SotiriosKastanas/try_new · Datasets at Hugging Face

id int64 37.5k 3.5M	image unknown	bboxes sequence	tokens sequence	ner_tags sequence
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"Neurology,", "The", "Robert", "F.", "Furchgott", "Center", "for", "Neural", "and", "Behavioral", "Science,", "State", "University", "of", "New", "York", "Health", "Science", "Center", "at", "Brooklyn,", "Brooklyn,", "NY", "11203", "3Institute", "of", "Experimental", "Pathology,", "Center", "for", "Molecular", "Biology", "of", "Inﬂammation,", "University", "of", "Münster,", "D-48149", "Münster,", "Germany", "B", "been", "implicated", "in", "local", "translational", "control", "mech-", "C1", "RNA", "is", "a", "dendritic", "untranslated", "RNA", "that", "has", "anisms", "in", "neurons.", "Prerequisite", "for", "a", "functional", "role", "of", "the", "RNA", "in", "synaptodendritic", "domains", "is", "its", "targeted", "delivery", "along", "the", "dendritic", "extent.", "We", "report", "here", "that", "the", "targeting-competent", "5′", "BC1", "domain", "carries", "two", "dendritic", "targeting", "codes.", "One", "code,", "specifying", "somatic", "export,", "is", "located", "in", "the", "medial-basal", "region", "of", "the", "5′", "BC1", "stem-loop", "structure.", "It", "is", "deﬁned", "by", "an", "export-determinant", "stem-bulge", "motif.", "The", "second", "code,", "specifying", "long-range", "dendritic", "delivery,", "is", "located", "in", "the", "apical", "part", "of", "the", "5′", "stem-loop", "domain.", "This", "element", "features", "a", "GA", "kink-turn", "(KT)", "motif", "that", "is", "indispensable", "for", "distal", "targeting.", "It", "spe-", "ciﬁcally", "interacts", "with", "heterogeneous", "nuclear", "ribonucleo-", "protein", "A2,", "a", "trans-acting", "targeting", "factor", "that", "has", "previously", "been", "implicated", "in", "the", "transport", "of", "MBP", "mRNA", "in", "oligodendrocytes", "and", "neurons.", "Our", "work", "suggests", "that", "a", "BC1", "KT", "motif", "encodes", "distal", "targeting", "via", "the", "A2", "pathway", "and", "that", "architectural", "RNA", "elements,", "such", "as", "KT", "motifs,", "may", "function", "as", "spatial", "codes", "in", "neural", "cells.", "Y", "G", "O", "L", "O", "I", "B", "L", "L", "E", "C", "F", "O", "L", "A", "N", "R", "U", "O", "J", "E", "H", "T", "Introduction", "The", "targeted", "delivery", "of", "select", "RNAs", "to", "synaptodendritic", "do-", "mains", "in", "neurons", "is", "an", "elemental", "mechanism", "in", "the", "spatiotemporal", "regulation", "of", "postsynaptic", "gene", "expression", "(for", "reviews", "see", "Smith,", "2004;", "Kindler", "et", "al.,", "2005).", "Activity-dependent", "on-site", "control", "of", "protein", "synthesis", "is", "now", "seen", "as", "one", "of", "the", "key", "under-", "pinnings", "of", "input-specific", "long-term", "synaptic", "plasticity,", "with", "dendritic", "RNA", "transport", "in", "turn", "serving", "as", "a", "functional", "prerequi-", "site", "for", "the", "local", "translation", "of", "mRNAs", "at", "the", "synapse", "(Wells", "et", "al.,", "2000;", "Job", "and", "Eberwine,", "2001;", "Richter,", "2001;", "Richter", "and", "Lorenz,", "2002;", "Steward", "and", "Schuman,", "2003;", "Smith,", "2004;", "Kindler", "et", "al.,", "2005).", "For", "these", "reasons,", "structural", "and", "functional", "determinants", "of", "dendritic", "RNA", "transport", "are", "of", "considerable", "interest", "to", "students", "of", "neuronal", "plasticity", "(Smith,", "2004).", "The", "number", "of", "RNAs", "that", "have", "been", "identified", "in", "dendrites", "has", "steadily", "increased", "over", "the", "past", "few", "years,", "and", "the", "total", "number", "of", "dendritic", "RNAs", "has", "been", "estimated", "at", "several", "hundred", "(Eberwine", "et", "al.,", "2001).", "Dendritic", "RNAs", "form", "a", "diverse", "and", "complex", "group.", "They", "include", "mRNAs", "that", "encode", "various", "types", "of", "synaptodendritic", "proteins", "(such", "as", "receptors,", "kinases,", "cytoskeletal", "components,", "etc.),", "as", "well", "as", "untranslated", "RNAs", "(Brosius", "and", "Tiedge,", "2004),", "such", "as", "ribosomal", "RNAs", "(rRNAs),", "Correspondence", "to", "Henri", "Tiedge:", "htiedge@downstate.edu", "Abbreviations", "used", "in", "this", "paper:", "ANOVA,", "analysis", "of", "variance;", "CaMKIIα,", "Ca2+/calmodulin-dependent", "kinase", "II", "α", "subunit;", "DTE,", "dendritic", "targeting", "ele-", "ment;", "EMSA,", "electrophoretic", "mobility", "shift", "assay;", "hnRNP,", "heterogeneous", "nuclear", "ribonucleoprotein;", "KT,", "kink-turn;", "MBP,", "myelin", "basic", "protein;", "PKMζ,", "protein", "kinase", "M", "ζ;", "RRM,", "RNA", "recognition", "motif;", "rRNA,", "ribosomal", "RNA;", "WC,", "Watson–Crick.", "©", "The", "Rockefeller", "University", "Press", "$8.00", "The", "Journal", "of", "Cell", "Biology,", "Vol.", "175,", "No.", "3,", "November", "6,", "2006", "427–439", "http://www.jcb.org/cgi/doi/10.1083/jcb.200607008", "tRNAs,", "micro", "RNAs,", "and", "small", "brain-specific", "cytoplasmic", "(BC)", "RNAs", "(Kindler", "et", "al.,", "2005;", "Cao", "et", "al.,", "2006).", "A", "further", "layer", "of", "complexity", "is", "introduced", "by", "the", "fact", "that", "dendritic", "RNAs", "are", "nonhomogeneously", "distributed", "along", "the", "dendritic", "extent", "and", "differentially", "localized", "to", "their", "individual", "destination", "sites", "within", "the", "dendritic", "arborization", "(Paradies", "and", "Steward,", "1997;", "Kindler", "et", "al.,", "2005).", "Another", "subset", "of", "neuronal", "RNAs,", "only", "partially", "overlapping", "with", "dendritic", "RNAs,", "is", "targeted", "to", "the", "axonal", "domain,", "in", "particular", "during", "periods", "of", "developmental", "or", "regenerative", "growth", "(for", "review", "see", "Giuditta", "et", "al.,", "2002).", "The", "complexities", "of", "neuronal", "RNA", "transport", "raise", "impor-", "tant", "questions.", "On", "the", "most", "fundamental", "level,", "spatial", "codes", "that", "are", "used", "by", "localized", "neuronal", "RNAs", "to", "specify", "their", "respective", "subcellular", "destinations", "remain", "poorly", "understood.", "Dendritic", "targeting", "elements", "(DTEs),", "which", "are", "cis-acting", "elements", "that", "contain", "codes", "to", "direct", "neuronal", "RNAs", "to", "or", "along", "dendrites,", "have", "been", "identified", "in", "several", "dendritic", "RNAs", "(Kindler", "et", "al.,", "2005).", "Frequently,", "however,", "the", "functional", "description", "of", "DTEs", "has", "been", "rudimentary,", "and", "code-carrying", "RNA", "motifs", "have", "not", "yet", "been", "deciphered", "(Smith,", "2004).", "Considerable", "progress", "has", "been", "made", "in", "recent", "years", "in", "the", "elucidation", "of", "structure-function", "relationships", "in", "RNAs", "(for", "review", "see", "Noller,", "2005).", "There", "has", "been", "growing", "awareness", "of", "the", "functional", "relevance", "of", "3D", "RNA", "motifs,", "and", "the", "question", "is", "thus", "raised", "whether", "dendritic", "targeting", "codes", "may", "find", "expres-", "sion", "in", "the", "architectural", "designs", "of", "such", "motifs.", "To", "address", "this", "question,", "we", "performed", "a", "functional", "dissection", "of", "cis-acting", "tar-", "geting", "elements", "in", "neuronal", "BC1", "RNA", "(Muslimov", "et", "al.,", "1997).", "JCB", "427" ]	[ 16, 16, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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[ 295, 1042, 315, 1052 ], [ 317, 1042, 331, 1052 ], [ 333, 1042, 354, 1052 ], [ 356, 1042, 403, 1052 ], [ 69, 1053, 149, 1063 ], [ 427, 1053, 450, 1063 ] ]	[ "Tumor", "Necrosis", "Factor", "Induces", "Hyperphosphorylation", "of", "Kinesin", "Light", "Chain", "and", "Inhibits", "Kinesin-mediated", "Transport", "of", "Mitochondria", "Kurt", "De", "Vos,", "Fedor", "Severin,‡§", "Franky", "Van", "Herreweghe,", "Katia", "Vancompernolle,", "Vera", "Goossens,", "Anthony", "Hyman,‡§", "and", "Johan", "Grooten", "Department", "of", "Molecular", "Biology,", "Flanders", "Interuniversity", "Institute", "for", "Biotechnology", "and", "Ghent", "University,", "B-9000", "Ghent,", "Belgium;", "and", "‡Cell", "Biology", "Program,", "European", "Molecular", "Biology", "Laboratory,", "D-69012", "Heidelberg,", "Germany;", "and", "§Max-Planck", "Institute", "for", "Cell", "Biology", "and", "Genetics,", "D-01307", "Dresden,", "Germany", "Abstract.", "The", "molecular", "motor", "kinesin", "is", "an", "ATPase", "that", "mediates", "plus", "end-directed", "transport", "of", "organelles", "along", "microtubules.", "Although", "the", "biochemical", "properties", "of", "kinesin", "are", "extensively", "studied,", "conclusive", "data", "on", "regu-", "lation", "of", "kinesin-mediated", "transport", "are", "largely", "lacking.", "Previously,", "we", "showed", "that", "the", "proinﬂammatory", "cytokine", "tumor", "necrosis", "factor", "induces", "perinuclear", "clustering", "of", "mitochondria.", "Here,", "we", "show", "that", "tumor", "necrosis", "factor", "impairs", "kinesin", "motor", "activity", "and", "hyperphosphorylates", "kinesin", "light", "chain", "through", "activation", "of", "two", "putative", "kinesin", "light", "chain", "kinases.", "Inactivation", "of", "kinesin,", "hyper-", "phosphorylation", "of", "kinesin", "light", "chain,", "and", "perinuclear", "clustering", "of", "mitochondria", "exhibit", "the", "same", "p38", "mitogen-", "activated", "kinase", "dependence,", "indicating", "their", "functional", "relationship.", "These", "data", "provide", "evidence", "for", "direct", "regu-", "lation", "of", "kinesin-mediated", "organelle", "transport", "by", "extra-", "cellular", "stimuli", "via", "cytokine", "receptor", "signaling", "pathways.", "Key", "words:", "microtubule", "•", "organelle", "•", "okadaic", "acid", "•", "mitogen-activated", "protein", "kinase", "•", "phosphorylation", "Introduction", "Conventional", "kinesin", "(KIF5),", "originally", "discovered", "in", "1985", "(Brady,", "1985;", "Vale", "et", "al.,", "1985),", "is", "a", "tetramer", "of", "two", "kine-", "sin", "heavy", "chains", "(KHCs)1", "and", "two", "kinesin", "light", "chains", "(KLCs).", "Three", "domains", "compose", "KHC:", "an", "NH2-terminal", "motor", "domain", "containing", "the", "ATPase", "activity", "and", "the", "mi-", "crotubule", "(MT)-binding", "sites", "(Yang", "et", "al.,", "1989);", "a", "central", "a-helical", "coiled-coil", "involved", "in", "dimerization", "(de", "Cuevas", "et", "al.,", "1992);", "and", "a", "COOH-terminal", "tail,", "which", "binds", "KLC", "(Diefenbach", "et", "al.,", "1998).", "The", "KHC-tail:KLC", "complex", "ap-", "pears", "to", "be", "a", "crucial", "regulatory", "target,", "involved", "in", "interac-", "tion", "with", "cargo", "(Brady", "and", "Pfister,", "1991;", "Stenoien", "and", "Brady,", "1997;", "Khodjakov", "et", "al.,", "1998)", "and", "controlling", "the", "motor", "activity", "of", "the", "motor", "protein", "(Hackney", "et", "al.,", "1991;", "Verhey", "et", "al.,", "1998;", "Coy", "et", "al.,", "1999;", "Friedman", "and", "Vale,", "1999;", "Rahman", "et", "al.,", "1999;", "Stock", "et", "al.,", "1999).", "Address", "correspondence", "to", "Johan", "Grooten,", "Department", "of", "Molecular", "Bi-", "ology,", "Flanders", "Interuniversity", "Institute", "for", "Biotechnology", "and", "Ghent", "University,", "K.", "L.", "Ledeganckstraat", "35,", "B-9000", "Ghent,", "Belgium.", "Tel.:", "32", "9", "264", "5310.", "Fax:", "32", "9", "264", "5348.", "E-mail:", "johan.grooten@dmb.rug.ac.be", "Kurt", "De", "Vos’", "present", "address", "is", "Department", "of", "Biological", "Sciences,", "Columbia", "University,", "New", "York,", "NY", "10027.", "1Abbreviations", "used", "in", "this", "paper:", "2-DE,", "two-dimensional", "gel", "electro-", "phoresis;", "Ab,", "antibody;", "KHC,", "kinesin", "heavy", "chain;", "KLC,", "kinesin", "light", "chain;", "MAP,", "microtubule-associated", "protein;", "MAPK,", "mitogen-activated", "protein", "kinase;", "MT,", "microtubule;", "OA,", "okadaic", "acid;", "PKA,", "protein", "kinase", "A;", "TNF,", "tumor", "necrosis", "factor.", "KHC", "and", "KLC", "are", "reversibly", "phosphorylated", "on", "serine", "residues", "in", "vivo,", "suggesting", "that", "phosphorylation", "is", "in-", "volved", "in", "kinesin", "regulation.", "Indeed,", "KHC", "of", "membrane-", "bound,", "presumably", "active", "kinesin", "is", "hyperphosphorylated", "in", "vivo", "(Lee", "and", "Hollenbeck,", "1995)", "and", "kinesin", "phosphor-", "ylation", "by", "protein", "kinase", "A", "(PKA)", "in", "vitro", "increased", "kine-", "sin", "ATPase", "activity", "and", "thus", "may", "stimulate", "transport", "(Matthies", "et", "al.,", "1993).", "However,", "phosphorylation", "by", "PKA", "also", "reduced", "binding", "of", "kinesin", "to", "synaptic", "vesicles", "sug-", "gesting", "to", "the", "contrary", "decreased", "vesicle", "transport", "(Sato-", "Yoshitake", "et", "al.,", "1992).", "In", "a", "different", "approach,", "using", "oka-", "daic", "acid", "(OA)", "to", "drive", "hyperphosphorylation", "of", "kinesin", "in", "cytosolic", "extracts,", "McIlvain", "et", "al.", "(1994)", "showed", "hyper-", "phosphorylation", "of", "three", "components", "of", "the", "kinesin", "com-", "plex,", "but", "not", "of", "KHC", "in", "correlation", "with", "increased", "kinesin", "activity", "in", "vitro.", "One", "of", "these", "associated", "proteins", "was", "re-", "cently", "identified", "as", "KLC,", "and", "hyperphosphorylation", "of", "this", "KLC", "isoform", "was", "sufficient", "to", "increase", "kinesin", "activity", "in", "vitro", "(Lindesmith", "et", "al.,", "1997).", "Similarly", "increased", "vesicle", "motility", "was", "observed", "in", "OA-treated", "CV-1", "cells", "(Hamm-Alvarez", "et", "al.,", "1993).", "However,", "in", "these", "cells", "no", "hyperphosphorylation", "of", "kinesin-associated", "proteins", "could", "be", "demonstrated,", "suggesting", "an", "indirect", "effect", "of", "OA", "on", "kinesin", "activity", "(McIlvain", "et", "al.,", "1994).", "Also,", "in", "melano-", "phores,", "melanocyte", "stimulating", "hormone-induced", "disper-", "sion", "of", "melanosomes", "by", "kinesin-II", "was", "dependent", "on", "PKA", "ª", "The", "Rockefeller", "University", "Press,", "0021-9525/2000/06/1207/8", "$5.00", "The", "Journal", "of", "Cell", "Biology,", "Volume", "149,", "Number", "6,", "June", "12,", "2000", "1207–1214", "http://www.jcb.org", "1207" ]	[ 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 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978 ], [ 566, 964, 620, 978 ], [ 627, 964, 658, 978 ], [ 665, 964, 700, 978 ], [ 708, 964, 721, 978 ], [ 728, 964, 772, 978 ], [ 434, 979, 487, 994 ], [ 490, 979, 513, 994 ], [ 516, 979, 569, 994 ], [ 572, 979, 624, 994 ], [ 627, 979, 674, 994 ] ]	[ "Int.", "J.", "Biol.", "Sci.", "2007,", "3", "Review", "420", "International", "Journal", "of", "Biological", "Sciences", "ISSN", "1449-2288", "www.biolsci.org", "2007", "3(7):420-427", "©Ivyspring", "International", "Publisher.", "All", "rights", "reserved", "Candidate", "Gene", "Identification", "Approach:", "Progress", "and", "Challenges", "Mengjin", "Zhu", "and", "Shuhong", "Zhao", "Key", "Laboratory", "of", "Agricultural", "Animal", "Genetics,", "Breeding", "and", "Reproduction", "of", "Ministry", "of", "Education,", "Huazhong", "Agricultural", "University,", "Wuhan", "430070,", "P.", "R.", "China", "Correspondence", "to:", "Shuhong", "Zhao,", "Key", "Laboratory", "of", "Agricultural", "Animal", "Genetics,", "Breeding", "and", "Reproduction", "of", "Ministry", "of", "Education,", "Huazhong", "Agricultural", "University,", "Wuhan", "430070,", "P.", "R.", "China.", "Tel:", "+86-27-87281306;", "Fax:", "+86-27-87280408;", "E-mail:", "shzhao@mail.hzau.edu.cn", "Received:", "2007.08.26;", "Accepted:", "2007.10.24;", "Published:", "2007.10.25", "Although", "it", "has", "been", "widely", "applied", "in", "identification", "of", "genes", "responsible", "for", "biomedically,", "economically,", "or", "even", "evolutionarily", "important", "complex", "and", "quantitative", "traits,", "traditional", "candidate", "gene", "approach", "is", "largely", "limited", "by", "its", "reliance", "on", "the", "priori", "knowledge", "about", "the", "physiological,", "biochemical", "or", "functional", "aspects", "of", "possible", "candidates.", "Such", "limitation", "results", "in", "a", "fatal", "information", "bottleneck,", "which", "has", "apparently", "become", "an", "obstacle", "for", "further", "applications", "of", "traditional", "candidate", "gene", "approach", "on", "many", "occasions.", "While", "the", "identification", "of", "candidate", "genes", "involved", "in", "genetic", "traits", "of", "specific", "interest", "remains", "a", "challenge,", "significant", "progress", "in", "this", "subject", "has", "been", "achieved", "in", "the", "last", "few", "years.", "Several", "strategies", "have", "been", "developed,", "or", "being", "developed,", "to", "break", "the", "barrier", "of", "information", "bottleneck.", "Recently,", "being", "a", "new", "developing", "method", "of", "candidate", "gene", "approach,", "digital", "candidate", "gene", "approach", "(DigiCGA)", "has", "emerged", "and", "been", "primarily", "applied", "to", "identify", "potential", "candidate", "genes", "in", "some", "studies.", "This", "review", "summarizes", "the", "progress,", "application", "software,", "online", "tools,", "and", "challenges", "related", "to", "this", "approach.", "Key", "words:", "candidate", "gene", "approach;", "information", "bottleneck;", "digital", "candidate", "gene", "approach", "1.", "Introduction", "Based", "on", "the", "polygenic", "hypothesis,", "classical", "quantitative", "genetics", "considers", "a", "black", "box", "to", "reveal", "the", "holistic", "status", "of", "all", "genes", "associated", "with", "variation", "of", "complex", "and", "quantitative", "traits", "by", "complicated", "statistical", "methods.", "Such", "strategy", "could", "not", "independently", "decompose", "individual", "genes,", "which", "usually", "follow", "the", "Mendel's", "law,", "from", "the", "polygenic", "system", "of", "the", "investigated", "traits.", "Advances", "in", "molecular", "methods", "and", "quantitative", "techniques", "have", "clearly", "changed", "this", "status,", "which", "are", "able", "to", "look", "inside", "the", "black", "box", "of", "polygenic", "control", "for", "complex", "and", "quantitative", "traits", "with", "a", "more", "accurate", "description", "of", "how", "genes", "act", "to", "determine", "the", "phenotypic", "variation.", "More", "recently,", "major", "progress", "has", "been", "made", "in", "this", "field", "with", "the", "advent", "of", "genomics", "and", "its", "potential", "contribution", "to", "development", "of", "quantitative", "genetics.", "One", "of", "the", "hot", "interests", "of", "current", "quantitative", "genetics", "is", "systematically", "exploring", "an", "exact", "genetic", "architecture", "of", "the", "number,", "distribution", "and", "interaction", "of", "loci", "affecting", "the", "variations", "of", "biomedically,", "economically,", "and", "evolutionarily", "important", "complex", "and", "quantitative", "traits.", "There", "are", "two", "approaches", "for", "genetic", "dissections", "of", "complex", "and", "quantitative", "traits,", "i.e.,", "genome-wide", "scanning", "and", "candidate", "gene", "approach,", "which", "each", "has", "specific", "advantages", "and", "disadvantages.", "Genome-wide", "scanning", "usually", "proceeds", "without", "any", "presuppositions", "regarding", "the", "importance", "of", "specific", "functional", "features", "of", "the", "investigated", "traits,", "but", "of", "which", "the", "principal", "disadvantage", "is", "expensive", "and", "resource", "intensive.", "In", "general,", "genome-wide", "scanning", "only", "locates", "the", "glancing", "chromosomal", "regions", "of", "quantitative", "trait", "loci", "(QTLs)", "at", "cM-level", "with", "the", "aid", "of", "DNA", "markers", "under", "family-based", "or", "population-based", "experimental", "designs,", "which", "usually", "embed", "a", "large", "number", "of", "candidate", "genes.", "In", "comparison,", "the", "alternative", "candidate", "gene", "approach", "has", "been", "proven", "to", "be", "extremely", "powerful", "for", "studying", "the", "genetic", "architecture", "of", "complex", "traits,", "which", "is", "a", "far", "more", "effective", "and", "economical", "method", "for", "direct", "gene", "discovery.", "Nevertheless,", "the", "practicability", "of", "traditional", "candidate", "gene", "approach", "is", "largely", "limited", "by", "its", "reliance", "on", "existing", "knowledge", "about", "the", "known", "or", "presumed", "biology", "of", "the", "phenotype", "under", "investigation,", "and", "unfortunately", "the", "detailed", "molecular", "anatomy", "of", "most", "biological", "traits", "remains", "unknown.", "It", "is", "quite", "necessary", "to", "develop", "new", "strategies", "to", "break", "the", "restriction", "of", "information", "bottleneck,", "although", "considerable", "candidate", "genes", "have", "already", "been", "identified.", "In", "this", "article,", "we", "review", "and", "summarize", "the", "main", "research", "advances", "in", "the", "subject,", "including", "the", "outline", "of", "candidate", "gene", "approach", "and", "the", "extended", "strategies", "for", "breaking", "the", "information", "bottleneck", "of", "traditional", "candidate", "gene", "approach.", "Finally,", "as", "a", "new", "development", "of", "candidate", "gene", "approach,", "digital", "candidate", "gene", "approach", "(DigiCGA)", "was", "discussed", "and", "some", "research", "outlooks", "were", "given", "to", "further", "promote", "this", "valuable", "research", "subject." ]	[ 0, 0, 0, 0, 0, 0, 16, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 7, 7, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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"Azary", "3,", "S.", "Mokhtarykhoee", "4", "1Associate", "Professor,", "Department", "of", "Prosthodontics,", "School", "of", "Dentistry,", "Tehran", "University", "of", "Medical", "Sciences,", "Tehran,", "Iran", "2Mechanical", "Engineer,", "Private", "Sector", "3Assistant", "Professor,", "Department", "of", "Prosthodontics,", "School", "of", "Dentistry,", "Tehran", "University", "of", "Medical", "Sciences,", "Tehran,", "Iran", "4Dentist,", "Private", "Practice", "Abstract:", "Objective:", "In", "all", "ceramic", "fixed", "partial", "dentures", "the", "connector", "area", "is", "a", "common", "fracture", "location.", "The", "survival", "time", "of", "three-unit", "fixed", "partial", "dentures", "may", "be", "improved", "by", "alter-", "ing", "the", "connector", "design", "in", "regions", "of", "maximum", "tension.", "The", "purpose", "of", "this", "study", "was", "to", "determine", "the", "effect", "of", "buccolingual", "increase", "of", "the", "connector", "width", "on", "the", "stress", "distribu-", "tion", "in", "posterior", "fixed", "partial", "dentures", "made", "of", "IPS", "Empress", "2.", "To", "simulate", "the", "anatomical", "condition,", "we", "used", "three-dimensional", "finite", "element", "analysis", "to", "generate.", "Materials", "and", "Methods:", "Three", "models", "of", "three-unit", "bridges", "replacing", "the", "first", "molar", "were", "prepared.", "The", "buccolingual", "connector", "width", "varied", "from", "3.0", "to", "5.0", "mm.", "Bridges", "were", "vertically", "loaded", "with", "600", "N", "at", "one", "point", "on", "the", "central", "fossa", "of", "the", "pontic,", "at", "12", "points", "along", "the", "cusp-fossa", "contact", "(50", "N", "each),", "or", "at", "eight", "points", "along", "the", "cusp-marginal", "ridge", "contact", "(75", "N", "each).", "Alternatively,", "a", "load", "of", "225", "N", "was", "applied", "at", "a", "45º", "angle", "from", "the", "lingual", "side.", "Results:", "Stress", "concentrations", "were", "observed", "within", "or", "near", "the", "connectors.", "The", "von", "Mis-", "es", "stress", "decreased", "by", "increasing", "connector", "width,", "regardless", "of", "whether", "the", "loading", "was", "", "Corresponding", "author:", "applied", "vertically", "or", "at", "an", "angle.", "F.", "Fallahi", "Arezodar,", "Mechanical", "Conclusion:", "Within", "the", "limitations", "of", "this", "study,", "we", "conclude", "that", "increasing", "the", "connect-", "Engineer,", "Private", "Sector,", "Tehran,", "or", "width", "decreases", "the", "failure", "probability", "when", "a", "vertical", "or", "angled", "load", "is", "applied.", "Iran.", "f.fallahi.a@gmail.com", "Key", "Words:", "Ceramics;", "Finite", "Element", "Analysis;", "Denture,", "Partial,", "Fixed", "Journal", "of", "Dentistry,", "Tehran", "University", "of", "Medical", "Sciences,", "Tehran,", "Iran", "(2011;", "Vol.", "8,", "No.2)", "Received:", "Accepted:", "INTRODUCTION", "Clinical", "stress", "distribution", "in", "ceramic", "dental", "restorations", "may", "be", "quite", "complex.", "Several", "factors", "are", "associated", "with", "crack", "initiation", "and", "propagation,", "including", "the", "shape", "of", "the", "resto-", "ration,", "micro", "structural", "nonhomogeneities,", "the", "size", "and", "distribution", "of", "surface", "flaws,", "residual", "stresses", "and", "stress", "gradients", "induced", "by", "polish-", "ing", "and/or", "thermal", "processing,", "the", "environ-", "ment", "in", "contact", "with", "the", "restoration,", "ceram-", "ic/cement", "interfacial", "features,", "thickness", "and", "thickness", "variation", "of", "the", "restoration,", "different", "2011;", "Vol.", "8,", "No.", "2", "elastic", "modules", "of", "the", "restoration", "components", "and", "the", "magnitude", "and", "orientation", "of", "the", "ap-", "plied", "load", "[1].", "Failure", "may", "be", "a", "mixed", "pattern", "of", "compressive,", "tensile,", "and/or", "shear", "failures", "[2].", "However,", "brittle", "materials", "(e.g.,", "dental", "ce-", "ramics)", "usually", "demonstrate", "the", "least", "strength", "when", "exposed", "to", "tensile", "stress.", "Thus,", "tensile", "stress", "is", "useful", "for", "assessing", "the", "service", "time", "of", "ceramic", "materials,", "especially", "when", "flaws", "are", "present.", "The", "long-term", "mechanical", "behavior", "of", "the", "restoration", "is", "also", "critical,", "since", "ceramics", "exhibit", "a", "time-dependent", "strength", "decrease", "due", "67" ]	[ 16, 16, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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"www.mdpi.com/journal/ijerph", "Article", "Parents’", "and", "Teachers’", "Opinions", "about", "the", "School", "Food", "Policy", "in", "Belgian", "Flemish", "Nursery", "Schools", "Carine", "Vereecken", "1,2,,", "Hilde", "van", "Houte", "3,4,", "Veerle", "Martens", "3,4,", "Isabelle", "Wittebroodt", "3", "and", "Lea", "Maes", "1", "1", "Department", "of", "Public", "Health,", "Ghent", "University,", "University", "Hospital", "BlokA,", "2nd", "floor,", "De", "Pintelaan", "185,", "9000", "Gent,", "Belgium;", "E-Mail:", "Lea.Maes@UGent.Be", "2", "Research", "Foundation", "Flanders", "(FWO)", "3", "Department", "of", "early", "childhood", "education,", "University", "College", "„Arteveldehogeschool‟,", "Gent", "9040,", "Belgium;", "E-Mails:", "hilde.vanhoute@arteveldehs.be", "(H-V.V.);", "veerle.martens@arteveldehs.be", "(V.M.);", "isabelle.wittebroodt@arteveldehs.be", "(I.W.)", "4", "Ghent", "University", "", "Author", "to", "whom", "correspondence", "should", "be", "addressed;", "E-Mail:", "Carine.Vereecken@UGent.Be;", "Tel.:", "+32-(0)9-3322081;", "Fax:", "+32-(0)9-3324994", "Received:", "24", "February", "2009", "/", "Accepted:", "19", "March", "2009", "/", "Published:", "24", "March", "2009", "Abstract:", "The", "partnership", "of", "parents,", "teachers,", "and", "schools", "is", "necessary", "to", "develop", "effective", "school", "food", "interventions.", "To", "gather", "parents‟", "and", "teachers‟", "opinions", "and", "perceptions", "about", "the", "school", "food", "policy,", "884", "parents", "and", "70", "teachers", "of", "preschoolers", "completed", "a", "questionnaire.", "School", "food", "policy", "is", "an", "issue", "of", "importance", "for", "parents", "and", "teachers:", "the", "majority", "agrees", "that", "schools", "should", "restrict", "the", "availability", "of", "snacks", "and", "soft", "drinks;", "however,", "to", "replace", "fruit", "juice", "and", "sugared", "milk", "drinks", "with", "sugarless", "alternatives", "will", "take", "special", "effort.", "Fruit", "is", "not", "always", "available", "at", "school,", "although", "parents", "would", "appreciate", "it.", "Parents", "of", "lower", "educational", "level", "are", "in", "general", "more", "permissive.", "Keywords:", "Preschool;", "school", "food", "policy;", "parents;", "teachers." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 9, 9, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 16, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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666, 1006, 696, 1019 ], [ 700, 1006, 706, 1019 ], [ 711, 1006, 756, 1019 ], [ 760, 1006, 770, 1019 ], [ 113, 1047, 136, 1059 ], [ 140, 1047, 161, 1059 ], [ 165, 1047, 168, 1059 ], [ 174, 1047, 257, 1059 ], [ 422, 1047, 428, 1059 ], [ 552, 1047, 588, 1059 ], [ 591, 1047, 614, 1059 ], [ 619, 1047, 622, 1059 ], [ 627, 1047, 663, 1059 ], [ 668, 1047, 674, 1059 ], [ 680, 1047, 683, 1059 ], [ 688, 1047, 712, 1059 ], [ 716, 1047, 722, 1059 ], [ 727, 1047, 730, 1059 ], [ 736, 1047, 770, 1059 ] ]	[ "Growth", "Parameter", "Components", "of", "Adaptive", "Specificity", "during", "Experimental", "Evolution", "of", "the", "UVR-Inducible", "Mutator", "Pseudomonas", "cichorii", "302959", "Michael", "R.", "Weigand", "1", ",", "Vinh", "N.", "Tran", "2", ",", "George", "W.", "Sundin1,2,3", "1", "Program", "in", "Genetics,", "Michigan", "State", "University,", "East", "Lansing,", "Michigan,", "United", "States", "of", "America,", "2", "Department", "of", "Plant", "Pathology,", "Michigan", "State", "University,", "East", "Lansing,", "Michigan,", "United", "States", "of", "America,", "3", "Centers", "for", "Microbial", "Ecology", "and", "Pathogenesis,", "Michigan", "State", "University,", "East", "Lansing,", "Michigan,", "United", "States", "of", "America", "Abstract", "Background:", "Mutagenic", "DNA", "repair", "(MDR)", "transiently", "increases", "mutation", "rate", "through", "the", "activation", "of", "low-fidelity", "repair", "polymerases", "in", "response", "to", "specific,", "DNA-damaging", "environmental", "stress", "conditions", "such", "as", "ultraviolet", "radiation", "(UVR)", "exposure.", "These", "repair", "polymerases", "also", "confer", "UVR", "tolerance,", "intimately", "linking", "mutability", "and", "survival", "in", "bacteria", "that", "colone", "habitats", "subject", "to", "regular", "UVR", "exposure.", "Methodology/Principal", "Findings:", "Here,", "we", "investigate", "adaptive", "specificity", "in", "experimental", "lineages", "of", "the", "highly", "UVR-", "mutable", "epiphytic", "plant", "pathogen", "Pseudomonas", "cichorii", "302959.", "Relative", "fitness", "measurements", "of", "isolates", "and", "population", "samples", "from", "replicate", "lineages", "indicated", "that", "adaptive", "improvements", "emerged", "early", "in", "all", "lineages", "of", "our", "evolution", "experiment", "and", "specific", "increases", "in", "relative", "fitness", "correlated", "with", "distinct", "improvements", "in", "doubling", "and", "lag", "times.", "Adaptive", "improvements", "gained", "under", "UVR", "and", "non-UVR", "conditions", "were", "acquired", "preferentially,", "and", "differentially", "contributed", "to", "relative", "fitness", "under", "varied", "growth", "conditions.", "Conclusions:", "These", "results", "support", "our", "earlier", "observations", "that", "MDR", "activation", "may", "contribute", "to", "gains", "in", "relative", "fitness", "without", "impeding", "normal", "patterns", "of", "adaptive", "specificity", "in", "P.", "cichorii", "302959.", "Citation:", "Weigand", "MR,", "Tran", "VN,", "Sundin", "GW", "(2011)", "Growth", "Parameter", "Components", "of", "Adaptive", "Specificity", "during", "Experimental", "Evolution", "of", "the", "UVR-Inducible", "Mutator", "Pseudomonas", "cichorii", "302959.", "PLoS", "ONE", "6(1):", "e15975.", "doi:10.1371/journal.pone.0015975", "Editor:", "Michael", "Otto,", "Laboratory", "of", "Human", "Bacterial", "Pathogenesis,", "National", "Institutes", "of", "Health,", "United", "States", "of", "America", "Received", "September", "21,", "2010;", "Accepted", "December", "7,", "2010;", "Published", "January", "14,", "2011", "Copyright:", "2011", "Weigand", "et", "al.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Funding:", "This", "work", "was", "funded", "by", "the", "Michigan", "Agricultural", "Experiment", "Station.", "The", "funders", "had", "no", "role", "in", "study", "design,", "data", "collection", "and", "analysis,", "decision", "to", "publish,", "or", "preparation", "of", "the", "manuscript.", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "", "E-mail:", "sundin@msu.edu", "Introduction", "Mutation", "is", "the", "most", "fundamental", "source", "of", "variation", "on", "which", "natural", "selection", "may", "drive", "evolution.", "However,", "the", "predomi-", "nantly", "deleterious", "nature", "of", "mutation", "maintains", "selection", "pressure", "in", "favor", "of", "lower", "mutation", "rates", "as", "evidenced", "by", "the", "conservation", "of", "multiple", "DNA", "error-avoidance", "and", "error-repair", "processes", "[1].", "Yet", "hypermutator", "(or", "mutator)", "strains", "of", "bacteria", "have", "been", "observed", "in", "a", "variety", "of", "clinical,", "environmental,", "and", "laboratory", "populations", "with", "mutation", "rates", "100-1000", "times", "greater", "than", "wild-", "type", "due", "to", "defects", "in", "DNA", "proofreading", "and", "repair", "machinery", "[2].", "The", "widespread", "existence", "of", "both", "constitutive", "and", "inducible", "mutator", "genotypes", "suggests", "that", "evolutionary", "strategies", "of", "bacteria", "include", "mechanisms", "for", "increasing", "mutability", "[3,4].", "These", "mutator", "genotypes", "have", "not", "been", "shown", "to", "confer", "an", "intrinsic", "fitness", "advantage", "and", "their", "abundance", "within", "natural", "populations", "likely", "results", "from", "hitchhiking", "with", "secondary,", "beneficial", "mutations", "which", "counterbalance", "the", "cost", "of", "accumulating", "deleterious", "mutations", "[5,6].", "Inducible", "mutability", "in", "the", "form", "of", "mutagenic", "DNA", "repair", "(MDR)", "transiently", "increases", "mutation", "rate", "through", "the", "activation", "of", "low-fidelity", "repair", "polymerases", "in", "response", "to", "specific", "environ-", "mental", "stress", "conditions", "such", "as", "ultraviolet", "radiation", "(UVR)", "exposure.", "UVR", "directly", "damages", "DNA", "causing", "lesions,", "including", "cyclobutane", "pyrimidine", "dimers", "and", "6-4", "photoproducts,", "that", "distort", "the", "helical", "structure,", "interrupting", "replication", "fork", "progression", "and", "inducing", "the", "SOS", "response.", "The", "SOS", "regulon", "coordinates", "the", "control", "of", "more", "than", "40", "unlinked", "genes", "involved", "in", "DNA", "repair,", "recombination,", "and", "cell", "cycle", "control", "[7,8].", "Among", "these,", "the", "Y", "family", "DNA", "polymerases", "polIV", "(Escherichia", "coli", "DinB)", "and", "polV", "(E.", "coli", "UmuDC)", "rescue", "stalled", "replication", 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"heinrich.herre@imise.uni-leipzig.de", "*", "Corresponding", "author", "Published:", "18", "November", "2009", "BMC", "Bioinformatics", "2009,", "10:377", "doi:10.1186/1471-2105-10-377", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1471-2105/10/377", "Received:", "18", "August", "2009", "Accepted:", "18", "November", "2009", "©", "2009", "Hoehndorf", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "Biological", "sequences", "play", "a", "major", "role", "in", "molecular", "and", "computational", "biology.", "They", "are", "studied", "as", "information-bearing", "entities", "that", "make", "up", "DNA,", "RNA", "or", "proteins.", "The", "Sequence", "Ontology,", "which", "is", "part", "of", "the", "OBO", "Foundry,", "contains", "descriptions", "and", "definitions", "of", "sequences", "and", "their", "properties.", "Yet", "the", "most", "basic", "question", "about", "sequences", "remains", "unanswered:", "what", "kind", "of", "entity", "is", "a", "biological", "sequence?", "An", "answer", "to", "this", "question", "benefits", "formal", "ontologies", "that", "use", "the", "notion", "of", "biological", "sequences", "and", "analyses", "in", "computational", "biology", "alike.", "Results:", "We", "provide", "both", "an", "ontological", "analysis", "of", "biological", "sequences", "and", "a", "formal", "representation", "that", "can", "be", "used", "in", "knowledge-based", "applications", "and", "other", "ontologies.", "We", "distinguish", "three", "distinct", "kinds", "of", "entities", "that", "can", "be", "referred", "to", "as", "\"biological", "sequence\":", "chains", "of", "molecules,", "syntactic", "representations", "such", "as", "those", "in", "biological", "databases,", "and", "the", "abstract", "information-bearing", "entities.", "For", "use", "in", "knowledge-based", "applications", "and", "inclusion", "in", "biomedical", "ontologies,", "we", "implemented", "the", "developed", "axiom", "system", "for", "use", "in", "automated", "theorem", "proving.", "Conclusion:", "Axioms", "are", "necessary", "to", "achieve", "the", "main", "goal", "of", "ontologies:", "to", "formally", "specify", "the", "meaning", "of", "terms", "used", "within", "a", "domain.", "The", "axiom", "system", "for", "the", "ontology", "of", "biological", "sequences", "is", "the", "first", "elaborate", "axiom", "system", "for", "an", "OBO", "Foundry", "ontology", "and", "can", "serve", "as", "starting", "point", "for", "the", "development", "of", "more", "formal", "ontologies", "and", "ultimately", "of", "knowledge-based", "applications.", "Background", "Biological", "sequences", "play", "a", "major", "role", "in", "genetics", "and", "bio-", "informatics", "research.", "They", "are", "important", "in", "the", "descrip-", "tion", "of", "DNA,", "RNA", "and", "proteins,", "and", "are", "among", "the", "basic", "entities", "studied", "in", "molecular", "and", "computational", "biology.", "In", "the", "realm", "of", "biological", "ontologies,", "the", "Sequence", "Ontol-", "ogy", "(SO)", "[1]", "was", "developed", "to", "describe", "sequences", "and", "their", "features", "semantically.", "Although", "many", "formal", "defini-", "tions", "are", "available", "for", "the", "SO", "categories,", "several", "categories", "remain", "defined", "using", "natural", "language.", "Formal", "ontologies", "are", "intended", "to", "formally", "specify", "a", "con-", "ceptualization", "of", "a", "domain", "[2],", "and", "therefore", "provide", "the", "foundation", "for", "data", "and", "information", "integration", "and", "exchange.", "Definitions", "alone", "are", "insufficient", "to", "achieve", "this", "goal.", "Axioms", "are", "required", "to", "provide", "meaning", "for", "primi-", "tive,", "undefined", "categories", "and", "relations.", "To", "provide", "an", "ontological", "analysis", "of", "\"biological", "sequence\"", "and", "to", "for-", "malize", "the", "basic", "categories", "used", "in", "the", "SO,", "several", "onto-", "logical", "questions", "about", "sequences", "must", "be", "answered,", "among", "them:", "what", "kind", "of", "entity", "is", "a", "biological", "sequence?", "Page", "1", "of", "11", "(page", "number", "not", "for", "citation", "purposes)" ]	[ 0, 0, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 0, 0, 9, 9, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 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"the", "Golgi", "apparatus", "Francis", "A.", "Barr,", "Christian", "Preisinger,", "Robert", "Kopajtich,", "and", "Roman", "Körner", "Department", "of", "Cell", "Biology,", "Max-Planck-Institute", "of", "Biochemistry,", "82152", "Martinsried,", "Germany", "T", "comprised", "of", "a", "stack", "of", "cisternal", "membranes", "on", "the", "he", "Golgi", "apparatus", "is", "a", "highly", "complex", "organelle", "secretory", "pathway", "from", "the", "ER", "to", "the", "cell", "surface.", "This", "structure", "is", "maintained", "by", "an", "exoskeleton", "or", "Golgi", "matrix", "constructed", "from", "a", "family", "of", "coiled-coil", "proteins,", "the", "golgins,", "and", "other", "peripheral", "membrane", "components", "such", "as", "GRASP55", "and", "GRASP65.", "Here", "we", "ﬁnd", "that", "TMP21,", "p24a,", "and", "gp25L,", "members", "of", "the", "p24", "cargo", "receptor", "family,", "are", "present", "in", "complexes", "with", "GRASP55", "and", "GRASP65", "Introduction", "The", "Golgi", "apparatus", "is", "an", "organelle", "on", "the", "secretory", "pathway", "required", "for", "the", "processing", "of", "complex", "sugar", "structures", "on", "many", "proteins", "and", "lipids,", "and", "for", "the", "sorting", "of", "these", "proteins", "and", "lipids", "to", "their", "correct", "subcellular", "destinations", "(Farquhar", "and", "Palade,", "1998).", "It", "is", "comprised", "of", "a", "series", "of", "cisternal", "membranes", "organized", "into", "a", "stacked", "structure,", "the", "first", "or", "cis-face", "receives", "material", "from", "the", "ER,", "whereas", "the", "final", "or", "trans-cisternae", "packages", "it", "for", "delivery", "to", "the", "plasma", "membrane", "and", "endocytic", "pathways", "(Farquhar", "and", "Palade,", "1998).", "This", "structure", "is", "maintained", "by", "an", "exoskeleton", "or", "Golgi", "matrix", "which", "has", "been", "proposed", "to", "be", "required", "for", "linking", "cisternae", "together", "into", "the", "characteristic", "Golgi", "stack", "structure,", "and", "also", "for", "vesicle", "recognition", "during", "membrane", "traffic", "(Warren", "and", "Malhotra,", "1998;", "Seeman", "et", "al.,", "2000).", "The", "most", "studied", "components", "of", "the", "Golgi", "matrix", "are", "p115,", "the", "GRASP65–GM130", "complex,", "and", "an", "integral", "membrane", "protein,", "giantin", "(Linstedt", "and", "Hauri,", "1993;", "Nakamura", "et", "al.,", "1995;", "Sapperstein", "et", "al.,", "1995;", "Barr", "et", "al.,", "1997;", "Shorter", "and", "Warren,", "1999).", "GRASP65", "was", "identified", "in", "a", "screen", "for", "factors", "involved", "in", "the", "stacking", "of", "cisternae,", "and", "later", "shown", "to", "be", "a", "specific", "binding", "partner", "of", "GM130", "Address", "correspondence", "to", "Francis", "Barr,", "Dept.", "of", "Cell", "Biology,", "Max-", "Planck-Institute", "of", "Biochemistry,", "Am", "Klopferspitz", "18a,", "82152", "Martinsried,", "Germany.", "Tel.:", "49-89-8578-3135.", "Fax:", "49-89-8578-3102.", "E-mail:", "barr@biochem.mpg.de", "Key", "words:", "GRASPs;", "p24", "proteins;", "Golgi", "matrix;", "protein", "transport;", "cargo", "receptors", "", "The", "Rockefeller", "University", "Press,", "0021-9525/2001/12/885/7", "$5.00", "The", "Journal", "of", "Cell", "Biology,", "Volume", "155,", "Number", "6,", "December", "10,", "2001", "885–891", "http://www.jcb.org/cgi/doi/10.1083/jcb.200108102", "in", "vivo.", "GRASPs", "interact", "directly", "with", "the", "cytoplasmic", "domains", "of", "speciﬁc", "p24", "cargo", "receptors", "depending", "on", "their", "oligomeric", "state,", "and", "mutation", "of", "the", "GRASP", "binding", "site", "in", "the", "cytoplasmic", "tail", "of", "one", "of", "these,", "p24a,", "results", "in", "it", "being", "transported", "to", "the", "cell", "surface.", "These", "results", "suggest", "that", "one", "function", "of", "the", "Golgi", "matrix", "is", "to", "aid", "efﬁcient", "retention", "or", "sequestration", "of", "p24", "cargo", "receptors", "and", "other", "membrane", "proteins", "in", "the", "Golgi", "apparatus.", "required", "to", "target", "it", "to", "the", "Golgi", "(Barr", "et", "al.,", "1998).", "GM130", "in", "turn", "is", "a", "receptor", "for", "p115,", "required", "for", "tethering", "vesicles", "to", "their", "target", "membrane", "(Barroso", "et", "al.,", "1995;", "Nakamura", "et", "al.,", "1997).", "More", "recently,", "the", "formation", "of", "Golgi", "stacks", "from", "cisternae", "in", "vitro", "was", "found", "to", "require", "p115,", "discrete", "from", "its", "membrane", "fusion", "function,", "and", "giantin", "(Shorter", "and", "Warren,", "1999).", "GM130", "and", "p115", "also", "make", "interactions", "with", "giantin", "during", "vesicle", "docking,", "and", "potentially", "during", "cisternal", "stacking", "(Shorter", "and", "Warren,", "1999;", "Dirac-Svejstrup", "et", "al.,", "2000;", "Lesa", "et", "al.,", "2000).", "The", "network", "of", "interactions", "between", "these", "proteins", "may", "be", "regulated", "by", "the", "rab", "GTPases,", "as", "both", "p115", "and", "GM130", "have", "been", "shown", "to", "interact", "with", "the", "active", "or", "GTP", "form", "of", "rab1", "(Allan", "et", "al.,", "2000;", "Moyer", "et", "al.,", "2001;", "Weide", "et", "al.,", "2001).", "Recruitment", "of", "p115", "to", "vesicles", "destined", "to", "fuse", "with", "the", "cis-Golgi", "is", "mediated", "via", "the", "interaction", "with", "rab1", "(Allan", "et", "al.,", "2000),", "whereas", "the", "consequences", "of", "rab1", "binding", "to", "GM130", "are", "unknown.", "A", "second", "GRASP", "complex,", "containing", "GRASP55", "and", "the", "coiled-coil", "protein", "golgin-45,", "exists", "in", "Golgi", "membranes", "(Shorter", "et", "al.,", "1999;", "Short", "et", "al.,", "2001).", "Like", "the", "GRASP65–", "GM130", "complex,", "this", "complex", "also", "binds", "a", "rab", "GTPase", "and", "is", "required", "for", 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660, 998, 705, 1008 ], [ 708, 998, 723, 1008 ], [ 248, 1009, 298, 1019 ], [ 300, 1009, 307, 1019 ], [ 310, 1009, 324, 1019 ], [ 326, 1009, 360, 1019 ], [ 362, 1009, 396, 1019 ], [ 399, 1009, 412, 1019 ], [ 415, 1009, 443, 1019 ], [ 446, 1009, 465, 1019 ], [ 467, 1009, 473, 1019 ], [ 476, 1009, 508, 1019 ], [ 510, 1009, 530, 1019 ] ]	[ "Paxton-Aiken", "et", "al.", "International", "Journal", "of", "Behavioral", "Nutrition", "and", "Physical", "Activity", "2012,", "9:30", "http://www.ijbnpa.org/content/9/1/30", "R", "E", "S", "E", "A", "R", "C", "H", "Open", "Access", "How", "accurate", "are", "parental", "responses", "concerning", "their", "fourth-grade", "children’s", "school-meal", "participation,", "and", "what", "is", "the", "relationship", "between", "children’s", "body", "mass", "index", "and", "school-", "meal", "participation", "based", "on", "parental", "responses?", "Amy", "E", "Paxton-Aiken1†,", "Suzanne", "Domel", "Baxter1†,", "Joshua", "M", "Tebbs2,", "Christopher", "J", "Finney1,", "Caroline", "H", "Guinn1", "and", "Julie", "A", "Royer1", "Abstract", "Background:", "This", "article", "investigated", "(1)", "parental", "response", "accuracy", "of", "fourth-grade", "children’s", "school-meal", "participation", "and", "whether", "accuracy", "differed", "by", "children’s", "body", "mass", "index", "(BMI),", "sex,", "and", "race,", "and", "(2)", "the", "relationship", "between", "BMI", "and", "school-meal", "participation", "(based", "on", "parental", "responses).", "Methods:", "Data", "were", "from", "four", "cross-sectional", "studies", "conducted", "from", "fall", "1999", "to", "spring", "2003", "with", "fourth-grade", "children", "from", "13", "schools", "total.", "Consent", "forms", "asked", "parents", "to", "report", "children’s", "usual", "school-meal", "participation.", "As", "two", "studies’", "consent", "forms", "did", "not", "ask", "about", "lunch", "participation,", "complete", "data", "were", "available", "for", "breakfast", "on", "1,496", "children", "(51%", "Black;", "49%", "boys)", "and", "for", "lunch", "on", "785", "children", "(46%", "Black;", "48%", "boys).", "Researchers", "compiled", "nametag", "records", "(during", "meal", "observations)", "of", "meal", "participation", "on", "randomly", "selected", "days", "during", "children’s", "fourth-grade", "school", "year", "for", "breakfast", "(average", "nametag", "days", "across", "studies:", "7-35)", "and", "for", "lunch", "(average", "nametag", "days", "across", "studies:", "4-10)", "and", "categorized", "participation", "as", "“usually”", "(≥", "50%", "of", "days)", "or", "“not", "usually”", "(<", "50%", "of", "days).", "Weight", "and", "height", "were", "measured.", "Concerning", "parental", "response", "accuracy,", "marginal", "regression", "was", "used", "with", "agreement", "between", "parental", "responses", "and", "nametag", "records", "as", "the", "dependent", "variable;", "independent", "variables", "were", "BMI,", "age,", "sex,", "race,", "and", "study.", "Concerning", "a", "relationship", "between", "BMI", "and", "school-meal", "participation,", "marginal", "regression", "was", "used", "with", "BMI", "as", "the", "dependent", "variable;", "independent", "variables", "were", "breakfast", "participation,", "lunch", "participation,", "age,", "sex,", "race,", "and", "study.", "Results:", "Concerning", "breakfast", "participation", "and", "lunch", "participation,", "74%", "and", "92%", "of", "parents", "provided", "accurate", "responses,", "respectively.", "Parental", "response", "accuracy", "was", "better", "for", "older", "children", "for", "breakfast", "and", "lunch", "participation,", "and", "for", "Black", "than", "White", "children", "for", "lunch", "participation.", "Usual", "school-meal", "participation", "was", "significantly", "related", "to", "children’s", "BMI", "but", "in", "opposite", "directions", "–", "positively", "for", "breakfast", "and", "inversely", "for", "lunch.", "Conclusions:", "Parental", "response", "accuracy", "of", "children’s", "school-meal", "participation", "was", "moderately", "high;", "however,", "disparate", "effects", "for", "children’s", "age", "and", "race", "warrant", "caution", "when", "relying", "on", "parental", "responses.", "The", "BMI", "results,", "which", "showed", "a", "relationship", "between", "school-meal", "participation", "(based", "on", "parental", "responses)", "and", "childhood", "obesity,", "conflict", "with", "results", "from", "a", "recent", "article", "that", "used", "data", "from", "the", "same", "four", "studies", "and", "found", "no", "significant", "relationship", "when", "participation", "was", "based", "on", "nametag", "records", "compiled", "for", "meal", "observations.", "Keywords:", "Children,", "School,", "Obesity,", "School-meal", "participation,", "Parental", "response", "accuracy", "", "Correspondence:", "paxtonae@mailbox.sc.edu", "†", "Contributed", "equally", "1Institute", "for", "Families", "in", "Society,", "University", "of", "South", 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"associated", "with", "human", "inherited", "disease.", "Here,", "we", "summarize", "the", "history", "of", "the", "database", "and", "its", "current", "resources.", "By", "December", "2008,", "the", "database", "contained", "over", "85,000", "different", "lesions", "detected", "in", "3,253", "different", "genes,", "with", "new", "entries", "currently", "accumulating", "at", "a", "rate", "exceeding", "9,000", "per", "annum.", "Although", "originally", "established", "for", "the", "scientific", "study", "of", "mutational", "mechanisms", "in", "human", "genes,", "HGMD", "has", "since", "acquired", "a", "much", "broader", "utility", "for", "researchers,", "physicians,", "clinicians", "and", "genetic", "counselors", "as", "well", "as", "for", "companies", "specializing", "in", "biopharmaceuticals,", "bioinformatics", "and", "personalized", "genomics.", "HGMD", "was", "first", "made", "publicly", "available", "in", "April", "1996,", "and", "a", "collaboration", "was", "initiated", "in", "2006", "between", "HGMD", "and", "BIOBASE", "GmbH.", "This", "cooperative", "agreement", "covers", "the", "exclusive", "worldwide", "marketing", "of", "the", "most", "up-to-date", "(subscription)", "version", "of", "HGMD,", "HGMD", "Professional,", "to", "academic,", "clinical", "and", "commercial", "users.", "The", "Human", "Gene", "Mutation", "Database", "(HGMD®)", "[1]", "records", "the", "first", "report", "of", "a", "disease-causing", "mutation", "or", "disease-", "associated/functional", "polymorphism", "and", "provides", "these", "data", "in", "a", "readily", "accessible", "form", "to", "all", "interested", "parties,", "whether", "they", "are", "from", "an", "academic,", "a", "clinical", "or", "a", "commercial", "background.", "HGMD", "has", "become", "the", "de", "facto", "central", "disease-associated", "mutation", "database", "available", "to", "the", "scientific", "community.", "The", "data", "comprise", "single", "base-pair", "substitutions", "in", "coding,", "regulatory", 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"potential", "use", "of", "portable", "ultrasound", "for", "mountainside", "diagnostics", "M.", "R.", "Nowak", "Æ", "A.", "W.", "Kirkpatrick", "Æ", "J.", "A.", "Bouffard", "Æ", "D.", "Amponsah", "Æ", "S.", "A.", "Dulchavsky", "Published", "online:", "7", "January", "2009", "The", "Author(s)", "2008.", "This", "article", "is", "published", "with", "open", "access", "at", "Springerlink.com", "Abstract", "Snowboarding", "has", "become", "a", "popular", "recrea-", "tional", "and", "professional", "sport.", "Participants", "suffer", "a", "variety", "of", "injuries,", "especially", "of", "the", "extremities,", "that", "require", "medical", "evaluation.", "This", "article", "reviews", "the", "reported", "inju-", "ries", "to", "both", "leisure", "and", "elite", "athletes.", "To", "many,", "an", "injured", "extremity", "requires", "travel", "to", "a", "medical", "facility", "for", "accurate", "evaluation.", "Musculoskeletal", "ultrasound", "is", "an", "accurate", "and", "portable", "technology", "that", "can", "be", "used", "for", "real", "time,", "moun-", "tainside", "diagnoses", "of", "these", "injuries.", "Keywords", "Mountainside", "ultrasound", "Remote", "guidance", "ultrasound", "Snowboarding", "injuries", "Diagnostic", "ultrasound", "Mountainside", "diagnostics", "M.", "R.", "Nowak", "(&)", "Departments", "of", "Emergency", "Medicine", "and", "Surgery,", "Henry", "Ford", "Hospital,", "Detroit,", "MI,", "USA", "e-mail:", "mnowak2@hfhs.org", "A.", "W.", "Kirkpatrick", "Regional", "Trauma", "Services,", "Foothills", "Medical", "Center,", "Calgary,", "AB,", "Canada", "J.", "A.", "Bouffard", "Department", "of", "Radiology,", "Henry", "Ford", "Hospital,", "Detroit,", "MI,", "USA", "D.", "Amponsah", "Department", "of", "Emergency", "Medicine,", "Henry", "Ford", "Hospital,", "Detroit,", "MI,", "USA", "S.", "A.", "Dulchavsky", "Department", "of", "Surgery,", "Henry", "Ford", "Hospital,", "Detroit,", "MI,", "USA", "Introduction", "Snowboarding", "has", "experienced", "a", "tremendous", "growth", "as", "a", "sport", "over", "the", "years.", "The", "National", "Sporting", "Goods", "Asso-", "ciation", "reported", "6.6", "million", "snowboarders", "participating", "in", "this", "sport", "in", "2004.", "To-date", "there", "has", "not", "been", "a", "careful", "overall", "review", "of", "the", "medical", "literature", "to", "summarize", "the", "injuries", "sustained", "by", "these", "individuals.", "Snowboarding", "is", "physically", "demanding", "and", "is", "often", "conducted", "in", "a", "chal-", "lenging", "physical", "environment", "such", "that", "the", "risks", "of", "serious", "injury", "or", "even", "death", "are", "real.", "Reviews", "of", "snowboarding", "injuries", "from", "around", "the", "world", "have", "demonstrated", "head,", "abdominal,", "spinal,", "and", "extremity", "trauma", "to", "be", "the", "most", "frequent", "serious,", "and", "occasionally", "fatal,", "injuries", "sustained", "[1–4].", "Fortunately,", "most", "snow-boarding", "injuries", "are", "not", "life-threatening,", "but", "when", "a", "professional", "or", "leisure", "snow-", "boarder", "suffers", "a", "potential", "traumatic", "injury,", "it", "can", "be", "extremely", "challenging", "for", "a", "non-physician", "on-mountain", "care-provider", "to", "make", "the", "correct", "diagnosis.", "This", "is", "because", "of", "the", "limited", "medical", "knowledge", "of", "the", "mountain", "patrol", "or", "sports", "trainers", "and", "the", "lack", "of", "radiological", "imaging", "support.", "Often", "the", "snowboarder", "must", "be", "trans-", "ported", "to", "a", "local", "hospital", "or", "to", "a", "specialty", "clinic", "for", "additional", "medical", "assessments", "[5].", "Generally,", "conditions", "in", "which", "snowboarders", "are", "injured", "preclude", "the", "ability", "to", "quickly", "assess", "injuries", "using", "imaging", "techniques", "such", "as", "magnetic", "resonance", "imaging", "(MRI),", "CAT", "scans,", "and", "even", "plain", "radiographs.", "As", "many", "snow-", "boarding", "facilities", "are", "located", "in", "relatively", "remote", "locations,", "an", "initial", "accurate", "diagnostic", "assessment", "would", "be", "critical", "to", "maximize", "the", "recovery", "of", "a", "patient.", "For", "example,", "in", "the", "case", "of", "an", "individual", "who", "suffers", "a", "potential", "joint", "injury", "of", "unknown", "severity,", "the", "decision", "must", "be", "made", "to", "apply", "ﬁrst", "aid", "principles", "(the", "application", "of", "cold", "and", "elevation", "to", "the", "affected", "area,", "anti-inﬂammatory", "medications,", "and", "rest", "for", "a" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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], [ 667, 1019, 679, 1033 ], [ 685, 1019, 744, 1033 ], [ 750, 1019, 763, 1033 ] ]	[ "Hindawi", "Publishing", "Corporation", "Mediators", "of", "Inﬂammation", "Volume", "2010,", "Article", "ID", "498980,", "9", "pages", "doi:10.1155/2010/498980", "Review", "Article", "Targeting", "Toll-Like", "Receptors", "for", "Treatment", "of", "SLE", "Christopher", "G.", "Horton,1,", "2", "Zi-jian", "Pan,2", "and", "A.", "Darise", "Farris1,", "2", "1", "Department", "of", "Microbiology", "and", "Immunology,", "University", "of", "Oklahoma", "Health", "Sciences", "Center,", "Oklahoma", "City,", "OK", "73104,", "USA", "2", "Arthritis", "and", "Immunology", "Program,", "Oklahoma", "Medical", "Research", "Foundation,", "825", "NE", "13th", "Street,", "Oklahoma", "City,", "OK", "73104,", "USA", "Correspondence", "should", "be", "addressed", "to", "A.", "Darise", "Farris,", "farrisd@omrf.org", "Received", "10", "December", "2009;", "Accepted", "24", "August", "2010", "Academic", "Editor:", "Kathy", "Triantaﬁlou", "Copyright", "©", "2010", "Christopher", "G.", "Horton", "et", "al.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Toll-like", "receptors", "(TLRs)", "are", "important", "innate", "immune", "receptors", "for", "the", "identiﬁcation", "and", "clearance", "of", "invading", "pathogens.", "Twelve", "TLRs", "that", "recognize", "various", "conserved", "components", "of", "microorganisms", "are", "currently", "known.", "Among", "these,", "the", "endosomal", "TLRs", "3,", "7/8,", "and", "9", "recognize", "dsRNA,", "ssRNA,", "and", "CpG", "DNA,", "respectively.", "Nucleic", "acid-sensing", "TLRs,", "TLR", "7", "in", "particular,", "have", "been", "implicated", "in", "systemic", "lupus", "erythematosus", "(SLE)", "and", "are", "thought", "to", "exacerbate", "disease", "pathology.", "Activation", "of", "these", "TLRs", "results", "in", "the", "production", "of", "inﬂammatory", "cytokines", "and", "type", "I", "interferon.", "Genome-wide", "association", "studies,", "single", "nucleotide", "polymorphism", "analyses", "as", "well", "as", "experimental", "mouse", "models", "have", "provided", "evidence", "of", "TLR", "signaling", "involvement", "in", "SLE", "and", "other", "autoimmune", "diseases.", "Since", "activation", "of", "these", "receptor", "pathways", "promotes", "autoimmune", "phenotypes,", "inhibitory", "drugs", "that", "target", "these", "pathways", "constitute", "important", "new", "therapeutic", "strategies", "for", "the", "treatment", "of", "systemic", "autoimmunity.", "1.", "Introduction", "Toll-like", "receptors", "(TLRs)", "are", "pattern", "recognition", "recep-", "tors", "of", "the", "innate", "immune", "system", "that", "recognize", "speciﬁc", "pathogen-associated", "molecular", "patterns", "(PAMPs)", "conserved", "among", "microorganisms.", "There", "are", "currently", "twelve", "known", "TLRs", "in", "mammals,", "which", "identify", "common", "constituents", "of", "invading", "pathogens", "including", "double-stranded", "and", "single-stranded", "RNA,", "unmethylated", "CpG", "DNA,", "bacterial", "lipopolysaccharide", "(LPS),", "lipoproteins,", "and", "ﬂagellin", "[1].", "Upon", "interaction", "with", "their", "ligands,", "TLRs", "signal", "through", "adapter", "proteins,", "most", "commonly", "Myeloid", "Diﬀerentia-", "tion", "Primary", "Response", "Gene", "88", "(MyD88),", "though", "TLR", "3", "alternatively", "signals", "via", "the", "TIR-Domain", "Containing", "Adaptor", "Inducing", "Interferon-β", "(TRIF)", "adapter", "[2].", "These", "adapters", "recruit", "other", "molecules", "to", "initiate", "signaling", "cascades", "ultimately", "leading", "to", "the", "production", "of", "proinﬂammatory", "cytokines", "and", "type", "I", "IFN", "[3].", "These", "TLR", "responses", "are", "important", "in", "the", "functioning", "of", "both", "the", "innate", "and", "adaptive", "arms", "of", "immunity", "[4,", "5].", "Although", "TLRs", "are", "important", "for", "antimicrobial", "immu-", "nity,", "they", "have", "also", "been", "implicated", "in", "the", "pathogenesis", "of", "autoimmune", "diseases.", "For", "example,", "TLRs", "2", "and", "4", "have", "been", "identiﬁed", "as", "factors", "involved", "in", "the", "onset", "of", "type", "I", "diabetes", "mellitus", "[6–9],", "and", "TLRs", "1–6", "are", "expressed", "by", "rheumatoid", "arthritis", "(RA)", "synovial", "ﬁbroblasts", "and", "are", "thought", "to", "provoke", "joint", "inﬂammation", "in", "RA", "[10,", "11].", "Moreover,", "the", "nucleic", "acid", "binding", "TLRs", "7", "and", "9", "have", "been", "connected", "to", "both", "human", "and", "mouse", "models", "of", "systemic", "lupus", "erythematosus", "(SLE)", "[12–17].", "Because", "of", "these", "links", "between", "TLRs", "and", "autoimmunity,", "a", "great", "deal", "of", "work", "has", "been", "directed", "toward", "understanding", "how", "these", "receptors", "act", "in", "disease", "progression.", "Two", "major", "possibilities", "arise", "in", "describing", "how", "TLRs", "might", "work", "in", "autoimmunity;", "either", "they", "are", "stimulated", "by", "exogenous", "antigens,", "like", "viral", "ssRNA,", "which", "then", "stimulate", "resident", "immune", "cells,", "or", "the", "TLRs", "recognize", "endogenous", "self-antigens", "to", "initiate", "and", "propagate", "inﬂammation", "and", "autoimmunity.", "The", "accumulation", "of", "evidence", "pointing", "towards", "TLRs", "in", "autoimmunity", "has", "opened", "the", "door", "for", "potential", "therapeutic", "interventions", "directed", "towards", "the", "modulation", "of", "Toll-like", "receptors", "and", "their", "signaling", "pathways.", "Since", "TLRs", "are", "normally", "responsive", "to", "microbial", "pathogens,", "there", "has", 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904, 748, 917 ], [ 528, 920, 591, 933 ], [ 594, 920, 616, 933 ], [ 619, 920, 651, 933 ], [ 654, 920, 699, 933 ], [ 701, 920, 712, 933 ], [ 714, 920, 748, 933 ], [ 528, 935, 580, 948 ], [ 585, 935, 610, 948 ], [ 614, 935, 637, 948 ], [ 641, 935, 668, 948 ], [ 673, 935, 682, 948 ], [ 686, 935, 701, 948 ], [ 706, 935, 723, 948 ], [ 727, 935, 748, 948 ], [ 528, 950, 553, 963 ], [ 556, 950, 562, 963 ], [ 565, 950, 577, 963 ], [ 580, 950, 589, 963 ], [ 592, 950, 625, 963 ], [ 627, 950, 666, 963 ], [ 670, 950, 720, 963 ], [ 722, 950, 736, 963 ], [ 739, 950, 748, 963 ], [ 528, 965, 575, 978 ], [ 579, 965, 594, 978 ], [ 597, 965, 615, 978 ], [ 618, 965, 653, 978 ], [ 656, 965, 691, 978 ], [ 695, 965, 718, 978 ], [ 721, 965, 748, 978 ], [ 528, 980, 537, 993 ], [ 541, 980, 556, 993 ], [ 560, 980, 592, 993 ], [ 595, 980, 618, 993 ], [ 621, 980, 648, 993 ], [ 652, 980, 675, 993 ], [ 678, 980, 706, 993 ], [ 709, 980, 748, 993 ], [ 528, 995, 545, 1008 ], [ 547, 995, 592, 1008 ], [ 594, 995, 605, 1008 ], [ 607, 995, 626, 1008 ], [ 627, 995, 636, 1008 ], [ 638, 995, 662, 1008 ], [ 663, 995, 720, 1008 ], [ 721, 995, 731, 1008 ], [ 733, 995, 748, 1008 ], [ 528, 1010, 551, 1023 ], [ 554, 1010, 574, 1023 ], [ 576, 1010, 591, 1023 ], [ 594, 1010, 621, 1023 ], [ 624, 1010, 661, 1023 ], [ 663, 1010, 681, 1023 ], [ 684, 1010, 711, 1023 ], [ 714, 1010, 723, 1023 ], [ 726, 1010, 748, 1023 ] ]	[ "Hematology", "Reports", "2012;", "volume", "4:e3", "Immunophenotyping", "of", "chronic", "B-cell", "neoplasms:", "flow", "cytometry", "versus", "immunohistochemistry", "Afaf", "Abdel-Aziz", "Abdel-Ghafar,", "Manal", "Ahmed", "Shams", "El", "Din", "El", "Telbany,", "Hanan", "Mohamed", "Mahmoud,", "Yasmin", "Nabil", "El-Sakhawy", "Clinical", "and", "Chemical", "Pathology,", "Faculty", "of", "Medicine,", "Ain", "Shams", "University,", "Cairo,", "Egypt", "Abstract", "Morphological", "differentiation", "between", "benign", "and", "malignant", "lymphoproliferative", "disorders", "(LPDs)", "can", "be", "challenging.", "Immunophenotyping", "(IPT)", "by", "either", "technique,", "flow", "cytometry", "or", "immunohistochemistry", "(IHC),", "is", "an", "important", "step", "in", "solving", "such", "difficulty.", "Thirty-five", "newly", "diagnosed", "patients", "with", "chronic", "B-cell", "neo-", "plasms", "(11", "chronic", "lymphocytic", "leukemia,", "22", "non", "Hodgkin", "lymphoma", "and", "2", "hairy", "cell", "leukemia)", "were", "included", "in", "this", "study", "with", "age", "range", "from", "20", "to", "70", "years.", "Monoclonal", "antibodies", "surface", "expression", "using", "lymphoproliferative", "disorders", "panel", "(CD45,", "CD19,", "CD5,", "CD10,", "CD11c,", "CD20,", "CD22,", "CD23,", "CD38,", "CD79b,", "FMC7,", "CD103,", "CD25,", "kappa", "and", "lambda", "light", "chains)", "by", "flow", "cytometry", "was", "done", "on", "bone", "marrow", "samples.", "CD20,", "CD5,", "CD23,", "Bcl-2,", "Bcl-6,", "kappa", "and", "lambda", "light", "chain", "immunostaining", "were", "performed", "on", "fixed", "bone", "marrow", "trephine", "biopsy", "specimen.", "The", "sensitiv-", "ity", "of", "IHC", "was", "81.8%", "in", "chronic", "lymphocytic", "leukemia", "(CLL)", "and", "100%", "in", "non", "Hodgkin", "lym-", "phoma", "(NHL)", "as", "regards", "CD20,", "100%", "in", "both", "groups", "as", "regards", "CD5,", "46%", "in", "CLL", "and", "66.7%", "in", "NHL", "as", "regards", "CD23,", "33.3%", "in", "CLL", "and", "50%", "in", "NHL", "as", "regards", "kappa", "chain,", "20%", "in", "CLL", "and", "33.3%", "in", "NHL", "as", "regards", "lambda", "chain.", "We", "found", "that", "IHC", "and", "flow", "cytometry", "are", "equally", "effective", "in", "diagnosing", "CLL;", "however,", "IHC", "might", "be", "slight-", "ly", "more", "sensitive", "than", "flow", "cytometry", "in", "detect-", "ing", "bone", "marrow", "infiltration", "in", "NHL", "and", "hairy", "cell", "leukemia", "(HCL).", "Introduction", "Distinguishing", "benign", "and", "malignant", "lympho-", "proliferative", "disorders", "(LPDs)", "by", "purely", "morpho-", "logic", "criteria", "can", "be", "difficult.", "Immunophenotypic", "analysis", "is", "a", "useful", "adjunct", "to", "the", "morphologic", "evaluation", "of", "LPDs", "and", "is", "of", "considerable", "assis-", "tance", "in", "resolving", "difficult", "diagnostic", "dilemmas.", "The", "advent", "of", "immunophenotyping", "(IPT)", "of", "sam-", "ples", "from", "patients", "with", "LPDs", "has", "added", "much", "for", "[page", "6]", "proper", "diagnosis", "and", "classification", "and", "for", "better", "understanding", "of", "the", "pathogenetic", "mechanisms", "underlying", "the", "development", "of", "these", "disorders.1", "There", "are", "several", "ways", "for", "testing", "cell", "mark-", "ers,", "such", "as", "flow", "cytometry", "in", "which", "suspensions", "of", "viable", "or", "fixed", "cells", "are", "tested,", "and", "immuno-", "histochemistry", "which", "studies", "cells", "in", "frozen", "or", "paraffin-embedded", "sections", "from", "bone", "marrow", "biopsy", "specimens", "or", "other", "hemopoietic", "tissues.2", "In", "immunohistochemistry", "(IHC),", "morphology", "and", "antigen", "label", "can", "be", "visualized", "simultane-", "ously", "by", "light", "microscopy", "which", "is", "not", "the", "case", "in", "flow", "cytometry,", "enabling", "accurate", "identification", "of", "the", "cells", "or", "region", "of", "interest.3", "It", "is", "considered", "more", "suitable", "in", "the", "detection", "of", "partial", "or", "focal", "involvement", "by", "neoplastic", "cells", "and", "it", "is", "also", "more", "beneficial", "in", "nuclear", "antigen", "assessment.4", "Another", "privilege", "of", "IHC", "is", "the", "long-term", "preser-", "vation", "of", "the", "biological", "specimen", "after", "process-", "ing", "and", "the", "ability", "to", "re-examine", "it", "at", "any", "time.5", "The", "aim", "of", "this", "study", "was", "to", "to", "identify", "the", "diagnostic", "role", "of", "IHC", "in", "chronic", "B-cell", "neo-", "plasms", "using", "a", "selected", "panel", "of", "monoclonal", "antibodies", "and", "to", "compare", "this", "role", "to", "that", "of", "flow", "cytometry.", "Materials", "and", "Methods", "Subjects", "This", "study", "comprised", "35", "newly", "diagnosed", "chronic", "B-cell", "neoplasms", "adult", "patients", "attend-", "ing", "the", "hematological", "unit", "of", "clinical", "pathology", "department,", "Ain", "Shams", "University,", "Cairo,", "Egypt.", "Patients", "were", "recruited", "to", "the", "study", "on", "the", "basis", "of", "clinical,", "laboratory,", "bone", "marrow", "aspirate", "and", "trephine", "biopsy", "findings", "and", "immunophenotypic", "criteria", "of", "chronic", "B-cell", "neoplasms.", "Sometimes", "lymph", "nodes", "biopsy", "results", "were", "provided", "to", "con-", "firm", "the", "diagnosis.", "They", "were", "22", "males", "and", "13", "females", "with", "a", "male", "to", "female", "ratio", "1.7:1.0.", "Their", "ages", "ranged", "from", "20", "to", "70", "years", "old", "with", "mean", "of", "51", "±", "15.2", "years.", "The", "35", "patients", "were", "divided", "into", "3", "groups:", "chronic", "lymphocytic", "leukemia", "(CLL)", "group", "(11", "patients),", "non", "Hodgkin", "lymphoma", "(NHL)", "group", "(22", "patients)", "and", "hairy", "cell", "leukemia", "(HCL)", "group", "(2", "patients).", "The", "22", "NHL", "cases", "comprised", "8", "mantle", "cell", "lymphomas,", "6", "follicular", "lymphomas,", "5", "diffuse", "large", "B-cell", "lymphomas", "and", "3", "Burkitt’s", "lymphomas.", "Patients", "were", "subjected", "to", "clinical", "sheet", "details", "(with", "special", "concern", "to", "organomegaly,", "lymphadenopathy,", "fever", "and", "weight", "loss),", "com-", "plete", "blood", "count", "with", "examination", "of", "peripheral", "blood", "smears", "stained", "with", "Leishman", "stain,", "bone", "marrow", "aspiration,", "bone", "marrow", "trephine", "biop-", "sy,", "flow", "cytometric", "immunophenotyping", "for", "cases", "in", "leukemic", "phase", "using", "lymphoproliferative", "dis-", "orders", "panel", "(CD45,", "CD19,", "CD5,", "CD10,", "CD11c,", "CD20,", "CD22,", "CD23,", "CD38,", "CD79b,", "FMC7,", "CD103,", "CD25,", "kappa", "and", "lambda", "light", "chains).", "CD20,", "CD5,", "CD23,", "Bcl-2,", "Bcl-6,", "kappa", "and", "lambda", "light", "[Hematology", "Reports", "2012;", "4:e3]", "Correspondence:", "Yasmin", "Nabil,", "Clinical", "and", "Chemical", "Pathology,", "Faculty", "of", "Medicine,", "Ain", "Shams", "University,", "El", "Abbassia", "Square,", "Cairo,", "Egypt.", "Tel.", "+20.224.845.802", "-", "Fax:", "+20.224.845.802.", "E-mail:", "yasminnabil@hotmail.com", "Key", "words:", "chronic", "B-", "LPD,", "immunohistochem-", "istry,", "immunophenotyping.", "Received", "for", "publication:", "26", "August", "2011.", "Revision", "received:", "4", "November", "2011.", "Accepted", "for", "publication:", "22", "December", "2011.", "This", "work", "is", "licensed", "under", "a", "Creative", "Commons", "Attribution", "NonCommercial", "3.0", "License", "(CC", "BY-", "NC", "3.0).", "©Copyright", "A.A.A.", "Abdel-Ghafar", "et", "al.,", "2012", "Licensee", "PAGEPress,", "Italy", "Hematology", "Reports", "2012;", "4:e3", "doi:10.4081/hr.2012.e3", "chain", "immunostaining", "was", "performed", "on", "fixed", "bone", "marrow", "trephine", "biopsy", "specimen.", "Specimens", "Two", "milliliters", "peripheral", "blood", "samples", "were", "collected", "in", "a", "sterile", "ethylene-diamine-tetra-", "acetic", "acid", "(EDTA)", "containing", "vaccutainers", "for", "CBC.", "Bone", "marrow", "(BM)", "aspiration", "was", "with-", "drawn;", "the", "first", "few", "drops", "were", "spread", "on", "glass", "slides", "for", "morphological", "examination", "and", "1", "mL", "into", "sterile", "EDTA", "containing", "vacutainers", "for", "IPT.", "For", "IPT", "by", "flow", "cytometry", 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988, 746, 998 ], [ 121, 996, 185, 1012 ], [ 187, 996, 232, 1012 ], [ 236, 999, 279, 1009 ], [ 281, 999, 310, 1009 ], [ 312, 999, 489, 1009 ], [ 492, 999, 516, 1009 ], [ 518, 999, 548, 1009 ], [ 550, 999, 597, 1009 ], [ 599, 999, 615, 1009 ], [ 617, 999, 664, 1009 ], [ 667, 999, 682, 1009 ], [ 685, 999, 736, 1009 ], [ 738, 999, 746, 1009 ], [ 236, 1010, 250, 1020 ], [ 252, 1010, 287, 1020 ], [ 288, 1010, 323, 1020 ], [ 325, 1010, 338, 1020 ], [ 340, 1010, 370, 1020 ], [ 371, 1010, 391, 1020 ], [ 392, 1010, 398, 1020 ], [ 400, 1010, 433, 1020 ], [ 434, 1010, 455, 1020 ] ]	[ "Szatmári", "et", "al.", "Critical", "Care", "2010,", "14:R50", "http://ccforum.com/content/14/2/R50", "R", "E", "S", "E", "A", "R", "C", "H", "Open", "Access", "IRmeseaprcahired", "cerebrovascular", "reactivity", "in", "sepsis-associated", "encephalopathy", "studied", "by", "acetazolamide", "test", "Szilárd", "Szatmári1,", "Tamás", "Végh1,", "Ákos", "Csomós2,", "Judit", "Hallay1,", "István", "Takács3,", "Csilla", "Molnár1", "and", "Béla", "Fülesdi1", "Abstract", "Introduction:", "The", "pathophysiology", "of", "sepsis-associated", "encephalopathy", "(SAE)", "is", "not", "entirely", "clear.", "One", "of", "the", "possible", "underlying", "mechanisms", "is", "the", "alteration", "of", "the", "cerebral", "microvascular", "function", "induced", "by", "the", "systemic", "inflammation.", "The", "aim", "of", "the", "present", "work", "was", "to", "test", "whether", "cerebral", "vasomotor-reactivity", "is", "impaired", "in", "patients", "with", "SAE.", "Methods:", "Patients", "fulfilling", "the", "criteria", "of", "clinical", "sepsis", "and", "showing", "disturbance", "of", "consciousness", "of", "any", "severity", "were", "included", "(n", "=", "14).", "Non-septic", "persons", "whithout", "previous", "diseases", "affecting", "cerebral", "vasoreactivity", "served", "as", "controls", "(n", "=", "20).", "Transcranial", "Doppler", "blood", "flow", "velocities", "were", "measured", "at", "rest", "and", "at", "5,", "10,", "15", "and", "20", "minutes", "after", "intravenous", "administration", "of", "15", "mg/kgBW", "acetazolamide.", "The", "time", "course", "of", "the", "acetazolamide", "effect", "on", "cerebral", "blood", "flow", "velocity", "(cerebrovascular", "reactivity,", "CVR)", "and", "the", "maximal", "vasodilatory", "effect", "of", "acetazolemide", "(cerebrovascular", "reserve", "capacity,", "CRC)", "were", "compared", "among", "the", "groups.", "Results:", "Absolute", "blood", "flow", "velocities", "after", "adminsitration", "of", "the", "vasodilator", "drug", "were", "higher", "among", "control", "subjects", "than", "in", "SAE.", "Assessment", "of", "the", "time-course", "of", "the", "vasomotor", "reaction", "showed", "that", "patients", "with", "SAE", "reacted", "slower", "to", "the", "vasodilatory", "stimulus", "than", "control", "persons.", "When", "assessing", "the", "maximal", "vasodilatory", "ability", "of", "the", "cerebral", "arterioles", "to", "acetazolamide", "during", "vasomotor", "testing,", "we", "found", "that", "patients", "with", "SAE", "reacted", "to", "a", "lesser", "extent", "to", "the", "drug", "than", "did", "control", "subjects", "(CRC", "controls:46.2", "±", "15.9%,", "CRC", "SAE:", "31,5", "±", "15.8%,", "P", "<", "0.01).", "Conclusions:", "We", "conclude", "that", "cerebrovascular", "reactivity", "is", "impaired", "in", "patients", "with", "SAE.", "The", "clinical", "significance", "of", "this", "pathophysiological", "finding", "has", "to", "be", "assessed", "in", "further", "studies.", "Introduction", "Sepsis-associated", "encephalopathy", "is", "defined", "as", "a", "diffuse", "cerebral", "dysfunction", "induced", "by", "the", "systemic", "response", "to", "the", "infection", "without", "clinical", "or", "laboratory", "evidence", "of", "direct", "infectious", "involvement", "of", "the", "central", "nervous", "sys-", "tem", "[1].", "Previous", "clinical", "observations", "have", "shown", "that", "the", "brain", "is", "often", "the", "first", "organ", "to", "be", "affected", "by", "sepsis,", "preceeding", "the", "clinical", "symptoms", "of", "other", "organ", "manifes-", "tations.", "According", "to", "the", "studies", "of", "Wilson", "and", "col-", "leagues", "and", "Young", "and", "colleagues,", "electroencephalogram", "(EEG)", "may", "be", "abnormal", "in", "87%", "of", "patients", "with", "bacteri-", "emia.", "They", "diagnosed", "70%", "with", "disturbance", "of", "con-", "sciousness", "of", "differing", "severity", "ranging", "from", "somnolence", "", "Correspondence:", "fulesdi@dote.hu", "1", "Department", "of", "Anesthesiology", "and", "Intensive", "Care,", "University", "of", "Debrecen,", "Health", "and", "Medical", "Science", "Center,", "H-4032.", "Debrecen,", "Nagyerdei", "krt.", "98,", "Hungary", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "to", "coma", "[1-3].", "Ebersoldt", "and", "colleagues,", "reviewing", "sepsis-", "associated", "delirium,", "reported", "on", "a", "prevalence", "ranging", "from", "9", "to", "71%", "[4].", "The", "exact", "pathomechanism", "involved", "is", "not", "yet", "fully", "understood.", "It", "is", "believed", "that", "microcircula-", "tory", "alterations,", "disturbance", "of", "cerebral", "autoregulation,", "damage", "of", "the", "blood-brain", "barrier,", "branched", "chain/aro-", "matic", "amino", "acid", "inbalance", "and", "the", "direct", "effect", "of", "the", "inflammatory", "process", "(e.g.", "free", "radicals,", "oxydative", "stress,", "cytokines,", "excitotoxicity", "apoptosis)", "on", "glial", "cells", "may", "play", "a", "decisive", "role.", "Sepsis-related", "encephalopathy", "is", "most", "likely", "to", "be", "a", "multifactorially", "determined", "syndrome", "[5].", "When", "assessing", "cerebral", "microvascular", "contributing", "factors,", "in", "previous", "human", "investigations", "Matta", "and", "Stow", "[6]", "found", "cerebral", "autoregulation", "and", "carbon", "dioxide", "reactivity", "to", "be", "normal", "in", "patients", "with", "sepsis,", "whereas", "Terborg", "and", "colleagues", "reported", "on", "severely", "disturbed", "vasomotor", "reactivity", "(VMR)", "[7].", "In", "the", "past", "two", "decades,", "©", "2010", "Szatmári", "et", "al.;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "BioMed", "Central", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 16, 16, 16, 16, 16, 16, 16, 16, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 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310, 1009, 324, 1019 ], [ 326, 1009, 360, 1019 ], [ 362, 1009, 396, 1019 ], [ 399, 1009, 412, 1019 ], [ 415, 1009, 443, 1019 ], [ 446, 1009, 465, 1019 ], [ 467, 1009, 473, 1019 ], [ 476, 1009, 508, 1019 ], [ 510, 1009, 530, 1019 ] ]	[ "Lünsdorf", "et", "al.", "Microbial", "Cell", "Factories", "2011,", "10:48", "http://www.microbialcellfactories.com/content/10/1/48", "R", "E", "S", "E", "A", "R", "C", "H", "Open", "Access", "Virus-like", "particle", "production", "with", "yeast:", "ultrastructural", "and", "immunocytochemical", "insights", "into", "Pichia", "pastoris", "producing", "high", "levels", "of", "the", "Hepatitis", "B", "surface", "antigen", "Heinrich", "Lünsdorf1,", "Chandrasekhar", "Gurramkonda2,3,", "Ahmad", "Adnan2,4,", "Navin", "Khanna3", "and", "Ursula", "Rinas2,5", "Abstract", "Background:", "A", "protective", "immune", "response", "against", "Hepatitis", "B", "infection", "can", "be", "obtained", "through", "the", "administration", "of", "a", "single", "viral", "polypeptide,", "the", "Hepatitis", "B", "surface", "antigen", "(HBsAg).", "Thus,", "the", "Hepatitis", "B", "vaccine", "is", "generated", "through", "the", "utilization", "of", "recombinant", "DNA", "technology,", "preferentially", "by", "using", "yeast-based", "expression", "systems.", "However,", "the", "polypeptide", "needs", "to", "assemble", "into", "spherical", "particles,", "so-called", "virus-like", "particles", "(VLPs),", "to", "elicit", "the", "required", "protective", "immune", "response.", "So", "far,", "no", "clear", "evidence", "has", "been", "presented", "showing", "whether", "HBsAg", "assembles", "in", "vivo", "inside", "the", "yeast", "cell", "into", "VLPs", "or", "later", "in", "vitro", "during", "down-stream", "processing", "and", "purification.", "Results:", "High", "level", "production", "of", "HBsAg", "was", "carried", "out", "with", "recombinant", "Pichia", "pastoris", "using", "the", "methanol", "inducible", "AOX1", "expression", "system.", "The", "recombinant", "vaccine", "was", "isolated", "in", "form", "of", "VLPs", "after", "several", "down-", "stream", "steps", "from", "detergent-treated", "cell", "lysates.", "Search", "for", "the", "intracellular", "localization", "of", "the", "antigen", "using", "electron", "microscopic", "studies", "in", "combination", "with", "immunogold", "labeling", "revealed", "the", "presence", "of", "HBsAg", "in", "an", "extended", "endoplasmic", "reticulum", "where", "it", "was", "found", "to", "assemble", "into", "defined", "multi-layered,", "lamellar", "structures.", "The", "distance", "between", "two", "layers", "was", "determined", "as", "~6", "nm", "indicating", "that", "these", "lamellas", "represent", "monolayers", "of", "well-ordered", "HBsAg", "subunits.", "We", "did", "not", "find", "any", "evidence", "for", "the", "presence", "of", "VLPs", "within", "the", "endoplasmic", "reticulum", "or", "other", "parts", "of", "the", "yeast", "cell.", "Conclusions:", "It", "is", "concluded", "that", "high", "level", "production", "and", "intrinsic", "slow", "HBsAg", "VLP", "assembly", "kinetics", "are", "leading", "to", "retention", "and", "accumulation", "of", "the", "antigen", "in", "the", "endoplasmic", "reticulum", "where", "it", "assembles", "at", "least", "partly", "into", "defined", "lamellar", "structures.", "Further", "transport", "of", "HBsAg", "to", "the", "Golgi", "apparatus", "is", "impaired", "thus", "leading", "to", "secretory", "pathway", "disfunction", "and", "the", "formation", "of", "an", "extended", "endoplasmic", "reticulum", "which", "bulges", "into", "irregular", "cloud-", "shaped", "formations.", "As", "VLPs", "were", "not", "found", "within", "the", "cells", "it", "is", "concluded", "that", "the", "VLP", "assembly", "process", "must", "take", "place", "during", "down-stream", "processing", "after", "detergent-mediated", "disassembly", "of", "HBsAg", "lamellas", "and", "subsequent", "reassembly", "of", "HBsAg", "into", "spherical", "VLPs.", "Background", "Unlike", "many", "other", "vaccines", "against", "virus-caused", "diseases,", "a", "single", "viral", "polypeptide", "is", "sufficient", "to", "elicit", "a", "protecting", "immune", "response", "against", "Hepatitis", "B", "infection", "[1].", "However,", "the", "polypeptide", "needs", "to", "assemble", "into", "spherical", "particles,", "so-called", "virus-like", "particles", "(VLPs),", "", "Correspondence:", "Ursula.Rinas@helmholtz-hzi.de", "2Helmholtz", "Centre", "for", "Infection", "Research", "(SB),", "Braunschweig,", "Germany", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "to", "initiate", "the", "required", "protective", "immune", "response", "[2].", "In", "HBV", "infected", "individuals,", "viral", "surface", "proteins", "are", "produced", "in", "large", "excess", "in", "liver", "cells", "over", "the", "amount", "needed", "for", "virus", "assembly", "and", "are", "secreted", "as", "a", "mixture", "of", "spherical", "particles", "and", "tubular", "forms.", "Thus,", "in", "the", "serum", "of", "HBV", "infected", "patients,", "intact", "viruses", "(Dane", "particles)", "but", "also", "“empty”", "spherical", "particles", "and", "tubu-", "lar", "forms", "consisting", "of", "the", "surface", "proteins", "of", "the", "Hepa-", "titis", "B", "virus", "are", "found", "[3,4].", "©", "2011", "Lünsdorf", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 16, 16, 16, 16, 16, 16, 16, 16, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 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769, 1065 ], [ 599, 1069, 624, 1079 ], [ 627, 1069, 660, 1079 ], [ 662, 1069, 676, 1079 ], [ 678, 1069, 690, 1079 ], [ 692, 1069, 723, 1079 ], [ 726, 1069, 770, 1079 ] ]	[ "BMC", "Medical", "Education", "Research", "article", "An", "interactive", "course", "to", "enhance", "self-efficacy", "of", "family", "practitioners", "to", "treat", "obesity", "Sara", "Katz1,", "Amiel", "Feigenbaum2,", "Shmuel", "Pasternak3", "and", "Shlomo", "Vinker2", "Address:", "1Technion", "–", "Israel", "Institute", "of", "Technology", "–", "Faculty", "of", "Medicine,", "Haifa,", "Israel,", "2Department", "of", "Family", "Medicine,", "Sackler", "School", "of", "Medicine,", "Tel", "Aviv", "University,", "Israel", "and", "3General", "Health", "Services,", "Holon,", "Israel", "Email:", "Sara", "Katz", "-", "sara1@tx.technion.ac.il;", "Amiel", "Feigenbaum", "-", "amielfe@netvision.net.il;", "Shmuel", "Pasternak", "-", "amielfe@netvision.net.il;", "Shlomo", "Vinker", "-", "vinker01@zahav.net.il", "*", "Corresponding", "author", "BioMed", "Central", "Open", "Access", "Published:", "29", "January", "2005", "BMC", "Medical", "Education", "2005,", "5:4", "doi:10.1186/1472-6920-5-4", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1472-6920/5/4", "Received:", "05", "July", "2004", "Accepted:", "29", "January", "2005", "©", "2005", "Katz", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "Physicians'", "awareness", "of", "their", "important", "role", "in", "defusing", "the", "obesity", "epidemic", "has", "increased.", "However,", "the", "number", "of", "family", "practitioners", "who", "treat", "obesity", "problems", "continues", "to", "be", "low.", "Self-efficacy", "refers", "to", "the", "belief", "in", "one's", "ability", "to", "organize", "and", "execute", "the", "courses", "of", "action", "required", "to", "produce", "given", "attainments.", "Thus,", "practitioners", "who", "judge", "themselves", "incapable", "of", "managing", "obesity", "do", "not", "even", "try.", "We", "hypothesized", "that", "practitioners'", "self-efficacy", "and", "motivation", "would", "be", "enhanced", "as", "a", "result", "of", "participating", "in", "an", "interactive", "course", "designed", "to", "enrich", "their", "knowledge", "of", "obesity", "management.", "Methods:", "Twenty-nine", "family", "practitioners", "participated", "in", "the", "course,", "which", "was", "accompanied", "by", "qualitative", "interviews.", "The", "difference", "between", "the", "physicians'", "pre-course", "and", "post-course", "appraisals", "was", "tested", "by", "paired", "t-test.", "The", "interviews", "were", "analyzed", "by", "qualitative", "methods.", "Results:", "Post-course", "efficacy", "appraisals", "were", "significantly", "higher", "than", "pre-course", "appraisals", "(p", "<", "0.0005).", "A", "deeper", "insight", "on", "the", "practitioners'", "self-efficacy", "processes", "was", "gained", "through", "reflection", "of", "the", "practitioners", "on", "their", "self-efficacy", "during", "the", "interviews.", "Conclusions:", "Up-to-date", "information", "and", "workshops", "where", "skills,", "attitudes", "and", "social", "support", "were", "addressed", "were", "important", "in", "making", "the", "program", "effective.", "Background", "Obesity", "is", "becoming", "increasingly", "common", "and", "is", "recog-", "nized", "as", "a", "major", "public", "health", "problem", "worldwide", "[1-3].", "In", "the", "UK,", "the", "overweight", "and", "obese", "population", "increased", "by", "almost", "15%", "between", "1980", "and", "1992.", "Similar", "increases", "have", "been", "noted", "in", "many", "countries,", "including", "the", "USA", "[4],", "Sweden", "[5]", "and", "the", "Netherlands", "[6].", "In", "Israel,", "55%", "of", "females", "and", "58%", "of", "males", "aged", "25–64", "were", "reported", "to", "be", "overweight", "or", "obese", "(Body", "Mass", "Index", ">25", "kg/m2)", "in", "a", "Mabat", "survey", "[7]", "in", "2000.", "Guidelines", "published", "in", "1996", "for", "the", "management", "of", "obesity", "recommended", "setting", "a", "modest", "weight", "loss", "and", "weight", "maintenance,", "rather", "than", "a", "targeted", "ideal", "weight,", "as", "goals", "[8].", "Lately,", "pharmacological", "therapies", "have", "been", "proposed", "as", "adjuncts", "to", "diet", "and", "lifestyle", "changes", "to", "improve", "long-term", "weight", "loss", "[9].", "The", "World", "Health", "Organization", "declared", "obesity", "an", "epidemic", "in", "developed", "countries.", "Awareness", "of", "physicians", "of", 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[ 593, 925, 639, 939 ], [ 646, 925, 697, 939 ], [ 703, 925, 772, 939 ], [ 436, 941, 456, 955 ], [ 463, 941, 512, 955 ], [ 518, 941, 598, 955 ], [ 605, 941, 657, 955 ], [ 663, 941, 771, 955 ], [ 436, 956, 460, 971 ], [ 465, 956, 550, 971 ], [ 556, 956, 602, 971 ], [ 607, 956, 620, 971 ], [ 625, 956, 645, 971 ], [ 650, 956, 710, 971 ], [ 715, 956, 772, 971 ], [ 436, 971, 474, 985 ], [ 489, 971, 512, 985 ], [ 525, 971, 538, 985 ], [ 552, 971, 655, 985 ], [ 668, 971, 682, 985 ], [ 695, 971, 771, 985 ], [ 436, 986, 506, 1000 ], [ 510, 986, 522, 1000 ], [ 525, 986, 545, 1000 ], [ 548, 986, 581, 1000 ], [ 584, 986, 622, 1000 ], [ 625, 986, 638, 1000 ], [ 641, 986, 716, 1000 ] ]	[ "Int.", "J.", "Biol.", "Sci.", "2006,", "2", "Research", "paper", "32", "International", "Journal", "of", "Biological", "Sciences", "ISSN", "1449-2288", "www.biolsci.org", "2006", "2(2):32-37", "©2006", "Ivyspring", "International", "Publisher.", "All", "rights", "reserved", "Metaphylogeny", "of", "82", "gene", "families", "sheds", "a", "new", "light", "on", "chordate", "evolution", "Alexandre", "Vienne", "and", "Pierre", "Pontarotti", "Phylogenomics", "Laboratory,", "EA", "3781", "Evolution", "Biologique,", "Université", "de", "Provence,", "13331", "MARSEILLE", "CEDEX", "03,", "FRANCE", "Corresponding", "to:", "Alexandre", "Vienne,", "Phylogenomics", "Laboratory,", "EA", "3781", "Evolution", "Biologique,", "Place", "V.", "HUGO,", "Université", "de", "Provence,", "13331", "MARSEILLE", "CEDEX", "03,", "France.", "Email:", "avienne@up.univ-mrs.fr.", "Phone:", "(33)", "4", "91", "10", "64", "89", "Received:", "2006.01.15;", "Accepted:", "2006.03.31;", "Published:", "2006.04.10", "Achieving", "a", "better", "comprehension", "of", "the", "evolution", "of", "species", "has", "always", "been", "an", "important", "matter", "for", "evolutionary", "biologists.", "The", "deuterostome", "phylogeny", "has", "been", "described", "for", "many", "years,", "and", "three", "phyla", "are", "distinguishable:", "Echinodermata", "(including", "sea", "stars,", "sea", "urchins,", "etc…),", "Hemichordata", "(including", "acorn", "worms", "and", "pterobranchs),", "and", "Chordata", "(including", "urochordates,", "cephalochordates", "and", "extant", "vertebrates).", "Inside", "the", "Chordata", "phylum,", "the", "position", "of", "vertebrate", "species", "is", "quite", "unanimously", "accepted.", "Nonetheless,", "the", "position", "of", "urochordates", "in", "regard", "with", "vertebrates", "is", "still", "the", "subject", "of", "debate,", "and", "has", "even", "been", "suggested", "by", "some", "authors", "to", "be", "a", "separate", "phylum", "from", "cephalochordates", "and", "vertebrates.", "It", "was", "also", "the", "case", "for", "agnathans", "species", "–myxines", "and", "hagfish–", "for", "which", "phylogenetic", "evidence", "was", "recently", "given", "for", "a", "controversial", "monophyly.", "This", "raises", "the", "following", "question:", "which", "one", "of", "the", "cephalochordata", "or", "urochordata", "is", "the", "sister", "group", "of", "vertebrates", "and", "what", "are", "their", "relationships?", "In", "the", "present", "work,", "we", "analyzed", "82", "protein", "families", "presenting", "homologs", "between", "urochordata", "and", "other", "deuterostomes", "and", "focused", "on", "two", "points:", "1)", "testing", "accurately", "the", "position", "of", "urochordata", "and", "cephalochordata", "phyla", "in", "regard", "with", "vertebrates", "as", "well", "as", "chordates", "monophyly,", "2)", "performing", "an", "estimation", "of", "the", "rate", "of", "gene", "loss", "in", "the", "Ciona", "intestinalis", "genome.", "We", "showed", "that", "the", "urochordate", "phyla", "is", "the", "vertebrate", "sister", "group", "and", "that", "gene", "loss", "played", "a", "major", "role", "in", "structuring", "the", "urochordate", "genome.", "Keywords:", "chordate", "monophyly,", "evolution,", "cephalochordate,", "urochordate,", "gene", "loss", "1.", "INTRODUCTION", "The", "positioning", "of", "species", "among", "the", "deuterostome", "phylum", "and", "the", "evolution", "of", "metazoans", "has", "fascinated", "researchers", "for", "decades,", "and", "has", "been", "the", "purpose", "of", "strong", "debates.", "Using", "for", "comparisons", "the", "morphological", "as", "well", "as", "the", "molecular", "data", "that", "are", "nowadays", "abundant", "and", "available", "through", "large", "number", "of", "databases,", "they", "all", "tried", "to", "describe", "as", "accurately", "as", "possible", "the", "reality", "of", "species", "evolutionary", "history.", "Inside", "deuterostomians,", "three", "major", "groups", "are", "quiet", "unanimously", "defined", "(Figure", "1):", "Echinodermata", "(including", "starfish,", "sea", "urchins,", "etc…),", "Hemichordata", "(including", "acorn", "worms", "and", "pterobranchs),", "and", "Chordata", "(including", "three", "subphyla:", "urochordates", "–composed", "of", "more", "than", "3.000", "species—,", "cephalochordates", "–composed", "of", "approximately", "29", "species—,", "and", "the", "extant", "vertebrates", "including", "hagfishes,", "lampreys,", "and", "jawed", "vertebrates", "–composed", "of", "approximately", "53.000", "species—)", "[1].", "The", "analysis", "of", "anatomical", "data", "has", "led", "to", "several", "hypotheses", "regarding", "deuterostome", "phylogeny", "[2]", "and", "the", "relationships", "inter", "and", "intra-", "groups", "are", "still", "subject", "to", "debates.", "One", "of", "the", "specificity", "of", "chordates", "is", "their", "morphological", "synapomorphic.", "These", "particularities", "shared", "between", "urochordates,", "cephalochordates", "and", "vertebrates", "are", "quiet", "well", "known–as", "for", "example", "the", "notochord,", "the", "dorsal", "hollow", "nerve", "cord,", "the", "tail", "extending", "behind", "the", "visceral", "cavity,", "the", "thyroid", "gland", "(endostyle),", "and", "some", "other", "features", "[3].", "Nonetheless,", "controversy", "is", "common", "among", "evolutionary", "biologists", "regarding", "the", "kind", "of", "data", "analysed,", "those", "data", "being", "tested", "as", "nucleic", "or", "protein", "sequences,", "considering", "them", "as", "fast", "or", "slow-evolving", "genes", "or", "parts", "of", "genes", "[4].", "These", "latter", "will", "give", "more", "or", "less", "phylogenetic", "signals", "from", "the", "data", "sets", "for", "recent", "or", "deeper", "events", "during", "evolution.", "Recent", "studies", "have", "led", "to", "the", "re-examination", "of", "some", "species", "relationships,", "and", "echinoderms", "+", "hemichordates", "were", "shown", "to", "constitute", "a", "monophyletic", "group.", "More", "recently,", "relationships", "of", "agnathans", "species", "–myxine", "and", "hagfish—were", "revisited", "[5],", "and", "this", "example", "is", "the", "best", "illustration", "of", "discussions.", "Indeed,", "strong", "support", "was", "given", "for", "the", "monophyly", "of", "jawless", "vertebrates", "which", "are", "the", "most", "basal", "group", "of", "vertebrates,", "by", "the", "analysis", "of", "35", "protein", "coding", "gene", "families", "after", "years", "of", "controversial", "debates.", "The", "concatenation", "of", "the", "different", "topologies", "obtained", "led", "to", "the", "assessment", "of", "a", "monophyletic", "group.", "This", "work", "can", "be", "extended", "to", "the", "present", "purpose", "concerning", "the", "existing", "relationships", "between", "cephalochordates", "and", "urochordates,", "leading", "to", "the", "following", "question:", "which", "one", "of", "cephalochordata", "or", "urochordata", "correspond", "to", "the", "sister", "group", "of", "vertebrates?" ]	[ 0, 0, 0, 0, 0, 0, 16, 16, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 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"Studies", "and", "Gerontology,", "University", "of", "Waterloo,", "Waterloo,", "ON,", "Canada", "Edited", "by:", "Elysia", "Davis,", "University", "of", "California", "at", "Irvine,", "USA", "Reviewed", "by:", "Nadine", "Fink,", "Harvard", "Medical", "School,", "USA", "Kerry-Ann", "Grant,", "Macquarie", "University,", "Australia", "Correspondence:", "Steven", "E.", "Mock,", "Department", "of", "Recreation", "and", "Leisure", "Studies,", "Department", "of", "Health", "Studies", "and", "Gerontology,", "University", "of", "Waterloo,", "200", "University", "Avenue", "West,", "Waterloo,", "ON,", "Canada", "N2L", "3G1.", "e-mail:", "smock@uwaterloo.ca", "Experiences", "of", "traumatic", "events", "in", "childhood", "have", "been", "shown", "to", "have", "long-term", "consequences", "for", "health", "in", "adulthood.", "With", "data", "from", "the", "2005", "Canadian", "Community", "Health", "Survey", "we", "take", "a", "life", "course", "perspective", "of", "cumulative", "disadvantage", "and", "examine", "the", "potential", "role", "of", "mental", "health", "and", "socioeconomic", "status", "in", "adulthood", "as", "multiple", "mediators", "of", "the", "link", "between", "childhood", "trauma", "and", "chronic", "illness", "in", "adulthood.", "Mental", "health", "and", "socioeconomic", "status", "are", "also", "tested", "as", "buffers", "against", "the", "typically", "adverse", "consequences", "of", "childhood", "trauma.", "The", "results", "suggest", "mental", "health", "and", "socioeconomic", "status", "partially", "explain", "the", "association", "of", "childhood", "trauma", "with", "chronic", "illness", "in", "adulthood,", "with", "mental", "health", "showing", "a", "stronger", "effect.", "In", "addition,", "an", "analysis", "of", "the", "interactions", "suggested", "higher", "socioeconomic", "status", "is", "a", "potential", "protective", "factor", "for", "those", "with", "a", "history", "of", "trauma.", "Results", "also", "suggest", "cumulative", "disadvantage", "following", "trauma", "may", "lead", "to", "chronic", "illness", "and", "suggest", "the", "need", "for", "public", "health", "expenditures", "on", "resources", "such", "as", "counseling", "and", "income", "supports", "to", "prevent", "or", "reduce", "psychological", "harm", "and", "chronic", "illness", "resulting", "from", "traumatic", "events.", "Keywords:", "childhood", "trauma,", "chronic", "illness,", "mental", "health,", "socioeconomic", "status,", "cumulative", "disadvantage", "IIcudortnno", "The", "experience", "of", "traumatic", "events", "in", "childhood", "has", "consequences", "for", "health", "in", "adulthood.", "A", "broad", "range", "of", "traumatic", "events", "expe-", "rienced", "in", "childhood", "including", "physical", "abuse,", "sexual", "abuse,", "pro-", "longed", "hospitalization,", "and", "family", "instability", "such", "as", "parental", "unemployment", "or", "substance", "abuse", "have", "been", "linked", "to", "chronic", "illness", "in", "adulthood", "stemming", "from", "poor", "immune", "functioning", "or", "poor", "cardiovascular", "health", "(Springer", "et", "al.,", "2003;", "Mulvihill,", "2005;", "O’Rand", "and", "Hamil-Luker,", "2005;", "Wickrama", "et", "al.,", "2005).", "According", "to", "a", "life", "course", "perspective,", "there", "are", "multiple", "potential", "pathways", "that", "may", "contribute", "to", "a", "process", "of", "cumulative", "disadvantage", "fol-", "lowing", "traumatic", "childhood", "events", "(Dannefer,", "2003;", "Pearlin", "et", "al.,", "2005).", "One", "potential", "pathway", "is", "through", "the", "negative", "mental", "health", "consequences", "in", "adulthood", "of", "trauma", "experienced", "in", "childhood", "(Turner", "and", "Lloyd,", "1995;", "Paolucci", "et", "al.,", "2001;", "Briere", "and", "Jordan,", "2009).", "Recent", "work", "also", "suggests", "that", "there", "are", "socioeconomic", "dis-", "advantages", "in", "adulthood", "resulting", "from", "trauma", "early", "in", "life", "that", "may", "contribute", "to", "chronic", "illness", "(Hyman,", "2000;", "Zielinski,", "2009;", "Currie", "and", "Spatz", "Widom,", "2010).", "In", "addition", "to", "being", "potential", "explanatory", "factors", "for", "the", "link", "between", "childhood", "trauma", "and", "chronic", "illness,", "adult", "mental", "health", "and", "socioeconomic", "status", "(SES)", "are", "plausible", "buffers", "of", "the", "negative", "effects", "of", "trauma", "on", "health", "(Melchior", "et", "al.,", "2007;", "Wethington", "et", "al.,", "2008).", "A", "traumatic", "experience", "is", "one", "that", "threatens", "death", "or", "injury", "to", "self", "or", "others", "and", "elicits", "intense", "feelings", "of", "fear,", "helplessness,", "or", "horror", "(American", "Psychiatric", "Association,", "2000).", "Examples", "of", "traumatic", "events", "include", "physical", "abuse,", "sexual", "abuse,", "combat,", "wit-", "nessing", "violence", "or", "disaster,", "or", "the", "sudden", "death", "of", "a", "loved", "one.", "Over", "a", "lifetime", "most", "people", "experience", "at", "least", "one", "potentially", "traumatic", "event", "(Klein", "and", "Alexander,", "2009).", "In", "a", "community-level", "study", "in", "the", "United", "States,", "it", "was", "found", "that", "74.2%", "of", "women", "and", "81.3%", "of", "men", "reported", "experiencing", "at", "least", "one", "traumatic", "event", "in", "their", "lifetime", "(Stein", "et", "al.,", "1997).", "A", "community", "study", "(Breslau,", "2009;", "Breslau", "et", "al.,", "1999)", "reported", "similar", "findings,", "78.1%", "for", "women", "and", "92.2%", "among", "men,", "for", "lifetime", "prevalence", "of", "exposure", "to", "traumatic", "events.", "Results", "from", "a", "national", "study", "in", "the", "United", "States", "indicate", "overall", "rates", "of", "child", "maltreatment", "at", "13.8%", "(8.0%", "having", "experi-", "enced", "sexual", "abuse,", "6.7%", "physical", "abuse,", "2.9%", "severe", "neglect,", "and", "3.2%", "reporting", "multiple", "forms", "of", "child", "maltreatment", "experienced;", "Zielinski,", "2009).", "Goodwin", "et", "al.", "(2003)", "reported", "physical", "abuse", "by", "parents", "at", "a", "rate", "of", "15.8%", "and", "similar", "rates", "have", "been", "reported", "in", "Canadian", "research", "(MacMillan", "et", "al.,", "1997).", "In", "a", "community-level", "study", "of", "traumatic", "experiences", "in", "childhood", "(Turner", "and", "Lloyd,", "1995)", "19.5%", "reported", "major", "illness", "or", "accident,", "9.6%", "parental", "divorce,", "17.7%", "repeating", "a", "year", "of", "school,", "9.4%", "parent", "unemploy-", "ment,", "26.5%", "experience", "of", "a", "significant", "scare,", "2.6%", "being", "sent", "away", "from", "home,", "8.2%", "parent", "alcohol", "or", "drug", "use,", "and", "3.8%", "physical", "abuse.", "The", "experience", "of", "traumatic", "events", "in", "childhood", "is", "associated", "with", "long-term", "health", "effects.", "In", "a", "study", "of", "the", "impact", "of", "child-", "hood", "trauma", "on", "health", "in", "adulthood,", "those", "who", "reported", "child-", "hood", "psychological", "or", "physical", "victimization", "had", "worse", "health", "than", "those", "who", "did", "not", "and", "also", "experienced", "significantly", "more", "decline", "in", "health", "over", "a", "10-year", "period", "in", "adulthood", "(Greenfield", "and", "Marks,", "2009).", "This", "is", "consistent", "with", "research", "that", "shows", "the", "negative", "impact", "of", "childhood", "adversity", "on", "cardiovascular", "health", "(O’Rand", "and", "Hamil-Luker,", "2005)", "and", "recent", "reviews", "documenting", "a", "consistent", "association", "between", "childhood", "trauma", "and", "negative", "health", "consequences", "in", "adulthood", "including", "pain,", "unexplained", "somatic", "symptoms,", "stress-related", "illnesses,", "and", "illnesses", "related", "to", 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", "The ", "results ", "were ", "compared ", "with ", "those ", "of ", "other ", "studies.", "Results ", "Among", " ", "the ", "index, ", "middle, ", "ring, ", "and ", "little ", "fingers ", "were ", "injured ", "in ", "9, ", "17, ", "16, ", "and ", "13 ", "fingers, ", "respectively. ", "The ", "injury ", "levels ", "varied ", "from ", "zone ", "1 ", "to ", "5. ", "Of ", "the ", "55 ", "digits ", "in ", "our ", "study, ", "there ", "were ", "26 ", "(47%) ", "isolated ", "flexor ", "digitorum ", "profundus ", "(FDP) ", "injuries ", "and ", "29 ", "(53%) ", "combined ", "FDP ", "and ", "with ", "flexor ", "digitorum ", "superficialis ", "injuries. ", "Pulley ", "repair ", "was ", "also ", "conducted. ", "Concomitant ", "injuries ", "of ", "blood ", "vessels ", "and ", "nerves ", "were ", "found ", "in ", "17 ", "patients ", "(23 ", "fingers); ", "nerve ", "injuries ", "occurred ", "in ", "5 ", "patients ", "(10 ", "fingers). ", "Two ", "patients ", "had ", "ruptures ", "(3.6%), ", "and ", "one ", "patient ", "had ", "two ", "adhesions ", "(3.6%). ", "Using ", "the ", "original ", "Strickland ", "criteria, ", "all ", "the ", "patients ", "were ", "assessed ", "to ", "be ", "excellent ", "or ", "good. ", "Also, ", "fibrosis ", "and ", "long-term ", "foreign ", "body ", "tissue ", "reactions ", "such ", "as ", "stitch ", "granuloma ", "were ", "less ", "likely ", "occurred ", "in ", "our ", "study. ", "Compared ", "to ", "the ", "Cullen’s ", "report ", "that ", "used ", "nonabsorbable ", "sutures, ", "there ", "was ", "no ", "significant ", "difference ", "in ", "the ", "rupture ", "or ", "adhesion ", "rates.", "Conclusions ", "Therefore,", " ", "this ", "study ", "suggests ", "that ", "appropriate ", "absorbable ", "core ", "sutures ", "can ", "be ", "used ", "safely ", "for ", "flexor ", "tendon ", "repairs.", "Keywords ", "Hand", " ", "/ ", "Polydioxanone ", "/ ", "Rupture ", "/ ", "Tendon ", "Injuries", "Received:", "8", "Mar", "2012", "•", "Revised:", "23", "May", "2012", "•", "Accepted:", "23", "May", "2012", "pISSN: 2234-6163 ", "• eISSN: 2234-6171 ", "• http://dx.doi.org/10.5999/aps.2012.39.4.397 ", "• Arch Plast Surg 2012;39:397-403", "Correspondence:", "Dong", "Chul", "Lee", "Department", "of", "Plastic", "and", "Reconstructive", "Surgery,", "Kwang-Myung", "Sung-Ae", "General", "Hospital,", "36", "Digital-ro,", "Gwangmyeong", "423-711,", "Korea", "Tel:", "+82-2-2680-7238", "Fax:", "+82-2-2615-7218", "E-mail:", "ophand@gmail.com", "O", "r", "i", "g", "i", "n", "a", "l", "A", "r", "t", "i", "c", "l", "e", "This", "article", "was", "presented", "at", "the", "Research", "and", "Reconstructive", "Forum", "on", "May", "12-13,", "2011", "in", "Daejeon,", "Korea.", "No", "potential", "conflict", "of", "interest", "relevant", "to", "this", "article", "was", "reported", "INTRODUCTION", "been", "performed", "since", "the", "beginning", "of", "the", "20th", "century.", "Since", "Kleinert", "et", "al.", "[1]", "conducted", "primary", "repair", "for", "a", "flexor", "tendon", "Various", "sutures", "can", "be", "used", "to", "repair", "a", "ruptured", "flexor", "tendon.", "rupture", "in", "the", "no", "man’s", "land,", "tendon", "repair", "has", "been", "commonly", "Since", "Avicenna", "first", "performed", "a", "tendon", "repair", "procedure,", "pri-", "performed", "on", "flexor", "tendon", "ruptures", "of", "the", "fingers;", "studies", "on", 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982, 618, 996 ], [ 621, 982, 642, 996 ], [ 705, 1052, 735, 1065 ], [ 738, 1052, 745, 1065 ], [ 748, 1052, 759, 1065 ], [ 762, 1052, 769, 1065 ], [ 599, 1069, 624, 1079 ], [ 627, 1069, 660, 1079 ], [ 662, 1069, 676, 1079 ], [ 678, 1069, 690, 1079 ], [ 692, 1069, 723, 1079 ], [ 726, 1069, 770, 1079 ] ]	[ "International", "Journal", "for", "Equity", "in", "Health", "Research", "Musculo-skeletal", "pain", "among", "40-", "and", "45-year", "olds", "in", "Oslo:", "differences", "between", "two", "socioeconomically", "contrasting", "areas,", "and", "their", "possible", "explanations", "Mette", "Brekke1", "and", "Per", "Hjortdahl2", "Address:", "1Department", "of", "General", "Practice", "and", "Community", "Medicine,", "University", "of", "Oslo,", "Box", "1130", "Blindern,", "N-0317", "Oslo,", "Norway", "and", "2Per", "Hjortdahl,", "Department", "of", "General", "Practice", "and", "Community", "Medicine,", "University", "of", "Oslo,", "Box", "1130", "Blindern,", "N-0317", "Oslo,", "Norway", "Email:", "Mette", "Brekke", "-", "mette.brekke@medisin.uio.no;", "Per", "Hjortdahl", "-", "per.hjortdahl@medisin.uio.no", "*", "Corresponding", "author", "BioMed", "Central", "Open", "Access", "Published:", "19", "October", "2004", "International", "Journal", "for", "Equity", "in", "Health", "2004,", "3:10", "doi:10.1186/1475-9276-3-10", "This", "article", "is", "available", "from:", "http://www.equityhealthj.com/content/3/1/10", "Received:", "27", "May", "2004", "Accepted:", "19", "October", "2004", "©", "2004", "Brekke", "and", "Hjortdahl;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "population", "surveysocial", "inequalities", "in", "healthmuskulo-skeletal", "disordersmental", "healthimmigrants", "Abstract", "Background:", "The", "objective", "of", "the", "study", "was", "to", "compare", "the", "prevalence", "and", "severity", "of", "musculo-", "skeletal", "pain", "between", "two", "socioeconomically", "contrasting", "areas", "in", "Oslo,", "Norway,", "and", "to", "explore", "possible", "explanatory", "factors.", "Methods:", "Questionnaire", "survey,", "carried", "out", "as", "part", "of", "The", "Oslo", "Health", "Study", "in", "2000–2001.", "Data", "from", "821", "persons", "(40", "and", "45", "year", "old)", "living", "in", "a", "less", "affluent", "inner", "city", "area", "(called", "east)", "were", "compared", "with", "854", "persons", "living", "in", "an", "affluent", "area", "of", "the", "city", "(called", "west).", "Bivariate", "comparisons", "(chi", "square", "test)", "and", "multiple", "regression", "analyses", "were", "performed", "to", "investigate", "differences", "between", "the", "samples.", "Results:", "61", "%", "in", "east", "and", "56", "%", "in", "west", "(p", "<", "0.05)", "reported", "pain/stiffness", "in", "muscles/joints", "during", "the", "last", "four", "weeks.", "30", "%", "in", "east", "versus", "19", "%", "in", "west", "(p", "<", "0.001)", "reported", "extensive", "pain.", "The", "between", "area", "difference", "in", "extensive", "pain", "was", "partially", "explained", "by", "physical", "inactivity,", "mental", "health", "problems", "and", "being", "of", "non-Western", "origin.", "Conclusion:", "Musculo-skeletal", "pain", "is", "reported", "by", "55–60", "%", "of", "middle", "aged", "persons", "in", "Oslo", "during", "a", "four", "week", "period,", "and", "must", "be", "considered", "a", "normal", "phenomenon.", "Poor", "social", "conditions,", "inactivity,", "mental", "health", "problems", "and", "being", "an", "immigrant", "imply", "increased", "risk", "of", "more", "severe", "symptoms", "with", "a", "concomitant", "demand", "of", "health", "care.", "Background", "In", "affluent", "societies", "like", "Norway,", "living", "conditions", "as", "well", "as", "general", "health", "status", "have", "improved", "during", "the", "last", "dec-", "ades.", "In", "spite", "of", "this,", "social", "health", "inequities", "still", "exist,", "and", "recent", "analyses", "from", "Oslo", "even", "indicate", "an", "increase", "during", "the", "last", "30", "years", "[1].", "Life", "expectancy", "for", "men", "living", "in", "the", "least", "affluent", "city", "area", "is", "69", "years,", "compared", "to", "76", "for", "men", "in", "the", "most", "affluent", "area", "[2].", "Well-known", "risk", "factors", "like", "smoking,", "physical", "inactivity", "and", "overweight,", "as", "well", "as", "the", "incidence", "of", "atherosclerotic", "disease", "and", "several", "forms", "of", "cancer", "show", "similar", "correlation", "[3].", "Page", "1", "of", "5", "(page", "number", "not", "for", "citation", "purposes)" ]	[ 0, 0, 0, 0, 0, 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947 ], [ 292, 930, 306, 947 ], [ 310, 930, 387, 947 ], [ 390, 930, 469, 947 ], [ 473, 930, 490, 947 ], [ 494, 930, 582, 947 ], [ 108, 977, 186, 994 ], [ 189, 977, 220, 994 ], [ 224, 977, 257, 994 ], [ 261, 977, 320, 994 ], [ 323, 977, 405, 994 ], [ 409, 977, 482, 994 ], [ 486, 977, 519, 994 ], [ 522, 977, 611, 994 ] ]	[ "Int.", "J.", "Mol.", "Sci.", "2009,", "10,", "4428-4434;", "doi:10.3390/ijms10104428", "OPEN", "ACCESS", "International", "Journal", "of", "Molecular", "Sciences", "ISSN", "1422-0067", "www.mdpi.com/journal/ijms", "Review", "Role", "of", "the", "Ubiquitin", "Proteasome", "System", "in", "Regulating", "Skin", "Pigmentation", "Hideya", "Ando", "1,2,", "Masamitsu", "Ichihashi", "1,2", "and", "Vincent", "J.", "Hearing", "3,", "1", "Skin", "Aging", "and", "Photo-aging", "Research", "Center,", "Doshisha", "University,", "Kizugawa,", "Kyoto", "619-0225,", "Japan;", "E-Mails:", "hideyaando@aol.com", "(H.A.);", "mm_ichihashi@hotmail.com", "(M.I.)", "2", "Kobe", "Skin", "Research", "Institute,", "Kobe,", "Hyogo", "650-0047,", "Japan", "3", "Laboratory", "of", "Cell", "Biology,", "National", "Cancer", "Institute,", "National", "Institutes", "of", "Health,", "Bethesda,", "MD", "20892,", "USA", "", "Author", "to", "whom", "correspondence", "should", "be", "addressed;", "E-Mail:", "hearingv@nih.gov;", "Tel.:", "+1-301-496-1564;", "Fax:", "+1-301-402-8787.", "Received:", "3", "September", "2009;", "in", "revised", "form:", "29", "September", "2009", "/", "Accepted:", "9", "October", "2009", "/", "Published:", "15", "October", "2009", "Abstract:", "Pigmentation", "of", "the", "skin,", "hair", "and", "eyes", "is", "regulated", "by", "tyrosinase,", "the", "critical", "rate-limiting", "enzyme", "in", "melanin", "synthesis", "by", "melanocytes.", "Tyrosinase", "is", "degraded", "endogenously,", "at", "least", "in", "part,", "by", "the", "ubiquitin", "proteasome", "system", "(UPS).", "Several", "types", "of", "inherited", "hypopigmentary", "diseases,", "such", "as", "oculocutaneous", "albinism", "and", "Hermansky-", "Pudlak", "syndrome,", "involve", "the", "aberrant", "processing", "and/or", "trafficking", "of", "tyrosinase", "and", "its", "subsequent", "degradation", "which", "can", "occur", "due", "to", "the", "quality-control", "machinery.", "Studies", "on", "carbohydrate", "modifications", "have", "revealed", "that", "tyrosinase", "in", "the", "endoplasmic", "reticulum", "(ER)", "is", "proteolyzed", "via", "ER-associated", "protein", "degradation", "and", "that", "tyrosinase", "degradation", "can", "also", "occur", "following", "its", "complete", "maturation", "in", "the", "Golgi.", "Among", "intrinsic", "factors", "that", "regulate", "the", "UPS,", "fatty", "acids", "have", "been", "shown", "to", "modulate", "tyrosinase", "degradation", "in", "contrasting", "manners", "through", "increased", "or", "decreased", "amounts", "of", "ubiquitinated", "tyrosinase", "that", "leads", "to", "its", "accelerated", "or", "decelerated", "degradation", "by", "proteasomes.", "Keywords:", "fatty", "acid;", "melanin;", "melanocyte;", "tyrosinase;", "skin;", "pigmentation" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 9, 9, 0, 0, 0, 0, 0, 0, 0, 0, 16, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 17, 17, 17, 17, 17, 17, 17, 17 ]
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568, 1016, 589, 1030 ], [ 595, 1016, 660, 1030 ], [ 665, 1016, 695, 1030 ], [ 701, 1016, 758, 1030 ], [ 429, 1034, 497, 1048 ], [ 505, 1034, 526, 1048 ], [ 534, 1034, 586, 1048 ], [ 594, 1034, 652, 1048 ], [ 660, 1034, 705, 1048 ], [ 713, 1034, 758, 1048 ] ]	[ "HD", "Jung,", "et", "al", "Ann", "Dermatol", "Vol.", "23,", "Suppl.", "2,", "2011", "CASE", "REPORT", "http://dx.doi.org/10.5021/ad.2011.23.S2.S270", "Multiple", "Granulocytic", "Sarcomas", "in", "a", "Patient", "with", "Longstanding", "Complete", "Remission", "of", "Acute", "Myelogenous", "Leukemia", "Hee-Dam", "Jung,", "M.D.,", "Hei-Sung", "Kim,", "M.D.,", "Young-Min", "Park,", "M.D.,", "Hyung-Ok", "Kim,", "M.D.,", "Jun-Young", "Lee,", "M.D.", "Department", "of", "Dermatology,", "Seoul", "St.", "Mary’s", "Hospital,", "College", "of", "Medicine,", "The", "Catholic", "University", "of", "Korea,", "Seoul,", "Korea", "Granulocytic", "sarcoma", "is", "an", "extramedullary", "tumor", "composed", "of", "granulocytic", "precursor", "cells.", "It", "usually", "presents", "as", "a", "nodular", "mass", "in", "the", "course", "of", "acute", "myelogenous", "leukemia.", "Rarely,", "the", "tumor", "develops", "in", "non-hematological", "conditions", "or", "in", "a", "patient", "with", "complete", "remission", "from", "the", "acute", "myelogenous", "leukemia.", "In", "such", "cases,", "aleukemic", "granulo-", "cytic", "sarcoma", "can", "be", "a", "preceding", "sign", "of", "systemic", "leukemia", "or", "a", "first", "sign", "of", "hematologic", "relapse", "of", "leukemia.", "We", "present", "an", "unusual", "case", "of", "multiple", "granulocytic", "sarcomas", "develo-", "ped", "in", "a", "patient", "with", "longstanding", "complete", "remission", "of", "acute", "myelogenous", "leukemia,", "who", "has", "not", "had", "bone", "marrow", "and", "peripheral", "blood", "involvement", "for", "a", "long", "time.", "(Ann", "Dermatol", "23(S2)", "S270∼S273,", "2011)", "-Keywords-", "Aleukemic", "leukemia", "cutis,", "AML", "M1,", "Granulocytic", "sarco-", "ma", "INTRODUCTION", "Granulocytic", "sarcomas", "usually", "occur", "during", "the", "course", "of", "Received", "March", "23,", "2011,", "Revised", "July", "12,", "2011,", "Accepted", "for", "publication", "August", "12,", "2011", "Corresponding", "author:", "Jun-Young", "Lee,", "M.D.,", "Department", "of", "Der-", "matology,", "Seoul", "St.", "Mary’s", "Hospital,", "College", "of", "Medicine,", "The", "Catholic", "University", "of", "Korea,", "505", "Banpo-dong,", "Seocho-gu,", "Seoul", "137-040,", "Korea.", "Tel:", "82-2-2258-1386,", "Fax:", "82-2-594-3255,", "E-mail:", "jylee@catholic.ac.kr", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "Non-Commercial", "License", "(http://", "creativecommons.org/licenses/by-nc/3.0)", "which", "permits", "unrestricted", "non-commercial", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "S270", "Ann", "Dermatol", "acute", "myelogenous", "leukemia", "(AML)", "and", "antecede", "blastic", "cirisis", "in", "myeloproliferative", "disease", "or", "myelodysplastic", "syndromes.", "However,", "the", "tumor", "can", "also", "develop", "in", "patients", "who", "have", "either", "no", "prior", "history", "of", "hematological", "disease", "or", "have", "shown", "complete", "remission", "from", "acute", "myelogenous", "leukemia.", "Herein,", "we", "describe", "a", "patient", "who", "has", "shown", "an", "unusual", "clinical", "course", "in", "that", "she", "was", "in", "complete", "remission", "from", "AML", "for", "a", "long", "time", "and", "that", "there", "were", "no", "signs", "of", "peripheral", "blood", "and", "bone", "marrow", "relapse", "for", "a", "long", "time", "following", "the", "development", "of", "granulocytic", "sarcoma.", "CASE", "REPORT", "A", "72-year-old", "Korean", "woman", "presented", "with", "a", "1-month", "history", "of", "rapidly", "growing", "multiple", "cutaneous", "nodules", "on", "the", "whole", "body.", "Physical", "examination", "revealed", "wide-", "spread", "well-demarcated", "variable-sized", "greenish", "firm", "cutaneous", "nodules", "over", "the", "face,", "trunk", "and", "extremities", "(Fig.", "1).", "She", "had", "a", "history", "of", "acute", "myeloblastic", "leukemia", "without", "maturation", "(AML", "M1),", "and", "achieved", "complete", "remission", "after", "the", "3rd", "consolidation", "chemotherapy,", "ten", "years", "ago.", "The", "patient", "remained", "asymptomatic", "for", "nine", "years", "and", "then", "visited", "the", "hospital", "presenting", "with", "an", "asymptomatic", "solitary", "firm", "mass", "on", "the", "left", "upper", "eyelid", "in", "September", "2009.", "An", "excisional", "biopsy", "of", "the", "lesion", "was", "performed", "and", "histopathologic", "findings", "were", "consistent", "with", "a", "granulocytic", "sarcoma.", "Bone", "marrow", "biopsy", "showed", "normocellular", "bone", "marrow", "without", "leukemic", "cell", "involvement", "and", "peripheral", "blood", "also", "revealed", "normal", "findings.", "In", "April", "2010,", "she", "complained", "of", "nasal", "stuffiness,", "bloody", "nasal", "discharge", "and", "hoarseness.", "Neck", "computed", "tomography", "and", "magnetic", "resonance", "imaging", "findings" ]	[ 0, 0, 0, 0, 7, 7, 7, 7, 7, 7, 7, 16, 16, 0, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 17, 17, 17, 17, 17, 17, 17, 17, 17, 1, 1, 1, 1, 1, 1, 1, 1, 1, 9, 9, 9, 9, 9, 9, 9, 9, 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], [ 300, 1009, 307, 1019 ], [ 310, 1009, 324, 1019 ], [ 326, 1009, 360, 1019 ], [ 362, 1009, 396, 1019 ], [ 399, 1009, 412, 1019 ], [ 415, 1009, 443, 1019 ], [ 446, 1009, 465, 1019 ], [ 467, 1009, 473, 1019 ], [ 476, 1009, 508, 1019 ], [ 510, 1009, 530, 1019 ] ]	[ "Pocock", "and", "Phua", "Globalization", "and", "Health", "2011,", "7:12", "http://www.globalizationandhealth.com/content/7/1/12", "R", "E", "V", "I", "E", "W", "Open", "Access", "Medical", "tourism", "and", "policy", "implications", "for", "health", "systems:", "a", "conceptual", "framework", "from", "a", "comparative", "study", "of", "Thailand,", "Singapore", "and", "Malaysia", "Nicola", "S", "Pocock", "and", "Kai", "Hong", "Phua", "Abstract", "Medical", "tourism", "is", "a", "growing", "phenomenon", "with", "policy", "implications", "for", "health", "systems,", "particularly", "of", "destination", "countries.", "Private", "actors", "and", "governments", "in", "Southeast", "Asia", "are", "promoting", "the", "medical", "tourist", "industry,", "but", "the", "potential", "impact", "on", "health", "systems,", "particularly", "in", "terms", "of", "equity", "in", "access", "and", "availability", "for", "local", "consumers,", "is", "unclear.", "This", "article", "presents", "a", "conceptual", "framework", "that", "outlines", "the", "policy", "implications", "of", "medical", "tourism’s", "growth", "for", "health", "systems,", "drawing", "on", "the", "cases", "of", "Thailand,", "Singapore", "and", "Malaysia,", "three", "regional", "hubs", "for", "medical", "tourism,", "via", "an", "extensive", "review", "of", "academic", "and", "grey", "literature.", "Variables", "for", "further", "analysis", "of", "the", "potential", "impact", "of", "medical", "tourism", "on", "health", "systems", "are", "also", "identified.", "The", "framework", "can", "provide", "a", "basis", "for", "empirical,", "in", "country", "studies", "weighing", "the", "benefits", "and", "disadvantages", "of", "medical", "tourism", "for", "health", "systems.", "The", "policy", "implications", "described", "are", "of", "particular", "relevance", "for", "policymakers", "and", "industry", "practitioners", "in", "other", "Southeast", "Asian", "countries", "with", "similar", "health", "systems", "where", "governments", "have", "expressed", "interest", "in", "facilitating", "the", "growth", "of", "the", "medical", "tourist", "industry.", "This", "article", "calls", "for", "a", "universal", "definition", "of", "medical", "tourism", "and", "medical", "tourists", "to", "be", "enunciated,", "as", "well", "as", "concerted", "data", "collection", "efforts,", "to", "be", "undertaken", "prior", "to", "any", "meaningful", "empirical", "analysis", "of", "medical", "tourism’s", "impact", "on", "health", "systems.", "Introduction", "Growing", "demand", "for", "health", "services", "is", "a", "global", "phenom-", "enon,", "linked", "to", "economic", "development", "that", "generates", "ris-", "ing", "incomes", "and", "education.", "Demographic", 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"patient", "flows.", "", "Correspondence:", "sppnp@nus.edu.sg", "Lee", "Kuan", "Yew", "School", "of", "Public", "Policy,", "National", "University", "of", "Singapore,", "469C", "Bukit", "Timah", "Road,", "OTH", "Building,", "Singapore", "259772,", "Singapore", "In", "Southeast", "Asia,", "the", "health", "sector", "is", "expanding", "rapidly,", "attributable", "to", "rapid", "growth", "of", "the", "private", "sector", "and", "notably,", "medical", "tourism,", "which", "is", "emerging", "as", "a", "lucrative", "business", "opportunity.", "Countries", "here", "are", "capita-", "lising", "on", "their", "popularity", "as", "tourist", "destinations", "by", "com-", "bining", "high", "quality", "medical", "services", "at", "competitive", "prices", "with", "tourist", "packages.", "Some", "countries", "are", "establishing", "comparative", "advantages", "in", "service", "provision", "based", "on", "their", "health", "system’s", "organizational", "structure", "(table", "1).", "Thailand", "has", 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301, 1010, 308, 1020 ], [ 311, 1010, 325, 1020 ], [ 326, 1010, 359, 1020 ], [ 362, 1010, 396, 1020 ], [ 398, 1010, 411, 1020 ], [ 413, 1010, 441, 1020 ], [ 443, 1010, 462, 1020 ], [ 464, 1010, 470, 1020 ], [ 472, 1010, 503, 1020 ], [ 505, 1010, 525, 1020 ] ]	[ "Hall", "et", "al.", "BMC", "Medical", "Informatics", "and", "Decision", "Making", "2012,", "12:69", "http://www.biomedcentral.com/1472-6947/12/69", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Implementation", "of", "automated", "reporting", "of", "estimated", "glomerular", "filtration", "rate", "among", "Veterans", "Affairs", "laboratories:", "a", "retrospective", "study", "Rasheeda", "K", "Hall1,2,", "Virginia", "Wang1,2,", "George", "L", "Jackson1,2,", "Bradley", "G", "Hammill2,", "Matthew", "L", "Maciejewski1,2,", "Elizabeth", "M", "Yano3,4,", "Laura", "P", "Svetkey2,5", "and", "Uptal", "D", "Patel1,2,6", "Abstract", "Background:", "Automated", "reporting", "of", "estimated", "glomerular", "filtration", "rate", "(eGFR)", "is", "a", "recent", "advance", "in", "laboratory", "information", "technology", "(IT)", "that", "generates", "a", "measure", "of", "kidney", "function", "with", "chemistry", "laboratory", "results", "to", "aid", "early", "detection", "of", "chronic", "kidney", "disease", "(CKD).", "Because", "accurate", "diagnosis", "of", "CKD", "is", "critical", "to", "optimal", "medical", "decision-making,", "several", "clinical", "practice", "guidelines", "have", "recommended", "the", "use", "of", "automated", "eGFR", "reporting.", "Since", "its", "introduction,", "automated", "eGFR", "reporting", "has", "not", "been", "uniformly", "implemented", "by", "U.", "S.", "laboratories", "despite", "the", "growing", "prevalence", "of", "CKD.", "CKD", "is", "highly", "prevalent", "within", "the", "Veterans", "Health", "Administration", "(VHA),", "and", "implementation", "of", "automated", "eGFR", "reporting", "within", "this", "integrated", "healthcare", "system", "has", "the", "potential", "to", "improve", "care.", "In", "July", "2004,", "the", "VHA", "adopted", "automated", "eGFR", "reporting", "through", "a", "system-wide", "mandate", "for", "software", "implementation", "by", "individual", "VHA", "laboratories.", "This", "study", "examines", "the", "timing", "of", "software", "implementation", "by", "individual", "VHA", "laboratories", "and", "factors", "associated", "with", "implementation.", "Methods:", "We", "performed", "a", "retrospective", "observational", "study", "of", "laboratories", "in", "VHA", "facilities", "from", "July", "2004", "to", "September", "2009.", "Using", "laboratory", "data,", "we", "identified", "the", "status", "of", "implementation", "of", "automated", "eGFR", "reporting", "for", "each", "facility", "and", "the", "time", "to", "actual", "implementation", "from", "the", "date", "the", "VHA", "adopted", "its", "policy", "for", "automated", "eGFR", "reporting.", "Using", "survey", "and", "administrative", "data,", "we", "assessed", "facility", "organizational", "characteristics", "associated", "with", "implementation", "of", "automated", "eGFR", "reporting", "via", "bivariate", "analyses.", "Results:", "Of", "104", "VHA", "laboratories,", "88%", "implemented", "automated", "eGFR", "reporting", "in", "existing", "laboratory", "IT", "systems", "by", "the", "end", "of", "the", "study", "period.", "Time", "to", "initial", "implementation", "ranged", "from", "0.2", "to", "4.0", "years", "with", "a", "median", "of", "1.8", "years.", "All", "VHA", "facilities", "with", "on-site", "dialysis", "units", "implemented", "the", "eGFR", "software", "(52%,", "p<0.001).", "Other", "organizational", "characteristics", "were", "not", "statistically", "significant.", "Conclusions:", "The", "VHA", "did", "not", "have", "uniform", "implementation", "of", "automated", "eGFR", "reporting", "across", "its", "facilities.", "Facility-level", "organizational", "characteristics", "were", "not", "associated", "with", "implementation,", "and", "this", "suggests", "that", "decisions", "for", "implementation", "of", "this", "software", "are", "not", "related", "to", "facility-level", "quality", "improvement", "measures.", "Additional", "studies", "on", "implementation", "of", "laboratory", "IT,", "such", "as", "automated", "eGFR", "reporting,", "could", "identify", "factors", "that", "are", "related", "to", "more", "timely", "implementation", "and", "lead", "to", "better", "healthcare", "delivery.", "Background", "Since", "its", "development,", "automated", "laboratory", "reporting", "of", "estimated", "glomerular", "filtration", "rate", "(eGFR)", "has", "facilitated", "diagnosis", "and", "management", "of", "chronic", "kidney", "disease", "", "Correspondence:", "uptal.patel@dm.duke.edu", "1Center", "for", "Health", "Services", "Research", "in", "Primary", "Care,", "Veterans", "Affairs", "Health", "Services", "Research", "&", "Development,", "Durham,", "NC,", "USA", "2Department", "of", "Medicine,", "Duke", "University", "School", "of", "Medicine,", "Durham,", "NC,", "USA", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "(CKD)", "[1].", "To", "report", "eGFR,", "clinical", "laboratories", "imple-", "ment", "software", "that", "calculates", "eGFR", "from", "equations", "based", "on", "serum", "creatinine", "and", "demographic", "variables.", "As", "a", "result,", "clinicians", "who", "receive", "laboratory", "reports", "of", "eGFR", "in", "addition", "to", "serum", "creatinine", "may", "make", "more", "informed", "clinical", "decisions.", "The", "importance", "of", "auto-", "mated", "eGFR", "reporting", "was", "established", "by", "National", "Kid-", "ney", "Foundation", "clinical", "guidelines", "in", "2002,", "and,", "later,", "endorsed", "by", "the", "National", "Kidney", "Disease", "Education", "©", "2012", "Hall", "et", "al.;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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"Lindsey", "A", "Criswell", "Address:", "The", "Rosalind", "Russell", "Medical", "Research", "Center", "for", "Arthritis,", "University", "of", "California", "San", "Francisco,", "374", "Parnassus", "Ave,", "San", "Francisco,", "California", "94143", "USA", "E-mail:", "Kimberly", "E", "Taylor", "-", "kim.taylor@ucsf.edu;", "Lindsey", "A", "Criswell", "-", "lindsey.criswell@ucsf.edu", "*Corresponding", "author", "BioMed", "Central", "Open", "Access", "from", "Genetic", "Analysis", "Workshop", "16", "St", "Louis,", "MO,", "USA", "17-20", "September", "2009", "Published:", "15", "December", "2009", "BMC", "Proceedings", "2009,", "3(Suppl", "7):S36", "doi:", "10.1186/1753-6561-3-S7-S36", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1753-6561/3/S7/S36", "©", "2009", "Taylor", "and", "Criswell;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "We", "performed", "a", "whole-genome", "association", "study", "of", "rheumatoid", "arthritis", "susceptibility", "using", "Illumina", "550k", "single-nucleotide", "polymorphism", "(SNP)", "genotypes", "of", "868", "cases", "and", "1194", "controls", "from", "the", "North", "American", "Rheumatoid", "Arthritis", "Consortium", "(NARAC).", "Structured", "association", "analysis", "with", "adjustment", "for", "potential", "population", "stratification", "yielded", "200", "SNPs", "with", "p", "<", "1", "×", "10-8", "for", "association", "with", "RA,", "all", "of", "which", "were", "on", "chromosome", "6", "in", "a", "2.7-Mb", "region", "of", "the", "major", "histocompatibility", "complex", "(MHC).", "Given", "the", "extensive", 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966, 551, 982 ], [ 555, 966, 572, 982 ], [ 575, 966, 597, 982 ], [ 600, 966, 674, 982 ], [ 677, 966, 697, 982 ], [ 700, 966, 718, 982 ], [ 721, 966, 742, 982 ], [ 428, 983, 445, 999 ], [ 447, 983, 491, 999 ], [ 494, 983, 514, 999 ], [ 516, 983, 538, 999 ], [ 541, 983, 565, 999 ], [ 567, 983, 587, 999 ], [ 590, 983, 664, 999 ], [ 666, 983, 742, 999 ], [ 428, 1000, 451, 1016 ], [ 454, 1000, 479, 1016 ], [ 482, 1000, 488, 1016 ], [ 491, 1000, 537, 1016 ], [ 541, 1000, 571, 1016 ], [ 573, 1000, 584, 1016 ], [ 587, 1000, 613, 1016 ], [ 617, 1000, 637, 1016 ], [ 640, 1000, 663, 1016 ], [ 666, 1000, 680, 1016 ], [ 683, 1000, 711, 1016 ], [ 714, 1000, 742, 1016 ] ]	[ "J", "Korean", "Med", "Sci", "2010;", "25:", "647-50", "ISSN", "1011-8934", "DOI:", "10.3346/jkms.2010.25.4.647", "Acute", "Shunt", "Malfunction", "after", "Cesarean", "Section", "Delivery:", "A", "Case", "Report", "Shunt", "malfunctions", "that", "require", "surgical", "intervention", "during", "pregnancy", "and", "the", "postpartum", "period", "are", "rare.", "Furthermore,", "no", "study", "has", "reported", "on", "an", "acute", "shunt", "malfunction", "immediately", "after", "cesarean", "section.", "Here,", "we", "describe", "the", "case", "of", "a", "32-yr-old", "woman", "who", "became", "drowsy", "12", "hr", "after", "cesarean", "section", "delivery", "of", "her", "second", "child.", "She", "had", "a", "ventriculoperitoneal", "shunt", "placed", "to", "treat", "hydrocephalus", "associated", "with", "meningitis", "at", "26", "yr", "of", "age.", "Marked", "ventriculomegaly", "was", "seen", "on", "brain", "computed", "tomography", "and", "her", "consciousness", "recovered", "temporarily", "after", "aspirating", "cerebrospinal", "fluid", "from", "the", "flushing", "device.", "At", "surgery,", "the", "distal", "catheter", "tip", "was", "plugged", "by", "a", "blood", "clot.", "We", "believe", "that", "the", "blood", "spilled", "over", "during", "the", "cesarean", "section.", "The", "clogged", "catheter", "end", "was", "simply", "cut", "off", "and", "the", "remaining", "catheter", "was", "repositioned", "in", "the", "peritoneal", "cavity.", "Her", "consciousness", "recovered", "fully.", "Key", "Words", ":", "Ventriculoperitoneal", "Shunt;", "Prosthesis", "Failure;", "Hydrocephalus;", "Cesarean", "Section", "ⓒ", "2010", "The", "Korean", "Academy", "of", "Medical", "Sciences.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "Non-Commercial", "License", "(http://creativecommons.org/licenses/by-nc/3.0)", "which", "permits", "unrestricted", "non-commercial", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Sun-Chul", "Hwang1,", "Tae-Hee", "Kim2,", "Bum-Tae", "Kim1,", "Soo-Bin", "Im1,", "and", "Won-Han", "Shin1", "Department", "of", "Neurosurgery1,", "and", "Obstetrics", "and", "Gynecology2,", "Soonchunhyang", "University", "Bucheon", "Hospital,", "Bucheon,", "Korea", "Received", ":", "25", "June", "2008", "Accepted", ":", "20", "January", "2009", "Address", "for", "Correspondence", "Sun-Chul", "Hwang,", "M.D.", "Department", "of", "Neurosurgery,", "Soonchunhyang", "University", "Bucheon", "Hospital,", "1174", "Jung-dong,", "Wonmi-gu,", "Bucheon", "420-747,", "Korea", "Tel", ":", "+82.32-621-5291,", "Fax", ":", "+82.32-621-5016", "E-mail", ":", "sunchulh@sch.ac.kr", "INTRODUCTION", "Cerebrospinal", "fluid", "(CSF)", "shunts", "are", "a", "definite", "treatment", "for", "hydrocephalus.", "As", "increasing", "numbers", "of", "women", "have", "CSF", "shunts", "placed", "to", "treat", "hydrocephalus,", "more", "shunt-depen-", "dent", "women", "are", "becoming", "pregnant", "(1,", "2).", "Although", "the", "maternal", "and", "fetal", "outcome", "in", "patients", "with", "ventriculoperi-", "toneal", "(VP)", "shunts", "is", "uniformly", "excellent,", "the", "changes", "in", "the", "abdominal", "cavity,", "such", "as", "the", "enlargement", "of", "the", "uterus", "and", "increased", "abdominal", "pressure,", "could", "cause", "shunt", "failure", "(1,", "3-5).", "The", "distal", "shunt", "catheter", "is", "frequently", "obstructed", "in", "pregnancy,", "especially", "during", "the", "third", "trimester", "when", "the", "intra-abdominal", "pressure", "is", "thought", "to", "be", "highest", "(3,", "4).", "Post-", "partum", "shunt", "complications", "are", "rare", "(1,", "4,", "6,", "7),", "and", "shunt", "obstruction", "immediately", "after", "a", "cesarean", "section", "had", "not", "been", "reported.", "We", "present", "a", "patient", "with", "a", "VP", "shunt", "who", "had", "reduced", "consciousness", "due", "to", "obstruction", "of", "the", "abdominal", "shunt", "catheter", "immediately", "after", "a", "cesarean", "section", "delivery.", "CASE", "REPORT", "A", "32-yr-old", "woman,", "G2P2A0L2,", "came", "to", "the", "emergency", "department", "complaining", "that", "she", "felt", "drowsy.", "She", "had", "under-", "gone", "a", "cesarean", "section", "delivery", "of", "a", "full-term", "healthy", "baby", "647", "(3,200", "gm)", "the", "day", "before.", "At", "the", "age", "of", "26", "yr,", "she", "had", "a", "VP", "shunt", "placed", "to", "treat", "hydrocephalus", "associated", "with", "menin-", "gitis.", "She", "underwent", "a", "shunt", "revision", "when", "she", "was", "29", "yr", "old.", "At", "that", "time,", "she", "was", "in", "the", "sixth", "month", "of", "her", "first", "preg-", "nancy", "and", "complained", "of", "drowsiness", "and", "headache.", "Her", "hus-", "band", "said", "that", "the", "reason", "for", "the", "shunt", "malfunction", "had", "not", "been", "determined", "and", "the", "malfunctioning", "VP", "shunt", "had", "been", "replaced", "with", "a", "new", "device.", "The", "revision", "surgery", "had", "success-", "fully", "relieved", "her", "symptoms.", "At", "full", "term,", "she", "underwent", "a", "lower", "segment", "cesarean", "section", "because", "of", "fetal", "distress", "and", "gave", "birth", "to", "her", "first", "child,", "who", "weighed", "3,580", "g.", "The", "post-", "partum", "course", "was", "unremarkable", "after", "the", "birth", "of", "her", "first", "child.", "At", "31", "yr", "of", "age,", "she", "became", "pregnant", "with", "her", "second", "child.", "She", "had", "no", "symptoms", "related", "to", "shunt", "malfunction", "during", "gestation.", "A", "repeated", "cesarean", "section", "was", "performed", "at", "the", "same", "private", "obstetrics", "clinic", "and", "a", "healthy", "baby", "was", "deliv-", "ered.", "The", "peritoneal", "cavity", "was", "not", "irrigated", "and", "the", "shunt", "tube", "was", "not", "observed", "at", "surgery.", "She", "began", "to", "complain", "of", "a", "headache", "12", "hr", "after", "the", "cesarean", "section.", "Her", "consciousness", "deteriorated", "gradually", "and", "she", "became", "drowsy.", "She", "was", "trans-", "ferred", 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"Ralph", "Schnitker,4", "Walter", "M", "o«ller-Hartmann5", "and", "Euphrosyne", "Gouzoulis-Mayfrank2", "1Department", "of", "Psychiatry", "and", "Psychotherapy,", "Division", "of", "Medical", "Psychology,", "University", "Hospital", "of", "Bonn,", "2Department", "of", "Psychiatry", "and", "Psychotherapy,", "University", "Hospital", "of", "Cologne,", "Germany,", "3Psychiatric", "University", "Hospital,", "Zu«", "rich,", "Switzerland,", "4Interdisciplinary", "Center", "for", "Clinical", "Research", "(ICCR),", "Functional", "Neuroimaging", "Unit,", "RWTH", "Aachen", "and", "5Department", "of", "Radiology,", "University", "Hospital", "of", "Cologne,", "Germany", "Correspondence", "to:", "Dr", "Knut", "Schnell,", "Abteilung", "f", "u«r", "Medizinische", "Psychologie,", "Zentrum", "f", "u«r", "Nervenheilkunde,", "Universita«", "tsklinikum", "Bonn,", "Sigmund-Freud-Strasse", "25,", "53105", "Bonn,", "Germany", "E-mail:", "knut.schnell@ukb.uni-bonn.de", "Passivity", "experiences", "are", "hallmark", "symptoms", "of", "schizophrenia", "that", "can", "be", "characterized", "by", "the", "belief", "that", "one’s", "thoughts", "or", "actions", "are", "controlled", "by", "an", "external", "agent.", "It", "has", "recently", "been", "suggested", "that", "these", "psychotic", "experiences", "result", "from", "defective", "monitoring", "of", "one’s", "own", "actions,", "i.e.", "disturbed", "comparison", "of", "actions", "and", "perceived", "outcomes.", "In", "this", "study,", "we", "examined", "the", "function", "of", "the", "previously", "characterized", "action", "monitoring", "network", "of", "the", "inferior", "parietal", "lobule", "(IPL),", "medial", "(mPFC)", "and", "lateral", "prefrontal", "cortices", "in", "patients", "with", "different", "levels", "of", "passivity", "symptoms", "with", "an", "fMRI", "task.The", "visuomotor", "fMRI", "task", "demanded", "control", "of", "visually", "perceived", "object", "movements", "by", "alternating", "button", "presses", "with", "the", "left", "and", "the", "right", "index", "finger.", "In", "the", "monitoring", "condition", "of", "this", "task", "subjects", "stopped", "their", "actions", "whenever", "they", "detected", "visuomotor", "incongru-", "ence.", "fMRI", "and", "behavioural", "data", "from", "15", "patients", "were", "tested", "for", "correlation", "with", "passivity", "symptoms", "using", "standardized", "Scale", "for", "Assessment", "of", "Positive", "Symptoms", "(SAPS)-", "and", "AMDP-", "passivity", "symptom", "ratings.", "Both", "types", "of", "data", "were", "tested", "for", "differences", "between", "the", "patients", "group", "and", "15", "healthy", "controls.", "In", "the", "patient", "group", "we", "found", "the", "expected", "correlation", "of", "passivity", "symptoms", "and", "visuomotor", "monitoring", "performance.There", "was", "a", "significant", "positive", "correlation", "of", "passivity", "symptoms", "with", "increased", "latency", "of", "incongruence", "detection", "and", "a", "negative", "correlation", "of", "SAPS-passivity", "with", "the", "number", "of", "detected", "events.", "fMRI", "data", "revealed", "correla-", "tions", "of", "passivity", "symptoms", "with", "activation", "in", "bilateral", "IPL,", "primary", "motor", "and", "sensory", "cortices", "in", "the", "action", "monitoring", "condition.", "A", "correlation", "of", "passivity", "symptoms", "with", "the", "main", "experimental", "effect", "(actions", "with", "^", "actions", "without", "monitoring)", "was", "found", "in", "the", "posterior", "cingulate", "cortex", "(PCC)", "and", "in", "the", "left", "IPL.", "No", "group", "differences", "or", "group", "by", "task", "interactions", "were", "found", "within", "the", "visuomotor-action-monitoring", "network.", "Our", "results", "demonstrate", "the", "association", "between", "passivity", "symptoms", "and", "the", "dysfunction", "of", "visuomotor", "action", "monitoring", "and", "support", "the", "idea", "that", "psychotic", "passivity", "experiences", "result", "from", "dysfunctions", "of", "central", "action", "monitoring", "mechanisms:", "According", "to", "pre-existing", "concepts", "of", "parietal", "cortex", "function,", "IPL-hyperactivation", "may", "represent", "an", "increase", "in", "false", "detections", "of", "visuomotor", "incongruence", "while", "the", "correlation", "between", "passiv-", "ity", "and", "the", "differential", "effect", "of", "monitoring", "on", "PCC-activation", "assumedly", "represents", "greater", "self-monitoring", "effort", "in", "passivity", "experiences.", "Keywords:", "action", "monitoring;", "visuomotor;", "schizophrenia;", "functional", "magnetic", "resonance", "imaging;", "parietal", "lobe", "Abbreviations:", "AIMS", "=", "Abnormal", "Involuntary", "Movement", "Scale;", "BA", "=", "Brodmann", "area;", "CC", "=", "control", "condition;", "EPI", "=", "echoplanar", "imaging;", "EPS", "=", "Extrapyramidal", "Motor", "Side", "Effects", "Scale;", "FDR", "=", "false", "discovery", "rate;", "HRF", "=", "hemodynamic", "response", "function;", "IPL", "=", "inferior", "parietal", "lobule;", "MC", "=", "monitoring", "condition;", "mPFC", "=", "medial", "prefrontal", "cortex;", "PCC", "=", "posterior", "cingulate", "cortex;", "SANS", "=", "Scale", "for", "Assessment", "of", "Negative", "Symptoms;", "SAPS", "=", "Scale", "for", "Assessment", "of", "Positive", "Symptoms;", "SCID", "=", "Structured", "Clinical", "Interview", "for", "DSM-IV", "Axis", "I", "Disorders;", "SPM", "=", "Statistical", "Parametric", "Mapping", "Received", "February", "25,", "2008.", "Revised", "July", "7,", "2008.", "Accepted", "July", "21,", "2008.", "Advance", "Access", "publication", "August", "19,", "2008", "2008", "The", "Author(s)", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "Non-Commercial", "License", "(http://creativecommons.org/licenses/by-nc/2.0/uk/)", "which", "permits", "unrestricted", "non-commercial", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]	[ 0, 0, 0, 0, 0, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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"Signaling", "Domains", "Is", "Inhibited", "in", "Tolerant", "B", "Cells", "By", "Bennett", "C.Weintraub,", "Jesse", "Eunsuk", "Jun,", "Anthony", "C.", "Bishop,‡", "Kevan", "M.", "Shokat,‡", "Matthew", "L.", "Thomas,†", "and", "Christopher", "C.", "Goodnow", "From", "the", "Australian", "Cancer", "Research", "Foundation", "Genetics", "Laboratory,", "Medical", "Genome", "Centre,", "John", "Curtin", "School", "of", "Medical", "Research,", "Canberra", "2601,Australia;", "the", "‡Department", "of", "Chemistry,", "Princeton", "University,", "Princeton,", "New", "Jersey", "08544;", "and", "the", "†Howard", "Hughes", "Medical", "Institute", "and", "Department", "of", "Pathology,Washington", "University", "School", "of", "Medicine,", "St.", "Louis,", "Missouri", "63110", "Abstract", "Signal", "transduction", "through", "the", "B", "cell", "antigen", "receptor", "(BCR)", "is", "altered", "in", "B", "cells", "that", "express", "a", "receptor", "that", "recognizes", "self-antigen.", "To", "understand", "the", "molecular", "basis", "for", "the", "change", "in", "sig-", "naling", "in", "autoreactive", "B", "cells,", "a", "transgenic", "model", "was", "used", "to", "isolate", "a", "homogeneous", "popula-", "tion", "of", "tolerant", "B", "lymphocytes.", "These", "cells", "were", "compared", "with", "a", "similar", "population", "of", "naive", "B", "lymphocytes.", "We", "show", "that", "the", "BCR", "from", "naive", "B", "cells", "enters", "a", "detergent-insoluble", "domain", "of", "the", "cell", "within", "6", "s", "after", "antigen", "binding,", "before", "a", "detectable", "increase", "in", "BCR", "phosphoryla-", "tion.", "This", "fraction", "appears", "to", "be", "important", "for", "signaling", "because", "it", "is", "enriched", "for", "lyn", "kinase", "but", "lacks", "CD45", "tyrosine", "phosphatase", "and", "because", "the", "BCR", "that", "moves", "into", "this", "domain", "becomes", "more", "highly", "phosphorylated.", "Partitioning", "of", "the", "BCR", "into", "this", "fraction", "is", "unaffected", "by", "src", "family", "kinase", "inhibition.", "Tolerant", "B", "cells", "do", "not", "efficiently", "partition", "the", "BCR", "into", "the", "deter-", "gent-insoluble", "domain,", "providing", "an", "explanation", "for", "their", "reduced", "tyrosine", "kinase", "activation", "and", "calcium", "flux", "in", "response", "to", "antigen.", "These", "results", "identify", "an", "early,", "regulated", "step", "in", "anti-", "gen", "receptor", "signaling", "and", "self-tolerance.", "Key", "words:", "B", "cell", "antigen", "receptor", "signaling", "•", "tyrosine", "phosphorylation", "•", "membrane", "raft", "•", "self-tolerance", "•", "anergy", "Introduction", "Mice", "expressing", "transgenes", "for", "anti–hen", "egg", "lysozyme", "(HEL)", "IgM/IgD", "B", "cell", "antigen", "receptor", "(BCR)", "contain", "large", "homogeneous", "populations", "of", "B", "cells", "that", "are", "func-", "tionally", "naive.", "When", "anti-HEL", "transgenic", "mice", "are", "crossed", "to", "transgenic", "mice", "expressing", "soluble", "HEL,", "the", "B", "cells", "in", "the", "double-transgenic", "offspring", "are", "constantly", "ex-", "posed", "to", "low", "levels", "of", "antigenic", "stimulation", "and", "become", "functionally", "tolerant", "(anergic).", "The", "tolerant", "cells", "lose", "some", "responses", "to", "antigen,", "notably", "BCR-induced", "proliferation,", "but", "retain", "other", "responses,", "including", "BCR-induced", "apop-", "tosis,", "changes", "in", "follicular", "homing,", "and", "inhibition", "of", "plas-", "macyte", "differentiation", "(1–3).", "Binding", "of", "HEL", "to", "the", "BCR", "on", "these", "cells", "results", "in", "only", "a", "subset", "of", "the", "biochemical", "re-", "sponses", "that", "are", "triggered", "by", "HEL", "in", "naive", "anti-HEL", "trans-", "genic", "B", "cells.", "For", "example,", "the", "BCR", "on", "tolerant", "B", "cells", "Address", "correspondence", "to", "Christopher", "C.", "Goodnow,", "Medical", "Genome", "Centre,", "John", "Curtin", "School", "of", "Medical", "Research,", "ANU,", "Mills", "Rd.,", "Can-", "berra", "2601", "ACT,", "Australia.", "Phone:", "61-2-6249-3621;", "Fax:", "61-2-6279-", "8512;", "E-mail:", "Chris.Goodnow@anu.edu.au", "continually", "activates", "low", "intracellular", "calcium", "oscillations", "and", "extracellular", "signal–regulated", "kinase", "(ERK),", "and", "nu-", "clear", "factor", "of", "activated", "T", "cells", "(NFAT)c", "pathways", "but", "does", "not", "produce", "high", "calcium", "elevations", "or", "activate", "the", "c-Jun", "NH2-terminal", "kinase", "(JNK)", "and", "nuclear", "factor", "(NF)-kB", "pathways", "(4).", "How", "the", "BCR", "is", "selectively", "uncoupled", "from", "some", "sig-", "naling", "pathways", "but", "not", "others", "is", "unclear.", "Antigen-induced", "protein", "tyrosine", "phosphorylation", "of", "the", "BCR", "and", "other", "molecules", "is", "greatly", "reduced", "in", "HEL-tolerant", "B", "cells", "(5).", "However,", "tolerant", "B", "cells", "express", "at", "normal", "levels", "and", "with", "normal", "basal", "activity", "proteins", "important", "for", "BCR-induced", "signal", "transduction,", "such", "as", "syk,", "lyn,", "CD45,", "and", "Src", "homol-", "ogy", "2", "domain–containing", "protein", "tyrosine", "phosphatase", "(SHP)-1.", "Here", "we", "present", "evidence", "for", "an", "early,", "regulated", "step", "in", "BCR", "signaling", "that", "may", "resolve", "this", "paradox.", "We", "find", "that", "in", "naive", "cells,", "the", "stimulated", "BCR", "becomes", "associated", "with", "a", "detergent-insoluble", "fraction", "containing", "lyn,", "and", "that", "in", "tolerant", "cells,", "the", "BCR", "does", "not", "efficiently", "associate", "with", "1443", "J.", "Exp.", "Med.", "The", "Rockefeller", "University", "Press", "•", "0022-1007/2000/04/1443/06", "$5.00", "Volume", "191,", "Number", "8,", "April", "17,", "2000", 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"of", "preplan", "MRI", "and", "preplan", "CT-based", "prostate", "volume", "with", "intraoperative", "ultrasound-based", "prostate", "volume", "in", "real-time", "permanent", "brachytherapy", "Hyeli", "Park,", "MD1,", "Ja", "Young", "Kim,", "MD1,", "Bo", "Mi", "Lee,", "MD1,", "Sei", "Kyung", "Chang,", "MD1,", "Seung", "Young", "Ko,", "BS1,", "Sung", "Jun", "Kim,", "MS1,", "Dong", "Soo", "Park,", "MD2,", "Hyun", "Soo", "Shin,", "MD1", "Departments", "of", "1Radiation", "Oncology,", "2Urology,", "CHA", "Bundang", "Medical", "Center,", "CHA", "University,", "Seougnam,", "Korea", "Purpose:", "The", "present", "study", "compared", "the", "difference", "between", "intraoperative", "transrectal", "ultrasound", "(iTRUS)-based", "prostate", "volume", "and", "preplan", "computed", "tomography", "(CT),", "preplan", "magnetic", "resonance", "imaging", "(MRI)-based", "prostate", "volume", "to", "estimate", "the", "number", "of", "seeds", "needed", "for", "appropriate", "dose", "coverage", "in", "permanent", "brachytherapy", "for", "prostate", "cancer.", "Materials", "and", "Methods:", "Between", "March", "2007", "and", "March", "2011,", "among", "112", "patients", "who", "underwent", "permanent", "brachytherapy", "with", "125I,", "60", "image", "scans", "of", "56", "patients", "who", "underwent", "preplan", "CT", "(pCT)", "or", "preplan", "MRI", "(pMRI)", "within", "2", "months", "before", "brachytherapy", "were", "retrospectively", "reviewed.", "Twenty-four", "cases", "among", "30", "cases", "with", "pCT", "and", "26", "cases", "among", "30", "cases", "with", "pMRI", "received", "neoadjuvant", "hormone", "therapy", "(NHT).", "In", "34", "cases,", "NHT", "started", "after", "acquisition", "of", "preplan", "image.", "The", "median", "duration", "of", "NHT", "after", "preplan", "image", "acquisition", "was", "17", "and", "21", "days", "for", "cases", "with", "pCT", "and", "pMRI,", "respectively.", "The", "prostate", "volume", "calculated", "by", "different", "modalities", "was", "compared.", "And", "retrospective", "planning", "with", "iTRUS", "image", "was", "performed", "to", "estimate", "the", "number", "of", "125I", "seed", "required", "to", "obtain", "recommended", "dose", "distribution", "according", "to", "prostate", "volume.", "Results:", "The", "mean", "difference", "in", "prostate", "volume", "was", "9.05", "mL", "between", "the", "pCT", "and", "iTRUS", "and", "6.84", "mL", "between", "the", "pMRI", "and", "iTRUS.", "The", "prostate", "volume", "was", "roughly", "overestimated", "by", "1.36", "times", "with", "pCT", "and", "by", "1.33", "times", "with", "pMRI.", "For", "34", "cases", "which", "received", "NHT", "after", "image", "acquisition,", "the", "prostate", "volume", "was", "roughly", "overestimated", "by", "1.45", "times", "with", "pCT", "and", "by", "1.37", "times", "with", "pMRI.", "A", "statistically", "signiﬁcant", "difference", "was", "found", "between", "preplan", "image-based", "volume", "and", "iTRUS-based", "volume", "(p", "<", "0.001).", "The", "median", "number", "of", "wasted", "seeds", "is", "approximately", "13,", "when", "the", "pCT", "or", "pMRI", "volume", "was", "accepted", "without", "modiﬁcation", "to", "assess", "the", "required", "number", "of", "seeds", "for", "brachytherapy.", "Conclusion:", "pCT-based", "volume", "and", "pMRI-based", "volume", "tended", "to", "overestimate", "prostate", "volume", "in", "comparison", "to", "iTRUS-based", "volume.", "To", "reduce", "wasted", "seeds", "and", "cost", "of", "the", "brachytherapy,", "we", "should", "take", "the", "volume", "discrepancy", "into", "account", "when", "we", "estimate", "the", "number", "of", "125I", "seeds", "for", "permanent", "brachytherapy.", "Keywords:", "Brachytherapy,", "Prostate", "cancer,", "Prostate", "volume", "Received", "25", "May", "2011,", "Revised", "5", "July", "2011,", "Accepted", "13", "July", "2011.", "Correspondence:", "Hyun", "Soo", "Shin,", "MD,", "Department", "of", "Radiation", "Oncology,", "CHA", "Bundang", "Medical", "Center,", "Yatap-dong,", "Bundang-gu,", "Seongnam", "463-712,", "Korea.", "Tel:", "+82-31-780-5426,", "Fax:", "+82-31-780-5420,", "E-mail:", "shin029@chamc.co.kr", "CC", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "Non-Commercial", "License", "(http://creativecommons.org/", "licenses/by-nc/3.0/)", "which", "permits", "unrestricted", "non-commercial", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "www.e-roj.org", "Copyright", "©", "2011.", "The", "Korean", "Society", "for", "Therapeutic", "Radiology", "and", "Oncology", "199" ]	[ 16, 16, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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"Dong3", "Abstract", "Introduction:", "Ralstonia", "pickettii", "is", "a", "gram-negative,", "oxidase-positive", "bacillus", "and", "is", "an", "emerging", "pathogen", "found", "in", "infections", "described", "in", "hospital", "settings.", "The", "cases", "reported", "in", "the", "literature", "mostly", "are", "nosocomial", "infections", "due", "to", "contaminated", "blood", "products,", "sterile", "water,", "saline,", "treatment", "fluids", "and", "venous", "catheters.", "Human", "infection", "unrelated", "to", "contaminated", "solutions", "is", "rare.", "We", "report", "a", "case", "of", "lobar", "pneumonia", "and", "pulmonary", "abscess", "caused", "by", "Ralstonia", "pickettii", "in", "an", "older", "patient.", "Case", "presentation:", "A", "sixty-five-year", "old", "Han", "Chinese", "man", "presented", "having", "had", "cough,", "expectoration,", "chest", "pain", "and", "fever", "lasting", "for", "twenty", "days.", "His", "medical", "history", "was", "notable", "for", "hypertension", "over", "the", "previous", "ten", "years,", "and", "the", "habit", "of", "smoking", "for", "forty", "years.", "A", "thoracic", "computed", "tomography", "scan", "supported", "the", "diagnosis", "of", "right-", "sided", "lobar", "pneumonia.", "A", "lung", "biopsy", "was", "done", "and", "pathological", "analysis", "confirmed", "lobar", "pneumonia.", "Two", "lung", "biopsy", "specimens", "from", "separate", "sites", "grew", "Ralstonia", "pickettii.", "After", "six", "days,", "a", "repeat", "thoracic", "scan", "revealed", "a", "right-", "sided", "abscess.", "A", "thoracentesis", "was", "performed", "and", "the", "purulent", "fluid", "grew", "Ralstonia", "pickettii.", "The", "chest", "tube", "remained", "inserted", "to", "rinse", "the", "cavity", "with", "sterile", "sodium", "chloride.", "He", "received", "an", "antibiotic", "course", "of", "intravenous", "cefoperazone", "sodium-sulbactam", "sodium", "for", "eighteen", "days", "and", "imipenem-cilastatin", "for", "twelve", "days.", "A", "repeat", "chest", "X-ray", "revealed", "resolution", "of", "the", "pulmonary", "abscess", "and", "improvement", "of", "pneumonia.", "He", "remained", "afebrile", "and", "free", "of", "respiratory", "symptoms", "after", "treatments.", "Conclusion:", "This", "case", "demonstrates", "a", "Ralstonia", "pickettii", "infection", "in", "the", "absence", "of", "an", "obvious", "nosocomial", "source.", "It", "is", "possible", "that", "such", "cases", "will", "become", "common", "in", "the", "future.", "Therefore,", "further", "studies", "are", "needed", "to", "evaluate", "its", "sensitivity", "to", "common", "antibiotics.", "Introduction", "Ralstonia", "pickettii", "(R.", "pickettii)", "is", "an", "emerging", "pathogen.", "It", "is", "ubiquitous", "in", "nature", "and", "is", "found", "naturally", "in", "soil", "and", "groundwater.", "R.", "pickettii", "was", "first", "isolated", "in", "1973", "and", "included", "in", "the", "genus", "Pseudomonas", "[1].", "The", "rod-", "shaped", "organism", "was", "reclassified", "in", "the", "Burkholderia", "and", "then", "the", "Ralstonia", "genera,", "receiving", "its", "current", "name", "in", "1995", "[2].", "R.", "pickettii", "is", "often", "confused", "with", "other", "similar", "bacteria,", "increasing", "the", "difficulty", "of", "classi-", "fying", "and", "treating", "this", "pathogen.", "R.", "pickettii", "can", "be", "isolated", "from", "various", "clinical", "speci-", "mens,", "such", "as", "sputum,", "blood,", "infected", "wounds,", "urine,", "", "Correspondence:", "pwszzmxx@sina.com.cn", "2Department", "of", "Reproductive", "Medicine,", "the", "Second", "Hospital", "of", "Hebei", "Medical", "University,", "Shijiazhuang,", "China", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "ear,", "nose", "swabs,", "and", "cerebrospinal", "fluid.", "It", "is", "also", "com-", "monly", "found", "in", "the", "respiratory", "tract", "secretions", "of", "cystic", "fibrosis", "patients.", "Most", "infections", "with", "R.", "pickettii", "are", "seen", "in", "the", "hospital", "setting", "resulting", "in", "bacteremia", "and/", "or", "septicemia", "and", "respiratory", "infections", "and/or", "pneumo-", "nia", "[3].", "The", "cases", "reported", "in", "the", "literature", "are", "mostly", "nosocomial", "infections", "due", "to", "contaminated", "solutions", "including", "blood", "products,", "sterile", "water,", "saline,", "chlorhexi-", "dine", "solution,", "treatment", "fluids", "for", "the", "respiratory", "tract,", "and", "contaminated", "venous", "catheters", "[4-7].", "Human", "infec-", "tion", "unrelated", "to", "contaminated", "solutions", "is", "rare.", "There", "is", "only", "one", "documented", "case", "of", "an", "empyema", "caused", "by", "R.", "pickettii,", "and", "our", "case", "is", "similar", "in", "some", "respects", "[8].", "Our", "case", "is", "perhaps", "the", "first", "one", "reported", "of", "a", "lobar", "pneumonia", "and", "pulmonary", "abscess", "caused", "by", "R.", "pickettii.", "©", "2011", "Pan", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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[ 428, 988, 477, 1002 ], [ 481, 988, 499, 1002 ], [ 503, 988, 572, 1002 ], [ 576, 988, 599, 1002 ], [ 603, 988, 615, 1002 ], [ 618, 988, 636, 1002 ], [ 640, 988, 675, 1002 ], [ 679, 988, 706, 1002 ], [ 710, 988, 763, 1002 ], [ 428, 1004, 446, 1018 ], [ 451, 1004, 495, 1018 ], [ 499, 1004, 511, 1018 ], [ 516, 1004, 537, 1018 ], [ 541, 1004, 577, 1018 ], [ 581, 1004, 590, 1018 ], [ 594, 1004, 650, 1018 ], [ 655, 1004, 667, 1018 ], [ 671, 1004, 717, 1018 ], [ 722, 1004, 762, 1018 ], [ 428, 1019, 454, 1033 ] ]	[ "Hindawi", "Publishing", "Corporation", "Journal", "of", "Pregnancy", "Volume", "2012,", "Article", "ID", "681306,", "9", "pages", "doi:10.1155/2012/681306", "Review", "Article", "Adrenocortical", "and", "Adipose", "Responses", "to", "High-Altitude-Induced,", "Long-Term", "Hypoxia", "in", "the", "Ovine", "Fetus", "Dean", "A.", "Myers1", "and", "Charles", "A.", "Ducsay2", "1", "Department", "of", "Obstetrics", "and", "Gynecology,", "University", "of", "Oklahoma", "Health", "Sciences", "Center,", "Oklahoma", "City,", "OK", "73104,", "USA", "2", "Center", "for", "Perinatal", "Biology,", "Loma", "Linda", "University", "School", "of", "Medicine,", "Loma", "Linda,", "CA", "92350,", "USA", "Correspondence", "should", "be", "addressed", "to", "Dean", "A.", "Myers,", "dean-myers@ouhsc.edu", "Received", "7", "February", "2012;", "Accepted", "2", "March", "2012", "Academic", "Editor:", "Timothy", "Regnault", "Copyright", "©", "2012", "D.", "A.", "Myers", "and", "C.", "A.", "Ducsay.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "By", "late", "gestation,", "the", "maturing", "hypothalamo-pituitary-adrenal", "(HPA)", "axis", "aids", "the", "fetus", "in", "responding", "to", "stress.", "Hypoxia", "represents", "a", "signiﬁcant", "threat", "to", "the", "fetus", "accompanying", "situations", "such", "as", "preeclampsia,", "smoking,", "high", "altitude,", "and", "preterm", "labor.", "We", "developed", "a", "model", "of", "high-altitude", "(3,820", "m),", "long-term", "hypoxia", "(LTH)", "in", "pregnant", "sheep.", "We", "describe", "the", "impact", "of", "LTH", "on", "the", "fetal", "HPA", "axis", "at", "the", "level", "of", "the", "hypothalamic", "paraventricular", "nucleus", "(PVN),", "anterior", "pituitary", "corticotrope,", "and", "adrenal", "cortex.", "At", "the", "PVN", "and", "anterior", "pituitary,", "the", "responses", "to", "LTH", "are", "consistent", "with", "hypoxia", "being", "a", "potent", "activator", "of", "the", "HPA", "axis", "and", "potentially", "maladaptive,", "while", "the", "adrenocortical", "response", "to", "LTH", "appears", "to", "be", "primarily", "adaptive.", "We", "discuss", "mechanisms", "involved", "in", "the", "delicate", "balance", "between", "these", "seemingly", "opposing", "responses", "that", "preserve", "the", "normal", "ontogenic", "rise", "in", "fetal", "plasma", "cortisol", "essential", "for", "organ", "maturation", "and", "in", "this", "species,", "birth.", "Further,", "we", "examine", "the", "response", "to,", "and", "ramiﬁcations", "of,", "an", "acute", "secondary", "stressor", "in", "the", "LTH", "fetus.", "We", "provide", "an", "integrative", "model", "on", "the", "potential", "role", "of", "adipose", "in", "modulating", "these", "responses", "to", "LTH.", "Integration", "of", "these", "adaptive", "responses", "to", "LTH", "plays", "a", "key", "role", "in", "promoting", "normal", "fetal", "growth", "and", "development", "under", "conditions", "of", "a", "chronic", "stress.", "1.", "Introduction", "Hypoxia", "represents", "a", "major", "threat", "to", "the", "developing", "fetus", "and", "often", "accompanies", "situations", "of", "preeclampsia,", "preterm", "labor,", "smoking,", "and", "high", "altitude.", "The", "impact", "that", "hypoxia", "has", "on", "the", "fetus", "depends", "on", "a", "variety", "of", "factors", "such", "as", "stage", "of", "gestation,", "severity", "of", "the", "hypoxic", "episode,", "duration", "of", "hypoxia,", "and", "the", "association", "with", "other", "confounders", "such", "as", "acidemia", "and", "hypercapnia.", "Severe", "hypoxic", "events", "can", "lead", "to", "fetal", "death", "or", "exert", "major", "deleterious", "impacts", "on", "develop-", "ment", "and", "function", "on", "fetal", "organs,", "including", "major", "damage", "of", "the", "CNS.", "However,", "fetuses", "are", "often", "and", "perhaps", "routinely", "exposed", "to", "less", "severe", "hypoxic", "episodes.", "While", "these", "hypoxic", "conditions", "may", "impact", "fetal", "growth,", "eﬀects", "on", "other", "organ", "systems", "are", "less", "clear.", "Due", "to", "its", "long", "gestational", "length,", "similarity", "of", "endocrine", "and", "physiological", "systems,", "and", "relative", "ease", "of", "fetal", "and", "maternal", "instrumentation,", "the", "sheep", "has", "emerged", "as", "a", "ma-", "jor", "animal", "model", "for", "studying", "the", "impact", "of", "hypoxia", "on", "the", "developing", "fetus.", "These", "studies", "have", "largely", "focused", "on", "so-called", "acute", "hypoxia", "in", "which", "a", "moderate-to-severe", "hypoxia", "(a", "decrease", "in", "fetal", "PO2", "of", "50%", "or", "greater)", "is", "induced", "for", "times", "ranging", "from", "minutes", "to", "several", "hours", "or", "chronic", "hypoxia", "in", "which", "the", "fetus", "is", "made", "hypoxic", "for", "one", "to", "several", "days.", "Experimentally,", "acute", "fetal", "hypoxia", "can", "be", "induced", "by", "maternal", "hypoxia", "[1–3],", "restricting", "blood", "ﬂow", "to", "the", "uterus", "and", "placenta", "on", "the", "maternal", "side", "[4],", "or", "reducing", "umbilical", "blood", "ﬂow", "by", "cord", "compression", "[5–", "7].", "More", "prolonged", "fetal", "hypoxemia", "can", "also", "be", "initiated", "by", "repeated", "umbilical", "cord", "compression", "[7–9],", "as", "well", "as", "placental", "embolization", "[10,", "11]", "and", "restriction", "of", "uterine", "blood", "ﬂow", "[12].", "These", "methods", "induce", "either", "a", "rather", "pure", "hypoxic", "episode", "or", "hypoxia", "accompanied", "with", "acidemia", "or", "hypoglycemia.", "Longer", "duration", "hypoxic", "situations", "(months)", "have", "been", "created", "in", "sheep", "by", "maternal", "carunclectomy,", "reducing", "the", "placentation", "area", "of", "the", "uterus", "[13].", "However,", "the", "hypoxia", "in", "this", "model", "is", "secondary", "to", "nutrient", "restric-", "tion." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 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"and", "Ilan", "Atlas", "Address:", "Department", "of", "Obstetrics", "&", "Gynecology,", "The", "Baruch", "Padeh", "Medical", "Center,", "Poriya,", "Lower", "Galilee", "15208.", "Israel", "Email:", "Samer", "R", "Tannus", "-", "stannus@bezeqint.net;", "Ilan", "Atlas", "-", "ilanatlas@gmail.com", "*", "Corresponding", "author", "BioMed", "Central", "Open", "Access", "Published:", "22", "December", "2009", "Cases", "Journal", "2009,", "2:9382", "doi:10.1186/1757-1626-2-9382", "This", "article", "is", "available", "from:", "http://www.casesjournal.com/content/2/1/9382", "Received:", "29", "November", "2009", "Accepted:", "22", "December", "2009", "©", "2009", "Tannus", "and", "Atlas;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Introduction:", "Endometrial", "cancer", "is", "the", "most", "common", "gynecologic", "malignancy.", "Most", "women", "present", "with", "abnormal", "vaginal", "bleeding.", "Cervical", "stenosis", "can", "prevent", "early", "uterine", "bleeding", "leading", "to", "delayed", "diagnosis", "of", "the", "disease.", "Case", "presentation:", "A", "67", "years", "old", "Caucasian", "woman", "presented", "with", "three", "days", "history", "of", "right", "flank", "pain", "and", "difficulty", "in", "urination.", "Her", "medical", "history", "included", "cervical", "cautery", "due", "to", "ectropion", "15", "years", "previously.", "In", "physical", "exam", "a", "huge", "cystic", "mass", "that", "proved", "to", "be", "a", "large", "hematocervix", "was", "bulging", "in", "the", "vagina.", "Computed", "tomography", "of", "the", "abdomen", "revealed", "a", "distended", 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999 ], [ 540, 985, 585, 999 ], [ 588, 985, 609, 999 ], [ 613, 985, 644, 999 ], [ 647, 985, 658, 999 ], [ 661, 985, 678, 999 ], [ 681, 985, 731, 999 ], [ 734, 985, 775, 999 ], [ 411, 1013, 439, 1027 ] ]	[ "Molecular", "Vision", "2010;", "16:1453-1466", "<http://www.molvis.org/molvis/v16/a159>", "Received", "15", "June", "2010", "\|", "Accepted", "23", "July", "2010", "\|", "Published", "31", "July", "2010", "©", "2010", "Molecular", "Vision", "Abnormal", "fiber", "end", "migration", "in", "Royal", "College", "of", "Surgeons", "rats", "during", "posterior", "subcapsular", "cataract", "formation", "Anita", "Joy,1", "Tabraiz", "A.", "Mohammed,1", "Kristin", "J.", "Al-Ghoul1,2", "1Department", "of", "Anatomy", "&", "Cell", "Biology,", "Rush", "University", "Medical", "Center,", "Chicago,", "IL;", "2Department", "of", "Ophthalmology,", "Rush", "University", "Medical", "Center,", "Chicago,", "IL", "Purpose:", "Prior", "structural", "studies", "of", "posterior", "subcapsular", "cataract", "(PSC)", "development", "in", "Royal", "College", "of", "Surgeons", "(RCS)", "rats", "suggest", "that", "migration", "of", "basal", "fiber", "ends", "was", "disrupted,", "ultimately", "resulting", "in", "a", "PSC.", "Therefore", "the", "goal", "of", "this", "study", "was", "to", "assess", "the", "overall", "migration", "patterns", "as", "well", "as", "changes", "to", "the", "structure", "and", "cytoskeleton", "of", "basal", "fiber", "ends", "during", "PSC", "development.", "Methods:", "Lenses", "from", "48", "RCS", "dystrophic", "rats", "(RCS/Lav)", "and", "24", "genetically", "matched", "control", "animals", "(RCS-rdy+/Lav)", "from", "2", "to", "8", "weeks", "old", "were", "examined.", "Equatorial", "diameters", "were", "measured", "and", "suture", "patterns", "were", "photographed", "immediately", "following", "enucleation/dissection.", "Right", "eye", "lenses", "were", "fixed", "and", "processed", "to", "visualize", "the", "actin", "cytoskeleton", "via", "laser", "scanning", "confocal", "microcopy", "(LSCM),", "left", "eye", "lenses", "were", "decapsulated,", "fixed", "and", "processed", "for", "scanning", "electron", "microscopy", "(SEM).", "Scaled", "3D-computer", "assisted", "drawings", "(CADs)", "and", "animations", "were", "constructed", "from", "the", "data", "to", "depict", "the", "changes", "in", "suture", "patterns", "and", "fiber", "end", "architecture.", "Results:", "At", "2", "weeks,", "dystrophic", "lenses", "displayed", "an", "inverted", "Y", "suture", "on", "the", "posterior,", "and", "by", "3", "weeks", "most", "lenses", "had", "at", "least", "one", "sub-branch.", "Additional", "sub-branches", "were", "observed", "with", "time,", "opacities", "being", "visible", "as", "early", "as", "4", "weeks", "and", "progressing", "into", "PSC", "plaques", "by", "6", "weeks.", "Control", "lenses", "displayed", "inverted", "Y", "sutures", "at", "all", "ages", "and", "were", "transparent.", "SEM", "of", "dystrophic", "lenses", "revealed", "fiber", "ends", "with", "normal", "size,", "shape,", "arrangement,", "and", "filopodia", "at", "2", "weeks;", "scattered", "areas", "of", "dome-shaped", "fiber", "ends", "and", "small", "filopodia", "were", "present", "at", "3", "weeks.", "At", "4", "weeks", "the", "irregularly", "arranged", "domed", "fiber", "ends", "had", "extremely", "long", "filopodia", "with", "‘boutons’", "at", "their", "tips.", "By", "6", "weeks", "all", "fiber", "ends", "within", "plaques", "displayed", "rounded", "or", "domed", "basal", "membranes", "and", "lacked", "filopodial", "extensions.", "Control", "lenses", "at", "all", "time", "points", "had", "comparable", "ultrastructure", "to", "the", "2", "week", "old", "dystrophic", "lenses.", "F-actin", "arrangement", "within", "the", "basal", "membrane", "complex", "(BMC)", "of", "control", "lenses", "showed", "the", "expected", "peripheral", "pattern", "of", "labeling", "at", "all", "ages.", "Dystrophic", "RCS", "lenses", "at", "2", "weeks", "were", "comparable", "to", "controls,", "however", "by", "3–4", "weeks", "they", "displayed", "scattered", "foci", "of", "F-actin", "within", "the", "BMC.", "At", "all", "time", "points", "thereafter,", "F-actin", "was", "rearranged", "into", "a", "‘rosette’", "pattern", "of", "prominent", "foci", "at", "cell", "vertices.", "Conclusions:", "The", "data", "are", "consistent", "with", "the", "hypothesis", "that", "migration", "of", "basal", "fiber", "ends", "is", "altered", "in", "a", "two", "stage", "process", "wherein", "initially,", "migration", "patterns", "undergo", "a", "rapid", "shift", "resulting", "in", "abnormal", "suture", "sub-branch", "formation.", "Subsequent", "cytological", "alterations", "are", "consistent", "with", "an", "eventual", "cessation", "of", "migration,", "precluding", "proper", "targeting", "of", "basal", "ends", "to", "their", "sutural", "destinations", "and", "leading", "to", "cataract", "plaque", "formation.", "Congenital", "retinal", "dystrophy", "in", "the", "Royal", "College", "of", "Surgeons", "(RCS)", "rat", "is", "a", "recessively", "inherited", "anomaly", "that", "results", "in", "the", "progressive", "degeneration", "of", "photoreceptor", "cells", "in", "the", "retina", "during", "the", "later", "stages", "of", "retinal", "development", "(third", "week", "postnatal)", "[1-3].", "One", "of", "the", "many", "deleterious", "effects", "of", "this", "disease", "includes", "the", "formation", "of", "a", "secondary", "cataract,", "specifically", "a", "posterior", "subcapsular", "cataract", "(PSC).", "Although", "the", "cataract", "was", "the", "first", "feature", "noted", "and", "described", "in", "the", "RCS", "rat", "[4],", "this", "animal", "model", "has", "been", "extensively", "used", "to", "study", "retinal", "degeneration.", "Since", "the", "first", "description", "of", "the", "genetic", "abnormality", "responsible", "for", "the", "retinal", "Correspondence", "to:", "Kristin", "J.", "Al-Ghoul,", "Ph.D.,", "Department", "of", "Anatomy", "and", "Cell", "Biology,", "Rush", "University", "Medical", "Center,", "600", "S.", "Paulina", "St.,", "Ste", "507,", "Chicago,", "IL,", "60612;", "Phone:", "(312)", "563-2672;", "FAX:", "(312)", "942-5744;", "email:", "kristin_j_al-ghoul@rush.edu", "Dr.", "Mohammed", "is", "currently", "at", "the", "Department", "of", "Medicine,", "University", "of", "Wisconsin", "Hospitals", "and", "Clinics,", "Madison,", "WI", "dystrophy", "by", "Bourne", "et", "al.", "[2,5],", "the", "early", "initiation,", "rapid", "progression,", "and", "the", "resultant", "PSC", "formation", "in", "these", "animals", "have", "also", "been", "well", "documented.", "Similarities", "between", "the", "rodent", "disease", "and", "retinitis", "pigmentosa", "in", "humans", "have", "been", "established", "[5-8],", "and", "the", "RCS", "rat", "is", "therefore", "an", "excellent", "model", "to", "study", "both", "autosomal", "recessive", "retinitis", "pigmentosa", "(ARRP)", "and", "PSCs.", "In", "the", "retina,", "the", "first", "damage", "occurs", "approximately", "12", "days", "postnatal", "in", "the", "rod", "outer", "segments", "and", "by", "18", "days", "postnatal,", "the", "outer", "segment", "layer", "is", "twice", "as", "thick", "when", "compared", "to", "normal.", "There", "is", "also", "the", "presence", "of", "outer", "segment", "debris", "within", "this", "thickened", "layer.", "At", "about", "4", "weeks", "postnatal,", "this", "layer", "reaches", "its", "maximum", "thickness", "and", "both", "the", "inner", "segments", "as", "well", "as", "the", "photoreceptor", "nuclei", "begin", "to", "degenerate.", "By", "about", "40", "days", "postnatal,", "both", "inner", "and", "outer", "rod", "segments", "have", "completely", "disintegrated", "[3,9-11].", "The", "temporal", "sequence", "of", "events", "that", "mark", "the", "maximal", "accumulation", "of", "outer", "segment", "debris", "and", "retinal", "breakdown", "closely", "mirror", "the", "changes", "that", "occur", "at", "the", "posterior", "surface", "1453" ]	[ 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 9, 9, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 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"Department", "of", "Obstetrics", "and", "Gynaecology,", "United", "Bulawayo", "Hospital,", "Bulawayo,", "Zimbabwe", "Abstract", "Background:", "Obstructed", "labour", "remains", "one", "of", "the", "leading", "causes", "of", "maternal", "and", "foetal", "death", "and", "morbidity", "in", "poorly", "resourced", "areas", "of", "the", "world,", "where", "the", "24", "hours", "availability", "of", "a", "caesarean", "section", "(CS)", "cannot", "be", "guaranteed,", "and", "the", "CS", "related", "mortality", "rate", "is", "still", "high.", "In", "these", "settings,", "reinstatement", "of", "symphysiotomy", "has", "been", "advocated.", "The", "objectives", "were,", "in1994;", "to", "study", "perioperative", "and", "long-term", "complications", "of", "symphysiotomy", "and", "compare", "them", "to", "those", "related", "to", "CS", "for", "similar", "indications,", "in", "1996;", "to", "measure", "the", "symphyseal", "width", "after", "symphysiotomy", "and", "compare", "it", "to", "that", "after", "normal", "vaginal", "delivery,", "and,", "in", "1998;", "to", "assess", "knowledge,", "attitudes", "and", "practice", "related", "to", "symphysiotomy", "among", "doctors", "and", "midwives", "in", "Zimbabwe.", "Methods", "and", "Findings:", "Thirty-four", "women", "who", "had", "undergone", "symphysiotomy", "and", "29", "women", "who", "had", "undergone", "a", "CS", "for", "obstructed", "labour", "were", "interviewed.", "The", "symphyseal", "widths", "of", "19", "women", "with", "a", "previous", "symphysiotomy", "were", "compared", "to", "that", "of", "92", "women", "with", "previous", "normal", "vaginal", "deliveries,", "using", "ultrasound", "technique.", "Forty-one", "doctors", "and", "39", "midwives,", "in", "three", "central", "hospitals", "and", "seven", "district", "hospitals", "in", "Zimbabwe,", "were", "interviewed", "about", "symphysiotomy.", "None", "of", "the", "34", "women", "reported", "serious", "soft", "tissue", "injuries", "or", "infections", "post", "symphysiotomy.", "Long-term", "complications", "after", "symphysiotomy", "do", "not", "differ", "notably", "from", "those", "after", "CS", "for", "similar", "indications.", "The", "intra-articular", "width", "of", "the", "symphysis", "pubis", "is", "increased", "after", "a", "symphysiotomy.", "Seventy-nine", "of", "the", "80", "interviewed", "health", "care", "workers", "knew", "about", "symphysiotomy.", "One", "obstetrician", "had", "performed", "symphysiotomies.", "Two-thirds", "of", "the", "participants", "considered", "symphysiotomy", "an", "obsolete", "and", "second-class", "operation,", "but", "lifesaving", "and", "appropriate", "in", "remote", "areas", "of", "Zimbabwe.", "Ten", "of", "13", "midwives", "in", "remote", "areas", "wanted", "to", "carry", "out", "symphysiotomies", "themselves.", "Conclusions:", "No", "severe", "complications", "due", "to", "symphysiotomy", "were", "revealed", "in", "this", "study.", "The", "results", "suggest", "that", "a", "modest", "permanent", "enlargement", "of", "the", "pelvis", "post", "symphysiotomy", "(together", "with", "the", "absence", "of", "a", "scarred", "uterus)", "may", "facilitate", "subsequent", "vaginal", "delivery.", "Doctors", "and", "midwives", "working", "in", "district", "hospitals", "have", "a", "more", "positive", "attitude", "to", "symphysiotomies", "than", "the", "colleagues", "in", "central", "hospitals.", "Obstetricians", "(who", "would", "have", "to", "do", "the", "teaching),", "working", "in", "the", "large", "urban", "hospitals", "almost", "exclude", "symphysiotomy", "as", "an", "alternative", "management", "in", "Zimbabwe.", "Citation:", "Ersdal", "HL,", "Verkuyl", "DAA,", "Bj", "o¨rklund", "K,", "Bergstro¨", "m", "S", "(2008)", "Symphysiotomy", "in", "Zimbabwe;", "Postoperative", "Outcome,", "Width", "of", "the", "Symphysis", "Joint,", "and", "Knowledge,", "Attitudes", "and", "Practice", "among", "Doctors", "and", "Midwives.", "PLoS", "ONE", "3(10):", "e3317.", "doi:10.1371/journal.pone.0003317", "Editor:", "Landon", "Myer,", "University", "of", "Cape", "Town,", "South", "Africa", "Received", "May", "9,", "2008;", "Accepted", "September", "12,", "2008;", "Published", "October", "10,", "2008", "Copyright:", "2008", "Ersdal", "et", "al.