OA	PT	AU	BA	BE	GP	AF	BF	CA	TI	SO	SE	LA	DT	CT	CY	CL	SP	HO	DE	ID	AB	C1	RP	EM	RI	FU	FX	CR	NR	TC	Z9	PU	PI	PA	SN	BN	J9	JI	PD	PY	VL	IS	PN	SU	SI	MA	BP	EP	AR	DI	D2	PG	WC	SC	GA	UT
true	J	Punta, M; Coggill, PC; Eberhardt, RY; Mistry, J; Tate, J; Boursnell, C; Pang, N; Forslund, K; Ceric, G; Clements, J; Heger, A; Holm, L; Sonnhammer, ELL; Eddy, SR; Bateman, A; Finn, RD				Punta, Marco; Coggill, Penny C.; Eberhardt, Ruth Y.; Mistry, Jaina; Tate, John; Boursnell, Chris; Pang, Ningze; Forslund, Kristoffer; Ceric, Goran; Clements, Jody; Heger, Andreas; Holm, Liisa; Sonnhammer, Erik L. L.; Eddy, Sean R.; Bateman, Alex; Finn, Robert D.			The Pfam protein families database	NUCLEIC ACIDS RESEARCH		English	Article							CRYSTAL-STRUCTURE; DOMAIN; IDENTIFICATION; ANNOTATION; HOMOLOGY; CAPSULE; REVEALS; SEARCH	Pfam is a widely used database of protein families, currently containing more than 13 000 manually curated protein families as of release 26.0. Pfam is available via servers in the UK (http://pfam.sanger.ac.uk/), the USA (http://pfam.janelia.org/) and Sweden (http://pfam.sbc.su.se/). Here, we report on changes that have occurred since our 2010 NAR paper (release 24.0). Over the last 2 years, we have generated 1840 new families and increased coverage of the UniProt Knowledgebase (UniProtKB) to nearly 80%. Notably, we have taken the step of opening up the annotation of our families to the Wikipedia community, by linking Pfam families to relevant Wikipedia pages and encouraging the Pfam and Wikipedia communities to improve and expand those pages. We continue to improve the Pfam website and add new visualizations, such as the 'sunburst' representation of taxonomic distribution of families. In this work we additionally address two topics that will be of particular interest to the Pfam community. First, we explain the definition and use of family-specific, manually curated gathering thresholds. Second, we discuss some of the features of domains of unknown function (also known as DUFs), which constitute a rapidly growing class of families within Pfam.	[Punta, Marco; Coggill, Penny C.; Eberhardt, Ruth Y.; Mistry, Jaina; Tate, John; Boursnell, Chris; Pang, Ningze; Bateman, Alex] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, England; [Forslund, Kristoffer; Sonnhammer, Erik L. L.] Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Swedish eSci Res Ctr,Stockholm Bioinformat Ctr, SE-17121 Solna, Sweden; [Ceric, Goran; Clements, Jody; Eddy, Sean R.; Finn, Robert D.] HHMI Janelia Farm Res Campus, Ashburn, VA 20147 USA; [Heger, Andreas] Univ Oxford, MRC Funct Genom Unit, Dept Physiol Anat & Genet, Oxford OX1 3QX, England; [Holm, Liisa] Univ Helsinki, Inst Biotechnol, Helsinki 00014, Finland; [Holm, Liisa] Univ Helsinki, Dept Biol & Environm Sci, FIN-00014 Helsinki, Finland	Punta, M (reprint author), Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton CB10 1SA, England.	mp13@sanger.ac.uk		Wellcome Trust [WT077044/Z/05/Z]; BBSRC [BB/F010435/1]; Howard Hughes Medical Institute; Stockholm University; Royal Institute of Technology; Swedish Natural Sciences Research Council	Wellcome Trust (grant numbers WT077044/Z/05/Z); BBSRC Bioinformatics and Biological Resources Fund (grant numbers BB/F010435/1); Howard Hughes Medical Institute (to G. C., J.C., S. R. E and R. D. F.); Stockholm University, Royal Institute of Technology and the Swedish Natural Sciences Research Council (to K. F. and E. L. L. S.) and Systems, Web and Database administration teams at Wellcome Trust Sanger Institute (WTSI) (infrastructure support). Funding for open access charge: Wellcome Trust (grant numbers WT077044/Z/05/Z); BBSRC Bioinformatics and Biological Resources Fund (grant numbers BB/F010435/1).		29	92	94	OXFORD UNIV PRESS	OXFORD	GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND	0305-1048		NUCLEIC ACIDS RES	Nucleic Acids Res.	JAN	2012	40	D1					D290	D301		10.1093/nar/gkr1065		12	Biochemistry & Molecular Biology	Biochemistry & Molecular Biology	869MD	WOS:000298601300043
false	J	Wong, E; Vaaje-Kolstad, G; Ghosh, A; Hurtado-Guerrero, R; Konarev, PV; Ibrahim, AFM; Svergun, DI; Eijsink, VGH; Chatterjee, NS; van Aalten, DMF				Wong, Edmond; Vaaje-Kolstad, Gustav; Ghosh, Avishek; Hurtado-Guerrero, Ramon; Konarev, Peter V.; Ibrahim, Adel F. M.; Svergun, Dmitri I.; Eijsink, Vincent G. H.; Chatterjee, Nabendu S.; van Aalten, Daan M. F.			The Vibrio cholerae Colonization Factor GbpA Possesses a Modular Structure that Governs Binding to Different Host Surfaces	PLOS PATHOGENS		English	Article							SMALL-ANGLE SCATTERING; SERRATIA-MARCESCENS; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; EPITHELIAL-CELLS; PROTEIN CBP21; ADHESIN FIMH; CHITIN; POLYSACCHARIDE; TOXIN	Vibrio cholerae is a bacterial pathogen that colonizes the chitinous exoskeleton of zooplankton as well as the human gastrointestinal tract. Colonization of these different niches involves an N-acetylglucosamine binding protein (GbpA) that has been reported to mediate bacterial attachment to both marine chitin and mammalian intestinal mucin through an unknown molecular mechanism. We report structural studies that reveal that GbpA possesses an unusual, elongated, four-domain structure, with domains 1 and 4 showing structural homology to chitin binding domains. A glycan screen revealed that GbpA binds to GlcNAc oligosaccharides. Structure-guided GbpA truncation mutants show that domains 1 and 4 of GbpA interact with chitin in vitro, whereas in vivo complementation studies reveal that domain 1 is also crucial for mucin binding and intestinal colonization. Bacterial binding studies show that domains 2 and 3 bind to the V. cholerae surface. Finally, mouse virulence assays show that only the first three domains of GbpA are required for colonization. These results explain how GbpA provides structural/functional modular interactions between V. cholerae, intestinal epithelium and chitinous exoskeletons.	[Wong, Edmond; Hurtado-Guerrero, Ramon; Ibrahim, Adel F. M.; van Aalten, Daan M. F.] Univ Dundee, Coll Life Sci, Div Mol Microbiol, Dundee, Scotland; [Vaaje-Kolstad, Gustav; Eijsink, Vincent G. H.] Norwegian Univ Life Sci, Dept Chem Biotechnol & Food Sci, As, Norway; [Ghosh, Avishek; Chatterjee, Nabendu S.] Scheme XM, Natl Inst Cholera & Enter Dis, Div Biochem, Calcutta, India; [Konarev, Peter V.; Svergun, Dmitri I.] DESY, European Mol Biol Lab, Outstn Hamburg, D-2000 Hamburg, Germany	Wong, E (reprint author), Natl Inst Med Res, Div Mol Struct, Mill Hill, London NW7 1AA, England.	dmfvanaalten@dundee.ac.uk	Ibrahim, Adel/E-5273-2012	Wellcome Trust [WT087590MA]; MRC [G0900138]	This work was funded by a Wellcome Trust Senior Research Fellowship to DvA (WT087590MA) and an MRC Programme Grant (G0900138) to DvA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.		52	4	4	PUBLIC LIBRARY SCIENCE	SAN FRANCISCO	1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA	1553-7374		PLOS PATHOG	PLoS Pathog.	JAN	2012	8	1							e1002373	10.1371/journal.ppat.1002373		12	Microbiology; Parasitology; Virology	Microbiology; Parasitology; Virology	898UI	WOS:000300767100003
true	J	Curjuric, I; Imboden, M; Nadif, R; Kumar, A; Schindler, C; Haun, M; Kronenberg, F; Kunzli, N; Phuleria, H; Postma, DS; Russi, EW; Rochat, T; Demenais, F; Probst-Hensch, NM				Curjuric, Ivan; Imboden, Medea; Nadif, Rachel; Kumar, Ashish; Schindler, Christian; Haun, Margot; Kronenberg, Florian; Kuenzli, Nino; Phuleria, Harish; Postma, Dirkje S.; Russi, Erich W.; Rochat, Thierry; Demenais, Florence; Probst-Hensch, Nicole M.			Different Genes Interact with Particulate Matter and Tobacco Smoke Exposure in Affecting Lung Function Decline in the General Population	PLOS ONE		English	Article							GENOME-WIDE ASSOCIATION; OBSTRUCTIVE PULMONARY-DISEASE; OXIDATIVE STRESS; CIGARETTE-SMOKE; AIR-POLLUTION; FOLLOW-UP; MITOCHONDRIAL LOCALIZATION; ENVIRONMENT INTERACTIONS; DUST EXPOSURE; SWISS COHORT	Background: Oxidative stress related genes modify the effects of ambient air pollution or tobacco smoking on lung function decline. The impact of interactions might be substantial, but previous studies mostly focused on main effects of single genes. Objectives: We studied the interaction of both exposures with a broad set of oxidative-stress related candidate genes and pathways on lung function decline and contrasted interactions between exposures. Methods: For 12679 single nucleotide polymorphisms (SNP5), change in forced expiratory volume in one second (FEV1), FEV1 over forced vital capacity (FEV1/FVC), and mean forced expiratory flow between 25 and 75% of the FVC (FEF25-75) was regressed on interval exposure to particulate matter < 10 mu m in diameter (PM10) or packyears smoked (a), additive SNP effects (b), and interaction terms between (a) and (b) in 669 adults with GWAS data. Interaction p-values for 152 genes and 14 pathways were calculated by the adaptive rank truncation product (ARTP) method, and compared between exposures. Interaction effect sizes were contrasted for the strongest SNPs of nominally significant genes (p(interaction) < 0.05). Replication was attempted for SNPs with MAF > 10% in 3320 SAPALDIA participants without GWAS. Results: On the SNP-level, rs2035268 in gene SNCA accelerated FEV1/FVC decline by 3.8% (p(interaction) = 2.5 x 10(-6)), and rs12190800 in PARK2 attenuated FEV1 decline by 95.1 ml p(interaction) = 9.7 x 10(-8)) over 11 years, while interacting with PM10. Genes and pathways nominally interacting with PM10 and packyears exposure differed substantially. Gene CRISP2 presented a significant interaction with PM10 (p(interaction) = 3.0 x 10(-4)) on FEV1/FVC decline. Pathway interactions were weak. Replications for the strongest SNPs in PARK2 and CRISP2 were not successful. Conclusions: Consistent with a stratified response to increasing oxidative stress, different genes and pathways potentially mediate PM10 and tobacco smoke effects on lung function decline. Ignoring environmental exposures would miss these patterns, but achieving sufficient sample size and comparability across study samples is challenging.	