS; DISORDERS; MOVEMENTS; RESPONSES; CIRCUITS; MOUSE AB The basal ganglia are subcortical nuclei that control voluntary actions, and they are affected by a number of debilitating neurological disorders(1-4). The prevailing model of basal ganglia function proposes that two orthogonal projection circuits originating from distinct populations of spiny projection neurons (SPNs) in the striatum(5,6)-the so-called direct and indirect pathways have opposing effects on movement: activity of direct-pathway SPNs is thought to facilitate movement, whereas activity of indirect-pathway SPNs is presumed to inhibit movement(1,2). This model has been difficult to test owing to the lack of methods to selectively measure the activity of direct- and indirect-pathway SPNs in freely moving animals: Here we develop a novel in vivo method to specifically measure direct- and indirect-pathway SPN activity, using Cre-dependent viral expression of the genetically encoded calcium indicator (GECI) GCaMP3 in the dorsal striatum of D1-Cre (direct-pathway-specific(6,7)) and A2A-Cre (indirect-pathway-specific(8,9)) mice. Using fibre optics and time-correlated single-photon counting (TCSPC) in mice performing an operant task, we observed transient-increases in neural activity in both direct- and indirect-pathway SPNs when animals initiated actions, but not when they were inactive. Concurrent activation of SPNs from both pathways in one hemisphere preceded the initiation of contraversive movements and predicted the occurrence of specific movements within 500 ms. These observations challenge the classical view of basal ganglia function and may have implications for understanding the origin of motor symptoms in basal ganglia disorders. C1 [Cui, Guohong; Jin, Xin; Pham, Michael D.; Lovinger, David M.; Costa, Rui M.] NIAAA, Sect Vivo Neural Funct, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. [Jun, Sang Beom] Ewha Womans Univ, Dept Elect Engn, Seoul 120750, South Korea. [Jin, Xin] Salk Inst Biol Studies, Mol Neurobiol Lab, La Jolla, CA 92037 USA. [Vogel, Steven S.] NIAAA, Sect Cellular Biophoton, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. [Lovinger, David M.] NIAAA, Sect Synapt Pharmacol, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. [Costa, Rui M.] Inst Gulbenkian Ciencias, Champalimaud Neurosci Programme, P-1400038 Lisbon, Portugal. [Costa, Rui M.] Champalimaud Ctr Unknown, P-1400038 Lisbon, Portugal. RP Vogel, SS (reprint author), NIAAA, Sect Cellular Biophoton, Lab Mol Physiol, NIH, 5625 Fishers Lane, Bethesda, MD 20892 USA. EM stevevog@mail.nih.gov; lovindav@mail.nih.gov; ruicosta@fchampalimaud.org OI Vogel, Steven/0000-0002-3005-2667; Costa, Rui/0000-0003-0495-8374 FU Division of Intramural Clinical and Biological Research of the NIAAA; European Research Council [STG 243393]; International Early Career Scientist grant from the Howard Hughes Medical Institute; National Research Foundation of Korea [2011-0029485, 2012-0004003]; SmartIT Convergence System Research Center from the Korean government (MEST) [SIRC-2011-0031866]; Ellison Medical Foundation [AG-NS-0944-12] FX We thank C. R. Gerfen for gifts of multiple bacterial artificial chromosome (BAC) transgenic mouse lines; L. L. Looger and the Howard Hughes Medical Institute (HHMI) for permission to use AAV GCaMP3 vectors and GCaMP3 mice; S. R. Ikeda for assistance with Ca2+ imaging in brain slices; G. Luo for mouse genotyping; C. Thaler for assistance with FLIM curve analysis; B. Mathur and M. Davis for assistance with brain slice electrophysiology and histology; and A. Martin for assistance with AAV vector injection. This work was supported by the Division of Intramural Clinical and Biological Research of the NIAAA, European Research Council STG 243393, an International Early Career Scientist grant from the Howard Hughes Medical Institute to R.M.C., a National Research Foundation of Korea grant (2011-0029485,2012-0004003) and SmartIT Convergence System Research Center (SIRC-2011-0031866) from the Korean government (MEST) to S.B.J., and by an Ellison Medical Foundation grant (AG-NS-0944-12) to X.J. NR 30 TC 235 Z9 237 U1 9 U2 85 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 14 PY 2013 VL 494 IS 7436 BP 238 EP 242 DI 10.1038/nature11846 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 092QS UT WOS:000315137700040 PM 23354054 ER PT J AU Haso, W Lee, DW Shah, NN Stetler-Stevenson, M Yuan, CM Pastan, IH Dimitrov, DS Morgan, RA FitzGerald, DJ Barrett, DM Wayne, AS Mackall, CL Orentas, RJ AF Haso, Waleed Lee, Daniel W. Shah, Nirali N. Stetler-Stevenson, Maryalice Yuan, Constance M. Pastan, Ira H. Dimitrov, Dimiter S. Morgan, Richard A. FitzGerald, David J. Barrett, David M. Wayne, Alan S. Mackall, Crystal L. Orentas, Rimas J. TI Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia SO BLOOD LA English DT Article ID T-CELLS; HEMATOLOGIC MALIGNANCIES; ANTITUMOR-ACTIVITY; RECOMBINANT IMMUNOTOXIN; SIGNAL-TRANSDUCTION; CHIMERIC RECEPTORS; CYTOTOXIC ACTIVITY; ENHANCED SURVIVAL; FLOW-CYTOMETRY; CLINICAL-TRIAL AB Immune targeting of B-cell malignancies using chimeric antigen receptors (CARs) is a promising new approach, but critical factors impacting CAR efficacy remain unclear. To test the suitability of targeting CD22 on precursor B-cell acute lymphoblastic leukemia (BCP-ALL), lymphoblasts from 111 patients with BCP-ALL were assayed for CD22 expression and all were found to be CD22-positive, with median CD22 expression levels of 3500 sites/cell. Three distinct binding domains targeting CD22 were fused to various TCR signaling domains +/- an IgG heavy chain constant domain (CH2CH3) to create a series of vector constructs suitable to delineate optimal CAR configuration. CARs derived from the m971 anti-CD22 mAb, which targets a proximal CD22 epitope demonstrated superior antileukemic activity compared with those incorporating other binding domains, and addition of a 4-1BB signaling domain to CD28. CD3 zeta constructs diminished potency, whereas increasing affinity of the anti-CD22 binding motif, and extending the CD22 binding domain away from the membrane via CH2CH3 had no effect. We conclude that second-generation m971 mAb-derived anti-CD22 CARs are promising novel therapeutics that should be tested in BCP-ALL. (Blood. 2013; 121(7): 1165-1174) C1 [Haso, Waleed; Lee, Daniel W.; Shah, Nirali N.; Wayne, Alan S.; Mackall, Crystal L.; Orentas, Rimas J.] NCI, Pediat Oncol Branch, CCR, NIH, Bethesda, MD 20892 USA. [Stetler-Stevenson, Maryalice; Yuan, Constance M.] NCI, Pathol Lab, CCR, NIH, Bethesda, MD 20892 USA. [Pastan, Ira H.; FitzGerald, David J.; Wayne, Alan S.] NCI, Mol Biol Lab, CCR, NIH, Bethesda, MD 20892 USA. [Dimitrov, Dimiter S.] Frederick Natl Lab, CCR Nanobiol Program, Frederick, MD USA. [Morgan, Richard A.] NCI, Surg Branch, CCR, NIH, Bethesda, MD 20892 USA. [Barrett, David M.] Univ Penn, Perelman Sch Med, Childrens Hosp Penn, Blood & Marrow Transplantat Program, Philadelphia, PA 19104 USA. RP Orentas, RJ (reprint author), NCI, Pediat Oncol Branch, CCR, NIH, 10 Ctr Dr,1W3840, Bethesda, MD 20892 USA. EM rimas.orentas@nih.gov FU NIH, CCR, NCI FX This research was supported by the Intramural Research Program of the NIH, CCR, NCI. NR 39 TC 115 Z9 119 U1 0 U2 25 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 14 PY 2013 VL 121 IS 7 BP 1165 EP 1174 DI 10.1182/blood-2012-06-438002 PG 10 WC Hematology SC Hematology GA 088XH UT WOS:000314870700020 PM 23243285 ER PT J AU Ren, XF Farias, GG Canagarajah, BJ Bonifacino, JS Hurley, JH AF Ren, Xuefeng Farias, Ginny G. Canagarajah, Bertram J. Bonifacino, Juan S. Hurley, James H. TI Structural Basis for Recruitment and Activation of the AP-1 Clathrin Adaptor Complex by Arf1 SO CELL LA English DT Article ID ADP-RIBOSYLATION FACTOR; CARGO-SORTING SIGNALS; GTP-BINDING PROTEIN; COATED VESICLES; MEMBRANE RECRUITMENT; GOLGI MEMBRANES; AP2 COMPLEX; HIV-1 NEF; RECOGNITION; SUBUNIT AB AP-1 is a clathrin adaptor complex that sorts cargo between the trans-Golgi network and endosomes. AP-1 recruitment to these compartments requires Arf1-GTP. The crystal structure of the tetrameric core of AP-1 in complex with Arf1-GTP, together with biochemical analyses, shows that Arf1 activates cargo binding by unlocking AP-1. Unlocking is driven by two molecules of Arf1 that bridge two copies of AP-1 at two interaction sites. The GTP-dependent switch I and II regions of Arf1 bind to the N terminus of the beta 1 subunit of one AP-1 complex, while the back side of Arf1 binds to the central part of the gamma subunit trunk of a second AP-1 complex. A third Arf1 interaction site near the N terminus of the gamma subunit is important for recruitment, but not activation. These observations lead to a model for the recruitment and activation of AP-1 by Arf1. C1 [Ren, Xuefeng; Farias, Ginny G.; Bonifacino, Juan S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Canagarajah, Bertram J.; Hurley, James H.] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Bonifacino, JS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. EM bonifacinoj@helix.nih.gov; james.hurley@nih.gov OI Bonifacino, Juan S./0000-0002-5673-6370 FU U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; NICHD; NIDDK, NIH FX We thank G. Mardones for assistance with constructs and W. Yang for critically reading the manuscript. Crystallographic data were collected at Southeast Regional Collaborative Access Team 22-ID beamline at the Advanced Photon Source, Argonne National Laboratory. Use of the Advanced Photon Source was supported by the U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38. This research was supported by the Intramural Programs of NICHD (J.S.B.) and NIDDK (J.H.H.), NIH. NR 48 TC 48 Z9 48 U1 1 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD FEB 14 PY 2013 VL 152 IS 4 BP 755 EP 767 DI 10.1016/j.cell.2012.12.042 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 089YJ UT WOS:000314945600011 PM 23415225 ER PT J AU Visel, A Taher, L Girgis, H May, D Golonzhka, O Hoch, RV McKinsey, GL Pattabiraman, K Silberberg, SN Blow, MJ Hansen, DV Nord, AS Akiyama, JA Holt, A Hosseini, R Phouanenavong, S Plajzer-Frick, I Shoukry, M Afzal, V Kaplan, T Kriegstein, AR Rubin, EM Ovcharenko, I Pennacchio, LA Rubenstein, JLR AF Visel, Axel Taher, Leila Girgis, Hani May, Dalit Golonzhka, Olga Hoch, Renee V. McKinsey, Gabriel L. Pattabiraman, Kartik Silberberg, Shanni N. Blow, Matthew J. Hansen, David V. Nord, Alex S. Akiyama, Jennifer A. Holt, Amy Hosseini, Roya Phouanenavong, Sengthavy Plajzer-Frick, Ingrid Shoukry, Malak Afzal, Veena Kaplan, Tommy Kriegstein, Arnold R. Rubin, Edward M. Ovcharenko, Ivan Pennacchio, Len A. Rubenstein, John L. R. TI A High-Resolution Enhancer Atlas of the Developing Telencephalon SO CELL LA English DT Article ID TRANSCRIPTION FACTOR-BINDING; RECOMBINASE ACTIVITY; BRAIN-DEVELOPMENT; RANDOM FORESTS; EXPRESSION; SCHIZOPHRENIA; DATABASE; AUTISM; CHROMOSOMES; ASSOCIATION AB The mammalian telencephalon plays critical roles in cognition, motor function, and emotion. Though many of the genes required for its development have been identified, the distant-acting regulatory sequences orchestrating their in vivo expression are mostly unknown. Here, we describe a digital atlas of in vivo enhancers active in subregions of the developing telencephalon. We identified more than 4,600 candidate embryonic forebrain enhancers and studied the in vivo activity of 329 of these sequences in transgenic mouse embryos. We generated serial sets of histological brain sections for 145 reproducible forebrain enhancers, resulting in a publicly accessible web-based data collection comprising more than 32,000 sections. We also used epigenomic analysis of human and mouse cortex tissue to directly compare the genome-wide enhancer architecture in these species. These data provide a primary resource for investigating gene regulatory mechanisms of telencephalon development and enable studies of the role of distant-acting enhancers in neurodevelopmental disorders. C1 [Visel, Axel; May, Dalit; Nord, Alex S.; Akiyama, Jennifer A.; Holt, Amy; Hosseini, Roya; Phouanenavong, Sengthavy; Plajzer-Frick, Ingrid; Shoukry, Malak; Afzal, Veena; Rubin, Edward M.; Pennacchio, Len A.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Genom Div, Berkeley, CA 94720 USA. [Visel, Axel; Blow, Matthew J.; Rubin, Edward M.; Pennacchio, Len A.] US DOE, Joint Genome Inst, Walnut Creek, CA 94598 USA. [Taher, Leila; Girgis, Hani; Ovcharenko, Ivan] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Golonzhka, Olga; Hoch, Renee V.; McKinsey, Gabriel L.; Pattabiraman, Kartik; Silberberg, Shanni N.; Rubenstein, John L. R.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94158 USA. [Hansen, David V.; Kriegstein, Arnold R.] Univ Calif San Francisco, Eli & Edythe Broad, Ctr Regenerat Med & Stem Cell Res, San Francisco, CA 94143 USA. [Hansen, David V.; Kriegstein, Arnold R.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Kaplan, Tommy] Univ Calif Berkeley, Calif Inst Quantitat Biosci, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Kaplan, Tommy] Hebrew Univ Jerusalem, Sch Comp Sci & Engn, IL-91904 Jerusalem, Israel. RP Visel, A (reprint author), Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Genom Div, MS 84-171, Berkeley, CA 94720 USA. EM avisel@lbl.gov RI Visel, Axel/A-9398-2009; Blow, Matthew/G-6369-2012; OI Visel, Axel/0000-0002-4130-7784; Blow, Matthew/0000-0002-8844-9149; Hansen, David/0000-0001-9679-7189; Hoch, Renee/0000-0003-0042-3751 FU NINDS [R01NS062859A, R01NS34661, R01NS075998]; NHGRI [R01HG003988]; Nina Ireland; Weston Havens Foundation; NIMH [R01MH081880, R37MH049428]; CIRM [RB2-1602]; NARSAD; Intramural Research Program of the NIH; National Library of Medicine; Department of Energy [DE-AC02-05CH11231]; [T32 GM007449]; [T32 GMO7618]; [F32 MH081431] FX The authors thank Julian Golder and Noah Efron for help with digital image acquisition and data processing; Bing Ren and Zirong Li for help with chromatin immunoprecipitation from embryonic mouse tissue; Inna Dubchak, Simon Minovitsky, and Alexandre Poliakov for website support; and staff at San Francisco General Hospital Women's Options Center for their consideration in allowing us to access donated fetal tissue. A.V. and L.A.P. were supported by NINDS grant R01NS062859A and by NHGRI grant R01HG003988. J.L.R.R. was supported by the Nina Ireland, Weston Havens Foundation, NINDS grant R01NS34661, NIMH grant R01MH081880, and NIMH grant R37MH049428. J.L.R.R. and A.R.K were supported by CIRM RB2-1602. G.M. and S.N.S. were supported by T32 GM007449, K.P. was supported by T32 GMO7618, R.H. was supported by F32 MH081431, and O.G. was supported by NARSAD. A.R.K. was supported by NINDS grant R01NS075998. I.O. was supported by the Intramural Research Program of the NIH, National Library of Medicine. Research was conducted at the E.O. Lawrence Berkeley National Laboratory and performed under Department of Energy Contract DE-AC02-05CH11231, University of California. NR 55 TC 87 Z9 87 U1 0 U2 32 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD FEB 14 PY 2013 VL 152 IS 4 BP 895 EP 908 DI 10.1016/j.cell.2012.12.041 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 089YJ UT WOS:000314945600022 PM 23375746 ER PT J AU Berezhkovskii, AM Dagdug, L Vazquez, MV Lizunov, VA Zimmerberg, J Bezrukov, SM AF Berezhkovskii, Alexander M. Dagdug, Leonardo Vazquez, Marco-Vinicio Lizunov, Vladimir A. Zimmerberg, Joshua Bezrukov, Sergey M. TI Trapping of diffusing particles by clusters of absorbing disks on a reflecting wall with disk centers on sites of a square lattice SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID 1ST PASSAGE TIME; LIGAND-BINDING; LIPID RAFTS; ASYMPTOTIC ANALYSIS; CELL-MEMBRANES; RATE CONSTANTS; RECEPTORS; SURFACES AB A simple approximate formula is derived for the rate constant that describes steady-state flux of diffusing particles through a cluster of perfectly absorbing disks on the otherwise reflecting flat wall, assuming that the disk centers occupy neighboring sites of a square lattice. A distinctive feature of trapping by a disk cluster is that disks located at the cluster periphery shield the disks in the center of the cluster. This competition of the disks for diffusing particles makes it impossible to find an exact analytical solution for the rate constant in the general case. To derive the approximate formula, we use a recently suggested approach [A. M. Berezhkovskii, L. Dagdug, V. A. Lizunov, J. Zimmerberg, and S. M. Bezrukov, J. Chem. Phys. 136, 211102 (2012)], which is based on the replacement of the disk cluster by an effective uniform partially absorbing spot. The formula shows how the rate constant depends on the size and shape of the cluster. To check the accuracy of the formula, we compare its predictions with the values of the rate constant obtained from Brownian dynamics simulations. The comparison made for 18 clusters of various shapes and sizes shows good agreement between the theoretical predictions and numerical results. (C) 2013 American Institute of Physics. [http://dx.doi.org/10.1063/1.4790370] C1 [Berezhkovskii, Alexander M.; Dagdug, Leonardo] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Berezhkovskii, Alexander M.; Dagdug, Leonardo; Lizunov, Vladimir A.; Zimmerberg, Joshua; Bezrukov, Sergey M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Dagdug, Leonardo; Vazquez, Marco-Vinicio] Univ Autonoma Metropolitana, Dept Fis, Mexico City 09340, DF, Mexico. RP Berezhkovskii, AM (reprint author), NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. RI Lizunov, Vladimir/B-5468-2009 FU National Institutes of Health (NIH), Center for Information Technology; Eunice Kennedy Shriver National Institute of Child Health and Human Development; CONACyT [176452] FX We are grateful to Super Computer Division of Universidad Autonoma Metropolitana-Iztapalapa for the use of their computational facilities. This study was supported by the Intramural Research Program of the National Institutes of Health (NIH), Center for Information Technology and Eunice Kennedy Shriver National Institute of Child Health and Human Development and partially supported by CONACyT under Grant No. 176452. NR 32 TC 1 Z9 1 U1 0 U2 5 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 EI 1089-7690 J9 J CHEM PHYS JI J. Chem. Phys. PD FEB 14 PY 2013 VL 138 IS 6 AR 064105 DI 10.1063/1.4790370 PG 6 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 091MS UT WOS:000315054400009 ER PT J AU Buckley, DM Burroughs-Garcia, J Lewandoski, M Waters, ST AF Buckley, Desire M. Burroughs-Garcia, Jessica Lewandoski, Mark Waters, Samuel T. TI Characterization of the Gbx1(-/-) Mouse Mutant: A Requirement for Gbx1 in Normal Locomotion and Sensorimotor Circuit Development SO PLOS ONE LA English DT Article ID DORSAL SPINAL-CORD; MOTOR-NEURON IDENTITY; ROOT GANGLION NEURONS; MID/HINDBRAIN ORGANIZER; TRANSCRIPTIONAL CODES; SUBTYPE IDENTITY; NERVOUS-SYSTEM; GENE-FUNCTION; SPECIFICATION; EXPRESSION AB The Gbx class of homeobox genes encodes DNA binding transcription factors involved in regulation of embryonic central nervous system (CNS) development. Gbx1 is dynamically expressed within spinal neuron progenitor pools and becomes restricted to the dorsal mantle zone by embryonic day (E) 12.5. Here, we provide the first functional analysis of Gbx1. We generated mice containing a conditional Gbx1 allele in which exon 2 that contains the functional homeodomain is flanked with loxP sites (Gbx1(flox)); Cre-mediated recombination of this allele results in a Gbx1 null allele. In contrast to mice homozygous for a loss-of-function allele of Gbx2, mice homozygous for the Gbx1 null allele, Gbx1(-/-), are viable and reproductively competent. However, Gbx1(-/-) mice display a gross locomotive defect that specifically affects hindlimb gait. Analysis of embryos homozygous for the Gbx1 null allele reveals disrupted assembly of the proprioceptive sensorimotor circuit within the spinal cord, and a reduction in ISL1(+) ventral motor neurons. These data suggest a functional requirement for Gbx1 in normal development of the neural networks that contribute to locomotion. The generation of this null allele has enabled us to functionally characterize a novel role for Gbx1 in development of the spinal cord. C1 [Buckley, Desire M.; Burroughs-Garcia, Jessica; Waters, Samuel T.] Univ Missouri, Div Biol Sci, Columbia, MO 65211 USA. [Buckley, Desire M.; Burroughs-Garcia, Jessica; Waters, Samuel T.] Univ Missouri, Christopher S Bond Life Sci Ctr, Columbia, MO USA. [Lewandoski, Mark] NCI, Canc & Dev Biol Lab, NIH, Frederick, MD 21701 USA. RP Waters, ST (reprint author), Univ Missouri, Div Biol Sci, Columbia, MO 65211 USA. EM waterssa@missouri.edu FU University of Missouri; National Science Foundation [1021288] FX This work was supported by startup funds from the University of Missouri (STW) and by the National Science Foundation award 1021288. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 5 Z9 5 U1 0 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 FEB 13 PY 2013 VL 8 IS 2 AR e56214 DI 10.1371/journal.pone.0056214 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 104DM UT WOS:000315970300128 PM 23418536 ER PT J AU Gaughan, AE Stevens, FR Linard, C Jia, P Tatem, AJ AF Gaughan, Andrea E. Stevens, Forrest R. Linard, Catherine Jia, Peng Tatem, Andrew J. TI High Resolution Population Distribution Maps for Southeast Asia in 2010 and 2015 SO PLOS ONE LA English DT Article ID LAND-COVER; ACCURACY; CENSUS; HEALTH; RISK AB Spatially accurate, contemporary data on human population distributions are vitally important to many applied and theoretical researchers. The Southeast Asia region has undergone rapid urbanization and population growth over the past decade, yet existing spatial population distribution datasets covering the region are based principally on population count data from censuses circa 2000, with often insufficient spatial resolution or input data to map settlements precisely. Here we outline approaches to construct a database of GIS-linked circa 2010 census data and methods used to construct fine-scale (similar to 100 meters spatial resolution) population distribution datasets for each country in the Southeast Asia region. Landsat-derived settlement maps and land cover information were combined with ancillary datasets on infrastructure to model population distributions for 2010 and 2015. These products were compared with those from two other methods used to construct commonly used global population datasets. Results indicate mapping accuracies are consistently higher when incorporating land cover and settlement information into the AsiaPop modelling process. Using existing data, it is possible to produce detailed, contemporary and easily updatable population distribution datasets for Southeast Asia. The 2010 and 2015 datasets produced are freely available as a product of the AsiaPop Project and can be downloaded from: www.asiapop.org. C1 [Gaughan, Andrea E.; Stevens, Forrest R.; Jia, Peng; Tatem, Andrew J.] Univ Florida, Dept Geog, Gainesville, FL 32611 USA. [Gaughan, Andrea E.; Stevens, Forrest R.; Jia, Peng; Tatem, Andrew J.] Univ Florida, Emerging Pathogens Inst, Gainesville, FL USA. [Gaughan, Andrea E.; Stevens, Forrest R.] Univ Florida, Land Use Environm Change Inst, Gainesville, FL USA. [Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Linard, Catherine] Fonds Natl Rech Sci, B-1050 Brussels, Belgium. [Linard, Catherine] Univ Libre Brussels, Brussels, Belgium. RP Gaughan, AE (reprint author), Univ Florida, Dept Geog, Gainesville, FL 32611 USA. EM aegaughan@gmail.com RI Stevens, Forrest/B-1673-2013 OI Stevens, Forrest/0000-0002-9328-3753 FU RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Bill and Melinda Gates Foundation [49446, 1032350]; Fogarty International Center, National Institutes of Health FX AJT acknowledges funding support from the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health, and is also supported by grants from the Bill and Melinda Gates Foundation (#49446 and #1032350). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 36 Z9 39 U1 5 U2 19 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 13 PY 2013 VL 8 IS 2 AR e55882 DI 10.1371/journal.pone.0055882 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 104DM UT WOS:000315970300060 PM 23418469 ER PT J AU Zhang, XZ Daucher, M Armistead, D Russell, R Kottilil, S AF Zhang, Xiaozhen Daucher, Marybeth Armistead, David Russell, Rodney Kottilil, Shyam TI MicroRNA Expression Profiling in HCV-Infected Human Hepatoma Cells Identifies Potential Anti-Viral Targets Induced by Interferon-alpha SO PLOS ONE LA English DT Article ID CHRONIC HEPATITIS-C; VIRUS-INFECTION; HEPATOCELLULAR-CARCINOMA; CELLULAR MICRORNAS; PLUS RIBAVIRIN; LIVER-DISEASES; GENE; MET; MODULATION; MECHANISM AB Objective: Increasing evidence suggests that miRNAs have a profound impact on host defense to Hepatitis C virus (HCV) infection and clinical outcome of standard HCV therapy. In this study, we investigated modulation of miRNA expression in Huh7.5 hepatoma cells by HCV infection and in vitro interferon-alpha treatment. Methods: MiRNA expression profiling was determined using Human miRNA TaqMan (R) Arrays followed by rigorous pairwise statistical analysis. MiRNA inhibitors assessed the functional effects of miRNAs on HCV replication. Computational analysis predicted anti-correlated mRNA targets and their involvement in host cellular pathways. Quantitative RTPCR confirmed the expression of predicted miRNA-mRNA correlated pairs in HCV-infected Huh7.5 cells with and without interferon-alpha. Results: Seven miRNAs (miR-30b, miR-30c, miR-130a, miR-192, miR-301, miR-324-5p, and miR-565) were down-regulated in HCV-infected Huh7.5 cells (p<0.05) and subsequently up-regulated following interferon-alpha treatment (p<0.01). The miR-30(a-d) cluster and miR-130a/301 and their putative mRNA targets were predicted to be associated with cellular pathways that involve Hepatitis C virus entry, propagation and host response to viral infection. Conclusions: HCV differentially modulates miRNAs to facilitate entry and early establishment of infection in vitro. Interferon-alpha appears to neutralize the effect of HCV replication on miRNA regulation thus providing a potential mechanism of action in eradicating HCV from hepatocytes. C1 [Zhang, Xiaozhen; Daucher, Marybeth; Kottilil, Shyam] NIAID, Immunopathogenesis Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Armistead, David] Life Technol Inc, Gaithersburg, MD USA. [Russell, Rodney] Mem Univ Newfoundland, Fac Med, Hlth Sci Ctr, St John, NF, Canada. RP Kottilil, S (reprint author), NIAID, Immunopathogenesis Sect, Immunoregulat Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM skottilil@niaid.nih.gov FU Intramural Research Program of the NIH, [National Institute of Allergy and Infectious Diseases] FX The authors declare that they do not have anything to disclose regarding the funding or conflict of interest with respect to this manuscript. The content of this publication does not necessarily reflect the views of 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 whole by the Intramural Research Program of the NIH, [National Institute of Allergy and Infectious Diseases]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 35 Z9 35 U1 1 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 13 PY 2013 VL 8 IS 2 AR e55733 DI 10.1371/journal.pone.0055733 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 104DM UT WOS:000315970300044 PM 23418453 ER PT J AU Shao, W Boltz, VF Spindler, JE Kearney, MF Maldarelli, F Mellors, JW Stewart, C Volfovsky, N Levitsky, A Stephens, RM Coffin, JM AF Shao, Wei Boltz, Valerie F. Spindler, Jonathan E. Kearney, Mary F. Maldarelli, Frank Mellors, John W. Stewart, Claudia Volfovsky, Natalia Levitsky, Alexander Stephens, Robert M. Coffin, John M. TI Analysis of 454 sequencing error rate, error sources, and artifact recombination for detection of Low-frequency drug resistance mutations in HIV-1 DNA SO RETROVIROLOGY LA English DT Article DE 454 pyrosequencing; HIV-1; Error rate; PCR induced recombination ID REVERSE-TRANSCRIPTASE; MINORITY VARIANTS; VIRAL VARIANTS; PCR; IMPACT; DIVERSITY; AMPLICONS; ACCURACY; THERAPY; QUALITY AB Background: 454 sequencing technology is a promising approach for characterizing HIV-1 populations and for identifying low frequency mutations. The utility of 454 technology for determining allele frequencies and linkage associations in HIV infected individuals has not been extensively investigated. We evaluated the performance of 454 sequencing for characterizing HIV populations with defined allele frequencies. Results: We constructed two HIV-1 RT clones. Clone A was a wild type sequence. Clone B was identical to clone A except it contained 13 introduced drug resistant mutations. The clones were mixed at ratios ranging from 1% to 50% and were amplified by standard PCR conditions and by PCR conditions aimed at reducing PCR-based recombination. The products were sequenced using 454 pyrosequencing. Sequence analysis from standard PCR amplification revealed that 14% of all sequencing reads from a sample with a 50:50 mixture of wild type and mutant DNA were recombinants. The majority of the recombinants were the result of a single crossover event which can happen during PCR when the DNA polymerase terminates synthesis prematurely. The incompletely extended template then competes for primer sites in subsequent rounds of PCR. Although less often, a spectrum of other distinct crossover patterns was also detected. In addition, we observed point mutation errors ranging from 0.01% to 1.0% per base as well as indel (insertion and deletion) errors ranging from 0.02% to nearly 50%. The point errors (single nucleotide substitution errors) were mainly introduced during PCR while indels were the result of pyrosequencing. We then used new PCR conditions designed to reduce PCR-based recombination. Using these new conditions, the frequency of recombination was reduced 27-fold. The new conditions had no effect on point mutation errors. We found that 454 pyrosequencing was capable of identifying minority HIV-1 mutations at frequencies down to 0.1% at some nucleotide positions. Conclusion: Standard PCR amplification results in a high frequency of PCR-introduced recombination precluding its use for linkage analysis of HIV populations using 454 pyrosequencing. We designed a new PCR protocol that resulted in a much lower recombination frequency and provided a powerful technique for linkage analysis and haplotype determination in HIV-1 populations. Our analyses of 454 sequencing results also demonstrated that at some specific HIV-1 drug resistant sites, mutations can reliably be detected at frequencies down to 0.1%. C1 [Shao, Wei; Volfovsky, Natalia; Levitsky, Alexander; Stephens, Robert M.] Frederick Natl Lab Canc Res, Adv Biomed Comp Ctr, SAIC Frederick, Frederick, MD USA. [Boltz, Valerie F.; Spindler, Jonathan E.; Kearney, Mary F.; Maldarelli, Frank; Coffin, John M.] NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. [Mellors, John W.] Univ Pittsburgh, Div Infect Dis, Pittsburgh, PA USA. [Stewart, Claudia] Frederick Natl Lab Canc Res, LMT, SAIC Frederick, Frederick, MD USA. [Coffin, John M.] Tufts Univ, Boston, MA 02111 USA. RP Shao, W (reprint author), Frederick Natl Lab Canc Res, Adv Biomed Comp Ctr, SAIC Frederick, POB B, Frederick, MD USA. EM shaow@mail.nih.gov FU National Cancer Institute's intramural Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; F.M. Kirby Foundation FX The authors thank Dr. Steve Hughes and Dr. Paul Boyer for reagents, Dr. Helene Mens, Ann Wiegand for valuable discussion, and Dan Kordella for assisting making figures. Funding for this research was provided by the National Cancer Institute's intramural Center for Cancer Research and in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. JMC was a research professor of the American Cancer Society, with support from the F.M. Kirby Foundation. NR 32 TC 49 Z9 49 U1 2 U2 19 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 FEB 13 PY 2013 VL 10 AR 18 DI 10.1186/1742-4690-10-18 PG 16 WC Virology SC Virology GA 118WX UT WOS:000317058500001 PM 23402264 ER PT J AU Enose-Akahata, Y Abrams, A Massoud, R Bialuk, I Johnson, KR Green, PL Maloney, EM Jacobson, S AF Enose-Akahata, Yoshimi Abrams, Anna Massoud, Raya Bialuk, Izabela Johnson, Kory R. Green, Patrick L. Maloney, Elizabeth M. Jacobson, Steven TI Humoral immune response to HTLV-1 basic leucine zipper factor (HBZ) in HTLV-1-infected individuals SO RETROVIROLOGY LA English DT Article DE HTLV-1; Antibody; HAM/TSP; ATL; Asymptomatic carriers; Serum; CSF ID VIRUS TYPE-I; CELL LEUKEMIA-VIRUS; TROPICAL SPASTIC PARAPARESIS; CD8(+) T-CELLS; NF-KAPPA-B; HUMAN MONOCLONAL-ANTIBODIES; CEREBROSPINAL-FLUID; PROVIRAL LOAD; INTRATHECAL SYNTHESIS; NEUROLOGIC DISEASE AB Background: Human T cell lymphotropic virus type 1 (HTLV-1) infection can lead to development of adult T cell leukemia/lymphoma (ATL) or HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in a subset of infected subjects. HTLV-1 basic leucine zipper factor (HBZ) gene has a critical role in HTLV-1 infectivity and the development of ATL and HAM/TSP. However, little is known about the immune response against HBZ in HTLV-1-infected individuals. In this study, we examined antibody responses against HBZ in serum/plasma samples from 436 subjects including HTLV-1 seronegative donors, asymptomatic carriers (AC), ATL, and HAM/TSP patients using the luciferase immunoprecipitation system. Results: Immunoreactivity against HBZ was detected in subsets of all HTLV-1-infected individuals but the test did not discriminate between AC, ATL and HAM/TSP. However, the frequency of detection of HBZ-specific antibodies in the serum of ATL patients with the chronic subtype was higher than in ATL patients with the lymphomatous subtype. Antibody responses against HBZ were also detected in cerebrospinal fluid of HAM/TSP patients with anti-HBZ in serum. Antibody responses against HBZ did not correlate with proviral load and HBZ mRNA expression in HAM/TSP patients, but the presence of an HBZ-specific response was associated with reduced CD4(+) T cell activation in HAM/TSP patients. Moreover, HBZ-specific antibody inhibited lymphoproliferation in the PBMC of HAM/TSP patients. Conclusions: This is the first report demonstrating humoral immune response against HBZ associated with HTLV-I infection. Thus, a humoral immune response against HBZ might play a role in HTLV-1 infection. C1 [Enose-Akahata, Yoshimi; Abrams, Anna; Massoud, Raya; Jacobson, Steven] NINDS, Viral Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [Bialuk, Izabela] Med Univ Bialystok, Dept Gen & Expt Pathol, Bialystok, Poland. [Johnson, Kory R.] NINDS, Bioinformat Sect, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Green, Patrick L.] Ohio State Univ, Ctr Retrovirus Res, Columbus, OH 43210 USA. [Maloney, Elizabeth M.] NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Jacobson, S (reprint author), NINDS, Viral Immunol Sect, Neuroimmunol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM JacobsonS@ninds.nih.gov FU Intramural Research Program of the NINDS, NIH FX We thank Dr. James Goedert (National Cancer Institute, National Institutes of Health, Bethesda, MD) for coordinating the specimens and subjects for this analysis, and Ms. Norma Kim (Research Triangle Institute, Rockville, MD) for identifying the subjects for this analysis and arranging for the selection of serum/plasma samples. We thank Dr. Barrie Hanchard and Ms. Beverley Cranston (the University of the West Indies, Jamaica) for patient recruitment. We also thank Dr. Peter Burbelo (National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD) for kindly providing us with HTLV-1 Gag, Env and Tax/pRen2 plasmids, and Dr. Genoveffa Franchini (National Cancer Institute, National Institutes of Health, Bethesda, MD) for HBZ cDNA clone. This research was supported by the Intramural Research Program of the NINDS, NIH. NR 58 TC 9 Z9 9 U1 0 U2 3 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 FEB 13 PY 2013 VL 10 AR 19 DI 10.1186/1742-4690-10-19 PG 13 WC Virology SC Virology GA 098ZN UT WOS:000315587900001 PM 23405908 ER PT J AU Padayatty, SJ Levine, M AF Padayatty, Sebastian J. Levine, Mark TI Standard-Dose vs High-Dose Multivitamin Supplements for HIV SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Padayatty, Sebastian J.; Levine, Mark] NIH, Intramural Res Program, Bethesda, MD 20892 USA. RP Padayatty, SJ (reprint author), NIH, Intramural Res Program, Bldg 10, Bethesda, MD 20892 USA. EM spadayatty@gmail.com RI Padayatty, Sebastian/A-8581-2012 OI Padayatty, Sebastian/0000-0001-8758-3170 NR 4 TC 1 Z9 1 U1 0 U2 6 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 FEB 13 PY 2013 VL 309 IS 6 BP 545 EP 546 DI 10.1001/jama.2012.216991 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 087PH UT WOS:000314773700016 PM 23403670 ER PT J AU Suren, P Roth, C Bresnahan, M Haugen, M Hornig, M Hirtz, D Lie, KK Lipkin, WI Magnus, P Reichborn-Kjennerud, T Schjolberg, S Smith, GD Oyen, AS Susser, E Stoltenberg, C AF Suren, Pal Roth, Christine Bresnahan, Michaeline Haugen, Margaretha Hornig, Mady Hirtz, Deborah Lie, Kari Kveim Lipkin, W. Ian Magnus, Per Reichborn-Kjennerud, Ted Schjolberg, Synnve Smith, George Davey Oyen, Anne-Siri Susser, Ezra Stoltenberg, Camilla TI Association Between Maternal Use of Folic Acid Supplements and Risk of Autism Spectrum Disorders in Children SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID NEURAL-TUBE DEFECTS; NORWEGIAN MOTHER; PREGNANT-WOMEN; COHORT; PREVENTION; VITAMIN; MOBA; PREVALENCE; FOLATE; DELAY AB Importance Prenatal folic acid supplements reduce the risk of neural tube defects in children, but it has not been determined whether they protect against other neurodevelopmental disorders. Objective To examine the association between maternal use of prenatal folic acid supplements and subsequent risk of autism spectrum disorders (ASDs) (autistic disorder, Asperger syndrome, pervasive developmental disorder-not otherwise specified [PDD-NOS]) in children. Design, Setting, and Patients The study sample of 85 176 children was derived from the population-based, prospective Norwegian Mother and Child Cohort Study (MoBa). The children were born in 2002-2008; by the end of follow-up on March 31, 2012, the age range was 3.3 through 10.2 years (mean, 6.4 years). The exposure of primary interest was use of folic acid from 4 weeks before to 8 weeks after the start of pregnancy, defined as the first day of the last menstrual period before conception. Relative risks of ASDs were estimated by odds ratios (ORs) with 95% CIs in a logistic regression analysis. Analyses were adjusted for maternal education level, year of birth, and parity. Main Outcome Measure Specialist-confirmed diagnosis of ASDs. Results At the end of follow-up, 270 children in the study sample had been diagnosed with ASDs: 114 with autistic disorder, 56 with Asperger syndrome, and 100 with PDD-NOS. In children whose mothers took folic acid, 0.10% (64/61 042) had autistic disorder, compared with 0.21% (50/24 134) in those unexposed to folic acid. The adjusted OR for autistic disorder in children of folic acid users was 0.61 (95% CI, 0.41-0.90). No association was found with Asperger syndrome or PDD-NOS, but power was limited. Similar analyses for prenatal fish oil supplements showed no such association with autistic disorder, even though fish oil use was associated with the same maternal characteristics as folic acid use. Conclusions and Relevance Use of prenatal folic acid supplements around the time of conception was associated with a lower risk of autistic disorder in the MoBa cohort. Although these findings cannot establish causality, they do support prenatal folic acid supplementation. JAMA. 2013;309(6):570-577 www.jama.com C1 [Suren, Pal; Roth, Christine; Haugen, Margaretha; Lie, Kari Kveim; Magnus, Per; Reichborn-Kjennerud, Ted; Schjolberg, Synnve; Oyen, Anne-Siri; Stoltenberg, Camilla] Norwegian Inst Publ Hlth, N-0403 Oslo, Norway. [Suren, Pal] UCL Inst Child Hlth, Ctr Paediat Epidemiol & Biostat, London, England. [Roth, Christine; Bresnahan, Michaeline; Hornig, Mady; Lipkin, W. Ian; Susser, Ezra] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. [Bresnahan, Michaeline; Susser, Ezra] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Hirtz, Deborah] NINDS, Bethesda, MD 20892 USA. [Reichborn-Kjennerud, Ted] Univ Oslo, Inst Psychiat, Oslo, Norway. [Smith, George Davey] Univ Bristol, MRC Ctr Causal Anal Translat Epidemiol, Bristol, Avon, England. [Oyen, Anne-Siri] Lovisenberg Hosp, Nic Waals Inst, Oslo, Norway. [Stoltenberg, Camilla] Univ Bergen, Dept Publ Hlth & Primary Hlth Care, Bergen, Norway. RP Suren, P (reprint author), Norwegian Inst Publ Hlth, POB 4404, N-0403 Oslo, Norway. EM pal.suren@fhi.no OI Monsalve, Beatriz Elena/0000-0002-5994-866X; Davey Smith, George/0000-0002-1407-8314 FU Norwegian Ministry of Health and Care Services; Norwegian Ministry of Education and Research; Research Council of Norway/FUGE [151918]; National Institute of Neurological Disorders and Stroke (NINDS) [NS47537]; National Institute of Environmental Health Sciences (NIEHS) [NO-ES-75558]; NINDS [NS47537]; Research Council of Norway [185476, 190694] FX The Norwegian Mother and Child Cohort is supported by the Norwegian Ministry of Health and Care Services, the Norwegian Ministry of Education and Research, the Research Council of Norway/FUGE (grant 151918), the National Institute of Neurological Disorders and Stroke (NINDS) (grant NS47537 [Dr Lipkin]), and the National Institute of Environmental Health Sciences (NIEHS) (contract NO-ES-75558). The Autism Birth Cohort study is funded by the NINDS (grant NS47537 [Dr Lipkin]). Dr Suren's salary is funded by the Research Council of Norway (grants 185476 and 190694). NR 25 TC 124 Z9 135 U1 10 U2 75 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 FEB 13 PY 2013 VL 309 IS 6 BP 570 EP 577 DI 10.1001/jama.2012.155925 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 087PH UT WOS:000314773700029 PM 23403681 ER PT J AU Meinhardt, MW Hansson, AC Perreau-Lenz, S Bauder-Wenz, C Stahlin, O Heilig, M Harper, C Drescher, KU Spanagel, R Sommer, WH AF Meinhardt, Marcus W. Hansson, Anita C. Perreau-Lenz, Stephanie Bauder-Wenz, Christina Staehlin, Oliver Heilig, Markus Harper, Clive Drescher, Karla U. Spanagel, Rainer Sommer, Wolfgang H. TI Rescue of Infralimbic mGluR(2) Deficit Restores Control Over Drug-Seeking Behavior in Alcohol Dependence SO JOURNAL OF NEUROSCIENCE LA English DT Article ID CORTICOTROPIN-RELEASING-FACTOR; PREFRONTAL CORTEX; GLUTAMATE TRANSMISSION; INDUCED REINSTATEMENT; ETHANOL EXPOSURE; COCAINE-SEEKING; GENE-EXPRESSION; NEGATIVE AFFECT; RATS; WITHDRAWAL AB A key deficit in alcohol dependence is disrupted prefrontal function leading to excessive alcohol seeking, but the molecular events underlying the emergence of addictive responses remain unknown. Here we show by convergent transcriptome analysis that the pyramidal neurons of the infralimbic cortex are particularly vulnerable for the long-term effects of chronic intermittent ethanol intoxication. These neurons exhibit a pronounced deficit in metabotropic glutamate receptor subtype 2 (mGluR(2)). Also, alcohol-dependent rats do not respond to mGluR(2/3) agonist treatment with reducing extracellular glutamate levels in the nucleus accumbens. Together these data imply a loss of autoreceptor feedback control. Alcohol-dependent rats show escalation of ethanol seeking, which was abolished by restoring mGluR(2) expression in the infralimbic cortex via viral-mediated gene transfer. Human anterior cingulate cortex from alcoholic patients shows a significant reduction in mGluR(2) transcripts compared to control subjects, suggesting that mGluR(2) loss in the rodent and human corticoaccumbal neurocircuitry may be a major consequence of alcohol dependence and a key pathophysiological mechanism mediating increased propensity to relapse. Normalization of mGluR(2) function within this brain circuit may be of therapeutic value. C1 [Meinhardt, Marcus W.; Hansson, Anita C.; Perreau-Lenz, Stephanie; Bauder-Wenz, Christina; Staehlin, Oliver; Spanagel, Rainer; Sommer, Wolfgang H.] Heidelberg Univ, Med Fac Mannheim, Inst Psychopharmacol, Cent Inst Mental Hlth, D-68159 Mannheim, Germany. [Heilig, Markus] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Harper, Clive] Univ Sydney, New S Wales Tissue Resource Ctr, Sydney, NSW 2006, Australia. [Drescher, Karla U.] Abbott Neurosci Res, D-67061 Ludwigshafen, Germany. RP Sommer, WH (reprint author), Cent Inst Mental Hlth, Sq J5, D-68159 Mannheim, Germany. EM wolfgang.sommer@zi-mannheim.de RI Perreau-Lenz, Stephanie/D-2309-2014 OI Perreau-Lenz, Stephanie/0000-0001-9529-6403 FU Bundesministerium fur Bildung und Forschung within the frameworks of NGFN Plus [FKZ 01GS08151, 01GS08152, 01GS08155]; ERA-Net TRANSALC [FKZ 01EW1112]; European Commission FP-6 Integrated Project IMAGEN [PL037286]; Deutsche Forschungsgemeinschaft [SFB636, HA 6102/1-1, SP 383/5-1]; Intramural Research Program of the NIAAA FX This work was supported by the Bundesministerium fur Bildung und Forschung within the frameworks of NGFN Plus (FKZ 01GS08151, 01GS08152, and 01GS08155; see www.ngfn-alkohol.de, Spanagel et al., 2010) and ERA-Net TRANSALC (FKZ 01EW1112), the European Commission FP-6 Integrated Project IMAGEN (PL037286), the Deutsche Forschungsgemeinschaft (Center Grant SFB636; project Grant HA 6102/1-1 to A. C. H.; Reinhart-Koselleck Award SP 383/5-1 to R. S.), and the Intramural Research Program of the NIAAA (M. H.). We thank Elisabeth Robel and Fernando Leonardi-Essmann for assistance in laboratory experiments. NR 64 TC 46 Z9 47 U1 0 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 FEB 13 PY 2013 VL 33 IS 7 BP 2794 EP 2806 DI 10.1523/JNEUROSCI.4062-12.2013 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 089CQ UT WOS:000314887200007 PM 23407939 ER PT J AU Alexander-Bloch, A Raznahan, A Bullmore, ET Giedd, J AF Alexander-Bloch, Aaron Raznahan, Armin Bullmore, Ed T Giedd, Jay TI The Convergence of Maturational Change and Structural Covariance in Human Cortical Networks SO JOURNAL OF NEUROSCIENCE LA English DT Article ID STATE FUNCTIONAL CONNECTIVITY; GRAPH-THEORETICAL ANALYSIS; DEFAULT MODE NETWORK; HUMAN BRAIN; CEREBRAL-CORTEX; MRI; SCHIZOPHRENIA; THICKNESS; ORGANIZATION; ARCHITECTURE AB Large-scale covariance of cortical thickness or volume in distributed brain regions has been consistently reported by human neuroimaging studies. The mechanism of this population covariance of regional cortical anatomy has been hypothetically related to synchronized maturational changes in anatomically connected neuronal populations. Brain regions that grow together, i.e., increase or decrease in volume at the same rate over the course of years in the same individual, are thus expected to demonstrate strong structural covariance or anatomical connectivity across individuals. To test this prediction, we used a structural MRI dataset on healthy young people (N = 108; aged 9-22 years at enrollment), comprising 3-6 longitudinal scans on each participant over 6-12 years of follow-up. At each of 360 regional nodes, and for each participant, we estimated the following: (1) the cortical thickness in the median scan and (2) the linear rate of change in cortical thickness over years of serial scanning. We constructed structural and maturational association matrices and networks from these measurements. Both structural and maturational networks shared similar global and nodal topological properties, as well as mesoscopic features including a modular community structure, a relatively small number of highly connected hub regions, and a bias toward short distance connections. Using resting-state functional magnetic resonance imaging data on a subset of the sample (N = 32), we also demonstrated that functional connectivity and network organization was somewhat predictable by structural/maturational networks but demonstrated a stronger bias toward short distance connections and greater topological segregation. Brain structural covariance networks are likely to reflect synchronized developmental change in distributed cortical regions. C1 [Alexander-Bloch, Aaron; Bullmore, Ed T] Univ Cambridge, Dept Psychiat, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England. [Alexander-Bloch, Aaron; Raznahan, Armin; Giedd, Jay] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. [Alexander-Bloch, Aaron] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Bullmore, Ed T] Addenbrookes Hosp, GlaxoSmithKline, Clin Unit Cambridge, Cambridge CB2 2GG, England. [Bullmore, Ed T] Cambridgeshire & Peterborough NHS Fdn Trust, Cambridge CB21 5EF, England. RP Alexander-Bloch, A (reprint author), NIMH, Child Psychiat Branch, 10 Ctr Dr,MSC 1367,Bldg 10,Room 4C110, Bethesda, MD 20892 USA. EM aalexanderbloch@gmail.com; jgiedd@mail.nih.gov RI Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015; Bullmore, Edward/C-1706-2012; OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978; Bullmore, Edward/0000-0002-8955-8283; Alexander-Bloch, Aaron/0000-0001-6554-1893 FU National Institute of Mental Health, National Institutes of Health Intramural Research Program; National Institutes of Health-Oxford-Cambridge Scholarship Program; Medical Research Council (UK); Wellcome Trust FX This study was funded through the National Institute of Mental Health, the National Institutes of Health Intramural Research Program, and the National Institutes of Health-Oxford-Cambridge Scholarship Program (A. A. B.). The Behavioural and Clinical Neuroscience Institute is supported by the Medical Research Council (UK) and the Wellcome Trust. We wish to thank Francois Lalonde and Liv Clasen for help with data collection and analysis, Budhachandra Khundrakpam for assistance with the AAL atlas, and also the participants who took part in this study. NR 72 TC 85 Z9 85 U1 1 U2 25 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 FEB 13 PY 2013 VL 33 IS 7 BP 2889 EP + DI 10.1523/JNEUROSCI.3554-12.2013 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 089CQ UT WOS:000314887200015 PM 23407947 ER PT J AU Lehmann, ML Brachman, RA Martinowich, K Schloesser, RJ Herkenham, M AF Lehmann, Michael L. Brachman, Rebecca A. Martinowich, Keri Schloesser, Robert J. Herkenham, Miles TI Glucocorticoids Orchestrate Divergent Effects on Mood through Adult Neurogenesis SO JOURNAL OF NEUROSCIENCE LA English DT Article ID PITUITARY-ADRENOCORTICAL AXIS; RECEPTOR MESSENGER-RNA; CORTICOTROPIN-RELEASING HORMONE; HIPPOCAMPAL NEUROGENESIS; VOLUNTARY EXERCISE; DENTATE GYRUS; CHRONIC STRESS; VENTRAL HIPPOCAMPUS; MAJOR DEPRESSION; RAT-BRAIN AB Both social defeat stress and environmental enrichment stimulate adrenal glucocorticoid secretion, but they have opposing effects on hippocampal neurogenesis and mood. Hypothalamic-pituitary-adrenal axis dysregulation and decreased neurogenesis are consequences of social defeat. These outcomes are correlated with depressive states, but a causal role in the etiology of depression remains elusive. The antidepressant actions of environmental enrichment are neurogenesis-dependent, but the contribution of enrichment-elevated glucocorticoids is unexplored. Importantly, for both social defeat and environmental enrichment, how glucocorticoids interact with neurogenesis to alter mood is unknown. Here, we investigate causal roles of glucocorticoids and neurogenesis in induction of depressive-like behavior and its amelioration by environmental enrichment in mice. By blocking neurogenesis and surgically clamping adrenal hormone secretions, we showed that neurogenesis, via hypothalamic-pituitary-adrenal axis interactions, is directly involved in precipitating the depressive phenotype after social defeat. Mice adrenalectomized before social defeat showed enhanced behavioral resiliency and increased survival of adult-born hippocampal neurons compared with sham-operated defeated mice. However, mice lacking hippocampal neurogenesis did not show protective effects of adrenalectomy. Moreover, glucocorticoids secreted during environmental enrichment promoted neurogenesis and were required for restoration of normal behavior after social defeat. The data demonstrate that glucocorticoid-dependent declines in neurogenesis drive changes in mood after social defeat and that glucocorticoids secreted during enrichment promote neurogenesis and restore normal behavior after defeat. These data provide new evidence for direct involvement of neurogenesis in the etiology of depression, suggesting that treatments promoting neurogenesis can enhance stress resilience. C1 [Lehmann, Michael L.; Brachman, Rebecca A.; Herkenham, Miles] NIMH, Funct Neuroanat Sect, NIH, Bethesda, MD 20892 USA. [Martinowich, Keri; Schloesser, Robert J.] NIMH, Mol Pathophysiol Lab, NIH, Bethesda, MD 20892 USA. RP Lehmann, ML (reprint author), NIMH, Funct Neuroanat Sect, NIH, Bethesda, MD 20892 USA. EM Michael.lehmann@nih.gov RI Martinowich, Keri/F-9841-2012; OI Brachman, Rebecca/0000-0002-1221-0414; Martinowich, Keri/0000-0002-5237-0789; Herkenham, Miles/0000-0003-2228-4238; Lehmann, Michael/0000-0003-4476-8268 FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health. We thank Jason Snyder for helpful comments on the manuscript. NR 72 TC 50 Z9 53 U1 0 U2 40 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 FEB 13 PY 2013 VL 33 IS 7 BP 2961 EP 2972 DI 10.1523/JNEUROSCI.3878-12.2013 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 089CQ UT WOS:000314887200022 PM 23407954 ER PT J AU Koizumi, H Koshiya, N Chia, JX Cao, F Nugent, J Zhang, RL Smith, JC AF Koizumi, Hidehiko Koshiya, Naohiro Chia, Justine X. Cao, Fang Nugent, Joseph Zhang, Ruli Smith, Jeffrey C. TI Structural-Functional Properties of Identified Excitatory and Inhibitory Interneurons within Pre-Botzinger Complex Respiratory Microcircuits SO JOURNAL OF NEUROSCIENCE LA English DT Article ID MAMMALIAN BRAIN-STEM; RAT SPINAL-CORD; KNOCK-IN MOUSE; RHYTHM GENERATION; PREBOTZINGER COMPLEX; PACEMAKER NEURONS; MEMBRANE-PROPERTIES; PATTERN GENERATION; DENDRITIC SPINES; NETWORK AB We comparatively analyzed cellular and circuit properties of identified rhythmic excitatory and inhibitory interneurons within respiratory microcircuits of the neonatal rodent pre-Botzinger complex (pre-BotC), the structure generating inspiratory rhythm in the brainstem. We combined high-resolution structural-functional imaging, molecular assays for neurotransmitter phenotype identification in conjunction with electrophysiological property phenotyping, and morphological reconstruction of interneurons in neonatal rat and mouse slices in vitro. This approach revealed previously undifferentiated structural-functional features that distinguish excitatory and inhibitory interneuronal populations. We identified distinct subpopulations of pre-BotC glutamatergic, glycinergic, GABAergic, and glycine-GABA coexpressing interneurons. Most commissural pre-BotC inspiratory interneurons were glutamatergic, with a substantial subset exhibiting intrinsic oscillatory bursting properties. Commissural excitatory interneurons projected with nearly planar trajectories to the contralateral pre-BotC, many also with axon collaterals to areas containing inspiratory hypoglossal (XII) premotoneurons and motoneurons. Inhibitory neurons as characterized in the present study did not exhibit intrinsic oscillatory bursting properties, but were electrophysiologically distinguished by more pronounced spike frequency adaptation properties. Axons of many inhibitory neurons projected ipsilaterally also to regions containing inspiratory XII premotoneurons and motoneurons, whereas a minority of inhibitory neurons had commissural axonal projections. Dendrites of both excitatory and inhibitory interneurons were arborized asymmetrically, primarily in the coronal plane. The dendritic fields of inhibitory neurons were more spatially compact than those of excitatory interneurons. Our results are consistent with the concepts of a compartmental circuit organization, a bilaterally coupled excitatory rhythmogenic kernel, and a role of pre-BotC inhibitory neurons in shaping inspiratory pattern as well as coordinating inspiratory and expiratory activity. C1 [Koizumi, Hidehiko; Koshiya, Naohiro; Chia, Justine X.; Cao, Fang; Nugent, Joseph; Zhang, Ruli; Smith, Jeffrey C.] Natl Inst Neurol Disorders & Stroke, Cellular & Syst Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Smith, JC (reprint author), NINDS, NIH, 49 Convent Dr,Room 2A10, Bethesda, MD 20892 USA. EM smithj2@helix.nih.gov OI Nugent, Joseph/0000-0002-6863-4523 FU NIH, National Institute of Neurological Disorders and Stroke FX This research was supported by the Intramural Research Program of the NIH, National Institute of Neurological Disorders and Stroke. We thank Professor Yuchio Yanagawa of Gunma University, Japan for generously providing GAD67-GFP knock-in mice. NR 54 TC 29 Z9 29 U1 0 U2 13 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 FEB 13 PY 2013 VL 33 IS 7 BP 2994 EP 3009 DI 10.1523/JNEUROSCI.4427-12.2013 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 089CQ UT WOS:000314887200025 PM 23407957 ER PT J AU De Pisapia, N Bornstein, MH Rigo, P Esposito, G De Falco, S Venuti, P AF De Pisapia, Nicola Bornstein, Marc H. Rigo, Paola Esposito, Gianluca De Falco, Simona Venuti, Paola TI Sex differences in directional brain responses to infant hunger cries SO NEUROREPORT LA English DT Article DE brain; default-mode network; infant cry; medial prefrontal cortex; mind wandering; parenting; posterior cingulate cortex ID DEFAULT; NETWORKS; TASK; FMRI AB Infant cries are a critical survival mechanism that draw the attention of adult caregivers, who can then satisfy the basic needs of otherwise helpless infants. Here, we used functional neuroimaging to determine the effects of infant hunger cries on the brain activity of adults who were in a cognitively nondemanding mental state of awake rest. We found that the brains of men and women, independent of parental status (parent or nonparent), reacted differently to infant cries. Specifically, the dorsal medial prefrontal and posterior cingulate areas, known to be involved in mind wandering (the stream of thought typical of awake rest), remained active in men during exposure to infant cries, whereas in women, activity in these regions decreased. These results show sex-dependent modulation of brain responses to infant requests to be fed, and specifically, they indicate that women interrupt mind wandering when exposed to the sounds of infant hunger cries, whereas men carry on without interruption. NeuroReport 24:142-146 (c) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [De Pisapia, Nicola; Rigo, Paola; De Falco, Simona; Venuti, Paola] Univ Trent, Dept Cognit Sci & Educ, Trento, Italy. [Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Publ Hlth Serv, Rockville, MD USA. [Esposito, Gianluca] RIKEN Brain Sci Inst, Kuroda Res Unit Affiliat Social Behav, Saitama, Japan. RP De Pisapia, N (reprint author), Univ Trent, DiSCoF Dept Cognit Sci, I-38068 Rovereto, Italy. EM nicola.depisapia@unitn.it RI Esposito, Gianluca/B-1374-2012; Esposito, Gianluca/K-9353-2013; OI Esposito, Gianluca/0000-0002-9442-0254; Esposito, Gianluca/0000-0002-9442-0254; De Pisapia, Nicola/0000-0002-1089-8841 FU Intramural Research Program of the NIH, NICHD FX This research was supported by the Intramural Research Program of the NIH, NICHD. NR 25 TC 23 Z9 23 U1 2 U2 32 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD FEB 13 PY 2013 VL 24 IS 3 BP 142 EP 146 DI 10.1097/WNR.0b013e32835df4fa PG 5 WC Neurosciences SC Neurosciences & Neurology GA 082CI UT WOS:000314368900008 PM 23282991 ER PT J AU Hickman, HD Reynoso, GV Ngudiankama, BF Rubin, EJ Magadan, JG Cush, SS Gibbs, J Molon, B Bronte, V Bennink, JR Yewdell, JW AF Hickman, Heather D. Reynoso, Glennys V. Ngudiankama, Barbara F. Rubin, Erica J. Magadan, Javier G. Cush, Stephanie S. Gibbs, James Molon, Barbara Bronte, Vincenzo Bennink, Jack R. Yewdell, Jonathan W. TI Anatomically Restricted Synergistic Antiviral Activities of Innate and Adaptive Immune Cells in the Skin SO CELL HOST & MICROBE LA English DT Article ID CD8 T-CELLS; SUBCAPSULAR SINUS MACROPHAGES; VACCINIA VIRUS-INFECTION; LYMPH-NODES; IN-VIVO; RESPONSES; MICE; REPLICATION; EXPRESSION; PROTECTION AB Despite extensive ex vivo investigation, the spatiotemporal organization of immune cells interacting with virus-infected cells in tissues remains uncertain. To address this, we used intravital multiphoton microscopy to visualize immune cell interactions with virus-infected cells following epicutaneous vaccinia virus (VV) infection of mice. VV infects keratinocytes in epidermal foci and numerous migratory dermal inflammatory monocytes that outlie the foci. We observed Ly6G(+) innate immune cells infiltrating and controlling foci, while CD8(+) T cells remained on the periphery killing infected monocytes. Most antigen-specific CD8(+) T cells in the skin did not interact with virus-infected cells. Blocking the generation of reactive nitrogen species relocated CD8(+) T cells into foci, modestly reducing viral titers. Depletion of Ly6G(+) and CD8(+) cells dramatically increased viral titers, consistent with their synergistic but spatially segregated viral clearance activities. These findings highlight previously unappreciated differences in the anatomic specialization of antiviral immune cell subsets. C1 [Hickman, Heather D.; Reynoso, Glennys V.; Ngudiankama, Barbara F.; Rubin, Erica J.; Magadan, Javier G.; Cush, Stephanie S.; Gibbs, James; Bennink, Jack R.; Yewdell, Jonathan W.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Molon, Barbara] IRCCS, Ist Oncol Veneto, I-35128 Padua, Italy. [Bronte, Vincenzo] Verona Univ Hosp, Dept Pathol, Immunol Sect, I-37134 Verona, Italy. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM jyewdell@mail.nih.gov RI Bronte, Vincenzo/K-7902-2016 OI Bronte, Vincenzo/0000-0002-3741-5141 FU National Institute of Allergy and Infectious Diseases Division of Intramural Research FX We thank the Comparative Medicine Branch and staff of the NIH Building 33 vivarium for excellence in animal husbandry. This work was generously supported by the National Institute of Allergy and Infectious Diseases Division of Intramural Research. NR 38 TC 19 Z9 19 U1 0 U2 7 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 FEB 13 PY 2013 VL 13 IS 2 BP 155 EP 168 DI 10.1016/j.chom.2013.01.004 PG 14 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AA1IQ UT WOS:000330850200007 PM 23414756 ER PT J AU Chamanian, M Purzycka, KJ Wille, PT Ha, JS McDonald, D Gao, Y Le Grice, SFJ Arts, EJ AF Chamanian, Mastooreh Purzycka, Katarzyna J. Wille, Paul T. Ha, Janice S. McDonald, David Gao, Yong Le Grice, Stuart F. J. Arts, Eric J. TI A cis-Acting Element in Retroviral Genomic RNA Links Gag-Pol Ribosomal Frameshifting to Selective Viral RNA Encapsidation SO CELL HOST & MICROBE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HIV-1 LEADER RNA; SECONDARY STRUCTURE; INFECTIOUS TITER; PROTEIN; DIMERIZATION; IDENTIFICATION; SITE; RECOMBINATION; RECOGNITION AB During retroviral RNA encapsidation, two full-length genomic (g) RNAs are selectively incorporated into assembling virions. Packaging involves a cis-acting packaging element (Psi) within the 5' untranslated region of unspliced HIV-1 RNA genome. However, the mechanism(s) that selects and limits gRNAs for packaging remains uncertain. Using a dual complementation system involving bipartite HIV-1 gRNA, we observed that gRNA packaging is additionally dependent on a cis-acting RNA element, the genomic RNA packaging enhancer (GRPE), found within the gag p1-p6 domain and overlapping the Gag-Pol ribosomal frameshift signal. Deleting or disrupting the two conserved GRPE stem loops diminished gRNA packaging and infectivity >50-fold, while deleting gag sequences between Psi and GRPE had no effect. Downregulating the translation termination factor eRF1 produces defective virus particles containing 20 times more gRNA. Thus, only the HIV-1 RNAs employed for Gag-Pol translation may be specifically selected for encapsidation, possibly explaining the limitation of two gRNAs per virion. C1 [Chamanian, Mastooreh; McDonald, David; Gao, Yong; Arts, Eric J.] Case Western Reserve Univ, Dept Mol Biol & Microbiol, Cleveland, OH 44106 USA. [Purzycka, Katarzyna J.; Le Grice, Stuart F. J.] NCI, RT Biochem Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Wille, Paul T.; Ha, Janice S.; Gao, Yong; Arts, Eric J.] Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. RP Arts, EJ (reprint author), Case Western Reserve Univ, Dept Mol Biol & Microbiol, Cleveland, OH 44106 USA. EM eja3@case.edu FU Center for Cancer Research, NCI, NIH; NIAID, NIH [R01 AI49170, AI084816] FX We want to thank Mianda Wu for helping with real-time PCR. S.F.J.L. and K.J.P. were supported by the Intramural Research Program of the Center for Cancer Research, NCI, NIH. This study and all remaining authors were funded by NIAID, NIH R01 AI49170 and AI084816. Core support was provided by the CWRU/UH CFAR (AI36219). NR 42 TC 19 Z9 19 U1 1 U2 11 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 FEB 13 PY 2013 VL 13 IS 2 BP 181 EP 192 DI 10.1016/j.chom.2013.01.007 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AA1IQ UT WOS:000330850200009 PM 23414758 ER PT J AU Chowell, G Viboud, C AF Chowell, Gerardo Viboud, Cecile TI A practical method to target individuals for outbreak detection and control SO BMC MEDICINE LA English DT Editorial Material DE contact network; hotspot; dynamic network; contact pattern; wireless sensing devices; collocation ranking; class schedule; high school; influenza; disease transmission ID INFECTIOUS-DISEASE; SOCIAL NETWORKS; INFLUENZA; TRANSMISSION; CLOSURE AB Identification of individuals or subpopulations that contribute the most to disease transmission is key to target surveillance and control efforts. In a recent study in BMC Medicine, Smieszek and Salathe introduced a novel method based on readily available information about spatial proximity in high schools, to help identify individuals at higher risk of infection and those more likely to be infected early in the outbreak. By combining simulation models for influenza transmission with high-resolution data on school contact patterns, the authors showed that their proximity method compares favorably to more sophisticated methods using detailed contact tracing information. The proximity method is simple and promising, but further research is warranted to confront this method against real influenza outbreak data, and to assess the generalizability of the approach to other important transmission units, such as work, households, and transportation systems. See related research article here http://www.biomedcentral.com/1741-7015/11/35 C1 [Chowell, Gerardo] Arizona State Univ, Sch Human Evolut & Social Change, Math & Computat Modeling Sci Ctr, Tempe, AZ 85069 USA. [Chowell, Gerardo; Viboud, Cecile] NIH, Fogarty Int Ctr, Div Int Epidemiol & Populat Studies, Bethesda, MD 20892 USA. RP Chowell, G (reprint author), Arizona State Univ, Sch Human Evolut & Social Change, Math & Computat Modeling Sci Ctr, Tempe, AZ 85069 USA. EM gchowell@asu.edu RI Chowell, Gerardo/F-5038-2012; Chiang, Vincent, Ming-Hsien/D-4312-2016 OI Chowell, Gerardo/0000-0003-2194-2251; Chiang, Vincent, Ming-Hsien/0000-0002-2029-7863 NR 18 TC 4 Z9 4 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD FEB 12 PY 2013 VL 11 AR 36 DI 10.1186/1741-7015-11-36 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 137IW UT WOS:000318430200002 PM 23402649 ER PT J AU Spencer, KL Malinowski, J Carty, CL Franceschini, N Fernandez-Rhodes, L Young, A Cheng, I Ritchie, MD Haiman, CA Wilkens, L ChunyuanWu Matise, TC Carlson, CS Brennan, K Park, A Rajkovic, A Hindorff, LA Buyske, S Crawford, DC AF Spencer, Kylee L. Malinowski, Jennifer Carty, Cara L. Franceschini, Nora Fernandez-Rhodes, Lindsay Young, Alicia Cheng, Iona Ritchie, Marylyn D. Haiman, Christopher A. Wilkens, Lynne ChunyuanWu Matise, Tara C. Carlson, Christopher S. Brennan, Kathleen Park, Amy Rajkovic, Aleksandar Hindorff, Lucia A. Buyske, Steven Crawford, Dana C. TI Genetic Variation and Reproductive Timing: African American Women from the Population Architecture Using Genomics and Epidemiology (PAGE) Study SO PLOS ONE LA English DT Article ID BODY-MASS INDEX; CARDIOVASCULAR-DISEASE RISK; LIFE-STYLE FACTORS; NATURAL MENOPAUSE; WIDE ASSOCIATION; BREAST-CANCER; CAUCASIAN FEMALES; BREAKTHROUGH GENERATIONS; FUNCTIONAL-ANALYSIS; ENDOMETRIAL CANCER AB Age at menarche (AM) and age at natural menopause (ANM) define the boundaries of the reproductive lifespan in women. Their timing is associated with various diseases, including cancer and cardiovascular disease. Genome-wide association studies have identified several genetic variants associated with either AM or ANM in populations of largely European or Asian descent women. The extent to which these associations generalize to diverse populations remains unknown. Therefore, we sought to replicate previously reported AM and ANM findings and to identify novel AM and ANM variants using the Metabochip (n = 161,098 SNPs) in 4,159 and 1,860 African American women, respectively, in the Women's Health Initiative (WHI) and Atherosclerosis Risk in Communities (ARIC) studies, as part of the Population Architecture using Genomics and Epidemiology (PAGE) Study. We replicated or generalized one previously identified variant for AM, rs1361108/CENPW, and two variants for ANM, rs897798/BRSK1 and rs769450/APOE, to our African American cohort. Overall, generalization of the majority of previously-identified variants for AM and ANM, including LIN28B and MCM8, was not observed in this African American sample. We identified three novel loci associated with ANM that reached significance after multiple testing correction (LDLR rs189596789, p = 5 x 10(-08); KCNQ1 rs79972789, p = 1.9 x 10(-07); COL4A3BP rs181686584, p = 2.9 x 10(-07)). Our most significant AM association was upstream of RSF1, a gene implicated in ovarian and breast cancers (rs11604207, p = 1.6 x 10(-06)). While most associations were identified in either AM or ANM, we did identify genes suggestively associated with both: PHACTR1 and ARHGAP42. The lack of generalization coupled with the potentially novel associations identified here emphasize the need for additional genetic discovery efforts for AM and ANM in diverse populations. C1 [Malinowski, Jennifer; Ritchie, Marylyn D.; Crawford, Dana C.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Ctr Human Genet Res, Nashville, TN 37232 USA. [Matise, Tara C.; Buyske, Steven] Rutgers State Univ, Dept Genet, Piscataway, NJ USA. [Buyske, Steven] Rutgers State Univ, Dept Stat, Piscataway, NJ USA. [Franceschini, Nora; Fernandez-Rhodes, Lindsay] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Carty, Cara L.; Young, Alicia; ChunyuanWu; Carlson, Christopher S.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Cheng, Iona; Wilkens, Lynne] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Brennan, Kathleen] Univ Calif Los Angeles, Dept Obstet & Gynecol, Los Angeles, CA 90024 USA. [Park, Amy] Georgetown Univ, Sch Med, Dept Obstet & Gynecol, Washington, DC 20007 USA. [Rajkovic, Aleksandar] Univ Pittsburgh, Magee Womens Res Inst, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Hindorff, Lucia A.] NHGRI, Off Populat Genom, NIH, Bethesda, MD 20892 USA. [Spencer, Kylee L.] Heidelberg Univ, Dept Biol & Environm Sci, Tiffin, OH USA. [Ritchie, Marylyn D.] Penn State Univ, University Pk, MD USA. RP Crawford, DC (reprint author), Vanderbilt Univ, Dept Mol Physiol & Biophys, Ctr Human Genet Res, Nashville, TN 37232 USA. EM dana.c.crawford@vanderbilt.edu OI Buyske, Steven/0000-0001-8539-5416 FU National Human Genome Research Institute (NHGRI); Causal Variants Across the Life Course, known as CALiCo [U01HG004803]; Epidemiologic Architecture for Genes Linked to Environment, known as EAGLE [U01HG004798]; Multiethnic Cohort, known as MEC [U01HG004802]; Women's Health Initiative, known as WHI [U01HG004790]; Coordinating Center [U01HG004801]; NHLBI [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022]; National Cancer Institute [R37CA54281, R01 CA63, P01CA33619, U01CA136792, U01CA98758]; National Heart, Lung, and Blood Institute (NHLBI) (NIH); U.S. Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]; National Institutes of Mental Health FX The Population Architecture Using Genomics and Epidemiology (PAGE) program is funded by the National Human Genome Research Institute (NHGRI), supported by U01HG004803 (Causal Variants Across the Life Course, known as CALiCo), U01HG004798 (Epidemiologic Architecture for Genes Linked to Environment, known as EAGLE), U01HG004802 (the Multiethnic Cohort, known as MEC), U01HG004790 (Women's Health Initiative, known as WHI), and U01HG004801 (Coordinating Center). The Atherosclerosis Risk in Communities (ARIC) Study is carried out as a collaborative study supported by NHLBI contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022. The Multiethnic Cohort (MEC) study is funded through the National Cancer Institute (R37CA54281, R01 CA63, P01CA33619, U01CA136792, and U01CA98758). The Women's Health Initiative (WHI) program is funded by the National Heart, Lung, and Blood Institute (NHLBI) (NIH) and by U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. The National Institutes of Mental Health also contributes to the support for the Coordinating Center. NHGRI collaborators (LAH) assisted in the study design, analysis, and preparation of the manuscript. NR 95 TC 14 Z9 14 U1 1 U2 9 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 FEB 12 PY 2013 VL 8 IS 2 AR e55258 DI 10.1371/journal.pone.0055258 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 104BU UT WOS:000315965100014 PM 23424626 ER PT J AU Mannisto, T Mendola, P Vaarasmaki, M Jarvelin, MR Hartikainen, AL Pouta, A Suvanto, E AF Maennistoe, Tuija Mendola, Pauline Vaarasmaki, Marja Jarvelin, Marjo-Riitta Hartikainen, Anna-Liisa Pouta, Anneli Suvanto, Eila TI Elevated Blood Pressure in Pregnancy and Subsequent Chronic Disease Risk SO CIRCULATION LA English DT Article DE epidemiology; hypertension; myocardial infarction; pregnancy; prevention; stroke ID HOSPITAL DISCHARGE REGISTER; ISCHEMIC-HEART-DISEASE; HYPERTENSIVE PREGNANCY; CARDIOVASCULAR-DISEASE; RETROSPECTIVE COHORT; UNITED-STATES; LATER LIFE; PREECLAMPSIA; COMPLICATIONS; MORTALITY AB Background-Preeclampsia, a new-onset hypertensive disorder of pregnancy, is associated with lifetime cardiovascular disease risk, but less is known about risk after other pregnancy-related hypertension. Methods and Results-The Northern Finland Birth Cohort 1966 included all expected births from 1 year (N=12 055 women). Blood pressure measurements and other prospective data were determined from prenatal care records and questionnaires for 10 314 women. Subsequent diagnoses were ascertained from Finnish registries (average follow-up, 39.4 years). Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) estimate risks in hypertensive women compared with normotensive women. Hypertension during pregnancy was associated with increased risk of subsequent cardiovascular disease and arterial hypertension. Women with chronic hypertension and superimposed preeclampsia/eclampsia had high risk for future diseases. Gestational hypertension was associated with increased risk of ischemic heart disease (HR, 1.44 [95% CI, 1.24-1.68]), myocardial infarcts (HR, 1.75 [95% CI, 1.40-2.19]), myocardial infarct death (HR, 3.00 [95% CI, 1.98-4.55]), heart failure (HR, 1.78 [95% CI, 1.43-2.21]), ischemic stroke (HR, 1.59 [95% CI, 1.24-2.04]), kidney disease (HR, 1.91 [95% CI, 1.18-3.09]), and diabetes mellitus (HR, 1.52 [95% CI, 1.21-1.89]). Isolated systolic hypertension was associated with increased risk of myocardial infarct death (HR, 2.15 [95% CI, 1.35-3.41]), heart failure (HR, 1.43 [95% CI, 1.13-1.82]), and diabetes mellitus (HR, 1.42 [95% CI, 1.13-1.78]), whereas isolated diastolic hypertension was associated with increased risk of ischemic heart disease (HR, 1.26 [95% CI, 1.05-1.50]). Results were similar in nonsmoking women aged <35 years with normal weight and no diabetes mellitus during pregnancy. Conclusions-Elevated blood pressure during pregnancy, regardless of type and even without known risk factors, signals high risk of later cardiovascular disease, chronic kidney disease, and diabetes mellitus. Clinical monitoring, risk factor evaluation, and early intervention could benefit women with hypertension in pregnancy. (Circulation. 2013;127:681-690.) C1 [Maennistoe, Tuija; Mendola, Pauline] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Epidemiol Branch, NIH, Bethesda, MD 20892 USA. [Vaarasmaki, Marja; Hartikainen, Anna-Liisa; Pouta, Anneli; Suvanto, Eila] Oulu Univ Hosp, Dept Obstet & Gynecol, Oulu, Finland. [Jarvelin, Marjo-Riitta; Pouta, Anneli] Natl Inst Hlth & Welf, Dept Children Young People & Families, Helsinki, Finland. [Jarvelin, Marjo-Riitta] Univ Oulu, Inst Hlth Sci, Oulu, Finland. [Jarvelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England. RP Mannisto, T (reprint author), NICHD, NIH, DESPR, Epidemiol Branch, 6100 Execut Blvd,7B05, Rockville, MD 20852 USA. EM mannistoTI@mail.nih.gov OI Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Mannisto, Tuija/0000-0002-6382-9153; Mendola, Pauline/0000-0001-5330-2844 FU National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development; Academy of Finland FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and by the Academy of Finland. NR 41 TC 82 Z9 90 U1 5 U2 18 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 12 PY 2013 VL 127 IS 6 BP 681 EP 690 DI 10.1161/CIRCULATIONAHA.112.128751 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 088XR UT WOS:000314871700012 PM 23401113 ER PT J AU Kotlyanskaya, L McLinden, KA Giniger, E AF Kotlyanskaya, Lucy McLinden, Kristina A. Giniger, Edward TI Of Proneurotrophins and Their Antineurotrophic Effects SO SCIENCE SIGNALING LA English DT Article ID DEVELOPING NEUROMUSCULAR SYNAPSES; NERVE GROWTH-FACTOR; RECEPTOR P75; CELL-DEATH; BDNF; ROLES; GASTRULATION; RETRACTION; DPP; TRK AB Neurotrophins perform essential processes throughout neural development. They signal through Trk receptor proteins, typically in association with a "low affinity" p75(NTR) pan-neurotrophin co-receptor. Neurotrophins are synthesized as proproteins; the pro domains are removed proteolytically to yield the mature, presumably functional forms of the neurotrophins. Recent findings, however, have revealed a positive role for the proneurotrophins themselves. The proproteins bind with high affinity to the p75(NTR) pan-neurotrophin receptor in the absence of Trks to initiate a separate set of signaling cascades that actively oppose the effects of the mature growth factors. These experiments suggest that the balance between pro- and mature neurotrophin plays a critical role in tuning downstream signaling. This view changes the neurotrophin field substantially, and also points to the broader idea that the potential activities of precursor proteins deserve a closer look. C1 [Kotlyanskaya, Lucy; McLinden, Kristina A.; Giniger, Edward] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20854 USA. [Kotlyanskaya, Lucy] Univ N Carolina, Neurobiol Curriculum, Chapel Hill, NC 27599 USA. RP Giniger, E (reprint author), Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20854 USA. EM ginigere@ninds.nih.gov RI Giniger, Edward/C-1764-2015 OI Giniger, Edward/0000-0002-8340-6158 FU National Institute of Neurological Disorders and Stroke, NIH [Z01-NS003013]; NSF FX The authors were supported by the Basic Neuroscience Program in the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, NIH (Z01-NS003013). L. K. was supported by a predoctoral fellowship from the NSF. NR 22 TC 3 Z9 3 U1 0 U2 7 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD FEB 12 PY 2013 VL 6 IS 262 AR pe6 DI 10.1126/scisignal.2003824 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 088ZP UT WOS:000314877400001 PM 23405011 ER PT J AU Jinde, S Zsiros, V Nakazawa, K AF Jinde, Seiichiro Zsiros, Veronika Nakazawa, Kazu TI Hilar mossy cell circuitry controlling dentate granule cell excitability SO FRONTIERS IN NEURAL CIRCUITS LA English DT Review DE mossy cells; granule cells; excitability; epileptogenesis; lateral inhibition; hippocampal mossy fibers; pattern separation; temporal lobe epilepsy ID TEMPORAL-LOBE EPILEPSY; CA3 PYRAMIDAL CELLS; INDUCED STATUS EPILEPTICUS; RAT HIPPOCAMPAL SLICES; PATTERN SEPARATION; FASCIA-DENTATA; INHIBITORY INTERNEURONS; IN-VIVO; SYNAPTIC REORGANIZATION; FEEDFORWARD INHIBITION AB Glutamatergic hilar mossy cells of the dentate gyrus can either excite or inhibit distant granule cells, depending on whether their direct excitatory projections to granule cells or their projections to local inhibitory interneurons dominate. However, it remains controversial whether the net effect of mossy cell loss is granule cell excitation or inhibition. Clarifying this controversy has particular relevance to temporal lobe epilepsy, which is marked by dentate granule cell hyperexcitability and extensive loss of dentate hilar mossy cells. Two diametrically opposed hypotheses have been advanced to explain this granule cell hyperexcitability-the "dormant basket cell" and the "irritable mossy cell" hypotheses. The "dormant basket cell" hypothesis proposes that mossy cells normally exert a net inhibitory effect on granule cells and therefore their loss causes dentate granule cell hyperexcitability. The "irritable mossy cell" hypothesis takes the opposite view that mossy cells normally excite granule cells and that the surviving mossy cells in epilepsy increase their activity, causing granule cell excitation. The inability to eliminate mossy cells selectively has made it difficult to test these two opposing hypotheses. To this end, we developed a transgenic toxin-mediated, mossy cell-ablation mouse line. Using these mutants, we demonstrated that the extensive elimination of hilar mossy cells causes granule cell hyperexcitability, although the mossy cell loss observed appeared insufficient to cause clinical epilepsy. In this review, we focus on this topic and also suggest that different interneuron populations may mediate mossy cell-induced translamellar lateral inhibition and intralamellar recurrent inhibition. These unique local circuits in the dentate hilar region may be centrally involved in the functional organization of the dentate gyrus. C1 [Jinde, Seiichiro] Univ Tokyo, Dept Neuropsychiat, Grad Sch Med, Tokyo, Japan. [Zsiros, Veronika; Nakazawa, Kazu] NIMH, Unit Genet Cognit & Behav, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Nakazawa, K (reprint author), NIMH, Unit Genet Cognit & Behav, NIH, Dept Hlth & Human Serv, 35 Convent Dr, Bethesda, MD 20892 USA. EM nakazawk@mail.nih.gov RI Nakazawa, Kazutoshi/J-6195-2015 OI Nakazawa, Kazutoshi/0000-0001-5699-9093 FU NIMH; Ministry of Education, Culture, Sports, Science, and Technology, Japan [22591274]; Japan Society for the Promotion of Science (JSPS) FX We thank Stefan Kolata for his critical reading of this manuscript. This research was supported by the Intramural Research Programs of the NIMH. This research was partially supported by the Grant-in-Aid for Scientific Research of Ministry of Education, Culture, Sports, Science, and Technology, Japan (Grant number: 22591274). Seiichiro Jinde was supported in part by a Japan Society for the Promotion of Science (JSPS) fellowship. NR 87 TC 23 Z9 24 U1 0 U2 21 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5110 J9 FRONT NEURAL CIRCUIT JI Front. Neural Circuits PD FEB 12 PY 2013 VL 7 AR 14 DI 10.3389/fncir.2013.00014 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 088LU UT WOS:000314836800001 PM 23407806 ER PT J AU Absinta, M Sati, P Gaitan, M Maggi, P Cortese, I Filippi, M Reich, D AF Absinta, Martina Sati, Pascal Gaitan, Maria Maggi, Pietro Cortese, Irene Filippi, Massimo Reich, Daniel TI Architectural Development of Acute MS Lesions at 7T Phase Contrast SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Absinta, Martina; Sati, Pascal; Gaitan, Maria; Maggi, Pietro; Cortese, Irene; Reich, Daniel] NINDS, NIH, Bethesda, MD 20892 USA. [Filippi, Massimo] Ist Sci San Raffaele, Inst Expt Neurol, Neuroimaging Res Unit, I-20132 Milan, Italy. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA S21005 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068606072 ER PT J AU Anderson, C Biffi, A Nalls, M Devan, W Schwab, K Ayres, A Valant, V Ross, O Rost, N Saxena, R Viswanathan, A Worrall, B Brott, T Goldstein, J Brown, D Broderick, J Norrving, B Greenberg, S Silliman, S Hansen, B Tirschwell, D Lindgren, A Slowik, A Schmidt, R Selim, M Gonzalez, JR Montaner, J Singleton, A Kidwell, C Woo, D Furie, K Meschia, J Rosand, J AF Anderson, Christopher Biffi, Alessandro Nalls, Michael Devan, William Schwab, Kristin Ayres, Alison Valant, Valerie Ross, Owen Rost, Natalia Saxena, Richa Viswanathan, Anand Worrall, Bradford Brott, Thomas Goldstein, Joshua Brown, Devin Broderick, Joseph Norrving, Bo Greenberg, Steven Silliman, Scott Hansen, Bjorn Tirschwell, David Lindgren, Arne Slowik, Agnieszka Schmidt, Reinhold Selim, Magdy Roquer Gonzalez, Jaume Montaner, Joan Singleton, Andrew Kidwell, Chelsea Woo, Daniel Furie, Karen Meschia, James Rosand, Jonathan TI Common Variants within Oxidative Phosphorylation Genes Influence Risk of Ischemic Stroke and Intracerebral Hemorrhage SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Anderson, Christopher; Biffi, Alessandro; Devan, William; Schwab, Kristin; Ayres, Alison; Valant, Valerie; Rost, Natalia; Saxena, Richa; Viswanathan, Anand; Goldstein, Joshua; Greenberg, Steven; Rosand, Jonathan] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Nalls, Michael; Singleton, Andrew] NIA, Bethesda, MD 20892 USA. [Ross, Owen; Brott, Thomas; Meschia, James] Mayo Clin, Jacksonville, FL 32224 USA. [Worrall, Bradford] Univ Virginia, Charlottesville, VA USA. [Brown, Devin] Univ Michigan, Ann Arbor, MI 48109 USA. [Broderick, Joseph; Woo, Daniel] Univ Cincinnati, Cincinnati, OH USA. [Norrving, Bo; Hansen, Bjorn; Lindgren, Arne] Lund Univ, Lund, Sweden. [Silliman, Scott] Univ Florida, Jacksonville, FL USA. [Tirschwell, David] Univ Washington, Seattle, WA 98195 USA. [Slowik, Agnieszka] Jagiellonian Univ, Krakow, Poland. [Schmidt, Reinhold] Graz Univ, St Radegund, Austria. [Selim, Magdy] BIDMC, Boston, MA USA. [Roquer Gonzalez, Jaume] Hosp del Mar, Barcelona, Spain. [Montaner, Joan] Univ Vall Dhebron, Barcelona, Spain. [Kidwell, Chelsea] Georgetown Univ, Washington, DC USA. [Furie, Karen] Brown Univ, Providence, RI 02912 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA S42002 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068606203 ER PT J AU Anderson, C Biffi, A Nalls, M Devan, W Schwab, K Ayres, A Valant, V Ross, O Rost, N Saxena, R Viswanathan, A Worrall, B Brott, T Goldstein, J Brown, D Broderick, J Norrving, B Greenberg, S Silliman, S Hansen, B Tirschwell, D Lindgren, A Slowik, A Schmidt, R Selim, M Gonzalez, JR Montaner, J Singleton, A Kidwell, C Woo, D Furie, K Meschia, J Rosand, J AF Anderson, Christopher Biffi, Alessandro Nalls, Michael Devan, William Schwab, Kristin Ayres, Alison Valant, Valerie Ross, Owen Rost, Natalia Saxena, Richa Viswanathan, Anand Worrall, Bradford Brott, Thomas Goldstein, Joshua Brown, Devin Broderick, Joseph Norrving, Bo Greenberg, Steven Silliman, Scott Hansen, Bjorn Tirschwell, David Lindgren, Arne Slowik, Agnieszka Schmidt, Reinhold Selim, Magdy Roquer Gonzalez, Jaume Montaner, Joan Singleton, Andrew Kidwell, Chelsea Woo, Daniel Furie, Karen Meschia, James Rosand, Jonathan TI Common Variants within Oxidative Phosphorylation Genes Influence Risk of Ischemic Stroke and Intracerebral Hemorrhage SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Anderson, Christopher; Biffi, Alessandro; Devan, William; Schwab, Kristin; Ayres, Alison; Valant, Valerie; Rost, Natalia; Saxena, Richa; Viswanathan, Anand; Goldstein, Joshua; Greenberg, Steven; Rosand, Jonathan] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Nalls, Michael] NIA, Bethesda, MD 20892 USA. [Ross, Owen; Brott, Thomas; Meschia, James] Mayo Clin, Jacksonville, FL 32224 USA. [Worrall, Bradford] Univ Virginia, Charlottesville, VA USA. [Brown, Devin] Univ Michigan, Ann Arbor, MI 48109 USA. [Broderick, Joseph; Woo, Daniel] Univ Cincinnati, Cincinnati, OH USA. [Norrving, Bo; Hansen, Bjorn; Lindgren, Arne] Lund Univ, Lund, Sweden. [Silliman, Scott] Univ Florida, Jacksonville, FL USA. [Tirschwell, David] Univ Washington, Seattle, WA 98195 USA. [Slowik, Agnieszka] Jagiellonian Univ, Krakow, Poland. [Schmidt, Reinhold] Graz Univ, St Radegund, Austria. [Selim, Magdy] BIDMC, Boston, MA USA. [Roquer Gonzalez, Jaume] Hosp del Mar, Barcelona, Spain. [Montaner, Joan] Univ Vall Dhebron, Barcelona, Spain. [Kidwell, Chelsea] Georgetown Univ, Washington, DC USA. [Furie, Karen] Brown Univ, Providence, RI 02912 USA. RI Montaner, Joan/D-3063-2015; IBIS, NEUROVASCULAR/O-1855-2015 NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA IN71001 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068600087 ER PT J AU Bagnato, F Hametner, S Ikonomidou, V Van Gelderen, P Cantor, F Ohayon, J Richert, N Lassmann, H Duyn, J Yao, B AF Bagnato, Francesca Hametner, Simon Ikonomidou, Vasiliki Van Gelderen, Peter Cantor, Fredric Ohayon, Joan Richert, Nancy Lassmann, Hans Duyn, Jeff Yao, Bing TI Slowly Expanding Lesions in Multiple Sclerosis: An In Vivo Demonstration SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Bagnato, Francesca] Univ Maryland, Baltimore, MD 21201 USA. [Hametner, Simon; Lassmann, Hans] Univ Vienna, Vienna, Austria. [Ikonomidou, Vasiliki] George Mason Univ, Dept Elect & Comp Engn, Fairfax, MD USA. [Van Gelderen, Peter; Cantor, Fredric; Ohayon, Joan; Duyn, Jeff; Yao, Bing] NIH, Bethesda, MD 20892 USA. [Richert, Nancy] Biogen Inc, Cambridge, MA 02142 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA S21006 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068606073 ER PT J AU Benninger, D Lin, P Kida, T Iseki, K Wasaka, T Bai, O Hallett, M AF Benninger, David Lin, Peter Kida, Tetsuo Iseki, Kazumi Wasaka, Toshi Bai, Ou Hallett, Mark TI Correlation of High-Frequency Oscillations in Focal Hand Dystonia with Therapeutic Response after Botulinum Toxin Treatment SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Benninger, David] CHU Vaudois, Dept Neurosci Clin, Serv Neurol, Lausanne, Switzerland. [Lin, Peter] NIH, Rockville, MD USA. [Kida, Tetsuo; Wasaka, Toshi] NINDS, Human Motor Control Sect, Med Neurol Branch, Bethesda, MD 20892 USA. [Iseki, Kazumi; Bai, Ou] NIH, Bethesda, MD 20892 USA. [Hallett, Mark] NINDS, NIH, Bethesda, MD 20892 USA. RI Benninger, David/A-8157-2015 OI Benninger, David/0000-0002-1049-9533 NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA P07194 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068605176 ER PT J AU Burke, A Fischbeck, K Grunseich, C AF Burke, Ailbhe Fischbeck, Kenneth Grunseich, Christopher TI Spironolactone Treatment in a Cell Culture Model of Spinal and Bulbar Muscular Atrophy SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Burke, Ailbhe] UCL, London, England. [Fischbeck, Kenneth] NINDS, NIH, Bethesda, MD 20892 USA. [Grunseich, Christopher] NINDS, NIH, Columbia, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA P02174 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068601238 ER PT J AU Burke, A Fischbeck, K Grunseich, C AF Burke, Ailbhe Fischbeck, Kenneth Grunseich, Christopher TI Spironolactone Treatment in a Cell Culture Model of Spinal and Bulbar Muscular Atrophy SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Burke, Ailbhe] UCL, London, England. [Fischbeck, Kenneth] NINDS, NIH, Bethesda, MD 20892 USA. [Grunseich, Christopher] NINDS, NIH, Columbia, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA IN81003 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068600104 ER PT J AU Calvo, A Cistaro, A Pagani, M Montuschi, A Moglia, C Canosa, A Restagno, G Traynor, B Nobili, F Carrara, G Lopiano, L Valentini, C Chio, A AF Calvo, Andrea Cistaro, Angelina Pagani, Marco Montuschi, Anna Moglia, Cristina Canosa, Antonio Restagno, Gabriella Traynor, Bryan Nobili, Flavio Carrara, Giovanna Lopiano, Leonardo Valentini, Consuelo Chio, Adriano TI PET in in ALS Patients with C9ORF72 Mutations SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Calvo, Andrea; Montuschi, Anna; Moglia, Cristina; Canosa, Antonio; Lopiano, Leonardo; Chio, Adriano] Univ Turin, Dept Neurosci, Turin, Italy. [Cistaro, Angelina] IRMET SpA, Positron Emiss Tomog Ctr, Turin, Italy. [Pagani, Marco] CNR, Rome, Italy. [Restagno, Gabriella] AO Citta Salute & Sci, Mol Genet Lab, Turin, Italy. [Traynor, Bryan] NIA, Neuromuscular Dis Res Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Nobili, Flavio] Univ Genoa, Dept Neurosci Ophthalmol & Genet, Clin Neurophysiol Unit, Genoa, Italy. [Carrara, Giovanna; Valentini, Consuelo] AO Citta Salute & Sci, Neuroradiol Unit, Turin, Italy. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA P06131 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068604199 ER PT J AU Chen, HL Guo, XG Park, Y Freedman, N Shinha, R Hollenbeck, A Blair, A AF Chen, Honglei Guo, Xuguang Park, Yikyung Freedman, Neal Shinha, Rashmi Hollenbeck, Albert Blair, Aaron TI Sweetened-Beverages, Coffee, and Tea in Relation to Depression among Older US Adults SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Chen, Honglei] NIEHS, Res Triangle Pk, NC 27709 USA. [Guo, Xuguang] Westat Corp, Durham, NC USA. [Park, Yikyung; Freedman, Neal; Shinha, Rashmi; Blair, Aaron] NCI, Rockville, MD USA. [Hollenbeck, Albert] AARP, Washington, DC USA. NR 0 TC 0 Z9 0 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA P05122 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068603275 ER PT J AU Czarnecki, K Toledo, R Hallett, M AF Czarnecki, Kathrin Toledo, Ryan Hallett, Mark TI Heart Rate Variability and Cortisol Diurnal Profiles in Functional Movement Disorder Patients SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Czarnecki, Kathrin; Toledo, Ryan; Hallett, Mark] NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA P03059 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068602028 ER PT J AU Flinders, A Sanossian, N Starkman, S Liebeskind, D Eckstein, M Stratton, S Pratt, F Hamilton, S Olivas, E Chatfield, F Conwit, R Saver, J AF Flinders, Abraham Sanossian, Nerses Starkman, Sidney Liebeskind, David Eckstein, Marc Stratton, Samuel Pratt, Frank Hamilton, Scott Olivas, Edgar Chatfield, Fiona Conwit, Robin Saver, Jeffrey TI Frequency and Speed of Early Antihypertensive Treatment of Severe Hypertension in Acute Intracerebral Hemorrhage Patients in a Broad Community Setting SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Flinders, Abraham; Sanossian, Nerses; Eckstein, Marc; Olivas, Edgar] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Starkman, Sidney; Liebeskind, David; Saver, Jeffrey] Univ Calif Los Angeles, Stroke Ctr, Los Angeles, CA USA. [Pratt, Frank] Los Angeles Cty Fire Dept, Torrance, CA USA. [Hamilton, Scott] Stanford Univ, San Francisco, CA USA. [Chatfield, Fiona] Fast Mag, Los Angeles, CA USA. [Conwit, Robin] NINHS, NIH, Lutherville Timonium, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA S07007 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068605376 ER PT J AU Flinders, A Sanossian, N Starkman, S Liebeskind, D Eckstein, M Stratton, S Pratt, F Hamilton, S Olivas, E Chatfield, F Conwit, R Saver, J AF Flinders, Abraham Sanossian, Nerses Starkman, Sidney Liebeskind, David Eckstein, Marc Stratton, Samuel Pratt, Frank Hamilton, Scott Olivas, Edgar Chatfield, Fiona Conwit, Robin Saver, Jeffrey TI Management of Early Severe Hypertension in Acute Intracerebral Hemorrhage in Primary Stroke Centers vs. Non-Stroke Center Hospitals SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Flinders, Abraham] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Sanossian, Nerses; Eckstein, Marc; Olivas, Edgar] USC Keck Sch Med, Los Angeles, CA USA. [Starkman, Sidney; Liebeskind, David; Saver, Jeffrey] UCLA Stroke Ctr, Los Angeles, CA USA. [Stratton, Samuel] Orange Cty EMS Agcy, Santa Ana, CA USA. [Pratt, Frank] Los Angeles Cty Fire Dept, Torrance, CA USA. [Hamilton, Scott] Stanford Univ, Stanford, CA 94305 USA. [Chatfield, Fiona] Fast Mag Coordinating Ctr, Los Angeles, CA USA. [Conwit, Robin] NINHS, NIH, Lutherville Timonium, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA P01022 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068600179 ER PT J AU Gelber, R Launer, L Petrovitch, H Masaki, K Ross, W White, L AF Gelber, Rebecca Launer, Lenore Petrovitch, Helen Masaki, Kamal Ross, Web White, Lon TI Beta-Blocker Treatment of Hypertensive Older Persons Decreases Risk of Cognitive Impairment: The HonoluluAsia Aging Study SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Gelber, Rebecca; Ross, Web] VA Pacific Isl Hlth Care Syst, Honolulu, HI USA. [Launer, Lenore] NIA, Washington, DC USA. [Petrovitch, Helen] VA Pacific Isl Hlth Care Syst, Kailua, HI USA. [Masaki, Kamal; White, Lon] Univ Hawaii, John A Burns Sch Med, Honolulu, HI 96822 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA P03094 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068602063 ER PT J AU Ghosh, P Considine, E Karp, B Hallett, M Lungu, C Alter, K AF Ghosh, Pritha Considine, Elaine Karp, Barbara Hallett, Mark Lungu, Codrin Alter, Katharine TI Features and Challenges in Runner's Dystonia SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Ghosh, Pritha; Considine, Elaine; Karp, Barbara; Hallett, Mark; Lungu, Codrin] NINDS, NIH, Bethesda, MD 20892 USA. [Alter, Katharine] NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA P07199 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068605181 ER PT J AU Ilieva, H Ling, SC Parone, P Da Cruz, S Tokunaga, S Bui, N Swing, D Marsala, M Tessarollo, L Shaw, C Cleveland, D AF Ilieva, Hristelina Ling, Shuo-Chien Parone, Philippe Da Cruz, Sandrine Tokunaga, Seiya Bui, Ngoc Swing, Debbie Marsala, Martin Tessarollo, Lino Shaw, Christopher Cleveland, Don TI Dose-Dependent and Mutant Enhanced Neurotoxicity in Mice Expressing Wild Type or ALS-Linked Mutants of FUS/TLS SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Ilieva, Hristelina] Methodist Hosp, Dept Neurol, Houston, TX 77030 USA. [Ling, Shuo-Chien; Parone, Philippe; Da Cruz, Sandrine; Tokunaga, Seiya; Bui, Ngoc] Ludwig Inst Canc Res, La Jolla, CA USA. [Swing, Debbie] NCI, Frederick, MD 21701 USA. [Marsala, Martin] Univ Calif San Diego, Dept Anesthesiol, La Jolla, CA 92093 USA. [Tessarollo, Lino] NCI, Neural Dev Sect, Frederick, MD 21701 USA. [Shaw, Christopher] MRC Ctr Neurodegenerat Res, London, England. [Cleveland, Don] Ludwig Inst Canc Res, La Jolla, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA S06006 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068605369 ER PT J AU Kapogiannis, D AF Kapogiannis, Dimitrios TI Precuneus Glucose Reflects CSF A beta 42 in Early Alzheimer's Disease SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Kapogiannis, Dimitrios] NIA, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA P06043 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068604111 ER PT J AU Kearney, M Ecklund, D Simpson, E Bosch, M Sweet, B Jackson, K Mahoney, K McCourt, M Thornell, B Titus, S Soodoo, N O'Brien, J Gloer, K Costigan, M Logsden-Sackett, N Huff, T Shefner, J Gutmann, L Clarke, W Torner, J Long, J Chaloner, K Bayman, E McNeil, D Koroshetz, W Kaufmann, P Cudkowicz, M Coffey, C AF Kearney, Marianne Ecklund, Dixie Simpson, Elizabeth Bosch, Michael Sweet, Bryan Jackson, Katherine Mahoney, Katy McCourt, Michelle Thornell, Brenda Titus, Sarah Soodoo, Natasha O'Brien, Janice Gloer, Katherine Costigan, Michele Logsden-Sackett, Nyla Huff, Trevis Shefner, Jeremy Gutmann, Laurie Clarke, William Torner, James Long, Jeffrey Chaloner, Kathryn Bayman, Emine McNeil, Dawn Koroshetz, Walter Kaufmann, Petra Cudkowicz, Merit Coffey, Christopher TI Network for Excellence in Neuroscience Clinical Trials, NeuroNEXT: Concept to Implementation SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Kearney, Marianne; Simpson, Elizabeth; Mahoney, Katy; McCourt, Michelle; Thornell, Brenda; Titus, Sarah; Soodoo, Natasha; O'Brien, Janice; Cudkowicz, Merit] MGH, Charlestown, MA USA. [Ecklund, Dixie; Bosch, Michael; Gloer, Katherine; Costigan, Michele; Logsden-Sackett, Nyla; Huff, Trevis; Clarke, William; Torner, James; Long, Jeffrey; Chaloner, Kathryn; Bayman, Emine; Coffey, Christopher] U Iowa, Iowa City, IA USA. [Sweet, Bryan; Jackson, Katherine] Massachusetts Gen Hosp, Charlestown, MA USA. [Shefner, Jeremy] SUNY Upstate Med Ctr, Syracuse, NY USA. [Gutmann, Laurie] W Virginia Univ, Morgantown, WV 26506 USA. [McNeil, Dawn; Koroshetz, Walter] NINDS, Bethesda, MD 20892 USA. [Kaufmann, Petra] NINDS, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA P04245 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068603134 ER PT J AU Lu-Emerson, C Snuderl, M Kirkpatrick, N Goveia, J Davidson, C Huang, Y Riedemann, L Ivy, P Ancukiewicz, M Stemmer-Rachamimov, A Batchelor, T Jain, R AF Lu-Emerson, Christine Snuderl, Matija Kirkpatrick, Nathaniel Goveia, Jermaine Davidson, Christian Huang, Yuhui Riedemann, Lars Ivy, Percy Ancukiewicz, Marek Stemmer-Rachamimov, Anat Batchelor, Tracy Jain, Rakesh TI Direct Evidence That Increase in Tumor-Associated Macrophages (TAMs) after Antiangiogenic Therapy Is Associated with Poor Survival in Recurrent Glioblastoma (GBM) Patients SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Lu-Emerson, Christine] Massachusetts Gen Hosp, Dept Neurooncol, Boston, MA 02114 USA. [Snuderl, Matija; Batchelor, Tracy] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kirkpatrick, Nathaniel; Goveia, Jermaine; Huang, Yuhui; Riedemann, Lars; Ancukiewicz, Marek; Jain, Rakesh] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Davidson, Christian; Stemmer-Rachamimov, Anat] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Ivy, Percy] NCI, Invest Drug Branch, Rockville, MD USA. RI Riedemann, Lars/J-5725-2014 OI Riedemann, Lars/0000-0002-9510-1845 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA S35001 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068606159 ER PT J AU Lu-Emerson, C Snuderl, M Kirkpatrick, N Goveia, J Davidson, C Huang, YH Riedemann, L Ivy, P Ancukiewicz, M Stemmer-Rachamimov, A Batchelor, T Jain, R AF Lu-Emerson, Christine Snuderl, Matija Kirkpatrick, Nathaniel Goveia, Jermaine Davidson, Christian Huang, Yuhui Riedemann, Lars Ivy, Percy Ancukiewicz, Marek Stemmer-Rachamimov, Anat Batchelor, Tracy Jain, Rakesh TI Direct Evidence That Increase in Tumor-Associated Macrophages (TAMs) after Antiangiogenic Therapy Is Associated with Poor Survival in Recurrent Glioblastoma (GBM) Patients SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Lu-Emerson, Christine] Massachusetts Gen Hosp, Dept Neurooncol, Boston, MA 02114 USA. [Snuderl, Matija; Batchelor, Tracy] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kirkpatrick, Nathaniel; Goveia, Jermaine; Huang, Yuhui; Riedemann, Lars; Ancukiewicz, Marek; Jain, Rakesh] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Davidson, Christian; Stemmer-Rachamimov, Anat] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Ivy, Percy] NCI, Invest Drug Branch, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA IN102001 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068600138 ER PT J AU Lublin, F Cofield, S Cutter, G Salter, A Wang, J Conwit, R Narayana, P Nelson, F Gustafson, T Wolinsky, J AF Lublin, Fred Cofield, Stacey Cutter, Gary Salter, Amber Wang, Jing Conwit, Robin Narayana, Ponnada Nelson, Flavia Gustafson, Tarah Wolinsky, Jerry TI Relapse Activity in the CombiRx Trial: Blinded, 7-Year Extension Results SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Lublin, Fred; Gustafson, Tarah] Mt Sinai Sch Med, New York, NY USA. [Cofield, Stacey; Cutter, Gary; Salter, Amber; Wang, Jing] Univ Alabama Birmingham, Birmingham, AL USA. [Conwit, Robin] NINDS, NIH, Lutherville Timonium, MD USA. [Narayana, Ponnada; Nelson, Flavia; Wolinsky, Jerry] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA S01002 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068605334 ER PT J AU Lublin, F Cofield, S Cutter, G Salter, A Wang, J Conwit, R Narayana, P Nelson, F Gustafson, T Wolinsky, J AF Lublin, Fred Cofield, Stacey Cutter, Gary Salter, Amber Wang, Jing Conwit, Robin Narayana, Ponnada Nelson, Flavia Gustafson, Tarah Wolinsky, Jerry TI EDSS Changes in CombiRx: Blinded, 7-Year Extension Results for Progression and Improvement SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Lublin, Fred; Gustafson, Tarah] Mt Sinai Sch Med, New York, NY USA. [Cofield, Stacey; Cutter, Gary; Salter, Amber; Wang, Jing] Univ Alabama Birmingham, Birmingham, AL USA. [Conwit, Robin] NINDS, NIH, Lutherville Timonium, MD USA. [Narayana, Ponnada; Nelson, Flavia; Wolinsky, Jerry] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA P04121 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068603010 ER PT J AU Masdeu, J Gonzalez-Pinto, A Matute, C de Azua, SR Palomino, A De Leon, J Dalmau, J AF Masdeu, Joseph Gonzalez-Pinto, Ana Matute, Carlos Ruiz de Azua, Sonia Palomino, Aitor De Leon, Jose Dalmau, Josep TI Absence of Serum IgG Antibodies Against the NR1 Subunit of the NMDA Receptor in Patients with Schizophrenia SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Masdeu, Joseph] NIH, Bethesda, MD 20892 USA. [Gonzalez-Pinto, Ana; Ruiz de Azua, Sonia] Univ Hosp Alava, Vitoria, Spain. [Matute, Carlos; Palomino, Aitor] Univ Basque Country, EHU, Leioa, Spain. [De Leon, Jose] Eastern State Hosp, Mental Hlth Res Ctr, Lexington, KY USA. [Dalmau, Josep] Univ Barcelona, Barcelona, Spain. RI de Leon, Jose/F-2709-2013 OI de Leon, Jose/0000-0002-7756-2314 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA P06062 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068604130 ER PT J AU Oh, J Saidha, S Chen, M Smith, S Prince, J Jones, C Van Zijl, P Diener-West, M Reich, D Calabresi, P AF Oh, Jiwon Saidha, Shiv Chen, Min Smith, Seth Prince, Jerry Jones, Craig Van Zijl, Peter Diener-West, Marie Reich, Daniel Calabresi, Peter TI Relative Clinical Utility of Quantitative MRI Measures in the Spinal Cord in Multiple Sclerosis Patients SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Oh, Jiwon; Chen, Min; Prince, Jerry; Jones, Craig; Van Zijl, Peter; Diener-West, Marie; Calabresi, Peter] Johns Hopkins Univ, Baltimore, MD USA. [Saidha, Shiv] Johns Hopkins Univ, Dublin, Ireland. [Smith, Seth] Vanderbilt Univ, Nashville, TN 37235 USA. [Reich, Daniel] NIH, Bethesda, MD 20892 USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA PD6006 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068605311 ER PT J AU Oh, J Seigo, M Saidha, S Sotirchos, E Zackowski, K Chen, M Prince, J Diener-West, M Calabresi, P Reich, D AF Oh, Jiwon Seigo, Michaela Saidha, Shiv Sotirchos, Elias Zackowski, Kathleen Chen, Min Prince, Jerry Diener-West, Marie Calabresi, Peter Reich, Daniel TI Normalization of the Spinal Cord in Multiple Sclerosis SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Oh, Jiwon; Seigo, Michaela; Sotirchos, Elias; Zackowski, Kathleen; Chen, Min; Prince, Jerry; Diener-West, Marie; Calabresi, Peter] Johns Hopkins Univ, Baltimore, MD USA. [Saidha, Shiv] Johns Hopkins Univ, Dublin, Ireland. [Reich, Daniel] NIH, Bethesda, MD 20892 USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA P06106 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068604174 ER PT J AU Patel, R Starkman, S Hamilton, S Craig, S Yanes, A Conwit, R Saver, J AF Patel, Richa Starkman, Sidney Hamilton, Scott Craig, Sharon Yanes, Anna Conwit, Robin Saver, Jeffrey TI Improving the Reliability of Rankin Scale Stroke Disability Grading in Clinical Trials and Clinical Practice: The Rankin Focused Assessment - Ambulation (RFA - A) SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Patel, Richa] Univ Calif Los Angeles, Stroke Ctr, Laguna Niguel, CA USA. [Starkman, Sidney; Saver, Jeffrey] Univ Calif Los Angeles, Los Angeles, CA USA. [Craig, Sharon; Yanes, Anna] Univ Calif Los Angeles, Stroke Ctr, Los Angeles, CA USA. [Conwit, Robin] NINDS, NIH, Lutherville Timonium, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA S32003 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068606144 ER PT J AU Reich-Slotky, R Andrews, J Buchsbaum, R Levy, D Kaufmann, P Thompson, J AF Reich-Slotky, Ronit Andrews, Jinsy Buchsbaum, Richard Levy, Diane Kaufmann, Petra Thompson, John TI Body Mass Index (BMI) as Predictor of ALSFRS-r Score Decline in ALS Patients SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Reich-Slotky, Ronit] Columbia Univ, New York, NY USA. [Andrews, Jinsy] Hosp Special Care, New Britain, CT USA. [Buchsbaum, Richard; Levy, Diane; Thompson, John] Columbia Univ, Dept Biostat, New York, NY USA. [Kaufmann, Petra] NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA P07085 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068605067 ER PT J AU Richardson, SP Beck, S Bliem, B Hallett, M AF Richardson, Sarah Pirio Beck, Sandra Bliem, Barbara Hallett, Mark TI A Potential Biomarker for Focal Dystonia: Abnormal Dorsal Premotor-Motor Inhibition in Writer's Cramp SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Richardson, Sarah Pirio] Univ New Mexico, Albuquerque, NM 87131 USA. [Beck, Sandra] Univ Freiburg, D-79106 Freiburg, Germany. [Bliem, Barbara; Hallett, Mark] NINDS, NIH, HMCS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA S33006 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068606153 ER PT J AU Ross, W Inaba, M Masaki, K Abbott, R Fong, KO Bell, C Petrovitch, H Tanner, C Launer, L White, L AF Ross, Web Inaba, Michiko Masaki, Kamal Abbott, Robert Fong, Ka-on Bell, Christina Petrovitch, Helen Tanner, Caroline Launer, Lenore White, Lon TI Association of Slow Reaction Time with Future Risk of Parkinson's Disease in the Honolulu-Asia Aging Study SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Ross, Web] Vet Affairs Pacific Isl Hlth Care Syst, Honolulu, HI USA. [Inaba, Michiko; Masaki, Kamal; Bell, Christina] Univ Hawaii, John A Burns Sch Med, Honolulu, HI 96822 USA. [Abbott, Robert] Univ Virginia, Sch Med, Div Biostat, Charlottesville, VA 22908 USA. [Fong, Ka-on] Kuakini Med Ctr, Honolulu, HI USA. [Petrovitch, Helen; White, Lon] Pacific Hlth Res & Educ Inst, Kailua, HI USA. [Tanner, Caroline] Parkinsons Inst, Sunnyvale, CA USA. [Launer, Lenore] NIA, NIH, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA P03063 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068602032 ER PT J AU Santos-Modesitt, W Yaffe, K Byers, A Penninx, B Simonsick, E Satterfield, S Cauley, J Harris, T Metti, A Patel, K Koster, A Barnes, D AF Santos-Modesitt, Wendy Yaffe, Kristine Byers, Amy Penninx, Brenda Simonsick, Eleanor Satterfield, Suzanne Cauley, Jane Harris, Tamara Metti, Andrea Patel, Kushang Koster, Annemarie Barnes, Deborah TI Cross Sectional and Longitudinal Associations between Serum Brain-Derived Neurotrophic Factor (sBDNF) and Depressive Symptoms - The Health, Aging and Body Composition (Health ABC) Study SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Santos-Modesitt, Wendy; Yaffe, Kristine; Byers, Amy; Barnes, Deborah] Univ Calif San Francisco, San Francisco Vet Affairs, San Francisco, CA 94143 USA. [Penninx, Brenda] Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands. [Simonsick, Eleanor] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Satterfield, Suzanne] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Cauley, Jane; Metti, Andrea] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Harris, Tamara] NIA, Bethesda, MD 20892 USA. [Patel, Kushang] Univ Washington, Seattle, WA 98195 USA. [Koster, Annemarie] Maastricht Univ, Maastricht, Netherlands. RI Koster, Annemarie/E-7438-2010 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA P05113 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068603266 ER PT J AU Von Geldern, G Nath, A AF Von Geldern, Gloria Nath, Avindra TI Abnormal Brain Pathology in Virologically Controlled HIV-Infected Individuals SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Von Geldern, Gloria; Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA S38003 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068606179 ER PT J AU White, L Gelber, R Launer, L Zarow, C Sonnen, J Uyehara-Lock, J Masaki, K Ross, G Petrovitch, H AF White, Lon Gelber, Rebecca Launer, Lenore Zarow, Chris Sonnen, Joshua Uyehara-Lock, Jane Masaki, Kamal Ross, George Petrovitch, Helen TI Beta Blocker Treatment of Hypertensive Older Persons Ameliorates the Brain Lesions of Dementia Measured at Autopsy: The Honolulu-Asia Aging Study SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [White, Lon; Petrovitch, Helen] Pacific Hlth Res & Educ Inst, Honolulu, HI USA. [Gelber, Rebecca; Ross, George] Hawaii Dept Vet Affairs, Honolulu, HI USA. [Launer, Lenore] NIA, Lab Epidemiol Demog & Biometry, NIH, Washington, DC USA. [Zarow, Chris] Univ So Calif, Sch Med, Downey, CA USA. [Sonnen, Joshua] Univ Washington, Sch Med, Seattle, WA USA. [Uyehara-Lock, Jane; Masaki, Kamal] Univ Hawaii, John A Burns Sch Med, Honolulu, HI 96822 USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA S44005 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068606220 ER PT J AU Wolinsky, J Salter, A Narayana, P Datta, S Nelson, F Cofield, S Cutter, G Conwit, R Gustafson, T Lublin, F AF Wolinsky, Jerry Salter, Amber Narayana, Ponnada Datta, Sushmita Nelson, Flavia Cofield, Stacey Cutter, Gary Conwit, Robin Gustafson, Tarah Lublin, Fred TI MRI Outcomes in CombiRx: Blinded, 7-Year Extension Results SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Wolinsky, Jerry; Narayana, Ponnada; Datta, Sushmita; Nelson, Flavia] Univ Texas HSCH, Houston, TX USA. [Salter, Amber; Cofield, Stacey; Cutter, Gary] Univ Alabama Birmingham, Birmingham, AL USA. [Conwit, Robin] NINDS, NIH, Lutherville Timonium, MD USA. [Gustafson, Tarah; Lublin, Fred] Mt Sinai Sch Med, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA S01003 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068605335 ER PT J AU Zhao, E Zhang, W Peddada, S Chen, HL AF Zhao, Edward Zhang, Wen Peddada, Shyamal Chen, Honglei TI Meta-Analysis on the Prevalence of Selected Premotor Symptoms of Parkinson Disease before and after Diagnosis SO NEUROLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Neurology (AAN) CY MAR 16-23, 2013 CL San Diego, CA SP Amer Acad Neurol C1 [Zhao, Edward; Zhang, Wen; Peddada, Shyamal] NIEHS RTP, Res Triangle Pk, NC USA. [Chen, Honglei] NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2013 VL 80 SU S MA P06097 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA AB8VR UT WOS:000332068604165 ER PT J AU Sani, MA Weber, DK Delaglio, F Separovic, F Gehman, JD AF Sani, Marc-Antoine Weber, Daniel K. Delaglio, Frank Separovic, Frances Gehman, John D. TI A practical implementation of de-Pake-ing via weighted Fourier transformation SO PEERJ LA English DT Article DE dePake; NMRPipe; Membrane perturbation; Lipid biophysics; Deuterium NMR AB We provide an NMRPipe macro to meet an increasing need in membrane biophysics for facile de-Pake-ing of axially symmetric deuterium, and to an extent phosphorous, static lineshapes. The macro implements the development of McCabe & Wassall (1997), and is run as a simple replacement for the usual Fourier transform step in an NMRPipe processing procedure. C1 [Sani, Marc-Antoine; Weber, Daniel K.; Separovic, Frances; Gehman, John D.] Univ Melbourne, Inst Bio21, Sch Chem, Melbourne, Vic 3010, Australia. [Delaglio, Frank] NIDDK, Phys Chem Lab, NIH, Bethesda, MD USA. RP Gehman, JD (reprint author), Univ Melbourne, Inst Bio21, Sch Chem, Melbourne, Vic 3010, Australia. EM jgehman@unimelb.edu.au RI Separovic, Frances/D-9698-2011; OI Separovic, Frances/0000-0002-6484-2763; Gehman, John D/0000-0002-2599-6292; Weber, Daniel/0000-0001-8400-767X; Sani, Marc-antoine/0000-0003-3284-2176 FU Australian Research Council Future Fellowship FX JD Gehman is funded under an Australian Research Council Future Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 6 Z9 6 U1 0 U2 6 PU PEERJ INC PI LONDON PA 341-345 OLD ST, THIRD FLR, LONDON, EC1V 9LL, ENGLAND SN 2167-8359 J9 PEERJ JI PeerJ PD FEB 12 PY 2013 VL 1 AR e30 DI 10.7717/peerj.30 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36AF UT WOS:000209185300025 PM 23638366 ER PT J AU Cohen, JM Dlamini, S Novotny, JM Kandula, D Kunene, S Tatem, AJ AF Cohen, Justin M. Dlamini, Sabelo Novotny, Joseph M. Kandula, Deepika Kunene, Simon Tatem, Andrew J. TI Rapid case-based mapping of seasonal malaria transmission risk for strategic elimination planning in Swaziland SO MALARIA JOURNAL LA English DT Article ID SUB-SAHARAN AFRICA; PLASMODIUM-FALCIPARUM; SPECIES DISTRIBUTIONS; WETNESS INDEXES; DISEASE BURDEN; ENDEMICITY; PREDICTION; REGRESSION; HIGHLANDS; HABITAT AB Background: As successful malaria control programmes move towards elimination, they must identify residual transmission foci, target vector control to high-risk areas, focus on both asymptomatic and symptomatic infections, and manage importation risk. High spatial and temporal resolution maps of malaria risk can support all of these activities, but commonly available malaria maps are based on parasite rate, a poor metric for measuring malaria at extremely low prevalence. New approaches are required to provide case-based risk maps to countries seeking to identify remaining hotspots of transmission while managing the risk of transmission from imported cases. Methods: Household locations and travel histories of confirmed malaria patients during 2011 were recorded through routine surveillance by the Swaziland National Malaria Control Programme for the higher transmission months of January to April and the lower transmission months of May to December. Household locations for patients with no travel history to endemic areas were compared against a random set of background points sampled proportionate to population density with respect to a set of variables related to environment, population density, vector control, and distance to the locations of identified imported cases. Comparisons were made separately for the high and low transmission seasons. The Random Forests regression tree classification approach was used to generate maps predicting the probability of a locally acquired case at 100 m resolution across Swaziland for each season. Results: Results indicated that case households during the high transmission season tended to be located in areas of lower elevation, closer to bodies of water, in more sparsely populated areas, with lower rainfall and warmer temperatures, and closer to imported cases than random background points (all p < 0.001). Similar differences were evident during the low transmission season. Maps from the fit models suggested better predictive ability during the high season. Both models proved useful at predicting the locations of local cases identified in 2012. Conclusions: The high-resolution mapping approaches described here can help elimination programmes understand the epidemiology of a disappearing disease. Generating case-based risk maps at high spatial and temporal resolution will allow control programmes to direct interventions proactively according to evidence-based measures of risk and ensure that the impact of limited resources is maximized to achieve and maintain malaria elimination. C1 [Cohen, Justin M.; Novotny, Joseph M.; Kandula, Deepika] Clinton Hlth Access Initiat, Boston, MA USA. [Dlamini, Sabelo; Kunene, Simon] Natl Malaria Control Programme, Mbabane, Swaziland. [Novotny, Joseph M.; Kandula, Deepika] Univ Calif San Francisco, Global Hlth Grp, San Francisco, CA 94143 USA. [Tatem, Andrew J.] Univ Southampton, Dept Geog & Environm, Southampton, Hants, England. [Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Cohen, JM (reprint author), Clinton Hlth Access Initiat, Boston, MA USA. EM jcohen@clintonhealthaccess.org OI Cohen, Justin/0000-0003-4481-6784 FU Global Health Group at University of California, San Francisco; Bill and Melinda Gates Foundation [1013170, 49446, 1032350]; Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; NIH/NIAID [U19AI089674] FX JMC, JN, and DK acknowledge funding support for this work from the Global Health Group at University of California, San Francisco and the Bill and Melinda Gates Foundation (#1013170). AJT acknowledges funding support from the RAPIDD programme of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health, and is also supported by grants from NIH/NIAID (U19AI089674) and the Bill and Melinda Gates Foundation (#49446 and #1032350). NR 52 TC 25 Z9 25 U1 0 U2 12 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 FEB 11 PY 2013 VL 12 AR 61 DI 10.1186/1475-2875-12-61 PG 12 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 137GF UT WOS:000318422900001 PM 23398628 ER PT J AU Khandanpour, C Phelan, JD Vassen, L Schutte, J Chen, RY Horman, SR Gaudreau, MC Krongold, J Zhu, JF Paul, WE Duhrsen, U Gottgens, B Grimes, HL Moroy, T AF Khandanpour, Cyrus Phelan, James D. Vassen, Lothar Schuette, Judith Chen, Riyan Horman, Shane R. Gaudreau, Marie-Claude Krongold, Joseph Zhu, Jinfang Paul, William E. Duehrsen, Ulrich Goettgens, Bertie Grimes, H. Leighton Moeroey, Tarik TI Growth Factor Independence 1 Antagonizes a p53-Induced DNA Damage Response Pathway in Lymphoblastic Leukemia SO CANCER CELL LA English DT Article ID ZINC-FINGER PROTEIN; T-CELL LYMPHOMAGENESIS; C-MYC; HUMAN NEUTROPENIA; TRANSGENIC MICE; IN-VIVO; GFI-1; ACTIVATION; EXPRESSION; NOTCH1 AB Most patients with acute lymphoblastic leukemia (ALL) fail current treatments highlighting the need for better therapies. Because oncogenic signaling activates a p53-dependent DNA damage response and apoptosis, leukemic cells must devise appropriate countermeasures. We show here that growth factor independence 1 (Gfi1) can serve such a function because Gfi1 ablation exacerbates p53 responses and lowers the threshold for p53-induced cell death. Specifically, Gfi1 restricts p53 activity and expression of proapoptotic p53 targets such as Box, Noxa (Pmaip1), and Puma (Bbc3). Subsequently, Gfi1 ablation cures mice from leukemia and limits the expansion of primary human T-ALL xenografts in mice. This suggests that targeting Gfi1 could improve the prognosis of patients with T-ALL or other lymphoid leukemias. C1 [Khandanpour, Cyrus; Vassen, Lothar; Chen, Riyan; Gaudreau, Marie-Claude; Krongold, Joseph; Moeroey, Tarik] Inst Rech Clin Montreal, Montreal, PQ H2W 1R7, Canada. [Gaudreau, Marie-Claude; Moeroey, Tarik] Univ Montreal, Dept Microbiol & Immunol, Montreal, PQ H3C 3J7, Canada. [Khandanpour, Cyrus] Univ Duisburg Essen, Univ Hosp, Dept Haematol, D-45122 Essen, Germany. [Phelan, James D.; Horman, Shane R.; Grimes, H. Leighton] Cincinnati Childrens Hosp Med Ctr, Div Cellular & Mol Immunol, Cincinnati, OH 45229 USA. [Grimes, H. Leighton] Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol, Cincinnati, OH 45229 USA. [Schuette, Judith; Goettgens, Bertie] Univ Cambridge, Cambridge Inst Med Res, Cambridge CB2 0XY, England. [Schuette, Judith; Goettgens, Bertie] Univ Cambridge, Wellcome Trust, Cambridge Stem Cell Inst, MRC, Cambridge CB2 0XY, England. [Krongold, Joseph; Moeroey, Tarik] McGill Univ, Div Expt Med, Montreal, PQ H3A 1A3, Canada. [Zhu, Jinfang; Paul, William E.] NIAID, Immunol Lab, NIH, Bethesda, MD 20829 USA. RP Grimes, HL (reprint author), Cincinnati Childrens Hosp Med Ctr, Div Cellular & Mol Immunol, Cincinnati, OH 45229 USA. EM lee.grimes@cchmc.org; tarik.moroy@ircm.qc.ca RI Zhu, Jinfang/B-7574-2012; OI Krongold, Joseph/0000-0001-9100-7459; Gaudreau, Marie-Claude/0000-0003-2833-7951; Gottgens, Berthold/0000-0001-6302-5705; Grimes, H. Leighton/0000-0001-8162-6758 FU Cole Foundation; University Clinic of Essen; Max-Eder fellowship from the German Cancer fund; University of Cincinnati Cancer Therapeutics T32 training grant [T32-CA117846]; Leukaemia and Lymphoma Research UK; CancerFree Kids; Division of Intramural Research, National Institute of Allergy and Infectious Diseases; Leukemia and Lymphoma Society of America; NIH [CA105152, CA159845]; Center of Excellence in Molecular Hematology [DK090971]; Canada Research Chair (Tier 1); Canadian Institutes of Health Research (CIHR) [MOP-84238, MOP-111011] FX We thank David Hildeman, Anil Jegga, Patrick Zweidler-McKay, Michelle Kelliher, Tom Look, and Paul Jolicouer for expertise and for kindly providing plasmids, cell lines, reagents, and mice. C.K. was supported by a fellowship of the Cole Foundation, the IFZ fellowship of the University Clinic of Essen, and a Max-Eder fellowship from the German Cancer fund. J.D.P. is a Pelotonia Fellow and was supported by the University of Cincinnati Cancer Therapeutics T32 training grant (T32-CA117846). J.S. was supported by a Gordon Piller PhD studentship from Leukaemia and Lymphoma Research UK, S.R.H. by a fellowship from CancerFree Kids, and J.Z. and W.E.P. by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases. H.L.G. was supported by the Leukemia and Lymphoma Society of America, NIH CA105152, CA159845, Alex's Lemonade Stand, and thanks the Center of Excellence in Molecular Hematology P30 award (DK090971). T.M. was supported by a Canada Research Chair (Tier 1) and grants from the Canadian Institutes of Health Research (CIHR, MOP-84238, MOP-111011). C.K. and J.D.P. designed and performed experiments, analyzed data, and wrote the manuscript. M.-C.G., L.V., J.S., R.C., S.R.H., J.K., and B.G. performed experiments and assisted analyses. J.Z. and W.E.P. provided the Gfi1f/f mouse strain. U.D. provided funding and oversaw research. H.L.G. and T.M. were responsible for concept and design of experiments, oversaw research, wrote the manuscript, and provided funding. NR 48 TC 23 Z9 24 U1 1 U2 16 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD FEB 11 PY 2013 VL 23 IS 2 BP 200 EP 214 DI 10.1016/j.ccr.2013.01.011 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 091RO UT WOS:000315067700010 PM 23410974 ER PT J AU Sourbier, C Scroggins, BT Ratnayake, R Prince, TL Lee, S Lee, MJ Nagy, PL Lee, YH Trepel, JB Beutler, JA Linehan, WM Neckers, L AF Sourbier, Carole Scroggins, Bradley T. Ratnayake, Ranjala Prince, Thomas L. Lee, Sunmin Lee, Min-Jung Nagy, Peter Literati Lee, Young H. Trepel, Jane B. Beutler, John A. Linehan, W. Marston Neckers, Len TI Englerin A Stimulates PKC theta to Inhibit Insulin Signaling and to Simultaneously Activate HSF1: Pharmacologically Induced Synthetic Lethality SO CANCER CELL LA English DT Article ID PROTEIN-KINASE-C; TRANSCRIPTION FACTOR HSF1; HEAT-SHOCK FACTOR-1; CELL-LINE; HSP90 COMPLEX; CANCER; RESISTANCE; MODEL; PATHWAY; KIDNEY AB The natural product englerin A (EA) binds to and activates protein kinase C-theta (PKC theta). EA-dependent activation of PKC theta induces an insulin-resistant phenotype, limiting the access of tumor cells to glucose. At the same time, EA causes PKC theta-mediated phosphorylation and activation of the transcription factor heat shock factor 1, an inducer of glucose dependence. By promoting glucose addiction, while simultaneously starving cells of glucose, EA proves to be synthetically lethal to highly glycolytic tumors. C1 [Sourbier, Carole; Scroggins, Bradley T.; Prince, Thomas L.; Lee, Min-Jung; Linehan, W. Marston; Neckers, Len] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lee, Sunmin; Lee, Min-Jung; Trepel, Jane B.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ratnayake, Ranjala; Beutler, John A.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Nagy, Peter Literati] N Gene Res Labs Inc, H-1137 Budapest, Hungary. RP Neckers, L (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM neckersl@mail.nih.gov RI Beutler, John/B-1141-2009 OI Beutler, John/0000-0002-4646-1924 FU Intramural Research Program of the National Cancer Institute FX We thank Drs. S. Calderwood (Harvard University, Cambridge, MA) and L. Whitesell (Whitehead Institute, Cambridge, MA) for generously providing reagents. We thank Dr. P.L. Nagy (N-Gene Research Laboratories, Budapest, Hungary) for generously providing BGP-15. We thank Drs. N. Kedei and P. Blumberg (National Cancer Institute, Bethesda, MD) and P. Csermely (Semmelweis University, Budapest, Hungary) for helpful discussions. This research was supported with funds provided by the Intramural Research Program of the National Cancer Institute. NR 41 TC 28 Z9 28 U1 2 U2 28 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD FEB 11 PY 2013 VL 23 IS 2 BP 228 EP 237 DI 10.1016/j.ccr.2012.12.007 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 091RO UT WOS:000315067700012 PM 23352416 ER PT J AU Menon, MP Hutchinson, L Garver, J Jaffe, ES Woda, BA AF Menon, Madhu P. Hutchinson, Lloyd Garver, Joanne Jaffe, Elaine S. Woda, Bruce A. TI Transformation of Follicular Lymphoma to Epstein-Barr Virus-Related Hodgkin-Like Lymphoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; STERNBERG-LIKE CELLS; CENTER B-CELL; CD30 EXPRESSION; DISEASE; ANTIGEN; TISSUE C1 [Menon, Madhu P.; Jaffe, Elaine S.