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Funding:", "The", "work", "presented", "is", "partly", "financed", "by", "The", "Research", "Council", "of", "Norway", "(student", "scholarship", "for", "the", "first", "auther", "HLE).", "The", "funder", "had", "no", "role", "in", "study", "design,", "data", "collection", "and", "analysis,", "decision", "to", "publish,", "or", "preparation", "of", "the", "manuscript", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "", "E-mail:", "hege@ersdal.com", "{", "Deceased.", "Introduction", "Symphysiotomy", "was", "developed", "in", "Europe", "late", "in", "the", "18th", "century", "as", "a", "means", "to", "save", "the", "lives", "of", "mother", "and", "child", "in", "obstructed", "labour.", "In", "the", "early", "days", "the", "separation", "of", "the", "bones", "was", "performed", "after", "exposing", "the", "symphysis.", "With", "the", "introduc-", "tion", "of", "aseptic", "techniques", "in", "the", "mid", "19th", "century", "and", "the", "subcutaneous", "symphysiotomy", "by", "Frank", "[1],", "using", "local", "anaesthet-", "ics,", "the", "operation", "gained", "acceptance", "and", "became", "part", "of", "the", "obstetric", "arsenal", "in", "many", "parts", "of", "Europe", "[2–5].", "The", "technique", "was", "further", "refined", "by", "Za´rate", "in", "Argentina", "[6],", "and", "symphysiot-", "omy", "was", "extensively", "practised", "in", "Latin", "America", "and", "Ireland", "up", "to", "the", "mid", "20th", "century", "[4,7,8].", "Seedat", "and", "Crichton", "in", "Durban,", "South", "Africa,", "further", "developed", "the", "technique", "[9]", "and", "symphy-", "siotomy", "came", "to", "be", "used", "in", "Africa", "for", "the", "ensuing", "decades", "[9–12].", "Currently,", "outside", "Africa,", "symphysiotomies", "are", "still", "performed", "in", "Papua", "New", "Guinea", "[13].", "Mechanical", "obstruction", "in", "the", "second", "stage", "complicates", "1–2%", "of", "labours", "[14].", "In", "developing", "countries", "this", "percentage", "might", "be", "higher", "because", "women", "often", "do", "not", "attain", "their", "(pelvic)", "growth", "potential", "due", "to", "stunting.", "The", "facilities", "and", "staffing", "level", "of", "non-", "private", "hospitals", "in", "developing", "countries", "make", "it", "often", "inevitable", "that", "CSs", "are", "associated", "with", "an", "appreciable", "mortality", "rate.", "In", "addition,", "there", "is", "no", "guarantee", "that", "a", "woman", "with", "a", "scar", "in", "the", "uterus", "can,", "or", "even", "would", "like", "to,", "reach", "in", "time", "a", "(still", "adequately", "staffed)", "hospital", "for", "the", "next", "delivery.", "The", "World", "Health", "Organization", "(WHO)", "PLoS", "ONE", "\|", "www.plosone.org", "1", "October", "2008", "\|", "Volume", "3", "\|", "Issue", "10", "\|", "e3317" ]	[ 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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490, 1015, 568, 1026 ], [ 570, 1015, 603, 1026 ], [ 606, 1015, 773, 1026 ], [ 59, 1028, 107, 1039 ], [ 110, 1028, 137, 1039 ], [ 139, 1028, 173, 1039 ], [ 176, 1028, 229, 1039 ], [ 232, 1028, 304, 1039 ], [ 307, 1028, 325, 1039 ], [ 328, 1028, 383, 1039 ], [ 386, 1028, 403, 1039 ], [ 406, 1028, 464, 1039 ], [ 467, 1028, 476, 1039 ], [ 479, 1028, 496, 1039 ], [ 499, 1028, 538, 1039 ], [ 541, 1028, 581, 1039 ], [ 584, 1028, 598, 1039 ], [ 601, 1028, 636, 1039 ], [ 639, 1028, 662, 1039 ], [ 665, 1028, 672, 1039 ], [ 675, 1028, 713, 1039 ], [ 717, 1028, 741, 1039 ] ]	[ "6774–6786", "Nucleic", "Acids", "Research,", "2012,", "Vol.", "40,", "No.", "14", "doi:10.1093/nar/gks388", "Published", "online", "7", "May", "2012", "Biochemical", "analyses", "indicate", "that", "binding", "and", "cleavage", "specificities", "define", "the", "ordered", "processing", "of", "human", "Okazaki", "fragments", "by", "Dna2", "and", "FEN1", "Jason", "W.", "Gloor1,", "Lata", "Balakrishnan", "1", ",", "Judith", "L.", "Campbell2", "and", "Robert", "A.", "Bambara1,", "1Department", "of", "Microbiology", "and", "Immunology,", "University", "of", "Rochester", "School", "of", "Medicine", "and", "Dentistry,", "Rochester,", "NY", "14642", "and", "2Braun", "Laboratories,", "California", "Institute", "of", "Technology,", "Pasadena,", "CA", "91125,", "USA", "Received", "March", "12,", "2012;", "Revised", "April", "5,", "2012;", "Accepted", "April", "13,", "2012", "ABSTRACT", "In", "eukaryotic", "Okazaki", "fragment", "processing,", "the", "RNA", "primer", "is", "displaced", "into", "a", "single-stranded", "flap", "prior", "to", "removal.", "Evidence", "suggests", "that", "some", "flaps", "become", "long", "before", "they", "are", "cleaved,", "and", "that", "this", "cleavage", "involves", "the", "sequential", "action", "of", "two", "nucleases.", "Strand", "displacement", "characteristics", "of", "the", "polymerase", "show", "that", "a", "short", "gap", "precedes", "the", "flap", "during", "synthesis.", "Using", "biochemical", "tech-", "niques,", "binding", "and", "cleavage", "assays", "presented", "here", "indicate", "that", "when", "the", "flap", "is", "30", "nt", "long", "the", "nuclease", "Dna2", "can", "bind", "with", "high", "affinity", "to", "the", "flap", "and", "downstream", "double", "strand", "and", "begin", "cleavage.", "When", "the", "polymerase", "idles", "or", "dissociates", "the", "Dna2", "can", "reorient", "for", "additional", "contacts", "with", "the", "upstream", "primer", "region,", "allowing", "the", "nuclease", "to", "remain", "stably", "bound", "as", "the", "flap", "is", "further", "shortened.", "The", "DNA", "can", "then", "equilibrate", "to", "a", "double", "flap", "that", "can", "bind", "Dna2", "and", "flap", "endonucle-", "ase", "(FEN1)", "simultaneously.", "When", "Dna2", "shortens", "the", "flap", "even", "more,", "FEN1", "can", "displace", "the", "Dna2", "and", "cleave", "at", "the", "flap", "base", "to", "make", "a", "nick", "for", "ligation.", "INTRODUCTION", "In", "both", "prokaryotic", "and", "eukaryotic", "DNA", "replication,", "one", "strand", "of", "DNA,", "called", "lagging,", "is", "initially", "made", "in", "discon-", "tinuous", "segments", "termed", "Okazaki", "fragments.", "In", "humans,", "each", "fragment", "is", "initiated", "by", "an", "RNA", "primer", "8–10", "nt", "in", "length", "and", "extended", "150–200", "nt", "with", "DNA", "(1).", "The", "fragments", "need", "to", "be", "joined", "to", "make", "a", "continuous", "strand.", "This", "involves", "strand", "displacement", "synthesis", "from", "one", "fragment", "to", "raise", "the", "RNA", "primer", "region", "of", "the", "adjacent", "fragment", "into", "a", "ﬂap.", "Genetic", "experiments", "and", "reconstitutions", "in", "vitro", "suggest", "that", "ﬂap", "creation", "and", "removal", "occurs", "via", "two", "pathways.", "One", "employs", "the", "ﬂap", "endonuclease", "(FEN1),", "which", "removes", "the", "ﬂap", "containing", "the", "initiator", "RNA", "leaving", "a", "nick", "for", "ligation.", "If", "a", "ﬂap", "escapes", "FEN1", "to", "grow", "long", "enough", "to", "acquire", "the", "eukary-", "otic", "DNA-binding", "protein", "(RPA),", "nucleolytic", "cleavage", "will", "be", "blocked.", "If", "so,", "the", "ﬂap", "is", "processed", "by", "the", "second", "pathway", "in", "which", "the", "nuclease/helicase", "Dna2", "displaces", "the", "RPA.", "Dna2", "then", "successively", "cleaves", "the", "ﬂap", "until", "it", "is", "too", "short", "to", "bind", "RPA", "and", "becomes", "a", "substrate", "for", "FEN1", "(2,3).", "Biochemical", "analyses", "have", "demonstrated", "that", "both", "FEN1", "(4–13)", "and", "Dna2", "(14)", "employ", "a", "threading", "mechan-", "ism", "for", "binding", "and", "cleavage", "of", "the", "ﬂap", "substrate.", "Recent", "results", "show", "that", "both", "nucleases", "recognize", "and", "bind", "to", "the", "base", "of", "the", "ﬂap", "and", "then", "thread", "the", "50", "end", "of", "the", "ﬂap", "through", "the", "protein", "(15–17).", "Dna2", "cleaves", "periodically", "during", "the", "threading", "(18,19),", "and", "FEN1", "cleaves", "speciﬁc-", "ally", "at", "the", "base", "(4,20,21).", "Previous", "analyses", "with", "puriﬁed", "proteins", "from", "Saccharo-", "myces", "cerevisiae", "clariﬁed", "how", "these", "proteins", "act", "in", "succes-", "sion", "to", "process", "Okazaki", "fragments", "(8,22–25).", "On", "a", "long", "ﬂap", "substrate,", "S.", "cerevisiae", "Dna2", "(scDna2)", "was", "shown", "to", "displace", "bound", "scRPA", "in", "a", "reaction", "that", "did", "not", "require", "cleavage", "(26).", "scFEN1", "was", "shown", "to", "displace", "the", "scDna2,", "so", "that", "it", "could", "have", "access", "to", "its", "cleavage", "site", "at", "the", "ﬂap", "base", "(17).", "In", "addition", "to", "the", "role", "it", "plays", "in", "Okazaki", "fragment", "pro-", "cessing,", "Dna2", "functions", "in", "conjunction", "with", "30–50", "helicases", "and", "RPA", "to", "resect", "the", "50", "end", "of", "DNA", "during", "double-strand", "break", "(DSB)", "repair", "and", "telomere", "maintenance", "(27).", "Human", "and", "yeast", "systems", "employ", "redundant", "pathways", "during", "these", "processes,", "one", "of", "which", "utilizes", "Dna2", "(28–30).", "Once", "recruited", "to", "the", "DSB,", "a", "30–50", "helicase", "separ-", "ates", "the", "two", "strands", "of", "the", "DNA", "creating", "a", "pseudo-Y", "struc-", "ture", "consisting", "of", "a", "30", "single-stranded", "(ss)", "DNA", "tail,", "a", "50", "ssDNA", "tail", "and", "a", "double-stranded", "region.", "These", "single-", "stranded", "tails", "can", "then", "be", "coated", "by", "RPA.", "Similar", "to", "its", "role", "in", "the", "long", "ﬂap", "Okazaki", "fragment", "pathway,", "Dna2", "cleaves", "the", "50-ssDNA.", "Surprisingly,", "even", "though", "Dna2", "possesses", "a", "30", "nuclease", "activity,", "RPA", "prevents", "cleavage", "of", "the", "30-ssDNA", "(30,31).", "Dna2", "interacts", "with", "the", "RPA1", "(70", "kDa)", "subunit", "of", "RPA", "(22).", "The", "N", "terminus", "of", "RPA1", "To", "whom", "correspondence", "should", "be", "addressed.", "Tel:", "+1", "585", "275", "3269;", "Fax:", "+1", "585", "275", "6007;", "Email:", "robert_bambara@urmc.rochester.edu", "The", "Author(s)", "2012.", "Published", "by", "Oxford", "University", "Press.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "Non-Commercial", "License", "(http://creativecommons.org/licenses/", "by-nc/3.0),", "which", "permits", "unrestricted", "non-commercial", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 7, 7, 7, 7, 7, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 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[ 748, 1052, 759, 1065 ], [ 762, 1052, 769, 1065 ], [ 599, 1069, 624, 1079 ], [ 627, 1069, 660, 1079 ], [ 662, 1069, 676, 1079 ], [ 678, 1069, 690, 1079 ], [ 692, 1069, 723, 1079 ], [ 726, 1069, 770, 1079 ] ]	[ "BMC", "Bioinformatics", "Research", "article", "Evolutionary", "distance", "estimation", "and", "fidelity", "of", "pair", "wise", "sequence", "alignment", "Michael", "S", "Rosenberg", "Address:", "Center", "for", "Evolutionary", "Functional", "Genomics,", "The", "Biodesign", "Institute,", "and", "the", "School", "of", "Life", "Sciences,", "Arizona", "State", "University,", "Tempe,", "AZ", "84287-4501,", "USA", "Email:", "Michael", "S", "Rosenberg", "-", "msr@asu.edu", "*", "Corresponding", "author", "BioMed", "Central", "Open", "Access", "Published:", "19", "April", "2005", "BMC", "Bioinformatics", "2005,", "6:102", "doi:10.1186/1471-2105-6-102", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1471-2105/6/102", "Received:", "16", "December", "2004", "Accepted:", "19", "April", "2005", "©", "2005", "Rosenberg;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "Evolutionary", "distances", "are", "a", "critical", "measure", "in", "comparative", "genomics", "and", "molecular", "evolutionary", "biology.", "A", "simulation", "study", "was", "used", "to", "examine", "the", "effect", "of", "alignment", "accuracy", "of", "DNA", "sequences", "on", "evolutionary", "distance", "estimation.", "Results:", "Under", "the", "studied", "conditions,", "distance", "estimation", "was", "relatively", "unaffected", "by", "alignment", "error", "(50%", "or", "more", "of", "the", "sites", "incorrectly", "aligned)", "as", "long", "as", "50%", "or", "more", "of", "the", "sites", "were", "identical", "among", "the", "sequences", "(observed", "P-distance", "<", "0.5).", "Beyond", "this", "threshold,", "the", "alignment", "procedure", "artificially", "inflates", "the", "apparent", "sequence", "identity,", "skewing", "distance", "estimates,", "and", "creating", "alignments", "that", "are", "essentially", "indistinguishable", "from", "random", "data.", "This", "general", "result", "was", "independent", "of", "substitution", "model,", "sequence", "length,", "and", "insertion", "and", "deletion", "size", "and", "rate.", "Conclusion:", "Examination", "of", "the", "estimated", "sequence", "identity", "may", "yield", "some", "guidance", "as", "to", "the", "accuracy", "of", "the", "alignment.", "Inaccurate", "alignments", "are", "expected", "to", "have", "large", "effects", "on", "analyses", "dependent", "on", "site", "specificity,", "but", "analyses", "that", "depend", "on", "evolutionary", "distance", "may", "be", "somewhat", "robust", "to", "alignment", "error", "as", "long", "as", "fewer", "than", "half", "of", "the", "sites", "have", "diverged.", "Background", "Evolutionary", "distance,", "the", "number", "of", "substitutions", "per", "site", "separating", "a", "pair", "of", "homologous", "sequences", "since", "they", "diverged", "from", "their", "common", "ancestral", "sequence,", "is", "an", "extremely", "important", "measure", "in", "molecular", "evolution", "and", "comparative", "genomics.", "It", "is", "used", "for", "a", "wide", "variety", "of", "pur-", "poses,", "ranging", "from", "phylogenetic", "analysis", "[1,2],", "to", "esti-", "mating", "times", "of", "divergence", "[3,4],", "the", "tempo", "and", "mode", "of", "evolutionary", "change", "[5],", "and", "functional", "constraints", "[6,7].", "Evolutionary", "distance", "estimation", "is", "often", "one", "of", "the", "first", "steps", "in", "high-throughput", "sequence", "analysis;", "errors", "in", "these", "estimates", "may", "have", "wide-ranging", "consequences", "on", "downstream", "analyses", "and", "conclusions.", "There", "are", "many", "ways", "to", "estimate", "evolutionary", "distance;", "accuracy", "of", "various", "methods", "tends", "to", "be", "dependent", "on", "proper", "specification", "of", "the", "substitution", "model", "and", "sequence", "length", "[8,9].", "One", "factor", "that", "has", "not", "been", "well", "examined", "with", "respect", "to", "evolutionary", "distance", "estima-", "tion,", "however,", "is", "alignment", "(although", "see", "[10-12]).", "Sequence", "alignment", "is", "an", "extremely", "common", "analytical", "tool", "used", "in", "comparative", "genomics.", "The", "purpose", "of", "align-", "ment", "is", "to", "identify", "positions", "in", "homologous", "sequences", "that", "are", "descended", "from", "a", "common", "ancestor.", "Because", "alignment", "is", "the", "first", "step", "in", "many", "complex,", "high-", "throughput", "studies", "[13],", "it", "is", "often", "forgotten", "that", "align-", "ment", "algorithms", "produce", "a", "hypothesis", "of", "homology", "(just", "as", "a", "phylogenetic", "tree", "is", "a", "hypothesis", "of", "evolutionary", "Page", "1", "of", "9", "(page", "number", "not", "for", "citation", "purposes)" ]	[ 0, 0, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 0, 0, 9, 9, 7, 7, 7, 7, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 7, 7, 7, 7, 7, 7, 7, 7, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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"Medicine", "2011,", "4:9", "http://www.intarchmed.com/content/4/1/9", "C", "A", "S", "E", "R", "E", "P", "O", "R", "T", "Open", "Access", "Co-existing", "sarcoidosis", "and", "Takayasu", "arteritis:", "report", "of", "a", "case", "Amira", "Hamzaoui1,", "Randa", "Salem2,", "Rim", "Klii1,", "Olfa", "Harzallah1,", "Olfa", "Berriche1,", "Mondher", "Golli2,", "Silvia", "Mahjoub1", "Abstract", "Introduction:", "Takayasu", "arteritis", "(TA)", "is", "a", "chronic", "vasculitis", "of", "unknown", "origin,", "affecting", "mainly", "the", "aorta", "and", "its", "main", "branches.", "As", "a", "result", "of", "the", "inflammation,", "stenosis,", "occlusion", "or", "dilatation", "of", "the", "involved", "vessels", "may", "occur", "and", "cause", "a", "wide", "range", "of", "symptoms.", "It", "has", "been", "described", "in", "association", "with", "various", "auto-immune", "disorders", "(mainly", "inflammatory", "digestive", "tract", "diseases).", "However,", "only", "few", "cases", "of", "TA", "associated", "with", "sarcoidosis", "have", "been", "reported,", "raising", "the", "question", "of", "an", "association", "by", "chance.", "Case", "report:", "We", "report", "a", "case", "of", "a", "34", "year-old", "woman,", "with", "one", "year", "history", "of", "sarcoidosis,", "who", "presented", "with", "asymmetric", "high", "hypertension", "revealing", "inflammatory", "humeral,", "axillary", "and", "subclavian", "arteritis", "related", "to", "TA,", "successfully", "treated", "by", "steroid", "and", "immunosuppressive", "therapy(MethotrexateR).", "Conclusion:", "TA", "and", "sarcoidosis", "may", "be", "related,", "rising", "the", "hypothesis", "that", "TA", "or", "Takayasu", "arteritis-like", "granulomatous", "vasculitis", "may", "be,", "in", "fact,", "a", "complication", "of", "sarcoidosis.", "Introduction", "Takayasu", "arteritis", "(TA)", "is", "a", "chronic", "inflammatory", "dis-", "ease", "of", "large", "arteries", "which", "progressively", "develop", "steno-", "sis,", "occlusion", "or", "aneurismal", "degeneration.", "The", "clinical", "presentation", "is", "characterised", "by", "an", "acute", "phase", "with", "constitutional", "symptoms,", "followed,", "months", "or", "years", "later,", "by", "a", "chronic", "phase", "in", "which", "symptoms", "relate", "to", "fibrosis", "or", "occlusion", "of", "vessels.", "Angiography", "is", "the", "gold", "standard", "for", "diagnosis", "and", "for", "topographical", "classifica-", "tion", "and", "it", "correlates", "with", "symptoms", "and", "prognosis.", "Proinflammatory", "cytokines", "and,", "among", "these,", "tumor", "necrosis", "factor-alpha", "(TNF-alpha)", "are", "increased", "and", "play", "a", "pathogenetic", "role", "in", "the", "development", "of", "disease.", "Laboratory", "findings", "are", "non-specific.", "Treatment", "of", "active", "disease", "is", "primarily", "based", "on", "corticosteroids", "but", "other", "immunosuppressive", "drugs", "are", "frequently", "needed.", "Anti-platelets", "agents,", "statins", "and", "antihypertensive", "drugs", "are", "frequently", "considered", "[1].", "Sarcoidosis,", "too,", "is", "a", "systemic", "inflammatory", "disease", "which", "can", "affect", "virtually", "any", "organ", "system.", "The", "lungs", "are", "most", "commonly", "affected,", "but", "often", "there", "is", "also", "affection", "of", "the", "musculoskeletal", "system,", "the", "cutaneous", "", "Correspondence:", "hamzaoui.amira@yahoo.fr", "1Department", "of", "Internal", "Medicine-", "Fattouma", "Bourguiba", "Hospital-", "Monastir-", "Tunisia", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "and", "central", "nervous", "systems,", "and", "the", "heart.", "Histology", "shows", "granulomas", "consisting", "of", "a", "central", "zone", "with", "macrophages,", "epithelioid", "cells,", "and", "multinucleated", "giant", "cells", "in", "addition", "to", "activated", "CD4", "lymphocytes,", "and", "a", "peripheral", "zone", "with", "macrophages,", "fibroblasts,", "and", "CD4", "and", "CD8", "lymphocytes.", "Inclusion", "bodies", "are", "commonly", "found.", "Vasculitis", "may", "be", "found", "occasionally", "in", "patients", "with", "sarcoidosis.", "It", "has", "not", "been", "confirmed,", "however,", "whether", "vasculitis", "is", "a", "true", "manifestation", "of", "the", "disease", "or", "an", "occasional,", "incidentally", "concurring", "abnormality.", "Concurrence", "of", "sarcoidosis", "and", "TA", "were", "reported", "in", "few", "cases.", "Case", "Report", "A", "34", "year", "old", "woman", "was", "admitted", "to", "the", "hospital", "with", "dyspnea,", "submandubular", "gland", "tumefaction", "and", "parotid", "swelling.", "On", "physical", "examination,", "we", "found", "the", "tumefaction", "of", "the", "parotid", "and", "the", "submandibular", "gland.", "The", "respira-", "tory", "frequency", "was", "24", "cycles", "per", "minute.", "The", "rest", "of", "the", "clinical", "examination", "was", "without", "abnormalities.", "Laboratory", "results", "were", "as", "follows:", "Haemoglobin", "10", "g/dl,", "white", "blood", "cell", "count", "(WBC)", "11", "200/mm3,", "platelets", "450", "000/mm3,", "erythrocyte", "sedimentation", "rate", "(ESR)", "76", "mm/h,", "calcium", "12", "mg/dl", "(normal:", "9-11", "mg/dl", ").", "Muscle", "©", "2011", "Hamzaoui", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 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"10.3341/kjo.2009.23.4.329", "A", "Case", "of", "Pseudo-Duane’s", "Retraction", "Syndrome", "With", "Old", "Medial", "Orbital", "Wall", "Fracture", "Seung", "Hee", "Lee,", "MD,", "Jae", "Hyung", "Lee,", "MD,", "Soo", "Yoon", "Lee,", "MD,", "Sook", "Young", "Kim,", "MD", "Department", "of", "Ophthalmology,", "Daegu", "Catholic", "University", "College", "of", "Medicine,", "Daegu,", "Korea", "We", "report", "a", "case", "of", "pseudo-Duane’s", "retraction", "syndrome", "with", "entrapment", "of", "the", "medial", "rectus", "muscle", "in", "an", "old", "medial", "orbital", "wall", "fracture", "presenting", "identical", "clinical", "symptoms", "as", "Duane’s", "retraction", "syndrome.", "A15-year-old", "boy", "presented", "with", "persistent", "limited", "right", "eye", "movement", "since", "a", "young", "age.", "Examination", "showed", "marked", "limited", "abduction,", "mildly", "limited", "adduction,", "and", "globe", "retraction", "accompanied", "by", "narrowing", "of", "the", "palpebral", "fissure", "during", "attempted", "adduction", "in", "the", "right", "eye.", "He", "showed", "a", "right", "esotropia", "of", "16", "prism", "diopters", "and", "his", "head", "turned", "slightly", "to", "the", "right.", "A", "slight", "enophthalmos", "was", "noted", "in", "his", "right", "eye.", "A", "computed", "tomography", "scan", "demonstrated", "entrapment", "of", "the", "medial", "rectus", "muscle", "and", "surrounding", "tissues", "in", "an", "old", "medial", "orbital", "wall", "fracture.", "A", "forced", "duction", "test", "revealed", "a", "marked", "restriction", "of", "abduction", "in", "the", "right", "eye.", "A", "5", "mm", "recession", "of", "the", "right", "medial", "rectus", "muscle", "was", "performed.", "Post-", "operatively,", "the", "patient’s", "head", "turn", "and", "esotropia", "in", "the", "primary", "position", "were", "successfully", "corrected,", "but", "there", "was", "still", "some", "limitations", "to", "his", "ocular", "movement.", "The", "importance", "of", "several", "tests", "such", "as", "the", "forced", "duction", "test", "and", "an", "imaging", "study", "should", "be", "emphasized", "in", "making", "a", "diagnosis", "for", "limitation", "of", "eye", "movement.", "Korean", "J", "Ophthalmol", "2009;23:329-331", "ⓒ", "2009", "by", "the", "Korean", "Ophthalmological", "Society.", "Key", "Words:", "Duane’s", "retraction", "syndrome,", "Medial", "orbital", "wall", "fracture,", "Pseudo-Duane’s", "retraction", "syndrome", "Since", "Alexander", "Duane", "published", "a", "paper", "in", "1905", "des-", "cribing", "what", "has", "come", "to", "be", "known", "as", "Duane’s", "retraction", "syndrome,", "Thomas", "Duane", "reported", "a", "similar,", "yet", "different", "set", "of", "symptoms", "and", "signs", "as", "‘pseudo-Duane’s", "retraction", "syndrome’", "in", "1976.1", "In", "the", "most", "common", "type", "of", "Duane’s", "retraction", "syndrome,", "there", "is", "markedly", "restricted", "abduction", "with", "eyeball", "retraction", "and", "narrowing", "of", "the", "palpebral", "fissure", "on", "adduction.2", "In", "pseudo-Duane’s", "retraction", "syndrome,", "how-", "ever,", "abduction", "of", "the", "affected", "eye", "is", "possible", "to", "some", "extent,", "and", "the", "globe", "retraction", "occurs", "on", "abduction", "accompanied", "by", "narrowing", "of", "the", "palpebral", "fissure", "presenting", "the", "opposite", "features", "as", "those", "of", "classic", "Duane’s", "retraction", "syndrome.", "The", "etiology", "is", "also", "completely", "different", "from", "those", "of", "Duane’s", "retraction", "syndrome.", "Pseudo-Duane’s", "retraction", "syndrome", "has", "been", "reported", "as", "being", "caused", "by", "acquired", "or", "congenital", "factors", "that", "affect", "the", "medial", "rectus", "muscle.", "Entrapment", "of", "the", "medial", "rectus", "muscle", "in", "a", "medial", "orbital", "wall", "fracture", "has", "been", "known", "to", "be", "the", "most", "common", "cause.3", "We", "report", "a", "case", "of", "pseudo-Duane’s", "retraction", "syndrome", "with", "entrapment", "of", "the", "medial", "rectus", "muscle", "in", "an", "old", "medial", "orbital", "wall", "fracture,", "presenting", "very", "similar", "clinical", "features", "as", "those", "of", "classic", "Duane’s", "retraction", "syndrome.", "The", "pre-", "Received:", "April", "22,", "2009", "Accepted:", "October", "29,", "2009", "Reprint", "requests", "to", "Sook", "Young", "Kim,", "MD.", "Department", "of", "Ophthalmology,", "Daegu", "Catholic", "University", "College", "of", "Medicine,", "#3056-6", "Daemyeong", "4-dong,", "Nam-gu,", "Daegu", "705-718,", "Korea.", "Tel:", "82-53-650-4728,", "E-mail:", "kimsy@cu.ac.kr", "sentation", "is", "contradictory", "to", "previous", "reports", "of", "pseudo-", "Duane’s", "retraction", "syndrome.", "Case", "Repo", "rt", "A", "15-year-old", "boy", "had", "complained", "of", "motility", "limitation", "in", "the", "right", "eye", "since", "a", "young", "age.", "His", "visual", "acuity", "was", "20/20", "in", "each", "eye,", "although", "an", "ocular", "motility", "examination", "revealed", "markedly", "limited", "abduction", "and", "mildly", "limited", "adduction", "in", "his", "right", "eye", "(Fig.", "1).", "On", "attempted", "adduction", "of", "the", "right", "eye,", "globe", "retraction", "(Fig.", "2)", "with", "narrowing", "of", "the", "palpebral", "fissure", "was", "observed,", "and", "there", "mild", "upshoot", "and", "downshoot", "were", "also", "observed", "(Fig.", "1).", "The", "palpebral", "fissure", "of", "the", "right", "eye", "was", "slightly", "widened", "on", "attempted", "abduction.", "An", "alternate", "prism", "cover", "test", "revealed", "a", "16", "prism", "diopters", "(PD)", "right", "esotropia", "(ET)", "in", "the", "primary", "position,", "25", "PD", "ET", "in", "right", "gaze,", "10", "PD", "ET", "in", "left", "gaze", "at", "dist-", "ance", "fixation,", "and", "4", "PD", "ET", "at", "near", "fixation.", "He", "assumed", "a", "compensatory", "face", "turn", "to", "the", "right", "and", "did", "not", "comp-", "lain", "of", "diplopia.", "No", "living", "member", "on", "either", "the", "paternal", "or", "maternal", "side", "had", "a", "squint.", "Duane’s", "retraction", "syndrome", "was", "inferred", "as", "the", "diagnosis", "until", "we", "noted", "that", "the", "patient’s", "right", "eye", "had", "slight", "enophthalmos.", "Hertel’s", "exophthalmo-", "metry", "revealed", "a", "1.5", "mm", "difference", "between", "both", "eyes", "and", "the", "margin", "reflex", "distance", "1", "was", "0.5", "mm", "in", "the", "right", "eye.", "Computed", "tomography", "of", "the", "orbits", "was", "performed", "and", "demonstrated", "an", "old", "medial", "orbital", "wall", "fracture", "with", "entrapment", "of", "the", "medial", "rectus", "muscle", "and", "surrounding", "tissues", "(Fig.", "3).", "However,", "there", "was", "no", "history", "of", "trauma", "329" ]	[ 7, 7, 0, 0, 0, 0, 0, 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], [ 199, 996, 210, 1010 ], [ 214, 996, 227, 1010 ], [ 230, 996, 304, 1010 ], [ 307, 996, 374, 1010 ], [ 705, 1052, 735, 1065 ], [ 738, 1052, 745, 1065 ], [ 748, 1052, 759, 1065 ], [ 762, 1052, 769, 1065 ], [ 599, 1070, 624, 1080 ], [ 627, 1070, 660, 1080 ], [ 662, 1070, 676, 1080 ], [ 678, 1070, 690, 1080 ], [ 692, 1070, 723, 1080 ], [ 726, 1070, 770, 1080 ] ]	[ "BMC", "Public", "Health", "Research", "article", "Rubella", "seroprevalence", "among", "primary", "and", "pre-", "primary", "school", "pupils", "at", "Moi's", "Bridge", "location,", "Uasin", "Gishu", "District,", "Kenya", "Janeth", "J", "Kombich,", "Paul", "C", "Muchai,", "Peter", "Tukei", "and", "Peter", "K", "Borus", "BioMed", "Central", "Open", "Access", "Address:", "Centre", "for", "Virus", "Research,", "Kenya", "Medical", "Research", "Institute,", "Nairobi,", "Kenya", "Email:", "Janeth", "J", "Kombich", "-", "jkombich@kemri.org;", "Paul", "C", "Muchai", "-", "pmuchai@kemri.org;", "Peter", "Tukei", "-", "ptukei@kemri.org;", "Peter", "K", "Borus", "-", "pborus@kemri.org", "*", "Corresponding", "author", "Published:", "29", "July", "2009", "BMC", "Public", "Health", "2009,", "9:269", "doi:10.1186/1471-2458-9-269", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1471-2458/9/269", "Received:", "19", "August", "2008", "Accepted:", "29", "July", "2009", "©", "2009", "Kombich", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "Rubella", "is", "an", "infectious", "and", "generally", "mild", "childhood", "viral", "disease.", "The", "disease", "is", "of", "public", "health", "importance", "because", "infection", "acquired", "during", "early", "pregnancy", "often", "results", "in", "foetal", "abnormalities", "that", "are", "classified", "as", "congenital", "rubella", "syndrome", "(CRS).", "The", "burden", "of", "rubella", "infection", "in", "most", "developing", "countries", "in", "not", "well", "documented", "because", "of", "limited", "epidemiological", "data.", "However,", "availability", "of", "an", "effective", "vaccine", "has", "made", "it", "necessary", "to", "have", "all", "the", "countries", "with", "no", "routine", "vaccination", "schedule", "to", "evaluate", "the", "burden", "of", "disease", "in", "order", "to", "make", "informed", "decisions", "on", "rubella", "vaccination", "and", "strategy.", "To", "address", "this", "gap", "we", "conducted", "a", "study", "to", "determine", "age-specific", "rubella", "seroprevalence", "rates", "and", "related", "risk", "factors", "among", "primary", "and", "pre-primary", "school", "children", "in", "Uasin", "Gishu", "district,", "Moi's", "Bridge", "location", "of", "Kenya.", "Methods:", "Subjects", "of", "the", "study", "were", "498", "pupils", "from", "seven", "primary", "schools", "aged", "4–20", "years.", "Questionnaire", "surveys", "with", "blood", "sampling", "were", "conducted", "between", "January", "to", "July", "2005.", "Samples", "were", "tested", "for", "rubella", "specific", "IgG", "antibody", "using", "ELISA", "test", "kit", "(Enzygnost®", "Behring,", "Germany).", "Results:", "Overall,", "rubella", "seropositivity", "rate", "was", "80%", "and", "it", "increased", "with", "age", "from", "59%", "(among", "ages", "4–6", "years)", "to", "94%", "(ages", "14–20", "years).", "Multivariate", "logistic", "regression", "analysis", "model,", "showed", "that", "age", "of", "child", "and", "ownership", "of", "a", "television", "set", "which", "is", "a", "proxy", "measure", "of", "socio-economic", "status", "of", "family", "were", "significantly", "associated", "with", "rubella", "seropositivity.", "The", "odds", "of", "rubella", "seropositivity", "in", "a", "child", "older", "than", "13", "years", "was", "more", "than", "that", "in", "children", "younger", "than", "7", "years", "(OR", "=", "3.8", "95%", "CI", "2.56–5.78).", "The", "odds", "of", "rubella", "seropositivity", "in", "a", "child", "whose", "family", "did", "not", "own", "a", "television", "set", "was", "3", "times", "higher", "than", "that", "of", "child", "whose", "family", "owned", "a", "set", "(OR", "3.06,", "95%", "CI", "1.17–7.97).", "Conclusion:", "The", "study", "provides", "important", "and", "highly", "useful", "information", "on", "rubella", "age", "specific", "seroprevalence", "rates", "in", "Kenya.", "Advancing", "age", "was", "found", "to", "be", "associated", "with", "increased", "risk", "of", "rubella.", "Low", "socio-economic", "factors", "suggest", "an", "increased", "risk", "of", "infection", "in", "certain", "categories", "of", "society,", "and", "control", "measures", "need", "to", "target", "this.", "Overall,", "the", "findings", "can", "also", "be", "used", "by", "policy", "makers", "to", "model", "introduction", "of", "routine", "rubella", "vaccination", "in", "the", "country", "and", "also", "other", "developing", "countries", "facing", "similar", "challenges.", "More", "than", "half", "of", "the", "children", "got", "infected", "in", "pre-", "primary", "and", "efforts", "to", "control", "rubella", "should", "target", "pre-school", "children.", "These", "data", "provides", "pre-", "vaccination", "information", "that", "can", "be", "used", "to", "guide", "immunization", "strategy", "as", "well", "as", "to", "determine", "success", "of", "an", "immunization", "programme.", "Page", "1", "of", "5", "(page", "number", "not", "for", "citation", "purposes)" ]	[ 0, 0, 0, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 0, 0, 9, 9, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 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1032 ], [ 485, 1018, 540, 1032 ], [ 544, 1018, 556, 1032 ], [ 560, 1018, 578, 1032 ], [ 582, 1018, 635, 1032 ], [ 640, 1018, 676, 1032 ], [ 681, 1018, 705, 1032 ], [ 709, 1018, 762, 1032 ] ]	[ "Hindawi", "Publishing", "Corporation", "Journal", "of", "Biomedicine", "and", "Biotechnology", "Volume", "2010,", "Article", "ID", "130265,", "6", "pages", "doi:10.1155/2010/130265", "Research", "Article", "Monocyte", "Chemoattractant", "Protein-1", "−2518", "A/G", "Single", "Nucleotide", "Polymorphism", "Might", "Be", "Associated", "with", "Renal", "Disease", "and", "Thrombocytopenia", "of", "SLE", "Piotr", "Piotrowski,1,", "2", "Margarita", "Lianeri,1", "Robert", "Gasik,1,", "3", "Andrzej", "Roszak,1,", "4", "Marzena", "Olesi", "n´ska,3", "and", "Paweł", "P.", "Jagodzi", "n´ski1", "1", "Department", "of", "Biochemistry", "and", "Molecular", "Biology,", "Poznan´", "University", "of", "Medical", "Sciences,", "6", "S´wi¸ecickiego", "St.,", "60-781", "Poznan´,", "Poland", "2", "Medical", "Research", "Centre,", "Polish", "Academy", "of", "Sciences,", "Warsaw,", "Poland", "3", "Institute", "of", "Rheumatology,", "Warsaw,", "Poland", "4", "Department", "of", "Radiotherapy", "and", "Gynecological", "Oncology,", "Greater", "Poland", "Cancer", "Centre,", "15", "Garbary", "St.,", "61-866", "Poznan,", "Poland", "Correspondence", "should", "be", "addressed", "to", "Paweł", "P.", "Jagodzi", "n´ski,", "pjagodzi@am.poznan.pl", "Received", "30", "November", "2009;", "Revised", "13", "February", "2010;", "Accepted", "14", "March", "2010", "Academic", "Editor:", "Timothy", "B.", "Niewold", "Copyright", "©", "2010", "Piotr", "Piotrowski", "et", "al.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "There", "is", "conﬂicting", "evidence", "on", "the", "contribution", "of", "the", "MCP-1", "−2518", "A>G", "(rs", "1024611)", "polymorphism", "to", "SLE", "incidence", "and", "clinical", "manifestations.", "We", "examined", "the", "prevalence", "of", "the", "MCP-1", "−2518", "A>G", "polymorphism", "in", "SLE", "patients", "(n", "=", "199)", "and", "controls", "(n", "=", "250)", "in", "Poland.", "We", "did", "not", "observe", "a", "signiﬁcant", "diﬀerence", "in", "the", "distribution", "of", "MCP-1", "−2518", "A>G", "polymorphic", "variants", "in", "patients", "with", "SLE", "and", "healthy", "individuals.", "However,", "we", "found", "an", "association", "between", "the", "GG", "versus", "AG", "and", "AA", "genotypes", "as", "well", "as", "the", "AG", "and", "GG", "versus", "AA", "genotypes", "with", "renal", "manifestations", "of", "SLE", "OR", "=", "3.614", "(1.123–11.631,", "P", "=", "0.0345)", "and", "OR", "=", "2.297", "(1.301–4.057,", "P", "=", "0.0046),", "respectively.", "We", "also", "observed", "that", "the", "MCP-1", "AG", "and", "GG", "-genotypes", "contribute", "to", "the", "occurrence", "of", "thrombocytopenia", "in", "SLE", "patients", "OR", "=", "2.618", "(1.280–5.352,", "P", "=", "0.0089).", "Our", "observations", "indicate", "that", "either", "MCP-1", "−2518", "G", "variant", "can", "be", "associated", "with", "some", "clinical", "ﬁndings", "in", "patients", "with", "SLE.", "1.", "Introduction", "Systemic", "lupus", "erythematosus", "(SLE)", "is", "a", "chronic", "and", "pro-", "gressive", "multisystem", "autoimmune", "connective", "tissue", "disorder,", "which", "is", "characterized", "by", "immune-mediated", "host", "tissue", "destruction", "[1].", "Occupational", "exposure,", "chemicals,", "drugs,", "food,", "as", "well", "as", "viral", "and", "bacterial", "infectious", "agents", "can", "contribute", "signiﬁcantly", "to", "changes", "in", "the", "immune", "system", "[2,", "3].", "Immune", "cells", "from", "patients", "with", "SLE", "exhibit", "various", "defects", "including", "skewed", "cytokine", "production,", "a", "decrease", "in", "cytotoxic", "T", "cell", "function,", "and", "an", "increase", "in", "the", "humoral", "response", "[4–7].", "The", "defective", "function", "of", "CD4+", "T", "cells", "asso-", "ciated", "with", "abnormal", "stimulation", "of", "B", "cells", "causes", "abundant", "autoantibody", "production", "[4,", "6].", "These", "autoantibodies", "form", "immune", "complexes", "with", "antigens", "on", "the", "patient’s", "own", "cells", "and", "are", "accumulated", "in", "the", "skin,", "synovium,", "lungs,", "renal", "glomeruli,", "and", "other", "organs", "and", "tissues.", "This", "results", "in", "the", "clinical", "presentation", "of", "SLE", "[1,", "8].", "The", "pathogenesis", "of", "SLE", "remains", "unclear,", "though", "there", "is", "much", "evidence", "demonstrating", "the", "involvement", "of", "genetic", "factors", "in", "the", "incidence", "of", "this", "autoimmune", "disease", "[9–13].", "The", "genetic", "background", "contributing", "to", "SLE", "development", "includes,", "in", "particular,", "genes", "encoding", "disparate", "proteins", "that", "control", "immune", "system", "pathways", "[9,", "10,", "13].", "The", "monocyte", "chemoattractant", "protein", "1", "(MCP-1),", "cur-", "rently", "also", "designated", "CCL2,", "belongs", "to", "the", "family", "of", "chemo-", "tactic", "cytokines.", "MCP-1", "functions", "as", "a", "potent", "agonist", "for", "monocytes,", "memory", "T", "cells,", "and", "basophils", "[14].", "Evidence", "in", "animal", "and", "human", "studies", "suggests", "a", "signiﬁcant", "role", "of", "MCP-", "1", "in", "the", "progression", "of", "glomerular", "and", "tubulointerstitial", "injuries", "and", "glomerulonephriti", "in", "patients", "with", "SLE", "[15–19].", "It", "has", "been", "demonstrated", "that", "the", "MCP-1", "–2518", "A>G", "(rs", "1024611)", "transition", "in", "the", "promoter", "region", "may", "modulate" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 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"of", "weaning", "influences", "serum", "levels", "of", "acute-phase", "proteins,", "iron-binding", "proteins,", "inflammatory", "cytokines,", "cortisol,", "and", "leukocyte", "subsets", "in", "Holstein", "calves", "Myung-Hoo", "Kim1,†,", "Ji-Young", "Yang1,†,", "Santi", "Devi", "Upadhaya1,", "Hyun-Jun", "Lee2,", "Cheol-Heui", "Yun1,", "Jong", "K.", "Ha1,", "1Department", "of", "Agricultural", "Biotechnology", "and", "Research", "Institute", "for", "Agriculture", "and", "Life", "Sciences,", "College", "of", "Agriculture", "and", "Life", "Sciences,", "Seoul", "National", "University,", "Seoul", "151-742,", "Korea", "2Dairy", "Science", "Division,", "National", "Institute", "of", "Animal", "Science,", "Cheonan", "330-801,", "Korea", "The", "purpose", "of", "our", "study", "was", "to", "investigate", "changes", "in", "immunological", "parameters", "induced", "by", "weaning", "stress", "(including", "milk", "restriction)", "in", "calves.", "Fifteen", "Holstein", "calves", "were", "subjected", "to", "weaning", "at", "6", "weeks", "of", "age.", "Blood", "samples", "were", "collected", "at", "−14,", "−7,", "−2,", "1,", "3,", "and", "5", "days", "post-weaning", "(DPW;", "0", "DPW", "=", "42", "days).", "Weaning", "caused", "significant", "(p", "＜", "0.01)", "increases", "in", "the", "neutrophil", "(NE):lymphocyte", "(LY)", "ratio", "at", "5", "DPW", "with", "a", "significant", "(p", "＜", "0.05)", "reduction", "of", "LYs.", "The", "concentration", "of", "acute-phase", "proteins", "(haptoglobin", "and", "serum", "amyloid", "A)", "also", "increased", "significantly", "(p", "＜", "0.05)", "at", "3", "and", "5", "DPW", "compared", "to", "−2", "DPW.", "Levels", "of", "the", "iron-binding", "protein", "lactoferrin", "decreased", "significantly", "(p", "＜", "0.05)", "after", "weaning.", "Serum", "tumor", "necrosis", "factor-α", "and", "cortisol", "levels", "were", "elevated", "(p", "＜", "0.05)", "at", "3", "DPW,", "while", "those", "of", "serum", "interferon-γ", "decreased", "(p", "＜", "0.05)", "at", "1", "and", "3", "DPW", "compared", "to", "levels", "observed", "before", "weaning.", "Weaning", "significantly", "(p", "＜", "0.05)", "decreased", "the", "percentage", "of", "CD25+", "T", "cells", "in", "the", "peripheral", "blood.", "In", "conclusion,", "weaning", "stress", "affected", "the", "NE:LY", "ratio", "along", "with", "the", "levels", "of", "acute", "phase", "proteins,", "lactoferrin,", "cortisol,", "and", "inflammatory", "cytokines", "in", "the", "peripheral", "blood", "of", "calves.", "Weaning", "stress", "may", "induce", "an", "acute", "phase", "response", "possibly", "through", "the", "elevation", "of", "cortisol", "production", "and", "modulation", "of", "inflammatory", "cytokines.", "Keywords:", "acute", "phase", "protein,", "immune", "inflammatory", "cytokines,", "stress,", "weaning", "response,", "Introduction", "Stress", "can", "be", "defined", "as", "the", "biological", "response", "elicited", "Corresponding", "author", "Tel:", "+82-2-880-4809;", "Fax:", "+82-2-785-8710", "E-mail:", "jongha@snu.ac.kr", "†The", "first", "two", "authors", "contributed", "equally", "to", "this", "work.", "when", "a", "threat", "to", "homeostasis", "is", "perceived.", "The", "effects", "of", "several", "types", "of", "stressors,", "such", "as", "transportation,", "heat,", "and", "weaning,", "have", "been", "studied", "in", "various", "animals", "[2,10,", "11,30].", "Stress", "is", "an", "important", "factor", "in", "the", "animal", "industry", "because", "it", "has", "been", "directly", "linked", "to", "growth,", "reproduction,", "meat", "quality,", "animal", "welfare,", "and", "disease", "susceptibility", "[27,28,37],", "thereby", "giving", "it", "the", "potential", "for", "making", "a", "substantial", "economic", "impact", "[8].", "Weaning", "and", "transportation", "are", "regarded", "as", "the", "top", "stressors", "that", "calves", "may", "experience", "[14,27].", "Although", "the", "effects", "of", "all", "stages", "of", "transportation", "on", "cattle", "are", "well-documented", "in", "the", "literature,", "there", "has", "been", "limited", "research", "on", "the", "effects", "of", "weaning", "alone", "or", "weaning", "and", "grouping", "on", "calves.", "The", "majority", "of", "reports", "focus", "on", "weaning", "and", "transportation", "together", "since", "both", "of", "these", "stressors", "often", "occur", "at", "the", "same", "time", "in", "agriculture", "[11].", "Previous", "studies", "have", "found", "that", "weaning", "stress", "alters", "the", "concentration", "of", "plasma", "acute", "phase", "protein", "(APP)", "[24]", "and", "the", "neutrophil", "(NE):", "lymphocyte", "(LY)", "ratio,", "and", "increases", "norepinephrine", "and", "cortisol", "levels", "[6,8,12].", "Lactoferrin", "(Lf)", "and", "transferrin", "(Tf),", "two", "iron-binding", "proteins,", "play", "many", "physiological", "roles", "including", "regulation", "of", "iron", "metabolism,", "protection", "against", "microbial", "infection,", "and", "regulation", "of", "immune", "functions", "[33].", "The", "acute", "phase", "response", "is", "considered", "to", "be", "an", "exclusive", "biomarker", "of", "inflammation", "and/or", "infection", "[20].", "Accordingly,", "the", "concentration", "of", "APPs", "is", "a", "useful", "indicator", "of", "stress", "response", "in", "calves.", "The", "elevation", "of", "APPs", "by", "transportation", "and", "weaning", "stress", "has", "already", "been", "reported", "[2,21,25].", "Triggered", "by", "inflammatory", "signals", "(predominantly", "cytokines),", "the", "circulating", "concentrations", "of", "APPs", "are", "elevated", "in", "a", "nonspecific", "manner", "in", "animals", "[32].", "In", "particular,", "inflammatory", "cytokines", "including", "interleukin", "(IL)-1,", "IL-6,", "tumor", "necrosis", "factor-α", "(TNF-α),", "and", "interferon-γ", "(IFN-γ)", "are", "considered", "to", "be", "the", "mediators", "of", "immunological", "and", "pathological", "responses", "to", "stress", "and", "infection", "[15,35].", "The", "goal", "of", "this", "study", "was", "to", "elucidate", "the", "interaction" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 16, 16, 11, 11, 11, 11, 11, 11, 11, 11, 11, 0, 0, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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[ 705, 1052, 735, 1065 ], [ 738, 1052, 745, 1065 ], [ 748, 1052, 759, 1065 ], [ 762, 1052, 769, 1065 ], [ 599, 1070, 624, 1080 ], [ 627, 1070, 660, 1080 ], [ 662, 1070, 676, 1080 ], [ 678, 1070, 690, 1080 ], [ 692, 1070, 723, 1080 ], [ 726, 1070, 770, 1080 ] ]	[ "Human", "Resources", "for", "Health", "Research", "Mid-level", "providers", "in", "emergency", "obstetric", "and", "newborn", "health", "care:", "factors", "affecting", "their", "performance", "and", "retention", "within", "the", "Malawian", "health", "system", "Susan", "Bradley", "and", "Eilish", "McAuliffe", "Address:", "Centre", "for", "Global", "Health,", "Trinity", "College", "Dublin,", "3-4", "Foster", "Place,", "Dublin", "2,", "Ireland", "Email:", "Susan", "Bradley", "-", "susan.bradley@tcd.ie;", "Eilish", "McAuliffe", "-", "eilish.mcauliffe@tcd.ie", "*", "Corresponding", "author", "BioMed", "Central", "Open", "Access", "Published:", "19", "February", "2009", "Human", "Resources", "for", "Health", "2009,", "7:14", "doi:10.1186/1478-4491-7-14", "This", "article", "is", "available", "from:", "http://www.human-resources-health.com/content/7/1/14", "Received:", "5", "May", "2008", "Accepted:", "19", "February", "2009", "©", "2009", "Bradley", "and", "McAuliffe;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "Malawi", "has", "a", "chronic", "shortage", "of", "human", "resources", "for", "health.", "This", "has", "a", "significant", "impact", "on", "maternal", "health,", "with", "mortality", "rates", "amongst", "the", "highest", "in", "the", "world.", "Mid-level", "cadres", "of", "health", "workers", "provide", "the", "bulk", "of", "emergency", "obstetric", "and", "neonatal", "care.", "In", "this", "context", "these", "cadres", "are", "defined", "as", "those", "who", "undertake", "roles", "and", "tasks", "that", "are", "more", "usually", "the", "province", "of", "internationally", "recognised", "cadres,", "such", "as", "doctors", "and", "nurses.", "While", "there", "have", "been", "several", "studies", "addressing", "retention", "factors", "for", "doctors", "and", "registered", "nurses,", "data", "and", "studies", "addressing", "the", "perceptions", "of", "these", "mid-level", "cadres", "on", "the", "factors", "that", "influence", "their", "performance", "and", "retention", "within", "health", "care", "systems", "are", "scarce.", "Methods:", "This", "exploratory", "qualitative", "study", "took", "place", "in", "four", "rural", "mission", "hospitals", "in", "Malawi.", "The", "study", "population", "was", "mid-level", "providers", "of", "emergency", "obstetric", "and", "neonatal", "care.", "Focus", "group", "discussions", "took", "place", "with", "nursing", "and", "medical", "cadres.", "Semi-structured", "interviews", "with", "key", "human", "resources,", "training", "and", "administrative", "personnel", "were", "used", "to", "provide", "context", "and", "background.", "Data", "were", "analysed", "using", "a", "framework", "analysis.", "Results:", "Participants", "confirmed", "the", "difficulties", "of", "their", "working", "conditions", "and", "the", "clear", "commitment", "they", "have", "to", "serving", "the", "rural", "Malawian", "population.", "Although", "insufficient", "financial", "remuneration", "had", "a", "negative", "impact", "on", "retention", "and", "performance,", "the", "main", "factors", "identified", "were", "limited", "opportunities", "for", "career", "development", "and", "further", "education", "(particularly", "for", "clinical", "officers)", "and", "inadequate", "or", "non-existent", "human", "resources", "management", "systems.", "The", "lack", "of", "performance-related", "rewards", "and", "recognition", "were", "perceived", "to", "be", "particularly", "demotivating.", "Conclusion:", "Mid-level", "cadres", "are", "being", "used", "to", "stem", "Africa's", "brain", "drain.", "It", "is", "in", "the", "interests", "of", "both", "the", "government", "and", "mission", "organizations", "to", "protect", "their", "investment", "in", "these", "workers.", "For", "optimal", "performance", "and", "quality", "of", "care", "they", "need", "to", "be", "supported", "and", "properly", "motivated.", "A", "structured", "system", "of", "continuing", "professional", "development", "and", "functioning", "human", "resources", "management", "would", "show", "commitment", "to", "these", "cadres", "and", "support", "them", "as", "professionals.", "Action", "needs", "to", "be", "taken", "to", "prevent", "staff", "members", "from", "leaving", "the", "health", "sector", "for", "less", "stressful,", "more", "financially", "rewarding", "alternatives.", "Page", "1", "of", "8", "(page", "number", "not", "for", "citation", "purposes)" ]	[ 0, 0, 0, 0, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 0, 0, 9, 9, 7, 7, 7, 7, 0, 0, 0, 0, 0, 0, 0, 1, 1, 1, 1, 1, 1, 7, 7, 7, 7, 7, 7, 7, 7, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4 ]
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1047, 168, 1059 ], [ 174, 1047, 257, 1059 ], [ 422, 1047, 428, 1059 ], [ 533, 1047, 582, 1059 ], [ 585, 1047, 608, 1059 ], [ 613, 1047, 616, 1059 ], [ 622, 1047, 658, 1059 ], [ 663, 1047, 669, 1059 ], [ 674, 1047, 677, 1059 ], [ 682, 1047, 706, 1059 ], [ 711, 1047, 723, 1059 ], [ 727, 1047, 730, 1059 ], [ 736, 1047, 770, 1059 ] ]	[ "Amyloid-b", "Oligomer", "Specificity", "Mediated", "by", "the", "IgM", "Isotype", "–", "Implications", "for", "a", "Specific", "Protective", "Mechanism", "Exerted", "by", "Endogenous", "Auto-Antibodies", "Malin", "Lindhagen-Persson", "1", ",", "Kristoffer", "Bra¨", "nnstro¨", "m1,", "Monika", "Vestling", "1", ",", "Michael", "Steinitz2,", "Anders", "1", "Olofsson", "", "1", "Department", "of", "Medical", "Biochemistry", "and", "Biophysics,", "Umea˚", "University,", "Umea˚,", "Sweden,", "2", "Department", "of", "Pathology,", "Hebrew", "University", "Hadassah", "Medical", "School,", "Jerusalem,", "Israel", "Abstract", "Background:", "Alzheimers", "disease", "(AD)", "has", "been", "strongly", "linked", "to", "an", "anomalous", "self-assembly", "of", "the", "amyloid-b", "peptide", "(Ab).", "The", "correlation", "between", "clinical", "symptoms", "of", "AD", "and", "Ab", "depositions", "is,", "however,", "weak.", "Instead", "small", "and", "soluble", "Ab", "oligomers", "are", "suggested", "to", "exert", "the", "major", "pathological", "effects.", "In", "strong", "support", "of", "this", "notion,", "immunological", "targeting", "of", "Ab", "oligomers", "in", "AD", "mice-models", "shows", "that", "memory", "impairments", "can", "be", "restored", "without", "affecting", "the", "total", "burden", "of", "Ab", "deposits.", "Consequently", "a", "specific", "immunological", "targeting", "of", "Ab", "oligomers", "is", "of", "high", "therapeutic", "interest.", "Methodology/Principal", "Findings:", "Previously", "the", "generation", "of", "conformational-dependent", "oligomer", "specific", "anti-Ab", "antibodies", "has", "been", "described.", "However,", "to", "avoid", "the", "difficult", "task", "of", "identifying", "a", "molecular", "architecture", "only", "present", "on", "oligomers,", "we", "have", "focused", "on", "a", "more", "general", "approach", "based", "on", "the", "hypothesis", "that", "all", "oligomers", "expose", "multiple", "identical", "epitopes", "and", "therefore", "would", "have", "an", "increased", "binding", "to", "a", "multivalent", "receptor.", "Using", "the", "polyvalent", "IgM", "immunoglobulin", "we", "have", "developed", "a", "monoclonal", "anti-Ab", "antibody", "(OMAB).", "OMAB", "only", "demonstrates", "a", "weak", "interaction", "with", "Ab", "monomers", "and", "dimers", "having", "fast", "on", "and", "off-rate", "kinetics.", "However,", "as", "an", "effect", "of", "avidity,", "its", "interaction", "with", "Ab-", "oligomers", "results", "in", "a", "strong", "complex", "with", "an", "exceptionally", "slow", "off-rate.", "Through", "this", "mechanism", "a", "selectivity", "towards", "Ab", "oligomers", "is", "acquired", "and", "OMAB", "fully", "inhibits", "the", "cytotoxic", "effect", "exerted", "by", "Ab(1-42)", "at", "highly", "substoichiometric", "ratios.", "Anti-Ab", "auto-antibodies", "of", "IgM", "isotype", "are", "frequently", "present", "in", "the", "sera", "of", "humans.", "Through", "a", "screen", "of", "endogenous", "anti-", "Ab", "IgM", "auto-antibodies", "from", "a", "group", "of", "healthy", "individuals", "we", "show", "that", "all", "displays", "a", "preference", "for", "oligomeric", "Ab.", "Conclusions/Significance:", "Taken", "together", "we", "provide", "a", "simple", "and", "general", "mechanism", "for", "targeting", "of", "oligomers", "without", "the", "requirement", "of", "conformational-dependent", "epitopes.", "In", "addition,", "our", "results", "suggest", "that", "IgM", "anti-Ab", "auto-antibodies", "may", "exert", "a", "more", "specific", "protective", "mechanism", "in", "vivo", "than", "previously", "anticipated.", "Citation:", "Lindhagen-Persson", "M,", "Bra¨nnstro¨", "m", "K,", "Vestling", "M,", "Steinitz", "M,", "Olofsson", "A", "(2010)", "Amyloid-b", "Oligomer", "Specificity", "Mediated", "by", "the", "IgM", "Isotype", "–", "Implications", "for", "a", "Specific", "Protective", "Mechanism", "Exerted", "by", "Endogenous", "Auto-Antibodies.", "PLoS", "ONE", "5(11):", "e13928.", "doi:10.1371/journal.pone.0013928", "Editor:", "Ashley", "I.", "Bush,", "Mental", "Health", "Research", "Institute", "of", "Victoria,", "Australia", "Received", "July", "5,", "2010;", "Accepted", "October", "18,", "2010;", "Published", "November", "10,", "2010", "Copyright:", "2010", "Lindhagen-Persson", "et", "al.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Funding:", "This", "work", "was", "supported", "by", "Ernst", "and", "Lili", "Rosenhain", "fund,", "Bruxelles,", "Belgium,", "J.", "C.", "Kempe,", "the", "Swedish", "research", "council,", "Socialstyrelsen,", "FAMY", "and", "the", "Medical", "Faculty", "of", "Umea˚", "University.", "The", "funders", "had", "no", "role", "in", "study", "design,", "data", "collection", "and", "analysis,", "decision", "to", "publish,", "or", "preparation", "of", "the", "manuscript.", "Competing", "Interests:", "The", "monoclonal", "antibody", "OMAB", "presented", "in", "this", "investigation", "is", "fully", "own", "by", "Alexo-Tech", "AB", "(www.alexotech.com).", "A.O.", "is", "a", "shareholder", "of", "Alexo-Tech", "AB.", "Alexo-Tech", "AB", "had", "no", "role", "in", "study", "design,", "data", "collection", "and", "analysis,", "decision", "to", "publish,", "or", "preparation", "of", "the", "manuscript", "and", "does", "not", "in", "any", "other", "way", "interfere", "with", "the", "study.", "This", "does", "not", "alter", "the", "authors’", "adherence", "to", "all", "the", "PLoS", "ONE", "policies", "on", "sharing", "data", "and", "materials.", "", "E-mail:", "anders.olofsson@medchem.umu.se", "Introduction", "Amyloid", "is", "today", "linked", "to", "more", "than", "twenty-five", "different", "syndromes,", "of", "which", "the", "neurodegenerative", "disorder", "Alzheimer’s", "disease", "(AD)", "represents", "the", "most", "prominent", "example.", "Amyloid", "depositions", "in", "AD", "patients", "are", "largely", "composed", "of", "the", "Ab-", "peptide,", "derived", "from", "the", "proteolytic", "cleavage", "of", "the", "amyloid", "precursor", "protein", "(APP).", "Ab", "peptides", "of", "39–43", "residues", "all", "have", "clinical", "relevance,", "but", "Ab(1–40)", "and", "Ab(1–42)", "represent", "the", "most", "abundant", "variants.", "Ab(1–42),", "in", "particular,", "has", "a", "significantly", "higher", "propensity", "to", "aggregate,", "and", "has", "been", "strongly", "implicated", "in", "the", "etiology", "of", "AD", "[1].", "Although", "the", "histopathological", "features", "of", "Ab", "depositions", "(plaques)", "are", "striking,", "the", "correlation", "between", "Ab", "depositions", "and", "the", "clinical", "symptoms", "of", "AD", "is", "weak", "[2].", "Small", "and", "soluble", "Ab", "assemblies,", "known", "as", "Ab", "oligomers,", "correlate", "better", "with", "negative", "clinical", "status", "and", "have", "been", "suggested", "to", "be", "the", "Ab", "species", "primarily", "responsible", "for", "cytotoxicity.", "The", "structural", "features", "of", "Ab", "oligomers", "are", "largely", "unknown.", "Ab-targeting", "immunization,", "both", "passive", "and", "active,", "has", "been", "studied", "in", "AD", "mouse", "models", "and", "both", "types", "of", "immunizations", "have", "shown", "a", "dramatic", "improvement", "regarding", "memory", "and", "behavior", "[3,4,5,6,7,8].", "Interestingly,", "passive", "Ab", "vaccination", "improved", "cognitive", "performance", "within", "days,", "without", "reducing", "plaque", "burden,", "suggesting", "that", "the", "removal", "of", "soluble", "Ab", "is", "an", "adequate", "treatment", "to", "restore", "cognitive", "function", "[6].", "Ab", "and", "its", "precursor", "APP", "has", "both", "been", "suggested", "to", "have", "important", "roles", "concerning", "neuroprotection", "and", "neurotrophicity", "[9,10,11].", "Therefore,", "to", "avoid", "interfering", "with", "the", "homeostatic", "functions", "of", "amyloid", "proteins,", "a", "therapeutic", "approach", "focused", "on", "clearance", "of", "Ab", "should", "preferentially", "target", "Ab", "oligomers", "while", "PLoS", "ONE", "\|", "www.plosone.org", "1", "November", "2010", "\|", "Volume", "5", "\|", "Issue", "11", "\|", "e13928" ]	[ 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 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"“Pulsed-laser-induced", "nanoscale", "island", "formation", "in", "thin", "metal-on-", "oxide", "films,”", "Phys.", "Rev.", "B", "72(19),", "195408", "(2005).", "7.", "J.", "Trice,", "D.", "Thomas,", "C.", "Favazza,", "R.", "Rureshkumar,", "and", "R.", "Kalyanaraman,", "“Pulsed-laser-induced", "dewetting", "in", "nanoscopic", "metal", "films:", "Theory", "and", "experiments,”", "Phys.", "Rev.", "B", "75(23),", "235439", "(2007).", "8.", "E.", "D.", "Tsagarakis,", "C.", "Lew,", "M.", "O.", "Thompson,", "and", "E.", "P.", "Giannelis,", "“Nanocrystalline", "barium", "titanate", "films", "on", "flexible", "plastic", "substrates", "via", "pulsed", "laser", "annealing,”", "Appl.", "Phys.", "Lett.", "89(20),", "20910", "(2006).", "9.", "C.", "F.", "Bohren,", "and", "D.", "R.", "Huffman,", "Absorption", "and", "Scattering", "of", "Light", "by", "Small", "Particles", "(Wiley,", "New", "York,", "1983).", "10.", "P.", "Mulvaney,", "“Surface", "plasmon", "spectroscopy", "of", "nanosized", "metal", "particles,”", "Langmuir", "12(3),", "788–800", "(1996).", "11.", "C.", "E.", "Brennen,", "“Phase", "change,", "nucleation", "and", "cavitation,”", "in", "Cavitation", "and", "Bubble", "Dynamics,", "(Oxford", "University", "Press,", "New", "York,", "2005).", "12.", "G.", "Mie,", "“Articles", "on", "the", "optical", "characteristics", "of", "turbid", "tubes,", "especially", "colloidal", "metal", "solutions,”", "Ann.", "Phys.", "(Leipzig)", "25,", "377", "(1908).", "13.", "P.", "K.", "Jain,", "K.", "S.", "Lee,", "I.", "H.", "El-Sayed,", "and", "M.", "A.", "El-Sayed,", "“Calculated", "absorption", "and", "scattering", "properties", "of", "gold", "nanoparticles", "of", "different", "size,", "shape,", "and", "composition:", "applications", "in", "biological", "imaging", "and", "biomedicine,”", "J.", "Phys.", "Chem.", "B", "110(14),", "7238–7248", "(2006).", "14.", "P.", "B.", "Johnson,", "and", "R.", "W.", "Christy,", "“Optical", "constants", "of", "the", "noble", "metals,”", 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1010, 308, 1020 ], [ 311, 1010, 325, 1020 ], [ 326, 1010, 359, 1020 ], [ 362, 1010, 396, 1020 ], [ 398, 1010, 411, 1020 ], [ 413, 1010, 441, 1020 ], [ 443, 1010, 462, 1020 ], [ 464, 1010, 470, 1020 ], [ 472, 1010, 503, 1020 ], [ 505, 1010, 525, 1020 ] ]	[ "Wang", "et", "al.", "Molecular", "Brain", "2012,", "5:21", "http://www.molecularbrain.com/content/5/1/21", "R", "E", "S", "E", "A", "R", "C", "H", "Open", "Access", "Activation", "of", "c-jun", "N-terminal", "kinase", "in", "spinal", "cord", "contributes", "to", "breast", "cancer", "induced", "bone", "pain", "in", "rats", "Xiao-Wei", "Wang,", "Shan", "Hu,", "Qi-Liang", "Mao-Ying,", "Qian", "Li,", "Chang-Jiang", "Yang,", "Hui", "Zhang,", "Wen-Li", "Mi,", "Gen-Cheng", "Wu", "and", "Yan-Qing", "Wang", "Abstract", "Background:", "The", "most", "frequent", "pain", "in", "patients", "with", "metastatic", "breast", "and", "prostate", "cancer", "is", "bone", "pain,", "which", "can", "be", "severe", "and", "difficult", "to", "treat.", "The", "mechanisms", "underlying", "this", "pain", "remain", "unclear.", "Here", "we", "investigated", "the", "role", "of", "c-jun", "N-terminal", "kinase", "(JNK)", "pathway", "in", "the", "spinal", "cord", "in", "cancer-induced", "bone", "pain", "(CIBP).", "Results:", "In", "this", "study,", "we", "used", "an", "established", "rat", "CIBP", "model", "to", "investigate", "the", "possible", "role", "of", "JNK", "activation", "in", "the", "spinal", "cord.", "After", "intra-tibial", "inoculation", "with", "Walker", "256", "rat", "mammary", "gland", "carcinoma", "cells,", "the", "rats", "displayed", "mechanical", "allodynia", "on", "day", "5,", "which", "lasted", "to", "day", "16.", "The", "activation", "of", "JNK", "in", "neurons", "and", "astrocytes", "in", "the", "spinal", "cord", "was", "found", "on", "day", "12", "and", "day", "16", "after", "intra-tibial", "inoculation", "with", "carcinoma", "cells.", "A", "single", "intrathecal", "injection", "with", "JNK", "inhibitor", "SP600125", "by", "lumbar", "puncture", "attenuated", "mechanical", "allodynia", "on", "day", "12,", "and", "repeated", "intrathecal", "injection", "of", "SP600126", "from", "day", "10", "to", "day", "14", "had", "a", "cumulative", "analgesic", "effect", "on", "CIBP.", "Conclusions:", "Taken", "together,", "our", "results", "demonstrated", "for", "the", "first", "time", "that", "JNK", "activation", "in", "the", "spinal", "cord", "is", "required", "in", "the", "maintenance", "of", "CIBP.", "Inhibition", "of", "the", "spinal", "JNK", "pathway", "may", "provide", "a", "new", "therapy", "for", "CIBP", "management.", "Keywords:", "c-Jun", "N-terminal", "kinase,", "Cancer-induced", "bone", "pain,", "Spinal", "cord,", "Rats", "Background", "The", "c-jun", "N-terminal", "kinase", "(JNK)", "is", "an", "evolutionarily", "conserved", "sub-group", "of", "mitogen-activated", "protein", "kinases", "(MAPK)", "that", "participates", "in", "survival", "signaling,", "apoptosis", "and", "pain", "[1-3].", "The", "JNK", "family", "is", "encoded", "by", "three", "genes:", "jnk1,", "jnk2", "and", "jnk3.", "Recent", "studies", "have", "demonstrated", "that", "JNK1", "and", "JNK2", "activation", "play", "important", "roles", "in", "the", "development", "and", "maintenance", "of", "chronic", "pain", "[4];", "JNK3", "has", "different", "functions", "from", "JNK1", "and", "JNK2", "and", "has", "been", "reported", "to", "participate", "in", "apoptosis", "in", "the", "brain.", "JNK", "acti-", "vation", "is", "mediated", "by", "the", "dual", "phosphorylation", "on", "Thr", "and", "Tyr", "by", "two", "MAPK", "kinases", "(MKK4/7),", "and", "several", "transcriptional", "factors", "can", "be", "regulated", "by", "JNK", "activation", "[5].", "JNK1/2", "was", "shown", "to", "be", "activated", "in", "the", "spinal", "cord", "at", "6", "h", "after", "intra-plantar", "injection", "of", "complete", "Freund’s", "", "Correspondence:", "wangyanqing@shmu.edu.cn", "Department", "of", "Integrative", "Medicine", "and", "Neurobiology,", "State", "Key", "Laboratory", "of", "Medical", "Neurobiology,", "Shanghai", "Medical", "College;", "Institute", "of", "Acupuncture", "Research", "(WHO", "Collaborating", "Center", "for", "Traditional", "Medicine),", "Fudan", "University,", "P.O.", "Box", "291138", "Yi", "Xue", "Yuan", "Road,", "Shanghai,", "200032,", "China", "adjuvant", "(CFA)", "[6]", "and", "at", "day", "3", "after", "spinal", "nerve", "ligation", "(SNL)", "[7].", "Moreover,", "intrathecal", "injection", "of", "JNK", "inhibitor", "SP600125", "decreased", "pain", "behavior", "in", "animals", "with", "inflam-", "matory", "pain,", "neuropathic", "pain", "and", "skin", "cancer", "pain", "[8-10].", "Cancer-induced", "bone", "pain", "(CIBP)", "is", "a", "severe", "problem", "for", "patients", "with", "end-stage", "cancer.", "The", "preferential", "metas-", "tasis", "of", "cancer", "cells", "to", "bone", "disrupts", "the", "process", "of", "bone", "remodeling", "and", "results", "in", "lesions", "that", "cause", "significant", "pain", "[11].", "The", "model", "of", "bone", "cancer", "induced", "by", "intrame-", "dullary", "inoculation", "with", "tumor", "cells", "has", "been", "the", "most", "frequently", "encountered", "type", "of", "cancer-induced", "pain", "in", "cancer", "patients", "with", "bone", "metastasis", "[12].", "Several", "animal", "models", "of", "CIBP", "have", "been", "developed", "recently,", "and", "these", "models", "contributed", "to", "our", "understanding", "of", "CIBP", "[13-15].", "A", "widely", "used", "model", "of", "CIBP", "is", "induced", "by", "intra-tibial", "in-", "oculation", "with", "Walker", "256", "rat", "mammary", "gland", "carcinoma", "cells", "[16-18].", "Rats", "inoculated", "with", "carcinoma", "cells", "devel-", "oped", "mechanical", "allodynia", "from", "day", "5", "as", "indicated", "by", "decreased", "paw", "withdrawal", "thresholds", "for", "the", "ipsilateral", "©", "2012", "Wang", "et", "al.;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 16, 16, 16, 16, 16, 16, 16, 16, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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"15,", "2005", "DDBJ/EMBL/GenBank", "accession", "nos+", "ABSTRACT", "Recently,", "the", "phenomenon", "of", "clustering", "of", "co-expressed", "genes", "on", "chromosomes", "was", "dis-", "covered", "in", "eukaryotes.", "To", "explore", "the", "hypothesis", "that", "genes", "within", "clusters", "occupy", "shared", "chroma-", "tin", "domains,", "we", "performed", "a", "detailed", "analysis", "of", "transcription", "pattern", "and", "chromatin", "structure", "of", "a", "cluster", "of", "co-expressed", "genes.", "We", "found", "that", "five", "non-homologous", "genes", "(Crtp,", "Yu,", "CK2btes,", "Pros28.1B", "and", "CG13581)", "are", "expressed", "exclusively", "in", "Drosophila", "melanogaster", "male", "germ-line", "and", "form", "a", "non-interrupted", "cluster", "in", "the", "15", "kb", "region", "of", "chromosome", "2.", "The", "cluster", "is", "surrounded", "by", "genes", "with", "broader", "transcription", "patterns.", "Analysis", "of", "DNase", "I", "sensitivity", "revealed", "‘open’", "chromatin", "conformation", "in", "the", "cluster", "and", "adjacent", "regions", "in", "the", "male", "germ-line", "cells,", "where", "all", "studied", "genes", "are", "transcribed.", "In", "contrast,", "in", "somatic", "tissues", "where", "the", "cluster", "genes", "are", "silent,", "the", "domain", "of", "repressed", "chromatin", "encompassed", "four", "out", "of", "five", "cluster", "genes", "and", "an", "adjacent", "non-cluster", "gene", "CG13589", "that", "is", "also", "silent", "in", "analyzed", "somatic", "tissues.", "The", "fifth", "cluster", "gene", "(CG13581)", "appears", "to", "be", "excluded", "from", "the", "chromatin", "domain", "occupied", "by", "the", "other", "four", "genes.", "Our", "results", "suggest", "that", "extensive", "clustering", "of", "co-expressed", "genes", "in", "eukaryotic", "genomes", "does", "in", "general", "reflect", "the", "domain", "organization", "of", "chro-", "matin,", "although", "domain", "borders", "may", "not", "exactly", "correspond", "to", "the", "margins", "of", "gene", "clusters.", "INTRODUCTION", "It", "has", "been", "suggested", "that", "eukaryotic", "genome", "is", "functionally", "divided", "into", "domains", "that", "contain", "all", "regulatory", "elements", "necessary", "for", "full,", "correct", "and", "positionally", "independent", "expression", "of", "resident", "gene(s)", "(1,2).", "These", "domains", "are", "evident", "at", "the", "level", "of", "local", "chromatin", "structure,", "where", "tran-", "scriptionally", "active", "genes", "are", "associated", "with", "‘open’", "and", "acetylated", "chromatin,", "whereas", "silent", "genes", "are", "embedded", "in", "compacted", "and", "hypermethylated", "chromatin", "[reviewed", "in", "(3–5)].", "The", "assumption", "that", "not", "only", "single", "genes", "such", "as", "chicken", "glyceraldehyde-3-phosphate", "dehydrogenase", "(6),", "human", "apoB", "(7),", "and", "chicken", "lysozyme", "(8,9)", "genes,", "but", "also", "multigenic", "loci", "may", "be", "regulated", "at", "the", "level", "of", "common", "chromatin", "domains,", "originated", "from", "the", "data", "obtained", "on", "sev-", "eral", "intensively", "studied", "gene", "clusters.", "The", "examples", "include,", "but", "are", "not", "limited", "to,", "the", "cluster", "of", "b-globin", "genes", "in", "chicken,", "mouse", "and", "human", "(10–17);", "growth", "hormone", "genes", "(18,19),", "IL-4/IL-13", "genes", "(20)", "and", "PRM1-PRM2-TNP", "genes", "in", "human", "(21);", "ovalbumin", "genes", "in", "chicken", "(22);", "and", "heat-shock", "genes", "in", "Drosophila", "(23).", "All", "these", "clusters", "comprise", "paralogous", "genes", "that", "most", "likely", "have", "originated", "from", "ancestral", "genes", "through", "local", "duplications.", "It", "is", "not", "clear", "whether", "the", "infer-", "ences", "from", "the", "studies", "on", "these", "models", "can", "be", "extrapolated", "to", "the", "organization", "of", "entire", "genome,", "where", "clusters", "of", "para-", "logous", "genes", "occur", "rather", "rarely.", "Recently,", "a", "number", "of", "reports", "have", "demonstrated", "non-", "random", "clustering", "of", "co-expressed", "genes", "on", "chromosomes.", "First", "observations", "of", "this", "phenomenon,", "that", "we", "are", "aware", "of,", "date", "back", "to", "1991", "(24),", "but", "in", "2002", "an", "inﬂux", "of", "publications", "based", "on", "the", "analysis", "of", "whole-genome", "transcription", "data", "from", "different", "organisms", "indicated", "that", "mechanisms", "of", "transcrip-", "tional", "co-regulation,", "that", "operate", "with", "chromatin", "domains,", "are", "common", "from", "yeast", "to", "higher", "eukaryotes", "[reviewed", "in", "(25)].", "Moreover,", "according", "to", "the", "data", "of", "Spellman", "and", "Rubin", "(26)", "over", "20%", "of", "all", "Drosophila", "genes", "are", "clustered", "on", "chromo-", "somes", "according", "to", "their", "expression", "patterns", "and", "thus", "may", "share", "common", "chromatin", "domains.", "However,", "direct", "evidence", "that", "would", "link", "the", "observed", "gene", "clusters", "to", "the", "chromatin", "domains", "was", "still", "missing.", "To", "address", "this", "issue,", "we", "thoroughly", "characterized", "the", "cluster", "of", "non-homologous", "testes-speciﬁc", "To", "whom", "correspondence", "should", "be", "addressed.", "Tel:", "+7", "095", "1960809;", "Fax:", "+7", "095", "1960221;", "Email:", "shevelev@img.ras.ru", "+AF197938,", "AY078076", "and", "AY078077", "ª", "The", "Author", "2005.", "Published", "by", "Oxford", "University", "Press.", "All", "rights", "reserved.", "The", "online", "version", "of", "this", "article", "has", "been", "published", "under", "an", "open", "access", "model.", "Users", "are", "entitled", "to", "use,", "reproduce,", "disseminate,", "or", "display", "the", "open", "access", "version", "of", "this", "article", "for", "non-commercial", "purposes", "provided", "that:", "the", "original", "authorship", "is", "properly", "and", "fully", "attributed;", "the", "Journal", "and", "Oxford", "University", "Press", "are", "attributed", "as", "the", "original", "place", "of", "publication", "with", "the", "correct", "citation", "details", "given;", "if", "an", "article", "is", "subsequently", "reproduced", "or", "disseminated", "not", "in", "its", "entirety", "but", "only", "in", "part", "or", "as", "a", "derivative", "work", "this", "must", "be", "clearly", "indicated.", "For", "commercial", "re-use,", "please", "contact", "journals.permissions@oupjournals.org" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 1, 1, 1, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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[ 617, 830, 654, 843 ], [ 366, 845, 378, 858 ], [ 382, 845, 416, 858 ], [ 418, 845, 436, 858 ], [ 440, 845, 452, 858 ], [ 455, 845, 473, 858 ], [ 476, 845, 542, 858 ], [ 546, 845, 558, 858 ], [ 562, 845, 569, 858 ], [ 573, 845, 618, 858 ], [ 620, 845, 636, 858 ], [ 641, 845, 653, 858 ], [ 366, 860, 394, 873 ], [ 395, 860, 412, 873 ], [ 414, 860, 462, 873 ], [ 464, 860, 540, 873 ], [ 542, 860, 577, 873 ], [ 579, 860, 608, 873 ], [ 609, 860, 641, 873 ], [ 643, 860, 655, 873 ], [ 636, 908, 644, 921 ] ]	[ "Indian", "J.", "PsychiaL,", "1994,36(1),", "25-29.", "PLEA", "OF", "INSANITY", "AS", "A", "DEFENSE", "IN", "CRIMINAL", "CASES:", "AN", "UPDATE", "SAYEED", "AKHTAR,", "TUSHAR", "JAGAWAT", "Mc'Naughten", "Rule", "is", "die", "commonest", "formulation", "for", "plea", "of", "insanity", "in", "most", "countries.", "Althougjk", "assessment", "of", "the", "mental", "state", "at", "thetimeofoffence", "is", "difficult,", "few", "instruments", "have", "been", "devised", "for", "this", "purpose.", "In", "the", "USA.,", "efforts", "are", "being", "made", "to", "abolish", "the", "insanity", "defense", "and", "in", "the", "United", "Kingdom,", "amendments", "in", "the", "provisions", "of", "insanity", "defense", "have", "been", "proposed.", "The", "authors", "have", "stressed", "the", "need", "for", "some", "changes", "in", "the", "relevant", "sections", "of", "Indian", "Penal", "Code", "to", "increase", "the", "credibility", "ofPsychiatric", "testimony", "in", "such", "cases.", "INTRODUCTION", "Plea", "of", "insanity", "is", "used", "as", "a", "defense", "in", "criminal", "cases", "and", "when", "successful", "the", "accused", "is", "acquitted", "of", "the", "charge", "on", "the", "ground", "of", "insanity.", "The", "term", "'insanity'", "is", "not", "a", "medical", "term", "but", "a", "legal", "concept", "meaning", "that", "degree", "of", "mental", "disorder", "that", "relieves", "toe", "offender", "of", "the", "criminal", "responsibility", "for", "his", "action.", "In", "the", "Western", "countries,", "it", "is", "estimated", "that", "plea", "of", "insanity", "is", "used", "as", "a", "defense", "in", "1-2%", "of", "the", "criminal", "cases", "(Pasewik", "&", "Craig,", "1980).", "Not", "Guilty", "By", "Reason", "of", "Insanity", "(NGBRI)", "defendants", "tend", "to", "be", "older,", "married", "and", "un", "employed", "at", "the", "time", "of", "commission", "of", "the", "crime.", "Most", "of", "them", "have", "a", "prior", "psychiatric", "treatment", "history", "and", "there", "is", "a", "history", "of", "drug", "and", "alcohol", "abuse", "(Roger,", "1987).", "Acquitees", "differed", "from", "those", "convicted,", "in", "being", "female", "(Roger,", "1984),", "older", "and", "more", "educated,", "and", "more", "likely", "to", "be", "schizophrenic", "(Somasundaram,", "1960", "&", "1974;", "Benezech", "et", "aL", "1984).", "Li", "a", "study", "of", "187", "men", "found", "NGBRI", "(Taylor", "&", "London,", "1982),", "34%", "of", "the", "defendants", "using", "the", "insanity", "plea", "were", "patients", "with", "Bipolar", "Affective", "Disorder.", "A", "high", "concordance", "rate", "(88%)", "was", "found", "between", "psychiatric", "evaluation", "of", "insanity", "and", "the", "verdict", "of", "the", "court.", "It", "reflects", "the", "influence", "of", "the", "psychiatrist's", "recommendations", "in", "the", "court's", "decision", "of", "insanity", "plea.", "HISTORICAL", "BACKGROUND", "The", "defence", "of", "insanity", "has", "been", "recognized", "in", "English", "courts", "for", "over", "700", "years", "beginning", "from", "the", "reign", "of", "Edward", "HI", "in", "the", "fourteenth", "century,", "when", "complete", "madness", "was", "considered", "as", "a", "defense", "to", "a", "criminal", "charge", "(Simon,", "1967).", "By", "1518,", "it", "was", "well", "established", "that", "the", "lack", "of", "guilty", "mind", "and", "intellect", "meant", "a", "lack", "of", "criminal", "responsibility.", "Some", "250", "years", "ago", "an", "English", "judge,", "in", "the", "trial", "of", "Edward", "Arnold", "said,", "\"in", "order", "to", "avail", "oneself", "of", "defense", "of", "insanity,", "a", "man", "must", "be", "totally", "deprived", "of", "under", "standing", "and", "memory", "that", "be", "is", "not", "to", "know", "what", "i", "x", "was", "doing,", "not", "more", "than", "an", "infant,", "brute", "or", "a", "wild", "beast", "(Simon,", "1983).", "The", "\"wild-beast\"", "test", "along", "with", "determination", "of", "ability", "to", "distinguish", "between", "right", "and", "wrong", "remained", "the", "standard", "of", "judging", "criminal", "responsibility", "until", "the", "year", "1800", "A", "D", ".", ",", "when", "the", "landmark", "trial", "of", "Hadfield", "set", "a", "new", "stand", "ard", "(Whitlock,", "1963).", "A", "former", "soldier.", "James", "Hadfield", "attempted", "as", "sassination", "of", "reigning", "English", "monarch,", "George", "m", "with", "the", "belief", "that", "be", "was", "the", "savior", "of", "mankind.", "He", "thought", "that", "in", "order", "to", "become", "popular", "he", "should", "sacrifice", "his", "life", "like", "Jesus", "Christ", "and", "for", "this", "he", "chose", "to", "carry", "out", "an", "act", "for", "which", "he", "would", "be", "hanged.", "The", "prosecution", "argued", "that", "the", "defendant's", "behavior", "(purchase", "of", "gunpowder,", "concealment", "of", "pistol", "etc.)", "clearly", "indicated", "that", "he", "was", "neither", "an", "idiot", "nor", "a", "madman,", "so", "\"afflicted", "by", "absolute", "priva", "tion", "of", "reason\".", "The", "jury", "acquitted", "him", "because", "he", "was", "insane", "at", "the", "time", "of", "commission", "of", "the", "crime.", "This", "decision", "was", "a", "landmark", "because", "it", "rejected", "two", "concepts", "previously", "held", "by", "the", "court.", "First,", "it", "is", "not", "necessary", "for", "acquittal", "on", "the", "ground", "of", "insanity", "that", "be", "must", "be", "completely", "deprived", "of", "his", "mental", "faculties;", "second,", "it", "severed", "the", "tie", "between", "insanity", "and", "ability", "to", "distinguish", "between", "right", "and", "wrong,", "MC'NAUGHTEN", "RULE", "Daniel", "Mc'Naughten", "was", "a", "Scottish", "woodcutter", "who", "assassinated", "Edward", "Drummond", "who", "was", "secretary", "to", "the", "Prime", "Minister", "Sir", "Robert", "Peel,", "in", "the", "mistaken", "belief", "that", "Drummond", "was", "the", "Prime", "Minister.", "Mc'Naughten", "was", "described", "by", "nine", "medical", "witnesses", "as", "'an", "extreme", "paranoiac", "en", "tangled", "in", "an", "elaborate", "system", "of", "delusions'", "and", "be", "believed,", "albeit", "falsely,", "that", "the", "Prime", "Minister", "was", "responsible", "for", "all", "his", "financial", "and", "personal", "misfor", "tunes.", "His", "trial,", "acquittal", "and", "reference", "to", "the", "House", "of", "Lords", "led", "to", "the", "formulation", "of", "a", "popular", "set", "of", "rules", "for", "criminal", "responsibility", "which", "have", "come", "to", "»" ]	[ 0, 0, 0, 0, 0, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 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"Sayrac,", "Sonya", "Vengrova,", "Emma", "L.", "Godfrey,", "Jacob", "Z.", "Dalgaard", "Clinical", "Sciences", "Research", "Institute,", "Gibbet", "Hill", "Campus,", "University", "of", "Warwick,", "Coventry,", "United", "Kingdom", "Abstract", "Asymmetrical", "segregation", "of", "differentiated", "sister", "chromatids", "is", "thought", "to", "be", "important", "for", "cellular", "differentiation", "in", "higher", "eukaryotes.", "Similarly,", "in", "fission", "yeast,", "cellular", "differentiation", "involves", "the", "asymmetrical", "segregation", "of", "a", "chromosomal", "imprint.", "This", "imprint", "has", "been", "shown", "to", "consist", "of", "two", "ribonucleotides", "that", "are", "incorporated", "into", "the", "DNA", "during", "lagging-", "strand", "synthesis", "in", "response", "to", "a", "replication", "pause,", "but", "the", "underlying", "mechanism", "remains", "unknown.", "Here", "we", "present", "key", "novel", "discoveries", "important", "for", "unravelling", "this", "process.", "Our", "data", "show", "that", "cis-acting", "sequences", "within", "the", "mat1", "cassette", "mediate", "pausing", "of", "replication", "forks", "at", "the", "proximity", "of", "the", "imprinting", "site,", "and", "the", "results", "suggest", "that", "this", "pause", "dictates", "specific", "priming", "at", "the", "position", "of", "imprinting", "in", "a", "sequence-independent", "manner.", "Also,", "we", "identify", "a", "novel", "type", "of", "cis-acting", "spacer", "region", "important", "for", "the", "imprinting", "process", "that", "affects", "where", "subsequent", "primers", "are", "put", "down", "after", "the", "replication", "fork", "is", "released", "from", "the", "pause.", "Thus,", "our", "data", "suggest", "that", "the", "imprint", "is", "formed", "by", "ligation", "of", "a", "not-fully-", "processed", "Okazaki", "fragment", "to", "the", "subsequent", "fragment.", "The", "presented", "work", "addresses", "how", "differentiated", "sister", "chromatids", "are", "established", "during", "DNA", "replication", "through", "the", "involvement", "of", "replication", "barriers.", "Citation:", "Sayrac", "S,", "Vengrova", "S,", "Godfrey", "EL,", "Dalgaard", "JZ", "(2011)", "Identification", "of", "a", "Novel", "Type", "of", "Spacer", "Element", "Required", "for", "Imprinting", "in", "Fission", "Yeast.", "PLoS", "Genet", "7(3):", "e1001328.", "doi:10.1371/journal.pgen.1001328", "Editor:", "James", "E.", "Haber,", "Brandeis", "University,", "United", "States", "of", "America", "Received", "July", "15,", "2010;", "Accepted", "February", "7,", "2011;", "Published", "March", "10,", "2011", "Copyright:", "2011", "Sayrac", "et", "al.