[Curjuric, Ivan; Imboden, Medea; Kumar, Ashish; Schindler, Christian; Kuenzli, Nino; Phuleria, Harish; Probst-Hensch, Nicole M.] Swiss Trop & Publ Hlth Inst SwissTPH, Dept Epidemiol & Publ Hlth, Basel, Switzerland; [Curjuric, Ivan; Imboden, Medea; Kumar, Ashish; Schindler, Christian; Kuenzli, Nino; Phuleria, Harish; Probst-Hensch, Nicole M.] Univ Basel, Basel, Switzerland; [Nadif, Rachel] CESP Ctr Res Epidemiol & Populat Hlth, INSERM, U1018, Resp & Environm Epidemiol Team, Villejuif, France; [Nadif, Rachel] Univ Paris 11, UMRS 1018, Villejuif, France; [Kumar, Ashish] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England; [Haun, Margot; Kronenberg, Florian] Innsbruck Med Univ, Dept Med Genet Mol & Clin Pharmacol, Div Genet Epidemiol, Innsbruck, Austria; [Postma, Dirkje S.] Univ Groningen, Univ Med Ctr Groningen, Dept Pulm Med & TB, Groningen, Netherlands; [Russi, Erich W.] Univ Zurich Hosp, Div Pulm Med, CH-8091 Zurich, Switzerland; [Rochat, Thierry] Univ Hosp Geneva, Div Pulm Med, Geneva, Switzerland; [Demenais, Florence] INSERM, U946, Genet Variat & Human Dis Unit, Paris, France; [Demenais, Florence] Fdn Jean Dausset, CEPH, Paris, France; [Demenais, Florence] Univ Paris Diderot, Inst Univ Hematol, Paris, France	Curjuric, I (reprint author), Swiss Trop & Publ Hlth Inst SwissTPH, Dept Epidemiol & Publ Hlth, Basel, Switzerland.	Nicole.Probst@unibas.ch	Kronenberg, Florian/B-1736-2008	Swiss National Science Foundation [33CS30_134276/1, 33CSCO-108796, 3247BO-104283, 3247BO-104288, 3247BO-104284, 3247-065896, 3100-059302, 3200-052720, 3200-042532, 4026-028099, 3233-054996, PDFMP3-123171]; Federal Office for Forest, Environment and Landscape; Federal Office of Public Health; Federal Office of Roads and Transport; canton government of Aargau; canton government of Basel-Stadt; canton government of Basel-Land; canton government of Geneva; canton government of Luzern; canton government of Ticino; canton government of Valais; canton government of Zurich; Swiss Lung League; canton Lung League of Basel Stadt; canton Lung League of Basel Landschaft; canton Lung League of Geneva; canton Lung League of Ticino; canton Lung League of Valais; canton Lung League of Zurich; Schweizerische Unfallversicherungsanstalt (SUVA); Freiwillige Akademische Gesellschaft; UBS Wealth Foundation; Talecris Biotherapeutics GmbH; Abbott Diagnostics; European Commission [018996]; Wellcome Trust [WT 084703MA]; French National Research Agency (Bio2nea project) [ANR-CES 2009]	The Swiss Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) was supported by the Swiss National Science Foundation (grants no 33CS30_134276/1, 33CSCO-108796, 3247BO-104283, 3247BO-104288, 3247BO-104284, 3247-065896, 3100-059302, 3200-052720, 3200-042532, 4026-028099, 3233-054996, PDFMP3-123171), the Federal Office for Forest, Environment and Landscape, the Federal Office of Public Health, the Federal Office of Roads and Transport, the canton's government of Aargau, Basel-Stadt, Basel-Land, Geneva, Luzern, Ticino, Valais, Zurich, the Swiss Lung League, the canton's Lung League of Basel Stadt/Basel Landschaft, Geneva, Ticino, Valais and Zurich, Schweizerische Unfallversicherungsanstalt (SUVA), Freiwillige Akademische Gesellschaft, UBS Wealth Foundation, Talecris Biotherapeutics GmbH, and Abbott Diagnostics. Genotyping in the GABRIEL framework was supported by grants European Commission 018996 and Wellcome Trust WT 084703MA. Identification of pathways was supported by the French National Research Agency (Bio2nea project ANR-CES 2009). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.I have read the journal's policy and have the following conflicts: The SAPALDIA study was supported by the UBS Wealth Foundation, Talecris Biotherapeutics GmbH, and Abbott Diagnostics in terms of unrestricted grants for personnel and genotyping. The support of these institutions did not influence the scientific work regarding study design, data collection, data analysis, interpretation of results, decision to publish, or preparation of the manuscript in any way. Also, this does not alter our adherence to all the PLoS ONE policies on sharing data and materials.		64	0	0	PUBLIC LIBRARY SCIENCE	SAN FRANCISCO	1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA	1932-6203		PLOS ONE	PLoS One	JUL 6	2012	7	7							e40175	10.1371/journal.pone.0040175		11	Multidisciplinary Sciences	Science & Technology - Other Topics	974UB	WOS:000306461800046
false	J	Knight, JC				Knight, Julian C.			Genomic modulators of the immune response	TRENDS IN GENETICS		English	Review						immunity; major histocompatibility complex; gene regulation; autoimmunity; immunodeficiency; leukocyte	GLOBAL GENE-EXPRESSION; WIDE ASSOCIATION; DISEASE SUSCEPTIBILITY; HLA-C; EPIGENETIC REGULATION; RHEUMATOID-ARTHRITIS; AUTOIMMUNE-DISEASES; DNA METHYLATION; COMPLEX DISEASE; INBORN-ERRORS	Our understanding of immunity has historically been informed by studying heritable mutations in both the adaptive and innate immune responses, including primary immunodeficiency and autoimmune diseases. Recent advances achieved through the application of genomic and epigenomic approaches are reshaping the study of immune dysfunction and opening up new avenues for therapeutic interventions. Moreover, applying genomic techniques to resolve functionally important genetic variation between individuals is providing new insights into immune function in health. This review describes progress in the study of rare variants and primary immunodeficiency diseases arising from whole-exome sequencing (WES), and discusses the application, success, and challenges of applying genome-wide association studies (GWAS) to disorders of immune function and how they may inform more rational use of therapeutics. In addition, the application of expression quantitative-trait mapping to immune phenotypes, progress in understanding MHC disease associations, and insights into epigenetic mechanisms at the interface of immunity and the environment are reviewed.	Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England	Knight, JC (reprint author), Univ Oxford, Wellcome Trust Ctr Human Genet, Roosevelt Dr, Oxford OX3 7BN, England.	julian@well.ox.ac.uk		Wellcome Trust [074318, 075491/Z/04]; European Research Council (ERC) under European Commission [281824]; Medical Research Council [98082]; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre	Work in the laboratory of J.K. has been supported by the Wellcome Trust (074318 and 075491/Z/04 to core facilities Wellcome Trust Centre for Human Genetics), the European Research Council (ERC) under European Commission 7th Framework Programme (FP7/2007-2013)/ERC grant agreement No. 281824, the Medical Research Council (98082), and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre.		85	0	0	ELSEVIER SCIENCE LONDON	LONDON	84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND	0168-9525		TRENDS GENET	Trends Genet.	FEB	2013	29	2					74	83		10.1016/j.tig.2012.10.006		10	Genetics & Heredity	Genetics & Heredity	087EP	WOS:000314744400005
false	J	Seden, K; Khoo, S; Back, D; Prevatt, N; Lamorde, M; Byakika-Kibwika, P; Mayito, J; Ryan, M; Merry, C				Seden, Kay; Khoo, Saye; Back, David; Prevatt, Natalie; Lamorde, Mohammed; Byakika-Kibwika, Pauline; Mayito, Jonathan; Ryan, Mairin; Merry, Concepta			Drug-drug interactions between antiretrovirals and drugs used in the management of neglected tropical diseases: important considerations in the WHO 2020 Roadmap and London Declaration on Neglected Tropical Diseases	AIDS		English	Review						drug interactions; HIV/AIDS; neglected tropical diseases; pharmacokinetics	INTRAVENOUS-SODIUM STIBOGLUCONATE; MEGLUMINE ANTIMONIATE; DENGUE VIRUS; PHARMACOKINETIC INTERACTION; CLINICAL PHARMACOKINETICS; VISCERAL LEISHMANIASIS; HEALTHY-VOLUNTEERS; IN-VITRO; LIVER; BENZNIDAZOLE	The group of infections known as the neglected tropical diseases (NTDs) collectively affect one billion people worldwide, equivalent to one-sixth of the world's population. The NTDs cause severe physical and emotional morbidity, and have a profound effect on cycles of poverty; it is estimated that NTDs account for 534 000 deaths per year. NTDs such as soil-transmitted helminth infections and the vector-borne protozoal infections leishmaniasis and trypanosomiasis occur predominantly in the most economically disadvantaged and marginalized communities. It is estimated that all low-income countries harbour at least five of the NTDs simultaneously. NTDs are neglected because they do not individually rank highly in terms of mortality data, and because they affect populations with little political voice. There is considerable geographic overlap between areas with high prevalence of NTDs and HIV, raising the possibility of complex polypharmacy and drug-drug interactions. Antiretrovirals pose a particularly high risk for potential drug-drug interactions, which may be pharmacokinetic or pharmacodynamic in nature and can result in raising or lowering plasma or tissue concentrations of co-prescribed drugs. Elevated drug concentrations may be associated with drug toxicity and lower drug concentrations may be associated with therapeutic failure. The aim of this paper is to review the currently available data on interactions between antiretrovirals and drugs used in the management of NTDs. It is intended to serve as a resource for policy makers and clinicians caring for these patients, and to support the recent WHO 2020 Roadmap and the 2012 London Declaration on NTDs. (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins AIDS 2013, 27:675-686	[Seden, Kay; Khoo, Saye; Back, David] Univ Liverpool, Inst Translat Med, Dept Mol & Clin Pharmacol, Liverpool L69 3GF, Merseyside, England; [Prevatt, Natalie] London Deanery, London, England; [Lamorde, Mohammed; Byakika-Kibwika, Pauline; Mayito, Jonathan; Merry, Concepta] Makerere Univ, Coll Hlth Sci, Infect Dis Inst, Kampala, Uganda; [Lamorde, Mohammed; Byakika-Kibwika, Pauline; Ryan, Mairin; Merry, Concepta] Trinity Coll Dublin, Dept Pharmacol & Therapeut, Dublin, Ireland; [Merry, Concepta] Northwestern Univ, Feinberg Sch Med, Ctr Global Hlth, Chicago, IL 60611 USA	Seden, K (reprint author), Univ Liverpool, Dept Pharmacol, Block H,1st Floor,70 Pembroke Pl, Liverpool L69 3GF, Merseyside, England.	