FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Moir, S Fauci, AS AF Moir, Susan Fauci, Anthony S. TI Insights into B cells and HIV-specific B-cell responses in HIV-infected individuals SO IMMUNOLOGICAL REVIEWS LA English DT Review DE B cells; HIV; memory; differentiation; immune activation ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-FOLLICULAR-HELPER; ACTIVE ANTIRETROVIRAL THERAPY; HUMAN MONOCLONAL-ANTIBODIES; CXC CHEMOKINE RECEPTOR-5; CHRONIC VIRAL-INFECTION; TUMOR-NECROSIS-FACTOR; NEUTRALIZING ANTIBODIES; LYMPHOID-TISSUE; DISEASE PROGRESSION AB Human immunodeficiency virus (HIV) disease is associated with dysregulation and dysfunction involving all major lymphocyte populations, including B cells. Such perturbations occur early in the course of infection and are driven in large part by immune activation resulting from ongoing HIV replication leading to bystander effects on B cells. While most of the knowledge regarding immune cell abnormalities in HIV-infected individuals has been gained from studies conducted on the peripheral blood, it is clear that the virus is most active and most damaging in lymphoid tissues. Here, we discuss B-cell perturbations in HIV-infected individuals, focusing on the skewing of B-cell subsets that circulate in the peripheral blood and their counterparts that reside in lymphoid tissues. This review also highlights recent advances in evaluating HIV-specific B-cell responses both in the memory B-cell compartment, as well as in circulating antibody-secreting plasmablasts and the more differentiated plasma cells residing in tissues. Finally, we consider how knowledge gained by investigating B cells in HIV-infected individuals may help inform the development of an effective antibody-based HIV vaccine. C1 [Moir, Susan; Fauci, Anthony S.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Moir, S (reprint author), NIH, Bldg 10,Room 6A02,9000 Rockville Pike, Bethesda, MD 20892 USA. EM smoir@niaid.nih.gov FU Intramural Research Program of NIAID, NIH FX This work was funded by the Intramural Research Program of NIAID, NIH. The authors have no conflicts of interest to disclose. NR 183 TC 58 Z9 58 U1 0 U2 25 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD JUL PY 2013 VL 254 BP 207 EP 224 DI 10.1111/imr.12067 PG 18 WC Immunology SC Immunology GA 164EE UT WOS:000320390900012 PM 23772622 ER PT J AU Mascola, JR Haynes, BF AF Mascola, John R. Haynes, Barton F. TI HIV-1 neutralizing antibodies: understanding nature's pathways SO IMMUNOLOGICAL REVIEWS LA English DT Review DE monoclonal antibodies (mAbs); broadly neutralizing antibodies (BNAbs); unmutated ancestor (UA); B-cell lineages; immune tolerance ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN MONOCLONAL-ANTIBODIES; B-CELL RESPONSES; RECOMBINANT GLYCOPROTEIN-120 VACCINE; GP120 ENVELOPE GLYCOPROTEIN; CROSS-CLADE NEUTRALIZATION; 2ND HYPERVARIABLE REGION; DEFICIENCY SYNDROME AIDS; HTLV-III LAV; SUBTYPE-B AB The development of an effective vaccine has been hindered by the enormous diversity of human immunodeficiency virus-1 (HIV-1) and its ability to escape a myriad of host immune responses. In addition, conserved vulnerable regions on the HIV-1 envelope glycoprotein are often poorly immunogenic and elicit broadly neutralizing antibody responses (BNAbs) in a minority of HIV-1-infected individuals and only after several years of infection. All of the known BNAbs demonstrate high levels of somatic mutations and often display other unusual traits, such as a long heavy chain complementarity determining region 3 (CDRH3) and autoreactivity that can be limited by host tolerance controls. Nonetheless, the demonstration that HIV-1-infected individuals can make potent BNAbs is encouraging, and recent progress in isolating such antibodies and mapping their immune pathways of development is providing new strategies for vaccination. C1 [Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Haynes, Barton F.] Duke Univ, Sch Med, Dept Med, Human Vaccine Inst, Durham, NC 27706 USA. [Haynes, Barton F.] Duke Univ, Sch Med, Dept Immunol, Human Vaccine Inst, Durham, NC USA. RP Mascola, JR (reprint author), 40 Convent Dr, Bethesda, MD 20892 USA. EM jmascola@nih.gov FU Vaccine Research Center, NIAID, NIH; NIH, NIAID Center for HIV/AIDS Vaccine immunology-Immunogen Design [UM1 AI100645]; Collaboration for AIDS Vaccine Discovery grants FX We thank Tony Moody and Rebecca Lynch for their review and suggestions for this manuscript. Supported by the intramural research program of the Vaccine Research Center, NIAID, NIH and by the NIH, NIAID Center for HIV/AIDS Vaccine immunology-Immunogen Design UM1 AI100645 and by Collaboration for AIDS Vaccine Discovery grants to B. F. H. The authors have no conflicts of interest to declare. NR 211 TC 180 Z9 184 U1 6 U2 73 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD JUL PY 2013 VL 254 BP 225 EP 244 DI 10.1111/imr.12075 PG 20 WC Immunology SC Immunology GA 164EE UT WOS:000320390900013 PM 23772623 ER PT J AU Martin, MP Carrington, M AF Martin, Maureen P. Carrington, Mary TI Immunogenetics of HIV disease SO IMMUNOLOGICAL REVIEWS LA English DT Review DE HLA; KIR; CTL; NK cells; GWAS; host genetic variation ID IMMUNODEFICIENCY-VIRUS TYPE-1; NATURAL-KILLER-CELLS; CLASS-I MOLECULES; GENOME-WIDE ASSOCIATION; CD8(+) T-CELLS; EXPOSED UNINFECTED INDIVIDUALS; HLA-C EXPRESSION; MHC CLASS-I; IMMUNOGLOBULIN-LIKE RECEPTORS; HUMAN MONOCLONAL-ANTIBODIES AB Host genetic factors are a major contributing factor to the inter-individual variation observed in response to human immunodeficiency virus (HIV) infection and are linked to resistance to HIV infection among exposed individuals, as well as rate of disease progression and the likelihood of viral transmission. Of the genetic variants that have been shown to affect the natural history of HIV infection, the human leukocyte antigen (HLA) class I genes exhibit the strongest and most consistent association, underscoring a central role for CD8+ T cells in resistance to the virus. HLA proteins play important roles in T-cell-mediated adaptive immunity by presenting immunodominant HIV epitopes to cytotoxic T lymphocytes (CTLs) and CD4+ T cells. Genetic and functional data also indicate a function for HLA in natural killer cell-mediated innate immunity against HIV by interacting with killer cell immunoglobulin-like receptors (KIR). We review the HLA and KIR associations with HIV disease and discuss the mechanisms underlying these associations. C1 [Martin, Maureen P.; Carrington, Mary] SAIC Frederick Inc, Canc & Inflammat Program, Expt Immunol Lab, NCI Frederick, Frederick, MD USA. [Carrington, Mary] Ragon Inst MGH MIT & Harvard, Boston, MA USA. RP Carrington, M (reprint author), NCI Frederick, Bldg 560,Rm 21-89B Miller Dr, Frederick, MD 21702 USA. EM carringm@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This Research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We thank Arman Bashirova for helpful comments. The authors have no conflicts of interest to declare. NR 207 TC 38 Z9 38 U1 0 U2 23 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD JUL PY 2013 VL 254 BP 245 EP 264 DI 10.1111/imr.12071 PG 20 WC Immunology SC Immunology GA 164EE UT WOS:000320390900014 PM 23772624 ER PT J AU Swaminathan, S Murray, DD Kelleher, AD AF Swaminathan, Sanjay Murray, Daniel D. Kelleher, Anthony D. TI miRNAs and HIV: unforeseen determinants of host-pathogen interaction SO IMMUNOLOGICAL REVIEWS LA English DT Review DE miRNA; HIV-1; CD4+T cell; monocytes; cytokines; biomarkers ID IMMUNODEFICIENCY-VIRUS TYPE-1; RNA-BINDING PROTEIN; IN-VIVO DELIVERY; CD4(+) T-CELLS; MESSENGER-RNA; MICRORNA EXPRESSION; CELLULAR MICRORNA; CIRCULATING MICRORNAS; SILENCING PATHWAY; POLYMERASE-II AB Our understanding of the complexity of gene regulation has significantly improved in the last decade as the role of small non-coding RNAs, called microRNAs (miRNAs), has been appreciated. These 19-22 nucleotide RNA molecules are critical regulators of mRNA translation and turnover. The miRNAs bind via a protein complex to the 3 untranslated region (3 UTR) of mRNA, ultimately leading to mRNA translational inhibition, degradation, or repression. Although many mechanisms by which human immunodeficiency virus-1 (HIV-1) infection eventually induces catastrophic immune destruction have been elucidated, the important role that miRNAs play in HIV-1 pathogenesis is only now emerging. Accumulating evidence demonstrates that changes to endogenous miRNA levels following infection is important: in maintaining HIV-1 latency in resting CD4+ T cells, potentially affect immune function via changes to cytokines such as interleukin-2 (IL-2) and IL-10 and may predict disease progression. We review the roles that both viral and host miRNAs play in different cell types and disease conditions that are important in HIV-1 infection and discuss how miRNAs affect key immunomodulatory molecules contributing to immune dysfunction. Further, we discuss whether miRNAs may be used as novel biomarkers in serum and the potential to modulate miRNA levels as a unique approach to combating this pathogen. C1 [Swaminathan, Sanjay] Sci Applicat Int Corp SAIC Frederick Inc, Lab Human Retrovirol, Appl & Dev Res Directorate ADD, Frederick Natl Lab Canc Res, Frederick, MD USA. [Murray, Daniel D.; Kelleher, Anthony D.] St Vincents Ctr Appl Med Res, Immunovirol Lab, Darlinghurst, NSW 2010, Australia. [Murray, Daniel D.; Kelleher, Anthony D.] Univ New S Wales, Kirby Inst, Kensington, NSW 2033, Australia. RP Kelleher, AD (reprint author), St Vincents Ctr Appl Med Res, Immunovirol Lab, Kirby Inst, 405 Liverpool St, Darlinghurst, NSW 2010, Australia. EM t.kelleher@amr.org.au OI Swaminathan, Sanjay/0000-0001-5315-6445 FU Australian Government Department of Health and Ageing; National Health and Medical Research Council; Australian Postgraduate Research Scholarship FX This study was supported by the Australian Government Department of Health and Ageing, the National Health and Medical Research Council via a Program Grant, Project Grants, and a practitioner fellowship (to A. D. K.) and an Australian Postgraduate Research Scholarship (to D. M.). The authors report no conflicts of interest. NR 123 TC 17 Z9 17 U1 1 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD JUL PY 2013 VL 254 BP 265 EP 280 DI 10.1111/imr.12077 PG 16 WC Immunology SC Immunology GA 164EE UT WOS:000320390900015 PM 23772625 ER PT J AU Klatt, NR Chomont, N Douek, DC Deeks, SG AF Klatt, Nichole R. Chomont, Nicolas Douek, Daniel C. Deeks, Steven G. TI Immune activation and HIV persistence: implications for curative approaches to HIV infection SO IMMUNOLOGICAL REVIEWS LA English DT Review DE AIDS; immunodeficiency diseases; cell activation; cell differentiation; cell proliferation; inflammation ID ACTIVE ANTIRETROVIRAL THERAPY; CD4(+) T-CELLS; IMMUNODEFICIENCY-VIRUS TYPE-1; PLASMACYTOID DENDRITIC CELLS; TISSUE FACTOR EXPRESSION; INNATE LYMPHOID-CELLS; CHRONIC SIV INFECTION; NATURAL-KILLER-CELL; MICROBIAL TRANSLOCATION; VIRAL REPLICATION AB Despite complete or near-complete suppression of human immunodeficiency virus (HIV) replication with combination antiretroviral therapy, both HIV and chronic inflammation/immune dysfunction persist indefinitely. Untangling the association between the virus and the host immune environment during therapy might lead to novel interventions aimed at either curing the infection or preventing the development of inflammation-associated end-organ disease. Chronic inflammation and immune dysfunction might lead to HIV persistence by causing virus production, generating new target cells, enabling infecting of activated and resting target cells, altering the migration patterns of susceptible target cells, increasing the proliferation of infected cells, and preventing normal HIV-specific clearance mechanisms from function. Chronic HIV production or replication might contribute to persistent inflammation and immune dysfunction. The rapidly evolving data on these issues strongly suggest that a vicious cycle might exist in which HIV persistence causes inflammation that in turn contributes to HIV persistence. C1 [Klatt, Nichole R.] Univ Washington, Dept Pharmaceut, Washington Natl Primate Res Ctr, Seattle, WA 98195 USA. [Chomont, Nicolas] Vaccine & Gene Therapy Inst Florida, Port St Lucie, FL USA. [Douek, Daniel C.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Deeks, Steven G.] Univ Calif San Francisco, San Francisco, CA 94110 USA. RP Deeks, SG (reprint author), Univ Calif San Francisco, Sch Med, Dept Med, San Francisco Gen Hosp, Bldg 80,1001 Potrero Ave, San Francisco, CA 94110 USA. EM sdeeks@php.ucsf.edu FU National Institute of Allergy and Infectious Diseases [R01 AI087145, K24 AI069994]; DARE: Delaney AIDS Research Enterprise (DARE) [U19AI096109]; American Foundation for AIDS Research (amfAR); Intramural Program of the National Institute of Allergy and Infectious Diseases FX This work was supported by grants from the National Institute of Allergy and Infectious Diseases (R01 AI087145, K24 AI069994), the DARE: Delaney AIDS Research Enterprise (DARE; U19AI096109), the American Foundation for AIDS Research (amfAR), and the Intramural Program of the National Institute of Allergy and Infectious Diseases. The authors have no conflicts of interest to declare. NR 238 TC 86 Z9 87 U1 2 U2 26 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD JUL PY 2013 VL 254 BP 326 EP 342 DI 10.1111/imr.12065 PG 17 WC Immunology SC Immunology GA 164EE UT WOS:000320390900019 PM 23772629 ER PT J AU Wilson, EMP Sereti, I AF Wilson, Eleanor M. P. Sereti, Irini TI Immune restoration after antiretroviral therapy: the pitfalls of hasty or incomplete repairs SO IMMUNOLOGICAL REVIEWS LA English DT Review DE IRIS; monocytes; macrophages; AIDS; T cells; cytokines ID RECONSTITUTION INFLAMMATORY SYNDROME; HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELL RECOVERY; CHRONIC HIV-INFECTION; SUSTAINED VIROLOGICAL SUPPRESSION; RANDOMIZED CONTROLLED-TRIAL; LYMPHOID-TISSUE STRUCTURE; WHITE-NOSE SYNDROME; RISK-FACTORS; HIV-1-INFECTED PATIENTS AB Antiretroviral therapy (ART) is a life-saving intervention in human immunodeficiency virus (HIV) infection. Immune restoration after ART dramatically reduces the incidence and severity of opportunistic diseases and death. On some occasions, immune restoration may be erratic, leading to acute inflammatory responses (known as immune reconstitution inflammatory syndrome) shortly after ART initiation, or incomplete, with residual inflammation despite chronic treatment, leading to non-infectious morbidity and mortality. We propose that ART may not always restore the perfect balance of innate and adaptive immunity in strategic milieus, predisposing HIV-infected persons to complications of acute or chronic inflammation. The best current strategy for fully successful immune restoration is early antiretroviral therapy, which can prevent acquired immunodeficiency syndrome (AIDS)-associated events, restrict cell subset imbalances and dysfunction, while preserving structural integrity of lymphoid tissues. Future HIV research should capitalize on innovative techniques and move beyond the static study of T-cell subsets in peripheral blood or isolated tissues. Improved targeted therapeutic strategies could stem from a better understanding of how HIV perturbs the environmental niches and the mobility and trafficking of cells that affect the dynamic cell-to-cell interactions and determine the outcome of innate and adaptive immune responses. C1 [Wilson, Eleanor M. P.; Sereti, Irini] NIAID, HIV Pathogenesis Unit, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Sereti, I (reprint author), 10 Ctr Dr,Bldg 10,Room 11B-07A, Bethesda, MD 20892 USA. EM isereti@niaid.nih.gov OI Wilson, Eleanor/0000-0002-4855-514X FU NIAID/NIH FX This study was supported by the Intramural Research Program of NIAID/NIH. The authors have no conflicts of interest to declare. NR 131 TC 20 Z9 20 U1 0 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD JUL PY 2013 VL 254 BP 343 EP 354 DI 10.1111/imr.12064 PG 12 WC Immunology SC Immunology GA 164EE UT WOS:000320390900020 PM 23772630 ER PT J AU Ittiprasert, W Miller, A Su, XZ Mu, JB Bhusudsawang, G Ukoskit, K Knight, M AF Ittiprasert, Wannaporn Miller, Andre Su, Xin-zhuan Mu, Jianbing Bhusudsawang, Ganlayarat Ukoskit, Kitipat Knight, Matty TI Identification and characterisation of functional expressed sequence tags-derived simple sequence repeat (eSSR) markers for genetic linkage mapping of Schistosoma mansoni juvenile resistance and susceptibility loci in Biomphalaria glabrata SO INTERNATIONAL JOURNAL FOR PARASITOLOGY LA English DT Article DE Expressed sequence tags; Genetic linkage mapping; Resistance; Susceptibility; Biomphalaria glabrata; Schistosoma mansoni ID FIBRINOGEN-RELATED PROTEINS; SNAIL HOST; INFECTION; HEMOCYTES; GENOME; COMPATIBILITY; CONSTRUCTION; INVERTEBRATE; MODEL; BURST AB Biomphalaria glabrata susceptibility to Schistosoma mansoni has a strong genetic component, offering the possibility for investigating host-parasite interactions at the molecular level, perhaps leading to novel control approaches. The identification, mapping and molecular characterisation of genes that influence the outcome of parasitic infection in the intermediate snail host is, therefore, seen as fundamental to the control of schistosomiasis. To better understand the evolutionary processes driving disease resistance/susceptibility phenotypes, we previously identified polymorphic random amplification of polymorphic DNA and genomic simple sequence repeats from B. glabrata. In the present study we identified and characterised polymorphic expressed simple sequence repeats markers (Bg-eSSR) from existing B. glabrata expressed sequence tags. Using these markers, and with previously identified genomic simple sequence repeats, genetic linkage mapping for parasite refractory and susceptibility phenotypes, the first known for B. glabrata, was initiated. Data mining of 54,309 expressed sequence tag, produced 660 expressed simple sequence repeats of which dinucleotide motifs (TA)(n) were the most common (37.88%), followed by trinucleotide (29.55%), mononucleotide (18.64%) and tetranucleotide (10.15%). Penta- and hexanucleotide motifs represented <3% of the Bg-eSSRs identified. While the majority (71%) of Bg-eSSRs were monomorphic between resistant and susceptible snails, several were, however, useful for the construction of a genetic linkage map based on their inheritance in segregating F2 progeny snails derived from crossing juvenile BS-90 and. NMRI snails. Polymorphic Bg-eSSRs assorted into six linkage groups at a logarithm of odds score of 3. Interestingly, the heritability of four markers (Prim1_910, Prim1_771, Prim6_1024 and Prim7_823) with juvenile snail resistance were, by t-test, significant (P < 0.05) while an allelic marker, Prim24_524, showed linkage with the juvenile snail susceptibility phenotype. On the basis of our results it is possible that the gene(s) controlling juvenile resistance and susceptibility to S. mansoni infection in B. glabrata are not only on the same linkage group but lie within a short distance (42 cM) of each other. (C) 2013 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved. C1 [Ittiprasert, Wannaporn; Miller, Andre; Knight, Matty] Biomed Res Inst, Rockville, MD 20852 USA. [Su, Xin-zhuan; Mu, Jianbing] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Bhusudsawang, Ganlayarat; Ukoskit, Kitipat] Thammasat Univ, Fac Sci & Technol, Pathum Thani, Thailand. RP Knight, M (reprint author), Biomed Res Inst, 12111 Parklawn Dr, Rockville, MD 20852 USA. EM matty_knight@gwu.edu OI Su, Xinzhuan/0000-0003-3246-3248 FU National Institute of Allergy and Infectious Diseases, National Institute of Health, USA [R01-AI063480]; Intramural Research Program of the Division of Intramural Research at the National Institute of Allergy and Infectious Diseases, National Institute of Health FX This work was supported by a grant from the National Institute of Allergy and Infectious Diseases, National Institute of Health, USA, R01-AI063480 and the Intramural Research Program of the Division of Intramural Research at the National Institute of Allergy and Infectious Diseases, National Institute of Health. We are grateful to Ms Frances Barnes for technical support and to Dr. Fred Lewis for his helpful editing of the manuscript. We also thank Drs. Nithya Raghavan and Peter FitzGerald for their guidance with the determination of SSR sequences for B. glabrata in GenBank. NR 53 TC 5 Z9 5 U1 0 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0020-7519 J9 INT J PARASITOL JI Int. J. Parasit. PD JUL PY 2013 VL 43 IS 8 BP 669 EP 677 DI 10.1016/j.ijpara.2013.03.007 PG 9 WC Parasitology SC Parasitology GA 175MA UT WOS:000321233600007 PM 23643514 ER PT J AU Kaur, G Behrsing, H Parchment, RE Millin, MD Teicher, BA AF Kaur, Gurmeet Behrsing, Holger Parchment, Ralph E. Millin, Myrtle Davis Teicher, Beverly A. TI Analyses of the combination of 6-MP and dasatinib in cell culture SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE 6-mercaptopurine; dasatinib; combination index; isobologram; response surface ID DRUG-COMBINATION; IN-VITRO; INVITRO CULTIVATION; EXPERIMENTAL-DESIGN; BREAST CARCINOMA; HUMAN TUMORS; LUNG-CANCER; LINES; MODEL; P53 AB A major tenet of cancer therapeutics is that combinations of anticancer agents with different mechanisms of action and different toxicities may be effective treatment regimens. Evaluation of additivity/synergy in cell culture may be used to identify drug combination opportunities and to assess risk of additive/synergistic toxicity. The combination of 6-mercaptopurine and dasatinib was assessed for additivity/synergy using the combination index (CI) method and a response surface method in six human tumor cell lines including MCF-7 and MDA-MB-468 breast cancer, NCI-H23 and NCI-H460 non-small cell lung cancer, and A498 and 786-O renal cell cancer, based on two experimental end-points: ATP content and colony formation. Clonal colony formation by human bone marrow CFU-GM was used to assess risk of enhanced toxicity. The concentration ranges tested for each drug were selected to encompass the clinical C-max concentrations. The combination regimens were found to be additive to sub-additive by both methods of data analysis, but synergy was not detected. The non-small cell lung cancer cell lines were the most responsive among the tumor lines tested and the renal cell carcinoma lines were the least responsive. The bone marrows CFU-GM were more sensitive to the combination regimens than were the tumor cell lines. Based upon these data, it appears that the possibility of enhanced efficacy from combining 6-mercaptopurine (6-MP) and dasatinib would be associated with increased risk of severe bone marrow toxicity, so the combination is unlikely to provide a therapeutic advantage for treating solid tumor patients where adequate bone marrow function must be preserved. C1 [Kaur, Gurmeet] Frederick Natl Lab Canc Res, Div Canc Treatment & Diag, Dev Therapeut Program, Mol Pharmacol Branch, Frederick, MD 21702 USA. [Behrsing, Holger; Parchment, Ralph E.] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Dev Res Directorate, Lab Invest Toxicol, Frederick, MD 21702 USA. [Millin, Myrtle Davis] NCI, Toxicol & Pharmacol Branch, Rockville, MD 20852 USA. [Teicher, Beverly A.] NCI, Div Canc Treatment & Diag, Dev Therapeut Program, Mol Pharmacol Branch, Rockville, MD 20852 USA. RP Kaur, G (reprint author), Frederick Natl Lab Canc Res, Div Canc Treatments & Diag, Dev Therapeut Program, Mol Pharmacol Branch, 1050 Boyles St,Bldg 321 Room 122, Frederick, MD 21702 USA. EM kaurgu@mail.nih.gov FU Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This research was supported (in part) by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. NR 55 TC 1 Z9 1 U1 0 U2 5 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD JUL PY 2013 VL 43 IS 1 BP 13 EP 22 DI 10.3892/ijo.2013.1930 PG 10 WC Oncology SC Oncology GA 172RR UT WOS:000321023100002 PM 23652925 ER PT J AU Hasan, UA Zannetti, C Parroche, P Goutagny, N Malfroy, M Roblot, G Carreira, C Hussain, I Muller, M Taylor-Papadimitriou, J Picard, D Sylla, BS Trinchieri, G Medzhitov, R Tommasino, M AF Hasan, Uzma A. Zannetti, Claudia Parroche, Peggy Goutagny, Nadege Malfroy, Marine Roblot, Guillaume Carreira, Christine Hussain, Ishraq Mueller, Martin Taylor-Papadimitriou, Joyce Picard, Didier Sylla, Bakary S. Trinchieri, Giorgio Medzhitov, Ruslan Tommasino, Massimo TI The Human papillomavirus type 16 E7 oncoprotein induces a transcriptional repressor complex on the Toll-like receptor 9 promoter SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID PLASMACYTOID DENDRITIC CELLS; HISTONE DEACETYLASE INHIBITORS; CERVICAL-CANCER; IMMUNE FUNCTIONS; GENE-EXPRESSION; MOUSE MODEL; ESTROGEN; TLR9; RECOGNITION; SKIN AB Human papillomavirus type 16 (HPV16) and other oncogenic viruses have been reported to deregulate immunity by suppressing the function of the double-stranded DNA innate sensor TLR9. However, the mechanisms leading to these events remain to be elucidated. We show that infection of human epithelial cells with HPV16 promotes the formation of an inhibitory transcriptional complex containing NF-kappa Bp50-p65 and ER alpha induced by the E7 oncoprotein. The E7-mediated transcriptional complex also recruited the histone demethylase JARID1B and histone deacetylase HDAC1. The entire complex bound to a specific region on the TLR9 promoter, which resulted in decreased methylation and acetylation of histones upstream of the TLR9 transcriptional start site. The involvement of NF-kappa B and ER alpha in the TLR9 down-regulation by HPV16 E7 was fully confirmed in cervical tissues from human patients. Importantly, we present evidence that the HPV16-induced TLR9 down-regulation affects the interferon response which negatively regulates viral infection. Our studies highlight a novel HPV16-mediated mechanism that combines epigenetic and transcriptional events to suppress a key innate immune sensor. C1 [Hasan, Uzma A.; Carreira, Christine; Sylla, Bakary S.; Tommasino, Massimo] Int Agcy Res Canc, Infect & Canc Biol Grp, F-69008 Lyon, France. [Hasan, Uzma A.; Zannetti, Claudia; Parroche, Peggy; Roblot, Guillaume] Univ Lyon, Ecole Normale Super, INSERM U1111, CIRI,Hosp Civils Lyon,CNRS UMR5308, F-69000 Lyon, France. [Goutagny, Nadege; Malfroy, Marine] Ctr Leon Berard, UMR INSERM CNRS 1052 5286, CRCL, F-69008 Lyon, France. [Hussain, Ishraq] SK Alusteng, Div Vet Biochem FVSc & AH, Kashmir 190006, India. [Mueller, Martin] DKFZ, Programme Infect & Canc, D-69120 Heidelberg, Germany. [Taylor-Papadimitriou, Joyce] Kings Coll London, Sch Med, Guys Hosp, Breast Canc Biol Grp, London SE1 9RT, England. [Picard, Didier] Univ Geneva, CH-1211 Geneva 4, Switzerland. [Trinchieri, Giorgio] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Medzhitov, Ruslan] Yale Univ, Sch Med, New Haven, CT 06510 USA. RP Hasan, UA (reprint author), Int Agcy Res Canc, Infect & Canc Biol Grp, F-69008 Lyon, France. EM uzma.hasan@inserm.fr; tommasinom@iarc.fr RI hasan, uzma/G-3247-2013; OI Hussain, Ishraq/0000-0001-8449-1617 FU EMBO Fellowship Program; La Ligue Regionale de la Loire contre le Cancer; la Fondation pour la Recherche Medicale; l'Association Research sur la Cancer; CLARA Procan Axe II innate sensors platform, Lyon FX This study was supported by the EMBO Fellowship Program (U.A. Hasan), La Ligue Regionale de la Loire contre le Cancer (U.A. Hasan), la Fondation pour la Recherche Medicale (U.A. Hasan), l'Association Research sur la Cancer (U.A. Hasan), and CLARA Procan Axe II innate sensors platform, Lyon (M. Tommasino). NR 85 TC 32 Z9 32 U1 2 U2 16 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUL 1 PY 2013 VL 210 IS 7 BP 1369 EP 1387 DI 10.1084/jem.20122394 PG 19 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 170NY UT WOS:000320860700006 PM 23752229 ER PT J AU Yang, JJ Zhang, RH Lu, GM Shen, Y Peng, L Zhu, C Cui, M Wang, WD Arnaboldi, P Tang, M Gupta, M Qi, CF Jayaraman, P Zhu, HF Jiang, B Chen, SH He, JCJ Ting, AT Zhou, MM Kuchroo, VK Morse, HC Ozato, K Sikora, AG Xiong, HB AF Yang, Jianjun Zhang, Ruihua Lu, Geming Shen, Yu Peng, Liang Zhu, Chen Cui, Miao Wang, Weidong Arnaboldi, Paul Tang, Meng Gupta, Monica Qi, Chen-Feng Jayaraman, Padmini Zhu, Hongfa Jiang, Bo Chen, Shu-hsia He, John Cijiang Ting, Adrian T. Zhou, Ming-Ming Kuchroo, Vijay K. Morse, Herbert C., III Ozato, Keiko Sikora, Andrew G. Xiong, Huabao TI T cell-derived inducible nitric oxide synthase switches off T(H)17 cell differentiation SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; KAPPA-B ACTIVATION; HELPER-CELLS; TH17 CELLS; TGF-BETA; EXPERIMENTAL STROKE; TYROSINE NITRATION; INFLAMMATION; RECEPTOR AB ROR gamma t is necessary for the generation of T(H)17 cells but the molecular mechanisms for the regulation of T(H)17 cells are still not fully understood. We show that activation of CD4(+) T cells results in the expression of inducible nitric oxide synthase (iNOS). iNOS-deficient mice displayed enhanced T(H)17 cell differentiation but without major effects on either T(H)1 or T(H)2 cell lineages, whereas endothelial NOS (eNOS) or neuronal NOS (nNOS) mutant mice showed comparable T(H)17 cell differentiation compared with wild-type control mice. The addition of N6-(1-iminoethyl)-L-lysine dihydrochloride (L-NIL), the iNOS inhibitor, significantly enhanced T(H)17 cell differentiation, and S-nitroso-N-acetylpenicillamine (SNAP), the NO donor, dose-dependently reduced the percentage of IL-17-producing CD4(+) T cells. NO mediates nitration of tyrosine residues in ROR gamma t, leading to the suppression of ROR gamma t-induced IL-17 promoter activation, indicating that NO regulates IL-17 expression at the transcriptional level. Finally, studies of an experimental model of colitis showed that iNOS deficiency results in more severe inflammation with an enhanced T(H)17 phenotype. These results suggest that NO derived from iNOS in activated T cells plays a negative role in the regulation of T(H)17 cell differentiation and highlight the importance of intrinsic programs for the control of T(H)17 immune responses. C1 [Yang, Jianjun; Zhang, Ruihua; Lu, Geming; Shen, Yu; Peng, Liang; Cui, Miao; Arnaboldi, Paul; Jayaraman, Padmini; Jiang, Bo; Chen, Shu-hsia; He, John Cijiang; Ting, Adrian T.; Sikora, Andrew G.; Xiong, Huabao] Mt Sinai Sch Med, Dept Med, Inst Immunol, New York, NY 10029 USA. [Jayaraman, Padmini; Sikora, Andrew G.] Mt Sinai Sch Med, Dept Otolaryngol Head & Neck Surg, New York, NY 10029 USA. [Zhu, Hongfa] Mt Sinai Sch Med, Dept Pathol, New York, NY 10029 USA. [Zhou, Ming-Ming] Mt Sinai Sch Med, Dept Struct & Chem Biol, New York, NY 10029 USA. [Zhu, Chen; Kuchroo, Vijay K.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA. [Wang, Weidong] Cornell Univ, Weill Med Coll, Ronald O Perelman & Claudia Cohen Ctr Reprod Med, New York, NY 10021 USA. [Tang, Meng] Southeast Univ, Sch Publ Hlth, Minist Educ, Key Lab Environm Med & Engn, Nanjing 210009, Jiangsu, Peoples R China. [Gupta, Monica; Ozato, Keiko] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Programs Genom Differentiat, Bethesda, MD 20892 USA. [Morse, Herbert C., III] NIAID, Immunogenet Lab, NIH, Bethesda, MD 20892 USA. RP Xiong, HB (reprint author), Mt Sinai Sch Med, Dept Med, Inst Immunol, New York, NY 10029 USA. EM Huabao.Xiong@mssm.edu OI Morse, Herbert/0000-0002-9331-3705; Arnaboldi, Paul/0000-0002-4005-4412 FU National Institutes of Health (NIH) [P01 DK072201, R56AI091871]; Broad Medical Research Program of The Broad Foundation; National Natural Science Foundation of China [30972504]; National Important Project on Scientific Research of China [2011CB933404]; Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases FX H. Xiong was supported by the National Institutes of Health (NIH) funding (P01 DK072201 and R56AI091871) and The Broad Medical Research Program of The Broad Foundation. M. Tang was supported by National Natural Science Foundation of China (No. 30972504) and National Important Project on Scientific Research of China (No. 2011CB933404). This work was supported in part by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. NR 51 TC 30 Z9 32 U1 0 U2 11 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUL 1 PY 2013 VL 210 IS 7 BP 1447 EP 1462 DI 10.1084/jem.20122494 PG 16 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 170NY UT WOS:000320860700011 PM 23797094 ER PT J AU Zanker, D Waithman, J Yewdell, JW Chen, WS AF Zanker, Damien Waithman, Jason Yewdell, Jonathan W. Chen, Weisan TI Mixed Proteasomes Function To Increase Viral Peptide Diversity and Broaden Antiviral CD8(+) T Cell Responses SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INFLUENZA-A VIRUS; ANTIGEN PRESENTATION; IMMUNODOMINANCE HIERARCHY; IN-VIVO; IMMUNOGENICITY; EPITOPES; REPERTOIRE; RESIDUES; MEMORY AB The three proteasome subunits with proteolytic activity are encoded by standard or immunoproteasome genes. Many proteasomes expressed by normal cells and cells exposed to cytokines are "mixed", that is, contain both standard and immunoproteasome subunits. Using a panel of 38 defined influenza A virus-derived epitopes recognized by C57BL/6 mouse CD8(+) T cells, we used mice with targeted disruption of beta 1i, beta 2i, or beta 5i/beta 2i genes to examine the contribution of mixed proteasomes to the immunodominance hierarchy of antiviral CD8(+) T cells. We show that each immunoproteasome subunit has large effects on the primary and recall immunodominance hierarchies due to modulating both the available T cell repertoire and generation of individual epitopes as determined both biochemically and kinetically in Ag presentation assays. These findings indicate that mixed proteasomes function to enhance the diversity of peptides and support a broad CD8(+) T cell response. The Journal of Immunology, 2013, 191: 52-59. C1 [Zanker, Damien; Chen, Weisan] La Trobe Univ, Sch Mol Sci, Bundoora, Vic 3086, Australia. [Waithman, Jason] Univ Western Australia, Ctr Child Hlth Res, Telethon Inst Child Hlth Res, Perth, WA 6872, Australia. [Yewdell, Jonathan W.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Chen, WS (reprint author), La Trobe Univ, Sch Mol Sci, Bundoora, Vic 3086, Australia. EM weisan.chen@latrobe.edu.au OI Zanker, Damien/0000-0003-1163-9902 FU National Health and Medical Research Council [433608, 542508, 567122, 487926, 603100, 603104] FX This work was supported in part by National Health and Medical Research Council Project Grants 433608 and 542508 (to W.C.) and by National Health and Medical Research Council Program Grant 567122. D.Z. was supported by National Health and Medical Research Council Biomedical Postgraduate Scholarship 487926. J.W. is a National Health and Medical Research Council Biomedical Training Fellow (Grant 603100), and W.C. is a National Health and Medical Research Council Senior Research Fellow (Grant 603104). NR 33 TC 19 Z9 19 U1 0 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 1 PY 2013 VL 191 IS 1 BP 52 EP 59 DI 10.4049/jimmunol.1300802 PG 8 WC Immunology SC Immunology GA 169FQ UT WOS:000320765000009 PM 23709680 ER PT J AU Sandgren, KJ Smed-Sorensen, A Forsell, MN Soldemo, M Adams, WC Liang, F Perbeck, L Koup, RA Wyatt, RT Hedestam, GBK Lore, K AF Sandgren, Kerrie J. Smed-Sorensen, Anna Forsell, Mattias N. Soldemo, Martina Adams, William C. Liang, Frank Perbeck, Leif Koup, Richard A. Wyatt, Richard T. Hedestam, Gunilla B. Karlsson Lore, Karin TI Human Plasmacytoid Dendritic Cells Efficiently Capture HIV-1 Envelope Glycoproteins via CD4 for Antigen Presentation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; EPIDERMAL LANGERHANS CELLS; T-CELLS; ANTIBODY-RESPONSES; CROSS-PRESENTATION; IN-VIVO; DC-SIGN; TRANS-INFECTION; MEDIATED UPTAKE; TYPE-1 GP120 AB Advances in HIV-1 vaccine clinical trials and preclinical research indicate that the virus envelope glycoproteins (Env) are likely to be an essential component of a prophylactic vaccine. Efficient Ag uptake and presentation by dendritic cells (DCs) is important for strong CD4(+) Th cell responses and the development of effective humoral immune responses. In this study, we examined the capacity of distinct primary human DC subsets to internalize and present recombinant Env to CD4(+) T cells. Consistent with their specific receptor expression, skin DCs bound and internalized Env via C-type lectin receptors, whereas blood DC subsets, including CD1c(+) myeloid DCs, CD123(+) plasmacytoid DCs (PDCs), and CD141(+) DCs exhibited a restricted repertoire of C-type lectin receptors and relied on CD4 for uptake of Env. Despite a generally poor capacity for Ag uptake compared with myeloid DCs, the high expression of CD4 on PDCs allowed them to bind and internalize Env very efficiently. CD4-mediated uptake delivered Env to EEA1(+) endosomes that progressed to Lamp1(+) and MHC class II+ lysosomes where internalized Env was degraded rapidly. Finally, all three blood DC subsets were able to internalize an Env-CMV pp65 fusion protein via CD4 and stimulate pp65-specific CD4(+) T cells. Thus, in the in vitro systems described in this paper, CD4-mediated uptake of Env is a functional pathway leading to Ag presentation, and this may therefore be a mechanism used by blood DCs, including PDCs, for generating immune responses to Env-based vaccines. The Journal of Immunology, 2013, 191: 60-69. C1 [Sandgren, Kerrie J.; Adams, William C.; Liang, Frank; Lore, Karin] Karolinska Inst, Dept Med Huddinge, Ctr Infect Med, S-14186 Huddinge, Sweden. [Smed-Sorensen, Anna; Soldemo, Martina; Hedestam, Gunilla B. Karlsson] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, S-14186 Huddinge, Sweden. [Forsell, Mattias N.] Karolinska Inst, Dept Med Solna, S-17176 Stockholm, Sweden. [Perbeck, Leif] Karolinska Univ Hosp Solna, Dept Surg, S-17176 Stockholm, Sweden. [Koup, Richard A.; Lore, Karin] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Wyatt, Richard T.] Scripps Res Inst, Int AIDS Vaccine Initiat Neutralizing Antibody Ct, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. RP Lore, K (reprint author), Karolinska Inst, Karolinska Univ Hosp Huddinge, Ctr Infect Med, F59, S-14186 Huddinge, Sweden. EM karin.lore@ki.se FU Swedish International Development Agency; Swedish Research Council; Swedish Governmental Agency for Innovation Systems (Vinnova); Swedish Society of Medicine; Swedish Society of Medical Research; Fernstrom Foundation; Foundation for AIDS Research (amfAR) in basic biomedical research FX This work was supported by grants from the Swedish International Development Agency (to A.S.-S., G.B.K.H., and K.L.), the Swedish Research Council (to K.L.), and the Swedish Governmental Agency for Innovation Systems (Vinnova) (to K.L.). K.J.S. and F.L. are recipients of scholarships from the Swedish Society of Medicine, the Swedish Society of Medical Research, and the Fernstrom Foundation. M.N.F. is supported by a Mathilde Krim fellowship from The Foundation for AIDS Research (amfAR) in basic biomedical research. NR 69 TC 11 Z9 11 U1 0 U2 8 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 1 PY 2013 VL 191 IS 1 BP 60 EP 69 DI 10.4049/jimmunol.1202489 PG 10 WC Immunology SC Immunology GA 169FQ UT WOS:000320765000010 PM 23729440 ER PT J AU Shi, GP Vistica, BP Nugent, LF Tan, CY Wawrousek, EF Klinman, DM Gery, I AF Shi, Guangpu Vistica, Barbara P. Nugent, Lindsey F. Tan, Cuiyan Wawrousek, Eric F. Klinman, Dennis M. Gery, Igal TI Differential Involvement of Th1 and Th17 in Pathogenic Autoimmune Processes Triggered by Different TLR Ligands SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TOLL-LIKE RECEPTORS; REGULATORY T-CELLS; RHEUMATOID-ARTHRITIS SYNOVIUM; ANTIGEN-PRESENTING CELLS; DENDRITIC CELLS; IMMUNE-RESPONSES; CYTOKINE PRODUCTION; B-CELLS; DISEASE; ACTIVATION AB The interaction between TLRs and their cognate ligands triggers both the innate and adaptive immune systems, and thus can play a pivotal role in the defense against pathogen invasion. This work investigates the differentiation of naive CD4 cells into Th1 or Th17 phenotypes in mice treated with different TLR ligands. We use a model system in which naive transgenic cells specific to hen egg lysozyme are adoptively transferred into recipients that express hen egg lysozyme in the lens of the eye. The transferred naive T cells induce ocular inflammation only in recipients treated with TLR ligands. Treatment with LPS preferentially stimulated IL-17 production, whereas CpG oligodeoxynucleotide and polyinosinic: polycytidylic acid primarily stimulated Th1 cells. Peptidoglycan stimulated the two Th subpopulations equally. The preferential induction of Th1 or Th17 by the four ligands was detected in the spleen (where a major portion of the adoptively transferred cells homed) and in the eyes, where activated Th cells initiate inflammation. Analysis of the cytokines present in recipient mice suggests that Th1 induction is elicited by IL-12 and/or IFN-alpha, whereas Th17 generation is preferentially mediated by IL-6. Importantly, we show in this article that treatment with LPS selectively promoted in the recipient mice the generation of IL-6-producing activated B cells. An inverse correlation was found between the level of regulatory T cells and severity of inflammation induced by the donor cells. Taken together, our data show that specific TLR ligands differentially activate the immune system as evidenced by the generation of distinct Th phenotypes from naive CD4 cells. C1 [Shi, Guangpu; Vistica, Barbara P.; Nugent, Lindsey F.; Tan, Cuiyan; Gery, Igal] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Wawrousek, Eric F.] NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. [Klinman, Dennis M.] NCI, Canc & Inflammat Program, NIH, Frederick, MD 21702 USA. RP Gery, I (reprint author), NEI, Immunol Lab, NIH, Bldg 10,Room 10N208, Bethesda, MD 20892 USA. EM geryi@nei.nih.gov FU National Eye Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Eye Institute, National Institutes of Health. NR 42 TC 15 Z9 16 U1 0 U2 10 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 1 PY 2013 VL 191 IS 1 BP 415 EP 423 DI 10.4049/jimmunol.1201732 PG 9 WC Immunology SC Immunology GA 169FQ UT WOS:000320765000047 PM 23720812 ER PT J AU Ramos, VFML Karp, BI Lungu, C Alter, K Hallett, M AF Ramos, V. F. M. L. Karp, B., I Lungu, C. Alter, K. Hallett, M. TI Response to incobotulinumtoxinA after resistance to onabotulinumtoxinA and rimabotulinumtoxinB SO JOURNAL OF NEURAL TRANSMISSION LA English DT Meeting Abstract CT 2nd International Congress on Treatment of Dystonia together with the 1st International Congress on Rehabilitation of Dystonia CY MAY 08-11, 2013 CL Hannover, GERMANY C1 [Ramos, V. F. M. L.; Karp, B., I; Lungu, C.; Hallett, M.] NIH, Bethesda, MD 20892 USA. [Alter, K.] NIH, Funct & Appl Biomech Sect, Bethesda, MD 20892 USA. [Alter, K.] Mt Washington Pediat Hosp, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0300-9564 J9 J NEURAL TRANSM JI J. Neural Transm. PD JUL PY 2013 VL 120 IS 7 BP 1153 EP 1153 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 169RV UT WOS:000320798800061 ER PT J AU Ramos, VFML Karp, BI Hallett, M AF Ramos, V. F. M. L. Karp, B., I Hallett, M. TI Tricks to treatments: sensory tricks in dystonia SO JOURNAL OF NEURAL TRANSMISSION LA English DT Meeting Abstract CT 2nd International Congress on Treatment of Dystonia together with the 1st International Congress on Rehabilitation of Dystonia CY MAY 08-11, 2013 CL Hannover, GERMANY C1 [Ramos, V. F. M. L.; Karp, B., I; Hallett, M.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0300-9564 J9 J NEURAL TRANSM JI J. Neural Transm. PD JUL PY 2013 VL 120 IS 7 BP 1153 EP 1153 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 169RV UT WOS:000320798800060 ER PT J AU Penzes, P Buonanno, A Passafaro, M Sala, C Sweet, RA AF Penzes, Peter Buonanno, Andres Passafaro, Maria Sala, Carlo Sweet, Robert A. TI Developmental vulnerability of synapses and circuits associated with neuropsychiatric disorders SO JOURNAL OF NEUROCHEMISTRY LA English DT Review DE Alzheimer's disease; autism; dendritic spine; dopamine; ErbB4; GABAergic interneuron ID LINKED MENTAL-RETARDATION; AUTISM SPECTRUM DISORDER; CENTRAL-NERVOUS-SYSTEM; PARVALBUMIN-POSITIVE INTERNEURONS; HIPPOCAMPAL GAMMA OSCILLATIONS; DENDRITIC SPINE MORPHOGENESIS; GLUTAMIC-ACID DECARBOXYLASE; 22Q13.3 DELETION SYNDROME; INCREASED FAMILIAL RISK; EARLY-ONSET PSYCHOSIS AB Psychiatric and neurodegenerative disorders, including intellectual disability, autism spectrum disorders (ASD), schizophrenia (SZ), and Alzheimer's disease, pose an immense burden to society. Symptoms of these disorders become manifest at different stages of life: early childhood, adolescence, and late adulthood, respectively. Progress has been made in recent years toward understanding the genetic substrates, cellular mechanisms, brain circuits, and endophenotypes of these disorders. Multiple lines of evidence implicate excitatory and inhibitory synaptic circuits in the cortex and hippocampus as key cellular substrates of pathogenesis in these disorders. Excitatory/inhibitory balance - modulated largely by dopamine - critically regulates cortical network function, neural network activity (i.e. gamma oscillations) and behaviors associated with psychiatric disorders. Understanding the molecular underpinnings of synaptic pathology and neuronal network activity may thus provide essential insight into the pathogenesis of these disorders and can reveal novel drug targets to treat them. Here, we discuss recent genetic, neuropathological, and molecular studies that implicate alterations in excitatory and inhibitory synaptic circuits in the pathogenesis of psychiatric disorders across the lifespan. C1 [Penzes, Peter] Northwestern Univ, Dept Physiol, Feinberg Sch Med, Chicago, IL 60611 USA. [Penzes, Peter] Northwestern Univ, Dept Psychiat & Behav Sci, Feinberg Sch Med, Chicago, IL 60611 USA. [Buonanno, Andres] Eunice Shriver Kennedy NICHD, Mol Neurobiol Sect, NIH, Program Dev Neurobiol, Bethesda, MD USA. [Passafaro, Maria; Sala, Carlo] Univ Milan, CNR Inst Neurosci, Milan, Italy. [Passafaro, Maria; Sala, Carlo] Univ Milan, Dept Med Biotechnol & Translat Med, Milan, Italy. [Passafaro, Maria] CNR, Inst Neurosci, Dulbecco Telethon Inst, I-20133 Milan, Italy. [Sala, Carlo] Neurol Inst, Milan, Italy. [Sala, Carlo] Fdn Carlo Besta, Milan, Italy. [Sweet, Robert A.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Sweet, Robert A.] VA Pittsburgh Healthcare Syst, VISN Mental Illness Res Educ & Clin Ctr 4, Pittsburgh, PA USA. [Sweet, Robert A.] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15261 USA. RP Penzes, P (reprint author), Northwestern Univ, Dept Physiol, Feinberg Sch Med, 303 E,Chicago Ave, Chicago, IL 60611 USA. EM p-penzes@northwestern.edu RI Penzes, Peter/L-3987-2016; Sala, Carlo/A-2493-2009 OI Penzes, Peter/0000-0001-5449-1640; Sala, Carlo/0000-0003-0662-9523 FU NIH [MH071316, MH097216, MH071533, AG027224]; Eunice Shriver Kennedy National Institute of Child Health and Human Development Intramural Research Program; Veterans Health Administration [BX000452]; Comitato Telethon Fondazione Onlus [GGP09196, GGP11095, GGP12097, GGP11116B]; Fondazione CARI-PLO project [2009.264]; Italian Institute of Technology, Seed Grant, Ministry of Health in the frame of ERA-NET NEURON and PNR-CNR Aging Program FX This study was supported by NIH grants MH071316 and MH097216 to P. P., Eunice Shriver Kennedy National Institute of Child Health and Human Development Intramural Research Program to A. B., Veterans Health Administration Grant BX000452 and NIH Grants MH071533 and AG027224 to R. A. S. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Department of Veterans Affairs, the National Institutes of Health, or the United States government. We thank Ruoqi Gao for assistance with editing the manuscript. This study was financially supported by Comitato Telethon Fondazione Onlus, grant n. GGP09196 and GGP11095 (to CS), n. GGP12097 and GGP11116B (to MP) Fondazione CARI-PLO project number 2009.264, Italian Institute of Technology, Seed Grant, Ministry of Health in the frame of ERA-NET NEURON and PNR-CNR Aging Program 2012-2014 (to CS). The authors declare no conflicts of interest. NR 217 TC 40 Z9 41 U1 5 U2 28 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD JUL PY 2013 VL 126 IS 2 BP 165 EP 182 DI 10.1111/jnc.12261 PG 18 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 175DY UT WOS:000321211700004 PM 23574039 ER PT J AU Whiting, DM Tomycz, ND Bailes, J de Jonge, L Lecoultre, V Wilent, B Alcindor, D Prostko, ER Cheng, BC Angle, C Cantella, D Whiting, BB Mizes, JS Finnis, KW Ravussin, E Oh, MY AF Whiting, Donald M. Tomycz, Nestor D. Bailes, Julian de Jonge, Lilian Lecoultre, Virgile Wilent, Bryan Alcindor, Dunbar Prostko, E. Richard Cheng, Boyle C. Angle, Cynthia Cantella, Diane Whiting, Benjamin B. Mizes, J. Scott Finnis, Kirk W. Ravussin, Eric Oh, Michael Y. TI Lateral hypothalamic area deep brain stimulation for refractory obesity: a pilot study with preliminary data on safety, body weight, and energy metabolism Clinical article SO JOURNAL OF NEUROSURGERY LA English DT Article DE obesity; weight loss; deep brain stimulation; energy metabolism; functional neurosurgery; respiratory chamber ID VENTROMEDIAL HYPOTHALAMUS; RATS; LESIONS; PREVALENCE; OVERWEIGHT; HUMANS; GAIN AB Object. Deep brain stimulation (DBS) of the lateral hypothalamic area (LHA) has been suggested as a potential treatment for intractable obesity. The authors present the 2-year safety results as well as early efficacy and metabolic effects in 3 patients undergoing bilateral LHA DBS in the first study of this approach in humans. Methods. Three patients meeting strict criteria for intractable obesity, including failed bariatric surgery, underwent bilateral implantation of LHA DBS electrodes as part of an institutional review board and FDA-approved pilot study. The primary focus of the study was safety; however, the authors also received approval to collect data on early efficacy including weight change and energy metabolism. Results. No serious adverse effects, including detrimental psychological consequences, were observed with continuous LHA DBS after a mean follow-up of 35 months (range 30-39 months). Three-dimensional nonlinear transformation of postoperative imaging superimposed onto brain atlas anatomy was used to confirm and study DBS contact proximity to the LHA. No significant weight loss trends were seen when DBS was programmed using standard settings derived from movement disorder DBS surgery. However, promising weight loss trends have been observed when monopolar DBS stimulation has been applied via specific contacts found to increase the resting metabolic rate measured in a respiratory chamber. Conclusions. Deep brain stimulation of the LHA may be applied safely to humans with intractable obesity. Early evidence for some weight loss under metabolically optimized settings provides the first "proof of principle" for this novel antiobesity strategy. A larger follow-up study focused on efficacy along with a more rigorous metabolic analysis is planned to further explore the benefits and therapeutic mechanism behind this investigational therapy. C1 [Whiting, Donald M.; Tomycz, Nestor D.; Alcindor, Dunbar; Prostko, E. Richard; Cheng, Boyle C.; Angle, Cynthia; Cantella, Diane; Whiting, Benjamin B.; Oh, Michael Y.] Allegheny Gen Hosp, Dept Neurosurg, Pittsburgh, PA 15212 USA. [Lecoultre, Virgile; Ravussin, Eric] Pennington Biomed Res Ctr, Baton Rouge, LA USA. [Wilent, Bryan] Sentient Med Syst, Clin Neurophysiol, Philadelphia, PA USA. [Mizes, J. Scott] W Virginia Univ, Sch Med, Morgantown, WV 26506 USA. [Bailes, Julian] Univ Chicago, Pritzker Sch Med, NorthShore Univ Hlth Syst, Evanston, IL USA. [de Jonge, Lilian] NIH, Bethesda, MD 20892 USA. [Finnis, Kirk W.] Medtron Neuromodulat, Minneapolis, MN USA. RP Tomycz, ND (reprint author), Allegheny Gen Hosp, 420 East North Ave,Suite 302, Pittsburgh, PA 15212 USA. EM ndtomycz@gmail.com FU Medtronic Co.; West Virginia University FX Medtronic Co. provided DBS hardware and financial support for this study. Medtronic Co. was not involved in preparation or submission of the manuscript. West Virginia University supplied grant support for this study. Dr. Tomycz participated on the Surgeon Advisory Board for St. Jude. Dr. Finnis is an employee of Medtronic. Dr. Oh is a consultant for St. Jude. NR 21 TC 33 Z9 34 U1 1 U2 10 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD JUL PY 2013 VL 119 IS 1 BP 56 EP 63 DI 10.3171/2013.2.JNS12903 PG 8 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 168WT UT WOS:000320739300015 PM 23560573 ER PT J AU Johnson, KA Minoshima, S Bohnen, NI Donohoe, KJ Foster, NL Herscovitch, P Karlawish, JH Rowe, CC Hedrick, S Pappas, V Carrillo, MC Hartley, DM AF Johnson, Keith A. Minoshima, Satoshi Bohnen, Nicolaas I. Donohoe, Kevin J. Foster, Norman L. Herscovitch, Peter Karlawish, Jason H. Rowe, Christopher C. Hedrick, Saima Pappas, Virginia Carrillo, Maria C. Hartley, Dean M. TI Update on Appropriate Use Criteria for Amyloid PET Imaging: Dementia Experts, Mild Cognitive Impairment, and Education SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE amyloid PET; dementia; Alzheimer disease ID ALZHEIMERS ASSOCIATION WORKGROUPS; DIAGNOSTIC GUIDELINES; NATIONAL INSTITUTE; RECOMMENDATIONS; DISEASE AB Amyloid PET imaging is a novel diagnostic test that can detect in living humans one of the two defining pathologic lesions of Alzheimer disease, amyloid-beta deposition in the brain. The Amyloid Imaging Task Force of the Alzheimer's Association and Society for Nuclear Medicine and Molecular Imaging previously published appropriate use criteria for amyloid PET as an important tool for increasing the certainty of a diagnosis of Alzheimer disease in specific patient populations. Here, the task force further clarifies and expands 3 topics discussed in the original paper: first, defining dementia experts and their use of proper documentation to demonstrate the medical necessity of an amyloid PET scan; second, identifying a specific subset of individuals with mild cognitive impairment for whom an amyloid PET scan is appropriate; and finally, developing educational programs to increase awareness of the amyloid PET appropriate use criteria and providing instructions on how this test should be used in the clinical decision-making process. C1 [Johnson, Keith A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Johnson, Keith A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. [Minoshima, Satoshi] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [Bohnen, Nicolaas I.] Univ Michigan, Dept Radiol, Ann Arbor, MI 48109 USA. [Bohnen, Nicolaas I.] Univ Michigan, Dept Neurol, Ann Arbor, MI USA. [Bohnen, Nicolaas I.] VA Ann Arbor Healthcare Syst, Ann Arbor, MI USA. [Donohoe, Kevin J.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Foster, Norman L.] Univ Utah, Dept Neurol, Salt Lake City, UT USA. [Herscovitch, Peter] NIH, PET Dept, Ctr Clin, Bethesda, MD 20892 USA. [Karlawish, Jason H.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Rowe, Christopher C.] Austin Hlth, Dept Nucl Med, Melbourne, Vic, Australia. [Rowe, Christopher C.] Austin Hlth, Ctr PET, Melbourne, Vic, Australia. [Hedrick, Saima; Pappas, Virginia] Soc Nucl Med & Mol Imaging, Reston, VA USA. [Carrillo, Maria C.; Hartley, Dean M.] Alzheimers Assoc, Div Med & Sci Relat, Chicago, IL 60601 USA. RP Carrillo, MC (reprint author), Alzheimers Assoc, Div Med & Sci Relat, 225 N Michigan Ave, Chicago, IL 60601 USA. EM maria.carrillo@alz.org FU NIA NIH HHS [P30 AG010124] NR 4 TC 19 Z9 19 U1 0 U2 3 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD JUL 1 PY 2013 VL 54 IS 7 BP 1011 EP 1013 DI 10.2967/jnumed.113.127068 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 173WR UT WOS:000321113500005 PM 23753186 ER PT J AU Gill, JM Saligan, L Lee, H Rotolo, S Szanton, S AF Gill, Jessica M. Saligan, Leorey Lee, Hyunhwa Rotolo, Susan Szanton, Sarah TI Women in recovery from PTSD have similar inflammation and quality of life as non-traumatized controls (vol 74, pg 301, 2013) SO JOURNAL OF PSYCHOSOMATIC RESEARCH LA English DT Correction C1 [Gill, Jessica M.; Saligan, Leorey; Lee, Hyunhwa] NINR, NIH, Bethesda, MD 20892 USA. [Gill, Jessica M.] George Mason Univ, Sch Nursing, Fairfax, VA 22030 USA. [Szanton, Sarah] Johns Hopkins Univ, Sch Nursing, Baltimore, MD 21218 USA. RP Gill, JM (reprint author), NINR, NIH, Bethesda, MD 20892 USA. EM jgill1376@yahoo.com NR 1 TC 0 Z9 0 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3999 J9 J PSYCHOSOM RES JI J. Psychosomat. Res. PD JUL PY 2013 VL 75 IS 1 BP 92 EP 92 DI 10.1016/j.jpsychores.2013.03.012 PG 1 WC Psychiatry SC Psychiatry GA 170CF UT WOS:000320826500017 ER PT J AU Madden, JT Toth, SJ Dettmar, CM Newman, JA Oglesbee, RA Hedderich, HG Everly, RM Becker, M Ronau, JA Buchanan, SK Cherezov, V Morrow, ME Xu, SL Ferguson, D Makarov, O Das, C Fischetti, R Simpson, GJ AF Madden, Jeremy T. Toth, Scott J. Dettmar, Christopher M. Newman, Justin A. Oglesbee, Robert A. Hedderich, Hartmut G. Everly, R. Michael Becker, Michael Ronau, Judith A. Buchanan, Susan K. Cherezov, Vadim Morrow, Marie E. Xu, Shenglan Ferguson, Dale Makarov, Oleg Das, Chittaranjan Fischetti, Robert Simpson, Garth J. TI Integrated nonlinear optical imaging microscope for on-axis crystal detection and centering at a synchrotron beamline SO JOURNAL OF SYNCHROTRON RADIATION LA English DT Article DE XRD; NLO; SHG; SONICC; centering; protein; TPE-UVF; microscopy; LCP; two-photon ID X-RAY-DIFFRACTION; THROUGHPUT MACROMOLECULAR CRYSTALLOGRAPHY; PROTEIN CRYSTALS; LIPIDIC MESOPHASES; MEMBRANE-PROTEINS; RADIATION-DAMAGE; FLUORESCENCE; CRYSTALLIZATION; PHOTODAMAGE; SCATTERING AB Nonlinear optical (NLO) instrumentation has been integrated with synchrotron X-ray diffraction (XRD) for combined single-platform analysis, initially targeting applications for automated crystal centering. Second-harmonic-generation microscopy and two-photon-excited ultraviolet fluorescence microscopy were evaluated for crystal detection and assessed by X-ray raster scanning. Two optical designs were constructed and characterized; one positioned downstream of the sample and one integrated into the upstream optical path of the diffractometer. Both instruments enabled protein crystal identification with integration times between 80 and 150 ms per pixel, representing a similar to 10(3)-10(4)-fold reduction in the per-pixel exposure time relative to X-ray raster scanning. Quantitative centering and analysis of phenylalanine hydroxylase from Chromobacterium violaceum cPAH, Trichinella spiralis deubiquitinating enzyme TsUCH37, human kappa-opioid receptor complex kOR-T4L produced in lipidic cubic phase (LCP), intimin prepared in LCP, and alpha-cellulose samples were performed by collecting multiple NLO images. The crystalline samples were characterized by single-crystal diffraction patterns, while alpha-cellulose was characterized by fiber diffraction. Good agreement was observed between the sample positions identified by NLO and XRD raster measurements for all samples studied. C1 [Madden, Jeremy T.; Toth, Scott J.; Dettmar, Christopher M.; Newman, Justin A.; Oglesbee, Robert A.; Hedderich, Hartmut G.; Everly, R. Michael; Ronau, Judith A.; Morrow, Marie E.; Das, Chittaranjan; Simpson, Garth J.] Purdue Univ, Dept Chem, W Lafayette, IN 47906 USA. [Becker, Michael; Xu, Shenglan; Ferguson, Dale; Makarov, Oleg; Fischetti, Robert] Argonne Natl Lab, Adv Photon Source, GM CA APS, Argonne, IL 60439 USA. [Buchanan, Susan K.] NIDDK, NIH, Bethesda, MD 20814 USA. [Cherezov, Vadim] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. RP Simpson, GJ (reprint author), Purdue Univ, Dept Chem, 560 Oval Dr, W Lafayette, IN 47906 USA. EM gsimpson@purdue.edu RI Cherezov, Vadim/L-9812-2013 OI Cherezov, Vadim/0000-0002-5265-3914 FU US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-SC0000997]; NIH-NIGMS [R01GM-103401]; National Cancer Institute [Y1-CO-1020]; National Institute of General Medical Sciences [Y1-GM-1104]; US Department of Energy, Basic Energy Sciences, Office of Science [DE-AC02-06CH11357]; NIH [P50 GM073197]; Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases FX The authors acknowledge Huixian Wu, Victoria J. Hall, Emma L. DeWalt, Valerie Pye, Martin Caffrey, Nicholas Noinaj and James W. Fairman for aiding in sample preparation. Instrumentation development was supported in part by the Center for Direct Catalytic Conversion of Biomass to Biofuels (C3Bio), an Energy Frontier Research Center funded by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, Award No. DE-SC0000997, and by the NIH-NIGMS through the R01GM-103401. GM/CA@APS has been funded in whole or in part with federal funds from the National Cancer Institute (Y1-CO-1020) and the National Institute of General Medical Sciences (Y1-GM-1104). Use of the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract No. DE-AC02-06CH11357. Support is also acknowledged from the NIH Common Fund in Structural Biology, grant P50 GM073197. SKB is supported by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. NR 46 TC 15 Z9 15 U1 2 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0909-0495 J9 J SYNCHROTRON RADIAT JI J. Synchrot. Radiat. PD JUL PY 2013 VL 20 BP 531 EP 540 DI 10.1107/S0909049513007942 PN 4 PG 10 WC Instruments & Instrumentation; Optics; Physics, Applied SC Instruments & Instrumentation; Optics; Physics GA 163UZ UT WOS:000320363700003 PM 23765294 ER PT J AU McDermott, A Jesus, AA Liu, Y Kim, P Jacks, J Sanchez, GAM Chen, YQ Kannan, A Schnebelen, A Emanuel, PD Shalin, S Hiatt, K Goldbach-Mansky, R Gao, L AF McDermott, Amelia Jesus, Adriana Almeida Liu, Yin Kim, Peter Jacks, Jennifer Sanchez, Gina A. Montealegre Chen, Yongqing Kannan, Aarthi Schnebelen, Alicia Emanuel, Peter D. Shalin, Sara Hiatt, Kim Goldbach-Mansky, Raphaela Gao, Ling TI A case of proteasome-associated auto-inflammatory syndrome with compound heterozygous mutations SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Letter ID SUBUNIT; LIPODYSTROPHY C1 [McDermott, Amelia] Univ Arkansas Med Sci, Coll Med, Little Rock, AR 72205 USA. [Kannan, Aarthi; Gao, Ling] Univ Arkansas Med Sci, Dept Dermatol, Little Rock, AR 72205 USA. [Schnebelen, Alicia; Shalin, Sara] Univ Arkansas Med Sci, Dept Pathol, Little Rock, AR 72205 USA. [Emanuel, Peter D.] Univ Arkansas Med Sci, Div Hematol Oncol, Little Rock, AR 72205 USA. [Jesus, Adriana Almeida; Liu, Yin; Kim, Peter; Sanchez, Gina A. Montealegre; Chen, Yongqing; Goldbach-Mansky, Raphaela] NIAMSD, Bethesda, MD 20892 USA. [Jacks, Jennifer] Jacks Dermatol, Pine Bluff, AR USA. [Hiatt, Kim] Dermatol PLLC PA, Little Rock, AR USA. RP Gao, L (reprint author), Univ Arkansas Med Sci, Dept Dermatol, 4301 W Markham,Slot 576, Little Rock, AR 72205 USA. EM LGAO@uams.edu OI Hiatt, Kim/0000-0003-3214-4917; Emanuel, Peter/0000-0002-9764-2434 FU Intramural NIH HHS [ZIA AR041138-08, ZIA AR041138-09, ZIA AR041138-10] NR 5 TC 6 Z9 6 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD JUL PY 2013 VL 69 IS 1 BP E29 EP E32 DI 10.1016/j.jaad.2013.01.015 PG 5 WC Dermatology SC Dermatology GA 165UG UT WOS:000320510100011 PM 23768303 ER PT J AU Osinusi, A Naggie, S AF Osinusi, Anuoluwapo Naggie, Susanna TI Boceprevir for HCV in patients with HIV: where next? SO LANCET INFECTIOUS DISEASES LA English DT Editorial Material ID CHRONIC HEPATITIS-C; ALPHA-2A PLUS RIBAVIRIN; GENOTYPE 1 INFECTION; VIRUS C1 [Osinusi, Anuoluwapo] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Naggie, Susanna] Duke Univ, Med Ctr, Div Infect Dis, Durham, NC 27710 USA. RP Osinusi, A (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM susanna.naggie@duke.edu NR 15 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1473-3099 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD JUL PY 2013 VL 13 IS 7 BP 563 EP 564 DI 10.1016/S1473-3099(13)70162-2 PG 2 WC Infectious Diseases SC Infectious Diseases GA 172UN UT WOS:000321030500004 PM 23768748 ER PT J AU Redd, AD Quinn, TC Tobian, AAR AF Redd, Andrew D. Quinn, Thomas C. Tobian, Aaron A. R. TI Frequency and implications of HIV superinfection SO LANCET INFECTIOUS DISEASES LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; INJECTION-DRUG USERS; TYPE-1 SUPERINFECTION; PRIMARY INFECTION; VIRAL LOAD; ANTIRETROVIRAL THERAPY; DISEASE PROGRESSION; MALE CIRCUMCISION; AMSTERDAM COHORT; SEXUAL-BEHAVIOR AB HIV superinfection occurs when an individual with HIV is infected with a new distinct HIV viral strain. Superinfection has been reported throughout the world, and studies have recorded incidence rates of 0-7-7% per year. Use of next-generation sequencing has improved detection of superinfection, which can be transmitted by injecting drug use and sexual intercourse. Superinfection might have incidence rates comparable to those of initial HIV infection. Clinicians should encourage safe sexual and injecting drug use practices for HIV-infected patients because superinfection has detrimental effects on clinical outcomes and could pose a concern for large-scale antiretroviral treatment plans. The occurrence of superinfection has implications for vaccine research, since it seems initial HIV infection is not fully protective against a subsequent infection. Additional collaborative research could benefit care of patients and inform future vaccine design. C1 [Redd, Andrew D.; Quinn, Thomas C.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Tobian, Aaron A. R.] Johns Hopkins Univ, Dept Pathol, Sch Med, Baltimore, MD 21287 USA. RP Tobian, AAR (reprint author), Johns Hopkins Univ, Dept Pathol, Carnegie 437,600 North Wolfe St, Baltimore, MD 21287 USA. EM atobian1@jhmi.edu FU NIH [1K23AI093152-01A1]; Doris Duke Charitable Foundation Clinician Scientist Development Award [22006.02]; Division of Intramural Research, National Institutes of Allergy and Infectious Diseases, National Institutes of Health FX AART is supported by the NIH (1K23AI093152-01A1) and Doris Duke Charitable Foundation Clinician Scientist Development Award (#22006.02). ADR and TCQ are supported by the Division of Intramural Research, National Institutes of Allergy and Infectious Diseases, National Institutes of Health. These funding sources had no involvement in the writing of the manuscript or the decision to submit it for publication. NR 73 TC 34 Z9 37 U1 0 U2 18 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1473-3099 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD JUL PY 2013 VL 13 IS 7 BP 622 EP 628 DI 10.1016/S1473-3099(13)70066-5 PG 7 WC Infectious Diseases SC Infectious Diseases GA 172UN UT WOS:000321030500022 PM 23726798 ER PT J AU Scalzo, F Alger, JR Hu, X Saver, JL Dani, KA Muir, KW Demchuk, AM Coutts, SB Luby, M Warach, S Liebeskind, DS AF Scalzo, Fabien Alger, Jeffry R. Hu, Xiao Saver, Jeffrey L. Dani, Krishna A. Muir, Keith W. Demchuk, Andrew M. Coutts, Shelagh B. Luby, Marie Warach, Steven Liebeskind, David S. CA STIR VISTA Imaging Investigators TI Multi-center prediction of hemorrhagic transformation in acute ischemic stroke using permeability imaging features SO MAGNETIC RESONANCE IMAGING LA English DT Article DE Brain ischemia; Hemorrhagic transformation; Prediction; Acute stroke diagnostic; Stroke; Permeability ID BRAIN-BARRIER-PERMEABILITY; TISSUE FATE; THROMBOLYSIS; MODEL; MRI AB Permeability images derived from magnetic resonance (MR) perfusion images are sensitive to blood brain barrier derangement of the brain tissue and have been shown to correlate with subsequent development of hemorrhagic transformation (HT) in acute ischemic stroke. This paper presents a multi-center retrospective study that evaluates the predictive power in terms of HT of six permeability MRI measures including contrast slope (CS), final contrast (FC), maximum peak bolus concentration (MPB), peak bolus area (PB), relative recirculation (rR), and percentage recovery (%R). Dynamic T2*-weighted perfusion MR images were collected from 263 acute ischemic stroke patients from four medical centers. An essential aspect of this study is to exploit a classifier-based framework to automatically identify predictive patterns in the overall intensity distribution of the permeability maps. The model is based on normalized intensity histograms that are used as input features to the predictive model. Linear and nonlinear predictive models are evaluated using a cross-validation to measure generalization power on new patients and a comparative analysis is provided for the different types of parameters. Results demonstrate that perfusion imaging in acute ischemic stroke can predict HT with an average accuracy of more than 85% using a predictive model based on a nonlinear regression model. Results also indicate that the permeability feature based on the percentage of recovery performs significantly better than the other features. This novel model may be used to refine treatment decisions in acute stroke. (c) 2013 Elsevier Inc. All rights reserved. C1 [Scalzo, Fabien; Alger, Jeffry R.; Saver, Jeffrey L.; Liebeskind, David S.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90095 USA. [Hu, Xiao] Univ Calif Los Angeles, Neurosurg Neural Syst & Dynam Lab NSDL, Los Angeles, CA USA. [Dani, Krishna A.; Muir, Keith W.] Univ Glasgow, Inst Neurosci & Psychol, Glasgow G12 8QQ, Lanark, Scotland. [Demchuk, Andrew M.; Coutts, Shelagh B.] Univ Calgary, Hotchkiss Brain Inst, Dept Radiol, Calgary, AB, Canada. [Demchuk, Andrew M.; Coutts, Shelagh B.] Univ Calgary, Hotchkiss Brain Inst, Dept Clin Neurosci, Calgary, AB, Canada. [Luby, Marie; Warach, Steven] NIH, Sect Stroke Diagnost & Therapeut, Bethesda, MD 20892 USA. RP Scalzo, F (reprint author), Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90095 USA. EM fabien.scalzo@gmail.com RI Muir, Keith/A-7670-2011; OI Muir, Keith/0000-0001-9535-022X; Saver, Jeffrey/0000-0001-9141-2251 FU National Institute of Neurological Disorders and Stroke (NINDS); National Institutes of Health [K23-NS054084, P50-NS044378, R01-NS066008]; Canadian Institutes for Health Research (CIHR) [MOP-118096]; Heart and Stroke Foundation (HSF) of Alberta; NWT; Nunavut FX This work was supported by the National Institute of Neurological Disorders and Stroke (NINDS), grants from the National Institutes of Health K23-NS054084, P50-NS044378, R01-NS066008, and the Canadian Institutes for Health Research (CIHR MOP-118096) and Heart and Stroke Foundation (HSF) of Alberta, NWT and Nunavut. STIR and VISTA Imaging steering committee: Steven Warach (co-chair), Gregory Albers, Stephen Davis, Geoffrey Donnan, Marc Fisher, Tony Furlan, James Grotta, Werner Hacke, Dong-Wha Kang, Chelsea Kidwell, Walter Koroshetz, Kennedy R. Lees, Michael Lev, David Liebeskind, A. Gregory Sorensen, Vincent Thijs, Gotz Thomalla, Joanna Wardlaw, Max Wintermark (co-chair). NR 31 TC 12 Z9 13 U1 0 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0730-725X J9 MAGN RESON IMAGING JI Magn. Reson. Imaging PD JUL PY 2013 VL 31 IS 6 BP 961 EP 969 DI 10.1016/j.mri.2013.03.013 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 169ZF UT WOS:000320818600020 PM 23587928 ER PT J AU Lopez, G Sidransky, E AF Lopez, Grisel Sidransky, Ellen TI Predicting parkinsonism: New opportunities from Gaucher disease SO MOLECULAR GENETICS AND METABOLISM LA English DT Editorial Material DE Parkinson disease; Gaucher disease; Presymptomatic; Optical coherence tomography; Glucocerebrosidase; Biomarker C1 [Lopez, Grisel; Sidransky, Ellen] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Sidransky, E (reprint author), NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bldg 35,Room 1A213,35 Convent Dr,MSC 3708, Bethesda, MD 20892 USA. EM sidranse@mail.nih.gov FU Intramural NIH HHS [Z99 HG999999] NR 14 TC 1 Z9 1 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JUL PY 2013 VL 109 IS 3 BP 235 EP 236 DI 10.1016/j.ymgme.2013.04.012 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 170DB UT WOS:000320829000001 PM 23665160 ER PT J AU Kano, S Colantuoni, C Han, F Zhou, Z Yuan, Q Wilson, A Takayanagi, Y Lee, Y Rapoport, J Eaton, W Cascella, N Ji, H Goldman, D Sawa, A AF Kano, S. Colantuoni, C. Han, F. Zhou, Z. Yuan, Q. Wilson, A. Takayanagi, Y. Lee, Y. Rapoport, J. Eaton, W. Cascella, N. Ji, H. Goldman, D. Sawa, A. TI Genome-wide profiling of multiple histone methylations in olfactory cells: further implications for cellular susceptibility to oxidative stress in schizophrenia SO MOLECULAR PSYCHIATRY LA English DT Letter ID CHIP-SEQ DATA C1 [Kano, S.; Colantuoni, C.; Wilson, A.; Cascella, N.; Sawa, A.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Colantuoni, C.; Han, F.; Ji, H.] Johns Hopkins Univ, Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Zhou, Z.; Yuan, Q.; Goldman, D.] NIAAA, Neurogenet Lab, Bethesda, MD USA. [Takayanagi, Y.; Eaton, W.] Johns Hopkins Univ, Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Lee, Y.; Rapoport, J.] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Sawa, A (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. EM asawa1@jhmi.edu RI Goldman, David/F-9772-2010; Kano, Shin-ichi/F-4144-2015 OI Goldman, David/0000-0002-1724-5405; Kano, Shin-ichi/0000-0002-5171-3436 FU Intramural NIH HHS [Z01 AA000301-09]; NIMH NIH HHS [K99 MH093458] NR 10 TC 34 Z9 34 U1 0 U2 2 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 JUL PY 2013 VL 18 IS 7 BP 740 EP 742 DI 10.1038/mp.2012.120 PG 3 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 168NL UT WOS:000320712700001 PM 22925834 ER PT J AU Kano, S Colantuoni, C Han, F Zhou, Z Yuan, Q Wilson, A Takayanagi, Y Lee, Y Rapoport, J Eaton, W Cascella, N Ji, H Goldman, D Sawa, A AF Kano, S. Colantuoni, C. Han, F. Zhou, Z. Yuan, Q. Wilson, A. Takayanagi, Y. Lee, Y. Rapoport, J. Eaton, W. Cascella, N. Ji, H. Goldman, D. Sawa, A. TI PAC1 receptor (ADCYAP1R1) genotype is associated with dark-enhanced startle in children SO MOLECULAR PSYCHIATRY LA English DT Letter ID POSTTRAUMATIC-STRESS-DISORDER; ANXIETY C1 [Kano, S.; Colantuoni, C.; Wilson, A.; Cascella, N.; Sawa, A.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Colantuoni, C.; Han, F.] Johns Hopkins Univ, Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Zhou, Z.; Yuan, Q.; Goldman, D.] NIAAA, Neurogenet Lab, Bethesda, MD USA. [Takayanagi, Y.; Eaton, W.] Johns Hopkins Univ, Dept Mental Hlth, Sch Publ Hlth, Baltimore, MD USA. [Lee, Y.; Rapoport, J.] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Sawa, A (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. EM asawa1@jhmi.edu OI Ressler, Kerry/0000-0002-5158-1103 NR 10 TC 0 Z9 0 U1 1 U2 3 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 JUL PY 2013 VL 18 IS 7 BP 742 EP 743 DI 10.1038/mp.2012.98 PG 3 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 168NL UT WOS:000320712700002 ER PT J AU Stewart, SE Yu, D Scharf, JM Neale, BM Fagerness, JA Mathews, CA Arnold, PD Evans, PD Gamazon, ER Osiecki, L McGrath, L Haddad, S Crane, J Hezel, D Illman, C Mayerfeld, C Konkashbaev, A Liu, C Pluzhnikov, A Tikhomirov, A Edlund, CK Rauch, SL Moessner, R Falkai, P Maier, W Ruhrmann, S Grabe, HJ Lennertz, L Wagner, M Bellodi, L Cavallini, MC Richter, MA Cook, EH Kennedy, JL Rosenberg, D Stein, DJ Hemmings, SMJ Lochner, C Azzam, A Chavira, DA Fournier, E Garrido, H Sheppard, B Umana, P Murphy, DL Wendland, JR Veenstra-VanderWeele, J Denys, D Blom, R Deforce, D Van Nieuwerburgh, F Westenberg, HGM Walitza, S Egberts, K Renner, T Miguel, EC Cappi, C Hounie, AG do Rosario, MC Sampaio, AS Vallada, H Nicolini, H Lanzagorta, N Camarena, B Delorme, R Leboyer, M Pato, CN Pato, MT Voyiaziakis, E Heutink, P Cath, DC Posthuma, D Smit, JH Samuels, J Bienvenu, OJ Cullen, B Fyer, AJ Grados, MA Greenberg, BD McCracken, JT Riddle, MA Wang, Y Coric, V Leckman, JF Bloch, M Pittenger, C Eapen, V Black, DW Ophoff, RA Strengman, E Cusi, D Turiel, M Frau, F Macciardi, F Gibbs, JR Cookson, MR Singleton, A Hardy, J Crenshaw, AT Parkin, MA Mirel, DB Conti, DV Purcell, S Nestadt, G Hanna, GL Jenike, MA Knowles, JA Cox, N Pauls, DL AF Stewart, S. E. Yu, D. Scharf, J. M. Neale, B. M. Fagerness, J. A. Mathews, C. A. Arnold, P. D. Evans, P. D. Gamazon, E. R. Osiecki, L. McGrath, L. Haddad, S. Crane, J. Hezel, D. Illman, C. Mayerfeld, C. Konkashbaev, A. Liu, C. Pluzhnikov, A. Tikhomirov, A. Edlund, C. K. Rauch, S. L. Moessner, R. Falkai, P. Maier, W. Ruhrmann, S. Grabe, H-J Lennertz, L. Wagner, M. Bellodi, L. Cavallini, M. C. Richter, M. A. Cook, E. H., Jr. Kennedy, J. L. Rosenberg, D. Stein, D. J. Hemmings, S. M. J. Lochner, C. Azzam, A. Chavira, D. A. Fournier, E. Garrido, H. Sheppard, B. Umana, P. Murphy, D. L. Wendland, J. R. Veenstra-VanderWeele, J. Denys, D. Blom, R. Deforce, D. Van Nieuwerburgh, F. Westenberg, H. G. M. Walitza, S. Egberts, K. Renner, T. Miguel, E. C. Cappi, C. Hounie, A. G. do Rosario, M. Conceicao Sampaio, A. S. Vallada, H. Nicolini, H. Lanzagorta, N. Camarena, B. Delorme, R. Leboyer, M. Pato, C. N. Pato, M. T. Voyiaziakis, E. Heutink, P. Cath, D. C. Posthuma, D. Smit, J. H. Samuels, J. Bienvenu, O. J. Cullen, B. Fyer, A. J. Grados, M. A. Greenberg, B. D. McCracken, J. T. Riddle, M. A. Wang, Y. Coric, V. Leckman, J. F. Bloch, M. Pittenger, C. Eapen, V. Black, D. W. Ophoff, R. A. Strengman, E. Cusi, D. Turiel, M. Frau, F. Macciardi, F. Gibbs, J. R. Cookson, M. R. Singleton, A. Hardy, J. Crenshaw, A. T. Parkin, M. A. Mirel, D. B. Conti, D. V. Purcell, S. Nestadt, G. Hanna, G. L. Jenike, M. A. Knowles, J. A. Cox, N. Pauls, D. L. CA North Amer Brain Expression Consor UK Brain Expression Database TI Genome-wide association study of obsessive-compulsive disorder SO MOLECULAR PSYCHIATRY LA English DT Article DE DLGAP; genetic; genomic; GWAS; neurodevelopmental disorder; obsessive-compulsive disorder ID OCD COLLABORATIVE GENETICS; FAMILY-BASED ASSOCIATION; QUANTITATIVE TRAIT LOCI; TRANSPORTER GENE; LINKAGE; SLC1A1; SNPS; TWIN; REPLICATION; EXPRESSION AB Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1465 cases, 5557 ancestry-matched controls and 400 complete trios remained, with a common set of 469 410 autosomal and 9657 X-chromosome single nucleotide polymorphisms (SNPs). Ancestry-stratified case-control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case-control analysis, the lowest two P-values were located within DLGAP1 (P = 2.49 x 10(-6) and P = 3.44 x 10(-6)), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a P-value = 3.84 x 10(-8). However, when trios were meta-analyzed with the case-control samples, the P-value for this variant was 3.62 x 10(-5), losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio-case-control sample, a significant enrichment of methylation QTLs (P < 0.001) and frontal lobe expression quantitative trait loci (eQTLs) (P = 0.001) was observed within the top-ranked SNPs (P < 0.01) from the trio-case-control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD. C1 [Stewart, S. E.; Yu, D.; Scharf, J. M.; Neale, B. M.; Fagerness, J. A.; Osiecki, L.; McGrath, L.; Haddad, S.; Crane, J.; Hezel, D.; Illman, C.; Mayerfeld, C.; Purcell, S.; Jenike, M. A.; Pauls, D. L.] Harvard Univ, Sch Med, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA USA. [Stewart, S. E.; Yu, D.; Scharf, J. M.; Fagerness, J. A.; Osiecki, L.; McGrath, L.; Haddad, S.; Crane, J.; Hezel, D.; Illman, C.; Mayerfeld, C.; Purcell, S.; Jenike, M. A.; Pauls, D. L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Stewart, S. E.] Univ British Columbia, British Columbia Mental Hlth & Addict Res Inst, Vancouver, BC V5Z 1M9, Canada. [Scharf, J. M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Scharf, J. M.; Purcell, S.] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. [Neale, B. M.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Scharf, J. M.; Neale, B. M.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Mathews, C. A.; Azzam, A.; Sheppard, B.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Arnold, P. D.] Hosp Sick Children, Program Genet & Genome Biol, Toronto, ON M5G 1X8, Canada. [Arnold, P. D.; Richter, M. A.; Kennedy, J. L.] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Evans, P. D.; Gamazon, E. R.; Konkashbaev, A.; Pluzhnikov, A.; Tikhomirov, A.; Cox, N.] Univ Chicago, Dept Med, Med Genet Sect, Chicago, IL 60637 USA. [Liu, C.] Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. [Edlund, C. K.; Conti, D. V.] Univ So Calif, Zilkha Neurogenet Inst, Keck Sch Med, Dept Preventat Med,Div Biostat, Los Angeles, CA USA. [Edlund, C. K.; Conti, D. V.] Univ So Calif, Keck Sch Med, Epigenome Ctr, Los Angeles, CA 90033 USA. [Rauch, S. L.] Partners Psychiat, Boston, MA USA. [Rauch, S. L.] McLean Hosp, Boston, MA USA. [Moessner, R.; Maier, W.; Lennertz, L.; Wagner, M.] Univ Bonn, Dept Psychiat & Psychotherapy, Bonn, Germany. [Falkai, P.] Univ Gottingen, Dept Psychiat & Psychotherapy, D-37073 Gottingen, Germany. [Ruhrmann, S.] Univ Cologne, Dept Psychiat & Psychotherapy, D-50931 Cologne, Germany. [Grabe, H-J] Univ Med Greifswald, Helios Hosp Stralsund, Dept Psychiat & Psychotherapy, Greifswald, Germany. [Bellodi, L.] Psychiat Univ Vita Salute San Raffaele, Milan, Italy. [Cavallini, M. C.] Fdn Ctr San Raffaele Monte Tabor, Milan, Italy. [Richter, M. A.] Sunnybrook Hlth Sci Ctr, Dept Psychiat, Toronto, ON M4N 3M5, Canada. [Cook, E. H., Jr.] Univ Illinois, Dept Psychiat, Inst Juvenile Res, Chicago, IL 60612 USA. [Kennedy, J. L.] Ctr Addict & Mental Hlth, Toronto, ON, Canada. [Rosenberg, D.] Wayne State Univ, Detroit, MI USA. [Rosenberg, D.] Childrens Hosp Michigan, Detroit, MI 48201 USA. [Stein, D. J.] Univ Cape Town, ZA-7925 Cape Town, South Africa. [Hemmings, S. M. J.; Lochner, C.] Univ Stellenbosch, ZA-7600 Stellenbosch, South Africa. [Chavira, D. A.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Fournier, E.; Garrido, H.; Umana, P.] Hosp Nacl Ninos Dr Carlos Saenz Herrera, San Jose, Costa Rica. [Murphy, D. L.; Wendland, J. R.] NIMH, Lab Clin Sci, Intramural Res Program, Bethesda, MD 20892 USA. [Wendland, J. R.] F Hoffmann Roche Ltd, CNS Clin Biomarker Grp, Pharma Res & Early Dev, Basel, Switzerland. [Veenstra-VanderWeele, J.] Vanderbilt Univ, Kennedy Ctr Res Human Dev, Dept Psychiat, Nashville, TN 37235 USA. [Veenstra-VanderWeele, J.] Vanderbilt Univ, Kennedy Ctr Res Human Dev, Dept Pediat, Nashville, TN 37235 USA. [Veenstra-VanderWeele, J.] Vanderbilt Univ, Kennedy Ctr Res Human Dev, Dept Pharmacol, Nashville, TN 37235 USA. [Veenstra-VanderWeele, J.] Vanderbilt Univ, Inst Brain, Nashville, TN 37235 USA. [Denys, D.; Blom, R.; Westenberg, H. G. M.] Univ Amsterdam, Acad Med Ctr, Dept Psychiat, NL-1105 AZ Amsterdam, Netherlands. [Denys, D.; Blom, R.; Westenberg, H. G. M.] Netherlands Inst Neurosci, Amsterdam, Netherlands. [Deforce, D.; Van Nieuwerburgh, F.] Univ Ghent, Lab Pharmaceut Biotechnol, B-9000 Ghent, Belgium. [Walitza, S.] Univ Zurich, Dept Child & Adolescent Psychiat, Zurich, Switzerland. [Egberts, K.; Renner, T.] Univ Wurzburg, Dept Child & Adolescent Psychiat Psychosomat & Ps, D-97070 Wurzburg, Germany. [Miguel, E. C.; Cappi, C.; Hounie, A. G.; do Rosario, M. Conceicao; Sampaio, A. S.; Vallada, H.] Univ Sao Paulo, Fac Med, Dept Psychiat, Sao Paulo, Brazil. [Sampaio, A. S.] Univ Fed Bahia, Univ Hlth Care Serv SMURB, Salvador, BA, Brazil. [Nicolini, H.] Univ Mexico City, Ctr Genom Sci, Mexico City, DF, Mexico. [Nicolini, H.; Lanzagorta, N.] Carracci Med Grp, Mexico City, DF, Mexico. [Camarena, B.] Inst Nacl Psiquiatria Ramon de la Fuente Muniz, Depto Genet Psiquiatr, Mexico City, DF, Mexico. [Delorme, R.; Leboyer, M.] Hop Robert Debre, AP HP, Dept Child & Adolescent Psychiat, INSERM,U955, F-75019 Paris, France. [Delorme, R.; Leboyer, M.] Inst Mondor Rech Biomed, Creteil, France. [Delorme, R.; Leboyer, M.] French Natl Sci Fdn, Fdn Fondamental, Creteil, France. [Pato, C. N.; Pato, M. T.; Voyiaziakis, E.; Knowles, J. A.] Univ So Calif, Keck Sch Med, Zilkha Neurogenet Inst, Dept Psychiat & Behav Sci, Los Angeles, CA 90033 USA. [Heutink, P.; Posthuma, D.] Vrije Univ Amsterdam, Med Ctr Amsterdam, Dept Clin Genet, Sect Med Gen, Amsterdam, Netherlands. [Cath, D. C.] Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Utrecht, Netherlands. [Cath, D. C.] Univ Utrecht, Dept Clin & Hlth Psychol, Utrecht, Netherlands. [Cath, D. C.; Smit, J. H.] Vrije Univ Amsterdam, Med Ctr, EMGO Inst, Dept Psychiat, Utrecht, Netherlands. [Samuels, J.; Bienvenu, O. J.; Cullen, B.; Grados, M. A.; Riddle, M. A.; Wang, Y.; Nestadt, G.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Fyer, A. J.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. [Fyer, A. J.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Greenberg, B. D.] Butler Hosp, Brown Med Sch, Dept Psychiat & Human Behav, Providence, RI 02906 USA. [McCracken, J. T.] Univ Calif Los Angeles, Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Coric, V.; Leckman, J. F.; Bloch, M.; Pittenger, C.] Yale Univ, Ctr Child Study, New Haven, CT 06520 USA. [Coric, V.; Bloch, M.; Pittenger, C.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Eapen, V.] Univ New S Wales, Acad Unit Child Psychiat, South West Sydney AUCS, Sydney, NSW, Australia. [Black, D. W.] Univ Iowa, Roy J & Lucille A Carver Coll Med, Iowa City, IA USA. [Ophoff, R. A.; Strengman, E.] UCLA Ctr Neurobehav Genet, Los Angeles, CA USA. [Ophoff, R. A.; Strengman, E.] Univ Med Ctr Utrecht, Utrecht, Netherlands. [Cusi, D.; Frau, F.] Univ Milan, Grad Sch Nephrol, Dept Med Surg & Dent, Milan, Italy. [Cusi, D.] San Paolo Hosp, Div Nephrol, Milan, Italy. [Turiel, M.] Univ Milan, Dept Hlth Technol, Milan, Italy. [Frau, F.] Filarete Fdn, Milan, Italy. [Macciardi, F.] Univ Calif Irvine, Sch Med, Dept Psychiat & Human Behav, Irvine, CA 92717 USA. [Gibbs, J. R.; Cookson, M. R.; Singleton, A.] NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. [Hardy, J.] UCL, Dept Mol Neurosci, Inst Neurol, London, England. [Crenshaw, A. T.; Parkin, M. A.; Mirel, D. B.; Purcell, S.] Broad Inst Harvard MIT, Cambridge, MA USA. RP Stewart, SE (reprint author), Univ British Columbia, Dept Psychiat, OCD Clin, BCMHARI,CFRI, A3-118,938 West 28th Ave, Vancouver, BC V5Z 4H4, Canada. EM sevelynstewart@gmail.com; dpauls@pngu.mgh.harvard.edu RI Macciardi, Fabio/N-3768-2014; Wagner, Michael/E-2325-2011; Stein, Dan/A-1752-2008; Trabzuni, Daniah/C-4034-2012; Vallada, Homero/D-1333-2014; Traynor, Bryan/G-5690-2010; Renner, Tobias/I-2120-2013; Hardy, John/C-2451-2009; Deforce, Dieter/J-4725-2013; SAMPAIO, ALINE/M-1229-2013; Singleton, Andrew/C-3010-2009; Weale, Michael/F-2587-2010; Stewart, Evelyn/K-6961-2014; Van Nieuwerburgh, Filip/H-9697-2015; Veenstra-VanderWeele, Jeremy/K-1935-2015; OI Macciardi, Fabio/0000-0003-0537-4266; Wagner, Michael/0000-0003-2589-6440; Stein, Dan/0000-0001-7218-7810; Trabzuni, Daniah/0000-0003-4826-9570; Nicolini, Humberto/0000-0003-2494-0067; Hanna, Gregory/0000-0002-0742-6990; Samuels, Jack/0000-0002-6715-7905; Azzam, Amin/0000-0002-7024-7450; Walitza, Susanne/0000-0002-8161-8683; Vallada, Homero/0000-0001-5123-8295; Deforce, Dieter/0000-0002-0635-661X; SAMPAIO, ALINE/0000-0001-5568-6167; Weale, Michael/0000-0003-4593-1186; Van Nieuwerburgh, Filip/0000-0001-8815-5485; Veenstra-VanderWeele, Jeremy/0000-0002-6349-1076; Hemmings, Sian/0000-0001-8461-1017; Zonderman, Alan B/0000-0002-6523-4778; Stewart, S. Evelyn/0000-0002-0994-6383; Lanzagorta, Nuria/0000-0001-6769-6813; Gamazon, Eric/0000-0003-4204-8734 FU Judah Foundation; NIH [MH079489, MH073250]; American Recovery and Re-investment Act (ARRA) awards [NS40024-07S1, NS16648-29S1]; American Academy of Child and Adolescent Psychiatry (AACAP); Anxiety Disorders Association of America (ADAA); University of British Columbia; Michael Smith Foundation Clinical Research Scholar Award; Tourette Syndrome Association; American Academy of Neurology Foundation; National Center for Research Resources [RR020278]; NIH Genes, Environment and Health Initiative [GEI] [U01 HG004422]; NIH GEI [U01HG004438]; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; NIH contract 'High throughput genotyping for studying the genetic contributions to human disease' [HHSN268200782096C]; UK Medical Research Council; National Institute on Aging, National Institutes of Health, Department of Health and Human Services [Z01 AG000932-02] FX The authors would like to express their utmost gratitude to the OCD-affected families who participated in this research. In addition, they would like to thank the International OCD Foundation (IOCDF) for their role in establishing the IOCDF Genetics Collaborative, as well as other individuals who played roles in assisting this study, including Rhonda Ellwyn, Katherine Beattie, Colm O'Dushlaine, Doug Ruderfer, Priya Moorjani and V. Guttenthaler. This work was supported primarily by a grant from the Judah Foundation (a private, non-industry related foundation established by a family affected by OCD), NIH grants MH079489 and MH073250 to DLP, American Recovery and Re-investment Act (ARRA) awards NS40024-07S1 and NS16648-29S1 to DLP, by an American Academy of Child and Adolescent Psychiatry (AACAP) Early Investigator Research Grant, an Anxiety Disorders Association of America (ADAA) Junior Investigator Research Grant, the University of British Columbia and a Michael Smith Foundation Clinical Research Scholar Award to SES, and grants from the Tourette Syndrome Association (DLP and JMS), the American Academy of Neurology Foundation (JMS) and NIH grant MH085057 to JMS. The Broad Institute Center for Genotyping and Analysis was supported by grant U54 RR020278 from the National Center for Research Resources. Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment and Health Initiative [GEI] (U01 HG004422). SAGE is one of the genome-wide association studies funded as part of the Gene Environment Association Studies (GENEVA) under GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of data sets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (COGA; U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the Family Study of Cocaine Dependence (FSCD; R01 DA013423). Funding support for related genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the NIH contract 'High throughput genotyping for studying the genetic contributions to human disease' (HHSN268200782096C). The data sets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi/study_id = phs000092.v1.p1 through dbGaP accession number phs000092.v1.p. Frontal lobe eQTL data was provided by the North American Brain Expression Consortium and the UK Human Brain Expression Database. Funding support for generation of the eQTL data was provided by the UK Medical Research Council and the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services project Z01 AG000932-02. The North American Brain Expression Consortium comprises: Sampath Arepalli, Mark R Cookson, Allissa Dillman, Luigi Ferrucci, J Raphael Gibbs, Dena G Hernandez, Robert Johnson, Dan L Longo, Michael A Nalls, Richard O0Brien, Andrew Singleton, Bryan Traynor, Juan Troncoso, Marcel van der Brug, H Ronald Zielke and Alan Zonderman.; The UK Human Brain Expression Database membership comprises: John A Hardy, Mina Ryten, Colin Smith, Daniah Trabzuni, Robert Walker and Mike Weale. None of the funding sources supporting this work had any influence or played any role in: (a) the design or conduct of the study; (b) management, analysis or interpretation of the data; or c) preparation, review or approval of the manuscript. NR 71 TC 76 Z9 79 U1 4 U2 54 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 JUL PY 2013 VL 18 IS 7 BP 788 EP 798 DI 10.1038/mp.2012.85 PG 11 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 168NL UT WOS:000320712700012 PM 22889921 ER PT J AU Gunduz-Cinar, O MacPherson, KP Cinar, R Gamble-George, J Sugden, K Williams, B Godlewski, G Ramikie, TS Gorka, AX Alapafuja, SO Nikas, SP Makriyannis, A Poulton, R Patel, S Hariri, AR Caspi, A Moffitt, TE Kunos, G Holmes, A AF Gunduz-Cinar, O. MacPherson, K. P. Cinar, R. Gamble-George, J. Sugden, K. Williams, B. Godlewski, G. Ramikie, T. S. Gorka, A. X. Alapafuja, S. O. Nikas, S. P. Makriyannis, A. Poulton, R. Patel, S. Hariri, A. R. Caspi, A. Moffitt, T. E. Kunos, G. Holmes, A. TI Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity SO MOLECULAR PSYCHIATRY LA English DT Article DE amygdala; anxiety; cannabinoid; fear; gene; stress ID ACID AMIDE HYDROLASE; PROBLEM DRUG-USE; ENDOCANNABINOID SYSTEM; INDIVIDUAL-DIFFERENCES; BASOLATERAL AMYGDALA; CONDITIONED FEAR; CB1 RECEPTORS; SHORT-TERM; MONOACYLGLYCEROL LIPASE; PREFRONTAL CORTEX AB Endocannabinoids are released 'on-demand' on the basis of physiological need, and can be pharmacologically augmented by inhibiting their catabolic degradation. The endocannabinoid anandamide is degraded by the catabolic enzyme fatty acid amide hydrolase (FAAH). Anandamide is implicated in the mediation of fear behaviors, including fear extinction, suggesting that selectively elevating brain anandamide could modulate plastic changes in fear. Here we first tested this hypothesis with preclinical experiments employing a novel, potent and selective FAAH inhibitor, AM3506 (5-(4-hydroxyphenyl)pentanesulfonyl fluoride). Systemic AM3506 administration before extinction decreased fear during a retrieval test in a mouse model of impaired extinction. AM3506 had no effects on fear in the absence of extinction training, or on various non-fear-related measures. Anandamide levels in the basolateral amygdala were increased by extinction training and augmented by systemic AM3506, whereas application of AM3506 to amygdala slices promoted long-term depression of inhibitory transmission, a form of synaptic plasticity linked to extinction. Further supporting the amygdala as effect-locus, the fear-reducing effects of systemic AM3506 were blocked by intra-amygdala infusion of a CB1 receptor antagonist and were fully recapitulated by intra-amygdala infusion of AM3506. On the basis of these preclinical findings, we hypothesized that variation in the human FAAH gene would predict individual differences in amygdala threat-processing and stress-coping traits. Consistent with this, carriers of a low-expressing FAAH variant (385A allele; rs324420) exhibited quicker habituation of amygdala reactivity to threat, and had lower scores on the personality trait of stress-reactivity. Our findings show that augmenting amygdala anandamide enables extinction-driven reductions in fear in mouse and may promote stress-coping in humans. C1 [Gunduz-Cinar, O.; MacPherson, K. P.; Holmes, A.] NIAAA, Lab Behav & Genom Neurosci, Sect Behav Sci & Genet, NIH, Bethesda, MD USA. [Gunduz-Cinar, O.] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Cinar, R.; Godlewski, G.; Kunos, G.] NIAAA, Lab Physiol Studies, NIH, Bethesda, MD USA. [Gamble-George, J.; Ramikie, T. S.; Patel, S.] Vanderbilt Univ, Med Ctr, Dept Psychiat & Mol Physiol & Biophys, Nashville, TN USA. [Sugden, K.; Williams, B.; Gorka, A. X.; Hariri, A. R.; Caspi, A.; Moffitt, T. E.] Duke Univ, Dept Psychol & Neurosci, Durham, NC USA. [Sugden, K.; Williams, B.; Caspi, A.; Moffitt, T. E.] Duke Univ, Dept Psychiat & Behav Sci, Durham, NC USA. [Sugden, K.; Williams, B.; Hariri, A. R.; Caspi, A.; Moffitt, T. E.] Duke Univ, Inst Genome Sci & Policy, Durham, NC USA. [Sugden, K.; Williams, B.; Caspi, A.; Moffitt, T. E.] Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Res Ctr, London WC2R 2LS, England. [Alapafuja, S. O.; Nikas, S. P.; Makriyannis, A.] Northeastern Univ, Ctr Drug Discovery, Boston, MA 02115 USA. [Poulton, R.] Univ Otago, Dunedin Sch Med, Dunedin, New Zealand. RP Holmes, A (reprint author), NIAAA, Lab Behav & Genom Neurosci, Sect Behav Sci & Genet, NIH, 5625 Fishers Lane,Room 2N09, Rockville, MD 20852 USA. EM Andrew.Holmes@nih.gov RI Patel, Sachin/E-5608-2012; caspi, avshalom/D-5294-2011; Moffitt, Terrie/D-5295-2011; Gunduz Cinar, Ozge/E-5756-2010 OI CINAR, RESAT/0000-0002-8597-7253; Moffitt, Terrie/0000-0002-8589-6760; Gamble-George, Joyonna/0000-0002-5492-9216; Gunduz Cinar, Ozge/0000-0002-3826-8905 FU NIAAA Intramural Research Program; Department of Defense in the Center for Neuroscience and Regenerative Medicine; NIA [AG032282]; MRC [G0100527]; NIDA [DA031579]; NIMH [MH077874, MH072837, MH090412]; Royal Society FX This work was supported by the NIAAA Intramural Research Program (OGC, KPM, RC, GK, AH), Department of Defense in the Center for Neuroscience and Regenerative Medicine (OGC, AH), NIA (AG032282 to TEM), MRC (G0100527 to TEM), NIDA (DA031579 to ARH) and NIMH (MH077874 to AC; MH072837 to ARH, MH090412 to SP). AC is a Royal Society Wolfson Merit Award holder. We thank Daniel Fisher and Caitlin Schaapveld for assistance with behavioral experiments. NR 58 TC 75 Z9 75 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 JUL PY 2013 VL 18 IS 7 BP 813 EP 823 DI 10.1038/mp.2012.72 PG 11 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 168NL UT WOS:000320712700015 PM 22688188 ER PT J AU Kerkar, SP Leonardi, AJ van Panhuys, N Zhang, L Yu, ZY Crompton, JG Pan, JH Palmer, DC Morgan, RA Rosenberg, SA Restifo, NP AF Kerkar, Sid P. Leonardi, Anthony J. van Panhuys, Nicolas Zhang, Ling Yu, Zhiya Crompton, Joseph G. Pan, Jenny H. Palmer, Douglas C. Morgan, Richard A. Rosenberg, Steven A. Restifo, Nicholas P. TI Collapse of the Tumor Stroma is Triggered by IL-12 Induction of Fas SO MOLECULAR THERAPY LA English DT Article ID T-CELL THERAPY; IMMUNE ESCAPE; ANTITUMOR IMMUNITY; SUPPRESSOR-CELLS; GENE-EXPRESSION; DENDRITIC CELLS; INTERLEUKIN-12; CANCER; MICROENVIRONMENT; IMMUNOTHERAPY AB Engineering CD8(+) T cells to deliver interleukin 12 -(IL-12) to the tumor site can lead to striking improvements in the ability of adoptively transferred T cells to induce the regression of established murine cancers. We have recently shown that IL-12 triggers an acute inflammatory environment that reverses dysfunctional antigen presentation by myeloid-derived cells within tumors and leads to an increase in the infiltration of adoptively transferred antigen-specific CD8(+) T cells. Here, we find that local delivery of IL-12 increased the expression of Fas within tumor-infiltrating macrophages, dendritic cells, and myeloid-derived suppressor cells (MDSC), and that these changes were abrogated in mice deficient in IL-12-receptor signaling. Importantly, upregulation of Fas in host mice played a critical role in the proliferation and antitumor activity of adoptively transferred IL-12-modified CD8(+) T cells. We also observed higher percentages of myeloid-derived cell populations within tumors in Fas-deficient mice, indicating that tumor stromal destruction was dependent on the Fas death receptor. Taken together, these results describe the likely requirement for costimulatory reverse signaling through Fasl on T cells that successfully infiltrate tumors, a mechanism triggered by the induction of Fas expression on myeloid-derived cells by IL-12 and the subsequent collapse of the tumor stroma. C1 [Leonardi, Anthony J.; Zhang, Ling; Yu, Zhiya; Crompton, Joseph G.; Pan, Jenny H.; Palmer, Douglas C.; Morgan, Richard A.; Rosenberg, Steven A.; Restifo, Nicholas P.] NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kerkar, Sid P.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD USA. [van Panhuys, Nicolas] NIAID, Lymphocyte Biol Sect, NIH, Bethesda, MD 20892 USA. RP Kerkar, SP (reprint author), NCI, NIH, Room 3-5762,10 Ctr Dr, Bethesda, MD 20892 USA. EM kerkars@mail.nih.gov; restifon@nih.gov RI Palmer, Douglas/B-9454-2008; van Panhuys, Nicholas/E-1812-2011; OI Palmer, Douglas/0000-0001-5018-5734; Restifo, Nicholas P./0000-0003-4229-4580; van Panhuys, Nicholas/0000-0003-2199-852X 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. The authors declare no conflict of interest. NR 43 TC 33 Z9 33 U1 1 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD JUL PY 2013 VL 21 IS 7 BP 1369 EP 1377 DI 10.1038/mt.2013.58 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 173WL UT WOS:000321112500011 PM 23568260 ER PT J AU Mendell, JR Lloyd-Puryear, M AF Mendell, Jerry R. Lloyd-Puryear, Michele TI Report of MDA muscle disease symposium on newborn screening for Duchenne muscular dystrophy SO MUSCLE & NERVE LA English DT Article DE Committee on Heritable Disorders for Newborns and Children; Department of Health and Human Services; Duchenne muscular dystrophy; Newborn Screening; Recommended Uniform Screening Panel; Secretary's Advisory ID CORTICOSTEROID TREATMENT; FOLLOW-UP; RESTORATION; PREDNISONE; PRO051; TRIAL; GENE AB This report summarizes the progress made in newborn screening for Duchenne muscular dystrophy (DMD). This subject was discussed fully at a symposium held on September 11-12, 2012, in Bethesda, Maryland, by a group of experts from multiple disciplines. The meeting was triggered by the simultaneous combination of improvements in methods for newborn screening for DMD and greater potential for treatment. On the screening side, a two-tier system of newborn screening was introduced that enabled creatine kinase levels and DMD gene analysis to be done on the same dried blood spots obtained at birth. Treatment improvements included promising results from exon skipping as well as multiple studies showing long-term benefits of glucocorticoids and data indicating that early intervention of both forms of therapy was the most beneficial. Conclusions from this symposium with supportive data could have a significant impact on propelling efforts for approval of newborn screening for DMD. Muscle Nerve, 2013 C1 [Mendell, Jerry R.] Ohio State Univ, Nationwide Childrens Hosp, Paul D Wellstone Muscular Dystrophy Cooperat Res, Columbus, OH 43205 USA. [Mendell, Jerry R.] Ohio State Univ, Dept Pediat, Columbus, OH 43205 USA. [Lloyd-Puryear, Michele] NIH, Off Dis Prevent, Bethesda, MD 20892 USA. RP Mendell, JR (reprint author), Ohio State Univ, Nationwide Childrens Hosp, Paul D Wellstone Muscular Dystrophy Cooperat Res, 700 Childrens Dr, Columbus, OH 43205 USA. EM jerry.mendell@nationwidechildrens.org FU Muscular Dystrophy Association; Centers for Disease Control and Prevention [5U50DD000030, 1R18DD000344]; Research Institute at Nationwide Children's Hospital, Columbus, OH FX The following individuals significantly contributed to the success of this Symposium through discussions on individual topics or participation in Panels: Sanjay Bidichandani, Jeffrey Bosco, Amy Brower, Michele Caggana, Ram Chandrasekar, Pat Furlong, Scott Grosse, Madhuri Hedge, R. Rodney Howell, Alex Kemper, Anne Kennedy, Bruce Korf, Fred Lorey, Craig McDonald, Francesco Muntoni, John Porter, Piero Rinaldo, Robert Saul, Robert Weiss. The symposium was supported by the Muscular Dystrophy Association. The Symposium was dependent on the organization of Sanjay Bidichandani, MBBS, Ph.D., Vice President of Research and Paul Muhlrad, Ph.D., Director of Basic Research at the Muscular Dystrophy Association. The Muscular Dystrophy Association supported the Symposium on Newborn Screening. The two-tier system of screening used in the State of Ohio newborn screening was supported by cooperative agreements from the Centers for Disease Control and Prevention (5U50DD000030 and 1R18DD000344) and the Research Institute at Nationwide Children's Hospital, Columbus, OH; Paul D. Wellstone Cooperative Muscular Dystrophy Center, Nationwide Children's Hospital (1U54HD066409-01;JRM); and Ohio Department of Health (J.R.M.). NR 19 TC 33 Z9 33 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0148-639X J9 MUSCLE NERVE JI Muscle Nerve PD JUL PY 2013 VL 48 IS 1 BP 21 EP 26 DI 10.1002/mus.23810 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 169NT UT WOS:000320787700003 PM 23716304 ER PT J AU Belkaid, Y Naik, S AF Belkaid, Yasmine Naik, Shruti TI Compartmentalized and systemic control of tissue immunity by commensals SO NATURE IMMUNOLOGY LA English DT Article ID DENDRITIC CELLS; INTESTINAL MICROBIOTA; SKIN MICROBIOME; GUT MICROBIOTA; TOXOPLASMA-GONDII; INNATE IMMUNITY; GERM-FREE; BACTERIA; DISEASE; INFLAMMATION AB The body is composed of various tissue microenvironments with finely tuned local immunosurveillance systems, many of which are in close apposition with distinct commensal niches. Mammals have formed an evolutionary partnership with the microbiota that is critical for metabolism, tissue development and host defense. Despite our growing understanding of the impact of this host-microbe alliance on immunity in the gastrointestinal tract, the extent to which individual microenvironments are controlled by resident microbiota remains unclear. In this Perspective, we discuss how resident commensals outside the gastrointestinal tract can control unique physiological niches and the potential implications of the dialog between these commensals and the host for the establishment of immune homeostasis, protective responses and tissue pathology. C1 [Belkaid, Yasmine; Naik, Shruti] NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Belkaid, Y (reprint author), NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ybelkaid@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, US National Institutes of Health FX Supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, US National Institutes of Health. We thank members of the Belkaid laboratory for helpful discussions, particularly S. Spencer and J. Grainger for critical reading of the manuscript. NR 102 TC 70 Z9 70 U1 4 U2 64 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD JUL PY 2013 VL 14 IS 7 BP 646 EP 653 DI 10.1038/ni.2604 PG 8 WC Immunology SC Immunology GA 165UB UT WOS:000320509100002 PM 23778791 ER PT J AU Van Rhijn, I Kasmar, A de Jong, A Gras, S Bhati, M Doorenspleet, ME de Vries, N Godfrey, DI Altman, JD de Jager, W Rossjohn, J Moody, DB AF Van Rhijn, Ildiko Kasmar, Anne de Jong, Annemieke Gras, Stephanie Bhati, Mugdha Doorenspleet, Marieke E. de Vries, Niek Godfrey, Dale I. Altman, John D. de Jager, Wilco Rossjohn, Jamie Moody, D. Branch TI A conserved human T cell population targets mycobacterial antigens presented by CD1b SO NATURE IMMUNOLOGY LA English DT Article ID TUBERCULOSIS INFECTION; LIPID ANTIGENS; ALPHA-CHAIN; MAIT CELLS; RECEPTOR; RECOGNITION; RESPONSES; EXPRESSION; LYMPHOCYTES; MEMORY AB Human T cell antigen receptors (TCRs) pair in millions of combinations to create complex and unique T cell repertoires for each person. Through the use of tetramers to analyze TCRs reactive to the antigen-presenting molecule CD1b, we detected T cells with highly stereotyped TCR alpha-chains present among genetically unrelated patients with tuberculosis. The germline-encoded, mycolyl lipid-reactive (GEM) TCRs had an alpha-chain bearing the variable (V) region TRAV1-2 rearranged to the joining (J) region TRAJ9 with few nontemplated (N)-region additions. Analysis of TCRs by high-throughput sequencing, binding and crystallography showed linkage of TCR alpha sequence motifs to high-affinity recognition of antigen. Thus, the CD1-reactive TCR repertoire is composed of at least two compartments: high-affinity GEM TCRs, and more-diverse TCRs with low affinity for CD1b-lipid complexes. We found high interdonor conservation of TCRs that probably resulted from selection by a nonpolymorphic antigen-presenting molecule and an immunodominant antigen. C1 [Van Rhijn, Ildiko; Kasmar, Anne; de Jong, Annemieke; Moody, D. Branch] Harvard Univ, Sch Med, Dept Rheumatol & Immunol, Brigham & Womens Hosp, Boston, MA 02115 USA. [Van Rhijn, Ildiko] Univ Utrecht, Fac Vet Med, Dept Infect Dis & Immunol, Utrecht, Netherlands. [Gras, Stephanie; Bhati, Mugdha; Rossjohn, Jamie] Monash Univ, Sch Biomed Sci, Dept Biochem & Mol Biol, Clayton, Vic, Australia. [Doorenspleet, Marieke E.; de Vries, Niek] Univ Amsterdam, Acad Med Ctr, Dept Clin Immunol & Rheumatol, NL-1012 WX Amsterdam, Netherlands. [Godfrey, Dale I.] Univ Melbourne, Dept Microbiol & Immunol, Parkville, Vic 3052, Australia. [Altman, John D.] NIH Tetramer Core Facil, Emory Vaccine Ctr, Atlanta, GA USA. [de Jager, Wilco] Univ Utrecht, Med Ctr, Dept Pediat Immunol, Utrecht, Netherlands. [Rossjohn, Jamie] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff CF10 3AX, S Glam, Wales. RP Moody, DB (reprint author), Harvard Univ, Sch Med, Dept Rheumatol & Immunol, Brigham & Womens Hosp, Boston, MA 02115 USA. EM i.vanrhijn@uu.nl; bmoody@rics.bwh.harvard.edu RI de Vries, Niek/J-9348-2013; OI de Vries, Niek/0000-0002-6257-8604; de Jong, Annemieke/0000-0001-6707-6585; Rossjohn, Jamie/0000-0002-2020-7522 FU US National Institute of Allergy and Infectious Diseases [AI04393, AR048632, K08 AI089858]; Burroughs Wellcome Fund; Nederlands Wetenschappelijk Onderzoek (Meervoud) [836.08.001]; National Health and Medical Research Council; Australian Research Council FX We thank the Tetramer Core Facility of the US National Institutes of Health for CD1b protein; M. Turner, C. Seshadri and the Shattuck Hospital for clinical collaboration; L. Tan for technical help; and the beamline staff at the Australian synchrotron for assistance with data collection. Supported by the US National Institute of Allergy and Infectious Diseases (AI04393, AR048632 to D. B. M., and K08 AI089858 to A. K.) the Burroughs Wellcome Fund, Nederlands Wetenschappelijk Onderzoek (Meervoud 836.08.001 to I. V. R.), the National Health and Medical Research Council (D. I. G. and J.R.) and the Australian Research Council (S.G.). NR 48 TC 65 Z9 65 U1 1 U2 19 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD JUL PY 2013 VL 14 IS 7 BP 706 EP + DI 10.1038/ni.2630 PG 10 WC Immunology SC Immunology GA 165UB UT WOS:000320509100012 PM 23727893 ER PT J AU Bunting, SF Nussenzweig, A AF Bunting, Samuel F. Nussenzweig, Andre TI End-joining, translocations and cancer SO NATURE REVIEWS CANCER LA English DT Review ID DOUBLE-STRAND BREAKS; CLASS-SWITCH RECOMBINATION; DNA-DAMAGE-RESPONSE; RECURRENT CHROMOSOMAL TRANSLOCATIONS; FRAGILE SITE INSTABILITY; CYTIDINE DEAMINASE AID; HOMOLOGOUS RECOMBINATION; MAMMALIAN-CELLS; NONHOMOLOGOUS RECOMBINATION; SACCHAROMYCES-CEREVISIAE AB Fusion genes that are caused by chromosome translocations have been recognized for several decades as drivers of deregulated cell growth in certain types of cancer. In recent years, oncogenic fusion genes have been found in many haematological and solid tumours, demonstrating that translocations are a common cause of malignancy. Sequencing approaches have now confirmed that numerous, non-clonal translocations are a typical feature of cancer cells. These chromosome rearrangements are often highly complex and contain DNA sequence from multiple genomic sites. The factors and pathways that promote translocations are becoming clearer, with non-homologous end-joining implicated as a key source of genomic rearrangements. C1 [Bunting, Samuel F.] Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. [Nussenzweig, Andre] NIH, Lab Genome Integr, Bethesda, MD 20892 USA. RP Bunting, SF (reprint author), Rutgers State Univ, Ctr Adv Biotechnol & Med, Room 337, Piscataway, NJ 08854 USA. EM bunting@cabm.rutgers.edu; andre_nussenzweig@nih.gov FU NCI R00 award [RCA 160574A]; Intramural Research Program of the National Institutes of Health, National Cancer Institute; Center for Cancer Research; Department of Defense [BC 102335] FX S.F.B. is a recipient of NCI R00 award RCA 160574A. A.N. was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and the Center for Cancer Research, and by a Department of Defense grant (BC 102335). NR 130 TC 110 Z9 111 U1 4 U2 51 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X EI 1474-1768 J9 NAT REV CANCER JI Nat. Rev. Cancer PD JUL PY 2013 VL 13 IS 7 BP 443 EP 454 DI 10.1038/nrc3537 PG 12 WC Oncology SC Oncology GA 169HH UT WOS:000320770200007 PM 23760025 ER PT J AU Pancera, M Shahzad-ul-Hussan, S Doria-Rose, NA McLellan, JS Bailer, RT Dai, KF Loesgen, S Louder, MK Staupe, RP Yang, YP Zhang, BS Parks, R Eudailey, J Lloyd, KE Blinn, J Alam, SM Haynes, BF Amin, MN Wang, LX Burton, DR Koff, WC Nabel, GJ Mascola, JR Bewley, CA Kwong, PD AF Pancera, Marie Shahzad-ul-Hussan, Syed Doria-Rose, Nicole A. McLellan, Jason S. Bailer, Robert T. Dai, Kaifan Loesgen, Sandra Louder, Mark K. Staupe, Ryan P. Yang, Yongping Zhang, Baoshan Parks, Robert Eudailey, Joshua Lloyd, Krissey E. Blinn, Julie Alam, S. Munir Haynes, Barton F. Amin, Mohammed N. Wang, Lai-Xi Burton, Dennis R. Koff, Wayne C. Nabel, Gary J. Mascola, John R. Bewley, Carole A. Kwong, Peter D. TI Structural basis for diverse N-glycan recognition by HIV-1-neutralizing V1-V2-directed antibody PG16 SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; BROADLY NEUTRALIZING ANTIBODIES; HIV-1 ENVELOPE GLYCOPROTEINS; HAMSTER OVARY CELLS; GLYCOSYLATION SITES; CRYSTAL-STRUCTURE; 2G12 RECOGNIZES; GP120; POTENT; COMPLEX AB HIV-1 uses a diverse N-linked-glycan shield to evade recognition by antibody. Select human antibodies, such as the clonally related PG9 and PG16, recognize glycopeptide epitopes in the HIV-1 V1-V2 region and penetrate this shield, but their ability to accommodate diverse glycans is unclear. Here we report the structure of antibody PG16 bound to a scaffolded V1-V2, showing an epitope comprising both high mannose-type and complex-type N-linked glycans. We combined structure, NMR and mutagenesis analyses to characterize glycan recognition by PG9 and PG16. Three PG16-specific residues, arginine, serine and histidine (RSH), were critical for binding sialic acid on complex-type glycans, and introduction of these residues into PG9 produced a chimeric antibody with enhanced HIV-1 neutralization. Although HIV-1-glycan diversity facilitates evasion, antibody somatic diversity can overcome this and can provide clues to guide the design of modified antibodies with enhanced neutralization. C1 [Pancera, Marie; Doria-Rose, Nicole A.; McLellan, Jason S.; Bailer, Robert T.; Dai, Kaifan; Louder, Mark K.; Staupe, Ryan P.; Yang, Yongping; Zhang, Baoshan; Nabel, Gary J.; Mascola, John R.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Shahzad-ul-Hussan, Syed; Loesgen, Sandra; Bewley, Carole A.] NIDDK, Lab Bioorgan Chem, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Parks, Robert; Eudailey, Joshua; Lloyd, Krissey E.; Blinn, Julie; Alam, S. Munir; Haynes, Barton F.] Duke Univ, Med Ctr, Duke Human Vaccine Inst, Durham, NC USA. [Amin, Mohammed N.; Wang, Lai-Xi] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. [Amin, Mohammed N.; Wang, Lai-Xi] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. [Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Burton, Dennis R.] Scripps Res Inst, Int AIDS Vaccine Initiat, Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Burton, Dennis R.] Massachusetts Gen Hosp, Ragon Inst, MIT, Cambridge, MA USA. [Burton, Dennis R.] Harvard Univ, Cambridge, MA 02138 USA. [Burton, Dennis R.] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. [Koff, Wayne C.] Int AIDS Vaccine Initiat, New York, NY USA. RP Bewley, CA (reprint author), NIDDK, Lab Bioorgan Chem, US Natl Inst Hlth, Bethesda, MD 20892 USA. EM caroleb@mail.nih.gov; pdkwong@nih.gov FU US National Institutes of Health; International AIDS Vaccine Initiative's Neutralizing Antibody Consortium; Center for HIV AIDS Vaccine Immunology from the US National Institutes of Health [AI 5U19 AI 067854-06]; US National Institutes of Health [1R21 AI101035]; US National Institutes of Health (NIH/NCRR) [P41 RR018502-01]; US Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX We thank J. Stuckey for assistance with figures and members of the Structural Biology Section and Structural Bioinformatics Core, Vaccine Research Center for discussions or comments on the manuscript; A. Kumar for sharing the ELISA binding protocol with biotinylated lectins; P. Azadi and S. Archer-Hartmann, University of Georgia, for performing glycan analyses and glycopeptide mapping; J. Baalwa (Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA), D. Ellenberger (International Laboratory Branch, Division of Global HIV/AIDS, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USA), D. Gabuzda (Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA), F. Gao (Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA), B. Hahn (Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA), K. Hong (State Key Laboratory for Infectious Disease Control and Prevention, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China), J. Kim (US Military HIV Research Program, Henry M. Jackson Foundation, Bethesda, Maryland, USA), F. McCutchan (US Military HIV Research Program, Henry M. Jackson Foundation, Bethesda, Maryland, USA), D. Montefiori (Department of Surgery, Duke University, Durham, North Carolina, USA), L. Morris, (Centre for HIV and STIs, National Institute for Communicable Diseases, Johannesburg, South Africa), J. Overbaugh (Program for Appropriate Technology in Health, Seattle, Washington, USA), E. Sanders-Buell (US Military HIV Research Program, Henry M. Jackson Foundation, Bethesda, Maryland, USA), G. Shaw (Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA), R. Swanstrom (University of North Carilina Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA), M. Thomson (University of Birmingham, Birmingham, UK), S. Tovanabutra (Department of Retrovirology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand), C. Williamson (Institute of Infectious Diseases and Molecular Medicine, Division of Medical Virology, University of Cape Town and National Health Laboratory Services, Cape Town, South Africa) and L. Zhang (Department of Public Health, Center for Disease Control and Prevention in Jiangxi Province, Nanchang, China) contributing the HIV-1 Envelope plasmids used in our neutralization panel. Support for this work was provided by the US National Institutes of Health Intramural Research Programs (Vaccine Research Center, National Institute of Allergy and Infectious Diseases, and the National Institute of Diabetes and Digestive and Kidney Diseases), by grants from the International AIDS Vaccine Initiative's Neutralizing Antibody Consortium and by the Center for HIV AIDS Vaccine Immunology Grant AI 5U19 AI 067854-06 from the US National Institutes of Health (J. E., K. E. L., J. B., S. M. A. and B. F. H.), by US National Institutes of Health grant 1R21 AI101035 (M. N. A. and L-X. W.) and by the US National Institutes of Health (NIH/NCRR)-funded grant P41 RR018502-01 to the Complex Carbohydrate Research Center. Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science under contract number W-31-109-Eng-38. NR 62 TC 116 Z9 117 U1 1 U2 42 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD JUL PY 2013 VL 20 IS 7 BP 804 EP + DI 10.1038/nsmb.2600 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 175SM UT WOS:000321253300008 PM 23708607 ER PT J AU Yadav, H Jain, S AF Yadav, Hariom Jain, Shalini TI Herbo-probiotic therapy in cardioprotection: A new way of nature to nurture SO NUTRITION LA English DT Letter C1 [Yadav, Hariom; Jain, Shalini] NIH, Natl Diabet & Digest & Kidney Dis, Bethesda, MD 20892 USA. RP Yadav, H (reprint author), NIH, Natl Diabet & Digest & Kidney Dis, Bldg 10, Bethesda, MD 20892 USA. EM yadavhariom@gmail.com OI Yadav, Hariom/0000-0003-4504-1597 NR 10 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0899-9007 J9 NUTRITION JI Nutrition PD JUL-AUG PY 2013 VL 29 IS 7-8 BP 1070 EP 1071 DI 10.1016/j.nut.2012.11.001 PG 2 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 172UF UT WOS:000321029700025 PM 23352466 ER PT J AU Shih, LC LaFaver, K Lim, C Papavassiliou, E Tarsy, D AF Shih, Ludy C. LaFaver, Kathrin Lim, Chen Papavassiliou, Efstathios Tarsy, Daniel TI Loss of benefit in VIM thalamic deep brain stimulation (DBS) for essential tremor (ET): How prevalent is it? SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE Essential tremor; Deep brain stimulation; Long-term outcome ID LONG-TERM EFFICACY; MOVEMENT-DISORDERS; FOLLOW-UP; TOLERANCE; NUCLEUS AB Ventralis intermedius (Vim) thalamic deep brain stimulation for medication-refractory essential tremor (ET) has been shown to significantly improve severity of limb tremor in several large case series with significant reduction in objective motor scores. A variable proportion of patients experience decline in benefit over time, however, most studies have not been designed to describe the phenomenon of waning benefit in terms that are helpful for patient counseling. In this retrospective single center study, we define waning benefit as a phenomenon that occurs after patients begin to require reprogramming visits to optimize DBS benefit on tremor. We employed a survival analysis with time to escape (TTE) as a quantitative measure of time elapsed between implantation and the need for subsequent reprogramming. In our cohort of ET patients operated on with Vim DBS from 1994 to 2009, among 45 subjects who met inclusion criteria, 73% reported waning benefit at some point during a mean follow-up period of 56 months (range 12-152 months). The mean TTE from implantation date was 18 months (range 3-75 months). We conclude that loss of benefit over time from Vim DBS for ET is more prevalent than previously published estimates have indicated and should be discussed during patient counseling regarding durability of expected benefit. In addition, this data suggests that a disease-based explanation rather than technical factors are more likely to explain the decline in benefit. (c) 2013 Elsevier Ltd. All rights reserved. C1 [Shih, Ludy C.; Tarsy, Daniel] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Neurol, Boston, MA 02215 USA. [LaFaver, Kathrin] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Lim, Chen] New York Med Coll, Valhalla, NY 10595 USA. [Papavassiliou, Efstathios] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Neurosurg,Dept Surg, Boston, MA 02215 USA. RP Shih, LC (reprint author), Beth Israel Deaconess Med Ctr, Dept Neurol, Kirstein 228,330 Brookline Ave, Boston, MA 02215 USA. EM lshih@bidmc.harvard.edu FU Clinical Investigator Training Program: Beth Israel Deaconess Medical Center; Harvard/MIT Health Science and Technology; Pfizer, Inc.; Merck Co. FX L.C. Shih was supported in part by the Clinical Investigator Training Program: Beth Israel Deaconess Medical Center and Harvard/MIT Health Science and Technology, in collaboration with Pfizer, Inc. and Merck & Co. The authors have no relevant financial disclosures to make regarding relevant companies involved in this work over the past three years. NR 22 TC 17 Z9 17 U1 1 U2 6 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 JUL PY 2013 VL 19 IS 7 BP 676 EP 679 DI 10.1016/j.parkreldis.2013.03.006 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 169AW UT WOS:000320750300006 PM 23582712 ER PT J AU Samal, B Ait-Ali, D Bunn, S Mustafa, T Eiden, LE AF Samal, Babru Ait-Ali, Djida Bunn, Stephen Mustafa, Tomris Eiden, Lee E. TI Discrete signal transduction pathway utilization by a neuropeptide (PACAP) and a cytokine (TNF-alpha) first messenger in chromaffin cells, inferred from coupled transcriptome-promoter analysis of regulated gene cohorts SO PEPTIDES LA English DT Article DE Affymetrix; Agilent; Chromaffin cell; Cyclic AMP; ERK; Gene induction; Microarray; NF-kB; PACAP; PAC1; Signal transduction; TNF-alpha; Transcriptional regulation; TNFR2 ID CYCLASE-ACTIVATING POLYPEPTIDE; NF-KAPPA-B; TUMOR-NECROSIS-FACTOR; CONTROL MAQC PROJECT; IN-VIVO; CATECHOLAMINE SECRETION; RECEPTOR ACTIVATION; PC12 CELLS; EXPRESSION; NEUROENDOCRINE AB Cultured bovine adrenal chromaffin cells (BCCs) are employed to study first messenger-specific signaling by cytokines and neurotransmitters occurring in the adrenal medulla following immune-related stress responses. Here, we show that the cytokine TNF-alpha, and the neuropeptide transmitter PACAP, acting through the TNFR2 and PAC1 receptors, activate distinct signaling pathways, with correspondingly distinct transcriptomic signatures in chromaffin cells. We have carried out a comprehensive integrated transcriptome analysis of TNF-alpha and PACAP gene regulation in BCCs using two microarray platforms to maximize transcript identification. Microarray data were validated using qRT-PCR. More than 90% of the transcripts up-regulated either by TNF-alpha or PACAP were specific to a single first messenger. The final list of transcripts induced by each first messenger was subjected to multiple algorithms to identify promoter/ enhancer response elements for trans-acting factors whose activation could account for gene expression by either TNF-alpha or PACAP. Distinct groups of transcription factors potentially controlling the expression of TNF-alpha or PACAP-responsive genes were found: most of the genes up-regulated by TNF-alpha contained transcription factor binding sites for members of the Rel transcription factor family, suggesting TNF-alpha-TNFR2 signaling occurs mainly through the NF-KB signaling pathway. Surprisingly, EGR1 was predicted to be the primary transcription factor controlling PACAP-modulated genes, suggesting PACAP signaling to the nucleus occurs predominantly through ERK, rather than CREB activation. Comparison of TNFR2-dependent versus TNFR1-dependent gene induction, and EGR1-mediated transcriptional activation, may provide a pharmacological avenue to the unique pathways activated by the first messengers TNF-alpha and PACAP in neuronal and endocrine cells. Published by Elsevier Inc. C1 [Samal, Babru; Ait-Ali, Djida; Mustafa, Tomris; Eiden, Lee E.] NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. [Bunn, Stephen] Univ Otego, Sch Med Sci, Dept Anat, Ctr Neuroendocrinol, Dunedin, New Zealand. RP Eiden, LE (reprint author), NIMH, Mol Neurosci Sect, Bldg 49,Room 5A-38,9000 Rockville Pike, Bethesda, MD 20892 USA. EM eidenl@mail.nih.gov OI Eiden, Lee/0000-0001-7524-944X FU NIMH [ZO1-MH002386] FX The authors thank Chang-Mei Hsu for expert assistance in chromaffin cell preparation, treatment, harvesting, and RNA preparation. This work was supported by the NIMH intramural research program (ZO1-MH002386). NR 48 TC 2 Z9 2 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD JUL PY 2013 VL 45 BP 48 EP 60 DI 10.1016/j.peptides.2013.03.020 PG 13 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 170KW UT WOS:000320850300008 PM 23608709 ER PT J AU Davenport, AP Alexander, SPH Sharman, JL Pawson, AJ Benson, HE Monaghan, AE Liew, WC Mpamhanga, CP Bonner, TI Neubig, RR Pin, JP Spedding, M Harmar, AJ AF Davenport, Anthony P. Alexander, Stephen P. H. Sharman, Joanna L. Pawson, Adam J. Benson, Helen E. Monaghan, Amy E. Liew, Wen Chiy Mpamhanga, Chidochangu P. Bonner, Tom I. Neubig, Richard R. Pin, Jean Philippe Spedding, Michael Harmar, Anthony J. TI International Union of Basic and Clinical Pharmacology. LXXXVIII. G Protein-Coupled Receptor List: Recommendations for New Pairings with Cognate Ligands SO PHARMACOLOGICAL REVIEWS LA English DT Review ID LYSOPHOSPHATIDIC ACID RECEPTOR; L-ALPHA-LYSOPHOSPHATIDYLINOSITOL; RAT ADRENOMEDULLIN RECEPTOR; NEUROPEPTIDE-Y RECEPTOR; BREAST-CANCER CELLS; ORPHAN RECEPTOR; CANNABINOID RECEPTOR; FATTY-ACIDS; CONSTITUTIVE ACTIVITY; INSULIN-SECRETION AB In 2005, the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR) published a catalog of all of the human gene sequences known or predicted to encode G protein-coupled receptors (GPCRs), excluding sensory receptors. This review updates the list of orphan GPCRs and describes the criteria used by NC-IUPHAR to recommend the pairing of an orphan receptor with its cognate ligand(s). The following recommendations are made for new receptor names based on 11 pairings for class A GPCRs: hydroxycarboxylic acid receptors [HCA(1) (GPR81) with lactate, HCA(2) (GPR109A) with 3-hydroxybutyric acid, HCA(3) (GPR109B) with 3-hydroxyoctanoic acid]; lysophosphatidic acid receptors [LPA(4) (GPR23), LPA(5) (GPR92), LPA(6) (P2Y5)]; free fatty acid receptors [FFA4 (GPR120) with omega-3 fatty acids]; chemerin receptor (CMKLR1; ChemR23) with chemerin; CXCR7 (CMKOR1) with chemokines CXCL12 (SDF-1) and CXCL11 (ITAC); succinate receptor (SUCNR1) with succinate; and oxoglutarate receptor [OXGR1 with 2-oxoglutarate]. Pairings are highlighted for an additional 30 receptors in class A where further input is needed from the scientific community to validate these findings. Fifty-seven human class A receptors (excluding pseudogenes) are still considered orphans; information has been provided where there is a significant phenotype in genetically modified animals. In class B, six pairings have been reported by a single publication, with 28 (excluding pseudogenes) still classified as orphans. Seven orphan receptors remain in class C, with one pairing described by a single paper. The objective is to stimulate research into confirming pairings of orphan receptors where there is currently limited information and to identify cognate ligands for the remaining GPCRs. Further information can be found on the IUPHAR Database website (http://www.iuphar-db.org). C1 [Davenport, Anthony P.] Univ Cambridge, Clin Pharmacol Unit, Cambridge CB2 0QQ, England. [Alexander, Stephen P. H.] Univ Nottingham, Sch Med, Sch Biomed Sci, Nottingham, England. [Sharman, Joanna L.; Pawson, Adam J.; Benson, Helen E.; Monaghan, Amy E.; Liew, Wen Chiy; Mpamhanga, Chidochangu P.; Harmar, Anthony J.] Univ Edinburgh, Queens Med Res Inst, Univ BHF Ctr Cardiovasc Sci, Edinburgh, Midlothian, Scotland. [Bonner, Tom I.] NIMH, Sect Funct Neurosci, Bethesda, MD 20892 USA. [Neubig, Richard R.] Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA. [Pin, Jean Philippe] Univ Montpellier, CNRS, Inst Funct Genom, Dept Mol Pharmacol,UMR5203, F-34059 Montpellier, France. [Spedding, Michael] Les Labs Servier, Suresnes, France. RP Davenport, AP (reprint author), Univ Cambridge, Ctr Clin Invest, Addenbrookes Hosp, Clin Pharmacol Unit, Level 6,Box 110, Cambridge CB2 0QQ, England. EM apd10@medschl.cam.ac.uk RI Alexander, Steve/B-8105-2009; Davenport, Anthony/A-5773-2008; Pawson, Adam/Q-5678-2016; OI Alexander, Steve/0000-0003-4417-497X; Davenport, Anthony/0000-0002-2096-3117; Pawson, Adam/0000-0003-2280-845X; Benson, Helen/0000-0002-7830-2477; Spedding, Michael/0000-0002-1248-8221; Sharman, Joanna/0000-0002-5275-6446 FU International Union of Basic and Clinical Pharmacology; British Pharmacological Society; Wellcome Trust [268427, 085686/2/08, 099156/Z/12/Z]; British Heart Foundation [PS/02/001, PG/09/050/27734]; Pulmonary Hypertension Association; National Institute for Health Research Cambridge Biomedical Research Centre; National Institutes of Health [National Institute of Mental Health] FX The authors thank the International Union of Basic and Clinical Pharmacology and British Pharmacological Society for support.; This work was supported in part by the Wellcome Trust [Grants 268427, 085686/2/08; Biomedical Resources Grant 099156/Z/12/Z] for support for IUPHAR-DB (to A. H., S. P. H. A., and A. P. D.); the British Heart Foundation [Grants PS/02/001 and PG/09/050/27734] (to A. P. D.); Pulmonary Hypertension Association; the National Institute for Health Research Cambridge Biomedical Research Centre; the Intramural Research Program of the National Institutes of Health [National Institute of Mental Health] (to T.B.). NR 238 TC 71 Z9 71 U1 3 U2 37 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0031-6997 EI 1521-0081 J9 PHARMACOL REV JI Pharmacol. Rev. PD JUL PY 2013 VL 65 IS 3 BP 967 EP 986 DI 10.1124/pr.112.007179 PG 20 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 172FV UT WOS:000320986500004 PM 23686350 ER PT J AU Kleitman, N Rao, MS Owens, DF AF Kleitman, Naomi Rao, Mahendra S. Owens, David F. TI Pluripotent Stem Cells in Translation: A Food and Drug Administration-National Institutes of Health Collaboration SO STEM CELLS TRANSLATIONAL MEDICINE LA English DT Article DE Pluripotent stem cells; Stem cells; Clinical translation; Clinical trials AB Recently, the U.S. Food and Drug Administration (FDA), the U.S. National Institutes of Health, and the stem cell research community have collaborated on a series of workshops that address moving pluripotent stem cell therapies into the clinic. The first two workshops in the series focused on preclinical science, and a third, future workshop will focus on clinical trials. This summary addresses major points from both of the recent preclinically focused meetings. When entering into a therapeutics developmental program based on pluripotent cells, investigators must make decisions at the very early stages that will have major ramifications during later phases of development. Presentations and discussions from both invited participants and FDA staff described the need to characterize and document the quality, variability, and suitability of the cells and commercial reagents used at every translational stage. This requires consideration of future regulatory requirements, ranging from donor eligibility of the original source material to the late-stage manufacturing protocols. Federal, industrial, and academic participants agreed that planning backward is the best way to anticipate what evidence will be needed to justify human testing of novel therapeutics and to eliminate wasted efforts. C1 [Kleitman, Naomi; Owens, David F.] NINDS, NIH, Bethesda, MD 20892 USA. [Rao, Mahendra S.] NIH, Ctr Regenerat Med, Bethesda, MD 20892 USA. RP Rao, MS (reprint author), 50 South Dr, Bethesda, MD 20892 USA. EM mahendra.rao@nih.gov OI Kleitman, Naomi/0000-0003-1089-0257 FU NIH FX We thank the participants of both workshops for providing invaluable insights into this emerging area, our FDA colleagues for comments on a draft of this report, and Drs. Story Landis (NINDS/NIH) and Celia Witten (CBER/FDA) for providing overall leadership. We also thank members of the planning committees from both the FDA and the NIH for making these workshops a reality. FDA: Drs. Rachael F. Anatol, Patrick Au, Kimberly A. Benton, Theresa T. Chen, Donald W. Fink, Thomas P. Finn, Ying Huang, Deborah A. Hursh, Wei Liang, Malcolm C. Moos, Stephanie L. Simek, and Steven O. Winitsky. NIH: Drs. Kristin Abraham (National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK]), Rosemarie Hunziker (National Institute of Biomedical Imaging and Bioengineering [NIBIB]), Christine Kelley (NIBIB), Naomi Kleitman (NINDS), Susan Marino (NINDS), David Owens (NINDS), Mahendra Rao (National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS]), Pamela Robey (National Institute of Dental and Craniofacial Research), Sheryl Sato (NIDDK), Sonia Skarlatos (National Heart, Lung, and Blood Institute [NHLBI]), and John W. Thomas (NHLBI). We would like to also acknowledge the contributions made by Dr. Laura Cole (National Institute on Deafness and Other Communication Disorders [NIDCD]), Buck Wong (NIDCD), Dr. Scott Lipnick (Office of the Director), and Megan Laycock (NIAMS). Funding for both workshops was provided by the NIH. NR 7 TC 4 Z9 4 U1 0 U2 5 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 2157-6564 J9 STEM CELL TRANSL MED JI Stem Cells Transl. Med. PD JUL PY 2013 VL 2 IS 7 BP 483 EP 487 DI 10.5966/sctm.2013-0042 PG 5 WC Cell & Tissue Engineering SC Cell Biology GA 175MU UT WOS:000321235600010 PM 23757505 ER PT J AU Orihuela, R Kojima, C Tokar, EJ Person, RJ Xu, YY Qu, W Waalkes, MP AF Orihuela, Ruben Kojima, Chikara Tokar, Erik J. Person, Rachel J. Xu, Yuanyuan Qu, Wei Waalkes, Michael P. TI Oxidative DNA damage after acute exposure to arsenite and monomethylarsonous acid in biomethylation-deficient human cells SO TOXICOLOGY MECHANISMS AND METHODS LA English DT Article DE Arsenic; immuno-spin trapping; reactive oxygen species ID PYRUVATE-DEHYDROGENASE; METHYLATED ARSENICALS; ENDOTHELIAL-CELLS; HUMAN HEPATOCYTES; REACTIVE OXYGEN; FREE-RADICALS; HUMAN-DISEASE; AS-III; GLUTATHIONE; STRESS AB The carcinogen inorganic arsenic (iAs) undergoes biomethylation (BMT) in some cells. The methylated metabolite, monomethylarsonous (MMA(3+)), may cause oxidative DNA damage (ODD). With chronic iAs exposure, BMT-competent cells show ODD while BMT-deficient do not. To further define these events, we studied ODD produced by acute iAs or MMA(3+) in the BMT-deficient human prostate cell line, RWPE-1. ODD, measured by the immuno-spin trapping method, was assessed after exposure to iAs or MMA(3+) alone, with the arsenic BMT inhibitor selenite or after glutathione (GSH) depletion. The expression of oxidative stress-related genes (HO-1, SOD-1, SOD-2, Nrf2 and Keap-1) was also assessed. Exposure to iAs at 24 h (0-20 mu M), stimulated ODD only at levels above the LC50 of a 48 h exposure (17 mu M). If iAs induced ODD, it also activated oxidative stress-related genes. Selenium did not alter iAs-induced ODD. MMA(3+) at 24 h (0-0.5 mu M) caused ODD at levels below the LC50 of a 48 h exposure (1.5 mu M), which were greatly increased by GSH depletion but not selenite. MMA(3+) induced ODD at levels not activating oxidant stress response genes. Overall, iAs induced ODD in BMT-deficient cells only at toxic levels. MMA(3+) caused ODD at non-toxic levels, independently of cellular BMT capacity and in a fashion not requiring further BMT. C1 [Orihuela, Ruben; Kojima, Chikara; Tokar, Erik J.; Person, Rachel J.; Xu, Yuanyuan; Qu, Wei; Waalkes, Michael P.] NIEHS, Div Natl Toxicol Program, Natl Toxicol Program Lab, Inorgan Toxicol Grp, Res Triangle Pk, NC 27709 USA. RP Waalkes, MP (reprint author), NIEHS, Div Natl Toxicol Program, Natl Toxicol Program Lab, Inorgan Toxicol Grp, POB 12233,Mail Drop E1-07,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM waalkes@niehs.nih.gov OI ORIHUELA, RUBEN/0000-0001-6718-6194 NR 44 TC 2 Z9 2 U1 0 U2 5 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1537-6516 J9 TOXICOL MECH METHOD JI Toxicol. Mech. Methods PD JUL PY 2013 VL 23 IS 6 BP 389 EP 395 DI 10.3109/15376516.2012.762570 PG 7 WC Toxicology SC Toxicology GA 173GE UT WOS:000321065600002 PM 23301828 ER PT J AU Perkins, NJ Schisterman, EF Vexler, A AF Perkins, Neil J. Schisterman, Enrique F. Vexler, Albert TI Multivariate Normally Distributed Biomarkers Subject to Limits of Detection and Receiver Operating Characteristic Curve Inference SO ACADEMIC RADIOLOGY LA English DT Article DE Area under the curve; left censoring; limit of detection; maximum likelihood; ROC ID ROC ANALYSIS; SAMPLES AB Rationale and Objectives: Biomarkers are of ever-increasing importance to clinical practice and epidemiologic research. Multiple biomarkers are often measured per patient. Measurement of true biomarker levels is limited by laboratory precision, specifically measuring relatively low, or high, biomarker levels resulting in undetectable levels below, or above, a limit of detection (LOD). Ignoring these missing observations or replacing them with a constant are methods commonly used although they have been shown to lead to biased estimates of several parameters of interest, including the area under the receiver operating characteristic (ROC) curve and regression coefficients. Materials and Methods: We developed asymptotically consistent, efficient estimators, via maximum likelihood techniques, for the mean vector and covariance matrix of multivariate normally distributed biomarkers affected by LOD. We also developed an approximation for the Fisher information and covariance matrix for our maximum likelihood estimations (MLEs). We apply these results to an ROC curve setting, generating an MLE for the area under the curve for the best linear combination of multiple biomarkers and accompanying confidence-interval. Results: Point and confidence interval estimates are scrutinized by simulation study, with bias and root mean square error and coverage probability, respectively, displaying behavior consistent with MLEs. An example using three polychlorinated biphenyls to classify women with and without endometriosis illustrates how the underlying distribution of multiple biomarkers with LOD can be assessed and display increased discriminatory ability over naive methods. Conclusions: Properly addressing LODs can lead to optimal biomarker combinations with increased discriminatory ability that may have been ignored because of measurement obstacles. C1 [Perkins, Neil J.; Schisterman, Enrique F.; Vexler, Albert] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, DHHS, Rockville, MD 20852 USA. [Vexler, Albert] SUNY Buffalo, Dept Biostat, Buffalo, NY 14260 USA. RP Perkins, NJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, DHHS, 6100 Execut Blvd, Rockville, MD 20852 USA. EM perkinsn@mail.nih.gov OI Perkins, Neil/0000-0002-6802-4733; Schisterman, Enrique/0000-0003-3757-641X FU NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This research was supported by the Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 25 TC 4 Z9 4 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 EI 1878-4046 J9 ACAD RADIOL JI Acad. Radiol. PD JUL PY 2013 VL 20 IS 7 BP 838 EP 846 DI 10.1016/j.acra.2013.04.001 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 168YT UT WOS:000320744600007 PM 23747152 ER PT J AU Tang, LL Kang, L Liu, CL Schisterman, EF Liu, AY AF Tang, Liansheng Larry Kang, Le Liu, Chunling Schisterman, Enrique F. Liu, Aiyi TI An Additive Selection of Markers to Improve Diagnostic Accuracy Based on a Discriminatory Measure SO ACADEMIC RADIOLOGY LA English DT Article DE Receiver operating characteristic (ROC); area under the ROC curves (AUC); discriminatory score; Box-Cox transformation ID OPERATING CHARACTERISTIC CURVES; MAXIMUM-LIKELIHOOD-ESTIMATION; CHARACTERISTIC ROC CURVES; STATISTICAL VALIDATION; MODEL; AREAS AB Rationale and Objectives: The estimation of the area under the receiver operating characteristic (ROC) curve (AUC) often relies on the assumption that the truly positive population tends to have higher marker results than the truly negative population. The authors propose a discriminatory measure to relax such an assumption and apply the measure to identify the appropriate set of markers for combination. Materials and Methods: The proposed measure is based on the maximum of the AUC and 1-AUC. The existing methods are applied to estimate the measure. The subset of markers is selected using a combination method that maximizes a function of the proposed discriminatory score with the number of markers as a penalty in the function. Results: The properties of the estimators for the proposed measure were studied through large-scale simulation studies. The application was illustrated through a real example to identify the set of markers to combine. Conclusion: Simulation results showed excellent small-sample performance of the estimators for the proposed measure. The application in the example yielded a reasonable subset of markers for combination. C1 [Tang, Liansheng Larry] George Mason Univ, Dept Stat, Fairfax, VA 22030 USA. [Kang, Le] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Liu, Chunling] Hong Kong Polytech Univ, Dept Appl Math, Hong Kong, Hong Kong, Peoples R China. [Schisterman, Enrique F.; Liu, Aiyi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Bethesda, MD USA. RP Liu, AY (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd, Bethesda, MD USA. EM liua@mail.nih.gov RI Liu, Chunling/A-4827-2015; OI Liu, Chunling/0000-0003-3410-445X; Liu, Aiyi/0000-0002-6618-5082; Schisterman, Enrique/0000-0003-3757-641X FU Intramural NIH HHS [ZIA HD008875-01] NR 33 TC 2 Z9 2 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 EI 1878-4046 J9 ACAD RADIOL JI Acad. Radiol. PD JUL PY 2013 VL 20 IS 7 BP 854 EP 862 DI 10.1016/j.acra.2013.02.009 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 168YT UT WOS:000320744600009 PM 23611438 ER PT J AU Liu, DP Zhou, XH AF Liu, Danping Zhou, Xiao-Hua TI ROC Analysis in Biomarker Combination with Covariate Adjustment SO ACADEMIC RADIOLOGY LA English DT Article DE Biomarker combination; covariate adjustment; AUC; covariate standardization ID OPERATING CHARACTERISTIC CURVE; REGRESSION; ACCURACY; MARKERS; AREA AB Rational and Objectives: Receiver operating characteristic (ROC) analysis is often used to find the optimal combination of biomarkers. When the subject level covariates affect the magnitude and/or accuracy of the biomarkers, the combination rule should take into account of the covariate adjustment. The authors propose two new biomarker combination methods that make use of the covariate information. Materials and Methods: The first method is to maximize the area under the covariate-adjusted ROC curve (AAUC). To overborne the limitations of the AAUC measure, the authors further proposed the area under covariate-standardized ROC curve (SAUC), which is an extension of the covariate-specific ROC curve. With a series of simulation studies, the proposed optimal AAUC and SAUC methods are compared with the optimal AUC method that ignores the covariates. The biomarker combination methods are illustrated by an example from Alzheimer's disease research. Results: The simulation results indicate that the optimal AAUC combination performs well in the current study population. The optimal SAUC method is flexible to choose any reference populations, and allows the results to be generalized to different populations. Conclusions: The proposed optimal AAUC and SAUC approaches successfully address the covariate adjustment problem in estimating the optimal marker combination. The optimal SAUC method is preferred-for practical use, because the biomarker combination rule can be easily evaluated for different population of interest. C1 [Liu, Danping] NICHD, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. [Zhou, Xiao-Hua] VA Puget Sound Hlth Care Syst, HSR&D Ctr Excellence, Seattle, WA 98101 USA. [Zhou, Xiao-Hua] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. RP Liu, DP (reprint author), NICHD, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, NIH, 6100 Execut Blvd, Bethesda, MD 20892 USA. EM danping.liu@nih.gov FU National Institute of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); NIH/NIA [U01AG016976] FX D.L.'s research is supported by the Intramural Research Program of the National Institute of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). This work was supported in part by NIH/NIA grant U01AG016976. NR 16 TC 5 Z9 5 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 EI 1878-4046 J9 ACAD RADIOL JI Acad. Radiol. PD JUL PY 2013 VL 20 IS 7 BP 874 EP 882 DI 10.1016/j.acra.2013.03.009 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 168YT UT WOS:000320744600011 PM 23747153 ER PT J AU Rudzinski, ER Teot, LA Anderson, JR Moore, J Bridge, JA Barr, FG Gastier-Foster, JM Skapek, SX Hawkins, DS Parham, DM AF Rudzinski, Erin R. Teot, Lisa A. Anderson, James R. Moore, Julie Bridge, Julia A. Barr, Frederic G. Gastier-Foster, Julie M. Skapek, Stephen X. Hawkins, Douglas S. Parham, David M. TI Dense Pattern of Embryonal Rhabdomyosarcoma, a Lesion Easily Confused With Alveolar Rhabdomyosarcoma A Report From the Soft Tissue Sarcoma Committee of the Children's Oncology Group SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE Alveolar rhabdomyosarcoma; Embryonal rhabdomyosarcoma; Histologic classification; Rhabdomyosarcoma; Myogenin ID INTERGROUP-RHABDOMYOSARCOMA; FUSION STATUS; STUDY-III; CLASSIFICATION; DIAGNOSIS; MYOGENIN; VARIANT AB Objectives: To examine whether the frequency of fusion-negative alveolar rhabdomyosarcoma (ARMSn) increased coincident with changes in the definition of alveolar histology. Methods: We re-reviewed alveolar rhabdomyosarcoma (ARMS) in the Children's Oncology Group study D9803, comparing histopathology with fusion status. Results: Our review of 255 original ARMS cases (compared with a control group of 38 embryonal rhabdomyosarcomas [ERMS] cases) revealed that many had an ARMS-like densely cellular pattern with cytologic features and myogenin expression more typical of ERMS. Following re-review, 84 (33%) cases of original ARMS were rediagnosed as ERMS. All reclassified ERMS, including dense ERMS, were fusion negative, whereas 82% of confirmed ARMS cases were fusion positive. Total ARMS diagnoses returned to historic rates of 25% to 30% of all rhabdomyosarcomas, and ARMSn decreased from 37% to 18% of ARMS cases. The outcome of reclassified ERMS was similar to confirmed ERMS. Conclusions: To address the role of fusion status in risk stratification, pathologists should include both a histologic diagnosis and an evaluation of fusion status for all new ARMS diagnoses. C1 [Rudzinski, Erin R.; Hawkins, Douglas S.] Seattle Childrens Hosp, Seattle, WA 98015 USA. [Teot, Lisa A.] Boston Childrens Hosp, Boston, MA USA. [Anderson, James R.; Bridge, Julia A.] Univ Nebraska Med Ctr, Omaha, NE USA. [Moore, Julie] Nationwide Childrens Hosp, Columbus, OH USA. [Barr, Frederic G.] NCI, Bethesda, MD USA. [Gastier-Foster, Julie M.] Ohio State Univ, Coll Med, Columbus, OH 43210 USA. [Skapek, Stephen X.] Univ Texas SW Med Ctr Dallas, Dallas, TX USA. [Hawkins, Douglas S.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Hawkins, Douglas S.] Univ Washington, Seattle, WA 98195 USA. [Parham, David M.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. RP Rudzinski, ER (reprint author), Seattle Childrens Hosp, Dept Labs, M-S OC-8-720,4800 Sandpoint Way NE, Seattle, WA 98015 USA. EM erin.rudzinski@seattlechildrens.org FU St Baldrick's Foundation, Monrovia, CA [179772]; National Institutes of Health, Bethesda, MD [NIH-RC2-CA148216, NIH-R01-CA104896, NIH-U10-CA098412, NIH-U10-CA98543]; Joanna McAfee Childhood Cancer Foundation, Warner Robins, GA [U-10-CA98543-07] FX Research support was provided by research grant 179772 from St Baldrick's Foundation, Monrovia, CA (E.R.R); NIH-RC2-CA148216 (S.X.S., J.M.; J.A.B., F.G.B., and J.M.G.-F), NIH-R01-CA104896 (F.G.B., J.M.G.-F), NIH-U10-CA098412 (J.R.A.), and NIH-U10-CA98543 (COG Chair's grant) from the National Institutes of Health, Bethesda, MD; and grants (F.G.B) and U-10-CA98543-07 (J.A.B.) from the Joanna McAfee Childhood Cancer Foundation, Warner Robins, GA. NR 24 TC 20 Z9 20 U1 0 U2 4 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 JUL PY 2013 VL 140 IS 1 BP 82 EP 90 DI 10.1309/AJCPA1WN7ARPCMKQ PG 9 WC Pathology SC Pathology GA 167LS UT WOS:000320634100009 PM 23765537 ER PT J AU Chen, YT Zheng, TZ Lan, Q Kim, C Qin, Q Foss, F Chen, XZ Holford, T Leaderer, B Boyle, P Wang, CF Dai, M Liu, ZJ Ma, SG Chanock, SJ Rothman, N Zhang, YW AF Chen, Yingtai Zheng, Tongzhang Lan, Qing Kim, Christopher Qin, Qin Foss, Francine Chen, Xuezhong Holford, Theodore Leaderer, Brian Boyle, Peter Wang, Chengfeng Dai, Min Liu, Zhenjiang Ma, Shuangge Chanock, Stephen J. Rothman, Nathaniel Zhang, Yawei TI Polymorphisms in DNA repair pathway genes, body mass index, and risk of non-Hodgkin lymphoma SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID RAT SKELETAL-MUSCLE; CANCER-RISK; PHYSICAL-ACTIVITY; OXIDATIVE STRESS; POOLED ANALYSIS; LUNG-CANCER; OBESITY; EXERCISE; WOMEN; MEN AB We conducted a population-based case-control study in Connecticut women to test the hypothesis that genetic variations in DNA repair pathway genes may modify the relationship between body mass index (BMI) and risk of non-Hodgkin lymphoma (NHL). Compared to those with BMI <25, women with BMI 25 had significantly increased risk of NHL among women who carried BRCA1 (rs799917) CT/TT, ERCC2 (rs13181) AA, XRCC1 (rs1799782) CC, and WRN (rs1801195) GG genotypes, but no increase in NHL risk among women who carried BRCA1 CC, ERCC2 AC/CC, XRCC1 CT/TT, and WRN GT/TT genotypes. A significant interaction with BMI was only observed for WRN (rs1801195; P=0.004) for T-cell lymphoma and ERCC2 (rs13181; P=0.002) for diffuse large B-cell lymphoma. The results suggest that common genetic variation in DNA repair pathway genes may modify the association between BMI and NHL risk. Am. J. Hematol. 88:606-611, 2013. (c) 2013 Wiley Periodicals, Inc. C1 [Chen, Yingtai; Wang, Chengfeng; Dai, Min] Chinese Acad Med Sci, Canc Inst Hosp, Beijing 100730, Peoples R China. [Chen, Yingtai; Zheng, Tongzhang; Kim, Christopher; Holford, Theodore; Leaderer, Brian; Ma, Shuangge; Zhang, Yawei] Yale Univ, Sch Publ Hlth, New Haven, CT 06520 USA. [Lan, Qing; Kim, Christopher; Chanock, Stephen J.; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Rockville, MD USA. [Qin, Qin] Univ So Maine, Wise Lab Environm & Genet Toxicol, Portland, ME 04103 USA. [Foss, Francine] Yale Univ, Sch Med, New Haven, CT USA. [Chen, Xuezhong] Gansu Prov Canc Hosp, Lanzhou, Peoples R China. [Boyle, Peter] Int Prevent Res Inst, Lyon, France. [Liu, Zhenjiang] Gansu Prov Coll Chinese Med, Lanzhou, Peoples R China. [Chanock, Stephen J.] NCI, Core Genotyping Facil, Adv Technol Ctr, NIH,DHHS, Gaithersburg, MD USA. RP Zhang, YW (reprint author), Yale Univ, Sch Publ Hlth, 60 Coll St LEPH 440, New Haven, CT 06520 USA. EM yawei.zhang@yale.edu RI Boyle, Peter/A-4380-2014 OI Boyle, Peter/0000-0001-6251-0610 FU NIH [CA62006, CA165923, 1D43TW008323, 1D43TW007864, HD70324]; Intramural Research Program of the National Cancer Institute FX This research was supported by the NIH grants CA62006, CA165923, 1D43TW008323, 1D43TW007864, and HD70324, and the Intramural Research Program of the National Cancer Institute. NR 50 TC 6 Z9 7 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD JUL PY 2013 VL 88 IS 7 BP 606 EP 611 DI 10.1002/ajh.23463 PG 6 WC Hematology SC Hematology GA 167VB UT WOS:000320662200013 PM 23619945 ER PT J AU Chou, CF Cotch, MF Vitale, S Zhang, XZ Klein, R Friedman, DS Klein, BEK Saaddine, JB AF Chou, Chiu-Fang Cotch, Mary Frances Vitale, Susan Zhang, Xinzhi Klein, Ronald Friedman, David S. Klein, Barbara E. K. Saaddine, Jinan B. TI Age-Related Eye Diseases and Visual Impairment Among U.S. Adults SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID ANGELES LATINO EYE; BLUE MOUNTAINS EYE; QUALITY-OF-LIFE; UNDERCORRECTED REFRACTIVE ERRORS; UNITED-STATES; MACULAR DEGENERATION; SOCIOECONOMIC-FACTORS; VISION IMPAIRMENT; OLDER POPULATION; RISK INDICATORS AB Background: Visual impairment is a common health-related disability in the U.S. The association between clinical measurements of age-related eye diseases and visual impairment in data from a national survey has not been reported. Purpose: To examine common eye conditions and other correlates associated with visual impairment in the U.S. Methods: Data from the 2005-2008 National Health and Nutrition Examination Survey of 5222 Americans aged >= 40 years were analyzed in 2012 for visual impairment (presenting distance visual acuity worse than 20/40 in the better-seeing eye), and visual impairment not due to refractive error (distance visual acuity worse than 20/40 after refraction). Diabetic retinopathy (DR) and age-related macular degeneration (AMD) were assessed from retinal fundus images; glaucoma was assessed from two successive frequency-doubling tests and a cup-to-disc ratio measurement. Results: Prevalence of visual impairment and of visual impairment not due to refractive error was 7.5% (95% CI=6.9%, 8.1%) and 2.0% (1.7%, 2.3%), respectively. The prevalence of visual impairment not due to refractive error was significantly higher among people with AMD (2.2%) compared to those without AMD (0.8%), or with DR (3.5%) compared to those without DR (1.2%). Independent predictive factors of visual impairment not due to refractive error were AMD (OR=4.52, 95% CI=2.50, 8.17); increasing age (OR=1.09 per year, 95% CI=1.06, 1.13); and less than a high school education (OR=2.99, 95% CI=1.18, 7.55). Conclusions: Visual impairment is a public health problem in the U.S. Visual impairment in two thirds of adults could be eliminated with refractive correction. Screening of the older population may identify adults at increased risk of visual impairment due to eye diseases. C1 [Chou, Chiu-Fang; Zhang, Xinzhi; Saaddine, Jinan B.] CDC, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Diabet Translat, Atlanta, GA 30341 USA. [Cotch, Mary Frances; Vitale, Susan] NIH, NEI, Div Epidemiol & Clin Applicat, Bethesda, MD USA. [Friedman, David S.] Johns Hopkins Sch Med, Wilmer Eye Inst, Baltimore, MD USA. [Klein, Ronald; Klein, Barbara E. K.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI USA. RP Chou, CF (reprint author), CDC, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Diabet Translat, 4770 Buford Hwy,NE K-10, Atlanta, GA 30341 USA. EM CChou@cdc.gov OI Cotch, Mary Frances/0000-0002-2046-4350; Klein, Ronald/0000-0002-4428-6237 FU National Center for Health Statistics (NCHS), CDC; Division of Diabetes Translation, CDC [05FED47304]; National Eye Institute, NIH [ZIAEY000402] FX This study was supported by the National Center for Health Statistics (NCHS), CDC. Funding for the National Health and Nutrition Examination Survey (NHANES) retinal and frequency-doubling technology component was provided by the Intra Agency Agreement 05FED47304 from the Division of Diabetes Translation, CDC. Funding for the vision component was provided by the National Eye Institute, NIH, Intramural Research Program award ZIAEY000402. NR 39 TC 17 Z9 17 U1 1 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD JUL PY 2013 VL 45 IS 1 BP 29 EP 35 DI 10.1016/j.amepre.2013.02.018 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 170CO UT WOS:000320827500004 PM 23790986 ER PT J AU Schnabel, RB Yin, XY Larson, MG Yamamoto, JF Fontes, JD Kathiresan, S Rong, J Levy, D Keaney, JF Wang, TJ Murabito, JM Vasan, RS Benjamin, EJ AF Schnabel, Renate B. Yin, Xiaoyan Larson, Martin G. Yamamoto, Jennifer F. Fontes, Joao D. Kathiresan, Sekar Rong, Jian Levy, Daniel Keaney, John F., Jr. Wang, Thomas J. Murabito, Joanne M. Vasan, Ramachandran S. Benjamin, Emelia J. TI Multiple Inflammatory Biomarkers in Relation to Cardiovascular Events and Mortality in the Community SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE cardiovascular disease; cohort; epidemiology; inflammation; mortality ID C-REACTIVE PROTEIN; TUMOR-NECROSIS-FACTOR; CORONARY-HEART-DISEASE; INTERCELLULAR-ADHESION MOLECULE-1; TYPE-2 DIABETIC-PATIENTS; RHEUMATOID-ARTHRITIS; BODY-COMPOSITION; RISK-FACTORS; OLDEST-OLD; MARKERS AB Objective Evidence suggests that chronic low-grade inflammation and oxidative stress are related to cardiovascular disease (CVD) and mortality. Approach and Results We examined 11 established and novel biomarkers representing inflammation and oxidative stress (C-reactive protein, fibrinogen, interleukin-6, intercellular adhesion molecule-1, lipoprotein-associated phospholipase-A2 [mass and activity], monocyte chemoattractant protein-1, myeloperoxidase, CD40 ligand, P-selectin, and tumor necrosis factor receptor II [TNFRII]) in relation to incident major CVD and mortality in the community. We studied 3035 participants (mean age, 61 +/- 9 years; 53% women). During follow-up (median, 8.9 years), 253 participants experienced a CVD event and 343 died. C-reactive protein (hazard ratio [HR] reported per SD ln-transformed biomarker, 1.18; 95% confidence interval [CI], 1.02-1.35; nominal P=0.02) and TNFRII (HR, 1.15; 95% CI, 1.01-1.32; nominal P=0.04) were retained in multivariable-adjusted models for major CVD, but were not significant after adjustment for multiple testing. The biomarkers related to mortality were TNFRII (HR, 1.33; 95% CI, 1.19-1.49; P<0.0001), ICAM-1 (HR, 1.24; 95% CI, 1.12-1.37; P<0.0001), and interleukin-6 (HR, 1.25; 95% CI, 1.12-1.39; P<0.0001). The addition of these markers to the model, including traditional risk factors, increased discrimination and reclassification for risk of death (P<0.0001), but not for CVD. Conclusions Of 11 inflammatory biomarkers tumor necrosis factor receptor II was related to cardiovascular disease and mortality in the Framingham Heart Study. The combination of TNFRII with C-reactive protein in relation to CVD and with interleukin-6 to mortality increased the predictive ability in addition to CVD risk factors for total mortality but not for incident CVD. C1 [Schnabel, Renate B.; Yin, Xiaoyan; Larson, Martin G.; Yamamoto, Jennifer F.; Fontes, Joao D.; Rong, Jian; Levy, Daniel; Murabito, Joanne M.; Vasan, Ramachandran S.; Benjamin, Emelia J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Math & Stat, Boston, MA USA. [Yin, Xiaoyan; Larson, Martin G.; Yamamoto, Jennifer F.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Evans Mem Med Dept, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Sect Prevent Med, Boston, MA 02118 USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Fontes, Joao D.; Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Wang, Thomas J.] Vanderbilt Univ, Div Cardiovasc Med, Nashville, TN 37235 USA. [Kathiresan, Sekar] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Keaney, John F., Jr.] Univ Massachusetts, Sch Med, Worcester, MA USA. [Kathiresan, Sekar] MIT, Broad Inst Harvard, Cambridge, MA 02139 USA. RP Schnabel, RB (reprint author), Univ Med Ctr Hamburg Eppendorf, Dept Gen & Intervent Cardiol, Bldg E 70 O70,Martinistr 52, D-20246 Hamburg, Germany. EM schnabelr@gmx.de RI Schnabel, Renate/F-6527-2014; OI Murabito, Joanne/0000-0002-0192-7516; Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute [N01-/HC-/25195, 6R01-/NS17950]; NIH [HL064753, HL076784, AG028321, 1 RO1HL71039, K24 HL04334]; Deutsche Forschungsgemeinschaft (German Research Foundation) [SCHN 1149/1-/1, SCHN 1149/3-/1]; Doris Duke Charitable Foundation Clinical Scientist Development Award [1K23HL083102] FX This work was supported by National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute contract N01-/HC-/25195, 6R01-/NS17950, and NIH grants HL064753, HL076784, AG028321 (E.J. Benjamin), and 1 RO1HL71039 (R.S. Vasan); NIH Research career award K24 HL04334 (R.S. Vasan); Deutsche Forschungsgemeinschaft (German Research Foundation) Research Fellowship SCHN 1149/1-/1 and Emmy Noether Program SCHN 1149/3-/1 (R.B. Schnabel); 1K23HL083102, Doris Duke Charitable Foundation Clinical Scientist Development Award (S. Kathiresan). NR 49 TC 26 Z9 27 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD JUL PY 2013 VL 33 IS 7 BP 1728 EP 1733 DI 10.1161/ATVBAHA.112.301174 PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 167YP UT WOS:000320671800040 PM 23640499 ER PT J AU Foran, JM Pavletic, SZ Logan, BR Agovi-Johnson, MA Perez, WS Bolwell, BJ Bornhauser, M Bredeson, CN Cairo, MS Camitta, BM Copelan, EA Dehn, J Gale, RP George, B Gupta, V Hale, GA Lazarus, HM Litzow, MR Maharaj, D Marks, DI Martino, R Maziarz, RT Rowe, JM Rowlings, PA Savani, BN Savoie, ML Szer, J Waller, EK Wiernik, PH Weisdorf, DJ AF Foran, James M. Pavletic, Steven Z. Logan, Brent R. Agovi-Johnson, Manza A. Perez, Waleska S. Bolwell, Brian J. Bornhaeuser, Martin Bredeson, Christopher N. Cairo, Mitchell S. Camitta, Bruce M. Copelan, Edward A. Dehn, Jason Gale, Robert P. George, Biju Gupta, Vikas Hale, Gregory A. Lazarus, Hillard M. Litzow, Mark R. Maharaj, Dipnarine Marks, David I. Martino, Rodrigo Maziarz, Richard T. Rowe, Jacob M. Rowlings, Philip A. Savani, Bipin N. Savoie, Mary Lynn Szer, Jeffrey Waller, Edmund K. Wiernik, Peter H. Weisdorf, Daniel J. TI Unrelated Donor Allogeneic Transplantation after Failure of Autologous Transplantation for Acute Myelogenous Leukemia: A Study from the Center for International Blood and Marrow Transplantation Research SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Acute myelogenous leukemia; Unrelated donor; Transplantation; Allogeneic; Autologous ID ACUTE MYELOID-LEUKEMIA; STEM-CELL TRANSPLANTATION; CONDITIONING REGIMEN; ADULT PATIENTS; 1ST REMISSION; HEMATOLOGIC MALIGNANCIES; RELAPSE; SURVIVAL; CHEMOTHERAPY; THERAPY AB The survival of patients with relapsed acute myelogenous leukemia (AML) after autologous hematopoietic stem cell transplantation (auto-HCT) is very poor. We studied the outcomes of 302 patients who underwent secondary allogeneic hematopoietic cell transplantation (allo-HCT) from an unrelated donor (URD) using either myeloablative (n = 242) or reduced-intensity conditioning (RIC; n = 60) regimens reported to the Center for International Blood and Marrow Transplantation Research. After a median follow-up of 58 months (range, 2 to 160 months), the probability of treatment-related mortality was 44% (95% confidence interval [CI], 38%-50%) at 1-year. The 5-year incidence of relapse was 32% (95% CI, 27%-38%), and that of overall survival was 22% (95% CI, 18%-27%). Multivariate analysis revealed a significantly better overal survival with RIC regimens (hazard ratio [HR], 0.51; 95% CI, 0.35-0.75; P < .001), with Karnofsky Performance Status score >= 90% (HR, 0.62; 95% CI, 0.47-0.82: P = .001) and in cytomegalovirus-negative recipients (HR, 0.64; 95% CI, 0.44-0.94; P = .022). A longer interval (>18 months) from auto-HCT to URD allo-HCT was associated with significantly lower riak of relapse (HR, 0.19; 95% CI, 0.09-0:38; P < .001) and improved leukemia-free survival (HR, 0.53; 95% CI, 0.34-0.84; P = .006). URD allo-HCT after auto-HCT relapse resulted in 20% long-term leukemia-free survival, with the best results seen in patients with a longer interval to secondary URD transplantation, with a Karnofsky Performance Status score >90%, in complete remission, and using an RIC regimen. Further efforts to reduce treatment-related mortaility and relapse are still needed. (C) 2013 American Society for Blood and Marrow Transplantation. C1 [Foran, James M.] Mayo Clin Florida, Jacksonville, FL USA. [Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Logan, Brent R.; Perez, Waleska S.] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Agovi-Johnson, Manza A.] Univ S Carolina, Norman J Arnold Sch Publ Hlth, Columbia, SC 29208 USA. [Bolwell, Brian J.; Copelan, Edward A.] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Bornhaeuser, Martin] Univ Klinikum Carl Gustav Carus, Dresden, Germany. [Bredeson, Christopher N.] Ottawa Hosp, Blood & Marrow Transplant Program, Ottawa, ON, Canada. [Cairo, Mitchell S.] New York Med Coll, Valhalla, NY 10595 USA. [Camitta, Bruce M.] Childrens Hosp Wisconsin, Milwaukee, WI 53201 USA. [Dehn, Jason] Natl Marrow Donor Program, Minneapolis, MN USA. [Gale, Robert P.] Univ London Imperial Coll Sci Technol & Med, London, England. [George, Biju] Christian Med Coll & Hosp, Vellore, Tamil Nadu, India. [Gupta, Vikas] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Hale, Gregory A.] Univ S Florida, All Childrens Hosp, St Petersburg, FL 33701 USA. [Lazarus, Hillard M.] Univ Hosp Cleveland, Case Med Ctr, Cleveland, OH 44106 USA. [Litzow, Mark R.] Mayo Clin, Rochester, MN USA. [Maharaj, Dipnarine] Bethesda Hlth City, Boynton Beach, FL USA. [Marks, David I.] Bristol Childrens Hosp, Bristol, Avon, England. [Martino, Rodrigo] Hosp Santa Creu & Sant Pau, Barcelona, Spain. [Maziarz, Richard T.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Rowe, Jacob M.] Rambam Med Ctr, Haifa, Israel. [Rowlings, Philip A.] Calvary Mater Newcastle, Waratah, NSW, Australia. [Savani, Bipin N.] Vanderbilt Univ, Med Ctr, Brentwood, TN USA. [Savoie, Mary Lynn] Tom Baker Canc Clin, Calgary, AB, Canada. [Szer, Jeffrey] Royal Melbourne Hosp, Melbourne, Vic, Australia. [Waller, Edmund K.] Emory Univ Hosp, Atlanta, GA 30322 USA. [Wiernik, Peter H.] St Lukes Roosevelt & Beth Israel Med Ctr, Continuum Canc Ctr New York, New York, NY USA. [Weisdorf, Daniel J.] Univ Minnesota, Minneapolis, MN 55455 USA. RP Weisdorf, DJ (reprint author), Univ Minnesota, Med Ctr, 420 Delaware St SE,MMC 480, Minneapolis, MN 55455 USA. EM weisd001@umn.edu OI Szer, Jeff/0000-0001-6783-2301 FU Public Health Service Grant/Cooperative Agreement, National Cancer Institute [U24-CA76518]; National Heart, Lung and Blood Institute; National Institute of Allergy and Infectious Diseases; National Cancer Institute [5U01HL069294]; Health Resources and Services Administration [HHSH234200637015C]; Office of Naval Research [N00014-06-1-0704, N00014-08-1-0058]; Allos; Amgen; Angioblast FX The Center for International Blood and Marrow Transplant Research is supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 from the National Cancer Institute, the National Heart, Lung and Blood Institute, and the National Institute of Allergy and Infectious Diseases; Grant/Cooperative Agreement 5U01HL069294 from the National Cancer Institute and the National Heart, Lung and Blood Institute; Contract HHSH234200637015C with the Health Resources and Services Administration; Grants N00014-06-1-0704 and N00014-08-1-0058 from the Office of Naval Research; and grants from Allos, Amgen, Angioblast, anonymous donation to the Medical College of Wisconsin, Ariad, Be the Match Foundation, Blue Cross and Blue Shield Association, Buchanan Family Foundation, CaridianBCT, Celgene, CellGenix, Children's Leukemia Research Association, Fresenius-Biotech North America, Gamida Cell Teva Joint Venture, Genentech, Genzyme, GlaxoSmithKline, HistoGenetics, Kiadis Pharma, Leukemia and Lymphoma Society, Medical College of Wisconsin, Merck & Co, Millennium: Takeda Oncology, Milliman USA, Miltenyi Biotec, National Marrow Donor Program, Optum Healthcare Solutions, Osiris Therapeutics, Otsuka America Pharmaceutical, RemedyMD, Sanofi, Seattle Genetics, Sigma-Tau Pharmaceuticals, Soligenix, StemCyte, Stemsoft Software, Swedish Orphan Biovitrum, Tarix Pharmaceuticals, Teva Neuroscience, Therakos, and Wellpoint. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, or any other agency of the US Government. NR 34 TC 8 Z9 8 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD JUL PY 2013 VL 19 IS 7 BP 1102 EP 1108 DI 10.1016/j.bbmt.2013.04.022 PG 7 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 173QH UT WOS:000321093500017 PM 23632091 ER PT J AU Wee, J Mortimer, PS Lindhurst, M Biesecker, L Holden, CA AF Wee, J. Mortimer, P. S. Lindhurst, M. Biesecker, L. Holden, C. A. TI Expanding the spectrum of Proteus syndrome: bilateral cerebriform plantar collagenomas and varicose veins secondary to a mosaic AKT1 mutation SO BRITISH JOURNAL OF DERMATOLOGY LA English DT Meeting Abstract CT 93rd Annual Meeting of the British-Association-of-Dermatologists CY JUL 09-11, 2013 CL Liverpool, ENGLAND SP British Assoc Dermatologists C1 [Wee, J.; Mortimer, P. S.] St George Hosp, London, England. [Lindhurst, M.; Biesecker, L.] NHGRI, Bethesda, MD 20892 USA. [Holden, C. A.] St Heliers Hosp, Surrey, England. 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 0007-0963 J9 BRIT J DERMATOL JI Br. J. Dermatol. PD JUL PY 2013 VL 169 SU 1 SI SI BP 13 EP 14 PG 2 WC Dermatology SC Dermatology GA 178JI UT WOS:000321443500027 ER PT J AU Eichmann, K Krause, RM AF Eichmann, Klaus Krause, Richard M. TI Fred Neufeld and pneumococcal serotypes: foundations for the discovery of the transforming principle SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Article DE History of infectious diseases; History of bacteriology; Bile solubility; Quellung reaction; Bacteriotropin ID SOLUBLE SPECIFIC SUBSTANCE; LOBAR PNEUMONIA; SERUM TREATMENT; ANTIPNEUMOCOCCIC SERUM; LECTURE AB During the first decade of the twentieth century, the German bacteriologist Fred Neufeld, later Director of the Robert Koch-Institute in Berlin, first described the differentiation of pneumococci into serotypes on the basis of type-specific antisera. This finding was essential for subsequent research at the Rockefeller Institute of Medical Research (RIMR) in New York, and elsewhere, aiming for the conquest of human pneumococcal pneumonia, including antiserum therapy, the discovery that the type-specific antigens were carbohydrates, and the development of effective multivalent pneumococcal polysaccharide vaccines. Moreover, on the basis of pneumococcal serotypes Fred Griffith, in 1928 in London, discovered pneumococcal transformation, and Oswald T. Avery and coworkers, in 1944 at RIMR, identified DNA as the transforming substance. This sequence of events, leading to today's knowledge that genes consist of DNA, was initiated by a farsighted move of Simon Flexner, first Director of the RIMR, who asked Neufeld to send his pneumococcal typing strains, thus setting the stage for pneumococcal research at RIMR. Here, we describe Fred Neufeld's contributions in this development, which have remained largely unknown. C1 [Eichmann, Klaus] Max Planck Inst Immunobiol & Epigenet, D-79108 Freiburg, Germany. [Krause, Richard M.] NIAID, NIH, Bethesda, MD 20892 USA. RP Eichmann, K (reprint author), Max Planck Inst Immunobiol & Epigenet, Stubeweg 51, D-79108 Freiburg, Germany. EM eichmann@immunbio.mpg.de; Richard_Krause@nih.gov NR 65 TC 1 Z9 2 U1 1 U2 20 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD JUL PY 2013 VL 70 IS 13 BP 2225 EP 2236 DI 10.1007/s00018-013-1351-z PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 163JR UT WOS:000320332600002 PM 23689587 ER PT J AU Linehan, WM Rouault, TA AF Linehan, W. Marston Rouault, Tracey A. TI Molecular Pathways: Fumarate Hydratase-Deficient Kidney Cancer-Targeting the Warburg Effect in Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID RENAL-CELL CARCINOMA; HEREDITARY LEIOMYOMATOSIS; UTERINE LEIOMYOMAS; MET PROTOONCOGENE; HLRCC SYNDROME; MUTATIONS; TUMORS; HIF; FH; INHIBITION AB Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a hereditary cancer syndrome in which affected individuals are at risk for development of cutaneous and uterine leiomyomas and an aggressive form of type II papillary kidney cancer. HLRCC is characterized by germline mutation of the tricarboxylic acid (TCA) cycle enzyme, fumarate hydratase (FH). FH-deficient kidney cancer is characterized by impaired oxidative phosphorylation and a metabolic shift to aerobic glycolysis, a form of metabolic reprogramming referred to as the Warburg effect. Increased glycolysis generates ATP needed for increased cell proliferation. In FH-deficient kidney cancer, levels of AMP-activated protein kinase (AMPK), a cellular energy sensor, are decreased resulting in diminished p53 levels, decreased expression of the iron importer, DMT1, leading to low cellular iron levels, and to enhanced fatty acid synthesis by diminishing phosphorylation of acetyl CoA carboxylase, a rate-limiting step for fatty acid synthesis. Increased fumarate and decreased iron levels in FH-deficient kidney cancer cells inactivate prolyl hydroxylases, leading to stabilization of hypoxia-inducible factor (HIF)-1 alpha and increased expression of genes such as VEGF and glucose transporter 1 (GLUT1) to provide fuel needed for rapid growth demands. Several therapeutic approaches for targeting the metabolic basis of FH-deficient kidney cancer are under development or are being evaluated in clinical trials, including the use of agents such as metformin, which would reverse the inactivation of AMPK, approaches to inhibit glucose transport, lactate dehydrogenase A (LDHA), the antioxidant response pathway, the heme oxygenase pathway, and approaches to target the tumor vasculature and glucose transport with agents such as bevacizumab and erlotinib. These same types of metabolic shifts, to aerobic glycolysis with decreased oxidative phosphorylation, have been found in a wide variety of other cancer types. Targeting the metabolic basis of a rare cancer such as FH-deficient kidney cancer will hopefully provide insights into the development of effective forms of therapies for other, more common forms of cancer. (C)2013 AACR. C1 [Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Rouault, Tracey A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Mol Med, NIH, Bethesda, MD USA. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, 10 Ctr Dr MSC 1107,CRC Room 1W-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 work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 54 TC 35 Z9 35 U1 0 U2 24 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 1 PY 2013 VL 19 IS 13 BP 3345 EP 3352 DI 10.1158/1078-0432.CCR-13-0304 PG 8 WC Oncology SC Oncology GA 173RF UT WOS:000321095900004 PM 23633457 ER PT J AU Shibata, SI Chung, V Synold, TW Longmate, JA Suttle, AB Ottesen, LH Lenz, HJ Kummar, S Harvey, RD Hamilton, AL O'Neil, BH Lenz, HJ Kummar, S Harvey, RD Hamilton, AL O'Neil, BH Sarantopoulos, J LoRusso, P Rudek, MA Dowlati, A Mulkerin, DL Belani, CP Gandhi, L Lau, SC Ivy, SP Newman, EM AF Shibata, Stephen I. Chung, Vincent Synold, Timothy W. Longmate, Jeffrey A. Suttle, A. Benjamin Ottesen, Lone H. Lenz, Heinz-Josef Kummar, Shivaani Harvey, R. Donald Hamilton, Anne L. O'Neil, Bert H. Lenz, Heinz-Josef Kummar, Shivaani Harvey, R. Donald Hamilton, Anne L. O'Neil, Bert H. Sarantopoulos, John LoRusso, Patricia Rudek, Michelle A. Dowlati, Afshin Mulkerin, Daniel L. Belani, Chandra P. Gandhi, Leena Lau, S. Cecilia Ivy, S. Percy Newman, Edward M. TI Phase I Study of Pazopanib in Patients with Advanced Solid Tumors and Hepatic Dysfunction: A National Cancer Institute Organ Dysfunction Working Group Study SO CLINICAL CANCER RESEARCH LA English DT Article ID ORAL PAZOPANIB; INHIBITOR; TRIAL AB Purpose: Pazopanib is a potent, multitargeted receptor tyrosine kinase inhibitor; however, there is limited information regarding the effects of liver function on pazopanib metabolism and pharmacokinetics. The objective of this study was to establish the maximum-tolerated dose (MTD) and pharmacokinetic profile of pazopanib in patients with varying degrees of hepatic dysfunction. Experimental Design: Patients with any solid tumors or lymphoma were stratified into four groups based on the degree of hepatic dysfunction according to the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria. Pazopanib was given orally once a day on a 21-day cycle. A modified 3+3 design was used. Results: Ninety-eight patients were enrolled. Patients in the mild group tolerated 800 mg per day. The moderate and severe groups tolerated 200 mg per day. Pharmacokinetic data in the mild group were similar to the data in the normal group. Comparison of the median C-max and area under the curve [AUC((0-24))] in the moderate or severe groups at 200 mg per day to the values in the normal and mild groups at 800 mg per day indicated less than dose-proportional systemic exposures in patients with moderate and severe hepatic impairment. This suggests that the lower maximum-tolerated dose in the moderate and severe group is not due to a decrease in drug clearance or alteration in the proportion of metabolites. Conclusions: In patients with mild liver dysfunction, pazopanib is well tolerated at the Food and Drug Administration (FDA)-approved dose of 800 mg per day. Patients with moderate and severe liver dysfunction tolerated 200 mg per day. Clin Cancer Res; 19(13); 3631-9. (C)2013 AACR. C1 [Shibata, Stephen I.; Chung, Vincent; Synold, Timothy W.; Longmate, Jeffrey A.; Lau, S. Cecilia; Newman, Edward M.] City Hope Natl Med Ctr, Duarte, CA USA. [Lenz, Heinz-Josef] Univ So Calif, Los Angeles, CA USA. [Kummar, Shivaani] Natl Canc Inst, Bethesda, MD 20892 USA. [Ivy, S. Percy] Natl Canc Inst, Bethesda, MD USA. [Ivy, S. Percy] NCI, Div Canc Treatment, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Rudek, Michelle A.] Sidney Kimmel Canc Ctr, Baltimore, MD USA. [Harvey, R. Donald] Emory Univ, Sch Med, Atlanta, GA USA. [O'Neil, Bert H.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Sarantopoulos, John] Inst Drug Dev CTRC, San Antonio, TX USA. [LoRusso, Patricia] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Mulkerin, Daniel L.] Univ Wisconsin, Madison, WI USA. [Belani, Chandra P.] Penn State Milton S Hershey Med Ctr, Hershey, PA USA. [Gandhi, Leena] Dana Farber Canc Inst, Boston, MA 02115 USA. [Hamilton, Anne L.] Royal Prince Alfred Hosp, Sydney, NSW, Australia. RP Newman, EM (reprint author), City Hope Natl Med Ctr, Beckman Res Inst, North,Room 2000A,1500 East Duarte Rd, Duarte, CA 91010 USA. EM enewman@coh.org OI Belani, Chandra/0000-0001-5049-5329; Gandhi, Leena/0000-0002-2398-9179 FU NIH [U01-CA062505, P30-CA033572, U01-CA062487, U01-CA099168, U01-CA70095, P30-CA006973, U01-CA069853, P30-CA054174, U01-CA062490, U01-CA062502, U01-C 062491] FX The study was supported by NIH grants: U01-CA062505 and P30-CA033572 (Beckman Research Institute of City of Hope, Duarte, CA); U01-CA062487 (Karmanos Cancer Institute, Detroit, MI); U01-CA099168 (University of Pittsburgh, Pittsburgh, PA); U01-CA70095 and P30-CA006973 (Johns Hopkins University, Baltimore, MD); U01-CA069853 and P30-CA054174 (Cancer Therapy and Research Center at University of Texas Health Science Center, San Antonio, TX); U01-CA062490 (Dana-Farber Cancer Institute, Boston, MA); U01-CA062502 (Case Western Reserve, Cleveland, OH); and U01-C 062491 (University of Wisconsin Paul P Carbone Comprehensive Cancer Center, Madison, WI). NR 10 TC 15 Z9 15 U1 1 U2 5 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 JUL 1 PY 2013 VL 19 IS 13 BP 3631 EP 3639 DI 10.1158/1078-0432.CCR-12-3214 PG 9 WC Oncology SC Oncology GA 173RF UT WOS:000321095900030 PM 23653147 ER PT J AU Brauer, MJ Zhuang, GL Schmidt, M Yao, J Wu, XM Kaminker, JS Jurinka, SS Kolumam, G Chung, AS Jubb, A Modrusan, Z Ozawa, T James, CD Phillips, H Haley, B Tam, RNW Clermont, AC Cheng, JH Yang, SX Swain, SM Chen, D Scherer, SJ Koeppen, H Yeh, RF Yue, P Stephan, JP Hegde, P Ferrara, N Singh, M AF Zhuang, Guanglei Schmidt, Maike Yao, Jenny Wu, Xiumin Kaminker, Joshua S. Jurinka, Stefanie S. Kolumam, Ganesh Chung, Alicia S. Jubb, Adrian Modrusan, Zora Ozawa, Tomoko James, C. David Phillips, Heidi Haley, Benjamin Tam, Rachel N. W. Clermont, Anne C. Cheng, Jason H. Yang, Sherry X. Swain, Sandra M. Chen, Daniel Scherer, Stefan J. Koeppen, Hartmut Yeh, Ru-Fang Yue, Peng Stephan, Jean-Philippe Hegde, Priti Ferrara, Napoleone Singh, Mallika Bais, Carlos TI Identification and Analysis of In Vivo VEGF Downstream Markers Link VEGF Pathway Activity with Efficacy of Anti-VEGF Therapies SO CLINICAL CANCER RESEARCH LA English DT Article ID METASTATIC COLORECTAL-CANCER; RENAL-CELL CARCINOMA; TUMOR-GROWTH; ANTIANGIOGENIC THERAPY; INDUCED ANGIOGENESIS; BREAST-CANCER; BEVACIZUMAB; RESISTANCE; INHIBITION; CHEMOTHERAPY AB Purpose: The aim of this study was to identify conserved pharmacodynamic and potential predictive biomarkers of response to anti-VEGF therapy using gene expression profiling in preclinical tumor models and in patients. Experimental Design: Surrogate markers of VEGF inhibition [VEGF-dependent genes or VEGF-dependent vasculature (VDV)] were identified by profiling gene expression changes induced in response to VEGF blockade in preclinical tumor models and in human biopsies from patients treated with anti-VEGF monoclonal antibodies. The potential value of VDV genes as candidate predictive biomarkers was tested by correlating high or low VDV gene expression levels in pretreatment clinical samples with the subsequent clinical efficacy of bevacizumab (anti-VEGF)-containing therapy. Results: We show that VDV genes, including direct and more distal VEGF downstream endothelial targets, enable detection of VEGF signaling inhibition in mouse tumor models and human tumor biopsies. Retrospective analyses of clinical trial data indicate that patients with higher VDV expression in pretreatment tumor samples exhibited improved clinical outcome when treated with bevacizumab-containing therapies. Conclusions: In this work, we identified surrogate markers(VDV genes) for in vivo VEGF signaling in tumors and showed clinical data supporting a correlation between pretreatment VEGF bioactivity and the subsequent efficacy of anti-VEGF therapy. We propose that VDV genes are candidate biomarkers with the potential to aid the selection of novel indications as well as patients likely to respond to anti-VEGF therapy. The data presented here define a diagnostic biomarker hypothesis based on translational research that warrants further evaluation in additional retrospective and prospective trials. Clin Cancer Res; 19(13); 3681-92. (C)2013 AACR. C1 [Zhuang, Guanglei; Schmidt, Maike; Yao, Jenny; Wu, Xiumin; Kaminker, Joshua S.; Jurinka, Stefanie S.; Kolumam, Ganesh; Chung, Alicia S.; Jubb, Adrian; Modrusan, Zora; Phillips, Heidi; Haley, Benjamin; Tam, Rachel N. W.; Clermont, Anne C.; Cheng, Jason H.; Chen, Daniel; Scherer, Stefan J.; Koeppen, Hartmut; Yeh, Ru-Fang; Yue, Peng; Stephan, Jean-Philippe; Hegde, Priti; Ferrara, Napoleone; Bais, Carlos] Genentech Inc, San Francisco, CA 94131 USA. [Ozawa, Tomoko; James, C. David] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA. [Ozawa, Tomoko; James, C. David] Univ Calif San Francisco, Brain Tumor Res Ctr, San Francisco, CA USA. [Singh, Mallika] Novartis Inst Biomed Res, Emeryville, CA USA. [Yang, Sherry X.] NCI, NIH, Div Canc Treatment & Diag, Nat Clin Target Validat Lab, Bethesda, MD USA. [Swain, Sandra M.] Medstar Washington Hosp, Washington Canc Inst, Washington, DC USA. RP Singh, M (reprint author), Genentech Inc, 1 DNA Way, San Francisco, CA 94131 USA. EM mallika.singh@novartis.com RI Zhuang, Guanglei/K-6097-2013; OI Swain, Sandra/0000-0002-1320-3830 NR 50 TC 18 Z9 18 U1 3 U2 19 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 JUL 1 PY 2013 VL 19 IS 13 BP 3681 EP 3692 DI 10.1158/1078-0432.CCR-12-3635 PG 12 WC Oncology SC Oncology GA 173RF UT WOS:000321095900035 PM 23685835 ER PT J AU Gilbert, J Lee, JW Argiris, A Haigentz, M Feldman, LE Jang, M Arun, P Van Waes, C Forastiere, AA AF Gilbert, Jill Lee, Ju Whei Argiris, Athanassios Haigentz, Missak, Jr. Feldman, Lawrence Eric Jang, Minyoung Arun, Pattatheyil Van Waes, Carter Forastiere, Arlene A. TI Phase II 2-arm trial of the proteasome inhibitor, PS-341 (bortezomib) in combination with irinotecan or PS-341 alone followed by the addition of irinotecan at time of progression in patients with locally recurrent or metastatic squamous cell carcinoma of the head and neck (E1304): A trial of the Eastern Cooperative Oncology Group SO HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK LA English DT Article DE head and neck cancer; chemotherapy; bortezomib; irinotecan; phase II ID FACTOR-KAPPA-B; TUMOR-CELLS; CANCER; THERAPY; DOCETAXEL; CISPLATIN; ACTIVATOR; PATHWAY; EGFR AB Background Constitutive activation of nuclear factor B (NF-B) is associated with poor prognosis. Irinotecan demonstrates single-agent activity in head and neck cancer but activates NF-B, promoting cell survival and resistance. Bortezomib is a proteasome inhibitor that inactivates NF-B. Patients and Methods We performed a randomized phase II trial of bortezomib on days 1, 4, 8, and 11 and irinotecan on days 1 and 8 of each 21-day cycle or single-agent bortezomib on days 1, 4, 8, and 11 on a 21-day cycle. The addition of irinotecan to bortezomib was allowed in patients who progressed on bortezomib alone. Results The response rate of bortezomib and irinotecan was 13%. One patient had a partial response to bortezomib alone (response rate 3%). No responses were seen in patients with addition of irinotecan at time of progression on bortezomib. Conclusions The bortezomib-based regimens evaluated in this study have minimal activity in recurrent or metastatic head and neck cancer. Head Neck, 2013 C1 [Gilbert, Jill] Vanderbilt Univ, Med Ctr, Nashville, TN 37232 USA. [Lee, Ju Whei] Dana Farber Canc Inst, Boston, MA 02115 USA. [Argiris, Athanassios] Univ Pittsburgh, Pittsburgh, PA USA. [Haigentz, Missak, Jr.] Montefiore Hosp & Med Ctr, Bronx, NY USA. [Feldman, Lawrence Eric] Univ Illinois Chicago MBCCOP, Chicago, IL USA. [Jang, Minyoung; Arun, Pattatheyil; Van Waes, Carter] NIDCD, Head & Neck Surgey Branch, NIH, Bethesda, MD USA. [Forastiere, Arlene A.] Johns Hopkins Univ, Baltimore, MD USA. RP Gilbert, J (reprint author), Vanderbilt Univ, Med Ctr, 2220 Pierce Ave,777 PRB, Nashville, TN 37232 USA. EM jill.gilbert@vanderbilt.edu FU Public Health Service from the National Cancer Institute, National Institutes of Health [CA23318, CA66636, CA21115, CA39229, CA49957, CA14958, CA16116]; Department of Health and Human Services; Milllennium Pharmaceuticals FX This study was conducted by the Eastern Cooperative Oncology Group (Robert L. Comis, M. D., Chair) and supported in part by Public Health Service Grants CA23318, CA66636, CA21115, CA39229, CA49957, CA14958, CA16116 and from the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.; Milllennium Pharmaceuticals provided bortezomib for prior preclinical studies6 to C. V. W. and bortezomib and funding to NCI for a prior clinical trial and correlative studies.16 NR 18 TC 10 Z9 12 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1043-3074 J9 HEAD NECK-J SCI SPEC JI Head Neck-J. Sci. Spec. Head Neck PD JUL PY 2013 VL 35 IS 7 BP 942 EP 948 DI 10.1002/hed.23046 PG 7 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 168RI UT WOS:000320723000013 PM 22791234 ER PT J AU Mumford, SL Dasharathy, SS Pollack, AZ Perkins, NJ Mattison, DR Cole, SR Wactawski-Wende, J Schisterman, EF AF Mumford, Sunni L. Dasharathy, Sonya S. Pollack, Anna Z. Perkins, Neil J. Mattison, Donald R. Cole, Stephen R. Wactawski-Wende, Jean Schisterman, Enrique F. TI Serum uric acid in relation to endogenous reproductive hormones during the menstrual cycle: findings from the BioCycle study SO HUMAN REPRODUCTION LA English DT Article DE anovulation; estradiol; menstrual cycle; premenopausal women; uric acid ID POLYCYSTIC-OVARY-SYNDROME; MARGINAL STRUCTURAL MODELS; ESTRADIOL-17-BETA E2; PREMENOPAUSAL WOMEN; CARDIOVASCULAR RISK; INSULIN-RESISTANCE; OXIDATIVE STRESS; SEX-DIFFERENCES; METABOLISM; THERAPY AB Do uric acid levels across the menstrual cycle show associations with endogenous estradiol (E-2) and reproductive hormone concentrations in regularly menstruating women? Mean uric acid concentrations were highest during the follicular phase, and were inversely associated with E-2 and progesterone, and positively associated with FSH. E-2 may decrease serum levels of uric acid in post-menopausal women; however, the interplay between endogenous reproductive hormones and uric acid levels among regularly menstruating women has not been elucidated. The BioCycle study was a prospective cohort study conducted at the University at Buffalo research centre from 2005 to 2007, which followed healthy women for one (n 9) or 2 (n 250) menstrual cycle(s). Participants were healthy women aged 1844 years. Hormones and uric acid were measured in serum eight times each cycle for up to two cycles. Marginal structural models with inverse probability of exposure weights were used to evaluate the associations between endogenous hormones and uric acid concentrations. Uric acid levels were observed to vary across the menstrual cycle, with the lowest levels observed during the luteal phase. Every log-unit increase in E-2 was associated with a decrease in uric acid of 1.1 ( 0.011; 95 confidence interval (CI): 0.019, 0.004; persistent-effects model), and for every log-unit increase in progesterone, uric acid decreased by 0.8 ( 0.008; 95 CI: 0.012, 0.004; persistent-effects model). FSH was positively associated with uric acid concentrations, such that each log-unit increase was associated with a 1.6 increase in uric acid ( 0.016; 95 CI: 0.005, 0.026; persistent-effects model). Progesterone and FSH were also associated with uric acid levels in acute-effects models. Of 509 cycles, 42 were anovulatory (8.3). Higher uric acid levels were associated with increased odds of anovulation (odds ratio 2.39, 95 CI: 1.25, 4.56). The change in uric acid levels among this cohort of healthy women was modest, and analysis was limited to two menstrual cycles. The women in this study were healthy and regularly menstruating, and as such there were few women with high uric acid levels and anovulatory cycles. These findings demonstrate the importance of taking menstrual cycle phase into account when measuring uric acid in premenopausal women, and confirm the hypothesized beneficial lowering effects of endogenous E-2 on uric acid levels. These findings suggest that there could be an underlying association affecting both sporadic anovulation and high uric acid levels among young, regularly menstruating women. Further studies are needed to confirm these findings and elucidate the connection between uric acid and reproductive and later cardiovascular health. This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contract HHSN275200403394C). No competing interests declared. C1 [Mumford, Sunni L.; Dasharathy, Sonya S.; Pollack, Anna Z.; Perkins, Neil J.; Mattison, Donald R.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH,DHHS, Rockville, MD 20852 USA. [Cole, Stephen R.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14214 USA. [Mattison, Donald R.] Risk Sci Int, Ottawa, ON K1N7G2, Canada. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH,DHHS, 6100 Execut Blvd 7B03, Rockville, MD 20852 USA. EM schistee@mail.nih.gov RI Mattison, Donald/L-4661-2013; OI Mattison, Donald/0000-0001-5623-0874; Perkins, Neil/0000-0002-6802-4733; Pollack, Anna/0000-0002-4313-3298; Schisterman, Enrique/0000-0003-3757-641X FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN275200403394C] FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contract # HHSN275200403394C). NR 42 TC 12 Z9 12 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD JUL PY 2013 VL 28 IS 7 BP 1853 EP 1862 DI 10.1093/humrep/det085 PG 10 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 170MK UT WOS:000320855600015 PM 23562957 ER PT J AU Chen, CZ Southall, N Xiao, JB Marugan, JJ Ferrer, M Hu, X Jones, RE Feng, S Agoulnik, IU Zheng, W Agoulnik, AI AF Chen, Catherine Z. Southall, Noel Xiao, Jingbo Marugan, Juan J. Ferrer, Marc Hu, Xin Jones, Raisa E. Feng, Shu Agoulnik, Irina U. Zheng, Wei Agoulnik, Alexander I. TI Identification of Small-Molecule Agonists of Human Relaxin Family Receptor 1 (RXFP1) by Using a Homogenous Cell-Based cAMP Assay SO JOURNAL OF BIOMOLECULAR SCREENING LA English DT Article DE relaxin; GPCR; RXFP1; qHTS; agonist; small molecule ID PROTEIN-COUPLED RECEPTOR-7; LEUCINE-RICH REPEAT; PEPTIDE RECEPTORS; SPLICE VARIANTS; LGR7; MEMBRANE AB The relaxin hormone is involved in a variety of biological functions, including female reproduction and parturition, as well as regulation of cardiovascular, renal, pulmonary, and hepatic functions. It regulates extracellular matrix remodeling, cell invasiveness, proliferation, differentiation, and overall tissue homeostasis. The G protein-coupled receptor (GPCR) relaxin family receptor 1 (RXFP1) is a cognate relaxin receptor that mainly signals through cyclic AMP second messenger. Although agonists of the receptor could have a wide range of pharmacologic utility, until now there have been no reported small-molecule agonists for relaxin receptors. Here, we report the development of a quantitative high-throughput platform for an RXFP1 agonist screen based on homogenous cell-based HTRF cyclic AMP (cAMP) assay technology. Two small molecules of similar structure were independently identified from a screen of more than 365 677 compounds. Neither compound showed activity in a counterscreen with HEK293T cells transfected with an unrelated GPCR vasopressin 1b receptor. These small-molecule agonists also demonstrated selectivity against the RXFP2 receptor, providing a basis for future medicinal chemistry optimization of selective relaxin receptor agonists. C1 [Chen, Catherine Z.; Southall, Noel; Xiao, Jingbo; Marugan, Juan J.; Ferrer, Marc; Hu, Xin; Jones, Raisa E.; Zheng, Wei] NIH, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Feng, Shu] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA. [Agoulnik, Irina U.] Florida Int Univ, Dept Cellular Biol & Pharmacol, Miami, FL 33199 USA. [Agoulnik, Alexander I.] Florida Int Univ, Dept Human & Mol Genet, Miami, FL 33199 USA. RP Zheng, W (reprint author), NIH, 9800 Med Ctr Dr,MSC 3370, Bethesda, MD 20892 USA. EM wzheng@mail.nih.gov; aagoulni@fiu.edu RI Southall, Noel/H-8991-2012; Zheng, Wei/J-8889-2014; OI Southall, Noel/0000-0003-4500-880X; Zheng, Wei/0000-0003-1034-0757; Agoulnik, Irina/0000-0003-4889-0324; Agoulnik, Alexander/0000-0001-6587-6845 FU Molecular Libraries Initiative of the NIH Roadmap for Medical Research [U54MH084681, R03 MH085705]; Intramural Research Program of the National Human Genome Research Institute; National Center for Advancing Translational Sciences, National Institutes of Health FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by the Molecular Libraries Initiative of the NIH Roadmap for Medical Research U54MH084681 and R03 MH085705 (to A. I. A.) and the Intramural Research Program of the National Human Genome Research Institute and National Center for Advancing Translational Sciences, National Institutes of Health. NR 19 TC 9 Z9 9 U1 1 U2 9 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0571 J9 J BIOMOL SCREEN JI J. Biomol. Screen PD JUL PY 2013 VL 18 IS 6 BP 670 EP 677 DI 10.1177/1087057112469406 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry GA 170XI UT WOS:000320888100004 PM 23212924 ER PT J AU McCallum, MM Nandhikonda, P Temmer, JJ Eyermann, C Simeonov, A Jadhav, A Yasgar, A Maloney, D Arnold, A AF McCallum, Megan M. Nandhikonda, Premchendar Temmer, Jonathan J. Eyermann, Charles Simeonov, Anton Jadhav, Ajit Yasgar, Adam Maloney, David Arnold, Alexander (Leggy) TI High-Throughput Identification of Promiscuous Inhibitors from Screening Libraries with the Use of a Thiol-Containing Fluorescent Probe SO JOURNAL OF BIOMOLECULAR SCREENING LA English DT Article DE promiscuous inhibitors; glutathione; fluorescence; high-throughput screening; thiol-reactive or electrophilic compound ID COMPOUND LIBRARIES; FALSE POSITIVES; ASSAY; DISCOVERY; REACTIVITY; RECEPTOR; FILTERS; HTS AB Testing small molecules for their ability to modify cysteine residues of proteins in the early stages of drug discovery is expected to accelerate our ability to develop more selective drugs with lesser side effects. In addition, this approach also enables the rapid evaluation of the mode of binding of new drug candidates with respect to thiol reactivity and metabolism by glutathione. Herein, we describe the development of a fluorescence-based high-throughput assay that allows the identification of thiol-reactive compounds. A thiol-containing fluorescent probe, MSTI, was synthesized and used to evaluate small molecules from the Library of Pharmacologically Active Compounds (LOPAC) collection of bioactive molecules. LOPAC compounds that are known to react with sulfur nucleophiles were identified with this assay, for example, irreversible protease inhibitors, nitric oxide-releasing compounds, and proton-pump inhibitors. The results confirm that both electrophilic and redox reactive compounds can be quickly identified in a high-throughput manner, enabling the assessment of screening libraries with respect to thiol-reactive compounds. C1 [McCallum, Megan M.; Nandhikonda, Premchendar; Temmer, Jonathan J.; Arnold, Alexander (Leggy)] Univ Wisconsin, Milwaukee, WI 53211 USA. [Eyermann, Charles; Simeonov, Anton; Jadhav, Ajit; Yasgar, Adam; Maloney, David] NIH, Bethesda, MD 20892 USA. RP Arnold, A (reprint author), Univ Wisconsin, Dept Chem & Biochem, 3210 N Cramer St, Milwaukee, WI 53211 USA. EM Arnold2@uwm.edu RI Nandhikonda, Premchendar/K-1473-2014 FU University of Wisconsin Milwaukee; UWM Research Growth Initiative (RGI), National Institute of Drug Abuse [R03DA031090]; UWM Research Foundation; Lynde and Harry Bradley Foundation; Richard and Ethel Herzfeld Foundation; Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research [U54MH084681] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The work was supported in part by the University of Wisconsin Milwaukee, the UWM Research Growth Initiative (RGI), National Institute of Drug Abuse (R03DA031090), the UWM Research Foundation, the Lynde and Harry Bradley Foundation, the Richard and Ethel Herzfeld Foundation, and the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research (U54MH084681). NR 27 TC 7 Z9 7 U1 2 U2 24 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0571 J9 J BIOMOL SCREEN JI J. Biomol. Screen PD JUL PY 2013 VL 18 IS 6 BP 705 EP 713 DI 10.1177/1087057113476090 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry GA 170XI UT WOS:000320888100008 PM 23446699 ER PT J AU Fox, NA Barker, TV White, LK Suway, JG Pine, DS AF Fox, Nathan A. Barker, Tyson V. White, Lauren K. Suway, Jenna G. Pine, Daniel S. TI Commentary: To intervene or not? Appreciating or treating individual differences in childhood temperament - remarks on Rapee (2013) SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Editorial Material ID SOCIAL ANXIETY DISORDER; BEHAVIORAL-INHIBITION; CHILDREN; RISK C1 [Fox, Nathan A.; Barker, Tyson V.; White, Lauren K.; Suway, Jenna G.] Univ Maryland, Dept Human Dev & Quantitat Methodol, College Pk, MD 20742 USA. [Pine, Daniel S.] NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. RP Fox, NA (reprint author), Univ Maryland, Dept Human Dev & Quantitat Methodol, College Pk, MD 20742 USA. EM fox@umd.edu FU NICHD NIH HHS [T32 HD007542]; NIMH NIH HHS [U01 MH093349] NR 10 TC 1 Z9 1 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9630 EI 1469-7610 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry PD JUL PY 2013 VL 54 IS 7 BP 789 EP 790 DI 10.1111/jcpp.12101 PG 2 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA 169KF UT WOS:000320778200010 PM 23746203 ER PT J AU Ryschkewitsch, CF Jensen, PN Major, EO AF Ryschkewitsch, Caroline F. Jensen, Peter N. Major, Eugene O. TI Multiplex qPCR assay for ultra sensitive detection of JCV DNA with simultaneous identification of genotypes that discriminates non-virulent from virulent variants SO JOURNAL OF CLINICAL VIROLOGY LA English DT Article DE qPCR; JC Virus; Variants; PML diagnostics ID PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; REAL-TIME PCR; NUCLEOTIDE-SEQUENCES; BONE-MARROW; VIRUS-DNA; POLYOMAVIRUS; PATHOGENESIS; INDIVIDUALS; REGIONS; URINE AB Background: JC virus (JCV) is the etiologic agent for progressive multifocal leukoencephalopathy (PML), a demyelinating disease occurring in the brain of patients with underlying immune compromised states. All viable JCV genomes contain a conserved region in the T protein coding nucleotide sequence that when detected by PCR in CSF is a confirmatory diagnostic marker for PML along with clinical and neuroradio-logical evidence. The non-coding regulatory region (NCRR) is hypervariable, as evidenced by nucleotide sequence of the non-virulent variant, which is predominantly excreted in urine, versus that of virulent variants found in brain and CSF of PML patients. All variants can be found in blood. Objective: A single assay that quantifies and identifies JCV DNA in clinical samples and discriminates between variants has significant value to physicians and patients at risk for PML. Study design: Separate primer pairs were tested together to quantitatively detect conserved viral DNA nucleotide sequence in patient samples, while simultaneously detecting the NCRR specific for the non-virulent variant. Results: In testing using control plasmids and patients' CSF, blood, and urine, PML patients predictably demonstrated the non-virulent, archetype NCRR in urine, but virulent NCRR variants in CSF and blood. Conclusion: The JCV qPCR multiplex assay targets two regions in JCV genomes to simultaneously identify and measure viral DNA, as well as distinguish between variants associated with PML and those that are not. The multiplex results could signal risk for PML if patients are viremic with JCV variants closely associated with PML pathogenesis. Published by Elsevier B. V. C1 [Ryschkewitsch, Caroline F.; Jensen, Peter N.; Major, Eugene O.] Natl Inst Neurol Disorders & Stroke, Natl Inst Hlth, Lab Mol Med & Neurosci, Bethesda, MD 20892 USA. RP Major, EO (reprint author), Natl Inst Neurol Disorders & Stroke, Natl Inst Hlth, Lab Mol Med & Neurosci, 10 Ctr Dr,Bldg 10,Room 3B14, Bethesda, MD 20892 USA. EM ryschkec@ninds.nih.gov; JensenP@ninds.nih.gov; majorg@ninds.nih.gov FU Division of Intramural Research, National Institute of Neurological Disorders and Stroke FX Funding is provided through the Division of Intramural Research, National Institute of Neurological Disorders and Stroke. NR 19 TC 25 Z9 25 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1386-6532 J9 J CLIN VIROL JI J. Clin. Virol. PD JUL PY 2013 VL 57 IS 3 BP 243 EP 248 DI 10.1016/j.jcv.2013.03.009 PG 6 WC Virology SC Virology GA 166XL UT WOS:000320593300011 PM 23619054 ER PT J AU Metayer, C Colt, JS Buffler, PA Reed, HD Selvin, S Crouse, V Ward, MH AF Metayer, Catherine Colt, Joanne S. Buffler, Patricia A. Reed, Helen D. Selvin, Steve Crouse, Vonda Ward, Mary H. TI Exposure to herbicides in house dust and risk of childhood acute lymphoblastic leukemia SO JOURNAL OF EXPOSURE SCIENCE AND ENVIRONMENTAL EPIDEMIOLOGY LA English DT Article DE childhood leukemia; herbicides; pesticides; dust ID NON-HODGKINS-LYMPHOMA; AGRICULTURAL HEALTH; PESTICIDE EXPOSURE; CANCER INCIDENCE; FARM-WORKERS; CHILDREN; CALIFORNIA; GERMANY; COHORT; POLLUTANTS AB We examine the association between exposure to herbicides and childhood acute lymphoblastic leukemia (ALL). Dust samples were collected from homes of 269 ALL cases and 333 healthy controls (<8 years of age at diagnosis/reference date and residing in same home since diagnosis/reference date) in California, using a high-volume surface sampler or household vacuum bags. Amounts of agricultural or professional herbicides (alachlor, metolachlor, bromoxynil, bromoxynil octanoate, pebulate, butylate, prometryn, simazine, ethalfluralin, and pendimethalin) and residential herbicides (cyanazine, trifluralin, 2-methyl-4-chlorophenoxyacetic acid (MCPA), mecoprop, 2,4-dichlorophenoxyacetic acid (2,4-D), chlorthal, and dicamba) were measured. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression. Models included the herbicide of interest, age, sex, race/ethnicity, household income, year and season of dust sampling, neighborhood type, and residence type. The risk of childhood ALL was associated with dust levels of chlorthal; compared to homes with no detections, ORs for the first, second, and third tertiles were 1.49 (95% CI: 0.82-2.72), 1.49 (95% CI: 0.83-2.67), and 1.57 (95% CI: 0.90-2.73), respectively (P-value for linear trend = 0.05). The magnitude of this association appeared to be higher in the presence of alachlor. No other herbicides were identified as risk factors of childhood ALL. The data suggest that home dust levels of chlorthal, and possibly alachlor, are associated with increased risks of childhood ALL. C1 [Metayer, Catherine; Buffler, Patricia A.; Selvin, Steve] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94704 USA. [Colt, Joanne S.; Ward, Mary H.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, US Dept HHS,NIH, Bethesda, MD 20892 USA. [Reed, Helen D.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, US Dept HHS,NIH, Bethesda, MD 20892 USA. [Crouse, Vonda] Childrens Hosp Cent Calif, Dept Pediat Oncol, Madera, CA USA. RP Metayer, C (reprint author), Univ Calif Berkeley, Sch Publ Hlth, 1995 Univ Ave,Suite 460, Berkeley, CA 94704 USA. EM cmetayer@berkeley.edu FU National Institute of Environmental Health Sciences [R01 ES09137, P42-ES04705]; National Cancer Institute [7590-S-04, 7590-S-01, N02-CP-11015]; National Institutes of Health FX This research could not have been conducted without the important support from our clinical collaborators and participating hospitals, which include: University of California Davis Medical Center (Dr. Jonathan Ducore), University of California San Francisco (Dr. Mignon Loh and Dr. Katherine Matthay), Children's Hospital of Central California (Dr. Vonda Crouse), Lucile Packard Children's Hospital (Dr. Gary Dahl), Children's Hospital Oakland (Dr. James Feusner), Kaiser Permanente Sacramento (Dr. Vincent Kiley), Kaiser Permanente Santa Clara (Dr. Carolyn Russo and Dr. Alan Wong), Kaiser Permanente San Francisco (Dr. Kenneth Leung), and Kaiser Permanente Oakland (Dr. Stacy Month), and the families of the study participants. We also wish to acknowledge the effort and dedication of all our collaborators at the Northern California Childhood Leukemia Study who helped make this study possible, and the staff at the Battelle Memorial Institute, Columbus, OH who performed laboratory analyses. This work was financially supported by National Institute of Environmental Health Sciences, Grants R01 ES09137 and P42-ES04705; the Intramural Research Program of the National Cancer Institute (subcontracts 7590-S-04, 7590-S-01); the National Cancer Institute (contract N02-CP-11015), and from the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Environmental Health Sciences or the National Cancer Institute. NR 61 TC 16 Z9 17 U1 6 U2 41 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1559-0631 J9 J EXPO SCI ENV EPID JI J. Expo. Sci. Environ. Epidemiol. PD JUL-AUG PY 2013 VL 23 IS 4 BP 363 EP 370 DI 10.1038/jes.2012.115 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 166VG UT WOS:000320586200005 PM 23321862 ER PT J AU Schmitt, KC Rothman, RB Reith, MEA AF Schmitt, Kyle C. Rothman, Richard B. Reith, Maarten E. A. TI Nonclassical Pharmacology of the Dopamine Transporter: Atypical Inhibitors, Allosteric Modulators, and Partial Substrates SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID NEUROTRANSMITTER-SODIUM SYMPORTER; PROTEIN-PROTEIN INTERACTIONS; BIOGENIC-AMINE TRANSPORTERS; BINDING-SITES; MONOAMINE TRANSPORTERS; BACTERIAL HOMOLOG; CRYSTAL-STRUCTURE; COCAINE; LEUT; IDENTIFICATION AB The dopamine transporter (DAT) is a sodium-coupled symporter protein responsible for modulating the concentration of extraneuronal dopamine in the brain. The DAT is a principle target of various psychostimulant, nootropic, and antidepressant drugs, as well as certain drugs used recreationally, including the notoriously addictive stimulant cocaine. DAT ligands have traditionally been divided into two categories: cocaine-like inhibitors and amphetamine-like substrates. Whereas inhibitors block monoamine uptake by the DAT but are not translocated across the membrane, substrates are actively translocated and trigger DAT-mediated release of dopamine by reversal of the translocation cycle. Because both inhibitors and substrates increase extraneuronal dopamine levels, it is often assumed that all DAT ligands possess an addictive liability equivalent to that of cocaine. However, certain recently developed ligands, such as atypical benztropine-like DAT inhibitors with reduced or even a complete lack of cocaine-like rewarding effects, suggest that addictiveness is not a constant property of DAT-affecting compounds. These atypical ligands do not conform to the classic preconception that all DAT inhibitors (or substrates) are functionally and mechanistically alike. Instead, they suggest the possibility that the DAT exhibits some of the ligand-specific pleiotropic functional qualities inherent to G-protein-coupled receptors. That is, ligands with different chemical structures induce specific conformational changes in the transporter protein that can be differentially transduced by the cell, ultimately eliciting unique behavioral and psychological effects. The present overview discusses compounds with conformation-specific activity, useful not only as tools for studying the mechanics of dopamine transport, but also as leads for medication development in addictive disorders. C1 [Schmitt, Kyle C.] NYU, Sch Med, Dept Neurosurg, New York, NY 10016 USA. [Reith, Maarten E. A.] NYU, Sch Med, Dept Pharmacol, New York, NY 10016 USA. [Reith, Maarten E. A.] NYU, Sch Med, Dept Psychiat, New York, NY 10016 USA. [Rothman, Richard B.] NIDA, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD USA. RP Schmitt, KC (reprint author), NYU, Sch Med, Dept Neurosurg, Publ Hlth Labs, 455 1st Ave,8th Floor, New York, NY 10016 USA. EM kyle.schmitt@nyumc.org FU National Institutes of Health National Institute on Drug Abuse [R01 DA019676]; National Institutes of Health National Institute of Mental Health [R01 MH083840]; National Institutes of Health [National Institute on Drug Abuse] FX This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grant R01 DA019676]; the National Institutes of Health National Institute of Mental Health [Grant R01 MH083840]; and the Intramural Research Program of the National Institutes of Health [National Institute on Drug Abuse]. NR 67 TC 29 Z9 30 U1 3 U2 11 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JUL PY 2013 VL 346 IS 1 BP 2 EP 10 DI 10.1124/jpet.111.191056 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 164XQ UT WOS:000320446100001 PM 23568856 ER PT J AU Niciu, MJ Grunschel, BDG Corlett, PR Pittenger, C Bloch, MH AF Niciu, Mark J. Grunschel, Beth D. G. Corlett, Philip R. Pittenger, Christopher Bloch, Michael H. TI Two cases of delayed-onset suicidal ideation, dysphoria and anxiety after ketamine infusion in patients with obsessive-compulsive disorder and a history of major depressive disorder SO JOURNAL OF PSYCHOPHARMACOLOGY LA English DT Article DE Ketamine; OCD; depression; SAE; suicidality ID RECEPTOR ANTAGONIST RESPONSE AB Ketamine is a non-competitive N-methyl-D-aspartate receptor antagonist that is Food and Drug Administration-approved in the United States for anesthesia due to its sedative effects with low risk of severe respiratory depression. Subanesthetic dose intravenous ketamine has rapidly acting antidepressant effects in treatment-resistant unipolar and bipolar depression. We recently reported an open-label trial of ketamine in 10 subjects with treatment-refractory obsessive-compulsive disorder, seven of whom had active comorbid depression. Although ketamine had no sustained anti-obsessive effect, four of the seven subjects with comorbid depression experienced an acute antidepressant effect. However, we unexpectedly observed delayed-onset dysphoria, worsening anxiety and suicidal thinking in two of the three subjects with obsessive-compulsive disorder and extensive psychiatric comorbidity but minimal depressive symptoms at the start of infusion. The implications of these adverse neuropsychiatric effects in two patients with similar psychiatric comorbidity are discussed. We conclude that there remains insufficient data on therapeutic ketamine in the presence of comorbid psychiatric disorders to promote its off-label use in a non-research milieu. C1 [Niciu, Mark J.; Grunschel, Beth D. G.; Corlett, Philip R.; Pittenger, Christopher; Bloch, Michael H.] Yale Univ, Dept Psychiat, CMHC, CNRU, New Haven, CT 06520 USA. [Niciu, Mark J.] NIMH, NIH, Bethesda, MD 20814 USA. [Pittenger, Christopher; Bloch, Michael H.] Yale Univ, Sch Med, Yale Child Study Ctr, New Haven, CT USA. RP Niciu, MJ (reprint author), NIMH, NIH, Clin Res Ctr, 10 Ctr Dr,Bldg 10,Room 7-5545, Bethesda, MD 20814 USA. EM mark.niciu@nih.gov RI Niciu, Mark/J-1766-2014 OI Niciu, Mark/0000-0002-5612-3021 FU National Institutes of Health (NIH)/National Institute of Mental Health (NIMH) [T32MH19961]; Robert L. McNeil Jr. Fellowship in Translational Research; VA-Connecticut Alcohol Research Center; Yale University Department of Psychiatry; CTSA from the National Center for Research Resources (NCRR) [UL1RR024139]; National Center for Advancing Translational Science (NCATS), NIH; NIH Roadmap for Medical Research; NIH/NIMH from the NCRR [UL1RR024139, K08MH081190]; NIH/NIMH [K23MH091240-01]; American Psychiatric Institute for Research and Education (APIRE)/Eli Lilly and Co. Psychiatric Research Fellowship; American Academy of Child and Adolescent Psychiatry/Eli Lilly and Co. Pilot Research Award; Trichotillomania Learning Center; National Alliance for Research on Schizophrenia and Depression (NARSAD) from the NCRR [UL1RR024139] FX Salary support was provided to each author by the following sources: MJN: National Institutes of Health (NIH)/National Institute of Mental Health (NIMH) T32MH19961, the Robert L. McNeil Jr. Fellowship in Translational Research and the VA-Connecticut Alcohol Research Center. BDGG: Yale University Department of Psychiatry. PRC: CTSA Grant Number UL1RR024139 from the National Center for Research Resources (NCRR) and the National Center for Advancing Translational Science (NCATS), components of the NIH, and NIH Roadmap for Medical Research. CP: NIH/NIMH K08MH081190, UL1RR024139 from the NCRR and the NIH Roadmap for Medical Research. MHB: NIH/NIMH support of the Yale Child Study Center Research Training Program, K23MH091240-01, the American Psychiatric Institute for Research and Education (APIRE)/Eli Lilly and Co. Psychiatric Research Fellowship, the American Academy of Child and Adolescent Psychiatry/Eli Lilly and Co. Pilot Research Award, the Trichotillomania Learning Center, The National Alliance for Research on Schizophrenia and Depression (NARSAD), UL1RR024139 from the NCRR and the NIH Roadmap for Medical Research. The State of Connecticut also provided resource support to all authors via the Abraham Ribicoff Research Facilities/CNRU at CMHC, where this research was conducted. NR 21 TC 15 Z9 15 U1 3 U2 14 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0269-8811 J9 J PSYCHOPHARMACOL JI J. Psychopharmacol. PD JUL PY 2013 VL 27 IS 7 BP 651 EP 654 DI 10.1177/0269881113486718 PG 4 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 168JZ UT WOS:000320703100010 PM 23676198 ER PT J AU Akhtar, A Kamal, AK AF Akhtar, Anjum Kamal, Ayeesha Kamran TI CLEAR: The Intraventricular Haemorrhage Thrombolysis Trial SO JOURNAL OF THE PAKISTAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Kamal, Ayeesha Kamran] Aga Khan Univ Hosp, Fogarty Int Ctr, Int Cerebrovasc Translat Clin Res Training Progra, Stroke Serv & Vasc Fellowship Program, Karachi, Pakistan. Aga Khan Univ Hosp, Natl Inst Neurol Disorders & Stroke, Karachi, Pakistan. RP Kamal, AK (reprint author), Aga Khan Univ Hosp, Fogarty Int Ctr, Int Cerebrovasc Translat Clin Res Training Progra, Stroke Serv & Vasc Fellowship Program, Karachi, Pakistan. EM ayeesha.kamal@aku.edu FU FIC NIH HHS [D43TW008660, D43 TW008660] NR 0 TC 1 Z9 1 U1 0 U2 2 PU PAKISTAN MEDICAL ASSOC PI KARACHI PA PMA HOUSE, AGA KHAN III RD, KARACHI, 00000, PAKISTAN SN 0030-9982 J9 J PAK MED ASSOC JI J. Pak. Med. Assoc. PD JUL PY 2013 VL 63 IS 7 BP 928 EP 928 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 165LQ UT WOS:000320485800028 PM 23901725 ER PT J AU Lubaki, NM Ilinykh, P Pietzsch, C Tigabu, B Freiberg, AN Koup, RA Bukreyev, A AF Lubaki, Ndongala M. Ilinykh, Philipp Pietzsch, Colette Tigabu, Bersabeh Freiberg, Alexander N. Koup, Richard A. Bukreyev, Alexander TI The Lack of Maturation of Ebola Virus-Infected Dendritic Cells Results from the Cooperative Effect of at Least Two Viral Domains SO JOURNAL OF VIROLOGY LA English DT Article ID ACTIVATED PROTEIN-KINASE; DOUBLE-STRANDED-RNA; INFLUENZA-A VIRUS; VP35 PROTEIN; HEMORRHAGIC-FEVER; MARBURG VIRUSES; IN-VITRO; NONHUMAN-PRIMATES; INTERFERON ANTAGONISM; VIRION GLYCOPROTEINS AB Ebola virus (EBOV) infections are characterized by deficient T lymphocyte responses, T lymphocyte apoptosis, and lymphopenia in the absence of direct infection of T lymphocytes. In contrast, dendritic cells (DC) are infected but fail to mature appropriately, thereby impairing the T cell response. We investigated the contributions of EBOV proteins in modulating DC maturation by generating recombinant viruses expressing enhanced green fluorescent protein and carrying mutations affecting several potentially immunomodulating domains. They included envelope glycoprotein (GP) domains, as well as innate response antagonist domains (IRADs) previously identified in the VP24 and VP35 proteins. GP expressed by an unrelated vector, but not the wild-type EBOV, was found to strongly induce DC maturation, and infections with recombinant EBOV carrying mutations disabling GP functional domains did not restore DC maturation. In contrast, each of the viruses carrying mutations disabling any IRAD in VP35 induced a dramatic upregulation of DC maturation markers. This was dependent on infection, but not interaction with GP. Disabling of IRADs also resulted in up to a several hundredfold increase in secretion of cytokines and chemokines. Furthermore, these mutations induced formation of homotypic DC clusters, which represent close correlates of their maturation and presumably facilitate transfer of antigen from migratory DC to lymph node DC. Thus, an individual IRAD is insufficient to suppress DC maturation; rather, the suppression of DC maturation and the "immune paralysis" observed during EBOV infections results from a cooperative effect of two or more individual IRADs. C1 [Lubaki, Ndongala M.; Ilinykh, Philipp; Pietzsch, Colette; Tigabu, Bersabeh; Freiberg, Alexander N.; Bukreyev, Alexander] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA. [Bukreyev, Alexander] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA. [Lubaki, Ndongala M.; Ilinykh, Philipp; Pietzsch, Colette; Tigabu, Bersabeh; Freiberg, Alexander N.; Bukreyev, Alexander] Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77555 USA. [Koup, Richard A.] NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Bukreyev, A (reprint author), Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA. EM alexander.bukreyev@utmb.edu RI Ilinykh, Philipp/L-5404-2014 FU University of Texas Medical Branch; John Sealy Memorial Endowment Fund Pilot Grant "Mechanisms of 'immune paralysis' in Ebola infections"; McLaughlin Fellowship FX The study was supported by a departmental startup grant from the University of Texas Medical Branch (A.B.), the John Sealy Memorial Endowment Fund Pilot Grant "Mechanisms of 'immune paralysis' in Ebola infections" (A.B.), and the McLaughlin Fellowship (N.M.L.). NR 82 TC 24 Z9 25 U1 0 U2 16 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JUL PY 2013 VL 87 IS 13 BP 7471 EP 7485 DI 10.1128/JVI.03316-12 PG 15 WC Virology SC Virology GA 160JT UT WOS:000320116500024 PM 23616668 ER PT J AU Rasheed, MAU Latner, DR Aubert, RD Gourley, T Spolski, R Davis, CW Langley, WA Ha, SJ Ye, LL Sarkar, S Kalia, V Konieczny, BT Leonard, WJ Ahmed, R AF Rasheed, Mohammed Ata Ur Latner, Donald R. Aubert, Rachael D. Gourley, Tania Spolski, Rosanne Davis, Carl W. Langley, William A. Ha, Sang-Jun Ye, Lilin Sarkar, Surojit Kalia, Vandana Konieczny, Bogumila T. Leonard, Warren J. Ahmed, Rafi TI Interleukin-21 Is a Critical Cytokine for the Generation of Virus-Specific Long-Lived Plasma Cells SO JOURNAL OF VIROLOGY LA English DT Article ID FOLLICULAR-HELPER-CELLS; CHRONIC VIRAL-INFECTION; GERMINAL CENTER RESPONSES; CXC CHEMOKINE RECEPTOR-5; CD4(+) T-CELLS; HUMAN B-CELLS; IMMUNOGLOBULIN PRODUCTION; ANTIBODY-PRODUCTION; HUMORAL IMMUNITY; BCL-6 EXPRESSION AB Long-lived plasma cells that reside in the bone marrow constitutively produce antibody in the absence of antigen and are the cellular basis of durable humoral immunity. The generation of these long-lived plasma cells depends upon a series of highly orchestrated interactions between antigen-specific CD4 T cells and B cells and the formation of germinal centers (GCs). In this study, we have examined the role of the cytokine interleukin-21 (IL-21) in regulating humoral immunity during acute viral infections. Using IL-21 receptor-deficient (IL-21R(-/-)) mice, we found that virus-specific CD4 T cells were generated after infection with lymphocytic choriomeningitis virus (LCMV) and that these CD4 T cells differentiated into T follicular helper (T-FH)-like cells in the absence of IL-21 signaling. There was also no defect in the formation of GCs, although after day 15 these GCs disappeared faster in IL-21R(-/-) mice than in wild-type mice. Isotype switching and the initial LCMV-specific IgG response were normal in IL-21R(-/-) mice. However, these mice exhibited a profound defect in generating long-lived plasma cells and in sustaining antibody levels over time. Similar results were seen after infection of IL-21R(-/-) mice with vesicular stomatitis virus and influenza virus. Using chimeric mice containing wild-type or IL-21R(-/-) CD4 T cells and B cells, we showed that both B and CD4 T cells need IL-21 signaling for generating long-term humoral immunity. Taken together, our results highlight the importance of IL-21 in humoral immunity to viruses. C1 [Rasheed, Mohammed Ata Ur; Latner, Donald R.; Aubert, Rachael D.; Gourley, Tania; Davis, Carl W.; Langley, William A.; Ha, Sang-Jun; Ye, Lilin; Sarkar, Surojit; Kalia, Vandana; Konieczny, Bogumila T.; Ahmed, Rafi] Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Rasheed, Mohammed Ata Ur; Latner, Donald R.; Aubert, Rachael D.; Gourley, Tania; Davis, Carl W.; Langley, William A.; Ha, Sang-Jun; Ye, Lilin; Sarkar, Surojit; Kalia, Vandana; Konieczny, Bogumila T.; Ahmed, Rafi] Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. [Spolski, Rosanne; Leonard, Warren J.] NHLBI, Lab Mol Immunol, Bethesda, MD 20892 USA. [Spolski, Rosanne; Leonard, Warren J.] NHLBI, Ctr Immunol, Bethesda, MD 20892 USA. RP Ahmed, R (reprint author), Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. EM rahmed@emory.edu RI Rasheed, Mohammed/N-2749-2013; OI Ha, Sang-Jun/0000-0002-1192-6031 FU National Institutes of Health (NIH) [P01 AI097092-01A1, RO1 A1030048]; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery grant [UM1AI100663]; Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH FX This work was supported by National Institutes of Health (NIH) grants P01 AI097092-01A1 (to R.A.) and RO1 A1030048 (to R.A.) and Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery grant UM1AI100663 (to R.A.). This work was also supported in part by the Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH (to W.J.L. and R.S.). NR 45 TC 42 Z9 42 U1 1 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2013 VL 87 IS 13 BP 7737 EP 7746 DI 10.1128/JVI.00063-13 PG 10 WC Virology SC Virology GA 160JT UT WOS:000320116500047 PM 23637417 ER PT J AU Savage, SA Pulsipher, MA Romano, A Berlyne, D AF Savage, Sharon A. Pulsipher, Michael A. Romano, Alessandra Berlyne, Deborah TI Aplastic Anemia & MDS International Foundation (AA&MDSIF): Bone marrow failure disease scientific symposium 2012 SO LEUKEMIA RESEARCH LA English DT Article DE Myelodysplastic syndromes; Aplastic anemia; Paroxysmal nocturnal hemoglobinuria; Bone marrow failure; Epigenetic therapy; Immunosuppressive therapy; Stem cell transplantation; Complement ID MYELODYSPLASTIC SYNDROMES AB Aplastic anemia (AA), myelodysplastic syndrome (MDS), and paroxysmal nocturnal hemoglobinuria (PNH) are rare disorders of bone marrow failure. Once considered distinct entities, these three diseases are now believed to have overlapping pathophysiologies. The Aplastic Anemia and MDS International Foundation, a nonprofit organization that supports patients and families living with bone marrow failure disorders, sponsored a scientific symposium in Bethesda, MD, in March 2012. This report summarizes the symposium presentations by 30 of the world's leading AA, MDS, and PNH researchers on recent findings, current areas of controversy, and recommendations for basic and clinical research to advance the field. (c) 2013 Published by Elsevier Ltd. C1 [Savage, Sharon A.] Natl Canc Inst, Div Canc Epidemiol & Genet, Rockville, MD USA. [Pulsipher, Michael A.] Univ Utah, Huntsman Canc Inst, Div Hematol & Hematol Malignancies, Salt Lake City, UT USA. [Romano, Alessandra] Univ Catania, Osped Ferrarotto, Div Clinicizzata Ematol, Catania, Italy. [Berlyne, Deborah] Aplast Anemia & Myelodysplast Syndrome Int Fdn, Rockville, MD USA. RP Savage, SA (reprint author), NCI, Div Canc Epidemiol & Genet, Clin Genet Branch, 6120 Execut Blvd,EPS 7018, Bethesda, MD 20892 USA. EM savagesh@mail.nih.gov RI Savage, Sharon/B-9747-2015; ROMANO, ALESSANDRA/I-9201-2012 OI Savage, Sharon/0000-0001-6006-0740; ROMANO, ALESSANDRA/0000-0002-6333-4433 FU National Institutes of Health, National Heart, Lung, and Blood Institute [1R13HL112578-01]; Office of Rare Disease Research; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health FX The authors thank all meeting participants for a highly productive meeting. Funding for this conference was made possible in part by 1R13HL112578-01 from the National Institutes of Health, National Heart, Lung, and Blood Institute and the Office of Rare Disease Research. This work was supported, in part, by the intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (S.A.S.). The views expressed in written conference materials or publications and by speakers or moderators do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention of trade names, commercial practices, or organizations imply endorsement by the U.S. Government. Author contributions. All authors participated in the AA&MDSIF meeting and in writing the manuscript. All authors approved of the final version. NR 8 TC 1 Z9 2 U1 0 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD JUL PY 2013 VL 37 IS 7 BP 848 EP 851 DI 10.1016/j.leukres.2013.04.013 PG 4 WC Oncology; Hematology SC Oncology; Hematology GA 166UF UT WOS:000320583100022 PM 23643149 ER PT J AU Fernandez-Duenas, V Gomez-Soler, M Morato, X Nunez, F Das, A Kumar, TS Jauma, S Jacobson, KA Ciruela, F AF Fernandez-Duenas, Victor Gomez-Soler, Maricel Morato, Xavier Nunez, Fabiana Das, Arijit Kumar, T. Santhosh Jauma, Serge Jacobson, Kenneth A. Ciruela, Francisco TI Dopamine D-2 receptor-mediated modulation of adenosine A(2A) receptor agonist binding within the A(2A)R/D2R oligomer framework SO NEUROCHEMISTRY INTERNATIONAL LA English DT Article DE A(2A)R; D2R; Parkinson's disease; Receptor-receptor allosterism; Antiparkinsonian drugs ID PARKINSONS-DISEASE; HETEROMERS; SUBTYPES AB The molecular interaction between adenosine A(2A) and dopamine D-2 receptors (A(2A)Rs and D(2)Rs, respectively) within an oligomeric complex has been postulated to play a pivotal role in the adenosine-dopamine interplay in the central nervous system, in both normal and pathological conditions (e.g. Parkinson's disease). While the effects of A(2A)R challenge on D2R functioning have been largely studied, the reverse condition is still unexplored, a fact that might have impact in therapeutics. Here, we aimed to examine in a real-time mode the D2R-mediated allosteric modulation of A(2A)R binding when an A(2A)R/D2R oligomer is established. Thus, we synthesized fluorescent A(2A)R agonists and evaluated, by means of a flow cytometry homogeneous no-wash assay and a real-time fluorescence resonance energy transfer (FRET)-based approach, the effects on A(2A)R binding of distinct antiparkinsonian drugs in current clinical use (i.e. pramipexole, rotigotine and apomorphine). Our results provided evidence for the existence of a differential D2R-mediated negative allosteric modulation on A(2A)R agonist binding that was oligomer-formation dependent, and with apomorphine being the best antiparkinsonian drug attenuating A(2A)R agonist binding. Overall, the here-developed methods were found valid to explore the ability of drugs acting on D(2)Rs to modulate A(2A)R binding, thus serving to facilitate the preliminary selection of D2R-like candidate drugs in the management of Parkinson's disease. (c) 2013 Elsevier Ltd. All rights reserved. C1 [Fernandez-Duenas, Victor; Gomez-Soler, Maricel; Morato, Xavier; Nunez, Fabiana; Ciruela, Francisco] Univ Barcelona, Fac Med, IDIBELL, Dept Patol & Terapeut Expt,Unitat Farmacol, Barcelona 08907, Spain. [Das, Arijit; Kumar, T. Santhosh; Jacobson, Kenneth A.] Natl Inst Diabet & Digest & Kidney Dis, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Jauma, Serge] Hosp Univ Bellvitge, Neurol Serv, Movement Disorders Unit, Barcelona 08907, Spain. RP Ciruela, F (reprint author), Fac Med Bellvitge, Dept Patol & Terapeut Expt, Unitat Farmacol, Pavello Govern,Av Feixa Llarga S-N, Barcelona 08907, Spain. EM fciruela@ub.edu RI Jacobson, Kenneth/A-1530-2009; Ciruela, Francisco/A-5096-2013; OI Jacobson, Kenneth/0000-0001-8104-1493; Ciruela, Francisco/0000-0003-0832-3739; Fernandez Duenas, Victor/0000-0001-7834-2965 FU "Ministerio de Economia y Competitividad" (MINECO) [SAF2011-24779, CSD2008-00005]; ICREA Academia from the Catalan Institution for Research and Advanced Studies (ICREA); NIDDK Intramural Research Program of the National Institutes of Health, Bethesda FX This work was supported by grants SAF2011-24779 and Consolider-Ingenio CSD2008-00005 from "Ministerio de Economia y Competitividad" (MINECO) and ICREA Academia-2010 from the Catalan Institution for Research and Advanced Studies (ICREA) to FC. Also, VF-D, MG-S, FN and FC belong to the "Neuropharmacology and Pain" accredited research group (Generalitat de Catalunya, 2009 SGR 232). Support to KAJ, AD, and TSK from the NIDDK Intramural Research Program of the National Institutes of Health, Bethesda, MD, USA is acknowledged. We thank Esther Castano, Eva Julia, and Benjamin Torrejon, from the Scientific and Technical Services (SCT)-Bellvitge Campus of the University of Barcelona for the technical assistance. NR 13 TC 5 Z9 5 U1 1 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0197-0186 J9 NEUROCHEM INT JI Neurochem. Int. PD JUL PY 2013 VL 63 IS 1 BP 42 EP 46 DI 10.1016/j.neuint.2013.04.006 PG 5 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 169BE UT WOS:000320751100005 PM 23619397 ER PT J AU Jarcho, JM Feier, NA Bert, A Labus, JA Lee, M Stains, J Ebrat, B Groman, SM Tillisch, K Brody, AL London, ED Mandelkern, MA Mayer, EA AF Jarcho, Johanna M. Feier, Natasha A. Bert, Alberto Labus, Jennifer A. Lee, Maunoo Stains, Jean Ebrat, Bahar Groman, Stephanie M. Tillisch, Kirsten Brody, Arthur L. London, Edythe D. Mandelkern, Mark A. Mayer, Emeran A. TI Diminished neurokinin-1 receptor availability in patients with two forms of chronic visceral pain SO PAIN LA English DT Article DE PET; NK-1 receptor; Irritable bowel syndrome; Inflammatory bowel disease; Somatic pain; Quality of life ID IRRITABLE-BOWEL-SYNDROME; POSITRON-EMISSION-TOMOGRAPHY; QUALITY-OF-LIFE; SUBSTANCE-P; NK1 RECEPTOR; SPINAL-CORD; HUMAN BRAIN; INFLAMMATORY PAIN; PLACEBO ANALGESIA; PERSISTENT PAIN AB Central sensitization and dysregulation of peripheral substance P and neurokinin-1 receptor (NK-1R) signaling are associated with chronic abdominal pain in inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Although positron emission tomography (PET) has demonstrated that patients with injury-related chronic pain have diminished NK-1R availability in the brain, it is unknown whether these deficits are present in IBD and IBS patients, who have etiologically distinct forms of non-injury-related chronic pain. This study's aim was to determine if patients with IBD or IBS exhibit deficits in brain expression of NK-1Rs relative to healthy controls (HCs), the extent to which expression patterns differ across patient populations, and if these patterns differentially relate to clinical parameters. PET with [F-18] SPA-RQ was used to measure NK-1R availability by quantifying binding potential (BP) in the 3 groups. Exploratory correlation analyses were performed to detect associations between NK-1R BP and physical symptoms. Compared to HCs, IBD patients had NK-1R BP deficits across a widespread network of cortical and subcortical regions. IBS patients had similar, but less pronounced deficits. BP in a subset of these regions was robustly related to discrete clinical parameters in each patient population. Widespread deficits in NK-1R BP occur in IBD and, to a lesser extent, IBS; however, discrete clinical parameters relate to NK-1R BP in each patient population. This suggests that potential pharmacological interventions that target NK-1R signaling may be most effective for treating distinct symptoms in IBD and IBS. (C) 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. C1 [Jarcho, Johanna M.] NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. [Jarcho, Johanna M.; Feier, Natasha A.; Labus, Jennifer A.; Lee, Maunoo; Stains, Jean; Ebrat, Bahar; Tillisch, Kirsten; Mayer, Emeran A.] Univ Calif Los Angeles, David Geffen Sch Med, Gail & Gerald Oppenheimer Family Ctr Neurobiol St, Los Angeles, CA 90095 USA. [Feier, Natasha A.] McGill Univ, Fac Dent, Alan Edwards Ctr Res Pain, Montreal, PQ, Canada. [Bert, Alberto] SpA, Med Imaging Lab Im3D, Turin, Italy. [Groman, Stephanie M.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. [Brody, Arthur L.; London, Edythe D.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Brody, Arthur L.; London, Edythe D.; Mandelkern, Mark A.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [London, Edythe D.