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Funding:", "This", "work", "was", "supported", "by", "a", "grant", "from", "Marie", "Curie", "Cancer", "Care.", "The", "funders", "had", "no", "role", "in", "study", "design,", "data", "collection", "and", "analysis,", "decision", "to", "publish,", "or", "preparation", "of", "the", "manuscript.", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "", "E-mail:", "j.z.dalgaard@warwick.ac.uk", "Introduction", "Differentiated", "sister", "chromatids,", "coupled", "with", "non-random", "segregation,", "have", "been", "proposed", "to", "control", "cell", "fate", "during", "the", "development", "and", "differentiation", "of", "multicellular", "organisms", "[1].", "Similarly,", "cellular", "differentiation", "in", "the", "fission", "yeast", "Schizosacchar-", "omyces", "pombe", "involves", "the", "establishment", "of", "differentiated", "chromatids", "and", "their", "asymmetrical", "segregation.", "The", "nature", "of", "this", "epigenetic", "mark", "or", "imprint", "that", "acts", "to", "discriminate", "the", "chromatids", "has", "been", "defined,", "however,", "the", "mechanism", "that", "leads", "to", "its", "introduction", "remains", "unknown.", "Fission", "yeast", "cells", "exhibit", "two", "different", "mating-", "types", "denoted", "as", "M", "and", "P.", "Homothallic", "strains", "are", "able", "to", "switch", "between", "mating-types", "in", "a", "pattern", "where", "only", "one", "granddaughter", "of", "a", "newly", "switched", "cell", "will", "have", "switched", "mating-type", "(Figure", "1A)", "[2–6].", "The", "mating-type", "of", "a", "cell", "is", "determined", "by", "the", "transcriptionally", "expressed", "mat1", "locus", "located", "on", "chromosome", "II,", "which", "encodes", "either", "an", "M-", "or", "a", "P-specific", "gene", "cassette", "(Figure", "1B)", "[7,8].", "Switching", "between", "the", "two", "mating-types", "occurs", "through", "a", "recombination", "event", "that", "replaces", "the", "cassette", "present", "at", "mat1", "with", "that", "of", "the", "opposite", "mating-type,", "using", "one", "of", "the", "two", "transcriptionally", "silenced", "loci,", "mat2P", "and", "mat3M,", "as", "a", "donor", "of", "the", "information.", "The", "molecular", "mechanism", "underlying", "mating-type", "switching", "is", "tightly", "linked", "to", "DNA", "replication,", "and", "the", "asymmetrical", "pattern", "of", "switching", "reflects", "the", "asymmetry", "of", "the", "replication", "process.", "The", "mat1", "locus", "is", "replicated", "unidirectionally", "in", "the", "centromere-", "proximal", "direction", "(see", "below).", "An", "imprint,", "which", "marks", "the", "mat1", "locus", "of", "switchable", "cells", "(Figure", "1B,", "1C),", "is", "introduced", "during", "lagging-strand", "synthesis", "of", "the", "mat1", "DNA", "in", "only", "one", "of", "the", "two", "sister", "chromatids", "formed", "in", "S", "phase", "[9,10].", "This", "imprint", "is", "maintained", "for", "one", "cell", "cycle,", "then", "during", "the", "next", "S", "phase,", "the", "imprint", "acts", "as", "a", "barrier", "for", "leading-strand", "replication,", "resulting", "in", "the", "replication-coupled", "recombination", "event", "that", "underlies", "mating-type", "switching", "[11–13].", "The", "recombination", "event", "pro-", "gresses", "by", "the", "‘‘synthesis", "dependent", "single-strand", "annealing", "mechanism’’", "where", "only", "one", "DNA", "strand", "at", "the", "donor", "locus", "provides", "the", "genetic", "information", "that", "is", "transferred", "to", "mat1", "[14].", "The", "homology", "needed", "for", "both", "the", "initiation", "and", "resolution", "of", "this", "recombination", "event", "is", "provided", "by", "short", "homology", "domains,", "named", "H1", "and", "H2,", "that", "flank", "both", "the", "mat1", "locus", "and", "each", "of", "the", "two", "donor", "loci,", "mat2P", "and", "mat3M", "(Figure", "1B)", "[8,15].", "As", "a", "result", "of", "this", "recombination", "event,", "the", "mating-type", "cassette", "of", "only", "one", "of", "the", "two", "sister", "chromatids", "is", "replaced", "by", "a", "cassette", "containing", "the", "opposite", "mating-type", "information,", "such", "that", "the", "subsequent", "cell", "division", "gives", "rise", "to", "two", "cells", "with", "opposite", "mating-types.", "The", "imprint", "was", "first", "identified", "genetically", "as", "a", "strand-specific,", "chromosomally", "inherited", "mark", "that", "is", "linked", "to", "the", "mat1", "locus", "and", "is", "required", "for", "the", "induction", "of", "switching", "[4–6,16].", "Subsequently", "it", "was", "shown", "that", "the", "imprint", "consists", "of", "two", "ribonucleotides", "that", "are", "incorporated", "into", "the", "DNA", "duplex", "in", "a", "strand-", "and", "site-specific", "manner", "([12]", "and", "reviewed", "in", "[17]).", "These", "two", "ribonucleotides", "are", "located", "at", "the", "junction", "between", "the", "mating-type", "cassette", "and", "the", "homology", "domain", "H1", "(Figure", "1B)", "[18].", "The", "bonds", "of", "the", "RNA-", "DNA", "hybrid", "at", "the", "imprint", "site", "appear", "to", "be", "efficiently", "hydrolyzed", "by", "cellular", "enzymes,", "making", "purification", "of", "intact", "imprinted", "DNA", "difficult.", "During", "standard", "purification", "methods,", "the", "imprint", "is", "converted", "into", "a", "double-stranded", "break", "that", "can", "be", "detected", "by", "Southern", "analysis", "[10,19].", "However,", "we", "have", "managed", "to", "purify", "PLoS", "Genetics", "\|", "www.plosgenetics.org", "1", "March", "2011", "\|", "Volume", "7", "\|", "Issue", "3", "\|", "e1001328" ]	[ 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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"Stefan", "N", "Willich1,", "Claudia", "M", "Witt1", "Abstract", "Background:", "Very", "little", "is", "known", "about", "the", "range", "of", "diagnoses,", "course", "of", "treatment", "and", "long-term", "outcome", "in", "elderly", "patients", "who", "choose", "to", "receive", "homeopathic", "medical", "treatment.", "We", "investigated", "homeopathic", "practice", "in", "an", "industrialised", "country", "under", "everyday", "conditions.", "The", "aim", "of", "the", "study", "was", "to", "determine", "the", "spectrum", "of", "diagnoses", "and", "treatments,", "as", "well", "as", "to", "describe", "the", "course", "of", "illness", "over", "time", "among", "older", "patients", "who", "chose", "to", "receive", "homeopathic", "treatment.", "Methods:", "In", "this", "subgroup", "analysis", "of", "a", "prospective,", "multicentre", "cohort", "study", "totally", "including", "3981", "patients", "treated", "by", "homeopathic", "physicians", "in", "primary", "care", "practices", "in", "Germany", "and", "Switzerland,", "data", "was", "analysed", "from", "all", "patients", ">", "70", "years", "consulting", "the", "physician", "for", "the", "first", "time.", "The", "main", "outcome", "measures", "were:", "assessment", "by", "patient", "of", "the", "severity", "of", "complaints", "(numeric", "rating", "scales)", "and", "quality", "of", "life", "(SF-36)", "and", "by", "the", "physician", "of", "the", "severity", "of", "diagnoses", "(numeric", "rating", "scales)", "at", "baseline,", "and", "after", "3,", "12,", "and", "24", "months.", "Results:", "A", "total", "of", "83", "patients", "were", "included", "in", "the", "subgroup", "analysis", "(41%", "men,", "mean", "age", "73.2", "±", "(SD)", "3.1", "years;", "59%", "women,", "74.3", "±", "3.8", "years).", "98.6", "percent", "of", "all", "diagnoses", "were", "chronic", "with", "an", "average", "duration", "of", "11.5", "±", "11.5", "years.", "82", "percent", "of", "the", "patients", "were", "taking", "medication", "at", "baseline.", "The", "most", "frequent", "diagnoses", "were", "hypertension", "(20.5%,", "11.1", "±", "7.5", "years)", "and", "sleep", "disturbances", "(15.7%,", "22.1", "±", "25.8", "years).", "The", "severity", "of", "complaints", "decreased", "significantly", "between", "baseline", "and", "24", "months", "in", "both", "patients", "(from", "6.3", "(95%", "CI:", "5.7-6.8)", "to", "4.6", "(4.0-5.1),", "p", "<", "0.001)", "and", "physicians’", "assessments", "(from", "6.6", "(6.0-7.1)", "to", "3.7", "(3.2-4.3),", "p", "<", "0.001);", "qual-", "ity", "of", "life", "(SF", "36)", "and", "the", "number", "of", "medicines", "taken", "did", "not", "significantly", "change.", "Conclusion:", "The", "severity", "of", "disease", "showed", "marked", "and", "sustained", "improvements", "under", "homeopathic", "treatment,", "but", "this", "did", "not", "lead", "to", "an", "improvement", "of", "quality", "of", "life.", "Our", "findings", "might", "indicate", "that", "homeopathic", "medical", "therapy", "may", "play", "a", "beneficial", "role", "in", "the", "long-term", "care", "of", "older", "adults", "with", "chronic", "diseases", "and", "studies", "on", "comparative", "effectiveness", "are", "needed", "to", "evaluate", "this", "hypothesis.", "Background", "Homeopathy", "is", "one", "of", "the", "most", "frequently", "used", "but", "con-", "troversial", "forms", "of", "complementary", "and", "alternative", "medi-", "cine", "(CAM).", "It", "is", "based", "on", "the", "ancient", "‘principle", "of", "similars’.", "Highly", "diluted", "preparations", "of", "substances", "that", "cause", "symptoms", "in", "healthy", "individuals", "are", "used", "to", "stimu-", "late", "healing", "reactions", "in", "patients", "who", "display", "similar", "", "Correspondence:", "michael.teut@charite.de", "1Institute", "for", "Social", "Medicine,", "Epidemiology", "and", "Health", "Economics,", "Charité", "University", "Medical", "Center,", "Luisenstr.", "57,", "D-10017", "Berlin,", "Germany", "symptoms", "when", "ill", "[1].", "In", "classical", "homeopathy", "a", "single", "homeopathic", "remedy", "is", "selected,", "based", "on", "a", "patient’s", "total", "spectrum", "of", "symptoms", "[2].", "The", "proportion", "of", "patients", "obtaining", "homeopathic", "care", "has", "quadrupled", "in", "the", "last", "seven", "years", "according", "to", "a", "US", "survey", "[3].", "For", "Germany", "a", "recent", "survey", "demonstrated", "that", "approxi-", "mately", "10%", "of", "men", "and", "20%", "of", "women", "in", "the", "general", "population", "used", "homeopathic", "medicines", "during", "the", "pre-", "vious", "year", "[4].", "To", "date,", "few", "studies", "have", "evaluated", "the", "use", "of", "complementary", "therapies", "in", "geriatric", "patients", "[5].", "In", "Germany,", "73%", "of", "adults", "over", "60", "years", "of", "age", "use", "©", "2010", "Teut", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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"appear", "to", "have", "signiﬁcant", "beneﬁts", "for", "managing", "patients", "with", "chronic", "low", "back", "pain", "(CLBP)", "in", "terms", "of", "decreasing", "pain", "and", "improving", "function.", "In", "addition,", "because", "chronic", "pain", "is", "complex", "and", "does", "not", "ﬁt", "a", "simple", "model,", "there", "have", "also", "been", "numerous", "trials", "investigating", "and", "demonstrating", "the", "efﬁcacy", "of", "multidisciplinary", "pain", "programs", "for", "CLBP.", "It", "follows", "that", "interventions", "that", "treat", "more", "than", "one", "aspect", "of", "LBP", "would", "have", "signiﬁcant", "ben-", "eﬁts", "for", "this", "patient", "population.", "Yoga", "and", "Pilates", "which", "have,", "both", "been", "gaining", "in", "popularity", "over", "the", "last", "decade", "are", "two", "mind–body", "exercise", "interventions", "that", "address", "both", "the", "physical", "and", "mental", "aspects", "of", "pain", "with", "core", "strengthening,", "ﬂexibility,", "and", "relaxation.", "There", "has", "been", "a", "slow", "evolution", "of", "these", "nontraditional", "exercise", "regimens", "into", "treatment", "paradigms", "for", "LBP,", "although", "few", "studies", "S.", "Sorosky", "(&)", "Desert", "Pain", "Institute,", "Phoenix,", "AZ,", "USA", "e-mail:", "ssorosky@cox.net", "S.", "Sorosky", "Midwestern", "University,", "Glendale,", "AZ,", "USA", "S.", "Stilp", "Boulder", "Orthopedics,", "Boulder,", "CO,", "USA", "S.", "Stilp", "V.", "Akuthota", "Department", "of", "Physical", "Medicine", "and", "Rehabilitation,", "University", "of", "Colorado", "School", "of", "Medicine,", "New", "York,", "USA", "V.", "Akuthota", "The", "Spine", "Center", "at", "the", "University", "of", "Colorado", "Hospital,", "Aurora,", "CO,", "USA", "examining", "their", "effects", "have", "been", "published.", "The", "following", "article", "will", "focus", "on", "the", "scientiﬁc", "and", "theoretical", "basis", "of", "using", "yoga", "and", "Pilates", 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161, 1059 ], [ 165, 1047, 168, 1059 ], [ 174, 1047, 257, 1059 ], [ 422, 1047, 428, 1059 ], [ 569, 1047, 588, 1059 ], [ 591, 1047, 614, 1059 ], [ 619, 1047, 622, 1059 ], [ 627, 1047, 663, 1059 ], [ 668, 1047, 674, 1059 ], [ 680, 1047, 683, 1059 ], [ 688, 1047, 712, 1059 ], [ 716, 1047, 722, 1059 ], [ 727, 1047, 730, 1059 ], [ 736, 1047, 770, 1059 ] ]	[ "Cytotoxic", "Effect", "of", "Poly-Dispersed", "Single", "Walled", "Carbon", "Nanotubes", "on", "Erythrocytes", "In", "Vitro", "and", "In", "Vivo", "Sumedha", "Sachar,", "Rajiv", "K.", "Saxena", "School", "of", "Life", "Sciences,", "Jawaharlal", "Nehru", "University,", "New", "Delhi,", "India", "Abstract", "Single", "wall", "Carbon", "Nanotubes", "(SWCNTs)", "are", "hydrophobic", "and", "do", "not", "disperse", "in", "aqueous", "solvents.", "Acid", "functionalization", "of", "SWCNTs", "results", "in", "attachment", "of", "carboxy", "and", "sulfonate", "groups", "to", "carbon", "atoms", "and", "the", "resulting", "acid", "functionalized", "product", "(AF-SWCNTs)", "is", "negatively", "charged", "and", "disperses", "easily", "in", "water", "and", "buffers.", "In", "the", "present", "study,", "effect", "of", "AF-", "SWCNTs", "on", "blood", "erythrocytes", "was", "examined.", "Incubation", "of", "mouse", "erythrocytes", "with", "AF-SWCNTs", "and", "not", "with", "control", "SWCNTs,", "resulted", "in", "a", "dose", "and", "time", "dependent", "lysis", "of", "erythrocyte.", "Using", "fluorescence", "tagged", "AF-SWCNTs,", "binding", "of", "AF-", "SWCNTs", "with", "erythrocytes", "could", "be", "demonstrated.", "Confocal", "microscopy", "results", "indicated", "that", "AF-SWCNTs", "could", "enter", "the", "erythrocytes.", "Treatment", "with", "AF-SWCNTs", "resulted", "in", "exposure", "of", "hydrophobic", "patches", "on", "erythrocyte", "membrane", "that", "is", "indicative", "of", "membrane", "damage.", "A", "time", "and", "dose", "dependent", "increase", "in", "externalization", "of", "phosphatidylserine", "on", "erythrocyte", "membrane", "bilayer", "was", "also", "found.", "Administration", "of", "AF-SWCNTs", "through", "intravenous", "route", "resulted", "in", "a", "transient", "anemia", "as", "seen", "by", "a", "sharp", "decline", "in", "blood", "erythrocyte", "count", "accompanied", "with", "a", "significant", "drop", "in", "blood", "haemoglobin", "level.", "Administration", "of", "AF-SWCNTs", "through", "intratracheal", "administration", "also", "showed", "significant", "decline", "in", "RBC", "count", "while", "administration", "through", "other", "routes", "(gavage", "and", "intra-peritoneal)", "was", "not", "effective.", "By", "using", "a", "recently", "developed", "technique", "of", "a", "two", "step", "in", "vivo", "biotinylation", "of", "erythrocytes", "that", "enables", "simultaneous", "enumeration", "of", "young", "(age", ",10", "days)", "and", "old", "(age.40", "days)", "erythrocytes", "in", "mouse", "blood,", "it", "was", "found", "that", "the", "in", "vivo", "toxic", "effect", "of", "AF-SWCNTs", "was", "more", "pronounced", "on", "older", "subpopulation", "of", "erythrocytes.", "Subpopulation", "of", "old", "erythrocytes", "fell", "after", "treatment", "with", "AF-SWCNTs", "but", "recovered", "by", "third", "day", "after", "the", "intravenous", "administration", "of", "AF-SWCNTs.", "Taken", "together", "our", "results", "indicate", "that", "treatment", "with", "AF-SWCNTs", "results", "in", "acute", "membrane", "damage", "and", "eventual", "lysis", "of", "erythrocytes.", "Intravenous", "administration", "of", "AF-SWCNTs", "resulted", "in", "a", "transient", "anemia", "in", "which", "older", "erythrocytes", "are", "preferably", "lysed.", "Citation:", "Sachar", "S,", "Saxena", "RK", "(2011)", "Cytotoxic", "Effect", "of", "Poly-Dispersed", "Single", "Walled", "Carbon", "Nanotubes", "on", "Erythrocytes", "In", "Vitro", "and", "In", "Vivo.", "PLoS", "ONE", "6(7):", "e22032.", "doi:10.1371/journal.pone.0022032", "Editor:", "David", "L.", "McCormick,", "IIT", "Research", "Institute,", "United", "States", "of", "America", "Received", "March", "11,", "2011;", "Accepted", "June", "13,", "2011;", "Published", "July", "19,", "2011", "Copyright:", "2011", "Sachar,", "Saxena.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Funding:", "This", "study", "was", "supported", "by", "a", "Department", "of", "Science", "and", "Technology", "(DST)", "grant", "(SR/SO/HS-133/2007)", "to", "RKS,", "and", "a", "fellowship", "from", "DBT", "to", "SS.", "The", "funders", "had", "no", "role", "in", "study", "design,", "data", "collection", "and", "analysis,", "decision", "to", "publish,", "or", "preparation", "of", "the", "manuscript.", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "", "E-mail:", "rajivksaxena@hotmail.com", "Introduction", "Nano-sized", "particles", "are", "finding", "increasing", "practical", "applica-", "tions", "and", "commercial", "use.", "Consequently,", "the", "possibility", "of", "occupational", "exposure", "to", "nano-particles", "has", "increased.", "Further-", "more,", "as", "the", "use", "of", "nanoparticles", "increases,", "they", "may", "diffuse", "and", "accumulate", "in", "environment", "increasing", "the", "risk", "of", "environmental", "exposure.", "Health", "effects", "of", "exposure", "to", "nanoparticles", "are", "now", "under", "investigation", "by", "many", "researchers", "[1],", "[2],", "[3].", "Nanopar-", "ticles", "have", "a", "tendency", "to", "agglomerate", "into", "particles", "of", "larger", "size", "that", "may", "not", "have", "the", "same", "biological", "effects", "as", "non-agglomerated", "nanoparticles.", "For", "studying", "the", "biological", "effects", "therefore", "it", "is", "necessary", "to", "test", "non-agglomerated", "forms", "of", "nanoparticles.", "For", "Single", "walled", "Carbon", "Nanotubes", "(SWCNTs)", "disaggregation", "can", "be", "achieved", "by", "acid", "functionalization", "that", "introduces", "negative", "charge,", "without", "changing", "the", "essential", "structural", "features", "of", "SWCNTs", "[4],", "[5].", "We", "have", "previously", "reported", "cytostatic", "and", "toxic", "effects", "of", "acid", "functionalized", "SWCNTs", "(AF-SWCNTs)", "on", "LA4", "lung", "epithelial", "cell", "line", "[5].", "We", "also", "found", "that", "the", "administration", "of", "AF-SWCNTs", "intratracheally", "resulted", "in", "cardiac", "damage", "in", "mice", "[6].", "Since", "AF-SWCNTs", "were", "toxic", "to", "some", "types", "of", "nucleated", "cells", "that", "are", "capable", "of", "self", "repair,", "we", "hypothesized", "that", "the", "AF-", "SWCNTs", "may", "have", "a", "more", "aggravated", "toxic", "effect", "on", "erythrocytes", "that", "have", "no", "nucleus", "and", "lack", "substantial", "cellular", "repair", "mechanisms.", "This", "proposition", "was", "examined", "in", "the", "present", "study.", "Our", "results", "indicate", "that", "unlike", "pristine", "SWCNTs,", "AF-", "SWCNTs", "are", "significantly", "toxic", "to", "mouse", "blood", "derived", "erythrocytes", "in", "vitro", "as", "well", "as", "in", "vivo.", "AF-SWCNTs", "were", "found", "to", "bind", "with", "erythrocytes", "and", "cause", "significant", "membrane", "damage", "as", "well", "as", "externalization", "of", "phosphatidylserine.", "Administration", "of", "AF-SWCNTs", "intravenously", "induced", "a", "significant", "though", "transient", "anemia", "in", "mice.", "Older", "as", "compared", "to", "the", "younger", "subpopulation", "of", "erythrocyte", "in", "blood", "circulation,", "was", "more", "susceptible", "to", "the", "toxic", "effect", "of", "AF-SWCNTs.", "Taken", "together", "our", "results", "show", "that", "non-agglomerated", "form", "of", "SWCNTs", "may", "exert", "significant", "and", "rapid", "toxic", "effects", "on", "blood", "erythrocytes.", "Materials", "and", "Methods", "Experimental", "model", "Inbred", "Swiss", "and", "C57BL/6", "female", "mice", "(6–12", "weeks", "old,", "20–25", "g", "body", "weight)", "were", "used", "throughout", "this", "study.", "Animals", "were", "bred", "and", "maintained", "in", "the", "animal", "house", "facility", "at", "JNU,", "New", "Delhi", "or", "obtained", "from", "the", "National", "Institute", "of", "Nutrition,", "Hyderabad.", "The", "animals", "were", "housed", "in", "positive-pressure", "air", "PLoS", "ONE", "\|", "www.plosone.org", "1", "July", "2011", "\|", "Volume", "6", "\|", "Issue", "7", "\|", "e22032" ]	[ 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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] ]	[ "BMC", "Genomics", "Research", "article", "Small", "noncoding", "RNA", "GcvB", "is", "a", "novel", "regulator", "of", "acid", "resistance", "in", "Escherichia", "coli", "Ye", "Jin1,", "Rory", "M", "Watt2,", "Antoine", "Danchin3", "and", "Jian-dong", "Huang1", "BioMed", "Central", "Open", "Access", "Address:", "1Department", "of", "Biochemistry,", "Li", "Ka", "Shing", "Faculty", "of", "Medicine,", "University", "of", "Hong", "Kong,", "Pok", "Fu", "Lam,", "Hong", "Kong", "SAR,", "PR", "China,", "2Oral", "Biosciences,", "Faculty", "of", "Dentistry,", "University", "of", "Hong", "Kong,", "Pok", "Fu", "Lam,", "Hong", "Kong", "SAR,", "PR", "China", "and", "3Genetics", "of", "Bacterial", "Genomes,", "CNRS", "URA2171,", "Institut", "Pasteur,", "28,", "rue", "du", "Docteur", "Roux,", "Paris", "Cedex", "15,", "75724,", "France", "Email:", "Ye", "Jin", "-", "yejin@hkucc.hku.hk;", "Rory", "M", "Watt", "-", "rmwatt@hku.hk;", "Antoine", "Danchin", "-", "antoine.danchin@normalesup.org;", "Jian-", "dong", "Huang", "-", "jdhuang@hkucc.hku.hk", "*", "Corresponding", "author", "Published:", "20", "April", "2009", "BMC", "Genomics", "2009,", "10:165", "doi:10.1186/1471-2164-10-165", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1471-2164/10/165", "Received:", "26", "January", "2009", "Accepted:", "20", "April", "2009", "©", "2009", "Jin", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "The", "low", "pH", "environment", "of", "the", "human", "stomach", "is", "lethal", "for", "most", "microorganisms;", "but", "not", "Escherichia", "coli,", "which", "can", "tolerate", "extreme", "acid", "stress.", "Acid", "resistance", "in", "E.", "coli", "is", "hierarchically", "controlled", "by", "numerous", "regulators", "among", "which", "are", "small", "noncoding", "RNAs", "(sncRNA).", "Results:", "In", "this", "study,", "we", "individually", "deleted", "seventy-nine", "sncRNA", "genes", "from", "the", "E.", "coli", "K12-", "MG1655", "chromosome,", "and", "established", "a", "single-sncRNA", "gene", "knockout", "library.", "By", "systematically", "screening", "the", "sncRNA", "mutant", "library,", "we", "show", "that", "the", "sncRNA", "GcvB", "is", "a", "novel", "regulator", "of", "acid", "resistance", "in", "E.", "coli.", "We", "demonstrate", "that", "GcvB", "enhances", "the", "ability", "of", "E.", "coli", "to", "survive", "low", "pH", "by", "upregulating", "the", "levels", "of", "the", "alternate", "sigma", "factor", "RpoS.", "Conclusion:", "GcvB", "positively", "regulates", "acid", "resistance", "by", "affecting", "RpoS", "expression.", "These", "data", "advance", "our", "understanding", "of", "the", "sncRNA", "regulatory", "network", "involved", "in", "modulating", "acid", "resistance", "in", "E.", "coli.", "Background", "The", "ability", "to", "survive", "the", "extremely", "low", "pH", "environment", "present", "within", "the", "stomach", "(pH", "values", "<", "2.5)", "is", "essential", "for", "colonization", "of", "the", "intestine", "by", "commensals", "and", "for", "the", "pathogenesis", "of", "enteric", "bacteria.", "Three", "distinct", "acid", "resistance", "(AR)", "systems", "are", "responsible", "for", "protecting", "bac-", "terial", "cells", "from", "acid", "shock", "[1-3].", "AR", "system", "1", "is", "a", "glucose-", "repressed", "system", "and", "does", "not", "require", "any", "external", "amino", "acids", "to", "function", "at", "low", "pH", "[1].", "Unidentified", "components", "of", "this", "system", "are", "controlled", "by", "the", "alternate", "sigma", "factor", "RpoS,", "with", "the", "underlying", "mechanism", "remaining", "unclear", "[1].", "In", "contrast,", "AR", "systems", "2", "and", "3", "provide", "AR", "by", "con-", "suming", "intracellular", "protons", "via", "the", "glutamate", "(AR2)", "and", "arginine", "(AR3)", "decarboxylation", "reactions", "[2,3].", "AR2", "is", "the", "most", "efficient", "AR", "system.", "It", "involves", "two", "isozymes", "of", "glutamate", "decarboxylase,", "encoded", "by", "genes", "gadA", "and", "gadB,", "and", "a", "membrane-associated", "antiporter", "(GadC)", "that", "exchanges", "external", "glutamate", "for", "the", "intracellular", "decar-", "boxylation", "product", "γ-aminobutyric", "acid", "(GABA)", "[2].", "AR2", "is", "hierarchically", "regulated", "by", "multiple", "regulators,", "which", "include", "small", "noncoding", "RNAs", "(sncRNA)", "DsrA", "and", "possibly", "GadY.", "DsrA", "activates", "the", "expression", "of", "rpoS", "[4]", "and", "several", "AR", "genes", "including", "hdeAB,", "gadAX,", "and", "gadBC", "[5].", "GadY,", "whose", "effects", "on", "AR", "have", "yet", "to", "be", "determined,", "controls", "the", "synthesis", "of", "GadX", "and", "GadW,", "which", "are", "reg-", "Page", "1", "of", "7", "(page", "number", "not", "for", "citation", "purposes)" ]	[ 0, 0, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 0, 0, 9, 9, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 0, 0, 0, 0, 0, 9, 9, 9, 9, 9, 9, 7, 7, 7, 7, 7, 7, 7, 7, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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987, 584, 997 ], [ 586, 987, 609, 997 ], [ 611, 987, 624, 997 ], [ 626, 987, 647, 997 ], [ 650, 987, 658, 997 ], [ 661, 987, 674, 997 ], [ 676, 987, 707, 997 ], [ 709, 987, 748, 997 ], [ 248, 998, 289, 1008 ], [ 291, 998, 319, 1008 ], [ 322, 998, 493, 1008 ], [ 496, 998, 519, 1008 ], [ 522, 998, 551, 1008 ], [ 553, 998, 598, 1008 ], [ 601, 998, 616, 1008 ], [ 618, 998, 663, 1008 ], [ 666, 998, 681, 1008 ], [ 683, 998, 732, 1008 ], [ 736, 998, 743, 1008 ], [ 248, 1009, 262, 1019 ], [ 264, 1009, 298, 1019 ], [ 300, 1009, 334, 1019 ], [ 337, 1009, 350, 1019 ], [ 352, 1009, 380, 1019 ], [ 384, 1009, 403, 1019 ], [ 405, 1009, 411, 1019 ], [ 414, 1009, 446, 1019 ], [ 448, 1009, 469, 1019 ] ]	[ "Fluch", "et", "al.", "BMC", "Research", "Notes", "2011,", "4:401", "http://www.biomedcentral.com/1756-0500/4/401", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Characterization", "of", "variable", "EST", "SSR", "markers", "for", "Norway", "spruce", "(Picea", "abies", "L.)", "Silvia", "Fluch1,", "Agnes", "Burg1,", "Dieter", "Kopecky1,", "Andreas", "Homolka1,", "Nadine", "Spiess1", "and", "Giovanni", "G", "Vendramin2", "Abstract", "Background:", "Norway", "spruce", "is", "widely", "distributed", "across", "Europe", "and", "the", "predominant", "tree", "of", "the", "Alpine", "region.", "Fast", "growth", "and", "the", "fact", "that", "timber", "can", "be", "harvested", "cost-effectively", "in", "relatively", "young", "populations", "define", "its", "status", "as", "one", "of", "the", "economically", "most", "important", "tree", "species", "of", "Northern", "Europe.", "In", "this", "study,", "EST", "derived", "simple", "sequence", "repeat", "(SSR)", "markers", "were", "developed", "for", "the", "assessment", "of", "putative", "functional", "diversity", "in", "Austrian", "Norway", "spruce", "stands.", "Results:", "SSR", "sequences", "were", "identified", "by", "analyzing", "14,022", "publicly", "available", "EST", "sequences.", "Tri-nucleotide", "repeat", "motifs", "were", "most", "abundant", "in", "the", "data", "set", "followed", "by", "penta-", "and", "hexa-nucleotide", "repeats.", "Specific", "primer", "pairs", "were", "designed", "for", "sixty", "loci.", "Among", "these,", "27", "displayed", "polymorphism", "in", "a", "testing", "population", "of", "16", "P.", "abies", "individuals", "sampled", "across", "Austria", "and", "in", "an", "additional", "screening", "population", "of", "96", "P.", "abies", "individuals", "from", "two", "geographically", "distinct", "Austrian", "populations.", "Allele", "numbers", "per", "locus", "ranged", "from", "two", "to", "17", "with", "observed", "heterozygosity", "ranging", "from", "0.075", "to", "0.99.", "Conclusions:", "We", "have", "characterized", "variable", "EST", "SSR", "markers", "for", "Norway", "spruce", "detected", "in", "expressed", "genes.", "Due", "to", "their", "moderate", "to", "high", "degree", "of", "variability", "in", "the", "two", "tested", "screening", "populations,", "these", "newly", "developed", "SSR", "markers", "are", "well", "suited", "for", "the", "analysis", "of", "stress", "related", "functional", "variation", "present", "in", "Norway", "spruce", "populations.", "Background", "Natural", "populations", "of", "Picea", "abies", "L.", "(Norway", "spruce)", "are", "found", "from", "north-western", "Europe", "outside", "perma-", "frost", "areas", "down", "to", "northern", "Greece,", "westwards", "to", "the", "Massif", "Central", "(France)", "and", "east", "to", "the", "Ural", "Mountains.", "Picea", "abies", "is", "growing", "above", "400-500", "m", "and", "ascends", "close", "to", "2000", "m", "in", "the", "Alps.", "Studies", "on", "genetic", "variation", "based", "on", "allozymes", "have", "shown", "that", "Picea", "abies", "genetic", "differentiation", "among", "populations", "is", "rather", "low", "over", "its", "whole", "distribution", "range", "[1,2].", "Previous", "studies", "on", "the", "genetic", "structure", "of", "P.", "abies", "using", "organelle", "markers", "showed", "pronounced", "differentiation", "between", "north-east", "boreal", "origins", "and", "areas", "in", "the", "central", "European", "moun-", "tains", "[3,4],", "supporting", "the", "hypothesis", "of", "two", "distinct", "main", "glacial", "refugia", "as", "postulated", "from", "pollen", "data", "[5].", "Initial", "reports", "on", "the", "occurrence", "of", "SSRs", "in", "conifers", "such", "as", "Pinus", "radiata", "[6],", "Pinus", "sylvestris", "[7]", "or", "Picea", "", "Correspondence:", "silvia.fluch@ait.ac.at", "1AIT", "Austrian", "Institute", "of", "Technology", "GmbH,", "Health", "&", "Environment", "Department,", "Bioresources,", "3430", "Tulln,", "Austria", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "abies", "[8]", "have", "shown", "that", "marker", "development", "for", "such", "complex", "genomes", "is", "difficult.", "Frequently", "several", "DNA", "fragments", "in", "addition", "to", "the", "expected", "ones", "are", "amplified", "when", "using", "primers", "flanking", "putative", "SSR", "regions.", "This", "can", "be", "attributed", "to", "the", "very", "large", "size", "of", "the", "conifer", "genomes,", "with", "Norway", "spruce", "having", "39.140", "Mb", "in", "the", "diploid", "genome", "(2n", "=", "24)", "as", "well", "as", "the", "high", "proportion", "of", "repetitive", "DNA", "in", "the", "conifer", "genomes", "[9].", "These", "repetitive", "elements", "as", "well", "as", "pseudogenes", "frequently", "produce", "complex", "amplification", "products", "from", "multiple", "loci", "[10,11].", "To", "overcome", "this", "problem,", "Scotti", "et", "al.", "[12]", "showed", "that", "by", "isolating", "di-nucleotide", "SSRs", "from", "cDNA", "libraries", "of", "conifer", "species", "this", "problem", "can", "be", "over-", "come", "relying", "on", "the", "fact", "that", "expressed", "genes", "are", "less", "likely", 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"Beyazit,1", "Tugrul", "Purnak,2", "Gulay", "Sain", "Guven,3", "and", "Ibrahim", "C.", "Haznedaroglu1", "1", "Department", "of", "Gastroenterology,", "Turkiye", "Yuksek", "Ihtisas", "Teaching", "and", "Research", "Hospital,", "06100", "Ankara,", "Turkey", "2", "Department", "of", "Gastroenterology,", "Ankara", "Numune", "Education", "and", "Research", "Hospital,", "06100", "Ankara,", "Turkey", "3", "Department", "of", "Internal", "Medicine,", "Faculty", "of", "Medicine,", "Hacettepe", "University,", "06100", "Ankara,", "Turkey", "Correspondence", "should", "be", "addressed", "to", "Yavuz", "Beyazit,", "yavuzbeyaz@yahoo.com", "Received", "28", "September", "2010;", "Revised", "14", "October", "2010;", "Accepted", "23", "October", "2010", "Academic", "Editor:", "Masaki", "Mogi", "Copyright", "©", "2011", "Yavuz", "Beyazit", "et", "al.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Local", "hematopoietic", "bone", "marrow", "(BM)", "renin-angiotensin", "system", "(RAS)", "aﬀects", "the", "growth,", "production,", "proliferation", "diﬀerentiation,", "and", "function", "of", "hematopoietic", "cells.", "Angiotensin", "II", "(Ang", "II),", "the", "dominant", "eﬀector", "peptide", "of", "the", "RAS,", "regulates", "cellular", "growth", "in", "a", "wide", "variety", "of", "tissues", "in", "pathobiological", "states.", "RAS,", "especially", "Ang", "II", "and", "Ang", "II", "type", "1", "receptor", "(AT1R),", "has", "considerable", "proinﬂammatory", "and", "proatherogenic", "eﬀects", "on", "the", "vessel", "wall,", "causing", "progression", "of", "atherosclerosis.", "Recent", "investigations,", "by", "analyzing", "several", "BM", "chimeric", "mice", "whose", "BM", "cells", "were", "positive", "or", "negative", "for", "AT1R,", "disclosed", "that", "AT1R", "in", "BM", "cells", "participates", "in", "the", "pathogenesis", "of", "atherosclerosis.", "Therefore,", "AT1R", "blocking", "not", "only", "in", "vascular", "cells", "but", "also", "in", "the", "BM", "could", "be", "an", "important", "therapeutic", "approach", "to", "prevent", "atherosclerosis.", "The", "aim", "of", "this", "paper", "is", "to", "review", "the", "function", "of", "local", "BM", "RAS", "in", "the", "pathogenesis", "of", "atherosclerosis.", "1.", "Introduction", "The", "renin-angiotensin", "system", "(RAS)", "plays", "a", "crucial", "role", "in", "the", "control", "of", "blood", "pressure,", "blood", "ﬂow,", "ﬂuid", "volume,", "and", "electrolyte", "balance,", "and", "overactivity", "of", "this", "system", "contributes", "to", "the", "pathogenesis", "of", "a", "variety", "of", "clinical", "conditions,", "including", "onset,", "progression,", "and", "outcome", "of", "atherosclerosis", "[1–3].", "Angiotensinogen", "(AGT)", "produced", "in", "the", "liver", "is", "the", "precursor", "of", "angiotensin", "I", "(Ang", "I),", "an", "inactive", "decapeptide", "that", "is", "converted", "into", "Ang", "II,", "the", "main", "eﬀector", "of", "the", "RAS.", "Its", "only", "role", "known", "is", "as", "a", "substrate", "for", "renin,", "a", "highly", "speciﬁc", "aspartyl", "protease.", "Renin", "that", "is", "secreted", "from", "juxtaglomerular", "apparatus", "of", "the", "kidney", "cleaves", "the", "N-", "terminal", "end", "of", "AGT", "to", "generate", "Ang", "I.", "Ang", "I", "is", "then", "activated", "to", "the", "Ang", "II", "by", "angiotensin", "converting", "enzyme", "(ACE),", "which", "is", "predominantly", "expressed", "in", "high", "concentrations", "on", "the", "surface", "of", "endothelial", "cells", "in", "the", "pulmonary", "circulation", "[4].", "Ang", "II", "plays", "a", "main", "role", "in", "the", "RAS", "mediated", "mainly", "by", "two", "seven", "transmembrane", "domain", "receptors", "termed", "Ang", "II", "type", "1", "receptor", "(AT1R)", "and", "Ang", "II", "type", "2", "receptor", "(AT2R)", "showing", "a", "complex", "pattern", "of", "regulation", "and", "function", "[5].", "Most", "of", "the", "well-known", "actions", "of", "Ang", "II-AT1R", "interaction", "causes", "vasoconstriction", "and", "aldosterone", "release", "from", "the", "adrenal", "gland.", "This", "classical", "description", "of", "the", "RAS", "has", "been", "expanded", "by", "recent", "ﬁndings", "that", "RAS", "is", "activated", "locally,", "particularly", "in", "the", "vessel", "wall,", "heart,", "the", "kidney,", "and", "the", "brain", "[6–14].", "Ang", "II", "was", "also", "described", "to", "be", "produced", "by", "other", "enzymes", "such", "as", "chymase,", "an", "eﬃcient", "Ang", "II-forming", "serine", "protease", "[15].", "It", "is", "not", "aﬀected", "by", "ACE", "inhibition", "and", "has", "been", "suggested", "as", "relevant", "for", "alternative", "pathways", "of", "Ang", "II", "generation", "[16–18].", "Although", "several", "other", "alternative", "enzymes", "involved", "in", "Ang", "II", "formation", "such", "as", "tonin", "and", "cathepsins,", "chymase", "deserves", "special", "attention", "due", "to", "its", "high", "substrate", "speciﬁcity.", "The", "enzyme", "is", "also", "expressed", "in", "the", "vascular", "wall,", "where", "it", "has", "been", "suggested", "as", "a", "possible", "player", "in", "Ang", "II-mediated", "arteriosclerosis", "[15].", "Inﬂammatory", "cells", "detected", "in", "atherosclerotic", "lesions", "are", "mainly", "originated", "from", "bone", "marrow", "(BM).", "The", "presence", "of", "a", "locally", "activated", "bone", "marrow", "(BM)", "RAS", "aﬀecting", "the", "growth,", "production,", "proliferation,", "and", "diﬀerentiation", "of", "hematopoietic", "cells", "was", "suggested", "in", "1996", "[19].", "Other", "than", "a", "wide", "variety", "of", "evidences", "disclosed", "the", "existence", "of", "a", "functional", "local", "BM", "RAS.", "Angiotensin", "II,", "through", "interacting" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 18, 18, 18, 18, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 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]	[ "BioPsychoSocial", "Medicine", "Research", "General", "practitioners'", "responses", "to", "the", "initial", "presentation", "of", "medically", "unexplained", "symptoms:", "a", "quantitative", "analysis", "Teus", "Kappen", "and", "Sandra", "van", "Dulmen", "BioMed", "Central", "Open", "Access", "Address:", "NIVEL", "(Netherlands", "Institute", "for", "Health", "Services", "Research),", "P.O.Box", "1568,", "3500", "BN", "Utrecht,", "The", "Netherlands", "Email:", "Teus", "Kappen", "-", "t.kappen@umcutrecht.nl;", "Sandra", "van", "Dulmen", "-", "s.vandulmen@nivel.nl", "*", "Corresponding", "author", "Published:", "17", "November", "2008", "BioPsychoSocial", "Medicine", "2008,", "2:22", "doi:10.1186/1751-0759-2-22", "This", "article", "is", "available", "from:", "http://www.bpsmedicine.com/content/2/1/22", "Received:", "27", "June", "2008", "Accepted:", "17", "November", "2008", "©", "2008", "Kappen", "and", "van", "Dulmen;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "Physicians", "in", "primary", "and", "secondary", "care", "are", "frequently", "confronted", "with", "patients", "with", "medically", "unexplained", "symptoms", "(MUS).", "In", "order", "to", "solve", "their", "patients'", "problems", "and", "out", "of", "a", "fear", "of", "overlooking", "a", "serious", "disease,", "many", "physicians", "give", "their", "patients", "full", "physical", "examinations", "and", "interventions,", "thereby", "incorrectly", "confirming", "the", "somatic", "nature", "of", "their", "condition.", "Preventing", "somatization", "could", "be", "achieved", "by", "examining", "the", "patient's", "symptom", "presentation", "for", "clues", "to", "underlying", "psychosocial", "issues", "and", "by", "an", "appropriate", "physician", "response.", "Methods:", "Ninety-seven", "videotaped", "medical", "visits", "from", "primary", "care", "patients", "presenting", "MUS", "for", "the", "first", "time", "were", "analyzed.", "Patients'", "presentations", "were", "categorized", "in:", "(1)", "symptoms", "only;", "(2)", "symptoms", "with", "a", "clue", "to", "an", "underlying", "concern;", "or", "(3)", "symptoms", "with", "an", "explicit", "concern.", "General", "practitioners'", "(GPs')", "responses", "to", "patients'", "presentation", "were", "classified", "into", "ignoring", "or", "more", "or", "less", "exploring", "responses.", "Exploring", "responses", "were", "further", "subdivided", "in", "non-directional", "explorations,", "clue", "explorations", "and", "medical", "explorations.", "Results:", "Results", "show", "that", "most", "patients", "presented", "their", "symptoms", "together", "with", "a", "reference", "to", "an", "underlying", "concern.", "Yet,", "most", "of", "them", "did", "so", "in", "an", "implicit", "way.", "GPs", "usually", "explored", "the", "concern", "presented", "by", "the", "patients,", "but", "most", "often", "in", "a", "medical", "way", "only.", "Conclusion:", "To", "address", "the", "potential", "psychological", "basis", "of", "patients'", "medically", "unexplained", "symptoms,", "GPs", "should", "pay", "more", "attention", "to", "the", "specific", "clues", "patients", "present", "to", "them.", "Likewise,", "in", "order", "to", "receive", "full", "attention,", "patients", "should", "try", "to", "present", "their", "concerns", "more", "explicitly.", "Background", "In", "primary", "as", "well", "as", "secondary", "care", "a", "large", "number", "of", "patients", "commonly", "present", "with", "persistent", "physical", "symp-", "toms", "for", "which", "no", "somatic", "origin", "can", "be", "found.", "The", "major", "issue", "in", "these", "medically", "unexplained", "symptoms", "(MUS)", "is", "that", "there", "is", "a", "delicate", "balance", "between", "diagnosing", "MUS", "and", "the", "physician", "missing", "a", "somatic", "disease.", "Because", "phy-", "sicians", "take", "responsibility", "for", "solving", "their", "patients'", "prob-", "lems", "and", "because", "they", "are", "afraid", "of", "overlooking", "serious", "diseases,", "many", "patients", "receive", "a", "whole", "spectrum", "of", "phys-", "ical", "examinations,", "interventions", "and", "referrals,", "to", "exclude", "potential", "somatic", "causes.", "This", "contributes", "to", "their", "beliefs", "that", "the", "presented", "symptoms", "are", "indeed", "of", "physical", "ori-", "gin,", "which", "was", "described", "by", "Quill", "[1]", "and", "others", "as", "a", "path-", "ologic", "intervention", "cycle,", "suggesting", "the", "chronic", "nature", "of", "these", "symptoms", "to", "be", "of", "iatrogenic", "origin.", "Page", "1", "of", "8", "(page", "number", "not", "for", "citation", "purposes)" ]	[ 0, 0, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 0, 0, 9, 9, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 0, 0, 0, 0, 0, 9, 9, 9, 9, 9, 9, 7, 7, 7, 7, 7, 7, 7, 7, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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1001 ], [ 734, 987, 762, 1001 ], [ 428, 1003, 482, 1017 ], [ 489, 1003, 555, 1017 ], [ 563, 1003, 603, 1017 ], [ 610, 1003, 692, 1017 ], [ 698, 1003, 710, 1017 ], [ 716, 1003, 762, 1017 ], [ 428, 1019, 485, 1033 ], [ 488, 1019, 549, 1033 ], [ 551, 1019, 575, 1033 ], [ 578, 1019, 591, 1033 ], [ 594, 1019, 641, 1033 ] ]	[ "Hindawi", "Publishing", "Corporation", "Clinical", "and", "Developmental", "Immunology", "Volume", "2011,", "Article", "ID", "235142,", "6", "pages", "doi:10.1155/2011/235142", "Review", "Article", "Adaptive", "Immune", "Responses", "in", "Primary", "Cutaneous", "Sarcoidosis", "Matteo", "Bordignon,1", "Paola", "Rottoli,2", "Carlo", "Agostini,3", "and", "Mauro", "Alaibac1", "1", "Unit", "of", "Dermatology,", "University", "of", "Padua,", "Via", "Cesare", "Battisti", "206,", "35128", "Padua,", "Italy", "2", "Respiratory", "Diseases", "Section,", "Department", "of", "Clinical", "Medicine", "and", "Immunological", "Sciences,", "Siena", "University,", "53100", "Siena,", "Italy", "3", "Department", "of", "Clinical", "and", "Experimental", "Medicine,", "University", "of", "Padua,", "Via", "Cesare", "Battisti", "206,", "35128", "Padua,", "Italy", "Correspondence", "should", "be", "addressed", "to", "Mauro", "Alaibac,", "mauro.alaibac@unipd.it", "Received", "31", "July", "2010;", "Accepted", "27", "January", "2011", "Academic", "Editor:", "E.", "Shevach", "Copyright", "©", "2011", "Matteo", "Bordignon", "et", "al.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Sarcoidosis", "is", "a", "multisystemic", "inﬂammatory", "disorder", "with", "cutaneous", "lesions", "present", "in", "about", "one-quarter", "of", "the", "patients.", "Cutaneous", "lesions", "have", "been", "classiﬁed", "as", "speciﬁc", "and", "nonspeciﬁc,", "depending", "on", "the", "presence", "of", "nonnecrotizing", "epithelial", "cell", "granulomas", "on", "histologic", "studies.", "The", "development", "and", "progression", "of", "speciﬁc", "cutaneous", "sarcoidosis", "involves", "a", "complex", "interaction", "between", "cells", "of", "the", "adaptive", "immune", "systems,", "notably", "T-lymphocytes", "and", "dendritic", "cells.", "In", "this", "paper,", "we", "will", "discuss", "the", "role", "of", "T-cells", "and", "skin", "dendritic", "cells", "in", "the", "development", "of", "primary", "cutaneous", "sarcoidosis", "and", "comment", "on", "the", "potential", "antigenic", "stimuli", "that", "may", "account", "for", "the", "development", "of", "the", "immunological", "response.", "We", "will", "further", "explore", "the", "contributions", "of", "selected", "cytokines", "to", "the", "immunopathological", "process.", "The", "knowledge", "of", "the", "adaptive", "immunological", "mechanisms", "operative", "in", "cutaneous", "sarcoidosis", "may", "subsequently", "be", "useful", "for", "identifying", "prevention", "and", "treatment", "strategies", "of", "systemic", "sarcoidosis.", "1.", "Introduction", "Sarcoidosis", "is", "a", "multisystemic", "inﬂammatory", "disorder", "charac-", "terized", "by", "the", "accumulation", "of", "mononuclear", "phagocytes", "with", "the", "formation", "of", "nonnecrotizing", "epithelial", "cell", "granulomas.", "Multiple", "organs", "may", "be", "involved,", "including", "lungs,", "mediasti-", "nal", "and", "peripheral", "lymph", "nodes,", "liver,", "spleen,", "skin,", "eyes,", "and", "parotid", "glands;", "central", "nervous", "system,", "heart,", "upper", "respir-", "atory", "tract,", "bones,", "and", "joints", "are", "less", "frequently", "but", "usually", "more", "severely", "involved", "[1,", "2].", "Sarcoidosis", "is", "characterized", "by", "local", "immune", "hyperacti-", "vation", "associated", "with", "clinical", "anergy", "[3].", "The", "pathogenesis", "of", "sarcoidosis", "is", "suspected", "to", "be", "a", "host", "immunologic", "response", "to", "an", "antigenic", "exposure", "[4].", "The", "role", "of", "T-lymphocytes", "in", "the", "recognition", "of", "speciﬁc", "antigens", "and", "in", "the", "ampliﬁcation", "of", "inﬂammatory", "responses", "has", "been", "well", "established", "[5].", "In", "addition,", "dendritic", "cells", "have", "recently", "been", "shown", "to", "have", "a", "prominent", "role", "in", "the", "immunopathological", "processes", "op-", "erating", "in", "this", "condition", "[6,", "7].", "Cutaneous", "involvement", "in", "sarcoidosis", "occurs", "in", "about", "one-quarter", "of", "the", "patients", "and", "is", "generally", "observed", "at", "the", "onset", "of", "the", "disease", "process", "although", "it", "may", "occur", "coincident", "with", "or", "after", "systemic", "involvement", "[8,", "9].", "Therefore,", "cuta-", "neous", "lesions", "can", "be", "an", "initial", "presentation", "and", "are", "probably", "an", "important", "factor", "in", "the", "investigation", "of", "the", "etiology", "of", "sarcoidosis.", "Skin", "lesions", "may", "be", "classiﬁed", "in", "speciﬁc,", "when", "histology", "shows", "typical", "noncaseating", "granulomatous", "inﬂammation,", "or", "non", "speciﬁc,", "in", "presence", "of", "reactive", "process", "without", "granu-", "lomas.", "2.", "Clinical", "Aspects", "of", "Primary", "Cutaneous", "Sarcoidosis", "The", "frequency", "of", "speciﬁc", "skin", "involvement", "ranges", "from", "9%", "to", "37%", "[10].", "All", "speciﬁc", "cutaneous", "lesions", "exhibit", "non-", "caseating", "granulomas", "on", "biopsy.", "Histological", "ﬁndings", "in", "speciﬁc", "sarcoid", "lesions", "show", "aggregates", "of", "epithelioid", "histi-", "ocytes", "with", "occasional", "Langhans", "giant", "cells", "and", "few", "or", "no", "other", "inﬂammatory", "cells,", "the", "so-called", "naked", "or", "sarcoidal", "noncaseating", "granulomas.", "Frequently,", "there", "are", "inclusion", "bodies", "in", "giant", "cells", "[11].", "The", "centre", "of", "granulomas", "is", "typically", "surrounded", "by", "CD4+", "lymphocytes,", "rare", "CD8+", "lymphocytes", "and", "mature", "macrophages.", "Despite", "the", "same", "histologic", "appearance,", "clinical", "manifestations", "of", "primary", "cutaneous", "sarcoidosis", "may", "be", "variable." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 7, 7, 7, 7, 18, 18, 18, 18, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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1008 ], [ 538, 998, 561, 1008 ], [ 564, 998, 593, 1008 ], [ 595, 998, 640, 1008 ], [ 643, 998, 658, 1008 ], [ 660, 998, 705, 1008 ], [ 708, 998, 723, 1008 ], [ 248, 1009, 297, 1019 ], [ 300, 1009, 307, 1019 ], [ 310, 1009, 324, 1019 ], [ 326, 1009, 360, 1019 ], [ 362, 1009, 396, 1019 ], [ 399, 1009, 412, 1019 ], [ 415, 1009, 443, 1019 ], [ 446, 1009, 465, 1019 ], [ 467, 1009, 473, 1019 ], [ 476, 1009, 508, 1019 ], [ 510, 1009, 530, 1019 ] ]	[ "Erbudak", "and", "Erzan", "Theoretical", "Biology", "and", "Medical", "Modelling", "2010,", "7:30", "http://www.tbiomed.com/content/7/1/30", "R", "E", "S", "E", "A", "R", "C", "H", "Open", "Access", "Tracking", "tumor", "evolution", "via", "prostate-specific", "antigen:", "an", "individual", "post-operative", "study", "Mehmet", "Erbudak1,", "Ayşe", "Erzan2", "", "Correspondence:", "erbudak@phys.", "ethz.ch", "1Laboratory", "for", "Solid", "State", "Physics,", "ETH", "Zurich,", "CH-8093", "Zurich,", "Switzerland", "Abstract", "Background:", "The", "progress", "of", "the", "prostate-specific", "antigen", "(PSA)", "level", "after", "radical", "prostatectomy", "is", "observed", "for", "a", "patient", "in", "order", "to", "extract", "information", "about", "the", "mode", "of", "tumor", "cell", "growth.", "Although", "PSA", "values", "are", "determined", "routinely", "to", "find", "the", "doubling", "time", "of", "the", "prostate", "marker,", "to", "our", "knowledge,", "this", "analysis", "is", "the", "first", "in", "the", "literature.", "Results:", "The", "prostate", "tumor", "marker", "values", "were", "determined", "regularly", "after", "the", "surgery", "and", "plotted", "on", "a", "logarithmic", "scale", "against", "time.", "An", "initial", "rapid-growth", "mode", "changed", "to", "a", "slower", "power-law", "regime", "within", "two", "years", "of", "surgery.", "Our", "analysis", "associates", "this", "observation", "with", "a", "transition", "in", "the", "growth", "mode", "from", "unrestricted", "growth", "of", "dispersed", "cells", "to", "their", "clumping", "into", "macroscopic", "structures.", "Conclusions:", "Such", "studies", "may", "help", "determine", "the", "appropriate", "time", "window", "for", "postoperative", "therapies", "in", "order", "to", "increase", "the", "life", "expectancy", "of", "the", "patient.", "Background", "Cancer", "of", "the", "prostate", "gland", "is", "one", "of", "the", "most", "frequently", "diagnosed", "male", "illnesses", "and", "may", "lead", "to", "death", "of", "the", "patient.", "The", "carcinoma", "is", "routinely", "detected", "by", "a", "straight-", "forward", "blood", "test", "that", "measures", "a", "glycoprotein", "called", "prostate-specific", "antigen", "(PSA).", "At", "an", "early", "stage", "of", "cancer", "growth", "with", "a", "localized", "tumor,", "radical", "removal", "of", "the", "pros-", "tate", "gland", "has", "proved", "to", "be", "the", "optimum", "treatment.", "If", "the", "PSA", "value", "rises", "after", "radical", "prostatectomy,", "different", "alternatives", "for", "treatment", "are", "currently", "under", "debate.", "The", "doubling", "time", "(DT)", "of", "the", "PSA", "value", "is", "accepted", "as", "a", "strong", "prognostic", "factor", "for", "the", "risk", "of", "cancer", "death.", "In", "a", "group", "of", "379", "patients,", "almost", "no", "prostate", "cancer", "deaths", "were", "recorded", "within", "approximately", "4", "years", "of", "prostate", "removal", "for", "3", "<", "DT", "<", "8.9", "months,", "while", "some", "patients", "with", "DT", "<", "3", "months", "died", "within", "1.5", "years", "[1].", "It", "is", "therefore", "rea-", "sonable", "to", "infer", "that", "findings", "during", "the", "last", "few", "years", "based", "on", "long-term", "statistics", "suggest", "a", "longer", "life", "expectancy", "for", "patients", "with", "postoperative", "radiotherapy", "that", "fol-", "lows", "(within", "6", "months", "of)", "radical", "prostate", "surgery", "[2].", "Transdermal", "radiotherapy", 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"subjective", "pain", "with", "physical", "disability,", "clinical", "and", "radiographic", "scores", "in", "recent", "onset", "rheumatoid", "arthritis", "Piercarlo", "Sarzi-Puttini1,", "Tania", "Fiorini2,", "Benedetta", "Panni1,", "Maurizio", "Turiel2,", "Marco", "Cazzola1", "and", "Fabiola", "Atzeni1", "Address:", "1Rheumatology", "Unit,", "University", "Hospital", "L.", "Sacco,", "Milan,", "Italy", "and", "2Istituto", "di", "Scienze", "Biomediche,", "Università", "di", "Milano,", "Italy", "E-mail:", "Piercarlo", "Sarzi-Puttini", "-", "sarzi@tiscalinet.it;", "Tania", "Fiorini", "-", "tania@posta.statfac.unibo.it;", "Benedetta", "Panni", "-", "benedetta_p@virgilio.it;", "Maurizio", "Turiel", "-", "maurizio.turiel@unimi.it;", "Marco", "Cazzola", "-", "marco.cazzola@tiscalinet.it;", "Fabiola", "Atzeni", "-", "atzenifabiola@hotmail.com", "*Corresponding", "author", "Published:", "19", "July", "2002", "BMC", "Musculoskeletal", "Disorders", "2002,", "3:18", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1471-2474/3/18", "Received:", "12", "December", "2001", "Accepted:", "19", "July", "2002", "©", "2002", "Sarzi-Puttini", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "Verbatim", "copying", "and", "redistribution", "of", "this", "article", "are", "permitted", "in", "any", "medium", "for", "any", "purpose,", "provided", "this", "notice", "is", "preserved", "along", "with", "the", "article's", "original", "URL.", "Keywords:", "Rheumatoid", "arthritis,", "pain,", "pain", "measurement", "Abstract", "Background:", "To", "analyse", "the", "relationship", "between", "subjective", "pain", "score", "and", "other", "measures", "of", "clinical,", "radiographic", "and", "functional", "status;", "in", "particular", "Larsen", "radiographic", "scores", "and", "Health", "Assessment", "Questionnaire", "(HAQ);", "in", "patients", "with", "severe", "rheumatoid", "arthritis", "(RA)", "with", "a", "disease", "duration", "of", "less", "than", "3", "years.", "Methods:", "In", "this", "cross", "sectional", "study", "of", "105", "patients", "with", "RA", "(76", "women,", "29", "men:", "mean", "age", "50.93;", "mean", "disease", "duration", "15.86", "months;", "71%", "rheumatoid", "factor", "positive)", "subjective", "pain", "was", "assessed", "according", "to", "the", "Visual", "Analog", "Scale", "(VAS).", "Correlation", "coefficients", "between", "pain", "score", "and", "disease", "activity", "measures", "(patients'", "global", "assessment", "of", "disease", "by", "VAS,", "number", "of", "tender", "and", "swollen", "joints,", "morning", "stiffness,", "erythrocyte", "sedimentation", "rate", "[ESR],", "C-reactive", "protein", "[CRP]", "and", "titre", "of", "rheumatoid", "factor,", "radiographic", "evaluations", "(Larsen-Dale", "scores", "for", "radiographic", "damage", "of", "the", "small", "joints", "of", "the", "hands,", "wrist", "and", "feet),", "disability", "measures", "(health", "assessment", "questionnaire", "[HAQ]),", "and", "demographic", "variables", "were", "calculated;", "hierarchical", "regression", "analysis", "was", "done", "with", "subjective", "pain", "score", "as", "the", "dependent", "variable.", "Results:", "The", "Spearman's", "correlation", "coefficient", "comparing", "subjective", "pain", "and", "HAQ", "was", "0.421", "(p", "<", "0.001),", "between", "subjective", "pain", "and", "global", "assessment", "of", "disease", "and", "morning", "stiffness", "was", "0.573", "(p", "<", "0.001)", "and", "0.427", "(p", "<", "0.001)", "respectively,", "and", "between", "pain", "and", "number", "of", "tender", "and", "swollen", "joints", "0.037", "and", "0.050", "respectively", "(p", ">", "0.05).", "In", "regression", "analysis,", "global", "assessment", "of", "disease", "by", "patients", "explained", "32.8%", "of", "the", "variation", "in", "pain", "intensity", "score,", "morning", "stiffness", "10.7%,", "CRP", "4.0%,", "HAQ", "3.8%", "and", "Larsen-Dale", "scores", "explained", "2.1%;", "other", "variables", "were", "not", "significant", "in", "the", "model.", "Conclusions:", "Pain", "scores", "of", "patients", "with", "early", "severe", "rheumatoid", "arthritis", "are", "correlated", "at", "higher", "levels", "with", "patients'", "global", "assessment", "of", "disease", "and", "with", "morning", "stiffness", "rather", "than", "with", "radiographic", "or", "other", "clinical", "variables", "such", "as", "number", "of", "tender", "and", "swollen", "joints.", "Page", "1", "of", "4", "(page", "number", "not", "for", "citation", "purposes)" ]	[ 0, 0, 0, 0, 0, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 7, 7, 7, 7, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 7, 7, 7, 7, 7, 7, 7, 7, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 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"Thailand,", "3Bureau", "of", "TB,", "Thailand", "Ministry", "of", "Public", "Health,", "Nonthaburi,", "Thailand,", "4Chiang", "Rai", "Provincial", "Public", "Health", "Office,", "Chiang", "Rai,", "Thailand,", "5Research", "Institute", "of", "Tuberculosis", "(Japan),", "Chiang", "Rai,", "Thailand,", "6AIDS,", "TB,", "STI", "and", "Leprosy", "Section,", "Office", "of", "Disease", "Prevention", "and", "Control", "7,", "Ubon-ratchathani,", "Thailand,", "7Phuket", "Provincial", "Public", "Health", "Office,", "Phuket,", "Thailand,", "8Health", "Center", "41,", "Bangkok", "Metropolitan", "Health", "Administration,", "Bangkok,", "Thailand,", "9Medicine", "Department,", "Bamrasnaradura", "Institute,", "Nonthaburi,", "Thailand", "and", "10Division", "of", "TB", "Elimination,", "U.S.", "Centers", "for", "Disease", "Control", "and", "Prevention,", "Atlanta,", "USA", "Email:", "Rangsima", "Lolekha", "-", "rangsimaL@th.cdc.gov;", "Amornrat", "Anuwatnonthakate", "-", "AmornratA@th.cdc.gov;", "Sriprapa", "Nateniyom", "-", "nateniyoms@yahoo.com;", "Surin", "Sumnapun", "-", "angvcr@hotmail.com;", "Norio", "Yamada", "-", "nyamada@jata.or.jp;", "Wanpen", "Wattanaamornkiat", "-", "Wanpen_wa@yahoo.com;", "Wanchai", "Sattayawuthipong", "-", "wanchaig@health.moph.go.th;", "Pricha", "Charusuntonsri", "-", "pcharu@gmail.com;", "Natpatou", "Sanguanwongse", "-", "natpatou@yahoo.com;", "Charles", "D", "Wells", "-", "cdwells6@bellsouth.net;", "Jay", "K", "Varma", "-", "jvarma@cdc.gov", "BioMed", "Central", "Open", "Access", "*", "Corresponding", "author", "Published:", "18", "July", "2008", "BMC", "Infectious", "Diseases", "2008,", "8:94", "doi:10.1186/1471-2334-8-94", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1471-2334/8/94", "Received:", "26", "December", "2007", "Accepted:", "18", "July", "2008", "©", "2008", "Lolekha", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "Of", "the", "9.2", "million", "new", "TB", "cases", "occurring", "each", "year,", "about", "10%", "are", "in", "children.", "Because", "childhood", "TB", "is", "usually", "non-infectious", "and", "non-fatal,", "national", "programs", "do", "not", "prioritize", "childhood", "TB", "diagnosis", "and", "treatment.", "We", "reviewed", "data", "from", "a", "demonstration", "project", "to", "learn", "more", "about", "the", "epidemiology", "of", "childhood", "TB", "in", "Thailand.", "Methods:", "In", "four", "Thai", "provinces", "and", "one", "national", "hospital,", "we", "contacted", "healthcare", "facilities", "monthly", "to", "record", "data", "about", "persons", "diagnosed", "with", "TB,", "assist", "with", "patient", "care,", "provide", "HIV", "counseling", "and", "testing,", "and", "obtain", "sputum", "for", "culture", "and", "susceptibility", "testing.", "We", "analyzed", "clinical", "and", "treatment", "outcome", "data", "for", "patients", "age", "<", "15", "years", "old", "registered", "in", "2005", "and", "2006.", "Results:", "Only", "279", "(2%)", "of", "14,487", "total", "cases", "occurred", "in", "children.", "The", "median", "age", "of", "children", "was", "8", "years", "(range:", "4", "months,", "14", "years).", "Of", "197", "children", "with", "pulmonary", "TB,", "63", "(32%)", "were", "bacteriologically-confirmed:", "56", "(28%)", "were", "smear-positive", "and", "7", "(4%)", "were", "smear-negative,", "but", "culture-positive.", "One", "was", "diagnosed", "with", "multi-drug", "resistant", "TB.", "HIV", "infection", "was", "documented", "in", "75", "(27%).", "Thirteen", "(17%)", "of", "75", "HIV-infected", "children", "died", "during", "TB", "treatment", "compared", "with", "4", "(2%)", "of", "204", "not", "known", "to", "be", "HIV-infected", "(p", "<", "0.01).", "Conclusion:", "Childhood", "TB", "is", "infrequently", "diagnosed", "in", "Thailand.", "Understanding", "whether", "this", "is", "due", "to", "absence", "of", "disease", "or", "diagnostic", "effort", "requires", "further", "research.", "HIV", "contributes", "substantially", "to", "the", "childhood", "TB", "burden", "in", "Thailand", "and", "is", "associated", "with", "high", "mortality.", "Page", "1", "of", "9", "(page", "number", "not", "for", "citation", "purposes)" ]	[ 0, 0, 0, 16, 16, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 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524, 988, 559, 1002 ], [ 563, 988, 577, 1002 ], [ 581, 988, 595, 1002 ], [ 599, 988, 658, 1002 ], [ 662, 988, 724, 1002 ], [ 728, 988, 760, 1002 ], [ 764, 988, 775, 1002 ], [ 307, 1045, 364, 1057 ], [ 367, 1045, 399, 1057 ], [ 401, 1045, 410, 1057 ], [ 413, 1045, 444, 1057 ], [ 447, 1045, 490, 1057 ], [ 493, 1045, 533, 1057 ], [ 307, 1059, 316, 1071 ], [ 318, 1059, 341, 1071 ], [ 343, 1059, 368, 1071 ], [ 371, 1059, 406, 1071 ], [ 408, 1059, 432, 1071 ], [ 435, 1059, 471, 1071 ], [ 473, 1059, 486, 1071 ], [ 488, 1059, 513, 1071 ], [ 517, 1059, 557, 1071 ], [ 752, 1044, 776, 1058 ] ]	[ "R", "E", "V", "I", "E", "W", "Defect", "of", "alveolar", "regeneration", "in", "pulmonary", "emphysema:", "Role", "of", "lung", "ﬁbroblasts", "Laurent", "Plantier1,2", "Jorge", "Boczkowski1,3", "Bruno", "Crestani1,4", "1INSERM,", "U700,", "Faculté", "Xavier", "Bichat,", "Paris,", "France;", "2Assistance", "Publique-", "Hôpitaux", "de", "Paris,", "Hôpital", "Bichat,", "Service", "de", "Pneumologie", "B,", "Paris,", "France;", "3Assistance", "Publique-Hôpitaux", "de", "Paris,", "Hôpital", "Bichat,", "CIC", "07,", "Paris,", "France;", "4Assistance", "Publique-Hôpitaux", "de", "Paris,", "Hôpital", "Bichat,", "Service", "de", "Pneumologie", "A,", "Paris,", "France", "Correspondence:", "Bruno", "Crestani", "Service", "de", "Pneumologie", "A,", "Hôpital", "Bichat,", "16", "rue", "Henri", "Huchard,", "75877,", "Paris", "Cedex", "18,", "France", "Tel", "+33", "1", "40256800", "Fax", "+33", "1", "40258818", "Email", "bruno.crestani@bch.aphp.fr", "Abstract:", "Pulmonary", "emphysema", "is", "characterized", "by", "the", "irreversible", "loss", "of", "pulmonary", "alveoli.", "Despite", "recent", "advances", "in", "the", "understanding", "this", "disease,", "its", "treatment", "remains", "palliative.", "In", "this", "review,", "we", "will", "successively", "review", "the", "data", "suggesting", "(1)", "that", "alveolar", "regeneration", "systems", "are", "functional", "in", "the", "mammalian", "lung", "and", "have", "the", "potential", "to", "regrow", "lost", "alveoli,", "(2)", "that", "cigarette", "smoke,", "the", "main", "etiologic", "factor", "of", "emphysema,", "inhibits", "those", "systems", "under", "experimental", "conditions,", "and", "(3)", "that", "alveolar", "regeneration", "systems", "are", "dysfunctional", "in", "the", "human", "emphysematous", "lung", "and", "may", "be", "a", "target", "for", "therapeutic", "intervention", "in", "this", "disease.", "Special", "emphasis", "will", "be", "put", "on", "the", "role", "of", "alveolar", "ﬁbroblasts", "in", "those", "processes.", "Keywords:", "emphysema,", "repair,", "regeneration,", "HGF,", "ﬁbroblasts", "Introduction", "Pulmonary", "emphysema", "is", "characterized", "by", "the", "progressive", "destruction", "of", "pulmonary", "alveoli.", "It", "is", "one", "of", "the", "most", "common", "diseases", "worldwide", "(Halbert", "et", "al", "2006)", "and", "its", "incidence", "keeps", "growing", "along", "with", "the", "large", "diffusion", "of", "its", "main", "etiologic", "factor,", "tobacco", "smoking.", "The", "ever-increasing", "use", "of", "tobacco", "in", "the", "developing", "world", "allows", "for", "the", "prediction", "of", "a", "huge", "increase", "in", "the", "number", "of", "cases", "in", "the", "near", "and", "distant", "future.", "The", "prognosis", "of", "pulmonary", "emphysema", "is", "poor,", "with", "airﬂow", "limitation", "progressing", "to", "chronic", "respiratory", "insufﬁciency,", "disability", "and", "premature", "death.", "To", "this", "day,", "therapeutic", "options", "for", "pulmonary", "emphysema", "are", "few", "and", "scarcely", "effective.", "Patients", "who", "stop", "smoking", "do", "beneﬁt", "in", "terms", "of", "lung", "function", "and", "survival,", "but", "the", "decline", "in", "lung", "function", "is", "not", "reversed,", "merely", "slowed.", "Apart", "from", "long-term", "oxygen", "therapy,", "pharmacological", "intervention", "is", "unsatisfactory", "and", "is", "mainly", "limited", "to", "the", "control", "of", "symptoms", "related", "to", "frequently-associated", "chronic", "bronchitis", "(Sutherland", "and", "Cherniack", "2004).", "Lung", "volume", "reduction", "surgery", "can", "be", "of", "interest", "in", "selected", "patients", "(Fishman", "et", "al", "2003)", "as", "may", "be", "the", "implantation", "of", "endobronchial", "one-way", "valves", "(Wood", "et", "al", "2007)", "but", "those", "techniques", "do", "not", "remedy", "the", "underlying", "condition.", "Lung", "transplantation,", "while", "beneﬁcial", "in", "terms", "of", "symptoms-related", "quality", "of", "life,", "does", "not", "improve", "survival", "in", "patients", "with", "pulmonary", "emphysema", "(Hosenpud", "et", "al", "1998).", "Overall,", "treatment", "of", "pulmonary", "emphysema", "is", "palliative.", "Most", "studies", "of", "the", "pathogenesis", "of", "emphysema", "focused", "on", "the", "mechanisms", "involved", "in", "chronic", "injury", "induced", "by", "cigarette", "smoke", "to", "the", "pulmonary", "parenchyma.", "In", "particular,", "the", "role", "of", "protease-antiprotease", "imbalance,", "persistent", "inﬂammation,", "oxi-", "dative", "stress", "and", "excessive", "apoptosis", "of", "alveolar", "cells", "was", "demonstrated", "(Barnes", "et", "al", "2003).", "However,", "while", "great", "advances", "were", "made", "towards", "the", "comprehension", "of", "those", "phenomenons,", "they", "have", "not", "translated", "into", "new", "therapeutic", "prospects", "until", "now.", "Alveolar", "regeneration", "systems", "may", "be", "important", "actors", "in", "the", "course", "of", "emphysema.", "On", "the", "one", "hand,", "alterations", "or", "defects", "in", "those", "systems", "may", "account", "for", "the", "deﬁciency", "in", "tissue", "repair", "which", "is", "observed", "in", "the", "emphysematous", "lung.", "On", "the", "other", "hand,", "the", "induction", "of", "alveolar", "regeneration", "would", "be", "an", "interesting", "therapeutic", "target", "in", "International", "Journal", "of", "COPD", "2007:2(4)", "463–469", "©", "2007", "Dove", "Medical", "Press", "Limited.", "All", "rights", "reserved", "463" ]	[ 16, 16, 16, 16, 16, 16, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 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"a", "model", "in", "which", "Ub", "cargo", "is", "passed", "sequentially", "from", "S.B.", "Shields", "and", "A.J.", "Oestreich", "contributed", "equally", "to", "this", "paper.", "Correspondence", "to", "David", "J.", "Katzmann:", "katzmann.david@mayo.edu;", "or", "Robert", "Piper:", "Robert-piper@uiowa.edu", "Abbreviations", "used", "in", "this", "paper:", "CPY,", "carboxypeptidase", "Y;", "ESCRT,", "endosomal", "sorting", "complexes", "required", "for", "transport;", "DIC,", "differential", "interference", "contrast;", "HSQC,", "heteronuclear", "single", "quantum", "coherence;", "MVB,", "multivesicular", "body;", "NMR,", "nuclear", "magnetic", "resonance;", "NZF,", "Npl4", "zinc", "finger;", "TAP,", "tandem", "affinity", "purification;", "Ub,", "ubiquitin;", "UBD,", "Ub-binding", "domain;", "UEV,", "Ub", "E2", "variant;", "UIM,", "Ub-interacting", "motif.", "The", "Rockefeller", "University", "Press", "$30.00", "J.", "Cell", "Biol.", "Vol.", "185", "No.", "2", "213–224", "www.jcb.org/cgi/doi/10.1083/jcb.200811130", "ESCRT-0", "to", "ESCRT-I", "and", "to", "ESCRT-II", "for", "final", "deposit", "into", "the", "forming", "lumenal", "vesicles", "(Katzmann", "et", "al.,", "2002;", "Gruenberg", "and", "Stenmark,", "2004;", "Hurley,", "2008).", "Previous", "studies", "have", "indi-", "cated", "the", "importance", "of", "these", "UBDs", "during", "MVB", "sorting;", "how-", "ever,", "recent", "high", "resolution", "structures", "that", "detail", "Ub", "interactions", "have", "enabled", "a", "more", "precise", "approach", "to", "dissect", "the", "contri-", "butions", "of", "these", "UBDs", "to", "MVB", "sorting", "(Alam", "et", "al.,", "2004,", "2006;", "Sundquist", "et", "al.,", "2004;", "Teo", "et", "al.,", "2004;", "Hirano", "et", "al.,", "2006).", "Surprisingly,", "we", "found", "that", "mutant", "forms", "of", "Vps23", "and", "Vps36", "unable", "to", "bind", "Ub", "had", "no", "defects", "in", "MVB", "sorting,", "even", "in", "combi-", "nation.", "This", "led", "us", "to", "search", "for", "additional", "UBDs", "within", "ESCRT-I", "and", "resulted", "in", "the", "discovery", "of", "a", "novel", "UBD", "within", "Mvb12.", "The", "UBD", "of", "Mvb12", "works", "in", "concert", "with", "the", "UBDs", "of", "the", "ESCRTs", "to", "promote", "cargo", "recognition", "and", "MVB", "sorting.", "Results", "and", "discussion", "Mutants", "of", "Vps23", "and", "Vps36", "defective", "for", "Ub", "binding", "Cocrystal", "structures", "of", "Ub", "with", "the", "UEV", "domains", "of", "Vps23", "and", "TSG101", "were", "used", "to", "guide", "mutagenesis", "experiments", "rendering", "Vps23", "unable", "to", "bind", "Ub", "(Sundquist", "et", "al.,", "2004;", "Teo", "et", "al.", "2004).", "The", "structures", "show", "that", "the", "UEV", "domains", "bind", "to", "Ub", "via", "a", "", "hairpin", "tongue", "and", "a", "lip", "(Fig.", "1", "A).", "The", "structure", "of", "the", "©", "2009", "Shields", "et", "al.", "This", "article", "is", 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"prior", "hospitalization", "in", "adult", "patients", "with", "cystic", "fibrosis", "David", "A", "Ngan,", "Pearce", "G", "Wilcox,", "May", "Aldaabil,", "Yuexin", "Li,", "Jonathon", "A", "Leipsic,", "Don", "D", "Sin", "and", "SF", "Paul", "Man", "Abstract", "Background:", "In", "cystic", "fibrosis", "(CF)", "patients,", "it", "has", "been", "suggested", "that", "systemic", "inflammation", "may", "be", "an", "important", "risk", "factor", "for", "poor", "health", "outcomes.", "The", "relationship", "of", "plasma", "inflammatory", "biomarkers", "to", "lung", "function", "and", "hospitalization", "history", "remains", "largely", "unexplored.", "Methods:", "This", "cross-sectional", "study", "included", "58", "consecutive,", "clinically", "stable", "adults", "from", "the", "CF", "Clinic", "at", "St.", "Paul’s", "Hospital", "(Vancouver,", "Canada).", "Blood", "levels", "of", "interleukin", "(IL)-6,", "IL-1b,", "C-reactive", "protein", "(CRP),", "interleukin", "(IL)-6,", "IL-", "1b,", "granzyme", "B", "(GzmB),", "chemokine", "C-C", "motif", "ligand", "18", "(CCL18/PARC),", "surfactant", "protein", "D", "(SP-D),", "lipopolysaccharide", "(LPS)-binding", "protein,", "and", "soluble", "cluster", "of", "differentiation", "14", "(sCD14)", "were", "measured", "using", "enzyme-linked", "immunosorbent", "assays,", "and", "LPS", "levels", "were", "measured", "using", "a", "Limulus", "amebocyte", "lysate", "assay.", "Spirometry", "was", "also", "performed.", "Multivariable", "linear", "regression", "analysis", "was", "used", "to", "assess", "relationships", "of", "the", "blood", "biomarkers", "to", "lung", "function.", "Results:", "Lung", "function", "impairment", "was", "independently", "associated", "with", "elevated", "plasma", "levels", "of", "CRP", "(P", "<", "0.01),", "IL-", "6", "(P", "=", "0.04),", "IL-1b", "(P", "<", "0.01),", "and", "LBP", "(P", "<", "0.01).", "Increasing", "age", "(P", "<", "0.01),", "reduced", "body", "mass", "index", "(P", "=", "0.02),", "prior", "hospitalizations", "(P", "=", "0.03),", "and", "presence", "of", "Pseudomonas", "aeruginosa", "in", "sputum", "cultures", "(P", "<", "0.01)", "were", "also", "associated", "with", "reduced", "lung", "function.", "Elevated", "concentrations", "of", "LPS", "in", "plasma", "were", "associated", "with", "a", "previous", "history", "of", "hospitalization", "(P", "<", "0.05).", "There", "was", "a", "trend", "towards", "an", "increase", "in", "plasma", "IL-6", "(P", "=", "0.07)", "and", "IL-1b", "(P", "=", "0.06)", "levels", "in", "patients", "who", "were", "previously", "hospitalized.", "Conclusions:", "IL-6", "and", "IL-1b", "are", "promising", "systemic", "biomarkers", "for", "lung", "function", "impairment", "and", "history", "of", "hospitalization", "in", "adult", "patients", "with", "CF.", "Background", "Cystic", "fibrosis", "(CF)", "is", "a", "progressive,", "debilitating", "disease", "that", "affects", "nearly", "30,000", "Americans", "and", "occurs", "with", "a", "frequency", "of", "about", "1", "in", "3500", "births", "[1].", "It", "is", "character-", "ized", "by", "persistent", "lung", "infection", "and", "lung", "function", "impairment.", "It", "also", "affects", "other", "organs", "including", "the", "sinuses,", "gastrointestinal", "tract,", "endocrine", "glands,", "and", "the", "bone", "[2-5].", "Although", "all", "CF", "cases", "are", "caused", "by", "a", "muta-", "tion", "in", "the", "gene", "for", "the", "CF", "transmembrane", "conductance", "regulator,", "there", "is", "considerable", "heterogeneity", "in", "the", "rate", "at", "which", "the", "disease", "progresses", "[6].", "The", "traditional", "risk", "factors", "for", "rapid", "progression", "include", "reduced", "body", "mass", "", "Correspondence:", "pman@providencehealth.bc.ca", "UBC", "James", "Hogg", "Research", "Centre,", "Institute", "for", "Heart", "+", "Lung", "Health", "at", "St.", "Paul’s", "Hospital", "and", "Department", "of", "Medicine,", "University", "of", "British", "Columbia,", "Vancouver,", "BC,", "Canada", "index,", "colonization", "of", "the", "airways", "with", "pathogenic", "bac-", "teria", "such", "as", "Pseudomonas", "aeruginosa,", "and", "female", "sex", "[7-9].", "More", "recently,", "some", "have", "suggested", "that", "systemic", "inflammation", "may", "be", "another", "important", "risk", "factor", "for", "poor", "health", "outcomes", "in", "CF", "independent", "of", "these", "tradi-", "tional", "risk", "factors", "[3,8,10,11].", "However,", "the", "studies", "that", "have", "evaluated", "this", "issue", "have", "produced", "inconsistent", "results", "and", "have", "measured", "different", "components", "of", "the", "immune", "system,", "making", "cross", "comparisons", "difficult.", "Moreover,", "none", "of", "these", "studies", "have", "evaluated", "these", "biomarkers", "on", "hard", "clinical", "outcomes", "such", "as", "exacerba-", "tions", "or", "hospitalizations,", "which", "are", "important", "endpoints", "in", "CF.", "In", "this", "study,", "we", "determined", "the", "relationship", "of", "plasma", "inflammatory", "biomarkers", "to", "lung", "function", "and", "hospitalization", "history", "in", "adult", "patients", "with", "CF.", "The", "plasma", "biomarkers", "were", "carefully", "chosen", "to", "represent", "©", "2012", "Ngan", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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], [ 493, 1060, 507, 1072 ], [ 510, 1060, 539, 1072 ], [ 543, 1060, 587, 1072 ], [ 752, 1045, 775, 1059 ] ]	[ "R", "E", "V", "I", "E", "W", "Carotid", "ultrasound", "assessment", "of", "patients", "with", "coronar", "y", "ar", "ter", "y", "disease:", "a", "useful", "index", "for", "risk", "stratification", "Roman", "Komorovsky", "Alessandro", "Desideri", "Cardiovascular", "Research", "Foundation,", "S", "Giacomo", "Hospital,", "Castelfranco", "Veneto,", "Italy", "Correspondence:", "Roman", "Komorovsky", "Cardiovascular", "Research", "Foundation,", "Ospedale", "S", "Giacomo,", "31033", "Castelfranco", "Veneto", "(TV),", "Italy", "Tel", "+39", "0423", "732", "306", "Fax", "+39", "0423", "732", "301", "Email", "roman_komor@yahoo.com", "Abstract:", "Carotid", "disease", "is", "a", "common", "finding", "in", "patients", "with", "coronary", "artery", "disease", "(CAD)", "and", "its", "presence", "is", "associated", "with", "worse", "clinical", "outcomes.", "Intima-media", "thickness", "provides", "incremental", "value", "over", "traditional", "risk", "factors", "in", "predicting", "cardiovascular", "events;", "however,", "it", "does", "not", "predict", "the", "absence", "of", "CAD", "or", "its", "extent", "and", "severity.", "The", "presence", "of", "carotid", "plaques", "is", "associated", "with", "an", "increased", "risk", "of", "cardiovascular", "events", "in", "patients", "with", "CAD", "regardless", "of", "the", "treatment", "strategy", "(medical", "therapy", "alone", "or", "myocardial", "revascularization).", "Hence,", "we", "advocate", "the", "screening", "of", "patients", "with", "diagnosed", "CAD", "for", "carotid", "atherosclerosis.", "The", "prognostic", "impact", "of", "ultrasound", "characteristics", "of", "carotid", "plaques", "on", "cardiovascular", "outcomes", "of", "patients", "with", "CAD", "remains", "controversial.", "Keywords:", "intima-media", "thickness,", "carotid", "plaques,", "coronary", "artery", "disease,", "ultrasound", "Introduction", "The", "coexistence", "of", "carotid", "and", "coronary", "artery", "disease", "(CAD)", "is", "a", "challenge", "to", "cardiologists,", "vascular", "and", "cardiothoracic", "surgeons,", "and", "neurologists.", "Patients", "with", "coexistent", "narrowing", "of", "carotid", "and", "coronary", "arteries", "represent", "a", "particularly", "high-", "risk", "group", "and", "to", "date", "there", "has", "been", "no", "consensus", "with", "regard", "to", "their", "management.", "Carotid", "endarterectomy", "in", "these", "patients", "is", "associated", "with", "an", "increased", "incidence", "of", "perioperative", "myocardial", "infarction", "(Biller", "et", "al", "1998),", "and", "coronary", "artery", "bypass", "grafting", "is", "accompanied", "by", "an", "elevated", "risk", "of", "neurological", "injury", "(Jones", "et", "al", "1984).", "Epidemiological", "data", "While", "in", "a", "general", "adult", "population", "the", "prevalence", "of", "carotid", "stenosis", "approaches", "4%", "(Mathiesen,", "Joakimsen,", "et", "al", "2001),", "in", "patients", "with", "coronary", "artery", "disease", "it", "can", "reach", "30%–70%", "(Kallikazaros", "et", "al", "1999;", "Held", "et", "al", "2001;", "Komorovsky", "et", "al", "2004;", "Lombardo", "et", "al", "2004).", "For", "those", "undergoing", "coronary", "artery", "bypass", "grafting,", "the", "prevalence", "of", ">", "50%", "narrowing", "of", "at", "least", "one", "internal", "carotid", "artery", "is", "thought", "to", "be", "around", "20%,", "and", ">", "70%", "carotid", "stenosis", "is", "found", "in", "2%–12%", "of", "cases", "(Schwartz", "et", "al", "1995;", "Evangelopoulos", "et", "al", "2000).", "Carotid", "artery", "disease", "as", "a", "marker", "of", "increased", "risk", "of", "cardiovascular", "events", "Carotid", "artery", "disease,", "even", "in", "its", "preclinical", "stage", "(intima-media", "thickness", "[IMT]", "≥", "1", "mm", "and", "non-obstructive", "[<", "50%]", "carotid", "plaques),", "has", "been", "associated", "with", "CAD", "and", "an", "increased", "risk", "of", "cardiovascular", "events.", "Vascular", "Health", "and", "Risk", "Management", "2005:1(2)", "131–136", "©", "2005", "Dove", "Medical", "Press", "Limited.", "All", "rights", "reserved", "131" ]	[ 16, 16, 16, 16, 16, 16, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 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"E", "Structure", "Reports", "Online", "ISSN", "1600-5368", "3-Oxo-18a-olean-28,13b-olide", "R.", "C.", "Santos,a", "R.", "M.", "A.", "Pinto,a", "A.", "Matos", "Beja,b", "J.", "A.", "R.", "Salvadora", "and", "J.", "A.", "Paix˜aob*", "aLaborato´", "rio", "de", "Qu´ımica", "Farmaceˆutica,", "Faculdade", "de", "Farma´cia,", "Universidade", "de", "Coimbra,", "Po´", "lo", "das", "Cieˆncias", "da", "Sau´", "de,", "Azinhaga", "de", "Santa", "Comba,", "P-3000-548", "Coimbra,", "Portugal,", "and", "bCEMDRX,", "Departamento", "de", "F´ısica,", "Faculdade", "de", "Cieˆncias", "e", "Tecnologia,", "Universidade", "de", "Coimbra,", "P-3004-516", "Coimbra,", "Portugal", "Correspondence", "e-mail:", "jap@pollux.fis.uc.pt", "Received", "15", "July", "2010;", "accepted", "20", "July", "2010", "Key", "indicators:", "single-crystal", "X-ray", "study;", "T", "=", "295", "K;", "mean", "(C–C)", "=", "0.005", "A˚;", "R", "factor", "=", "0.042;", "wR", "factor", "=", "0.100;", "data-to-parameter", "ratio", "=", "8.3.", "The", "title", "terpene,", "C30H46O3,", "is", "a", "28,13", "-lactone", "of", "oleanolic", "acid", "prepared", "with", "bismuth", "triﬂuoromethanesulfonate", "(OTf),", "Bi(OTf)3", "xH2O.", "All", "rings", "are", "trans-fused.", "The", "X-ray", "study", "shows", "the", "inversion", "of", "the", "orientation", "of", "18-H", "in", "the", "lactonization", "reaction.", "A", "quantum", "chemical", "ab-initio", "Roothaan", "Hartree–Fock", "calculation", "of", "the", "equilibrium", "geometry", "of", "the", "isolated", "molecule", "gives", "values", "for", "bond", "lengths", "and", "valency", "angles", "in", "close", "agreement", "with", "experi-", "mental", "values.", "The", "calculation", "also", "reproduces", "the", "observed", "molecular", "conformation,", "with", "puckering", "parameters", "that", "agree", "well", "with", "those", "determined", "from", "the", "crystallographic", "study.", "Related", "literature", "For", "general", "background", "to", "the", "use", "of", "natural", "products", "as", "sources", "of", "anticancer", "drugs,", "see:", "Koehn", "&", "Carter", "(2005).", "For", "the", "biological", "activity", "of", "oleanolic", "acid,", "see:", "Ringbom", "et", "al.", "(1998);", "Ma", "et", "al.", "(2000);", "Tokuda", "et", "al.", "(1986);", "Horiuchi", "et", "al.", "(2007);", "Lee", "et", "al.", "(1994);", "Sohn", "et", "al.", "(1995).", "For", "the", "biosyn-", "thesis", "of", "pentacyclic", "triterpenoids,", "see:", "Gershenzon", "&", "Dudareva", "(2007);", "Salvador", "(2010);", "Dzubak", "et", "al.", "(2006).", "For", "the", "lactonization", "reaction", "of", "oleanane-type", "triterpenoids,", "see:", "Cheriti", "et", "al.", "(1994).", "For", "the", "synthesis", "of", "the", "title", "compound,", "see:", "Salvador", "et", "al.", "(2009).", "For", "related", "structures,", "see:", "Eggle-", "ston", "(1987);", "Chang", "et", "al.", "(1982);", "Sutthivaiyakit", "et", "al.", "(2001);", "Wang", "et", "al.", "(2006).", "For", "puckering", 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969 ], [ 654, 955, 709, 969 ], [ 712, 955, 723, 969 ], [ 726, 955, 762, 969 ], [ 427, 972, 441, 986 ], [ 443, 972, 489, 986 ], [ 491, 972, 502, 986 ], [ 504, 972, 527, 986 ], [ 530, 972, 578, 986 ], [ 581, 972, 608, 986 ], [ 610, 972, 620, 986 ], [ 622, 972, 638, 986 ], [ 641, 972, 671, 986 ], [ 674, 972, 694, 986 ], [ 696, 972, 706, 986 ], [ 708, 972, 724, 986 ], [ 727, 972, 761, 986 ], [ 427, 988, 443, 1002 ], [ 448, 988, 493, 1002 ], [ 496, 988, 526, 1002 ], [ 530, 988, 541, 1002 ], [ 545, 988, 556, 1002 ], [ 560, 988, 583, 1002 ], [ 586, 988, 621, 1002 ], [ 625, 988, 662, 1002 ], [ 666, 988, 734, 1002 ], [ 738, 988, 762, 1002 ], [ 749, 1055, 775, 1064 ], [ 785, 1055, 811, 1064 ] ]	[ "JCB:", "ARTICLE", "Neural", "crest", "stem", "cell", "maintenance", "by", "combinatorial", "Wnt", "and", "BMP", "signaling", "Maurice", "Kléber,1", "Hye-Youn", "Lee,1", "Heiko", "Wurdak,1", "Johanna", "Buchstaller,1", "Martin", "M.", "Riccomagno,2", "Lars", "M.", "Ittner,3", "Ueli", "Suter,1", "Douglas", "J.", "Epstein,2", "and", "Lukas", "Sommer1", "1Institute", "of", "Cell", "Biology,", "Department", "of", "Biology,", "Swiss", "Federal", "Institute", "of", "Technology,", "ETH-Hönggerberg,", "CH-8093", "Zurich,", "Switzerland", "2Department", "of", "Genetics,", "University", "of", "Pennsylvania", "School", "of", "Medicine,", "Philadelphia,", "PA", "19104", "3Research", "Laboratory", "for", "Calcium", "Metabolism,", "University", "Hospital", "Balgrist,", "University", "of", "Zurich,", "CH-8008", "Zurich,", "Switzerland", "Y", "G", "O", "L", "O", "I", "B", "L", "L", "E", "C", "F", "O", "L", "A", "N", "R", "U", "O", "J", "E", "H", "T", "C", "sensory", "anonical", "neurogenesis", "Wnt", "signaling", "in", "early", "instructively", "neural", "crest", "promotes", "stem", "cells", "(eNCSCs)", "(Lee,", "H.Y.,", "M.", "Kléber,", "L.", "Hari,", "V.", "Brault,", "U.", "Suter,", "M.M.", "Taketo,", "R.", "Kemler,", "and", "L.", "Sommer.", "2004.", "Science.", "303:1020–1023).", "However,", "during", "nor-", "mal", "development", "Wnt", "signaling", "induces", "a", "sensory", "fate", "only", "in", "a", "subpopulation", "of", "eNCSCs", "while", "other", "cells", "maintain", "their", "stem", "cell", "features,", "despite", "the", "presence", "of", "Wnt", "activity.", "Hence,", "factors", "counteracting", "Wnt", "signaling", "must", "exist.", "Here,", "we", "show", "that", "bone", "morphogenic", "protein", "Introduction", "Because", "of", "its", "broad", "developmental", "potential,", "the", "neural", "crest", "represents", "an", "ideal", "model", "system", "to", "study", "stem", "cell", "biology.", "Neural", "crest", "cells", "delaminate", "from", "the", "developing", "dorsal", "neural", "tube,", "migrate", "to", "various", "locations", "within", "the", "embryo,", "and", "gen-", "erate", "multiple", "neural", "cell", "types", "of", "the", "vertebrate", "peripheral", "ner-", "vous", "system", "(PNS)", "as", "well", "as", "several", "nonneural", "tissues", "(Le", "Douarin", "and", "Dupin,", "2003).", "At", "least", "some", "neural", "crest", "cells", "are", "multipotent,", "giving", "rise", "to", "neuronal,", "glial,", "and", "nonneural", "deriv-", "atives,", "as", "has", "been", "shown", "by", "clonal", "analysis", "in", "culture", "and", "in", "vivo.", "Moreover,", "some", "crest", "cells", "have", "features", "of", "stem", "cells", "with", "the", "capacity", "to", "self-renew.", "Both", "in", "migrating", "neural", "crest", "and", "in", "crest-derived", "tissues,", "such", "multipotent", "stem", "and", "progen-", "itor", "cells", "coexist", "with", "cells", "that", "display", "more", "restricted", "devel-", "opmental", "potential.", "Recently", "we", "have", "described", "an", "early", "population", "of", "neural", "crest", "stem", "cells", "(eNCSCs)", "that", "is", "highly", "homogeneous", "with", "respect", "to", "marker", "expression", "and", "the", "potential", "to", "generate", "au-", "tonomic", "and", "sensory", "neurons,", "glia,", "and", "smooth", "muscle", "cells", "(Lee", "et", "al.,", "2004).", "Clonal", "cell", "culture", "experiments", "revealed", "the", "responsiveness", "of", "these", "cells", "to", "several", "instructive", "growth", "Correspondence", "to", "Lukas", "Sommer:", "sommer@cell.biol.ethz.ch", "Abbreviations", "used", "in", "this", "paper:", "BMP,", "bone", "morphogenic", "protein;", "DRG,", "dorsal", "root", "ganglia;", "eNCSC,", "early", "neural", "crest", "stem", "cell;", "GFAP,", "glial", "fibrillary", "acidic", "protein;", "NCSC,", "neural", "crest", "stem", "cell;", "NF,", "neurofilament;", "NRG,", "neuregulin;", "PNS,", "peripheral", "nervous", "system;", "SMA,", "smooth", "muscle", "actin.", "©", "The", "Rockefeller", "University", "Press", "$8.00", "The", "Journal", "of", "Cell", "Biology,", "Vol.", "169,", "No.", "2,", "April", "25,", "2005", "309–320", "http://www.jcb.org/cgi/doi/10.1083/jcb.200411095", "(BMP)", "signaling", "antagonizes", "the", "sensory", "fate-inducing", "activity", "of", "Wnt/", "-catenin.", "Intriguingly,", "Wnt", "and", "BMP", "act", "synergistically", "to", "suppress", "differentiation", "and", "to", "maintain", "NCSC", "marker", "expression", "and", "multipotency.", "Similar", "to", "NCSCs", "in", "vivo,", "NCSCs", "maintained", "in", "culture", "alter", "their", "responsiveness", "to", "instructive", "growth", "factors", "with", "time.", "Thus,", "stem", "cell", "development", "is", "regulated", "by", "combinatorial", "growth", "factor", "activities", "that", "interact", "with", "changing", "cell-", "intrinsic", "cues.", "factors", "that", "promote", "the", "generation", "of", "specific", "cell", "fates", "at", "the", "expense", "of", "other", "possible", "fates.", "These", "factors", "include", "members", "of", "the", "TGF", "factor", "family", "that", "promote", "autonomic", "neuro-", "genesis", "and", "the", "development", "of", "smooth", "muscle–like", "cells,", "neuregulin1", "(NRG1)", "isoforms", "that", "induce", "the", "generation", "of", "pe-", "ripheral", "glia,", "and", "Wnt", "signaling", "that", "promotes", "sensory", "neuro-", "genesis", "in", "a", "-catenin–dependent", "manner", "(Le", "Douarin", "and", "Dupin,", "2003;", "Kléber", "and", "Sommer,", "2004).", "In", "vivo", "and", "in", "cell", "cul-", "ture,", "eNCSCs", "that", "lack", "the", "Wnt", "signaling", "component", "-catenin", "fail", "to", "generate", "sensory", "neurons", "(Hari", "et", "al.,", "2002).", "Comple-", "mentary", "to", "this,", "embryos", "that", "express", "a", "constitutively", "active", "form", "of", "-catenin", "specifically", "in", "NCSCs", "generate", "almost", "ex-", "clusively", "sensory", "neural", "cells", "at", "the", "expense", "of", "other", "possible", "neural", "crest–derived", "lineages", "(Lee", "et", "al.,", "2004).", "Thus,", "unlike", "in", "other", "stem", "cell", "types,", "canonical", "Wnt", "signaling", "on", "its", "own", "does", "not", "support", "stem", "cell", "expansion", "in", "NCSCs,", "but", "rather", "promotes", "sensory", "neurogenesis.", "So", "far,", "the", "signals", "supporting", "NCSC", "maintenance", "and", "self-renewal", "have", "not", "been", "identified,", "al-", "though", "it", "has", "been", "possible", "to", "passage", "both", "migratory", "and", "postmigratory", "NCSCs", "for", "some", "generations", "in", "a", "nondefined", "medium", "(Stemple", "and", "Anderson,", "1992;", "Bixby", "et", "al.,", "2002).", "Given", "the", "expression", "of", "Wnts", "in", "the", "dorsal", "neural", "tube", "at", "the", "time", "of", "neural", "crest", "emigration", "and", "the", "sensitivity", "of", "almost", "all", "eNCSCs", "to", "Wnt", "signaling", "(Parr", "et", "al.,", "1993;", "Lee", "et", "al.,", "2004),", "the", "question", "arises", "as", "to", "why", "during", "normal", "development", "only", "JCB", "309" ]	[ 16, 16, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 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"Natarajan", "et", "al.", "BMC", "Genomics", "2010,", "11:606", "http://www.biomedcentral.com/1471-2164/11/606", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Gene", "discovery", "from", "Jatropha", "curcas", "by", "sequencing", "of", "ESTs", "from", "normalized", "and", "full-length", "enriched", "cDNA", "library", "from", "developing", "seeds", "Purushothaman", "Natarajan,", "Deepa", "Kanagasabapathy,", "Gnanasekaran", "Gunadayalan,", "Jasintha", "Panchalingam,", "Noopur", "shree,", "Priyanka", "Annabel", "Sugantham,", "Kavita", "Kumari", "Singh,", "Parani", "Madasamy", "Abstract", "Background:", "Jatropha", "curcas", "L.", "is", "promoted", "as", "an", "important", "non-edible", "biodiesel", "crop", "worldwide.", "Jatropha", "oil,", "which", "is", "a", "triacylglycerol,", "can", "be", "directly", "blended", "with", "petro-diesel", "or", "transesterified", "with", "methanol", "and", "used", "as", "biodiesel.", "Genetic", "improvement", "in", "jatropha", "is", "needed", "to", "increase", "the", "seed", "yield,", "oil", "content,", "drought", "and", "pest", "resistance,", "and", "to", "modify", "oil", "composition", "so", "that", "it", "becomes", "a", "technically", "and", "economically", "preferred", "source", "for", "biodiesel", "production.", "However,", "genetic", "improvement", "efforts", "in", "jatropha", "could", "not", "take", "advantage", "of", "genetic", "engineering", "methods", "due", "to", "lack", "of", "cloned", "genes", "from", "this", "species.", "To", "overcome", "this", "hurdle,", "the", "current", "gene", "discovery", "project", "was", "initiated", "with", "an", "objective", "of", "isolating", "as", "many", "functional", "genes", "as", "possible", "from", "J.", "curcas", "by", "large", "scale", "sequencing", "of", "expressed", "sequence", "tags", "(ESTs).", "Results:", "A", "normalized", "and", "full-length", "enriched", "cDNA", "library", "was", "constructed", "from", "developing", "seeds", "of", "J.", "curcas.", "The", "cDNA", "library", "contained", "about", "1", "×", "106", "clones", "and", "average", "insert", "size", "of", "the", "clones", "was", "2.1", "kb.", "Totally", "12,084", "ESTs", "were", "sequenced", "to", "average", "high", "quality", "read", "length", "of", "576", "bp.", "Contig", "analysis", "revealed", "2258", "contigs", "and", "4751", "singletons.", "Contig", "size", "ranged", "from", "2-23", "and", "there", "were", "7333", "ESTs", "in", "the", "contigs.", "This", "resulted", "in", "7009", "unigenes", "which", "were", "annotated", "by", "BLASTX.", "It", "showed", "3982", "unigenes", "with", "significant", "similarity", "to", "known", "genes", "and", "2836", "unigenes", "with", "significant", "similarity", "to", "genes", "of", "unknown,", "hypothetical", "and", "putative", "proteins.", "The", "remaining", "191", "unigenes", "which", "did", "not", "show", "similarity", "with", "any", "genes", "in", "the", "public", "database", "may", "encode", "for", "unique", "genes.", "Functional", "classification", "revealed", "unigenes", "related", "to", "broad", "range", "of", "cellular,", "molecular", "and", "biological", "functions.", "Among", "the", "7009", "unigenes,", "6233", "unigenes", "were", "identified", "to", "be", "potential", "full-length", "genes.", "Conclusions:", "The", "high", "quality", "normalized", "cDNA", "library", "was", "constructed", "from", "developing", "seeds", "of", "J.", "curcas", "for", "the", "first", "time", "and", "7009", "unigenes", "coding", "for", "diverse", "biological", "functions", "including", "oil", "biosynthesis", "were", "identified.", "These", "genes", "will", "serve", "as", "invaluable", "genetic", "resource", "for", "crop", "improvement", "in", "jatropha", "to", "make", "it", "an", "ideal", "and", "profitable", "crop", "for", "biodiesel", "production.", "Background", "Jatropha", "curcas", "L.,", "one", "of", "the", "175", "species", "in", "genus", "Jatropha", "of", "the", "family", "Euphorbiaceae", "is", 