k.seden@liv.ac.uk		Wellcome Trust [083851/Z/07/Z]; European and Developing Countries Clinical Trials Partnership grants [TA.09.40200.020, TA.11.40200.047]; Viiv; BMS; Gilead; Janssen; Merck; Boehringer-Ingelheim; Sewankambo scholarship at IDI; Gilead Foundation	We acknowledge support from a Wellcome Trust Programme Grant award: PK-PD modelling to optimize treatment for HIV, TB and malaria. (ref 083851/Z/07/Z).M.L. and P.B. are supported by European and Developing Countries Clinical Trials Partnership grants (TA.09.40200.020 and TA.11.40200.047).Transparency Declaration: D.J.B. and S.H.K. have received research funding for development of the web site www.hiv-druginteractions.org from Viiv, BMS, Gilead, Janssen, Merck, Boehringer-Ingelheim. DJB has received honoria for lectures or Advisory Boards from Viiv, BMS, Gilead, Janssen, Merck.M.L. has received grants from Janssen and is supported by the Sewankambo scholarship at IDI which is funded by Gilead Foundation.		56	0	0	LIPPINCOTT WILLIAMS & WILKINS	PHILADELPHIA	530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA	0269-9370		AIDS	Aids	MAR 13	2013	27	5					675	686		10.1097/QAD.0b013e32835ca9b4		12	Immunology; Infectious Diseases; Virology	Immunology; Infectious Diseases; Virology	098CY	WOS:000315524700001
true	J	Mero, IL; Gustavsen, MW; Saether, HS; Flam, ST; Berg-Hansen, P; Sondergaard, HB; Jensen, PEH; Berge, T; Bjolgerud, A; Muggerud, A; Aarseth, JH; Myhr, KM; Celius, EG; Sellebjerg, F; Hillert, J; Alfredsson, L; Olsson, T; Oturai, AB; Kockum, I; Lie, BA; Andreassen, BK; Harbo, HF				Mero, Inger-Lise; Gustavsen, Marte W.; Saether, Hanne S.; Flam, Siri T.; Berg-Hansen, Pal; Sondergaard, Helle B.; Jensen, Poul Erik H.; Berge, Tone; Bjolgerud, Anja; Muggerud, Aslaug; Aarseth, Jan H.; Myhr, Kjell-Morten; Celius, Elisabeth G.; Sellebjerg, Finn; Hillert, Jan; Alfredsson, Lars; Olsson, Tomas; Oturai, Annette Bang; Kockum, Ingrid; Lie, Benedicte A.; Andreassen, Bettina Kulle; Harbo, Hanne F.		Int Multiple Sclerosis Genetics	Oligoclonal Band Status in Scandinavian Multiple Sclerosis Patients Is Associated with Specific Genetic Risk Alleles	PLOS ONE		English	Article							CEREBROSPINAL-FLUID; DIAGNOSTIC-CRITERIA; CLINICAL-FEATURES; INTERFERON-BETA; SUSCEPTIBILITY; POPULATION; HLA-DRB1; GENOMEWIDE; DISABILITY; GUIDELINES	The presence of oligoclonal bands (OCB) in cerebrospinal fluid (CSF) is a typical finding in multiple sclerosis (MS). We applied data from Norwegian, Swedish and Danish (i.e. Scandinavian) MS patients from a genome-wide association study (GWAS) to search for genetic differences in MS relating to OCB status. GWAS data was compared in 1367 OCB positive and 161 OCB negative Scandinavian MS patients, and nine of the most associated SNPs were genotyped for replication in 3403 Scandinavian MS patients. HLA-DRB1 genotypes were analyzed in a subset of the OCB positive (n = 2781) and OCB negative (n = 292) MS patients and compared to 890 healthy controls. Results from the genome-wide analyses showed that single nucleotide polymorphisms (SNPs) from the HLA complex and six other loci were associated to OCB status. In SNPs selected for replication, combined analyses showed genome-wide significant association for two SNPs in the HLA complex; rs3129871 (p = 5.7x10(-15)) and rs3817963 (p = 5.7x10(-10)) correlating with the HLA-DRB1*15 and the HLA-DRB1*04 alleles, respectively. We also found suggestive association to one SNP in the Calsyntenin-2 gene (p = 8.83x10(-7)). In HLA-DRB1 analyses HLA-DRB1*15:01 was a stronger risk factor for OCB positive than OCB negative MS, whereas HLA-DRB1*04:04 was associated with increased risk of OCB negative MS and reduced risk of OCB positive MS. Protective effects of HLA-DRB1*01:01 and HLA-DRB1*07:01 were detected in both groups. The groups were different with regard to age at onset (AAO), MS outcome measures and gender. This study confirms both shared and distinct genetic risk for MS subtypes in the Scandinavian population defined by OCB status and indicates different clinical characteristics between the groups. This suggests differences in disease mechanisms between OCB negative and OCB positive MS with implications for patient management, which need to be further studied.	[Mero, Inger-Lise; Gustavsen, Marte W.; Saether, Hanne S.; Berg-Hansen, Pal; Berge, Tone; Bjolgerud, Anja; Muggerud, Aslaug; Celius, Elisabeth G.; Harbo, Hanne F.] Oslo Univ Hosp, Dept Neurol, Oslo, Norway; [Mero, Inger-Lise; Saether, Hanne S.; Flam, Siri T.; Lie, Benedicte A.] Univ Oslo, Dept Med Genet, Oslo, Norway; [Mero, Inger-Lise; Saether, Hanne S.; Flam, Siri T.; Lie, Benedicte A.] Oslo Univ Hosp, Oslo, Norway; [Sondergaard, Helle B.; Jensen, Poul Erik H.; Sellebjerg, Finn; Oturai, Annette Bang] Rigshosp, Dept Neurol, Danish Multiple Sclerosis Ctr, DK-2100 Copenhagen, Denmark; [Berge, Tone] Univ Oslo, Inst Basic Med Sci, Oslo, Norway; [Aarseth, Jan H.; Myhr, Kjell-Morten] Norwegian Multiple Sclerosis Registry, Bergen, Norway; [Aarseth, Jan H.; Myhr, Kjell-Morten] Haukeland Hosp, Dept Neurol, Biobank, N-5021 Bergen, Norway; [Myhr, Kjell-Morten] Univ Bergen, Dept Clin Med, KG Jebsen Ctr MS Res, Bergen, Norway; [Hillert, Jan] Karolinska Inst, Dept Clin Neurosci, Multiple Sclerosis Res Grp, Ctr Mol Med, Stockholm, Sweden; [Alfredsson, Lars] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden; [Olsson, Tomas; Kockum, Ingrid] Karolinska Inst, Dept Clin Neurosci, Neuroimmunol Res Grp, Stockholm, Sweden; [Andreassen, Bettina Kulle] Univ Oslo, Inst Clin Med, Dept Clin Mol Biol & Lab Sci EpiGen, Oslo, Norway; [Andreassen, Bettina Kulle] Univ Oslo, Inst Basic Med Sci, Dept Biostat, Oslo, Norway; [Gustavsen, Marte W.; Berg-Hansen, Pal; Bjolgerud, Anja; Muggerud, Aslaug; Harbo, Hanne F.] Univ Oslo, Inst Clin Med, Oslo, Norway	Harbo, HF (reprint author), Oslo Univ Hosp, Dept Neurol, Oslo, Norway.	h.f.harbo@medisin.uio.no		South-Eastern Norway Regional Health Authority; Research Council of Norway; Odd Fellow MS society; Danish Multiple Sclerosis Society; Swedish Medical Research Council; AFA foundation; Knut and Alice and Wallenbergs foundations; Council for Working Life and Social Research; Wellcome Trust, as part of the Wellcome Trust Case Control Consortium2 project [085475/B/08/Z, 085475/Z/08/Z]	The current study is funded by grants from the South-Eastern Norway Regional Health Authority, the Research Council of Norway, the Odd Fellow MS society, the Danish Multiple Sclerosis Society, the Swedish Medical Research Council, the AFA foundation, Knut and Alice and Wallenbergs foundations and Council for Working Life and Social Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.We thank all patients and healthy controls for their participation. The International Multiple Sclerosis Genetics Consortium and the Wellcome Trust Case Control Consortium2 provided the genotypes used in the screening phase of this study. We acknowledge the collaboration and principal funding for the genome-wide study provided by the Wellcome Trust, as part of the Wellcome Trust Case Control Consortium2 project (085475/B/08/Z and 085475/Z/08/Z). We thank all contributors to the collection of samples and clinical data in the Norwegian MS Registry and Biobank. The Norwegian Bone Marrow Donor Registry, Rikshospitalet, Oslo University Hospital are acknowledged for providing Norwegian controls. The Centre for Integrative Genetics; CIGENE, Norwegian University of Life Sciences (UMB) Aas is thanked for performing Sequenom analyses.		42	0	0	PUBLIC LIBRARY SCIENCE	SAN FRANCISCO	1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA	1932-6203		PLOS ONE	PLoS One	MAR 5	2013	8	3							e58352	10.1371/journal.pone.0058352		9	Multidisciplinary Sciences	Science & Technology - Other Topics	099RC	WOS:000315637900131