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Mandelkern, Mark A.] Univ Calif Irvine, Dept Phys, Irvine, CA 92717 USA. RP Mayer, EA (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Div Digest Dis, Gail & Gerald Oppenheimer Family Ctr Neurobiol St, CHS 42-210 MC737818,10833 Le Conte Ave, Los Angeles, CA 90095 USA. EM emayer@ucla.edu OI Bert, Alberto/0000-0001-8391-7508; Jarcho, Johanna/0000-0001-9075-6968 FU National Institutes of Health [F31-DA021951, T32-MH017140, F31-DA028812, NIH AT00268]; Tobacco-Related Disease Research Program [19XT-0135]; Department of Veterans Affairs, Office of Research and Development (Merit Review Award) FX This work was supported in part by National Institutes of Health Grants F31-DA021951, T32-MH017140 (J.M.J.), F31-DA028812 (S.M.G.), NIH AT00268 (E.A.M.), and endowments from the Marjorie Greene Family Trust and National Institute on Drug Abuse (A.L.B. [R01 DA20872]), the Tobacco-Related Disease Research Program (A.L.B. [19XT-0135]), the Department of Veterans Affairs, Office of Research and Development (Merit Review Award [A.L.B.]), and the Thomas P. and Katherine K. Pike Chair in Addiction Studies (E.D.L.). NR 85 TC 12 Z9 12 U1 1 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD JUL PY 2013 VL 154 IS 7 BP 987 EP 996 DI 10.1016/j.pain.2013.02.026 PG 10 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 166XD UT WOS:000320592200007 PM 23582152 ER PT J AU Huang, B Liu, M Huang, SG Wu, B Guo, H Su, XZ Lu, FL AF Huang, Bo Liu, Man Huang, Shiguang Wu, Bin Guo, Hong Su, Xin-zhuan Lu, Fangli TI Expression of Tim-1 and Tim-3 in Plasmodium berghei ANKA infection SO PARASITOLOGY RESEARCH LA English DT Article ID MURINE CEREBRAL MALARIA; IMMUNE-RESPONSE; MICE; CYTOKINES; SUSCEPTIBILITY; ENCEPHALITIS; PATHOGENESIS; FALCIPARUM; CHILDREN; ASTHMA AB Cerebral malaria (CM) is a serious and often fatal complication of Plasmodium falciparum infections; however, the precise mechanisms leading to CM is poorly understood. Mouse malaria models have provided insight into the key events in pathogenesis of CM. T-cell immune response is known to play an important role in malaria infection, and members of the T-cell immunoglobulin- and mucin-domain-containing molecule (Tim) family have roles in T-cell-mediated immune responses. Tim-1 and Tim-3 are expressed on terminally differentiated Th2 and Th1 cells, respectively, and participate in the regulation of Th immune response. Until now, the role of Tim family proteins in Plasmodium infection remains unclear. In the present study, the mRNA levels of Tim-1, Tim-3, and some key Th1 and Th2 cytokines in the spleen of Kunming outbred mice infected with Plasmodium berghei ANKA (PbANKA) were determined using real-time polymerase chain reaction (qRT-PCR). Compared with uninfected controls, Tim-1 expression was significantly decreased in infected mice with CM at day 10 postinfection (p.i.) but significantly increased in infected mice with non-CM at day 22 p.i.; in contrast, Tim-3 expression was significantly increased in infected mice both with CM at day 10 p.i. and with non-CM at day 22 p.i. The expressions of IFN-gamma, TNF-alpha, IL-10, and IL-12 were significantly increased but IL-4 was significantly decreased in infected mice with CM at days 10 p.i., whereas the expressions of IFN-gamma, TNF-alpha, IL-4, IL-10, and TGF-beta were significantly increased but IL-12 was significantly decreased in infected mice with non-CM at days 22 p.i. Furthermore, the expression of Tim-1 and Tim-3 could reflect Th2 and Th1 immune response in the spleen of PbANKA-infected mice, respectively. Our data suggest that PbANKA infection could inhibit the differentiation of T lymphocytes toward Th2 cells, promote the Th1 cell differentiation, and induce Th1-biased immune response in the early infective stage, whereas the infection could promote Th2 cell differentiation and induce Th2-biased immune response in the late infective stage. Our data indicate that both Tim-1 and Tim-3 may play a role in the process of PbANKA infection, which may represent a potential therapeutic target. C1 [Huang, Bo; Liu, Man; Wu, Bin; Lu, Fangli] Sun Yat Sen Univ, Zhongshan Sch Med, Dept Parasitol, Guangzhou 510080, Guangdong, Peoples R China. [Huang, Bo; Liu, Man; Wu, Bin; Lu, Fangli] Sun Yat Sen Univ, Key Lab Trop Dis Control, Minist Educ, Guangzhou 510080, Guangdong, Peoples R China. [Huang, Shiguang] Jinan Univ, Sch Med, Guangzhou 510632, Guangdong, Peoples R China. [Guo, Hong] Hainan Med Univ, Publ Lab, Haikou 571199, Hainan Province, Peoples R China. [Su, Xin-zhuan] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Su, Xin-zhuan] Xiamen Univ, State Key Lab Cellular Stress Biol, Xiamen 361005, Fujian Province, Peoples R China. [Su, Xin-zhuan] Xiamen Univ, Sch Life Sci, Xiamen 361005, Fujian Province, Peoples R China. [Liu, Man] Medprin Regenerat Med Technol Co Ltd, Guangzhou 510663, Guangdong, Peoples R China. RP Lu, FL (reprint author), Sun Yat Sen Univ, Key Lab Trop Dis Control, Minist Educ, Guangzhou 510080, Guangdong, Peoples R China. EM thshg@126.com; fanglilu@yahoo.com OI Su, Xinzhuan/0000-0003-3246-3248 FU Fogarty International Center of the National Institutes of Health [R01TW008151]; Divisions of Intramural Research at the National Institute of Allergy and Infectious Diseases, National Institutes of Health; Ministry of Education of China [B12003, B06016]; 111 Project; State Bureau of Foreign Experts FX Research reported in this publication was supported in part by the Fogarty International Center of the National Institutes of Health under Award Number R01TW008151, the Divisions of Intramural Research at the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the "111 Project" sponsored by the State Bureau of Foreign Experts and Ministry of Education of China (B12003 and B06016). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 36 TC 4 Z9 7 U1 1 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0932-0113 J9 PARASITOL RES JI Parasitol. Res. PD JUL PY 2013 VL 112 IS 7 BP 2713 EP 2719 DI 10.1007/s00436-013-3442-z PG 7 WC Parasitology SC Parasitology GA 165WO UT WOS:000320516500034 PM 23653017 ER PT J AU Jiang, JY Ahn, J Huang, WY Hayes, RB AF Jiang, Jieying Ahn, Jiyoung Huang, Wen-Yi Hayes, Richard B. TI Association of obesity with cardiovascular disease mortality in the PLCO trial SO PREVENTIVE MEDICINE LA English DT Article DE Cardiovascular disease; Body-mass index; Obesity ID BODY-MASS INDEX; CANCER SCREENING TRIAL; CORONARY-HEART-DISEASE; RISK-FACTORS; OVERWEIGHT; STROKE; WOMEN; PARTICIPANTS; PROSTATE; WEIGHT AB Objective. Obesity is a risk factor for cardiovascular disease (CVD) mortality, but the association between obesity and specific causes of CVD mortality is still under investigation. Method. We prospectively examined body-mass index (BMI) in relation to CVD-specific causes of death in approximately 86,000 US men and women in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, followed for up to 13 years. BMI was calculated from self-reported weight and height at baseline. Hazard ratios (HRs) were calculated overall and stratified by sex, smoking status, and educational level. Result Overweight non-obese participants (BMI: 25.0-29.9) were not at excess risk for CVD mortality (HR and Cis are 1.02 [0.92-1.13]), compared to participants of normal BMI (18.5-24.9). Excess CVD mortality was observed for participants of BMI 30.0-34.9 (HR and Cis: 129[1.13-1.48]), BMI 35.0-39.9 (HR and CIs: 1.87[1.51-232]) and BMI 40.0 + (HR and Us: 221 [1.57-321]) (p < 0.001 for trend). BMI was unrelated to mortality due to stroke. The observed association of BMI with CVD was independent of gender, smoking status and educational level. Conclusion. Obesity is associated with increased mortality due to CVD. (C) 2013 Elsevier Inc. All rights reserved. C1 [Jiang, Jieying; Ahn, Jiyoung; Hayes, Richard B.] NYU, Div Epidemiol, Dept Populat Hlth, Sch Med, New York, NY 10016 USA. [Huang, Wen-Yi] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Hayes, RB (reprint author), NYU, Div Epidemiol, Dept Populat Hlth, Sch Med, 650 1st Ave, New York, NY 10016 USA. EM Richard.B.Hayes@nyumc.org OI Hayes, Richard/0000-0002-0918-661X FU New York University School of Medicine; Intramural Research Program of the Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, National Institutes of Health; Department of Health and Human Services (DHHS) FX This research was supported by New York University School of Medicine, by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services (DHHS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 13 Z9 13 U1 1 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 J9 PREV MED JI Prev. Med. PD JUL PY 2013 VL 57 IS 1 BP 60 EP 64 DI 10.1016/j.ypmed.2013.04.014 PG 5 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 164SI UT WOS:000320429400012 PM 23632233 ER PT J AU Moreno, M Economidou, D Mar, AC Lopez-Granero, C Caprioli, D Theobald, DE Fernando, A Newman, AH Robbins, TW Dalley, JW AF Moreno, M. Economidou, D. Mar, A. C. Lopez-Granero, C. Caprioli, D. Theobald, D. E. Fernando, A. Newman, A. H. Robbins, T. W. Dalley, Jeffrey W. TI Divergent effects of D-2/3 receptor activation in the nucleus accumbens core and shell on impulsivity and locomotor activity in high and low impulsive rats SO PSYCHOPHARMACOLOGY LA English DT Article DE Impulsivity; Locomotion; Quinpirole; Nafadotride; Dopamine; Nucleus accumbens ID REACTION-TIME-TASK; DOPAMINE D-3 RECEPTOR; ROMAN HIGH-AVOIDANCE; ATTENTIONAL PERFORMANCE; DRUG-ADDICTION; BRAIN; ANTAGONIST; LESIONS; STIMULATION; MODULATION AB Previously we demonstrated reduced D-2/3 receptor availability in the ventral striatum of hyper-impulsive rats on the five-choice serial reaction time task (5-CSRTT). However, the anatomical locus of D-2/3 receptor dysfunction in high impulsive (HI) rats is unknown. In the present study, we investigated whether D-2/3 receptor dysfunction in HI rats is localised to the core or shell sub-regions of the nucleus accumbens (NAcb). Rats were selected for low (low impulsive, LI) and high impulsivity on the 5-CSRTT and implanted with guide cannulae targeting the NAcb core and shell. The D-2/3 receptor agonist quinpirole was locally injected in the NAcb (0.1, 0.3 and 1 mu g per infusion) and its effects investigated on the performance of LI and HI rats on the 5-CSRTT as well as spontaneous locomotor activity in an open field. Intra-NAcb core quinpirole increased premature responding in HI rats but not in LI rats. In contrast, intra-NAcb shell quinpirole strongly increased locomotor activity in HI rats, unlike LI rats. This effect was blocked by intra-NAcb shell infusions of the D-2/3 receptor antagonist nafadotride (0.03 mu g). However, nafadotride was ineffective in blocking the effects of intra-NAcb core quinpirole on premature responding in HI rats. These findings indicate that impulsivity and hyperactivity are separately regulated by core and shell sub-regions of the NAcb and that HI rats show an enhanced response to D-2/3 receptor activation in these regions. These results suggest that the symptom clusters of hyperactivity and impulsivity in attention-deficit hyperactivity disorder may be neurally dissociable at the level of the NAcb. C1 [Moreno, M.; Lopez-Granero, C.] Univ Almeria, Dept Psychol, Almeria, Spain. [Economidou, D.; Mar, A. C.; Caprioli, D.; Theobald, D. E.; Fernando, A.; Robbins, T. W.; Dalley, Jeffrey W.] Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England. [Economidou, D.; Mar, A. C.; Caprioli, D.; Theobald, D. E.; Fernando, A.; Robbins, T. W.; Dalley, Jeffrey W.] Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England. [Newman, A. H.] NIDA, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD USA. [Dalley, Jeffrey W.] Univ Cambridge, Dept Psychiat, Cambridge CB2 2QQ, England. RP Dalley, JW (reprint author), Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England. EM jwd20@cam.ac.uk RI Lopez-Granero, Caridad/C-8316-2013; OI Lopez-Granero, Caridad/0000-0001-7781-3497; Moreno, Margarita/0000-0001-7336-6167 FU Medical Research Council [G0701500]; Ministerio de Ciencia e Innovacion of Spain [PSI2009-08626]; MRC; Wellcome Trust; NIDA-IRP, NIH FX This study was funded by grants from the Medical Research Council (G0701500) and the Ministerio de Ciencia e Innovacion of Spain (PSI2009-08626) and by a joint award from the MRC and Wellcome Trust in support of the Behavioural and Clinical Neuroscience Institute at Cambridge University. AHN was supported by the NIDA-IRP, NIH. NR 55 TC 16 Z9 17 U1 0 U2 19 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUL PY 2013 VL 228 IS 1 BP 19 EP 30 DI 10.1007/s00213-013-3010-3 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 163VM UT WOS:000320365100002 PM 23407782 ER PT J AU Sutherland, MT Carroll, AJ Salmeron, BJ Ross, TJ Stein, EA AF Sutherland, Matthew T. Carroll, Allison J. Salmeron, Betty Jo Ross, Thomas J. Stein, Elliot A. TI Insula's functional connectivity with ventromedial prefrontal cortex mediates the impact of trait alexithymia on state tobacco craving SO PSYCHOPHARMACOLOGY LA English DT Article DE Alexithymia; Craving; Nicotine; Varenicline; Resting-state functional connectivity; Insula; Ventromedial prefrontal cortex; fMRI ID IOWA GAMBLING TASK; DECISION-MAKING; EMOTIONAL INTELLIGENCE; INDIVIDUAL-DIFFERENCES; INTEROCEPTIVE AWARENESS; MAINTAINING ABSTINENCE; SMOKING-CESSATION; BRAIN ACTIVATION; CINGULATE CORTEX; NEGATIVE FACTOR AB Alexithymia is a personality trait characterized by difficulty indentifying and describing subjective emotional experiences. Decreased aptitude in the perception, evaluation, and communication of affectively laden mental states has been associated with reduced emotion regulation, more severe drug craving in addicts, and structural/functional alterations in insula and anterior cingulate cortex (ACC). The insula and ACC represent sites of convergence between the putative neural substrates of alexithymia and those perpetuating cigarette smoking. We examined the interrelations between alexithymia, tobacco craving, and insula/ACC neurocircuitry using resting-state functional connectivity (rsFC). Overnight-deprived smokers (n = 24) and nonsmokers (n = 20) completed six neuroimaging assessments on different days both in the absence of, and following, varenicline and/or nicotine administration. In this secondary analysis of data from a larger study, we assessed trait alexithymia and state tobacco craving using self-reports and examined the rsFC of bilateral insular subregions (anterior, middle, posterior) and dorsal ACC. Higher alexithymia in smokers predicted reduced rsFC strength between the right anterior insula (aI) and ventromedial prefrontal cortex (vmPFC). Higher alexithymia also predicted more severe tobacco craving during nicotine withdrawal. Critically, the identified aI-vmPFC circuit fully mediated this alexithymia-craving relation. That is, elevated alexithymia predicted decreased aI-vmPFC rsFC and, in turn, decreased aI-vmPFC rsFC predicted increased craving during withdrawal. A moderated mediation analysis indicated that this aI-vmPFC mediational effect was not observed following drug administration. These results suggest that a weakened right aI-vmPFC functional circuit confers increased liability for tobacco craving during smoking abstinence. Individual differences in alexithymia and/or aI-vmPFC functional coupling may be relevant factors for smoking cessation success. C1 [Sutherland, Matthew T.] Florida Int Univ, Dept Psychol, Miami, FL 33199 USA. [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. [Sutherland, Matthew T.] Florida Int Univ, Dept Psychol, Deuxieme Maison, Miami, FL 33199 USA. RP Sutherland, MT (reprint author), Florida Int Univ, Dept Psychol, Deuxieme Maison, RM 295,11299 SW 8th St, 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, Anita Signau and the NIDA-IRP nurses, pharmacy, and recruitment staff for assistance with data collection. NR 103 TC 18 Z9 18 U1 3 U2 20 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUL PY 2013 VL 228 IS 1 BP 143 EP 155 DI 10.1007/s00213-013-3018-8 PG 13 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 163VM UT WOS:000320365100013 PM 23455594 ER PT J AU Kakiuchi-Kiyota, S Crabbs, TA Arnold, LL Pennington, KL Cook, JC Malarkey, DE Cohen, SM AF Kakiuchi-Kiyota, Satoko Crabbs, Torrie A. Arnold, Lora L. Pennington, Karen L. Cook, Jon C. Malarkey, David E. Cohen, Samuel M. TI Evaluation of Expression Profiles of Hematopoietic Stem Cell, Endothelial Cell, and Myeloid Cell Antigens in Spontaneous and Chemically Induced Hemangiosarcomas and Hemangiomas in Mice SO TOXICOLOGIC PATHOLOGY LA English DT Article DE mouse; hemangiosarcomas; hemangiomas; hematopoietic stem cells; endothelial progenitor cells; immunohistochemistry ID PROGENITOR CELLS; HUMAN RELEVANCE; FACTOR-VIII; P53; ANGIOSARCOMAS; TROGLITAZONE; TUMORS; DIFFERENTIATION; PROLIFERATION; PRECURSORS AB It is unclear whether the process of spontaneous and chemically induced hemangiosarcoma and hemangioma formation in mice involves the transformation of differentiated endothelial cells (ECs) or recruitment of multipotential bone marrow-derived hematopoietic stem cells or endothelial progenitor cells (EPCs), which show some degree of endothelial differentiation. In the present study, immunohistochemical staining for hematopoietic stem cell markers (CD45 and CD34), EC markers (vascular endothelial growth factor receptor 2 [VEGFR2], CD31, and factor VIII-related antigen), and a myeloid lineage marker (CD14) was employed to better define the origin of hemangiosarcomas and hemangiomas in mice. Staining was negative for CD45, factor VIII-related antigen, and CD14 and positive for CD34, VEGFR2, and CD31, indicating that mouse hemangiosarcomas and hemangiomas are composed of cells derived from EPCs expressing CD34, VEGFR2, and CD31 but not factor VIII-related antigen. The lack of CD45 expression suggests that mouse vascular tumors may arise from EPCs that are at a stage later than hematopoietic stem cells. Since factor VIII-related antigen expression is known to occur later than CD31 expression in EPCs, our observations may indicate that these tumor cells are arrested at a stage prior to complete differentiation. In addition, myeloid lineage cells do not appear to contribute to hemangiosarcoma and hemangioma formation in mice. C1 [Kakiuchi-Kiyota, Satoko; Arnold, Lora L.; Pennington, Karen L.; Cohen, Samuel M.] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. [Kakiuchi-Kiyota, Satoko; Cook, Jon C.] Pfizer Inc, Drug Safety Res & Dev, Groton, CT 06340 USA. [Crabbs, Torrie A.] Expt Pathol Labs Inc, Res Triangle Pk, NC USA. [Malarkey, David E.] NIEHS, Natl Toxicol Program, Cellular & Mol Pathol Branch, Res Triangle Pk, NC 27709 USA. [Malarkey, David E.] NIEHS, Res Triangle Pk, NC 27709 USA. RP Cohen, SM (reprint author), 983135 Nebraska Med Ctr, Omaha, NE 68198 USA. EM scohen@unmc.edu FU Division of the National Toxicology Program of the NIH; National Institute of Environmental Health Sciences FX The authors gratefully acknowledge Dr. Norimitsu Shirai at Pfizer, Inc., for his pathological expertise and the individuals at EPL, Inc.: the Histology Lab for retrieving the paraffin blocks and cutting sections, the Photo Lab for taking photos of immunostaining, and Beth Mahler for editing images. We also gratefully acknowledge the technical expertise of Heather Jensen, Otis Lyght, Geoffrey Hurlburt, Yvette Rebolloso, David Olson, Quashana Brown, and Natasha Clayton in the Immunohistochemistry Lab of the Pathology Support Group of the Cellular and Molecular Pathology Branch of the National Toxicology Program, NIEHS for development of the methodology and performance of the immunohistochemistry. Heather Jensen was particularly helpful technically and in assisting in preparation of the manuscript. This research was supported (in part) by the Division of the National Toxicology Program of the NIH, National Institute of Environmental Health Sciences. This article may be the work product of an employee or group of employees of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH); however, the statements, opinions, or conclusions contained therein do not necessarily represent the statements, opinions, or conclusions of NIEHS, NIH, or the U.S. government. NR 41 TC 8 Z9 8 U1 0 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUL PY 2013 VL 41 IS 5 BP 709 EP 721 DI 10.1177/0192623312464309 PG 13 WC Pathology; Toxicology SC Pathology; Toxicology GA 169FK UT WOS:000320764000002 PM 23125116 ER PT J AU Surh, I Brix, A French, JE Collins, BJ Sanders, JM Vallant, M Dunnick, JK AF Surh, Inok Brix, Amy French, John E. Collins, Bradley J. Sanders, J. Michael Vallant, Molly Dunnick, June K. TI Toxicology and Carcinogenesis Study of Senna in C3B6.129F1-Trp53 (tm1Brd) N12 Haploinsufficient Mice SO TOXICOLOGIC PATHOLOGY LA English DT Article DE senna; Trp53; carcinogenesis; toxicity; laxative; large intestine ID TRANSGENIC MOUSE MODELS; ABERRANT CRYPT FOCI; ANTHRAQUINONE GLYCOSIDES; CELL-PROLIFERATION; P53-DEFICIENT MICE; COLORECTAL-CANCER; EATING-DISORDERS; LAXATIVE ABUSE; RAT COLON; IN-VITRO AB Senna is a pod or leaf of Senna alexandrina P. Mill and is used as a stimulant laxative. In the large intestine, bacterial enzymes reduce sennosides to rhein-9-anthrone, the active form for the laxative effect. To determine the potential toxic effects of senna, a 5-week dose range finding study in the C57BL/6N mouse and a 40-week toxicology and carcinogenesis study in the C3B6.129F1-Trp53(tm1Brd) N12 haploinsufficient (p53(+/-)) mouse were conducted. In the 5-week study, C57BL/6N mice were exposed to up to 10,000 ppm senna in feed. Increased incidences of epithelial hyperplasia of the cecum and colon were observed in males and females exposed to 5,000 or 10,000 ppm senna. These intestinal lesions were not considered to be of sufficient severity to cause mortality and, thus, in the p53(+/-) mouse 40-week study, the high dose of 10,000 ppm was selected. Significant increases in the incidences of epithelial hyperplasia of the colon and cecum were observed at 10,000 ppm in p53(+/-) males and females, and the incidence of hyperplasia of the colon was significantly increased at 3,000 ppm in females. In conclusion, the large intestine was the major target of senna-induced toxicity in both wild-type and the p53(+/-) mouse model. There was no neoplastic change when senna was administered to p53(+/-) mouse. C1 [Surh, Inok; Brix, Amy; French, John E.; Collins, Bradley J.; Sanders, J. Michael; Vallant, Molly; Dunnick, June K.] NIEHS, Res Triangle Pk, NC 27709 USA. [Surh, Inok] Expt Pathol Labs Inc, Res Triangle Pk, NC USA. RP Dunnick, JK (reprint author), NIEHS, POB 12233,MD K2-13, Res Triangle Pk, NC 27709 USA. EM dunnickj@niehs.nih.gov FU NIEHS [N01-ES-65406, N01-ES-55536] FX This article may be the work product of an employee or group of employees of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH). However, the statements, opinions, or conclusions contained therein do not necessarily represent the statements, opinions, or conclusions of NIEHS, NIH, or the U.S. government. We greatly acknowledge the expert review by Ms. Kristine Witt and Dr. Arun Pandiri. The in life phase of the study was conducted under NIEHS contracts N01-ES-65406 and N01-ES-55536. The authors would like to thank Drs. Milton Hejtmancik, Diane Gerken, Daphne Vasconcelos, and other staff at Battelle Memorial Institute for helping to conduct these studies. NR 66 TC 0 Z9 0 U1 1 U2 16 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUL PY 2013 VL 41 IS 5 BP 770 EP 778 DI 10.1177/0192623312464304 PG 9 WC Pathology; Toxicology SC Pathology; Toxicology GA 169FK UT WOS:000320764000007 PM 23125117 ER PT J AU Xi, ZX Li, X Li, J Peng, XQ Song, R Gaal, J Gardner, EL AF Xi, Zheng-Xiong Li, Xia Li, Jie Peng, Xiao-Qing Song, Rui Gaal, Jozsef Gardner, Eliot L. TI Blockade of dopamine D-3 receptors in the nucleus accumbens and central amygdala inhibits incubation of cocaine craving in rats SO ADDICTION BIOLOGY LA English DT Article DE Cocaine; craving; D-3 receptor; dopamine; drug seeking; incubation; relapse; SB-277011A ID SELF-ADMINISTERED COCAINE; INDUCED CONDITIONED LOCOMOTION; CUE-INDUCED REINSTATEMENT; DRUG-SEEKING BEHAVIOR; BASOLATERAL AMYGDALA; DORSAL STRIATUM; D-AMPHETAMINE; EXCITOTOXIC LESIONS; HUMAN BRAIN; EXTRACELLULAR DOPAMINE AB Cue-induced drug seeking progressively increases over time of withdrawal from drug self-administration in rats, a phenomenon called incubation of craving'. The underlying mechanisms have been linked to increased expression of brain-derived neurotrophic factor and GluR2-lacking AMPA receptors in the mesolimbic dopamine (DA) system and also to increased extracellular signal-regulated kinase activation in the central amygdala (CeA). However, it remains unclear whether any DA mechanism is also involved in incubation of craving. Recent research demonstrates that cue-induced cocaine seeking appears to parallel increased DA D3, but not D1 or D2, receptor expression in the nucleus accumbens (NAc) of rats over time of withdrawal, suggesting possible involvement of D3 receptors (D3Rs) in incubation of cocaine craving. Here, we report that systemic or local administration of SB-277011A, a highly selective D3R antagonist, into the NAc (core and shell) or the CeA, but not the dorsal striatum or basolateral amygdala, significantly inhibits expression of incubation of cocaine craving in rats after 2-30 days of withdrawal from previous cocaine self-administration but had no effect on sucrose-seeking behavior in rats after 10-30 days of withdrawal. These data suggest that DA D3Rs in both the NAc and the CeA play an important role in incubation of cocaine craving in rats and support the potential utility of D3R antagonists in the treatment of cocaine addiction. C1 [Xi, Zheng-Xiong; Li, Xia; Li, Jie; Peng, Xiao-Qing; Song, Rui; Gardner, Eliot L.] NIDA, Intramural Res Program, Baltimore, MD USA. RP Xi, ZX (reprint author), NIDA, Intramural Res Program, Baltimore, MD USA. EM zxi@intra.nida.nih.gov OI PENG, XIAOQING/0000-0002-7272-5428 FU US National Institute on Drug Abuse Intramural Research Program FX This work was supported by the US National Institute on Drug Abuse Intramural Research Program. NR 82 TC 12 Z9 13 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1355-6215 J9 ADDICT BIOL JI Addict. Biol. PD JUL PY 2013 VL 18 IS 4 BP 665 EP 677 DI 10.1111/j.1369-1600.2012.00486.x PG 13 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA 169IW UT WOS:000320774700007 PM 22913325 ER PT J AU Hoofnagle, JH Van Natta, ML Kleiner, DE Clark, JM Kowdley, KV Loomba, R Neuschwander-Tetri, BA Sanyal, AJ Tonascia, J AF Hoofnagle, J. H. Van Natta, M. L. Kleiner, D. E. Clark, J. M. Kowdley, K. V. Loomba, R. Neuschwander-Tetri, B. A. Sanyal, A. J. Tonascia, J. CA Non-alcoholic Steatohepatitis TI Vitamin E and changes in serum alanine aminotransferase levels in patients with non-alcoholic steatohepatitis SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID FATTY LIVER-DISEASE; RANDOMIZED CONTROLLED-TRIAL; TERM-FOLLOW-UP; E-DEFICIENCY; NATURAL-HISTORY; CANCER; PIOGLITAZONE; PREVENTION; SUPPLEMENTATION; EPIDEMIOLOGY AB Background Non-alcoholic steatohepatitis (NASH) is a common cause of serum alanine aminotransferase (ALT) elevations and chronic liver disease, but it is unclear how well ALT elevations reflect the liver injury. Aim To assess how well changes in ALT elevations reflect improvements in liver histology in response to vitamin E therapy. Methods The vitamin E and placebo arms of the Pioglitazone vs. Vitamin E vs. Placebo in Non-alcoholic Steatohepatitis (PIVENS) trial were reassessed for associations among changes in ALT levels, body weight and liver histology. An ALT response was defined as a decrease to 40U/L and by 30% of baseline. Liver biopsies taken before and after treatment were scored for non-alcoholic fatty liver disease activity (NAS) and fibrosis. Results ALT responses were more frequent among vitamin E (48%) than placebo (16%) recipients (P<0.001). Among vitamin E recipients, ALT responses were associated with decreases in NAS (P<0.001), but not fibrosis scores (P=0.34), whereas among placebo recipients, ALT responses were associated with significant decreases in both (P<0.05). Weight loss (2kg) was also associated with ALT response (P<0.001), improvements in NAS (P <0.001) and fibrosis (P<0.02), but vitamin E had an added effect both with and without weight loss. Weight gain (2kg) was associated with lack of ALT response and worsening NAS and fibrosis scores in patients not on vitamin E. Conclusions Decrease of ALT levels to normal in patients with NASH is usually associated with improved histological activity. Management should stress the value of weight loss and strongly discourage weight gain. Vitamin E can improve both ALT levels and histology with and without weight loss. Clinical Trial Number: NCT00063622. C1 [Hoofnagle, J. H.] NIDDK, Liver Dis Res Branch, Div Digest Dis & Nutr, NIH, Bethesda, MD USA. [Van Natta, M. L.; Clark, J. M.; Tonascia, J.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Kleiner, D. E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Kowdley, K. V.] Virginia Mason Med Ctr, Inst Digest Dis, Seattle, WA 98101 USA. [Loomba, R.] Univ Calif San Diego, Div Gastroenterol & Epidemiol, San Diego, CA 92103 USA. [Neuschwander-Tetri, B. A.] St Louis Univ, Div Gastroenterol & Hepatol, St Louis, MO 63103 USA. [Sanyal, A. J.] Virginia Commonwealth Univ, Sch Med, Richmond, VA USA. RP Hoofnagle, JH (reprint author), NIH, Room 644,6707 Democracy Blvd, Bethesda, MD 20892 USA. EM HoofnagleJ@extra.niddk.nih.gov RI Vaughn, Ivana/B-6138-2016; OI Vaughn, Ivana/0000-0002-7201-0289; Kleiner, David/0000-0003-3442-4453 FU Daiichi Sankyo Inc.; Bayer-Onxy; Exhalenz; Genentech; Gilead; Gore; Ikaria; Intercept; Salix; National Institute of Diabetes and Digestive and Kidney Diseases [U01DK061718, U01DK061728, U01DK061731, U01DK061732, U01DK061734, U01DK061737, U01DK0 61738, U01DK061730, U01DK061713]; General Clinical Research Centers or Clinical and Translational Science Awards [UL1RR024989, UL1RR025761, M01RR00188, UL1RR 024131, UL1RR025014, UL1RR031990, UL1RR025741, UL1RR029887, UL1RR24156, UL1RR025055, UL1RR 031980]; National Institute of Child Health and Human Development (NICHD); National Cancer (NCI); NIDDK; Takeda Pharmaceuticals North America; Pharmavite FX Declaration of personal interests: JHH, MLVN, DEK, JMC, KVK, RL, BANT and JT have no conflicts of interest to report. RL serves as a consultant to Gilead, Corgenix and Daiichi Sankyo Inc and has received research grant support from Daiichi Sankyo Inc. AJS serves as a consultant to Abbott, Genfit, Ikaria, Merck, Norgene, Salix and Roche and has research grant support from Bayer-Onxy, Exhalenz, Genentech, Gilead, Gore, Ikaria, Intercept and Salix and receives royalties from Uptodate. Declaration of funding interests: The NASH CRN is a multicentre prospective study of the natural history and treatment of non-alcoholic steatohepatitis funded as a cooperative agreement by the National Institute of Diabetes and Digestive and Kidney Diseases (Grant numbers: U01DK061718, U01DK061728, U01DK061731, U01DK061732, U01DK061734, U01DK061737, U01DK0 61738, U01DK061730, U01DK061713). In conduct of the NASH CRN studies, several clinical centres use support from General Clinical Research Centers or Clinical and Translational Science Awards (Grant numbers: UL1RR024989, UL1RR025761, M01RR00188, UL1RR 024131, UL1RR025014, UL1RR031990, UL1RR025741, UL1RR029887, UL1RR24156, UL1RR025055, UL1RR 031980). Further support is provided by the National Institute of Child Health and Human Development (NICHD) and by the intramural programme of the National Cancer (NCI). The PIVENS trial was conducted by the NASH CRN and supported in part by Collaborative Research and Development Agreement (CRADA) between NIDDK and Takeda Pharmaceuticals North America (for pioglitazone and placebo tablets and for additional financial support) and a Clinical Trial Agreement between NIDDK and Pharmavite (for vitamin E and placebo capsules). Full membership of the NASH CRN is listed in the Table S1. NR 27 TC 47 Z9 49 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD JUL PY 2013 VL 38 IS 2 BP 134 EP 143 DI 10.1111/apt.12352 PG 10 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 165GV UT WOS:000320472400006 PM 23718573 ER PT J AU Consonni, D Matteis, SD Pesatori, AC Cattaneo, A Cavallo, DM Lubin, JH Tucker, M Bertazzi, PA Caporaso, NE Wacholder, S Landi, MT AF Consonni, Dario Matteis, Sara De Pesatori, Angela C. Cattaneo, Andrea Cavallo, Domenico M. Lubin, Jay H. Tucker, Margaret Bertazzi, Pier Alberto Caporaso, Neil E. Wacholder, Sholom Landi, Maria Teresa TI Increased lung cancer risk among bricklayers in an italian population-based case-control study (vol 55, pg 423, 2012) SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Correction C1 Dept Prevent Med, Epidemiol Unit, Fondazione IRCCS Ca Granda Osped Maggiore Policli, Milan, Italy. Univ Studi Milano, Dept Occupat & Environm Hlth, Milan, Italy. Univ Studi dellInsubria, Dept Chem & Environm Sci, Como, Italy. Natl Canc Inst, Div Canc Epidemiol & Genet, NIH, Bethesda, MD USA. RP Consonni, D (reprint author), Dept Prevent Med, Epidemiol Unit, Fondazione IRCCS Ca Granda Osped Maggiore Policli, Via San Barnaba, I-820122 Milan, Italy. RI Cavallo, Domenico Maria/F-9881-2013; Tucker, Margaret/B-4297-2015; Consonni, Dario/K-7943-2016; bertazzi, pietro alberto/D-5039-2017 OI Cavallo, Domenico Maria/0000-0003-1853-2999; Consonni, Dario/0000-0002-8935-3843; bertazzi, pietro alberto/0000-0003-3475-2449 NR 1 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD JUL PY 2013 VL 56 IS 7 BP 825 EP 825 DI 10.1002/ajim.22154 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 165GM UT WOS:000320471400010 ER PT J AU Gilbert, JR Pillai, AS Horwitz, B AF Gilbert, Jessica R. Pillai, Ajay S. Horwitz, Barry TI Assessing crossmodal matching of abstract auditory and visual stimuli in posterior superior temporal sulcus with MEG SO BRAIN AND COGNITION LA English DT Article DE Crossmodal matching; Audio-visual processing; pSTS; Magnetoencephalography ID MULTISENSORY INTEGRATION; AUDIOVISUAL SPEECH; BRAIN OSCILLATIONS; MEMORY; CORTEX; FMRI; TIME; MAGNETOENCEPHALOGRAPHY; SYNCHRONIZATION; INFORMATION AB Associating crossmodal auditory and visual stimuli is an important component of perception, with the posterior superior temporal sulcus (pSTS) hypothesized to support this. However, recent evidence has argued that the pSTS serves to associate two stimuli irrespective of modality. To examine the contribution of pSTS to crossmodal recognition, participants (N = 13) learned 12 abstract, non-linguistic pairs of stimuli over 3 weeks. These paired associates comprised four types: auditory-visual (AV), auditory-auditory (AA), visual-auditory (VA), and visual-visual (VV). At week four, participants were scanned using magnetoencephalography (MEG) while performing a correct/incorrect judgment on pairs of items. Using an implementation of synthetic aperture magnetometry that computes real statistics across trials (SAMspm), we directly contrasted crossmodal (AV and VA) with unimodal (AA and VV) pairs from stimulus-onset to 2 s in theta (4-8 Hz), alpha (9-15 Hz), beta (16-30 Hz), and gamma (31-50 Hz) frequencies. We found pSTS showed greater desynchronization in the beta frequency for crossmodal compared with unimodal trials, suggesting greater activity during the crossmodal pairs, which was not influenced by congruency of the paired stimuli. Using a sliding window SAM analysis, we found the timing of this difference began in a window from 250 to 750 ms after stimulus-onset. Further, when we directly contrasted all sub-types of paired associates from stimulus-onset to 2 s, we found that pSTS seemed to respond to dynamic, auditory stimuli, rather than crossmodal stimuli per se. These findings support an early role for pSTS in the processing of dynamic, auditory stimuli, and do not support claims that pSTS is responsible for associating two stimuli irrespective of their modality. Published by Elsevier Inc. C1 [Gilbert, Jessica R.; Pillai, Ajay S.; Horwitz, Barry] Natl Inst Deafness & Other Commun Disorders, Brain Imaging & Modeling Sect, Bethesda, MD 20892 USA. RP Gilbert, JR (reprint author), Natl Inst Deafness & Other Commun Disorders NIDCD, NIH, Brain Imaging & Modeling Sect, 10 Ctr Dr,Room 5039, Bethesda, MD 20892 USA. EM jessica.gilbert@nih.gov FU National Institute on Deafness and Other Communication Disorders of the National Institutes of Health FX This work was supported by the intramural program of the National Institute on Deafness and Other Communication Disorders of the National Institutes of Health. The authors thank Tom Holroyd, Fred Carver, and Jason Smith for technical advice and helpful discussions. NR 37 TC 0 Z9 0 U1 1 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0278-2626 J9 BRAIN COGNITION JI Brain Cogn. PD JUL PY 2013 VL 82 IS 2 BP 161 EP 170 DI 10.1016/j.bandc.2013.03.004 PG 10 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 160WZ UT WOS:000320152500005 PM 23665947 ER PT J AU Zhou, Q Gil-Krzewska, A Peruzzi, G Borrego, F AF Zhou, Q. Gil-Krzewska, A. Peruzzi, G. Borrego, F. TI Matrix metalloproteinases inhibition promotes the polyfunctionality of human natural killer cells in therapeutic antibody-based anti-tumour immunotherapy SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Article DE monoclonal antibody; NK cell; polyfunctionality; tumour immunotherapy ID VIRUS TYPE-1 INFECTION; IFN-GAMMA; TUMOR-DEVELOPMENT; FC-RECEPTORS; NK CELLS; T-CELLS; IN-VIVO; IGG FC; CD16; CANCER AB Activation of human natural killer (NK) cells is associated with the cleavage of CD16 from the cell surface, a process mediated by matrix metalloproteinases (MMPs). In this report, we examined whether inhibition of MMPs would lead to improved NK cell antibody-dependent cell-mediated cytotoxicity (ADCC) function. Using an in-vitroADCC assay, we tested the anti-tumour function of NK cells with three different therapeutic monoclonal antibodies (mAbs) in the presence of MMPs inhibitor GM6001 or its control. Loss of CD16 was observed when NK cells were co-cultured with tumour targets in the presence of specific anti-tumour antibodies, and was found particularly on the majority of degranulating NK responding cells. Treatment with MMPs inhibitors not only prevented CD16 down-regulation, but improved the quality of the responding cells significantly, as shown by an increase in the percentage of polyfunctional NK cells that are capable of both producing cytokines and degranulation. Furthermore, MMPs inhibition resulted in augmented and sustained CD16-mediated signalling, as shown by increased tyrosine phosphorylation of CD3 and other downstream signalling intermediates, which may account for the improved NK cell function. Collectively, our results provide a foundation for combining MMPs inhibitors and therapeutic mAbs in new clinical trials for cancer treatment. C1 [Zhou, Q.; Gil-Krzewska, A.; Borrego, F.] US FDA, Lab Mol & Dev Immunol, Div Monoclonal Antibodies, OBP,CDER, Bethesda, MD 20892 USA. [Peruzzi, G.] NIAID, Receptor Cell Biol Sect, Immunogenet Lab, Rockville, MD USA. RP Borrego, F (reprint author), US FDA, Lab Mol & Dev Immunol, Div Monoclonal Antibodies, OBP,CDER, Bldg 29B,Room 3NN18,29 Lincoln Dr,HFD 123, Bethesda, MD 20892 USA. EM Francisco.BorregoRabasco@osakidetza.net OI Peruzzi, Giovanna/0000-0002-6517-9107 FU US Food and Drug Administration; NCI-FDA Interagency Oncology Task Force fellowship programme FX This work was supported by the intramural programme of the US Food and Drug Administration and by the NCI-FDA Interagency Oncology Task Force fellowship programme. The authors would like to thank Dr Wen Jin Wu and Dr Milos Dokmanovic for their generous gift of trastuzumab. NR 42 TC 20 Z9 20 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9104 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD JUL PY 2013 VL 173 IS 1 BP 131 EP 139 DI 10.1111/cei.12095 PG 9 WC Immunology SC Immunology GA 159GA UT WOS:000320032400015 PM 23607800 ER PT J AU Chinn, IK Milner, JD Scheinberg, P Douek, DC Markert, ML AF Chinn, I. K. Milner, J. D. Scheinberg, P. Douek, D. C. Markert, M. L. TI Thymus transplantation restores the repertoires of forkhead box protein 3 (FoxP3)+ and FoxP3-T cells in complete DiGeorge anomaly SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Article DE DiGeorge; FoxP3; repertoire; thymus; transplantation ID REGULATORY T-CELLS; EXPRESSION; IMMUNODEFICIENCY; ENTEROPATHY AB The development of T cells with a regulatory phenotype after thymus transplantation has not been examined previously in complete DiGeorge anomaly (cDGA). Seven athymic infants with cDGA and non-maternal pretransplantation T cell clones were assessed. Pretransplantation forkhead box protein 3 (Foxp3)+ T cells were detected in five of the subjects. Two subjects were studied in greater depth. T cell receptor variable chain (TCR-V) expression was assessed by flow cytometry. In both subjects, pretransplantation FoxP3+ and total CD4+ T cells showed restricted TCR-V expression. The development of naive T cells and diverse CD4+ TCR-V repertoires following thymic transplantation indicated successful thymopoiesis from the thymic tissue grafts. Infants with atypical cDGA develop rashes and autoimmune phenomena before transplantation, requiring treatment with immunosuppression, which was discontinued successfully subsequent to the observed thymopoiesis. Post-transplantation, diverse TCR-V family expression was also observed in FoxP3+ CD4+ T cells. Interestingly, the percentages of each of the TCR-V families expressed on FoxP3+ and total CD4+ T cells differed significantly between these T lymphocyte subpopulations before transplantation. By 16 months post-transplantation, however, the percentages of expression of each TCR-V family became significantly similar between FoxP3+ and total CD4+ T cells. Sequencing of TCRBV DNA confirmed the presence of clonally amplified pretransplantation FoxP3+ and FoxP3- T cells. After thymus transplantation, increased polyclonality was observed for both FoxP3+ and FoxP3- cells, and pretransplantation FoxP3+ and FoxP3- clonotypes essentially disappeared. Thus, post-transplantation thymic function was associated with the development of a diverse repertoire of FoxP3+ T cells in cDGA, corresponding with immunological and clinical recovery. C1 [Chinn, I. K.; Markert, M. L.] Duke Univ, Med Ctr, Dept Pediat, Div Allergy & Immunol, Durham, NC 27710 USA. [Markert, M. L.] Duke Univ, Med Ctr, Dept Immunol, Durham, NC 27710 USA. [Milner, J. D.] NIAID, Lab Allerg Dis, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Scheinberg, P.; Douek, D. C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Scheinberg, P.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Chinn, IK (reprint author), Duke Univ, Med Ctr, Box 103020, Durham, NC 27710 USA. EM chinn001@mc.duke.edu OI Scheinberg, Phillip/0000-0002-9047-4538 FU American Academy of Allergy, Asthma and Immunology Senior Allergy/Immunology Fellow Transition Award; NIH [R01 AI 047040, R01 AI 054843, M03 RR 30, T32 AI 007062 28A2, 2 K12 HD043494 06]; National Institute of Allergy and Infectious Diseases FX This work was supported by the American Academy of Allergy, Asthma and Immunology 2008 Senior Allergy/Immunology Fellow Transition Award and NIH grants R01 AI 047040, R01 AI 054843, M03 RR 30 (General Clinical Research Center, National Center for Research Resources), T32 AI 007062 28A2 and 2 K12 HD043494 06. This effort was also supported by the intramural research programme of the National Institute of Allergy and Infectious Diseases. The authors appreciate the assistance of Dr J. Michael Cook of the Duke Comprehensive Cancer Center flow cytometry facility in processing samples. The statistical support provided by Dr Yi-Ju Li of the Duke Translational Medicine Institute is kindly acknowledged. The authors express gratitude to Dr Gregory D. Sempowski of the Duke Human Vaccine Institute for assistance with reviewing the manuscript. The authors thank Dr Blythe H. Devlin, Jie Li, Chia-San Hsieh, Dr Bin Li, Stephanie E. Gupton, Elizabeth A. McCarthy, Michele E. Cox and Judy Stelling for technical, laboratory and clinical research support. The clinical care of the subjects provided by the Duke Pediatric Allergy and Immunology faculty and fellows is appreciated. The authors are grateful for the efforts of the referring physicians in obtaining and sending blood samples and data for the research. NR 32 TC 8 Z9 8 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9104 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD JUL PY 2013 VL 173 IS 1 BP 140 EP 149 DI 10.1111/cei.12088 PG 10 WC Immunology SC Immunology GA 159GA UT WOS:000320032400016 PM 23607606 ER PT J AU Zhao, Z Moley, KH Gronowski, AM AF Zhao, Zhen Moley, Kelle H. Gronowski, Ann M. TI Diagnostic potential for miRNAs as biomarkers for pregnancy-specific diseases SO CLINICAL BIOCHEMISTRY LA English DT Review DE miRNA; Pregnancy; Biomarker ID RECURRENT SPONTANEOUS-ABORTION; CIRCULATING MICRORNAS; MATERNAL CIRCULATION; ECTOPIC PREGNANCY; HUMAN PLACENTAS; UNITED-STATES; PREECLAMPSIA; EXPRESSION; PLASMA; GROWTH AB Discovery of circulating miRNAs in maternal blood has not only facilitated the understanding of their role in normal pregnancy, but also paved new avenues for biomarker discovery to detect pregnancy-associated complications, such as preeclampsia, ectopic pregnancy, gestational diabetes mellitus, fetal growth restriction, recurrent pregnancy loss, and preterm delivery. In this review, we summarize the studies to date of miRNAs in maternal circulation and placental tissue in human. This brief review does not cover all aspects of this intriguing field but focuses on some new and interesting findings of diagnostic potential for miRNAs as biomarkers for pregnancy-specific diseases. (C) 2013 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. C1 [Zhao, Zhen] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Moley, Kelle H.; Gronowski, Ann M.] Washington Univ, Sch Med, Dept Obstet & Gynecol, St Louis, MO 63110 USA. [Gronowski, Ann M.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. RP Gronowski, AM (reprint author), Washington Univ, Sch Med, Dept Pathol & Immunol, Box 8118,660 S Euclid, St Louis, MO 63110 USA. EM gronowski@wustl.edu NR 47 TC 31 Z9 32 U1 3 U2 16 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0009-9120 J9 CLIN BIOCHEM JI Clin. Biochem. PD JUL PY 2013 VL 46 IS 10-11 SI SI BP 953 EP 960 DI 10.1016/j.clinbiochem.2013.01.026 PG 8 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 163PS UT WOS:000320350000015 PM 23396163 ER PT J AU Roux, A Mourin, G Fastenackels, S Almeida, JR Iglesias, MC Boyd, A Gostick, E Larsen, M Price, DA Sacre, K Douek, DC Autran, B Picard, C de Miranda, S Sauce, D Stern, M Appay, V AF Roux, Antoine Mourin, Gisele Fastenackels, Solene Almeida, Jorge R. Iglesias, Maria Candela Boyd, Anders Gostick, Emma Larsen, Martin Price, David A. Sacre, Karim Douek, Daniel C. Autran, Brigitte Picard, Clement de Miranda, Sandra Sauce, Delphine Stern, Marc Appay, Victor TI CMV driven CD8(+) T-cell activation is associated with acute rejection in lung transplantation SO CLINICAL IMMUNOLOGY LA English DT Article DE Cytomegalovirus; T-lymphocyte; Immune activation; Lung transplantation; Acute rejection ID CYTOMEGALOVIRUS-SPECIFIC CD4(+); ALLOGRAFT-REJECTION; PREVENT CYTOMEGALOVIRUS; ANTIGEN-EXPRESSION; IMMUNE-RESPONSE; INFECTION; RECIPIENTS; DISEASE; DIFFERENTIATION; LYMPHOCYTES AB Lung transplantation is the definitive treatment for terminal respiratory disease, but the associated mortality rate is high. Acute rejection of the transplanted lung is a key determinant of adverse prognosis. Furthermore, an epidemiological relationship has been established between the occurrence of acute lung rejection and cytomegalovirus infection. However, the reasons for this association remain unclear. Here, we performed a longitudinal characterization of CMV-specific T-cell responses and immune activation status in the peripheral blood and bronchoalveolar lavage fluid of forty-four lung transplant patients. Acute rejection was associated with high levels of cellular activation in the periphery, reflecting strong CMV-specific CD8(+) T-cell activity post-transplant. Peripheral and lung CMV-specific CD8(+) T-cell responses were very similar, and related to the presence of CMV in the transplanted organ. These findings support that activated CMV-specific CD8(+) T-cells in the lung may play a role in promoting acute rejection. (C) 2013 Elsevier Inc. All rights reserved. C1 [Roux, Antoine; Mourin, Gisele; Fastenackels, Solene; Iglesias, Maria Candela; Larsen, Martin; Sacre, Karim; Autran, Brigitte; Sauce, Delphine; Appay, Victor] Univ Paris 06, Hop La Pitie Salpetriere, INSERM, UMR S 945, F-75013 Paris, France. [Roux, Antoine; Picard, Clement; de Miranda, Sandra; Stern, Marc] Hop Foch, Serv Pneumol, F-92151 Suresnes, France. [Almeida, Jorge R.; Price, David A.; Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Boyd, Anders] Univ Paris 06, Hop St Antoine, INSERM, UMR S 707, F-75012 Paris, France. [Gostick, Emma; Price, David A.] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff CF14 4XN, S Glam, Wales. [Autran, Brigitte; Appay, Victor] Grp Hosp Pitie Salpetriere, AP HP, Lab Immunol Cellulaire & Tissulaire, F-75013 Paris, France. RP Roux, A (reprint author), Hop La Pitie Salpetriere, INSERM, U945, F-75013 Paris, France. EM a.roux@hopital-foch.org; victor.appay@upmc.fr RI Price, David/C-7876-2013; sauce, delphine/H-1990-2014; Larsen, Martin/A-7316-2014; OI Price, David/0000-0001-9416-2737; sauce, delphine/0000-0003-4596-7373; Larsen, Martin/0000-0003-1375-4816; Ramos de Almeida, Jorge/0000-0002-5009-8478; STERN, Marc/0000-0001-5275-6959 FU Vaincre la Mucoviscidose (VLM); National Institutes of Allergy and Infectious Diseases; Fondation pour la Recherche Medicate (FRM) FX This work was supported by Vaincre la Mucoviscidose (VLM), as well as by the Intramural Program of the National Institutes of Allergy and Infectious Diseases (DCD and JRA). AR is supported by VLM and the Fondation pour la Recherche Medicate (FRM). NR 55 TC 7 Z9 8 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUL PY 2013 VL 148 IS 1 BP 16 EP 26 DI 10.1016/j.clim.2013.03.012 PG 11 WC Immunology SC Immunology GA 164RN UT WOS:000320427300003 PM 23644452 ER PT J AU Degheidy, HA Gadalla, SM Farooqui, MZH Abbasi, F Arthur, DC Bauer, SR Wilson, WH Wiestner, A Stetler-Stevenson, MA Marti, GE AF Degheidy, Heba A. Gadalla, Shahinaz M. Farooqui, Mohammed Z. H. Abbasi, Fatima Arthur, Diane C. Bauer, Steven R. Wilson, Wyndham H. Wiestner, Adrian Stetler-Stevenson, M. A. Marti, Gerald E. TI Bcl-2 level as a biomarker for 13q14 deletion in CLL SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Article DE chronic lymphocytic leukemia; Bcl-2; flow cytometry; del 13q14; hemizygous; homozygous deletion ID CHRONIC-LYMPHOCYTIC-LEUKEMIA; B-CELLS; EXPRESSION; APOPTOSIS; MICRORNAS; SURVIVAL; ASSOCIATION; GENES; RNA; ACCUMULATION AB Background Deletion 13q14.3 is the most common cytogenetic abnormality in chronic lymphocytic leukemia (CLL). Previously it was reported that miR-15/16 is the target of 13q14 deletions and plays a tumor suppressor role by suppressing Bcl-2. Therefore, Bcl-2 expression was examined more closely to determine whether it would predict 13q14 deletion status. Methods A multi-color flow panel consisting of anti-Bcl-2/anti-lambda/anti-kappa/CD19/CD5/CD3/CD20 was performed. The ability of Bcl-2 to predict 13q14 deletion was tested using the conventional Bcl-2 index (c-index): mean fluorescence intensity (MFI) of CLL clone/MFI of residual T cells. Fifty-four untreated CLL/MBL patients were studied. Bimodal Bcl-2 expression was evaluated to test the ability of Bcl-2 to detect intraclonal heterogeneity. Other CLL prognostic markers including CD38, CD49d, CD26, and CD69 were evaluated. FISH was performed on selected sorted populations. Results The Bcl-2 c-index strongly predicts del13q14 P < 0.0001. A statistically significant association was observed between the percentage of cells carrying the deletion and the level of Bcl-2 expression P < 0.05. Cells sorted based on Bcl-2 expression showed enrichment of both hemizygous and homozygous del 13q14 cells. Also, we observed that an alteration in Bcl-2 level over time predicts changes in 13q14 deletion status. And a statistically significant correlation between the bimodal pattern of CD69 expression and the presence of 13q14 deletion was found P < 0.0001. Conclusion Bcl-2 expression using the c-index strongly predicts 13q14 deletion and can be used to distinguish homozygous, heterozygous, and diploid CLL clonal cells. Further systematic studies of this biomarker are needed for confirmation and expansion of these findings. Published 2013 Wiley-Periodicals, Inc. C1 [Degheidy, Heba A.; Abbasi, Fatima; Bauer, Steven R.; Marti, Gerald E.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. [Degheidy, Heba A.; Marti, Gerald E.] Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Gadalla, Shahinaz M.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Farooqui, Mohammed Z. H.; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Arthur, Diane C.; Stetler-Stevenson, M. A.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Wilson, Wyndham H.] NCI, Metab Branch, Bethesda, MD 20892 USA. RP Marti, GE (reprint author), 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM gemarti@mac.com OI Bauer, Steven/0000-0003-2831-846X FU Oak Ridge Institute for Science and Education through US DOE; Oak Ridge Institute for Science and Education through US FDA; National, Heart, Lung and Blood Institute, National Institutes of Health and the National Cancer Institute FX Grant sponsor: Oak Ridge Institute for Science and Education through US DOE and US FDA (Heba Degheidy's appointment to the Research Participation Program at CBER); Intramural Research Program of the National, Heart, Lung and Blood Institute, National Institutes of Health and the National Cancer Institute. NR 39 TC 6 Z9 7 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD JUL-AUG PY 2013 VL 84B IS 4 BP 237 EP 247 DI 10.1002/cyto.b.21090 PG 11 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 168VC UT WOS:000320732900006 PM 23674504 ER PT J AU Paul, R Minniti, CP Nouraie, M Luchtman-Jones, L Campbell, A Rana, S Onyekwere, O Darbari, DS Ajayi, O Arteta, M Ensing, G Sable, C Dham, N Kato, GJ Gladwin, MT Castro, OL Gordeuk, VR AF Paul, Rabindra Minniti, Caterina P. Nouraie, Mehdi Luchtman-Jones, Lori Campbell, Andrew Rana, Sohail Onyekwere, Onyinye Darbari, Deepika S. Ajayi, Olaid Arteta, Manuel Ensing, Gregory Sable, Craig Dham, Niti Kato, Gregory J. Gladwin, Mark T. Castro, Oswaldo L. Gordeuk, Victor R. TI Clinical correlates of acute pulmonary events in children and adolescents with sickle cell disease SO EUROPEAN JOURNAL OF HAEMATOLOGY LA English DT Article DE sickle cell disease; acute chest syndrome; vaso-occlusive crisis; asthma; pain ID ACUTE CHEST SYNDROME; REGURGITANT JET VELOCITY; SOCIETY-OF-ECHOCARDIOGRAPHY; RISK-FACTORS; TASK-FORCE; HYPERTENSION; ANEMIA; ASTHMA; COMPLICATIONS; ASSOCIATION AB Objectives We aimed to identify risk factors for acute pulmonary events in children and adolescents in the Pulmonary Hypertension and the Hypoxic Response in SCD (PUSH) study. Methods Patients with hemoglobin SS (n=376) and other sickle cell genotypes (n=127) aged 3-20yrs were studied at four centers in a cross-sectional manner. A subgroup (n=293) was followed for a median of 21months (range 9-35). Results A patient-reported history of one or more acute pulmonary events, either acute chest syndrome (ACS) or pneumonia, was obtained in 195 hemoglobin SS patients (52%) and 51 patients with other genotypes (40%). By logistic regression, history of acute pulmonary events was independently associated with patient-reported history of asthma (P<0.0001), older age (P=0.001), >3 severe pain episodes in the preceding 12months (P=0.002), higher tricuspid regurgitation velocity (TRV) (P=0.028), and higher white blood cell (WBC) count (P=0.043) among hemoglobin SS patients. History of acute pulmonary events was associated with >3 severe pain episodes (P=0.009) among patients with other genotypes. During follow-up, 43 patients (15%) had at least one new ACS episode including 11 without a baseline history of acute pulmonary events. History of acute pulmonary events (odds ratio 5.0; P<0.0001) and younger age (odds ratio 0.9; P=0.007) were independently associated with developing a new episode during follow-up. Conclusions Asthma history, frequent pain, and higher values for TRV and WBC count were independently associated with history of acute pulmonary events in hemoglobin SS patients and frequent pain was associated in those with other genotypes. Measures to reduce pain episodes and control asthma may help to decrease the incidence of acute pulmonary events in SCD. C1 [Paul, Rabindra; Nouraie, Mehdi; Rana, Sohail; Onyekwere, Onyinye; Ajayi, Olaid; Castro, Oswaldo L.] Howard Univ, Washington, DC 20059 USA. [Minniti, Caterina P.; Darbari, Deepika S.; Kato, Gregory J.] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Luchtman-Jones, Lori; Darbari, Deepika S.; Sable, Craig; Dham, Niti] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Campbell, Andrew; Arteta, Manuel; Ensing, Gregory] Univ Michigan, Ann Arbor, MI 48109 USA. [Gladwin, Mark T.] Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA USA. [Gladwin, Mark T.] Univ Pittsburgh, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA USA. [Gordeuk, Victor R.] Univ Illinois, Chicago, IL 60612 USA. RP Gordeuk, VR (reprint author), Univ Illinois, Sickle Cell Ctr M C 712, Suite 172,Clin Sci Bldg,820 South Wood St, Chicago, IL 60612 USA. EM vgordeuk@uic.edu RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 FU NHLBI [2 R25 HL003679-08, 1 R01 HL079912-02]; Howard University GCRC from NCRR, NIH, Bethesda, MD [2MOI RR10284-10]; NIH [1 ZIA HL006016-03] FX Supported in part by grant nos. 2 R25 HL003679-08 and 1 R01 HL079912-02 from NHLBI, by Howard University GCRC grant no 2MOI RR10284-10 from NCRR, NIH, Bethesda, MD, and by NIH intramural funding 1 ZIA HL006016-03. NR 38 TC 6 Z9 6 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0902-4441 J9 EUR J HAEMATOL JI Eur. J. Haematol. PD JUL PY 2013 VL 91 IS 1 BP 62 EP 68 DI 10.1111/ejh.12118 PG 7 WC Hematology SC Hematology GA 168QO UT WOS:000320720800008 PM 23560516 ER PT J AU Orjuela-Sanchez, P Sa, JM Brandi, MCC Rodrigues, PT Bastos, MS Amaratunga, C Duong, S Fairhurst, RM Ferreira, MU AF Orjuela-Sanchez, Pamela Sa, Juliana M. Brandi, Michelle C. C. Rodrigues, Priscila T. Bastos, Melissa S. Amaratunga, Chanaki Duong, Socheat Fairhurst, Rick M. Ferreira, Marcelo U. TI Higher microsatellite diversity in Plasmodium vivax than in sympatric Plasmodium falciparum populations in Pursat, Western Cambodia SO EXPERIMENTAL PARASITOLOGY LA English DT Article DE Plasmodium vivax; Plasmodium falciparum; Population structure; Genetic diversity; Microsatellites ID GENETIC DIVERSITY; RURAL AMAZONIA; MALARIA; INFECTIONS; MARKERS; DYNAMICS; SAMPLES; REGION; PREVALENCE; FREQUENCY AB Previous microsatellite analyses of sympatric populations of Plasmodium vivax and Plasmodium falciparum in Brazil revealed higher diversity in the former species. However, it remains unclear whether regional species-specific differences in prevalence and transmission levels might account for these findings. Here, we examine sympatric populations of P. vivax (n = 87) and P. falciparum (n = 164) parasites from Pursat province, Western Cambodia, where both species are similarly prevalent. Using 10 genome-wide microsatellites for P. falciparum and 13 for P. vivax, we found that the P. vivax population was more diverse than the sympatric P. falciparum population (average virtual heterozygosity [H-E], 0.87 vs. 0.66, P = 0.003), with more multiple-clone infections (89.6% vs. 47.6%) and larger mean number of alleles per marker (16.2 vs. 11.1, P = 0.07). Both populations showed significant multi-locus linkage disequilibrium suggestive of a predominantly clonal mode of parasite reproduction. The higher microsatellite diversity found in P. vivax isolates, compared to sympatric P. falciparum isolates, does not necessarily result from local differences in transmission level and may reflect differences in population history between species or increased mutation rates in P. vivax. (C) 2013 Elsevier Inc. All rights reserved. C1 [Orjuela-Sanchez, Pamela; Brandi, Michelle C. C.; Rodrigues, Priscila T.; Bastos, Melissa S.; Ferreira, Marcelo U.] Univ Sao Paulo, Inst Biomed Sci, Dept Parasitol, Sao Paulo, Brazil. [Orjuela-Sanchez, Pamela] La Jolla Bioengn Inst, San Diego, CA USA. [Sa, Juliana M.; Amaratunga, Chanaki; Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Duong, Socheat] Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia. RP Ferreira, MU (reprint author), Univ Sao Paulo, Inst Biomed Sci, Dept Parasitol, Sao Paulo, Brazil. EM muferrei@usp.br RI Ferreira, Marcelo/G-8289-2011 OI Ferreira, Marcelo/0000-0002-5293-9090 FU National Institutes of Health (NIH) [RO1 AI 075416]; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [470570/2006-7]; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [07/51199-0]; National Institute of Allergy and Infectious Diseases (NIAID), NIH; CNPq; FAPESP FX This research was supported by funds from the National Institutes of Health (NIH) Grant RO1 AI 075416 to M.U.F., the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) Grant 470570/2006-7 to M.U.F. and the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) Grant 07/51199-0 to M.U.F. This study was supported in part by funds from the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), NIH, provided to R.M.F. P.O.S. and M.U.F. received scholarships from CNPq, and P.T.R. received a scholarship from FAPESP. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank the patients from Pursat province for their cooperation, and Seila Suon and Sokunthea Sreng for their collaborative efforts in Pursat. We also thank Carmen S. A. Takata, Marcio M. Yamamoto, Erika S. Phelps and Michael A. Krause for laboratory and analytical support. NR 41 TC 21 Z9 21 U1 0 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4894 J9 EXP PARASITOL JI Exp. Parasitol. PD JUL PY 2013 VL 134 IS 3 BP 318 EP 326 DI 10.1016/j.exppara.2013.03.029 PG 9 WC Parasitology SC Parasitology GA 165JX UT WOS:000320481300009 PM 23562882 ER PT J AU Egervari, K Potter, G Guzman-Hernandez, ML Salmon, P Balla, T Wehrle-Haller, B Kiss, JZ AF Egervari, K. Potter, G. Guzman-Hernandez, M. -L. Salmon, P. Balla, T. Wehrle-Haller, B. Kiss, J. Z. TI INTRACELLULAR TRAFFICKING, MATRIX ASSOCIATION AND FUNCTION OF VEGF IN ASTROGLIAL CELLS SO GLIA LA English DT Meeting Abstract CT 11th European Meeting on Glial Cell Function in Health and Disease CY JUL 03-06, 2013 CL Berlin, GERMANY C1 [Egervari, K.; Potter, G.; Salmon, P.; Wehrle-Haller, B.; Kiss, J. Z.] Univ Geneva, Geneva, Switzerland. [Guzman-Hernandez, M. -L.; Balla, T.] NICHHD, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-1491 J9 GLIA JI Glia PD JUL PY 2013 VL 61 SU 1 BP S88 EP S88 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 164KQ UT WOS:000320408400273 ER PT J AU Fields, RD AF Fields, R. D. TI REGULATION OF SCHWANN CELL DEVELOPMENT AND MYELINATION BY ACTION POTENTIALS SO GLIA LA English DT Meeting Abstract CT 11th European Meeting on Glial Cell Function in Health and Disease CY JUL 03-06, 2013 CL Berlin, GERMANY C1 [Fields, R. D.] NICHD, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-1491 J9 GLIA JI Glia PD JUL PY 2013 VL 61 SU 1 BP S47 EP S47 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 164KQ UT WOS:000320408400144 ER PT J AU Gao, H Zhou, H Hong, JS AF Gao, H. Zhou, H. Hong, J. -S. TI PATTERN RECOGNITION-RELATED INFLAMMATORY OXIDATIVE INSULT FROM MICROGLIA MEDIATES CHRONIC NEURODEGENERATION SO GLIA LA English DT Meeting Abstract CT 11th European Meeting on Glial Cell Function in Health and Disease CY JUL 03-06, 2013 CL Berlin, GERMANY C1 [Gao, H.] Nanjing Univ, Nanjing 210008, Jiangsu, Peoples R China. [Zhou, H.; Hong, J. -S.] NIEHS, NIH, Lab Toxicol & Pharmacol, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-1491 J9 GLIA JI Glia PD JUL PY 2013 VL 61 SU 1 BP S19 EP S19 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 164KQ UT WOS:000320408400041 ER PT J AU Tata, AM Uggenti, C De Stefano, ME Pisano, A Costantino, M Loreti, S Talora, C Wess, J Magnaghi, V Ricordy, R AF Tata, A. M. Uggenti, C. De Stefano, M. E. Pisano, A. Costantino, M. Loreti, S. Talora, C. Wess, J. Magnaghi, V. Ricordy, R. TI ACETYLCHOLINE AND M2 MUSCARINIC RECEPTOR CONTRIBUTE TO MODULATE SCHWANN CELL PROLIFERATION AND DIFFERENTIATION SO GLIA LA English DT Meeting Abstract CT 11th European Meeting on Glial Cell Function in Health and Disease CY JUL 03-06, 2013 CL Berlin, GERMANY C1 [Tata, A. M.; Uggenti, C.; De Stefano, M. E.; Pisano, A.; Costantino, M.; Loreti, S.; Talora, C.] Univ Roma La Sapienza, I-00185 Rome, Italy. [Wess, J.] NIDDK, NIH, Bethesda, MD 20892 USA. [Magnaghi, V.] Univ Milan, Dept Pharmacol & Biomol Sci, Milan, Italy. [Ricordy, R.] CNR, Biol & Mol Pathol 3Inst, Rome, Italy. 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 0894-1491 J9 GLIA JI Glia PD JUL PY 2013 VL 61 SU 1 BP S47 EP S48 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 164KQ UT WOS:000320408400147 ER PT J AU Zhang, CL Bao, W Rong, Y Yang, HX Bowers, K Yeung, E Kiely, M AF Zhang, Cuilin Bao, Wei Rong, Ying Yang, Huixia Bowers, Katherine Yeung, Edwina Kiely, Michele TI Genetic variants and the risk of gestational diabetes mellitus: a systematic review SO HUMAN REPRODUCTION UPDATE LA English DT Article DE gestational diabetes mellitus; single nucleotide polymorphism; gene; genetic factors ID GENOME-WIDE ASSOCIATION; BETA(3)-ADRENERGIC RECEPTOR GENE; POLYCYSTIC-OVARY-SYNDROME; INSULIN-SECRETION; TCF7L2 GENE; TRANSCRIPTION-FACTOR-7-LIKE-2 TCF7L2; TRP(64)ARG POLYMORPHISM; MEXICAN-AMERICANS; GREEK POPULATION; GLUCOKINASE GENE AB Several studies have examined associations between genetic variants and the risk of gestational diabetes mellitus (GDM). However, inferences from these studies were often hindered by limited statistical power and conflicting results. We aimed to systematically review and quantitatively summarize the association of commonly studied single nucleotide polymorphisms (SNPs) with GDM risk and to identify important gaps that remain for consideration in future studies. Genetic association studies of GDM published through 1 October 2012 were searched using the HuGE Navigator and PubMed databases. A SNP was included if the SNPGDM associations were assessed in three or more independent studies. Two reviewers independently evaluated the eligibility for inclusion and extracted the data. The allele-specific odds ratios (ORs) and 95 confidence intervals (CIs) were pooled using random effects models accounting for heterogeneity. Overall, 29 eligible articles capturing associations of 12 SNPs from 10 genes were included for the systematic review. The minor alleles of rs7903146 (TCF7L2), rs12255372 (TCF7L2), rs1799884 (30G/A, GCK), rs5219 (E23K, KCNJ11), rs7754840 (CDKAL1), rs4402960 (IGF2BP2), rs10830963 (MTNR1B), rs1387153 (MTNR1B) and rs1801278 (Gly972Arg, IRS1) were significantly associated with a higher risk of GDM. Among them, genetic variants in TCF7L2 showed the strongest association with GDM risk, with ORs (95 CIs) of 1.44 (1.291.60, P 0.001) per T allele of rs7903146 and 1.46 (1.151.84, P 0.002) per T allele of rs12255372. In this systematic review, we found significant associations of GDM risk with nine SNPs in seven genes, most of which have been related to the regulation of insulin secretion. C1 [Zhang, Cuilin; Bao, Wei; Bowers, Katherine; Yeung, Edwina; Kiely, Michele] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD 20852 USA. [Rong, Ying] Huazhong Univ Sci & Technol, Dept Nutr & Food Hyg, Hubei Key Lab Food Nutr & Safety, Sch Publ Hlth,Tongji Med Coll, Wuhan 430030, Peoples R China. [Yang, Huixia] Peking Univ, Hosp 1, Dept Obstet & Gynecol, Beijing 100034, Peoples R China. RP Zhang, CL (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 zhangcu@mail.nih.gov; wei.bao@nih.gov RI Yeung, Edwina/F-5992-2015; Bowers, Katherine/N-5226-2015; OI Yeung, Edwina/0000-0002-3851-2613; Bao, Wei/0000-0002-7301-5786 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX W.B., K.B., E.Y., M.K. and C.Z. are supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 70 TC 52 Z9 55 U1 0 U2 22 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1355-4786 EI 1460-2369 J9 HUM REPROD UPDATE JI Hum. Reprod. Update PD JUL-AUG PY 2013 VL 19 IS 4 BP 376 EP 390 DI 10.1093/humupd/dmt013 PG 15 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 165DP UT WOS:000320463500006 PM 23690305 ER PT J AU Bourbakis, N Makrogiannis, SK Dakopoulos, D AF Bourbakis, Nikolaos Makrogiannis, Sokratis K. Dakopoulos, Dimitrios TI A System-Prototype Representing 3D Space via Alternative-Sensing for Visually Impaired Navigation SO IEEE SENSORS JOURNAL LA English DT Article DE 2-D vibration arrays; alternative sensing; assistive technologies; blind's navigation; high-to-low image representation; human computer interface; motion detection ID BLIND; AID; TECHNOLOGY; WATERSHEDS AB Offering an alternative mode of interaction with the surrounding 3-D space to the visually impaired for collision free navigation is a goal of great significance that includes several key challenges. In this paper, we study the alternative 3-D space sensation that is interpreted by our computer vision prototype system and transferred to the user via a vibration array. There are two main tasks for conducting such a study. The first task is to detect obstacles in close proximity, and motion patterns in image sequences, both important issues for a safe navigation in a 3-D dynamic space. To achieve this task, the images from the left and right cameras are acquired to produce new stereo images, followed by video stabilization as a preprocessing stage, a nonlinear spatio-temporal diffusion and kernel based density estimation method to assess the motion activity, and finally watershed-based detection of moving regions (or obstacles) of interest. The second task is to efficiently represent the information of the captured static and dynamic visual scenes as 3-D detectable patterns of vibrations applied on the human body to create a 3-D sensation of the space during navigation. To accomplish this task, considering the current limitations imposed by the technology, we create a high-to-low (H-L) image resolution representation scheme to facilitate the mapping onto a low-resolution 2-D array of vibrators. The H-L scheme uses pyramidal modeling to obtain low-resolution images of interest-preserving motion and obstacles-that are mapped onto a vibration array. These patterns are utilized to train and test the performance of the users in free space navigation. Thus, in this paper we study the synergy of these two important schemes to offer an alternative sensation of the 3-D space to the visually impaired via an array of vibrators. Particularly, the motion component is employed as an element for the identification of visual information of interest to be retained during the H-L transformation. The role of the array vibrators is to create a small-scale front representation of the space via various levels of vibrations. Thus, 3-D vibrations applied on the user's body (chest, abdomen) offer a 3-D sensation of the surrounding space and the motion in it. In addition, we present experimental results that indicate the efficiency of this navigation scheme in creating low-resolution 3-D views of the free navigation space and detecting obstacles and moving areas. C1 [Bourbakis, Nikolaos; Dakopoulos, Dimitrios] Wright State Univ, Assist Technol Res Ctr, Dayton, OH 45435 USA. [Makrogiannis, Sokratis K.] NIA, NIH, Baltimore, MD 21225 USA. RP Bourbakis, N (reprint author), Wright State Univ, Assist Technol Res Ctr, Dayton, OH 45435 USA. EM nikolaos.bourbakis@wright.edu; makrogianniss@mail.nih.gov; dakopoulos.2@wright.edu FU NSF; AIIS Inc. FX Manuscript received November 5, 2012; revised January 29, 2013; accepted March 11, 2013. Date of publication March 19, 2013; date of current version May 29, 2013. This work was supported by NSF and AIIS Inc. for the Tyflos Project. The associate editor coordinating the review of this paper and approving it for publication was Prof. Subhas C. Mukhopadhyay. NR 34 TC 8 Z9 8 U1 0 U2 17 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1530-437X EI 1558-1748 J9 IEEE SENS J JI IEEE Sens. J. PD JUL PY 2013 VL 13 IS 7 BP 2535 EP 2547 DI 10.1109/JSEN.2013.2253092 PG 13 WC Engineering, Electrical & Electronic; Instruments & Instrumentation; Physics, Applied SC Engineering; Instruments & Instrumentation; Physics GA 158VF UT WOS:000320001100005 ER PT J AU Vahedi, G Kanno, Y Sartorelli, V O'Shea, JJ AF Vahedi, Golnaz Kanno, Yuka Sartorelli, Vittorio O'Shea, John J. TI Transcription factors and CD4 T cells seeking identity: masters, minions, setters and spikers SO IMMUNOLOGY LA English DT Review DE enhancers; epigenomics; master regulators; STATs; T helper cells ID ENHANCER LANDSCAPE; DIFFERENTIATION; SPECIFICATION AB Naive T cells differentiate and become distinct subsets in response to changes in the cytokine milieu. Such specialization arises through a complex and dynamic utilization of cis-regulatory enhancer elements. In this brief essay, we review recent findings on the relative contributions of sensors of the cytokine milieu, especially the signal transducer and activator of transcription family transcription factors, master regulators', and other transcription factors in the enhancer architecture of T cells. These findings provide new insights into how signal transduction impinges upon the genome. C1 [Vahedi, Golnaz; Kanno, Yuka; O'Shea, John J.] Mol Immunol & Inflammat Branch, Lymphocyte Cell Biol Sect, Bethesda, MD USA. [Sartorelli, Vittorio] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. RP Vahedi, G (reprint author), 10 Ctr Dr,Bldg 10,Room 13C103, Bethesda, MD 20892 USA. EM vahedig@mail.nih.gov; osheaj@arb.niams.nih.gov RI Kanno, Yuka/B-5802-2013; OI Kanno, Yuka/0000-0001-5668-9319 NR 17 TC 16 Z9 16 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD JUL PY 2013 VL 139 IS 3 BP 294 EP 298 DI 10.1111/imm.12113 PG 5 WC Immunology SC Immunology GA 164EU UT WOS:000320392500004 PM 23586907 ER PT J AU Kim, SH Thurm, A Shumway, S Lord, C AF Kim, So Hyun Thurm, Audrey Shumway, Stacy Lord, Catherine TI Multisite Study of New Autism Diagnostic Interview-Revised (ADI-R) Algorithms for Toddlers and Young Preschoolers SO JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS LA English DT Article DE Early diagnosis; Autism spectrum disorders; Autism diagnostic interview-revised ID SPECTRUM DISORDERS; OBSERVATION SCHEDULE; AGREEMENT; VALIDITY; CHILDREN; ADOS AB Using two independent datasets provided by National Institute of Health funded consortia, the Collaborative Programs for Excellence in Autism and Studies to Advance Autism Research and Treatment (n = 641) and the National Institute of Mental Health (n = 167), diagnostic validity and factor structure of the new Autism Diagnostic Interview (ADI-R) algorithms for toddlers and young preschoolers were examined as a replication of results with the 2011 Michigan sample (Kim and Lord in J Autism Dev Disord 42(1): 82-93, 2012). Sensitivities and specificities and a three-factor solution were replicated. Results suggest that the new ADI-R algorithms can be appropriately applied to existing research databases with children from 12 to 47 months and down to nonverbal mental ages of 10 months for diagnostic grouping. C1 [Kim, So Hyun] Yale Univ, Sch Med, Yale Child Study Ctr, New Haven, CT 06510 USA. [Thurm, Audrey; Shumway, Stacy] NIMH, Pediat & Dev Neurosci Branch, Bethesda, MD 20892 USA. [Lord, Catherine] Weill Cornell Med Coll, Ctr Autism & Developing Brain, White Plains, NY 10605 USA. RP Kim, SH (reprint author), Yale Univ, Sch Med, Yale Child Study Ctr, 40 Temple St,Suite 7-D, New Haven, CT 06510 USA. EM so-hyun.kim@yale.edu OI Manwaring, Stacy/0000-0002-0835-9398 FU Intramural NIH HHS; NIMH NIH HHS [R25MH067723, F32 MH066469, R01MH066469, R25 MH067723] NR 31 TC 13 Z9 13 U1 4 U2 29 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0162-3257 J9 J AUTISM DEV DISORD JI J. Autism Dev. Disord. PD JUL PY 2013 VL 43 IS 7 BP 1527 EP 1538 DI 10.1007/s10803-012-1696-4 PG 12 WC Psychology, Developmental SC Psychology GA 165TO UT WOS:000320507200004 PM 23114567 ER PT J AU Atsawasuwan, P Lu, X Ito, Y Chen, Y Gopinathan, G Evans, CA Kulkarni, AB Gibson, CW Luan, X Diekwisch, TGH AF Atsawasuwan, P. Lu, X. Ito, Y. Chen, Y. Gopinathan, G. Evans, C. A. Kulkarni, A. B. Gibson, C. W. Luan, X. Diekwisch, T. G. H. TI Expression and Function of Enamel-related Gene Products in Calvarial Development SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE amelogenin; ameloblastin; osteoblast; calvaria; evolution; suture ID BONE-MARROW; AMELOGENIN; CELLS; AMELOBLASTIN; PROTEIN; PROLIFERATION; OSTEOCLASTOGENESIS; DIFFERENTIATION; EVOLUTION; MICE AB Enamel-related gene products (ERPs) are detected in non-enamel tissues such as bone. We hypothesized that, if functional, ERP expression corresponds with distinct events during osteoblast differentiation and affects bone development and mineralization. In mouse calvariae and MC3T3 cells, expression profiles of enamel-related gene products (ERPs) correlated with key events in post-natal calvarial development and MC3T3 cell mineralization. Developing skulls from both Amel- and Ambn-deficient animals were approximately 15% shorter when compared with those of wild-type controls, and their sutures remained patent for a longer period of time. Analysis of Amel- and Ambn-deficient calvariae and calvarial osteoblast cultures revealed a dramatic reduction in mineralized nodules, a significant reduction in Runx2, Sp7, Ibsp, and Msx2 expression, and a reduction in Alx4 in Amel-deficient calvariae vs. an increase in Alx4 in Ambn-deficient calvariae. Analysis of these data indicates that ERP expression follows defined developmental profiles and affects osteoblast differentiation, mineralization, and calvarial bone development. We propose that, in parallel to their role in the developing enamel matrix, ERPs have retained an evolutionary conserved function related to the biomineralization of bones. C1 [Atsawasuwan, P.; Lu, X.; Ito, Y.; Gopinathan, G.; Luan, X.; Diekwisch, T. G. H.] Univ Illinois, Brodie Lab Craniofacial Genet, Chicago, IL 60612 USA. [Atsawasuwan, P.; Chen, Y.; Evans, C. A.; Luan, X.; Diekwisch, T. G. H.] Univ Illinois, Dept Orthodont, Chicago, IL 60612 USA. [Luan, X.; Diekwisch, T. G. H.] Coll Dent, UIC Dept Oral Biol, Chicago, IL USA. [Kulkarni, A. B.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Gibson, C. W.] Univ Penn, Sch Dent Med, Dept Anat & Cell Biol, Philadelphia, PA 19104 USA. RP Diekwisch, TGH (reprint author), Univ Illinois, Brodie Lab Craniofacial Genet, Chicago, IL 60612 USA. EM tomdkw@uic.edu OI Atsawasuwan, Phimon/0000-0002-2576-060X FU NIDCR [DE18057, DE19155, DE18900]; Thomas M. Graber AAOF fellowship FX This study was supported by the NIDCR (grants DE18057 and DE19155 to XL; grant DE18900 to TGHD) and by the Thomas M. Graber AAOF fellowship (to PA). The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. NR 26 TC 13 Z9 14 U1 1 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD JUL PY 2013 VL 92 IS 7 BP 622 EP 628 DI 10.1177/0022034513487906 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 164TH UT WOS:000320432100009 PM 23625374 ER PT J AU Zadeh, ES Lungu, AO Cochran, EK Brown, RJ Ghany, MG Heller, T Kleiner, DE Gorden, P AF Zadeh, Elika Safar Lungu, Andreea O. Cochran, Elaine K. Brown, Rebecca J. Ghany, Marc G. Heller, Theo Kleiner, David E. Gorden, Phillip TI The liver diseases of lipodystrophy: The long-term effect of leptin treatment SO JOURNAL OF HEPATOLOGY LA English DT Article DE Lipodystrophy; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; Leptin; Metabolic syndrome ID NONALCOHOLIC FATTY LIVER; INSULIN-RESISTANCE; METABOLIC SYNDROME; STEATOHEPATITIS; MODELS AB Background & Aims: Lipodystrophies are hypoleptinemic conditions characterized by fat loss, severe insulin resistance, hypertriglyceridemia, and ectopic fat accumulation. Non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are also features of this condition. We studied the spectrum of liver disease in lipodystrophy and the effects of leptin replacement. Methods: This was an open-label, prospective study of leptin therapy in patients with inherited and acquired lipodystrophy at the National Institutes of Health. Liver biopsies were performed at baseline (N = 50) and after leptin replacement (N = 27). NASH activity was assessed using the NASH Clinical Research Network (CRN) scoring system. Fasting blood glucose, triglyceride, hemoglobin A(1c), and liver enzymes were measured at baseline and at the time of the final liver biopsy. Results: In leptin-treated patients, 86% met criteria for NASH at baseline, while only 33% had NASH after leptin replacement for 25.8 +/- 3.7 months (mean SE, p = 0.0003). There were significant improvements in steatosis grade (reduction of mean score from 1.8 to 0.9) and ballooning injury scores (from 1.2 to 0.4), with a 44.2% reduction in mean NAFLD activity score (p <0.0001). Patients who already had fibrosis remained stable on leptin replacement. We observed significant improvement in metabolic profile, ALT and AST. In addition to NASH, four patients with acquired generalized lipodystrophy (AGL) had autoimmune hepatitis. Conclusions: The fundamental liver disease of lipodystrophy is NASH, although autoimmune hepatitis was observed in some patients with AGL. Leptin appears to be a highly effective therapy for NASH in hypoleptinemic lipodystrophic patients. Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver. C1 [Zadeh, Elika Safar; Lungu, Andreea O.; Cochran, Elaine K.; Brown, Rebecca J.; Gorden, Phillip] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Ghany, Marc G.; Heller, Theo] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Gorden, P (reprint author), NIDDK, NIH, Clin Res Ctr, Room 6-5952,10 Ctr Dr, Bethesda, MD 20892 USA. EM PhillipG@intra.niddk.nih.gov OI Kleiner, David/0000-0003-3442-4453 FU National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute FX This work was supported by the intramural research programs of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute. NR 25 TC 36 Z9 37 U1 2 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD JUL PY 2013 VL 59 IS 1 BP 131 EP 137 DI 10.1016/j.jhep.2013.02.007 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 165KF UT WOS:000320482100021 ER PT J AU Emmert, S Kraemer, KH AF Emmert, Steffen Kraemer, Kenneth H. TI Do Not Underestimate Nucleotide Excision Repair: It Predicts Not Only Melanoma Risk but Also Survival Outcome SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Editorial Material ID CUTANEOUS MELANOMA; XERODERMA-PIGMENTOSUM; POLYMORPHISMS; LIGHT AB Nucleotide excision repair (NER) removes UV-induced DNA damage and other bulky DNA lesions, thereby maintaining genomic integrity. Dr Qingyi Wei's group demonstrated over the last decade that NER fidelity and single-nucleotide polymorphisms (SNPs) in NER genes constitute melanoma risk biomarkers. In this issue, Li et al. provide evidence that SNPs in NER genes may also predict melanoma survival. C1 [Emmert, Steffen] Univ Med Ctr Gottingen, Dept Dermatol Venerol & Allergol, Gottingen, Germany. [Kraemer, Kenneth H.] NCI, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Kraemer, KH (reprint author), NCI, Dermatol Branch, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. EM kraemerk@nih.gov FU Intramural NIH HHS [Z01 BC004517-31] NR 11 TC 2 Z9 2 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JUL PY 2013 VL 133 IS 7 BP 1713 EP 1717 DI 10.1038/jid.2013.72 PG 5 WC Dermatology SC Dermatology GA 164RY UT WOS:000320428400006 PM 23760049 ER PT J AU Sengupta, A Lichti, UF Carlson, BA Cataisson, C Ryscavage, AO Mikulec, C Conrad, M Fischer, SM Hatfield, DL Yuspa, SH AF Sengupta, Aniruddha Lichti, Ulrike F. Carlson, Bradley A. Cataisson, Christophe Ryscavage, Andrew O. Mikulec, Carol Conrad, Marcus Fischer, Susan M. Hatfield, Dolph L. Yuspa, Stuart H. TI Targeted Disruption of Glutathione Peroxidase 4 in Mouse Skin Epithelial Cells Impairs Postnatal Hair Follicle Morphogenesis that Is Partially Rescued through Inhibition of COX-2 SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID THIOREDOXIN REDUCTASE; LIPID-PEROXIDATION; CHOLESTEROL HYDROPEROXIDES; CYCLOOXYGENASE-2; EXPRESSION; PHGPX; MICE; GENE; CARCINOGENESIS; SELENIUM AB Selenoproteins are essential molecules for the mammalian antioxidant network. We previously demonstrated that targeted loss of all selenoproteins in mouse epidermis disrupted skin and hair development, and caused premature death. In the current study, we targeted specific selenoproteins for epidermal deletion to determine whether similar phenotypes developed. Keratinocyte-specific knockout mice lacking either the glutathione peroxidase 4 (GPx4) or thioredoxin reductase 1 (TR1) gene were generated by cre-lox technology using K14-cre. TR1 knockout mice had a normal phenotype in resting skin, whereas GPx4 loss in the epidermis caused epidermal hyperplasia, dermal inflammatory infiltrate, dysmorphic hair follicles, and alopecia in perinatal mice. Unlike epidermal ablation of all selenoproteins, mice ablated for GPx4 recovered after 5 weeks and had a normal life span. GPx1 and TR1 were upregulated in the skin and keratinocytes of GPx4-knockout mice. GPx4 deletion reduces keratinocyte adhesion in culture and increases lipid peroxidation and cyclooxygenase-2 (COX-2) levels in cultured keratinocytes and whole skin. Feeding a COX-2 inhibitor to nursing mothers partially prevents development of the abnormal skin phenotype in knockout pups. These data link the activity of cutaneous GPx4 to the regulation of COX-2 and hair follicle morphogenesis, and provide insight into the function of individual selenoprotein activity in maintaining cutaneous homeostasis. C1 [Sengupta, Aniruddha; Carlson, Bradley A.; Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, NIH, Bethesda, MD 20892 USA. [Lichti, Ulrike F.; Cataisson, Christophe; Ryscavage, Andrew O.; Yuspa, Stuart H.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Mikulec, Carol; Fischer, Susan M.] Univ Texas MD Anderson Canc Ctr, Div Sci Pk Res, Dept Mol Carcinogenesis, Smithville, TX USA. [Conrad, Marcus] DZNE German Ctr Neurodegenerat Dis, Munich, Germany. [Conrad, Marcus] Helmholtz Ctr, Munich, Germany. [Conrad, Marcus] German Res Ctr Environm Hlth, Inst Dev Genet, Neuherberg, Germany. RP Yuspa, SH (reprint author), NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. EM yuspas@dc37a.nci.nih.gov OI Conrad, Marcus/0000-0003-1140-5612 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health; Deutsche Forschungsgemeinschaft (DFG) [CO 291/2-3]; DFG-Priority Program [SPP1087] FX We thank Histoserv, Germantown, MD, for preparation of tissue sections, and members of the Pathology/Histotechnology Laboratory, Center for Cancer Research, NCI, Frederick, MD, for their help with immunohistochemical analysis. The help from Raghunath Chatterjee and Petra Tsuji, NCI, NIH, with the Ingenuity Pathway Analysis is also acknowledged. This research was supported by the Intramural Research Program at the Center for Cancer Research, National Cancer Institute, National Institutes of Health (to DLH and SHY), and by the Deutsche Forschungsgemeinschaft (DFG) CO 291/2-3 and the DFG-Priority Program SPP1087 (MC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 11 Z9 11 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JUL PY 2013 VL 133 IS 7 BP 1731 EP 1741 DI 10.1038/jid.2013.52 PG 11 WC Dermatology SC Dermatology GA 164RY UT WOS:000320428400010 PM 23364477 ER PT J AU Perdivara, I Perera, L Sricholpech, M Terajima, M Pleshko, N Yamauchi, M Tomer, KB AF Perdivara, Irina Perera, Lalith Sricholpech, Marnisa Terajima, Masahiko Pleshko, Nancy Yamauchi, Mitsuo Tomer, Kenneth B. TI Unusual Fragmentation Pathways in Collagen Glycopeptides SO JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY LA English DT Article DE Collagen; Glycopeptide; Hydroxyproline; Galactosylhydroxylysine; Tandem mass spectrometry; Fragmentation pathway; Mobile proton ID TANDEM MASS-SPECTROMETRY; O-GLYCOSYLATION SITES; TRIPLE-HELICAL DOMAIN; SEQUENCE-ANALYSIS; CROSS-LINKING; I COLLAGEN; GELATINASE-B; AMINO-ACID; PEPTIDE; DISSOCIATION AB Collagens are the most abundant glycoproteins in the body. One characteristic of this protein family is that the amino acid sequence consists of repeats of three amino acids -(X-Y-Gly)(n). Within this motif, the Y residue is often 4-hydroxyproline (HyP) or 5-hydroxylysine (HyK). Glycosylation in collagen occurs at the 5-OH group in HyK in the form of two glycosides, galactosylhydroxylysine (Gal-HyK) and glucosyl galactosylhydroxylysine (GlcGal-HyK). In collision induced dissociation (CID), collagen tryptic glycopeptides exhibit unexpected gas-phase dissociation behavior compared to typical N- and O-linked glycopeptides (i.e., in addition to glycosidic bond cleavages, extensive cleavages of the amide bonds are observed). The Gal- or GlcGal- glycan modifications are largely retained on the fragment ions. These features enable unambiguous determination of the amino acid sequence of collagen glycopeptides and the location of the glycosylation site. This dissociation pattern was consistent for all analyzed collagen glycopeptides, regardless of their length or amino acid composition, collagen type or tissue. The two fragmentation pathways-amide bond and glycosidic bond cleavage-are highly competitive in collagen tryptic glycopeptides. The number of ionizing protons relative to the number of basic sites (i.e., Arg, Lys, HyK, and N-terminus) is a major driving force of the fragmentation. We present here our experimental results and employ quantum mechanics calculations to understand the factors enhancing the labile character of the amide bonds and the stability of hydroxylysine glycosides in gas phase dissociation of collagen glycopeptides. C1 [Perdivara, Irina; Tomer, Kenneth B.] NIEHS, Mass Spectrometry Grp, NIH, Res Triangle Pk, NC 27709 USA. [Perera, Lalith] NIEHS, Computat Chem Grp, NIH, Res Triangle Pk, NC 27709 USA. [Sricholpech, Marnisa] Srinakharinwirot Univ, Fac Dent, Bangkok, Thailand. [Terajima, Masahiko; Yamauchi, Mitsuo] Univ N Carolina, Sch Dent, Chapel Hill, NC USA. [Pleshko, Nancy] Temple Univ, Dept Bioengn, Philadelphia, PA 19122 USA. RP Perdivara, I (reprint author), NIEHS, Mass Spectrometry Grp, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM perdivarai@niehs.nih.gov; tomer@niehs.nih.gov OI Sricholpech, Marnisa/0000-0003-2139-0688 FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [ES050171, ES043010]; NIH [AR060978, R01 AR056145] FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (ES050171 to K. B. T. and ES043010 to L. P.), and by the NIH grants AR060978 (M.Y.) and R01 AR056145 (N.P.). The authors acknowledge Dr. Joshua Sharp (CCRC, Athens, GA) and Dr. Lee Pedersen (NIEHS/NIH) for the critical review of the manuscript, and the NIEHS Protein Microcharacterization Core Facility for the assistance with the in-gel digests. NR 51 TC 8 Z9 9 U1 3 U2 38 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1044-0305 J9 J AM SOC MASS SPECTR JI J. Am. Soc. Mass Spectrom. PD JUL PY 2013 VL 24 IS 7 BP 1072 EP 1081 DI 10.1007/s13361-013-0624-y PG 10 WC Biochemical Research Methods; Chemistry, Analytical; Chemistry, Physical; Spectroscopy SC Biochemistry & Molecular Biology; Chemistry; Spectroscopy GA 162RW UT WOS:000320284000013 PM 23633013 ER PT J AU Fair, C Wiener, L Zadeh, S Albright, J Mellins, CA Mancilla, M Tepper, V Trexler, C Purdy, J Osherow, J Lovelace, S Kapetanovic, S AF Fair, Cynthia Wiener, Lori Zadeh, Sima Albright, Jamie Mellins, Claude Ann Mancilla, Michael Tepper, Vicki Trexler, Connie Purdy, Julia Osherow, Janet Lovelace, Susan Kapetanovic, Suad TI Reproductive Health Decision-Making in Perinatally HIV-Infected Adolescents and Young Adults SO MATERNAL AND CHILD HEALTH JOURNAL LA English DT Article DE HIV and reproductive health; Perinatal HIV; HIV-infected youth; Adolescent reproductive health ID HUMAN-IMMUNODEFICIENCY-VIRUS; CENTRAL-NERVOUS-SYSTEM; ANTIRETROVIRAL THERAPY; FERTILITY DESIRES; POSITIVE WOMEN; NEURODEVELOPMENTAL OUTCOMES; MEDICATION ADHERENCE; VASCULAR DYSFUNCTION; PREGNANT-WOMEN; CHILDREN AB With widespread access to antiretroviral therapy in the United States, many perinatally HIV-infected (PHIV+) children are surviving into adolescence and adulthood, becoming sexually active and making decisions about their reproductive health. The literature focusing on the reproductive decisions of individuals behaviorally infected with HIV can serve as a springboard for understanding the decision-making process of PHIV+ youth. Yet, there are many differences that critically distinguish reproductive health and related decision-making of PHIV+ youth. Given the potential public health implications of their reproductive decisions, better understanding of factors influencing the decision-making process is needed to help inform the development of salient treatment and prevention interventions. To begin addressing this understudied area, a "think tank" session, comprised of clinicians, medical providers, and researchers with expertise in the area of adolescent HIV, was held in Bethesda, MD, on September 21, 2011. The focus was to explore what is known about factors that influence the reproductive decision-making of PHIV+ adolescents and young adults, determine what important data are needed in order to develop appropriate intervention for PHIV+ youth having children, and to recommend future directions for the field in terms of designing and carrying out collaborative studies. In this report, we summarize the findings from this meeting. The paper is organized around the key themes that emerged, including utilizing a developmental perspective to create an operational definition of reproductive decision-making, integration of psychosocial services with medical management, and how to design future research studies. Case examples are presented and model program components proposed. C1 [Fair, Cynthia; Albright, Jamie] Elon Univ, Elon, NC 27244 USA. [Wiener, Lori] NCI, Ctr Canc Res, Pediat Clin SE 1, Bethesda, MD 20892 USA. [Zadeh, Sima] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Mellins, Claude Ann] Columbia Univ, HIV Ctr Clin & Behav Studies, Dept Psychiat, New York, NY 10032 USA. [Mellins, Claude Ann] Columbia Univ, HIV Ctr Clin & Behav Studies, Dept Sociomed Sci, New York, NY 10032 USA. [Mellins, Claude Ann] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Mancilla, Michael] Childrens Natl Med Ctr, Burgess SIS Clin, Washington, DC 20010 USA. [Tepper, Vicki] Univ Maryland, Sch Med, Pediat AIDS Program, Baltimore, MD 21201 USA. [Trexler, Connie] Childrens Natl Med Ctr, Burgess Clin, Washington, DC 20010 USA. [Purdy, Julia] NIH, Ctr Clin, CCMD, Bethesda, MD 20892 USA. [Osherow, Janet] Georgetown Univ Hosp, Pediat Infect Dis Dept, PHC, Washington, DC 20007 USA. [Lovelace, Susan] Univ Maryland, Baltimore, MD 21201 USA. [Kapetanovic, Suad] NIMH, Div Intramural Res Programs, NIH, Bethesda, MD 20892 USA. RP Fair, C (reprint author), Elon Univ, CB 2338, Elon, NC 27244 USA. EM cfair@elon.edu; wienerl@mail.nih.gov; zadehsl@Mail.nih.gov; jalbright6@elon.edu; cmellins@gmail.com; MMancill@cnmc.org; vtepper@peds.umaryland.edu; ctrexler@childrensnational.org; purdyj@cc.nih.gov; JXO10@gunet.georgetown.edu; slovelac@peds.umaryland.edu; suad.kapetanovic@nih.gov FU Intramural NIH HHS; NIMH NIH HHS [R01 MH069133] NR 105 TC 10 Z9 10 U1 2 U2 8 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1092-7875 J9 MATERN CHILD HLTH J JI Matern. Child Health J. PD JUL PY 2013 VL 17 IS 5 BP 797 EP 808 DI 10.1007/s10995-012-1070-3 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 163FK UT WOS:000320321100004 PM 22736033 ER PT J AU El-Mohandes, AAE Windsor, R Tan, S Perry, DC Gantz, MG Kiely, M AF El-Mohandes, Ayman A. E. Windsor, Richard Tan, Sylvia Perry, David C. Gantz, Marie G. Kiely, Michele TI A Randomized Clinical Trial of Trans-Dermal Nicotine Replacement in Pregnant African-American Smokers SO MATERNAL AND CHILD HEALTH JOURNAL LA English DT Article DE Pregnancy; African-Americans; Smoking; Nicotine replacement therapy ID SMOKING-CESSATION; BIRTH-WEIGHT; THERAPY AB We compared acceptability, adherence and efficacy of trans-dermal nicotine patches and cognitive behavioral therapy (Group 1) to cognitive behavioral therapy alone (Group 2) in minority pregnant smokers. This is a randomized controlled trial. 52 women were recruited during pregnancy with a mean gestational age 18.5 +/- A 5.0 weeks and followed through delivery. Randomization was by site and initial cotinine levels. Interventionists and interviewers were blinded to group assignment. Two different nicotine replacement therapy dosing regiments were administered according to the baseline salivary cotinine level. A process evaluation model summarized patient adherence. The main outcome measure was self-report of cessation since last visit, confirmed by exhaled carbon monoxide. Analyses of categorical and continuous measures were conducted as well as linear trend tests of salivary cotinine levels. Women lost to follow-up were considered treatment failures. Participants were on average 27.5 +/- A 5.4 years old, 81 % were single, 69 % unemployed and 96 % were Medicaid eligible. A process evaluation indicated patients in both groups were adherent to scheduled program procedures through Visit 4, but not for Visits 5 and 6. Confirmed quit rates were: at visit 3, 23 (Group 1) and 0 % (Group 2) (p = 0.02); at visits 4 and 5, no difference; at visit 6, 19 (Group 1) and 0 % (Group 2) (p = 0.05). Group 1 delivered infants with a mean gestational age of 39.4 weeks versus 38.4 weeks in Group 2 (p = 0.02). 73 % (52/71) of the eligible smokers agreed to participate and 65 % (17/26) of Group 1 completed the protocol (i.e. attended 6 visits). A comparison of Group 1 and 2 quit rates confirmed a non-significant difference. C1 [El-Mohandes, Ayman A. E.] Univ Nebraska Med Ctr, Coll Publ Hlth, Omaha, NE USA. [Windsor, Richard] George Washington Univ, Sch Publ Hlth, Washington, DC USA. [Tan, Sylvia; Gantz, Marie G.] RTI Int, Rockville, MD USA. [Perry, David C.] George Washington Univ, Dept Physiol & Pharmacol, Washington, DC USA. [Kiely, Michele] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD 20852 USA. RP Kiely, M (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, 6100 Execut Blvd,Rm 7B-05, Rockville, MD 20852 USA. EM kielym@nih.gov FU Intramural NIH HHS; NICHD NIH HHS [U10 HD036104, U18 HD031206, U18 HD031206-07] NR 27 TC 4 Z9 4 U1 2 U2 8 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1092-7875 J9 MATERN CHILD HLTH J JI Matern. Child Health J. PD JUL PY 2013 VL 17 IS 5 BP 897 EP 906 DI 10.1007/s10995-012-1069-9 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 163FK UT WOS:000320321100014 PM 22761006 ER PT J AU Scharf, M Neef, S Freund, R Geers-Knorr, C Franz-Wachtel, M Brandis, A Krone, D Schneider, H Groos, S Menon, MB Chang, KC Kraft, T Meissner, JD Boheler, KR Maier, LS Gaestel, M Scheibe, RJ AF Scharf, Madeleine Neef, Stefan Freund, Robert Geers-Knoerr, Cornelia Franz-Wachtel, Mirita Brandis, Almuth Krone, Dorothee Schneider, Heike Groos, Stephanie Menon, Manoj B. Chang, Kin-Chow Kraft, Theresia Meissner, Joachim D. Boheler, Kenneth R. Maier, Lars S. Gaestel, Matthias Scheibe, Renate J. TI Mitogen-Activated Protein Kinase-Activated Protein Kinases 2 and 3 Regulate SERCA2a Expression and Fiber Type Composition To Modulate Skeletal Muscle and Cardiomyocyte SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID GENE-EXPRESSION; RETICULUM CA2+-ATPASE; TWITCH MUSCLE; HEART-FAILURE; SLOW-TWITCH; P38 MAPK; TRANSCRIPTIONAL COACTIVATOR; METABOLIC ADAPTATION; GAMMA COACTIVATOR-1; SIGNAL-TRANSDUCTION AB The mitogen-activated protein kinase (MAPK)-activated protein kinases 2 and 3 (MK2/3) represent protein kinases downstream of the p38 MAPK. Using MK2/3 double-knockout (MK2/3(-/-)) mice, we analyzed the role of MK2/3 in cross-striated muscle by transcriptome and proteome analyses and by histology. We demonstrated enhanced expression of the slow oxidative skeletal muscle myofiber gene program, including the peroxisome proliferator-activated receptor gamma (PPAR gamma) coactivator 1 alpha (PGC-1 alpha). Using reporter gene and electrophoretic gel mobility shift assays, we demonstrated that MK2 catalytic activity directly regulated the promoters of the fast fiber-specific myosin heavy-chain IId/x and the slow fiber-specific sarco/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2) gene. Elevated SERCA2a gene expression caused by a decreased ratio of transcription factor Egr-1 to Sp1 was associated with accelerated relaxation and enhanced contractility in MK2/3(-/-) cardiomyocytes, concomitant with improved force parameters in MK2/3(-/-) soleus muscle. These results link MK2/3 to the regulation of calcium dynamics and identify enzymatic activity of MK2/3 as a critical factor for modulating cross-striated muscle function by generating a unique muscle phenotype exhibiting both reduced fatigability and enhanced force in MK2/3(-/-) mice. Hence, the p38-MK2/3 axis may represent a novel target for the design of therapeutic strategies for diseases related to fiber type changes or impaired SERCA2 function. C1 [Scharf, Madeleine; Freund, Robert; Krone, Dorothee; Schneider, Heike; Menon, Manoj B.; Gaestel, Matthias; Scheibe, Renate J.] Hannover Med Sch, Dept Biochem, Hannover, Germany. [Neef, Stefan; Maier, Lars S.] Univ Gottingen, Dept Cardiol & Pneumol, D-37073 Gottingen, Germany. [Geers-Knoerr, Cornelia; Kraft, Theresia] Hannover Med Sch, Dept Mol & Cellular Physiol, Hannover, Germany. [Franz-Wachtel, Mirita] Univ Tubingen, Proteome Ctr Tubingen, Interfac Inst Cell Biol, Tubingen, Germany. [Brandis, Almuth] Hannover Med Sch, Dept Pathol, Hannover, Germany. [Groos, Stephanie] Hannover Med Sch, Inst Cell Biol, Ctr Anat, Hannover, Germany. [Chang, Kin-Chow] Univ Nottingham, Sch Vet Med & Sci, Loughborough, England. [Meissner, Joachim D.] Hannover Med Sch, Dept Vegetat Physiol, Hannover, Germany. [Boheler, Kenneth R.] NIA, Mol Cardiol & Stem Cell Unit, NIH, Baltimore, MD 21224 USA. [Boheler, Kenneth R.] Univ Hong Kong, Li Ka Shing Fac Med, Stem Cell & Regenerat Med Consortium, Hong Kong, Hong Kong, Peoples R China. RP Scheibe, RJ (reprint author), Hannover Med Sch, Dept Biochem, Hannover, Germany. EM scheibe.renate@mh-hannover.de RI Menon, Manoj/P-1543-2015 OI Menon, Manoj/0000-0001-5859-0347 FU Deutsche Forschungsgemeinschaft [SCHE 309/5-1] FX This work was supported by the Deutsche Forschungsgemeinschaft (SCHE 309/5-1). NR 83 TC 15 Z9 15 U1 3 U2 9 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 JUL PY 2013 VL 33 IS 13 BP 2586 EP 2602 DI 10.1128/MCB.01692-12 PG 17 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 159FN UT WOS:000320030900007 PM 23608535 ER PT J AU Kondilis-Mangum, HD Wade, PA AF Kondilis-Mangum, Hrisavgi D. Wade, Paul A. TI Epigenetics and the adaptive immune response SO MOLECULAR ASPECTS OF MEDICINE LA English DT Review DE T cells; B cells; Adaptive immunity; Memory; Secondary immune response; Epigenetics; Histone modifications; DNA methylation; DNA methyltransferase ID T-CELL DEVELOPMENT; BETA ALLELIC EXCLUSION; HEAVY-CHAIN GENE; DNA METHYLTRANSFERASE 1; IFN-GAMMA PROMOTER; V(D)J RECOMBINATION; CHROMATIN-STRUCTURE; HISTONE H3; CYTIDINE DEAMINASE; B-LYMPHOCYTES AB Cells of the adaptive immune response undergo dynamic epigenetic changes as they develop and respond to immune challenge. Plasticity is a necessary prerequisite for the chromosomal dynamics of lineage specification, development, and the immune effector function of the mature cell types. The alterations in DNA methylation and histone modification that characterize activation may be integral to the generation of immunologic memory, thereby providing an advantage on secondary exposure to pathogens. While the immune system benefits from the dynamic nature of the epigenome, such benefit comes at a cost - increased likelihood of disease-causing mutation. Published by Elsevier Ltd. C1 [Kondilis-Mangum, Hrisavgi D.; Wade, Paul A.] NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Wade, PA (reprint author), NIEHS, Mol Carcinogenesis Lab, 111 TW Alexander Dr MD D4-04, Res Triangle Pk, NC 27709 USA. EM wadep2@niehs.nih.gov FU Intramural Research Program of the National Institute of Environmental Health Sciences, NIH [ES101965] FX This work was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH (ES101965 to P.A.W.). We thank the members of the Wade laboratory for useful discussions throughout the course of preparation of this manuscript. We apologize to our many colleagues whose work could not be cited here due to space constraints. NR 102 TC 13 Z9 13 U1 5 U2 30 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0098-2997 J9 MOL ASPECTS MED JI Mol. Asp. Med. PD JUL-AUG PY 2013 VL 34 IS 4 SI SI BP 813 EP 825 DI 10.1016/j.mam.2012.06.008 PG 13 WC Biochemistry & Molecular Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Research & Experimental Medicine GA 165KI UT WOS:000320482400004 PM 22789989 ER PT J AU Liao, XH Buggey, J Lee, YK Kimmel, AR AF Liao, Xin-Hua Buggey, Jonathan Lee, Yun Kyung Kimmel, Alan R. TI Chemoattractant stimulation of TORC2 is regulated by receptor/G protein-targeted inhibitory mechanisms that function upstream and independently of an essential GEF/Ras activation pathway in Dictyostelium SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID DIRECTIONAL CELL-MOVEMENT; HETEROTRIMERIC G-PROTEINS; MEDIATED CGMP RESPONSE; ADENYLYL-CYCLASE; LEADING-EDGE; SPATIOTEMPORAL REGULATION; EUKARYOTIC CHEMOTAXIS; RAS ACTIVATION; DISCOIDEUM; CAMP AB Global stimulation of Dictyostelium with different chemoattractants elicits multiple transient signaling responses, including synthesis of cAMP and cGMP, actin polymerization, activation of kinases ERK2, TORC2, and phosphatidylinositide 3-kinase, and Ras-GTP accumulation. Mechanisms that down-regulate these responses are poorly understood. Here we examine transient activation of TORC2 in response to chemically distinct chemoattractants, cAMP and folate, and suggest that TORC2 is regulated by adaptive, desensitizing responses to stimulatory ligands that are independent of downstream, feedback, or feedforward circuits. Cells with acquired insensitivity to either folate or cAMP remain fully responsive to TORC2 activation if stimulated with the other ligand. Thus TORC2 responses to cAMP or folate are not cross-inhibitory. Using a series of signaling mutants, we show that folate and cAMP activate TORC2 through an identical GEF/Ras pathway but separate receptors and G protein couplings. Because the common GEF/Ras pathway also remains fully responsive to one chemoattractant after desensitization to the other, GEF/Ras must act downstream and independent of adaptation to persistent ligand stimulation. When initial chemoattractant concentrations are immediately diluted, cells rapidly regain full responsiveness. We suggest that ligand adaptation functions in upstream inhibitory pathways that involve chemoattractant-specific receptor/G protein complexes and regulate multiple response pathways. C1 [Liao, Xin-Hua; Buggey, Jonathan; Lee, Yun Kyung; Kimmel, Alan R.] NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Kimmel, AR (reprint author), NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. EM alank@helix.nih.gov FU Intramural Research Program of the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases FX We thank dictyBase (Fey et al., 2009) and colleagues for various strains. We thank Leung Kim, Pascale Charest, Rick Firtel, and Shi Shu for providing the Ras-related reagents. This research was supported by the Intramural Research Program of the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases. NR 51 TC 3 Z9 4 U1 1 U2 1 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JUL 1 PY 2013 VL 24 IS 13 BP 2146 EP 2155 DI 10.1091/mbc.E13-03-0130 PG 10 WC Cell Biology SC Cell Biology GA 175AP UT WOS:000321201800008 PM 23657816 ER PT J AU Moon, K Six, DA Lee, HJ Raetz, CRH Gottesman, S AF Moon, Kyung Six, David A. Lee, Hyun-Jung Raetz, Christian R. H. Gottesman, Susan TI Complex transcriptional and post-transcriptional regulation of an enzyme for lipopolysaccharide modification SO MOLECULAR MICROBIOLOGY LA English DT Article ID ESCHERICHIA-COLI LIPOPOLYSACCHARIDE; SMALL RNA; SALMONELLA-ENTERICA; ENVELOPE-STRESS; OUTER-MEMBRANE; SIGMA-FACTOR; LIPID-A; SYSTEM; PHOSPHORYLATION; CHROMOSOME AB The PhoQ/PhoP two-component system activates many genes for lipopolysaccharide (LPS) modification when cells are grown at low Mg2+ concentrations. An additional target of PhoQ and PhoP is MgrR, an Hfq-dependent small RNA that negatively regulates expression of eptB, also encoding a protein that carries out LPS modification. Examination of LPS confirmed that MgrR effectively silences EptB; the phosphoethanolamine modification associated with EptB is found in mgrR::kan but not mgrR+ cells. Sigma E has been reported to positively regulate eptB, although the eptB promoter does not have the expected Sigma E recognition motifs. The effects of Sigma E and deletion of mgrR on levels of eptB mRNA were independent, and the same 5 end was found in both cases. In vitro transcription and the behaviour of transcriptional and translational fusions demonstrate that Sigma E acts directly at the level of transcription initiation for eptB, from the same start point as Sigma 70. The results suggest that when Sigma E is active, synthesis of eptB transcript outstrips MgrR-dependent degradation; presumably the modification of LPS is important under these conditions. Adding to the complexity of eptB regulation is a second sRNA, ArcZ, which also directly and negatively regulates eptB. C1 [Moon, Kyung; Lee, Hyun-Jung; Gottesman, Susan] NCI, Mol Biol Lab, Bethesda, MD 20892 USA. [Six, David A.; Raetz, Christian R. H.] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. RP Gottesman, S (reprint author), NCI, Mol Biol Lab, Bldg 37, Bethesda, MD 20892 USA. EM Gottesms@helix.nih.gov RI Six, David/D-6523-2011 OI Six, David/0000-0002-9013-1711 FU NIH, National Cancer Institute, Center for Cancer Research; NIH [GM-51310]; LIPID MAPS Large Scale Collaborative from NIH [GM-069338] FX We thank V. Rhodius for his thoughts on the eptB promoter, Dale Lewis for help with the in vitro transcription experiments, H. Nikaido for discussions, and K. Potrykus and M. Cashel for providing Sigma E protein. We thank M. S. Trent, D. Schu, S. Tong, N. De Lay and K. Ramamurthi for advice and comments on this article. This work was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and by NIH Grant GM-51310 to C.R.H.R. The mass spectrometry facility in the Department of Biochemistry of the Duke University Medical Center is supported by the LIPID MAPS Large Scale Collaborative Grant number GM-069338 from NIH. D.A.S. and S.G. dedicate this article to the memory of co-author Christian R. H. Raetz, whose deep knowledge and interest played a key role in bringing this work to fruition. NR 37 TC 14 Z9 16 U1 3 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD JUL PY 2013 VL 89 IS 1 BP 52 EP 64 DI 10.1111/mmi.12257 PG 13 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 168TN UT WOS:000320728800004 PM 23659637 ER PT J AU Penet, MF Artemov, D Farahani, K Bhujwalla, ZM AF Penet, Marie-France Artemov, Dmitri Farahani, Keyvan Bhujwalla, Zaver M. TI MR - eyes for cancer: looking within an impenetrable disease SO NMR IN BIOMEDICINE LA English DT Article DE MR probes; cancer; tumor microenvironment; receptors imaging; theranostics ID MAGNETIC-RESONANCE-SPECTROSCOPY; LYMPH-NODE METASTASES; SUPERPARAMAGNETIC IRON-OXIDE; TUMOR-ASSOCIATED MACROPHAGES; HUMAN BREAST-CANCER; IN-VIVO; EXTRACELLULAR PH; NONINVASIVE DETECTION; NMR-SPECTROSCOPY; PROSTATE-CANCER AB Probe development is a critical component in cancer imaging, and novel probes are making major inroads in several aspects of cancer detection and image-guided treatments. Intrinsic MR probes such as signals from metabolites and their chemical shifts have been used for more than a decade to understand cancer physiology and metabolism. Through the integration of technology, molecular biology, and chemistry, the last few years have witnessed an explosion of extrinsic probes for molecular and functional imaging of cancer that, together with techniques such as CEST and hyperpolarization, have significantly expanded the repertoire of MR techniques in basic and translational investigations of many different aspects of cancer. Furthermore, incorporation of MR probes into multifunctional nanoparticles and multimodality imaging platforms have opened new opportunities for MR in image-guided diagnosis and therapy of cancer. Here we have provided an overview of recent innovations that have occurred in the development of MRI probes for molecular and functional imaging of cancer. Although most of these novel probes are not clinically available, they offer significant promise for future translational applications. In this review, we have highlighted the areas of future development that are likely to have a profound impact on cancer detection and treatment. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Penet, Marie-France; Artemov, Dmitri; Bhujwalla, Zaver M.] Johns Hopkins Univ, Russell H Morgan Dept Radiol & Radiol Sci, Sch Med, JHU ICMIC Program,Div Canc Imaging Res, Baltimore, MD 21218 USA. [Artemov, Dmitri; Bhujwalla, Zaver M.