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"food", "crops.", "It", "reduces", "the", "dependence", "on", "fossil", "fuel", "which", "is", "often", "imported", "by", "using", "precious", "foreign", "currency.", "Its", "decentralized", "production", "will", "provide", "income", "for", "a", "large", "number", "of", "small", "and", "marginal", "farmers.", "Biodiesel", "is", "also", "less", "harm-", "ful", "to", "the", "environment", "in", "that", "its", "production", "and", "com-", "bustion", "reduces", "emission", "of", "greenhouse", "gases", "by", "41%", "relative", "to", "fossil", "fuel", "[2].", "It", "is", "reported", "that", "biodiesel", "©", "2010", "Natarajan", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", 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1042, 150, 1052 ], [ 152, 1042, 189, 1052 ], [ 191, 1042, 225, 1052 ], [ 227, 1042, 246, 1052 ], [ 248, 1042, 283, 1052 ], [ 285, 1042, 293, 1052 ], [ 295, 1042, 328, 1052 ], [ 330, 1042, 344, 1052 ], [ 346, 1042, 367, 1052 ], [ 369, 1042, 406, 1052 ], [ 69, 1053, 149, 1063 ], [ 427, 1053, 444, 1063 ] ]	[ "Brief", "Report", "nSec1", "Binds", "a", "Closed", "Conformation", "of", "Syntaxin1A", "Bin", "Yang,", "Martin", "Steegmaier,", "Lino", "C.", "Gonzalez,", "Jr.,", "and", "Richard", "H.", "Scheller", "Howard", "Hughes", "Medical", "Institute,", "Department", "of", "Molecular", "and", "Cellular", "Physiology,", "Stanford", "University", "School", "of", "Medicine,", "Stanford,", "California", "94305-5428", "Abstract.", "The", "Sec1", "family", "of", "proteins", "is", "proposed", "to", "function", "in", "vesicle", "trafﬁcking", "by", "forming", "complexes", "with", "target", "membrane", "SNAREs", "(soluble", "N-ethylmale-", "imide-sensitive", "factor", "[NSF]", "attachment", "protein", "[SNAP]", "receptors)", "of", "the", "syntaxin", "family.", "Here,", "we", "demonstrate,", "by", "using", "in", "vitro", "binding", "assays,", "nondena-", "turing", "gel", "electrophoresis,", "and", "speciﬁc", "neurotoxin", "treat-", "ment,", "that", "the", "interaction", "of", "syntaxin1A", "with", "the", "core", "SNARE", "components,", "SNAP-25", "(synaptosome-associ-", "ated", "protein", "of", "25", "kD)", "and", "VAMP2", "(vesicle-associated", "membrane", "protein", "2),", "precludes", "the", "interaction", "with", "nSec1", "(also", "called", "Munc18", "and", "rbSec1).", "Inversely,", "asso-", "ciation", "of", "nSec1", "and", "syntaxin1A", "prevents", "assembly", "of", "the", "ternary", "SNARE", "complex.", "Furthermore,", "using", "chemical", "cross-linking", "of", "rat", "brain", "membranes,", "we", "iden-", "tiﬁed", "nSec1", "complexes", "containing", "syntaxin1A,", "but", "not", "SNAP-25", "or", "VAMP2.", "These", "results", "support", "the", "hypoth-", "esis", "that", "Sec1", "proteins", "function", "as", "syntaxin", "chaperons", "during", "vesicle", "docking,", "priming,", "and", "membrane", "fusion.", "Key", "words:", "membrane", "fusion", "•", "synaptic", "vesicles", "•", "exocytosis", "•", "SNARE", "•", "synapse", "Introduction", "Two", "of", "the", "most", "intensively", "studied", "membrane", "transport", "processes", "are", "the", "fusion", "of", "Golgi", "apparatus-derived", "vesi-", "cles", "with", "the", "plasma", "membrane", "in", "yeast", "and", "the", "secretion", "of", "neurotransmitter", "from", "the", "mammalian", "presynaptic", "nerve", "terminal", "(Bennett", "and", "Scheller,", "1994;", "Jahn", "and", "Süd-", "hof,", "1994;", "Rothman,", "1994).", "These", "membrane", "fusion", "events", "are", "mediated", "by", "a", "set", "of", "structurally", "and", "likely", "functionally", "related", "proteins", "called", "SNAREs1", "(soluble", "N-ethylmale-", "imide-sensitive", "factor", "[NSF]", "attachment", "protein", "[SNAP]", "receptors;", "Bennett,", "1995).", "These", "proteins", "include", "vesicle-", "associated", "membrane", "proteins", "(VAMP)", "1", "and", "2", "(synap-", "tobrevin),", "a", "synaptosome-associated", "protein", "of", "25", "kD", "(SNAP-25),", "and", "syntaxin1A", "and", "B", "in", "mammals;", "and", "their", "yeast", "orthologues", "Snc1", "and", "2,", "Sec9,", "and", "Sso1", "and", "2,", "re-", "spectively", "(Bennett", "and", "Scheller,", "1994;", "Brennwald", "et", "al.,", "Address", "correspondence", "to", "Richard", "H.", "Scheller,", "Howard", "Hughes", "Medical", "Institute,", "Department", "of", "Molecular", "and", "Cellular", "Physiology,", "Stanford", "University", "School", "of", "Medicine,", "Stanford,", "CA", "94305-5428.", "Tel.:", "650-723-", "9075.", "Fax:", "650-725-4436.", "E-mail:", "scheller@cmgm.stanford.edu", "1Abbreviations", "used", "in", "this", "paper:", "DSS,", "disuccinimidyl", "suberate;", "GST,", "glutathione", "S-transferase;", "NSF,", "N-ethylmaleimide-sensitive", "factor;", "SNAP,", "soluble", "NSF", "attachment", "protein;", "SNAP-25,", "synaptosome-associated", "pro-", "tein", "of", "25", "kD;", "SNARE,", "SNAP", "receptor;", "VAMP,", "vesicle-associated", "mem-", "brane", "protein.", "1994).", "The", "pairing", "of", "SNAREs", "across", "membranes", "to", "form", "four-stranded", "helical", "bundles", "is", "a", "late", "event", "in", "the", "fusion", "process,", "perhaps", "driving", "the", "actual", "mixing", "of", "the", "lipid", "bi-", "layers", "(Poirier", "et", "al.,", "1998;", "Sutton", "et", "al.,", "1998;", "Weber", "et", "al.,", "1998;", "Chen", "et", "al.,", "1999).", "In", "addition", "to", "SNAREs,", "a", "critical", "component", "of", "the", "fu-", "sion", "process", "is", "the", "Sec1p", "protein,", "known", "in", "mammals", "as", "munc18,", "nSec1,", "or", "rbSec1", "(Hata", "et", "al.,", "1993;", "Garcia", "et", "al.,", "1994;", "Pevsner", "et", "al.,", "1994b).", "This", "soluble", "protein", "is", "critical", "for", "vesicle", "trafficking", "in", "yeast", "and", "is", "proposed", "to", "play", "an", "important", "role", "in", "the", "exocytosis", "process.", "Loss", "of", "Sec1", "function", "results", "in", "an", "accumulation", "of", "vesicles", "at", "specific", "steps", "in", "secretion", "(Novick", "and", "Scheckman,", "1979;", "Ossig", "et", "al.,", "1991;", "Cowles", "et", "al.,", "1994),", "and", "overexpression", "of", "Sec1", "in", "Drosophila", "melanogaster", "results", "in", "a", "reduction", "of", "synap-", "tic", "transmission", "(Schulze", "et", "al.,", "1994;", "Wu", "et", "al.,", "1998).", "Bio-", "chemical", "studies", "conducted", "with", "the", "mammalian", "proteins", "showed", "that", "nSec1", "from", "brain", "extracts,", "bacterially", "ex-", "pressed", "recombinant,", "or", "in", "vitro", "translated", "nSec1,", "binds", "directly", "to", "syntaxin", "(Hata", "et", "al.,", "1993;", "Garcia", "et", "al.,", "1994;", "Hodel", "et", "al.,", "1994;", "Pevsner", "et", "al.,", "1994b).", "Further", "investi-", "gations", "demonstrated", "that", "when", "syntaxin", "is", "bound", "to", "nSec1,", "the", "binding", "to", "either", "VAMP", "or", "SNAP-25", "is", "inhib-", "ited", "(Pevsner", "et", "al.,", "1994a).", "A", "model", "for", "Sec1/syntaxin", "function", "was", "suggested", "from", "an", "early", "study", "demonstrating", "that", "binding", "of", "the", "NH2-ter-", "ª", "The", "Rockefeller", "University", "Press,", "0021-9525/2000/01/247/6", "$5.00", "The", "Journal", "of", "Cell", "Biology,", "Volume", "148,", "Number", "2,", "January", "24,", "2000", "247–252", "http://www.jcb.org", "247" ]	[ 16, 16, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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"Pavlovian-to-instrumental", "transfer", "Pedro", "Morgado1,2,", "Miguel", "Silva1,2,", "Nuno", "Sousa1,2", "and", "João", "J.", "Cerqueira1,2", "1", "Life", "and", "Health", "Sciences", "Research", "Institute,", "School", "of", "Health", "Sciences,", "University", "of", "Minho,", "Braga,", "Portugal", "2", "ICVS-3Bs", "PT", "Government", "Associate", "Laboratory,", "Braga/Guimarães,", "Portugal", "Edited", "by:", "Scott", "A.", "Huettel,", "Duke", "University,", "USA", "Reviewed", "by:", "Jack", "Van", "Honk,", "Utrecht", "University,", "Netherlands", "Mauricio", "R.", "Delgado,", "Rutgers-Newark:", "The", "State", "University", "of", "New", "Jersey,", "USA", "Correspondence:", "João", "J.", "Cerqueira,", "Life", "and", "Health", "Sciences", "Research", "Institute,", "School", "of", "Health", "Sciences,", "University", "of", "Minho,", "Campus", "de", "Gualtar,", "4710-057", "Braga,", "Portugal.", "e-mail:", "jcerqueira@ecsaude.uminho.pt", "Stress", "has", "a", "strong", "impact", "in", "the", "brain,", "impairing", "decision-making", "processes", "as", "a", "result", "of", "changes", "in", "circuits", "involving", "the", "prefrontal", "and", "orbitofrontal", "cortices", "and", "the", "striatum.", "Given", "that", "these", "same", "circuits", "are", "key", "for", "action", "control", "and", "outcome", "encoding,", "we", "hypothesized", "that", "adaptive", "responses", "to", "which", "these", "are", "essential", "functions,", "could", "also", "be", "targeted", "by", "stress.", "To", "test", "this", "hypothesis", "we", "herein", "assessed", "the", "impact", "of", "chronic", "stress", "in", "a", "Pavlovian-to-instrumental", "transfer", "(PIT)", "paradigm,", "a", "model", "of", "an", "adaptive", "response", "in", "which", "a", "previously", "conditioned", "cue", "biases", "an", "instrumental", "goal-directed", "action.", "Data", "reveals", "that", "rats", "submitted", "to", "chronic", "unpredictable", "stress", "did", "not", "display", "deﬁcits", "in", "pavlovian", "condition-", "ing", "nor", "on", "the", "learning", "of", "the", "instrumental", "task,", "but", "were", "impaired", "in", "PIT;", "importantly,", "after", "a", "stress-free", "period", "the", "PIT", "deﬁcits", "were", "no", "longer", "observed.", "These", "results", "are", "relevant", "to", "understand", "how", "stress", "biases", "multiple", "incentive", "processes", "that", "contribute", "to", "instrumental", "performance.", "Keywords:", "stress,", "conditioning,", "pavlovian-to-instrumental", "transfer,", "choices", "INTRODUCTION", "Exposure", "to", "a", "stressful", "stimulus", "activates", "a", "physiological", "response", "intended", "to", "restore", "the", "organism’s", "homeostasis.", "However,", "when", "stressors", "are", "maintained", "for", "long", "periods", "of", "time,", "this", "response", "becomes", "maladaptive", "and", "results", "in", "several", "disruptions", "at", "the", "level", "of", "the", "regulatory", "systems,", "of", "which", "the", "brain", "is", "a", "key", "element.", "Thus,", "it", "is", "not", "surprising", "that", "chronic", "stress", "exposure", "is", "associated", "with", "signiﬁcant", "behavioral", "impairments", "such", "as", "deﬁcits", "in", "spatial", "reference", "and", "working", "memory", "(Mizoguchi", "et", "al.,", "2000;", "Cerqueira", "et", "al.,", "2007),", "behavioral", "ﬂexibility", "(Cerqueira", "et", "al.,", "2007),", "anxiety", "(Pêgo", "et", "al.,", "2006),", "and", "mood", "(Bessa", "et", "al.,", "2009).", "Such", "func-", "tional", "deﬁcits", "are", "paralleled", "by", "structural", "changes", "in", "several", "brain", "regions", "(Sousa", "and", "Almeida,", "2002),", "that", "render", "chronic", "stress", "as", "an", "important", "risk-factor", "for", "the", "development", "of", "several", "neuropsychi-", "atric", "disorders.", "Importantly,", "several", "studies", "have", "also", "shown", "that", "the", "behavioral", "and", "structural", "effects", "of", "stress", "are", "transient,", "and", "important", "plastic", "phenomena", "take", "place", "after", "the", "removal", "of", "the", "stressful", "stimuli", "(Sousa", "et", "al.,", "2000;", "Bloss", "et", "al.,", "2010).", "Recent", "studies", "from", "our", "laboratory", "show", "that", "chronic", "stress", "bias", "decision-making", "processes,", "by", "favoring", "the", "shift", "from", "goal-", "directed", "actions", "to", "habit", "based", "behaviors", "(Dias-Ferreira", "et", "al.,", "2009).", "These", "alterations", "in", "instrumental", "behavior", "are", "correlated", "with", "changes", "in", "neuronal", "circuits", "involving", "different", "areas", "of", "the", "prefrontal", "cortex", "(PFC)", "[including", "the", "medial", "PFC", "(mPFC)", "and", "orbitofrontal", "cortex", "(OFC)]", "and", "dorsal", "striatum", "(Dias-Ferreira", "et", "al.,", "2009).", "Given", "that", "these", "regions", "are", "implicated", "in", "action", "control", "(Balleine", "and", "O’Doherty,", "2010)", "and", "outcome", "encoding", "necessary", "for", "adaptive", "responses", "(Chudasama", "and", "Robbins,", "2003;", "Hornak", "et", "al.,", "2004),", "we", "hypothesized", "that", "stress-induced", "changes", "in", "neuronal", "circuits", "involving", "the", "PFC", "and", "the", "striatum", "could", "lead", "to", "outcome", "encoding", "deﬁcits", "and", "to", "changes", "in", "the", "multiple", "incentive", "processes", "that", "contribute", "to", "instrumental", "performance.", "One", "of", "these", "processes", "is", "Pavlovian-to-instrumental", "transfer", "(PIT;", "Estes,", "1948;", "Colwill", "and", "Rescorla,", "1986).", "PIT", "encompasses", "three", "distinct", "components:(1)", "Pavlovian", "learning,", "in", "which", "stim-", "uli", "are", "associated", "with", "rewards;", "(2)", "instrumental", "conditioning,", "in", "which", "associations", "between", "actions", "and", "out", "comes", "are", "learned;", "and", "(3)", "a", "test", "phase,", "in", "which", "the", "impact", "of", "previous", "cues", "on", "instrumental", "response", "is", "assessed.", "The", "associative", "value", "of", "cue", "and", "its", "motivational", "signiﬁcance", "are", "determinants", "found", "crucial", "to", "proper", "transfer,", "a", "phenomenon", "which", "resembles", "cue-mediated", "increased", "drive", "seeking", "for", "drugs", "seen", "in", "drug", "abusers", "(Dickinson", "et", "al.,", "2000;", "Corbit", "and", "Janak,", "2007).", "Because", "of", "that,", "PIT", "has", "been", "used", "as", "a", "useful", "model", "of", "maladaptive", "learning", "observed", "in", "several", "conditions,", "namely", "addictive", "disorders.", "The", "neural", "basis", "of", "PIT", "is", "not", "completely", "established", "but", "sev-", "eral", "studies", "implicate", "regions", "associated", "with", "emotional", "processing", "[amygdala", "and", "nucleus", "accumbens", "(NAc)],", "executive", "commands", "(dorsal", "striatum),", "and", "their", "integration", "(mPFC", "and", "OFC);", "impor-", "tantly,", "it", "is", "known", "that", "key", "regions", "involved", "in", "PIT", "operate", "in", "parallel.", "In", "fact,", "lesion", "studies", "in", "the", "amygdala", "and", "NAc", "have", "demonstrated", "that", "these", "brain", "regions", "are", "necessary", "for", "the", "behav-", "ioral", "expression", "of", "PIT", "(Corbit", "et", "al.,", "2001;", "Hall", "et", "al.,", "2001;", "de", "Borchgrave", "et", "al.,", "2002;", "Holland", "and", "Gallagher,", "2004).", "Moreover,", "it", "is", "relevant", "to", "note", "that", "different", "regions", "of", "the", "amygdala", "and", "NAc", "display", "different", "roles", "in", "this", "process.", "While", "the", "amygdala", "baso-", "lateral", "nucleus", "(BLA)", "mediates", "the", "association", "between", "speciﬁc", "sensory", "and", "emotional", "features", "of", "stimulus", "and", "the", "responses", "that", "are", "elicited", "by", "each", "one", "(consummatory", "conditioning),", "the", "central", "nucleus", "(CN)", "mediates", "the", 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"dependencies", "of", "rate", "constants", "for", "channel", "closure", "(koff)", "predict", "different", "positions", "of", "rate-limiting", "barriers", "on", "the", "energy-area", "proﬁles", "for", "WT", "and", "GOF", "MscL.", "The", "data", "support", "the", "two-gate", "mechanism", "in", "which", "the", "ﬁrst", "subtransition", "(C→S)", "can", "be", "viewed", "as", "opening", "of", "the", "central", "(M1)", "gate,", "resulting", "in", "an", "expanded", "water-ﬁlled", "“leaky”", "conformation.", "Strong", "facilitation", "of", "this", "step", "by", "polar", "GOF", "substitutions", "suggests", "that", "separation", "of", "M1", "helices", "associated", "with", "hydration", "of", "the", "pore", "in", "WT", "MscL", "is", "the", "major", "energetic", "barrier", "for", "opening.", "Mutants", "with", "a", "stabilized", "S1", "gate", "demonstrate", "impeded", "transitions", "from", "low-conducting", "substates", "to", "the", "fully", "open", "state,", "whereas", "extensions", "of", "S1–M1", "linkers", "result", "in", "a", "much", "higher", "probability", "of", "reverse", "O→S", "transitions.", "These", "data", "strongly", "suggest", "that", "the", "bulk", "of", "conductance", "gain", "in", "the", "second", "subtransition", "(S→O)", "occurs", "through", "the", "opening", "of", "the", "NH2-terminal", "(S1)", "gate", "and", "the", "linkers", "are", "coupling", "elements", "between", "the", "M1", "and", "S1", "gates.", "k", "e", "y", "w", "o", "r", "d", "s", ":", "mechanosensitive", "channel", "•", "tension", "•", "thermodynamics", "•", "subconducting", "states", "•", "hydration", "I", "N", "T", "R", "O", "D", "U", "C", "T", "I", "O", "N", "Uniﬁed", "mainly", "by", "function,", "mechanosensitive", "ion", "chan-", "nels", "form", "a", "diverse", "group", "of", "sensory", "receptors,", "com-", "prising", "members", "of", "structurally", "unrelated", "channel", "fam-", "ilies", "(for", "review", "see", "Sukharev", "and", "Corey,", "2004).", "The", "multiplicity", "of", "mechanoreceptor", "types", "suggests", "that", "similar", "functions", "can", "be", "implemented", "with", "different", "se-", "quences", "and", "structural", "designs,", "thus", "emphasizing", "the", "importance", "of", "unifying", "biophysical", "principles", "of", "gating", "by", "mechanical", "force.", "Bacterial", "mechanosensitive", "channels", "are", "convenient", "model", "systems", "for", "the", "basic", "channel", "biophysics.", "They", "fulﬁll", "the", "role", "of", "turgor", "pressure", "regulators", "in", "small", "prokaryotic", "cells,", "which", "in", "the", "wild", "are", "subjected", "to", "a", "constantly", "changing", "environment.", "Three", "bacterial", "mechanosensitive", "channels", "have", "been", "identiﬁed", "in", "Escherichia", "coli:", "MscL,", "MscS,", "and", "MscK", "(Sukharev", "et", "al.,", "1994;", "Levina", "et", "al.,", "1999;", "Pivetti", "et", "al.,", "2003).", "Two", "of", "A.", "Anishkin", "and", "C.-S.", "Chiang", "contributed", "equally", "to", "this", "work.", "Correspondence", "to", "Sergei", "Sukharev:", "sukharev@umd.edu", "them,", "MscL", "and", "MscS,", "were", "isolated,", "reconstituted,", "and", "shown", "to", "be", "gated", "directly", "by", "tension", "in", "the", "lipid", "bilayer", "(Hase", "et", "al.,", "1995;", "Blount", "et", "al.,", "1996a;", "Okada", "et", "al.,", "2002;", "Sukharev,", "2002).", "Successful", "efforts", "in", "crystallization", "of", "MscS", "from", "E.", "coli", "(Bass", "et", "al.,", "2002)", "and", "the", "MscL", "homologue", "from", "M.", "tuberculosis", "(Chang", "et", "al.,", "1998)", "(TbMscL)", "have", "opened", "rich", "opportunities", "for", "detailed", "structure-based", "studies", "of", "their", "gating", "mechanisms.", "Since", "then,", "MscL", "has", "been", "the", "best", "understood", "“simple”", "chan-", "nel", "gated", "by", "membrane", "stretch", "(Blount,", "2003;", "Perozo", "and", "Rees,", "2003;", "Sukharev", "and", "Anishkin,", "2004).", "Identiﬁcation", "of", "the", 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"McGill", "University,", "Montreal,", "Quebec,", "Canada,", "4", "Department", "of", "Pharmacology", "and", "Therapeutics,", "McGill", "University,", "Montreal,", "Quebec,", "Canada,", "5", "McGill", "Centre", "for", "Bioinformatics,", "McGill", "University,", "Montreal,", "Quebec,", "Canada,", "6", "McGill", "Group", "for", "Suicide", "Studies,", "Douglas", "Mental", "Health", "University", "Institute,", "Montreal,", "Quebec,", "Canada", "Abstract", "Background:", "Alterations", "in", "gene", "expression", "in", "the", "suicide", "brain", "have", "been", "reported", "and", "for", "several", "genes", "DNA", "methylation", "as", "an", "epigenetic", "regulator", "is", "thought", "to", "play", "a", "role.", "rRNA", "genes,", "that", "encode", "ribosomal", "RNA,", "are", "the", "backbone", "of", "the", "protein", "synthesis", "machinery", "and", "levels", "of", "rRNA", "gene", "promoter", "methylation", "determine", "rRNA", "transcription.", "Methodology/Principal", "Findings:", "We", "test", "here", "by", "sodium", "bisulfite", "mapping", "of", "the", "rRNA", "promoter", "and", "quantitative", "real-", "time", "PCR", "of", "rRNA", "expression", "the", "hypothesis", "that", "epigenetic", "differences", "in", "critical", "loci", "in", "the", "brain", "are", "involved", "in", "the", "pathophysiology", "of", "suicide.", "Suicide", "subjects", "in", "this", "study", "were", "selected", "for", "a", "history", "of", "early", "childhood", "neglect/abuse,", "which", "is", "associated", "with", "decreased", "hippocampal", "volume", "and", "cognitive", "impairments.", "rRNA", "was", "significantly", "hypermethylated", "throughout", "the", "promoter", "and", "59", "regulatory", "region", "in", "the", "brain", "of", "suicide", "subjects,", "consistent", "with", "reduced", "rRNA", "expression", "in", "the", "hippocampus.", "This", "difference", "in", "rRNA", "methylation", "was", "not", "evident", "in", "the", "cerebellum", "and", "occurred", "in", "the", "absence", "of", "genome-wide", "changes", "in", "methylation,", "as", "assessed", "by", "nearest", "neighbor.", "Conclusions/Significance:", "This", "is", "the", "first", "study", "to", "show", "aberrant", "regulation", "of", "the", "protein", "synthesis", "machinery", "in", "the", "suicide", "brain.", "The", "data", "implicate", "the", "epigenetic", "modulation", "of", "rRNA", "in", "the", "pathophysiology", "of", "suicide.", "Citation:", "McGowan", "PO,", "Sasaki", "A,", "Huang", "TCT,", "Unterberger", "A,", "Suderman", "M,", "et", "al.", "(2008)", "Promoter-Wide", "Hypermethylation", "of", "the", "Ribosomal", "RNA", "Gene", "Promoter", "in", "the", "Suicide", "Brain.", "PLoS", "ONE", "3(5):", "e2085.", "doi:10.1371/journal.pone.0002085", "Editor:", "Jo¨", "rg", "Hoheisel,", "Deutsches", "Krebsforschungszentrum,", "Germany", "Received", "October", "28,", "2007;", "Accepted", "March", "20,", "2008;", "Published", "May", "7,", "2008", "Copyright:", "2008", "McGowan", "et", "al.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Funding:", "This", "work", "was", "funded", "by", "a", "grant", "from", "the", "National", "Cancer", "Institute", "to", "MS,", "NICHD", "to", "MJM", "and", "MS,", "HSFP", "to", "MJM", "and", "MS,", "the", "Maternal", "Adversity,", "Vulnerability", "and", "Neurodevelopment", "Project", "grant", "from", "the", "Canadian", "Institutes", "for", "Health", "Research", "(CIHR)", "to", "MJM", "and", "MS,", "as", "well", "as", "grants", "from", "CIHR", "to", "GT.", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "*", "E-mail:", "gustvao.turecki@mcgill.ca", "(GT);", "moshe.szyf@mcgill.ca", "(MS)", "Introduction", "Suicide", "is", "a", "leading", "cause", "of", "death,", "particularly", "in", "males", "[1,2].", "Although", "many", "suicide", "subjects", "have", "a", "diagnosable", "psychiatric", "illness,", "most", "persons", "with", "a", "psychiatric", "disorder", "never", "attempt", "suicide", "[2].", "Suicidal", "behavior", "aggregates", "in", "families", "[1],", "and", "studies", "of", "twins", "show", "that", "monozygotic", "individuals", "have", "a", "greater", "concordance", "for", "suicide", "completion", "and", "suicide", "attempts", "com-", "pared", "to", "dizygotic", "individuals", "[2–4].", "Non-genetic", "familial", "factors,", "including", "a", "history", "of", "abuse", "or", "neglect", "during", "childhood,", "are", "also", "risk", "factors", "for", "suicidal", "behavior", "[5,6].", "Similarly,", "childhood", "abuse", "is", "associated", "with", "an", "increased", "risk", "for", "psychopathology", "[7,8]", "and", "altered", "neural", "development", "[9].", "Several", "lines", "of", "evidence", "suggest", "that", "changes", "in", "gene", "expression", "in", "the", "brain", "occur", "in", "the", "context", "of", "psychiatric", "disorders", "and", "suicide", "[10–15].", "Alterations", "in", "gene", "regulation", "can", "be", "caused", "by", "epigenetic", "programming", "of", "gene", "expression", "in", "response", "to", "environmental", "exposure,", "including", "social", "and", "physical", "adversity", "[16].", "The", "genome", "is", "epigenetically", "programmed", "by", "changes", "in", "the", "chromatin", "state", "and", "by", "a", "pattern", "of", "modification", "of", "the", "DNA", "molecule", "itself", "through", "methylation", "[17].", "DNA", "methylation", "is", "a", "stable", "epigenetic", "mark", "associated", "with", "long-lasting", "silencing", "of", "gene", "expression", "[18].", "In", "rodents,", "genes", "responsive", "to", "differences", "in", "the", "quality", "of", "maternal", "care", "early", "in", "life", "are", "altered", "through", "epigenetic", "mechanisms", "[19,20].", "In", "the", "human", "brain,", "aberrant", "DNA", "methylation", "of", "specific", "genes", "also", "occurs", "in", "the", "context", "of", "psychiatric", "disorders", "[21–26].", "Decreased", "expression", "of", "ribosomal", "RNA", "(rRNA),", "a", "bottleneck", "gene", "for", "protein", "production", "in", "the", "cell,", "occurs", "in", "patients", "with", "mild", "cognitive", "impairment", "and", "early", "Alzheimer’s", "disease", "[27,28].", "DNA", "methylation", "can", "regulate", "gene", "expression", "in", "two", "ways.", "One", "is", "site-specific", "methylation,", "involving", "direct", "interference", "with", "the", "binding", "of", "transcription", "factors", "[29].", "The", "second", "is", "site-", "independent", "promoter-wide", "methylation,", "attracting", "methylated", "DNA", "binding", "proteins", "and", "leading", "to", "an", "inactive", "chromatin", "structure.", "In", "the", "latter", "case,", "the", "density", "of", "methylated", "CpGs", "determines", "the", "extent", "of", "gene", "silencing", "[30].", "Both", "mechanisms", "can", "regulate", "rRNA", "expression.", "Previous", "work", "in", "cultured", "mouse", "cells", "indicated", "that", "rRNA", "is", "regulated", "by", "methylation", "of", "a", "single", "CpG", "dinucleotide", "at", "position", "2133", "residing", "at", "the", "upstream", "control", "element", "(UCE)", "[31].", "In", "human", "cell", "culture,", "the", "transcriptionally", "active", "fraction", "of", "rRNA", "promoters", "associated", "with", "RNA", "polymerase", "I", "(pol", "I)", "is", "completely", "unmethylated", "whereas", "the", "fraction", "not", "associated", "with", "pol", "I", "is", "almost", "completely", "methylated", "[32],", "thus", "determining", "transcription", "by", "defining", "the", "fraction", "of", "unmethylated", "rRNA.", "Mouse", "and", "human", "rRNA", "promoters", "show", "PLoS", "ONE", "\|", "www.plosone.org", "1", "May", "2008", "\|", "Volume", 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"lungs,", "and", "kidneys.", "Cardiac", "involvement", "with", "an", "intracardiac", "mass", "is", "an", "exceedingly", "rare", "manifestation", "of", "this", "disease,", "especially", "in", "the", "pediatric", "population", "where,", "to", "our", "knowledge,", "only", "one", "article", "exists", "to", "date", "that", "has", "described", "such", "a", "finding.", "In", "this", "report,", "we", "present", "the", "case", "of", "an", "adolescent", "female", "who", "initially", "presented", "with", "renal", "failure", "and", "an", "intracardiac", "mass.", "Subsequent", "work-up", "led", "to", "a", "diagnosis", "of", "granulomatosis", "with", "polyangiitis", "(GPA).", "Cardiac", "manifestations", "in", "pediatric", "GPA", "are", "not", "common;", "however,", "they", "may", "be", "more", "prevalent", "than", "reported", "given", "recent", "adult", "literature", "and", "concern", "for", "clinically", "silent", "abnormalities.", "Keywords:", "Granulomatosis", "with", "polyangiitis,", "Wegener’s", "granulomatosis,", "Intracardiac", "mass", "Background", "Granulomatosis", "with", "polyangiitis", "(GPA;", "Wegener’s", "granulo-", "matosis)", "is", "a", "systemic", "vasculitis", "characterized", "by", "acute", "nec-", "rotizing", "granulomas", "of", "the", "upper", "respiratory", "tract", "and", "lungs,", "necrotizing", "or", "granulomatous", "vasculitis", "affecting", "small", "to", "medium-sized", "vessels", "and", "pauci-immune,", "necrotiz-", "ing,", "and", "crescentic", "glomerulonephritis;", "however,", "this", "disease", "can", "affect", "virtually", "any", "organ", "system", "[1-7].", "In", "this", "report,", "we", "describe", "a", "case", "of", "GPA", "presenting", "as", "renal", "failure", "with", "discovery", "of", "an", "intracardiac", "mass", "in", "an", "adolescent", "patient.", "We", "will", "discuss", "the", "significance", "of", "this", "finding", "in", "light", "of", "re-", "cent", "literature.", "Case", "Presentation", "A", "14-year-old", "girl", "presented", "with", "a", "6-week", "history", "of", "fa-", "tigue,", "persistent", "rhinorrhea,", "and", "intermittent", "epistaxis.", "Her", "history", "was", "also", "significant", "for", "recurrent", "sinusitis,", "rash,", "decreased", "urine", "output,", "and", "myalgias.", "The", "patient", "was", "seen", "by", "her", "pediatrician", "with", "concerns", "that", "her", "nose", "was", "“col-", "lapsing.”", "Past", "medical", "history", "includes", "atopic", "dermatitis", "as", "a", "child", "and", "allergic", "rhinitis.", "", "Correspondence:", "jgharris@mcw.edu", "1Medical", "College", "of", "Wisconsin,", "Children’s", "Hospital", "of", "Wisconsin,", "Milwaukee,", "WI,", "USA", "4Children’s", "Hospital", "of", "Wisconsin,", "9000", "West", "Wisconsin", "Avenue,", "Wauwatosa,", "WI", "53226,", "USA", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "On", "admission", "to", "our", "hospital,", "the", "patient’s", 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"(MBT,", "Switzerland)", "produce", "footwear", "which", "they", "claim", "simulate", "walking", "barefoot", "on", "soft", "undulating", "ground.", "This", "paper", "reports", "an", "investigation", "into", "the", "effect", "of", "MBT", "sandals", "on", "the", "motion", "of", "the", "ankle", "and", "subtalar", "joint", "complex", "during", "walking.", "Methods:", "Range", "of", "motion", "data", "was", "collected", "in", "the", "sagittal,", "frontal", "and", "transverse", "plane", "from", "the", "ankle", "and", "subtalar", "joint", "complex", "from", "32", "asymptomatic", "subjects", "using", "the", "CODA", "MPX30", "motion", "analysis", "system", "during", "both", "barefoot", "walking", "and", "walking", "in", "the", "MBT", "sandal.", "Shod", "and", "un-shod", "data", "were", "compared", "using", "the", "Wilcoxon", "signed", "ranks", "test.", "Results:", "A", "significantly", "greater", "range", "of", "motion", "in", "the", "frontal", "and", "sagittal", "planes", "was", "recorded", "when", "walking", "in", "the", "MBT", "sandal", "(p", "=", "0.031,", "and", "p", "=", "0.015", "respectively).", "In", "the", "transverse", "plane,", "no", "significant", "difference", "was", "found", "(p", "=", "0.470).", "Conclusions:", "MBT", "sandals", "increase", "the", "range", "of", "motion", "of", "the", "ankle", "and", "subtalar", "joint", "complex", "in", "the", "frontal", "and", "sagittal", "planes.", "MBT", "footwear", "could", "therefore", "have", "a", "role", "to", "play", "in", "the", "management", "of", "musculoskeletal", "disorders", "where", "an", "increase", "in", "frontal", "and", "sagittal", "plane", "range", "of", "motion", "is", "desirable.", "Background", "With", "the", "growth", "in", "the", "health", "and", "fitness", "industry,", "sports", "footwear", "has", "shown", "technological", "advances", "and", "diversification.", "The", "introduction", "of", "footwear", "such", "as", "the", "MBT", "shoe", "(manufactured", "by", "Masai", "Barefoot", "Technolo-", "gies)", "is", "an", "example", "of", "this", "diversification.", "MBT", "have", "based", "their", "shoe", "design", "on", "observations", "of", "the", "Masai,", "a", "semi-nomadic", "tribe", "from", "Africa", "who", "are", "well", "known", "for", "their", "posture", "and", "for", "walking", "long", "distances", "on", "uneven", "terrain.", "The", "MBT", "shoe", "construction", "is", "based", "on", "a", "mid-", "sole", "pivot", "with", "a", "rounded", "sole", "in", "the", "anterior-posterior", "direction,", "and", "a", "soft", "heel", "pad.", "It", "is", "claimed", "that", "the", "effect", "of", "the", "angled", "soft", "sole", "not", "only", "creates", "anterior/", "posterior", "facilitation", "of", "movement,", "by", "purposefully", "creating", "medial", "and", "lateral", "instability", "in", "the", "shoe", "[1].", "*", "Correspondence:", "sophieroberts@thegaitlab.co.uk;", "s.otter@brighton.ac.uk", "1Outpatients", "Department,", "Parkside", "Hospital,", "53", "Parkside,", "London,", "SW19", "5NX,", "UK", "3University", "of", "Brighton,", "School", "of", "Health", "Sciences,", "49", "Darley", "Rd,", "Eastbourne,", "BN20", "7UR,", "UK", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "According", "to", "Romkes", "et", "al", "[2],", "MBT", "shoes", "have", "been", "used", "to", "treat", "foot", "problems", "such", "as", "hallux", "valgus,", "pes", "planus,", "heel", "and", "tendo-achilles", "pain", "as", "well", "as", "circula-", "tory", "problems.", "Nigg", "et", "al", "[3]", "found", "that", "MBT", "shoes", "may", "be", "useful", "as", "a", "training", "device", "for", "stability", "and", "mus-", "cle", "strengthening", "adding", "another", "dimension", "to", "their", "use.", "However,", "New", "et", "al", "[4]", "and", "Nigg", "et", "al", "[3]", "found", "that", "subjects", "from", "many", "of", "the", "studies", "conducted", "using", "MBT", "shoes", "received", "an", "instruction", "session", "in", "which", "they", "were", "taught", "how", "to", "use", "the", "shoes", "correctly", "by", "a", "qualified", "instructor", "and", "given", "a", "long", "training", "period", "to", "acclimatise", "to", "the", "shoes.", "As", "such", "there", "remains", "debate", "as", "to", "whether", "the", "reported", "changes", "in", "gait", "were", "as", "a", "result", "of", "the", "MBT", "shoe", "or", "the", "professional", "instruction", "in", "gait", "and", "posture", "the", "subjects", "received", "and", "the", "train-", "ing", "period", "they", "had", "[4].", "Nigg", "et", "al", "[3]", "described", "that", "an", "increase", "in", "the", "angle", "of", "ankle", "dorsiflexion", "in", "MBT", "shoes", "was", "evident", "com-", "pared", "to", "a", "standard", "training", "shoe.", "Vernon", "et", "al", "[5]", "also", "reported", "subjects", "exhibited", "significantly", "higher", "maxi-", "mum", "dorsiflexion", "angle", "at", "the", "ankle", "joint", "when", "wearing", "©", "2011", "Roberts", "et", 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982 ], [ 429, 983, 454, 999 ], [ 458, 983, 484, 999 ], [ 488, 983, 529, 999 ], [ 534, 983, 578, 999 ], [ 582, 983, 610, 999 ], [ 614, 983, 644, 999 ], [ 649, 983, 678, 999 ], [ 682, 983, 712, 999 ], [ 716, 983, 743, 999 ], [ 429, 1000, 485, 1016 ], [ 487, 1000, 512, 1016 ], [ 514, 1000, 539, 1016 ], [ 541, 1000, 576, 1016 ], [ 578, 1000, 622, 1016 ], [ 625, 1000, 653, 1016 ], [ 655, 1000, 683, 1016 ], [ 685, 1000, 712, 1016 ], [ 714, 1000, 742, 1016 ] ]	[ "J", "Korean", "Med", "Sci", "2008;", "23:", "146-8", "ISSN", "1011-8934", "DOI:", "10.3346/jkms.2008.23.1.146", "Copyright", "The", "Korean", "Academy", "of", "Medical", "Sciences", "Unrelated", "Bone", "Marrow", "Transplantation", "with", "a", "Reduced", "Toxicity", "Myeloablative", "Conditioning", "Regimen", "in", "Wiskott-Aldrich", "Syndrome", "Wiskott-Aldrich", "syndrome", "(WAS)", "is", "an", "X-linked", "congenital", "immune-deficiency", "syn-", "drome,", "and", "bone", "marrow", "transplantation", "(BMT)", "has", "become", "a", "curative", "modality.", "However,", "the", "transplant", "with", "the", "alternative", "donor", "needed", "more", "intensive", "condi-", "tioning", "with", "increased", "treatment-related", "toxicities.", "Recently,", "fludarabine-based", "reduc-", "ed", "toxicity", "myeloablative", "conditioning", "regimens", "have", "been", "developed", "for", "adult", "myeloid", "malignancies", "with", "promising", "results", "of", "good", "engraftment", "and", "low", "treatment-relat-", "ed", "toxicities.", "To", "increase", "the", "engraftment", "potential", "without", "serious", "complications,", "a", "boy", "with", "WAS", "received", "successful", "unrelated", "BMT", "with", "a", "reduced", "toxicity", "myeloab-", "lative", "conditioning", "regimen", "composed", "of", "fludarabine", "(40", "mg/m2", "on", "days", "-8,", "-7,", "-6,", "-5,", "-4,", "-3),", "busulfan", "(0.8", "mg/kg", "i.", "v.", "q", "6", "hr", "on", "days", "-6,", "-5,", "-4,", "-3),", "and", "thymoglobulin", "(2.5", "mg/kg", "on", "days", "-4,", "-3,", "-2).", "This", "novel", "conditioning", "regimen", "could", "improve", "the", "outcome", "of", "allogeneic", "transplantation", "for", "other", "non-malignant", "diseases", "such", "as", "congenital", "immune-deficiency", "syndromes", "or", "metabolic", "storage", "diseases.", "Key", "Words", ":", "Wiskott-Aldrich", "Syndrome;", "Bone", "Marrow", "Transplantation;", "Busulfan;", "Fludarabine", "Hyoung", "Jin", "Kang,", "Hee", "Young", "Shin,", "Sun", "Hie", "Ko,", "Jeong", "Ah", "Park,", "Eun", "Kyung", "Kim,", "Jung", "Woo", "Rhim,", "Joong", "Gon", "Kim,", "Hyo", "Seop", "Ahn", "Department", "of", "Pediatrics,", "Cancer", "Research", "Institute,", "Seoul", "National", "University", "College", "of", "Medicine,", "Seoul,", "Korea", "Received", ":", "8", "January", "2007", "Accepted", ":", "21", "February", "2007", "Address", "for", "correspondence", "Hyo", "Seop", "Ahn,", "M.D.", "Department", "of", "Pediatrics,", "Cancer", "Research", "Institute,", "Seoul", "National", "University", "College", "of", "Medicine,", "28", "Yeongeon-dong,", "Jongno-gu,", "Seoul", "110-744,", "Korea", "Tel", ":", "+82.2-2072-3625,", "Fax", ":", "+82.2-743-3455", "E-mail", ":", "hsahn@snu.ac.kr", "*This", "study", "was", "supported", "by", "grant", "of", "the", "Korea", "Health", "21", "R&D", "Project,", "Ministry", "of", "Health", "&", "Welfare,", "Republic", "of", "Korea", "(A050089).", "INTRODUCTION", "Wiskott-Aldrich", "syndrome", "(WAS)", "is", "an", "X-linked", "congen-", "ital", "immune-deficiency", "syndrome", "characterized", "by", "the", "triad", "of", "recurrent", "infection,", "eczema,", "and", "thrombocytopenia,", "and", "bone", "marrow", "transplantation", "(BMT)", "from", "an", "HLA-matched", "related", "donor", "is", "an", "effective", "treatment", "(1,", "2).", "Patients", "with-", "out", "an", "appropriate", "related", "donor", "could", "receive", "an", "alternative", "stem", "cell", "source", "such", "as", "matched", "unrelated", "donor", "or", "cord", "blood.", "However,", "the", "transplant", "with", "the", "alternative", "donor", "needed", "more", "intensive", "conditioning", "to", "overcome", "the", "hema-", "tologic", "and", "immunologic", "barrier", "with", "increased", "treatment-", "related", "toxicity.", "Recently,", "fludarabine-based", "reduced", "toxici-", "ty", "myeloablative", "conditioning", "regimens", "have", "been", "develop-", "ed", "for", "adult", "myeloid", "malignancies", "with", "promising", "results", "of", "good", "engraftment", "and", "low", "treatment", "related", "toxicities", "(3-5).", "To", "increase", "the", "engraftment", "potential", "without", "serious", "com-", "plications,", "a", "boy", "with", "WAS", "received", "BMT", "from", "a", "matched", "unrelated", "donor", "with", "a", "reduced", "toxicity", "myeloablative", "con-", "ditioning", "regimen.", "CASE", "REPORT", "A", "3-yr-old", "boy", "was", "admitted", "because", "of", "eczema,", "recurrent", "146", 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706, 1069, 719, 1086 ] ]	[ "Int.", "J.", "Mol.", "Sci.", "2011,", "12,", "4975-4990;", "doi:10.3390/ijms12084975", "OPEN", "ACCESS", "International", "Journal", "of", "Molecular", "Sciences", "ISSN", "1422-0067", "www.mdpi.com/journal/ijms", "Article", "Transient", "Co-Expression", "of", "Post-Transcriptional", "Gene", "Silencing", "Suppressors", "for", "Increased", "in", "Planta", "Expression", "of", "a", "Recombinant", "Anthrax", "Receptor", "Fusion", "Protein", "Lucas", "Arzola", "1,", "Junxing", "Chen", "1,", "Kittipong", "Rattanaporn", "1,", "James", "M.", "Maclean", "2", "and", "Karen", "A.", "McDonald", "1,", "1", "Department", "of", "Chemical", "Engineering", "and", "Materials", "Science,", "University", "of", "California,", "Davis,", "One", "Shields", "Ave,", "Davis,", "CA", "95616,", "USA;", "E-Mails:", "larzola@ucdavis.edu", "(L.A.);", "cicchen@ucdavis.edu", "(J.C.);", "krattanaporn@ucdavis.edu", "(K.R.)", "2", "Planet", "Biotechnology", "Inc.,", "25571", "Clawiter", "Road,", "Hayward,", "CA", "94545,", "USA;", "E-Mail:", "jmaclean@planetbiotechnology.com", "", "Author", "to", "whom", "correspondence", "should", "be", "addressed;", "E-Mail:", "kamcdonald@ucdavis.edu;", "Tel.:", "+1-530-752-1979;", "Fax:", "+1-530-752-8058.", "Received:", "1", "April", "2011;", "in", "revised", "form:", "18", "June", "2011", "/", "Accepted:", "20", "July", "2011", "/", "Published:", "5", "August", "2011", "Abstract:", "Potential", "epidemics", "of", "infectious", "diseases", "and", "the", "constant", "threat", "of", "bioterrorism", "demand", "rapid,", "scalable,", "and", "cost-efficient", "manufacturing", "of", "therapeutic", "proteins.", "Molecular", "farming", "of", "tobacco", "plants", "provides", "an", "alternative", "for", "the", "recombinant", "production", "of", "therapeutics.", "We", "have", "developed", "a", "transient", "production", "platform", "that", "uses", "Agrobacterium", "infiltration", "of", "Nicotiana", "benthamiana", "plants", "to", "express", "a", "novel", "anthrax", "receptor", "decoy", "protein", "(immunoadhesin),", "CMG2-Fc.", "This", "chimeric", "fusion", "protein,", "designed", "to", "protect", "against", "the", "deadly", "anthrax", "toxins,", "is", "composed", "of", "the", "von", "Willebrand", "factor", "A", "(VWA)", "domain", "of", "human", "capillary", "morphogenesis", "2", "(CMG2),", "an", "effective", "anthrax", "toxin", "receptor,", "and", "the", "Fc", "region", "of", "human", "immunoglobulin", "G", "(IgG).", "We", "evaluated,", "in", "N.", "benthamiana", "intact", "plants", "and", "detached", "leaves,", "the", "expression", "of", "CMG2-Fc", "under", "the", "control", "of", "the", "constitutive", "CaMV", "35S", "promoter,", "and", "the", "co-expression", "of", "CMG2-Fc", "with", "nine", "different", "viral", "suppressors", "of", "post-transcriptional", "gene", "silencing", "(PTGS):", "p1,", "p10,", "p19,", "p21,", "p24,", "p25,", "p38,", "2b,", "and", "HCPro.", "Overall,", "transient", "CMG2-Fc", "expression", 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"De´veloppement’’,", "CNRS", "URA", "2578,", "Institut", "Pasteur,", "Paris,", "France,", "4", "INSERM,", "U841,", "Team", "10,", "Cre´teil,", "France,", "5", "AP-HP,", "Groupe", "Hospitalier", "Albert", "Chenevier-Henri", "Mondor,", "De´partement", "de", "Pathologie,", "Cre´teil,", "France,", "6", "Universite´", "Paris", "XII,", "Faculte´", "de", "Me´decine,", "Cre´teil,", "France,", "7", "Groupe", "‘‘Immunobiologie", "des", "Cellules", "Dendritiques’’,", "Institut", "Pasteur,", "Paris,", "France,", "8", "INSERM", "U818,", "Paris,", "France,", "9", "Unite´", "‘‘Interactions", "Bacte´ries-Cellules’’,", "Institut", "Pasteur,", "Paris,", "France,", "10", "De´partement", "de", "Gyne´cologie", "et", "Obste´trique,", "Groupe", "Hospitalier", "Sud-Re´union,", "Saint-Pierre,", "La", "Re´union,", "France,", "11", "Plateforme", "de", "Microscopie", "Ultrastructurale,", "Institut", "Pasteur,", "Paris,", "France,", "12", "Centre", "National", "de", "Re´fe´rence", "des", "Arbovirus,", "Institut", "Pasteur", "Lyon,", "France,", "13", "Unite´", "‘‘Interactions", "Mole´culaires", "Flavivirus-Hoˆtes’’,", "Institut", "Pasteur,", "Paris,", "France,", "14", "Laboratoire", "‘‘Pathoge´nie", "Virale", "Mole´culaire’’,", "Institut", "Pasteur,", "Paris,", "France,", "15", "CNRS", "URA", "3015,", "Paris,", "France,", "16", "Laboratoire", "de", "Microbiologie,", "Groupe", "Hospitalier", "Sud-Re´union,", "Saint-Pierre,", "Ile", "de", "la", "Re´union,", "France,", "17", "Centre", "d’Infectiologie", "Necker-Pasteur,", "Hoˆ", "pital", "Necker-Enfants", "malades,", "Assistance", "Publique-Hoˆpitaux", "de", "Paris,", "Universite´", "Paris", "Descartes,", "Paris,", "France", "Chikungunya", "virus", "(CHIKV)", "is", "a", "re-emerging", "arbovirus", "responsible", "for", "a", "massive", "outbreak", "currently", "afflicting", "the", "Indian", "Ocean", "region", "and", "India.", "Infection", "from", "CHIKV", "typically", "induces", "a", "mild", "disease", "in", "humans,", "characterized", "by", "fever,", "myalgia,", "arthralgia,", "and", "rash.", "Cases", "of", "severe", "CHIKV", "infection", "involving", "the", "central", "nervous", "system", "(CNS)", "have", "recently", "been", "described", "in", "neonates", "as", "well", "as", "in", "adults", "with", "underlying", "conditions.", "The", "pathophysiology", "of", "CHIKV", "infection", "and", "the", "basis", "for", "disease", "severity", "are", "unknown.", "To", "address", "these", "critical", "issues,", "we", "have", "developed", "an", "animal", "model", "of", "CHIKV", "infection.", "We", "show", "here", "that", "whereas", "wild", "type", "(WT)", "adult", "mice", "are", "resistant", "to", "CHIKV", "infection,", "WT", "mouse", "neonates", "are", "susceptible", "and", "neonatal", "disease", "severity", "is", "age-dependent.", "Adult", "mice", "with", "a", "partially", "(IFN-a/bRþ/", ")", "or", "totally", "(IFN-a/bR", "/", ")", "abrogated", "type-I", "IFN", "pathway", "develop", "a", "mild", "or", "severe", "infection,", "respectively.", "In", "mice", "with", "a", "mild", "infection,", "after", "a", "burst", "of", "viral", "replication", "in", "the", "liver,", "CHIKV", "primarily", "targets", "muscle,", "joint,", "and", "skin", "fibroblasts,", "a", "cell", "and", "tissue", "tropism", "similar", "to", "that", "observed", "in", "biopsy", "samples", "of", "CHIKV-infected", "humans.", "In", "case", "of", "severe", "infections,", "CHIKV", "also", "disseminates", "to", "other", "tissues", "including", "the", "CNS,", "where", "it", "specifically", "targets", "the", "choroid", "plexuses", "and", "the", "leptomeninges.", "Together,", "these", "data", "indicate", "that", "CHIKV-associated", "symptoms", "match", "viral", "tissue", "and", "cell", "tropisms,", "and", "demonstrate", "that", "the", "fibroblast", "is", "a", "predominant", "target", "cell", "of", "CHIKV.", "These", "data", "also", "identify", "the", "neonatal", "phase", "and", "inefficient", "type-I", "IFN", "signaling", "as", "risk", "factors", "for", "severe", "CHIKV-associated", "disease.", "The", "development", "of", "a", "permissive", "small", "animal", "model", "will", "expedite", "the", "testing", "of", "future", "vaccines", "and", "therapeutic", "candidates.", "Citation:", "Couderc", "T,", "Chre´tien", "F,", "Schilte", "C,", "Disson", "O,", "Brigitte", "M,", "et", "al.", "(2008)", "A", "mouse", "model", "for", "Chikungunya:", "young", "age", "and", "inefficient", "type-I", "interferon", "signaling", "are", "risk", "factors", "for", "severe", "disease.", "PLoS", "Pathog", "4(2):", "e29.", "doi:10.1371/journal.ppat.0040029", "Introduction", "Chikungunya", "virus", "(CHIKV)", "was", "ﬁrst", "isolated", "in", "Tanzania", "in", "1953", "[1],", "and", "has", "recently", "emerged", "in", "islands", "of", "the", "Indian", "Ocean", "in", "2005,", "and", "engendered", "the", "largest", "Chikungunya", "fever", "epidemic", "on", "record", "[2].", "The", "most", "affected", "region", "was", "the", "island", "of", "La", "Re´", "union,", "where", "CHIKV", "infected", "approx-", "imately", "a", "third", "of", "the", "island’s", "inhabitants", "(i.e.,", ";300,000)", "[3–", "5].", "The", "outbreak,", "which", "now", "also", "involves", "India", "with", "an", "estimated", "1.3", "million", "cases", "[6–8],", "has", "a", "signiﬁcant", "potential", "to", "spread", "globally", "given", "the", "wide", "distribution", "of", "its", "arthropod", "vector", "[9,10].", "CHIKV", "is", "a", "member", "of", "the", "genus", "Alphavirus", "in", "the", "family", "of", "Togaviridae.", "Alphaviruses", "are", "small,", "enveloped", "viruses", "with", "a", "message-sense", "RNA", "genome", "that", "encodes", "four", "non-structural", "proteins", "(nsP1–4)", "and", "three", "structural", "proteins", "(C,", "E1–2).", "This", "arbovirus", "is", "maintained", "in", "nature", "by", "uninterrupted", "cycles", "of", "transmission", "between", "mosquitoes", "and", "vertebrate", "hosts", "such", "as", "macaques", "[11–13].", "Several", "alphaviruses", "cause", "disease", "in", "humans,", "primarily", "as", "a", "result", "of", "epizootic", "infections.", "These", "include", "the", "American", "encephalitic", "alphavi-", "ruses", "and", "several", "species", "in", "the", "Semliki", "Forest", "Virus", "group,", "principally", "the", "Afro-Asian", "CHIKV,", "the", "African", "O’Nyong-", "Nyong", "virus,", "as", "well", "as", "the", "Australasian", "Barmah", "Forest", "virus", "and", "Ross", "River", "virus", "[14].", "CHIKV", "infection", "is", "characterized", "by", "fever,", "arthralgia,", "myalgia,", "rash", "and", "headache.", "During", "the", "La", "R", "e´union", "Island", "outbreak,", "previously", "unreported", "severe", "forms", "of", "Chikungunya", "infection", "were", "observed", "in", "adults,", "compli-", "Editor:", "Michael", "J.", "Buchmeier,", "The", "Scripps", "Research", "Institute,", "United", "States", "of", "America", "Received", "August", "24,", "2007;", "Accepted", "December", "28,", "2007;", "Published", "February", "15,", "2008", "Copyright:", "2008", "Couderc", "et", "al.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Abbreviations:", "BBB,", "blood-brain", "barrier;", "CNS,", "central", "nervous", "system;", "CSF,", "cerebrospinal", "fluid;", "D,", "day;", "DAB,", "diaminobenzidine;", "HRP,", "horseradish-peroxidase;", "ID,", "intra-dermal;", "IFN-a/bR,", "IFN-a/b", "receptor;", "LD50,", "lethal", "dose", "50;", "MOI,", "multiplicity", "of", "infection;", "pi,", "post", "infection;", "TCID50,", "tissue", "cytopathic", "infectious", "dose", "50", "", "To", "whom", "correspondence", "should", "be", "addressed.", "E-mail:", "mlecuit@pasteur.fr", "[", "These", "authors", "contributed", "equally", "to", "this", "work.", "PLoS", "Pathogens", "\|", "www.plospathogens.org", "0001", "February", "2008", "\|", "Volume", "4", "\|", "Issue", "2", "\|", "e29" ]	[ 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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[ 680, 987, 688, 997 ], [ 690, 987, 703, 997 ], [ 706, 987, 737, 997 ], [ 248, 998, 287, 1008 ], [ 289, 998, 330, 1008 ], [ 333, 998, 361, 1008 ], [ 364, 998, 535, 1008 ], [ 538, 998, 561, 1008 ], [ 564, 998, 593, 1008 ], [ 595, 998, 640, 1008 ], [ 643, 998, 658, 1008 ], [ 660, 998, 705, 1008 ], [ 708, 998, 723, 1008 ], [ 248, 1009, 297, 1019 ], [ 300, 1009, 307, 1019 ], [ 310, 1009, 324, 1019 ], [ 326, 1009, 360, 1019 ], [ 362, 1009, 396, 1019 ], [ 399, 1009, 412, 1019 ], [ 415, 1009, 443, 1019 ], [ 446, 1009, 465, 1019 ], [ 467, 1009, 473, 1019 ], [ 476, 1009, 508, 1019 ], [ 510, 1009, 530, 1019 ] ]	[ "Ratnapalan", "et", "al.", "BMC", "Medical", "Ethics", "2010,", "11:1", "http://www.biomedcentral.com/1472-6939/11/1", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Documentation", "of", "best", "interest", "by", "intensivists:", "a", "retrospective", "study", "in", "an", "Ontario", "critical", "care", "unit", "Mohana", "Ratnapalan1,", "Andrew", "B", "Cooper2,3,", "Damon", "C", "Scales3,4,", "Ruxandra", "Pinto4", "Abstract", "Background:", "Intensive", "care", "physicians", "often", "must", "rely", "on", "substitute", "decision", "makers", "to", "address", "all", "dimensions", "of", "the", "construct", "of", "“best", "interest”", "for", "incapable,", "critically", "ill", "patients.", "This", "task", "involves", "identifying", "prior", "wishes", "and", "to", "facilitate", "the", "substitute", "decision", "maker’s", "understanding", "of", "the", "incapable", "patient’s", "condition", "and", "their", "likely", "response", "to", "treatment.", "We", "sought", "to", "determine", "how", "well", "such", "discussions", "are", "documented", "in", "a", "typical", "intensive", "care", "unit.", "Methods:", "Using", "a", "quality", "of", "communication", "instrument", "developed", "from", "a", "literature", "search", "and", "expert", "opinion,", "2", "investigators", "transcribed", "and", "analyzed", "260", "handwritten", "communications", "for", "105", "critically", "ill", "patients", "who", "died", "in", "the", "intensive", "care", "unit", "between", "January", "and", "June", "2006.", "Cohen’s", "kappa", "was", "calculated", "before", "analysis", "and", "then", "disagreements", "were", "resolved", "by", "consensus.", "We", "report", "results", "on", "a", "per-patient", "basis", "to", "represent", "documented", "communication", "as", "a", "process", "leading", "up", "to", "the", "time", "of", "death", "in", "the", "ICU.", "We", "report", "frequencies", "and", "percentages", "for", "discrete", "data,", "median", "(m)", "and", "interquartile", "range", "(IQR)", "for", "continuous", "data.", "Results:", "Our", "cohort", "was", "elderly", "(m", "72,", "IQR", "58-81", "years)", "and", "had", "high", "APACHE", "II", "scores", "predictive", "of", "a", "high", "probability", "of", "death", "(m", "28,", "IQR", "23-36).", "Length", "of", "stay", "in", "the", "intensive", "care", "unit", "prior", "to", "death", "was", "short", "(m", "2,", "IQR", "1-5", "days),", "and", "withdrawal", "of", "life", "support", "preceded", "death", "for", "more", "than", "half", "(n", "57,", "54%).", "Brain", "death", "criteria", "were", "present", "for", "18", "patients", "(17%).", "Although", "intensivists’", "communications", "were", "timely", "(median", "17", "h", "from", "admission", "to", "critical", "care),", "the", "person", "consenting", "on", "behalf", "of", "the", "incapable", "patient", "was", "explicitly", "documented", "for", "only", "10%", "of", "patients.", "Life", "support", "strategies", "at", "the", "time", "of", "communication", "were", "noted", "in", "45%", "of", "charts,", "and", "options", "for", "their", "future", "use", "were", "presented", "in", "88%.", "Considerations", "relevant", "to", "determining", "the", "patient’s", "best", "interest", "in", "relation", "to", "the", "treatment", "plan", "were", "not", "well", "documented.", "While", "explicit", "survival", "estimates", "were", "noted", "in", "50%", "of", "charts,", "physicians", "infrequently", "documented", "their", "own", "predictions", "of", "the", "patient’s", "functional", "status", "(20%),", "anticipated", "need", "for", "chronic", "care", "(0%),", "or", "post", "ICU", "quality", "of", "life", "(3%).", "Similarly,", "documentation", "of", "the", "patient’s", "own", "perspectives", "on", "these", "ranged", "from", "2-18%.", "Conclusions:", "Intensivists’", "documentation", "of", "their", "communication", "with", "substitute", "decision", "makers", "frequently", "outlined", "the", "proposed", "plan", "of", "treatment,", "but", "often", "lacked", "evidence", "of", "discussion", "relevant", "to", "whether", "the", "treatment", "plan", "was", "expected", "to", "improve", "the", "patient’s", "condition.", "Legislative", "standards", "for", "determination", "of", "best", "interest,", "such", "as", "the", "Health", "Care", "Consent", "Act", "in", "Ontario,", "Canada,", "may", "provide", "guidance", "for", 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"University", "of", "Giessen,", "Giessen,", "Germany,", "2", "Institute", "of", "Biochemistry", "II,", "University", "Clinic", "of", "Frankfurt,", "Frankfurt", "am", "Main,", "Germany", "Abstract", "Fibroblast", "growth", "factor", "receptor", "substrate", "2", "(FRS2a)", "is", "a", "signaling", "adaptor", "protein", "that", "regulates", "downstream", "signaling", "of", "many", "receptor", "tyrosine", "kinases.", "During", "signal", "transduction,", "FRS2", "can", "be", "both", "tyrosine", "and", "threonine", "phosphorylated", "and", "forms", "signaling", "complexes", "with", "other", "adaptor", "proteins", "and", "tyrosine", "phosphatases.", "We", "have", "here", "identified", "flotillin-1", "and", "the", "cbl-associated", "protein/ponsin", "(CAP)", "as", "novel", "interaction", "partners", "of", "FRS2.", "Flotillin-1", "binds", "to", "the", "phosphotyrosine", "binding", "domain", "(PTB)", "of", "FRS2", "and", "competes", "for", "the", "binding", "with", "the", "fibroblast", "growth", "factor", "receptor.", "Flotillin-1", "knockdown", "results", "in", "increased", "Tyr", "phosphorylation", "of", "FRS2,", "in", "line", "with", "the", "inhibition", "of", "ERK", "activity", "in", "the", "absence", "of", "flotillin-1.", "CAP", "directly", "interacts", "with", "FRS2", "by", "means", "of", "its", "sorbin", "homology", "(SoHo)", "domain,", "which", "has", "previously", "been", "shown", "to", "interact", "with", "flotillin-1.", "In", "addition,", "the", "third", "SH3", "domain", "in", "CAP", "binds", "to", "FRS2.", "Due", "to", "the", "overlapping", "binding", "domains,", "CAP", "and", "flotillin-1", "appear", "to", "compete", "for", "the", "binding", "to", "FRS2.", "Thus,", "our", "results", "reveal", "a", "novel", "signaling", "network", "containing", "FRS2,", "CAP", "and", "flotillin-1,", "whose", "successive", "interactions", "are", "most", "likely", "required", "to", "regulate", "receptor", "tyrosine", "kinase", "signaling,", "especially", "the", "mitogen", "activated", "protein", "kinase", "pathway.", "Citation:", "Tomasovic", "A,", "Traub", "S,", "Tikkanen", "R", "(2012)", "Molecular", "Networks", "in", "FGF", "Signaling:", "Flotillin-1", "and", "Cbl-Associated", "Protein", "Compete", "for", "the", "Binding", "to", "Fibroblast", "Growth", "Factor", "Receptor", "Substrate", "2.", "PLoS", "ONE", "7(1):", "e29739.", "doi:10.1371/journal.pone.0029739", "Editor:", "Henning", "Ulrich,", "University", "of", "Sa˜o", "Paulo,", "Brazil", "Received", "July", "12,", "2011;", "Accepted", "December", "4,", "2011;", "Published", "January", "3,", "2012", "Copyright:", "2012", "Tomasovic", "et", "al.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Funding:", "Funds", "were", "received", "from", "Deutsche", "Forschungsgemeinschaft", "DFG", "(www.dfg.de),", "personal", "grant", "to", "RT", "(Ti", "291/6-1).", "The", "funders", "had", "no", "role", "in", "study", "design,", "data", "collection", "and", "analysis,", "decision", "to", "publish,", "or", "preparation", "of", "the", "manuscript.", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "", "E-mail:", "Ritva.Tikkanen@biochemie.med.uni-giessen.de", "¤", "Current", "address:", "Dermatology,", "University", "Clinic", "of", "Cologne,", "Cologne,", "Germany", "Introduction", "Fibroblast", "growth", "factor", "receptor", "substrate", "2", "(FRS2/FRS2a/", "SNT1)", "is", "a", "membrane", "linked", "docking", "protein", "originally", "identified", "as", "a", "protein", "that", "becomes", "tyrosine", "phosphorylated", "upon", "nerve", "growth", "factor", "(NGF)", "or", "fibroblast", "growth", "factor", "(FGF)", "stimulation", "in", "PC12", "cells", "[1,2,3].", "Together", "with", "FGF", "receptor", "substrate", "3", "(FRS3/FRS2b/SNT2),", "it", "belongs", "to", "the", "FRS", "adaptor", "protein", "family", "[4].", "In", "this", "paper,", "we", "will", "use", "the", "name", "FRS2", "for", "FRS2a/", "SNT1,", "and", "FRS3", "for", "FRS2b/SNT2", "for", "the", "sake", "of", "clarity.", "FRS2", "and", "FRS3", "share", "a", "similar", "structure", "and", "48%", "of", "amino", "acid", "sequence", "identity.", "In", "the", "N-terminus,", "they", "contain", "a", "consensus", "myristoylation", "sequence", "which", "is", "important", "for", "the", "membrane", "localization", "[1].", "This", "sequence", "is", "followed", "by", "a", "phosphotyrosine", "binding", "(PTB)", "domain", "that", "is", "highly", "similar", "between", "the", "two", "proteins.", "The", "PTB", "domain", "binds", "specific", "peptides", "of", "certain", "receptor", "tyrosine", "kinases", "(RTKs)", "with", "or", "without", "tyrosine", "phosphorylated", "residues", "[5,6].", "FRS2", "is", "ubiquitously", "expressed", "with", "the", "highest", "expression", "in", "brain,", "kidney,", "lung,", "ovary", "and", "testis", "and", "can", "be", "detected", "at", "all", "developmental", "stages", "of", "a", "mouse", "[7].", "FRS2", "knockout", "mice", "show", "embryonic", "lethality", "due", "to", "severe", "problems", "in", "gastrulation", "[8,9],", "demonstrating", "how", "crucial", "FGF", "signaling", "is", "in", "animal", "development.", "In", "contrast", "to", "FRS2,", "the", "expression", "of", "FRS3", "protein", "begins", "around", "day", "9", "and", "is", "restricted", "to", "tissues", "of", "neuronal", "origin", "[7,10].", "When", "exogenously", "expressed", "in", "FRS2-null", "mouse", "embryonic", "fibroblasts,", "FRS3", "compensates", "for", "the", "loss", "of", "FRS2", "by", "stimulating", "FGF", "induced", "activation", "of", "extracellularly", "regulated", "kinase", "(ERK),", "a", "member", "of", "the", "mitogen", "activated", "protein", "(MAP)", "kinase", "family", "[10].", "Both", "FRS2", "and", "FRS3", "are", "tyrosine", "phosphorylated", "in", "response", "to", "NGF,", "FGF", "[9,11]", "and", "glial", "derived", "neurotrophic", "factor", "(GDNF)", "[12,13],", "but", "only", "FRS2", "is", "threonine", "phosphorylated.", "Phosphor-", "ylation", "of", "8", "threonine", "residues", "in", "FRS2", "occurs", "as", "a", "response", "to", "stimulation", "with", "FGF,", "epidermal", "growth", "factor", "(EGF),", "insulin", "and", "platelet", "derived", "growth", "factor", "(PDGF).", "This", "represents", "a", "negative", "feedback", "mechanism", "in", "which", "activated", "ERK", "inhibits", "further", "tyrosine", "phosphorylation", "of", "FRS2", "by", "phosphorylating", "its", "threo-", "nine", "residues", "[14,15].", "FRS2", "plays", "an", "important", "role", "in", "FGF", "dependent", "proliferation", "and", "migration", "of", "the", "cells", "[1]", "and", "in", "differentiation", "of", "PC12", "cells", "by", 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253, 1010, 261, 1020 ], [ 262, 1010, 277, 1020 ], [ 278, 1010, 313, 1020 ], [ 314, 1010, 349, 1020 ], [ 351, 1010, 364, 1020 ], [ 366, 1010, 396, 1020 ], [ 397, 1010, 417, 1020 ], [ 418, 1010, 424, 1020 ], [ 426, 1010, 459, 1020 ], [ 461, 1010, 482, 1020 ] ]	[ "Hermsdorff", "et", "al.", "Nutrition", "&", "Metabolism", "2010,", "7:42", "http://www.nutritionandmetabolism.com/content/7/1/42", "R", "E", "S", "E", "A", "R", "C", "H", "Open", "Access", "RFerseuaricth", "and", "vegetable", "consumption", "and", "proinflammatory", "gene", "expression", "from", "peripheral", "blood", "mononuclear", "cells", "in", "young", "adults:", "a", "translational", "study", "Helen", "Hermana", "M", "Hermsdorff,", "María", "Ángeles", "Zulet,", "Blanca", "Puchau", "and", "José", "Alfredo", "Martínez", "Abstract", "Background:", "Fruits", "and", "vegetables", "are", "important", "sources", "of", "fiber", "and", "nutrients", "with", "a", "recognized", "antioxidant", "capacity,", "which", "could", "have", "beneficial", "effects", "on", "the", "proinflammatory", "status", "as", "well", "as", "some", "metabolic", "syndrome", "and", "cardiovascular", "disease", "features.", "The", "current", "study", "assessed", "the", "potential", "relationships", "of", "fruit", "and", "vegetable", "consumption", "with", "the", "plasma", "concentrations", "and", "mRNA", "expression", "values", "of", "some", "proinflammatory", "markers", "in", "young", "adults.", "Methods:", "One-hundred", "and", "twenty", "healthy", "subjects", "(50", "men/70", "women;", "20.8", "±", "2.6", "y;", "22.3", "±", "2.8", "kg/m2)", "were", "enrolled.", "Experimental", "determinations", "included", "anthropometry,", "blood", "pressure", "and", "lifestyle", "features", "as", "well", "as", "blood", "biochemical", "and", "inflammatory", "measurements.", "The", "mRNA", "was", "isolated", "from", "peripheral", "blood", "mononuclear", "cells", "(PBMC)", "and", "the", "gene", "expression", "concerning", "selected", "inflammatory", "markers", "was", "assessed", "by", "quantitative", "real-time", "PCR.", "Nutritional", "intakes", "were", "estimated", "by", "a", "validated", "semi-quantitative", "food-frequency", "questionnaire.", "Results:", "The", "highest", "tertile", "of", "energy-adjusted", "fruit", "and", "vegetable", "consumption", "(>660", "g/d)", "was", "associated", "with", "lower", "plasma", "concentrations", "of", "C-reactive", "protein", "(CRP)", "and", "homocysteine", "and", "with", "lower", "ICAM1,", "IL1R1,", "IL6,", "TNFα", "and", "NFκB1", "gene", "expression", "in", "PBMC", "(P", "for", "trend", "<", "0.05),", "independently", "of", "gender,", "age,", "energy", "intake,", "physical", "activity,", "smoking,", "body", "mass", "index,", "systolic", "blood", "pressure", "and", "circulating", "non-esterified", "fatty", "acids.", "In", "addition,", "plasma", "CRP,", "homocysteine", "and", "TNFα", "concentrations", "and", "ICAM1,", "TNFα", "and", "NFκB1", "gene", "expression", "in", "PBMC", "showed", "a", "descending", "trend", "as", "increased", "fiber", "intake", "(>19.5", "g/d)", "from", "fruits", "and", "vegetables", "(P", "for", "trend", "<", "0.05).", "Furthermore,", "the", "participants", "within", "the", "higher", "tertile", "(>11.8", "mmol/d)", "of", "dietary", "total", "antioxidant", "capacity", "showed", "lower", "plasma", "CRP", "and", "mRNA", "values", "of", "ICAM1,", "IL1R1,", "IL6,", "TNFα", "and", "NFκB1", "genes", "(P", "for", "trend", "<", "0.05).", "The", "inverse", "association", "between", "fruit", "and", "vegetable", "consumption", "and", "study", "proinflammatory", "markers", "followed", "the", "same", "trend", "and", "remained", "statistically", "significant,", "after", "the", "inclusion", "of", "other", "foods/nutrients", "in", "the", "linear", "regression", "models.", "Conclusion:", "A", "higher", "fruit", "and", "vegetable", "consumption", "was", "independently", "associated", "not", "only", "with", "reduced", "CRP", "and", "homocysteine", "concentrations", "but", "also", "with", "a", "lower", "mRNA", "expression", "in", "PBMC", "of", "some", "relevant", "proinflammatory", "markers", "in", "healthy", "young", "adults.", "Background", "A", "low-chronic", "inflammatory", "status", "is", "a", "recognized", "link", "between", "excessive", "adiposity", "and", "metabolic", "syndrome", "fea-", "tures,", "diabetes,", "and", "atherosclerosis", "[1,2].", "In", "fact,", "a", "num-", "ber", "of", "studies", "has", "demonstrated", "an", "increased", "expression", "", "Correspondence:", "jalfmtz@unav.es", "1", "Department", "of", "Nutrition,", "Food", "Science,", "Physiology", "and", "Toxicology,", "University", "of", "Navarra,", "Pamplona,", "Spain", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "of", "transcription", "nuclear", "factors", "such", "as", "nuclear-factor-", "kappa-B", "(NFκB)", "as", "well", "as", "of", "interleukins", "(IL)", "and", "tumor", "necrosis", 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998, 392, 1008 ], [ 394, 998, 565, 1008 ], [ 567, 998, 590, 1008 ], [ 592, 998, 621, 1008 ], [ 623, 998, 668, 1008 ], [ 670, 998, 685, 1008 ], [ 686, 998, 731, 1008 ], [ 733, 998, 748, 1008 ], [ 248, 1009, 297, 1019 ], [ 300, 1009, 307, 1019 ], [ 310, 1009, 324, 1019 ], [ 326, 1009, 360, 1019 ], [ 362, 1009, 396, 1019 ], [ 399, 1009, 412, 1019 ], [ 415, 1009, 443, 1019 ], [ 446, 1009, 465, 1019 ], [ 467, 1009, 473, 1019 ], [ 476, 1009, 508, 1019 ], [ 510, 1009, 530, 1019 ] ]	[ "IMMUNOME", "RESEARCH", "Open", "Access", "EL-Manzalawy", "and", "Honavar", "Immunome", "Research", "2010,", "6(Suppl", "2):S2", "http://www.immunome-research.com/content/6/S2/S2", "R", "E", "V", "I", "E", "W", "Abstract", "Recent", "advances", "in", "B-cell", "epitope", "prediction", "methods", "Yasser", "EL-Manzalawy1,2,", "Vasant", "Honavar2", "Identification", "of", "epitopes", "that", "invoke", "strong", "responses", "from", "B-cells", "is", "one", "of", "the", "key", "steps", "in", "designing", "effective", "vaccines", "against", "pathogens.", "Because", "experimental", "determination", "of", "epitopes", "is", "expensive", "in", "terms", "of", "cost,", "time,", "and", "effort", "involved,", "there", "is", "an", "urgent", "need", "for", "computational", "methods", "for", "reliable", "identification", "of", "B-cell", "epitopes.", "Although", "several", "computational", "tools", "for", "predicting", "B-cell", "epitopes", "have", "become", "available", "in", "recent", "years,", "the", "pre-", "dictive", "performance", "of", "existing", "tools", "remains", "far", "from", "ideal.", "We", "review", "recent", "advances", "in", "computational", "methods", "for", "B-cell", "epitope", "prediction,", "identify", "some", "gaps", "in", "the", "current", "state", "of", "the", "art,", "and", "outline", "some", "promising", "direc-", "tions", "for", "improving", "the", "reliability", "of", "such", "methods.", "Review", "Antigen-antibody", "interactions", "play", "a", "pivotal", "role", "in", "the", "humoral", "immune", "response.", "Antibodies", "bind", "to", "antigens", "at", "specific", "sites", "which", "correspond", "to", "the", "antigenic", "deter-", "minants", "or", "B-cell", "epitopes.", "Identification", "and", "characteri-", "zation", "of", "B-cell", "epitopes", "in", "target", "antigens", "is", "one", "of", "the", "key", "steps", "in", "epitope-driven", "vaccine", "design,", "immunodiag-", "nostic", "tests,", "and", "antibody", "production.", "B-cell", "epitopes", "typically", "belong", "to", "one", "of", "two", "classes:", "linear", "(continuous", "or", "sequential)", "epitopes", "or", "conformational", "(discontinu-", "ous)", "epitopes.", "Linear", "epitopes", "are", "short", "peptides", "that", "correspond", "to", "a", "contiguous", "amino", "acid", "sequence", "frag-", "ment", "of", "a", "protein", "[1,2].", "Linear", "epitopes", "are", "usually", "iden-", "tified", "using", "assays", "such", "as", "PEPSCAN.", "Consequently,", "current", "experimental", "methods", "offer", "little", "direct", "evidence", "indicating", "that", "each", "residue", "in", "the", "epitope", "does", "in", "fact", "make", "contact", "with", "one", "or", "more", "residues", "in", "the", "paratope", "(the", "part", "in", "the", "antibody", "that", "binds", "to", "the", "antigen)", "[3].", "Conformational", "epitopes", "are", "composed", "of", "amino", "acids", "that", "although", "not", "contiguous", "in", "primary", "sequence,", "are", "brought", "into", "close", "proximity", "within", "the", "folded", "3-dimen-", "sional", "protein", "structure.", "Most", "B-cell", "epitopes,", "although", "they", "are", "composed", "of", "short", "linear", "peptides,", "appear", "to", "be", "conformational", "epitopes.", "*", "Correspondence:", "yasser@iastate.edu;", "honavar@iastate.edu", "1Department", "of", "Systems", "and", "Computer", "Engineering,", "Al-Azhar", "University,", "Egypt", "2Department", "of", "Computer", "Science,", "Artificial", "Intelligence", "Research", "Laboratory,", "Center", "for", "Computational", "Intelligence,", "Learning,", "and", "Discovery,", "Iowa", "State", "University,", "USA", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "Several", "experimental", "techniques", "are", "currently", "available", "for", "experimental", "mapping", "of", "B-cell", "epitopes", "[4].", "How-", "ever,", "the", "high", "cost", "and", "effort", "involved", "makes", "them", "impractical", "for", "application", "on", "a", "genomic", "scale.", "Compu-", "tational", "techniques", "offer", "a", "fast,", "scalable,", "and", "cost-effec-", "tive", "approach", "for", "predicting", "B-cell", "epitopes,", "for", "focusing", "experimental", "investigations", "and", "for", "improving", "our", "understanding", "of", "antigen-antibody", "interactions.", "Hence,", "there", "is", "a", "growing", "interest", "in", "the", "development", "of", "sophis-", "ticated", "computational", "tools", "for", "reliable", "prediction", "of", "B-cell", "epitopes.", "Several", "computational", "methods", "for", "B-cell", "epitope", "pre-", "diction", "have", "been", "developed", "in", "recent", "years", "(e.g.,", "[5-14]).", "However,", "the", "predictive", "performance", "of", "current", "methods", "is", "far", "from", "ideal", "[15].", "To", "complicate", "matters,", "immunogenicity", "of", "proteins", "is", "poorly", "understood", "[16]", "and", "whether", "B-cell", "epitopes", "could", "be", "deciphered", "as", "an", "intrinsic", "features", "of", "the", "protein", "remains", "an", "open", "ques-", "tion", "[17].", "Recent", "studies", "have", "pointed", "out", "some", "of", "the", "limitations", "of", "current", "epitope", "prediction", "methods", "[6,17,18].", "Hence,", "increasing", "the", "reliability", "of", "computa-", "tional", "methods", "for", "B-cell", "epitope", "prediction", "remains", "a", "major", "challenge", "in", "computational", "vaccinology", "[19].", "In", "2007,", "the", "National", "Institute", "of", "Allergy", "and", "Infectious", "Diseases", "(NIAID)", "sponsored", "a", "workshop", "and", "a", "meeting", "of", "a", "panel", "of", "immunologists", "and", "bioinformaticians", "in", "order", "to", "assess", "the", "current", "state", "of", "the", "art", "in", "epitope", "prediction", "and", "to", "identify", "some", "areas", "for", "further", "research", "[15].", "One", "of", "the", "key", "goals", "of", "the", "workshop", "was", "to", "facilitate", "and", "expedite", "the", "development", "of", "improved", "©", "2010", "EL-Manzalawy", "and", "Honavar;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", 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997 ], [ 500, 987, 521, 997 ], [ 524, 987, 549, 997 ], [ 552, 987, 575, 997 ], [ 577, 987, 618, 997 ], [ 621, 987, 644, 997 ], [ 646, 987, 659, 997 ], [ 662, 987, 684, 997 ], [ 686, 987, 694, 997 ], [ 697, 987, 710, 997 ], [ 712, 987, 743, 997 ], [ 248, 998, 287, 1008 ], [ 289, 998, 330, 1008 ], [ 333, 998, 361, 1008 ], [ 364, 998, 535, 1008 ], [ 538, 998, 561, 1008 ], [ 564, 998, 593, 1008 ], [ 595, 998, 640, 1008 ], [ 643, 998, 658, 1008 ], [ 660, 998, 705, 1008 ], [ 708, 998, 723, 1008 ], [ 248, 1009, 297, 1019 ], [ 300, 1009, 307, 1019 ], [ 310, 1009, 324, 1019 ], [ 326, 1009, 360, 1019 ], [ 362, 1009, 396, 1019 ], [ 399, 1009, 412, 1019 ], [ 415, 1009, 443, 1019 ], [ 446, 1009, 465, 1019 ], [ 467, 1009, 473, 1019 ], [ 476, 1009, 508, 1019 ], [ 510, 1009, 530, 1019 ] ]	[ "Toranza", "and", "Arim", "BMC", "Ecology", "2010,", "10:18", "http://www.biomedcentral.com/1472-6785/10/18", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Carolina", "Toranza1,", "Matías", "Arim2,3", "Abstract", "Cross-taxon", "congruence", "and", "environmental", "conditions", "Open", "Access", "Background:", "Diversity", "patterns", "of", "different", "taxa", "typically", "covary", "in", "space,", "a", "phenomenon", "called", "cross-taxon", "congruence.", "This", "pattern", "has", "been", "explained", "by", "the", "effect", "of", "one", "taxon", "diversity", "on", "taxon", "diversity,", "shared", "biogeographic", "histories", "of", "different", "taxa,", "and/or", "common", "responses", "to", "environmental", "conditions.", "A", "meta-analysis", "of", "the", "association", "between", "environment", "and", "diversity", "patterns", "found", "that", "in", "83", "out", "of", "85", "studies,", "more", "than", "60%", "of", "the", "spatial", "variability", "in", "species", "richness", "was", "related", "to", "variables", "representing", "energy,", "water", "or", "their", "interaction.", "The", "role", "of", "the", "environment", "determining", "taxa", "diversity", "patterns", "leads", "us", "to", "hypothesize", "that", "this", "would", "explain", "the", "observed", "cross-taxon", "congruence.", "However,", "recent", "analyses", "reported", "the", "persistence", "of", "cross-taxon", "congruence", "when", "environmental", "effect", "was", "statistically", "removed.", "Here", "we", "evaluate", "this", "hypothesis,", "analyzing", "the", "cross-taxon", "congruence", "between", "birds", "and", "mammals", "in", "the", "Brazilian", "Cerrado,", "and", "assess", "the", "environmental", "role", "on", "the", "spatial", "covariation", "in", "diversity", "patterns.", "Results:", "We", "found", "a", "positive", "association", "between", "avian", "and", "mammal", "richness", "and", "a", "positive", "latitudinal", "trend", "for", "both", "groups", "in", "the", "Brazilian", "Cerrado.", "Regression", "analyses", "indicated", "an", "effect", "of", "latitude,", "PET,", "and", "mean", "temperature", "over", "both", "biological", "groups.", "In", "addition,", "we", "show", "that", "NDVI", "was", "only", "associated", "with", "avian", "diversity;", "while", "the", "annual", "relative", "humidity,", "was", "only", "correlated", "with", "mammal", "diversity.", "We", "determined", "the", "environmental", "effects", "on", "diversity", "in", "a", "path", "analysis", "that", "accounted", "for", "73%", "and", "76%", "of", "the", "spatial", "variation", "in", "avian", "and", "mammal", "richness.", "However,", "an", "association", "between", "avian", "and", "mammal", "diversity", "remains", "significant.", "Indeed,", "the", "importance", "of", "this", "link", "between", "bird", "and", "mammal", "diversity", "was", "also", "supported", "by", "a", "significant", "association", "between", "birds", "and", "mammal", "spatial", "autoregressive", "model", "residuals.", "Conclusion:", "Our", "study", "corroborates", "the", "main", "role", "of", "environmental", "conditions", "on", "diversity", "patterns,", "but", "suggests", "that", "other", "important", "mechanisms,", "which", "have", "not", "been", "properly", "evaluated,", "are", "involved", "in", "the", "observed", "cross-", "taxon", "congruence.", "The", "approaches", "introduced", "here", "indicate", "that", "the", "prevalence", "of", "a", "significant", "association", "among", "taxa,", "after", "considering", "the", "environmental", "determinant,", "could", "indicate", "both", "the", "need", "to", "incorporate", "additional", "processes", "(e.g.", "biogeographic", "and", "evolutionary", "history", "or", "trophic", "interactions)", "and/or", "the", "existence", "of", "a", "shared", "trend", "in", "detection", "biases", "among", "taxa", "and", "regions.", "Background", "Spatial", "concordance", "in", "diversity", "of", "different", "taxa", "is", "a", "recurrent", "feature", "in", "nature", "[1-3].", "The", "strength", "of", "this", "association,", "known", "as", "cross-taxon", "congruence,", "depends", "on", "the", "studied", "taxonomic", "groups", "and", "the", "scale", "of", "analy-", "sis", "[4].", "This", "is", "because", "the", "spatial", "association", "in", "diversity", "patterns", "of", "related", "taxa", "is", "typically", "larger", "than", "that", "observed", "between", "weakly", "related", "taxa", "[5]", "and", "is", "more", "", "Correspondence:", "ctoranza@gmail.com", "1Instituto", "de", "Ecología", "y", "Ciencias", "Ambientales,", "Facultad", "de", "Ciencias,", "Universidad", "de", "la", "República,", "Uruguay,", "Iguá", "4225", "Piso", "8", "Sur,", "Montevideo,", "Uruguay", "common", "over", "large", "geographic", "scales", "[6].", "This", "scale", "dependence", "in", "the", "strength", "of", "spatial", "taxonomic", "covaria-", "tion", "would", "be", "associated", "with", "changes", "in", "the", "factors", "determining", "species", "richness", "at", "different", "scales", "[7-9].", "A", "finer", "spatial", "scale", "would", "increase", "the", "role", "of", "biological", "interactions", "like", "competition", "[10],", "which", "may", "lessen", "the", "spatial", "congruence", "between", "different", "groups.", "Several", "hypotheses", "have", "been", "proposed", "to", "explain", "the", "cross", "cor-", "relation", "between", "major", "taxa", "diversity.", "These", "can", "be", "grouped", "into", "those", "that", "focus", "on", "the", "diversity", "effect", "of", "one", "taxon", "on", "another", "taxon’s", "diversity;", "those", "that", "pro-", "pose", "that", "the", "diversity", "patterns", "of", "different", "taxa", "are", "©", "2010", "Toranza", "and", "Arim;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 11, 11, 11, 11, 11, 11, 11, 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], [ 322, 998, 493, 1008 ], [ 496, 998, 519, 1008 ], [ 522, 998, 551, 1008 ], [ 553, 998, 598, 1008 ], [ 601, 998, 616, 1008 ], [ 618, 998, 663, 1008 ], [ 666, 998, 681, 1008 ], [ 683, 998, 732, 1008 ], [ 736, 998, 743, 1008 ], [ 248, 1009, 262, 1019 ], [ 264, 1009, 298, 1019 ], [ 300, 1009, 334, 1019 ], [ 337, 1009, 350, 1019 ], [ 352, 1009, 380, 1019 ], [ 384, 1009, 403, 1019 ], [ 405, 1009, 411, 1019 ], [ 414, 1009, 446, 1019 ], [ 448, 1009, 469, 1019 ] ]	[ "Gresback", "et", "al.", "Nanoscale", "Research", "Letters", "2011,", "6:68", "http://www.nanoscalereslett.com/content/6/1/68", "N", "A", "N", "O", "E", "X", "P", "R", "E", "S", "S", "Open", "Access", "Combined", "plasma", "gas-phase", "synthesis", "and", "colloidal", "processing", "of", "InP/ZnS", "core/shell", "nanocrystals", "Ryan", "Gresback1,", "Ryan", "Hue2,", "Wayne", "L", "Gladfelter2,", "Uwe", "R", "Kortshagen1", "Abstract", "Indium", "phosphide", "nanocrystals", "(InP", "NCs)", "with", "diameters", "ranging", "from", "2", "to", "5", "nm", "were", "synthesized", "with", "a", "scalable,", "flow-through,", "nonthermal", "plasma", "process", "at", "a", "rate", "ranging", "from", "10", "to", "40", "mg/h.", "The", "NC", "size", "is", "controlled", "through", "the", "plasma", "operating", "parameters,", "with", "the", "residence", "time", "of", "the", "gas", "in", "the", "plasma", "region", "strongly", "influencing", "the", "NC", "size.", "The", "NC", "size", "distribution", "is", "narrow", "with", "the", "standard", "deviation", "being", "less", "than", "20%", "of", "the", "mean", "NC", "size.", "Zinc", "sulfide", "(ZnS)", "shells", "were", "grown", "around", "the", "plasma-synthesized", "InP", "NCs", "in", "a", "liquid", "phase", "reaction.", "Photoluminescence", "with", "quantum", "yields", "as", "high", "as", "15%", "were", "observed", "for", "the", "InP/ZnS", "core-shell", "NCs.", "Introduction", "Over", "the", "last", "two", "decades,", "semiconductor", "nanocrystals", "(NCs)", "have", "attracted", "significant", "attention", "because", "of", "their", "various", "unique", "properties.", "Semiconductor", "NCs", "provide", "size-tunable", "optical", "and", "electrical", "properties,", "based", "on", "quantum", "confinement", "of", "charge", "carriers", "within", "them,", "high", "surface-to-volume", "ratios,", "and", "other", "attributes", "that", "have", "led", "to", "the", "development", "of", "a", "new", "generation", "of", "materials", "and", "devices", "[1,2].", "A", "significant", "amount", "of", "study", "has", "focused", "on", "compound", "semiconduc-", "tor", "NCs", "of", "the", "II-VI", "and", "IV-VI", "systems", "because", "of", "the", "relative", "ease", "of", "synthesizing", "high", "quality", "materials", "using", "colloidal", "techniques", "[3,4].", "While", "synthesis", "and", "surface", "functionalization", "methods", "for", "these", "NC", "materials", "are", "well", "established", "and", "NCs", "have", "shown", "impressive", "optical", "and", "electronic", "properties,", "there", "exists", "considerable", "inter-", "est", "to", "produce", "systems", "consisting", "of", "NCs", "of", "other", "mate-", "rials", "whose", "constituent", "elements", "pose", "less", "of", "an", "environmental", "concern,", "which", "are", "more", "radiation", "resis-", "tant,", "and", "less", "prone", "to", "photo-oxidation.", "Compound", "semiconductor", "NCs", "of", "the", "III-V", "systems", "may", "offer", "some", "of", "these", "desirable", "attributes.", "While", "III-V", "semiconductors", "are", "known", "to", "be", "“radiation-hard,”", "they", "also", "are", "direct", "bandgap", "semiconductors,", "which", "is", "a", "big", "advantage", "for", "optical", "applications", "compared", "to,", "for", "", "Correspondence:", "kortshagen@umn.edu", "1Department", "of", "Mechanical", "Engineering,", "University", "of", "Minnesota,", "Minneapolis,", "MN,", "USA", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "instance,", "group", "IV", "NC", "materials", "[5].", "Hence,", "there", "has", "been", "considerable", "interest", "in", "the", "synthesis", "of", "high", "qual-", "ity", "III-V", "compound", "NCs,", "such", "as", "indium", "phosphide", "(InP).", "While", "synthesizing", "methods", "similar", "to", "those", "of", "II-", "VI", "semiconductor", "NCs", "can", "be", "applied", "to", "InP", "NCs,", "these", "have", "turned", "out", "to", "be", "very", "difficult", "and", "time", "consuming,", "often", "requiring", "days", "to", "produce", "NCs", "of", "high", "quality", "[6,7].", "More", "recently,", "synthesis", "of", "high", "quality", "InP", "NCs", "has", "been", "achieved", "with", "non-coordinating", "solvents", "[8]", "and", "weak-coordinating", "solvents", "[9].", "However,", "as", "these", "synthesizing", "methods", "require", "organic", "surfactants", "to", "sta-", "bilize", "NCs", "in", "solution", "during", "synthesis,", "they", "provide", "challenges", "for", "applications", "of", "the", "synthesized", "NCs", "in", "devices", "because", "of", "the", "often", "electrically", "insulating", "nature", "of", "the", "ligands.", "Synthesis", "of", "NCs", "using", "nonthermal", "plasmas", "has", "become", "a", "viable", "method", "even", "for", "materials,", "which", "need", "to", "be", "produced", "in", "crystalline", "form", "requiring", "high", "tem-", "peratures,", "such", "as", "Si", "[10,11]", "and", "Ge", "[12].", "An", "added", "advantage", "of", "plasma", "synthesis", "as", "compared", "to", "liquid", "phase", "routes", "is", "that", "the", "resulting", "material", "is", "free", "of", "ligands", "or", "surfactants,", "and", "that", "the", "ligands", "can", "be", "added", "later", "depending", "on", "the", "targeted", "application.", "This", "makes", "integration", "of", "plasma-produced", "NCs", "into", "devices", "easier,", "as", "it", "eliminates", "intermediate", "steps", "of", "ligand", "exchanges", "often", "required", "for", "II-VI", "and", "IV-VI", "NCs.", "In", "this", "article,", "we", "propose", "a", "method", "to", "synthesize", "InP", "NCs", "with", "a", "nonthermal", "plasma.", "In", "addition,", "we", "show", "that", "solution", "chemistry", "routes", "can", "be", "used", "for", "post-synthesis", "©", "2011", "Gresback", "et", "al;", "licensee", "Springer.