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hutchinson, Lloyd; Garver, Joanne; Woda, Bruce A.] Univ Massachusetts, Sch Med, Mem Med Ctr, Worcester, MA USA. RP Menon, MP (reprint author), NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. OI Jaffe, Elaine/0000-0003-4632-0301 NR 26 TC 5 Z9 5 U1 0 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2013 VL 31 IS 5 BP E53 EP E56 DI 10.1200/JCO.2012.43.2377 PG 4 WC Oncology SC Oncology GA 088FY UT WOS:000314820400001 PM 23295788 ER PT J AU Szarama, KB Gavara, N Petralia, RS Chadwick, RS Kelley, MW AF Szarama, Katherine B. Gavara, Nuria Petralia, Ronald S. Chadwick, Richard S. Kelley, Matthew W. TI Thyroid hormone increases fibroblast growth factor receptor expression and disrupts cell mechanics in the developing organ of corti SO BMC DEVELOPMENTAL BIOLOGY LA English DT Article DE Young's modulus; Hair cell; Pillar cell; Hypothyroid; Cell mechanics ID AUDITORY SENSORY EPITHELIUM; ATOMIC-FORCE MICROSCOPY; DEVELOPING INNER-EAR; ACTIN POLYMERIZATION; MOUSE COCHLEA; RAT COCHLEA; IN-VITRO; F-ACTIN; TRANSCRIPTIONAL REGULATION; MICROTUBULE STABILITY AB Background: Thyroid hormones regulate growth and development. However, the molecular mechanisms by which thyroid hormone regulates cell structural development are not fully understood. The mammalian cochlea is an intriguing system to examine these mechanisms, as cellular structure plays a key role in tissue development, and thyroid hormone is required for the maturation of the cochlea in the first postnatal week. Results: In hypothyroid conditions, we found disruptions in sensory outer hair cell morphology and fewer microtubules in non-sensory supporting pillar cells. To test the functional consequences of these cytoskeletal defects on cell mechanics, we combined atomic force microscopy with live cell imaging. Hypothyroidism stiffened outer hair cells and supporting pillar cells, but pillar cells ultimately showed reduced cell stiffness, in part from a lack of microtubules. Analyses of changes in transcription and protein phosphorylation suggest that hypothyroidism prolonged expression of fibroblast growth factor receptors, and decreased phosphorylated Cofilin. Conclusions: These findings demonstrate that thyroid hormones may be involved in coordinating the processes that regulate cytoskeletal dynamics and suggest that manipulating thyroid hormone sensitivity might provide insight into the relationship between cytoskeletal formation and developing cell mechanical properties. C1 [Szarama, Katherine B.; Kelley, Matthew W.] NIDCD, Sect Dev Neurosci, Lab Cochlear Dev, NIH, Bethesda, MD USA. [Szarama, Katherine B.; Gavara, Nuria; Chadwick, Richard S.] NIDCD, Sect Auditory Mech, Lab Cellular Biol, NIH, Bethesda, MD USA. [Szarama, Katherine B.] Karolinska Inst, Ctr Hearing & Commun Res, Stockholm, Sweden. [Szarama, Katherine B.] Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden. [Petralia, Ronald S.] NIDCD, Adv Imaging Core, NIH, Bethesda, MD USA. RP Szarama, KB (reprint author), St Jude Childrens Res Hosp, Dept Biochem, Lab Joseph Opferman, 262 Danny Thomas Pl, Memphis, TN 38105 USA. EM Katherine.Szarama@stjude.org FU National Institute on Deafness and Other Communication Disorders (NIDCD) [DC000059, DC00003333]; NIH FX We thank Ya-Xian Wang for help with tissue preparation for TEM, and S. Raft, D.S. Sharlin, and A. Fridberger for comments on earlier versions of this manuscript. This research was supported by the National Institute on Deafness and Other Communication Disorders (NIDCD) Intramural Research Program [DC000059 to M.W.K., DC00003333 to R.S.C.] and in part with an Intramural Fellowship to Promote Diversity, from the NIH Office of the Director to K.B.S. NR 103 TC 4 Z9 4 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-213X J9 BMC DEV BIOL JI BMC Dev. Biol. PD FEB 9 PY 2013 VL 13 AR 6 DI 10.1186/1471-213X-13-6 PG 18 WC Developmental Biology SC Developmental Biology GA 101KJ UT WOS:000315773600001 PM 23394545 ER PT J AU Tana, MM Hoofnagle, JH AF Tana, Michele M. Hoofnagle, Jay H. TI Scar undone: long-term therapy of hepatitis B SO LANCET LA English DT Editorial Material ID INTERFERON-ALPHA THERAPY; LAMIVUDINE; IMPROVEMENT; ENTECAVIR; ADEFOVIR C1 [Tana, Michele M.; Hoofnagle, Jay H.] NIDDKD, Liver Dis Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Hoofnagle, JH (reprint author), NIDDKD, Liver Dis Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. EM hoofnaglej@extra.niddk.nih.gov NR 16 TC 3 Z9 3 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD FEB 9 PY 2013 VL 381 IS 9865 BP 433 EP 434 DI 10.1016/S0140-6736(12)61721-8 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 088CH UT WOS:000314810900010 PM 23234726 ER PT J AU Pyo, CW Wang, RH Vu, QY Cereb, N Yang, SY Duh, FM Wolinsky, S Martin, MP Carrington, M Geraghty, DE AF Pyo, Chul-Woo Wang, Ruihan Vu, Quyen Cereb, Nezih Yang, Soo Young Duh, Fuh-Mei Wolinsky, Steven Martin, Maureen P. Carrington, Mary Geraghty, Daniel E. TI Recombinant structures expand and contract inter and intragenic diversification at the KIR locus SO BMC GENOMICS LA English DT Article DE Natural killer cells; Human; KIR; Recombinant structures ID IMMUNOGLOBULIN-LIKE RECEPTOR; KILLER-CELL RECEPTOR; CLASS-I MOLECULES; COPY NUMBER VARIATION; HLA-G; ALLELIC POLYMORPHISM; INHIBITORY RECEPTORS; ADAPTIVE IMMUNITY; VIRUS-INFECTION; HUMAN-DISEASE AB Background: The human KIR genes are arranged in at least six major gene-content haplotypes, all of which are combinations of four centromeric and two telomeric motifs. Several less frequent or minor haplotypes also exist, including insertions, deletions, and hybridization of KIR genes derived from the major haplotypes. These haplotype structures and their concomitant linkage disequilibrium among KIR genes suggest that more meaningful correlative data from studies of KIR genetics and complex disease may be achieved by measuring haplotypes of the KIR region in total. Results: Towards that end, we developed a KIR haplotyping method that reports unambiguous combinations of KIR gene-content haplotypes, including both phase and copy number for each KIR. A total of 37 different gene content haplotypes were detected from 4,512 individuals and new sequence data was derived from haplotypes where the detailed structure was not previously available. Conclusions: These new structures suggest a number of specific recombinant events during the course of KIR evolution, and add to an expanding diversity of potential new KIR haplotypes derived from gene duplication, deletion, and hybridization. C1 [Pyo, Chul-Woo; Wang, Ruihan; Vu, Quyen; Geraghty, Daniel E.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Cereb, Nezih; Yang, Soo Young] Histogenetics LLC, Ossining, NY USA. [Duh, Fuh-Mei; Martin, Maureen P.; Carrington, Mary] Frederick Natl Lab Canc Res, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD USA. [Martin, Maureen P.] Northwestern Univ, Feinberg Sch Med, Div Infect Dis, Chicago, IL 60611 USA. RP Geraghty, DE (reprint author), Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. EM geraghty@fhcrc.org OI Wolinsky, Steven/0000-0002-9625-6697 FU National Institutes of Health [RR018669] FX This work was supported by the National Institutes of Health [RR018669 to D.E.G.]. The expert contributions of Dr. Shu Shen in the preparation of the manuscript are gratefully acknowledged. We thank the organizers of the UCLA International Cell Exchange for the KIR reference panel (www.hla.ucla.edu/cellDna.htm). NR 61 TC 19 Z9 19 U1 0 U2 8 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 FEB 8 PY 2013 VL 14 AR 89 DI 10.1186/1471-2164-14-89 PG 17 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 110VV UT WOS:000316476200001 PM 23394822 ER PT J AU Pan, HQ Ardini, MA Bakalov, V DeLatte, M Eggers, P Ganapathi, L Hollingsworth, CR Levy, J Li, SP Pratt, J Pugh, N Qin, Y Rasooly, R Ray, H Richardson, JE Riley, AF Rogers, SM Tan, S Turner, CF White, S Cooley, PC AF Pan, Huaqin Ardini, Mary-Anne Bakalov, Vesselina DeLatte, Michael Eggers, Paul Ganapathi, Laxminarayana Hollingsworth, Craig R. Levy, Joshua Li, Sheping Pratt, Joseph Pugh, Norma Qin, Ying Rasooly, Rebekah Ray, Helen Richardson, Jean E. Riley, Amanda Flynn Rogers, Susan M. Tan, Sylvia Turner, Charles F. White, Stacie Cooley, Philip C. TI 'What's in the NIDDK CDR?'-public query tools for the NIDDK central data repository SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION LA English DT Article AB The National Institute of Diabetes and Digestive Disease (NIDDK) Central Data Repository (CDR) is a web-enabled resource available to researchers and the general public. The CDR warehouses clinical data and study documentation from NIDDK funded research, including such landmark studies as The Diabetes Control and Complications Trial (DCCT, 1983-93) and the Epidemiology of Diabetes Interventions and Complications (EDIC, 1994-present) follow-up study which has been ongoing for more than 20 years. The CDR also houses data from over 7 million biospecimens representing 2 million subjects. To help users explore the vast amount of data stored in the NIDDK CDR, we developed a suite of search mechanisms called the public query tools (PQTs). Five individual tools are available to search data from multiple perspectives: study search, basic search, ontology search, variable summary and sample by condition. PQT enables users to search for information across studies. Users can search for data such as number of subjects, types of biospecimens and disease outcome variables without prior knowledge of the individual studies. This suite of tools will increase the use and maximize the value of the NIDDK data and biospecimen repositories as important resources for the research community. Database URL:https://www.niddkrepository.org/niddk/home.do C1 [Pan, Huaqin; Ardini, Mary-Anne; Bakalov, Vesselina; DeLatte, Michael; Ganapathi, Laxminarayana; Hollingsworth, Craig R.; Levy, Joshua; Li, Sheping; Pratt, Joseph; Pugh, Norma; Qin, Ying; Ray, Helen; Richardson, Jean E.; Riley, Amanda Flynn; Rogers, Susan M.; Tan, Sylvia; Turner, Charles F.; White, Stacie; Cooley, Philip C.] RTI Int Social Stat & Environm Sci, Res Triangle Pk, NC 27709 USA. [Eggers, Paul; Rasooly, Rebekah] NIDDK, Div Kidney Urol & Hematol Dis, Bethesda, MD 20892 USA. [Turner, Charles F.] CUNY Queens Coll, Flushing, NY 11367 USA. [Turner, Charles F.] CUNY Grad Ctr, Flushing, NY 11367 USA. RP Cooley, PC (reprint author), RTI Int Social Stat & Environm Sci, POB 12194, Res Triangle Pk, NC 27709 USA. EM pcc@rtii.org OI Qin, Ying/0000-0002-6099-2190; Rasooly, Rebekah/0000-0002-6357-5528 FU [HHSN267200800016C] FX National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health, NIH American Recovery and Reinvestment Act (ARRA) of 2009, Department of Health and Human Services, under Contracts (HHSN: 267200800015C, 267200800016C and 267200800018C). Funding for open access charge: HHSN267200800016C. NR 5 TC 2 Z9 2 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1758-0463 J9 DATABASE-OXFORD JI Database PD FEB 8 PY 2013 AR bas058 DI 10.1093/database/bas058 PG 11 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA 106XZ UT WOS:000316180000001 ER PT J AU Liu, ZG Yedidi, RS Wang, Y Dewdney, TG Reiter, SJ Brunzelle, JS Kovari, IA Kovari, LC AF Liu, Zhigang Yedidi, Ravikiran S. Wang, Yong Dewdney, Tamaria G. Reiter, Samuel J. Brunzelle, Joseph S. Kovari, Iulia A. Kovari, Ladislau C. TI Insights into the mechanism of drug resistance: X-ray structure analysis of multi-drug resistant HIV-1 protease ritonavir complex SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE HIV-1 protease; Multi-drug resistance; X-ray crystallography; IC50; Ritonavir ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE-SITE; INHIBITOR; REFINEMENT; MUTATIONS; VARIANTS; THERAPY; ABT-538; MODEL AB Ritonavir (RTV) is a first generation HIV-1 protease inhibitor with rapidly emerging drug resistance. Mutations at residues 46, 54, 82 and 84 render the HIV-1 protease drug resistant against RTV. We report the crystal structure of multi-drug resistant (MDR) 769 HIV-1 protease (carrying resistant mutations at residues 10, 36, 46, 54, 62, 63, 71, 82, 84 and 90) complexed with RTV and the in vitro enzymatic IC50 of RTV against MDR HIV-1 protease. The structural and functional studies demonstrate significant drug resistance of MDR HIV-1 protease against RTV, arising from reduced hydrogen bonds and Van der Waals interactions between RTV and MDR HIV-1 protease. (C) 2013 Published by Elsevier Inc. C1 [Liu, Zhigang; Yedidi, Ravikiran S.; Wang, Yong; Dewdney, Tamaria G.; Reiter, Samuel J.; Kovari, Iulia A.; Kovari, Ladislau C.] Wayne State Univ, Dept Biochem & Mol Biol, Sch Med, Detroit, MI 48201 USA. [Liu, Zhigang] Harbor Hosp Baltimore, Div Internal Med, Baltimore, MD 21225 USA. [Yedidi, Ravikiran S.] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. [Brunzelle, Joseph S.] Northwestern Univ, Feinberg Sch Med, Life Sci Collaborat Access Team, Chicago, IL 60611 USA. [Brunzelle, Joseph S.] Northwestern Univ, Feinberg Sch Med, Dept Mol Pharmacol & Biol Chem, Chicago, IL 60611 USA. RP Kovari, LC (reprint author), 540 E Canfield Ave,4263 Scott Hall, Detroit, MI 48201 USA. EM kovari@med.wayne.edu RI Liu, Zhigang/A-2003-2014; OI Yedidi, Ravikiran/0000-0003-2755-1307 FU National Institutes of Health [AI65294]; American Foundation for AIDS Research [106457-34-RGGN] FX This research was supported by the National Institutes of Health Grant AI65294 and a Grant from the American Foundation for AIDS Research (106457-34-RGGN). NR 26 TC 2 Z9 2 U1 0 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD FEB 8 PY 2013 VL 431 IS 2 BP 232 EP 238 DI 10.1016/j.bbrc.2012.12.127 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 095HM UT WOS:000315325300021 PM 23313846 ER PT J AU Hong, JJ Feng, HQ Zhou, Z Ghirlando, R Bai, YW AF Hong, Jingjun Feng, Hanqiao Zhou, Zheng Ghirlando, Rodolfo Bai, Yawen TI Identification of Functionally Conserved Regions in the Structure of the Chaperone/CenH3/H4 Complex SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE NMR; Cse4; CENP-A; centromere; histone ID CENTROMERE-SPECIFIC NUCLEOSOMES; E3 UBIQUITIN LIGASE; FISSION YEAST SCM3; HISTONE H3 VARIANT; CENP-A; ANALYTICAL ULTRACENTRIFUGATION; SEDIMENTATION-VELOCITY; BUDDING YEAST; HJURP; CHROMATIN AB In eukaryotes, a variant of conventional histone H3 termed CenH3 epigenetically marks the centromere. The conserved CenH3 chaperone specifically recognizes CenH3 and is required for CenH3 deposition at the centromere. Recently, the structures of the chaperone/CenH3/H4 complexes have been determined for Homo sapiens (Hs) and the budding yeasts Saccharomyces cerevisiae (Sc) and Kluyveromyces lactis (KI). Surprisingly, the three structures are very different, leading to different proposed structural bases for chaperone function. The question of which structural region of CenH3 provides the specificity determinant for the chaperone recognition is not fully answered. Here, we investigated these issues using solution NMR and site-directed mutagenesis. We discovered that, in contrast to previous findings, the structures of the KI and Sc chaperone/CenH3/H4 complexes are actually very similar. This new finding reveals that both budding yeast and human chaperones use a similar structural region to block DNA from binding to the histones. Our mutational analyses further indicate that the N-terminal region of the CenH3 alpha 2 helix is sufficient for specific recognition by the chaperone for both budding yeast and human. Thus, our studies have identified conserved structural bases of how the chaperones recognize CenH3 and perform the chaperone function. Published by Elsevier Ltd. C1 [Hong, Jingjun; Feng, Hanqiao; Bai, Yawen] NCI, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20892 USA. [Zhou, Zheng] Chinese Acad Sci, Natl Lab Biomacromol, Inst Biophys, Beijing 100101, Peoples R China. [Ghirlando, Rodolfo] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Bai, YW (reprint author), NCI, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20892 USA. EM yawen@helix.nih.gov OI 周, 政/0000-0002-1423-7231 FU National Cancer. Institute; National Institute of Diabetes and Digestive and Kidney Diseases FX We thank Mr. Shipeng Li for purification of proteins and Dr. Jemima Barrowman for editing the manuscript. This research was supported by the Intramural Research Programs of the National Cancer. Institute and the National Institute of Diabetes and Digestive and Kidney Diseases. NR 31 TC 6 Z9 6 U1 0 U2 9 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD FEB 8 PY 2013 VL 425 IS 3 BP 536 EP 545 DI 10.1016/j.jmb.2012.11.021 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 095BG UT WOS:000315308900008 PM 23178171 ER PT J AU Jiang, CT Kim, JH Li, F Qu, AJ Gavrilova, O Shah, YM Gonzalez, FJ AF Jiang, Changtao Kim, Jung-Hwan Li, Fei Qu, Aijuan Gavrilova, Oksana Shah, Yatrik M. Gonzalez, Frank J. TI Hypoxia-inducible Factor 1 alpha Regulates a SOCS3-STAT3-Adiponectin Signal Transduction Pathway in Adipocytes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INSULIN-RESISTANCE; ADIPOSE-TISSUE; GENE-EXPRESSION; DSBA-L; METABOLIC SYNDROME; OBESITY; ADIPONECTIN; MICE; SECRETION; CELLS AB Obesity has been identified as a major risk factor for type 2 diabetes, characterized by insulin resistance in insulin target tissues. Hypoxia-inducible factor 1 alpha (HIF1 alpha) regulates pathways in energy metabolism that become dysregulated in obesity. Earlier studies revealed that HIF1 alpha in adipose tissue is markedly elevated in high-fat diet-fed mice that are obese and insulin-resistant. Genetic ablation of HIF1 alpha in adipose tissue decreased insulin resistance and obesity, accompanied by increased serum adiponectin levels. However, the exact mechanism whereby HIF1 alpha regulates adiponectin remains unclear. Here, acriflavine (ACF), an inhibitor of HIF1 alpha, induced the expression of adiponectin and reduced the expression of SOCS3 in cultured 3T3-L1 adipocytes. Mechanistic studies revealed that HIF1 alpha suppressed the expression of adiponectin through a SOCS3-STAT3 pathway. Socs3 was identified as a novel HIF1 alpha target gene based on chromatin immunoprecipitation and luciferase assays. STAT3 directly regulated adiponectin in vitro in cultured 3T3-L1 adipocytes. ACF was found to prevent diet-induced obesity and insulin resistance. In vivo, ACF also regulated the SOCS3-STAT3-adiponectin pathway, and inhibition of HIF1 alpha in adipose tissue was essential for ACF to improve the SOCS3-STAT3-adiponectin pathway to counteract insulin resistance. This study provides evidence for a novel target gene and signal transduction pathway in adipocytes and indicates that inhibitors of HIF1 alpha have potential utility for the treatment of obesity and type 2 diabetes. C1 [Jiang, Changtao; Kim, Jung-Hwan; Li, Fei; Qu, Aijuan; Shah, Yatrik M.; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. [Gavrilova, Oksana] NIDDK, Mouse Metab Core Lab, NIH, Bethesda, MD 20892 USA. [Shah, Yatrik M.] Univ Michigan, Div Gastroenterol, Sch Med, Dept Mol & Integrat Physiol & Internal Med, Ann Arbor, MI 48109 USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. EM gonzalef@mail.nih.gov RI Li, Fei/F-6849-2013 FU NCI; NIDDK; National Institutes of Health [CA148828] FX This work was supported, in whole or in part, by the NCI and NIDDK Intramural Research Programs and National Institutes of Health Grant CA148828 (to Y. M. S.). NR 52 TC 15 Z9 18 U1 0 U2 18 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 8 PY 2013 VL 288 IS 6 BP 3844 EP 3857 DI 10.1074/jbc.M112.426338 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 088OP UT WOS:000314845000016 PM 23255598 ER PT J AU Henderson, MJ Richie, CT Airavaara, M Wang, Y Harvey, BK AF Henderson, Mark J. Richie, Christopher T. Airavaara, Mikko Wang, Yun Harvey, Brandon K. TI Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) Secretion and Cell Surface Binding Are Modulated by KDEL Receptors SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RETICULUM STRESS-RESPONSE; ISCHEMIC BRAIN-INJURY; DOPAMINERGIC-NEURONS; BREFELDIN-A; IN-VITRO; PROTEIN; EXPRESSION; ER; HEART; GOLGI AB Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) stress-responsive protein with neuroprotective effects in animal models of neuro-degeneration, but the underlying mechanism is not understood. We constructed a set of lentiviral vectors that contain or lack the highly conserved final four amino acids of MANF ("RTDL"), which resemble the canonical ER retention signal ("KDEL"), to study MANF regulation in neuroblastoma cells and rat primary cortical neurons. The RTDL sequence was required for both ER retention and secretory response to ER stress. Overexpression of KDEL receptor paralogs (KDELRs) differentially reduced MANF secretion but had no effect on MANF lacking RTDL. MANF binding to the plasma membrane also required the RTDL sequence and was inhibited with a peptide known to interact with KDELRs, suggesting MANF binds KDELRs at the surface. We detected surface localization of FLAG-tagged KDELRs, with levels increasing following ER stress. Our study provides new insight into the regulation of MANF trafficking and has implications for other secreted proteins containing a KDEL-like retention signal. C1 [Henderson, Mark J.; Richie, Christopher T.; Airavaara, Mikko; Wang, Yun; Harvey, Brandon K.] NIDA, Intramural Res Program, Baltimore, MD 21224 USA. [Airavaara, Mikko] Univ Helsinki, Inst Biotechnol, Helsinki 00014, Finland. [Wang, Yun] Natl Hlth Res Inst, Ctr Neuropsychiat Res, Zhunan, Taiwan. RP Harvey, BK (reprint author), NIDA, Intramural Res Program, Ste 200,Rm 06A729,251 Bayview Blvd, Baltimore, MD 21224 USA. EM BHarvey@intra.nida.nih.gov OI Airavaara, Mikko/0000-0002-2026-1609 FU National Institutes of Health Intramural Research Program, National Institute on Drug Abuse FX This work was supported, in whole or in part, by National Institutes of Health Intramural Research Program, National Institute on Drug Abuse. NR 40 TC 23 Z9 23 U1 1 U2 23 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 8 PY 2013 VL 288 IS 6 BP 4209 EP 4225 DI 10.1074/jbc.M112.400648 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 088OP UT WOS:000314845000048 PM 23255601 ER PT J AU Mollan, TL Banerjee, S Wu, G Siburt, CJP Tsai, AL Olson, JS Weiss, MJ Crumbliss, AL Alayash, AI AF Mollan, Todd L. Banerjee, Sambuddha Wu, Gang Siburt, Claire J. Parker Tsai, Ah-Lim Olson, John S. Weiss, Mitchell J. Crumbliss, Alvin L. Alayash, Abdu I. TI alpha-Hemoglobin Stabilizing Protein (AHSP) Markedly Decreases the Redox Potential and Reactivity of alpha-Subunits of Human HbA with Hydrogen Peroxide SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BETA-THALASSEMIA; IN-VIVO; MOLECULAR-MECHANISM; HUMAN OXYHEMOGLOBIN; GLOBIN BINDING; GUINEA-PIGS; CHAINS; OXIDATION; HEME; MYOGLOBIN AB alpha-Hemoglobin stabilizing protein (AHSP) is a molecular chaperone that binds monomeric alpha-subunits of human hemoglobin A (HbA) and modulates heme iron oxidation and subunit folding states. Although AHSP center dot alpha Hb complexes autoxidize more rapidly than HbA, the redox mechanisms appear to be similar. Both metHbA and isolated met-beta-subunits undergo further oxidation in the presence of hydrogen peroxide (H2O2) to form ferryl heme species. Surprisingly, much lower levels of H2O2-induced ferryl heme are produced by free met-alpha-subunits as compared with met-beta-subunits, and no ferryl heme is detected in H2O2-treated AHSP center dot met-alpha-complex at pH values from 5.0 to 9.0 at 23 degrees C. Ferryl heme species were similarly not detected in AHSP center dot met-alpha Pro-30 mutants known to exhibit different rates of autoxidation and hemin loss. EPR data suggest that protein-based radicals associated with the ferryl oxidation state exist within HbA alpha- and beta-subunits. In contrast, treatment of free alpha-subunits with H2O2 yields much smaller radical signals, and no radicals are detected when H2O2 is added to AHSP center dot alpha-complexes. AHSP binding also dramatically reduces the redox potential of alpha-subunits, from +40 to -78 mV in 1 M glycine buffer, pH 6.0, at 8 degrees C, demonstrating independently that AHSP has a much higher affinity for Fe(III) versus Fe(II) alpha-subunits. Hexacoordination in the AHSP center dot met-alpha complex markedly decreases the rate of the initial H2O2 reaction with iron and thus provides alpha-subunits protection against damaging oxidative reactions. C1 [Mollan, Todd L.; Alayash, Abdu I.] US FDA, Lab Biochem & Vasc Biol, Div Hematol, Ctr Biol Evaluat & Res, Bethesda, MD 20852 USA. [Banerjee, Sambuddha; Siburt, Claire J. Parker; Crumbliss, Alvin L.] Duke Univ, Dept Chem, Durham, NC 27708 USA. [Wu, Gang; Tsai, Ah-Lim] Univ Texas Houston, Sch Med, Dept Internal Med, Div Hematol, Houston, TX 77030 USA. [Olson, John S.] Rice Univ, Dept Biochem & Cell Biol, Houston, TX 77251 USA. [Weiss, Mitchell J.] Univ Penn, Cell & Mol Biol Grp, Philadelphia, PA 19104 USA. RP Alayash, AI (reprint author), US FDA, CBER, NIH, 8800 Rockville Pike,Bldg 29,Rm 112, Bethesda, MD 20852 USA. EM abdu.alayash@fda.hhs.gov FU National Institutes of Health [HL110900, HL095821, HL47020, GM35649, DK61692, HL087427, GM008362]; Welch Grant [C-0612]; National Science Foundation [CHE 0809466]; United States Food and Drug Administration [MODSCI 2011]; Duke University FX This work was supported, in whole or in part, by National Institutes of Health Grants HL110900 (to A. I. A.), HL095821 (to A.-L. T.), HL47020 (to J. S. O.), HL110900 (to J. S. O.), GM35649 (to J. S. O.), DK61692 (to M. J. W.), HL087427 (to M. J. W.), and GM008362 (to T. L. M.), Welch Grant C-0612 (to J. S. O.), National Science Foundation Grant CHE 0809466 (to A. L. C.), and the United States Food and Drug Administration (MODSCI 2011) (to A. I. A.).; Supported by a grant from Duke University. NR 58 TC 11 Z9 11 U1 0 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 8 PY 2013 VL 288 IS 6 BP 4288 EP 4298 DI 10.1074/jbc.M112.412064 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 088OP UT WOS:000314845000057 PM 23264625 ER PT J AU Amaral, J Lee, JW Chou, J Campos, MM Rodriguez, IR AF Amaral, Juan Lee, Jung Wha Chou, Joshua Campos, Maria M. Rodriguez, Ignacio R. TI 7-Ketocholesterol Induces Inflammation and Angiogenesis In Vivo: A Novel Rat Model SO PLOS ONE LA English DT Article ID EXPERIMENTAL CHOROIDAL NEOVASCULARIZATION; LOW-DENSITY-LIPOPROTEIN; MACULAR DEGENERATION; CELLS; OXYSTEROLS; VEGF; CHOLESTEROL; MACROPHAGES; OXIDATION; MEMBRANE AB Accumulation of 7-Ketocholesterol (7KCh) in lipid deposits has been implicated in a variety of chronic diseases including atherosclerosis, Alzheimer's disease and age-related macular degeneration. 7KCh is known to be pro-inflammatory and cytotoxic to various types of cultured cells but little is known about its effects in vivo. In this study we have investigated the effects of 7KCh in vivo by implanting biodegradable wafers into the anterior chamber of the rat eye. The wafers were prepared using a mixture of two biodegradable polymers with different amounts of 7KCh. The 7KCh-containing implants induced massive angiogenesis and inflammation. By contrast, no angiogenesis and very little inflammation were observed with cholesterol-containing implants. The neovessel growth was monitored by fluorescein angiography. Neovessels were observed 4 days post implantation and peaked between 7 to 10 days. The angiography and isolectin IB4 labeling demonstrated that the neovessels originated from the limbus and grew through the cornea. Immunolabeling with anti-CD68 suggested that the 7KCh-containing implants had extensive macrophage infiltration as well as other cell types. A significant increase in VEGF was also observed in 7KCh-containing implants by fluorescent immunolabeling and by immunoblot of the aqueous humor (AH). Direct measurement of VEGF, IL-1 beta and GRO/KC demonstrated a marked elevation of these factors in the AH of the 7KCh-implants. In summary this study demonstrates two important things: 1) 7KCh is pro-angiogenic and pro-inflammatory in vivo and 2) implants containing 7KCh may be used to create a novel angiogenesis model in rats. C1 [Amaral, Juan; Lee, Jung Wha; Chou, Joshua; Rodriguez, Ignacio R.] NEI, Mech Retinal Dis Sect, Lab Retinal Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Campos, Maria M.] NEI, Biol Imaging Core, NIH, Bethesda, MD 20892 USA. RP Rodriguez, IR (reprint author), NEI, Mech Retinal Dis Sect, Lab Retinal Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. EM rodriguezi@nei.nih.gov FU National Eye Institute FX National Eye Institute intramural research program (IRR). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 25 TC 16 Z9 16 U1 0 U2 9 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 FEB 8 PY 2013 VL 8 IS 2 AR e56099 DI 10.1371/journal.pone.0056099 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 086CJ UT WOS:000314660300058 PM 23409131 ER PT J AU Mukherjee, R Evans, P Singh, LN Hannenhalli, S AF Mukherjee, Rithun Evans, Perry Singh, Larry N. Hannenhalli, Sridhar TI Correlated Evolution of Positions within Mammalian cis Elements SO PLOS ONE LA English DT Article ID TRANSCRIPTION FACTOR-BINDING; COMPENSATORY EVOLUTION; MAXIMUM-LIKELIHOOD; RESPONSE ELEMENTS; DNA; SITES; SEQUENCE; GENE; CONSERVATION; SPECIFICITY AB Transcriptional regulation critically depends on proper interactions between transcription factors (TF) and their cognate DNA binding sites. The widely used model of TF-DNA binding - the Positional Weight Matrix (PWM) - presumes independence between positions within the binding site. However, there is evidence to show that the independence assumption may not always hold, and the extent of interposition dependence is not completely known. We hypothesize that the interposition dependence should partly be manifested as correlated evolution at the positions. We report a Maximum-Likelihood (ML) approach to infer correlated evolution at any two positions within a PWM, based on a multiple alignment of 5 mammalian genomes. Application to a genome-wide set of putative cis elements in human promoters reveals a prevalence of correlated evolution within cis elements. We found that the interdependence between two positions decreases with increasing distance between the positions. The interdependent positions tend to be evolutionarily more constrained and moreover, the dependence patterns are relatively similar across structurally related transcription factors. Although some of the detected mutational dependencies may be due to context-dependent genomic hyper-mutation, notably CG to TG, the majority is likely due to context-dependent preferences for specific nucleotide combinations within the cis elements. Patterns of evolution at individual nucleotide positions within mammalian TF binding sites are often significantly correlated, suggesting interposition dependence. The proposed methodology is also applicable to other classes of non-coding functional elements. A detailed investigation of mutational dependencies within specific motifs could reveal preferred nucleotide combinations that may help refine the DNA binding models. C1 [Mukherjee, Rithun] Fred Hutchinson Canc Res Ctr, Computat Biol Program, Seattle, WA 98104 USA. [Evans, Perry] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. [Singh, Larry N.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Hannenhalli, Sridhar] Univ Maryland, Dept Cell & Mol Biol, Ctr Bioinformat & Computat Biol, College Pk, MD 20742 USA. RP Mukherjee, R (reprint author), Fred Hutchinson Canc Res Ctr, Computat Biol Program, 1124 Columbia St, Seattle, WA 98104 USA. EM rmukherj@fhcrc.org; sridhar@umiacs.umd.edu FU NIH [GM085226] FX Source of funding: The work was supported by NIH GM085226 to SH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 2 Z9 2 U1 0 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 FEB 8 PY 2013 VL 8 IS 2 AR e55521 DI 10.1371/journal.pone.0055521 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 086CJ UT WOS:000314660300020 PM 23408994 ER PT J AU Di Virgilio, M Callen, E Yamane, A Zhang, WZ Jankovic, M Gitlin, AD Feldhahn, N Resch, W Oliveira, TY Chait, BT Nussenzweig, A Casellas, R Robbiani, DF Nussenzweig, MC AF Di Virgilio, Michela Callen, Elsa Yamane, Arito Zhang, Wenzhu Jankovic, Mila Gitlin, Alexander D. Feldhahn, Niklas Resch, Wolfgang Oliveira, Thiago Y. Chait, Brian T. Nussenzweig, Andre Casellas, Rafael Robbiani, Davide F. Nussenzweig, Michel C. TI Rif1 Prevents Resection of DNA Breaks and Promotes Immunoglobulin Class Switching SO SCIENCE LA English DT Article ID B-LYMPHOCYTES; END RESECTION; 53BP1; RECOMBINATION; REPLICATION; REPAIR; DAMAGE; AID; REGULATOR; TELOMERES AB DNA double-strand breaks (DSBs) represent a threat to the genome because they can lead to the loss of genetic information and chromosome rearrangements. The DNA repair protein p53 binding protein 1 (53BP1) protects the genome by limiting nucleolytic processing of DSBs by a mechanism that requires its phosphorylation, but whether 53BP1 does so directly is not known. Here, we identify Rap1-interacting factor 1 (Rif1) as an ATM (ataxia-telangiectasia mutated) phosphorylation-dependent interactor of 53BP1 and show that absence of Rif1 results in 5'-3' DNA-end resection in mice. Consistent with enhanced DNA resection, Rif1 deficiency impairs DNA repair in the G(1) and S phases of the cell cycle, interferes with class switch recombination in B lymphocytes, and leads to accumulation of chromosome DSBs. C1 [Di Virgilio, Michela; Jankovic, Mila; Gitlin, Alexander D.; Feldhahn, Niklas; Oliveira, Thiago Y.; Robbiani, Davide F.; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Nussenzweig, Michel C.] Rockefeller Univ, Howard Hughes Med Inst HHMI, New York, NY 10065 USA. [Callen, Elsa; Nussenzweig, Andre] NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. [Callen, Elsa; Nussenzweig, Andre] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Yamane, Arito; Resch, Wolfgang; Casellas, Rafael] NCI, Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, NIH, Bethesda, MD 20892 USA. [Zhang, Wenzhu; Chait, Brian T.] Rockefeller Univ, Lab Mass Spectrometry & Gaseous Ion Chem, New York, NY 10065 USA. [Oliveira, Thiago Y.] Univ Sao Paulo, Fac Med, Dept Genet, BR-14049 Ribeirao Preto, Brazil. [Oliveira, Thiago Y.] Natl Inst Sci & Technol Stem Cells & Cell Therapy, BR-14049 Ribeirao Preto, Brazil. RP Nussenzweig, MC (reprint author), Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. EM nussen@rockefeller.edu RI Yamane, Arito/A-2959-2013; OI Oliveira, Thiago/0000-0002-2654-0879 FU NIH [GM007739, AI037526, RR022220, RR00862, GM103314]; NIAMS at the NIH; NCI at the NIH; Center for Cancer Research FX We thank all members of the Nussenzweig laboratory for discussion, D. Bosque and T. Eisenreich for help in managing mouse colonies, A. Gazumyan for assistance with Igh germline and AID transcript levels analysis, and K. Yao for help with genotyping. We thank T. de Lange (The Rockefeller University, New York) for Rif1F/F mice; S. Buonomo (European Molecular Biology Laboratory Mouse Biology Unit, Monterotondo, Italy) for the anti-mouse Rif1 serum #1240; G. Gutierrez (NIAMS, NIH, Bethesda, MD) for Illumina sequencing; N. Zampieri (Columbia University, New York) for assistance with immunofluorescence image processing, and M. P. Rout, J. LaCava, S. Obado, and L. Hough (The Rockefeller University) for invaluable help, discussions, and protocols for cryolysis and magnetic bead-mediated immunoisolation. The data presented in the manuscript are tabulated in the main text and in the supplementary materials. Sequence data shown in Fig. 4 have been deposited in the Gene Expression Omnibus database (accession number GSE42298) at www.ncbi.nlm.nih.gov/geo/. M. D. V. was a Fellow of the American Italian Cancer Foundation, and A. D. G. was supported by NIH Medical Scientist Training Program grant GM007739. This work was supported in part by NIH grants AI037526 (M. C. N.), RR022220 (B. T. C.), RR00862 (B. T. C.), and GM103314 (B. T. C.); and by the intramural program of NIAMS at the NIH (R. C.); and the intramural research program of NCI at the NIH and Center for Cancer Research (A. N. and E. C.). M. C. N. is an HHMI Investigator. NR 26 TC 141 Z9 142 U1 0 U2 15 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD FEB 8 PY 2013 VL 339 IS 6120 BP 711 EP 715 DI 10.1126/science.1230624 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 085BM UT WOS:000314585600047 PM 23306439 ER PT J AU Hu, GQ Cui, KR Northrup, D Liu, CY Wang, CC Tang, QS Ge, K Levens, D Crane-Robinson, C Zhao, KJ AF Hu, Gangqing Cui, Kairong Northrup, Daniel Liu, Chengyu Wang, Chaochen Tang, Qingsong Ge, Kai Levens, David Crane-Robinson, Colyn Zhao, Keji TI H2A.Z Facilitates Access of Active and Repressive Complexes to Chromatin in Embryonic Stem Cell Self-Renewal and Differentiation SO CELL STEM CELL LA English DT Article ID HISTONE VARIANT H2A.Z; HUMAN GENOME; DNA METHYLATION; METHYLTRANSFERASE ACTIVITY; REGULATORY SEQUENCES; ES CELLS; ENHANCERS; ACETYLATION; PROMOTERS; GENES AB Chromatin modifications have been implicated in the self-renewal and differentiation of embryonic stem cells (ESCs). However, the function of histone variant H2A.Z in ESCs remains unclear. We show that H2A.Z is highly enriched at promoters and enhancers and is required for both efficient self-renewal and differentiation of murine ESCs. H2A.Z deposition leads to an abnormal nucleosome structure, decreased nucleosome occupancy, and increased chromatin accessibility. In self-renewing ESCs, knockdown of H2A.Z compromises OCT4 binding to its target genes and leads to decreased binding of MLL complexes to active genes and of PRC2 complex to repressed genes. During differentiation of ESCs, inhibition of H2A.Z also compromises RA-induced RAR alpha binding, activation of differentiation markers, and the repression of pluripotency genes. We propose that H2A.Z mediates such contrasting activities by acting as a general facilitator that generates access for a variety of complexes, both activating and repressive. C1 [Hu, Gangqing; Cui, Kairong; Northrup, Daniel; Tang, Qingsong; Zhao, Keji] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Liu, Chengyu] NHLBI, Transgen Mouse Facil, NIH, Bethesda, MD 20892 USA. [Wang, Chaochen; Ge, Kai] Natl Inst Diabet & Digest & Kidney Dis, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. [Levens, David] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Crane-Robinson, Colyn] Univ Portsmouth, Biophys Labs, Portsmouth PO1 2DT, Hants, England. RP Zhao, KJ (reprint author), NHLBI, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM zhaok@nhlbi.nih.gov RI HU, GANGQING/K-5849-2012; Levens, David/C-9216-2009; OI Levens, David/0000-0002-7616-922X; Ge, Kai/0000-0002-7442-5138 FU NHLBI, NIH FX We thank Zhibin Wang, Dustin E. Schones, Iouri Chepelev, Brian J. Abraham, Gang Wei, Daniel Kraushaar, and Benjamin Kidder for helpful discussions. The DNA Sequencing Core and the Flow Cytometry Core of the National Institute of Heart, Lung, and Blood Institute (NHLBI) assisted with this work. Support was provided by the Division of Intramural Research Program of the NHLBI, NIH. NR 52 TC 98 Z9 98 U1 2 U2 22 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD FEB 7 PY 2013 VL 12 IS 2 BP 180 EP 192 DI 10.1016/j.stem.2012.11.003 PG 13 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 287VB UT WOS:000329569300009 PM 23260488 ER PT J AU Pepin, KM Wang, J Webb, CT Hoeting, JA Poss, M Hudson, PJ Hong, WS Zhu, HC Guan, Y Riley, S AF Pepin, Kim M. Wang, Jia Webb, Colleen T. Hoeting, Jennifer A. Poss, Mary Hudson, Peter J. Hong, Wenshan Zhu, Huachen Guan, Yi Riley, Steven TI Anticipating the Prevalence of Avian Influenza Subtypes H9 and H5 in Live-Bird Markets SO PLOS ONE LA English DT Article ID TRANSMISSION CHARACTERISTICS; PANDEMIC PREPAREDNESS; MATHEMATICAL-MODELS; RELATIVE-HUMIDITY; MEASLES EPIDEMICS; HUMAN INFECTIONS; COUNT DATA; A VIRUS; DYNAMICS; TEMPERATURE AB An ability to forecast the prevalence of specific subtypes of avian influenza viruses (AIV) in live-bird markets would facilitate greatly the implementation of preventative measures designed to minimize poultry losses and human exposure. The minimum requirement for developing predictive quantitative tools is surveillance data of AIV prevalence sampled frequently over several years. Recently, a 4-year time series of monthly sampling of hemagglutinin subtypes 1-13 in ducks, chickens and quail in live-bird markets in southern China has become available. We used these data to investigate whether a simple statistical model, based solely on historical data (variables such as the number of positive samples in host X of subtype Y time t months ago), could accurately predict prevalence of H5 and H9 subtypes in chickens. We also examined the role of ducks and quail in predicting prevalence in chickens within the market setting because between-species transmission is thought to occur within markets but has not been measured. Our best statistical models performed remarkably well at predicting future prevalence (pseudo-R-2 = 0.57 for H9 and 0.49 for H5), especially considering the multi-host, multi-subtype nature of AIVs. We did not find prevalence of H5/H9 in ducks or quail to be predictors of prevalence in chickens within the Chinese markets. Our results suggest surveillance protocols that could enable more accurate and timely predictive statistical models. We also discuss which data should be collected to allow the development of mechanistic models. C1 [Pepin, Kim M.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Pepin, Kim M.; Webb, Colleen T.] Colorado State Univ, Dept Biol, Ft Collins, CO 80523 USA. [Wang, Jia; Hong, Wenshan; Zhu, Huachen; Guan, Yi] Shantou Univ, Coll Med, Int Inst Infect & Immun, Shantou, Peoples R China. [Wang, Jia; Zhu, Huachen; Guan, Yi; Riley, Steven] Univ Hong Kong, State Key Lab Emerging Infect Dis, Hong Kong, Hong Kong, Peoples R China. [Hoeting, Jennifer A.] Colorado State Univ, Dept Stat, Ft Collins, CO 80523 USA. [Poss, Mary; Hudson, Peter J.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Riley, Steven] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Infect Dis Epidemiol, London, England. RP Guan, Y (reprint author), Shantou Univ, Coll Med, Int Inst Infect & Immun, Shantou, Peoples R China. EM yguan@hkucc.hku.hk; s.riley@imperial.ac.uk RI Zhu, Huachen/A-8252-2017 OI Zhu, Huachen/0000-0003-2711-0501 FU RAPIDD program of the Science and Technology Directorate; U.S. Department of Homeland Security; Fogarty International Center, NIH; NIH Fogarty Center [R01 TW008246-01]; Wellcome Trust [093488/Z/10/Z]; Medical Research Council (UK) [MR/J008761/1]; European Union [278433-PREDEMICS] FX This work was supported by the RAPIDD program of the Science and Technology Directorate, U.S. Department of Homeland Security, and the Fogarty International Center, NIH. SR was also funded by: the NIH Fogarty Center (R01 TW008246-01), the Wellcome Trust (University Award 093488/Z/10/Z), The Medical Research Council (UK, Project Grant MR/J008761/1) and European Union Seventh Framework Programme (FP7/2007-2013, Grant Agreement no278433-PREDEMICS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 5 Z9 5 U1 0 U2 21 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 FEB 7 PY 2013 VL 8 IS 2 AR e56157 DI 10.1371/journal.pone.0056157 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 092XV UT WOS:000315157200118 PM 23409145 ER PT J AU Girirajan, S Dennis, MY Baker, C Malig, M Coe, BP Campbell, CD Mark, K Vu, TH Alkan, C Cheng, Z Biesecker, LG Bernier, R Eichler, EE AF Girirajan, Santhosh Dennis, Megan Y. Baker, Carl Malig, Maika Coe, Bradley P. Campbell, Catarina D. Mark, Kenneth Vu, Tiffany H. Alkan, Can Cheng, Ze Biesecker, Leslie G. Bernier, Raphael Eichler, Evan E. TI Refinement and Discovery of New Hotspots of Copy-Number Variation Associated with Autism Spectrum Disorder SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; DE-NOVO MUTATIONS; 17Q21.31 MICRODELETION SYNDROME; STRUCTURAL VARIATION; DIAGNOSTIC INTERVIEW; HUMAN-DISEASE; KANSL1 CAUSE; GENE; DUPLICATIONS; RESOURCE AB Rare copy-number variants (CNVs) have been implicated in autism and intellectual disability. These variants are large and affect many genes but lack clear specificity toward autism as opposed to developmental-delay phenotypes. We exploited the repeat architecture of the genome to target segmental duplication-mediated rearrangement hotspots (n = 120, median size 1.78 Mbp, range 240 kbp to 13 Mbp) and smaller hotspots flanked by repetitive sequence (n = 1,247, median size 79 kbp, range 3-96 kbp) in 2,588 autistic individuals from simplex and multiplex families and in 580 controls. Our analysis identified several recurrent large hotspot events, including association with 1q21 duplications, which are more likely to be identified in individuals with autism than in those with developmental delay (p = 0.01; OR = 2.7). Within larger hotspots, we also identified smaller atypical CNVs that implicated CHD1L and ACACA for the 1q21 and 17q12 deletions, respectively. Our analysis, however, suggested no overall increase in the burden of smaller hotspots in autistic individuals as compared to controls. By focusing on gene-disruptive events, we identified recurrent CNVs, including DPP10, PLCB1, TRPM1, NRXN1, FHIT, and HYDIN, that are enriched in autism. We found that as the size of deletions increases, nonverbal IQ significantly decreases, but there is no impact on autism severity; and as the size of duplications increases, autism severity significantly increases but nonverbal IQ is not affected. The absence of an increased burden of smaller CNVs in individuals with autism and the failure of most large hotspots to refine to single genes is consistent with a model where imbalance of multiple genes contributes to a disease state. C1 [Girirajan, Santhosh; Dennis, Megan Y.; Baker, Carl; Malig, Maika; Coe, Bradley P.; Campbell, Catarina D.; Mark, Kenneth; Vu, Tiffany H.; Alkan, Can; Cheng, Ze; Eichler, Evan E.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Biesecker, Leslie G.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Bernier, Raphael] Univ Washington, Dept Psychiat, Seattle, WA 98195 USA. [Eichler, Evan E.] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. RP Eichler, EE (reprint author), Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. EM eee@gs.washington.edu RI Alkan, Can/D-2982-2009; Coe, Bradley/A-2878-2009; OI Alkan, Can/0000-0002-5443-0706; Mark, Kenneth/0000-0003-1867-6212 FU US National Institutes of Health (NIH) Ruth L. Kirchstein National Research Service Award (NRSA) Fellowship through Eunice Kennedy Shriver National Institute of Child Health and Human Development [F32HD071698]; NIH National Human Genome Research Institute NRSA [F32HG006070]; Simons Foundation Autism Research Initiative award SFARI [137578]; NIH [HD065285] FX We thank Tonia Brown, Emre Karakoc, Nik Krumm, Arthur Ko, Daryl Dhanraj, Jason Lu, John Huddleston, and Ben Nelson for valuable discussions and technical assistance. We also thank the Autism Genetic Resource Exchange (AGRE) for providing DNA samples. We are grateful to all of the families at the participating Simons Simplex Collection (SSC) sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren, and E. Wijsman). We appreciate obtaining access to phenotypic data on SFARI Base. Approved researchers can obtain the SSC population dataset described in this study by applying at Simons Simplex Collection online (see Web Resources). M.Y.D. is supported by a US National Institutes of Health (NIH) Ruth L. Kirchstein National Research Service Award (NRSA) Fellowship through Eunice Kennedy Shriver National Institute of Child Health and Human Development (F32HD071698). C.D.C. was supported by NIH National Human Genome Research Institute NRSA (F32HG006070). This work was supported by Simons Foundation Autism Research Initiative award SFARI 137578 (E.E.E.) and NIH grant HD065285 (E.E.E.). E.E.E. is an investigator with the Howard Hughes Medical Institute. NR 59 TC 98 Z9 101 U1 3 U2 34 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD FEB 7 PY 2013 VL 92 IS 2 BP 221 EP 237 DI 10.1016/j.ajhg.2012.12.016 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA 093GL UT WOS:000315179600006 PM 23375656 ER PT J AU Hammer, MB Eleuch-Fayache, G Schottlaender, LV Nehdi, H Gibbs, JR Arepalli, SK Chong, SB Hernandez, DG Sailer, A Liu, GX Mistry, PK Cai, HB Shrader, G Sassi, C Bouhlal, Y Houlden, H Hentati, F Amouri, R Singleton, AB AF Hammer, Monia B. Eleuch-Fayache, Ghada Schottlaender, Lucia V. Nehdi, Houda Gibbs, J. Raphael Arepalli, Sampath K. Chong, Sean B. Hernandez, Dena G. Sailer, Anna Liu, Guoxiang Mistry, Pramod K. Cai, Huaibin Shrader, Ginamarie Sassi, Celeste Bouhlal, Yosr Houlden, Henry Hentati, Faycal Amouri, Rim Singleton, Andrew B. TI Mutations in GBA2 Cause Autosomal-Recessive Cerebellar Ataxia with Spasticity SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID ACID BETA-GLUCOSIDASE; NONLYSOSOMAL GLUCOSYLCERAMIDASE; BETA-GLUCOSIDASE-2; DISEASE; FEATURES AB Autosomal-recessive cerebellar ataxia (ARCA) comprises a large and heterogeneous group of neurodegenerative disorders with more than 20 different forms currently recognized, many of which are also associated with increased tone and some of which have limb spasticity. Gaucher disease is a lysosomal storage disease resulting from a defect in the enzyme acid beta-glucosidase 1. beta-glucosidase 2 is an enzyme with similar glucosylceramidase activity but to date has not been associated with a monogenic disorder. We studied four unrelated consanguineous families of Tunisian decent diagnosed with cerebellar ataxia of unknown origin. We performed homozygosity mapping and whole-exome sequencing in an attempt to identify the genetic origin of their disorder. We were able to identify mutations responsible for autosomal-recessive ataxia in these families within the gene encoding beta-glucosidase 2, GBA2. Two nonsense mutations (c.363C>A [p.Tyr121*] and c.1018C>T [p.Arg340*]) and a substitution (c.2618G>A [p.Arg873His]) were identified, probably resulting in nonfunctional enzyme. This study suggests GBA2 mutations are a cause of recessive spastic ataxia and responsible for a form of glucosylceramide storage disease in humans. C1 [Hammer, Monia B.; Gibbs, J. Raphael; Arepalli, Sampath K.; Chong, Sean B.; Hernandez, Dena G.; Liu, Guoxiang; Cai, Huaibin; Shrader, Ginamarie; Sassi, Celeste; Singleton, Andrew B.] NIA, Mol Genet Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Hammer, Monia B.; Eleuch-Fayache, Ghada; Nehdi, Houda; Hentati, Faycal; Amouri, Rim] Natl Inst Neurol, Dept Mol Neurobiol & Neuropathol, Tunis 1007, Tunisia. [Schottlaender, Lucia V.; Gibbs, J. Raphael; Hernandez, Dena G.; Sailer, Anna; Sassi, Celeste; Houlden, Henry] UCL Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. [Schottlaender, Lucia V.; Sailer, Anna; Houlden, Henry] UCL Inst Neurol, MRC Ctr Neuromuscular Dis, London WC1N 3BG, England. [Schottlaender, Lucia V.; Sailer, Anna; Houlden, Henry] Natl Hosp Neurol & Neurosurg, London WC1N 3BG, England. [Gibbs, J. Raphael; Hernandez, Dena G.; Sassi, Celeste] UCL Inst Neurol, Reta Lila Weston Labs, London WC1N 3BG, England. [Mistry, Pramod K.] Yale Univ, Dept Pediat & Med, Sch Med, Sect Pediat Gastroenterol & Hepatol, New Haven, CT 06520 USA. [Bouhlal, Yosr] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. RP Singleton, AB (reprint author), NIA, Mol Genet Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM singleta@mail.nih.gov RI Cai, Huaibin/H-3359-2013; Houlden, Henry/C-1532-2008; liu, guoxiang/I-8174-2013; Singleton, Andrew/C-3010-2009 OI Cai, Huaibin/0000-0002-8596-6108; Houlden, Henry/0000-0002-2866-7777; FU National Institute on Aging, National Institutes of Health, part of the Department of Health and Human Services [ZIA AG000958-09]; National Ataxia Foundation; Medical Research Council (MRC); Brain Research Trust; NORD; MRC/Wellcome Trust Parkinson's disease consortium; UCLH/UCL Department of Health's NIHR Biomedical Research Centres FX The authors thank J. Hammer for his contribution in the correction of the manuscript and his help with the figures. We also thank the affected individuals and their families for taking part in this work. This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, part of the Department of Health and Human Services (project number ZIA AG000958-09) and the National Ataxia Foundation. We are also grateful to the Medical Research Council (MRC), the Brain Research Trust, and NORD for funding to H.H., L.V.S., and A.S. and also the MRC/Wellcome Trust Parkinson's disease consortium grant and the UCLH/UCL Department of Health's NIHR Biomedical Research Centres funding scheme. NR 20 TC 44 Z9 45 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD FEB 7 PY 2013 VL 92 IS 2 BP 245 EP 251 DI 10.1016/j.ajhg.2012.12.012 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 093GL UT WOS:000315179600008 PM 23332917 ER PT J AU Lindsley, DL Roote, J Kennison, JA AF Lindsley, Dan L. Roote, John Kennison, James A. TI Anent the Genomics of Spermatogenesis in Drosophila melanogaster SO PLOS ONE LA English DT Article ID BIASED GENE-EXPRESSION; STERILE MUTATIONS; MALE-FERTILITY; X-CHROMOSOME; REGION; DEMASCULINIZATION; LETHAL AB An appreciable fraction of the Drosophila melanogaster genome is dedicated to male fertility. One approach to characterizing this subset of the genome is through the study of male-sterile mutations. We studied the relation between vital and male-fertility genes in three large autosomal regions that were saturated for lethal and male-sterile mutations. The majority of male-sterile mutations affect genes that are exclusively expressed in males. These genes are required only for male fertility, and several mutant alleles of each such gene were encountered. A few male-sterile mutations were alleles of vital genes that are expressed in both males and females. About one-fifth of the genes in Drosophila melanogaster show male-specific expression in adults. Although some earlier studies found a paucity of genes on the X chromosome showing male-biased expression, we did not find any significant differences between the X chromosome and the autosomes either in the relative frequencies of mutations to male sterility or in the frequencies of genes with male-specific expression in adults. Our results suggest that as much as 25% of the Drosophila genome may be dedicated to male fertility. C1 [Lindsley, Dan L.] Univ Calif San Diego, Dept Cell & Dev Biol, La Jolla, CA 92093 USA. [Roote, John] Univ Cambridge, Dept Genet, Cambridge CB2 3EH, England. [Kennison, James A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. RP Kennison, JA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. EM Jim_Kennison@nih.gov FU Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Department of Genetics, University of Cambridge FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the Department of Genetics, University of Cambridge. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 3 Z9 3 U1 0 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 FEB 7 PY 2013 VL 8 IS 2 AR e55915 DI 10.1371/journal.pone.0055915 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 092XV UT WOS:000315157200089 PM 23409089 ER PT J AU Shimizu, YK Hijikata, M Oshima, M Shimizu, K Alter, HJ Purcell, RH Yoshikura, H Hotta, H AF Shimizu, Yohko K. Hijikata, Minako Oshima, Masamichi Shimizu, Kazufumi Alter, Harvey J. Purcell, Robert H. Yoshikura, Hiroshi Hotta, Hak TI Isolation of Human Monoclonal Antibodies to the Envelope E2 Protein of Hepatitis C Virus and Their Characterization SO PLOS ONE LA English DT Article ID CELL-CULTURE SYSTEMS; NON-B HEPATITIS; NEUTRALIZING ANTIBODIES; NON-A; GLYCOPROTEIN; INFECTION; IDENTIFICATION; CHIMPANZEES; BINDING; ESCAPE AB We isolated and characterized two human monoclonal antibodies to the envelope E2 protein of hepatitis C virus (HCV). Lymphoblastoid cell lines stably producing antibodies were obtained by immortalizing peripheral blood mononuclear cells of a patient with chronic hepatitis C using Epstein-Barr virus. Screening for antibody-positive clones was carried out by immunofluorescence with Huh7 cells expressing the E2 protein of HCV strain H (genotype 1a) isolated from the same patient. Isotype of resulting antibodies, #37 and #55, was IgG1/kappa and IgG1/lambda, respectively. Epitope mapping revealed that #37 and #55 recognize conformational epitopes spanning amino acids 429 to 652 and 508 to 607, respectively. By immunofluorescence using virus-infected Huh7.5 cells as targets both antibodies were reactive with all of the nine different HCV genotypes/subtypes tested. The antibodies showed a different pattern of immuno-staining; while #37 gave granular reactions mostly located in the periphery of the nucleus, #55 gave diffuse staining throughout the cytoplasm. Both antibodies were shown by immuno-gold electron microscopy to bind to intact viral particles. In a neutralization assay (focus-forming unit reduction using chimeric infectious HCV containing structural proteins derived from genotypes 1a, 1b, 2a, 2b, 3a, 4a, 5a, 6a, and 7a), #55 inhibited the infection of all HCV genotypes tested but genotype 7a to a lesser extent. #37 did not neutralize any of these viruses. As a broadly cross-neutralizing human antibody, #55 may be useful for passive immunotherapy of HCV infection. C1 [Shimizu, Yohko K.; Hotta, Hak] Kobe Univ, Div Microbiol, Ctr Infect Dis, Grad Sch Med, Kobe, Hyogo 657, Japan. [Hijikata, Minako] Natl Ctr Global Hlth & Med, Dept Resp Dis, Res Inst, Tokyo, Japan. [Oshima, Masamichi] Natl Inst Infect Dis, Dept Immunol, Tokyo, Japan. [Shimizu, Kazufumi] Nihon Univ, Sch Med, Dept Gynecol, Tokyo, Japan. [Alter, Harvey J.] NIH, Dept Transfus Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Purcell, Robert H.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Yoshikura, Hiroshi] Minist Hlth Labor & Welf, Food Safety Div, Tokyo, Japan. RP Shimizu, YK (reprint author), Kobe Univ, Div Microbiol, Ctr Infect Dis, Grad Sch Med, Kobe, Hyogo 657, Japan. EM yshimizu@nih.go.jp FU Science and Technology Partnership for Sustainable Development (SATREPS) program of Japan; Science and Technology Agency (JST); Japan International Cooperation Agency (JICA); Intramural Research Program of the National Institute of Allergy and Infectious Diseases FX This work was supported, in part, by the Science and Technology Partnership for Sustainable Development (SATREPS) program of Japan Science and Technology Agency (JST) and Japan International Cooperation Agency (JICA) and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 1 Z9 1 U1 0 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 7 PY 2013 VL 8 IS 2 AR e55874 DI 10.1371/journal.pone.0055874 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 092XV UT WOS:000315157200082 PM 23409074 ER PT J AU Fulzele, K Krause, DS Panaroni, C Saini, V Barry, KJ Liu, XL Lotinun, S Baron, R Bonewald, L Feng, JQ Chen, M Weinstein, LS Wu, JY Kronenberg, HM Scadden, DT Pajevic, PD AF Fulzele, Keertik Krause, Daniela S. Panaroni, Cristina Saini, Vaibhav Barry, Kevin J. Liu, Xiaolong Lotinun, Sutada Baron, Roland Bonewald, Lynda Feng, Jian Q. Chen, Min Weinstein, Lee S. Wu, Joy Y. Kronenberg, Henry M. Scadden, David T. Pajevic, Paola Divieti TI Myelopoiesis is regulated by osteocytes through Gs alpha-dependent signaling SO BLOOD LA English DT Article ID STEM-CELL NICHE; HEMATOPOIETIC STEM; BONE-FORMATION; G-PROTEIN; PROGENITOR CELLS; RECEPTOR; OSTEOBLASTS; SCLEROSTIN; MARROW; DIFFERENTIATION AB Hematopoietic progenitors are regulated in their respective niches by cells of the bone marrow microenvironment. The bone marrow microenvironment is composed of a variety of cell types, and the relative contribution of each of these cells for hematopoietic lineage maintenance has remained largely unclear. Osteocytes, the most abundant yet least understood cells in bone, are thought to initiate adaptive bone remodeling responses via osteoblasts and osteoclasts. Here we report that these cells regulate hematopoiesis, constraining myelopoiesis through a Gs alpha-mediated mechanism that affects G-CSF production. Mice lacking Gs alpha in osteocytes showed a dramatic increase in myeloid cells in bone marrow, spleen, and peripheral blood. This hematopoietic phenomenon was neither intrinsic to the hematopoietic cells nor dependent on osteoblasts but was a consequence of an altered bone marrow microenvironment imposed by Gs alpha deficiency in osteocytes. Conditioned media from osteocyte-enriched bone explants significantly increased myeloid colony formation in vitro, which was blocked by G-CSF-neutralizing antibody, indicating a critical role of osteocyte-derived G-CSF in the myeloid expansion. (Blood. 2013;121(6):930-939) C1 [Fulzele, Keertik; Panaroni, Cristina; Saini, Vaibhav; Barry, Kevin J.; Liu, Xiaolong; Baron, Roland; Wu, Joy Y.; Kronenberg, Henry M.; Pajevic, Paola Divieti] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Endocrine Unit, Boston, MA USA. [Krause, Daniela S.; Scadden, David T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Regenerat Med, Boston, MA USA. [Lotinun, Sutada; Baron, Roland] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. [Bonewald, Lynda] Univ Missouri, Dept Oral Biol, Kansas City, MO 64110 USA. [Feng, Jian Q.] Baylor Coll Dent, Dept Biomed Sci, Texas A&M Hlth Sci Ctr, Dallas, TX 75246 USA. [Chen, Min; Weinstein, Lee S.] NIDDKD, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. RP Pajevic, PD (reprint author), Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St,Thier 1101, Boston, MA 02114 USA. EM divieti@helix.mgh.harvard.edu FU National Institutes of Health [AR060221, DK079161, K08CA138916]; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Harvard Stem Cell Institute FX This work was supported by the National Institutes of Health (grants AR060221 and DK079161, P. D. P.; grant K08CA138916, D. S. K.), the Intramural Research Program of National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (L. S. W.), and the Harvard Stem Cell Institute (J.Y.W.). NR 33 TC 46 Z9 46 U1 0 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 7 PY 2013 VL 121 IS 6 BP 930 EP 939 DI 10.1182/blood-2012-06-437160 PG 10 WC Hematology SC Hematology GA 088WO UT WOS:000314868800014 PM 23160461 ER PT J AU Genest, O Reidy, M Street, TO Hoskins, JR Camberg, JL Agard, DA Masison, DC Wickner, S AF Genest, Olivier Reidy, Michael Street, Timothy O. Hoskins, Joel R. Camberg, Jodi L. Agard, David A. Masison, Daniel C. Wickner, Sue TI Uncovering a Region of Heat Shock Protein 90 Important for Client Binding in E. coli and Chaperone Function in Yeast SO MOLECULAR CELL LA English DT Article ID CONFORMATIONAL DYNAMICS; MOLECULAR CHAPERONE; ATPASE ACTIVITY; SUBSTRATE-BINDING; TERMINAL DIMERIZATION; STRUCTURAL-ANALYSIS; CRYSTAL-STRUCTURE; STEROID-RECEPTOR; HSP90; DOMAIN AB The heat shock protein 90 (Hsp90) family of heat shock proteins is an abundantly expressed and highly conserved family of ATP-dependent molecular chaperones. Hsp90 facilitates remodeling and activation of hundreds of proteins. In this study, we developed a screen to identify Hsp90-defective mutants in E. coli. The mutations obtained define a region incorporating residues from the middle and C-terminal domains of E. coli Hsp90. The mutant proteins are defective in chaperone activity and client binding in vitro. We constructed homologous mutations in S. cerevisiae Hsp82 and identified several that caused defects in chaperone activity in vivo and in vitro. However, the Hsp82 mutant proteins were less severely defective in client binding to a model substrate than the corresponding E. coli mutant proteins. Our results identify a region in Hsp90 important for client binding in E. coli Hsp90 and suggest an evolutionary divergence in the mechanism of client interaction by bacterial and yeast Hsp90. C1 [Genest, Olivier; Hoskins, Joel R.; Camberg, Jodi L.; Wickner, Sue] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Reidy, Michael; Masison, Daniel C.] NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. [Street, Timothy O.; Agard, David A.] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA. [Agard, David A.] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94158 USA. RP Wickner, S (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM wickners@mail.nih.gov OI Reidy, Michael/0000-0002-9290-7595 FU Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research; National Institute of Diabetes and Digestive and Kidney Diseases; Howard Hughes Medical Institute FX We thank Jill Johnson (University of Idaho) for the Ste11 Delta N plasmid, Len Neckers (NCI) for yeast plasmids, and Shannon Doyle and Danielle Johnston for critical reading of the manuscript and helpful discussions. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, National Institute of Diabetes and Digestive and Kidney Diseases, and Howard Hughes Medical Institute. O.G., J.R.H., T.O.S., J.L.C., and M.R. designed experiments, performed experiments, interpreted data, and wrote the paper; S.W., D.A.A., and D.C.M. designed experiments, interpreted data, and wrote the paper. NR 46 TC 30 Z9 30 U1 1 U2 26 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD FEB 7 PY 2013 VL 49 IS 3 BP 464 EP 473 DI 10.1016/j.molcel.2012.11.017 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 087VO UT WOS:000314792500010 PM 23260660 ER PT J AU Zuo, W Huang, F Chiang, YJ Li, M Du, J Ding, Y Zhang, T Lee, HW Jeong, LS Chen, YL Deng, HT Feng, XH Luo, SW Gao, CJ Chen, YG AF Zuo, Wei Huang, Fei Chiang, Y. Jeffrey Li, Meng Du, Jun Ding, Yi Zhang, Ting Lee, Hyuk Woo Jeong, Lak Shin Chen, Yuling Deng, Haiteng Feng, Xin-Hua Luo, Shiwen Gao, Chunji Chen, Ye-Guang TI c-Cbl-Mediated Neddylation Antagonizes Ubiquitination and Degradation of the TGF-beta Type II Receptor SO MOLECULAR CELL LA English DT Article ID REGULATORY T-CELLS; HEMATOPOIETIC STEM-CELLS; GROWTH-FACTOR-BETA; MYELOID-LEUKEMIA; ENDOCYTIC REGULATION; TYROSINE KINASES; IN-VIVO; NEDD8; LIGASE; PROTEIN AB Transforming growth factor beta (TGF-beta) is a potent antiproliferative factor in multiple types of cells. Deregulation of TGF-beta signaling is associated with the development of many cancers, including leukemia, though the molecular mechanisms are largely unclear. Here, we show that Casitas B-lineage lymphoma (c-Cbl), a known proto-oncogene encoding an ubiquitin E3 ligase, promotes TGF-beta signaling by neddylating and stabilizing the type II receptor (T beta RII). Knockout of c-Cbl decreases the T beta RII protein level and desensitizes hematopoietic stem or progenitor cells to TGF-beta stimulation, while c-Cbl overexpression stabilizes T beta RII and sensitizes leukemia cells to TGF-beta. c-Cbl conjugates neural precursor cell-expressed, developmentally downregulated 8 (NEDD8), a ubiquitin-like protein, to T beta RII at Lys556 and Lys567. Neddylation of T beta RII promotes its endocytosis to EEA1-positive early endosomes while preventing its endocytosis to caveolin-positive compartments, therefore inhibiting T beta RII ubiquitination and degradation. We have also identified a neddylation-activity-defective c-Cbl mutation from leukemia patients, implying a link between aberrant T beta RII neddylation and leukemia development. C1 [Zuo, Wei; Huang, Fei; Du, Jun; Ding, Yi; Zhang, Ting; Chen, Ye-Guang] Tsinghua Univ, State Key Lab Biomembrane & Membrane Biotechnol, Tsinghua Peking Ctr Life Sci, Sch Life Sci, Beijing 100084, Peoples R China. [Chen, Yuling; Deng, Haiteng] Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China. [Chiang, Y. Jeffrey] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Li, Meng; Gao, Chunji] Chinese Peoples Liberat Army Gen Hosp, Ctr Hematol, Beijing 100853, Peoples R China. [Lee, Hyuk Woo; Jeong, Lak Shin] Ewha Womans Univ, Dept Bioinspired Sci, Seoul 120750, South Korea. [Feng, Xin-Hua] Zhejiang Univ, Inst Life Sci, Hangzhou 310058, Zhejiang, Peoples R China. [Luo, Shiwen] Nanchang Univ, Affiliated Hosp 1, Nanchang 330006, Jiangxi, Peoples R China. RP Chen, YG (reprint author), Tsinghua Univ, State Key Lab Biomembrane & Membrane Biotechnol, Tsinghua Peking Ctr Life Sci, Sch Life Sci, Beijing 100084, Peoples R China. EM ygchen@mail.tsinghua.edu.cn FU 973 Program [2010CB833706, 2011CB943803]; National Natural Science Foundation of China [30930050, 30921004]; Tsinghua University Initiative Scientific Research Program [2010THZ0]; Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute FX We thank Drs. Wallace Y. Langdon, Stanley Lipkowitz, and Xuetao Cao for c-Cbl and Cbl-b constructs, Drs. Qiang Wang and Chengcheng Jin for generating the anti-T beta RII (ECD) antibody, Dr. Jun Wen for technical assistance, and Drs. Hai Qi, Wei Guo and Li Yu for helpful suggestions. This work was supported by grants from the 973 Program (2010CB833706, 2011CB943803), the National Natural Science Foundation of China (30930050, 30921004), and the Tsinghua University Initiative Scientific Research Program (2010THZ0) to Y.G.C. This research was also supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute to Y.J.C. NR 48 TC 36 Z9 37 U1 2 U2 33 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD FEB 7 PY 2013 VL 49 IS 3 BP 499 EP 510 DI 10.1016/j.molcel.2012.12.002 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 087VO UT WOS:000314792500013 PM 23290524 ER PT J AU Arpitha, P Gao, CY Tripathi, BK Saravanamuthu, S Zelenka, P AF Arpitha, Parthasarathy Gao, Chun Y. Tripathi, Brajendra K. Saravanamuthu, Senthil Zelenka, Peggy TI Cyclin-dependent kinase 5 promotes the stability of corneal epithelial cell junctions SO MOLECULAR VISION LA English DT Article ID CANINE KIDNEY-CELLS; E-CADHERIN; P120 CATENIN; ACTIN CYTOSKELETON; ADHERENS JUNCTIONS; RHO ACTIVITY; ADHESION; CDK5; P120-CATENIN; ACTIVATION AB Purpose: Although cyclin-dependent kinase 5 (Cdk5) inhibits the formation of junctions containing N-cadherin, the effect of Cdk5 on junctions containing E-cadherin is less clear. The present study investigates the functional significance of Cdk5 in forming and maintaining cell-cell stability in corneal epithelial cells. Methods: A Cdk5-deficient human corneal limbal epithelial cell line was generated by lentiviral transduction of small hairpin RNA specific for Cdk5 (shCdk5-HCLE cells). A blasticidin-inducible vector for expression of Cdk5-specific short hairpin RNA (ShCdk5) was generated by recombination and packaged into non-replicative lentiviral particles for transduction of human corneal limbal epithelial (HCLE) cells. Blasticidin-resistant cells were isolated for analysis. Cell aggregations were performed using HCLE, Cdk5 inhibitor olomoucine, ShCdk5, and MDA-MB 231 cells in the presence and absence of calcium, and particle size was measured using image analysis software. Relative protein concentrations were measured with immunoblotting and quantitative densitometry. Total internal reflection fluorescence (TIRF) microscopy was performed on cells transfected with green fluorescent protein (GFP)-E-cadherin or GFP-p120, and internalization of boundary-localized proteins was analyzed with particle tracking software. The stability of surface-exposed proteins was determined by measuring the recovery of biotin-labeled proteins with affinity chromatography. Rho and Rac activity was measured with affinity chromatography and immunoblotting. Results: Examining the effect of Cdk5 on E-cadherin containing epithelial cell-cell adhesions using a corneal epithelial cell line (HCLE), we found that Cdk5 and Cdk5 (pY15) coimmunoprecipitate with E-cadherin and Cdk5 (pY15) colocalizes with E-cadherin at cell-cell junctions. Inhibiting Cdk5 activity in HCLE or suppressing Cdk5 expression in a stable HCLE-derived cell line (ShHCLE) decreased calcium-dependent cell adhesion, promoted the cytoplasmic localization of E-cadherin, and accelerated the loss of surface-biotinylated E-cadherin. TIRF microscopy of GFP-E-cadherin in transfected HCLE cells showed an actively internalized sub-population of E-cadherin, which was not bound to p120 as it was trafficked away from the cell-cell boundary. This population increased in the absence of Cdk5 activity, suggesting that Cdk5 inhibition promotes dissociation of p120/E-cadherin junctional complexes. These effects of Cdk5 inhibition or suppression were accompanied by decreased Rac activity, increased Rho activity, and enhanced binding of E-cadherin to the Rac effector Ras GTPase-activating-like protein (IQGAP1). Cdk5 inhibition also reduced adhesion in a cadherin-deficient cell line (MDA-MB-231) expressing exogenous E-cadherin, although Cdk5 inhibition promoted adhesion when these cells were transfected with N-cadherin, as previous studies of Cdk5 and N-cadherin predicted. Moreover, Cdk5 inhibition induced N-cadherin expression and formation of N-cadherin/p120 complexes in HCLE cells. Conclusions: These results indicate that loss of Cdk5 activity destabilizes junctional complexes containing E-cadherin, leading to internalization of E-cadherin and upregulation of N-cadherin. Thus, Cdk5 activity promotes stability of E-cadherin-based cell-cell junctions and inhibits the E-cadherin-to-N-cadherin switch typical of epithelial-mesenchymal transitions. C1 [Arpitha, Parthasarathy; Gao, Chun Y.; Tripathi, Brajendra K.; Saravanamuthu, Senthil; Zelenka, Peggy] NEI, NIH, Rockville, MD 20852 USA. [Gao, Chun Y.] NEI, NIH, Bethesda, MD 20892 USA. RP Arpitha, P (reprint author), NEI, NIH, Bldg 5635,Room 1S-02,Fishers Lane, Rockville, MD 20852 USA. EM arpithaparthasarathy@yahoo.com FU National Eye Institute, NIH [Z01EY000238] FX This research is supported by Intramural Research Program, Z01EY000238, National Eye Institute, NIH. We acknowledge use of HCLE cell line, a generous gift of Dr. Ilene Gipson, Schepens Eye research Institute, Boston; Dr. Keith Burridge, University of North Carolina, Chapel Hill for p120 and E-cadherin clones and Dr. Robert Farris for confocal imaging facility at the NEI/NIH core facility. Author-Arpitha Parthasarathy1 is currently at the University of Kentucky, Dept of Ophthalmology, Lexington NR 50 TC 0 Z9 0 U1 0 U2 3 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 FEB 7 PY 2013 VL 19 BP 319 EP 332 PG 14 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 089LM UT WOS:000314912000001 PM 23401660 ER PT J AU Shao, W Zhang, SZ Tang, M Zhang, XH Zhou, Z Yin, YQ Zhou, QB Huang, YY Liu, YJ Wawrousek, E Chen, T Li, SB Xu, M Zhou, JN Hu, G Zhou, JW AF Shao, Wei Zhang, Shu-zhen Tang, Mi Zhang, Xin-hua Zhou, Zheng Yin, Yan-qing Zhou, Qin-bo Huang, Yuan-yuan Liu, Ying-jun Wawrousek, Eric Chen, Teng Li, Sheng-bin Xu, Ming Zhou, Jiang-ning Hu, Gang Zhou, Jia-wei TI Suppression of neuroinflammation by astrocytic dopamine D2 receptors via alpha B-crystallin SO NATURE LA English DT Article ID HUMAN-BRAIN; INFLAMMATION; DISEASE; MICROGLIA; PATHWAY; INNATE; MICE AB Chronic neuroinflammation is a common feature of the ageing brain and some neurodegenerative disorders. However, the molecular and cellular mechanisms underlying the regulation of innate immunity in the central nervous system remain elusive. Here we show that the astrocytic dopamine D2 receptor (DRD2) modulates innate immunity through alpha B-crystallin (CRYAB), which is known to suppress neuroinflammation(1,2). We demonstrate that knockout mice lacking Drd2 showed remarkable inflammatory response in multiple central nervous system regions and increased the vulnerability of nigral dopaminergic neurons to neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity(3). Astrocytes null for Drd2 became hyper-responsive to immune stimuli with a marked reduction in the level of CRYAB. Preferential ablation of Drd2 in astrocytes robustly activated astrocytes in the substantia nigra. Gain- or loss-of-function studies showed that CRYAB is critical for DRD2-mediated modulation of innate immune response in astrocytes. Furthermore, treatment of wildtype mice with the selective DRD2 agonist quinpirole increased resistance of the nigral dopaminergic neurons to MPTP through partial suppression of inflammation. Our study indicates that astrocytic DRD2 activation normally suppresses neuroinflammation in the central nervous system through a CRYAB-dependent mechanism, and provides a new strategy for targeting the astrocyte-mediated innate immune response in the central nervous system during ageing and disease. C1 [Shao, Wei; Zhang, Shu-zhen; Tang, Mi; Zhang, Xin-hua; Zhou, Zheng; Yin, Yan-qing; Zhou, Qin-bo; Huang, Yuan-yuan; Liu, Ying-jun; Zhou, Jia-wei] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Neurosci, State Key Lab Neurosci, Shanghai 200031, Peoples R China. [Tang, Mi; Hu, Gang] Nanjing Med Univ, Dept Pharmacol, Jiangsu Key Lab Neurodegenerat, Nanjing 210029, Jiangsu, Peoples R China. [Wawrousek, Eric] NEI, NIH, Bethesda, MD 20892 USA. [Chen, Teng; Li, Sheng-bin] Xi An Jiao Tong Univ, Sch Med, Dept Forens Sci, Xian 710061, Shanxi, Peoples R China. [Xu, Ming] Univ Chicago, Dept Anesthesia & Crit Care, Chicago, IL 60637 USA. [Zhou, Jiang-ning] Univ Sci & Technol China, Sch Life Sci, CAS Key Lab Brain Funct & Dis, Hefei 230027, Anhui, Peoples R China. RP Zhou, JW (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Neurosci, State Key Lab Neurosci, Shanghai 200031, Peoples R China. EM jwzhou@ion.ac.cn OI Zhou, Jiawei/0000-0002-1844-9178; Zhou, Qinbo/0000-0002-7967-2138 FU Chinese Academy of Sciences; National Basic Research Program of China [2011CBA00408, 2011CB504102]; Natural Science Foundation of China [31021063, 31123002]; Shanghai Metropolitan Fund for Research and Development FX We thank B. Zhang and Y.J. Yan for technical assistance; L. Zhu for technical support in DNA microarray analysis; the Optical Imaging Center of ION and the Cell Biology Analysis Center of IBCB for technical support in confocal microscopy; T. L. Hagemann for providing the CRYAB construct; R. Quinlan for anti-CRYAB antibodies, Y. Q. Ding for providing the Drd1 and Drd2 gene null mice; we also thank Shanghai Research Center for Model Organisms for creating Drd2-floxed mice. This work was supported by grants from the Chinese Academy of Sciences, National Basic Research Program of China (nos 2011CBA00408 and 2011CB504102), Natural Science Foundation of China (nos 31021063 and 31123002), and Shanghai Metropolitan Fund for Research and Development. NR 22 TC 89 Z9 101 U1 4 U2 91 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 7 PY 2013 VL 494 IS 7435 BP 90 EP 94 DI 10.1038/nature11748 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 087DJ UT WOS:000314741200040 PM 23242137 ER PT J AU Thanassoulis, G Campbell, CY Owens, DS Smith, JG Smith, AV Peloso, GM Kerr, KF Pechlivanis, S Budoff, MJ Harris, TB Malhotra, R O'Brien, KD Kamstrup, PR Nordestgaard, BG Tybjaerg-Hansen, A Allison, MA Aspelund, T Criqui, MH Heckbert, SR Hwang, SJ Liu, YM Sjogren, M van der Pals, J Kalsch, H Muhleisen, TW Nothen, MM Cupples, LA Caslake, M Di Angelantonio, E Danesh, J Rotter, JI Sigurdsson, S Wong, Q Erbel, R Kathiresan, S Melander, O Gudnason, V O'Donnell, CJ Post, WS AF Thanassoulis, George Campbell, Catherine Y. Owens, David S. Smith, J. Gustav Smith, Albert V. Peloso, Gina M. Kerr, Kathleen F. Pechlivanis, Sonali Budoff, Matthew J. Harris, Tamara B. Malhotra, Rajeev O'Brien, Kevin D. Kamstrup, Pia R. Nordestgaard, Borge G. Tybjaerg-Hansen, Anne Allison, Matthew A. Aspelund, Thor Criqui, Michael H. Heckbert, Susan R. Hwang, Shih-Jen Liu, Yongmei Sjogren, Marketa van der Pals, Jesper Kaelsch, Hagen Muehleisen, Thomas W. Noethen, Markus M. Cupples, L. Adrienne Caslake, Muriel Di Angelantonio, Emanuele Danesh, John Rotter, Jerome I. Sigurdsson, Sigurdur Wong, Quenna Erbel, Raimund Kathiresan, Sekar Melander, Olle Gudnason, Vilmundur O'Donnell, Christopher J. Post, Wendy S. CA CHARGE Extracoronary Calcium Worki TI Genetic Associations with Valvular Calcification and Aortic Stenosis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID GENOME-WIDE ASSOCIATION; CORONARY-ARTERY CALCIUM; RISK-FACTORS; VALVE CALCIFICATION; MYOCARDIAL-INFARCTION; LP(A) LIPOPROTEIN; HEART-DISEASE; LONG-TERM; DESIGN; ATHEROSCLEROSIS AB Background Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease. Methods We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis. Results One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P = 9.0x10(-10)), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P = 1.5x10(-8) and P = 1.8x10(-8), respectively), but the findings were not replicated consistently. Conclusions Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.) C1 [Thanassoulis, George] McGill Univ, Dept Med, Ctr Hlth, Montreal, PQ, Canada. [Thanassoulis, George] McGill Univ, Res Inst, Ctr Hlth, Montreal, PQ, Canada. [Hwang, Shih-Jen; O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Framingham, MA USA. [Thanassoulis, George; Peloso, Gina M.; Hwang, Shih-Jen; Cupples, L. Adrienne; Kathiresan, Sekar; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Peloso, Gina M.; Malhotra, Rajeev; Kathiresan, Sekar; O'Donnell, Christopher J.] Boston Univ, Sch Med, Dept Med, Massachusetts Gen Hosp, Boston, MA 02118 USA. [Campbell, Catherine Y.; Post, Wendy S.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Budoff, Matthew J.] Harbor UCLA, Los Angeles Biomed Res Inst, Los Angeles, CA USA. [Liu, Yongmei] Wake Forest Sch Med, Winston Salem, NC USA. [Kerr, Kathleen F.; Wong, Quenna] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Heckbert, Susan R.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Allison, Matthew A.; Criqui, Michael H.] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Owens, David S.; O'Brien, Kevin D.] Univ Washington, Dept Med, Seattle, WA USA. [Smith, Albert V.; Aspelund, Thor; Sigurdsson, Sigurdur; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Harris, Tamara B.] NIA, Bethesda, MD 20892 USA. [Caslake, Muriel] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Di Angelantonio, Emanuele; Danesh, John] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Smith, J. Gustav] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Smith, J. Gustav; van der Pals, Jesper] Lund Univ, Dept Cardiol, Lund, Sweden. [Sjogren, Marketa; Melander, Olle] Lund Univ, Dept Clin Sci, Malmo, Sweden. [Pechlivanis, Sonali] Univ Essen Gesamthsch, Inst Med Informat Biometry & Epidemiol, Essen, Germany. [Kaelsch, Hagen; Erbel, Raimund] W German Heart Ctr, Dept Cardiol, Essen, Germany. [Muehleisen, Thomas W.; Noethen, Markus M.] Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany. [Muehleisen, Thomas W.; Noethen, Markus M.] Univ Bonn, Inst Human Genet, Bonn, Germany. [Noethen, Markus M.] Univ Bonn, German Ctr Neurodegenerat Dis, Bonn, Germany. [Kamstrup, Pia R.; Tybjaerg-Hansen, Anne] Copenhagen Univ Hosp, Rigshosp, Dept Clin Biochem, Copenhagen, Denmark. [Nordestgaard, Borge G.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Copenhagen, Denmark. [Nordestgaard, Borge G.; Tybjaerg-Hansen, Anne] Univ Copenhagen, Fac Hlth Sci, Copenhagen, Denmark. RP Post, WS (reprint author), Carnegie 568,600 N Wolfe St, Baltimore, MD 21287 USA. EM wpost@jhmi.edu RI Aspelund, Thor/C-5983-2008; Gudnason, Vilmundur/K-6885-2015; Smith, Albert/K-5150-2015; Kerr, Kathleen/A-2893-2013; OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084; Smith, Albert/0000-0003-1942-5845; Cupples, L. Adrienne/0000-0003-0273-7965; Di Angelantonio, Emanuele/0000-0001-8776-6719; Owens, David/0000-0002-7293-9688; Nothen, Markus/0000-0002-8770-2464; Allison, Matthew/0000-0003-0777-8272 FU National Heart, Lung, and Blood Institute (NHLBI) [N01-HC-25195, N02-HL-6-4278, N01-HC-95159, 95169, RR-024156, R01-HL-071739, R01-HL-071051, R01-HL-071205, R01-HL-071250, R01-HL-071251, R01-HL-071252, R01-HL-071258, R01-HL-071259, N01-HC-65226]; Affymetrix for genotyping services; National Institute on Aging [N01-AG-12100]; National Eye Institute; National Institute on Deafness and Other Communication Disorders; National Institute on Aging Intramural Research Program, Hjartavernd (the Icelandic Heart Association); Althingi (Icelandic parliament); MESA; MESA Family; MESA CARe; MESA SHARe project; Heinz Nixdorf Recall Study; Heinz Nixdorf Foundation; German Foundation of Research (DFG); Malmo Diet and Cancer study; Swedish Cancer Society; Swedish Medical Research Council; Swedish Dairy Association; Albert Pahlsson Foundation; Gunnar Nilsson Foundation; Malmo city council; Copenhagen City Heart Study; Danish Heart Foundation FX The Framingham Heart Study was supported by a grant (N01-HC-25195) from the National Heart, Lung, and Blood Institute (NHLBI) and an NHLBI contract (N02-HL-6-4278) with Affymetrix for genotyping services; the Age, Gene/Environment Susceptibility-Reykjavik Study, by a grant from the National Institute on Aging (N01-AG-12100) and by the National Eye Institute, the National Institute on Deafness and Other Communication Disorders, the NHLBI, the National Institute on Aging Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (Icelandic parliament); the MESA, MESA Family, MESA CARe, and the MESA SHARe project, by grants (N01-HC-95159 through 95169, RR-024156, R01-HL-071739, R01-HL-071051, R01-HL-071205, R01-HL-071250, R01-HL-071251, R01-HL-071252, R01-HL-071258, R01-HL-071259, N02-HL-6-4278, and N01-HC-65226) from the NHLBI; the Heinz Nixdorf Recall Study, by the Heinz Nixdorf Foundation and the German Foundation of Research (DFG); the Malmo Diet and Cancer study, by the Swedish Cancer Society, the Swedish Medical Research Council, the Swedish Dairy Association, the Albert Pahlsson and Gunnar Nilsson Foundations, and the Malmo city council; and the Copenhagen City Heart Study, by the Danish Heart Foundation. Detailed information on support for individual authors and analyses is available in the Supplementary Appendix. NR 47 TC 164 Z9 170 U1 3 U2 31 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 7 PY 2013 VL 368 IS 6 BP 503 EP 512 DI 10.1056/NEJMoa1109034 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 083VU UT WOS:000314494100001 PM 23388002 ER PT J AU Nabel, GJ AF Nabel, Gary J. TI GLOBAL HEALTH Designing Tomorrow's Vaccines SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID BROADLY NEUTRALIZING ANTIBODIES; CELLULAR-IMMUNITY; INFLUENZA VACCINE; RATIONAL DESIGN; CLINICAL-TRIALS; VIRUS-VACCINES; SIV INFECTION; HIV VACCINE; POTENT; PROTECTION C1 [Nabel, Gary J.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Nabel, GJ (reprint author), Sanofi, 640 Mem Dr, Cambridge, MA 02139 USA. EM gary.nabel@sanofi.com RI Chiang, Vincent, Ming-Hsien/D-4312-2016 OI Chiang, Vincent, Ming-Hsien/0000-0002-2029-7863 FU Intramural NIH HHS [Z01 AI005002-06, Z99 AI999999, ZIA AI005002-08, ZIA AI005003-08, ZIA AI005058-07, Z01 AI005003-06] NR 52 TC 77 Z9 78 U1 2 U2 46 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 7 PY 2013 VL 368 IS 6 BP 551 EP 560 DI 10.1056/NEJMra1204186 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 083VU UT WOS:000314494100006 PM 23388006 ER PT J AU Zarin, DA Tse, T AF Zarin, Deborah A. Tse, Tony TI Unambiguous Identification of Obesity Trials SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Zarin, Deborah A.; Tse, Tony] Natl Lib Med, Bethesda, MD USA. RP Zarin, DA (reprint author), Natl Lib Med, Bethesda, MD USA. EM dzarin@mail.nih.gov NR 4 TC 0 Z9 0 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 7 PY 2013 VL 368 IS 6 BP 580 EP 581 DI 10.1056/NEJMc1215018 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 083VU UT WOS:000314494100025 PM 23388022 ER PT J AU Klase, ZA Sampey, GC Kashanchi, F AF Klase, Zachary A. Sampey, Gavin C. Kashanchi, Fatah TI Retrovirus infected cells contain viral microRNAs SO RETROVIROLOGY LA English DT Editorial Material DE Retrovirus; microRNA; Bovine leukemia virus; Human immunodeficiency virus; West nile virus; Transcriptional gene silencing; RNA polymerase III ID SMALL NONCODING RNAS; HIV-1-INFECTED CELLS; INTERFERENCE; REPLICATION AB The encoding of microRNAs in retroviral genomes has remained a controversial hypothesis despite significant supporting evidence in recent years. A recent publication demonstrating the production of functional miRNAs from the retrovirus bovine leukemia virus adds further credence to the fact that retroviruses do indeed encode their own miRNAs. Here we comment on the importance of this paper to the field, as well as examine the other known examples of miRNAs encoded by RNA viruses. C1 [Klase, Zachary A.] NIAID, Mol Virol Sect, Mol Microbiol Lab, Bethesda, MD 20810 USA. [Sampey, Gavin C.; Kashanchi, Fatah] George Mason Univ, Natl Ctr Biodef & Infect Dis, Sch Syst Biol, Manassas, VA 20108 USA. RP Kashanchi, F (reprint author), George Mason Univ, Natl Ctr Biodef & Infect Dis, Sch Syst Biol, 10900 Univ Blvd, Manassas, VA 20108 USA. EM fkashanc@gmu.edu FU NIAID NIH HHS [AI074410, AI078859] NR 15 TC 8 Z9 8 U1 0 U2 9 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 FEB 7 PY 2013 VL 10 AR 15 DI 10.1186/1742-4690-10-15 PG 4 WC Virology SC Virology GA 088JZ UT WOS:000314831600001 PM 23391025 ER PT J AU Mehta, B Snellman, J Chen, S Li, W Zenisek, D AF Mehta, Bhupesh Snellman, Josefin Chen, Shan Li, Wei Zenisek, David TI Synaptic Ribbons Influence the Size and Frequency of Miniature-like Evoked Postsynaptic Currents SO NEURON LA English DT Article ID MULTIVESICULAR RELEASE; SPONTANEOUS NEUROTRANSMISSION; TRANSMITTER RELEASE; BIPOLAR CELLS; MOUSE RETINA; RAT RETINA; SYNAPSES; ROD; EXOCYTOSIS; LUMINANCE AB Nonspiking cells of several sensory systems respond to stimuli with graded changes in neurotransmitter release and possess specialized synaptic ribbons. Here, we show that manipulations to synaptic ribbons caused dramatic effects on mEPSC-like (mIEPSC) amplitude and frequency. Damage to rod-bipolar cell ribbons using fluorophore-assisted light inactivation resulted in the immediate reduction of mIEPSC amplitude and frequency, whereas the first evoked response after damage remained largely intact. The reduction in amplitude could not be recovered by increasing release frequency after ribbon damage. In parallel experiments, we looked at mIEPSCs from cones of hibernating ground squirrels, which exhibit dramatically smaller ribbons than awake animals. Fewer and smaller mIEPSCs were observed postsynaptic to cones from hibernating animals, although depolarized cones were able to generate larger mIEPSCs. Our results indicate that ribbon size may influence mIEPSC frequency and support a role for ribbons in coordinating multivesicular release. C1 [Mehta, Bhupesh; Snellman, Josefin; Zenisek, David] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06520 USA. [Zenisek, David] Yale Univ, Sch Med, Dept Ophthalmol & Visual Sci, New Haven, CT 06520 USA. [Zenisek, David] Yale Univ, Sch Med, Program Cellular Neurosci Neurodegenerat & Repair, New Haven, CT 06520 USA. [Chen, Shan; Li, Wei] NEI, Unit Retinal Neurophysiol, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Li, W (reprint author), NEI, Unit Retinal Neurophysiol, Intramural Res Program, NIH, 35 Convent Dr,Room 2A-108, Bethesda, MD 20892 USA. EM liwei2@nei.nih.gov; david.zenisek@yale.edu FU National Institutes of Health [EY014990]; National Eye Institute Intramural Research Program FX This work was funded by the National Institutes of Health (grant no. EY014990, to D.Z.) and the National Eye Institute Intramural Research Program (W.L.). NR 47 TC 15 Z9 16 U1 0 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD FEB 6 PY 2013 VL 77 IS 3 BP 516 EP 527 DI 10.1016/j.neuron.2012.11.024 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 118MY UT WOS:000317030800013 PM 23395377 ER PT J AU Alemayehu, M Dragan, M Pape, C Siddiqui, I Sacks, DB Di Guglielmo, GM Babwah, AV Bhattacharya, M AF Alemayehu, Mistre Dragan, Magdalena Pape, Cynthia Siddiqui, Iram Sacks, David B. Di Guglielmo, Gianni M. Babwah, Andy V. Bhattacharya, Moshmi TI beta-Arrestin2 Regulates Lysophosphatidic Acid-Induced Human Breast Tumor Cell Migration and Invasion via Rap1 and IQGAP1 SO PLOS ONE LA English DT Article ID STRESS FIBER FORMATION; BETA-ARRESTIN; CANCER METASTASIS; EPITHELIAL-CELLS; PROSTATE-CANCER; LEADING-EDGE; ACTIVATION; RECEPTOR; PROTEINS; ADHESION AB beta-arrestins play critical roles in chemotaxis and cytoskeletal reorganization downstream of several receptor types, including G protein-coupled receptors (GPCRs), which are targets for greater than 50% of all pharmaceuticals. Among them, receptors for lysophosphatidic acid (LPA), namely LPA(1) are overexpressed in breast cancer and promote metastatic spread. We have recently reported that beta-arrestin2 regulates LPA(1)-mediated breast cancer cell migration and invasion, although the underlying molecular mechanisms are not clearly understood. We show here that LPA induces activity of the small G protein, Rap1 in breast cancer cells in a beta-arrestin2-dependent manner, but fails to activate Rap1 in non-malignant mammary epithelial cells. We found that Rap1A mRNA levels are higher in human breast tumors compared to healthy patient samples and Rap1A is robustly expressed in human ductal carcinoma in situ and invasive tumors, in contrast to the normal mammary ducts. Rap1A protein expression is also higher in aggressive breast cancer cells (MDA-MB-231 and Hs578t) relative to the weakly invasive MCF-7 cells or non-malignant MCF10A mammary cells. Depletion of Rap1A expression significantly impaired LPA-stimulated migration of breast cancer cells and invasiveness in three-dimensional Matrigel cultures. Furthermore, we found that beta-arrestin2 associates with the actin binding protein IQGAP1 in breast cancer cells, and is necessary for the recruitment of IQGAP1 to the leading edge of migratory cells. Depletion of IQGAP1 blocked LPA-stimulated breast cancer cell invasion. Finally, we have identified that LPA enhances the binding of endogenous Rap1A to beta-arrestin2, and also stimulates Rap1A and IQGAP1 to associate with LPA1. Thus our data establish novel roles for Rap1A and IQGAP1 as critical regulators of LPA-induced breast cancer cell migration and invasion. C1 [Alemayehu, Mistre; Dragan, Magdalena; Pape, Cynthia; Di Guglielmo, Gianni M.; Babwah, Andy V.; Bhattacharya, Moshmi] Univ Western Ontario, Dept Physiol & Pharmacol, London, ON, Canada. [Siddiqui, Iram] Univ Western Ontario, Dept Pathol, London, ON, Canada. [Babwah, Andy V.] Univ Western Ontario, Childrens Hlth Res Inst, London, ON, Canada. [Babwah, Andy V.] Univ Western Ontario, Lawson Hlth Res Inst, London, ON, Canada. [Babwah, Andy V.] Univ Western Ontario, Dept Obstet & Gynecol, London, ON, Canada. [Sacks, David B.] NIH, Dept Lab Med, Bethesda, MD 20892 USA. RP Bhattacharya, M (reprint author), Univ Western Ontario, Dept Physiol & Pharmacol, London, ON, Canada. EM moshmi.bhattacharya@schulich.uwo.ca FU Canadian Institutes of Health Research (CIHR) [MOP 107972]; National Institutes of Health; CIHR Strategic Training Program/Translational Breast Cancer Research Unit FX This study was supported by a grant awarded to MB by the Canadian Institutes of Health Research (CIHR) MOP 107972. DS is supported by the Intramural Research Program of the National Institutes of Health. The following are recipients of salary awards and studentships: MB and AB, CIHR Canadian Institute of Health Research New Investigator Awards; MA, CIHR Strategic Training Program/Translational Breast Cancer Research Unit studentships. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 62 TC 15 Z9 17 U1 0 U2 13 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 FEB 6 PY 2013 VL 8 IS 2 AR e56174 DI 10.1371/journal.pone.0056174 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 092WJ UT WOS:000315153400210 PM 23405264 ER PT J AU Cahoon, EK Wheeler, DC Kimlin, MG Kwok, RK Alexander, BH Little, MP Linet, MS Freedman, DM AF Cahoon, Elizabeth Khaykin Wheeler, David C. Kimlin, Michael G. Kwok, Richard K. Alexander, Bruce H. Little, Mark P. Linet, Martha S. Freedman, Daryl Michal TI Individual, Environmental, and Meteorological Predictors of Daily Personal Ultraviolet Radiation Exposure Measurements in a United States Cohort Study SO PLOS ONE LA English DT Article ID CANCER-MORTALITY RATES; SUN EXPOSURE; VITAMIN-D; RADIOLOGIC TECHNOLOGISTS; MEASUREMENT ERROR; OCULAR MELANOMA; SKIN; RISK; REPRODUCIBILITY; POPULATION AB Background: Individual exposure to ultraviolet radiation (UVR) is challenging to measure, particularly for diseases with substantial latency periods between first exposure and diagnosis of outcome, such as cancer. To guide the choice of surrogates for long-term UVR exposure in epidemiologic studies, we assessed how well stable sun-related individual characteristics and environmental/meteorological factors predicted daily personal UVR exposure measurements. Methods: We evaluated 123 United States Radiologic Technologists subjects who wore personal UVR dosimeters for 8 hours daily for up to 7 days (N = 837 days). Potential predictors of personal UVR derived from a self-administered questionnaire, and public databases that provided daily estimates of ambient UVR and weather conditions. Factors potentially related to personal UVR exposure were tested individually and in a model including all significant variables. Results: The strongest predictors of daily personal UVR exposure in the full model were ambient UVR, latitude, daily rainfall, and skin reaction to prolonged sunlight (R-2 = 0.30). In a model containing only environmental and meteorological variables, ambient UVR, latitude, and daily rainfall were the strongest predictors of daily personal UVR exposure (R-2 = 0.25). Conclusions: In the absence of feasible measures of individual longitudinal sun exposure history, stable personal characteristics, ambient UVR, and weather parameters may help estimate long-term personal UVR exposure. C1 [Cahoon, Elizabeth Khaykin; Little, Mark P.; Linet, Martha S.; Freedman, Daryl Michal] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Wheeler, David C.] Virginia Commonwealth Univ, Sch Med, Dept Biostat, Richmond, VA USA. [Kimlin, Michael G.] Queensland Univ Technol, Inst Hlth & Biomed Innovat, AusSun Res Lab, Brisbane, Qld 4001, Australia. [Kwok, Richard K.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Alexander, Bruce H.] Univ Minnesota, Sch Publ Hlth, Div Environm Hlth Sci, Minneapolis, MN USA. RP Cahoon, EK (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM khaykine@mail.nih.gov RI Kwok, Richard/B-6907-2017; OI Kwok, Richard/0000-0002-6794-8360; Kimlin, Michael/0000-0002-9536-8646; Little, Mark/0000-0003-0980-7567 FU Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services FX This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 6 Z9 6 U1 0 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 FEB 6 PY 2013 VL 8 IS 2 AR e54983 DI 10.1371/journal.pone.0054983 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 092WJ UT WOS:000315153400046 PM 23405102 ER PT J AU Goldenberg, DM Gold, DV Loo, M Liu, DL Chang, CH Jaffe, ES AF Goldenberg, David M. Gold, David V. Loo, Meiyu Liu, Donglin Chang, Chien-Hsing Jaffe, Elaine S. TI Horizontal Transmission of Malignancy: In-Vivo Fusion of Human Lymphomas with Hamster Stroma Produces Tumors Retaining Human Genes and Lymphoid Pathology SO PLOS ONE LA English DT Article ID REED-STERNBERG CELLS; HODGKINS-DISEASE; NUDE-MICE; B-CELL; METASTATIC PHENOTYPE; HOST-CELLS; CANCER; TRANSFORMATION; CHROMOSOME; BIOLOGY AB We report the in-vivo fusion of two Hodgkin lymphomas with golden hamster cheek pouch cells, resulting in serially transplanted (over 5-6 years) GW-532 and GW-584 heterosynkaryon tumor cells displaying both human and hamster DNA (by FISH), lymphoma-like morphology, aggressive metastasis, and retention of 7 human genes (CD74, CXCR4, CD19, CD20, CD71, CD79b, and VIM) out of 24 tested by PCR. The prevalence of B-cell restricted genes (CD19, CD20, and CD79b) suggests that this uniform population may be the clonal initiating (malignant) cells of Hodgkin lymphoma, despite their not showing translation to their respective proteins by immunohistochemical analysis. This is believed to be the first report of in-vivo cell-cell fusion of human lymphoma and rodent host cells, and may be a method to disclose genes regulating both organoid and metastasis signatures, suggesting that the horizontal transfer of tumor DNA to adjacent stromal cells may be implicated in tumor heterogeneity and progression. The B-cell gene signature of the hybrid xenografts suggests that Hodgkin lymphoma, or its initiating cells, is a B-cell malignancy. C1 [Goldenberg, David M.; Gold, David V.] Garden State Canc Ctr, Ctr Mol Med & Immunol, Morris Plains, NJ USA. [Loo, Meiyu; Liu, Donglin; Chang, Chien-Hsing] Immunomedics Inc, Morris Plains, NJ USA. [Jaffe, Elaine S.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Goldenberg, DM (reprint author), Garden State Canc Ctr, Ctr Mol Med & Immunol, Morris Plains, NJ USA. EM dmg.gscancer@att.net OI Jaffe, Elaine/0000-0003-4632-0301 FU National Cancer Institute, National Institutes of Health; National Institutes of Health [CA11327] FX This work was supported in part by the intramural research program of the National Cancer Institute, National Institutes of Health (ESJ), and USPHS grant CA11327 from the National Institutes of Health (DMG) for establishing the original GW-532 and GW-584 tumors. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 10 Z9 13 U1 0 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 FEB 6 PY 2013 VL 8 IS 2 AR e55324 DI 10.1371/journal.pone.0055324 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 092WJ UT WOS:000315153400080 PM 23405135 ER PT J AU Page, S Birerdinc, A Estep, M Stepanova, M Afendy, A Petricoin, E Younossi, Z Chandhoke, V Baranova, A AF Page, Sandra Birerdinc, Aybike Estep, Michael Stepanova, Maria Afendy, Arian Petricoin, Emanuel Younossi, Zobair Chandhoke, Vikas Baranova, Ancha TI Knowledge-Based Identification of Soluble Biomarkers: Hepatic Fibrosis in NAFLD as an Example SO PLOS ONE LA English DT Article ID FATTY LIVER-DISEASE; NONALCOHOLIC STEATOHEPATITIS; METABOLIC SYNDROME; FAS LIGAND; ADIPOKINES; DISCOVERY; CIRRHOSIS AB The discovery of biomarkers is often performed using high-throughput proteomics-based platforms and is limited to the molecules recognized by a given set of purified and validated antigens or antibodies. Knowledge-based, or systems biology, approaches that involve the analysis of integrated data, predominantly molecular pathways and networks may infer quantitative changes in the levels of biomolecules not included by the given assay from the levels of the analytes profiled. In this study we attempted to use a knowledge-based approach to predict biomarkers reflecting the changes in underlying protein phosphorylation events using Nonalcoholic Fatty Liver Disease (NAFLD) as a model. Two soluble biomarkers, CCL-2 and FasL, were inferred in silico as relevant to NAFLD pathogenesis. Predictive performance of these biomarkers was studied using serum samples collected from patients with histologically proven NAFLD. Serum levels of both molecules, in combination with clinical and demographic data, were predictive of hepatic fibrosis in a cohort of NAFLD patients. Our study suggests that (1) NASH-specific disruption of the kinase-driven signaling cascades in visceral adipose tissue lead to detectable changes in the levels of soluble molecules released into the bloodstream, and (2) biomarkers discovered in silico could contribute to predictive models for non-malignant chronic diseases. C1 [Page, Sandra; Birerdinc, Aybike; Stepanova, Maria; Petricoin, Emanuel; Chandhoke, Vikas; Baranova, Ancha] George Mason Univ, Coll Sci, Sch Syst Biol, Ctr Study Chron Metab Dis, Fairfax, VA 22030 USA. [Page, Sandra; Birerdinc, Aybike; Estep, Michael; Stepanova, Maria; Afendy, Arian; Younossi, Zobair; Baranova, Ancha] Inova Hlth Syst, Betty & Guy Beatty Liver & Obes Program, Falls Church, VA USA. [Estep, Michael; Afendy, Arian; Younossi, Zobair] Inova Fairfax Hosp, Ctr Liver Dis, Falls Church, VA USA. [Estep, Michael; Afendy, Arian; Younossi, Zobair] Inova Fairfax Hosp, Dept Med, Falls Church, VA USA. [Petricoin, Emanuel] George Mason Univ, Coll Sci, Sch Syst Biol, Ctr Appl Prote & Mol Med, Fairfax, VA 22030 USA. [Baranova, Ancha] Res Ctr Med Genet RAMS, Moscow, Russia. [Page, Sandra] NIDDKD, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. RP Baranova, A (reprint author), George Mason Univ, Coll Sci, Sch Syst Biol, Ctr Study Chron Metab Dis, Fairfax, VA 22030 USA. EM abaranov@gmu.edu OI Estep, J. Michael/0000-0001-7735-2133 NR 20 TC 8 Z9 8 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 6 PY 2013 VL 8 IS 2 AR e56009 DI 10.1371/journal.pone.0056009 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 092WJ UT WOS:000315153400189 PM 23405244 ER PT J AU Christian, BT Wooten, DW Hillmer, AT Tudorascu, DL Converse, AK Moore, CF Ahlers, EO Barnhart, TE Kalin, NH Barr, CS Schneider, ML AF Christian, Bradley T. Wooten, Dustin W. Hillmer, Ansel T. Tudorascu, Dana L. Converse, Alexander K. Moore, Colleen F. Ahlers, Elizabeth O. Barnhart, Todd E. Kalin, Ned H. Barr, Christina S. Schneider, Mary L. TI Serotonin Transporter Genotype Affects Serotonin 5-HT1A Binding in Primates SO JOURNAL OF NEUROSCIENCE LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; GENE VARIATION; HUMAN BRAIN; FUNCTIONAL POLYMORPHISM; REARING CONDITION; RECEPTOR-BINDING; NONHUMAN PRIMATE; PROMOTER REGION; RHESUS-MONKEYS; STRESS AB Disruption of the serotonin system has been implicated in anxiety and depression and a related genetic variation has been identified that may predispose individuals for these illnesses. The relationship of a functional variation of the serotonin transporter promoter gene (5-HTTLPR) on serotonin transporter binding using in vivo imaging techniques have yielded inconsistent findings when comparing variants for short (s) and long (l) alleles. However, a significant 5-HTTLPR effect on receptor binding at the 5-HT1A receptor site has been reported in humans, suggesting the 5-HTTLPR polymorphism may play a role in serotonin (5-HT) function. Rhesus monkeys possess a 5-HTTLPR length polymorphism similar to humans and serve as an excellent model for studying the effects of this orthologous genetic variation on behaviors and neurochemical functions related to the 5-HT system. In this study, PET imaging of [F-18]mefway was performed on 58 rhesus monkeys (33 l/l, 25 s-carriers) to examine the relation between 5-HT1A receptor-specific binding and 5-HTTLPR genotypes. Significantly lower 5-HT1A binding was found in s-carrier subjects throughout both cortical brain regions and the raphe nuclei. These results demonstrate that the underlying 5-HT neurochemical system is influenced by this functional polymorphism and illustrate the strong potential for extending the nonhuman primate model into investigating the role of this genetic variant on behavior and gene-environment interactions. C1 [Christian, Bradley T.; Wooten, Dustin W.; Hillmer, Ansel T.; Barnhart, Todd E.] Univ Wisconsin, Dept Med Phys, Madison, WI 53705 USA. [Schneider, Mary L.] Univ Wisconsin, Dept Kinesiol, Madison, WI 53705 USA. [Christian, Bradley T.; Kalin, Ned H.] Univ Wisconsin, Dept Psychiat, Madison, WI 53705 USA. [Moore, Colleen F.; Kalin, Ned H.; Schneider, Mary L.] Univ Wisconsin, Dept Psychol, Madison, WI 53705 USA. [Christian, Bradley T.; Converse, Alexander K.; Ahlers, Elizabeth O.; Kalin, Ned H.] Univ Wisconsin, Waisman Ctr, Madison, WI 53705 USA. [Tudorascu, Dana L.] Univ Pittsburgh, Dept Med & Biostat, Pittsburgh, PA 15312 USA. [Barr, Christina S.] NIAAA, NIH, Bethesda, MD 20892 USA. RP Christian, BT (reprint author), Univ Wisconsin, Waisman Ctr, Brain Imaging Lab, 1500 Highland Ave, Madison, WI 53705 USA. EM bchristian@wisc.edu OI Barnhart, Todd/0000-0002-9981-2150 FU NIH [AA017706, MH086014, AA12277, AA10079, T32CA009206, S10RR015801, P30HD003352, S10RR023033] FX This work was supported by NIH Grants AA017706, MH086014, AA12277, AA10079, and T32CA009206. Additional support was provided by NIH Grants S10RR015801, P30HD003352, and S10RR023033. We thank the following for their contribution to this research: Professor R. Jerry Nickles and Dr. Jonathan Engle for assistance with isotope production; Maxim Slesarev and Julie Larson and the staff at the Harlow Center for Biological Psychology at the University of Wisconsin for nonhuman primate handling; Andrew Higgins for data processing; and Professor Jim Holden and Professor Jogesh Mukherjee (University of California, Irvine) for technical discussions. NR 35 TC 12 Z9 12 U1 6 U2 17 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 FEB 6 PY 2013 VL 33 IS 6 BP 2512 EP 2516 DI 10.1523/JNEUROSCI.4182-12.2013 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 088CS UT WOS:000314812000025 PM 23392679 ER PT J AU Camprubi-Robles, M Mair, N Andratsch, M Benetti, C Beroukas, D Rukwied, R Langeslag, M Proia, RL Schmelz, M Montiel, AVF Haberberger, RV Kress, M AF Camprubi-Robles, Maria Mair, Norbert Andratsch, Manfred Benetti, Camilla Beroukas, Dimitra Rukwied, Roman Langeslag, Michiel Proia, Richard L. Schmelz, Martin Ferrer Montiel, Antonio V. Haberberger, Rainer V. Kress, Michaela TI Sphingosine-1-Phosphate-Induced Nociceptor Excitation and Ongoing Pain Behavior in Mice and Humans Is Largely Mediated by S1P3 Receptor SO JOURNAL OF NEUROSCIENCE LA English DT Article ID RAT SENSORY NEURONS; SPHINGOSINE 1-PHOSPHATE RECEPTOR; ROOT GANGLION NEURONS; INFLAMMATORY MEDIATORS; ENDOTHELIAL-CELLS; HUMAN PLATELETS; ACTIVATION; PLASMA; KINASE; ROLES AB The biolipid sphingosine-1-phosphate (S1P) is an essential modulator of innate immunity, cell migration, and wound healing. It is released locally upon acute tissue injury from endothelial cells and activated thrombocytes and, therefore, may give rise to acute post-traumatic pain sensation via a yet elusive molecular mechanism. We have used an interdisciplinary approach to address this question, and we find that intradermal injection of S1P induced significant licking and flinching behavior in wild-type mice and a dose-dependent flare reaction in human skin as a sign of acute activation of nociceptive nerve terminals. Notably, S1P evoked a small excitatory ionic current that resulted in nociceptor depolarization and action potential firing. This ionic current was preserved in "cation-free" solution and blocked by the nonspecific Cl- channel inhibitor niflumic acid and by preincubation with the G-protein inhibitor GDP-beta-S. Notably, S1P(3) receptor was detected in virtually all neurons in human and mouse DRG. In line with this finding, S1P-induced neuronal responses and spontaneous pain behavior in vivo were substantially reduced in S1P(3)(-/-) mice, whereas in control S1P(1) floxed (S1P(1)(fl/fl)) mice and mice with a nociceptor-specific deletion of S1P(1)(-/-) receptor (SNS-S1P(1)(-/-)), neither the S1P-induced responses in vitro nor the S1P-evoked pain-like behavior was altered. Therefore, these findings indicate that S1P evokes significant nociception via G-protein-dependent activation of an excitatory Cl- conductance that is largely mediated by S1P(3) receptors present in nociceptors, and point to these receptors as valuable therapeutic targets for post-traumatic pain. C1 [Camprubi-Robles, Maria; Mair, Norbert; Andratsch, Manfred; Benetti, Camilla; Langeslag, Michiel; Kress, Michaela] Med Univ Innsbruck, Dept Physiol & Med Phys, Div Physiol, A-6020 Innsbruck, Austria. [Camprubi-Robles, Maria; Ferrer Montiel, Antonio V.] Miguel Hernandez Univ, Inst Mol & Cellular Biol, Alicante 03202, Spain. [Beroukas, Dimitra; Haberberger, Rainer V.] Flinders Univ S Australia, Dept Anat & Histol, Bedford Pk, SA 5042, Australia. [Beroukas, Dimitra; Haberberger, Rainer V.] Flinders Univ S Australia, Ctr Neurosci, Bedford Pk, SA 5042, Australia. [Rukwied, Roman; Schmelz, Martin] Heidelberg Univ, Dept Anaesthesiol & Intens Care Med, Med Fac Mannheim, D-68167 Mannheim, Germany. [Proia, Richard L.] NIDDK, Bethesda, MD 20892 USA. RP Camprubi-Robles, M (reprint author), Miguel Hernandez Univ, Inst Mol & Cellular Biol, Avda Univ S-N, Alicante 03202, Spain. EM mcamprubi@umh.es; michaela.kress@i-med.ac.at RI Ferrer-Montiel, Antonio/C-3072-2015; OI Ferrer-Montiel, Antonio/0000-0002-2973-6607; Schmelz, Martin/0000-0002-9736-7241; Haberberger, Rainer Viktor/0000-0001-8043-3786 FU la Generalitat Valenciana; Ministerio de Economia y Competitividad; Australian National Health and Medical Research Council [535055]; National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; Austrian Research Funding Agency FWF Project [P20562, P25345, SPIN] FX The authors thank K. Braun, T. Martha, and M. Doblander for expert technical assistance. This work was supported by la Generalitat Valenciana and the Ministerio de Economia y Competitividad (A.V.F.M.), the Australian National Health and Medical Research Council Project Grant 535055 to R.V.H., the Intramural Research Programs of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases to R.L.P., and the Austrian Research Funding Agency FWF Project Grants P20562, P25345, and SPIN to M.K. NR 63 TC 15 Z9 15 U1 1 U2 12 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 FEB 6 PY 2013 VL 33 IS 6 BP 2582 EP 2592 DI 10.1523/JNEUROSCI.4479-12.2013 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 088CS UT WOS:000314812000032 PM 23392686 ER PT J AU Rao, TSC Saha, S Raolji, GB Patro, B Risbood, P Difilippantonio, MJ Tomaszewski, JE Malhotra, SV AF Rao, T. S. Chinta Saha, Sanjay Raolji, Gajendra B. Patro, Balaram Risbood, Prabhaker Difilippantonio, Michael J. Tomaszewski, Joseph E. Malhotra, Sanjay V. TI Microwave assisted Westphal condensation and its application to synthesis of sempervirine and related compounds SO TETRAHEDRON LETTERS LA English DT Article DE Sempervirine; Westphal condensation; Microwave assisted; DNA intercalator; Antiproliferative agent ID ZWITTERIONIC INDOLE ALKALOIDS; DIRECTED METALATION ROUTE; CANCER-CELLS; DIHYDROFLAVOPEREIRINE; SALTS; MDM2; P53 AB A concise synthesis of a potent lead in anticancer therapeutics, sempervirine, was achieved by one pot Westphal condensation, ester hydrolysis, and decarboxylation under microwave irradiation. The method was extended to the synthesis of several similar heterocycles. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Rao, T. S. Chinta; Saha, Sanjay; Raolji, Gajendra B.; Patro, Balaram] GVK Biosci Pvt Ltd, Div Med Chem, Hyderabad, Andhra Pradesh, India. [Rao, T. S. Chinta; Saha, Sanjay] JNT Univ, Dept Chem, Hyderabad, Andhra Pradesh, India. [Risbood, Prabhaker; Difilippantonio, Michael J.; Tomaszewski, Joseph E.] NCI, Div Canc Treatment & Diagnosis, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Malhotra, Sanjay V.] SAIC Frederick Inc, Lab Synthet Chem, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Patro, B (reprint author), GVK Biosci Pvt Ltd, Div Med Chem, Hyderabad, Andhra Pradesh, India. EM balaram.patro@gvkbio.com; malhotrasa@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; GVK Biosciences Private Limited FX This project has been funded in whole or in part with Federal Funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. T.S.C.R., S.S., B.P,. and G.B.R. sincerely thank GVK Biosciences Private Limited for financial support and encouragement. Support from analytical department is also acknowledged. NR 24 TC 3 Z9 3 U1 2 U2 17 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4039 J9 TETRAHEDRON LETT JI Tetrahedron Lett. PD FEB 6 PY 2013 VL 54 IS 6 BP 487 EP 490 DI 10.1016/j.tetlet.2012.11.059 PG 4 WC Chemistry, Organic SC Chemistry GA 082JO UT WOS:000314388300010 ER PT J AU Brown, VL Drake, JM Stallknecht, DE Brown, JD Pedersen, K Rohani, P AF Brown, V. L. Drake, J. M. Stallknecht, D. E. Brown, J. D. Pedersen, K. Rohani, P. TI Dissecting a wildlife disease hotspot: the impact of multiple host species, environmental transmission and seasonality in migration, breeding and mortality SO JOURNAL OF THE ROYAL SOCIETY INTERFACE LA English DT Article DE avian influenza; multi-host mathematical model; environmental transmission; disease hotspot ID AVIAN INFLUENZA-VIRUS; DELAWARE BAY; A VIRUS; BIRDS; WATER; INFECTION; DYNAMICS; DUCKS; SURVEILLANCE; TEMPERATURE AB Avian influenza viruses (AIVs) have been implicated in all human influenza pandemics in recent history. Despite this, surprisingly little is known about the mechanisms underlying the maintenance and spread of these viruses in their natural bird reservoirs. Surveillance has identified an AIV 'hotspot' in shorebirds at Delaware Bay, in which prevalence is estimated to exceed other monitored sites by an order of magnitude. To better understand the factors that create an AIV hotspot, we developed and parametrized a mechanistic transmission model to study the simultaneous epizootiological impacts of multi-species transmission, seasonal breeding, host migration and mixed transmission routes. We scrutinized our model to examine the potential for an AIV hotspot to serve as a 'gateway' for the spread of novel viruses into North America. Our findings identify the conditions under which a novel influenza virus, if introduced into the system, could successfully invade and proliferate. C1 [Brown, V. L.; Rohani, P.] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Brown, V. L.; Rohani, P.] Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA. [Drake, J. M.] Univ Georgia, Odum Sch Ecol, Athens, GA 30602 USA. [Stallknecht, D. E.; Brown, J. D.] Univ Georgia, SE Cooperat Wildlife Dis Study, Athens, GA 30602 USA. [Pedersen, K.] Anim & Plant Hlth Inspect Serv, USDA, Wildlife Serv, Natl Wildlife Dis Program, Ft Collins, CO 80521 USA. [Rohani, P.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Brown, VL (reprint author), Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. EM vlbrown@umich.edu RI Drake, John/D-6622-2012; OI Drake, John/0000-0003-4646-1235 FU James S. McDonnell Foundation; National Science Foundation [DEB-0917853]; RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN266200700007C] FX This work was supported by the James S. McDonnell Foundation and the National Science Foundation (DEB-0917853). P.R. was also supported by the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. D. S. and J.B. were also supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract HHSN266200700007C. Data were collected by numerous biologists from state and federal agencies participating in the US Early Detection System for HPAI in wild birds, and made available through the USDA-APHIS Wildlife Services National Wildlife Disease Program. The opinions expressed herein are those of the author(s) and do not necessarily reflect the views of any of the funding agencies. NR 55 TC 7 Z9 7 U1 0 U2 204 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1742-5689 J9 J R SOC INTERFACE JI J. R. Soc. Interface PD FEB 6 PY 2013 VL 10 IS 79 AR 20120804 DI 10.1098/rsif.2012.0804 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 048VB UT WOS:000311940200009 PM 23173198 ER PT J AU White, C Yuan, XJ Schmidt, PJ Bresciani, E Samuel, TK Campagna, D Hall, C Bishop, K Calicchio, ML Lapierre, A Ward, DM Liu, P Fleming, MD Hamza, I AF White, Carine Yuan, Xiaojing Schmidt, Paul J. Bresciani, Erica Samuel, Tamika K. Campagna, Dean Hall, Caitlin Bishop, Kevin Calicchio, Monica L. Lapierre, Ariane Ward, Diane M. Liu, Paul Fleming, Mark D. Hamza, Iqbal TI HRG1 Is Essential for Heme Transport from the Phagolysosome of Macrophages during Erythrophagocytosis SO CELL METABOLISM LA English DT Article ID IRON-METABOLISM; GENE-EXPRESSION; SYSTEM; IDENTIFICATION; OXYGENASE; MICE; ERYTHROPOIESIS; OVERLOAD; ANEMIA; BACH1 AB Adult humans have about 25 trillion red blood cells (RBCs), and each second we recycle about 5 million RBCs by erythrophagocytosis (EP) in macrophages of the reticuloendothelial system. Despite the central role for EP in mammalian iron metabolism, the molecules and pathways responsible for heme trafficking during EP remain unknown. Here, we show that the mammalian homolog of HRG1, a transmembrane heme permease in C. elegans, is essential for macrophage iron homeostasis and transports heme from the phagolysosome to the cytoplasm during EP. HRG1 is strongly expressed in macrophages of the reticuloendothelial system and specifically localizes to the phagolysosomal membranes during EP. Depletion of Hrg1 in mouse macrophages causes attenuation of heme transport from the phagolysosomal compartment. Importantly, missense polymorphisms in human HRG1 are defective in heme transport. Our results reveal HRG1 as the long-sought heme transporter for heme-iron recycling in macrophages and suggest that genetic variations in HRG1 could be modifiers of human iron metabolism. C1 [White, Carine; Yuan, Xiaojing; Samuel, Tamika K.; Hall, Caitlin; Hamza, Iqbal] Univ Maryland, Dept Anim & Avian Sci, College Pk, MD 20742 USA. [White, Carine; Yuan, Xiaojing; Samuel, Tamika K.; Hall, Caitlin; Hamza, Iqbal] Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. [Schmidt, Paul J.; Campagna, Dean; Calicchio, Monica L.; Lapierre, Ariane; Fleming, Mark D.] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Pathol, Boston, MA 02115 USA. [Bresciani, Erica; Liu, Paul] NHGRI, Oncogenesis & Dev Sect, NIH, Bethesda, MD 20892 USA. [Bishop, Kevin] NHGRI, Zebrafish Core, NIH, Bethesda, MD 20892 USA. [Ward, Diane M.] Univ Utah, Sch Med, Dept Internal Med, Salt Lake City, UT 84132 USA. RP Hamza, I (reprint author), Univ Maryland, Dept Anim & Avian Sci, College Pk, MD 20742 USA. EM hamza@umd.edu RI Liu, Paul/A-7976-2012 OI Liu, Paul/0000-0002-6779-025X FU National Institutes of Health [F32DK088439, R01DK80011, HL26922, DK85035]; NIH/NHGRI Intramural Research Program FX We thank Norma Andrews for the adenoviral plasmids, Vivek Malhotra for HRP plasmid, Caiyong Chen for synthesis of HRP targeting plasmids, Naoko Makise for help with macrophage setup, and Raman Sood for helpful discussions. This work was supported by funding from the National Institutes of Health F32DK088439 (C. W.), R01DK80011 (M. D. F.), HL26922 (D. M. W.), DK85035 (I. H.), and the NIH/NHGRI Intramural Research Program (P. L.). Experimental design and execution were as follows: macrophage and mammalian cell culture, C. W., T. K. S., X.Y., C. H., D. M. W., and I. H.; yeast experiments, X.Y. and I. H.; mice and human data, P.J.S., D. C., A. L., M. L. C., and M. D. F.; zebrafish experiments, E. B., K. B., P. L., and I. H.; C. W. and I. H. wrote the manuscript. All authors commented on the manuscript. NR 57 TC 41 Z9 41 U1 0 U2 7 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 FEB 5 PY 2013 VL 17 IS 2 BP 261 EP 270 DI 10.1016/j.cmet.2013.01.005 PG 10 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 242TL UT WOS:000326265000012 PM 23395172 ER PT J AU Ghosh, MC Zhang, DL Jeong, SY Kovtunovych, G Ollivierre-Wilson, H Noguchi, A Tu, T Senecal, T Robinson, G Crooks, DR Tong, WH Ramaswamy, K Singh, A Graham, BB Tuder, RM Yu, ZX Eckhaus, M Lee, J Springer, DA Rouault, TA AF Ghosh, Manik C. Zhang, De-Liang Jeong, Suh Young Kovtunovych, Gennadiy Ollivierre-Wilson, Hayden Noguchi, Audrey Tu, Tiffany Senecal, Thomas Robinson, Gabrielle Crooks, Daniel R. Tong, Wing-Hang Ramaswamy, Kavitha Singh, Anamika Graham, Brian B. Tuder, Rubin M. Yu, Zu-Xi Eckhaus, Michael Lee, Jaekwon Springer, Danielle A. Rouault, Tracey A. TI Deletion of Iron Regulatory Protein 1 Causes Polycythemia and Pulmonary Hypertension in Mice through Translational Derepression of HIF2 alpha SO CELL METABOLISM LA English DT Article ID HYPOXIA-INDUCIBLE FACTORS; ARTERIAL-HYPERTENSION; CHUVASH POLYCYTHEMIA; TARGETED DELETION; MUTATION; HOMEOSTASIS; ERYTHROCYTOSIS; DEFICIENCY; METABOLISM; PHYSIOLOGY AB Iron regulatory proteins (Irps) 1 and 2 posttranscriptionally control the expression of transcripts that contain iron-responsive element (IRE) sequences, including ferritin, ferroportin, transferrin receptor, and hypoxia-inducible factor 2 alpha (HIF2 alpha). We report here that mice with targeted deletion of Irp1 developed pulmonary hypertension and polycythemia that was exacerbated by a low-iron diet. Hematocrits increased to 65% in iron-starved mice, and many polycythemic mice died of abdominal hemorrhages. Irp1 deletion enhanced HIF2a protein expression in kidneys of Irp1(-/-) mice, which led to increased erythropoietin (EPO) expression, polycythemia, and concomitant tissue iron deficiency. Increased HIF2a expression in pulmonary endothelial cells induced high expression of endothelin-1, likely contributing to the pulmonary hypertension of Irp1(-/-) mice. Our results reveal why anemia is an early physiological consequence of iron deficiency, highlight the physiological significance of Irp1 in regulating erythropoiesis and iron distribution, and provide important insights into the molecular pathogenesis of pulmonary hypertension. C1 [Ghosh, Manik C.; Zhang, De-Liang; Jeong, Suh Young; Kovtunovych, Gennadiy; Ollivierre-Wilson, Hayden; Tu, Tiffany; Senecal, Thomas; Robinson, Gabrielle; Crooks, Daniel R.; Tong, Wing-Hang; Ramaswamy, Kavitha; Singh, Anamika; Rouault, Tracey A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Mol Med, Bethesda, MD 20892 USA. [Noguchi, Audrey; Yu, Zu-Xi; Springer, Danielle A.] NHLBI, Murine Phenotyping Core, Bethesda, MD 20892 USA. [Graham, Brian B.; Tuder, Rubin M.] Univ Colorado, Sch Med, Div Pulm Sci & Crit Care Med, Program Translat Lung Res,Dept Med, Denver, CO 80262 USA. [Eckhaus, Michael] NIH, Vet Resources Program, Bethesda, MD 20892 USA. [Lee, Jaekwon] Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. RP Rouault, TA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Mol Med, Bethesda, MD 20892 USA. EM rouault@mail.nih.gov RI Zhang, Deliang/F-7848-2013; OI Zhang, Deliang/0000-0001-9478-5344; Jeong, Suh Young/0000-0002-6376-7001 FU NICHD; NHLBI; NIH [RC1HL100849] FX This work was supported by the intramural programs of NICHD and NHLBI. We thank Gregory Holmes-Hampton for helpful discussions, Michele Allen for her help in mouse studies, Shawn Kozlov for blood gas measurements, and Javier Seravalli for performing metal measurements. R.M.T.'s research was supported by NIH (RC1HL100849). M. C. G. and D.-L.Z. designed the study, generated data, performed analyses, and wrote the paper. S.Y.J. and D. A. S. generated data, performed analyses, and wrote the paper. G. K., A.N., D. R. C., B. B. G., Z.-X.Y., M. E., and J.L. generated data and performed analyses. H.O.-W., T. T., T. S., G. R., K. R., and A. S. generated data. W.