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Sch Med, Baltimore, MD USA. [Farahani, Keyvan] NCI, Image Guided Intervent Branch, Canc Imaging Program, Bethesda, MD 20892 USA. RP Bhujwalla, ZM (reprint author), Johns Hopkins Univ, Russell H Morgan Dept Radiol & Radiol Sci, Sch Med, JHU ICMIC Program,Div Canc Imaging Res, Baltimore, MD 21218 USA. EM zaver@mri.jhu.edu FU NIH [P50 CA103175, P30 CA006973, R01 CA73850, R01 CA82337, R01 CA136576, R01 CA138515, R01 CA138264]; Honorable Tina Brozman Foundation FX Support from NIH P50 CA103175, P30 CA006973, R01 CA73850, R01 CA82337, R01 CA136576, R01 CA138515, R01 CA138264 and the Honorable Tina Brozman Foundation (MFP) is gratefully acknowledged. NR 86 TC 5 Z9 5 U1 1 U2 24 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3480 J9 NMR BIOMED JI NMR Biomed. PD JUL PY 2013 VL 26 IS 7 SI SI BP 745 EP 755 DI 10.1002/nbm.2980 PG 11 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 168UC UT WOS:000320730300004 PM 23784955 ER PT J AU Baidoo, KE Milenic, DE Brechbiel, MW AF Baidoo, Kwamena E. Milenic, Diane E. Brechbiel, Martin W. TI Methodology for labeling proteins and peptides with lead-212 (Pb-212) SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE Radioimmunotherapy; Alpha targeted therapy; Lead-212; Trastuzumab; Cancer therapy ID DISSEMINATED PERITONEAL DISEASE; ALPHA-PARTICLE RADIOIMMUNOTHERAPY; DNA-DAMAGE REPAIR; CANCER-THERAPY; MONOCLONAL-ANTIBODY; GASTRIC-CANCER; TARGETING HER2; IN-VIVO; TUMOR; RADIATION AB Introduction: Alpha particles possess an exquisite degree of cytotoxicity when employed for targeted alpha-particle therapy (TAT) or radioimmunotherapy (RIT). Pb-212, which acts as an in vivo generator of the alpha-emitting nuclide Bi-212 has shown great promise in pre-clinical studies when used to label the HER2 binding antibody, trastuzumab. Currently, the first RIT clinical trial employing Pb-212 radiolabeled trastuzumab is in progress. This report provides detailed current protocol operations and steps that were generated for use in the clinical trial as well as the relevant pre-clinical experimentation, and describes in detail the labeling of proteins or peptides with Pb-212 as provided via a Ra-224 based generator system. Methods: Pb-212 was eluted from the Ra-224/Pb-212 generator using hydrochloric acid (2 M). The generator eluate was evaporated and digested with nitric acid (8 M) followed by extraction of the Pb-212 with dilute nitric acid (0.1 M). The dilute nitric acid solution of Pb-212 was used to label the immunoconjugate Trastuzumab-TCMC (2-(4-isothiocyanatobenzyl-1,4,7,10-tetraaza-1,4,7,10,tetra-(2-carbamonylmethyl)-cyclododecane) at pH 5.5. Results: Elution of Pb-212 from the generator was efficient yielding>90% of available Pb-212. Trastuzumab-TCMC was efficiently labeled with a radiochemical yield of 94% +/- 4% (n = 7) by ITLC and an isolated yield of 73% +/- 3% (n = 7). Conclusions: The results show the feasibility of generating radioimmunoconjugates and peptide conjugates for use as in vivo alpha generator systems in the clinic. The technology holds promise in applications involving the treatment of minimal disease such as micrometastases and residual tumor after surgical debulking, hematological cancers, infections, and compartmental cancers, such as ovarian cancer. Published by Elsevier Inc. C1 [Baidoo, Kwamena E.; Milenic, Diane E.; Brechbiel, Martin W.] NCI, NIH, Radiat Oncol Branch, Radioimmune & Inorgan Chem Sect, Bethesda, MD 20892 USA. RP Baidoo, KE (reprint author), NCI, NIH, Radiat Oncol Branch, Radioimmune & Inorgan Chem Sect, Bethesda, MD 20892 USA. EM baidook@mail.nih.gov FU 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 41 TC 8 Z9 8 U1 0 U2 25 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD JUL PY 2013 VL 40 IS 5 BP 592 EP 599 DI 10.1016/j.nucmedbio.2013.01.010 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 161TS UT WOS:000320216800002 PM 23602604 ER PT J AU Kang, CS Song, HA Milenic, DE Baidoo, KE Brechbiel, MW Chong, HS AF Kang, Chi Soo Song, Hyun A. Milenic, Diane E. Baidoo, Kwamena E. Brechbiel, Martin W. Chong, Hyun-Soon TI Preclinical evaluation of NETA-based bifunctional ligand for radioimmunotherapy applications using Bi-212 and Bi-213: Radiolabeling, serum stability, and biodistribution and tumor uptake studies SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE Bi-212; Bi-213; Bifunctional chelator; Serum stability, biodistribution; Radiolabeling ID IN-VIVO EVALUATION; MONOCLONAL-ANTIBODY; LEUKEMIA; THERAPY; CANCER; LU-177; ACID AB Introduction: Despite the great potential of targeted alpha-radioimmunotherapy (RIT) as demonstrated by preclinical and clinical trials, limited progress has been made on the improvement of chelation chemistry for Bi-212 and Bi-213. A new bifunctional ligand 3p-C-NETA was evaluated for targeted alpha RIT using Bi-212 and Bi-213. Methods: Radiolabeling of 3p-C-NETA with Bi-205/6, a surrogate of Bi-212 and Bi-213, was evaluated at pH 5.5 and room temperature. In vitro stability of the Bi-205/6-3p-C-NETA-trastuzumab conjugate was evaluated using human serum (pH 7, 37 degrees C). Immunoreactivity and specific activity of the Bi-205/6-3p-C-NETA-trastuzumab conjugate were measured. An in vivo biodistribution study was performed to evaluate the in vivo stability and tumor targeting properties of the Bi-205/6-3p-C-NETA-trastuzumab conjugate in athymic mice bearing subcutaneous LS174T tumor xenografts. Result: The 3p-C-NETA-trastuzumab conjugate was extremely rapid in complexing with Bi-205/6, and the corresponding Bi-205/6-3p-C-NETA-trastuzumab was stable in human serum. Bi-205/6-3p-C-NETA-trastuzumab was prepared with a high specific activity and retained immunoreactivity. Bi-205/6-3p-C-NETA-trastuzumab conjugate displayed excellent in vivo stability and targeting as evidenced by low normal organ and high tumor uptake. Conclusion: The results of the in vitro and in vivo studies indicate that 3p-C-NETA is a promising chelator for RIT applications using Bi-212 and Bi-213. Further detailed in vivo evaluations of 3p-C-NETA for targeted alpha RIT are warranted. (C) 2013 Elsevier Inc. All rights reserved. C1 [Kang, Chi Soo; Song, Hyun A.; Chong, Hyun-Soon] IIT, Biol & Chem Sci Dept, Div Chem, Chicago, IL 60616 USA. [Milenic, Diane E.; Baidoo, Kwamena E.; Brechbiel, Martin W.] Natl Canc Inst, NIH, Ctr Canc Res, Radiat Oncol Branch,Radioimmune & Inorgan Chem Se, Bethesda, MD USA. RP Chong, HS (reprint author), IIT, Biol & Chem Sci Dept, Div Chem, Chicago, IL 60616 USA. EM chong@iit.edu FU National Institutes of Health [R01CA112503]; NIH FX Supported by National Institutes of Health (R01CA112503) and NIH intramural research program. NR 22 TC 11 Z9 11 U1 4 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD JUL PY 2013 VL 40 IS 5 BP 600 EP 605 DI 10.1016/j.nucmedbio.2013.01.012 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 161TS UT WOS:000320216800003 PM 23541026 ER PT J AU Peterson, KL Reid, WC Freeman, AF Holland, SM Pettigrew, RI Gharib, AM Hammoud, DA AF Peterson, Kristin L. Reid, William C. Freeman, Alexandra F. Holland, Steven M. Pettigrew, Roderic I. Gharib, Ahmed M. Hammoud, Dima A. TI The use of C-14-FIAU to predict bacterial thymidine kinase presence: Implications for radiolabeled FIAU bacterial imaging SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE Bacterial imaging; PET; FIAU; Thymidine kinase ID POSITRON-EMISSION-TOMOGRAPHY; HYPER-IGE SYNDROMES; INFECTIONS AB Currently available infectious disease imaging techniques cannot differentiate between infection and sterile inflammation or between different types of infections. Recently, radiolabeled FIAU was found to be a substrate for the thymidine kinase (TK) enzyme of multiple pathogenic bacteria, leading to its translational use in the imaging of bacterial infections. Patients with immunodeficiencies, however, are susceptible to a different group of pathogenic bacteria when compared to immunocompetent subjects. In this study, we wanted to predict the usefulness of radiolabeled FIAU in the detection of bacterial infections commonly occurring in patients with immunodeficiencies, in vitro, prior to attempting in vivo imaging with I-124-FIAU-PET. Methods: We obtained representative strains of bacterial pathogens isolated from actual patients with genetic immunodeficiencies. We evaluated the bacterial susceptibility of different strains to the effect of incubation with FIAU, which would implicate the presence of the thymidine kinase (TK) enzyme. We also incubated the bacteria with C-14-FIAU and consequently measured its rate of incorporation in the bacterial DNA using a liquid scintillation counter. Results: Unlike the other bacterial strains, the growth of Pseudomonas aeruginosa was not halted by FIAU at any concentration. All the tested clinical isolates demonstrated different levels of C-14-FIAU uptake, except for P. aeruginosa. Conclusion: Radiolabeled FIAU has been successful in delineating bacterial infections, both in preclinical and pilot translational studies. In patients with immunodeficiencies, Pseudomonas infections are commonly encountered and are usually difficult to differentiate from fungal infections. The use of radiolabeled FIAU for in vivo imaging of those patients, however, would not be useful, considering the apparent lack of TK enzyme in Pseudomonas. One has to keep in mind that not all pathogenic bacteria possess the TK enzyme and as such will not all retain FIAU. Our technique is simple, and can be easily used to assess whether a certain bacterial strain of interest can or cannot be visualized using radiolabeled FIAU. Published by Elsevier Inc. C1 [Peterson, Kristin L.; Reid, William C.; Hammoud, Dima A.] NIH, Ctr Infect Dis Imaging Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20814 USA. [Pettigrew, Roderic I.; Gharib, Ahmed M.] NIDDK, Biomed & Metab Imaging Branch, NIH, Bethesda, MD USA. [Freeman, Alexandra F.; Holland, Steven M.] NIAID, NIH, Immunopathogenesis Sect, LCID, Bethesda, MD 20892 USA. RP Hammoud, DA (reprint author), NIH, Ctr Clin, Bethesda, MD 20814 USA. EM hammoudd@cc.nih.gov RI Hammoud, Dima/C-2286-2015; Gharib, Ahmed/O-2629-2016; OI Gharib, Ahmed/0000-0002-2476-481X; Peterson, Kristin/0000-0003-0796-3611 FU National Institutes of Health FX National Institutes of Health, Bench to Bedside intramural research grant (2011-2012). NR 21 TC 5 Z9 6 U1 2 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD JUL PY 2013 VL 40 IS 5 BP 638 EP 642 DI 10.1016/j.nucmedbio.2013.01.005 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 161TS UT WOS:000320216800008 PM 23541824 ER PT J AU Bowers, K Laughon, SK Kim, S Mumford, SL Brite, J Kiely, M Zhang, CL AF Bowers, Katherine Laughon, S. Katherine Kim, Sungduk Mumford, Sunni L. Brite, Jennifer Kiely, Michele Zhang, Cuilin TI The Association between a Medical History of Depression and Gestational Diabetes in a Large Multi-ethnic Cohort in the United States SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE depression; pregnancy; gestational diabetes ID INCREASING PREVALENCE; MELLITUS; PREGNANCY; WOMEN; HEALTH; RISK AB Background Both major depression and gestational diabetes mellitus (GDM) are prevalent among women of reproductive age. Our objective was to determine whether a medical history of depression is related to subsequent development of GDM. Methods The Consortium on Safe Labor was a US retrospective cohort study of 228562 births between 2002 and 2008. Exclusion criteria for the present analysis included multiple gestation pregnancies (n=5059), pre-existing diabetes (n=12771), deliveries <24 weeks (n=395), site GDM prevalence (<1%) (n=20721) and missing data on pre-pregnancy body mass index (BMI) (n=61321). Using generalised estimating equations, we estimated the association between a history of depression and a pregnancy complicated by GDM. Results The final analytic population included 121260 women contributing 128295 pregnancies, of which 5606 were affected by GDM. A history of depression was significantly associated with an increased risk of developing GDM (multivariate odds ratio [aOR]=1.42 [95% confidence interval (CI) 1.26, 1.60]). Adjusting for pre-pregnancy BMI and weight gain during pregnancy attenuated the association, although it remained statistically significant (aOR=1.17 [95% CI 1.03, 1.33]). Conclusions A history of depression was significantly associated with an increased GDM risk among a large multi-ethnic US cohort of women. If the association is confirmed, depression presents a potentially modifiable risk factor of GDM and provides additional clues to the underlying pathophysiology of GDM. C1 [Bowers, Katherine; Laughon, S. Katherine; Kim, Sungduk; Mumford, Sunni L.; Kiely, Michele; Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Bowers, Katherine] Cincinnati Childrens Hosp Med Ctr, Div Biostat & Epidemiol, Cincinnati, OH 45229 USA. [Brite, Jennifer] CUNY, Sch Publ Hlth, New York, NY 10021 USA. RP Bowers, K (reprint author), Cincinnati Childrens Hosp Med Ctr, Div Biostat & Epidemiol, 3333 Burnet Ave,MLC 5041, Cincinnati, OH 45229 USA. EM katherine.bowers@cchmc.org; zhangcu@mail.nih.gov RI Bowers, Katherine/N-5226-2015; OI Grantz, Katherine/0000-0003-0276-8534 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN267200603425C] FX The data included in this paper were obtained from the Consortium on Safe Labor, which was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, through Contract No. HHSN267200603425C. Institutions involved in the Consortium include, in alphabetical order, Baystate Medical Center, Springfield, MA; Cedars-Sinai Medical Center Burnes Allen Research Center, Los Angeles, CA; Christiana Care Health System, Newark, DE; Georgetown University Hospital, MedStar Health, Washington, DC; Indiana University Clarian Health, Indianapolis, IN; Inter-mountain Healthcare and the University of Utah, Salt Lake City, Utah; Maimonides Medical Center, Brooklyn, NY; MetroHealth Medical Center, Cleveland, OH.; Summa Health System, Akron City Hospital, Akron, OH; The EMMES Corporation, Rockville MD (Data Coordinating Center); University of Illinois at Chicago, Chicago, IL; University of Miami, Miami, FL; and the University of Texas Health Science Center at Houston, Houston, TX. The named authors alone are responsible for the views expressed in this manuscript, which does not necessarily represent the decisions or the stated policy of the NICHD. NR 23 TC 10 Z9 10 U1 2 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD JUL PY 2013 VL 27 IS 4 BP 323 EP 328 DI 10.1111/ppe.12057 PG 6 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 165HQ UT WOS:000320474700002 PM 23772933 ER PT J AU Jin, TC Curry, J Smith, P Jiang, JS Xiao, TS AF Jin, Tengchuan Curry, James Smith, Patrick Jiang, Jiansheng Xiao, T. Sam TI Structure of the NLRP1 caspase recruitment domain suggests potential mechanisms for its association with procaspase-1 SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE NLRP1; CARD; death domain fold; electrostatic attraction ID INFLAMMASOME; ACTIVATION; PLATFORM; NALP1 AB The NLRP1 inflammasome responds to microbial challenges such as Bacillus anthracis infection and is implicated in autoimmune disease such as vitiligo. Human NLRP1 contains both an N-terminal pyrin domain (PYD) and a C-terminal caspase recruitment domain (CARD), with the latter being essential for its association with the downstream effector procaspase-1. Here we report a 2.0 angstrom crystal structure of the human NLRP1 CARD as a fusion with the maltose-binding protein. The structure reveals the six-helix bundle fold of the NLRP1 CARD, typical of the death domain superfamily. The charge surface of the NLRP1 CARD structure and a procaspase-1 CARD model suggests potential mechanisms for their association through electrostatic attraction. Proteins 2013; 81:1266-1270. (c) 2013 Wiley Periodicals, Inc. C1 [Jin, Tengchuan; Curry, James; Smith, Patrick; Jiang, Jiansheng; Xiao, T. Sam] NIAID, Struct Immunobiol Unit, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Xiao, TS (reprint author), NIAID, Struct Immunobiol Unit, Immunol Lab, NIH, 4 Mem Dr,Bldg 4,Room 228, Bethesda, MD 20892 USA. EM xiaot@niaid.nih.gov RI Xiao, Tsan/I-7616-2013; Xiao, Tsan/A-8590-2010; Jin, Tengchuan/B-5883-2014 OI Xiao, Tsan/0000-0001-9688-475X; Jin, Tengchuan/0000-0002-1395-188X FU National Cancer Institute [Y1-CO-1020]; National Institute of General Medical Sciences [Y1-GM-1104]; US Department of Energy [DE-AC02-06CH11357]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH FX Grant sponsor: National Cancer Institute; Grand number: Y1-CO-1020; Grant sponsor: National Institute of General Medical Sciences; Grand number: Y1-GM-1104; Grant sponsor: US Department of Energy; Grand number: DE-AC02-06CH11357; Grant sponsor: Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH. NR 18 TC 17 Z9 17 U1 1 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-3585 J9 PROTEINS JI Proteins PD JUL PY 2013 VL 81 IS 7 BP 1266 EP 1270 DI 10.1002/prot.24287 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 165HK UT WOS:000320474100016 PM 23508996 ER PT J AU Ling, D Liu, BY Jawad, S Thompson, IA Nagineni, CN Dailey, J Chien, J Sredni, B Nussenblatt, RB AF Ling, Diamond Liu, Baoying Jawad, Shayma Thompson, Ian A. Nagineni, Chandrasekharam N. Dailey, Jennifer Chien, Jason Sredni, Benjamin Nussenblatt, Robert B. TI The tellurium redox immunomodulating compound AS101 inhibits IL-1 beta-activated inflammation in the human retinal pigment epithelium SO BRITISH JOURNAL OF OPHTHALMOLOGY LA English DT Article ID NF-KAPPA-B; MACULAR DEGENERATION; GENE-EXPRESSION; CELLS; IL-6; MECHANISMS; SECRETION; UVEITIS; MICE AB Purpose AS101 is a non-toxic organotellurium-IV compound with demonstrated immunomodulating activity in vitro and in vivo. Inflammatory responses are attributed to the pathophysiology of numerous ocular diseases. In this study, we wished to elucidate whether AS101 could mitigate pro-inflammatory activity in human retinal pigment epithelial (RPE) cells, which are heavily involved in ocular immune responses, induced by pro-inflammatory IL-beta activity. Methods Primary and transformed RPE cells treated with varying concentrations of AS101 were used in this study. Real-time PCR and ELISA assays were used to detect cytokine/chemokine mRNA expression and protein production. Western blot was used to detect changes in the NF kappa B pathway. Cell viability and proliferation were detected using a Vi-Cell XR cell counter. To measure the cytoprotective capacity of AS101, cell numbers were compared between cells treated with IL-1 beta or lipopolysaccharide (LPS) and cells treated with IL-1 beta or LPS in the presence of AS101. Results AS101 inhibited IL-1 beta-induced mRNA expression and protein production of IL-6 and IL-8 in RPE cells. The viability of RPE cells treated with IL-1 beta and LPS was unaffected. AS101 slightly inhibited RPE cell growth in the presence of higher levels of IL-1 beta. Also, AS101 downregulated the IL-1 beta activity by inhibiting the phosphorylation of p65, an NF kappa B subunit. Conclusions The results demonstrate that AS101 reduces IL-1 beta-induced inflammatory responses in the RPE. In previous studies, AS101 exhibited therapeutic effects in various disease models and was a safe profile in clinical trials. These results suggest that AS101 may have potent anti-inflammatory potential in the eye and confer the downregulation of RPE inflammatory responses in a pathological environment. C1 [Ling, Diamond; Liu, Baoying; Jawad, Shayma; Thompson, Ian A.; Nagineni, Chandrasekharam N.; Dailey, Jennifer; Chien, Jason; Nussenblatt, Robert B.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Sredni, Benjamin] Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Safdie AIDS & Immunol Res Ctr, CAIR Inst, Tel Aviv, Israel. RP Nussenblatt, RB (reprint author), NEI, Immunol Lab, NIH, Bldg 10,Room 10N109,10 Ctr Dr, Bethesda, MD 20892 USA. EM drbob@nei.nih.gov FU Intramural Research Program of NIH, National Eye Institute, Bethesda, USA FX This research was supported by the Intramural Research Program of NIH, National Eye Institute, Bethesda, USA. NR 25 TC 5 Z9 6 U1 0 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0007-1161 J9 BRIT J OPHTHALMOL JI Br. J. Ophthalmol. PD JUL PY 2013 VL 97 IS 7 BP 934 EP 938 DI 10.1136/bjophthalmol-2012-301962 PG 5 WC Ophthalmology SC Ophthalmology GA 161YH UT WOS:000320229800028 PM 23624272 ER PT J AU Chen, D Chen, Y Forrest, D Bremner, R AF Chen, D. Chen, Y. Forrest, D. Bremner, R. TI E2f2 induces cone photoreceptor apoptosis independent of E2f1 and E2f3 SO CELL DEATH AND DIFFERENTIATION LA English DT Article DE retinoblastoma; E2f; p53; cone photoreceptor; retina ID LENS FIBER CELLS; S-PHASE ENTRY; E2F1-INDUCED APOPTOSIS; DNA-SYNTHESIS; MUTANT MICE; MOUSE MODEL; RB; RETINOBLASTOMA; P53; CYCLE AB The 'activating' E2fs (E2f1-3) are transcription factors that potently induce quiescent cells to divide. Work on cultured fibroblasts suggested they were essential for division, but in vivo analysis in the developing retina and other tissues disproved this notion. The retina, therefore, is an ideal location to assess other in vivo adenovirus E2 promoter binding factor (E2f) functions. It is thought that E2f1 directly induces apoptosis, whereas other activating E2fs only induce death indirectly by upregulating E2f1 expression. Indeed, mouse retinoblastoma (Rb)-null retinal neuron death requires E2f1, but not E2f2 or E2f3. However, we report an entirely distinct mechanism in dying cone photoreceptors. These neurons survive Rb loss, but undergo apoptosis in the cancer-prone retina lacking both Rb and its relative p107. We show that while E2f1 killed Rb/p107 null rod, bipolar and ganglion neurons, E2f2 was required and sufficient for cone death, independent of E2f1 and E2f3. Moreover, whereas E2f1-dependent apoptosis was p53 and p73-independent, E2f2 caused p53-dependent cone death. Our in vivo analysis of cone photoreceptors provides unequivocal proof that E2f-induces apoptosis independent of E2f1, and reveals distinct E2f1- and E2f2-activated death pathways in response to a single tumorigenic insult. C1 [Chen, D.; Chen, Y.; Bremner, R.] Univ Toronto, Dept Ophthalmol & Visual Sci, Toronto Western Res Inst, Univ Hlth Network, Toronto, ON, Canada. [Chen, D.; Chen, Y.; Bremner, R.] Univ Toronto, Dept Lab Med & Pathobiol, Toronto Western Res Inst, Univ Hlth Network, Toronto, ON, Canada. [Chen, D.; Chen, Y.; Bremner, R.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Chen, D.] Sichuan Univ, Dept Ophthalmol, Ophthalm Lab, Mol Med Res Ctr, Chengdu 610064, Peoples R China. [Chen, D.] Sichuan Univ, Torsten Wiesel Res Inst, World Eye Org, State Key Lab Biotherapy,West China Hosp, Chengdu 610064, Peoples R China. [Forrest, D.] NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD USA. RP Bremner, R (reprint author), Univ Toronto, Toronto Western Res Inst, Dept Genet & Dev, 399 Bathurst St,Room Mc6-424, Toronto, ON M5T 2S8, Canada. EM rbremner@uhnres.utoronto.ca RI Bremner, Rod/I-6490-2012 OI Bremner, Rod/0000-0001-9184-7212 FU Canadian Institutes for Health Research; Foundation Fighting Blindness Canada FX We thank G Leone and L van Parijs for plasmids; CM Craft, PA Hargrave, T Mak and R Molday for antibodies; G Leone and F McKeon for mice and P Monnier and R Slack for comments on the manuscript. This work was supported by grants from the Canadian Institutes for Health Research and the Foundation Fighting Blindness Canada to RB. NR 60 TC 10 Z9 10 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD JUL PY 2013 VL 20 IS 7 BP 931 EP 940 DI 10.1038/cdd.2013.24 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 160EO UT WOS:000320100000013 PM 23558950 ER PT J AU Cahoon, EK Rozhko, A Hatch, M Polyanskaya, O Ostroumova, E Tang, M Nadirov, E Yauseyenka, V Savasteeva, I McConnell, RJ Pfeiffer, RM Brenner, AV AF Cahoon, Elizabeth K. Rozhko, Alexander Hatch, Maureen Polyanskaya, Olga Ostroumova, Evgenia Tang, Min Nadirov, Eldar Yauseyenka, Vasilina Savasteeva, Irina McConnell, Robert J. Pfeiffer, Ruth M. Brenner, Alina V. TI Factors associated with serum thyroglobulin levels in a population living in Belarus SO CLINICAL ENDOCRINOLOGY LA English DT Article ID DIFFERENTIATED THYROID-CANCER; CHERNOBYL ACCIDENT; IODINE DEFICIENCY; HEALTHY-SUBJECTS; MARKER; TG; RADIOIMMUNOASSAY; AUTOANTIBODIES; CARCINOMA; DISEASE AB Objective Serum thyroglobulin (Tg) has been associated with a number of thyroid disorders and has been proposed as an indicator of iodine deficiency in a population. However, few studies have addressed the epidemiology of Tg in a population-based setting or in the context of exposure to radioactive iodine-131 (I-131). Our objective was to evaluate baseline levels of Tg in relation to sociodemographic characteristics, iodine status and thyroid function for individuals exposed to I-131. Design A population-based cohort assembled in Belarus following the Chornobyl accident provided demographic factors, clinical data and physiological measurements. Participants Our analytical sample included 10344 subjects of whom 7890 had no thyroid disease and 2454 had evidence of structural or functional thyroid abnormality. Measurements Standardized assays were used to measure serum Tg, urinary iodine, TSH and antibodies to Tg and thyroid peroxidase. Ultrasound was used to assess the presence of nodules and estimate thyroid volume. Results In the fully adjusted model, percent change in Tg was significantly increased among females, smokers and subjects of older age and Tg increased with decreasing urinary iodine concentration, increasing serum TSH and increasing thyroid volume (P-values for trend <0 center dot 0001), and presence of thyroid nodules (P<0 center dot 05). We found a complex interaction between region of residence, rural/urban living, presence/absence of thyroid abnormalities and serum Tg (P<0 center dot 0001). Conclusions In residents of Belarus, serum Tg is significantly related to presence of thyroid abnormalities as well as indicators of thyroid function and iodine deficiency and, therefore, could be used to characterize the iodine status and thyroid function of individuals in the context of epidemiological study. C1 [Cahoon, Elizabeth K.; Hatch, Maureen; Ostroumova, Evgenia; Brenner, Alina V.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, DHHS,NIH, Bethesda, MD 20892 USA. [Rozhko, Alexander; Polyanskaya, Olga; Nadirov, Eldar; Yauseyenka, Vasilina; Savasteeva, Irina] Republican Ctr Radiat Med & Human Ecol, Res Dept, Gomel, Byelarus. [Tang, Min] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Tang, Min] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [McConnell, Robert J.] Columbia Univ, Coll Phys & Surg, Dept Med, Thyroid Ctr, New York, NY USA. [Pfeiffer, Ruth M.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, DHHS,NIH, Bethesda, MD 20892 USA. RP Cahoon, EK (reprint author), 6120 Execut Blvd,EPS,Room 7053,MSC 7238, Bethesda, MD 20892 USA. EM khaykine@mail.nih.gov FU Intramural NIH HHS [ZIA CP010132-17] NR 35 TC 5 Z9 5 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-0664 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD JUL PY 2013 VL 79 IS 1 BP 120 EP 127 DI 10.1111/cen.12107 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 158SP UT WOS:000319993500018 PM 23190420 ER PT J AU Schoonveld, C Donsante, A del Gaudio, D Waggoner, D Das, S Kaler, SG AF Schoonveld, C. Donsante, A. del Gaudio, D. Waggoner, D. Das, S. Kaler, S. G. TI Prenatal diagnostic conundrum involving anovel ATP7A duplication SO CLINICAL GENETICS LA English DT Letter ID DISEASES C1 [Schoonveld, C.] Univ Minnesota, Med Ctr, Fairview Hlth Serv, Minneapolis, MN 55455 USA. [Donsante, A.; Kaler, S. G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Mol Med, NIH, Bethesda, MD USA. [del Gaudio, D.; Waggoner, D.; Das, S.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. RP Kaler, SG (reprint author), NICHD, Program Mol Med, NIH, Bldg 10,Room 10N313,MSC 1853, Bethesda, MD 20892 USA. EM kalers@mail.nih.gov FU Intramural NIH HHS [ZIA HD008768-10] NR 7 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9163 J9 CLIN GENET JI Clin. Genet. PD JUL PY 2013 VL 84 IS 1 BP 97 EP 98 DI 10.1111/cge.12041 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 160QE UT WOS:000320133500019 PM 23151012 ER PT J AU Williams, KW Word, C Streck, MR Titus, MO AF Williams, Kelli W. Word, Carolyn Streck, Maria R. Titus, M. Olivia TI Parental Education on Asthma Severity in the Emergency Department and Primary Care Follow-up Rates SO CLINICAL PEDIATRICS LA English DT Article DE asthma; severity; education; emergency department; follow-up ID INNER-CITY CHILDREN; NATIONAL GUIDELINES; RANDOMIZED-TRIAL; VISIT; BARRIERS; MANAGEMENT; EXACERBATIONS; MEDICATION; INITIATION; ADHERENCE AB Asthma is the most prevalent chronic condition affecting children and a common chief complaint in emergency departments (EDs). We aimed to improve parents' understanding of their child's asthma severity on accessing our pediatric ED for an acute asthma exacerbation. A retrospective chart review was conducted to determine outpatient follow-up rates from our ED in 2010-2011. In an attempt to educate parents at ED discharge about their child's asthma severity at presentation, we included a visual severity scale on their discharge instructions. Postdischarge telephone interviews were completed to determine postintervention follow-up rates. Asthma follow-up rates at 1 week improved from 20.8% to 50% after intervention. This difference was statistically significant after controlling for age and clinical asthma score with logistic regression (P < .0001). Offering predischarge education about a child's initial asthma severity is a simple intervention that significantly improved follow-up rates for children seen in the ED for asthma exacerbation. C1 [Williams, Kelli W.; Word, Carolyn; Streck, Maria R.; Titus, M. Olivia] Med Univ S Carolina, Charleston, SC 29425 USA. RP Williams, KW (reprint author), NIAID, ICMOB, DCR, NIH, 10 Ctr Dr,Bldg 10,Room 12C103, Bethesda, MD 20892 USA. EM kelli.williams@nih.gov RI Webster, Susan/C-7360-2015 OI Webster, Susan/0000-0002-0684-4226 NR 24 TC 3 Z9 3 U1 2 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0009-9228 J9 CLIN PEDIATR JI Clin. Pediatr. PD JUL PY 2013 VL 52 IS 7 BP 612 EP 619 DI 10.1177/0009922813479163 PG 8 WC Pediatrics SC Pediatrics GA 156IW UT WOS:000319816300006 PM 23471520 ER PT J AU Mandemakers, W Abuhatzira, L Xu, H Caromile, LA Hebert, SS Snellinx, A Morais, VA Matta, S Cai, T Notkins, AL De Strooper, B AF Mandemakers, W. Abuhatzira, L. Xu, H. Caromile, L. A. Hebert, S. S. Snellinx, A. Morais, V. A. Matta, S. Cai, T. Notkins, A. L. De Strooper, B. TI Co-regulation of intragenic microRNA miR-153 and its host gene Ia-2 beta: identification of miR-153 target genes with functions related to IA-2 beta in pancreas and brain SO DIABETOLOGIA LA English DT Article DE Diabetes; Glucose stimulation; IA-2 beta; MicroRNA; miR-153; Neurodegeneration ID AMYLOID PRECURSOR PROTEIN; INSULIN-SECRETION; MONOCLONAL-ANTIBODIES; EXPRESSION; PHOSPHATASE; DISRUPTION; MICE; GRANULES; PHOGRIN; ROLES AB We analysed the genomic organisation of miR-153, a microRNA embedded in genes that encode two of the major type 1 diabetes autoantigens, islet-associated protein (IA)-2 and IA-2 beta. We also identified miR-153 target genes that correlated with IA-2 beta localisation and function. A bioinformatics approach was used to identify miR-153's genomic organisation. To analyse the co-regulation of miR-153 and IA-2 beta, quantitative PCR analysis of miR-153 and Ia-2 beta (also known as Ptprn2) was performed after a glucose stimulation assay in MIN6B cells and isolated murine pancreatic islets, and also in wild-type Ia-2 (also known as Ptprn), Ia-2 beta single knockout and Ia-2/Ia-2 beta double knockout mouse brain and pancreatic islets. Bioinformatics identification of miR-153 target genes and validation via luciferase reporter assays, western blotting and quantitative PCR were also carried out. Two copies of miR-153, miR-153-1 and miR-153-2, are localised in intron 19 of Ia-2 and Ia-2 beta, respectively. In rodents, only miR-153-2 is conserved. We demonstrated that expression of miR-153-2 and Ia-2 beta in rodents is partially co-regulated as demonstrated by a strong reduction of miR-153 expression levels in Ia-2 beta knockout and Ia-2/Ia-2 beta double knockout mice. miR-153 levels were unaffected in Ia-2 knockout mice. In addition, glucose stimulation, which increases Ia-2 and Ia-2 beta expression, also significantly increased expression of miR-153. Several predicted targets of miR-153 were reduced after glucose stimulation in vitro, correlating with the increase in miR-153 levels. This study suggests the involvement of miR-153, IA-2 beta and miR-153 target genes in a regulatory network, which is potentially relevant to insulin and neurotransmitter release. C1 [Mandemakers, W.; Hebert, S. S.; Snellinx, A.; Morais, V. A.; Matta, S.; De Strooper, B.] VIB Ctr Biol Dis, Gasthuisberg O&N4, B-3000 Louvain, Belgium. [Mandemakers, W.; Hebert, S. S.; Snellinx, A.; Morais, V. A.; Matta, S.; De Strooper, B.] KULeuven, Ctr Human Genet, LIND, Louvain, Belgium. [Mandemakers, W.; Hebert, S. S.; Snellinx, A.; Morais, V. A.; Matta, S.; De Strooper, B.] KULeuven, Univ Ziekenhuizen, Louvain, Belgium. [Abuhatzira, L.; Xu, H.; Caromile, L. A.; Cai, T.; Notkins, A. L.] Natl Inst Dent & Craniofacial Res, Expt Med Sect, Oral Infect & Immun Branch, NIH, Bethesda, MD USA. [De Strooper, B.] VIB Ctr Biol Dis VIB11, Ctr Human Genet CB4, Gasthuisberg O&N4, B-3000 Louvain, Belgium. RP De Strooper, B (reprint author), VIB Ctr Biol Dis VIB11, Ctr Human Genet CB4, Gasthuisberg O&N4, Herestr 49 Bus 602, B-3000 Louvain, Belgium. EM bart.destrooper@cme.vib-kuleuven.be RI Caromile, Leslie/Q-2980-2016 OI Caromile, Leslie/0000-0003-2193-5190 FU National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA; Marie Curie Intra-European Fellowship (EIF) [041333]; Flemish community; University of Leuven, Belgium; European Research Commission (ERC) grant (EU Commission) FX This work was supported, in part, by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA, a Marie Curie Intra-European Fellowship (EIF proposal number 041333) awarded to W. Mandemakers, and a Methusalem grant (Flemish community and University of Leuven, Belgium) and European Research Commission (ERC) grant (EU Commission) to B. De Strooper. NR 48 TC 13 Z9 13 U1 1 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD JUL PY 2013 VL 56 IS 7 BP 1547 EP 1556 DI 10.1007/s00125-013-2901-5 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 157FL UT WOS:000319881300012 PM 23595248 ER PT J AU Goedert, JJ AF Goedert, James J. TI The microbiota and human health: beyond exploration SO EUROPEAN JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID DIVERSITY C1 NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. RP Goedert, JJ (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 7068, Rockville, MD 20852 USA. EM goedertj@mail.nih.gov FU Intramural NIH HHS [ZIA CP010214-03] NR 5 TC 3 Z9 3 U1 0 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2972 J9 EUR J CLIN INVEST JI Eur. J. Clin. Invest. PD JUL PY 2013 VL 43 IS 7 BP 657 EP 659 DI 10.1111/eci.12100 PG 3 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 160NW UT WOS:000320127400001 PM 23611431 ER PT J AU Bataller, R Gao, B AF Bataller, Ramon Gao, Bin TI Dissecting the role of CB1 receptors on chronic liver diseases SO GUT LA English DT Editorial Material ID MICE C1 [Bataller, Ramon] Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA. [Bataller, Ramon] Univ N Carolina, Dept Nutr, Chapel Hill, NC 27599 USA. [Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. RP Bataller, R (reprint author), Univ N Carolina, Dept Med, 2209 McGavran Greenberg, Chapel Hill, NC 27599 USA. EM bataller@med.unc.edu; bgao@mail.nih.gov FU Intramural NIH HHS [Z99 AA999999, ZIA AA000369-11] NR 9 TC 1 Z9 1 U1 0 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 J9 GUT JI Gut PD JUL PY 2013 VL 62 IS 7 BP 957 EP 958 DI 10.1136/gutjnl-2012-303664 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 158MO UT WOS:000319975900002 PM 23197412 ER PT J AU Narendra, DP Wang, CX Youle, RJ Walker, JE AF Narendra, Derek P. Wang, Chunxin Youle, Richard J. Walker, John E. TI PINK1 rendered temperature sensitive by disease-associated and engineered mutations SO HUMAN MOLECULAR GENETICS LA English DT Article ID RECESSIVE PARKINSONISM; DAMAGED MITOCHONDRIA; ACTIVATION SEGMENT; CRYSTAL-STRUCTURE; PROTEIN-KINASES; MITOPHAGY; RECRUITMENT; P62/SQSTM1; RECOGNITION; PROTEASOME AB Mutations in Parkin or PINK1 are the most common cause of recessively inherited parkinsonism. Parkin and PINK1 function in a conserved mitochondrial quality control pathway, in which PINK1, a putative mitochondrial kinase, directs Parkin, a cytosolic E3 ubiquitin ligase, selectively to dysfunctional mitochondria to promote their isolation, immobilization and degradation by macroautophagy (hereafter, mitophagy). As Parkin recruitment to mitochondria is robustly induced by PINK1 expression on the outer mitochondrial membrane, Parkin recruitment to mitochondria was used as an assay for PINK1 function. Unexpectedly, mutation of serine residues within the activation segment of PINK1 uncovered a temperature-sensitive variant of PINK1 (tsPINK1). tsPINK1 allowed for the first time the disassociation of PINK1 activity from its expression and localization. Additionally, extensive mutagenesis identified three disease-associated variants in the activation segment and one in an -helix N-terminal to kinase domain (Q126P) that are similarly thermally labile, suggesting that their activity could be restored post-translationally (e.g. by reducing the temperature or by a chemical or pharmacologic chaperone). Together, these findings suggest that tsPINK1 may represent a valuable tool for the analysis of the PINK1/Parkin pathway in human cells; additionally, as the serine residue promoting thermal lability is conserved among Mus musculus, Danio rerio, Drosophila melanogaster and Caenorhabditis elegans, it may serve as the basis for developing other temperature-sensitive models for the study of recessive parkinsonism and mitophagy. Finally, these results suggest that PINK1 kinase function could be restored for a subset of patients with PINK1 mutations, and perhaps alter the course of their disease. C1 [Narendra, Derek P.; Walker, John E.] MRC, Mitochondrial Biol Unit, Cambridge CB0 2XY, England. [Narendra, Derek P.; Wang, Chunxin; Youle, Richard J.] NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Walker, JE (reprint author), MRC Mitochondrial Biol Unit, Wellcome Trust MRC Bldg,Hills Rd, Cambridge CB2 OXY, England. EM john.walker@mrc-mbu.cam.ac.uk RI Wang, Chunxin/B-9312-2016 OI Wang, Chunxin/0000-0001-6015-6806 FU Medical Research Council; National Institute of Neurological Disorders and Stroke; NIH [1F30AG039185-01] FX This work received funding support from the Medical Research Council (J.E.W. and D.P.N.), the intramural program at the National Institute of Neurological Disorders and Stroke (R.J.Y. and D.P.N.) and NIH training grant 1F30AG039185-01 (D.P.N.). NR 42 TC 9 Z9 10 U1 5 U2 11 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 JUL 1 PY 2013 VL 22 IS 13 BP 2572 EP 2589 DI 10.1093/hmg/ddt106 PG 18 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 160MZ UT WOS:000320125100003 PM 23459931 ER PT J AU Schumacher, FR Wang, ZM Skotheim, RI Koster, R Chung, CC Hildebrandt, MAT Kratz, CP Bakken, AC Bishop, DT Cook, MB Erickson, RL Fossa, SD Greene, MH Jacobs, KB Kanetsky, PA Kolonel, LN Loud, JT Korde, LA Le Marchand, L Lewinger, JP Lothe, RA Pike, MC Rahman, N Rubertone, MV Schwartz, SM Siegmund, KD Skinner, EC Turnbull, C Van den Berg, DJ Wu, XF Yeager, M Nathanson, KL Chanock, SJ Cortessis, VK McGlynn, KA AF Schumacher, Fredrick R. Wang, Zhaoming Skotheim, Rolf I. Koster, Roelof Chung, Charles C. Hildebrandt, Michelle A. T. Kratz, Christian P. Bakken, Anne C. Bishop, D. Timothy Cook, Michael B. Erickson, R. Loren Fossa, Sophie D. Greene, Mark H. Jacobs, Kevin B. Kanetsky, Peter A. Kolonel, Laurence N. Loud, Jennifer T. Korde, Larissa A. Le Marchand, Loic Lewinger, Juan Pablo Lothe, Ragnhild A. Pike, Malcolm C. Rahman, Nazneen Rubertone, Mark V. Schwartz, Stephen M. Siegmund, Kimberly D. Skinner, Eila C. Turnbull, Clare Van den Berg, David J. Wu, Xifeng Yeager, Meredith Nathanson, Katherine L. Chanock, Stephen J. Cortessis, Victoria K. McGlynn, Katherine A. TI Testicular germ cell tumor susceptibility associated with the UCK2 locus on chromosome 1q23 SO HUMAN MOLECULAR GENETICS LA English DT Article ID CANCER; RISK; GENES; POLYMORPHISMS; METABOLISM; EXPRESSION; VARIANTS; RECEPTOR; URIDINE; TRENDS AB Genome-wide association studies (GWASs) have identified multiple common genetic variants associated with an increased risk of testicular germ cell tumors (TGCTs). A previous GWAS reported a possible TGCT susceptibility locus on chromosome 1q23 in the UCK2 gene, but failed to reach genome-wide significance following replication. We interrogated this region by conducting a meta-analysis of two independent GWASs including a total of 940 TGCT cases and 1559 controls for 122 single-nucleotide polymorphisms (SNPs) on chromosome 1q23 and followed up the most significant SNPs in an additional 2202 TGCT cases and 2386 controls from four casecontrol studies. We observed genome-wide significant associations for several UCK2 markers, the most significant of which was for rs3790665 (P-Combined 6.0 10(9)). Additional support is provided from an independent familial study of TGCT where a significant over-transmission for rs3790665 with TGCT risk was observed (P-FBAT 2.3 10(3)). Here, we provide substantial evidence for the association between UCK2 genetic variation and TGCT risk. C1 [Schumacher, Fredrick R.; Lewinger, Juan Pablo; Siegmund, Kimberly D.; Van den Berg, David J.; Cortessis, Victoria K.] Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. [Wang, Zhaoming; Chung, Charles C.; Cook, Michael B.; Greene, Mark H.; Jacobs, Kevin B.; Loud, Jennifer T.; Korde, Larissa A.; Yeager, Meredith; Chanock, Stephen J.; McGlynn, Katherine A.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Wang, Zhaoming; Jacobs, Kevin B.; Yeager, Meredith] NCI Frederick, Canc Genome Res Lab, Div Canc Epidemiol & Genet, Adv Technol Program,SAIC Frederick Inc, Frederick, MD USA. [Skotheim, Rolf I.; Bakken, Anne C.; Lothe, Ragnhild A.] Oslo Univ Hosp, Norwegian Radium Hosp, Inst Canc Res, Dept Canc Prevent, Oslo, Norway. [Skotheim, Rolf I.; Bakken, Anne C.; Lothe, Ragnhild A.] Univ Oslo, Fac Med, Ctr Canc Biomed, Oslo, Norway. [Koster, Roelof; Nathanson, Katherine L.] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kanetsky, Peter A.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Kanetsky, Peter A.] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Hildebrandt, Michelle A. T.; Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Kratz, Christian P.] Hannover Med Sch, Dept Pediat Hematol & Oncol, Ctr Pediat & Adolescent Med, Hannover, Germany. [Bishop, D. Timothy] St James Univ Hosp, Canc Res UK Clin Ctr Leeds, Leeds Inst Mol Med, Epidemiol & Biostat Sect, Leeds LS9 7TF, W Yorkshire, England. [Erickson, R. Loren] Walter Reed Army Inst Res, Silver Spring, MD USA. [Fossa, Sophie D.] Univ Oslo, Norwegian Radium Hosp, Oslo Univ Hosp, Dept Oncol, Oslo, Norway. [Kolonel, Laurence N.; Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Korde, Larissa A.] Univ Washington, Div Med Oncol, Seattle Canc Care Alliance, Seattle, WA 98195 USA. [Pike, Malcolm C.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Rahman, Nazneen; Turnbull, Clare] Inst Canc Res, Div Canc Genet, Sutton, Surrey, England. [Rubertone, Mark V.] USA, Ctr Hlth Promot & Prevent Med, Silver Spring, MD USA. [Schwartz, Stephen M.] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. [Schwartz, Stephen M.] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. [Skinner, Eila C.] Stanford Univ, Dept Urol, Stanford, CA 94305 USA. RP Chanock, SJ (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM preethi.raj@nih.gov; mcglynnk@mail.nih.gov RI Cook, Michael/A-5641-2009; Koster, Roelof/E-2158-2016; OI Cook, Michael/0000-0002-0533-7302; Koster, Roelof/0000-0003-1424-8579; Schwartz, Stephen/0000-0001-7499-8502; Nathanson, Katherine/0000-0002-6740-0901; Bishop, Tim/0000-0002-8752-8785 FU Intramural Research Program of the National Cancer Institute; Westat, Inc.; California Cancer Research Program [99-00505V-10260, 03-00174VRS-30021]; National Cancer Institute [1R01 CA102042-01A1]; Whittier Foundation; Abramson Cancer Center at the University of Pennsylvania; National Institutes of Health [R01CA114478, R01CA085914]; MD Anderson Senior Research Trust Fellowship; Movember; Cancer Research UK; [HHSN261200655004C] FX A portion of this work was supported by the Intramural Research Program of the National Cancer Institute and by support services contract HHSN261200655004C with Westat, Inc. Support was also provided as follows: USC GWAS controls were supported by the Multiethnic Cohort Study (NCI U01-CA98758). USC GWAS testicular cases and Familial Study were supported by the California Cancer Research Program (99-00505V-10260, 03-00174VRS-30021) and National Cancer Institute (1R01 CA102042-01A1) grants to V. K. C. and a Whittier Foundation award to the Norris Comprehensive Cancer Center. Replication effort for the TestPAC study was supported by the Abramson Cancer Center at the University of Pennsylvania and National Institutes of Health grant R01CA114478 to P. A. K. and K.L.N. Replication effort for the ATLAS study was supported by the National Institutes of Health grant R01CA085914 to S. M. S. MD Anderson: Center for Translational and Public Health Genomics of the Duncan Family Institute for Cancer Prevention and Risk Assessment and by MD Anderson Senior Research Trust Fellowship to X. W. The UK Genetics of Testicular Cancer Study was supported by Movember and Cancer Research UK. NR 33 TC 29 Z9 30 U1 0 U2 11 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 JUL 1 PY 2013 VL 22 IS 13 BP 2748 EP 2753 DI 10.1093/hmg/ddt109 PG 6 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 160MZ UT WOS:000320125100017 PM 23462292 ER PT J AU Stambolian, D Wojciechowski, R Oexle, K Pirastu, M Li, XH Raffel, LJ Cotch, MF Chew, EY Klein, B Klein, R Wong, TY Simpson, CL Klaver, CCW van Duijn, CM Verhoeven, VJM Baird, PN Vitart, V Paterson, AD Mitchell, P Saw, SM Fossarello, M Kazmierkiewicz, K Murgia, F Portas, L Schache, M Richardson, A Xie, J Wang, JJ Rochtchina, E Viswanathan, AC Hayward, C Wright, AF Polasek, O Campbell, H Rudan, I Oostra, BA Uitterlinden, AG Hofman, A Rivadeneira, F Amin, N Karssen, LC Vingerling, JR Hosseini, SM Doring, A Bettecken, T Vatavuk, Z Gieger, C Wichmann, HE Wilson, JF Fleck, B Foster, PJ Topouzis, F McGuffin, P Sim, XL Inouye, M Holliday, EG Attia, J Scott, RJ Rotter, JI Meitinger, T Bailey-Wilson, JE AF Stambolian, Dwight Wojciechowski, Robert Oexle, Konrad Pirastu, Mario Li, Xiaohui Raffel, Leslie J. Cotch, Mary Frances Chew, Emily Y. Klein, Barbara Klein, Ronald Wong, Tien Y. Simpson, Claire L. Klaver, Caroline C. W. van Duijn, Cornelia M. Verhoeven, Virginie J. M. Baird, Paul N. Vitart, Veronique Paterson, Andrew D. Mitchell, Paul Saw, Seang Mei Fossarello, Maurizio Kazmierkiewicz, Krista Murgia, Federico Portas, Laura Schache, Maria Richardson, Andrea Xie, Jing Wang, Jie Jin Rochtchina, Elena Viswanathan, Ananth C. Hayward, Caroline Wright, Alan F. Polasek, Ozren Campbell, Harry Rudan, Igor Oostra, Ben A. Uitterlinden, Andre G. Hofman, Albert Rivadeneira, Fernando Amin, Najaf Karssen, Lennart C. Vingerling, Johannes R. Hosseini, S. M. Doring, Angela Bettecken, Thomas Vatavuk, Zoran Gieger, Christian Wichmann, H. -Erich Wilson, James F. Fleck, Brian Foster, Paul J. Topouzis, Fotis McGuffin, Peter Sim, Xueling Inouye, Michael Holliday, Elizabeth G. Attia, John Scott, Rodney J. Rotter, Jerome I. Meitinger, Thomas Bailey-Wilson, Joan E. CA DCCT EDIC Res Grp TI Meta-analysis of genome-wide association studies in five cohorts reveals common variants in RBFOX1, a regulator of tissue-specific splicing, associated with refractive error SO HUMAN MOLECULAR GENETICS LA English DT Article ID HEPATOCYTE GROWTH-FACTOR; HIGH-GRADE MYOPIA; BEAVER DAM EYE; FAMILIAL AGGREGATION; SUSCEPTIBILITY LOCUS; OCULAR REFRACTION; OUTDOOR ACTIVITY; POPULATION; HERITABILITY; CHILDREN AB Visual refractive errors (REs) are complex genetic traits with a largely unknown etiology. To date, genome-wide association studies (GWASs) of moderate size have identified several novel risk markers for RE, measured here as mean spherical equivalent (MSE). We performed a GWAS using a total of 7280 samples from five cohorts: the Age-Related Eye Disease Study (AREDS); the KORA study (Cooperative Health Research in the Region of Augsburg); the Framingham Eye Study (FES); the Ogliastra Genetic Park-Talana (OGP-Talana) Study and the Multiethnic Study of Atherosclerosis (MESA). Genotyping was performed on Illumina and Affymetrix platforms with additional markers imputed to the HapMap II reference panel. We identified a new genome-wide significant locus on chromosome 16 (rs10500355, P 3.9 10(9)) in a combined discovery and replication set (26 953 samples). This single nucleotide polymorphism (SNP) is located within the RBFOX1 gene which is a neuron-specific splicing factor regulating a wide range of alternative splicing events implicated in neuronal development and maturation, including transcription factors, other splicing factors and synaptic proteins. C1 [Stambolian, Dwight; Kazmierkiewicz, Krista] Univ Penn, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Wojciechowski, Robert] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Bethesda, MD USA. [Wojciechowski, Robert; Simpson, Claire L.; Bailey-Wilson, Joan E.] NHGRI, Bethesda, MD 20892 USA. [Cotch, Mary Frances; Chew, Emily Y.] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Oexle, Konrad; Meitinger, Thomas] Tech Univ Munich, Inst Human Genet, D-80290 Munich, Germany. [Pirastu, Mario; Murgia, Federico; Portas, Laura] Natl Res Council Italy, Inst Populat Genet, Sassari, Italy. [Li, Xiaohui; Raffel, Leslie J.; Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Klein, Barbara; Klein, Ronald] Univ Wisconsin, Sch Med & Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Wong, Tien Y.] Natl Univ Singapore, Singapore Eye Res Inst, Singapore 117548, Singapore. [Saw, Seang Mei] Natl Univ Singapore, Dept Epidemiol & Publ Hlth, Yong Loo Lin Sch Med, Singapore 117548, Singapore. [Sim, Xueling] Natl Univ Singapore, Ctr Mol Epidemiol, Singapore 117548, Singapore. [Wong, Tien Y.] Univ Melbourne, Ctr Eye Res Australia, Melbourne, Vic 3010, Australia. [Klaver, Caroline C. W.; Verhoeven, Virginie J. M.; Vingerling, Johannes R.] Erasmus MC, Dept Ophthalmol & Epidemiol, Rotterdam, Netherlands. [van Duijn, Cornelia M.; Uitterlinden, Andre G.; Hofman, Albert; Rivadeneira, Fernando; Amin, Najaf; Karssen, Lennart C.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Baird, Paul N.; Schache, Maria; Richardson, Andrea; Xie, Jing; Wang, Jie Jin] Univ Melbourne, Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia, Melbourne, Vic, Australia. [Vitart, Veronique; Hayward, Caroline; Wright, Alan F.] Univ Edinburgh, IGMM, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland. [Campbell, Harry; Rudan, Igor; Wilson, James F.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Paterson, Andrew D.; Hosseini, S. M.] Hosp Sick Children, Program Genet & Genome Biol, Toronto, ON M5G 1X8, Canada. [Mitchell, Paul; Wang, Jie Jin; Rochtchina, Elena] Univ Sydney, Ctr Vis Res, Dept Ophthalmol, Sydney, NSW 2006, Australia. [Mitchell, Paul; Wang, Jie Jin; Rochtchina, Elena] Univ Sydney, Westmead Millennium Inst, Sydney, NSW 2006, Australia. [Fossarello, Maurizio] Univ Cagliari, Clin Oculist, Dipartimento Sci Chirurg, Cagliari, Italy. [DCCT EDIC Res Grp] George Washington Univ, Biostat Ctr, Rockville, MD USA. [Viswanathan, Ananth C.; Foster, Paul J.] Moorfields Eye Hosp NHS Fdn Trust, NIHR Biomed Res Ctr, London EC1V 2PD, England. [Viswanathan, Ananth C.; Foster, Paul J.] UCL Inst Ophthalmol, London EC1V 2PD, England. [Polasek, Ozren] Univ Split Med Sch, Croatian Ctr Global Hlth, Split, Croatia. [Oostra, Ben A.] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands. [Uitterlinden, Andre G.; Rivadeneira, Fernando] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Doring, Angela; Gieger, Christian; Wichmann, H. -Erich] Helmholtz Zentrum Munchen, Inst Epidemiol 1, Neuherberg, Germany. [Bettecken, Thomas; Meitinger, Thomas] Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany. [Vatavuk, Zoran] Hosp Sestre Milosrdnice, Dept Ophthalmol, Zagreb, Croatia. [Fleck, Brian] Princess Alexandra Eye Pavil, Edinburgh, Midlothian, Scotland. [Topouzis, Fotis] Aristotle Univ Thessaloniki, AHEPA Hosp, Sch Med, Dept Ophthalmol, GR-54006 Thessaloniki, Greece. [McGuffin, Peter] Kings Coll London, Inst Psychiat, MRC Social Genet & Dev Psychiat Res Ctr, London WC2R 2LS, England. [Inouye, Michael] Univ Melbourne, Dept Pathol, Parkville, Vic 3010, Australia. [Inouye, Michael] Univ Melbourne, Dept Microbiol & Immunol, Parkville, Vic 3010, Australia. [Holliday, Elizabeth G.; Attia, John; Scott, Rodney J.] Univ Newcastle, Sch Med & Publ Hlth, Newcastle, NSW 2300, Australia. [Holliday, Elizabeth G.; Attia, John; Scott, Rodney J.] Hunter Med Res Inst, Newcastle, NSW, Australia. [Scott, Rodney J.] Univ Newcastle, Ctr Informat Based Med, Newcastle, NSW 2300, Australia. [Scott, Rodney J.] Univ Newcastle, Sch Biomed Sci & Pharm, Newcastle, NSW 2300, Australia. [Scott, Rodney J.] John Hunter Hosp, Div Genet, Hunter Area Pathol Serv, Newcastle, NSW, Australia. RP Bailey-Wilson, JE (reprint author), NHGRI, NIH, 333 Cassell Dr Suite 1200, Baltimore, MD 21131 USA. EM jebw@mail.nih.gov RI McGuffin, Peter/A-1565-2012; Attia, John/F-5376-2013; Wang, Jie Jin/P-1499-2014; Mitchell, Paul/P-1498-2014; Wilson, James F/A-5704-2009; Polasek, Ozren/B-6002-2011; Meitinger, Thomas/O-1318-2015; Rivadeneira, Fernando/O-5385-2015; Klaver, Caroline/A-2013-2016; Paterson, Andrew/A-4088-2011; Rudan, Igor/I-1467-2012; Hayward, Caroline/M-8818-2016 OI Bailey-Wilson, Joan/0000-0002-9153-2920; Wojciechowski, Robert/0000-0002-9593-4652; Baird, Paul/0000-0002-1305-3502; Cotch, Mary Frances/0000-0002-2046-4350; Gieger, Christian/0000-0001-6986-9554; Klein, Ronald/0000-0002-4428-6237; Fossarello, Maurizio/0000-0003-1520-7760; Karssen, Lennart C./0000-0002-1959-342X; McGuffin, Peter/0000-0002-9888-2907; Hosseini, Mohsen/0000-0003-3626-9928; Attia, John/0000-0001-9800-1308; Wang, Jie Jin/0000-0001-9491-4898; Wilson, James F/0000-0001-5751-9178; Polasek, Ozren/0000-0002-5765-1862; Rivadeneira, Fernando/0000-0001-9435-9441; Paterson, Andrew/0000-0002-9169-118X; Rudan, Igor/0000-0001-6993-6884; Hayward, Caroline/0000-0002-9405-9550 FU Intramural Research Program of the National Human Genome Research Institute; National Eye Institute; National Institutes of Health; NIH [RO1EY020483, K08EY022943]; Helmholtz Center Munich; German Federal Ministry of Education and Research (BMBF); National Heart, Lung and Blood Institute (NHLBI); MESA; NHLBI [N02-HL-6-4278]; Intramural Research Program of the National Eye Institute [ZIAEY000403]; National Center for Research Resources [UL1RR033176]; National Center for Advancing Translational Sciences [UL1TR000124]; Australian National Health & Medical Research Council (NHMRC) [974159, 991407, 211069, 457349]; Centre for Clinical Research Excellence (CCRE) in Translational Clinical Research in Eye Diseases, CCRE in TCR-Eye [529923]; Australian NHMRC project [512423, 475604, 529912, 590204]; Wellcome Trust, UK, as part of Wellcome Trust Case Control Consortium 2 [085475/B/08/Z, 085475/08/Z]; NHMRC fellowship scheme [631096, 1028444, 358702, 632909]; Victorian government; Italian Ministry of Education, University and Research (MIUR) [5571/DSPAR/2002]; Italian Ministry of Education, University and Research (FIRB) [718/Ric/2005]; National Institute of Diabetes, Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [N01-DK-6-2204, R01-DK-077510]; Netherlands Organization of Scientific Research (NWO) [Vidi 91796357]; Erasmus Medical Center and Erasmus University, Rotterdam, The Netherlands; Netherlands Organization for Health Research and Development (ZonMw); UitZicht; Research Institute for Diseases in the Elderly; Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; Netherlands Genomics Initiative/NWO; Center for Medical Systems Biology of NGI; Lijf en Leven; M.D. Fonds; Henkes Stichting; Stichting Nederlands Oogheelkundig Onderzoek; Swart van Essen; Bevordering van Volkskracht; Blindenhulp; Landelijke Stichting voor Blinden en Slechtzienden; Rotterdamse Vereniging voor Blindenbelangen; OOG; Algemene Nederlandse Vereniging ter Voorkoming van Blindheid; Rotterdam Eye Hospital Research Foundation; Topcon Europe; Medical Research Council (UK); Republic of Croatia Ministry of Science, Education and Sports [108-1080315-0302]; EU [LSHG-CT-2006-018947]; Chief Scientist Office of the Scottish Government; Royal Society; Medical Research Council Human Genetics Unit; European Union framework program 6 EURO-SPAN project [LSHG-CT-2006-018947]; [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]; [RR-024156] FX This work was funded in part by the Intramural Research Program of the National Human Genome Research Institute (J.E.B.W., R. W., C. L. S.) and the National Eye Institute (M. C., E.Y.C.), National Institutes of Health and NIH RO1EY020483 (D. S., J.E.B.W.) and K08EY022943 (R. W.). The KORA Study is supported by funds from Helmholtz Center Munich and the German Federal Ministry of Education and Research (BMBF). 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, 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 and RR-024156. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-6-4278. Funding for the collection of RE data was supported by the Intramural Research Program of the National Eye Institute (ZIAEY000403). Support was also provided by the National Center for Research Resources, Grant UL1RR033176, and is now at the National Center for Advancing Translational Sciences, Grant UL1TR000124. The Blue Mountains Eye Study was supported by the Australian National Health & Medical Research Council (NHMRC) project grants (IDs 974159, 991407, 211069 and 457349) and Centre for Clinical Research Excellence (CCRE) in Translational Clinical Research in Eye Diseases, CCRE in TCR-Eye (ID 529923). The Blue Mountains Eye Study GWAS and genotyping costs were supported by Australian NHMRC project grants (IDs 512423, 475604, 529912 and 590204), and the Wellcome Trust, UK, as part of Wellcome Trust Case Control Consortium 2 (grant IDs 085475/B/08/Z and 085475/08/Z). E. G. H. (631096), P.N.B. (1028444) and J.W. (358702 and 632909) are supported by the NHMRC fellowship scheme. The Center for Eye Research Australia receives Operational Infrastructure Support from the Victorian government. OGP-Talana was supported by grants from the Italian Ministry of Education, University and Research (MIUR) No. 5571/DSPAR/2002 and (FIRB) D. M no. 718/Ric/2005. The DCCT Research Group is sponsored through research contracts from the National Institute of Diabetes, Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, N01-DK-6-2204, R01-DK-077510) and the National Institutes of Health. A. D. P. holds a Canada Research Chair in the Genetics of Complex Diseases. The Rotterdam Study and ERF were supported by the Netherlands Organization of Scientific Research (NWO) (Vidi 91796357); Erasmus Medical Center and Erasmus University, Rotterdam, The Netherlands; Netherlands Organization for Health Research and Development (ZonMw); UitZicht; 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); the Municipality of Rotterdam; the Netherlands Genomics Initiative/NWO; Center for Medical Systems Biology of NGI; Lijf en Leven; M.D. Fonds; Henkes Stichting; Stichting Nederlands Oogheelkundig Onderzoek; Swart van Essen; Bevordering van Volkskracht; Blindenhulp; Landelijke Stichting voor Blinden en Slechtzienden; Rotterdamse Vereniging voor Blindenbelangen; OOG; Algemene Nederlandse Vereniging ter Voorkoming van Blindheid; the Rotterdam Eye Hospital Research Foundation and Topcon Europe.; The Croatian studies were funded by grants from the Medical Research Council (UK), from the Republic of Croatia Ministry of Science, Education and Sports (108-1080315-0302). We acknowledge the Wellcome Trust Clinical facility (Edinburgh) for the genotyping of the CROATIA-Vis study, an EU framework 6 project EUROSPAN (contract no LSHG-CT-2006-018947) for the genotyping of the CROATIA-Korcula study that was performed at the Helmholtz Zentrum Munchen (Munich, Germany). ORCADES was supported by the Chief Scientist Office of the Scottish Government, the Royal Society, the Medical Research Council Human Genetics Unit and the European Union framework program 6 EURO-SPAN project (contract no. LSHG-CT-2006-018947). NR 57 TC 20 Z9 21 U1 0 U2 12 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 JUL 1 PY 2013 VL 22 IS 13 BP 2754 EP 2764 DI 10.1093/hmg/ddt116 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 160MZ UT WOS:000320125100018 PM 23474815 ER PT J AU Salehi, B Preuss, N van der Veen, JW Shen, J Neumeister, A Drevets, WC Hodgkinson, C Goldman, D Wendland, JR Singleton, A Gibbs, JR Cookson, MR Hasler, G AF Salehi, Basira Preuss, Nora van der Veen, Jan Willem Shen, Jun Neumeister, Alexander Drevets, Wayne C. Hodgkinson, Colin Goldman, David Wendland, Jens R. Singleton, Andrew Gibbs, Jesse R. Cookson, Mark R. Hasler, Gregor TI Age-modulated association between prefrontal NAA and the BDNF gene SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE BDNF; genetic variation; N-acetyl-aspartate; proton magnetic resonance spectroscopy; SNP ID MAGNETIC-RESONANCE-SPECTROSCOPY; N-ACETYL-ASPARTATE; MAJOR DEPRESSIVE DISORDER; AMINOBUTYRIC-ACID LEVELS; NEUROTROPHIC FACTOR; ALZHEIMERS-DISEASE; IN-VIVO; BIPOLAR DISORDER; METABOLITE CHANGES; MOOD DISORDERS AB Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of psychiatric and neurological disorders and in the mechanisms of antidepressant pharmacotherapy. Psychiatric and neurological conditions have also been associated with reduced brain levels of N-acetyl-aspartate (NAA), which has been used as a putative marker of neural integrity. However, few studies have explored the relationship between BDNF polymorphisms and NAA levels directly. Here, we present data from a single-voxel proton magnetic resonance spectroscopy study of 64 individuals and explore the relationship between BDNF polymorphisms and prefrontal NAA level. Our results indicate an association between a single nucleotide polymorphism (SNP) within BDNF, known as rs1519480, and reduced NAA level (p=0.023). NAA levels were further predicted by age and Asian ancestry. There was a significant rs1519480 x age interaction on NAA level (p=0.031). Specifically, the effect of rs1519480 on NAA level became significant at age >= 34.17 yr. NAA level decreased with advancing age for genotype TT (p=0.001) but not for genotype CT (p=0.82) or CC (p=0.34). Additional in silico analysis of 142 post-mortem brain samples revealed an association between the same SNP and reduced BDNF mRNA expression in the prefrontal cortex. The rs1519480 SNP influences BDNF mRNA expression and has an impact on prefrontal NAA level over time. This genetic mechanism may contribute to inter-individual variation in cognitive performance seen during normal ageing, as well as contributing to the risk for developing psychiatric and neurological conditions. C1 [Salehi, Basira; Hasler, Gregor] Univ Bern, Psychiat Univ Hosp, Bern, Switzerland. [Preuss, Nora] Univ Bern, Dept Psychol, Bern, Switzerland. [van der Veen, Jan Willem; Shen, Jun] NIMH, Magnet Resonance Spect Core, Bethesda, MD 20892 USA. [Neumeister, Alexander] NYU, Sch Med, New York, NY USA. [Drevets, Wayne C.] NIMH, Sect Neuroimaging Mood & Anxiety Disorders, Bethesda, MD 20892 USA. [Drevets, Wayne C.] Univ Oklahoma, Coll Med, Laureate Inst Brain Res, Tulsa, OK USA. [Hodgkinson, Colin; Goldman, David] NIAAA, Neurogenet Lab, Bethesda, MD USA. [Wendland, Jens R.] NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. [Singleton, Andrew; Gibbs, Jesse R.; Cookson, Mark R.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Hasler, G (reprint author), Psychiat Univ Hosp, Bolligenstr 111, CH-3000 Bern 60, Switzerland. EM g.hasler@bluewin.ch RI Singleton, Andrew/C-3010-2009; Hasler, Gregor/E-4845-2012; Goldman, David/F-9772-2010 OI Hasler, Gregor/0000-0002-8311-0138; Goldman, David/0000-0002-1724-5405 FU Lundebck; Servier; Lilly; Bistol-Myers Squibb; GlaxoSmithKline; Astra Zeneca; Johnson Johnson; Myriad/Rules Based Medicine; Pfizer; Eisai FX G. H. received honoraria or consulting fees from Lundebck, Servier, Lilly, Bistol-Myers Squibb, GlaxoSmithKline and Astra Zeneca for projects unrelated to this study. W. C. D. received consulting fees from Johnson & Johnson, Myriad/Rules Based Medicine, Pfizer and Eisai for projects unrelated to this study. J.R.W. is a current employee of F. Hoffmann-La Roche. NR 54 TC 2 Z9 3 U1 0 U2 3 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUL PY 2013 VL 16 IS 6 BP 1185 EP 1193 DI 10.1017/S1461145712001204 PG 9 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 158LS UT WOS:000319973200001 PM 23253771 ER PT J AU Yap, MNF Bernstein, HD AF Yap, Mee-Ngan F. Bernstein, Harris D. TI Mutations in the Escherichia coli Ribosomal Protein L22 Selectively Suppress the Expression of a Secreted Bacterial Virulence Factor SO JOURNAL OF BACTERIOLOGY LA English DT Article ID NASCENT POLYPEPTIDE; TRANSLATION ARREST; EXIT TUNNEL; ERYTHROMYCIN RESISTANCE; STRUCTURAL BASIS; GENE-EXPRESSION; SECA REGULATION; OUTER-MEMBRANE; RNA; RECOGNITION AB Mutations in the ribosomal protein L22 that impair peptide-mediated translation arrest in Escherichia coli have been shown to reduce the expression of several genes, including secA, which encodes an ATPase that drives protein export via the Sec pathway. Here, we used a comparative proteomic approach to obtain insight into the global effects of the L22(Delta 82-84) mutation on gene expression and protein synthesis. While the mutation did not affect or modestly affected the level of most soluble proteins, it dramatically reduced the level of antigen 43 (Ag43), a secreted virulence factor that promotes autoaggregation. The reduced protein concentration correlated with a sharp decrease in the abundance and stability of Ag43 mRNA. We found that the overexpression of secA or the inactivation of genes that encode presecretory and membrane proteins restored Ag43 production in the L22 mutant strain. Furthermore, impairment of the Sec pathway in a wild-type strain reduced Ag43 production but did not significantly affect the synthesis of other presecretory proteins. Taken together, these results indicate that Ag43 gene expression is exquisitely sensitive to the status of the Sec machinery and strongly suggest that the L22 mutation decreases the Ag43 concentration indirectly by reducing secA expression. Our results imply the existence of a novel regulatory mechanism in which the efficiency of protein export is coupled to gene expression and help to explain the modulation of SecA synthesis that has been observed in response to secretion stress. C1 [Yap, Mee-Ngan F.; Bernstein, Harris D.] NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. [Yap, Mee-Ngan F.] St Louis Univ, Sch Med, Edward A Doisy Dept Biochem & Mol Biol, St Louis, MO 63104 USA. RP Bernstein, HD (reprint author), NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. EM myap1@slu.edu; harris_bernstein@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of General Medical Sciences [R00GM094212] FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and by grant R00GM094212 (National Institute of General Medical Sciences) to M.-N.F.Y. NR 54 TC 3 Z9 3 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD JUL PY 2013 VL 195 IS 13 BP 2991 EP 2999 DI 10.1128/JB.00211-13 PG 9 WC Microbiology SC Microbiology GA 160HH UT WOS:000320109000005 PM 23625843 ER PT J AU Gungor, D Bornstein, MH De Leersnyder, J Cote, L Ceulemans, E Mesquita, B AF Gungor, Derya Bornstein, Marc H. De Leersnyder, Jozefien Cote, Linda Ceulemans, Eva Mesquita, Batja TI Acculturation of Personality: A Three-Culture Study of Japanese, Japanese Americans, and European Americans SO JOURNAL OF CROSS-CULTURAL PSYCHOLOGY LA English DT Article DE personality; acculturation; Japanese Americans; cultural fit ID SOJOURNER ADJUSTMENT; PARENTING COGNITIONS; MATERNAL PERSONALITY; UNITED-STATES; CULTURAL FIT; TRAITS; PROFILES; SELF; PERSPECTIVE; UNIVERSAL AB The present study tests the hypothesis that involvement with a new culture instigates changes in personality of immigrants that result in (a) better fit with the norms of the culture of destination and (b) reduced fit with the norms of the culture of origin. Participants were 40 Japanese first-generation immigrants to the United States, 57 Japanese monoculturals, and 60 U.S. monoculturals. All participants completed the Jackson Personality Inventory as a measure of the Big Five; immigrants completed the Japanese American Acculturation Scale. Immigrants' fits with the cultures of destination and origin were calculated by correlating Japanese American mothers' patterns of ratings on the Big Five with the average patterns of ratings of European Americans and Japanese on the same personality dimensions. Japanese Americans became more American and less Japanese in their personality as they reported higher participation in the U.S. culture. The results support the view that personality can be subject to cultural influence. C1 [Gungor, Derya; De Leersnyder, Jozefien; Ceulemans, Eva; Mesquita, Batja] Univ Louvain, B-3000 Louvain, Belgium. [Bornstein, Marc H.; Cote, Linda] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, US Dept HHS, Bethesda, MD USA. [Cote, Linda] Marymount Univ, Arlington, VA USA. RP Gungor, D (reprint author), Univ Louvain, Ctr Social & Cultural Psychol, Tiensestr 102,Bus 3727, B-3000 Louvain, Belgium. EM Derya.Gungor@ppw.kuleuven.be OI De Leersnyder, Jozefien/0000-0002-4486-878X FU Intramural NIH HHS [ZIA HD001119-25, ZIA HD001119-24] NR 62 TC 8 Z9 8 U1 3 U2 35 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0221 J9 J CROSS CULT PSYCHOL JI J. Cross-Cult. Psychol. PD JUL PY 2013 VL 44 IS 5 BP 701 EP 718 DI 10.1177/0022022112470749 PG 18 WC Psychology, Social SC Psychology GA 158OZ UT WOS:000319983200003 PM 23935211 ER PT J AU Hobbs, CV Tanaka, TQ Muratova, O Van Vliet, J Borkowsky, W Williamson, KC Duffy, PE AF Hobbs, Charlotte V. Tanaka, Takeshi Q. Muratova, Olga Van Vliet, Jillian Borkowsky, William Williamson, Kim C. Duffy, Patrick E. TI HIV Treatments Have Malaria Gametocyte Killing and Transmission Blocking Activity SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HIV; malaria; antiretrovirals; TMP-SMX; gametocytes; transmission ID PLASMODIUM-FALCIPARUM GAMETOCYTES; TYPE-1 PROTEASE INHIBITORS; SULFADOXINE-PYRIMETHAMINE; COTRIMOXAZOLE PROPHYLAXIS; ANTIMALARIAL-DRUGS; GENE-EXPRESSION; IN-VITRO; SULFAMETHOXAZOLE; TRIMETHOPRIM; MOSQUITO AB Background. Millions of individuals being treated for human immunodeficiency virus (HIV) live in malaria-endemic areas, but the effects of these treatments on malaria transmission are unknown. While drugs like HIV protease inhibitors (PIs) and trimethoprim-sulfamethoxazole (TMP-SMX) have known activity against parasites during liver or asexual blood stages, their effects on transmission stages require further study. Methods. The HIV PIs lopinavir and saquinavir, the nonnucleoside reverse-transcriptase inhibitor nevirapine, and the antibiotic TMP-SMX were assessed for activity against Plasmodium falciparum transmission stages. The alamarBlue assay was used to determine the effects of drugs on gametocyte viability, and exflagellation was assessed to determine the effects of drugs on gametocyte maturation. The effects of drug on transmission were assessed by calculating the mosquito oocyst count as a marker for infectivity, using standard membrane feeding assays. Results. Lopinavir and saquinavir have gametocytocidal and transmission blocking activities at or approaching clinically relevant treatment levels, while nevirapine does not. TMP-SMX is not gametocytocidal, but at prophylactic levels it blocks transmission. Conclusions. Specific HIV treatments have gametocyte killing and transmission-blocking effects. Clinical studies are warranted to evaluate these findings and their potential impact on eradication efforts. C1 [Hobbs, Charlotte V.; Muratova, Olga; Van Vliet, Jillian; Duffy, Patrick E.] NIAID, Lab Malaria Vaccinol & Immunol, NIH, Bethesda, MD 20892 USA. [Tanaka, Takeshi Q.; Williamson, Kim C.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Borkowsky, William] NYU, Dept Pediat, Div Infect Dis & Immunol, New York, NY 10016 USA. [Williamson, Kim C.] Loyola Univ, Dept Biol, Chicago, IL 60626 USA. RP Hobbs, CV (reprint author), NIAID, Lab Malaria Immunol & Vaccinol, NIH, 12735 Twinbrook Pkwy, Rockville, MD 20852 USA. EM charlotte.hobbs@nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Disease, National Institutes of Health; US Public Health Service, National Institute of Allergy and Infectious Disease, National Institutes of Health [AI069314] FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Disease, National Institutes of Health; and by the US Public Health Service, National Institute of Allergy and Infectious Disease, National Institutes of Health (grant AI069314). NR 47 TC 12 Z9 13 U1 0 U2 17 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 JUL 1 PY 2013 VL 208 IS 1 BP 139 EP 148 DI 10.1093/infdis/jit132 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 156NX UT WOS:000319830300019 PM 23539746 ER PT J AU Moormann, AM Sumba, PO Chelimo, K Fang, H Tisch, DJ Dent, AE John, CC Long, CA Vulule, J Kazura, JW AF Moormann, Ann M. Sumba, Peter Odada Chelimo, Kiprotich Fang, Hua Tisch, Daniel J. Dent, Arlene E. John, Chandy C. Long, Carole A. Vulule, John Kazura, James W. TI Humoral and Cellular Immunity to Plasmodium falciparum Merozoite Surface Protein 1 and Protection From Infection With Blood-Stage Parasites SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE human immunity; Merozoite Surface Protein 1; humoral immunity; cellular immunity; interferongamma; interleukin-10; sickle cell trait; longitudinal study; observational study ID NATURALLY ACQUIRED-IMMUNITY; MALARIA VACCINE; ANTIBODY-RESPONSES; INTERFERON-GAMMA; KENYAN ADULTS; CHILDREN; FRAGMENT; ANTIGEN; AREA; TRANSMISSION AB Background. Acquired immunity to malaria develops with increasing age and repeated infections. Understanding immune correlates of protection from malaria would facilitate vaccine development and identification of biomarkers that reflect changes in susceptibility resulting from ongoing malaria control efforts. Methods. The relationship between immunoglobulin G (IgG) antibody and both interferon gamma (IFN-gamma) and interleukin 10 (IL-10) responses to the 42-kD C-terminal fragment of Plasmodium falciparum merozoite surface protein 1 (MSP142) and the risk of (re) infection were examined following drug-mediated clearance of parasitemia in 94 adults and 95 children in an area of holoendemicity of western Kenya. Results. Positive IFN-gamma enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immunosorbent spot assay (ELISPOT) responses to MSP1(42) 3D7 were associated with delayed time to (re) infection, whereas high-titer IgG antibodies to MSP1(42) 3D7 or FVO alleles were not independently predictive of the risk of (re) infection. When IFN-gamma and IL-10 responses were both present, the protective effect of IFN-gamma was abrogated. A Cox proportional hazard model including IFN-gamma, IL-10, MSP1(42) 3D7 IgG antibody responses, hemoglobin S genotype, age, and infection status at baseline showed that the time to blood-stage infection correlated positively with IFN-gamma responses and negatively with IL-10 responses, younger age, and asymptomatic parasitemia. Conclusions. Evaluating combined allele-specific cellular and humoral immunity elicited by malaria provides a more informative measure of protection relative to evaluation of either measure alone. C1 [Moormann, Ann M.; Tisch, Daniel J.; Dent, Arlene E.; Kazura, James W.] Case Western Reserve Univ, Ctr Global Hlth & Dis, Cleveland, OH 44106 USA. [Dent, Arlene E.] Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA. [Moormann, Ann M.] Univ Massachusetts, Sch Med, Dept Pediat, Worcester, MA 01605 USA. [Moormann, Ann M.; Fang, Hua] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Worcester, MA 01605 USA. [John, Chandy C.] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. [Long, Carole A.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Sumba, Peter Odada; Chelimo, Kiprotich; Vulule, John] Kenya Govt Med Res Ctr, Ctr Global Hlth Res, Kisumu, Kenya. [Chelimo, Kiprotich] Maseno Univ, Dept Biomed Sci & Technol, Kisumu, Kenya. RP Moormann, AM (reprint author), Univ Massachusetts, Sch Med, Worcester, MA 01605 USA. EM ann.moormann@umassmed.edu FU National Institutes of Health [RO1 AI43906, R01 CA134051]; Fogarty International Center [1D43TW006576]; Burroughs Wellcome Fund [1006818, UL1RR031982]; National Center for Research Resources; Division of Intramural Research, National Institute of Allergy and Infectious Diseases FX This work was supported by National Institutes of Health RO1 AI43906 (J. W. K.), R01 CA134051 (A. M. M.), Fogarty International Center 1D43TW006576 (P. O. S., K. C.), Burroughs Wellcome Fund 1006818 (A. E. D.), UL1RR031982, National Center for Research Resources (H. J. F.) and the intramural research program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (C.L.). NR 50 TC 16 Z9 16 U1 0 U2 14 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 JUL 1 PY 2013 VL 208 IS 1 BP 149 EP 158 DI 10.1093/infdis/jit134 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 156NX UT WOS:000319830300020 PM 23539744 ER PT J AU Kutty, G England, KJ Kovacs, JA AF Kutty, Geetha England, Katherine J. Kovacs, Joseph A. TI Expression of Pneumocystis jirovecii Major Surface Glycoprotein in Saccharomyces cerevisiae SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Pneumocystis jirovecii; major surface glycoprotein; upstream conserved sequence; antigenic variation; GPI anchored protein ID CULTURED LUNG-CELLS; CARINII; PROTEINS; SEQUENCE; GENES; WALL; SITE; VARIANTS; ANTIGEN; REGION AB The major surface glycoprotein (Msg), which is the most abundant protein expressed on the cell surface of Pneumocystis organisms, plays an important role in the attachment of this organism to epithelial cells and macrophages. In the present study, we expressed Pneumocystis jirovecii Msg in Saccharomyces cerevisiae, a phylogenetically related organism. Full-length P. jirovecii Msg was expressed with a DNA construct that used codons optimized for expression in yeast. Unlike in Pneumocystis organisms, recombinant Msg localized to the plasma membrane of yeast rather than to the cell wall. Msg expression was targeted to the yeast cell wall by replacing its signal peptide, serine-threonine-rich region, and glycophosphatidylinositol anchor signal region with the signal peptide of cell wall protein a-agglutinin of S. cerevisiae, the serine-threonine-rich region of epithelial adhesin (Epa1) of Candida glabrata, and the carboxyl region of the cell wall protein (Cwp2) of S. cerevisiae, respectively. Immunofluorescence analysis and treatment with beta-1,3 glucanase demonstrated that the expressed Msg fusion protein localized to the yeast cell wall. Surface expression of Msg protein resulted in increased adherence of yeast to A549 alveolar epithelial cells. Heterologous expression of Msg in yeast will facilitate studies of the biologic properties of Pneumocystis Msg. C1 [Kutty, Geetha; England, Katherine J.; Kovacs, Joseph A.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Kovacs, JA (reprint author), Bldg 10,Rm 2C145,MSC 1662, Bethesda, MD 20892 USA. EM jkovacs@mail.nih.gov FU National Institutes of Health Clinical Center FX This work was supported by the Intramural Research Program of the National Institutes of Health Clinical Center. NR 33 TC 2 Z9 3 U1 1 U2 7 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 JUL 1 PY 2013 VL 208 IS 1 BP 170 EP 179 DI 10.1093/infdis/jit131 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 156NX UT WOS:000319830300022 PM 23532098 ER PT J AU Kiesel, BF Parise, RA Tjornelund, J Christensen, MK Loza, E Tawbi, H Chu, E Kummar, S Beumer, JH AF Kiesel, Brian F. Parise, Robert A. Tjornelund, Jette Christensen, Mette K. Loza, Einars Tawbi, Hussein Chu, Edward Kummar, Shivaani Beumer, Jan H. TI LC-MS/MS assay for the quantitation of the HDAC inhibitor belinostat and five major metabolites in human plasma SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE HDAC; Belinostat; Tandem mass spectrometry; Metabolites; Assay; Validation ID HISTONE DEACETYLASE; CANCER AB The histone deacetylase inhibitor belinostat is being evaluated clinically as a single agent in the treatment of peripheral T-cell lymphomas and in combination with other anticancer agents to treat a wide range of human cancers including acute leukemias and solid tumors. To determine the pharmacokinetics of belinostat in the NCI ODWG liver dysfunction study, we developed and validated an LC-MS/MS assay for the quantitation of belinostat and five major metabolites in 0.05 mL human plasma. After protein precipitation, chromatographic separation was achieved with a Waters Acquity BEH C18 column and a linear gradient of 0.1% formic acid in acetonitrile and water. Detection with an ABI 4000Q mass spectrometer utilized both electrospray positive and negative mode ionization. The assay was linear from 30 to 5000 ng/mL for all six analytes and proved to be accurate (92.0-104.4%) and precise (CV <13.7%), and fulfilled FDA criteria for bioanalytical method validation. We demonstrated the suitability of this assay for measuring parent drug and five major metabolites in plasma from a patient who was administered belinostat IV at a dose of 400 mg/m(2). The LC-MS/MS assay that has been developed will be an essential tool to further define the metabolism and pharmacology of belinostat in the ongoing liver organ dysfunction as well as other studies that investigate belinostat with other anticancer agents. (C) 2013 Elsevier B.V. All rights reserved. C1 [Kiesel, Brian F.; Parise, Robert A.; Tawbi, Hussein; Chu, Edward; Beumer, Jan H.] Univ Pittsburgh, Inst Canc, Mol Therapeut Drug Discovery Program, Pittsburgh, PA 15213 USA. [Parise, Robert A.; Beumer, Jan H.] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15213 USA. [Tjornelund, Jette; Christensen, Mette K.] Topotarget AS, Copenhagen, Denmark. [Loza, Einars] Latvian Inst Organ Synth, Riga, Latvia. [Chu, Edward] Univ Pittsburgh, Sch Med, Dept Med, Div Hematol Oncol, Pittsburgh, PA 15213 USA. [Kummar, Shivaani] NCI, Bethesda, MD 20892 USA. RP Beumer, JH (reprint author), Univ Pittsburgh, Inst Canc, Room G27E,Hillman Res Pavilion,5117 Ctr Ave, Pittsburgh, PA 15213 USA. EM beumerj@gmail.com OI Beumer, Jan/0000-0002-8978-9401 FU Spectrum Pharmaceuticals Inc.; Topotarget A/S [U01-CA099168, N01-CM62209]; [P30-CA47904] FX Support: Spectrum Pharmaceuticals Inc., Topotarget A/S, grant U01-CA099168 and contract N01-CM62209 (NCI-CTEP). This project used the UPCI Clinical Pharmacology Analytical Facility (CPAF) and was supported in part by award P30-CA47904. NR 8 TC 6 Z9 6 U1 0 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0731-7085 J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD JUL-AUG PY 2013 VL 81-82 BP 89 EP 98 DI 10.1016/j.jpba.2013.03.025 PG 10 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 156AX UT WOS:000319793500013 PM 23644904 ER PT J AU Barrett, MO Sesma, JI Ball, CB Jayasekara, PS Jacobson, KA Lazarowski, ER Harden, TK AF Barrett, Matthew O. Sesma, Juliana I. Ball, Christopher B. Jayasekara, P. Suresh Jacobson, Kenneth A. Lazarowski, Eduardo R. Harden, T. Kendall TI A Selective High-Affinity Antagonist of the P2Y(14) Receptor Inhibits UDP-Glucose-Stimulated Chemotaxis of Human Neutrophils SO MOLECULAR PHARMACOLOGY LA English DT Article ID PROTEIN-COUPLED RECEPTOR; PHOSPHOLIPASE-C; MOLECULAR-MECHANISMS; GPR105 KIAA0001; NUCLEOTIDE; CELLS; ATP; RELEASE; PATHOPHYSIOLOGY; IDENTIFICATION AB The nucleotide-sugar-activated P2Y(14) receptor (P2Y(14)-R) is highly expressed in hematopoietic cells. Although the physiologic functions of this receptor remain undefined, it has been strongly implicated recently in immune and inflammatory responses. Lack of availability of receptor-selective high-affinity antagonists has impeded progress in studies of this and most of the eight nucleotide-activated P2Y receptors. A series of molecules recently were identified by Gauthier et al. (Gauthier et al., 2011) that exhibited antagonist activity at the P2Y(14)-R. We synthesized one of these molecules, a 4,7-disubstituted 2-naphthoic acid derivative (PPTN), and studied its pharmacological properties in detail. The concentration-effect curve of UDP-glucose for promoting inhibition of adenylyl cyclase in C6 glioma cells stably expressing the P2Y(14)-R was shifted to the right in a concentration-dependent manner by PPTN. Schild analyses revealed that PPTN-mediated inhibition followed competitive kinetics, with a K-B of 434 pM observed. In contrast, 1 mu M PPTN exhibited no agonist or antagonist effect at the P2Y(1), P2Y(2), P2Y(4), P2Y(6), P2Y(11), P2Y(12), or P2Y(13) receptors. UDP-glucose-promoted chemotaxis of differentiated HL-60 human promyelocytic leukemia cells was blocked by PPTN with a concentration dependence consistent with the K-B determined with recombinant P2Y(14)-R. In contrast, the chemotactic response evoked by the chemoattractant peptide fMetLeuPhe was unaffected by PPTN. UDP-glucose-promoted chemotaxis of freshly isolated human neutrophils also was blocked by PPTN. In summary, this work establishes PPTN as a highly selective high-affinity antagonist of the P2Y(14)-R that is useful for interrogating the action of this receptor in physiologic systems. C1 [Barrett, Matthew O.; Ball, Christopher B.; Harden, T. Kendall] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Sesma, Juliana I.; Lazarowski, Eduardo R.] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC 27599 USA. [Jayasekara, P. Suresh; Jacobson, Kenneth A.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Harden, TK (reprint author), Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. EM tkh@med.unc.edu RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU National Institutes of Health National Institute of General Medical Sciences [GM38213]; National Institutes of Health National Heart, Lung, and Blood Institute [HL34322]; Intramural Research Program of the National Institutes of Health [National Institute of Diabetes and Digestive and Kidney Diseases] FX This research was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant GM38213]; the National Institutes of Health National Heart, Lung, and Blood Institute [Grant HL34322]; and the Intramural Research Program of the National Institutes of Health [National Institute of Diabetes and Digestive and Kidney Diseases]. NR 43 TC 23 Z9 23 U1 0 U2 5 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD JUL PY 2013 VL 84 IS 1 BP 41 EP 49 DI 10.1124/mol.113.085654 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 163YF UT WOS:000320373900004 PM 23592514 ER PT J AU Cullinane, AR Schaffer, AA Huizing, M AF Cullinane, Andrew R. Schaeffer, Alejandro A. Huizing, Marjan TI The BEACH Is Hot: A LYST of Emerging Roles for BEACH-Domain Containing Proteins in Human Disease SO TRAFFIC LA English DT Review DE autophagy; LRBA; NBEA; NBEAL1; NBEAL2; NSMAF; WDFY3; WDFY4; WDR81 ID CHEDIAK-HIGASHI-SYNDROME; GRAY PLATELET SYNDROME; PLECKSTRIN HOMOLOGY DOMAINS; NEUTRAL SPHINGOMYELINASE ACTIVATION; SYSTEMIC-LUPUS-ERYTHEMATOSUS; WD-REPEAT PROTEINS; UNDIAGNOSED DISEASES; AGGREGATED PROTEINS; CRYSTAL-STRUCTURE; DIVERSE FUNCTIONS AB BEACH (named after Beige and Chediak-Higashi') is a conserved approximate to 280 residue domain, present in nine human BEACH domain containing proteins (BDCPs). Most BDCPs are large, containing a PH-like domain for membrane association preceding their BEACH domain, and containing WD40 and other domains for ligand binding. Recent studies found that mutations in individual BDCPs cause several human diseases. BDCP alterations affect lysosome size (LYST and NSMAF), apoptosis (NSMAF), autophagy (LYST, WDFY3, LRBA), granule size (LYST, NBEAL2, NBEA) or synapse formation (NBEA). However, the roles of each BDCP in these membrane events remain controversial. After reviewing studies on individual BDCPs, we propose a unifying hypothesis that BDCPs act as scaffolding proteins that facilitate membrane events, including both fission and fusion, determined by their binding partners. BDCPs may also bind each other, enabling fusion or fission of vesicles that are not necessarily of the same type. Such mechanisms explain why different BDCPs may have roles in autophagy; each BDCP is specific for the cell type or the cargo, but not necessarily specific for attaching to the autophagosome. Further elucidation of these mechanisms, preferably carrying out the same experiment on multiple BDCPs, and possibly using patients' cells, may identify potential targets for therapy. C1 [Cullinane, Andrew R.; Huizing, Marjan] NHGRI, Med Genet Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Schaeffer, Alejandro A.] NIH, Natl Biotechnol Ctr, US Dept HHS, Bethesda, MD 20894 USA. RP Huizing, M (reprint author), NHGRI, Med Genet Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM mhuizing@mail.nih.gov FU National Institutes of Health; NHGRI; NLM FX We thank Dr Murat Sincam for his skillful assistance with identifying genetic variants in human BDCPs. We thank the NIH Undiagnosed Diseases program for providing access to their exome sequencing database. We thank two reviewers for their helpful corrections and suggestions. This research was supported by the Intramural Research Programs of the National Institutes of Health, NHGRI and NLM. NR 80 TC 35 Z9 35 U1 1 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-9219 J9 TRAFFIC JI Traffic PD JUL PY 2013 VL 14 IS 7 BP 749 EP 766 DI 10.1111/tra.12069 PG 18 WC Cell Biology SC Cell Biology GA 161GL UT WOS:000320180400002 PM 23521701 ER PT J AU Hermone, AR Gussio, R AF Hermone, Ann R. Gussio, Rick TI Calculation Methods for the Enhancement of Pharmaceutical Properties in Small Molecules: Estimating the Cationic pK(a) SO CURRENT PHARMACEUTICAL DESIGN LA English DT Article DE Solvation energy; continuum dielectric; scoring function; training set; pK(a) calculations; cations; physical chemical properties; computational chemistry; small molecules; pharmaceutics ID AQUEOUS-SOLUTION; PREDICTING PK(A); AB-INITIO; COMPUTER-SIMULATIONS; CHEMICAL-PROCESSES; FREE-ENERGIES; AMINO-ACIDS; SOLVATION; MODEL; CONTINUUM AB In this review, a summary of methodologies is covered to enable medicinal chemists to access an overview of pK(a) estimation devices. In order to stave overutilization of costly synthetic resources, the chemist requires an accurate and computationally tractable solution for estimating a pK(a) of a candidate molecule. We focus on the cationic moieties, since they are so fundamentally important in the chemistry of drugs, and possess unique requirements to obtain a reasonably reliable pK(a) estimation. C1 [Hermone, Ann R.] NCI, Computat Drug Dev Grp, SAIC Frederick Inc, Frederick, MD 21702 USA. [Gussio, Rick] NCI, Informat Technol Branch, Computat Drug Dev Grp, Dev Therapeut Program,Div Canc Treatment & Diag, Frederick, MD 21702 USA. RP Hermone, AR (reprint author), NCI, Computat Drug Dev Grp, SAIC Frederick Inc, POB B, Frederick, MD 21702 USA. EM hermonea@mail.nih.gov; gussior@mail.nih.gov FU Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research, 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 the mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 48 TC 1 Z9 1 U1 1 U2 36 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 JUL PY 2013 VL 19 IS 23 BP 4310 EP 4315 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 148SC UT WOS:000319266600012 PM 23170887 ER PT J AU Kabirov, KK Kapetanovic, IM Benbrook, DM Dinger, N Mankovskaya, I Zakharov, A Detrisac, C Pereira, M Martin-Jimenez, T Onua, E Banerjee, A van Breemen, RB Nikolic, D Chen, L Lyubimov, AV AF Kabirov, Kasim K. Kapetanovic, Izet M. Benbrook, Doris M. Dinger, Nancy Mankovskaya, Irina Zakharov, Alexander Detrisac, Carol Pereira, Marcia Martin-Jimenez, Tomas Onua, Emmanuel Banerjee, Aryamitra van Breemen, Richard B. Nikolic, Dejan Chen, Lian Lyubimov, Alexander V. TI Oral toxicity and pharmacokinetic studies of SHetA2, a new chemopreventive agent, in rats and dogs SO DRUG AND CHEMICAL TOXICOLOGY LA English DT Article DE SHetA2; chemoprevention; toxicity; pharmacokinetic; rat; Beagle dog ID RETINOIC ACID RECEPTOR; FLEXIBLE-HETEROAROTINOIDS; INDUCE APOPTOSIS; CANCER CELLS; MITOCHONDRIA; SUFFICIENT; CARCINOMA AB SHetA2 is a heteroarotinoid that has shown selective inhibition of cancer cell growth and an induction of apoptosis without activation of nuclear retinoic acid receptors. In the rat study, SHetA2 was administered in 1% aqueous methylcellulose/0.2% Tween 80 by oral gavage at 0, 100, 500, and 2,000 mg/kg/day for 28 days. The high-dose administration induced decreased activity in male rats, decreased body-weight gains and food consumption, and changes in organ weights. The major metabolite of SHetA2 in rat plasma was monohydroxy SHetA2, which was considerably higher than the parent compound after oral and intravenous administration. Pharmacokinetic analysis showed extremely low (<1%) systemic bioavailability of SHetA2 for all doses tested. The dose of 2,000 mg/kg/day was considered as the lowest observed adverse effect level. The no observed adverse effect level (NOAEL) was 500 mg/kg/day. In the dog study, no toxicity of SHetA2 in 30% aqueous Solutol (R) HS 15 was observed in any tested dose groups (0, 100, 400, and 1,500 mg/kg/day). The major metabolite of SHetA2 in dog plasma was also monohydroxy SHetA2, which was equal to or lower than the parent compound after oral administration. SHetA2 levels in dog plasma were notably higher, when compared to levels in rat plasma. However, exposure was not dose proportional, as exemplified by a lack of proportional increase in maximum concentration or area under the plasma concentration-time curve with increasing dose. The NOAEL was not established and was considered to be above 1,500 mg/kg/day. C1 [Kabirov, Kasim K.; Dinger, Nancy; Mankovskaya, Irina; Zakharov, Alexander; Onua, Emmanuel; Banerjee, Aryamitra; Lyubimov, Alexander V.] Univ Illinois, Dept Pharmacol, Toxicol Res Lab, Chicago, IL 60612 USA. [Kapetanovic, Izet M.] NCI, Canc Prevent Div, Chemoprevent Agent Dev Res Grp, Bethesda, MD 20892 USA. [Benbrook, Doris M.] Univ Oklahoma HSC, Dept Obstet & Gynecol, Gynecol Oncol Sect, Oklahoma City, OK USA. [Benbrook, Doris M.] Univ Oklahoma HSC, Dept Biochem & Mol Biol, Oklahoma City, OK USA. [Detrisac, Carol] Charles River Co, Chicago Div, Pathol Associates Int, Chicago, IL USA. [Pereira, Marcia] Histo Sci Res Labs, Mt Jackson, VA USA. [Martin-Jimenez, Tomas] Univ Tennessee, Coll Vet Med, Knoxville, TN USA. [van Breemen, Richard B.; Nikolic, Dejan; Chen, Lian] Univ Illinois, Dept Med Chem & Pharmacognosy, Chicago, IL USA. RP Lyubimov, AV (reprint author), Univ Illinois, Toxicol Res Lab, 808 South Wood St, Chicago, IL 60612 USA. EM lyubimov@uic.edu RI Chen, Lian/C-5948-2017 FU National Cancer Institute, Division of Cancer Prevention [N01-CN-43306] FX These studies were supported by contract number N01-CN-43306 from the National Cancer Institute, Division of Cancer Prevention. NR 21 TC 2 Z9 2 U1 0 U2 50 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0148-0545 J9 DRUG CHEM TOXICOL JI Drug Chem. Toxicol. PD JUL PY 2013 VL 36 IS 3 BP 284 EP 295 DI 10.3109/01480545.2012.710632 PG 12 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy; Toxicology SC Chemistry; Pharmacology & Pharmacy; Toxicology GA 154RB UT WOS:000319692500004 PM 22947079 ER PT J AU Trabert, B Graubard, BI Erickson, RL Zhang, YW McGlynn, KA AF Trabert, Britton Graubard, Barry I. Erickson, Ralph L. Zhang, Yawei McGlynn, Katherine A. TI Second to fourth digit ratio, handedness and. testicular germ cell tumors SO EARLY HUMAN DEVELOPMENT LA English DT Article DE Case-control; Testicular cancer; Hand pattern; Left-handed dominance; Digit ratio ID BREAST-CANCER RISK; 2D 4D; WOMEN; TESTOSTERONE; LENGTH; COHORT; DIETHYLSTILBESTROL; LATERALIZATION; LANGUAGE; SIZE AB Background: Research on early life exposures and testicular germ cell tumors (TGCT) risk has focused on a possible perinatal etiology with a well-known hypothesis suggesting that hormonal involvement during fetal life is associated with risk. Second-to-fourth digit ratio (2D:4D) and left-hand dominance have been proposed as markers of prenatal hormone exposure. Aim: To evaluate associations between 2D:4D digit ratio, right minus left 2D:4D (Delta(R-L)), and left-hand dominance and TGCT in the U.S. Servicemen's Testicular Tumor Environmental and Endocrine Determinants Study. Methods: A total of 246 TGCT cases and 236 non-testicular cancer controls participated in the current study, and completed a self-administered questionnaire. Associations between digit ratio, hand dominance and TGCT were estimated using unconditional logistic regression adjusting for identified covariates. Results: Right 2D:4D was not associated with TGCT [odds ratio (OR) for a one-standard deviation (SD) increase in right-hand 2D:4D: 1.12, 95% confidence interval (CI): 0.93-1.34]. The results were consistent when evaluating the association based on the left hand. The difference between right and left-hand 2D:4D was also not associated with TGCT risk [OR for a one-SD increase in Delta(R-L): 1.03,95% CI: 0.87-1.23]. Compared to men who reported right-hand dominance, ambidexterity [OR (95% CI) = 0.65 (0.30-1.41)] and left-hand dominance [OR (95% Cl) = 0.79 (0.44-1.44)] were not associated with risk. Conclusions: These results do not support the hypothesis that prenatal hormonal imbalance is associated with TGCT risk. Given the limited sample size, further evaluation of the relationship between TGCT and prenatal hormonal factors using digit ratio, Delta(R-L), or left-hand dominance and larger sample size are warranted. Published by Elsevier Ireland Ltd. C1 [Trabert, Britton; McGlynn, Katherine A.] Natl Canc Inst, Natl Inst Hlth, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch,DHHS, Rockville, MD 20852 USA. [Graubard, Barry I.] Natl Canc Inst, Natl Inst Hlth, Div Canc Epidemiol & Genet, Biostat Branch, Rockville, MD 20852 USA. [Erickson, Ralph L.] Walter Reed Army Inst Res, Silver Spring, MD USA. [Zhang, Yawei] Yale Univ, Yale Sch Publ Hlth, New Haven, CT USA. RP Trabert, B (reprint author), Natl Canc Inst, Natl Inst Hlth, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch,DHHS, Suite 550,6120 Execut Blvd, Rockville, MD 20852 USA. EM trabertbl@mail.nih.gov RI Trabert, Britton/F-8051-2015 FU National Cancer Institute [CA130110] FX This work was supported by the Intramural Research Program of the National Cancer Institute and by grant CA130110 from the National Cancer Institute. NR 34 TC 2 Z9 2 U1 2 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-3782 J9 EARLY HUM DEV JI Early Hum. Dev. PD JUL PY 2013 VL 89 IS 7 BP 463 EP 466 DI 10.1016/j.earlhumdev.2013.04.001 PG 4 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 154YV UT WOS:000319713500004 PM 23623693 ER PT J AU Ranguelova, K Rice, AB Lardinois, OM Triquigneaux, M Steinckwich, N Deterding, LJ Garantziotis, S Mason, RP AF Ranguelova, Kalina Rice, Annette B. Lardinois, Olivier M. Triquigneaux, Mathilde Steinckwich, Natacha Deterding, Leesa J. Garantziotis, Stavros Mason, Ronald P. TI Sulfite-mediated oxidation of myeloperoxidase to a free radical: Immuno-spin trapping detection in human neutrophils SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Human neutrophils; Immuno-spin trapping; Sulfite radicals; Sulfite toxicity; Free radicals ID HYDROGEN-PEROXIDE; SULFUR-DIOXIDE; EOSINOPHIL PEROXIDASE; CATALYZED OXIDATION; ASTHMATIC-PATIENTS; REDOX PROPERTIES; SO5-RADICALS; OXIDASE; INVOLVEMENT; ACTIVATION AB Previous studies focused on catalyzed oxidation of (bi)sulfite, leading to the formation of the reactive sulfur trioxide ((SO3-)-S-center dot), peroxymonosulfate ((-O3SOO center dot)), and sulfate (SO4(center dot-)) anion radicals, which can damage target proteins and oxidize them to protein radicals. It is known that these very reactive sulfur- and oxygen-centered radicals can be formed by oxidation of (bi)sulfite by peroxidases. Myeloperoxidase (MPO), an abundant heme protein secreted from activated neutrophils that play a central role in host defense mechanisms, allergic reactions, and asthma, is a likely candidate for initiating the respiratory damage caused by sulfur dioxide. The objective of this study was to examine the oxidative damage caused by (bi)sulfite-derived free radicals in human neutrophils through formation of protein radicals. We used immuno-spin trapping and confocal microscopy to study the protein oxidations driven by sulfite-derived radicals. We found that the presence of sulfite can cause MPO-catalyzed oxidation of MPO to a protein radical in phorbol 12-myristate 13-acetate-activated human neutrophils. We trapped the MPO-derived radicals in situ using the nitrone spin trap 5,5-dimethyl-1-pyrroline N- oxide and detected them immunologically as nitrone adducts in cells. Our present study demonstrates that myeloperoxidase initiates (bi)sulfite oxidation leading to MPO radical damage, possibly leading to (bi)sulfite-exacerbated allergic reactions. Published by Elsevier Inc. C1 [Ranguelova, Kalina; Triquigneaux, Mathilde; Mason, Ronald P.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Rice, Annette B.; Garantziotis, Stavros] NIEHS, Clin Res Unit, NIH, Res Triangle Pk, NC 27709 USA. [Lardinois, Olivier M.; Deterding, Leesa J.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Steinckwich, Natacha] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Mason, RP (reprint author), NIEHS, Lab Toxicol & Pharmacol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM mason4@niehs.nih.gov RI Garantziotis, Stavros/A-6903-2009 OI Garantziotis, Stavros/0000-0003-4007-375X FU NIH, NIEHS FX The authors thank Mrs. Mary J. Mason and Dr. Ann Motten for their help in the preparation of the manuscript and Jason Williams, Katina Johnson, and Andrea Adams from the protein micro characterization core facility of NIEHS for helpful suggestions and assistance. Also, we thank Ms. Brenda Yingling and Ms. Jamie D. Marshburn for their technical assistance. This work was supported by the Intramural Research Program of the NIH, NIEHS. NR 50 TC 8 Z9 9 U1 3 U2 35 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JUL PY 2013 VL 60 BP 98 EP 106 DI 10.1016/j.freeradbiomed.2013.01.022 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 151UU UT WOS:000319486500013 PM 23376232 ER PT J AU Valente, AJ Yoshida, T Clark, RA Delafontaine, P Siebenlist, U Chandrasekar, B AF Valente, Anthony J. Yoshida, Tadashi Clark, Robert A. Delafontaine, Patrice Siebenlist, Ulrich Chandrasekar, Bysani TI Advanced oxidation protein products induce cardiomyocyte death via Nox2/Rac1/superoxide-dependent TRAF3IP2/JNK signaling SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE AOPPs; TRAF3IP2; Oxidative stress; Cell death; Myocardial injury; Free radicals ID GLYCATION END-PRODUCTS; NF-KAPPA-B; ACUTE CORONARY SYNDROMES; C-REACTIVE PROTEIN; NADPH OXIDASE; OXIDIZED LDL; ARTERY-DISEASE; NOX FAMILY; CIKS ACT1; APOPTOSIS AB Advanced oxidation protein products (AOPPs) are formed during chronic oxidative stress as a result of reactions between plasma proteins and chlorinated oxidants. Their levels are elevated during various cardiovascular diseases. Because elevated AOPPs serve as independent risk factors for ischemic heart disease, and cardiomyocyte death is a hallmark of ischemic heart disease, we hypothesized that AOPPs will induce cardiomyocyte death. AOPP-modified mouse serum albumin (AOPP-MSA) induced significant death of neonatal mouse cardiomyocytes that was attenuated by knockdown of the receptor for advanced glycation end products, but not CD36. Notably, TRAF3-interacting protein 2 (TRAF3IP2; also known as CIKS or Act1) knockdown blunted AOPP-induced apoptosis. AOPP-MSA stimulated Nox2/Rac1-dependent superoxide generation, TRAF3IP2 expression, and TRAF3IP2-dependent JNK activation. The superoxide anion generating xanthine/xanthine oxidase system and hydrogen peroxide both induced TRAF3IP2 expression. Further, AOPP-MSA induced mitochondrial Bax translocation and release of cytochrome c into cytoplasm. Moreover, AOPP-MSA suppressed antiapoptotic Bcl-2 and Bcl-xL expression. These effects were reversed by TRAF3IP2 knockdown or forced expression of mutant JNK. Similar to its effects in neonatal cardiomyocytes, AOPP-MSA induced adult cardiomyocyte death in part via TRAF3IP2. These results demonstrate for the first time that AOPPs induce cardiomyocyte death via Nox2/Rac1/superoxide-dependent TRAF3IP2/JNK activation in vitro and suggest that AOPPs may contribute to myocardial injury in vivo. Thus TRAF3IP2 may represent a potential therapeutic target in ischemic heart disease. (C) 2013 Elsevier Inc. All rights reserved. C1 [Valente, Anthony J.; Clark, Robert A.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Valente, Anthony J.; Clark, Robert A.] South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Yoshida, Tadashi; Delafontaine, Patrice; Chandrasekar, Bysani] Tulane Univ, Sch Med, Inst Heart & Vasc, New Orleans, LA 70112 USA. [Siebenlist, Ulrich] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Chandrasekar, Bysani] Southeast Louisiana Vet Hlth Care Syst, Res Serv, New Orleans, LA 70161 USA. RP Chandrasekar, B (reprint author), Tulane Univ, Sch Med, Inst Heart & Vasc, 1430 Tulane Ave, New Orleans, LA 70112 USA. EM bchandra@tulane.edu OI Delafontaine, Patrice/0000-0003-3744-3617; Yoshida, Tadashi/0000-0002-4544-1497 FU Department of Veterans Affairs Research Career Scientist Award; VA Office of Research and Development Biomedical Laboratory Research and Development Service Award [11O1BX000246]; NHLBI/NIH [HL-86787]; NHLBI [HL-70241, HL-80682] FX B.C. is a recipient of the Department of Veterans Affairs Research Career Scientist Award and is supported by VA Office of Research and Development Biomedical Laboratory Research and Development Service Award 11O1BX000246 and NHLBI/NIH Grant HL-86787. The contents of this report do not represent the views of the Department of Veterans Affairs or the U.S. government. PD is supported by NHLBI Grants HL-70241 and HL-80682. NR 49 TC 23 Z9 25 U1 2 U2 19 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JUL PY 2013 VL 60 BP 125 EP 135 DI 10.1016/j.freeradbiomed.2013.02.012 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 151UU UT WOS:000319486500016 PM 23453926 ER PT J AU Abdelmegeed, MA Jang, S Banerjee, A Hardwick, JP Song, BJ AF Abdelmegeed, Mohamed A. Jang, Sehwan Banerjee, Atrayee Hardwick, James P. Song, Byoung-Joon TI Robust protein nitration contributes to acetaminophen-induced mitochondrial dysfunction and acute liver injury SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Acute liver injury; Acetaminophen; CYP2E1; 3-Nitrotyrosine; Protein nitration; N-acetylcysteine; Mitochondrial dysfunction; Free radicals ID NITRIC-OXIDE SYNTHASE; INDUCED HEPATOTOXICITY; COVALENT BINDING; IMMUNOHISTOCHEMICAL LOCALIZATION; SUPEROXIDE-DISMUTASE; N-ACETYLCYSTEINE; OXIDATIVE STRESS; TERMINAL KINASE; KNOCKOUT MICE; MOUSE-LIVER AB Acetaminophen (APAP), a widely used analgesic/antipyretic agent, can cause liver injury through increased nitrative stress, leading to protein nitration. However, the identities of nitrated proteins and their roles in hepatotoxicity are poorly understood. Thus, we aimed at studying the mechanism of APAP-induced hepatotoxicity by systematic identification and characterization of nitrated proteins in the absence or presence of an antioxidant, N-acetylcysteine (NAC). The levels of nitrated proteins markedly increased at 2 h in mice exposed to a single APAP dose (350 mg/kg ip), which caused severe liver necrosis at 24 h. Protein nitration and liver necrosis were minimal in mice exposed to nontoxic 3-hydroxyacetanilide or animals co-treated with APAP and NAC. Mass-spectral analysis of the affinity-purified nitrated proteins identified numerous mitochondrial and cytosolic proteins, including mitochondrial aldehyde dehydrogenase, Mn-superoxide dismutase, glutathione peroxidase, ATP synthase, and 3-ketoacyl-CoA thiolase, involved in antioxidant defense, energy supply, or fatty acid metabolism. Immunoprecipitation followed by immunoblot with anti-3-nitrotyrosine antibody confirmed that the aforementioned proteins were nitrated in APAP-exposed mice but not in NAC-cotreated mice. Consistently, NAC cotreatment significantly restored the suppressed activity of these enzymes. Thus, we demonstrate a new mechanism by which many nitrated proteins with concomitantly suppressed activity promotes APAP-induced mitochondrial dysfunction and hepatotoxicity. Published by Elsevier Inc. C1 [Abdelmegeed, Mohamed A.; Jang, Sehwan; Banerjee, Atrayee; Song, Byoung-Joon] NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. [Hardwick, James P.] NE Ohio Med Univ, Coll Med, Dept Integrat Med Sci, Rootstown, OH 44272 USA. RP Song, BJ (reprint author), NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. EM bj.song@nih.gov FU National Institute on Alcohol Abuse and Alcoholism FX This research was supported by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism. We are thankful to Dr. Klaus Gawrisch for supporting this study. We are grateful to ProtTech, Inc and Protea Biosciences, Inc. for determining the protein sequences by mass-spectral analyses. NR 69 TC 30 Z9 31 U1 2 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JUL PY 2013 VL 60 BP 211 EP 222 DI 10.1016/j.freeradbiomed.2013.02.018 PG 12 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 151UU UT WOS:000319486500025 PM 23454065 ER PT J AU Ehrenshaft, M Roberts, JE Mason, RP AF Ehrenshaft, Marilyn Roberts, Joan E. Mason, Ronald P. TI Hypericin-mediated photooxidative damage of alpha-crystallin in human lens epithelial cells SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Singlet oxygen; Hypericin; alpha-Crystallin; Actin; Human lens epithelial cells; N-formylkynurenine; Free radicals ID ST-JOHNS-WORT; N-FORMYLKYNURENINE; IMMUNOLOGICAL DETECTION; FLUORESCENCE; PROTEINS; PHOTOTOXICITY; PERFORATUM; DEPRESSION; CULTURE; DRUGS AB St. John's wort (Hypericum perforatum), a perennial herb native to Europe, is widely used for and seems to be effective in treatment of mild to moderate depression. Hypericin, a singlet oxygen-generating photosensitizer that absorbs in both the visible and the UVA range, is considered to be one of the bioactive ingredients of St John's wort, and commercial preparations are frequently calibrated to contain a standard concentration. Hypericin can accumulate in ocular tissues, including lenses, and can bind in vitro to alpha-crystallin, a major lens protein. alpha-crystallin is required for lens transparency and also acts as a chaperone to ensure its own integrity and the integrity of all lens proteins. Because there is no crystallin turnover, damage to alpha-crystallin is cumulative over the lifetime of the lens and can lead to cataracts, the principal cause of blindness worldwide. In this work we study hypericin photosensitization of alpha-crystallin and detect extensive polymerization of bovine cc-crystallin exposed in vitro to hypericin and UVA. We use fluorescence confocal microscopy to visualize binding between hypericin and alpha-crystallin in a human lens epithelial (HLE) cell line. Further, we show that UVA irradiation of hypericin-treated HLE cells results in a dramatic decrease in alpha-crystallin detection concurrent with a dramatic accumulation of the tryptophan oxidation product N-formylkynurenine (NFK). Examination of actin in HLE cells indicates that this cytoskeleton protein accumulates NFK resulting from hypericin-mediated photosensitization. This work also shows that filtration of wavelengths <400 nm provides incomplete protection against cc-crystallin modification and NFK accumulation, suggesting that even by wearing UV-blocking sunglasses, routine users of St. John's wort cannot adequately shield their lenses from hypericin-mediated photosensitized damage. Published by Elsevier Inc. C1 [Ehrenshaft, Marilyn; Roberts, Joan E.; Mason, Ronald P.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Roberts, Joan E.] Fordham Univ, Dept Nat Sci, New York, NY 10023 USA. RP Ehrenshaft, M (reprint author), NIEHS, Lab Toxicol & Pharmacol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM ehrensh1@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health; National Institute of Environmental Health Sciences FX The authors thank B. Jean Corbett and Mary Mason for their valuable help in the preparation of the manuscript. We are grateful to Jeff Tucker and Dr. Agnes Janoshazi for their expert help with confocal microscopy. This work was supported by the Intramural Research Program of the National Institutes of Health and the National Institute of Environmental Health Sciences. NR 36 TC 4 Z9 5 U1 1 U2 27 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JUL PY 2013 VL 60 BP 347 EP 354 DI 10.1016/j.freeradbiomed.2013.02.023 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 151UU UT WOS:000319486500038 PM 23453985 ER PT J AU Muller, HK Wegener, G Liebenberg, N Zarate, CA Popoli, M Elfving, B AF Muller, Heidi Kaastrup Wegener, Gregers Liebenberg, Nico Zarate, Carlos A., Jr. Popoli, Maurizio Elfving, Betina TI Ketamine regulates the presynaptic release machinery in the hippocampus SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Ketamine; SNARE; Synapsin; Synaptotagmin; CaMKII; Antidepressant ID RAT PREFRONTAL CORTEX; SYNAPTIC VESICLE PROTEINS; EVOKED GLUTAMATE RELEASE; NMDA RECEPTOR BLOCKADE; METHYL-D-ASPARTATE; MOOD DISORDERS; SNARE COMPLEX; KINASE-II; NEUROTRANSMITTER RELEASE; DIFFERENTIAL EXPRESSION AB In the search for new drug targets, that may help point the way to develop fast-acting treatments for mood disorders, we have explored molecular pathways regulated by ketamine, an NMDA receptor antagonist, which has consistently shown antidepressant response within a few hours of administration. Using Sprague-Dawley rats we investigated the effects of ketamine on the presynaptic release machinery responsible for neurotransmitter release at I, 2 and 4 h as well as 7 days after administration of a single subanesthetic dose of ketamine (15 mg/kg). A large reduction in the accumulation of SNARE complexes was observed in hippocampal synaptic membranes after I, 2 and 4 h of ketamine administration. In parallel, we found a selective reduction in the expression of the synaptic vesicle protein synaptotagmin I and an increase in the levels of synapsin I in hippocampal synaptosomes suggesting a mechanism by which ketamine reduces SNARE complex formation, in part, by regulating the number of synaptic vesicles in the nerve terminals. Moreover, ketamine reduced Thr(286)-phosphorylated alpha CaMKII and its interaction with syntaxin 1A, which identifies CaMKII as a potential target for second messenger-mediated actions of ketamine. In addition, despite previous reports of ketamine-induced inhibition of GSK-3, we were unable to detect regulation of its activity after ketamine administration. Our findings demonstrate that ketamine rapidly induces changes in the hippocampal presynaptic machinery similar to those that are obtained only with chronic treatments with traditional antidepressants. This suggests that reduction of neurotransmitter release in the hippocampus has possible relevance for the rapid antidepressant effect of ketamine. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Muller, Heidi Kaastrup; Wegener, Gregers; Liebenberg, Nico; Elfving, Betina] Aarhus Univ Hosp, Ctr Psychiat Res, DK-8240 Risskov, Denmark. [Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, Div Intramural Res Programs, NIH, Bethesda, MD 20892 USA. [Popoli, Maurizio] Univ Milan, Ctr Excellence Neurodegenerat Dis, Lab Neuropsychopharmacol & Funct Neurogen, Dept Pharmacol & Biomol Sci, Milan, Italy. RP Muller, HK (reprint author), Aarhus Univ Hosp, Ctr Psychiat Res, Skovagervej 2, DK-8240 Risskov, Denmark. EM heidmull@rm.dk OI Elfving, Betina/0000-0001-6939-5088; Wegener, Gregers/0000-0002-0081-0068 FU AU Ideas; Lundbeck Foundation; Augustinus Foundation; Aase and Ejnar Danielsens Foundation; Gangsted Foundation; Overlaege Dr. Med. Einar Geert-Jorgensen and Hustru Ellen Geert-Jorgensens Foundation; Direktor Kurt Bonnelycke and Hustru Fru Grethe Bonnelyckes Foundation; Dagmar Marshalls Foundation; Else and Mogens Wedell-Wedellsborgs Foundation; Direktor Jacob Madsen and Hustru Olga Madsens Foundation; Torben and Alice Frimodts Foundation; Kong Christian den Tiendes Foundation FX This study was supported by Grants from AU Ideas, the Lundbeck Foundation, Augustinus Foundation, Aase and Ejnar Danielsens Foundation, Gangsted Foundation, Overlaege Dr. Med. Einar Geert-Jorgensen and Hustru Ellen Geert-Jorgensens Foundation, Direktor Kurt Bonnelycke and Hustru Fru Grethe Bonnelyckes Foundation, Dagmar Marshalls Foundation, Else and Mogens Wedell-Wedellsborgs Foundation, Direktor Jacob Madsen and Hustru Olga Madsens Foundation, Torben and Alice Frimodts Foundation, and Kong Christian den Tiendes Foundation. The authors thank Laura Musazzi for technical advices and Pia Hogh Plougmann for her technical assistance. NR 55 TC 19 Z9 19 U1 0 U2 16 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD JUL PY 2013 VL 47 IS 7 BP 892 EP 899 DI 10.1016/j.jpsychires.2013.03.008 PG 8 WC Psychiatry SC Psychiatry GA 152RR UT WOS:000319549300006 PM 23548331 ER PT J AU Enoch, MA Hodgkinson, CA Gorodetsky, E Goldman, D Roy, A AF Enoch, Mary-Anne Hodgkinson, Colin A. Gorodetsky, Elena Goldman, David Roy, Alec TI Independent effects of 5 ' and 3 ' functional variants in the serotonin transporter gene on suicidal behavior in the context of childhood trauma SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE SLC6A4; 5-HTTLPR; Substance dependence; rs3813034; rs1042173; Suicide attempt ID 5-HTT GENE; POLYMORPHISM; AMYGDALA; STRESS; POPULATION; EXPRESSION; DEPRESSION; GENOTYPE; REGION; ABUSE AB The serotonin transporter, encoded by the SLC6A4 gene, influences the synaptic actions of serotonin and is responsive to stress hormones. We hypothesized that 5-HTTLPR, a functional SLC6A4 promoter polymorphism, and two tightly-linked, putatively functional 3' UTR SNPs (rs3813034, rs1042173) might have independent effects on suicidal behavior in the context of childhood trauma (CT). DNA and Childhood Trauma Questionnaire scores were available for a total of 474 African Americans, including 112 suicide attempters and 362 non-suicide attempters. Genotyping was performed for the triallelic 5-HTTLPR polymorphism, 14 SLC6A4 haplotype-tagging SNPs, and 186 ancestry informative markers. There were independent G x E interactive effects of 5-HTTLPR (p = 0.017) and the rs3813034 -rs1042173 diplotype (p = 0.011) on suicidal behavior. In individuals exposed to high CT the risk of suicide attempt was 0.52 in carriers of the low activity 5-HTTLPR variant and 0.32 in medium/high activity variant carriers. Likewise, CT exposed carriers of the major rs3813034 rs1042173 ATAT diplotype had an increased risk of suicidal behavior relative to the ATCG/CGCG diplotype carriers (0.40 vs 0.31). Neither the 5' nor the 3' functional variants had an effect in individuals without CT: suicide attempt risk = 0.12-0.22. In individuals exposed to high CT the prevalence of suicide attempt was 0.56 in carriers of both 5' and 3' risk variants, 0.39 in carriers of one risk variant and 0.25 in individuals without either risk variant. Our findings suggest that the 5' and 3' SLC6A4 functional variants have independent effects on the risk for suicidal behavior in CT exposed individuals. Published by Elsevier Ltd. C1 [Enoch, Mary-Anne; Hodgkinson, Colin A.; Gorodetsky, Elena; Goldman, David] NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Roy, Alec] New Jersey VA Hlth Care Syst, Dept Vet Affairs, Psychiat Serv, E Orange, NJ USA. RP Enoch, MA (reprint author), NIAAA, NIH, DICBR, LNG, 5625 Fishers Lane,Room 3S32,MSC 9412, Bethesda, MD 20892 USA. EM maenoch@niaaa.nih.gov RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU National Institute on Alcohol Abuse and Alcoholism, NIH; National Institute of Drug Abuse, NIH [RO1 DA 10336-02] FX This research was supported by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, NIH and in part by grant RO1 DA 10336-02 to AR from the National Institute of Drug Abuse, NIH. NR 28 TC 7 Z9 7 U1 3 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD JUL PY 2013 VL 47 IS 7 BP 900 EP 907 DI 10.1016/j.jpsychires.2013.03.007 PG 8 WC Psychiatry SC Psychiatry GA 152RR UT WOS:000319549300007 PM 23558235 ER PT J AU Goldwyn, EE Rohani, P AF Goldwyn, Eli E. Rohani, Pejman TI Bias in Pertussis Incidence Data and Its Implications for Public Health Epidemiology SO JOURNAL OF PUBLIC HEALTH MANAGEMENT AND PRACTICE LA English DT Editorial Material ID UNITED-STATES; ADULT VACCINATION; DYNAMICS; POPULATION; STRATEGIES; SIMULATIONS; INFECTIONS; ENGLAND; IMPACT; WALES C1 [Goldwyn, Eli E.] Univ Calif Davis, Dept Math, Davis, CA 95616 USA. [Rohani, Pejman] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Rohani, Pejman] Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA. [Rohani, Pejman] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Goldwyn, EE (reprint author), Univ Calif Davis, Dept Math, 1 Shields Ave, Davis, CA 95616 USA. EM eegoldwyn@ucdavis.edu FU NIAID NIH HHS [R01AI101155] NR 36 TC 2 Z9 2 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1078-4659 J9 J PUBLIC HEALTH MAN JI J. Public Health Manag. Pract. PD JUL-AUG PY 2013 VL 19 IS 4 BP 379 EP 382 DI 10.1097/PHH.0b013e31826d7f95 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 154FQ UT WOS:000319657800018 PM 23128362 ER PT J AU Pandya, AA Yakel, JL AF Pandya, Anshul A. Yakel, Jerrel L. TI Activation of the alpha 7 nicotinic ACh receptor induces anxiogenic effects in rats which is blocked by a 5-HT1a receptor antagonist SO NEUROPHARMACOLOGY LA English DT Article DE 5-HT1a receptor (5-HT1a R); Alpha7 (alpha 7) receptor agonist; Anxiety; Memory and learning; Nicotinic acetylcholine receptors (nAChRs); Positive allosteric modulators (PAMs) ID POSITIVE ALLOSTERIC MODULATOR; SOCIAL-INTERACTION TEST; ELEVATED PLUS-MAZE; ACETYLCHOLINE-RECEPTOR; HIPPOCAMPAL INTERNEURONS; SYNAPTIC-TRANSMISSION; DORSAL HIPPOCAMPUS; PARTIAL AGONISTS; ANIMAL-MODELS; IN-VIVO AB The alpha 7 nicotinic acetylcholine receptor (nAChR) is highly expressed in different regions of the brain and is associated with cognitive function as well as anxiety. Agonists and positive allosteric modulators (PAMs) of the alpha 7 subtype of nAChRs have been shown to improve cognition. Previously nicotine, which activates both alpha 7 and non-alpha 7 subtypes of nAChRs, has been shown to have an anxiogenic effect in behavioral tests. In this study, we compared the effects of the alpha 7-selective agonist (PNU-282987) and PAM (PNU-120596) in a variety of behavioral tests in Sprague Dawley rats to look at their effects on learning and memory as well as anxiety. We found that neither PNU-282987 nor PNU-120596 improved spatial-learning or episodic memory by themselves. However when cognitive impairment was induced in the rats with scopolamine (1 mg/kg), both PNU-120596 and PNU-282987 were able to reverse this memory impairment and restore it back to normal levels. While PNU-120596 reversed the scopolamineinduced cognitive impairment, it did not have any adverse effect on anxiety. PNU-282987 on the other hand displayed an increase in anxiety-like behavior at a higher dose (10 mg/kg) that was significantly reduced by the serotonin 5-HT1a receptor antagonist WAY-100135. However the alpha 7 receptor antagonist methyllycaconitine was unable to reverse these anxiety-like effects seen with PNU-282987. These results suggest that alpha 7 nAChR PAMs are pharmacologically advantageous over agonists, and should be considered for further development as therapeutic drugs targeting the alpha 7 receptors. Published by Elsevier Ltd. C1 [Pandya, Anshul A.; Yakel, Jerrel L.] NIEHS, Neurobiol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Yakel, JL (reprint author), NIEHS, Neurobiol Lab, NIH, Dept Hlth & Human Serv, MD F2-08,POB 12233, Res Triangle Pk, NC 27709 USA. EM pandyaaa@niehs.nih.gov; yakel@niehs.nih.gov FU National Institute of Environmental Health Sciences, NIH FX We would like to thank the NIEHS animal facility and specifically Hanna Harris for taking care of the rats and for performing injections for this study. We would also like to thank Pattie Lamb for her involvement in the process of writing the animal safety protocols for behavior tests described here. We extend our appreciation to C. Erxleben and R. Saha for advice in preparing the manuscript. This research was supported by the Intramural Research Program of National Institute of Environmental Health Sciences, NIH. NR 70 TC 23 Z9 23 U1 0 U2 16 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD JUL PY 2013 VL 70 BP 35 EP 42 DI 10.1016/j.neuropharm.2013.01.004 PG 8 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 153YB UT WOS:000319637600005 PM 23321689 ER PT J AU Li, JM Xue, ZQ Deng, SH Luo, XG Patrylo, PR Rose, GW Cai, HB Cai, Y Yan, XX AF Li, Jian-Ming Xue, Zhi-Qin Deng, Si-Hao Luo, Xue-Gang Patrylo, Peter R. Rose, Gregory W. Cai, Huaibin Cai, Yan Yan, Xiao-Xin TI Amyloid plaque pathogenesis in 5XFAD mouse spinal cord: retrograde transneuronal modulation after peripheral nerve injury SO NEUROTOXICITY RESEARCH LA English DT Article DE Alzheimer's disease; Amyloidogenesis; BACE1; Neuritic dystrophy; Synaptoplasticity ID A-BETA PEPTIDES; ALZHEIMERS-DISEASE; BETA-SECRETASE-1 ELEVATION; PERMANENT AXOTOMY; MEMORY DEFICITS; TRANSGENIC MICE; NEURON LOSS; ADULT CAT; IN-VIVO; MOTONEURONS AB The spinal cord is composed of distinct neuronal groups with well-defined anatomic connections. In some transgenic (Tg) models of Alzheimer's disease (AD), amyloid plaques develop in this structure, although the underlying cellular mechanism remains elusive. We attempted to explore the origin, evolution, and modulation of spinal beta-amyloid (A beta) deposition using Tg mice harboring five familiar AD-related mutations (5XFAD) as an experiential model. Dystrophic neuritic elements with enhanced beta-secretase-1 (BACE1) immunoreactivity (IR) appeared as early as 2 months of age, and increased with age up to 12 months examined in this study, mostly over the ventral horn (VH). Extracellular A beta IR emerged and developed during this same period, site-specifically co-existing with BACE1-labeled neurites often in the vicinity of large VH neurons that expressed the mutant human APP. The BACE1-labeled neurites almost invariably colocalized with beta-amyloid precursor protein (APP) and synaptophysin, and frequently with the vesicular glutamate transporter-1 (VGLUT). Reduced IR for the neuronal-specific nuclear antigen (NeuN) occurred in the VH by 12 months of age. In 8-month-old animals surviving 6 months after a unilateral sciatic nerve transection, there were significant increases of A beta, BACE1, and VGLUT IR in the VN of the ipsilateral relative to contralateral lumbar spinal segments. These results suggest that extracellular A beta deposition in 5XFAD mouse spinal cord relates to a progressive and amyloidogenic synaptic pathology largely involving presynaptic axon terminals from projection neurons in the brain. Spinal neuritic plaque formation is enhanced after peripheral axotomy, suggesting a retrograde transneuronal modulation on pathogenesis. C1 [Li, Jian-Ming] Changsha Med Univ, Neurosci Res Ctr, Changsha 410219, Hunan, Peoples R China. [Li, Jian-Ming; Xue, Zhi-Qin; Deng, Si-Hao; Luo, Xue-Gang; Cai, Yan; Yan, Xiao-Xin] Cent South Univ Xiangya Sch Med, Dept Anat & Neurobiol, Changsha 410013, Hunan, Peoples R China. [Xue, Zhi-Qin] Xinjiang Med Univ, Dept Anat, Urumqi 830011, Xinjiang, Peoples R China. [Patrylo, Peter R.; Rose, Gregory W.; Yan, Xiao-Xin] Southern Illinois Univ Sch Med, Ctr Integrated Res Cognit & Neural Sci, Carbondale, IL 62901 USA. [Cai, Huaibin] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Yan, XX (reprint author), Cent South Univ Xiangya Sch Med, Dept Anat & Neurobiol, Changsha 410013, Hunan, Peoples R China. EM yanxiaoxin@csu.edu.cn RI Cai, Huaibin/H-3359-2013 OI Cai, Huaibin/0000-0002-8596-6108 FU Illinois Department of Public Health; National Natural Science Foundation of China [81171091, 81171160]; Hunan Natural Science Foundation [11jj5072]; National Institute on Aging, NIH [Z01-IAAG000944-04] FX This study was supported by the Illinois Department of Public Health (X.X.Y.), the National Natural Science Foundation of China (#81171091 to X.X.Y. and #81171160 to X.G.L), Hunan Natural Science Foundation (11jj5072 to J.M.L) and the intramural research program of National Institute on Aging, NIH (Z01-IAAG000944-04 to H.C.). We thank Elan Pharmaceuticals for providing the 3D6 antibody. NR 60 TC 4 Z9 5 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1029-8428 J9 NEUROTOX RES JI Neurotox. Res. PD JUL PY 2013 VL 24 IS 1 BP 1 EP 14 DI 10.1007/s12640-012-9355-2 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 154NK UT WOS:000319682500001 PM 23055086 ER PT J AU Vandenberg, LN Colborn, T Hayes, TB Heindel, JJ Jacobs, DR Lee, DH Myers, JP Shioda, T Soto, AM vom Saal, FS Welshons, WV Zoeller, RT AF Vandenberg, Laura N. Colborn, Theo Hayes, Tyrone B. Heindel, Jerrold J. Jacobs, David R., Jr. Lee, Duk-Hee Myers, John Peterson Shioda, Toshi Soto, Ana M. vom Saal, Frederick S. Welshons, Wade V. Zoeller, R. Thomas TI Regulatory decisions on endocrine disrupting chemicals should be based on the principles of endocrinology SO REPRODUCTIVE TOXICOLOGY LA English DT Review DE Weight of evidence; Organizational; Adaptive effect; Hormesis; Human exposure; Epidemiology; Flare ID ORGANIZATIONAL-ACTIVATIONAL HYPOTHESIS; PRENATAL PHTHALATE EXPOSURE; NUCLEAR RECEPTOR SUPERFAMILY; NONMONOTONIC DOSE-RESPONSES; GOOD LABORATORY PRACTICES; BISPHENOL-A EXPOSURE; OF-EVIDENCE ANALYSIS; BREAST-CANCER CELLS; ANOGENITAL DISTANCE; RISK-ASSESSMENT AB For years, scientists from various disciplines have studied the effects of endocrine disrupting chemicals (EDCs) on the health and wellbeing of humans and wildlife. Some studies have specifically focused on the effects of low doses, i.e. those in the range that are thought to be safe for humans and/or animals. Others have focused on the existence of non-monotonic dose response curves. These concepts challenge the way that chemical risk assessment is performed for EDCs. Continued discussions have clarified exactly what controversies and challenges remain. We address several of these issues, including why the study and regulation of EDCs should incorporate endocrine principles; what level of consensus there is for low dose effects; challenges to our understanding of non-monotonicity; and whether EDCs have been demonstrated to produce adverse effects. This discussion should result in a better understanding of these issues, and allow for additional dialog on their impact on risk assessment. (c) 2013 Elsevier Inc. All rights reserved. C1 [Vandenberg, Laura N.] Tufts Univ, Ctr Regenerat & Dev Biol, Medford, MA 02155 USA. [Vandenberg, Laura N.] Tufts Univ, Dept Biol, Medford, MA 02155 USA. [Colborn, Theo] Endocrine Disrupt Exchange, Paonia, CO USA. [Hayes, Tyrone B.] Univ Calif Berkeley, Museum Vertebrate Zool, Energy & Resources Grp, Grp Endocrinol,Lab Integrat Studies Amphibian Bio, Berkeley, CA 94720 USA. [Hayes, Tyrone B.] Univ Calif Berkeley, Dept Integrat Biol, Berkeley, CA 94720 USA. [Heindel, Jerrold J.] NIEHS, Div Extramural Res & Training, NIH DHHS, Res Triangle Pk, NC 27709 USA. [Jacobs, David R., Jr.] Univ Minnesota, Div Epidemiol & Community Hlth, Sch Publ Hlth, Minneapolis, MN USA. [Lee, Duk-Hee] Kyungpook Natl Univ, Sch Med, Dept Prevent Med, Taegu, South Korea. [Shioda, Toshi] Massachusetts Gen Hosp, Ctr Canc Res, Mol Profiling Lab, Charlestown, MA USA. [Soto, Ana M.] Tufts Univ, Sch Med, Dept Anat & Cell Biol, Medford, MA 02155 USA. [vom Saal, Frederick S.] Univ Missouri, Div Biol Sci, Columbia, MO 65211 USA. [Welshons, Wade V.] Univ Missouri, Dept Biomed Sci, Columbia, MO USA. [Zoeller, R. Thomas] Univ Massachusetts, Dept Biol, Amherst, MA 01003 USA. RP Vandenberg, LN (reprint author), Tufts Univ, Ctr Regenerat & Dev Biol, 200 Boston Ave,Suite 4600, Medford, MA 02155 USA. EM laura.vandenberg@tufts.edu FU NIH [GM 087107, ES 08314, ES 010026, ES 018764, HL 53560, UMC MO-VMFC0018]; Susan G. Komen for Cure grant [FAS0703860]; Mitchell Kapor Foundation; Cornell-Douglas Foundation; Wallace Global Fund; Kendeda Foundation FX The authors gratefully acknowledge the following funding sources: NIH grants GM 087107 (to LNV), ES 08314 (to AMS), ES 010026 (to RTZ), ES 018764 (to FSvS), HL 53560 (to DRJ), UMC MO-VMFC0018 (to WVW), a Susan G. Komen for Cure grant FAS0703860 (to TS), grants from the Mitchell Kapor Foundation, the Cornell-Douglas Foundation, and the Wallace Global Fund (to TBH) and a grant from the Kendeda Foundation (to JPM). The funders had no role in the preparation of this manuscript. NR 216 TC 54 Z9 58 U1 10 U2 108 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD JUL PY 2013 VL 38 BP 1 EP 15 DI 10.1016/j.reprotox.2013.02.002 PG 15 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 152MG UT WOS:000319535200001 PM 23411111 ER PT J AU Okpechi, I Swanepoel, C Rayner, B Gcelu, A Hodkinson, B Kalla, A Ramesar, R Vorster, A Adeyemo, A Heering, P Tiffin, N AF Okpechi, I Swanepoel, C. Rayner, B. Gcelu, A. Hodkinson, B. Kalla, A. Ramesar, R. Vorster, A. Adeyemo, A. Heering, P. Tiffin, N. TI Systemic lupus erythematosus (SLE) in Cape Town: A precursory report of the ALUGEN registry SO CLINICAL RHEUMATOLOGY LA English DT Meeting Abstract C1 [Okpechi, I; Swanepoel, C.; Rayner, B.] Univ Cape Town, Div Nephrol & Hypertens, ZA-7700 Rondebosch, South Africa. [Gcelu, A.; Hodkinson, B.; Kalla, A.] Univ Cape Town, Div Rheumatol, ZA-7700 Rondebosch, South Africa. [Ramesar, R.; Vorster, A.] Univ Cape Town, Dept Human Genet, ZA-7700 Rondebosch, South Africa. [Adeyemo, A.] NHGRI, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. [Heering, P.] Univ Dusseldorf Germany, Dept Nephrol, Dusseldorf, Germany. [Tiffin, N.] Univ Western Cape, MRC Unit Bioinformat Capac Dev, South African Natl Bioinformat Inst, ZA-7535 Bellville, South Africa. RI Ramesar, Raj/I-6941-2015 OI Ramesar, Raj/0000-0001-5688-1634 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0770-3198 EI 1434-9949 J9 CLIN RHEUMATOL JI Clin. Rheumatol. PD JUL PY 2013 VL 32 SU 2 MA P4 BP S140 EP S141 PG 2 WC Rheumatology SC Rheumatology GA AU4HN UT WOS:000345571500064 ER PT J AU Merikangas, K AF Merikangas, Kathleen TI Breaking Down the Boundaries : Comorbidity of Mental and Physical Disorders SO EUROPEAN CHILD & ADOLESCENT PSYCHIATRY LA English DT Meeting Abstract DE comorbidity; epidemiology; medical disorders; mood disorders; anxiety disorders; behavior disorders; ADHD C1 [Merikangas, Kathleen] NIMH, Intramural Res Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1018-8827 EI 1435-165X J9 EUR CHILD ADOLES PSY JI Eur. Child Adolesc. Psych. PD JUL PY 2013 VL 22 SU 2 MA W2-01 BP S212 EP S212 PG 1 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA V41LO UT WOS:000209547900338 ER PT J AU Anderson, BL Pearlman, M Griffin, J Schulkin, J AF Anderson, Britta L. Pearlman, Mark Griffin, Jennifer Schulkin, Jay TI Conflicting and Changing Breast Cancer Screening Recommendations: Survey Study of a National Sample of ob-gyns after the Release of the 2009 USPSTF Guidelines SO JOURNAL FOR HEALTHCARE QUALITY LA English DT Article DE breast cancer; evidence-based practice/guidelines; health promotion and screening; research quantitative AB Objective: To assess obstetrician-gynecologists' (obgyns') use of multiple conflicting guidelines assess after the release of the 2009 U.S. Preventive Services Task Force (USPSTF) breast cancer screening recommendations. Study Design: A nationally representative sample of American College of Obstetricians and Gynecologists (ACOG) Fellows were invited to complete a survey. Results: A total of 235 of 399 ob-gyns responded (59% response rate). Twenty percent and 89% indicated that USPSTF and ACOG guidelines influence their practice, respectively, 84% are influenced by more than one guideline. The plurality of respondents was able to correctly identify ACOG and USPSTF guidelines on 10 of 12 questions. One-third agreed with both ACOG's and USPSTF's recommendations regarding mammography screening for women 40-49 years old. A total of 42% of the sample made at least one change in their practice after the release of the 2009 USPSTF breast cancer screening guidelines. Conclusion: Some ob-gyns made changes to their practices after the release of the USPSTF guidelines. When multiple guidelines exist, as in the case with breast cancer screening, physicians utilize multiple, and at times conflicting, guidelines. More research will be needed to better understand the impact (negative or positive) of multiple guidelines on the quality of healthcare. C1 [Anderson, Britta L.; Schulkin, Jay] Amer Coll Obstetricians & Gynecologists, New York, NY 10029 USA. [Pearlman, Mark] Univ Michigan Hosp & Hlth Ctr, Dept Obstet & Gynecol, Ann Arbor, MI USA. [Pearlman, Mark] Univ Michigan Hosp & Hlth Ctr, Dept Surg, Ann Arbor, MI USA. [Pearlman, Mark] Univ Michigan, Ann Arbor, MI 48109 USA. [Griffin, Jennifer] Univ Nebraska Med Ctr, Dept Obstet & Gynecol, Omaha, NE USA. [Schulkin, Jay] Georgetown Univ, Dept Neurosci, Washington, DC 20057 USA. [Schulkin, Jay] NIMH, Behav Endocrinol Branch, Bethesda, MD USA. RP Anderson, BL (reprint author), Amer Coll Obstetricians & Gynecologists, New York, NY 10029 USA. EM banderson@acog.org FU U.S. Department of Health and Human Services, Health Resources and Services Administration, Maternal and Child Health Research Program [UA6MC19010] FX This study is funded by grant, UA6MC19010, through the U.S. Department of Health and Human Services, Health Resources and Services Administration, Maternal and Child Health Research Program. NR 20 TC 7 Z9 7 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1062-2551 EI 1945-1474 J9 J HEALTHC QUAL JI J. Healthc. Qual. PD JUL-AUG PY 2013 VL 35 IS 4 BP 25 EP 35 DI 10.1111/jhq.12009 PG 11 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA V36OU UT WOS:000209221800003 PM 23590634 ER PT J AU Komarow, HD Young, M Nelson, C Metcalfe, DD AF Komarow, Hirsh D. Young, Michael Nelson, Celeste Metcalfe, Dean D. TI Vocal Cord Dysfunction as Demonstrated by Impulse Oscillometry SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE LA English DT Article DE Vocal cord dysfunction; impulse oscillometry; asthma; laryngoscopy; spirometry AB BACKGROUND: Vocal cord dysfunction (VCD) is a respiratory disorder characterized by inappropriate vocal cord adduction during inspiration. The diagnosis of VCD is challenging, because expected flow volume loop abnormalities are uncommonly noted, and laryngoscopy must be timed to coincide with symptoms. OBJECTIVE: We wanted to determine the potential role of impulse oscillometry (IOS) in the diagnosis of VCD. METHODS: We conducted an analysis of six patients in which the diagnosis of VCD was being considered as well as seven healthy subjects and five subjects with asthma. All were evaluated with IOS and spirometry, and patients underwent laryngoscopy. Two patients with suspected VCD who did not exhibit symptoms or abnormal pulmonary function at baseline underwent exercise challenge and repeat studies. One patient with suspected VCD underwent an additional irritant challenge. RESULTS: VCD was diagnosed by laryngoscopy in three of the six patients in whom the diagnosis of VCD was entertained. These three patients as a group all exhibited higher amplitude (mean, 9.3 cm H(2)0/L/second) and more variable spikes (SD, 4.8 cm H(2)0/L/second) on IOS impedance during inspiration, whereas the three patients in whom the diagnosis was not confirmed by endoscopy did not show these findings (mean, 2.0 cm H(2)0/L/second; P < .0002; SD, 0.8 cm H(2)0/L/second; P < .0001). This pattern was also not observed in the healthy volunteers (mean +/- SD, 1.8 +/- 0.7 cm H(2)0/L/second) and patients with asthma at baseline (mean, 4.2 +/- 1.2 cm H(2)0/L/second) or after exercise challenge (mean, 1.5 +/- 0.5 cm H(2)0/L/second). CONCLUSIONS: These findings support the conclusion that IOS displays a characteristic pattern in patients with VCD and thus may offer a rapid and noninvasive adjunct to the assessment and diagnosis of patients suspected to have this disorder. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology C1 [Komarow, Hirsh D.; Nelson, Celeste; Metcalfe, Dean D.] NIAID, NIH, LAD, Bethesda, MD 20892 USA. [Young, Michael] SAIC Frederick Inc, Frederick Natl Lab Clin Res, Clin Monitoring Res Program, Clin Res Directorate, Frederick, MD USA. RP Komarow, HD (reprint author), NIAID, NIH, LAD, Bldg 10,Rm 1C129A1,10 Ctr Dr, Bethesda, MD 20892 USA. EM komarowh@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and in whole or in part by the National Cancer Institute, National Institutes of Health, contract no. HHSN261200800001E (M.Y.). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. NR 32 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2198 EI 2213-2201 J9 J ALLER CL IMM-PRACT JI J. Allergy Clin. Immunol.-Pract. PD JUL-AUG PY 2013 VL 1 IS 4 BP 387 EP + DI 10.1016/j.jaip.2013.05.005 PG 9 WC Allergy; Immunology SC Allergy; Immunology GA V38WW UT WOS:000209374500010 PM 24565544 ER PT J AU Spencer, RG Pleshko, N AF Spencer, Richard G. Pleshko, Nancy TI How Do Statistical Differences in Matrix-sensitive Magnetic Resonance Outcomes Translate Into Clinical Assignment Rules? SO JOURNAL OF THE AMERICAN ACADEMY OF ORTHOPAEDIC SURGEONS LA English DT Editorial Material C1 [Spencer, Richard G.] NIA, Magnet Resonance Imaging & Spect Sect, NIH, Baltimore, MD 21224 USA. [Pleshko, Nancy] Temple Univ, Dept Bioengn, Tissue Imaging & Spect Lab, Philadelphia, PA 19122 USA. RP Spencer, RG (reprint author), NIA, Magnet Resonance Imaging & Spect Sect, NIH, Baltimore, MD 21224 USA. FU Intramural NIH HHS [ZIA AG000922-05] NR 5 TC 7 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1067-151X EI 1940-5480 J9 J AM ACAD ORTHOP SUR JI J. Am. Acad. Orthop. Surg. PD JUL PY 2013 VL 21 IS 7 BP 438 EP 439 DI 10.5435/JAAOS-21-07-438 PG 2 WC Orthopedics; Surgery SC Orthopedics; Surgery GA V37MX UT WOS:000209281000009 PM 23818031 ER PT J AU Bulea, TC Kilicarslan, A Ozdemir, R Paloski, WH Contreras-Vidal, JL AF Bulea, Thomas C. Kilicarslan, Atilla Ozdemir, Recep Paloski, William H. Contreras-Vidal, Jose L. TI Simultaneous Scalp Electroencephalography (EEG), Electromyography (EMG), and Whole-body Segmental Inertial Recording for Multi-modal Neural Decoding SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Behavior; Issue 77; Neuroscience; Neurobiology; Medicine; Anatomy; Physiology; Biomedical Engineering; Molecular Biology; Electroencephalography; EEG; Electromyography; EMG; electroencephalograph; gait; brain-computer interface; brain machine interface; neural decoding; over-ground walking; robotic gait; brain; imaging; clinical techniques AB Recent studies support the involvement of supraspinal networks in control of bipedal human walking. Part of this evidence encompasses studies, including our previous work, demonstrating that gait kinematics and limb coordination during treadmill walking can be inferred from the scalp electroencephalogram (EEG) with reasonably high decoding accuracies. These results provide impetus for development of non-invasive brain-machine-interface (BMI) systems for use in restoration and/or augmentation of gait-a primary goal of rehabilitation research. To date, studies examining EEG decoding of activity during gait have been limited to treadmill walking in a controlled environment. However, to be practically viable a BMI system must be applicable for use in everyday locomotor tasks such as over ground walking and turning. Here, we present a novel protocol for non-invasive collection of brain activity (EEG), muscle activity (electromyography (EMG)), and whole-body kinematic data (head, torso, and limb trajectories) during both treadmill and over ground walking tasks. By collecting these data in the uncontrolled environment insight can be gained regarding the feasibility of decoding unconstrained gait and surface EMG from scalp EEG. C1 [Bulea, Thomas C.] NIH, Bethesda, MD 20892 USA. [Bulea, Thomas C.; Kilicarslan, Atilla; Ozdemir, Recep; Contreras-Vidal, Jose L.] Univ Houston, Dept Elect & Comp Engn, Lab Noninvas Brain Machine Interface Syst, Houston, TX 77004 USA. [Ozdemir, Recep; Paloski, William H.] Univ Houston, Dept Hlth & Human Performance, Houston, TX 77004 USA. [Ozdemir, Recep; Paloski, William H.; Contreras-Vidal, Jose L.] Univ Houston, Ctr Neuromotor & Biomech Res, Houston, TX 77004 USA. [Contreras-Vidal, Jose L.] Univ Houston, Dept Biomed Engn, Houston, TX 77004 USA. RP Bulea, TC (reprint author), NIH, Bethesda, MD 20892 USA. EM thomas.bulea@nih.gov FU National Institute of Neurological Disorders and Stroke (NINDS) [R01NS075889-01]; Intramural Research Program of the NIH, Clinical Center; APDM, Inc. (Portland, OR) FX This work was supported by the National Institute of Neurological Disorders and Stroke (NINDS) grant # R01NS075889-01. This research was supported in part by the Intramural Research Program of the NIH, Clinical Center. The authors also thank Shahriar Iqbal and Yongtian He for assistance with data collection. The cost of open-access publication of this article was sponsored by APDM, Inc. (Portland, OR; http://apdm.com). NR 22 TC 3 Z9 3 U1 1 U2 9 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD JUL PY 2013 IS 77 AR UNSP e50602 DI 10.3791/50602 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36RG UT WOS:000209227900053 ER PT J AU Swamydas, M Lionakis, MS AF Swamydas, Muthulekha Lionakis, Michail S. TI Isolation, Purification and Labeling of Mouse Bone Marrow Neutrophils for Functional Studies and Adoptive Transfer Experiments SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Immunology; Issue 77; Cellular Biology; Infection; Infectious Diseases; Molecular Biology; Medicine; Biomedical Engineering; Bioengineering; Neutrophils; Adoptive Transfer; immunology; Neutrophils; mouse; bone marrow; adoptive transfer; density gradient; labeling; CellTracker; cell; isolation; flow cytometry; animal model AB Neutrophils are critical effector cells of the innate immune system. They are rapidly recruited at sites of acute inflammation and exert protective or pathogenic effects depending on the inflammatory milieu. Nonetheless, despite the indispensable role of neutrophils in immunity, detailed understanding of the molecular factors that mediate neutrophils' effector and immunopathogenic effects in different infectious diseases and inflammatory conditions is still lacking, partly because of their short half life, the difficulties with handling of these cells and the lack of reliable experimental protocols for obtaining sufficient numbers of neutrophils for downstream functional studies and adoptive transfer experiments. Therefore, simple, fast, economical and reliable methods are highly desirable for harvesting sufficient numbers of mouse neutrophils for assessing functions such as phagocytosis, killing, cytokine production, degranulation and trafficking. To that end, we present a reproducible density gradient centrifugation-based protocol, which can be adapted in any laboratory to isolate large numbers of neutrophils from the bone marrow of mice with high purity and viability. Moreover, we present a simple protocol that uses CellTracker dyes to label the isolated neutrophils, which can then be adoptively transferred into recipient mice and tracked in several tissues for at least 4 hr post-transfer using flow cytometry. Using this approach, differential labeling of neutrophils from wild-type and gene-deficient mice with different CellTracker dyes can be successfully employed to perform competitive repopulation studies for evaluating the direct role of specific genes in trafficking of neutrophils from the blood into target tissues in vivo. C1 [Swamydas, Muthulekha; Lionakis, Michail S.] NIAID, Fungal Pathogenesis Unit, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Lionakis, MS (reprint author), NIAID, Fungal Pathogenesis Unit, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. EM lionakism@mail.nih.gov FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Health (NIH), USA; Animal Care and Use Committee of the NIAID FX This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Health (NIH), USA.; All mice were maintained at an American Association for the Accreditation of Laboratory Animal Care-accredited animal facility at the National Institute of Allergy and Infectious Diseases (NIAID) and housed in accordance with the procedures outlined in the Guide for the Care and Use of Laboratory Animals under the auspices of a protocol approved by the Animal Care and Use Committee of the NIAID. NR 22 TC 13 Z9 13 U1 3 U2 14 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD JUL PY 2013 IS 77 AR UNSP e50586 DI 10.3791/50586 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36RG UT WOS:000209227900050 PM 23892876 ER PT J AU Horkay, F AF Horkay, Ferenc TI Ion Polymer Interactions in DNA Solutions and Gels SO MACROMOLECULAR SYMPOSIA LA English DT Proceedings Paper CT Polymer Networks Conference (PNG) CY AUG 12-16, 2012 CL WY DE calcium ion; DNA; osmotic pressure; polyelectrolyte; small angle neutron scattering; swelling ID POLYELECTROLYTE SOLUTIONS; CONDENSATION; TRANSITION; NETWORKS; CATIONS AB Systematic investigations using small angle neutron scattering (SANS) were made to reveal the effect of calcium ions on the structure of DNA gels and solutions in near-physiological salt solutions. To describe the neutron scattering response two characteristic distances are required. The shorter length scale, R (approximate to 10 angstrom), was found to be governed by the geometry of the DNA chain and is close to the cross-sectional radius of the double helix. The longer length scale L corresponds to the mesh size of the network of overlapping polymer chains. L decreases with increasing DNA concentration as L proportional to C-DNA(-0.73). With increasing CaCl2 concentration both L and the scattering intensity increase. The increase in the scattering intensity reflects the reduction of the osmotic modulus as the calcium ion concentration increases. The values of the osmotic modulus derived from osmotic swelling pressure measurements are in reasonable agreement with those obtained from SANS. C1 NICHD, Sect Tissue Biophys & Biomimet, NIH, Bethesda, MD 20892 USA. RP Horkay, F (reprint author), NICHD, Sect Tissue Biophys & Biomimet, NIH, 13 South Dr, Bethesda, MD 20892 USA. EM horkayf@helix.nih.gov NR 42 TC 0 Z9 0 U1 2 U2 5 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1022-1360 EI 1521-3900 J9 MACROMOL SYMP JI Macromol. Symp. PD JUL PY 2013 VL 329 IS 1 BP 19 EP 26 DI 10.1002/masy.201300028 PG 8 WC Polymer Science SC Polymer Science GA AG5BR UT WOS:000335434600003 ER PT J AU Betz, JM AF Betz, J. M. TI Nature Exposed to Our Method of Questioning: Reliability of Natural Product Measurements SO PLANTA MEDICA LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Pharmacognosy on Natural Products at a Crossroad - Current and Future Directions CY JUL 14-17, 2013 CL St Louis, MO SP Amer Soc Pharmacognosy C1 [Betz, J. M.] US NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 EI 1439-0221 J9 PLANTA MED JI Planta Med. PD JUL PY 2013 VL 79 IS 10 MA AL1 BP 819 EP 819 PG 1 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA AK8RG UT WOS:000338695100048 ER PT J AU Downey, T Bosserman, M Noinaj, N Buchanan, SK Rohr, J AF Downey, T. Bosserman, M. Noinaj, N. Buchanan, S. K. Rohr, J. TI Investigating and Re-Engineering Baeyer-Villiger Monooxygenase MtmOIV for Combinatorial Biosynthesis of Novel Aureolic Acid Anticancer Drug Analogues SO PLANTA MEDICA LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Pharmacognosy on Natural Products at a Crossroad - Current and Future Directions CY JUL 14-17, 2013 CL St Louis, MO SP Amer Soc Pharmacognosy C1 [Downey, T.; Bosserman, M.; Rohr, J.] Univ Kentucky, Dept Pharmaceut Sci, Lexington, KY 40536 USA. [Noinaj, N.; Buchanan, S. K.] NIDDK, Lab Mol Biol, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 EI 1439-0221 J9 PLANTA MED JI Planta Med. PD JUL PY 2013 VL 79 IS 10 MA PA5 BP 826 EP 826 PG 1 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA AK8RG UT WOS:000338695100076 ER PT J AU Divlianska, DB Wright, AE Francis, S Walters, MA Salomon, CE Diaz, PW Hassig, CA O'Keefe, BR Reed, JC Roth, GP AF Divlianska, D. B. Wright, A. E. Francis, S. Walters, M. A. Salomon, C. E. Diaz, P. W. Hassig, C. A. O'Keefe, B. R. Reed, J. C. Roth, G. P. TI In Search of Novel Cancer Therapeutics: Assessing the NCI Natural Product Library against Ten Anti-Apoptotic Protein Targets SO PLANTA MEDICA LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Pharmacognosy on Natural Products at a Crossroad - Current and Future Directions CY JUL 14-17, 2013 CL St Louis, MO SP Amer Soc Pharmacognosy C1 [Divlianska, D. B.; Diaz, P. W.; Hassig, C. A.; Roth, G. P.] Sanford Burnham Med Res Inst, Orlando, FL 32827 USA. [Wright, A. E.] Florida Atlantic Univ, Oceanog Inst, Harbor Branch, Ft Pierce, FL 34946 USA. [Francis, S.; Walters, M. A.] Univ Minnesota, Inst Therapeut Discovery & Dev, Minneapolis, MN 55414 USA. [Salomon, C. E.] Univ Minnesota, Ctr Drug Design, Minneapolis, MN 55455 USA. [O'Keefe, B. R.] NCI, Mol Targets Lab, CCR, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Reed, J. C.] F Hoffmann La Roche Ltd, PRED, CH-4070 Basel, Switzerland. RI Divlianska, Daniela/I-3567-2016 OI Divlianska, Daniela/0000-0002-6871-2122 NR 0 TC 0 Z9 0 U1 0 U2 2 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 EI 1439-0221 J9 PLANTA MED JI Planta Med. PD JUL PY 2013 VL 79 IS 10 MA PF4 BP 834 EP 834 PG 1 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA AK8RG UT WOS:000338695100110 ER PT J AU Castro, A Smith, EA Krumpe, LRH O'Keefe, BR Staudt, LM McMahon, JB Gustafson, KR AF Castro, A. Smith, E. A. Krumpe, Haugh L. R. O'Keefe, B. R. Staudt, L. M. McMahon, J. B. Gustafson, K. R. TI Natural Product Inhibitors of the Arginine-Specific Protease Activity of MALT1 SO PLANTA MEDICA LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Pharmacognosy on Natural Products at a Crossroad - Current and Future Directions CY JUL 14-17, 2013 CL St Louis, MO SP Amer Soc Pharmacognosy C1 [Castro, A.; Smith, E. A.; Krumpe, Haugh L. R.; O'Keefe, B. R.; McMahon, J. B.; Gustafson, K. R.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Krumpe, Haugh L. R.] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Staudt, L. M.] NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 EI 1439-0221 J9 PLANTA MED JI Planta Med. PD JUL PY 2013 VL 79 IS 10 MA PK9 BP 845 EP 845 PG 1 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA AK8RG UT WOS:000338695100156 ER PT J AU Sunassee, SN Ransom, T Heinrich, CJ McMahon, JB Gustafson, KR AF Sunassee, S. N. Ransom, T. Heinrich, C. J. McMahon, J. B. Gustafson, K. R. TI New Steroidal Alkaloids from the Marine Sponge Corticium niger that Inhibit Growth of Human Colon Carcinoma Cells SO PLANTA MEDICA LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Pharmacognosy on Natural Products at a Crossroad - Current and Future Directions CY JUL 14-17, 2013 CL St Louis, MO SP Amer Soc Pharmacognosy C1 [Sunassee, S. N.; Ransom, T.; Heinrich, C. J.; McMahon, J. B.; Gustafson, K. R.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 EI 1439-0221 J9 PLANTA MED JI Planta Med. PD JUL PY 2013 VL 79 IS 10 MA PK11 BP 845 EP 845 PG 1 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA AK8RG UT WOS:000338695100158 ER PT J AU Zuck, KM Rosario, M Widmer, TL Newman, DJ AF Zuck, K. M. Rosario, M. Widmer, T. L. Newman, D. J. TI New Analogs Produced by the Co-Culture of the Endophyte Xylaria sp and Phytophthora SO PLANTA MEDICA LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Pharmacognosy on Natural Products at a Crossroad - Current and Future Directions CY JUL 14-17, 2013 CL St Louis, MO SP Amer Soc Pharmacognosy C1 [Zuck, K. M.] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Nat Prod Support Grp, Frederick, MD 21702 USA. [Rosario, M.; Newman, D. J.] NCI, Frederick Natl Lab Canc Res, DTP, Nat Prod Branch, Frederick, MD 21702 USA. [Widmer, T. L.] ARS, USDA, FDWSRU, Ft Detrick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 EI 1439-0221 J9 PLANTA MED JI Planta Med. PD JUL PY 2013 VL 79 IS 10 MA PL24 BP 852 EP 852 PG 1 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA AK8RG UT WOS:000338695100188 ER PT J AU Chan, STS Popplewell, W Henrich, CJ Linehan, WM Bottaro, DP McMahon, JB McKee, TC Gustafson, KR AF Chan, S. T. S. Popplewell, W. Henrich, C. J. Linehan, W. M. Bottaro, D. P. McMahon, J. B. McKee, T. C. Gustafson, K. R. TI Isolation and Identification of Natural Products from Artocarpus communis SO PLANTA MEDICA LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Pharmacognosy on Natural Products at a Crossroad - Current and Future Directions CY JUL 14-17, 2013 CL St Louis, MO SP Amer Soc Pharmacognosy C1 [Chan, S. T. S.; Popplewell, W.; McMahon, J. B.; McKee, T. C.; Gustafson, K. R.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Henrich, C. J.] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Linehan, W. M.; Bottaro, D. P.] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 EI 1439-0221 J9 PLANTA MED JI Planta Med. PD JUL PY 2013 VL 79 IS 10 MA PN58 BP 870 EP 870 PG 1 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA AK8RG UT WOS:000338695100262 ER PT J AU Deal, C AF Deal, C. TI CHALLENGES AND OPPORTUNITIES: POTENTIALS IN RESEARCH ON AMR GONOCOCCI SO SEXUALLY TRANSMITTED INFECTIONS LA English DT Meeting Abstract C1 [Deal, C.] NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1368-4973 EI 1472-3263 J9 SEX TRANSM INFECT JI Sex. Transm. Infect. PD JUL PY 2013 VL 89 SU 1 MA S05.2 BP A11 EP A11 DI 10.1136/sextrans-2013-051184.0032 PG 1 WC Infectious Diseases SC Infectious Diseases GA V40SD UT WOS:000209497400028 ER PT J AU Grabowski, MK Gray, RH Serwadda, D Kigozi, G Gravitt, PE Nalugoda, F Renyolds, SJ Wawer, M Quinn, TC Tobian, AAR AF Grabowski, M. K. Gray, R. H. Serwadda, D. Kigozi, G. Gravitt, P. E. Nalugoda, F. Renyolds, S. J. Wawer, M. Quinn, T. C. Tobian, A. A. R. TI HIGH RISK HUMAN PAPILLOMAVIRUS VIRAL LOAD AND PERSISTENCE AMONG HIV-NEGATIVE AND HIV-POSITIVE MEN SO SEXUALLY TRANSMITTED INFECTIONS LA English DT Meeting Abstract C1 [Grabowski, M. K.; Gray, R. H.; Gravitt, P. E.; Renyolds, S. J.; Wawer, M.; Quinn, T. C.; Tobian, A. A. R.] Johns Hopkins, Baltimore, MD USA. [Gray, R. H.; Serwadda, D.; Nalugoda, F.; Renyolds, S. J.; Wawer, M.] Rakai Hlth Sci Program, Entebbe, Uganda. [Serwadda, D.] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. [Kigozi, G.] Rakai Hlth Sci Program, En, Uganda. [Gravitt, P. E.] Perdana Univ, Grad Sch Med, Serdang, Malaysia. [Renyolds, S. J.; Quinn, T. C.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Tobian, A. A. R.] Rakai Hlth Sci Program, Entebbe, Austria. NR 0 TC 0 Z9 0 U1 1 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1368-4973 EI 1472-3263 J9 SEX TRANSM INFECT JI Sex. Transm. Infect. PD JUL PY 2013 VL 89 SU 1 MA P3.222 BP A217 EP A218 DI 10.1136/sextrans-2013-051184.0679 PG 3 WC Infectious Diseases SC Infectious Diseases GA V40VR UT WOS:000209506600071 ER PT J AU Grabowski, MK Lessler, J Redd, A Kagaayi, J Laeyendecker, O Nalugoda, F Serwadda, D Wawer, M Quinn, TC Gray, RH AF Grabowski, M. K. Lessler, J. Redd, A. Kagaayi, J. Laeyendecker, O. Nalugoda, F. Serwadda, D. Wawer, M. Quinn, T. C. Gray, R. H. TI FREQUENT VIRAL INTRODUCTIONS SUSTAIN LOCAL HIV EPIDEMICS IN RURAL AFRICA SO SEXUALLY TRANSMITTED INFECTIONS LA English DT Meeting Abstract C1 [Grabowski, M. K.; Lessler, J.; Laeyendecker, O.; Wawer, M.; Quinn, T. C.; Gray, R. H.] Johns Hopkins, Baltimore, MD USA. [Redd, A.; Laeyendecker, O.; Quinn, T. C.] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Kagaayi, J.; Nalugoda, F.; Serwadda, D.; Wawer, M.; Gray, R. H.] Rakai Hlth Sci Program, Kalisizo, Uganda. [Serwadda, D.] Makerere Univ, Sch Med, Kampala, Uganda. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1368-4973 EI 1472-3263 J9 SEX TRANSM INFECT JI Sex. Transm. Infect. PD JUL PY 2013 VL 89 SU 1 MA S15.1 BP A22 EP A22 DI 10.1136/sextrans-2013-051184.0070 PG 1 WC Infectious Diseases SC Infectious Diseases GA V40SD UT WOS:000209497400066 ER PT J AU Kenney, J Derby, N Aravantinou, M Rana, S Lifson, JD Piatak, M Gettie, A Blanchard, J Robbiani, M AF Kenney, J. Derby, N. Aravantinou, M. Rana, S. Lifson, J. D. Piatak, M., Jr. Gettie, A. Blanchard, J. Robbiani, M. TI A REPEATED LOW DOSE CO-CHALLENGE MODEL OF SHIV-RT AND HSV-2 IN RHESUS MACAQUES SO SEXUALLY TRANSMITTED INFECTIONS LA English DT Meeting Abstract C1 [Kenney, J.; Derby, N.; Aravantinou, M.; Rana, S.; Robbiani, M.] Populat Council, New York, NY 10021 USA. [Lifson, J. D.; Piatak, M., Jr.] NCI, SAIC Frederick Inc, Frederick, MD 21701 USA. [Gettie, A.] Aaron Diamond AIDS Res Ctr, New York, NY USA. [Blanchard, J.] Tulane Natl Primate Res Ctr, Covington, LA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1368-4973 EI 1472-3263 J9 SEX TRANSM INFECT JI Sex. Transm. Infect. PD JUL PY 2013 VL 89 SU 1 MA P2.091 BP A116 EP A116 DI 10.1136/sextrans-2013-051184.0355 PG 1 WC Infectious Diseases SC Infectious Diseases GA V40SD UT WOS:000209497400351 ER PT J AU Marrazzo, J Rabe, L Kelly, C Livant, T Chirenje, M Richardson, B Deal, C Piper, J Hillier, S AF Marrazzo, J. Rabe, L. Kelly, C. Livant, T. Chirenje, M. Richardson, B. Deal, C. Piper, J. Hillier, S. TI HERPES SIMPLEX VIRUS (HSV) INFECTION IN THE VOICE (MTN 003) STUDY: PRE-EXPOSURE PROPHYLAXIS (PREP) FOR HIV WITH DAILY USE OF ORAL TENOFOVIR, ORAL TENOFOVIR-EMTRICITABINE, OR VAGINAL TENOFOVIR GEL SO SEXUALLY TRANSMITTED INFECTIONS LA English DT Meeting Abstract C1 [Marrazzo, J.] Univ Washington, Seattle, WA 98195 USA. [Rabe, L.; Livant, T.; Hillier, S.] Magee Womens Res Inst, Pittsburgh, PA USA. [Kelly, C.; Richardson, B.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Chirenje, M.] Univ Harare, Harare, Zimbabwe. [Deal, C.; Piper, J.] NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1368-4973 EI 1472-3263 J9 SEX TRANSM INFECT JI Sex. Transm. Infect. PD JUL PY 2013 VL 89 SU 1 MA O11.1 BP A46 EP A46 DI 10.1136/sextrans-2013-051184.0143 PG 1 WC Infectious Diseases SC Infectious Diseases GA V40SD UT WOS:000209497400139 ER PT J AU Plankey, MW Hoffman, HJ Springer, G Cox, C Young, MA Margolick, JB Torre, P AF Plankey, M. W. Hoffman, H. J. Springer, G. Cox, C. Young, M. A. Margolick, J. B. Torre, P. TI THE PREVALENCE OF HEARING SENSITIVITY AMONG HIV-SEROPOSITIVE AND HIV-SERONEGATIVE MEN AND WOMEN SO SEXUALLY TRANSMITTED INFECTIONS LA English DT Meeting Abstract C1 [Plankey, M. W.; Young, M. A.] Georgetown Univ, Med Ctr, Washington, DC 20007 USA. [Hoffman, H. J.] NIDCD, Bethesda, MD USA. [Springer, G.; Cox, C.; Margolick, J. B.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Torre, P.] San Diego State Univ, San Diego, CA 92182 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1368-4973 EI 1472-3263 J9 SEX TRANSM INFECT JI Sex. Transm. Infect. PD JUL PY 2013 VL 89 SU 1 MA P2.119 BP A124 EP A124 DI 10.1136/sextrans-2013-051184.0383 PG 1 WC Infectious Diseases SC Infectious Diseases GA V40SD UT WOS:000209497400379 ER PT J AU Quinn, TC AF Quinn, T. C. TI HIV TRANSMISSION DYNAMICS; CAN WE TRANSLATE KNOWLEDGE INTO ACTION SO SEXUALLY TRANSMITTED INFECTIONS LA English DT Meeting Abstract C1 [Quinn, T. C.] NIAID, Baltimore, MD USA. [Quinn, T. C.] Johns Hopkins Univ, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1368-4973 EI 1472-3263 J9 SEX TRANSM INFECT JI Sex. Transm. Infect. PD JUL PY 2013 VL 89 SU 1 MA PL02.3 BP A2 EP A3 DI 10.1136/sextrans-2013-051184.0005 PG 3 WC Infectious Diseases SC Infectious Diseases GA V40SD UT WOS:000209497400005 ER PT J AU Jiraporn, P Chintrakarn, P AF Jiraporn, P. Chintrakarn, P. TI Corporate social responsibility (CSR) and CEO luck: are lucky CEOs socially responsible? SO APPLIED ECONOMICS LETTERS LA English DT Article DE corporate social responsibility; lucky CEOs; option backdating; agency theory; G30; G34 AB Lucky' CEOs are given stock option grants on days when the stock price is the lowest in the month of the grant, implying opportunistic timing, severe agency problems and poor corporate governance. We find that lucky (opportunistic) CEOs invest significantly less in CSR. The evidence thus does not support the notion that CSR is primarily used to enhance managers' private benefits at the expense of shareholders. Rather, lucky CEOs appear to view CSR investments as depriving them of the free cash flow they could otherwise exploit. C1 [Jiraporn, P.] Penn State Univ, Sch Grad Profess Studies, Malvern, PA 19355 USA. [Jiraporn, P.] Thammasat Univ, Bangkok, Thailand. [Jiraporn, P.] Mahidol Univ, Coll Management, Bangkok 10700, Thailand. [Jiraporn, P.] NIDA, Fac Business Adm, Bangkok, Thailand. [Chintrakarn, P.] MUIC, Nakhon Pathom, Thailand. RP Jiraporn, P (reprint author), Penn State Univ, Sch Grad Profess Studies, Malvern, PA 19355 USA. EM pjiraporn@gmail.com NR 6 TC 4 Z9 4 U1 0 U2 34 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1350-4851 J9 APPL ECON LETT JI Appl. Econ. Lett. PD JUL 1 PY 2013 VL 20 IS 11 BP 1036 EP 1039 DI 10.1080/13504851.2013.772291 PG 4 WC Economics SC Business & Economics GA 150HB UT WOS:000319379700003 ER PT J AU Forrest, D Visser, TJ AF Forrest, Douglas Visser, Theo J. TI Thyroid hormone signaling Preface SO BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS LA English DT Editorial Material C1 [Forrest, Douglas] NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD USA. [Visser, Theo J.] Erasmus Univ, Dept Internal Med, Med Ctr, Rotterdam, Netherlands. RP Forrest, D (reprint author), NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD USA. EM forrestd@niddk.nih.gov FU Intramural NIH HHS NR 0 TC 2 Z9 2 U1 0 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4165 J9 BBA-GEN SUBJECTS JI Biochim. Biophys. Acta-Gen. Subj. PD JUL PY 2013 VL 1830 IS 7 SI SI BP 3859 EP 3859 DI 10.1016/j.bbagen.2013.03.001 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 148KJ UT WOS:000319243200001 PM 23651664 ER PT J AU Grimaldi, A Buisine, N Miller, T Shi, YB Sachs, LM AF Grimaldi, Alexis Buisine, Nicolas Miller, Thomas Shi, Yun-Bo Sachs, Laurent M. TI Mechanisms of thyroid hormone receptor action during development: Lessons from amphibian studies SO BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS LA English DT Review DE Thyroid hormone; Transcriptional regulation; Histone modification; Chromatin remodeling; Coregulator; Amphibian metamorphosis ID RETINOIC ACID RECEPTORS; CHROMATIN REMODELING COMPLEXES; XENOPUS-LAEVIS METAMORPHOSIS; GENE-EXPRESSION CHANGES; INTESTINAL STEM-CELLS; HISTONE DEACETYLASE; TRANSCRIPTIONAL REPRESSION; N-COR; NUCLEAR RECEPTORS; POSTEMBRYONIC DEVELOPMENT AB Background: Thyroid hormone (TH) receptor (TR) plays critical roles in vertebrate development. However, the in vivo mechanism of TR action remains poorly explored. Scope of review: Frog metamorphosis is controlled by TH and mimics the postembryonic period in mammals when high levels of TH are also required. We review here some of the findings on the developmental functions of TH and TR and the associated mechanisms obtained from this model system. Major conclusion: A dual function model for TR in Anuran development was proposed over a decade ago. That is, unliganded TR recruits corepressors to TH response genes in premetamorphic tadpoles to repress these genes and prevent premature metamorphic changes. Subsequently, when TH becomes available, liganded TR recruits coactivators to activate these same genes, leading to metamorphic changes. Over the years, molecular and genetic approaches have provided strong support for this model. Specifically, it has been shown that unliganded TR recruits histone deacetylase containing corepressor complexes during larval stages to control metamorphic timing, while liganded TR recruits multiple histone modifying and chromatin remodeling coactivator complexes during metamorphosis. These complexes can alter chromatin structure via nucleosome position alterations or eviction and histone modifications to contribute to the recruitment of transcriptional machinery and gene activation. General significance: The molecular mechanisms of TR action in vivo as revealed from studies on amphibian metamorphosis are very likely applicable to mammalian development as well. These findings provide a new perspective for understanding the diverse effects of TH in normal physiology and diseases caused by TH dysfunction. This article is part of a Special Issue entitled Thyroid hormone signalling. (C) 2012 Elsevier B.V. All rights reserved. C1 [Grimaldi, Alexis; Buisine, Nicolas; Sachs, Laurent M.] Museum Natl Hist Nat, Dept Regulat Dev & Diversite Mol, CNRS UMR7221, Sect Thyroid Hormone Receptor Funct & Mech Act, F-75231 Paris, France. [Miller, Thomas; Shi, Yun-Bo] NICHD, Sect Mol Morphogenesis, Program Cellular Regulat & Metab, NIH, Bethesda, MD 20892 USA. RP Sachs, LM (reprint author), MNHN, CNRS, UMR7221, CP 32,7 Rue Cuvier, F-75231 Paris 05, France. EM sachs@mnhn.fr FU Centre National de la Recherche Scientifique; Museum National d'Histoire Naturelle; CRESCENDO; IDEAL [259679]; TRIGGER [ANR-08-JCIC-0100-01]; National Institute of Child Health and Human Development, NIH; [LSHM-CT-2005-018652] FX This work was supported by the "Centre National de la Recherche Scientifique", the "Museum National d'Histoire Naturelle", "CRESCENDO", a European Integrated Project funding from FP6 (contract no. LSHM-CT-2005-018652), "IDEAL", a European Large Integrated Project funding from FP7 (no. 259679) and "TRIGGER" (ANR-08-JCIC-0100-01), and the Intramural Research Program of the National Institute of Child Health and Human Development, NIH. NR 120 TC 18 Z9 18 U1 3 U2 58 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4165 J9 BBA-GEN SUBJECTS JI Biochim. Biophys. Acta-Gen. Subj. PD JUL PY 2013 VL 1830 IS 7 SI SI BP 3882 EP 3892 DI 10.1016/j.bbagen.2012.04.020 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 148KJ UT WOS:000319243200005 PM 22565053 ER PT J AU Kim, WG Cheng, SY AF Kim, Won Gu Cheng, Sheue-yann TI Thyroid hormone receptors and cancer SO BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS LA English DT Review DE Thyroid hormone receptor mutant; Thyroid cancer; Phosphatidylinositol 3 kinase; Src kinase; beta-Catenin; Mouse model ID FOCAL ADHESION KINASE; C-ERBA-BETA; TRANSFORMING GENE PTTG; CLEAR-CELL CARCINOMA; MOUSE MODEL; PITUITARY-TUMOR; TR-BETA; V-ERBA; PHOSPHATIDYLINOSITOL 3-KINASE; NUCLEAR RECEPTOR AB Background: Thyroid hormone receptors (TRs) are ligand-dependent transcription factors that mediate the actions of the thyroid hormone (T3) in development, growth, and differentiation. The THRA and THRB genes encode several TR isoforms that express in a tissue- and development-dependent manner. In the past decades, a significant advance has been made in the understanding of TR actions in maintaining normal cellular functions. However, the roles of TR.s in human cancer are less well understood. The reduced expression of TRs because of hypermethylation, or deletion of TR genes found in human cancers suggests that TRs could function as tumor suppressors. A close association of somatic mutations of TRs with human cancers further supports the notion that the loss of normal functions of TR could lead to uncontrolled growth and loss of cell differentiation. Scope of review: In line with the findings from association studies in human cancers, mice deficient in total functional TRs (Thra1(-/-)Thrb(-/-) mice) or with a targeted homozygous mutation of the Thrb gene (denoted PV; Thrb(PV/PV) mice) spontaneously develop metastatic thyroid carcinoma. This review will examine the evidence learned from these genetically engineered mice that provided strong evidence to support the critical role of TRs in human cancer. Major conclusions: Loss of normal functions of TR by deletion or by mutations could contribute to cancer development, progression and metastasis. General significance: Novel mechanistic insights are revealed in how aberrant TR activities lead to carcinogenesis. Mouse models of thyroid cancer provide opportunities to identify molecular targets as potential treatment modalities. This article is part of a Special Issue entitled Thyroid hormone signalling. Published by Elsevier B.V. C1 [Kim, Won Gu; Cheng, Sheue-yann] NCI, Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Cheng, SY (reprint author), NCI, Bldg 37,Rm 5128,37 Convent Dr MSC 4264, Bethesda, MD 20892 USA. EM chengs@mail.nih.gov OI Kim, Won Gu/0000-0002-8404-7759 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX We regret any reference omissions due to length limitation. We wish to thank all colleagues and collaborators who have contributed to the work described in this review. The research described in this review by the authors and their colleagues at National Cancer Institute was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 97 TC 24 Z9 25 U1 3 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4165 J9 BBA-GEN SUBJECTS JI Biochim. Biophys. Acta-Gen. Subj. PD JUL PY 2013 VL 1830 IS 7 SI SI BP 3928 EP 3936 DI 10.1016/j.bbagen.2012.04.002 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 148KJ UT WOS:000319243200010 PM 22507269 ER PT J AU Galindo-Fraga, A Ortiz-Hernandez, AA Ramirez-Venegas, A Vazquez, RV Moreno-Espinosa, S Llamosas-Gallardo, B Perez-Patrigeon, S Salinger, M Freimanis, L Huang, CY Gu, WJ Guerrero, ML Beigel, J Ruiz-Palacios, GM AF Galindo-Fraga, Arturo Ortiz-Hernandez, Ana A. Ramirez-Venegas, Alejandra Valdez Vazquez, Rafael Moreno-Espinosa, Sarbelio Llamosas-Gallardo, Beatriz Perez-Patrigeon, Santiago Salinger, Maggie Freimanis, Laura Huang, Chiung-yu Gu, Wenjuan Lourdes Guerrero, M. Beigel, John Ruiz-Palacios, Guillermo M. CA La Red ILI 002 Study Grp TI Clinical characteristics and outcomes of influenza and other influenza-like illnesses in Mexico City SO INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Respiratory viral pathogens; Epidemiology; Hospital burden of disease; Influenza; Respiratory syncytial virus; Rhinovirus; Coronavirus ID COMMUNITY-ACQUIRED PNEUMONIA; RESPIRATORY VIRAL-INFECTIONS; CRITICALLY-ILL PATIENTS; HOSPITALIZED CHILDREN; A H1N1; ETIOLOGY; VIRUSES; ADULTS; EPIDEMIOLOGY; SURVEILLANCE AB Background: Influenza-like illnesses (ILI) are estimated to cause millions of deaths annually. Despite this disease burden, the etiologic causes of ILI are poorly described for many geographical regions. Methods: Beginning in April 2010, we conducted an observational cohort study at five hospitals in Mexico City, enrolling subjects who met the criteria for ILI. Evaluations were conducted at enrollment and on day 28, with the collection of clinical data and a nasopharyngeal swab (or nasal aspirate in children). Swabs were tested by multiplex PCR for 15 viral pathogens and real-time PCR for influenza. Results: During the first year, 1065 subjects were enrolled in this study, 55% of whom were hospitalized; 24% of all subjects were children. One or more pathogens were detected by PCR in 64% of subjects, most commonly rhinovirus (25% of all isolates) and influenza (24% of isolates). Six percent of subjects died, and of those, 54% had no pathogen identified. Rhinovirus was the most common pathogen among those who died, although it did not have the highest case fatality rate. Conclusions: Multiple respiratory viruses beyond influenza are associated with significant morbidity and mortality among adults and children in Mexico City. Detection of these agents could be useful for the adjustment of antibiotic treatment in severe cases. (C) 2013 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. C1 [Galindo-Fraga, Arturo; Perez-Patrigeon, Santiago; Lourdes Guerrero, M.; Ruiz-Palacios, Guillermo M.] Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Mexico City 14000, DF, Mexico. [Ortiz-Hernandez, Ana A.; Llamosas-Gallardo, Beatriz] Inst Nacl Pediat, Mexico City, DF, Mexico. [Ramirez-Venegas, Alejandra] Inst Nacl Enfermedades Resp, Mexico City, DF, Mexico. [Valdez Vazquez, Rafael] Hosp Gen Dr Manuel Gea Gonzalez, Mexico City, DF, Mexico. [Moreno-Espinosa, Sarbelio] Hosp Infantil Mexico Dr Federico Gomez, Mexico City, DF, Mexico. [Salinger, Maggie; Huang, Chiung-yu] NIAID, Bethesda, MD 20892 USA. [Freimanis, Laura] WESTAT Corp, Rockville, MD 20850 USA. [Gu, Wenjuan; Beigel, John] NIAID, SAIC Frederick, Bethesda, MD 20892 USA. RP Galindo-Fraga, A (reprint author), Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Vasco de Quiroga 15,Col Secc 16, Mexico City 14000, DF, Mexico. EM galindofraga@yahoo.com FU Mexico Ministry of Health; U.S. National Institute of Allergy and Infectious Diseases; CONACYT through FONSEC SSA/IMSS/ISSSTE [71260, 127088]; Westat, Inc. [HHSN2722009000031]; National Cancer Institute, National Institutes of Health, 318 [HHSN261200800001E] FX La Red is funded by the Mexico Ministry of Health and the U.S. National Institute of Allergy and Infectious Diseases. This project has been funded in part by funding provided by: CONACYT through FONSEC SSA/IMSS/ISSSTE No. 71260 and No. 127088. Intramural Research Programs of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) through a contract with Westat, Inc., Contract Number: HHSN2722009000031, Task Order Number: HHSN27200002. And through the National Cancer Institute, National Institutes of Health, 318 under Contract No. HHSN261200800001E. NR 36 TC 9 Z9 9 U1 0 U2 12 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1201-9712 J9 INT J INFECT DIS JI Int. J. Infect. Dis. PD JUL PY 2013 VL 17 IS 7 BP E510 EP E517 DI 10.1016/j.ijid.2013.01.006 PG 8 WC Infectious Diseases SC Infectious Diseases GA 144XT UT WOS:000318976300008 PM 23416208 ER PT J AU Lin, CL Peng, GCY Karniadakis, G AF Lin, Ching-Long Peng, Grace C. Y. Karniadakis, George TI Multi-Scale modeling and simulation of biological systems Preface SO JOURNAL OF COMPUTATIONAL PHYSICS LA English DT Editorial Material C1 [Lin, Ching-Long] Univ Iowa, Iowa City, IA 52242 USA. [Peng, Grace C. Y.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. [Karniadakis, George] Brown Univ, Providence, RI 02912 USA. RP Lin, CL (reprint author), Univ Iowa, Iowa City, IA 52242 USA. EM ching-long-lin@uiowa.edu NR 1 TC 1 Z9 1 U1 0 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0021-9991 J9 J COMPUT PHYS JI J. Comput. Phys. PD JUL 1 PY 2013 VL 244 BP 1 EP 3 DI 10.1016/j.jcp.2013.02.004 PG 3 WC Computer Science, Interdisciplinary Applications; Physics, Mathematical SC Computer Science; Physics GA 151JO UT WOS:000319456900001 ER PT J AU Cheung, CSF Lui, JC Baron, J AF Cheung, Crystal S. F. Lui, Julian C. Baron, Jeffrey TI Identification of chondrocyte-binding peptides by phage display SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE phage display; peptide; cartilage; chondrocytes; targeted therapy ID MURINE HYPOPHOSPHATASIA; ENZYME REPLACEMENT; HOMING PEPTIDES; CELLS; VASCULATURE; CARTILAGE; BONE; OLIGOPEPTIDE; SELECTION; DELIVERY AB As an initial step toward targeting cartilage tissue for potential therapeutic applications, we sought cartilage-binding peptides using phage display, a powerful technology for selection of peptides that bind to molecules of interest. A library of phage displaying random 12-amino acid peptides was iteratively incubated with cultured chondrocytes to select phage that bind cartilage. The resulting phage clones demonstrated increased affinity to chondrocytes by ELISA, when compared to a wild-type, insertless phage. Furthermore, the selected phage showed little preferential binding to other cell types, including primary skin fibroblast, myocyte and hepatocyte cultures, suggesting a tissue-specific interaction. Immunohistochemical staining revealed that the selected phage bound chondrocytes themselves and the surrounding extracellular matrix. FITC-tagged peptides were synthesized based on the sequence of cartilage-binding phage clones. These peptides, but not a random peptide, bound cultured chondrocytes, and extracelluar matrix. In conclusion, using phage display, we identified peptide sequences that specifically target chondrocytes. We anticipate that such peptides may be coupled to therapeutic molecules to provide targeted treatment for cartilage disorders. (c) 2013 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 31:10531058, 2013 C1 [Cheung, Crystal S. F.; Lui, Julian C.; Baron, Jeffrey] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Dev Endocrinol Branch, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. RP Baron, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Dev Endocrinol Branch, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. EM jeffrey.baron@nih.gov RI Lui, Chun Kin Julian/E-2253-2012 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Grant sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (Intramural Research Program). NR 23 TC 5 Z9 5 U1 1 U2 23 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0736-0266 J9 J ORTHOP RES JI J. Orthop. Res. PD JUL PY 2013 VL 31 IS 7 BP 1053 EP 1058 DI 10.1002/jor.22325 PG 6 WC Orthopedics SC Orthopedics GA 149VW UT WOS:000319350500009 PM 23440926 ER PT J AU Huppmann, AR Xi, LQ Raffeld, M Pittaluga, S Jaffe, ES AF Huppmann, Alison R. Xi, Liqiang Raffeld, Mark Pittaluga, Stefania Jaffe, Elaine S. TI Subcutaneous panniculitis-like T-cell lymphoma in the pediatric age group: A lymphoma of low malignant potential SO PEDIATRIC BLOOD & CANCER LA English DT Article DE lupus panniculitis; pediatric; subcutaneous panniculitis-like T-cell lymphoma ID HIGH-DOSE CHEMOTHERAPY; CLASSIFICATION AB Background Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare neoplasm of mature cytotoxic T-cells. Most commonly occurring in young adults, few reports are described in children. A separate analysis of a significant cohort of pediatric patients has not previously been performed. Procedure We analyzed the pathology including molecular results as well as available clinical data from 16 pediatric patients (age 5 months to 21 years) who had a total of 19 biopsies submitted to the National Cancer Institute from 1999 to 2011. This included 6 males and 10 females. Results Most patients (10/16, 62.5%) had multiple skin lesions at the time of biopsy. Histologic features included rimming of adipocytes by atypical lymphocytes, fat necrosis, and karyorrhectic debris. Four biopsies showed only partial involvement by lymphoma; and plasma cells were identified in 14/19 (74%) cases, including three in which they were focally prominent. The neoplastic cells in general were positive for CD3, CD8, TIA-1, and F1 and were negative for CD4 and CD56. CD5 expression was weak to negative in 5/8 cases (63%). A clonal T-cell receptor gene rearrangement was demonstrated in 11/17 (65%). Patients were treated with a variety of agents. While 5/9 (56%) patients had evidence of recurrent skin lesions, no deaths were attributed to disease for the seven patients with follow-up information. Conclusions Pediatric SPTCL shares many clinical and pathologic features with adult SPTCL. The presence of partial involvement or admixed plasma cells makes the differential diagnosis with reactive conditions challenging in some cases. Pediatr Blood Cancer 2013; 60: 11651170. (c) 2013 Wiley Periodicals, Inc. C1 [Huppmann, Alison R.; Xi, Liqiang; Raffeld, Mark; Pittaluga, Stefania; Jaffe, Elaine S.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Jaffe, ES (reprint author), NCI, NIH, 10 Ctr Dr Bldg 10,Room 2B42, Bethesda, MD 20892 USA. EM elainejaffe@nih.gov OI Jaffe, Elaine/0000-0003-4632-0301 NR 9 TC 17 Z9 18 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUL PY 2013 VL 60 IS 7 BP 1165 EP 1170 DI 10.1002/pbc.24462 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 149ZZ UT WOS:000319361300026 PM 23382035 ER PT J AU Lock, RB Carol, H Maris, JM Kang, MH Reynolds, CP Kolb, EA Gorlick, R Keir, ST Billups, CA Kurmasheva, RT Houghton, PJ Smith, MA AF Lock, Richard B. Carol, Hernan Maris, John M. Kang, Min H. Reynolds, C. Patrick Kolb, E. Anders Gorlick, Richard Keir, Stephen T. Billups, Catherine A. Kurmasheva, Raushan T. Houghton, Peter J. Smith, Malcolm A. TI Initial testing (stage 1) of ganetespib, an Hsp90 inhibitor, by the pediatric preclinical testing program SO PEDIATRIC BLOOD & CANCER LA English DT Article DE developmental therapeutics; Hsp90 inhibitors; preclinical testing ID ACUTE LYMPHOBLASTIC-LEUKEMIA; B-PROGENITOR; ALK; MUTATION; MODELS; CRLF2; REARRANGEMENT; RESISTANCE; IKZF1; JAK AB Ganetespib, an Hsp90 inhibitor, was tested against the PPTP in vitro cell line panel and selected xenografts in vivo, including JAK2- and BRAF-mutated models. Ganetespib demonstrated potent in vitro cytotoxic activity (median rIC50 8.8nM, range 4.427.1nM). In vivo, ganetespib induced significant differences in EFS distribution for 4 of 11 xenografts. Intermediate activity (EFS T/C>2) was noted only for the MV4;11 xenograft, and there were no objective responses. Administered as single agents, Hsp90 inhibitors examined by the PPTP have shown limited evidence for a therapeutic window against both solid tumor and leukemia pediatric preclinical models. Pediatr Blood Cancer 2013; 60: E42E45. (c) 2013 Wiley Periodicals, Inc. C1 [Lock, Richard B.; Carol, Hernan] Childrens Canc Inst Australia Med Res, Randwick, NSW 2, Australia. [Maris, John M.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA. [Maris, John M.] Abramson Family Canc Res Inst, Philadelphia, PA USA. [Kang, Min H.; Reynolds, C. Patrick] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. [Kolb, E. Anders] Alfred I DuPont Hosp Children, Wilmington, DE USA. [Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC USA. [Billups, Catherine A.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Kurmasheva, Raushan T.; Houghton, Peter J.] Nationwide Childrens Hosp, Columbus, OH USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Lock, RB (reprint author), Australia Lowy Canc Res Ctr, Leukemia Biol Program, Childrens Canc Inst, High St, Randwick, NSW 2031, Australia. EM rlock@ccia.unsw.edu.au RI Carol, Hernan/F-5750-2013; Houghton, Peter/E-3265-2011; Lock, Richard/G-4253-2013; OI Carol, Hernan/0000-0002-9443-8032; Reynolds, C. Patrick/0000-0002-2827-8536 FU National Cancer Institute [NO1-CM-42216, CA21765, CA108786] FX Grant sponsor: National Cancer Institute; Grant numbers: NO1-CM-42216, CA21765, CA108786. NR 23 TC 5 Z9 5 U1 0 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUL PY 2013 VL 60 IS 7 BP E42 EP E45 DI 10.1002/pbc.24451 PG 4 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 149ZZ UT WOS:000319361300007 PM 23303741 ER PT J AU Borthwick, LA Wynn, TA Fisher, AJ AF Borthwick, Lee A. Wynn, Thomas A. Fisher, Andrew J. TI Cytokine mediated tissue fibrosis SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Review DE Fibrosis; Cytokine; Macrophage; Fibroblast; Myoflbroblast; Inflammation ID TUMOR-NECROSIS-FACTOR; BRONCHIOLITIS OBLITERANS SYNDROME; EPITHELIAL-MESENCHYMAL TRANSITION; GROWTH-FACTOR-BETA; IDIOPATHIC PULMONARY-FIBROSIS; PERIPHERAL-BLOOD FIBROCYTES; LUNG-TRANSPLANT RECIPIENTS; HEPATIC STELLATE CELLS; HETEROTOPIC TRACHEAL TRANSPLANTATION; EGG-INDUCED IMMUNOPATHOLOGY AB Acute inflammation is a recognised part of normal wound healing. However, when inflammation fails to resolve and a chronic inflammatory response is established this process can become dysregulated resulting in pathological wound repair, accumulation of permanent fibrotic scar tissue at the site of injury and the failure to return the tissue to normal function. Fibrosis can affect any organ including the lung, skin, heart, kidney and liver and it is estimated that 45% of deaths in the western world can now be attributed to diseases where fibrosis plays a major aetiological role. In this review we examine the evidence that cytokines play a vital role in the acute and chronic inflammatory responses that drive fibrosis in injured tissues. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease. (C) 2012 Elsevier B.V. All rights reserved. C1 [Borthwick, Lee A.; Fisher, Andrew J.] Newcastle Univ, Sch Med, Inst Cellular Med, Tissue Fibrosis & Repair Grp, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. [Borthwick, Lee A.; Wynn, Thomas A.] NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Fisher, Andrew J.] Freeman Rd Hosp, Inst Transplantat, Newcastle Upon Tyne NE7 7DN, Tyne & Wear, England. RP Borthwick, LA (reprint author), Newcastle Univ, Sch Med, Inst Cellular Med, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. EM Lee.Borthwick@Newcastle.ac.uk OI Borthwick, Lee/0000-0003-2885-3382 FU European Union; Intramural Research Program of the NIH/NIAID FX We would like to express our sincere appreciation and thanks to all of our colleagues, both past and present, for their guidance and support. We also thank Aaron Gardner for assistance with figure preparation. LAB is supported by a Marie Curie international outgoing fellowship from the European Union Framework Programme 7. TAW is supported by the Intramural Research Program of the NIH/NIAID. NR 267 TC 49 Z9 53 U1 1 U2 50 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD JUL PY 2013 VL 1832 IS 7 SI SI BP 1049 EP 1060 DI 10.1016/j.bbadis.2012.09.014 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 143SC UT WOS:000318887500023 PM 23046809 ER PT J AU Gao, B Radaeva, S AF Gao, Bin Radaeva, Svetlana TI Natural killer and natural killer T cells in liver fibrosis SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Review DE Viral hepatitis; Alcoholic liver disease; NKG2D; NAFLD; IFN-gamma ID CHRONIC HEPATITIS-C; ACTIVATED STELLATE CELLS; INNATE IMMUNE-SYSTEM; PHASE I/II TRIAL; NKT CELLS; ALPHA-GALACTOSYLCERAMIDE; INTERFERON-ALPHA; VIRUS-INFECTION; HCV INFECTION; PIT CELLS AB The liver lymphocyte population is enriched with natural killer (NK) cells, which plays key role in host defense against viral infection and tumor transformation. Recent evidence from animal models suggests that NK cells also play an important role in inhibiting liver fibrosis by selectively killing early or senescence activated hepatic stellate cells (HSCs) and by producing the-anti-fibrotic cytokine IFN-gamma. Furthermore, clinical studies have revealed that human NK cells can kill primary human HSCs and that the ability of NK cells from HCV patients to kill HSCs is enhanced and correlates inversely with the stages of liver fibrosis. IFN-alpha treatment enhances, while other factors (e.g., alcohol, TGF-beta) attenuate, the cytotoxicity of NK cells against HSCs, thereby differentially regulating liver fibrogenesis. In addition, the mouse liver lymphocyte population is also enriched for natural killer T (NKT) cells, whereas human liver lymphocytes have a much lower percentage of NKT cells. Many studies suggest that NKT cells promote liver fibrogenesis by producing pro-fibrotic cytokines such as IL-4, IL-13, hedgehog ligands, and osteopontin; however, NKT cells may also attenuate liver fibrosis under certain conditions by killing HSCs and by producing IFN-gamma. Finally, the potential for NK and NKT cells to be used as therapeutic targets for anti-fibrotic therapy is discussed. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease. Published by Elsevier B.V. C1 [Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. [Radaeva, Svetlana] NIAAA, Div Metab & Hlth Effect, NIH, Bethesda, MD 20892 USA. RP Gao, B (reprint author), NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. EM bgao@mail.nih.gov FU Intramural NIH HHS [ZIA AA000368-10, Z99 AA999999, ZIA AA000369-10] NR 94 TC 37 Z9 42 U1 0 U2 33 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD JUL PY 2013 VL 1832 IS 7 SI SI BP 1061 EP 1069 DI 10.1016/j.bbadis.2012.09.008 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 143SC UT WOS:000318887500024 PM 23022478 ER PT J AU Tanofsky-Kraff, M Engel, S Yanovski, JA Pine, DS Nelson, EE AF Tanofsky-Kraff, Marian Engel, Scott Yanovski, Jack A. Pine, Daniel S. Nelson, Eric E. TI Pediatric disinhibited eating: Toward a research domain criteria framework SO INTERNATIONAL JOURNAL OF EATING DISORDERS LA English DT Article ID DISORDERS C1 [Tanofsky-Kraff, Marian] USUHS, Dept Med & Clin Psychol, Bethesda, MD 20814 USA. [Tanofsky-Kraff, Marian; Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH,DHHS, Bethesda, MD USA. [Engel, Scott] Neuropsychiat Res Inst, Fargo, ND USA. [Pine, Daniel S.; Nelson, Eric E.] NIMH, Sect Dev & Affect Neurosci, NIH, DHHS, Bethesda, MD 20892 USA. RP Tanofsky-Kraff, M (reprint author), USUHS, Dept Med & Clin Psychol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM marian.tanofsky-kraff@usuhs.edu OI Yanovski, Jack/0000-0001-8542-1637; Nelson, Eric/0000-0002-3376-2453 FU Intramural NIH HHS [Z99 HD999999, Z99 MH999999, ZIA HD000641-17, ZIA MH002781-11]; NCRR NIH HHS [L30 RR033197]; NIDDK NIH HHS [R01 DK080906]; NIMH NIH HHS [L30 MH078171] NR 7 TC 7 Z9 7 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0276-3478 J9 INT J EAT DISORDER JI Int. J. Eating Disord. PD JUL PY 2013 VL 46 IS 5 SI SI BP 451 EP 455 DI 10.1002/eat.22101 PG 5 WC Psychology, Clinical; Nutrition & Dietetics; Psychiatry; Psychology SC Psychology; Nutrition & Dietetics; Psychiatry GA 142EJ UT WOS:000318779000016 PM 23658090 ER PT J AU Sykora, P Yang, JL Ferrarelli, LK Tian, JY Tadokoro, T Kulkarni, A Weissman, L Keijzers, G Wilson, DM Mattson, MP Bohr, VA AF Sykora, Peter Yang, Jenq-Lin Ferrarelli, Leslie K. Tian, Jingyan Tadokoro, Takashi Kulkarni, Avanti Weissman, Lior Keijzers, Guido Wilson, David M., III Mattson, Mark P. Bohr, Vilhelm A. TI Modulation of DNA base excision repair during neuronal differentiation SO NEUROBIOLOGY OF AGING LA English DT Article DE BER; Differentiation; DNA repair; Postmitotic; Aging; Neuron; DNA damage ID OXIDATIVELY DAMAGED DNA; ALZHEIMERS-DISEASE; STRAND BREAKS; CELL-DEATH; GLYCOSYLASE; NUCLEAR; BRAIN; REPLICATION; EXPRESSION; PATHWAYS AB Neurons are terminally differentiated cells with a high rate of metabolism and multiple biological properties distinct from their undifferentiated precursors. Previous studies showed that nucleotide excision DNA repair is downregulated in postmitotic muscle cells and neurons. Here, we characterize DNA damage susceptibility and base excision DNA repair (BER) capacity in undifferentiated and differentiated human neural cells. The results show that undifferentiated human SH-SY5Y neuroblastoma cells are less sensitive to oxidative damage than their differentiated counterparts, in part because they have robust BER capacity, which is heavily attenuated in postmitotic neurons. The reduction in BER activity in differentiated cells correlates with diminished protein levels of key long patch BER components, flap endonuclease-1, proliferating cell nuclear antigen, and ligase I. Thus, because of their higher BER capacity, proliferative neural progenitor cells are more efficient at repairing DNA damage compared with their neuronally differentiated progeny. Published by Elsevier Inc. C1 [Sykora, Peter; Yang, Jenq-Lin; Ferrarelli, Leslie K.; Tian, Jingyan; Tadokoro, Takashi; Weissman, Lior; Keijzers, Guido; Wilson, David M., III; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Yang, Jenq-Lin; Mattson, Mark P.] NIA, Neurosci Lab, NIH, Baltimore, MD 21224 USA. [Kulkarni, Avanti] Roche Palo Alto LLC, Palo Alto, CA USA. [Keijzers, Guido] Univ Copenhagen, Ctr Hlth Aging, Fac Hlth Sci, DK-1168 Copenhagen, Denmark. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, 251 Bayview Blvd,Ste 100,Room 6B133, Baltimore, MD 21224 USA. EM bohrv@grc.nia.nih.gov OI Yang, Jenq-Lin/0000-0002-9897-8087 FU National Institute on Aging, National Institutes of Health FX The authors thank Dr Robert Bambara for reagents provided, and Dr Misiak and Dr Illuzzi for critical reading of the manuscript. This research is supported by intramural research program of National Institute on Aging, National Institutes of Health. NR 38 TC 20 Z9 20 U1 0 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2013 VL 34 IS 7 BP 1717 EP 1727 DI 10.1016/j.neurobiolaging.2012.12.016 PG 11 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 140TS UT WOS:000318678900001 PM 23375654 ER PT J AU Baxter, MG Roberts, MT Gee, NA Lasley, BL Morrison, JH Rapp, PR AF Baxter, Mark G. Roberts, Mary T. Gee, Nancy A. Lasley, Bill L. Morrison, John H. Rapp, Peter R. TI Multiple clinically relevant hormone therapy regimens fail to improve cognitive function in aged ovariectomized rhesus monkeys SO NEUROBIOLOGY OF AGING LA English DT Article DE Ovarian hormones; Aging; Macaque; Learning; Memory; Prefrontal; Temporal ID HEALTH INITIATIVE MEMORY; CONJUGATED EQUINE ESTROGENS; SURGICALLY MENOPAUSAL MONKEYS; RANDOMIZED CONTROLLED-TRIAL; POSTMENOPAUSAL WOMEN; PREFRONTAL CORTEX; MACACA-FASCICULARIS; RECOGNITION MEMORY; ALZHEIMERS-DISEASE; PLUS PROGESTIN AB Preclinical studies in aged, surgically-menopausal rhesus monkeys have revealed powerful benefits of intermittent estrogen injections on prefrontal cortex-dependent working memory, together with corresponding effects on dendritic spine morphology in the prefrontal cortex. This contrasts with the inconsistent effects of hormone therapy (HT) reported in clinical studies in women. Factors contributing to this discrepancy could include differences in the formulation and sequence of HT regimens, resulting in different neurobiological outcomes. The current study evaluated, in aging surgically menopausal rhesus monkeys, the cognitive effects of 4 HT regimens modeled directly on human clinical practice, including continuous estrogen treatment opposed by progesterone. None of the regimens tested produced any cognitive effect, despite yielding physiologically relevant serum hormone levels, as intended. These findings have implications for the design of regimens that might optimize the benefits of hormone treatment for healthy aging, and suggest that common HT protocols used by women may fail to result in substantial cognitive benefit, at least via direct effects on the prefrontal cortex. (C) 2013 Elsevier Inc. All rights reserved. C1 [Baxter, Mark G.; Morrison, John H.] Mt Sinai Sch Med, Dept Neurosci, New York, NY 10029 USA. [Baxter, Mark G.; Morrison, John H.] Mt Sinai Sch Med, Friedman Brain Inst, New York, NY 10029 USA. [Roberts, Mary T.; Gee, Nancy A.; Lasley, Bill L.] Calif Natl Primate Res Ctr, Davis, CA USA. [Gee, Nancy A.; Lasley, Bill L.] Univ Calif, Sch Vet Med, Ctr Hlth & Environm, Dept Populat Hlth & Reprod, Davis, CA USA. [Rapp, Peter R.] NIA, Lab Expt Gerontol, Baltimore, MD 21224 USA. RP Baxter, MG (reprint author), Mt Sinai Sch Med, Dept Neurosci, 1 Gustave L Levy Pl,Box 1065, New York, NY 10029 USA. FU NIA [P01-AG016765]; NCRR [P51-RR000169] FX We thank Carmel Stanko, Tracy Ojakangas, and Lisa Novik for technical assistance, and Dr Kari Christe for veterinary advice and support. This research was supported by NIA grant P01-AG016765, in part by the Intramural Research Program of the NIA, and was carried out at the California National Primate Research Center, supported by NCRR grant P51-RR000169. NR 43 TC 14 Z9 14 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2013 VL 34 IS 7 BP 1882 EP 1890 DI 10.1016/j.neurobiolaging.2012.12.017 PG 9 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 140TS UT WOS:000318678900018 PM 23369546 ER PT J AU Majounie, E Cross, W Newsway, V Dillman, A Vandrovcova, J Morris, CM Nalls, MA Ferrucci, L Owen, MJ O'Donovan, MC Cookson, MR Singleton, AB de Silva, R Morris, HR AF Majounie, Elisa Cross, William Newsway, Victoria Dillman, Allissa Vandrovcova, Jana Morris, Christopher M. Nalls, Michael A. Ferrucci, Luigi Owen, Michael J. O'Donovan, Michael C. Cookson, Mark R. Singleton, Andrew B. de Silva, Rohan Morris, Huw R. TI Variation in tau isoform expression in different brain regions and disease states SO NEUROBIOLOGY OF AGING LA English DT Article DE Progressive supranuclear palsy; Tauopathies; MAPT ID PROGRESSIVE SUPRANUCLEAR PALSY; MESSENGER-RNA ISOFORMS; ALZHEIMERS-DISEASE; CORTICOBASAL DEGENERATION; PARKINSONS-DISEASE; GENE-EXPRESSION; MAPT LOCUS; HAPLOTYPE; ASSOCIATION; IDENTIFICATION AB Progressive supranuclear palsy (PSP) is the most common atypical parkinsonian disorder. Abnormal tau inclusions, in selected regions of the brain, are a hallmark of the disease and the H1 haplotype of MAPT, the gene encoding tau, is the major risk factor in PSP. A 3-repeat and 4-repeat (4R) tau isoform ratio imbalance has been strongly implicated as a cause of disease. Thus, understanding tau isoform regional expression in disease and pathology-free states is crucial to elucidating the mechanisms involved in PSP and other tauopathies. We used a tau isoform-specific fluorescent assay to investigate relative 4R-tau expression in 6 different brain regions in PSP cases and healthy control samples. We identified a marked difference in 4R-tau relative expression, across brain regions and between MAPT haplotypes. Highest 4R-tau expression levels were identified in the globus pallidus compared with pons, cerebellum, and frontal cortex. 4R-tau expression levels were related to the MAPT H1 and H1c haplotypes. Similar regional variation was seen in PSP case and in control samples. (C) 2013 Elsevier Inc. All rights reserved. C1 [Majounie, Elisa; Cross, William; Newsway, Victoria; Owen, Michael J.; O'Donovan, Michael C.; Morris, Huw R.] Cardiff Univ, Sch Med, MRC Ctr Neuropsychat Genet & Genom, Cardiff CF10 3AX, S Glam, Wales. [Majounie, Elisa; Dillman, Allissa; Nalls, Michael A.; Cookson, Mark R.; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Vandrovcova, Jana; de Silva, Rohan] UCL Inst Neurol, Reta Lila Weston Inst, London, England. [Morris, Christopher M.] Newcastle Univ, Inst Neurosci, Med Toxicol Ctr, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Morris, Christopher M.] Newcastle Univ, Inst Ageing & Hlth, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, NIH, Baltimore, MD 21224 USA. RP Morris, HR (reprint author), Univ Wales Hosp, Cardiff CF14 4XN, S Glam, Wales. EM morrishr@cf.ac.uk RI Morris, Huw/B-8527-2008; Singleton, Andrew/C-3010-2009; Cross, William/G-1299-2015; OI Morris, Huw/0000-0002-5473-3774; O'Donovan, Michael/0000-0001-7073-2379 FU Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services [Z01 AG000932-03]; PSP (Europe) Association; UK Medical Research Council [G0501560, G0400074]; Alzheimer's Society; Alzheimer's Research Trust, Brains for Dementia Research Project; National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust; Newcastle University FX This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project number Z01 AG000932-03. This study was funded by the PSP (Europe) Association and UK Medical Research Council research grant G0501560 to RdS.; Tissue for this study was provided by the Newcastle Brain Tissue Resource which is funded in part by a grant from the UK Medical Research Council (G0400074), the Alzheimer's Society and Alzheimer's Research Trust as part of the Brains for Dementia Research Project, and by the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. NR 22 TC 8 Z9 8 U1 2 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2013 VL 34 IS 7 AR 1922.e7 DI 10.1016/j.neurobiolaging.2013.01.017 PG 6 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 140TS UT WOS:000318678900026 PM 23428180 ER PT J AU Agster, KL Mejias-Aponte, CA Clark, BD Waterhouse, BD AF Agster, Kara L. Mejias-Aponte, Carlos A. Clark, Brian D. Waterhouse, Barry D. TI Evidence for a regional specificity in the density and distribution of noradrenergic varicosities in rat cortex SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE norepinephrine; prefrontal; somatosensory; motor; locus coeruleus; stereology ID MEDIAL PREFRONTAL CORTEX; CENTRAL-NERVOUS-SYSTEM; LOCUS-COERULEUS; CEREBRAL-CORTEX; VOLUME TRANSMISSION; AXON TERMINALS; LAMINAR DISTRIBUTION; AWAKE RAT; NOREPINEPHRINE; INNERVATION AB The brainstem nucleus locus coeruleus (LC) is the sole source of norepinephrine (NE)-containing fibers in the mammalian cortex. Previous studies suggest that the density of noradrenergic fibers in rat is relatively uniform across cortical regions and that cells in the nucleus discharge en masse. This implies that activation of the LC results in equivalent release of NE throughout the cortex. However, it is possible that there could be differences in the density of axonal varicosities across regions, and that these differences, rather than a difference in fiber density, may contribute to the regulation of NE efflux. Quantification of dopamine -hydroxylase (DH)-immunostained varicosities was performed on several cortical regions and in the ventral posterior medial (VPM) thalamus by using unbiased sampling methods. The density of DH varicosities is greater in the prefrontal cortex than in motor, somatosensory, or piriform cortices, greater in superficial than in deep layers of cortex, and greater in the VPM than in the somatosensory cortex. Our results provide anatomical evidence for non-uniform release of NE across functionally discrete cortical regions. This morphology may account for a differential, region-specific, impact of LC output on different cortical areas. J. Comp. Neurol. 521:21952207, 2013. (c) 2012 Wiley Periodicals, Inc. C1 [Agster, Kara L.; Clark, Brian D.; Waterhouse, Barry D.] Drexel Univ, Coll Med, Dept Neurobiol & Anat, Philadelphia, PA 19129 USA. [Mejias-Aponte, Carlos A.] NIDA, Baltimore, MD 21224 USA. RP Waterhouse, BD (reprint author), Drexel Univ, Coll Med, Dept Neurobiol & Anat, Philadelphia, PA 19129 USA. EM waterhouse@drexelmed.edu FU National Institute of Drug Abuse [DA017960]; Pennsylvania Department of Health; National Institute of Neurological Disorders and Stroke fellowship [T32 NINDS NS 007440] FX Grant sponsor: National Institute of Drug Abuse; Grant number: DA017960 (to B. D. W.); Grant sponsor: the Pennsylvania Department of Health (to B. D. W.); Grant sponsor: National Institute of Neurological Disorders and Stroke fellowship; Grant number: T32 NINDS NS 007440 (to K.L.A.). NR 50 TC 10 Z9 10 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD JUL 1 PY 2013 VL 521 IS 10 BP 2195 EP 2207 DI 10.1002/cne.23270 PG 13 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 133SO UT WOS:000318160400002 PM 23184811 ER PT J AU Dimitrov, EL Yanagawa, Y Usdin, TB AF Dimitrov, Eugene L. Yanagawa, Yuchio Usdin, Ted B. TI Forebrain GABAergic projections to locus coeruleus in mouse SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE noradrenergic; forebrain; brainstem; GAD67-GFP knockin; anatomical tract tracing ID CORTICOTROPIN-RELEASING-FACTOR; IN-SITU HYBRIDIZATION; VENTROLATERAL PREOPTIC NUCLEUS; LOWER BRAIN-STEM; AFFERENT-PROJECTIONS; HYPOTHALAMIC PROJECTIONS; NORADRENERGIC SYSTEM; EFFERENT CONNECTIONS; GALANINERGIC NEURONS; PROTEIN EXPRESSION AB The noradrenergic locus coeruleus (LC) regulates arousal, memory, sympathetic nervous system activity, and pain. Forebrain projections to LC have been characterized in rat, cat, and primates, but not systematically in mouse. We surveyed mouse forebrain LC-projecting neurons by examining retrogradely labeled cells following LC iontophoresis of Fluoro-Gold and anterograde LC labeling after forebrain injection of biotinylated dextran amine or viral tracer. Similar to other species, the central amygdalar nucleus (CAmy), anterior hypothalamus, paraventricular nucleus, and posterior lateral hypothalamic area (PLH) provide major LC inputs. By using mice expressing green fluorescent protein in -aminobutyric acid (GABA)ergic neurons, we found that more than one-third of LC-projecting CAmy and PLH neurons are GABAergic. LC colocalization of biotinylated dextran amine, following CAmy or PLH injection, with either green fluorescent protein or glutamic acid decarboxylase (GAD)65/67 immunoreactivity confirmed these GABAergic projections. CAmy injection of adeno-associated virus encoding channelrhodopsin-2-Venus showed similar fiber labeling and association with GAD65/67-immunoreactive (ir) and tyrosine hydroxylase (TH)-ir neurons. CAmy and PLH projections were densest in a pericoerulear zone, but many fibers entered the LC proper. Close apposition between CAmy GABAergic projections and TH-ir processes suggests that CAmy GABAergic neurons may directly inhibit noradrenergic principal neurons. Direct LC neuron targeting was confirmed by anterograde transneuronal labeling of LC TH-ir neurons following CAmy or PLH injection of a herpes virus that expresses red fluorescent protein following activation by Cre recombinase in mice that express Cre recombinase in GABAergic neurons. This description of GABAergic projections from the CAmy and PLH to the LC clarifies important forebrain sources of inhibitory control of central nervous system noradrenergic activity. J. Comp. Neurol. 521:23732397, 2013. (c) 2012 Wiley Periodicals, Inc. C1 [Dimitrov, Eugene L.; Usdin, Ted B.] NIMH, Sect Fundamental Neurosci, Bethesda, MD 20892 USA. [Yanagawa, Yuchio] Gunma Univ, Grad Sch Med, Dept Genet & Behav Neurosci, Maebashi, Gumma 3718511, Japan. [Yanagawa, Yuchio] JST, CREST, Maebashi, Gumma 3718511, Japan. RP Usdin, TB (reprint author), NIMH, Sect Fundamental Neurosci, 35 Convent Dr, Bethesda, MD 20892 USA. EM usdint@mail.nih.gov FU National Institute of Mental Health [ZIA MH002685-16] FX Grant sponsor: the Intramural Program of the National Institute of Mental Health; Grant number: ZIA MH002685-16. NR 74 TC 9 Z9 10 U1 0 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9967 EI 1096-9861 J9 J COMP NEUROL JI J. Comp. Neurol. PD JUL 1 PY 2013 VL 521 IS 10 BP 2373 EP 2397 DI 10.1002/cne.23291 PG 25 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 133SO UT WOS:000318160400011 PM 23296594 ER PT J AU Pearce, S Nezich, CL Spinazzola, A AF Pearce, Sarah Nezich, Catherine Laura Spinazzola, Antonella TI Mitochondrial diseases: Translation matters SO MOLECULAR AND CELLULAR NEUROSCIENCE LA English DT Article DE Mitochondrial encephalopathies; Translation; Ribosome; Assembly factors ID HEREDITARY OPTIC NEUROPATHY; SIDEROBLASTIC ANEMIA-MLASA; KEARNS-SAYRE SYNDROME; 12S RIBOSOMAL-RNA; NADH-QUINONE OXIDOREDUCTASE; NON-SYNDROMIC DEAFNESS; C-OXIDASE DEFICIENCY; STROKE-LIKE EPISODES; M-AAA PROTEASE; DIABETES-MELLITUS AB Mitochondrial diseases comprise a heterogeneous group of disorders characterized by compromised energy production. Since the early days of mitochondrial medical genetics, it has been known that these can be caused by defects in mitochondrial protein synthesis. However, only in recent years have we begun to develop a broader picture of the array of proteins required for mitochondrial translation. With this new knowledge has come the realization that there are many more neurological and other, diseases attributable to impaired mitochondrial translation than previously thought. Perturbation of any part of this intricate machinery, from the primary sequence of transfer or ribosomal RNAs, to the proteolytic processing of ribosomal proteins, can cause mitochondrial dysfunction and disease. In this review we discuss the current understanding of the mechanisms and factors involved in mammalian mitochondrial translation, and the diverse pathologies resulting when it malfunctions. This article is part of a Special Issue entitled 'Mitochondrial function and dysfunction in neurodegeneration'. (C) 2012 Published by Elsevier Inc. C1 [Pearce, Sarah; Nezich, Catherine Laura; Spinazzola, Antonella] MRC, Mitochondrial Biol Unit, Cambridge CB2 0XY, England. [Nezich, Catherine Laura] NINDS, NIH, Bethesda, MD 20892 USA. RP Spinazzola, A (reprint author), MRC, Mitochondrial Biol Unit, Wellcome Trust MRC Bldg,Hills Rd, Cambridge CB2 0XY, England. EM as1@mrc-mbu.cam.ac.uk FU Medical Research Council, UK; European Union; National Institutes of Health, Bethesda, USA FX The authors are supported by the Medical Research Council, UK. A.S. is in receipt of a European Union Marie Curie Fellowship. C.L.N is supported by the National Institutes of Health, Bethesda, USA. NR 132 TC 15 Z9 15 U1 0 U2 32 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1044-7431 EI 1095-9327 J9 MOL CELL NEUROSCI JI Mol. Cell. Neurosci. PD JUL PY 2013 VL 55 SI SI BP 1 EP 12 DI 10.1016/j.mcn.2012.08.013 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 131MZ UT WOS:000317999100001 PM 22986124 ER PT J AU Maris, E Womelsdorf, T Desimone, R Fries, P AF Maris, Eric Womelsdorf, Thilo Desimone, Robert Fries, Pascal TI Rhythmic neuronal synchronization in visual cortex entails spatial phase relation diversity that is modulated by stimulation and attention SO NEUROIMAGE LA English DT Article DE Phase; Synchronization; Oscillation; Gamma; Alpha; Theta; Attention; Selection; Monkey; Visual ID FALSE DISCOVERY RATE; BAND SYNCHRONIZATION; OLFACTORY-BULB; GAMMA CYCLE; OSCILLATIONS; WAVES; DYNAMICS; V1; SEQUENCES; SELECTION AB Groups of neurons tend to synchronize in distinct frequency bands. Within a given frequency band, synchronization is defined as the consistency of phase relations between site pairs, over time. This synchronization has been investigated in numerous studies and has been found to be modulated by sensory stimulation or cognitive conditions. Here, we investigate local field potentials (LFPs) and multi-unit activity (MUA) recorded from area V4 of two monkeys performing a selective visual attention task. We show that phase relations, that are consistent over time, are typically diverse across site pairs. That is, across site pairs, mean phase relations differ substantially and this across-site-pair phase-relation diversity (SPHARED, for Spatial PHAse RElation Diversity) is highly reliable. Furthermore, we show that visual stimulation and selective attention can shift the pattern of phase relations across site pairs. These shifts are again diverse and this across-site-pair phase-relation-shift diversity (SPHARESD) is again highly reliable. We find SPHARED for LFP-LFP, LFP-MUA and MUA-MUA pairs, stimulus-induced SPHARESD for LFP-LFP and LFP-MUA pairs, and attention-induced SPHARESD for LFP-LFP pairs. SPHARESD is a highly interesting signal from the perspective of impact on downstream neuronal activity. We provide several pieces of evidence for such a role. (C) 2013 Elsevier Inc. All rights reserved. C1 [Maris, Eric; Womelsdorf, Thilo; Fries, Pascal] Radboud Univ Nijmegen, Donders Ctr Brain Cognit & Behav, NL-6525 EN Nijmegen, Netherlands. [Womelsdorf, Thilo] York Univ, Dept Biol, Fac Sci & Engn, N York, ON M3J 1P3, Canada. [Desimone, Robert] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. [Desimone, Robert] MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA. [Fries, Pascal] Max Planck Gesell, Ernst Strungmann Inst ESI Neurosci, D-60528 Frankfurt, Germany. RP Maris, E (reprint author), Radboud Univ Nijmegen, Donders Ctr Brain Cognit & Behav, NL-6525 EN Nijmegen, Netherlands. EM e.maris@donders.ru.nl RI Fries, Pascal/E-3196-2010; Maris, Eric/E-4876-2012; OI Fries, Pascal/0000-0002-4270-1468; Maris, Eric/0000-0001-5166-1800; Womelsdorf, Thilo/0000-0001-6921-4187 FU BrainGain Smart Mix Programme of the Ministry of Economic Affairs; Ministry of Education, Culture and Science of the Netherlands; Human Frontier Science Program Organization [RGP0070/2003]; Volkswagen Foundation [I/79876]; European Science Foundation European Young Investigator Award Program; European Union [HEALTH-F2-2008-200728]; Netherlands Organization for Scientific Research [452-03-344, 016-071-079]; National Institute of Mental Health Intramural Research Program; National Institutes of Health [R01-EY017292] FX The authors gratefully acknowledge the support of the BrainGain Smart Mix Programme of the Ministry of Economic Affairs and the Ministry of Education, Culture and Science of the Netherlands. This work was supported by Human Frontier Science Program Organization grant RGP0070/2003 (P.F.), the Volkswagen Foundation grant I/79876 (P.F.), the European Science Foundation European Young Investigator Award Program (P.F.), the European Union (HEALTH-F2-2008-200728 to P.F.), the Netherlands Organization for Scientific Research grants 452-03-344 (P.F.) and 016-071-079 (T.W.), the National Institute of Mental Health Intramural Research Program (R.D.), and National Institutes of Health grant R01-EY017292 (R.D.). We thank J. H. Reynolds, A E. Rorie, A. F. Rossi, and R C. Saunders for help during the experiments. NR 40 TC 14 Z9 14 U1 1 U2 29 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 JUL 1 PY 2013 VL 74 BP 99 EP 116 DI 10.1016/j.neuroimage.2013.02.007 PG 18 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 124CL UT WOS:000317441300012 PM 23416733 ER PT J AU Edwards, D Cortes, M Datta, A Minhas, P Wassermann, EM Bikson, M AF Edwards, Dylan Cortes, Mar Datta, Abhishek Minhas, Preet Wassermann, Eric M. Bikson, Marom TI Physiological and modeling evidence for focal transcranial electrical brain stimulation in humans: A basis for high-definition tDCS SO NEUROIMAGE LA English DT Article DE tDCS; TES; TMS; Targeted stimulation; Human head model; Electric fields ID HUMAN MOTOR CORTEX; RANDOM NOISE STIMULATION; MAGNETIC STIMULATION; CHRONIC STROKE; COIL DESIGN; CORTICAL STIMULATION; DC STIMULATION; EXCITABILITY; ACTIVATION; ELECTRODES AB Transcranial Direct Current Stimulation (tDCS) is a non-invasive, low-cost, well-tolerated technique producing lasting modulation of cortical excitability. Behavioral and therapeutic outcomes of tDCS are linked to the targeted brain regions, but there is little evidence that current reaches the brain as intended. We aimed to: (1) validate a computational model for estimating cortical electric fields in human transcranial stimulation, and (2) assess the magnitude and spread of cortical electric field with a novel High-Definition tDCS (HD-tDCS) scalp montage using a 4 x 1-Ring electrode configuration. In three healthy adults, Transcranial Electrical Stimulation (TES) over primary motor cortex (M1) was delivered using the 4 x 1 montage (4x cathode, surrounding a single central anode; montage radius similar to 3 cm) with sufficient intensity to elicit a discrete muscle twitch in the hand. The estimated current distribution in M1 was calculated using the individualized MRI-based model, and compared with the observed motor response across subjects. The response magnitude was quantified with stimulation over motor cortex as well as anterior and posterior to motor cortex. In each case the model data were consistent with the motor response across subjects. The estimated cortical electric fields with the 4 x 1 montage were compared (area, magnitude, direction) for TES and tDCS in each subject. We provide direct evidence in humans that TES with a 4 x 1-Ring configuration can activate motor cortex and that current does not substantially spread outside the stimulation area. Computational models predict that both TES and tDCS waveforms using the 4 x 1-Ring configuration generate electric fields in cortex with comparable gross current distribution, and preferentially directed normal (inward) currents. The agreement of modeling and experimental data for both current delivery and focality support the use of the HD-tDCS 4 x 1-Ring montage for cortically targeted neuromodulation. (c) 2013 Published by Elsevier Inc. C1 [Edwards, Dylan; Cortes, Mar] Cornell Univ, Coll Med, Burke Med Res Inst, White Plains, NY 10605 USA. [Edwards, Dylan; Cortes, Mar] Weill Cornell Med Coll, Dept Neurol & Neurosci, New York, NY USA. [Edwards, Dylan] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Berenson Allen Ctr Noninvas Brain Stimulat, Boston, MA 02215 USA. [Edwards, Dylan] Univ Western Australia, Australian Neuromuscular Res Inst, Nedlands, WA 6009, Australia. [Edwards, Dylan] Univ Western Australia, Ctr Neuromuscular & Neurol Disorders, Nedlands, WA 6009, Australia. [Datta, Abhishek; Minhas, Preet; Bikson, Marom] CUNY City Coll, Dept Biomed Engn, New York, NY 10031 USA. [Wassermann, Eric M.] Natl Inst Neurol Disorders & Stroke, Behav Neurol Unit, Bethesda, MD USA. RP Edwards, D (reprint author), Weill Cornell Med Coll, Dept Neurol & Neurosci, New York, NY USA. EM dedwards@burke.org FU NICHD NIH HHS [R01 HD069776] NR 55 TC 83 Z9 83 U1 2 U2 39 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 JUL 1 PY 2013 VL 74 BP 266 EP 275 DI 10.1016/j.neuroimage.2013.01.042 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 124CL UT WOS:000317441300026 PM 23370061 ER PT J AU Lam, KH Ji, HF Zheng, F Ren, W Zhou, QF Shung, KK AF Lam, Kwok Ho Ji, Hong Fen Zheng, Fan Ren, Wei Zhou, Qifa Shung, K. Kirk TI Development of lead-free single-element ultrahigh frequency (170-320 MHz) ultrasonic transducers SO ULTRASONICS LA English DT Article DE UHF ultrasonic transducer; Lead-free; Composite sol-gel; Thick film ID MEDICAL IMAGING APPLICATIONS; FREE PIEZOELECTRIC CERAMICS; FERROELECTRIC THICK-FILMS; INTRAVASCULAR ULTRASOUND; 0-3 COMPOSITE; PZT; FABRICATION; DESIGN; SYSTEM; BIOMICROSCOPY AB This paper presents the design, fabrication and characterization of single-element ultrahigh frequency (UHF) ultrasonic transducers in which the center frequency ranged from 170 to 320 MHz. The center frequency of > 300 MHz is the highest value of lead-free ceramic ultrasonic transducers ever reported. With concern in the environmental pollution of lead-based materials, the transducer elements presented in this work were lead-free K0.5Na0.5NbO3/Bi0.5Na0.5TiO3 (KNN/BNT) composite thick films. All transducers were evaluated in a pulse-echo arrangement. The measured -6 dB bandwidth of the transducers ranged from 35% to 64%. With the optimized piezoelectric properties of the composite film, the insertion loss of the UHF transducers was measured and determined to range from -50 to -60 dB. In addition to the pulse-echo measurement, a 6 mu m tungsten wire phantom was also imaged with a 205 MHz transducer to demonstrate the imaging capability. The measured -6 dB axial and lateral resolutions were found to be 12 mu m and 50 mu m, respectively. The transducer performance presented in this work is shown to be better or comparable to previously reported results even though the frequency is much higher. (C) 2013 Elsevier B. V. All rights reserved. C1 [Lam, Kwok Ho; Zheng, Fan; Zhou, Qifa; Shung, K. Kirk] Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. [Lam, Kwok Ho; Zheng, Fan; Zhou, Qifa; Shung, K. Kirk] Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. [Ji, Hong Fen; Ren, Wei] Xi An Jiao Tong Univ, Minist Educ, Key Lab, Elect Mat Res Lab, Xian 710049, Peoples R China. [Ji, Hong Fen; Ren, Wei] Xi An Jiao Tong Univ, Int Ctr Dielect Res, Xian 710049, Peoples R China. RP Lam, KH (reprint author), Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. EM kokokhlam@gmail.com RI Lam, K.H./B-7765-2014 OI Lam, K.H./0000-0003-1456-9049 FU NIH [P41-EB2182] FX This work was financially supported by NIH Grant P41-EB2182. NR 39 TC 10 Z9 10 U1 4 U2 76 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0041-624X J9 ULTRASONICS JI Ultrasonics PD JUL PY 2013 VL 53 IS 5 BP 1033 EP 1038 DI 10.1016/j.ultras.2013.01.012 PG 6 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 120PW UT WOS:000317184400014 PM 23485349 ER PT J AU Camalier, CE Yi, M Yu, LR Hood, BL Conrads, KA Lee, YJ Lin, YM Garneys, LM Bouloux, GF Young, MR Veenstra, TD Stephens, RM Colburn, NH Conrads, TP Beck, GR AF Camalier, Corinne E. Yi, Ming Yu, Li-Rong Hood, Brian L. Conrads, Kelly A. Lee, Young Jae Lin, Yiming Garneys, Laura M. Bouloux, Gary F. Young, Matthew R. Veenstra, Timothy D. Stephens, Robert M. Colburn, Nancy H. Conrads, Thomas P. Beck, George R., Jr. TI An integrated understanding of the physiological response to elevated extracellular phosphate SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID FIBROBLAST-GROWTH-FACTOR; INHIBITED 3T3 CELLS; FACTOR-I RECEPTOR; PROTEIN-KINASE PATHWAY; OSTEOBLAST-LIKE CELLS; INORGANIC-PHOSPHATE; C-FOS; BONE MINERALIZATION; DIETARY PHOSPHATE; VITAMIN-D AB Recent studies have suggested that changes in serum phosphate levels influence pathological states associated with aging such as cancer, bone metabolism, and cardiovascular function, even in individuals with normal renal function. The causes are only beginning to be elucidated but are likely a combination of endocrine, paracrine, autocrine, and cell autonomous effects. We have used an integrated quantitative biology approach, combining transcriptomics and proteomics to define a multi-phase, extracellular phosphate-induced, signaling network in pre-osteoblasts as well as primary human and mouse mesenchymal stromal cells. We identified a rapid mitogenic response stimulated by elevated phosphate that results in the induction of immediate early genes including c-fos. The mechanism of activation requires FGF receptor signaling followed by stimulation of N-Ras and activation of AP-1 and serum response elements. A distinct long-term response also requires FGF receptor signaling and results in N-Ras activation and expression of genes and secretion of proteins involved in matrix regulation, calcification, and angiogenesis. The late response is synergistically enhanced by addition of FGF23 peptide. The intermediate phase results in increased oxidative phosphorylation and ATP production and is necessary for the late response providing a functional link between the phases. Collectively, the results define elevated phosphate, as a mitogen and define specific mechanisms by which phosphate stimulates proliferation and matrix regulation. Our approach provides a comprehensive understanding of the cellular response to elevated extracellular phosphate, functionally connecting temporally coordinated signaling, transcriptional, and metabolic events with changes in long-term cell behavior. J. Cell. Physiol. 228: 15361550, 2013. (c) 2012 Wiley Periodicals, Inc. C1 [Camalier, Corinne E.; Lee, Young Jae; Lin, Yiming; Garneys, Laura M.; Beck, George R., Jr.] Emory Univ, Div Endocrinol, Dept Med, Atlanta, GA 30322 USA. [Yi, Ming; Stephens, Robert M.] SAIC Frederick Inc, Adv Biomed Comp Ctr, Frederick Natl Lab Canc Res, Frederick, MD USA. [Yu, Li-Rong; Veenstra, Timothy D.] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Lab Prote & Analyt Technol, Adv Technol Program, Frederick, MD USA. [Hood, Brian L.; Conrads, Thomas P.] Inova Hlth Syst, Gynecol Canc Ctr Excellence, Womens Hlth Integrated Res Ctr, Annandale, VA USA. [Conrads, Kelly A.; Young, Matthew R.; Colburn, Nancy H.] NCI, Lab Canc Prevent, Frederick, MD 21701 USA. [Lee, Young Jae] Jeju Natl Univ, Coll Vet Med, Cheju, South Korea. [Bouloux, Gary F.] Emory Univ, Dept Surg, Div Oral & Maxillofacial Surg, Atlanta, GA 30322 USA. RP Beck, GR (reprint author), Emory Univ, Div Endocrinol Metab & Lipids, Dept Med, 101 Woodruff Circle,Room 1026, Atlanta, GA 30322 USA. EM george.beck@emory.edu FU National Cancer Institute [CA84573, CA136059, CA136716]; Emory University-URC1433; Jeju National University, Korea; National Cancer Institute, National Institutes of Health [NO1-CO-12400] FX This project has been funded by grants from the National Cancer Institute CA84573, CA136059, CA136716, and Emory University-URC1433 (CEC, KAC, YJL, YL, LMG, and GRB Jr.). YJL is also supported by a research grant from Jeju National University, Korea (2010). This project has also been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract NO1-CO-12400. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 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 United States Government. NR 118 TC 23 Z9 23 U1 1 U2 60 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD JUL PY 2013 VL 228 IS 7 BP 1536 EP 1550 DI 10.1002/jcp.24312 PG 15 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 113PX UT WOS:000316681100020 PM 23280476 ER PT J AU Rasmussen, B Allen, S Rasmussen, ZA Bajwa, R AF Rasmussen, Bruce Allen, Sheldon Rasmussen, Zeba A. Bajwa, Rashid TI Learning from disasters to save lives every day in Pakistan SO LANCET LA English DT Editorial Material ID FUTURE IMPLICATIONS; NEWBORN SURVIVAL; DECADE; FLOODS C1 [Rasmussen, Zeba A.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Bajwa, Rashid] Natl Rural Support Programme, Islamabad, Pakistan. EM rasmussenbruce@hotmail.com NR 16 TC 2 Z9 2 U1 1 U2 4 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 JUN 29 PY 2013 VL 381 IS 9885 BP 2232 EP 2234 DI 10.1016/S0140-6736(13)60652-2 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 173SU UT WOS:000321100300008 PM 23684253 ER PT J AU Berezhkovskii, AM Shvartsman, SY AF Berezhkovskii, Alexander M. Shvartsman, Stanislav Y. TI Kinetics of receptor occupancy during morphogen gradient formation SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID NERVOUS-SYSTEM; DIFFUSION AB During embryogenesis, sheets of cells are patterned by concentration profiles of morphogens, molecules that act as dose-dependent regulators of gene expression and cell differentiation. Concentration profiles of morphogens can be formed by a source-sink mechanism, whereby an extracellular protein is secreted from a localized source, diffuses through the tissue and binds to cell surface receptors. A morphogen molecule bound to its receptor can either dissociate or be internalized by the cell. The effects of morphogens on cells depend on the occupancy of surface receptors, which in turn depends on morphogen concentration. In the simplest case, the local concentrations of the morphogen and morphogen-receptor complexes monotonically increase with time from zero to their steady-state values. Here, we derive analytical expressions for the time scales which characterize the formation of the steady-state concentrations of both the diffusible morphogen molecules and orphogen-receptor complexes at a given point in the patterned tissue. (C) 2013 AIP Publishing LLC. C1 [Berezhkovskii, Alexander M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Shvartsman, Stanislav Y.] Princeton Univ, Dept Chem & Biol Engn, Princeton, NJ 08544 USA. [Shvartsman, Stanislav Y.] Princeton Univ, Lewis Singler Inst Integrat Genom, Princeton, NJ 08544 USA. RP Berezhkovskii, AM (reprint author), NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. FU NIH, Center for Information Technology; National Science Foundation [DMS-1119714, DMS-0718604] FX A.M.B. was supported by the Intramural Research Program of the NIH, Center for Information Technology. S.Y.S. acknowledges partial support by the National Science Foundation [grants DMS-1119714 and DMS-0718604]. The authors thank Bomyi Lim (Princeton) for preparing the figure used in this paper. NR 28 TC 4 Z9 4 U1 1 U2 10 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 J9 J CHEM PHYS JI J. Chem. Phys. PD JUN 28 PY 2013 VL 138 IS 24 AR 244105 DI 10.1063/1.4811654 PG 7 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 174IF UT WOS:000321148200006 ER PT J AU Mizurini, DM Francischetti, IMB Monteiro, RQ AF Mizurini, Daniella M. Francischetti, Ivo M. B. Monteiro, Robson Q. TI Aegyptin inhibits collagen-induced coagulation activation in vitro and thromboembolism in vivo SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Aegyptin; Mosquito saliva; Collagen; Platelets; Blood coagulation; Pulmonary thromboembolism ID PLATELET GLYCOPROTEIN-VI; VON-WILLEBRAND-FACTOR; THROMBUS FORMATION; SALIVARY-GLAND; FACTOR-XII; HEMOSTASIS; ANTICOAGULANTS; TARGETS; BINDING; MODEL AB Aegyptin is a mosquito salivary gland protein and potent inhibitor of platelet aggregation. Aegyptin binds to the von Willebrand factor-binding site on collagen and prevents its interaction with platelets. Because collagen also induces plasma clotting by activation of factor XII, we evaluated the effects of aegyptin on collagen-induced coagulation activation and how it interferes with thrombosis in three different in vivo models. Our results demonstrate that aegyptin abolishes collagen-induced clot formation and thrombin generation in platelet-free plasma. Aegyptin has no antithrombotic activity in the arteriovenous shunt model (collagen-independent) but it prevents laser-induced collagen-mediated thrombus formation in rats. Furthermore, aegyptin protects mice from collagen and epinephrine-induced thromboembolism. Therefore, aegyptin has a dual antithrombotic mechanism: inhibition of platelet-collagen interaction and collagen's pro-coagulant activity. This is the first description of a collagen-binding protein that also inhibits collagen-mediated coagulant activity. (C) 2013 Elsevier Inc. All rights reserved. C1 [Mizurini, Daniella M.; Monteiro, Robson Q.] Univ Fed Rio de Janeiro, Inst Med Biochem, BR-21941 Rio De Janeiro, RJ, Brazil. [Francischetti, Ivo M. B.] NIAID, Sect Vector Biol, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Monteiro, RQ (reprint author), Inst Bioquim Med CCS UFRJ, Ave Carlos Chagas Filho 373,Cidade Univ, BR-21941590 Rio De Janeiro, Brazil. EM robsonqm@bioqmed.ufrj.br RI Monteiro, Robson/B-8007-2014 FU Brazilian agency: Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq); Brazilian agency: Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro Carlos Chagas Filho (FAPERJ); Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA FX This research was supported by the following Brazilian agencies: Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro Carlos Chagas Filho (FAPERJ), and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. NR 24 TC 7 Z9 8 U1 1 U2 13 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 JUN 28 PY 2013 VL 436 IS 2 BP 235 EP 239 DI 10.1016/j.bbrc.2013.05.082 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 180NG UT WOS:000321601300022 PM 23726920 ER PT J AU Wyatt, MK Tsai, JY Mishra, S Campos, M Jaworski, C Fariss, RN Bernstein, SL Wistow, G AF Wyatt, M. Keith Tsai, Jen-Yue Mishra, Sanghamitra Campos, Maria Jaworski, Cynthia Fariss, Robert N. Bernstein, Steven L. Wistow, Graeme TI Interaction of Complement Factor H and Fibulin3 in Age-Related Macular Degeneration SO PLOS ONE LA English DT Article ID C-REACTIVE PROTEIN; MALATTIA LEVENTINESE; OXIDATIVE STRESS; TISSUE INHIBITOR; VARIANT; DRUSEN; RISK; POLYMORPHISM; GENE; SUSCEPTIBILITY AB Age-related macular degeneration (AMD) is a major cause of vision loss. It is associated with development of characteristic plaque-like deposits (soft drusen) in Bruch's membrane basal to the retinal pigment epithelium (RPE). A sequence variant (Y402H) in short consensus repeat domain 7 (SCR7) of complement factor H (CFH) is associated with risk for "dry'' AMD. We asked whether the eye-targeting of this disease might be related to specific interactions of CFH SCR7 with proteins expressed in the aging human RPE/choroid that could contribute to protein deposition in drusen. Yeast 2-hybrid (Y2H) screens of a retinal pigment epithelium/choroid library derived from aged donors using CFH SCR7 baits detected an interaction with EFEMP1/Fibulin 3 (Fib3), which is the locus for an inherited macular degeneration and also accumulates basal to macular RPE in AMD. The CFH/Fib3 interaction was validated by co-immunoprecipitation of native proteins. Quantitative Y2H and ELISA assays with different recombinant protein constructs both demonstrated higher affinity for Fib3 for the disease-related CFH 402H variant. Immuno-labeling revealed colocalization of CFH and Fib3 in globular deposits within cholesterol-rich domains in soft drusen in two AMD donors homozygous for CFH 402H (H/H). This pattern of labeling was quite distinct from those seen in examples of eyes with Y/Y and H/Y genotypes. The CFH 402H/Fib3 interaction could contribute to the development of pathological aggregates in soft drusen in some patients and as such might provide a target for therapeutic intervention in some forms of AMD. C1 [Wyatt, M. Keith; Mishra, Sanghamitra; Wistow, Graeme] NEI, Sect Mol Struct & Funct Genom, NIH, Bethesda, MD 20892 USA. [Tsai, Jen-Yue; Campos, Maria; Fariss, Robert N.] NEI, Biol Imaging Core, NIH, Bethesda, MD 20892 USA. [Jaworski, Cynthia] NEI, Lab Retinal Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Bernstein, Steven L.] Univ Maryland, Sch Med, Dept Ophthalmol, Baltimore, MD 21201 USA. [Bernstein, Steven L.] Univ Maryland, Sch Med, Dept Neurobiol & Genet, Baltimore, MD 21201 USA. RP Wistow, G (reprint author), NEI, Sect Mol Struct & Funct Genom, NIH, Bethesda, MD 20892 USA. EM graeme@helix.nih.gov FU NEI Intramural Research Program FX This work was supported by the NEI Intramural Research Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 15 Z9 15 U1 0 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 JUN 28 PY 2013 VL 8 IS 6 AR e68088 DI 10.1371/journal.pone.0068088 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 174IH UT WOS:000321148400162 PM 23840815 ER PT J AU Koulaouzidis, A Rondonotti, E Karargyris, A AF Koulaouzidis, Anastasios Rondonotti, Emanuele Karargyris, Alexandros TI Small-bowel capsule endoscopy: A ten-point contemporary review SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Review DE Capsule endoscopy; Calprotectin; Meta-analysis; Review; Preparation; Reading software; Complication; Indications ID DOUBLE-BALLOON ENTEROSCOPY; SUSPECTED BLOOD INDICATOR; COMPUTED VIRTUAL CHROMOENDOSCOPY; FAMILIAL ADENOMATOUS POLYPOSIS; DIAGNOSTIC YIELD; CROHNS-DISEASE; TRACHEAL ASPIRATION; FECAL CALPROTECTIN; COLOR ENHANCEMENT; PILLCAM SB AB The introduction of capsule endoscopy (CE) in clinical practice increased the interest for the study of the small-bowel. Consequently, in about 10 years, an impressive quantity of literature on indications, diagnostic yield (DY), safety profile and technical evolution of CE has been published as well as several reviews. At present time, there are 5 small-bowel capsule enteroscopy (SBCE) models in the worldwide market. Head-to-head trials have showed in the great majority of studies comparable results in terms of DY, image quality and completion rate. CE meta-analyses formed the basis of national/international guidelines; these guidelines place CE in a prime position for the diagnostic workup of patients with obscure gastrointestinal bleeding, known and/or suspected Crohn's disease and possible small-bowel neoplasia. A 2-L polyethylene glycol-based purge, administered the day before the procedure, is the most widely practiced preparation regimen. Whether this regimen can be further improved (i.e., by further decreasing its volume, changing the timing of administration, coupling it with prokinetics and/or other factors) or if it can really affect the DY, is still under discussion. Faecal calprotectin has been used in SBCE studies in two settings: in patients taking nonsteroidal anti-inflammatory drugs, to evaluate the type and extent of mucosal damage and, more importantly from a clinical point of view, in patients with known or suspected Crohn's disease for assessment of inflammation activity. Although there is still a lot of debate around the exact reasons of SBCE poor performance in various small-bowel segments, it is worth to remember that the capsule progress is non-steerable, hence more rapid in the proximal than in lower segments of the small-bowel. Capsule aspiration, a relatively unexpected complication, has been reported with increasing frequency. This is probably related with the increase in the mean age of patients undergoing CE. CE video review is a time-consuming procedure. Therefore, several attempts have been made to develop technical software features, in order to make CE video analysis easier and shorter (without jeopardizing its accuracy). Suspected Blood Indicator, QuickView and Fujinon Intelligent Chromo Endoscopy are some of the software tools that have been checked in various clinical studies to date. (C) 2013 Baishideng. All rights reserved. C1 [Koulaouzidis, Anastasios] Royal Infirm Edinburgh NHS Trust, Ctr Liver & Digest Disorders, Edinburgh EH16 4SA, Midlothian, Scotland. [Rondonotti, Emanuele] Osped Valduce, Gastroenterol Unit, I-22100 Como, Italy. [Karargyris, Alexandros] NIH, Natl Lib Med, Bethesda, MD 20814 USA. RP Koulaouzidis, A (reprint author), Royal Infirm Edinburgh NHS Trust, Ctr Liver & Digest Disorders, Endoscopy Unit, 51 Little France Crescent,Old Dalkeith Rd, Edinburgh EH16 4SA, Midlothian, Scotland. EM akoulaouzidis@hotmail.com NR 144 TC 58 Z9 60 U1 3 U2 14 PU BAISHIDENG PUBLISHING GROUP INC PI PLEASANTON PA 8226 REGENCY DR, PLEASANTON, CA 94588 USA SN 1007-9327 EI 2219-2840 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD JUN 28 PY 2013 VL 19 IS 24 BP 3726 EP 3746 DI 10.3748/wjg.v19.i24.3726 PG 21 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 173XG UT WOS:000321115100003 PM 23840112 ER PT J AU Friis, S Sales, KU Godiksen, S Peters, DE Lin, CY Vogel, LK Bugge, TH AF Friis, Stine Sales, Katiuchia Uzzun Godiksen, Sine Peters, Diane E. Lin, Chen-Yong Vogel, Lotte K. Bugge, Thomas H. TI A Matriptase-Prostasin Reciprocal Zymogen Activation Complex with Unique Features PROSTASIN AS A NON-ENZYMATIC CO-FACTOR FOR MATRIPTASE ACTIVATION SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EPITHELIAL SODIUM-CHANNEL; EPIDERMAL BARRIER FUNCTION; SERINE-PROTEASE INHIBITOR; HAIR FOLLICLE DEVELOPMENT; NEURAL-TUBE CLOSURE; PLASMINOGEN ACTIVATION; CELL-SURFACE; PLACENTAL DEVELOPMENT; MONOCLONAL-ANTIBODY; PROTEOLYTIC CASCADE AB Matriptase and prostasin are part of a cell surface proteolytic pathway critical for epithelial development and homeostasis. Here we have used a reconstituted cell-based system and transgenic mice to investigate the mechanistic interrelationship between the two proteases. We show that matriptase and prostasin form a reciprocal zymogen activation complex with unique features. Prostasin serves as a critical co-factor for matriptase activation. Unexpectedly, however, prostasin-induced matriptase activation requires neither prostasin zymogen conversion nor prostasin catalytic activity. Prostasin zymogen conversion to active prostasin is dependent on matriptase but does not require matriptase zymogen conversion. Consistent with these findings, wild type prostasin, activation cleavage site-mutated prostasin, and catalytically inactive prostasin all were biologically active in vivo when overexpressed in the epidermis of transgenic mice, giving rise to a severe skin phenotype. Our finding of non-enzymatic stimulation of matriptase activation by prostasin and activation of prostasin by the matriptase zymogen provides a tentative mechanistic explanation for several hitherto unaccounted for genetic and biochemical observations regarding these two membrane-anchored serine proteases and their downstream targets. C1 [Bugge, Thomas H.] NIDCR, Proteases & Tissue Remodeling Sect, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Sales, Katiuchia Uzzun] NIDCR, Clin Res Core, NIH, Bethesda, MD 20892 USA. [Friis, Stine; Godiksen, Sine; Vogel, Lotte K.] Univ Copenhagen, Fac Hlth Sci, Dept Cellular & Mol Med, DK-2200 Copenhagen, Denmark. [Godiksen, Sine] Univ Copenhagen, Fac Sci, Dept Biol, DK-2200 Copenhagen, Denmark. [Peters, Diane E.] Tufts Univ, Sch Med, Program Pharmacol & Expt Therapeut, Boston, MA 02111 USA. Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. RP Bugge, TH (reprint author), NIDCR, Proteases & Tissue Remodeling Sect, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Rm 211, Bethesda, MD 20892 USA. EM thomas.bugge@nih.gov FU National Institutes of Health, NIDCR, Intramural Research Program; Harboe Foundation; Lundbeck Foundation; Foundation of 17.12.1981; Augustinus Foundation; Kobmand Kristian Kjaer og Hustrus Foundation; Kjaer-Foundation; Dagmar Marshalls Foundation; Snedkermester Sophus Jacobsen og Hustru Astrid Jacobsens Foundation; Grosserer Valdemar Foersom og Hustru Thyra Foersoms Foundation; Fabrikant Einar Willumsens Mindelegat FX This work was supported, in whole or in part, by the National Institutes of Health, NIDCR, Intramural Research Program (to T. H. B). This work was also supported by the Harboe Foundation, the Lundbeck Foundation, and the Foundation of 17.12.1981 (to S. F.) and the Augustinus Foundation, the Kobmand Kristian Kjaer og Hustrus Foundation, the Kjaer-Foundation, the Dagmar Marshalls Foundation, the Snedkermester Sophus Jacobsen og Hustru Astrid Jacobsens Foundation, the Grosserer Valdemar Foersom og Hustru Thyra Foersoms Foundation, and Fabrikant Einar Willumsens Mindelegat (to S.G.). NR 51 TC 28 Z9 28 U1 0 U2 6 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 JUN 28 PY 2013 VL 288 IS 26 BP 19028 EP 19039 DI 10.1074/jbc.M113.469932 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 176WB UT WOS:000321335800038 PM 23673661 ER PT J AU He, XM Chatterjee, R John, S Bravo, H Sathyanarayana, BK Biddie, SC FitzGerald, PC Stamatoyannopoulos, JA Hager, GL Vinson, C AF He, Ximiao Chatterjee, Raghunath John, Sam Bravo, Hector Sathyanarayana, B. K. Biddie, Simon C. FitzGerald, Peter C. Stamatoyannopoulos, John A. Hager, Gordon L. Vinson, Charles TI Contribution of nucleosome binding preferences and co-occurring DNA sequences to transcription factor binding SO BMC GENOMICS LA English DT Article DE TFBS; Nucleosome; GR; c-Jun ID GLUCOCORTICOID-RECEPTOR-BINDING; UCSC GENOME BROWSER; CHIP-SEQ; CHROMATIN ACCESSIBILITY; GENE-REGULATION; DROSOPHILA; OCCUPANCY; PROMOTERS; SITES; ORGANIZATION AB Background: Chromatin plays a critical role in regulating transcription factors (TFs) binding to their canonical transcription factor binding sites (TFBS). Recent studies in vertebrates show that many TFs preferentially bind to genomic regions that are well bound by nucleosomes in vitro. Co-occurring secondary motifs sometimes correlated with functional TFBS. Results: We used a logistic regression to evaluate how well the propensity for nucleosome binding and co-occurrence of a secondary motif identify which canonical motifs are bound in vivo. We used ChIP-seq data for three transcription factors binding to their canonical motifs: c-Jun binding the AP-1 motif (TGA(C)/(G)TCA), GR (glucocorticoid receptor) binding the GR motif (G-ACA-(T)/(C)GT-C), and Hoxa2 (homeobox a2) binding the Pbx (Pre-B-cell leukemia homeobox) motif (TGATTGAT). For all canonical TFBS in the mouse genome, we calculated intrinsic nucleosome occupancy scores (INOS) for its surrounding 150-bps DNA and examined the relationship with in vivo TF binding. In mouse mammary 3134 cells, c-Jun and GR proteins preferentially bound regions calculated to be well-bound by nucleosomes in vitro with the canonical AP-1 and GR motifs themselves contributing to the high INOS. Functional GR motifs are enriched for AP-1 motifs if they are within a nucleosome-sized 150-bps region. GR and Hoxa2 also bind motifs with low INOS, perhaps indicating a different mechanism of action. Conclusion: Our analysis quantified the contribution of INOS and co-occurring sequence to the identification of functional canonical motifs in the genome. This analysis revealed an inherent competition between some TFs and nucleosomes for binding canonical TFBS. GR and c-Jun cooperate if they are within 150-bps. Binding of Hoxa2 and a fraction of GR to motifs with low INOS values suggesting they are not in competition with nucleosomes and may function using different mechanisms. C1 [He, Ximiao; Chatterjee, Raghunath; Vinson, Charles] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [John, Sam; Biddie, Simon C.; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Sathyanarayana, B. K.] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [FitzGerald, Peter C.] NCI, Genome Anal Unit, Genet Branch, NIH, Bethesda, MD 20892 USA. [Bravo, Hector] Univ Maryland, Ctr Bioinformat & Computat Biol, College Pk, MD 20742 USA. [John, Sam; Stamatoyannopoulos, John A.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. RP Vinson, C (reprint author), NCI, Lab Metab, NIH, Room 3128,Bldg 37,37 Convent Dr, Bethesda, MD 20892 USA. EM Vinsonc@mail.nih.gov OI Biddie, Simon/0000-0002-8253-0253; Corrada Bravo, Hector/0000-0002-1255-4444 NR 50 TC 9 Z9 9 U1 0 U2 6 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 JUN 28 PY 2013 VL 14 AR 428 DI 10.1186/1471-2164-14-428 PG 15 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 177QV UT WOS:000321391200001 PM 23805837 ER PT J AU Jones, JC Freeman, GJ AF Jones, Jennifer C. Freeman, Gordon J. TI Costimulatory Genes: Hotspots of Conflict between Host Defense and Autoimmunity SO IMMUNITY LA English DT Editorial Material C1 [Jones, Jennifer C.] NCI, Vaccine Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Freeman, Gordon J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. RP Freeman, GJ (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM Gordon_Freeman@dfci.harvard.edu RI Jones, Jennifer/C-8691-2015 OI Jones, Jennifer/0000-0002-9488-7719 FU NIAID NIH HHS [R01 AI089955, P01 AI056299, P01 AI080192, U19 AI082630] NR 10 TC 2 Z9 2 U1 1 U2 3 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 JUN 27 PY 2013 VL 38 IS 6 BP 1083 EP 1085 DI 10.1016/j.immuni.2013.06.008 PG 4 WC Immunology SC Immunology GA AA2TR UT WOS:000330947500002 PM 23809156 ER PT J AU Tai, X Erman, B Alag, A Mu, J Kimura, M Katz, G Guinter, T McCaughtry, T Etzensperger, R Feigenbaum, L Singer, DS Singer, A AF Tai, Xuguang Erman, Batu Alag, Amala Mu, Jie Kimura, Motoko Katz, Gil Guinter, Terry McCaughtry, Tom Etzensperger, Ruth Feigenbaum, Lionel Singer, Dinah S. Singer, Alfred TI Foxp3 Transcription Factor Is Proapoptotic and Lethal to Developing Regulatory T Cells unless Counterbalanced by Cytokine Survival Signals SO IMMUNITY LA English DT Article ID NEGATIVE SELECTION; LINEAGE FATE; GENE; SPECIFICITY; APOPTOSIS; THYMUS; SELF; BIM; DIFFERENTIATION; AUTOIMMUNITY AB Immune tolerance requires regulatory T (Treg) cells to prevent autoimmune disease, with the transcription factor Foxp3 functioning as the critical regulator of Treg cell development and function. We report here that Foxp3 was lethal to developing Treg cells in the thymus because it induced a unique proapoptotic protein signature (Puma(++) p-Bim(++) p-JNK(++) DUSP6(-)) and repressed expression of prosurvival Bcl-2 molecules. However, Foxp3 lethality was prevented by common gamma chain (gc)-dependent cytokine signals that were present in the thymus in limiting amounts sufficient to support only similar to 1 million Treg cells. Consequently, most newly arising Treg cells in the thymus were deprived of this signal and underwent Foxp3-induced death, with Foxp3(+)CD25(-) Treg precursor cells being the most susceptible. Thus, we identify Foxp3 as a proapoptotic protein that requires developing Treg cells to compete with one another for limiting amounts of gamma c-dependent survival signals in the thymus. C1 [Tai, Xuguang; Alag, Amala; Mu, Jie; Kimura, Motoko; Katz, Gil; Guinter, Terry; McCaughtry, Tom; Etzensperger, Ruth; Singer, Dinah S.; Singer, Alfred] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Erman, Batu] Sabanci Univ, Fac Engn & Nat Sci, Biol Sci & Bioengn Program, TR-34956 Istanbul, Turkey. [Feigenbaum, Lionel] SAIC Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Singer, A (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM singera@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We are grateful to P. Henkart for editorial assistance; J. Bluestone, V. Kuchroo, A. Strasser, and M. A. Farrar for mice; and R. Hodes, J.-H. Park, and N. Taylor for reading the manuscript. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 44 TC 55 Z9 57 U1 1 U2 11 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 JUN 27 PY 2013 VL 38 IS 6 BP 1116 EP 1128 DI 10.1016/j.immuni.2013.02.022 PG 13 WC Immunology SC Immunology GA AA2TR UT WOS:000330947500008 PM 23746651 ER PT J AU Chappert, P Bouladoux, N Naik, S Schwartz, RH AF Chappert, Pascal Bouladoux, Nicolas Naik, Shruti Schwartz, Ronald H. TI Specific Gut Commensal Flora Locally Alters T Cell Tuning to Endogenous Ligands SO IMMUNITY LA English DT Article ID SEGMENTED FILAMENTOUS BACTERIA; ADAPTIVE TOLERANCE; IMMUNE-SYSTEM; INTESTINAL MICROBIOTA; ACTIVATION THRESHOLD; VIRAL-INFECTION; IN-VIVO; RESPONSES; INDUCTION; CD4(+) AB Differences in gut commensal flora can dramatically influence autoimmune responses, but the mechanisms behind this are still unclear. We report, in a Th1-cell-driven murine model of autoimmune arthritis, that specific gut commensals, such as segmented filamentous bacteria, have the ability to modulate the activation threshold of self-reactive T cells. In the local microenvironment of gut-associated lymphoid tissues, inflammatory cytokines elicited by the commensal flora dynamically enhanced the antigen responsiveness of T cells that were otherwise tuned down to a systemic self-antigen. Together with subtle differences in early lineage differentiation, this ultimately led to an enhanced recruitment of pathogenic Th1 cells and the development of a more severe form of autoimmune arthritis. These findings define a key role for the gut commensal flora in sustaining ongoing autoimmune responses through the local fine tuning of T-cell-receptor-proximal activation events in autoreactive T cells. C1 [Chappert, Pascal; Schwartz, Ronald H.] NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. [Bouladoux, Nicolas; Naik, Shruti] NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Chappert, P (reprint author), Univ Paris 05, Sorbonne Paris Cite, INSERM U1013, F-75743 Paris 15, France. EM pascal.chappert@inserm.fr OI chappert, pascal/0000-0002-9799-4608 FU Intramural Research Program of the NIAID at the National Institutes of Health, Bethesda, MD, USA FX We thank N.J. Singh for helpful discussions and comments on the design of the experiments; N.J. Singh, Y. Belkaid, J. Davoust, and D.A. Gross for helpful comments on the manuscript; N. Shulzhenko and A. Morgun for help on the design of the antibiotic-treatment experiments and the analysis of SFB colonization; E.J. Chuang for technical assistance; and D. Trageser-celser, C. Acevedo, and the National Institutes of Allergy and Infectious Diseases (NIAID) germ-free facility for maintaining the mice used in these experiments and technical assistance. This work was supported by the Intramural Research Program of the NIAID at the National Institutes of Health, Bethesda, MD, USA. NR 47 TC 19 Z9 20 U1 0 U2 8 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 JUN 27 PY 2013 VL 38 IS 6 BP 1198 EP 1210 DI 10.1016/j.immuni.2013.06.005 PG 13 WC Immunology SC Immunology GA AA2TR UT WOS:000330947500015 PM 23809163 ER PT J AU Sonda, N Simonato, F Peranzoni, E Cali, B Bortoluzzi, S Bisognin, A Wang, E Marincola, FM Naldini, L Gentner, B Trautwein, C Sackett, SD Zanovello, P Molon, B Bronte, V AF Sonda, Nada Simonato, Francesca Peranzoni, Elisa Cali, Bianca Bortoluzzi, Stefania Bisognin, Andrea Wang, Ena Marincola, Francesco M. Naldini, Luigi Gentner, Bernhard Trautwein, Christian Sackett, Sara Dutton Zanovello, Paola Molon, Barbara Bronte, Vincenzo TI miR-142-3p Prevents Macrophage Differentiation during Cancer-Induced Myelopoiesis SO IMMUNITY LA English DT Article ID COLONY-STIMULATING FACTOR; DENDRITIC CELL-DIFFERENTIATION; SUPPRESSOR-CELLS; PANCREATIC-CANCER; T-CELLS; GM-CSF; MYELOID CELLS; MICRORNAS; BETA; PROGRESSION AB Tumor progression is accompanied by an altered myelopoiesis causing the accumulation of immunosuppressive cells. Here, we showed that miR-142-3p downregulation promoted macrophage differentiation and determined the acquisition of their immunosuppressive function in tumor. Tumorreleased cytokines signaling through gp130, the common subunit of the interleukin-6 cytokine receptor family, induced the LAP* isoform of C/EBP beta transcription factor, promoting macrophage generation. miR-142-3p downregulated gp130 by canonical binding to its messenger RNA (mRNA) 3' UTR and repressed C/EBP beta LAP* by noncanonical binding to its 5' mRNA coding sequence. Enforced miR expression impaired macrophage differentiation both in vitro and in vivo. Mice constitutively expressing miR-142-3p in the bone marrow showed a marked increase in survival following immunotherapy with tumor-specific T lymphocytes. By modulating a specific miR in bone marrow precursors, we thus demonstrated the feasibility of altering tumor-induced macrophage differentiation as a potent tool to improve the efficacy of cancer immunotherapy. C1 [Sonda, Nada; Simonato, Francesca; Cali, Bianca; Zanovello, Paola] Univ Padua, Dept Surg Oncol & Gastroenterol, Oncol & Immunol Sect, I-35128 Padua, Italy. [Sonda, Nada; Peranzoni, Elisa; Zanovello, Paola; Molon, Barbara] IRCCS, Ist Oncol Veneto, I-35128 Padua, Italy. [Molon, Barbara] Venetian Inst Mol Med, I-35129 Padua, Italy. [Bortoluzzi, Stefania; Bisognin, Andrea] Univ Padua, Dept Biol, I-35121 Padua, Italy. [Wang, Ena; Marincola, Francesco M.] NIH, Dept Transfus Med, Infect Dis & Immunogenet Sect, Ctr Clin, Bethesda, MD 20892 USA. [Wang, Ena; Marincola, Francesco M.] NIH, Ctr Human Immunol, Bethesda, MD 20892 USA. [Marincola, Francesco M.] Sidra Med & Res Ctr, Doha, Qatar. [Naldini, Luigi; Gentner, Bernhard] Ist Sci San Raffaele, San Raffaele Telethon Inst Gene Therapy, I-20132 Milan, Italy. [Naldini, Luigi; Gentner, Bernhard] Ist Sci San Raffaele, Div Regenerat Med Gene Therapy & Stem Cells, I-20132 Milan, Italy. [Naldini, Luigi; Gentner, Bernhard] Univ Vita Salute San Raffaele, Sch Med, I-20132 Milan, Italy. [Trautwein, Christian; Sackett, Sara Dutton] RWTH Univ Hosp, Dept Med 3, D-52074 Aachen, Germany. [Bronte, Vincenzo] Univ Verona, Verona Univ Hosp, I-37134 Verona, Italy. [Bronte, Vincenzo] Univ Verona, Dept Pathol, Immunol Sect, I-37134 Verona, Italy. RP Bronte, V (reprint author), Univ Verona, Verona Univ Hosp, I-37134 Verona, Italy. EM vincenzo.bronte@univr.it RI Bronte, Vincenzo/K-7902-2016; Bisognin, Andrea/J-3619-2013; OI Bronte, Vincenzo/0000-0002-3741-5141; Bisognin, Andrea/0000-0002-9114-1508; Bortoluzzi, Stefania/0000-0001-8240-3070; Gentner, Bernhard/0000-0001-6024-4718 FU Italian Ministry of Education, University and Research [RBAP11T3WB_003, 2009NREAT2_003]; Italian Association for Cancer Research (AIRC) [IG10400, 12182, AGIMM 100005, 6599]; AIRC-Cariparo; BMBF [01KU1214B]; OBIHEP [360365]; Fondazione Telethon FX We thank Maurizio Buggio, Serena Zilio, and Stefano Ugel for help with the in vivo experiments and Andrea Predonzani for the generation of plasmids. This work was supported by grants from the Italian Ministry of Education, University and Research (FIRB project RBAP11T3WB_003 and MIUR project 2009NREAT2_003), Italian Association for Cancer Research (AIRC, Grants IG10400, 12182, AGIMM 100005, and 6599), and AIRC-Cariparo, Regional Grant 2008. The work of C.T. was supported by the BMBF 01KU1214B (OBIHEP 360365). NR 56 TC 39 Z9 40 U1 3 U2 13 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 JUN 27 PY 2013 VL 38 IS 6 BP 1236 EP 1249 DI 10.1016/j.immuni.2013.06.004 PG 14 WC Immunology SC Immunology GA AA2TR UT WOS:000330947500018 PM 23809164 ER PT J AU Nee, R Jindal, RM Little, D Ramsey-Goldman, R Agodoa, L Hurst, FP Abbott, KC AF Nee, Robert Jindal, Rahul M. Little, Dustin Ramsey-Goldman, Rosalind Agodoa, Lawrence Hurst, Frank P. Abbott, Kevin C. TI Racial Differences and Income Disparities Are Associated With Poor Outcomes in Kidney Transplant Recipients With Lupus Nephritis SO TRANSPLANTATION LA English DT Article DE USRDS; Lupus nephritis; Median household income ID 3 ETHNIC-GROUPS; RENAL-TRANSPLANTATION; SOCIOECONOMIC-FACTORS; ERYTHEMATOSUS; SURVIVAL; RACE/ETHNICITY; FEATURES; RACE AB Background. An analysis of income and racial/ethnic disparities on renal transplant outcomes in recipients with lupus nephritis (LN) has not been reported. We analyzed the United States Renal Data System database to assess the impact of these disparities on graft loss and death in the LN and non-LN cohorts. Methods. We identified 4214 patients with LN as the cause of end-stage renal disease in a retrospective cohort of 150,118 patients first transplanted from January 1, 1995 to July 1, 2006. We merged data on median household income from the United States Census based on the ZIP code. Results. In multivariate Cox regression analyses, African-Americans (AF) recipients with LN (vs. non-AF) had an increased risk of graft loss (adjusted hazard ratio [AHR], 1.39; 95% confidence interval [CI], 1.21-1.60) and death (AHR, 1.33; 95% CI, 1.09-1.63). Furthermore, there were significant associations of lower-income quintiles with higher risk for graft loss and death among AF with LN. In comparison, among non-AF recipients with LN, income levels did not predict risk for transplant outcomes. The racial disparity for both graft loss and death outcomes among AF with LN was greater than among AF without LN (AHR, 1.32; 95% CI, 1.29-1.36 for graft loss and AHR, 1.02; 95% CI, 0.99-1.05 for death). Conclusions. AF kidney transplant recipients with LN were at increased risk for graft loss and death compared with non-AF. Income levels were associated with the risk of graft loss and death in AF but not in non-AF recipients with LN. C1 [Nee, Robert; Little, Dustin; Hurst, Frank P.; Abbott, Kevin C.] Walter Reed Natl Mil Med Ctr, Bethesda, MD 20889 USA. [Jindal, Rahul M.] Walter Reed Natl Mil Med Ctr, Dept Surg, Bethesda, MD 20889 USA. [Jindal, Rahul M.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Ramsey-Goldman, Rosalind] Northwestern Univ, Feinberg Sch Med, Div Rheumatol, Chicago, IL 60611 USA. [Agodoa, Lawrence] NIDDK, NIH, Bethesda, MD 20892 USA. RP Jindal, RM (reprint author), Walter Reed Natl Mil Med Ctr, Dept Transplantat, 8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM jindalr@msn.com OI Abbott, Kevin/0000-0003-2111-7112 NR 30 TC 11 Z9 11 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUN 27 PY 2013 VL 95 IS 12 BP 1471 EP 1478 DI 10.1097/TP.0b013e318292520e PG 8 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 299EF UT WOS:000330377600012 PM 23680929 ER PT J AU Gea-Banacloche, JC AF Gea-Banacloche, Juan C. TI Antiviral cell therapy: is this the future? SO BLOOD LA English DT Editorial Material ID T-LYMPHOCYTES; DISEASE C1 NCI, Bethesda, MD 20892 USA. RP Gea-Banacloche, JC (reprint author), NCI, Bethesda, MD 20892 USA. NR 10 TC 2 Z9 3 U1 0 U2 2 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 JUN 27 PY 2013 VL 121 IS 26 BP 5108 EP 5109 DI 10.1182/blood-2013-05-500082 PG 4 WC Hematology SC Hematology GA 184OJ UT WOS:000321900700002 PM 23813935 ER PT J AU Morellato-Castillo, L Acharya, P Combes, O Michiels, J Descours, A Ramos, OHP Yang, YP Vanham, G Alien, KK Kwong, PD Martin, L Kessler, P AF Morellato-Castillo, Laurence Acharya, Priyamvada Combes, Olivier Michiels, Johan Descours, Anne Ramos, Oscar H. P. Yang, Yongping Vanham, Guido Alien, Kevin K. Kwong, Peter D. Martin, Loic Kessler, Pascal TI Interfacial Cavity Filling To Optimize CD4-Mimetic Miniprotein Interactions with HIV-1 Surface Glycoprotein SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; GP120 ENVELOPE GLYCOPROTEIN; CD4-BOUND CONFORMATION; ENTRY INHIBITORS; CD4 RECEPTOR; ANTIBODY; BINDING; DESIGN; CORE; PROTEINS AB Ligand affinities can be optimized by interfacial cavity filling. A hollow (Phe43 cavity) between HIV-1 surface glycoprotein (gp120) and cluster of differentiation 4 (CD4) receptor extends beyond residue phenylalanine 43 of CD4 and cannot be fully accessed by natural amino acids. To increase HIV-1 gp120 affinity for a family of CD4-mimetic miniproteins (miniCD4s), we targeted the gp120 Phe43 cavity with 11 nonnatural phenylalanine derivatives, introduced into a miniCD4 named M48 (1). The best derivative, named M48U12 (13), bound HIV-1 YU2 gp120 with 8 pM affinity and showed potent HIV-1 neutralization. It contained a methylcyclohexyl derivative of 4-aminophenylalanine, and its cocrystal structure. with gp120 revealed the cyclohexane ring buried within the gp120 hydrophobic core but able to assume multiple orientations in the binding pocket, and the aniline nitrogen potentially providing a focus for further improvement Altogether, the results provide a framework for filling the interfacial Phe43 cavity to enhance miniCD4 affinity. C1 [Morellato-Castillo, Laurence; Combes, Olivier; Descours, Anne; Ramos, Oscar H. P.; Martin, Loic; Kessler, Pascal] CEA, IBiTecS, Serv Ingn Mol Prot, F-91191 Gif Sur Yvette, France. [Acharya, Priyamvada; Yang, Yongping; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Michiels, Johan; Vanham, Guido; Alien, Kevin K.] Inst Trop Med, Dept Biomed Sci, Virol Unit, B-2000 Antwerp, Belgium. RP Martin, L (reprint author), CEA, IBiTecS, Serv Ingn Mol Prot, F-91191 Gif Sur Yvette, France. EM loic.martin@cea.fr; pascal.kessler@cea.fr FU sixth European Union Framework Program Microbicide Project (EMPRO); Intramural AIDS Targeted Anti-Retroviral Program (IATAP), NIH; Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Seventh Framework Program (FP7) [242135]; EU program EVA/MRC [QLKZ-CT-1999-00609, GP828102]; UK Medical Research Council; U.S. Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX This work was supported by the sixth European Union Framework Program Microbicide Project (EMPRO), by the Intramural AIDS Targeted Anti-Retroviral Program (IATAP), NIH, by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and Seventh Framework Program (FP7/2007-2013) under grant agreement no. 242135 (CHAARM). L120.3 Ab was provided by the Centralised Facility for AIDS Reagents supported by EU program EVA/MRC (contract QLKZ-CT-1999-00609 and GP828102) and the UK Medical Research Council. We also thank Novartis Vaccine for providing gp120SF162. Synchrotron: Use of sector 22 (South-east Region Collaborative Access team) at the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under Contract W-31-109-Eng-38. NR 47 TC 10 Z9 10 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD JUN 27 PY 2013 VL 56 IS 12 BP 5033 EP 5047 DI 10.1021/jm4002988 PG 15 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 175NJ UT WOS:000321237100017 PM 23710622 ER PT J AU Chen, JW Feng, G Song, Y Wardenburg, JB Lin, S Inoshima, I Otto, M Wunderink, RG AF Chen, Jiwang Feng, Gang Song, Yang Wardenburg, Juliane B. Lin, Simon Inoshima, Ichiro Otto, Michael Wunderink, Richard G. TI Linezolid Exerts Greater Bacterial Clearance but No Modification of Host Lung Gene Expression Profiling: A Mouse MRSA Pneumonia Model SO PLOS ONE LA English DT Article ID RESISTANT STAPHYLOCOCCUS-AUREUS; PANTON-VALENTINE LEUKOCIDIN; ILLUMINA MICROARRAY; DISEASE-ONTOLOGY; ANTIBIOTICS; INFECTION; SEPSIS; PATHOGENESIS; MANAGEMENT; CELLS AB Background: Linezolid (LZD) is beneficial to patients with MRSA pneumonia, but whether and how LZD influences global host lung immune responses at the mRNA level during MRSA-mediated pneumonia is still unknown. Methods: A lethal mouse model of MRSA pneumonia mediated by USA300 was employed to study the influence of LZD on survival, while the sublethal mouse model was used to examine the effect of LZD on bacterial clearance and lung gene expression during MRSA pneumonia. LZD (100mg/kg/day, IP) was given to C57Bl6 mice for three days. On Day 1 and Day 3 post infection, bronchoalveolar lavage fluid (BALF) protein concentration and levels of cytokines including IL6, TNF alpha, IL1 beta, Interferon-gamma and IL17 were measured. In the sublethal model, left lungs were used to determine bacterial clearance and right lungs for whole-genome transcriptional profiling of lung immune responses. Results: LZD therapy significantly improved survival and bacterial clearance. It also significantly decreased BALF protein concentration and levels of cytokines including IL6, IL1 beta, Interferon-gamma and IL17. No significant gene expression changes in the mouse lungs were associated with LZD therapy. Conclusion: LZD is beneficial to MRSA pneumonia, but it does not modulate host lung immune responses at the transcriptional level. C1 [Chen, Jiwang; Wunderink, Richard G.] Northwestern Univ, Dept Med, Chicago, IL 60611 USA. [Chen, Jiwang] Univ Illinois, Sect Pulm Crit Care Med Allergy & Sleep, Chicago, IL USA. [Feng, Gang; Lin, Simon] Northwestern Univ, Biomed Informat Ctr, Chicago, IL 60611 USA. [Song, Yang] Illinois State Univ, Microbiol Grp, Sch Biol Sci, Normal, IL 61761 USA. [Wardenburg, Juliane B.; Inoshima, Ichiro] Univ Chicago, Dept Pediat, Chicago, IL 60637 USA. [Lin, Simon] Marshfield Clin Res Fdn, Biomed Informat Res Ctr, Marshfield, WI USA. [Otto, Michael] NIAID, Bethesda, MD 20892 USA. RP Chen, JW (reprint author), Northwestern Univ, Dept Med, Chicago, IL 60611 USA. EM chenjw@uic.edu RI song, yang/P-1033-2015; OI Otto, Michael/0000-0002-2222-4115; Wunderink, Richard/0000-0002-8527-4195 FU Pfizer [WS1826185]; National Center for Advancing Translational Sciences Grant [8UL1TR000150]; NCI Cancer Center Support Grant [NCI CA060553]; Intramural Research Program of the NIAID FX This study was supported by Pfizer ASPIRE Award, Pfizer Investigator-Initiated Grant (WS1826185, to JC), the National Center for Advancing Translational Sciences Grant (8UL1TR000150) and the NCI Cancer Center Support Grant (NCI CA060553 to GF and SL) and the Intramural Research Program of the NIAID (to MO). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 1 Z9 1 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 27 PY 2013 VL 8 IS 6 AR e67994 DI 10.1371/journal.pone.0067994 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 174IX UT WOS:000321150000107 PM 23826353 ER PT J AU Famooto, A Almujtaba, M Dareng, E Akarolo-Anthony, S Ogbonna, C Offiong, R Olaniyan, O Wheeler, CM Doumatey, A Rotimi, CN Adeyemo, A Adebamowo, CA AF Famooto, Ayo Almujtaba, Maryam Dareng, Eileen Akarolo-Anthony, Sally Ogbonna, Celestine Offiong, Richard Olaniyan, Olayinka Wheeler, Cosette M. Doumatey, Ayo Rotimi, Charles N. Adeyemo, Adebowale Adebamowo, Clement A. TI RPS19 and TYMS SNPs and Prevalent High Risk Human Papilloma Virus Infection in Nigerian Women SO PLOS ONE LA English DT Article ID DIAMOND-BLACKFAN-ANEMIA; CERVICAL-CANCER; REGISTRY; ASSOCIATION; TUMORS; TOOL AB High risk HPV (hrHPV) infection is a necessary cause of cervical cancer but the host genetic determinants of infection are poorly understood. We enrolled 267 women who presented to our cervical cancer screening program in Abuja, Nigeria between April 2012 and August 2012. We collected information on demographic characteristics, risk factors of cervical cancer and obtained samples of blood and cervical exfoliated cells from all participants. We used Roche Linear Array HPV Genotyping Test(R) to characterize the prevalent HPV according to manufacturer's instruction; Sequenom Mass Array to test 21 SNPs in genes/regions previously associated with hrHPV and regression models to examine independent factors associated with HPV infection. We considered a p<0.05 as significant because this is a replication study. There were 65 women with and 202 women without hrHPV infection. Under the allelic model, we found significant association between two SNPs, rs2305809 on RPS19 and rs2342700 on TYMS, and prevalent hrHPV infection. Multivariate analysis of hrHPV risk adjusted for age, body mass index, smoking, age of menarche, age at sexual debut, lifetime total number of sexual partners and the total number of pregnancies as covariates, yielded a p-value of 0.071 and 0.010 for rs2305809 and rs2342700, respectively. Our findings in this unique population suggest that a number of genetic risk variants for hrHPV are shared with other population groups. Definitive studies with larger sample sizes and using genome wide approaches are needed to understand the genetic architecture of hrHPV risk in multiple populations. C1 [Famooto, Ayo; Almujtaba, Maryam; Dareng, Eileen; Akarolo-Anthony, Sally; Ogbonna, Celestine; Adebamowo, Clement A.] Inst Human Virol, Dept Res & Training, Abuja, FCT, Nigeria. [Akarolo-Anthony, Sally; Adebamowo, Clement A.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Offiong, Richard] Univ Abuja, Teaching Hosp, Gwagwalada, FCT, Nigeria. [Olaniyan, Olayinka] Natl Hosp, Abuja, FCT, Nigeria. [Wheeler, Cosette M.] Univ New Mexico, Dept Pathol, Hlth Sci Ctr, Albuquerque, NM 87131 USA. [Doumatey, Ayo; Rotimi, Charles N.; Adeyemo, Adebowale] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Adebamowo, Clement A.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Inst Human Virol, Baltimore, MD 21201 USA. [Adebamowo, Clement A.] Univ Maryland, Sch Med, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. RP Adebamowo, CA (reprint author), Inst Human Virol, Dept Res & Training, Abuja, FCT, Nigeria. EM cadebamowo@som.umaryland.edu OI Adebamowo, Sally/0000-0003-4713-2433; Adeyemo, Adebowale/0000-0002-3105-3231 FU National Cancer Institute [D43CA153792] FX The project described was supported by Award Number D43CA153792 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 23 TC 2 Z9 2 U1 1 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 JUN 27 PY 2013 VL 8 IS 6 AR e66930 DI 10.1371/journal.pone.0066930 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 174IX UT WOS:000321150000018 PM 23826176 ER PT J AU Gandolfi, B Alhaddad, H Affolter, VK Brockman, J Haggstrom, J Joslin, SEK Koehne, AL Mullikin, JC Outerbridge, CA Warren, WC Lyons, LA AF Gandolfi, Barbara Alhaddad, Hasan Affolter, Verena K. Brockman, Jeffrey Haggstrom, Jens Joslin, Shannon E. K. Koehne, Amanda L. Mullikin, James C. Outerbridge, Catherine A. Warren, Wesley C. Lyons, Leslie A. TI To the Root of the Curl: A Signature of a Recent Selective Sweep Identifies a Mutation That Defines the Cornish Rex Cat Breed SO PLOS ONE LA English DT Article ID AUTOSOMAL RECESSIVE HYPOTRICHOSIS; PROTEIN-COUPLED RECEPTOR; HYPOHIDROTIC ECTODERMAL DYSPLASIA; HAIR FOLLICLE DEVELOPMENT; WOOLLY HAIR; DOMESTIC CAT; COAT MUTANT; P2RY5 GENE; LYSOPHOSPHATIDIC ACID; PHOSPHATIDIC-ACID AB The cat (Felis silvestris catus) shows significant variation in pelage, morphological, and behavioral phenotypes amongst its over 40 domesticated breeds. The majority of the breed specific phenotypic presentations originated through artificial selection, especially on desired novel phenotypic characteristics that arose only a few hundred years ago. Variations in coat texture and color of hair often delineate breeds amongst domestic animals. Although the genetic basis of several feline coat colors and hair lengths are characterized, less is known about the genes influencing variation in coat growth and texture, especially rexoid - curly coated types. Cornish Rex is a cat breed defined by a fixed recessive curly coat trait. Genome-wide analyses for selection (d(i), Tajima's D and nucleotide diversity) were performed in the Cornish Rex breed and in 11 phenotypically diverse breeds and two random bred populations. Approximately 63K SNPs were used in the analysis that aimed to localize the locus controlling the rexoid hair texture. A region with a strong signature of recent selective sweep was identified in the Cornish Rex breed on chromosome A1, as well as a consensus block of homozygosity that spans approximately 3 Mb. Inspection of the region for candidate genes led to the identification of the lysophosphatidic acid receptor 6 (LPAR6). A 4 bp deletion in exon 5, c.250_253_delTTTG, which induces a premature stop codon in the receptor, was identified via Sanger sequencing. The mutation is fixed in Cornish Rex, absent in all straight haired cats analyzed, and is also segregating in the German Rex breed. LPAR6 encodes a G protein-coupled receptor essential for maintaining the structural integrity of the hair shaft; and has mutations resulting in a wooly hair phenotype in humans. C1 [Gandolfi, Barbara; Alhaddad, Hasan; Joslin, Shannon E. K.; Lyons, Leslie A.] Univ Calif Davis, Sch Vet Med, Dept Populat Hlth & Reprod, Davis, CA 95616 USA. [Affolter, Verena K.; Koehne, Amanda L.] Univ Calif Davis, Sch Vet Med, Dept Pathol, Davis, CA 95616 USA. [Brockman, Jeffrey] Hills Pet Nutr Ctr, Topeka, KS USA. [Haggstrom, Jens] Swedish Univ Agr Sci, Fac Vet Med & Anim Sci, Dept Clin Sci, Uppsala, Sweden. [Mullikin, James C.] NHGRI, Comparat Genom Unit, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Outerbridge, Catherine A.] Univ Calif Davis, Sch Vet Med, Dept Vet Med & Epidemiol, Davis, CA 95616 USA. [Warren, Wesley C.] Washington Univ, Sch Med, Genome Inst, St Louis, MO USA. RP Gandolfi, B (reprint author), Univ Calif Davis, Sch Vet Med, Dept Populat Hlth & Reprod, Davis, CA 95616 USA. EM bgandolfi@ucdavis.edu OI Alhaddad, Hasan/0000-0001-7904-2913 FU National Center for Research Resources; Office of Research Infrastructure Programs of the National Institute of Health [R24 RR016094]; Winn Feline Foundation [W10-14, W11-041]; Center for Companion Animal Health at University of California Davis [2010-09-F]; George and Phyllis Miller Feline Health Fund of the San Francisco Foundation [2008-36-F] FX This project was supported by the National Center for Research Resources and the Office of Research Infrastructure Programs of the National Institute of Health through Grant Number R24 RR016094, the Winn Feline Foundation (W10-14, W11-041), the Center for Companion Animal Health at University of California Davis (2010-09-F) (http://www.vetmed.ucdavis.edu/ccah/index.cfm), and the George and Phyllis Miller Feline Health Fund of the San Francisco Foundation (2008-36-F). Support for the development of the Illumina Infinium Feline 63K iSelect DNA array was provided by the Morris Animal Foundation (http://www.morrisanimalfoundation.org)via a donation from Hill's Pet Food, Inc. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 75 TC 11 Z9 11 U1 1 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 JUN 27 PY 2013 VL 8 IS 6 AR e67105 DI 10.1371/journal.pone.0067105 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 174IX UT WOS:000321150000027 PM 23826204 ER PT J AU Lee, SY Chen, SL Chang, YH Chen, PS Huang, SY Tzeng, NS Wang, YS Wang, LJ Lee, IH Wang, TY Yeh, TL Yang, YK Hong, JS Lu, RB AF Lee, Sheng-Yu Chen, Shiou-Lan Chang, Yun-Hsuan Chen, Po See Huang, San-Yuan Tzeng, Nian-Sheng Wang, Yu-Shan Wang, Liang-Jen Lee, I. Hui Wang, Tzu-Yun Yeh, Tzung Lieh Yang, Yen Kuang Hong, Jau-Shyong Lu, Ru-Band TI Inflammation's Association with Metabolic Profiles before and after a Twelve-Week Clinical Trial in Drug-Naive Patients with Bipolar II Disorder SO PLOS ONE LA English DT Article ID C-REACTIVE PROTEIN; TUMOR-NECROSIS-FACTOR; GROWTH-FACTOR-BETA; INSULIN-RESISTANCE; MAJOR DEPRESSION; ADIPOSE-TISSUE; FACTOR-ALPHA; LITHIUM TREATMENT; RATING-SCALE; DOUBLE-BLIND AB Inflammation is thought to be involved in the pathophysiology of bipolar disorder (BP) and metabolic syndrome. Prior studies evaluated the association between metabolic profiles and cytokines only during certain mood states instead of their changes during treatment. We enrolled drug-naive patients with BP-II and investigated the correlation between changes in mood symptoms and metabolic indices with changes in plasma cytokine levels after 12 weeks of pharmacological treatment. Drug-naive patients (n = 117) diagnosed with BP-II according to DSM-IV criteria were recruited. Metabolic profiles (cholesterol, triglyceride, HbA1C, fasting serum glucose, body mass index (BMI) and plasma cytokines (TNF-alpha, CRP, IL-6, and TGF-beta) were measured at baseline and 2, 8, and 12 weeks post-treatment. To adjust within-subject dependence over repeated assessments, multiple linear regressions with generalized estimating equation methods were used. Seventy-six (65.0%) patients completed the intervention. Changes in plasma CRP were significantly associated with changes in BMI (P = 1.7E-7) and triglyceride (P = 0.005) levels. Changes in plasma TGF-beta 1 were significantly associated with changes in BMI (P = 8.2E-6), cholesterol (P = 0.004), and triglyceride (P = 0.006) levels. However, changes in plasma TNF-alpha and IL-6 were not associated with changes in any of the metabolic indices. Changes in Hamilton Depression Rating Scale scores were significantly associated with changes in IL-6 (P = 0.003) levels; changes in Young Mania Rating Scale scores were significantly associated with changes in CRP (P = 0.006) and TNF-alpha (P = 0.039) levels. Plasma CRP and TGF-beta 1 levels were positively correlated with several metabolic indices in BP-II after 12 weeks of pharmacological intervention. We also hypothesize that clinical symptoms are correlated with certain cytokines. These new findings might be important evidence that inflammation is the pathophysiology of clinical symptoms and metabolic disturbance in BP-II. C1 [Lee, Sheng-Yu; Chen, Shiou-Lan; Chen, Po See; Lee, I. Hui; Yeh, Tzung Lieh; Yang, Yen Kuang; Lu, Ru-Band] Natl Cheng Kung Univ, Dept Psychiat, Tainan 70101, Taiwan. [Chen, Shiou-Lan; Wang, Yu-Shan; Lu, Ru-Band] Natl Cheng Kung Univ, Inst Behav Med, Tainan 70101, Taiwan. [Chang, Yun-Hsuan; Lu, Ru-Band] Natl Cheng Kung Univ, Coll Med & Hosp, Inst Allied Hlth Sci, Tainan 70101, Taiwan. [Huang, San-Yuan; Tzeng, Nian-Sheng] Triserv Gen Hosp, Natl Def Med Ctr, Dept Psychiat, Taipei, Taiwan. [Wang, Liang-Jen] Kaohsiung Chang Gung Mem Hosp, Dept Child & Adolescent Psychiat, Kaohsiung, Taiwan. [Wang, Liang-Jen] Chang Gung Univ, Coll Med, Kaohsiung, Taiwan. [Lu, Ru-Band] Natl Cheng Kung Univ, Addict Res Ctr, Tainan 70101, Taiwan. [Wang, Tzu-Yun] Tainan Hosp, Dept Hlth, Dept Psychiat, Tainan, Taiwan. [Hong, Jau-Shyong] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. RP Lu, RB (reprint author), Natl Cheng Kung Univ, Dept Psychiat, Tainan 70101, Taiwan. EM rblu@mail.ncku.edu.tw FU Taiwan National Science Council [NSC98-2314-B-006-022-MY3]; Taiwan Department of Health [DOH 95-TD-M-113-055]; Taiwan National Health Research Institute [NHRI-EX-97-9738NI]; National Cheng Kung University Project for Promoting Academic Excellence and Developing World Class Research Centers FX This work was supported in part by grant NSC98-2314-B-006-022-MY3 (to RBL) and NSC98-2314-B-006-022-MY3 (to SYL) from the Taiwan National Science Council, grant DOH 95-TD-M-113-055 (to RBL) from the Taiwan Department of Health, grant NHRI-EX-97-9738NI (to RBL) from the Taiwan National Health Research Institute, and the National Cheng Kung University Project for Promoting Academic Excellence and Developing World Class Research Centers. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 75 TC 17 Z9 17 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 JUN 27 PY 2013 VL 8 IS 6 AR e66847 DI 10.1371/journal.pone.0066847 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 174IX UT WOS:000321150000016 PM 23826157 ER PT J AU Masaoka, A Gassman, NR Horton, JK Kedar, PS Witt, KL Hobbs, CA Kissling, GE Tano, K Asagoshi, K Wilson, SH AF Masaoka, Aya Gassman, Natalie R. Horton, Julie K. Kedar, Padmini S. Witt, Kristine L. Hobbs, Cheryl A. Kissling, Grace E. Tano, Keizo Asagoshi, Kenjiro Wilson, Samuel H. TI Interaction between DNA Polymerase beta and BRCA1 SO PLOS ONE LA English DT Article ID BASE EXCISION-REPAIR; CELL NUCLEAR ANTIGEN; DOUBLE-STRAND BREAKS; HOMOLOGOUS RECOMBINATION; MOUSE FIBROBLASTS; OXIDATIVE STRESS; COMET ASSAY; DAMAGE; CANCER; RADIATION AB The breast cancer 1 (BRCA1) protein is a tumor suppressor playing roles in DNA repair and cell cycle regulation. Studies of DNA repair functions of BRCA1 have focused on double-strand break (DSB) repair pathways and have recently included base excision repair (BER). However, the function of BRCA1 in BER is not well defined. Here, we examined a BRCA1 role in BER, first in relation to alkylating agent (MMS) treatment of cells and the BER enzyme DNA polymerase beta (pol beta). MMS treatment of BRCA1 negative human ovarian and chicken DT40 cells revealed hypersensitivity, and the combined gene deletion of BRCA1 and pol beta in DT40 cells was consistent with these factors acting in the same repair pathway, possibly BER. Using cell extracts and purified proteins, BRCA1 and pol beta were found to interact in immunoprecipitation assays, yet in vivo and in vitro assays for a BER role of BRCA1 were negative. An alternate approach with the human cells of immunofluorescence imaging and laser-induced DNA damage revealed negligible BRCA1 recruitment during the first 60 s after irradiation, the period typical of recruitment of pol beta and other BER factors. Instead, 15 min after irradiation, BRCA1 recruitment was strong and there was gamma-H2AX co-localization, consistent with DSBs and repair. The rapid recruitment of pol beta was similar in BRCA1 positive and negative cells. However, a fraction of pol beta initially recruited remained associated with damage sites much longer in BRCA1 positive than negative cells. Interestingly, pol beta expression was required for BRCA1 recruitment, suggesting a partnership between these repair factors in DSB repair. C1 [Masaoka, Aya; Gassman, Natalie R.; Horton, Julie K.; Kedar, Padmini S.; Asagoshi, Kenjiro; Wilson, Samuel H.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Witt, Kristine L.] NIEHS, Natl Toxicol Program, NIH, Res Triangle Pk, NC USA. [Kissling, Grace E.] NIEHS, Biostatist Branch, NIH, Res Triangle Pk, NC USA. [Hobbs, Cheryl A.] Integrated Lab Syst Inc, Res Triangle Pk, NC USA. [Tano, Keizo] Kyoto Univ, Inst Res Reactor, Dept Radiat Life Sci & Radiat Med Sci, Kumatori, Osaka 59004, Japan. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01-ES050158, Z01-ES050159]; Ministry of Education, Culture, Sports, Science and Technology of Japan [20510051, 24510072] FX This research was supported by Research Project Numbers Z01-ES050158 and Z01-ES050159 from the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences(to SHW), and by Grants-in-Aid (20510051, 24510072) for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to KT). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 9 Z9 9 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 JUN 27 PY 2013 VL 8 IS 6 AR e66801 DI 10.1371/journal.pone.0066801 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 174IX UT WOS:000321150000010 PM 23826138 ER PT J AU Monfredi, O Maltseva, LA Spurgeon, HA Boyett, MR Lakatta, EG Maltsev, VA AF Monfredi, Oliver Maltseva, Larissa A. Spurgeon, Harold A. Boyett, Mark R. Lakatta, Edward G. Maltsev, Victor A. TI Beat-to-Beat Variation in Periodicity of Local Calcium Releases Contributes to Intrinsic Variations of Spontaneous Cycle Length in Isolated Single Sinoatrial Node Cells SO PLOS ONE LA English DT Article ID PACEMAKER CELLS; DIASTOLIC DEPOLARIZATION; RYANODINE RECEPTOR; CA2+ RELEASES AB Spontaneous, submembrane local Ca2+ releases LCRs) generated by the sarcoplasmic reticulum in sinoatrial nodal cells, the cells of the primary cardiac pacemaker, activate inward Na+/Ca2+-exchange current to accelerate the diastolic depolarization rate, and therefore to impact on cycle length. Since LCRs are generated by Ca2+ release channel i.e. ryanodine receptor) openings, they exhibit a degree of stochastic behavior, manifested as notable cycle-to-cycle variations in the time of their occurrence. Aim: The present study tested whether variation in LCR periodicity contributes to intrinsic beat-to-beat) cycle length variability in single sinoatrial nodal cells. Methods: We imaged single rabbit sinoatrial nodal cells using a 2D-camera to capture LCRs over the entire cell, and, in selected cells, simultaneously measured action potentials by perforated patch clamp. Results: LCRs begin to occur on the descending part of the action potential-induced whole-cell Ca2+ transient, at about the time of the maximum diastolic potential. Shortly after the maximum diastolic potential mean 54 +/- 7.7 ms, n = 14), the ensemble of waxing LCR activity converts the decay of the global Ca2+ transient into a rise, resulting in a late, whole-cell diastolic Ca2+ elevation, accompanied by a notable acceleration in diastolic depolarization rate. On average, cells n = 9) generate 13.2 +/- 3.7 LCRs per cycle mean +/- SEM), varying in size 7.1 +/- 4.2 mu m) and duration 44.2 +/- 27.1 ms), with both size and duration being greater for later-occurring LCRs. While the timing of each LCR occurrence also varies, the LCR period i.e. the time from the preceding Ca2+ transient peak to an LCR's subsequent occurrence) averaged for all LCRs in a given cycle closely predicts the time of occurrence of the next action potential, i.e. the cycle length. Conclusion: Intrinsic cycle length variability in single sinoatrial nodal cells is linked to beat-to-beat variations in the average period of individual LCRs each cycle. C1 [Monfredi, Oliver; Maltseva, Larissa A.; Spurgeon, Harold A.; Lakatta, Edward G.; Maltsev, Victor A.] NIA, Cardiovasc Sci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Monfredi, Oliver; Boyett, Mark R.] Univ Manchester, Inst Cardiovasc Sci, Manchester, Lancs, England. RP Maltsev, VA (reprint author), NIA, Cardiovasc Sci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM MaltsevVi@grc.nia.nih.gov OI Boyett, Mark/0000-0003-3931-2020; Monfredi, Oliver/0000-0003-1292-2902 FU National Institutes of Health, National Institute on Aging; British Cardiovascular Society; University of Manchester; Higher Education Funding Council for England FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging and by the British Cardiovascular Society (OM), the University of Manchester (OM, MRB) and the Higher Education Funding Council for England (MRB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 19 TC 11 Z9 11 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 JUN 27 PY 2013 VL 8 IS 6 AR e67247 DI 10.1371/journal.pone.0067247 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 174IX UT WOS:000321150000048 PM 23826247 ER PT J AU Little, MP Zablotska, LB Lipshultz, SE AF Little, Mark P. Zablotska, Lydia B. Lipshultz, Steven E. TI Ischemic Heart Disease after Breast Cancer Radiotherapy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID CIRCULATORY DISEASE; CHILDHOOD-CANCER; RADIATION; MORTALITY; EXPOSURE C1 [Little, Mark P.] NCI, Bethesda, MD 20892 USA. [Zablotska, Lydia B.] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. [Lipshultz, Steven E.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. RP Little, MP (reprint author), NCI, Bethesda, MD 20892 USA. EM mark.little@nih.gov NR 6 TC 4 Z9 4 U1 0 U2 5 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 JUN 27 PY 2013 VL 368 IS 26 BP 2523 EP 2524 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 171KQ UT WOS:000320926900020 PM 23802524 ER PT J AU Sharma, V Misteli, T AF Sharma, Vivek Misteli, Tom TI Non-coding RNAs in DNA damage and repair SO FEBS LETTERS LA English DT Review DE Non-coding RNA; DNA damage; Repair; miRNA; Long non-coding RNA; Genome integrity ID DOUBLE-STRAND BREAKS; CELL-CYCLE; MICRORNA BIOGENESIS; TUMOR-SUPPRESSOR; DOWN-REGULATION; CHROMATIN-STRUCTURE; IONIZING-RADIATION; END RESECTION; HOMOLOGOUS RECOMBINATION; TRANSLATIONAL REPRESSION AB Non-coding RNAs (ncRNAs) are increasingly recognized as central players in diverse biological processes. Upon DNA damage, the DNA damage response (DDR) elicits a complex signaling cascade, which includes the induction of multiple ncRNA species. Recent studies indicate that DNA-damage induced ncRNAs contribute to regulation of cell cycle, apoptosis and DNA repair, and thus play a key role in maintaining genome stability. This review summarizes the emerging role of ncRNAs in DNA damage and repair. Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. C1 [Sharma, Vivek; Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov FU NIH DBT Khorana-Nirenberg Fellowship; NIH, National Cancer Institute, Center for Cancer Research FX V.S. is supported by an NIH DBT Khorana-Nirenberg Fellowship. Work in the Misteli laboratory is supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The authors would like to thank Misteli laboratory members for helpful feedback on the manuscript. NR 127 TC 27 Z9 27 U1 1 U2 43 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 EI 1873-3468 J9 FEBS LETT JI FEBS Lett. PD JUN 27 PY 2013 VL 587 IS 13 SI SI BP 1832 EP 1839 DI 10.1016/j.febslet.2013.05.006 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 171FK UT WOS:000320910300003 PM 23684639 ER PT J AU Rebello, A Smith, MG Neumeier, JJ White, BD Yu, YK AF Rebello, A. Smith, M. G. Neumeier, J. J. White, B. D. Yu, Yi-Kuo TI Transition from one-dimensional antiferromagnetism to three-dimensional antiferromagnetic order in single-crystalline CuSb2O6 SO PHYSICAL REVIEW B LA English DT Article ID SPIN-PEIERLS TRANSITION; HEISENBERG-CHAINS; COMPOUND CUGEO3; MAGNETIC ORDER; RANGE; STATE AB Measurements of magnetic susceptibility, heat capacity, and thermal expansion are reported for single-crystalline CuSb2O6 in the temperature range 5 < T < 350 K. The magnetic susceptibility exhibits a broad peak centered near 60 K that is typical of one-dimensional antiferromagnetic compounds. Long-range antiferromagnetic order at T-N = 8.7 K is accompanied by an energy gap [Delta = 17.48(6) K]. This transition represents a crossover from one- to three-dimensional antiferromagnetic behavior. Both heat capacity and the thermal expansion coefficients exhibit distinct jumps at TN, which are similar to those observed at the normal-superconducting phase transition in a superconductor. This behavior is quite unusual and is presumably associated with a spin-Peierls transition occurring as a result of three-dimensional phonons coupling with Jordan-Wigner-transformed fermions. C1 [Rebello, A.; Smith, M. G.; Neumeier, J. J.; White, B. D.] Montana State Univ, Dept Phys, Bozeman, MT 59717 USA. [Yu, Yi-Kuo] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Rebello, A (reprint author), Montana State Univ, Dept Phys, POB 173840, Bozeman, MT 59717 USA. FU National Science Foundation [DMR-0907036] FX We thank Anton Vorontsov for valuable discussions. This material is based on the work supported by the National Science Foundation under Contract No. DMR-0907036. NR 33 TC 7 Z9 7 U1 3 U2 27 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1098-0121 J9 PHYS REV B JI Phys. Rev. B PD JUN 27 PY 2013 VL 87 IS 22 AR 224427 DI 10.1103/PhysRevB.87.224427 PG 7 WC Physics, Condensed Matter SC Physics GA 172JS UT WOS:000320999800004 ER PT J AU Roychoudhuri, R Hirahara, K Mousavi, K Clever, D Klebanoff, CA Bonelli, M Sciume, G Zare, H Vahedi, G Dema, B Yu, ZY Liu, H Takahashi, H Rao, M Muranski, P Crompton, JG Punkosdy, G Bedognetti, D Wang, E Hoffmann, V Rivera, J Marincola, FM Nakamura, A Sartorelli, V Kanno, Y Gattinoni, L Muto, A Igarashi, K O'Shea, JJ Restifo, NP AF Roychoudhuri, Rahul Hirahara, Kiyoshi Mousavi, Kambiz Clever, David Klebanoff, Christopher A. Bonelli, Michael Sciume, Giuseppe Zare, Hossein Vahedi, Golnaz Dema, Barbara Yu, Zhiya Liu, Hui Takahashi, Hayato Rao, Mahadev Muranski, Pawel Crompton, Joseph G. Punkosdy, George Bedognetti, Davide Wang, Ena Hoffmann, Victoria Rivera, Juan Marincola, Francesco M. Nakamura, Atsushi Sartorelli, Vittorio Kanno, Yuka Gattinoni, Luca Muto, Akihiko Igarashi, Kazuhiko O'Shea, John J. Restifo, Nicholas P. TI BACH2 represses effector programs to stabilize T-reg-mediated immune homeostasis SO NATURE LA English DT Article ID GENOME-WIDE ASSOCIATION; GENE-EXPRESSION; CELL-DIFFERENTIATION; SUSCEPTIBILITY LOCI; RISK LOCI; B-CELLS; TRANSCRIPTION; DISEASE; INTERLEUKIN-4; METAANALYSIS AB Through their functional diversification, distinct lineages of CD4(+) T cells can act to either drive or constrain immune-mediated pathology. Transcription factors are critical in the generation of cellular diversity, and negative regulators antagonistic to alternate fates often act in conjunction with positive regulators to stabilize lineage commitment(1). Genetic polymorphisms within a single locus encoding the transcription factor BACH2 are associated with numerous autoimmune and allergic diseases including asthma(2), Crohn's disease(3,4), coeliac disease(5), vitiligo(6), multiple sclerosis(7) and type 1 diabetes(8). Although these associations point to a shared mechanism underlying susceptibility to diverse immune-mediated diseases, a function for BACH2 in the maintenance of immune homeostasis has not been established. Here, by studying mice in which the Bach2 gene is disrupted, we define BACH2 as a broad regulator of immune activation that stabilizes immunoregulatory capacity while repressing the differentiation programs of multiple effector lineages in CD4(+) T cells. BACH2 was required for efficient formation of regulatory (T-reg) cells and consequently for suppression of lethal inflammation in a manner that was T-reg-cell-dependent. Assessment of the genome-wide function of BACH2, however, revealed that it represses genes associated with effector cell differentiation. Consequently, its absence during T-reg polarization resulted in inappropriate diversion to effector lineages. In addition, BACH2 constrained full effector differentiation within T(H)1, T(H)2 and T(H)17 cell lineages. These findings identify BACH2 as a key regulator of CD4(+) T-cell differentiation that prevents inflammatory disease by controlling the balance between tolerance and immunity. C1 [Roychoudhuri, Rahul; Clever, David; Klebanoff, Christopher A.; Yu, Zhiya; Rao, Mahadev; Muranski, Pawel; Crompton, Joseph G.; Gattinoni, Luca; Restifo, Nicholas P.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hirahara, Kiyoshi; Bonelli, Michael; Sciume, Giuseppe; Vahedi, Golnaz; Takahashi, Hayato; Kanno, Yuka; O'Shea, John J.] NIAMSD, Mol Immunol & Inflammat Branch, Bethesda, MD 20892 USA. [Mousavi, Kambiz; Zare, Hossein; Sartorelli, Vittorio] NIAMS, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. [Dema, Barbara; Rivera, Juan] NIAMS, Lab Mol Immunogenet, NIH, Bethesda, MD 20892 USA. [Liu, Hui; Bedognetti, Davide; Wang, Ena; Marincola, Francesco M.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. [Punkosdy, George] NIAID, NIH, Bethesda, MD 20892 USA. [Hoffmann, Victoria] NIH, Div Vet Resources, Bethesda, MD 20892 USA. [Marincola, Francesco M.] Sidra Med & Res Ctr, Doha, Qatar. [Nakamura, Atsushi; Muto, Akihiko; Igarashi, Kazuhiko] Tohoku Univ, Grad Sch Med, Dept Biochem, Sendai, Miyagi 9808575, Japan. [Muto, Akihiko; Igarashi, Kazuhiko] Japan Sci & Technol Agcy, CREST, Sendai, Miyagi 9808575, Japan. [Restifo, Nicholas P.] NIH, Ctr Regenerat Med, Bethesda, MD 20892 USA. RP Roychoudhuri, R (reprint author), NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM roychoudhuri@mail.nih.gov; osheajo@mail.nih.gov; restifo@nih.gov RI Gattinoni, Luca/A-2281-2008; Roychoudhuri, Rahul/A-7442-2010; Kanno, Yuka/B-5802-2013; Sciume, Giuseppe/K-8985-2016; Hirahara, Kiyoshi/E-2460-2017; OI Gattinoni, Luca/0000-0003-2239-3282; Roychoudhuri, Rahul/0000-0002-5392-1853; Sciume, Giuseppe/0000-0003-0131-512X; Hirahara, Kiyoshi/0000-0002-9128-9449; Kanno, Yuka/0000-0001-5668-9319; Bedognetti, Davide/0000-0002-5857-773X; Restifo, Nicholas P./0000-0003-4229-4580; Igarashi, Kazuhiko/0000-0002-2470-2475 FU Intramural Research Programs of the National Cancer Institute (NIH); National Institute of Arthritis and Musculoskeletal and Skin Diseases; NIH Center for Regenerative Medicine; JSPS Research Fellowship for Japanese Biomedical and Behavioural Researchers at NIH FX This research was supported by the Intramural Research Programs of the National Cancer Institute (NIH) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the NIH Center for Regenerative Medicine and the JSPS Research Fellowship for Japanese Biomedical and Behavioural Researchers at NIH. We thank D. N. Roychoudhuri, D. C. Macallan, G. E. Griffin, S. A. Rosenberg, M. S. Rao, Y. Ji, D. Palmer, M. Sukumar, G. Fabozzi, K. Hanada, E. Lugli, J. H. Pan and N. Van Panhuys for discussions, A. Mixon and S. Farid for cell sorting, G. McMullen for mouse handling and Y. Luo, Y. Wakabayashi, J. Zhu, G. Gutierrez-Cruz and H. W. Sun for help with sequencing and analysis. NR 35 TC 91 Z9 94 U1 4 U2 38 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUN 27 PY 2013 VL 498 IS 7455 BP 506 EP + DI 10.1038/nature12199 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 171LH UT WOS:000320929400057 PM 23728300 ER PT J AU Chong, A Child, R Wehrly, TD Rockx-Brouwer, D Qin, AP Mann, BJ Celli, J AF Chong, Audrey Child, Robert Wehrly, Tara D. Rockx-Brouwer, Dedeke Qin, Aiping Mann, Barbara J. Celli, Jean TI Structure-Function Analysis of DipA, a Francisella tularensis Virulence Factor Required for Intracellular Replication SO PLOS ONE LA English DT Article ID OUTER-MEMBRANE PROTEIN; COILED-COIL DOMAINS; PATHOGENICITY ISLAND; ESCHERICHIA-COLI; LEGIONELLA-PNEUMOPHILA; MURINE MACROPHAGES; STREPTOCOCCUS-PNEUMONIAE; PHAGOSOMAL ESCAPE; LIVE VACCINE; VI SECRETION AB Francisella tularensis is a highly infectious bacterium whose virulence relies on its ability to rapidly reach the macrophage cytosol and extensively replicate in this compartment. We previously identified a novel Francisella virulence factor, DipA (FTT0369c), which is required for intramacrophage proliferation and survival, and virulence in mice. DipA is a 353 amino acid protein with a Sec-dependent signal peptide, four Sel1-like repeats (SLR), and a C-terminal coiled-coil (CC) domain. Here, we determined through biochemical and localization studies that DipA is a membrane-associated protein exposed on the surface of the prototypical F. tularensis subsp. tularensis strain SchuS4 during macrophage infection. Deletion and substitution mutagenesis showed that the CC domain, but not the SLR motifs, of DipA is required for surface exposure on SchuS4. Complementation of the dipA mutant with either DipA CC or SLR domain mutants did not restore intracellular growth of Francisella, indicating that proper localization and the SLR domains are required for DipA function. Co-immunoprecipitation studies revealed interactions with the Francisella outer membrane protein FopA, suggesting that DipA is part of a membrane-associated complex. Altogether, our findings indicate that DipA is positioned at the host-pathogen interface to influence the intracellular fate of this pathogen. C1 [Chong, Audrey; Child, Robert; Wehrly, Tara D.; Rockx-Brouwer, Dedeke; Celli, Jean] NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. [Qin, Aiping; Mann, Barbara J.] Univ Virginia, Dept Med, Charlottesville, VA USA. [Mann, Barbara J.] Univ Virginia, Dept Microbiol, Charlottesville, VA 22908 USA. RP Chong, A (reprint author), NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. EM chonga@niaid.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases [AI000953-01] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases, project number AI000953-01. The funders have no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 87 TC 6 Z9 6 U1 0 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 JUN 26 PY 2013 VL 8 IS 6 AR e67965 DI 10.1371/journal.pone.0067965 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 178DN UT WOS:000321424400125 PM 23840797 ER PT J AU Fozzatti, L Park, JW Zhao, L Willingham, MC Cheng, SY AF Fozzatti, Laura Park, Jeong Won Zhao, Li Willingham, Mark C. Cheng, Sheue-yann TI Oncogenic Actions of the Nuclear Receptor Corepressor (NCOR1) in a Mouse Model of Thyroid Cancer SO PLOS ONE LA English DT Article ID HISTONE DEACETYLASE INHIBITOR; HORMONE-BETA-RECEPTOR; TUMOR-SUPPRESSOR P53; VALPROIC ACID; CO-REPRESSOR; IN-VIVO; TRANSCRIPTIONAL ACTIVITY; BREAST-CANCER; CELL-LINES; GENE AB Studies have suggested that the nuclear receptor corepressor 1 (NCOR1) could play an important role in human cancers. However, the detailed molecular mechanisms by which it functions in vivo to affect cancer progression are not clear. The present study elucidated the in vivo actions of NCOR1 in carcinogenesis using a mouse model (Thrb(PV/PV) mice) that spontaneously develops thyroid cancer. Thrb(PV/PV) mice harbor a dominantly negative thyroid hormone receptor beta (TR beta) mutant (denoted as PV). We adopted the loss-of-the function approach by crossing Thrb(PV) mice with mice that globally express an NCOR1 mutant protein (NCOR1 Delta ID) in which the receptor interaction domains have been modified so that it cannot interact with the TR beta, or PV, in mice. Remarkably, expression of NCOR1 Delta ID protein reduced thyroid tumor growth, markedly delayed tumor progression, and prolonged survival of Thrb(PV/PV) Ncor1(Delta ID/Delta ID) mice. Tumor cell proliferation was inhibited by increased expression of cyclin-dependent kinase inhibitor 1 (p21(waf1/cip1); Cdkn1A), and apoptosis was activated by elevated expression of pro-apoptotic BCL-Associated X (Bax). Further analyses showed that p53 was recruited to the p53-binding site on the proximal promoter of the Cdkn1A and the Bax gene as a co-repressor complex with PV/NCOR1/histone deacetylas-3 (HDAC-3), leading to repression of the Cdkn1A as well as the Bax gene in thyroids of Thrb(PV/PV) mice. In thyroids of Thrb(PV/PV) Ncor1(Delta ID/Delta ID) mice, the p53/PV complex could not recruit NCOR1 Delta ID and HDAC-3, leading to de-repression of both genes to inhibit cancer progression. The present studies provided direct evidence in vivo that NCOR1 could function as an oncogene via transcription regulation in a mouse model of thyroid cancer. C1 [Fozzatti, Laura; Park, Jeong Won; Zhao, Li; Willingham, Mark C.; Cheng, Sheue-yann] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Cheng, SY (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM chengs@mail.nih.gov FU Intramural Research Program at the Center for Cancer Research, National Cancer Institute, National Institutes of Health FX The present research was supported by the Intramural Research Program at the Center for Cancer Research, National Cancer 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.; We thank Dr. A. Hollenberg (Harvard Medical School) for providing Ncor1 Delta ID mice. The present research was supported by the Intramural Research Program at the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 52 TC 2 Z9 2 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 JUN 26 PY 2013 VL 8 IS 6 AR e67954 DI 10.1371/journal.pone.0067954 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 178DN UT WOS:000321424400122 PM 23840792 ER PT J AU Guo, R Abdelmohsen, K Morin, PJ Gorospe, M AF Guo, Rong Abdelmohsen, Kotb Morin, Patrice J. Gorospe, Myriam TI Novel MicroRNA Reporter Uncovers Repression of Let-7 by GSK-3 beta SO PLOS ONE LA English DT Article ID GLYCOGEN-SYNTHASE KINASE-3-BETA; OVARIAN-CANCER CELLS; KINASE 3-BETA; POSTTRANSCRIPTIONAL REGULATION; COLORECTAL-CANCER; INDUCE APOPTOSIS; TUMOR-GROWTH; EXPRESSION; RNA; P53 AB Several members of the let-7 microRNA family are downregulated in ovarian and other cancers. They are thought to act as tumor suppressors by lowering growth-promoting and anti-apoptotic proteins. In order to measure cellular let-7 levels systematically, we have developed a highly sensitive let-7 reporter assay system based on the expression of a chimeric mRNA that contains the luciferase coding region and a 3'-untranslated region (UTR) bearing two let-7-binding sites. In cells expressing the reporter construct, termed pmirGLO-let7, luciferase activity was high when let-7 was absent, while luciferase activity was low when let-7 levels were elevated. The ovarian cancer cell lines BG-1 and UCI-101 were transfected with the let-7 reporter and surveyed with a library of kinase inhibitors in order to identify pathways affecting let-7 activity. Among the inhibitors causing changes in endogenous let-7 abundance, the lowering of glycogen synthase kinase 3 (GSK-3)beta function specifically increased let-7 levels and lowered luciferase activity. Similarly, silencing GSK-3 beta increased both mature and primary-let-7 levels in BG-1 cells, and decreased BG-1 cell survival. Further studies identified p53 as a downstream effector of the GSK-3 beta-mediated repression of let-7 biosynthesis. Our studies highlight GSK-3 beta as a novel therapeutic target in ovarian tumorigenesis. C1 [Guo, Rong; Abdelmohsen, Kotb; Gorospe, Myriam] NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Morin, Patrice J.] NIA, Lab Mol Biol & Immunol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Morin, Patrice J.] Amer Assoc Canc Res, Philadelphia, PA USA. RP Morin, PJ (reprint author), NIA, Lab Mol Biol & Immunol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM pat.morin@aacr.org; myriam-gorospe@nih.gov FU National Institute on Aging-Intramural Research Program of the National Institutes of Health FX The work was funded entirely by the National Institute on Aging-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 61 TC 4 Z9 4 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 JUN 26 PY 2013 VL 8 IS 6 AR e66330 DI 10.1371/journal.pone.0066330 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 178DN UT WOS:000321424400023 PM 23840442 ER PT J AU Jimeno-Yepes, AJ Plaza, L Mork, JG Aronson, AR Diaz, A AF Jimeno-Yepes, Antonio J. Plaza, Laura Mork, James G. Aronson, Alan R. Diaz, Alberto TI MeSH indexing based on automatically generated summaries SO BMC BIOINFORMATICS LA English DT Article ID BIOMEDICAL TEXT; RETRIEVAL; DOCUMENTS; MEDLINE AB Background: MEDLINE citations are manually indexed at the U. S. National Library of Medicine (NLM) using as reference the Medical Subject Headings (MeSH) controlled vocabulary. For this task, the human indexers read the full text of the article. Due to the growth of MEDLINE, the NLM Indexing Initiative explores indexing methodologies that can support the task of the indexers. Medical Text Indexer (MTI) is a tool developed by the NLM Indexing Initiative to provide MeSH indexing recommendations to indexers. Currently, the input to MTI is MEDLINE citations, title and abstract only. Previous work has shown that using full text as input to MTI increases recall, but decreases precision sharply. We propose using summaries generated automatically from the full text for the input to MTI to use in the task of suggesting MeSH headings to indexers. Summaries distill the most salient information from the full text, which might increase the coverage of automatic indexing approaches based on MEDLINE. We hypothesize that if the results were good enough, manual indexers could possibly use automatic summaries instead of the full texts, along with the recommendations of MTI, to speed up the process while maintaining high quality of indexing results. Results: We have generated summaries of different lengths using two different summarizers, and evaluated the MTI indexing on the summaries using different algorithms: MTI, individual MTI components, and machine learning. The results are compared to those of full text articles and MEDLINE citations. Our results show that automatically generated summaries achieve similar recall but higher precision compared to full text articles. Compared to MEDLINE citations, summaries achieve higher recall but lower precision. Conclusions: Our results show that automatic summaries produce better indexing than full text articles. Summaries produce similar recall to full text but much better precision, which seems to indicate that automatic summaries can efficiently capture the most important contents within the original articles. The combination of MEDLINE citations and automatically generated summaries could improve the recommendations suggested by MTI. On the other hand, indexing performance might be dependent on the MeSH heading being indexed. Summarization techniques could thus be considered as a feature selection algorithm that might have to be tuned individually for each MeSH heading. C1 [Jimeno-Yepes, Antonio J.; Mork, James G.; Aronson, Alan R.] Natl Lib Med, Bethesda, MD 20894 USA. [Jimeno-Yepes, Antonio J.] Natl ICT Australia, Victoria Res Lab, Melbourne, Vic, Australia. [Plaza, Laura] UNED NLP & IR Grp, Madrid 28040, Spain. [Diaz, Alberto] UCM NIL Grp, Madrid 28040, Spain. RP Jimeno-Yepes, AJ (reprint author), Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM antonio.jimeno@gmail.com OI Diaz, Alberto/0000-0002-7641-8919; DIAZ ESTEBAN, ALBERTO/0000-0003-1966-3421; Jimeno Yepes, Antonio Jose/0000-0002-6581-094X FU NIH, National Library of Medicine; National Library of Medicine; Spanish Government [TIN2009-14659-C03-01]; Australian Government as by the Department of Broadband, Communications; Australian Research Council through the ICT Centre of Excellence program; Digital Economy FX This work was supported in part by the Intramural Research Program of the NIH, National Library of Medicine and by an appointment of A. Jimeno-Yepes to the NLM Research Participation Program sponsored by the National Library of Medicine and administered by the Oak Ridge Institute for Science and Education.; This research was also supported by the Spanish Government through the project TIN2009-14659-C03-01.; National ICT Australia (NICTA) is funded by the Australian Government as represented by the Department of Broadband, Communications and the Digital Economy and the Australian Research Council through the ICT Centre of Excellence program. NR 41 TC 9 Z9 9 U1 0 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD JUN 26 PY 2013 VL 14 AR 208 DI 10.1186/1471-2105-14-208 PG 12 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 179FM UT WOS:000321505200001 PM 23802936 ER PT J AU Tovar, A Hennessy, E Must, A Hughes, SO Gute, DM Sliwa, S Boulos, RJ Vikre, EK Kamins, CL Tofuri, K Pirie, A Economos, CD AF Tovar, Alison Hennessy, Erin Must, Aviva Hughes, Sheryl O. Gute, David M. Sliwa, Sarah Boulos, Rebecca J. Vikre, Emily Kuross Kamins, Christina Luongo Tofuri, Kerline Pirie, Alex Economos, Christina D. TI Feeding styles and evening family meals among recent immigrants SO INTERNATIONAL JOURNAL OF BEHAVIORAL NUTRITION AND PHYSICAL ACTIVITY LA English DT Article DE Family meal; Feeding styles; Children; Obesity; Immigrants ID BODY-MASS INDEX; UNITED-STATES; PARENTING STYLES; WEIGHT STATUS; LONGITUDINAL ASSOCIATIONS; ADOLESCENT OVERWEIGHT; CHILDHOOD OVERWEIGHT; AMERICAN CHILDREN; PHYSICAL-ACTIVITY; RISK-FACTORS AB The protective effect of family meals on unhealthy weight gain and diet has been shown across multiple age groups; however, it is unknown whether a similar effect is present among diverse immigrant populations. In addition, little research has focused on factors associated with the frequency of evening family meals, such as feeding styles (how parents interact with their child around feeding). Therefore the goals of this paper are to explore the 1) association between the frequency of evening family meals and child weight status among new immigrant families, and 2) influence of immigrant mothers' feeding styles on the frequency of evening family meals. Baseline self-reported socio-demographic information and measured heights and weights were collected for both mother and child (age range: 3-12 years) among 387 mother-child dyads enrolled in Live Well, a community-based, participatory-research, randomized controlled lifestyle intervention to prevent excessive weight gain in recent (<10 years in the U. S.) immigrant mothers and children. For children, height and weight measurements were transformed into BMI z-scores using age-and sex-specific CDC standards and categorized as overweight (85th-94th percentile) and obese (>= 95th percentile); mothers' BMI was calculated. Frequency of evening family meals, eating dinner in front of the TV, acculturation and responses to the Caregiver's Feeding Styles Questionnaire (CFSQ) were also obtained from the mother. Children were categorized as "eating evening family meals regularly" if they had an evening family meal >= 5 times per week. Overall, 20% of children were overweight and 25% were obese. Less than half (40.9%) of families had regular evening family meals. In multivariate analyses, adjusting for covariates, children who were overweight/obese were significantly less likely to have >= 5 evening family meals/week compared with normal weight children (OR = 0.51, 95% CI 0.32-0.82). Mothers who had a low demanding/high responsive or a low demanding/low responsive feeding style, were less likely to have >= 5 evening family meals/week compared to mothers with a high demanding/high responsive feeding style (OR = 0.41, 95% CI 0.18-0.0.96, OR = 0.33, 95% CI 0.13-0.87, respectively). Future interventions and programs that seek to help parents establish healthy household routines, such as family meals, may consider tailoring to specific maternal feeding styles. C1 [Tovar, Alison] Univ Rhode Isl, Dept Nutr & Food Sci, Kingston, RI 02818 USA. [Hennessy, Erin] NCI, Hlth Behav Res Branch, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Must, Aviva] Tufts Univ, Dept Publ Hlth & Community Med, Sch Med, Boston, MA 02111 USA. [Hughes, Sheryl O.] Baylor Coll Med, Childrens Nutr Res Ctr, Houston, TX 77030 USA. [Gute, David M.] Tufts Univ, Sch Engn, Dept Civil & Environm Engn, Medford, MA 02155 USA. [Sliwa, Sarah; Boulos, Rebecca J.; Vikre, Emily Kuross; Kamins, Christina Luongo; Tofuri, Kerline; Economos, Christina D.] Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. [Pirie, Alex] Immigrant Serv Providers Grp Hlth, Somerville, MA 02143 USA. RP Tovar, A (reprint author), Univ Rhode Isl, Dept Nutr & Food Sci, 112 Ranger Hall, Kingston, RI 02818 USA. EM alison_tovar@mail.uri.edu FU National Institutes of Health (NIH), Bethesda MD [5R01HD057841]; NIH FX We would like to thank these members of the Live Well Steering Committee (Nesly Metayer, Franklin Dalembert, Raymond R. Hyatt, Warren Goldstein-Gelb, Maria Landaverde, Melissa McWhinney, Joyce Guilhermino de Padua, Helen Sinzker, Heloisa Galvao, and Ismael Vasquez). In addition, we thank the Live Well women and their children for participating in this study. Funding for this research was provided by grant 5R01HD057841 from the National Institutes of Health (NIH), Bethesda MD. Postdoctoral research funds for Alison Tovar were provided by an NIH supplement from this grant. NR 47 TC 4 Z9 4 U1 4 U2 23 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5868 J9 INT J BEHAV NUTR PHY JI Int. J. Behav. Nutr. Phys. Act. PD JUN 26 PY 2013 VL 10 AR 84 DI 10.1186/1479-5868-10-84 PG 8 WC Nutrition & Dietetics; Physiology SC Nutrition & Dietetics; Physiology GA 181IV UT WOS:000321662100001 PM 23803223 ER PT J AU Shrestha, S Foxman, B Weinberger, DM Steiner, C Viboud, C Rohani, P AF Shrestha, Sourya Foxman, Betsy Weinberger, Daniel M. Steiner, Claudia Viboud, Cecile Rohani, Pejman TI Identifying the Interaction Between Influenza and Pneumococcal Pneumonia Using Incidence Data SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID TIME-SERIES ANALYSIS; HONG KONG INFLUENZA; STREPTOCOCCUS-PNEUMONIAE; PANDEMIC INFLUENZA; BACTERIAL PNEUMONIA; RESPIRATORY VIRUSES; UNITED-STATES; A H1N1; DISEASE; ASSOCIATION AB The association between influenza virus and the bacterium Streptococcus pneumoniae (pneumococcus) has been proposed as a polymicrobial system, whereby transmission and pathogenicity of one pathogen (the bacterium) are affected by interactions with the other (the virus). However, studies focusing on different scales of resolution have painted an inconsistent picture: Individual-scale animal experiments have unequivocally demonstrated an association, whereas epidemiological support in human populations is, at best, inconclusive. We integrate weekly incidence reports and a mechanistic transmission model within a likelihood-based inference framework to characterize the nature, timing, and magnitude of this interaction. We find support for a strong but short-lived interaction, with influenza infection increasing susceptibility to pneumococcal pneumonia similar to 100-fold. We infer modest population-level impacts arising from strong processes at the level of an individual, thereby resolving the dichotomy in seemingly inconsistent observations across scales. An accurate characterization of the influenza-pneumococcal interaction can form a basis for more effective clinical care and public health measures for pneumococcal pneumonia. C1 [Shrestha, Sourya; Rohani, Pejman] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Shrestha, Sourya; Rohani, Pejman] Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA. [Foxman, Betsy] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Weinberger, Daniel M.; Viboud, Cecile] NIH, Div Int Epidemiol & Populat Studies, Bethesda, MD 20892 USA. [Weinberger, Daniel M.] Yale Univ, Sch Publ Hlth, Dept Epidemiol Microbial Dis, New Haven, CT 06520 USA. [Steiner, Claudia] US Dept HHS, Healthcare Cost & Utilizat Project, Ctr Delivery Org & Markets, Agcy Healthcare Res & Qual, Rockville, MD 20850 USA. [Rohani, Pejman] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Shrestha, S (reprint author), Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. EM sourya@umich.edu RI Foxman, Betsy/E-1836-2015; OI Shrestha, Sourya/0000-0002-6106-6834; Foxman, Betsy/0000-0001-6682-238X; Weinberger, Daniel/0000-0003-1178-8086 FU Vaccine Modeling Initiative of the Bill & Melinda Gates Foundation; Research and Policy in Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security, the Fogarty International Center, NIH FX Funding: S.S. and P. R. were supported by the Vaccine Modeling Initiative of the Bill & Melinda Gates Foundation. P. R. also received support from the Research and Policy in Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security, the Fogarty International Center, NIH. NR 62 TC 28 Z9 30 U1 2 U2 16 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 JUN 26 PY 2013 VL 5 IS 191 AR 191ra84 DI 10.1126/scitranslmed.3005982 PG 9 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 171KX UT WOS:000320928000005 PM 23803706 ER PT J AU Yewdell, JW Spiro, DJ Golding, H Quill, H Mittelman, A Nabel, GJ AF Yewdell, Jonathan W. Spiro, David J. Golding, Hana Quill, Helen Mittelman, Abraham Nabel, Gary J. TI Getting to the Heart of Influenza SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Editorial Material C1 [Yewdell, Jonathan W.] NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. [Mittelman, Abraham; Nabel, Gary J.] NIAID, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Spiro, David J.] NIAID, Div Microbiol & Infect Dis, Bethesda, MD 20892 USA. [Quill, Helen] NIAID, Div Allergy Immunol & Transplantat, Bethesda, MD 20892 USA. [Golding, Hana] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. EM gary.nabel@sanofi.com FU Intramural NIH HHS [ZIA AI001055-05] NR 4 TC 0 Z9 0 U1 0 U2 4 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 JUN 26 PY 2013 VL 5 IS 191 AR 191ed8 DI 10.1126/scitranslmed.3006735 PG 2 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 171KX UT WOS:000320928000001 PM 23803701 ER PT J AU Amin-ul Mannan, M Shadrick, WR Biener, G Shin, BS Anshu, A Raicu, V Frick, DN Dey, M AF Amin-ul Mannan, M. Shadrick, William R. Biener, Gabriel Shin, Byung-Sik Anshu, Ashish Raicu, Valerica Frick, David N. Dey, Madhusudan TI An Ire1-Phk1 Chimera Reveals a Dispensable Role of Autokinase Activity in Endoplasmic Reticulum Stress Response SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE Ire1; RNA splicing; RNase; protein kinase; unfolded protein response ID UNFOLDED PROTEIN RESPONSE; MESSENGER-RNA; TRANSMEMBRANE PROTEIN; TRANSCRIPTION FACTOR; FLUORESCENT PROTEIN; CATALYTIC SUBUNIT; KINASE-ACTIVITY; IRE1 KINASE; MECHANISM; INSIGHTS AB The endoplasmic reticulunn transmembrane receptor Ire1 senses over-accumulation of unfolded proteins in the endoplasnnic reticulunn and initiates the unfolded protein response (UPR). The cytoplasmic portion of Ire1 has a protein kinase domain (KD) and a kinase extension nuclease (KEN) domain that cleaves an mRNA for encoding the Had transcription factor needed to express UPR genes. During this UPR signaling, Ire1 proteins self-assemble into an oligomer of dimers, which essentially requires autophosphorylation of a constituent activation loop in the KD. However, it is not clear how dimerization, autophosphorylation, and KEN domain function are precisely coordinated. In this study, we uncoupled the KD and KEN domain functions, by removing the activation loop along with an extended region that we called the auto-inhibitory region (AIR), or by swapping the activation loop with a homologous loop from phosphorylase kinase 1 (Ire1(PHK)). Both Ire1(Delta AIR) and Ire1(PHK) activated the UPR even when either protein contained a mutation (D797A) that abolished the ability of Ire1 KD to transfer phosphates to the AIR. Neither protein functioned when containing mutations in key ATP binding residues (E746A and N749A) or in residues that disrupted Ire1 dimer interface (W426A or R697D). We interpret these results as evidence supporting the notion that the primary function of the kinase domain is to autophosphorylate the AIR in order to relieve auto-inhibition and that ADP acts as a switch to activate the KEN domain-catalyzed HAC1 mRNA cleavage. Published by Elsevier Ltd. C1 [Amin-ul Mannan, M.; Anshu, Ashish; Raicu, Valerica; Dey, Madhusudan] Univ Wisconsin, Dept Biol Sci, Milwaukee, WI 53211 USA. [Shadrick, William R.; Frick, David N.] Univ Wisconsin, Dept Chem & Biochem, Milwaukee, WI 53211 USA. [Biener, Gabriel; Raicu, Valerica] Univ Wisconsin, Dept Phys, Milwaukee, WI 53211 USA. [Shin, Byung-Sik] NIH, Bethesda, MD 20892 USA. RP Dey, M (reprint author), Univ Wisconsin, Dept Biol Sci, Room 460,Lapham Hall,3209 North Maryland Ave, Milwaukee, WI 53211 USA. EM deym@umw.edu FU RGI grants (UWM internal funds); National Science Foundation [IIP-1114305, PHY-1058470, PHY-1126386] FX We thank Dr. Thomas E. Dever (National Institute of Child Health & Human Development, National Institutes of Health) for reagents and helpful discussion throughout the project. We thank Dr. Alan G. Hinnebusch (National Institute of Child Health & Human Development, National Institutes of Health) and Prof. Colin Scanes (UW-Milwaukee) for reading the manuscript and for useful suggestions. This work was partly supported by RGI grants (UWM internal funds) awarded to M.D. and National Science Foundation grants (IIP-1114305, PHY-1058470 and PHY-1126386) awarded to V.R. NR 43 TC 0 Z9 0 U1 1 U2 6 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 JUN 26 PY 2013 VL 425 IS 12 BP 2083 EP 2099 DI 10.1016/j.jmb.2013.02.036 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 164MN UT WOS:000320414300001 ER PT J AU Johnson, BC Metifiot, M Ferris, A Pommier, Y Hughes, SH AF Johnson, Barry C. Metifiot, Mathieu Ferris, Andrea Pommier, Yves Hughes, Stephen H. TI A Homology Model of HIV-1 Integrase and Analysis of Mutations Designed to Test the Model SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE HIV; integration; dimerization; infectivity; modeling ID VIRUS TYPE-1 INTEGRASE; DNA-BINDING DOMAIN; PROTEIN IN-VITRO; TERMINAL DOMAIN; RETROVIRAL INTEGRATION; MOLECULAR-MECHANISMS; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; FLEXIBLE LOOP; ACTIVE-SITE AB Although there are structures of the different domains of human immunodeficiency virus type 1 (HIV-1) integrase (IN), there is no structure of the entire protein. The recently determined crystal structures of the prototype foamy virus (PFV) IN tetramer, in complexes with viral DNA, led to the generation of models of full-length HIV-1 IN. These models were generated, in part, by superimposing the structures of the domains of HIV-1 IN onto the structure of full-length PFV IN. We developed a model for HIV-1 IN-based solely on its sequence alignment with PFV IN-that differs in several ways from the previous models. Specifically, in our model, the junction between the catalytic core domain and C-terminal domain adopts a helix-loop-helix motif that is similar to the corresponding segment of PFV IN and differs from the crystal structures of these two HIV-1 IN domains. The alignment of residues in the C-terminal domain also differs from the previous models. Our model can be used to explain the phenotype of previously published HIV-1 IN mutants. We made additional mutants, and the behavior of these new mutants provides additional support for the model. (c) 2013 Published by Elsevier Ltd. C1 [Johnson, Barry C.; Ferris, Andrea; Hughes, Stephen H.] NCI, HIV Drug Resistance Program, Ctr Canc Res, Ft Detrick, MD 21702 USA. [Metifiot, Mathieu; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Ft Detrick, MD 21702 USA. RP Hughes, SH (reprint author), NCI, HIV Drug Resistance Program, Ctr Canc Res, POB B, Ft Detrick, MD 21702 USA. EM hughesst@mail.nih.gov FU National Institutes of Health Intramural Program; Center for Cancer Research; National Cancer Institute; National Institutes of Health grants from the AIDS Intramural AIDS Targeted Antiviral Program FX Our studies were supported by the National Institutes of Health Intramural Program, Center for Cancer Research, National Cancer Institute and by National Institutes of Health grants from the AIDS Intramural AIDS Targeted Antiviral Program. We thank Ferri Soheilian and Kunio Nagashima at the Electron Microscopy Laboratory at Frederick National Laboratory for electron microscopy imaging and Al Kane for assistance with figures. NR 51 TC 20 Z9 20 U1 0 U2 16 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 JUN 26 PY 2013 VL 425 IS 12 BP 2133 EP 2146 DI 10.1016/j.jmb.2013.03.027 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 164MN UT WOS:000320414300003 PM 23542006 ER PT J AU Lu, J Frerich, JM Turtzo, LC Li, SQ Chiang, J Yang, CZ Wang, XP Zhang, C Wu, CX Sun, ZC Niu, G Zhuang, ZP Brady, RO Chen, XY AF Lu, Jie Frerich, Jason M. Turtzo, L. Christine Li, Siqi Chiang, Jeffrey Yang, Chunzhang Wang, Xiaoping Zhang, Chao Wu, Chenxi Sun, Zhongchan Niu, Gang Zhuang, Zhengping Brady, Roscoe O. Chen, Xiaoyuan TI Histone deacetylase inhibitors are neuroprotective and preserve NGF-mediated cell survival following traumatic brain injury SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID NERVE GROWTH-FACTOR; H3 ACETYLATION; UP-REGULATION; HEAD-INJURY; EXPRESSION; RATS; MICE; ASTROCYTES; ACTIVATION; MECHANISMS AB Acute traumatic brain injury (TBI) is associated with long-term cognitive and behavioral dysfunction. In vivo studies have shown histone deacetylase inhibitors (HDACis) to be neuroprotective following TBI in rodent models. HDACis are intriguing candidates because they are capable of provoking widespread genetic changes and modulation of protein function. By using known HDACis and a unique small-molecule pan-HDACi (LB-205), we investigated the effects and mechanisms associated with HDACi-induced neuroprotection following CNS injury in an astrocyte scratch assay in vitro and a rat TBI model in vivo. We demonstrate the preservation of sufficient expression of nerve growth factor (NGF) and activation of the neurotrophic tyrosine kinase receptor type 1 (TrkA) pathway following HDACi treatment to be crucial in stimulating the survival of CNS cells after TBI. HDACi treatment up-regulated the expression of NGF, phospho-TrkA, phospho-protein kinase B (p-AKT), NF-kappa B, and B-cell lymphoma 2 (Bcl-2) cell survival factors while down-regulating the expression of p75 neurotrophin receptor (NTR), phospho-JNK, and Bcl-2-associated X protein apoptosis factors. HDACi treatment also increased the expression of the stem cell biomarker nestin, and decreased the expression of reactive astrocyte biomarker GFAP within damaged tissue following TBI. These findings provide further insight into the mechanisms by which HDACi treatment after TBI is neuroprotective and support the continued study of HDACis following acute TBI. C1 [Lu, Jie; Turtzo, L. Christine; Wu, Chenxi; Sun, Zhongchan; Niu, Gang; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, Bethesda, MD 20892 USA. [Frerich, Jason M.; Li, Siqi; Yang, Chunzhang; Wang, Xiaoping; Zhang, Chao; Zhuang, Zhengping; Brady, Roscoe O.] NINDS, Surg Neurol Branch, Bethesda, MD 20892 USA. [Chiang, Jeffrey] NCI, NIH, Bethesda, MD 20892 USA. [Lu, Jie; Turtzo, L. Christine; Chen, Xiaoyuan] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. RP Zhuang, ZP (reprint author), NINDS, Surg Neurol Branch, Bethesda, MD 20892 USA. EM zhuangp@ninds.nih.gov; bradyr@ninds.nih.gov; shawn.chen@nih.gov FU Department of Defense in the Center for Neuroscience and Regenerative Medicine; Intramural Research Programs of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), NINDS; Imaging Sciences Training Program (sponsored by Radiology and Imaging Sciences in the Clinical Center and Intramural Research Programs of the NIBIB); Howard Hughes Medical Institute-NIH Medical Research Scholars Program FX We thank Dr. Paul E. Gallant [National Institute of Neurological Disorders and Stroke (NINDS) Light Microscopy Facility] for assistance with confocal microscopy, Dr. Dragan Maric (NINDS Flow Cytometry Core Facility) for assistance with flow cytometry, and Lixte Biotechnology Holdings for providing LB-205. This work was supported by the Department of Defense in the Center for Neuroscience and Regenerative Medicine, Intramural Research Programs of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), NINDS, Imaging Sciences Training Program (sponsored by Radiology and Imaging Sciences in the Clinical Center and Intramural Research Programs of the NIBIB) (J.L.), and Howard Hughes Medical Institute-NIH Medical Research Scholars Program (J.M.F.). NR 39 TC 26 Z9 28 U1 1 U2 10 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 JUN 25 PY 2013 VL 110 IS 26 BP 10747 EP 10752 DI 10.1073/pnas.1308950110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 179EY UT WOS:000321503700067 PM 23754423 ER PT J AU Chen, Y Pasapera, AM Koretsky, AP Waterman, CM AF Chen, Yun Pasapera, Ana M. Koretsky, Alan P. Waterman, Clare M. TI Orientation-specific responses to sustained uniaxial stretching in focal adhesion growth and turnover SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE mechanosensing; integrin; tissue mechanics ID CALPAIN-MEDIATED PROTEOLYSIS; ENDOTHELIAL-CELLS; GENE-EXPRESSION; CYCLIC STRETCH; CARDIAC MYOCYTES; KINASE INHIBITOR; SKELETAL-MUSCLE; SRC; ACTIVATION; FAK AB Cells are mechanosensitive to extracellular matrix (ECM) deformation, which can be caused by muscle contraction or changes in hydrostatic pressure. Focal adhesions (FAs) mediate the linkage between the cell and the ECM and initiate mechanically stimulated signaling events. We developed a stretching apparatus in which cells grown on fibronectin-coated elastic substrates can be stretched and imaged live to study how FAs dynamically respond to ECM deformation. Human bone osteosarcoma epithelial cell line U2OS was transfected with GFP-paxillin as an FA marker and subjected to sustained uniaxial stretching. Two responses at different timescales were observed: rapid FA growth within seconds after stretching, and delayed FA disassembly and loss of cell polarity that occurred over tens of minutes. Rapid FA growth occurred in all cells; however, delayed responses to stretch occurred in an orientation-specificmanner, specifically in cells with their long axes perpendicular to the stretching direction, but not in cells with their long axes parallel to stretch. Pharmacological treatments demonstrated that FA kinase (FAK) promotes but Src inhibits rapid FA growth, whereas FAK, Src, and calpain 2 all contribute to delayed FA disassembly and loss of polarity in cells perpendicular to stretching. Immunostaining for phospho-FAK after stretching revealed that FAK activation was maximal at 5 s after stretching, specifically in FAs oriented perpendicular to stretch. We hypothesize that orientation-specific activation of strain/stress-sensitive proteins in FAs upstream to FAK and Src promote orientation-specific responses in FA growth and disassembly that mediate polarity rearrangement in response to sustained stretch. C1 [Chen, Yun; Koretsky, Alan P.] NINDS, Lab Funct Mol Imaging, NIH, Bethesda, MD 20892 USA. [Pasapera, Ana M.; Waterman, Clare M.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. RP Waterman, CM (reprint author), NINDS, Lab Funct Mol Imaging, NIH, Bethesda, MD 20892 USA. EM watermancm@nhlbi.nih.gov RI Koretsky, Alan/C-7940-2015; OI Koretsky, Alan/0000-0002-8085-4756; Waterman, Clare/0000-0001-6142-6775; Chen, Yun/0000-0001-6917-7814 FU National Research Council Fellowship; National Heart, Lung, and Blood Institute; National Institute of Neurological Disorders and Stroke FX We thank Sergey Plotinikov, Robert Fischer, and Ingo Thievessen for helpful discussions; Bill Shin for maintaining microscopes in the C.M.W. laboratory; and Ruperto Villadiego for helping build the cell stretcher. This work was supported by the National Research Council Fellowship (to Y.C.) and the intramural programs of the National Heart, Lung, and Blood Institute (A.M.P. and C.M.W.) and the National Institute of Neurological Disorders and Stroke (Y.C. and A.P.K.). NR 55 TC 15 Z9 15 U1 2 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 JUN 25 PY 2013 VL 110 IS 26 BP E2352 EP E2361 DI 10.1073/pnas.1221637110 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 179EY UT WOS:000321503700007 PM 23754369 ER PT J AU Truong, QA Hayden, D Woodard, PK Kirby, R Chou, ET Nagurney, JT Wiviott, SD Fleg, JL Schoenfeld, DA Udelson, JE Hoffmann, U AF Truong, Quynh A. Hayden, Douglas Woodard, Pamela K. Kirby, Ruth Chou, Eric T. Nagurney, John T. Wiviott, Stephen D. Fleg, Jerome L. Schoenfeld, David A. Udelson, James E. Hoffmann, Udo TI Sex Differences in the Effectiveness of Early Coronary Computed Tomographic Angiography Compared With Standard Emergency Department Evaluation for Acute Chest Pain The Rule-Out Myocardial Infarction With Computer-Assisted Tomography (ROMICAT)-II Trial SO CIRCULATION LA English DT Article DE acute coronary syndrome; chest pain; emergency service, hospital; sex; tomography; x-ray computed ID AMERICAN-HEART-ASSOCIATION; CT ANGIOGRAPHY; ARTERY-DISEASE; CARDIOVASCULAR-RADIOLOGY; DIAGNOSTIC PERFORMANCE; CLINICAL-CARDIOLOGY; DOSE REDUCTION; RADIATION; RISK; INTERVENTION AB Background We evaluate sex-based differences in the effectiveness of early cardiac computed tomographic angiography (CCTA) and standard emergency department (ED) evaluation in patients with acute chest pain. Methods and Results In the Rule-Out Myocardial Infarction With Computer-Assisted Tomography (ROMICAT)-II multicenter, controlled trial, we randomized 1000 patients (47% women) 40 to 74 years of age with symptoms suggestive of acute coronary syndrome to an early CCTA or standard ED evaluation. In this prespecified analysis, women in the CCTA arm had a greater reduction in length of stay, lower hospital admission rates, and lesser increased cumulative radiation dose than men in a comparison of ED strategies (P for interaction 0.02). Although women had lower acute coronary syndrome rates than men (3% versus 12%; P<0.0001), sex differences in length of stay persisted after adjustment for baseline differences, including acute coronary syndrome rate (P for interaction <0.03). Length of stay was similar between sexes with normal CCTA findings (P=0.11). There was no missed acute coronary syndrome for either sex. No difference was observed in major adverse cardiac events between sexes and ED strategies (P for interaction =0.39). Women had more normal CCTA examinations than men (58% versus 37%; P<0.0001), less obstructive coronary disease by CCTA (5% versus 17%; P=0.0001), but similar normalcy rates for functional testing (P=0.65). Men in the CCTA arm had the highest rate of invasive coronary angiography (18%), whereas women had comparable low 5% rates regardless of ED strategy. Conclusions This trial provides data supporting an early CCTA strategy as an attractive option in women presenting to the ED with symptoms suggestive of acute coronary syndrome. The findings may be explained by lower CAD prevalence and severity in women than men. C1 [Truong, Quynh A.; Hoffmann, Udo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac MR PET CT Program,Div Cardiol, Boston, MA 02114 USA. [Truong, Quynh A.; Hoffmann, Udo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. [Nagurney, John T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Emergency Dept, Boston, MA 02114 USA. [Hayden, Douglas; Schoenfeld, David A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Woodard, Pamela K.] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO USA. [Kirby, Ruth; Fleg, Jerome L.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Chou, Eric T.] Kaiser Permanente Fontana Med Ctr, Fontana, CA USA. [Wiviott, Stephen D.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02114 USA. [Udelson, James E.] Tufts Med Ctr, Div Cardiol, Boston, MA USA. [Udelson, James E.] Tufts Med Ctr, Ctr Cardiovasc, Boston, MA USA. RP Truong, QA (reprint author), Massachusetts Gen Hosp, Cardiac MR PET CT Program, Div Cardiol, 165 Cambridge St,Ste 400, Boston, MA 02114 USA. EM qtruong@partners.org FU National Institutes of Health/National Heart, Lung, and Blood Institute [U01HL092040, U01HL092022, K23HL098370, L30HL093896]; Qi Imaging; St. Jude Medical; American College of Radiology Imaging Network; Duke Clinical Research Institute FX The study was supported by the National Institutes of Health/National Heart, Lung, and Blood Institute (U01HL092040 and U01HL092022). Dr Truong was supported by the National Institutes of Health/National Heart, Lung, and Blood Institute (K23HL098370 and L30HL093896).; Dr Truong receives grant support from Qi Imaging, St. Jude Medical, American College of Radiology Imaging Network, and Duke Clinical Research Institute. The other authors report no conflicts. NR 22 TC 9 Z9 9 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUN 25 PY 2013 VL 127 IS 25 BP 2494 EP 2502 DI 10.1161/CIRCULATIONAHA.113.001736 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 171HU UT WOS:000320916900013 PM 23685743 ER PT J AU Sommers, CL Rouquette-Jazdanian, AK Robles, AI Kortum, RL Merrill, RK Li, WM Nath, N Wohlfert, E Sixt, KM Belkaid, Y Samelson, LE AF Sommers, Connie L. Rouquette-Jazdanian, Alexandre K. Robles, Ana I. Kortum, Robert L. Merrill, Robert K. Li, Wenmei Nath, Nandan Wohlfert, Elizabeth Sixt, Katherine M. Belkaid, Yasmine Samelson, Lawrence E. TI miRNA Signature of Mouse Helper T Cell Hyper-Proliferation SO PLOS ONE LA English DT Article ID LYMPHOPROLIFERATIVE DISEASE; HOMEOSTATIC PROLIFERATION; ERK ACTIVATION; MUTANT MICE; EXPRESSION; MIR-146A; CANCER; LAT; MICRORNA-21; PATHWAY AB Helper T cells from a mutant mouse model, LAT Y136F, hyper-proliferate and cause a severe lymphoproliferative disease that kills the mice by six months of age. LAT Y136F mice carry a tyrosine to phenylalanine mutation in the Linker for Activation of T cells (LAT) gene. This mutation leads to a number of changes in T cells that result in altered cytokine production including increased IL-4 production, increased proliferation, and decreased apoptosis. Hyper-proliferation of the mutant T cells contributes to lymphadenopathy, splenomegaly, and multi-organ T cell infiltration. miRNAs are short non-coding RNAs that regulate expression of cohorts of genes. This study investigates which miRNAs are expressed in LAT Y136F T cells and compares these to miRNAs expressed in wild type T cells that are undergoing proliferation in two other settings. The first setting is homeostatic proliferation, which was modeled by adoptive transfer of wild type T cells into T cell-deficient mice. The second setting is proliferation in response to infection, which was modeled by infection of wild type mice with the nematode H. polygyrus. By comparing miRNA expression in these three proliferative states (LAT Y136F hyper-proliferation, homeostatic proliferation and proliferation in response to H. polygyrus infection) to expression in wild type naive CD4(+) T cells, we found miRNAs that were highly regulated in all three proliferative states (miR-21 and miR-146a) and some that were more specific to individual settings of proliferation such as those more specific for LAT Y136F lymphoproliferative disease (miR-669f, miR-155 and miR-466a/b). Future experiments that modulate levels of the miRNAs identified in this study may reveal the roles of these miRNAs in T cell proliferation and/or lymphoproliferative disease. C1 [Sommers, Connie L.; Rouquette-Jazdanian, Alexandre K.; Kortum, Robert L.; Merrill, Robert K.; Li, Wenmei; Nath, Nandan; Sixt, Katherine M.; Samelson, Lawrence E.] NCI, Lab Cellular & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Robles, Ana I.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Sommers, Connie L.; Wohlfert, Elizabeth; Belkaid, Yasmine] NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Sommers, CL (reprint author), NCI, Lab Cellular & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM sommersc@helix.nih.gov FU National Cancer Institute Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Cancer Institute Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 3 Z9 3 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 JUN 25 PY 2013 VL 8 IS 6 AR e66709 DI 10.1371/journal.pone.0066709 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 175IB UT WOS:000321223000023 PM 23825558 ER PT J AU Krist, AH Glenn, BA Glasgow, RE Balasubramanian, BA Chambers, DA Fernandez, ME Heurtin-Roberts, S Kessler, R Ory, MG Phillips, SM Ritzwoller, DP Roby, DH Rodriguez, HP Sabo, RT Gorin, SNS Stange, KC AF Krist, Alex H. Glenn, Beth A. Glasgow, Russell E. Balasubramanian, Bijal A. Chambers, David A. Fernandez, Maria E. Heurtin-Roberts, Suzanne Kessler, Rodger Ory, Marcia G. Phillips, Siobhan M. Ritzwoller, Debra P. Roby, Dylan H. Rodriguez, Hector P. Sabo, Roy T. Gorin, Sherri N. Sheinfeld Stange, Kurt C. CA MOHR Study Grp TI Designing a valid randomized pragmatic primary care implementation trial: the my own health report (MOHR) project SO IMPLEMENTATION SCIENCE LA English DT Article DE Patient-reported measures; Health behaviors; Mental health; Pragmatic trial; Electronic health record; Primary care ID BEHAVIORAL-COUNSELING INTERVENTIONS; DECISION-MAKING; UNDERSERVED COMMUNITY; EDUCATIONAL OUTREACH; PREVENTIVE-SERVICES; SCREENING-TEST; SCIENCE; CANCER; PHYSICIANS; CONTEXT AB Background: There is a pressing need for greater attention to patient-centered health behavior and psychosocial issues in primary care, and for practical tools, study designs and results of clinical and policy relevance. Our goal is to design a scientifically rigorous and valid pragmatic trial to test whether primary care practices can systematically implement the collection of patient-reported information and provide patients needed advice, goal setting, and counseling in response. Methods: This manuscript reports on the iterative design of the My Own Health Report (MOHR) study, a cluster randomized delayed intervention trial. Nine pairs of diverse primary care practices will be randomized to early or delayed intervention four months later. The intervention consists of fielding the MOHR assessment - addresses 10 domains of health behaviors and psychosocial issues - and subsequent provision of needed counseling and support for patients presenting for wellness or chronic care. As a pragmatic participatory trial, stakeholder groups including practice partners and patients have been engaged throughout the study design to account for local resources and characteristics. Participatory tasks include identifying MOHR assessment content, refining the study design, providing input on outcomes measures, and designing the implementation workflow. Study outcomes include the intervention reach (percent of patients offered and completing the MOHR assessment), effectiveness (patients reporting being asked about topics, setting change goals, and receiving assistance in early versus delayed intervention practices), contextual factors influencing outcomes, and intervention costs. Discussion: The MOHR study shows how a participatory design can be used to promote the consistent collection and use of patient-reported health behavior and psychosocial assessments in a broad range of primary care settings. While pragmatic in nature, the study design will allow valid comparisons to answer the posed research question, and findings will be broadly generalizable to a range of primary care settings. Per the pragmatic explanatory continuum indicator summary (PRECIS) framework, the study design is substantially more pragmatic than other published trials. The methods and findings should be of interest to researchers, practitioners, and policy makers attempting to make healthcare more patient-centered and relevant. C1 [Krist, Alex H.] Virginia Commonwealth Univ, Dept Family Med & Populat Hlth, Richmond, VA 23298 USA. [Glenn, Beth A.; Roby, Dylan H.; Rodriguez, Hector P.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Hlth Policy & Management, Los Angeles, CA 90095 USA. [Glasgow, Russell E.; Heurtin-Roberts, Suzanne; Phillips, Siobhan M.] NCI, Implementat Sci Team, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. [Balasubramanian, Bijal A.] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Div Epidemiol Human Genet & Environm Sci, Dallas, TX 75390 USA. [Chambers, David A.] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. [Fernandez, Maria E.] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Houston, TX 77030 USA. [Kessler, Rodger] Vermont Coll Med, Dept Family Med, Burlington, VT 05405 USA. [Ory, Marcia G.] Texas A&M Hlth Sci Ctr, Sch Rural Publ Hlth, Dept Hlth Promot & Community Hlth Sci, College Stn, TX 77843 USA. [Ritzwoller, Debra P.] Kaiser Permanente Colorado, Inst Hlth Res, Denver, CO 80231 USA. [Sabo, Roy T.] Virginia Commonwealth Univ, Dept Biostat, Richmond, VA 23298 USA. [Gorin, Sherri N. Sheinfeld] NCI, SAIC Frederick, NIH, DCCPS, Bethesda, MD 20892 USA. [Gorin, Sherri N. Sheinfeld] NYPAC, Herbert Irving Comprehens Canc Ctr, New York, NY USA. [Stange, Kurt C.] Case Western Reserve Univ, Cleveland, OH 44106 USA. RP Krist, AH (reprint author), Virginia Commonwealth Univ, Dept Family Med & Populat Hlth, POB 980251, Richmond, VA 23298 USA. EM ahkrist@vcu.edu FU National Cancer Institute; Agency for Healthcare Research and Quality; Office of Behavioral and Social Sciences Research; National Center for Advancing Translational Sciences (CTSA) [ULTR00058] FX Funding for the MOHR project was provided by the National Cancer Institute, Agency for Healthcare Research and Quality, Office of Behavioral and Social Sciences Research, and National Center for Advancing Translational Sciences (CTSA Grant Number ULTR00058). Dr. Stange's time is supported in part by a Clinical Research Professorship from the American Cancer Society and by the National Cancer Society through the Intergovernmental Personnel Act. The opinions expressed in this manuscript are those of the authors and do not necessarily reflect those of the funders. For their support and guidance of the MOHR project we would like to thank Janice Genervro PhD MSW, David Meyers MD, Robert M Kaplan PhD, Holly Jimison PhD, Richard Wood MHA, Kayla Fair RN MPH, Jennifer Leeman PHD MPH, Catherine L Rohweder DrPH, Alexis Moore MPH, Maria E Fernandez PhD, John Quillin PhD CGC, Melissa Hayes BS, Paul Estabrooks PhD, Christine Nelson PhD RN, and John Heintzman MD MPH. NR 71 TC 19 Z9 19 U1 1 U2 19 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD JUN 25 PY 2013 VL 8 AR 73 DI 10.1186/1748-5908-8-73 PG 13 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 171NB UT WOS:000320935000001 PM 23799943 ER PT J AU Pearson, GD Kaltman, JR Lauer, MS AF Pearson, Gail D. Kaltman, Jonathan R. Lauer, Michael S. TI Evidence-Based Medicine Comes of Age in Pediatric Cardiology SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE congenital heart disease; congenital heart surgery; pediatric cardiovascular research. ID NATIONAL HEART; LUNG AB Outcomes have improved significantly in pediatric cardiovascular disease in recent decades. The challenge now is to sustain these advances through innovative clinical trials, fundamental molecular investigations, genetics and genomics, and outreach to families, emphasizing the importance of participating in research. We describe several such efforts and provide a vision of the future for pediatric cardiovascular research. (J Am Coll Cardiol 2013;61:2565-7) (C) 2013 by the American College of Cardiology Foundation C1 [Pearson, Gail D.; Kaltman, Jonathan R.; Lauer, Michael S.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. RP Pearson, GD (reprint author), NHLBI, Adult & Pediat Cardiac Res Program, Div Cardiovasc Sci, NIH, 6701 Rockledge Dr,Room 8132, Bethesda, MD 20892 USA. EM pearsong@mail.nih.gov RI Lauer, Michael/L-9656-2013 OI Lauer, Michael/0000-0002-9217-8177 NR 11 TC 2 Z9 2 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUN 25 PY 2013 VL 61 IS 25 BP 2565 EP 2567 DI 10.1016/j.jacc.2013.03.054 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 167AO UT WOS:000320602700011 PM 23623909 ER PT J AU Emery, AC Eiden, MV Mustafa, T Eiden, LE AF Emery, Andrew C. Eiden, Maribeth V. Mustafa, Tomris Eiden, Lee E. TI Rapgef2 Connects GPCR-Mediated cAMP Signals to ERK Activation in Neuronal and Endocrine Cells SO SCIENCE SIGNALING LA English DT Article ID NUCLEOTIDE-EXCHANGE FACTOR; HYPOTHALAMIC PARAVENTRICULAR NUCLEUS; NERVE GROWTH-FACTOR; DROSOPHILA PDZ-GEF; PROTEIN-KINASE; FACTOR CNRASGEF; CYCLIC-AMP; SYNAPTIC PLASTICITY; POLYPEPTIDE PACAP; PC12 CELLS AB G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR)-mediated increases in the second messenger cyclic adenosine monophosphate (cAMP) activate the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (ERK), and in neuroendocrine cells, this pathway leads to cAMP-dependent neuritogenesis mediated through Rap1 and B-Raf. We found that the Rap guanine nucleotide exchange factor Rapgef2 was enriched from primary bovine neuroendocrine cells by cAMP-agarose affinity chromatography and that it was specifically eluted by cAMP. With loss-of-function experiments in the rat neuronal cell line Neuroscreen-1 (NS-1) and gain-of-function experiments in human embryonic kidney 293T cells, we demonstrated that Rapgef2 connected GPCR-dependent activation of adenylate cyclase and increased cAMP concentration with the activation of ERK in neurons and endocrine cells. Furthermore, knockdown of Rapgef2 blocked cAMP-and ERK-dependent neuritogenesis. Our data are consistent with a pathway involving the cAMP-mediated activation of Rapgef2, which then stimulates Rap1, leading to increases in B-Raf, MEK, and ERK activity. C1 [Emery, Andrew C.; Mustafa, Tomris; Eiden, Lee E.] NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, Intramural Res Program, Bethesda, MD 20892 USA. [Eiden, Maribeth V.] NIMH, Sect Directed Gene Transfer, Lab Cellular & Mol Regulat, Intramural Res Program, Bethesda, MD 20892 USA. RP Eiden, LE (reprint author), NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, Intramural Res Program, Bethesda, MD 20892 USA. EM eidenl@mail.nih.gov OI Emery, Andrew/0000-0002-6760-2570; Eiden, Lee/0000-0001-7524-944X FU NIH [1ZIAMH002386, 1ZIAMH002592] FX This work was funded by the Intramural Research Program of the NIH Projects 1ZIAMH002386 (to L.E.E.) and 1ZIAMH002592 (to M.V.E.). NR 58 TC 14 Z9 20 U1 0 U2 14 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1945-0877 J9 SCI SIGNAL JI Sci. Signal. PD JUN 25 PY 2013 VL 6 IS 281 AR ra51 DI 10.1126/scisignal.2003993 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 170LU UT WOS:000320853200002 PM 23800469 ER PT J AU Harper, MT Londono, JEC Quick, K Londono, JC Flockerzi, V Philipp, SE Birnbaumer, L Freichel, M Poole, AW AF Harper, Matthew T. Londono, Juan E. Camacho Quick, Kathryn Londono, Julia Camacho Flockerzi, Veit Philipp, Stephan E. Birnbaumer, Lutz Freichel, Marc Poole, Alastair W. TI Transient Receptor Potential Channels Function as a Coincidence Signal Detector Mediating Phosphatidylserine Exposure SO SCIENCE SIGNALING LA English DT Article ID OPERATED CALCIUM-CHANNELS; SMOOTH-MUSCLE-CELLS; HUMAN-PLATELETS; NA+/CA2+ EXCHANGER; CA2+ ENTRY; TRPC3 CHANNELS; ACTIVATION; THROMBIN; MOUSE; ORAI1 AB Blood platelet aggregation must be tightly controlled to promote clotting at injury sites but avoid inappropriate occlusion of blood vessels. Thrombin, which cleaves and activates G(q)-coupled protease-activated receptors, and collagen-related peptide, which activates the receptor glycoprotein VI, stimulate platelets to aggregate and form thrombi. Coincident activation by these two agonists synergizes, causing the exposure of phosphatidylserine on the cell surface, which is a marker of cell death in many cell types. Phosphatidylserine exposure is also essential to produce additional thrombin on platelet surfaces, which contributes to thrombosis. We found that activation of either thrombin receptors or glycoprotein VI alone produced a calcium signal that was largely dependent only on store-operated Ca2+ entry. In contrast, experiments with platelets from knockout mice showed that the presence of both ligands activated nonselective cation channels of the transient receptor potential C(TRPC) family, TRPC3 and TRPC6. These channels principally allowed entry of Na+, which coupled to reverse-mode Na+/Ca2+ exchange to allow calcium influx and thereby contribute to Ca2+ signaling and phosphatidylserine exposure. Thus, TRPC channels act as coincidence detectors to coordinate responses to multiple signals in cells, thereby indirectly mediating in platelets an increase in intracellular calcium concentrations and exposure of prothrombotic phosphatidylserine. C1 [Harper, Matthew T.; Poole, Alastair W.] Univ Bristol, Sch Physiol & Pharmacol, Bristol BS8 1TD, Avon, England. [Londono, Juan E. Camacho; Freichel, Marc] Heidelberg Univ, Inst Pharmacol, D-69120 Heidelberg, Germany. [Londono, Juan E. Camacho; Londono, Julia Camacho; Flockerzi, Veit; Philipp, Stephan E.; Freichel, Marc] Univ Saarland, Fac Med, Dept Expt & Clin Pharmacol & Toxicol, D-66424 Homburg, Germany. [Quick, Kathryn] UCL, Wolfson Inst Bioned Res, Mol Nocicept Grp, London WC1E 6BT, England. [Birnbaumer, Lutz] NIH, Transmembrane Signaling Grp, Res Triangle Pk, NC 27709 USA. RP Harper, MT (reprint author), Univ Bristol, Sch Physiol & Pharmacol, Bristol BS8 1TD, Avon, England. EM m.harper@bris.ac.uk; a.poole@bris.ac.uk RI Harper, Matthew/G-5630-2013 OI Harper, Matthew/0000-0002-4740-637X FU British Heart Foundation [RG/10/006/28299]; Klinische Forschergruppe [196]; DZHK (German Centre for Cardiovascular Research); BMBF (German Ministry of Education and Research); "Forschungsausschuss" and "HOMFOR" program der Universitat des Saarlandes; Deutsche Forschungsgemeinschaft [GK 1326, SFB 530]; Biotechnology and Biological Sciences Research Council [BB/F000227/1]; NIH [Z01-ES101684] FX This work was supported by the British Heart Foundation (program grant RG/10/006/28299; M.T.H. and A.W.P.), the Klinische Forschergruppe 196, DZHK (German Centre for Cardiovascular Research), the BMBF (German Ministry of Education and Research), the "Forschungsausschuss" and "HOMFOR" program der Universitat des Saarlandes (M.F.), the Deutsche Forschungsgemeinschaft (GK 1326 and SFB 530; S.E.P.), the Biotechnology and Biological Sciences Research Council (BB/F000227/1; K.Q.), and the Intramural Research Program of the NIH (project Z01-ES101684; L.B.). NR 59 TC 26 Z9 26 U1 1 U2 6 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1945-0877 EI 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD JUN 25 PY 2013 VL 6 IS 281 AR ra50 DI 10.1126/scisignal.2003701 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 170LU UT WOS:000320853200001 PM 23800468 ER PT J AU Yan, Y Kong, H Wu, EJ Newman, AH Xu, M AF Yan, Y. Kong, H. Wu, E. J. Newman, A. H. Xu, M. TI DOPAMINE D3 RECEPTORS REGULATE RECONSOLIDATION OF COCAINE MEMORY SO NEUROSCIENCE LA English DT Article DE dopamine D3 receptor; reconsolidation; reward learning; cocaine; mutant mice; antagonist PG01037 ID NUCLEUS-ACCUMBENS CORE; DRUG-SEEKING BEHAVIOR; D-3 RECEPTORS; PROTEIN-SYNTHESIS; INDUCED REINSTATEMENT; BASOLATERAL AMYGDALA; PROGRESSIVE-RATIO; BRAIN REWARD; ADDICTION; EXTINCTION AB Memories of learned associations between the rewarding properties of drugs of abuse and environmental cues contribute to craving and relapse in humans. Disruption of reconsolidation dampens or even erases previous memories. Dopamine (DA) mediates the acquisition of reward memory and drugs of abuse can pathologically change related neuronal circuits in the mesolimbic DA system. Previous studies showed that DA D3 receptors are involved in cocaine-conditioned place preference (CPP) and reinstatement of cocaine-seeking behavior. However, the role of D3 receptors in reconsolidation of cocaine-induced reward memory remains unclear. In the present study, we combined genetic and pharmacological approaches to investigate the role of D3 receptors in reconsolidation of cocaine-induced CPP. We found that the mutation of the D3 receptor gene weakened reconsolidation of cocaine-induced CPP in mice triggered by a 3-min (min) retrieval. Furthermore, treatment of a selective D3 receptor antagonist PG01037 immediately following the 3-min retrieval disrupted reconsolidation of cocaine-induced CPP in wild-type mice and such disruption remained at least 1 week after the 3-min retrieval. These results suggest that D3 receptors play a key role in reconsolidation of cocaine-induced CPP in mice, and that pharmacological blockade of these receptors may be therapeutic for the treatment of cocaine craving and relapse in clinical settings. (c) 2013 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Yan, Y.; Kong, H.; Xu, M.] Univ Chicago, Dept Anesthesia & Crit Care, Chicago, IL 60637 USA. [Wu, E. J.] Univ Colorado, Boulder, CO 80309 USA. [Newman, A. H.] NIDA, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD USA. RP Xu, M (reprint author), Univ Chicago, Dept Anesthesia & Crit Care, Box 428, Chicago, IL 60637 USA. EM mxu@dacc.uchicago.edu FU NIDA [DA17323, DA025088]; NIDA Intramural Research Program FX We greatly appreciate Dr. H. Jiao's assistance for mouse genotyping, Dr. J. Katz for discussions and suggestions, and J. Cao for synthesizing PG01037. M.X. was supported by Grants from NIDA (DA17323 and DA025088). A.H.N was supported by the NIDA Intramural Research Program. NR 67 TC 7 Z9 7 U1 0 U2 19 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD JUN 25 PY 2013 VL 241 BP 32 EP 40 DI 10.1016/j.neuroscience.2013.03.005 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 146MY UT WOS:000319096400004 PM 23506736 ER PT J AU Keil, MF Briassoulis, G Nesterova, M Miraftab, N Gokarn, N Wu, TJ Stratakis, CA AF Keil, M. F. Briassoulis, G. Nesterova, M. Miraftab, N. Gokarn, N. Wu, T. J. Stratakis, C. A. TI THREAT BIAS IN MICE WITH INACTIVATING MUTATIONS OF Prkar1a SO NEUROSCIENCE LA English DT Article DE protein kinase A; amygdala; orbitofrontal cortex; anxiety; Prkar1a; threat detection ID PROTEIN-KINASE-A; LONG-TERM POTENTIATION; PREFRONTAL CORTEX; MEMORY CONSOLIDATION; BASOLATERAL AMYGDALA; SIGNALING PATHWAYS; REGULATORY SUBUNIT; CARNEY COMPLEX; DEFENSIVE BEHAVIORS; ANATOMICAL LOCATION AB Anxiety disorders are associated with abnormalities in the neural processing of threat-related stimuli. However, the neurobiological mechanisms underlying threat bias in anxiety are not well understood. We recently reported that a Prkar1a heterozygote (Prkar1a(+/-)) mouse with haploinsufficiency for the main regulatory subunit (R1 alpha) of protein kinase A (PKA) exhibits an anxiety-like phenotype associated with increased cAMP signaling in the amygdala. Prkar1a(+/-) mice provide a novel model to test the direct effect of altered PKA expression and subsequent anxiety-like behavioral phenotype on the response to threat. We hypothesized that Prkar1a(+/-) mice would exhibit a bias in threat detection since increased amygdala activity during emotional stimuli is associated with a maladaptive response. We measured behavior and PKA activity in brain areas after exposure to predator or control odor exposure in male Prkar1a(+/-) and wild-type (WT) littermates. Indeed, there were significant differences in the behavioral response to threat detection; WT mice showed the expected response of decrease in exploratory behavior during predator vs. control odor exposure, while Prkar1a(+/-) mice did not alter their behavior between conditions. Basal and total PICA activity was independently associated with genotype, with an interaction between genotype and threat condition. Prkar1a(+/-) mice had higher PICA activity in amygdala and ventromedial hypothalamus in response to predator odor. In contrast, WT mice had higher PKA activity in amygdala and orbitofrontal cortex after exposure to control odor. Dysregulated PKA activity in the amygdala-prefrontal cortex circuitry in Prkar1a(+/-) mice is associated with behavioral phenotype of anxiety and a bias for threat. This is likely related to a failure to inhibit the amydgala response, which is an effect of the genotype. These results suggest that the alteration in PKA signaling in Prkar1a(+/-) mice is not ubiquitous in the brain; tissue-specific effects of the cAMP/PKA pathway are related to threat detection and fear sensitization. Published by Elsevier Ltd. on behalf of IBRO. C1 [Keil, M. F.; Briassoulis, G.; Nesterova, M.; Miraftab, N.; Gokarn, N.; Stratakis, C. A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Keil, M. F.; Wu, T. J.] Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bethesda, MD 20814 USA. [Keil, M. F.; Wu, T. J.] Uniformed Serv Univ Hlth Sci, Program Neurosci, Bethesda, MD 20814 USA. RP Keil, MF (reprint author), NICHD, NIH, PDEGEN, 10 Ctr Dr,Bldg 10 CRC,Room 1 E 3330, Bethesda, MD 20892 USA. EM keilm@mail.nih.gov FU NICHD, NIH [Z01-HD-000642-04]; Department of Pediatrics, University of Crete, Heraklion, Crete, Greece; Uniformed Services University of the Health Sciences; Department of Defense [CO85DP, DMRDP 061 I-10 J6 125] FX This work was supported by NICHD, NIH intramural project Z01-HD-000642-04 to Dr. C. A. Stratakis. It was also supported in part by the Department of Pediatrics, University of Crete, Heraklion, Crete, Greece (G. Briassoulis). Finally, part of this work was also supported by intramural graduate student grant from the Uniformed Services University of the Health Sciences (MFK) and Department of Defense grants CO85DP and DMRDP 061 I-10 J6 125 (TJW). NR 67 TC 3 Z9 4 U1 1 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD JUN 25 PY 2013 VL 241 BP 206 EP 214 DI 10.1016/j.neuroscience.2013.03.027 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 146MY UT WOS:000319096400020 PM 23531435 ER PT J AU Becker, AM Dao, KH Han, BK Kornu, R Lakhanpal, S Mobley, AB Li, QZ Lian, Y Wu, TF Reimold, AM Olsen, NJ Karp, DR Chowdhury, FZ Farrar, JD Satterthwaite, AB Mohan, C Lipsky, PE Wakeland, EK Davis, LS AF Becker, Amy M. Dao, Kathryn H. Han, Bobby Kwanghoon Kornu, Roger Lakhanpal, Shuchi Mobley, Angela B. Li, Quan-Zhen Lian, Yun Wu, Tianfu Reimold, Andreas M. Olsen, Nancy J. Karp, David R. Chowdhury, Fatema Z. Farrar, J. David Satterthwaite, Anne B. Mohan, Chandra Lipsky, Peter E. Wakeland, Edward K. Davis, Laurie S. TI SLE Peripheral Blood B Cell, T Cell and Myeloid Cell Transcriptomes Display Unique Profiles and Each Subset Contributes to the Interferon Signature SO PLOS ONE LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; DISEASE-ACTIVITY; GENE-EXPRESSION; AUTOIMMUNE-DISEASE; PROTEIN-INTERACTION; IFN-ALPHA; MEMORY; ACTIVATION; ANTIBODIES; PATHWAYS AB Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by defective immune tolerance combined with immune cell hyperactivity resulting in the production of pathogenic autoantibodies. Previous gene expression studies employing whole blood or peripheral blood mononuclear cells (PBMC) have demonstrated that a majority of patients with active disease have increased expression of type I interferon (IFN) inducible transcripts known as the IFN signature. The goal of the current study was to assess the gene expression profiles of isolated leukocyte subsets obtained from SLE patients. Subsets including CD19(+) B lymphocytes, CD3(+) CD4(+) T lymphocytes and CD33(+) myeloid cells were simultaneously sorted from PBMC. The SLE transcriptomes were assessed for differentially expressed genes as compared to healthy controls. SLE CD33(+) myeloid cells exhibited the greatest number of differentially expressed genes at 208 transcripts, SLE B cells expressed 174 transcripts and SLE CD3(+) CD4(+) T cells expressed 92 transcripts. Only 4.4% (21) of the 474 total transcripts, many associated with the IFN signature, were shared by all three subsets. Transcriptional profiles translated into increased protein expression for CD38, CD63, CD107a and CD169. Moreover, these studies demonstrated that both SLE lymphoid and myeloid subsets expressed elevated transcripts for cytosolic RNA and DNA sensors and downstream effectors mediating IFN and cytokine production. Prolonged upregulation of nucleic acid sensing pathways could modulate immune effector functions and initiate or contribute to the systemic inflammation observed in SLE. C1 [Becker, Amy M.; Mobley, Angela B.; Li, Quan-Zhen; Lian, Yun; Chowdhury, Fatema Z.; Farrar, J. David; Satterthwaite, Anne B.; Mohan, Chandra; Wakeland, Edward K.] Univ Texas SW Med Ctr Dallas, Dept Immunol, Dallas, TX 75390 USA. [Becker, Amy M.; Dao, Kathryn H.; Han, Bobby Kwanghoon; Kornu, Roger; Lakhanpal, Shuchi; Wu, Tianfu; Reimold, Andreas M.; Olsen, Nancy J.; Karp, David R.; Satterthwaite, Anne B.; Mohan, Chandra; Davis, Laurie S.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Lipsky, Peter E.] NIAMSD, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. RP Davis, LS (reprint author), Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. EM Laurie.Davis@UTSouthwestern.edu OI Wu, Tianfu/0000-0001-8235-5929 FU National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases [P50AR055503, R01AR45293]; UT Southwestern Arthritis Center Flow Cytometry Core; MedImmune; Novo Nordisk; Novo Nordisk, Genentech/Roche; Human Genome Sciences FX This work was supported by the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases grant P50AR055503 (Mohan), the UT Southwestern Arthritis Center Flow Cytometry Core (Davis) and the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases grant R01AR45293 (Davis). Dr. Nancy Olsen has equity interest in a company, ArthroChip LLC, which develops assays for autoimmune diseases and she has also obtained funding from MedImmune, Novo Nordisk, Genentech/Roche and Human Genome Sciences. Dr. David Karp has received research funding from Human Genome Sciences. None of these funds were used for the current study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 77 TC 33 Z9 33 U1 2 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 JUN 24 PY 2013 VL 8 IS 6 AR e67003 DI 10.1371/journal.pone.0067003 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 182JP UT WOS:000321738400092 PM 23826184 ER PT J AU Harel, A Bentin, S AF Harel, Assaf Bentin, Shlomo TI Are All Types of Expertise Created Equal? Car Experts Use Different Spatial Frequency Scales for Subordinate Categorization of Cars and Faces SO PLOS ONE LA English DT Article ID OBJECT RECOGNITION; VISUAL EXPERTISE; BASIC-LEVEL; AREA; PERCEPTION; INFORMATION; CORTEX; INTERFERENCE; SENSITIVITY; COMPETITION AB A much-debated question in object recognition is whether expertise for faces and expertise for non-face objects utilize common perceptual information. We investigated this issue by assessing the diagnostic information required for different types of expertise. Specifically, we asked whether face categorization and expert car categorization at the subordinate level relies on the same spatial frequency (SF) scales. Fifteen car experts and fifteen novices performed a category verification task with spatially filtered images of faces, cars, and airplanes. Images were categorized based on their basic (e.g. "car'') and subordinate level (e.g. "Japanese car'') identity. The effect of expertise was not evident when objects were categorized at the basic level. However, when the car experts categorized faces and cars at the subordinate level, the two types of expertise required different kinds of SF information. Subordinate categorization of faces relied on low SFs more than on high SFs, whereas subordinate expert car categorization relied on high SFs more than on low SFs. These findings suggest that expertise in the recognition of objects and faces do not utilize the same type of information. Rather, different types of expertise require different types of diagnostic visual information. C1 [Harel, Assaf] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Bentin, Shlomo] Hebrew Univ Jerusalem, Dept Psychol, IL-91905 Jerusalem, Israel. [Bentin, Shlomo] Hebrew Univ Jerusalem, Ctr Neural Computat, Jerusalem, Israel. RP Harel, A (reprint author), NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. EM assaf.harel@nih.gov OI Harel, Assaf/0000-0002-4899-6156 FU NIMH [R01 MH 64458] FX This study was funded by NIMH grant R01 MH 64458 to Shlomo Bentin. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 8 Z9 8 U1 2 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 JUN 24 PY 2013 VL 8 IS 6 AR e67024 DI 10.1371/journal.pone.0067024 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 182JP UT WOS:000321738400095 PM 23826188 ER PT J AU Hoobler, EK Rai, G Warrilow, AGS Perry, SC Smyrniotis, CJ Jadhav, A Simeonov, A Parker, JE Kelly, DE Maloney, DJ Kelly, SL Holman, TR AF Hoobler, Eric K. Rai, Ganesha Warrilow, Andrew G. S. Perry, Steven C. Smyrniotis, Christopher J. Jadhav, Ajit Simeonov, Anton Parker, Josie E. Kelly, Diane E. Maloney, David J. Kelly, S. L. Holman, Theodore R. TI Discovery of a Novel Dual Fungal CYP51/Human 5-Lipoxygenase Inhibitor: Implications for Anti-Fungal Therapy SO PLOS ONE LA English DT Article ID MONOXIDE-BINDING PIGMENT; SELECTIVE INHIBITORS; CANDIDA-ALBICANS; PHENYLENEDIAMINE DERIVATIVES; NORDIHYDROGUAIARETIC ACID; SEBORRHEIC DERMATITIS; LIVER MICROSOMES; ACCURATE DOCKING; WHOLE-BLOOD; LIPOXYGENASE AB We report the discovery of a novel dual inhibitor targeting fungal sterol 14 alpha-demethylase (CYP51 or Erg11) and human 5-lipoxygenase (5-LOX) with improved potency against 5-LOX due to its reduction of the iron center by its phenylenediamine core. A series of potent 5-LOX inhibitors containing a phenylenediamine core, were synthesized that exhibit nanomolar potency and >30-fold selectivity against the LOX paralogs, platelet-type 12-human lipoxygenase, reticulocyte 15-human lipoxygenase type-1, and epithelial 15-human lipoxygenase type-2, and >100-fold selectivity against ovine cyclooxygenase-1 and human cyclooxygnease-2. The phenylenediamine core was then translated into the structure of ketoconazole, a highly effective anti-fungal medication for seborrheic dermatitis, to generate a novel compound, ketaminazole. Ketaminazole was found to be a potent dual inhibitor against human 5-LOX (IC50 = 700 nM) and CYP51 (IC50 = 43 nM) in vitro. It was tested in whole blood and found to down-regulate LTB4 synthesis, displaying 45% inhibition at 10 mu M. In addition, ketaminazole selectively inhibited yeast CYP51 relative to human CYP51 by 17-fold, which is greater selectivity than that of ketoconazole and could confer a therapeutic advantage. This novel dual anti-fungal/anti-inflammatory inhibitor could potentially have therapeutic uses against fungal infections that have an anti-inflammatory component. C1 [Hoobler, Eric K.; Perry, Steven C.; Smyrniotis, Christopher J.; Holman, Theodore R.] Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95064 USA. [Rai, Ganesha; Jadhav, Ajit; Simeonov, Anton; Maloney, David J.] NIH, Chem Genom Ctr, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Warrilow, Andrew G. S.; Parker, Josie E.; Kelly, Diane E.; Kelly, S. L.] Swansea Univ, Coll Med, Inst Life Sci, Swansea, W Glam, Wales. RP Maloney, DJ (reprint author), NIH, Chem Genom Ctr, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. EM maloneyd@mail.nih.gov; s.l.kelly@swansea.ac.uk; holman@ucsc.edu OI Warrilow, Andrew/0000-0003-0183-8334; Parker, Josie/0000-0002-3855-4194 FU National Institutes of Health [GM56062, S10-RR20939]; Welsh Government (SLK); ERDF, via the Beacon project FX This work was supported by the National Institutes of Health (GM56062 (TRH) S10-RR20939 (UCSC MS Equipment grant), the Welsh Government (SLK) and the ERDF, via the Beacon project (SLK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 5 Z9 5 U1 0 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 JUN 24 PY 2013 VL 8 IS 6 AR e65928 DI 10.1371/journal.pone.0065928 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 182JP UT WOS:000321738400006 PM 23826084 ER PT J AU Perl, S Perlman, J Weitzel, RP Phang, O Hsieh, MM Tisdale, J AF Perl, Shira Perlman, Jordan Weitzel, R. P. Phang, Oswald Hsieh, Matthew M. Tisdale, John TI Addition of Rapamycin to Anti-CD3 Antibody Improves Long-Term Glycaemia Control in Diabetic NOD Mice SO PLOS ONE LA English DT Article ID T-CELLS; TYPE-1; TRIAL AB Aims/Hypothesis: Non-Fc-binding Anti CD3 antibody has proven successful in reverting diabetes in the non-obese diabetes mouse model of type 1 diabetes and limited efficacy has been observed in human clinical trials. We hypothesized that addition of rapamycin, an mTOR inhibitor capable of inducing operational tolerance in allogeneic bone marrow transplantation, would result in improved diabetes reversal rates and overall glycemia. Methods: Seventy hyperglycemic non-obese diabetic mice were randomized to either a single injection of anti CD3 alone or a single injection of anti CD3 followed by 14 days of intra-peritoneal rapamycin. Mice were monitored for hyperglycemia and metabolic control. Results: Mice treated with the combination of anti CD3 and rapamycin had similar rates of diabetes reversal compared to anti CD3 alone (25/35 vs. 22/35). Mice treated with anti CD3 plus rapamycin had a significant improvement in glycemia control as exhibited by lower blood glucose levels in response to an intra-peritoneal glucose challenge; average peak blood glucose levels 30 min post intra-peritoneal injection of 2 gr/kg glucose were 6.9 mmol/L in the anti CD3 plus rapamycin group vs. 10 mmo/L in the anti CD3 alone (P<0.05). Conclusions/Interpretation: The addition of rapamycin to anti CD3 results in significant improvement in glycaemia control in diabetic NOD mice. C1 [Perl, Shira] NHLBI, Ctr Human Immunol, NIH, Bethesda, MD 20892 USA. [Perl, Shira; Perlman, Jordan; Weitzel, R. P.; Phang, Oswald; Hsieh, Matthew M.; Tisdale, John] NHLBI, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Perl, S (reprint author), NHLBI, Ctr Human Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM perls@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute at the National Institutes of Health FX This work is supported by the intramural research program of the National Heart, Lung, and Blood Institute at 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 11 TC 4 Z9 4 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 JUN 24 PY 2013 VL 8 IS 6 AR e67189 DI 10.1371/journal.pone.0067189 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 182JP UT WOS:000321738400116 PM 23826229 ER PT J AU Wang, XJ Misawa, R Zielinski, MC Cowen, P Jo, JH Periwal, V Ricordi, C Khan, A Szust, J Shen, JH Millis, M Witkowski, P Hara, M AF Wang, Xiaojun Misawa, Ryosuke Zielinski, Mark C. Cowen, Peter Jo, Junghyo Periwal, Vipul Ricordi, Camillo Khan, Aisha Szust, Joel Shen, Junhui Millis, Michael Witkowski, Piotr Hara, Manami TI Regional Differences in Islet Distribution in the Human Pancreas - Preferential Beta-Cell Loss in the Head Region in Patients with Type 2 Diabetes SO PLOS ONE LA English DT Article ID RAT; ARCHITECTURE; POLYPEPTIDE; CANCER; SECRETION; SURVIVAL; INSULIN; MICE; MASS; QUANTIFICATION AB While regional heterogeneity in islet distribution has been well studied in rodents, less is known about human pancreatic histology. To fill gaps in our understanding, regional differences in the adult human pancreas were quantitatively analyzed including the pathogenesis of type 2 diabetes (T2D). Cadaveric pancreas specimens were collected from the head, body and tail regions of each donor, including subjects with no history of diabetes or pancreatic diseases (n = 23) as well as patients with T2D (n = 12). The study further included individuals from whom islets were isolated (n = 7) to study islet yield and function in a clinical setting of islet transplantation. The whole pancreatic sections were examined using an innovative large-scale image capture and unbiased detailed quantitative analyses of the characteristics of islets from each individual (architecture, size, shape and distribution). Islet distribution/density is similar between the head and body regions, but is >2-fold higher in the tail region. In contrast to rodents, islet cellular composition and architecture were similar throughout the pancreas and there was no difference in glucose-stimulated insulin secretion in islets isolated from different regions of the pancreas. Further studies revealed preferential loss of large islets in the head region in patients with T2D. The present study has demonstrated distinct characteristics of the human pancreas, which should provide a baseline for the future studies integrating existing research in the field and helping to advance bi-directional research between humans and preclinical models. C1 [Wang, Xiaojun; Misawa, Ryosuke; Millis, Michael; Witkowski, Piotr] Univ Chicago, Dept Surg, Chicago, IL 60637 USA. [Wang, Xiaojun] Third Mil Med Univ, Southwest Hosp, Inst Hepatobiliary Surg, Chongqing, Peoples R China. [Zielinski, Mark C.; Cowen, Peter; Shen, Junhui; Hara, Manami] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Jo, Junghyo; Periwal, Vipul] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD USA. [Ricordi, Camillo; Khan, Aisha; Szust, Joel] Univ Miami, Cell Transplant Ctr, Miami, FL USA. RP Hara, M (reprint author), Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA. EM mhara@uchicago.edu RI Jo, Junghyo/D-4889-2011; OI Zielinski, Mark/0000-0002-6950-6689; Ricordi, Camillo/0000-0001-8092-7153 FU US Public Health Service Grant [DK-020595, DK-072473, AG-042151]; intramural research program of the NIH, NIDDK FX The study is supported by US Public Health Service Grant DK-020595 to the University of Chicago Diabetes Research and Training Center (Animal Models Core), DK-072473, AG-042151, and a gift from the Kovler Family Foundation (to MH); and the intramural research program of the NIH, NIDDK (to JJ and VP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 25 Z9 25 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 JUN 24 PY 2013 VL 8 IS 6 AR e67454 DI 10.1371/journal.pone.0067454 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 182JP UT WOS:000321738400149 PM 23826303 ER PT J AU Schwartz, JAT Pearson, SD AF Schwartz, Jennifer A. T. Pearson, Steven D. TI Cost Consideration in the Clinical Guidance Documents of Physician Specialty Societies in the United States SO JAMA INTERNAL MEDICINE LA English DT Article ID PRACTICE GUIDELINES; AMERICAN-COLLEGE; TASK-FORCE; HEART-ASSOCIATION; MEDICINE; ALLOCATION; CARDIOLOGY; ISSUES; CARE AB Importance: Despite increasing concerns regarding the cost of health care, the consideration of costs in the development of clinical guidance documents by physician specialty societies has received little analysis. Objective: To evaluate the approach to consideration of cost in publicly available clinical guidance documents and methodological statements produced between 2008 and 2012 by the 30 largest US physician specialty societies. Design: Qualitative document review. Main Outcomes and Measures: Whether costs are considered in clinical guidance development, mechanism of cost consideration, and the way that cost issues were used in support of specific clinical practice recommendations. Results: Methodological statements for clinical guidance documents indicated that 17 of 30 physician societies (57%) explicitly integrated costs, 4 (13%) implicitly considered costs, 3 (10%) intentionally excluded costs, and 6 (20%) made no mention. Of the 17 societies that explicitly integrated costs, 9 (53%) consistently used a formal system in which the strength of recommendation was influenced in part by costs, whereas 8 (47%) were inconsistent in their approach or failed to mention the exact mechanism for considering costs. Among the 138 specific recommendations in these guidance documents that included cost as part of the rationale, the most common form of recommendation (50 [36%]) encouraged the use of a specific medical service because of equal effectiveness and lower cost. Conclusions and Relevance: Slightly more than half of the largest US physician societies explicitly consider costs in developing their clinical guidance documents; among these, approximately half use an explicit mechanism for integrating costs into the strength of recommendations. Many societies remain vague in their approach. Physician specialty societies should demonstrate greater transparency and rigor in their approach to cost consideration in documents meant to influence care decisions. C1 [Schwartz, Jennifer A. T.; Pearson, Steven D.] NIH, Ctr Clin, Dept Bioeth, Bethesda, MD 20892 USA. [Pearson, Steven D.] Massachusetts Gen Hosp, Inst Clin & Econ Review, Inst Technol Assessment, Boston, MA 02114 USA. RP Pearson, SD (reprint author), NIH, 10 Ctr Dr,Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM pearsonsd@cc.nih.gov NR 39 TC 19 Z9 19 U1 0 U2 1 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 JUN 24 PY 2013 VL 173 IS 12 BP 1091 EP 1097 DI 10.1001/jamainternmed.2013.817 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 170OE UT WOS:000320861700014 PM 23649494 ER PT J AU Weigert, R Porat-Shliom, N Amornphimoltham, P AF Weigert, Roberto Porat-Shliom, Natalie Amornphimoltham, Panomwat TI Imaging cell biology in live animals: Ready for prime time SO JOURNAL OF CELL BIOLOGY LA English DT Review ID RAMAN SCATTERING MICROSCOPY; INTRAVITAL 2-PHOTON MICROSCOPY; GREEN FLUORESCENT PROTEIN; CD8(+) T-CELLS; IN-VIVO; SKELETAL-MUSCLE; DRUG-DELIVERY; LIVING MICE; BLOOD-FLOW; TUMOR MICROENVIRONMENT AB Time-lapse fluorescence microscopy is one of the main tools used to image subcellular structures in living cells. Yet for decades it has been applied primarily to in vitro model systems. Thanks to the most recent advancements in intravital microscopy, this approach has finally been extended to live rodents. This represents a major breakthrough that will provide unprecedented new opportunities to study mammalian cell biology in vivo and has already provided new insight in the fields of neurobiology, immunology, and cancer biology. C1 [Weigert, Roberto; Porat-Shliom, Natalie; Amornphimoltham, Panomwat] Natl Inst Dent & Craniofacial Res, Intracellular Membrane Trafficking Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Weigert, R (reprint author), Natl Inst Dent & Craniofacial Res, Intracellular Membrane Trafficking Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. EM weigertr@mail.nih.gov FU National Institutes of Health, National Institute of Dental and Craniofacial Research FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research. NR 128 TC 34 Z9 35 U1 1 U2 43 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD JUN 24 PY 2013 VL 201 IS 7 BP 969 EP 979 DI 10.1083/jcb.201212130 PG 11 WC Cell Biology SC Cell Biology GA 169IK UT WOS:000320773500003 PM 23798727 ER PT J AU Michailidis, E Ryan, EM Hachiya, A Kirby, KA Marchand, B Leslie, MD Huber, AD Ong, YT Jackson, JC Singh, K Kodama, EN Mitsuya, H Parniak, MA Sarafianos, SG AF Michailidis, Eleftherios Ryan, Emily M. Hachiya, Atsuko Kirby, Karen A. Marchand, Bruno Leslie, Maxwell D. Huber, Andrew D. Ong, Yee T. Jackson, Jacob C. Singh, Kamalendra Kodama, Eiichi N. Mitsuya, Hiroaki Parniak, Michael A. Sarafianos, Stefan G. TI Hypersusceptibility mechanism of Tenofovir-resistant HIV to EFdA SO RETROVIROLOGY LA English DT Article DE HIV-1; RT; EFdA; K65R ID HUMAN-IMMUNODEFICIENCY-VIRUS; TYPE-1 REVERSE-TRANSCRIPTASE; IN-VITRO SELECTION; DEPENDENT PRIMER UNBLOCKING; THYMIDINE ANALOG MUTATIONS; TREATMENT-NAIVE PATIENTS; HIGH-LEVEL RESISTANCE; DRUG-RESISTANCE; MOLECULAR-MECHANISMS; ANGSTROM RESOLUTION AB Background: The K65R substitution in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is the major resistance mutation selected in patients treated with first-line antiretroviral tenofovir disoproxil fumarate (TDF). 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), is the most potent nucleoside analog RT inhibitor (NRTI) that unlike all approved NRTIs retains a 3'-hydroxyl group and has remarkable potency against wild-type (WT) and drug-resistant HIVs. EFdA acts primarily as a chain terminator by blocking translocation following its incorporation into the nascent DNA chain. EFdA is in preclinical development and its effect on clinically relevant drug resistant HIV strains is critically important for the design of optimal regimens prior to initiation of clinical trials. Results: Here we report that the K65R RT mutation causes hypersusceptibility to EFdA. Specifically, in single replication cycle experiments we found that EFdA blocks WT HIV ten times more efficiently than TDF. Under the same conditions K65R HIV was inhibited over 70 times more efficiently by EFdA than TDF. We determined the molecular mechanism of this hypersensitivity using enzymatic studies with WT and K65R RT. This substitution causes minor changes in the efficiency of EFdA incorporation with respect to the natural dATP substrate and also in the efficiency of RT translocation following incorporation of the inhibitor into the nascent DNA. However, a significant decrease in the excision efficiency of EFdA-MP from the 3' primer terminus appears to be the primary cause of increased susceptibility to the inhibitor. Notably, the effects of the mutation are DNA-sequence dependent. Conclusion: We have elucidated the mechanism of K65R HIV hypersusceptibility to EFdA. Our findings highlight the potential of EFdA to improve combination strategies against TDF-resistant HIV-1 strains. C1 [Michailidis, Eleftherios; Ryan, Emily M.; Kirby, Karen A.; Marchand, Bruno; Leslie, Maxwell D.; Huber, Andrew D.; Ong, Yee T.; Jackson, Jacob C.; Singh, Kamalendra; Sarafianos, Stefan G.] Univ Missouri, Christopher Bond Life Sci Ctr, Dept Mol Microbiol & Immunol, Columbia, MO 65211 USA. [Hachiya, Atsuko] Natl Hosp Org, Nagoya Med Ctr, Dept Infect Dis & Immunol, Clin Res Ctr, Nagoya, Aichi 4600001, Japan. [Kodama, Eiichi N.] Tohoku Univ, Div Emerging Infect Dis, Sendai, Miyagi 9808575, Japan. [Mitsuya, Hiroaki] Kumamoto Univ, Dept Internal Med, Kumamoto 8608556, Japan. [Mitsuya, Hiroaki] NIH, Expt Retrovirol Sect, HIV AIDS Malignancy Branch, Bethesda, MD 20892 USA. [Parniak, Michael A.] Univ Pittsburgh, Dept Microbiol & Mol Genet, Pittsburgh, PA 15219 USA. [Sarafianos, Stefan G.] Univ Missouri, Dept Biochem, Columbia, MO 65211 USA. RP Sarafianos, SG (reprint author), Univ Missouri, Christopher Bond Life Sci Ctr, Dept Mol Microbiol & Immunol, Columbia, MO 65211 USA. EM sarafianoss@missouri.edu RI Kodama, Eiichi /C-4032-2009; OI Kodama, Eiichi /0000-0002-6622-2752; Sarafianos, Stefan G/0000-0002-5840-154X; Kirby, Karen A./0000-0003-2468-4796 FU National Institutes of Health [AI076119, AI074389, AI076119-S1, AI076119-02S1, AI100890, AI099284, GM103368, AI079801] FX Dr. Tatiana Ilina's contribution in the preparation of the RT plasmids is acknowledged. This work was supported, in whole or in part, by National Institutes of Health grants AI076119, AI074389, AI076119-S1, AI076119-02S1, AI100890, AI099284, and GM103368 (S. G. S.) and AI079801 (M. A. P.). NR 72 TC 12 Z9 12 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 JUN 24 PY 2013 VL 10 AR 65 DI 10.1186/1742-4690-10-65 PG 12 WC Virology SC Virology GA 172QC UT WOS:000321018200001 PM 23800377 ER PT J AU Iordanova, MD Haralambous, T McNally, GP Westbrook, RF AF Iordanova, Mihaela D. Haralambous, Tatiana McNally, Gowan P. Westbrook, R. Frederick TI Accumbal opioid receptors modulate cue competition in one-trial overshadowing SO BRAIN RESEARCH LA English DT Article DE Fear; Rat; Ventral striatum; Attention; Morphine; Learning; Memory ID STIMULI; BLOCKING; LESIONS; SHELL; MODEL; RATS AB The contribution of opioid receptors in the nucleus accumbens to contextual and auditory fear conditioning was examined. Impairment in contextual fear conditioning was found when training occurred under accumbal infusions of the opioid receptor agonist morphine in a dose-dependent and receptor specific fashion, only when shock onset coincided with auditory stimulus offset. Contextual fear conditioning was spared, however when the delivery of shock was not signalled by an auditory stimulus, the auditory stimulus was of low intensity (70 dB), or an interval (10 s or 30 s) was interpolated between auditory stimulus offset and shock onset. These results provide evidence that opioid receptors in the nucleus accumbens regulate competition between contextual and discrete auditory stimuli for association formation. (C) 2013 Elsevier B.V. All rights reserved. C1 [Iordanova, Mihaela D.; Haralambous, Tatiana; McNally, Gowan P.; Westbrook, R. Frederick] Univ New S Wales, Sch Psychol, Sydney, NSW 2031, Australia. [Iordanova, Mihaela D.] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Iordanova, Mihaela D.] NIDA, Intramural Res Program, Baltimore, MD 21224 USA. RP Iordanova, MD (reprint author), Univ Maryland, Sch Med, Dept Anat & Neurobiol, 20 Penn St,HSF 2, Baltimore, MD 21201 USA. EM iordanovam@gmail.com OI Iordanova, Mihaela/0000-0001-6232-448X FU Australian Research Council [DP110105136]; Australian Commonwealth Post Graduate Award [K99DA032649] FX This work was supported by a grant DP110105136 from the Australian Research Council to RFW, an Australian Commonwealth Post Graduate Award to TH, and grant K99DA032649 to MDI. NR 20 TC 1 Z9 1 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUN 23 PY 2013 VL 1517 BP 57 EP 67 DI 10.1016/j.brainres.2013.04.019 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 173ME UT WOS:000321082800006 PM 23603410 ER PT J AU Golubeva, YG Smith, RM Sternberg, LR AF Golubeva, Yelena G. Smith, Roberta M. Sternberg, Lawrence R. TI Optimizing Frozen Sample Preparation for Laser Microdissection: Assessment of CryoJane Tape-Transfer System (R) SO PLOS ONE LA English DT Article ID CAPTURE MICRODISSECTION; TISSUE SAMPLES; EXPRESSION; SECTIONS; CANCER; BONE; RNA; DNA AB Laser microdissection is an invaluable tool in medical research that facilitates collecting specific cell populations for molecular analysis. Diversity of research targets (e.g., cancerous and precancerous lesions in clinical and animal research, cell pellets, rodent embryos, etc.) and varied scientific objectives, however, present challenges toward establishing standard laser microdissection protocols. Sample preparation is crucial for quality RNA, DNA and protein retrieval, where it often determines the feasibility of a laser microdissection project. The majority of microdissection studies in clinical and animal model research are conducted on frozen tissues containing native nucleic acids, unmodified by fixation. However, the variable morphological quality of frozen sections from tissues containing fat, collagen or delicate cell structures can limit or prevent successful harvest of the desired cell population via laser dissection. The CryoJane Tape-Transfer System (R), a commercial device that improves cryosectioning outcomes on glass slides has been reported superior for slide preparation and isolation of high quality osteocyte RNA (frozen bone) during laser dissection. Considering the reported advantages of CryoJane for laser dissection on glass slides, we asked whether the system could also work with the plastic membrane slides used by UV laser based microdissection instruments, as these are better suited for collection of larger target areas. In an attempt to optimize laser microdissection slide preparation for tissues of different RNA stability and cryosectioning difficulty, we evaluated the CryoJane system for use with both glass (laser capture microdissection) and membrane (laser cutting microdissection) slides. We have established a sample preparation protocol for glass and membrane slides including manual coating of membrane slides with CryoJane solutions, cryosectioning, slide staining and dissection procedure, lysis and RNA extraction that facilitated efficient dissection and high quality RNA retrieval from CryoJane preparations. CryoJane technology therefore has the potential to facilitate standardization of laser microdissection slide preparation from frozen tissues. C1 [Golubeva, Yelena G.; Smith, Roberta M.; Sternberg, Lawrence R.] Sci Applicat Int Corp, Pathol Histotechnol Lab, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Golubeva, YG (reprint author), Sci Applicat Int Corp, Pathol Histotechnol Lab, Frederick Natl Lab Canc Res, Frederick, MD USA. EM golubevay@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX The 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. No additional external funding 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 20 TC 2 Z9 2 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 JUN 21 PY 2013 VL 8 IS 6 AR e66854 DI 10.1371/journal.pone.0066854 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 170JP UT WOS:000320846500109 PM 23805281 ER PT J AU Parra, GI Azure, J Fischer, R Bok, K Sandoval-Jaime, C Sosnovtsev, SV Sander, P Green, KY AF Parra, Gabriel I. Azure, JoLynn Fischer, Renate Bok, Karin Sandoval-Jaime, Carlos Sosnovtsev, Stanislav V. Sander, Peter Green, Kim Y. TI Identification of a Broadly Cross-Reactive Epitope in the Inner Shell of the Norovirus Capsid SO PLOS ONE LA English DT Article ID VIRUS-LIKE PARTICLES; BLOOD GROUP ANTIGENS; MONOCLONAL-ANTIBODIES; GENOGROUP-II; PROTEIN; GASTROENTERITIS; EXPRESSION; INFECTION; VACCINE; DETERMINANTS AB Noroviruses are major pathogens associated with acute gastroenteritis. They are diverse viruses, with at least six genogroups (GI-GVI) and multiple genotypes defined by differences in the major capsid protein, VP1. This diversity has challenged the development of broadly cross-reactive vaccines as well as efficient detection methods. Here, we report the characterization of a broadly cross-reactive monoclonal antibody (MAb) raised against the capsid protein of a GII. 3 norovirus strain. The MAb reacted with VLPs and denatured VP1 protein from GI, GII, GIV and GV noroviruses, and mapped to a linear epitope located in the inner shell domain. An alignment of all available VP1 sequences showed that the putative epitope (residues 52-56) is highly conserved across the genus Norovirus. This broadly cross-reactive MAb thus constitutes a valuable reagent for the diagnosis and study of these diverse viruses. C1 [Parra, Gabriel I.; Azure, JoLynn; Bok, Karin; Sandoval-Jaime, Carlos; Sosnovtsev, Stanislav V.; Green, Kim Y.] NIAID, Caliciviruses Sect, Infect Dis Lab, DHHS,NIH, Bethesda, MD 20892 USA. [Fischer, Renate; Sander, Peter] R Biopharm AG, Clin Diagnost, Darmstadt, Germany. RP Parra, GI (reprint author), NIAID, Caliciviruses Sect, Infect Dis Lab, DHHS,NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM parrag@niaid.nih.gov; kgreen@niaid.nih.gov OI Parra, Gabriel/0000-0002-1102-4740 FU NIH, NIAID FX This research was partially supported by the Intramural Research Program of the NIH, NIAID. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study. NR 43 TC 14 Z9 14 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 JUN 21 PY 2013 VL 8 IS 6 AR e67592 DI 10.1371/journal.pone.0067592 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 170JP UT WOS:000320846500147 PM 23805319 ER PT J AU Yin, J Wang, C Mody, A Bao, L Hung, SH Svoronos, SA Tseng, Y AF Yin, Jun Wang, Chengyuan Mody, Aaron Bao, Lin Hung, Shen-Hsiu Svoronos, Spyros A. Tseng, Yiider TI The Effect of Z-Ligustilide on the Mobility of Human Glioblastoma T98G Cells SO PLOS ONE LA English DT Article ID PC12 CELLS; IN-VITRO; RHO AB Z-ligustilide (LIG), an essential oil extract from Radix Angelica sinensis, has broad pharmaceutical applications in treating cardio-vascular diseases and ischemic brain injury. Recently, LIG has been connected to Glioblastoma multiforme (GBM) because of its structural similarity to 3-n-alkyphthalide (NBP), which is specifically cytotoxic to GBM cells. Hence, we investigated LIG's effect on GBM T98G cells. The study shows that LIG can significantly reduce T98G cells' migration in a dose-dependent manner. Furthermore, the attenuation of cellular mobility can be linked to the activity of the Rho GTPases (RhoA, Rac1 and Cdc42), the three critical molecular switches governing cytoskeleton remodeling; thus, regulating cell migration. LIG significantly reduces the expression of RhoA and affects in a milder manner the expression of Cdc42 and Rac1. C1 [Yin, Jun; Mody, Aaron; Bao, Lin; Hung, Shen-Hsiu; Svoronos, Spyros A.; Tseng, Yiider] Univ Florida, Dept Chem Engn, Gainesville, FL 32611 USA. [Wang, Chengyuan] Chongqing Technol & Business Univ, Res Ctr Med Chem & Chem Biol, Chongqing, Peoples R China. [Yin, Jun; Hung, Shen-Hsiu; Tseng, Yiider] NCI, Phys Sci Oncol Ctr, Gainesville, FL USA. [Tseng, Yiider] Inst Cell Engn & Regenerat Med, Gainesville, FL USA. RP Tseng, Y (reprint author), Univ Florida, Dept Chem Engn, Gainesville, FL 32611 USA. EM ytseng@che.ufl.edu FU NIH/NCI [U54CA143868] FX This study was supported in part by grants from NIH/NCI U54CA143868. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study. NR 17 TC 7 Z9 8 U1 1 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 JUN 21 PY 2013 VL 8 IS 6 AR e66598 DI 10.1371/journal.pone.0066598 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 170JP UT WOS:000320846500073 PM 23805245 ER PT J AU Johnson, TP Tyagi, R Patel, K Schiess, N Calabresi, PA Nath, A AF Johnson, Tory P. Tyagi, Richa Patel, Karan Schiess, Nicoline Calabresi, Peter A. Nath, Avindra TI Impaired toll-like receptor 8 signaling in multiple sclerosis SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE Toll-like receptor; Multiple sclerosis; Gene expression; Interleukin 12; TLR8 ID T-CELLS; ACTIVATION; DISEASE; ALPHA AB Background: The etiology and immunopathology of multiple sclerosis (MS) is not well understood. It is recognized that although autoreactive T cells are the main early mediators of disease, other cell types, including cells of the innate immune system contribute to MS pathogenesis. The objective of this study was to determine if Toll-like receptor (TLR) signaling is functionally altered in patients with MS. Findings: Peripheral blood mononuclear cells from healthy donors and patients with relapsing remitting MS were stimulated with specific agonists of TLRs 3, 7, 8 and 9. Using quantitative polymerase chain reaction transcript levels of tumor necrosis factor-a, interferon-a and interleukin (IL)-12 beta were quantified from patients with MS and healthy donors. TLR8-induced production of IL12B transcripts and protein was functionally impaired in patients with MS as compared to healthy controls (P < 0.05 and P < 0.005, respectively). Patients with MS also expressed lower baseline levels of TLR8 as compared to healthy controls (P < 0.05). Conclusions: TLR8 expression and signaling is impaired in peripheral blood mononuclear cells from patients with MS. This finding suggests that loss of TLR8 signaling may be contributing to autoimmune processes in MS. C1 [Johnson, Tory P.; Tyagi, Richa; Patel, Karan; Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. [Schiess, Nicoline; Calabresi, Peter A.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. RP Nath, A (reprint author), NINDS, Sect Infect Nervous Syst, NIH, Bldg 10,7C-103,10 Ctr Dr, Bethesda, MD 20892 USA. EM avindra.nath@nih.gov FU National Multiple Sclerosis Society [TR 3760-A-3]; Stegg family; NINDS FX The authors would like to acknowledge Dr. Steve Jacobson for providing the clinical samples. This work was supported by the National Multiple Sclerosis Society (grant number TR 3760-A-3); a generous grant from the Stegg family; and NINDS intramural funds. NR 18 TC 7 Z9 8 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD JUN 21 PY 2013 VL 10 AR 74 DI 10.1186/1742-2094-10-74 PG 4 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 171IS UT WOS:000320920000001 PM 23787171 ER PT J AU Xu, Y Liu, YF Lee, JG Ye, YH AF Xu, Yue Liu, Yanfen Lee, Jin-Gu Ye, Yihong TI A Ubiquitin-like Domain Recruits an Oligomeric Chaperone to a Retrotranslocation Complex in Endoplasmic Reticulum-associated Degradation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID QUALITY-CONTROL; MEMBRANE-PROTEINS; LIGASE; HRD1P; GP78; BAT3; DIMETHYLATION; POLYPEPTIDES; ELIMINATION; INTEGRATION AB The Bag6-Ubl4A-Trc35 complex is a multifunctional chaperone that regulates various cellular processes. The diverse functions of Bag6 are supported by its ubiquitous localization to the cytoplasm, the nucleus, and membranes of the endoplasmic reticulum (ER) in cells. In ER-associated degradation (ERAD) pathways, Bag6 can interact with the membrane-associated ubiquitin ligase gp78 via its ubiquitin-like (UBL) domain, but the relative low affinity of this interaction does not reconcile with the fact that a fraction of Bag6 is tightly bound to the membranes. Here, we demonstrate that the UBL domain of Bag6 is required for interaction with the ER membranes. We find that in addition to gp78, the Bag6 UBL domain also binds a UBL-binding motif in UbxD8, an essential component of the gp78 ubiquitinating machinery. Importantly, Bag6 contains a proline-rich (PR) domain termed PDP (Proline rich-DUF3587-Proline rich) that forms homo-oligomer, allowing the UBL domain to form multivalent interactions with gp78 and UbxD8, which are essential for recruitment of Bag6 to the ER membrane. Furthermore, the PR domain comprises largely intrinsically disordered segments, which are sufficient for interaction with an unfolded substrate. We propose that simultaneous association with multiple ERAD factors helps to anchor a disordered chaperone oligomer to the site of retrotranslocation to prevent protein aggregation in ERAD. C1 [Xu, Yue; Liu, Yanfen; Lee, Jin-Gu; Ye, Yihong] NIH, NIDDK, Mol Biol Lab, Bethesda, MD 20892 USA. RP Ye, YH (reprint author), NIH, NIDDK, Mol Biol Lab, 5 Ctr Dr, Bethesda, MD 20892 USA. EM yihongy@mail.nih.gov RI Xu, Yue/F-8188-2015 FU NIDDK at the National Institutes of Health FX This work was supported by the Intramural Research Program of the NIDDK at the National Institutes of Health. NR 35 TC 24 Z9 24 U1 0 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 JUN 21 PY 2013 VL 288 IS 25 BP 18068 EP 18076 DI 10.1074/jbc.M112.449199 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 168QZ UT WOS:000320721900013 PM 23665563 ER PT J AU Chertova, E Bergamaschi, C Chertov, O Sowder, R Bear, J Roser, JD Beach, RK Lifson, JD Felber, BK Pavlakis, GN AF Chertova, Elena Bergamaschi, Cristina Chertov, Oleg Sowder, Raymond Bear, Jenifer Roser, James D. Beach, Rachel K. Lifson, Jeffrey D. Felber, Barbara K. Pavlakis, George N. TI Characterization and Favorable in Vivo Properties of Heterodimeric Soluble IL-15 center dot IL-15R alpha Cytokine Compared to IL-15 Monomer SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CD8(+) T-CELLS; RECEPTOR-ALPHA-CHAIN; NATURAL-KILLER-CELLS; SIGNAL PEPTIDE; INTERLEUKIN (IL)-15; ESTABLISHED TUMORS; TRANS PRESENTATION; NONHUMAN-PRIMATES; RHESUS MACAQUES; CD4(+) CELLS AB Interleukin-15 (IL-15), a 114-amino acid cytokine related to IL-2, regulates immune homeostasis and the fate of many lymphocyte subsets. We reported that, in the blood of mice and humans, IL-15 is present as a heterodimer associated with soluble IL-15 receptor alpha (sIL-15R alpha). Here, we show efficient production of this noncovalently linked but stable heterodimer in clonal human HEK293 cells and release of the processed IL-15 center dot sIL-15R alpha heterodimer in the medium. Purification of the IL-15 and sIL-15R alpha polypeptides allowed identification of the proteolytic cleavage site of IL-15R alpha and characterization of multiple glycosylation sites. Administration of the IL-15 center dot sIL-15R alpha heterodimer reconstituted from purified subunits resulted in sustained plasma IL-15 levels and in robust expansion of NK and T cells in mice, demonstrating pharmacokinetics and in vivo bioactivity superior to single chain IL-15. These identified properties of heterodimeric IL-15 provide a strong rationale for the evaluation of this molecule for clinical applications. C1 [Chertova, Elena; Sowder, Raymond; Roser, James D.; Lifson, Jeffrey D.] Frederick Natl Lab, AIDS & Canc Virus Program, Ft Detrick, MD 21702 USA. [Chertov, Oleg] Frederick Natl Lab, Prot Chem Lab, Adv Technol Program, SAIC Frederick Inc, Ft Detrick, MD 21702 USA. [Bergamaschi, Cristina; Beach, Rachel K.; Pavlakis, George N.] NCI, Ctr Canc Res, Vaccine Branch, Human Retrovirus Sect, Frederick, MD 21702 USA. [Bear, Jenifer; Beach, Rachel K.; Felber, Barbara K.] NCI, Ctr Canc Res, Vaccine Branch, Human Retrovirus Pathogenesis Sect, Frederick, MD 21702 USA. RP Pavlakis, GN (reprint author), NCI, Ctr Canc Res, Vaccine Branch, Human Retrovirus Sect, Frederick, MD 21702 USA. EM pavlakig@mail.nih.gov FU Intramural Research Program, National Cancer Institute, National Institutes of Health (NCI/National Institutes of Health); National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported by the Intramural Research Program, National Cancer Institute, National Institutes of Health (NCI/National Institutes of Health) and federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. NR 60 TC 22 Z9 22 U1 1 U2 12 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 JUN 21 PY 2013 VL 288 IS 25 BP 18093 EP 18103 DI 10.1074/jbc.M113.461756 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 168QZ UT WOS:000320721900015 PM 23649624 ER PT J AU Zhang, SF Schones, DE Malicet, C Rochman, M Zhou, M Foisner, R Bustin, M AF Zhang, Shaofei Schones, Dustin E. Malicet, Cedric Rochman, Mark Zhou, Ming Foisner, Roland Bustin, Michael TI High Mobility Group Protein N5 (HMGN5) and Lamina-associated Polypeptide 2 alpha (LAP2 alpha) Interact and Reciprocally Affect Their Genome-wide Chromatin Organization SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CHROMOSOMAL-PROTEINS; LINKER HISTONE; RNA-SEQ; DIFFERENTIATION; H1; NUCLEOSOMES; COMPLEXES AB The interactions of nuclear lamins with the chromatin fiber play an important role in regulating nuclear architecture and chromatin function; however, the full spectrum of these interactions is not known. We report that the N-terminal domain of the nucleosome-binding protein HMGN5 interacts with the C-terminal domain of the lamin-binding protein LAP2 alpha and that these proteins reciprocally alter their interaction with chromatin. Chromatin immunoprecipitation analysis of cells lacking either HMGN5 or LAP2 alpha reveals that loss of either protein affects the genome-wide distribution of the remaining partner. Our study identifies a new functional link between chromatin-binding and lamin-binding proteins. C1 [Zhang, Shaofei; Malicet, Cedric; Rochman, Mark; Bustin, Michael] NCI, NIH, Prot Sect, Lab Metab,Ctr Canc Res, Bethesda, MD 20892 USA. [Schones, Dustin E.] Beckman Res Inst City Hope, Dept Canc Biol, Duarte, CA 91010 USA. [Zhou, Ming] NCI Frederick, SAIC Frederick Inc, Adv Technol Program, Lab Prote & Analyt Technol, Frederick, MD 21702 USA. [Foisner, Roland] Med Univ Vienna, Max Perutz Labs, A-1030 Vienna, Austria. RP Bustin, M (reprint author), NCI, NIH, Prot Sect, Lab Metab,Ctr Canc Res, Bethesda, MD 20892 USA. EM Bustin@helix.nih.gov RI Bustin, Michael/G-6155-2015 FU Center for Cancer Research, Intramural Program of the NCI, National Institutes of Health; United States-Israel Binational Science Foundation (BSF) [2009236]; NCI [K22 HL101950]; Austrian Research Fund (FWF) [P22043-B12] FX This work was supported, in whole or in part, by the Center for Cancer Research, Intramural Program of the NCI, National Institutes of Health (to M. B.). This work was also supported by United States-Israel Binational Science Foundation (BSF) Grants 2009236 (to M. B.) and NCI Grant K22 HL101950 (to D. E. S.) and by Grant P22043-B12 of the Austrian Research Fund (FWF) (to R. F.). NR 27 TC 10 Z9 10 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 21 PY 2013 VL 288 IS 25 BP 18104 EP 18109 DI 10.1074/jbc.C113.469544 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 168QZ UT WOS:000320721900016 PM 23673662 ER PT J AU Allende, ML Sipe, LM Tuymetova, G Wilson-Henjum, KL Chen, WP Proia, RL AF Allende, Maria L. Sipe, Laura M. Tuymetova, Galina Wilson-Henjum, Kelsey L. Chen, Weiping Proia, Richard L. TI Sphingosine-1-phosphate Phosphatase 1 Regulates Keratinocyte Differentiation and Epidermal Homeostasis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PERMEABILITY BARRIER; CELL-DEATH; IN-VITRO; SKIN; PHOSPHOHYDROLASE; SPHINGOLIPIDS; CERAMIDE; METABOLISM; EXPRESSION; RECEPTOR AB Sphingosine 1-phosphate (S1P) is a bioactive lipid whose levels are tightly regulated by its synthesis and degradation. Intracellularly, S1P is dephosphorylated by the actions of two S1P-specific phosphatases, sphingosine-1-phosphate phosphatases 1 and 2. To identify the physiological functions of S1P phosphatase 1, we have studied mice with its gene, Sgpp1, deleted. Sgpp1(-/-) mice appeared normal at birth, but during the 1st week of life they exhibited stunted growth and suffered desquamation, with most dying before weaning. Both Sgpp1(-/-) pups and surviving adults exhibited multiple epidermal abnormalities. Interestingly, the epidermal permeability barrier developed normally during embryogenesis in Sgpp1(-/-) mice. Keratinocytes isolated from the skin of Sgpp1(-/-) pups had increased intracellular S1P levels and displayed a gene expression profile that indicated overexpression of genes associated with keratinocyte differentiation. The results reveal S1P metabolism as a regulator of keratinocyte differentiation and epidermal homeostasis. C1 [Allende, Maria L.; Sipe, Laura M.; Tuymetova, Galina; Wilson-Henjum, Kelsey L.; Chen, Weiping; Proia, Richard L.] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Proia, RL (reprint author), NIDDK, Genet Dev & Dis Branch, Bldg 10,Rm 9D-06,10 Ctr Dr MSC 1821, Bethesda, MD 20892 USA. EM rp36y@nih.gov FU National Institutes of Health from NIDDK [P30 CA138313, P20 RR017677] FX This work was supported, in whole or in part, by National Institutes of Health grants from NIDDK, Grant P30 CA138313 (to Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina), and Grant P20 RR017677 (to Lipidomics Core in the South Carolina Lipidomics and Pathobiology COBRE). NR 63 TC 10 Z9 10 U1 1 U2 7 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 JUN 21 PY 2013 VL 288 IS 25 BP 18381 EP 18391 DI 10.1074/jbc.M113.478420 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 168QZ UT WOS:000320721900041 PM 23637227 ER PT J AU Jorgensen, NW Sibley, CT McClelland, RL AF Jorgensen, Neal W. Sibley, Christopher T. McClelland, Robyn L. TI Using imputed pre-treatment cholesterol in a propensity score model to reduce confounding by indication: results from the multi-ethnic study of atherosclerosis SO BMC MEDICAL RESEARCH METHODOLOGY LA English DT Article DE Multiple imputation; Confounding by indication; Propensity score; Inverse probability of treatment weights; Statins ID RANDOMIZED CONTROLLED-TRIALS; MULTIPLE IMPUTATION; MISSING-DATA; METAANALYSIS; ASSOCIATIONS; SURVIVAL; THERAPY; WEIGHTS; STATINS; RISK AB Background: Studying the effects of medications on endpoints in an observational setting is an important yet challenging problem due to confounding by indication. The purpose of this study is to describe methodology for estimating such effects while including prevalent medication users. These techniques are illustrated in models relating statin use to cardiovascular disease (CVD) in a large multi-ethnic cohort study. Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) includes 6814 participants aged 45-84 years free of CVD. Confounding by indication was mitigated using a two step approach: First, the untreated values of cholesterol were treated as missing data and the values imputed as a function of the observed treated value, dose and type of medication, and participant characteristics. Second, we construct a propensity-score modeling the probability of medication initiation as a function of measured covariates and estimated pre-treatment cholesterol value. The effect of statins on CVD endpoints were assessed using weighted Cox proportional hazard models using inverse probability weights based on the propensity score. Results: Based on a meta-analysis of randomized controlled trials (RCT) statins are associated with a reduced risk of CVD (relative risk ratio = 0.73, 95% CI: 0.70, 0.77). In an unweighted Cox model adjusting for traditional risk factors we observed little association of statins with CVD (hazard ratio (HR) = 0.97, 95% CI: 0.60, 1.59). Using weights based on a propensity model for statins that did not include the estimated pre-treatment cholesterol we observed a slight protective association (HR = 0.92, 95% CI: 0.54-1.57). Results were similar using a new-user design where prevalent users of statins are excluded (HR = 0.91, 95% CI: 0.45-1.80). Using weights based on a propensity model with estimated pre-treatment cholesterol the effects of statins (HR = 0.74, 95% CI: 0.38, 1.42) were consistent with the RCT literature. Conclusions: The imputation of pre-treated cholesterol levels for participants on medication at baseline in conjunction with a propensity score yielded estimates that were consistent with the RCT literature. These techniques could be useful in any example where inclusion of participants exposed at baseline in the analysis is desirable, and reasonable estimates of pre-exposure biomarker values can be estimated. C1 [Jorgensen, Neal W.; McClelland, Robyn L.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Sibley, Christopher T.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Jorgensen, NW (reprint author), Univ Washington, Dept Biostat, Seattle, WA 98195 USA. EM njorgens@u.washington.edu FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95169]; [R01 HL 103729-01A1] FX Analysis for this project was supported by R01 HL 103729-01A1. The MESA study was supported by contracts N01-HC-95159 through N01-HC-95169 from the National Heart, Lung, and Blood Institute. NR 25 TC 0 Z9 0 U1 1 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2288 J9 BMC MED RES METHODOL JI BMC Med. Res. Methodol. PD JUN 21 PY 2013 VL 13 AR 81 DI 10.1186/1471-2288-13-81 PG 10 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 171LU UT WOS:000320931200001 PM 23800038 ER PT J AU Kellman, P Arai, AE Xue, H AF Kellman, Peter Arai, Andrew E. Xue, Hui TI T1 and extracellular volume mapping in the heart: estimation of error maps and the influence of noise on precision SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE T1 Map; Error; Precision; MOLLI; Extracellular; Diffuse Fibrosis; Cardiovascular Magnetic Resonance ID DIFFUSE MYOCARDIAL FIBROSIS; INVERSION-RECOVERY MOLLI; MAGNETIC-RESONANCE; QUANTIFICATION; INFARCTION; VALIDATION; REGRESSION AB Background: Quantitative measurements in the myocardium may be used to detect both focal and diffuse disease processes that result in an elevation of T1 and/or extracellular volume (ECV) fraction. Detection of abnormal myocardial tissue by these methods is affected by both the accuracy and precision. The sensitivity for detecting abnormal elevation of T1 and ECV is limited by the precision of T1 estimates which is a function of the number and timing of measurements along the T1-inversion recovery curve, the signal-to-noise ratio (SNR), the tissue T1, and the method of fitting. Methods: The standard deviation (SD) of T1 and ECV estimates are formulated and SD maps are calculated on a pixel-wise basis using the Modified Look-Locker Inversion recovery (MOLLI) method. SD estimates are validated by numerical simulation using Monte-Carlo analysis and with phantoms using repeated trials. SD estimates are provided for pre- and post-contrast optimized protocols for a range of T1s and SNRs. In-vivo examples are provide for normal, myocarditis, and HCM in human subjects. The formulation of SD maps was extended to R1 and ECV. Results: The measured myocardial SNR ranged from 23 to 43 across the heart using the specific T1-mapping protocol in this study. In this range of SNRs, the estimated SD for T1 was approximately 20-45 ms for pre-contrast myocardial T1 around 1000 ms, and was approximately 10-20 ms for post contrast T1 around 400 ms. The proposed estimate of SD was an unbiased estimate of the standard deviation of T1 validated by numerical simulation and had > 99% correlation with phantom measurements. The measured SD maps exhibited variation across the heart due to drop off in surface coil sensitivity as expected for the variation in SNR. Focal elevation in T1 and ECV was shown to have statistical significance on a pixel-wise basis for in-vivo examples. Conclusions: Pixel-wise estimates of T1 mapping errors have been formulated and validated, and the formulation has been extended to ECV. The ability to quantify the measurement error has potential to determine the statistical significance of subtle abnormalities that arise due to diffuse disease processes involving fibrosis and/or edema and is useful both as a confidence metric for overall quality, and in optimization and comparison of imaging protocols. C1 [Kellman, Peter; Arai, Andrew E.; Xue, Hui] Natl Heart Lung & Blood Inst, Natl Inst Hlth, DHHS, Bethesda, MD 20892 USA. RP Kellman, P (reprint author), Natl Heart Lung & Blood Inst, Natl Inst Hlth, DHHS, 10 Ctr Dr MSC 1061, Bethesda, MD 20892 USA. EM kellman@nih.gov FU National Heart, Lung and Blood Institute, National Institutes of Health by the Division of Intramural Research, NHLBI, NIH, DHHS [HL004607-14CPB] FX Supported by the National Heart, Lung and Blood Institute, National Institutes of Health by the Division of Intramural Research, NHLBI, NIH, DHHS (HL004607-14CPB). NR 29 TC 37 Z9 37 U1 0 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD JUN 21 PY 2013 VL 15 AR 56 DI 10.1186/1532-429X-15-56 PG 12 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 177KP UT WOS:000321374200001 PM 23800276 ER PT J AU Rietveld, CA Medland, SE Derringer, J Yang, J Esko, T Martin, NW Westra, HJ Shakhbazov, K Abdellaoui, A Agrawal, A Albrecht, E Alizadeh, BZ Amin, N Bamard, J Baumeister, SE Benke, KS Bielak, LF Boatman, JA Boyle, PA Davies, G De Leeuw, C Eklund, N Evans, DS Ferhmann, R Fischer, K Gieger, C Gjessing, HK Hagg, S Harris, JR Hayward, C Holzapfel, C Ibrahim-Verbaas, CA Ingelsson, E Jacobsson, B Joshi, PK Jugessur, A Kaakinen, M Kanoni, S Karjalainen, J Kolcic, I Kristiansson, K Kutalik, Z Lahti, J Lee, SH Lin, P Lind, PA Liu, YM Lohman, K Loitfelder, M McMahon, G Vidal, PM Meirelles, O Milani, L Myhre, R Nuotio, ML Oldmeadow, CJ Petrovic, KE Peyrot, WJ Polasek, O Quaye, L Reinmaa, E Rice, JP Rizzi, TS Schmidt, H Schmidt, R Smith, AV Smith, JA Tanaka, T Terracciano, A van der Loos, MJHM Vitart, V Volzke, H Wellmann, J Yu, L Zhao, W Allik, J Attia, JR Bandinelli, S Bastardot, F Beauchamp, J Bennett, DA Berger, K Bierut, LJ Boomsma, DI Bultmann, U Campbell, H Chabris, CF Cherkas, L Chung, MK Cucca, F de Andrade, M De Jager, PL De Neve, JE Deary, IJ Dedoussis, GV Deloukas, P Dimitriou, M Eiriksdottir, G Elderson, MF Eriksson, JG Evans, DM Faul, JD Ferrucci, L Garcia, ME Gronberg, H Guonason, V Hall, P Harris, JM Harris, TB Hastie, ND Heath, AC Hernandez, DG Hoffmann, W Hofman, A Holle, R Holliday, EG Hottenga, JJ Iacono, WG Illig, T Jarvelin, MR Kahonen, M Kaprio, J Kirkpatrick, RM Kowgier, M Latvala, A Launer, LJ Lawlor, DA Lehtimaki, T Li, JM Lichtenstein, P Lichtner, P Liewald, DC Madden, PA Magnusson, PKE Makinen, TE Masala, M McGue, M Metspalu, A Mielck, A Miller, MB Montgomery, GW Mukherjee, S Nyholt, DR Oostra, BA Palmer, LJ Palotie, A Penninx, BWJH Perola, M Peyser, PA Preisig, M Raikkonen, K Raitakari, OT Realo, A Ring, SM Ripatti, S Rivadeneira, F Rudan, I Rustichini, A Salomaa, V Sarin, AP Schlessinger, D Scott, RJ Snieder, H St Pourcain, B Starr, JM Sul, JH Surakka, I Svento, R Teumer, A Tiemeier, H van Rooij, FJA Van Wagoner, DR Vartiainen, E Viikari, J Vollenweider, P Vonk, JM Waeber, G Weir, DR Wichmann, HE Widen, E Willemsen, G Wilson, JF Wright, AF Conley, D Davey-Smith, G Franke, L Groenen, PJF Hofman, A Johannesson, M Kardia, SLR Krueger, RF Laibson, D Martin, NG Meyer, MN Posthuma, D Thurik, AR Timpson, NJ Uitterlinden, AG van Duijn, CM Visscher, PM Benjamin, DJ Cesarini, D Koellinger, PD AF Rietveld, Cornelius A. Medland, Sarah E. Derringer, Jaime Yang, Jian Esko, Tonu Martin, Nicolas W. Westra, Harm-Jan Shakhbazov, Konstantin Abdellaoui, Abdel Agrawal, Arpana Albrecht, Eva Alizadeh, Behrooz Z. Amin, Najaf Bamard, John Baumeister, Sebastian E. Benke, Kelly S. Bielak, Lawrence F. Boatman, Jeffrey A. Boyle, Patricia A. Davies, Gail De Leeuw, Christiaan Eklund, Niina Evans, Daniel S. Ferhmann, Rudolf Fischer, Krista Gieger, Christian Gjessing, Hakon K. Haegg, Sara Harris, Jennifer R. Hayward, Caroline Holzapfel, Christina Ibrahim-Verbaas, Carla A. Ingelsson, Erik Jacobsson, Bo Joshi, Peter K. Jugessur, Astanand Kaakinen, Marika Kanoni, Stavroula Karjalainen, Juha Kolcic, Ivana Kristiansson, Kati Kutalik, Zoltan Lahti, Jari Lee, Sang H. Lin, Peng Lind, Penelope A. Liu, Yongmei Lohman, Kurt Loitfelder, Marisa McMahon, George Vidal, Pedro Marques Meirelles, Osorio Milani, Lili Myhre, Ronny Nuotio, Marja-Liisa Oldmeadow, Christopher J. Petrovic, Katja E. Peyrot, Wouter J. Polasek, Ozren Quaye, Lydia Reinmaa, Eva Rice, John P. Rizzi, Thais S. Schmidt, Helena Schmidt, Reinhold Smith, Albert V. Smith, Jennifer A. Tanaka, Toshiko Terracciano, Antonio van der Loos, Matthijs J. H. M. Vitart, Veronique Voelzke, Henry Wellmann, Juergen Yu, Lei Zhao, Wei Allik, Jueri Attia, John R. Bandinelli, Stefania Bastardot, Franois Beauchamp, Jonathan Bennett, David A. Berger, Klaus Bierut, Laura J. Boomsma, Dorret I. Bueltmann, Ute Campbell, Harry Chabris, Christopher F. Cherkas, Lynn Chung, Mina K. Cucca, Francesco de Andrade, Mariza De Jager, Philip L. De Neve, Jan-Emmanuel Deary, Ian J. Dedoussis, George V. Deloukas, Panos Dimitriou, Maria Eiriksdottir, Guony Elderson, Martin F. Eriksson, Johan G. Evans, David M. Faul, Jessica D. Ferrucci, Luigi Garcia, Melissa E. Groenberg, Henrik Guonason, Vilmundur Hall, Per Harris, Juliette M. Harris, Tamara B. Hastie, Nicholas D. Heath, Andrew C. Hernandez, Dena G. Hoffmann, Wolfgang Hofman, Adriaan Holle, Rolf Holliday, Elizabeth G. Hottenga, Jouke-Jan Iacono, William G. Illig, Thomas Jaervelin, Marjo-Riitta Kaehoenen, Mika Kaprio, Jaakko Kirkpatrick, Robert M. Kowgier, Matthew Latvala, Antti Launer, Lenore J. Lawlor, Debbie A. Lehtimaeki, Terho Li, Jingmei Lichtenstein, Paul Lichtner, Peter Liewald, David C. Madden, Pamela A. Magnusson, Patrik K. E. Maekinen, Tomi E. Masala, Marco McGue, Matt Metspalu, Andres Mielck, Andreas Miller, Michael B. Montgomery, Grant W. Mukherjee, Sutapa Nyholt, Dale R. Oostra, Ben A. Palmer, Lyle J. Palotie, Aarno Penninx, Brenda W. J. H. Perola, Markus Peyser, Patricia A. Preisig, Martin Raeikkoenen, Katri Raitakari, Olli T. Realo, Anu Ring, Susan M. Ripatti, Samuli Rivadeneira, Fernando Rudan, Igor Rustichini, Aldo Salomaa, Veikko Sarin, Antti-Pekka Schlessinger, David Scott, Rodney J. Snieder, Harold St Pourcain, Beate Starr, John M. Sul, Jae Hoon Surakka, Ida Svento, Rauli Teumer, Alexander Tiemeier, Henning van Rooij, Frank J. A. Van Wagoner, David R. Vartiainen, Erkki Viikari, Jorma Vollenweider, Peter Vonk, Judith M. Waeber, Gerard Weir, David R. Wichmann, H. -Erich Widen, Elisabeth Willemsen, Gonneke Wilson, James F. Wright, Alan F. Conley, Dalton Davey-Smith, George Franke, Lude Groenen, Patrick J. F. Hofman, Albert Johannesson, Magnus Kardia, Sharon L. R. Krueger, Robert F. Laibson, David Martin, Nicholas G. Meyer, Michelle N. Posthuma, Danielle Thurik, A. Roy Timpson, Nicholas J. Uitterlinden, Andre G. van Duijn, Cornelia M. Visscher, Peter M. Benjamin, Daniel J. Cesarini, David Koellinger, Philipp D. CA LifeLines Cohort Study TI GWAS of 126,559 Individuals Identifies Genetic Variants Associated with Educational Attainment SO SCIENCE LA English DT Article ID ENVIRONMENT; PREFERENCES; LOCI AB A genome-wide association study (GWAS) of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent single-nucleotide polymorphisms (SNPs) are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (coefficient of determination R-2 approximate to 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for approximate to 2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics. C1 [Rietveld, Cornelius A.; van der Loos, Matthijs J. H. M.; Thurik, A. Roy; Koellinger, Philipp D.] Erasmus Univ, Erasmus Sch Econ, Dept Appl Econ, NL-3000 DR Rotterdam, Netherlands. [Rietveld, Cornelius A.; van der Loos, Matthijs J. H. M.; Rivadeneira, Fernando; Tiemeier, Henning; van Rooij, Frank J. A.; Hofman, Albert; Uitterlinden, Andre G.; Koellinger, Philipp D.] Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. [Medland, Sarah E.; Martin, Nicolas W.; Lee, Sang H.; Lind, Penelope A.; Montgomery, Grant W.; Nyholt, Dale R.; Martin, Nicholas G.; Visscher, Peter M.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Derringer, Jaime] Univ Colorado, Inst Behav Genet, Boulder, CO 80309 USA. [Yang, Jian; Shakhbazov, Konstantin; Visscher, Peter M.] Univ Queensland, Princess Alexandra Hosp, Diamantina Inst, Brisbane, Qld 4102, Australia. [Esko, Tonu; Fischer, Krista; Milani, Lili; Reinmaa, Eva; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia. [Martin, Nicolas W.] Univ Queensland, Sch Psychol, Brisbane, Qld 4072, Australia. [Westra, Harm-Jan; Ferhmann, Rudolf; Karjalainen, Juha; Franke, Lude] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9713 GZ Groningen, Netherlands. [Shakhbazov, Konstantin; Visscher, Peter M.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia. [Abdellaoui, Abdel; Boomsma, Dorret I.; Hottenga, Jouke-Jan; Willemsen, Gonneke] Vrije Univ Amsterdam, Dept Biol Psychol, NL-1081 BT Amsterdam, Netherlands. [Agrawal, Arpana; Lin, Peng; Rice, John P.; Bierut, Laura J.; Madden, Pamela A.] Washington Univ, Dept Psychiat, Sch Med, St Louis, MO 63110 USA. [Albrecht, Eva; Gieger, Christian] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, D-85764 Neuherberg, Germany. [Alizadeh, Behrooz Z.; Snieder, Harold; Vonk, Judith M.] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-9700 RB Groningen, Netherlands. [Amin, Najaf; Ibrahim-Verbaas, Carla A.; Oostra, Ben A.; van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, NL-3000 CA Rotterdam, Netherlands. [Bamard, John; Chung, Mina K.; Van Wagoner, David R.] Cleveland Clin, Heart & Vasc & Lerner Res Inst, Cleveland, OH 44195 USA. [Baumeister, Sebastian E.; Voelzke, Henry; Hoffmann, Wolfgang] Univ Med Greifswald, Inst Community Med, D-17489 Greifswald, Germany. [Benke, Kelly S.] Univ Toronto, Samuel Lunenfeld Res Inst, Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. [Bielak, Lawrence F.; Smith, Jennifer A.; Zhao, Wei; Peyser, Patricia A.; Kardia, Sharon L. R.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Boatman, Jeffrey A.] Univ Minnesota, Div Biostat, Minneapolis, MN 55455 USA. [Boyle, Patricia A.; Yu, Lei; Bennett, David A.] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. [Davies, Gail; Deary, Ian J.; Liewald, David C.; Starr, John M.] Univ Edinburgh, Ctr Cognit Aging & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland. [De Leeuw, Christiaan; Rizzi, Thais S.; Posthuma, Danielle] Vrije Univ Amsterdam, Dept Funct Genom, NL-1081 HV Amsterdam, Netherlands. [De Leeuw, Christiaan; Rizzi, Thais S.; Posthuma, Danielle] Vrije Univ Amsterdam Med Ctr, NL-1081 HV Amsterdam, Netherlands. Radboud Univ Nijmegen, Machine Learning Grp, Inst Comp & Informat Sci, Fac Sci, NL-6500 GL Nijmegen, Netherlands. [Eklund, Niina; Kristiansson, Kati; Nuotio, Marja-Liisa; Kaprio, Jaakko; Palotie, Aarno; Perola, Markus; Ripatti, Samuli; Sarin, Antti-Pekka; Surakka, Ida; Widen, Elisabeth] Univ Helsinki, Inst Mol Med Finland, FIN-00014 Helsinki, Finland. [Eklund, Niina; Kristiansson, Kati; Nuotio, Marja-Liisa; Perola, Markus; Ripatti, Samuli; Surakka, Ida] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Publ Hlth Genom Unit, Helsinki 00014, Finland. [Evans, Daniel S.; Perola, Markus] Calif Pacific Med Ctr, Res Inst, San Francisco, CA 94107 USA. [Gjessing, Hakon K.; Harris, Jennifer R.; Jacobsson, Bo; Jugessur, Astanand; Myhre, Ronny] Norwegian Inst Publ Hlth, Div Epidemiol, Dept Genes & Environm, N-0403 Oslo, Norway. [Haegg, Sara; Ingelsson, Erik] Uppsala Univ, Dept Med Sci, S-75185 Uppsala, Sweden. [Haegg, Sara; Ingelsson, Erik] Uppsala Univ, Sci Life Lab, S-75123 Uppsala, Sweden. [Haegg, Sara; Ingelsson, Erik; Groenberg, Henrik; Hall, Per; Lichtenstein, Paul; Magnusson, Patrik K. E.] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Hayward, Caroline; Vitart, Veronique; Hastie, Nicholas D.; Wright, Alan F.] Univ Edinburgh, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland. [Holzapfel, Christina] Tech Univ Munich, Univ Hosp, Klinikum Rechts Isar, Else Kroener Fresenius Ctr Nutr Med, D-81675 Munich, Germany. [Holzapfel, Christina; Illig, Thomas] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany. [Ibrahim-Verbaas, Carla A.] Erasmus MC, Dept Neurol, NL-3000 CA Rotterdam, Netherlands. [Jacobsson, Bo] Sahgrenska Univ Hosp, Sahlgrenska Acad, Inst Publ Hlth, Dept Obstet & Gynecol, S-41345 Gothenburg, Sweden. [Joshi, Peter K.; Campbell, Harry; Rudan, Igor; Wilson, James F.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh EH8 9AG, Midlothian, Scotland. [Kaakinen, Marika; Jaervelin, Marjo-Riitta] Univ Oulu, Inst Hlth Sci, Oulu 90014, Finland. [Kaakinen, Marika; Jaervelin, Marjo-Riitta] Univ Oulu, Bioctr Oulu, Oulu 90014, Finland. [Kanoni, Stavroula; Deloukas, Panos; Palotie, Aarno; Ripatti, Samuli] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, England. [Kolcic, Ivana; Polasek, Ozren] Univ Split, Fac Med, Split 21000, Croatia. [Kutalik, Zoltan] Univ Lausanne, Dept Med Genet, CH-1005 Lausanne, Switzerland. [Kutalik, Zoltan] Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland. [Lahti, Jari; Raeikkoenen, Katri] Univ Helsinki, Inst Behav Sci, FIN-00014 Helsinki, Finland. [Liu, Yongmei] Wake Forest Univ Hlth Sci, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC 27157 USA. [Lohman, Kurt] Wake Forest Univ Hlth Sci, Div Publ Hlth Sci, Dept Biostat Sci, Winston Salem, NC 27157 USA. [Loitfelder, Marisa; Schmidt, Reinhold] Med Univ Graz, Dept Neurol, Div Neurogeriatr, A-8036 Graz, Austria. [McMahon, George; Ring, Susan M.] Univ Bristol, Sch Social & Community Med, Bristol BS8 2PR, Avon, England. [Vidal, Pedro Marques] Univ Lausanne Hosp, Inst Social & Prevent Med, CH-1005 Lausanne, Switzerland. [Meirelles, Osorio; Tanaka, Toshiko; Terracciano, Antonio; Ferrucci, Luigi; Garcia, Melissa E.; Harris, Tamara B.; Hernandez, Dena G.; Launer, Lenore J.; Schlessinger, David] NIA, NIH, Baltimore, MD 20892 USA. [Oldmeadow, Christopher J.; Attia, John R.; Holliday, Elizabeth G.; Scott, Rodney J.] Univ Newcastle, Hunter Med Res Inst, Newcastle, NSW 2308, Australia. [Oldmeadow, Christopher J.; Attia, John R.; Holliday, Elizabeth G.; Scott, Rodney J.] Univ Newcastle, Fac Hlth, Newcastle, NSW 2308, Australia. [Petrovic, Katja E.] Gen Hosp, Div Gen Neurol, Dept Neurol, A-8036 Graz, Austria. [Petrovic, Katja E.] Med Univ Graz, A-8036 Graz, Austria. [Peyrot, Wouter J.; Penninx, Brenda W. J. H.] Vrije Univ Amsterdam Med Ctr, Dept Psychiat, NL-1081 HL Amsterdam, Netherlands. [Quaye, Lydia; Cherkas, Lynn; Harris, Juliette M.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England. [Schmidt, Helena] Med Univ Graz, Inst Mol Biol & Biochem, A-8036 Graz, Austria. [Smith, Albert V.; Eiriksdottir, Guony; Guonason, Vilmundur] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Smith, Albert V.; Guonason, Vilmundur] Univ Iceland, Dept Med, IS-101 Reykjavik, Iceland. [Terracciano, Antonio] Florida State Univ, Coll Med, Tallahassee, FL 32306 USA. [Wellmann, Juergen; Berger, Klaus] Univ Munster, Inst Epidemiol & Social Med, D-48129 Munster, Germany. [Allik, Jueri; Realo, Anu] Univ Tartu, Dept Psychol, EE-50410 Tartu, Estonia. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Unit, I-50125 Florence, Italy. [Bastardot, Franois; Preisig, Martin; Vollenweider, Peter; Waeber, Gerard] Univ Lausanne Hosp, Dept Internal Med, CH-1011 Lausanne, Switzerland. [Beauchamp, Jonathan] Harvard Univ, Dept Econ, Cambridge, MA 02138 USA. [Bueltmann, Ute] Univ Groningen, Univ Med Ctr Groningen, Dept Hlth Sci Community & Occupat Med, NL-9700 AD Groningen, Netherlands. [Chabris, Christopher F.] Union Coll, Dept Psychol, Schenectady, NY 12308 USA. [Cucca, Francesco; Masala, Marco] Consejo Invest Nacl Italiano CNR, Ist Ric Genet & Biomed, I-09042 Cagliari, Italy. [Cucca, Francesco] Univ Sassari, Dipartimento Sci Biomed, I-07100 Ss, Italy. [de Andrade, Mariza] Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN 55905 USA. [De Jager, Philip L.] Brigham & Womens Hosp, Dept Neurol, Program Translat Neuropsychiat Genom, Boston, MA 02115 USA. [De Neve, Jan-Emmanuel] UCL, Sch Publ Policy, London WC1H 9QU, England. [De Neve, Jan-Emmanuel] London Sch Econ, Ctr Econ Performance, London WC2A 2AE, England. [Deary, Ian J.] Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Dedoussis, George V.; Dimitriou, Maria] Harokopio Univ Athens, Dept Nutr & Dietet, Athens 17671, Greece. [Elderson, Martin F.; LifeLines Cohort Study] Univ Groningen, Univ Med Ctr Groningen, LifeLines Cohort Study, NL-9700 RB Groningen, Netherlands. [Eriksson, Johan G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, FIN-00014 Helsinki, Finland. [Eriksson, Johan G.] Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki 00280, Finland. [Eriksson, Johan G.] Folkhalsan Res Ctr, Helsinki 00250, Finland. [Eriksson, Johan G.] Vaasa Cent Hosp, Vaasa 65130, Finland. [Evans, David M.; Lawlor, Debbie A.; St Pourcain, Beate; Davey-Smith, George; Timpson, Nicholas J.] Univ Bristol, Sch Social & Community Med, MRC Ctr Causal Anal Translat Epidemiol, Bristol BS8 2PR, Avon, England. [Faul, Jessica D.; Weir, David R.] Univ Michigan, Survey Res Ctr, Inst Social Res, Ann Arbor, MI 48106 USA. [Heath, Andrew C.] Washington Univ, Div Biol & Biomed Sci, St Louis, MO 63110 USA. [Hofman, Adriaan] Univ Groningen, Fac Behav & Social Sci, NL-9747 AD Groningen, Netherlands. [Iacono, William G.; Kirkpatrick, Robert M.; McGue, Matt; Miller, Michael B.; Krueger, Robert F.] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. [Holle, Rolf; Mielck, Andreas] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Hlth Econ & Hlth Care Management, D-85764 Neuherberg, Germany. [Illig, Thomas] Hannover Med Sch, Hannover Unified Biobank, D-30625 Hannover, Germany. [Jaervelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, MRC HPA Ctr Environm & Hlth, Dept Epidemiol & Biostat, London W2 1PG, England. [Jaervelin, Marjo-Riitta] Oulu Univ Hosp, Unit Primary Care, Oulu 90220, Finland. [Jaervelin, Marjo-Riitta] Natl Inst Hlth & Welf, Dept Children & Young People & Families, Oulu 90101, Finland. [Kaehoenen, Mika] Tampere Univ Hosp, Dept Clin Physiol, Tampere 33520, Finland. [Kaehoenen, Mika] Univ Tampere, Sch Med, Tampere 33520, Finland. [Kaprio, Jaakko; Latvala, Antti] Univ Helsinki, Dept Publ Hlth, Helsinki 00014, Finland. [Kaprio, Jaakko; Latvala, Antti] Natl Inst Hlth & Welf, Dept Mental Hlth & Subst Abuse Serv, Helsinki 00300, Finland. [Kowgier, Matthew; Palmer, Lyle J.] Ontario Inst Canc Res, Toronto, ON M5G 0A3, Canada. [Lehtimaeki, Terho] Tampere Univ Hosp, Dept Clin Chem, Fimlab Labs, Tampere 33520, Finland. [Li, Jingmei] Genome Inst Singapore, Singapore 138672, Singapore. [Lichtner, Peter] German Res Ctr Environm Hlth, Helmholtz Ctr Munich, Inst Human Genet, D-85764 Neuherberg, Germany. [Maekinen, Tomi E.] Natl Inst Hlth & Welf, Dept Hlth Funct Capac & Welf, Helsinki 00271, Finland. [Mukherjee, Sutapa] Sir Charles Gairdner Hosp, Western Australia Sleep Disorders Res Inst, Perth, WA 6009, Australia. [Mukherjee, Sutapa] Univ Toronto, Dept Med, Toronto, ON M5S 1A8, Canada. [Mukherjee, Sutapa] Univ Toronto, Womens Coll Res Inst, Toronto, ON M5G 1N8, Canada. [Palotie, Aarno] Univ Helsinki, Dept Med Genet, Helsinki 00014, Finland. [Raitakari, Olli T.] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, FIN-20520 Turku, Finland. [Raitakari, Olli T.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, FIN-20520 Turku, Finland. [Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands. [Rustichini, Aldo] Univ Minnesota, Dept Econ, Minneapolis, MN 55455 USA. [Salomaa, Veikko] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Chron Dis Epidemiol Unit, Helsinki 00271, Finland. [St Pourcain, Beate] Univ Bristol, Sch Oral & Dent Sci, Bristol BS1 2LY, Avon, England. [Starr, John M.] Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh EH8 9JZ, Midlothian, Scotland. [Sul, Jae Hoon] Univ Calif Los Angeles, Dept Comp Sci, Los Angeles, CA 90095 USA. [Svento, Rauli] Univ Oulu, Oulu Business Sch, Dept Econ, Oulu 90014, Finland. [Teumer, Alexander] Univ Med Greifswald, Dept Funct Genom, Interfac Inst Genet & Funct Genom, D-17487 Greifswald, Germany. [Tiemeier, Henning; Posthuma, Danielle] Erasmus MC, Dept Child & Adolescent Psychiat, NL-3000 CB Rotterdam, Netherlands. [Vartiainen, Erkki] Natl Inst Hlth & Welf, Div Welf & Hlth Promot, Helsinki 00271, Finland. [Viikari, Jorma] Turku Univ Hosp, Dept Med, FIN-20520 Turku, Finland. [Wichmann, H. -Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, Chair Epidemiol, D-81377 Munich, Germany. [Wichmann, H. -Erich] Klinikum Grosshadern, D-81377 Munich, Germany. [Wichmann, H. -Erich] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 1, D-85764 Neuherberg, Germany. [Conley, Dalton] NYU, Dept Sociol, New York, NY 10012 USA. [Laibson, David] Harvard Univ, Dept Econ, Cambridge, MA 02138 USA. [Meyer, Michelle N.] Harvard Univ, Sch Law, Petrie Flom Ctr Hlth Law Policy Biotechnol & Bioe, Cambridge, MA 02138 USA. [Meyer, Michelle N.] SUNY Albany, Nelson A Rockefeller Inst Govt, Albany, NY 12203 USA. [Posthuma, Danielle] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, NL-1081 BT Amsterdam, Netherlands. [Groenen, Patrick J. F.] Erasmus Univ, Econometr Inst, Erasmus Sch Econ, NL-3000 DR Rotterdam, Netherlands. [Johannesson, Magnus] Stockholm Sch Econ, Dept Econ, S-11383 Stockholm, Sweden. [Thurik, A. Roy] Panteia, NL-2701 AA Zoetermeer, Netherlands. [Thurik, A. Roy] GSCM Montpellier Business Sch, F-34185 Montpellier, France. [van Duijn, Cornelia M.] Leiden Univ, Med Ctr, Ctr Med Syst Biol, NL-2300 RC Leiden, Netherlands. [Cesarini, David] Cornell Univ, Dept Econ, Ithaca, NY 14853 USA. [Cesarini, David] NYU, Ctr Expt Social Sci, Dept Econ, New York, NY 10012 USA. [Cesarini, David] New York Univ Abu Dhabi, Div Social Sci, Abu Dhabi, U Arab Emirates. [Cesarini, David] Res Inst Ind Econ, S-10215 Stockholm, Sweden. RP Benjamin, DJ (reprint author), Cornell Univ, Dept Econ, Ithaca, NY 14853 USA. EM visscher@uq.edu.au; db468@cornell.edu; dac12@nyu.edu; koellinger@ese.eur.nl RI Attia, John/F-5376-2013; Lin, P/G-7702-2014; Nyholt, Dale/C-8384-2013; Palmer, Lyle/K-3196-2014; Lee, Sang Hong/A-2569-2011; Evans, David/H-6325-2013; Li, Jingmei/I-2904-2012; Johannesson, Magnus/E-9680-2011; terracciano, antonio/B-1884-2008; Lind, Penelope/B-2553-2009; Van Wagoner, David/C-6783-2008; Colaus, PsyColaus/K-6607-2013; Deloukas, Panos/B-2922-2013; Rudan, Igor/I-1467-2012; Smith, Albert/K-5150-2015; Yang, Jian/A-5852-2010; Holle, Rolf/D-9333-2013; Hayward, Caroline/M-8818-2016; Realo, Anu/M-9524-2016; Franke, Lude/P-7036-2016; Fox, Laura /C-6249-2016; Karjalainen, Juha/P-8624-2016; Davey Smith, George/A-7407-2013; Magnusson, Patrik/C-4458-2017; Kolcic, Ivana/E-2713-2017; Thurik, Roy/A-9386-2012; Medland, Sarah/C-7630-2013; Fehrmann, Rudolf/E-2551-2011; Marques-Vidal, Pedro/C-9449-2009; Allik, Juri/D-5609-2009; Milani, Lili/C-8759-2011; Gudnason, Vilmundur/K-6885-2015; Ripatti, Samuli/H-9446-2014; Wilson, James F/A-5704-2009; Polasek, Ozren/B-6002-2011; Montgomery, Grant/B-7148-2008; Rivadeneira, Fernando/O-5385-2015 OI Visscher, Peter/0000-0002-2143-8760; Eriksson, Johan/0000-0002-2516-2060; Evans, David/0000-0003-0663-4621; Smith, Jennifer/0000-0002-3575-5468; Kaprio, Jaakko/0000-0002-3716-2455; Timpson, Nicholas/0000-0002-7141-9189; Lawlor, Debbie A/0000-0002-6793-2262; Lahti, Jari/0000-0002-4310-5297; Attia, John/0000-0001-9800-1308; Palmer, Lyle/0000-0002-1628-3055; Lee, Sang Hong/0000-0001-9701-2718; Li, Jingmei/0000-0001-8587-7511; Johannesson, Magnus/0000-0001-8759-6393; Van Wagoner, David/0000-0001-8250-9828; Deloukas, Panos/0000-0001-9251-070X; Tiemeier, Henning/0000-0002-4395-1397; Esko, Tonu/0000-0003-1982-6569; lichtenstein, paul/0000-0003-3037-5287; Kristiansson, Kati/0000-0003-4688-107X; Maki-Opas, Tomi/0000-0002-0472-719X; Gieger, Christian/0000-0001-6986-9554; Rudan, Igor/0000-0001-6993-6884; Smith, Albert/0000-0003-1942-5845; Yang, Jian/0000-0003-2001-2474; Holle, Rolf/0000-0001-5395-2695; Hayward, Caroline/0000-0002-9405-9550; Franke, Lude/0000-0002-5159-8802; Davey Smith, George/0000-0002-1407-8314; Kolcic, Ivana/0000-0001-7918-6052; Peyrot, Wouter/0000-0001-7954-8383; St Pourcain, Beate/0000-0002-4680-3517; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Groenen, Patrick/0000-0001-6683-8971; Nuotio, Marja-Liisa/0000-0002-6688-027X; Latvala, Antti/0000-0001-5695-117X; Joshi, Peter/0000-0002-6361-5059; Kaakinen, Marika/0000-0002-9228-0462; Koellinger, Philipp/0000-0001-7413-0412; Cesarini, David/0000-0002-0043-009X; Ziad Alizadeh, Behrooz/0000-0002-1415-8007; Lind, Penelope/0000-0002-3887-2598; Raikkonen, Katri/0000-0003-3124-3470; Martin, Nicholas/0000-0003-4069-8020; Thurik, Roy/0000-0002-0242-6908; Medland, Sarah/0000-0003-1382-380X; Fehrmann, Rudolf/0000-0002-7516-315X; Marques-Vidal, Pedro/0000-0002-4548-8500; Allik, Juri/0000-0002-8358-4747; Milani, Lili/0000-0002-5323-3102; Gudnason, Vilmundur/0000-0001-5696-0084; Ripatti, Samuli/0000-0002-0504-1202; Wilson, James F/0000-0001-5751-9178; Polasek, Ozren/0000-0002-5765-1862; Montgomery, Grant/0000-0002-4140-8139; Rivadeneira, Fernando/0000-0001-9435-9441 FU Social Science Genetic Association Consortium (SSGAC); EAGER grant from the NSF; NIH Office of Behavioral and Social Sciences Research [SES-1064089]; Ragnar Soderberg Foundation [E9/11]; National Institute on Aging (NIA)/NIH [P01-AG005842, P01-AG005842-20S2, P30-AG012810, T32-AG000186-23] FX This research was carried out under the auspices of the Social Science Genetic Association Consortium (SSGAC), a cooperative enterprise among medical researchers and social scientists that coordinates genetic-association studies for social-science variables. Data for our analyses come from many studies and organizations, some of which are subject to a materials transfer agreement (5). Results from the meta-analysis are available at the Web site of the consortium, www.ssgac.org. The formation of the SSGAC was made possible by an EAGER grant from the NSF and a supplemental grant from the NIH Office of Behavioral and Social Sciences Research (SES-1064089). This research was also funded in part by the Ragnar Soderberg Foundation (E9/11); the National Institute on Aging (NIA)/NIH through grants P01-AG005842, P01-AG005842-20S2, P30-AG012810, and T32-AG000186-23; and the Intramural Research Program of the NIA/NIH. For a full list of acknowledgments, see (5). NR 21 TC 186 Z9 186 U1 6 U2 135 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 JUN 21 PY 2013 VL 340 IS 6139 BP 1467 EP 1471 DI 10.1126/science.1235488 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 167QL UT WOS:000320647000046 PM 23722424 ER PT J AU Gilbert, MR Dignam, J Won, M Blumenthal, DT Vogelbaum, MA Aldape, KD Colman, H Chakravarti, A Jeraj, R Armstrong, TS Wefel, JS Brown, PD Jaeckle, KA Schiff, D Atkins, JN Brachman, D Werner-Wasik, M Komaki, R Sulman, EP Mehta, MP AF Gilbert, Mark R. Dignam, James Won, Minhee Blumenthal, Deborah T. Vogelbaum, Michael A. Aldape, Kenneth D. Colman, Howard Chakravarti, Arnab Jeraj, Robert Armstrong, Terri S. Wefel, Jeffrey Scott Brown, Paul D. Jaeckle, Kurt A. Schiff, David Atkins, James Norman Brachman, David Werner-Wasik, Maria Komaki, Ritsuko Sulman, Erik P. Mehta, Minesh P. TI RTOG 0825: Phase III double-blind placebo-controlled trial evaluating bevacizumab (Bev) in patients (Pts) with newly diagnosed glioblastoma (GBM). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA. Radiat Therapy Oncol Grp, Philadelphia, PA USA. Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, IL-69978 Tel Aviv, Israel. Cleveland Clin Fdn, Cleveland, OH 44195 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. Ohio State Univ, Arthur G James Canc Ctr, Columbus, OH 43210 USA. Univ Wisconsin, Dept Med Phys, Madison, WI 53706 USA. Univ Texas Hlth Sci Ctr Houston, Sch Nursing, Houston, TX 77030 USA. Mayo Clin, Jacksonville, FL 32224 USA. Univ Virginia, Med Ctr, Charlottesville, VA USA. Natl Surg Adjuvant Breast & Bowel Project, Goldboro, NC USA. SCCC CCOP, Goldboro, NC USA. Arizona Oncol Serv Fdn, Phoenix, AZ USA. Thomas Jefferson Univ Hosp, Philadelphia, PA 19107 USA. Univ Maryland, Baltimore, MD 21201 USA. RI Gilbert, Mark/J-7494-2016 OI Gilbert, Mark/0000-0003-2556-9722 NR 0 TC 0 Z9 0 U1 0 U2 3 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 JUN 20 PY 2013 VL 31 IS 18 SU S MA 1 PG 1 WC Oncology SC Oncology GA AG6YC UT WOS:000335564000002 ER PT J AU Sulman, EP Won, M Blumenthal, DT Vogelbaum, MA Colman, H Jenkins, RB Chakravarti, A Jeraj, R Brown, PD Jaeckle, KA Schiff, D Dignam, J Atkins, JN Brachman, D Werner-Wasik, M Komaki, R Gilbert, MR Mehta, MP Aldape, KD AF Sulman, Erik P. Won, Minhee Blumenthal, Deborah T. Vogelbaum, Michael A. Colman, Howard Jenkins, Robert B. Chakravarti, Arnab Jeraj, Robert Brown, Paul D. Jaeckle, Kurt A. Schiff, David Dignam, James Atkins, James Norman Brachman, David Werner-Wasik, Maria Komaki, Ritsuko Gilbert, Mark R. Mehta, Minesh P. Aldape, Kenneth D. TI Molecular predictors of outcome and response to bevacizumab (BEV) based on analysis of RTOG 0825, a phase III trial comparing chemoradiation (CRT) with and without BEV in patients with newly diagnosed glioblastoma (GBM). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Radiat Therapy Oncol Grp, Philadelphia, PA USA. Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, IL-69978 Tel Aviv, Israel. Cleveland Clin Fdn, Cleveland, OH 44195 USA. Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. Mayo Clin, Rochester, MN USA. Ohio State Univ, Arthur G James Canc Ctr, Columbus, OH 43210 USA. Univ Wisconsin, Dept Med Phys, Madison, WI 53706 USA. Mayo Clin, Jacksonville, FL 32224 USA. Univ Virginia, Med Ctr, Charlottesville, VA USA. Natl Surg Adjuvant Breast & Bowel Project, Goldboro, NC USA. SCCC CCOP, Goldboro, NC USA. Arizona Oncol Serv Fdn, Phoenix, AZ USA. Thomas Jefferson Univ Hosp, Philadelphia, PA 19107 USA. Univ Maryland, Baltimore, MD 21201 USA. RI Gilbert, Mark/J-7494-2016 OI Gilbert, Mark/0000-0003-2556-9722 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 JUN 20 PY 2013 VL 31 IS 18 SU S MA LBA2010 PG 2 WC Oncology SC Oncology GA AG6YC UT WOS:000335564000020 ER PT J AU Bellon, M Ko, NL Lee, MJ Yao, Y Waldmann, TA Trepel, JB Nicot, C AF Bellon, Marcia Ko, Nga Ling Lee, Min-Jung Yao, Yuan Waldmann, Thomas A. Trepel, Jane B. Nicot, Christophe TI Adult T-cell leukemia cells overexpress Wnt5a and promote osteoclast differentiation SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; BETA-CATENIN; SIGNALING PATHWAY; CONSTITUTIVE ACTIVATION; IN-VIVO; HYPERCALCEMIA; CANCER; PROLIFERATION; EXPRESSION; TARGET AB Adult T-cell leukemia/lymphoma (ATL) is etiologically linked to infection with the human T-cell leukemia/lymphoma virus type 1 (HTLV-I). ATL is classified into 4 distinct clinical diseases: acute, lymphoma, chronic, and smoldering. Acute ATL is the most aggressive form, representing 60% of cases and has a 4-year survival of <5%. A frequent complication and cause of death in acute ATL patients is the presence of lytic bone lesions and hypercalcemia. We analyzed the Wnt/beta-catenin pathway because of its common role in cancer and bone remodeling. Our study demonstrated that ATL cells do not express high levels of beta-catenin but displayed high levels of LEF-1/TCF genes along with elevated levels of beta-catenin (LEF-1/TCF target genes) responsive genes. By profiling Wnt gene expression, we discovered that ATL patient leukemia cells shifted expression toward the noncanonical Wnt pathway. Interestingly, ATL cells overexpressed the osteolytic-associated genes-Wnt5a, PTHLH, and RANKL. We further show that Wnt5a secreted by ATL cells favors osteoclast differentiation and expression of RANK. Our results suggest that Wnt5a is a major contributing factor to the increase in osteolytic bone lesions and hypercalcemia found in ATL patients. Anti-Wnt5a therapy may prevent or reduce osteolytic lesions found in ATL patients and improve therapy outcome. C1 [Bellon, Marcia; Ko, Nga Ling; Yao, Yuan; Nicot, Christophe] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Ctr Viral Oncol, Kansas City, KS 66103 USA. [Lee, Min-Jung; Trepel, Jane B.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Waldmann, Thomas A.] NIH, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Nicot, C (reprint author), Ctr Viral Oncol, 3901 Rainbow Blvd,3025 Wahl Hall West, Kansas City, KS 66160 USA. EM cnicot@kumc.edu FU National Institutes of Health [AI 058944, CA106258]; National Cancer Institute; Biomedical Research Training Program FX This work was supported by the National Institutes of Health (AI 058944, CA106258) (C.N.), the Intramural Research Program of the National Cancer Institute (T.A.W., J.B.T.), and the Biomedical Research Training Program (M.B.). NR 42 TC 9 Z9 9 U1 0 U2 12 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 JUN 20 PY 2013 VL 121 IS 25 BP 5045 EP 5054 DI 10.1182/blood-2012-07-439109 PG 10 WC Hematology SC Hematology GA 184NR UT WOS:000321898500013 PM 23660959 ER PT J AU Niesen, MJM Bhattacharya, S Grisshammer, R Tate, CG Vaidehi, N AF Niesen, Michiel J. M. Bhattacharya, Supriyo Grisshammer, Reinhard Tate, Christopher G. Vaidehi, Nagarajan TI Thermostabilization of the beta(1)-Adrenergic Receptor Correlates with Increased Entropy of the Inactive State SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID PROTEIN-COUPLED RECEPTORS; MOLECULAR-DYNAMICS SIMULATIONS; ADENOSINE A(2A) RECEPTOR; BETA(2)-ADRENERGIC RECEPTOR; CONFORMATIONAL ENSEMBLES; STRUCTURAL INSIGHTS; CRYSTAL-STRUCTURE; AGONIST; ACTIVATION; STABILITY AB The dynamic nature of GPCRs is a major hurdle in their purification and crystallization. Thermostabilization can facilitate GPCR structure determination, as has been shown by the structure of the thermostabilized beta(1)-adrenergic receptor (beta(1)AR) mutant, m23-beta(1)AR, which has been thermostabilized in the inactive state. However, it is undear from the structure how the six thermostabilizing mutations in m23-beta(1)AR affect receptor dynamics. We have used molecular dynamics simulations in explicit solvent to compare the conformational ensembles for both wild type beta(1)AR (wt-beta(1)AR) and m23-beta(1)AR. Thermostabilization results in an increase in the number of accessible microscopic conformational states within the inactive state ensemble, effectively increasing the side chain entropy of the inactive state at room temperature, while suppressing large-scale main chain conformational changes that lead to activation. We identified several diverse mechanisms of thermostabilization upon mutation. These include decrease of long-range correlated movement between residues in the G-protein coupling site to the extracellular region (Y227A(5.58), F338M(7.48)), formation of new hydrogen bonds (R68S), and reduction of local stress (Y227(5.58), F327(7.37), and F338(7.48)). This study provides insights into microscopic mechanisms underlying thermostability that leads to an understanding of the effect of these mutations on the structure of the receptor. C1 [Niesen, Michiel J. M.; Bhattacharya, Supriyo; Vaidehi, Nagarajan] City Hope Natl Med Ctr, Beckman Res Inst, Div Immunol, Duarte, CA 91010 USA. [Grisshammer, Reinhard] NINDS, Membrane Prot Struct Funct Unit, NIH, Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Tate, Christopher G.] MRC Lab Mol Biol, Cambridge CB2 0QH, England. RP Vaidehi, N (reprint author), City Hope Natl Med Ctr, Beckman Res Inst, Div Immunol, 1500 E Duarte Rd, Duarte, CA 91010 USA. EM NVaidehi@coh.org RI Niesen, Michiel/L-8985-2013; Grisshammer, Reinhard/C-3089-2015 FU NIH [RO1-GM097261] FX The authors thank Mr. Jeffrey Wagner for help with some of the scripts used for analysis. This work was supported by NIH RO1-GM097261. NR 56 TC 8 Z9 8 U1 0 U2 17 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD JUN 20 PY 2013 VL 117 IS 24 BP 7283 EP 7291 DI 10.1021/jp403207c PG 9 WC Chemistry, Physical SC Chemistry GA 171FQ UT WOS:000320910900016 PM 23697892 ER PT J AU Morens, DM Taubenberger, JK Fauci, AS AF Morens, David M. Taubenberger, Jeffery K. Fauci, Anthony S. TI Pandemic Influenza Viruses - Hoping for the Road Not Taken SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Morens, David M.; Fauci, Anthony S.] Natl Inst Allergy & Infect Dis, Natl Inst Hlth, Off Director, Bethesda, MD USA. [Taubenberger, Jeffery K.] Natl Inst Allergy & Infect Dis, Natl Inst Hlth, Viral Pathogenesis & Evolut Sect, Lab Infect Dis, Bethesda, MD USA. RP Morens, DM (reprint author), Natl Inst Allergy & Infect Dis, Natl Inst Hlth, Off Director, Bethesda, MD USA. FU Intramural NIH HHS [ZIA AI000986-06] NR 5 TC 31 Z9 34 U1 0 U2 6 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 JUN 20 PY 2013 VL 368 IS 25 BP 2345 EP 2348 DI 10.1056/NEJMp1307009 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 167AE UT WOS:000320601700001 PM 23738514 ER PT J AU Hudson, KL Guttmacher, AE Collins, FS AF Hudson, Kathy L. Guttmacher, Alan E. Collins, Francis S. TI In Support of SUPPORT - A View from the NIH SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID SEVERE RETINOPATHY; INFANTS C1 [Hudson, Kathy L.; Guttmacher, Alan E.; Collins, Francis S.] Natl Inst Hlth, Bethesda, MD USA. RP Hudson, KL (reprint author), Natl Inst Hlth, Bethesda, MD USA. NR 4 TC 27 Z9 27 U1 1 U2 7 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 JUN 20 PY 2013 VL 368 IS 25 BP 2349 EP 2351 DI 10.1056/NEJMp1306986 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 167AE UT WOS:000320601700003 PM 23738511 ER PT J AU Wang, P Dong, Q Zhang, C Kuan, PF Liu, Y Jeck, WR Andersen, JB Jiang, W Savich, GL Tan, TX Auman, JT Hoskins, JM Misher, AD Moser, CD Yourstone, SM Kim, JW Cibulskis, K Getz, G Hunt, HV Thorgeirsson, SS Roberts, LR Ye, D Guan, KL Xiong, Y Qin, LX Chiang, DY AF Wang, P. Dong, Q. Zhang, C. Kuan, P-F Liu, Y. Jeck, W. R. Andersen, J. B. Jiang, W. Savich, G. L. Tan, T-X Auman, J. T. Hoskins, J. M. Misher, A. D. Moser, C. D. Yourstone, S. M. Kim, J. W. Cibulskis, K. Getz, G. Hunt, H. V. Thorgeirsson, S. S. Roberts, L. R. Ye, D. Guan, K-L Xiong, Y. Qin, L-X Chiang, D. Y. TI Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas SO ONCOGENE LA English DT Article DE DNA methylation; epigenetics; tumor metabolism ID CELL SELF-RENEWAL; IDH2 MUTATIONS; COLORECTAL-CANCER; MAFFUCCI SYNDROME; OLLIER DISEASE; MAMMALIAN DNA; TET PROTEINS; STEM-CELLS; PHENOTYPE; 5-CARBOXYLCYTOSINE AB Mutations in the genes encoding isocitrate dehydrogenase, IDH1 and IDH2, have been reported in gliomas, myeloid leukemias, chondrosarcomas and thyroid cancer. We discovered IDH1 and IDH2 mutations in 34 of 326 (10%) intrahepatic cholangiocarcinomas. Tumor with mutations in IDH1 or IDH2 had lower 5-hydroxymethylcytosine and higher 5-methylcytosine levels, as well as increased dimethylation of histone H3 lysine 79 (H3K79). Mutations in IDH1 or IDH2 were associated with longer overall survival (P = 0.028) and were independently associated with a longer time to tumor recurrence after intrahepatic cholangiocarcinoma resection in multivariate analysis (P = 0.021). IDH1 and IDH2 mutations were significantly associated with increased levels of p53 in intrahepatic cholangiocarcinomas, but no mutations in the p53 gene were found, suggesting that mutations in IDH1 and IDH2 may cause a stress that leads to p53 activation. We identified 2309 genes that were significantly hypermethylated in 19 cholangiocarcinomas with mutations in IDH1 or IDH2, compared with cholangiocarcinomas without these mutations. Hypermethylated CpG sites were significantly enriched in CpG shores and upstream of transcription start sites, suggesting a global regulation of transcriptional potential. Half of the hypermethylated genes overlapped with DNA hypermethylation in IDH1-mutant gliobastomas, suggesting the existence of a common set of genes whose expression may be affected by mutations in IDH1 or IDH2 in different types of tumors. C1 [Wang, P.; Jiang, W.; Guan, K-L; Xiong, Y.] Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Shanghai 200032, Peoples R China. [Wang, P.; Jiang, W.; Ye, D.; Guan, K-L; Xiong, Y.] Fudan Univ, Inst Biomed Sci, Mol & Cell Biol Lab, Shanghai 200032, Peoples R China. [Dong, Q.; Qin, L-X] Fudan Univ, Liver Canc Inst, Shanghai 200032, Peoples R China. [Dong, Q.; Qin, L-X] Fudan Univ, Zhongshan Hosp, Inst Biomed Sci, Shanghai 200032, Peoples R China. [Zhang, C.; Liu, Y.] Univ N Carolina, Carolina Ctr Genome Sci, Dept Stat & Operat Res, Chapel Hill, NC 27599 USA. [Kuan, P-F] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. [Kuan, P-F; Jeck, W. R.; Savich, G. L.; Tan, T-X; Auman, J. T.; Hoskins, J. M.; Misher, A. D.; Yourstone, S. M.; Xiong, Y.; Chiang, D. Y.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Jeck, W. R.; Savich, G. L.; Tan, T-X; Yourstone, S. M.; Chiang, D. Y.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Andersen, J. B.; Thorgeirsson, S. S.] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Auman, J. T.; Hoskins, J. M.; Misher, A. D.] Univ N Carolina, Inst Pharmacogen & Individualized Med, Chapel Hill, NC 27599 USA. [Moser, C. D.; Roberts, L. R.] Mayo Clin, Ctr Canc, Ctr Cell Signaling Gastroenterol, Div Gastroenterol & Hepatol, Rochester, MN USA. [Kim, J. W.] Wake Forest Univ, Baptist Med Ctr, Ctr Canc Genom, Winston Salem, NC 27109 USA. [Cibulskis, K.; Getz, G.] 7 Cambridge Ctr, Broad Inst, Genome Sequencing Anal Program & Platform, Cambridge, MA USA. [Hunt, H. V.] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. [Guan, K-L] Fudan Univ, Shanghai Med Coll, Dept Biochem, Shanghai 200032, Peoples R China. [Guan, K-L] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA. [Guan, K-L] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Xiong, Y.] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. RP Xiong, Y (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, CB 7295,450 West Dr, Chapel Hill, NC 27599 USA. EM yxiong@email.unc.edu; qin.lunxiu@zs-hospital.sh.cn; chiang@med.unc.edu OI Chiang, Derek/0000-0002-1131-6065; Roberts, Lewis/0000-0001-7885-8574; Andersen , Jesper B/0000-0003-1760-5244 FU 985 Program from the Chinese Ministry of Education; MOST 973 [2009CB918401, 2011CB910600, 2012CB910300, 2012CB910101]; NSFC Program of International Cooperation and Exchanges [81120108016]; China National Key Projects for Infectious Disease [2008ZX10002-021, 2012ZX10002-012]; National Institutes of Health; James S McDonnell Foundation; Samuel Waxman Cancer Research Foundation; American Gastroenterological Association Foundation for Digestive Health and Nutrition; Alfred P Sloan Foundation; Nancy Stegman Cancer Research Fund; University Cancer Research Fund FX The UNC Biospecimen Core Facility, Mammalian Genotyping Core Facility and Translational Pathology Laboratory provided technical assistance for this study. Funding for this research was provided by: the 985 Program from the Chinese Ministry of Education (KLG, YX), MOST 973 (No. 2009CB918401, No. 2011CB910600, No. 2012CB910300, No. 2012CB910101; DY, YX and KLG); the NSFC Program of International Cooperation and Exchanges (No. 81120108016; LXQ, YX) and the China National Key Projects for Infectious Disease (2008ZX10002-021, 2012ZX10002-012; LZQ), the National Institutes of Health (KLG, YX, SST, LRR), the James S McDonnell Foundation (YX), the Samuel Waxman Cancer Research Foundation (YX), the American Gastroenterological Association Foundation for Digestive Health and Nutrition (LRR), the Alfred P Sloan Foundation fellowship (DYC), the Nancy Stegman Cancer Research Fund (DYC) and the University Cancer Research Fund (DYC, YX). NR 46 TC 86 Z9 89 U1 0 U2 23 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN 20 PY 2013 VL 32 IS 25 BP 3091 EP 3100 DI 10.1038/onc.2012.315 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 168KX UT WOS:000320705700009 PM 22824796 ER PT J AU Findley, K Oh, J Yang, J Conlan, S Deming, C Meyer, JA Schoenfeld, D Nomicos, E Park, M Kong, HH Segre, JA AF Findley, Keisha Oh, Julia Yang, Joy Conlan, Sean Deming, Clayton Meyer, Jennifer A. Schoenfeld, Deborah Nomicos, Effie Park, Morgan Kong, Heidi H. Segre, Julia A. CA NIH Intramural Sequencing Ctr Comp TI Topographic diversity of fungal and bacterial communities in human skin SO NATURE LA English DT Article ID RIBOSOMAL-RNA SEQUENCES; HUMAN MICROBIOME; RISK-FACTORS; TINEA-PEDIS; PREVALENCE; ALIGNMENT; ACCURACY; DISEASES; PROJECT; SAMPLES AB Traditional culture-based methods have incompletely defined the microbial landscape of common recalcitrant human fungal skin diseases, including athlete's foot and toenail infections. Skin protects humans from invasion by pathogenic microorganisms and provides a home for diverse commensal microbiota(1). Bacterial genomic sequence data have generated novel hypotheses about species and community structures underlying human disorders(2-4). However, microbial diversity is not limited to bacteria; microorganisms such as fungi also have major roles in microbial community stability, human health and disease(5). Genomic methodologies to identify fungal species and communities have been limited compared with those that are available for bacteria(6). Fungal evolution can be reconstructed with phylogenetic markers, including ribosomal RNA gene regions and other highly conserved genes(7). Here we sequenced and analysed fungal communities of 14 skin sites in 10 healthy adults. Eleven core-body and arm sites were dominated by fungi of the genus Malassezia, with only species-level classifications revealing fungal-community composition differences between sites. By contrast, three foot sites-plantar heel, toenail and toe web-showed high fungal diversity. Concurrent analysis of bacterial and fungal communities demonstrated that physiologic attributes and topography of skin differentially shape these two microbial communities. These results provide a framework for future investigation of the contribution of interactions between pathogenic and commensal fungal and bacterial communities to the maintainenace of human health and to disease pathogenesis. C1 [Findley, Keisha; Oh, Julia; Yang, Joy; Conlan, Sean; Deming, Clayton; Meyer, Jennifer A.; Segre, Julia A.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Schoenfeld, Deborah; Nomicos, Effie; Kong, Heidi H.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Park, Morgan] NHGRI, NIH Intramural Sequencing Ctr, NIH, Rockville, MD 20852 USA. RP Kong, HH (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM konghe@mail.nih.gov; jsegre@nhgri.nih.gov RI Conlan, Sean/B-4401-2008; OI Conlan, Sean/0000-0001-6848-3465; Kong, Heidi/0000-0003-4424-064X FU US National Institutes of Health (NIH) NHGRI and NCI Intramural Research Programs; NIH [1K99AR059222, 1UH2AR057504-01, 4UH3AR057504-02] FX We thank J. Heitman, A. Amend, Y. Shea, M. Turner, I. Brownell and M. Udey for helpful discussions. We thank J. Fekecs for assistance with the figures. This work was supported by the US National Institutes of Health (NIH) NHGRI and NCI Intramural Research Programs, and in part by NIH grant no. 1K99AR059222 (to H. H. K.). Sequencing was funded by grants from the NIH (1UH2AR057504-01 and 4UH3AR057504-02). NR 41 TC 198 Z9 206 U1 23 U2 218 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 JUN 20 PY 2013 VL 498 IS 7454 BP 367 EP + DI 10.1038/nature12171 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 166XI UT WOS:000320592900041 PM 23698366 ER PT J AU Lammermann, T Afonso, PV Angermann, BR Wang, JM Kastenmuller, W Parent, CA Germain, RN AF Laemmermann, Tim Afonso, Philippe V. Angermann, Bastian R. Wang, Ji Ming Kastenmueller, Wolfgang Parent, Carole A. Germain, Ronald N. TI Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo SO NATURE LA English DT Article ID INNATE IMMUNE-RESPONSE; STERILE INFLAMMATION; AMMATORY ARTHRITIS; IMAGING REVEALS; HOST-DEFENSE; MICE LACKING; LYMPH-NODES; BONE-MARROW; MIGRATION; RECEPTOR AB Neutrophil recruitment from blood to extravascular sites of sterile or infectious tissue damage is a hallmark of early innate immune responses, and the molecular events leading to cell exit from the bloodstream have been well defined(1,2). Once outside the vessel, individual neutrophils often show extremely coordinated chemotaxis and cluster formation reminiscent of the swarming behaviour of insects(3-11). The molecular players that direct this response at the single-cell and population levels within the complexity of an inflamed tissue are unknown. Using two-photon intravital microscopy in mouse models of sterile injury and infection, we show a critical role for intercellular signal relay among neutrophils mediated by the lipid leukotriene B4, which acutely amplifies local cell death signals to enhance the radius of highly directed interstitial neutrophil recruitment. Integrin receptors are dispensable for long-distance migration(12), but have a previously unappreciated role in maintaining dense cellular clusters when congregating neutrophils rearrange the collagenous fibre network of the dermis to form a collagen-free zone at the wound centre. In this newly formed environment, integrins, in concert with neutrophil-derived leukotriene B4 and other chemoattractants, promote local neutrophil interaction while forming a tight wound seal. This wound seal has borders that cease to grow in kinetic concert with late recruitment of monocytes and macrophages at the edge of the displaced collagen fibres. Together, these data provide an initial molecular map of the factors that contribute to neutrophil swarming in the extravascular space of a damaged tissue. They reveal how local events are propagated over large-range distances, and how auto-signalling produces coordinated, self-organized neutrophil-swarming behaviour that isolates the wound or infectious site from surrounding viable tissue. C1 [Laemmermann, Tim; Angermann, Bastian R.; Kastenmueller, Wolfgang; Germain, Ronald N.] NIAID, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Afonso, Philippe V.; Parent, Carole A.] NCI, Lab Cellular & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wang, Ji Ming] NCI, Lab Mol Immunoregulat, Canc & Inflammat Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA. [Kastenmueller, Wolfgang] Univ Bonn, Inst Mol Med, D-53105 Bonn, Germany. [Kastenmueller, Wolfgang] Univ Bonn, Inst Expt Immunol, D-53105 Bonn, Germany. RP Lammermann, T (reprint author), NIAID, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM laemmermannt@niaid.nih.gov; rgermain@niaid.nih.gov RI Afonso, Philippe/D-2234-2014 OI Afonso, Philippe/0000-0002-4828-3797 FU Human Frontiers Science Program Long-Term Fellowship; Deutsche Forschungsgemeinschaft (DFG); National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Cancer Institute, National Institutes of Health FX We thank L. Birnbaumer, R. Fassler, E. Tuomanen, P. M. Murphy, S. Akira, S. Monkley, D. Critchley, R. Wedlich-Soldner and M. Sixt for providing mice for this study, J.G. Egen and J. Tang for assistance with imaging, M. Parsek for providing P. aeruginosa-GFP, J. H. Kehrl, P. M. Murphy, R. Varma and members of the Germain laboratory for discussions. This work was supported by the Intramural Research Program of National Institute of Allergy and Infectious Diseases and National Cancer Institute, National Institutes of Health. T. L. was supported by a Human Frontiers Science Program Long-Term Fellowship. W. K. is presently a member of the Deutsche Forschungsgemeinschaft (DFG)-funded excellence cluster ImmunoSensation, Bonn, Germany. NR 49 TC 170 Z9 172 U1 9 U2 71 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUN 20 PY 2013 VL 498 IS 7454 BP 371 EP + DI 10.1038/nature12175 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 166XI UT WOS:000320592900042 PM 23708969 ER PT J AU Cooper, A Garcia, M Petrovas, C Yamamoto, T Koup, RA Nabel, GJ AF Cooper, Arik Garcia, Mayra Petrovas, Constantinos Yamamoto, Takuya Koup, Richard A. Nabel, Gary J. TI HIV-1 causes CD4 cell death through DNA-dependent protein kinase during viral integration SO NATURE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; INFECTIOUS MOLECULAR CLONE; T-CELLS; IN-VIVO; RETROVIRAL INFECTION; QUANTITATIVE ASSAY; LYMPHOCYTES; INHIBITOR; DEPLETION; DYNAMICS AB Human immunodeficiency virus-1 (HIV-1) has infected more than 60 million people and caused nearly 30 million deaths worldwide(1), ultimately the consequence of cytolytic infection of CD4(+) T cells. In humans and in macaque models, most of these cells contain viral DNA and are rapidly eliminated at the peak of viraemia(2-4), yet the mechanism by which HIV-1 induces helper T-cell death has not been defined. Here we show that virus-induced cell killing is triggered by viral integration. Infection by wild-type HIV-1, but not an integrase-deficient mutant, induced the death of activated primary CD4 lymphocytes. Similarly, raltegravir, a pharmacologic integrase inhibitor, abolished HIV-1-induced cell killing both in cell culture and in CD4(+) T cells from acutely infected subjects. The mechanism of killing during viral integration involved the activation of DNA-dependent protein kinase (DNA-PK), a central integrator of the DNA damage response, which caused phosphorylation of p53 and histone H2AX. Pharmacological inhibition of DNA-PK abolished cell death during HIV-1 infection in vitro, suggesting that processes which reduce DNA-PK activation in CD4 cells could facilitate the formation of latently infected cells that give rise to reservoirs in vivo. We propose that activation of DNA-PK during viral integration has a central role in CD4(+) T-cell depletion, raising the possibility that integrase inhibitors and interventions directed towards DNA-PK may improve T-cell survival and immune function in infected individuals. C1 [Cooper, Arik; Garcia, Mayra; Nabel, Gary J.] NIAID, Virol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Petrovas, Constantinos; Yamamoto, Takuya; Koup, Richard A.] NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Nabel, GJ (reprint author), NIAID, Virol Lab, Vaccine Res Ctr, NIH, Bldg 40,Room 4502,MSC 3005,40 Convent Dr, Bethesda, MD 20892 USA. EM Gary.Nabel@sanofi.com RI Yamamoto, Takuya/L-2642-2013 OI Yamamoto, Takuya/0000-0003-3753-1211 FU Intramural Research Program of the Vaccine Research Center, NIAID, National Institutes of Health FX We thank D. Ambrozak, R. Nguyen, and S. Perfetto for help with cell sorting, U. Olshevsky, J. Casazza, D. Bolton, A. Pegu and M. Louder for discussions and technical help, and A. Tislerics and B. Hartman for manuscript preparation. This research was supported by the Intramural Research Program of the Vaccine Research Center, NIAID, National Institutes of Health. The findings and conclusions in this report are those of the authors and do not necessarily reflect the views of the funding agency. NR 39 TC 90 Z9 92 U1 5 U2 56 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUN 20 PY 2013 VL 498 IS 7454 BP 376 EP + DI 10.1038/nature12274 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 166XI UT WOS:000320592900043 PM 23739328 ER PT J AU Prater, SN Patel, TT Buckley, AF Mandel, H Vlodavski, E Banugaria, SG Feeney, EJ Raben, N Kishnani, PS AF Prater, Sean N. Patel, Trusha T. Buckley, Anne F. Mandel, Hanna Vlodavski, Eugene Banugaria, Suhrad G. Feeney, Erin J. Raben, Nina Kishnani, Priya S. TI Skeletal muscle pathology of infantile Pompe disease during long-term enzyme replacement therapy SO ORPHANET JOURNAL OF RARE DISEASES LA English DT Article DE Pompe disease; Glycogen storage disease type II; Enzyme replacement therapy; rhGAA; Alglucosidase alfa; Myozyme; Skeletal muscle; Pathology; Autophagy; Genetic diseases ID ACID ALPHA-GLUCOSIDASE; STORAGE-DISEASE; ALGLUCOSIDASE ALPHA; CLINICAL-OUTCOMES; DISORDERS; TETRASACCHARIDE; ULTRASTRUCTURE; BIOMARKER AB Background: Pompe disease is an autosomal recessive metabolic neuromuscular disorder caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). It has long been believed that the underlying pathology leading to tissue damage is caused by the enlargement and rupture of glycogen-filled lysosomes. Recent studies have also implicated autophagy, an intracellular lysosome-dependent degradation system, in the disease pathogenesis. In this study, we characterize the long-term impact of enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) on lysosomal glycogen accumulation and autophagy in some of the oldest survivors with classic infantile Pompe disease (IPD). Methods: Muscle biopsies from 8 [4 female, 4 male; 6 cross-reactive immunologic material (CRIM)-positive, 2 CRIM-negative] patients with a confirmed diagnosis of classic IPD were examined using standard histopathological approaches. In addition, muscle biopsies were evaluated by immunostaining for lysosomal marker (lysosomal-associated membrane protein-2; LAMP2), autophagosomal marker (microtubule-associated protein 1 light chain 3; LC3), and acid and alkaline ATPases. All patients received rhGAA by infusion at cumulative biweekly doses of 20-40 mg/kg. Results: Median age at diagnosis of classic IPD was 3.4 months (range: 0 to 6.5 months; n = 8). At the time of muscle biopsy, the patients' ages ranged from 1 to 103 months and ERT duration ranged from 0 (i.e., baseline, pre-ERT) to 96 months. The response to therapy varied considerably among the patients: some patients demonstrated motor gains while others experienced deterioration of motor function, either with or without a period of initial clinical benefit. Skeletal muscle pathology included fiber destruction, lysosomal vacuolation, and autophagic abnormalities (i.e., buildup), particularly in fibers with minimal lysosomal enlargement. Overall, the pathology reflected clinical status. Conclusions: This is the first study to investigate the impact of rhGAA ERT on lysosomal glycogen accumulation and autophagic buildup in patients with classic IPD beyond 18 months of treatment. Our findings indicate that ERT does not fully halt or reverse the underlying skeletal muscle pathology in IPD. The best outcomes were observed in the two patients who began therapy early, namely at 0.5 and 1.1 months of age. C1 [Prater, Sean N.; Patel, Trusha T.; Banugaria, Suhrad G.; Kishnani, Priya S.] Duke Univ, Med Ctr, Dept Pediat, Div Med Genet, Durham, NC 27710 USA. [Buckley, Anne F.] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Mandel, Hanna] Technion Israel Inst Technol, Rambam Med Ctr, Fac Med, Metab Unit,Meyer Childrens Hosp, Haifa, Israel. [Vlodavski, Eugene] Technion Israel Inst Technol, Rambam Med Ctr, Fac Med, Dept Pathol, Haifa, Israel. [Feeney, Erin J.; Raben, Nina] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. RP Raben, N (reprint author), NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. EM rabenn@mail.nih.gov; priya.kishnani@dm.duke.edu FU Lysosomal Disease Network, a part of National Institutes of Health Rare Diseases Clinical Research Network (RDCRN); National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health FX We thank the patients, their families and the health-care providers who participated in and contributed to this study. This project was funded in part by the Lysosomal Disease Network, a part of National Institutes of Health Rare Diseases Clinical Research Network (RDCRN). This research was also supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. NR 34 TC 14 Z9 14 U1 1 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1172 J9 ORPHANET J RARE DIS JI Orphanet J. Rare Dis. PD JUN 20 PY 2013 VL 8 AR 90 DI 10.1186/1750-1172-8-90 PG 12 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA 171WC UT WOS:000320959800001 PM 23787031 ER PT J AU Kummar, S Allen, D Monks, A Polley, EC Hose, CD Ivy, SP Turkbey, IB Lawrence, S Kinders, RJ Choyke, P Simon, R Steinberg, SM Doroshow, JH Helman, L AF Kummar, Shivaani Allen, Deborah Monks, Anne Polley, Eric C. Hose, Curtis D. Ivy, S. Percy Turkbey, Ismail B. Lawrence, Scott Kinders, Robert J. Choyke, Peter Simon, Richard Steinberg, Seth M. Doroshow, James H. Helman, Lee TI Cediranib for Metastatic Alveolar Soft Part Sarcoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID FACTOR SIGNALING INHIBITOR; SOLID TUMORS; GENE; MET; AZD2171; CANCER; ADOLESCENTS; PATTERNS; CHILDREN AB Purpose Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor, for which no effective standard systemic treatment exists for patients with unresectable disease. Cediranib is a potent, oral small-molecule inhibitor of all three vascular endothelial growth factor receptors (VEGFRs). Patients and Methods We conducted a phase II trial of once-daily cediranib (30 mg) given in 28-day cycles for patients with metastatic, unresectable ASPS to determine the objective response rate (ORR). We also compared gene expression profiles in pre- and post-treatment tumor biopsies and evaluated the effect of cediranib on tumor proliferation and angiogenesis using positron emission tomography and dynamic contrast-enhanced magnetic resonance imaging. Results Of 46 patients enrolled, 43 were evaluable for response at the time of analysis. The ORR was 35%, with 15 of 43 patients achieving a partial response. Twenty-six patients (60%) had stable disease as the best response, with a disease control rate (partial response + stable disease) at 24 weeks of 84%. Microarray analysis with validation by quantitative real-time polymerase chain reaction on paired tumor biopsies from eight patients demonstrated downregulation of genes related to vasculogenesis. Conclusion In this largest prospective trial to date of systemic therapy for metastatic ASPS, we observed that cediranib has substantial single-agent activity, producing an ORR of 35% and a disease control rate of 84% at 24 weeks. On the basis of these results, an open-label, multicenter, randomized phase II registration trial is currently being conducted for patients with metastatic ASPS comparing cediranib with another VEGFR inhibitor, sunitinib. (C) 2013 by American Society of Clinical Oncology C1 [Kummar, Shivaani; Allen, Deborah; Polley, Eric C.; Ivy, S. Percy; Turkbey, Ismail B.; Choyke, Peter; Simon, Richard; Steinberg, Seth M.; Doroshow, James H.; Helman, Lee] NCI, Bethesda, MD 20892 USA. [Monks, Anne; Hose, Curtis D.; Lawrence, Scott; Kinders, Robert J.] Frederick Natl Lab Canc Res, SAIC Frederick, Frederick, MD USA. RP Kummar, S (reprint author), NCI, NIH, Bldg 31,Room 3A44,31 Ctr Dr, Bethesda, MD 20892 USA. EM kummars@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX Supported in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. NR 25 TC 59 Z9 59 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 JUN 20 PY 2013 VL 31 IS 18 BP 2296 EP U106 DI 10.1200/JCO.2012.47.4288 PG 8 WC Oncology SC Oncology GA 164XV UT WOS:000320446700015 PM 23630200 ER PT J AU Virgo, KS Lerro, CC Klabunde, CN Earle, C Ganz, PA AF Virgo, Katherine S. Lerro, Catherine C. Klabunde, Carrie N. Earle, Craig Ganz, Patricia A. TI Barriers to Breast and Colorectal Cancer Survivorship Care: Perceptions of Primary Care Physicians and Medical Oncologists in the United States SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID FOLLOW-UP; SOCIETY; EXPERIENCE; PROVIDERS; QUALITY; UPDATE; ACCESS AB Purpose High-quality, well-coordinated cancer survivorship care is needed yet barriers remain owing to fragmentation in the United States health care system. This article is a nationwide survey of barriers perceived by primary care physicians (PCPs) and medical oncologists (MOs) regarding breast and colorectal cancer survivorship care beyond 5 years after treatment. Methods The Survey of Physician Attitudes Regarding the Care of Cancer Survivors was mailed out in 2009 to a nationally-representative sample (n = 3,596) of US PCPs and MOs. Ten physician-perceived cancer survivorship care barriers/concerns were compared between the two provider types. Using weighted multinomial logistic regression, we modeled each barrier, adjusting for physician demographics, reimbursement, training, and practice characteristics. Results We received responses from 2,202 physicians (1,072 PCPs; 1,130 MOs; 65.1% cooperation rate). In adjusted patient-related barriers models, MOs were more likely than PCPs to report patient language barriers (odds ratio, [OR], 1.72; 95% CI, 1.22 to 2.42), insurance restrictions impeding test/treatment use (OR, 1.42; 95% CI, 1.03 to 1.96), and patients requesting more aggressive testing (OR, 4.08; 95% CI, 2.73 to 6.10). In adjusted physician-related barriers models, PCPs were more likely to report inadequate training (OR, 3.06; 95% CI, 2.03 to 4.61) and ordering additional tests/treatments because of malpractice concerns (OR, 1.87; 95% CI, 1.20 to 2.93). MOs were more likely to report uncertainty regarding general preventive care responsibility (often/always: OR, 1.97; 95% CI, 1.13 to 3.43; sometimes: OR, 2.16; 95% CI, 1.60 to 2.93). Conclusion MOs and PCPs perceive different cancer follow-up care barriers/concerns to be problematic. Resolving inadequate training, malpractice-driven test ordering, and preventive-care responsibility concerns may require continuing education, explicit guidelines, and survivorship care plans. Reviewing care plans with survivors may also reduce patients' requests for unnecessary testing. (C) 2013 by American Society of Clinical Oncology C1 [Virgo, Katherine S.] Emory Univ, Atlanta, GA 30329 USA. [Lerro, Catherine C.] Yale Univ, New Haven, CT USA. [Klabunde, Carrie N.