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 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], [ 482, 986, 538, 1000 ], [ 540, 986, 563, 1000 ], [ 566, 986, 591, 1000 ], [ 594, 985, 640, 1000 ], [ 642, 986, 692, 1000 ], [ 695, 986, 726, 1000 ], [ 728, 986, 739, 1000 ], [ 741, 986, 748, 1000 ] ]	[ "CASE", "REPORT", "http://dx.doi.org/10.4070/kcj.2011.41.12.763", "Print", "ISSN", "1738-5520", "/", "On-line", "ISSN", "1738-5555", "Copyright", "©", "2011", "The", "Korean", "Society", "of", "Cardiology", "Open", "Access", "ABSTRACT", "Stent", "Fracture", "at", "the", "Proximal", "Shaft", "of", "the", "Left", "Main", "Stem", "Jae", "Ho", "Lee,", "MD1,", "Suk", "Min", "Seo,", "MD1,2,", "Eun", "Oh", "Kim,", "MD1,", "Hyo", "Jun", "Ahn,", "MD1,", "Yang", "Won", "Lee,", "MD1,", "Yul-Hee", "Cho,", "MD1,", "Inwoon", "Baek,", "MD1,", "You", "Suk", "Oh,", "MD1,", "Jihyun", "Yu,", "MD1,", "and", "Ki-Bae", "Seung,", "MD1,2", "1Department", "of", "Internal", "Medicine", "and", "2Cardiovascular", "Center", "and", "Cardiology", "Division,", "Seoul", "St.", "Mary’s", "Hospital,", "College", "of", "Medicine,", "The", "Catholic", "University", "of", "Korea,", "Seoul,", "Korea", "Stent", "fracture", "is", "likely", "to", "be", "caused", "due", "to", "mechanical", "stress", "at", "the", "hinge", "point", "or", "kinking", "movement", "at", "the", "point", "of", "aneurysm", "formation", "with", "stent", "malapposition.", "To", "our", "knowledge,", "this", "is", "the", "first", "published", "report", "of", "stent", "fracture", "at", "the", "proximal", "shaft", "of", "the", "left", "main", "stem", "in", "a", "patient", "with", "acute", "myocardial", "infarction.", "(Korean", "Circ", "J", "2011;41:763-765)", "KEY", "WORDS:", "Stent", "fracture;", "Left", "main", "stem;", "Acute", "myocardial", "infarction.", "Introduction", "The", "suggested", "predisposing", "factors", "associated", "with", "frac-", "tures", "of", "coronary", "stent", "are", "sites", "of", "increased", "vessel", "movement,", "lengthy", "coronary", "stents,", "right", "coronary", "artery", "stents,", "overlapp-", "ing", "stents,", "sirolimus-eluting", "stents", "(SES),", "and", "saphenous", "vein", "graft", "stents.1)2)", "In", "addition,", "stent", "fracture", "is", "likely", "to", "be", "caused", "due", "to", "bending", "movement", "such", "as", "torsion,", "flexion,", "and", "rotation", "at", "the", "hinge", "point", "or", "kinking", "movement", "at", "the", "point", "of", "aneu-", "rysm", "formation", "with", "stent", "malapposition.3)", "We", "report", "the", "first", "case", "of", "stent", "fracture", "at", "the", "proximal", "shaft", "of", "the", "left", "main", "stem", "(LMS).", "Case", "A", "55-year-old", "man", "visited", "our", "hospital", "for", "follow-up", "coron-", "ary", "angiography.", "He", "had", "no", "particular", "symptoms", "prior", "to", "ad-", "mission,", "but", "he", "wanted", "to", "undergo", "coronary", "angiography.", "Sm-", "oking", "was", "the", "only", "cardiovascular", "risk", "factor.", "Received:", "February", "10,", "2011", "Revision", "Received:", "March", "8,", "2011", "Accepted:", "March", "22,", "2011", "Correspondence:", "Ki-Bae", "Seung,", "MD,", "Department", "of", "Internal", "Medicine", "and", "Cardiovascular", "Center", "and", "Cardiology", "Division,", "Seoul", "St.", "Mary’s", "Hos-", "pital,", "College", "of", "Medicine,", "The", "Catholic", "University", "of", "Korea,", "222", "Banpo-", "daero,", "Seocho-gu,", "Seoul", "137-701,", "Korea", "Tel:", "82-2-2258-1134,", "Fax:", "82-2-591-1506", "E-mail:", "kbseung@catholic.ac.kr", "•", "The", "authors", "have", "no", "financial", "conflicts", "of", "interest.", "cc", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Cre-", "ative", "Commons", "Attribution", "Non-Commercial", "License", "(http://creativecom-", "mons.org/licenses/by-nc/3.0)", "which", "permits", "unrestricted", "non-commer-", "cial", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "origi-", "nal", "work", "is", "properly", "cited.", "763", "Twenty-one", "months", "ago,", "primary", "percutaneous", "coronary", "intervention", "was", "performed", "because", "of", "symptoms", "of", "progres-", "sive", "angina", "and", "ST-segment", "elevation", "on", "the", "electrocardio-", "gram.", "He", "was", "diagnosed", "with", "acute", "myocardial", "infarction", "(AMI)", "with", "the", "culprit", "lesion", "being", "a", "long", "stenotic", "lesion", "in-", "volving", "the", "segment", "from", "the", "ostium", "of", "the", "LMS", "to", "the", "mid", "left", "anterior", "descending", "coronary", "artery", "(LAD)", "(Fig.", "1A).", "We", "implanted", "SES", "(Cypher®,", "Cordis,", "3.5×23", "mm)", "from", "the", "ostium", "of", "the", "LMS", "to", "the", "proximal", "LAD", "and", "then", "overlapped", "paclitaxel-eluting", "stent", "(Taxus®,", "Boston,", "3.0×32", "mm)", "at", "the", "proximal", "to", "mid-LAD.", "Additional", "ballooning", "was", "also", "per-", "formed,", "using", "high-pressure", "balloon", "(Quantum®,", "Schneider,", "4.0×12", "mm)", "up", "to", "10", "atm", "for", "15", "seconds", "(Fig.", "1B).", "Intravas-", "cular", "ultrasound", "(IVUS;", "42", "mHz,", "Clear", "View,", "MA,", "Boston,", "USA)", "confirmed", "well-positioned", "stents.", "Follow-up", "coronary", "angiography", "showed", "stent", "fracture", "at", "the", "proximal", "shaft", "of", "the", "LMS", "with", "minimal", "luminal", "narrow-", "ing", "(Fig.", "2A", "and", "B).", "IVUS", "revealed", "the", "absence", "of", "the", "stent", "strut", "corresponding", "to", "stent", "fracture", "and", "ectatic", "change", "with", "malapposition", "of", "stent", "around", "the", "site", "of", "stent", "fracture", "(Fig.", "2C,", "D", "and", "E).", "Based", "on", "these", "findings,", "the", "lesion", "was", "redi-", "lated", "up", "to", "16", "atm", "for", "15", "seconds", "with", "high-pressure", "balloon", "(Quantum®,", "Schneider,", "4.0×12", "mm).", "Finally,", "IVUS", "confirm-", "ed", "well-apposite", 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598, 1008 ], [ 601, 998, 616, 1008 ], [ 618, 998, 663, 1008 ], [ 666, 998, 681, 1008 ], [ 683, 998, 732, 1008 ], [ 736, 998, 743, 1008 ], [ 248, 1009, 262, 1019 ], [ 264, 1009, 298, 1019 ], [ 300, 1009, 334, 1019 ], [ 337, 1009, 350, 1019 ], [ 352, 1009, 380, 1019 ], [ 384, 1009, 403, 1019 ], [ 405, 1009, 411, 1019 ], [ 414, 1009, 446, 1019 ], [ 448, 1009, 469, 1019 ] ]	[ "Lu", "et", "al.", "Journal", "of", "Neuroinflammation", "2010,", "7:46", "http://www.jneuroinflammation.com/content/7/1/46", "R", "E", "S", "E", "A", "R", "C", "H", "JOURNAL", "OF", "NEUROINFLAMMATION", "Open", "Access", "Resveratrol", "differentially", "modulates", "inflammatory", "responses", "of", "microglia", "and", "astrocytes", "Xiaofeng", "Lu1†,", "Lili", "Ma1†,", "Lingfei", "Ruan1,2,", "Yan", "Kong1,2,", "Haiwei", "Mou1,2,", "Zhijie", "Zhang1,", "Zhijun", "Wang4,", "Ji", "Ming", "Wang3,", "Yingying", "Le1,2", "Abstract", "Background:", "Inflammatory", "responses", "in", "the", "CNS", "mediated", "by", "activated", "glial", "cells", "play", "an", "important", "role", "in", "host-", "defense", "but", "are", "also", "involved", "in", "the", "development", "of", "neurodegenerative", "diseases.", "Resveratrol", "is", "a", "natural", "polyphenolic", "compound", "that", "has", "cardioprotective,", "anticancer", "and", "anti-inflammatory", "properties.", "We", "investigated", "the", "capacity", "of", "resveratrol", "to", "protect", "microglia", "and", "astrocyte", "from", "inflammatory", "insults", "and", "explored", "mechanisms", "underlying", "different", "inhibitory", "effects", "of", "resveratrol", "on", "microglia", "and", "astrocytes.", "Methods:", "A", "murine", "microglia", "cell", "line", "(N9),", "primary", "microglia,", "or", "astrocytes", "were", "stimulated", "by", "LPS", "with", "or", "without", "different", "concentrations", "of", "resveratrol.", "The", "expression", "and", "release", "of", "proinflammatory", "cytokines", "(TNF-a,", "IL-", "1b,", "IL-6,", "MCP-1)", "and", "iNOS/NO", "by", "the", "cells", "were", "measured", "by", "PCR/real-time", "PCR", "and", "ELISA,", "respectively.", "The", "phosphorylation", "of", "the", "MAP", "kinase", "superfamily", "was", "analyzed", "by", "western", "blotting,", "and", "activation", "of", "NF-", "B", "and", "AP-", "1", "was", "measured", "by", "luciferase", "reporter", "assay", "and/or", "electrophoretic", "mobility", "shift", "assay.", "Results:", "We", "found", "that", "LPS", "stimulated", "the", "expression", "of", "TNF-a,", "IL-1b,", "IL-6,", "MCP-1", "and", "iNOS", "in", "murine", "microglia", "and", "astrocytes", "in", "which", "MAP", "kinases,", "NF-", "B", "and", "AP-1", "were", "differentially", "involved.", "Resveratrol", "inhibited", "LPS-", "induced", "expression", "and", "release", "of", "TNF-a,", "IL-6,", "MCP-1,", "and", "iNOS/NO", "in", "both", "cell", "types", "with", "more", "potency", "in", "microglia,", "and", "inhibited", "LPS-induced", "expression", "of", "IL-1b", "in", "microglia", "but", "not", "astrocytes.", "Resveratrol", "had", "no", "effect", "on", "LPS-stimulated", "phosphorylation", "of", "ERK1/2", "and", "p38", "in", "microglia", "and", "astrocytes,", "but", "slightly", "inhibited", "LPS-", "stimulated", "phosphorylation", "of", "JNK", "in", "astrocytes.", "Resveratrol", "inhibited", "LPS-induced", "NF-", "B", "activation", "in", "both", "cell", "types,", "but", "inhibited", "AP-1", "activation", "only", "in", "microglia.", "Conclusion:", "These", "results", "suggest", "that", "murine", "microglia", "and", "astrocytes", "produce", "proinflammatory", "cytokines", "and", "NO", "in", "response", "to", "LPS", "in", "a", "similar", "pattern", "with", "some", "differences", "in", "signaling", "molecules", "involved,", "and", "further", "suggest", "that", "resveratrol", "exerts", "anti-inflammatory", "effects", "in", "microglia", "and", "astrocytes", "by", "inhibiting", "different", "proinflammatory", "cytokines", "and", "key", "signaling", "molecules.", "Background", "Microglia,", "the", "resident", "macrophage-like", "cells", "in", "the", "brain,", "play", "an", "important", "role", "in", "host", "defense", "and", "tissue", "repair", "in", "CNS", "[1,2].", "Activated", "microglia", "produce", "a", "vari-", "ety", "of", "pro-inflammatory", "mediators,", "including", "tumor", "necrosis", "factor", "a", "(TNF-a),", "interleukin-1b", "(IL-1b),", "IL-6,", "monocyte", "chemotactic", "protein", "1", "(MCP-1,", "CCL2),", "nitric", "oxide", "(NO),", "and", "reactive", "oxygen", "species", "(ROS).", "", "Correspondence:", "yyle@sibs.ac.cn", "†", "Contributed", "equally", "1Key", "laboratory", "of", "Nutrition", "and", "Metabolism,", "Institute", "for", "Nutritional", "Sciences,", "Shanghai", "Institutes", "for", "Biological", "Sciences;", "Chinese", "Academy", "of", "Sciences,", "Shanghai", "200031,", "China", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "Activated", "microglia", "serve", "immune", "surveillance", "functions", "by", "removing", "foreign", "microorganisms,", "but", "may", "also", "result", "in", "excessive", "inflammatory", "responses", "in", "the", "CNS", "[1,2].", "Astrocytes", "are", "the", "main", "glial", "cell", "type", "in", "the", "brain", "involved", "in", "maintaining", "CNS", "homeostasis.", "They", "also", "respond", "promptly", "to", "injury", "and", "regulate", "neuroinflam-", "matory", "events", "[2-4].", "Both", "in", "vitro", "and", "in", "vivo", "studies", "have", "documented", "the", "ability", "of", "astrocytes", "to", "produce", "a", "variety", "of", "cytokines,", "including", "IL-1,", "IL-6,", "IL-10,", "inter-", "feron-a", "(INF-a),", "IFN-b,", "TNF-a,", "TNF-b;", "and", "chemo-", "kines,", "including", "RANTES", "(CCL5),", "IL-8", "(CXCL8)", "and", "MCP-1", "[3].", "Over-activation", "of", "glial", "cells", "and", "release", "of", "proinflammatory", "cytokines", "may", "lead", "to", "neuronal", "death", "[5-7],", "causing", "neuropathological", "changes", "in", "CNS", "©", "2010", "Lu", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 16, 16, 16, 16, 16, 16, 16, 16, 0, 0, 0, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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"Joo", "Hwa", "Moon,", "MD,", "and", "Jong", "Bum", "Choi,", "MD", "Trigger", "point", "injection", "treatment", "is", "an", "effective", "and", "widely", "applied", "treatment", "for", "myofascial", "pain", "syndrome.", "The", "trapezius", "muscle", "frequently", "causes", "myofascial", "pain", "in", "neck", "area.", "We", "herein", "report", "a", "case", "in", "which", "direct", "pulsed", "radiofrequency", "(RF)", "treatment", "was", "applied", "to", "the", "trapezius", "muscle.", "We", "observed", "that", "the", "RF", "treatment", "produced", "continuous", "pain", "relief", "when", "the", "effective", "duration", "of", "trigger", "point", "injection", "was", "temporary", "in", "myofascial", "pain.", "(Korean", "J", "Pain", "2012;", "25:", "52-54)", "Key", "Words:", "myofascial", "pain,", "pulsed", "RF", "(radiofrequency),", "trigger", "point", "injection.", "Myofascial", "pain", "syndrome", "is", "a", "common", "disease.", "The", "rary", "treatment", "method.", "Therefore,", "we", "report", "on", "a", "my-", "main", "treatment", "includes", "injection", "therapy", "at", "the", "trigger", "ofascial", "pain", "syndrome", "case", "where", "direct", "pulsed", "radio-", "point", "and", "medication", "in", "which", "an", "analgesic", "anti-inflam-", "frequency", "treatment", "was", "applied", "to", "the", "trapezius", "muscle", "matory", "agent", "and", "muscle", "relaxant", "are", "administrated", "on", "which", "TPI", "had", "been", "sufficiently", "effective", "but", "of", "short", "together.", "Trigger", "point", "injection", "(TPI)", "is", "widely", "applied", "duration.", "Moreover,", "the", "analgesic", "effect", "of", "the", "pulsed", "RF", "since", "it", "is", "effective", "in", "most", "cases", "and", "easily", "performed", "on", "treatment", "was", "maintained", "for", "a", "considerable", "duration.", "outpatients.", "However,", "the", "duration", "of", "pain", "relief", "may,", "in", "some", "cases,", "be", "short.", "Hence,", "many", "patients", "return", "to", "the", "clinic", "as", "outpatients", "when", "the", "analgesic", "effect", "diminishes.", "TPI", "may", "be", "used", "many", "times,", "but", "repetitive", "TPI", "may", "be", "CASE", "REPORT", "A", "47-year", "old", "female", "patient", "visited", "our", "clinic", "with", "the", "rejected", "because", "of", "its", "cost", "and", "the", "fact", "that", "it", "relies", "on", "main", "complaint", "of", "neck", "pain", "that", "had", "become", "severe", "over", "a", "needle", "injection.", "Some", "patients", "consider", "TPI", "as", "a", "tempo-", "the", "past", "year.", "The", "medical", "history", "showed", "that", "the", "patient", "Received", "September", "30,", "2011.", "Revised", "November", "15,", "2011.", "Accepted", "November", "15,", "2011.", "Correspondence", "to:", "Jong", "Bum", "Choi,", "MD", "Department", "of", "Anesthesioligy", "and", "Pain", "Medicine,", "Gangnam", "Severance", "Hospital,", "712,", "Eonju-ro,", "Gangnam-gu,", "Seoul", "135-720,", "Korea", "Tel:", "＋82-2-2019-3520,", "Fax:", "＋82-2-3463-0940,", "E-mail:", "romeojb@yuhs.ac", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "Non-Commercial", "License", "(http://", "creativecommons.org/licenses/by-nc/3.0/),", "which", "permits", "unrestricted", "non-commercial", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Copyright", "ⓒ", "The", "Korean", "Pain", "Society,", "2012" ]	[ 16, 16, 16, 16, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 16, 16, 16, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 0, 0, 0, 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"Victor", "B.", "Rybakovb*", "aSouth-Russia", "State", "Technical", "University,", "346428", "Novocherkassk,", "Russian", "Federation,", "and", "bDepartment", "of", "Chemistry,", "Moscow", "State", "University,", "119992", "Moscow,", "Russian", "Federation", "Correspondence", "e-mail:", "rybakov20021@yandex.ru", "Received", "8", "January", "2011;", "accepted", "17", "January", "2011", "Key", "indicators:", "single-crystal", "X-ray", "study;", "T", "=", "295", "K;", "mean", "(C–C)", "=", "0.003", "A˚;", "R", "factor", "=", "0.042;", "wR", "factor", "=", "0.109;", "data-to-parameter", "ratio", "=", "15.8.", "In", "the", "cation", "of", "the", "title", "compound,", "C7H8N5+", "Cl", "H2O,", "the", "mean", "planes", "of", "the", "pyridine", "and", "1,2,4-triazole", "rings", "form", "a", "dihedral", "angle", "of", "2.3", "(1)", ".", "The", "N", "atom", "of", "the", "amino", "group", "adopts", "a", "trigonal–pyramidal", "conﬁguration.", "The", "N", "atom", "of", "the", "pyridine", "ring", "is", "protonated,", "forming", "a", "chloride", "salt.", "In", "the", "crystal,", "intermolecular", "N—H", "O,", "N—H", "N,", "N—H", "Cl", "and", "O—H", "Cl", "hydrogen", "bonds", "link", "the", "cations,", "anions", "and", "water", "molecules", "into", "layers", "parallel", "to", "the", "(1,", "0,", "12)", "plane.", "Related", "literature", "For", "the", "use", "of", "3-pyridyl-substituted", "5-amino-1,2,4-triazoles", "in", "the", "synthesis", "of", "biologically", "active", "compounds,", "see:", "Lipinski", "(1983);", "Ram", "(1988);", "Akahoshi", "et", "al.", "(1998);", "Young", "et", "al.", "(2001);", "Ouyang", "et", "al.", "(2005);", "Dolzhenko", "et", "al.", "(2007).", "For", "metal", "complexes", "of", "3-pyridyl-substituted", "5-amino-1,2,4-tri-", "azoles,", "see:", "Mishra", "et", "al.", "(1989);", "Ferrer", "et", "al.", "(2004);", "Castineiras", "&", "Garcia-Santos", "(2008).", "For", "a", "theoretical", "investigation", "of", "the", "protonation", "of", "C-amino-1,2,4-triazoles,", "see:", "Anders", "et", "al.", "(1997).", "For", "the", "crystal", "structures", "of", "protonated", "C-amino-1,2,4-", "triazoles,", "see:", "Lynch", "et", "al.", "(1999);", "Baouab", "et", "al.", "(2000);", "Bichay", "et", "al.", "(2006);", "Guerfel", "et", "al.", "(2007);", "Matulkova´", "et", "al.", "(2007).", "For", "the", "ionization", "constants", "(pK", ")", "of", "3-substituted", "5-amino-1H-", "1,2,4-triazoles,", "see:", "Voronkov", "et", "al.", "(1976).", "For", "the", "1H", "and", "13C", "NMR", "spectra", "of", "3-pyridyl-substituted", "5-amino-1,2,4-triazoles,", "see:", "Dolzhenko", "et", "al.", "(2009a).", "For", "typical", "NMR", "chemical", "shifts", "of", "3-substituted", "5-amino-1,2,4-triazoles", "and", "their", "salts,", "see:", "Chernyshev", "et", "al.", "(2010).", "For", "the", "crystal", "structures", "of", "3-", "substituted", "5-amino-1H-1,2,4-triazoles,", "see:", "Rusinov", "et", "al.", "(1991);", "Daro", "et", "al.", "(2000);", "Boechat", "et", "al.", "(2004);", "Dolzhenko", "et", "al.", "(2009b,c).", "For", "the", "crystal", "structures", "of", "3(5)-pyridyl-substi-", "tuted", "1,2,4-triazoles", "protonated", "at", "the", "pyridine", "ring,", "see:", "Ren", "&", "Jian", "(2008);", "Xie", "et", "al.", "(2009);", "Du", "et", "al.", "(2009).", "For", "values", "of", "bond", "lengths", "in", "organic", "compounds,", "see:", "Allen", "et", "al.", "(1987).", "For", "the", "correlation", "of", "bond", "lengths", "with", "bond", "orders", "between", "sp2-hybridized", "C", "and", "N", "atoms,", "see:", "Burke-Laing", "&", "Laing", "(1976).", "Experimental", "Crystal", "data", "C7H8N5+", "Cl", "H2O", "Mr", "=", "215.65", "Monoclinic,", "P21=c", "a", "=", "5.3411", "(5)", "A˚", "b", "=", "24.656", "(3)", "A˚", "c", "=", "7.3488", "(7)", "A˚", "=", "97.62", "(2)", "Data", "collection", "Enraf–Nonius", "CAD-4", "diffractometer", "Absorption", "correction:", "reﬁned", "from", "F", "(Walker", "&", "Stuart,", "1983)", 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"THOMPSON1,2,", "MIKAEL", "S.", "LINDSTRÖM1", "&", "MONICA", "NISTÉR1,2", "1Department", "of", "Oncology-Pathology,", "Karolinska", "Institutet,", "CCK", "R8:04,", "Karolinska", "University", "Hospital", "Solna,", "SE-17176", "Stockholm,", "Sweden,", "2Karolinska", "Healthcare", "Research", "Biobank", "(KHRBB),", "Clinical", "Pathology/Cytology,", "Karolinska", "University", "Hospital,", "SE-17176", "Stockholm,", "Sweden,", "and", "3(currently)", "Uppsala", "University,", "Rudbeck", "Laboratory,", "Department", "of", "Immunology,", "Genetics", "and", "Pathology,", "SE-751", "85", "Uppsala,", "Sweden", "Abstract", "The", "family", "of", "platelet-derived", "growth", "factors", "(PDGFs)", "plays", "a", "number", "of", "critical", "roles", "in", "normal", "embryonic", "development,", "cellular", "differentiation,", "and", "response", "to", "tissue", "damage.", "Not", "surprisingly,", "as", "it", "is", "a", "multi-faceted", "regulatory", "system,", "numerous", "pathological", "conditions", "are", "associated", "with", "aberrant", "activity", "of", "the", "PDGFs", "and", "their", "receptors.", "As", "we", "and", "others", "have", "shown,", "human", "gliomas,", "especially", "glioblastoma,", "express", "all", "PDGF", "ligands", "and", "both", "the", "two", "cell", "surface", "receptors,", "PDGFR-a", "and", "-b.", "The", "cellular", "distribution", "of", "these", "proteins", "in", "tumors", "indicates", "that", "glial", "tumor", "cells", "are", "stimulated", "via", "PDGF/PDGFR-a", "autocrine", "and", "paracrine", "loops,", "while", "tumor", "vessels", "are", "stimulated", "via", "the", "PDGFR-b.", "Here", "we", "summarize", "the", "initial", "discoveries", "on", "the", "role", "of", "PDGF", "and", "PDGF", "receptors", "in", "gliomas", "and", "provide", "a", "brief", "overview", "of", "what", "is", "known", "in", "this", "ﬁeld.", "Key", "words:", "Animal", "tumor", "model,", "brain", "tumor,", "cancer", "stem", "cell,", "glioma,", "neural", "stem", "cell,", "platelet-derived", "growth", "factor", "(PDGF),", "PDGF", "receptor", "Introduction", "Gliomas", "are", "the", "most", "common", "form", "of", "primary", "malignancies", "of", "the", "central", "nervous", "system", "(CNS)", "mainly", "affecting", "adults.", "These", "tumors", "have", "a", "histo-", "logical", "resemblance", "to", "different", "types", "of", "glial", "cells", "and", "are", "categorized", "into", "astrocytomas,", "oligodendroglio-", "mas,", "oligoastrocytomas,", "and", "ependymomas,", "based", "on", "the", "predominant", "cell", "type(s)", "in", "the", "respective", "tumor", "(1).", "Initial", "discovery", "and", "extensive", "studies", "of", "the", "epi-", "dermal", "growth", "factor", "(EGF)", "and", "transforming", "growth", "factor", "alpha", "(TGF-a),", "as", "well", "as", "the", "platelet-", "derived", "growth", "factor", "(PDGF)", "family,", "revealed", "their", "presence", "in", "glioblastoma", "cell", "cultures", "and", "tissues.", "These", "growth", "factors,", "by", "signaling", "via", "their", "cell", "sur-", "face", "tyrosine", "kinase", "receptors,", "EGFR", "and", "PDGFR-a", "and", "-b,", "were", "able", "not", "only", "to", "induce", "normal", "mitogenic", "and", "migratory", "responses,", "but", "when", "aberrantly", "activated", "they", "were", "also", "able", "to", "transform", "cells.", "Knowledge", "gained", "from", "in", "vitro", "experiments", "was", "transferred", "to", "in", "vivo", "systems,", "and", "several", "mouse", "models", "were", "created", "showing", "that", "gliomas", "can", "be", "induced", "by", "forced", "expression", "of", "PDGF-B", "in", "the", "brain.", "However,", "treatment", "with", "single", "tyrosine", "kinase", "inhibitors", "(TKIs)", "given", "to", "glioma", "patients", "has", "gener-", "ally", "not", "been", "successful.", "Ever", "since", "the", "initial", "discoveries,", "investigations", "on", "the", "molecular", "mechanisms", "and", "signaling", "pathways", "involved", "in", "glioma", "have", "provided", "a", "more", "detailed", "insight", "into", "the", "key", "events", "behind", "brain", "tumor", "initi-", "ation,", "maintenance,", "and", "progression", "and", "have", "resulted", "in", "signiﬁcantly", "improved", "cancer", "drug", "discov-", "eries.", "However,", "the", "prognosis", "for", "patients", "with", "aggres-", "sive", "brain", "tumors", "is", "still", "very", "poor.", "One", "intriguing", "hypothesis", "is", "that", "glioblastoma", "resistance", "to", "therapy", "and", "its", "rapid", "recurrence", "is", "due", "to", "the", "presence", "of", "a", "subpopulation", "of", "tumor", "cells", "displaying", "stem", "cell", "Correspondence:", "Monica", "Nistér", "MD", "PhD,", "Department", "of", "Oncology-Pathology,", "Karolinska", "Institutet,", "CCK", "R8:04,", "Karolinska", "University", "Hospital", "Solna,", "SE-17176", "Stockholm,", "Sweden.", "E-mail:", "Monica.Nister@ki.se", "(Received", "24", "January", "2012;", "accepted", "6", "February", "2012)", "ISSN", "0300-9734", "print/ISSN", "2000-1967", "online", "2012", "Informa", "Healthcare", "DOI:", "10.3109/03009734.2012.665097" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 16, 16, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 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1012 ], [ 561, 998, 582, 1012 ], [ 585, 998, 620, 1012 ], [ 623, 998, 678, 1012 ], [ 681, 998, 702, 1012 ], [ 704, 998, 736, 1012 ], [ 739, 998, 775, 1012 ], [ 307, 1045, 385, 1057 ], [ 387, 1045, 422, 1057 ], [ 425, 1045, 441, 1057 ], [ 443, 1045, 490, 1057 ], [ 492, 1045, 535, 1057 ], [ 538, 1045, 588, 1057 ], [ 307, 1059, 316, 1071 ], [ 318, 1059, 341, 1071 ], [ 343, 1059, 368, 1071 ], [ 371, 1059, 406, 1071 ], [ 408, 1059, 432, 1071 ], [ 435, 1059, 471, 1071 ], [ 473, 1059, 486, 1071 ], [ 488, 1059, 513, 1071 ], [ 517, 1059, 557, 1071 ], [ 744, 1044, 775, 1058 ] ]	[ "R", "E", "V", "I", "E", "W", "Treatment", "of", "Lennox-Gastaut", "syndrome:", "overview", "and", "recent", "f", "indings", "Kenou", "van", "Rijckevorsel", "Reference", "Centre", "of", "Refractory", "Epilepsy,", "Cliniques", "Universitaires", "St", "Luc,", "Université", "Catholique", "de", "Louvain,", "Brussels,", "Belgium", "Correspondence:", "Kenou", "van", "Rijckevorsel", "Reference", "Centre", "for", "Refractory", "Epilepsy,", "Cliniques", "Universitaires", "St", "Luc,Avenue", "Hippocrate,", "10,", "B-1200", "Brussels,", "Belgium", "Tel", "+32", "2", "7643308", "Fax", "+32", "2", "7642142", "Email", "vanrijckevorsel@nops.ucl.ac.be", "Abstract:", "Lennox-Gastaut", "syndrome", "(LGS)", "is", "a", "rare,", "age-related", "syndrome,", "characterized", "by", "multiple", "seizure", "types,", "a", "speciﬁc", "electro-encephalographic", "pattern,", "and", "mental", "regression.", "However,", "published", "data", "on", "the", "etiology,", "evolution,", "and", "therapeutic", "approach", "of", "LGS", "are", "contradictory,", "partly", "because", "the", "precise", "deﬁnition", "of", "LGS", "used", "in", "the", "literature", "varies.", "In", "the", "most", "recent", "classiﬁcation,", "LGS", "belongs", "to", "the", "epileptic", "encephalopathies", "and", "is", "highly", "refractory", "to", "all", "antiepileptic", "drugs.", "Numerous", "treatments,", "medical", "and", "non-medical,", "have", "been", "proposed", "and", "results", "mostly", "from", "open", "studies", "or", "case", "series", "have", "been", "published.", "Sometimes,", "patients", "with", "LGS", "are", "included", "in", "a", "more", "global", "group", "of", "patients", "with", "refractory", "epilepsy.", "Only", "6", "randomized", "double-blind", "controlled", "trials", "of", "medical", "treatments,", "which", "included", "patients", "with", "LGS,", "have", "been", "published.", "Overall,", "treatment", "is", "rarely", "effective", "and", "the", "ﬁnal", "prognosis", "remains", "poor", "in", "spite", "of", "new", "therapeutic", "strategies.", "Co-morbidities", "need", "speciﬁc", "treatment.", "This", "paper", "summarizes", "the", "deﬁnition,", "diagnosis", "and", "therapeutic", "approach", "to", "LGS,", "including", "not", "only", "recognized", "antiepileptic", "drugs,", "but", "also", "“off", "label”", "medications,", "immune", "therapy,", "diet,", "surgery", "and", "some", "perspectives", "for", "the", "future.", "Keywords:", "Lennox-Gastaut", "syndrome,", "treatment,", "VNS,", "surgery,", "epileptic", "encephalopathies,", "LGS,", "refractory", "Introduction", "The", "term", "Lennox-Gastaut", "syndrome", "(LGS)", "appeared", "in", "the", "literature", "for", "the", "ﬁrst", "time", "in", "1969", "(Niedermeyer", "1969),", "but", "this", "syndrome", "was", "actually", "ﬁrst", "described", "by", "Lennox", "and", "Davis", "in", "1950", "and", "by", "Gastaut", "et", "al", "in", "1966.", "The", "International", "League", "Against", "Epilepsy", "(ILAE)", "Commission", "(Classiﬁcation", "Epilepsia", "1989)", "classiﬁed", "LGS", "among", "the", "cryptogenic", "or", "symptomatic", "generalized", "epilepsies,", "but,", "more", "recently,", "the", "ILAE", "Task", "Force", "classiﬁed", "it", "among", "the", "age-related", "epileptic", "encephalopathies", "(Engel", "2001).", "LGS", "comprises", "atypical", "absences", "with", "slow", "spike-and-wave", "(SW)", "complexes,", "tonic", "seizures", "that", "are", "mostly", "sleep-related,", "and", "cognitive", "deterioration", "(ILAE).", "However,", "LGS", "has", "also", "been", "deﬁned", "as", "diffuse", "SW", "pattern", "on", "electroencephalogram", "(EEG),", "mental", "retardation,", "and", "multiple", "types", "of", "seizures", "without", "reference", "to", "age", "or", "to", "nocturnal", "tonic", "seizures", "(French", "et", "al", "2004).", "This", "broader", "deﬁnition,", "mostly", "used", "in", "the", "US,", "may", "include", "for", "example,", "Dravet", "syndrome,", "Doose", "syndrome,", "or", "focal", "cryptogenic", "epilepsies,", "especially", "of", "frontal", "lobe", "origin.", "According", "to", "Genton", "et", "al", "(2000),", "EEG", "criteria", "should", "include", "not", "only", "bilateral", "slow", "SW", "but", "also", "10–20", "Hz", "epileptic", "fast", "rhythms,", "predominantly", "in", "sleep.", "Furthermore,", "this", "syndrome", "belongs", "to", "the", "age-related", "epileptic", "encephalopathies", "and", "starts", "during", "childhood.", "When", "using", "these", "full", "criteria,", "LGS", "appears", "to", "be", "rare.", "Largely", "as", "a", "result", "of", "the", "different", "deﬁnitions,", "the", "literature", "presents,", "or", "seems", "to", "present,", "contradictory", "data", "about", "the", "frequency", "of", "seizure", "types,", "epidemiology,", "treatment", "options,", "prognosis,", "and", "long", "term", "evolution", "of", "LGS.", "Furthermore,", "results", "of", "clinical", "studies", "are", "difﬁcult", "to", "compare", "in", "terms", "of", "efﬁcacy", "and", "most", "of", "them,", "especially", "randomized", "studies,", "do", "not", "cover", "more", "than", "a", "few", "weeks", "(Hancock", "and", "Cross", "2003).", "Neuropsychiatric", "Disease", "and", "Treatment", "2008:4(6)", "1001–1019", "©", "2008", "Dove", "Medical", "Press", "Limited.", "All", "rights", "reserved", "1001" ]	[ 16, 16, 16, 16, 16, 16, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 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], [ 278, 1027, 318, 1040 ], [ 322, 1027, 344, 1040 ], [ 347, 1027, 390, 1040 ], [ 393, 1027, 403, 1040 ], [ 408, 1027, 443, 1040 ], [ 447, 1027, 463, 1040 ], [ 466, 1027, 491, 1040 ], [ 496, 1027, 540, 1040 ], [ 278, 1042, 383, 1055 ] ]	[ "Endothelial", "Cells", "Modify", "the", "Costimulatory", "Capacity", "of", "Transmigrating", "Leukocytes", "and", "Promote", "CD28-mediated", "CD41", "T", "Cell", "Alloactivation", "By", "Mark", "D.", "Denton,‡", "Christopher", "S.", "Geehan,", "Steve", "I.", "Alexander,", "Mohamed", "H.", "Sayegh,‡", "and", "David", "M.", "Briscoe", "From", "the", "*Division", "of", "Nephrology,", "Department", "of", "Medicine,", "Children’s", "Hospital,", "and", "the", "‡Laboratory", "of", "Immunogenetics", "and", "Transplantation,", "Renal", "Division,", "Department", "of", "Medicine,", "Brigham", "and", "Women’s", "Hospital,", "and", "Harvard", "Medical", "School,", "Boston,", "Massachusetts", "02115", "Summary", "Activated", "vascular", "endothelial", "cells", "(ECs)", "express", "major", "histocompatibility", "complex", "(MHC)", "class", "II", "molecules", "in", "vitro", "and", "in", "vivo", "in", "acute", "and", "chronic", "allograft", "rejection.", "However,", "hu-", "man", "ECs", "may", "be", "limited", "in", "their", "ability", "to", "effectively", "activate", "CD41", "T", "cells,", "because", "they", "do", "not", "express", "members", "of", "the", "B7", "family", "(CD80", "and", "CD86)", "of", "costimulatory", "molecules.", "In", "this", "study,", "we", "show", "that", "ECs", "promote", "the", "full", "activation", "of", "CD41", "T", "cells", "via", "trans-costimulatory", "interactions.", "By", "reverse", "transcriptase", "polymerase", "chain", "reaction,", "Western", "blot,", "and", "FACS®", "analysis,", "we", "could", "not", "detect", "the", "expression", "of", "CD80", "and", "CD86", "on", "activated", "ECs", "and", "found", "minimal", "expression", "on", "purified", "CD41", "T", "cells.", "In", "contrast,", "both", "CD80", "and", "CD86", "were", "ex-", "pressed", "in", "allogeneic", "CD41", "T", "cell–EC", "cocultures.", "Expression", "of", "CD86", "peaked", "at", "early", "times", "between", "12", "and", "24", "h", "after", "coculture,", "whereas", "CD80", "was", "not", "expressed", "until", "72", "h.", "Addition", "of", "anti-CD86", "but", "not", "anti-CD80", "monoclonal", "antibodies", "to", "cocultures", "inhibited", "IL-2", "production", "and", "the", "proliferation", "of", "CD41", "T", "cells", "to", "allogeneic", "donor", "human", "umbilical", "vein", "ECs", "(HU-", "VECs),", "as", "well", "as", "to", "skin", "and", "lung", "microvascular", "ECs.", "Furthermore,", "we", "found", "that", "interferon", "g–activated", "ECs", "but", "not", "untreated", "ECs", "induced", "mRNA", "and", "cell", "surface", "expression", "of", "CD80", "and", "CD86", "on", "CD41", "T", "cells,", "and", "these", "T", "cells", "were", "functional", "to", "provide", "a", "trans-costimulatory", "signal", "to", "autologous", "CD41", "T", "cells.", "Blockade", "of", "MHC", "class", "II", "and", "lymphocyte", "function–associ-", "ated", "antigen", "3", "but", "not", "other", "EC", "cell", "surface", "molecules", "on", "IFN-g–activated", "ECs", "inhibited", "the", "induction", "of", "CD86", "on", "CD41", "T", "cells.", "Transmigration", "of", "purified", "populations", "of", "monocytes", "across", "EC", "monolayers", "similarly", "resulted", "in", "the", "induction", "of", "functional", "CD86,", "but", "also", "induced", "the", "de", "novo", "expression", "of", "the", "cytokines", "interleukin", "(IL)-1a", "and", "IL-12.", "In", "addition,", "EC-modi-", "fied", "monocytes", "supported", "enhanced", "proliferation", "of", "allogeneic", "and", "autologous", "CD41", "T", "cells.", "Taken", "together,", "these", "data", "define", "the", "ability", "of", "the", "endothelium", "to", "modify", "CD41", "T", "cells", "and", "monocytes", "for", "trans-costimulatory", "events.", "This", "unique", "function", "of", "the", 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"Faculty", "of", "Medicine,", "Kuwait", "University,", "Kuwait", "City,", "Kuwait", "Email:", "Al-Anoud", "Jaber", "-", "Gad1978@hotmail.com;", "Suhail", "Ahmad", "-", "suhail_ah@hsc.edu.kw;", "Eiman", "Mokaddas", "-", "e.mokaddas@hsc.edu.kw", "*", "Corresponding", "author", "Published:", "15", "January", "2009", "Annals", "of", "Clinical", "Microbiology", "and", "Antimicrobials", "2009,", "8:2", "doi:10.1186/1476-0711-8-2", "This", "article", "is", "available", "from:", "http://www.ann-clinmicrob.com/content/8/1/2", "Received:", "2", "November", "2008", "Accepted:", "15", "January", "2009", "©", "2009", "Jaber", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "Ethambutol", "(EMB)", "is", "a", "first-line", "drug", "for", "the", "treatment", "of", "tuberculosis", "(TB).", "Resistance", "to", "EMB", "in", "Mycobacterium", "tuberculosis", "isolates", "is", "mediated", "by", "mutations", "in", "several", "genes", "involved", "in", "arabinan", "synthesis", "notably", "three", "emb", "(arabinosyl", "transferase)", "and", "iniA", "(isoniazid-", "inducible)", "genes.", "Most", "epidemiologically", "unrelated", "EMB-resistant", "M.", "tuberculosis", "strains", "contain", "mutations", "at", "embB", "codons", "306,", "406", "and", "497,", "embC-embA", "intergenic", "region", "(IGR)", "and", "iniA", "codon", "501", "(iniA501).", "Objective:", "To", "develop", "a", "more", "comprehensive", "molecular", "screen", "for", "EMB-resistance", "detectioamong", "epidemiologically", "unrelated", "EMB-resistant", "M.", "tuberculosis", "strains", "previously", "analyzed", "for", "embB", "codon", "306,", "406", "and", "497", "mutations", "by", "including", "analysis", "of", "mutations", "at", "iniA501", "and", "in", "embC-embA", "IGR.", "Methods:", "Fifty", "consecutive", "and", "phenotypically", "documented", "EMB-resistant", "and", "25", "pansusceptible", "M.", "tuberculosis", "strains", "isolated", "from", "75", "different", "TB", "patients", "over", "a", "four-year", "period", "in", "Kuwait", "were", "analyzed.", "Mutations", "at", "iniA501", "were", "detected", "by", "PCR", "amplification", "followed", "by", "restriction", "fragment", "length", "polymorphism", "(RFLP)", "patterns", "generated", "with", "Hpy", "99", "I.", "Direct", "DNA", "sequencing", "was", "used", "to", "confirm", "RFLP", "results", "and", "for", "detecting", "mutations", "in", "embC-embA", "IGR.", "Results:", "Nearly", "same", "number", "of", "EMB-resistant", "M.", "tuberculosis", "strains", "were", "resistant", "to", "EMB", "alone", "and", "EMB", "together", "with", "additional", "resistance", "to", "rifampicin", "and", "isoniazid", "(9", "of", "50,", "18%", "and", "11", "of", "50,", "22%,", "respectively).", "All", "the", "25", "pansusceptible", "strains", "contained", "wild-type", "sequences", "at", "iniA501", "and", "in", "embC-embA", "IGR.", "The", "analysis", "of", "50", "EMB-resistant", "M.", "tuberculosis", "isolates", "showed", "that", "only", "one", "strain", "contained", "a", "mutated", "iniA501", "while", "no", "mutation", "was", "detected", "in", "embC-embA", "IGR", "in", "any", "of", "the", "isolate.", "Conclusion:", "Analysis", "of", "iniA501", "and", "embC-embA", "IGR", "in", "epidemiologically", "unrelated", "EMB-resistant", "M.", "tuberculosis", "isolates", "in", "Kuwait", "indicate", "that", "mutations", "at", "these", "locations", "occur", "very", "infrequently", "and", "their", "inclusion", "for", "the", "development", "of", "a", "comprehensive", "molecular", "screen", "will", "make", "only", "minor", "contribution", "towards", "rapid", "EMB", "resistance", "detection.", "Page", "1", "of", "9", "(page", "number", "not", "for", "citation", "purposes)" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 7, 7, 7, 7, 0, 0, 0, 0, 0, 0, 0, 0, 0, 9, 9, 9, 9, 9, 9, 7, 7, 7, 7, 7, 7, 7, 7, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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], [ 664, 1032, 712, 1045 ], [ 717, 1032, 754, 1045 ], [ 604, 1059, 614, 1073 ], [ 618, 1060, 644, 1074 ], [ 649, 1060, 723, 1074 ], [ 726, 1060, 753, 1074 ] ]	[ "DATABASES", "Human", "Mutation", "dbNSFP:", "A", "Lightweight", "Database", "of", "Human", "Nonsynonymous", "SNPs", "and", "Their", "Functional", "Predictions", "Xiaoming", "Liu,", "Xueqiu", "Jian,", "and", "Eric", "Boerwinkle", "Human", "Genetics", "Center,", "School", "of", "Public", "Health,", "The", "University", "of", "Texas", "Health", "Science", "Center", "at", "Houston,", "Houston,", "Texas", "Communicated", "by", "George", "Patrinos", "Received", "23", "February", "2011;", "accepted", "revised", "manuscript", "13", "April", "2011.", "Published", "online", "21", "April", "2011", "in", "Wiley", "Online", "Library", "(www.wiley.com/humanmutation).", "DOI", "10.1002/humu.21517", "OFFICIAL", "JOURNAL", "www.hgvs.org", "ABSTRACT:", "With", "the", "advance", "of", "sequencing", "technologies,", "whole", "exome", "sequencing", "has", "increasingly", "been", "used", "to", "identify", "mutations", "that", "cause", "human", "diseases,", "especially", "rare", "Mendelian", "diseases.", "Among", "the", "analysis", "steps,", "functional", "prediction", "(of", "being", "deleterious)", "plays", "an", "important", "role", "in", "filtering", "or", "prioritizing", "nonsynonymous", "SNP", "(NS)", "for", "further", "analysis.", "Unfortunately,", "different", "prediction", "algorithms", "use", "different", "information", "and", "each", "has", "its", "own", "strength", "and", "weakness.", "It", "has", "been", "suggested", "that", "investigators", "should", "use", "predictions", "from", "multiple", "algorithms", "instead", "of", "relying", "on", "a", "single", "one.", "However,", "querying", "predictions", "from", "different", "databases/Web-servers", "for", "different", "algorithms", "is", "both", "tedious", "and", "time", "consum-", "ing,", "especially", "when", "dealing", "with", "a", "huge", "number", "of", "NSs", "identified", "by", "exome", "sequencing.", "To", "facilitate", "the", "process,", "we", "developed", "dbNSFP", "(database", "for", "nonsynonymous", "SNPs’", "functional", "predictions).", "It", "compiles", "prediction", "scores", "from", "four", "new", "and", "popular", "algorithms", "(SIFT,", "Polyphen2,", "LRT,", "and", "MutationTaster),", "along", "with", "a", "conservation", "score", "(PhyloP)", "and", "other", "related", "information,", "for", "every", "potential", "NS", "in", "the", "human", "genome", "(a", "total", "of", "75,931,005).", "It", "is", "the", "first", "integrated", "database", "of", "functional", "predictions", "from", "multiple", "algorithms", "for", "the", "comprehensive", "collection", "of", "human", "NSs.", "dbNSFP", "is", "freely", "available", "for", "download", "at", "http://sites.google.com/site/jpopgen/dbNSFP.", "Hum", "Mutat", "32:894–899,", "2011.", "&", "2011", "Wiley-Liss,", "Inc.", "KEY", "WORDS:", "dbNSFP;", "functional", "prediction;", "database;", "SIFT;", "Polyphen2;", "LRT;", "MutationTaster;", "PhyloP", "Introduction", "A", "nonsynonymous", "SNP", "(NS)", "is", "a", "single", "nucleotide", "variant", "that", "causes", "an", "amino", "acid", "change", "of", "its", "corresponding", "protein.", "Because", "of", "their", "direct", "link", "to", "protein", "changes,", "NSs", "are", "believed", "to", "be", "the", "major", "contributor", "to", "heritable", "human", "diseases", "among", "all", "types", "of", "variants", "in", "the", "human", "genome.", "As", "evidence,", "NSs", "constitute", "more", "than", "half", "of", "the", "entries", "of", "disease-causing", "genetic", "changes", "in", "the", "Human", "Gene", "Mutation", "Database", "(HGMD)", "[Stenson", "et", "al.,", "2009].", "Additional", "Supporting", "Information", "may", "be", "found", "in", "the", "online", "version", "of", "this", "article.", "Correspondence", "to:", "Xiaoming", "Liu,", "Human", "Genetics", "Center,", "School", "of", "Public", "Health,", "The", "University", "of", "Texas", "Health", "Science", "Center", "at", "Houston,", "1200", "Herman", "Pressler", "Drive,", "E529,", "Houston,", "Texas", "77030.", "E-mail:", "xiaoming.liu@uth.tmc.edu", "Contract", "grant", "sponsor:", "The", "National", "Institutes", "of", "Health;", "Contract", "grant", "numbers:", "RC2-HL02419-01;", "RC2", "HL103010-01;", "1U01HG005728-01.", "Based", "on", "current", "technologies,", "it", "is", "too", "costly", "and", "time-", "consuming", "to", "investigate", "the", "functional", "effect", "of", "every", "NS", "experimentally.", "Fortunately,", "there", "are", "algorithms", "available", "to", "help", "to", "predict", "the", "potential", "of", "a", "NS", "being", "functional", "or", "deleterious.", "Functional", "prediction", "algorithms", "for", "NS", "have", "been", "developed", "in", "recent", "years", "with", "the", "advance", "of", "phylogenetics,", "structure", "biology,", "bioinformatics", "and", "population", "genetics", "(see", "reviews", "by", "[Horner", "et", "al.,", "2010;", "Karchin,", "2009;", "Ng", "and", "Henikoff,", "2006;", "Thusberg", "and", "Vihinen,", "2009]).", "Usually,", "the", "algorithms", "output", "a", "score", "measuring", "how", "likely", "an", "NS", "is", "deleterious,", "along", "with", "its", "binary", "prediction.", "Functional", "predictions", "play", "an", "important", "role", "in", "sequencing", "based", "genotype–phenotype", "association", "analyses.", "Prediction", "scores", "have", "been", "used", "to", "weight", "different", "NSs", "in", "order", "to", "increase", "the", "power", "of", "detecting", "genes", "influencing", "a", "trait", "[Price", "et", "al.,", "2010].", "More", "importantly,", "functional", "prediction", "has", "become", "an", "indispensable", "step", "in", "identifying", "genes", "causing", "rare", "Mendelian", "diseases", "using", "an", "exome-sequencing", "approach", "[Cooper", "et", "al.,", "2010;", "Ng", "et", "al.,", "2010a,b,c].", "Functional", "predictions", "or", "conservation", "information", "are", "used", "to", "filter", "or", "prioritize", "the", "novel", "NSs", "for", "further", "analysis", "or", "confirmation", "[Ng", "et", "al.,", "2010].", "Because", "different", "algorithms", "use", "different", "information", "and", "are", "based", "on", "different", "training", "data,", "each", "has", "its", "own", "strength", "and", "weakness.", "It", "has", "been", "suggested", "to", "use", "the", "outputs", "from", "multiple", "algorithms", "to", "make", "a", "more", "reliable", "prediction", "for", "a", "NS", "(e.g.,", "by", "using", "consensus", "prediction", "or", "majority", "vote)", "[Chun", "and", "Fay,", "2009].", "Because", "querying", "predictions", "from", "different", "databases/Web-", "servers", "for", "different", "algorithms", "is", "both", "tedious", "and", "time", "consuming,", "we", "developed", "dbNSFP", "(database", "for", "nonsynonymous", "SNPs’", "functional", "predictions)", "to", "facilitate", "the", "process.", "We", "first", "compiled", "a", "collection", "of", "all", "possible", "NSs", "in", "the", "human", "genome", "(a", "total", "of", "75,931,005)", "based", "on", "the", "annotation", "of", "the", "Consensus", "Coding", "Sequence", "(CCDS)", "project", "[Pruitt", "et", "al.,", "2009].", "We", "next", "collected", "their", "corresponding", "prediction", "scores", "from", "four", "new", "and", "popular", "prediction", "algorithms", "(SIFT", "[Kumar", "et", "al.,", "2009],", "Polyphen2", "[Adzhubei", "et", "al.,", "2010],", "LRT", "[Chun", "and", "Fay,", "2009],", "and", "MutationTaster", "[Schwarz", "et", "al.,", "2010]).", "We", "also", "added", "other", "related", "information", "including", "a", "conservation", "score", "(PhyloP)", "[Siepel", "et", "al.,", "2006],", "degenerate", "type,", "and", "corresponding", "codons", "and", "genes.", "The", "dbNSFP", "is", "the", "first", "known", "integrated", "database", "of", "functional", "predictions", "from", "multiple", "algorithms", "for", "the", 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"complexity", "in", "the", "human", "auditory", "and", "visual", "system", "Sarah", "Lippé1,", "Natasa", "Kovacevic", "2", "and", "Anthony", "Randal", "McIntosh", "2", "1", "Centre", "de", "Recherche", "CHU", "Ste-Justine,", "University", "of", "Montreal,", "Montreal,", "Quebec,", "Canada", "2", "The", "Rotman", "Research", "Institute,", "University", "ofToronto,Toronto,", "Ontario,", "Canada", "REVIEW", "ARTICLE", "published:", "16", "November", "2009", "doi:", "10.3389/neuro.09.048.2009", "Edited", "by:", "Silvia", "A.", "Bunge,", "University", "of", "California,", "USA", "Reviewed", "by:", "Rick", "O.", "Gilmore,The", "Pennyslvania", "State", "University,", "USA", "Correspondence:", "Sarah", "Lippé,", "Département", "de", "Psychologie", "Université", "de", "Montréal,", "C.P.", "6128,", "succursale", "Centre-Ville", "Montréal,", "Québec,", "H3C", "3J7,", "Canada.", "e-mail:", "sarah.lippe@umontreal.ca", "Brain", "development", "carries", "with", "it", "a", "large", "number", "of", "structural", "changes", "at", "the", "local", "level", "which", "impact", "on", "the", "functional", "interactions", "of", "distributed", "neuronal", "networks", "for", "perceptual", "processing.", "Such", "changes", "enhance", "information", "processing", "capacity,", "which", "can", "be", "indexed", "by", "estimation", "of", "neural", "signal", "complexity.", "Here,", "we", "show", "that", "during", "development,", "EEG", "signal", "complexity", "increases", "from", "one", "month", "to", "5", "years", "of", "age", "in", "response", "to", "auditory", "and", "visual", "stimulation.", "However,", "the", "rates", "of", "change", "in", "complexity", "were", "not", "equivalent", "for", "the", "two", "responses.", "Infants’", "signal", "complexity", "for", "the", "visual", "condition", "was", "greater", "than", "auditory", "signal", "complexity,", "whereas", "adults", "showed", "the", "same", "level", "of", "complexity", "to", "both", "types", "of", "stimuli.", "The", "differential", "rates", "of", "complexity", "change", "may", "reﬂect", "a", "combination", "of", "innate", "and", "experiential", "factors", "on", "the", "structure", "and", "function", "of", "the", "two", "sensory", "systems.", "Keywords:", "development,", "EEG,", "signal,", "entropy,", "complexity,", "vision,", "audition,", "infant", "INTRODUCTION", "Infancy", "is", "a", "time", "of", "enormous", "changes", "in", "brain", "structure", "and", "function.", "For", "example,", "glucose", "metabolism", "rises", "(Chugani,", "1998)", "and", "brain", "volume", "shows", "a", "4-fold", "increase", "during", "the", "ﬁrst", "4", "years", "of", "life", "(Courchesne", "et", "al.,", "2000).", "Increases", "in", "synaptic", "density", "are", "followed", "by", "a", "declining", "slope", "within", "this", "period", "(Huttenlocher", "and", "Dabholkar,", "1997),", "whereas", "myelination", "continues", "well", "into", "adolescence", "(Paus", "et", "al.,", "1999).", "The", "functional", "consequence", "of", "these", "changes", "should", "be", "reﬂected", "in", "the", "increasing", "processing", "capacities", "of", "the", "developing", "child.", "More", "precisely,", "the", "changes", "in", "functional", "responses", "are", "thought", "to", "represent", "an", "increase", "in", "the", "integration", "within", "local", "neural", "ensembles", "together", "with", "more", "precise", "re-entrant", "interactions", "between", "distal", "ensembles", "(Thatcher", "et", "al.,", "2007;", "Fair", "et", "al.,", "2009).", "The", "balance", "between", "local", "integration", "and", "distal", "segregation", "is", "a", "characteristic", "architecture", "for", "a", "complex", "system", "that", "has", "an", "optimal", "capacity", "for", "information", "inte-", "gration", "(Tononi", "et", "al.,", "1994).", "Thus,", "development", "can", "be", "conceived", "of", "as", "the", "movement", "of", "the", "brain", "towards", "a", "complex", "system.", "Measures", "of", "complexity", "may", "be", "a", "sensitive", "index", "of", "maturational", "changes", "in", "brain", "function.", "For", "example,", "a", "marked", "increase", "with", "age", "in", "complex-", "ity", "of", "the", "brain’s", "electrical", "resting", "state", "activity", "has", "been", "shown", "by", "(Meyer-Lindenberg,", "1996)", "using", "two", "measures", "of", "complexity,", "cor-", "relation", "dimensions", "and", "the", "Lyapunov", "coefﬁcient.", "A", "recent", "study", "by", "McIntosh", "et", "al.", "(2008)", "showed", "an", "increase", "in", "EEG", "signal", "complexity", "with", "maturation", "in", "pre-adolescent", "children.", "Critically,", "they", "showed", "that", "this", "increase", "in", "complexity", "was", "strongly", "correlated", "with", "more", "stable", "and", "accurate", "behavioural", "performance.", "There", "does", "appear", "to", "be", "a", "general", "increase", "in", "brain", "signal", "com-", "plexity", "with", "maturation.", "However,", "the", "maturational", "rates", "of", "different", "neural", "systems", "are", "not", "uniform.", "For", "example,", "rates", "of", "neuroana-", "tomical", "and", "functional", "development", "for", "the", "visual", "and", "the", "auditory", "systems", "are", "distinct.", "The", "subcortical", "auditory", "pathways", "seem", "to", "mature", "earlier", "compared", "to", "the", "visual", "subcortical", "system.", "Brainstem", "auditory", "evoked", "potential", "of", "a", "few", "milliseconds", "post", "stimulus", "can", "be", "measured", "from", "birth", "(Jiang", "et", "al.,", "2001).", "Conversely,", "at", "the", "thalamocortical", "level,", "the", "tendency", "may", "be", "reversed.", "The", "genicu-", "localcarine", "tract", "(visual", "thalamocortical", "pathway)", "shows", "relative", "maturity", "at", "5", "months", "of", "age,", "whereas", "the", "maturation", "of", "the", "tha-", "lamic", "projections", "to", "the", "auditory", "cortex", "continues", "until", "6", "years", "of", "age", "(Yakovlev", "and", "Lecours,", "1967;", "Moore", "and", "Linthicum,", "2007).", "In", "addition,", "myelination", "begins", "earlier", "in", "the", "occipital", "lobe", "than", "in", "the", "temporal", "lobe", "(Yakovlev", "and", "Lecours,", "1967).", "Synapse", "density", "shows", "a", "rapid", "increase", "in", "the", "occipital", "cortex", "until", "about", "8", "months", "of", "age", "that", "is", "followed", "by", "a", "decline", "(Huttenlocher", "and", "Dabholkar,", "1997),", "whereas", "the", "synaptic", "density", "of", "the", "auditory", "cortex", "increases", "until", "50", "months", "before", "connections", "are", "pruned", "(Huttenlocher", "and", "Dabholkar,", "1997).", "Even", "at", "later", "ages", "of", "childhood,", "the", "time", "course", "of", "grey", "matter", "thickness", "change", "differs", "across", "brain", "regions", "(Giedd", "et", "al.,", "2006).", "The", "differences", "in", "prenatal", "exposure", "of", "the", "sensory", "sys-", "tem", "to", "environmental", "stimulation", "may", "have", "an", "impact", "on", "the", "func-", "tional", "state.", "Human", "foetuses", "and", "newborns", "detect", "sound", "changes", "in", "frequencies", "(Draganova", "et", "al.,", "2005).", "Auditory", "abilities", "in", "the", "early", "post-natal", "months", "include", "discrimination", "of", "musical", "features", "(Leppanen", "and", "Lyytinen,", "1997;", "Ceponiene", "et", "al.,", "2002;", "Morr", "et", "al.,", "2002),", "phonemic", "identity", "(Cheour", "et", "al.,", "1998),", "and", "gap", "detection", "(Trehub", "et", "al.,", "1995).", "By", "8", "months", "of", "age,", "infants", "already", "discrimi-", "nate", "their", "native", "language", "better", "than", "any", "other", "languages", "(Kuhl,", "2000).", "On", "the", "contrary,", "intrauterine", "visual", "competences", "of", "the", "infant", "have", "not", "been", "well", "explored.", "Prematurely", "born", "infants", "show", "a", "visual", "evoked", "potential", "response", "that", "is", "not", "advanced", "after", "term", "compared", "to", "infants", "born", "at", "term", "(Roy", "et", "al.,", "1995).", "The", "development", "of", "visual", "capacities", "is", "rapid", "in", "the", "ﬁrst", "post-natal", "months.", "By", "4", "months", "of", "age,", "infants", "born", "at", "term", "show", "ﬁxation/orientation", "abilities,", "saccades,", "binocular", "vision,", "and", "the", "visual", "ﬁelds", "are", "enlarged", "(Speeg-Schatz,", "2007).", "Infants", "of", "4–6", "months", "of", "age", "and", "on", "can", "segment", "objects", "from", "texture", "orientations", "(Atkinson", "and", "Braddick,", "1992;", "Burkhalter,", "1993;", "Norcia", "et", "al.,", "2005),", "resulting", "in", "visuomotor", "behaviours", "devel-", "opment", "such", "as", "reaching", "and", "grasping", "capacities.", "Frontiers", "in", "Human", "Neuroscience", "www.frontiersin.org", "November", "2009", "\|", "Volume", "3", "\|", "Article", "48", "\|", "1" ]	[ 0, 0, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 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"Box", "1).", "That", "meant", "describing:", "a)", "the", "history", "of", "the", "ﬁeld", "in", "our", "country", "(short", "as", "the", "history", "of", "the", "ﬁeld", "itself", "is", "short);", "b)", "the", "current", "state", "of", "the", "ﬁeld", "in", "Brazil;", "c)", "the", "inﬂuence", "of", "computational", "biology–related", "technologies", "on", "the", "development", "of", "the", "national", "economy;", "d)", "the", "entrepreneurship", "that", "is", "rising", "from", "already-established", "academic", "activities;", "and", "e)", "educational", "activities", "ongoing", "or", "planned", "which", "are", "deemed", "necessary", "to", "establish", "the", "required", "critical", "mass", "of", "well-trained", "specialists.", "Why", "is", "an", "article", "like", "this", "important", "now?", "It", "is", "estimated", "that", "Brazil", "combined", "with", "China,", "Russia,", "and", "India", "will", "have", "a", "larger", "gross", "national", "product", "(GNP)", "than", "the", "US,", "Japan,", "Germany,", "and", "the", "UK", "combined", "by", "2020.", "In", "short,", "we", "can", "expect", "Brazil", "to", "have", "signiﬁcant", "impact", "on", "the", "ﬁeld", "of", "computational", "biology", "in", "the", "years", "to", "come,", "and", "now", "is", "the", "time", "to", "explore", "that", "promise.", "Increased", "Economic", "Activity", "Boosted", "Research", "Investment", "Brazil", "is", "a", "country", "with", "almost", "190", "million", "inhabitants", "that", "occupies", "an", "area", "equal", "to", "81%", "of", "the", "area", "of", "Europe", "and", "115%", "of", "the", "area", "of", "the", "US,", "excluding", "Alaska", "and", "Hawaii.", "In", "the", "late", "1980s,", "Brazil", "left", "behind", "its", "mantle", "as", "a", "simple", "coffee", "producer", "with", "an", "agricultural", "boom,", "offering", "the", "world", "market", "major", "commodities", "such", "as", "soybeans,", "meat,", "poultry,", "and,", "more", "recently,", "fruit", "and", "ﬂour.", "The", "rise", "in", "agricultural", "production", "came", "via", "a", "well-constructed", "socioeconomic", "plan", "put", "together", "by", "the", "Brazilian", "government,", "including", "targeted", "investment", "in", "supporting", "science", "and", "technology.", "As", "a", "consequence,", "Brazil", "became,", "for", "example,", "one", "of", "the", "major", "exporters", "of", "medium-sized", "aircraft.", "Further,", "the", "Brazilian", "petroleum", "company,", "Petrobras,", "provides", "Brazil", "self-", "sufﬁciency", "in", "oil,", "and", "is", "a", "major", "catalyst", "for", "the", "widespread", "use", "of", "ethanol", "in", "automobiles.", "The", "increasing", "economic", "activity", "enabled", "the", "country", "to", "invest", "proportionally", "in", "its", "scientiﬁc", "research.", "Government", "Policies", "for", "Research", "and", "Development", "As", "part", "of", "this", "investment,", "the", "Brazilian", "government", "showed", "speciﬁc", "interest", "in", "biotechnology,", "and", "I", "would", "argue", "that", "the", "current", "favorable", "situation,", "in", "which", "computational", "biologists", "ﬁnd", "themselves,", "has", "deep", "roots", "in", "the", "long-term", "dedication", "of", "policymakers", "to", "biotechnology.", "In", "the", "1920s", "and", "1930s", "the", "ﬁrst", "Brazilian", "universities", "were", "established.", "The", "largest", "of", "them", "all,", "USP", "(University", "of", "Sa˜", "o", "Paulo),", "was", "started", "in", "1934.", "Today,", "USP", "is", "responsible", "for", "more", "than", "a", "quarter", "of", "the", "total", "publications", "in", "Brazil", "in", "almost", "every", "scientiﬁc", "area,", "even", "though", "there", "are", "more", "than", "100", "universities", "in", "Brazil", "now.", "In", "terms", "of", "productivity,", "three", "other", "universities", "closely", "follow:", "UNICAMP", "in", "Campinas,", "in", "the", "state", "of", "Sa˜", "o", "Paulo,", "UFRJ", "in", "Rio", "de", "Janeiro,", "and", "UFMG", "in", "Belo", "Horizonte.", "Notably,", "these", "four", "universities", "together", "with", "EMBRAPA", "(Brazilian", "enterprise", "for", "research", "in", "agriculture,", "a", "close", "equivalent", "to", "the", "US", "Department", "of", "Agriculture),", "Fiocruz,", "and", "Ludwig", "Institute,", "both", "of", "which", "are", "involved", "in", "human", "health", "related", "research,", "and", "the", "National", "Laboratory", "for", "Scientiﬁc", "Computation", "(LNCC),", "are", "responsible", "for", "most", "of", "the", "scientiﬁc", "publications", "in", "computational", "biology.", "To", "consolidate", "its", "efforts", "in", "building", "consistent", "policies", "for", "scientiﬁc", "growth", "and", "to", "create", "a", "critical", "mass", "of", "specialists", "in", "various", "areas", "of", "science,", "in", "1951", "the", "Brazilian", "government", "established", "the", "National", "Research", "Council", "(CNPq),", "and", "the", "National", "Agency", "for", "Scholarly", "Advancement", "in", "Scientiﬁc", "Research", "(CAPES).", "The", "former", "agency", "was", "focused", "on", "guiding", "national", "scientiﬁc", "advancement", "through", "ﬁnancing", "research", "projects", "and", "collaborations,", "while", "the", "latter", "provided", "scholarships", "to", "anyone", "who", "wanted", "to", "obtain", "higher", "degrees", "(Master’s,", "Ph.D.)", "and", "to", "undertake", "postdoctoral", "training,", "either", "here", "in", "Brazil", "or", "abroad.", "In", "parallel,", "Brazilian", "states", "initiated", "their", "own", "Scientiﬁc", "Research", "Agencies", "(FAP)", "and", "Sa˜", "o", "Paulo", "started", "with", "its", "own,", "FAPESP,", "in", "1958.", "As", "Sa˜", "o", "Paulo", "is", "the", "richest", "state", "in", "the", "Brazilian", "federation,", "the", "impact", "of", "FAPESP", "investments", "on", "science", "and", "technology", "in", "that", "particular", "region", "were,", "and", "are,", "substantial.", "The", "positive", "impact", "of", "FAPESP", "can", "be", "attributed", "to", "at", "least", "two", "factors.", "First,", "Sa˜", "o", "Paulo", "has", "a", "law", "stating", "that", "1%", "of", "the", "tax", "revenue", "collected", "by", "the", "state", "has", "to", "be", "given", "to", "FAPESP,", "and,", "second,", "the", "administrative", "costs", "of", "FAPESP", "are", "limited", "to", "not", "more", "than", "5%", "of", "its", "total", "budget.", "On", "the", "national", "level,", "in", "1981", "the", "Brazilian", "government", "initiated", "a", "broad", "program", "(PRONAB)", "for", "supporting", "scientiﬁc", "research", "in", "biotechnology.", "A", "further", "government", "program,", "PADCT,", "was", "initiated", "in", "1984.", "As", "a", "consequence", "of", "these", "national", "programs,", "Brazil", "has", "established", "a", "critical", "mass", "of", "well-trained", "specialists", "and", "equipped", "many", "laboratories,", "which", "were", "fully", "functional", "by", "the", "early", "1990s.", "These", "programs", "notwithstanding,", "Brazil", "remains", "below", "many", "countries", "with", "only", "12%", "of", "17-", "to", "25-year-olds", "studying", "at", "universities", "compared", "with", "approximately", "50%", "in", "the", "United", "States.", "Genomics", "and", "Bioinformatics", "In", "1997", "FAPESP", "began", "to", "invest", "both", "ﬁnancial", "and", "human", "resources", "in", "genome", "sequencing.", "No", "central", "sequencing", "Editor:", "Philip", "E.", "Bourne,", "University", "of", "California", "San", "Diego,", "United", "States", "of", "America", "Citation:", "Neshich", "G", "(2007)", "Computational", "Biology", "in", "Brazil.", "PLoS", "Comput", "Biol", "3(10):", "e185.", "doi:10.1371/journal.pcbi.0030185", "Copyright:", "2007", "Goran", "Neshich.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", 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380, 1019 ], [ 384, 1009, 403, 1019 ], [ 405, 1009, 411, 1019 ], [ 414, 1009, 446, 1019 ], [ 448, 1009, 469, 1019 ] ]	[ "Bisgin", "et", "al.", "BMC", "Cancer", "2012,", "12:58", "http://www.biomedcentral.com/1471-2407/12/58", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Increased", "serum", "sTRAIL", "levels", "were", "correlated", "with", "survival", "in", "bevacizumab-treated", "metastatic", "colon", "cancer", "Atil", "Bisgin1,", "Aysegul", "Kargi2,", "Arzu", "D", "Yalcin3,", "Cigdem", "Aydin1,", "Deniz", "Ekinci2,", "Burhan", "Savas2", "and", "Salih", "Sanlioglu1", "Abstract", "Background:", "Colorectal", "cancer", "is", "the", "third", "most", "common", "cancer", "and", "the", "third", "leading", "cause", "of", "cancer-related", "death.", "Bevacizumab", "is", "a", "humanized", "monoclonal", "antibody", "developed", "against", "vascular", "endothelial", "growth", "factor", "(VEGF)", "for", "the", "treatment", "of", "metastatic", "cancer.", "The", "parameters", "of", "RECIST", "(Response", "Evaluation", "Criteria", "for", "Solid", "Tumors)", "are", "not", "adequate", "to", "detect", "important", "treatment", "effects", "and", "response.", "Our", "goal", "was", "to", "evaluate", "the", "possibility", "of", "using", "sTRAIL", "(serum-soluble", "TNF-related", "apoptosis-inducing", "ligand)", "and", "VEGF", "as", "markers", "of", "treatment", "efficacy", "and", "prognosis", "in", "patients", "with", "metastatic", "colon", "cancer.", "Methods:", "sTRAIL", "and", "VEGF", "levels", "were", "measured", "by", "ELISA", "in", "the", "sera", "of", "16", "bevacizumab-treated", "metastatic", "colon", "cancer", "patients", "and", "10", "presumably", "healthy", "age-matched", "controls.", "The", "measurements", "were", "taken", "before", "and", "after", "treatment", "for", "comparison", "purposes.", "Results:", "Elevated", "levels", "of", "sTRAIL", "were", "found", "in", "seven", "out", "of", "16", "patients", "after", "bevacizumab", "treatment.", "Although", "these", "patients", "had", "a", "median", "survival", "time", "of", "20.6", "months,", "the", "remaining", "bevacizumab-treated", "patients", "who", "did", "not", "show", "an", "increase", "in", "sTRAIL", "had", "a", "median", "survival", "time", "of", "9.4", "months.", "As", "expected,", "serum", "VEGF", "levels", "were", "decreased", "in", "all", "patients", "who", "received", "bevacizumab", "therapy", "and", "showed", "no", "correlation", "between", "serum", "VEGF", "levels", "and", "patient", "survival", "(data", "not", "shown).", "Conclusions:", "Serum", "sTRAIL", "levels", "might", "be", "a", "useful", "predictor", "of", "prognosis", "in", "metastatic", "colon", "cancer,", "in", "the", "early", "evaluation", "stages", "following", "bevacizumab", "treatment.", "Background", "Colorectal", "cancer", "is", "the", "third", "most", "common", "cancer", "and", "the", "second", "leading", "cause", "of", "cancer-related", "death", "[1].", "Overall,", "the", "5-year", "survival", "rate", "is", "<10%", "for", "stage", "IV", "cancer", "[2].", "The", "cure", "rate", "with", "surgery", "alone", "is", "very", "low", "and", "chemotherapy", "and", "radiotherapy", "are", "usually", "needed", "in", "patients", "with", "untreated", "metastatic", "colon", "cancer.", "The", "development", "of", "colorectal", "cancer", "is", "characterized", "by", "a", "sequence", "of", "events", "during", "which", "normal", "colonic", "epithe-", "lium", "gradually", "transforms", "to", "carcinoma", "tissue,", "in", "most", "cases,", "via", "the", "development", "of", "colorectal", "adenomas", "[3].", "This", "sequence", "of", "events", "is", "driven", "by", "an", "accumulation", "of", "molecular", "(epi)genetic", "alterations", "causing", "progressive", "disorders", "in", "cell", "growth,", "differentiation", "and", "apoptosis", "", "Correspondence:", "atilbisgin@yahoo.co.uk", "1Human", "Gene", "and", "Cell", "Therapy", "Center", "of", "Akdeniz", "University", "Hospitals", "and", "Clinics,", "Department", "of", "Medical", "Genetics,", "Antalya,", "Turkey", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "[4,5].", "Apoptosis,", "or", "programmed", "cell", "death,", "plays", "an", "important", "role", "in", "the", "development", "and", "maintenance", "of", "tissue", "homeostasis", "but", "also", "represents", "an", "effective", "mechanism", "by", "which", "abnormal", "cells,", "such", "as", "tumor", "cells,", "can", "be", "eliminated", "[6-8].", "Abnormalities", "in", "apoptotic", "function", "or", "resistance", "to", "apoptosis", "have", "been", "identified", "as", "important", "events", "in", "the", "pathogenesis", "of", "colorectal", "cancer", "and", "its", "resistance", "to", "chemotherapeutic", "drugs", "and", "radiotherapy", "[9,10].", "In", "recent", "years,", "bevacizumab,", "a", "novel", "humanized", "monoclonal", "antibody", "directed", "against", "vascular", "endothe-", "lial", "growth", "factor", "(VEGF)", "has", "found", "widespread", "clinical", "use", "as", "an", "angiogenesis", "inhibitor", "for", "certain", "types", "of", "metastatic", "cancers", "[11].", "Treatment", "with", "bevacizumab", "with/without", "the", "combination", "of", "other", "chemotherapeu-", "tic", "agents", "inhibits", "VEGF", "receptor", "activation", "and", "vascular", "permeability,", "which", "eventually", "lead", "to", "tumor", "cell", "apop-", "tosis", "[12,13].", "Apoptosis", "can", "be", "induced", "passively,", "©", "2012", "Bisgin", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." 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"die:", "asymmetric", "dimethylarginine", "and", "septic", "shock", "Rainer", "H", "Böger", "Clinical", "Pharmacology", "Unit,", "Institute", "of", "Experimental", "and", "Clinical", "Pharmacology,", "University", "Hospital", "Hamburg-Eppendorf,", "Germany", "Corresponding", "author:", "Rainer", "H", "Böger,", "boeger@uke.uni-hamburg.de", "Published:", "3", "November", "2006", "This", "article", "is", "online", "at", "http://ccforum.com/content/10/6/169", "©", "2006", "BioMed", "Central", "Ltd", "See", "related", "research", "by", "O’Dwyer", "et", "al.,", "http://ccforum.com/content/10/5/R139", "Critical", "Care", "2006,", "10:169", "(doi:10.1186/cc5076)", "Abstract", "Nitric", "oxide", "(NO)", "is", "an", "important", "mediator", "of", "host", "defence", "and", "of", "vascular", "tone.", "In", "septic", "shock,", "upregulation", "of", "inducible", "NO", "synthase", "leads", "to", "the", "production", "of", "vast", "amounts", "of", "NO,", "which", "contribute", "to", "pathogen", "elimination", "but", "also", "to", "inappropriate", "vaso-", "dilation", "and", "to", "loss", "of", "vascular", "resistance.", "Asymmetric", "dimethyl-", "arginine", "(ADMA)", "is", "an", "endogenous", "inhibitor", "of", "NO", "synthases", "shown", "to", "contribute", "to", "the", "regulation", "of", "vascular", "tone.", "ADMA", "was", "recently", "identified", "as", "a", "marker", "of", "organ", "dysfunction", "and", "mortality", "in", "intensive", "care", "patients", "and", "as", "a", "novel", "cardiovascular", "risk", "factor.", "In", "the", "present", "issue", "of", "Critical", "Care,", "a", "study", "by", "O’Dwyer", "and", "colleagues", "identifies", "ADMA", "as", "a", "potential", "regulator", "of", "NO", "production", "in", "septic", "shock.", "Being", "an", "inhibitor", "of", "NO", "production,", "ADMA", "may", "at", "least", "partly", "counteract", "pathological", "hypotension,", "but", "at", "the", "same", "time", "may", "impair", "the", "NO-dependent", "host", "defence.", "A", "mechanism", "is", "proposed", "by", "which", "the", "interplay", "between", "ADMA", "and", "inducible", "NO", "synthase", "activity", "is", "mediated.", "ADMA", "levels", "should", "be", "determined", "in", "future", "studies", "evaluating", "the", "regulation", "of", "NO", "in", "the", "intensive", "care", "setting.", "In", "the", "present", "issue", "of", "Critical", "Care,", "O’Dwyer", "and", "colleagues", "[1]", "report", "the", "results", "of", "a", "study", "in", "47", "patients", "with", "septic", "shock.", "Asymmetric", "dimethylarginine", "(ADMA)", "levels", "were", "elevated", "in", "these", "patients", "at", "the", "time", "of", "admission", "to", "the", "intensive", "care", "unit", "(ICU)", "as", "compared", "with", "a", "group", "of", "10", "healthy", "controls.", "ADMA", "levels", "in", "septic", "patients", "directly", "correlated", "with", "the", "Sequential", "Organ", "Failure", "Assessment", "scores,", "with", "the", "degree", "of", "acidaemia", "and", "lactaemia,", "and", "with", "vasopressor", "requirements.", "Interestingly", "enough,", "ADMA", "levels", "were", "higher", "in", "patients", "requiring", "vasoactive", "infusions", "than", "in", "those", "not", "requiring", "vasoactive", "infusions.", "ADMA", "levels", "further", "increased", "during", "the", "subsequent", "7", "days", "of", "ICU", "treatment.", "Nonsurvivors", "tended", "to", "have", "higher", "ADMA", "plasma", "levels", "on", "days", "1", "and", "7", "of", "ICU", "treatment", "as", "compared", "with", "survivors,", "although", "this", "trend", "was", "insignificant", "in", "the", "small", "patient", "group.", "The", "authors", "also", "demonstrated", "that", "a", "genetic", "polymorphism", "in", "the", "promoter", "region", "of", "the", "dimethylarginine", "dimethylaminohydrolase", "(DDAH)", "II", "gene", "was", "significantly", "associated", "with", "ADMA", "levels", "in", "these", "patients,", "suggesting", "that", "the", "genetically", "anchored", "dysfunction", "of", "the", "enzyme", "that", "metabolises", "ADMA", "may", "importantly", "regulate", "ADMA", "levels.", "Standard", "therapy", "for", "patients", "with", "sepsis", "includes", "ICU", "admission,", "careful", "selection", "of", "antibiotic", "therapy,", "and,", "if", "needed,", "haemodynamic", "and", "ventilatory", "support", "[2].", "Despite", "the", "use", "of", "these", "intensive", "therapies,", "however,", "mortality", "from", "sepsis", "has", "remained", "at", "levels", "between", "35%", "and", "50%", "[2].", "Nitric", "oxide", "(NO)", "is", "referred", "to", "as", "a", "key", "mediator", "of", "vasodilatation", "and", "catecholamine", "resistance", "in", "septic", "shock", "[3,4].", "Whereas", "in", "physiological", "conditions", "NO", "is", "mainly", "formed", "in", "the", "endothelium", "at", "low", "rates", "by", "the", "activity", "of", "the", "constitutive,", "endothelial", "isoform", "of", "the", "enzyme", "NO", "synthase,", "inflammatory", "stimuli", "such", "as", "bacterial", "lipopolysaccharides", "and", "cytokines", "released", "during", "sepsis", "result", "in", "a", "strong", "upregulation", "of", "an", "inducible", "isofom", "of", "NO", "synthase", "(iNOS).", "This", "isoform,", "once", "upregulated,", "releases", "huge", "amounts", "of", "NO", "during", "prolonged", "time", "intervals.", "The", "iNOS-derived", "NO", "contributes", "to", "pathogen", "elimination.", "NO-induced", "vaso-", "dilatation,", "however,", "also", "contributes", "to", "widespread", "vascular", "loss", "of", "tone", "and", "has", "been", "implicated", "in", "the", "cardiovascular", "failure", "in", "septic", "shock", "[5].", "There", "has", "been", "controversy", "about", "the", "pathophysiological", "roles", "of", "iNOS", "and", "NO", "in", "the", "development", "of", "septic", "shock", "after", "a", "phase", "III", "trial", "with", "NG-", "monomethyl-L-arginine,", "a", "nonselective", "NO", "synthase", "inhibitor,", "resulted", "in", "excess", "mortality", "[6].", "Indeed,", "experimental", "studies", "have", "suggested", "that", "iNOS-derived", "NO", "plays", "an", "important", "role", "in", "host", "defence", "and", "organ", "protection", "[7].", "During", "the", "past", "decade", "knowledge", "has", "accumulated", "of", "endogenous", "compounds", "that", "inhibit", "NO", "synthase", "activity,", "and", "thereby", "regulate", "NO-dependent", "vascular", "function.", "The", "major", "molecule", "endogenously", "present", "in", "the", "circulation", "at", "concentrations", "sufficiently", "high", "to", "exert", "inhibitory", "effects", "on", "ADMA", "=", "asymmetric", "dimethylarginine;", "DDAH", "=", "dimethylarginine", "dimethylaminohydrolase;", "ICU", "=", "intensive", "care", "unit;", "iNOS", "=", "inducible", "NO", "synthase;", "NO", "=", "nitric", "oxide.", "Page", "1", "of", "3", "(page", "number", "not", "for", "citation", "purposes)" ]	[ 0, 0, 0, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 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1059 ] ]	[ "PDHK-2", "Deficiency", "Is", "Associated", "with", "Attenuation", "of", "Lipase-Mediated", "Fat", "Consumption", "for", "the", "Increased", "Survival", "of", "Caenorhabditis", "elegans", "Dauers", "Sunhee", "Kim,", "E-Jin", "Shin,", "Jeong-Hoon", "Hahm,", "Pil-Jong", "Park,", "Ji-Eun", "Hwang,", "Young-Ki", "Paik", "Department", "of", "Biochemistry", "and", "Integrated", "Omics", "for", "Biomedical", "Science,", "World", "Class", "University", "Program,", "College", "of", "Life", "Science", "and", "Biotechnology,", "Yonsei", "Proteome", "Research", "Center,", "Yonsei", "University,", "Seoul,", "Korea", "Abstract", "In", "Caenorhabditis", "elegans,", "slow", "fat", "consumption", "has", "been", "suggested", "to", "contribute", "to", "the", "extension", "of", "the", "survival", "rate", "during", "nutritionally", "adverse", "conditions.", "Here,", "we", "investigated", "the", "potential", "role", "of", "pyruvate", "dehydrogenase", "kinase", "(PDHK)-", "2,", "the", "C.", "elegans", "homolog", "of", "mammalian", "PDK,", "effects", "on", "fat", "metabolism", "under", "nutritional", "conditions.", "PDHK-2", "was", "expressed", "at", "low", "levels", "under", "well-fed", "conditions", "but", "was", "highly", "induced", "during", "long-term", "starvation", "and", "in", "the", "dauer", "state.", "This", "increase", "in", "pdhk-2", "expression", "was", "regulated", "by", "both", "DAF-16", "and", "NHR-49.", "Dauer-specific", "induction", "of", "PDHK-2", "was", "abolished", "upon", "entry", "into", "the", "post-dauer", "stage.", "Interestingly,", "in", "the", "long-term", "dauer", "state,", "stored", "fat", "levels", "were", "higher", "in", "daf-2(e1370);pdhk-2", "double", "mutants", "than", "in", "daf-2(e1370),", "suggesting", "a", "positive", "relationship", "between", "PDHK-2", "activity", "and", "fat", "consumption.", "PDHK-2", "deficiency", "has", "been", "shown", "to", "lead", "to", "greater", "preservation", "of", "residual", "fats,", "which", "would", "be", "predicted", "to", "contribute", "to", "survival", "during", "the", "dauer", "state.", "A", "test", "of", "this", "prediction", "showed", "that", "the", "survival", "rates", "of", "daf-2(e1370);pdhk-", "2(tm3075)", "and", "daf-2(e1370);pdhk-2(tm3086)", "double", "mutants", "were", "higher", "than", "that", "of", "daf-2(e1370),", "suggesting", "that", "loss", "of", "either", "the", "ATP-binding", "domain", "(tm3075)", "or", "branched", "chain", "keto-acid", "dehydrogenase", "kinase", "domain", "(tm3086)", "of", "PDHK-2", "leads", "to", "reduced", "fat", "consumption", "and", "thus", "favors", "increased", "dauer", "survival.", "This", "attenuated", "fat", "consumption", "in", "the", "long-", "term", "dauer", "state", "of", "C.", "elegans", "daf-2", "(e1370);pdhk-2", "mutants", "was", "associated", "with", "concomitant", "down-regulation", "of", "the", "lipases", "ATGL", "(adipose", "triglyceride", "lipase),", "HSL", "(hormone-sensitive", "lipase),", "and", "C07E3.9", "(phospholipase).", "In", "contrast,", "PDHK-2", "overexpression", "in", "wild-type", "starved", "worms", "induced", "lipase", "expression", "and", "promoted", "abnormal", "dauer", "formation.", "Thus,", "we", "propose", "that", "PDHK-2", "serves", "as", "a", "molecular", "bridge,", "connecting", "fat", "metabolism", "and", "survival", "under", "nutritionally", "adverse", "conditions", "in", "C.", "elegans.", "Citation:", "Kim", "S,", "Shin", "E-J,", "Hahm", "J-H,", "Park", "P-J,", "Hwang", "J-E,", "et", "al.", "(2012)", "PDHK-2", "Deficiency", "Is", "Associated", "with", "Attenuation", "of", "Lipase-Mediated", "Fat", "Consumption", "for", "the", "Increased", "Survival", "of", "Caenorhabditis", "elegans", "Dauers.", "PLoS", "ONE", "7(7):", "e41755.", "doi:10.1371/journal.pone.0041755", "Editor:", "Howard", "Riezman,", "University", "of", "Geneva,", "Switzerland", "Received", "June", "18,", "2012;", "Accepted", "June", "25,", "2012;", "Published", "July", "27,", "2012", "Copyright:", "2012", "Kim", "et", "al.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Funding:", "This", "study", "was", "supported", "by", "the", "National", "Research", "Foundation", "of", "Korea", "(NRF)", "grant", "(No.", "2011-0028112", "to", "YKP)", "and", "WCU", "Program", "(R31-2008-000-", "10086-0)", "funded", "by", "the", "Korean", "government", "(MEST),", "and", "the", "National", "Project", "for", "Personalized", "Genomic", "Medicine", "(A111218-11-CP01", "to", "YKP).", "The", "funders", "had", "no", "role", "in", "study", "design,", "data", "collection", "and", "analysis,", "decision", "to", "publish,", "or", "preparation", "of", "the", "manuscript.", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "", "E-mail:", "paikyk@yonsei.ac.kr", "Introduction", "It", "has", "been", "well", "documented", "that", "a", "close", "relationship", "exists", "between", "energy", "metabolism", "and", "aging", "processes", "in", "animals,", "including", "the", "nematode", "Caenorhabditis", "elegans", "[1,2].", "In", "C.", "elegans,", "in", "particular,", "the", "critical", "role", "of", "insulin/insulin-like", "growth", "factor-1", "(IGF-1)", "signaling", "(IIS)", "in", "metabolism", "and", "the", "control", "of", "aging", "has", "been", "well", "established.", "For", "example,", "suppression", "of", "the", "IIS", "pathway", "has", "been", "shown", "to", "cause", "a", "substantial", "increase", "in", "both", "mean", "lifespan", "(MLS)", "and", "fat", "accumulation", "[1–3].", "This", "pathway", "also", "controls", "the", "dauer", "state,", "a", "non-aging", "condition", "that", "is", "important", "in", "determining", "the", "relationship", "between", "metabolism", "and", "aging", "[4,5].", "When", "C.", "elegans", "encounters", "unfavorable", "growth", "conditions", "(e.g.,", "lack", "of", "food", "or", "high", "temperatures)", "or", "high", "concentrations", "of", "dauer", "pheromones", "(daumones", "or", "ascarosides),", "it", "can", "enter", "the", "dauer", "state", "[5–10].", "Studies", "on", "dauer", "entry", "in", "C.", "elegans", "have", "suggested", "that", "this", "process", "is", "compartmentalized", "according", "to", "metabolic", "phase", "and", "growth", "time", "[11].", "When", "L2", "larvae", "prepare", "for", "dauer", "entry,", "nutritional", "adaptation", "accompanies", "intestinal", "and", "hypodermal", "fat", "accumulation,", "enabling", "C.", "elegans", "to", "survive", "an", "extended", "dormant", "period", "[12].", "The", "dauer", "state", "is", "controlled", "by", "an", "IIS", "mechanism", "in", "which", "DAF-16", "serves", "as", "a", "downstream", "effector", "[11–13].", "The", "dauer", "state", "is", "resistant", "to", "environmental", "stresses,", "such", "as", "heat", "and", "cold,", "as", "well", "as", "oxidative", "stress,", "and", "the", "metabolic", "activity", "of", "dauer", "larvae", "is", "generally", "reduced", "[12].", "Because", "dauer", "larvae", "do", "not", "feed,", "they", "use", "mostly", "stored", "triglycerides", "(TGs)", "as", "an", "energy", "source", "[12,13];", "TGs,", "in", "turn,", "are", "hydrolyzed", "to", "fatty", "acids", "by", "lipases", "[14].", "Additional", "macronutrients", "that", "are", "stored", "and", "metabolized", "in", "dauer", "larvae", "include", "glycogen", "and", "trehalose", "[15].", "Because", "their", "supply", "of", "stored", "nutrients", "is", "limited,", "dauers", "must", "suppress", "energy-consuming", "metabolic", "activities", "to", "survive", "[16].", "Microarray", "and", "SAGE", "(serial", "analysis", "of", "gene", "expression)", "assays", "of", "dauer", "larvae,", "recovered", "dauers,", "and", "mixed-stage", "populations", "have", "suggested", "that", "the", "expression", "of", "enzymes", "involved", "in", "b-oxidation", "of", "fatty", "acids,", "glycolysis,", "glyoxylate,", "and", "gluconeogenesis", "pathways", "are", "enhanced", "under", "nutritionally", "adverse", "conditions,", "indicating", "that", "TGs", "are", "degraded", "by", "lipases", "and", "converted", "into", "sugars", "that", "are", "used", "for", "survival", "[17–21].", "Slow", "energy", "release", "and", "tightly", "controlled", "energy", "consumption", "may", "be", "critical", "to", "long-term", "survival", "through", "diapause,", "hibernation,", "or", "long-term", "fasting", "in", "a", "PLoS", "ONE", "\|", "www.plosone.org", "1", "July", "2012", "\|", "Volume", "7", "\|", "Issue", "7", "\|", "e41755" ]	[ 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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"http://www.cardiab.com/content/10/1/55", "O", "R", "I", "G", "I", "N", "A", "L", "I", "N", "V", "E", "S", "T", "I", "G", "A", "T", "I", "O", "N", "CARDIO", "VASCULAR", "DIABETOLOGY", "Open", "Access", "Circulating", "angiopoietin-2", "and", "soluble", "Tie-2", "in", "type", "2", "diabetes", "mellitus:", "a", "cross-sectional", "study", "Sazan", "Rasul1,", "Marie", "Helene", "Reiter2,", "Aysegul", "Ilhan3,", "Katharina", "Lampichler2,", "Ludwig", "Wagner3", "and", "Alexandra", "Kautzky-Willer1", "Abstract", "Background:", "Type", "2", "diabetes", "is", "associated", "with", "increased", "levels", "of", "Angiopoietin-2", "(Ang-2)", "and", "soluble", "Tie-2", "(sTie-", "2),", "but", "its", "impact", "on", "vascular", "disease", "is", "still", "unknown.", "This", "study", "aimed", "to", "further", "explore", "the", "associations", "of", "Ang-2", "and", "sTie-2", "with", "metabolic", "control", "and", "diabetic", "complications.", "Methods:", "In", "a", "cross-sectional", "designed", "study,", "levels", "of", "Ang-2", "and", "sTie-2", "as", "well", "as", "their", "relationships", "to", "cardiometabolic", "parameters", "were", "determined", "in", "80", "type", "2", "diabetic", "subjects", "(age", "65", "±", "7", "years,", "female", "47.4%).", "Results:", "After", "controlling", "for", "age", "and", "BMI,", "Ang-2", "levels", "were", "associated", "with", "levels", "of", "sTie-2,", "diastolic", "blood", "pressure,", "plasma", "insulin,", "homeostasis", "model", "assessment", "of", "insulin", "resistance", "(HOMA-IR),", "creatinine,", "glomerular", "filtration", "rate", "(GFR),", "and", "gamma-glutamyl", "transferase", "(GGT)", "(all", "p", "<", "0.02).", "Presence", "of", "diabetic", "macrovascular", "complications,", "polyneuropathy", "and", "insulin", "therapy", "were", "associated", "with", "higher", "Ang-2", "levels", "(p", "<", "0.05).", "Conversely,", "sTie-2", "levels", "were", "associated", "with", "glycated", "hemoglobin", "(HbA1c),", "fasting", "plasma", "glucose", "and", "insulin,", "HOMA-IR,", "triglyceride,", "and", "liver", "function", "parameters", "(all", "p", "<", "0.03).", "Multiple", "linear", "regression", "analysis", "showed", "that", "Ang-2", "remained", "significantly", "associated", "only", "with", "levels", "of", "GGT", "(p", "<", "0.04),", "whereas", "sTie-2", "remained", "significantly", "associated", "with", "HbA1c,", "insulin", "levels,", "and", "HOMA-IR", "(p", "<", "0.03).", "No", "differences", "in", "Ang-2", "and", "sTie-2", "levels", "were", "observed", "with", "regard", "to", "gender", "of", "participants.", "Conclusions:", "Ang-2", "is", "independently", "associated", "with", "levels", "of", "GGT", "while", "sTie-2", "is", "independently", "associated", "with", "levels", "of", "HbA1c,", "plasma", "insulin", "and", "HOMA-IR", "in", "type", "2", "diabetic", "subjects.", "Therefore", "we", "suggest", "that", "the", "associations", "of", "Ang-2", "and", "sTie-2", "with", "type", "2", "diabetes", "are", "based", "on", "different", "patho-physiological", "mechanisms.", "Background", "Angiopoietins", "are", "growth", "factors", "that", "promote", "angiogen-", "esis", "together", "with", "vascular", "endothelial", "growth", "factor", "(VEGF).", "Among", "the", "four", "identified", "angiopoietins", "(1-4),", "Angiopoietin", "(Ang)-1", "and", "Ang-2", "are", "reported", "to", "be", "required", "for", "the", "formation", "of", "mature", "blood", "vessels,", "as", "demonstrated", "by", "mouse", "knock", "out", "studies", "[1,2].", "Ang-2", "is", "expressed", "primarily", "in", "the", "vascular", "endothelium", "at", "sites", "of", "vascular", "remodeling", "[3].", "Both", "Ang-1", "and", "Ang-2", "act", "by", "binding", "to", "the", "endothelium-specific", "receptor", "tyrosine", "kinase", "2", "(Tie-2).", "A", "soluble", "form", "of", "the", "Tie-2", "receptor", "can", "be", "detected", "in", "human", "biological", "fluids", "[4].", "The", "Ang/Tie", "system", "tightly", "controls", "the", "endothelial", "phenotype", "during", "", "Correspondence:", "Alexandra.kautzky-willer@meduniwien.ac.at", "1Department", "of", "Internal", "Medicine", "III,", "Division", "of", "Endocrinology", "and", "Metabolism,", "Unit", "of", "Gender", "Medicine,", "Medical", "University", "of", "Vienna,", "Vienna,", "Austria", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "angiogenesis", "and", "vascular", "inflammation", "in", "a", "unique", "fash-", "ion.", "While", "Ang-1", "has", "an", "agonistic", "effect", "on", "Tie-2", "through", "induction", "of", "autophosphorylation", "of", "the", "receptor", "neces-", "sary", "for", "the", "stabilization", "of", "the", "blood", "vessels", "[5],", "Ang-2", "appears", "to", "have", "an", "antagonistic", "effect.", "It", "acts", "as", "a", "competi-", "tive", "inhibitor", "of", "Ang-1", "for", "Tie-2", "binding,", "thereby", "inhibit-", "ing", "Ang-1/Tie-2", "signaling", "[6].", "Consequently,", "the", "loss", "of", "Tie-2", "signaling", "destabilizes", "the", "endothelium", "and", "facilitates", "the", "angiogenic", "and", "inflammatory", "response", "to", "growth", "factors", "and", "cytokines", "[7].", "Ang-2", "promotes", "also", "VEGF", "induced", "neovascularization.", "Growing", "evidence", "suggests", "an", "involvement", "of", "Ang-2", "and", "its", "receptor", "Tie-2", "in", "the", "pathophysiology", "of", "differ-", "ent", "vascular", "and", "inflammatory", "diseases", "such", "as", "arterio-", "sclerosis", "[8],", "hypertension", "[9],", "idiopathic", "pulmonary", "arterial", "hypertension", "[10],", "chronic", "kidney", "disease", "[11],", "and", "rheumatoid", "arthritis", "[12].", "©", "2011", "Rasul", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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"Yingqian", "Huo,", "Parakalan", "Rangarajan,", "Eng-Ang", "Ling", "and", "S", "Thameem", "Dheen", "Abstract", "Background:", "Nox-2", "(also", "known", "as", "gp91phox),", "a", "subunit", "component", "of", "NADPH", "oxidases,", "generates", "reactive", "oxygen", "species", "(ROS).", "Nox-dependent", "ROS", "generation", "and", "nitric", "oxide", "(NO)", "release", "by", "microglia", "have", "been", "implicated", "in", "a", "variety", "of", "diseases", "in", "the", "central", "nervous", "system.", "Dexamethasone", "(Dex)", "has", "been", "shown", "to", "suppress", "the", "ROS", "production,", "NO", "release", "and", "inflammatory", "reaction", "of", "activated", "microglial", "cells.", "However,", "the", "underlying", "mechanisms", "remain", "unclear.", "Results:", "The", "present", "study", "showed", "that", "the", "increased", "ROS", "production", "and", "NO", "release", "in", "activated", "BV-2", "microglial", "cells", "by", "LPS", "were", "associated", "with", "increased", "expression", "of", "Nox-2", "and", "iNOS.", "Dex", "suppressed", "the", "upregulation", "of", "Nox-2", "and", "iNOS,", "as", "well", "as", "the", "subsequent", "ROS", "production", "and", "NO", "synthesis", "in", "activated", "BV-2", "cells.", "This", "inhibition", "caused", "by", "Dex", "appeared", "to", "be", "mediated", "by", "upregulation", "of", "MAPK", "phosphatase-1", "(MKP-1),", "which", "antagonizes", "the", "activity", "of", "mitogen-activated", "protein", "kinases", "(MAPKs).", "Dex", "induced-suppression", "of", "Nox-2", "and", "-upregulation", "of", "MKP-", "1", "was", "also", "evident", "in", "the", "activated", "microglia", "from", "corpus", "callosum", "of", "postnatal", "rat", "brains.", "The", "overexpression", "of", "MKP-1", "or", "inhibition", "of", "MAPKs", "(by", "specific", "inhibitors", "of", "JNK", "and", "p38", "MAPKs),", "were", "found", "to", "downregulate", "the", "expression", "of", "Nox-2", "and", "iNOS", "and", "thereby", "inhibit", "the", "synthesis", "of", "ROS", "and", "NO", "in", "activated", "BV-2", "cells.", "Moreover,", "Dex", "was", "unable", "to", "suppress", "the", "LPS-induced", "synthesis", "of", "ROS", "and", "NO", "in", "BV-2", "cells", "transfected", "with", "MKP-1", "siRNA.", "On", "the", "other", "hand,", "knockdown", "of", "Nox-2", "in", "BV-2", "cells", "suppressed", "the", "LPS-induced", "ROS", "production", "and", "NO", "release.", "Conclusion:", "In", "conclusion,", "it", "is", "suggested", "that", "downregulation", "of", "Nox-2", "and", "overexpression", "of", "MKP-1", "that", "regulate", "ROS", "and", "NO", "may", "form", "the", "potential", "therapeutic", "strategy", "for", "the", "treatment", "of", "neuroinflammation", "in", "neurodegenerative", "diseases.", "Keywords:", "microglia,", "Nox-2,", "MAPKs,", "ROS,", "dexamethasone", "Background", "An", "inflammatory", "process", "in", "the", "central", "nervous", "system", "(CNS)", "is", "considered", "to", "be", "a", "prominent", "feature", "in", "a", "num-", "ber", "of", "neurodegenerative", "diseases", "and", "is", "mediated", "by", "the", "activated", "microglia,", "the", "resident", "immune", "cells", "of", "the", "CNS.", "The", "microglia", "normally", "respond", "to", "neuronal", "damage", "and", "remove", "the", "damaged", "cells", "by", "phagocytosis", "[1].", "The", "chronic", "activation", "of", "these", "cells", "appears", "to", "cause", "neuronal", "damage", "through", "enhanced", "release", "of", "potentially", "cytotoxic", "molecules", "such", "as", "proinflammatory", "cytokines", "including", "tumor", "necrosis", "factor-a", "(TNF-a)", "and", "", "Correspondence:", "antstd@nus.edu.sg", "Department", "of", "Anatomy", "Yong", "Loo", "Lin", "school", "of", "Medicine", "National", "University", "of", "Singapore,", "117597,", "Singapore", "interleukin-1b", "(IL-1b),", "nitric", "oxide", "(NO),", "reactive", "oxygen", "intermediates,", "proteinases", "and", "complement", "proteins", "[2-5].", "Moreover,", "microglia-derived", "free", "radicals", "as", "well", "as", "the", "reactive", "reaction", "products,", "hydrogen", "peroxide", "and", "peroxynitrite,", "have", "the", "potential", "to", "harm", "cells", "and", "have", "been", "implicated", "in", "contributing", "to", "oxidative", "damage", "and", "neurodegeneration", "in", "neurological", "diseases", "[6,7].", "There-", "fore,", "suppression", "of", "microglia-mediated", "inflammation", "has", "been", "considered", "as", "an", "important", "strategy", "in", "neurode-", "generative", "disease", "therapy.", "Nicotinamide", "adenine", "dinuceotide", "phosphate", "(NADPH)", "oxidase,", "a", "multi-component", "enzyme", "complex", "is", "an", "impor-", "tant", "source", "of", "reactive", "oxygen", "species", "(ROS)", "in", "respiratory", "oxidative", "stress", "and", "intracellular", "signaling", "pathways", "[8,9].", "©", "2011", "Huo", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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1,808,587