-H. T. and R. M. T. provided substantial intellectual contribution. T. A. R. designed the study, performed analyses, and wrote the paper. NR 37 TC 48 Z9 48 U1 0 U2 12 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 FEB 5 PY 2013 VL 17 IS 2 BP 271 EP 281 DI 10.1016/j.cmet.2012.12.016 PG 11 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 242TL UT WOS:000326265000013 PM 23395173 ER PT J AU Mandal, S Mandal, A Johansson, HE Orjalo, AV Park, MH AF Mandal, Swati Mandal, Ajeet Johansson, Hans E. Orjalo, Arturo V. Park, Myung Hee TI Depletion of cellular polyamines, spermidine and spermine, causes a total arrest in translation and growth in mammalian cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE polyamine depletion; translational regulation; cell proliferation; RNA-FISH ID INITIATION-FACTOR 5A; YEAST SACCHAROMYCES-CEREVISIAE; HAMSTER OVARY CELLS; ORNITHINE-DECARBOXYLASE; HYPUSINE MODIFICATION; TRANSGENIC MICE; S-PHASE; N-1-ACETYLTRANSFERASE; OVEREXPRESSION; CANCER AB The polyamines, putrescine, spermidine, and spermine, are essential polycations, intimately involved in the regulation of cellular proliferation. Although polyamines exert dynamic effects on the conformation of nucleic acids and macromolecular synthesis in vitro, their specific functions in vivo are poorly understood. We investigated the cellular function of polyamines by overexpression of a key catabolic enzyme, spermidine/spermine N-1-acetyltransferase 1 (SAT1) in mammalian cells. Transient cotransfection of HeLa cells with GFP and SAT1 vectors suppressed GFP protein expression without lowering its mRNA level, an indication that the block in GFP expression was not at transcription, but at translation. Fluorescence single-cell imaging also revealed specific inhibition of endogenous protein synthesis in the SAT1 overexpressing cells, without any inhibition of synthesis of DNA or RNA. Overexpression of SAT1 using a SAT1 adenovirus led to rapid depletion of cellular spermidine and spermine, total inhibition of protein synthesis, and growth arrest within 24 h. The SAT1 effect is most likely due to depletion of spermidine and spermine, because stable polyamine analogs that are not substrates for SAT1 restored GFP and endogenous protein synthesis. Loss of polysomes with increased 80S monosomes in the polyamine-depleted cells suggests a direct role for polyamines in translation initiation. Our data provide strong evidence for a primary function of polyamines, spermidine and spermine, in translation in mammalian cells. C1 [Mandal, Swati; Mandal, Ajeet; Park, Myung Hee] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Johansson, Hans E.; Orjalo, Arturo V.] Biosearch Technol, Novato, CA 94949 USA. RP Park, MH (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. EM mhpark@nih.gov OI Johansson, Hans/0000-0001-9495-6107 FU Intramural Research Program of NIDCR, NIH FX We thank Edith C. Wolff [National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH)] for helpful suggestions on the manuscript; and Bill Swaim (NIDCR, NIH), Michael J. Kruhlak (National Cancer Institute, NIH), and Duck-Yeon Lee (National Heart, Blood, and Lung Institute, NIH) for providing their core facilities and technical instructions. The research was supported in part by the Intramural Research Program of NIDCR, NIH. NR 39 TC 48 Z9 50 U1 2 U2 36 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 FEB 5 PY 2013 VL 110 IS 6 BP 2169 EP 2174 DI 10.1073/pnas.1219002110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 093RQ UT WOS:000315209800048 PM 23345430 ER PT J AU Yan, D Zhu, Y Walsh, T Xie, DH Yuan, HJ Sirmaci, A Fujikawa, T Wong, ACY Loh, TL Du, LL Grati, M Vlajkovic, SM Blanton, S Ryan, AF Chen, ZY Thorne, PR Kachar, B Tekin, M Zhao, HB Housley, GD King, MC Liu, XZ AF Yan, Denise Zhu, Yan Walsh, Tom Xie, Dinghua Yuan, Huijun Sirmaci, Asli Fujikawa, Taro Wong, Ann Chi Yan Loh, Tze L. Du, Lilin Grati, M'hamed Vlajkovic, Srdjan M. Blanton, Susan Ryan, Allen F. Chen, Zheng-Yi Thorne, Peter R. Kachar, Bechara Tekin, Mustafa Zhao, Hong-Bo Housley, Gary D. King, Mary-Claire Liu, Xue Z. TI Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE channel; deafness; genomics; presbycusis ID ION CHANNELS; AUDITORY NEUROTRANSMISSION; SOUND TRANSDUCTION; COCHLEAR FUNCTION; RAT COCHLEA; SUBUNIT; MOUSE; LOCALIZATION; STEREOCILIA; EXPRESSION AB Age-related hearing loss and noise-induced hearing loss are major causes of human morbidity. Here we used genetics and functional studies to showthat a shared cause of these disordersmay be loss of function of the ATP-gated P2X(2) receptor (ligand-gated ion channel, purinergic receptor 2) that is expressed in sensory and supporting cells of the cochlea. Genomic analysis of dominantly inherited, progressive sensorineural hearing loss DFNA41 in a six-generation kindred revealed a rare heterozygous allele, P2RX2 c.178G > T (p.V60L), at chr12: 133,196,029, which cosegregated with fully penetrant hearing loss in the index family, and also appeared in a second family with the same phenotype. The mutation was absent from more than 7,000 controls. P2RX2 p.V60L abolishes two hallmark features of P2X(2) receptors: ATP-evoked inward current response and ATP-stimulated macropore permeability, measured as loss of ATP-activated FM1-43 fluorescence labeling. Coexpression of mutant and WT P2X(2) receptor subunits significantly reduced ATP-activated membrane permeability. P2RX2-null mice developed severe progressive hearing loss, and their early exposure to continuous moderate noise led to high-frequency hearing loss as young adults. Similarly, among family members heterozygous for P2RX2 p.V60L, noise exposure exacerbated high-frequency hearing loss in young adulthood. Our results suggest that P2X(2) function is required for life-long normal hearing and for protection from exposure to noise. C1 [Yan, Denise; Du, Lilin; Grati, M'hamed; Liu, Xue Z.] Univ Miami, Sch Med, Dept Otolaryngol, Miami, FL 33136 USA. [Zhu, Yan; Zhao, Hong-Bo] Univ Kentucky, Med Ctr, Dept Otolaryngol, Lexington, KY 40536 USA. [Walsh, Tom; King, Mary-Claire] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Walsh, Tom; King, Mary-Claire] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Xie, Dinghua; Liu, Xue Z.] Cent S Univ, Dept Otolaryngol Head & Neck Surg, Xiangya Hosp 2, Changsha 410011, Hunan, Peoples R China. [Yuan, Huijun] Chinese Peoples Liberat Army Gen Hosp, Inst Otolaryngol, Beijing 100853, Peoples R China. [Sirmaci, Asli; Blanton, Susan; Tekin, Mustafa; Liu, Xue Z.] Univ Miami, Sch Med, Dept Human Genet, Miami, FL 33136 USA. [Fujikawa, Taro; Grati, M'hamed; Kachar, Bechara] Natl Inst Deafness & Other Commun Disorders, Lab Cell Struct & Dynam, Sect Struct Cell Biol, NIH, Bethesda, MD 20892 USA. [Wong, Ann Chi Yan; Loh, Tze L.; Housley, Gary D.] Univ New S Wales, Sch Med Sci, Translat Neurosci Facil, Sydney, NSW 2052, Australia. [Wong, Ann Chi Yan; Loh, Tze L.; Housley, Gary D.] Univ New S Wales, Sch Med Sci, Dept Physiol, Sydney, NSW 2052, Australia. [Vlajkovic, Srdjan M.; Thorne, Peter R.] Univ Auckland, Sch Med Sci, Dept Physiol, Auckland 1, New Zealand. [Vlajkovic, Srdjan M.; Thorne, Peter R.] Univ Auckland, Sch Med Sci, Ctr Brain Res, Auckland 1, New Zealand. [Vlajkovic, Srdjan M.; Thorne, Peter R.] Univ Auckland, Sch Populat Hlth, Sect Audiol, Auckland 1, New Zealand. [Ryan, Allen F.] Univ Calif San Diego, Dept Otolaryngol, La Jolla, CA 92093 USA. [Ryan, Allen F.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Chen, Zheng-Yi] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Eaton Peabody Lab,Dept Otol & Laryngol, Boston, MA 02114 USA. RP King, MC (reprint author), Univ Washington, Dept Med, Seattle, WA 98195 USA. EM mcking@u.washington.edu; xliu@med.miami.edu OI Walsh, Tom/0000-0002-8875-0310; Wong, Ann CY/0000-0001-7011-0369; Housley, Gary/0000-0002-8413-588X; Vlajkovic, Srdjan/0000-0001-8548-6844 FU National Institutes of Health, National Institute on Deafness and Other Communication Disorders [R01 DC012546, R01 DC005575, R01 DC005989, R01 HL105631, R01 DC009645, R01 DC000139, R01 DC005641]; Veterans' Administration; Australia National Health and Medical Research Council [630618]; New Zealand Marsden Fund; Health Research Council and Deafness Research Foundation; People's Republic of China National Natural Science Foundation [30528025] FX We thank the families for their participation in the study. We thank Menwei Cai, Pu Dai, Dongyi Han, Kaisun Li, Chunyu Liang, Zian Xiao, and Shiming Yang for contributions to the fieldwork in China; Anne Thornton, Ming Lee, Xiaomai Ouyang, and Suleyman Gulsuner for contributions to genomics and bioinformatics; Kwang Pak, Eduardo Chavez, Jeremy Pinyon, Rachel Morton-Jones, Sherif Tadros, and Yogeesan Sivakumaran for contributions to the mouse experiments; Debra Cockayne for supporting the establishment of the mouse model; Edward Crawford for designing and engineering the environmental chambers; and Karen B. Avraham, Walter Nance, Yanbin Zhang, and Jianxin Bao for helpful discussions. This work was supported by the National Institutes of Health, National Institute on Deafness and Other Communication Disorders [Grants R01 DC012546 (to X.Z.L.), R01 DC005575 (to X.Z.L.), R01 DC005989 (to H.-B.Z.), R01 HL105631 (to Y.Z.), R01 DC009645 (to M. T.), R01 DC000139 (to A. F. R.), and R01 DC005641 (to M.-C. K. and T. W.), and the intramural program (B. K.)], the Veterans' Administration (A. F. R.), the Australia National Health and Medical Research Council [Grant 630618 (to G. D. H. and A. F. R.)], the New Zealand Marsden Fund (G. D. H.) and Health Research Council and Deafness Research Foundation (P. R. T., G. D. H., and S. M. V.), and the People's Republic of China National Natural Science Foundation [Grant 30528025 (to X.Z.L.)]. NR 40 TC 31 Z9 36 U1 3 U2 19 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 FEB 5 PY 2013 VL 110 IS 6 BP 2228 EP 2233 DI 10.1073/pnas.1222285110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 093RQ UT WOS:000315209800058 PM 23345450 ER PT J AU Baruch, K Ron-Harel, N Gal, H Deczkowska, A Shifrut, E Ndifon, W Mirlas-Neisberg, N Cardon, M Vaknin, I Cahalon, L Berkutzki, T Mattson, MP Gomez-Pinilla, F Friedman, N Schwartz, M AF Baruch, Kuti Ron-Harel, Noga Gal, Hilah Deczkowska, Aleksandra Shifrut, Eric Ndifon, Wilfred Mirlas-Neisberg, Nataly Cardon, Michal Vaknin, Ilan Cahalon, Liora Berkutzki, Tamara Mattson, Mark P. Gomez-Pinilla, Fernando Friedman, Nir Schwartz, Michal TI CNS-specific immunity at the choroid plexus shifts toward destructive Th2 inflammation in brain aging SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE blood-cerebrospinal fluid barrier; brain senescence; neuroinflammation ID CENTRAL-NERVOUS-SYSTEM; CD4(+) T-CELLS; CENTRAL MEMORY; CEREBROSPINAL-FLUID; DENDRITIC CELLS; IFN-GAMMA; RAT-BRAIN; NEUROGENESIS; IL-4; LUNG AB The adaptive arm of the immune system has been suggested as an important factor in brain function. However, given the fact that interactions of neurons or glial cells with T lymphocytes rarely occur within the healthy CNS parenchyma, the underlying mechanism is still a mystery. Here we found that at the interface between the brain and blood circulation, the epithelial layers of the choroid plexus (CP) are constitutively populated with CD4(+) effector memory cells with a T-cell receptor repertoire specific to CNS antigens. With age, whereas CNS specificity in this compartment was largely maintained, the cytokine balance shifted in favor of the T helper type 2 (Th2) response; the Th2-derived cytokine IL-4 was elevated in the CP of old mice, relative to IFN-gamma, which decreased. We found this local cytokine shift to critically affect the CP epithelium, triggering it to produce the chemokine CCL11 shown to be associated with cognitive dysfunction. Partial restoration of cognitive ability in aged mice, by lymphopenia-induced homeostasis-driven proliferation of memory T cells, was correlated with restoration of the IL-4:IFN-gamma ratio at the CP and modulated the expression of plasticity-related genes at the hippocampus. Our data indicate that the cytokine milieu at the CP epithelium is affected by peripheral immunosenescence, with detrimental consequences to the aged brain. Amenable to immunomodulation, this interface is a unique target for arresting age-related cognitive decline. C1 [Baruch, Kuti; Deczkowska, Aleksandra; Mirlas-Neisberg, Nataly; Cardon, Michal; Vaknin, Ilan; Cahalon, Liora; Berkutzki, Tamara; Schwartz, Michal] Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel. [Gal, Hilah; Shifrut, Eric; Ndifon, Wilfred; Friedman, Nir] Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel. [Ron-Harel, Noga] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Gomez-Pinilla, Fernando] Univ Calif Los Angeles, Dept Integrat Biol & Physiol, Los Angeles, CA 90095 USA. [Gomez-Pinilla, Fernando] Univ Calif Los Angeles, Dept Neurosurg, Los Angeles, CA 90095 USA. RP Schwartz, M (reprint author), Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel. EM michal.schwartz@weizmann.ac.il RI Baruch, Kuti/I-3535-2016; OI Baruch, Kuti/0000-0002-1466-8795; Shifrut, Eric/0000-0001-6827-0128 FU European Research Council; National Institute on Aging FX We thank Dr. Gilad Kunis for technical assistance, Dr. Shelley Schwarzbaum for editing the manuscript, Dr. Hillary Voet for statistical consultation, and Margalit Azoulay for animal handling. This research was supported by a European Research Council Grant Award, a Seventh Framework Programme HEALTH-2011 Grant (to M. S.), and by the Intramural Research Program of the National Institute on Aging (to M. P. M.). N.F. is the incumbent Pauline Recanati Career Development Chair of Immunology. M. S. holds The Maurice and Ilse Katz Professorial Chair in Neuroimmunology. NR 47 TC 71 Z9 71 U1 1 U2 11 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 FEB 5 PY 2013 VL 110 IS 6 BP 2264 EP 2269 DI 10.1073/pnas.1211270110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 093RQ UT WOS:000315209800064 PM 23335631 ER PT J AU Khormaee, S Choi, Y Shen, MJ Xu, BY Wu, HT Griffiths, GL Chen, RJ Slater, NKH Park, JK AF Khormaee, Sariah Choi, Yong Shen, Michael J. Xu, Biying Wu, Haitao Griffiths, Gary L. Chen, Rongjun Slater, Nigel K. H. Park, John K. TI Endosomolytic Anionic Polymer for the Cytoplasmic Delivery of siRNAs in Localized In Vivo Applications SO ADVANCED FUNCTIONAL MATERIALS LA English DT Article DE siRNA delivery; anionic polymers; endosomes; tumor treatment; glioblastoma; stathmin ID RESPONSIVE PSEUDO-PEPTIDES; MAMMALIAN-CELLS; PH; RNAI; INTERFERENCE; NITROSOUREAS; DISRUPTION; CONJUGATE; STATHMIN AB The use of small interfering RNAs (siRNAs) to down-regulate the expression of disease-associated proteins carries significant promise for the treatment of a variety of clinical disorders. One of the main barriers to the widespread clinical use of siRNAs, however, is their entrapment and degradation within the endolysosomal pathway of target cells. Here, the trafficking and function of PP75, a nontoxic, biodegradable, lipid membrane disruptive anionic polymer composed of phenylalanine derivatized poly(L-lysine isophthalamide) is reported. PP75 is readily endocytosed by cells, safely permeabilizes endolysosomes in a pH dependent manner and facilitates the transfer of co-endocytosed materials directly into the cytoplasm. The covalent attachment of siRNAs to PP75 using disulfide linkages generates conjugates that effectively traffic siRNAs to the cytoplasm of target cells both in vitro and in vivo. In a subcutaneous malignant glioma tumor model, a locally delivered PP75-stathmin siRNA conjugate decreases stathmin expression in tumor cells and, in combination with the nitrosourea chemotherapy carmustine, is highly effective at inhibiting tumor growth. PP75 may be clinically useful for the local delivery of siRNAs, in particular for the treatment of solid tumors. C1 [Khormaee, Sariah; Choi, Yong; Shen, Michael J.; Park, John K.] NINDS, Surg & Mol Neurooncol Unit, NIH, Bethesda, MD 20892 USA. [Khormaee, Sariah; Slater, Nigel K. H.] Univ Cambridge, Dept Chem Engn & Biotechnol, Cambridge CB2 3RA, England. [Xu, Biying; Wu, Haitao; Griffiths, Gary L.] NHLBI, Imaging Probe Dev Ctr, NIH, Rockville, MD 20850 USA. [Chen, Rongjun] Univ Leeds, Ctr Mol Nanosci, Sch Chem, Leeds LS2 9JT, W Yorkshire, England. RP Khormaee, S (reprint author), NINDS, Surg & Mol Neurooncol Unit, NIH, Bethesda, MD 20892 USA. EM parkjk@ninds.nih.gov OI Chen, Rongjun/0000-0002-8133-5472 FU NINDS intramural research program of the NIH; NHLBI intramural research program of the NIH; NIH/Marshall fund; NIH Roadmap for Medical Research Initiative of the NIH FX This work was supported by the NINDS and NHLBI intramural research programs of the NIH and the NIH/Marshall fund. The Imaging Probe Development Center is supported by the NIH Roadmap for Medical Research Initiative of the NIH. We thank Dragan Maric for assistance with FACS analyses and Carolyn Smith for assistance with microscopy. There are no conflicts of interest to report. NR 25 TC 8 Z9 8 U1 1 U2 51 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1616-301X J9 ADV FUNCT MATER JI Adv. Funct. Mater. PD FEB 5 PY 2013 VL 23 IS 5 BP 565 EP 574 DI 10.1002/adfm.201201945 PG 10 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 083MO UT WOS:000314468600005 ER PT J AU Himes, SK Scheidweiler, KB Tassiopoulos, K Kacanek, D Hazra, R Rich, K Huestis, MA AF Himes, Sarah K. Scheidweiler, Karl B. Tassiopoulos, Katherine Kacanek, Deborah Hazra, Rohan Rich, Kenneth Huestis, Marilyn A. CA Pediat HIV AIDS Cohort Study TI Development and Validation of the First Liquid Chromatography-Tandem Mass Spectrometry Assay for Simultaneous Quantification of Multiple Antiretrovirals in Meconium SO ANALYTICAL CHEMISTRY LA English DT Article ID PERSISTENT MITOCHONDRIAL DYSFUNCTION; REVERSE-TRANSCRIPTASE INHIBITOR; UNINFECTED CHILDREN; IN-UTERO; MATERNAL INTERVIEW; AMNIOTIC-FLUID; LC-MS; EXPOSURE; PREGNANCY; PLASMA AB A novel method for the simultaneous quantification of 16 antiretroviral (ARV) drugs and 4 metabolites in meconium was developed and validated. Quantification of 6 nucleoside/nucleotide reverse transcriptase inhibitors, 2 non-nucleoside reverse transcriptase inhibitors, 7 protease inhibitors, and 1 integrase inhibitor was achieved in 0.25 g of meconium. Specimen preparation included methanol homogenization and solid-phase extraction. Separate positive and negative polarity multiple reaction monitoring mode injections were required to achieve sufficient sensitivity. Linearity ranged from 10 to 75 ng/g up to 2500 ng/g for most analytes and 100-500 ng/g up to 25 000 ng/g for some; all correlation coefficients were >= 99. Extraction efficiencies from meconium were 32.8-119.5% with analytical recovery of 80.3-108.3% and total imprecision of 2.2-11.0% for all quantitative analytes. Two analytes with analytical recovery (70.0-138.5%) falling outside the 80-120% criteria range were considered semiquantitative. Matrix effects were -98.3-47.0% and -98.0-67.2% for analytes and internal standards, respectively. Analytes were stable (>75%) at room temperature for 24 h, 4 degrees C for 3 days, -20 degrees C for 3 freeze-thaw cycles over 3 days, and on the autosampler. Method applicability was demonstrated by analyzing meconium from HIV-uninfected infants born to HIV-positive mothers on ARV therapy. This method can be used as a tool to investigate the potential effects of in utero ARV exposure on childhood health and neurodevelopmental outcomes. C1 [Himes, Sarah K.; Scheidweiler, Karl B.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab Sect, Intramural Res Program, Baltimore, MD 21224 USA. [Tassiopoulos, Katherine] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Kacanek, Deborah] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Hazra, Rohan] NICHD, Pediat Adolescent & Maternal AIDS Branch, NIH, Bethesda, MD 20892 USA. [Rich, Kenneth] Univ Illinois, Dept Pediat, Chicago, IL 60612 USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab Sect, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Drug Abuse; National Institute of Allergy and Infectious Diseases; Office of AIDS Research; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Institute on Deafness and Other Communication Disorders; National Heart Lung and Blood Institute; National Institute of Dental and Craniofacial Research; National Institute on Alcohol Abuse and Alcoholism through Harvard University School of Public Health [HD052102, 3 U01 HD052102-05S1, 3 U01 HD052102-06S3]; Tulane University School of Medicine [HD052104, 3U01HD052104-06S1] FX We thank the children and families for their participation in PHACS and the individuals and institutions involved in the conduct of PHACS. The study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development with cofunding from the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the Office of AIDS Research, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication Disorders, the National Heart Lung and Blood Institute, the National Institute of Dental and Craniofacial Research, and the National Institute on Alcohol Abuse and Alcoholism, through cooperative agreements with the Harvard University School of Public Health (HD052102, 3 U01 HD052102-05S1, 3 U01 HD052102-06S3) (Principal Investigator: George Seage; Project Director: Julie Alperen) and the Tulane University School of Medicine (HD052104, 3U01HD052104-06S1) (Principal Investigator: Russell Van Dyke; Co-Principal Investigator: Kenneth Rich; Project Director: Patrick Davis). Data management services were provided by Frontier Science and Technology Research Foundation (PI: Suzanne Siminski), and regulatory services and logistical support were provided by Westat, Inc (PI: Julie Davidson). NR 36 TC 7 Z9 7 U1 1 U2 20 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD FEB 5 PY 2013 VL 85 IS 3 BP 1896 EP 1904 DI 10.1021/ac303188j PG 9 WC Chemistry, Analytical SC Chemistry GA 086IA UT WOS:000314676100092 PM 23256731 ER PT J AU Jensen, RA Sim, XL Li, XH Cotch, MF Ikram, MK Holliday, EG Eiriksdottir, G Harris, TB Jonasson, F Klein, BEK Launer, LJ Smith, AV Boerwinkle, E Cheung, N Hewitt, AW Liew, G Mitchell, P Wang, JJ Attia, J Scott, R Glazer, NL Lumley, T McKnight, B Psaty, BM Taylor, K Hofman, A de Jong, PTVM Rivadeneira, F Uitterlinden, AG Tay, WT Teo, YY Seielstad, M Liu, JJ Cheng, CY Saw, SM Aung, T Ganesh, SK O'Donnell, CJ Nalls, MA Wiggins, KL Kuo, JZ van Duijn, CM Gudnason, V Klein, R Siscovick, DS Rotter, JI Tai, ES Vingerling, J Wong, TY AF Jensen, Richard A. Sim, Xueling Li, Xiaohui Cotch, Mary Frances Ikram, M. Kamran Holliday, Elizabeth G. Eiriksdottir, Gudny Harris, Tamara B. Jonasson, Fridbert Klein, Barbara E. K. Launer, Lenore J. Smith, Albert Vernon Boerwinkle, Eric Cheung, Ning Hewitt, Alex W. Liew, Gerald Mitchell, Paul Wang, Jie Jin Attia, John Scott, Rodney Glazer, Nicole L. Lumley, Thomas McKnight, Barbara Psaty, Bruce M. Taylor, Kent Hofman, Albert de Jong, Paulus T. V. M. Rivadeneira, Fernando Uitterlinden, Andre G. Tay, Wan-Ting Teo, Yik Ying Seielstad, Mark Liu, Jianjun Cheng, Ching-Yu Saw, Seang-Mei Aung, Tin Ganesh, Santhi K. O'Donnell, Christopher J. Nalls, Mike A. Wiggins, Kerri L. Kuo, Jane Z. van Duijn, Cornelia M. Gudnason, Vilmundur Klein, Ronald Siscovick, David S. Rotter, Jerome I. Tai, E. Shong Vingerling, Johannes Wong, Tien Y. CA Blue Mt Eye Study GWAS Team CKDGen Consortium TI Genome-Wide Association Study of Retinopathy in Individuals without Diabetes SO PLOS ONE LA English DT Article ID RETINAL MICROVASCULAR ABNORMALITIES; ANTIHYPERTENSIVE DRUG THERAPIES; ATHEROSCLEROSIS RISK; BLOOD-PRESSURE; CARDIOVASCULAR HEALTH; HYPERTENSION; COMMUNITIES; MORTALITY; DESIGN; STROKE AB Background: Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes. Methods: A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy. Results: No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, -1.3 +/- 0.23 (beta +/- standard error), p=6.6x10(-9). Evidence suggests this was a false positive finding. The minor allele frequency was low (similar to 2%), the quality of the imputation was moderate (r(2) similar to 0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension. Conclusions: This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases. C1 [Jensen, Richard A.; Lumley, Thomas; McKnight, Barbara; Psaty, Bruce M.; Wiggins, Kerri L.; Siscovick, David S.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Jensen, Richard A.; Psaty, Bruce M.; Wiggins, Kerri L.; Siscovick, David S.] Univ Washington, Dept Med, Seattle, WA USA. [Sim, Xueling; Teo, Yik Ying] Natl Univ Singapore, Ctr Mol Epidemiol, Singapore 117548, Singapore. [Li, Xiaohui; Taylor, Kent; Kuo, Jane Z.; Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Cotch, Mary Frances] NEI, Div Epidemiol & Clin Applicat, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Ikram, M. Kamran; Tay, Wan-Ting; Cheng, Ching-Yu; Saw, Seang-Mei; Aung, Tin; Wong, Tien Y.] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore. [Ikram, M. Kamran; Vingerling, Johannes] Erasmus MC, Dept Ophthalmol, Rotterdam, Netherlands. [Holliday, Elizabeth G.; Attia, John] Univ Newcastle, Sch Med & Publ Hlth, Newcastle, NSW 2300, Australia. [Eiriksdottir, Gudny; Smith, Albert Vernon; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Jonasson, Fridbert; Smith, Albert Vernon; Gudnason, Vilmundur] Univ Iceland, Dept Med, Reykjavik, Iceland. [Jonasson, Fridbert] Landspitalinn Univ Hosp, Dept Ophthalmol, Reykjavik, Iceland. [Klein, Barbara E. K.; Klein, Ronald] Univ Wisconsin, Sch Med & Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX USA. [Cheung, Ning; Hewitt, Alex W.; Liew, Gerald; Wang, Jie Jin; Wong, Tien Y.] Univ Melbourne, Ctr Eye Res Australia, Melbourne, Vic, Australia. [Liew, Gerald; Mitchell, Paul; Wang, Jie Jin] Univ Sydney, Ctr Vis Res, Dept Ophthalmol, Sydney, NSW 2006, Australia. [Liew, Gerald; Mitchell, Paul; Wang, Jie Jin] Univ Sydney, Westmead Millennium Inst, Sydney, NSW 2006, Australia. [Attia, John] John Hunter Hosp, Dept Med, Newcastle, NSW, Australia. [Attia, John] Hunter Med Res Inst, Newcastle, NSW, Australia. [Scott, Rodney] Univ Newcastle, Sch Biomed Sci, Newcastle, NSW 2300, Australia. [Glazer, Nicole L.] Boston Univ, Sch Med, Sect Prevent Med & Epidemiol, Boston, MA 02118 USA. [Lumley, Thomas] Univ Auckland, Dept Stat, Auckland 1, New Zealand. [McKnight, Barbara] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Psaty, Bruce M.; Siscovick, David S.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G.; van Duijn, Cornelia M.; Vingerling, Johannes] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [de Jong, Paulus T. V. M.] Netherlands Inst Neurosci, Amsterdam, Netherlands. [de Jong, Paulus T. V. M.] Univ Amsterdam, Acad Med Ctr, Dept Ophthalmol, NL-1105 AZ Amsterdam, Netherlands. [Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Uitterlinden, Andre G.] Erasmus MC, Dept Clin Chem, Rotterdam, Netherlands. [Teo, Yik Ying; Cheng, Ching-Yu; Saw, Seang-Mei; Tai, E. Shong] Natl Univ Singapore, Dept Epidemiol & Publ Hlth, Singapore 117548, Singapore. [Teo, Yik Ying] Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore 117548, Singapore. [Teo, Yik Ying] Natl Univ Singapore, NUS Grad Sch Integrat Sci & Engn, Singapore 117548, Singapore. [Teo, Yik Ying; Liu, Jianjun] Agcy Sci Technol & Res, Genome Inst Singapore, Singapore, Singapore. [Seielstad, Mark] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Cheng, Ching-Yu; Saw, Seang-Mei; Aung, Tin; Wong, Tien Y.] Natl Univ Singapore, Dept Ophthalmol, Singapore 117548, Singapore. [Ganesh, Santhi K.] Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. [O'Donnell, Christopher J.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [O'Donnell, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Nalls, Mike A.] NIA, Neurogenet Lab, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Tai, E. Shong] Natl Univ Singapore, Singapore 117548, Singapore. [Tai, E. Shong] Duke Natl Univ Singapore, Grad Sch Med, Singapore, Singapore. RP Jensen, RA (reprint author), Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. EM richaj@uw.edu RI Cheng, Ching-Yu/K-7017-2013; Attia, John/F-5376-2013; Wang, Jie Jin/P-1499-2014; Mitchell, Paul/P-1498-2014; Hewitt, Alex/D-1936-2013; Cheung, Ning Danny/F-2043-2013; Gudnason, Vilmundur/K-6885-2015; Rivadeneira, Fernando/O-5385-2015; Smith, Albert/K-5150-2015; OI Klein, Ronald/0000-0002-4428-6237; Ikram, Mohammad Kamran/0000-0003-0173-9571; Tai, E Shyong/0000-0003-2929-8966; Cheng, Ching-Yu/0000-0003-0655-885X; Attia, John/0000-0001-9800-1308; Wang, Jie Jin/0000-0001-9491-4898; Hewitt, Alex/0000-0002-5123-5999; Gudnason, Vilmundur/0000-0001-5696-0084; Rivadeneira, Fernando/0000-0001-9435-9441; Smith, Albert/0000-0003-1942-5845; Cotch, Mary Frances/0000-0002-2046-4350; Seielstad, Mark/0000-0001-5783-1401 FU National Institutes of Health (NIH) [N01-AG-12100]; National Institute on Aging Intramural Research Program at the NIH [ZIAAG007380, ZIAEY000401]; National Eye Institute Intramural Research Program at the NIH [ZIAAG007380, ZIAEY000401]; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health [HHSN268200625226C]; National Institutes of Health and NIH Roadmap for Medical Research [UL1RR025005]; Australian National Health & Medical Research Council (NHMRC) [974159, 991407, 211069, 457349]; NHMRC [512423, 475604, 529912, 590204]; Wellcome Trust, UK as part of Wellcome Trust Case Control Consortium; genotyping costs of the entire BMES population [085475/B/08/Z, 085475/08/Z]; National Heart, Lung, and Blood Institute (NHLBI) [N01-HC-85239, N01-HC-85079, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133]; NHLBI [HL080295, HL075366, HL087652, HL105756, N02-HL-6-4278]; National Institute on Aging [AG-023629, AG-15928, AG-20098, AG-027058]; Clinical Translational Science Institute [UL1RR033176]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; Cedars-Sinai Board of Governors' Chair in Medical Genetics (JIR); Netherlands Organization of Scientific Research NWO [175.010.2005.011]; Erasmus Medical Center, Rotterdam; Erasmus University, Rotterdam; Netherlands Organization for Scientific Research; Netherlands Organization for Health Research and Development; Research Institute for Diseases in the Elderly; Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (DG XII) the Netherlands; Municipality of Rotterdam; Lijf en Leven, Krimpen a/d Lek the Netherlands; MD Fonds, Utrecht the Netherlands; Oogfonds Nederland, Utrecht the Netherlands; Stichting Nederlands Oogheelkundig Onderzoek, Nijmegen/Rotterdam the Netherlands; Swart van Essen, Rotterdam the Netherlands; Netherlands Organisation for Scientific Research the Netherlands; Bevordering van Volkskracht, Rotterdam the Netherlands; Blindenhulp, The Hague the Netherlands; Rotterdamse Vereniging Blindenbelangen, Rotterdam the Netherlands; OOG, The Hague the Netherlands; Algemene Nederlandse Vereniging ter Voorkoming van Blindheid, Doorn the Netherlands; Blinden-Penning, Amsterdam the Netherlands; Blindenhulp, 's Gravenzande the Netherlands; Henkes Stichting, Rotterdam the Netherlands; Topcon Europe BV, Capelle aan de IJssel the Netherlands; Medical Workshop BV, Groningen the Netherlands; [N01 HC-95159]; [N01-HC-95169]; [RR-024156] FX The authors declare that they have no relevant financial interests. Age, Gene/Environment Susceptibility-Reykjavik Study has been funded by National Institutes of Health (NIH) contract N01-AG-12100, the National Institute on Aging and National Eye Institute Intramural Research Programs at the NIH (ZIAAG007380 and ZIAEY000401), Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. The Blue Mountains Eye Study (BMES) was supported by the Australian National Health & Medical Research Council (NHMRC) grants (IDs 974159, 991407, 211069 and 457349). The genome-wide association study was supported by the following grants: NHMRC project grants IDs 512423, 475604, 529912 and 590204, and funding by the Wellcome Trust, UK as part of Wellcome Trust Case Control Consortium 2 (A Viswanathan, P McGuffin, P Mitchell, F Topouzis, P Foster), which supported the genotyping costs of the entire BMES population (Grant numbers 085475/B/08/Z and 085475/08/Z). The Cardiovascular Health Study research was supported by National Heart, Lung, and Blood Institute (NHLBI) contracts N01-HC-85239, N01-HC-85079 through N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133 and NHLBI grants HL080295, HL075366, HL087652, HL105756 with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the National Institute on Aging. See also http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping was supported in part by the Clinical Translational Science Institute grant UL1RR033176 to the Cedars-Sinai General Clinical Research Center Genotyping core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Additional funding was provided by the Cedars-Sinai Board of Governors' Chair in Medical Genetics (JIR). The Multi-Ethnic Study of Atherosclerosis (MESA) and MESA SNP Health Association Resource (SHARe) are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support is provided by grants and contracts N01 HC-95159 through N01-HC-95169 and RR-024156. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-6-4278. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. The GWA database of the Rotterdam Study was funded through the Netherlands Organization of Scientific Research NWO (nr. 175.010.2005.011).; The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University, Rotterdam; the Netherlands Organization for Scientific Research, the Netherlands Organization for Health Research and Development, the Research Institute for Diseases in the Elderly, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The ophthalmologic part of the Rotterdam Study was supported by Lijf en Leven, Krimpen a/d Lek; MD Fonds, Utrecht. Oogfonds Nederland, Utrecht; Stichting Nederlands Oogheelkundig Onderzoek, Nijmegen/Rotterdam; Swart van Essen, Rotterdam; Netherlands Organisation for Scientific Research; Bevordering van Volkskracht, Rotterdam; Blindenhulp, The Hague; Rotterdamse Vereniging Blindenbelangen, Rotterdam; OOG, The Hague; Algemene Nederlandse Vereniging ter Voorkoming van Blindheid, Doorn; Blinden-Penning, Amsterdam; Blindenhulp, 's Gravenzande; Henkes Stichting, Rotterdam; Topcon Europe BV, Capelle aan de IJssel; Medical Workshop BV, Groningen; all in the Netherlands; Heidelberg Engineering, Dossenheim, Germany. The Singapore Indian Eye Study was funded by grants from the Biomedical Research Council of Singapore (BMRC 09/1/35/19/616 and BMRC 08/1/35/19/550) and the National Medical Research Council of Singapore (NMRC/STaR/0003/2008). The Singapore BioBank and the Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore provided services for tissue archival and genotyping. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 5 Z9 5 U1 0 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 FEB 5 PY 2013 VL 8 IS 2 AR e54232 DI 10.1371/journal.pone.0054232 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 086NV UT WOS:000314692800009 PM 23393555 ER PT J AU Sun, YL Chen, JJ Kumar, P Chen, K Sodani, K Patel, A Chen, YL Chen, SD Jiang, WQ Chen, ZS AF Sun, Yue-Li Chen, Jun-Jiang Kumar, Priyank Chen, Kang Sodani, Kamlesh Patel, Atish Chen, Yang-Lu Chen, Si-Dong Jiang, Wen-Qi Chen, Zhe-Sheng TI Reversal of MRP7 (ABCC10)-Mediated Multidrug Resistance by Tariquidar SO PLOS ONE LA English DT Article ID P-GLYCOPROTEIN INHIBITOR; ABC TRANSPORTERS; PROTEIN BCRP/ABCG2; SIGNALING PATHWAY; PHASE-I; CANCER; XR9576; PACLITAXEL; CELLS; CHEMOTHERAPY AB Multidrug resistance protein 7 (MRP7, ABCC10) is a recently discovered member of the ATP-binding cassette (ABC) family which are capable of conferring resistance to a variety of anticancer drugs, including taxanes and nucleoside analogs, in vivo. MRP7 is highly expressed in non-small cell lung cancer cells, and Mrp7-KO mice are highly sensitive to paclitaxel, making MRP7 an attractive chemotherapeutic target of non-small cell lung cancer. However, only a few inhibitors of MRP7 are currently identified, with none of them having progressed to clinical trials. We used MRP7-expressing cells to investigate whether tariquidar, a third generation inhibitor of P-glycoprotein, could inhibit MRP7-mediated multidrug resistance (MDR). We found that tariquidar, at 0.1 and 0.3 mu M, significantly potentiated the sensitivity of MRP7-transfected HEK293 cells to MRP7 substrates and increased the intracellular accumulation of paclitaxel. We further demonstrated that tariquidar directly impaired paclitaxel efflux and could downregulate MRP7 protein expression in a concentration-and time-dependent manner after prolonged treatment. Our findings suggest that tariquidar, at pharmacologically achievable concentrations, reverses MRP7-mediated MDR through inhibition of MRP7 protein expression and function, and thus represents a promising therapeutic agent in the clinical treatment of chemoresistant cancer patients. C1 [Sun, Yue-Li; Jiang, Wen-Qi] State Key Lab Oncol S China, Guangzhou, Guangdong, Peoples R China. [Sun, Yue-Li; Jiang, Wen-Qi] Sun Yat Sen Univ, Ctr Canc, Dept Med Oncol, Guangzhou 510275, Guangdong, Peoples R China. [Sun, Yue-Li; Chen, Jun-Jiang; Kumar, Priyank; Sodani, Kamlesh; Patel, Atish; Chen, Yang-Lu; Chen, Zhe-Sheng] St Johns Univ, Dept Pharmaceut Sci, Coll Pharm & Hlth Sci, Queens, NY USA. [Chen, Jun-Jiang; Chen, Si-Dong] Guangdong Pharmaceut Univ, Sch Publ Hlth, Guangdong Key Lab Mol Epidemiol, Guangzhou, Guangdong, Peoples R China. [Chen, Kang] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Chen, Kang] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Bethesda, MD USA. [Chen, Yang-Lu] Montgomery High Sch, Skillman, NJ USA. RP Jiang, WQ (reprint author), State Key Lab Oncol S China, Guangzhou, Guangdong, Peoples R China. EM wqjiang@yahoo.com; chenz@stjohns.edu RI Patel, Atish/J-4699-2014 OI Kumar, Priyank/0000-0002-4772-2073; Patel, Atish/0000-0002-5549-9166 FU National Institutes of Health [1R15CA143701]; St. John's University Research Seed Grant [579-1110-7002] FX This work was supported by funds from National Institutes of Health (number 1R15CA143701) and St. John's University Research Seed Grant (number 579-1110-7002) to Z.S. Chen. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 14 Z9 14 U1 1 U2 15 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 FEB 5 PY 2013 VL 8 IS 2 AR e55576 DI 10.1371/journal.pone.0055576 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 086NV UT WOS:000314692800048 PM 23393594 ER PT J AU Stevens, AJ Guan, LR Bebenek, K Kunkel, TA Greenberg, MM AF Stevens, Adam J. Guan, Lirui Bebenek, Katarzyna Kunkel, Thomas A. Greenberg, Marc M. TI DNA Polymerase lambda Inactivation by Oxidized Abasic Sites SO BIOCHEMISTRY LA English DT Article ID BASE-EXCISION-REPAIR; HISTONE-CATALYZED CLEAVAGE; DOUBLE-STRAND CLEAVAGE; CROSS-LINK FORMATION; ESCHERICHIA-COLI; LYASE ACTIVITY; FE BLEOMYCIN; A-RULE; LESION; MECHANISM AB Base excision repair (BER) plays a vital role in maintaining genomic integrity in mammalian cells. DNA polymerase lambda (Pol lambda) is believed to play a backup role to DNA polymerase beta (Pol beta) in base excision repair. Two oxidized abasic lesions that are produced by a variety of DNA-damaging agents, including several antitumor antibiotics, the C4'-oxidized abasic site following Ape1 incision (pC4-AP), and 5'-(2-phosphoryl-1,4-dioxobutane) (DOB), irreversibly inactivate Pol beta and Pol lambda. The interactions of DOB and pC4-AP with Pol lambda are examined in detail using DNA substrates containing these lesions at defined sites. Single-turnover kinetic experiments show that Pol lambda excises DOB almost 13 times more slowly than a 5'-phosphorylated 2-deoxyribose (dRP). pC4-AP is excised approximately twice as fast as DOB. The absolute rate constants are considerably slower than those reported for Pol beta for the respective reactions, suggesting that Pol lambda may be an inefficient backup in BER DOB inactivates Pol lambda approximately 3-fold less efficiently than it does Pol beta, and the difference can be attributed to a higher K-1 (33 +/- 7 nM). Inactivation of Pol lambda's lyase activity by DOB also prevents the enzyme from conducting polymerization following preincubation of the protein and DNA. Mass spectral analysis of GluC-digested Pol lambda inactivated by DOB shows that Lys324 is modified. There is inferential support for the idea that Lys312 may also be modified. Both residues are within the Pol lambda lyase active site. When acting on pC4-AP, Pol lambda achieves approximately four turnovers on average before being inactivated. Lyase inactivation by pC4-AP is also accompanied by loss of polymerase activity, and mass spectrometry indicates that Lys312 and Lys324 are modified by the lesion. The ability of DOB and pC4-AP to inactivate Pol lambda provides additional evidence that these lesions are significant sources of the cytotoxicity of DNA-damaging agents that produce them. C1 [Stevens, Adam J.; Guan, Lirui; Greenberg, Marc M.] Johns Hopkins Univ, Dept Chem, Baltimore, MD 21218 USA. [Bebenek, Katarzyna; Kunkel, Thomas A.] NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP Greenberg, MM (reprint author), Johns Hopkins Univ, Dept Chem, 3400 N Charles St, Baltimore, MD 21218 USA. EM mgreenberg@jhu.edu RI Guan, Lirui/E-5611-2013 FU National Institute of General Medical Sciences [GM- 063028]; Division of Intramural Research of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES065070] FX We are grateful for support of this research by National Institute of General Medical Sciences Grant GM- 063028 to M.M.G. This work was supported in part by Project Z01 ES065070 to T.A.K. from the Division of Intramural Research of the National Institutes of Health, National Institute of Environmental Health Sciences. NR 55 TC 8 Z9 8 U1 0 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 5 PY 2013 VL 52 IS 5 BP 975 EP 983 DI 10.1021/bi301592x PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 086HX UT WOS:000314675800021 PM 23330920 ER PT J AU Ramsden, CE Zamora, D Leelarthaepin, B Majchrzak-Hong, SF Faurot, KR Suchindran, CM Ringel, A Davis, JM Hibbeln, JR AF Ramsden, Christopher E. Zamora, Daisy Leelarthaepin, Boonseng Majchrzak-Hong, Sharon F. Faurot, Keturah R. Suchindran, Chirayath M. Ringel, Amit Davis, John M. Hibbeln, Joseph R. TI Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Article ID POLYUNSATURATED FATTY-ACIDS; HUMAN ATHEROSCLEROTIC LESIONS; RANDOMIZED CONTROLLED-TRIALS; LOW-DENSITY-LIPOPROTEIN; SMOOTH-MUSCLE-CELLS; CARDIOVASCULAR-DISEASE; SERUM-CHOLESTEROL; OXIDIZED LDL; EICOSAPENTAENOIC ACID; MYOCARDIAL-INFARCTION AB Objective To evaluate the effectiveness of replacing dietary saturated fat with omega 6 linoleic acid, for the secondary prevention of coronary heart disease and death. Design Evaluation of recovered data from the Sydney Diet Heart Study, a single blinded, parallel group, randomized controlled trial conducted in 1966-73; and an updated meta-analysis including these previously missing data. Setting Ambulatory, coronary care clinic in Sydney, Australia. Participants 458 men aged 30-59 years with a recent coronary event. Interventions Replacement of dietary saturated fats (from animal fats, common margarines, and shortenings) with omega 6 linoleic acid (from safflower oil and safflower oil polyunsaturated margarine). Controls received no specific dietary instruction or study foods. All non-dietary aspects were designed to be equivalent in both groups. Outcome measures All cause mortality (primary outcome), cardiovascular mortality, and mortality from coronary heart disease (secondary outcomes). We used an intention to treat, survival analysis approach to compare mortality outcomes by group. Results The intervention group (n=221) had higher rates of death than controls (n=237) (all cause 17.6% v 11.8%, hazard ratio 1.62 (95% confidence interval 1.00 to 2.64), P=0.05; cardiovascular disease 17.2% v 11.0%, 1.70 (1.03 to 2.80), P=0.04; coronary heart disease 16.3% v 10.1%, 1.74 (1.04 to 2.92), P=0.04). Inclusion of these recovered data in an updated meta-analysis of linoleic acid intervention trials showed non-significant trends toward increased risks of death from coronary heart disease (hazard ratio 1.33 (0.99 to 1.79); P=0.06) and cardiovascular disease (1.27 (0.98 to 1.65); P=0.07). Conclusions Advice to substitute polyunsaturated fats for saturated fats is a key component of worldwide dietary guidelines for coronary heart disease risk reduction. However, clinical benefits of the most abundant polyunsaturated fatty acid, omega 6 linoleic acid, have not been established. In this cohort, substituting dietary linoleic acid in place of saturated fats increased the rates of death from all causes, coronary heart disease, and cardiovascular disease. An updated meta-analysis of linoleic acid intervention trials showed no evidence of cardiovascular benefit. These findings could have important implications for worldwide dietary advice to substitute omega 6 linoleic acid, or polyunsaturated fats in general, for saturated fats. Trial registration Clinical trials NCT01621087. C1 [Ramsden, Christopher E.; Majchrzak-Hong, Sharon F.; Ringel, Amit; Hibbeln, Joseph R.] NIAAA, Lab Membrane Biophys & Biochem, NIH, Bethesda, MD 20892 USA. [Ramsden, Christopher E.; Zamora, Daisy; Faurot, Keturah R.] Univ N Carolina, Sch Med, Dept Phys Med & Rehabil, Chapel Hill, NC USA. [Leelarthaepin, Boonseng] Univ New S Wales, Sydney, NSW, Australia. [Suchindran, Chirayath M.] Univ N Carolina, Sch Publ Hlth, Dept Biostat, Chapel Hill, NC USA. [Davis, John M.] Univ Illinois, Dept Psychiat, Chicago, IL 60612 USA. RP Ramsden, CE (reprint author), NIAAA, Lab Membrane Biophys & Biochem, NIH, Bethesda, MD 20892 USA. EM Chris.Ramsden@nih.gov FU Life Insurance Medical Research Fund of Australia; Life Insurance Medical Research Fund of New Zealand; Intramural Program of the National Institute on Alcohol Abuse and Alcoholism FX All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: support from the Life Insurance Medical Research Fund of Australia and New Zealand and the Intramural Program of the National Institute on Alcohol Abuse and Alcoholism for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. NR 81 TC 144 Z9 149 U1 6 U2 65 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD FEB 5 PY 2013 VL 346 AR e8707 DI 10.1136/bmj.e8707 PG 18 WC Medicine, General & Internal SC General & Internal Medicine GA 088AR UT WOS:000314806700001 PM 23386268 ER PT J AU Klimuk, E Akulenko, N Makarova, KS Ceyssens, PJ Volchenkov, I Lavigne, R Severinov, K AF Klimuk, Evgeny Akulenko, Natalia Makarova, Kira S. Ceyssens, Pieter-Jan Volchenkov, Ivan Lavigne, Rob Severinov, Konstantin TI Host RNA polymerase inhibitors encoded by phi KMV-like phages of pseudomonas SO VIROLOGY LA English DT Article DE Bacteriophages T7 and phi KMV; Pseudomonas; RNA polymerase; RNA polymerase inhibitor ID COMPLETE GENOMIC SEQUENCE; DNA RESTRICTION SYSTEM; GENE 2 PROTEIN; ESCHERICHIA-COLI; BACTERIOPHAGE T7; IN-VITRO; TRANSCRIPTION; PURIFICATION; INITIATION; TRANSLOCATION AB Escherichia coli bacteriophage T7 is a founding member of a large clade of podoviruses encoding a single-subunit RNA polymerase (RNAP). Phages of the family rely on host RNAP for transcription of early viral genes; viral RNAP transcribes non-early viral genes. T7 and its close relatives encode an inhibitor of host RNAP, the gp2 protein. Gp2 is essential for phage development and ensures that host RNAP does not interfere with viral RNAP transcription at late stages of infection. Here, we identify host RNAP inhibitors encoded by a subset of T7 clade phages related to phi KMV phage of Pseudomonas aeruginosa. We demonstrate that these proteins are functionally identical to T7 gp2 in vivo and in vitro. The ability of some Pseudomonas phage gp2-like proteins to inhibit RNAP is modulated by N-terminal domains, which are absent from the T7 phage homolog. This finding indicates that Pseudomonas phages may use external or internal cues to initiate inhibition of host RNAP transcription and that gp2-like proteins from these phages may be receptors of these cues. (C) 2012 Elsevier Inc. All rights reserved. C1 [Klimuk, Evgeny; Akulenko, Natalia; Severinov, Konstantin] Russian Acad Sci, Inst Mol Genet, Moscow 123182, Russia. [Klimuk, Evgeny; Akulenko, Natalia; Severinov, Konstantin] Russian Acad Sci, Inst Gene Biol, Moscow, Russia. [Klimuk, Evgeny; Volchenkov, Ivan; Severinov, Konstantin] Evrogen JSC, Moscow 117997, Russia. [Makarova, Kira S.] NIH, Natl Ctr Biotechnol Informat, NLM, Bethesda, MD 20894 USA. [Ceyssens, Pieter-Jan; Lavigne, Rob] Katholieke Univ Leuven, Biosyst Dept, Lab Gene Technol, Louvain, Belgium. [Severinov, Konstantin] Rutgers State Univ, Waksman Inst Microbiol, Piscataway, NJ 08854 USA. [Severinov, Konstantin] Rutgers State Univ, Dept Mol Biol & Biochem, Piscataway, NJ 08854 USA. RP Severinov, K (reprint author), Rutgers State Univ, Waksman Inst, 190 Frelinghuysen Rd, Piscataway, NJ 08854 USA. EM severik@waksman.rutgers.edu RI Severinov, Konstantin/C-8545-2016; Klimuk, Evgeny/E-5920-2017 OI Klimuk, Evgeny/0000-0001-5314-038X FU NIH [GM59295]; Russian Academy of Sciences Presidium; Federal Program "Scientific and scientific-pedagogical personnel of innovative Russia"; Ministry of education and science of the Russian Federation [02.740.11.0771, 16.740.11.0748]; Russian Foundation of Basic Research [12-04-01600-a, P1166]; SBO of the IWT Vlaanderen [IWT 100042]; FWO Vlaanderen; Department of Health and Human Services intramural program (NIH, National Library of Medicine) FX This work was partially supported by NIH grant GM59295, a grant from Program "Molecular and Cellular Biology" of the Russian Academy of Sciences Presidium and Federal Program "Scientific and scientific-pedagogical personnel of innovative Russia 2009-2013", state contract 02.740.11.0771 and contract no. 16.740.11.0748 from the Ministry of education and science of the Russian Federation to KS. NA was partially supported by the Russian Foundation of Basic Research 12-04-01600-a and state contract no.P1166. Work in the RL laboratory was supported by the SBO grant 'IWT 100042' of the IWT Vlaanderen. PJC holds a postdoctoral fellowship of the FWO Vlaanderen. KSM is supported by the Department of Health and Human Services intramural program (NIH, National Library of Medicine). NR 36 TC 7 Z9 7 U1 1 U2 16 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD FEB 5 PY 2013 VL 436 IS 1 BP 67 EP 74 DI 10.1016/j.virol.2012.10.021 PG 8 WC Virology SC Virology GA 077BV UT WOS:000314003800008 PM 23127595 ER PT J AU Ilinskaya, A Derse, D Hill, S Princler, G Heidecker, G AF Ilinskaya, Anna Derse, David Hill, Shawn Princler, Gerald Heidecker, Gisela TI Cell-cell transmission allows human T-lymphotropic virus 1 to circumvent tetherin restriction SO VIROLOGY LA English DT Article DE HTLV-1; Tetherin; Cell-cell transmission; Virological synapse ID VIROLOGICAL SYNAPSES; HIV-INFECTION; TYPE-1; VPU; SPREAD; GENE; RELEASE; HTLV-1; RETROTRANSPOSITION; LYMPHOCYTES AB Tetherin is part of the cellular innate immunity and impedes cell-free transmission of viruses that bud from the plasma membrane by retaining them on the cell surface. Some viruses have evolved activities in different proteins such as Vpu (HIV-1), K-protein (KSHV), Nef (SIV) or Env (HIV-2) to downregulate tetherin and overcome its restriction. We found that chronically HTLV-1 infected T-cell lines express eightfold more tetherin than uninfected transformed T-cell lines suggesting that tetherin expression is not inhibited by the virus. We observed that even small amounts of exogenous tetherin caused the retention of HTLV-1 on the cell surface and severely reduced cell-free infectivity of HTLV-1, but that cell-cell transmission, which is more relevant for HTLV-1, was significantly less decreased. However, knock-down of tetherin expresssion resulted in a slight increase in cell-cell infection indicating that the protein does not enhance this route of transmission. Published by Elsevier Inc. C1 [Ilinskaya, Anna; Derse, David; Hill, Shawn; Princler, Gerald; Heidecker, Gisela] Frederick Natl Lab Canc Res, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Heidecker, G (reprint author), Frederick Natl Lab Canc Res, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM ilinskaa@mail.nih.gov; hillshaw@mail.nih.gov; jerryprin@comcast.net; heidecke@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We are thankful to Dr. M. Mitchell for help with writing this manuscript and Dr. Stephen Hughes for helpful discussions. We thank Dr. P. Bieniasz for the generous gift of the tetherin plasmids. The rabbit anti-tetherin antiserum was obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH: Anti-Bst-2 (cat# 11722) from Drs. Klaus Strebel and Amy Andrew. We thank Pat Lloyd for help with plasmid constructions. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 70 TC 8 Z9 9 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD FEB 5 PY 2013 VL 436 IS 1 BP 201 EP 209 DI 10.1016/j.virol.2012.11.012 PG 9 WC Virology SC Virology GA 077BV UT WOS:000314003800023 PM 23260108 ER PT J AU Groffen, DAI Koster, A Bosma, H van den Akker, M Aspelund, T Siggeirsdottir, K Kempen, GIJM van Eijk, JTM Eiriksdottir, G Jonsson, PV Launer, LJ Gudnason, V Harris, TB AF Groffen, Danielle A. I. Koster, Annemarie Bosma, Hans van den Akker, Marjan Aspelund, Thor Siggeirsdottir, Kristin Kempen, Gertrudis I. J. M. van Eijk, Jacques Th M. Eiriksdottir, Gudny Jonsson, Palmi V. Launer, Lenore J. Gudnason, Vilmundur Harris, Tamara B. CA Age Gene Environm Susceptibility-R TI Socioeconomic factors from midlife predict mobility limitation and depressed mood three decades later; Findings from the AGES-Reykjavik Study SO BMC PUBLIC HEALTH LA English DT Article DE Socioeconomic status; Mobility limitation; Depressed mood; Midlife; Old age ID HOUSING TENURE; CAR ACCESS; HEALTH; INCOME AB Background: Taking into account our rapidly ageing population, older people are of particular interest in studying health inequalities. Most studies of older persons only include measures of current socioeconomic status (SES) and do not take into account data from earlier stages of life. In addition, only classic SES measures are used, while alternative measures, such as car ownership and house ownership, might equally well predict health. The present study aims to examine the effect of midlife socioeconomic factors on mobility limitation and depressed mood three decades later. Methods: Data were from 4,809 men and women aged 33-65 years who participated in the Reykjavik Study (1967-1992) and who were re-examined in old age in the Age, Gene/Environment Susceptibility (AGES) -Reykjavik Study (2002-2006). Results: Education and occupation predicted mobility limitation and depressed mood. Independently, home and car ownership and the availability of housing features predicted mobility limitation. Shortages of food in childhood and lack of a car in midlife predicted depressed mood. Conclusion: Socioeconomic factors from midlife and from childhood affect mobility limitation and depressed mood in old age. Prevention of health problems in old age should begin as early as midlife. C1 [Groffen, Danielle A. I.; Koster, Annemarie; Bosma, Hans; van Eijk, Jacques Th M.] Maastricht Univ, CAPHRI Sch Publ Hlth & Primary Care, Dept Social Med, NL-6200 MD Maastricht, Netherlands. [van den Akker, Marjan] Maastricht Univ, Sch Publ Hlth & Primary Care CAPHRI, Dept Gen Practice, NL-6200 MD Maastricht, Netherlands. [van den Akker, Marjan] Katholieke Univ Leuven, Dept Gen Practice, Louvain, Belgium. [Aspelund, Thor; Siggeirsdottir, Kristin; Eiriksdottir, Gudny; Jonsson, Palmi V.; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Aspelund, Thor; Eiriksdottir, Gudny; Jonsson, Palmi V.; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Kempen, Gertrudis I. J. M.] Maastricht Univ, CAPHRI Sch Publ Hlth & Primary Care, Dept Hlth Serv Res, NL-6200 MD Maastricht, Netherlands. [Launer, Lenore J.; Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. RP Groffen, DAI (reprint author), Maastricht Univ, CAPHRI Sch Publ Hlth & Primary Care, Dept Social Med, POB 616, NL-6200 MD Maastricht, Netherlands. EM D.Groffen@maastrichtuniversity.nl RI Aspelund, Thor/C-5983-2008; Koster, Annemarie/E-7438-2010; Gudnason, Vilmundur/K-6885-2015; Kempen, Gertrudis/H-5978-2016; Bosma, Hans/A-6184-2013 OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084; Kempen, Gertrudis/0000-0002-7053-2198; FU NIH [N01-AG-12100]; NIA Intramural Research Program; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament) FX The Age, Gene/Environment Susceptibility Reykjavik Study is funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The researchers are indebted to the participants for their willingness to participate in the study. NR 24 TC 7 Z9 7 U1 0 U2 9 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 FEB 4 PY 2013 VL 13 AR 101 DI 10.1186/1471-2458-13-101 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 128HQ UT WOS:000317760400001 PM 23379351 ER PT J AU Salive, ME AF Salive, Marcel E. TI Multimorbidity in Older Adults SO EPIDEMIOLOGIC REVIEWS LA English DT Article DE aged; chronic disease; comorbidity; prevalence ID MULTIPLE CHRONIC CONDITIONS; CHRONIC DISEASE; UNITED-STATES; RISK-FACTORS; PREVALENCE; HEALTH; COMORBIDITY; POPULATION; DISABILITY; MORBIDITY AB Multimorbidity, the coexistence of 2 or more chronic conditions, has become prevalent among older adults as mortality rates have declined and the population has aged. We examined population-based administrative claims data indicating specific health service delivery to nearly 31 million Medicare fee-for-service beneficiaries for 15 prevalent chronic conditions. A total of 67% had multimorbidity, which increased with age, from 50% for persons under age 65 years to 62% for those aged 65-74 years and 81.5% for those aged >= 85 years. A systematic review identified 16 other prevalence studies conducted in community samples that included older adults, with median prevalence of 63% and a mode of 67%. Prevalence differences between studies are probably due to methodological biases; no studies were comparable. Key methodological issues arise from elements of the case definition, including type and number of chronic conditions included, ascertainment methods, and source population. Standardized methods for measuring multimorbidity are needed to enable public health surveillance and prevention. Multimorbidity is associated with elevated risk of death, disability, poor functional status, poor quality of life, and adverse drug events. Additional research is needed to develop an understanding of causal pathways and to further develop and test potential clinical and population interventions targeting multimorbidity. C1 [Salive, Marcel E.] NIA, Bethesda, MD 20892 USA. RP Salive, ME (reprint author), NIA, Geriatr Branch, Div Geriatr & Clin Gerontol, 7201 Wisconsin Ave,Suite 3C307, Bethesda, MD 20892 USA. EM saliveme@nia.nih.gov NR 44 TC 98 Z9 101 U1 5 U2 34 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0193-936X J9 EPIDEMIOL REV JI Epidemiol. Rev. PD FEB 4 PY 2013 VL 35 SI SI BP 75 EP 83 DI 10.1093/epirev/mxs009 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 100LT UT WOS:000315703400007 PM 23372025 ER PT J AU Newman, AB Murabito, JM AF Newman, Anne B. Murabito, Joanne M. TI The Epidemiology of Longevity and Exceptional Survival SO EPIDEMIOLOGIC REVIEWS LA English DT Article DE aging; exome; genetics; genome; longevity ID GENOME-WIDE ASSOCIATION; CAUSE-SPECIFIC MORTALITY; DENSITY-LIPOPROTEIN CHOLESTEROL; LONG-LIVED INDIVIDUALS; MIDLIFE RISK-FACTORS; ALL-CAUSE MORTALITY; 37-YEAR FOLLOW-UP; MIDDLE-AGED MEN; GROWTH-FACTOR-I; LIFE-SPAN AB The field of the "epidemiology of longevity" has been expanding rapidly in recent years. Several long-term cohort studies have followed older adults long enough to identify the most long-lived and to define many factors that lead to a long life span. Very long-lived people such as centenarians have been examined using case-control study designs. Both cohort and case-control studies have been the subject of genome-wide association studies that have identified genetic variants associated with longevity. With growing recognition of the importance of rare variations, family studies of longevity will be useful. Most recently, exome and whole-genome sequencing, gene expression, and epigenetic studies have been undertaken to better define functional variation and regulation of the genome. In this review, we consider how these studies are leading to a deeper understanding of the underlying biologic pathways to longevity. C1 [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Newman, Anne B.] Univ Pittsburgh, Div Geriatr Med, Sch Med, Pittsburgh, PA 15261 USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Murabito, Joanne M.] NHLBI, Framingham Heart Study, Framingham, MA USA. RP Newman, AB (reprint author), Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, A529 Crabtree Hall,130 DeSoto St, Pittsburgh, PA 15261 USA. EM newmana@edc.pitt.edu RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU National Institutes of Health [U01 AG023744, R01 AG023629, R01 AG029451] FX This work was supported by National Institutes of Health grants U01 AG023744, R01 AG023629 (Anne B. Newman), and R01 AG029451 (Joanne M. Murabito). NR 128 TC 23 Z9 24 U1 1 U2 32 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0193-936X J9 EPIDEMIOL REV JI Epidemiol. Rev. PD FEB 4 PY 2013 VL 35 SI SI BP 181 EP 197 DI 10.1093/epirev/mxs013 PG 17 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 100LT UT WOS:000315703400014 PM 23372024 ER PT J AU Moreno-Macias, H Dockery, DW Schwartz, J Gold, DR Laird, NM Sienra-Monge, JJ Del Rio-Navarro, BE Ramirez-Aguilar, M Barraza-Villarreal, A Li, HL London, SJ Romieu, I AF Moreno-Macias, Hortensia Dockery, Douglas W. Schwartz, Joel Gold, Diane R. Laird, Nan M. Sienra-Monge, Juan J. Del Rio-Navarro, Blanca E. Ramirez-Aguilar, Matiana Barraza-Villarreal, Albino Li, Huiling London, Stephanie J. Romieu, Isabelle TI Ozone exposure, vitamin C intake, and genetic susceptibility of asthmatic children in Mexico City: a cohort study SO RESPIRATORY RESEARCH LA English DT Article DE Air pollution; Asthmatic children; Antioxidant genes; Mexico City; Vitamin C ID S-TRANSFERASE P1; LUNG-FUNCTION; CHILDHOOD ASTHMA; AIR-POLLUTION; ANTIOXIDANT SUPPLEMENTATION; RESPIRATORY HEALTH; OXIDATIVE STRESS; SCHOOL-CHILDREN; YOUNG-ADULTS; RISK-FACTORS AB Background: We previously reported that asthmatic children with GSTM1 null genotype may be more susceptible to the acute effect of ozone on the small airways and might benefit from antioxidant supplementation. This study aims to assess the acute effect of ozone on lung function (FEF25-75) in asthmatic children according to dietary intake of vitamin C and the number of putative risk alleles in three antioxidant genes: GSTM1, GSTP1 (rs1695), and NQO1 (rs1800566). Methods: 257 asthmatic children from two cohort studies conducted in Mexico City were included. Stratified linear mixed models with random intercepts and random slopes on ozone were used. Potential confounding by ethnicity was assessed. Analyses were conducted under single gene and genotype score approaches. Results: The change in FEF25-75 per interquartile range (60 ppb) of ozone in persistent asthmatic children with low vitamin C intake and GSTM1 null was -91.2 ml/s (p = 0.06). Persistent asthmatic children with 4 to 6 risk alleles and low vitamin C intake showed an average decrement in FEF25-75 of 97.2 ml/s per 60 ppb of ozone (p = 0.03). In contrast in children with 1 to 3 risk alleles, acute effects of ozone on FEF25-75 did not differ by vitamin C intake. Conclusions: Our results provide further evidence that asthmatic children predicted to have compromised antioxidant defense by virtue of genetic susceptibility combined with deficient antioxidant intake may be at increased risk of adverse effects of ozone on pulmonary function. C1 [Moreno-Macias, Hortensia; Del Rio-Navarro, Blanca E.] Univ Autonoma Metropolitana, Unidad Iztapalapa, Mexico City 09430, DF, Mexico. [Dockery, Douglas W.; Schwartz, Joel; Gold, Diane R.] Harvard Univ, Sch Med, Dept Environm Hlth, Boston, MA USA. [Laird, Nan M.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Sienra-Monge, Juan J.; Del Rio-Navarro, Blanca E.] Hosp Infantil Federico Gomez, Mexico City, DF, Mexico. [Ramirez-Aguilar, Matiana] Comis Fed Protecc Riesgos Sanitarios, SSA, Mexico City, DF, Mexico. [Barraza-Villarreal, Albino] Inst Nacl Salud Publ, Cuernavaca, Morelos, Mexico. [Li, Huiling; London, Stephanie J.] NIEHS, US Dept Hlth & Human Serv, Epidemiol Branch, NIH, Bethesda, MD 20892 USA. [Romieu, Isabelle] Int Agcy Res Canc, F-69372 Lyon, France. RP Moreno-Macias, H (reprint author), Univ Autonoma Metropolitana, Unidad Iztapalapa, Ave San Rafael Atlixco 186,Edificio H-001, Mexico City 09430, DF, Mexico. EM hmm@xanum.uam.mx OI London, Stephanie/0000-0003-4911-5290 FU National Council on Science and Technology, in Mexico [26206-M, 38911-M]; Division of Intramural Research, National Institutes of Health, U.S. Department of Health and Human Services [ZO1 ES 49019, ES 25045]; National Institute of Mental Health FX The authors thank the children who took part in the study and Irma Lara who carried out the field work. This work was supported in part by the National Council on Science and Technology (26206-M, 38911-M), in Mexico, and the Division of Intramural Research, National Institutes of Health, U.S. Department of Health and Human Services (ZO1 ES 49019, ES 25045). The National Institute of Mental Health supported Dr Laird. NR 38 TC 11 Z9 12 U1 1 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-993X J9 RESP RES JI Respir. Res. PD FEB 4 PY 2013 VL 14 AR 14 DI 10.1186/1465-9921-14-14 PG 10 WC Respiratory System SC Respiratory System GA 098ZA UT WOS:000315586400001 PM 23379631 ER PT J AU Suwannasai, N Martin, MP Phosri, C Sihanonth, P Whalley, AJS Spouge, JL AF Suwannasai, Nuttika Martin, Maria P. Phosri, Cherdchai Sihanonth, Prakitsin Whalley, Anthony J. S. Spouge, John L. TI Fungi in Thailand: A Case Study of the Efficacy of an ITS Barcode for Automatically Identifying Species within the Annulohypoxylon and Hypoxylon Genera SO PLOS ONE LA English DT Article ID INTERNAL TRANSCRIBED SPACER; RIBOSOMAL DNA-SEQUENCES; LAND PLANTS; PHYLOGENETIC-RELATIONSHIPS; IDENTIFICATION; XYLARIACEAE; TAXONOMY; NUCLEAR; ALGORITHMS; EVOLUTION AB Thailand, a part of the Indo-Burma biodiversity hotspot, has many endemic animals and plants. Some of its fungal species are difficult to recognize and separate, complicating assessments of biodiversity. We assessed species diversity within the fungal genera Annulohypoxylon and Hypoxylon, which produce biologically active and potentially therapeutic compounds, by applying classical taxonomic methods to 552 teleomorphs collected from across Thailand. Using probability of correct identification (PCI), we also assessed the efficacy of automated species identification with a fungal barcode marker, ITS, in the model system of Annulohypoxylon and Hypoxylon. The 552 teleomorphs yielded 137 ITS sequences; in addition, we examined 128 GenBank ITS sequences, to assess biases in evaluating a DNA barcode with GenBank data. The use of multiple sequence alignment in a barcode database like BOLD raises some concerns about non-protein barcode markers like ITS, so we also compared species identification using different alignment methods. Our results suggest the following. (1) Multiple sequence alignment of ITS sequences is competitive with pairwise alignment when identifying species, so BOLD should be able to preserve its present bioinformatics workflow for species identification for ITS, and possibly therefore with at least some other non-protein barcode markers. (2) Automated species identification is insensitive to a specific choice of evolutionary distance, contributing to resolution of a current debate in DNA barcoding. (3) Statistical methods are available to address, at least partially, the possibility of expert misidentification of species. Phylogenetic trees discovered a cryptic species and strongly supported monophyletic clades for many Annulohypoxylon and Hypoxylon species, suggesting that ITS can contribute usefully to a barcode for these fungi. The PCIs here, derived solely from ITS, suggest that a fungal barcode will require secondary markers in Annulohypoxylon and Hypoxylon, however. The URL http://tinyurl.com/spouge-barcode contains computer programs and other supplementary material relevant to this article. C1 [Suwannasai, Nuttika] Srinakharinwirot Univ, Fac Sci, Dept Biol, Bangkok, Thailand. [Martin, Maria P.] Real Jardin Botan CSIC, Dept Mycol, Madrid, Spain. [Phosri, Cherdchai] Pibulsongkram Rajabhat Univ, Fac Sci & Technol, Microbiol Programme, Phitsanulok, Thailand. [Sihanonth, Prakitsin] Chulalongkorn Univ, Fac Sci, Dept Microbiol, Bangkok, Thailand. [Whalley, Anthony J. S.] Liverpool John Moores Univ, Sch Pharm & Biomol Sci, Liverpool L3 5UX, Merseyside, England. [Spouge, John L.] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Spouge, JL (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM spouge@ncbi.nlm.nih.gov RI phosri, Cherdchai/H-2747-2014; Martin, Maria /H-8069-2012; OI Martin, Maria /0000-0002-1235-4418; Phosri, Cherdchai/0000-0003-3963-752X FU Royal Golden Jubilee Ph.D. Program (RGJ); National Research Council of Thailand; International Foundation for Science (IFS); British Council; Liverpool John Moores University; British Mycological Society; Plan Nacional I+D+I (Ministerio de Ciencia y Tecnologia, Spain) [REN2002-04068-CO2-01GLO]; Intramural Research Program of the National Institutes of Health (NIH) (National Library of Medicine, USA) FX This research was supported in part by the Royal Golden Jubilee Ph.D. Program (RGJ), National Research Council of Thailand, International Foundation for Science (IFS), the British Council, Liverpool John Moores University, the British Mycological Society, the Plan Nacional I+D+I (REN2002-04068-CO2-01GLO, Ministerio de Ciencia y Tecnologia, Spain), and the Intramural Research Program of the National Institutes of Health (NIH) (National Library of Medicine, USA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 67 TC 7 Z9 8 U1 1 U2 41 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 FEB 4 PY 2013 VL 8 IS 2 AR e54529 DI 10.1371/journal.pone.0054529 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 086NH UT WOS:000314691100015 PM 23390499 ER PT J AU Gray, JJ Zommer, AE Bouchard, RJ Duval, N Blackstone, C Linseman, DA AF Gray, Josie J. Zommer, Amelia E. Bouchard, Ron J. Duval, Nathan Blackstone, Craig Linseman, Daniel A. TI N-terminal cleavage of the mitochondrial fusion GTPase OPA1 occurs via a caspase-independent mechanism in cerebellar granule neurons exposed to oxidative or nitrosative stress SO BRAIN RESEARCH LA English DT Article DE Mitochondrial dynamics; Apoptosis; Aging; Complex I; Reactive oxygen species; Nitric oxide; Caspase ID DOMINANT OPTIC ATROPHY; DYNAMIN-RELATED PROTEIN; CYTOCHROME-C RELEASE; PARKINSONS-DISEASE; NEURODEGENERATIVE DISEASES; PROTEOLYTIC ACTIVATION; ALZHEIMERS-DISEASE; MAP KINASES; MOUSE MODEL; APOPTOSIS AB Neuronal cell death via apoptosis or necrosis underlies several devastating neurodegenerative diseases associated with aging. Mitochondrial dysfunction resulting from oxidative or nitrosative stress often acts as an initiating stimulus for intrinsic apoptosis or necrosis. These events frequently occur in conjunction with imbalances in the mitochondrial fission and fusion equilibrium, although the cause and effect relationships remain elusive. Here, we demonstrate in primary rat cerebellar granule neurons (CGNs) that oxidative or nitrosative stress induces an N-terminal cleavage of optic atrophy-1 (OPA1), a dynamin-like GTPase that regulates mitochondrial fusion and maintenance of cristae architecture. This cleavage event is indistinguishable from the N-terminal cleavage of OPA1 observed in CGNs undergoing caspase-mediated apoptosis (Loucks et al., 2009) and results in removal of a key lysine residue (K301) within the GTPase domain. OPA1 cleavage in CGNs occurs coincident with extensive mitochondrial fragmentation, disruption of the microtubule network, and cell death. In contrast to OPA1 cleavage induced in CGNs by removing depolarizing extracellular potassium (5K apoptotic conditions), oxidative or nitrosative stress-induced OPA1 cleavage caused by complex I inhibition or nitric oxide, respectively, is caspase-independent N-terminal cleavage of OPA1 is also observed in vivo in aged rat and mouse midbrain and hippocampal tissues. We conclude that N-terminal cleavage and subsequent inactivation of OPA1 may be a contributing factor in the neuronal cell death processes underlying neurodegenerative diseases, particularly those associated with aging. Furthermore, these data suggest that OPA1 cleavage is a likely convergence point for mitochondrial dysfunction and imbalances in mitochondrial fission and fusion induced by oxidative or nitrosative stress. Published by Elsevier B.V. C1 [Gray, Josie J.; Zommer, Amelia E.; Duval, Nathan; Linseman, Daniel A.] Univ Denver, Dept Biol Sci, Denver, CO 80208 USA. [Gray, Josie J.; Zommer, Amelia E.; Duval, Nathan; Linseman, Daniel A.] Univ Denver, Eleanor Roosevelt Inst, Denver, CO 80208 USA. [Bouchard, Ron J.; Linseman, Daniel A.] Eastern Colorado Hlth Care Syst, Vet Affairs Med Ctr, Denver, CO 80220 USA. [Blackstone, Craig] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Linseman, Daniel A.] Univ Colorado Denver, Div Clin Pharmacol & Toxicol, Aurora, CO 80045 USA. [Linseman, Daniel A.] Univ Colorado Denver, Neurosci Program, Aurora, CO 80045 USA. RP Linseman, DA (reprint author), Univ Denver, Dept Biol Sci, 2199 S Univ Blvd, Denver, CO 80208 USA. EM josie.gray@du.edu; azommer@du.edu; ron.bouchard@ucdenver.edu; nathan.duval@du.edu; craigblackstc@ninds.nih.gov; daniel.linseman@du.edu FU NINDS [R01NS062766]; NINDS, NIH FX Funding was provided by a VA Merit Review Grant and a R01NS062766 grant from NINDS to D.A.L. and the Intramural Research Program of the NINDS, NIH to C.B. The authors acknowledge Emily Schroeder, Natalie Kelsey, and Alexandra Loucks for technical assistance. NR 72 TC 5 Z9 5 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD FEB 4 PY 2013 VL 1494 BP 28 EP 43 DI 10.1016/j.brainres.2012.12.001 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 084SP UT WOS:000314559700004 PM 23220553 ER PT J AU Migliano, AB Romero, IG Metspalu, M Leavesley, M Pagani, L Antao, T Huang, DW Sherman, BT Siddle, K Scholes, C Hudjashov, G Kaitokai, E Babalu, A Belatti, M Cagan, A Hopkinshaw, B Shaw, C Nelis, M Metspalu, E Magi, R Lempicki, RA Villems, R Lahr, MM Kivisild, T AF Migliano, Andrea Bamberg Romero, Irene Gallego Metspalu, Mait Leavesley, Matthew Pagani, Luca Antao, Tiago Huang, Da-Wei Sherman, Brad T. Siddle, Katharine Scholes, Clarissa Hudjashov, Georgi Kaitokai, Elton Babalu, Avis Belatti, Maggie Cagan, Alex Hopkinshaw, Bryony Shaw, Colin Nelis, Mari Metspalu, Ene Maegi, Reedik Lempicki, Richard A. Villems, Richard Lahr, Marta Mirazon Kivisild, Toomas TI Evolution of the Pygmy Phenotype: Evidence of Positive Selection from Genome-wide Scans in African, Asian, and Melanesian Pygmies SO HUMAN BIOLOGY LA English DT Article DE PYGMIES; NEGRITOS; EVOLUTION; PHENOTYPE; GENOTYPE; NATURAL SELECTION; CONVERGENT ADAPTATION ID GROWTH-FACTOR-I; MULTILOCUS GENOTYPE DATA; FAMILIAL SHORT STATURE; HORMONE-RECEPTOR GENE; POPULATION-STRUCTURE; ANDAMAN ISLANDERS; HUNTER-GATHERERS; ADULT HEIGHT; BROWN FAT; MUTATION AB Human pygmy populations inhabit different regions of the world, from Africa to Melanesia. In Asia, short-statured populations are often referred to as "negritos." Their short stature has been interpreted as a consequence of thermoregulatory, nutritional, and/or locomotory adaptations to life in tropical forests. A more recent hypothesis proposes that their stature is the outcome of a life history trade-off in high-mortality environments, where early reproduction is favored and, consequently, early sexual maturation and early growth cessation have coevolved. Some serological evidence of deficiencies in the growth hormone/insulin-like growth factor axis have been previously associated with pygmies' short stature. Using genome-wide single-nucleotide polymorphism genotype data, we first tested whether different negrito groups living in the Philippines and Papua New Guinea are closely related and then investigated genomic signals of recent positive selection in African, Asian, and Papuan pygmy populations. We found that negritos in the Philippines and Papua New Guinea are genetically more similar to their nonpygmy neighbors than to one another and have experienced positive selection at different genes. These results indicate that geographically distant pygmy groups are likely to have evolved their short stature independently. We also found that selection on common height variants is unlikely to explain their short stature and that different genes associated with growth, thyroid function, and sexual development are under selection in different pygmy groups. C1 [Migliano, Andrea Bamberg] UCL, Dept Anthropol, London WC1E 6BT, England. [Romero, Irene Gallego; Pagani, Luca; Antao, Tiago; Siddle, Katharine; Scholes, Clarissa; Belatti, Maggie; Cagan, Alex; Hopkinshaw, Bryony; Shaw, Colin; Lahr, Marta Mirazon; Kivisild, Toomas] Univ Cambridge, Dept Biol Anthropol, Leverhulme Ctr Human Evolutionary Studies, Cambridge CB2 3DZ, England. [Metspalu, Mait; Hudjashov, Georgi; Nelis, Mari; Metspalu, Ene; Maegi, Reedik; Villems, Richard; Kivisild, Toomas] Univ Tartu, Dept Evolutionary Biol, EE-50090 Tartu, Estonia. [Metspalu, Mait; Hudjashov, Georgi; Nelis, Mari; Metspalu, Ene; Maegi, Reedik; Villems, Richard; Kivisild, Toomas] Estonian Bioctr, Tartu, Estonia. [Leavesley, Matthew] James Cook Univ, Archaeol Dept, Cairns, Australia. [Huang, Da-Wei; Sherman, Brad T.; Lempicki, Richard A.] NCI, Lab Immunopathogenesis & Bioinformat, Clin Serv Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Kaitokai, Elton; Babalu, Avis] Univ Papua New Guinea, Port Moresby, Papua N Guinea. [Maegi, Reedik] Univ Oxford, Genet & Genom Epidemiol Unit, Wellcome Trust Ctr Human Genet, Oxford, England. RP Migliano, AB (reprint author), UCL, Dept Anthropol, Mortimer St, London WC1E 6BT, England. EM a.migliano@ucl.ac.uk RI Antao, Tiago/C-3615-2009; James Cook University, TESS/B-8171-2012; Lempicki, Richard/E-1844-2012; Hudjashov, Georgi/H-1254-2015; Metspalu, Mait/G-8671-2015; OI Antao, Tiago/0000-0002-7269-5513; Lempicki, Richard/0000-0002-7059-409X; Metspalu, Mait/0000-0003-3099-9161; Pagani, Luca/0000-0002-6639-524X FU Clare College fellowship; Newnham Gibbs travel fellowship; Leverhulme Programme Grant/Hunter-Gatherers Resilience; Natural Environment Research Council (NERC)/Environmental Factors in the Chronology of Human Evolution; Dispersal Programme (EFCHED) grant; E.U. European Regional Development Fund through the Centre of Excellence in Genomics; Estonian Basic Research grant [SF0182474]; Tartu University grant [PBGMR06901] FX This project was funded by a Clare College fellowship, a Newnham Gibbs travel fellowship, and the Leverhulme Programme Grant/Hunter-Gatherers Resilience to A.B.M.; a Natural Environment Research Council (NERC)/Environmental Factors in the Chronology of Human Evolution and Dispersal Programme (EFCHED) grant to M.M.L.; the E.U. European Regional Development Fund through the Centre of Excellence in Genomics and Estonian Basic Research grant SF0182474 to R.V.; and Tartu University grant PBGMR06901 to T.K. NR 94 TC 22 Z9 22 U1 2 U2 28 PU WAYNE STATE UNIV PRESS PI DETROIT PA 4809 WOODWARD AVE, DETROIT, MI 48201-1309 USA SN 0018-7143 EI 1534-6617 J9 HUM BIOL JI Hum. Biol. PD FEB-JUN PY 2013 VL 85 IS 1-3 SI SI BP 251 EP 284 PG 34 WC Anthropology; Biology; Genetics & Heredity SC Anthropology; Life Sciences & Biomedicine - Other Topics; Genetics & Heredity GA 259VN UT WOS:000327554500012 PM 24297229 ER PT J AU Hohman, TJ Peynircioglu, ZF Beason-Held, LL AF Hohman, Timothy J. Peynircioglu, Zehra F. Beason-Held, Lori L. TI Flexibility of event boundaries in autobiographical memory SO MEMORY LA English DT Article DE Autobiographical memory; Ageing; Event; Memory ID EPISODIC MEMORIES; TIME; PERCEPTION; SEGMENTATION; BEHAVIOR; MODEL; SELF AB Events have clear and consistent boundaries that are defined during perception in a manner that influences memory performance. The natural process of event segmentation shapes event definitions during perception, and appears to play a critical role in defining distinct episodic memories at encoding. However, the role of retrieval processes in modifying event definitions is not clear. We explored how such processes changed event boundary definitions at recall. In Experiment 1 we showed that distance from encoding is related to boundary flexibility. Participants were more likely to move self-reported event boundaries to include information reported beyond those boundaries when recalling more distant events compared to more recent events. In Experiment 2 we showed that age also influenced boundary flexibility. Older Age adults were more likely to move event boundaries than College Age adults, and the relationship between distance from encoding and boundary flexibility seen in Experiment 1 was present only in College Age and Middle Age adults. These results suggest that factors at retrieval have a direct impact on event definitions in memory and that, although episodic memories may be initially defined at encoding, these definitions are not necessarily maintained in long-term memory. C1 [Hohman, Timothy J.; Peynircioglu, Zehra F.] Amer Univ, Dept Psychol, Washington, DC 20016 USA. [Hohman, Timothy J.; Beason-Held, Lori L.] NIA, NIH, Baltimore, MD 21224 USA. RP Hohman, TJ (reprint author), Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, 519 Light Hall, Nashville, TN 37232 USA. EM Timothyjhohman@gmail.com OI Hohman, Timothy/0000-0002-3377-7014 FU Intramural NIH HHS [Z99 AG999999] NR 33 TC 0 Z9 0 U1 1 U2 6 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 0965-8211 EI 1464-0686 J9 MEMORY JI Memory PD FEB 1 PY 2013 VL 21 IS 2 BP 249 EP 260 DI 10.1080/09658211.2012.725737 PG 12 WC Psychology, Experimental SC Psychology GA 263EW UT WOS:000327790600008 PM 22989194 ER PT J AU Goto, K Iso, T Hanaoka, H Yamaguchi, A Suga, T Hattori, A Irie, Y Shinagawa, Y Matsui, H Syamsunarno, MRAA Matsui, M Haque, A Arai, M Kunimoto, F Yokoyama, T Endo, K Gonzalez, FJ Kurabayashi, M AF Goto, Kosaku Iso, Tatsuya Hanaoka, Hirofumi Yamaguchi, Aiko Suga, Toshihiro Hattori, Akinari Irie, Yasunori Shinagawa, Yuji Matsui, Hiroki Syamsunarno, Mas Rizky A. A. Matsui, Miki Haque, Anwarul Arai, Masashi Kunimoto, Fumio Yokoyama, Tomoyuki Endo, Keigo Gonzalez, Frank J. Kurabayashi, Masahiko TI Peroxisome Proliferator-Activated Receptor-gamma in Capillary Endothelia Promotes Fatty Acid Uptake by Heart During Long-Term Fasting SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE capillaries; cardiac metabolism; endothelium; fatty acids; transcription factors ID PPAR-GAMMA; CD36 DEFICIENCY; BINDING PROTEINS; GENE-EXPRESSION; ADIPOSE-TISSUE; MICE; MUSCLE; DIFFERENTIATION; TRANSPORT; INSULIN AB Background-Endothelium is a crucial blood-tissue interface controlling energy supply according to organ needs. We investigated whether peroxisome proliferator-activated receptor-gamma (PPAR gamma) induces expression of fatty acid-binding protein 4 (FABP4) and fatty acid translocase (FAT)/CD36 in capillary endothelial cells (ECs) to promote FA transport into the heart. Methods and Results-Expression of FABP4 and CD36 was induced by the PPAR gamma agonist pioglitazone in human cardiac microvessel ECs (HCMECs), but not in human umbilical vein ECs. Real-time PCR and immunohistochemistry of the heart tissue of control (Pparg(fl/null)) mice showed an increase in expression of FABP4 and CD36 in capillary ECs by either pioglitazone treatment or 48 hours of fasting, and these effects were not found in mice deficient in endothelial PPAR gamma (Pparg(Delta EC/null)). Luciferase reporter constructs of the Fabp4 and CD36 promoters were markedly activated by pioglitazone in HCMECs through canonical PPAR-responsive elements. Activation of PPAR gamma facilitated FA uptake by HCMECs, which was partially inhibited by knockdown of either FABP4 or CD36. Uptake of an FA analogue, I-125-BMIPP, was significantly reduced in heart, red skeletal muscle, and adipose tissue in Pparg(Delta EC/null) mice as compared with Pparg(fl/null) mice after olive oil loading, whereas those values were comparable between Pparg(fl/null) and Pparg(Delta EC/null) null mice on standard chow and a high-fat diet. Furthermore, Pparg(Delta EC/null) mice displayed slower triglyceride clearance after olive oil loading. Conclusions-These findings identified a novel role for capillary endothelial PPAR gamma as a regulator of FA handing in FA-metabolizing organs including the heart in the postprandial state after long-term fasting. C1 [Iso, Tatsuya; Kurabayashi, Masahiko] Gunma Univ, Grad Sch Hlth Sci, Educ & Res Support Ctr, Maebashi, Gumma 371, Japan. [Goto, Kosaku; Iso, Tatsuya; Suga, Toshihiro; Matsui, Hiroki; Syamsunarno, Mas Rizky A. A.; Matsui, Miki; Arai, Masashi; Kurabayashi, Masahiko] Gunma Univ, Grad Sch Hlth Sci, Dept Med & Biol Sci, Maebashi, Gumma 371, Japan. [Hanaoka, Hirofumi; Yamaguchi, Aiko] Gunma Univ, Grad Sch Hlth Sci, Dept Bioimaging Informat Anal, Maebashi, Gumma 371, Japan. [Endo, Keigo] Gunma Univ, Grad Sch Hlth Sci, Dept Diagnost Radiol & Nucl Med, Maebashi, Gumma 371, Japan. [Haque, Anwarul; Kunimoto, Fumio] Gunma Univ, Grad Sch Hlth Sci, Dept Anesthesiol & Intens Care Med, Maebashi, Gumma 371, Japan. [Hattori, Akinari; Irie, Yasunori; Shinagawa, Yuji; Matsui, Hiroki; Yokoyama, Tomoyuki] Gunma Univ, Grad Sch Med, Lab Sci, Maebashi, Gumma 371, Japan. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Iso, T (reprint author), 3-39-22 Showa Machi, Maebashi, Gumma 3718511, Japan. EM isot@gunma-u.ac.jp FU Japan Society for the Promotion of Science; Japan Cardiovascular Foundation; Takeda Science Foundation; Therapeutic Research for Metabolic Syndrome; AstraZeneca; Vehicle Racing Commemorative Foundation FX This work was supported, in part, by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (to M. K. and T. I.), a grant from the Japan Cardiovascular Foundation (to M. K.), and grants from Takeda Science Foundation, Therapeutic Research for Metabolic Syndrome, AstraZeneca, and the Vehicle Racing Commemorative Foundation (to T.I.). NR 38 TC 11 Z9 11 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD FEB PY 2013 VL 2 IS 1 AR UNSP e004861 DI 10.1161/JAHA.112.004861 PG 15 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 243SF UT WOS:000326336800013 PM 23525438 ER PT J AU Harford, JB Aljawi, DM AF Harford, Joe B. Aljawi, Deena M. TI The need for more and better palliative care for Muslim patients SO PALLIATIVE & SUPPORTIVE CARE LA English DT Editorial Material C1 [Harford, Joe B.] NCI, Bethesda, MD 20892 USA. [Aljawi, Deena M.] King Faisal Specialist Hosp & Res Ctr, Riyadh 11211, Saudi Arabia. RP Harford, JB (reprint author), NCI, Bethesda, MD 20892 USA. NR 1 TC 3 Z9 3 U1 0 U2 2 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1478-9515 J9 PALLIAT SUPPORT CARE JI Palliat. Support Care PD FEB PY 2013 VL 11 IS 1 BP 1 EP 4 DI 10.1017/S1478951512000053 PG 4 WC Health Policy & Services SC Health Care Sciences & Services GA 219VP UT WOS:000324539500001 PM 22874103 ER PT J AU Wiener, L Mcconnell, DG Latella, L Ludi, E AF Wiener, Lori Mcconnell, Denice Grady Latella, Lauren Ludi, Erica TI Cultural and religious considerations in pediatric palliative care SO PALLIATIVE & SUPPORTIVE CARE LA English DT Article DE Culture; Pediatric palliative care; Religion; Spirituality; Children; Ethnicity ID OF-LIFE CARE; HEALTH-CARE; DECISION-MAKING; PAIN MANAGEMENT; CANCER; CHILDREN; END; BARRIERS; DEATH; PARENTS AB Objective: A growing multicultural society presents healthcare providers with a difficult task of providing appropriate care for individuals who have different life experiences, beliefs, value systems, religions, languages, and notions of healthcare. This is especially vital when end-of-life care is needed during childhood. There is a dearth of literature addressing cultural considerations in the pediatric palliative care field. As members of a specific culture often do not ascribe to the same religious traditions, the purpose of this article was to explore and review how culture and religion informs and shapes pediatric palliative care. Method: Comprehensive literature searches were completed through an online search of nine databases for articles published between 1980 and 2011: PsychINFO, MEDLINE (R), Journal of Citation Reports-Science Edition, Embase, Scopus, CINAHL (R), Social Sciences Citation Index (SSCI), EBSCO, and Ovid. Key terms included: culture, transcultural, spiritual, international, ethnic, customs or religion AND end-of-life, palliative care, death, dying, cancer, or hospice, and children, pediatrics, or pediatric oncology. Reference lists in the retrieved articles were examined for additional studies that fit the inclusion criteria, and relevant articles were included for review. In addition, web-based searches of specific journals were conducted. These included, but were not limited to: Qualitative Health Research, Psycho-Oncology, Journal of Psychosocial Oncology, Journal of Pediatric Psychology, Journal of Pediatric Health Care, Journal of Pediatric Oncology Nursing, Omega, Social Work in Health Care, and Journal of Palliative Medicine. Results: Thirty-seven articles met eligibility criteria. From these, seven distinct themes emerged that have implications for pediatric palliative care. These include the role of culture in decision-making, faith and the involvement of clergy, communication (spoken and unspoken language), communicating to children about death (truth telling), the meaning of pain and suffering, the meaning of death and dying, and location of end-of-life care. Significance of results: The review of the literature provides insight into the influence of religion and how culture informs lifestyle and shapes the experiences of illness, pain, and end-of-life care. Recommendations for providing culturally sensitive end-of-life care are offered through the framework outlined in the Initiative for Pediatric Palliative Care Quality Improvement Project of 2002. Cultural traditions are dynamic, never static, and cannot be generalized to all families. Guidelines to aid in approaches to palliative care are provided, and providers are encouraged to define these important differences for each family under their care. C1 [Wiener, Lori; Latella, Lauren] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Mcconnell, Denice Grady] Adams Hanover Counseling Serv Inc, Hanover, PA USA. [Latella, Lauren] Cornell Univ, Ithaca, NY USA. [Ludi, Erica] NIMH, NIH, Bethesda, MD 20892 USA. RP Wiener, L (reprint author), NCI, NIH, Pediat Clin, 10 Ctr Dr,1-6466, Bethesda, MD 20892 USA. EM wienerl@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 106 TC 26 Z9 28 U1 7 U2 69 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1478-9515 J9 PALLIAT SUPPORT CARE JI Palliat. Support Care PD FEB PY 2013 VL 11 IS 1 BP 47 EP 67 DI 10.1017/S1478951511001027 PG 21 WC Health Policy & Services SC Health Care Sciences & Services GA 219VP UT WOS:000324539500007 PM 22617619 ER PT J AU Falcone, EL Holland, SM AF Falcone, E. Liana Holland, Steven M. TI Streptococcal Infections in Patients with Chronic Granulomatous Disease: Case Report and Review of the Literature SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Letter C1 [Falcone, E. Liana; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, CRC, Bethesda, MD 20892 USA. RP Falcone, EL (reprint author), NIAID, Lab Clin Infect Dis, NIH, CRC, Rm B3 4141,MSC 1684, Bethesda, MD 20892 USA. EM emilia.falcone@nih.gov; smh@nih.gov FU Intramural NIH HHS [Z01 AI000646-16] NR 2 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 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD FEB PY 2013 VL 33 IS 2 BP 310 EP 310 DI 10.1007/s10875-012-9823-8 PG 1 WC Immunology SC Immunology GA 201DX UT WOS:000323122000004 PM 23108438 ER PT J AU Lo, B Ramaswamy, M Davis, J Price, S Rao, VK Siegel, RM Lenardo, MJ AF Lo, Bernice Ramaswamy, Madhu Davis, Joie Price, Susan Rao, V. Koneti Siegel, Richard M. Lenardo, Michael J. TI A Rapid Ex Vivo Clinical Diagnostic Assay for Fas Receptor-Induced T Lymphocyte Apoptosis SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE Apoptosis; Fas; Autoimmune Lymphoproliferative syndrome; diagnosis; effector memory T cells; double-negative T cells ID AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; MUTATIONS; PENETRANCE; COMMON; CELLS AB Deleterious mutations in genes involved in the Fas apoptosis pathway lead to Autoimmune Lymphoproliferative Syndrome (ALPS). Demonstration of an apoptosis defect is critical for the diagnosis and study of ALPS. The traditional in vitro apoptosis assay, however, requires a week of experimental procedures. Here, we show that defects in Fas-induced apoptosis in PBMCs can be evaluated directly ex vivo using multicolor flow cytometry to analyze the apoptosis of effector memory T cells, a Fas-sensitive subset of PBMCs. This method allowed us to sensitively quantify defective apoptosis in ALPS patients within a few hours. Some ALPS patients (ALPS-sFAS) without germline mutations have somatic mutations in Fas specifically in double-negative alpha beta T cells (DNTs), an unusual lymphocyte population that is characteristically expanded in ALPS. Since DNTs have been notoriously difficult to culture, defective apoptosis has not been previously demonstrated for ALPS-sFAS patients. Using our novel ex vivo apoptosis assay, we measured Fas-induced apoptosis of DNTs for the first time and found that ALPS-sFAS patients had significant apoptosis defects in these cells compared to healthy controls. Hence, this rapid apoptosis assay can expedite the diagnosis of new ALPS patients, including those with somatic mutations, and facilitate clinical and molecular investigation of these diseases. C1 [Lo, Bernice; Lenardo, Michael J.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Ramaswamy, Madhu; Siegel, Richard M.] NIAMSD, Immunoregulat Sect, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. [Davis, Joie; Price, Susan; Rao, V. Koneti] NIAID, ALPS Unit, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Lenardo, MJ (reprint author), Bldg 10,Room 11N311,10 Ctr Dr,MSC 1892, Bethesda, MD 20892 USA. EM Lenardo@nih.gov OI Lo, Bernice/0000-0002-1087-6845 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank the patients and healthy blood donors. We also thank Josh Milner for use of his LSRFortessa. We thank Julie Niemela for assistance in mutation nomenclature. We also thank Claire Liu for assay name recommendations, and we thank Helen Su and Chryssa Kanellopoulou for critical reading of the manuscript. This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 23 TC 4 Z9 4 U1 0 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD FEB PY 2013 VL 33 IS 2 BP 479 EP 488 DI 10.1007/s10875-012-9811-z PG 10 WC Immunology SC Immunology GA 201DX UT WOS:000323122000024 PM 23054345 ER PT J AU La Merrill, M Emond, C Kim, MJ Antignac, JP Le Bizec, B Clement, K Birnbaum, LS Barouki, R AF La Merrill, Michele Emond, Claude Kim, Min Ji Antignac, Jean-Philippe Le Bizec, Bruno Clement, Karine Birnbaum, Linda S. Barouki, Robert TI Toxicological Function of Adipose Tissue: Focus on Persistent Organic Pollutants SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review DE adipose tissue; aryl hydrocarbon receptor; development; diabetes; dioxin; inflammation; obesity; obesogens; polychlorinated biphenyls; toxicity; toxicokinetics ID ARYL-HYDROCARBON RECEPTOR; ENDOCRINE-DISRUPTING CHEMICALS; LOW-DENSITY-LIPOPROTEIN; LIPID-METABOLISM; FAT MASS; BODY-FAT; POLYCHLORINATED-BIPHENYLS; ADIPOCYTE DIFFERENTIATION; LIPOPHILIC CHEMICALS; PERINATAL EXPOSURE AB BACKGROUND: Adipose tissue (AT) is involved in several physiological functions, including metabolic regulation, energy storage, and endocrine functions. OBJECTIVES: In this review we examined the evidence that an additional function of AT is to modulate persistent organic pollutant (POP) toxicity through several mechanisms. METHODS: We reviewed the literature on the interaction of AT with POPs to provide a comprehensive model for this additional function of AT. DISCUSSION: As a storage compartment for lipophilic POPs, AT plays a critical role in the toxicokinetics of a variety of drugs and pollutants, in particular, POPs. By sequestering POPs, AT can protect other organs and tissues from POPs overload. However, this protective function could prove to be a threat in the long run. The accumulation of lipophilic POPs will increase total body burden. These accumulated POPs are slowly released into the bloodstream, and more so during weight loss. Thus, AT constitutes a continual source of internal exposure to POPs. In addition to its buffering function, AT is also a target of POPs and may mediate part of their metabolic effects. This is particularly relevant because many POPs induce obesogenic effects that may lead to quantitative and qualitative alterations of AT. Some POPs also induce a proinflammatory state in AT, which may lead to detrimental metabolic effects. CONCLUSION: AT appears to play diverse functions both as a modulator and as a target of POPs toxicity. C1 [La Merrill, Michele] Mt Sinai Sch Med, Dept Prevent Med, New York, NY USA. [Emond, Claude] BioSimulat Consulting Inc, Newark, DE USA. [Emond, Claude] Univ Montreal, Dept Sante Environm & Sante Travail, Montreal, PQ, Canada. [Kim, Min Ji; Barouki, Robert] INSERM, UMR S 747, Paris, France. [Kim, Min Ji; Barouki, Robert] Univ Paris 05, Ctr Univ St Peres, F-75270 Paris 06, France. [Kim, Min Ji; Barouki, Robert] Hop Necker Enfants Malad, Assistance Publ Hop Paris, Paris, France. [Kim, Min Ji] Univ Paris 13, Sorbonne Paris Cite, INSERM, U698, Bobigny, France. [Antignac, Jean-Philippe; Le Bizec, Bruno] Atlanpole La Chantrerie, LABERCA, USC INRA 2013, ONIRIS, Nantes, France. [Clement, Karine] INSERM, U872, Nutriom Equipe 7, Paris, France. [Clement, Karine] Univ Paris 06, UMR S 872, Ctr Rech Cordeliers, Paris, France. [Clement, Karine] Hop La Pitie Salpetriere, Assistance Publ Hop Paris, Dept Nutr & Endocrinol, Paris, France. [Clement, Karine] CRNH Ile France, Paris, France. [Birnbaum, Linda S.] NCI, Res Triangle Pk, NC USA. [Birnbaum, Linda S.] Natl Inst Environm Hlth Sci, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC USA. RP Barouki, R (reprint author), Univ Paris 05, INSERM, UMRS 747, Ctr Univ St Peres, 45 Rue St Peres, F-75270 Paris 06, France. EM robert.barouki@parisdescartes.fr RI Tuomisto, Jouko/J-7450-2012; OI LE BIZEC, Bruno/0000-0002-0600-5895; ANTIGNAC, Jean-Philippe/0000-0001-9512-9314 FU INSERM (Institut National de la Sante et de la Recherche Medicale); National Institute of Environmental Health Sciences (NIEHS); Universite Paris Descartes; Universite Pierre et Marie Curie; INRA (Institut National de la Recherche Agronomique) FX This study was funded by INSERM (Institut National de la Sante et de la Recherche Medicale), the National Institute of Environmental Health Sciences (NIEHS), the Universite Paris Descartes, the Universite Pierre et Marie Curie, and INRA (Institut National de la Recherche Agronomique). NR 98 TC 46 Z9 47 U1 6 U2 80 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD FEB PY 2013 VL 121 IS 2 BP 162 EP 169 DI 10.1289/ehp.1205485 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 208SX UT WOS:000323700900016 PM 23221922 ER PT J AU Behl, M Rao, D Aagaard, K Davidson, TL Levin, ED Slotkin, TA Srinivasan, S Wallinga, D White, MF Walker, VR Thayer, KA Holloway, AC AF Behl, Mamta Rao, Deepa Aagaard, Kjersti Davidson, Terry L. Levin, Edward D. Slotkin, Theodore A. Srinivasan, Supriya Wallinga, David White, Morris F. Walker, Vickie R. Thayer, Kristina A. Holloway, Alison C. TI Evaluation of the Association between Maternal Smoking, Childhood Obesity, and Metabolic Disorders: A National Toxicology Program Workshop Review SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review DE animal; chemically induced/epidemiology; diabetes; environmental epidemiology; glucose; insulin; maternal smoking toxicity; metabolism; nicotine toxicity; obesity ID BODY-MASS INDEX; NEONATAL NICOTINE EXPOSURE; DIABETES-RELATED AUTOANTIBODIES; ENVIRONMENTAL RISK-FACTORS; PROSPECTIVE BIRTH COHORT; ADIPOSE-TISSUE FUNCTION; ENZYME GENE-EXPRESSION; BETA-CELL APOPTOSIS; CORD BLOOD LEPTIN; RAPID WEIGHT-GAIN AB BACKGROUND: An emerging literature suggests that environmental chemicals may play a role in the development of childhood obesity and metabolic disorders, especially when exposure occurs early in life. OBJECTIVE: Here we assess the association between these health outcomes and exposure to maternal smoking during pregnancy as part of a broader effort to develop a research agenda to better understand the role of environmental chemicals as potential risk factors for obesity and metabolic disorders. METHODS: PubMed was searched up to 8 March 2012 for epidemiological and experimental animal studies related to maternal smoking or nicotine exposure during pregnancy and childhood obesity or metabolic disorders at any age. A total of 101 studies-83 in humans and 18 in animals-were identified as the primary literature. DISCUSSION: Current epidemiological data support a positive association between maternal smoking and increased risk of obesity or overweight in offspring. The data strongly suggest a causal relation, although the possibility that the association is attributable to unmeasured residual confounding cannot be completely ruled out. This conclusion is supported by findings from laboratory animals exposed to nicotine during development. The existing literature on human exposures does not support an association between maternal smoking during pregnancy and type 1 diabetes in offspring. Too few human studies have assessed outcomes related to type 2 diabetes or metabolic syndrome to reach conclusions based on patterns of findings. There may be a number of mechanistic pathways important for the development of aberrant metabolic outcomes following perinatal exposure to cigarette smoke, which remain largely unexplored. CONCLUSIONS: From a toxicological perspective, the linkages between maternal smoking during pregnancy and childhood overweight/obesity provide proof-of-concept of how early-life exposure to an environmental toxicant can be a risk factor for childhood obesity. C1 [Behl, Mamta] Kelly Govt Solut, Res Triangle Pk, NC USA. [Behl, Mamta] Natl Inst Environm Sci NIEHS, Div Natl Toxicol Program, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Rao, Deepa] Integrated Lab Syst Inc, Res Triangle Pk, NC USA. [Aagaard, Kjersti] Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. [Davidson, Terry L.] Purdue Univ, Dept Psychol Sci, W Lafayette, IN 47907 USA. [Levin, Edward D.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC USA. [Slotkin, Theodore A.] Duke Univ, Dept Pharmacol & Canc Biol, Durham, NC USA. [Srinivasan, Supriya] Scripps Res Inst, Dept Chem Physiol, La Jolla, CA 92037 USA. [Wallinga, David] Inst Agr & Trade Policy, Food & Hlth Program, Minneapolis, MN USA. [White, Morris F.] Childrens Hosp Boston, Howard Hughes Med Inst, Div Endocrinol, Boston, MA USA. [Walker, Vickie R.; Thayer, Kristina A.] NIEHS, Div Natl Toxicol Program, Off Hlth Assessment & Translat, NIH,DHHS, Res Triangle Pk, NC 27709 USA. [Holloway, Alison C.] McMaster Univ, Dept Obstet & Gynecol, Reprod Biol Div, Hamilton, ON, Canada. RP Holloway, AC (reprint author), McMaster Univ, Dept Obstet & Gynecol, HSC 3N52,1280 Main St West, Hamilton, ON L8S 4K1, Canada. EM hollow@mcmaster.ca FU National Institute of Environmental Health Sciences/National Toxicology Program (NIEHS/NTP); U.S. Environmental Protection Agency (EPA); Food and Drug Administration National Center for Toxicological Research (FDA/NCTR) FX This review is based on deliberations that occurred at an 11-13 January 2011 workshop sponsored by the National Institute of Environmental Health Sciences/National Toxicology Program (NIEHS/NTP), U.S. Environmental Protection Agency (EPA), and the Food and Drug Administration National Center for Toxicological Research (FDA/NCTR) (http://ntp.niehs.nih.gov/go/36433). NR 144 TC 43 Z9 43 U1 3 U2 39 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD FEB PY 2013 VL 121 IS 2 BP 170 EP 180 DI 10.1289/ehp.1205404 PG 11 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 208SX UT WOS:000323700900017 PM 23232494 ER PT J AU Louis, GMB Sundaram, R Schisterman, EF Sweeney, AM Lynch, CD Gore-Langton, RE Maisog, J Kim, S Chen, Z Barr, DB AF Louis, Germaine M. Buck Sundaram, Rajeshwari Schisterman, Enrique F. Sweeney, Anne M. Lynch, Courtney D. Gore-Langton, Robert E. Maisog, Jose Kim, Sungduk Chen, Zhen Barr, Dana B. TI Persistent Environmental Pollutants and Couple Fecundity: The LIFE Study SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE conception; cotinine; fecundity; organochlorine pesticides; polybrominated diphenyl ethers; polychlorinated biphenyls; perfluorochemicals; time to pregnancy ID ENDOCRINE-DISRUPTING CHEMICALS; MENSTRUAL-CYCLE; HUMAN-SERUM; POLYCHLORINATED-BIPHENYLS; EXPOSURE MEASUREMENT; DYSGENESIS SYNDROME; PROSPECTIVE COHORT; REGRESSION-MODELS; PREGNANCY; TIME AB BACKGROUND: Evidence suggesting that persistent environmental pollutants may be reproductive toxicants underscores the need for prospective studies of couples for whom exposures are measured. OBJECTIVES: We examined the relationship between selected persistent pollutants and couple fecundity as measured by time to pregnancy. METHODS: A cohort of 501 couples who discontinued contraception to become pregnant was prospectively followed for 12 months of trying to conceive or until a human chorionic gonadotrophin (hCG) test confirmed pregnancy. Couples completed daily journals on lifestyle and provided biospecimens for the quantification of 9 organochlorine pesticides, 1 polybrominated biphenyl, 10 polybrominated diphenyl ethers, 36 polychlorinated biphenyls (PCBs), and 7 perfluorochemicals (PFCs) in serum. Using Cox models for discrete time, we estimated fecundability odds ratios (FORs) and 95% CIs separately for each partner's concentrations adjusting for age, body mass index, serum cotinine, serum lipids (except for PFCs), and study site (Michigan or Texas); sensitivity models were further adjusted for left truncation or time off of contraception (<= 2 months) before enrollment. RESULTS: The adjusted reduction in fecundability associated with standard deviation increases in log-transformed serum concentrations ranged between 18% and 21% for PCB congeners 118, 167, 209, and perfluorooctane sulfonamide in females; and between 17% and 29% for p,p'-DDE and PCB congeners 138, 156, 157, 167, 170, 172, and 209 in males. The strongest associations were observed for PCB 167 (FOR 0.79; 95% CI: 0.64, 0.97) in females and PCB 138 (FOR = 0.71; 95% CI: 0.52, 0.98) in males. CONCLUSIONS: In this couple-based prospective cohort study with preconception enrollment and quantification of exposures in both female and male partners, we observed that a subset of persistent environmental chemicals were associated with reduced fecundity. C1 [Louis, Germaine M. Buck; Sundaram, Rajeshwari; Schisterman, Enrique F.; Maisog, Jose; Kim, Sungduk; Chen, Zhen] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Sweeney, Anne M.] Texas A&M Hlth Sci Ctr, Sch Rural Publ Hlth, Dept Epidemiol & Biostat, College Stn, TX USA. [Lynch, Courtney D.] Ohio State Univ, Coll Med, Dept Obstet & Gynecol, Columbus, OH 43210 USA. [Gore-Langton, Robert E.] EMMES Corp, Rockville, MD USA. [Barr, Dana B.] Emory Univ, Rollins Sch Publ Hlth, Dept Occupat & Environm Hlth, Atlanta, GA 30322 USA. RP Louis, GMB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,Room 7B03, Rockville, MD 20852 USA. EM louisg@mail.nih.gov OI Sundaram, Rajeshwari/0000-0002-6918-5002; Schisterman, Enrique/0000-0003-3757-641X; Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural Research Program of the NICHD [N01-HD-3-3355, N01-HD-3-3356, NOH-HD-3-3358] FX This research was supported by the Intramural Research Program of the NICHD (contracts N01-HD-3-3355, N01-HD-3-3356, and NOH-HD-3-3358). NR 61 TC 49 Z9 51 U1 3 U2 28 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD FEB PY 2013 VL 121 IS 2 BP 231 EP 236 DI 10.1289/ehp.1205301 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 208SX UT WOS:000323700900026 PM 23151773 ER PT J AU Bertelsen, RJ Carlsen, KCL Calafat, AM Hoppin, JA Haland, G Mowinckel, P Carlsen, KH Lovik, M AF Bertelsen, Randi J. Carlsen, Karin C. Lodrup Calafat, Antonia M. Hoppin, Jane A. Haland, Geir Mowinckel, Petter Carlsen, Kai-Hakon Lovik, Martinus TI Urinary Biomarkers for Phthalates Associated with Asthma in Norwegian Children SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE asthma; biomarkers; children; endocrine disruptors; phthalates ID NUTRITION EXAMINATION SURVEY; INTERIOR SURFACE MATERIALS; NEW-YORK-CITY; METABOLITE LEVELS; NATIONAL-HEALTH; BIRTH COHORT; EXPOSURE; VARIABILITY; PRODUCTS; OSLO AB BACKGROUND: High-molecular-weight phthalates in indoor dust have been associated with asthma in children, but few studies have evaluated phthalate biomarkers in association with respiratory outcomes. OBJECTIVES: We explored the association between urinary concentrations of phthalate metabolites and current asthma. METHODS: In a cross-sectional analysis, 11 metabolites of 8 phthalates [including four metabolites of di(2-ethylhexyl) phthalate] were measured in one first morning void collected from 2001 through 2004 from 623 10-year-old Norwegian children. Logistic regression models controlling for urine specific gravity, sex, parental asthma, and income were used to estimate associations between current asthma and phthalate metabolite concentrations by quartiles or as log(10)-transformed variables. RESULTS: Current asthma was associated with both mono(carboxyoctyl) phthalate (MCOP) and mono(carboxynonyl) phthalate (MCNP), although the association was limited to those in the highest quartile of these chemicals. The adjusted odds ratio (aOR) for current asthma was 1.9 (95% CI: 1.0, 3.3) for the highest MCOP quartile compared with the lowest quartile, and 1.3 (95% CI: 0.98, 1.7) for an interquartile-range increase. The aOR for current asthma was 2.2 (95% CI: 1.2, 4.0) for the highest MCNP quartile and 1.3 (95% CI: 1.0, 1.7) for an interquartile-range increase. The other phthalate metabolites were not associated with current asthma. CONCLUSIONS: Current asthma was associated with the highest quartiles of MCOP and MCNP, metabolites of two high molecular weight phthalates, diisononyl phthalate and diisodecyl phthalate, respectively. Given the short biological half-life of the phthalates and the cross-sectional design, our findings should be interpreted cautiously. C1 [Bertelsen, Randi J.; Lovik, Martinus] Norwegian Inst Publ Hlth, Dept Food Water & Cosmet, N-0403 Oslo, Norway. [Bertelsen, Randi J.; Hoppin, Jane A.] Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC USA. [Carlsen, Karin C. Lodrup; Haland, Geir; Mowinckel, Petter; Carlsen, Kai-Hakon] Oslo Univ Hosp, Dept Pediat, Oslo, Norway. [Carlsen, Karin C. Lodrup; Haland, Geir; Carlsen, Kai-Hakon] Univ Oslo, Fac Med, Oslo, Norway. [Calafat, Antonia M.] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA USA. RP Bertelsen, RJ (reprint author), Norwegian Inst Publ Hlth, Dept Food Water & Cosmet, POB 4404 Nydalen, N-0403 Oslo, Norway. EM randi.jacobsen.bertelsen@fhi.no FU Norwegian Institute of Public Health; Research Council of Norway; Oslo University Hospital; Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS); AstraZeneca Norway; Sixth EU Framework program for research [FOOD-CT-2004-506378] FX The study was funded by the Norwegian Institute of Public Health, Research Council of Norway, and Oslo University Hospital, and supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS). An unrestricted grant from the AstraZeneca Norway fund for research within pulmonology was given in 2006 to G.H. for the cost of phthalate analyses in urine. The sponsor had no influence on the analyses, interpretation, or presentation. The study was performed within ORAACLE (the Oslo Research Group of Asthma and Allergy in Childhood: the Lung and Environment), a member of GA2LEN (Global Allergy and Asthma European Network), supported by the Sixth EU Framework program for research, contract FOOD-CT-2004-506378. NR 38 TC 40 Z9 40 U1 6 U2 39 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD FEB PY 2013 VL 121 IS 2 BP 251 EP 256 DI 10.1289/ehp.1205256 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 208SX UT WOS:000323700900029 PM 23164678 ER PT J AU Guha, N Ward, MH Gunier, R Colt, JS Lea, CS Buffler, PA Metayer, C AF Guha, Neela Ward, Mary H. Gunier, Robert Colt, Joanne S. Lea, C. Suzanne Buffler, Patricia A. Metayer, Catherine TI Characterization of Residential Pesticide Use and Chemical Formulations through Self-Report and Household Inventory: The Northern California Childhood Leukemia Study SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE exposure assessment; pesticides; population-based study; residential pesticide use; US EPA ID NON-HODGKIN-LYMPHOMA; EXPOSURES; CANCER; RISK; CHILDRENS; HOME AB BACKGROUND: Home and garden pesticide use has been linked to cancer and other health outcomes in numerous epidemiological studies. Exposure has generally been self-reported, so the assessment is potentially limited by recall bias and lack of information on specific chemicals. OBJECTIVES: As part of an integrated assessment of residential pesticide exposure, we identified active ingredients and described patterns of storage and use. METHODS: During a home interview of 500 residentially stable households enrolled in the Northern California Childhood Leukemia Study during 2001-2006, trained interviewers inventoried residential pesticide products and queried participants about their storage and use. U.S. Environmental Protection Agency registration numbers, recorded from pesticide product labels, and pesticide chemical codes were matched to public databases to obtain information on active ingredients and chemical class. Poisson regression was used to identify independent predictors of pesticide storage. Analyses were restricted to 259 participating control households. RESULTS: Ninety-five percent (246 of 259) of the control households stored at least one pesticide product (median, 4). Indicators of higher sociodemographic status predicted more products in storage. We identified the most common characteristics: storage areas (garage, 40%; kitchen, 20%), pests treated (ants, 33%; weeds, 20%), pesticide types (insecticides, 46%; herbicides, 24%), chemical classes (pyrethroids, 77%; botanicals, 50%), active ingredients (pyrethrins, 43%) and synergists (piperonyl butoxide, 42%). Products could contain multiple active ingredients. CONCLUSIONS: Our data on specific active ingredients and patterns of storage and use will inform future etiologic analyses of residential pesticide exposures from self-reported data, particularly among households with young children. C1 [Guha, Neela; Gunier, Robert; Buffler, Patricia A.; Metayer, Catherine] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Guha, Neela] Int Agcy Res Canc, F-69372 Lyon, France. [Ward, Mary H.; Colt, Joanne S.] NCI, Bethesda, MD 20892 USA. [Lea, C. Suzanne] E Carolina Univ, Brody Sch Med, Dept Publ Hlth, Greenville, NC USA. RP Metayer, C (reprint author), 1995 Univ Ave,Suite 460, Berkeley, CA 94704 USA. EM cmetayer@berkeley.edu OI Guha, Neela/0000-0003-3991-4662; Gunier, Robert/0000-0001-5485-9919 FU National Institute of Environmental Health Sciences (NIEHS) [R01ES009137, P42ES04705]; National Cancer Institute (NCI), National Institutes of Health (NIH) [7590-S-04, 7590-S-01, N02-CP-11015] FX This work was supported by the National Institute of Environmental Health Sciences (NIEHS; grants R01ES009137 and P42ES04705), and partially funded by the Intramural Research Program of the National Cancer Institute (NCI), National Institutes of Health (NIH; subcontracts 7590-S-04 and 7590-S-01, and contract N02-CP-11015). NR 37 TC 7 Z9 9 U1 2 U2 32 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD FEB PY 2013 VL 121 IS 2 BP 276 EP 282 DI 10.1289/ehp.1204926 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 208SX UT WOS:000323700900033 PM 23110983 ER PT J AU Birnbaum, LS AF Birnbaum, Linda S. TI 15 Years Out: Reinventing ICCVAM SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material C1 [Birnbaum, Linda S.] NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Birnbaum, Linda S.] NIH, NTP, Dept Hlth & Human Serv, Res Triangle Pk, NC USA. RP Birnbaum, LS (reprint author), NIEHS, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM birnbaumls@niehs.nih.gov NR 2 TC 8 Z9 8 U1 0 U2 0 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD FEB PY 2013 VL 121 IS 2 BP A40 EP A40 DI 10.1289/ehp.1206292 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 208SX UT WOS:000323700900001 PM 23380598 ER PT J AU Moni, M Rajda, J Lakshmanadoss, U AF Moni, Monika Rajda, Jay Lakshmanadoss, Umashankar TI Artefactual spikes in electrocardiography: a worthwhile introspection SO SINGAPORE MEDICAL JOURNAL LA English DT Article DE artifacts; electrocardiography; implanted neurostimulator AB Electrical devices, which have become an integral part of our daily life, may influence the electrical recording of the heart. These disturbances from external sources outside of the heart's own activity produce changes in the electrocardiography (ECG) of the patient, simulating rhythmic disturbances of the heart. Understanding these disturbances is essential in order to better interprete the ECG. Common sources of electrical interferences include external devices, such as alternating current and improper earthing, and surgical procedures like diathermy. We report a case of electrical interference in a patient's ECG due to an inserted bladder stimulator. This case report highlights the importance of precise identification of artefacts in the interpretation of ECG, as well as prompt localisation and elimination of the source of interference. C1 [Moni, Monika] NIA, Clin Res Branch, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. [Rajda, Jay] Unity Hlth Syst, Dept Internal Med, New York, NY USA. [Lakshmanadoss, Umashankar] Guthrie Clin, Div Cardiovasc Med, Sayre, PA USA. RP Lakshmanadoss, U (reprint author), Guthrie Clin, Div Cardiovasc Med, 1 Guthrie Sq, Sayre, PA USA. EM drlumashankar@gmail.com NR 6 TC 0 Z9 0 U1 0 U2 2 PU SINGAPORE MEDICAL ASSOC PI SINGAPORE PA LEVEL 2 ALUMNI MEDICAL CENTRE, 2 COLLEGE RD, SINGAPORE 169850, SINGAPORE SN 0037-5675 J9 SINGAP MED J JI Singap. Med. J. PD FEB PY 2013 VL 54 IS 2 BP E46 EP E49 DI 10.11622/smedj.2013040 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 203TM UT WOS:000323316400007 PM 23462843 ER PT J AU Gliwa, C Berkman, BE AF Gliwa, Catherine Berkman, Benjamin E. TI Do Researchers Have an Obligation to Actively Look for Genetic Incidental Findings? SO AMERICAN JOURNAL OF BIOETHICS LA English DT Article DE genetics (clinical); genetic research; human subjects research; research ethics ID ANCILLARY-CARE RESPONSIBILITIES; RESEARCH PARTICIPANTS; MEDICAL RESEARCHERS; ETHICAL FRAMEWORK; CLINICAL-PRACTICE; GENOMIC RESEARCH; WORKING GROUP; RECOMMENDATIONS; CHALLENGES; VARIANTS AB The rapid growth of next-generation genetic sequencing has prompted debate about the responsibilities of researchers toward genetic incidental findings. Assuming there is a duty to disclose significant incidental findings, might there be an obligation for researchers to actively look for these findings? We present an ethical framework for analyzing whether there is a positive duty to look for genetic incidental findings. Using the ancillary care framework as a guide, we identify three main criteria that must be present to give rise to an obligation to look: high benefit to participants, lack of alternative access for participants, and reasonable burden on researchers. Our analysis indicates that there is no obligation to look for incidental findings today, but during the ongoing translation of genomic analysis from research to clinical care, this obligation may arise. C1 [Gliwa, Catherine; Berkman, Benjamin E.] NIH, Bethesda, MD 20892 USA. [Berkman, Benjamin E.] NHGRI, Bethesda, MD USA. RP Berkman, BE (reprint author), NIH, Bldg 10 Room 1C118,10 Ctr Dr,MSC 1156, Bethesda, MD 20892 USA. EM berkmanbe@mail.nih.gov FU Intramural Research Program of NHGRI, NIH FX The authors would like to thank Ben Solomon, Sara Hull, Karen Rothenberg, Justin Lowenthal, and all of our colleagues in the NIH Department of Bioethics for their thoughtful advice and careful reviews throughout this project. The opinions expressed in this article are those of the authors. No statement in this article should be construed as an official position of the National Human Genome Research Institute, National Institutes of Health, or Department of Health and Human Services. This research was supported by the Intramural Research Program of NHGRI, NIH. NR 42 TC 50 Z9 50 U1 4 U2 16 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 J9 AM J BIOETHICS JI Am. J. Bioeth. PD FEB 1 PY 2013 VL 13 IS 2 BP 32 EP 42 DI 10.1080/15265161.2012.754062 PG 11 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 189YG UT WOS:000322303600013 PM 23391059 ER PT J AU Biesecker, LG AF Biesecker, Leslie G. TI The Nirvana Fallacy and the Return of Results SO AMERICAN JOURNAL OF BIOETHICS LA English DT Editorial Material C1 [Biesecker, Leslie G.] NHGRI, Bethesda, MD USA. RP Biesecker, LG (reprint author), 49 Convent Dr,Room 4A56, Bethesda, MD 20892 USA. EM lesb@mail.nih.gov FU Intramural Research Program of the National Human Genome Research Institute of the National Institutes of Health FX This commentary represents the individual views of the author and does not necessarily represent the views of the institutions to which the author is affiliated. The author is supported by the Intramural Research Program of the National Human Genome Research Institute of the National Institutes of Health. NR 3 TC 6 Z9 6 U1 0 U2 2 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 EI 1536-0075 J9 AM J BIOETHICS JI Am. J. Bioeth. PD FEB 1 PY 2013 VL 13 IS 2 BP 43 EP 44 DI 10.1080/15265161.2013.755826 PG 2 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 189YG UT WOS:000322303600014 PM 23391060 ER PT J AU Karamzadeh, N Medvedev, A Azari, A Gandjbakhche, A Najafizadeh, L AF Karamzadeh, Nader Medvedev, Andrei Azari, Afrouz Gandjbakhche, Amir Najafizadeh, Laleh TI Capturing dynamic patterns of task-based functional connectivity with EEG SO NEUROIMAGE LA English DT Article DE Electroencephalography (EEG); Functional connectivity; Clustering analysis ID EVENT-RELATED POTENTIALS; QUANTIFYING STATISTICAL INTERDEPENDENCE; INDEPENDENT COMPONENT ANALYSIS; ODDBALL TASK; ALZHEIMERS-DISEASE; POINT-PROCESSES; WORKING-MEMORY; VISUAL P300; SCHIZOPHRENIA; NETWORKS AB A new approach to trace the dynamic patterns of task-based functional connectivity, by combining signal segmentation, dynamic time warping (DTW), and Quality Threshold (QT) clustering techniques, is presented. Electroencephalography (EEG) signals of 5 healthy subjects were recorded as they performed an auditory oddball and a visual modified oddball tasks. To capture the dynamic patterns of functional connectivity during the execution of each task, EEG signals are segmented into durations that correspond to the temporal windows of previously well-studied event-related potentials (ERPs). For each temporal window, DTW is employed to measure the functional similarities among channels. Unlike commonly used temporal similarity measures, such as cross correlation, DTW compares time series by taking into consideration that their alignment properties may vary in time. QT clustering analysis is then used to automatically identify the functionally connected regions in each temporal window. For each task, the proposed approach was able to establish a unique sequence of dynamic pattern (observed in all 5 subjects) for brain functional connectivity. Published by Elsevier Inc. C1 [Karamzadeh, Nader; Azari, Afrouz; Gandjbakhche, Amir; Najafizadeh, Laleh] NICHHD, Natl Inst Hlth, SAFB, Bethesda, MD 20892 USA. [Karamzadeh, Nader] George Mason Univ, Sch Phys Astron & Computat Sci, Fairfax, VA 22030 USA. [Medvedev, Andrei] Georgetown Univ, Ctr Funct & Mol Imaging, Washington, DC USA. [Azari, Afrouz] Univ Calif Davis, Dept Biomed Engn, Davis, CA 95616 USA. [Najafizadeh, Laleh] Rutgers State Univ, Dept Elect & Comp Engn, Piscataway, NJ 08855 USA. [Karamzadeh, Nader; Najafizadeh, Laleh] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. RP Gandjbakhche, A (reprint author), NICHHD, Natl Inst Hlth, SAFB, Bethesda, MD 20892 USA. EM amir@helix.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; Department of Defense in the Center for Neuroscience and Regenerative Medicine FX We acknowledge the funding of the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Also support for this work included funding from Department of Defense in the Center for Neuroscience and Regenerative Medicine. NR 58 TC 10 Z9 10 U1 1 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 1 PY 2013 VL 66 BP 311 EP 317 DI 10.1016/j.neuroimage.2012.10.032 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 190QR UT WOS:000322355800034 PM 23142654 ER PT J AU Cho, YST Fromm, S Guyer, AE Detloff, A Pine, DS Fudge, JL Ernst, M AF Cho, Youngsun T. Fromm, Stephen Guyer, Amanda E. Detloff, Allison Pine, Daniel S. Fudge, Julie L. Ernst, Monique TI Nucleus accumbens, thalamus and insula connectivity during incentive anticipation in typical adults and adolescents SO NEUROIMAGE LA English DT Article ID WHITE-MATTER DEVELOPMENT; RISKY DECISION-MAKING; PREFRONTAL CORTEX; NEURAL RESPONSES; RHESUS-MONKEY; BASAL GANGLIA; PARAVENTRICULAR NUCLEUS; PHYSIOLOGICAL CONDITION; REWARD ANTICIPATION; NEURONAL-ACTIVITY AB Reward neurocircuitry links motivation with complex behavioral responses. Studies of incentive processing have repeatedly demonstrated activation of nucleus accumbens (NAc), thalamus, and anterior insula, three key components of reward neurocircuitry. The contribution of the thalamus to this circuitry in humans has been relatively ignored, a gap that needs to be filled, given the central role of this structure in processing and filtering information. This study aimed to understand how these three regions function as a network during gain or loss anticipation in adults and youth. Towards this goal, functional magnetic resonance imaging (fMRI) and dynamic causal modeling (DCM) were used to examine effective connectivity among these three nodes in healthy adults and adolescents who performed the monetary incentive delay (MID) task. Seven connectivity models, based on anatomic connections, were tested. They were estimated for incentive anticipation and underwent Bayesian Model Selection (BMS) to determine the best-fit model for each adult and adolescent group. Connection strengths were extracted from the best-fit model and examined for significance in each group. These variables were then entered into a linear mixed model to test between-group effects on effective connectivity in reward neurocircuitry. The best-fit model for both groups included all possible anatomic connections. Three main findings emerged: (1) Across the task, thalamus and insula significantly influenced NAc; (2) A broader set of significant connections was found for the loss-cue condition than the gain-cue condition in both groups; (3) Finally, between-group comparisons of connectivity strength failed to detect statistical differences, suggesting that adults and adolescents use this incentive-processing network in a similar manner. This study demonstrates the way in which the thalamus and insula influence the NAc during incentive processing in humans. Specifically, this is the first study to demonstrate in humans the key role of thalamus projections onto the NAc in support of reward processing. Our results suggest that anticipation of gain/loss involves an 'alerting' signal (thalamus) that converges with interoceptive information (insula) to shape action selection programs in the ventral striatum. Published by Elsevier Inc. C1 [Cho, Youngsun T.; Fudge, Julie L.] Univ Rochester, Med Ctr, Dept Neurobiol & Anat, Rochester, NY 14627 USA. [Fromm, Stephen; Detloff, Allison; Pine, Daniel S.; Ernst, Monique] NIMH, NIH, DHHS, Sect Dev & Affect Neurosci Branch, Bethesda, MD 20892 USA. [Guyer, Amanda E.] Univ Calif Davis, Ctr Mind & Brain, Davis, CA 95616 USA. RP Ernst, M (reprint author), NIMH, Natl Inst Hlth, Emot Dev & Affect Neurosci Branch EDAN, 15K North Dr, Bethesda, MD 20892 USA. EM ernstm@mail.nih.gov FU Intramural Research Program-NIMH [F30 MH091926-02] FX F30 MH091926-02 (YTC); Intramural Research Program-NIMH. NR 98 TC 27 Z9 27 U1 6 U2 22 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 1 PY 2013 VL 66 BP 508 EP 521 DI 10.1016/j.neuroimage.2012.10.013 PG 14 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 190QR UT WOS:000322355800053 PM 23069809 ER PT J AU Sutherland, MT Carroll, AJ Salmeron, BJ Ross, TJ Hong, LE Stein, EA AF Sutherland, Matthew T. Carroll, Allison J. Salmeron, Betty Jo Ross, Thomas J. Hong, L. Elliot Stein, Elliot A. TI Individual differences in amygdala reactivity following nicotinic receptor stimulation in abstinent smokers SO NEUROIMAGE LA English DT Article DE Varenicline; Nicotine; Withdrawal; Amygdala; Emotion; Functional magnetic resonance imaging (fMRI) ID SUSTAINED-RELEASE BUPROPION; RANDOMIZED CONTROLLED-TRIAL; SMOKING-CESSATION; PARTIAL AGONIST; COGNITIVE PERFORMANCE; BRAIN ACTIVITY; QUANTITATIVE METAANALYSIS; TRANSDERMAL NICOTINE; TOBACCO WITHDRAWAL; VARENICLINE AB Hyperactive amygdala functioning may. underlie emotional dysregulation during smoking abstinence and represents one neurobiological target for pharmacological cessation aids. Available pharmacotherapies (e.g., nicotine replacement and varenicline) aid only a subset of individuals with smoking cessation and therefore elucidating the neurobiological impact of these medications is critical to expedite improved interventions. In a fMRI study employing a within-subject, double-blind, placebo-controlled design, we assessed task performance and amygdala functioning during an emotional face matching paradigm following administration of nicotine and varenicline to 24 abstinent smokers and 20 nonsmokers. All participants underwent similar to 17 days of varenicline and placebo pill administration and were scanned, on different days under each condition, wearing a transdermal nicotine or placebo patch. During the amygdala reactivity paradigm, nicotinic acetylcholine receptor (nAChR) stimulation by nicotine and varenicline decreased reaction time (RT) in abstinent smokers but not in nonsmokers. When considering all smokers as a single homogenous group, no drug-induced effects on amygdala reactivity were detected. However, in an exploratory analysis we parsed participants into subgroups according to individual differences in the propensity to demonstrate stable performance augmentation following nAChR stimulation (stable RT-improvers [SI] vs. variable RT-improvers [VI]). Using this exploratory approach, drugs appeared to modulate amygdala reactivity in only one smoker subgroup but not in either nonsmoker subgroup. Specifically, in the SI-smoker cohort abstinence-induced elevated amygdala reactivity was down-regulated by nAChR stimulation. In contrast, varenicline and nicotine did not modulate amygdala functioning in the VI-smoker cohort who displayed moderate levels of amygdala reactivity in the absence of drug administration. These results suggest that pharmacotherapies most robustly dampened amygdala functioning in smokers appearing susceptible to abstinence-induced effects. Such findings provide a step towards fractionating the smoker phenotype by discrete neurobiological characteristics. Published by Elsevier Inc. C1 [Sutherland, Matthew T.; Carroll, Allison J.; Salmeron, Betty Jo; Ross, Thomas J.; Stein, Elliot A.] NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH DHHS, Baltimore, MD USA. [Hong, L. Elliot] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat, Baltimore, MD 21201 USA. RP Sutherland, MT (reprint author), Florida Int Univ, Dept Psychol, Miami, FL 33199 USA. EM masuther@fiu.edu RI Salmeron, Betty Jo/M-1793-2016; OI Salmeron, Betty Jo/0000-0003-1699-9333; Ross, Thomas/0000-0002-7745-3572 FU National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Department of Health and Human Services (NIDA-IRP/NIH/DHHS) FX This work was sponsored by the National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Department of Health and Human Services (NIDA-IRP/NIH/DHHS). We thank Eliscia Smith, Angela Neal, Kimberly Slater, Loretta Spurgeon, and the NIDA-IRP nurses, pharmacy, and recruitment staff for their assistance with data collection. NR 57 TC 3 Z9 3 U1 1 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 1 PY 2013 VL 66 BP 585 EP 593 DI 10.1016/j.neuroimage.2012.10.043 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 190QR UT WOS:000322355800060 PM 23110878 ER PT J AU Misaki, M Luh, WM Bandettini, PA AF Misaki, Masaya Luh, Wen-Ming Bandettini, Peter A. TI Accurate decoding of sub-TR timing differences in stimulations of sub-voxel regions from multi-voxel response patterns SO NEUROIMAGE LA English DT Article DE Multi-voxel pattern analysis; Deconvolved hemodynamic response; Hyper-spatiotemporal resolution; Complex spatiotemporal filter voxel ID PRIMARY VISUAL-CORTEX; INFERIOR TEMPORAL CORTEX; EVENT-RELATED FMRI; IMPULSE-RESPONSE; FUNCTIONAL MRI; BOLD RESPONSES; NEGATIVE BOLD; INFORMATION; TIME; CLASSIFICATION AB We investigated the decoding of ocular dominance stimulations with millisecond-order timing difference from the blood oxygen level dependent (BOLD) signal in human functional magnetic resonance imaging (fMRI). In our experiment, ocular dominance columns were activated by monocular visual stimulation with 500- or 100- ms onset differences. We observed that the event-related hemodynamic response (HDR) in the human visual cortex was sensitive to the subtle onset difference. The HDR shapes were related to the stimulus timings in various manners: the timing difference was represented in either the amplitude of positive peak, amplitude of negative peak, delay of peak time, or response duration of HDR. These complex relationships were different across voxels and subjects. To find an informative feature of HDR for discriminating the subtle timing difference of ocular dominance stimulations, we examined various characteristics of HDR including response amplitude, time to peak, full width at half-maximum response, as inputs for decoding analysis. Using a canonical HDR function for estimating the voxel's response did not yield good decoding scores, suggesting that information may reside in the variability of HDR shapes. Using all the values from the deconvolved HDR also showed low performance, which could be due to an over-fitting problem with the large data dimensionality. When using either positive or negative peak amplitude of the deconvolved HDR, high decoding performance could be achieved for both the 500 ms and the 100 ms onset differences. The high accuracy even for the 100 ms difference, given that the signal was sampled at a TR of 250 ms and 2 x 2 x 3-mm voxels, implies a possibility of spatiotemporally hyper-resolution decoding. Furthermore, both down-sampling and smoothing did not affect the decoding accuracies very much. These results suggest a complex spatiotemporal relationship between the multi-voxel pattern of the BOLD response and the population activation of neuronal columns. The demonstrated possibility of decoding stimulations for columnar-level organization with 100-ms onset difference using lower resolution imaging data may broaden the scope of application of the BOLD fMRI. Published by Elsevier Inc. C1 [Misaki, Masaya; Bandettini, Peter A.] NIMH, Sect Funct Imaging Methods, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Luh, Wen-Ming; Bandettini, Peter A.] NIMH, Funct MRI Facil, NIH, Bethesda, MD 20892 USA. RP Misaki, M (reprint author), Laureate Inst Brain Res, 6655 S Yale Ave, Tulsa, OK 74136 USA. EM mmisaki@laureateinstitute.org FU National Institutes of Health, National Institute of Mental Health (NIMH) FX This study was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Mental Health (NIMH). This study utilized the high performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). NR 52 TC 2 Z9 2 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 1 PY 2013 VL 66 BP 623 EP 633 DI 10.1016/j.neuroimage.2012.10.069 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 190QR UT WOS:000322355800064 PM 23128073 ER PT J AU Blagoev, KB Wilkerson, J Stein, WD Motzer, RJ Bates, SE Fojo, AT AF Blagoev, Krastan B. Wilkerson, Julia Stein, Wilfred D. Motzer, Robert J. Bates, Susan E. Fojo, A. Tito TI Sunitinib Does Not Accelerate Tumor Growth in Patients with Metastatic Renal Cell Carcinoma SO CELL REPORTS LA English DT Article ID INTERFERON-ALPHA; ANGIOGENESIS; INHIBITOR; SURVIVAL; CANCER AB Preclinical studies have suggested that sunitinib accelerates metastases in animals, ascribing this to inhibition of the vascular endothelial growth factor receptor or the tumor's adaptation. To address whether sunitinib accelerates tumors in humans, we analyzed data from the pivotal randomized phase III trial comparing sunitinib and interferon alfa in patients with metastatic renal cell carcinoma. The evidence clearly shows that sunitinib was not harmful, did not accelerate tumor growth, and did not shorten survival. Specifically, neither longer sunitinib treatment nor a greater effect of sunitinib on tumors reduced survival. Sunitinib did reduce the tumor's growth rate while administered, thereby improving survival, without appearing to alter tumor biology after discontinuation. Concerns arising from animal models do not apply to patients receiving sunitinib and likely will not apply to similar agents. C1 [Blagoev, Krastan B.] Natl Sci Fdn, Arlington, VA 22030 USA. [Wilkerson, Julia; Stein, Wilfred D.; Bates, Susan E.; Fojo, A. Tito] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Stein, Wilfred D.] Hebrew Univ Jerusalem, Jerusalem, Israel. [Motzer, Robert J.] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. RP Blagoev, KB (reprint author), Natl Sci Fdn, Arlington, VA 22030 USA. EM kblagoev@nsf.gov; fojot@mail.nih.gov OI Wilkerson, Julia/0000-0002-6965-0867 FU National Science Foundation FX K.B.B. was supported by the National Science Foundation, while working at the Foundation. Any opinion, finding, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation. NR 15 TC 23 Z9 25 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD FEB PY 2013 VL 3 IS 2 BP 277 EP 281 DI 10.1016/j.celrep.2013.01.015 PG 5 WC Cell Biology SC Cell Biology GA 184MS UT WOS:000321895200002 PM 23395639 ER PT J AU Zanivan, S Meves, A Behrendt, K Schoof, EM Neilson, LJ Cox, J Tang, HR Kalna, G van Ree, JH van Deursen, JM Trempus, CS Machesky, LM Linding, R Wickstrom, SA Fassler, R Mann, M AF Zanivan, Sara Meves, Alexander Behrendt, Kristina Schoof, Erwin M. Neilson, Lisa J. Cox, Juergen Tang, Hao R. Kalna, Gabriela van Ree, Janine H. van Deursen, Jan M. Trempus, Carol S. Machesky, Laura M. Linding, Rune Wickstroem, Sara A. Faessler, Reinhard Mann, Matthias TI In Vivo SILAC-Based Proteomics Reveals Phosphoproteome Changes during Mouse Skin Carcinogenesis SO CELL REPORTS LA English DT Article ID SQUAMOUS-CELL CARCINOMA; RESOLUTION MASS-SPECTROMETRY; GENE-EXPRESSION; QUANTITATIVE PROTEOMICS; FEEDBACK PHOSPHORYLATION; RETINOBLASTOMA PROTEIN; RETINOIC ACID; AMINO-ACIDS; CANCER; PROGRESSION AB Cancer progresses through distinct stages, and mouse models recapitulating traits of this progression are frequently used to explore genetic, morphological, and pharmacological aspects of tumor development. To complement genomic investigations of this process, we here quantify phosphoproteomic changes in skin cancer development using the SILAC mouse technology coupled to high-resolution mass spectrometry. We distill protein expression signatures from our data that distinguish between skin cancer stages. A distinct phosphoproteome of the two stages of cancer progression is identified that correlates with perturbed cell growth and implicates cell adhesion as a major driver of malignancy. Importantly, integrated analysis of phosphoproteomic data and prediction of kinase activity revealed PAK4-PKC/SRC network to be highly deregulated in SCC but not in papilloma. This detailed molecular picture, both at the proteome and phosphoproteome level, will prove useful for the study of mechanisms of tumor progression. C1 [Zanivan, Sara; Cox, Juergen; Mann, Matthias] Max Planck Inst Biochem, Dept Prote & Signal Transduct, D-82152 Martinsried, Germany. [Meves, Alexander; Faessler, Reinhard] Max Planck Inst Biochem, Dept Mol Med, D-82152 Martinsried, Germany. [Zanivan, Sara; Neilson, Lisa J.; Tang, Hao R.; Kalna, Gabriela; Machesky, Laura M.] Beatson Inst Canc Res, Glasgow G61 1BD, Lanark, Scotland. [Meves, Alexander] Mayo Clin, Coll Med, Dept Dermatol, Rochester, MN 55905 USA. [van Ree, Janine H.; van Deursen, Jan M.] Mayo Clin, Coll Med, Dept Pediat & Adolescent Med, Rochester, MN 55905 USA. [Behrendt, Kristina; Wickstroem, Sara A.] Max Planck Inst Biol Ageing, Paul Gerson Unna Grp Skin Homeostasis & Ageing, D-50931 Cologne, Germany. [Schoof, Erwin M.; Linding, Rune] Tech Univ Denmark, Dept Syst Biol, Ctr Biol Sequence Anal CBS, Cellular Signal Integrat Grp, DK-2800 Lyngby, Denmark. [Trempus, Carol S.] NIEHS, Matrix Biol Grp, Lab Resp Biol, Res Triangle Pk, NC 27709 USA. [Mann, Matthias] Univ Copenhagen, Fac Hlth Sci, Novo Nordisk Fdn Ctr Prot Res, DK-2200 Copenhagen, Denmark. RP Zanivan, S (reprint author), Max Planck Inst Biochem, Dept Prote & Signal Transduct, Klopferspitz 18, D-82152 Martinsried, Germany. EM s.zanivan@beatson.gla.ac.uk; mmann@biochem.mpg.de RI Mann, Matthias/A-3454-2013; Cox, Jurgen/B-9481-2008 OI Mann, Matthias/0000-0003-1292-4799; Cox, Jurgen/0000-0001-8597-205X FU Max-Planck Society; EC-FP7 (Metafight); PROSPECT, a 7th framework program of the European Union [HEALTH-F4-2008-201648]; Cancer Research UK; Danish Council for Independent Research; Human Frontier Science Program; Fondazione Italiana per la Ricerca sul Cancro (FIRC); Associazione Italiana per la Ricerca sul Cancro FX We thank Mark Pittelkow for fruitful discussions. This work was supported by the Max-Planck Society, EC-FP7 (Metafight), PROSPECT, a 7th framework program of the European Union (grant agreement HEALTH-F4-2008-201648), and Cancer Research UK. C.S.T.'s work was conducted in the Intramural Division of the NIEHS. R.L. is a Lundbeck Foundation Fellow and is supported by a Sapere Aude Starting Grant from The Danish Council for Independent Research and a Career Development Award from Human Frontier Science Program. S.Z. was partially supported by the fellowship "L. Fontana e M. Lionello" granted by Fondazione Italiana per la Ricerca sul Cancro (FIRC). NR 62 TC 45 Z9 50 U1 0 U2 35 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 FEB PY 2013 VL 3 IS 2 BP 552 EP 566 DI 10.1016/j.celrep.2013.01.003 PG 15 WC Cell Biology SC Cell Biology GA 184MS UT WOS:000321895200027 PM 23375375 ER PT J AU Ke, RA Aaskov, J Holmes, EC Lloyd-Smith, JO AF Ke, Ruian Aaskov, John Holmes, Edward C. Lloyd-Smith, James O. TI Phylodynamic Analysis of the Emergence and Epidemiological Impact of Transmissible Defective Dengue Viruses SO PLOS PATHOGENS LA English DT Article ID WEST-NILE-VIRUS; VESICULAR STOMATITIS-VIRUS; COOPERATIVE INTERACTIONS; RNA VIRUSES; DIVERSITY; MOSQUITOS; DYNAMICS; MICROEVOLUTION; TRANSCRIPTASE; POPULATION AB Intra-host sequence data from RNA viruses have revealed the ubiquity of defective viruses in natural viral populations, sometimes at surprisingly high frequency. Although defective viruses have long been known to laboratory virologists, their relevance in clinical and epidemiological settings has not been established. The discovery of long-term transmission of a defective lineage of dengue virus type 1 (DENV-1) in Myanmar, first seen in 2001, raised important questions about the emergence of transmissible defective viruses and their role in viral epidemiology. By combining phylogenetic analyses and dynamical modeling, we investigate how evolutionary and ecological processes at the intra-host and inter-host scales shaped the emergence and spread of the defective DENV-1 lineage. We show that this lineage of defective viruses emerged between June 1998 and February 2001, and that the defective virus was transmitted primarily through co-transmission with the functional virus to uninfected individuals. We provide evidence that, surprisingly, this co-transmission route has a higher transmission potential than transmission of functional dengue viruses alone. Consequently, we predict that the defective lineage should increase overall incidence of dengue infection, which could account for the historically high dengue incidence reported in Myanmar in 2001-2002. Our results show the unappreciated potential for defective viruses to impact the epidemiology of human pathogens, possibly by modifying the virulence-transmissibility trade-off, or to emerge as circulating infections in their own right. They also demonstrate that interactions between viral variants, such as complementation, can open new pathways to viral emergence. C1 [Ke, Ruian; Lloyd-Smith, James O.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. [Aaskov, John] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld 4001, Australia. [Holmes, Edward C.] Univ Sydney, Sch Biol Sci, Sydney, NSW 2006, Australia. [Holmes, Edward C.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Holmes, Edward C.; Lloyd-Smith, James O.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Ke, RA (reprint author), Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. EM ruian@ucla.edu; jlloydsmith@ucla.edu RI Lloyd-Smith, James/K-4080-2012; OI Lloyd-Smith, James/0000-0001-7941-502X; Holmes, Edward/0000-0001-9596-3552 FU National Science Foundation [EF-0928690]; De Logi Chair in Biological Sciences; RAPIDD program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; National Health and Medical Research Council of Australia; ECH by the National Institutes of Health [5R01GM087405-03, R01GM080533-06] FX JOLS and RK are supported by National Science Foundation (EF-0928690). JOLS is grateful for support from the De Logi Chair in Biological Sciences, and from the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. JA is supported by the National Health and Medical Research Council of Australia, and ECH by the National Institutes of Health (5R01GM087405-03 and R01GM080533-06). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 13 Z9 13 U1 2 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD FEB PY 2013 VL 9 IS 2 AR e1003193 DI 10.1371/journal.ppat.1003193 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 184CE UT WOS:000321863200013 PM 23468631 ER PT J AU Mendoza, D Migueles, SA Rood, JE Peterson, B Johnson, S Doria-Rose, N Schneider, D Rakasz, E Trivett, MT Trubey, CM Coalter, V Hallahan, CW Watkins, D Franchini, G Lifson, JD Connors, M AF Mendoza, Daniel Migueles, Stephen A. Rood, Julia E. Peterson, Bennett Johnson, Sarah Doria-Rose, Nicole Schneider, Douglas Rakasz, Eva Trivett, Matthew T. Trubey, Charles M. Coalter, Vicky Hallahan, Claire W. Watkins, David Franchini, Genoveffa Lifson, Jeffrey D. Connors, Mark TI Cytotoxic Capacity of SIV-Specific CD8(+) T Cells against Primary Autologous Targets Correlates with Immune Control in SIV-Infected Rhesus Macaques SO PLOS PATHOGENS LA English DT Article ID HIV-INFECTION; VIRUS-REPLICATION; ELITE CONTROLLER; ACTIVATION; NONPROGRESSORS; HETEROGENEITY; TRANSDUCTION; INDIVIDUALS; LYMPHOCYTES; INHIBITION AB Although the study of non-human primates has resulted in important advances for understanding HIV-specific immunity, a clear correlate of immune control over simian immunodeficiency virus (SIV) replication has not been found to date. In this study, CD8(+) T-cell cytotoxic capacity was examined to determine whether this function is a correlate of immune control in the rhesus macaque (RM) SIV infection model as has been suggested in chronic HIV infection. SIVmac251-infected human reverse transcriptase (hTERT)-transduced CD4(+) T-cell clone targets were co-incubated with autologous macaque effector cells to measure infected CD4(+) T-cell elimination (ICE). Twenty-three SIV-infected rhesus macaques with widely varying plasma viral RNA levels were evaluated in a blinded fashion. Nineteen of 23 subjects (83%) were correctly classified as long-term nonprogressor/elite controller (LTNP/EC), slow progressor, progressor or SIV-negative rhesus macaques based on measurements of ICE (weighted Kappa 0.75). LTNP/EC had higher median ICE than progressors (67.3% [22.0-91.7%] vs. 23.7% [0.0-58.0%], p = 0.002). In addition, significant correlations between ICE and viral load (r = 20.57, p = 0.01), and between granzyme B delivery and ICE (r = 0.89, p < 0.001) were observed. Furthermore, the CD8(+) T cells of LTNP/EC exhibited higher per-cell cytotoxic capacity than those of progressors (p = 0.004). These findings support that greater lytic granule loading of virus-specific CD8(+) T cells and efficient delivery of active granzyme B to SIV-infected targets are associated with superior control of SIV infection in rhesus macaques, consistent with observations of HIV infection in humans. Therefore, such measurements appear to represent a correlate of control of viral replication in chronic SIV infection and their role as predictors of immunologic control in the vaccine setting should be evaluated. C1 [Mendoza, Daniel; Migueles, Stephen A.; Rood, Julia E.; Peterson, Bennett; Johnson, Sarah; Doria-Rose, Nicole; Connors, Mark] NIAID, HIV Specif Immun Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Schneider, Douglas; Trivett, Matthew T.; Trubey, Charles M.; Coalter, Vicky; Lifson, Jeffrey D.] Frederick Natl Lab Canc Res, SAIC Frederick Inc, AIDS & Canc Virus Program, Frederick, MD USA. [Rakasz, Eva; Watkins, David] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI USA. [Hallahan, Claire W.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Watkins, David] Univ Miami, Miller Sch Med, Dept Pathol Clin Res Bldg, Miami, FL 33136 USA. [Franchini, Genoveffa] NCI, Vaccine Branch, NIH, Bethesda, MD 20892 USA. RP Connors, M (reprint author), NIAID, HIV Specif Immun Sect, Immunoregulat Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM mconnors@nih.gov OI Mendoza, Daniel/0000-0002-6362-0771 FU NIAID; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded in part with federal funds from the Intramural Research Programs of NIAID and the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 13 Z9 13 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD FEB PY 2013 VL 9 IS 2 AR e1003195 DI 10.1371/journal.ppat.1003195 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 184CE UT WOS:000321863200014 PM 23468632 ER PT J AU Magnani, JW Wang, N Nelson, KP Connelly, S Deo, R Rodondi, N Schelbert, EB Garcia, ME Phillips, CL Shlipak, MG Harris, TB Ellinor, PT Benjamin, EJ AF Magnani, Jared W. Wang, Na Nelson, Kerrie P. Connelly, Stephanie Deo, Rajat Rodondi, Nicolas Schelbert, Erik B. Garcia, Melissa E. Phillips, Caroline L. Shlipak, Michael G. Harris, Tamara B. Ellinor, Patrick T. Benjamin, Emelia J. CA Hlth Aging Body Composition Study TI Electrocardiographic PR Interval and Adverse Outcomes in Older Adults The Health, Aging, and Body Composition Study SO CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY LA English DT Article DE atrial fibrillation; ECG; epidemiology; heart failure; risk factors ID CONGESTIVE-HEART-FAILURE; MIDDLE-AGED MEN; ATRIAL-FIBRILLATION; METABOLIC SYNDROME; ATHEROSCLEROSIS RISK; ATRIOVENTRICULAR-BLOCK; CARDIOVASCULAR-DISEASE; COMMUNITIES; OBESITY; SCORE AB Background- The electrocardiographic PR interval increases with aging, differs by race, and is associated with atrial fibrillation (AF), pacemaker implantation, and all-cause mortality. We sought to determine the associations between PR interval and heart failure, AF, and mortality in a biracial cohort of older adults. Methods and Results- The Health, Aging, and Body Composition (Health ABC) Study is a prospective, biracial cohort. We used multivariable Cox proportional hazards models to examine PR interval (hazard ratios expressed per SD increase) and 10-year risks of heart failure, AF, and all-cause mortality. Multivariable models included demographic, anthropometric, and clinical variables in addition to established cardiovascular risk factors. We examined 2722 Health ABC participants (aged 74 +/- 3 years, 51.9% women, and 41% black). We did not identify significant effect modification by race for the outcomes studied. After multivariable adjustment, every SD increase (29 ms) in PR interval was associated with a 13% greater 10-year risk of heart failure (95% confidence interval, 1.02-1.25) and a 13% increased risk of incident AF (95% confidence interval, 1.04-1.23). PR interval >200 ms was associated with a 46% increased risk of incident heart failure (95% confidence interval, 1.11-1.93). PR interval was not associated with increased all-cause mortality. Conclusions- We identified significant relationships of PR interval to heart failure and AF in older adults. Our findings extend prior investigations by examining PR interval and associations with adverse outcomes in a biracial cohort of older men and women. C1 [Magnani, Jared W.; Benjamin, Emelia J.] Boston Univ, Sch Med, Evans Dept Med, Cardiol Sect,Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Magnani, Jared W.; Benjamin, Emelia J.] NHLBI, Framingham, MA USA. [Magnani, Jared W.; Benjamin, Emelia J.] Boston Univ, Framingham Heart Study, Framingham, MA 02118 USA. [Wang, Na] Boston Univ, Sch Publ Hlth, Data Coordinating Ctr, Boston, MA 02118 USA. [Nelson, Kerrie P.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02118 USA. [Connelly, Stephanie] Univ Tennessee, Dept Med, Memphis, TN 38104 USA. [Deo, Rajat] Univ Penn, Div Cardiovasc Med, Sect Electrophysiol, Philadelphia, PA 19104 USA. [Rodondi, Nicolas] Univ Bern, Dept Gen Internal Med, Bern, Switzerland. [Schelbert, Erik B.] Univ Pittsburgh, Cardiovasc Inst, Pittsburgh, PA USA. [Garcia, Melissa E.; Phillips, Caroline L.; Harris, Tamara B.] NIA, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco VA Med Ctr, Dept Med, San Francisco, CA 94143 USA. [Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown & Cardiac Arrhythmia Serv, Boston, MA 02114 USA. RP Magnani, JW (reprint author), Boston Univ, Sch Med, 88 E Newton St, Boston, MA 02118 USA. EM jmagnani@bu.edu OI Benjamin, Emelia/0000-0003-4076-2336 FU Intramural Research Program of the National Institutes of Health, National Institute on Aging; American Heart Association Award [09FTF2190028]; National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NIA grant [R01-AG028050]; National Institute of Nursing Research grant [R01-NR012459]; National Institutes of Health [1RC1HL101056, 1RO1HL092577, 5R21DA027021, 1RO1HL104156, 1K24HL105780, K23DK089118] FX This research was supported, in part, by the Intramural Research Program of the National Institutes of Health, National Institute on Aging.; This research was funded by American Heart Association Award 09FTF2190028 (J.W.M.); by National Institute on Aging (NIA) Contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106; NIA grant R01-AG028050; National Institute of Nursing Research grant R01-NR012459, and by National Institutes of Health grants 1RC1HL101056 (E.J.B.), 1RO1HL092577 (E.J.B. and P.T.E.), 5R21DA027021, 1RO1HL104156, 1K24HL105780 (P.T.E.), and K23DK089118 (R.D.). NR 31 TC 32 Z9 33 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-3149 J9 CIRC-ARRHYTHMIA ELEC JI Circ.-Arrhythmia Electrophysiol. PD FEB PY 2013 VL 6 IS 1 BP 84 EP 90 DI 10.1161/CIRCEP.112.975342 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 167YE UT WOS:000320670700016 PM 23243193 ER PT J AU Sulima, A Cheng, KJ Jacobson, AE Rice, KC Gawrisch, K Lee, YS AF Sulima, Agnieszka Cheng, Kejun Jacobson, Arthur E. Rice, Kenner C. Gawrisch, Klaus Lee, Yong-Sok TI Z and E rotamers of N-formyl-1-bromo-4-hydroxy-3-methoxymorphinan-6-one and their interconversion as studied by H-1/C-13 NMR spectroscopy and quantum chemical calculations SO MAGNETIC RESONANCE IN CHEMISTRY LA English DT Article DE H-1/C-13 NMR; NOE; Z and E rotamers; morphine intermediate; quantum chemistry; transition state ID NUCLEAR-MAGNETIC-RESONANCE; HINDERED ROTATION; DERIVATIVES; INVERSION; SPECTRA; AMIDES; SHIFTS; H-1 AB N-Formyl-1-bromo-4-hydroxy-3-methoxymorphinan-6-one (compound 2), an important intermediate in the NIH Opiate Total Synthesis, presumably exists as a mixture of two rotamers (Z and E) in both CHCl3 and DMSO at room temperature due to the hindered rotation of its N-C18 bond in the amide moiety. By comparing the experimental H-1 and C-13 chemical shifts of a single rotamer and the mixture of compound 2 in CDCl3 with the calculated chemical shifts of the geometry optimized Z and E rotamers utilizing density functional theory, the crystalline rotamer of compound 2 was characterized as having the E configuration. The energy barrier between the two rotamers was also determined with the temperature dependence of H-1 and C-13 NMR coalescence experiments, and then compared with that from the reaction path for the interconversion of the two rotamers calculated at the level of B3LYP/6-31G*. Detailed geometry of the ground state and the transition states of both rotamers are given and discussed. Copyright (c) 2012 This article is a US Government work and is in the public domain in the USA. C1 [Sulima, Agnieszka; Cheng, Kejun; Jacobson, Arthur E.; Rice, Kenner C.] NIDA, Drug Design & Synth Sect, Chem Biol Res Branch, Bethesda, MD 20892 USA. [Sulima, Agnieszka; Cheng, Kejun; Jacobson, Arthur E.; Rice, Kenner C.] NIAAA, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Sulima, Agnieszka] NHLBI, Imaging Probe Dev Ctr, NIH, Bethesda, MD 20892 USA. [Gawrisch, Klaus] NIAAA, Lab Membrane Biochem & Biophys, Bethesda, MD USA. [Lee, Yong-Sok] NIH, Ctr Mol Modeling, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Lee, YS (reprint author), NIH, Ctr Mol Modeling, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. EM leeys@mail.nih.gov FU NIH Intramural Research Programs of the National Institute on Drug Abuse; National Institute of Alcohol Abuse and Alcoholism; National Institute of Diabetes and Digestive and Kidney Diseases; NIH Intramural Research Program through the Center for Information Technology; NIAAA FX This work was initiated while the authors (AS, AEJ, and KCR) were members of the Drug Design and Synthesis Section, Laboratory of Medicinal Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, NIH. The research of the Drug Design and Synthesis Section, CBRB, NIDA, and NIAAA, was supported by the NIH Intramural Research Programs of the National Institute on Drug Abuse, the National Institute of Alcohol Abuse and Alcoholism, and the National Institute of Diabetes and Digestive and Kidney Diseases. The quantum chemical study utilized PC/LINUX clusters at the Center for Molecular Modeling of the NIH (http://cit.nih.gov), and this research was supported by the NIH Intramural Research Program through the Center for Information Technology and NIAAA. The authors thank Drs. Umesha Shetty and Victor Pike, PET Radiopharmaceutical Sciences Molecular Imaging Branch National Institute of Mental Health, NIH for their help with the high-temperature NMR experiments (1H and 13C NMR), and Dr. John Lloyd (Mass Spectrometry Facility, NIDDK, NIH) for the mass spectra. NR 25 TC 5 Z9 5 U1 0 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0749-1581 J9 MAGN RESON CHEM JI Magn. Reson. Chem. PD FEB PY 2013 VL 51 IS 2 BP 82 EP 88 DI 10.1002/mrc.3909 PG 7 WC Chemistry, Multidisciplinary; Chemistry, Physical; Spectroscopy SC Chemistry; Spectroscopy GA 158JR UT WOS:000319966500004 PM 23233124 ER PT J AU Chen, JJ Mikelis, CM Zhang, YQ Gutkind, JS Zhang, BL AF Chen, Jun-Jie Mikelis, Constantinos M. Zhang, Yaqin Gutkind, J. Silvio Zhang, Baolin TI TRAIL induces apoptosis in oral squamous carcinoma cells - a crosstalk with oncogenic Ras regulated cell surface expression of death receptor 5 SO ONCOTARGET LA English DT Article DE oral cancer; TRAIL; death receptors; apoptosis; Ras; oncotarget ID CANCER-CELLS; MEDIATED APOPTOSIS; TUMOR-GROWTH; NECK-CANCER; LIGAND; ACTIVATION; INHIBITION; PATHWAY; HEAD; TRANSFORMATION AB TNF-related apoptosis inducing ligand (TRAIL) induces apoptosis through its death receptors (DRs) 4 and/or 5 expressed on the surface of target cells. The selectivity of TRAIL towards cancer cells has promoted clinical evaluation of recombinant human TRAIL (rhTRAIL) and its agonistic antibodies in treating several major human cancers including colon and non-Hodgkin's lymphoma. However, little is known about their ability in killing oral squamous cell carcinoma (OSCC) cells. In this study, we tested the apoptotic responses of a panel of seven human OSCC cell lines (HN31, HN30, HN12, HN6, HN4, Cal27, and OSCC3) to rhTRAIL and monoclonal antibodies against DR4 or DR5. We found that rhTRAIL is a potent inducer of apoptosis in most of the oral cancer cell lines tested both in vitro and in vivo. We also showed that DR5 was expressed on the surface of the tested cell lines which correlated with the cellular susceptibility to apoptosis induced by rhTRAIL and anti-DR5 antibody. By contrast, little or no DR4 was detected on the surface of OSCC3 and HN6 cells rendering cellular resistance to DR4 antibody and a reduced sensitivity to rhTRAIL. Notably, the overall TRAIL sensitivity correlated well with the levels of endogenous active Ras in the cell lines tested. Expression of a constitutively active Ras mutant (RasV12) in OSCC3 cells selectively upregulated surface expression of DR5, but not DR4, and restored TRAIL sensitivity. Our findings could have implications for the use of TRAIL receptor targeted therapies in the treatment of human OSCC tumors particularly the ones harboring constitutively active Ras mutant. C1 [Chen, Jun-Jie; Zhang, Yaqin; Zhang, Baolin] US FDA, Ctr Drug Evaluat & Res, Div Therapeut Prot, Off Biotechnol Prod, Bethesda, MD 20014 USA. [Mikelis, Constantinos M.; Gutkind, J. Silvio] NIH, Oral & Pharyngeal Canc Branch, Bethesda, MD 20892 USA. RP Zhang, BL (reprint author), US FDA, Ctr Drug Evaluat & Res, Div Therapeut Prot, Off Biotechnol Prod, Bethesda, MD 20014 USA. EM Baolin.Zhang@fda.hhs.gov FU U.S. FDA Critical Path Research FX This project is supported by funding from the U.S. FDA Critical Path Research. NR 42 TC 15 Z9 16 U1 0 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 FEB PY 2013 VL 4 IS 2 BP 206 EP 217 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 142FO UT WOS:000318782500008 PM 23470485 ER PT J AU Tarlykov, PV Zholdybayeva, EV Akilzhanova, AR Nurkina, ZM Sabitov, ZM Rahypbekov, TK Ramanculov, EM AF Tarlykov, Pavel V. Zholdybayeva, Elena V. Akilzhanova, Ainur R. Nurkina, Zhannur M. Sabitov, Zhaxylyk M. Rahypbekov, Tolubay K. Ramanculov, Erlan M. TI Mitochondrial and Y-chromosomal profile of the Kazakh population from East Kazakhstan SO CROATIAN MEDICAL JOURNAL LA English DT Article ID CENTRAL-ASIAN POPULATIONS; GENETIC-VARIATION; DNA SEQUENCES; SILK ROAD; DIVERSITY; MTDNA; ANCESTRY; SIBERIA; HISTORY; REGION AB Aim To study the genetic relationship of Kazakhs from East Kazakhstan to other Eurasian populations by examining paternal and maternal DNA lineages. Methods Whole blood samples were collected in 2010 from 160 unrelated healthy Kazakhs residing in East Kazakhstan. Genomic DNA was extracted with Wizard genomic DNA Purification Kit. Nucleotide sequence of hypervariable segment I of mitochondrial DNA (mtDNA) was determined and analyzed. Seventeen Y-short tandem repeat (STR) loci were studied in 67 samples with the Amp-FiSTR Y-filer PCR Amplification Kit. In addition, mtDNA data for 2701 individuals and Y-SIR data for 677 individuals were retrieved from the literature for comparison. Results There was a high degree of genetic differentiation on the level of mitochondrial DNA. The majority of maternal lineages belonged to haplogroups common in Central Asia. In contrast, Y-STR data showed very low genetic diversity, with the relative frequency of the predominant haplotype of 0.612. Conclusion The results revealed different migration patterns in the population sample, showing there had been more migration among women. mtDNA genetic diversity in this population was equivalent to that in other Central Asian populations. Genetic evidence suggests the existence of a single paternal founder lineage in the population of East Kazakhstan, which is consistent with verbal genealogical data of the local tribes. C1 [Tarlykov, Pavel V.; Zholdybayeva, Elena V.; Akilzhanova, Ainur R.; Nurkina, Zhannur M.; Ramanculov, Erlan M.] Natl Ctr Biotechnol Republ Kazakhstan, Astana 010000, Kazakhstan. [Sabitov, Zhaxylyk M.] LN Gumilyov Eurasian Natl Univ, Astana, Kazakhstan. [Rahypbekov, Tolubay K.] Semey State Med Univ, Semey, Kazakhstan. RP Tarlykov, PV (reprint author), Natl Ctr Biotechnol Republ Kazakhstan, 13-1 Valikhanov St, Astana 010000, Kazakhstan. EM pavel.tarlykov@gmail.com RI Ramanculov, Erlan/E-2823-2013; Sabitov, Zhaxylyk/P-7576-2014; Tarlykov, Pavel/C-2587-2012 OI Sabitov, Zhaxylyk/0000-0001-7186-156X; Tarlykov, Pavel/0000-0003-2075-307X FU Ministry of Education and Science of the Republic of Kazakhstan [1.04.01]; Russian Foundation for Basic Research [12-04-90915] FX Funding received from the Ministry of Education and Science of the Republic of Kazakhstan, grant No. 1.04.01. This study was also partially funded by Russian Foundation for Basic Research, grant 12-04-90915. NR 28 TC 6 Z9 6 U1 0 U2 16 PU MEDICINSKA NAKLADA PI ZAGREB PA VLASKA 69, HR-10000 ZAGREB, CROATIA SN 0353-9504 EI 1332-8166 J9 CROAT MED J JI Croat. Med. J. PD FEB PY 2013 VL 54 IS 1 BP 17 EP 24 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 140OZ UT WOS:000318666100004 PM 23444242 ER PT J AU Kawamoto, EM Scavone, C Mattson, MP Camandola, S AF Kawamoto, E. M. Scavone, C. Mattson, M. P. Camandola, S. TI Curcumin Requires Tumor Necrosis Factor alpha Signaling to Alleviate Cognitive Impairment Elicited by Lipopolysaccharide SO NEUROSIGNALS LA English DT Article DE Curcumin; Tumor necrosis factor alpha; Cognition; Inflammation; Lipopolysaccharide ID ADULT HIPPOCAMPAL NEUROGENESIS; ISCHEMIC BRAIN-INJURY; TOLL-LIKE RECEPTORS; GLIAL TNF-ALPHA; ALZHEIMERS-DISEASE; MICE LACKING; SPATIAL MEMORY; IN-VITRO; DEFICIENT MICE; KAPPA-B AB A decline in cognitive ability is a typical feature of the normal aging process, and of neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases. Although their etiologies differ, all of these disorders involve local activation of innate immune pathways and associated inflammatory cytokines. However, clinical trials of anti-inflammatory agents in neurodegenerative disorders have been disappointing, and it is therefore necessary to better understand the complex roles of the inflammatory process in neurological dysfunction. The dietary phytochemical curcumin can exert anti-inflammatory, antioxidant and neuroprotective actions. Here we provide evidence that curcumin ameliorates cognitive deficits associated with activation of the innate immune response by mechanisms requiring functional tumor necrosis factor alpha receptor 2 (TNFR2) signaling. In vivo, the ability of curcumin to counteract hippocampus-dependent spatial memory deficits, to stimulate neuroprotective mechanisms such as upregulation of BDNF, to decrease glutaminase levels, and to modulate N-methyl-D-aspartate receptor levels was absent in mice lacking functional TNFRs. Curcumin treatment protected cultured neurons against glutamate-induced excitotoxicity by a mechanism requiring TNFR2 activation. Our results suggest the possibility that therapeutic approaches against cognitive decline designed to selectively enhance TNFR2 signaling are likely to be more beneficial than the use of anti-inflammatory drugs per se. Copyright (C) 2012 S. Karger AG, Basel C1 [Kawamoto, E. M.; Mattson, M. P.; Camandola, S.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Scavone, C.] Univ Sao Paulo, Dept Pharmacol, Inst Biomed Sci, Sao Paulo, Brazil. RP Camandola, S (reprint author), NIA, Neurosci Lab, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM camandolasi@mail.nih.gov RI Kawamoto, Elisa/E-3485-2012 OI Kawamoto, Elisa/0000-0001-8637-414X FU Intramural Research Program of the National Institute on Aging of the National Institutes of Health; Program and Fundacao de Amparo a Pesquisa do Estado de Sao Paulo-FAPESP FX We thank E. Okun for advice on the behavioral testing procedures and S. Rothman for assistance in preparing the manuscript for publication. This research was supported by the Intramural Research Program of the National Institute on Aging of the National Institutes of Health, and by Program and Fundacao de Amparo a Pesquisa do Estado de Sao Paulo-FAPESP. NR 69 TC 8 Z9 8 U1 1 U2 7 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1424-862X J9 NEUROSIGNALS JI Neurosignals PD FEB PY 2013 VL 21 IS 1-2 BP 75 EP 88 DI 10.1159/000336074 PG 14 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology; Neurosciences SC Biochemistry & Molecular Biology; Biophysics; Cell Biology; Neurosciences & Neurology GA 138EH UT WOS:000318491000007 PM 22572473 ER PT J AU Kassab, E Darwish, M Timsah, Z Liu, SH Leppla, SH Frankel, AE Abi-Habib, RJ AF Kassab, Elias Darwish, Manal Timsah, Zahra Liu, ShiHui Leppla, Stephen H. Frankel, Arthur E. Abi-Habib, Ralph J. TI Cytotoxicity of Anthrax Lethal Toxin to Human Acute Myeloid Leukemia Cells Is Nonapoptotic and Dependent on Extracellular Signal-Regulated Kinase 1/2 Activity SO TRANSLATIONAL ONCOLOGY LA English DT Article ID ACUTE MYELOGENOUS LEUKEMIA; MELANOMA-CELLS; ACTIVATION; APOPTOSIS; PATHWAYS; RECEPTOR; MEK; INACTIVATION; INHIBITION; CANCER AB In this study, we attempt to target the mitogen-activated protein kinase (MAPK) pathway in acute myeloid leukemia (AML) cells using a recombinant anthrax lethal toxin (LeTx). LeTx consists of protective antigen (PrAg) and lethal factor (LF). PrAg binds cells, is cleaved by furin, oligomerizes, binds three to four molecules of LF, and undergoes endocytosis, releasing LF into the cytosol. LF cleaves MAPK kinases, inhibiting the MAPK pathway. We tested potency of LeTx on a panel of 11 human AML cell lines. Seven cell lines showed cytotoxic responses to LeTx. Cytotoxicity of LeTx was mimicked by the specific mitogen-activated protein/extracellular signal-regulated kinase kinase 1/2 (MEK1/2) inhibitor U0126, indicating that LeTx-induced cell death is mediated through the MEK1/2-extracellular signal-regulated kinase (ERK1/2) branch of the MAPK pathway. The four LeTx-resistant cell lines were sensitive to the phosphatidylinositol 3-kinase inhibitor LY294002. Co-treatment of AML cells with both LeTx and LY294002 did not lead to increased sensitivity, showing a lack of additive/synergistic effects when both pathways are inhibited. Flow cytometry analysis of MAPK pathway activation revealed the presence of phospho-ERK1/2 only in LeTx-sensitive cells. Staining for Annexin V/propidium iodide and active caspases showed an increase in double-positive cells and the absence of caspase activation following treatment, indicating that LeTx-induced cell death is caspase-independent and nonapoptotic. We have shown that a majority of AML cell lines are sensitive to the LF-mediated inhibition of the MAPK pathway. Furthermore, we have demonstrated that LeTx-induced cytotoxicity in AML cells is nonapoptotic and dependent on phospho-ERK1/2 levels. C1 [Kassab, Elias; Darwish, Manal; Timsah, Zahra; Abi-Habib, Ralph J.] Lebanese Amer Univ, Sch Arts & Sci, Dept Nat Sci, Beirut 11022801, Lebanon. [Liu, ShiHui; Leppla, Stephen H.] NIAID, Microbial Pathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Frankel, Arthur E.] Scott & White Mem Hosp & Clin, Canc Res Inst, Temple, TX 76508 USA. RP Abi-Habib, RJ (reprint author), Lebanese Amer Univ, Sch Arts & Sci, Beirut 11022801, Lebanon. EM ralph.abihabib@lau.edu.lb FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases (Bethesda, MD) FX This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (Bethesda, MD). The authors have no conflict of interest to declare. NR 33 TC 5 Z9 5 U1 0 U2 5 PU NEOPLASIA PRESS PI ANN ARBOR PA 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA SN 1944-7124 J9 TRANSL ONCOL JI Transl. Oncol. PD FEB PY 2013 VL 6 IS 1 BP 25 EP 32 DI 10.1593/tlo.12313 PG 8 WC Oncology SC Oncology GA 139YC UT WOS:000318620200005 PM 23418614 ER PT J AU Yeganeh, B Hashemi, M de Serres, FJ Los, MJ Ghavami, S AF Yeganeh, Behzad Hashemi, Mohammad de Serres, Fredrick J. Los, Marek J. Ghavami, Saeid TI Different Faces of Hepatocellular Carcinoma as a Health Threat in 21st Century SO HEPATITIS MONTHLY LA English DT Editorial Material DE Biological Markers; Alpha 1 Antitrypsin; lobaplatin; Aflatoxins; Hepatitis B Virus; Hepatitis C ID HEPATITIS-B; ALPHA-1-ANTITRYPSIN DEFICIENCY; LIVER-TRANSPLANTATION; GENETIC EPIDEMIOLOGY; VIRAL-HEPATITIS; VIRUS-INFECTION; S100 PROTEINS; PATHOGENESIS; LOBAPLATIN; CANCER C1 [Yeganeh, Behzad; Ghavami, Saeid] Univ Manitoba, Dept Physiol, Winnipeg, MB, Canada. [Hashemi, Mohammad] Zahedan Univ Med Sci, Cellular & Mol Res Ctr, Zahedan, Iran. [Hashemi, Mohammad] Zahedan Univ Med Sci, Sch Med, Dept Clin Biochem, Zahedan, Iran. [de Serres, Fredrick J.] NIEHS, Ctr Evaluat Risks Human Reprod, Chapel Hill, NC USA. [Los, Marek J.] Linkoping Univ, Div Cell Biol, Dept Clin & Expt Med, Integrat Regenerat Med Ctr IGEN, Linkoping, Sweden. [Ghavami, Saeid] Manitoba Inst Child Hlth, Winnipeg, MB, Canada. [Ghavami, Saeid] Univ Manitoba, St Boniface Res Ctr, Winnipeg, MB, Canada. RP Los, MJ (reprint author), Linkoping Univ, Div Cell Biol, Deptartment Clin & Expt Med, Integrat Regenerat Med Ctr IGEN, Linkoping, Sweden. EM marek.los@liu.se; saeid.ghavami@gmail.com RI Hashemi, Mohammad/H-2446-2016; Ghavami, Saeid/Q-8918-2016; OI Hashemi, Mohammad/0000-0002-6074-7101; Los, Marek/0000-0001-9518-1411 NR 46 TC 3 Z9 3 U1 0 U2 4 PU KOWSAR PUBL PI HOENSBROEK PA PATERSWEG 22,, HOENSBROEK, LIMBURG 6431 GC, NETHERLANDS SN 1735-143X EI 1735-3408 J9 HEPAT MON JI Hepat. Mon. PD FEB PY 2013 VL 13 IS 2 AR e9308 DI 10.5812/hepatmon.9308 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 134BA UT WOS:000318183500012 PM 23613688 ER PT J AU Das, C Jaeger, A Pohida, T Morgan, N Gottesman, M AF Das, C. Jaeger, A. Pohida, T. Morgan, N. Gottesman, M. TI Microfabricated Polymeric Vessel Mimetics for Oxygenation of 3-D Cancer Cell Cultures SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 66th Annual Cancer Symposium of the Society-of-Surgical-Oncology (SSO) CY MAR 06-09, 2013 CL National Harbor, MD SP Soc Surg Oncol (SSO) C1 [Das, C.; Jaeger, A.; Pohida, T.; Morgan, N.; Gottesman, M.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2013 VL 20 SU 1 BP S110 EP S110 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 133XR UT WOS:000318174700320 ER PT J AU Golas, BJ Magge, D Zureikat, AH Zeh, HJ Alexander, HR Libutti, SK Royal, RE Holtzman, MP Hughes, MS Turaga, KK Pappas, SG Gamblin, T Bartlett, DL Pingpank, JF AF Golas, B. J. Magge, D. Zureikat, A. H. Zeh, H. J. Alexander, H. R. Libutti, S. K. Royal, R. E. Holtzman, M. P. Hughes, M. S. Turaga, K. K. Pappas, S. G. Gamblin, T. Bartlett, D. L. Pingpank, J. F. TI Analysis of Toxicity and Outcomes in Patients Undergoing Hyperthermic Isolated Hepatic Perfusion with Melphalan for Metastatic Melanoma to the Liver SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 66th Annual Cancer Symposium of the Society-of-Surgical-Oncology (SSO) CY MAR 06-09, 2013 CL National Harbor, MD SP Soc Surg Oncol (SSO) C1 [Golas, B. J.; Magge, D.; Zureikat, A. H.; Zeh, H. J.; Holtzman, M. P.; Bartlett, D. L.; Pingpank, J. F.] Univ Pittsburgh, Pittsburgh, PA USA. [Hughes, M. S.] NCI, Surg Branch, Bethesda, MD 20892 USA. [Alexander, H. R.] Univ Maryland, Baltimore, MD 21201 USA. [Royal, R. E.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Libutti, S. K.] Albert Einstein Montefiore Med Ctr, New York, NY USA. [Turaga, K. K.; Pappas, S. G.; Gamblin, T.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2013 VL 20 SU 1 BP S20 EP S20 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 133XR UT WOS:000318174700041 ER PT J AU Mamounas, EP Tang, G Paik, S Baehner, FL Liu, Q Jeong, J Kim, S Butler, SM Jamshidian, F Cherbavaz, DB Sing, AP Shak, S Julian, TB Lembersky, BC Wickerham, DL Costantino, JP Wolmark, N AF Mamounas, E. P. Tang, G. Paik, S. Baehner, F. L. Liu, Q. Jeong, J. Kim, S. Butler, S. M. Jamshidian, F. Cherbavaz, D. B. Sing, A. P. Shak, S. Julian, T. B. Lembersky, B. C. Wickerham, D. L. Costantino, J. P. Wolmark, N. TI The 21-gene Recurrence Score (RS) Predicts Risk of Loco-regional Recurrence (LRR) in Node (+), ER (+) Breast Cancer (BC) after Adjuvant Chemotherapy and Tamoxifen: Results from NSABP B-28 SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 66th Annual Cancer Symposium of the Society-of-Surgical-Oncology (SSO) CY MAR 06-09, 2013 CL National Harbor, MD SP Soc Surg Oncol (SSO) C1 [Mamounas, E. P.] NSABP, Operat Ctr, Canton, OH USA. [Mamounas, E. P.] NSABP, Biostat Ctr, Canton, OH USA. [Mamounas, E. P.] Aultman Hosp, Canton, OH USA. [Tang, G.; Paik, S.; Liu, Q.; Jeong, J.; Kim, S.; Julian, T. B.; Lembersky, B. C.; Wickerham, D. L.; Costantino, J. P.; Wolmark, N.] NSABP, Pittsburgh, PA USA. [Tang, G.; Liu, Q.; Jeong, J.; Costantino, J. P.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Baehner, F. L.; Butler, S. M.; Jamshidian, F.; Cherbavaz, D. B.; Sing, A. P.; Shak, S.] Genom Hlth Inc, Redwood City, CA USA. [Julian, T. B.; Wickerham, D. L.; Wolmark, N.] Allegheny Gen Hosp, Allegheny Canc Ctr, Pittsburgh, PA 15212 USA. [Lembersky, B. C.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. NR 0 TC 7 Z9 7 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2013 VL 20 SU 1 BP S6 EP S6 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 133XR UT WOS:000318174700003 ER PT J AU Weisbrod, A Kitano, M Thomas, F Williams, D Gulati, N Gesuwan, K Liu, Y Venzon, D Venkatesan, A Yao, J Libutti, SK Nilubol, N Kebebew, E AF Weisbrod, A. Kitano, M. Thomas, F. Williams, D. Gulati, N. Gesuwan, K. Liu, Y. Venzon, D. Venkatesan, A. Yao, J. Libutti, S. K. Nilubol, N. Kebebew, E. TI Pancreatic Neuroendocrine Tumors in Von Hippel Lindau Syndrome: An Assessment of Tumor Growth and Radiographic Density SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 66th Annual Cancer Symposium of the Society-of-Surgical-Oncology (SSO) CY MAR 06-09, 2013 CL National Harbor, MD SP Soc Surg Oncol (SSO) C1 [Thomas, F.; Williams, D.; Gulati, N.; Gesuwan, K.; Liu, Y.; Venzon, D.; Venkatesan, A.; Yao, J.; Nilubol, N.; Kebebew, E.] NIH, Bethesda, MD 20892 USA. [Weisbrod, A.] Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. [Kitano, M.; Libutti, S. K.] Montefiore Med Ctr, Bronx, NY 10467 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2013 VL 20 SU 1 BP S83 EP S84 PG 2 WC Oncology; Surgery SC Oncology; Surgery GA 133XR UT WOS:000318174700233 ER PT J AU Boyce, CA Maholmes, V AF Boyce, Cheryl Anne Maholmes, Valerie TI Attention to the Neglected: Prospects for Research on Child Neglect for the Next Decade SO CHILD MALTREATMENT LA English DT Editorial Material DE child neglect; child health; children; families ID INITIAL PAPERS; SPECIAL-ISSUE; PROJECTS; NIH AB In 1997, the National Institutes of Health within the United States Department of Health and Human Services reviewed the state of its research on child abuse and neglect (US Department of Health and Human Services, National Institutes of Health, 1997). The findings suggested that although neglect was the most frequent type of child maltreatment, research studies were lacking. Through an unprecedented partnership across federal funding agencies for research on child neglect, research was encouraged in several areas. Over the past fifteen years, consortia of researchers have continued to increase our knowledge of child neglect and to shape the field. Nonetheless, challenges for research on child neglect remain, including the changing demographics of the nation and health disparities. Evidenced-based early interventions and treatments may be an opportunity for prevention of child neglect and improving child welfare services, particularly in an era of health care reform. Developmental researchers across the translational pipeline are encouraged to integrate child neglect research in future studies to inform prevention, treatment and policy efforts for the improved health and well-being of children, families and communities. C1 [Boyce, Cheryl Anne] NIDA, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Maholmes, Valerie] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Dept Hlth & Human Serv, NIH, Bethesda, MD USA. RP Boyce, CA (reprint author), NIDA, Dept Hlth & Human Serv, NIH, 6001 Execut Blvd, Bethesda, MD 20892 USA. EM cboyce@mail.nih.gov NR 27 TC 4 Z9 4 U1 0 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1077-5595 J9 CHILD MALTREATMENT JI Child Maltreatment PD FEB PY 2013 VL 18 IS 1 SI SI BP 65 EP 68 DI 10.1177/1077559513480426 PG 4 WC Family Studies; Social Work SC Family Studies; Social Work GA 132BW UT WOS:000318043800007 PM 23444199 ER PT J AU Shabalina, SA Spiridonov, NA Kashina, A AF Shabalina, Svetlana A. Spiridonov, Nikolay A. Kashina, Anna TI Sounds of silence: synonymous nucleotides as a key to biological regulation and complexity SO NUCLEIC ACIDS RESEARCH LA English DT Article ID RNA SECONDARY STRUCTURE; EUKARYOTIC MESSENGER-RNAS; ZIPCODE-BINDING-PROTEIN; CODON USAGE BIAS; RETICULOCYTE TRANSFER-RNA; GENOME-WIDE MEASUREMENT; BETA-ACTIN SYNTHESIS; ESCHERICHIA-COLI; GENE-EXPRESSION; CODING REGIONS AB Messenger RNA is a key component of an intricate regulatory network of its own. It accommodates numerous nucleotide signals that overlap protein coding sequences and are responsible for multiple levels of regulation and generation of biological complexity. A wealth of structural and regulatory information, which mRNA carries in addition to the encoded amino acid sequence, raises the question of how these signals and overlapping codes are delineated along non-synonymous and synonymous positions in protein coding regions, especially in eukaryotes. Silent or synonymous codon positions, which do not determine amino acid sequences of the encoded proteins, define mRNA secondary structure and stability and affect the rate of translation, folding and post-translational modifications of nascent polypeptides. The RNA level selection is acting on synonymous sites in both prokaryotes and eukaryotes and is more common than previously thought. Selection pressure on the coding gene regions follows three-nucleotide periodic pattern of nucleotide base-pairing in mRNA, which is imposed by the genetic code. Synonymous positions of the coding regions have a higher level of hybridization potential relative to non-synonymous positions, and are multifunctional in their regulatory and structural roles. Recent experimental evidence and analysis of mRNA structure and interspecies conservation suggest that there is an evolutionary tradeoff between selective pressure acting at the RNA and protein levels. Here we provide a comprehensive overview of the studies that define the role of silent positions in regulating RNA structure and processing that exert downstream effects on proteins and their functions. C1 [Shabalina, Svetlana A.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20984 USA. [Spiridonov, Nikolay A.] US FDA, Div Therapeut Prot, Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. [Kashina, Anna] Univ Penn, Sch Vet Med, Dept Anim Biol, Philadelphia, PA 19104 USA. RP Shabalina, SA (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20984 USA. EM shabalin@ncbi.nlm.nih.gov RI Shabalina, Svetlana/N-8939-2013; Spiridonov, Nikolay/B-6287-2014 OI Shabalina, Svetlana/0000-0003-2272-7473; FU DHHS (NIH, National Library of Medicine); NIH [R01HL084419] FX DHHS (NIH, National Library of Medicine) intramural funds; NIH [R01HL084419 to A.K.]. Funding for open access charge: DHHS (NIH, National Library of Medicine) intramural funds. NR 221 TC 65 Z9 67 U1 0 U2 39 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB PY 2013 VL 41 IS 4 BP 2073 EP 2094 DI 10.1093/nar/gks1205 PG 22 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 132IV UT WOS:000318062000009 PM 23293005 ER PT J AU Aduri, R Briggs, KT Gorelick, RJ Marino, JP AF Aduri, Raviprasad Briggs, Katharine T. Gorelick, Robert J. Marino, John P. TI Molecular determinants of HIV-1 NCp7 chaperone activity in maturation of the HIV-1 dimerization initiation site SO NUCLEIC ACIDS RESEARCH LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; NUCLEOCAPSID PROTEIN NCP7; ZINC-FINGER STRUCTURES; PLUS-STRAND TRANSFER; PRIMER BINDING-SITE; RNA IN-VITRO; GENOMIC RNA; REVERSE TRANSCRIPTION; KISSING-LOOP; SECONDARY STRUCTURE AB Human immunodeficiency virus genome dimerization is initiated through an RNA-RNA kissing interaction formed via the dimerization initiation site (DIS) loop sequence, which has been proposed to be converted to a more thermodynamically stable linkage by the viral p7 form of the nucleocapsid protein (NC). Here, we systematically probed the role of specific amino acids of NCp7 in its chaperone activity in the DIS conversion using 2-aminopurine (2-AP) fluorescence and nuclear magnetic resonance spectroscopy. Through comparative analysis of NCp7 mutants, the presence of positively charged residues in the N-terminus was found to be essential for both helix destabilization and strand transfer functions. It was also observed that the presence and type of the Zn finger is important for NCp7 chaperone activity, but not the order of the Zn fingers. Swapping single aromatic residues between Zn fingers had a significant effect on NCp7 activity; however, these mutants did not exhibit the same activity as mutants in which the order of the Zn fingers was changed, indicating a functional role for other flanking residues. RNA chaperone activity is further correlated with NCp7 structure and interaction with RNA through comparative analysis of nuclear magnetic resonance spectra of NCp7 variants, and complexes of these proteins with the DIS dimer. C1 [Aduri, Raviprasad; Briggs, Katharine T.; Marino, John P.] Univ Maryland, Inst Biosci & Biotechnol Res, Rockville, MD 20850 USA. [Aduri, Raviprasad; Briggs, Katharine T.; Marino, John P.] NIST, Rockville, MD 20850 USA. [Gorelick, Robert J.] NCI, AIDS & Canc Virus Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Marino, JP (reprint author), Univ Maryland, Inst Biosci & Biotechnol Res, Rockville, MD 20850 USA. EM john.marino@nist.gov FU National Institutes of Health [GM 59107]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; SAIC-Frederick, Inc.; National Institutes of Health graduate training fellowship; NMR instrumentation at IBBR; W.M. Keck Foundation; National Institutes of Health; National Institute of Standards and Technology; NIST intramural funds FX National Institutes of Health [GM 59107 to J.P.M. in part]; National Cancer Institute, National Institutes of Health, under contract [HHSN261200800001E] with SAIC-Frederick, Inc. (to R.J.G.); National Institutes of Health graduate training fellowship to UMd (to K. T. B.); NMR instrumentation at IBBR with support from the W.M. Keck Foundation, the National Institutes of Health and the National Institute of Standards and Technology. Funding for open access charge: NIST intramural funds. NR 78 TC 1 Z9 1 U1 2 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB PY 2013 VL 41 IS 4 BP 2565 EP 2580 DI 10.1093/nar/gks1350 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 132IV UT WOS:000318062000046 PM 23275531 ER PT J AU Chan, L Chin, LMK Kennedy, M Woolstenhulme, JG Nathan, SD Weinstein, AA Connors, G Weir, NA Drinkard, B Lamberti, J Keyser, RE AF Chan, Leighton Chin, Lisa M. K. Kennedy, Michelle Woolstenhulme, Joshua G. Nathan, Steven D. Weinstein, Ali A. Connors, Gerilynn Weir, Nargues A. Drinkard, Bart Lamberti, James Keyser, Randall E. TI Benefits of Intensive Treadmill Exercise Training on Cardiorespiratory Function and Quality of Life in Patients With Pulmonary Hypertension SO CHEST LA English DT Article ID 6-MINUTE WALK TEST; CLINICAL-PRACTICE GUIDELINES; CHRONIC HEART-FAILURE; ARTERIAL-HYPERTENSION; GAS-EXCHANGE; RISK STRATIFICATION; CONSENSUS DOCUMENT; PHYSICAL-ACTIVITY; TASK-FORCE; DISEASE AB Background: Pulmonary hypertension (PH) restricts the ability to engage in physical activity and decreases longevity. We examined the impact of aerobic exercise training on function and quality of life in patients with World Health Organization group 1 PH. Methods: Patients were randomized to a 10-week education only (EDU) or education/exercise combined (EXE) group. The exercise program consisted of 24-30 sessions of treadmill walking for 30-45 min per session at 70% to 80% of heart rate reserve. Outcome variables included changes in 6-min walk test (6MWT) distance, time to exercise intolerance, peak work rate (WR) from a cardiopulmonary treadmill test, and quality-of-life measures, including the Short Form Health Survey, version 2 (SF-36v2) and Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR). Results: Data are presented as mean +/- SD. Twenty-three women (age, 54 +/- 11 years; BMI, 31 +/- 7 kg/m(2)) were randomized to the EDU (n = 13) or EXE (n = 10) groups. Following 10 weeks of intervention, patients in the EXE group demonstrated an improvement in 6MWT distance (56 +/- 45 m; P = .002), increased time to exercise intolerance (1.9 +/- 1.3 min; P = .001), and peak WR (26 +/- 23 W; P = .004). Additionally, the EXE group scored significantly (P < .050) better on six of the eight scales on SF-36v2, and five of the six scales on CAMPHOR. In contrast, no significant improvement was observed for any of the outcome measures following EDU. No adverse events were noted in either group. Conclusion: Ten weeks of brisk treadmill walking improved 6MWT distance, cardiorespiratory function, and patient-reported quality of life in female patients with group 1 PH. Trial registry: ClinicalTrials.gov; No.: NCT00678821; URL: clinicaltrials.gov CHEST 2013; 143(2):333-343 C1 [Chan, Leighton; Chin, Lisa M. K.; Kennedy, Michelle; Woolstenhulme, Joshua G.; Drinkard, Bart; Keyser, Randall E.] NIH, Dept Rehabil Med, Bethesda, MD 20892 USA. [Woolstenhulme, Joshua G.; Weinstein, Ali A.; Keyser, Randall E.] George Mason Univ, Dept Rehabil Sci, Fairfax, VA 22030 USA. [Nathan, Steven D.; Weir, Nargues A.; Lamberti, James] Inova Fairfax Hosp, Dept Med, Falls Church, VA USA. [Connors, Gerilynn] Inova Fairfax Hosp, Pulm Rehabil Ctr, Falls Church, VA USA. RP Chan, L (reprint author), NIH, Dept Rehabil Med, Ctr Clin, Bldg 10,Room 1-1469,10 Ctr Dr,MSC 1604, Bethesda, MD 20892 USA. EM chanle@cc.nih.gov RI Chin, Lisa/O-4706-2014 OI Chin, Lisa/0000-0002-0178-739X FU US National Institutes of Health [1 Z01 CL060068-05 CC]; Actelion Pharmaceuticals US Inc; Gilead Sciences Inc; United Therapeutics Corporation FX This work was supported by the US National Institutes of Health [Intramural Funds 1 Z01 CL060068-05 CC].; The authors have reported to CHEST the following conflicts of interest: Dr Nathan has received research funding, has been. a consultant, and is on the speaker's bureau for Actelion Pharmaceuticals US Inc, Gilead Sciences Inc, and United Therapeutics Corporation. Dr Lamberti is on the speaker's bureau for GlaxoSmithKline plc and Boehringer Ingelheim GmbH. The remaining authors have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. NR 57 TC 52 Z9 54 U1 3 U2 19 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD FEB PY 2013 VL 143 IS 2 BP 333 EP 343 DI 10.1378/chest.12-0993 PG 11 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 129VC UT WOS:000317871100012 PM 22922554 ER PT J AU Lorenzo, MMG Fenton, MJ AF Lorenzo, Margarita M. Gomez Fenton, Matthew J. TI Immunobiology of Influenza Vaccines SO CHEST LA English DT Article ID MEMORY B-CELLS; PANDEMIC INFLUENZA; SYSTEMS BIOLOGY; IMMUNE-RESPONSE; SEASONAL INFLUENZA; ANTIBODY-RESPONSES; H5N1 INFLUENZA; VIRUS-VACCINES; A VIRUS; VACCINATION AB Vaccination is the primary strategy for prevention and control of influenza. The surface hemagglutinin (HA) protein of the influenza virus contains two structural elements (head and stalk) that differ in their potential utility as vaccine targets. The head of the HA protein is the primary target of antibodies that confer protective immunity to influenza viruses. The underlying health status, age, and gene polymorphisms of vaccine recipients and, just as importantly, the extent of the antigenic match between the viruses in the vaccine and those that are circulating modulate influenza vaccine protection. Vaccine adjuvants and live attenuated influenza vaccine improve the breadth of immunity to seasonal and pandemic virus strains. Eliciting antibodies against, the conserved HA stem region that cross-react with HAs within influenza virus types or subtypes would allow for the development of a universal influenza vaccine. The highly complex network of interactions generated after influenza infection and vaccination can be studied with the use of systems biology tools, such as DNA microarray chips. The use of systems vaccinology has allowed for the generation of gene expression signatures that represent key transcriptional differences between asymptomatic and symptomatic host responses to influenza infection. Additionally, the use of systems vaccinology tools have resulted in the identification of novel surrogate gene markers that are predictors of the magnitude of host responses to vaccines, which is critical to both vaccine development and public health. Identifying associations between variations in vaccine immune responses and gene polymorphisms is critical in the development of universal influenza vaccines. CHEST 2013; 143(2):502-510 C1 [Lorenzo, Margarita M. Gomez; Fenton, Matthew J.] NIAID, NIH, Bethesda, MD 20892 USA. RP Lorenzo, MMG (reprint author), NIAID, Asthma Allergy & Airway Biol Branch, NIH, Dept Hlth & Human Serv, 6610 Rockledge Dr,Room 6508,Mail Stop 6601, Bethesda, MD 20892 USA. EM gomezmm@niaid.nih.gov NR 75 TC 6 Z9 7 U1 1 U2 13 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD FEB PY 2013 VL 143 IS 2 BP 502 EP 510 DI 10.1378/chest.12-1711 PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 129VC UT WOS:000317871100033 ER PT J AU Davidov, O Peddada, S AF Davidov, Ori Peddada, Shyamal TI THE LINEAR STOCHASTIC ORDER AND DIRECTED INFERENCE FOR MULTIVARIATE ORDERED DISTRIBUTIONS SO ANNALS OF STATISTICS LA English DT Article DE Nonparametric tests; order-restricted statistical inference; stochastic order relations ID N-BOOTSTRAP; ESTIMATOR AB Researchers are often interested in drawing inferences regarding the order between two experimental groups on the basis of multivariate response data. Since standard multivariate methods are designed for two-sided alternatives, they may not be ideal for testing for. order between two groups. In this article we introduce the notion of the linear stochastic order and investigate its properties. Statistical theory and methodology are developed to both estimate the direction which best separates two arbitrary ordered distributions and to test for order between the two groups. The new methodology generalizes Roy's classical largest root test to the nonparametric setting and is applicable to random vectors with discrete and/or continuous components. The proposed methodology is illustrated using data obtained from a 90-day pre-chronic rodent cancer bioassay study conducted by the National Toxicology Program (NTP). C1 [Davidov, Ori] Univ Haifa, Dept Stat, IL-31905 Haifa, Israel. [Peddada, Shyamal] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Davidov, O (reprint author), Univ Haifa, Dept Stat, IL-31905 Haifa, Israel. EM davidov@stat.haifa.ac.il; peddada@niehs.nih.gov FU Israeli Science Foundation [875/09]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES101744-04] FX Supported in part by the Israeli Science Foundation Grant No 875/09.; Supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES101744-04). NR 38 TC 3 Z9 3 U1 1 U2 10 PU INST MATHEMATICAL STATISTICS PI CLEVELAND PA 3163 SOMERSET DR, CLEVELAND, OH 44122 USA SN 0090-5364 J9 ANN STAT JI Ann. Stat. PD FEB PY 2013 VL 41 IS 1 BP 1 EP 40 DI 10.1214/12-AOS1062 PG 40 WC Statistics & Probability SC Mathematics GA 124GG UT WOS:000317451200001 PM 23543786 ER PT J AU Tang, ZW Qian, M Ho, M AF Tang, Zhewei Qian, Min Ho, Mitchell TI The Role of Mesothelin in Tumor Progression and Targeted Therapy SO ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY LA English DT Article DE Antibody dependent cell mediated cytotoxicity/ADCC; Apoptosis; Cell surface proteins; Cell survival/proliferation; Complement dependent cytotoxicity/CDC; Human monoclonal antibodies; Immunotoxin; Mesothelin; MORAb-009/amatuximab; MUC16/CA125; NF-kappa B; PI3K/Akt; SS1P ID CANCER CELL-PROLIFERATION; HUMAN MONOCLONAL-ANTIBODY; PANCREATIC-CANCER; HIGH-AFFINITY; OVARIAN-CANCER; PHASE-I; RECOMBINANT IMMUNOTOXIN; OVEREXPRESSION; IMMUNOTHERAPY; EXPRESSION AB Mesothelin, a glycosylphosphatidylinositol (GPI) anchored cell surface protein, is a potential target for antibody-based cancer therapy due to its high expression in mesothelioma, ovarian cancer, pancreatic cancer, cholangiocarcinoma and other cancers. The SS1P immunotoxin and MORAb-009 (amatuximab), a chimeric monoclonal antibody, are currently being evaluated in clinical trials. In this review, we discuss the role of mesothelin in cancer progression and provide new insights into mesothelin-targeted cancer therapy. Recent studies highlight three mechanisms by which mesothelin plays a role in cancer progression. First, mesothelin may aid in the peritoneal implantation and metastasis of tumors through its interaction with mucin MUC16 (also known as CA125). Second, mesothelin may promote cancer cell survival and proliferation via the NF-kappa B signaling pathway. Finally, mesothelin expression promotes resistance to certain chemotherapy drugs such as TNF-alpha, paclitaxel, and a combination of platinum and cyclophosphamide. However, its cancer-specific expression makes mesothelin a potential target for monoclonal antibody therapy. New human monoclonal antibodies targeting mesothelin have been isolated by phage display technology and may provide opportunities for novel cancer therapy. C1 [Tang, Zhewei; Qian, Min] E China Normal Univ, Sch Life Sci, Inst Biomed Sci, Shanghai 200062, Peoples R China. [Tang, Zhewei; Ho, Mitchell] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Ho, M (reprint author), NCI, Antibody Therapy Sect, Mol Biol Lab, 37 Convent Dr,Room 5002C, Bethesda, MD 20892 USA. EM homi@mail.nih.gov RI Ho, Mitchell/F-5059-2015 FU National Institutes of Health (NIH), NCI, Center for Cancer Research; NCI Director's Intramural Innovation Award for Principal Investigators; Ovarian Cancer Research Fund Individual Investigator Award; Mesothelioma Applied Research Foundation Craig Kozicki Memorial Grant FX This research is supported by the Intramural Research Program of the National Institutes of Health (NIH), NCI, Center for Cancer Research. Dr. Mitchell Ho is also supported by the NCI Director's Intramural Innovation Award for Principal Investigators, an Ovarian Cancer Research Fund Individual Investigator Award, and a Mesothelioma Applied Research Foundation Craig Kozicki Memorial Grant. Dr. Ho is a Zi-jiang Lecture Professor of East China Normal University. Zhewei Tang is in the Graduate Partnerships Program of the NIH. 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. The authors have no conflict of interest directly relevant to the content of this review. We thank the NIH Fellows Editorial Board and Yen Phung (NCI) for editorial assistance. NR 40 TC 32 Z9 34 U1 1 U2 20 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5206 J9 ANTI-CANCER AGENT ME JI Anti-Cancer Agents Med. Chem. PD FEB PY 2013 VL 13 IS 2 BP 276 EP 280 PG 5 WC Oncology; Chemistry, Medicinal SC Oncology; Pharmacology & Pharmacy GA 129NV UT WOS:000317848800014 PM 22721387 ER PT J AU Zheng, P Baibakov, B Wang, XH Dean, J AF Zheng, Ping Baibakov, Boris Wang, Xi-hong Dean, Jurrien TI PtdIns(3,4,5)P-3 is constitutively synthesized and required for spindle translocation during meiosis in mouse oocytes SO JOURNAL OF CELL SCIENCE LA English DT Article DE PtdIns(3,4,5)P-3; Oocyte meiosis; Spindle translocation; Filamentous actin; Cdc42 ID MATERNAL EFFECT GENE; MEIOTIC SPINDLE; ASYMMETRIC DIVISION; PHOSPHATIDYLINOSITOL 3-KINASE; GROWTH-FACTOR; RHO-GTPASES; ACTIN; FORMIN-2; PROTEIN; WORTMANNIN AB Prior to ovulation, mammalian oocytes complete their first meiotic division and arrest at metaphase II. During this marked asymmetric cell division, the meiotic spindle moves dramatically from the center of the oocyte to the cortex to facilitate segregation of half of its chromosomal content into the diminutive first polar body. Recent investigations have documented crucial roles for filamentous actin (F-actin) in meiotic spindle translocation. However, the identity of the upstream regulators responsible for these carefully orchestrated movements has remained elusive. Utilizing fluorescently tagged probes and time-lapse confocal microscopy, we document that phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P-3] is constitutively synthesized with spatial and temporal dynamics similar to that of F-actin and Formin 2 (Fmn2). Blockage of PtdIns(3,4,5) P-3 synthesis by LY294002, a specific inhibitor of phosphoinositide 3-kinase (PI3K), disrupts cytoplasmic F-actin organization and meiotic spindle migration to the cortex. F-actin nucleator Fmn2 and Rho GTPase Cdc42 play roles in mediating the effect of PtdIns(3,4,5)P-3 on F-actin assembly. Moreover, the spatial and temporal dynamics of PtdIns(3,4,5)P-3 is impaired by depletion of MATER or Filia, two oocyte proteins encoded by maternal effect genes. Thus, PtdIns(3,4,5)P-3 is synthesized during meiotic maturation and acts upstream of Cdc42 and Fmn2, but downstream of MATER/Filia proteins to regulate the F-actin organization and spindle translocation to the cortex during mouse oocyte meiosis. C1 [Zheng, Ping] Chinese Acad Sci, Kunming Inst Zool, State Key Lab Genet Resources & Evolut, Kunming 650223, Yunnan, Peoples R China. [Zheng, Ping; Wang, Xi-hong] Chinese Acad Sci, Kunming Inst Zool, Yunnan Key Lab Anim Reprod Biol, Kunming 650223, Yunnan, Peoples R China. [Baibakov, Boris; Dean, Jurrien] NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Zheng, P (reprint author), Chinese Acad Sci, Kunming Inst Zool, State Key Lab Genet Resources & Evolut, Kunming 650223, Yunnan, Peoples R China. EM zhengp@mail.kiz.ac.cn; jurrien@helix.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, USA; Natural Science Foundation of China [31071274] FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, USA (to J. D.); and the Natural Science Foundation of China [grant number 31071274 to P. Zheng]. Deposited in PMC for release after 12 months. NR 47 TC 9 Z9 9 U1 0 U2 9 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD FEB 1 PY 2013 VL 126 IS 3 BP 715 EP 721 DI 10.1242/jcs.118042 PG 7 WC Cell Biology SC Cell Biology GA 121YN UT WOS:000317281700002 PM 23264738 ER PT J AU Hayton, K Dumoulin, P Henschen, B Liu, A Papakrivos, J Wellems, TE AF Hayton, Karen Dumoulin, Peter Henschen, Bruce Liu, Anna Papakrivos, Janni Wellems, Thomas E. TI Various PfRH5 polymorphisms can support Plasmodium falciparum invasion into the erythrocytes of owl monkeys and rats SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE Malaria; Virulence; Aotus nancymaae; Sialic acid; Rattus norvegicus; Mus musculus ID RETICULOCYTE BINDING-PROTEINS; HUMAN MALARIA PARASITES; RECEPTOR HETEROGENEITY; MEROZOITE PROTEINS; HOST ERYTHROCYTES; GLYCOPHORIN-B; LIGAND; VIVAX; ACID; SPECIFICITY AB Aotus nancymaae, the owl monkey, provides a useful laboratory model for research to develop drugs and vaccines against human falciparum malaria; however, many Plasmodium falciparum parasites are unable to invade A. nancymaae erythrocytes, rendering the parasites noninfective to the monkeys. In previous work, we identified a key polymorphism that determined the inheritance of erythrocyte invasion in a genetic cross of two P. falciparum clones that were virulent (GB4) or noninfective (7G8) to A. nancymaae. This polymorphism, an isoleucine-to-lysine polymorphism at position 204 (I204K) of the GB4 erythrocyte binding protein PfRH5, was nevertheless not found in several other P. falciparum lines that could also invade A. nancymaae erythrocytes. Alternative PfRH5 polymorphisms occur at different positions in these virulent parasites, and additional polymorphisms are found in P. falciparum parasites that cannot infect A. nancymaae. By allelic replacement methods, we have introduced the polymorphisms of these A. nancymaae-virulent or noninfective parasites at codons 204, 347, 358, 362, 410, and 429 of the endogenous PfRH5 gene in the noninfective 7G8 line. 7G8 transformants expressing the polymorphisms of the A. nancymaae-virulent parasites show neuraminidase-sensitive (sialic acid-dependent) invasion into the monkey erythrocytes, whereas 7G8 transformants expressing the PfRH5 alleles of noninfective parasites show little or no invasion of these erythrocytes. Parasites harboring PfRH5 polymorphisms 204K or 204R are also able to invade rat erythrocytes and are differentially sensitive to the removal of surface sialic acids by neuraminidase. These studies offer insights into the PfRH5 receptor-binding domain and interactions that support the invasion of various primate and rodent erythrocytes by P. falciparum. Published by Elsevier B.V. C1 [Hayton, Karen; Dumoulin, Peter; Henschen, Bruce; Liu, Anna; Papakrivos, Janni; Wellems, Thomas E.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Wellems, TE (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM twellems@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank Lynn Lambert, Angela Lunger, and Sachy Orr-Gonzalez for the provision of blood samples; Osamu Kaneko for helpful discussions; and NIAID intramural editor Brenda Marshall for assistance. This research was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 62 TC 15 Z9 15 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-6851 J9 MOL BIOCHEM PARASIT JI Mol. Biochem. Parasitol. PD FEB PY 2013 VL 187 IS 2 BP 103 EP 110 DI 10.1016/j.molbiopara.2012.12.005 PG 8 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 120LW UT WOS:000317172800005 PM 23305874 ER PT J AU Shi, K Parekh, VI Roy, S Desai, SS Agarwal, SK AF Shi, Kerong Parekh, Vaishali I. Roy, Swarnava Desai, Shruti S. Agarwal, Sunita K. TI The embryonic transcription factor Hlxb9 is a menin interacting partner that controls pancreatic beta-cell proliferation and the expression of insulin regulators SO ENDOCRINE-RELATED CANCER LA English DT Article DE multiple endocrine neoplasias; gene regulation; gene expression; islet cells ID MISSENSE MUTANTS; HOMEOBOX GENE; MLL; MICE; SECRETION; PROTEINS; AGENESIS; JUND; SUPPRESSION; LEUKEMIA AB The multiple endocrine neoplasia type 1 (MEN1) syndrome is caused by germline mutations in the MEN1 gene encoding menin, with tissue-specific tumors of the parathyroids, anterior pituitary, and enteropancreatic endocrine tissues. Also, 30-40% of sporadic pancreatic endocrine tumors show somatic MEN1 gene inactivation. Although menin is expressed in all cell types of the pancreas, mouse models with loss of menin in either pancreatic alpha-cells, or beta-cells, or total pancreas develop beta-cell-specific endocrine tumors (insulinomas). Loss of widely expressed tumor suppressor genes may produce tissue-specific tumors by reactivating one or more embryonic-specific differentiation factors. Therefore, we determined the effect of menin overexpression or knockdown on the expression of beta-cell differentiation factors in a mouse b-cell line (MIN6). We show that the beta-cell differentiation factor Hlxb9 is posttranscriptionally upregulated upon menin knockdown, and it interacts with menin. Hlxb9 reduces cell proliferation and causes apoptosis in the presence of menin, and it regulates genes that modulate insulin level. Thus, upon menin loss or from other causes, dysregulation of Hlxb9 predicts a possible combined mechanism for beta-cell proliferation and insulin production in insulinomas. These observations help to understand how a ubiquitously expressed protein such as menin might control tissue-specific tumorigenesis. Also, our findings identify Hlxb9 as an important factor for beta-cell proliferation and insulin regulation. C1 [Shi, Kerong; Parekh, Vaishali I.; Roy, Swarnava; Desai, Shruti S.; Agarwal, Sunita K.] NIDDKD, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. RP Agarwal, SK (reprint author), NIDDKD, Metab Dis Branch, NIH, Bldg 10,Room 8C-101, Bethesda, MD 20892 USA. EM sunitaa@mail.nih.gov RI Agarwal, Sunita/D-1428-2016 OI Agarwal, Sunita/0000-0002-7557-3191 FU Division of Intramural Research of the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA FX This research was funded by the Division of Intramural Research of the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA. NR 42 TC 9 Z9 9 U1 0 U2 2 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD FEB PY 2013 VL 20 IS 1 BP 111 EP 122 DI 10.1530/ERC-12-0077 PG 12 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA 121RZ UT WOS:000317263200012 PM 23419452 ER PT J AU Dallal, CM Brinton, LA Bauer, DC Buist, DSM Cauley, JA Hue, TF LaCroix, A Tice, JA Chia, VM Falk, R Pfeiffer, R Pollak, M Veenstra, TD Xu, X Lacey, JV AF Dallal, Cher M. Brinton, Louise A. Bauer, Douglas C. Buist, Diana S. M. Cauley, Jane A. Hue, Trisha F. LaCroix, Andrea Tice, Jeffrey A. Chia, Victoria M. Falk, Roni Pfeiffer, Ruth Pollak, Michael Veenstra, Timothy D. Xu, Xia Lacey, James V., Jr. CA B FIT Res Grp TI Obesity-related hormones and endometrial cancer among postmenopausal women: a nested case-control study within the B similar to FIT cohort SO ENDOCRINE-RELATED CANCER LA English DT Article DE endometrial cancer; adiponectin; leptin; obesity ID FRACTURE INTERVENTION TRIAL; BODY-MASS-INDEX; BIOLOGICAL MECHANISMS; VERTEBRAL FRACTURES; INSULIN SENSITIVITY; RANDOMIZED-TRIAL; STEROID-HORMONES; ADIPOSE-TISSUE; ADIPONECTIN; RISK AB Endometrial cancer risk is strongly influenced by obesity, but the mechanisms of action remain unclear. Leptin and adiponectin, secreted from adipose tissue, reportedly play a role in such carcinogenic processes as cell proliferation, angiogenesis, and insulin regulation. In this case-control study, nested within the Breast and Bone Follow-up of the Fracture Intervention Trial (n = 15 595), we assessed pre-diagnostic serum leptin, total adiponectin, and high-molecular-weight (HMW) adiponectin in relation to endometrial cancer among postmenopausal women. During the 10-year follow-up, 62 incident endometrial cases were identified and matched to 124 controls on age, geographical site, time of fasting blood draw at baseline (1992-1993), and trial participation status. Adipokines and C-peptide were measured by ELISA. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated via conditional logistic regression, with exposures categorized in tertiles (T). Multivariable models considered C-peptide, BMI (kg/m(2)), and estradiol (E2) as potential confounders. Endometrial cancer risk was significantly associated with higher leptin levels, adjusted for E2 and C-peptide (ORT3 (vs) (T1) = 2.96; 95% CI, 1.21-7.25; P trend < 0.01). After further adjustment for BMI, the estimates were attenuated and the positive trend was no longer statistically significant (ORT3 (vs) (T1) = 2.11; 95% CI, 0.69-6.44; P trend = 0.18). No significant associations were observed with adiponectin or HMW adiponectin and endometrial cancer. Our findings with leptin suggest that the leptin-BMI axis might increase endometrial cancer risk through mechanisms other than estrogen-driven proliferation. Continued exploration of these pathways in larger prospective studies may help elucidate mechanisms underlying observed obesity-endometrial cancer associations. C1 [Dallal, Cher M.; Brinton, Louise A.; Chia, Victoria M.; Falk, Roni] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20852 USA. [Dallal, Cher M.] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, NIH, Bethesda, MD 20852 USA. [Bauer, Douglas C.; Tice, Jeffrey A.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Buist, Diana S. M.] Grp Hlth Res Inst, Seattle, WA 98101 USA. [Cauley, Jane A.] Univ Pittsburgh, Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Hue, Trisha F.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94107 USA. [LaCroix, Andrea] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Pfeiffer, Ruth] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20852 USA. [Pollak, Michael] McGill Univ, Jewish Gen Hosp, Montreal, PQ H3T 1E2, Canada. [Veenstra, Timothy D.; Xu, Xia] SAIC Frederick Inc, Adv Technol Program, Lab Prote & Analyt Technol, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Lacey, James V., Jr.] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Div Canc Etiol, Duarte, CA 91010 USA. RP Dallal, CM (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Suite 550, Bethesda, MD 20852 USA. EM cher.dallal@nih.gov RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 FU Merck Research Laboratories; National Cancer Institute [N02-CP-01019] FX The original FIT study was funded by Merck Research Laboratories. B similar to FIT was funded by the National Cancer Institute (contract #N02-CP-01019). NR 33 TC 18 Z9 19 U1 0 U2 5 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD FEB PY 2013 VL 20 IS 1 BP 151 EP 160 DI 10.1530/ERC-12-0229 PG 10 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA 121RZ UT WOS:000317263200015 PM 23222000 ER PT J AU Stratakis, CA AF Stratakis, Constantine A. TI Joy and discovery are inseparable from academic commitment SO ENDOCRINE-RELATED CANCER LA English DT Editorial Material ID PHOSPHODIESTERASE 11A4 PDE11A; ADRENOCORTICAL DISEASE; CUSHING-SYNDROME; CARNEY COMPLEX; MUTATIONS; HYPERPLASIA; TUMORS C1 [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Stratakis, Constantine A.] Program Dev Endocrinol & Genet, Sect Endocrinol & Genet SEGEN, Bethesda, MD 20892 USA. [Stratakis, Constantine A.] NIH, Interinst Pediat Endocrinol Training Program, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov NR 18 TC 0 Z9 0 U1 0 U2 3 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD FEB PY 2013 VL 20 IS 1 BP P1 EP P6 DI 10.1530/ERC-12-0351 PG 6 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA 121RZ UT WOS:000317263200001 PM 23250906 ER PT J AU Dyer, KD Percopo, CM Rosenberg, HF AF Dyer, Kimberly D. Percopo, Caroline M. Rosenberg, Helene F. TI IL-33 promotes eosinophilia in vivo and antagonizes IL-5-dependent eosinophil hematopoiesis ex vivo SO IMMUNOLOGY LETTERS LA English DT Article DE Eosinophil; IL-5; IL-33; GM-CSF ID MOUSE BONE-MARROW; AIRWAY INFLAMMATION; CYTOKINE IL-33; STEM-CELLS; RECEPTOR; ST2; MACROPHAGES; INTERLEUKIN-33; EXPANSION; LIGAND AB IL-33 is an IL-1 family cytokine that elicits IL-5-dependent eosinophilia in vivo. We show here that IL-33 promotes minimal eosinophil hematopoiesis via direct interactions with mouse bone marrow progenitors ex vivo and that it antagonizes eosinophil hematopoiesis promoted by IL-5 on SCF and Flt3L primed bone marrow progenitor cells in culture. SCF and Flt3L primed progenitors respond to IL-33 by acquiring an adherent, macrophage-like phenotype, and by releasing macrophage-associated cytokines into the culture medium. IL-33-mediated antagonism of IL-5 was reproduced in part by the addition of GM-CSF and was inhibited by the actions of neutralizing anti-GM-CSF antibody. These findings suggest that the direct actions of IL-33 on bone marrow progenitors primed with SCF and Flt3L are antagonistic to the actions of IL-5 and are mediated in part by GM-CSF. Published by Elsevier B.V. C1 [Dyer, Kimberly D.; Percopo, Caroline M.; Rosenberg, Helene F.] NIAID, Lab Allerg Dis, Inflammat Immunobiol Sect, NIH, Bethesda, MD 20892 USA. RP Dyer, KD (reprint author), 10 Ctr Dr MSC 1883,Bldg 10 Room 11C216, Bethesda, MD 20892 USA. EM kdyer@niaid.nih.gov FU NIAID DIR [AI000941] FX The authors thank Dr. Paul S. Foster, University of Newcastle, New South Wales, Australia, for providing the IL-5 gene-deleted mice on the BALB/c background, Dr. Ricardo Dreyfuss for preparing the photomicrographs, and Dr. Alfonso Gozalo (CMB/NIAID) and his staff at the 14BS animal facility for care of the mice used in this work. This work is supported by NIAID DIR funding #AI000941 to HFR. NR 43 TC 16 Z9 16 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2478 J9 IMMUNOL LETT JI Immunol. Lett. PD FEB PY 2013 VL 150 IS 1-2 BP 41 EP 47 DI 10.1016/j.imlet.2012.12.002 PG 7 WC Immunology SC Immunology GA 122JW UT WOS:000317315400005 PM 23246474 ER PT J AU Olivera, A Dillahunt, SE Rivera, J AF Olivera, Ana Dillahunt, Sandra E. Rivera, Juan TI Interrogation of sphingosine-1-phosphate receptor 2 function in vivo reveals a prominent role in the recovery from IgE and IgG-mediated anaphylaxis with minimal effect on its onset SO IMMUNOLOGY LETTERS LA English DT Article DE Sphingosine-1-phosphate; S1PR(2); Mast cell degranulation; Anaphylaxis; IgE; IgG ID FC-EPSILON-RI; MAST-CELL ACTIVATION; SYSTEMIC-ANAPHYLAXIS; SPHINGOSINE KINASE-1; FYN KINASE; ANTIBODY; MOUSE; GAMMA; DEGRANULATION; INFLAMMATION AB Autocrine stimulation of S1PR(2), a receptor for the lipid mediator sphingosine-1-phosphate (S1P), has been implicated in mast cell degranulation to IgE/antigen (Ag) although, paradoxically, its ligand cannot trigger substantial degranulation. Additionally, the in vivo role of S1PR(2) in the overall allergic responses is unclear since S1PR(2) was reported to be required for the onset of systemic anaphylaxis by IgE/Ag but, in apparent contradiction, also for the recovery from histamine-induced anaphylaxis in a mast cell independent manner. Here, we sought to clarify the role of S1PR(2) in mast cell degranulation and in IgE and IgG-mediated anaphylaxis. Lack of S1PR(2) reduced IgE/Ag-induced degranulation in in vitro experiments with mucosal mast cells, but had no effect on connective tissue type mast cells. This latter response correlated with a lack of involvement of S1PR(2) in the onset of non-lethal IgE/Ag-mediated systemic and cutaneous anaphylaxis. However, S1pr2(-/-) mice were slow to recover (or did not recover) from Fc epsilon RI-mediated anaphylaxis, an outcome that mirrored their known impairment in histamine clearance due to defective vascular tone. A minor role for S1PR(2) in mast cell degranulation was uncovered upon engagement of low affinity receptors for IgG and in the onset of IgG-mediated anaphylaxis. Our findings show that S1PR(2) is dispensable for initiating IgE/Ag-mediated connective tissue mast cell degranulation and anaphylaxis, but it is required for normal recovery from anaphylaxis. Published by Elsevier B.V. C1 [Olivera, Ana; Dillahunt, Sandra E.; Rivera, Juan] NIAMSD, Immunogenet Mol Lab, NIH, Bethesda, MD 20892 USA. RP Olivera, A (reprint author), NIAMS, NIH, Bldg 10,Room 13C103, Bethesda, MD 20892 USA. EM oliveraa@ep.niams.nih.gov; juan_rivera@nih.gov FU Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health (NIH) [AR041101-19, AR041155-06] FX This research was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health (NIH) (Grant numbers AR041101-19; AR041155-06). We gratefully acknowledge the contributions of the Office of Science and Technology (Flow Cytometry and Laboratory Animal Care and Use Sections), NIAMS. NR 48 TC 10 Z9 10 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2478 J9 IMMUNOL LETT JI Immunol. Lett. PD FEB PY 2013 VL 150 IS 1-2 BP 89 EP 96 DI 10.1016/j.imlet.2013.01.005 PG 8 WC Immunology SC Immunology GA 122JW UT WOS:000317315400013 PM 23337656 ER PT J AU Zou, W Izawa, T Zhu, TT Chappel, J Otero, K Monkley, SJ Critchley, DR Petrich, BG Morozov, A Ginsberg, MH Teitelbaum, SL AF Zou, Wei Izawa, Takashi Zhu, Tingting Chappel, Jean Otero, Karel Monkley, Susan J. Critchley, David R. Petrich, Brian G. Morozov, Alexei Ginsberg, Mark H. Teitelbaum, Steven L. TI Talin1 and Rap1 Are Critical for Osteoclast Function SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID INTEGRIN ACTIVATION; C-FMS; ALPHA-V-BETA-3 INTEGRIN; BONE-RESORPTION; BETA-3 INTEGRIN; CYTOSKELETON; SYK; DIFFERENTIATION; RECRUITMENT; PRECURSORS AB To determine talin1's role in osteoclasts, we mated TLN1(beta/beta) mice with those expressing cathepsin K-Cre (CtsK-TLN1) to delete the gene in mature osteoclasts or with lysozyme M-Cre (LysM-TLN1) mice to delete TLN1 in all osteoclast lineage cells. Absence of TLN1 impairs macrophage colony-stimulating factor (M-CSF)-stimulated inside-out integrin activation and cytoskeleton organization in mature osteoclasts. Talin1-deficient precursors normally express osteoclast differentiation markers when exposed to M-CSF and receptor activator of nuclear factor kappa B (RANK) ligand but attach to substrate and migrate poorly, arresting their development into mature resorptive cells. In keeping with inhibited resorption, CtsK-TLN1 mice exhibit an similar to 5-fold increase in bone mass. Osteoclast-specific deletion of Rap1 (CtsK-Rap1), which promotes talin/beta integrin recognition, yields similar osteopetrotic mice. The fact that the osteopetrosis of CtsK-TLN1 and CtsK-Rap1 mice is substantially more severe than that of those lacking alpha v beta 3 is likely due to added failed activation of beta 1 integrins. In keeping with osteoclast dysfunction, mice in whom talin is deleted late in the course of osteoclastogenesis are substantially protected from ovariectomy-induced osteoporosis and the periarticular osteolysis attending inflammatory arthritis. Thus, talin1 and Rap1 are critical for resorptive function, and their selective inhibition in mature osteoclasts retards pathological bone loss. C1 [Zou, Wei; Izawa, Takashi; Zhu, Tingting; Chappel, Jean; Otero, Karel; Teitelbaum, Steven L.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63130 USA. [Teitelbaum, Steven L.] Washington Univ, Sch Med, Dept Med, Div Bone & Mineral Dis, St Louis, MO 63110 USA. [Monkley, Susan J.; Critchley, David R.] Univ Leicester, Dept Biochem, Leicester LE1 7RH, Leics, England. [Petrich, Brian G.; Ginsberg, Mark H.] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Morozov, Alexei] NIMH, Unit Behav Genet, Mol Pathophysiol Lab, NIH, Bethesda, MD 20892 USA. RP Teitelbaum, SL (reprint author), Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63130 USA. EM teitelbs@wustl.edu OI Teitelbaum, Steven/0000-0002-4054-6679 FU National Institutes of Health [AR032788, AR046523, AR054618, AR057037, AR057235, AR027214] FX This work was supported by National Institutes of Health grants AR032788, AR046523, AR054618, AR057037, and AR057235 (S.L.T.) and AR027214 (M.H.G.). NR 38 TC 22 Z9 24 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2013 VL 33 IS 4 BP 830 EP 844 DI 10.1128/MCB.00790-12 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 121TK UT WOS:000317267000015 PM 23230271 ER PT J AU Sengupta, P Jovanovic-Talisman, T Lippincott-Schwartz, J AF Sengupta, Prabuddha Jovanovic-Talisman, Tijana Lippincott-Schwartz, Jennifer TI Quantifying spatial organization in point-localization superresolution images using pair correlation analysis SO NATURE PROTOCOLS LA English DT Article ID OPTICAL RECONSTRUCTION MICROSCOPY; SINGLE-MOLECULE LOCALIZATION; HIGH-DENSITY LOCALIZATION; FLUORESCENT-PROBES; PROTEIN HETEROGENEITY; RESOLUTION; PALM; DYNAMICS AB he distinctive distributions of proteins within subcellular compartments both at steady state and during signaling events have essential roles in cell function. Here we describe a method for delineating the complex arrangement of proteins within subcellular structures visualized using point-localization superresolution (PL-SR) imaging. The approach, called pair correlation photoactivated localization microscopy (PC-PALM), uses a pair-correlation algorithm to precisely identify single molecules in PL-SR imaging data sets, and it is used to decipher quantitative features of protein organization within subcellular compartments, including the existence of protein clusters and the size, density and number of proteins in these clusters. We provide a step-by-step protocol for PC-PALM, illustrating its analysis capability for four plasma membrane proteins tagged with photoactivatable GFP (PAGFP). The experimental steps for PC-PALM can be carried out in 3 d and the analysis can be done in similar to 6-8 h. Researchers need to have substantial experience in single-molecule imaging and statistical analysis to conduct the experiments and carry out this analysis. C1 [Sengupta, Prabuddha; Jovanovic-Talisman, Tijana; Lippincott-Schwartz, Jennifer] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Lippincott-Schwartz, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. EM jlippin@helix.nih.gov OI Sengupta, Prabuddha/0000-0001-7094-6967; Jovanovic-Talisman, Tijana/0000-0003-1928-4763 FU Intramural NIH HHS [Z99 HD999999] NR 40 TC 40 Z9 40 U1 6 U2 50 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1754-2189 J9 NAT PROTOC JI Nat. Protoc. PD FEB PY 2013 VL 8 IS 2 BP 345 EP 354 DI 10.1038/nprot.2013.005 PG 10 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 119PN UT WOS:000317109900008 PM 23348362 ER PT J AU Reis, JP Loria, CM Launer, LJ Sidney, S Liu, K Jacobs, DR Zhu, N Lloyd-Jones, DM He, K Yaffe, K AF Reis, Jared P. Loria, Catherine M. Launer, Lenore J. Sidney, Stephen Liu, Kiang Jacobs, David R., Jr. Zhu, Na Lloyd-Jones, Donald M. He, Ka Yaffe, Kristine TI Cardiovascular health through young adulthood and cognitive functioning in midlife SO ANNALS OF NEUROLOGY LA English DT Article ID RISK-FACTORS; METABOLIC SYNDROME; INCIDENT DEMENTIA; BLOOD-PRESSURE; US ADULTS; IMPAIRMENT; LIFE; DECLINE; CARDIA; ASSOCIATION AB Objective A study was undertaken to examine the association between overall cardiovascular health as recently defined by the American Heart Association in young adulthood to middle age and cognitive function in midlife. Overall ideal cardiovascular health incorporates 7 metrics, including the avoidance of overweight or obesity, a healthful diet, nonsmoking, and physical activity, total cholesterol, blood pressure, and fasting glucose at goal levels. Methods This analysis of the Coronary Artery Risk Development in Young Adults study, a multicenter community-based study with 25 years of follow-up, included 2,932 participants aged 18 to 30 years at baseline (year 0) who attended follow-up examinations at years 7 and 25. Cardiovascular health metrics were measured at each examination. The Digit Symbol Substitution Test (DSST), modified Stroop test, and Rey Auditory Verbal Learning Test (RAVLT) were completed at year 25. Results A greater number of ideal cardiovascular metrics in young adulthood and middle age were independently associated with better cognitive function in midlife (p for trend < 0.01, for all). Specifically, each additional ideal metric was associated with 1.32 more symbols on the DSST (95% confidence interval [CI] = 0.93 1.71), a 0.77-point lower interference score on the Stroop test (95% CI=1.03 to 0.45), and 0.12 more words on the RAVLT (95% CI = 0.04 to 0.20). Participants who had 5 ideal metrics at a greater number of the 3 examinations over the 25-year period exhibited better performance on each cognitive test in middle age (p for trend < 0.01, for all). Interpretation Ideal cardiovascular health in young adulthood and its maintenance to middle age is associated with better psychomotor speed, executive function, and verbal memory in midlife. ANN NEUROL 2013;73:170179 C1 [Reis, Jared P.; Loria, Catherine M.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Sidney, Stephen] Kaiser Permanente Northern Calif, Div Res, Oakland, CA USA. [Liu, Kiang; Lloyd-Jones, Donald M.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Jacobs, David R., Jr.; Zhu, Na] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Jacobs, David R., Jr.] Univ Oslo, Dept Nutr, Oslo, Norway. [He, Ka] Univ N Carolina, Dept Nutr, Chapel Hill, NC USA. [He, Ka] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. [Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA USA. RP Reis, JP (reprint author), NHLBI, Div Cardiovasc Sci, 6701 Rockledge Dr,Suite 10197, Bethesda, MD 20892 USA. EM reisjp@mail.nih.gov FU National Heart, Lung, and Blood Institute; University of Alabama at Birmingham [N01-HC95095, N01-HC48047]; Kaiser Foundation Research Institute [N01-HC48050]; Northwestern University [N01-HC48049]; University of Minnesota [N01-HC48048] FX CARDIA is conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with the University of Alabama at Birmingham (N01-HC95095, N01-HC48047), Kaiser Foundation Research Institute (N01-HC48050), Northwestern University (N01-HC48049), and University of Minnesota (N01-HC48048). NR 38 TC 40 Z9 41 U1 0 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD FEB PY 2013 VL 73 IS 2 BP 170 EP 179 DI 10.1002/ana.23836 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 113UA UT WOS:000316693200006 PM 23443990 ER PT J AU Fitzgerald, KC O'Reilly, EJ Fondell, E Falcone, GJ McCullough, ML Park, Y Kolonel, LN Ascherio, A AF Fitzgerald, Kathryn C. O'Reilly, Eilis J. Fondell, Elinor Falcone, Guido J. McCullough, Marjorie L. Park, Yikyung Kolonel, Laurence N. Ascherio, Alberto TI Intakes of vitamin C and carotenoids and risk of amyotrophic lateral sclerosis: Pooled results from 5 cohort studies SO ANNALS OF NEUROLOGY LA English DT Article ID FOOD-FREQUENCY QUESTIONNAIRE; HEALTH-AMERICAN-ASSOCIATION; SOCIETY CANCER PREVENTION; BASE-LINE CHARACTERISTICS; RETIRED-PERSONS DIET; MOTOR-NEURON DISEASE; NATIONAL-INSTITUTES; OXIDATIVE STRESS; SURVIVAL; WOMEN AB Objective Prior research has suggested the possible role of oxidative stress in the pathogenesis of amyotrophic lateral sclerosis (ALS). Prospective data examining dietary antioxidants such carotenoids and vitamin C are limited. Methods Risk of ALS associated with carotenoid and vitamin C intake was investigated in 5 prospective cohorts: the National Institutes of HealthAssociation of American Retired Persons Diet and Health Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort, the Health Professionals Follow-up Study (HPFS), and the Nurses Health Study (NHS). ALS deaths were documented using the National Death Index, and confirmed nonfatal ALS cases were included from HPFS and NHS. A total of 1,153 ALS deaths occurred among 1,100,910 participants (562,942 men; 537,968 women). Participants were categorized into cohort-specific quintiles of intake for dietary variables. We applied Cox proportional hazards regression to calculate cohort-specific risk ratios (RRs), and pooled results using random-effects methods. Results A greater total major carotenoids intake was associated with a reduced risk of ALS (pooled, multivariate-adjusted RR for the highest to the lowest quintile = 0.75, 95% confidence interval [CI] = 0.610.91, p for trend = 0.004). Individually, higher dietary intakes of -carotene and lutein were inversely associated with ALS risk. The pooled multivariate RRs comparing the highest to the lowest quintile for -carotene and lutein were 0.85 (95% CI = 0.641.13, p for trend = 0.03) and 0.79 (95% CI = 0.640.96, p for trend = 0.01), respectively. Lycopene, -cryptoxanthin, and vitamin C were not associated with reduced risk of ALS. Interpretation Consumption of foods high in carotenoids may help prevent or delay onset of ALS. ANN NEUROL 2013;73:236245 C1 [Fitzgerald, Kathryn C.; O'Reilly, Eilis J.; Fondell, Elinor; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [O'Reilly, Eilis J.; Ascherio, Alberto] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [O'Reilly, Eilis J.; Ascherio, Alberto] Harvard Univ, Sch Med, Boston, MA USA. [Falcone, Guido J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Falcone, Guido J.; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [McCullough, Marjorie L.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Park, Yikyung] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Kolonel, Laurence N.] Univ Hawaii, Program Epidemiol, Ctr Canc, Honolulu, HI 96822 USA. RP Fitzgerald, KC (reprint author), 665 Huntington Ave, Boston, MA 02115 USA. EM hpkcf@channing.harvard.edu RI Falcone, Guido/L-2287-2016; OI Falcone, Guido/0000-0002-6407-0302; Park, Yikyung/0000-0002-6281-489X FU NIH/National Institute of Neurological Diseases and Stroke [R01 NS045893]; NIH/NCI [R37 CA54281]; neurological diseases and stroke (NIH) [P01 CA87969]; NIH [P01 CA055075]; Blanceflor Foundation (Stockholm, Sweden); Michael J Fox Foundation; Accelerated Cure Project; F. Hoffmann-La Roche; Merck Serono FX This work was supported by grant R01 NS045893 from the NIH/National Institute of Neurological Diseases and Stroke. The multiethnic cohort study was supported by NIH/NCI R37 CA54281. Nurses Health Study is funded by neurological diseases and stroke (NIH) program project P01 CA87969 and Health Professional Follow-up Study by NIH program project P01 CA055075. E.F. received a postdoctoral scholarship from the Blanceflor Foundation (Stockholm, Sweden).; K.C.F.: grants/grants pending, NIH. E.J.O.: grants/grants pending, NIH. A.A.: grants/grants pending, National Institutes of Health, Michael J Fox Foundation, Accelerated Cure Project; speaking fees, F. Hoffmann-La Roche, Merck Serono. NR 39 TC 19 Z9 21 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD FEB PY 2013 VL 73 IS 2 BP 236 EP 245 DI 10.1002/ana.23820 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 113UA UT WOS:000316693200012 PM 23362045 ER PT J AU Donsante, A Sullivan, P Goldstein, DS Brinster, LR Kaler, SG AF Donsante, Anthony Sullivan, Patricia Goldstein, David S. Brinster, Lauren R. Kaler, Stephen G. TI L-Threo-Dihydroxyphenylserine corrects neurochemical abnormalities in a menkes disease mouse model SO ANNALS OF NEUROLOGY LA English DT Article ID DOPAMINE-BETA-HYDROXYLASE; COPPER TRANSPORT; NEONATAL DIAGNOSIS; METABOLIC STRESS; ATP7A MUTATION; PC12 CELLS; 3,4-DIHYDROXYPHENYLACETALDEHYDE; NORADRENALINE; DEFICIENCY; 3,4-DIHYDROXYPHENYLGLYCOLALDEHYDE AB Objective Menkes disease is a lethal neurodegenerative disorder of infancy caused by mutations in a copper-transporting adenosine triphosphatase gene, ATP7A. Among its multiple cellular tasks, ATP7A transfers copper to dopamine beta hydroxylase (DBH) within the lumen of the Golgi network or secretory granules, catalyzing the conversion of dopamine to norepinephrine. In a well-established mouse model of Menkes disease, mottled-brindled (mo-br), we tested whether systemic administration of L-threo-dihydroxyphenylserine (L-DOPS), a drug used successfully to treat autosomal recessive norepinephrine deficiency, would improve brain neurochemical abnormalities and neuropathology. Methods At 8, 10, and 12 days of age, wild-type and mo-br mice received intraperitoneal injections of 200g/g body weight of L-DOPS, or mock solution. Five hours after the final injection, the mice were euthanized, and brains were removed. We measured catecholamine metabolites affected by DBH via high-performance liquid chromatography with electrochemical detection, and assessed brain histopathology. Results Compared to mock-treated controls, mo-br mice that received intraperitoneal L-DOPS showed significant increases in brain norepinephrine (p < 0.001) and its deaminated metabolite, dihydroxyphenylglycol (p < 0.05). The ratio of a nonbeta-hydroxylated metabolite in the catecholamine biosynthetic pathway, dihydroxyphenylacetic acid, to the beta-hydroxylated metabolite, dihydroxyphenylglycol, improved equivalently to results obtained previously with brain-directed ATP7A gene therapy (p < 0.01). However, L-DOPS treatment did not arrest global brain pathology or improve somatic growth, as gene therapy had. Interpretation We conclude that (1) L-DOPS crosses the bloodbrain barrier in mo-br mice and corrects brain neurochemical abnormalities, (2) norepinephrine deficiency is not the cause of neurodegeneration in mo-br mice, and (3) L-DOPS treatment may ameliorate noradrenergic hypofunction in Menkes disease. ANN NEUROL 2013;73:259265 C1 [Donsante, Anthony; Kaler, Stephen G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Human Copper Metab, Program Mol Med, Rockville, MD USA. [Sullivan, Patricia; Goldstein, David S.] NINDS, Clin Neurocardiol Sect, Bethesda, MD 20892 USA. [Brinster, Lauren R.] NIH, Div Vet Resources, Off Res Serv, Bethesda, MD 20892 USA. RP Kaler, SG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Mol Med, NIH, Bldg 10,Room 10N313,10 Ctr Dr MSC 1853, Bethesda, MD 20892 USA. EM kalers@mail.nih.gov FU National Institute of Child Health and Human Development; National Institute of Neurological Disorders and Stroke FX This work was supported by the intramural research programs of the National Institute of Child Health and Human Development and National Institute of Neurological Disorders and Stroke. NR 27 TC 8 Z9 8 U1 2 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD FEB PY 2013 VL 73 IS 2 BP 259 EP 265 DI 10.1002/ana.23787 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 113UA UT WOS:000316693200014 PM 23224983 ER PT J AU Bonucci, A Balducci, E Pistolesi, S Pogni, R AF Bonucci, Alessio Balducci, Enrico Pistolesi, Sara Pogni, Rebecca TI The defensin-lipid interaction: Insights on the binding states of the human antimicrobial peptide HNP-1 to model bacterial membranes SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES LA English DT Article DE HNP-1; Antimicrobial peptide; Bacterial model membrane; Bilayer interaction; Spectroscopic analysis; Partition coefficient ID PORE FORMATION; TRYPTOPHAN FLUORESCENCE; COMBINATORIAL DESIGN; INTERFACIAL ACTIVITY; MECHANISM; PHOSPHOLIPIDS; ANTIBIOTICS; INSERTION; MODULATE; BILAYERS AB Antimicrobial peptides are an important component of innate immunity and have generated considerable interest as a new potential class of natural antibiotics. The biological activity of antimicrobial peptides is strongly influenced by peptide membrane interactions. Human Neutrophil Peptide 1 (HNP-1) is a 30 aminoacid peptide, belonging to the class of alpha-defensins. Many biophysical studies have been performed on this peptide to define its mechanism of action. Combining spectroscopic and thermodynamic analysis, insights on the interaction of the alpha-defensin with POPE:POPG:CL negative charged bilayers are given. The binding states of the peptide below and above the threshold concentration have been analyzed showing that the interaction with lipid bilayers is dependent by peptide concentration. These novel results that indicate how affinity and biological activities of natural antibiotics are depending by their concentration, might open new way of investigation of the antimicrobial mode of action. (C) 2012 Elsevier B.V. All rights reserved. C1 [Bonucci, Alessio; Pogni, Rebecca] Univ Siena, Dept Chem, I-53100 Siena, Italy. [Balducci, Enrico] Univ Camerino, Sch Biosci & Biotechnol, I-62032 Camerino, Italy. [Pistolesi, Sara] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Pogni, R (reprint author), Univ Siena, Dept Chem, Via A de Gasperi 2, I-53100 Siena, Italy. EM rebecca.pogni@unisi.it NR 49 TC 9 Z9 9 U1 1 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2736 J9 BBA-BIOMEMBRANES JI Biochim. Biophys. Acta-Biomembr. PD FEB PY 2013 VL 1828 IS 2 BP 758 EP 764 DI 10.1016/j.bbamem.2012.11.011 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 090UD UT WOS:000315004600065 PM 23159481 ER PT J AU Mathe, D Horvath, I Szigeti, K Donohue, SR Pike, VW Jia, ZS Ledent, C Palkovits, M Freund, TF Halldin, C Gulyas, B AF Mathe, Domokos Horvath, Ildiko Szigeti, Krisztian Donohue, Sean R. Pike, Victor W. Jia, Zisheng Ledent, Catherine Palkovits, Miklos Freund, Tamas F. Halldin, Christer Gulyas, Balazs TI In vivo SPECT and ex vivo autoradiographic brain imaging of the novel selective CB1 receptor antagonist radioligand [I-125]SD7015 in CB1 knock-out and wildtype mouse SO BRAIN RESEARCH BULLETIN LA English DT Article DE Endocannabinoid CB1 receptor (CB1R); Single photon emission computed tomography (SPECT); Molecular imaging biomarker; [I-125]SD7015; Knock-out CB1R-/- mouse; Multiplexed multipinhole dedicated small animal SPECT/CT system ID POSITRON-EMISSION-TOMOGRAPHY; SITU HYBRIDIZATION HISTOCHEMISTRY; TYPE-1 CANNABINOID RECEPTOR; MESSENGER-RNA EXPRESSION; RAT-BRAIN; PARKINSONS-DISEASE; ENDOCANNABINOID SYSTEM; NERVOUS-SYSTEM; ENDOGENOUS CANNABINOIDS; COMPUTED-TOMOGRAPHY AB We aimed to evaluate the novel high-affinity and relatively lipophilic CB1 receptor (CB1R) antagonist radioligand [I-125]SD7015 for SPECT imaging of CB(1)Rs in vivo using the multiplexed multipinhole dedicated small animal SPECT/CT system, NanoSPECT/CTPLUS (Mediso, Budapest, Hungary), in knock-out CB1 receptor knock-out (CB1R-/-) and wildtype mice. In order to exclude possible differences in cerebral blood flow between the two types of animals, HMPAO SPECT scans were performed, whereas in order to confirm the brain uptake differences of the radioligand between knock-out mice and wildtype mice, in vivo scans were complemented with ex vivo autoradiographic measurements using the brains of the same animals. With SPECT/CT imaging, we measured the brain uptake of radioactivity, using %SUV (% standardised uptake values) in CB1R-/- mice (n = 3) and C57BL6 wildtype mice (n = 7) under urethane anaesthesia after injecting [I-125]SD7015 intravenously or intraperitoneally. The Brookhaven Laboratory mouse MRI atlas was fused to the SPECT/CT images by using a combination of rigid and non-rigid algorithms in the Mediso FuSiori (TM) (Mediso, Budapest, Hungary) and VivoQuant (inviCRO, Boston, MA, USA) softwares. Phosphor imager plate autoradiography (ARG) was performed on 4 mu m-thin cryostat sections of the excised brains. %SUV was 8.6 +/- 3.6 (average +/- SD) in (CBR)-R-1-/- mice and 22.1 +/- 12.4 in wildtype mice between 2 and 4 h after injection (p < 0.05). ARG of identically taken sections from wildtype mouse brain showed moderate radioactivity uptake when compared with the in vivo images, with a clear difference between grey matter and white matter, whereas ARG in CB1R(-/-) mice showed practically no radioactivity uptake. [I-125]SD7015 enters the mouse brain in sufficient amount to enable SPECT imaging. Brain radioactivity distribution largely coincides with that of the known CB1R expression pattern in rodent brain. We conclude that [I-125]SD7015 should be a useful SPECT radioligand for studying brain CB1R in mouse and rat disease models. (C) 2013 Elsevier Inc. All rights reserved. C1 [Mathe, Domokos; Horvath, Ildiko; Szigeti, Krisztian] Semmelweis Univ, Dept Biophys & Radiat Biol, H-1094 Budapest, Hungary. [Mathe, Domokos; Szigeti, Krisztian] CROmed Translat Res Ctr, H-1047 Budapest, Hungary. [Donohue, Sean R.; Pike, Victor W.] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. [Jia, Zisheng; Halldin, Christer; Gulyas, Balazs] Karolinska Inst, Dept Clin Neurosci, Psychiat Sect, S-17176 Stockholm, Sweden. [Ledent, Catherine] Univ Libre Brussels, IRIBHM, B-1070 Brussels, Belgium. [Palkovits, Miklos] Semmelweis Univ, Dept Anat, Neuromorphol Lab, H-1094 Budapest, Hungary. [Freund, Tamas F.] Hungarian Acad Sci, Inst Expt Med, H-1083 Budapest, Hungary. RP Gulyas, B (reprint author), Karolinska Inst, Dept Clin Neurosci, Psychiat Sect, S-17176 Stockholm, Sweden. EM balazs.gulyas@ki.se RI Palkovits, Miklos/F-2707-2013; Gulyas, Balazs/F-9508-2015; OI Palkovits, Miklos/0000-0003-0578-0387 FU EU FP7 INMIND Project (Imaging of Neuroinflammation in Neurodegenerative Diseases) FX The study was performed partly within a collaborative master research agreement between Karolinska Institutet, Mediso Medical Imaging Systems and CROmed Translational. This study was partially supported by the EU FP7 INMIND Project (Imaging of Neuroinflammation in Neurodegenerative Diseases). NR 60 TC 0 Z9 0 U1 0 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0361-9230 J9 BRAIN RES BULL JI Brain Res. Bull. PD FEB PY 2013 VL 91 BP 46 EP 51 DI 10.1016/j.brainresbull.2013.01.001 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 115UA UT WOS:000316836200007 PM 23318272 ER PT J AU Yang, MJ Li, XL Turkbey, B Choyke, PL Yan, PK AF Yang, Meijuan Li, Xuelong Turkbey, Baris Choyke, Peter L. Yan, Pingkun TI Prostate Segmentation in MR Images Using Discriminant Boundary Features SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article DE Discriminant analysis; image feature; prostate segmentation; statistical shape model (SSM) ID ACTIVE SHAPE MODEL; CT IMAGES; APPEARANCE AB Segmentation of the prostate in magnetic resonance image has become more in need for its assistance to diagnosis and surgical planning of prostate carcinoma. Due to the natural variability of anatomical structures, statistical shape model has been widely applied in medical image segmentation. Robust and distinctive local features are critical for statistical shape model to achieve accurate segmentation results. The scale invariant feature transformation (SIFT) has been employed to capture the information of the local patch surrounding the boundary. However, when SIFT feature being used for segmentation, the scale and variance are not specified with the location of the point of interest. To deal with it, the discriminant analysis in machine learning is introduced to measure the distinctiveness of the learned SIFT features for each landmark directly and to make the scale and variance adaptive to the locations. As the gray values and gradients vary significantly over the boundary of the prostate, separate appearance descriptors are built for each landmark and then optimized. After that, a two stage coarse-to-fine segmentation approach is carried out by incorporating the local shape variations. Finally, the experiments on prostate segmentation from MR image are conducted to verify the efficiency of the proposed algorithms. C1 [Yang, Meijuan; Li, Xuelong; Yan, Pingkun] Chinese Acad Sci, Ctr OPT IMagery Anal & Learning, State Key Lab Transient Opt & Photon, Xian Inst Opt & Precis Mech, Xian 710119, Shaanxi, Peoples R China. [Turkbey, Baris; Choyke, Peter L.] NCI, NIH, Bethesda, MD 20892 USA. RP Yan, PK (reprint author), Chinese Acad Sci, Ctr OPT IMagery Anal & Learning, State Key Lab Transient Opt & Photon, Xian Inst Opt & Precis Mech, Xian 710119, Shaanxi, Peoples R China. EM meijuan.yang@opt.ac.cn; xuelong-li@opt.ac.cn; turkbeyi@mail.nih.gov; pchoyke@mail.nih.gov; pingkun@ieee.org FU National Basic Research Program of China (973 Program) [2012CB719905]; National Natural Science Foundation of China [61105012, 61172142]; Open Project Program of the State Key Lab of CAD&CG, Zhejiang University [A1116] FX This work was supported in part by the National Basic Research Program of China (973 Program) under Grant 2012CB719905, the National Natural Science Foundation of China under Grant 61105012 and Grant 61172142, and the Open Project Program of the State Key Lab of CAD&CG under Grant A1116, Zhejiang University. Asterisk indicates corresponding author. NR 21 TC 9 Z9 9 U1 0 U2 9 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9294 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD FEB PY 2013 VL 60 IS 2 BP 479 EP 488 DI 10.1109/TBME.2012.2228644 PG 10 WC Engineering, Biomedical SC Engineering GA 115KA UT WOS:000316809800024 PM 23192474 ER PT J AU Morens, DM AF Morens, David M. TI Commentary: Cholera conundrums and proto-epidemiologic puzzles. The confusing epidemic world of John Lea and John Snow SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material C1 NIAID, Off Director, NIH, Bethesda, MD 20892 USA. RP Morens, DM (reprint author), NIAID, Off Director, NIH, Bldg 31,Room 7A-03,31 Ctr Dr, Bethesda, MD 20892 USA. EM dm270q@nih.gov NR 64 TC 2 Z9 2 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD FEB PY 2013 VL 42 IS 1 BP 43 EP 52 DI 10.1093/ije/dyt016 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 113WE UT WOS:000316699300004 PM 23508406 ER PT J AU Shi, M Umbach, DM Weinberg, CR AF Shi, Min Umbach, David M. Weinberg, Clarice R. TI Case-sibling studies that acknowledge unstudied parents and permit the inclusion of unmatched individuals SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Genetic association; case-sibling; missing parents; expectation-maximization algorithm; conditional logistic regression ID GENE-ENVIRONMENT INTERACTION; MISSING GENOTYPE DATA; FAMILY-BASED TESTS; LINKAGE DISEQUILIBRIUM; ASSOCIATION ANALYSIS; UNRELATED SUBJECTS; INCOMPLETE DATA; TRIADS; POWER; LIKELIHOOD AB Background Family-based designs enable assessment of genetic associations without bias from population stratification. When parents are not readily available - especially for diseases with onset later in life - the case-sibling design, where each case is matched with one or more unaffected siblings, is useful. Analysis typically accounts for within-family dependencies by using conditional logistic regression (CLR). Methods We consider an alternative to CLR that treats each case-sibling set as a nuclear family with both parents missing by design. One can carry out maximum likelihood analysis by using the Expectation-Maximization (EM) algorithm to account for missing parental genotypes. We compare conditional logistic regression and the missing-parents approach under several risk scenarios. Results We show that the missing-parents approach improves power when some families have more than one unaffected sibling and that under weak assumptions the approach permits the incorporation of supplemental cases who have no sibling available and supplemental controls whose case sibling is unavailable (e.g., due to disability or death). Conclusion The missing-parents approach offers both improved statistical efficiency and asymptotically unbiased estimation for genotype relative risks and genotype-by-exposure interaction parameters. C1 [Shi, Min; Umbach, David M.; Weinberg, Clarice R.] NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC USA. RP Shi, M (reprint author), NIEHS, Biostat Branch, A3-03 101-A352, Res Triangle Pk, NC 27709 USA. EM shi2@niehs.nih.gov FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES040007, Z01 ES045002] FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences, under project numbers Z01 ES040007 and Z01 ES045002. NR 31 TC 2 Z9 2 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD FEB PY 2013 VL 42 IS 1 BP 298 EP 307 DI 10.1093/ije/dys212 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 113WE UT WOS:000316699300037 PM 23248214 ER PT J AU De Matteis, S Consonni, D Lubin, JH Tucker, M Peters, S Vermeulen, RCH Kromhout, H Bertazzi, PA Caporaso, NE Pesatori, AC Wacholder, S Landi, MT AF De Matteis, Sara Consonni, Dario Lubin, Jay H. Tucker, Margaret Peters, Susan Vermeulen, Roel C. H. Kromhout, Hans Bertazzi, Pier Alberto Caporaso, Neil E. Pesatori, Angela C. Wacholder, Sholom Landi, Maria Teresa TI Authors' response to: Qualitative job-exposure matrix-a tool for the quantification of population-attributable fractions for occupational lung carcinogens? SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Letter ID CANCER RISK; EXPERT C1 [De Matteis, Sara; Consonni, Dario; Bertazzi, Pier Alberto; Pesatori, Angela C.] Fdn IRCCS Ca Granda Osped Maggiore Policlin, Epidemiol Unit, Dept Prevent Med, Milan, Italy. [De Matteis, Sara; Consonni, Dario; Bertazzi, Pier Alberto; Pesatori, Angela C.] Univ Milan, Dept Clin Sci & Community Hlth, Milan, Italy. [De Matteis, Sara; Lubin, Jay H.; Tucker, Margaret; Caporaso, Neil E.; Wacholder, Sholom; Landi, Maria Teresa] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Peters, Susan; Vermeulen, Roel C. H.; Kromhout, Hans] Univ Utrecht, Inst Risk Assessment Sci, Environm Epidemiol Div, Utrecht, Netherlands. [Peters, Susan] Univ Western Australia, Western Australian Inst Med Res, Nedlands, WA 6009, Australia. RP Landi, MT (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM landim@mail.nih.gov RI Peters, Susan/A-5845-2013; Tucker, Margaret/B-4297-2015; Consonni, Dario/K-7943-2016; Vermeulen, Roel/F-8037-2011; bertazzi, pietro alberto/D-5039-2017; OI Consonni, Dario/0000-0002-8935-3843; Vermeulen, Roel/0000-0003-4082-8163; bertazzi, pietro alberto/0000-0003-3475-2449; Peters, Susan/0000-0001-5662-1971; pesatori, angela/0000-0002-0261-3252 NR 14 TC 0 Z9 0 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD FEB PY 2013 VL 42 IS 1 BP 357 EP 358 DI 10.1093/ije/dys193 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 113WE UT WOS:000316699300044 PM 23266616 ER PT J AU Yeung, EH Zhang, C Albert, PS Mumford, SL Ye, A Perkins, NJ Wactawski-Wende, J Schisterman, EF AF Yeung, E. H. Zhang, C. Albert, P. S. Mumford, S. L. Ye, A. Perkins, N. J. Wactawski-Wende, J. Schisterman, E. F. TI Adiposity and sex hormones across the menstrual cycle: the BioCycle Study SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE adiposity; body mass index; body composition; sex hormones; menstrual cycle; estradiol ID EARLY MENOPAUSAL TRANSITION; PREMENOPAUSAL WOMEN; BODY-SIZE; REPRODUCTIVE HORMONES; OBESE WOMEN; WEIGHT; GONADOTROPIN; ETHNICITY; LEPTIN; FAT AB OBJECTIVE: To investigate the influence of adiposity on patterns of sex hormones across the menstrual cycle among regularly menstruating women. SUBJECTS: The BioCycle Study followed 239 healthy women for 1-2 menstrual cycles, with up to eight visits per cycle timed using fertility monitors. METHODS: Serum estradiol (E2), progesterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and sex hormone-binding globulin (SHBG) were measured at each visit. Adiposity was measured by anthropometry and by dual energy X-ray absorptiometry (DXA). Differences in hormonal patterns by adiposity measures were estimated using nonlinear mixed models, which allow for comparisons in overall mean levels, amplitude (i.e., lowest to highest level within each cycle) and shifts in timing of peaks while adjusting for age, race, energy intake and physical activity. RESULTS: Compared with normal weight women (n = 154), obese women (body mass index (BMI) >= 30 kgm(-2), n = 25) averaged lower levels of progesterone (-15%, P = 0.003), LH (-17%, P = 0.01), FSH (-23%, P = 0.001) and higher free E2 (+22%, P = 0.0001) across the cycle. To lesser magnitudes, overweight women (BMI: 25-30, n = 60) also exhibited differences in the same directions for mean levels of free E2, FSH and LH. Obese women experienced greater changes in amplitude of LH (9%, P = 0.002) and FSH (8%, P = 0.004), but no differences were observed among overweight women. Higher central adiposity by top compared to bottom tertile of trunk-to-leg fat ratio by DXA was associated with lower total E2 (-14%, P = 0.005), and FSH (-15%, P = 0.001). Peaks in FSH and LH occurred later (similar to 0.5 day) in the cycle among women with greater central adiposity. CONCLUSION: Greater total and central adiposity were associated with changes in mean hormone levels. The greater amplitudes observed among obese women suggest compensatory mechanisms at work to maintain hormonal homeostasis. Central adiposity may be more important in influencing timing of hormonal peaks than total adiposity. International Journal of Obesity (2013) 37, 237-243; doi:10.1038/ijo.2012.9; published online 7 February 2012 C1 [Yeung, E. H.; Zhang, C.; Albert, P. S.; Mumford, S. L.; Ye, A.; Perkins, N. J.; Schisterman, E. F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. [Wactawski-Wende, J.] SUNY Buffalo, Dept Biotech & Clin Lab Sci, Buffalo, NY 14260 USA. [Wactawski-Wende, J.] SUNY Buffalo, Sch Med, Dept Social & Prevent Med, Buffalo, NY 14260 USA. RP Yeung, EH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,7B03, Bethesda, MD 20892 USA. EM yeungedw@mail.nih.gov RI Yeung, Edwina/F-5992-2015; OI Yeung, Edwina/0000-0002-3851-2613; Perkins, Neil/0000-0002-6802-4733; Schisterman, Enrique/0000-0003-3757-641X FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health. We thank the BioCycle working group for comments and feedback on this work. NR 28 TC 11 Z9 12 U1 1 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD FEB PY 2013 VL 37 IS 2 BP 237 EP 243 DI 10.1038/ijo.2012.9 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 117DK UT WOS:000316932100013 PM 22310471 ER PT J AU Dorn, JD Ahuja, AK Caspi, A da Cruz, L Dagnelie, G Sahel, JA Greenberg, RJ McMahon, MJ AF Dorn, Jessy D. Ahuja, Ashish K. Caspi, Avi da Cruz, Lyndon Dagnelie, Gislin Sahel, Jose-Alain Greenberg, Robert J. McMahon, Matthew J. CA Argus II Study Grp TI The Detection of Motion by Blind Subjects With the Epiretinal 60-Electrode (Argus II) Retinal Prosthesis SO JAMA OPHTHALMOLOGY LA English DT Article ID RETINITIS-PIGMENTOSA; VISUAL PROSTHESIS; PHOTORECEPTORS; IMPLANTATION; FEASIBILITY; PERCEPTION; TRIAL AB Objective: To investigate the ability of 28 blind subjects implanted with a 60-electrode Argus II (Second Sight Medical Products Inc) retinal prosthesis system to detect the direction of a moving object. Methods: Blind subjects (bare light perception or worse in both eyes) with retinitis pigmentosa were implanted with the Argus II prosthesis as part of a phase 1/2 feasibility study at multiple clinical sites worldwide. The experiment measured their ability to detect the direction of motion of a high-contrast moving bar on a flatscreen monitor in 3 conditions: with the prosthesis system on and a 1-to-1 mapping of spatial information, with the system off, and with the system on but with randomly scrambled spatial information. Results: Fifteen subjects (54%) were able to perform the task significantly better with their prosthesis system than they were with their residual vision, 2 subjects had significantly better performance with their residual vision, and no difference was found for 11 subjects. Of the 15 better-performing subjects, 11 were available for follow-up testing, and 10 of them had significantly better performance with normal rather than with scrambled spatial information. Conclusions: This work demonstrates that blind subjects implanted with the Argus II retinal prosthesis were able to perform a motion detection task they could not do with their native vision, confirming that electrical stimulation of the retina provides spatial information from synchronized activation of multiple electrodes. C1 [Dorn, Jessy D.; Caspi, Avi; Greenberg, Robert J.] Second Sight Med Prod, Sylmar, CA 91342 USA. [Ahuja, Ashish K.] Univ So Calif, Los Angeles, CA USA. [da Cruz, Lyndon] Moorfields Eye Hosp, London, England. [Sahel, Jose-Alain] UCL, Inst Ophthalmol, London, England. [Dagnelie, Gislin] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [McMahon, Matthew J.] NEI, Bethesda, MD 20892 USA. [Sahel, Jose-Alain] Univ Paris 06, Dept Therapeut, Inst Vis, UMR S 968, Paris, France. [Sahel, Jose-Alain] CNRS, UMR 7210, Paris, France. [Sahel, Jose-Alain] Ctr Hosp Natl Ophtalmol Quinze Vingts, Clin Invest Ctr 503, Paris, France. RP Dorn, JD (reprint author), Second Sight Med Prod, 12744 San Fernando Rd,Bldg 3, Sylmar, CA 91342 USA. EM jdorn@2-sight.com RI Sahel, Jose-Alain/F-3172-2017 FU National Institutes of Health (National Eye Institute's Research/Development of Artificial Retinas for the Blind) [EY012893] FX This study was funded by grant EY012893 from the National Institutes of Health (National Eye Institute's Research/Development of Artificial Retinas for the Blind) to Dr Greenberg (principal investigator). NR 13 TC 41 Z9 43 U1 0 U2 31 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6165 J9 JAMA OPHTHALMOL JI JAMA Ophthalmol. PD FEB PY 2013 VL 131 IS 2 BP 183 EP 189 DI 10.1001/2013.jamaophthalmol.221 PG 7 WC Ophthalmology SC Ophthalmology GA 113RB UT WOS:000316684400008 PM 23544203 ER PT J AU Merikangas, KR He, JP Rapoport, J Vitiello, B Olfson, M AF Merikangas, Kathleen R. He, Jian-ping Rapoport, Judith Vitiello, Benedetto Olfson, Mark TI Medication Use in US Youth With Mental Disorders SO JAMA PEDIATRICS LA English DT Article ID SUPPLEMENT NCS-A; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; 2ND-GENERATION ANTIPSYCHOTIC MEDICATIONS; RANDOMIZED CONTROLLED-TRIAL; ATYPICAL ANTIPSYCHOTICS; ADOLESCENT DEPRESSION; BIPOLAR DISORDER; NATIONAL TRENDS; PSYCHOPHARMACOLOGICAL TREATMENT; PSYCHOTROPIC MEDICATIONS AB Objective: To evaluate the prevalence, demographic and clinical correlates, and specificity of classes of psychotropic medications indicated for mental disorders. Design: Cross-sectional survey. Setting: Direct household interviews of combined household and school samples representative of the general population of adolescents in the United States. Participants: Ten thousand one hundred twenty-three adolescents aged 13 to 18 years who participated in the National Comorbidity Survey Adolescent Supplement. Main Exposures: Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV) mental disorders and neurodevelopmental disorders. Outcome Measure: Psychotropic medication use in the past 12 months. Results: Among youth with any DSM-IV mental disorder, 14.2% reported that they had been treated with a psychotropic medication in the past 12 months. Strong associations emerged between specific disorders and classes of medications with evidence for efficacy. Antidepressants were most frequently used among those with primary mood disorders (14.1%); stimulant use was most common among those with attention-deficit/hyperactivity disorder (20.4%); and antipsychotic use was infrequent and mostly seen among those with serious developmental disorders. Less than 2.5% of adolescents without a 12-month mental disorder had been prescribed psychotropic medications, and most had evidence of psychological distress or impairment reflected in a previous mental disorder, subthreshold condition, or developmental disorder. Appropriate medication use was significantly more frequent among those in treatment in the mental health specialty sector than general medicine or other settings. Conclusions: These findings challenge recent concerns over widespread overmedication and misuse of psychotropic medications in US youth. In fact, these data highlight the need for greater recognition and appropriate treatment of youth with mental health disorders. JAMA Pediatr. 