false	J	Perugorria, MJ; Murphy, LB; Fullard, N; Chakraborty, JB; Vyrla, D; Wilson, CL; Oakley, F; Mann, J; Mann, DA				Perugorria, Maria J.; Murphy, Lindsay B.; Fullard, Nicola; Chakraborty, Jayashree B.; Vyrla, Dimitra; Wilson, Caroline L.; Oakley, Fiona; Mann, Jelena; Mann, Derek A.			Tumor progression locus 2/Cot is required for activation of extracellular regulated kinase in liver injury and toll-like receptorinduced TIMP-1 gene transcription in hepatic stellate cells in mice	HEPATOLOGY		English	Article							LPS-STIMULATED MACROPHAGES; FACTOR-KAPPA-B; TISSUE INHIBITOR; SIGNAL-TRANSDUCTION; MAP KINASE; TNF-ALPHA; FIBROSIS; EXPRESSION; RESPONSES; CIRRHOSIS	Toll-like receptors (TLRs) function as key regulators of liver fibrosis and are able to modulate the fibrogenic actions of nonparenchymal liver cells. The fibrogenic signaling events downstream of TLRs on Kupffer cells (KCs) and hepatic stellate cells (HSCs) are poorly defined. Here, we describe the MAP3K tumor progression locus 2 (Tpl2) as being important for the activation of extracellular regulated kinase (ERK) signaling in KCs and HSCs responding to stimulation of TLR4 and TLR9. KCs lacking Tpl2 display defects with TLR induction of cytokines interleukin (IL)-1, IL-10, and IL-23. tpl2/ HSCs were unable to increase expression of fibrogenic genes IL-1 and tissue inhibitor of metalloproteinase 1 (TIMP-1), with the latter being the result of defective stimulation of TIMP-1 promoter activity by TLRs. To determine the in vivo relevance of Tpl2 signaling in liver fibrosis, we compared the fibrogenic responses of wild-type (WT) and tpl2/ mice in three distinct models of chronic liver injury. In the carbon tetrachloride and methionine-cholinedeficient diet models, we observed a significant reduction in fibrosis in mice lacking Tpl2, compared to WT controls. However, in the bile duct ligation model, there was no effect of tpl2 deletion, which may reflect a lesser role for HSCs in wounding response to biliary injury. Conclusion: We conclude that Tpl2 is an important signal transducer for TLR activation of gene expression in KCs and HSCs by the ERK pathway and that suppression of its catalytic activity may be a route toward suppressing fibrosis caused by hepatocellular injuries. (HEPATOLOGY 2013)	[Perugorria, Maria J.; Murphy, Lindsay B.; Fullard, Nicola; Chakraborty, Jayashree B.; Wilson, Caroline L.; Oakley, Fiona; Mann, Jelena; Mann, Derek A.] Newcastle Univ, Inst Cellular Med, Fac Med Sci, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England; [Vyrla, Dimitra] Univ Crete, Sch Med, Iraklion, Crete, Greece	Mann, DA (reprint author), Newcastle Univ, Inst Cellular Med, Fac Med Sci, 4th Floor,William Leech Bldg,Framlington Pl, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England.	derek.mann@ncl.ac.uk		Wellcome Trust [WT086755MA]; European Commission [223151]	"The present study was supported by the Wellcome Trust (grant no.: WT086755MA) and a European Commission FP7 program grant ""INFLA-CARE"" (EC contract no.: 223151; http://inflacare.imbb.forth.gr/) (both to D.A.M.). The authors thank Dr. Steven C Ley (MRC National Institute for Medical Research, London, UK) for the generous gift of Tpl2<SUP>-/-</SUP> mice."		40	0	0	WILEY-BLACKWELL	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	0270-9139		HEPATOLOGY	Hepatology	MAR	2013	57	3					1238	1249		10.1002/hep.26108		12	Gastroenterology & Hepatology	Gastroenterology & Hepatology	099TG	WOS:000315644200043
false	J	Lopes, MC; Hysi, PG; Verhoeven, VJM; Macgregor, S; Hewitt, AW; Montgomery, GW; Cumberland, P; Vingerling, JR; Young, TL; van Duijn, CM; Oostra, B; Uitterlinden, AG; Rahi, JS; Mackey, DA; Klaver, CCW; Andrew, T; Hammond, CJ				Lopes, Margarida C.; Hysi, Pirro G.; Verhoeven, Virginie J. M.; Macgregor, Stuart; Hewitt, Alex W.; Montgomery, Grant W.; Cumberland, Phillippa; Vingerling, Johannes R.; Young, Terri L.; van Duijn, Cornelia M.; Oostra, Ben; Uitterlinden, Andre G.; Rahi, Jugnoo S.; Mackey, David A.; Klaver, Caroline C. W.; Andrew, Toby; Hammond, Christopher J.			Identification of a Candidate Gene for Astigmatism	INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE		English	Article							GENOME-WIDE ASSOCIATION; REFRACTIVE ERROR; EYE DEVELOPMENT; SUSCEPTIBILITY LOCUS; CORNEAL ASTIGMATISM; SCHOOL-CHILDREN; SONIC HEDGEHOG; HUMAN-DISEASES; IMPUTED DATA; MYOPIA	PURPOSE. Astigmatism is a common refractive error that reduces vision, where the curvature and refractive power of the cornea in one meridian are less than those of the perpendicular axis. It is a complex trait likely to be influenced by both genetic and environmental factors. Twin studies of astigmatism have found approximately 60% of phenotypic variance is explained by genetic factors. This study aimed to identify susceptibility loci for astigmatism. METHODS. We performed a meta-analysis of seven genome-wide association studies that included 22,100 individuals of European descent, where astigmatism was defined as the number of diopters of cylinder prescription, using fixed effect inverse variance-weighted methods. RESULTS. A susceptibility locus was identified with lead single nucleotide polymorphism rs3771395 on chromosome 2p13.3 (meta-analysis, P = 1.97 x 10(-7)) in the VAX2 gene. VAX2 plays an important role in the development of the dorsoventral axis of the eye. Animal studies have shown a gradient in astigmatism along the vertical plane, with corresponding changes in refraction, particularly in the ventral field. CONCLUSIONS. This finding advances the understanding of refractive error, and provides new potential pathways to be evaluated with regard to the development of astigmatism. (Invest Ophthalmol Vis Sci. 2013;54:1260-1267) DOI:10.1167/iovs.12-10463	[Lopes, Margarida C.; Hysi, Pirro G.; Andrew, Toby; Hammond, Christopher J.] Kings Coll London, Dept Twin Res & Genet Epidemiol, St Thomas Hosp, London WC2R 2LS, England; [Verhoeven, Virginie J. M.; Vingerling, Johannes R.; Klaver, Caroline C. W.] Erasmus MC, Dept Ophthalmol, Rotterdam, Netherlands; [Verhoeven, Virginie J. M.; Vingerling, Johannes R.; van Duijn, Cornelia M.; Oostra, Ben; Uitterlinden, Andre G.; Klaver, Caroline C. W.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands; [Macgregor, Stuart; Montgomery, Grant W.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia; [Hewitt, Alex W.] Univ Melbourne, Ctr Eye Res Australia, Royal Victorian Eye & Ear Hosp, Melbourne, Vic, Australia; [Cumberland, Phillippa] UCL, Ulverscroft Vis Res Grp, London, England; [Cumberland, Phillippa; Rahi, Jugnoo S.] UCL, MRC, Ctr Epidemiol Child Hlth, Inst Child Hlth, London, England; [Rahi, Jugnoo S.] UCL, Inst Ophthalmol, London, England; [Young, Terri L.] Duke Univ, Ctr Human Genet, Durham, NC USA; [Mackey, David A.] Univ Western Australia, Lions Eye Inst, Ctr Ophthalmol & Visual Sci, Perth, WA 6009, Australia	Hammond, CJ (reprint author), Kings Coll London, St Thomas Hosp Campus,3rd Floor South Wing Block, London SE1 7EH, England.	chris.hammond@kcl.ac.uk		European Union MyEuropia Marie Curie Research Training Network [MRTN-CT-2006-034021]; Guide Dogs for the Blind Association; EU FP7 [HEALTH-F2-2008-201865-GEFOS]; European Network of Genetic and Genomic Epidemiology [HEALTH-F4-2007-201413]; FP-5 GenomEUtwin Project [QLG2-CT-2002-01254]; US National Institutes of Health/National Eye Institute Grant [1RO1EY018246]; NIH Center for Inherited Disease Research; National Institute for Health Research comprehensive Biomedical Research Centre; St. Thomas' National Health Service Foundation Trust; King's College London; Netherlands Organisation of Scientific Research; Erasmus Medical Center; Netherlands Organization for Health Research and Development; UitZicht; Research Institute for Diseases in the Elderly; European Commission Directorate General XII; Municipality of Rotterdam; Netherlands Genomics Initiative; Lijf en Leven; MD Fonds; Henkes; Oogfonds; Stichting Wetenschappelijk Onderzoek Het Oogziekenhuis; Swart van Essen; Blindenhulp; Landelijke Stichting voor Blinden en Slechtzienden; Rotterdamse Vereniging voor Blindenbelangen; OOG Foundation; Algemene Nederlandse Vereniging ter Voorkoming van Blindheid; Rotterdam Eye Institute; Australian National Health and Medical Research Council; Clifford Craig Medical Research Trust; Ophthalmic Research Institute of Australia; American Health Assistance Foundation; Peggy and Leslie Cranbourne Foundation; Foundation for Children; NHMRC project Grant [350415]; Jack Brockhoff Foundation; NEI project Grant [RO1 EY 018246-01]; NHMRC Medical Genomics grant; NEI/NIH project grant; Netherlands Scientific Organization [NWO 480-05-003]; Medical Research Council's Health of the Public grant; Wellcome Trust [083478]; Institute of Child Health, University College London from the National Institute for Health Research as Specialist Biomedical Research Centres; Institute of Ophthalmology from the National Institute for Health Research as Specialist Biomedical Research Centres; Great Ormond Street hospital; Moorfields hospital; Ulverscroft Vision Research Group; Bevordering van Volkskracht	The TwinsUK study is supported by European Union MyEuropia Marie Curie Research Training Network (MRTN-CT-2006-034021), Wellcome Trust, Guide Dogs for the Blind Association, EU FP7 (HEALTH-F2-2008-201865-GEFOS), European Network of Genetic and Genomic Epidemiology (HEALTH-F4-2007-201413), FP-5 GenomEUtwin Project (QLG2-CT-2002-01254), and US National Institutes of Health/National Eye Institute Grant 1RO1EY018246; genotyping was supported by NIH Center for Inherited Disease Research. Also supported by a National Institute for Health Research comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service Foundation Trust in partnership with King's College London. Rotterdam and ERF studies are supported by Netherlands Organisation of Scientific Research, Erasmus Medical Center, Netherlands Organization for Health Research and Development, UitZicht, Research Institute for Diseases in the Elderly, European Commission Directorate General XII, Municipality of Rotterdam, Netherlands Genomics Initiative, Lijf en Leven, MD Fonds, Henkes, Oogfonds, Stichting Wetenschappelijk Onderzoek Het Oogziekenhuis, Swart van Essen, Bevordering van Volkskracht, Blindenhulp, Landelijke Stichting voor Blinden en Slechtzienden, Rotterdamse Vereniging voor Blindenbelangen, OOG Foundation, Algemene Nederlandse Vereniging ter Voorkoming van Blindheid, and Rotterdam Eye Institute. Australian Twin Registry is supported by an Australian National Health and Medical Research Council enabling grant (2004-2009), Clifford Craig Medical Research Trust, Ophthalmic Research Institute of Australia, American Health Assistance Foundation, Peggy and Leslie Cranbourne Foundation, Foundation for Children, NHMRC project Grant 350415 (2005-2007), Jack Brockhoff Foundation, and NEI project Grant RO1 EY 018246-01 (2007-2010). Genotyping for the Australian sample was funded in part by an NHMRC Medical Genomics grant and in part by an NEI/NIH project grant, performed by CIDR. Australian sample imputation analyses were carried out with the Genetic Cluster computer and were supported by the Netherlands Scientific Organization (NWO 480-05-003). The 1958 British cohort study is supported by Medical Research Council's Health of the Public grant, and genome-wide association studies were funded by project Grant 083478 from Wellcome Trust (JSR); analyses were carried out at the Institute of Child Health, University College London, and Institute of Ophthalmology, both of which receive support from the National Institute for Health Research as Specialist Biomedical Research Centres in partnership respectively with Great Ormond Street and Moorfields hospitals. Supported also by Ulverscroft Vision Research Group (PC). Sponsors and funding organizations had no role in the design or conduct of this research.		48	0	0	ASSOC RESEARCH VISION OPHTHALMOLOGY INC	ROCKVILLE	12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA	0146-0404		INVEST OPHTH VIS SCI	Invest. Ophthalmol. Vis. Sci.	FEB	2013	54	2					1260	1267		10.1167/iovs.12-10463		8	Ophthalmology	Ophthalmology	100BS	WOS:000315670300044