null

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[ "JCB:", "ARTICLE", "Spatial", "codes", "in", "dendritic", "BC1", "RNA", "Ilham", "A.", "Muslimov,1", "Anna", "Iacoangeli,1", "Jürgen", "Brosius,3", "and", "Henri", "Tiedge1,2", "1Department", "of", "Physiology", "and", "Pharmacology", "and", "2Department", "of", "Neurology,", "The", "Robert", "F.", "Furchgott", "Center", "for", "Neural", "and", "Behavioral", "Science,", "State", "University", "of", "New", "York", "Health", "Science", "Center", "at", "Brooklyn,", "Brooklyn,", "NY", "11203", "3Institute", "of", "Experimental", "Pathology,", "Center", "for", "Molecular", "Biology", "of", "Inﬂammation,", "University", "of", "Münster,", "D-48149", "Münster,", "Germany", "B", "been", "implicated", "in", "local", "translational", "control", "mech-", "C1", "RNA", "is", "a", "dendritic", "untranslated", "RNA", "that", "has", "anisms", "in", "neurons.", "Prerequisite", "for", "a", "functional", "role", "of", "the", "RNA", "in", "synaptodendritic", "domains", "is", "its", "targeted", "delivery", "along", "the", "dendritic", "extent.", "We", "report", "here", "that", "the", "targeting-competent", "5′", "BC1", "domain", "carries", "two", "dendritic", "targeting", "codes.", "One", "code,", "specifying", "somatic", "export,", "is", "located", "in", "the", "medial-basal", "region", "of", "the", "5′", "BC1", "stem-loop", "structure.", "It", "is", "deﬁned", "by", "an", "export-determinant", "stem-bulge", "motif.", "The", "second", "code,", "specifying", "long-range", "dendritic", "delivery,", "is", "located", "in", "the", "apical", "part", "of", "the", "5′", "stem-loop", "domain.", "This", "element", "features", "a", "GA", "kink-turn", "(KT)", "motif", "that", "is", "indispensable", "for", "distal", "targeting.", "It", "spe-", "ciﬁcally", "interacts", "with", "heterogeneous", "nuclear", "ribonucleo-", "protein", "A2,", "a", "trans-acting", "targeting", "factor", "that", "has", "previously", "been", "implicated", "in", "the", "transport", "of", "MBP", "mRNA", "in", "oligodendrocytes", "and", "neurons.", "Our", "work", "suggests", "that", "a", "BC1", "KT", "motif", "encodes", "distal", "targeting", "via", "the", "A2", "pathway", "and", "that", "architectural", "RNA", "elements,", "such", "as", "KT", "motifs,", "may", "function", "as", "spatial", "codes", "in", "neural", "cells.", "Y", "G", "O", "L", "O", "I", "B", "L", "L", "E", "C", "F", "O", "L", "A", "N", "R", "U", "O", "J", "E", "H", "T", "Introduction", "The", "targeted", "delivery", "of", "select", "RNAs", "to", "synaptodendritic", "do-", "mains", "in", "neurons", "is", "an", "elemental", "mechanism", "in", "the", "spatiotemporal", "regulation", "of", "postsynaptic", "gene", "expression", "(for", "reviews", "see", "Smith,", "2004;", "Kindler", "et", "al.,", "2005).", "Activity-dependent", "on-site", "control", "of", "protein", "synthesis", "is", "now", "seen", "as", "one", "of", "the", "key", "under-", "pinnings", "of", "input-specific", "long-term", "synaptic", "plasticity,", "with", "dendritic", "RNA", "transport", "in", "turn", "serving", "as", "a", "functional", "prerequi-", "site", "for", "the", "local", "translation", "of", "mRNAs", "at", "the", "synapse", "(Wells", "et", "al.,", "2000;", "Job", "and", "Eberwine,", "2001;", "Richter,", "2001;", "Richter", "and", "Lorenz,", "2002;", "Steward", "and", "Schuman,", "2003;", "Smith,", "2004;", "Kindler", "et", "al.,", "2005).", "For", "these", "reasons,", "structural", "and", "functional", "determinants", "of", "dendritic", "RNA", "transport", "are", "of", "considerable", "interest", "to", "students", "of", "neuronal", "plasticity", "(Smith,", "2004).", "The", "number", "of", "RNAs", "that", "have", "been", "identified", "in", "dendrites", "has", "steadily", "increased", "over", "the", "past", "few", "years,", "and", "the", "total", "number", "of", "dendritic", "RNAs", "has", "been", "estimated", "at", "several", "hundred", "(Eberwine", "et", "al.,", "2001).", "Dendritic", "RNAs", "form", "a", "diverse", "and", "complex", "group.", "They", "include", "mRNAs", "that", "encode", "various", "types", "of", "synaptodendritic", "proteins", "(such", "as", "receptors,", "kinases,", "cytoskeletal", "components,", "etc.),", "as", "well", "as", "untranslated", "RNAs", "(Brosius", "and", "Tiedge,", "2004),", "such", "as", "ribosomal", "RNAs", "(rRNAs),", "Correspondence", "to", "Henri", "Tiedge:", "htiedge@downstate.edu", "Abbreviations", "used", "in", "this", "paper:", "ANOVA,", "analysis", "of", "variance;", "CaMKIIα,", "Ca2+/calmodulin-dependent", "kinase", "II", "α", "subunit;", "DTE,", "dendritic", "targeting", "ele-", "ment;", "EMSA,", "electrophoretic", "mobility", "shift", "assay;", "hnRNP,", "heterogeneous", "nuclear", "ribonucleoprotein;", "KT,", "kink-turn;", "MBP,", "myelin", "basic", "protein;", "PKMζ,", "protein", "kinase", "M", "ζ;", "RRM,", "RNA", "recognition", "motif;", "rRNA,", "ribosomal", "RNA;", "WC,", "Watson–Crick.", "©", "The", "Rockefeller", "University", "Press", "$8.00", "The", "Journal", "of", "Cell", "Biology,", "Vol.", "175,", "No.", "3,", "November", "6,", "2006", "427–439", "http://www.jcb.org/cgi/doi/10.1083/jcb.200607008", "tRNAs,", "micro", "RNAs,", "and", "small", "brain-specific", "cytoplasmic", "(BC)", "RNAs", "(Kindler", "et", "al.,", "2005;", "Cao", "et", "al.,", "2006).", "A", "further", "layer", "of", "complexity", "is", "introduced", "by", "the", "fact", "that", "dendritic", "RNAs", "are", "nonhomogeneously", "distributed", "along", "the", "dendritic", "extent", "and", "differentially", "localized", "to", "their", "individual", "destination", "sites", "within", "the", "dendritic", "arborization", "(Paradies", "and", "Steward,", "1997;", "Kindler", "et", "al.,", "2005).", "Another", "subset", "of", "neuronal", "RNAs,", "only", "partially", "overlapping", "with", "dendritic", "RNAs,", "is", "targeted", "to", "the", "axonal", "domain,", "in", "particular", "during", "periods", "of", "developmental", "or", "regenerative", "growth", "(for", "review", "see", "Giuditta", "et", "al.,", "2002).", "The", "complexities", "of", "neuronal", "RNA", "transport", "raise", "impor-", "tant", "questions.", "On", "the", "most", "fundamental", "level,", "spatial", "codes", "that", "are", "used", "by", "localized", "neuronal", "RNAs", "to", "specify", "their", "respective", "subcellular", "destinations", "remain", "poorly", "understood.", "Dendritic", "targeting", "elements", "(DTEs),", "which", "are", "cis-acting", "elements", "that", "contain", "codes", "to", "direct", "neuronal", "RNAs", "to", "or", "along", "dendrites,", "have", "been", "identified", "in", "several", "dendritic", "RNAs", "(Kindler", "et", "al.,", "2005).", "Frequently,", "however,", "the", "functional", "description", "of", "DTEs", "has", "been", "rudimentary,", "and", "code-carrying", "RNA", "motifs", "have", "not", "yet", "been", "deciphered", "(Smith,", "2004).", "Considerable", "progress", "has", "been", "made", "in", "recent", "years", "in", "the", "elucidation", "of", "structure-function", "relationships", "in", "RNAs", "(for", "review", "see", "Noller,", "2005).", "There", "has", "been", "growing", "awareness", "of", "the", "functional", "relevance", "of", "3D", "RNA", "motifs,", "and", "the", "question", "is", "thus", "raised", "whether", "dendritic", "targeting", "codes", "may", "find", "expres-", "sion", "in", "the", "architectural", "designs", "of", "such", "motifs.", "To", "address", "this", "question,", "we", "performed", "a", "functional", "dissection", "of", "cis-acting", "tar-", "geting", "elements", "in", "neuronal", "BC1", "RNA", "(Muslimov", "et", "al.,", "1997).", "JCB", "427" ]

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2,175,118

null

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[ "Tumor", "Necrosis", "Factor", "Induces", "Hyperphosphorylation", "of", "Kinesin", "Light", "Chain", "and", "Inhibits", "Kinesin-mediated", "Transport", "of", "Mitochondria", "Kurt", "De", "Vos,*", "Fedor", "Severin,‡§", "Franky", "Van", "Herreweghe,*", "Katia", "Vancompernolle,*", "Vera", "Goossens,*", "Anthony", "Hyman,‡§", "and", "Johan", "Grooten*", "*Department", "of", "Molecular", "Biology,", "Flanders", "Interuniversity", "Institute", "for", "Biotechnology", "and", "Ghent", "University,", "B-9000", "Ghent,", "Belgium;", "and", "‡Cell", "Biology", "Program,", "European", "Molecular", "Biology", "Laboratory,", "D-69012", "Heidelberg,", "Germany;", "and", "§Max-Planck", "Institute", "for", "Cell", "Biology", "and", "Genetics,", "D-01307", "Dresden,", "Germany", "Abstract.", "The", "molecular", "motor", "kinesin", "is", "an", "ATPase", "that", "mediates", "plus", "end-directed", "transport", "of", "organelles", "along", "microtubules.", "Although", "the", "biochemical", "properties", "of", "kinesin", "are", "extensively", "studied,", "conclusive", "data", "on", "regu-", "lation", "of", "kinesin-mediated", "transport", "are", "largely", "lacking.", "Previously,", "we", "showed", "that", "the", "proinﬂammatory", "cytokine", "tumor", "necrosis", "factor", "induces", "perinuclear", "clustering", "of", "mitochondria.", "Here,", "we", "show", "that", "tumor", "necrosis", "factor", "impairs", "kinesin", "motor", "activity", "and", "hyperphosphorylates", "kinesin", "light", "chain", "through", "activation", "of", "two", "putative", "kinesin", "light", "chain", "kinases.", "Inactivation", "of", "kinesin,", "hyper-", "phosphorylation", "of", "kinesin", "light", "chain,", "and", "perinuclear", "clustering", "of", "mitochondria", "exhibit", "the", "same", "p38", "mitogen-", "activated", "kinase", "dependence,", "indicating", "their", "functional", "relationship.", "These", "data", "provide", "evidence", "for", "direct", "regu-", "lation", "of", "kinesin-mediated", "organelle", "transport", "by", "extra-", "cellular", "stimuli", "via", "cytokine", "receptor", "signaling", "pathways.", "Key", "words:", "microtubule", "•", "organelle", "•", "okadaic", "acid", "•", "mitogen-activated", "protein", "kinase", "•", "phosphorylation", "Introduction", "Conventional", "kinesin", "(KIF5),", "originally", "discovered", "in", "1985", "(Brady,", "1985;", "Vale", "et", "al.,", "1985),", "is", "a", "tetramer", "of", "two", "kine-", "sin", "heavy", "chains", "(KHCs)1", "and", "two", "kinesin", "light", "chains", "(KLCs).", "Three", "domains", "compose", "KHC:", "an", "NH2-terminal", "motor", "domain", "containing", "the", "ATPase", "activity", "and", "the", "mi-", "crotubule", "(MT)-binding", "sites", "(Yang", "et", "al.,", "1989);", "a", "central", "a-helical", "coiled-coil", "involved", "in", "dimerization", "(de", "Cuevas", "et", "al.,", "1992);", "and", "a", "COOH-terminal", "tail,", "which", "binds", "KLC", "(Diefenbach", "et", "al.,", "1998).", "The", "KHC-tail:KLC", "complex", "ap-", "pears", "to", "be", "a", "crucial", "regulatory", "target,", "involved", "in", "interac-", "tion", "with", "cargo", "(Brady", "and", "Pfister,", "1991;", "Stenoien", "and", "Brady,", "1997;", "Khodjakov", "et", "al.,", "1998)", "and", "controlling", "the", "motor", "activity", "of", "the", "motor", "protein", "(Hackney", "et", "al.,", "1991;", "Verhey", "et", "al.,", "1998;", "Coy", "et", "al.,", "1999;", "Friedman", "and", "Vale,", "1999;", "Rahman", "et", "al.,", "1999;", "Stock", "et", "al.,", "1999).", "Address", "correspondence", "to", "Johan", "Grooten,", "Department", "of", "Molecular", "Bi-", "ology,", "Flanders", "Interuniversity", "Institute", "for", "Biotechnology", "and", "Ghent", "University,", "K.", "L.", "Ledeganckstraat", "35,", "B-9000", "Ghent,", "Belgium.", "Tel.:", "32", "9", "264", "5310.", "Fax:", "32", "9", "264", "5348.", "E-mail:", "johan.grooten@dmb.rug.ac.be", "Kurt", "De", "Vos’", "present", "address", "is", "Department", "of", "Biological", "Sciences,", "Columbia", "University,", "New", "York,", "NY", "10027.", "1Abbreviations", "used", "in", "this", "paper:", "2-DE,", "two-dimensional", "gel", "electro-", "phoresis;", "Ab,", "antibody;", "KHC,", "kinesin", "heavy", "chain;", "KLC,", "kinesin", "light", "chain;", "MAP,", "microtubule-associated", "protein;", "MAPK,", "mitogen-activated", "protein", "kinase;", "MT,", "microtubule;", "OA,", "okadaic", "acid;", "PKA,", "protein", "kinase", "A;", "TNF,", "tumor", "necrosis", "factor.", "KHC", "and", "KLC", "are", "reversibly", "phosphorylated", "on", "serine", "residues", "in", "vivo,", "suggesting", "that", "phosphorylation", "is", "in-", "volved", "in", "kinesin", "regulation.", "Indeed,", "KHC", "of", "membrane-", "bound,", "presumably", "active", "kinesin", "is", "hyperphosphorylated", "in", "vivo", "(Lee", "and", "Hollenbeck,", "1995)", "and", "kinesin", "phosphor-", "ylation", "by", "protein", "kinase", "A", "(PKA)", "in", "vitro", "increased", "kine-", "sin", "ATPase", "activity", "and", "thus", "may", "stimulate", "transport", "(Matthies", "et", "al.,", "1993).", "However,", "phosphorylation", "by", "PKA", "also", "reduced", "binding", "of", "kinesin", "to", "synaptic", "vesicles", "sug-", "gesting", "to", "the", "contrary", "decreased", "vesicle", "transport", "(Sato-", "Yoshitake", "et", "al.,", "1992).", "In", "a", "different", "approach,", "using", "oka-", "daic", "acid", "(OA)", "to", "drive", "hyperphosphorylation", "of", "kinesin", "in", "cytosolic", "extracts,", "McIlvain", "et", "al.", "(1994)", "showed", "hyper-", "phosphorylation", "of", "three", "components", "of", "the", "kinesin", "com-", "plex,", "but", "not", "of", "KHC", "in", "correlation", "with", "increased", "kinesin", "activity", "in", "vitro.", "One", "of", "these", "associated", "proteins", "was", "re-", "cently", "identified", "as", "KLC,", "and", "hyperphosphorylation", "of", "this", "KLC", "isoform", "was", "sufficient", "to", "increase", "kinesin", "activity", "in", "vitro", "(Lindesmith", "et", "al.,", "1997).", "Similarly", "increased", "vesicle", "motility", "was", "observed", "in", "OA-treated", "CV-1", "cells", "(Hamm-Alvarez", "et", "al.,", "1993).", "However,", "in", "these", "cells", "no", "hyperphosphorylation", "of", "kinesin-associated", "proteins", "could", "be", "demonstrated,", "suggesting", "an", "indirect", "effect", "of", "OA", "on", "kinesin", "activity", "(McIlvain", "et", "al.,", "1994).", "Also,", "in", "melano-", "phores,", "melanocyte", "stimulating", "hormone-induced", "disper-", "sion", "of", "melanosomes", "by", "kinesin-II", "was", "dependent", "on", "PKA", "ª", "The", "Rockefeller", "University", "Press,", "0021-9525/2000/06/1207/8", "$5.00", "The", "Journal", "of", "Cell", "Biology,", "Volume", "149,", "Number", "6,", "June", "12,", "2000", "1207–1214", "http://www.jcb.org", "1207" ]

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2,043,166

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[ "Int.", "J.", "Biol.", "Sci.", "2007,", "3", "Review", "420", "International", "Journal", "of", "Biological", "Sciences", "ISSN", "1449-2288", "www.biolsci.org", "2007", "3(7):420-427", "©Ivyspring", "International", "Publisher.", "All", "rights", "reserved", "Candidate", "Gene", "Identification", "Approach:", "Progress", "and", "Challenges", "Mengjin", "Zhu", "and", "Shuhong", "Zhao", "Key", "Laboratory", "of", "Agricultural", "Animal", "Genetics,", "Breeding", "and", "Reproduction", "of", "Ministry", "of", "Education,", "Huazhong", "Agricultural", "University,", "Wuhan", "430070,", "P.", "R.", "China", "Correspondence", "to:", "Shuhong", "Zhao,", "Key", "Laboratory", "of", "Agricultural", "Animal", "Genetics,", "Breeding", "and", "Reproduction", "of", "Ministry", "of", "Education,", "Huazhong", "Agricultural", "University,", "Wuhan", "430070,", "P.", "R.", "China.", "Tel:", "+86-27-87281306;", "Fax:", "+86-27-87280408;", "E-mail:", "shzhao@mail.hzau.edu.cn", "Received:", "2007.08.26;", "Accepted:", "2007.10.24;", "Published:", "2007.10.25", "Although", "it", "has", "been", "widely", "applied", "in", "identification", "of", "genes", "responsible", "for", "biomedically,", "economically,", "or", "even", "evolutionarily", "important", "complex", "and", "quantitative", "traits,", "traditional", "candidate", "gene", "approach", "is", "largely", "limited", "by", "its", "reliance", "on", "the", "priori", "knowledge", "about", "the", "physiological,", "biochemical", "or", "functional", "aspects", "of", "possible", "candidates.", "Such", "limitation", "results", "in", "a", "fatal", "information", "bottleneck,", "which", "has", "apparently", "become", "an", "obstacle", "for", "further", "applications", "of", "traditional", "candidate", "gene", "approach", "on", "many", "occasions.", "While", "the", "identification", "of", "candidate", "genes", "involved", "in", "genetic", "traits", "of", "specific", "interest", "remains", "a", "challenge,", "significant", "progress", "in", "this", "subject", "has", "been", "achieved", "in", "the", "last", "few", "years.", "Several", "strategies", "have", "been", "developed,", "or", "being", "developed,", "to", "break", "the", "barrier", "of", "information", "bottleneck.", "Recently,", "being", "a", "new", "developing", "method", "of", "candidate", "gene", "approach,", "digital", "candidate", "gene", "approach", "(DigiCGA)", "has", "emerged", "and", "been", "primarily", "applied", "to", "identify", "potential", "candidate", "genes", "in", "some", "studies.", "This", "review", "summarizes", "the", "progress,", "application", "software,", "online", "tools,", "and", "challenges", "related", "to", "this", "approach.", "Key", "words:", "candidate", "gene", "approach;", "information", "bottleneck;", "digital", "candidate", "gene", "approach", "1.", "Introduction", "Based", "on", "the", "polygenic", "hypothesis,", "classical", "quantitative", "genetics", "considers", "a", "black", "box", "to", "reveal", "the", "holistic", "status", "of", "all", "genes", "associated", "with", "variation", "of", "complex", "and", "quantitative", "traits", "by", "complicated", "statistical", "methods.", "Such", "strategy", "could", "not", "independently", "decompose", "individual", "genes,", "which", "usually", "follow", "the", "Mendel's", "law,", "from", "the", "polygenic", "system", "of", "the", "investigated", "traits.", "Advances", "in", "molecular", "methods", "and", "quantitative", "techniques", "have", "clearly", "changed", "this", "status,", "which", "are", "able", "to", "look", "inside", "the", "black", "box", "of", "polygenic", "control", "for", "complex", "and", "quantitative", "traits", "with", "a", "more", "accurate", "description", "of", "how", "genes", "act", "to", "determine", "the", "phenotypic", "variation.", "More", "recently,", "major", "progress", "has", "been", "made", "in", "this", "field", "with", "the", "advent", "of", "genomics", "and", "its", "potential", "contribution", "to", "development", "of", "quantitative", "genetics.", "One", "of", "the", "hot", "interests", "of", "current", "quantitative", "genetics", "is", "systematically", "exploring", "an", "exact", "genetic", "architecture", "of", "the", "number,", "distribution", "and", "interaction", "of", "loci", "affecting", "the", "variations", "of", "biomedically,", "economically,", "and", "evolutionarily", "important", "complex", "and", "quantitative", "traits.", "There", "are", "two", "approaches", "for", "genetic", "dissections", "of", "complex", "and", "quantitative", "traits,", "i.e.,", "genome-wide", "scanning", "and", "candidate", "gene", "approach,", "which", "each", "has", "specific", "advantages", "and", "disadvantages.", "Genome-wide", "scanning", "usually", "proceeds", "without", "any", "presuppositions", "regarding", "the", "importance", "of", "specific", "functional", "features", "of", "the", "investigated", "traits,", "but", "of", "which", "the", "principal", "disadvantage", "is", "expensive", "and", "resource", "intensive.", "In", "general,", "genome-wide", "scanning", "only", "locates", "the", "glancing", "chromosomal", "regions", "of", "quantitative", "trait", "loci", "(QTLs)", "at", "cM-level", "with", "the", "aid", "of", "DNA", "markers", "under", "family-based", "or", "population-based", "experimental", "designs,", "which", "usually", "embed", "a", "large", "number", "of", "candidate", "genes.", "In", "comparison,", "the", "alternative", "candidate", "gene", "approach", "has", "been", "proven", "to", "be", "extremely", "powerful", "for", "studying", "the", "genetic", "architecture", "of", "complex", "traits,", "which", "is", "a", "far", "more", "effective", "and", "economical", "method", "for", "direct", "gene", "discovery.", "Nevertheless,", "the", "practicability", "of", "traditional", "candidate", "gene", "approach", "is", "largely", "limited", "by", "its", "reliance", "on", "existing", "knowledge", "about", "the", "known", "or", "presumed", "biology", "of", "the", "phenotype", "under", "investigation,", "and", "unfortunately", "the", "detailed", "molecular", "anatomy", "of", "most", "biological", "traits", "remains", "unknown.", "It", "is", "quite", "necessary", "to", "develop", "new", "strategies", "to", "break", "the", "restriction", "of", "information", "bottleneck,", "although", "considerable", "candidate", "genes", "have", "already", "been", "identified.", "In", "this", "article,", "we", "review", "and", "summarize", "the", "main", "research", "advances", "in", "the", "subject,", "including", "the", "outline", "of", "candidate", "gene", "approach", "and", "the", "extended", "strategies", "for", "breaking", "the", "information", "bottleneck", "of", "traditional", "candidate", "gene", "approach.", "Finally,", "as", "a", "new", "development", "of", "candidate", "gene", "approach,", "digital", "candidate", "gene", "approach", "(DigiCGA)", "was", "discussed", "and", "some", "research", "outlooks", "were", "given", "to", "further", "promote", "this", "valuable", "research", "subject." ]

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[ "Original", "Article", "Influence", "of", "Connector", "Width", "on", "the", "Stress", "Distribution", "of", "Posterior", "Bridges", "under", "Loading", "S.", "Mir", "Mohammad", "Rezaei", "1,", "H.", "Heidarifar", "2,", "F.", "Fallahi", "Arezodar", "2,", "A.", "Azary", "3,", "S.", "Mokhtarykhoee", "4", "1Associate", "Professor,", "Department", "of", "Prosthodontics,", "School", "of", "Dentistry,", "Tehran", "University", "of", "Medical", "Sciences,", "Tehran,", "Iran", "2Mechanical", "Engineer,", "Private", "Sector", "3Assistant", "Professor,", "Department", "of", "Prosthodontics,", "School", "of", "Dentistry,", "Tehran", "University", "of", "Medical", "Sciences,", "Tehran,", "Iran", "4Dentist,", "Private", "Practice", "Abstract:", "Objective:", "In", "all", "ceramic", "fixed", "partial", "dentures", "the", "connector", "area", "is", "a", "common", "fracture", "location.", "The", "survival", "time", "of", "three-unit", "fixed", "partial", "dentures", "may", "be", "improved", "by", "alter-", "ing", "the", "connector", "design", "in", "regions", "of", "maximum", "tension.", "The", "purpose", "of", "this", "study", "was", "to", "determine", "the", "effect", "of", "buccolingual", "increase", "of", "the", "connector", "width", "on", "the", "stress", "distribu-", "tion", "in", "posterior", "fixed", "partial", "dentures", "made", "of", "IPS", "Empress", "2.", "To", "simulate", "the", "anatomical", "condition,", "we", "used", "three-dimensional", "finite", "element", "analysis", "to", "generate.", "Materials", "and", "Methods:", "Three", "models", "of", "three-unit", "bridges", "replacing", "the", "first", "molar", "were", "prepared.", "The", "buccolingual", "connector", "width", "varied", "from", "3.0", "to", "5.0", "mm.", "Bridges", "were", "vertically", "loaded", "with", "600", "N", "at", "one", "point", "on", "the", "central", "fossa", "of", "the", "pontic,", "at", "12", "points", "along", "the", "cusp-fossa", "contact", "(50", "N", "each),", "or", "at", "eight", "points", "along", "the", "cusp-marginal", "ridge", "contact", "(75", "N", "each).", "Alternatively,", "a", "load", "of", "225", "N", "was", "applied", "at", "a", "45º", "angle", "from", "the", "lingual", "side.", "Results:", "Stress", "concentrations", "were", "observed", "within", "or", "near", "the", "connectors.", "The", "von", "Mis-", "es", "stress", "decreased", "by", "increasing", "connector", "width,", "regardless", "of", "whether", "the", "loading", "was", "", "Corresponding", "author:", "applied", "vertically", "or", "at", "an", "angle.", "F.", "Fallahi", "Arezodar,", "Mechanical", "Conclusion:", "Within", "the", "limitations", "of", "this", "study,", "we", "conclude", "that", "increasing", "the", "connect-", "Engineer,", "Private", "Sector,", "Tehran,", "or", "width", "decreases", "the", "failure", "probability", "when", "a", "vertical", "or", "angled", "load", "is", "applied.", "Iran.", "f.fallahi.a@gmail.com", "Key", "Words:", "Ceramics;", "Finite", "Element", "Analysis;", "Denture,", "Partial,", "Fixed", "Journal", "of", "Dentistry,", "Tehran", "University", "of", "Medical", "Sciences,", "Tehran,", "Iran", "(2011;", "Vol.", "8,", "No.2)", "Received:", "Accepted:", "INTRODUCTION", "Clinical", "stress", "distribution", "in", "ceramic", "dental", "restorations", "may", "be", "quite", "complex.", "Several", "factors", "are", "associated", "with", "crack", "initiation", "and", "propagation,", "including", "the", "shape", "of", "the", "resto-", "ration,", "micro", "structural", "nonhomogeneities,", "the", "size", "and", "distribution", "of", "surface", "flaws,", "residual", "stresses", "and", "stress", "gradients", "induced", "by", "polish-", "ing", "and/or", "thermal", "processing,", "the", "environ-", "ment", "in", "contact", "with", "the", "restoration,", "ceram-", "ic/cement", "interfacial", "features,", "thickness", "and", "thickness", "variation", "of", "the", "restoration,", "different", "2011;", "Vol.", "8,", "No.", "2", "elastic", "modules", "of", "the", "restoration", "components", "and", "the", "magnitude", "and", "orientation", "of", "the", "ap-", "plied", "load", "[1].", "Failure", "may", "be", "a", "mixed", "pattern", "of", "compressive,", "tensile,", "and/or", "shear", "failures", "[2].", "However,", "brittle", "materials", "(e.g.,", "dental", "ce-", "ramics)", "usually", "demonstrate", "the", "least", "strength", "when", "exposed", "to", "tensile", "stress.", "Thus,", "tensile", "stress", "is", "useful", "for", "assessing", "the", "service", "time", "of", "ceramic", "materials,", "especially", "when", "flaws", "are", "present.", "The", "long-term", "mechanical", "behavior", "of", "the", "restoration", "is", "also", "critical,", "since", "ceramics", "exhibit", "a", "time-dependent", "strength", "decrease", "due", "67" ]

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2,672,386

null

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[ "Int.", "J.", "Environ.", "Res.", "Public", "Health", "2009,", "6,", "1268-1281;", "doi:10.3390/ijerph6031268", "OPEN", "ACCESS", "International", "Journal", "of", "Environmental", "Research", "and", "Public", "Health", "ISSN", "1660-4601", "www.mdpi.com/journal/ijerph", "Article", "Parents’", "and", "Teachers’", "Opinions", "about", "the", "School", "Food", "Policy", "in", "Belgian", "Flemish", "Nursery", "Schools", "Carine", "Vereecken", "1,2,*,", "Hilde", "van", "Houte", "3,4,", "Veerle", "Martens", "3,4,", "Isabelle", "Wittebroodt", "3", "and", "Lea", "Maes", "1", "1", "Department", "of", "Public", "Health,", "Ghent", "University,", "University", "Hospital", "BlokA,", "2nd", "floor,", "De", "Pintelaan", "185,", "9000", "Gent,", "Belgium;", "E-Mail:", "Lea.Maes@UGent.Be", "2", "Research", "Foundation", "Flanders", "(FWO)", "3", "Department", "of", "early", "childhood", "education,", "University", "College", "„Arteveldehogeschool‟,", "Gent", "9040,", "Belgium;", "E-Mails:", "hilde.vanhoute@arteveldehs.be", "(H-V.V.);", "veerle.martens@arteveldehs.be", "(V.M.);", "isabelle.wittebroodt@arteveldehs.be", "(I.W.)", "4", "Ghent", "University", "*", "Author", "to", "whom", "correspondence", "should", "be", "addressed;", "E-Mail:", "Carine.Vereecken@UGent.Be;", "Tel.:", "+32-(0)9-3322081;", "Fax:", "+32-(0)9-3324994", "Received:", "24", "February", "2009", "/", "Accepted:", "19", "March", "2009", "/", "Published:", "24", "March", "2009", "Abstract:", "The", "partnership", "of", "parents,", "teachers,", "and", "schools", "is", "necessary", "to", "develop", "effective", "school", "food", "interventions.", "To", "gather", "parents‟", "and", "teachers‟", "opinions", "and", "perceptions", "about", "the", "school", "food", "policy,", "884", "parents", "and", "70", "teachers", "of", "preschoolers", "completed", "a", "questionnaire.", "School", "food", "policy", "is", "an", "issue", "of", "importance", "for", "parents", "and", "teachers:", "the", "majority", "agrees", "that", "schools", "should", "restrict", "the", "availability", "of", "snacks", "and", "soft", "drinks;", "however,", "to", "replace", "fruit", "juice", "and", "sugared", "milk", "drinks", "with", "sugarless", "alternatives", "will", "take", "special", "effort.", "Fruit", "is", "not", "always", "available", "at", "school,", "although", "parents", "would", "appreciate", "it.", "Parents", "of", "lower", "educational", "level", "are", "in", "general", "more", "permissive.", "Keywords:", "Preschool;", "school", "food", "policy;", "parents;", "teachers." ]

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[ "Growth", "Parameter", "Components", "of", "Adaptive", "Specificity", "during", "Experimental", "Evolution", "of", "the", "UVR-Inducible", "Mutator", "Pseudomonas", "cichorii", "302959", "Michael", "R.", "Weigand", "1", ",", "Vinh", "N.", "Tran", "2", ",", "George", "W.", "Sundin1,2,3*", "1", "Program", "in", "Genetics,", "Michigan", "State", "University,", "East", "Lansing,", "Michigan,", "United", "States", "of", "America,", "2", "Department", "of", "Plant", "Pathology,", "Michigan", "State", "University,", "East", "Lansing,", "Michigan,", "United", "States", "of", "America,", "3", "Centers", "for", "Microbial", "Ecology", "and", "Pathogenesis,", "Michigan", "State", "University,", "East", "Lansing,", "Michigan,", "United", "States", "of", "America", "Abstract", "Background:", "Mutagenic", "DNA", "repair", "(MDR)", "transiently", "increases", "mutation", "rate", "through", "the", "activation", "of", "low-fidelity", "repair", "polymerases", "in", "response", "to", "specific,", "DNA-damaging", "environmental", "stress", "conditions", "such", "as", "ultraviolet", "radiation", "(UVR)", "exposure.", "These", "repair", "polymerases", "also", "confer", "UVR", "tolerance,", "intimately", "linking", "mutability", "and", "survival", "in", "bacteria", "that", "colone", "habitats", "subject", "to", "regular", "UVR", "exposure.", "Methodology/Principal", "Findings:", "Here,", "we", "investigate", "adaptive", "specificity", "in", "experimental", "lineages", "of", "the", "highly", "UVR-", "mutable", "epiphytic", "plant", "pathogen", "Pseudomonas", "cichorii", "302959.", "Relative", "fitness", "measurements", "of", "isolates", "and", "population", "samples", "from", "replicate", "lineages", "indicated", "that", "adaptive", "improvements", "emerged", "early", "in", "all", "lineages", "of", "our", "evolution", "experiment", "and", "specific", "increases", "in", "relative", "fitness", "correlated", "with", "distinct", "improvements", "in", "doubling", "and", "lag", "times.", "Adaptive", "improvements", "gained", "under", "UVR", "and", "non-UVR", "conditions", "were", "acquired", "preferentially,", "and", "differentially", "contributed", "to", "relative", "fitness", "under", "varied", "growth", "conditions.", "Conclusions:", "These", "results", "support", "our", "earlier", "observations", "that", "MDR", "activation", "may", "contribute", "to", "gains", "in", "relative", "fitness", "without", "impeding", "normal", "patterns", "of", "adaptive", "specificity", "in", "P.", "cichorii", "302959.", "Citation:", "Weigand", "MR,", "Tran", "VN,", "Sundin", "GW", "(2011)", "Growth", "Parameter", "Components", "of", "Adaptive", "Specificity", "during", "Experimental", "Evolution", "of", "the", "UVR-Inducible", "Mutator", "Pseudomonas", "cichorii", "302959.", "PLoS", "ONE", "6(1):", "e15975.", "doi:10.1371/journal.pone.0015975", "Editor:", "Michael", "Otto,", "Laboratory", "of", "Human", "Bacterial", "Pathogenesis,", "National", "Institutes", "of", "Health,", "United", "States", "of", "America", "Received", "September", "21,", "2010;", "Accepted", "December", "7,", "2010;", "Published", "January", "14,", "2011", "Copyright:", "2011", "Weigand", "et", "al.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Funding:", "This", "work", "was", "funded", "by", "the", "Michigan", "Agricultural", "Experiment", "Station.", "The", "funders", "had", "no", "role", "in", "study", "design,", "data", "collection", "and", "analysis,", "decision", "to", "publish,", "or", "preparation", "of", "the", "manuscript.", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "*", "E-mail:", "sundin@msu.edu", "Introduction", "Mutation", "is", "the", "most", "fundamental", "source", "of", "variation", "on", "which", "natural", "selection", "may", "drive", "evolution.", "However,", "the", "predomi-", "nantly", "deleterious", "nature", "of", "mutation", "maintains", "selection", "pressure", "in", "favor", "of", "lower", "mutation", "rates", "as", "evidenced", "by", "the", "conservation", "of", "multiple", "DNA", "error-avoidance", "and", "error-repair", "processes", "[1].", "Yet", "hypermutator", "(or", "mutator)", "strains", "of", "bacteria", "have", "been", "observed", "in", "a", "variety", "of", "clinical,", "environmental,", "and", "laboratory", "populations", "with", "mutation", "rates", "100-1000", "times", "greater", "than", "wild-", "type", "due", "to", "defects", "in", "DNA", "proofreading", "and", "repair", "machinery", "[2].", "The", "widespread", "existence", "of", "both", "constitutive", "and", "inducible", "mutator", "genotypes", "suggests", "that", "evolutionary", "strategies", "of", "bacteria", "include", "mechanisms", "for", "increasing", "mutability", "[3,4].", "These", "mutator", "genotypes", "have", "not", "been", "shown", "to", "confer", "an", "intrinsic", "fitness", "advantage", "and", "their", "abundance", "within", "natural", "populations", "likely", "results", "from", "hitchhiking", "with", "secondary,", "beneficial", "mutations", "which", "counterbalance", "the", "cost", "of", "accumulating", "deleterious", "mutations", "[5,6].", "Inducible", "mutability", "in", "the", "form", "of", "mutagenic", "DNA", "repair", "(MDR)", "transiently", "increases", "mutation", "rate", "through", "the", "activation", "of", "low-fidelity", "repair", "polymerases", "in", "response", "to", "specific", "environ-", "mental", "stress", "conditions", "such", "as", "ultraviolet", "radiation", "(UVR)", "exposure.", "UVR", "directly", "damages", "DNA", "causing", "lesions,", "including", "cyclobutane", "pyrimidine", "dimers", "and", "6-4", "photoproducts,", "that", "distort", "the", "helical", "structure,", "interrupting", "replication", "fork", "progression", "and", "inducing", "the", "SOS", "response.", "The", "SOS", "regulon", "coordinates", "the", "control", "of", "more", "than", "40", "unlinked", "genes", "involved", "in", "DNA", "repair,", "recombination,", "and", "cell", "cycle", "control", "[7,8].", "Among", "these,", "the", "Y", "family", "DNA", "polymerases", "polIV", "(Escherichia", "coli", "DinB)", "and", "polV", "(E.", "coli", "UmuDC)", "rescue", "stalled", "replication", "forks", "and", "permit", "DNA", "synthesis", "across", "damaged", "regions", "of", "DNA", "in", "a", "template-", "independent", "manner", "by", "nature", "of", "their", "high", "processivity", "and", "low", "fidelity", "[9].", "Secondary", "mutations", "caused", "by", "these", "error-prone", "polymerases", "comprise", "the", "majority", "of", "sequence", "alterations", "derived", "from", "UVR", "exposure", "and", "define", "the", "inducible", "mutator", "phenotype.", "This", "translesion", "DNA", "synthesis", "activity", "confers", "both", "UVR", "tolerance", "and", "inducible", "mutability,", "intimately", "linking", "survival", "and", "mutation", "in", "habitats", "subject", "to", "regular", "UVR", "exposure.", "MDR-mediated", "UVR", "tolerance", "provides", "a", "critical", "ecological", "advantage", "to", "epiphytic", "plant", "pathogens", "harboring", "Y", "family", "polymerases", "that", "reside", "in", "habitats", "optimized", "for", "solar", "UVR", "exposure", "[10,11].", "We", "have", "previously", "reported", "our", "studies", "of", "experimental", "evolution", "with", "the", "highly", "UVR-mutable", "celery", "pathogen", "Pseudomonas", "cichorii", "302959", "[12].", "The", "major", "contributor", "of", "UVR-induced", "mutability", "in", "this", "strain", "is", "rulAB,", "a", "homolog", "of", "PLoS", "ONE", "|", "www.plosone.org", "1", "January", "2011", "|", "Volume", "6", "|", "Issue", "1", "|", "e15975" ]

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[ "BMC", "Bioinformatics", "Methodology", "article", "The", "ontology", "of", "biological", "sequences", "Robert", "Hoehndorf*1,2,3,", "Janet", "Kelso2", "and", "Heinrich", "Herre1,3", "BioMed", "Central", "Open", "Access", "Address:", "1Research", "Group", "Ontologies", "in", "Medicine,", "Institute", "for", "Medical", "Informatics,", "Statistics", "and", "Epidemiology,", "University", "of", "Leipzig,", "Haertelstrasse", "16-18,", "04107", "Leipzig,", "Germany,", "2Department", "of", "Evolutionary", "Genetics,", "Max", "Planck", "Institute", "for", "Evolutionary", "Anthropology,", "Deutscher", "Platz", "6,", "04103", "Leipzig,", "Germany", "and", "3Department", "of", "Computer", "Science,", "University", "of", "Leipzig,", "Johannesgasse", "26,", "04103", "Leipzig,", "Germany", "Email:", "Robert", "Hoehndorf*", "-", "leechuck@leechuck.de;", "Janet", "Kelso", "-", "kelso@eva.mpg.de;", "Heinrich", "Herre", "-", "heinrich.herre@imise.uni-leipzig.de", "*", "Corresponding", "author", "Published:", "18", "November", "2009", "BMC", "Bioinformatics", "2009,", "10:377", "doi:10.1186/1471-2105-10-377", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1471-2105/10/377", "Received:", "18", "August", "2009", "Accepted:", "18", "November", "2009", "©", "2009", "Hoehndorf", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "Biological", "sequences", "play", "a", "major", "role", "in", "molecular", "and", "computational", "biology.", "They", "are", "studied", "as", "information-bearing", "entities", "that", "make", "up", "DNA,", "RNA", "or", "proteins.", "The", "Sequence", "Ontology,", "which", "is", "part", "of", "the", "OBO", "Foundry,", "contains", "descriptions", "and", "definitions", "of", "sequences", "and", "their", "properties.", "Yet", "the", "most", "basic", "question", "about", "sequences", "remains", "unanswered:", "what", "kind", "of", "entity", "is", "a", "biological", "sequence?", "An", "answer", "to", "this", "question", "benefits", "formal", "ontologies", "that", "use", "the", "notion", "of", "biological", "sequences", "and", "analyses", "in", "computational", "biology", "alike.", "Results:", "We", "provide", "both", "an", "ontological", "analysis", "of", "biological", "sequences", "and", "a", "formal", "representation", "that", "can", "be", "used", "in", "knowledge-based", "applications", "and", "other", "ontologies.", "We", "distinguish", "three", "distinct", "kinds", "of", "entities", "that", "can", "be", "referred", "to", "as", "\"biological", "sequence\":", "chains", "of", "molecules,", "syntactic", "representations", "such", "as", "those", "in", "biological", "databases,", "and", "the", "abstract", "information-bearing", "entities.", "For", "use", "in", "knowledge-based", "applications", "and", "inclusion", "in", "biomedical", "ontologies,", "we", "implemented", "the", "developed", "axiom", "system", "for", "use", "in", "automated", "theorem", "proving.", "Conclusion:", "Axioms", "are", "necessary", "to", "achieve", "the", "main", "goal", "of", "ontologies:", "to", "formally", "specify", "the", "meaning", "of", "terms", "used", "within", "a", "domain.", "The", "axiom", "system", "for", "the", "ontology", "of", "biological", "sequences", "is", "the", "first", "elaborate", "axiom", "system", "for", "an", "OBO", "Foundry", "ontology", "and", "can", "serve", "as", "starting", "point", "for", "the", "development", "of", "more", "formal", "ontologies", "and", "ultimately", "of", "knowledge-based", "applications.", "Background", "Biological", "sequences", "play", "a", "major", "role", "in", "genetics", "and", "bio-", "informatics", "research.", "They", "are", "important", "in", "the", "descrip-", "tion", "of", "DNA,", "RNA", "and", "proteins,", "and", "are", "among", "the", "basic", "entities", "studied", "in", "molecular", "and", "computational", "biology.", "In", "the", "realm", "of", "biological", "ontologies,", "the", "Sequence", "Ontol-", "ogy", "(SO)", "[1]", "was", "developed", "to", "describe", "sequences", "and", "their", "features", "semantically.", "Although", "many", "formal", "defini-", "tions", "are", "available", "for", "the", "SO", "categories,", "several", "categories", "remain", "defined", "using", "natural", "language.", "Formal", "ontologies", "are", "intended", "to", "formally", "specify", "a", "con-", "ceptualization", "of", "a", "domain", "[2],", "and", "therefore", "provide", "the", "foundation", "for", "data", "and", "information", "integration", "and", "exchange.", "Definitions", "alone", "are", "insufficient", "to", "achieve", "this", "goal.", "Axioms", "are", "required", "to", "provide", "meaning", "for", "primi-", "tive,", "undefined", "categories", "and", "relations.", "To", "provide", "an", "ontological", "analysis", "of", "\"biological", "sequence\"", "and", "to", "for-", "malize", "the", "basic", "categories", "used", "in", "the", "SO,", "several", "onto-", "logical", "questions", "about", "sequences", "must", "be", "answered,", "among", "them:", "what", "kind", "of", "entity", "is", "a", "biological", "sequence?", "Page", "1", "of", "11", "(page", "number", "not", "for", "citation", "purposes)" ]

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[ "JCB", "Report", "Golgi", "matrix", "proteins", "interact", "with", "p24", "cargo", "receptors", "and", "aid", "their", "efﬁcient", "retention", "in", "the", "Golgi", "apparatus", "Francis", "A.", "Barr,", "Christian", "Preisinger,", "Robert", "Kopajtich,", "and", "Roman", "Körner", "Department", "of", "Cell", "Biology,", "Max-Planck-Institute", "of", "Biochemistry,", "82152", "Martinsried,", "Germany", "T", "comprised", "of", "a", "stack", "of", "cisternal", "membranes", "on", "the", "he", "Golgi", "apparatus", "is", "a", "highly", "complex", "organelle", "secretory", "pathway", "from", "the", "ER", "to", "the", "cell", "surface.", "This", "structure", "is", "maintained", "by", "an", "exoskeleton", "or", "Golgi", "matrix", "constructed", "from", "a", "family", "of", "coiled-coil", "proteins,", "the", "golgins,", "and", "other", "peripheral", "membrane", "components", "such", "as", "GRASP55", "and", "GRASP65.", "Here", "we", "ﬁnd", "that", "TMP21,", "p24a,", "and", "gp25L,", "members", "of", "the", "p24", "cargo", "receptor", "family,", "are", "present", "in", "complexes", "with", "GRASP55", "and", "GRASP65", "Introduction", "The", "Golgi", "apparatus", "is", "an", "organelle", "on", "the", "secretory", "pathway", "required", "for", "the", "processing", "of", "complex", "sugar", "structures", "on", "many", "proteins", "and", "lipids,", "and", "for", "the", "sorting", "of", "these", "proteins", "and", "lipids", "to", "their", "correct", "subcellular", "destinations", "(Farquhar", "and", "Palade,", "1998).", "It", "is", "comprised", "of", "a", "series", "of", "cisternal", "membranes", "organized", "into", "a", "stacked", "structure,", "the", "first", "or", "cis-face", "receives", "material", "from", "the", "ER,", "whereas", "the", "final", "or", "trans-cisternae", "packages", "it", "for", "delivery", "to", "the", "plasma", "membrane", "and", "endocytic", "pathways", "(Farquhar", "and", "Palade,", "1998).", "This", "structure", "is", "maintained", "by", "an", "exoskeleton", "or", "Golgi", "matrix", "which", "has", "been", "proposed", "to", "be", "required", "for", "linking", "cisternae", "together", "into", "the", "characteristic", "Golgi", "stack", "structure,", "and", "also", "for", "vesicle", "recognition", "during", "membrane", "traffic", "(Warren", "and", "Malhotra,", "1998;", "Seeman", "et", "al.,", "2000).", "The", "most", "studied", "components", "of", "the", "Golgi", "matrix", "are", "p115,", "the", "GRASP65–GM130", "complex,", "and", "an", "integral", "membrane", "protein,", "giantin", "(Linstedt", "and", "Hauri,", "1993;", "Nakamura", "et", "al.,", "1995;", "Sapperstein", "et", "al.,", "1995;", "Barr", "et", "al.,", "1997;", "Shorter", "and", "Warren,", "1999).", "GRASP65", "was", "identified", "in", "a", "screen", "for", "factors", "involved", "in", "the", "stacking", "of", "cisternae,", "and", "later", "shown", "to", "be", "a", "specific", "binding", "partner", "of", "GM130", "Address", "correspondence", "to", "Francis", "Barr,", "Dept.", "of", "Cell", "Biology,", "Max-", "Planck-Institute", "of", "Biochemistry,", "Am", "Klopferspitz", "18a,", "82152", "Martinsried,", "Germany.", "Tel.:", "49-89-8578-3135.", "Fax:", "49-89-8578-3102.", "E-mail:", "barr@biochem.mpg.de", "Key", "words:", "GRASPs;", "p24", "proteins;", "Golgi", "matrix;", "protein", "transport;", "cargo", "receptors", "", "The", "Rockefeller", "University", "Press,", "0021-9525/2001/12/885/7", "$5.00", "The", "Journal", "of", "Cell", "Biology,", "Volume", "155,", "Number", "6,", "December", "10,", "2001", "885–891", "http://www.jcb.org/cgi/doi/10.1083/jcb.200108102", "in", "vivo.", "GRASPs", "interact", "directly", "with", "the", "cytoplasmic", "domains", "of", "speciﬁc", "p24", "cargo", "receptors", "depending", "on", "their", "oligomeric", "state,", "and", "mutation", "of", "the", "GRASP", "binding", "site", "in", "the", "cytoplasmic", "tail", "of", "one", "of", "these,", "p24a,", "results", "in", "it", "being", "transported", "to", "the", "cell", "surface.", "These", "results", "suggest", "that", "one", "function", "of", "the", "Golgi", "matrix", "is", "to", "aid", "efﬁcient", "retention", "or", "sequestration", "of", "p24", "cargo", "receptors", "and", "other", "membrane", "proteins", "in", "the", "Golgi", "apparatus.", "required", "to", "target", "it", "to", "the", "Golgi", "(Barr", "et", "al.,", "1998).", "GM130", "in", "turn", "is", "a", "receptor", "for", "p115,", "required", "for", "tethering", "vesicles", "to", "their", "target", "membrane", "(Barroso", "et", "al.,", "1995;", "Nakamura", "et", "al.,", "1997).", "More", "recently,", "the", "formation", "of", "Golgi", "stacks", "from", "cisternae", "in", "vitro", "was", "found", "to", "require", "p115,", "discrete", "from", "its", "membrane", "fusion", "function,", "and", "giantin", "(Shorter", "and", "Warren,", "1999).", "GM130", "and", "p115", "also", "make", "interactions", "with", "giantin", "during", "vesicle", "docking,", "and", "potentially", "during", "cisternal", "stacking", "(Shorter", "and", "Warren,", "1999;", "Dirac-Svejstrup", "et", "al.,", "2000;", "Lesa", "et", "al.,", "2000).", "The", "network", "of", "interactions", "between", "these", "proteins", "may", "be", "regulated", "by", "the", "rab", "GTPases,", "as", "both", "p115", "and", "GM130", "have", "been", "shown", "to", "interact", "with", "the", "active", "or", "GTP", "form", "of", "rab1", "(Allan", "et", "al.,", "2000;", "Moyer", "et", "al.,", "2001;", "Weide", "et", "al.,", "2001).", "Recruitment", "of", "p115", "to", "vesicles", "destined", "to", "fuse", "with", "the", "cis-Golgi", "is", "mediated", "via", "the", "interaction", "with", "rab1", "(Allan", "et", "al.,", "2000),", "whereas", "the", "consequences", "of", "rab1", "binding", "to", "GM130", "are", "unknown.", "A", "second", "GRASP", "complex,", "containing", "GRASP55", "and", "the", "coiled-coil", "protein", "golgin-45,", "exists", "in", "Golgi", "membranes", "(Shorter", "et", "al.,", "1999;", "Short", "et", "al.,", "2001).", "Like", "the", "GRASP65–", "GM130", "complex,", "this", "complex", "also", "binds", "a", "rab", "GTPase", "and", "is", "required", "for", "the", "maintenance", "of", "normal", "Golgi", "structure", "and", "protein", "transport", "(Short", "et", "al.,", "2001).", "In", "addition", "to", "the", "Golgi", "matrix", "proteins", "discussed", "above,", "some", "membrane", "proteins", "are", "of", "potential", "importance", "to", "Golgi", "structure.", "One", "such", "group", "is", "the", "medial-Golgi", "enzymes,", "found", "to", "specifically", "bind", "to", "the", "Golgi", "matrix", "although", "the", "mechanism", "remains", "uncharacterized", "(Slusarewicz", "et", "al.,", "885" ]