2013; 167(2): 141-148. Published online December 3, 2012. doi: 10.1001/jamapediatrics.2013.431 C1 [Merikangas, Kathleen R.; He, Jian-ping; Rapoport, Judith; Vitiello, Benedetto] NIMH, Bethesda, MD 20892 USA. [Olfson, Mark] Columbia Univ, Sch Med, New York, NY USA. RP Merikangas, KR (reprint author), Genet Epidemiol Res Branch, 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 [Z01 MH002808-08]; National Institute of Mental Health [U01-MH60220] FX This work was supported by Intramural Research Program of the National Institute of Mental Health grant Z01 MH002808-08. The NCS-A and the larger program of related NCS surveys are supported by National Institute of Mental Health grant U01-MH60220. NR 62 TC 25 Z9 26 U1 1 U2 25 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6203 J9 JAMA PEDIATR JI JAMA Pediatr. PD FEB PY 2013 VL 167 IS 2 BP 141 EP 148 DI 10.1001/jamapediatrics.2013.431 PG 8 WC Pediatrics SC Pediatrics GA 115FQ UT WOS:000316798400007 PM 23403911 ER PT J AU Blanco, C Krueger, RF Hasin, DS Liu, SM Wang, S Kerridge, BT Saha, T Olfson, M AF Blanco, Carlos Krueger, Robert F. Hasin, Deborah S. Liu, Shang-Min Wang, Shuai Kerridge, Bradley T. Saha, Tulshi Olfson, Mark TI Mapping Common Psychiatric Disorders Structure and Predictive Validity in the National Epidemiologic Survey on Alcohol and Related Conditions SO JAMA PSYCHIATRY LA English DT Article ID INTERVIEW SCHEDULE AUDADIS; COMORBIDITY SURVEY REPLICATION; ENVIRONMENTAL RISK-FACTORS; GENERAL-POPULATION SAMPLE; DSM-IV DISORDERS; MENTAL-DISORDERS; DRUG MODULES; EXTERNALIZING PSYCHOPATHOLOGY; PERSONALITY-DISORDERS; META-STRUCTURE AB Context: Clinical experience and factor analytic studies suggest that some psychiatric disorders may be more closely related to one another, as indicated by the frequency of their co-occurrence, which may have etiologic and treatment implications. Objective: To construct a virtual space of common psychiatric disorders, spanned by factors reflecting major psychopathologic dimensions, and locate psychiatric disorders in that space, as well as to examine whether the location of disorders at baseline predicts the prevalence and incidence of disorders at 3-year follow-up. Design, Setting, and Patients: A total of 34 653 individuals participated in waves 1 and 2 of the National Epidemiologic Survey on Alcohol and Related Conditions. Main Outcome Measures: The distance between disorders at wave 1, calculated using the loadings of the factors spanning the space of disorders as coordinates. This distance was correlated with the adjusted odds ratios for age, sex, and race/ethnicity of the prevalence and incidence of Axis 1 disorders in wave 2, with the aim of determining whether smaller distances between disorders at wave 1 predicts higher disorder prevalence and incidence at wave 2. Results: A model with 3 correlated factors provided an excellent fit (Comparative Fit Index = 0.99, Tucker-Lewis Index = 0.98, root mean square error of approximation = 0.008) for the structure of common psychiatric disorders and was used to span the space of disorders. Distances ranged from 0.070 (between drug abuse and dysthymia) to 1.032 (between drug abuse and avoidant personality disorder). The correlation of distance between disorders in wave 1 with adjusted odds ratios of prevalence in wave 2 was -0.56. The correlation of distance in wave 1 with adjusted odds ratios of incidence in wave 2 was -0.57. Conclusions: Mapping psychiatric disorders can be used to quantify the distances among disorders. Proximity in turn can be used to predict prospectively the incidence and prevalence of Axis I disorders. JAMA Psychiatry. 2013;70(2):199-208. Published online December 24, 2012. doi:10.1001/jamapsychiatry.2013.281 C1 [Blanco, Carlos; Hasin, Deborah S.; Liu, Shang-Min; Wang, Shuai; Olfson, Mark] Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Hasin, Deborah S.] Columbia Univ Coll Phys & Surg, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. [Blanco, Carlos; Hasin, Deborah S.; Olfson, Mark] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Krueger, Robert F.] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. [Kerridge, Bradley T.] Univ Maryland, Dept Epidemiol & Biostat, Sch Publ Hlth, College Pk, MD 20742 USA. [Saha, Tulshi] NIAAA, Intramural Lab Epidemiol & Biometry, Rockville, MD 20852 USA. RP Blanco, C (reprint author), Columbia Univ Coll Phys & Surg, Dept Psychiat, 1051 Riverside Dr,Unit 69, New York, NY 10032 USA. EM cb255@columbia.edu RI Blanco, Carlos/I-4906-2013; OI Blanco, Carlos/0000-0001-6187-3057; Kerridge, Bradley/0000-0003-0459-9439 FU Eli Lilly and Company; Bristol-Myers Squibb; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; National Institutes of Health [DA019606, DA020783, DA023200, DA023973, CA133050, MH082773, AA014223, AA018111, F31DA025377]; New York State Psychiatric Institute FX Dr Olfson has worked on grants from Eli Lilly and Company and Bristol-Myers Squibb to Columbia University.; The National Epidemiologic Survey on Alcohol and Related Conditions was sponsored by the National Institute on Alcohol Abuse and Alcoholism, with supplemental support from the National Institute on Drug Abuse. Work on this article was supported by grants DA019606, DA020783, DA023200, DA023973, CA133050, and MH082773 to Dr Blanco, AA014223 and AA018111 to Dr Hasin, and F31DA025377 to Mr Kerridge from the National Institutes of Health, and the New York State Psychiatric Institute (Drs Blanco, Hasin, and Olfson). NR 53 TC 38 Z9 38 U1 0 U2 12 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-622X J9 JAMA PSYCHIAT JI JAMA Psychiatry PD FEB PY 2013 VL 70 IS 2 BP 199 EP 208 DI 10.1001/jamapsychiatry.2013.281 PG 10 WC Psychiatry SC Psychiatry GA 114GQ UT WOS:000316729500009 PM 23266570 ER PT J AU Wang, YC Graubard, BI Rosenberg, MA Kuntz, KM Zauber, AG Kahle, L Schechter, CB Feuer, EJ AF Wang, Y. Claire Graubard, Barry I. Rosenberg, Marjorie A. Kuntz, Karen M. Zauber, Ann G. Kahle, Lisa Schechter, Clyde B. Feuer, Eric J. TI Derivation of Background Mortality by Smoking and Obesity in Cancer Simulation Models SO MEDICAL DECISION MAKING LA English DT Article DE life tables; background mortality; cancer simulation ID EXCESS DEATHS; UNDERWEIGHT; OVERWEIGHT; WEIGHT AB Background. Simulation models designed to evaluate cancer prevention strategies make assumptions on background mortality-the competing risk of death from causes other than the cancer being studied. Researchers often use the U. S. life tables and assume homogeneous other-cause mortality rates. However, this can lead to bias because common risk factors such as smoking and obesity also predispose individuals for deaths from other causes such as cardiovascular disease. Methods. We obtained calendar year-, age-, and sex-specific other-cause mortality rates by removing deaths due to a specific cancer from U. S. all-cause life tables. Prevalence across 12 risk factor groups (3 smoking [never, past, and current smoker] and 4 body mass index [BMI] categories [<25, 25-30, 30-35, 35+ kg/m(2)]) were estimated from national surveys (National Health and Nutrition Examination Surveys [NHANES] 1971-2004). Using NHANES linked mortality data, we estimated hazard ratios for death by BMI/smoking using a Poisson regression model. Finally, we combined these results to create 12 sets of BMI and smoking-specific other-cause life tables for U. S. adults aged 40 years and older that can be used in simulation models of lung, colorectal, or breast cancer. Results. We found substantial differences in background mortality when accounting for BMI and smoking. Ignoring the heterogeneity in background mortality in cancer simulation models can lead to underestimation of competing risk of deaths for higher-risk individuals (e. g., male, 60-year old, white obese smokers) by as high as 45%. Conclusion. Not properly accounting for competing risks of death may introduce bias when using simulation modeling to evaluate population health strategies for prevention, screening, or treatment. Further research is warranted on how these biases may affect cancer-screening strategies targeted at high-risk individuals. C1 [Wang, Y. Claire] Columbia Mailman Sch Publ Hlth, Dept Hlth Policy & Management, New York, NY 10032 USA. [Graubard, Barry I.; Feuer, Eric J.] NCI, Washington, DC USA. [Rosenberg, Marjorie A.] Univ Wisconsin, Dept Actuarial Sci Risk Management & Insurance, Madison, WI USA. [Rosenberg, Marjorie A.] Univ Wisconsin, Dept Biostat & Med Informat, Madison, WI USA. [Kuntz, Karen M.] Univ Minnesota, Sch Publ Hlth, Div Hlth Policy & Management, Minneapolis, MN USA. [Zauber, Ann G.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Kahle, Lisa] IMS Inc, Washington, DC USA. [Schechter, Clyde B.] Albert Einstein Coll Med, New York, NY USA. RP Wang, YC (reprint author), Columbia Mailman Sch Publ Hlth, Dept Hlth Policy & Management, 600 W 168th St,6th Floor, New York, NY 10032 USA. EM ycw2102@columbia.edu FU National Cancer Institute [NIH U01 CA115953]; Clinical and Translational Science Award (CTSA) program of the National Center for Research Resources [NIH 1UL1RR025011] FX Received 9 December 2011 from the Department of Health Policy and Management, Columbia Mailman School of Public Health, New York, NY, USA (YCW); National Cancer Institute, Washington, DC, USA (BIG, EJF); Departments of Actuarial Science, Risk Management and Insurance and Biostatics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, USA (MAR); Division of Health Policy and Management, School of Public Health, University of Minnesota, Minneapolis, MN, USA (KMK); Memorial Sloan-Kettering Cancer Center, New York, NY, USA (AGZ); IMS, Inc., Washington, DC, USA (LK); and Albert Einstein College of Medicine, New York, NY, USA (CBS). An earlier version of this work was presented at the 29th Annual Meeting of the Society for Medical Decision Making. This work was supported in part by grants from the National Cancer Institute (NIH U01 CA115953) and from the Clinical and Translational Science Award (CTSA) program of the National Center for Research Resources (Dr. Rosenberg, NIH 1UL1RR025011). This work is solely the responsibility of the authors and does not represent official views of the National Cancer Institute. Revision accepted for publication 1 June 2012. NR 16 TC 1 Z9 1 U1 0 U2 8 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0272-989X J9 MED DECIS MAKING JI Med. Decis. Mak. PD FEB PY 2013 VL 33 IS 2 BP 176 EP 197 DI 10.1177/0272989X12458725 PG 22 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA 113QZ UT WOS:000316684200007 PM 23132901 ER PT J AU Di, LJ Byun, JS Wong, MM Wakano, C Taylor, T Bilke, S Baek, S Hunter, K Yang, H Lee, M Zvosec, C Khramtsova, G Cheng, F Perou, CM Miller, CR Raab, R Olopade, OI Gardner, K AF Di, Li-Jun Byun, Jung S. Wong, Madeline M. Wakano, Clay Taylor, Tara Bilke, Sven Baek, Songjoon Hunter, Kent Yang, Howard Lee, Maxwell Zvosec, Cecilia Khramtsova, Galina Cheng, Fan Perou, Charles M. Miller, C. Ryan Raab, Rachel Olopade, Olufunmilayo I. Gardner, Kevin TI Genome-wide profiles of CtBP link metabolism with genome stability and epithelial reprogramming in breast cancer SO NATURE COMMUNICATIONS LA English DT Article ID MESENCHYMAL TRANSITION; MOLECULAR PORTRAITS; NADH CONCENTRATION; COREPRESSOR CTBP; CO-REPRESSOR; STEM-CELLS; EXPRESSION; COMPLEX; LSD1; HALLMARKS AB The C-terminal binding protein (CtBP) is a NADH-dependent transcriptional repressor that links carbohydrate metabolism to epigenetic regulation by recruiting diverse histone-modifying complexes to chromatin. Here global profiling of CtBP in breast cancer cells reveals that it drives epithelial-to-mesenchymal transition, stem cell pathways and genome instability. CtBP expression induces mesenchymal and stem cell-like features, whereas CtBP depletion or caloric restriction reverses gene repression and increases DNA repair. Multiple members of the CtBP-targeted gene network are selectively downregulated in aggressive breast cancer subtypes. Differential expression of CtBP-targeted genes predicts poor clinical outcome in breast cancer patients, and elevated levels of CtBP in patient tumours predict shorter median survival. Finally, both CtBP promoter targeting and gene repression can be reversed by small molecule inhibition. These findings define broad roles for CtBP in breast cancer biology and suggest novel chromatin-based strategies for pharmacologic and metabolic intervention in cancer. C1 [Di, Li-Jun; Byun, Jung S.; Wong, Madeline M.; Wakano, Clay; Taylor, Tara; Bilke, Sven; Gardner, Kevin] NCI, Genet Branch, Bethesda, MD 20892 USA. [Baek, Songjoon] NCI, Lab Receptor Biol & Gene Express, Bethesda, MD 20892 USA. [Hunter, Kent] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Yang, Howard; Lee, Maxwell] NCI, Lab Populat Genet, Bethesda, MD 20892 USA. [Zvosec, Cecilia; Khramtsova, Galina; Olopade, Olufunmilayo I.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Cheng, Fan; Perou, Charles M.; Miller, C. Ryan] Univ N Carolina, Lineberger Comprehens Canc Care Ctr, Chapel Hill, NC 27599 USA. [Raab, Rachel] E Carolina Univ, Leo W Jenkins Canc Ctr, Greenville, NC 27834 USA. RP Gardner, K (reprint author), NCI, Genet Branch, Bethesda, MD 20892 USA. EM gardnerk@mail.nih.gov RI Di, Li-jun/B-3352-2011; Miller, Ryan/B-9365-2008; OI Miller, Ryan/0000-0002-0096-8762; Perou, Charles/0000-0001-9827-2247 FU US National Institutes of Health; US National Cancer Institute; US National Institute on Aging; US National Institute on Minority Health and Health Disparities; University of Chicago Breast Cancer SPORE [P50 CA125183] FX This research was supported by the Intramural Research Program of the US National Institutes of Health, the US National Cancer Institute, the US National Institute on Aging, the US National Institute on Minority Health and Health Disparities, and the University of Chicago Breast Cancer SPORE P50 CA125183. NR 57 TC 35 Z9 35 U1 2 U2 21 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2013 VL 4 AR 1449 DI 10.1038/ncomms2438 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 112TL UT WOS:000316616400025 PM 23385593 ER PT J AU Knox, SM Lombaert, IMA Haddox, CL Abrams, SR Cotrim, A Wilson, AJ Hoffman, MP AF Knox, Sarah M. Lombaert, Isabelle M. A. Haddox, Candace L. Abrams, Shaun R. Cotrim, Ana Wilson, Adrian J. Hoffman, Matthew P. TI Parasympathetic stimulation improves epithelial organ regeneration SO NATURE COMMUNICATIONS LA English DT Article ID GLAND BRANCHING MORPHOGENESIS; SUBMANDIBULAR-GLAND; GDNF FAMILY; NEURON DEVELOPMENT; NERVOUS-SYSTEM; DISTINCT ROLES; STEM-CELLS; NEURTURIN; GROWTH; GENE AB Parasympathetic nerves are a vital component of the progenitor cell niche during development, maintaining a pool of progenitors for organogenesis. Injured adult organs do not regenerate after parasympathectomy, and there are few treatments to improve organ regeneration, particularly after damage by therapeutic irradiation. Here we show that restoring parasympathetic function with the neurotrophic factor neurturin increases epithelial organ regeneration after damage. We use mouse salivary gland explant culture containing fluorescently labelled progenitors, and injure the tissue with irradiation. The progenitors survive, parasympathetic function is diminished and epithelial apoptosis reduces the expression of neurturin, which increases neuronal apoptosis. Treatment with neurturin reduces neuronal apoptosis, restores parasympathetic function and increases epithelial regeneration. Furthermore, adult human salivary glands damaged by irradiation also have reduced parasympathetic innervation. We propose that neurturin will protect the parasympathetic nerves from damage and improve organ regeneration. This concept may be applicable for other organs where parasympathetic innervation influences their function. C1 [Knox, Sarah M.; Lombaert, Isabelle M. A.; Haddox, Candace L.; Abrams, Shaun R.; Wilson, Adrian J.; Hoffman, Matthew P.] NIDCR, Matrix & Morphogenesis Sect, LCDB, NIH, Bethesda, MD 20892 USA. [Cotrim, Ana] NIDCR, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Hoffman, MP (reprint author), NIDCR, Matrix & Morphogenesis Sect, LCDB, NIH, 30 Convent Dr, Bethesda, MD 20892 USA. EM mhoffman@mail.nih.gov OI Haddox, Candace/0000-0003-4223-0632; Knox, Sarah/0000-0002-7567-083X FU Intramural Research Program of the National Institute of Dental and Craniofacial Research, NIH FX We would like to thank Dr Bruce Baum for helpful discussions and for providing human tissue samples. We would also like to thank Dr L. M. Angerer, Dr K. M. Yamada, Dr W. M. Knosp and S. Powers for discussions and critical reading of this manuscript. The study was supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, NIH. NR 29 TC 50 Z9 51 U1 1 U2 23 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2013 VL 4 AR 1494 DI 10.1038/ncomms2493 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 112TL UT WOS:000316616400064 PM 23422662 ER PT J AU Liu, XB Cotrim, A Teos, L Zheng, CY Swaim, W Mitchell, J Mori, Y Ambudkar, I AF Liu, Xibao Cotrim, Ana Teos, Leyla Zheng, Changyu Swaim, William Mitchell, James Mori, Yasuo Ambudkar, Indu TI Loss of TRPM2 function protects against irradiation-induced salivary gland dysfunction SO NATURE COMMUNICATIONS LA English DT Article ID QUALITY-OF-LIFE; RADIATION-INDUCED XEROSTOMIA; NECK-CANCER; POLY(ADP-RIBOSE) POLYMERASE; OXIDATIVE STRESS; IMMUNE-SYSTEM; MOUSE MODEL; TEMPOL; HEAD; PEROXYNITRITE AB Xerostomia as a result of salivary gland damage is a permanent and debilitating side effect of radiotherapy for head and neck cancers. Effective treatments for protecting, or restoring, salivary gland function are not available. Here we report that irradiation treatment leads to activation of the calcium-permeable channel, transient potential melastatin-like 2 (TRPM2), via stimulation of poly-ADP-ribose polymerase. Importantly, irradiation induced an irreversible loss of salivary gland fluid secretion in TRPM2+/+ mice while a transient loss was seen in TRPM2-/- mice with >60% recovery by 30 days after irradiation. Treatment of TRPM2+/+ mice with the free radical scavenger Tempol or the PARP1 inhibitor 3-aminobenzamide attenuated irradiation-induced activation of TRPM2 and induced significant recovery of salivary fluid secretion. Furthermore, TPL (4-hydroxy-2,2,6,6-tetra-methylpiperidine-N-oxyl) induced complete recovery of function in irradiated TRPM2-/- mice. These novel data demonstrate that TRPM2 is activated by irradiation, via PARP1 activation, and contributes to irreversible loss of salivary gland function. C1 [Liu, Xibao; Teos, Leyla; Swaim, William; Ambudkar, Indu] NCI, Secretory Physiol Sect, NIH, Bethesda, MD 20892 USA. [Cotrim, Ana; Zheng, Changyu] NCI, Translat Res Core, Mol Physiol & Therapeut Branch, Natl Inst Dent & Craniofacial Res,NIH, Bethesda, MD 20892 USA. [Mitchell, James] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. [Mori, Yasuo] Kyoto Univ, Grad Sch Engn, Dept Synthet Chem & Biol Chem, Mol Biol Lab, Kyoto 6158510, Japan. RP Ambudkar, I (reprint author), NCI, Secretory Physiol Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM indu.ambudkar@nih.gov FU NIDCR-DIR FX We acknowledge funding for this work from NIDCR-DIR (for IA). We thank Hwei Ling Ong and Biman Paria for their help during the course of this study. NR 49 TC 14 Z9 14 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2013 VL 4 AR 1515 DI 10.1038/ncomms2526 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 112TL UT WOS:000316616400085 PM 23443543 ER PT J AU Wu, T Wang, CD Wang, J Hallett, M Zang, YF Chan, P AF Wu, Tao Wang, Chaodong Wang, Jue Hallett, Mark Zang, Yufeng Chan, Piu TI Preclinical and clinical neural network changes in SCA2 parkinsonism SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE Parkinsonism; SCA2 mutation; Functional connectivity; Basal ganglia motor circuits; Compensation ID SPINOCEREBELLAR ATAXIA TYPE-2; EXTERNALLY TRIGGERED MOVEMENTS; BASAL GANGLIA; FUNCTIONAL CONNECTIVITY; COMPENSATORY MECHANISMS; DISEASE; MOTOR; CARRIERS; CIRCUITS; ALLELE AB Background: The pathophysiological changes before the presentation of clinical symptoms in parkinsonism are unclear. In this study, we investigated neural network modulations in persons in the preclinical stage of familial parkinsonism, and how the network interactions change at the clinical stage. Methods: We performed functional MRI in a family with SCA2 mutation, including 9 asymptomatic carriers and 10 mutation carriers with parkinsonian symptoms. Functional connectivity from the posterior putamen bilaterally and rostral supplementary motor area was used to explore network interactions in the subjects. Results: Both the asymptomatic carriers and patients had decreased connectivity within the basal ganglia-thalamus-cortical motor loop compared to controls. The asymptomatic carriers showed extensively increased connectivity compared to controls, including the cortico-cortical motor, cortico-cerebellar, cortico-brainstem, and part of the basal ganglia-thalamus-cortical motor circuits. In contrast, the connectivity of most of these networks was decreased in the patients. These abnormalities were relatively normalized after levodopa administration. Conclusions: In the preclinical stage of SCA2 parkinsonism, the connectivity of a part of the basal ganglia motor loop is weakened as a consequence of dopaminergic deficits; meanwhile, the connectivity of other large-scale brain networks is strengthened presumably to compensate for the dysfunction of the basal ganglia to maintain brain function in the early stage of dopaminergic deficits. The simultaneous effects of progressive disruption of basal ganglia motor circuits and failure of compensatory mechanisms as dopaminergic dysfunction progresses may contribute to the onset of clinical symptoms. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Wu, Tao; Wang, Chaodong; Chan, Piu] Capital Med Univ, Xuanwu Hosp, Dept Neurobiol,Beijing Inst Geriatr, Key Lab Neurodegenerat Disorders,Minist Educ, Beijing 100053, Peoples R China. [Wang, Jue; Zang, Yufeng] Hangzhou Normal Univ, Affiliated Hosp, Ctr Cognit & Brain Disorders, Hangzhou, Zhejiang, Peoples R China. [Hallett, Mark] NINDS, NIH, Med Neurol Branch, Human Motor Control Sect, Bethesda, MD 20892 USA. RP Chan, P (reprint author), Capital Med Univ, Xuanwu Hosp, Dept Neurobiol,Beijing Inst Geriatr, Key Lab Neurodegenerat Disorders,Minist Educ, Beijing 100053, Peoples R China. EM pbchan90@gmail.com RI ZANG, Yu-Feng/J-1558-2012 OI ZANG, Yu-Feng/0000-0003-1833-8010 FU National Science Foundation of China [30570530, 30870693, 81071012] FX This work was supported by grants from the National Science Foundation of China (30570530, 30870693, and 81071012). NR 30 TC 8 Z9 8 U1 0 U2 11 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD FEB PY 2013 VL 19 IS 2 BP 158 EP 164 DI 10.1016/j.parkreldis.2012.08.011 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 115RG UT WOS:000316829000004 PM 23000299 ER PT J AU Lee, HJ Lee, OJ Jang, KT Bae, YK Chung, JY Eom, DW Kim, JM Yu, E Hong, SM AF Lee, Hee Jin Lee, Ok-Jun Jang, Kee-Taek Bae, Young Kyung Chung, Joon-Yong Eom, Dae Woon Kim, Joon Mee Yu, Eunsil Hong, Seung-Mo TI Combined Loss of E-cadherin and Aberrant beta-Catenin Protein Expression Correlates With a Poor Prognosis for Small Intestinal Adenocarcinomas SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE Small intestine; Adenocarcinoma; E-cadherin; beta-catenin; Immunohistochemistry; Prognosis ID PANCREATIC INTRAEPITHELIAL NEOPLASIA; SMALL-BOWEL; IMMUNOHISTOCHEMICAL ANALYSIS; CARCINOMAS; CANCER; MUTATIONS; PATHOGENESIS; ACTIVATION; PHENOTYPE; DELETIONS AB Small intestinal adenocarcinomas (SLACs) are rare, and their molecular pathogenesis is largely unknown. To define the roles of E-cadherin and beta-catenin, we performed immunohistochemistry for E-cadherin and beta-catenin in 194 surgically resected SIACs with tissue microarrays and compared the data with clinicopathologic factors, including survival rates of patients with SIAC. Loss of E-cadherin expression and aberrant beta-catenin expression were observed in 41.8% (81/194 cases) and 40.7% (79/194 cases) of SIACs, respectively. Combined loss of E-cadherin and aberrant beta-catenin expression was observed in 24.2% (47/194 cases) of SIACs, and this feature was most frequently observed in mucinous adenocarcinomas and signet ring cell carcinomas (P < .001), poorly differentiated and undifferentiated carcinomas (P < .001), and tumors with advanced pT classification (P = .03). Survival times for patients with SIAC with both loss of E-cadherin and aberrant beta-catenin expression (median, 13.9 months) were significantly shorter than those for patients without aberrant expression of both proteins (49.9 months), as determined by univariate (P < .001) and multivariate (P = .01) analyses. In conclusion, loss of E-cadherin and aberrant beta-catenin expression correlate with poorly differentiated tumors, advanced T classification, and decreased patient survival time; therefore, it could be a prognostic factor in patients with SIAC. C1 [Lee, Hee Jin; Yu, Eunsil; Hong, Seung-Mo] Univ Ulsan, Coll Med, Dept Pathol, Asan Med Ctr, Seoul 138736, South Korea. [Lee, Ok-Jun] Chungbuk Natl Univ, Coll Med, Dept Pathol, Cheongju, South Korea. [Jang, Kee-Taek] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Pathol, Seoul, South Korea. [Bae, Young Kyung] Yeungnam Univ, Coll Med, Dept Pathol, Taegu, South Korea. [Chung, Joon-Yong] NCI, Appl Mol Pathol Lab, NIH, Bethesda, MD 20892 USA. [Chung, Joon-Yong] NCI, Tissue Array Res Program, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Eom, Dae Woon] Univ Ulsan, Coll Med, Gangneung Asan Hosp, Dept Pathol, Kangnung, South Korea. [Kim, Joon Mee] Inha Univ, Coll Med, Dept Pathol, Inchon, South Korea. RP Hong, SM (reprint author), Univ Ulsan, Coll Med, Dept Pathol, Asan Med Ctr, 388-1 Pungnap Dong, Seoul 138736, South Korea. EM smhong28@gmail.com OI Hong, Seung-Mo/0000-0002-8888-6007 FU National Research Foundation of Korea (NRF); Ministry of Education, Science, and Technology [2010-0004807]; Asan Institute for Life Sciences, Seoul, South Korea [2013-554] FX This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) and funded by the Ministry of Education, Science, and Technology (2010-0004807) and a grant (2013-554) from the Asan Institute for Life Sciences, Seoul, South Korea. NR 29 TC 12 Z9 13 U1 0 U2 9 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD FEB PY 2013 VL 139 IS 2 BP 167 EP 176 DI 10.1309/AJCPS54RTFCTHGWX PG 10 WC Pathology SC Pathology GA 109LD UT WOS:000316369100006 PM 23355201 ER PT J AU Valentino, C Kendrick, S Johnson, N Gascoyne, R Chan, WC Weisenburger, D Braziel, R Cook, JR Tubbs, R Campo, E Rosenwald, A Ott, G Delabie, J Jaffe, E Zhang, WJ Brunhoeber, P Nitta, H Grogan, T Rimsza, L AF Valentino, Carlo Kendrick, Samantha Johnson, Nathalie Gascoyne, Randy Chan, Wing C. Weisenburger, Dennis Braziel, Rita Cook, James R. Tubbs, Raymond Campo, Elias Rosenwald, Andreas Ott, German Delabie, Jan Jaffe, Elaine Zhang, Wenjun Brunhoeber, Patrick Nitta, Hiro Grogan, Tom Rimsza, Lisa TI Colorimetric In Situ Hybridization Identifies MYC Gene Signal Clusters Correlating With Increased Copy Number, mRNA, and Protein in Diffuse Large B-Cell Lymphoma SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE MYC; Colorimetric; In situ hybridization; Lymphoma; Ploidy; Gene expression; Immunohistochemistry; Survival ID POOR-PROGNOSIS; R-CHOP; AMPLIFICATION; REARRANGEMENT; EXPRESSION; PREDICT; RITUXIMAB; SURVIVAL; DLBCL; ALK AB Abnormalities of the MYC oncogene on chromosome 8 are characteristic of Burkitt lymphoma and other aggressive B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL). We recently described a colorimetric in situ hybridization (CISH) method for detecting extra copies of the MYC gene in DLBCL and the frequent occurrence of excess copies of discrete MYC signals in the context of diploidy or polyploidy of chromosome 8, which correlated with increased mRNA signals. We further observed enlarged MYC signals, which were counted as a single gene copy but, by their dimension and unusual shape, likely consisted of "clusters" of MYC genes. In this study, we sought to further characterize these clusters of MYC signals by determining whether the presence of these correlated with other genetic features, mRNA levels, protein, and overall survival. We found that MYC clusters correlated with an abnormal MYC locus and with increased mRNA. MYC mRNA correlated with protein levels, and both increased mRNA and protein correlated with poorer overall survival. MYC clusters were seen in both the germinal center and activated B-cell subtypes of DLBCL. Clusters of MYC signals may be an underappreciated, but clinically important, feature of aggressive B-cell lymphomas with potential prognostic and therapeutic relevance. C1 [Valentino, Carlo; Kendrick, Samantha; Grogan, Tom; Rimsza, Lisa] Univ Arizona, Coll Med, Dept Pathol, Tucson, AZ 85724 USA. [Johnson, Nathalie] McGill Univ, Dept Med, Montreal, PQ, Canada. [Gascoyne, Randy] British Columbia Canc Agcy, Pathol & Lab Med, Vancouver, BC V5Z 4E6, Canada. [Gascoyne, Randy] British Columbia Canc Agcy, Ctr Lymphoid Canc, Vancouver, BC V5Z 4E6, Canada. [Gascoyne, Randy] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Chan, Wing C.; Weisenburger, Dennis] Univ Nebraska, Med Ctr, Dept Pathol, Omaha, NE USA. [Braziel, Rita] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR USA. [Cook, James R.; Tubbs, Raymond] Cleveland Clin, Pathol & Lab Med Inst, Cleveland, OH 44106 USA. [Campo, Elias] Hosp Clin Barcelona, Barcelona, Spain. [Rosenwald, Andreas] Univ Wurzburg, Dept Pathol, Wurzburg, Germany. [Ott, German] Robert Bosch Krankenhaus, Dept Clin Pathol, Stuttgart, Germany. [Ott, German] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. [Delabie, Jan] Oslo Radium Hosp, Dept Pathol, Oslo, Norway. [Jaffe, Elaine] NCI, Bethesda, MD 20892 USA. [Zhang, Wenjun; Brunhoeber, Patrick; Nitta, Hiro; Grogan, Tom] Ventana Med Syst, Tucson, AZ USA. RP Rimsza, L (reprint author), Univ Arizona, Coll Med, Dept Pathol, 1501 N Campbell Ave,Room 5208A,POB 245043, Tucson, AZ 85724 USA. OI Jaffe, Elaine/0000-0003-4632-0301; Campo, elias/0000-0001-9850-9793; Delabie, Jan/0000-0001-5023-0689 FU Ventana Medical Systems FX Dr Grogan, Dr Brunhoeber, Dr Nitta, and Dr Zhang are employees of Ventana Medical Systems, which produced the MYC and CEN8 probes and funded a portion of this work. NR 26 TC 12 Z9 14 U1 2 U2 7 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD FEB PY 2013 VL 139 IS 2 BP 242 EP 254 DI 10.1309/AJCP2Z0TAGMUYJEB PG 13 WC Pathology SC Pathology GA 109LD UT WOS:000316369100014 PM 23355209 ER PT J AU Baker, SG AF Baker, Stuart G. TI Berrendero, J. R., and Carcamo, J. (2012), "The Tangent Classifier," The American Statistician, 66, 185-194: Comment by Baker and Response SO AMERICAN STATISTICIAN LA English DT Letter C1 NCI, Bethesda, MD 20892 USA. RP Baker, SG (reprint author), NCI, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 1 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 0003-1305 J9 AM STAT JI Am. Stat. PD FEB PY 2013 VL 67 IS 1 BP 64 EP 65 PG 2 WC Statistics & Probability SC Mathematics GA 104FR UT WOS:000315977800014 ER PT J AU Voortman, J Harada, T Chang, RP Killian, JK Suuriniemi, M Smith, WI Meltzer, PS Lucchi, M Wang, Y Giaccone, G AF Voortman, J. Harada, T. Chang, R. P. Killian, J. K. Suuriniemi, M. Smith, W. I., Jr. Meltzer, P. S. Lucchi, M. Wang, Y. Giaccone, G. TI Detection and Therapeutic Implications of c-Met Mutations in Small Cell Lung Cancer and Neuroendocrine Tumors SO CURRENT PHARMACEUTICAL DESIGN LA English DT Article DE c-Met; mutation; neuroendocrine tumor; tyrosine kinase inhibitor ID TYROSINE KINASE RECEPTOR; GROWTH-FACTOR RECEPTOR; JUXTAMEMBRANE DOMAIN; SOMATIC MUTATIONS; AMPLIFICATION; ACTIVATION; INHIBITORS; PROTOONCOGENE; RESISTANCE; GEFITINIB AB Background. We evaluated the mutation status of c-Met in small cell lung cancer (SCLC) and neuroendocrine tumors (NET), for which relatively limited therapeutic targets have been explored. Materials and Methods. c-Met was re-sequenced using cell lines and clinical samples. For in vitro studies, DNA constructs containing a juxtamembrane domain (JMD) and tyrosine kinase domain (TKD) were generated. Detected mutations were introduced into the construct and effects on c-Met phosphorylation and interaction with tyrosine kinase inhibitor drugs BMS777607 and SU11274 were assessed. Results. 97 specimens were analyzed: 13 SCLC and 2 pulmonary carcinoid cell lines, 46 SCLC and 36 NET clinical specimens. Mutations were only detected in the JMD. No mutations were detected in the TKD. Found mutations consisted of the previously reported R988C and T1010I mutations. One novel JMD mutation, P996S, was detected in a SCLC specimen. The mutation rate in SCLC cell lines was 25% (31% including a derivative cell line), and 6.5% in clinical specimens. The mutation rate in NET was 8.3%. In vitro, there were no differences between wild type, R988C or T1010I mutants regarding c-Met phosphorylation at Y1003, located in the JMD, and at Y1234/1235, located in the TKD. BMS777607 and SU11274 were shown to inhibit phosphorylation of c-Met in wild type and R988C and T1010I mutants in a similar fashion. Conclusions. In SCLC and neuroendocrine tumors MET mutations are relatively rare. Detected mutations were located in the juxtamembrane domain and were of no functional relevance as they did not influence c-Met phosphorylation, regardless of TKI treatment. C1 [Voortman, J.; Harada, T.; Wang, Y.; Giaccone, G.] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Chang, R. P.; Killian, J. K.; Suuriniemi, M.; Meltzer, P. S.] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Smith, W. I., Jr.] Suburban Hosp, Dept Pathol, Bethesda, MD USA. [Lucchi, M.] Univ Pisa, Div Thorac Surg, Cardiac & Thorac Dept, Pisa, Italy. RP Giaccone, G (reprint author), NCI, Bldg 10 Magnuson CC,Room 12N226,10 Ctr Dr, Bethesda, MD 20892 USA. EM giacconeg@mail.nih.gov RI Giaccone, Giuseppe/E-8297-2017; OI Giaccone, Giuseppe/0000-0002-5023-7562; LUCCHI, MARCO/0000-0001-9909-6820 FU Clinical and Molecular Profiling Core (CMPC), National Cancer Institute FX Mutation studies were in part supported by the Clinical and Molecular Profiling Core (CMPC), National Cancer Institute, with special thanks to Marbin Pineda, Cancer Genetics Branch, National Cancer Institute. NR 36 TC 13 Z9 16 U1 1 U2 8 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1381-6128 J9 CURR PHARM DESIGN JI Curr. Pharm. Design PD FEB PY 2013 VL 19 IS 5 BP 833 EP 840 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 110NE UT WOS:000316449900004 PM 22973954 ER PT J AU Mendive, S Bornstein, MH Sebastian, C AF Mendive, Susana Bornstein, Marc H. Sebastian, Christian TI The role of maternal attention-directing strategies in 9-month-old infants attaining joint engagement SO INFANT BEHAVIOR & DEVELOPMENT LA English DT Article DE Joint attention; Mother-infant interaction; Scaffolding; Attention-directing strategies; Sequential analysis ID LANGUAGE-DEVELOPMENT; MOTHER-INFANT; CHILD; RESPONSIVENESS; COMPETENCE; BEHAVIORS AB Coordinated joint engagement (CJE) is a behavioral measure used in the infant-caregiver interaction paradigm to measure joint attention. To know how mothers scaffold infant attention to prompt joint engagement states, this study attempted to determine (a) which specific maternal attention-directing strategies facilitate CJE in mother-infant interactions and (b) how attention-directing strategies precede a range of infant engagement states. Free play in 33 low-SES dyads was analyzed sequentially, a method that reveals temporal relations between the behaviors involved in an interaction. Maintaining was the only strategy that preceded CJE, and Introducing and Redirecting preceded infant Engagement with Object, Onlooking, and Supported Joint Engagement. The results point to the scaffolding role of Maintaining and the mediating role of Introducing and Redirecting maternal strategies. To understand how low-SES infants attain CJE is important given the relation between joint attention and cognitive development. Implications of the results for interventions aimed at reducing socioeconomic inequities in early cognitive development are discussed. (C) 2012 Elsevier Inc. All rights reserved. C1 [Mendive, Susana] Univ Catolica Chile, Fac Educ Pontificia, Santiago, Chile. [Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Sebastian, Christian] Pontificia Univ Catolica Chile, Escuela Psicol, Santiago, Chile. RP Mendive, S (reprint author), Fac Educ, Av Vicuna Mackenna 4860, Macul, Santiago De Chi, Chile. EM smendive@uc.cl RI Mendive, Susana/B-2095-2017 OI Mendive, Susana/0000-0002-9436-3974 FU Intramural NIH HHS [ZIA HD001119-25, Z99 HD999999] NR 52 TC 5 Z9 5 U1 1 U2 24 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0163-6383 J9 INFANT BEHAV DEV JI Infant Behav. Dev. PD FEB PY 2013 VL 36 IS 1 BP 115 EP 123 DI 10.1016/j.infbeh.2012.10.002 PG 9 WC Psychology, Developmental SC Psychology GA 111QV UT WOS:000316536700012 PM 23276727 ER PT J AU Fried, M Avril, M Chaturvedi, R Fernandez, P Lograsso, J Narum, D Nielsen, MA Oleinikov, AV Resende, M Salanti, A Saveria, T Williamson, K Dicko, A Scherf, A Smith, JD Theander, TG Duffy, PE AF Fried, Michal Avril, Marion Chaturvedi, Richa Fernandez, Pablo Lograsso, Joseph Narum, David Nielsen, Morten A. Oleinikov, Andrew V. Resende, Mafalda Salanti, Ali Saveria, Tracy Williamson, Kathryn Dicko, Alassane Scherf, Artur Smith, Joseph D. Theander, Thor G. Duffy, Patrick E. TI Multilaboratory Approach to Preclinical Evaluation of Vaccine Immunogens for Placental Malaria SO INFECTION AND IMMUNITY LA English DT Article ID CHONDROITIN SULFATE-A; PREGNANCY-ASSOCIATED MALARIA; CROSS-REACTIVE ANTIBODIES; FALCIPARUM-INFECTED ERYTHROCYTES; CSA-BINDING PARASITES; PLASMODIUM-FALCIPARUM; BLOCKING ANTIBODIES; IMMUNOGLOBULIN-G; VAR2CSA; DOMAINS AB Pregnancy malaria is caused by Plasmodium falciparum-infected erythrocytes that adhere to the placental receptor chondroitin sulfate A (CSA) and sequester in the placenta; women become resistant to pregnancy malaria as they acquire antiadhesion antibodies that target surface proteins of placental parasites. VAR2CSA, a member of the P. falciparum EMP1 variant surface antigen family, is the leading candidate for a pregnancy malaria vaccine. Because VAR2CSA is a high-molecular-weight protein, a vaccine based on the full-length protein may not be feasible. An alternative approach has been to develop a vaccine targeting individual Duffy binding-like (DBL) domains. In this study, a consortium of laboratories under the Pregnancy Malaria Initiative compared the functional activity of antiadhesion antibodies elicited by different VAR2CSA domains and variants produced in prokaryotic and eukaryotic expression systems. Antisera were initially tested against laboratory lines of maternal parasites, and the most promising reagents were evaluated in the field against fresh placental parasite samples. Recombinant proteins expressed in Escherichia coli elicited antibody levels similar to those expressed in eukaryotic systems, as did the two allelic forms of the DBL4 and DBL5 domains. The procedures developed for this head-to-head comparison will be useful for future evaluation and down-selection of malaria vaccine immunogens. C1 [Fried, Michal; Avril, Marion; Chaturvedi, Richa; Lograsso, Joseph; Oleinikov, Andrew V.; Saveria, Tracy; Williamson, Kathryn; Smith, Joseph D.; Duffy, Patrick E.] Seattle Biomed Res Inst, Seattle, WA 98109 USA. [Fried, Michal; Narum, David; Duffy, Patrick E.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD USA. [Fernandez, Pablo; Scherf, Artur] Inst Pasteur, Unite Biol Interact Hote Parasite, Paris, France. [Fernandez, Pablo; Scherf, Artur] CNRS URA2581, Paris, France. [Nielsen, Morten A.; Resende, Mafalda; Salanti, Ali; Theander, Thor G.] Univ Copenhagen, Rigshosp, Copenhagen Univ Hosp, Ctr Med Parasitol, DK-2100 Copenhagen, Denmark. [Dicko, Alassane] Univ Bamako, Immunoepidemiol Program IMEPP, Malaria Res & Training Ctr, Fac Med & Dent, Bamako, Mali. RP Fried, M (reprint author), Seattle Biomed Res Inst, 4 Nickerson St, Seattle, WA 98109 USA. EM michal.fried@nih.gov RI Scherf, Artur/A-9674-2014; Theander, Thor/F-6714-2015; OI Nielsen, Morten Agertoug/0000-0003-2668-4992; Theander, Thor G./0000-0002-3509-7514 FU Bill & Melinda Gates Foundation [47029]; U.S. National Institutes of Health [AI52059]; NIAID-NIH FX This work was supported by a grant from the Bill & Melinda Gates Foundation (grant 47029) and U.S. National Institutes of Health grant AI52059 (to P.E.D.). This research was supported in part by the Intramural Research Program of the NIAID-NIH. NR 39 TC 19 Z9 19 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD FEB PY 2013 VL 81 IS 2 BP 487 EP 495 DI 10.1128/IAI.01106-12 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 108RD UT WOS:000316312800011 PM 23208604 ER PT J AU Kurtz, SL Foreman, O Bosio, CM Anver, MR Elkins, KL AF Kurtz, Sherry L. Foreman, Oded Bosio, Catharine M. Anver, Miriam R. Elkins, Karen L. TI Interleukin-6 Is Essential for Primary Resistance to Francisella tularensis Live Vaccine Strain Infection SO INFECTION AND IMMUNITY LA English DT Article ID CELL-MEDIATED-IMMUNITY; ACUTE-PHASE RESPONSE; T-CELLS; IN-VIVO; CHLAMYDIA-TRACHOMATIS; RESPIRATORY TULAREMIA; PULMONARY INFECTION; GAMMA-INTERFERON; DENDRITIC CELLS; KNOCKOUT MICE AB We employed Francisella tularensis live vaccine strain (LVS) to study mechanisms of protective immunity against intracellular pathogens and, specifically, to understand protective correlates. One potential molecular correlate identified previously was interleukin-6 (IL-6), a cytokine with pleotropic roles in immunity, including influences on T and B cell functions. Given its role as an immune modulator and the correlation with successful anti-LVS vaccination, we examined the role IL-6 plays in the host response to LVS. IL-6-deficient (IL-6 knockout [KO]) mice infected with LVS intradermally or intranasally or anti-IL-6-treated mice, showed greatly reduced 50% lethal doses compared to wild-type (WT) mice. Increased susceptibility was not due to altered splenic immune cell populations during infection or decreased serum antibody production, as IL-6 KO mice had similar compositions of each compared to WT mice. Although LVS-infected IL-6 KO mice produced much less serum amyloid A and haptoglobin (two acute-phase proteins) than WT mice, there were no other obvious pathophysiological differences between LVS-infected WT and IL-6 KO mice. IL-6 KO or WT mice that survived primary LVS infection also survived a high-dose LVS secondary challenge. Using an in vitro overlay assay that measured T cell activation, cytokine production, and abilities of primed splenocytes to control intracellular LVS growth, we found that IL-6 KO total splenocytes or purified T cells were slightly defective in controlling intracellular LVS growth but were equivalent in cytokine production. Taken together, IL-6 is an integral part of a successful immune response to primary LVS infection, but its exact role in precipitating adaptive immunity remains elusive. C1 [Kurtz, Sherry L.; Elkins, Karen L.] US FDA, Lab Mycobacterial Dis & Cellular Immunol, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. [Foreman, Oded] Jackson Lab, Sacramento, CA USA. [Bosio, Catharine M.] NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. [Anver, Miriam R.] SAIC Frederick Inc, Pathol Histotechnol Lab, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Elkins, KL (reprint author), US FDA, Lab Mycobacterial Dis & Cellular Immunol, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. EM karen.elkins@fda.hhs.gov RI Bosio, Catharine/D-7456-2015 FU National Institute of Allergy and Infectious Diseases [Y1-AI-6153-01/224-06-1322]; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded in part by an interagency agreement with the National Institute of Allergy and Infectious Diseases (Y1-AI-6153-01/224-06-1322) and by federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. NR 54 TC 20 Z9 20 U1 0 U2 12 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD FEB PY 2013 VL 81 IS 2 BP 585 EP 597 DI 10.1128/IAI.01249-12 PG 13 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 108RD UT WOS:000316312800022 PM 23230288 ER PT J AU Reinisch, W Knobler, R Rutgeerts, PJ Ochsenkuhn, T Anderson, F von Tirpitz, C Kaatz, M van der Woude, CJ Parenti, D Mannon, PJ AF Reinisch, Walter Knobler, Robert Rutgeerts, Paul J. Ochsenkuehn, Thomas Anderson, Frank von Tirpitz, Christian Kaatz, Martin van der Woude, C. Janneke Parenti, Dennis Mannon, Peter J. TI Extracorporeal Photopheresis (ECP) in Patients with Steroid-dependent Crohn's Disease: An Open-label, Multicenter, Prospective Trial SO INFLAMMATORY BOWEL DISEASES LA English DT Article DE extracorporeal photopheresis; Crohn's disease; steroid dependent ID INFLAMMATORY-BOWEL-DISEASE; APOPTOTIC CELLS; T-CELLS; THERAPY; METHOTREXATE AB Background: Extracorporeal photopheresis (ECP) involves ex vivo leukocyte treatment with methoxsalen and UVA light to generate a tolerogenic response. A previous trial demonstrated that ECP permits corticosteroid withdrawal in steroid-dependent Crohn's disease (CD) patients who were in clinical remission. We studied the effect of ECP on steroid withdrawal in steroid-dependent CD. Methods: Patients with CD for >= 6 months, in remission at baseline while on steroids, but who had failed at >= 1 steroid withdrawal were included. Patients received two ECP treatments every 2 weeks for the 24-week steroid tapering period and underwent steroid-tapering. Patients completing steroid tapering could receive maintenance ECP (two treatments/week) every month for 24 weeks. Results: Thirty-one patients (Crohn's Disease Activity Index [CDAI] score 91; Inflammatory Bowel Disease Questionnaire [IBDQ] 172.5) were enrolled (baseline corticosteroid dose, 20 mg/day); 65% were refractory to/intolerant of anti-tumor necrosis factor (TNF) agents or immunosuppressants. After 24 weeks of ECP, 7 of 31 (22.6%) patients discontinued steroids while maintaining a CDAI of,150. At week 24, the steroid dose for the remaining patients on corticosteroids was 10 mg (P < 0.003 vs. baseline) with a CDAI of 110 and an IBDQ of 179. Following maintenance treatment, three patients remained in steroid-free remission. The 10 patients in the study and receiving ECP at week 48 had a steroid dose of 3.5 mg with a CDAI of 40 and an IBDQ of 188. Conclusions: ECP permitted discontinuation or reduction of steroids in a population of refractory steroid-dependent CD patients. ECP may be useful in permitting steroid withdrawal in selected steroid-dependent CD patients. Ideally, these results need to be confirmed in a "sham-controlled" clinical trial. (Inflamm Bowel Dis 2013;19:293-300) C1 [Reinisch, Walter; Knobler, Robert] Med Univ Vienna, A-1090 Vienna, Austria. [Rutgeerts, Paul J.] Katholieke Univ Leuven, Louvain, Belgium. [Ochsenkuehn, Thomas] Univ Munich, Munich, Germany. [Anderson, Frank] LAIR Ctr, Vancouver, BC, Canada. [von Tirpitz, Christian] Univ Ulm, D-89069 Ulm, Germany. [Kaatz, Martin] Univ Jena, Jena, Germany. [van der Woude, C. Janneke] Erasmus Univ, Rotterdam, Netherlands. [Parenti, Dennis] Johnson & Johnson, Therakos, Raritan, NJ USA. [Mannon, Peter J.] NIAID, Mucosal Immun Sect, NIH, Bethesda, MD 20892 USA. RP Reinisch, W (reprint author), Med Univ Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. EM walter.reinisch@meduniwien.ac.at FU Therakos, Inc., Raritan, NJ FX Supported by a grant from Therakos, Inc., Raritan, NJ. NR 16 TC 12 Z9 13 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1078-0998 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD FEB PY 2013 VL 19 IS 2 BP 293 EP 300 DI 10.1002/ibd.23012 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 110MM UT WOS:000316447300025 PM 22573600 ER PT J AU Swaroop, A AF Swaroop, Anand TI What's in a Name? RPGR Mutations Redefine the Genetic and Phenotypic Landscape in Retinal Degenerative Diseases SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Editorial Material ID RETINITIS-PIGMENTOSA C1 NEI, Neurobiol Neurodegenerat & Repair Lab, 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 OI Swaroop, Anand/0000-0002-1975-1141 NR 6 TC 3 Z9 3 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD FEB PY 2013 VL 54 IS 2 BP 1417 EP 1417 DI 10.1167/iovs.13-11750 PG 1 WC Ophthalmology SC Ophthalmology GA 100BS UT WOS:000315670300064 PM 23423174 ER PT J AU Bertelsen, RJ Brantsaeter, AL Haugen, M Meltzer, HM London, SJ AF Bertelsen, Randi J. Brantsaeter, Anne Lise Haugen, Margaretha Meltzer, Helle Margrethe London, Stephanie J. TI Maternal Probiotic Intake and Respiratory and Allergy Outcomes in Early Childhood SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI) CY FEB 22-26, 2013 CL San Antonio, TX SP Amer Acad Allergy, Asthma & Immunol (AAAAI) C1 [Bertelsen, Randi J.; Brantsaeter, Anne Lise; Haugen, Margaretha; Meltzer, Helle Margrethe] Norwegian Inst Publ Hlth, Oslo, Norway. [Bertelsen, Randi J.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [London, Stephanie J.] NIEHS, Res Triangle Pk, NC 27709 USA. RI Brantsaeter, Anne Lise/H-7014-2016 OI Brantsaeter, Anne Lise/0000-0001-6315-7134 NR 0 TC 0 Z9 0 U1 0 U2 6 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2013 VL 131 IS 2 SU S BP AB129 EP AB129 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 111WC UT WOS:000316550800461 ER PT J AU Busse, P Cohn, R Salo, PM Zeldin, DC AF Busse, Paula Cohn, Richard Salo, Paivi M. Zeldin, Darryl C. TI Characteristics of Allergic Sensitization Among Adult Asthmatics Older Than 55 Years: Results From the National Health and Nutrition Examination Survey 2005-2006 SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI) CY FEB 22-26, 2013 CL San Antonio, TX SP Amer Acad Allergy, Asthma & Immunol (AAAAI) C1 [Busse, Paula] Mt Sinai Sch Med, New York, NY USA. [Cohn, Richard] SRA Int Inc, Durham, NC USA. [Salo, Paivi M.; Zeldin, Darryl C.] NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2013 VL 131 IS 2 SU S BP AB160 EP AB160 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 111WC UT WOS:000316550800564 ER PT J AU Chang, LJ Mendoza, F Saunders, J Plummer, S Yamshchikov, GV Ledgerwood, JE Graham, BS AF Chang, Lee-Jah Mendoza, Floreliz Saunders, Jamie Plummer, Sarah Yamshchikov, Galina V. Ledgerwood, Julie E. Graham, Barney S. TI VRC 311: Phase I Clinical Trial of a Virus-Like Particle Chikungunya Vaccine in Healthy Adults SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI) CY FEB 22-26, 2013 CL San Antonio, TX SP Amer Acad Allergy, Asthma & Immunol (AAAAI) C1 [Chang, Lee-Jah; Mendoza, Floreliz; Saunders, Jamie; Plummer, Sarah; Yamshchikov, Galina V.; Ledgerwood, Julie E.; Graham, Barney S.] NIAID, NIH, VRC, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2013 VL 131 IS 2 SU S BP AB330 EP AB330 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 111WC UT WOS:000316550800858 ER PT J AU Chinn, I Milner, JD Scheinberg, P Douek, D Markert, ML AF Chinn, Ivan Milner, Joshua D. Scheinberg, Phillip Douek, Daniel Markert, M. Louise TI Thymus Transplantation Restores the Repertoire of Foxp3(+) T Cells in Complete DiGeorge Anomaly SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI) CY FEB 22-26, 2013 CL San Antonio, TX SP Amer Acad Allergy, Asthma & Immunol (AAAAI) C1 [Chinn, Ivan; Markert, M. Louise] Duke Univ, Med Ctr, Durham, NC USA. [Milner, Joshua D.; Scheinberg, Phillip; Markert, M. Louise] NIAID, Bethesda, MD 20892 USA. [Scheinberg, Phillip] NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2013 VL 131 IS 2 SU S BP AB196 EP AB196 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 111WC UT WOS:000316550800698 ER PT J AU Crank, MC Hu-Li, J Paul, WE AF Crank, Michelle C. Hu-Li, Jane Paul, William E. TI IL-1-Beta Maintains IL-2R-Alpha (CD25) Expression On the Surface of Th17 Cells and Partially Reverses IL-2 Mediated Inhibition of Th17 Differentiation SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI) CY FEB 22-26, 2013 CL San Antonio, TX SP Amer Acad Allergy, Asthma & Immunol (AAAAI) C1 [Crank, Michelle C.; Hu-Li, Jane; Paul, William E.] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2013 VL 131 IS 2 SU S BP AB7 EP AB7 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 111WC UT WOS:000316550800022 ER PT J AU Kirshenbaum, A Desai, A Bandara, G Cruse, G Fischer, E Gilfillan, AM Gahl, W Metcalfe, DD AF Kirshenbaum, Arnold Desai, Avanti Bandara, Geethani Cruse, Glenn Fischer, Elizabeth Gilfillan, Alasdair M. Gahl, William Metcalfe, Dean D. TI Establishment of the Hermansky Pudlak Mastocyte (HPM) Cell Line Which Has the HPS1 16-Bp Duplication (c.1470_1486dup16) SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI) CY FEB 22-26, 2013 CL San Antonio, TX SP Amer Acad Allergy, Asthma & Immunol (AAAAI) C1 [Kirshenbaum, Arnold; Desai, Avanti; Bandara, Geethani; Cruse, Glenn; Fischer, Elizabeth; Gilfillan, Alasdair M.; Metcalfe, Dean D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Gahl, William] NHGRI, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2013 VL 131 IS 2 SU S BP AB115 EP AB115 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 111WC UT WOS:000316550800417 ER PT J AU Komarow, HD Waites, C Young, ML Nelson, C Arceo, S Metcalfe, DD AF Komarow, Hirsh D. Waites, Cameron Young, Michael L. Nelson, Celeste Arceo, Sarah Metcalfe, Dean D. TI Basophil Activation Following Cold Challenge in Patients with Cold-Induced Urticaria SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI) CY FEB 22-26, 2013 CL San Antonio, TX SP Amer Acad Allergy, Asthma & Immunol (AAAAI) C1 [Komarow, Hirsh D.; Waites, Cameron; Nelson, Celeste; Arceo, Sarah; Metcalfe, Dean D.] NIAID, NIH, Lab Allerg Dis, Bethesda, MD 20892 USA. [Young, Michael L.] SAICl Frederick Inc, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2013 VL 131 IS 2 SU S BP AB119 EP AB119 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 111WC UT WOS:000316550800430 ER PT J AU Lawrence, MG Siegel, A DeRavin, SS Hanson, EP Moir, S Klein, C Holland, SM Uzel, G Milner, JD AF Lawrence, Monica G. Siegel, Andrea DeRavin, Suk See Hanson, Eric Paul Moir, Susan Klein, Christoph Holland, Steven M. Uzel, Gulbu Milner, Joshua D. TI IL-21 Receptor Mutation in Humans Leads to Disseminated Cryptosporidiosis, Antibody Defects, and Abnormal B and T Cell Function SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI) CY FEB 22-26, 2013 CL San Antonio, TX SP Amer Acad Allergy, Asthma & Immunol (AAAAI) C1 [Lawrence, Monica G.; Siegel, Andrea; DeRavin, Suk See; Moir, Susan; Holland, Steven M.; Uzel, Gulbu; Milner, Joshua D.] NIAID, Bethesda, MD 20892 USA. [Hanson, Eric Paul] NIAMSD, Bethesda, MD 20892 USA. [Klein, Christoph] Hannover Med Sch, Hannover, Germany. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2013 VL 131 IS 2 SU S BP AB328 EP AB328 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 111WC UT WOS:000316550800851 ER PT J AU Magnus, MC Nafstad, P Stene, LC Haberg, SE London, SJ Stigum, H Nystad, W AF Magnus, Maria C. Nafstad, Per Stene, Lars Christian Haberg, Siri Eldevik London, Stephanie J. Stigum, Hein Nystad, Wenche TI Maternal Vitamin D Status During Pregnancy and Asthma in the Offspring Among Participants in the Norwegian Mother and Child Cohort Study SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI) CY FEB 22-26, 2013 CL San Antonio, TX SP Amer Acad Allergy, Asthma & Immunol (AAAAI) C1 [Magnus, Maria C.; Nafstad, Per; Stene, Lars Christian; Haberg, Siri Eldevik; Stigum, Hein; Nystad, Wenche] Norwegian Inst Publ Hlth, Oslo, Norway. [Nafstad, Per] Univ Oslo, Oslo, Norway. [London, Stephanie J.] NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 10 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2013 VL 131 IS 2 SU S BP AB128 EP AB128 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 111WC UT WOS:000316550800460 ER PT J AU Mueller, G Pedersen, L Lih, F Glesner, J Chapman, MD Tomer, K London, R Pomes, A AF Mueller, Geoffrey Pedersen, Lars Lih, Fred Glesner, Jill Chapman, Martin D. Tomer, Ken London, Robert Pomes, Anna TI The Cockroach Allergen Bla g 1 Forms Alpha Helical Capsules with an Internal Lipid Binding Cavity: Implications for Allergenicity SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI) CY FEB 22-26, 2013 CL San Antonio, TX SP Amer Acad Allergy, Asthma & Immunol (AAAAI) C1 [Mueller, Geoffrey; Pedersen, Lars; Lih, Fred; Tomer, Ken; London, Robert] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Glesner, Jill; Chapman, Martin D.; Pomes, Anna] Indoor Biotechnol Inc, Charlottesville, VA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2013 VL 131 IS 2 SU S BP AB16 EP AB16 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 111WC UT WOS:000316550800057 ER PT J AU Sever, ML Thomas, J Calatroni, A Yeatts, K Visness, C Mitchell, H Zeldin, DC AF Sever, Michelle L. Thomas, James Calatroni, Agustin Yeatts, Karin Visness, Cynthia Mitchell, Herman Zeldin, Darryl C. TI Allergen Exposure Influences the Relationship Between Community Violence and Asthma Morbidity: The Inner City Asthma Study SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI) CY FEB 22-26, 2013 CL San Antonio, TX SP Amer Acad Allergy, Asthma & Immunol (AAAAI) C1 [Sever, Michelle L.; Zeldin, Darryl C.] NIEHS, Res Triangle Pk, NC 27709 USA. [Sever, Michelle L.; Thomas, James; Yeatts, Karin] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Calatroni, Agustin; Visness, Cynthia; Mitchell, Herman] Rho Inc, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2013 VL 131 IS 2 SU S BP AB55 EP AB55 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 111WC UT WOS:000316550800201 ER PT J AU Teng, M Fitzhugh, DJ Tran, K Lockey, RF Collins, P AF Teng, Michael Fitzhugh, David J. Kim Tran Lockey, Richard F. Collins, Peter TI Functional Characterization of A Cis-Acting Temperature Sensitive Mutation From A Respiratory Syncytial Virus Vaccine Candidate SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI) CY FEB 22-26, 2013 CL San Antonio, TX SP Amer Acad Allergy, Asthma & Immunol (AAAAI) C1 [Teng, Michael; Fitzhugh, David J.; Kim Tran; Lockey, Richard F.] Univ S Florida, Morsani Coll Med, Tampa, FL USA. [Teng, Michael; Collins, Peter] NIAID, Bethesda, MD 20892 USA. [Lockey, Richard F.] James A Haley Vet Hosp, Tampa, FL 33612 USA. RI Teng, Michael/I-5006-2012 OI Teng, Michael/0000-0002-0722-3659 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2013 VL 131 IS 2 SU S BP AB11 EP AB11 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 111WC UT WOS:000316550800037 ER PT J AU Merke, DP Chen, WY Morissette, R Xu, Z Van Ryzin, C Sachdev, V Hannoush, H Shanbhag, SM Acevedo, AT Nishitani, M Arai, AE McDonnell, NB AF Merke, Deborah P. Chen, Wuyan Morissette, Rachel Xu, Zhi Van Ryzin, Carol Sachdev, Vandana Hannoush, Hwaida Shanbhag, Sujata M. Acevedo, Ana T. Nishitani, Miki Arai, Andrew E. McDonnell, Nazli B. TI Tenascin-X Haploinsufficiency Associated with Ehlers-Danlos Syndrome in Patients with Congenital Adrenal Hyperplasia SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID STEROID 21-HYDROXYLASE DEFICIENCY; HYPERMOBILITY TYPE; GENE; DELETIONS; MUSCLE; CYP21; MICE AB Context: The gene for congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, CYP21A2, is flanked by the gene encoding tenascin-X (TNXB), a connective tissue extracellular matrix protein that has been linked to both autosomal dominant and autosomal recessive Ehlers-Danlos syndrome (EDS). A contiguous deletion of CYP21A2 and TNXB has been described. Objective: The objective of the study was to determine the frequency and clinical significance of TNXB haploinsufficiency in CAH patients. Design, Setting, and Participants: A total of 192 consecutive unrelated CAH patients being seen as part of an observational study at the National Institutes of Health Clinical Center (Bethesda, MD) were prospectively studied during 2006-2010. Patients were evaluated for clinical evidence of EDS, including cardiac evaluation. DNA was analyzed by PCR, multiplex ligation-dependent probe amplification, Southern blot, and TNXB sequencing. Tenascin-X expression was evaluated by Western blot analysis of fibroblasts and immunostaining of the skin. CAH patients with TNXB haploinsufficiency were compared with age-matched CAH patients with normal TNXB (controls). Phenotyping of 7 parents with TNXB haploinsufficiency was performed. Main Outcome Measures: The frequency of TNXB haploinsufficiency among CAH patients and the frequency of EDS symptomatology among CAH patients with TNXB haploinsufficiency and controls. Results: TNXB haploinsufficiency, here termed CAH-X syndrome, was present in 7% of CAH patients. Twelve of 91 patients carrying a CYP21A2 deletion (13%) carried a contiguous deletion that extended into TNXB. One patient carried a TNXB premature stop codon. Twelve of 13 patients with CAH-X had EDS clinical features. Patients with CAH-X were more likely than age-matched controls to have joint hypermobility (P < .001), chronic joint pain (P = .003), multiple joint dislocations (P = .004), a structural cardiac valve abnormality by echocardiography (P = .02), and reduced tenascin-X expression by Western blot and immunostaining. A subset of parents had clinical findings. Conclusions: Clinical evaluation for connective tissue dysplasia should be routinely performed in CAH patients, especially those harboring a CYP21A2 deletion. (J Clin Endocrinol Metab 98: E379-E387, 2013) C1 [Merke, Deborah P.; Van Ryzin, Carol; Acevedo, Ana T.; Nishitani, Miki] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Merke, Deborah P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Sachdev, Vandana; Hannoush, Hwaida; Shanbhag, Sujata M.; Arai, Andrew E.] NHLBI, Bethesda, MD 20892 USA. [Chen, Wuyan; Morissette, Rachel; Xu, Zhi; McDonnell, Nazli B.] NIA, Baltimore, MD 21224 USA. RP Merke, DP (reprint author), NIH, Ctr Clin, Bldg 10,CRC,Room 1-2740,10 Ctr Dr,MSC 1932, Bethesda, MD 20892 USA. EM dmerke@nih.gov RI Xu, Zhi/I-2546-2012 FU National Institutes of Health Clinical Center; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Heart, Lung, and Blood Institute; National Institute on Aging; Congenital Adrenal Hyperplasia Research, Education, and Support Foundation; Diurnal Limited FX This work was supported by the Intramural Research Programs of the National Institutes of Health Clinical Center, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Heart, Lung, and Blood Institute, and The National Institute on Aging and, in part, by The Congenital Adrenal Hyperplasia Research, Education, and Support Foundation.; W.C., R.M., Z.X., C.V.R., V.S., H.H., S.M.S., A.T.A., M.N., A.E.A., and N.B.M. have nothing to disclose. D.P.M. received research funding from Diurnal Limited in 2012. NR 36 TC 12 Z9 12 U1 0 U2 9 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2013 VL 98 IS 2 BP E379 EP E387 DI 10.1210/jc.2012-3148 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 108DE UT WOS:000316270900025 PM 23284009 ER PT J AU Nelson, WL Moser, RP Han, PKJ AF Nelson, Wendy L. Moser, Richard P. Han, Paul K. J. TI Exploring Objective and Subjective Numeracy at a Population Level: Findings From the 2007 Health Information National Trends Survey (HINTS) SO JOURNAL OF HEALTH COMMUNICATION LA English DT Article ID BREAST-CANCER RISK; MEDICAL DECISION-MAKING; PRIMARY-CARE; LITERACY; COMPREHENSION; PERCEPTIONS; SCALE; SKILLS; WOMEN AB Numeracy is a critical component of decision making in health, and low numeracy may adversely affect risk comprehension, medical treatment, and health outcomes. Health researchers have developed objective and subjective measures of numeracy that potentially could be used for clinical or health research purposes. To examine the association between objective and subjective numeracy at a population level, data were obtained from the 2007 Health Information National Trends Survey, a health communication survey that collects data from a nationally representative sample of the U.S. population. Associations between items from 2 published subjective numeracy measures (STAT-Confidence Scale; Subjective Numeracy Scale) and a single published objective numeracy measure were examined with respect to one another and with respect to sociodemographic characteristics using a multivariate logistic regression model. Controlling for demographic covariates, both subjective numeracy measures were significantly associated with each other (p<.0001) and with objective numeracy (p<.0001). Compared with respondents who regarded themselves as low in subjective numeracy, those who regarded themselves as high in subjective numeracy had significantly higher odds of answering the objective numeracy question correctly (STAT-Confidence Scale OR=1.42, CI [1.07, 1.90]; Subjective Numeracy Scale OR=1.71, CI [1.28, 2.28]). However, the subjective measures performed poorly as diagnostic indicators of objective numeracy. Sensitivity and specificity for the STAT-Confidence Scale and the Subjective Numeracy Scale were 67%/49% and 50%/71%, respectively. More work is needed to elucidate the relation between objective and subjective numeracy, at the conceptual and empirical levels, and to develop more robust measures of subjective numeracy that can better discriminate between individuals with low and high objective numeracy. C1 [Nelson, Wendy L.; Moser, Richard P.] NCI, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Han, Paul K. J.] Maine Med Ctr, Ctr Outcomes Res & Evaluat, Portland, ME 04102 USA. RP Nelson, WL (reprint author), NCI, 6130 Execut Blvd,EPN 4064,MSC 7363, Bethesda, MD 20892 USA. EM nelsonw@mail.nih.gov OI Han, Paul/0000-0003-0165-1940 NR 43 TC 5 Z9 5 U1 0 U2 14 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1081-0730 J9 J HEALTH COMMUN JI J. Health Commun. PD FEB 1 PY 2013 VL 18 IS 2 BP 192 EP 205 DI 10.1080/10810730.2012.688450 PG 14 WC Communication; Information Science & Library Science SC Communication; Information Science & Library Science GA 109OV UT WOS:000316378800005 PM 23066837 ER PT J AU Persky, S Sanderson, SC Koehly, LM AF Persky, Susan Sanderson, Saskia C. Koehly, Laura M. TI Online Communication About Genetics and Body Weight: Implications for Health Behavior and Internet-Based Education SO JOURNAL OF HEALTH COMMUNICATION LA English DT Article ID OBESITY; INFORMATION; FRAMEWORK; RISK AB Social media, specifically online weight loss message board communities, may become an important conduit for information about genetics and body weight. This information has the capacity to influence individuals as it is naturally encountered online, or it could be strategically disseminated for public health purposes. However, little is known about how the public engages with information that they encounter related to genetic underpinnings of body weight, or how their interpretation of this information shapes health beliefs. The present study examined discussions about genetics and weight in message board communities devoted to discussion of weight loss. Fifty-four online discussions, comprising 505 individual posts from 3 weight-loss themed message boards, were coded using a closed-ended procedure. Individuals who discussed genetics and weight in online message board communities initiated these discussions mainly for personal reasons and primarily cited mass mediasourced information. Genetic causes of weight tended to be endorsed alongside behavioral causes. There was no association between cause endorsements and expressed frustration. These findings help elucidate the effects of naturally encountered information about genetics of weight. They may also have implications for the creation of online evidence-based tools to aid communication about genetic advances in ways that encourage positive dietary and physical activity behavior. C1 [Persky, Susan; Koehly, Laura M.] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. [Sanderson, Saskia C.] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY USA. RP Persky, S (reprint author), NHGRI, NIH, 31 Ctr Dr,Room B1B54D, Bethesda, MD 20892 USA. EM perskys@mail.nih.gov FU Intramural NIH HHS [ZIA HG200383-01] NR 26 TC 4 Z9 4 U1 1 U2 14 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1081-0730 J9 J HEALTH COMMUN JI J. Health Commun. PD FEB 1 PY 2013 VL 18 IS 2 BP 241 EP 249 DI 10.1080/10810730.2012.727951 PG 9 WC Communication; Information Science & Library Science SC Communication; Information Science & Library Science GA 109OV UT WOS:000316378800008 PM 23194059 ER PT J AU Bashir, ZEH Latief, N Belyantseva, IA Iqbal, F Riazuddin, SA Khan, SN Friedman, TB Riazuddin, S Riazuddin, S AF Bashir, Zil-e-Huma Latief, Noreen Belyantseva, Inna A. Iqbal, Farheena Riazuddin, Sheikh Amer Khan, Shaheen N. Friedman, Thomas B. Riazuddin, Sheikh Riazuddin, Saima TI Phenotypic variability of CLDN14 mutations causing DFNB29 hearing loss in the Pakistani population SO JOURNAL OF HUMAN GENETICS LA English DT Article DE CLDN14; claudin 14; DFNB29; mild hearing loss; Pakistan; profound deafness ID RECESSIVE DEAFNESS DFNB29; TIGHT-JUNCTION; STRIA VASCULARIS; INTERCELLULAR-JUNCTIONS; INNER-EAR; PROTEIN; GENE; FREQUENCIES; OCCLUDIN; FAMILIES AB Human hereditary deafness at the DFNB29 locus on chromosome 21q22.1 is caused by recessive mutations of CLDN14, encoding claudin 14. This tight junction protein is tetramembrane spanning that localizes to the apical tight junctions of organ of Corti hair cells and in many other tissues. Typically, the DFNB29 phenotype is characterized by prelingual, bilateral, sensorineural hearing loss. The goal of this study was to define the identity and frequency of CLDN14 mutations and associated inner ear phenotypes in a cohort of 800 Pakistani families segregating deafness. Hearing loss in 15 multigenerational families was found to co-segregate with CLDN14-linked STR markers. The sequence of the six exons and regions flanking the introns of CLDN14 in these 15 families revealed five likely pathogenic alleles. Two are novel missense substitutions (p.Ser87Ile and p.Ala94Val), whereas p.Arg81His, p.Val85Asp and p.Met133ArgfsX23 have been reported previously. Haplotype analyses indicate that p.Val85Asp and p.Met133ArgfsX23 are founder mutations. The p.Val85Asp accounts for similar to 67% of the mutant alleles of CLDN14 in our cohort. Combined with the previously reported data, CLDN14 mutations were identified in 18 of 800 Pakistani families (2.25; 95% CI, 1.4-3.5). Hearing loss in the affected individuals homozygous for CLDN14 mutations varied from moderate to profound. This phenotypic variability may be due to environmental factors (for example drug and noise exposure) and/or genetic modifiers. Journal of Human Genetics (2013) 58, 102-108; doi:10.1038/jhg.2012.143; published online 13 December 2012 C1 [Bashir, Zil-e-Huma; Latief, Noreen; Riazuddin, Sheikh Amer; Khan, Shaheen N.; Riazuddin, Saima] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore, Pakistan. [Belyantseva, Inna A.; Friedman, Thomas B.] Natl Inst Deafness & Other Commun Disorders, Mol Genet Lab, Rockville, MD USA. [Iqbal, Farheena] Ctr Appl Mol Biol, Lahore, Pakistan. [Riazuddin, Sheikh Amer] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Riazuddin, Sheikh] Allama Iqbal Med Coll, Allama Iqbal Med Res Ctr, Lahore, Pakistan. [Riazuddin, Sheikh] Univ Lahore, Lahore, Pakistan. [Riazuddin, Saima] Cincinnati Childrens Hosp Med Ctr, Div Pediat Otolaryngol Head & Neck Surg, Cincinnati, OH 45229 USA. [Riazuddin, Saima] Univ Cincinnati, Coll Med, Dept Otolaryngol, Cincinnati, OH USA. RP Riazuddin, S (reprint author), Cincinnati Childrens Hosp Med Ctr, Div Pediat Otolaryngol Head & Neck Surg, 3333 Burnet Ave,LocR2-2409,MLC 2018, Cincinnati, OH 45229 USA. EM saima.riazuddin@cchmc.org RI Nasim Khan, Shaheen/F-2135-2015 FU Action on Hearing Loss grant; National Institute on Deafness and Other Communication Disorders (NIDCD/NIH) [R01 DC011803, R01 DC011748]; NIDCD [DC000039-15] FX We thank the families for the participation and cooperation, and R Bhatti and T Kausar for technical assistance and Drs D Drayna, G Nayak and K Kurima for critiques of the manuscript. This work was also supported by an Action on Hearing Loss grant and National Institute on Deafness and Other Communication Disorders (NIDCD/NIH) research grants R01 DC011803 and R01 DC011748 to SR and intramural funds from NIDCD DC000039-15 to TBF. NR 51 TC 5 Z9 6 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1434-5161 J9 J HUM GENET JI J. Hum. Genet. PD FEB PY 2013 VL 58 IS 2 BP 102 EP 108 DI 10.1038/jhg.2012.143 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 112SA UT WOS:000316612200010 PM 23235333 ER PT J AU Thomas, A Shanbhag, S Haglund, K Berman, A Jakopovic, M Szabo, E Arai, A Schrump, DS Kwong, KF Rajan, A Giaccone, G AF Thomas, Anish Shanbhag, Sujata Haglund, Karl Berman, Arlene Jakopovic, Marko Szabo, Eva Arai, Andrew Schrump, David S. Kwong, King F. Rajan, Arun Giaccone, Giuseppe TI Characterization and Management of Cardiac Involvement of Thymic Epithelial Tumors SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE Thymic epithelial tumors; Cardiac tumors; Cardiovascular magnetic resonance imaging ID MALIGNANT THYMOMA; INVASIVE THYMOMA; INTRACAVAL; NEOPLASMS; HEART AB Introduction: Although thymic epithelial tumors (TETs) commonly infiltrate mediastinal structures, cardiac involvement is uncommon and has not been systematically studied. The purpose of this study was to describe our single-institution experience of the clinical presentation, treatment, and follow-up of cardiac involvement in patients with TETs. Methods: A single-institution retrospective review of cardiac involvement among patients with TETs from 2008 to 2012. Results: The frequency of cardiac involvement was 4%. All five patients with confirmed cardiac disease had left heart involvement. Only one patient was symptomatic. Myocardial invasion was the most common mode of involvement followed by transvenous spread. Surgical resection of the involved area was attempted in three patients: in one, surgery was aborted because of extensive myocardial involvement; in the other two patients, resection was incomplete. Surgery averted a potentially catastrophic hemo-dynamic complication in one patient. However, cardiac tumor recurred in both patients who underwent incomplete resection. One patient underwent radiation therapy resulting in complete regression of an aortic root mass. Conclusions: This study represents the most comprehensive review of cardiac involvement in patients with TETs. In contrast to previous single-case reports, we found a preponderance of asymptomatic presentation, left heart involvement, and myocardial invasion. Dynamic cardiovascular magnetic resonance imaging should be considered in cases when cardiac involvement is suspected. Although immediate surgical resection is indicated for impending hemo-dynamic compromise, long-term palliation with surgery for myocardial involvement seems poor, especially when complete resection cannot be performed. Radiation therapy should be considered in selected patients. C1 [Thomas, Anish; Berman, Arlene; Rajan, Arun; Giaccone, Giuseppe] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Shanbhag, Sujata; Arai, Andrew] NHLBI, Cardiovasc & Pulm Branch, Bethesda, MD 20892 USA. [Haglund, Karl] NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Jakopovic, Marko] Univ Hosp Ctr Zagreb, Sch Med, Zagreb, Croatia. [Szabo, Eva] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Schrump, David S.; Kwong, King F.] NCI, Surg Branch, Bethesda, MD 20892 USA. RP Giaccone, G (reprint author), NCI, Room 12N226,10 Ctr Dr, Bethesda, MD 20892 USA. EM giacconeg@mail.nih.gov RI Giaccone, Giuseppe/E-8297-2017; OI Giaccone, Giuseppe/0000-0002-5023-7562; Thomas, Anish/0000-0003-3293-3115 FU Intramural Research Program of the National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institutes of Health. NR 15 TC 5 Z9 5 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD FEB PY 2013 VL 8 IS 2 BP 246 EP 249 DI 10.1097/JTO.0b013e31827bd931 PG 4 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 107HA UT WOS:000316204900021 PM 23328550 ER PT J AU Trask, SD Boehme, KW Dermody, TS Patton, JT AF Trask, Shane D. Boehme, Karl W. Dermody, Terence S. Patton, John T. TI Comparative analysis of Reoviridae reverse genetics methods SO METHODS LA English DT Article DE Reverse genetics systems; Infectious RNA; Recombinant virus; Reoviridae; Rotavirus; Bluetongue virus; Mammalian reovirus ID TEMPERATURE-SENSITIVE MUTANTS; BLUETONGUE VIRUS; GENOME REPLICATION; ROTAVIRUS; RNA; SYSTEM; REARRANGEMENT; GENERATION; SEGMENTS; TRANSCRIPTS AB Effective methods to engineer the segmented, double-stranded RNA genomes of Reoviridae viruses have only recently been developed. Mammalian orthoreoviruses (MRV) and bluetongue virus (BTV) can be recovered from entirely recombinant reagents, significantly improving the capacity to study the replication, pathogenesis, and transmission of these viruses. Conversely, rotaviruses (RVs), which are the major etiological agent of severe gastroenteritis in infants and children, have thus far only been modified using single-segment replacement methods. Reoviridae reverse genetics techniques universally rely on site-specific initiation of transcription by T7 RNA polymerase to generate the authentic 5' end of recombinant RNA segments, but they vary in how the RNAs are introduced into cells: recombinant BTV is recovered by transfection of in vitro transcribed RNAs, whereas recombinant MRV and RV RNAs are transcribed intra-cellularly from transfected plasmid cDNAs. Additionally, several parameters have been identified in each system that are essential for recombinant virus recovery. Generating recombinant BTV requires the use of 5' capped RNAs and is enhanced by multiple rounds of RNA transfection, suggesting that translation of viral proteins is likely the rate-limiting step. For RV, the efficiency of recovery is almost entirely dependent on the strength of the selection mechanism used to isolate the single-segment recombinant RV from the unmodified helper virus. The reverse genetics methods for BTV and RV are presented and compared to the previously described MRV methods. Analysis and comparison of each method suggest several key lines of research that might lead to a reverse genetics system for RV, analogous to those used for MRV and BTV. Published by Elsevier Inc. C1 [Trask, Shane D.; Patton, John T.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Boehme, Karl W.; Dermody, Terence S.] Vanderbilt Univ, Sch Med, Dept Pediat, Nashville, TN 37232 USA. [Boehme, Karl W.; Dermody, Terence S.] Vanderbilt Univ, Sch Med, Elizabeth B Lamb Ctr Pediat Res, Nashville, TN 37232 USA. [Dermody, Terence S.] Vanderbilt Univ, Sch Med, Dept Pathol Microbiol & Immunol, Nashville, TN 37232 USA. RP Patton, JT (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM jpatton@niaid.nih.gov RI Patton, John/P-1390-2014 FU Intramural Research Program of the National Institutes of Allergy and Infectious Diseases, National Institutes of Health [Z01 AI000788]; National Institutes of Allergy and Infectious Diseases, National Institutes of Health [T32 CA09385, F32 AI075776, R01 AI32539, R37 AI38296]; Elizabeth B. Lamb Center for Pediatric Research FX We thank M. Arnold, M. Morelli, and K. Ogden for careful review of the manuscript. We thank T. Kobayashi and P. Roy for helpful conversations and sharing of unpublished data. This work was supported by Public Health Service award Z01 AI000788 from the Intramural Research Program of the National Institutes of Allergy and Infectious Diseases, National Institutes of Health (S.D.T. and J.T.P.), Public Health Service awards T32 CA09385 (K.W.B.), F32 AI075776 (K.W.B.), R01 AI32539 (T.S.D.), and R37 AI38296 (T.S.D.) from the National Institutes of Allergy and Infectious Diseases, National Institutes of Health, and the Elizabeth B. Lamb Center for Pediatric Research. NR 49 TC 7 Z9 9 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 J9 METHODS JI Methods PD FEB PY 2013 VL 59 IS 2 BP 199 EP 206 DI 10.1016/j.ymeth.2012.05.012 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 113FE UT WOS:000316651100005 PM 22687622 ER PT J AU Gold, PW Licinio, J Pavlatou, MG AF Gold, P. W. Licinio, J. Pavlatou, M. G. TI Pathological parainflammation and endoplasmic reticulum stress in depression: potential translational targets through the CNS insulin, klotho and PPAR-gamma systems SO MOLECULAR PSYCHIATRY LA English DT Review DE depression; endoplasmic reticulum stress; parainflammation; translational ID CORTICOTROPIN-RELEASING HORMONE; C-REACTIVE PROTEIN; PROLIFERATOR-ACTIVATED RECEPTORS; CENTRAL-NERVOUS-SYSTEM; RAT CEREBRAL-CORTEX; MAJOR DEPRESSION; HIPPOCAMPAL NEUROGENESIS; CEREBROSPINAL-FLUID; OXIDATIVE STRESS; SERUM-LEVELS AB Major depression and bipolar disorder are heterogeneous conditions in which there can be dysregulation of (1) the stress system response, (2) its capacity for counterregulation after danger has passed and (3) the phase in which damaging molecules generated by the stress response are effectively neutralized. The response to stress and depressed mood share common circuitries and mediators, and each sets into motion not only similar affective and cognitive changes, but also similar systemic manifestations. We focus here on two highly interrelated processes, parainflammation and endoplasmic reticulum (ER) stress, each of which can potentially interfere with all phases of a normal stress response in affective illness, including adaptive neuroplastic changes and the ability to generate neural stem cells. Parainflammation is an adaptive response of the innate immune system that occurs in the context of stressors to which we were not exposed during our early evolution, including overfeeding, underactivity, aging, artificial lighting and novel foodstuffs and drugs. We postulate that humans were not exposed through evolution to the current level of acute or chronic social stressors, and hence, that major depressive illness is associated with a parainflammatory state. ER stress refers to a complex program set into motion when the ER is challenged by the production or persistence of more proteins than it can effectively fold. If the ER response is overwhelmed, substantial amounts of calcium are released into the cytoplasm, leading to apoptosis. Parainflammation and ER stress generally occur simultaneously. We discuss three highly interrelated mediators that can effectively decrease parainflammation and ER stress, namely the central insulin, klotho and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) systems and propose that these systems may represent conceptually novel therapeutic targets for the amelioration of the affective, cognitive and systemic manifestations of major depressive disorder. Molecular Psychiatry (2013) 18, 154-165; doi:10.1038/mp.2012.167; published online 27 November 2012 C1 [Gold, P. W.; Pavlatou, M. G.] NIMH, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Licinio, J.] Australian Natl Univ, John Curtin Sch Med Res, Dept Translat Med, Canberra, ACT 2601, Australia. RP Gold, PW (reprint author), NIMH, Intramural Res Program, NIH, Room 2D46,10 Ctr Dr, Bethesda, MD 20892 USA. EM philipgold@mail.nih.gov RI Licinio, Julio/L-4244-2013 OI Licinio, Julio/0000-0001-6905-5884 NR 156 TC 19 Z9 21 U1 1 U2 17 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD FEB PY 2013 VL 18 IS 2 BP 154 EP 165 DI 10.1038/mp.2012.167 PG 12 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 112BW UT WOS:000316567800007 PM 23183489 ER PT J AU Chen, DT Jiang, X Akula, N Shugart, YY Wendland, JR Steele, CJM Kassem, L Park, JH Chatterjee, N Jamain, S Cheng, A Leboyer, M Muglia, P Schulze, TG Cichon, S Nothen, MM Rietschel, M McMahon, F AF Chen, D. T. Jiang, X. Akula, N. Shugart, Y. Y. Wendland, J. R. Steele, C. J. M. Kassem, L. Park, J-H Chatterjee, N. Jamain, S. Cheng, A. Leboyer, M. Muglia, P. Schulze, T. G. Cichon, S. Noethen, M. M. Rietschel, M. McMahon, F. CA BiGS TI Genome-wide association study meta-analysis of European and Asian-ancestry samples identifies three novel loci associated with bipolar disorder SO MOLECULAR PSYCHIATRY LA English DT Article DE ANK3; bipolar disorder; LBA1; meta-analysis; TRANK1; 3p21 ID DEPRESSIVE-DISORDERS; SUSCEPTIBILITY LOCI; EXPRESSION LEVEL; VALPROIC ACID; TWIN; RISK; REPLICATION; GENETICS; HETEROGENEITY; HERITABILITY AB Meta-analyses of bipolar disorder (BD) genome-wide association studies (GWAS) have identified several genome-wide significant signals in European-ancestry samples, but so far account for little of the inherited risk. We performed a meta-analysis of similar to 750 000 high-quality genetic markers on a combined sample of similar to 14 000 subjects of European and Asian-ancestry (phase I). The most significant findings were further tested in an extended sample of similar to 17 700 cases and controls (phase II). The results suggest novel association findings near the genes TRANK1 (LBA1), LMAN2L and PTGFR. In phase I, the most significant single nucleotide polymorphism (SNP), rs9834970 near TRANK1, was significant at the P = 2.4 x 10(-11) level, with no heterogeneity. Supportive evidence for prior association findings near ANK3 and a locus on chromosome 3p21.1 was also observed. The phase II results were similar, although the heterogeneity test became significant for several SNPs. On the basis of these results and other established risk loci, we used the method developed by Park et al. to estimate the number, and the effect size distribution, of BD risk loci that could still be found by GWAS methods. We estimate that >63 000 case-control samples would be needed to identify the similar to 105BD risk loci discoverable by GWAS, and that these will together explain <6% of the inherited risk. These results support previous GWAS findings and identify three new candidate genes for BD. Further studies are needed to replicate these findings and may potentially lead to identification of functional variants. Sample size will remain a limiting factor in the discovery of common alleles associated with BD. Molecular Psychiatry (2013) 18, 195-205; doi:10.1038/mp.2011.157; published online 20 December 2011 C1 [Chen, D. T.; Jiang, X.; Akula, N.; Shugart, Y. Y.; Wendland, J. R.; Steele, C. J. M.; Kassem, L.; Schulze, T. G.; McMahon, F.] NIMH, Human Genet Branch, Intramural Res Program, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Park, J-H; Chatterjee, N.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MA USA. [Jamain, S.; Leboyer, M.] Univ Paris Est, Grp Hosp Henri Mondor Albert Chenevier, AP HP, Fdn FondaMental,Inserm U955,Dept Psychiat, Creteil, France. [Cheng, A.] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan. [Muglia, P.] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Schulze, T. G.] Univ Gottingen, Univ Med Ctr, Dept Psychiat & Psychotherapy, Sect Psychiat Genet, D-37073 Gottingen, Germany. [Cichon, S.; Noethen, M. M.] Inst Neurosci & Med, Julich, Germany. [Cichon, S.; Noethen, M. M.] Univ Bonn, Dept Genom, Life & Brain Ctr, Bonn, Germany. [Rietschel, M.] Univ Mannheim, Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, D-68131 Mannheim, Germany. RP Chen, DT (reprint author), NIMH, Human Genet Branch, Intramural Res Program, NIH,US Dept Hlth & Human Serv, 35 Convent Dr,Room 1A-208, Bethesda, MD 20892 USA. EM chend4@mail.nih.gov RI Schulze, Thomas/H-2157-2013; Cichon, Sven/H-8803-2013; Cichon, Sven/B-9618-2014; Zhang, Peng/N-2920-2014; Cohen-Woods, Sarah/F-8674-2014; OI Jamain, Stephane/0000-0002-4321-4100; Cichon, Sven/0000-0002-9475-086X; Cichon, Sven/0000-0002-9475-086X; Zhang, Peng/0000-0003-1182-1392; McMahon, Francis/0000-0002-9469-305X; Craig, Ian/0000-0002-4063-1005; Cohen-Woods, Sarah/0000-0003-2199-6129; Nothen, Markus/0000-0002-8770-2464 FU NIMH NIH HHS [R01 MH094483] NR 69 TC 53 Z9 53 U1 0 U2 28 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD FEB PY 2013 VL 18 IS 2 BP 195 EP 205 DI 10.1038/mp.2011.157 PG 11 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 112BW UT WOS:000316567800012 PM 22182935 ER PT J AU Yamaji, D Kang, K Robinson, GW Hennighausen, L AF Yamaji, Daisuke Kang, Keunsoo Robinson, Gertraud W. Hennighausen, Lothar TI Sequential activation of genetic programs in mouse mammary epithelium during pregnancy depends on STAT5A/B concentration SO NUCLEIC ACIDS RESEARCH LA English DT Article ID ALVEOLAR CELL FATE; GROWTH-HORMONE; GLAND DEVELOPMENT; TRANSGENIC MICE; RNA-SEQ; DIFFERENTIATION; TRANSCRIPTION; EXPRESSION; PROLIFERATION; MILK AB The transcription factors Signal Transducer and Activator of Transcription (STAT) 5A/B mediate prolactin-induced mammary development during pregnancy. However, it is not clear how the different processes, expansion and maturation of alveolar precursor cells and the differential induction of milk protein genes are regulated on a molecular level. We have used mouse genetics and genome-wide analyses to determine how altering concentrations of STAT5A and STAT5B impacts mammary epithelial development during pregnancy and the regulation of target genes. The presence of only a single Stat5a or Stat5b allele was sufficient for the establishment of histologically undifferentiated alveolar units and two alleles permitted the execution of a differentiation program similar to that found with all four alleles. While one copy of Stat5 induced limited expression of target genes, two copies activated a lactation-like gene signature. Using ChIP-seq analyses on intact tissue under physiological conditions, we found that highly expressed and regulated genes were bound by STAT5 in their promoter proximal regions, whereas upstream binding had minor biological consequences. Remarkably, 80% of the genes bound by STAT5 in vivo were not under STAT5 control. RNA polymerase II intensity was directly proportional to STAT5 concentration only on STAT5 regulated genes providing mechanistic insight by which STAT5 activates mammary specific genes. C1 [Yamaji, Daisuke; Kang, Keunsoo; Robinson, Gertraud W.; Hennighausen, Lothar] NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20815 USA. [Hennighausen, Lothar] Dankook Univ, Natl Dept Nanobiomed Sci, Cheonan 330714, Chungnam, South Korea. [Hennighausen, Lothar] Dankook Univ, WCU Res Ctr Nanobiomed Sci, Cheonan 330714, Chungnam, South Korea. RP Hennighausen, L (reprint author), NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20815 USA. EM lotharh@mail.nih.gov FU Intramural Research Program (IRP) of NIDDK, NIH; Intramural Research Programs (IRP) of NIDDK at the National Institutes of Health (NIH), USA; World Class University Program, Ministry of Education, Science and Technology, through the National Research Foundation of Korea, South Korea [R31-10069]; WCU Research Center, Dankook University FX This work was supported by the Intramural Research Program (IRP) of NIDDK, NIH. D.Y.: Experimental design, mouse experiments, RNA-seq and ChIP-seq experiments, data analysis, writing manuscript; K. K.: bioinformatics data analysis, writing paper; G. W. R.: experimental design, mouse experiments, data analysis, writing manuscript; L. H.: experimental design, data analysis, writing manuscript. We thank Dr. Harold Smith (NIDDK Genomics core) for sequencing RNA-seq and ChIP-seq libraries.; The Intramural Research Programs (IRP) of NIDDK at the National Institutes of Health (NIH), USA. Funding for the open access charge: the World Class University Program, Ministry of Education, Science and Technology, through the National Research Foundation of Korea, South Korea [R31-10069]; WCU Research Center, Dankook University. NR 47 TC 32 Z9 32 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB PY 2013 VL 41 IS 3 BP 1622 EP 1636 DI 10.1093/nar/gks1310 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 109FM UT WOS:000316351800028 PM 23275557 ER PT J AU McIntyre, J Vidal, AE McLenigan, MP Bomar, MG Curti, E McDonald, JP Plosky, BS Ohashi, E Woodgate, R AF McIntyre, Justyna Vidal, Antonio E. McLenigan, Mary P. Bomar, Martha G. Curti, Elena McDonald, John P. Plosky, Brian S. Ohashi, Eiji Woodgate, Roger TI Ubiquitin mediates the physical and functional interaction between human DNA polymerases eta and iota SO NUCLEIC ACIDS RESEARCH LA English DT Article ID CELL NUCLEAR ANTIGEN; TRANSLESION SYNTHESIS POLYMERASES; PIGMENTOSUM VARIANT CELLS; C-TERMINAL DOMAIN; XERODERMA-PIGMENTOSUM; STRUCTURAL BASIS; REPLICATION MACHINERY; CRYSTAL-STRUCTURE; BINDING MOTIFS; ERROR-PRONE AB Human DNA polymerases eta and iota are best characterized for their ability to facilitate translesion DNA synthesis (TLS). Both polymerases (pols) co-localize in 'replication factories' in vivo after cells are exposed to ultraviolet light and this co-localization is mediated through a physical interaction between the two TLS pols. We have mapped the pol eta-iota interacting region to their respective ubiquitin-binding domains (UBZ in pol mu and UBM1 and UBM2 in pol iota), and demonstrate that ubiquitination of either TLS polymerase is a prerequisite for their physical and functional interaction. Importantly, while monoubiquitination of pol eta precludes its ability to interact with proliferating cell nuclear antigen (PCNA), it enhances its interaction with poli. Furthermore, a pol iota-ubiquitin chimera interacts avidly with both pol eta and PCNA. Thus, the ubiquitination status of pol eta, or poli plays a key regulatory function in controlling the protein partners with which each polymerase interacts, and in doing so, determines the efficiency of targeting the respective polymerase to stalled replication forks where they facilitate TLS. C1 [McIntyre, Justyna; Vidal, Antonio E.; McLenigan, Mary P.; Bomar, Martha G.; Curti, Elena; McDonald, John P.; Plosky, Brian S.; Ohashi, Eiji; Woodgate, Roger] NICHHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. RP Woodgate, R (reprint author), NICHHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. EM woodgate@nih.gov RI McIntyre, Justyna/M-9186-2014 FU National Institute of Child Health and Human Development/National Institutes of Health Intramural Research Program; Programa Ramon y Cajal (Ministerio de Ciencia e Innovacion, Spain); NICHD Intramural Research program FX The National Institute of Child Health and Human Development/National Institutes of Health Intramural Research Program (to R. W.); Programa Ramon y Cajal (Ministerio de Ciencia e Innovacion, Spain) (to A. V.). Funding for open access charge: NICHD Intramural Research program. NR 43 TC 9 Z9 9 U1 0 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB PY 2013 VL 41 IS 3 BP 1649 EP 1660 DI 10.1093/nar/gks1277 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 109FM UT WOS:000316351800030 PM 23248005 ER PT J AU Freudenthal, BD Beard, WA Wilson, SH AF Freudenthal, Bret D. Beard, William A. Wilson, Samuel H. TI DNA polymerase minor groove interactions modulate mutagenic bypass of a templating 8-oxoguanine lesion SO NUCLEIC ACIDS RESEARCH LA English DT Article ID OXIDATIVELY DAMAGED DNA; ERROR-FREE REPLICATION; ACTIVE-SITE; NUCLEOTIDE INSERTION; CRYSTAL-STRUCTURE; KINETIC-ANALYSIS; STRUCTURAL BASIS; STEADY-STATE; BETA; OPPOSITE AB A major base lesion resulting from oxidative stress is 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxoG) that has ambiguous coding potential. Error-free DNA synthesis involves 8-oxoG adopting an anti-conformation to base pair with cytosine whereas mutagenic bypass involves 8-oxoG adopting a syn-conformation to base pair with adenine. Left unrepaired the syn-8-oxoG/dAMP base pair results in a G-C to T-A transversion. During base excision repair of this mispair, DNA polymerase (pol) beta is confronted with gap filling opposite 8-oxoG. To determine how pol beta discriminates between anti- and syn-8-oxoG, we introduced a point mutation (R283K) to alter insertion specificity. Kinetic studies demonstrate that this substitution results in an increased fidelity opposite 8-oxoG. Structural studies with R283K pol 13 show that the binary DNA complex has 8-oxoG in equilibrium between anti- and syn-forms. Ternary complexes with incoming dCTP resemble the wild-type enzyme, with templating anti-8-oxoG base pairing with incoming cytosine. In contrast to wild-type pol D, the ternary complex of the R283K mutant with an incoming dATP-analogue and templating 8-oxoG resembles a G-A mismatched structure with 8-oxoG adopting an anti-conformation. These results demonstrate that the incoming nucleotide is unable to induce a syn-8-oxoG conformation without minor groove DNA polymerase interactions that influence templating (anti-/syn-equilibrium) of 8-oxoG while modulating fidelity. C1 [Freudenthal, Bret D.; Beard, William A.; Wilson, Samuel H.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov FU Division of Intramural Research Program of the National Institutes of health; National Institute of Environmental Health Sciences; National Institutes of Health [1U19CA105010]; [Z01-ES050158]; [Z01-ES050159] FX Research Project Numbers [Z01-ES050158 and Z01-ES050159]; Division of Intramural Research Program of the National Institutes of health, National Institute of Environmental Health Sciences and was in association with the National Institutes of Health [1U19CA105010]. Funding for open access charge: Research Project [Z01-ES050158]. NR 51 TC 17 Z9 17 U1 0 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB PY 2013 VL 41 IS 3 BP 1848 EP 1858 DI 10.1093/nar/gks1276 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 109FM UT WOS:000316351800045 PM 23267011 ER PT J AU Pavon-Eternod, M David, A Dittmar, K Berglund, P Pan, T Bennink, JR Yewdell, JW AF Pavon-Eternod, Mariana David, Alexandre Dittmar, Kimberly Berglund, Peter Pan, Tao Bennink, Jack R. Yewdell, Jonathan W. TI Vaccinia and influenza A viruses select rather than adjust tRNAs to optimize translation SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SYNONYMOUS CODON USAGE; EXPRESSION; PROTEIN; BIAS; EFFICIENCY; GENES; HOST; IMMUNE; CANCER; HIV-1 AB Transfer RNAs (tRNAs) are central to protein synthesis and impact translational speed and fidelity by their abundance. Here we examine the extent to which viruses manipulate tRNA populations to favor translation of their own genes. We study two very different viruses: influenza A virus (IAV), a medium-sized (13 kB genome) RNA virus; and vaccinia virus (VV), a large (200 kB genome) DNA virus. We show that the total cellular tRNA population remains unchanged following viral infection, whereas the polysome-associated tRNA population changes dramatically in a virus-specific manner. The changes in polysome-associated tRNA levels reflect the codon usage of viral genes, suggesting the existence of local tRNA pools optimized for viral translation. C1 [Pavon-Eternod, Mariana; David, Alexandre; Berglund, Peter; Bennink, Jack R.; Yewdell, Jonathan W.] NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. [Dittmar, Kimberly; Pan, Tao] Univ Chicago, Dept Biochem & Mol Biol, Chicago, IL 60637 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. EM jyewdell@nih.gov OI David, Alexandre/0000-0003-3365-1339 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases; National Institutes of Health [DP1 GM105386] FX Division of Intramural Research, National Institute of Allergy and Infectious Diseases; National Institutes of Health [DP1 GM105386 to T. P.]. Funding for open access charge: Division of Intramural Research, National Institute of Allergy and Infectious Diseases. NR 37 TC 10 Z9 12 U1 1 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB PY 2013 VL 41 IS 3 BP 1914 EP 1921 DI 10.1093/nar/gks986 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 109FM UT WOS:000316351800051 PM 23254333 ER PT J AU Becchio, C Del Giudice, M Dal Monte, O Latini-Corazzini, L Pia, L AF Becchio, Cristina Del Giudice, Marco Dal Monte, Olga Latini-Corazzini, Luca Pia, Lorenzo TI In your place: neuropsychological evidence for altercentric remapping in embodied perspective taking SO SOCIAL COGNITIVE AND AFFECTIVE NEUROSCIENCE LA English DT Article DE perspective taking; unilateral neglect; space representation; social space; altercentric remapping ID REPRESENTATIONAL NEGLECT; UNILATERAL NEGLECT; TRANSFORMATIONS; COGNITION; SPACE AB Humans are able to mentally adopt the spatial perspective of others and represent the visual world from their point of view. Here, we present neuropsychological evidence that information inaccessible from an egocentric perspective can be accessed from the perspective of another person. Patients affected by left neglect were asked to describe arrays of objects from their own egocentric perspective, from an opposite perspective (disembodied perspective taking), and from the point of view of another person actually seated in front of them (embodied perspective taking). Although disembodied perspective-taking ameliorated neglect severity, there was an even stronger positive effect of embodied perspective-taking: items presented on the left and neglected when reported from the egocentric perspective were instead recovered when patients assumed the perspective of the other. These findings suggest that perspective-taking entails an altercentric remapping of space, i.e. remapping of objects and locations coded with reference to the other person's body. C1 [Becchio, Cristina; Del Giudice, Marco; Dal Monte, Olga; Latini-Corazzini, Luca; Pia, Lorenzo] Dept Psychol, I-10123 Turin, Italy. [Becchio, Cristina; Del Giudice, Marco] Ctr Cognit Sci, I-10123 Turin, Italy. [Becchio, Cristina; Latini-Corazzini, Luca; Pia, Lorenzo] NIT, I-10043 Turin, Italy. [Becchio, Cristina; Latini-Corazzini, Luca; Pia, Lorenzo] Univ Turin, I-10123 Turin, Italy. [Dal Monte, Olga] NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. [Dal Monte, Olga] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Henry M Jackson Fdn, Rockville, MD USA. RP Pia, L (reprint author), Univ Turin, Dept Psychol, Via Po 14, I-10123 Turin, Italy. EM lorenzo.pia@unito.it RI Del Giudice, Marco/F-7007-2010; OI Del Giudice, Marco/0000-0001-8526-1573; dal monte, olga/0000-0002-7823-4769; Becchio, Cristina/0000-0002-6845-0521; Pia, Lorenzo/0000-0002-0360-3152 FU PRIN [prot. 2007JLKBL9_003]; Regione Piemonte, bando Scienze Umane e Sociali [4/2006] FX This research was funded by PRIN (Year 2007, prot. 2007JLKBL9_003) (to L. P.); the Regione Piemonte, bando Scienze Umane e Sociali 2008, L.R. n. 4/2006 (to C.B.). NR 23 TC 10 Z9 10 U1 2 U2 19 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1749-5016 J9 SOC COGN AFFECT NEUR JI Soc. Cogn. Affect. Neurosci. PD FEB PY 2013 VL 8 IS 2 BP 165 EP 170 DI 10.1093/scan/nsr083 PG 6 WC Neurosciences; Psychology; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 110CH UT WOS:000316419200006 PM 22133561 ER PT J AU Wu, H Mitra, M McCauley, MJ Thomas, JA Rouzina, I Musier-Forsyth, K Williams, MC Gorelick, RJ AF Wu, Hao Mitra, Mithun McCauley, Micah J. Thomas, James A. Rouzina, Ioulia Musier-Forsyth, Karin Williams, Mark C. Gorelick, Robert J. TI Aromatic residue mutations reveal direct correlation between HIV-1 nucleocapsid protein's nucleic acid chaperone activity and retroviral replication SO VIRUS RESEARCH LA English DT Article DE HIV-1; Infectivity; Nucleic acid chaperone; Nucleocapsid; Single-molecule DNA stretching; Zinc finger ID HUMAN-IMMUNODEFICIENCY-VIRUS; PRIMER BINDING-SITE; PREMATURE REVERSE TRANSCRIPTION; TIME-RESOLVED FLUORESCENCE; FUSION INHIBITOR T-20; INTEGRATION IN-VITRO; RNA PACKAGING SIGNAL; PLUS-STRAND TRANSFER; ZINC-FINGER MOTIFS; STRUCTURAL DETERMINANTS AB The human immunodeficiency virus type 1 (HIV-1) nucleocapsid (NC) protein plays an essential role in several stages of HIV-1 replication. One important function of HIV-1 NC is to act as a nucleic acid chaperone, in which the protein facilitates nucleic acid rearrangements important for reverse transcription and recombination. NC contains only 55 amino acids, with 15 basic residues and two zinc fingers, each having a single aromatic residue (Phe16 and Trp37). Despite its simple structure, HIV-1 NC appears to have optimal chaperone activity, including the ability to strongly aggregate nucleic acids, destabilize nucleic acid secondary structure, and facilitate rapid nucleic acid annealing. Here we combine single molecule DNA stretching experiments with ensemble solution studies of protein-nucleic acid binding affinity, oligonucleotide annealing, and nucleic acid aggregation to measure the characteristics of wild-type (WT) and aromatic residue mutants of HIV-1 NC that are important for nucleic acid chaperone activity. These in vitro results are compared to in vivo HIV-1 replication for viruses containing the same mutations. This work allows us to directly relate HIV-1 NC structure with its function as a nucleic acid chaperone in vitro and in vivo. We show that replacement of either aromatic residue with another aromatic residue results in a protein that strongly resembles WT NC. In contrast, single amino acid substitutions of either Phel 6Ala or Trp37Ala significantly slow down NC's DNA interaction kinetics, while retaining some helixdestabilization capability. A double Phe16A1a/Trp37Ala substitution further reduces the latter activity. Surprisingly, the ensemble nucleic acid binding, annealing, and aggregation properties are not significantly altered for any mutant except the double aromatic substitution with Ala. Thus, elimination of a single aromatic residue from either zinc finger strongly reduces NC's chaperone activity as determined by single molecule DNA stretching experiments without significantly altering its ensemble-averaged biochemical properties. Importantly, the substitution of aromatic residues with Ala progressively decreases NC's nucleic acid chaperone activity while also progressively inhibiting viral replication. Taken together, these data support the critical role of HIV-1 NC's aromatic residues, and establish a direct and statistically significant correlation between nucleic acid chaperone activity and viral replication. (C) 2012 Elsevier B.V. All rights reserved. C1 [Wu, Hao; McCauley, Micah J.; Williams, Mark C.] Northeastern Univ, Dept Phys, Boston, MA 02115 USA. [Mitra, Mithun; Musier-Forsyth, Karin] Ohio State Univ, Dept Chem & Biochem, Ctr Retrovirus Res, Ctr RNA Biol, Columbus, OH 43210 USA. [Thomas, James A.; Gorelick, Robert J.] SAIC Frederick Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Rouzina, Ioulia] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA. RP Williams, MC (reprint author), Northeastern Univ, Dept Phys, Boston, MA 02115 USA. EM mark@neu.edu; gorelicr@mail.nih.gov RI Mitra, Mithun/A-2133-2015; OI Williams, Mark C./0000-0003-3219-376X; Thomas, James/0000-0002-2509-490X FU National Cancer Institute; National Institutes of Health [HHSN261200800001E, GM072462, GM065056]; National Science Foundation [MCB-0744456] 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 with SAIC-Frederick, Inc. (RJG). 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 work was also funded by grants from the National Institutes of Health (GM072462, MCW; GM065056, KMF) and National Science Foundation (MCB-0744456, MCW). We wish to thank Donald G. Johnson, Jeremy Miller, Catherine V. Hixson, and Teresa L. Shatzer for their assistance with preparing plasmids, expression and purification of recombinant proteins, and cell culture assistance. NR 108 TC 18 Z9 18 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 J9 VIRUS RES JI Virus Res. PD FEB PY 2013 VL 171 IS 2 SI SI BP 263 EP 277 PG 15 WC Virology SC Virology GA 111JL UT WOS:000316517500001 PM 22814429 ER PT J AU Lyonnais, S Gorelick, RJ Heniche-Boukhalfa, F Bouaziz, S Parissi, V Mouscadet, JF Restle, T Gatell, JM Le Cam, E Mirambeau, G AF Lyonnais, Sebastien Gorelick, Robert J. Heniche-Boukhalfa, Fatima Bouaziz, Serge Parissi, Vincent Mouscadet, Jean-Francois Restle, Tobias Maria Gatell, Jose Le Cam, Eric Mirambeau, Gilles TI A protein ballet around the viral genome orchestrated by HIV-1 reverse transcriptase leads to an architectural switch: From nucleocapsid-condensed RNA to Vpr-bridged DNA SO VIRUS RESEARCH LA English DT Article DE HIV-1; Nucleocapsid; Viral protein r; Reverse transcription; Pre-integration complex; Integrase ID IMMUNODEFICIENCY-VIRUS TYPE-1; ACID CHAPERONE ACTIVITY; CHAIN VARIABLE FRAGMENTS; INHIBIT EARLY STAGES; C-TERMINAL DOMAIN; ZINC-FINGER; STRAND TRANSFER; NUCLEIC-ACIDS; IN-VITRO; PREINTEGRATION COMPLEXES AB HIV-1 reverse transcription is achieved in the newly infected cell before viral DNA (vDNA) nuclear import. Reverse transcriptase (RT) has previously been shown to function as a molecular motor, dismantling the nucleocapsid complex that binds the viral genome as soon as plus-strand DNA synthesis initiates. We first propose a detailed model of this dismantling in close relationship with the sequential conversion from RNA to double-stranded (ds) DNA, focusing on the nucleocapsid protein (NCp7). The HIV-1 DNA-containing pre-integration complex (PIC) resulting from completion of reverse transcription is translocated through the nuclear pore. The PIC nucleoprotein architecture is poorly understood but contains at least two HIV-1 proteins initially from the virion core, namely integrase (IN) and the viral protein r (Vpr). We next present a set of electron micrographs supporting that Vpr behaves as a DNA architectural protein, initiating multiple DNA bridges over more than 500 base pairs (bp). These complexes are shown to interact with NCp7 bound to single-stranded nucleic acid regions that are thought to maintain IN binding during dsDNA synthesis, concurrently with nucleocapsid complex dismantling. This unexpected binding of Vpr conveniently leads to a compacted but filamentous folding of the vDNA that should favor its nuclear import. Finally, nucleocapsid-like aggregates engaged in dsDNA synthesis appear to efficiently bind to F-actin filaments, a property that may be involved in targeting complexes to the nuclear envelope. More generally, this article highlights unique possibilities offered by in vitro reconstitution approaches combined with macromolecular imaging to gain insights into the mechanisms that alter the nucleoprotein architecture of the HIV-1 genome, ultimately enabling its insertion into the nuclear chromatin. (C) 2012 Elsevier B.V. All rights reserved. C1 [Lyonnais, Sebastien; Maria Gatell, Jose; Mirambeau, Gilles] IDIBAPS, AIDS Res Grp, E-08036 Barcelona, Spain. [Gorelick, Robert J.] SAIC Frederick Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Heniche-Boukhalfa, Fatima; Le Cam, Eric] Univ Paris 11, UMR CNRS 8126, F-94805 Villejuif, France. [Bouaziz, Serge] Univ Paris 05, Lab Cristallog, F-75006 Paris, France. [Bouaziz, Serge] Univ Paris 05, RMN Biol, UMR CNRS 8015, F-75006 Paris, France. [Parissi, Vincent] Univ Bordeaux Segalen, Lab Microbiol Fondamentale & Pathogenicite, CNRS UMR5234, Bordeaux, France. [Mouscadet, Jean-Francois] CNRS, ENS Cachan, LBPA, F-75700 Paris, France. [Restle, Tobias] Med Univ Lubeck, Inst Mol Med, Ctr Struct & Cell Biol Med CSCM, D-23538 Lubeck, Germany. [Mirambeau, Gilles] UPMC Sorbonne Univ, Fac Biol, F-75005 Paris, France. RP Mirambeau, G (reprint author), IDIBAPS, NUCARCHIV Project, AIDS Res Grp, Villaroel 170, E-08036 Barcelona, Spain. EM gilles.mirambeau@gmail.com RI bouaziz, serge/C-1401-2014; OI Lyonnais, Sebastien/0000-0002-3154-8568 FU European Community [237738]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; SIDACTION [A02011-2013]; EC [LSHG-CT-2003-503480] FX S. L., J.-F.M., S.B., E.L. and G.M. are grateful to ANRS-AC 14.2 for its funding, paying a special tribute to Pr. Roger Monier f. S.L. and G.M. are indebted to the European Community's Seventh Framework Program for the Grant Agreement IEF No. 237738. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E with SAIC-Frederick, Inc. (RJG). V.P. is grateful to SIDACTION A02011-2013 for its funding. T.R. acknowledges funding by EC-grant LSHG-CT-2003-503480. G.M. thanks Dr. Kashif Sadiq for a "last minute" editing of this manuscript. We also wish to thank Donald G. Johnson and Catherine V. Hixson of the AIDS and Cancer Virus Program for their assistance in preparing the recombinant nucleocapsid proteins used in this study. NR 149 TC 13 Z9 13 U1 0 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 J9 VIRUS RES JI Virus Res. PD FEB PY 2013 VL 171 IS 2 SI SI BP 287 EP 303 DI 10.1016/j.virusres.2012.09:008 PG 17 WC Virology SC Virology GA 111JL UT WOS:000316517500003 PM 23017337 ER PT J AU O'Carroll, IP Soheilian, F Kamata, A Nagashima, K Rein, A AF O'Carroll, Ina P. Soheilian, Ferri Kamata, Anne Nagashima, Kunio Rein, Alan TI Elements in HIV-1 Gag contributing to virus particle assembly SO VIRUS RESEARCH LA English DT Article DE HIV-1; Gag; Assembly; In vivo; Oligomerization ID ROUS-SARCOMA-VIRUS; IN-VITRO; HELICAL STRUCTURE; TYPE-1; PROTEIN; DOMAIN; DIMERIZATION; MYRISTOYLATION; INFECTIVITY; PRECURSOR AB The Gag polyprotein is the building block of retroviral particles and its expression is sufficient for assembly in cells. In HIV-1, nucleic acid (NA) is required for recombinant Gag molecules to assemble in a defined system in vitro. Experiments performed by Barklis and co-workers suggested that NA contributes to assembly by promoting Gag oligomerization. Gag is composed of four main domains: the matrix (MA), capsid (CA), nucleocapsid (NC), and p6 domains. We have recently shown that the SP1 linker, which lies between the CA and NC domains, assumes a helical structure at high, but not low, concentrations. We suggested that Gag oligomerization mediates assembly via an SP1-dependent conformational switch that exposes new interfaces for assembly. Although NA is required for assembly in vitro, deletion of NC, the main RNA-binding domain, does not eliminate particle formation in vivo; these particles lack NA. We hypothesized that alternative pathways that lead to Gag oligomerization or an increase in local Gag concentration, namely Gag-membrane or inter-protein interactions, rescue assembly in the absence of NC-RNA binding. We constructed mutants in which either Gag-membrane binding, the Gag dimer interface, or NC-RNA binding are disrupted. None of these mutants disables assembly. However, combined mutations in any two of these three classes render Gag completely unable to form virus-like particles. Thus, it seems, Gag utilizes at least three types of interactions to form oligomers and any two out of the three are sufficient for assembly. (C) 2012 Published by Elsevier B.V. C1 [O'Carroll, Ina P.; Rein, Alan] NCI, HIV Drug Resistance Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Soheilian, Ferri; Kamata, Anne; Nagashima, Kunio] SAIC Frederick Inc, Adv Technol Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Rein, A (reprint author), NCI, HIV Drug Resistance Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM reina@mail.nih.gov FU Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research; NIH Intramural AIDS Targeted Antiviral Program; National Institutes of Health [HHSN26120080001E] FX We thank Demetria Harvin and Jane Mirro for technical assistance and Rachael Crist for participation in the project. We thank David Ott and Robert Gorelick for helpful discussions. This work was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, in part by the NIH Intramural AIDS Targeted Antiviral Program, and part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. NR 32 TC 17 Z9 17 U1 1 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 J9 VIRUS RES JI Virus Res. PD FEB PY 2013 VL 171 IS 2 SI SI BP 341 EP 345 DI 10.1016/j.virusres.2012.10.016 PG 5 WC Virology SC Virology GA 111JL UT WOS:000316517500007 PM 23099087 ER PT J AU Hergott, CB Mitra, M Guo, JH Wu, TY Miller, JT Iwatani, Y Gorelick, RJ Levin, JG AF Hergott, Christopher B. Mitra, Mithun Guo, Jianhui Wu, Tiyun Miller, Jennifer T. Iwatani, Yasumasa Gorelick, Robert J. Levin, Judith G. TI Zinc finger function of HIV-1 nucleocapsid protein is required for removal of 5 '-terminal genomic RNA fragments: A paradigm for RNA removal reactions in HIV-1 reverse transcription SO VIRUS RESEARCH LA English DT Article DE HIV-1 nucleocapsid protein; Nucleic acid chaperone; Helix destabilizing activity; 5 '-Terminal genomic RNA fragments; RNase H cleavage; Reverse transcription ID ACID-CHAPERONE ACTIVITY; STRONG-STOP DNA; PLUS-STRAND TRANSFER; H ACTIVITY; IN-VITRO; VIRUS; MECHANISM; INHIBITION; IDENTIFICATION; REPLICATION AB During (-) strong-stop DNA [(-) SSDNA] synthesis, RNase H cleavage of genomic viral RNA generates small 5'-terminal RNA fragments (14-18 nt) that remain annealed to the DNA. Unless these fragments are removed, the minus-strand transfer reaction, required for (-) SSDNA elongation, cannot occur. Here, we describe the mechanism of 5'-terminal RNA removal and the roles of HIV-1 nucleocapsid protein (NC) and RNase H cleavage in this process. Using an NC-dependent system that models minus-strand transfer, we show that the presence of short terminal fragments pre-annealed to (-) SSDNA has no impact on strand transfer, implying efficient fragment removal. Moreover, in reactions with an RNase H- reverse transcriptase mutant, NC alone is able to facilitate fragment removal, albeit less efficiently than in the presence of both RNase H activity and NC. Results obtained from novel electrophoretic gel mobility shift and Forster Resonance Energy Transfer assays, which each directly measure RNA fragment release from a duplex in the absence of DNA synthesis, demonstrate for the first time that the architectural integrity of NC's zinc finger (ZF) domains is absolutely required for this reaction. This suggests that NC's helix destabilizing activity (associated with the ZFs) facilitates strand exchange through the displacement of these short terminal RNAs by the longer 3' acceptor RNA, which forms a more stable duplex with (-) SSDNA. Taken together with previously published results, we conclude that NC-mediated fragment removal is linked mechanistically with selection of the correct primer for plus-strand DNA synthesis and tRNA removal step prior to plus-strand transfer. Thus, HIV-1 has evolved a single mechanism for these RNA removal reactions that are critical for successful reverse transcription. Published by Elsevier B.V. C1 [Hergott, Christopher B.; Mitra, Mithun; Guo, Jianhui; Wu, Tiyun; Iwatani, Yasumasa; Levin, Judith G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Viral Gene Regulat, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Miller, Jennifer T.] NCI, Reverse Transcriptase Biochem Sect, HIV Drug Resistance Program, NIH,Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Gorelick, Robert J.] SAIC Frederick Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Levin, JG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Viral Gene Regulat, Program Genom Differentiat, NIH, Bldg 6B,Room 216,6 Ctr Dr, Bethesda, MD 20892 USA. EM levinju@mail.nih.gov RI Mitra, Mithun/A-2133-2015 FU Intramural Research Program at the National Institutes of Health (Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Cancer Institute; Frederick National Laboratory for Cancer Research; National Institutes of Health [HHSN261200800001E] FX We thank Donald G. Johnson and Catherine V. Hixson for their valuable assistance with the production and purification of the recombinant NC proteins and Dr. Stuart Le Grice for RNase H- RT. This work was supported in part by the Intramural Research Program at the National Institutes of Health (Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.B.H., M.M., J.G., T.W., Y.I., J.G.L.) and the National Cancer Institute, Frederick National Laboratory for Cancer Research (J.T.M.)). 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 with SAIC-Frederick, Inc. (R.J.G.). 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 59 TC 6 Z9 6 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 J9 VIRUS RES JI Virus Res. PD FEB PY 2013 VL 171 IS 2 SI SI BP 346 EP 355 DI 10.1016/j.virusres.2012.08.013 PG 10 WC Virology SC Virology GA 111JL UT WOS:000316517500008 PM 23149014 ER PT J AU Levin, JG AF Levin, Judith G. TI Jianhui Guo 1959-2012 Obituary SO VIRUS RESEARCH LA English DT Biographical-Item C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Viral Gene Regulat, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. RP Levin, JG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Viral Gene Regulat, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. EM levinju@mail.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 J9 VIRUS RES JI Virus Res. PD FEB PY 2013 VL 171 IS 2 SI SI BP 356 EP 356 DI 10.1016/j.virusres.2012.11.001 PG 1 WC Virology SC Virology GA 111JL UT WOS:000316517500009 PM 23414628 ER PT J AU Chen, CY Liu, X Boris-Lawrie, K Sharma, A Jeang, KT AF Chen, Chia-Yen Liu, Xiang Boris-Lawrie, Kathleen Sharma, Amit Jeang, Kuan-Teh TI Cellular RNA helicases and HIV-1: Insights from genome-wide, proteomic, and molecular studies SO VIRUS RESEARCH LA English DT Article DE RNA helicases; Human immunodeficiency virus type 1; (HIV-1); DEAD-Box domain; Antiviral ID VIRUS TYPE-1 REPLICATION; DEAD-BOX PROTEINS; RIG-I; MICRORNA EXPRESSION; VIRAL REPLICATION; SILENCING PATHWAY; MOV10 PROTEIN; REV FUNCTION; HUMAN-CELLS; BINDING AB RNA helicases are ubiquitous in plants and animals and function in many cellular processes. Retroviruses, such as human immunodeficiency virus (HIV-1), encode no RNA helicases in their genomes and utilize host cellular RNA helicases at various stages of their life cycle. Here, we briefly summarize the roles RNA helicases play in HIV-1 replication that have been identified recently, in part, through genome-wide screenings, proteomics, and molecular studies. Some of these helicases augment virus propagation while others apparently participate in antiviral defenses against viral replication. Published by Elsevier B.V. C1 [Chen, Chia-Yen; Liu, Xiang; Jeang, Kuan-Teh] NIAID, Mol Virol Sect 1, Lab Mol, NIH, Bethesda, MD 20892 USA. [Boris-Lawrie, Kathleen; Sharma, Amit] Ohio State Univ, Dept Vet Biosci, Ctr Retrovirus Res, Columbus, OH 43210 USA. RP Jeang, KT (reprint author), 9000 Rockville Pike,Bldg 4,Room 303, Bethesda, MD 20892 USA. EM kjeang@niaid.nih.gov RI Liu, Xiang/F-5731-2014 FU NIAID, NIH, USA; NCI, NIH [P30CA100730, R01CA108882]; IATAP program from the office of the Director, NIH FX Research in KTJ's laboratory is supported by intramural funds from NIAID, NIH, USA; and by the IATAP program from the office of the Director, NIH. Research in KBL's laboratory is supported by grants P30CA100730 and R01CA108882 from NCI, NIH. NR 92 TC 4 Z9 4 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 EI 1872-7492 J9 VIRUS RES JI Virus Res. PD FEB PY 2013 VL 171 IS 2 SI SI BP 357 EP 365 DI 10.1016/j.virusres.2012.06.022 PG 9 WC Virology SC Virology GA 111JL UT WOS:000316517500010 PM 22814432 ER PT J AU Rajagopalan, S Long, EO AF Rajagopalan, Sumati Long, Eric O. TI A positive role for senescence in reproduction? SO AGING-US LA English DT Editorial Material ID NATURAL-KILLER-CELLS; CELLULAR SENESCENCE C1 [Rajagopalan, Sumati; Long, Eric O.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Rajagopalan, S (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM sumi@nih.gov; eLong@nih.gov RI Long, Eric/G-5475-2011 OI Long, Eric/0000-0002-7793-3728 NR 8 TC 2 Z9 2 U1 0 U2 0 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 FEB PY 2013 VL 5 IS 2 BP 96 EP 97 PG 2 WC Cell Biology SC Cell Biology GA 104HL UT WOS:000315982700002 PM 23518705 ER PT J AU Saini, N Zhang, Y Usdin, K Lobachev, KS AF Saini, Natalie Zhang, Yu Usdin, Karen Lobachev, Kirill S. TI When secondary comes first - The importance of non-canonical DNA structures SO BIOCHIMIE LA English DT Review DE Triplex; G-quartet; Hairpin; Cruciform; Holliday junction; RNA:DNA hybrid; Replication transcription collision ID G-QUADRUPLEXES; DISEASE AB Secondary structure-forming DNA motifs have achieved infamy because of their association with a variety of human diseases and cancer. The 3rd FASEB summer conference on dynamic DNA structures focused on the mechanisms responsible for the instabilities inherent to repetitive DNA and presented many exciting and novel aspects related to the metabolism of secondary structures. In addition, the meeting encompassed talks and posters on the dynamic structures that are generated during DNA metabolism including nicked DNA, Holliday junctions and RNA:DNA hybrids. New approaches for analysis and sequencing technologies put forth secondary structures and other DNA intermediates as vital regulators of a variety of cellular processes that contribute to evolution, polymorphisms and diseases. (c) 2012 Elsevier Masson SAS. All rights reserved. C1 [Saini, Natalie; Zhang, Yu; Lobachev, Kirill S.] Georgia Inst Technol, Sch Biol, Atlanta, GA 30332 USA. [Saini, Natalie; Zhang, Yu; Lobachev, Kirill S.] Georgia Inst Technol, Inst Bioengn & Biosci, Atlanta, GA 30332 USA. [Usdin, Karen] NIDDKD, Sect Gene Struct & Dis, NIH, Bethesda, MD 20892 USA. RP Lobachev, KS (reprint author), Georgia Inst Technol, Sch Biol, 310 Ferst Dr, Atlanta, GA 30332 USA. EM kirill.lobachev@biology.gatech.edu FU NSF [MCB-0818122]; NIH [R01GM082950] FX We are grateful to all the participants at the meeting who agreed to present unpublished results in this review. On behalf of the organizers, we would also like to thank ABCAM, American Society for Biochemistry and Molecular Biology, Annual Reviews, Elsevier, New England Biolabs, Inc., Public Library of Science and Tufts University, School of Arts and Sciences for their generous support for the meeting. The studies in KL laboratory were supported by the grants MCB-0818122 from NSF and R01GM082950 from NIH. NR 10 TC 10 Z9 12 U1 3 U2 38 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0300-9084 J9 BIOCHIMIE JI Biochimie PD FEB PY 2013 VL 95 IS 2 BP 117 EP 123 DI 10.1016/j.biochi.2012.10.005 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 099IH UT WOS:000315614200001 PM 23084930 ER PT J AU Perez, EA Press, MF Dueck, AC Jenkins, RB Kim, C Chen, BY Villalobos, I Paik, S Buyse, M Wiktor, AE Meyer, R Finnigan, M Zujewski, J Shing, M Stern, HM Lingle, WL Reinholz, MM Slamon, DJ AF Perez, Edith A. Press, Michael F. Dueck, Amylou C. Jenkins, Robert B. Kim, Chungyeul Chen, Beiyun Villalobos, Ivonne Paik, Soonmyung Buyse, Marc Wiktor, Anne E. Meyer, Reid Finnigan, Melanie Zujewski, JoAnne Shing, Mona Stern, Howard M. Lingle, Wilma L. Reinholz, Monica M. Slamon, Dennis J. TI Immunohistochemistry and fluorescence in situ hybridization assessment of HER2 in clinical trials of adjuvant therapy for breast cancer (NCCTG N9831, BCIRG 006, and BCIRG 005) SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Breast cancer; HER2 testing; FISH; IHC; Concordance ID HER-2/NEU GENE AMPLIFICATION; INTRATUMORAL HETEROGENEITY; CHROMOSOME-17; TRASTUZUMAB; CARCINOMAS; GUIDELINES; SPECIMENS; ONCOGENE AB A comprehensive, blinded, pathology evaluation of HER2 testing in HER2-positive/negative breast cancers was performed among three central laboratories. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analyses were performed on 389 tumor blocks from three large adjuvant trials: N9831, BCIRG-006, and BCIRG-005. In 123 cases, multiple blocks were examined. HER2 status was defined according to FDA-approved guidelines and was independently re-assessed at each site. Discordant cases were adjudicated at an on-site, face-to-face meeting. Results across three independent pathologists were concordant by IHC in 351/381 (92 %) and FISH in 343/373 (92 %) blocks. Upon adjudication, consensus was reached on 16/30 and 18/30 of discordant IHC and FISH cases, respectively, resulting in overall concordance rates of 96 and 97 %. Among 155 HER2-negative blocks, HER2 status was confirmed in 153 (99 %). In the subset of 102 HER2-positive patients from N9831/BCIRG-006, primary blocks from discordant cases were selected, especially those with discordant test between local and central laboratories. HER2 status was confirmed in 73 (72 %) of these cases. Among 118 and 113 cases with IHC and FISH results and > 1 block evaluable, block-to-block variability/heterogeneity in HER2 results was seen in 10 and 5 %, respectively. IHC-/FISH- was confirmed for 57/59 (97 %) primary blocks from N9831 (locally positive, but centrally negative); however, 5/22 (23 %) secondary blocks showed HER2 positivity. Among 53 N9831 patients with HER2-normal disease adjudicated as IHC-/FISH-(although locally positive), there was a non-statistically significant improvement in disease-free survival with concurrent trastuzumab compared to chemotherapy alone (adjusted hazard ratio 0.34; 95 % CI, 0.11-1.05; p = 0.06). There were similar agreements for IHC and FISH among pathologists (92 % each). Agreement was improved at adjudication (96 %). HER2 tumor heterogeneity appears to partially explain discordant results in cases initially tested as positive and subsequently called negative. C1 [Perez, Edith A.] Mayo Clin, Jacksonville, FL 32224 USA. [Press, Michael F.; Villalobos, Ivonne] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Dueck, Amylou C.] Mayo Clin, Scottsdale, AZ 85259 USA. [Jenkins, Robert B.; Chen, Beiyun; Wiktor, Anne E.; Meyer, Reid; Lingle, Wilma L.; Reinholz, Monica M.] Mayo Clin, Rochester, MN 55905 USA. [Kim, Chungyeul; Paik, Soonmyung; Finnigan, Melanie] Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA 15212 USA. [Buyse, Marc] IDDI, B-1340 Louvain, Belgium. [Zujewski, JoAnne] NCI, Bethesda, MD 20892 USA. [Shing, Mona; Stern, Howard M.] Genentech Inc, San Francisco, CA 94080 USA. [Slamon, Dennis J.] Univ Calif Los Angeles, Los Angeles, CA 90095 USA. RP Perez, EA (reprint author), Mayo Clin, 4500 San Pablo Rd S, Jacksonville, FL 32224 USA. EM perez.edith@mayo.edu OI kim, chungyeul/0000-0002-9636-5228 FU Genentech; GSK; NIH/NCI; Breast Cancer Research Foundation; Ventana FX Dr. Perez receives research funding from Genentech, GSK, NIH/NCI, and the Breast Cancer Research Foundation. Dr. Paik receives funding from GSK. Dr. Press is a consultant for Genentech, Ventana, Roche, GlaxoSmithKline, and Halozyme. He also receives research funding from Ventana. Dr. Slamon is a consultant for Genentech and Sanofi-Aventis. Dr. Shing receives remuneration for employment at Genentech Inc. Dr. Stern receives remuneration for employment at Genentech Research and Early Development. He also has stock ownership in Roche Holding AG. All other authors declare that they have no conflicts of interest. NR 29 TC 39 Z9 40 U1 1 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD FEB PY 2013 VL 138 IS 1 BP 99 EP 108 DI 10.1007/s10549-013-2444-y PG 10 WC Oncology SC Oncology GA 099CX UT WOS:000315598200010 PM 23420271 ER PT J AU Helenius, A Moss, B AF Helenius, Ari Moss, Bernard TI Virus entry - an unwilling collaboration by the cell Editorial overview SO CURRENT OPINION IN VIROLOGY LA English DT Editorial Material C1 [Helenius, Ari] ETH, Inst Biochem, CH-8093 Zurich, Switzerland. [Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Helenius, A (reprint author), ETH, Inst Biochem, HPM E 6-3,Schafmattstr 18, CH-8093 Zurich, Switzerland. EM ari.helenius@bc.biol.ethz.ch; bmoss@nih.gov FU Intramural NIH HHS [ZIA AI000539-26] NR 0 TC 3 Z9 3 U1 0 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1879-6257 J9 CURR OPIN VIROL JI Curr. Opin. Virol. PD FEB PY 2013 VL 3 IS 1 BP 1 EP 2 DI 10.1016/j.coviro.2013.01.003 PG 2 WC Virology SC Virology GA 101FE UT WOS:000315759800001 PM 23395460 ER PT J AU Pierson, TC Kielian, M AF Pierson, Theodore C. Kielian, Margaret TI Flaviviruses: braking the entering SO CURRENT OPINION IN VIROLOGY LA English DT Article ID BORNE ENCEPHALITIS-VIRUS; WEST-NILE-VIRUS; HUMAN DENDRITIC CELLS; ENVELOPE PROTEIN-E; DENGUE-VIRUS; MEMBRANE-FUSION; INFECTIOUS ENTRY; HEPARAN-SULFATE; DC-SIGN; ANTIVIRAL COMPOUNDS AB Flaviviruses are small spherical virus particles covered by a dense icosahedral array of envelope (E) proteins that mediate virus attachment to cells and the fusion of viral and cellular membranes. Our understanding of the mechanism by which flavivirus E proteins orchestrate entry into cells has been advanced by studies of E structure and arrangement on the virion at different steps of the virus entry/membrane fusion process. When combined with an increasingly clear (albeit still incomplete) view of the cell biology of virus entry, these advances suggest new antiviral strategies. Indeed, inhibitors that target cellular and viral processes involved in entry show promise as powerful tools to study this critical step of the viral lifecycle, and with luck, may ultimately lead to therapeutic advances. C1 [Pierson, Theodore C.] NIAID, Viral Pathogenesis Sect, NIH, Bethesda, MD 20892 USA. [Kielian, Margaret] Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA. RP Pierson, TC (reprint author), NIAID, Viral Pathogenesis Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM piersontc@mail.nih.gov FU intramural program of the National Institute of Allergy and Infectious Disease; National Institutes of Health [GM057454, AI075647, U54AI057158-Lipkin] FX Work in the authors' laboratories was supported by the intramural program of the National Institute of Allergy and Infectious Disease (TCP), and by National Institutes of Health grants GM057454, AI075647, and U54AI057158-Lipkin (MK). The authors wish to thank Dr. Heather Hickman and members of our laboratories for critical evaluation of this review. We would like to thank Ethan Tyler (NIH/OD) and Phong Lee (NIAID, NIH) for assistance with preparation of the figures. We acknowledge the important contributions of those researchers whose work was not fully cited due to space limitations. NR 86 TC 37 Z9 39 U1 3 U2 33 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1879-6257 J9 CURR OPIN VIROL JI Curr. Opin. Virol. PD FEB PY 2013 VL 3 IS 1 BP 3 EP 12 DI 10.1016/j.coviro.2012.12.001 PG 10 WC Virology SC Virology GA 101FE UT WOS:000315759800002 PM 23352692 ER PT J AU Mendola, P Brett, K DiBari, JN Pollack, AZ Tandon, R Shenassa, ED AF Mendola, Pauline Brett, Kate DiBari, Jessica N. Pollack, Anna Z. Tandon, Rashmi Shenassa, Edmond D. TI Menopause and lead body burden among US women aged 45-55, NHANES 1999-2010 SO ENVIRONMENTAL RESEARCH LA English DT Article DE Lead; Menopause; Women's health; Epidemiology; Environment ID NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; FOLLICLE-STIMULATING-HORMONE; POSTMENOPAUSAL WOMEN; REPRODUCTIVE HORMONES; LUTEINIZING-HORMONE; MENSTRUAL CYCLES; BONE; TRANSITION; GIRLS AB Background: Environmental factors in menopause have received limited attention. Lead is a known reproductive toxicant associated with delayed puberty in girls that may also affect menopause. Methods: The odds of menopause among US women aged 45-55 were estimated in the National Health and Nutrition Examination Survey, 1999-2010, in relation to quartiles of blood lead. Women still menstruating (n=2158) were compared to women with natural menopause (n=1063). Logistic regression models included age, race/ethnicity, current hormone use, poverty, smoking and where available, bone density or bone alkaline phosphatase. Results: Lead levels (ug/dL) were higher in menopausal women, geometric mean (standard error)=1.71 (0.04) vs. 1.23 (0.02). Adjusted odds of menopause and 95% confidence intervals for lead quartiles (lowest quartile referent) were 1.7 (1.0-2.8), 2.1 (1.2-3.6), and 4.2 (2.5-7.0) respectively. Results adjusting for bone markers were generally similar but had less precision. Conclusions: Blood lead was associated with natural menopause in US women even after adjustment for bone turnover. This raises concern that lead exposure, even at low levels, may shorten women's reproductive lifespan. Published by Elsevier Inc. C1 [Mendola, Pauline; Pollack, Anna Z.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Rockville, MD 20852 USA. [Brett, Kate; Tandon, Rashmi] CDC, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [DiBari, Jessica N.; Shenassa, Edmond D.] Univ Maryland, Dept Family Sci, Sch Publ Hlth, Maternal & Child Hlth Program, College Pk, MD 20742 USA. RP Mendola, P (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, 6100 Execut Blvd, Rockville, MD 20852 USA. EM pauline.mendola@nih.gov OI Pollack, Anna/0000-0002-4313-3298; Mendola, Pauline/0000-0001-5330-2844 FU Intramural Research Program of the NIH; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This research was supported in part by the Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 25 TC 6 Z9 6 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 J9 ENVIRON RES JI Environ. Res. PD FEB PY 2013 VL 121 BP 110 EP 113 DI 10.1016/j.envres.2012.12.009 PG 4 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 101CV UT WOS:000315753700015 PM 23352036 ER PT J AU Fujiwara, K Allison, RD Wang, RY Bare, P Matsuura, K Schechterly, C Murthy, K Marincola, FM Alter, HJ AF Fujiwara, Kei Allison, Robert D. Wang, Richard Y. Bare, Patricia Matsuura, Kentaro Schechterly, Cathy Murthy, Krishna Marincola, Francesco M. Alter, Harvey J. TI Investigation of Residual Hepatitis C Virus in Presumed Recovered Subjects SO HEPATOLOGY LA English DT Article ID SUSTAINED VIROLOGICAL RESPONSE; BLOOD MONONUCLEAR-CELLS; HCV-INFECTED PATIENTS; PERIPHERAL-BLOOD; ANTIVIRAL THERAPY; REPLICATION; PERSISTENCE; DONORS; RNA; REEMERGENCE AB Recent studies have found hepatitis C virus (HCV) RNA in peripheral blood mononuclear cells (PBMCs) of the majority of presumed recovered subjects. We investigated this unexpected finding using samples from patients whose HCV RNA and anti-HCV status had been serially confirmed. HCV RNA was detected in PBMCs from 66 of 67 chronic HCV carriers. Subpopulation analysis revealed that the viral load (log copies/10(6) cells) in B cells (4.14 +/- 0.71) was higher than in total PBMCs (3.62 +/- 0.71; P < 0.05), T cells (1.67 +/- 0.88; P < 0.05), and non-B/T cells (2.48 +/- 1.15; P < 0.05). HCV negative-strand RNA was not detected in PBMCs from any of 25 chronically infected patients. No residual viral RNA was detected in total PBMCs or plasma of 59 presumed recovered subjects (11 spontaneous and 48 treatment induced) using nested real-time polymerase chain reaction with a detection limit of 2 copies/mu g RNA (from similar to 1 x 10(6) cells). PBMCs from 2 healthy HCV-negative blood donors became HCV RNA positive, with B-cell predominance, when mixed in vitro with HCV RNA-positive plasma, thus passively mimicking cells from chronic HCV carriers. No residual HCV was detected in liver or other tissues from 2 spontaneously recovered chimpanzees. Conclusion: (1) HCV RNA was detected in PBMCs of most chronic HCV carriers and was predominant in the B-cell subpopulation; (2) HCV detected in PBMCs was in a nonreplicative form; (3) HCV passively adsorbed to PBMCs of healthy controls in vitro, becoming indistinguishable from PBMCs of chronic HCV carriers; and (4) residual HCV was not detected in plasma or PBMCs of any spontaneous or treatment-recovered subjects or in chimpanzee liver, suggesting that the classic pattern of recovery from HCV infection is generally equivalent to viral eradication. (HEPATOLOGY 2013;57:483-491) C1 [Fujiwara, Kei; Allison, Robert D.; Wang, Richard Y.; Bare, Patricia; Schechterly, Cathy; Marincola, Francesco M.; Alter, Harvey J.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Matsuura, Kentaro] Nagoya City Univ, Dept Gastroenterol & Metab, Nagoya, Aichi, Japan. [Murthy, Krishna] Texas Biomed Res Inst, San Antonio, TX USA. [Fujiwara, Kei] Nagoya Daini Red Cross Hosp, Dept Gastroenterol & Hepatol, Nagoya, Aichi, Japan. [Allison, Robert D.] USN, San Diego, CA 92152 USA. [Bare, Patricia] Acad Nacl Med Buenos Aires, Inst Invest Hematol, Buenos Aires, DF, Argentina. RP Alter, HJ (reprint author), NIH, Dept Transfus Med, Bldg 10,Room 1C-711,10 Ctr Dr, Bethesda, MD 20892 USA. EM HAlter@cc.nih.gov OI Allison, Robert/0000-0001-8458-5250 FU Intramural Research Program of the Warren G. Magnuson Clinical Center, National Institutes of Health; Hepatitis Virus Research Foundation of Japan FX This research was supported by the Intramural Research Program of the Warren G. Magnuson Clinical Center, National Institutes of Health. K.F. was supported by the Hepatitis Virus Research Foundation of Japan NR 33 TC 20 Z9 20 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD FEB PY 2013 VL 57 IS 2 BP 483 EP 491 DI 10.1002/hep.25921 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 099TA UT WOS:000315643400009 PM 22729600 ER PT J AU Vickers, KC Shoucri, BM Levin, MG Wu, H Pearson, DS Osei-Hwedieh, D Collins, FS Remaley, AT Sethupathy, P AF Vickers, Kasey C. Shoucri, Bassem M. Levin, Michael G. Wu, Han Pearson, Daniel S. Osei-Hwedieh, David Collins, Francis S. Remaley, Alan T. Sethupathy, Praveen TI MicroRNA-27b Is a Regulatory Hub in Lipid Metabolism and Is Altered in Dyslipidemia SO HEPATOLOGY LA English DT Article ID CHOLESTEROL HOMEOSTASIS; HEART-DISEASE; SMALL RNAS; IN-VIVO; PROTEIN; IDENTIFICATION; EXPRESSION; GENES; LIVER; MICE AB Cellular and plasma lipid levels are tightly controlled by complex gene regulatory mechanisms. Elevated plasma lipid content, or hyperlipidemia, is a significant risk factor for cardiovascular morbidity and mortality. MicroRNAs (miRNAs) are posttranscriptional regulators of gene expression and have emerged as important modulators of lipid homeostasis, but the extent of their role has not been systematically investigated. In this study we performed high-throughput small RNA sequencing and detected approximate to 150 miRNAs in mouse liver. We then employed an unbiased, in silico strategy to identify miRNA regulatory hubs in lipid metabolism, and miR-27b was identified as the strongest such hub in human and mouse liver. In addition, hepatic miR-27b levels were determined to be sensitive to plasma hyperlipidemia, as evidenced by its approximate to 3-fold up-regulation in the liver of mice on a highfat diet (42% calories from fat). Further, we showed in a human hepatocyte cell line (Huh7) that miR-27b regulates the expression (messenger RNA [mRNA] and protein) of several key lipid-metabolism genes, including Angptl3 and Gpam. Finally, we demonstrated that hepatic miR-27b and its target genes are inversely altered in a mouse model of dyslipidemia and atherosclerosis. Conclusion: miR-27b is responsive to lipid levels and controls multiple genes critical to dyslipidemia. (HEPATOLOGY 2013;57:533-542) C1 [Vickers, Kasey C.; Shoucri, Bassem M.; Levin, Michael G.; Osei-Hwedieh, David; Remaley, Alan T.] NHLBI, Lipoprot Metab Sect, NIH, Bethesda, MD 20892 USA. [Wu, Han] NHLBI, DNA Sequencing & Computat Biol Core, NIH, Bethesda, MD 20892 USA. [Pearson, Daniel S.; Collins, Francis S.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Sethupathy, Praveen] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Sethupathy, Praveen] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. RP Sethupathy, P (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. EM praveen_sethupathy@med.unc.edu RI Wu, Han/E-3455-2013 OI Wu, Han/0000-0002-3972-698X FU National Human Genome Research Institute (NHGRI); National Heart, Lung, and Blood Institute (NHLBI) [HL113039-01]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [4R00DK091318-02] FX Supported by the intramural programs of the National Human Genome Research Institute (NHGRI) and the National Heart, Lung, and Blood Institute (NHLBI), a K22 grant HL113039-01 (to K.C.V.) from the NHLBI, and an R00 grant 4R00DK091318-02 (to P.S.) from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). NR 55 TC 71 Z9 73 U1 0 U2 29 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD FEB PY 2013 VL 57 IS 2 BP 533 EP 542 DI 10.1002/hep.25846 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 099TA UT WOS:000315643400014 PM 22777896 ER PT J AU Tsuda, M Zhang, WC Yang, GX Tsuneyama, K Ando, Y Kawata, K Park, O Leung, PSC Coppel, RL Ansari, AA Ridgway, WM Gao, B Lian, ZX Flavell, R He, XS Gershwin, ME AF Tsuda, Masanobu Zhang, Weici Yang, Guo-Xiang Tsuneyama, Koichi Ando, Yugo Kawata, Kazuhito Park, Ogyi Leung, Patrick S. C. Coppel, Ross L. Ansari, Aftab A. Ridgway, William M. Gao, Bin Lian, Zhe-Xiong Flavell, Richard He, Xiao-Song Gershwin, M. Eric TI Deletion of Interleukin (IL)-12p35 Induces Liver Fibrosis in Dominant-Negative TGF beta Receptor Type II Mice SO HEPATOLOGY LA English DT Article ID PRIMARY BILIARY-CIRRHOSIS; T-CELLS; AUTOIMMUNE CHOLANGITIS; CYTOKINE PROFILE; ANTIMITOCHONDRIAL AUTOANTIBODIES; MOUSE MODEL; TH17 CELLS; INFLAMMATION; COLITIS; DISEASE AB Mice with a dominant-negative transforming growth factor beta receptor restricted to T cells (dnTGF beta RII mice) develop an inflammatory biliary ductular disease that strongly resembles human primary biliary cirrhosis (PBC). Furthermore, deletion of the gene encoding interleukin (IL)-12p40 resulted in a strain (IL-12p40(-/-) dnTGF beta RII) with dramatically reduced autoimmune cholangitis. To further investigate the role of the IL-12 cytokine family in dnTGF beta RII autoimmune biliary disease, we deleted the gene encoding the IL-12p35 subunit from dnTGF beta RII mice, resulting in an IL-12p35(-/-) dnTGF beta RII strain which is deficient in two members of the IL-12 family, IL-12 and IL-35. In contrast to IL-12p40(-/-) mice, the IL-12p35 2/2 mice developed liver inflammation and bile duct damage with similar severity but delayed onset as the parental dnTGF beta RII mice. The p35(-/-) mice also demonstrated a distinct cytokine profile characterized by a shift from a T-helper 1 (Th1) to a Th17 response. Strikingly, liver fibrosis was frequently observed in IL-12p35(-/-) mice. In conclusion, IL-12p35(-/-) dnTGF beta RII mice, histologically and immunologically, reflect key features of PBC, providing a useful generic model to understand the immunopathology of human PBC. (HEPATOLOGY 2013;57:806-816) C1 [Tsuda, Masanobu; Zhang, Weici; Yang, Guo-Xiang; Tsuneyama, Koichi; Ando, Yugo; Kawata, Kazuhito; Leung, Patrick S. C.; Lian, Zhe-Xiong; He, Xiao-Song; Gershwin, M. Eric] Univ Calif Davis, Div Rheumatol Allergy & Clin Immunol, Davis, CA 95616 USA. [Tsuda, Masanobu] Kansai Med Univ, Dept Emergency & Crit Care Med, Osaka, Japan. [Tsuneyama, Koichi] Toyama Univ, Grad Sch Med & Pharmaceut Sci Res, Dept Diagnost Pathol, Toyama 930, Japan. [Park, Ogyi; Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. [Coppel, Ross L.] Monash Univ, Dept Microbiol, Clayton, Vic 3800, Australia. [Ansari, Aftab A.] Emory Univ, Sch Med, Dept Pathol, Atlanta, GA 30322 USA. [Ridgway, William M.] Univ Cincinnati, Coll Med, Div Immunol Allergy & Rheumatol, Cincinnati, OH USA. [Lian, Zhe-Xiong] Univ Sci & Technol China, Inst Immunol, Hefei 230026, Peoples R China. [Lian, Zhe-Xiong] Univ Sci & Technol China, Sch Life Sci, Hefei 230026, Peoples R China. [Flavell, Richard] Yale Univ, Sch Med, Immunobiol Sect, New Haven, CT 06510 USA. RP Gershwin, ME (reprint author), Univ Calif Davis, Div Rheumatol Allergy & Clin Immunol, Sch Med, 451 Hlth Sci Dr,Ste 6510, Davis, CA 95616 USA. EM zxlian1@ustc.edu.cn; megershwin@ucdavis.edu RI Coppel, Ross/A-6626-2008 OI Coppel, Ross/0000-0002-4476-9124 FU National Institutes of Health [DK090019] FX Financial support provided by National Institutes of Health grant DK090019. NR 53 TC 45 Z9 45 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD FEB PY 2013 VL 57 IS 2 BP 806 EP 816 DI 10.1002/hep.25829 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 099TA UT WOS:000315643400039 PM 22576253 ER PT J AU McGarrity, GJ Hoyah, G Winemiller, A Andre, K Stein, D Blick, G Greenberg, RN Kinder, C Zolopa, A Binder-Scholl, G Tebas, P June, CH Humeau, LM Rebello, T AF McGarrity, Gerard J. Hoyah, Gloria Winemiller, April Andre, Kris Stein, David Blick, Gary Greenberg, Richard N. Kinder, Clifford Zolopa, Andrew Binder-Scholl, Gwen Tebas, Pablo June, Carl H. Humeau, Laurent M. Rebello, Tessio TI Patient monitoring and follow-up in lentiviral clinical trials SO JOURNAL OF GENE MEDICINE LA English DT Article DE clinical trials; lentiviral vectors; safety monitoring ID GENE-TRANSFER; VECTOR INTEGRATION; THERAPY; CELLS AB Background Lentiviral vectors are being used with increasing frequency in human clinical trials. We were the first to use lentiviral vectors in clinical trials in 2003. Our lentiviral vector encoded a long RNA antisense sequence to the HIV-1 envelope and was used in an ex vivo autologous setting to provide viral load control in HIV-1 positive subjects failing anti-HIV therapy. A total of 65 subjects have been treated in Phase 1 and Phase 2 trials in six institutions. Methods Good manufacturing practices (GMP) lots of the lentiviral vector used in our clinical trials were assayed for the presence of replication competent lentivirus (RCL). RCL assays were conducted at two stages. The first testing was performed on samples collected immediately following bulk harvest of the GMP product lot and consisted of 1x108 cells used in production. RCL assays were also performed on aliquots of the final fill of the vector by the inoculation of at least 5% of the GMP final fill volume into C8166 cells, passaged for at least ten passages and tested for RCL by p24 enzyme-linked immunosorbent assay and vesicular stomatitis virus-G envelope DNA. Results Following 263 infusions of autologous, transduced cells, no adverse events have been detected in these subjects, with some followed for more than 8years following infusions. More than 4.3x1012 VRX496 proviral copies were administered to these 65 subjects. Conclusions Data from this small population suggest that there is no apparent risk for serious adverse events with the use of lentiviral vectors. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [McGarrity, Gerard J.; Hoyah, Gloria; Winemiller, April; Andre, Kris; Humeau, Laurent M.; Rebello, Tessio] VIRxSYS Corp, Gaithersburg, MD 20878 USA. [Stein, David] Jacobi Med Ctr, Bronx, NY USA. [Blick, Gary] Circle Med Ctr, Norwalk, CT USA. [Greenberg, Richard N.] Univ Kentucky, Lexington, KY USA. [Kinder, Clifford] Kinder Med Grp, Miami, FL USA. [Zolopa, Andrew] Stanford Univ, Palo Alto, CA 94304 USA. [Binder-Scholl, Gwen; Tebas, Pablo; June, Carl H.] Univ Penn, Abramson Family Canc Inst, Philadelphia, PA 19104 USA. [Winemiller, April] NIH, Bethesda, MD 20892 USA. [Binder-Scholl, Gwen] Adaptimmune LLC, Philadelphia, PA USA. RP McGarrity, GJ (reprint author), VIRxSYS Corp, 105 Leekes Lot Way, Gaithersburg, MD 20878 USA. EM bgmcgarr@aol.com NR 17 TC 19 Z9 19 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1099-498X J9 J GENE MED JI J. Gene. Med. PD FEB PY 2013 VL 15 IS 2 BP 78 EP 82 DI 10.1002/jgm.2691 PG 5 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 097SS UT WOS:000315494400003 PM 23322669 ER PT J AU Baker, DG Woods, TA Butchi, NB Morgan, TM Taylor, RT Sunyakumthorn, P Mukherjee, P Lubick, KJ Best, SM Peterson, KE AF Baker, David G. Woods, Tyson A. Butchi, Niranjan B. Morgan, Timothy M. Taylor, R. Travis Sunyakumthorn, Piyanate Mukherjee, Piyali Lubick, Kirk J. Best, Sonja M. Peterson, Karin E. TI Toll-like receptor 7 suppresses virus replication in neurons but does not affect viral pathogenesis in a mouse model of Langat virus infection SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID WEST-NILE-VIRUS; TICK-BORNE ENCEPHALITIS; CD8(+) T-CELLS; IMMUNE-RESPONSES; PROTECTIVE ROLE; MICROGLIA; BRAIN; NEUROPATHOGENESIS; FLAVIVIRUS; PROTEIN AB Toll-like receptor 7 (TLR7) recognizes guanidine-rich viral ssRNA and is an important mediator of peripheral immune responses to several ssRNA viruses. However, the role that TLR7 plays in regulating the innate immune response to ssRNA virus infections in specific organs such as the central nervous system (CNS) is not as clear. This study examined the influence of TLR7 on the neurovirulence of Langat virus (LGTV), a ssRNA tick-borne flavivirus. TLR7 deficiency did not substantially alter the onset or incidence of LGTV-induced clinical disease; however, it did significantly affect virus levels in the CNS with a log(10) increase in virus titres in brain tissue from TLR7-deficient mice. This difference in virus load was also observed following intracranial inoculation, indicating a direct effect of TLR7 deficiency on regulating virus replication in the brain. LGTV-induced type I interferon responses in the CNS were not dependent on TLR7, being higher in TLR7-deficient mice compared with wild-type controls. In contrast, induction of proinflammatory cytokines including tumour necrosis factor, CCL3, CCL4 and CXCL13 were dependent on TLR7. Thus, although TLR7 is not essential in controlling LGTV pathogenesis, it is important in controlling virus infection in neurons in the CNS, possibly by regulating neuroinflammatory responses. C1 [Baker, David G.; Sunyakumthorn, Piyanate] Louisiana State Univ, Sch Vet Med, Dept Pathobiol Sci, Baton Rouge, LA 70803 USA. [Woods, Tyson A.; Butchi, Niranjan B.; Taylor, R. Travis; Mukherjee, Piyali; Lubick, Kirk J.; Best, Sonja M.; Peterson, Karin E.] NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Morgan, Timothy M.] Mississippi State Univ, Sch Vet Med, Dept Pathol, Mississippi State, MS 39762 USA. RP Peterson, KE (reprint author), NIAID, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM petersonka@niaid.nih.gov RI Peterson, Karin/D-1492-2016 OI Peterson, Karin/0000-0003-4177-7249 FU Louisiana State University School of Veterinary Medicine Competitive Organized Research Program; Division of Intramural Research, National Institutes of Health, National Institute of Allergy and Infectious Diseases FX The authors thank the Louisiana State University animal caretakers for providing excellent animal care throughout these experiments. The project was supported in part by Louisiana State University School of Veterinary Medicine Competitive Organized Research Program and in part by the Division of Intramural Research, National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 37 TC 9 Z9 9 U1 0 U2 8 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD FEB PY 2013 VL 94 BP 336 EP 347 DI 10.1099/vir.0.043984-0 PN 2 PG 12 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 098JR UT WOS:000315546100012 PM 23136362 ER PT J AU Groninger, H Burton, B Hendricks, D Sera, L Sullivan, M AF Groninger, Hunter Burton, Brad Hendricks, Danetta Sera, Leah Sullivan, Malgorzata TI Our Double-Edged Sword: Interdisciplinary Approaches to Balancing Symptom Control With Diversion and Safety Concerns in the Home Care Setting SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Meeting Abstract CT Annual Assembly of the American-Academy-of-Hospice-and-Palliative-Medicine and the Hospice-and-Palliative-Nurses-Association CY MAR 13-16, 2013 CL New Orleans, LA SP Amer Acad Hosp and Palliat Med, Hosp and Palliat Nurses Assoc C1 [Groninger, Hunter] NIH, Bethesda, MD 20892 USA. [Burton, Brad; Hendricks, Danetta; Sullivan, Malgorzata] Capital Caring, Washington, DC USA. [Sera, Leah] Univ Maryland, Sch Pharm, Baltimore, MD 21201 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD FEB PY 2013 VL 45 IS 2 BP 332 EP 332 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA 100GE UT WOS:000315684600042 ER PT J AU Groninger, H Heintz, J Murphy, B AF Groninger, Hunter Heintz, Jessica Murphy, Brian TI "Honor Thy Turf'': Advanced Consultant Etiquette Across Care Settings SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Meeting Abstract CT Annual Assembly of the American-Academy-of-Hospice-and-Palliative-Medicine and the Hospice-and-Palliative-Nurses-Association CY MAR 13-16, 2013 CL New Orleans, LA SP Amer Acad Hosp and Palliat Med, Hosp and Palliat Nurses Assoc C1 [Groninger, Hunter] NIH, Bethesda, MD 20892 USA. [Heintz, Jessica] Capital Caring, Falls Church, VA USA. [Murphy, Brian] Nathan Adelson Hosp, Las Vegas, NV USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD FEB PY 2013 VL 45 IS 2 BP 414 EP 415 PG 2 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA 100GE UT WOS:000315684600169 ER PT J AU Managadze, D Lobkovsky, AE Wolf, YI Shabalina, SA Rogozin, IB Koonin, EV AF Managadze, David Lobkovsky, Alexander E. Wolf, Yuri I. Shabalina, Svetlana A. Rogozin, Igor B. Koonin, Eugene V. TI The Vast, Conserved Mammalian lincRNome SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID LONG NONCODING RNAS; OPEN READING FRAMES; HUMAN GENOME; TRANSCRIPTIONAL ACTIVITY; NUCLEOTIDE RESOLUTION; GENE STRUCTURE; EXPRESSION; REVEALS; IDENTIFICATION; EVOLUTION AB We compare the sets of experimentally validated long intergenic non-coding (linc)RNAs from human and mouse and apply a maximum likelihood approach to estimate the total number of lincRNA genes as well as the size of the conserved part of the lincRNome. Under the assumption that the sets of experimentally validated lincRNAs are random samples of the lincRNomes of the corresponding species, we estimate the total lincRNome size at approximately 40,000 to 50,000 species, at least twice the number of protein-coding genes. We further estimate that the fraction of the human and mouse euchromatic genomes encoding lincRNAs is more than twofold greater than the fraction of protein-coding sequences. Although the sequences of most lincRNAs are much less strongly conserved than protein sequences, the extent of orthology between the lincRNomes is unexpectedly high, with 60 to 70% of the lincRNA genes shared between human and mouse. The orthologous mammalian lincRNAs can be predicted to perform equivalent functions; accordingly, it appears likely that thousands of evolutionarily conserved functional roles of lincRNAs remain to be characterized. C1 [Managadze, David; Lobkovsky, Alexander E.; Wolf, Yuri I.; Shabalina, Svetlana A.; Rogozin, Igor B.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Managadze, D (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM koonin@ncbi.nlm.nih.gov RI Shabalina, Svetlana/N-8939-2013 OI Shabalina, Svetlana/0000-0003-2272-7473 FU US Department of Health and Human Services (National Library of Medicine) FX This work was supported by intramural funds of the US Department of Health and Human Services (National Library of Medicine). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 64 TC 20 Z9 21 U1 0 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD FEB PY 2013 VL 9 IS 2 AR e1002917 DI 10.1371/journal.pcbi.1002917 PG 9 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 100NT UT WOS:000315708600025 PM 23468607 ER PT J AU Achyut, BR Bader, DA Robles, AI Wangsa, D Harris, CC Ried, T Yang, L AF Achyut, B. R. Bader, David A. Robles, Ana I. Wangsa, Darawalee Harris, Curtis C. Ried, Thomas Yang, Li TI Inflammation-Mediated Genetic and Epigenetic Alterations Drive Cancer Development in the Neighboring Epithelium upon Stromal Abrogation of TGF-beta Signaling SO PLOS GENETICS LA English DT Article ID SQUAMOUS-CELL CARCINOMA; GROWTH-FACTOR-BETA; TUMOR-SUPPRESSOR GENE; DNA-DAMAGE RESPONSE; BREAST-CANCER; COLON-CANCER; MOUSE MODEL; EXPRESSION; MICE; MICROENVIRONMENT AB Deletion of tumor suppressor genes in stromal fibroblasts induces epithelial cancer development, suggesting an important role of stroma in epithelial homoeostasis. However, the underlying mechanisms remain to be elucidated. Here we report that deletion of the gene encoding TGF beta receptor 2 (Tgfbr2) in the stromal fibroblasts (Tgfbr2(fspKO)) induces inflammation and significant DNA damage in the neighboring epithelia of the forestomach. This results in loss or down-regulation of cyclin-dependent kinase inhibitors p15, p16, and p21, which contribute to the development of invasive squamous cell carcinoma (SCC). Anti-inflammation treatment restored p21 expression, delayed tumorigenesis, and increased survival of Tgfbr2(fspKO) mice. Our data demonstrate for the first time that inflammation is a critical player in the epigenetic silencing of p21 in tumor progression. Examination of human esophageal SCC showed a down-regulation of TGF beta receptor 2 (T beta RII) in the stromal fibroblasts, as well as increased inflammation, DNA damage, and loss or decreased p15/p16 expression. Our study suggests anti-inflammation may be a new therapeutic option in treating human SCCs with down-regulation of T beta RII in the stroma. C1 [Achyut, B. R.; Yang, Li] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Bader, David A.] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Robles, Ana I.; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wangsa, Darawalee; Ried, Thomas] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Achyut, BR (reprint author), NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM yangl3@mail.nih.gov FU NCI FX This work was supported by NCI intramural funding to LY. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 29 Z9 29 U1 0 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD FEB PY 2013 VL 9 IS 2 AR e1003251 DI 10.1371/journal.pgen.1003251 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 099RG UT WOS:000315638300015 PM 23408900 ER PT J AU Porcu, E Medici, M Pistis, G Volpato, CB Wilson, SG Cappola, AR Bos, SD Deelen, J den Heijer, M Freathy, RM Lahti, J Liu, CY Lopez, LM Nolte, IM O'Connell, JR Tanaka, T Trompet, S Arnold, A Bandinelli, S Beekman, M Bohringer, S Brown, SJ Buckley, BM Camaschella, C de Craen, AJM Davies, G de Visser, MCH Ford, I Forsen, T Frayling, TM Fugazzola, L Gogele, M Hattersley, AT Hermus, AR Hofman, A Houwing-Duistermaat, JJ Jensen, RA Kajantie, E Kloppenburg, M Lim, EM Masciullo, C Mariotti, S Minelli, C Mitchell, BD Nagaraja, R Netea-Maier, RT Palotie, A Persani, L Piras, MG Psaty, BM Raikkonen, K Richards, JB Rivadeneira, F Sala, C Sabra, MM Sattar, N Shields, BM Soranzo, N Starr, JM Stott, DJ Sweep, FCGJ Usala, G van der Klauw, MM van Heemst, D van Mullem, A Vermeulen, SH Visser, WE Walsh, JP Westendorp, RGJ Widen, E Zhai, GJ Cucca, F Deary, IJ Eriksson, JG Ferrucci, L Fox, CS Jukema, JW Kiemeney, LA Pramstaller, PP Schlessinger, D Shuldiner, AR Slagboom, EP Uitterlinden, AG Vaidya, B Visser, TJ Wolffenbuttel, BHR Meulenbelt, I Rotter, JI Spector, TD Hicks, AA Toniolo, D Sanna, S Peeters, RP Naitza, S AF Porcu, Eleonora Medici, Marco Pistis, Giorgio Volpato, Claudia B. Wilson, Scott G. Cappola, Anne R. Bos, Steffan D. Deelen, Joris den Heijer, Martin Freathy, Rachel M. Lahti, Jari Liu, Chunyu Lopez, Lorna M. Nolte, Ilja M. O'Connell, Jeffrey R. Tanaka, Toshiko Trompet, Stella Arnold, Alice Bandinelli, Stefania Beekman, Marian Bohringer, Stefan Brown, Suzanne J. Buckley, Brendan M. Camaschella, Clara de Craen, Anton J. M. Davies, Gail de Visser, Marieke C. H. Ford, Ian Forsen, Tom Frayling, Timothy M. Fugazzola, Laura Goegele, Martin Hattersley, Andrew T. Hermus, Ad R. Hofman, Albert Houwing-Duistermaat, Jeanine J. Jensen, Richard A. Kajantie, Eero Kloppenburg, Margreet Lim, Ee M. Masciullo, Corrado Mariotti, Stefano Minelli, Cosetta Mitchell, Braxton D. Nagaraja, Ramaiah Netea-Maier, Romana T. Palotie, Aarno Persani, Luca Piras, Maria G. Psaty, Bruce M. Raikkonen, Katri Richards, J. Brent Rivadeneira, Fernando Sala, Cinzia Sabra, Mona M. Sattar, Naveed Shields, Beverley M. Soranzo, Nicole Starr, John M. Stott, David J. Sweep, Fred C. G. J. Usala, Gianluca van der Klauw, Melanie M. van Heemst, Diana van Mullem, Alies Vermeulen, Sita H. Visser, W. Edward Walsh, John P. Westendorp, Rudi G. J. Widen, Elisabeth Zhai, Guangju Cucca, Francesco Deary, Ian J. Eriksson, Johan G. Ferrucci, Luigi Fox, Caroline S. Jukema, J. Wouter Kiemeney, Lambertus A. Pramstaller, Peter P. Schlessinger, David Shuldiner, Alan R. Slagboom, Eline P. Uitterlinden, Andre G. Vaidya, Bijay Visser, Theo J. Wolffenbuttel, Bruce H. R. Meulenbelt, Ingrid Rotter, Jerome I. Spector, Tim D. Hicks, Andrew A. Toniolo, Daniela Sanna, Serena Peeters, Robin P. Naitza, Silvia TI A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; FACTOR BINDING PROTEIN-5; HORMONE PATHWAY GENES; SERUM TSH; COMMON VARIATION; CLEFT-PALATE; EXPRESSION; GROWTH; HYPOTHYROIDISM; THYROTROPIN AB Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism. C1 [Porcu, Eleonora; Piras, Maria G.; Usala, Gianluca; Cucca, Francesco; Sanna, Serena; Naitza, Silvia] CNR, IRGB, Cagliari, Italy. [Porcu, Eleonora; Cucca, Francesco] Univ Sassari, Dipartimento Sci Biomed, I-07100 Sassari, Italy. [Medici, Marco; Rivadeneira, Fernando; van Mullem, Alies; Visser, W. Edward; Uitterlinden, Andre G.; Visser, Theo J.; Peeters, Robin P.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Pistis, Giorgio; Camaschella, Clara; Masciullo, Corrado; Sala, Cinzia; Toniolo, Daniela] San Raffaele Res Inst, Div Genet & Cell Biol, Milan, Italy. [Pistis, Giorgio] Univ Trieste, Trieste, Italy. [Volpato, Claudia B.; Goegele, Martin; Minelli, Cosetta; Pramstaller, Peter P.; Hicks, Andrew A.] European Acad Bozen Bolzano EURAC, Ctr Biomed, Bolzano, Italy. [Volpato, Claudia B.; Goegele, Martin; Minelli, Cosetta; Pramstaller, Peter P.; Hicks, Andrew A.] Med Univ Lubeck, D-23538 Lubeck, Germany. [Wilson, Scott G.; Brown, Suzanne J.; Lim, Ee M.; Walsh, John P.] Sir Charles Gairdner Hosp, Dept Endocrinol & Diabet, Nedlands, WA 6009, Australia. [Wilson, Scott G.; Richards, J. Brent; Zhai, Guangju; Spector, Tim D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Wilson, Scott G.; Walsh, John P.] Univ Western Australia, Sch Med & Pharmacol, Crawley, WA, Australia. [Cappola, Anne R.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Bos, Steffan D.; Deelen, Joris; Beekman, Marian; Slagboom, Eline P.; Meulenbelt, Ingrid] Leiden Univ, Med Ctr, Leiden, Netherlands. [Bos, Steffan D.; Deelen, Joris; Beekman, Marian; Slagboom, Eline P.; Meulenbelt, Ingrid] Netherlands Consortium Hlth Ageing, Leiden, Netherlands. [den Heijer, Martin; Hermus, Ad R.; Netea-Maier, Romana T.] Radboud Univ Nijmegen, Med Ctr, Dept Endocrinol, NL-6525 ED Nijmegen, Netherlands. [den Heijer, Martin] Free Univ Amsterdam, Dept Internal Med, Med Ctr, Amsterdam, Netherlands. [Freathy, Rachel M.; Frayling, Timothy M.] Univ Exeter, Peninsula Coll Med & Dent, Exeter, Devon, England. [Lahti, Jari; Raikkonen, Katri] Univ Helsinki, Inst Behav Sci, Helsinki, Finland. [Liu, Chunyu] NHLBI, Ctr Populat Studies, Framingham, MA USA. [Lopez, Lorna M.; Starr, John M.; Deary, Ian J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland. [Lopez, Lorna M.; Davies, Gail; Deary, Ian J.] Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland. [Nolte, Ilja M.] Univ Groningen, Univ Med Ctr Groningen, Unit Genet Epidemiol & Bioinformat, Dept Epidemiol, Groningen, Netherlands. [O'Connell, Jeffrey R.; Mitchell, Braxton D.; Shuldiner, Alan R.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Trompet, Stella; Jukema, J. Wouter] Leiden Univ, Dept Cardiol, Med Ctr, Leiden, Netherlands. [Trompet, Stella; de Craen, Anton J. M.] Leiden Univ, Dept Gerontol & Geriatr, Med Ctr, Leiden, Netherlands. [Arnold, Alice; Jensen, Richard A.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Arnold, Alice; Jensen, Richard A.] Univ Washington, Dept Med, Seattle, WA USA. [Bandinelli, Stefania] ASF, Geriatr Unit, Florence, Italy. [Bohringer, Stefan; Houwing-Duistermaat, Jeanine J.; van Heemst, Diana; Westendorp, Rudi G. J.] Leiden Univ, Med Ctr, Leiden, Netherlands. [Buckley, Brendan M.] Natl Univ Ireland Univ Coll Cork, Dept Pharmacol & Therapeut, Cork, Ireland. [Camaschella, Clara] Vita & Salute Univ, San Raffaele Sci Inst, Milan, Italy. [de Visser, Marieke C. H.; Vermeulen, Sita H.; Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Dept Hlth Evidence, NL-6525 ED Nijmegen, Netherlands. [Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland. [Forsen, Tom; Kajantie, Eero; Eriksson, Johan G.] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Forsen, Tom; Eriksson, Johan G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland. [Forsen, Tom; Eriksson, Johan G.] Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki, Finland. [Forsen, Tom] Vaasa Hlth Care Ctr, Diabet Unit, Vaasa, Finland. [Fugazzola, Laura] Univ Milan, Fdn Ca Granda Policlin, Endocrine Unit, Milan, Italy. [Fugazzola, Laura] Univ Milan, Dept Clin Sci & Community Hlth, Milan, Italy. [Hattersley, Andrew T.; Shields, Beverley M.] Univ Exeter, Peninsula NIHR Clin Res Facil, Peninsula Coll Med & Dent, Exeter, Devon, England. [Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G.] NCHA, Rotterdam, Netherlands. [Kajantie, Eero] Univ Helsinki, Cent Hosp, Hosp Children & Adolescents, Helsinki, Finland. [Kajantie, Eero] Univ Helsinki, Helsinki, Finland. [Kloppenburg, Margreet] Leiden Univ, Dept Clin Epidemiol & Rheumatol, Med Ctr, Leiden, Netherlands. [Lim, Ee M.] Pathwest Lab Med WA, Nedlands, WA, Australia. [Mariotti, Stefano] Univ Cagliari, Dipartimento Scienze Med, Cagliari, Italy. [Nagaraja, Ramaiah; Schlessinger, David] NIA, Genet Lab, Baltimore, MD 21224 USA. [Palotie, Aarno; Soranzo, Nicole] Wellcome Trust Sanger Inst, Cambridge, England. [Palotie, Aarno; Widen, Elisabeth] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland. [Palotie, Aarno] Univ Helsinki, Dept Med Genet, Helsinki, Finland. [Palotie, Aarno] Univ Cent Hosp, Helsinki, Finland. [Persani, Luca] Univ Milan, Dept Clin Sci & Community Hlth, Milan, Italy. [Persani, Luca] IRCCS Osped San Luca, Div Endocrinol & Metab Dis, Milan, Italy. [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.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98121 USA. [Richards, J. Brent] McGill Univ, Jewish Gen Hosp, Dept Med, Montreal, PQ H3T 1E2, Canada. [Richards, J. Brent] McGill Univ, Jewish Gen Hosp, Dept Human Genet, Lady Davis Inst, Montreal, PQ H3T 1E2, Canada. [Richards, J. Brent] McGill Univ, Jewish Gen Hosp, Dept Epidemiol, Lady Davis Inst, Montreal, PQ H3T 1E2, Canada. [Richards, J. Brent] McGill Univ, Jewish Gen Hosp, Dept Biostat, Lady Davis Inst, Montreal, PQ H3T 1E2, Canada. [Sabra, Mona M.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Sattar, Naveed] Fac Med, BHF Glasgow Cardiovasc Res Ctr, Glasgow, Lanark, Scotland. [Starr, John M.] Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh, Midlothian, Scotland. [Stott, David J.] Univ Glasgow, Acad Sect Geriatr Med, Fac Med, Glasgow, Lanark, Scotland. [Sweep, Fred C. G. J.] Radboud Univ Nijmegen, Dept Lab Med, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [van der Klauw, Melanie M.; Wolffenbuttel, Bruce H. R.] Univ Groningen, Univ Med Ctr Groningen, LifeLines Cohort Study, Groningen, Netherlands. [van der Klauw, Melanie M.; Wolffenbuttel, Bruce H. R.] Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol, Groningen, Netherlands. [Zhai, Guangju] Mem Univ Newfoundland, Fac Med, Discipline Genet, St John, NF, Canada. [Eriksson, Johan G.] Folkhalsan Res Ctr, Helsinki, Finland. [Eriksson, Johan G.] Vasa Cent Hosp, Vaasa, Finland. [Fox, Caroline S.] NHLBI, Div Intramural Res, Framingham, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol Hypertens & Metab, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Jukema, J. Wouter] Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands. [Jukema, J. Wouter] Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands. [Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Dept Urol, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Pramstaller, Peter P.] Gen Cent Hosp, Dept Neurol, Bolzano, Italy. [Pramstaller, Peter P.] Med Univ Lubeck, Dept Neurol, D-23538 Lubeck, Germany. [Shuldiner, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21218 USA. [Vaidya, Bijay] Royal Devon & Exeter NHS Fdn Trust, Diabet Endocrinol & Vasc Hlth Ctr, Exeter, Devon, England. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Toniolo, Daniela] CNR, Inst Mol Genet, I-27100 Pavia, Italy. RP Porcu, E (reprint author), CNR, IRGB, Cittadella Univ Monserrato, Cagliari, Italy. EM serena.sanna@irgb.cnr.it; r.peeters@erasmusmc.nl; silvia.naitza@irgb.cnr.it RI Netea-Maier, R.T./L-4543-2015; Deary, Ian/C-6297-2009; Rivadeneira, Fernando/O-5385-2015; Vermeulen, H.H.M./L-4716-2015; van der Klauw, Melanie/A-2138-2014; Kiemeney, Lambertus/D-3357-2009; Pramstaller, Peter/C-2357-2008; Sweep, C.G.J./H-8096-2014; Camaschella, Clara/A-3289-2015; Peeters, Robin/P-3603-2014; Visser, W. Edward/C-4062-2015; Hermus, A.R.M.M./H-8043-2014; Netea, Mihai/N-5155-2014; Slagboom, P. Eline/R-4790-2016; Naitza, Silvia/D-5620-2017; Hicks, Andrew/E-9518-2017; OI Vaidya, Bijay/0000-0002-2223-0494; Wolffenbuttel, Bruce H.R./0000-0001-9262-6921; Eriksson, Johan/0000-0002-2516-2060; Mitchell, Braxton/0000-0003-4920-4744; Hattersley, Andrew/0000-0001-5620-473X; Lahti, Jari/0000-0002-4310-5297; Raikkonen, Katri/0000-0003-3124-3470; Persani, Luca/0000-0003-2068-9581; Rivadeneira, Fernando/0000-0001-9435-9441; van der Klauw, Melanie/0000-0001-7178-009X; Kiemeney, Lambertus/0000-0002-2368-1326; Visser, W. Edward/0000-0002-5248-863X; Slagboom, P. Eline/0000-0002-2875-4723; Hicks, Andrew/0000-0001-6320-0411; Freathy, Rachel/0000-0003-4152-2238; Walsh, John/0000-0002-1766-2612; piras, maria grazia/0000-0001-9004-0900; sanna, serena/0000-0002-3768-1749; Beekman, Marian/0000-0003-0585-6206; Deelen, Joris/0000-0003-4483-3701; Soranzo, Nicole/0000-0003-1095-3852 FU NIH [AG-023629, AG-15928, AG-20098, AG-027058, 263 MD 9164, 263 MD 821336,, _NO1-AG-1-2109, U01 HL72515, R01 AG18728]; NIH General Clinical Research Centers Program, National Center for Research Resources (NCRR); NHLBI [N01-HC-85239, N01-HC-85079, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HHSN268201200036C, HL080295, HL087652, HL105756, N01-HC-25195, N02-HL-6-4278]; MedStar Research Institute; NINDS; National Center of Advancing Translational Technologies CTSI [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; Robert Dawson Evans Endowment; Italian Ministry of Health [ICS110.1/RF97.71]; Ricerca Finalizzata; Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano; European Union [259679, 223004, HEALTH-F4-2007-201413, 257082, HEALTH-F5-2011-282510]; Dutch Innovation-Oriented Research Program on Genomics [SenterNovem IGE05007]; Netherlands Organization for Scientific Research (NWO) [050-060-810, 75.010.2005.011, 911-03-012, MW 904-61-095, 911-03-016, 917 66344, 175.010.2007.006]; South Tyrolean Sparkasse Foundation; Radboud University Nijmegen Medical Centre; University of Maryland General Clinical Research Center [M01 RR 16500]; Johns Hopkins University General Clinical Research Center [M01 RR 000052]; Baltimore Veterans Administration Geriatric Research and Education Clinical Center (GRECC); Netherlands Research Institute for Diseases in the Elderly [014-93-015, RIDE2]; Erasmus Medical Center and Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Dutch Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; German Bundesministerium fuer Forschung und Technology [01 AK 803 A-H, 01 IG 07015 G]; Wellcome Trust [WT089062, WT091310, 085541/Z/08/Z]; English Department of Health, National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre; Canadian Institutes of Health Research; Canadian Foundation for Innovation; Fonds de la Recherche en Sante Quebec; Ministere du Developpement Economique, de l'Innovation et de l'Exportation;; Lady Davis Institute of the Jewish General Hospital (JBR); Australian National Health and Medical Research Council [1010494, 1031422]; Sir Charles Gairdner Hospital Research Fund; Italian "Compagnia di San Paolo''; Italian "Fondazione Cariplo''; Leiden University Medical Centre; Dutch Arthritis Association; Pfizer, Groton, CT, USA; Dutch Centre of Medical System Biology; Netherlands Genomics Initiative (NGI); Netherlands Consortium of Healthy Aging [050-060-810]; Academy of Finland; Finnish Diabetes Research Society; Folkhalsan Research Foundation; Novo Nordisk Foundation; Finska Lakaresallskapet; Signe and Ane Gyllenberg Foundation; University of Helsinki; European Science Foundation (EUROSTRESS); Finnish Ministry of Education; Ahokas Foundation; Emil Aaltonen Foundation; Juho Vainio Foundation; Biotechnology and Biological Sciences Research Council (BBSRC); Engineering and Physical Sciences Research Council (EPSRC); Economic and Social Research Council (ESRC); Medical Research Council (MRC), as part of the cross-council Lifelong Health and Wellbeing Initiative; AXA Research Fund; Research Into Ageing; Help the Aged/Research Into Ageing (Disconnected Mind); Economic Structure Enhancing Fund (FES) of the Dutch government; Dutch Ministry of Economic Affairs; Dutch Ministry of Education, Culture and Science; Northern Netherlands Collaboration of Provinces (SNN); Province of Groningen; University of Groningen; Dutch Kidney Foundation and Dutch Diabetes Research Foundation; Bristol-Myers Squibb; Netherlands Heart Foundation [2001 D 032]; National Computing Facilities Foundation (NCF), Netherlands; Endocrine Research Fund FX This work was supported by Intramural Research Program of the NIH (grants AG-023629, AG-15928, AG-20098, AG-027058, 263 MD 9164, 263 MD 821336,_NO1-AG-1-2109, U01 HL72515, R01 AG18728) and NIH General Clinical Research Centers Program, National Center for Research Resources (NCRR); NHLBI contracts (N01-HC-85239, N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HHSN268201200036C, and NHLBI grants HL080295, HL087652, HL105756, contracts N01-HC-25195 and N02-HL-6-4278); R&D contract with MedStar Research Institute; NINDS contract; National Center of Advancing Translational Technologies CTSI grant UL1TR000124; National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491; Robert Dawson Evans Endowment; Italian Ministry of Health grants ICS110.1/RF97.71 and Ricerca Finalizzata 2008; Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano; European Union's Seventh Framework Programme (grant agreements FP7/2007-2011 and FP7/2007-2013, 259679, 223004 and ENGAGE project grant agreement HEALTH-F4-2007-201413, EPIGENESYS grant agreement 257082, BLUEPRINT grant agreement HEALTH-F5-2011-282510); Dutch Innovation-Oriented Research Program on Genomics (SenterNovem IGE05007); Netherlands Organization for Scientific Research (NWO) (grants 050-060-810, 175.010.2005.011, 911-03-012, 050-060-810, MW 904-61-095, 911-03-016, 917 66344, 911-03-012, 175.010.2007.; 006); South Tyrolean Sparkasse Foundation; Radboud University Nijmegen Medical Centre; University of Maryland General Clinical Research Center grant M01 RR 16500; Johns Hopkins University General Clinical Research Center, grant M01 RR 000052; Baltimore Veterans Administration Geriatric Research and Education Clinical Center (GRECC); Netherlands Research Institute for Diseases in the Elderly (grant 014-93-015; RIDE2); Erasmus Medical Center and Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Dutch Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; German Bundesministerium fuer Forschung und Technology grants 01 AK 803 A-H, 01 IG 07015 G; Wellcome Trust (grants WT089062, WT098051, WT091310,085541/Z/08/Z); English Department of Health, National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre; Canadian Institutes of Health Research, Canadian Foundation for Innovation; Fonds de la Recherche en Sante Quebec, Ministere du Developpement Economique, de l'Innovation et de l'Exportation; Lady Davis Institute of the Jewish General Hospital (JBR); Australian National Health and Medical Research Council (grants 1010494, 1031422); Sir Charles Gairdner Hospital Research Fund; Italian "Compagnia di San Paolo''; Italian "Fondazione Cariplo''; Leiden University Medical Centre; Dutch Arthritis Association; Pfizer, Groton, CT, USA; Dutch Centre of Medical System Biology; Netherlands Genomics Initiative (NGI), Netherlands Consortium of Healthy Aging'' (grant 050-060-810); Academy of Finland; Finnish Diabetes Research Society; Folkhalsan Research Foundation; Novo Nordisk Foundation; Finska Lakaresallskapet, Signe and Ane Gyllenberg Foundation; University of Helsinki; European Science Foundation (EUROSTRESS); Finnish Ministry of Education; Ahokas Foundation; Emil Aaltonen Foundation; Juho Vainio Foundation; Biotechnology and Biological Sciences Research Council (BBSRC); Engineering and Physical Sciences Research Council (EPSRC); Economic and Social Research Council (ESRC); Medical Research Council (MRC), as part of the cross-council Lifelong Health and Wellbeing Initiative; AXA Research Fund; Research Into Ageing and programme grants from Help the Aged/Research Into Ageing (Disconnected Mind); Economic Structure Enhancing Fund (FES) of the Dutch government; Dutch Ministry of Economic Affairs; Dutch Ministry of Education, Culture and Science; Northern Netherlands Collaboration of Provinces (SNN); Province of Groningen; University of Groningen; Dutch Kidney Foundation and Dutch Diabetes Research Foundation; Bristol-Myers Squibb; Netherlands Heart Foundation grant 2001 D 032; National Computing Facilities Foundation (NCF), Netherlands, for the use of supercomputer facilities; Endocrine Research Fund; http://www.chs-nhlbi.org/pi.htm. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 85 TC 44 Z9 45 U1 0 U2 30 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD FEB PY 2013 VL 9 IS 2 AR e1003266 DI 10.1371/journal.pgen.1003266 PG 20 WC Genetics & Heredity SC Genetics & Heredity GA 099RG UT WOS:000315638300025 PM 23408906 ER PT J AU Uthman, S Bar, C Scheidt, V Liu, SH ten Have, S Giorgini, F Stark, MJR Schaffrath, R AF Uthman, Shanow Baer, Christian Scheidt, Viktor Liu, Shihui ten Have, Sara Giorgini, Flaviano Stark, Michael J. R. Schaffrath, Raffael TI The Amidation Step of Diphthamide Biosynthesis in Yeast Requires DPH6, a Gene Identified through Mining the DPH1-DPH5 Interaction Network SO PLOS GENETICS LA English DT Article ID KLUYVEROMYCES-LACTIS ZYMOCIN; FUNGAL PROTEIN-SYNTHESIS; ADP-RIBOSYLATING TOXINS; ELONGATION-FACTOR EEF2; SACCHAROMYCES-CEREVISIAE; DIPHTHERIA-TOXIN; TRANSLATION ELONGATION-FACTOR-2; S-ADENOSYLMETHIONINE; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI AB Diphthamide is a highly modified histidine residue in eukaryal translation elongation factor 2 (eEF2) that is the target for irreversible ADP ribosylation by diphtheria toxin (DT). In Saccharomyces cerevisiae, the initial steps of diphthamide biosynthesis are well characterized and require the DPH1-DPH5 genes. However, the last pathway step-amidation of the intermediate diphthine to diphthamide-is ill-defined. Here we mine the genetic interaction landscapes of DPH1-DPH5 to identify a candidate gene for the elusive amidase (YLR143w/DPH6) and confirm involvement of a second gene (YBR246w/DPH7) in the amidation step. Like dph1-dph5, dph6 and dph7 mutants maintain eEF2 forms that evade inhibition by DT and sordarin, a diphthamide-dependent antifungal. Moreover, mass spectrometry shows that dph6 and dph7 mutants specifically accumulate diphthine-modified eEF2, demonstrating failure to complete the final amidation step. Consistent with an expected requirement for ATP in diphthine amidation, Dph6 contains an essential adenine nucleotide hydrolase domain and binds to eEF2. Dph6 is therefore a candidate for the elusive amidase, while Dph7 apparently couples diphthine synthase (Dph5) to diphthine amidation. The latter conclusion is based on our observation that dph7 mutants show drastically upregulated interaction between Dph5 and eEF2, indicating that their association is kept in check by Dph7. Physiologically, completion of diphthamide synthesis is required for optimal translational accuracy and cell growth, as indicated by shared traits among the dph mutants including increased ribosomal -1 frameshifting and altered responses to translation inhibitors. Through identification of Dph6 and Dph7 as components required for the amidation step of the diphthamide pathway, our work paves the way for a detailed mechanistic understanding of diphthamide formation. C1 [Uthman, Shanow; Baer, Christian; Giorgini, Flaviano; Schaffrath, Raffael] Univ Leicester, Dept Genet, Leicester LE1 7RH, Leics, England. [Baer, Christian; Scheidt, Viktor; Schaffrath, Raffael] Univ Kassel, Inst Biol, FG Mikrobiol, D-34125 Kassel, Germany. [Liu, Shihui] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [ten Have, Sara; Stark, Michael J. R.] Univ Dundee, Ctr Gene Regulat & Express, Coll Life Sci, Dundee, Scotland. RP Uthman, S (reprint author), Univ Leicester, Dept Genet, Univ Rd, Leicester LE1 7RH, Leics, England. EM m.j.r.stark@dundee.ac.uk; schaffrath@uni-kassel.de RI Stark, Michael/B-2815-2014 OI Stark, Michael/0000-0001-9086-191X FU Wellcome Trust [083524/Z/07/Z]; U.S. National Institute of Allergy and Infectious Diseases [1ZIAAI000929-09]; Biotechnology and Biological Sciences Research Council (BBSRC) [BB/F0191629/1, BB/F019106/1]; HOPE Against Cancer Foundation for Leicestershire and Rutland [RM33G0118]; Department of Genetics, University of Leicester; Institute of Biology, Division of Microbiology, University of Kassel, Germany; Alexander von Humboldt Foundation [3.1-3 FLFDEU-1037031]; Bonn Bad Godesberg, Germany; Royal Society, UK [2008/R2] FX We gratefully acknowledge support for this work from the Wellcome Trust (083524/Z/07/Z), by a grant from the U.S. National Institute of Allergy and Infectious Diseases Intramural Programme to SL (1ZIAAI000929-09), by joint research grants from the Biotechnology and Biological Sciences Research Council (BBSRC) to MJRS (BB/F0191629/1) as well as RS (BB/F019106/1), and by the HOPE Against Cancer Foundation for Leicestershire and Rutland through a OVCA1/DPH1 related PhD studentship (RM33G0118) awarded to SU. CB received support from the Department of Genetics, University of Leicester, and the Institute of Biology, Division of Microbiology, University of Kassel, Germany. RS gratefully acknowledges support from the Feodor Lynen Fellowship Alumnus Programme of the Alexander von Humboldt Foundation (3.1-3 FLFDEU-1037031), Bonn Bad Godesberg, Germany, and from the Royal Society (2008/R2 grant), UK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 83 TC 11 Z9 13 U1 1 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD FEB PY 2013 VL 9 IS 2 AR e1003334 DI 10.1371/journal.pgen.1003334 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 099RG UT WOS:000315638300073 PM 23468660 ER PT J AU Vimaleswaran, KS Berry, DJ Lu, C Tikkanen, E Pilz, S Hiraki, LT Cooper, JD Dastani, Z Li, R Houston, DK Wood, AR Michaelsson, K Vandenput, L Zgaga, L Yerges-Armstrong, LM McCarthy, MI Dupuis, J Kaakinen, M Kleber, ME Jameson, K Arden, N Raitakari, O Viikari, J Lohman, KK Ferrucci, L Melhus, H Ingelsson, E Byberg, L Lind, L Lorentzon, M Salomaa, V Campbell, H Dunlop, M Mitchell, BD Herzig, KH Pouta, A Hartikainen, AL Streeten, EA Theodoratou, E Jula, A Wareham, NJ Ohlsson, C Frayling, TM Kritchevsky, SB Spector, TD Richards, JB Lehtimaki, T Ouwehand, WH Kraft, P Cooper, C Marz, W Power, C Loos, RJF Wang, TJ Jarvelin, MR Whittaker, JC Hingorani, AD Hypponen, E AF Vimaleswaran, Karani S. Berry, Diane J. Lu, Chen Tikkanen, Emmi Pilz, Stefan Hiraki, Linda T. Cooper, Jason D. Dastani, Zari Li, Rui Houston, Denise K. Wood, Andrew R. Michaelsson, Karl Vandenput, Liesbeth Zgaga, Lina Yerges-Armstrong, Laura M. McCarthy, Mark I. Dupuis, Josee Kaakinen, Marika Kleber, Marcus E. Jameson, Karen Arden, Nigel Raitakari, Olli Viikari, Jorma Lohman, Kurt K. Ferrucci, Luigi Melhus, Hakan Ingelsson, Erik Byberg, Liisa Lind, Lars Lorentzon, Mattias Salomaa, Veikko Campbell, Harry Dunlop, Malcolm Mitchell, Braxton D. Herzig, Karl-Heinz Pouta, Anneli Hartikainen, Anna-Liisa Streeten, Elizabeth A. Theodoratou, Evropi Jula, Antti Wareham, Nicholas J. Ohlsson, Claes Frayling, Timothy M. Kritchevsky, Stephen B. Spector, Timothy D. Richards, J. Brent Lehtimaki, Terho Ouwehand, Willem H. Kraft, Peter Cooper, Cyrus Maerz, Winfried Power, Chris Loos, Ruth J. F. Wang, Thomas J. Jaervelin, Marjo-Riitta Whittaker, John C. Hingorani, Aroon D. Hyppoenen, Elina CA Genetic Invest Anthropometric Trai TI Causal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts SO PLOS MEDICINE LA English DT Article ID BODY-MASS INDEX; CARDIOVASCULAR-DISEASE RISK; GENOME-WIDE ASSOCIATION; GENETIC-VARIANTS; INSTRUMENTAL VARIABLES; D DEFICIENCY; 25-HYDROXYVITAMIN D; D INSUFFICIENCY; COMMON OBESITY; PREVALENCE AB Background: Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH) D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis. Methods and Findings: We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH) D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m(2) higher BMI was associated with 1.15% lower 25(OH) D (p = 6.52x10(-27)). The BMI allele score was associated both with BMI (p = 6.30x10(-62)) and 25(OH) D (20.06% [95% CI -0.10 to -0.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH) D (p <= 8.07x10(-57) for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH) D concentrations (IV ratio: -4.2 [95% CI -7.1 to -1.3], p = 0.005). No association was seen for genetically instrumented 25(OH) D with BMI, a finding that was confirmed using data from the GIANT consortium (p >= 0.57 for both vitamin D scores). Conclusions: On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH) D, while any effects of lower 25(OH) D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency. C1 [Vimaleswaran, Karani S.; Berry, Diane J.; Power, Chris; Hyppoenen, Elina] UCL Inst Child Hlth, Ctr Paediat Epidemiol & Biostat, London, England. [Vimaleswaran, Karani S.; Berry, Diane J.; Power, Chris; Hyppoenen, Elina] UCL Inst Child Hlth, MRC Ctr Epidemiol Child Hlth, London, England. [Lu, Chen; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Tikkanen, Emmi] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland. [Tikkanen, Emmi; Salomaa, Veikko; Jula, Antti] Natl Inst Hlth & Welf, Helsinki, Finland. [Pilz, Stefan] Med Univ Graz, Div Endocrinol & Metab, Dept Internal Med, Graz, Austria. [Pilz, Stefan] Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Dept Epidemiol & Biostat, Amsterdam, Netherlands. [Hiraki, Linda T.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Cooper, Jason D.] Univ Cambridge, Cambridge Inst Med Res, Dept Med Genet, Juvenile Diabet Res Fdn Wellcome Trust Diabet & I, Cambridge, England. [Dastani, Zari] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ H3T 1E2, Canada. [Li, Rui; Richards, J. Brent] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Dept Med, Montreal, PQ H3T 1E2, Canada. [Li, Rui; Richards, J. Brent] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Dept Human Genet, Montreal, PQ H3T 1E2, Canada. [Li, Rui; Richards, J. Brent] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Dept Epidemiol & Biostat, Montreal, PQ H3T 1E2, Canada. [Houston, Denise K.; Kritchevsky, Stephen B.] Wake Forest Sch Med, Sect Gerontol & Geriatr Med, Dept Internal Med, Winston Salem, NC USA. [Wood, Andrew R.; Frayling, Timothy M.] Univ Exeter, Peninsula Coll Med & Dent, Exeter, Devon, England. [Michaelsson, Karl; Byberg, Liisa] Uppsala Univ, Dept Surg Sci, Uppsala, Sweden. [Vandenput, Liesbeth; Lorentzon, Mattias; Ohlsson, Claes] Univ Gothenburg, Inst Med, Dept Internal Med, Ctr Bone & Arthrit Res, Gothenburg, Sweden. [Zgaga, Lina; Campbell, Harry; Theodoratou, Evropi] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Zgaga, Lina] Univ Zagreb, Sch Med, Andrija Stampar Sch Publ Hlth, Zagreb 41001, Croatia. [Yerges-Armstrong, Laura M.; Mitchell, Braxton D.; Streeten, Elizabeth A.] Univ Maryland, Sch Med, Div Endocrinol, Baltimore, MD 21201 USA. [McCarthy, Mark I.] Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [McCarthy, Mark I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [McCarthy, Mark I.] Churchill Hosp, Oxford NIHR Biomed Res Ctr, Oxford OX3 7LJ, England. [Dupuis, Josee] NHLBI, Framingham, MA USA. [Kaakinen, Marika; Herzig, Karl-Heinz; Jaervelin, Marjo-Riitta] Univ Oulu, Inst Hlth Sci, Oulu, Finland. [Kaakinen, Marika; Herzig, Karl-Heinz; Jaervelin, Marjo-Riitta] Univ Oulu, Bioctr Oulu, Oulu, Finland. [Kleber, Marcus E.] LURIC Study Non Profit LLC, Freiburg, Germany. [Kleber, Marcus E.] Heidelberg Univ, Mannheim Inst Publ Hlth, Mannheim Med Fac, Social & Prevent Med, Mannheim, Germany. [Jameson, Karen; Cooper, Cyrus] Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England. [Arden, Nigel] Botnar Res Ctr, NIHR Musculoskeletal BRU, Oxford, England. [Arden, Nigel] Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England. [Raitakari, Olli] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Raitakari, Olli] Univ Turku, Dept Clin Physiol & Nucl Med, Turku, Finland. [Raitakari, Olli; Viikari, Jorma] Turku Univ Hosp, FIN-20520 Turku, Finland. [Viikari, Jorma] Univ Turku, Dept Med, Turku, Finland. [Lohman, Kurt K.] Wake Sch Med, Div Publ Hlth Sci, Dept Biostat Sci, Winston Salem, NC USA. [Ferrucci, Luigi] Harbor Hosp, Clin Res Branch, Baltimore, MD USA. [Melhus, Hakan; Lind, Lars] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Ingelsson, Erik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Dunlop, Malcolm] Univ Edinburgh, Inst Genet & Mol Med, Colon Canc Genet Grp & Acad Coloproctol, Edinburgh EH8 9YL, Midlothian, Scotland. [Dunlop, Malcolm] Western Gen Hosp Edinburgh, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland. [Herzig, Karl-Heinz] Univ Oulu, Inst Biomed, Oulu, Finland. [Herzig, Karl-Heinz] Kuopio Univ Hosp, Dept Psychiat, SF-70210 Kuopio, Finland. [Pouta, Anneli] Univ Oulu, Dept Publ Hlth Sci & Gen Practice, Oulu, Finland. [Hartikainen, Anna-Liisa] Univ Oulu, Dept Obstet & Gynaecol & Publ Hlth & Gen Practice, Oulu, Finland. [Wareham, Nicholas J.; Loos, Ruth J. F.] Addenbrookes Hosp, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England. [Spector, Timothy D.; Richards, J. Brent] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Lehtimaki, Terho] Tampere Univ Hosp, Dept Clin Chem, Fimlab Labs, FIN-33521 Tampere, Finland. [Lehtimaki, Terho] Univ Tampere, FIN-33101 Tampere, Finland. [Ouwehand, Willem H.] Univ Cambridge, Dept Haematol, Cambridge CB2 1TN, England. [Ouwehand, Willem H.] Wellcome Trust Sanger Inst, Cambridge, England. [Ouwehand, Willem H.] NHS Blood & Transplant, Cambridge, England. [Maerz, Winfried] Synlab Acad, Mannheim, Germany. [Maerz, Winfried] Heidelberg Univ, Mannheim Inst Publ Hlth, Mannheim Med Fac, Social & Prevent Med, Mannheim, Germany. [Wang, Thomas J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Jaervelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, Dept Biostat & Epidemiol, Sch Publ Hlth, MRC HPA Ctr Environm & Hlth,Fac Med, London, England. [Jaervelin, Marjo-Riitta] Natl Inst Hlth & Welf, Dept Children Young People & Families, Oulu, Finland. [Whittaker, John C.] Univ London London Sch Hyg & Trop Med, Dept Epidemiol & Populat Hlth, London WC1E 7HT, England. [Whittaker, John C.] GlaxoSmithKline, Quantitat Sci, Stevenage, Herts, England. [Hingorani, Aroon D.] UCL, Div Populat Hlth, Dept Epidemiol & Publ Hlth, Genet Epidemiol Grp, London, England. [Hingorani, Aroon D.] UCL, Div Med, Ctr Clin Pharmacol, London, England. RP Vimaleswaran, KS (reprint author), UCL Inst Child Hlth, Ctr Paediat Epidemiol & Biostat, London, England. EM e.hypponen@ucl.ac.uk RI Smith, Albert Vernon/K-5150-2015; Aben, Katja/G-9686-2016; Rudan, Igor/I-1467-2012; kinnunen, leena/B-7059-2012; Visvikis-Siest, Sophie/H-2324-2014; Dunlop, Malcolm/F-1973-2011; Beckmann, Jacques S /A-9772-2008; Kolcic, Ivana/E-2713-2017; Feitosa, Mary/K-8044-2012; Ripatti, Samuli/H-9446-2014; Polasek, Ozren/B-6002-2011; Colaus, PsyColaus/K-6607-2013; Meitinger, Thomas/O-1318-2015; Hypponen, Elina/B-2596-2014; Theodoratou, Evropi/C-3430-2014; Kiemeney, Lambertus/D-3357-2009; Aspelund, Thor/C-5983-2008; Palmer, Lyle/K-3196-2014; Witte, Daniel/C-1722-2008; Lu, Chen/D-8514-2015; Gudnason, Vilmundur/K-6885-2015; OI Pichler, Irene/0000-0001-8251-0757; Magi, Reedik/0000-0002-2964-6011; Lango Allen, Hana/0000-0002-7803-8688; Esko, Tonu/0000-0003-1982-6569; Smith, Albert Vernon/0000-0003-1942-5845; Zgaga, Lina/0000-0003-4089-9703; Dupuis, Josee/0000-0003-2871-3603; Kritchevsky, Stephen/0000-0003-3336-6781; Luben, Robert/0000-0002-5088-6343; Scherag, Andre/0000-0002-9406-4704; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Vandenput, Liesbeth/0000-0002-1712-6131; Aben, Katja/0000-0002-0214-2147; Rudan, Igor/0000-0001-6993-6884; kinnunen, leena/0000-0001-8739-4812; Visvikis-Siest, Sophie/0000-0001-8104-8425; Dunlop, Malcolm/0000-0002-3033-5851; Beckmann, Jacques S /0000-0002-9741-1900; Kolcic, Ivana/0000-0001-7918-6052; Feitosa, Mary/0000-0002-0933-2410; Thiering, Elisabeth/0000-0002-5429-9584; Kaakinen, Marika/0000-0002-9228-0462; Karani, Vimal/0000-0002-8485-8930; Ripatti, Samuli/0000-0002-0504-1202; Polasek, Ozren/0000-0002-5765-1862; Hypponen, Elina/0000-0003-3670-9399; Theodoratou, Evropi/0000-0001-5887-9132; Kiemeney, Lambertus/0000-0002-2368-1326; Aspelund, Thor/0000-0002-7998-5433; Palmer, Lyle/0000-0002-1628-3055; Witte, Daniel/0000-0002-0769-2922; Gudnason, Vilmundur/0000-0001-5696-0084; Jorgensen, Torben/0000-0001-9453-2830; Mitchell, Braxton/0000-0003-4920-4744; Ouwehand, Willem/0000-0002-7744-1790; Lawlor, Debbie A/0000-0002-6793-2262; Hattersley, Andrew/0000-0001-5620-473X; de Geus, Eco/0000-0001-6022-2666; Kleber, Marcus/0000-0003-0663-7275 FU British Heart Foundation [PG/09/023]; UK Medical Research Council (MRC) [G0601653]; British Heart Foundation Senior Research Fellow(Award) [FS05/125]; MRC Centre of Epidemiology for Child Health; NHS Executive; Canada Institute of Research (CIHR) Fellowship award; Amgen; Eli Lilly; Medtronic; Merck; Novartis; Servier FX The authors thank the British Heart Foundation (grant PG/09/023) and the UK Medical Research Council (MRC; grant G0601653) for funding this work. ADH is a British Heart Foundation Senior Research Fellow (Award FS05/125). EH is a Department of Health (UK) Public Health Career Scientist. This work was undertaken at the Centre for Paediatric Epidemiology and Biostatistics, which benefits from funding support from the MRC in its capacity as the MRC Centre of Epidemiology for Child Health. Research at the University College London Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust benefits from R&D funding received from the NHS Executive. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; LTH is currently supported by a Canada Institute of Research (CIHR) Fellowship award. CC has received honoraria and consulting fees from Amgen, Eli Lilly, Medtronic, Merck, Novartis, and Servier. WM is an employee of synlab laboratory services GmbH. Synlab offers vitamin D testing. TJW is on the scientific advisory board for Diasorin Inc. and has received research support from them. JCW is 90% employed by GlaxoSmithKline (GSK) whilst maintaining a 10% appointment at London School of Hygiene & Tropical Medicine (LSHTM), and holds GSK shares. All other authors declare that no competing interests exist. NR 50 TC 206 Z9 212 U1 4 U2 80 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1549-1676 J9 PLOS MED JI PLos Med. PD FEB PY 2013 VL 10 IS 2 AR e1001383 DI 10.1371/journal.pmed.1001383 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 099BC UT WOS:000315592800005 PM 23393431 ER PT J AU Ribeiro, AL Sabino, EC Marcolino, MS Salemi, VMC Ianni, BM Fernandes, F Nastari, L Antunes, A Menezes, M Oliveira, CD Sachdev, V Carrick, DM Busch, MP Murphy, EL AF Ribeiro, Antonio L. Sabino, Ester C. Marcolino, Milena S. Salemi, Vera M. C. Ianni, Barbara M. Fernandes, Fabio Nastari, Luciano Antunes, Andre Menezes, Marcia Oliveira, Claudia Di Lorenzo Sachdev, Vandana Carrick, Danielle M. Busch, Michael P. Murphy, Eduard L. CA NHLBI Retrovirus Epidemiology TI Electrocardiographic Abnormalities in Trypanosoma cruzi Seropositive and Seronegative Former Blood Donors SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID CHRONIC CHAGAS-DISEASE; VENTRICULAR SYSTOLIC DYSFUNCTION; HEART-RATE-VARIABILITY; RISK STRATIFICATION; AUTONOMIC FUNCTION; FOLLOW-UP; MORTALITY; POPULATION; BRAZIL; CARDIOMYOPATHY AB Background: Blood donor screening leads to large numbers of new diagnoses of Trypanosoma cruzi infection, with most donors in the asymptomatic chronic indeterminate form. Information on electrocardiogram (ECG) findings in infected blood donors is lacking and may help in counseling and recognizing those with more severe disease. Objectives: To assess the frequency of ECG abnormalities in T. cruzi seropositive relative to seronegative blood donors, and to recognize ECG abnormalities associated with left ventricular dysfunction. Methods: The study retrospectively enrolled 499 seropositive blood donors in Sao Paulo and Montes Claros, Brazil, and 483 seronegative control donors matched by site, gender, age, and year of blood donation. All subjects underwent a health clinical evaluation, ECG, and echocardiogram (Echo). ECG and Echo were reviewed blindly by centralized reading centers. Left ventricular (LV) dysfunction was defined as LV ejection fraction (EF), 0.50%. Results: Right bundle branch block and left anterior fascicular block, isolated or in association, were more frequently found in seropositive cases (p<0.0001). Both QRS and QTc duration were associated with LVEF values (correlation coefficients -0.159, p<0.0003, and -0.142, p = 0.002) and showed a moderate accuracy in the detection of reduced LVEF (area under the ROC curve: 0.778 and 0.790, both p<0.0001). Several ECG abnormalities were more commonly found in seropositive donors with depressed LVEF, including rhythm disorders (frequent supraventricular ectopic beats, atrial fibrillation or flutter and pacemaker), intraventricular blocks (right bundle branch block and left anterior fascicular block) and ischemic abnormalities (possible old myocardial infarction and major and minor ST abnormalities). ECG was sensitive (92%) for recognition of seropositive donors with depressed LVEF and had a high negative predictive value (99%) for ruling out LV dysfunction. Conclusions: ECG abnormalities are more frequent in seropositive than in seronegative blood donors. Several ECG abnormalities may help the recognition of seropositive cases with reduced LVEF who warrant careful follow-up and treatment. C1 [Ribeiro, Antonio L.; Marcolino, Milena S.] Univ Fed Minas Gerais, Hosp Clin, Belo Horizonte, MG, Brazil. [Ribeiro, Antonio L.; Marcolino, Milena S.] Univ Fed Minas Gerais, Fac Med, Belo Horizonte, MG, Brazil. [Sabino, Ester C.] Univ Sao Paulo, Dept Infect Dis, Sao Paulo, Brazil. [Sabino, Ester C.] Univ Sao Paulo, Inst Trop Med, Sao Paulo, Brazil. [Salemi, Vera M. C.; Ianni, Barbara M.; Fernandes, Fabio; Nastari, Luciano] Univ Sao Paulo, Fac Med, Cardiomyopathy Unit, Heart Inst InCor, Sao Paulo, Brazil. [Antunes, Andre; Menezes, Marcia] Univ Estadual Montes Claros, Ctr Ciencias Biol & Saude, Montes Claros, Brazil. [Oliveira, Claudia Di Lorenzo] Univ Fed Sao Joao del Rei, Divinopolis, Brazil. [Sachdev, Vandana] NHLBI, Bethesda, MD 20892 USA. [Carrick, Danielle M.] WESTAT Corp, Rockville, MD 20850 USA. [Busch, Michael P.; Murphy, Eduard L.] Blood Syst Res Inst, San Francisco, CA USA. [Busch, Michael P.; Murphy, Eduard L.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Ribeiro, AL (reprint author), Univ Fed Minas Gerais, Hosp Clin, Belo Horizonte, MG, Brazil. EM tom@hc.ufmg.br RI Ribeiro, Antonio/C-2707-2009; Nastari, Luciano/C-8528-2012; Fernandes, Fabio/D-5994-2012; Sabino, Ester/F-7750-2010; Salemi, Vera/C-9104-2013; Ianni, Barbara/C-7689-2012 OI Ribeiro, Antonio/0000-0002-2740-0042; Nastari, Luciano/0000-0002-7959-3827; Sabino, Ester/0000-0003-2623-5126; Salemi, Vera/0000-0002-7152-1810; Ianni, Barbara/0000-0002-1588-5492 FU NIH/NHLBI [HHSN268201100007I] FX This study is part of NIH/NHLBI Retrovirus Epidemiology Donor Study-II (REDS-II) - International Component, funded by the NIH/NHLBI (grant HHSN268201100007I). ALR and ECS are researchers of the Brazilian Research Agency (CNPq). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 16 Z9 16 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD FEB PY 2013 VL 7 IS 2 AR e2078 DI 10.1371/journal.pntd.0002078 PG 8 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 099TM UT WOS:000315644900042 PM 23469305 ER PT J AU Guo, WP Lin, XD Wang, W Tian, JH Cong, ML Zhang, HL Wang, MR Zhou, RH Wang, JB Li, MH Xu, J Holmes, EC Zhang, YZ AF Guo, Wen-Ping Lin, Xian-Dan Wang, Wen Tian, Jun-Hua Cong, Mei-Li Zhang, Hai-Lin Wang, Miao-Ruo Zhou, Run-Hong Wang, Jian-Bo Li, Ming-Hui Xu, Jianguo Holmes, Edward C. Zhang, Yong-Zhen TI Phylogeny and Origins of Hantaviruses Harbored by Bats, Insectivores, and Rodents SO PLOS PATHOGENS LA English DT Article ID SHREW SUNCUS-MURINUS; THOTTAPALAYAM VIRUS; MOLECULAR PHYLOGENY; INFECTIOUS-DISEASES; NEWFOUND HANTAVIRUS; GENETIC DIVERSITY; EVOLUTION; BIOGEOGRAPHY; DIVERGENT; MAMMALIA AB Hantaviruses are among the most important zoonotic pathogens of humans and the subject of heightened global attention. Despite the importance of hantaviruses for public health, there is no consensus on their evolutionary history and especially the frequency of virus-host co-divergence versus cross-species virus transmission. Documenting the extent of hantavirus biodiversity, and particularly their range of mammalian hosts, is critical to resolving this issue. Here, we describe four novel hantaviruses (Huangpi virus, Lianghe virus, Longquan virus, and Yakeshi virus) sampled from bats and shrews in China, and which are distinct from other known hantaviruses. Huangpi virus was found in Pipistrellus abramus, Lianghe virus in Anourosorex squamipes, Longquan virus in Rhinolophus affinis, Rhinolophus sinicus, and Rhinolophus monoceros, and Yakeshi virus in Sorex isodon, respectively. A phylogenetic analysis of the available diversity of hantaviruses reveals the existence of four phylogroups that infect a range of mammalian hosts, as well as the occurrence of ancient reassortment events between the phylogroups. Notably, the phylogenetic histories of the viruses are not always congruent with those of their hosts, suggesting that cross-species transmission has played a major role during hantavirus evolution and at all taxonomic levels, although we also noted some evidence for virus-host co-divergence. Our phylogenetic analysis also suggests that hantaviruses might have first appeared in Chiroptera (bats) or Soricomorpha (moles and shrews), before emerging in rodent species. Overall, these data indicate that bats are likely to be important natural reservoir hosts of hantaviruses. C1 [Guo, Wen-Ping; Wang, Wen; Cong, Mei-Li; Zhou, Run-Hong; Wang, Jian-Bo; Li, Ming-Hui; Xu, Jianguo; Zhang, Yong-Zhen] Chinese Ctr Dis Control & Prevent, Natl Inst Communicable Dis Control & Prevent, Dept Zoonoses, State Key Lab Infect Dis Prevent & Control, Beijing, Peoples R China. [Lin, Xian-Dan] Wenzhou Ctr Dis Control & Prevent, Wenzhou, Zhejiang, Peoples R China. [Tian, Jun-Hua] Wuhan Ctr Dis Control & Prevent, Wuhan, Hubei Province, Peoples R China. [Zhang, Hai-Lin] Yunnan Inst Endem Dis Control & Prevent, Dali, Peoples R China. [Wang, Miao-Ruo] Longquan Ctr Dis Control & Prevent, Longquan, Zhejiang, Peoples R China. [Holmes, Edward C.] Univ Sydney, Sch Biol Sci, Sydney Emerging Infect & Biosecur Inst, Sydney, NSW 2006, Australia. [Holmes, Edward C.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Guo, WP (reprint author), Chinese Ctr Dis Control & Prevent, Natl Inst Communicable Dis Control & Prevent, Dept Zoonoses, State Key Lab Infect Dis Prevent & Control, Beijing, Peoples R China. EM zhangyongzhen@icdc.cn RI Zhang, YZ/H-8101-2013; OI Holmes, Edward/0000-0001-9596-3552 FU National Natural Science Foundation of China [81290343, 81273014]; State Key Laboratory for Infection Disease Prevention and Control [2011SKLID101]; Chinese Ministry of Science and Technology [2003BA712A08-02]; National Institutes of Health [R01 GM080533-06] FX This study was supported by National Natural Science Foundation of China (Grants 81290343, 81273014), State Key Laboratory for Infection Disease Prevention and Control (Grant 2011SKLID101), and the Chinese Ministry of Science and Technology (Grant 2003BA712A08-02), and grant R01 GM080533-06 (to ECH) from the 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 61 TC 76 Z9 82 U1 4 U2 67 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD FEB PY 2013 VL 9 IS 2 AR e1003159 DI 10.1371/journal.ppat.1003159 PG 13 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 099UU UT WOS:000315648900015 PM 23408889 ER PT J AU Hall, PR Elmore, BO Spang, CH Alexander, SM Manifold-Wheeler, BC Castleman, MJ Daly, SM Peterson, MM Sully, EK Femling, JK Otto, M Horswill, AR Timmins, GS Gresham, HD AF Hall, Pamela R. Elmore, Bradley O. Spang, Cynthia H. Alexander, Susan M. Manifold-Wheeler, Brett C. Castleman, Moriah J. Daly, Seth M. Peterson, M. Michal Sully, Erin K. Femling, Jon K. Otto, Michael Horswill, Alexander R. Timmins, Graham S. Gresham, Hattie D. TI Nox2 Modification of LDL Is Essential for Optimal Apolipoprotein B-mediated Control of agr Type III Staphylococcus aureus Quorum-sensing SO PLOS PATHOGENS LA English DT Article ID LOW-DENSITY-LIPOPROTEIN; CHRONIC GRANULOMATOUS-DISEASE; COMMUNITY-ASSOCIATED MRSA; ACCESSORY GENE REGULATOR; GUT-DERIVED ENDOTOXIN; VIRULENCE DETERMINANTS; SINGLET OXYGEN; IN-VIVO; MONOCLONAL AUTOANTIBODIES; HYPOCHLOROUS ACID AB Staphylococcus aureus contains an autoinducing quorum-sensing system encoded within the agr operon that coordinates expression of virulence genes required for invasive infection. Allelic variation within agr has generated four agr specific groups, agr I-IV, each of which secretes a distinct autoinducing peptide pheromone (AIP1-4) that drives agr signaling. Because agr signaling mediates a phenotypic change in this pathogen from an adherent colonizing phenotype to one associated with considerable tissue injury and invasiveness, we postulated that a significant contribution to host defense against tissue damaging and invasive infections could be provided by innate immune mechanisms that antagonize agr signaling. We determined whether two host defense factors that inhibit AIP1-induced agrI signaling, Nox2 and apolipoprotein B (apoB), also contribute to innate control of AIP3-induced agrIII signaling. We hypothesized that apoB and Nox2 would function differently against AIP3, which differs from AIP1 in amino acid sequence and length. Here we show that unlike AIP1, AIP3 is resistant to direct oxidant inactivation by Nox2 characteristic ROS. Rather, the contribution of Nox2 to defense against agrIII signaling is through oxidation of LDL. ApoB in the context of oxLDL, and not LDL, provides optimal host defense against S. aureus agrIII infection by binding the secreted signaling peptide, AIP3, and preventing expression of the agr-driven virulence factors which mediate invasive infection. ApoB within the context of oxLDL also binds AIP 1-4 and oxLDL antagonizes agr signaling by all four agr alleles. Our results suggest that Nox2-mediated oxidation of LDL facilitates a conformational change in apoB to one sufficient for binding and sequestration of all four AIPs, demonstrating the interdependence of apoB and Nox2 in host defense against agr signaling. These data reveal a novel role for oxLDL in host defense against S. aureus quorum-sensing signaling. C1 [Hall, Pamela R.; Elmore, Bradley O.; Spang, Cynthia H.; Manifold-Wheeler, Brett C.; Castleman, Moriah J.; Daly, Seth M.; Timmins, Graham S.] Univ New Mexico, Coll Pharm, San Francisco Joint Grad Grp Bioengn, Albuquerque, NM 87131 USA. [Hall, Pamela R.; Spang, Cynthia H.; Alexander, Susan M.; Manifold-Wheeler, Brett C.; Daly, Seth M.; Peterson, M. Michal; Sully, Erin K.; Gresham, Hattie D.] New Mexico Vet Affairs Hlth Care Serv, Res Serv, Albuquerque, NM USA. [Femling, Jon K.] Univ New Mexico, Dept Emergency Med, Albuquerque, NM 87131 USA. [Otto, Michael] NIAID, Lab Human Bacterial Pathogenesis, NIH, Bethesda, MD 20892 USA. [Horswill, Alexander R.] Univ Iowa, Dept Microbiol, Roy J & Lucille A Carver Coll Med, Iowa City, IA 52242 USA. [Gresham, Hattie D.] Univ New Mexico, Sch Med, Dept Internal Med, Albuquerque, NM 87131 USA. RP Hall, PR (reprint author), Univ New Mexico, Coll Pharm, San Francisco Joint Grad Grp Bioengn, Albuquerque, NM 87131 USA. EM phall@salud.unm.edu RI Hall, Pamela/O-5402-2016; OI Hall, Pamela/0000-0003-2367-3382; timmins, graham/0000-0002-4971-718X; Daly, Seth/0000-0002-3532-8810; Castleman, Moriah/0000-0001-7219-5044; Otto, Michael/0000-0002-2222-4115 FU University of New Mexico & Cancer Center Fluorescence Microscopy Shared Resource; NIH [AI090917, AI064926, AI078921]; National Institute of Allergy and Infectious Diseases, NIH, ZIA [AI000904-10]; Department of Veterans Affairs; University of New Mexico School of Medicine; University of New Mexico [T32-AI007538]; Research Supplements to Promote Diversity in Health-Related Research Program [AI091917-03S1] FX We thank Dr. Richard S. Larson for use of critical equipment and Genevieve Phillips for expert assistance in confocal microscopy. Images in this paper were generated in the University of New Mexico & Cancer Center Fluorescence Microscopy Shared Resource, funded as detailed at: http://hsc.unm.edu/crtc/microscopy/Facility.html.; This work was supported by NIH grants AI090917 (PRH), AI064926 (HDG), AI078921 (ARH), the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH, ZIA AI000904-10 (MO), and by the Department of Veterans Affairs (PRH, HDG). This project was also supported in part by the Dedicated Health Research Funds of the University of New Mexico School of Medicine allocated to the Signature Program in Cardiovascular and Metabolic Disease (PRH). SMD was supported by the University of New Mexico Biology of Infectious Diseases and Inflammation Training Grant (T32-AI007538) and MJC was supported under the Research Supplements to Promote Diversity in Health-Related Research Program (AI091917-03S1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 104 TC 16 Z9 16 U1 0 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD FEB PY 2013 VL 9 IS 2 AR e1003166 DI 10.1371/journal.ppat.1003166 PG 16 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 099UU UT WOS:000315648900019 PM 23459693 ER PT J AU Introini, A Vanpouille, C Lisco, A Grivel, JC Margolis, L AF Introini, Andrea Vanpouille, Christophe Lisco, Andrea Grivel, Jean-Charles Margolis, Leonid TI Interleukin-7 Facilitates HIV-1 Transmission to Cervico-Vaginal Tissue ex vivo SO PLOS PATHOGENS LA English DT Article ID HUMAN LYMPHOID-TISSUE; VAGINAL EPITHELIAL-CELLS; BLOOD MONONUCLEAR-CELLS; CD8(+) T-CELLS; SEXUAL TRANSMISSION; SEMINAL PLASMA; HIV-1-INFECTED INDIVIDUALS; INFECTION; SEMEN; IL-7 AB The majority of HIV-1 infections in women occur through vaginal intercourse, in which virus-containing semen is deposited on the cervico-vaginal mucosa. Semen is more than a mere carrier of HIV-1, since it contains many biological factors, in particular cytokines, that may affect HIV-1 transmission. The concentration of interleukin (IL)-7, one of the most prominent cytokines in semen of healthy individuals, is further increased in semen of HIV-1-infected men. Here, we investigated the potential role of IL-7 in HIV-1 vaginal transmission in an ex vivo system of human cervico-vaginal tissue. We simulated an in vivo situation by depositing HIV-1 on cervico-vaginal tissue in combination with IL-7 at concentrations comparable with those measured in semen of HIV-1-infected individuals. We found that IL-7 significantly enhanced virus replication in ex vivo infected cervico-vaginal tissue. Similarly, we observed an enhancement of HIV-1 replication in lymphoid tissue explants. Analysis of T cells isolated from infected tissues showed that IL-7 reduced CD4(+) T cell depletion preventing apoptosis, as shown by the decrease in the number of cells expressing the apoptotic marker APO2.7 and the increase in the expression of the anti-apoptotic protein B-cell lymphoma (Bcl)-2. Also, IL-7 increased the fraction of cycling CD4(+) T cells, as evidenced by staining for the nuclear factor Ki-67. High levels of seminal IL-7 in vivo may be relevant to the survival of the founder pool of HIV-1-infected cells in the cervico-vaginal mucosa at the initial stage of infection, promoting local expansion and dissemination of HIV infection. C1 [Introini, Andrea; Vanpouille, Christophe; Lisco, Andrea; Grivel, Jean-Charles; Margolis, Leonid] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Introini, Andrea] Univ Milan, Dept Biomed Sci & Technol, I-20133 Milan, Italy. RP Introini, A (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. EM margolis@helix.nih.gov OI Introini, Andrea/0000-0002-9929-8964 FU National Institutes of Health FX This work was supported by the Intramural Research Program of the 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 52 TC 20 Z9 22 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD FEB PY 2013 VL 9 IS 2 AR e1003148 DI 10.1371/journal.ppat.1003148 PG 10 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 099UU UT WOS:000315648900008 PM 23408885 ER PT J AU Nougairede, A De Fabritus, L Aubry, F Gould, EA Holmes, EC de Lamballerie, X AF Nougairede, Antoine De Fabritus, Lauriane Aubry, Fabien Gould, Ernest A. Holmes, Edward C. de Lamballerie, Xavier TI Random Codon Re-encoding Induces Stable Reduction of Replicative Fitness of Chikungunya Virus in Primate and Mosquito Cells SO PLOS PATHOGENS LA English DT Article ID NUCLEOTIDE SUBSTITUTIONS; ENCEPHALITIS-VIRUS; INVERTEBRATE CELLS; CAPSID PROTEIN; RNA VIRUSES; GENOME; EVOLUTION; OUTBREAK; REGION; USAGE AB Large-scale codon re-encoding represents a powerful method of attenuating viruses to generate safe and cost-effective vaccines. In contrast to specific approaches of codon re-encoding which modify genome-scale properties, we evaluated the effects of random codon re-encoding on the re-emerging human pathogen Chikungunya virus (CHIKV), and assessed the stability of the resultant viruses during serial in cellulo passage. Using different combinations of three 1.4 kb randomly re-encoded regions located throughout the CHIKV genome six codon re-encoded viruses were obtained. Introducing a large number of slightly deleterious synonymous mutations reduced the replicative fitness of CHIKV in both primate and arthropod cells, demonstrating the impact of synonymous mutations on fitness. Decrease of replicative fitness correlated with the extent of re-encoding, an observation that may assist in the modulation of viral attenuation. The wild-type and two re-encoded viruses were passaged 50 times either in primate or insect cells, or in each cell line alternately. These viruses were analyzed using detailed fitness assays, complete genome sequences and the analysis of intra-population genetic diversity. The response to codon re-encoding and adaptation to culture conditions occurred simultaneously, resulting in significant replicative fitness increases for both re-encoded and wild type viruses. Importantly, however, the most re-encoded virus failed to recover its replicative fitness. Evolution of these viruses in response to codon re-encoding was largely characterized by the emergence of both synonymous and non-synonymous mutations, sometimes located in genomic regions other than those involving re-encoding, and multiple convergent and compensatory mutations. However, there was a striking absence of codon reversion (<0.4%). Finally, multiple mutations were rapidly fixed in primate cells, whereas mosquito cells acted as a brake on evolution. In conclusion, random codon re-encoding provides important information on the evolution and genetic stability of CHIKV viruses and could be exploited to develop a safe, live attenuated CHIKV vaccine. C1 [Nougairede, Antoine; De Fabritus, Lauriane; Aubry, Fabien; Gould, Ernest A.; de Lamballerie, Xavier] Aix Marseille Univ, EHESP French Sch Publ Hlth, IRD French Inst Res Dev, UMR D Emergence Pathol Virales 190, Marseille, France. [Holmes, Edward C.] Univ Sydney, Sch Biol Sci, Sydney Emerging Infect & Biosecur Inst, Sydney, NSW 2006, Australia. [Holmes, Edward C.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Nougairede, A (reprint author), Aix Marseille Univ, EHESP French Sch Publ Hlth, IRD French Inst Res Dev, UMR D Emergence Pathol Virales 190, Marseille, France. EM antoine.nougairede@univ-amu.fr OI de Fabritus, Lauriane/0000-0003-0668-4629; Holmes, Edward/0000-0001-9596-3552 FU Aix-Marseille University FX This work was supported by Aix-Marseille University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 TC 14 Z9 14 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD FEB PY 2013 VL 9 IS 2 AR e1003172 DI 10.1371/journal.ppat.1003172 PG 18 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 099UU UT WOS:000315648900023 PM 23436995 ER PT J AU Leung, JM Olivier, KN AF Leung, Janice M. Olivier, Kenneth N. TI Nontuberculous Mycobacteria in Patients with Cystic Fibrosis SO SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Review DE cystic fibrosis; nontuberculous mycobacteria; mycobacterium infections; Mycobacterium avium complex; Mycobacterium abscessus ID LUNG-TRANSPLANT RECIPIENTS; FATAL PULMONARY INFECTION; ACETYL-L-CYSTEINE; AVIUM COMPLEX; ABSCESSUS INFECTION; PSEUDOMONAS-AERUGINOSA; MULTICENTER PREVALENCE; DECONTAMINATION METHOD; SODIUM HYDROXIDE; SPUTUM SAMPLES AB As a result of their underlying lung disease, patients with cystic fibrosis (CF) have a higher risk of developing nontuberculous mycobacteria (NTM) infections compared with the general population. Although NTM may be present intermittently in low amounts in the airways of CF patients without an apparent clinical effect, progressive respiratory decline due to NTM disease may also occur. Identifying this latter group of patients can be challenging for clinicians because the usual symptoms exhibited by infected individuals without CF may be difficult to distinguish from the baseline respiratory dysfunction of a patient with CF. The distinction, however, is of utmost importance because those patients with clinical worsening may benefit considerably from antimycobacterial treatment. For CF patients under evaluation for lung transplantation, NTM can play a critical role in determining overall outcomes, and treatment in the pre- and post-transplant period may be vital to success. A general approach to NTM in CF thus involves surveillance to detect NTM, careful monitoring for associated clinical decline, and consideration of treatment given for those with an otherwise unexplained deterioration. In this review, the epidemiology and clinical course of NTM in CF is described with an algorithm for management proposed. C1 [Leung, Janice M.] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Olivier, Kenneth N.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Leung, JM (reprint author), NIH, Dept Crit Care Med, 10 Ctr Dr,Rm 2C145, Bethesda, MD 20892 USA. EM Janice.leung@nih.gov FU Division of Intramural Research; National Institute of Allergy and Infectious Diseases; National Institutes of Health Clinical Center FX This work was supported in part by the Division of Intramural Research, the National Institute of Allergy and Infectious Diseases, and the National Institutes of Health Clinical Center. NR 130 TC 19 Z9 19 U1 0 U2 15 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1069-3424 J9 SEMIN RESP CRIT CARE JI Semin. Respir. Crit. Care Med. PD FEB PY 2013 VL 34 IS 1 BP 124 EP 134 DI 10.1055/s-0033-1333574 PG 11 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 101RY UT WOS:000315793300012 PM 23460012 ER PT J AU Fuhrman, BJ Freedman, DM Bhatti, P Doody, MM Fu, YP Chang, SC Linet, MS Sigurdson, AJ AF Fuhrman, Barbara J. Freedman, D. Michal Bhatti, Parveen Doody, Michele M. Fu, Yi-Ping Chang, Shih-Chen Linet, Martha S. Sigurdson, Alice J. TI Sunlight, Polymorphisms of Vitamin D-related Genes and Risk of Breast Cancer SO ANTICANCER RESEARCH LA English DT Article DE Vitamin D; sunlight; polymorphisms; breast cancer; gene; case-control ID US RADIOLOGIC TECHNOLOGISTS; PROSTATE-CANCER; UNITED-STATES; EXPOSURE; ASSOCIATION; RADIATION; VARIANTS; MORTALITY; CYP27B1; CYP24A1 AB Background/Aim: Geographic gradients in breast cancer incidence and mortality suggest that vitamin D may reduce risk. The enzyme 25-hydroxyvitamin D 24-hydroxylase (CYP24A1), which degrades the active form of vitamin D, and the vitamin D receptor (VDR) are both found in breast tissue. We investigated six polymorphisms in CYP24A1 and two in the VDR gene in association with breast cancer risk. Materials and Methods: We conducted a case control study within the nationwide U.S. Radiologic Technologists cohort, including 845 controls and 484 incident breast cancer cases. Associations of polymorphic variants and ecologic and personal measures of sun exposure with breast cancer risk were assessed using unconditional logistic regression. Results: Two polymorphisms in CYP24A1 were associated with increased breast cancer risk (rs34043203, P-trend=0.03; rs2762934, P-trend=0.005) and one with reduced breast cancer risk (rs1570669, P-trend=0.048). Risk was inversely associated with minor alleles for the VDR Bsm1 polymorphism (rs1544410, P-trend=0.05) but not Fok1 (rs2228570). Sunlight measures were not associated with breast cancer risk, however significant interactions between time outdoors in the teen years and three unlinked genotypes were found for VDR (rs1544410, rs2228570) and CYP24A1 (rs1570669). Conclusion: In this nation-wide breast cancer case-control study, we found that the vitamin D pathway was involved in disease etiology and our results further suggest that reduced cancer risk, in association with sunlight, may depend on timing of exposure and genetic background. These findings merit further investigation. C1 [Fuhrman, Barbara J.; Freedman, D. Michal; Doody, Michele M.; Linet, Martha S.; Sigurdson, Alice J.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Bhatti, Parveen] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Fu, Yi-Ping] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Gaithersburg, MD USA. [Chang, Shih-Chen] Genentic Inc, Patient Reported Outcomes & Healthcare Data Strat, Epidemiol, San Francisco, CA USA. RP Sigurdson, AJ (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 6120 Execut Blvd MSC 7238, Bethesda, MD 20892 USA. EM sigurdsa@mail.nih.gov FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX We are grateful to the radiologic technologists who participated in the U.S. Radio logic Technologists Study; Jerry Reid of the American Registry of Radio logic Technologists for continued support of this study; Diane Kampa and Allison Iwan of the University of Minnesota for data collection and study coordination; Laura Bowen of Information Management Systems for biomedical computing statistical support. This research was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 29 TC 20 Z9 20 U1 0 U2 8 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD FEB PY 2013 VL 33 IS 2 BP 543 EP 551 PG 9 WC Oncology SC Oncology GA 096SG UT WOS:000315424000025 PM 23393347 ER PT J AU Tsiouli, E Alexopoulos, EC Stefanaki, C Darviri, C Chrousos, GP AF Tsiouli, Elina Alexopoulos, Evangelos C. Stefanaki, Charikleia Darviri, Christina Chrousos, George P. TI Effects of diabetes-related family stress on glycemic control in young patients with type 1 diabetes Systematic review SO CANADIAN FAMILY PHYSICIAN LA English DT Review DE diabetes type 1; glycemic control; family stress; family conflict; family function ID QUALITY-OF-LIFE; METABOLIC-CONTROL; PSYCHOLOGICAL CARE; CHILDREN; ADOLESCENTS; MELLITUS; ADHERENCE; ENVIRONMENT; MANAGEMENT; PREDICTORS AB Objective To investigate the way that family stress influences glycemic control among patients with diabetes who are younger than 18 years of age. Data sources PubMed and Scopus were searched for relevant studies published since 1990 using the following key words: diabetes type 1, glycemic control, family stress, family conflict, and family function. Study selection In total, 1478 papers were identified in the initial search. The final review included 6 cohort studies, 3 cross-sectional studies, and 1 qualitative review in which family stress was assessed using specific diabetes-related conflict measurement instruments, and glycemic control was evaluated by glycosylated hemoglobin measurement. Synthesis In most studies family stress was negatively correlated with patients' glycemic control. Family function was strongly related to patients' glycemic control, while family conflict was adversely associated with glycemic control. Families of low socioeconomic status, those of adolescents with diabetes, and those of single parents were more prone to diabetes-related stress and thus more susceptible to worse glycemic control. Conclusion Therapeutic psychological interventions and educational programs can help alleviate family diabetes-related stress and will likely improve glycemic control. C1 [Alexopoulos, Evangelos C.; Darviri, Christina] Univ Athens, Sch Med, GR-10679 Athens, Greece. [Chrousos, George P.] Univ Athens, Sch Med, Dept Pediat 1, GR-10679 Athens, Greece. [Chrousos, George P.] UNESCO Chair Adolescent Hlth Care, Div Endocrinol Diabet & Metab, Delft, Netherlands. [Chrousos, George P.] NICHHD, NIH, Bethesda, MD 20892 USA. RP Darviri, C (reprint author), Acad Athens, Biomed Res Fdn, Soranou Ephessiou Str 4, GR-11527 Athens, Greece. EM cdarviri@yahoo.gr RI Alexopoulos, Evangelos/C-4730-2008 OI Alexopoulos, Evangelos/0000-0003-0449-918X NR 30 TC 17 Z9 17 U1 8 U2 30 PU COLL FAMILY PHYSICIANS CANADA PI MISSISSAUGA PA 2630 SKYMARK AVE, MISSISSAUGA, ONTARIO L4W 5A4, CANADA SN 0008-350X J9 CAN FAM PHYSICIAN JI Can. Fam. Phys. PD FEB PY 2013 VL 59 IS 2 BP 143 EP 149 PG 7 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 093QW UT WOS:000315207500013 PM 23418238 ER PT J AU Ruiz-Narvaez, EA Rosenberg, L Yao, S Rotimi, CN Cupples, AL Bandera, EV Ambrosone, CB Adams-Campbell, LL Palmer, JR AF Ruiz-Narvaez, Edward A. Rosenberg, Lynn Yao, Song Rotimi, Charles N. Cupples, Adrienne L. Bandera, Elisa V. Ambrosone, Christine B. Adams-Campbell, Lucile L. Palmer, Julie R. TI Fine-mapping of the 6q25 locus identifies a novel SNP associated with breast cancer risk in African-American women SO CARCINOGENESIS LA English DT Article ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; UNRELATED INDIVIDUALS; ADMIXTURE; REPLICATION; POPULATIONS; ANCESTRY; LINKAGE; SAMPLES; HEALTH AB The rs2046210 single nucleotide polymorphism (SNP) in the 6q25.1 region was identified in a breast cancer genome-wide association study of Chinese women. The SNP has been replicated in European ancestry populations, but replication efforts have failed in African ancestry populations. We evaluated a total of 13 tagging SNPs in the linkage disequilibrium block around rs2046210 in a case-control study of breast cancer nested within the Black Women's Health Study, which included 1191 cases and 1941 controls. Replication of initial significant findings was carried out in 665 cases and 821 controls of African ancestry from the Women's Circle of Health Study (WCHS). No significant association was found for rs2046210 in univariate analysis. A new SNP, rs2046211, was significantly associated with reduced risk of breast cancer and was replicated in data from WCHS. In joint analyses that included both SNPs, the rs2046210-A allele was associated with increased risk of breast cancer [ odds ratio (OR) = 1.14; 95% confidence interval (CI) = 1.02-1.28], and the rs2046211-G allele was associated with reduced risk (OR = 0.80; 95% CI = 0.67-0.95). Haplotype analysis confirmed these results and showed that the rs2046210-A allele is present in high-risk (rs2046211-C/rs2046210-A) and low-risk (rs2046211-G/rs2046210-A) haplo-types. Our results confirm the importance of 6q25.1 as a breast cancer susceptibility region. We replicated the rs2046210 association, after accounting for the haplotype background that included rs2046211 in African-American women, and we report the presence of a novel signal that is tagged by rs2046211. C1 [Ruiz-Narvaez, Edward A.; Rosenberg, Lynn; Palmer, Julie R.] Boston Univ, Slone Epidemiol Ctr, Boston, MA 02215 USA. [Ruiz-Narvaez, Edward A.; Rosenberg, Lynn; Palmer, Julie R.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02118 USA. [Yao, Song; Ambrosone, Christine B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Rotimi, Charles N.] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Cupples, Adrienne L.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Bandera, Elisa V.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, New Brunswick, NJ 08903 USA. [Adams-Campbell, Lucile L.] Georgetown Univ, Med Ctr, Washington, DC 20057 USA. RP Ruiz-Narvaez, EA (reprint author), Boston Univ, Slone Epidemiol Ctr, 1010 Commonwealth Ave, Boston, MA 02215 USA. EM eruiznar@bu.edu RI Bandera, Elisa/M-4169-2014; OI Bandera, Elisa/0000-0002-8789-2755; Ruiz-Narvaez, Edward/0000-0002-0339-5824; Palmer, Julie/0000-0002-6534-335X FU National Institutes of Health [R01 CA058420, R01 CA098663, R01 CA100598]; Susan G. Komen for the Cure Foundation; United States Army Medical Research and Material Command [DAMD-17-01-1-0334]; National Cancer Institute [P01 CA151135, K22 CA138563] FX National Institutes of Health (R01 CA058420 and R01 CA098663); and the Susan G. Komen for the Cure Foundation. The WCHS is supported by grants from National Institutes of Health (R01 CA100598); United States Army Medical Research and Material Command (DAMD-17-01-1-0334). The research teams of both BWHS and WCHS are also supported by the National Cancer Institute (P01 CA151135). National Cancer Institute (K22 CA138563 to E.V.B.). NR 22 TC 6 Z9 6 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD FEB PY 2013 VL 34 IS 2 BP 287 EP 291 DI 10.1093/carcin/bgs334 PG 5 WC Oncology SC Oncology GA 099NH UT WOS:000315627900006 PM 23104177 ER PT J AU Mao, KR Chen, SZ Chen, MK Ma, YL Wang, Y Huang, B He, ZY Zeng, Y Hu, Y Sun, SH Li, J Wu, XD Wang, XR Strober, W Chen, C Meng, GX Sun, B AF Mao, Kairui Chen, Shuzhen Chen, Mingkuan Ma, Yonglei Wang, Yan Huang, Bo He, Zhengyu Zeng, Yan Hu, Yu Sun, Shuhui Li, Jing Wu, Xiaodong Wang, Xiangrui Strober, Warren Chen, Chang Meng, Guangxun Sun, Bing TI Nitric oxide suppresses NLRP3 inflammasome activation and protects against LPS-induced septic shock SO CELL RESEARCH LA English DT Article DE nitric oxide; NLRP3 inflammasome; septic shock ID NALP3 INFLAMMASOME; IMMUNE-RESPONSES; MESSENGER-RNA; HOST-DEFENSE; SYNTHASE; MICE; EXPRESSION; DISEASE; CELLS; NITROSYLATION AB Inflammasomes are multi-protein complexes that trigger the activation of caspase-1 and the maturation of interleukin-1 beta (IL-1 beta), yet the regulation of these complexes remains poorly characterized. Here we show that nitric oxide (NO) inhibited the NLRP3-mediated ASC pyroptosome formation, caspase-1 activation and IL-1 beta secretion in myeloid cells from both mice and humans. Meanwhile, endogenous NO derived from iNOS (inducible form of NO synthase) also negatively regulated NLRP3 inflammasome activation. Depletion of iNOS resulted in increased accumulation of dysfunctional mitochondria in response to LPS and ATP, which was responsible for the increased IL-1 beta production and caspase-1 activation. iNOS deficiency or pharmacological inhibition of NO production enhanced NLRP3-dependent cytokine production in vivo, thus increasing mortality from LPS-induced sepsis in mice, which was prevented by NLRP3 deficiency. Our results thus identify NO as a critical negative regulator of the NLRP3 inflammasome via the stabilization of mitochondria. This study has important implications for the design of new strategies to control NLRP3-related diseases. C1 [Mao, Kairui; Chen, Shuzhen; Hu, Yu; Wu, Xiaodong; Sun, Bing] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Cell Biol, Shanghai 200031, Peoples R China. [Chen, Mingkuan; Ma, Yonglei; Wang, Yan; Zeng, Yan; Meng, Guangxun; Sun, Bing] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Pasteur Shanghai, Key Lab Mol Virol & Immunol, Shanghai 200025, Peoples R China. [Huang, Bo; Chen, Chang] Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing 100101, Peoples R China. [He, Zhengyu; Wang, Xiangrui] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Dept Anesthesiol, Shanghai 200127, Peoples R China. [Sun, Shuhui] Fudan Univ, Sch Med, Shanghai 200032, Peoples R China. [Li, Jing] Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Informat Ctr Life Sci, Shanghai 200031, Peoples R China. [Strober, Warren] NIAID, Mucosal Immun Sect, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Sun, B (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Cell Biol, Shanghai 200031, Peoples R China. EM changchen@moon.ibp.ac.cn; gxmeng@sibs.ac.cn; bsun@sibs.ac.cn RI huang, bo/B-4649-2008; OI Hu, Yu/0000-0002-9511-9383; huang, bo/0000-0001-5945-7601; 孟, 广勋/0000-0002-4253-9675 FU National Basic Research Program of China (973 program) [2013CB530504]; National Natural Science Foundation of China [31230024, 31030029, 31100662, 31030023, 91029707, 31170868]; Shanghai Natural Science Foundation [11ZR1442600]; National Ministry of Science and Technology [2007DFC31700]; National Science and Technology Major Project [2008ZX10004-002, 2008ZX10002-014, 2009ZX10004-105, 2009ZX10004-016, 2011ZX10004-001, 2012ZX10002007]; Shanghai Pasteur Health Research Foundation [SPHRF2008001, SPHRF2009001]; SA-SIBS Discovery Innovation Grant; Li Kha Shing Foundation; 100 Talent Program of Chinese Academy of Sciences FX We thank R Caspi (National Eye Institute, NIH, USA) and D Li (Shanghai Institutes for Biological Sciences, China) for helpful comments, and S Skinner for critical reading of the manuscript. This work was supported by the National Basic Research Program of China (973 program, 2013CB530504), the National Natural Science Foundation of China (31230024, 31030029, 31100662, 31030023, 91029707, 31170868), the Shanghai Natural Science Foundation (11ZR1442600), the National Ministry of Science and Technology (2007DFC31700), the National Science and Technology Major Project (2008ZX10004-002, 2008ZX10002-014, 2009ZX10004-105, 2009ZX10004-016, 2011ZX10004-001 and 2012ZX10002007), the Shanghai Pasteur Health Research Foundation (SPHRF2008001 and SPHRF2009001), the SA-SIBS Discovery Innovation Grant, the Li Kha Shing Foundation and the 100 Talent Program of the Chinese Academy of Sciences (to GM). NR 50 TC 91 Z9 101 U1 6 U2 41 PU INST BIOCHEMISTRY & CELL BIOLOGY PI SHANGHAI PA SIBS, CAS, 319 YUEYANG ROAD, SHANGHAI, 200031, PEOPLES R CHINA SN 1001-0602 EI 1748-7838 J9 CELL RES JI Cell Res. PD FEB PY 2013 VL 23 IS 2 BP 201 EP 212 DI 10.1038/cr.2013.6 PG 12 WC Cell Biology SC Cell Biology GA 096TE UT WOS:000315426400009 PM 23318584 ER PT J AU Chen, SY Li, H Gaudenz, K Paulson, A Guo, FL Trimble, R Peak, A Seidel, C Deng, CX Furuta, Y Xie, T AF Chen, Shuyi Li, Hua Gaudenz, Karin Paulson, Ariel Guo, Fengli Trimble, Rhonda Peak, Allison Seidel, Christopher Deng, Chuxia Furuta, Yasuhide Xie, Ting TI Defective FGF signaling causes coloboma formation and disrupts retinal neurogenesis SO CELL RESEARCH LA English DT Article DE optic fissure; coloboma; FGF signaling; retinal ganglion cells ID FIBROBLAST GROWTH-FACTORS; OPTIC FISSURE CLOSURE; EYE MORPHOGENESIS; VERTEBRATE RETINA; NEURAL RETINA; DROSOPHILA GASTRULATION; TARGETED DISRUPTION; PATTERNING DEFECTS; MOUSE GASTRULATION; PAX2 EXPRESSION AB The optic fissure (OF) is a transient opening on the ventral side of the developing vertebrate eye that closes before nearly all retinal progenitor cell differentiation has occurred. Failure to close the OF results in coloboma, a congenital disease that is a major cause of childhood blindness. Although human genetic studies and animal models have linked a number of genes to coloboma, the cellular and molecular mechanisms driving the closure of the OF are still largely unclear. In this study, we used Cre-LoxP-mediated conditional removal of fibroblast growth factor (FGF) receptors, Fgfr1 and Fgfr2, from the developing optic cup (OC) to show that FGF signaling regulates the closing of the OF. Our molecular, cellular and transcriptome analyses of Fgfr1 and Fgfr2 double conditional knockout OCs suggest that FGF signaling controls the OF closure through modulation of retinal progenitor cell proliferation, fate specification and morphological changes. Furthermore, Fgfr1 and Fgfr2 double conditional mutant retinal progenitor cells fail to initiate retinal ganglion cell (RGC) genesis. Taken together, our mouse genetic studies reveal that FGF signaling is essential for OF morphogenesis and RGC development. C1 [Chen, Shuyi; Li, Hua; Gaudenz, Karin; Paulson, Ariel; Guo, Fengli; Trimble, Rhonda; Peak, Allison; Seidel, Christopher; Xie, Ting] Stowers Inst Med Res, Kansas City, MO 64110 USA. [Chen, Shuyi; Xie, Ting] Univ Kansas, Sch Med, Dept Anat & Cell Biol, Kansas City, KS 66160 USA. [Deng, Chuxia] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Furuta, Yasuhide] Univ Texas MD Anderson Canc Ctr, Dept Biochem & Mol Biol, Houston, TX 77030 USA. RP Chen, SY (reprint author), Stowers Inst Med Res, 1000 E 50th St, Kansas City, MO 64110 USA. EM sch@stowers.org RI deng, chuxia/N-6713-2016 FU SIMR; MR and Evelyn Hudson Foundation; NIH [EY012128] FX We would like to thank D Ornitz for the Fgfr2 conditional allele, B Sandersan for help in qPCR experiments, R Krumlauf, W Neaves, M Lewallen and C Tanzie for comments, the Xie laboratory members for stimulating discussions, the Laboratory Animal Services Facility at SIMR for maintaining our mouse strains, and C Flournoy for administrative assistance. This work was supported by SIMR (T Xie), the MR and Evelyn Hudson Foundation (T Xie), and NIH grant (EY012128, Y Furuta). NR 97 TC 7 Z9 7 U1 0 U2 10 PU INST BIOCHEMISTRY & CELL BIOLOGY PI SHANGHAI PA SIBS, CAS, 319 YUEYAND ROAD, SHANGHAI, 200031, PEOPLES R CHINA SN 1001-0602 J9 CELL RES JI Cell Res. PD FEB PY 2013 VL 23 IS 2 BP 254 EP 273 DI 10.1038/cr.2012.150 PG 20 WC Cell Biology SC Cell Biology GA 096TE UT WOS:000315426400013 PM 23147794 ER PT J AU Rana, R Coulter, S Kinyamu, H Goldstein, JA AF Rana, Ritu Coulter, Sherry Kinyamu, Harriet Goldstein, Joyce A. TI RBCK1, an E3 Ubiquitin Ligase, Interacts with and Ubiquinates the Human Pregnane X Receptor SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID CONSTITUTIVE ANDROSTANE RECEPTOR; CYP3A4 GENE-EXPRESSION; NUCLEAR RECEPTOR; SIGNALING PATHWAY; HUMAN HEPATOCYTES; BINDING PROTEIN; CROSS-TALK; PXR; INDUCTION; IDENTIFICATION AB The pregnane X receptor (PXR, NR1I2) plays a pivotal role in the disposition and detoxification of numerous foreign and endogenous chemicals by increasing transcription of numerous target genes, including phase I and II drug-metabolizing enzymes and transporters. In the present study, yeast two-hybrid screening identified an E3 ubiquitin ligase, RBCK1 (Ring-B-box-coiled-coil protein interacting with protein kinase C-1), as a human pregnane X receptor (hPXR)-interacting protein. Coimmunoprecipitation studies confirmed the interaction between RBCK1 and hPXR when both were ectopically expressed in AD-293 cells. Domain mapping studies showed that the interaction between RBCK1 and hPXR involves all RBCK1 domains. We further demonstrate that RBCK1 ubiquitinates hPXR, and this may target hPXR for degradation by the ubiquitin-proteasome pathway. Simultaneous ectopic overexpression of RBCK1 and PXR decreased PXR levels in AD-293 cells, and this decrease was inhibited by the proteasomal inhibitor MG-132 (carbobenzoxy-Leu-Leu-leucinal). Furthermore, overexpression of RBCK1 decreased endogenous levels of PXR in HepG2 cells. Of importance, ectopic overexpression and silencing of endogenous RBCK1 in primary human hepatocytes resulted in a decrease and increase, respectively, in endogenous PXR protein levels and in the induction of PXR target genes by rifampicin. These results suggest that RBCK1 is important for the ubiquitination of PXR and may play a role in its proteasomal degradation. C1 [Rana, Ritu; Coulter, Sherry; Goldstein, Joyce A.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Kinyamu, Harriet] NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Goldstein, JA (reprint author), NIEHS, Lab Toxicol & Pharmacol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM goldste1@niehs.nih.gov OI Coulter, Sherry/0000-0002-2732-3470 FU Intramural Research Program of the National Institutes of Health National Institute of Environmental Health Sciences [Z01ES02124, Z01ES071006-12] FX This research was supported by the Intramural Research Program of the National Institutes of Health National Institute of Environmental Health Sciences [Grants Z01ES02124 and Z01ES071006-12]. NR 43 TC 9 Z9 10 U1 0 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD FEB PY 2013 VL 41 IS 2 BP 398 EP 405 DI 10.1124/dmd.112.048728 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 095RO UT WOS:000315352400019 PM 23160820 ER PT J AU Johnson, CH Bonzo, JA Cheng, J Krausz, KW Kang, DW Luecke, H Idle, JR Gonzalez, FJ AF Johnson, Caroline H. Bonzo, Jessica A. Cheng, Jie Krausz, Kristopher W. Kang, Dong Wook Luecke, Hans Idle, Jeffrey R. Gonzalez, Frank J. TI Cytochrome P450 Regulation by alpha-Tocopherol in Pxr-Null and PXR-Humanized Mice SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID PREGNANE-X-RECEPTOR; CONSTITUTIVE ANDROSTANE RECEPTOR; HUMAN CYP2C GENES; HEPG2 CELLS; ACTIVE/ANDROSTANE RECEPTOR; TRANSCRIPTIONAL REGULATION; PHENYTOIN INDUCTION; OMEGA-HYDROXYLASE; DRUG-INTERACTIONS; CYP3A INDUCTION AB The pregnane X receptor (PXR) has been postulated to play a role in the metabolism of alpha-tocopherol owing to the up-regulation of hepatic cytochrome P450 (P450) 3A in human cell lines and murine models after alpha-tocopherol treatment. However, in vivo studies confirming the role of PXR in alpha-tocopherol metabolism in humans presents significant difficulties and has not been performed. PXR-humanized (hPXR), wildtype, and Pxr-null mouse models were used to determine whether alpha-tocopherol metabolism is influenced by species-specific differences in PXR function in vivo. No significant difference in the concentration of the major alpha-tocopherol metabolites was observed among the hPXR, wild-type, and Pxr-null mice through mass spectrometry-based metabolomics. Gene expression analysis revealed significantly increased expression of Cyp3a11 as well as several other P450s only in wild-type mice, suggesting species-specificity for alpha-tocopherol activation of PXR. Luciferase reporter assay confirmed activation of mouse PXR by alpha-tocopherol. Analysis of the Cyp2c family of genes revealed increased expression of Cyp2c29, Cyp2c37, and Cyp2c55 in wild-type, hPXR, and Pxr-null mice, which suggests PXR-independent induction of Cyp2c gene expression. This study revealed that alpha-tocopherol is a partial agonist of PXR and that PXR is necessary for Cyp3a induction by alpha-tocopherol. The implications of a novel role for alpha-tocopherol in Cyp2c gene regulation are also discussed. C1 [Johnson, Caroline H.; Bonzo, Jessica A.; Cheng, Jie; Krausz, Kristopher W.; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kang, Dong Wook; Luecke, Hans] NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Idle, Jeffrey R.] Univ Bern, Hepatol Res Grp, Dept Clin Res, Bern, Switzerland. RP Gonzalez, FJ (reprint author), NCI, Bldg 37,Room 3106, Bethesda, MD 20892 USA. EM fjgonz@helix.nih.gov FU Intramural Research Program of the National Institutes of Health National Cancer Institute [1ZIABC005562-24]; National Institutes of Health Office of Dietary Supplements FX This work was supported by the Intramural Research Program of the National Institutes of Health National Cancer Institute [Grant 1ZIABC005562-24]; and an intramural award from the National Institutes of Health Office of Dietary Supplements (C.H.J.). NR 40 TC 4 Z9 5 U1 1 U2 7 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD FEB PY 2013 VL 41 IS 2 BP 406 EP 413 DI 10.1124/dmd.112.048009 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 095RO UT WOS:000315352400020 PM 23160821 ER PT J AU Merikangas, KR AF Merikangas, Kathleen R. TI Contributions of Epidemiology to Our Understanding of Migraine SO HEADACHE LA English DT Review DE epidemiology; incidence; migraine; second edition of the International Classification of Headache Disorders-2; adult; children ID TENSION-TYPE HEADACHE; GENOME-WIDE ASSOCIATION; GERMAN DMKG HEADACHE; HIGH-SCHOOL STUDENTS; UNITED-STATES; FOLLOW-UP; EUROLIGHT PROJECT; INTERNATIONAL CLASSIFICATION; CLINICAL CHARACTERISTICS; REPRESENTATIVE SAMPLE AB Background During the past decade, the introduction of the second edition of the International Classification of Headache Disorders (ICHD-II) and the initiation of active campaigns to increase awareness of the high magnitude, burden, and impact of migraine have stimulated numerous studies of population-based data on the prevalence, correlates, and impact of migraine. Objective This paper provides an update of the literature on the worldwide epidemiology of migraine from studies that included the ICHD-II criteria. The aims of this paper are: (1) to review evidence regarding the magnitude of migraine; (2) to summarize information on the correlates and impact of migraine; and (3) to discuss the contributions, challenges, and future directions in the epidemiology of migraine. Evidence on the magnitude of migraine is divided into the following types of data: (1) prevalence rates of ICHD-II-defined migraine and tension-type headache from international population-based studies of adults; (2) the magnitude of migraine in U.S. studies; (3) ICHD-II-based international prevalence rates of ICHD-II-defined migraine in children; and (4) incidence rates of migraine from prospective longitudinal studies. Methods A comprehensive review of the literature on the prevalence of migraine subtypes and tension-type headache defined by ICHD-II criteria during the past decade was conducted and aggregate weighted rates across studies were derived. Results Across the 19 studies of adults that employed the ICHD-II criteria, the aggregate weighted estimates of the 12-month prevalence of definite migraine are 11.5%, and probable migraine of 7%, yielding a total of 18.5%. The cross-study weighted aggregate rate of migraine with aura is 4.4%, chronic migraine is 0.5%, and of tension-type headache is 13%. There has been even greater growth in international prevalence data on migraine in children, with a total of 21 studies of children that have employed the ICDH-II criteria. The aggregate weighted rate of definite migraine in children is 10.1% and migraine with aura is 1.6%. The well-established demographic correlates of migraine including the equal sex ratio in childhood, with increasing prevalence of migraine in females across adolescence to mid-adulthood were confirmed in these studies. Despite increasing effort to increase awareness of migraine, approximately 50% of those with frequent and/or severe migraine do not receive professional treatment. Conclusions This review demonstrates that the descriptive epidemiology of migraine has reached its maturity. The prevalence rates and sociodemographic correlates have been stable across 50 years. These developments justify a shift in efforts to the application of the designs and methods of analytic epidemiology. Retrospective casecontrol studies followed by prospective cohort studies that test specific associations are likely to enhance our understanding of the predictors of incidence and progression of migraine, subtypes of migraine with differential patterns of onset and course, and specific environmental exposures that may have either causal or provocative influences on migraine etiology. C1 NIMH, Genet Epidemiol Res Branch, Bethesda, MD 20892 USA. RP Merikangas, KR (reprint author), NIMH, Genet Epidemiol Res Branch, 35 Convent Dr,MSC 3720, Bethesda, MD 20892 USA. FU National Institute of Mental Health [Z01 MH002804] FX This work was supported by the Intramural Research Program of the National Institute of Mental Health (Z01 MH002804). The views and opinions expressed in this article are those of the author and should not be construed to represent the views of any of the sponsoring organizations, agencies, or U.S. Government. The principal author takes full responsibility for the data presented in this study, analysis of the data, conclusions, and conduct of the research. The author had full access to those data and has maintained the right to publish any and all data independent of any third party. NR 126 TC 55 Z9 55 U1 1 U2 23 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0017-8748 EI 1526-4610 J9 HEADACHE JI Headache PD FEB PY 2013 VL 53 IS 2 BP 230 EP 246 DI 10.1111/head.12038 PG 17 WC Clinical Neurology SC Neurosciences & Neurology GA 096FN UT WOS:000315389700002 PM 23432441 ER PT J AU Thierry-Chef, I Dabin, J Friberg, EG Hermen, J Istad, TS Jahnen, A Krille, L Lee, C Maccia, C Nordenskjold, A Olerud, HM Rani, K Rehel, JL Simon, SL Struelens, L Kesminiene, A AF Thierry-Chef, Isabelle Dabin, Jeremie Friberg, Eva G. Hermen, Johannes Istad, Tore S. Jahnen, Andreas Krille, Lucian Lee, Choonsik Maccia, Carlo Nordenskjold, Arvid Olerud, Hilde M. Rani, Kaddour Rehel, Jean-Luc Simon, Steven L. Struelens, Lara Kesminiene, Ausrele TI Assessing Organ Doses from Paediatric CT Scans-A Novel Approach for an Epidemiology Study (the EPI-CT Study) SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH LA English DT Article DE paediatric computed tomography; organ dose reconstruction; scanner settings; leukaemia; cancer risk ID MONTE-CARLO-SIMULATION; COMPUTED-TOMOGRAPHY; CANCER-RISKS; RADIATION; PHANTOMS AB The increasing worldwide use of paediatric computed tomography (CT) has led to increasing concerns regarding the subsequent effects of exposure to radiation. In response to this concern, the international EPI-CT project was developed to study the risk of cancer in a large multi-country cohort. In radiation epidemiology, accurate estimates of organ-specific doses are essential. In EPI-CT, data collection is split into two time periods-before and after introduction of the Picture Archiving Communication System (PACS) introduced in the 1990s. Prior to PACS, only sparse information about scanner settings is available from radiology departments. Hence, a multi-level approach was developed to retrieve information from a questionnaire, surveys, scientific publications, and expert interviews. For the years after PACS was introduced, scanner settings will be extracted from Digital Imaging and Communications in Medicine (DICOM) headers, a protocol for storing medical imaging data. Radiation fields and X-ray interactions within the body will be simulated using phantoms of various ages and Monte-Carlo-based radiation transport calculations. Individual organ doses will be estimated for each child using an accepted calculation strategy, scanner settings, and the radiation transport calculations. Comprehensive analyses of missing and uncertain dosimetry data will be conducted to provide uncertainty distributions of doses. C1 [Thierry-Chef, Isabelle; Kesminiene, Ausrele] Int Agcy Res Canc, F-69008 Lyon, France. [Dabin, Jeremie; Struelens, Lara] CEN SCK, Belgian Nucl Res Ctr, B-2400 Mol, Belgium. [Friberg, Eva G.; Istad, Tore S.; Olerud, Hilde M.] Norwegian Radiat Protect Author, N-1332 Osteras, Norway. [Hermen, Johannes; Jahnen, Andreas; Rani, Kaddour] Publ Res Ctr Henri Tudor, L-1855 Luxembourg, Luxembourg. [Krille, Lucian] Johannes Gutenberg Univ Mainz, Inst Med Biostat Epidemiol & Informat, Univ Med Ctr, D-55131 Mainz, Germany. [Lee, Choonsik; Simon, Steven L.