false	J	Malone, IB; Cash, D; Ridgway, GR; MacManus, DG; Ourselin, S; Fox, NC; Schott, JM				Malone, Ian B.; Cash, David; Ridgway, Gerard R.; MacManus, David G.; Ourselin, Sebastien; Fox, Nick C.; Schott, Jonathan M.			MIRIAD-Public release of a multiple time point Alzheimer's MR imaging dataset	NEUROIMAGE		English	Article						Alzheimer's; MRI; Longitudinal; Imaging; Database	ATROPHY MEASUREMENT TECHNIQUES; SERIAL MRI; ACCURACY ASSESSMENT; CORTICAL THICKNESS; CEREBRAL ATROPHY; BRAIN ATROPHY; DISEASE; DIAGNOSIS; VOXEL; RATES	The Minimal Interval Resonance Imaging in Alzheimer's Disease (MIRIAD) dataset is a series of longitudinal volumetric T1 MRI scans of 46 mild-moderate Alzheimer's subjects and 23 controls. It consists of 708 scans conducted by the same radiographer with the same scanner and sequences at intervals of 2, 6, 14, 26, 38 and 52 weeks, 18 and 24 months from baseline, with accompanying information on gender, age and Mini Mental State Examination (MMSE) scores. Details of the cohort and imaging results have been described in peer-reviewed publications, and the data are here made publicly available as a common resource for researchers to develop, validate and compare techniques, particularly for measurement of longitudinal volume change in serially acquired MR. (c) 2013 Elsevier Inc. All rights reserved.	[Malone, Ian B.; Cash, David; Ourselin, Sebastien; Fox, Nick C.; Schott, Jonathan M.] UCL Inst Neurol, Dementia Res Ctr, London WC1N 3BG, England; [Cash, David; Ourselin, Sebastien] UCL, Ctr Med Image Comp, London WC1E 6BT, England; [MacManus, David G.] UCL Inst Neurol, NMR Res Unit, London WC1N 3BG, England; [Ridgway, Gerard R.] UCL Inst Neurol, Wellcome Trust Ctr Neuroimaging, London WC1N 3BG, England	Schott, JM (reprint author), UCL Inst Neurol, Dementia Res Ctr, Queen Sq, London WC1N 3BG, England.	j.schott@ucl.ac.uk	Schott, Jonathan/A-9065-2011; Ridgway, Gerard/F-5145-2010	UK Alzheimer's Society; GlaxoSmithKline; Medical Research Council; EPSRC [EP/H046410/1]; Comprehensive Biomedical Research Centre (CBRC) Strategic Investment Award [168]; Medical Research Council [MR/J014257/1]; National Institute for Health Research (NIHR) Biomedical Research Unit in Dementia based at University College London Hospitals (UCLH), University College London (UCL); Wellcome Trust [091593/Z/10/Z]	This dataset is made available through the support of the UK Alzheimer's Society. The original data collection was funded through an unrestricted educational grant from GlaxoSmithKline and funding from the UK Alzheimer's Society (to Dr Schott) and the Medical Research Council (to Professor Fox). Professor Ourselin receives funding from the EPSRC (EP/H046410/1) and the Comprehensive Biomedical Research Centre (CBRC) Strategic Investment Award (Ref. 168). Dr Ridgway is supported by the Medical Research Council [grant number MR/J014257/1]. This work was supported by the National Institute for Health Research (NIHR) Biomedical Research Unit in Dementia based at University College London Hospitals (UCLH), University College London (UCL). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The Dementia Research Centre is an Alzheimer's Research UK (ARUK) Coordinating Centre. The Wellcome Trust Centre for Neuroimaging is supported by core funding from the Wellcome Trust [grant number 091593/Z/10/Z].		37	0	0	ACADEMIC PRESS INC ELSEVIER SCIENCE	SAN DIEGO	525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA	1053-8119		NEUROIMAGE	Neuroimage	APR 15	2013	70						33	36		10.1016/j.neuroimage.2012.12.044		4	Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging	Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging	100LX	WOS:000315703800004
false	J	de Haas, B; Schwarzkopf, DS; Urner, M; Rees, G				de Haas, Benjamin; Schwarzkopf, D. Samuel; Urner, Maren; Rees, Geraint			Auditory modulation of visual stimulus encoding in human retinotopic cortex	NEUROIMAGE		English	Article						Multisensory; Audio-visual; V2; Decoding; MVPA; fMRI	MULTISENSORY INTERACTIONS; AUDIOVISUAL INTEGRATION; NEURONAL OSCILLATIONS; UNIMODAL NEURONS; INFORMATION; AREAS; PERCEPTION; ATTENTION; RESPONSES; CORTICES	Sounds can modulate visual perception as well as neural activity in retinotopic cortex. Most studies in this context investigated how sounds change neural amplitude and oscillatory phase reset in visual cortex. However, recent studies in macaque monkeys show that congruence of audio-visual stimuli also modulates the amount of stimulus information carried by spiking activity of primary auditory and visual neurons. Here, we used naturalistic video stimuli and recorded the spatial patterns of functional MRI signals in human retinotopic cortex to test whether the discriminability of such patterns varied with the presence and congruence of co-occurring sounds. We found that incongruent sounds significantly impaired stimulus decoding from area V2 and there was a similar trend for V3. This effect was associated with reduced inter-trial reliability of patterns (i.e. higher levels of noise), but was not accompanied by any detectable modulation of overall signal amplitude. We conclude that sounds modulate naturalistic stimulus encoding in early human retinotopic cortex without affecting overall signal amplitude. Subthreshold modulation, oscillatory phase reset and dynamic attentional modulation are candidate neural and cognitive mechanisms mediating these effects. (C) 2013 Elsevier Inc. All rights reserved.	UCL Inst Cognit Neurosci, London WC1N 3BG, England; UCL, Wellcome Trust Ctr Neuroimaging, London WC1N 3AR, England	de Haas, B (reprint author), UCL, Inst Cognit Neurosci, Alexandra House,17 Queen Sq, London WC1N 3AR, England.	benjamin.haas.09@ucl.ac.uk		Wellcome Trust [091593/Z/10/Z]	This work was funded by the Wellcome Trust. The Wellcome Trust Centre for Neuroimaging is supported by core funding from the Wellcome Trust 091593/Z/10/Z. We thank Martin Hebart for helpful comments and support staff for help with scanning. Jon Driver provided valuable input to the design of this study.		55	0	0	ACADEMIC PRESS INC ELSEVIER SCIENCE	SAN DIEGO	525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA	1053-8119		NEUROIMAGE	Neuroimage	APR 15	2013	70						258	267		10.1016/j.neuroimage.2012.12.061		10	Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging	Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging	100LX	WOS:000315703800026
false	J	Mohammadi, S; Freund, P; Feiweier, T; Curt, A; Weiskopf, N				Mohammadi, Siawoosh; Freund, Patrick; Feiweier, Thorsten; Curt, Armin; Weiskopf, Nikolaus			The impact of post-processing on spinal cord diffusion tensor imaging	NEUROIMAGE		English	Article						DTI; Fractional anisotropy; Spinal cord; Eddy current and motion correction; Robust fitting	WHITE-MATTER; EDDY-CURRENT; IN-VIVO; WALLERIAN DEGENERATION; WEIGHTED MRI; 3 T; ECHO; INJURY; FIELD; REORGANIZATION	Diffusion tensor imaging (DTI) provides information about the microstructure in the brain and spinal cord. While new neuroimaging techniques have significantly advanced the accuracy and sensitivity of DTI of the brain, the quality of spinal cord DTI data has improved less. This is in part due to the small size of the spinal cord (ca. 1 cm diameter) and more severe instrumental (e.g. eddy current) and physiological (e.g. cardiac pulsation) artefacts present in spinal cord DTI. So far, the improvements in image quality and resolution have resulted from cardiac gating and new acquisition approaches (e.g. reduced field-of-view techniques). The use of retrospective correction methods is not well established for spinal cord DTI. The aim of this paper is to develop an improved post-processing pipeline tailored for DTI data of the spinal cord with increased quality. For this purpose, we compared two eddy current and motion correction approaches using three-dimensional affine (3D-affine) and slice-wise registrations. We also introduced a new robust-tensor-fitting method that controls for whole-volume outliers. Although in general 3D-affine registration improves data quality, occasionally it can lead to misregistrations and biassed tensor estimates. The proposed robust tensor fitting reduced misregistiation-related bias and yielded more reliable tensor estimates. Overall, the combination of slice-wise motion correction, eddy current correction, and robust tensor fitting yielded the best results. It increased the contrast-to-noise ratio (CNR) in FA maps by about 30% and reduced intra-subject variation in fractional anisotropy (FA) maps by 18%. The higher quality of FA maps allows for a better distinction between grey and white matter without increasing scan time and is compatible with any multi-directional DTI acquisition scheme. (c) 2013 Elsevier Inc. All rights reserved.	[Mohammadi, Siawoosh; Freund, Patrick; Weiskopf, Nikolaus] UCL, Wellcome Trust Ctr Neuroimaging, UCL Inst Neurol, London WC1N 3BG, England; [Freund, Patrick] UCL, Dept Brain Repair & Rehabil, UCL Inst Neurol, London, England; [Freund, Patrick; Curt, Armin] Univ Zurich, Univ Zurich Hosp, Spinal Cord Injury Ctr Balgrist, Zurich, Switzerland; [Feiweier, Thorsten] Siemens AG, Healthcare Sect, D-91052 Erlangen, Germany	Mohammadi, S (reprint author), UCL, Wellcome Trust Ctr Neuroimaging, UCL Inst Neurol, London WC1N 3BG, England.	siawoosh.mohammadi@ucl.ac.uk	Weiskopf, Nikolaus/B-9357-2008	Wellcome Trust [091593/Z/10/Z]; Swiss Paraplegic Research, Nottwil, Switzerland; Deutsche Forschungsgemeinschaft (DFG) [MO 2397/1-1]	The Wellcome Trust Centre for Neuroimaging is supported by core funding from the Wellcome Trust 091593/Z/10/Z. This work was supported by the Wellcome Trust and Swiss Paraplegic Research, Nottwil, Switzerland. SM was supported by the Deutsche Forschungsgemeinschaft (DFG, MO 2397/1-1). Open access to the publication was supported by the Wellcome Trust.		74	0	0	ACADEMIC PRESS INC ELSEVIER SCIENCE	SAN DIEGO	525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA	1053-8119		NEUROIMAGE	Neuroimage	APR 15	2013	70						377	385		10.1016/j.neuroimage.2012.12.058		9	Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging	Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging	100LX	WOS:000315703800037