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. [Earle, Craig] Inst Clin Evaluat Sci, Toronto, ON, Canada. [Earle, Craig] Univ Toronto, Toronto, ON, Canada. RP Virgo, KS (reprint author), Emory Univ, Dept Hlth Policy & Management, RSPH, 1360 Stephens Dr NE, Atlanta, GA 30329 USA. EM kvirgo@emory.edu FU National Cancer Institute [HHSN261201000316C]; American Cancer Society National Home Office Intramural Research Department FX Supported by Grant No. HHSN261201000316C from the National Cancer Institute and American Cancer Society National Home Office Intramural Research Department. NR 34 TC 26 Z9 26 U1 4 U2 12 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 JUN 20 PY 2013 VL 31 IS 18 BP 2322 EP 2336 DI 10.1200/JCO.2012.45.6954 PG 15 WC Oncology SC Oncology GA 164XV UT WOS:000320446700018 PM 23690429 ER PT J AU Wang, LN Yin, QY He, GM Rossiter, SJ Holmes, EC Cui, J AF Wang, Lina Yin, Qiuyuan He, Guimei Rossiter, Stephen J. Holmes, Edward C. Cui, Jie TI Ancient invasion of an extinct gammaretrovirus in cetaceans SO VIROLOGY LA English DT Article DE Endogenous gammaretrovirus; Cetaceans; Molecular dating; Phylogeny ID ENDOGENOUS RETROVIRUSES; EVOLUTION; DISCOVERY; SEQUENCES AB Endogenous gammaretroviruses (EGVs) have been widely studied in terrestrial mammals but seldom so in marine species. A genomic mining of the bottlenose dolphin (Tursiops truncatus) genome revealed a new EGV, termed Tursiops truncatus endogenous retrovirus (TTEV), which is divergent from extant mammalian EGVs. Molecular clock dating estimated the invasion time of TTEV into the host genome to be approximately 10-19 million years ago (MYA), while a previously identified killer whale endogenous gammaretrovirus (KWERV) was estimated to have invaded the host genome approximately 3-5 MYA. Using a PCR-based technique, we then verified that similar endogenous viruses exist in nine cetacean genomes. Phylogenetic analysis revealed that these cetacean EGVs are highly divergent from their counterparts in other mammals, including KWERV from the killer whale. In sum, we conclude that there have been at least two invasion episodes of EGVs into cetaceans during their evolutionary history. (C) 2013 Elsevier Inc. All rights reserved. C1 [Wang, Lina; Yin, Qiuyuan; He, Guimei] E China Normal Univ, Inst Mol Ecol & Evolut, Inst Adv Interdisciplinary Res, Shanghai 200062, Peoples R China. [Rossiter, Stephen J.] Univ London, Sch Biol & Chem Sci, London E1 4NS, England. [Holmes, Edward C.; Cui, Jie] Univ Sydney, Sydney Emerging Infect & Biosecur Inst, Sch Biol Sci, Sydney, NSW 2006, Australia. [Holmes, Edward C.; Cui, Jie] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Cui, J (reprint author), Univ Sydney, Sydney Emerging Infect & Biosecur Inst, Sch Biol Sci, Sydney, NSW 2006, Australia. EM jiecui@yahoo.com RI Rossiter, Stephen/E-2111-2011; OI Cui, Jie/0000-0001-8176-9951; Holmes, Edward/0000-0001-9596-3552 NR 15 TC 3 Z9 3 U1 0 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 JUN 20 PY 2013 VL 441 IS 1 BP 66 EP 69 DI 10.1016/j.viro1.2013.03.006 PG 4 WC Virology SC Virology GA 147PU UT WOS:000319180300009 PM 23545142 ER PT J AU Cournil, A De Vincenzi, I Gaillard, P Cames, C Fao, P Luchters, S Rollins, N Newell, ML Bork, K Read, JS AF Cournil, Amandine De Vincenzi, Isabelle Gaillard, Philippe Cames, Cecile Fao, Paulin Luchters, Stanley Rollins, Nigel Newell, Marie-Louise Bork, Kirsten Read, Jennifer S. CA Kesho Bora Study Grp TI Relationship between mortality and feeding modality among children born to HIV-infected mothers in a research setting: the Kesho Bora Study SO AIDS LA English DT Article DE Africa; breastfeeding; HIV-exposed children; marginal structural models; mortality; replacement feeding ID UNINFECTED CHILDREN; POOLED ANALYSIS; INFANTS BORN; POSTNATAL TRANSMISSION; ANTIRETROVIRAL THERAPY; PROSPECTIVE COHORT; POSITIVE MOTHERS; FREE SURVIVAL; SOUTH-AFRICA; WOMEN AB Objective:To assess the relationship between infant feeding practices and mortality by 18 months of age among children born to HIV-infected mothers in the Kesho Bora trial (Burkina-Faso, Kenya and South Africa).Methods:Enrolled HIV-infected women were counseled to choose between breastfeeding up to 6 months or replacement feeding from delivery. Multivariable Cox models were used to compare the infant mortality risks according to feeding practices over time defined as never breastfed, weaned or still breastfed. The category still breastfed' was disaggregated as exclusively, predominantly or partially breastfed to compare modes of breastfeeding. The relationship between weaning and mortality was also assessed using marginal structural models to control for time-dependent confounders, such as maternal or infant morbidity (reverse causality).Results:Among 795 mothers, 618 (77.7%) initiated breastfeeding. Mortality rates by 18 months among uninfected and infected children were 6 and 38%, respectively. Never breastfed and weaned children were at greater risk of death compared with those still breastfed. Adjusted hazard ratios were 6.7 [95% confidence interval (CI)=2.5-17.9; P<0.001] and 6.9 (CI=2.8-17.2; P<0.001) for never breastfed and weaned children, respectively. Estimation of the effect of weaning using marginal structural models led to similar results. No statistically significant differences were observed according to mode of breastfeeding (exclusive, predominant or partial).Conclusion:Within 6 months after birth, weaned or never breastfed children were at about seven-fold higher risk of dying compared with children who were still breastfed despite a context in which interventions were provided to reduce risks associated with replacement feeding. C1 [Cournil, Amandine; Cames, Cecile; Bork, Kirsten] Univ Montpellier, Inst Rech Dev, F-34059 Montpellier, France. [De Vincenzi, Isabelle; Gaillard, Philippe] WHO, CH-1211 Geneva, Switzerland. [Fao, Paulin] Ctr Muraz, Bobo Dioulasso, Burkina Faso. [Luchters, Stanley] Int Ctr Reprod Hlth, Mombasa, Kenya. [Luchters, Stanley] Univ Ghent, Int Ctr Reprod Hlth, B-9000 Ghent, Belgium. [Luchters, Stanley] Burnet Inst, Ctr Int Hlth, Melbourne, Vic, Australia. [Rollins, Nigel] Univ KwaZulu Natal, Durban, South Africa. [Rollins, Nigel] WHO, Dept Maternal Newborn Child & Adolescent Hlth, CH-1211 Geneva, Switzerland. [Newell, Marie-Louise] Univ KwaZulu Natal, Africa Ctr Hlth & Populat Studies, Somkhele, South Africa. [Read, Jennifer S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Natl Inst Hlth, Bethesda, MD USA. [Read, Jennifer S.] NVPO OASH OS DHHS, Washington, DC USA. RP Cournil, A (reprint author), Inst Rech Dev, BP 64501, F-34394 Montpellier 5, France. EM amandine.cournil@ird.fr RI Van de Perre, Philippe/B-9692-2008; OI Van de Perre, Philippe/0000-0002-3912-0427; Bork, Kirsten/0000-0002-5909-7332; Newell, Marie-Louise/0000-0002-1074-7699; Njagi, Ephantus/0000-0002-1484-0241 FU l'Agence Nationale de Recherches sur le Sida et les Hepatites Virales (ANRS); UNDP/UNFPA/World Bank/WHO Special Programme of Research, Development and Research Training in Human Reproduction (WHO/HRP); ANRS; WHO/HRP; European and Developing Countries Clinical Trials Partnership (EDCTP); Thrasher Research Fund; Belgian Directorate General for International Cooperation FX The Bobo-Dioulasso site was funded by l'Agence Nationale de Recherches sur le Sida et les Hepatites Virales (ANRS) and UNDP/UNFPA/World Bank/WHO Special Programme of Research, Development and Research Training in Human Reproduction (WHO/HRP).; The Mombasa site was funded by ANRS, WHO/HRP, European and Developing Countries Clinical Trials Partnership (EDCTP), Thrasher Research Fund, Belgian Directorate General for International Cooperation. NR 45 TC 8 Z9 8 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD JUN 19 PY 2013 VL 27 IS 10 BP 1621 EP 1630 DI 10.1097/QAD.0b013e32835d5226 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 250HG UT WOS:000326840700011 PM 23262499 ER PT J AU Hobbs, CV De La Vega, P Penzak, SR Van Vliet, J Krzych, U Sinnis, P Borkowsky, W Duffy, PE AF Hobbs, Charlotte V. De La Vega, Patricia Penzak, Scott R. Van Vliet, Jillian Krzych, Urszula Sinnis, Photini Borkowsky, William Duffy, Patrick E. TI The effect of antiretrovirals on Plasmodium falciparum liver stages SO AIDS LA English DT Article ID TYPE-1 PROTEASE INHIBITORS; HUMAN HEPATOCYTE LINE; MALARIA PARASITES; IN-VITRO; SPOROZOITES; AGENTS C1 [Hobbs, Charlotte V.; Van Vliet, Jillian; Duffy, Patrick E.] NIAID, NIH, Lab Malaria Immunol & Vaccinol, Rockville, MD 20852 USA. [De La Vega, Patricia; Krzych, Urszula] Walter Reed Army Inst Res, Malaria Vaccine Branch, Dept Cellular Immunol, Silver Spring, MD USA. [Penzak, Scott R.] NIH, Dept Pharm, Ctr Clin, Clin Pharmacokinet Res Lab, Bethesda, MD 20892 USA. [Sinnis, Photini] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Borkowsky, William] NYU, Sch Med, Dept Pediat, Div Infect Dis & Immunol, New York, NY USA. RP Hobbs, CV (reprint author), NIAID, NIH, Rockville, MD 20852 USA. EM charlotte.hobbs@nih.gov FU NIH, NIAID, Division of Intramural Research; US Army and Materiel Command FX This work was funded by the NIH, NIAID, Division of Intramural Research and by the by the US Army and Materiel Command. NR 21 TC 8 Z9 8 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD JUN 19 PY 2013 VL 27 IS 10 BP 1674 EP 1677 DI 10.1097/QAD.0b013e3283621dd4 PG 4 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 250HG UT WOS:000326840700017 PM 23907270 ER PT J AU Liu, R Guo, XG Park, Y Wang, J Huang, XM Hollenbeck, A Blair, A Chen, HL AF Liu, Rui Guo, Xuguang Park, Yikyung Wang, Jian Huang, Xuemei Hollenbeck, Albert Blair, Aaron Chen, Honglei TI Alcohol Consumption, Types of Alcohol, and Parkinson's Disease SO PLOS ONE LA English DT Article ID FOOD-FREQUENCY QUESTIONNAIRE; HEALTH-AMERICAN-ASSOCIATION; RETIRED-PERSONS DIET; NATIONAL-INSTITUTES; PLASMA URATE; RISK; RESVERATROL; PREDICTOR; DEMENTIA; DECLINE AB Background: The epidemiologic evidence on alcohol consumption and Parkinson's disease (PD) is equivocal. We prospectively examined total alcohol consumption and consumption of specific types of alcoholic beverage in relation to future risk of PD. Methods: The study comprised 306,895 participants (180,235 male and 126,660 female) ages 50-71 years in 1995-1996 from the NIH-AARP Diet and Health Study. Consumption of alcoholic beverages in the past 12 months was assessed in 1995-1996. Multivariate odds ratios (OR) and 95% confidence intervals (CI) were obtained from logistic regression models. Results: A total of 1,113 PD cases diagnosed between 2000 and 2006 were included in the analysis. Total alcohol consumption was not associated with PD. However, the association differed by types of alcoholic beverages. Compared with non-beer drinkers, the multivariate ORs for beer drinkers were 0.79 (95% CI: 0.68, 0.92) for <1 drink/day, 0.73 (95% CI: 0.50, 1.07) for 1-1.99 drinks/day, and 0.86 (95% CI: 0.60, 1.21) for >= 2 drinks/day. For liquor consumption, a monotonic increase in PD risk was suggested: ORs (95% CI) were 1.06 (0.91, 1.23), 1.22 (0.94, 1.58), and 1.35 (1.02, 1.80) for<1, 1-1.99, and >= 2 drinks/day, respectively (P for trend <0.03). Additional analyses among exclusive drinkers of one specific type of alcoholic beverage supported the robustness of these findings. The results for wine consumption were less clear, although a borderline lower PD risk was observed when comparing wine drinkers of 1-1.99 drinks/day with none drinkers (OR = 0.74, 95% CI: 0.53, 1.02). Conclusions: Our results suggest that beer and liquor consumption may have opposite associations with PD: low to moderate beer consumption with lower PD risk and greater liquor consumption with higher risk. These findings and potential underlying mechanisms warrant further investigations. C1 [Liu, Rui; Chen, Honglei] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Guo, Xuguang] Westat Corp, Res Triangle Pk, NC USA. [Park, Yikyung; Blair, Aaron] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Wang, Jian] Fudan Univ, Dept Neurol, Huashan Hosp, Shanghai 200433, Peoples R China. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Neurol, Hershey, PA 17033 USA. [Hollenbeck, Albert] AARP, Washington, DC USA. RP Liu, R (reprint author), NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. EM liur2@niehs.nih.gov OI Chen, Honglei/0000-0003-3446-7779; Park, Yikyung/0000-0002-6281-489X FU National Institute of Health; National Institute of Environmental Health Sciences [Z01-ES-101986]; National Cancer Institute [Z01 CP010196-02] FX This study was supported by the intramural research program of the National Institute of Health, the National Institute of Environmental Health Sciences (Z01-ES-101986) and the National Cancer Institute (Z01 CP010196-02). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 24 TC 5 Z9 5 U1 1 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 JUN 19 PY 2013 VL 8 IS 6 AR e66452 DI 10.1371/journal.pone.0066452 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 190ST UT WOS:000322361200081 PM 23840473 ER PT J AU Manchia, M Adli, M Akula, N Ardau, R Aubry, JM Backlund, L Banzato, CEM Baune, BT Bellivier, F Bengesser, S Biernacka, JM Brichant-Petitjean, C Bui, E Calkin, CV Cheng, ATA Chillotti, C Cichon, S Clark, S Czerski, PM Dantas, C Del Zompo, M DePaulo, JR Detera-Wadleigh, SD Etain, B Falkai, P Frisen, L Frye, MA Fullerton, J Gard, S Garnham, J Goes, FS Grof, P Gruber, O Hashimoto, R Hauser, J Heilbronner, U Hoban, R Hou, LP Jamain, S Kahn, JP Kassem, L Kato, T Kelsoe, JR Kittel-Schneider, S Kliwicki, S Kuo, PH Kusumi, I Laje, G Lavebratt, C Leboyer, M Leckband, SG Jaramillo, CAL Maj, M Malafosse, A Martinsson, L Masui, T Mitchell, PB Mondimore, F Monteleone, P Nallet, A Neuner, M Novak, T O'Donovan, C Osby, U Ozaki, N Perlis, RH Pfennig, A Potash, JB Reich-Erkelenz, D Reif, A Reininghaus, E Richardson, S Rouleau, GA Rybakowski, JK Schalling, M Schofield, PR Schubert, OK Schweizer, B Seemuller, F Grigoroiu-Serbanescu, M Severino, G Seymour, LR Slaney, C Smoller, JW Squassina, A Stamm, T Steele, J Stopkova, P Tighe, SK Tortorella, A Turecki, G Wray, NR Wright, A Zandi, PP Zilles, D Bauer, M Rietschel, M McMahon, FJ Schulze, TG Alda, M AF Manchia, Mirko Adli, Mazda Akula, Nirmala Ardau, Raffaella Aubry, Jean-Michel Backlund, Lena Banzato, Claudio E. M. Baune, Bernhard T. Bellivier, Frank Bengesser, Susanne Biernacka, Joanna M. Brichant-Petitjean, Clara Bui, Elise Calkin, Cynthia V. Cheng, Andrew Tai Ann Chillotti, Caterina Cichon, Sven Clark, Scott Czerski, Piotr M. Dantas, Clarissa Del Zompo, Maria DePaulo, J. Raymond Detera-Wadleigh, Sevilla D. Etain, Bruno Falkai, Peter Frisen, Louise Frye, Mark A. Fullerton, Jan Gard, Sebastien Garnham, Julie Goes, Fernando S. Grof, Paul Gruber, Oliver Hashimoto, Ryota Hauser, Joanna Heilbronner, Urs Hoban, Rebecca Hou, Liping Jamain, Stephane Kahn, Jean-Pierre Kassem, Layla Kato, Tadafumi Kelsoe, John R. Kittel-Schneider, Sarah Kliwicki, Sebastian Kuo, Po-Hsiu Kusumi, Ichiro Laje, Gonzalo Lavebratt, Catharina Leboyer, Marion Leckband, Susan G. Lopez Jaramillo, Carlos A. Maj, Mario Malafosse, Alain Martinsson, Lina Masui, Takuya Mitchell, Philip B. Mondimore, Frank Monteleone, Palmiero Nallet, Audrey Neuner, Maria Novak, Tomas O'Donovan, Claire Osby, Urban Ozaki, Norio Perlis, Roy H. Pfennig, Andrea Potash, James B. Reich-Erkelenz, Daniela Reif, Andreas Reininghaus, Eva Richardson, Sara Rouleau, Guy A. Rybakowski, Janusz K. Schalling, Martin Schofield, Peter R. Schubert, Oliver K. Schweizer, Barbara Seemueller, Florian Grigoroiu-Serbanescu, Maria Severino, Giovanni Seymour, Lisa R. Slaney, Claire Smoller, Jordan W. Squassina, Alessio Stamm, Thomas Steele, Jo Stopkova, Pavla Tighe, Sarah K. Tortorella, Alfonso Turecki, Gustavo Wray, Naomi R. Wright, Adam Zandi, Peter P. Zilles, David Bauer, Michael Rietschel, Marcella McMahon, Francis J. Schulze, Thomas G. Alda, Martin TI Assessment of Response to Lithium Maintenance Treatment in Bipolar Disorder: A Consortium on Lithium Genetics (ConLiGen) Report SO PLOS ONE LA English DT Article ID MAPPING SUSCEPTIBILITY GENES; PROPHYLACTIC LITHIUM; OBSERVER AGREEMENT; MOOD DISORDERS; ONSET; ASSOCIATION; RELIABILITY; MORTALITY; ILLNESS; AGE AB Objective: The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the "Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder" scale currently used in the Consortium on Lithium Genetics (ConLiGen) study. Materials and Methods: Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (kappa)] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling. Results: Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (kappa = 0.66 and kappa = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (ICC1 = 0.71 and ICC2 = 0.75, respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders). Conclusions: We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study. C1 [Manchia, Mirko; Calkin, Cynthia V.; Garnham, Julie; O'Donovan, Claire; Slaney, Claire; Alda, Martin] Dalhousie Univ, Dept Psychiat, Halifax, NS, Canada. [Adli, Mazda; Stamm, Thomas] Charite, Dept Psychiat & Psychotherapy, D-13353 Berlin, Germany. [Akula, Nirmala; Bui, Elise; Detera-Wadleigh, Sevilla D.; Hou, Liping; Kassem, Layla; Laje, Gonzalo; Richardson, Sara; Steele, Jo; McMahon, Francis J.; Schulze, Thomas G.] NIMH, Human Genet Branch, Div Intramural Res Programs, NIH, Bethesda, MD 20892 USA. [Ardau, Raffaella; Chillotti, Caterina; Del Zompo, Maria] Univ Hosp Cagliari, Clin Pharmacol Unit, Cagliari, Italy. [Aubry, Jean-Michel; Malafosse, Alain; Nallet, Audrey] Hop Univ Geneve, Dept Mental Hlth & Psychiat, Geneva, Switzerland. [Backlund, Lena; Frisen, Louise; Martinsson, Lina] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. [Banzato, Claudio E. M.; Dantas, Clarissa] Univ Estadual Campinas, Dept Psychiat, Campinas, Brazil. [Baune, Bernhard T.; Clark, Scott; Schubert, Oliver K.] Univ Adelaide, Dept Psychiat, Adelaide, SA, Australia. [Bellivier, Frank; Brichant-Petitjean, Clara] Grp Hosp Lariboisiere F Widal, AP HP, Paris, France. [Bengesser, Susanne; Reininghaus, Eva] Med Univ Graz, Dept Psychiat, Graz, Austria. [Biernacka, Joanna M.; Frye, Mark A.; Seymour, Lisa R.] Mayo Clin, Dept Psychiat, Rochester, MN USA. [Cheng, Andrew Tai Ann] Acad Sinica, Inst Biomed Sci, Div Epidemiol & Genet, Taipei, Taiwan. [Cichon, Sven] Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany. [Cichon, Sven] Univ Bonn, Inst Human Genet, Bonn, Germany. [Czerski, Piotr M.] Poznan Univ Med Sci, Psychiat Genet Unit, Poznan, Poland. [Del Zompo, Maria; Severino, Giovanni; Squassina, Alessio] Univ Cagliari, Dept Biomed Sci, Sect Neurosci & Clin Pharmacol, Cagliari, Italy. [DePaulo, J. Raymond; Goes, Fernando S.; Mondimore, Frank; Potash, James B.; Schweizer, Barbara; Tighe, Sarah K.; Schulze, Thomas G.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Etain, Bruno; Jamain, Stephane; Leboyer, Marion] Fac Med, Equipe 15, Inst Mondor Rech Biomed, INSERM,Unite 955, Creteil, France. [Falkai, Peter; Seemueller, Florian] Univ Munich, Dept Psychiat & Psychotherapy, Munich, Germany. [Fullerton, Jan; Schofield, Peter R.] Neurosci Res Australia Genet Mental Illness & Bra, Sydney, NSW, Australia. [Gard, Sebastien] Hop Charles Perrens, Psychiat Serv, Bordeaux, France. [Grof, Paul] Mood Disorders Ctr Ottawa, Ottawa, ON, Canada. [Grof, Paul] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Gruber, Oliver; Heilbronner, Urs; Reich-Erkelenz, Daniela; Zilles, David; Schulze, Thomas G.] Univ Gottingen, Dept Psychiat & Psychotherapy, D-37073 Gottingen, Germany. [Hashimoto, Ryota] Osaka Univ, Grad Sch Med, Osaka, Japan. [Hauser, Joanna] Poznan Univ Med Sci, Psychiat Genet Unit, Poznan, Poland. [Hoban, Rebecca; Kelsoe, John R.; Leckband, Susan G.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Hoban, Rebecca; Kelsoe, John R.] Vet Affairs San Diego Healthcare Syst, Dept Psychiat, San Diego, CA USA. [Kahn, Jean-Pierre] Ctr Hosp Univ Nancy, Serv Psychiat & Psychol Clin, Nancy, France. [Kato, Tadafumi; Kusumi, Ichiro] RIKEN, Brain Sci Inst, Lab Mol Dynam Mental Disorders, Saitama, Japan. [Kittel-Schneider, Sarah; Neuner, Maria; Reif, Andreas] Univ Wurzburg, Dept Psychiat Psychosomat & Psychotherapy, D-97070 Wurzburg, Germany. [Kliwicki, Sebastian; Rybakowski, Janusz K.] Poznan Univ Med Sci, Dept Adult Psychiat, Poznan, Poland. [Kuo, Po-Hsiu] Natl Taiwan Univ, Inst Epidemiol & Prevent Med, Taipei 10764, Taiwan. [Kusumi, Ichiro; Masui, Takuya] Hokkaido Univ, Grad Sch Med, Dept Psychiat, Sapporo, Hokkaido, Japan. [Lavebratt, Catharina; Osby, Urban; Schalling, Martin] Karolinska Univ Hosp, Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Lavebratt, Catharina; Osby, Urban; Schalling, Martin] Karolinska Univ Hosp, Ctr Mol Med, Stockholm, Sweden. [Leckband, Susan G.] Vet Affairs San Diego Healthcare Syst, Dept Pharm, San Diego, CA USA. [Leckband, Susan G.] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, San Diego, CA 92103 USA. [Lopez Jaramillo, Carlos A.] Univ Antioquia, Dept Psychiat, Medellin, Colombia. [Maj, Mario; Monteleone, Palmiero; Tortorella, Alfonso] Univ Naples Federico II, Dept Psychiat, Naples, Italy. [Mitchell, Philip B.; Wright, Adam] Univ New S Wales, Sch Psychiat, Sydney, NSW, Australia. [Mitchell, Philip B.; Wright, Adam] Black Dog Inst, Sydney, NSW, Australia. [Novak, Tomas; Stopkova, Pavla] Univ Prague, Prague Psychiat Ctr, Prague, Czech Republic. [Ozaki, Norio] Fujita Hlth Univ, Sch Med, Dept Psychiat, Toyoake, Aichi 47011, Japan. [Ozaki, Norio] Nagoya Univ, Grad Sch Med, Dept Psychiat, Nagoya, Aichi 4648601, Japan. [Perlis, Roy H.; Smoller, Jordan W.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Perlis, Roy H.; Smoller, Jordan W.] Harvard Univ, Sch Med, Boston, MA USA. [Pfennig, Andrea; Bauer, Michael] Tech Univ Dresden, Dept Psychiat & Psychotherapy, Dresden, Germany. [Potash, James B.] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. [Rouleau, Guy A.] Univ Montreal, Ctr Hosp Univ Montreal, Ctr Excellence Neurosci, Montreal, PQ, Canada. [Rouleau, Guy A.] Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada. [Grigoroiu-Serbanescu, Maria] Alexandru Obregia Psychiat Hosp, Biometr Psychiat Genet Res Unit, Bucharest, Romania. [Turecki, Gustavo] Douglas Mental Hlth Univ Inst, McGill Grp Suicide Studies, Montreal, PQ, Canada. [Wray, Naomi R.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. [Zandi, Peter P.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Rietschel, Marcella; Schulze, Thomas G.] Heidelberg Univ, Univ Med Ctr Mannheim, Cent Inst Mental Hlth Mannheim, Dept Genet Epidemiol Psychiat, Mannheim, Germany. RP Schulze, TG (reprint author), NIMH, Human Genet Branch, Div Intramural Res Programs, NIH, Bethesda, MD 20892 USA. EM thomas.schulze@med.uni-goettingen.de; malda@dal.ca RI Banzato, Claudio/B-2517-2008; Cichon, Sven/H-8803-2013; Cichon, Sven/B-9618-2014; Ozaki, Norio/M-8908-2014; Hou, Liping/G-1648-2011; BELLIVIER, FRANK/H-5197-2012; Novak, Tomas/B-8008-2017; Kato, Tadafumi/J-3583-2014; Serbanescu, Maria/D-4306-2011; Hashimoto, Ryota/P-8572-2014; Wray, Naomi/C-8639-2015 OI Kuo, Po-Hsiu/0000-0003-0365-3587; Jamain, Stephane/0000-0002-4321-4100; McMahon, Francis/0000-0002-9469-305X; Backlund, Lena/0000-0001-9399-5024; Banzato, Claudio/0000-0002-8556-3982; Manchia, Mirko/0000-0003-4175-6413; Lavebratt, Catharina/0000-0003-4987-2718; Reininghaus, Eva/0000-0001-5964-4087; Kittel-Schneider, Sarah/0000-0003-3057-6150; Mitchell, Philip/0000-0002-7954-5235; Lopez, Carlos/0000-0002-1875-1369; Cichon, Sven/0000-0002-9475-086X; Cichon, Sven/0000-0002-9475-086X; Ozaki, Norio/0000-0002-7360-4898; Hou, Liping/0000-0003-3972-245X; Novak, Tomas/0000-0001-9156-9654; Kato, Tadafumi/0000-0001-7856-3952; Serbanescu, Maria/0000-0002-1304-6687; Hashimoto, Ryota/0000-0002-5941-4238; Wray, Naomi/0000-0001-7421-3357 FU Canadian Institutes of Health Research [64410]; Unitatea Executiva pentru Finantarea Invatamantului Superior, a Cercetarii, Dezvoltarii si Inovarii (UEFISCDI), Bucharest, Romania [89/2012]; Swiss National Foundation [32003B_125469/1]; National Institute of Mental Health (NIMH) at the National Institutes of Health (NIH), Department of Health and Human Services, United States Government; Deutsche Forschungsgemeinschaft [RI 908/7-1] FX The work on assessment of lithium response has been supported by a grant from Canadian Institutes of Health Research #64410 to MA. MG-S was supported by Unitatea Executiva pentru Finantarea Invatamantului Superior, a Cercetarii, Dezvoltarii si Inovarii (UEFISCDI), Bucharest, Romania (grant no. 89/2012). JMA and AN were supported by a grant from the Swiss National Foundation (#32003B_125469/1 to JM Aubry). ConLiGen is in part supported by funds from the Intramural Research Program of the National Institute of Mental Health (NIMH) at the National Institutes of Health (NIH), Department of Health and Human Services, United States Government. It is further supported by a grant from the Deutsche Forschungsgemeinschaft to MR, MB, and TGS (RI 908/7-1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 25 Z9 26 U1 7 U2 32 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 JUN 19 PY 2013 VL 8 IS 6 AR e65636 DI 10.1371/journal.pone.0065636 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 190ST UT WOS:000322361200028 PM 23840348 ER PT J AU Guo, ZY Li, CZ Li, XJ Wang, YL Mattson, MP Lu, CB AF Guo, Zhi Y. Li, Cheng Z. Li, Xiao J. Wang, Ya L. Mattson, Mark P. Lu, Cheng B. TI The developmental regulation of glutamate receptor-mediated calcium signaling in primary cultured rat hippocampal neurons SO NEUROREPORT LA English DT Article DE -amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor; calcium; cell culture; N-methyl-D-aspartate receptor; voltage-dependent calcium channels ID LONG-TERM POTENTIATION; NMDA RECEPTORS; AMPA RECEPTORS; CELL-DEATH AB We have studied the developmental changes of glutamate-induced calcium (Ca2+) response in primary cultured hippocampal neurons at three different stages of cultures, 3, 7-8, and 14-16 days in vitro (DIV), using fura-2 single-cell digital micro-fluorimetry. We found that glutamate-induced Ca2+ signaling was altered during development, and that two different ionotropic glutamate receptors, -amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPARs) and N-methyl-D-aspartate receptors (NMDARs), were differently involved in the modulation of calcium response at different stages of neuronal culture. In the stages of culture at 3 and 8 DIV, glutamate-induced Ca2+ influx was mostly because of AMPAR activation and subsequent opening of voltage-dependent calcium channels, as Ca2+ response can be largely reduced by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and by nifedipine. In the advanced culture (14-17 DIV), glutamate-induced Ca2+ response was less sensitive to 6-cyano-7-nitroquinoxaline-2,3-dione and nifedipine. Furthermore, AMPA-induced Ca2+ response increased in a time-dependent manner during the cultures of 3-8 DIV and then reduced in the advanced culture of 14-17 DIV. NMDA-induced Ca2+ influx increased in a time-dependent manner, with a marked increase in the advanced culture (14-17 DIV). These results suggest that glutamate-induced Ca2+ signaling switched from AMPA-voltage-dependent calcium channel to NMDA-calcium signaling during development. C1 [Guo, Zhi Y.; Li, Cheng Z.; Li, Xiao J.; Wang, Ya L.; Lu, Cheng B.] Xinxiang Med Univ, Dept Physiol & Neurobiol, Xinxiang 453003, Peoples R China. [Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Lu, CB (reprint author), Xinxiang Med Univ, Dept Physiol & Neurobiol, Key Lab Brain Res Henan Prov, Xinxiang 453003, Peoples R China. EM johnlu9001@hotmail.com FU National Science Foundation [31070938, 81271422]; Intramural Research Program of the National Institute on Aging, NIH FX This research was supported by the National Science Foundation (31070938; 81271422) and the Intramural Research Program of the National Institute on Aging, NIH. NR 21 TC 5 Z9 6 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD JUN 19 PY 2013 VL 24 IS 9 BP 492 EP 497 DI 10.1097/WNR.0b013e32836206b5 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 202KH UT WOS:000323213800009 PM 23660635 ER PT J AU Poland, GA Quill, H Togias, A AF Poland, Gregory A. Quill, Helen Togias, Alkis TI Understanding the human immune system in the 21st century: The Human Immunology Project Consortium SO VACCINE LA English DT Editorial Material C1 [Poland, Gregory A.] Mayo Clin & Mayo Fdn, Mayo Vaccine Res Grp, Rochester, MN 55905 USA. [Quill, Helen] NIAID, Basic Immunol Branch, Bethesda, MD 20817 USA. [Togias, Alkis] NIAID, Allergy Asthma & Airway Biol Branch, Bethesda, MD 20817 USA. RP Poland, GA (reprint author), Mayo Clin & Mayo Fdn, Mayo Vaccine Res Grp, Rochester, MN 55905 USA. EM poland.gregory@mayo.edu; helen.quill@nih.gov; alkis.togias@nih.gov NR 0 TC 5 Z9 5 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JUN 19 PY 2013 VL 31 IS 28 BP 2911 EP 2912 DI 10.1016/j.vaccine.2013.04.043 PG 2 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 175KW UT WOS:000321230600001 PM 23648045 ER PT J AU Shimp, RL Rowe, C Reiter, K Chen, B Nguyen, V Aebig, J Rausch, KM Kumar, K Wu, YM Jin, AJ Jones, DS Narum, DL AF Shimp, Richard L., Jr. Rowe, Christopher Reiter, Karine Chen, Beth Vu Nguyen Aebig, Joan Rausch, Kelly M. Kumar, Krishan Wu, Yimin Jin, Albert J. Jones, David S. Narum, David L. TI Development of a Pfs25-EPA malaria transmission blocking vaccine as a chemically conjugated nanoparticle SO VACCINE LA English DT Article DE Pfs25; Malaria; Transmission blocking vaccine; Nanoparticle; Chemical-conjugate; Recombinant protein ID SECONDARY STRUCTURE ANALYSES; PLASMODIUM-FALCIPARUM; MEMBRANE-PROTEIN; SURFACE-PROTEINS; CANDIDATE; ANTIBODY; CRYSTALLIZATION; IMMUNOGENICITY; RESPONSES; PEPTIDES AB Successful efforts to control infectious diseases have often required the use of effective vaccines. The current global strategy for control of malaria, including elimination and eradication will also benefit from the development of an effective vaccine that interrupts malaria transmission. To this end, a vaccine that disrupts malaria transmission within the mosquito host has been investigated for several decades targeting a 25 kDa ookinete specific surface protein, identified as Pfs25. Phase 1 human trial results using a recombinant Pfs25H/Montanide ISA51 formulation demonstrated that human Pfs25 specific antibodies block parasite infectivity to mosquitoes; however, the extent of blocking was likely insufficient for an effective transmission blocking vaccine. To overcome the poor immunogenicity, processes to produce and characterize recombinant Pfs25H conjugated to a detoxified form of Pseudomonas aeruginosa exoprotein A (EPA) have been developed and used to manufacture a cGMP pilot lot for use in human clinical trials. The Pfs25-EPA conjugate appears as a nanoparticle with an average molar mass in solution of approximately 600 kDa by static light scattering with an average diameter 20 nm (range 10-40 nm) by dynamic light scattering. The molar ratio of Pfs25H to EPA is about 3 to 1 by amino acid analysis, respectively. Outbred mice immunized with the Pfs25-EPA conjugated nanoparticle formulated on Alhydrogel(R) had a 75-110 fold increase in Pfs25H specific antibodies when compared to an unconjugated Pfs25H/Alhydrogel(R) formulation. A phase 1 human trial using the Pfs25-EPA/Alhydrogel(R) formulation is ongoing in the United States. Published by Elsevier Ltd. C1 [Shimp, Richard L., Jr.; Rowe, Christopher; Reiter, Karine; Chen, Beth; Vu Nguyen; Aebig, Joan; Rausch, Kelly M.; Kumar, Krishan; Wu, Yimin; Jones, David S.; Narum, David L.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD 20852 USA. [Jin, Albert J.] Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. RP Narum, DL (reprint author), NIAID, Lab Malaria Immunol & Vaccinol, NIH, Twinbrook 1,Room 1115, Rockville, MD 20852 USA. EM dnarum@niaid.nih.gov OI Jin, Albert/0000-0003-3826-1081 FU Intramural Research Program of the NIH, including NIAID and NIBIB FX We acknowledge the support of those within the units of the LMIV core, especially Emma Barnafo for formulation, Lynn Lambert for excellent animal husbandry, Dominique Jones for analytical support and Olga Muratova for performing the membrane feeding assays. Dr. Svetlana Kotova provided excellent technical support for the AFM studies. We thank Drs. Michael Nold (Waters Corp.) and L. Renee Olano (Research Technology Branch, NIAID, NIH) for their critical evaluation of the quantitative peptide mapping analysis. We appreciate the work of Brian Bell and Jay Wood for the successful technology transfer to the WRAIR Biopilot Production facility. This research was supported by the Intramural Research Program of the NIH, including NIAID and NIBIB. NR 29 TC 29 Z9 30 U1 2 U2 22 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JUN 19 PY 2013 VL 31 IS 28 BP 2954 EP 2962 DI 10.1016/j.vaccine.2013.04.034 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 175KW UT WOS:000321230600007 PM 23623858 ER PT J AU Guo, J Xu, XH Rasheed, TK Yoder, A Yu, DY Liang, HZ Yi, F Hawley, T Jin, T Ling, BH Wu, YT AF Guo, Jia Xu, Xuehua Rasheed, Taban K. Yoder, Alyson Yu, Dongyang Liang, Huizhi Yi, Fei Hawley, Todd Jin, Tian Ling, Binhua Wu, Yuntao TI Genistein interferes with SDF-1-and HIV-mediated actin dynamics and inhibits HIV infection of resting CD4 T cells SO RETROVIROLOGY LA English DT Article DE HIV-1; Actin; SDF-1; Genistein; Sunitinib; Cofilin; LIMK1 ID MATRIX-METALLOPROTEINASE TYPE-2; TYROSINE PHOSPHORYLATION; PROSTATE-CANCER; CORTICAL ACTIN; COFILIN PHOSPHORYLATION; CHEMOKINE RECEPTOR; HUMAN MACROPHAGES; BINDING PROTEINS; NEF PROTEIN; LIM-KINASE AB Background: Binding of HIV to the chemokine coreceptor CXCR4 mediates viral fusion and signal transduction that promotes actin dynamics critical for HIV infection of blood resting CD4 T cells. It has been suggested that this gp 120-mediated actin activity resembles the chemotactic actin dynamics mediated by chemokines such as SDF-1. To determine whether inhibiting SDF-1-mediated chemotactic activity can also inhibit HIV infection, we screened several inhibitors known to reduce SDF-1-mediated chemotaxis of T cells. Results: We found that a tyrosine kinase inhibitor, genistein, inhibited both SDF-1-mediated chemotaxis and HIV infection of resting CD4 T cells. Genistein was also found to interfere with SDF-1- and HIV-mediated actin dynamics in CD4 T cells. This reduction in actin activity correlates with genistein-mediated inhibition of viral DNA accumulation in resting CD4 T cells. In addition, we also tested two other tyrosine kinase inhibitors, sunitinib and AG1478. Sunitinib, but not AG1478, inhibited HIV infection of resting CD4 T cells. We further tested the safety of genistein in 3 Chinese rhesus macaques (Macaca mulatta), and each animal was given a monotherapy of genistein at 10 mg/kg orally for 12 weeks. No adverse drug effects were observed in these animals. Conclusions: Our results suggest that novel therapeutic strategies can be developed based on targeting cellular proteins involved in HIV-dependent signaling. This approach can interfere with HIV-mediated actin dynamics and inhibit HIV infection. C1 [Guo, Jia; Rasheed, Taban K.; Yoder, Alyson; Yu, Dongyang; Liang, Huizhi; Yi, Fei; Hawley, Todd; Wu, Yuntao] George Mason Univ, Natl Ctr Biodef & Infect Dis, Dept Mol & Microbiol, Manassas, VA 20110 USA. [Xu, Xuehua; Jin, Tian] NIAID, NIH, Twinbrook Facil, Immunogenet Lab,Chemotaxis Signal Sect, Rockville, MD 20852 USA. [Ling, Binhua] Tulane Univ, Hlth Sci Ctr, Tulane Natl Primate Res Ctr, Div Comparat Pathol, Covington, LA 70433 USA. RP Wu, YT (reprint author), George Mason Univ, Natl Ctr Biodef & Infect Dis, Dept Mol & Microbiol, Manassas, VA 20110 USA. EM ywu8@gmu.edu RI Guo, Jia/L-2102-2013; Guo, Jia/C-8678-2014; OI xu, xuehua/0000-0002-3863-9593 FU NIH Public Health Service Grant from NIAID [1R01AI081568]; NIAID [R01 AI093307-01A1]; National Center for Research Resources; Office of Research Infrastructure Programs (ORIP) of NIH [OD011104-51]; NYCDC AIDS Ride FX We thank the George Mason University (GMU) Student Health Center for blood donations; the NIH AIDS Research and Reference Reagent Program, NIAID, NIH for reagents; Ann-Marie Johnson for technical support; the veterinary staff at the Tulane National Primate Research Center; M. Rosen and the donors and riders from the 2010 NYCDC AIDS Ride. This work was supported by NIH Public Health Service Grant grants 1R01AI081568 from NIAID to YW; R01 AI093307-01A1 from NIAID to BL; the National Center for Research Resources, and the Office of Research Infrastructure Programs (ORIP) of NIH (through grant OD011104-51). The study was supported in part by the 2010 NYCDC AIDS Ride organized by M. Rosen. NR 83 TC 6 Z9 7 U1 2 U2 11 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 JUN 19 PY 2013 VL 10 AR 62 DI 10.1186/1742-4690-10-62 PG 15 WC Virology SC Virology GA 171SL UT WOS:000320949300001 PM 23782904 ER PT J AU Spong, CY AF Spong, Catherine Y. TI Defining "Term" Pregnancy Recommendations From the Defining "Term" Pregnancy Workgroup SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID HEALTH; CARE C1 [Spong, Catherine Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Spong, CY (reprint author), NICHHD, NIH, 6100 Execut Blvd,Room 4B03,MSC 7510, Bethesda, MD 20892 USA. EM spongc@mail.nih.gov NR 8 TC 95 Z9 99 U1 0 U2 9 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 19 PY 2013 VL 309 IS 23 BP 2445 EP 2446 DI 10.1001/jama.2013.6235 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 165SW UT WOS:000320505100023 PM 23645117 ER PT J AU Hsu, CH Ovcharenko, I AF Hsu, Chih-Hao Ovcharenko, Ivan TI Effects of gene regulatory reprogramming on gene expression in human and mouse developing hearts SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE gene regulation; lineage-specific heart enhancers; cis-regulatory evolution ID UCSC GENOME BROWSER; ELEMENTS; ENHANCERS; CHIP; TRANSCRIPTION; CHROMATIN; IDENTIFICATION; PROMOTERS; DYNAMICS; DATABASE AB Lineage-specific regulatory elements underlie adaptation of species and play a role in disease susceptibility. We compared functionally conserved and lineage-specific enhancers by cross-mapping 5042 human and 6564 mouse heart enhancers. Of these, 79 per cent are lineage-specific, lacking a functional orthologue. Heart enhancers tend to cluster and, commonly, there are multiple heart enhancers in a heart locus providing a regulatory stability to the locus. We observed little cross-clustering, however, between lineage-specific and functionally conserved heart enhancers suggesting regulatory function acquisition and development in loci previously lacking heart activity. We also identified 862 human-specific heart enhancers: 417 featuring sequence conservation with mouse (class II) and 445 with neither sequence nor function conservation (class III). Ninety-eight per cent of class III enhancers were deleted from the mouse genome, and we estimated a similar-sized enhancer gain in the human lineage. Human-specific enhancers display no detectable decrease in the negative selection pressure and are strongly associated with genes partaking in the heart regulatory programmes. The loss of a heart enhancer could be compensated by activity of a redundant heart enhancer; however, we observed redundancy in only 15 per cent of class II and III enhancer loci indicating a large-scale reprogramming of the heart regulatory programme in mammals. C1 [Hsu, Chih-Hao; Ovcharenko, Ivan] NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Ovcharenko, I (reprint author), NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM ovcharen@nih.gov FU Intramural Research Program of the NIH, National Library of Medicine FX This research was supported by the Intramural Research Program of the NIH, National Library of Medicine. We are also grateful to the reviewers of the manuscript for their input and suggestions, which have been invaluable in improving the manuscript. NR 35 TC 3 Z9 3 U1 0 U2 9 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 EI 1471-2970 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD JUN 19 PY 2013 VL 368 IS 1620 AR 20120366 DI 10.1098/rstb.2012.0366 PG 9 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 139WD UT WOS:000318614800008 PM 23650638 ER PT J AU Khadra, A Tomic, M Yan, ZH Zemkova, H Sherman, A Stojilkovic, SS AF Khadra, Anmar Tomic, Melanija Yan, Zonghe Zemkova, Hana Sherman, Arthur Stojilkovic, Stanko S. TI Dual Gating Mechanism and Function of P2X7 Receptor Channels SO BIOPHYSICAL JOURNAL LA English DT Article ID P2X(7) RECEPTOR; AGONIST BINDING; ACTIVATION; CALCIUM; INTERNALIZATION; PERMEATION; KINETICS; CURRENTS; CELLS; DYES AB The ATP-gated P2X7 receptor channel (P2X7R) operates as a cytolytic and apoptotic receptor but also controls sustained cellular responses, including cell growth and proliferation. However, it has not been clarified how the same receptor mediates such opposing effects. To address this question, we have combined electrophysiological, imaging, and mathematical studies using wild-type and mutant rat P2X7Rs. Activation of naive (not previously stimulated) receptors by low agonist concentrations caused monophasic slow desensitizing currents and internalization of receptors without other changes in the cellular morphology, much like other P2XRs. In contrast, saturating agonist concentrations induced high-amplitude biphasic currents, reflecting pore dilation and causing rapid cell swelling and lysis. The existence of these two signaling patterns was accounted for using a revised Markov-state model that included, in addition to naive and sensitized states, desensitized states. Occupancy of one or two ATP-binding sites of naive receptors favored a slow transition to desensitized states, whereas occupancy of the third binding site favored a transition to sensitized/dilated states. Consistent with model predictions, nondilating P2X7R mutants always generated desensitizing currents. These results suggest that the level of saturation of the ligand binding sites determines the nature of the P2X7R gating and cellular actions. C1 [Khadra, Anmar] McGill Univ, Dept Physiol, Montreal, PQ, Canada. [Tomic, Melanija; Yan, Zonghe; Stojilkovic, Stanko S.] NICHHD, Sect Cellular Signaling, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Zemkova, Hana] Acad Sci Czech Republic, Inst Phys, Dept Cellular & Mol Neuroendocrinol, Prague, Czech Republic. [Sherman, Arthur] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD USA. RP Khadra, A (reprint author), McGill Univ, Dept Physiol, Montreal, PQ, Canada. EM anmar.khadra@mcgill.ca RI Zemkova, Hana/C-1844-2012; Tomic, Melanija/C-3371-2016 FU National Institute of Child Health and Human Development; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Grant Agency of the Czech Republic [P304/12/G069]; McGill University FX This work was supported by the Intramural Research Program of the National Institute of Child Health and Human Development and National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, the Grant Agency of the Czech Republic (P304/12/G069), and the McGill University. NR 31 TC 17 Z9 17 U1 1 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JUN 18 PY 2013 VL 104 IS 12 BP 2612 EP 2621 DI 10.1016/j.bpj.2013.05.006 PG 10 WC Biophysics SC Biophysics GA 169DI UT WOS:000320757100006 PM 23790369 ER PT J AU Zheng, XH Mueller, GA DeRose, EF London, RE AF Zheng, Xunhai Mueller, Geoffrey A. DeRose, Eugene F. London, Robert E. TI Protein-Mediated Antagonism between HIV Reverse Transcriptase Ligands Nevirapine and MgATP SO BIOPHYSICAL JOURNAL LA English DT Article ID HIGH-RESOLUTION STRUCTURES; NONNUCLEOSIDE INHIBITOR; RESISTANCE MUTATIONS; CONFORMATIONAL FLEXIBILITY; CRYSTAL-STRUCTURES; DRUG-RESISTANCE; SLOW DYNAMICS; TROSY NMR; MECHANISM; COMPLEXES AB Nonnucleoside reverse transcriptase inhibitors (NNRTIs) play a central role in the treatment of AIDS, but their mechanisms of action are incompletely understood. The interaction of the NNRTI nevirapine (NVP) with HIV-1 reverse transcriptase (RT) is characterized by a preference for the open conformation of the fingers/thumb subdomains, and a reported variation of three orders of magnitude between the binding affinity of NVP for RT in the presence or absence of primer/template DNA. To investigate the relationship between conformation and ligand binding, we evaluated the use of methionine NMR probes positioned near the tip of the fingers or thumb subdomains. Such probes would be expected to be sensitive to changes in the local environment depending on the fractions of open and closed RT. Comparisons of the NMR spectra of three conservative mutations, I63M, L74M, and L289M, indicated that M63 showed the greatest shift sensitivity to the addition of NVP. The exchange kinetics of the M63 resonance are fast on the chemical shift timescale, but become slow in the presence of NVP due to the slow binding of RT with the inhibitor. The simplest model consistent with this behavior involves a rapid open/closed equilibrium coupled with a slow interaction of the inhibitor with the open conformation. Studies of RT in the presence of both NVP and MgATP indicate a strong negative cooperativity. Binding of MgATP reduces the fraction of RT bound to NVP, as indicated by the intensity of the NVP-perturbed M230 resonance, and enhances the dissociation rate constant of the NVP, resulting in an increase of the open/closed interconversion rate, so that the M63 resonance moves into the fast/intermediate-exchange regime. Protein-mediated interactions appear to explain most of the affinity variation of NVP for RT. C1 [Zheng, Xunhai; Mueller, Geoffrey A.; DeRose, Eugene F.; London, Robert E.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP London, RE (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM london@niehs.nih.gov RI Zheng, Xunhai/G-1187-2015 OI Zheng, Xunhai/0000-0003-0390-2491 FU Intramural National Institutes of Health (NIH) Research Program of the National Institute of Environmental Health Sciences (NIEHS) [Z01-ES050147]; NIEHS; NIH [HHSN273200700046U] FX This research was supported by the Intramural National Institutes of Health (NIH) Research Program of the National Institute of Environmental Health Sciences (NIEHS; grant Z01-ES050147 to R.E.L.). E.F.D. is supported by the NIEHS, NIH, under Delivery Order HHSN273200700046U. NVP was obtained from the NIH AIDS Research and Reference Reagent Program. NR 48 TC 5 Z9 5 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JUN 18 PY 2013 VL 104 IS 12 BP 2695 EP 2705 DI 10.1016/j.bpj.2013.04.015 PG 11 WC Biophysics SC Biophysics GA 169DI UT WOS:000320757100015 PM 23790378 ER PT J AU Xu, BY Zhi, N Hu, GQ Wan, ZH Zheng, XB Liu, XH Wong, SS Kajigaya, S Zhao, KJ Mao, Q Young, NS AF Xu, Baoyan Zhi, Ning Hu, Gangqing Wan, Zhihong Zheng, Xiaobin Liu, Xiaohong Wong, Susan Kajigaya, Sachiko Zhao, Keji Mao, Qing Young, Neal S. TI Hybrid DNA virus in Chinese patients with seronegative hepatitis discovered by deep sequencing SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE hepatitis-associated aplastic anemia; liver failure; Solexa sequencing; virological diagnosis ID NON-A; NON-B; TRANSPLANT PATIENTS; B19 PARVOVIRUS; UNITED-STATES; NON-C; DISEASE; EVOLUTION; LIVER; ETIOLOGY AB Seronegative hepatitis-non-A, non-B, non-C, non-D, non-E hepatitis-is poorly characterized but strongly associated with serious complications. We collected 92 sera specimens from patients with non-A-E hepatitis in Chongqing, China between 1999 and 2007. Ten sera pools were screened by Solexa deep sequencing. We discovered a 3,780-bp contig present in all 10 pools that yielded BLASTx E scores of 7e-05-0.008 against parvoviruses. The complete sequence of the in silico-assembled 3,780-bp contig was confirmed by gene amplification of overlapping regions over almost the entire genome, and the virus was provisionally designated NIH-CQV. Further analysis revealed that the contig was composed of two major ORFs. By protein BLAST, ORF1 and ORF2 were most homologous to the replication-associated protein of bat circovirus and the capsid protein of porcine parvovirus, respectively. Phylogenetic analysis indicated that NIH-CQV is located at the interface of Parvoviridae and Circoviridae. Prevalence of NIH-CQV in patients was determined by quantitative PCR. Sixty-three of 90 patient samples (70%) were positive, but all those from 45 healthy controls were negative. Average virus titer in the patient specimens was 1.05 e4 copies/mu L. Specific antibodies against NIH-CQV were sought by immunoblotting. Eighty-four percent of patients were positive for IgG, and 31% were positive for IgM; in contrast, 78% of healthy controls were positive for IgG, but all were negative for IgM. Although more work is needed to determine the etiologic role of NIH-CQV in human disease, our data indicate that a parvovirus-like virus is highly prevalent in a cohort of patients with non-A-E hepatitis. C1 [Xu, Baoyan; Zhi, Ning; Wan, Zhihong; Liu, Xiaohong; Wong, Susan; Kajigaya, Sachiko; Young, Neal S.] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Hu, Gangqing; Zhao, Keji] NHLBI, Syst Biol Ctr, Bethesda, MD 20892 USA. [Xu, Baoyan; Mao, Qing] Third Mil Med Univ, Southwest Hosp, Inst Infect Dis, Chongqing 400038, Peoples R China. [Zheng, Xiaobin] Carnegie Inst Sci, Dept Embryol, Baltimore, MD 21218 USA. RP Zhi, N (reprint author), NHLBI, Hematol Branch, Bethesda, MD 20892 USA. EM zhin@nhlbi.nih.gov; qingmao@yahoo.com RI HU, GANGQING/K-5849-2012 FU National Institutes of Health Intramural Research Program FX We thank Dr. Jun Zhu at the DNA Sequencing and Genomics Core of the National Heart, Lung, and Blood Institute (NHLBI) for assistance in deep-sequencing and data analysis; Dr. Amit Kapoor of Columbia University for technical advice; and Genoveffa Franchini of the National Cancer Institute, Leonid Margolis of the National Institute of Child Health and Development, Cynthia Dunbar of the NHLBI, and Mike Fang in our laboratory for their careful reading of the manuscript. This work was supported by the National Institutes of Health Intramural Research Program. NR 42 TC 24 Z9 24 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 JUN 18 PY 2013 VL 110 IS 25 BP 10264 EP 10269 DI 10.1073/pnas.1303744110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 179DU UT WOS:000321500200056 PM 23716702 ER PT J AU Chow, HM Horovitz, SG Carr, WS Picchioni, D Coddington, N Fukunaga, M Xu, YS Balkin, TJ Duyn, JH Braun, AR AF Chow, Ho Ming Horovitz, Silvina G. Carr, Walter S. Picchioni, Dante Coddington, Nate Fukunaga, Masaki Xu, Yisheng Balkin, Thomas J. Duyn, Jeff H. Braun, Allen R. TI Rhythmic alternating patterns of brain activity distinguish rapid eye movement sleep from other states of consciousness SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE EEG; fMRI; thalamus; slow-wave sleep; brain dynamics ID DEFAULT MODE NETWORK; FUNCTIONAL CONNECTIVITY; HZ OSCILLATIONS; LOW-FREQUENCY; REM-SLEEP; MEMORY; FLUCTUATIONS; WAKEFULNESS; CORTICES; CORTEX AB Rapid eye movement (REM) sleep constitutes a distinct "third state" of consciousness, during which levels of brain activity are commensurate with wakefulness, but conscious awareness is radically transformed. To characterize the temporal and spatial features of this paradoxical state, we examined functional interactions between brain regions using fMRI resting-state connectivity methods. Supporting the view that the functional integrity of the default mode network (DMN) reflects "level of consciousness," we observed functional uncoupling of the DMN during deep sleep and recoupling during REM sleep (similar to wakefulness). However, unlike either deep sleep or wakefulness, REM was characterized by a more widespread, temporally dynamic interaction between two major brain systems: unimodal sensorimotor areas and the higher-order association cortices (including the DMN), which normally regulate their activity. During REM, these two systems become anticorrelated and fluctuate rhythmically, in reciprocally alternating multisecond epochs with a frequency ranging from 0.1 to 0.01 Hz. This unique spatiotemporal pattern suggests a model for REM sleep that may be consistent with its role in dream formation and memory consolidation. C1 [Chow, Ho Ming; Xu, Yisheng; Braun, Allen R.] Natl Inst Deafness & Other Commun Disorders, Language Sect, Voice Speech & Language Branch, NIH, Bethesda, MD 20892 USA. [Horovitz, Silvina G.] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. [Horovitz, Silvina G.; Fukunaga, Masaki; Duyn, Jeff H.] NINDS, Sect Adv MRI, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Carr, Walter S.; Picchioni, Dante; Balkin, Thomas J.] Walter Reed Army Inst Res, Behav Biol Branch, Ctr Psychiat & Neurosci, Silver Spring, MD 20910 USA. [Coddington, Nate] Univ Virginia, Dept Neurosci, Charlottesville, VA 22903 USA. [Fukunaga, Masaki] Osaka Univ, World Premier Int Immunol Frontier Res Ctr, Osaka 5650871, Japan. RP Chow, HM (reprint author), Natl Inst Deafness & Other Commun Disorders, Language Sect, Voice Speech & Language Branch, NIH, Bethesda, MD 20892 USA. EM chowh@nidcd.nih.gov RI Fukunaga, Masaki/F-6441-2013 OI Fukunaga, Masaki/0000-0003-1010-2644 FU National Institute on Deafness and Other Communication Disorders, National Institute of Neurological Disorders and Stroke; Walter Reed Army Institute of Research FX The authors thank Carmen Brewer, Christopher Zalewski, Teresa Kessinger, and Jim Paterson for key collaboration and support; and Alex Martin and Kelly Barnes for insightful and critical reviews of this manuscript. This work was supported by the Intramural Research Programs of the National Institute on Deafness and Other Communication Disorders, National Institute of Neurological Disorders and Stroke, and the Walter Reed Army Institute of Research. NR 39 TC 35 Z9 35 U1 5 U2 38 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 JUN 18 PY 2013 VL 110 IS 25 BP 10300 EP 10305 DI 10.1073/pnas.1217691110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 179DU UT WOS:000321500200062 PM 23733938 ER PT J AU Kristensen, U Epanchintsev, A Rauschendorf, MA Laugel, V Stevnsner, T Bohr, VA Coin, F Egly, JM AF Kristensen, Ulrik Epanchintsev, Alexey Rauschendorf, Marc-Alexander Laugel, Vincent Stevnsner, Tinna Bohr, Vilhelm A. Coin, Frederic Egly, Jean-Marc TI Regulatory interplay of Cockayne syndrome B ATPase and stress-response gene ATF3 following genotoxic stress SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RNA-POLYMERASE-II; PURKINJE-CELL DEGENERATION; PLURIPOTENT STEM-CELLS; COUPLING FACTOR CSB/ERCC6; DE-LANGE-SYNDROME; DNA-REPAIR; ALPHA-AMANITIN; UV-IRRADIATION; NIPPED-B; IN-VIVO AB Cockayne syndrome type B ATPase (CSB) belongs to the SwItch/Sucrose nonfermentable family. Its mutations are linked to Cockayne syndrome phenotypes and classically are thought to be caused by defects in transcription-coupled repair, a subtype of DNA repair. Here we show that after UV-C irradiation, immediate early genes such as activating transcription factor 3 (ATF3) are overexpressed. Although the ATF3 target genes, including dihydrofolate reductase (DHFR), were unable to recover RNA synthesis in CSB-deficient cells, transcription was restored rapidly in normal cells. There the synthesis of DHFR mRNA restarts on the arrival of RNA polymerase II and CSB and the subsequent release of ATF3 from its cAMP response element/ATF target site. In CSB-deficient cells ATF3 remains bound to the promoter, thereby preventing the arrival of polymerase II and the restart of transcription. Silencing of ATF3, as well as stable introduction of wild-type CSB, restores RNA synthesis in UV-irradiated CSB cells, suggesting that, in addition to its role in DNA repair, CSB activity likely is involved in the reversal of inhibitory properties on a gene-promoter region. We present strong experimental data supporting our view that the transcriptional defects observed in UV-irradiated CSB cells are largely the result of a permanent transcriptional repression of a certain set of genes in addition to some defect in DNA repair. C1 [Kristensen, Ulrik; Epanchintsev, Alexey; Rauschendorf, Marc-Alexander; Coin, Frederic; Egly, Jean-Marc] Univ Strasbourg, CNRS, INSERM, Inst Genet & Mol & Cellular Biol,Dept Funct Genom, F-67404 Illkirch Graffenstaden, France. [Laugel, Vincent] Univ Strasbourg, Lab Med Genet, F-67404 Illkirch Graffenstaden, France. [Stevnsner, Tinna] Univ Aarhus, Dept Mol Biol, CDK-8000 Aarhus C, Denmark. [Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Coin, F (reprint author), Univ Strasbourg, CNRS, INSERM, Inst Genet & Mol & Cellular Biol,Dept Funct Genom, F-67404 Illkirch Graffenstaden, France. EM fredr@igbmc.fr; egly@igbmc.fr RI Coin, Frederic/F-5925-2013 FU European Research Council Advanced Scientists; Institut National du Cancer Grant [INCA-2008-041]; l'Association de la Recherche contre le Cancer (ARC) [3153]; Advanced European Research Council; ARC; French Ministere des Affaires Etrangeres FX We thank R. Velez Cruz, A. Zadorin, and E. Compe for fruitful discussions; Charlotte Saint-Andre for helping with antibody production and protein expression; and the Institute of Genetics and Molecular and Cellular Biology Cell Culture Facility. This study was supported by grants from the European Research Council Advanced Scientists (to J.-M.E.), the Institut National du Cancer Grant INCA-2008-041 (to F. C.), and l'Association de la Recherche contre le Cancer (ARC) Grant 3153. U. K, was supported by a JME (Jean-Marc Egly) Advanced European Research Council grant and by an ARC fellowship for young scientists. M.-A. R. was supported by the French Ministere des Affaires Etrangeres (Sejour Scientifique de Haut Niveau). NR 64 TC 5 Z9 5 U1 0 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 18 PY 2013 VL 110 IS 25 BP E2261 EP E2270 DI 10.1073/pnas.1220071110 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 179DU UT WOS:000321500200007 PM 23733932 ER PT J AU Chukoskie, L Snider, J Mozer, MC Krauzlis, RJ Sejnowski, TJ AF Chukoskie, Leanne Snider, Joseph Mozer, Michael C. Krauzlis, Richard J. Sejnowski, Terrence J. TI Learning where to look for a hidden target SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE ideal observer; oculomotor; reinforcement learning; saccades ID EYE-MOVEMENTS; VISUAL-SEARCH; PARIETAL CORTEX; SCENE CONTEXT; MATCHING BEHAVIOR; DECISION-MAKING; REINFORCEMENT; ATTENTION; SELECTION; FEATURES AB Survival depends on successfully foraging for food, for which evolution has selected diverse behaviors in different species. Humans forage not only for food, but also for information. We decide where to look over 170,000 times per day, approximately three times per wakeful second. The frequency of these saccadic eye movements belies the complexity underlying each individual choice. Experience factors into the choice of where to look and can be invoked to rapidly redirect gaze in a context and task-appropriate manner. However, remarkably little is known about how individuals learn to direct their gaze given the current context and task. We designed a task in which participants search a novel scene for a target whose location was drawn stochastically on each trial from a fixed prior distribution. The target was invisible on a blank screen, and the participants were rewarded when they fixated the hidden target location. In just a few trials, participants rapidly found the hidden targets by looking near previously rewarded locations and avoiding previously unrewarded locations. Learning trajectories were well characterized by a simple reinforcement-learning (RL) model that maintained and continually updated a reward map of locations. The RL model made further predictions concerning sensitivity to recent experience that were confirmed by the data. The asymptotic performance of both the participants and the RL model approached optimal performance characterized by an ideal-observer theory. These two complementary levels of explanation show how experience in a novel environment drives visual search in humans and may extend to other forms of search such as animal foraging. C1 [Chukoskie, Leanne; Snider, Joseph; Mozer, Michael C.; Sejnowski, Terrence J.] Univ Calif San Diego, Inst Neural Computat, La Jolla, CA 92093 USA. [Sejnowski, Terrence J.] Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 USA. [Mozer, Michael C.] Univ Colorado, Dept Comp Sci, Boulder, CO 80309 USA. [Mozer, Michael C.] Univ Colorado, Inst Cognit Sci, Boulder, CO 80309 USA. [Krauzlis, Richard J.] NEI, Lab Sensorimotor Res, NIH, Bethesda, MD 20892 USA. [Sejnowski, Terrence J.] Salk Inst Biol Studies, Howard Hughes Med Inst, La Jolla, CA 92037 USA. [Sejnowski, Terrence J.] Salk Inst Biol Studies, Computat Neurobiol Lab, La Jolla, CA 92037 USA. RP Sejnowski, TJ (reprint author), Univ Calif San Diego, Inst Neural Computat, La Jolla, CA 92093 USA. EM terry@salk.edu FU National Science Foundation (NSF) [SBE 0542013]; NSF Science of Learning Center; San Diego Foundation; Office of Naval Research Multidisciplinary University Research Initiative [N00014-10-1-0072]; Howard Hughes Medical Institute FX We thank Krista Kornylo and Natalie Dill for technical assistance. This work was supported in part by National Science Foundation (NSF) Grant SBE 0542013 to the Temporal Dynamics of Learning Center, an NSF Science of Learning Center grant (to L. C., J.S., M. C. M., and T.J.S.), a Blasker Rose-Miah grant from the San Diego Foundation (to L. C.), Office of Naval Research Multidisciplinary University Research Initiative Award N00014-10-1-0072 (to J.S. and T.J.S.), and Howard Hughes Medical Institute (T.J.S.). NR 66 TC 15 Z9 15 U1 2 U2 27 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 JUN 18 PY 2013 VL 110 SU 2 BP 10438 EP 10445 DI 10.1073/pnas.1301216110 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 179DZ UT WOS:000321500900015 PM 23754404 ER PT J AU El-Haibi, CP Sharma, P Singh, R Gupta, P Taub, DD Singh, S Lillard, JW AF El-Haibi, Christelle P. Sharma, Praveen Singh, Rajesh Gupta, Pranav Taub, Dennis D. Singh, Shailesh Lillard, James W., Jr. TI Differential G protein subunit expression by prostate cancer cells and their interaction with CXCR5 SO MOLECULAR CANCER LA English DT Article DE Prostate cancer; Chemokine; G proteins; G protein-coupled receptor ID HETEROTRIMERIC G-PROTEINS; CHEMOKINE RECEPTOR; SIGNAL-TRANSDUCTION; ALPHA-SUBUNIT; GAMMA-SUBUNIT; MEDIATED PHOSPHORYLATION; COUPLED RECEPTORS; BONE METASTASIS; BETA; GROWTH AB with PCa progression, and mediate PCa cell migration and invasion following interaction with CXCL13. However, the differential expression of G protein alpha,beta, and. subunits by PCa cell lines and the precise combination of these proteins with CXCR5 has not been elucidated. Methods: We examined differences in G protein expression of normal prostate (RWPE-1) and PCa cell lines (LNCaP, C4-2B, and PC3) by western blot analysis. Further, we immunoprecipitated CXCR5 with different G protein subunits, and CXCR4, following CXCL13 stimulation. To investigate constitutive coupling of CXCR5 with CXCR4 and PAR-1 we performed invasion assay in PCa cells transfected with G(aq/i2) or G(a13) siRNA, following CXCL13 treatment. We also investigated Rac and RhoA activity by G-LISA activation assay in PCa cells following CXCL13/thrombin stimulation. Result: Of the 22 G proteins studied, G(ai1-3), G(beta 1-4), G(Y5), G(Y7), and G.10 were expressed by both normal and PCa cell lines. Gas was moderately expressed in C4-2B and PC3 cell lines, G(aq/11) was only present in RWPE-1 and LNCaP cell lines, while G(a12) and Ga-13 were expressed in C4-2B and PC3 cell lines. G.9 was expressed only in PCa cell lines. G(a16), G(beta 5), G(Y1-4), and G(Y13) were not detected in any of the cell lines studied. Surprisingly, CXCR4 co-immunoprecipitated with CXCR5 in PCa cell lines irrespective of CXCL13 treatment. We also identified specific G protein isoforms coupled to CXCR5 in its resting and active states. G(aq/11/)G(beta 3)/G(Y9) in LNCaP and G(ai2)/G(beta 3)/G(Y9) in C4-2B and PC3 cell lines, were coupled to CXCR5 and disassociated following CXCL13 stimulation. Interestingly, G(a13) co-immunoprecipitated with CXCR5 in CXCL13-treated, but not in untreated PCa cell lines. Inhibition of G(aq/i2) significantly decreased the ability of cells to invade, whereas silencing Ga13 did not affect CXCL13-dependent cell invasion. Finally, CXCL13 treatment significantly increased Rac activity in G(aq/i2) dependent manner, but not RhoA activity, in PCa cell lines. Conclusions: These findings offer insight into molecular mechanisms of PCa progression and can help to design some therapeutic strategies involving CXCR5 and/or CXCL13 blockade and specific G protein inhibition to abrogate PCa metastasis. C1 [El-Haibi, Christelle P.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Sharma, Praveen] Cent Univ Jharkhand, Ctr Life Sci, Sch Nat Sci, Ranchi, Bihar, India. [Singh, Rajesh; Gupta, Pranav; Singh, Shailesh; Lillard, James W., Jr.] Morehouse Sch Med, Dept Microbiol Biochem & Immunol, Atlanta, GA 30310 USA. [Taub, Dennis D.] NIA, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Lillard, JW (reprint author), Morehouse Sch Med, Dept Microbiol Biochem & Immunol, Atlanta, GA 30310 USA. EM jlillard@msm.edu RI Sharma, Praveen/M-2810-2014 OI Sharma, Praveen/0000-0002-7020-3570 FU National Institute of Health [S21MD000101, G12RR03034, G12MD007602, U54CA118638]; Department of Defense (DoD); Prostate Cancer Research Program Award [W81XWH-06-1-0562, W81XWH-11-1-0109] FX The content of this manuscript benefited from many fruitful conversations with members of the Morehouse School of Medicine. This work benefited from the cooperation between investigators from the Morehouse School of Medicine and the Wallace Tumor Institute at the University of Alabama at Birmingham via the National Cancer Institute sponsored "Comprehensive Minority Institution / Cancer Center Partnership". This study was supported by funds from National Institute of Health Grants S21MD000101, G12RR03034, G12MD007602, U54CA118638, and Department of Defense (DoD) Prostate Cancer Research Program Award W81XWH-06-1-0562, and W81XWH-11-1-0109. NR 50 TC 9 Z9 9 U1 0 U2 2 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 JUN 18 PY 2013 VL 12 AR 64 DI 10.1186/1476-4598-12-64 PG 11 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 187SJ UT WOS:000322139200001 PM 23773523 ER PT J AU Ferreira, RD Zhou, DW Ferreira, JG Silva, MCC Silva-Lucca, RA Mentele, R Paredes-Gamero, EJ Bertolin, TC Correia, MTD Paiva, PMG Gustchina, A Wlodawer, A Oliva, MLV AF Ferreira, Rodrigo da Silva Zhou, Dongwen Ferreira, Joana Gasperazzo Cabral Silva, Mariana Cristina Silva-Lucca, Rosemeire Aparecida Mentele, Reinhard Paredes-Gamero, Edgar Julian Bertolin, Thiago Carlos dos Santos Correia, Maria Tereza Guedes Paiva, Patricia Maria Gustchina, Alla Wlodawer, Alexander Vilela Oliva, Maria Luiza TI Crystal Structure of Crataeva tapia Bark Protein (CrataBL) and Its Effect in Human Prostate Cancer Cell Lines SO PLOS ONE LA English DT Article ID TRYPSIN-INHIBITOR; SERINE RESIDUE; REACTIVE SITE; BINDING; LECTIN; APOPTOSIS; MECHANISM; SEEDS; DU145; GLYCOSAMINOGLYCANS AB A protein isolated from the bark of Crataeva tapia (CrataBL) is both a Kunitz-type plant protease inhibitor and a lectin. We have determined the amino acid sequence and three-dimensional structure of CrataBL, as well as characterized its selected biochemical and biological properties. We found two different isoforms of CrataBL isolated from the original source, differing in positions 31 (Pro/Leu); 92 (Ser/Leu); 93 (Ile/Thr); 95 (Arg/Gly) and 97 (Leu/Ser). CrataBL showed relatively weak inhibitory activity against trypsin (K-iapp = 43 mu M) and was more potent against Factor Xa (K-iapp = 8.6 mu M), but was not active against a number of other proteases. We have confirmed that CrataBL contains two glycosylation sites and forms a dimer at high concentration. The high-resolution crystal structures of two different crystal forms of isoform II verified the beta-trefoil fold of CrataBL and have shown the presence of dimers consisting of two almost identical molecules making extensive contacts (similar to 645 angstrom(2)). The structure differs from those of the most closely related proteins by the lack of the N-terminal beta-hairpin. In experiments aimed at investigating the biological properties of CrataBL, we have shown that addition of 40 mM of the protein for 48 h caused maximum growth inhibition in MTT assay (47% of DU145 cells and 43% of PC3 cells). The apoptosis of DU145 and PC3 cell lines was confirmed by flow cytometry using Annexin V/FITC and propidium iodide staining. Treatment with CrataBL resulted in the release of mitochondrial cytochrome c and in the activation of caspase-3 in DU145 and PC3 cells. C1 [Ferreira, Rodrigo da Silva; Ferreira, Joana Gasperazzo; Cabral Silva, Mariana Cristina; Paredes-Gamero, Edgar Julian; Vilela Oliva, Maria Luiza] Univ Fed Sao Paulo, Dept Bioquim, Sao Paulo, Brazil. [Zhou, Dongwen; Gustchina, Alla; Wlodawer, Alexander] NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21701 USA. [Silva-Lucca, Rosemeire Aparecida] Univ Estadual Oeste Parana, Ctr Engn & Ciencias Exatas, Toledo, Parana, Brazil. [Mentele, Reinhard] Max Planck Inst Biochem, Inst Clin Neuroimmunol LMU, Munich, Germany. [Mentele, Reinhard] Max Planck Inst Biochem, Dept Prot Analyt, Munich, Germany. [Bertolin, Thiago Carlos] Univ Fed Sao Paulo, Dept Biofis, Sao Paulo, Brazil. [dos Santos Correia, Maria Tereza; Guedes Paiva, Patricia Maria] Univ Fed Pernambuco, Dept Bioquim, Recife, PE, Brazil. RP Wlodawer, A (reprint author), NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21701 USA. EM wlodawer@nih.gov; olivaml.bioq@epm.br RI Silva, Mariana/B-9530-2012; Ferreira, Rodrigo/C-1763-2013; Oliva, Maria Luiza/B-9537-2012; Paredes-Gamero, Edgar/C-4791-2012; OI Ferreira, Rodrigo/0000-0003-4103-6870; Paredes-Gamero, Edgar/0000-0003-3686-8402; Paiva, Patricia/0000-0003-3467-708X FU U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; CAPES; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq); Sao Paulo Research Foundation (FAPESP) [09/53766-5]; Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research FX Use of the APS was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. W-31-109-Eng-38. The authors are grateful to CAPES, Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) and Sao Paulo Research Foundation (FAPESP) (Process 09/53766-5) for providing financial support. This project was also supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 69 TC 4 Z9 4 U1 0 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 18 PY 2013 VL 8 IS 6 AR e64426 DI 10.1371/journal.pone.0064426 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 166SA UT WOS:000320576400001 ER PT J AU Foltz, JL Makumbi, I Sejvar, JJ Malimbo, M Ndyomugyenyi, R Atai-Omoruto, AD Alexander, LN Abang, B Melstrom, P Kakooza, AM Olara, D Downing, RG Nutman, TB Dowell, SF Lwamafa, DKW AF Foltz, Jennifer L. Makumbi, Issa Sejvar, James J. Malimbo, Mugagga Ndyomugyenyi, Richard Atai-Omoruto, Anne Deborah Alexander, Lorraine N. Abang, Betty Melstrom, Paul Kakooza, Angelina M. Olara, Dennis Downing, Robert G. Nutman, Thomas B. Dowell, Scott F. Lwamafa, D. K. W. TI An Epidemiologic Investigation of Potential Risk Factors for Nodding Syndrome in Kitgum District, Uganda SO PLOS ONE LA English DT Article ID CLINICAL CLASSIFICATION; ONCHOCERCA-VOLVULUS; SOUTHERN SUDAN; EPILEPSY; TANZANIA; SEIZURES AB Introduction: Nodding Syndrome (NS), an unexplained illness characterized by spells of head bobbing, has been reported in Sudan and Tanzania, perhaps as early as 1962. Hypothesized causes include sorghum consumption, measles, and onchocerciasis infection. In 2009, a couple thousand cases were reportedly in Northern Uganda. Methods: In December 2009, we identified cases in Kitgum District. The case definition included persons who were previously developmentally normal who had nodding. Cases, further defined as 5- to 15-years-old with an additional neurological deficit, were matched to village controls to assess risk factors and test biological specimens. Logistic regression models were used to evaluate associations. Results: Surveillance identified 224 cases; most (95%) were 5-15-years-old (range = 2-27). Cases were reported in Uganda since 1997. The overall prevalence was 12 cases per 1,000 (range by parish = 0.6-46). The case-control investigation (n = 49 case/village control pairs) showed no association between NS and previously reported measles; sorghum was consumed by most subjects. Positive onchocerciasis serology [age-adjusted odds ratio (AOR(1)) = 14.4 (2.7, 78.3)], exposure to munitions [AOR(1)= 13.9 (1.4, 135.3)], and consumption of crushed roots [AOR(1)= 5.4 (1.3, 22.1)] were more likely in cases. Vitamin B6 deficiency was present in the majority of cases (84%) and controls (75%). Conclusion: NS appears to be increasing in Uganda since 2000 with 2009 parish prevalence as high as 46 cases per 1,000 5 to 15-year old children. Our results found no supporting evidence for many proposed NS risk factors, revealed association with onchocerciasis, which for the first time was examined with serologic testing, and raised nutritional deficiencies and toxic exposures as possible etiologies. C1 [Foltz, Jennifer L.] Ctr Dis Control & Prevent, Div Nutr Phys Activ & Obes, Atlanta, GA 30333 USA. [Makumbi, Issa; Malimbo, Mugagga; Ndyomugyenyi, Richard; Atai-Omoruto, Anne Deborah; Lwamafa, D. K. W.] Uganda Minist Hlth, Kampala, Uganda. [Sejvar, James J.] Ctr Dis Control & Prevent, Div High Consequence Pathogens & Pathol, Atlanta, GA USA. [Alexander, Lorraine N.; Abang, Betty; Olara, Dennis; Downing, Robert G.] Centers Dis Control & Prevent Uganda, Div Global HIV AIDS, Entebbe, Uganda. [Melstrom, Paul] Ctr Dis Control & Prevent, Div Environm Hazards & Hlth Effects, Atlanta, GA USA. [Kakooza, Angelina M.] Makerere Univ, Coll Hlth Sci, Sch Med, Kampala, Uganda. [Nutman, Thomas B.] NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. [Dowell, Scott F.] Ctr Dis Control & Prevent, Div Global Dis Detect & Emergency Response, Atlanta, GA USA. RP Foltz, JL (reprint author), Ctr Dis Control & Prevent, Div Nutr Phys Activ & Obes, Atlanta, GA 30333 USA. EM jfoltz@cdc.gov FU CDC; WHO; MoH Uganda for public health investigations FX The investigation was supported with resources available from CDC, WHO, and MoH Uganda for public health investigations. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 31 Z9 31 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 JUN 18 PY 2013 VL 8 IS 6 AR e66419 DI 10.1371/journal.pone.0066419 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 166SA UT WOS:000320576400106 PM 23823012 ER PT J AU Liu, HX Fang, YP Hu, Y Gonzalez, FJ Fang, JW Wan, YJY AF Liu, Hui-Xin Fang, Yaping Hu, Ying Gonzalez, Frank J. Fang, Jianwen Wan, Yu-Jui Yvonne TI PPAR beta Regulates Liver Regeneration by Modulating Akt and E2f Signaling SO PLOS ONE LA English DT Article ID ACTIVATED RECEPTOR-DELTA; CANCER CELL-LINES; ALPHA-NULL MICE; LIGAND ACTIVATION; PARTIAL-HEPATECTOMY; GENE-EXPRESSION; GROWTH-FACTOR; PEROXISOME; PROLIFERATION; METABOLISM AB The current study tests the hypothesis that peroxisome proliferator-activated receptor beta (PPAR beta) has a role in liver regeneration due to its effect in regulating energy homeostasis and cell proliferation. The role of PPARb in liver regeneration was studied using two-third partial hepatectomy (PH) in Wild-type (WT) and PPARb-null (KO) mice. In KO mice, liver regeneration was delayed and the number of Ki-67 positive cells reached the peak at 60 hr rather than at 36-48 hr after PH shown in WT mice. RNA-sequencing uncovered 1344 transcriptomes that were differentially expressed in regenerating WT and KO livers. About 70% of those differentially expressed genes involved in glycolysis and fatty acid synthesis pathways failed to induce during liver regeneration due to PPAR beta deficiency. The delayed liver regeneration in KO mice was accompanied by lack of activation of phosphoinositide-dependent kinase 1 (PDK1)/Akt. In addition, cell proliferation-associated increase of genes encoding E2f transcription factor (E2f) 1-2 and E2f7-8 as well as their downstream target genes were not noted in KO livers 36-48 hr after PH. E2fs have dual roles in regulating metabolism and proliferation. Moreover, transient steatosis was only found in WT, but not in KO mice 36 hr after PH. These data suggested that PPAR beta-regulated PDK1/Akt and E2f signaling that controls metabolism and proliferation is involved in the normal progression of liver regeneration. C1 [Liu, Hui-Xin; Hu, Ying; Wan, Yu-Jui Yvonne] Calif State Univ Sacramento, Dept Med Pathol & Lab Med, Sacramento, CA 95819 USA. [Fang, Yaping; Fang, Jianwen] Univ Kansas, Appl Bioinformat Lab, Lawrence, KS 66045 USA. [Gonzalez, Frank J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Wan, YJY (reprint author), Calif State Univ Sacramento, Dept Med Pathol & Lab Med, Sacramento, CA 95819 USA. EM yjywan@ucdavis.edu OI Fang, Yaping/0000-0001-6075-0768 FU National Institutes of Health [CA53596, DK092100] FX This study is supported by grants funded by National Institutes of Health CA53596 and DK092100. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 14 Z9 14 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 JUN 18 PY 2013 VL 8 IS 6 AR e65644 DI 10.1371/journal.pone.0065644 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 166SA UT WOS:000320576400016 PM 23823620 ER PT J AU Nguyen, HD Becker, J Thu, YM Costanzo, M Koch, EN Smith, S Myung, K Myers, CL Boone, C Bielinsky, AK AF Nguyen, Hai Dang Becker, Jordan Thu, Yee Mon Costanzo, Michael Koch, Elizabeth N. Smith, Stephanie Myung, Kyungjae Myers, Chad L. Boone, Charles Bielinsky, Anja-Katrin TI Unligated Okazaki Fragments Induce PCNA Ubiquitination and a Requirement for Rad59-Dependent Replication Fork Progression SO PLOS ONE LA English DT Article ID DNA-LIGASE-I; YEAST SACCHAROMYCES-CEREVISIAE; NUCLEOTIDE EXCISION-REPAIR; NEARBY INVERTED REPEATS; CELL NUCLEAR ANTIGEN; BUDDING YEAST; HOMOLOGOUS RECOMBINATION; MITOTIC RECOMBINATION; COMPLEX-FORMATION; ESSENTIAL GENES AB Deficiency in DNA ligase I, encoded by CDC9 in budding yeast, leads to the accumulation of unligated Okazaki fragments and triggers PCNA ubiquitination at a non-canonical lysine residue. This signal is crucial to activate the S phase checkpoint, which promotes cell cycle delay. We report here that a pol30-K107 mutation alleviated cell cycle delay in cdc9 mutants, consistent with the idea that the modification of PCNA at K107 affects the rate of DNA synthesis at replication forks. To determine whether PCNA ubiquitination occurred in response to nicks or was triggered by the lack of PCNA-DNA ligase interaction, we complemented cdc9 cells with either wild-type DNA ligase I or a mutant form, which fails to interact with PCNA. Both enzymes reversed PCNA ubiquitination, arguing that the modification is likely an integral part of a novel nick-sensory mechanism and not due to non-specific secondary mutations that could have occurred spontaneously in cdc9 mutants. To further understand how cells cope with the accumulation of nicks during DNA replication, we utilized cdc9-1 in a genome-wide synthetic lethality screen, which identified RAD59 as a strong negative interactor. In comparison to cdc9 single mutants, cdc9 rad59D double mutants did not alter PCNA ubiquitination but enhanced phosphorylation of the mediator of the replication checkpoint, Mrc1. Since Mrc1 resides at the replication fork and is phosphorylated in response to fork stalling, these results indicate that Rad59 alleviates nick-induced replication fork slowdown. Thus, we propose that Rad59 promotes fork progression when Okazaki fragment processing is compromised and counteracts PCNA-K107 mediated cell cycle arrest. C1 [Nguyen, Hai Dang; Becker, Jordan; Thu, Yee Mon; Bielinsky, Anja-Katrin] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA. [Costanzo, Michael; Boone, Charles] Univ Toronto, Donnelly Ctr, Banting & Best Dept Med Res, Toronto, ON, Canada. [Boone, Charles] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Koch, Elizabeth N.; Myers, Chad L.] Univ Minnesota, Dept Comp Sci & Engn, Minneapolis, MN USA. [Smith, Stephanie; Myung, Kyungjae] Natl Inst Hlth, Natl Human Genome Res Inst, Genet & Mol Biol Branch, Genome Instabil Sect, Bethesda, MD USA. RP Bielinsky, AK (reprint author), Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA. EM bieli003@umn.edu OI Bielinsky, Anja/0000-0003-1783-619X FU National Institutes of Health (NIH) [GM074917]; National Human Genome Research Institute; NIH [HG005084, HG005853]; NSF [DBI0953881]; Canadian Institutes of Health Research [MOP-102629, MOP-97939]; Ontario Research Fund [GL2-0122] FX This work was supported by National Institutes of Health (NIH) grant GM074917 to AKB, who is a Scholar of the Leukemia and Lymphoma Society. The intramural Research Programs of the National Human Genome Research Institute supported KM. EK is a National Science Foundation (NSF) Graduate Research Fellow. EK and CLM were supported by a grant from the NIH (HG005084), and the NSF (DBI0953881). CB and CLM are supported by a grant from the NIH (HG005853). CB is supported by grants from the Canadian Institutes of Health Research (MOP-102629 and MOP-97939) and the Ontario Research Fund (GL2-0122). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 64 TC 7 Z9 7 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 JUN 18 PY 2013 VL 8 IS 6 AR UNSP e66379 DI 10.1371/journal.pone.0066379 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 166SA UT WOS:000320576400098 PM 23824283 ER PT J AU Einhorn, PT Cushman, WC Whelton, PK AF Einhorn, Paula T. Cushman, William C. Whelton, Paul K. CA ALLHAT Collaborative Res Grp TI Chlorthalidone Versus Hydrochlorothiazide SO ANNALS OF INTERNAL MEDICINE LA English DT Letter ID LIPID-LOWERING TREATMENT; HEART-ATTACK TRIAL; HYPERTENSIVE PATIENTS C1 [Einhorn, Paula T.] NHLBI, Bethesda, MD 20892 USA. [Cushman, William C.] Vet Affairs Med Ctr, Memphis, TN USA. [Whelton, Paul K.] Tulane Univ, New Orleans, LA 70118 USA. RP Einhorn, PT (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [N01-HC-35130]; PHS HHS [HHSN268201100036C] NR 5 TC 1 Z9 1 U1 0 U2 0 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 JUN 18 PY 2013 VL 158 IS 12 BP 922 EP 923 DI 10.7326/0003-4819-158-12-201306180-00018 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 167PW UT WOS:000320645000027 PM 23778917 ER PT J AU Nandhikonda, P Yasgar, A Baranowski, AM Sidhu, PS McCallum, MM Pawlak, AJ Teske, K Feleke, B Yuan, NY Kevin, C Bikle, DD Ayers, SD Webb, P Rai, G Simeonov, A Jadhav, A Maloney, D Arnold, LA AF Nandhikonda, Premchendar Yasgar, Adam Baranowski, Athena M. Sidhu, Preetpal S. McCallum, Megan M. Pawlak, Alan J. Teske, Kelly Feleke, Belaynesh Yuan, Nina Y. Kevin, Chinedum Bikle, Daniel D. Ayers, Steven D. Webb, Paul Rai, Ganesha Simeonov, Anton Jadhav, Ajit Maloney, David Arnold, Leggy A. TI Peroxisome Proliferation-Activated Receptor delta Agonist GW0742 Interacts Weakly with Multiple Nuclear Receptors, Including the Vitamin D Receptor SO BIOCHEMISTRY LA English DT Article ID CANCER-CELL-LINES; HUMAN PROSTATIC-CARCINOMA; THYROID-HORMONE RECEPTOR; FACTOR BINDING PROTEIN-3; LIGAND ACTIVATION; 1-ALPHA,25-DIHYDROXYVITAMIN D-3; 1,25-DIHYDROXYVITAMIN D-3; CRYSTAL-STRUCTURES; ESTROGEN-RECEPTOR; LEUKEMIA-CELLS AB A high-throughput screening campaign was conducted to identify small molecules with the ability to inhibit the interaction between the vitamin D receptor (VDR) and steroid receptor coactivator 2. These inhibitors represent novel molecular probes for modulating gene regulation mediated by VDR. Peroxisome proliferator-activated receptor (PPAR) delta agonist GW0742 was among the identified VDR-coactivator inhibitors and has been characterized herein as a pan nuclear receptor antagonist at concentrations of >12.1 mu M. The highest antagonist activity for GW0742 was found for VDR and the androgen receptor. Surprisingly, GW0742 behaved as a PPAR agonist and antagonist, activating transcription at lower concentrations and inhibiting this effect at higher concentrations. A unique spectroscopic property of GW0742 was identified as well. In the presence of rhodamine-derived molecules, GW0742 increased the fluorescence intensity and level of fluorescence polarization at an excitation wavelength of 595 nm and an emission wavelength of 615 nm in a dose-dependent manner. The GW0742-inhibited NR-coactivator binding resulted in a reduced level of expression of five different NR target genes in LNCaP cells in the presence of agonist. Especially VDR target genes CYP24A1, IGFBP-3, and TRPV6 were negatively regulated by GW0742. GW0742 is the first VDR ligand inhibitor lacking the secosteroid structure of VDR ligand antagonists. Nevertheless, the VDR-meditated downstream process of cell differentiation was antagonized by GW0742 in HL-60 cells that were pretreated with the endogenous VDR agonist 1,25-dihydroxyvitamin D-3. C1 [Nandhikonda, Premchendar; Baranowski, Athena M.; Sidhu, Preetpal S.; McCallum, Megan M.; Pawlak, Alan J.; Teske, Kelly; Feleke, Belaynesh; Yuan, Nina Y.; Kevin, Chinedum; Arnold, Leggy A.] Univ Wisconsin, Dept Chem & Biochem, Milwaukee, WI 53211 USA. [Bikle, Daniel D.] Vet Affairs Med Ctr, Dept Med, Endocrine Res Unit, San Francisco, CA 94121 USA. [Ayers, Steven D.; Webb, Paul] Methodist Hosp, Res Inst, Houston, TX 77030 USA. [Yasgar, Adam; Rai, Ganesha; Simeonov, Anton; Jadhav, Ajit; Maloney, David] NHGRI, NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. RP Arnold, LA (reprint author), Univ Wisconsin, Dept Chem & Biochem, Milwaukee, WI 53211 USA. EM arnold2@uwm.edu RI Sidhu, Preetpal/L-5727-2013; Nandhikonda, Premchendar/K-1473-2014; Ayers, Stephen/O-4535-2014 OI Ayers, Stephen/0000-0003-1390-8969 FU University of Wisconsin-Milwaukee (UWM); UWM Research Growth Initiative (RGI Grant) [2012]; National Institutes of Health Grant [R03DA031090]; UWM Research Foundation (Catalyst grant); Lynde and Harry Bradley Foundation; Richard and Ethel Herzfeld Foundation; Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research [U54MH084681] FX This work was supported by the University of Wisconsin-Milwaukee (UWM) (L.A.A.), the UWM Research Growth Initiative (RGI Grant 2012) (L.A.A.), National Institutes of Health Grant R03DA031090 (L.A.A.), the UWM Research Foundation (Catalyst grant), the Lynde and Harry Bradley Foundation (L.A.A.), the Richard and Ethel Herzfeld Foundation (L.A.A.), and the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research (Grant U54MH084681) (G.R., A.S., A.J., A.Y., and D.M.). NR 71 TC 8 Z9 8 U1 0 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 18 PY 2013 VL 52 IS 24 BP 4193 EP 4203 DI 10.1021/bi400321p PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 169AC UT WOS:000320748300008 PM 23713684 ER PT J AU Ambroggio, XI Dommer, J Gopalan, V Dunham, EJ Taubenberger, JK Hurt, DE AF Ambroggio, Xavier I. Dommer, Jennifer Gopalan, Vivek Dunham, Eleca J. Taubenberger, Jeffery K. Hurt, Darrell E. TI HASP server: a database and structural visualization platform for comparative models of influenza A hemagglutinin proteins SO BMC BIOINFORMATICS LA English DT Article DE Influenza A; HASP; Hemagglutinin; Receptor binding; Membrane fusion; ROSETTA; Sialic acid; Flu; Homology modeling; Molecular visualization ID VIRUS HEMAGGLUTININ; SUBTYPES AB Background: Influenza A viruses possess RNA genomes that mutate frequently in response to immune pressures. The mutations in the hemagglutinin genes are particularly significant, as the hemagglutinin proteins mediate attachment and fusion to host cells, thereby influencing viral pathogenicity and species specificity. Large-scale influenza A genome sequencing efforts have been ongoing to understand past epidemics and pandemics and anticipate future outbreaks. Sequencing efforts thus far have generated nearly 9,000 distinct hemagglutinin amino acid sequences. Description: Comparative models for all publicly available influenza A hemagglutinin protein sequences (8,769 to date) were generated using the Rosetta modeling suite. The C-alpha root mean square deviations between a randomly chosen test set of models and their crystallographic templates were less than 2 angstrom, suggesting that the modeling protocols yielded high-quality results. The models were compiled into an online resource, the Hemagglutinin Structure Prediction (HASP) server. The HASP server was designed as a scientific tool for researchers to visualize hemagglutinin protein sequences of interest in a three-dimensional context. With a built-in molecular viewer, hemagglutinin models can be compared side-by-side and navigated by a corresponding sequence alignment. The models and alignments can be downloaded for offline use and further analysis. Conclusions: The modeling protocols used in the HASP server scale well for large amounts of sequences and will keep pace with expanded sequencing efforts. The conservative approach to modeling and the intuitive search and visualization interfaces allow researchers to quickly analyze hemagglutinin sequences of interest in the context of the most highly related experimental structures, and allow them to directly compare hemagglutinin sequences to each other simultaneously in their two- and three-dimensional contexts. The models and methodology have shown utility in current research efforts and the ongoing aim of the HASP server is to continue to accelerate influenza A research and have a positive impact on global public health. C1 [Ambroggio, Xavier I.; Dommer, Jennifer; Gopalan, Vivek; Hurt, Darrell E.] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, NIH, Bethesda, MD 20892 USA. [Dunham, Eleca J.; Taubenberger, Jeffery K.] NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Hurt, DE (reprint author), NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM darrellh@niaid.nih.gov FU Office of Science Management and Operations of the National Institute of Allergy and Infectious Diseases FX We are grateful to Dr. Yentram Huyen and Mike Tartakovsky for their support of the project. We also thank Dr. Michael Dolan for helpful comments on HASP, and Dr. Meghan Coakley for assistance in writing this manuscript. This research was supported in part by the Office of Science Management and Operations of the National Institute of Allergy and Infectious Diseases. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Maryland. (http://biowulf.nih.gov). NR 17 TC 0 Z9 0 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD JUN 18 PY 2013 VL 14 AR 197 DI 10.1186/1471-2105-14-197 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 171PM UT WOS:000320941500001 PM 23777206 ER PT J AU Mofenson, LM Cotton, MF AF Mofenson, Lynne M. Cotton, Mark F. TI The challenges of success: adolescents with perinatal HIV infection SO JOURNAL OF THE INTERNATIONAL AIDS SOCIETY LA English DT Editorial Material DE perinatal HIV infection; adolescents; HIV care ID CHILDREN; YOUTH; DISCLOSURE; DIAGNOSIS; BARRIERS AB The great success in the prevention and treatment of pediatric HIV in high resource countries, and now in low resource countries, has changed the face of the HIV epidemic in children from one of near certain mortality to that of a chronic disease. However, these successes pose new challenges as perinatally HIV-infected youth survive into adulthood. Increased survival of HIV-infected children is associated with challenges in maintaining adherence to what is likely life-long therapy, and in selecting successive antiretroviral drug regimens, given the limited availability of pediatric formulations, limitations in pharmacokinetic and safety data of drugs in children, and the development of extensive drug resistance in multi-drug-experienced children. Pediatric HIV care must now focus on morbidity related to long-term HIV infection and its treatment. Survival into adulthood of perinatally HIV-infected youth in high resource countries provides important lessons about how the epidemic will change with increasing access to antiretroviral therapy for children in low resource countries. This series of papers will focus on issues related to management of perinatally infected youth and young adults. C1 [Mofenson, Lynne M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, NIH, Rockville, MD 20852 USA. [Cotton, Mark F.] Univ Stellenbosch, Tygerberg Childrens Hosp, Div Infect Dis, Cape Town, South Africa. RP Mofenson, LM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, NIH, 6100 Execut Blvd,Room 4B11, Rockville, MD 20852 USA. OI Mofenson, Lynne/0000-0002-2818-9808 NR 24 TC 22 Z9 22 U1 0 U2 8 PU INT AIDS SOCIETY PI GENEVA PA AVENUE DE FRANCE 23, GENEVA, 1202, SWITZERLAND SN 1758-2652 J9 J INT AIDS SOC JI J. Int. AIDS Soc. PD JUN 18 PY 2013 VL 16 AR 18650 DI 10.7448/IAS.16.1.18650 PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 167CO UT WOS:000320608300001 PM 23782484 ER PT J AU Puthanakit, T Siberry, GK AF Puthanakit, Thanyawee Siberry, George K. TI Bone health in children and adolescents with perinatal HIV infection SO JOURNAL OF THE INTERNATIONAL AIDS SOCIETY LA English DT Review DE perinatal HIV infection; bone mineral density (BMD); fracture; dual-energy X-ray absorptiometry (DXA); peak bone mass (PBM) ID TENOFOVIR DISOPROXIL FUMARATE; B LIGAND RANKL; MINERAL DENSITY; ANTIRETROVIRAL THERAPY; ABACAVIR-LAMIVUDINE; FRACTURE RISK; MASS; CHILDHOOD; CALCIUM; COHORT AB The long-term impact on bone health of lifelong HIV infection and prolonged ART in growing and developing children is not yet known. Measures of bone health in youth must be interpreted in the context of expected developmental and physiologic changes in bone mass, size, density and strength that occur from fetal through adult life. Low bone mineral density (BMD) appears to be common in perinatally HIV-infected youth, especially outside of high-income settings, but data are limited and interpretation complicated by the need for better pediatric norms. The potential negative effects of tenofovir on BMD and bone mass accrual are of particular concern as this drug may be used more widely in younger children. Emphasizing good nutrition, calcium and vitamin D sufficiency, weight-bearing exercise and avoidance of alcohol and smoking are effective and available approaches to maintain and improve bone health in all settings. More data are needed to inform therapies and monitoring for HIV-infected youth with proven bone fragility. While very limited data suggest lack of marked increase in fracture risk for youth with perinatal HIV infection, the looming concern for these children is that they may fail to attain their expected peak bone mass in early adulthood which could increase their risk for fractures and osteoporosis later in adulthood. C1 [Puthanakit, Thanyawee] Chulalongkorn Univ, Fac Med, Dept Pediat, Bangkok 10330, Thailand. [Puthanakit, Thanyawee] Thai Red Cross AIDS Res Ctr, HIVNAT, Bangkok, Thailand. [Siberry, George K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis MPID Branch, NIH, Bethesda, MD 20892 USA. RP Siberry, GK (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis MPID Branch, NIH, 6100 Executive Blvd,Room 4B11H, Bethesda, MD 20892 USA. EM siberryg@mail.nih.gov FU National Research University Project of Commission of Higher Education; Ratchadapiseksomphot Endowment Fund [HR 1161A-55]; Senior Researcher Scholar, Thai Research Fund (TRF) FX Dr. Puthanakit is funded in part by the National Research University Project of Commission of Higher Education and the Ratchadapiseksomphot Endowment Fund (HR 1161A-55) and the Senior Researcher Scholar, Thai Research Fund (TRF). NR 71 TC 11 Z9 11 U1 0 U2 9 PU INT AIDS SOCIETY PI GENEVA PA AVENUE DE FRANCE 23, GENEVA, 1202, SWITZERLAND SN 1758-2652 J9 J INT AIDS SOC JI J. Int. AIDS Soc. PD JUN 18 PY 2013 VL 16 AR 18575 DI 10.7448/IAS.16.1.18575 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 167CG UT WOS:000320607500001 PM 23782476 ER PT J AU Sohn, AH Hazra, R AF Sohn, Annette H. Hazra, Rohan TI The changing epidemiology of the global paediatric HIV epidemic: keeping track of perinatally HIV-infected adolescents SO JOURNAL OF THE INTERNATIONAL AIDS SOCIETY LA English DT Review DE adolescent; HIV; outcomes; perinatal; surveillance ID ACTIVE ANTIRETROVIRAL THERAPY; HUMAN-IMMUNODEFICIENCY-VIRUS; REVERSE-TRANSCRIPTASE INHIBITOR; BONE-MINERAL DENSITY; ACQUIRED HIV; DRUG-RESISTANCE; OBSERVATIONAL DATABASE; PSYCHIATRIC-DISORDERS; VIROLOGICAL FAILURE; METABOLIC-CHANGES AB The global paediatric HIV epidemic is shifting into a new phase as children on antiretroviral therapy (ART) move into adolescence and adulthood, and face new challenges of living with HIV. UNAIDS reports that 3.4 million children aged below 15 years and 2 million adolescents aged between 10 and 19 years have HIV. Although the vast majority of children were perinatally infected, older children are combined with behaviourally infected adolescents and youth in global reporting, making it difficult to keep track of their outcomes. Perinatally HIV-infected adolescents (PHIVA) are a highly unique patient sub-population, having been infected before development of their immune systems, been subject to suboptimal ART options and formulations, and now face transition from complete dependence on adult caregivers to becoming their own caregivers. As we are unable to track long-term complications and survival of PHIVA through national and global reporting systems, local and regional cohorts are the main sources for surveillance and research among PHIVA. This global review will utilize those data to highlight the epidemiology of PHIVA infection, treatment challenges and chronic disease risks. Unless mechanisms are created to count and separate out PHIVA outcomes, we will have few opportunities to characterize the negative consequences of life-long HIV infection in order to find ways to prevent them. C1 [Sohn, Annette H.] TREAT Asia AmfAR Fdn AIDS Res, Bangkok, Thailand. [Hazra, Rohan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, NIH, Bethesda, MD USA. RP Sohn, AH (reprint author), TREAT Asia AmfAR Fdn AIDS Res, 388 Sukhumvit Rd,Suite 2104, Bangkok, Thailand. EM annette.sohn@treatasia.org NR 85 TC 24 Z9 24 U1 1 U2 14 PU INT AIDS SOCIETY PI GENEVA PA AVENUE DE FRANCE 23, GENEVA, 1202, SWITZERLAND SN 1758-2652 J9 J INT AIDS SOC JI J. Int. AIDS Soc. PD JUN 18 PY 2013 VL 16 AR 18555 DI 10.7448/IAS.16.1.18555 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 167CB UT WOS:000320606800001 PM 23782474 ER PT J AU Torchia, MLG Conze, DB Ashwell, JD AF Giardino Torchia, Maria Letizia Conze, Dietrich B. Ashwell, Jonathan D. TI c-IAP1 and c-IAP2 Redundancy Differs between T and B Cells SO PLOS ONE LA English DT Article ID NF-KAPPA-B; ALPHA-DEPENDENT APOPTOSIS; MULTIPLE-MYELOMA; ACTIVATION; CIAP2; TRAF2; UBIQUITINATION; RECEPTOR; IAPS; INHIBITOR AB Cellular Inhibitors of Apoptosis 1 and 2 (c-IAP1 and c-IAP2) are ubiquitin protein ligases (E3s) that constitutively ubiquitinate and induce proteasomal-mediated degradation of NF-kappa B Inducing Kinase (NIK) and repress non-canonical NF-kappa B activation. Mice expressing an E3-inactive c-IAP2 mutant (c-IAP2(H570A)) have constitutive activation of non-canonical NF-kappa B, resulting in B cell hyperplasia and T cell costimulation-independence. If, and if so to what extent, c-IAP1 and c-IAP2 are redundant in NF-kappa B regulation in these mice is not known. Here we have generated mice expressing a mutant c-IAP1 that lacks E3 activity (c-IAP1(H582A)). These mice were phenotypically normal and did not have constitutive NF-kappa B activation in B cells or MEFs. siRNA-mediated knockdown of c-IAP2 showed that accumulated c-IAP2, resulting from lack of c-IAP1-dependent degradation, compensated for absent c-IAP1 E3 activity. Surprisingly, c-IAP1(H582A) T cells had a lower p100/p52 ratio than wild type T cells, and in the absence of costimulation proliferated to a degree intermediate between wild type and c-IAP2(H570A) T cells. Therefore, although c-IAP1 and c-IAP2 both can repress constitutive NF-kappa B activation, the relative importance of each varies according to cell type. C1 [Giardino Torchia, Maria Letizia; Conze, Dietrich B.; Ashwell, Jonathan D.] NCI, Lab Immune Cell Biol, NIH, Bethesda, MD 20892 USA. RP Ashwell, JD (reprint author), NCI, Lab Immune Cell Biol, NIH, Bethesda, MD 20892 USA. EM jda@pop.nci.nih.gov FU National Institutes of Health, Center for Cancer Research, National Cancer Institute FX This work was supported by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 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 JUN 17 PY 2013 VL 8 IS 6 AR e66161 DI 10.1371/journal.pone.0066161 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 177TH UT WOS:000321397800026 ER PT J AU Liu, W Chen, Z Ma, YS Wu, XC Jin, YP Hou, S AF Liu, Wei Chen, Zhi Ma, Yansen Wu, Xiaochun Jin, Yaping Hou, Steven TI Genetic Characterization of the Drosophila Birt-Hogg-Dube Syndrome Gene SO PLOS ONE LA English DT Article ID MTOR ACTIVATION; AMINO-ACIDS; GROWTH; TUMORIGENESIS; REQUIREMENTS; MELANOGASTER; MECHANISMS; FOLLICULIN; INTERACTS; RAPAMYCIN AB Folliculin (FLCN) is a conserved tumor suppressor gene whose loss is associated with the human Birt-Hogg-Dube (BHD) syndrome. However, its molecular functions remain largely unknown. In this work, we generated a Drosophila BHD model through genomic deletion of the FLCN gene (DBHD-). The DBHD mutant larvae grew slowly and stopped development before pupation, displaying various characteristics of malnutrition. We found the growth delay was sensitive to the nutrient supplies. It became more severe upon restrictions of the dietary yeast; while high levels of yeast significantly restored the normal growth, but not viability. We further demonstrated that leucine was able to substitute for yeast to provide similar rescues. Moreover, the human FLCN could partially rescue the DBHD- phenotypes, indicating the two genes are involved in certain common mechanisms. Our work provides a new animal model of the BHD syndrome and suggests that modulation of the local nutrient condition might be a potential treatment of the BHD lesions. C1 [Liu, Wei; Chen, Zhi; Ma, Yansen; Wu, Xiaochun; Jin, Yaping] Northwest A&F Univ, Coll Vet Med, Minist Agr, Key Lab Anim Biotechnol, Yangling, Shaanxi, Peoples R China. [Liu, Wei; Hou, Steven] NCI, Mouse Canc Genet Program, NIH, Frederick, MD 21701 USA. RP Jin, YP (reprint author), Northwest A&F Univ, Coll Vet Med, Minist Agr, Key Lab Anim Biotechnol, Yangling, Shaanxi, Peoples R China. EM yapingjin@163.com; hous@mail.nih.gov FU NSAF Foundation; Doctoral Programs Foundation of Ministry of Education of China; Intramural Research Program of the National Institutes of Health, National Cancer Institute FX This work was supported by NSAF Foundation (W.L.), Doctoral Programs Foundation of Ministry of Education of China (Y.J.) and the Intramural Research Program of the National Institutes of Health, National Cancer Institute (S.H). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 9 Z9 9 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 JUN 17 PY 2013 VL 8 IS 6 AR e65869 DI 10.1371/journal.pone.0065869 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 177TH UT WOS:000321397800018 PM 23799055 ER PT J AU Xu, X Mackem, S AF Xu, Xing Mackem, Susan TI Tracing the Evolution of Avian Wing Digits SO CURRENT BIOLOGY LA English DT Review ID HOX GENES; SONIC HEDGEHOG; FRAME-SHIFT; LIMB BUD; BIRDS; ORIGIN; HOMOLOGY; IDENTITY; EXPRESSION; DINOSAURS AB It is widely accepted that birds are a subgroup of dinosaurs, but there is an apparent conflict: modern birds have been thought to possess only the middle three fingers (digits II-III-IV) of an idealized five-digit tetrapod hand based on embryological data, but their Mesozoic tetanuran dinosaur ancestors are considered to have the first three digits (I-II-III) based on fossil evidence. How could such an evolutionary quirk arise? Various hypotheses have been proposed to resolve this paradox. Adding to the confusion, some recent developmental studies support a designation for avian wing digits whereas some recent paleontological data are consistent with a identification of the Mesozoic tetanuran digits. A comprehensive analysis of both paleontological and developmental data suggests that the evolution of the avian wing digits may have been driven by homeotic transformations of digit identity, which are more likely to have occurred in a partial and piecemeal manner. Additionally, recent genetic studies in mouse models showing plausible mechanisms for central digit loss invite consideration of new alternative possibilities (I-II-IV or I-III-IV) for the homologies of avian wing digits. While much progress has been made, some advances point to the complexity of the problem and a final resolution to this ongoing debate demands additional work from both paleontological and developmental perspectives, which will surely yield new insights on mechanisms of evolutionary adaptation. C1 [Xu, Xing] Chinese Acad Sci, Inst Vertebrate Paleontol & Paleoanthropol, Key Lab Vertebrate Evolut & Human Origin, Beijing 100044, Peoples R China. [Mackem, Susan] NCI, Canc & Dev Biol Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Xu, X (reprint author), Chinese Acad Sci, Inst Vertebrate Paleontol & Paleoanthropol, Key Lab Vertebrate Evolut & Human Origin, Beijing 100044, Peoples R China. EM xu.xing@ivpp.ac.cn; mackems@mail.nih.gov FU National Natural Science Foundation of China [41120124002]; 973 program [2012CB821900] FX The author thanks James Clark, Jonah Choiniere, Corwin Sullivan, David W.E. Hone, and Mikio Tanaka for discussions, and James Clark and Corwin Sullivan for constructive comments on the manuscript. This project was supported by the National Natural Science Foundation of China (grant number: 41120124002) and 973 program (2012CB821900). NR 80 TC 4 Z9 5 U1 5 U2 58 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JUN 17 PY 2013 VL 23 IS 12 BP R538 EP R544 DI 10.1016/j.cub.2013.04.071 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 168CH UT WOS:000320682800015 PM 23787052 ER PT J AU Saleh, AD Simone, BA Palazzo, J Savage, JE Sano, Y Dan, T Jin, LJ Champ, CE Zhao, SP Lim, M Sotgia, F Camphausen, K Pestell, RG Mitchell, JB Lisanti, MP Simone, NL AF Saleh, Anthony D. Simone, Brittany A. Palazzo, Juan Savage, Jason E. Sano, Yuri Dan, Tu Jin, Lianjin Champ, Colin E. Zhao, Shuping Lim, Meng Sotgia, Frederica Camphausen, Kevin Pestell, Richard G. Mitchell, James B. Lisanti, Michael P. Simone, Nicole L. TI Caloric restriction augments radiation efficacy in breast cancer SO CELL CYCLE LA English DT Article DE caloric restriction; breast cancer; radiation; IGF; tumor regression; cytotoxic therapy ID GROWTH-FACTOR-I; RANDOMIZED CONTROLLED-TRIAL; ACTIVATED PROTEIN-KINASE; DIETARY RESTRICTION; GENE-EXPRESSION; FACTOR RECEPTOR; CELL-PROLIFERATION; OXIDATIVE STRESS; MAMMARY-TUMORS; OPEN-LABEL AB Dietary modification such as caloric restriction (CR) has been shown to decrease tumor initiation and progression. We sought to determine if nutrient restriction could be used as a novel therapeutic intervention to enhance cytotoxic therapies such as radiation (IR) and alter the molecular profile of triple-negative breast cancer (TNBC), which displays a poor prognosis. In two murine models of TNBC, significant tumor regression is noted with IR or diet modification, and a greater regression is observed combining diet modification with IR. Two methods of diet modification were compared, and it was found that a daily 30% reduction in total calories provided more significant tumor regression than alternate day feeding. At the molecular level, tumors treated with CR and IR showed less proliferation and more apoptosis. cDNA array analysis demonstrated the IGF-1R pathway plays a key role in achieving this physiologic response, and multiple members of the IGF-1R pathway including IGF-1R, IRS, PIK3ca and mTOR were found to be downregulated. The innovative use of CR as a novel therapeutic option has the potential to change the biology of tumors and enhance the opportunity for clinical benefit in the treatment of patients with TNBC. C1 [Saleh, Anthony D.; Savage, Jason E.; Zhao, Shuping; Camphausen, Kevin] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Simone, Brittany A.; Sano, Yuri; Dan, Tu; Jin, Lianjin; Champ, Colin E.; Lim, Meng; Simone, Nicole L.] Thomas Jefferson Univ, Jefferson Med Coll, Kimmel Canc Ctr, Dept Radiat Oncol, Philadelphia, PA 19107 USA. [Palazzo, Juan] Thomas Jefferson Univ, Jefferson Med Coll, Kimmel Canc Ctr, Dept Pathol, Philadelphia, PA 19107 USA. [Sotgia, Frederica; Pestell, Richard G.; Lisanti, Michael P.] Thomas Jefferson Univ, Dept Canc Biol, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. [Mitchell, James B.] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. RP Simone, NL (reprint author), Thomas Jefferson Univ, Jefferson Med Coll, Kimmel Canc Ctr, Dept Radiat Oncol, Philadelphia, PA 19107 USA. EM nicole.simone@jeffersonhospital.org OI Champ, Colin/0000-0002-1879-7463; Dan, Tu/0000-0003-1154-0507 FU American Society for Radiation Oncology; Intramural Research Program of the NIH; Kimmel Cancer Center Radiation Oncology Facility; NCI Cancer Center [P30 CA56036]; Thomas Jefferson University; Manchester Cancer Research Centre (MCRC); Breakthrough Breast Cancer (BBC); European Research Council (ERC) FX This research was supported in part by the American Society for Radiation Oncology, the Intramural Research Program of the NIH and the Kimmel Cancer Center Radiation Oncology Facility, which is supported partly by NCI Cancer Center Grant P30 CA56036. During the course of this work, Drs Lisanti and Sotgia were funded by the resources of Thomas Jefferson University. Also, Dr Lisanti's and Dr Sotgia's current affiliation is the University of Manchester, where they receive funding from the Manchester Cancer Research Centre (MCRC), Breakthrough Breast Cancer (BBC) and The European Research Council (ERC). NR 61 TC 16 Z9 21 U1 0 U2 11 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD JUN 15 PY 2013 VL 12 IS 12 BP 1955 EP 1963 DI 10.4161/cc.25016 PG 9 WC Cell Biology SC Cell Biology GA 201VD UT WOS:000323170200027 PM 23708519 ER PT J AU Jinnah, HA DeLong, MR Hallett, M AF Jinnah, H. A. DeLong, Mahlon R. Hallett, Mark TI The dystonias: Past, present, and future SO MOVEMENT DISORDERS LA English DT Editorial Material C1 [Jinnah, H. A.; DeLong, Mahlon R.] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. [Jinnah, H. A.] Emory Univ, Dept Human Genet, Atlanta, GA 30322 USA. [Jinnah, H. A.] Emory Univ, Dept Pediat, Atlanta, GA 30322 USA. [DeLong, Mahlon R.] Emory Univ, Dept Psychiat, Atlanta, GA 30322 USA. [Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Jinnah, HA (reprint author), Emory Univ, Sch Med, Dept Neurol, 6300 Woodruff Mem Bldg, Atlanta, GA 30322 USA. EM hjinnah@emory.edu FU NCATS NIH HHS [U54 TR001456]; NINDS NIH HHS [R01 NS040470, U54 NS065701] NR 15 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JUN 15 PY 2013 VL 28 IS 7 BP 849 EP 850 DI 10.1002/mds.25564 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 188ZH UT WOS:000322235700001 PM 23893441 ER PT J AU Albanese, A Bhatia, K Bressman, SB DeLong, MR Fahn, S Fung, VSC Hallett, M Jankovic, J Jinnah, HA Klein, C Lang, AE Mink, JW Teller, JK AF Albanese, Alberto Bhatia, Kailash Bressman, Susan B. DeLong, Mahlon R. Fahn, Stanley Fung, Victor S. C. Hallett, Mark Jankovic, Joseph Jinnah, Hyder A. Klein, Christine Lang, Anthony E. Mink, Jonathan W. Teller, Jan K. TI Phenomenology and classification of dystonia: A consensus update SO MOVEMENT DISORDERS LA English DT Review DE dystonia; classification; definition ID PRIMARY TORSION DYSTONIA; CLINICAL CHARACTERISTICS; DYT1 PHENOTYPE; FOCAL DYSTONIA; PATHOGENESIS; DIAGNOSIS; BLEPHAROSPASM; PARKINSONISM; GUIDELINES; DISEASE AB This report describes the consensus outcome of an international panel consisting of investigators with years of experience in this field that reviewed the definition and classification of dystonia. Agreement was obtained based on a consensus development methodology during 3 in-person meetings and manuscript review by mail. Dystonia is defined as a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Dystonic movements are typically patterned and twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation. Dystonia is classified along 2 axes: clinical characteristics, including age at onset, body distribution, temporal pattern and associated features (additional movement disorders or neurological features); and etiology, which includes nervous system pathology and inheritance. The clinical characteristics fall into several specific dystonia syndromes that help to guide diagnosis and treatment. We provide here a new general definition of dystonia and propose a new classification. We encourage clinicians and researchers to use these innovative definition and classification and test them in the clinical setting on a variety of patients with dystonia. (C) 2013 Movement Disorder Society C1 [Albanese, Alberto] Univ Cattolica Sacro Cuore, Dept Neurol, I-20123 Milan, Italy. [Albanese, Alberto] Ist Nazl Neurol Carlo Besta, Dept Neurol, Milan, Italy. [Bhatia, Kailash] UCL, Sobell Dept Motor Neurosci & Movement Disorders, Inst Neurol, London, England. [Bressman, Susan B.] Beth Israel Deaconess Med Ctr, Dept Neurol, New York, NY 10003 USA. [Bressman, Susan B.] Albert Einstein Coll Med, Dept Neurol, New York, NY USA. [Bressman, Susan B.] Beth Israel Deaconess Med Ctr, Dept Neurol, Bronx, NY USA. [Bressman, Susan B.] Albert Einstein Coll Med, Dept Neurol, Bronx, NY 10467 USA. [DeLong, Mahlon R.; Jinnah, Hyder A.] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. [Fahn, Stanley] Columbia Univ, Dept Neurol, New York, NY USA. [Fung, Victor S. C.] Univ Sydney, Movement Disorders Unit, Dept Neurol, Westmead Hosp, Sydney, NSW 2006, Australia. [Fung, Victor S. C.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Jankovic, Joseph] Baylor Coll Med, Parkinsons Dis Ctr, Houston, TX 77030 USA. [Jankovic, Joseph] Baylor Coll Med, Dept Neurol, Movement Disorders Clin, Houston, TX 77030 USA. [Jinnah, Hyder A.] Emory Univ, Dept Human Genet, Atlanta, GA 30322 USA. [Jinnah, Hyder A.] Emory Univ, Dept Pediat, Atlanta, GA 30322 USA. [Klein, Christine] Med Univ Lubeck, Sect Clin & Mol Neurogenet, Dept Neurol, D-23538 Lubeck, Germany. [Lang, Anthony E.] Toronto Western Hosp, Morton & Gloria Shulman Movement Disorders Clin, Toronto, ON M5T 2S8, Canada. [Lang, Anthony E.] Toronto Western Hosp, Edmond J Safra Program Parkinsons Dis, Toronto, ON M5T 2S8, Canada. [Lang, Anthony E.] Univ Toronto, Toronto, ON, Canada. [Mink, Jonathan W.] Univ Rochester, Dept Neurol, Rochester, NY USA. [Mink, Jonathan W.] Univ Rochester, Dept Neurobiol & Anat, Rochester, NY USA. [Mink, Jonathan W.] Univ Rochester, Dept Brain & Cognit Sci, Rochester, NY USA. [Mink, Jonathan W.] Univ Rochester, Dept Pediat, Rochester, NY USA. [Teller, Jan K.] Dystonia Med Res Fdn, Chicago, IL USA. RP Albanese, A (reprint author), Fdn Ist Neurol Carlo Besta, Via G Celoria 11, I-20133 Milan, Italy. EM alberto.albanese@unicatt.it OI Bhatia, Kailash/0000-0001-8185-286X FU Dystonia Medical Research Foundation; Dystonia Coalition; European Dystonia COST Action; Merz GmbH; Ipsen Pharma FX The efforts of the consensus committee were supported by the Dystonia Medical Research Foundation, The Dystonia Coalition, the European Dystonia COST Action, and unrestricted educational grants from Merz GmbH and Ipsen Pharma. NR 46 TC 298 Z9 302 U1 7 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JUN 15 PY 2013 VL 28 IS 7 BP 863 EP 873 DI 10.1002/mds.25475 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA 188ZH UT WOS:000322235700003 PM 23649720 ER PT J AU Jinnah, HA Berardelli, A Comella, C DeFazio, G DeLong, MR Factor, S Galpern, WR Hallett, M Ludlow, CL Perlmutter, JS Rosen, AR AF Jinnah, H. A. Berardelli, Alfredo Comella, Cynthia DeFazio, Giovanni DeLong, Mahlon R. Factor, Stewart Galpern, Wendy R. Hallett, Mark Ludlow, Christy L. Perlmutter, Joel S. Rosen, Ami R. CA Dystonia Coalition Investigators TI The focal dystonias: Current views and challenges for future research SO MOVEMENT DISORDERS LA English DT Review DE focal dystonia; cervical dystonia; blepharospasm; spasmodic dysphonia; focal hand dystonia ID DEEP-BRAIN-STIMULATION; IDIOPATHIC CERVICAL DYSTONIA; BENIGN ESSENTIAL BLEPHAROSPASM; PRIMARY TORSION DYSTONIA; BOTULINUM TOXIN TREATMENT;