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Rockville, MD 20852 USA. [Maccia, Carlo] CAATS 43, F-92340 Bourg La Reine, France. [Nordenskjold, Arvid] Karolinska Inst, Karolinska Univ Hosp, Clin Epidemiol Unit, Dept Med, SE-171 Stockholm 76, Sweden. [Olerud, Hilde M.] Univ Oslo, Inst Phys, N-0316 Oslo, Norway. [Rani, Kaddour] Univ Lorraine, Res Ctr Automat Control, F-54052 Nancy, France. [Rehel, Jean-Luc] PRP HOM SER UEM, Radiat Protect & Nucl Safety Inst, F-92262 Fontenay Aux Roses, France. RP Thierry-Chef, I (reprint author), Int Agcy Res Canc, 150 Cours Albert Thomas, F-69008 Lyon, France. EM thierrychefi@iarc.fr; jeremie.dabin@SCKCEN.BE; Eva.Friberg@nrpa.no; johannes.hermen@tudor.lu; Tore.Istad@nrpa.no; andreas.jahnen@tudor.lu; krille1@imbei.uni-mainz.de; leechoonsik@mail.nih.gov; carlo-maccia@neuf.fr; arvid.nordenskjold@ki.se; Hilde.Olerud@nrpa.no; kaddour.rani@tudor.lu; Jean-luc.rehel@irsn.fr; ssimon@mail.nih.gov; lara.struelens@SCKCEN.BE; kesminienea@iarc.fr RI Lee, Choonsik/C-9023-2015; OI Lee, Choonsik/0000-0003-4289-9870; Jahnen, Andreas/0000-0002-7379-5145 FU European Community's Seventh Framework Programme (FP7) [269912-EPI-CT] FX The study is supported by the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement number 269912-EPI-CT: Epidemiological study to quantify risks for paediatric computerized tomography and to optimise doses. The authors aknowledge the members of the EPI-CT consortium: Tina Veje Andersen, Sarah Baatout, Marie-Odile Bernier, Elisabeth Cardis, Florent de Vathaire, Maria Gomolka, Janet Hall, Michael Hauptmann, Christoffer Johansen, Magnus Kaijser, Kristina Kjaerheim, Dominique Laurier, Astrid Liland, Carita Lindholm, Mark Pearce, Hubert Thierens. NR 25 TC 16 Z9 17 U1 0 U2 10 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1660-4601 J9 INT J ENV RES PUB HE JI Int. J. Environ. Res. Public Health PD FEB PY 2013 VL 10 IS 2 BP 717 EP 728 DI 10.3390/ijerph10020717 PG 12 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 096ID UT WOS:000315396500020 PM 23429160 ER PT J AU Henry, DB Dymnicki, AB Schoeny, ME Meyer, AL Martin, NC AF Henry, David B. Dymnicki, Allison B. Schoeny, Michael E. Meyer, Aleta L. Martin, Nina C. CA Multisite Violence Prevention Proj TI Middle school students overestimate normative support for aggression and underestimate normative support for nonviolent problem-solving strategies SO JOURNAL OF APPLIED SOCIAL PSYCHOLOGY LA English DT Article ID MULTISITE VIOLENCE PREVENTION; PLURALISTIC IGNORANCE; COLLEGE-STUDENTS; DRINKING NORMS; FEEDBACK; BEHAVIOR; GENDER; PERCEPTIONS; CHILDREN; PROGRAM AB This study tested five hypotheses related to the accuracy of students' perceptions of school norms for aggression and nonviolent problem-solving strategies with two cohorts (ns = 852 and 968) of 6th-grade students in 12 schools. Students consistently overestimated peer normative support for aggression and underestimated peer normative support for nonviolent problem-solving strategies. This effect remained significant in tests of moderation by gender, ethnicity, and aggression level. Tests for moderation by the degree of provocation (e. g., if a student was hit first) and a test measuring actual norms from eighth graders and perceived norms from seventh graders suggested that the discrepancy was not due to self-serving bias or social desirability. Longitudinal analysis found that the discrepancy remained through 8th grade. The discrepancy between actual and perceived norms has implications for risk and violence prevention, which are discussed. C1 [Henry, David B.] Univ Illinois, Chicago, IL 60608 USA. [Dymnicki, Allison B.] Amer Inst Res, Washington, DC 20007 USA. [Schoeny, Michael E.] Univ Chicago, Chicago, IL 60637 USA. [Meyer, Aleta L.] NIDA, Bethesda, MD USA. [Martin, Nina C.; Multisite Violence Prevention Proj] Vanderbilt Univ, Nashville, TN USA. RP Henry, DB (reprint author), Univ Illinois, Inst Hlth Res & Policy, 1747 W Roosevelt Rd, Chicago, IL 60608 USA. EM dhenry@uic.edu NR 49 TC 4 Z9 4 U1 2 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9029 J9 J APPL SOC PSYCHOL JI J. Appl. Soc. Psychol. PD FEB PY 2013 VL 43 IS 2 BP 433 EP 445 DI 10.1111/j.1559-1816.2013.01027.x PG 13 WC Psychology, Social SC Psychology GA 091DB UT WOS:000315028100018 ER PT J AU Gliozzi, M Greenwell-Wild, T Jin, WW Moutsopoulos, NM Kapsogeorgou, E Moutsopoulos, HM Wahl, SM AF Gliozzi, Maria Greenwell-Wild, Teresa Jin, Wenwen Moutsopoulos, Niki M. Kapsogeorgou, Efstathia Moutsopoulos, Haralampos M. Wahl, Sharon M. TI A link between interferon and augmented plasmin generation in exocrine gland damage in Sjogren's syndrome SO JOURNAL OF AUTOIMMUNITY LA English DT Article DE tPA; Macrophage; Salivary gland; Cytokine; Plasminogen; MMP ID LEUKOCYTE PROTEASE INHIBITOR; LABIAL SALIVARY-GLANDS; SQUAMOUS-CELL CARCINOMA; NECROSIS-FACTOR-ALPHA; CARBOXYPEPTIDASE-M; CATHEPSIN-B; ANNEXIN-II; 1-MATRIX METALLOPROTEINASE; ACINAR STRUCTURE; HUMAN MONOCYTES AB Sjogren's syndrome is an autoimmune disease that targets exocrine glands, but often exhibits systemic manifestations. Infiltration of the salivary and lacrimal glands by lymphoid and myeloid cells orchestrates a perpetuating immune response leading to exocrine gland damage and dysfunction. Th1 and Th17 lymphocyte populations and their products recruit additional lymphocytes, including B cells, but also large numbers of macrophages, which accumulate with disease progression. In addition to cytokines, chemokines, chitinases, and lipid mediators, macrophages contribute to a proteolytic milieu, underlying tissue destruction,, inappropriate repair, and compromised glandular functions. Among the proteases enhanced in this local, environment are matrix metalloproteases (MMP) and plasmin, generated by plasminogen activation, dependent upon plasminogen activators, such as tissue plasminogen activator (tPA). Not previously associated with salivary gland pathology, our evidence implicates enhanced tPA in the context of inflamed salivary glands revolving around lymphocyte-mediated activation of macrophages. Tracking down the mechanism of macrophage plasmin activation, the cytokines IFN gamma and to a lesser extent, IFN alpha, via Janus kinase (JAK) and signal transducer and activator of transcription (STAT) activation, were found to be pivotal for driving the plasmin cascade of proteolytic events culminating in perpetuation of the inflammation and tissue damage, and suggesting intervention strategies to blunt irreversible tissue destruction. Published by Elsevier Ltd. C1 [Gliozzi, Maria; Greenwell-Wild, Teresa; Jin, Wenwen; Moutsopoulos, Niki M.; Wahl, Sharon M.] NIDCR, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. [Kapsogeorgou, Efstathia; Moutsopoulos, Haralampos M.] Natl Univ Athens, Sch Med, Dept Pathophysiol, Athens 11527, Greece. RP Wahl, SM (reprint author), NIDCR, Oral Infect & Immun Branch, NIH, Bldg 30,Room 320,30 Convent Dr,MSC 4352, Bethesda, MD 20892 USA. EM smwahl@dir.nidcr.nih.gov FU Intramural Research Program of the NIH, National Institute of Dental and Craniofacial Research FX The authors are grateful to Calley Grace for editorial assistance and Alfredo Molinolo, NIDCR, NIH for expertise in immunohistochemistry and scanning. This research was supported in part by the Intramural Research Program of the NIH, National Institute of Dental and Craniofacial Research. NR 69 TC 12 Z9 13 U1 3 U2 9 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0896-8411 EI 1095-9157 J9 J AUTOIMMUN JI J. Autoimmun. PD FEB PY 2013 VL 40 BP 122 EP 133 DI 10.1016/j.jaut.2012.09.003 PG 12 WC Immunology SC Immunology GA 095XJ UT WOS:000315368000012 PM 23110742 ER PT J AU Geller, J He, Z Perl, Y Morrey, CP Xu, J AF Geller, James He, Zhe Perl, Yehoshua Morrey, C. Paul Xu, Julia TI Rule-based support system for multiple UMLS semantic type assignments SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article DE UMLS; Semantic Network; Metathesaurus; UMLS editing; Semantic type definitions; Concept Insertion ID MEDICAL LANGUAGE SYSTEM; OBJECT-ORIENTED DATABASE; REPRESENTATION; ABSTRACTION; TERMINOLOGY; NETWORK AB Background: When new concepts are inserted into the UMLS, they are assigned one or several semantic types from the UMLS Semantic Network by the UMLS editors. However, not every combination of semantic types is permissible. It was observed that many concepts with rare combinations of semantic types have erroneous semantic type assignments or prohibited combinations of semantic types. The correction of such errors is resource-intensive. Objective: We design a computational system to inform UMLS editors as to whether a specific combination of two, three, four, or five semantic types is permissible or prohibited or questionable. Methods: We identify a set of inclusion and exclusion instructions in the UMLS Semantic Network documentation and derive corresponding rule-categories as well as rule-categories from the UMLS concept content. We then design an algorithm adviseEditor based on these rule-categories. The algorithm specifies rules for an editor how to proceed when considering a tuple (pair, triple, quadruple, quintuple) of semantic types to be assigned to a concept. Results: Eight rule-categories were identified. A Web-based system was developed to implement the adviseEditor algorithm, which returns for an input combination of semantic types whether it is permitted, prohibited or (in a few cases) requires more research. The numbers of semantic type pairs assigned to each rule-category are reported. Interesting examples for each rule-category are illustrated. Cases of semantic type assignments that contradict rules are listed, including recently introduced ones. Conclusion: The adviseEditor system implements explicit and implicit knowledge available in the UMLS in a system that informs UMLS editors about the permissibility of a desired combination of semantic types. Using adviseEditor might help accelerate the work of the UMLS editors and prevent erroneous semantic type assignments. (C) 2012 Elsevier Inc. All rights reserved. C1 [Geller, James; He, Zhe; Perl, Yehoshua] New Jersey Inst Technol, Newark, NJ 07102 USA. [Morrey, C. Paul] Utah Valley Univ, Orem, UT USA. [Xu, Julia] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP He, Z (reprint author), New Jersey Inst Technol, Dept Comp Sci, Newark, NJ 07102 USA. EM zh5@njit.edu RI He, Zhe/J-2336-2014; He, Zhe/E-1549-2017 OI He, Zhe/0000-0003-3608-0244; He, Zhe/0000-0003-3608-0244 FU NLM [R-01-LM008445-01A2] FX This work was partially supported by the NLM under Grant R-01-LM008445-01A2. We wish to thank O. Bodenreider for suggesting the need for an implementation of our Refined Semantic Network in the form of a computer system to support UMLS editors when performing new UMLS semantic type assignments. NR 25 TC 2 Z9 2 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1532-0464 J9 J BIOMED INFORM JI J. Biomed. Inform. PD FEB PY 2013 VL 46 IS 1 BP 97 EP 110 DI 10.1016/j.jbi.2012.09.007 PG 14 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA 095VE UT WOS:000315362300011 PM 23041716 ER PT J AU Foster, BL Nagatomo, KJ Tso, HW Tran, AB Nociti, FH Narisawa, S Yadav, MC McKee, MD Millan, JL Somerman, MJ AF Foster, B. L. Nagatomo, K. J. Tso, H. W. Tran, A. B. Nociti, F. H., Jr. Narisawa, S. Yadav, M. C. McKee, M. D. Millan, J. L. Somerman, M. J. TI Tooth Root Dentin Mineralization Defects in a Mouse Model of Hypophosphatasia SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE TISSUE-NONSPECIFIC ALKALINE PHOSPHATASE (TNAP); DENTIN; PYROPHOSPHATE; OSTEOPONTIN; MATRIX VESICLES ID ALKALINE-PHOSPHATASE ACTIVITY; EXTRACELLULAR-MATRIX PROTEINS; ENZYME-REPLACEMENT THERAPY; EXTRINSIC FIBER CEMENTUM; HYDROXYAPATITE FORMATION; APPOSITIONAL MINERALIZATION; INFANTILE HYPOPHOSPHATASIA; SKELETAL MINERALIZATION; PERIODONTAL-LIGAMENT; CIRCUMPULPAL DENTIN AB Tissue-nonspecific alkaline phosphatase (TNAP) is expressed in mineralizing tissues and functions to reduce pyrophosphate (PPi), a potent inhibitor of mineralization. Loss of TNAP function causes hypophosphatasia (HPP), a heritable disorder marked by increased PPi, resulting in rickets and osteomalacia. Tooth root cementum defects are well described in both HPP patients and in Alpl(-/-) mice, a model for infantile HPP. In Alpl(-/-) mice, dentin mineralization is specifically delayed in the root; however, reports from human HPP patients are variable and inconsistent regarding dentin defects. In the current study, we aimed to define the molecular basis for changes in dentinogenesis observed in Alpl(-/-) mice. TNAP was found to be highly expressed by mature odontoblasts, and Alpl(-/-) molar and incisor roots featured defective dentin mineralization, ranging from a mild delay to severely disturbed root dentinogenesis. Lack of mantle dentin mineralization was associated with disordered and dysmorphic odontoblasts having disrupted expression of marker genes osteocalcin and dentin sialophosphoprotein. The formation of, initiation of mineralization within, and rupture of matrix vesicles in Alpl(-/-) dentin matrix was not affected. Osteopontin (OPN), an inhibitor of mineralization that contributes to the skeletal pathology in Alpl(-/-) mice, was present in the generally unmineralized Alpl(-/-) mantle dentin at ruptured mineralizing matrix vesicles, as detected by immunohistochemistry and by immunogold labeling. However, ablating the OPN-encoding Spp1 gene in Alpl(-/-) mice was insufficient to rescue the dentin mineralization defect. Administration of bioengineered mineral-targeting human TNAP (ENB-0040) to Alpl(-/-) mice corrected defective dentin mineralization in the molar roots. These studies reveal that TNAP participates in root dentin formation and confirm that reduction of PPi during dentinogenesis is necessary for odontoblast differentiation, dentin matrix secretion, and mineralization. Furthermore, these results elucidate developmental mechanisms underlying dentin pathology in HPP patients, and begin to explain the reported variability in the dentin/pulp complex pathology in these patients. (C) 2013 American Society for Bone and Mineral Research. C1 [Foster, B. L.; Tran, A. B.; Nociti, F. H., Jr.; Somerman, M. J.] Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, NIH, Bethesda, MD 20892 USA. [Nagatomo, K. J.; Tso, H. W.] Univ Washington, Sch Dent, Dept Periodont, Seattle, WA 98195 USA. [Narisawa, S.; Yadav, M. C.; Millan, J. L.] Sanford Burnham Med Res Inst, Sanford Childrens Hlth Res Ctr, La Jolla, CA USA. [McKee, M. D.] McGill Univ, Fac Dent, Montreal, PQ, Canada. [McKee, M. D.] McGill Univ, Dept Anat & Cell Biol, Fac Med, Montreal, PQ, Canada. RP Foster, BL (reprint author), Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, NIH, Bldg 50,Room 4120, Bethesda, MD 20892 USA. EM brian.foster@nih.gov RI Nociti, Francisco/G-4907-2015; Foster, Brian/H-8375-2015 OI Foster, Brian/0000-0003-3444-0576 FU National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health (NIH) [NIH R01DE15109, NIH R01 AR47908, R01 DE12889, CIHR MOP-97858] FX This research was supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health (NIH). A portion of this research was completed when BLF, FHN, ABT, and MJS were affiliated with the University of Washington School of Dentistry, Department of Periodontics (Seattle, WA, USA). The authors thank Jirawan Wade for preparing histological sections, Lydia Malynowsky for her help with immunogold labeling and electron microscopy, Daisy Matsa Dunn for in situ hybridization, and Tracy Popowics for critical reading of the manuscript. Grant funding: NIH R01DE15109 (MJS), NIH R01 AR47908 and R01 DE12889 (JLM), and CIHR MOP-97858 (MDM). NR 50 TC 33 Z9 35 U1 1 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD FEB PY 2013 VL 28 IS 2 BP 271 EP 282 DI 10.1002/jbmr.1767 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 092FT UT WOS:000315105600006 PM 22991301 ER PT J AU Imoto, K Nadem, C Moriwaki, SI Nishigori, C Oh, KS Khan, SG Goldstein, AM Kraemer, KH AF Imoto, Kyoko Nadem, Carine Moriwaki, Shin-Ichi Nishigori, Chikako Oh, Kyu-Seon Khan, Sikandar G. Goldstein, Alisa M. Kraemer, Kenneth H. TI Ancient origin of a Japanese xeroderma pigmentosum founder mutation SO JOURNAL OF DERMATOLOGICAL SCIENCE LA English DT Letter ID DNA-REPAIR DEFICIENCY; GROUP-A; DISEASE C1 [Imoto, Kyoko; Nadem, Carine; Oh, Kyu-Seon; Khan, Sikandar G.; Kraemer, Kenneth H.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Imoto, Kyoko] Nara Med Univ, Dept Dermatol, Nara, Japan. [Moriwaki, Shin-Ichi] Osaka Med Coll, Dept Dermatol, Osaka, Japan. [Nishigori, Chikako] Kobe Univ, Grad Sch Med, Div Dermatol, Kobe, Hyogo 657, Japan. [Goldstein, Alisa M.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Kraemer, KH (reprint author), NCI, DNA Repair Sect, Dermatol Branch, Ctr Canc Res, Bldg 37 Room 4002 MSC 4258, Bethesda, MD 20892 USA. EM kraemerk@nih.gov FU Intramural NIH HHS [ZIA BC004517-36] NR 10 TC 2 Z9 3 U1 0 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0923-1811 EI 1873-569X J9 J DERMATOL SCI JI J. Dermatol. Sci. PD FEB PY 2013 VL 69 IS 2 BP 175 EP 176 DI 10.1016/j.jdermsci.2012.10.008 PG 2 WC Dermatology SC Dermatology GA 098HD UT WOS:000315538800012 PM 23194742 ER PT J AU Fleming, JM Ginsburg, E McAndrew, CW Heger, CD Cheston, L Rodriguez-Canales, J Vonderhaar, BK Goldsmith, P AF Fleming, J. M. Ginsburg, E. McAndrew, C. W. Heger, C. D. Cheston, L. Rodriguez-Canales, J. Vonderhaar, B. K. Goldsmith, P. TI Characterization of Delta 7/11, a functional prolactin-binding protein SO JOURNAL OF MOLECULAR ENDOCRINOLOGY LA English DT Article DE prolactin; prolactin receptor; mammary; alternative splicing; prolactin-binding protein ID MAMMARY-GLAND DEVELOPMENT; FACTOR 16K HPRL; BREAST-CANCER; N-GLYCOSYLATION; RECEPTOR GENE; TUMOR-GROWTH; CELL-LINES; EXPRESSION; MULTIPLE; ACTIVATION AB Prolactin is essential for normal mammary gland development and differentiation, and has been shown to promote tumor cell proliferation and chemotherapeutic resistance. Soluble isoforms of the prolactin receptor (PrlR) have been reported to regulate prolactin bioavailability by functioning as 'prolactin-binding proteins'. Included in this category is Delta 7/11, a product of alternate splicing of the PrlR primary transcript. However, the direct interactions of prolactin with Delta 7/11, and the resulting effect on cell behavior, have not been investigated. Herein, we demonstrate the ability of Delta 7/11 to bind prolactin using a novel proximity ligation assay and traditional immunoprecipitation techniques. Biochemical analyses demonstrated that Delta 7/11 was heavily glycosylated, similar to the extracellular domain of the primary PrlR, and that glycosylation regulated the cellular localization and secretion of Delta 7/11. Low levels of Delta 7/11 were detected in serum samples of healthy volunteers, but were undetectable in human milk samples. Expression of Delta 7/11 was also detected in six of the 62 primary breast tumor biopsies analyzed; however, no correlation was found with Delta 7/11 expression and tumor histotype or other patient demographics. Functional analysis demonstrated the ability of Delta 7/11 to inhibit prolactin-induced cell proliferation as well as alter prolactin-induced rescue of cell cycle arrest/early senescence events in breast epithelial cells. Collectively, these data demonstrate that Delta 7/11 is a novel regulatory mechanism of prolactin bioavailability and signaling. C1 [Fleming, J. M.; Ginsburg, E.; Vonderhaar, B. K.] NCI, Mammary Biol & Tumorigenesis Lab, NIH, Bethesda, MD 20892 USA. [McAndrew, C. W.; Heger, C. D.; Goldsmith, P.] NCI, Antibody Prod & Purificat Unit, NIH, Bethesda, MD 20892 USA. [Fleming, J. M.; Cheston, L.] N Carolina Cent Univ, Dept Biol, Coll Sci & Technol, Durham, NC 27707 USA. [Rodriguez-Canales, J.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Fleming, JM (reprint author), NCI, Mammary Biol & Tumorigenesis Lab, NIH, Bethesda, MD 20892 USA. EM jodie.fleming@nccu.edu FU Center for Cancer Research; Intramural Research Program of the National Cancer Institute; NCCU-BBRI-Lineberger Partnership in Cancer Research [U54 CA156735] FX This research was supported by the Center for Cancer Research, an Intramural Research Program of the National Cancer Institute, and by the NCCU-BBRI-Lineberger Partnership in Cancer Research U54 CA156735. NR 39 TC 3 Z9 3 U1 0 U2 3 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0952-5041 J9 J MOL ENDOCRINOL JI J. Mol. Endocrinol. PD FEB PY 2013 VL 50 IS 1 BP 79 EP 90 DI 10.1530/JME-12-0201 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 098ST UT WOS:000315569900009 PM 23048206 ER PT J AU Bai, Y Bandara, G Chan, EC Maric, I Simakova, O Bandara, SN Lu, WP Wise, SC Flynn, DL Metcalfe, DD Gilfillan, AM Wilson, TM AF Bai, Y. Bandara, G. Chan, E. Ching Maric, I. Simakova, O. Bandara, S. N. Lu, W-P Wise, S. C. Flynn, D. L. Metcalfe, D. D. Gilfillan, A. M. Wilson, T. M. TI Targeting the KIT activating switch control pocket: a novel mechanism to inhibit neoplastic mast cell proliferation and mast cell activation SO LEUKEMIA LA English DT Article DE mastocytosis; switch pocket; KIT; KIT D816V; tyrosine kinase inhibitor; mast cell ID TYROSINE KINASE INHIBITORS; SYSTEMIC MASTOCYTOSIS; C-KIT; DEPENDENT ACTIVATION; STI-571 INHIBITION; RI; MUTATIONS; PKC412; GROWTH; DASATINIB AB Activating mutations in the receptor tyrosine kinase KIT, most notably KIT D816V, are commonly observed in patients with systemic mastocytosis. Thus, inhibition of KIT has been a major focus for treatment of this disorder. Here we investigated a novel approach to such inhibition. Utilizing rational drug design, we targeted the switch pocket (SP) of KIT, which regulates its catalytic conformation. Two SP inhibitors thus identified, DP-2976 and DP-4851, were examined for effects on neoplastic mast cell proliferation and mast cell activation. Autophosphorylation of both wild-type and, where also examined, KIT D816V activation was blocked by these compounds in transfected 293T cells, HMC 1.1 and 1.2 human mast cell lines, and in CD34(+)-derived human mast cells activated by stem cell factor (SCF). Both inhibitors induced apoptosis in the neoplastic mast cell lines and reduced survival of primary bone marrow mast cells from patients with mastocytosis. Moreover, the SP inhibitors more selectively blocked SCF potentiation of Fc epsilon RI-mediated degranulation. Overall, SP inhibitors represent an innovative mechanism of KIT inhibition whose dual suppression of KIT D816V neoplastic mast cell proliferation and SCF-enhanced mast cell activation may provide significant therapeutic benefits. Leukemia (2013) 27, 278-285; doi:10.1038/leu.2012.218 C1 [Bai, Y.; Bandara, G.; Chan, E. Ching; Bandara, S. N.; Metcalfe, D. D.; Gilfillan, A. M.; Wilson, T. M.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Maric, I.; Simakova, O.] Ctr Clin, Dept Lab Med, Bethesda, MD USA. [Lu, W-P; Wise, S. C.; Flynn, D. L.] Deciphera Pharmaceut, Lawrence, KS USA. RP Wilson, TM (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Room 12S235A,10 Ctr Dr, Bethesda, MD 20892 USA. EM twilson@niaid.nih.gov FU Division of Intramural Research of the NIAID, NIH FX We thank Dr Cem Akin (Brigham and Women's Hospital) for technical advice with the ex vivo studies and Sarka Smrzova (LAD) for technical support with HuMC cultures. We thank all the subjects as well as the LAD clinical research staff for their contributions. This study was supported in part by the Division of Intramural Research of the NIAID, NIH. Deciphera Pharmaceuticals supplied the study compounds and performed the in vitro kinase assays. NR 33 TC 13 Z9 13 U1 0 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD FEB PY 2013 VL 27 IS 2 BP 278 EP 285 DI 10.1038/leu.2012.218 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA 098MO UT WOS:000315553600004 PM 22907049 ER PT J AU Bhambhani, V Introne, WJ Lungu, C Cullinane, A Toro, C AF Bhambhani, Vikas Introne, Wendy J. Lungu, Codrin Cullinane, Andrew Toro, Camilo TI Chediak-Higashi syndrome presenting as young-onset levodopa-responsive parkinsonism SO MOVEMENT DISORDERS LA English DT Article ID PHENOTYPE; GENOTYPE C1 [Bhambhani, Vikas; Cullinane, Andrew] NHGRI, Human Biochem Genet Sect, Bethesda, MD 20892 USA. [Introne, Wendy J.; Toro, Camilo] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Lungu, Codrin] Natl Inst Neurol Disorders & Stroke, Off Clin Director, NIH, Bethesda, MD USA. RP Toro, C (reprint author), NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. EM toroc@mail.nih.gov FU National Human Genome Research Institute Intramural Research Program FX This work was conducted through funding from the National Human Genome Research Institute Intramural Research Program. NR 9 TC 9 Z9 9 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD FEB PY 2013 VL 28 IS 2 BP 127 EP 129 DI 10.1002/mds.25386 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 096JF UT WOS:000315399300004 PM 23436631 ER PT J AU Lynch, DR Pandolfo, M Schulz, JB Perlman, S Delatycki, MB Payne, RM Shaddy, R Fischbeck, KH Farmer, J Kantor, P Raman, SV Hunegs, L Odenkirchen, J Miller, K Kaufmann, P AF Lynch, David R. Pandolfo, Massimo Schulz, Jorg B. Perlman, Susan Delatycki, Martin B. Payne, R. Mark Shaddy, Robert Fischbeck, Kenneth H. Farmer, Jennifer Kantor, Paul Raman, Subha V. Hunegs, Lisa Odenkirchen, Joanne Miller, Kristy Kaufmann, Petra TI Common data elements for clinical research in Friedreich's ataxia SO MOVEMENT DISORDERS LA English DT Article DE cerebellum; dorsal root ganglion; mitochondrion; clinical measure; NINDS Common Data Elements ID QUALITY-OF-LIFE; BRAIN-INJURY RECOMMENDATIONS; PLACEBO-CONTROLLED TRIAL; HIGH-DOSE IDEBENONE; PERFORMANCE-MEASURES; WORKING GROUP; DEMOGRAPHICS; DEFICIENCY; FEATURES; FRATAXIN AB To reduce study start-up time, increase data sharing, and assist investigators conducting clinical studies, the National Institute of Neurological Disorders and Stroke embarked on an initiative to create common data elements for neuroscience clinical research. The Common Data Element Team developed general common data elements, which are commonly collected in clinical studies regardless of therapeutic area, such as demographics. In the present project, we applied such approaches to data collection in Friedreich's ataxia (FRDA), a neurological disorder that involves multiple organ systems. To develop FRDA common data elements, FRDA experts formed a working group and subgroups to define elements in the following: ataxia and performance measures; biomarkers; cardiac and other clinical outcomes; and demographics, laboratory tests, and medical history. The basic development process included identification of international experts in FRDA clinical research, meeting by teleconference to develop a draft of standardized common data elements recommendations, vetting of recommendations across the subgroups, and dissemination of recommendations to the research community for public comment. The full recommendations were published online in September 2011 at http://www.commondataelements.ninds.nih.gov/FA.aspx. The subgroups recommendations are classified as core, supplemental, or exploratory. Template case report forms were created for many of the core tests. The present set of data elements should ideally lead to decreased initiation time for clinical research studies and greater ability to compare and analyze data across studies. Their incorporation into new, ongoing studies will be assessed in an ongoing fashion to define their utility in FRDA. (c) 2012 Movement Disorder Society C1 [Lynch, David R.] Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. [Lynch, David R.] Univ Penn, Dept Pediat, Philadelphia, PA 19104 USA. [Lynch, David R.; Shaddy, Robert] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Pandolfo, Massimo] Univ Libre Brussels, Brussels, Belgium. [Schulz, Jorg B.] Rhein Westfal TH Aachen, Univ Hosp, Dept Neurol, Aachen, Germany. [Schulz, Jorg B.] Rhein Westfal TH Aachen, Univ Hosp, JARA Brain, Aachen, Germany. [Perlman, Susan] Univ Calif Los Angeles, Los Angeles, CA USA. [Delatycki, Martin B.] Murdoch Childrens Res Inst, Melbourne, Vic, Australia. [Payne, R. Mark] Indiana Univ, Indianapolis, IN 46204 USA. [Shaddy, Robert] Univ Penn, Dept Pediat, Div Cardiol, Philadelphia, PA 19104 USA. [Fischbeck, Kenneth H.; Odenkirchen, Joanne; Kaufmann, Petra] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [Farmer, Jennifer] Friedreichs Ataxia Res Alliance, Downingtown, PA USA. [Kantor, Paul] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Raman, Subha V.] Ohio State Univ, Columbus, OH 43210 USA. [Hunegs, Lisa; Miller, Kristy] KAI Res Inc, Rockville, MD USA. RP Lynch, DR (reprint author), Childrens Hosp Philadelphia, Abramson Res Ctr, Div Neurol, Room 502,3615 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM lynchd@mail.med.upenn.edu RI Schulz, Jorg/D-9786-2012 OI Schulz, Jorg/0000-0002-8903-0593 FU National Institute of Neurological Disorders and Stroke; National Institutes of Health [N01-NS-7-2372]; Friedreich ataxia Research alliance for the CCRNFA; European Union Framework Programme 7 for EFACTS FX The Common Data Element Project is funded by the National Institute of Neurological Disorders and Stroke, National Institutes of Health (contract no.: N01-NS-7-2372). Additional support was received from the Friedreich ataxia Research alliance for the CCRNFA, and from the European Union Framework Programme 7 for EFACTS. Drs. Lynch and Pandolfo contributed equally to the present work. NR 34 TC 9 Z9 9 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD FEB PY 2013 VL 28 IS 2 BP 190 EP 195 DI 10.1002/mds.25201 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 096JF UT WOS:000315399300013 PM 23239403 ER PT J AU Rutkowski, A Bonnemann, C Brown, S Thorsteinsdottir, S Dominov, J Ruegg, MA Matter, ML Guttridge, D Crosbie-Watson, RH Kardon, G Nagaraju, K Girgenrath, M Burkin, DJ AF Rutkowski, Anne Boennemann, Carsten Brown, Susan Thorsteinsdottir, Solveig Dominov, Janice Ruegg, Markus A. Matter, Michelle L. Guttridge, Denis Crosbie-Watson, Rachelle H. Kardon, Gabrielle Nagaraju, Kanneboyina Girgenrath, Mahasweta Burkin, Dean J. TI Report on the Myomatrix Conference April 22-24, 2012, University of Nevada, Reno, Nevada, USA SO NEUROMUSCULAR DISORDERS LA English DT Article DE Conference report; Congenital muscular dystrophy; Translational Research Road Map; MDC1A; DMD; Dystroglycanopathy; Collagen VI related myopathy; Muscular dystrophy; Extracellular matrix; Fibrosis; Laminin; Integrin AB The Myomatrix 2012 conference held April 22-24th, 2012 at the University of Nevada, Reno convened 73 international participants to discuss the dynamic relationship between muscle and its matrix in muscular dystrophy with a specific focus on congenital muscular dystrophy. Seven sessions over 2 1/2 days defined three central themes: (1) the role of extracellular matrix proteins and compartments in development and specifically in congenital muscular dystrophy (CMD) (2) the role of extracellular matrix signaling and adhesion to membrane receptors and (3) the balance and interplay between inflammation and fibrosis as drivers of altered matrix stiffness, impaired regeneration and progressive dystrophy. This report highlights major conference findings and the translational roadmap as defined by conference attendees. (C) 2012 Elsevier B.V. All rights reserved. C1 [Rutkowski, Anne] Cure CMD, Kaiser SCPMG, Olathe, KS 66051 USA. [Boennemann, Carsten] NINDS, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. [Boennemann, Carsten] NINDS, Neurogenet Disorders Childhood Sect, Bethesda, MD 20892 USA. [Brown, Susan] Univ London, Royal Vet Coll, Dept Vet Basic Sci, London NW1 0TU, England. [Thorsteinsdottir, Solveig] Univ Lisbon, Dept Biol Anim, Ctr Biol Ambiental, P-1699 Lisbon, Portugal. [Dominov, Janice] Boston Biomed Res Inst, Watertown, MA 02472 USA. [Ruegg, Markus A.] Univ Basel, Biozentrum, CH-4003 Basel, Switzerland. [Matter, Michelle L.] Univ Hawaii Manoa, Honolulu, HI 96822 USA. [Guttridge, Denis] Ohio State Univ, Med Ctr, Columbus, OH 43210 USA. [Crosbie-Watson, Rachelle H.] Univ Calif Los Angeles, Dept Integrat Biol & Physiol, Los Angeles, CA 90095 USA. [Kardon, Gabrielle] Univ Utah, Dept Human Genet, Salt Lake City, UT 84112 USA. [Nagaraju, Kanneboyina] Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA. [Girgenrath, Mahasweta] Boston Univ, Coll Hlth & Rehabil Sci, Boston, MA 02215 USA. [Burkin, Dean J.] Univ Nevada, Sch Med, Dept Pharmacol, Ctr Mol Med, Reno, NV 89557 USA. RP Burkin, DJ (reprint author), Univ Nevada, Sch Med, Dept Pharmacol, Ctr Mol Med, Reno, NV 89557 USA. EM dburkin@medicine.nevada.edu RI Thorsteinsdottir, Solveig/M-3561-2013; OI Thorsteinsdottir, Solveig/0000-0002-9018-3431; Brown, Sue/0000-0001-8112-933X FU NIH/NIAMS [R13AR062995]; Muscular Dystrophy Association [MDA219240]; Genzyme Sanofi; AVIBioPharma; Cellular Dynamics; Cure Congenital Muscular Dystrophy (Cure CMD); LGMD2I Fund; PTC Therapeutics; Santhera Pharmaceuticals; Ultragenyx FX This conference was supported by NIH/NIAMS (R13AR062995) and Muscular Dystrophy Association (MDA219240). Sponsorship for the conference was provided by Genzyme Sanofi, AVIBioPharma, Cellular Dynamics, Cure Congenital Muscular Dystrophy (Cure CMD), LGMD2I Fund, PTC Therapeutics, Santhera Pharmaceuticals and Ultragenyx. The conference organizers wish to thank the University of Nevada, Reno for hosting the Myomatrix conference within the Center for Molecular Medicine and all conference participants. To view the Myomatrix conference program and abstracts: www.curecmd.org/myomatrix. NR 0 TC 3 Z9 3 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD FEB PY 2013 VL 23 IS 2 BP 188 EP 191 DI 10.1016/j.nmd.2012.06.353 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 098IO UT WOS:000315542900015 PM 22800409 ER PT J AU Leggio, L Zywiak, WH McGeary, JE Edwards, S Fricchione, SR Shoaff, JR Addolorato, G Swift, RM Kenna, GA AF Leggio, Lorenzo Zywiak, William H. McGeary, John E. Edwards, Steven Fricchione, Samuel R. Shoaff, Jessica R. Addolorato, Giovanni Swift, Robert M. Kenna, George A. TI A human laboratory pilot study with baclofen in alcoholic individuals SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE Baclofen; Alcoholism; Cue-reactivity; Alcohol self-administration; Biobehavioral mechanisms; Genetic polymorphisms ID PLACEBO-CONTROLLED TRIAL; DRD4 VNTR POLYMORPHISM; DEPENDENT PATIENTS; DOUBLE-BLIND; SEROTONIN TRANSPORTER; GABA(B) RECEPTOR; CUE REACTIVITY; VALIDATION; SEEKING; SAFETY AB Preclinical and clinical studies show that the GABA(B) receptor agonist baclofen may represent a pharmacotherapy for alcohol dependence (AD). However, the mechanisms by which baclofen affects drinking are not well characterized; thus this pilot study investigated possible baclofen's biobehavioral mechanisms. The design was a double-blind controlled randomized human laboratory pilot study. Fourteen non-treatment seeking alcohol-dependent heavy drinking subjects received either baclofen 10 mg t.i.d. or an active placebo (cyproheptadine 2 mg t.i.d., to control for sedation) for a 7-day period. At day 8, participants performed an alcohol cue-reactivity (CR) followed by an alcohol self-administration (ASA). Additionally, we explored possible moderators that might guide future larger studies, i.e. anxiety, family history and onset of alcoholism, and D4 dopamine receptor (DRD4) and 5-HTTLPR polymorphisms. The main results were a significant effect of baclofen for increasing stimulation (p=.001) and sedation (p<.01). Furthermore, when drinking during the ASA and the 2 days before was analyzed as a composite variable, there was a significant effect of baclofen to reduce alcohol consumption (p<.01). As for the exploratory analyses, baclofen's effects to increase alcohol sedation and to reduce alcohol consumption were limited to those individuals with DRD >= 7 repeats (DRD4L). Yet, baclofen's effects on alcohol consumption were also moderated by 5-HTTLPR LL genotype. In conclusion, baclofen's ability to reduce alcohol drinking may be related to its effects on the biphasic effects of alcohol, but larger studies are needed to confirm these preliminary findings. Published by Elsevier Inc. C1 [Leggio, Lorenzo; Zywiak, William H.; McGeary, John E.; Edwards, Steven; Fricchione, Samuel R.; Shoaff, Jessica R.; Swift, Robert M.; Kenna, George A.] Brown Univ, Ctr Alcohol & Addict Studies, Providence, RI 02912 USA. [Zywiak, William H.] PIRE, Decis Sci Inst, Pawtucket, RI USA. [McGeary, John E.; Swift, Robert M.] Vet Affairs Med Ctr, Providence, RI USA. [Addolorato, Giovanni] Univ Cattolica Sacro Cuore, Inst Internal Med, Rome, Italy. RP Leggio, L (reprint author), NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, 10 Ctr Dr 10CRC-15330 MSC 1108,Room 1-5429, Bethesda, MD 20892 USA. EM lorenzo.leggio@nih.gov RI Leggio, Lorenzo/M-2972-2016; OI Addolorato, Giovanni/0000-0002-1522-9946 FU Brown University Center for Alcohol and Addiction Studies FX This study was supported by a Research Excellence Award (REA) grant from the Brown University Center for Alcohol and Addiction Studies to the PI (Dr. Leggio). NR 50 TC 20 Z9 20 U1 5 U2 20 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD FEB PY 2013 VL 103 IS 4 BP 784 EP 791 DI 10.1016/j.pbb.2012.11.013 PG 8 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 099XX UT WOS:000315660300013 PM 23262301 ER PT J AU Wright, DB Trian, T Siddiqui, S Pascoe, CD Johnson, JR Dekkers, BGJ Dakshinamurti, S Bagchi, R Burgess, JK Kanabar, V Ojo, OO AF Wright, David B. Trian, Thomas Siddiqui, Sana Pascoe, Chris D. Johnson, Jill R. Dekkers, Bart G. J. Dakshinamurti, Shyamala Bagchi, Rushita Burgess, Janette K. Kanabar, Varsha Ojo, Oluwaseun O. TI Phenotype modulation of airway smooth muscle in asthma SO PULMONARY PHARMACOLOGY & THERAPEUTICS LA English DT Article DE Airway smooth muscle; Asthma; Phenotypic plasticity; Contractile response; Synthetic response ID EXTRACELLULAR-MATRIX PROTEINS; CCAAT/ENHANCER-BINDING-PROTEIN; ADENOVIRAL GENE-TRANSFER; SIGNAL-REGULATED KINASE; SERUM RESPONSE FACTOR; CELL-PROLIFERATION; ALLERGIC-ASTHMA; C/EBP-ALPHA; IN-VITRO; EXPRESSION AB The biological responses of airway smooth muscle (ASM) are diverse, in part due to ASM phenotype plasticity. ASM phenotype plasticity refers to the ability of ASM cells to change the degree of a variety of functions, including contractility, proliferation, migration and secretion of inflammatory mediators. This plasticity occurs due to intrinsic or acquired abnormalities in ASM cells, and these abnormalities or predisposition of the ASM cell may alter the ASM response and in some cases recapitulate disease hallmarks of asthma. These phenotypic changes are ultimately determined by multiple stimuli and occur due to alterations in the intricate balance or reversible state that maintains ASM cells in either a contractile or synthetic state, through processes termed maturation or modulation, respectively. To elucidate the role of ASM phenotype in disease states, numerous in vitro studies have suggested a phenotypic switch in ASM primary cell cultures as an explanation for the plethora of responses mediated by ASM cells. Moreover, there is overwhelming evidence suggesting that the immunomodulatory response of ASM is due to the acquisition of a synthetic phenotype; however, whether this degree of plasticity is present in vivo as opposed to cell culture-based models remains speculative. Nonetheless, this review will give an overall scope of ASM phenotypic markers, triggers of ASM phenotype modulation and novel therapeutic approaches to control ASM phenotype plasticity. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Wright, David B.] Kings Coll London, MRC, London WC2R 2LS, England. [Wright, David B.] Kings Coll London, Asthma UK Ctr Allerg Mech Asthma, London WC2R 2LS, England. [Trian, Thomas] Univ Bordeaux 2, Ctr Rech Cardiothorac Bordeaux, INSERM, U1045,Equipe Remodelage Bronch, F-33076 Bordeaux, France. [Siddiqui, Sana] McGill Univ, Meakins Christie Labs, Dept Med, Montreal, PQ, Canada. [Siddiqui, Sana] NIA, Receptor Pharmacol Unit, NIH, Baltimore, MD 21224 USA. [Pascoe, Chris D.] Univ British Columbia, Dept Med, Vancouver, BC V5Z 1M9, Canada. [Johnson, Jill R.] Univ London Imperial Coll Sci Technol & Med, Leukocyte Biol Sect, Natl Heart & Lung Inst, London, England. [Dekkers, Bart G. J.] Univ Groningen, Dept Mol Pharmacol, Groningen Res Inst Asthma, Groningen, Netherlands. [Dekkers, Bart G. J.] Univ Groningen, COPD, Groningen, Netherlands. [Dakshinamurti, Shyamala] Univ Manitoba, Sect Neonatol, Womens Hosp WS012, Winnipeg, MB R3E 3P4, Canada. [Bagchi, Rushita] Univ Manitoba, Dept Physiol, Inst Cardiovasc Sci, St Boniface Hosp Res Ctr, Winnipeg, MB R3E 3P4, Canada. [Burgess, Janette K.] Univ Sydney, Cell Biol Grp, Woolcock Inst Med Res, Sydney, NSW 2006, Australia. [Burgess, Janette K.] Univ Sydney, Discipline Pharmacol, Sydney, NSW 2006, Australia. [Kanabar, Varsha] Kings Coll London, Sackler Inst Pulm Pharmacol, London WC2R 2LS, England. [Ojo, Oluwaseun O.] Univ Manitoba, Dept Resp Physiol, Biol Breathing Grp, Manitoba Inst Child Hlth, Winnipeg, MB R3E 3P4, Canada. RP Ojo, OO (reprint author), Univ Manitoba, Dept Resp Physiol, Biol Breathing Grp, Manitoba Inst Child Hlth,John Buhler Res Ctr, Room 641,715 McDermott Ave, Winnipeg, MB R3E 3P4, Canada. EM ojoo3@cc.umanitoba.ca RI Burgess, Janette/A-3597-2010; OI Wright, David/0000-0003-1285-4655; Bagchi, Rushita/0000-0002-9075-0766 FU Alexander McFee Studentship, Faculty of Medicine, McGill University, Montreal, QC; Imperial College London; National Health & Medical Research Council, Australia Career Development Fellowship [1032695]; MHRC/SBRC Coordinated Graduate Studentship by the Manitoba Health Research Council, Canada FX Sana Siddiqui is the recipient of the Alexander McFee Studentship, Faculty of Medicine, McGill University, Montreal, QC. Jill R. Johnson is supported by a Research Fellowship from Imperial College London. Janette K. Burgess is supported by a National Health & Medical Research Council, Australia Career Development Fellowship #1032695. Rushita Bagchi is the recipient of an MHRC/SBRC Coordinated Graduate Studentship awarded by the Manitoba Health Research Council, Canada. NR 102 TC 19 Z9 21 U1 1 U2 5 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1094-5539 J9 PULM PHARMACOL THER JI Pulm. Pharmacol. Ther. PD FEB PY 2013 VL 26 IS 1 BP 42 EP 49 DI 10.1016/j.pupt.2012.08.005 PG 8 WC Pharmacology & Pharmacy; Respiratory System SC Pharmacology & Pharmacy; Respiratory System GA 090YE UT WOS:000315015100006 PM 22939888 ER PT J AU Wright, DB Trian, T Siddiqui, S Pascoe, CD Ojo, OO Johnson, JR Dekkers, BGJ Dakshinamurti, S Bagchi, R Burgess, JK Kanabar, V AF Wright, David B. Trian, Thomas Siddiqui, Sana Pascoe, Chris D. Ojo, Oluwaseun O. Johnson, Jill R. Dekkers, Bart G. J. Dakshinamurti, Shyamala Bagchi, Rushita Burgess, Janette K. Kanabar, Varsha TI Functional phenotype of airway myocytes from asthmatic airways SO PULMONARY PHARMACOLOGY & THERAPEUTICS LA English DT Article DE Airway smooth muscle; Vascular smooth muscle; Asthma; Extracellular matrix; Animal models ID SMOOTH-MUSCLE-CELLS; EXTRACELLULAR-MATRIX PROTEINS; GROWTH-FACTOR-BETA; BRONCHIAL EPITHELIAL-CELLS; MYOSIN ISOFORM EXPRESSION; ALLERGIC-ASTHMA; BASEMENT-MEMBRANE; HUMAN LUNG; RAT LUNG; SM-B AB In asthma, the airway smooth muscle (ASM) cell plays a central role in disease pathogenesis through cellular changes which may impact on its microenvironment and alter ASM response and function. The answer to the long debated question of what makes a 'healthy' ASM cell become 'asthmatic' still remains speculative. What is known of an 'asthmatic' ASM cell, is its ability to contribute to the hallmarks of asthma such as bronchoconstriction (contractile phenotype), inflammation (synthetic phenotype) and ASM hyperplasia (proliferative phenotype). The phenotype of healthy or diseased ASM cells or tissue for the most part is determined by expression of key phenotypic markers. ASM is commonly accepted to have different phenotypes: the contractile (differentiated) state versus the synthetic (dedifferentiated) state (with the capacity to synthesize mediators, proliferate and migrate). There is now accumulating evidence that the synthetic functions of ASM in culture derived from asthmatic and non-asthmatic donors differ. Some of these differences include an altered profile and increased production of extracellular matrix proteins, pro-inflammatory mediators and adhesion receptors, collectively suggesting that ASM cells from asthmatic subjects have the capacity to alter their environment, actively participate in repair processes and functionally respond to changes in their microenvironment. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Wright, David B.] Kings Coll London, MRC, London SE1 9NH, England. [Wright, David B.] Kings Coll London, Asthma UK Ctr Allerg Mech Asthma, London SE1 9NH, England. [Trian, Thomas] Univ Bordeaux 2, Ctr Rech Cardiothorac Bordeaux, INSERM, U1045,Equipe Remodelage Bronch, F-33076 Bordeaux, France. [Siddiqui, Sana] McGill Univ, Meakins Christie Labs, Dept Med, Montreal, PQ, Canada. [Siddiqui, Sana] NIA, Receptor Pharmacol Unit, NIH, Baltimore, MD 21224 USA. [Pascoe, Chris D.] Univ British Columbia, Dept Med, Vancouver, BC V5Z 1M9, Canada. [Ojo, Oluwaseun O.] Univ Manitoba, Dept Resp Physiol, Biol Breathing Grp, Manitoba Inst Child Hlth, Winnipeg, MB, Canada. [Johnson, Jill R.] Univ London Imperial Coll Sci Technol & Med, Leukocyte Biol Sect, Natl Heart & Lung Inst, London, England. [Dekkers, Bart G. J.] Univ Groningen, Dept Mol Pharmacol, Groningen Res Inst Asthma, Groningen, Netherlands. [Dekkers, Bart G. J.] Univ Groningen, COPD, Groningen, Netherlands. [Dakshinamurti, Shyamala] Univ Manitoba, Sect Neonatol, Womens Hosp WS012, Winnipeg, MB, Canada. [Bagchi, Rushita] Univ Manitoba, Dept Physiol, Inst Cardiovasc Sci, St Boniface Hosp Res Ctr, Winnipeg, MB, Canada. [Burgess, Janette K.] Univ Sydney, Cell Biol Grp, Woolcock Inst Med Res, Sydney, NSW 2006, Australia. [Burgess, Janette K.] Univ Sydney, Discipline Pharmacol, Sydney, NSW 2006, Australia. [Kanabar, Varsha] Kings Coll London, Sackler Inst Pulm Pharmacol, Div Pharmaceut Sci, London SE1 9NH, England. RP Kanabar, V (reprint author), Kings Coll London, Sackler Inst Pulm Pharmacol, Div Pharmaceut Sci, 150 Stamford St, London SE1 9NH, England. EM varsha.kanabar@kcl.ac.uk RI Burgess, Janette/A-3597-2010; OI Wright, David/0000-0003-1285-4655; Bagchi, Rushita/0000-0002-9075-0766 FU Alexander McFee Studentship, Faculty of Medicine, McGill University, Montreal, QC; National Health & Medical Research Council, Australia Career Development Fellowship [1032695]; Imperial College London Junior Research Fellowship; MHRC/SBRC Coordinated Graduate Studentship by the Manitoba Health Research Council, Canada FX Sana Siddiqui is the recipient of the Alexander McFee Studentship, Faculty of Medicine, McGill University, Montreal, QC. Janette Burgess is supported by a National Health & Medical Research Council, Australia Career Development Fellowship #1032695. Jill R. Johnson is supported by an Imperial College London Junior Research Fellowship. Rushita Bagchi is the recipient of an MHRC/SBRC Coordinated Graduate Studentship awarded by the Manitoba Health Research Council, Canada. NR 168 TC 5 Z9 6 U1 0 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1094-5539 J9 PULM PHARMACOL THER JI Pulm. Pharmacol. Ther. PD FEB PY 2013 VL 26 IS 1 BP 95 EP 104 DI 10.1016/j.pupt.2012.08.003 PG 10 WC Pharmacology & Pharmacy; Respiratory System SC Pharmacology & Pharmacy; Respiratory System GA 090YE UT WOS:000315015100011 PM 22921313 ER PT J AU Pineda, I Vazquez, MV Dagdug, L AF Pineda, I. Vazquez, M. -V. Dagdug, L. TI Equilibration in two chambers connected by a capillary of arbitrary shape SO REVISTA MEXICANA DE FISICA LA English DT Article DE Controlled release; micron-sized vesicle; unbiased diffusion; narrow channels; Fick-Jacobs' equation ID CHANNEL; DIFFUSIVITY; TRANSPORT; KINETICS AB The present work is devoted to the study of the unbiased diffusion of particles to escape from a micron-sized vesicle, through a channel of arbitrary geometry. The use of propagators allows us to describe the diffusion between the vesicle and the interstitial space. The computed relaxation time of the system only depends on its geometric parameters and the diffusion coefficient. It is noted that the whole problem can be reduced to the study of diffusion in the channel. Finally, we give a procedure to find the solution of the Fick-Jacobs' equation for a channel with radial symmetry but arbitrary shape and with constant diffusion coefficient. C1 [Pineda, I.; Vazquez, M. -V.; Dagdug, L.] Univ Autonoma Metropolitana Iztapalapa, Dept Fis, Mexico City 09340, DF, Mexico. [Dagdug, L.] NIH, Math & Stat Comp Lab, Bethesda, MD 20892 USA. RP Pineda, I (reprint author), Univ Autonoma Metropolitana Iztapalapa, Dept Fis, Apartado Postal 55-534, Mexico City 09340, DF, Mexico. FU National Council of Science and Technology (CONACyT) [27482] FX I. Pineda wishes to thank the National Council of Science and Technology (CONACyT) the financial support through grant No. 27482. NR 32 TC 0 Z9 0 U1 0 U2 3 PU SOC MEXICANA FISICA PI COYOACAN PA APARTADO POSTAL 70-348, COYOACAN 04511, MEXICO SN 0035-001X J9 REV MEX FIS JI Rev. Mex. Fis. PD FEB PY 2013 VL 59 IS 1 SU S BP 99 EP 105 PG 7 WC Physics, Multidisciplinary SC Physics GA 096SJ UT WOS:000315424300017 ER PT J AU Druz, A Chen, YC Guha, R Betenbaugh, M Martin, SE Shiloach, J AF Druz, Aliaksandr Chen, Yu-Chi Guha, Rajarshi Betenbaugh, Michael Martin, Scott E. Shiloach, Joseph TI Large-scale screening identifies a novel microRNA, miR-15a-3p, which induces apoptosis in human cancer cell lines SO RNA BIOLOGY LA English DT Article DE microRNA; Apoptosis; BCL-XL; Caspase; cancer cells ID HUMAN HEPATOCELLULAR-CARCINOMA; CHEMOTHERAPY-INDUCED APOPTOSIS; BCL-XL; PROSTATE-CANCER; LUNG-CANCER; ANTISENSE OLIGONUCLEOTIDES; CASPASE ACTIVATION; MAMMALIAN-CELLS; DOWN-REGULATION; HIT SELECTION AB MicroRNAs (miRNAs) have been found to be involved in cancer initiation, progression and metastasis and, as such, have been suggested as tools for cancer detection and therapy. In this work, a large-scale screening of the complete miRNA mimics library demonstrated that hsa-miR-15a-3p had a pro-apoptotic role in the following human cancer cells: HeLa, AsPc-1, MDA-MB-231, KB3, ME180, HCT-116 and A549. MiR-15a-3p is a novel member of the pro-apoptotic miRNA cluster, miR-15a/16, which was found to activate Caspase-3/7 and to cause viability loss in B/CMBA. Ov cells during preliminary screening. Subsequent microarrays and bioinformatics analyses identified the following four anti-apoptotic genes: bcl2l1, naip5, fgfr2 and mybl2 as possible targets for the mmu-miR-15a-3p in B/CMBA. Ov cells. Follow-up studies confirmed the pro-apoptotic role of hsa-miR-15a-3p in human cells by its ability to activate Caspase-3/7, to reduce cell viability and to inhibit the expression of bcl2l1 (bcl-x(L)) in HeLa and AsPc-1 cells. MiR-15-3p was also found to reduce viability in HE K293, MDA-MB-231, KB3, ME180, HC T-116 and A549 cell lines and, therefore, may be considered for apoptosis modulating therapies in cancers associated with high Bcl-x(L) expression (cervical, pancreatic, breast, lung and colorectal carcinomas). The capability of hsa-miR-15a-3p to induce apoptosis in these carcinomas may be dependent on the levels of Bcl-x(L) expression. The use of endogenous inhibitors of bcl-x(L) and other anti-apoptotic genes such as hsa-miR-15a-3p may provide improved options for apoptosis-modulating therapies in cancer treatment compared with the use of artificial antisense oligonucleotides. C1 [Druz, Aliaksandr; Shiloach, Joseph] NIDDKD, Biotechnol Core Lab, NIH, Bethesda, MD 20892 USA. [Druz, Aliaksandr; Betenbaugh, Michael] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD USA. [Chen, Yu-Chi; Guha, Rajarshi; Martin, Scott E.] NIH, NIH Chem Genom Ctr, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. RP Shiloach, J (reprint author), NIDDKD, Biotechnol Core Lab, NIH, Bethesda, MD 20892 USA. EM yossi@nih.gov RI Betenbaugh, Michael J./A-3252-2010 OI Betenbaugh, Michael J./0000-0002-6336-4659 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX Funding was provided by the intramural program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. The authors would like to thank Dr Chithra Keembiyehetty at NIDDK core lab for performing microarrays and Mrs D. Livnat for critical editorial assistance. NR 70 TC 17 Z9 18 U1 0 U2 17 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1547-6286 J9 RNA BIOL JI RNA Biol. PD FEB PY 2013 VL 10 IS 2 BP 287 EP 300 DI 10.4161/rna.23339 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 099AR UT WOS:000315591500014 PM 23353574 ER PT J AU Ward, MM Learch, TJ Gensler, LS Davis, JC Reveille, JD Weisman, MH AF Ward, Michael M. Learch, Thomas J. Gensler, Lianne S. Davis, John C., Jr. Reveille, John D. Weisman, Michael H. TI Regional radiographic damage and functional limitations in patients with ankylosing spondylitis: Differences in early and late disease SO ARTHRITIS CARE & RESEARCH LA English DT Article ID CERVICAL-SPINE INVOLVEMENT; QUALITY-OF-LIFE; PREDICTIVE FACTORS; RADIOLOGY INDEX; DISABILITY; MOBILITY; SPONDYLOARTHROPATHIES; QUESTIONNAIRE; ARTHRITIS; VARIABLES AB Objective Both radiographic damage and functional limitations increase with the duration of ankylosing spondylitis (AS). We examined whether radiographic damage contributed more to functional limitations in late AS than in early AS, and if the strength of association varied with the anatomic region of damage. Methods In this cross-sectional study of 801 patients with AS, we examined associations of the lumbar modified Stoke Ankylosing Spondylitis Spine Score (mSASSS), the cervical mSASSS, lumbar posterior fusion, cervical posterior fusion, and hip arthritis with the Bath Ankylosing Spondylitis Functional Index (BASFI) and the Health Assessment Questionnaire modified for the spondyloarthritides (HAQ-S). Results Higher lumbar and cervical mSASSS scores were associated with more functional limitations, but there was an interaction between mSASSS scores and the duration of AS, such that the strength of their association with functional limitations decreased with increasing duration of AS. Cervical posterior fusion was associated with worse functioning independent of mSASSS scores. Hip arthritis was significantly associated with functional limitations independent of spinal damage measures. Among patients with AS duration 40 years, the number of comorbid conditions accounted for most of the variation in functioning. Results were similar for both the BASFI and the HAQ-S. Conclusion Although both radiographic damage and functional limitations increase over time in AS, the relative contribution of radiographic damage to functional limitations is lower among patients with longstanding AS than with early AS, suggesting patients may accommodate to limited flexibility. Damage in different skeletal regions impacts functioning over the duration of AS. Functional limitations due to comorbidity supervene in late AS. C1 [Ward, Michael M.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Learch, Thomas J.; Weisman, Michael H.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Gensler, Lianne S.; Davis, John C., Jr.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Reveille, John D.] Univ Texas Houston, Hlth Sci Ctr, Houston, TX USA. RP Ward, MM (reprint author), NIAMSD, NIH, Bldg 10 CRC,Room 4-1339,10 Ctr Dr, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases [PO1-052915, RO1-AR-048465]; Cedars-Sinai General Clinical Research Center [MO1-RR-00425]; University of Texas at Houston General Clinical Research Center [MO1-RR-02558]; Rosalind Russell Center for Arthritis Research at the University of California, San Francisco; National Institute of Arthritis and Musculoskeletal and Skin Diseases/NIH FX Supported by the NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (grants PO1-052915 and RO1-AR-048465), the Cedars-Sinai General Clinical Research Center (MO1-RR-00425), the University of Texas at Houston General Clinical Research Center (MO1-RR-02558), The Rosalind Russell Center for Arthritis Research at the University of California, San Francisco, and the Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases/NIH. NR 41 TC 5 Z9 6 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X J9 ARTHRIT CARE RES JI Arthritis Care Res. PD FEB PY 2013 VL 65 IS 2 BP 257 EP 265 DI 10.1002/acr.21821 PG 9 WC Rheumatology SC Rheumatology GA 083LW UT WOS:000314466600012 PM 23042639 ER PT J AU Jarcho, JM Fox, NA Pine, DS Etkin, A Leibenluft, E Shechner, T Ernst, M AF Jarcho, Johanna M. Fox, Nathan A. Pine, Daniel S. Etkin, Amit Leibenluft, Ellen Shechner, Tomer Ernst, Monique TI The neural correlates of emotion-based cognitive control in adults with early childhood behavioral inhibition SO BIOLOGICAL PSYCHOLOGY LA English DT Article DE Behavioral inhibition; Conflict detection; Conflict adaptation; Emotion regulation; fMRI; Development ID GENERALIZED ANXIETY DISORDER; ANTERIOR CINGULATE CORTEX; ERROR-RELATED NEGATIVITY; PSYCHOMETRIC PROPERTIES; DEPRESSIVE-DISORDERS; IMPLICIT REGULATION; BRAIN ACTIVATION; CONFLICT; ADOLESCENTS; ATTENTION AB The present study is the first to assess whether the neural correlates of cognitive control processes differ in adults with and without a behaviorally inhibited temperament during early childhood. Adults with and without childhood behavioral inhibition completed an emotional conflict task while undergoing functional magnetic resonance imaging scanning. While no group differences in behavior were observed, adults with childhood behavioral inhibition, relative to adults without childhood behavioral inhibition, exhibited greater dorsomedial prefrontal cortex activity during conflict detection and greater putamen activity during conflict adaptation. Lifetime psychopathology predicted behavioral, but not brain-related, differences in conflict adaptation. These data suggest that the brain regions underlying cognitive control processes are differentially influenced by childhood behavioral inhibition, and may be differently related to psychopathology. Published by Elsevier B.V. C1 [Jarcho, Johanna M.; Pine, Daniel S.; Shechner, Tomer; Ernst, Monique] NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. [Fox, Nathan A.] Univ Maryland, Dept Human Dev, College Pk, MD 20742 USA. [Etkin, Amit] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Etkin, Amit] Vet Affairs Palo Alto Hlth Care Syst, Sierra Pacific Mental Illness Res Educ & Clin Ctr, Palo Alto, CA USA. [Leibenluft, Ellen] NIMH, Sect Bipolar Spectrum Disorders, Bethesda, MD 20892 USA. RP Jarcho, JM (reprint author), NIMH, Sect Dev & Affect Neurosci, NIH, 9000 Rockville Pike,Bldg 15K, Bethesda, MD 20892 USA. EM johanna.jarcho@nih.gov OI Jarcho, Johanna/0000-0001-9075-6968 FU Intramural Research Program of the National Institute of Health; National Institute of Mental Health [NAF: R01 MH 074454]; National Institute of Child Health and Development [NAF: 5R37 HD 017899-20] FX This work was supported by the Intramural Research Program of the National Institute of Health, and grants from the National Institute of Mental Health Grant (NAF: R01 MH 074454) and the National Institute of Child Health and Development Grant (NAF: 5R37 HD 017899-20). NR 51 TC 26 Z9 26 U1 2 U2 26 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0511 J9 BIOL PSYCHOL JI Biol. Psychol. PD FEB PY 2013 VL 92 IS 2 BP 306 EP 314 DI 10.1016/j.biopsycho.2012.09.008 PG 9 WC Psychology, Biological; Behavioral Sciences; Psychology; Psychology, Experimental SC Psychology; Behavioral Sciences GA 095DU UT WOS:000315315700029 PM 23046903 ER PT J AU Linhares, YPL Pavletic, S Gale, RP AF Linhares, Y. P. L. Pavletic, S. Gale, R. P. TI Chronic GVHD: Where are we? Where do we want to be? Will immunomodulatory drugs help? SO BONE MARROW TRANSPLANTATION LA English DT Review DE Chronic GVHD; IMiDs; thalidomide; lenalidomide; pomalidomide ID VERSUS-HOST-DISEASE; CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; BONE-MARROW-TRANSPLANTATION; STEM-CELL TRANSPLANTATION; CD4(+) T-CELLS; CHRONIC GRAFT; CLINICAL-TRIALS; THERAPEUTIC RESPONSE; THALIDOMIDE ANALOG AB Chronic GVHD (cGVHD) is an important problem after allotransplants. Some risk factors for cGVHD are similar to those of acute GVHD (aGVHD) but others are distinct indicating sometimes overlapping but unique pathogeneses. Precise incidence and prevalence data of cGVHD are lacking because of diverse diagnostic criteria but a 50% risk is a reasonable estimate. Incidence and prevalence of cGVHD are probably growing because of increased use of unrelated donors, blood rather than bone marrow (BM) grafts, decreased early transplant-related mortality (TRM) and increasing frequency of allotransplants. Pathophysiology of cGVHD is complex and poorly understood. Notably, no reliable surrogate end point to predict mechanism(s) of cGVHD has been identified. Therapy of cGVHD is unsatisfactory. Corticosteroids are effective but other drugs are controversial and few are rigorously tested in randomized trials. Highly variable response rates are reported because of small sample sizes and inconsistencies in eligibility, diagnostic and response criteria. We focus on the possible role of immunomodulatory drugs (IMiDs), thalidomide lenalidomide and pomalidomide, in preventing and treating cGVHD. The data suggest activity of thalidomide but at doses not clinically practical in many instances. There are few data with lenalidomide. Trials of pomalidomide, which has immune activities like thalidomide but with fewer adverse effects, are beginning. Because cGVHD is not recently reviewed in Bone Marrow Transplantation, we give a brief background and discuss challenges in diagnosing, understanding and treating cGVHD including the recently proposed National Institutes of Health consensus criteria for cGVHD. Bone Marrow Transplantation (2013) 48, 203-209; doi:10.1038/bmt.2012.76; published online 14 May 2012 C1 [Linhares, Y. P. L.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol Med Oncol, Los Angeles, CA 90095 USA. [Pavletic, S.] NCI, GVHD & Autoimmun Unit, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Gale, R. P.] Univ London Imperial Coll Sci Technol & Med, Dept Med, Sect Haematol, Div Expt Med, London, England. RP Gale, RP (reprint author), Imperial Coll, Dept Med, Sect Haematol, Div Expt Med, 11693 San Vicente Blvd,Suite 335, Los Angeles, CA 90049 USA. EM robertpetergale@aol.com FU NIHR Biomedical Research Centre; NCI; Celgene [02328] FX RPG acknowledges support from the NIHR Biomedical Research Centre funding scheme. Statements included in this article do not represent the official position of the NCI, NIH or the US government. SZP receives partial research funding support through the Cooperative Research and Development Agreement for intramural-PHS clinical research executed between the NCI and Celgene (CRADA #02328). Our many collaborators over several decades, especially who criticized us and making us better scientists and clinicians and this a better typescript. Special thanks to Iskra Pusic (Washington Univerity, St Louis, MO) and Lana Grkovic (Rebro University Hospital, Zagreb, Croatia) for their input to an earlier review section of this typescript. Hillard M Lazarus (Case Western Reserve University, Celevland, OH) suggested a review of cGVHD and IMiDs and provided many helpful comments. NR 91 TC 14 Z9 16 U1 1 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD FEB PY 2013 VL 48 IS 2 BP 203 EP 209 DI 10.1038/bmt.2012.76 PG 7 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 094BY UT WOS:000315239200013 PM 22580766 ER PT J AU Foglietta, M Neelapu, SS Kwak, LW Jiang, Y Nattamai, D Lee, ST Fowler, DH Sportes, C Gress, RE Steinberg, SM Vence, LM Radvanyi, L Dwyer, KC Qazilbash, MH Bryant, RNK Bishop, MR AF Foglietta, M. Neelapu, S. S. Kwak, L. W. Jiang, Y. Nattamai, D. Lee, S-T Fowler, D. H. Sportes, C. Gress, R. E. Steinberg, S. M. Vence, L. M. Radvanyi, L. Dwyer, K. C. Qazilbash, M. H. Bryant, R. N. K. Bishop, M. R. TI Neoantigen and tumor antigen-specific immunity transferred from immunized donors is detectable early after allogeneic transplantation in myeloma patients SO BONE MARROW TRANSPLANTATION LA English DT Article DE myeloma; allogeneic; donor vaccination; idiotype ID BONE-MARROW-TRANSPLANTATION; STEM-CELL TRANSPLANTATION; REGULATORY T-CELLS; INFLUENZAE TYPE-B; MULTIPLE-MYELOMA; PERIPHERAL-BLOOD; IDIOTYPE VACCINATION; FOLLICULAR LYMPHOMA; DENDRITIC CELLS; RESPONSES AB To enhance the therapeutic index of allogeneic hematopoietic SCT (HSCT), we immunized 10 HLA-matched sibling donors before stem cell collection with recipient-derived clonal myeloma Ig, idiotype (Id), as a tumor antigen, conjugated with keyhole limpet hemocyanin (KLH). Vaccinations were safe in donors and recipients. Donor-derived KLH- and Id-specific humoral and central and effector memory T-cell responses were detectable by day 30 after HSCT and were boosted by post-transplant vaccinations at 3 months in most recipients. One patient died before booster vaccinations. Specifically, after completing treatment, 8/9 myeloma recipients had persistent Id-specific immune responses and 5/9 had improvement in disease status. Although regulatory T cells increased after vaccination, they did not impact immune responses. At a median potential follow-up period of 74 months, 6 patients are alive, the 10 patients have a median PFS of 28.5 months and median OS has not been reached. Our results provide proof of principle that neoantigen and tumor antigen-specific humoral and cellular immunity could be safely induced in HSCT donors and passively transferred to recipients. This general strategy may be used to reduce relapse of malignancies and augment protection against infections after allogeneic HSCT. Bone Marrow Transplantation (2013) 48, 269-277; doi:10.1038/bmt.2012.132; published online 9 July 2012 C1 [Foglietta, M.; Neelapu, S. S.; Kwak, L. W.; Jiang, Y.; Nattamai, D.; Lee, S-T] Univ Texas MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Div Canc Med, Houston, TX 77030 USA. [Foglietta, M.; Neelapu, S. S.; Kwak, L. W.; Jiang, Y.; Nattamai, D.; Lee, S-T; Vence, L. M.; Radvanyi, L.; Dwyer, K. C.] Univ Texas MD Anderson Canc Ctr, Ctr Canc Immunol Res, Houston, TX 77030 USA. [Fowler, D. H.; Sportes, C.; Gress, R. E.; Bryant, R. N. K.; Bishop, M. R.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Steinberg, S. M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, Rockville, MD USA. [Vence, L. M.; Radvanyi, L.] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Div Canc Med, Houston, TX 77030 USA. [Dwyer, K. C.; Qazilbash, M. H.] Univ Texas MD Anderson Canc Ctr, Dept Stem Cell Transplantat & Cellular Therapy, Div Canc Med, Houston, TX 77030 USA. RP Kwak, LW (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Div Canc Med, 1515 Holcombe Blvd,Unit 429, Houston, TX 77030 USA. EM lkwak@mdanderson.org FU Center for Cancer Research, the National Cancer Institute, the National Institutes of Health; Leukemia and Lymphoma Society (Specialized Center of Research) [7262-08]; National Institutes of Health [R21 CA123860, K23CA123149]; Gateway Foundation; American Society of Clinical Oncology Career Development Award; American Society of Hematology Junior Faculty Scholar Award in Clinical/Translational Research; Doris Duke Charitable Foundation Clinical Scientist Development Award; Cancer Center Support Grant [CA16672] FX This work was supported by the Center for Cancer Research, the National Cancer Institute, the National Institutes of Health; the Leukemia and Lymphoma Society (Specialized Center of Research Grant No. 7262-08 (LWK)); the National Institutes of Health Grant R21 CA123860 (LWK); the Gateway Foundation (LWK); the American Society of Clinical Oncology Career Development Award (SSN); the American Society of Hematology Junior Faculty Scholar Award in Clinical/Translational Research (SSN); the National Institutes of Health Grant K23CA123149 (SSN); and the Doris Duke Charitable Foundation Clinical Scientist Development Award (SSN). The Immune Monitoring Core Facility and the Flow Cytometry Core Facility at the MD Anderson Cancer Center are supported by the Cancer Center Support Grant CA16672 (National Institutes of Health). NR 41 TC 5 Z9 5 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD FEB PY 2013 VL 48 IS 2 BP 269 EP 277 DI 10.1038/bmt.2012.132 PG 9 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 094BY UT WOS:000315239200024 PM 22773122 ER PT J AU Johnson, LM Price, DK Figg, WD AF Johnson, Linda M. Price, Douglas K. Figg, William D. TI Treatment-induced secretion of WNT16B promotes tumor growth and acquired resistance to chemotherapy Implications for potential use of inhibitors in cancer treatment SO CANCER BIOLOGY & THERAPY LA English DT Editorial Material DE prostate cancer; WNT16B; chemotherapy resistance; tumor microenvironment; NF kappa B; cytotoxic drugs; DNA damage response program ID DRUG-RESISTANCE C1 [Johnson, Linda M.; Price, Douglas K.; Figg, William D.] NCI, Mol Pharmacol Sect, Med Oncol Branch, Bethesda, MD 20892 USA. [Figg, William D.] NCI, Clin Pharmacol Sect, Med Oncol Branch, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Mol Pharmacol Sect, Med Oncol Branch, Bethesda, MD 20892 USA. EM figgw@helix.nih.gov RI Figg Sr, William/M-2411-2016 NR 6 TC 5 Z9 6 U1 1 U2 12 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD FEB PY 2013 VL 14 IS 2 BP 90 EP 91 DI 10.4161/cbt.22636 PG 2 WC Oncology SC Oncology GA 083MP UT WOS:000314468700003 PM 23114711 ER PT J AU Ierano, C Basseville, A To, KKW Zhan, ZR Robey, RW Wilkerson, J Bates, SE Scala, S AF Ierano, Caterina Basseville, Agnes To, Kenneth K. W. Zhan, Zhirong Robey, Robert W. Wilkerson, Julia Bates, Susan E. Scala, Stefania TI Histone deacetylase inhibitors induce CXCR4 mRNA but antagonize CXCR4 migration SO CANCER BIOLOGY & THERAPY LA English DT Article DE CXCR4; CXCL12; histone deacetylase inhibitor; romidepsin; migration ID RENAL-CELL-CARCINOMA; BREAST-CANCER CELLS; CHEMOKINE RECEPTOR; VALPROIC ACID; DEPSIPEPTIDE FR901228; LUNG-CANCER; UP-REGULATION; TUMOR-CELLS; EXPRESSION; ACTIVATION AB The stromal cell-derived factor-1 alpha SDF-1 alpha (CXCL12)/CXCR4 axis has been linked to poor prognosis in some cancers. As histone deacetylase inhibitors (HDIs) exert antitumor effects by targeting proteins affecting cell migration, we sought to evaluate the effects of the HDIs apicidin, vorinostat, entinostat (MS-275) and romidepsin on the expression and function of CXCR4 in human cancer cell lines. After treatment with romidepsin, CXCR4 mRNA expression increased 12-fold in UOK121 renal cancer cells, 16-fold in H460 non-small cell cancer cells and 4-fold in SF295 glioma cells; treatment with other HDIs yielded similar effects. CXCR4 induction was not observed in MCF7 breast cancer cells or SW620 colon cancer cells. To evaluate the corresponding functional increase, the effect of CXCR4 ligand, CXCL12, on ERK1/2, STAT3 and c-SRC activation and cell migration was examined in UOK121, SF295 and H460 cells. Alone, the HDIs increased pERK1/2, while reducing pSTAT-3 and pSRC. Following CXCL12 exposure, pERK1/2 induction was maintained, but STAT3 and SRC phosphorylation was impaired. These findings resulted in reduced basal and CXCL12-mediated cell migration. In conclusion, HDIs upregulated CXCR4 mRNA expression but impaired CXCL12-dependent signaling cascades through STAT3 and c-SRC, suggesting a potential role for HDIs in delaying or preventing metastatic processes in solid tumors. C1 [Ierano, Caterina; Basseville, Agnes; To, Kenneth K. W.; Zhan, Zhirong; Robey, Robert W.; Wilkerson, Julia; Bates, Susan E.] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Ierano, Caterina; Scala, Stefania] G Pascale Fdn, Natl Canc Inst Naples, Naples, Italy. RP Robey, RW (reprint author), NCI, Med Oncol Branch, Bethesda, MD 20892 USA. EM robeyr@mail.nih.gov RI To, Kenneth /M-4500-2013; Scala, Stefania/K-1380-2016; Ierano, Caterina/K-1676-2016; OI To, Kenneth /0000-0003-2755-0283; Scala, Stefania/0000-0001-9524-2616; Ierano, Caterina/0000-0003-3138-1873; Wilkerson, Julia/0000-0002-6965-0867 FU Intramural Research Program of the National Cancer Institute; CRADA FX This work was supported in part by the Intramural Research Program of the National Cancer Institute. This work was supported in part by a CRADA between the NCI and Celgene Corp. NR 48 TC 3 Z9 3 U1 0 U2 6 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD FEB PY 2013 VL 14 IS 2 BP 175 EP 183 DI 10.4161/cbt.22957 PG 9 WC Oncology SC Oncology GA 083MP UT WOS:000314468700014 PM 23192271 ER PT J AU Wentzensen, N Wacholder, S AF Wentzensen, Nicolas Wacholder, Sholom TI From Differences in Means between Cases and Controls to Risk Stratification: A Business Plan for Biomarker Development SO CANCER DISCOVERY LA English DT Review ID OVARIAN-CANCER; PERFORMANCE; MARKER; TESTS AB Researchers developing biomarkers for early detection can determine the potential for clinical benefit at early stages of development. We provide the theoretical background showing the quantitative connection between biomarker levels in cases and controls and clinically meaningful risk measures, as well as a spreadsheet for researchers to use in their own research. We provide researchers with tools to decide whether a test is useful, whether it needs technical improvement, whether it may work only in specific populations, or whether any further development is futile. The methods described here apply to any method that aims to estimate risk of disease based on biomarkers, clinical tests, genetics, environment, or behavior. Significance: Many efforts go into futile biomarker development and premature clinical testing. In many instances, predictions for translational success or failure can be made early, simply based on critical analysis of case-control data. Our article presents well-established theory in a form that can be appreciated by biomarker researchers. Furthermore, we provide an interactive spreadsheet that links biomarker performance with specific disease characteristics to evaluate the promise of biomarker candidates at an early stage. Cancer Discov; 3(2); 148-57. (C) 2012 AACR. C1 [Wentzensen, Nicolas; Wacholder, Sholom] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. RP Wacholder, S (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 5050, Rockville, MD 20852 USA. EM WacholdS@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 13 TC 23 Z9 23 U1 0 U2 12 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 J9 CANCER DISCOV JI Cancer Discov. PD FEB PY 2013 VL 3 IS 2 BP 148 EP 157 DI 10.1158/2159-8290.CD-12-0196 PG 10 WC Oncology SC Oncology GA 088IA UT WOS:000314826300021 PM 23299199 ER PT J AU Fox, ER Musani, SK Barbalic, M Lin, HH Yu, B Ogunyankin, KO Smith, NL Kutlar, A Glazer, NL Post, WS Paltoo, DN Dries, DL Farlow, DN Duarte, CW Kardia, SL Meyers, KJ Sun, YV Arnett, DK Patki, AA Sha, J Cui, XQ Samdarshi, TE Penman, AD Bibbins-Domingo, K Buzkova, P Benjamin, EJ Bluemke, DA Morrison, AC Heiss, G Carr, JJ Tracy, RP Mosley, TH Taylor, HA Psaty, BM Heckbert, SR Cappola, TP Vasan, RS AF Fox, Ervin R. Musani, Solomon K. Barbalic, Maja Lin, Honghuang Yu, Bing Ogunyankin, Kofo O. Smith, Nicholas L. Kutlar, Abdullah Glazer, Nicole L. Post, Wendy S. Paltoo, Dina N. Dries, Daniel L. Farlow, Deborah N. Duarte, Christine W. Kardia, Sharon L. Meyers, Kristin J. Sun, Yan V. Arnett, Donna K. Patki, Amit A. Sha, Jin Cui, Xiangqui Samdarshi, Tandaw E. Penman, Alan D. Bibbins-Domingo, Kirsten Buzkova, Petra Benjamin, Emelia J. Bluemke, David A. Morrison, Alanna C. Heiss, Gerardo Carr, J. Jeffrey Tracy, Russell P. Mosley, Thomas H. Taylor, Herman A. Psaty, Bruce M. Heckbert, Susan R. Cappola, Thomas P. Vasan, Ramachandran S. TI Genome-Wide Association Study of Cardiac Structure and Systolic Function in African Americans The Candidate Gene Association Resource (CARe) Study SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE echocardiography; ethnic; genome-wide association studies; left atrium genetics; left ventricular mass genetics ID LEFT-VENTRICULAR MASS; COMMON DISEASES; HYPERTROPHY; VARIANTS; SUSCEPTIBILITY; CONTRACTILITY; HYPERTENSION; HYPERGEN; LINKAGE; MARKERS AB Background-Using data from 4 community-based cohorts of African Americans, we tested the association between genome-wide markers (single-nucleotide polymorphisms) and cardiac phenotypes in the Candidate-gene Association Resource study. Methods and Results-Among 6765 African Americans, we related age, sex, height, and weight-adjusted residuals for 9 cardiac phenotypes (assessed by echocardiogram or magnetic resonance imaging) to 2.5 million single-nucleotide polymorphisms genotyped using Genome-wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within the cohort, genome-wide association analysis was conducted, followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0x10(-7)). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested lookups in 1 consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (P=1.43x10(-7)) for left ventricular mass, rs7213314 in WIPI1 (P=1.68x10(-7)) for left ventricular internal diastolic diameter, rs1571099 in PPAPDC1A (P=2.57x10(-8)) for interventricular septal wall thickness, and rs9530176 in KLF5 (P=4.02x10(-7)) for ejection fraction. Associated variants were enriched in 3 signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry was confirmed in lookups in EchoGEN. Conclusions-In the largest genome-wide association study of cardiac structure and function to date in African Americans, we identified 4 genetic loci related to left ventricular mass, interventricular septal wall thickness, left ventricular internal diastolic diameter, and ejection fraction, which reached genome-wide significance. Replication results suggest that these loci may be unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes. (Circ Cardiovasc Genet. 2013;6:37-46.) C1 [Fox, Ervin R.; Musani, Solomon K.; Yu, Bing; Samdarshi, Tandaw E.; Penman, Alan D.; Mosley, Thomas H.; Taylor, Herman A.] Univ Mississippi, Sch Med, Dept Med, Jackson, MS 39216 USA. [Barbalic, Maja; Morrison, Alanna C.] Univ Texas Hlth Sci Ctr, Sch Publ Hlth, Ctr Human Genet, Houston, TX USA. [Lin, Honghuang; Glazer, Nicole L.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Ogunyankin, Kofo O.] Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Smith, Nicholas L.] Univ Washington, Dept Epidemiol, Sch Med, Seattle, WA 98195 USA. [Smith, Nicholas L.] US Dept Vet Affairs, Seattle Epidemiol Res & Informat Ctr, Off Res & Dev, Grp Hlth Res Inst,Grp Hlth Cooperat, Seattle, WA USA. [Kutlar, Abdullah] Georgia Hlth Sci Univ, Dept Med, Augusta, GA USA. [Post, Wendy S.] Johns Hopkins Sch Med, Dept Med, Div Cardiol, Baltimore, MD USA. [Paltoo, Dina N.] NHLBI, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Dries, Daniel L.] Yale Univ, Sch Med, Dept Med, Div Cardiovasc, New Haven, CT 06510 USA. [Farlow, Deborah N.] Broad Inst Massachusetts Inst Technol & Harvard U, Boston, MA USA. [Duarte, Christine W.; Patki, Amit A.; Cui, Xiangqui] Univ Alabama Birmingham, Sch Publ Hlth, Dept Biostat, Birmingham, AL 35294 USA. [Arnett, Donna K.; Sha, Jin] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. [Kardia, Sharon L.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Meyers, Kristin J.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI 53706 USA. [Sun, Yan V.] Emory Univ, Sch Med, Dept Epidemiol, Rollins Sch Publ Hlth, Atlanta, GA USA. [Bibbins-Domingo, Kirsten] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Buzkova, Petra] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Bluemke, David A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Heiss, Gerardo] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Carr, J. Jeffrey] Wake Forest Univ, Sch Med Publ Hlth & Translat Sci, Salem, NC USA. [Tracy, Russell P.] Univ Vermont, Coll Med, Dept Pathol & Lab Med, Burlington, VT 05405 USA. [Psaty, Bruce M.; Heckbert, Susan R.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, Bruce M.; Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.; Heckbert, Susan R.] Univ Washington, Dept Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Carr, J. Jeffrey] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. RP Fox, ER (reprint author), Univ Mississippi, Med Ctr, Dept Med, 2500 North State St, Jackson, MS 39216 USA. EM efox@medicine.umsmed.edu RI Carr, John/A-1938-2012; OI Carr, John/0000-0002-4398-8237; Lin, Honghuang/0000-0003-3043-3942; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336; Bluemke, David/0000-0002-8323-8086 FU National Institutes of Health (NIH)/National Institute on Minority Health and Health Disparities (NIMHD) [P20]; Novartis; Celgene Corp; Global Iron Summit; NIH [HL 100245, R01 HL09257, RC1 HD101056, R01 HL102214, R01 AG028321]; Candidate Gene Association Resource Study, Exome Sequencing Project; ARIC, NIH; NIH; National Heart, Lung, and Blood Institute [HL 087652]; University of North Carolina at Chapel Hill [N01-HC-55015]; Baylor Medical College [N01-HC-55016]; University of Mississippi Medical Center [N01-HC-55021]; University of Minnesota [N01-HC-55019, N01-HC-48048]; Johns Hopkins University [N01-HC-55020, N01-HC-85081, N01 HC-15103]; University of Texas, Houston [N01-HC-55017]; University of North Carolina, Forsyth County [N01-HC-55018]; University of Washington [N01-HC-85079, N01 HC-55222, U01 HL080295, N01-HC-95159]; Wake Forest University [N01-HC-85080, N01-HC-45205]; University of Pittsburgh [N01-HC-85082]; University of California, Davis [N01-HC-85083]; University of California, Irvine [N01-HC-85084, N01-HC-45134, N01-HC-95100]; New England Medical Center [N01-HC-85085]; University of Vermont [N01-HC-85086]; Georgetown University [N01-HC-35129]; University of Wisconsin [N01-HC-75150]; Geisinger Clinic [N01-HC-45133]; Case Western Reserve University [RO1 HL46380-01-16]; University of Illinois [N01-HB-72982, N01-HB-97062]; Howard University [N01-HB-72991, N01-HB-97061]; University of Miami [N01-HB-72992, N01-HB-97064]; Duke University [N01-HB-72993]; George Washington University [N01-HB-72994]; University of Tennessee [N01-HB-72995, N01-HB-97070]; Yale University [N01-HB-72996, N01-HB-97072]; Children's Hospital-Philadelphia [N01-HB-72997, N01-HB-97056]; University of Chicago [N01-HB-72998, N01-HB-97053]; Medical College of Georgia [N01-HB-73000, N01-HB-97060]; Washington University [N01-HB-73001, N01-HB-97071]; Jewish Hospital and Medical Center of Brooklyn [N01-HB-73002]; Trustees of Health and Hospitals of the City of Boston, Inc. [N01-HB-73003]; Children's Hospital-Oakland [N01-HB-73004, N01-HB-97054]; University of Mississippi [N01-HB-73005, N01-HC-95171]; St. Luke's Hospital-New York [N01-HB-73006]; Alta Bates-Herrick Hospital [N01-HB-97051]; Columbia University [N01-HB-97058]; St. Jude's Children's Research Hospital [N01-HB-97066]; Research Foundation, State University of New York-Albany [N01-HB-97068, N01-HB-97069]; New England Research Institute [N01-HB-97073]; Interfaith Medical Center-Brooklyn [N01-HB-97085]; University of Alabama at Birmingham [N01-HC-48047, N01-HC-95095]; Northwestern University [N01-HC-48049]; Kaiser Foundation Research Institute [N01-HC-48050]; Tufts-New England Medical Center [N01-HC-45204]; Harbor-UCLA Research and Education Institute [N01-HC-05187]; Boston University [N01-HC-25195]; Jackson State University [N01-HC-95170]; Tougaloo College [N01-HC-95172]; Regents of the University of California [N01-HC-95160]; [R01 HD067264]; [RC4 AG039029]; [R01 HL101161-01-A1]; [R01 DK077950-03]; [RC1 HL100185]; [P60 MD002249] FX Dr Kutlar received research grants from National Institutes of Health (NIH)/National Institute on Minority Health and Health Disparities (NIMHD)-P20, Novartis, Celgene Corp. (>=$10000), and Global Iron Summit (<$10000). Dr Paltoo has ownership interest in a 529 College Plan and a Thrift Saving Plan (>$10000). Dr Kardia received research grants from R01 HD067264, RC4 AG039029, R01 HL101161-01-A1, R01 DK077950-03, RC1 HL100185, and P60 MD002249 (>$10000). Dr Sun received research grants from NIH HL 100245, Genetics of Hypertension Risk Factors, and Sequela in African Americans (>$10000). Dr Benjamin received research grants from R01 HL09257, RC1 HD101056, R01 HL102214, and R01 AG028321 (all NIH grants >$10000). Dr Tracy received research grants from Candidate Gene Association Resource Study, Exome Sequencing Project (>$10000). Dr Mosley received research grants from ARIC, ARIC-Neurocognitive Study, Predictors of Coronary Artery Calcification in an African American Cohort, GWAS of Ischemic Brain Vascular Injury, ARIC PET Amyloid Imaging Study, the Intracranial Atherosclerosis Disease and Cognitive Impairment Study, Parkinson Disease and Olfactory Function in the ARIC Study, and Identify Epidemiological Risk Factors for Abdominal Aortic Aneurysm Study (all NIH grants >$10000). Dr Taylor received research grants for the Jackson Heart Study (NIH grant >$10000). Dr Psaty received NIH grants (<$10000); he serves on the Data and Safety Monitoring Board for a clinical trial for a device (Zoll Life Cor <$10000) and service on the Steering Committee for Yale Open Data Project (Medtronic <$10000). Dr Heckbert received research grants from HL 087652 Whole Genome Association Study in the Cardiovascular Health Study (National Heart, Lung, and Blood Institute >$10000). Dr Vasan received an NIH grant (>$10000). The other authors report no conflicts.; Atherosclerotic Risk in Communities: University of North Carolina at Chapel Hill (N01-HC-55015), Baylor Medical College (N01-HC-55016), University of Mississippi Medical Center (N01-HC-55021), University of Minnesota (N01-HC-55019), Johns Hopkins University (N01-HC-55020), University of Texas, Houston (N01-HC-55017), and University of North Carolina, Forsyth County (N01-HC-55018); Cardiovascular Health Study: University of Washington (N01-HC-85079), Wake Forest University (N01-HC-85080), Johns Hopkins University (N01-HC-85081), University of Pittsburgh (N01-HC-85082), University of California, Davis (N01-HC-85083), University of California, Irvine (N01-HC-85084), New England Medical Center (N01-HC-85085), University of Vermont (N01-HC-85086), Georgetown University (N01-HC-35129), Johns Hopkins University (N01 HC-15103), University of Wisconsin (N01-HC-75150), Geisinger Clinic (N01-HC-45133), and University of Washington (N01 HC-55222, U01 HL080295); Cleveland Family Study: Case Western Reserve University (RO1 HL46380-01-16); Cooperative Study of Sickle Cell Disease: University of Illinois (N01-HB-72982, N01-HB-97062), Howard University (N01-HB-72991, N01-HB-97061), University of Miami (N01-HB-72992, N01-HB-97064), Duke University (N01-HB-72993), George Washington University (N01-HB-72994), University of Tennessee (N01-HB-72995, N01-HB-97070), Yale University (N01-HB-72996, N01-HB-97072), Children's Hospital-Philadelphia (N01-HB-72997, N01-HB-97056), University of Chicago (N01-HB-72998, N01-HB-97053), Medical College of Georgia (N01-HB-73000, N01-HB-97060), Washington University (N01-HB-73001, N01-HB-97071), Jewish Hospital and Medical Center of Brooklyn (N01-HB-73002), Trustees of Health and Hospitals of the City of Boston, Inc. (N01-HB-73003), Children's Hospital-Oakland (N01-HB-73004, N01-HB-97054), University of Mississippi (N01-HB-73005), St. Luke's Hospital-New York (N01-HB-73006), Alta Bates-Herrick Hospital (N01-HB-97051), Columbia University (N01-HB-97058), St.; Jude's Children's Research Hospital (N01-HB-97066), Research Foundation, State University of New York-Albany (N01-HB-97068, N01-HB-97069), New England Research Institute (N01-HB-97073), and Interfaith Medical Center-Brooklyn (N01-HB-97085); Coronary Artery Risk in Young Adults: University of Alabama at Birmingham (N01-HC-48047), University of Minnesota (N01-HC-48048), Northwestern University (N01-HC-48049), Kaiser Foundation Research Institute (N01-HC-48050), University of Alabama at Birmingham (N01-HC-95095), Tufts-New England Medical Center (N01-HC-45204), Wake Forest University (N01-HC-45205), Harbor-UCLA Research and Education Institute (N01-HC-05187), and University of California, Irvine (N01-HC-45134, N01-HC-95100); Framingham Heart Study: Boston University (N01-HC-25195); Jackson Heart Study: Jackson State University (N01-HC-95170), University of Mississippi (N01-HC-95171), and Tougaloo College (N01-HC-95172); Multi-Ethnic Study of Atherosclerosis: University of Washington (N01-HC-95159), Regents of the University of California (N01-HC-95160), Columbia University (N01-HC-95161), Johns Hopkins University (N01-HC-95162), University of Minnesota (N01-HC-95163), Northwestern University (N01-HC-95164), Wake Forest University (N01-HC-95165), University of Vermont (N01-HC-95166), New England Medical Center (N01-HC-95167), Johns Hopkins University (N01-HC-95168), and Harbor-UCLA Research and Education Institute (N01-HC-95169); Sleep Heart Health Study: Johns Hopkins University (U01 HL064360), Case Western University (U01 HL063463), University of California, Davis (U01 HL053916), University of Arizona (U01 HL053938), University of Minnesota (relocating in 2006 to University Arizona) (U01 HL053934), University of Pittsburgh (U01 HL077813), Boston University (U01 HL053941), MedStar Research Institute (U01 HL063429), and Johns Hopkins University (U01 HL053937). NR 28 TC 15 Z9 15 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-325X J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD FEB PY 2013 VL 6 IS 1 BP 37 EP 46 DI 10.1161/CIRCGENETICS.111.962365 PG 10 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA 094YL UT WOS:000315301500008 PM 23275298 ER PT J AU Yu, B Barbalic, M Brautbar, A Nambi, V Hoogeveen, RC Tang, WH Mosley, TH Rotter, JI deFilippi, CR O'Donnell, CJ Kathiresan, S Rice, K Heckbert, SR Ballantyne, CM Psaty, BM Boerwinkle, E AF Yu, Bing Barbalic, Maja Brautbar, Ariel Nambi, Vijay Hoogeveen, Ron C. Tang, Weihong Mosley, Thomas H. Rotter, Jerome I. deFilippi, Christopher R. O'Donnell, Christopher J. Kathiresan, Sekar Rice, Ken Heckbert, Susan R. Ballantyne, Christie M. Psaty, Bruce M. Boerwinkle, Eric CA CARDIoGRAM Consortium TI Association of Genome-Wide Variation With Highly Sensitive Cardiac Troponin-T Levels in European Americans and Blacks A Meta-Analysis From Atherosclerosis Risk in Communities and Cardiovascular Health Studies SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE genetics; genome-wide association study; troponin ID CORONARY-ARTERY-DISEASE; FAMILIAL HYPERTROPHIC CARDIOMYOPATHY; SARCOMERE PROTEIN GENES; DILATED CARDIOMYOPATHY; MYOCARDIAL-INFARCTION; ALPHA-TROPOMYOSIN; HEART-FAILURE; MUTATIONS; ASSAY; MORTALITY AB Background-High levels of cardiac troponin T, measured by a highly sensitive assay (hs-cTnT), are strongly associated with incident coronary heart disease and heart failure. To date, no large-scale genome-wide association study of hs-cTnT has been reported. We sought to identify novel genetic variants that are associated with hs-cTnT levels. Methods and Results-We performed a genome-wide association in 9491 European Americans and 2053 blacks free of coronary heart disease and heart failure from 2 prospective cohorts: the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study. Genome-wide association studies were conducted in each study and race stratum. Fixed-effect meta-analyses combined the results of linear regression from 2 cohorts within each race stratum and then across race strata to produce overall estimates and probability values. The meta-analysis identified a significant association at chromosome 8q13 (rs10091374; P=9.06x10(-9)) near the nuclear receptor coactivator 2 (NCOA2) gene. Overexpression of NCOA2 can be detected in myoblasts. An additional analysis using logistic regression and the clinically motivated 99th percentile cut point detected a significant association at 1q32 (rs12564445; P=4.73x10(-8)) in the gene TNNT2, which encodes the cardiac troponin T protein itself. The hs-cTnT-associated single-nucleotide polymorphisms were not associated with coronary heart disease in a large case-control study, but rs12564445 was significantly associated with incident heart failure in Atherosclerosis Risk in Communities Study European Americans (hazard ratio=1.16; P=0.004). Conclusions-We identified 2 loci, near NCOA2 and in the TNNT2 gene, at which variation was significantly associated with hs-cTnT levels. Further use of the new assay should enable replication of these results. (Circ Cardiovasc Genet. 2013;6:82-88.) C1 [Yu, Bing; Barbalic, Maja; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA. [Brautbar, Ariel; Nambi, Vijay; Hoogeveen, Ron C.; Ballantyne, Christie M.] Baylor Coll Med, Deptartment Med, Houston, TX 77030 USA. [Boerwinkle, Eric] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Tang, Weihong] Univ Minnesota, Deptartment Epidemiol, Minneapolis, MN USA. [Mosley, Thomas H.] Univ Mississippi, Med Ctr, Div Geriatr, Jackson, MS 39216 USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [deFilippi, Christopher R.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [O'Donnell, Christopher J.] NHLBI, Bethesda, MD 20892 USA. [O'Donnell, Christopher J.] NIH, Framingham Heart Study, Bethesda, MD 20892 USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Kathiresan, Sekar] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Rice, Ken] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Heckbert, Susan R.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [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.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. RP Boerwinkle, E (reprint author), Univ Texas Sch Publ Hlth, Ctr Human Genet, 1200 Herman Pressler E-447, Houston, TX 77030 USA. EM Eric.Boerwinkle@uth.tmc.edu FU National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN2682011000 08C, HHSN268201100009C, HHSN268201100010C, HHSN2682 01100011C, HHSN268201100012C, R01HL087641, R01HL59 367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health [HHSN268200625226C, UL1RR025005]; National Institute on Aging [AG-023629, AG-15928, AG-20098, AG-027058]; National Center for Research Resources CTSI [UL 1RR033176]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; Burroughs Wellcome Fund; Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium; National Heart, Lung, and Blood Institute. [N01-HC-85239, N01-HC-85079, N01-HC-85086, N01-HC-35129, N01-HC-15103, N01-HC-55222, N01-HC-75150, N01-HC-45133, HL080295, HL075366, HL085251, HL087652, HL105756] FX The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN2682011000 08C, HHSN268201100009C, HHSN268201100010C, HHSN2682 01100011C, and HHSN268201100012C), R01HL087641, R01HL59 367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health, and NIH Roadmap for Medical Research. This Cardiovascular Health Study research was supported by the National Heart, Lung, and Blood Institute contracts N01-HC-85239, N01-HC-85079 through N01-HC-85086; N01-HC-35129, N01-HC-15103, N01-HC-55222, N01-HC-75150, and N01-HC-45133,; and National Heart, Lung, and Blood Institute grants HL080295, HL075366, HL085251, HL087652, and HL105756, with additional contributions from National Institute of Neurological Disorders and Stroke. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the National Institute on Aging. See also http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping was supported in part by National Center for Research Resources CTSI grant UL 1RR033176 and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center and the Cedars-Sinai Board of Governors' Chair in Medical Genetics (to Dr Rotter).; We acknowledge the essential role of The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium in developing and supporting this article. CHARGE members include the ARIC, the CHS, Framingham Heart Study (FHS) and Rotterdam Study (RS), and Age, Gene/Environment Susceptibility. The authors also thank the staff and participants of the ARIC and CHS study for their important contributions. Dr Yu is supported in part by the Burroughs Wellcome Fund. NR 30 TC 8 Z9 8 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-325X J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD FEB PY 2013 VL 6 IS 1 BP 82 EP 88 DI 10.1161/CIRCGENETICS.112.963058 PG 7 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA 094YL UT WOS:000315301500013 PM 23247143 ER PT J AU Liberti, SE Larrea, AA Kunkel, TA AF Liberti, Sascha E. Larrea, Andres A. Kunkel, Thomas A. TI Exonuclease 1 preferentially repairs mismatches generated by DNA polymerase alpha SO DNA REPAIR LA English DT Article DE Exo1; Mismatch repair; Genome stability; Replication fidelity ID SACCHAROMYCES-CEREVISIAE EXO1; EUKARYOTIC REPLICATION FORK; ESCHERICHIA-COLI; SYSTEM; YEAST; ERRORS; DELTA; IDENTIFICATION; RECONSTITUTION; MUTATIONS AB The Saccharomyces cerevisiae EXO1 gene encodes a 5' exonuclease that participates in mismatch repair (MMR) of DNA replication errors. Deleting EXO1 was previously shown to increase mutation rates to a greater extent when combined with a mutator variant (pol3-L612M) of the lagging strand replicase, DNA polymerase delta (Pol delta), than when combined with a mutator variant (pol2-M644G) of the leading strand replicase, DNA polymerase epsilon (Pol epsilon). Here we confirm that result, and extend the approach to examine the effect of deleting EXO1 in a mutator variant (pol1-L868M) of Pol alpha, the proofreading-deficient and least accurate of the three nuclear replicases that is responsible for initiating Okazaki fragment synthesis. We find that deleting EXO1 increases the mutation rate in the Pol alpha mutator strain to a significantly greater extent than in the Pol delta or Pol epsilon mutator strains, thereby preferentially reducing the efficiency of MMR of replication errors generated by Pol alpha. Because these mismatches are closer to the 5' ends of Okazaki fragments than are mismatches made by Pol delta or Pol epsilon, the results not only support the previous suggestion that Exo1 preferentially excises lagging strand replication errors during mismatch repair, they further imply that the 5' ends serve as entry points for 5' excision of replication errors made by Pol alpha, and possibly as strand discrimination signals for MMR. Nonetheless, mutation rates in the Pol alpha mutator strain are 5- to 25-fold lower in an exo1 Delta strain as compared to an msh2 Delta strain completely lacking MMR, indicating that in the absence of Exo1, most replication errors made by Pol alpha can still be removed in an Msh2-dependent manner by other nucleases and/or by strand displacement. Published by Elsevier B.V. C1 [Kunkel, Thomas A.] NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Kunkel, TA (reprint author), NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov FU Division of Intramural Research of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES065089] FX We thank Kasia Bebenek and Dmitry Gordenin for thoughtful comments on the manuscript, and the NIEHS Molecular Genetics Core Facility for sequencing mutants. This work was supported by Project Z01 ES065089 to TAK from the Division of Intramural Research of the National Institutes of Health, National Institute of Environmental Health Sciences. NR 34 TC 20 Z9 20 U1 0 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD FEB 1 PY 2013 VL 12 IS 2 BP 92 EP 96 DI 10.1016/j.dnarep.2012.11.001 PG 5 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 083TC UT WOS:000314487100003 PM 23245696 ER PT J AU Clausen, AR Zhang, S Burgers, PM Lee, MY Kunkel, TA AF Clausen, Anders R. Zhang, Sufang Burgers, Peter M. Lee, Marietta Y. Kunkel, Thomas A. TI Ribonucleotide incorporation, proofreading and bypass by human DNA polymerase delta SO DNA REPAIR LA English DT Article DE DNA polymerase delta; Ribonucleotide; Incorporation; Proofreading; Bypass ID YEAST REPLICATIVE POLYMERASES; EPSILON; REPAIR; INSTABILITY; MUTATIONS AB In both budding and fission yeast, a large number of ribonucleotides are incorporated into DNA during replication by the major replicative polymerases (Pols alpha, delta and epsilon). They are subsequently removed by RNase H2-dependent repair, which if defective leads to replication stress and genome instability. To extend these studies to humans, where an RNase H2 defect results in an autoimmune disease, here we compare the ability of human and yeast Pol delta to incorporate, proofread, and bypass ribonucleotides during DNA synthesis. In reactions containing nucleotide concentrations estimated to be present in mammalian cells, human Pol delta stably incorporates one rNTP for approximately 2000 dNTPs, a ratio similar to that for yeast Pol delta. This result predicts that human Pol delta may introduce more than a million ribonucleotides into the nuclear genome per replication cycle, an amount recently reported to be present in the genome of RNase H2-defective mouse cells. Consistent with such abundant stable incorporation, we show that the 3'-exonuclease activity of yeast and human Pol delta largely fails to edit ribonucleotides during polymerization. We also show that, like yeast Pol delta, human Pol delta pauses as it bypasses ribonucleotides in DNA templates, with four consecutive ribonucleotides in a DNA template being more problematic than single ribonucleotides. In conjunction with recent studies in yeast and mice, this ribonucleotide incorporation may be relevant to impaired development and disease when RNase H2 is defective in mammals. As one tool to investigate ribonucleotide incorporation by Pol delta in human cells, we show that human Pol delta containing a Leu606Met substitution in the polymerase active site incorporates 7-fold more ribonucleotides into DNA than does wild type Pol delta. Published by Elsevier B.V. C1 [Clausen, Anders R.; Kunkel, Thomas A.] NIEHS, Mol Genet Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Clausen, Anders R.; Kunkel, Thomas A.] NIEHS, Struct Biol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Zhang, Sufang; Lee, Marietta Y.] New York Med Coll, Dept Biochem & Mol Biol, Valhalla, NY 10595 USA. [Burgers, Peter M.] Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. RP Kunkel, TA (reprint author), NIEHS, Mol Genet Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov RI Clausen, Anders R./I-7229-2012; OI Clausen, Anders Ranegaard/0000-0002-5069-0930 FU [Z01 ES065070]; [GM032431]; [5RO1 GM031973] FX We thank Roel M. Schaaper and Jessica S. Williams for helpful comments on the manuscript. This work was supported by Project Z01 ES065070 to T.A.K., Project GM032431 to P.M.B. and Project 5RO1 GM031973 to M.Y.L. NR 25 TC 34 Z9 34 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD FEB 1 PY 2013 VL 12 IS 2 BP 121 EP 127 DI 10.1016/j.dnarep.2012.11.006 PG 7 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 083TC UT WOS:000314487100006 PM 23245697 ER PT J AU Grisshammer, R AF Grisshammer, Reinhard TI Why we need many more G protein-coupled receptor structures SO EXPERT REVIEW OF PROTEOMICS LA English DT Editorial Material DE crystallization; G protein-coupled receptor; lipidic cubic phase; neurotensin receptor; structure determination; x-ray ID RESOLUTION CRYSTAL-STRUCTURE; MEMBRANE-PROTEINS; CRYSTALLIZATION; YIELDS C1 NINDS, Membrane Prot Struct Funct Unit, NIH, Dept Hlth & Human Serv, Rockville, MD 20852 USA. RP Grisshammer, R (reprint author), NINDS, Membrane Prot Struct Funct Unit, NIH, Dept Hlth & Human Serv, Rockville, MD 20852 USA. EM rkgriss@helix.nih.gov RI Grisshammer, Reinhard/C-3089-2015 FU Intramural NIH HHS [ZIA NS003016-08] NR 21 TC 3 Z9 3 U1 1 U2 13 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1478-9450 J9 EXPERT REV PROTEOMIC JI Expert Rev. Proteomics PD FEB PY 2013 VL 10 IS 1 BP 1 EP 3 DI 10.1586/EPR.12.76 PG 3 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 093AB UT WOS:000315163000001 PM 23414351 ER PT J AU Parashar, U Steele, D Neuzil, K De Quadros, C Tharmaphornpilas, P Serhan, F Santosham, M Patel, M Glass, R AF Parashar, Umesh Steele, Duncan Neuzil, Kathleen De Quadros, Ciro Tharmaphornpilas, Piyanit Serhan, Fatima Santosham, Mathu Patel, Manish Glass, Roger TI Progress with rotavirus vaccines: summary of the Tenth International Rotavirus Symposium SO EXPERT REVIEW OF VACCINES LA English DT Editorial Material ID REASSORTANT ROTAVIRUS; AFRICAN INFANTS; GASTROENTERITIS; VACCINATION; CHILDREN; IMMUNOGENICITY; INFECTION; SAFETY; PROTECTION; EFFICACY AB Over 350 scientific, public and private sector experts from 47 countries convened at the Tenth International Rotavirus Symposium in Bangkok, Thailand on 19-21 September 2012 to discuss progress in the prevention and control of rotavirus, the leading cause of diarrhea hospitalizations and deaths among young children worldwide. Participants discussed data on the burden and epidemiology of rotavirus disease, results of trials of rotavirus vaccines, postmarketing data on vaccine impact and safety from countries that have implemented rotavirus vaccination programs, new insights in rotavirus pathogenesis, immunity and strain diversity, and key issues related to vaccine policy and introduction. C1 [Parashar, Umesh; Patel, Manish] CDC, Atlanta, GA USA. [Steele, Duncan] Bill & Melinda Gates Fdn, Seattle, WA USA. [Neuzil, Kathleen] Program Appl Technol Hlth, Seattle, WA USA. [De Quadros, Ciro] Sabin Vaccine Inst, Washington, DC USA. [Tharmaphornpilas, Piyanit] Minist Hlth, Bangkok, Thailand. [Serhan, Fatima] WHO, CH-1211 Geneva, Switzerland. [Santosham, Mathu] Johns Hopkins Univ, Baltimore, MD USA. [Glass, Roger] NIH, Bethesda, MD 20892 USA. RP Parashar, U (reprint author), CDC, Atlanta, GA USA. EM uap2@cdc.gov NR 26 TC 12 Z9 12 U1 0 U2 8 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1476-0584 J9 EXPERT REV VACCINES JI Expert Rev. Vaccines PD FEB PY 2013 VL 12 IS 2 BP 113 EP 117 DI 10.1586/ERV.12.148 PG 5 WC Immunology SC Immunology GA 093BS UT WOS:000315167300009 PM 23414403 ER PT J AU Ferreira, JR Hirsch, ML Zhang, L Park, Y Samulski, RJ Hu, WS Ko, CC AF Ferreira, J. R. Hirsch, M. L. Zhang, L. Park, Y. Samulski, R. J. Hu, W-S Ko, C-C TI Three-dimensional multipotent progenitor cell aggregates for expansion, osteogenic differentiation and 'in vivo' tracing with AAV vector serotype 6 SO GENE THERAPY LA English DT Article DE MAPC; bone formation; adeno-associated virus ID MESENCHYMAL STEM-CELLS; ADENOASSOCIATED VIRAL VECTORS; RECEPTOR-RELATED PROTEIN-5; EFFICIENT GENE-TRANSFER; PIG PAROTID-GLANDS; BONE-MARROW; STROMAL CELLS; BETA-CATENIN; TRANSDUCTION; WNT AB Multipotent adult progenitor cells (MAPCs) are bone marrow-derived stem cells with a high growth rate suitable for therapeutical applications as three-dimensional (3D) aggregates. Combined applications of osteogenically differentiated MAPC (OD-MAPC) aggregates and adeno-associated viral vectors (AAV) in bone bioengineering are still deferred until information with regard to expansion technologies, osteogenic potential, and AAV cytotoxicity and transduction efficiency is better understood. In this study, we tested whether self-complementary AAV (scAAV) can potentially be used as a gene delivery system in an OD-MAPC-based 'in vivo' bone formation model in the craniofacial region. Both expansion of rat MAPC (rMAPC) and osteogenic differentiation with dexamethasone were also tested in 3D aggregate culture systems 'in vitro' and 'vivo'. rMAPCs grew as undifferentiated aggregates for 4 days, with a population doubling time of 37 h. After expansion, constant levels of Oct4 transcripts, and Oct4 and CD31 surface markers were observed, which constitute a hallmark of undifferentiated stage of rMAPCs. Dexamethasone effectively mediated rMAPC osteogenic differentiation by inducing the formation of a mineralized collagen type I network, and facilitated the activation of the wnt/beta-catenin, a crucial pathway in skeletal development. To investigate the genetic modification of rMAPCs grown as 3D aggregates before implantation, scAAV serotypes 2, 3 and 6 were evaluated. scAAV6 packaged with the enhanced green fluorescent protein expression cassette efficiently mediated long-term transduction (10 days) 'in vitro' and 'vivo'. The reporter transduction event allowed the tracing of OD-rMAPC (induced by dexamethasone) aggregates following OD-rMAPC transfer into a macro-porous hydroxyapatite scaffold implanted in a rat calvaria model. Furthermore, the scAAV6-transduced OD-rMAPCs generated a bone-like matrix with a collagenous matrix rich in bone-specific proteins (osteocalcin and osteopontin) in the scaffold macro-pores 10 days post-implantation. Newly formed bone was also observed in the interface between native bone and scaffold. The collective work supports future bone tissue engineering applications of 3D MAPC cultures for expansion, bone formation and the ability to alter genetically these cells using scAAV vectors. Gene Therapy (2013) 20, 158-168; doi:10.1038/gt.2012.16; published online 8 March 2012 C1 [Ferreira, J. R.; Ko, C-C] Univ N Carolina, Sch Dent, Chapel Hill, NC USA. [Ferreira, J. R.] NIDCR, Matrix & Morphogenesis Sect, Bethesda, MD 20892 USA. [Hirsch, M. L.; Samulski, R. J.] Univ N Carolina, Gene Therapy Ctr, Chapel Hill, NC USA. [Zhang, L.] Capital Med Univ, Fac Stomatol, Beijing, Peoples R China. [Park, Y.] Catholic Univ Louvain, Interdept Stem Cell Inst, B-3000 Louvain, Belgium. [Hu, W-S] Univ Minnesota, Minneapolis, MN USA. [Ko, C-C] N Carolina State Univ, Raleigh, NC 27695 USA. RP Ferreira, JR (reprint author), NIDCR, Matrix & Morphogenesis Sect, LCDB, NIH, 30 Convent Dr,Room 429, Bethesda, MD 20892 USA. EM andraderequicj@nidcr.nih.gov RI Ferreira, Joao/M-1517-2016; Ferreira, Joao/G-4015-2013 OI Ferreira, Joao/0000-0002-4230-4593; Ferreira, Joao/0000-0002-2411-6273 FU FCT-Portuguese Foundation for Science and Technology [SFRH/BD/36841/2007]; NIH/NIDCR [K08DE018695]; NC Biotech Center, American Association for Orthodontist Foundation; Northwest Genome Engineering Consortium; Wellstone [5U54AR056953]; NH [5R01Al072176] FX We thank Sandra Horton at North Carolina State University for processing 'in vivo' tissue specimens for immunohistochemistry and Victoria Madden at UNC Microscopy Services Laboratory for processing in vitro cell matrices for electron microscopy. Also, we would like to acknowledge Dr Ganokon Urkasemsin for her contribution towards the statistical analysis of this project. Joao Ferreira was supported by the doctoral fellowship of FCT-Portuguese Foundation for Science and Technology (SFRH/BD/36841/2007). This work was supported in part by grants from the: NIH/NIDCR (K08DE018695), NC Biotech Center, American Association for Orthodontist Foundation awarded to C-CK; Northwest Genome Engineering Consortium pilot awarded to MLH; and Wellstone (5U54AR056953) and NH (5R01Al072176) awarded to RJS. NR 47 TC 4 Z9 4 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD FEB PY 2013 VL 20 IS 2 BP 158 EP 168 DI 10.1038/gt.2012.16 PG 11 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 091UD UT WOS:000315074400007 PM 22402320 ER PT J AU Aloia, AL Duffy, L Pak, V Lee, KE Sanchez-Martinez, S Derse, D Heidecker, G Cornetta, K Rein, A AF Aloia, A. L. Duffy, L. Pak, V. Lee, K. E. Sanchez-Martinez, S. Derse, D. Heidecker, G. Cornetta, K. Rein, A. TI A reporter system for replication-competent gammaretroviruses: the inGluc-MLV-DERSE assay SO GENE THERAPY LA English DT Article DE replication-competent gannmaretrovirus; gene-therapy vectors; infectivity assay ID PACKAGING CELL-LINE; RECOMBINATION EVENTS; GAUSSIA LUCIFERASE; INDICATOR GENE; RETROVIRUS; VIRUS; CULTURE; VECTOR; RETROTRANSPOSITION; EXPRESSION AB Although novel retroviral vectors for use in gene-therapy products are reducing the potential for formation of replication-competent retrovirus (RCR), it remains crucial to screen products for RCR for both research and clinical purposes. For clinical-grade gammaretrovirus-based vectors, RCR screening is achieved by an extended S+L- or marker-rescue assay, whereas standard methods for replication-competent lentivirus detection are still in development. In this report, we describe a rapid and sensitive method for replication-competent gammaretrovirus detection. We used this assay to detect three members of the gammaretrovirus family and compared the sensitivity of our assay with well-established methods for retrovirus detection, including the extended S(+)1(-) assay. Results presented here demonstrate that this assay should be useful for gene-therapy product testing. Gene Therapy (2013) 20, 169-176; doi:10.1038/gt.2012.18; published online 8 March 2012 C1 [Aloia, A. L.; Pak, V.; Lee, K. E.; Sanchez-Martinez, S.; Derse, D.; Heidecker, G.; Rein, A.] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Duffy, L.; Cornetta, K.] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN USA. [Cornetta, K.] Indiana Univ Sch Med, Dept Med, Indianapolis, IN USA. [Cornetta, K.] Indiana Univ Sch Med, Dept Microbiol & Immunol, Indianapolis, IN USA. RP Rein, A (reprint author), NCI, HIV Drug Resistance Program, 1050 Boyles St,Bldg 535,Room 211, Frederick, MD 21702 USA. EM reina@mail.nih.gov FU Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research; National Center for Research Resource (National Gene Vector Biorepository) [P40 RR024928] FX We thank Jane Mirro, Gerry Princler, Patricia Lloyd and Shawn Hill for superb technical assistance, and Vineet KewalRamani for many helpful discussions. This work was supported in part by the Intramural Research Program of the NIH, National Cancer Institute and Center for Cancer Research. Work at Indiana University is supported by the NIH, National Center for Research Resource (National Gene Vector Biorepository P40 RR024928). NR 29 TC 2 Z9 2 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD FEB PY 2013 VL 20 IS 2 BP 169 EP 176 DI 10.1038/gt.2012.18 PG 8 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 091UD UT WOS:000315074400008 PM 22402321 ER PT J AU Sommers, R Goold, SD McGlynn, EA Pearson, SD Danis, M AF Sommers, Roseanna Goold, Susan Dorr McGlynn, Elizabeth A. Pearson, Steven D. Danis, Marion TI Focus Groups Highlight That Many Patients Object To Clinicians' Focusing On Costs SO HEALTH AFFAIRS LA English DT Article ID HEALTH-CARE; PHYSICIANS; DECISIONS AB Having patients weigh costs when making medical decisions has been proposed as a way to rein in health care spending. We convened twenty-two focus groups of people with insurance to examine their willingness to discuss health care costs with clinicians and consider costs when deciding among nearly comparable clinical options. We identified the following four barriers to patients' taking cost into account: a preference for what they perceive as the best care, regardless of expense; inexperience with making trade-offs between health and money; a lack of interest in costs borne by insurers and society as a whole; and noncooperative behavior characteristic of a "commons dilemma," in which people act in their own self-interest although they recognize that by doing so, they are depleting limited resources. Surmounting these barriers will require new research in patient education, comprehensive efforts to shift public attitudes about health care costs, and training to prepare clinicians to discuss costs with their patients. C1 [Sommers, Roseanna] Yale Univ, Sch Law, New Haven, CT 06520 USA. [Goold, Susan Dorr] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Goold, Susan Dorr] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [McGlynn, Elizabeth A.] Kaiser Permanente Ctr Effectiveness & Safety Res, Oakland, CA USA. [Pearson, Steven D.] Massachusetts Gen Hosp, Inst Clin & Econ Review, Boston, MA 02114 USA. [Danis, Marion] NIH, Sect Eth & Hlth Policy, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Danis, Marion] NIH, Eth Consultat Serv, Ctr Clin, Bethesda, MD 20892 USA. RP Sommers, R (reprint author), Yale Univ, Sch Law, New Haven, CT 06520 USA. EM mdanis@nih.gov OI Goold, Susan Dorr/0000-0002-0258-9774 FU Office of the Director; Department of Bioethics at the National Institutes of Health FX An earlier version of this article was presented at the 2012 annual meeting of the American Society for Bioethics and Humanities, Washington, D. C., October 21, 2012. This project was funded by the Office of the Director and the Department of Bioethics at the National Institutes of Health. The authors thank Beverly Weidmer, Shirley Chen, Jean Logan, and Greer Donley for assistance with the survey design, data collection, and data coding. The views expressed here are those of the authors and do not necessarily reflect the policies of the American Medical Association, the National Institutes of Health, or the Department of Health and Human Services. NR 23 TC 20 Z9 20 U1 0 U2 13 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD FEB PY 2013 VL 32 IS 2 BP 338 EP 346 DI 10.1377/hlthaff.2012.0686 PG 9 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 093QQ UT WOS:000315206900019 PM 23381527 ER PT J AU Danis, M Solomon, M AF Danis, Marion Solomon, Mildred TI Providers, Payers, The Community, And Patients Are All Obliged To Get Patient Activation And Engagement Ethically Right SO HEALTH AFFAIRS LA English DT Article ID HEALTH-PROMOTION; MANAGEMENT; PROGRAM; OUTCOMES; CARE AB Active and engaged patients seek the understanding, knowledge, and skills to promote their own health. Efforts to promote such patient activation and engagement are ethically justified because they are consonant with the well-established principle of respect for persons and, as the evidence shows, because they are likely to produce better outcomes for patients. Yet patient activation and engagement can also go ethically awry if, for example, nonadherent patients are abandoned or are unduly disadvantaged by punitive policies and practices, or if the conditions for successful activation and engagement are missing. In this article we discuss the ethical issues and responsibilities that pertain to patients, clinicians, health care organizations, delivery systems, insurers, payers, and communities. For example, physicians or payers could hold patients blameworthy for not following recommendations, but we suggest that a better approach would be for providers and payers to empower patients to effectively share responsibility for defining goals and achieving them. An ethical approach to patient activation and engagement should place obligations not only on patients but also on clinicians, health care organizations and delivery systems, insurers, and communities. C1 [Danis, Marion] NIH, Sect Eth & Hlth Policy, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Solomon, Mildred] Hastings Ctr, Garrison, NY USA. RP Danis, M (reprint author), NIH, Sect Eth & Hlth Policy, Dept Bioeth, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM mdanis@nih.gov FU National Institutes of Health FX This work was funded in part by the intramural program of the National Institutes of Health. The authors thank Steve Pearson, Amina White, Peter Lichstein, and Elizabeth Gamble for their advice during the preparation of this article. The views expressed here are those of the authors and not necessarily a reflection of policies of the Department of Health and Human Services or the National Institutes of Health. NR 29 TC 5 Z9 5 U1 0 U2 8 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD FEB PY 2013 VL 32 IS 2 BP 401 EP 407 DI 10.1377/hlthaff.2012.1081 PG 7 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 093QQ UT WOS:000315206900026 PM 23381534 ER PT J AU Popovic-Kuzmanovic, D Novakovic, I Stojanovich, L Aksentijevich, I Zogovic, N Tovilovic, G Trajkovic, V AF Popovic-Kuzmanovic, Dragana Novakovic, Ivana Stojanovich, Ljudmila Aksentijevich, Ivona Zogovic, Nevena Tovilovic, Gordana Trajkovic, Vladimir TI Increased activity of interleukin-23/interleukin-17 cytokine axis in primary antiphospholipid syndrome SO IMMUNOBIOLOGY LA English DT Article DE Antiphospholipid syndrome; IL-17; IL-23; TGF-beta; Gene polymorphism ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; INFLAMMATORY-BOWEL-DISEASE; FACTOR-ALPHA LEVELS; REGULATORY T-CELLS; MULTIPLE-SCLEROSIS; TGF-BETA; RHEUMATOID-ARTHRITIS; GROWTH-FACTOR; SYNDROME APS; IN-VIVO AB The aim of the study was to investigate serum concentrations of interleukin (IL)-17 and IL-17-inducing cytokines IL-23 and transforming growth factor (TGF)-beta, as well as IL-17 single nucleotide polymorphism (SNP) rs2275913 in patients with primary antiphospholipid syndrome (PAPS). We studied fifty patients with PAPS and fifty age- and sex-matched healthy controls. The cytokine levels were measured by ELISA, while the rs2275913 SNP located in promoter region of IL-17 gene was genotyped using real-time PCR. The significantly higher levels of IL-17 (p = 0.002), IL-23 (p < 0.001) and TGF-beta (p = 0.042) were found in PAPS patients (median 13.1, 9.4, and 125.6 pg/ml, respectively) compared to the control group (6.8, 4.9 and 44.4 pg/ml). There was a significant positive correlation between concentrations of IL-17 and IL-23 (r = 0.540, p < 0.001), but not between those of IL-17 and TGF-beta. No statistically significant differences were observed in the distribution of genotypes and alleles of the IL-17 rs2275913 variants in patients with PAPS compared to healthy subjects. The blood concentrations of IL-17 did not differ in subjects with different rs2275913 genotypes or patients with or without antiphospholipid antibodies. Finally, a trend toward higher IL-17 levels (p = 0.063) and the significantly higher IL-17 concentrations (p = 0.012) were observed in PAPS patients with deep vein thrombosis and thrombocytopenia, respectively. These data demonstrate that IL-23/IL-17 axis, stimulated independently of TGF-beta increase IL-17A gene polymorphism and antiphospholipid antibody production, might contribute to vascular manifestations of PAPS. (C) 2012 Elsevier GmbH. All rights reserved. C1 [Popovic-Kuzmanovic, Dragana; Stojanovich, Ljudmila] Univ Belgrade, Med Ctr Bezanijska Kosa, Belgrade, Serbia. [Novakovic, Ivana] Univ Belgrade, Sch Med, Inst Biol, Belgrade, Serbia. [Aksentijevich, Ivona] NIAMSD, Genet & Genom Branch, NIH, Bethesda, MD 20892 USA. [Zogovic, Nevena; Tovilovic, Gordana] Univ Belgrade, Inst Biol Res, Belgrade, Serbia. [Trajkovic, Vladimir] Univ Belgrade, Sch Med, Inst Microbiol & Immunol, Belgrade 11000, Serbia. RP Trajkovic, V (reprint author), Univ Belgrade, Sch Med, Inst Microbiol & Immunol, Belgrade 11000, Serbia. EM vtrajkovic@med.bg.ac.rs OI Tovilovic-Kovacevic, Gordana/0000-0001-6150-3996; Zogovic, Nevena/0000-0003-4240-3193 FU Ministry of Education and Science of the Republic of Serbia [41025, 175091] FX The study was supported by the Ministry of Education and Science of the Republic of Serbia (Grant Number 41025 and 175091). NR 56 TC 7 Z9 7 U1 0 U2 8 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 0171-2985 J9 IMMUNOBIOLOGY JI Immunobiology PD FEB PY 2013 VL 218 IS 2 BP 186 EP 191 DI 10.1016/j.imbio.2012.03.002 PG 6 WC Immunology SC Immunology GA 095CJ UT WOS:000315312000008 PM 22559912 ER PT J AU Greenaway, HY Ng, B Price, DA Douek, DC Davenport, MP Venturi, V AF Greenaway, Hui Yee Ng, Benedict Price, David A. Douek, Daniel C. Davenport, Miles P. Venturi, Vanessa TI NKT and MAIT invariant TCR alpha sequences can be produced efficiently by VJ gene recombination SO IMMUNOBIOLOGY LA English DT Article DE Invariant T cell receptor; MAIT cell; NKT cell; Public T cell response; T cell receptor; T cell repertoire ID T-CELL-RECEPTOR; ANTIGEN RECEPTOR; GENOME SEQUENCE; CONVERGENT RECOMBINATION; MULTIPLE-SCLEROSIS; PERIPHERAL-BLOOD; CDR3 REGION; CHAIN; RECOGNITION; REPERTOIRE AB Semi-invariant T cell receptors (TCRs) found on natural killer T (NKT) and mucosal-associated invariant T (MAIT) cells are characterized by the use of invariant variable (V) and joining (J) gene combinations in the TCR alpha-chain, as well as ubiquitous canonical TCR alpha amino acid sequences that are dominant in many individuals and similar across species. That they are so prevalent indicates that they occupy an important niche within the immune system. However, these TCRs are produced by a largely random gene recombination process, which seems a risky approach for the immune system to acquire these innate-like cells. We surveyed studies reporting NKT and MAIT TCR alpha sequences for six and four different species, respectively. Although the germline nature of the canonical human and mouse NKT and mouse MAIT TCR alpha sequences and an overlap of nucleotides between the mouse MAIT-related V alpha and J alpha genes have been noted in previous studies, in this study we demonstrate that, for all reported species, the canonical TCR amino acid sequences can be encoded by at least one germline-derived nucleotide sequence. Moreover, these nucleotide sequences can utilize an overlap between the V alpha and J alpha genes in their production, which enables them to be produced by a large variety of recombination mechanisms. We investigated the role of these TCR alpha features in the production of the canonical NKT and MAIT TCRa sequences. In computer simulations of a random recombination process involving the invariant NKT and MAIT TCR alpha gene combinations for each species, the canonical NKT and MAIT TCR alpha sequences were the first or second most generated of all sequences with the CDR3 alpha length restrictions associated with NKT and MAIT cells. These results suggest that the immune machinery enables the canonical NKT and MAIT TCR alpha sequences to be produced with great efficiency through the Process of convergent recombination, ensuring their prevalence across individuals and species. (C) 2012 Elsevier GmbH. All rights reserved. C1 [Greenaway, Hui Yee; Ng, Benedict; Venturi, Vanessa] Univ New S Wales, Ctr Vasc Res, Computat Biol Grp, Kensington, NSW 2052, Australia. [Price, David A.] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff, S Glam, Wales. [Price, David A.; Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Davenport, Miles P.] Univ New S Wales, Ctr Vasc Res, Complex Syst Biol Grp, Kensington, NSW 2052, Australia. RP Davenport, MP (reprint author), Univ New S Wales, Ctr Vasc Res, Kensington, NSW 2052, Australia. EM m.davenport@unsw.edu.au; v.venturi@unsw.edu.au RI Price, David/C-7876-2013 OI Price, David/0000-0001-9416-2737 FU Australian Research Council (ARC); Australian National Health and Medical Research Council (NHMRC); Australian Postgraduate Award FX This work was supported by the Australian Research Council (ARC) and Australian National Health and Medical Research Council (NHMRC). HYG is supported by an Australian Postgraduate Award, DAP is a Medical Research Council (UK) Senior Clinical Fellow, MPD is an NHMRC Senior Research Fellow and VV is an ARC Future Fellow. NR 81 TC 25 Z9 26 U1 2 U2 11 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 0171-2985 J9 IMMUNOBIOLOGY JI Immunobiology PD FEB PY 2013 VL 218 IS 2 BP 213 EP 224 DI 10.1016/j.imbio.2012.04.003 PG 12 WC Immunology SC Immunology GA 095CJ UT WOS:000315312000011 PM 22647874 ER PT J AU Banegas, MP Yabroff, KR AF Banegas, Matthew P. Yabroff, K. Robin TI Out of Pocket, Out of Sight? An Unmeasured Component of the Burden of Cancer SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID UNITED-STATES; DRUGS; CARE; COST C1 [Banegas, Matthew P.; Yabroff, K. Robin] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. RP Banegas, MP (reprint author), NCI, Hlth Serv & Econ Branch Appl Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,Rm 4019, Bethesda, MD 20892 USA. EM banegasmp@mail.nih.gov OI Yabroff, K. Robin/0000-0003-0644-5572 NR 18 TC 5 Z9 5 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD FEB PY 2013 VL 105 IS 4 BP 252 EP 254 DI 10.1093/jnci/djs641 PG 4 WC Oncology SC Oncology GA 093PD UT WOS:000315202900004 PM 23349251 ER PT J AU Burns, KM Evans, F Pearson, GD Berul, CI Kaltman, JR AF Burns, Kristin M. Evans, Frank Pearson, Gail D. Berul, Charles I. Kaltman, Jonathan R. TI Rising Charges and Costs for Pediatric Catheter Ablation SO JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY LA English DT Article DE catheter ablation; congenital heart defects; epidemiology; health care costs; pediatrics ID CONGENITAL HEART-DISEASE; HEALTH-CARE COSTS; SUPRAVENTRICULAR TACHYCARDIA; RADIOFREQUENCY ABLATION; HOSPITAL CHARGES; INTENSIVE-CARE; YOUNG-ADULTS; CHILDREN; OUTCOMES; INFANTS AB Pediatric Ablation Charges and Costs Are Rising.Introduction: Catheter ablation has been shown to be effective for pediatric tachyarrhythmias, but the associated charges and costs have not been described in the recent era. Understanding such contemporary trends may identify ways to keep an effective therapy affordable while optimizing clinical outcomes. Methods: We used the 19972009 Kids' Inpatient Databases to examine trends in charges and costs for pediatric catheter ablation and identify determinants of temporal changes. Results: There were 7,130 discharges for catheter ablation in the sample. Mean age at ablation was 12.1 +/- 0.2 years. Patients with congenital heart disease (CHD) made up 10% of the sample. Complications occurred in 8% of discharges. Mean total charges rose 219% above inflation (from $23,798 +/- 1,072 in 1997 to $75,831 +/- 2,065 in 2009). From 2003 to 2009, costs rose 25% (from $20,459 +/- 780 in 2003 to $25,628 +/- 992 in 2009). Charges for ablation increased markedly relative to surgical procedures, but with a similar slope to other catheter-based interventions. Multivariable analysis revealed that year (P < 0.0001), payer (P = 0.0002), CHD (P < 0.0001), valvular heart disease (P = 0.0004), cardiomyopathy (P = 0.0009), hospital region (P < 0.0001), length of stay (P < 0.0001), and complications (P < 0.0001) predicted increased charges. The same factors also predicted increased costs. Charges and costs varied considerably by region, particularly for high-volume centers (P < 0.0001). Conclusions: Charges and costs for pediatric catheter ablation increased relative to other procedures and significantly outstripped inflation. Further study of complications, length of stay, and regional differences may help control rising costs while maintaining quality of care. (J Cardiovasc Electrophysiol, Vol. 24, pp. 162-169, February 2013) C1 [Burns, Kristin M.; Evans, Frank; Pearson, Gail D.; Kaltman, Jonathan R.] NHLBI, NIH, Bethesda, MD 20892 USA. [Burns, Kristin M.; Pearson, Gail D.; Berul, Charles I.; Kaltman, Jonathan R.] Childrens Natl Med Ctr, Washington, DC 20010 USA. RP Burns, KM (reprint author), NHLBI, Heart Dev & Struct Dis Branch, Div Cardiovasc Sci, NIH, 6701 Rockledge Dr,Room 8107, Bethesda, MD 20892 USA. EM kristin.burns@nih.gov NR 32 TC 3 Z9 3 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1045-3873 EI 1540-8167 J9 J CARDIOVASC ELECTR JI J. Cardiovasc. Electrophysiol. PD FEB PY 2013 VL 24 IS 2 BP 162 EP 169 DI 10.1111/j.1540-8167.2012.02446.x PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 083NF UT WOS:000314470500011 PM 23066833 ER PT J AU Okur, A Miller, BT Joo, K Lee, J Brooks, BR AF Okur, Asim Miller, Benjamin T. Joo, Keehyoung Lee, Jooyoung Brooks, Bernard R. TI Generating Reservoir Conformations for Replica Exchange through the Use of the Conformational Space Annealing Method SO JOURNAL OF CHEMICAL THEORY AND COMPUTATION LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; TRP-CAGE MINIPROTEIN; PROTEIN-STRUCTURE PREDICTION; FREE-ENERGY LANDSCAPE; CIS PEPTIDE-BONDS; EXPLICIT SOLVENT; FOLDING SIMULATIONS; MINI-PROTEIN; BETA-HAIRPIN; WATER AB Temperature replica exchange molecular dynamics (T-REM) has been successfully used to improve the conformational search for model peptides and small proteins. However, for larger and more complicated systems, the use of T-REM is computationally intensive since the complexity of the free energy landscape and number of required replicas increase with system size. Achieving convergence of systems with slow transition kinetics is often difficult. Several methods have been proposed to overcome the size and convergence speed issues of standard T-REM. One of these is the Reservoir Replica Exchange Method (R-REM), in which the conformational search and temperature equilibration are separated by exchanging with a pre-existing reservoir of structures. This approach allows the integration of computationally efficient search algorithms with replica exchange. The Conformational Space Annealing (CSA) method has been shown to be able to determine the global energy minimum of proteins efficiently and has been used in structure prediction successfully. CSA uses a genetic algorithm to generate a diverse set of conformations to determine the minimum energy structure. We combine these methods by using conformations generated by the CSA method to build a reservoir. R-REM is then used to seed the top replica with the structures from the reservoir; fast convergence at every temperature is observed. The efficiency of this method is then demonstrated with model peptides and small proteins, and significant improvement of efficiency is observed while maintaining the overall shape of the free energy landscape. C1 [Okur, Asim; Miller, Benjamin T.; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Joo, Keehyoung; Lee, Jooyoung] Korea Inst Adv Study, Sch Computat Sci, Seoul, South Korea. [Joo, Keehyoung; Lee, Jooyoung] Korea Inst Adv Study, Ctr Adv Computat, Seoul, South Korea. RP Okur, A (reprint author), NHLBI, Lab Computat Biol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM okura@mail.nih.gov OI Miller, Benjamin/0000-0003-1647-0122 FU Intramural Research Program of the NIH; NHLBI; National Research Foundation of Korea (NRF); Korea government (MEST) [20120001222] FX This research was supported by the Intramural Research Program of the NIH, NHLBI, and utilized the high-performance computational capabilities of the LoBoS (www.lobos.nih.gov) computer cluster. K.J. and J.L. are supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST; No. 20120001222). We also would like to thank Rich Pastor and Michael Shirts for useful discussions. NR 50 TC 3 Z9 3 U1 2 U2 20 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9618 J9 J CHEM THEORY COMPUT JI J. Chem. Theory Comput. PD FEB PY 2013 VL 9 IS 2 BP 1115 EP 1124 DI 10.1021/ct300996m PG 10 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 090ZK UT WOS:000315018300029 PM 23585739 ER PT J AU Craig, MT Mayne, EW Bettler, B Paulsen, O McBain, CJ AF Craig, Michael T. Mayne, Elizabeth W. Bettler, Bernhard Paulsen, Ole McBain, Chris J. TI Distinct roles of GABAB1a- and GABAB1b-containing GABAB receptors in spontaneous and evoked termination of persistent cortical activity SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID SLOW OSCILLATION; INHIBITORY INTERNEURONS; NEOCORTICAL NEURONS; PYRAMIDAL NEURONS; NETWORK ACTIVITY; CELLULAR BASIS; IN-VIVO; LAYER-I; SLEEP; RAT AB During slow-wave sleep, cortical neurons display synchronous fluctuations between periods of persistent activity (UP states') and periods of relative quiescence (DOWN states'). Such UP and DOWN states are also seen in isolated cortical slices. Recently, we reported that both spontaneous and evoked termination of UP states in slices from the rat medial entorhinal cortex (mEC) involves GABAB receptors. Here, in order to dissociate the roles of GABAB1a- and GABAB1b-containing receptors in terminating UP states, we used mEC slices from mice in which either the GABAB1a or the GABAB1b subunit had been genetically ablated. Pharmacological blockade of GABAB receptors using the antagonist CGP55845 prolonged the UP state duration in both wild-type mice and those lacking the GABAB1b subunit, but not in those lacking the GABAB1a subunit. Conversely, electrical stimulation of layer 1 could terminate an ongoing UP state in both wild-type mice and those lacking the GABAB1a subunit, but not in those lacking the GABAB1b subunit. Together with previous reports, indicating a preferential presynaptic location of GABAB1a- and postsynaptic location of GABAB1b-containing receptors, these results suggest that presynaptic GABAB receptors contribute to spontaneous DOWN state transitions, whilst postsynaptic GABAB receptors are essential for the afferent termination of the UP state. Inputs to layer 1 from other brain regions could thus provide a powerful mechanism for synchronizing DOWN state transitions across cortical areas via activation of GABAergic interneurons targeting postsynaptic GABAB receptors. C1 [Craig, Michael T.; Mayne, Elizabeth W.; McBain, Chris J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Neurobiol, NIH, Bethesda, MD 20892 USA. [Craig, Michael T.; Mayne, Elizabeth W.; Paulsen, Ole] Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 3PT, England. [Bettler, Bernhard] Univ Basel, Inst Physiol, Dept Biomed, CH-4056 Basel, Switzerland. [Paulsen, Ole] Univ Cambridge, Physiol Lab, Dept Physiol Dev & Neurosci, Cambridge CB2 3EG, England. RP McBain, CJ (reprint author), NICHD, LCSN, Sect Cellular & Synapt Neurophysiol, Porter Neurosci Ctr, Bldg 35,Rm 3C903,35 Lincoln Dr, Bethesda, MD 20892 USA. EM op210@cam.ac.uk; mcbainc@mail.nih.gov RI Craig, Michael/E-7070-2011 OI Craig, Michael/0000-0001-8481-6709 FU Wellcome Trust OXION initiative; National Institute of Child Health and Human Development (NICHD) intramural award; Wellcome Trust; British Embassy Science and Innovation Division; NIHMD/PhD Partnership Training programme; Rhodes Trust FX This work was supported by the Wellcome Trust OXION initiative (M. T. C., O.P.) and a National Institute of Child Health and Human Development (NICHD) intramural award (C.J.M.). M. T. C. held a Wellcome Trust Prize Studentship, received travel funding from the British Embassy Science and Innovation Division, and is an NIH Visiting Fellow. E. W. M. is supported by the NIHMD/PhD Partnership Training programme and by the Rhodes Trust. We are grateful to Olivia Shipton for useful discussions and help with animal breeding. NR 35 TC 15 Z9 15 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD FEB PY 2013 VL 591 IS 4 BP 835 EP 843 DI 10.1113/jphysiol.2012.248088 PG 9 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 092VB UT WOS:000315150000011 PM 23266934 ER PT J AU Berger, VW AF Berger, Vance W. TI ON THE INSUFFICIENCY OF REPORTING MASKING SO JOURNAL OF REHABILITATION MEDICINE LA English DT Letter C1 [Berger, Vance W.] NCI, Biometry Res Grp, Bethesda, MD 20892 USA. [Berger, Vance W.] UMBC, Bethesda, MD 20892 USA. RP Berger, VW (reprint author), NCI, Biometry Res Grp, Execut Plaza N,Suite 3131,6130 Execut Blvd,MSC 73, Bethesda, MD 20892 USA. EM vb78c@nih.gov NR 0 TC 3 Z9 3 U1 0 U2 0 PU FOUNDATION REHABILITATION INFORMATION PI UPPSALA PA TRADGARDSGATAN 14, UPPSALA, SE-753 09, SWEDEN SN 1650-1977 J9 J REHABIL MED JI J. Rehabil. Med. PD FEB PY 2013 VL 45 IS 2 BP 221 EP 221 DI 10.2340/16501977-1108 PG 1 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 093GM UT WOS:000315179700019 PM 23303555 ER PT J AU Stewart, R Weyant, RJ Garcia, ME Harris, T Launer, LJ Satterfield, S Sirnonsick, EM Yaffe, K Newman, AB AF Stewart, Robert Weyant, Robert J. Garcia, Melissa E. Harris, Tamara Launer, Lenore J. Satterfield, Suzanne Sirnonsick, Eleanor M. Yaffe, Kristine Newman, Anne B. TI Adverse Oral Health and Cognitive Decline: The Health, Aging and Body Composition Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE cognitive decline; cognitive impairment; periodontitis; periodontal disease; gingivitis ID ATHEROSCLEROTIC VASCULAR-DISEASE; PERIODONTAL-DISEASE; INFLAMMATORY MARKERS; ALZHEIMERS-DISEASE; CASE DEFINITIONS; DENTAL-HEALTH; TOOTH LOSS; POPULATION; DEMENTIA; RISK AB OBJECTIVES: To investigate the relationship between periodontal disease and cognitive decline. DESIGN: Analysis of a prospective cohort study. SETTING: The Health, Aging and Body Composition (Health ABC) Study. PARTICIPANTS: One thousand fifty-three participants who were administered the Modified Mini-Mental State Examination (3MS) at Year 1 (baseline) and Year 3 and had participated in a comprehensive periodontal examination at Year 2. MEASUREMENTS: The prospective association between a range of oral health parameters and cognitive function was examined. Decline in 3MS score from Year 3 to 5 was investigated in 947 (89.9%) participants. Covariates included age, sex, education, race, cardiovascular disease and risk, and depressive symptoms. RESULTS: Most indicators of adverse oral health at Year 2 were associated with cognitive impairment based on averaged 3MS scores less than 80 for Years 1 and 3, but education and race substantially confounded these associations. Higher gingival index, a measure of gingival inflammation, at Year 2 remained independently associated with this definition of cognitive impairment and, in fully adjusted analyses, was also an independent predictor of a more-than-5-point cognitive decline from Year 3 to S. CONCLUSION: Periodontitis may be a risk factor for cognitive decline. Gingivitis is reversible, and periodontitis to some degree is preventable and controllable when manifest. Therefore, further research is needed to clarify potential underlying mechanisms and oral health interventions that might ameliorate cognitive decline. J Am Geriatr Soc 61:177-184, 2013. C1 [Stewart, Robert] Kings Coll London, London Inst Psychiat, London WC2R 2LS, England. [Weyant, Robert J.] Univ Pittsburgh, Sch Dent Med, Dept Dent Publ Hlth, Pittsburgh, PA USA. [Garcia, Melissa E.; Harris, Tamara; Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Satterfield, Suzanne] Univ Tennessee, Dept Prevent Med, Knoxville, TN USA. [Sirnonsick, Eleanor M.] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Ctr Aging & Populat Hlth, Pittsburgh, PA USA. RP Stewart, R (reprint author), Inst Psychiat, Epidemiol Sect, Box 60,De Crespigny Pk, London SE5 8AF, England. EM r.stewart@iop.kcl.ac.uk RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Stewart, Robert/0000-0002-4435-6397 FU Wellcome Trust; National Institute for Health Research (NIHR) Biomedical Research Centre; Dementia Biomedical Research Unit at South London; Maudsley NHS Foundation Trust; King's College London; Pfizer; Eisai; Lunbeck; JJ; Roche; National Institute for Drug Abuse; National Institute for Dental and Craniofacial Research; Health Resources and Services Administration; University of Padua; University of Verona; Imperial College London; U.S. Public Health Service [N01-AG-6-2103, 1R01AG028050, N01-AG-6-2106]; NIH FX Robert Stewart has received research funding in the last 2 years from the Wellcome Trust and from the National Institute for Health Research (NIHR) Biomedical Research Centre and Dementia Biomedical Research Unit at South London and Maudsley NHS Foundation Trust and King's College London, and has received research support, travel support, and honoraria from Pfizer, Eisai, Lunbeck, J&J, and Roche. Robert Weyant receives an honorarium as Editor-in-Chief of the Journal of Public Health Dentistry and has received research funding from the National Institute for Drug Abuse, the National Institute for Dental and Craniofacial Research, and the Health Resources and Services Administration. Tamara Harris is a U.S. government employee and declares that all funding sources have been from U.S. federal government and academic centers, that travel support has been received from University of Padua, University of Verona, and Imperial College London, spouse consultancy fees from Imperial College London and children's stock holding in Web MD. Suzanne Satterfield declares that the Memphis Clinical Site for Health ABC received support from U.S. Public Health Service Contracts N01-AG-6-2103, 1R01AG028050, and N01-AG-6-2106. Eleanor M. Simonsick is a full-time employee of the U.S. federal government with all funding from NIH and has no financial relationships to declare. Kristine Yaffe has served as a consultant to Novartis and serves on data and safety monitoring boards for the National Institute of Mental Health, Pfizer, and Medivation as well as the National Institute on Aging/Beeson Scientific Advisory Committee. Anne B. Newman has a consultancy with Merck in 2008. NR 45 TC 17 Z9 18 U1 2 U2 29 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD FEB PY 2013 VL 61 IS 2 BP 177 EP 184 DI 10.1111/jgs.12094 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 094HY UT WOS:000315254800001 PM 23405916 ER PT J AU Chang, M Saczynski, JS Snaedal, J Bjornsson, S Einarsson, B Garcia, M Aspelund, T Siggeirsdottir, K Gudnason, V Launer, LJ Harris, TB Jonsson, PV AF Chang, Milan Saczynski, Jane S. Snaedal, Jon Bjornsson, Sigurbjorn Einarsson, Bjorn Garcia, Melissa Aspelund, Thor Siggeirsdottir, Kristine Gudnason, Vilrnundur Launer, Lenore J. Harris, Tamara B. Jonsson, Palmi V. TI Midlife Physical Activity Preserves Lower Extremity Function in Older Adults: Age Gene/Environment Susceptibility-Reykjavik Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE midlife physical activity; mobility; aging; cognitive function; lower extremity function ID INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW; CORONARY-HEART-DISEASE; BODY-COMPOSITION; COGNITIVE IMPAIRMENT; EXECUTIVE FUNCTION; MUSCLE STRENGTH; GAIT SPEED; DSM-IV; PERFORMANCE; DISABILITY AB OBJECTIVES: To examine the long-term association between midlife physical activity (PA) and lower extremity function (LEF) in late life. DESIGN: Longitudinal study with an average of 25 years of follow-up. SETTING: Community-dwelling old population in Reykjavik, Iceland. PARTICIPANTS: Four thousand seven hundred fifty-three community-dwelling men and women (mean age 76 +/- 6) in Reykjavik, Iceland. MEASUREMENTS: On the basis of weekly hours of regular PA reported at the midlife examination, participants were classified as active or inactive. Measures of LEF in late life were gait speed on a 6-m walk, Timed Up and Go (TUG), and knee extension (KE) strength tests. Linear regression analysis was used to examine the association. RESULTS: Participants who were active in midlife had significantly better LEF (faster gait speed, beta = 0.50, P <= .001; faster TUG time, beta = -0.53 P <= .001; stronger KE strength, beta = 1.3, P <= .001) in late life than those who were not active in midlife after adjusting for sociodemographic and cardiovascular risk factors. After adjustment for cognitive function in late life (speed of processing, memory, and executive function), participants who were active in midlife had significantly faster gait speed (beta = 0.04, P <= .001), faster TUG time (beta = -0.34, P <= .001), and greater KE strength (beta = 0.87, P <= .001) in old age than those who were not active in midlife. CONCLUSION: Regular PA in midlife is associated with better performance of LEF in later life, even after controlling for late-life cognitive function. J Am Geriatr Soc 61:237-242, 2013. C1 [Chang, Milan; Snaedal, Jon; Bjornsson, Sigurbjorn; Einarsson, Bjorn; Gudnason, Vilrnundur; Jonsson, Palmi V.] Landspitali Univ Hosp, Geriatr Res Ctr, IS-101 Reykjavik, Iceland. [Saczynski, Jane S.] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA. [Saczynski, Jane S.] Univ Massachusetts, Sch Med, Meyers Primary Care Inst, Worcester, MA USA. [Snaedal, Jon; Jonsson, Palmi V.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Aspelund, Thor] Univ Iceland, Fac Sci, Reykjavik, Iceland. [Aspelund, Thor; Siggeirsdottir, Kristine; Gudnason, Vilrnundur] Iceland Heart Assoc, Kopavogur, Iceland. [Garcia, Melissa; Launer, Lenore J.; Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Chang, M (reprint author), Landspitali Univ Hosp, Geriatr Res Ctr, Aegisgata 26, IS-101 Reykjavik, Iceland. EM changmilan@gmail.com RI Aspelund, Thor/C-5983-2008; Gudnason, Vilmundur/K-6885-2015 OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084 FU Intramural Research Program of the National Institutes of Health; National Institute on Aging [N01-AG-12100]; Icelandic Heart Association; Landspitali University Hospital; Icelandic Parliament FX All authors declare no financial interest/conflict of interest. This study was funded in part by the Intramural Research Program of the National Institutes of Health, the National Institute on Aging (N01-AG-12100), the Icelandic Heart Association, Landspitali University Hospital, and the Icelandic Parliament. NR 30 TC 6 Z9 6 U1 4 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD FEB PY 2013 VL 61 IS 2 BP 237 EP 242 DI 10.1111/jgs.12077 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 094HY UT WOS:000315254800009 PM 23320618 ER PT J AU Leishear, K Studenski, SA Ferrucci, L de Rekeneire, N Kritchevsky, SB Vinik, AI Hogervorst, E Harris, TB Newman, AB Strotmeyer, ES AF Leishear, Kira Studenski, Stephanie A. Ferrucci, Luigi de Rekeneire, Nathalie Kritchevsky, Stephen B. Vinik, Aaron I. Hogervorst, Eva Harris, Tamara B. Newman, Anne B. Strotmeyer, Elsa S. TI VITAMIN B-12 AND PERIPHERAL NERVE FUNCTION IN ELDERLY ADULTS: "FUNCTIONAL" B-12 DEFICIENCY AS A CONFOUNDING VARIABLE RESPONSE SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Letter C1 [Leishear, Kira; Newman, Anne B.; Strotmeyer, Elsa S.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Leishear, Kira] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD USA. [Studenski, Stephanie A.; Newman, Anne B.] Univ Pittsburgh, Sch Med, Dept Med, Div Geriatr Med, Pittsburgh, PA 15213 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. [de Rekeneire, Nathalie] Yale Univ, Sch Med, Sect Geriatr, New Haven, CT USA. [Kritchevsky, Stephen B.] Wake Forest Univ, Bowman Gray Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Vinik, Aaron I.] Eastern Virginia Med Sch, Div Endocrinol & Metab, Dept Med, Strelitz Diabet Ctr, Norfolk, VA 23501 USA. [Hogervorst, Eva] Univ Loughborough, Dept Human Sci, Loughborough, Leics, England. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. RP Leishear, K (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. RI Newman, Anne/C-6408-2013; Strotmeyer, Elsa/F-3015-2014 OI Newman, Anne/0000-0002-0106-1150; FU NIA NIH HHS [R01 AG028050, N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, P30 AG024827, P30-AG024827, R01-AG-028050, T32 AG000181, T32-AG-000181]; NINR NIH HHS [R01 NR012459, R01-NR012459] NR 4 TC 0 Z9 0 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD FEB PY 2013 VL 61 IS 2 BP 312 EP 313 PG 2 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 094HY UT WOS:000315254800037 PM 23405939 ER PT J AU Kim, HJ Hagan, M Butman, JA Baggenstos, M Brewer, C Zalewski, C Linehan, WM Lonser, RR AF Kim, H. Jeffrey Hagan, Marygrace Butman, John A. Baggenstos, Martin Brewer, Carmen Zalewski, Christopher Linehan, W. Marston Lonser, Russell R. TI Surgical resection of endolymphatic sac tumors in von Hippel-Lindau disease: Findings, results, and indications SO LARYNGOSCOPE LA English DT Article DE Endolymphatic sac tumor; von Hippel-Lindau; hearing loss; outcome; vertigo; surgery ID MORBID HEARING-LOSS; COCHLEAR IMPLANTATION; TEMPORAL BONE; ADENOCARCINOMA; ORIGIN; GENE AB Objectives/Hypothesis: To define the surgical treatment and outcomes of von Hippel-Lindau (VHL) disease-associated endolymphatic sac tumors (ELSTs), we analyzed consecutive VHL patients who underwent ELST resection. Study Design: Retrospective investigation of consecutive VHL patients who underwent resection of ELSTs at a clinical research center between 1999 and 2010. Methods: Analysis of serial clinical examinations, audiograms, imaging studies, and operative findings were analyzed. Results: Thirty-one consecutive patients with ELSTs (15 males, 16 females) underwent resection of 33 tumors (mean follow-up, 49.9 +/- 48.0 months; range, 1.0116 months). One patient had bilateral ELST resections and one patient underwent reoperation for recurrence. Mean age at surgery was 38.2 +/- 10.2 years (range, 1267 years). Whereas 29 ears (88%) had direct radiographic evidence of an ELST, four ears (12%) did not. Mean tumor size was 1.3 +/- 1.1 cm (range, 0.25.2 cm). Whereas two patients (two ears, 6%) were asymptomatic, 29 patients (31 ears, 94% of ears) had associated audiovestibular symptoms, including sensorineural hearing loss (28 ears, 84%), tinnitus (24 ears,73%), and vertigo (21 patients, 68%). Postoperatively, hearing was stabilized (27) or improved (three) in 97% of 31 ears. Complete tumor resection was achieved in 30 ears (91% of 33 ears). Complications included cerebrospinal fluid leak in two ears (6%) and transient lower cranial nerve palsy in one ear (3%). Conclusions: Surgical resection of ELSTs can be performed with hearing preservation and a reduction in audiovestibular dysfunction. Early surgical resection can prevent or decrease disabling audiovestibular symptoms, enhance the opportunity for complete resection, and preserve hearing. Laryngoscope, 2012 C1 [Kim, H. Jeffrey; Brewer, Carmen; Zalewski, Christopher] Natl Inst Deafness & Other Commun Disorders, Off Clin Director, NIH, Bethesda, MD USA. [Kim, H. Jeffrey; Brewer, Carmen; Zalewski, Christopher] Natl Inst Deafness & Other Commun Disorders, Otolaryngol Branch, NIH, Bethesda, MD USA. [Hagan, Marygrace; Baggenstos, Martin; Lonser, Russell R.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Butman, John A.] NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. [Linehan, W. Marston] NIH, Urol Oncol Branch, Natl Canc Ctr, Bethesda, MD 20892 USA. [Kim, H. Jeffrey] Georgetown Univ, Med Ctr, Dept Otolaryngol Head & Neck Surg, Washington, DC 20007 USA. RP Kim, HJ (reprint author), Georgetown Univ, Med Ctr, Dept Otolaryngol Head & Neck Surg, 3800 Reservoir Rd NW, Washington, DC 20007 USA. EM hk7@georgetown.edu RI Butman, John/J-2780-2013 OI Butman, John/0000-0002-1547-9195 FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke; National Institute on Deafness and Communication Disorders at the National Institutes of Health FX This work was funded by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke and National Institute on Deafness and Communication Disorders at the National Institutes of Health. NR 26 TC 8 Z9 9 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD FEB PY 2013 VL 123 IS 2 BP 477 EP 483 DI 10.1002/lary.23646 PG 7 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 090NH UT WOS:000314985400042 PM 23070752 ER PT J AU Blouin, AM Han, SH Pearce, AM Cheng, KL Lee, JJ Johnson, AW Wang, CS During, MJ Holland, PC Shaham, Y Baraban, JM Reti, IM AF Blouin, Ashley M. Han, Sungho Pearce, Anne M. Cheng, KaiLun Lee, JongAh J. Johnson, Alexander W. Wang, Chuansong During, Matthew J. Holland, Peter C. Shaham, Yavin Baraban, Jay M. Reti, Irving M. TI Role of medial prefrontal cortex Narp in the extinction of morphine conditioned place preference SO LEARNING & MEMORY LA English DT Article ID COCAINE-SEEKING BEHAVIOR; AMPA RECEPTORS; NUCLEUS-ACCUMBENS; NEURONAL-ACTIVITY; PKM-ZETA; EXCITATORY SYNAPSES; INFRALIMBIC CORTEX; FEAR EXTINCTION; AMYGDALA; EXPRESSION AB Narp knockout (KO) mice demonstrate an impaired extinction of morphine conditioned place preference (CPP). Because the medial prefrontal cortex (mPFC) has been implicated in extinction learning, we tested whether Narp cells in this region play a role in the extinction of morphine CPP. We found that intracranial injections of adenoassociated virus (AAV) expressing wild-type (WT) Narp into the mPFC of Narp KO mice rescued the extinction and the injection of AAV expressing a dominant negative form of Narp (NarpN) into the mPFC of WT mice impaired the extinction of morphine CPP. These findings suggest that Narp in the mPFC mediates the extinction of morphine CPP. C1 [Blouin, Ashley M.; Han, Sungho; Cheng, KaiLun; Lee, JongAh J.; Baraban, Jay M.; Reti, Irving M.] Johns Hopkins Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Pearce, Anne M.; Johnson, Alexander W.; Holland, Peter C.] Johns Hopkins Univ, Dept Psychol & Brain Sci, Baltimore, MD 21218 USA. [Wang, Chuansong; During, Matthew J.] Ohio State Univ, Dept Mol Virol Immunol & Mol Genet, Columbus, OH 43210 USA. [Holland, Peter C.; Baraban, Jay M.; Reti, Irving M.] Johns Hopkins Sch Med, Solomon Snyder Dept Neurosci, Baltimore, MD 21205 USA. [Shaham, Yavin] NIDA, NIH, Intramural Res Program, Baltimore, MD 21224 USA. RP Blouin, AM (reprint author), Johns Hopkins Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. EM ablouin1@jhmi.edu RI shaham, yavin/G-1306-2014; OI Baraban, Jay/0000-0002-8165-2638 FU NIDA [5R25DA21630-3]; [RO1 DA016303] FX We thank Zhi Li and Edward Retzbach for technical assistance. The Narp antibody was provided by Dr. Paul Worley (Solomon Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD). This work was funded by RO1 DA016303 and NIDA 5R25DA21630-3. The write-up of this manuscript was also supported in part by funds to the intramural research program of NIDA. NR 41 TC 6 Z9 7 U1 1 U2 4 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1072-0502 J9 LEARN MEMORY JI Learn. Mem. PD FEB PY 2013 VL 20 IS 2 BP 75 EP 79 DI 10.1101/lm.028621.112 PG 5 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 093NL UT WOS:000315198500002 PM 23322555 ER PT J AU Clemens, JQ Clauw, D Kreder, K Kusek, J Lai, H Rodriguez, L Williams, D AF Clemens, J. Quentin Clauw, Daniel Kreder, Karl Kusek, John Lai, Henry Rodriguez, Larissa Williams, David TI COMPARISON OF BASELINE UROLOGIC SYMPTOMS IN MEN AND WOMEN IN THE MULTIDISCIPLINARY APPROACH TO THE STUDY OF CHRONIC PELVIC PAIN (MAPP) RESEARCH COHORT SO NEUROUROLOGY AND URODYNAMICS LA English DT Meeting Abstract CT Winter Meeting of the Society-for-Urodynamics-and-Female-Urology (SUFU) CY FEB 26-MAR 02, 2013 CL Las Vegas, NV SP Soc Urodynam & Female Urol (SUFU) C1 [Clemens, J. Quentin; Clauw, Daniel; Williams, David] Univ Michigan, Med Ctr, Ann Arbor, MI USA. [Kreder, Karl] Univ Iowa, Iowa City, IA USA. [Kusek, John] NIDDK, Bethesda, MD USA. [Lai, Henry] Washington Univ, St Louis, MO USA. [Rodriguez, Larissa] Univ Calif Los Angeles, Los Angeles, CA 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 0733-2467 J9 NEUROUROL URODYNAM JI Neurourol. Urodyn. PD FEB PY 2013 VL 32 IS 2 BP 145 EP 145 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 093WG UT WOS:000315223200088 ER PT J AU Miller, PE Lazarus, P Lesko, SM Cross, AJ Sinha, R Laio, J Zhu, J Harper, G Muscat, JE Hartman, TJ AF Miller, Paige E. Lazarus, Philip Lesko, Samuel M. Cross, Amanda J. Sinha, Rashmi Laio, Jason Zhu, Jay Harper, Gregory Muscat, Joshua E. Hartman, Terryl J. TI Meat-Related Compounds and Colorectal Cancer Risk by Anatomical Subsite SO NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL LA English DT Article ID FOOD FREQUENCY QUESTIONNAIRE; HETEROCYCLIC AMINE EXPOSURE; RED MEAT; DIETARY PATTERNS; DISTAL COLON; PROSPECTIVE COHORT; DOSE-RESPONSE; CONSUMPTION; ADENOMA; POLYMORPHISMS AB Since meat may be involved in the etiology of colorectal cancer, associations between meat-related compounds were examined to elucidate underlying mechanisms in a population-based case-control study. Participants (989 cases/1,033 healthy controls) completed a food frequency questionnaire with a meat-specific module. Multivariable logistic regression was used to examine associations between meat variables and colorectal cancer; polytomous logistic regression was used for subsite-specific analyses. The following significant positive associations were observed for meat-related compounds: 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx) and colorectal, distal colon, and rectal tumors; 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and colorectal and colon cancer tumors; nitrites/nitrates and proximal colon cancer; 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and rectal cancer; and benzo[a]pyrene and rectal cancer (P-trends < 0.05). For analyses by meat type, cooking method, and doneness preference, positive associations between red processed meat and proximal colon cancer and pan-fried red meat and colorectal cancer were found (P-trends < 0.05). Inverse associations were observed between unprocessed poultry and colorectal, colon, proximal colon, and rectal tumors; grilled/barbequed poultry and proximal colon cancer; and well-done/charred poultry and colorectal, colon, and proximal colon tumors (P-trends < 0.05). HCAs, PAHs, nitrites, and nitrates may be involved in colorectal cancer etiology. Further examination into the unexpected inverse associations between poultry and colorectal cancer is warranted. C1 [Miller, Paige E.] NCI, Canc Prevent Fellowship Program, NIH, Bethesda, MD 20892 USA. [Lazarus, Philip] Penn State Coll Med, Dept Pharmacol, Hershey, PA USA. [Lazarus, Philip; Laio, Jason; Zhu, Jay; Muscat, Joshua E.] Penn State Coll Med, Dept Publ Hlth Sci, Hershey, PA USA. [Lesko, Samuel M.; Laio, Jason; Harper, Gregory; Muscat, Joshua E.; Hartman, Terryl J.] Penn State Canc Inst, Canc Prevent & Control Program, Hershey, PA USA. [Lesko, Samuel M.] Northeast Reg Canc Inst, Scranton, PA USA. [Cross, Amanda J.; Sinha, Rashmi] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Harper, Gregory] Lehigh Valley Hlth Network, Morgan Canc Ctr, Allentown, PA USA. [Hartman, Terryl J.] Penn State Univ, Dept Nutr Sci, University Pk, PA 16802 USA. RP Miller, PE (reprint author), Exponent Inc, Ctr Epidemiol Biostat & Computat Biol, 525 W Monroe St,Suite 1050, Chicago, IL 60661 USA. EM pmiller@exponent.com RI Sinha, Rashmi/G-7446-2015 OI Sinha, Rashmi/0000-0002-2466-7462 FU Pennsylvania Department of Health [4100038714] FX This research was supported by the Pennsylvania Department of Health Grant #4100038714. We thank the dedicated staff of this study: Karen Ryzcak [Northeast Regional Cancer Institute (NRCI)], Gladys Escobar [Penn State Cancer Institute (PSCI)], Tammy Ryder (PSCI), Christine Christ (PSCI), Anne Greetcher (PSCI), Wendy Stanton (NRCI), Kimberlee Welsh (NRCI), PaulineKozik (NRCI), Margaret Fox-Dougherty (NRCI), Nancy Ziegler (NRCI), Stefanie Crouse (NRCI), Judith Rose (NRCI), Nicholas Kelly (NRCI), and Corey Lazarus (PSCI). We also would like to acknowledge the many residents of Pennsylvania for their generous participation in our study. NR 64 TC 23 Z9 26 U1 2 U2 37 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0163-5581 EI 1532-7914 J9 NUTR CANCER JI Nutr. Cancer PD FEB 1 PY 2013 VL 65 IS 2 BP 202 EP 226 DI 10.1080/01635581.2013.756534 PG 25 WC Oncology; Nutrition & Dietetics SC Oncology; Nutrition & Dietetics GA 095RM UT WOS:000315352200006 PM 23441608 ER PT J AU Grigoriu, S Bond, R Cossio, P Chen, JA Ly, N Hummer, G Page, R Cyert, MS Peti, W AF Grigoriu, Simina Bond, Rachel Cossio, Pilar Chen, Jennifer A. Ly, Nina Hummer, Gerhard Page, Rebecca Cyert, Martha S. Peti, Wolfgang TI The Molecular Mechanism of Substrate Engagement and Immunosuppressant Inhibition of Calcineurin SO PLOS BIOLOGY LA English DT Article ID CYCLOPHILIN-CYCLOSPORINE-A; PHOSPHATASE-ACTIVITY; PROTEIN PHOSPHATASE; TRANSCRIPTION FACTOR; CRYSTAL-STRUCTURE; IN-VIVO; COMPLEX; AFFINITY; DYNAMICS; DEPHOSPHORYLATION AB Ser/thr phosphatases dephosphorylate their targets with high specificity, yet the structural and sequence determinants of phosphosite recognition are poorly understood. Calcineurin (CN) is a conserved Ca2+/calmodulin-dependent ser/thr phosphatase and the target of immunosuppressants, FK506 and cyclosporin A (CSA). To investigate CN substrate recognition we used X-ray crystallography, biochemistry, modeling, and in vivo experiments to study A238L, a viral protein inhibitor of CN. We show that A238L competitively inhibits CN by occupying a critical substrate recognition site, while leaving the catalytic center fully accessible. Critically, the 1.7 angstrom structure of the A238L-CN complex reveals how CN recognizes residues in A238L that are analogous to a substrate motif, "LxVP." The structure enabled modeling of a peptide substrate bound to CN, which predicts substrate interactions beyond the catalytic center. Finally, this study establishes that "LxVP" sequences and immunosuppressants bind to the identical site on CN. Thus, FK506, CSA, and A238L all prevent "LxVP"-mediated substrate recognition by CN, highlighting the importance of this interaction for substrate dephosphorylation. Collectively, this work presents the first integrated structural model for substrate selection and dephosphorylation by CN and lays the groundwork for structure-based development of new CN inhibitors. C1 [Grigoriu, Simina; Peti, Wolfgang] Brown Univ, Dept Mol Pharmacol Physiol & Biotechnol, Providence, RI 02912 USA. [Grigoriu, Simina; Page, Rebecca] Brown Univ, Dept Mol Biol Cell Biol & Biochem, Providence, RI 02912 USA. [Bond, Rachel; Chen, Jennifer A.; Ly, Nina; Cyert, Martha S.] Stanford Univ, Dept Biol, Stanford, CA 94305 USA. [Cossio, Pilar; Hummer, Gerhard] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Peti, Wolfgang] Brown Univ, Dept Chem, Providence, RI 02912 USA. RP Grigoriu, S (reprint author), Brown Univ, Dept Mol Pharmacol Physiol & Biotechnol, Providence, RI 02912 USA. EM mcyert@stanford.edu; wolfgang_peti@brown.edu RI Peti, Wolfgang/L-3492-2014; Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X FU National Institute of Neurological Disorders and Stroke [R01NS056128]; National Institute of General Medicine and an American Cancer Society [R01GM098482, RSG-08-067-01-LIB]; National Institute of General Medicine [R01GM48729]; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Departmental NIH [T32-GM007276]; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-98CH10886] FX The work was supported by grant R01NS056128 from the National Institute of Neurological Disorders and Stroke to W.P., grant R01GM098482 from the National Institute of General Medicine and an American Cancer Society research scholar grant RSG-08-067-01-LIB to R.P., and grant R01GM48729 from the National Institute of General Medicine to M.S. C.P.C. and G.H. were supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. R.B. was funded by Departmental NIH training grant T32-GM007276. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; The authors thank Dr. M. Allaire (National Synchrotron Light Source, NSLS) for his support at NSLS beamline X25. Use of the NSLS at Brookhaven National Laboratory was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under contract no. DE-AC02-98CH10886. MD calculations were performed on the Biowulf computing cluster at NIH. The authors thank Dr. Linda Dixon for providing information and materials relating to A238L and Dan Herschlag, Jagoree Roy, and Evan Guiney for helpful discussion and reading of the manuscript. We thank Dara Dowlatshahi for technical advice and Dr. V. Kaila (National Institutes of Health) for his support with the quantum mechanical calculations of the model substrate. NR 55 TC 36 Z9 37 U1 4 U2 26 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1545-7885 J9 PLOS BIOL JI PLoS. Biol. PD FEB PY 2013 VL 11 IS 2 AR e1001492 DI 10.1371/journal.pbio.1001492 PG 13 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 095SR UT WOS:000315355500016 PM 23468591 ER PT J AU Guo, MQ Huang, BX AF Guo, Mingquan Huang, Bill X. TI Integration of phosphoproteomic, chemical, and biological strategies for the functional analysis of targeted protein phosphorylation SO PROTEOMICS LA English DT Review DE Chemical cross-linking; Forward functional analysis; HDX-MS; Kinase substrates; Phosphoproteomics; Reverse functional analysis; Technology ID EXCHANGE MASS-SPECTROMETRY; PLECKSTRIN HOMOLOGY DOMAIN; MAMMALIAN 2-HYBRID ASSAYS; C-TERMINAL DOMAIN; CONFORMATIONAL-CHANGES; TYROSINE KINASE; CROSS-LINKING; QUANTITATIVE PHOSPHOPROTEOMICS; SIGNAL-TRANSDUCTION; IN-VIVO AB Reversible phosphorylation, tightly controlled by protein kinases and phosphatases, plays a central role in mediating biological processes, such as proteinprotein interactions, subcellular translocation, and activation of cellular enzymes. MS-based phosphoproteomics has now allowed the detection and quantification of tens of thousands of phosphorylation sites from a typical biological sample in a single experiment, which has posed new challenges in functional analysis of each and every phosphorylation site on specific signaling phosphoproteins of interest. In this article, we review recent advances in the functional analysis of targeted phosphorylation carried out by various chemical and biological approaches in combination with the MS-based phosphoproteomics. This review focuses on three types of strategies, including forward functional analysis, defined for the result-driven phosphoproteomics efforts in determining the substrates of a specific protein kinase; reverse functional analysis, defined for tracking the kinase(s) for specific phosphosite(s) derived from the discovery-driven phosphoproteomics efforts; and MS-based analysis on the structurefunction relationship of phosphoproteins. It is expected that this review will provide a state-of-the-art overview of functional analysis of site-specific phosphorylation and explore new perspectives and outline future challenges. C1 [Guo, Mingquan] Chinese Acad Sci, Wuhan Bot Garden, Key Lab Plant Germplasm Enhancement & Specialty A, Wuhan 430074, Peoples R China. [Huang, Bill X.] NIAAA, Lab Mol Signaling, NIH, Bethesda, MD USA. RP Guo, MQ (reprint author), Chinese Acad Sci, Wuhan Bot Garden, Key Lab Plant Germplasm Enhancement & Specialty A, Wuhan 430074, Peoples R China. EM zhaoguo2000@yahoo.com; bhuang@mail.nih.gov NR 108 TC 16 Z9 17 U1 3 U2 63 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1615-9853 EI 1615-9861 J9 PROTEOMICS JI Proteomics PD FEB PY 2013 VL 13 IS 3-4 SI SI BP 424 EP 437 DI 10.1002/pmic.201200274 PG 14 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 092DO UT WOS:000315099400003 PM 23125184 ER PT J AU Linehan, WM Ricketts, CJ AF Linehan, W. Marston Ricketts, Christopher J. TI The metabolic basis of kidney cancer SO SEMINARS IN CANCER BIOLOGY LA English DT Review DE Cancer metabolism; Renal cell carcinoma (RCC); Hereditary kidney cancer; Cancer metabolism targeted therapy; Warburg effect ID RENAL-CELL CARCINOMA; HIPPEL-LINDAU-DISEASE; HOGG-DUBE-SYNDROME; TUMOR-SUPPRESSOR PROTEIN; PARENCHYMAL SPARING SURGERY; TUBEROUS SCLEROSIS COMPLEX; TYROSINE KINASE DOMAIN; HEREDITARY LEIOMYOMATOSIS; FUMARATE-HYDRATASE; CHROMOSOME-TRANSLOCATION AB Kidney cancer is not a single disease; it is made up of a number of different types of cancer that occur in the kidney. Each of these different types of kidney cancer can have a different histology, have a different clinical course, can respond differently to therapy and is caused by a different gene. Kidney cancer is essentially a metabolic disease; each of the known genes for kidney cancer, VHL, MET, FLCN, TSC1, TSC2, TFE3, TFEB, MITF, fumarate hydratase (FH), succinate dehydrogenase B (SDHB), succinate dehydrogenase D (SDHD), and PTEN genes is involved in the cells ability to sense oxygen, iron, nutrients or energy. Understanding the metabolic basis of kidney cancer will hopefully provide the foundation for the development of effective forms of therapy for this disease. Published by Elsevier Ltd. C1 [Linehan, W. Marston; Ricketts, Christopher J.] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, 10 Ctr Dr,MSC 1107,CRC Room 1-5940, Bethesda, MD 20892 USA. EM WML@nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 94 TC 26 Z9 29 U1 2 U2 16 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-579X J9 SEMIN CANCER BIOL JI Semin. Cancer Biol. PD FEB PY 2013 VL 23 IS 1 BP 46 EP 55 DI 10.1016/j.semcancer.2012.06.002 PG 10 WC Oncology SC Oncology GA 094CI UT WOS:000315240200007 PM 22705279 ER PT J AU Mckew, JC Pilon, AM AF McKew, John C. Pilon, Andre M. TI NIH TRND program: successes in preclinical therapeutic development SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Editorial Material C1 [McKew, John C.; Pilon, Andre M.] NIH, Therapeut Rare & Neglected Dis TRND Program, NCATS, Rockville, MD 20850 USA. RP Mckew, JC (reprint author), NIH, Therapeut Rare & Neglected Dis TRND Program, NCATS, 9800 Med Ctr Dr,Bldg B,Room B3005, Rockville, MD 20850 USA. EM john.mckew@nih.gov FU Intramural NIH HHS [ZII HG200364-03] NR 7 TC 5 Z9 5 U1 2 U2 8 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD FEB PY 2013 VL 34 IS 2 BP 87 EP 89 DI 10.1016/j.tips.2012.10.001 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 096UX UT WOS:000315431200002 PM 23174531 ER PT J AU Wolff, S Ebihara, H Groseth, A AF Wolff, Svenja Ebihara, Hideki Groseth, Allison TI Arenavirus Budding: A Common Pathway with Mechanistic Differences SO VIRUSES-BASEL LA English DT Review DE arenavirus; budding; ESCRT pathway; matrix protein; nucleoprotein; late domain ID VIRUS-LIKE PARTICLES; LYMPHOCYTIC CHORIOMENINGITIS VIRUS; MATRIX PROTEIN-Z; HEMORRHAGIC-FEVER ARENAVIRUSES; I INTERFERON INDUCTION; PROLINE-RICH MOTIF; ROUS-SARCOMA-VIRUS; FINGER Z-PROTEIN; LASSA-VIRUS; SIGNAL PEPTIDE AB The Arenaviridae is a diverse and growing family of viruses that includes several agents responsible for important human diseases. Despite the importance of this family for public health, particularly in Africa and South America, much of its biology remains poorly understood. However, in recent years significant progress has been made in this regard, particularly relating to the formation and release of new enveloped virions, which is an essential step in the viral lifecycle. While this process is mediated chiefly by the viral matrix protein Z, recent evidence suggests that for some viruses the nucleoprotein (NP) is also required to enhance the budding process. Here we highlight and compare the distinct budding mechanisms of different arenaviruses, concentrating on the role of the matrix protein Z, its known late domain sequences, and the involvement of cellular endosomal sorting complex required for transport (ESCRT) pathway components. Finally we address the recently described roles for the nucleoprotein NP in budding and ribonucleoprotein complex (RNP) incorporation, as well as discussing possible mechanisms related to its involvement. C1 [Wolff, Svenja] Univ Marburg, Inst Virol, D-35043 Marburg, Germany. [Ebihara, Hideki; Groseth, Allison] NIAID, Lab Virol, Div Intramural Res, NIH, Hamilton, MT 59840 USA. RP Groseth, A (reprint author), NIAID, Lab Virol, Div Intramural Res, NIH, Hamilton, MT 59840 USA. EM wolffs@staff.uni-marburg.de; ebiharah@niaid.nih.gov; allison.groseth@nih.gov FU Jurgen Manchot Stiftung; Canadian Institutes of Health Research; Philipps Universitat Marburg; Division of Intramural Research, NIAID, NIH FX The authors are very grateful to Stephen Becker (Philipps Universitat Marburg) for helpful discussion and Olga Dolnik (Philipps Universitat Marburg) for conceptual assistance with some of the figures. This work was funded by grants of the Jurgen Manchot Stiftung (S.W.) and the Canadian Institutes of Health Research (A.G.) as well being funded in part by the Philipps Universitat Marburg and the Division of Intramural Research, NIAID, NIH. NR 94 TC 7 Z9 7 U1 0 U2 13 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD FEB PY 2013 VL 5 IS 2 BP 528 EP 549 DI 10.3390/v5020528 PG 22 WC Virology SC Virology GA 096HH UT WOS:000315394300004 PM 23435234 ER PT J AU Kerns, EH AF Kerns, Edward H. TI Pharmaceutical Profiling Case Study in Disruption SO ACS MEDICINAL CHEMISTRY LETTERS LA English DT Editorial Material ID DRUG DISCOVERY; OPTIMIZATION; BINDING C1 NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. RP Kerns, EH (reprint author), NIH, Natl Ctr Adv Translat Sci, 1 Democracy Plaza,9th Floor,6701 Democracy Blvd,M, Bethesda, MD 20892 USA. EM edward.kerns@nih.gov NR 9 TC 1 Z9 1 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-5875 J9 ACS MED CHEM LETT JI ACS Med. Chem. Lett. PD FEB PY 2013 VL 4 IS 2 BP 150 EP 152 DI 10.1021/ml300448g PG 3 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 093HJ UT WOS:000315182000002 PM 24936241 ER PT J AU Yang, ZH Sun, R Grinchuk, V Blanco, JAF Notari, L Bohl, JA McLean, LP Ramalingam, TR Wynn, TA Urban, JF Vogel, SN Shea-Donohue, T Zhao, AP AF Yang, Zhonghan Sun, Rex Grinchuk, Viktoriya Blanco, Joan Antoni Fernandez Notari, Luigi Bohl, Jennifer A. McLean, Leon P. Ramalingam, Thirumalai R. Wynn, Thomas A. Urban, Joseph F., Jr. Vogel, Stefanie N. Shea-Donohue, Terez Zhao, Aiping TI IL-33-induced alterations in murine intestinal function and cytokine responses are MyD88, STAT6, and IL-13 dependent SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE IL-33; intestinal function; IL-13; STAT6; MYD88 ID EPITHELIAL-CELL FUNCTION; NIPPOSTRONGYLUS-BRASILIENSIS INFECTION; ALTERNATIVELY ACTIVATED MACROPHAGES; SMOOTH-MUSCLE-CELLS; AIRWAY INFLAMMATION; HELMINTH INFECTION; TYPE-2 IMMUNITY; ENTERIC NERVES; LYMPHOID-CELLS; MAST-CELLS AB Yang Z, Sun R, Grinchuk V, Fernandez Blanco JA, Notari L, Bohl JA, McLean LP, Ramalingam TR, Wynn TA, Urban JF, Vogel SN, Shea-Donohue T, Zhao A. IL-33-induced alterations in murine intestinal function and cytokine responses are MyD88, STAT6, and IL-13 dependent. Am J Physiol Gastrointest Liver Physiol 304: G381-G389, 2013. First published December 20, 2012; doi: 10.1152/ajpgi.00357.2012.-IL-33 is a recently identified cytokine member of the IL-1 family. The biological activities of IL-33 are associated with promotion of Th2 and inhibition of Th1/Th17 immune responses. Exogenous IL-33 induces a typical "type 2" immune response in the gastrointestinal tract, yet the underlying mechanisms remain to be fully elucidated. In addition, the role of IL-33 in the regulation of gastrointestinal function is not known. The present study investigated IL-33-dependent intestinal immunity and function in mice. Exogenous IL-33 induced a polarized type 2 cytokine response in the intestine that was entirely MyD88 dependent but STAT6 and IL-13 independent. Mice injected with recombinant IL-33 exhibited intestinal smooth muscle hypercontractility, decreased epithelial responses to acetylcholine and glucose, and increased mucosal permeability. IL-33 effects on intestinal epithelial function were STAT6 dependent, and both IL-4 and IL-13 appeared to play a role. The effects on smooth muscle function, however, were attributable to both STAT6-dependent and -independent mechanisms. In addition, IL-13 induction of insulin-like growth factor-1 was implicated in IL-33-induced smooth muscle hypertrophy. Finally, alternative activation of macrophages induced by IL-33 revealed a novel pathway that is IL-4, IL-13, and STAT6 independent. Thus manipulating IL-33 or related signaling pathways represents a potential therapeutic strategy for treating inflammatory diseases associated with dysregulated intestinal function. C1 [Yang, Zhonghan; Sun, Rex; Grinchuk, Viktoriya; Blanco, Joan Antoni Fernandez; Notari, Luigi; Bohl, Jennifer A.; McLean, Leon P.; Shea-Donohue, Terez; Zhao, Aiping] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Yang, Zhonghan; Sun, Rex; Grinchuk, Viktoriya; Blanco, Joan Antoni Fernandez; Notari, Luigi; Bohl, Jennifer A.; McLean, Leon P.; Shea-Donohue, Terez; Zhao, Aiping] Univ Maryland, Sch Med, Mucosal Biol Res Ctr, Baltimore, MD 21201 USA. [Urban, Joseph F., Jr.] ARS, USDA, Beltsville Human Nutr Res Ctr, Diet Genom & Immunol Lab, Beltsville, MD USA. [Ramalingam, Thirumalai R.; Wynn, Thomas A.] NIAID, Div Parasitol, NIH, Bethesda, MD 20892 USA. [Vogel, Stefanie N.] Univ Maryland, Sch Med, Dept Microbiol Immunol, Baltimore, MD 21201 USA. RP Zhao, AP (reprint author), Univ Maryland, Sch Med, Dept Med, 20 Penn St,HSF 2,R S349, Baltimore, MD 21201 USA. EM azhao@mbrc.umaryland.edu OI Urban, Joseph/0000-0002-1590-8869 FU National Institutes of Health [DK-083418, AI/DK-49316, AI-18797]; USDA CRIS [1235-51000-055] FX This work was supported by National Institutes of Health Grants DK-083418 (A. Zhao), AI/DK-49316 (T. Shea-Donohue), and AI-18797 (S. N. Vogel) and USDA CRIS project no. 1235-51000-055 (J. F. Urban). The opinions and assertions in this article are those of the authors and do not necessarily represent those of the U.S. Department of Agriculture. NR 47 TC 17 Z9 17 U1 0 U2 10 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD FEB PY 2013 VL 304 IS 4 BP G381 EP G389 DI 10.1152/ajpgi.00357.2012 PG 9 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 092SW UT WOS:000315143600008 PM 23257921 ER PT J AU Li, LL Mizel, D Huang, YN Eisner, C Hoerl, M Thiel, M Schnermann, J AF Li, Lingli Mizel, Diane Huang, Yuning Eisner, Christoph Hoerl, Marion Thiel, Manfred Schnermann, Jurgen TI Tubuloglomerular feedback and renal function in mice with targeted deletion of the type 1 equilibrative nucleoside transporter SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE stop flow pressure; micropuncture; adenosine; plasma renin; blood pressure ID GLOMERULAR-FILTRATION-RATE; ADENOSINE RECEPTORS; IN-VIVO; KNOCKOUT MICE; KIDNEY; DILAZEP; DIPYRIDAMOLE; RESPONSES; AFFERENT; ABSENCE AB Li L, Mizel D, Huang Y, Eisner C, Hoerl M, Thiel M, Schnermann J. Tubuloglomerular feedback and renal function in mice with targeted deletion of the type 1 equilibrative nucleoside transporter. Am J Physiol Renal Physiol 304: F382-F389, 2013. First published December 26, 2012; doi:10.1152/ajprenal.00581.2012.-A1 adenosine receptors (A1AR) are required for the modulation of afferent arteriolar tone by changes in luminal NaCl concentration implying that extracellular adenosine concentrations need to change in synchrony with NaCl. The present experiments were performed in mice with a null mutation in the gene for the major equilibrative nucleoside transporter ENT1 to test whether interference with adenosine disposition by cellular uptake of adenosine may modify TGF characteristics. Responses of stop flow pressure (PSF) to maximum flow stimulation were measured in mice with either C57Bl/6 or SWR/J genetic backgrounds. Maximum flow stimulation reduced PSF in ENT1(-/-) compared with wild-type (WT) mice by 1.6 +/- 0.4 mmHg (n = 28) and 5.8 +/- 1.1 mmHg (n = 17; P < 0.001) in C57Bl/6 and by 1.4 +/- 0.4 mmHg (n = 15) and 9 +/- 1.5 mmHg (n = 9; P < 0.001) in SWR/J. Plasma concentrations of adenosine and inosine were markedly higher in ENT1(-/-) than WT mice (ado: 1,179 +/- 78 and 225 +/- 48 pmol/ml; ino: 179 +/- 24 and 47.5 +/- 9 pmol/ml). Renal mRNA expressions of the four adenosine receptors, ENT2, and adenosine deaminase were not significantly different between WT and ENT1(-/-) mice. No significant differences of glomerular filtration rate or mean arterial blood pressure were found while plasma renin concentration, and heart rates were significantly lower in ENT1(-/-) animals. In conclusion, TGF responsiveness is significantly attenuated in the absence of ENT1, pointing to a role of nucleoside transport in the NaCl-synchronous changes of extracellular adenosine levels in the juxtaglomerular apparatus interstitium. C1 [Li, Lingli; Mizel, Diane; Huang, Yuning; Eisner, Christoph; Schnermann, Jurgen] NIDDK, Kidney Dis Branch, NIH, Bethesda, MD 20892 USA. [Eisner, Christoph; Thiel, Manfred] Med Fac Mannheim, Dept Anesthesiol, Mannheim, Germany. [Hoerl, Marion] Univ Munich, Dept Anesthesiol, Munich, Germany. RP Schnermann, J (reprint author), NIDDK, NIH, Bldg 10,Rm 4D51,10 Ctr Dr,MSC 1370, Bethesda, MD 20892 USA. EM jurgens@intra.niddk.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program. NR 39 TC 7 Z9 8 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD FEB PY 2013 VL 304 IS 4 BP F382 EP F389 DI 10.1152/ajprenal.00581.2012 PG 8 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 092HA UT WOS:000315109500006 PM 23269643 ER PT J AU Nedialkov, YA Opron, K Assaf, F Artsimovitch, I Kireeva, ML Kashlev, M Cukier, RI Nudler, E Burton, ZF AF Nedialkov, Yuri A. Opron, Kristopher Assaf, Fadi Artsimovitch, Irma Kireeva, Maria L. Kashlev, Mikhail Cukier, Robert I. Nudler, Eygeny Burton, Zachary F. TI The RNA polymerase bridge helix YFI motif in catalysis, fidelity and translocation SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS LA English DT Article DE RNA polymerase; Bridge helix; Termination; Pausing; Transcriptional fidelity; Translocation ID II ELONGATION COMPLEX; TRANSCRIPTION ELONGATION; STRUCTURAL BASIS; TRIGGER LOOP; REGULATES TRANSCRIPTION; NUCLEOTIDE ADDITION; MOLECULAR-DYNAMICS; ALLOSTERIC CONTROL; KINETIC-ANALYSIS; SITE AB The bridge alpha-helix in the beta' subunit of RNA polymerase (RNAP) borders the active site and may have roles in catalysis and translocation. In Escherichia coli RNAP, a bulky hydrophobic segment near the N-terminal end of the bridge helix is identified (beta' 772-YFI-774; the YFI motif). YFI is located at a distance from the active center and adjacent to a glycine hinge (beta' 778-GARKG-782) involved in dynamic bending of the bridge helix. Remarkably, amino acid substitutions in YFI significantly alter intrinsic termination, pausing, fidelity and translocation of RNAP. F773V RNAP largely ignores the lambda tR2 terminator at 200 mu M NTPs and is strongly reduced in lambda tR2 recognition at 1 mu M NTPs. F773V alters RNAP pausing and backtracking and favors misincorporation. By contrast, the adjacent Y772A substitution increases fidelity and exhibits other transcriptional defects generally opposite to those of F773V. All atom molecular dynamics simulation revealed two separate functional connections emanating from YFI explaining the distinct effects of substitutions: Y772 communicates with the active site through the link domain in the beta subunit, whereas F773 communicates through the fork domain in the beta subunit. 1774 interacts with the F-loop, which also contacts the glycine hinge of the bridge helix. These results identified negative and positive circuits coupled at YFI and employed for regulation of catalysis, elongation, termination and translocation. (c) 2012 Elsevier B.V. All rights reserved. C1 [Nedialkov, Yuri A.; Opron, Kristopher; Assaf, Fadi; Burton, Zachary F.] Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA. [Nedialkov, Yuri A.; Nudler, Eygeny] NYU, Med Ctr, Dept Biochem, New York, NY 10016 USA. [Artsimovitch, Irma] Ohio State Univ, Dept Microbiol, Columbus, OH 43210 USA. [Kireeva, Maria L.; Kashlev, Mikhail] NCI, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. [Cukier, Robert I.] Michigan State Univ, Dept Chem, E Lansing, MI 48824 USA. RP Burton, ZF (reprint author), Michigan State Univ, Dept Biochem & Mol Biol, 603 Wilson Rd, E Lansing, MI 48824 USA. EM burton@cns.msu.edu OI Nudler, Evgeny/0000-0002-8811-3071 FU National Science Foundation [MCB-1050867]; National Institutes of Health [R01 GM 092949, R01 GM58750]; Michigan State University; Michigan State University Agricultural Experiment Station; Michigan State University College of Osteopathic Medicine FX This work was supported by the National Science Foundation MCB-1050867 (70%) (to ZFB (PI) and RIC (co-I)) and the National Institutes of Health R01 GM 092949 (30%) to Michael Feig (PI) and ZFB (co-I). This work was supported by National Institutes of Health grant R01 GM58750 to EN. ZFB receives support from Michigan State University, the Michigan State University Agricultural Experiment Station, and the Michigan State University College of Osteopathic Medicine. The contents of this publication do not necessarily reveal 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 40 TC 13 Z9 13 U1 0 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-9399 J9 BBA-GENE REGUL MECH JI Biochim. Biophys. Acta-Gene Regul. Mech. PD FEB PY 2013 VL 1829 IS 2 BP 187 EP 198 DI 10.1016/j.bbagrm.2012.11.005 PG 12 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 091PU UT WOS:000315063100001 PM 23202476 ER PT J AU Zhou, ZL Yu, PP Geller, HM Ober, CK AF Zhou, Zhaoli Yu, Panpan Geller, Herbert M. Ober, Christopher K. TI Biomimetic Polymer Brushes Containing Tethered Acetylcholine Analogs for Protein and Hippocampal Neuronal Cell Patterning SO BIOMACROMOLECULES LA English DT Article ID TRANSFER RADICAL POLYMERIZATION; SURFACE WETTABILITY; ATTACHMENT; HYDROGELS; ADHESION; GROWTH; OUTGROWTH; SILICON; CHARGE AB This paper describes a method to control neuronal cell adhesion and differentiation with both chemical and topographic cues by using a spatially defined polymer brush pattern. First, biomimetic methacrylate polymer brushes containing tethered neurotransmitter acetylcholine functionalities in the form of dimethylaminoethyl methacrylate or free hydroxyl-terminated poly(ethylene glycol) units were prepared using the "grown from" method through surface-initiated atom transfer radical polymerization reactions. The surface properties of the resulting brushes were thoroughly characterized with various techniques and hippocampal neuronal cell culture on the brush surfaces exhibit cell viability and differentiation comparable to, or even better than, those on commonly used poly-L-lysine coated glass coverslips. The polymer brushes were then patterned via UV photolithography techniques to provide specially designed surface features with different sizes (varying from 2 to 200 mu m) and orientations (horizontal and vertical). Protein absorption experiments and hippocampal neuronal cell culture tests on the brush patterns showed that both protein and neurons can adhere to the patterns and therefore be guided by such patterns. These results also demonstrate that, because of their unique chemical composition and well-defined nature, the developed polymer brushes may find many potential applications in cell material interactions studies and neural tissue engineering. C1 [Zhou, Zhaoli; Ober, Christopher K.] Cornell Univ, Dept Mat Sci & Engn, Ithaca, NY 14853 USA. [Zhou, Zhaoli; Ober, Christopher K.] Cornell Univ, Dept Chem & Chem Biol, Ithaca, NY 14853 USA. [Yu, Panpan; Geller, Herbert M.] NHLBI, Dev Neurobiol Sect, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Ober, CK (reprint author), Cornell Univ, Dept Mat Sci & Engn, Ithaca, NY 14853 USA. EM cko3@cornell.edu RI Yu, Panpan/A-4962-2013; OI Geller, Herbert/0000-0002-7048-6144 FU National Science Foundation [DMR-1105253]; ONR Grant [N000141110330]; NIH [NSR01-044287]; NHLBI Division of Intramural Research FX We thank Dr. Youyong Xu for help with polymer brush preparation, Prof. E. J. Kramer, Dr. Warren Taylor and Dr. Daniel A. Fisher for XPS and NEXAFS analysis. We would like to acknowledge the use of the Microscopy and Imaging Facility at Cornell University, the Cornell Center for Materials Research (CCMR), the Cornell Nano Scale Science and Technology Facility (CNF), and the Nanobiotechnology Center (NBTC) at Cornell University. We also acknowledge the assistance of the NHLBI DIR Light Microscopy Core Facility. This work was partially supported through the National Science Foundation (DMR-1105253) and through ONR Grant (N000141110330), NIH (NSR01-044287), as well as the NHLBI Division of Intramural Research (P.Y. and H.M.G). NR 34 TC 16 Z9 16 U1 1 U2 70 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1525-7797 J9 BIOMACROMOLECULES JI Biomacromolecules PD FEB PY 2013 VL 14 IS 2 BP 529 EP 537 DI 10.1021/bm301785b PG 9 WC Biochemistry & Molecular Biology; Chemistry, Organic; Polymer Science SC Biochemistry & Molecular Biology; Chemistry; Polymer Science GA 089KD UT WOS:000314908500028 PM 23336729 ER PT J AU Oh, SY Kwon, HC Kim, SH Lee, S Lee, JH Hwang, JA Hong, SH Graves, CA Camphausen, K Kim, HJ Lee, YS AF Oh, Sung Yong Kwon, Hyuk-Chan Kim, Sung Hyun Lee, Suee Lee, Ji Hyun Hwang, Jung-Ah Hong, Seung Hyun Graves, Christian A. Camphausen, Kevin Kim, Hyo-Jin Lee, Yeon-Su TI The relationship of Vascular endothelial growth factor gene polymorphisms and clinical outcome in advanced gastric cancer patients treated with FOLFOX: VEGF polymorphism in gastric cancer SO BMC CANCER LA English DT Article DE VEGF; Polymorphism; Gastric cancer ID GENDER-SPECIFIC ASSOCIATION; GLUTATHIONE-S-TRANSFERASE; COLORECTAL-CANCER; THYMIDYLATE-SYNTHASE; PROGNOSTIC VALUE; COLON-CANCER; CHEMOTHERAPY; EXPRESSION; 5-FLUOROURACIL; CARCINOMA AB Background: The aim of this study is to evaluate the associations between vascular endothelial growth factor (VEGF) Single-nucleotide polymorphisms (SNPs) and clinical outcome in advanced gastric cancer patients treated with oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX). Methods: Genomic DNA was isolated from whole blood, and six VEGF (-2578C/A, -2489C/T, -1498 T/C, -634 G/C, +936C/T, and +1612 G/A) gene polymorphisms were analyzed by PCR. Levels of serum VEGF were measured using enzyme-linked immunoassays. Results: Patients with G/G genotype for VEGF -634 G/C gene polymorphism showed a lower response rate (22.2%) than those with G/C or C/C genotype (32.3%, 51.1%; P = 0.034). Patients with the VEGF -634 G/C polymorphism G/C + C/C genotype had a longer progression free survival (PFS) of 4.9 months, compared with the PFS of 3.5 months for those with the G/G (P = 0.043, log-rank test). By multivariate analysis, this G/G genotype of VEGF -634 G/C polymorphism was identified as an independent prognostic factor (Hazard ratio 1.497, P = 0.017). Conclusion: Our data suggest that G/G genotype of VEGF -634 G/C polymorphism is related to the higher serum levels of VEGF, and poor clinical outcome in advanced gastric cancer patients. C1 [Oh, Sung Yong; Kwon, Hyuk-Chan; Kim, Sung Hyun; Lee, Suee; Lee, Ji Hyun; Kim, Hyo-Jin] Dong A Univ, Coll Med, Dept Internal Med, Pusan, South Korea. [Hwang, Jung-Ah; Hong, Seung Hyun; Lee, Yeon-Su] Natl Canc Ctr, Res Inst, Canc Genom Branch, Goyang 410769, Gyeonggi Do, South Korea. [Graves, Christian A.; Camphausen, Kevin] Natl Canc Inst, Radiat Oncol Branch, Bethesda, MD USA. RP Lee, YS (reprint author), Natl Canc Ctr, Res Inst, Canc Genom Branch, Goyang 410769, Gyeonggi Do, South Korea. EM yslee2@ncc.re.kr FU Dong-A University Research Fund FX This paper was supported by the Dong-A University Research Fund. NR 31 TC 19 Z9 21 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD FEB 1 PY 2013 VL 13 AR 43 DI 10.1186/1471-2407-13-43 PG 8 WC Oncology SC Oncology GA 091CX UT WOS:000315027700001 PM 23374220 ER PT J AU Darragh, TM Tokugawa, D Castle, PE Follansbee, S Borgonovo, S LaMere, BJ Schwartz, L Gage, JC Fetterman, B Lorey, T Wentzensen, N AF Darragh, Teresa M. Tokugawa, Diane Castle, Philip E. Follansbee, Stephen Borgonovo, Sylvia LaMere, Brandon J. Schwartz, Lauren Gage, Julia C. Fetterman, Barbara Lorey, Thomas Wentzensen, Nicolas TI Interrater agreement of anal cytology SO CANCER CYTOPATHOLOGY LA English DT Article DE anal cancer screening; cytology; human papillomavirus (HPV); human immunodeficiency virus (HIV); men who have sex with men (MSM); biomarkers ID HUMAN-PAPILLOMAVIRUS; HUMAN IMMUNODEFICIENCY; CANCER; MEN; HISTOPATHOLOGY; INDIVIDUALS; PROGRAM; LESIONS; RISK AB BACKGROUND: The majority of anal cancers are caused by persistent infections with carcinogenic human papillomaviruses (HPV). Similar to cervical carcinogenesis, the progression from HPV infection to anal cancer occurs through precancerous lesions that can be treated to prevent invasion. In analogy to cervical cytology, anal cytology has been proposed as a screening tool for anal cancer precursors in high-risk populations. METHODS: The authors analyzed the interobserver reproducibility of anal cytology in a population of 363 human immunodeficiency virus (HIV)-infected men who have sex with men (MSM). Liquid-based cytology (LBC) specimens were collected in the anal dysplasia clinic before the performance of high-resolution anoscopy on all patients. Papanicolaou-stained LBC slides were evaluated by 2 cytopathologists, each of whom was blinded to the clinical outcome and the other pathologist's results, using the revised Bethesda terminology. RESULTS: Overall agreement between the 2 observers was 66% (kappa, 0.54; linear-weighted kappa, 0.69). Using dichotomizing cytology results (atypical squamous cells of undetermined significance [ASC-US] or worse vs less than ASC-US), the agreement increased to 86% (kappa, 0.69). An increasing likelihood of testing positive for markers associated with HPV-related transformation, p16/Ki-67, and HPV oncogene messenger RNA was observed, with increasing severity of cytology results noted both for individual cytologists and for consensus cytology interpretation (P value for trend [ptrend] < .0001 for all). CONCLUSIONS: Moderate to good agreement was observed between 2 cytopathologists evaluating anal cytology samples collected from HIV-positive MSM. A higher severity of anal cytology was associated with biomarkers of anal precancerous lesions. Anal cytology may be used for anal cancer screening in high-risk populations, and biomarkers of HPV-related transformation can serve as quality control for anal cytology. Cancer (Cancer Cytopathol) 2013. Published 2012 by the American Cancer Society. C1 [Darragh, Teresa M.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94140 USA. [Tokugawa, Diane; LaMere, Brandon J.; Fetterman, Barbara; Lorey, Thomas] Kaiser Permanente, TPMG Reg Lab, Berkeley, CA USA. [Castle, Philip E.] Amer Soc Clin Pathol Inst, Washington, DC USA. [Follansbee, Stephen; Borgonovo, Sylvia] Kaiser Permanente Med Ctr, Dept Med, Div Infect Dis, San Francisco, CA USA. [Schwartz, Lauren; Gage, Julia C.; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. RP Wentzensen, N (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 5024, Rockville, MD 20852 USA. EM wentzenn@mail.nih.gov FU Intramural Research Program of the National Institutes of Health/National Cancer Institute FX Supported by the Intramural Research Program of the National Institutes of Health/National Cancer Institute. NR 20 TC 15 Z9 16 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1934-662X J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD FEB PY 2013 VL 121 IS 2 BP 72 EP 78 DI 10.1002/cncy.21218 PG 7 WC Oncology; Pathology SC Oncology; Pathology GA 090NQ UT WOS:000314986300004 PM 22811048 ER PT J AU Mitchem, JB Brennan, DJ Knolhoff, BL Belt, BA Zhu, Y Sanford, DE Belaygorod, L Carpenter, D Collins, L Piwnica-Worms, D Hewitt, S Udupi, GM Gallagher, WM Wegner, C West, BL Wang-Gillam, A Goedegebuure, P Linehan, DC DeNardo, DG AF Mitchem, Jonathan B. Brennan, Donal J. Knolhoff, Brett L. Belt, Brian A. Zhu, Yu Sanford, Dominic E. Belaygorod, Larisa Carpenter, Danielle Collins, Lynne Piwnica-Worms, David Hewitt, Stephen Udupi, Girish Mallya Gallagher, William M. Wegner, Craig West, Brian L. Wang-Gillam, Andrea Goedegebuure, Peter Linehan, David C. DeNardo, David G. TI Targeting Tumor-Infiltrating Macrophages Decreases Tumor-Initiating Cells, Relieves Immunosuppression, and Improves Chemotherapeutic Responses SO CANCER RESEARCH LA English DT Article ID CANCER STEM-CELLS; PANCREATIC DUCTAL ADENOCARCINOMA; BREAST-CANCER; INFLAMMATORY MONOCYTES; MYELOID CELLS; GROWTH-FACTOR; MICE; METASTASIS; IMMUNITY; MICROENVIRONMENT AB Tumor-infiltrating immune cells can promote chemoresistance and metastatic spread in aggressive tumors. Consequently, the type and quality of immune responses present in the neoplastic stroma are highly predictive of patient outcome in several cancer types. In addition to host immune responses, intrinsic tumor cell activities that mimic stem cell properties have been linked to chemoresistance, metastatic dissemination, and the induction of immune suppression. Cancer stem cells are far from a static cell population; rather, their presence seems to be controlled by highly dynamic processes that are dependent on cues from the tumor stroma. However, the impact immune responses have on tumor stem cell differentiation or expansion is not well understood. In this study, we show that targeting tumor-infiltrating macrophages (TAM) and inflammatory monocytes by inhibiting either the myeloid cell receptors colony-stimulating factor-1 receptor (CSF1R) or chemokine (C-C motif) receptor 2 (CCR2) decreases the number of tumor-initiating cells (TIC) in pancreatic tumors. Targeting CCR2 or CSF1R improves chemotherapeutic efficacy, inhibits metastasis, and increases antitumor T-cell responses. Tumor-educated macrophages also directly enhanced the tumor-initiating capacity of pancreatic tumor cells by activating the transcription factor STAT3, thereby facilitating macrophage-mediated suppression of CD8(+) T lymphocytes. Together, our findings show how targeting TAMs can effectively overcome therapeutic resistance mediated by TICs. Cancer Res; 73(3); 1128-41. (c) 2012 AACR. C1 [Mitchem, Jonathan B.; Belt, Brian A.; Sanford, Dominic E.; Goedegebuure, Peter; Linehan, David C.] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. [Knolhoff, Brett L.; Zhu, Yu; Belaygorod, Larisa; Wang-Gillam, Andrea; DeNardo, David G.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Carpenter, Danielle; DeNardo, David G.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Collins, Lynne; Piwnica-Worms, David] Washington Univ, Sch Med, Mol Imaging Ctr, Mallinckrodt Inst Radiol, St Louis, MO 63110 USA. [Collins, Lynne; Piwnica-Worms, David] Washington Univ, Sch Med, BRIGHT Inst, St Louis, MO 63110 USA. [Piwnica-Worms, David; Goedegebuure, Peter; Linehan, David C.; DeNardo, David G.] Washington Univ, Sch Med, Siteman Canc Ctr, St Louis, MO 63110 USA. [Wegner, Craig] Pfizer Inc, St Louis, MO USA. [Hewitt, Stephen] NCI, Adv Technol Ctr, Bethesda, MD 20892 USA. [West, Brian L.] Plexxikon Inc, Berkeley, CA USA. [Brennan, Donal J.] Univ Queensland, Queensland Ctr Gynaecol Canc, Cent Clin Div, Sch Med, Brisbane, Qld, Australia. [Udupi, Girish Mallya; Gallagher, William M.] Univ Coll Dublin, UCD Conway Inst, UCD Sch Biomol & Biomed Sci, Dublin 2, Ireland. RP DeNardo, DG (reprint author), Washington Univ, Sch Med, Dept Med, 660 S Euclid Ave,Box 8069, St Louis, MO 63110 USA. EM ddenardo@dom.wustl.edu OI Hewitt, Stephen/0000-0001-8283-1788; Mitchem, Jonathan/0000-0002-5385-7038; Gallagher, William/0000-0002-4307-5999 FU Pfizer Oncology; Novartis Oncology; WU/Pfizer Biomedical Research Grant [PW0457]; NIH [P50 CA 94056]; NCI grant [T32 CA 009621] FX D.J. Brennan has ownership interest (including patents) in patent for CD8: CD68 signature. D.C. Linehan has other commercial research support from Pfizer Oncology and Novartis Oncology. No potential conflicts of interest were disclosed by the other authors.; This study was supported by WU/Pfizer Biomedical Research Grant PW0457 (D.C. Linehan), NIH P50 CA 94056 (D. Piwnica-Worms), and NCI grant T32 CA 009621 (J.B. Mitchem and D.E. Sanford). NR 48 TC 163 Z9 171 U1 11 U2 57 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2013 VL 73 IS 3 BP 1128 EP 1141 DI 10.1158/0008-5472.CAN-12-2731 PG 14 WC Oncology SC Oncology GA 091DD UT WOS:000315028300011 PM 23221383 ER PT J AU Baidoo, KE Yong, K Brechbiel, MW AF Baidoo, Kwamena E. Yong, Kwon Brechbiel, Martin W. TI Molecular Pathways: Targeted alpha-Particle Radiation Therapy SO CLINICAL CANCER RESEARCH LA English DT Article ID DOUBLE-STRAND BREAKS; MYELOID-LEUKEMIA; CELL-DEATH; RADIOIMMUNOTHERAPY; DOSIMETRY; PHARMACOKINETICS; IMMUNOTHERAPY; IRRADIATION; MECHANISMS; INDUCTION AB An alpha-particle, a He-4 nucleus, is exquisitely cytotoxic and indifferent to many limitations associated with conventional chemo-and radiotherapy. The exquisite cytotoxicity of alpha-radiation, the result of its high mean energy deposition [high linear energy transfer (LET)] and limited range in tissue, provides for a highly controlled therapeutic modality that can be targeted to selected malignant cells [targeted alpha-therapy (TAT)] with minimal normal tissue effects. A burgeoning interest in the development of TAT is buoyed by the increasing number of ongoing clinical trials worldwide. The short path length renders alpha-emitters suitable for treatment and management of minimal disease such as micrometastases or residual tumor after surgical debulking, hematologic cancers, infections, and compartmental cancers such as ovarian cancer or neoplastic meningitis. Yet, despite decades of study of high LET radiation, the mechanistic pathways of the effects of this modality remain not well defined. The modality is effectively presumed to follow a simple therapeutic mechanism centered on catastrophic double-strand DNA breaks without full examination of the actual molecular pathways and targets that are activated that directly affect cell survival or death. This Molecular Pathways article provides an overview of the mechanisms and pathways that are involved in the response to and repair of TAT-induced DNA damage as currently understood. Finally, this article highlights the current state of clinical translation of TAT as well as other high-LET radionuclide radiation therapy using alpha-emitters such as Ac-225, At-211, Bi-213, Pb-212, and Ra-223. Clin Cancer Res; 19(3); 530-7. (C)2012 AACR. C1 [Baidoo, Kwamena E.; Yong, Kwon; Brechbiel, Martin W.] NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Brechbiel, MW (reprint author), NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, 10 Ctr Dr,Bldg 10,Rm B3B69, Bethesda, MD 20892 USA. EM martinwb@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 39 TC 31 Z9 31 U1 2 U2 28 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 1 PY 2013 VL 19 IS 3 BP 530 EP 537 DI 10.1158/1078-0432.CCR-12-0298 PG 8 WC Oncology SC Oncology GA 088UQ UT WOS:000314863000005 PM 23230321 ER PT J AU Ferris, M Norwood, V Radeva, M Gassman, JJ Al-Uzri, A Askenazi, D Matoo, T Pinsk, M Sharma, A Smoyer, W Stults, J Vyas, S Weiss, R Gipson, D Kaskel, F Friedman, A Moxey-Mims, M Trachtman, H AF Ferris, Maria Norwood, Victoria Radeva, Milena Gassman, Jennifer J. Al-Uzri, Amira Askenazi, David Matoo, Tej Pinsk, Maury Sharma, Amita Smoyer, William Stults, Jenna Vyas, Shefali Weiss, Robert Gipson, Debbie Kaskel, Frederick Friedman, Aaron Moxey-Mims, Marva Trachtman, Howard TI Patient Recruitment into a Multicenter Randomized Clinical Trial for Kidney Disease: Report of the Focal Segmental Glomerulosclerosis Clinical Trial (FSGS CT) SO CTS-CLINICAL AND TRANSLATIONAL SCIENCE LA English DT Article DE clinical trials; kidney; nephrology; pediatrics ID RARE DISEASES; ENROLLMENT; CHILDREN AB We describe the experience of the focal segmental glomerulosclerosis clinical trial (FSGS CT) in the identification and recruitment of participants into the study. This National Institutes of Health funded study, a multicenter, open-label, randomized comparison of cyclosporine versus oral dexamethasone pulses plus mycophenolate mofetil, experienced difficulty and delays meeting enrollment goals. These problems occurred despite the support of patient advocacy groups and aggressive recruitment strategies. Multiple barriers were identified including: (1) inaccurate estimates of the number of potential incident FSGS patients at participating centers; (2) delays in securing one of the test agents; (3) prolonged time between IRB approval and execution of a subcontract (mean 7.5 +/- 0.8 months); (4) prolonged time between IRB approval and enrollment of the first patient at participating sites (mean 19.6 +/- 1.4 months); and (5) reorganization of clinical coordinating core infrastructure to align resources with enrollment. A Web-based anonymous survey of site investigators revealed site-related barriers to patient recruitment. The value of a variety of recruitment tools was of marginal utility in facilitating patient enrollment. We conclude that improvements in the logistics of study approval and regulatory start-up and testing of promising novel agents are important factors in promoting enrollment into randomized clinical trials in nephrology. Clin Trans Sci 2013; Volume 6: 1320 C1 [Ferris, Maria] Univ N Carolina, Chapel Hill, NC USA. [Norwood, Victoria] Univ Virginia, Charlottesville, VA USA. [Radeva, Milena; Gassman, Jennifer J.] Cleveland Clin, Cleveland, OH 44106 USA. [Al-Uzri, Amira] Doernbecher Childrens Hosp, Portland, OR USA. [Askenazi, David] Univ Alabama Birmingham, Birmingham, AL USA. [Matoo, Tej] Childrens Hosp Michigan, Detroit, MI 48201 USA. [Pinsk, Maury] Univ Alberta, Edmonton, AB, Canada. [Sharma, Amita] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Smoyer, William] Nationwide Childrens Hosp, Columbus, OH USA. [Stults, Jenna] Seattle Childrens Hosp, Seattle, WA USA. [Vyas, Shefali] St Barnabas Hosp, Livingston, NJ USA. [Weiss, Robert] New York Med Coll, Valhalla, NY 10595 USA. [Gipson, Debbie] Univ Michigan, Ann Arbor, MI 48109 USA. [Kaskel, Frederick] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Friedman, Aaron] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Moxey-Mims, Marva] NIDDK, NIH, Bethesda, MD USA. [Trachtman, Howard] NYU Langone Med Ctr, New York, NY USA. RP Trachtman, H (reprint author), NYU Langone Med Ctr, New York, NY USA. EM howard.trachtman@nyumc.org OI Pinsk, Maury/0000-0001-7668-665X; Trachtman, Howard/0000-0001-7447-9489 FU NIH-NIDDK [U01-DK063385, DK063490, DK063455, DK063549]; National Center for Research Resources: University of North Carolina [UL1 RR025747]; National Center for Research Resources: University of Michigan [UL1 RR0249860]; National Center for Research Resources: Harvard University [UL1 RR05758]; National Center for Research Resources: Albert Einstein College of Medicine [UL1 RR025750]; National Center for Research Resources: Medical University of South Carolina [UL1 RR029882] FX This study was sponsored by the NIH-NIDDK Grants U01-DK063385, DK063490, DK063455, and DK063549. In addition, the trial was supported by the following Clinical and Translational Science Awards from the National Center for Research Resources: University of North Carolina (UL1 RR025747), University of Michigan (UL1 RR0249860), Harvard University (UL1 RR05758), Albert Einstein College of Medicine (UL1 RR025750), and Medical University of South Carolina (UL1 RR029882). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. Th e authors thank Edward Iglesia for his assistance in preparing Figure 2. NR 21 TC 5 Z9 5 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1752-8054 J9 CTS-CLIN TRANSL SCI JI CTS-Clin. Transl. Sci. PD FEB PY 2013 VL 6 IS 1 BP 13 EP 20 DI 10.1111/cts.12003 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 089OK UT WOS:000314919700007 PM 23399084 ER PT J AU Price, DW Ma, Y Rubin, RR Perreault, L Bray, GA Marrero, D Knowler, WC Barrett-Connor, E LaCoursiere, DY AF Price, David W. Ma, Yong Rubin, Richard R. Perreault, Leigh Bray, George A. Marrero, David Knowler, William C. Barrett-Connor, Elizabeth LaCoursiere, D. Yvette CA Diabet Prevention Program Res Grp TI Depression as a Predictor of Weight Regain Among Successful Weight Losers in the Diabetes Prevention Program SO DIABETES CARE LA English DT Article ID ANTIDEPRESSANT MEDICINE USE; LIFE-STYLE; SELF-CARE; SYMPTOMS; OBESITY; RISK; PARTICIPANTS; METAANALYSIS; ASSOCIATION; DIAGNOSIS AB OBJECTIVE-To determine whether depression symptoms or antidepressant medication use predicts weight regain in overweight individuals with impaired glucose tolerance (IGT) who are successful with initial weight loss. RESEARCH DESIGN AND METHODS-A total of 1,442 participants who successfully lost at least 3% of their baseline body weight after 12 months of participation in the randomized controlled Diabetes Prevention Program (DPP) continued in their assigned treatment group (metformin, intensive lifestyle, or placebo) and were followed into the Diabetes Prevention Program Outcome Study (DPPOS). Weight regain was defined as a return to baseline DPP body weight. Participant weight and antidepressant medication use were assessed every 6 months. Depression symptoms (Beck Depression Inventory [BDI] score >= 11) were assessed every 12 months. RESULTS-Only 2.7% of the overall cohort had moderate to severe depression symptoms at baseline; most of the participants with BDI score >= 11 had only mild symptoms during the period of observation. In unadjusted analyses, both depression symptoms (hazard ratio 1.31 [95% CI 1.03-1.67], P = 0.03) and antidepressant medication use at either the previous visit (1.72 [1.37-2.15], P < 0.0001) or cumulatively as percent of visits (1.005 [1.002-1.008], P = 0.0003) were predictors of subsequent weight regain. After adjustment for multiple covariates, antidepressant use remained a significant predictor of weight regain (P < 0.0001 for the previous study visit; P = 0.0005 for the cumulative measure), while depression symptoms did not. CONCLUSIONS-In individuals with IGT who do not have severe depression and who initially lose weight, antidepressant use may increase the risk of weight regain. Diabetes Care 36: 216-221, 2013 C1 [Price, David W.] Kaiser Permanente Colorado, Inst Hlth Res, Denver, CO USA. [Price, David W.] Univ Colorado, Dept Family Med, Aurora, CO USA. [Ma, Yong] George Washington Univ, Ctr Biostat, Rockville, MD USA. [Rubin, Richard R.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Rubin, Richard R.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. [Perreault, Leigh] Univ Colorado, Dept Endocrinol, Aurora, CO USA. [Bray, George A.] Pennington Biomed Res Ctr, Baton Rouge, LA USA. [Marrero, David] Indiana Univ Sch Med, Dept Med, Indianapolis, IN USA. [Knowler, William C.] NIDDK, Phoenix, AZ USA. [Barrett-Connor, Elizabeth] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [LaCoursiere, D. Yvette] Univ Calif San Diego, Dept Reprod Med, La Jolla, CA 92093 USA. RP Price, DW (reprint author), Kaiser Permanente Colorado, Inst Hlth Res, Denver, CO USA. EM dppmail@biostat.bsc.gwu.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health; NIDDK; Indian Health Service; National Institute of Child Health and Human Development; National Institute on Aging; National Eye Institute; National Heart, Lung and Blood Institute; Office of Research on Women's Health; National Institute on Minority Health and Health Disparities; Centers for Disease Control and Prevention; American Diabetes Association; Bristol-Myers Squibb; Parke-Davis FX During the DPPOS, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health provided funding to the clinical centers and the coordinating center for the design and conduct of the study and collection, management, analysis, and interpretation of the data. The Southwestern American Indian Centers were supported directly by the NIDDK, including its Intramural Research Program, and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources, supported data collection at many of the clinical centers. Funding was also provided by the National Institute of Child Health and Human Development, the National Institute on Aging, the National Eye Institute, the National Heart, Lung and Blood Institute, the Office of Research on Women's Health, the National Institute on Minority Health and Health Disparities, the Centers for Disease Control and Prevention, and the American Diabetes Association.; Bristol-Myers Squibb and Parke-Davis provided additional funding and material support during the DPP. Lipha (Merck-Sante) provided medication, and LifeScan Inc. donated materials during the DPP and DPPOS. No other potential conflicts of interest relevant to this article were reported. NR 26 TC 9 Z9 9 U1 3 U2 11 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD FEB PY 2013 VL 36 IS 2 BP 216 EP 221 DI 10.2337/dc12-0293 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 083MA UT WOS:000314467100016 PM 23002085 ER PT J AU Pomeroy, J Renstrom, F Gradmark, AM Mogren, I Persson, M Bluck, L Wright, A Kahn, SE Domellof, M Franks, PW AF Pomeroy, Jeremy Renstrom, Frida Gradmark, Anna M. Mogren, Ingrid Persson, Margareta Bluck, Les Wright, Antony Kahn, Steven E. Domellof, Magnus Franks, Paul W. TI Maternal Physical Activity and Insulin Action in Pregnancy and Their Relationships With Infant Body Composition SO DIABETES CARE LA English DT Article ID SENSITIVITY; WOMEN; SECRETION AB OBJECTIVE-We sought to assess the association between maternal gestational physical activity and insulin action and body composition in early infancy. RESEARCH DESIGN AND METHODS-At 28-32 weeks' gestation, pregnant women participating in an observational study in Sweden underwent assessments of height, weight, and body composition, an oral glucose tolerance test, and 10 days of objective physical activity assessment. Thirty mothers and infants returned at 11-19 weeks postpartum. Infants underwent assessments of weight, length, and body composition. RESULTS-Early insulin response was correlated with total physical activity (r = 0.47; P = 0.007). Early insulin response (r = -0.36; P = 0.045) and total physical activity (r = 0.52; P = 0.037) were also correlated with infant fat-free mass. No maternal variable was significantly correlated with infant adiposity. CONCLUSIONS-The relationships between maternal physical activity, insulin response, and infant fat-free mass suggest that physical activity during pregnancy may affect metabolic outcomes in the mother and her offspring. Diabetes Care 36:267-269, 2013 C1 [Pomeroy, Jeremy; Renstrom, Frida; Franks, Paul W.] Lund Univ, Skane Univ Hosp, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden. [Pomeroy, Jeremy] NIH, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ USA. [Renstrom, Frida; Franks, Paul W.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Renstrom, Frida; Gradmark, Anna M.; Franks, Paul W.] Umea Univ, Med Sect, Genet Epidemiol & Clin Res Grp, Dept Publ Hlth & Clin Med, Umea, Sweden. [Mogren, Ingrid; Persson, Margareta] Umea Univ, Dept Clin Sci, Obstet & Gynecol Unit, Umea, Sweden. [Persson, Margareta] Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden. [Bluck, Les; Wright, Antony] MRC Human Nutr Res, Cambridge, England. [Kahn, Steven E.] VA Puget Sound Hlth Care Syst, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA USA. [Kahn, Steven E.] Univ Washington, Seattle, WA 98195 USA. [Domellof, Magnus] Umea Univ, Dept Pediat, Umea, Sweden. RP Franks, PW (reprint author), Lund Univ, Skane Univ Hosp, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden. EM jeremy.pomeroy@nih.gov; paul.franks@med.lu.se RI Domellof, Magnus/E-5307-2011; OI Domellof, Magnus/0000-0002-0726-7029; Mogren, Ingrid/0000-0003-2985-1135; Franks, Paul/0000-0002-0520-7604; Kahn, Steven/0000-0001-7307-9002 FU Torsten Soderberg foundation; Ragnar Soderberg foundation; Fredrik and Ingrid Thurings Foundation; Vasterbotten regional health authority; Medical Research Council Unit [U1059]; National Institute of Diabetes and Digestive and Kidney Diseases; U.S. Department of Veterans Affairs FX This study was a preparatory project for the LifeGene Study (www.lifegene.se) and was funded by the Torsten and Ragnar Soderberg foundations, Fredrik and Ingrid Thurings Foundation, and Vasterbotten regional health authority (all grants to P.W.F.). The stable isotope measurements were conducted under the Medical Research Council Unit Program U1059. J.P. was supported by the National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program. S.E.K. was supported in part by the U.S. Department of Veterans Affairs. NR 9 TC 8 Z9 8 U1 0 U2 11 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD FEB PY 2013 VL 36 IS 2 BP 267 EP 269 DI 10.2337/dc12-0885 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 083MA UT WOS:000314467100023 PM 22966095 ER PT J AU Lin, SSX Berlin, I Younge, R Jin, ZZ Sibley, CT Schreiner, P Szklo, M Bertoni, AG AF Lin, Susan X. Berlin, Ivan Younge, Richard Jin, Zhezhen Sibley, Christopher T. Schreiner, Pamela Szklo, Moyses Bertoni, Alain G. TI Does Elevated Plasma Triglyceride Level Independently Predict Impaired Fasting Glucose? The Multi-Ethnic Study of Atherosclerosis (MESA) SO DIABETES CARE LA English DT Article ID NUTRITION EXAMINATION SURVEY; TYPE-2 DIABETES-MELLITUS; LIFE-STYLE INTERVENTION; METABOLIC SYNDROME; INSULIN-RESISTANCE; CARDIOVASCULAR-DISEASE; NATIONAL-HEALTH; US POPULATION; YOUNG MEN; TOLERANCE AB OBJECTIVE-Elevated plasma triglycerides (TGs) have been included in diabetes risk prediction models. This study examined whether elevated TGs predict risk for impaired fasting glucose (IFG). RESEARCH DESIGN AND METHODS-This study used the baseline and longitudinal follow-up data from the Multi-Ethnic Study of Atherosclerosis (MESA). The analysis included non-Hispanic whites, African Americans, Hispanics, and Chinese Americans 45-84 years of age who had fasting glucose <100 mg/dL at baseline and who did not have clinically evident cardiovascular disease or diabetes. Cox proportional regression models were used to examine the association of elevated TGs with incidence of IFG adjusting for central obesity, low HDL cholesterol, elevated blood pressure, baseline fasting glucose, and BMI. Area under the receiver operating characteristic curve (AUC), sensitivity, and specificity of elevated TGs in predicting IFG were calculated. RESULTS-The incidence rate of developing IFG was 59.1 per 1,000 person-years during the median 4.75 years of follow-up. African Americans and Hispanics had a higher incidence rate of IFG compared with non-Hispanic whites among people with normal TG concentrations. Elevated TGs (>150 mg/dL) at baseline were independently associated with the incidence of IFG with an adjusted hazard ratio of 1.19 (95% CI 1.04-1.37). However, its predictive value for identifying people at risk for IFG was poor, with <57% AUC. Interactions of elevated TGs with race/ethnicity in predicting IFG were not statistically significant. CONCLUSIONS-Elevated TGs were moderately associated with risk for IFG, and it was a poor risk prediction tool for IFG. Diabetes Care 36:342-347, 2013 C1 [Lin, Susan X.; Younge, Richard] Columbia Univ, Ctr Family & Community Med, New York, NY 10027 USA. [Berlin, Ivan] Univ Paris 06, AP HP, Hop La Pitie Salpetriere, Fac Med,INSERM,U894, Paris, France. [Jin, Zhezhen] Columbia Univ, Mailman Sch Publ Hlth, Dept Biostat, New York, NY USA. [Sibley, Christopher T.] NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Schreiner, Pamela] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Szklo, Moyses] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Bertoni, Alain G.] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. RP Lin, SSX (reprint author), Columbia Univ, Ctr Family & Community Med, New York, NY 10027 USA. EM xl18@columbia.edu RI Sibley, Christopher/C-9900-2013 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-95167, N01-HC-95168, N01-HC-95169] FX The MESA study was supported by contracts N01-HC-95159 through N01-HC-95169 from the National Heart, Lung, and Blood Institute. NR 38 TC 6 Z9 8 U1 2 U2 12 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD FEB PY 2013 VL 36 IS 2 BP 342 EP 347 DI 10.2337/dc12-0355 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 083MA UT WOS:000314467100036 PM 23033247 ER PT J AU Buse, JB Kaufman, FR Linder, B Hirst, K El Ghormli, L Willi, S AF Buse, John B. Kaufman, Francine R. Linder, Barbara Hirst, Kathryn El Ghormli, Laure Willi, Steven CA Hlth Study Grp TI Diabetes Screening With Hemoglobin A(1c) Versus Fasting Plasma Glucose in a Multiethnic Middle-School Cohort SO DIABETES CARE LA English DT Article ID A1C AB OBJECTIVE-To characterize middle-school students from the HEALTHY study with glycemic abnormalities, specifically high-risk hemoglobin A(1c) (A1C) (hrA1C; A1C = 5.7-6.4%) and impaired fasting glucose (IFG; fasting plasma glucose [FPG] = 100-125 mg/dL). RESEARCH DESIGN AND METHODS-History was collected by self-report, physical measurement was collected by trained study staff, and fasting blood was drawn by trained phlebotomists and analyzed centrally. RESULTS-At baseline, among 3,980 sixth graders, 128 (3.2%) had hrA1C and 635 (16.0%) had IFG. Compared with A1C <5.7%, hrA1C was associated with non-Hispanic black race/ethnicity, family history of diabetes, and higher measurements of BMI, waist circumference, and fasting insulin. Compared with FPG <100 mg/dL, IFG was associated with Hispanic ethnicity; increased BMI, waist circumference, and fasting insulin; higher frequency of high blood pressure; and higher mean triglycerides. Two years later, children with hrA1C persisted as hrA1C in 59.4%, and one child (0.8%) developed A1C >= 6.5%; children with IFG persisted with IFG in 46.9%, and seven children (1.1%) developed FPG >= 126 mg/dL. Those with hrA1C compared with IFG had a higher BMI in sixth grade, which persisted to eighth grade. CONCLUSIONS-In the HEALTHY study cohort, hrA1C and IFG define different groups of youth with differentially increased diabetes risk markers. IFG is approximately fivefold more common, but hrA1C is more persistent over time. Optimal screening strategies for diabetes in youth remain unresolved. Diabetes Care 36:429-435, 2013 C1 [Buse, John B.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Kaufman, Francine R.] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Linder, Barbara] NIDDKD, Bethesda, MD 20892 USA. [Hirst, Kathryn; El Ghormli, Laure] George Washington Univ, Ctr Biostat, Rockville, MD USA. [Willi, Steven] Childrens Hosp Philadelphia, Dept Endocrinol & Diabet, Philadelphia, PA 19104 USA. RP Hirst, K (reprint author), George Washington Univ, Ctr Biostat, Rockville, MD USA. EM khirst@bsc.gwu.edu FU National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health [U01-DK-61230, U01-DK-61249, U01-DK-61231, U01-DK-61223]; American Diabetes Association FX This work was completed with funding from the National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health grants U01-DK-61230, U01-DK-61249, U01-DK-61231, and U01-DK-61223, with additional support from the American Diabetes Association. NR 15 TC 12 Z9 12 U1 0 U2 5 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD FEB PY 2013 VL 36 IS 2 BP 429 EP 435 DI 10.2337/dc12-0295 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 083MA UT WOS:000314467100048 PM 23193207 ER PT J AU Neofytos, D Lu, K Hatfield-Seung, A Blackford, A Marr, KA Treadway, S Ostrander, D Nussenblatt, V Karp, J AF Neofytos, Dionissios Lu, Kit Hatfield-Seung, Amy Blackford, Amanda Marr, Kieren A. Treadway, Suzanne Ostrander, Darin Nussenblatt, Veronique Karp, Judith TI Epidemiology, outcomes, and risk factors of invasive fungal infections in adult patients with acute myelogenous leukemia after induction chemotherapy SO DIAGNOSTIC MICROBIOLOGY AND INFECTIOUS DISEASE LA English DT Article DE Invasive fungal infections; Acute myeloid leukemia; Epidemiology; Risk factors; Survival ID ACUTE MYELOID-LEUKEMIA; NEUTROPENIC PATIENTS; HEMATOLOGIC MALIGNANCIES; PULMONARY ASPERGILLOSIS; FLUCONAZOLE PROPHYLAXIS; RESPIRATORY-TRACT; CONTROLLED-TRIAL; DOUBLE-BLIND; POSACONAZOLE; DIAGNOSIS AB This is a retrospective, single-center study of adult patients with newly diagnosed acute myelogenous leukemia (AML), who received intensive induction timed sequential chemotherapy from 1/2005 to 6/2010. Among 254 consecutive AML patients, 123 (48.4%) developed an invasive fungal infection (IFI): 14 (5.5%) patients with invasive candidiasis (IC) and 108 (42.5%) patients with invasive mould infections (IMI). Among 108 IMI identified, 4 (3.7%) were proven, 1 (0.9%) probable, and 103 (95.4%) were possible, using current definitions. Overall, 6-month mortality was 23.7% (27/114) and 20.6% (26/126) for patients with and without an IFI, respectively. Older age (>= 50 years; hazard ratio [HR] 2.5, P < 0.001), female gender (HR: 1.7, P = 0.006), and baseline renal and/or liver dysfunction (HR: 2.4, P < 0.001) were the strongest mortality predictors. We report relatively low rates of IC despite lack of routine primary antifungal prophylaxis, albeit associated with poor long-term survival. High rates of IMI, the vast majority with a possible diagnosis, were observed. Host-related variables (demographics and baseline organ dysfunction) were identified as the most significant risk factors for IFI and mortality predictors in this series. (C) 2013 Elsevier Inc. All rights reserved. C1 [Neofytos, Dionissios; Lu, Kit; Marr, Kieren A.; Treadway, Suzanne; Ostrander, Darin; Nussenblatt, Veronique] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Lu, Kit] NIH, Dept Oncol, Bethesda, MD 20892 USA. [Hatfield-Seung, Amy] Johns Hopkins Univ Hosp, Dept Pharm, Baltimore, MD 21287 USA. [Blackford, Amanda; Marr, Kieren A.; Karp, Judith] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. RP Neofytos, D (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. EM dneofyt1@jhmi.edu FU Pfizer; Astellas; Merck; Pfizer [WS297422]; National Cancer Institute [2P30-06973-48]; National Institute of Health [AI85118] FX D.N. has received research grants from Pfizer and has served on advisory boards for Roche. K.A.M. has received grant support from Astellas, Merck, and Pfizer, and has served on advisory boards or as a consultant for Astellas. Basilea, Merck, and Pfizer. J.K. has received grants from Pfizer. All other authors: no conflicts of interest.; The study was supported, in part, by a grant from Pfizer (WS297422), a National Cancer Institute grant (2P30-06973-48), and a National Institute of Health K24 grant (AI85118). NR 22 TC 20 Z9 21 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0732-8893 J9 DIAGN MICR INFEC DIS JI Diagn. Microbiol. Infect. Dis. PD FEB PY 2013 VL 75 IS 2 BP 144 EP 149 DI 10.1016/j.diagmicrobio.2012.10.001 PG 6 WC Infectious Diseases; Microbiology SC Infectious Diseases; Microbiology GA 088SV UT WOS:000314858300007 PM 23142166 ER PT J AU Ratnayaka, K Faranesh, AZ Hansen, MS Stine, AM Halabi, M Barbash, IM Schenke, WH Wright, VJ Grant, LP Kellman, P Kocaturk, O Lederman, RJ AF Ratnayaka, Kanishka Faranesh, Anthony Z. Hansen, Michael S. Stine, Annette M. Halabi, Majdi Barbash, Israel M. Schenke, William H. Wright, Victor J. Grant, Laurie P. Kellman, Peter Kocaturk, Ozgur Lederman, Robert J. TI Real-time MRI-guided right heart catheterization in adults using passive catheters SO EUROPEAN HEART JOURNAL LA English DT Article DE Catheterization; Magnetic resonance imaging; Interventional cardiovascular MRI; Pulmonary artery ID IN-VIVO VALIDATION; CARDIAC-CATHETERIZATION; PULMONARY-HYPERTENSION; CLINICAL-APPLICATION; RESONANCE; INTERVENTIONS; CHILDREN; DISEASE; CLOSURE AB Real-time MRI creates images with superb tissue contrast that may enable radiation-free catheterization. Simple procedures are the first step towards novel interventional procedures. We aim to perform comprehensive transfemoral diagnostic right heart catheterization in an unselected cohort of patients entirely using MRI guidance. We performed X-ray and MRI-guided transfemoral right heart catheterization in consecutive patients undergoing clinical cardiac catheterization. We sampled both cavae and both pulmonary arteries. We compared success rate, time to perform key steps, and catheter visibility among X-ray and MRI procedures using air-filled or gadolinium-filled balloon-tipped catheters. Sixteen subjects (four with shunt, nine with coronary artery disease, three with other) underwent paired X-ray and MRI catheterization. Complete guidewire-free catheterization was possible in 15 of 16 under both. MRI using gadolinium-filled balloons was at least as successful as X-ray in all procedure steps, more successful than MRI using air-filled balloons, and better than both in entering the left pulmonary artery. Total catheterization time and individual procedure steps required approximately the same amount of time irrespective of image guidance modality. Catheter conspicuity was best under X-ray and next-best using gadolinium-filled MRI balloons. In this early experience, comprehensive transfemoral right heart catheterization appears feasible using only MRI for imaging guidance. Gadolinium-filled balloon catheters were more conspicuous than air-filled ones. Further workflow and device enhancement are necessary for clinical adoption. C1 [Ratnayaka, Kanishka; Faranesh, Anthony Z.; Hansen, Michael S.; Stine, Annette M.; Halabi, Majdi; Barbash, Israel M.; Schenke, William H.; Wright, Victor J.; Grant, Laurie P.; Kellman, Peter; Kocaturk, Ozgur; Lederman, Robert J.] NHLBI, Div Intramural Res, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Ratnayaka, Kanishka] Childrens Natl Med Ctr, Dept Cardiol, Washington, DC 20010 USA. RP Lederman, RJ (reprint author), NHLBI, Div Intramural Res, Cardiovasc & Pulm Branch, NIH, Bldg 10,Room 2C713,MSC 1538, Bethesda, MD 20892 USA. EM lederman@nih.gov RI Hansen, Michael/J-5391-2015; Kocaturk, Ozgur/A-1419-2016 OI Hansen, Michael/0000-0002-8087-8731; FU Division of Intramural Research, National Heart Lung and Blood Institute, National Institutes of Health, USA [Z01-HL005062-08, Z01-HL006039-01, Z01-HL006041-01, Z01-HL006061-01] FX This work was supported by the Division of Intramural Research (Z01-HL005062-08, Z01-HL006039-01, Z01-HL006041-01, and Z01-HL006061-01), National Heart Lung and Blood Institute, National Institutes of Health, USA. NR 17 TC 23 Z9 23 U1 0 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD FEB PY 2013 VL 34 IS 5 BP 380 EP 389 DI 10.1093/eurheartj/ehs189 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 089EW UT WOS:000314893900011 PM 22855740 ER PT J AU Myers, RC King, RG Carter, RH Justement, LB AF Myers, Riley C. King, R. Glenn Carter, Robert H. Justement, Louis B. TI Lymphotoxin alpha(1)beta(2) expression on B cells is required for follicular dendritic cell activation during the germinal center response SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE CD19; Follicular dendritic cell; Germinal center; Membrane lymphotoxin ID TUMOR-NECROSIS-FACTOR; SECONDARY LYMPHOID-TISSUES; FC-GAMMA-RII; COMPLEMENT RECEPTORS; ADHESION MOLECULE-1; SPLENIC FOLLICLES; ALPHA-DEFICIENT; GENE-EXPRESSION; MARGINAL SINUS; STROMAL CELLS AB CD19-deficient mice were used as a model to study follicular dendritic cell (FDC) activation because these mice have normal numbers of FDC-containing primary follicles, but lack the ability to activate FDCs or form GCs. It was hypothesized that CD19 expression is necessary for B-cell activation and upregulation of membrane lymphotoxin (mLT) expression, which promotes FDC activation. Using VCAM-1 and FcRII/III as FDC activation markers, it was determined that the adoptive transfer of CD19+ wild-type B cells into CD19-deficient hosts rescued GC formation and FDC activation, demonstrating that CD19 expression on B cells is required for FDC activation. In contrast, CD19+ donor B cells lacking mLT were unable to induce VCAM-1 expression on FDCs, furthermore FcRII/III upregulation was impaired in FDCs stimulated with mLT-deficient B cells. VCAM-1 expression on FDCs, but not FcRII/III, was rescued when CD19-deficient B cells expressing transgenic mLT were cotransferred into recipient mice with CD19+, mLT-deficient B cells, suggesting that FDC activation requires the CD19-dependent upregulation of mLT on activated B cells. Collectively, these data demonstrate that activated B cells are responsible for the initiation of FDC activation resulting in a microenvironment supportive of GC development and maintenance. C1 [Myers, Riley C.; King, R. Glenn; Justement, Louis B.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. [Carter, Robert H.] NIAMSD, Bethesda, MD 20892 USA. RP Justement, LB (reprint author), Univ Alabama Birmingham, Dept Microbiol, 1825 Univ Blvd,Room 502 SHEL, Birmingham, AL 35294 USA. EM lbjust@uab.edu OI Justement, Louis/0000-0001-7058-867X FU National Institutes of Health [AI042265-13] FX We would like to thank Jason G. Cyster for kappa LT alpha-Tg mice, Sergei A. Nedospasov and David D. Chaplin for LT beta floxed mice, Jeffery Browning for anti-LT beta, the UAB High Resolution Imaging facility, and the UAB Arthritis and Musculoskeletal Flow Core facility. This work was supported by the National Institutes of Health (grant AI042265-13 to L. B. Justement). NR 53 TC 8 Z9 8 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD FEB PY 2013 VL 43 IS 2 BP 348 EP 359 DI 10.1002/eji.201242471 PG 12 WC Immunology SC Immunology GA 091LN UT WOS:000315051100009 PM 23112125 ER PT J AU Leung, WH Tarasenko, T Biesova, Z Kole, H Walsh, ER Bolland, S AF Leung, Wai-Hang Tarasenko, Tatiana Biesova, Zuzana Kole, Hemanta Walsh, Elizabeth R. Bolland, Silvia TI Aberrant antibody affinity selection in SHIP-deficient B cells SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Affinity maturation; B cell; Negative selection; SHIP ID INOSITOL PHOSPHATASE SHIP; CLASS-SWITCH RECOMBINATION; 5'-PHOSPHATASE SHIP; NEGATIVE REGULATOR; 5-PHOSPHATASE SHIP; SOMATIC MUTATION; MARGINAL ZONE; IN-VIVO; RECEPTOR; ACTIVATION AB The strength of the Ag receptor signal influences development and negative selection of B cells, and it might also affect B-cell survival and selection in the GC. Here, we have used mice with B-cell-specific deletion of the 5-inositol phosphatase SHIP as a model to study affinity selection in cells that are hyperresponsive to Ag and cytokine receptor stimulation. In the absence of SHIP, B cells have lower thresholds for Ag- and interferon (IFN)-induced activation, resulting in augmented negative selection in the BM and enhanced B-cell maturation in the periphery. Despite a tendency to spontaneously downregulate surface IgM expression, SHIP deficiency does not alter anergy induction in response to soluble hen-egg lysozyme Ag in the MDA4 transgenic model. SHIP-deficient B cells spontaneously produce isotype-switched antibodies; however, they are poor responders in immunization and infection models. While SHIP-deficient B cells form GCs and undergo mutation, they are not properly selected for high-affinity antibodies. These results illustrate the importance of negative regulation of B-cell responses, as lower thresholds for B-cell activation promote survival of low affinity and deleterious receptors to the detriment of optimal Ab affinity maturation. C1 [Leung, Wai-Hang; Tarasenko, Tatiana; Biesova, Zuzana; Kole, Hemanta; Walsh, Elizabeth R.; Bolland, Silvia] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Bolland, S (reprint author), 12441 Parklawn Dr, Rockville, MD 20852 USA. EM sbolland@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank Drs. Jack R. Bennink and Jonathan W. Yewdell (NIAID) for providing the VSV-IND, Bethany Scott for managing the mouse work. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 48 TC 9 Z9 9 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD FEB PY 2013 VL 43 IS 2 BP 371 EP 381 DI 10.1002/eji.201242809 PG 11 WC Immunology SC Immunology GA 091LN UT WOS:000315051100011 PM 23135975 ER PT J AU Pagan, AJ Peters, NC Debrabant, A Ribeiro-Gomes, F Pepper, M Karp, CL Jenkins, MK Sacks, DL AF Pagan, Antonio J. Peters, Nathan C. Debrabant, Alain Ribeiro-Gomes, Flavia Pepper, Marion Karp, Christopher L. Jenkins, Marc K. Sacks, David L. TI Tracking antigen-specific CD4+T cells throughout the course of chronic Leishmania major infection in resistant mice SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE CD4+T cells; IFN-; IL-10; Leishmania major; Tetramer ID REGULATORY T-CELLS; TRANSCRIPTION FACTOR; IN-VIVO; C-MAF; MEMORY; NAIVE; EXPANSION; CD8(+); PERSISTENCE; PROTECTION AB Primary Leishmania major infection typically produces cutaneous lesions that not only heal but also harbor persistent parasites. While the opposing roles of CD4+ T-cell-derived IFN- and IL-10 in promoting parasite killing and persistence have been well established, how these responses develop from naive precursors has not been directly monitored throughout the course of infection. We used peptide:Major Histocompatibility Complex class II (pMHCII) tetramers to investigate the endogenous, parasite-specific primary CD4+ T-cell response to L. major in mice resistant to infection. Maximal frequencies of IFN-+ CD4+ T cells were observed in the spleen and infected ears within a month after infection and were maintained into the chronic phase. In contrast, peak frequencies of IL-10+ CD4+ T cells emerged within 2 weeks of infection, persisted into the chronic phase, and accumulated in the infected ears but not the spleen, via a process that depended on local antigen presentation. T helper type-1 (Th1) cells, not Foxp3+ regulatory T cells, were the chief producers of IL-10 and were not exhausted. Therefore, tracking antigen-specific CD4+ T cells revealed that IL-10 production by Th1 cells is not due to persistent T-cell antigen receptor stimulation, but rather driven by early antigen encounter at the site of infection. C1 [Pagan, Antonio J.; Pepper, Marion; Jenkins, Marc K.] Univ Minnesota, Sch Med, Dept Microbiol, Ctr Immunol, Minneapolis, MN 55455 USA. [Peters, Nathan C.; Ribeiro-Gomes, Flavia; Sacks, David L.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Debrabant, Alain] US FDA, Div Emerging & Transfus Transmitted Dis, OBRR, CBER, Bethesda, MD 20014 USA. [Karp, Christopher L.] Cincinnati Childrens Hosp Res Fdn, Div Mol Immunol, Div Infect Dis, Cincinnati, OH USA. [Karp, Christopher L.] Univ Cincinnati, Coll Med, Cincinnati, OH USA. RP Sacks, DL (reprint author), NIAID, Parasit Dis Lab, Bldg 4,Room B1-12,4 Ctr Dr,MSC 0425, Bethesda, MD 20892 USA. EM dsacks@nih.gov RI Jenkins, Marc/G-1063-2012; Ribeiro-Gomes, Flavia/F-7609-2015; OI Jenkins, Marc/0000-0001-8009-7655; Karp, Christopher/0000-0002-0832-2659 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health; US National Institutes of Health [R37 AI027998, R01 AI039614, R01 AI066016, T32 AI07313, T32 CA9138]; Minnesota Medical Foundation FX We thank Kim Beacht, J. Walter, and R. Speier for expert technical assistance. This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and by grants from the US National Institutes of Health, R37 AI027998, R01 AI039614, and R01 AI066016 (M. K. J.), T32 AI07313 (A. J. P.), and T32 CA9138 (M. P.), and a Frieda M. Kunze Fellowship from the Minnesota Medical Foundation (A.J.P.). NR 56 TC 15 Z9 15 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD FEB PY 2013 VL 43 IS 2 BP 427 EP 438 DI 10.1002/eji.201242715 PG 12 WC Immunology SC Immunology GA 091LN UT WOS:000315051100016 PM 23109292 ER PT J AU Groelz, D Sobin, L Branton, P Compton, C Wyrich, R Rainen, L AF Groelz, Daniel Sobin, Leslie Branton, Philip Compton, Carolyn Wyrich, Ralf Rainen, Lynne TI Non-formalin fixative versus formalin-fixed tissue: A comparison of histology and RNA quality SO EXPERIMENTAL AND MOLECULAR PATHOLOGY LA English DT Article DE PAXgene Tissue; RNA; RNA integrity score; H&E histology; Quantitative RT PCR ID PARAFFIN-EMBEDDED TISSUE; PROTEOMIC ANALYSIS; NUCLEIC-ACIDS; INTEGRITY; SAMPLES; OPTIMIZATION; PRESERVATION; RECOVERY; CANCERS; NUMBER AB Preanalytical handling of tissue samples can influence bioanalyte quality and ultimately outcome of analytical results. The aim of this study was to compare RNA quality, performance in real time RT PCR and histology of formalin-fixed tissue to that of tissue fixed and stabilized with a formalin-free fixative, the PAXgene Tissue System (PAXgene), in an animal model under highly controlled preanalytical conditions. Samples of rat liver, kidney, spleen, intestine, lung, heart muscle, brain, and stomach tissue were either fixed in formalin or fixed in PAXgene or fresh frozen in liquid nitrogen. RNA was extracted from all samples, examined for integrity in microcapillary electrophoresis, and used in a series of quantitative RT PCR assays with increasing amplicon length. Histology of paraffin-embedded samples was determined by staining with hematoxylin and eosin. Histology of all formalin-fixed and PAXgene fixed samples was comparable. RNA with acceptable integrity scores could be isolated from all embedded tissues, 4.0 to 7.2 for formalin and 6.4 to 7.7 for PAXgene, as compared to 8.0 to 9.2 for fresh frozen samples. While RNA with acceptable RINs (RNA integrity number) could be isolated from formalin-fixed samples, in microcapillary electrophoresis this RNA separated with a slower migration rate and displayed diffuse, less focused peaks for ribosomal RNA as compared to RNA from frozen or PAXgene fixed samples. Furthermore, RNA from formalin-fixed tissues exhibited inhibition in quantitative RI PCR assays which increased with increasing amplicon length, while RNA from PAXgene fixed samples did not show such inhibition. In conclusion, our results demonstrate that excluding other preanalytical factors, PAXgene Tissue System preserves histology similarly to formalin, but unlike formalin, does not chemically modify RNA. RNA purified from PAXgene fixed tissues is of high integrity and performs as well as RNA from fresh frozen tissue in RI PCR regardless of amplicon length. (C) 2012 Elsevier Inc. All rights reserved. C1 [Groelz, Daniel; Wyrich, Ralf] Qiagen GmbH, Res & Dev, D-40724 Hilden, Germany. [Rainen, Lynne] PreAnalytiX GmbH, Res & Dev, Franklin Lakes, NJ USA. [Branton, Philip; Compton, Carolyn] NCI, Off Biorepositories & Biospecimen Res, NIH, Bethesda, MD 20892 USA. [Sobin, Leslie] NCI, Frederick Natl Lab Canc Res, Rockville, MD USA. [Compton, Carolyn] Crit Path Inst C Path, Tucson, AZ USA. RP Groelz, D (reprint author), QIAGEN GmbH, QIAGEN Str 1, D-40724 Hilden, Germany. EM Daniel.groelz@qiagen.com; leslie.sobin@nih.gov; philip.branton@nih.gov; CCompton@c-path.org; Ralf.Wyrich@qiagen.com; Lynne_Rainen@bd.com FU European Union [222916] FX The authors wish to thank Nadine Dettmann, Isabell Blassnig and Evelyn Traenert for their technical assistance. The research leading to these results has received funding from the European Union Seventh Framework Programme [FP7/2007-2013] under grant agreement no. 222916. NR 28 TC 23 Z9 24 U1 1 U2 28 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4800 J9 EXP MOL PATHOL JI Exp. Mol. Pathol. PD FEB PY 2013 VL 94 IS 1 BP 188 EP 194 DI 10.1016/j.yexmp.2012.07.002 PG 7 WC Pathology SC Pathology GA 090UW UT WOS:000315006500028 PM 22814231 ER PT J AU Espey, MG AF Espey, Michael Graham TI Role of oxygen gradients in shaping redox relationships between the human intestine and its microbiota SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Review DE Gut; Hydrogen peroxide; Hydrogen sulfide; Innate immunity; Microbiome; Nitric oxide; NADPH oxidase; NOX; Oxygen; Free radicals ID SULFATE-REDUCING BACTERIA; INFLAMMATORY-BOWEL-DISEASE; NITRIC-OXIDE SYNTHASES; COLON EPITHELIAL-CELLS; HUMAN GUT MICROBIOME; ULCERATIVE-COLITIS; HYDROGEN-SULFIDE; REACTIVE OXYGEN; GASTROINTESTINAL-TRACT; ESCHERICHIA-COLI AB The unique anatomy and physiology of the intestine in conjunction with its microbial content create the steepest oxygen gradients in the body, which plunge to near anoxia at the luminal midpoint. Far from static, intestinal oxygen gradients ebb and flow with every meal. This in turn governs the redox effectors nitric oxide, hydrogen sulfide, and reactive oxygen species of both host and bacterial origin. This review illustrates how the intestine and microbes utilize oxygen gradients as a backdrop for mechanistically shaping redox relationships and a functional coexistence. Published by Elsevier Inc. C1 NIDDKD, Off Sci Director, NIH, Bethesda, MD 20892 USA. RP Espey, MG (reprint author), NIDDKD, Off Sci Director, NIH, Bethesda, MD 20892 USA. EM SP@nih.gov FU Intramural Research Program of the NIDDK, NIH FX This research was supported by the Intramural Research Program of the NIDDK, NIH. NR 160 TC 54 Z9 55 U1 8 U2 72 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD FEB PY 2013 VL 55 BP 130 EP 140 DI 10.1016/j.freeradbiomed.2012.10.554 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 090WB UT WOS:000315009600015 PM 23127782 ER PT J AU Wong, GS Habibollahi, P Heidari, P Lee, JS Klein-Szanto, AJ Waldron, TJ Gimotty, P Nakagawa, H Taylor, PR Wang, TC Mahmood, U Rustgi, AK AF Wong, Gabrielle S. Habibollahi, Peiman Heidari, Pedram Lee, Ju-Seog Klein-Szanto, Andres J. Waldron, Todd J. Gimotty, Phyllis Nakagawa, Hiroshi Taylor, Philip R. Wang, Timothy C. Mahmood, Umar Rustgi, Anil K. TI Optical Imaging of Periostin Enables Early Endoscopic Detection and Characterization of Esophageal Cancer in Mice SO GASTROENTEROLOGY LA English DT Article DE Mouse Model; Esophageal Cancer; Extracellular; Matrix; POSTN; Tumor Microenvironment ID TUMOR MICROENVIRONMENT; CELL; IDENTIFICATION; INVASION AB Imaging strategies that detect early stage esophageal squamous cell carcinoma (ESCC) could improve clinical outcomes, when combined with endoscopic approaches. Periostin is an integrin-binding protein that is important in the tumor microenvironment. We created a fluorescent-labeled antibody that recognizes periostin and binds specifically to ESCC xenograft tumors in mice. In L2-cre; p120ctnLoxP/LoxP mice, which develop squamous cell cancers that resemble human ESCC, we visualized the probe in preneoplastic and neoplastic esophageal lesions using near-infrared fluorescent imaging with upper-gastrointestinal endoscopy. Periostin might be a biomarker of the esophageal tumor microenvironment that can be used to detect preneoplastic lesions. C1 [Wong, Gabrielle S.; Waldron, Todd J.; Nakagawa, Hiroshi; Rustgi, Anil K.] Univ Penn, Perelman Sch Med, Div Gastroenterol, Philadelphia, PA 19104 USA. [Wong, Gabrielle S.; Waldron, Todd J.; Nakagawa, Hiroshi; Rustgi, Anil K.] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Wong, Gabrielle S.; Waldron, Todd J.; Gimotty, Phyllis; Nakagawa, Hiroshi; Rustgi, Anil K.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Gimotty, Phyllis] Univ Penn, Ctr Clin Epidemiol & Biostat, Div Biostat, Philadelphia, PA 19104 USA. [Rustgi, Anil K.] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA. [Habibollahi, Peiman; Heidari, Pedram; Mahmood, Umar] Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. [Lee, Ju-Seog] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. [Klein-Szanto, Andres J.] Fox Chase Canc Ctr, Dept Pathol & Canc Biol, Philadelphia, PA 19111 USA. [Taylor, Philip R.] NCI, Genet Epidemiol Branch, DCEG, NIH, Bethesda, MD 20892 USA. [Wang, Timothy C.] Columbia Univ, Med Ctr, Dept Med, Div Digest & Liver Dis, New York, NY USA. [Wang, Timothy C.] Columbia Univ, Med Ctr, Herbert Irving Comprehens Canc Ctr, New York, NY USA. RP Rustgi, AK (reprint author), Univ Penn, 951 BRB,421 Curie Blvd, Philadelphia, PA 19104 USA. EM anil2@mail.med.upenn.edu FU National Institutes of Health/NCI [P01-CA098101, U01-CA14305603]; National Institutes of Health [T32-CA115299, F32-CA162719]; National Institutes of Health/NIDDK [T32-DK007066]; National Institutes of Health/NIDDK Center for Molecular Studies in Digestive and Liver Diseases [P30DK050306]; American Cancer Society [RP-10-033-01-CCE]; Intramural Research Program of the US National Institutes of Health, NCI; Division of Cancer Epidemiology and Genetics FX Supported by National Institutes of Health/NCI grant P01-CA098101, National Institutes of Health grant T32-CA115299, National Institutes of Health/NIDDK (T32-DK007066), National Institutes of Health (F32-CA162719), National Institutes of Health/NCI grant U01-CA14305603, National Institutes of Health/NIDDK Center for Molecular Studies in Digestive and Liver Diseases (P30DK050306), American Cancer Society (RP-10-033-01-CCE), and the Intramural Research Program of the US National Institutes of Health, NCI, and the Division of Cancer Epidemiology and Genetics. NR 15 TC 11 Z9 12 U1 1 U2 12 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD FEB PY 2013 VL 144 IS 2 BP 294 EP 297 DI 10.1053/j.gastro.2012.10.030 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 086VL UT WOS:000314716300022 PM 23085486 ER PT J AU Takeda, H Koso, H Tessarollo, L Copeland, NG Jenkins, NA AF Takeda, Haruna Koso, Hideto Tessarollo, Lino Copeland, Neal G. Jenkins, Nancy A. TI Musashi1-CreER(T2): A new cre line for conditional mutagenesis in neural stem cells SO GENESIS LA English DT Article DE Msi1; NSCs; SVZ; olfactory epithelium; knock-in mice ID RNA-BINDING PROTEIN; ADULT NEUROGENESIS; RECOMBINASE ACTIVITY; IDENTIFICATION; EXPRESSION; PROGENITOR; MUSASHI-1; MARKER AB The RNA-binding protein Musashi1 (Msi1) is one of two mammalian homologues of DrosophilaMusashi, which is required for the asymmetric cell division of sensory organ precursor cells. In the mouse central nervous system (CNS), Msi1 is preferentially expressed in mitotically active progenitor cells in the ventricular zone (VZ) of the neural tube during embryonic development and in the subventricular zone (SVZ) of the postnatal brain. Previous studies showed that cells in the SVZ can contribute to long-term neurogenesis in the olfactory bulb (OB), but it remains unclear whether Msi1-expressing cells have self-renewing potential and can contribute to neurogenesis in the adult. Here, we describe the generation of Msi1-CreERT2 knock-in mice and show by cell lineage tracing that Msi1-CreERT2-expressing cells mark neural stem cells (NSCs) in both the embryonic and adult brain. Msi1-CreERT2 mice thus represent a new tool in our arsenal for genetically manipulating NSCs, which will be essential for understanding the molecular mechanisms underlying neural development. genesis, 51:128134, 2013. (c) 2012 Wiley Periodicals, Inc. C1 [Takeda, Haruna; Koso, Hideto; Copeland, Neal G.; Jenkins, Nancy A.] Agcy Sci Technol & Res, Div Genom & Genet, Inst Mol & Cell Biol, Singapore, Singapore. [Takeda, Haruna] Univ Tokyo, Dept Microbiol, Grad Sch Med, Tokyo, Japan. [Takeda, Haruna] Univ Tokyo, Fac Med, Tokyo 113, Japan. [Koso, Hideto] Univ Tokyo, Inst Med Sci, Div Mol & Dev Biol, Tokyo, Japan. [Tessarollo, Lino] NCI, Neural Dev Grp, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21701 USA. [Copeland, Neal G.; Jenkins, Nancy A.] Methodist Hosp, Canc Res Program, Res Inst, Houston, TX 77030 USA. RP Jenkins, NA (reprint author), Agcy Sci Technol & Res, Div Genom & Genet, Inst Mol & Cell Biol, Singapore, Singapore. EM njenkins2@tmhs.org RI ASTAR, IMCB/E-2320-2012 FU Agency for Science, Technology and Research (A-STAR), Singapore; Cancer Prevention Research Institute of Texas; NCI, Center for Cancer Research, NIH FX Contract grant sponsors: Agency for Science, Technology and Research (A-STAR), Singapore; Cancer Prevention Research Institute of Texas.; We thank Keith Rogers, Susan M. Rogers, and Vanessa Shiyun Tay for technical support. N.A.J. and N.G.C. are both CPRIT Scholars in Cancer Research. L.T. was supported by the Intramural Research Program of the NCI, Center for Cancer Research, NIH. The authors declare no conflict of interests. NR 26 TC 6 Z9 6 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1526-954X J9 GENESIS JI Genesis PD FEB PY 2013 VL 51 IS 2 BP 128 EP 134 DI 10.1002/dvg.22357 PG 7 WC Developmental Biology; Genetics & Heredity SC Developmental Biology; Genetics & Heredity GA 092DE UT WOS:000315098300006 PM 23132814 ER PT J AU Schoenebeck, JJ Ostrander, EA AF Schoenebeck, Jeffrey J. Ostrander, Elaine A. TI The Genetics of Canine Skull Shape Variation SO GENETICS LA English DT Editorial Material ID RADIATION HYBRID MAP; DOMESTIC DOG; LINKAGE DISEQUILIBRIUM; GENOME; ASSOCIATION; TCOF1; CRANIOSYNOSTOSIS; CHROMOSOME; MULTIPLE; SEQUENCE AB A dog's craniofacial diversity is the result of continual human intervention in natural selection, a process that began tens of thousands of years ago. To date, we know little of the genetic underpinnings and developmental mechanisms that make dog skulls so morphologically plastic. In this Perspectives, we discuss the origins of dog skull shapes in terms of history and biology and highlight recent advances in understanding the genetics of canine skull shapes. Of particular interest are those molecular genetic changes that are associated with the development of distinct breeds. C1 [Schoenebeck, Jeffrey J.; Ostrander, Elaine A.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Ostrander, EA (reprint author), NHGRI, NIH, Bldg 50,Room 5351, Bethesda, MD 20892 USA. EM eostrand@mail.nih.gov OI Ostrander, Elaine/0000-0001-6075-9738 FU Intramural NIH HHS NR 62 TC 17 Z9 17 U1 8 U2 109 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 J9 GENETICS JI Genetics PD FEB PY 2013 VL 193 IS 2 BP 317 EP + DI 10.1534/genetics.112.145284 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 088GH UT WOS:000314821300001 PM 23396475 ER PT J AU Wesolowska, N Rong, YS AF Wesolowska, Natalia Rong, Yikang S. TI Long-Range Targeted Manipulation of the Drosophila Genome by Site-Specific Integration and Recombinational Resolution SO GENETICS LA English DT Article ID HOMOLOGOUS RECOMBINATION; MELANOGASTER; REPAIR; REPLACEMENT; INSERTION; PHI-C31; GENES; YEAST AB Significant advances in genomics underscore the importance of targeted mutagenesis for gene function analysis. Here we have developed a scheme for long-range targeted manipulation of genes in the Drosophila genome. Utilizing an attP attachment site for the phiC31 integrase previously targeted to the nbs gene, we integrated an 80-kb genomic fragment at its endogenous locus to generate a tandem duplication of the region. We achieved reduction to a single copy by inducing recombination via a site-specific DNA break. We report that, despite the large size of the DNA fragment, both plasmid integration and duplication reduction can be accomplished efficiently. Importantly, the integrating genomic fragment can serve as a venue for introducing targeted modifications to the entire region. We successfully introduced a new attachment site 70 kb from the existing attP using this two-step scheme, making a new region susceptible to targeted mutagenesis. By experimenting with different placements of the future DNA break site in the integrating vector, we established a vector configuration that facilitates the recovery of desired modifications. We also show that reduction events can occur efficiently through unequal meiotic crossing over between the large duplications. Based on our results, we suggest that a collection of 1200 lines with attachment sites inserted every 140 kb throughout the genome would render all Drosophila genes amenable to targeted mutagenesis. Excitingly, all of the components involved are likely functional in other eukaryotes, making our scheme for long-range targeted manipulation readily applicable to other systems. C1 [Wesolowska, Natalia; Rong, Yikang S.] NCI, Biochem & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Wesolowska, Natalia] Johns Hopkins Univ, Natl Inst Hlth Grad Partnership Program, Bethesda, MD 20892 USA. RP Rong, YS (reprint author), NIH, Bldg 37,Room 6056,37 Convent Dr, Bethesda, MD 20892 USA. EM rongy@mail.nih.gov FU Intramural Program of the National Cancer Institute FX We are grateful to Flavia Amariei for aiding us with screening for spontaneous reductions and to Jemima Barrowman for her assistance in editing the manuscript. Research in our laboratory is supported by the Intramural Program of the National Cancer Institute. NR 25 TC 6 Z9 6 U1 1 U2 15 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 J9 GENETICS JI Genetics PD FEB PY 2013 VL 193 IS 2 BP 411 EP + DI 10.1534/genetics.112.145631 PG 19 WC Genetics & Heredity SC Genetics & Heredity GA 088GH UT WOS:000314821300007 PM 23150601 ER PT J AU Biesecker, LG AF Biesecker, Leslie G. TI Secondary variants and human subjects research SO GENETICS IN MEDICINE LA English DT Letter C1 NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Biesecker, LG (reprint author), NHGRI, Genet Dis Res Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM lesb@mail.nih.gov FU Intramural NIH HHS [ZIA HG200359-05] NR 1 TC 5 Z9 5 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD FEB PY 2013 VL 15 IS 2 BP 157 EP 157 DI 10.1038/gim.2012.161 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 087WK UT WOS:000314794900011 PM 23386183 ER PT J AU Holland, SM AF Holland, Steven M. TI Chronic Granulomatous Disease SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Article DE Chronic granulomatous disease; Gene defects; NADPH oxidase; Immune defect; Inflammatory bowel disease ID DISCOID LUPUS-ERYTHEMATOSUS; INTERFERON-GAMMA THERAPY; INVASIVE ASPERGILLOSIS; CLINICAL-FEATURES; GRANULIBACTER-BETHESDENSIS; INCREASED SUSCEPTIBILITY; HEMATOPOIETIC ALLOGRAFT; NEOSARTORYA-UDAGAWAE; EUROPEAN EXPERIENCE; NADPH OXIDASE AB Chronic granulomatous disease (CGD) is a paradigm for nonlymphoid primary immune defects, and has guided elucidation of oxygen metabolism in the phagocyte, vasculature, and brain. It has been in the forefront of the development of antimicrobial prophylaxis before the advent of advanced HIV and before its routine use in neutropenia. It has been an attractive target for gene therapy and bone marrow transplantation for nonmalignant diseases. Therefore, CGD is worthy of attention for its historical interest and because it is a disease for which expert management is imperative. C1 NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Holland, SM (reprint author), NIAID, Lab Clin Infect Dis, NIH, CRC B3-4141,MSC 1684, Bethesda, MD 20892 USA. EM smh@nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 71 TC 55 Z9 58 U1 0 U2 13 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8588 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD FEB PY 2013 VL 27 IS 1 BP 89 EP + DI 10.1016/j.hoc.2012.11.002 PG 12 WC Oncology; Hematology SC Oncology; Hematology GA 090TC UT WOS:000315001900007 PM 23351990 ER EF