true	J	Walker, RW; Jusabani, A; Aris, E; Gray, WK; Mugusi, F; Swai, M; Alberti, KG; Unwin, N				Walker, R. W.; Jusabani, A.; Aris, E.; Gray, W. K.; Mugusi, F.; Swai, M.; Alberti, K. G.; Unwin, N.			Correlates of short- and long-term case fatality within an incident stroke population in Tanzania	SAMJ SOUTH AFRICAN MEDICAL JOURNAL		English	Article							ACUTE ISCHEMIC-STROKE; RISK-FACTORS; MORTALITY; PREDICTORS; SURVIVAL; RECURRENCE; SEVERITY; BURDEN; RATES; DEATH	Background. This study aimed to identify correlates of case fatality within an incident stroke population in rural Tanzania. Methods. Stroke patients, identified by the Tanzanian Stroke Incidence Project, underwent a full examination and assessment around the time of incident stroke. Records were made of demographic data, blood pressure, pulse rate and rhythm, physical function (Barthel index), neurological status (communication, swallowing, vision, muscle activity, sensation), echocardiogram, chest X-ray and computed tomography (CT) head scan. Cases were followed up over the next 3 - 6 years. Results. In 130 incident cases included in this study, speech, language and swallowing problems, reduced muscle power, and reduced physical function were all significantly correlated with case fatality at 28 days and 3 years. Age was significantly correlated with case fatality at 3 years, but not at 28 days post-stroke. Smoking history was the only significant correlate of case fatality at 28 days that pre-dated the incident stroke. All other significant correlates were measures of neurological recovery from stroke. Conclusions. This is the first published study of the correlates of post-stroke case fatality in sub-Saharan Africa (SSA) from an incident stroke population. Case fatality was correlated with the various motor impairments resulting from the incident stroke. Improving post-stroke care may help to reduce stroke case fatality in SSA. S Afr Med J 2013;103(2):107-112. DOI:10.7196/SAMJ.5793	[Walker, R. W.; Gray, W. K.] N Tyneside Gen Hosp, Newcastle Upon Tyne, Tyne & Wear, England; [Walker, R. W.; Unwin, N.] Newcastle Univ, Inst Hlth & Soc, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England; [Jusabani, A.; Swai, M.] Kilimanjaro Christian Med Ctr, Moshi, Tanzania; [Aris, E.; Mugusi, F.] Muhimbili Univ Hosp, Dept Neurol, Dar Es Salaam, Tanzania; [Alberti, K. G.] Univ London Imperial Coll Sci Technol & Med, Dept Endocrinol & Metab, London, England; [Unwin, N.] Univ W Indies, Fac Med Sci, Bridgetown, Barbados	Walker, RW (reprint author), N Tyneside Gen Hosp, Newcastle Upon Tyne, Tyne & Wear, England.	richard.walker@nhct.nhs.uk		Wellcome Trust [066939]	This work was funded by a grant from the Wellcome Trust (grant number 066939).		28	0	0	SA MEDICAL ASSOC	PRETORIA	BLOCK F CASTLE WALK CORPORATE PARK, NOSSOB STREET, ERASMUSKLOOF EXT3, PRETORIA, 0002, SOUTH AFRICA	0256-9574		SAMJ S AFR MED J	SAMJ S. Afr. Med. J.	FEB	2013	103	2					107	112		10.7196/SAMJ.5793		6	Medicine, General & Internal	General & Internal Medicine	101GV	WOS:000315764100018
false	J	Loebbermann, J; Durant, L; Thornton, H; Johansson, C; Openshaw, PJ				Loebbermann, Jens; Durant, Lydia; Thornton, Hannah; Johansson, Cecilia; Openshaw, Peter J.			Defective immunoregulation in RSV vaccine-augmented viral lung disease restored by selective chemoattraction of regulatory T cells	PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA		English	Article						chemokines; lung infection; bronchiolitis	SYNCYTIAL VIRUS-INFECTION; CHEMOKINE RECEPTORS; MICE; INFLAMMATION; RECRUITMENT; EXPRESSION; RESPONSES; CHILDREN; IMMUNITY; PROFILE	Human trials of formaldehyde-inactivated respiratory syncytial virus (FI-RSV) vaccine in 1966-1967 caused disastrous worsening of disease and death in infants during subsequent natural respiratory syncytial virus (RSV) infection. The reasons behind vaccine-induced augmentation are only partially understood, and fear of augmentation continues to hold back vaccine development. We now show that mice vaccinated with FI-RSV show enhanced local recruitment of conventional CD4(+) T cells accompanied by a profound loss of regulatory T cells (Tregs) in the airways. This loss of Tregs was so complete that additional depletion of Tregs (in transgenic depletion of regulatory T-cell mice) produced no additional disease enhancement. Transfer of conventional CD4(+) T cells from FI-RSV-vaccinated mice into naive RSV-infected recipients also caused a reduction in airway Treg responses; boosting Tregs with IL-2 immune complexes failed to restore normal levels of Tregs or to ameliorate disease. However, delivery of chemokine ligands (CCL) 17/22 via the airway selectively recruited airway Tregs and attenuated vaccine-augmented disease, reducing weight loss and inhibiting local recruitment of pathogenic CD4(+) T cells. These findings reveal an unexpected mechanism of vaccine-induced disease augmentation and indicate that selective chemoattraction of Tregs into diseased sites may offer a novel approach to the modulation of tissue-specific inflammation.	[Loebbermann, Jens; Durant, Lydia; Thornton, Hannah; Johansson, Cecilia; Openshaw, Peter J.] Univ London Imperial Coll Sci Technol & Med, Fac Med, Natl Heart & Lung Inst, Ctr Resp Infect,Dept Resp Med, London W2 1PG, England	Openshaw, PJ (reprint author), Univ London Imperial Coll Sci Technol & Med, Fac Med, Natl Heart & Lung Inst, Ctr Resp Infect,Dept Resp Med, London W2 1PG, England.	p.openshaw@imperial.ac.uk		Centre of Respiratory Infections; Medical Research Council (MRC); Asthma UK Centre in Allergic Mechanisms of Asthma, Wellcome Trust Programme [087805/Z/08/Z]; MRC [G0800311]	We thank T. Sparwasser for providing DEREG mice and K. Webster and J. Sprent for providing protocols and advice on the preparation and administration of the IL-2 complexes. We also thank S. Makris for help with experiments. This work was supported by the Centre of Respiratory Infections, the Medical Research Council (MRC) and Asthma UK Centre in Allergic Mechanisms of Asthma, Wellcome Trust Programme 087805/Z/08/Z (P.J.O.), and MRC career development award, Grant G0800311 (to C.J.).		31	0	0	NATL ACAD SCIENCES	WASHINGTON	2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA	0027-8424		P NATL ACAD SCI USA	Proc. Natl. Acad. Sci. U. S. A.	FEB 19	2013	110	8					2987	2992		10.1073/pnas.1217580110		6	Multidisciplinary Sciences	Science & Technology - Other Topics	103YC	WOS:000315954400078
false	J	Hambleton, S; Goodbourn, S; Young, DF; Dickinson, P; Mohamad, SMB; Valappil, M; McGovern, N; Cant, AJ; Hackett, SJ; Ghazal, P; Morgan, NV; Randall, RE				Hambleton, Sophie; Goodbourn, Stephen; Young, Dan F.; Dickinson, Paul; Mohamad, Siti M. B.; Valappil, Manoj; McGovern, Naomi; Cant, Andrew J.; Hackett, Scott J.; Ghazal, Peter; Morgan, Neil V.; Randall, Richard E.			STAT2 deficiency and susceptibility to viral illness in humans	PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA		English	Article						measles vaccine; viruses; rare diseases	HERPES-SIMPLEX ENCEPHALITIS; ALPHA/BETA-INTERFERON; TARGETED DISRUPTION; VIRUS ENCEPHALITIS; SIGNALING PATHWAY; TLR3 DEFICIENCY; INBORN-ERRORS; HOST-DEFENSE; V-PROTEIN; IFN-BETA	Severe infectious disease in children may be a manifestation of primary immunodeficiency. These genetic disorders represent important experiments of nature with the capacity to elucidate nonredundant mechanisms of human immunity. We hypothesized that a primary defect of innate antiviral immunity was responsible for unusually severe viral illness in two siblings; the proband developed disseminated vaccine strain measles following routine immunization, whereas an infant brother died after a 2-d febrile illness from an unknown viral infection. Patient fibroblasts were indeed abnormally permissive for viral replication in vitro, associated with profound failure of type I IFN signaling and absence of STAT2 protein. Sequencing of genomic DNA and RNA revealed a homozygous mutation in intron 4 of STAT2 that prevented correct splicing in patient cells. Subsequently, other family members were identified with the same genetic lesion. Despite documented infection by known viral pathogens, some of which have been more severe than normal, surviving STAT2-deficient individuals have remained generally healthy, with no obvious defects in their adaptive immunity or developmental abnormalities. These findings imply that type I IFN signaling [through interferon-stimulated gene factor 3 (ISGF3)] is surprisingly not essential for host defense against the majority of common childhood viral infections.	[Hambleton, Sophie; Mohamad, Siti M. B.; McGovern, Naomi; Cant, Andrew J.] Newcastle Univ, Inst Cellular Med, Primary Immunodeficiency Grp, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England; [Hambleton, Sophie; Cant, Andrew J.] Great North Childrens Hosp, Pediat Immunol Serv, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England; [Goodbourn, Stephen] Univ London, Div Biomed Sci, London SW17 0RE, England; [Young, Dan F.; Randall, Richard E.] Univ St Andrews, Sch Biol, St Andrews KY16 9TS, Fife, Scotland; [Dickinson, Paul; Ghazal, Peter] Univ Edinburgh, Div Pathway Med, Edinburgh EH16 4SB, Midlothian, Scotland; [Mohamad, Siti M. B.] Univ Sains Malaysia, Adv Med & Dent Inst, Usm Penang 11800, Malaysia; [Valappil, Manoj] Royal Victoria Infirm, Hlth Protect Agcy, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England; [Hackett, Scott J.] Heartlands Hosp, Pediat Immunol Dept, Birmingham B9 5SS, W Midlands, England; [Morgan, Neil V.] Univ Birmingham, Inst Biomed Res, Ctr Cardiovasc Sci, Birmingham B15 2TT, W Midlands, England	Hambleton, S (reprint author), Newcastle Univ, Inst Cellular Med, Primary Immunodeficiency Grp, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England.	sophie.hambleton@ncl.ac.uk; rer@st-andrews.ac.uk		Medical Research Council [G0701897]; Bubble Foundation; Wellcome Trust [AL087751/B, 087751/A/08/Z]	We thank the subjects' families for their trust, our many colleagues in National Health Service hospitals and laboratories who contributed to patient care, and Catherine Thompson and colleagues at the Respiratory Virus Unit, Health Protection Agency (London, United Kingdom), where influenza serology was assessed. This work was supported by Medical Research Council Fellowship G0701897 (to S. H.), the Bubble Foundation (S. H.), and Wellcome Trust Grants AL087751/B (to S. G.) and 087751/A/08/Z (to R.E.R.).		46	0	0	NATL ACAD SCIENCES	WASHINGTON	2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA	0027-8424		P NATL ACAD SCI USA	Proc. Natl. Acad. Sci. U. S. A.	FEB 19	2013	110	8					3053	3058		10.1073/pnas.1220098110		6	Multidisciplinary Sciences	Science & Technology - Other Topics	103YC	WOS:000315954400089
true	J	Gupta, A; Wood, R; Kaplan, R; Bekker, LG; Lawn, SD				Gupta, Ankur; Wood, Robin; Kaplan, Richard; Bekker, Linda-Gail; Lawn, Stephen D.			Prevalent and Incident Tuberculosis Are Independent Risk Factors for Mortality among Patients Accessing Antiretroviral Therapy in South Africa	PLOS ONE		English	Article							HIV-ASSOCIATED TUBERCULOSIS; IMMUNE RECONSTITUTION DISEASE; SUB-SAHARAN AFRICA; PULMONARY TUBERCULOSIS; TREATMENT PROGRAM; INFECTED PATIENTS; EARLY OUTCOMES; RURAL UGANDA; ADULTS; DETERMINANTS	Background: Patients with prevalent or incident tuberculosis (TB) in antiretroviral treatment (ART) programmes in sub-Saharan Africa have high mortality risk. However, published data are contradictory as to whether TB is a risk factor for mortality that is independent of CD4 cell counts and other patient characteristics. Methods/Findings: This observational ART cohort study was based in Cape Town, South Africa. Deaths from all causes were ascertained among patients receiving ART for up to 8 years. TB diagnoses and 4-monthly CD4 cell counts were recorded. Mortality rates were calculated and Poisson regression models were used to calculate incidence rate ratios (IRR) and identify risk factors for mortality. Of 1544 patients starting ART, 464 patients had prevalent TB at baseline and 424 developed incident TB during a median of 5.0 years follow-up. Most TB diagnoses (73.6%) were culture-confirmed. A total of 208 (13.5%) patients died during ART and mortality rates were 8.84 deaths/100 person-years during the first year of ART and decreased to 1.14 deaths/100 person-years after 5 years. In multivariate analyses adjusted for baseline and time-updated risk factors, both prevalent and incident TB were independent risk factors for mortality (IRR 1.7 [95% CI, 1.2-2.3] and 2.7 [95% CI, 1.9-3.8], respectively). Adjusted mortality risks were higher in the first 6 months of ART for those with prevalent TB at baseline (IRR 2.33; 95% CI, 1.5-3.5) and within the 6 months following diagnoses of incident TB (IRR 3.8; 95% CI, 2.6-5.7). Conclusions: Prevalent TB at baseline and incident TB during ART were strongly associated with increased mortality risk. This effect was time-dependent, suggesting that TB and mortality are likely to be causally related and that TB is not simply an epiphenomenon among highly immunocompromised patients. Strategies to rapidly diagnose, treat and prevent TB prior to and during ART urgently need to be implemented.	[Gupta, Ankur; Lawn, Stephen D.] London Sch Hyg & Trop Med, Dept Clin Res, Fac Infect & Trop Dis, London WC1, England; [Wood, Robin; Kaplan, Richard; Bekker, Linda-Gail; Lawn, Stephen D.] Univ Cape Town, Desmond Tutu HIV Ctr, Inst Infect Dis & Mol Med, Fac Hlth Sci, ZA-7925 Cape Town, South Africa	Lawn, SD (reprint author), London Sch Hyg & Trop Med, Dept Clin Res, Fac Infect & Trop Dis, London WC1, England.	stephen.lawn@lshtm.ac.uk		Wellcome Trust, London, UK [074641]; International Epidemiologic Database to Evaluate Aids; National Institute of Allergy and Infectious Diseases (NIAID) [5U01AI069924-02]; National Institutes of Health (NIH) [5R01AI058736-02]; USAID Right to Care [CA 674 A 00 08 0000 700]; South African Centre for Epidemiological Modelling and Analysis (SACEMA); Cost-Effectiveness of Preventing AIDS Complications (CEPAC)	SDL is funded by the Wellcome Trust, London, UK with grant number 074641. RW was funded in part by the International Epidemiologic Database to Evaluate Aids with a grant from the National Institute of Allergy and Infectious Diseases (NIAID: 5U01AI069924-02); Cost-Effectiveness of Preventing AIDS Complications (CEPAC) funded by the National Institutes of Health (NIH, 5R01AI058736-02); USAID Right to Care (CA 674 A 00 08 0000 700) and the South African Centre for Epidemiological Modelling and Analysis (SACEMA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.		47	0	0	PUBLIC LIBRARY SCIENCE	SAN FRANCISCO	1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA	1932-6203		PLOS ONE	PLoS One	FEB 13	2013	8	2							e55824	10.1371/journal.pone.0055824		8	Multidisciplinary Sciences	Science & Technology - Other Topics	104DM	WOS:000315970300054
true	J	Munro, PRT; Rigon, L; Ignatyev, K; Lopez, FCM; Dreossi, D; Speller, RD; Olivo, A				Munro, Peter R. T.; Rigon, Luigi; Ignatyev, Konstantin; Lopez, Frances C. M.; Dreossi, Diego; Speller, Robert D.; Olivo, Alessandro			A quantitative, non-interferometric X-ray phase contrast imaging technique	OPTICS EXPRESS		English	Article							SYNCHROTRON-RADIATION; RETRIEVAL; ABSORPTION; SYSTEMS; MAMMOGRAPHY; TOMOGRAPHY; ALGORITHMS; SCATTERING; OBJECTS	We present a quantitative, non-interferometric, X-ray differential phase contrast imaging technique based on the edge illumination principle. We derive a novel phase retrieval algorithm which requires only two images to be acquired and verify the technique experimentally using synchrotron radiation. The technique is useful for planar imaging but is expected to be important for quantitative phase tomography also. The properties and limitations of the technique are studied in detail. (C) 2013 Optical Society of America	[Munro, Peter R. T.] Univ Western Australia, Sch Elect Elect & Comp Engn, Opt Biomed Engn Lab, Crawley, WA 6009, Australia; [Munro, Peter R. T.] Univ Western Australia, Ctr Microscopy Characterisat & Anal, Crawley, WA 6009, Australia; [Rigon, Luigi; Lopez, Frances C. M.] Ist Nazl Fis Nucl, Sez Trieste, I-34127 Trieste, Italy; [Ignatyev, Konstantin; Speller, Robert D.; Olivo, Alessandro] UCL, Dept Med Phys & Bioengn, London WC1E 6BT, England; [Lopez, Frances C. M.] Univ Trieste, Dept Phys, I-34127 Trieste, Italy; [Dreossi, Diego] Sincrotrone Trieste SCpA, I-34012 Trieste, TS, Italy	Munro, PRT (reprint author), Univ Western Australia, Sch Elect Elect & Comp Engn, Opt Biomed Engn Lab, 35 Stirling Highway, Crawley, WA 6009, Australia.	peter.munro@uwa.edu.au		UK Engineering and Physical Sciences Research Council [EP/G004250/1, EP/I021884/1]; Wellcome Trust [085856/Z/08/Z]; Australian Research Council [DE120101331]; Prof. Giulio Brautti PhD Memorial Fellowship	This work was funded by the UK Engineering and Physical Sciences Research Council (EP/G004250/1 and EP/I021884/1). K. I. was supported by the Wellcome Trust (085856/Z/08/Z) and P. M. is supported by a Discovery Early Career Research Award from the Australian Research Council (DE120101331). F. L. is supported by the Prof. Giulio Brautti PhD Memorial Fellowship. We would like to thank the personnel from the Elettra synchrotron and the University of Trieste working on the SYRMEP beamline for assistance with obtaining the experimental results.		44	1	1	OPTICAL SOC AMER	WASHINGTON	2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA	1094-4087		OPT EXPRESS	Opt. Express	JAN 14	2013	21	1					647	661				15	Optics	Optics	104JF	WOS:000315988100089
false	J	Longstaff, C; Varju, I; Sotonyi, P; Szabo, L; Krumrey, M; Hoell, A; Bota, A; Varga, Z; Komorowicz, E; Kolev, K				Longstaff, Colin; Varju, Imre; Sotonyi, Peter; Szabo, Laszlo; Krumrey, Michael; Hoell, Armin; Bota, Attila; Varga, Zoltan; Komorowicz, Erzsebet; Kolev, Krasimir			Mechanical Stability and Fibrinolytic Resistance of Clots Containing Fibrin, DNA, and Histones	JOURNAL OF BIOLOGICAL CHEMISTRY		English	Article							NEUTROPHIL EXTRACELLULAR TRAPS; DEEP-VEIN THROMBOSIS; TISSUE-PLASMINOGEN ACTIVATOR; STREPTOCOCCUS-PYOGENES; INNATE IMMUNITY; PLATELET; COAGULATION; GENERATION; RELEASE; BLOOD	Neutrophil extracellular traps are networks of DNA and associated proteins produced by nucleosome release from activated neutrophils in response to infection stimuli and have recently been identified as key mediators between innate immunity, inflammation, and hemostasis. The interaction of DNA and histones with a number of hemostatic factors has been shown to promote clotting and is associated with increased thrombosis, but little is known about the effects of DNA and histones on the regulation of fibrin stability and fibrinolysis. Here we demonstrate that the addition of histone-DNA complexes to fibrin results in thicker fibers (increase in median diameter from 84 to 123 nm according to scanning electron microscopy data) accompanied by improved stability and rigidity (the critical shear stress causing loss of fibrin viscosity increases from 150 to 376 Pa whereas the storage modulus of the gel increases from 62 to 82 pascals according to oscillation rheometric data). The effects of DNA and histones alone are subtle and suggest that histones affect clot structure whereas DNA changes the way clots are lysed. The combination of histones + DNA significantly prolongs clot lysis. Isothermal titration and confocal microscopy studies suggest that histones and DNA bind large fibrin degradation products with 191 and 136 nM dissociation constants, respectively, interactions that inhibit clot lysis. Heparin, which is known to interfere with the formation of neutrophil extracellular traps, appears to prolong lysis time at a concentration favoring ternary histone-DNA-heparin complex formation, and DNase effectively promotes clot lysis in combination with tissue plasminogen activator.	[Longstaff, Colin] Natl Inst Biol Stand & Controls, Haemostasis Sect, Potters Bar EN6 3QG, Herts, England; [Varju, Imre; Komorowicz, Erzsebet; Kolev, Krasimir] Semmelweis Univ Med, Dept Med Biochem, H-1094 Budapest, Hungary; [Sotonyi, Peter] Semmelweis Univ Med, Dept Vasc Surg, H-1122 Budapest, Hungary; [Szabo, Laszlo] Hungarian Acad Sci, Res Ctr Nat Sci, Inst Mat & Environm Chem, H-1025 Budapest, Hungary; [Bota, Attila; Varga, Zoltan] Hungarian Acad Sci, Res Ctr Nat Sci, Inst Mol Pharmacol, Dept Biol Nanochem, H-1025 Budapest, Hungary; [Krumrey, Michael] PTB, D-10587 Berlin, Germany; [Hoell, Armin] HZB, D-14109 Berlin, Germany	Longstaff, C (reprint author), Natl Inst Biol Stand & Controls, Biotherapeut Grp, S Mimms EN6 3QG, Herts, England.	colin.longstaff@nibsc.hpa.org.uk		Wellcome Trust [083174]; Hungarian Scientific Research Fund [OTKA 75430, 83023]; German Academic Exchange Service [DAAD A/12/01760]	This work was supported by Wellcome Trust Grant 083174, Hungarian Scientific Research Fund Grants OTKA 75430 and 83023, and German Academic Exchange Service Grant DAAD A/12/01760.		37	0	0	AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC	BETHESDA	9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA	0021-9258		J BIOL CHEM	J. Biol. Chem.	MAR 8	2013	288	10					6946	6956		10.1074/jbc.M112.404301		11	Biochemistry & Molecular Biology	Biochemistry & Molecular Biology	104NY	WOS:000316002400017
false	J	Whiteman, P; de Madrid, BH; Taylor, P; Li, DM; Heslop, R; Viticheep, N; Tan, JZ; Shimizu, H; Callaghan, J; Masiero, M; Li, JL; Banham, AH; Harris, AL; Lea, SM; Redfield, C; Baron, M; Handford, PA				Whiteman, Pat; de Madrid, Beatriz Hernandez; Taylor, Paul; Li, Demin; Heslop, Rebecca; Viticheep, Nattnee; Tan, Joyce Zi; Shimizu, Hideyuki; Callaghan, Juliana; Masiero, Massimo; Li, Ji Liang; Banham, Alison H.; Harris, Adrian L.; Lea, Susan M.; Redfield, Christina; Baron, Martin; Handford, Penny A.			Molecular Basis for Jagged-1/Serrate Ligand Recognition by the Notch Receptor	JOURNAL OF BIOLOGICAL CHEMISTRY		English	Article							HUMAN FACTOR-IX; DROSOPHILA-MELANOGASTER; PROTEOLYTIC ACTIVATION; FRINGE; DOMAIN; BINDING; MODULATION; ANTIBODIES; CLEAVAGE; JAGGED1	We have mapped a Jagged/Serrate-binding site to specific residues within the 12th EGF domain of human and Drosophila Notch. Two critical residues, involved in a hydrophobic interaction, provide a ligand-binding platform and are adjacent to a Fringe-sensitive residue that modulates Notch activity. Our data suggest that small variations within the binding site fine-tune ligand specificity, which may explain the observed sequence heterogeneity in mammalian Notch paralogues, and should allow the development of paralogue-specific ligand-blocking antibodies. As a proof of principle, we have generated a Notch-1-specific monoclonal antibody that blocks binding, thus paving the way for antibody tools for research and therapeutic applications.	[Whiteman, Pat; Taylor, Paul; Heslop, Rebecca; Viticheep, Nattnee; Callaghan, Juliana; Redfield, Christina; Handford, Penny A.] Univ Oxford, Dept Biochem, Oxford OX1 3QU, England; [de Madrid, Beatriz Hernandez; Shimizu, Hideyuki; Baron, Martin] Univ Manchester, Fac Life Sci, Manchester M13 9PT, Lancs, England; [Tan, Joyce Zi; Lea, Susan M.] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England; [Li, Demin; Masiero, Massimo; Banham, Alison H.] Univ Oxford, Nuffield Dept Clin Lab Sci, Oxford Natl Inst Hlth Res NIHR, Biomed Res Ctr,John Radcliffe Hosp, Oxford OX3 9DU, England; [Masiero, Massimo; Li, Ji Liang; Harris, Adrian L.] Univ Oxford, Weatherall Inst Mol Med, Mol Oncol Labs, Dept Oncol,John Radcliffe Hosp, Oxford OX3 9DU, England	Handford, PA (reprint author), Univ Oxford, Dept Biochem, S Parks Rd, Oxford OX1 3QU, England.	penny.handford@bioch.ox.ac.uk	Lea, Susan/B-7678-2009	Wellcome Trust [087928, 079440]; Cancer Research UK [A10702]; Biotechnology and Biological Sciences Research Council	This work was supported by The Wellcome Trust Grants 087928 (to P. A. H., S. M. L., and M. B.) and 079440 (to C. R.), Cancer Research UK Programme Grant A10702 (to A. H. B., A. L. H., P. H., and S. M. L.), and Biotechnology and Biological Sciences Research Council studentship (to P. T.).		35	0	0	AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC	BETHESDA	9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA	0021-9258		J BIOL CHEM	J. Biol. Chem.	MAR 8	2013	288	10					7305	7312		10.1074/jbc.M112.428854		8	Biochemistry & Molecular Biology	Biochemistry & Molecular Biology	104NY	WOS:000316002400050
false	J	Sarell, CJ; Woods, LA; Su, YC; Debelouchina, GT; Ashcroft, AE; Griffin, RG; Stockley, PG; Radford, SE				Sarell, Claire J.; Woods, Lucy A.; Su, Yongchao; Debelouchina, Galia T.; Ashcroft, Alison E.; Griffin, Robert G.; Stockley, Peter G.; Radford, Sheena E.			Expanding the Repertoire of Amyloid Polymorphs by Co-polymerization of Related Protein Precursors	JOURNAL OF BIOLOGICAL CHEMISTRY		English	Article							FIBRIL FORMATION; ROTATING SOLIDS; NEUTRAL PH; ALZHEIMERS-DISEASE; MASS-SPECTROMETRY; ALPHA-SYNUCLEIN; H/D-EXCHANGE; IN-VITRO; A-BETA; BETA(2)-MICROGLOBULIN	Amyloid fibrils can be generated from proteins with diverse sequences and folds. Although amyloid fibrils assembled in vitro commonly involve a single protein precursor, fibrils formed in vivo can contain more than one protein sequence. How fibril structure and stability differ in fibrils composed of single proteins (homopolymeric fibrils) from those generated by co-polymerization of more than one protein sequence (heteropolymeric fibrils) is poorly understood. Here we compare the structure and stability of homo and heteropolymeric fibrils formed from human beta(2)-microglobulin and its truncated variant Delta N6. We use an array of approaches (limited proteolysis, magic angle spinning NMR, Fourier transform infrared spectroscopy, and fluorescence) combined with measurements of thermodynamic stability to characterize the different fibril types. The results reveal fibrils with different structural properties, different side-chain packing, and strikingly different stabilities. These findings demonstrate how co-polymerization of related precursor sequences can expand the repertoire of structural and thermodynamic polymorphism in amyloid fibrils to an extent that is greater than that obtained by polymerization of a single precursor alone.	[Sarell, Claire J.; Woods, Lucy A.; Ashcroft, Alison E.; Stockley, Peter G.; Radford, Sheena E.] Univ Leeds, Astbury Ctr Struct Mol Biol, Leeds LS2 9JT, W Yorkshire, England; [Sarell, Claire J.; Woods, Lucy A.; Ashcroft, Alison E.; Stockley, Peter G.; Radford, Sheena E.] Univ Leeds, Sch Mol & Cellular Biol, Leeds LS2 9JT, W Yorkshire, England; [Su, Yongchao; Griffin, Robert G.] MIT, Dept Chem, Cambridge, MA 02139 USA; [Su, Yongchao; Griffin, Robert G.] MIT, Francis Bitter Magnet Lab, Cambridge, MA 02139 USA; [Debelouchina, Galia T.] Princeton Univ, Dept Chem, Princeton, NJ 08544 USA	Radford, SE (reprint author), Univ Leeds, Astbury Ctr Struct Mol Biol, Leeds LS2 9JT, W Yorkshire, England.	s.e.radford@leeds.ac.uk		National Institutes of Health [EB003151, EB002026]; Medical Research Council [G0900958]; Wellcome Trust [075099/Z/04/Z]; NMR [094232]; Biotechnology and Biological Sciences Research Council, Swindon, United Kingdom [BB/526502/1, BB/E012558/I]	This work was supported, in whole or in part, by National Institutes of Health Grants EB003151 and EB002026. This work was also supported by Medical Research Council Grant G0900958, the Wellcome Trust (grant code 075099/Z/04/Z (LCT Premier, mass spectrometry facility) and NMR (094232)), and the Biotechnology and Biological Sciences Research Council, Swindon, United Kingdom (BB/526502/1) (BB/E012558/I, for the Synapt HDMS).		61	0	0	AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC	BETHESDA	9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA	0021-9258		J BIOL CHEM	J. Biol. Chem.	MAR 8	2013	288	10					7327	7337		10.1074/jbc.M112.447524		11	Biochemistry & Molecular Biology	Biochemistry & Molecular Biology	104NY	WOS:000316002400052