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3,342,903

null

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[ "Paxton-Aiken", "et", "al.", "International", "Journal", "of", "Behavioral", "Nutrition", "and", "Physical", "Activity", "2012,", "9:30", "http://www.ijbnpa.org/content/9/1/30", "R", "E", "S", "E", "A", "R", "C", "H", "Open", "Access", "How", "accurate", "are", "parental", "responses", "concerning", "their", "fourth-grade", "children’s", "school-meal", "participation,", "and", "what", "is", "the", "relationship", "between", "children’s", "body", "mass", "index", "and", "school-", "meal", "participation", "based", "on", "parental", "responses?", "Amy", "E", "Paxton-Aiken1*†,", "Suzanne", "Domel", "Baxter1†,", "Joshua", "M", "Tebbs2,", "Christopher", "J", "Finney1,", "Caroline", "H", "Guinn1", "and", "Julie", "A", "Royer1", "Abstract", "Background:", "This", "article", "investigated", "(1)", "parental", "response", "accuracy", "of", "fourth-grade", "children’s", "school-meal", "participation", "and", "whether", "accuracy", "differed", "by", "children’s", "body", "mass", "index", "(BMI),", "sex,", "and", "race,", "and", "(2)", "the", "relationship", "between", "BMI", "and", "school-meal", "participation", "(based", "on", "parental", "responses).", "Methods:", "Data", "were", "from", "four", "cross-sectional", "studies", "conducted", "from", "fall", "1999", "to", "spring", "2003", "with", "fourth-grade", "children", "from", "13", "schools", "total.", "Consent", "forms", "asked", "parents", "to", "report", "children’s", "usual", "school-meal", "participation.", "As", "two", "studies’", "consent", "forms", "did", "not", "ask", "about", "lunch", "participation,", "complete", "data", "were", "available", "for", "breakfast", "on", "1,496", "children", "(51%", "Black;", "49%", "boys)", "and", "for", "lunch", "on", "785", "children", "(46%", "Black;", "48%", "boys).", "Researchers", "compiled", "nametag", "records", "(during", "meal", "observations)", "of", "meal", "participation", "on", "randomly", "selected", "days", "during", "children’s", "fourth-grade", "school", "year", "for", "breakfast", "(average", "nametag", "days", "across", "studies:", "7-35)", "and", "for", "lunch", "(average", "nametag", "days", "across", "studies:", "4-10)", "and", "categorized", "participation", "as", "“usually”", "(≥", "50%", "of", "days)", "or", "“not", "usually”", "(<", "50%", "of", "days).", "Weight", "and", "height", "were", "measured.", "Concerning", "parental", "response", "accuracy,", "marginal", "regression", "was", "used", "with", "agreement", "between", "parental", "responses", "and", "nametag", "records", "as", "the", "dependent", "variable;", "independent", "variables", "were", "BMI,", "age,", "sex,", "race,", "and", "study.", "Concerning", "a", "relationship", "between", "BMI", "and", "school-meal", "participation,", "marginal", "regression", "was", "used", "with", "BMI", "as", "the", "dependent", "variable;", "independent", "variables", "were", "breakfast", "participation,", "lunch", "participation,", "age,", "sex,", "race,", "and", "study.", "Results:", "Concerning", "breakfast", "participation", "and", "lunch", "participation,", "74%", "and", "92%", "of", "parents", "provided", "accurate", "responses,", "respectively.", "Parental", "response", "accuracy", "was", "better", "for", "older", "children", "for", "breakfast", "and", "lunch", "participation,", "and", "for", "Black", "than", "White", "children", "for", "lunch", "participation.", "Usual", "school-meal", "participation", "was", "significantly", "related", "to", "children’s", "BMI", "but", "in", "opposite", "directions", "–", "positively", "for", "breakfast", "and", "inversely", "for", "lunch.", "Conclusions:", "Parental", "response", "accuracy", "of", "children’s", "school-meal", "participation", "was", "moderately", "high;", "however,", "disparate", "effects", "for", "children’s", "age", "and", "race", "warrant", "caution", "when", "relying", "on", "parental", "responses.", "The", "BMI", "results,", "which", "showed", "a", "relationship", "between", "school-meal", "participation", "(based", "on", "parental", "responses)", "and", "childhood", "obesity,", "conflict", "with", "results", "from", "a", "recent", "article", "that", "used", "data", "from", "the", "same", "four", "studies", "and", "found", "no", "significant", "relationship", "when", "participation", "was", "based", "on", "nametag", "records", "compiled", "for", "meal", "observations.", "Keywords:", "Children,", "School,", "Obesity,", "School-meal", "participation,", "Parental", "response", "accuracy", "*", "Correspondence:", "paxtonae@mailbox.sc.edu", "†", "Contributed", "equally", "1Institute", "for", "Families", "in", "Society,", "University", "of", "South", "Carolina,", "1600", "Hampton", "Street,", "Suite", "507,", "Columbia,", "SC", "29208,", "USA", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "©", "2012", "Paxton-Aiken", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

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[ "Correspondence", "The", "Human", "Gene", "Mutation", "Database:", "2008", "update", "Peter", "D", "Stenson,", "Matthew", "Mort,", "Edward", "V", "Ball,", "Katy", "Howells,", "Andrew", "D", "Phillips,", "Nick", "ST", "Thomas", "and", "David", "N", "Cooper", "Address:", "Institute", "of", "Medical", "Genetics,", "Cardiff", "University,", "Heath", "Park,", "Cardiff", "CF14", "4XN,", "UK.", "Correspondence:", "David", "N", "Cooper.", "Email:", "cooperdn@cardiff.ac.uk", "Published:", "22", "January", "2009", "Genome", "Medicine", "2009,", "1:13", "(doi:10.1186/gm13)", "The", "electronic", "version", "of", "this", "article", "is", "the", "complete", "one", "and", "can", "be", "found", "online", "at", "http://genomemedicine.com/content/1/1/13", "©", "2009", "BioMed", "Central", "Ltd", "Abstract", "The", "Human", "Gene", "Mutation", "Database", "(HGMD®)", "is", "a", "comprehensive", "core", "collection", "of", "germline", "mutations", "in", "nuclear", "genes", "that", "underlie", "or", 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"in", "2006", "between", "HGMD", "and", "BIOBASE", "GmbH.", "This", "cooperative", "agreement", "covers", "the", "exclusive", "worldwide", "marketing", "of", "the", "most", "up-to-date", "(subscription)", "version", "of", "HGMD,", "HGMD", "Professional,", "to", "academic,", "clinical", "and", "commercial", "users.", "The", "Human", "Gene", "Mutation", "Database", "(HGMD®)", "[1]", "records", "the", "first", "report", "of", "a", "disease-causing", "mutation", "or", "disease-", "associated/functional", "polymorphism", "and", "provides", "these", "data", "in", "a", "readily", "accessible", "form", "to", "all", "interested", "parties,", "whether", "they", "are", "from", "an", "academic,", "a", "clinical", "or", "a", "commercial", "background.", "HGMD", "has", "become", "the", "de", "facto", "central", "disease-associated", "mutation", "database", "available", "to", "the", "scientific", "community.", "The", "data", "comprise", "single", "base-pair", "substitutions", "in", "coding,", "regulatory", "and", "splicing-relevant", "regions", "of", "human", "nuclear", "genes,", "micro-deletions", "and", "micro-", "insertions,", "combined", "insertions/deletions", "(indels),", "repeat", "expansions,", "gross", "lesions", "(deletions,", "insertions", "and", "duplica-", "tions)", "and", "complex", "rearrangements", "(including", "inversions).", "These", "categories", "of", "mutation", "data", "are", "summarized", "in", "Table", "1.", "Mutation", "and", "polymorphism", "data", "are", "obtained", "by", "means", "of", "a", "combination", "of", "manual", "and", "computerized", "search", "proce-", "dures.", "Thus,", "online", "library", "screening,", "the", "PubMed", "database", "and", "publicly", "available", "locus-specific", "mutation", "databases", "(LSDBs)", "are", "all", "used", "to", "optimize", "data", "acquisition.", "Each", "mutation", "or", "disease-associated/functional", "polymorphism", "is", "entered", "into", "HGMD", "only", "once", "under", "its", "earliest", "literature", "citation.", "Silent", "mutations", "within", "the", "coding", "region", "that", "do", "not", "alter", "the", "encoded", "amino", "acid", "are", "not", "recorded", "unless", "there", "is", "clear", "evidence", "of", "altered", "splicing", "and/or", "a", "direct", "disease", "association.", "Mutations", "that", "have", "not", "been", "ade-", "quately", "or", "unambiguously", "described", "in", "the", "corresponding", "literature", "report", "are", "also", "excluded", "unless", "full", "details", "can", "sub-", "sequently", "be", "obtained", "from", "the", "authors.", "Disease-associated/", "functional", "polymorphisms", "(see", "below)", "are", "excluded", "if", "the", "published", "data", "are", "deemed", "to", "be", "of", "insufficient", "quality", "(either", "because", "of", "the", "description", "provided", "or", "because", "of", "a", "tenuous/", "non-significant", "association", "with", "a", "clinical", "or", "laboratory", "phenotype).", "HGMD", "does", "not", "include", "somatic", "lesions", "or", "mitochondrial", "genome", "mutations.", "These", "are", "well", "covered", "by", "COSMIC", "[2]", "and", "MITOMAP", "[3],", "respectively.", "Mutation", "data", "are", "viewable", "on", "a", "gene-wise", "basis", "and", "access", "to", "the", "subcategorized", "mutation", "data", "is", "available", "via", "hyper-", "text", "link", "from", "each", "gene", "page.", "Additional", "links", "to", "Genome", "Medicine", "2009,", "1:13" ]

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2,684,950

null

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[ "Curr", "Rev", "Musculoskelet", "Med", "(2009)", "2:25–29", "DOI", "10.1007/s12178-008-9040-5", "Snowboarding", "injuries:", "a", "review", "of", "the", "literature", "and", "an", "analysis", "of", "the", "potential", "use", "of", "portable", "ultrasound", "for", "mountainside", "diagnostics", "M.", "R.", "Nowak", "Æ", "A.", "W.", "Kirkpatrick", "Æ", "J.", "A.", "Bouffard", "Æ", "D.", "Amponsah", "Æ", "S.", "A.", "Dulchavsky", "Published", "online:", "7", "January", "2009", "The", "Author(s)", "2008.", "This", "article", "is", "published", "with", "open", "access", "at", "Springerlink.com", "Abstract", "Snowboarding", "has", "become", "a", "popular", "recrea-", "tional", "and", "professional", "sport.", "Participants", "suffer", "a", "variety", "of", "injuries,", "especially", "of", "the", "extremities,", "that", "require", "medical", "evaluation.", "This", "article", "reviews", "the", "reported", "inju-", "ries", "to", "both", "leisure", "and", "elite", "athletes.", "To", "many,", "an", "injured", "extremity", "requires", "travel", "to", "a", "medical", "facility", "for", "accurate", "evaluation.", "Musculoskeletal", "ultrasound", "is", "an", "accurate", "and", "portable", "technology", "that", "can", "be", "used", "for", "real", "time,", "moun-", "tainside", "diagnoses", "of", "these", "injuries.", "Keywords", "Mountainside", "ultrasound", "Remote", "guidance", "ultrasound", "Snowboarding", "injuries", "Diagnostic", "ultrasound", "Mountainside", "diagnostics", "M.", "R.", "Nowak", "(&)", "Departments", "of", "Emergency", "Medicine", "and", "Surgery,", "Henry", "Ford", "Hospital,", "Detroit,", "MI,", "USA", "e-mail:", "mnowak2@hfhs.org", "A.", "W.", "Kirkpatrick", "Regional", "Trauma", "Services,", "Foothills", "Medical", "Center,", "Calgary,", "AB,", "Canada", "J.", "A.", "Bouffard", "Department", "of", "Radiology,", "Henry", "Ford", "Hospital,", "Detroit,", "MI,", "USA", "D.", "Amponsah", "Department", "of", "Emergency", "Medicine,", "Henry", "Ford", "Hospital,", "Detroit,", "MI,", "USA", "S.", "A.", "Dulchavsky", "Department", "of", "Surgery,", "Henry", "Ford", "Hospital,", "Detroit,", "MI,", "USA", "Introduction", "Snowboarding", "has", "experienced", "a", "tremendous", "growth", "as", "a", "sport", "over", "the", "years.", "The", "National", "Sporting", "Goods", "Asso-", "ciation", "reported", "6.6", "million", "snowboarders", "participating", "in", "this", "sport", "in", "2004.", "To-date", "there", "has", "not", "been", "a", "careful", "overall", "review", "of", "the", "medical", "literature", "to", "summarize", "the", "injuries", "sustained", "by", "these", "individuals.", "Snowboarding", "is", "physically", "demanding", "and", "is", "often", "conducted", "in", "a", "chal-", "lenging", "physical", "environment", "such", "that", "the", "risks", "of", "serious", "injury", "or", "even", "death", "are", "real.", "Reviews", "of", "snowboarding", "injuries", "from", "around", "the", "world", "have", "demonstrated", "head,", "abdominal,", "spinal,", "and", "extremity", "trauma", "to", "be", "the", "most", "frequent", "serious,", "and", "occasionally", "fatal,", "injuries", "sustained", "[1–4].", "Fortunately,", "most", "snow-boarding", "injuries", "are", "not", "life-threatening,", "but", "when", "a", "professional", "or", "leisure", "snow-", "boarder", "suffers", "a", "potential", "traumatic", "injury,", "it", "can", "be", "extremely", "challenging", "for", "a", "non-physician", "on-mountain", "care-provider", "to", "make", "the", "correct", "diagnosis.", "This", "is", "because", "of", "the", "limited", "medical", "knowledge", "of", "the", "mountain", "patrol", "or", "sports", "trainers", "and", "the", "lack", "of", "radiological", "imaging", "support.", "Often", "the", "snowboarder", "must", "be", "trans-", "ported", "to", "a", "local", "hospital", "or", "to", "a", "specialty", "clinic", "for", "additional", "medical", "assessments", "[5].", "Generally,", "conditions", "in", "which", "snowboarders", "are", "injured", "preclude", "the", "ability", "to", "quickly", "assess", "injuries", "using", "imaging", "techniques", "such", "as", "magnetic", "resonance", "imaging", "(MRI),", "CAT", "scans,", "and", "even", "plain", "radiographs.", "As", "many", "snow-", "boarding", "facilities", "are", "located", "in", "relatively", "remote", "locations,", "an", "initial", "accurate", "diagnostic", "assessment", "would", "be", "critical", "to", "maximize", "the", "recovery", "of", "a", "patient.", "For", "example,", "in", "the", "case", "of", "an", "individual", "who", "suffers", "a", "potential", "joint", "injury", "of", "unknown", "severity,", "the", "decision", "must", "be", "made", "to", "apply", "ﬁrst", "aid", "principles", "(the", "application", "of", "cold", "and", "elevation", "to", "the", "affected", "area,", "anti-inﬂammatory", "medications,", "and", "rest", "for", "a" ]

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2,945,668

null

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[ "Hindawi", "Publishing", "Corporation", "Mediators", "of", "Inﬂammation", "Volume", "2010,", "Article", "ID", "498980,", "9", "pages", "doi:10.1155/2010/498980", "Review", "Article", "Targeting", "Toll-Like", "Receptors", "for", "Treatment", "of", "SLE", "Christopher", "G.", "Horton,1,", "2", "Zi-jian", "Pan,2", "and", "A.", "Darise", "Farris1,", "2", "1", "Department", "of", "Microbiology", "and", "Immunology,", "University", "of", "Oklahoma", "Health", "Sciences", "Center,", "Oklahoma", "City,", "OK", "73104,", "USA", "2", "Arthritis", "and", "Immunology", "Program,", "Oklahoma", "Medical", "Research", "Foundation,", "825", "NE", "13th", "Street,", "Oklahoma", "City,", "OK", "73104,", "USA", "Correspondence", "should", "be", "addressed", "to", "A.", "Darise", "Farris,", "farrisd@omrf.org", "Received", "10", "December", "2009;", "Accepted", "24", "August", "2010", "Academic", "Editor:", "Kathy", "Triantaﬁlou", "Copyright", "©", "2010", "Christopher", "G.", "Horton", "et", "al.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Toll-like", "receptors", "(TLRs)", "are", "important", "innate", "immune", "receptors", "for", "the", "identiﬁcation", "and", "clearance", "of", "invading", "pathogens.", "Twelve", "TLRs", "that", "recognize", "various", "conserved", "components", "of", "microorganisms", "are", "currently", "known.", "Among", "these,", "the", "endosomal", "TLRs", "3,", "7/8,", "and", "9", "recognize", "dsRNA,", "ssRNA,", "and", "CpG", "DNA,", "respectively.", "Nucleic", "acid-sensing", "TLRs,", "TLR", "7", "in", "particular,", "have", "been", "implicated", "in", "systemic", "lupus", "erythematosus", "(SLE)", "and", "are", "thought", "to", "exacerbate", "disease", "pathology.", "Activation", "of", "these", "TLRs", "results", "in", "the", "production", "of", "inﬂammatory", "cytokines", "and", "type", "I", "interferon.", "Genome-wide", "association", "studies,", "single", "nucleotide", "polymorphism", "analyses", "as", "well", "as", "experimental", "mouse", "models", "have", "provided", "evidence", "of", "TLR", "signaling", "involvement", "in", "SLE", "and", "other", "autoimmune", "diseases.", "Since", "activation", "of", "these", "receptor", "pathways", "promotes", "autoimmune", "phenotypes,", "inhibitory", "drugs", "that", "target", "these", "pathways", "constitute", "important", "new", "therapeutic", "strategies", "for", "the", "treatment", "of", "systemic", "autoimmunity.", "1.", "Introduction", "Toll-like", "receptors", "(TLRs)", "are", "pattern", "recognition", "recep-", "tors", "of", "the", "innate", "immune", "system", "that", "recognize", "speciﬁc", "pathogen-associated", "molecular", "patterns", "(PAMPs)", "conserved", "among", "microorganisms.", "There", "are", "currently", "twelve", "known", "TLRs", "in", "mammals,", "which", "identify", "common", "constituents", "of", "invading", "pathogens", "including", "double-stranded", "and", "single-stranded", "RNA,", "unmethylated", "CpG", "DNA,", "bacterial", "lipopolysaccharide", "(LPS),", "lipoproteins,", "and", "ﬂagellin", "[1].", "Upon", "interaction", "with", "their", "ligands,", "TLRs", "signal", "through", "adapter", "proteins,", "most", "commonly", "Myeloid", "Diﬀerentia-", "tion", "Primary", "Response", "Gene", "88", "(MyD88),", "though", "TLR", "3", "alternatively", "signals", "via", "the", "TIR-Domain", "Containing", "Adaptor", "Inducing", "Interferon-β", "(TRIF)", "adapter", "[2].", "These", "adapters", "recruit", "other", "molecules", "to", "initiate", "signaling", "cascades", "ultimately", "leading", "to", "the", "production", "of", "proinﬂammatory", "cytokines", "and", "type", "I", "IFN", "[3].", "These", "TLR", "responses", "are", "important", "in", "the", "functioning", "of", "both", "the", "innate", "and", "adaptive", "arms", "of", "immunity", "[4,", "5].", "Although", "TLRs", "are", "important", "for", "antimicrobial", "immu-", "nity,", "they", "have", "also", "been", "implicated", "in", "the", "pathogenesis", "of", "autoimmune", "diseases.", "For", "example,", "TLRs", "2", "and", "4", "have", "been", "identiﬁed", "as", "factors", "involved", "in", "the", "onset", "of", "type", "I", "diabetes", "mellitus", "[6–9],", "and", "TLRs", "1–6", "are", "expressed", "by", "rheumatoid", "arthritis", "(RA)", "synovial", "ﬁbroblasts", "and", "are", "thought", "to", "provoke", "joint", "inﬂammation", "in", "RA", "[10,", "11].", "Moreover,", "the", "nucleic", "acid", "binding", "TLRs", "7", "and", "9", "have", "been", "connected", "to", "both", "human", "and", "mouse", "models", "of", "systemic", "lupus", "erythematosus", "(SLE)", "[12–17].", "Because", "of", "these", "links", "between", "TLRs", "and", "autoimmunity,", "a", "great", "deal", "of", "work", "has", "been", "directed", "toward", "understanding", "how", "these", "receptors", "act", "in", "disease", "progression.", "Two", "major", "possibilities", "arise", "in", "describing", "how", "TLRs", "might", "work", "in", "autoimmunity;", "either", "they", "are", "stimulated", "by", "exogenous", "antigens,", "like", "viral", "ssRNA,", "which", "then", "stimulate", "resident", "immune", "cells,", "or", "the", "TLRs", "recognize", "endogenous", "self-antigens", "to", "initiate", "and", "propagate", "inﬂammation", "and", "autoimmunity.", "The", "accumulation", "of", "evidence", "pointing", "towards", "TLRs", "in", "autoimmunity", "has", "opened", "the", "door", "for", "potential", "therapeutic", "interventions", "directed", "towards", "the", "modulation", "of", "Toll-like", "receptors", "and", "their", "signaling", "pathways.", "Since", "TLRs", "are", "normally", "responsive", "to", "microbial", "pathogens,", "there", "has", "been", "some", "speculation", "as", "to", "the", "application", "of", "TLR", "agonists", "as", "vaccine", "adjuvants", "to", "stimulate", "more", "robust", "immune", "responses", "[18,", "19].", "On", "the", "other", "side", "of", "the", "spectrum,", "for", "autoimmunity,", "disease", "can", "result", "from", "aberrant", "hyperac-", "tive", "signaling;", "therefore,", "the", "application", "of", "inhibitory,", "or" ]

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3,343,452

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[ "Hematology", "Reports", "2012;", "volume", "4:e3", "Immunophenotyping", "of", "chronic", "B-cell", "neoplasms:", "flow", "cytometry", "versus", "immunohistochemistry", "Afaf", "Abdel-Aziz", "Abdel-Ghafar,", "Manal", "Ahmed", "Shams", "El", "Din", "El", "Telbany,", "Hanan", "Mohamed", "Mahmoud,", "Yasmin", "Nabil", "El-Sakhawy", "Clinical", "and", "Chemical", "Pathology,", "Faculty", "of", "Medicine,", "Ain", "Shams", "University,", "Cairo,", "Egypt", "Abstract", "Morphological", "differentiation", "between", "benign", "and", "malignant", "lymphoproliferative", "disorders", "(LPDs)", "can", "be", "challenging.", "Immunophenotyping", "(IPT)", "by", "either", "technique,", "flow", "cytometry", "or", "immunohistochemistry", "(IHC),", "is", "an", "important", "step", "in", "solving", "such", "difficulty.", "Thirty-five", "newly", "diagnosed", "patients", "with", "chronic", "B-cell", "neo-", "plasms", "(11", "chronic", "lymphocytic", "leukemia,", "22", "non", "Hodgkin", "lymphoma", "and", "2", "hairy", "cell", "leukemia)", "were", "included", "in", "this", "study", "with", "age", "range", "from", "20", "to", "70", "years.", "Monoclonal", "antibodies", "surface", "expression", "using", "lymphoproliferative", "disorders", "panel", "(CD45,", "CD19,", "CD5,", "CD10,", "CD11c,", "CD20,", "CD22,", "CD23,", "CD38,", "CD79b,", "FMC7,", "CD103,", "CD25,", "kappa", "and", "lambda", "light", "chains)", "by", "flow", "cytometry", "was", "done", "on", "bone", "marrow", "samples.", "CD20,", "CD5,", "CD23,", "Bcl-2,", "Bcl-6,", "kappa", "and", "lambda", "light", "chain", "immunostaining", "were", "performed", "on", "fixed", "bone", "marrow", "trephine", "biopsy", "specimen.", "The", "sensitiv-", "ity", "of", "IHC", "was", "81.8%", "in", "chronic", "lymphocytic", "leukemia", "(CLL)", "and", "100%", "in", "non", "Hodgkin", "lym-", "phoma", "(NHL)", "as", "regards", "CD20,", "100%", "in", "both", "groups", "as", "regards", "CD5,", "46%", "in", "CLL", "and", "66.7%", "in", "NHL", "as", "regards", "CD23,", "33.3%", "in", "CLL", "and", "50%", "in", "NHL", "as", "regards", "kappa", "chain,", "20%", "in", "CLL", "and", "33.3%", "in", "NHL", "as", "regards", "lambda", "chain.", "We", "found", "that", "IHC", "and", "flow", "cytometry", "are", "equally", "effective", "in", "diagnosing", "CLL;", "however,", "IHC", "might", "be", "slight-", "ly", "more", "sensitive", "than", "flow", "cytometry", "in", "detect-", "ing", "bone", "marrow", "infiltration", "in", "NHL", "and", "hairy", "cell", "leukemia", "(HCL).", "Introduction", "Distinguishing", "benign", "and", "malignant", "lympho-", "proliferative", "disorders", "(LPDs)", "by", "purely", "morpho-", "logic", "criteria", "can", "be", "difficult.", "Immunophenotypic", "analysis", "is", "a", "useful", "adjunct", "to", "the", "morphologic", "evaluation", "of", "LPDs", "and", "is", "of", "considerable", "assis-", "tance", "in", "resolving", "difficult", "diagnostic", "dilemmas.", "The", "advent", "of", "immunophenotyping", "(IPT)", "of", "sam-", "ples", "from", "patients", "with", "LPDs", "has", "added", "much", "for", "[page", "6]", "proper", "diagnosis", "and", "classification", "and", "for", "better", "understanding", "of", "the", "pathogenetic", "mechanisms", "underlying", "the", "development", "of", "these", "disorders.1", "There", "are", "several", "ways", "for", "testing", "cell", "mark-", "ers,", "such", "as", "flow", "cytometry", "in", "which", "suspensions", "of", "viable", "or", "fixed", "cells", "are", "tested,", "and", "immuno-", "histochemistry", "which", "studies", "cells", "in", "frozen", "or", "paraffin-embedded", "sections", "from", "bone", "marrow", "biopsy", "specimens", "or", "other", "hemopoietic", "tissues.2", "In", "immunohistochemistry", "(IHC),", "morphology", "and", "antigen", "label", "can", "be", "visualized", "simultane-", "ously", "by", "light", "microscopy", "which", "is", "not", "the", "case", "in", "flow", "cytometry,", "enabling", "accurate", "identification", "of", "the", "cells", "or", "region", "of", "interest.3", "It", "is", "considered", "more", "suitable", "in", "the", "detection", "of", "partial", "or", "focal", "involvement", "by", "neoplastic", "cells", "and", "it", "is", "also", "more", "beneficial", "in", "nuclear", "antigen", "assessment.4", "Another", "privilege", "of", "IHC", "is", "the", "long-term", "preser-", "vation", "of", "the", "biological", "specimen", "after", "process-", "ing", "and", "the", "ability", "to", "re-examine", "it", "at", "any", "time.5", "The", "aim", "of", "this", "study", "was", "to", "to", "identify", "the", "diagnostic", "role", "of", "IHC", "in", "chronic", "B-cell", "neo-", "plasms", "using", "a", "selected", "panel", "of", "monoclonal", "antibodies", "and", "to", "compare", "this", "role", "to", "that", "of", "flow", "cytometry.", "Materials", "and", "Methods", "Subjects", "This", "study", "comprised", "35", "newly", "diagnosed", "chronic", "B-cell", "neoplasms", "adult", "patients", "attend-", "ing", "the", "hematological", "unit", "of", "clinical", "pathology", "department,", "Ain", "Shams", "University,", "Cairo,", "Egypt.", "Patients", "were", "recruited", "to", "the", "study", "on", "the", "basis", "of", "clinical,", "laboratory,", "bone", "marrow", "aspirate", "and", "trephine", "biopsy", "findings", "and", "immunophenotypic", "criteria", "of", "chronic", "B-cell", "neoplasms.", "Sometimes", "lymph", "nodes", "biopsy", "results", "were", "provided", "to", "con-", "firm", "the", "diagnosis.", "They", "were", "22", "males", "and", "13", "females", "with", "a", "male", "to", "female", "ratio", "1.7:1.0.", "Their", "ages", "ranged", "from", "20", "to", "70", "years", "old", "with", "mean", "of", "51", "±", "15.2", "years.", "The", "35", "patients", "were", "divided", "into", "3", "groups:", "chronic", "lymphocytic", "leukemia", "(CLL)", "group", "(11", "patients),", "non", "Hodgkin", "lymphoma", "(NHL)", "group", "(22", "patients)", "and", "hairy", "cell", "leukemia", "(HCL)", "group", "(2", "patients).", "The", "22", "NHL", "cases", "comprised", "8", "mantle", "cell", "lymphomas,", "6", "follicular", "lymphomas,", "5", "diffuse", "large", "B-cell", "lymphomas", "and", "3", "Burkitt’s", "lymphomas.", "Patients", "were", "subjected", "to", "clinical", "sheet", "details", "(with", "special", "concern", "to", "organomegaly,", "lymphadenopathy,", "fever", "and", "weight", "loss),", "com-", "plete", "blood", "count", "with", "examination", "of", "peripheral", "blood", "smears", "stained", "with", "Leishman", "stain,", "bone", "marrow", "aspiration,", "bone", "marrow", "trephine", "biop-", "sy,", "flow", "cytometric", "immunophenotyping", "for", "cases", "in", "leukemic", "phase", "using", "lymphoproliferative", "dis-", "orders", "panel", "(CD45,", "CD19,", "CD5,", "CD10,", "CD11c,", "CD20,", "CD22,", "CD23,", "CD38,", "CD79b,", "FMC7,", "CD103,", "CD25,", "kappa", "and", "lambda", "light", "chains).", "CD20,", "CD5,", "CD23,", "Bcl-2,", "Bcl-6,", "kappa", "and", "lambda", "light", "[Hematology", "Reports", "2012;", "4:e3]", "Correspondence:", "Yasmin", "Nabil,", "Clinical", "and", "Chemical", "Pathology,", "Faculty", "of", "Medicine,", "Ain", "Shams", "University,", "El", "Abbassia", "Square,", "Cairo,", "Egypt.", "Tel.", "+20.224.845.802", "-", "Fax:", "+20.224.845.802.", "E-mail:", "yasminnabil@hotmail.com", "Key", "words:", "chronic", "B-", "LPD,", "immunohistochem-", "istry,", "immunophenotyping.", "Received", "for", "publication:", "26", "August", "2011.", "Revision", "received:", "4", "November", "2011.", "Accepted", "for", "publication:", "22", "December", "2011.", "This", "work", "is", "licensed", "under", "a", "Creative", "Commons", "Attribution", "NonCommercial", "3.0", "License", "(CC", "BY-", "NC", "3.0).", "©Copyright", "A.A.A.", "Abdel-Ghafar", "et", "al.,", "2012", "Licensee", "PAGEPress,", "Italy", "Hematology", "Reports", "2012;", "4:e3", "doi:10.4081/hr.2012.e3", "chain", "immunostaining", "was", "performed", "on", "fixed", "bone", "marrow", "trephine", "biopsy", "specimen.", "Specimens", "Two", "milliliters", "peripheral", "blood", "samples", "were", "collected", "in", "a", "sterile", "ethylene-diamine-tetra-", "acetic", "acid", "(EDTA)", "containing", "vaccutainers", "for", "CBC.", "Bone", "marrow", "(BM)", "aspiration", "was", "with-", "drawn;", "the", "first", "few", "drops", "were", "spread", "on", "glass", "slides", "for", "morphological", "examination", "and", "1", "mL", "into", "sterile", "EDTA", "containing", "vacutainers", "for", "IPT.", "For", "IPT", "by", "flow", "cytometry", "samples", "were", "processed", "within", "24", "hours.", "BM", "trephine", "core", "biopsy", "was", "obtained", "and", "transferred", "immediate-", "ly", "in", "a", "sterile", "plastic", "cup", "containing", "aldehyde", "solution", "as", "a", "fixative.", "Methods", "Flow", "cytometry", "Samples", "were", "processed", "using", "whole", "blood", "lysis", "method", "and", "analysis", "was", "done", "using", "4", "colour", "flow", "cytometric", "analyzer", "(Coulter", "EPICS-", "XL", "flow", "cytometer", "with", "system", "II", "software)", "USA.", "FCM", "quality", "control", "including", "alignment,", "calibra-", "tion,", "and", "color", "compensation", "was", "performed", "before", "sample", "acquisition", "according", "to", "manufac-", "turer’s", "instructional", "manual.", "Samples", "were", "dilut-", "ed", "1:1", "with", "phosphate", "buffered-saline", "(PBS),", "pH", "7.4", "(Sigma", "Chemicals,", "St", "Louis).", "The", "final", "cell", "count", "suspension", "was", "adjusted", "between", "5", "and", "10¥109/L:", "50", "uL", "of", "each", "sample", "was", "pipetted", "in", "two", "tubes", "(one", "test", "tube", "and", "one", "control", "tube);", "5", "uL", "of", "MoAbs", "fluorescin", "isothiocyanate", "(FITC),", "or", "phycoerythrin", "(PE)", "labeled", "(Provided", "by", "Coulter", "electronics,", "USA)", "were", "added", "to", "the", "test", "tube", "while", "5", "uL", "of", "isotype", "matched", "conjugated", "Igs", "to", "determine", "the", "non", "specific", "binding", "were", "added", "to", "the", "control", "tube.", "Tubes", "were", "gently", "vortexed", "and", "incubated", "15", "min", "at", "room", "temperature", "in", "the", "dark.", "One", "mL", "lysing", "solution", "was", "added", "to", "each" ]

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[ "Szatmári", "et", "al.", "Critical", "Care", "2010,", "14:R50", "http://ccforum.com/content/14/2/R50", "R", "E", "S", "E", "A", "R", "C", "H", "Open", "Access", "IRmeseaprcahired", "cerebrovascular", "reactivity", "in", "sepsis-associated", "encephalopathy", "studied", "by", "acetazolamide", "test", "Szilárd", "Szatmári1,", "Tamás", "Végh1,", "Ákos", "Csomós2,", "Judit", "Hallay1,", "István", "Takács3,", "Csilla", "Molnár1", "and", "Béla", "Fülesdi*1", "Abstract", "Introduction:", "The", "pathophysiology", "of", "sepsis-associated", "encephalopathy", "(SAE)", "is", "not", "entirely", "clear.", "One", "of", "the", "possible", "underlying", "mechanisms", "is", "the", "alteration", "of", "the", "cerebral", "microvascular", "function", "induced", "by", "the", "systemic", "inflammation.", "The", "aim", "of", "the", "present", "work", "was", "to", "test", "whether", "cerebral", "vasomotor-reactivity", "is", "impaired", "in", "patients", "with", "SAE.", "Methods:", "Patients", "fulfilling", "the", "criteria", "of", "clinical", "sepsis", "and", "showing", "disturbance", "of", "consciousness", "of", "any", "severity", "were", "included", "(n", "=", "14).", "Non-septic", "persons", "whithout", "previous", "diseases", "affecting", "cerebral", "vasoreactivity", "served", "as", "controls", "(n", "=", "20).", "Transcranial", "Doppler", "blood", "flow", "velocities", "were", "measured", "at", "rest", "and", "at", "5,", "10,", "15", "and", "20", "minutes", "after", "intravenous", "administration", "of", "15", "mg/kgBW", "acetazolamide.", "The", "time", "course", "of", "the", "acetazolamide", "effect", "on", "cerebral", "blood", "flow", "velocity", "(cerebrovascular", "reactivity,", "CVR)", "and", "the", "maximal", "vasodilatory", "effect", "of", "acetazolemide", "(cerebrovascular", "reserve", "capacity,", "CRC)", "were", "compared", "among", "the", "groups.", "Results:", "Absolute", "blood", "flow", "velocities", "after", "adminsitration", "of", "the", "vasodilator", "drug", "were", "higher", "among", "control", "subjects", "than", "in", "SAE.", "Assessment", "of", "the", "time-course", "of", "the", "vasomotor", "reaction", "showed", "that", "patients", "with", "SAE", "reacted", "slower", "to", "the", "vasodilatory", "stimulus", "than", "control", "persons.", "When", "assessing", "the", "maximal", "vasodilatory", "ability", "of", "the", "cerebral", "arterioles", "to", "acetazolamide", "during", "vasomotor", "testing,", "we", "found", "that", "patients", "with", "SAE", "reacted", "to", "a", "lesser", "extent", "to", "the", "drug", "than", "did", "control", "subjects", "(CRC", "controls:46.2", "±", "15.9%,", "CRC", "SAE:", "31,5", "±", "15.8%,", "P", "<", "0.01).", "Conclusions:", "We", "conclude", "that", "cerebrovascular", "reactivity", "is", "impaired", "in", "patients", "with", "SAE.", "The", "clinical", "significance", "of", "this", "pathophysiological", "finding", "has", "to", "be", "assessed", "in", "further", "studies.", "Introduction", "Sepsis-associated", "encephalopathy", "is", "defined", "as", "a", "diffuse", "cerebral", "dysfunction", "induced", "by", "the", "systemic", "response", "to", "the", "infection", "without", "clinical", "or", "laboratory", "evidence", "of", "direct", "infectious", "involvement", "of", "the", "central", "nervous", "sys-", "tem", "[1].", "Previous", "clinical", "observations", "have", "shown", "that", "the", "brain", "is", "often", "the", "first", "organ", "to", "be", "affected", "by", "sepsis,", "preceeding", "the", "clinical", "symptoms", "of", "other", "organ", "manifes-", "tations.", "According", "to", "the", "studies", "of", "Wilson", "and", "col-", "leagues", "and", "Young", "and", "colleagues,", "electroencephalogram", "(EEG)", "may", "be", "abnormal", "in", "87%", "of", "patients", "with", "bacteri-", "emia.", "They", "diagnosed", "70%", "with", "disturbance", "of", "con-", "sciousness", "of", "differing", "severity", "ranging", "from", "somnolence", "*", "Correspondence:", "fulesdi@dote.hu", "1", "Department", "of", "Anesthesiology", "and", "Intensive", "Care,", "University", "of", "Debrecen,", "Health", "and", "Medical", "Science", "Center,", "H-4032.", "Debrecen,", "Nagyerdei", "krt.", "98,", "Hungary", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "to", "coma", "[1-3].", "Ebersoldt", "and", "colleagues,", "reviewing", "sepsis-", "associated", "delirium,", "reported", "on", "a", "prevalence", "ranging", "from", "9", "to", "71%", "[4].", "The", "exact", "pathomechanism", "involved", "is", "not", "yet", "fully", "understood.", "It", "is", "believed", "that", "microcircula-", "tory", "alterations,", "disturbance", "of", "cerebral", "autoregulation,", "damage", "of", "the", "blood-brain", "barrier,", "branched", "chain/aro-", "matic", "amino", "acid", "inbalance", "and", "the", "direct", "effect", "of", "the", "inflammatory", "process", "(e.g.", "free", "radicals,", "oxydative", "stress,", "cytokines,", "excitotoxicity", "apoptosis)", "on", "glial", "cells", "may", "play", "a", "decisive", "role.", "Sepsis-related", "encephalopathy", "is", "most", "likely", "to", "be", "a", "multifactorially", "determined", "syndrome", "[5].", "When", "assessing", "cerebral", "microvascular", "contributing", "factors,", "in", "previous", "human", "investigations", "Matta", "and", "Stow", "[6]", "found", "cerebral", "autoregulation", "and", "carbon", "dioxide", "reactivity", "to", "be", "normal", "in", "patients", "with", "sepsis,", "whereas", "Terborg", "and", "colleagues", "reported", "on", "severely", "disturbed", "vasomotor", "reactivity", "(VMR)", "[7].", "In", "the", "past", "two", "decades,", "©", "2010", "Szatmári", "et", "al.;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "BioMed", "Central", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

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3,142,206

null

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[ "Lünsdorf", "et", "al.", "Microbial", "Cell", "Factories", "2011,", "10:48", "http://www.microbialcellfactories.com/content/10/1/48", "R", "E", "S", "E", "A", "R", "C", "H", "Open", "Access", "Virus-like", "particle", "production", "with", "yeast:", "ultrastructural", "and", "immunocytochemical", "insights", "into", "Pichia", "pastoris", "producing", "high", "levels", "of", "the", "Hepatitis", "B", "surface", "antigen", "Heinrich", "Lünsdorf1,", "Chandrasekhar", "Gurramkonda2,3,", "Ahmad", "Adnan2,4,", "Navin", "Khanna3", "and", "Ursula", "Rinas2,5*", "Abstract", "Background:", "A", "protective", "immune", "response", "against", "Hepatitis", "B", "infection", "can", "be", "obtained", "through", "the", "administration", "of", "a", "single", "viral", "polypeptide,", "the", "Hepatitis", "B", "surface", "antigen", "(HBsAg).", "Thus,", "the", "Hepatitis", "B", "vaccine", "is", "generated", "through", "the", "utilization", "of", "recombinant", "DNA", "technology,", "preferentially", "by", "using", "yeast-based", "expression", "systems.", "However,", "the", "polypeptide", "needs", "to", "assemble", "into", "spherical", "particles,", "so-called", "virus-like", "particles", "(VLPs),", "to", "elicit", "the", "required", "protective", "immune", "response.", "So", "far,", "no", "clear", "evidence", "has", "been", "presented", "showing", "whether", "HBsAg", "assembles", "in", "vivo", "inside", "the", "yeast", "cell", "into", "VLPs", "or", "later", "in", "vitro", "during", "down-stream", "processing", "and", "purification.", "Results:", "High", "level", "production", "of", "HBsAg", "was", "carried", "out", "with", "recombinant", "Pichia", "pastoris", "using", "the", "methanol", "inducible", "AOX1", "expression", "system.", "The", "recombinant", "vaccine", "was", "isolated", "in", "form", "of", "VLPs", "after", "several", "down-", "stream", "steps", "from", "detergent-treated", "cell", "lysates.", "Search", "for", "the", "intracellular", "localization", "of", "the", "antigen", "using", "electron", "microscopic", "studies", "in", "combination", "with", "immunogold", "labeling", "revealed", "the", "presence", "of", "HBsAg", "in", "an", "extended", "endoplasmic", "reticulum", "where", "it", "was", "found", "to", "assemble", "into", "defined", "multi-layered,", "lamellar", "structures.", "The", "distance", "between", "two", "layers", "was", "determined", "as", "~6", "nm", "indicating", "that", "these", "lamellas", "represent", "monolayers", "of", "well-ordered", "HBsAg", "subunits.", "We", "did", "not", "find", "any", "evidence", "for", "the", "presence", "of", "VLPs", "within", "the", "endoplasmic", "reticulum", "or", "other", "parts", "of", "the", "yeast", "cell.", "Conclusions:", "It", "is", "concluded", "that", "high", "level", "production", "and", "intrinsic", "slow", "HBsAg", "VLP", "assembly", "kinetics", "are", "leading", "to", "retention", "and", "accumulation", "of", "the", "antigen", "in", "the", "endoplasmic", "reticulum", "where", "it", "assembles", "at", "least", "partly", "into", "defined", "lamellar", "structures.", "Further", "transport", "of", "HBsAg", "to", "the", "Golgi", "apparatus", "is", "impaired", "thus", "leading", "to", "secretory", "pathway", "disfunction", "and", "the", "formation", "of", "an", "extended", "endoplasmic", "reticulum", "which", "bulges", "into", "irregular", "cloud-", "shaped", "formations.", "As", "VLPs", "were", "not", "found", "within", "the", "cells", "it", "is", "concluded", "that", "the", "VLP", "assembly", "process", "must", "take", "place", "during", "down-stream", "processing", "after", "detergent-mediated", "disassembly", "of", "HBsAg", "lamellas", "and", "subsequent", "reassembly", "of", "HBsAg", "into", "spherical", "VLPs.", "Background", "Unlike", "many", "other", "vaccines", "against", "virus-caused", "diseases,", "a", "single", "viral", "polypeptide", "is", "sufficient", "to", "elicit", "a", "protecting", "immune", "response", "against", "Hepatitis", "B", "infection", "[1].", "However,", "the", "polypeptide", "needs", "to", "assemble", "into", "spherical", "particles,", "so-called", "virus-like", "particles", "(VLPs),", "*", "Correspondence:", "Ursula.Rinas@helmholtz-hzi.de", "2Helmholtz", "Centre", "for", "Infection", "Research", "(SB),", "Braunschweig,", "Germany", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "to", "initiate", "the", "required", "protective", "immune", "response", "[2].", "In", "HBV", "infected", "individuals,", "viral", "surface", "proteins", "are", "produced", "in", "large", "excess", "in", "liver", "cells", "over", "the", "amount", "needed", "for", "virus", "assembly", "and", "are", "secreted", "as", "a", "mixture", "of", "spherical", "particles", "and", "tubular", "forms.", "Thus,", "in", "the", "serum", "of", "HBV", "infected", "patients,", "intact", "viruses", "(Dane", "particles)", "but", "also", "“empty”", "spherical", "particles", "and", "tubu-", "lar", "forms", "consisting", "of", "the", "surface", "proteins", "of", "the", "Hepa-", "titis", "B", "virus", "are", "found", "[3,4].", "©", "2011", "Lünsdorf", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

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548,513

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[ "BMC", "Medical", "Education", "Research", "article", "An", "interactive", "course", "to", "enhance", "self-efficacy", "of", "family", "practitioners", "to", "treat", "obesity", "Sara", "Katz*1,", "Amiel", "Feigenbaum2,", "Shmuel", "Pasternak3", "and", "Shlomo", "Vinker2", "Address:", "1Technion", "–", "Israel", "Institute", "of", "Technology", "–", "Faculty", "of", "Medicine,", "Haifa,", "Israel,", "2Department", "of", "Family", "Medicine,", "Sackler", "School", "of", "Medicine,", "Tel", "Aviv", "University,", "Israel", "and", "3General", "Health", "Services,", "Holon,", "Israel", "Email:", "Sara", "Katz*", "-", "sara1@tx.technion.ac.il;", "Amiel", "Feigenbaum", "-", "amielfe@netvision.net.il;", "Shmuel", "Pasternak", "-", "amielfe@netvision.net.il;", "Shlomo", "Vinker", "-", "vinker01@zahav.net.il", "*", "Corresponding", "author", "BioMed", "Central", "Open", "Access", "Published:", "29", "January", "2005", "BMC", "Medical", "Education", "2005,", "5:4", "doi:10.1186/1472-6920-5-4", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1472-6920/5/4", "Received:", "05", "July", "2004", "Accepted:", "29", "January", "2005", "©", "2005", "Katz", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "Physicians'", "awareness", "of", "their", "important", "role", "in", "defusing", "the", "obesity", "epidemic", "has", "increased.", "However,", "the", "number", "of", "family", "practitioners", "who", "treat", "obesity", "problems", "continues", "to", "be", "low.", "Self-efficacy", "refers", "to", "the", "belief", "in", "one's", "ability", "to", "organize", "and", "execute", "the", "courses", "of", "action", "required", "to", "produce", "given", "attainments.", "Thus,", "practitioners", "who", "judge", "themselves", "incapable", "of", "managing", "obesity", "do", "not", "even", "try.", "We", "hypothesized", "that", "practitioners'", "self-efficacy", "and", "motivation", "would", "be", "enhanced", "as", "a", "result", "of", "participating", "in", "an", "interactive", "course", "designed", "to", "enrich", "their", "knowledge", "of", "obesity", "management.", "Methods:", "Twenty-nine", "family", "practitioners", "participated", "in", "the", "course,", "which", "was", "accompanied", "by", "qualitative", "interviews.", "The", "difference", "between", "the", "physicians'", "pre-course", "and", "post-course", "appraisals", "was", "tested", "by", "paired", "t-test.", "The", "interviews", "were", "analyzed", "by", "qualitative", "methods.", "Results:", "Post-course", "efficacy", "appraisals", "were", "significantly", "higher", "than", "pre-course", "appraisals", "(p", "<", "0.0005).", "A", "deeper", "insight", "on", "the", "practitioners'", "self-efficacy", "processes", "was", "gained", "through", "reflection", "of", "the", "practitioners", "on", "their", "self-efficacy", "during", "the", "interviews.", "Conclusions:", "Up-to-date", "information", "and", "workshops", "where", "skills,", "attitudes", "and", "social", "support", "were", "addressed", "were", "important", "in", "making", "the", "program", "effective.", "Background", "Obesity", "is", "becoming", "increasingly", "common", "and", "is", "recog-", "nized", "as", "a", "major", "public", "health", "problem", "worldwide", "[1-3].", "In", "the", "UK,", "the", "overweight", "and", "obese", "population", "increased", "by", "almost", "15%", "between", "1980", "and", "1992.", "Similar", "increases", "have", "been", "noted", "in", "many", "countries,", "including", "the", "USA", "[4],", "Sweden", "[5]", "and", "the", "Netherlands", "[6].", "In", "Israel,", "55%", "of", "females", "and", "58%", "of", "males", "aged", "25–64", "were", "reported", "to", "be", "overweight", "or", "obese", "(Body", "Mass", "Index", ">25", "kg/m2)", "in", "a", "Mabat", "survey", "[7]", "in", "2000.", "Guidelines", "published", "in", "1996", "for", "the", "management", "of", "obesity", "recommended", "setting", "a", "modest", "weight", "loss", "and", "weight", "maintenance,", "rather", "than", "a", "targeted", "ideal", "weight,", "as", "goals", "[8].", "Lately,", "pharmacological", "therapies", "have", "been", "proposed", "as", "adjuncts", "to", "diet", "and", "lifestyle", "changes", "to", "improve", "long-term", "weight", "loss", "[9].", "The", "World", "Health", "Organization", "declared", "obesity", "an", "epidemic", "in", "developed", "countries.", "Awareness", "of", "physicians", "of", "their", "important", "role", "in", "defusing", "the", "obesity", "epidemic", "has", "increased.", "Yet,", "the", "number", "of", "family", "practitioners", "(FP)", "treating", "obesity", "prob-", "lems", "continues", "to", "be", "low", "[10].", "Page", "1", "of", "8", "(page", "number", "not", "for", "citation", "purposes)" ]

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[ "Int.", "J.", "Biol.", "Sci.", "2006,", "2", "Research", "paper", "32", "International", "Journal", "of", "Biological", "Sciences", "ISSN", "1449-2288", "www.biolsci.org", "2006", "2(2):32-37", "©2006", "Ivyspring", "International", "Publisher.", "All", "rights", "reserved", "Metaphylogeny", "of", "82", "gene", "families", "sheds", "a", "new", "light", "on", "chordate", "evolution", "Alexandre", "Vienne", "and", "Pierre", "Pontarotti", "Phylogenomics", "Laboratory,", "EA", "3781", "Evolution", "Biologique,", "Université", "de", "Provence,", "13331", "MARSEILLE", "CEDEX", "03,", "FRANCE", "Corresponding", "to:", "Alexandre", "Vienne,", "Phylogenomics", "Laboratory,", "EA", "3781", "Evolution", "Biologique,", "Place", "V.", "HUGO,", "Université", "de", "Provence,", "13331", "MARSEILLE", "CEDEX", "03,", "France.", "Email:", "avienne@up.univ-mrs.fr.", "Phone:", "(33)", "4", "91", "10", "64", "89", "Received:", "2006.01.15;", "Accepted:", "2006.03.31;", "Published:", "2006.04.10", "Achieving", "a", "better", "comprehension", "of", "the", "evolution", "of", "species", "has", "always", "been", "an", "important", "matter", "for", "evolutionary", "biologists.", "The", "deuterostome", "phylogeny", "has", "been", "described", "for", "many", "years,", "and", "three", "phyla", "are", "distinguishable:", "Echinodermata", "(including", "sea", "stars,", "sea", "urchins,", "etc…),", "Hemichordata", "(including", "acorn", "worms", "and", "pterobranchs),", "and", "Chordata", "(including", "urochordates,", "cephalochordates", "and", "extant", "vertebrates).", "Inside", "the", "Chordata", "phylum,", "the", "position", "of", "vertebrate", "species", "is", "quite", "unanimously", "accepted.", "Nonetheless,", "the", "position", "of", "urochordates", "in", "regard", "with", "vertebrates", "is", "still", "the", "subject", "of", "debate,", "and", "has", "even", "been", "suggested", "by", "some", "authors", "to", "be", "a", "separate", "phylum", "from", "cephalochordates", "and", "vertebrates.", "It", "was", "also", "the", "case", "for", "agnathans", "species", "–myxines", "and", "hagfish–", "for", "which", "phylogenetic", "evidence", "was", "recently", "given", "for", "a", "controversial", "monophyly.", "This", "raises", "the", "following", "question:", "which", "one", "of", "the", "cephalochordata", "or", "urochordata", "is", "the", "sister", "group", "of", "vertebrates", "and", "what", "are", "their", "relationships?", "In", "the", "present", "work,", "we", "analyzed", "82", "protein", "families", "presenting", "homologs", "between", "urochordata", "and", "other", "deuterostomes", "and", "focused", "on", "two", "points:", "1)", "testing", "accurately", "the", "position", "of", "urochordata", "and", "cephalochordata", "phyla", "in", "regard", "with", "vertebrates", "as", "well", "as", "chordates", "monophyly,", "2)", "performing", "an", "estimation", "of", "the", "rate", "of", "gene", "loss", "in", "the", "Ciona", "intestinalis", "genome.", "We", "showed", "that", "the", "urochordate", "phyla", "is", "the", "vertebrate", "sister", "group", "and", "that", "gene", "loss", "played", "a", "major", "role", "in", "structuring", "the", "urochordate", "genome.", "Keywords:", "chordate", "monophyly,", "evolution,", "cephalochordate,", "urochordate,", "gene", "loss", "1.", "INTRODUCTION", "The", "positioning", "of", "species", "among", "the", "deuterostome", "phylum", "and", "the", "evolution", "of", "metazoans", "has", "fascinated", "researchers", "for", "decades,", "and", "has", "been", "the", "purpose", "of", "strong", "debates.", "Using", "for", "comparisons", "the", "morphological", "as", "well", "as", "the", "molecular", "data", "that", "are", "nowadays", "abundant", "and", "available", "through", "large", "number", "of", "databases,", "they", "all", "tried", "to", "describe", "as", "accurately", "as", "possible", "the", "reality", "of", "species", "evolutionary", "history.", "Inside", "deuterostomians,", "three", "major", "groups", "are", "quiet", "unanimously", "defined", "(Figure", "1):", "Echinodermata", "(including", "starfish,", "sea", "urchins,", "etc…),", "Hemichordata", "(including", "acorn", "worms", "and", "pterobranchs),", "and", "Chordata", "(including", "three", "subphyla:", "urochordates", "–composed", "of", "more", "than", "3.000", "species—,", "cephalochordates", "–composed", "of", "approximately", "29", "species—,", "and", "the", "extant", "vertebrates", "including", "hagfishes,", "lampreys,", "and", "jawed", "vertebrates", "–composed", "of", "approximately", "53.000", "species—)", "[1].", "The", "analysis", "of", "anatomical", "data", "has", "led", "to", "several", "hypotheses", "regarding", "deuterostome", "phylogeny", "[2]", "and", "the", "relationships", "inter", "and", "intra-", "groups", "are", "still", "subject", "to", "debates.", "One", "of", "the", "specificity", "of", "chordates", "is", "their", "morphological", "synapomorphic.", "These", "particularities", "shared", "between", "urochordates,", "cephalochordates", "and", "vertebrates", "are", "quiet", "well", "known–as", "for", "example", "the", "notochord,", "the", "dorsal", "hollow", "nerve", "cord,", "the", "tail", "extending", "behind", "the", "visceral", "cavity,", "the", "thyroid", "gland", "(endostyle),", "and", "some", "other", "features", "[3].", "Nonetheless,", "controversy", "is", "common", "among", "evolutionary", "biologists", "regarding", "the", "kind", "of", "data", "analysed,", "those", "data", "being", "tested", "as", "nucleic", "or", "protein", "sequences,", "considering", "them", "as", "fast", "or", "slow-evolving", "genes", "or", "parts", "of", "genes", "[4].", "These", "latter", "will", "give", "more", "or", "less", "phylogenetic", "signals", "from", "the", "data", "sets", "for", "recent", "or", "deeper", "events", "during", "evolution.", "Recent", "studies", "have", "led", "to", "the", "re-examination", "of", "some", "species", "relationships,", "and", "echinoderms", "+", "hemichordates", "were", "shown", "to", "constitute", "a", "monophyletic", "group.", "More", "recently,", "relationships", "of", "agnathans", "species", "–myxine", "and", "hagfish—were", "revisited", "[5],", "and", "this", "example", "is", "the", "best", "illustration", "of", "discussions.", "Indeed,", "strong", "support", "was", "given", "for", "the", "monophyly", "of", "jawless", "vertebrates", "which", "are", "the", "most", "basal", "group", "of", "vertebrates,", "by", "the", "analysis", "of", "35", "protein", "coding", "gene", "families", "after", "years", "of", "controversial", "debates.", "The", "concatenation", "of", "the", "different", "topologies", "obtained", "led", "to", "the", "assessment", "of", "a", "monophyletic", "group.", "This", "work", "can", "be", "extended", "to", "the", "present", "purpose", "concerning", "the", "existing", "relationships", "between", "cephalochordates", "and", "urochordates,", "leading", "to", "the", "following", "question:", "which", "one", "of", "cephalochordata", "or", "urochordata", "correspond", "to", "the", "sister", "group", "of", "vertebrates?" ]

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[ "Olangirhcaser", "elcitra", "published:", "31", "January", "2011", "doi:", "10.3389/fpsyg.2010.00246", "Childhood", "trauma", "and", "chronic", "illness", "in", "adulthood:", "mental", "health", "and", "socioeconomic", "status", "as", "explanatory", "factors", "and", "buffers", "Steven", "E.", "Mock*", "and", "Susan", "M.", "Arai", "Department", "of", "Recreation", "and", "Leisure", "Studies,", "Department", "of", "Health", "Studies", "and", "Gerontology,", "University", "of", "Waterloo,", "Waterloo,", "ON,", "Canada", "Edited", "by:", "Elysia", "Davis,", "University", "of", "California", "at", "Irvine,", "USA", "Reviewed", "by:", "Nadine", "Fink,", "Harvard", "Medical", "School,", "USA", "Kerry-Ann", "Grant,", "Macquarie", "University,", "Australia", "*Correspondence:", "Steven", "E.", "Mock,", "Department", "of", "Recreation", "and", "Leisure", "Studies,", "Department", "of", "Health", "Studies", "and", "Gerontology,", "University", "of", "Waterloo,", "200", "University", "Avenue", "West,", "Waterloo,", "ON,", "Canada", "N2L", "3G1.", "e-mail:", "smock@uwaterloo.ca", "Experiences", "of", "traumatic", "events", "in", "childhood", "have", "been", "shown", "to", "have", "long-term", "consequences", "for", "health", "in", "adulthood.", "With", "data", "from", "the", "2005", "Canadian", "Community", "Health", "Survey", "we", "take", "a", "life", "course", "perspective", "of", "cumulative", "disadvantage", "and", "examine", "the", "potential", "role", "of", "mental", "health", "and", "socioeconomic", "status", "in", "adulthood", "as", "multiple", "mediators", "of", "the", "link", "between", "childhood", "trauma", "and", "chronic", "illness", "in", "adulthood.", "Mental", "health", "and", "socioeconomic", "status", "are", "also", "tested", "as", "buffers", "against", "the", "typically", "adverse", "consequences", "of", "childhood", "trauma.", "The", "results", "suggest", "mental", "health", "and", "socioeconomic", "status", "partially", "explain", "the", "association", "of", "childhood", "trauma", "with", "chronic", "illness", "in", "adulthood,", "with", "mental", "health", "showing", "a", "stronger", "effect.", "In", "addition,", "an", "analysis", "of", "the", "interactions", "suggested", "higher", "socioeconomic", "status", "is", "a", "potential", "protective", "factor", "for", "those", "with", "a", "history", "of", "trauma.", "Results", "also", "suggest", "cumulative", "disadvantage", "following", "trauma", "may", "lead", "to", "chronic", "illness", "and", "suggest", "the", "need", "for", "public", "health", "expenditures", "on", "resources", "such", "as", "counseling", "and", "income", "supports", "to", "prevent", "or", "reduce", "psychological", "harm", "and", "chronic", "illness", "resulting", "from", "traumatic", "events.", "Keywords:", "childhood", "trauma,", "chronic", "illness,", "mental", "health,", "socioeconomic", "status,", "cumulative", "disadvantage", "IIcudortnno", "The", "experience", "of", "traumatic", "events", "in", "childhood", "has", "consequences", "for", "health", "in", "adulthood.", "A", "broad", "range", "of", "traumatic", "events", "expe-", "rienced", "in", "childhood", "including", "physical", "abuse,", "sexual", "abuse,", "pro-", "longed", "hospitalization,", "and", "family", "instability", "such", "as", "parental", "unemployment", "or", "substance", "abuse", "have", "been", "linked", "to", "chronic", "illness", "in", "adulthood", "stemming", "from", "poor", "immune", "functioning", "or", "poor", "cardiovascular", "health", "(Springer", "et", "al.,", "2003;", "Mulvihill,", "2005;", "O’Rand", "and", "Hamil-Luker,", "2005;", "Wickrama", "et", "al.,", "2005).", "According", "to", "a", "life", "course", "perspective,", "there", "are", "multiple", "potential", "pathways", "that", "may", "contribute", "to", "a", "process", "of", "cumulative", "disadvantage", "fol-", "lowing", "traumatic", "childhood", "events", "(Dannefer,", "2003;", "Pearlin", "et", "al.,", "2005).", "One", "potential", "pathway", "is", "through", "the", "negative", "mental", "health", "consequences", "in", "adulthood", "of", "trauma", "experienced", "in", "childhood", "(Turner", "and", "Lloyd,", "1995;", "Paolucci", "et", "al.,", "2001;", "Briere", "and", "Jordan,", "2009).", "Recent", "work", "also", "suggests", "that", "there", "are", "socioeconomic", "dis-", "advantages", "in", "adulthood", "resulting", "from", "trauma", "early", "in", "life", "that", "may", "contribute", "to", "chronic", "illness", "(Hyman,", "2000;", "Zielinski,", "2009;", "Currie", "and", "Spatz", "Widom,", "2010).", "In", "addition", "to", "being", "potential", "explanatory", "factors", "for", "the", "link", "between", "childhood", "trauma", "and", "chronic", "illness,", "adult", "mental", "health", "and", "socioeconomic", "status", "(SES)", "are", "plausible", "buffers", "of", "the", "negative", "effects", "of", "trauma", "on", "health", "(Melchior", "et", "al.,", "2007;", "Wethington", "et", "al.,", "2008).", "A", "traumatic", "experience", "is", "one", "that", "threatens", "death", "or", "injury", "to", "self", "or", "others", "and", "elicits", "intense", "feelings", "of", "fear,", "helplessness,", "or", "horror", "(American", "Psychiatric", "Association,", "2000).", "Examples", "of", "traumatic", "events", "include", "physical", "abuse,", "sexual", "abuse,", "combat,", "wit-", "nessing", "violence", "or", "disaster,", "or", "the", "sudden", "death", "of", "a", "loved", "one.", "Over", "a", "lifetime", "most", "people", "experience", "at", "least", "one", "potentially", "traumatic", "event", "(Klein", "and", "Alexander,", "2009).", "In", "a", "community-level", "study", "in", "the", "United", "States,", "it", "was", "found", "that", "74.2%", "of", "women", "and", "81.3%", "of", "men", "reported", "experiencing", "at", "least", "one", "traumatic", "event", "in", "their", "lifetime", "(Stein", "et", "al.,", "1997).", "A", "community", "study", "(Breslau,", "2009;", "Breslau", "et", "al.,", "1999)", "reported", "similar", "findings,", "78.1%", "for", "women", "and", "92.2%", "among", "men,", "for", "lifetime", "prevalence", "of", "exposure", "to", "traumatic", "events.", "Results", "from", "a", "national", "study", "in", "the", "United", "States", "indicate", "overall", "rates", "of", "child", "maltreatment", "at", "13.8%", "(8.0%", "having", "experi-", "enced", "sexual", "abuse,", "6.7%", "physical", "abuse,", "2.9%", "severe", "neglect,", "and", "3.2%", "reporting", "multiple", "forms", "of", "child", "maltreatment", "experienced;", "Zielinski,", "2009).", "Goodwin", "et", "al.", "(2003)", "reported", "physical", "abuse", "by", "parents", "at", "a", "rate", "of", "15.8%", "and", "similar", "rates", "have", "been", "reported", "in", "Canadian", "research", "(MacMillan", "et", "al.,", "1997).", "In", "a", "community-level", "study", "of", "traumatic", "experiences", "in", "childhood", "(Turner", "and", "Lloyd,", "1995)", "19.5%", "reported", "major", "illness", "or", "accident,", "9.6%", "parental", "divorce,", "17.7%", "repeating", "a", "year", "of", "school,", "9.4%", "parent", "unemploy-", "ment,", "26.5%", "experience", "of", "a", "significant", "scare,", "2.6%", "being", "sent", "away", "from", "home,", "8.2%", "parent", "alcohol", "or", "drug", "use,", "and", "3.8%", "physical", "abuse.", "The", "experience", "of", "traumatic", "events", "in", "childhood", "is", "associated", "with", "long-term", "health", "effects.", "In", "a", "study", "of", "the", "impact", "of", "child-", "hood", "trauma", "on", "health", "in", "adulthood,", "those", "who", "reported", "child-", "hood", "psychological", "or", "physical", "victimization", "had", "worse", "health", "than", "those", "who", "did", "not", "and", "also", "experienced", "significantly", "more", "decline", "in", "health", "over", "a", "10-year", "period", "in", "adulthood", "(Greenfield", "and", "Marks,", "2009).", "This", "is", "consistent", "with", "research", "that", "shows", "the", "negative", "impact", "of", "childhood", "adversity", "on", "cardiovascular", "health", "(O’Rand", "and", "Hamil-Luker,", "2005)", "and", "recent", "reviews", "documenting", "a", "consistent", "association", "between", "childhood", "trauma", "and", "negative", "health", "consequences", "in", "adulthood", "including", "pain,", "unexplained", "somatic", "symptoms,", "stress-related", "illnesses,", "and", "illnesses", "related", "to", "www.frontiersin.org", "January", "2011", "|", "Volume", "1", "|", "Article", "246", "|", "1" ]

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3,408,287

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[ "Flexor", "Tenorrhaphy", "Using", "Absorbable", "Suture", "Materials", "Hyung", "Joo", "Kang,", "Dong", "Chul", "Lee,", "Jin", "Soo", "Kim,", "Sae", "Hwi", "Ki,", "Si", "Young", "Roh,", "Jae", "Won", "Yang", "Department", "of", "Plastic", "and", "Reconstructive", "Surgery,", "Kwang-Myung", "Sung-Ae", "General", "Hospital,", "Gwangmyeong", ",", "Korea", "Background ", "Nonabsorbable", " ", "sutures ", "are ", "favorable ", "for ", "repairing ", "flexor ", "tendons. ", "However, ", "absorbable ", "sutures ", "have ", "performed ", "favorably ", "in ", "an ", "animal ", "model.", "Methods ", "Two-strand", " ", "sutures ", "using ", "the ", "interlocking ", "modified ", "Kessler ", "method ", "with ", "polydioxanone ", "absorbable ", "sutures ", "4-0 ", "were ", "used ", "to ", "repair ", "completely ", "ruptured ", "flexor ", "tendons ", "in ", "55 ", "fingers ", "from ", "41 ", "consecutive ", "patients. ", "The ", "medical ", "records ", "of ", "average ", "42 ", "follow ", "up ", "weeks ", "were ", "analyzed ", "retrospectively. ", "The ", "data ", "analyzed ", "using ", "the ", "chi-squared ", "test, ", "and ", "Fisher’s ", "exact ", "test ", "was ", "used ", "for ", "postoperative ", "complications. ", "The ", "results ", "were ", "compared ", "with ", "those ", "of ", "other ", "studies.", "Results ", "Among", " ", "the ", "index, ", "middle, ", "ring, ", "and ", "little ", "fingers ", "were ", "injured ", "in ", "9, ", "17, ", "16, ", "and ", "13 ", "fingers, ", "respectively. ", "The ", "injury ", "levels ", "varied ", "from ", "zone ", "1 ", "to ", "5. ", "Of ", "the ", "55 ", "digits ", "in ", "our ", "study, ", "there ", "were ", "26 ", "(47%) ", "isolated ", "flexor ", "digitorum ", "profundus ", "(FDP) ", "injuries ", "and ", "29 ", "(53%) ", "combined ", "FDP ", "and ", "with ", "flexor ", "digitorum ", "superficialis ", "injuries. ", "Pulley ", "repair ", "was ", "also ", "conducted. ", "Concomitant ", "injuries ", "of ", "blood ", "vessels ", "and ", "nerves ", "were ", "found ", "in ", "17 ", "patients ", "(23 ", "fingers); ", "nerve ", "injuries ", "occurred ", "in ", "5 ", "patients ", "(10 ", "fingers). ", "Two ", "patients ", "had ", "ruptures ", "(3.6%), ", "and ", "one ", "patient ", "had ", "two ", "adhesions ", "(3.6%). ", "Using ", "the ", "original ", "Strickland ", "criteria, ", "all ", "the ", "patients ", "were ", "assessed ", "to ", "be ", "excellent ", "or ", "good. ", "Also, ", "fibrosis ", "and ", "long-term ", "foreign ", "body ", "tissue ", "reactions ", "such ", "as ", "stitch ", "granuloma ", "were ", "less ", "likely ", "occurred ", "in ", "our ", "study. ", "Compared ", "to ", "the ", "Cullen’s ", "report ", "that ", "used ", "nonabsorbable ", "sutures, ", "there ", "was ", "no ", "significant ", "difference ", "in ", "the ", "rupture ", "or ", "adhesion ", "rates.", "Conclusions ", "Therefore,", " ", "this ", "study ", "suggests ", "that ", "appropriate ", "absorbable ", "core ", "sutures ", "can ", "be ", "used ", "safely ", "for ", "flexor ", "tendon ", "repairs.", "Keywords ", "Hand", " ", "/ ", "Polydioxanone ", "/ ", "Rupture ", "/ ", "Tendon ", "Injuries", "Received:", "8", "Mar", "2012", "•", "Revised:", "23", "May", "2012", "•", "Accepted:", "23", "May", "2012", "pISSN: 2234-6163 ", "• eISSN: 2234-6171 ", "• http://dx.doi.org/10.5999/aps.2012.39.4.397 ", "• Arch Plast Surg 2012;39:397-403", "Correspondence:", "Dong", "Chul", "Lee", "Department", "of", "Plastic", "and", "Reconstructive", "Surgery,", "Kwang-Myung", "Sung-Ae", "General", "Hospital,", "36", "Digital-ro,", "Gwangmyeong", "423-711,", "Korea", "Tel:", "+82-2-2680-7238", "Fax:", "+82-2-2615-7218", "E-mail:", "ophand@gmail.com", "O", "r", "i", "g", "i", "n", "a", "l", "A", "r", "t", "i", "c", "l", "e", "This", "article", "was", "presented", "at", "the", "Research", "and", "Reconstructive", "Forum", "on", "May", "12-13,", "2011", "in", "Daejeon,", "Korea.", "No", "potential", "conflict", "of", "interest", "relevant", "to", "this", "article", "was", "reported", "INTRODUCTION", "been", "performed", "since", "the", "beginning", "of", "the", "20th", "century.", "Since", "Kleinert", "et", "al.", "[1]", "conducted", "primary", "repair", "for", "a", "flexor", "tendon", "Various", "sutures", "can", "be", "used", "to", "repair", "a", "ruptured", "flexor", "tendon.", "rupture", "in", "the", "no", "man’s", "land,", "tendon", "repair", "has", "been", "commonly", "Since", "Avicenna", "first", "performed", "a", "tendon", "repair", "procedure,", "pri-", "performed", "on", "flexor", "tendon", "ruptures", "of", "the", "fingers;", "studies", "on", "mary", "tendon", "repair", "has", "rarely", "been", "performed", "because", "primary", "the", "repair", "of", "the", "flexor", "tendon", "have", "been", "also", "conducted.", "Suture", "tenorrhaphy", "is", "a", "controversial", "procedure", "[1].", "Until", "the", "mid-20th", "materials", "used", "for", "tendon", "repair", "have", "been", "developed", "over", "time.", "century,", "using", "a", "tendon", "graft", "had", "been", "preferred", "over", "tendon", "Many", "surgeons", "prefer", "sutures", "made", "of", "nonabsorbable", "materials", "repair", "for", "treating", "the", "“no", "man’s", "land”", "section", "of", "the", "hand.", "Stud-", "such", "as", "nylon,", "braided", "polyester,", "and", "polypropylene", "[2].", "How-", "ies", "on", "flexor", "tendon", "healing", "of", "the", "digital", "sheath,", "however,", "have", "ever,", "Trail", "et", "al.", "[3]", "reported", "that", "using", "sutures", "made", "of", "nonab-", "Copyright", "©", "2012", "The", "Korean", "Society", "of", "Plastic", "and", "Reconstructive", "Surgeons", "This", "is", "an", "OpenAccess", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "CommonsAttribution", "Non-Commercial", "License", "(http://creativecommons.org/", "licenses/by-nc/3.0/)", "which", "permits", "unrestricted", "non-commercial", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "www.e-aps.org", "397" ]

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529,299

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[ "International", "Journal", "for", "Equity", "in", "Health", "Research", "Musculo-skeletal", "pain", "among", "40-", "and", "45-year", "olds", "in", "Oslo:", "differences", "between", "two", "socioeconomically", "contrasting", "areas,", "and", "their", "possible", "explanations", "Mette", "Brekke*1", "and", "Per", "Hjortdahl2", "Address:", "1Department", "of", "General", "Practice", "and", "Community", "Medicine,", "University", "of", "Oslo,", "Box", "1130", "Blindern,", "N-0317", "Oslo,", "Norway", "and", "2Per", "Hjortdahl,", "Department", "of", "General", "Practice", "and", "Community", "Medicine,", "University", "of", "Oslo,", "Box", "1130", "Blindern,", "N-0317", "Oslo,", "Norway", "Email:", "Mette", "Brekke*", "-", "mette.brekke@medisin.uio.no;", "Per", "Hjortdahl", "-", "per.hjortdahl@medisin.uio.no", "*", "Corresponding", "author", "BioMed", "Central", "Open", "Access", "Published:", "19", "October", "2004", "International", "Journal", "for", "Equity", "in", "Health", "2004,", "3:10", "doi:10.1186/1475-9276-3-10", "This", "article", "is", "available", "from:", "http://www.equityhealthj.com/content/3/1/10", "Received:", "27", "May", "2004", "Accepted:", "19", "October", "2004", "©", "2004", "Brekke", "and", "Hjortdahl;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "population", "surveysocial", "inequalities", "in", "healthmuskulo-skeletal", "disordersmental", "healthimmigrants", "Abstract", "Background:", "The", "objective", "of", "the", "study", "was", "to", "compare", "the", "prevalence", "and", "severity", "of", "musculo-", "skeletal", "pain", "between", "two", "socioeconomically", "contrasting", "areas", "in", "Oslo,", "Norway,", "and", "to", "explore", "possible", "explanatory", "factors.", "Methods:", "Questionnaire", "survey,", "carried", "out", "as", "part", "of", "The", "Oslo", "Health", "Study", "in", "2000–2001.", "Data", "from", "821", "persons", "(40", "and", "45", "year", "old)", "living", "in", "a", "less", "affluent", "inner", "city", "area", "(called", "east)", "were", "compared", "with", "854", "persons", "living", "in", "an", "affluent", "area", "of", "the", "city", "(called", "west).", "Bivariate", "comparisons", "(chi", "square", "test)", "and", "multiple", "regression", "analyses", "were", "performed", "to", "investigate", "differences", "between", "the", "samples.", "Results:", "61", "%", "in", "east", "and", "56", "%", "in", "west", "(p", "<", "0.05)", "reported", "pain/stiffness", "in", "muscles/joints", "during", "the", "last", "four", "weeks.", "30", "%", "in", "east", "versus", "19", "%", "in", "west", "(p", "<", "0.001)", "reported", "extensive", "pain.", "The", "between", "area", "difference", "in", "extensive", "pain", "was", "partially", "explained", "by", "physical", "inactivity,", "mental", "health", "problems", "and", "being", "of", "non-Western", "origin.", "Conclusion:", "Musculo-skeletal", "pain", "is", "reported", "by", "55–60", "%", "of", "middle", "aged", "persons", "in", "Oslo", "during", "a", "four", "week", "period,", "and", "must", "be", "considered", "a", "normal", "phenomenon.", "Poor", "social", "conditions,", "inactivity,", "mental", "health", "problems", "and", "being", "an", "immigrant", "imply", "increased", "risk", "of", "more", "severe", "symptoms", "with", "a", "concomitant", "demand", "of", "health", "care.", "Background", "In", "affluent", "societies", "like", "Norway,", "living", "conditions", "as", "well", "as", "general", "health", "status", "have", "improved", "during", "the", "last", "dec-", "ades.", "In", "spite", "of", "this,", "social", "health", "inequities", "still", "exist,", "and", "recent", "analyses", "from", "Oslo", "even", "indicate", "an", "increase", "during", "the", "last", "30", "years", "[1].", "Life", "expectancy", "for", "men", "living", "in", "the", "least", "affluent", "city", "area", "is", "69", "years,", "compared", "to", "76", "for", "men", "in", "the", "most", "affluent", "area", "[2].", "Well-known", "risk", "factors", "like", "smoking,", "physical", "inactivity", "and", "overweight,", "as", "well", "as", "the", "incidence", "of", "atherosclerotic", "disease", "and", "several", "forms", "of", "cancer", "show", "similar", "correlation", "[3].", "Page", "1", "of", "5", "(page", "number", "not", "for", "citation", "purposes)" ]

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[ "Int.", "J.", "Mol.", "Sci.", "2009,", "10,", "4428-4434;", "doi:10.3390/ijms10104428", "OPEN", "ACCESS", "International", "Journal", "of", "Molecular", "Sciences", "ISSN", "1422-0067", "www.mdpi.com/journal/ijms", "Review", "Role", "of", "the", "Ubiquitin", "Proteasome", "System", "in", "Regulating", "Skin", "Pigmentation", "Hideya", "Ando", "1,2,", "Masamitsu", "Ichihashi", "1,2", "and", "Vincent", "J.", "Hearing", "3,*", "1", "Skin", "Aging", "and", "Photo-aging", "Research", "Center,", "Doshisha", "University,", "Kizugawa,", "Kyoto", "619-0225,", "Japan;", "E-Mails:", "hideyaando@aol.com", "(H.A.);", "mm_ichihashi@hotmail.com", "(M.I.)", "2", "Kobe", "Skin", "Research", "Institute,", "Kobe,", "Hyogo", "650-0047,", "Japan", "3", "Laboratory", "of", "Cell", "Biology,", "National", "Cancer", "Institute,", "National", "Institutes", "of", "Health,", "Bethesda,", "MD", "20892,", "USA", "*", "Author", "to", "whom", "correspondence", "should", "be", "addressed;", "E-Mail:", "hearingv@nih.gov;", "Tel.:", "+1-301-496-1564;", "Fax:", "+1-301-402-8787.", "Received:", "3", "September", "2009;", "in", "revised", "form:", "29", "September", "2009", "/", "Accepted:", "9", "October", "2009", "/", "Published:", "15", "October", "2009", "Abstract:", "Pigmentation", "of", "the", "skin,", "hair", "and", "eyes", "is", "regulated", "by", "tyrosinase,", "the", "critical", "rate-limiting", "enzyme", "in", "melanin", "synthesis", "by", "melanocytes.", "Tyrosinase", "is", "degraded", "endogenously,", "at", "least", "in", "part,", "by", "the", "ubiquitin", "proteasome", "system", "(UPS).", "Several", "types", "of", "inherited", "hypopigmentary", "diseases,", "such", "as", "oculocutaneous", "albinism", "and", "Hermansky-", "Pudlak", "syndrome,", "involve", "the", "aberrant", "processing", "and/or", "trafficking", "of", "tyrosinase", "and", "its", "subsequent", "degradation", "which", "can", "occur", "due", "to", "the", "quality-control", "machinery.", "Studies", "on", "carbohydrate", "modifications", "have", "revealed", "that", "tyrosinase", "in", "the", "endoplasmic", "reticulum", "(ER)", "is", "proteolyzed", "via", "ER-associated", "protein", "degradation", "and", "that", "tyrosinase", "degradation", "can", "also", "occur", "following", "its", "complete", "maturation", "in", "the", "Golgi.", "Among", "intrinsic", "factors", "that", "regulate", "the", "UPS,", "fatty", "acids", "have", "been", "shown", "to", "modulate", "tyrosinase", "degradation", "in", "contrasting", "manners", "through", "increased", "or", "decreased", "amounts", "of", "ubiquitinated", "tyrosinase", "that", "leads", "to", "its", "accelerated", "or", "decelerated", "degradation", "by", "proteasomes.", "Keywords:", "fatty", "acid;", "melanin;", "melanocyte;", "tyrosinase;", "skin;", "pigmentation" ]

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[ "HD", "Jung,", "et", "al", "Ann", "Dermatol", "Vol.", "23,", "Suppl.", "2,", "2011", "CASE", "REPORT", "http://dx.doi.org/10.5021/ad.2011.23.S2.S270", "Multiple", "Granulocytic", "Sarcomas", "in", "a", "Patient", "with", "Longstanding", "Complete", "Remission", "of", "Acute", "Myelogenous", "Leukemia", "Hee-Dam", "Jung,", "M.D.,", "Hei-Sung", "Kim,", "M.D.,", "Young-Min", "Park,", "M.D.,", "Hyung-Ok", "Kim,", "M.D.,", "Jun-Young", "Lee,", "M.D.", "Department", "of", "Dermatology,", "Seoul", "St.", "Mary’s", "Hospital,", "College", "of", "Medicine,", "The", "Catholic", "University", "of", "Korea,", "Seoul,", "Korea", "Granulocytic", "sarcoma", "is", "an", "extramedullary", "tumor", "composed", "of", "granulocytic", "precursor", "cells.", "It", "usually", "presents", "as", "a", "nodular", "mass", "in", "the", "course", "of", "acute", "myelogenous", "leukemia.", "Rarely,", "the", "tumor", "develops", "in", "non-hematological", "conditions", "or", "in", "a", "patient", "with", "complete", "remission", "from", "the", "acute", "myelogenous", "leukemia.", "In", "such", "cases,", "aleukemic", "granulo-", "cytic", "sarcoma", "can", "be", "a", "preceding", "sign", "of", "systemic", "leukemia", "or", "a", "first", "sign", "of", "hematologic", "relapse", "of", "leukemia.", "We", "present", "an", "unusual", "case", "of", "multiple", "granulocytic", "sarcomas", "develo-", "ped", "in", "a", "patient", "with", "longstanding", "complete", "remission", "of", "acute", "myelogenous", "leukemia,", "who", "has", "not", "had", "bone", "marrow", "and", "peripheral", "blood", "involvement", "for", "a", "long", "time.", "(Ann", "Dermatol", "23(S2)", "S270∼S273,", "2011)", "-Keywords-", "Aleukemic", "leukemia", "cutis,", "AML", "M1,", "Granulocytic", "sarco-", "ma", "INTRODUCTION", "Granulocytic", "sarcomas", "usually", "occur", "during", "the", "course", "of", "Received", "March", "23,", "2011,", "Revised", "July", "12,", "2011,", "Accepted", "for", "publication", "August", "12,", "2011", "Corresponding", "author:", "Jun-Young", "Lee,", "M.D.,", "Department", "of", "Der-", "matology,", "Seoul", "St.", "Mary’s", "Hospital,", "College", "of", "Medicine,", "The", "Catholic", "University", "of", "Korea,", "505", "Banpo-dong,", "Seocho-gu,", "Seoul", "137-040,", "Korea.", "Tel:", "82-2-2258-1386,", "Fax:", "82-2-594-3255,", "E-mail:", "jylee@catholic.ac.kr", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "Non-Commercial", "License", "(http://", "creativecommons.org/licenses/by-nc/3.0)", "which", "permits", "unrestricted", "non-commercial", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "S270", "Ann", "Dermatol", "acute", "myelogenous", "leukemia", "(AML)", "and", "antecede", "blastic", "cirisis", "in", "myeloproliferative", "disease", "or", "myelodysplastic", "syndromes.", "However,", "the", "tumor", "can", "also", "develop", "in", "patients", "who", "have", "either", "no", "prior", "history", "of", "hematological", "disease", "or", "have", "shown", "complete", "remission", "from", "acute", "myelogenous", "leukemia.", "Herein,", "we", "describe", "a", "patient", "who", "has", "shown", "an", "unusual", "clinical", "course", "in", "that", "she", "was", "in", "complete", "remission", "from", "AML", "for", "a", "long", "time", "and", "that", "there", "were", "no", "signs", "of", "peripheral", "blood", "and", "bone", "marrow", "relapse", "for", "a", "long", "time", "following", "the", "development", "of", "granulocytic", "sarcoma.", "CASE", "REPORT", "A", "72-year-old", "Korean", "woman", "presented", "with", "a", "1-month", "history", "of", "rapidly", "growing", "multiple", "cutaneous", "nodules", "on", "the", "whole", "body.", "Physical", "examination", "revealed", "wide-", "spread", "well-demarcated", "variable-sized", "greenish", "firm", "cutaneous", "nodules", "over", "the", "face,", "trunk", "and", "extremities", "(Fig.", "1).", "She", "had", "a", "history", "of", "acute", "myeloblastic", "leukemia", "without", "maturation", "(AML", "M1),", "and", "achieved", "complete", "remission", "after", "the", "3rd", "consolidation", "chemotherapy,", "ten", "years", "ago.", "The", "patient", "remained", "asymptomatic", "for", "nine", "years", "and", "then", "visited", "the", "hospital", "presenting", "with", "an", "asymptomatic", "solitary", "firm", "mass", "on", "the", "left", "upper", "eyelid", "in", "September", "2009.", "An", "excisional", "biopsy", "of", "the", "lesion", "was", "performed", "and", "histopathologic", "findings", "were", "consistent", "with", "a", "granulocytic", "sarcoma.", "Bone", "marrow", "biopsy", "showed", "normocellular", "bone", "marrow", "without", "leukemic", "cell", "involvement", "and", "peripheral", "blood", "also", "revealed", "normal", "findings.", "In", "April", "2010,", "she", "complained", "of", "nasal", "stuffiness,", "bloody", "nasal", "discharge", "and", "hoarseness.", "Neck", "computed", "tomography", "and", "magnetic", "resonance", "imaging", "findings" ]

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3,114,730

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[ "Pocock", "and", "Phua", "Globalization", "and", "Health", "2011,", "7:12", "http://www.globalizationandhealth.com/content/7/1/12", "R", "E", "V", "I", "E", "W", "Open", "Access", "Medical", "tourism", "and", "policy", "implications", "for", "health", "systems:", "a", "conceptual", "framework", "from", "a", "comparative", "study", "of", "Thailand,", "Singapore", "and", "Malaysia", "Nicola", "S", "Pocock*", "and", "Kai", "Hong", "Phua", "Abstract", "Medical", "tourism", "is", "a", "growing", "phenomenon", "with", "policy", "implications", "for", "health", "systems,", "particularly", "of", "destination", "countries.", "Private", "actors", "and", "governments", "in", "Southeast", "Asia", "are", "promoting", "the", "medical", "tourist", "industry,", "but", "the", "potential", "impact", "on", "health", "systems,", "particularly", "in", "terms", "of", "equity", "in", "access", "and", "availability", "for", "local", "consumers,", "is", "unclear.", "This", "article", "presents", "a", "conceptual", "framework", "that", "outlines", "the", "policy", "implications", "of", "medical", "tourism’s", "growth", "for", "health", "systems,", "drawing", "on", "the", "cases", "of", "Thailand,", "Singapore", "and", "Malaysia,", "three", "regional", "hubs", "for", "medical", "tourism,", "via", "an", "extensive", "review", "of", "academic", "and", "grey", "literature.", "Variables", "for", "further", "analysis", "of", "the", "potential", "impact", "of", "medical", "tourism", "on", "health", "systems", "are", "also", "identified.", "The", "framework", "can", "provide", "a", "basis", "for", "empirical,", "in", "country", "studies", "weighing", "the", "benefits", "and", "disadvantages", "of", "medical", "tourism", "for", "health", "systems.", "The", "policy", "implications", "described", "are", "of", "particular", "relevance", "for", "policymakers", "and", "industry", "practitioners", "in", "other", "Southeast", "Asian", "countries", "with", "similar", "health", "systems", "where", "governments", "have", "expressed", "interest", "in", "facilitating", "the", "growth", "of", "the", "medical", "tourist", "industry.", "This", "article", "calls", "for", "a", "universal", "definition", "of", "medical", "tourism", "and", "medical", "tourists", "to", "be", "enunciated,", "as", "well", "as", "concerted", "data", "collection", "efforts,", "to", "be", "undertaken", "prior", "to", "any", "meaningful", "empirical", "analysis", "of", "medical", "tourism’s", "impact", "on", "health", "systems.", "Introduction", "Growing", "demand", "for", "health", "services", "is", "a", "global", "phenom-", "enon,", "linked", "to", "economic", "development", "that", "generates", "ris-", "ing", "incomes", "and", "education.", "Demographic", "change,", "especially", "population", "ageing", "and", "older", "people’s", "require-", "ments", "for", "more", "medical", "services,", "coupled", "with", "epidemiolo-", "gical", "change,", "i.e.", "rising", "incidence", "of", "chronic", "conditions,", "also", "fuel", "demand", "for", "more", "and", "better", "health", "services.", "Wait-", "ing", "times", "and/or", "the", "increasing", "cost", "of", "health", "services", "at", "home,", "coupled", "with", "the", "availability", "of", "cheaper", "alternatives", "in", "developing", "countries,", "has", "lead", "new", "healthcare", "consu-", "mers,", "or", "medical", "tourists,", "to", "seek", "treatment", "overseas", "[1].", "The", "correspondent", "growth", "in", "the", "global", "health", "service", "sec-", "tor", "reflects", "this", "demand.", "The", "globalisation", "of", "healthcare", "is", "marked", "by", "increasing", "international", "trade", "in", "health", "products", "and", "services,", "strikingly", "via", "cross", "border", "patient", "flows.", "*", "Correspondence:", "sppnp@nus.edu.sg", "Lee", "Kuan", "Yew", "School", "of", "Public", "Policy,", "National", "University", "of", "Singapore,", "469C", "Bukit", "Timah", "Road,", "OTH", "Building,", "Singapore", "259772,", "Singapore", "In", "Southeast", "Asia,", "the", "health", "sector", "is", "expanding", "rapidly,", "attributable", "to", "rapid", "growth", "of", "the", "private", "sector", "and", "notably,", "medical", "tourism,", "which", "is", "emerging", "as", "a", "lucrative", "business", "opportunity.", "Countries", "here", "are", "capita-", "lising", "on", "their", "popularity", "as", "tourist", "destinations", "by", "com-", "bining", "high", "quality", "medical", "services", "at", "competitive", "prices", "with", "tourist", "packages.", "Some", "countries", "are", "establishing", "comparative", "advantages", "in", "service", "provision", "based", "on", "their", "health", "system’s", "organizational", "structure", "(table", "1).", "Thailand", "has", "established", "a", "niche", "for", "cosmetic", "surgery", "and", "sex", "change", "operations,", "whilst", "Singapore", "is", "attracting", "patients", "at", "the", "high", "end", "of", "the", "market", "for", "advanced", "treat-", "ments", "like", "cardiovascular,", "neurological", "surgery", "and", "stem", "cell", "therapy", "[2].", "In", "Singapore,", "Malaysia", "and", "Thailand", "alone,", "an", "estimated", "2", "million", "medical", "travellers", "visited", "in", "2006", "-", "7,", "earning", "these", "countries", "over", "US$", "3", "billion", "in", "treatment", "costs", "(table", "2).", "Carrera", "and", "Bridges", "(2006)", "define", "medical", "tourism", "as", "“the", "organized", "travel", "outside", "one’s", "natural", "healthcare", "©", "2011", "Pocock", "and", "Phua;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

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[ "Hall", "et", "al.", "BMC", "Medical", "Informatics", "and", "Decision", "Making", "2012,", "12:69", "http://www.biomedcentral.com/1472-6947/12/69", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Implementation", "of", "automated", "reporting", "of", "estimated", "glomerular", "filtration", "rate", "among", "Veterans", "Affairs", "laboratories:", "a", "retrospective", "study", "Rasheeda", "K", "Hall1,2,", "Virginia", "Wang1,2,", "George", "L", "Jackson1,2,", "Bradley", "G", "Hammill2,", "Matthew", "L", "Maciejewski1,2,", "Elizabeth", "M", "Yano3,4,", "Laura", "P", "Svetkey2,5", "and", "Uptal", "D", "Patel1,2,6*", "Abstract", "Background:", "Automated", "reporting", "of", "estimated", "glomerular", "filtration", "rate", "(eGFR)", "is", "a", "recent", "advance", "in", "laboratory", "information", "technology", "(IT)", "that", "generates", "a", "measure", "of", "kidney", "function", "with", "chemistry", "laboratory", "results", "to", "aid", "early", "detection", "of", "chronic", "kidney", "disease", "(CKD).", "Because", "accurate", "diagnosis", "of", "CKD", "is", "critical", "to", "optimal", "medical", "decision-making,", "several", "clinical", "practice", "guidelines", "have", "recommended", "the", "use", "of", "automated", "eGFR", "reporting.", "Since", "its", "introduction,", "automated", "eGFR", "reporting", "has", "not", "been", "uniformly", "implemented", "by", "U.", "S.", "laboratories", "despite", "the", "growing", "prevalence", "of", "CKD.", "CKD", "is", "highly", "prevalent", "within", "the", "Veterans", "Health", "Administration", "(VHA),", "and", "implementation", "of", "automated", "eGFR", "reporting", "within", "this", "integrated", "healthcare", "system", "has", "the", "potential", "to", "improve", "care.", "In", "July", "2004,", "the", "VHA", "adopted", "automated", "eGFR", "reporting", "through", "a", "system-wide", "mandate", "for", "software", "implementation", "by", "individual", "VHA", "laboratories.", "This", "study", "examines", "the", "timing", "of", "software", "implementation", "by", "individual", "VHA", "laboratories", "and", "factors", "associated", "with", "implementation.", "Methods:", "We", "performed", "a", "retrospective", "observational", "study", "of", "laboratories", "in", "VHA", "facilities", "from", "July", "2004", "to", "September", "2009.", "Using", "laboratory", "data,", "we", "identified", "the", "status", "of", "implementation", "of", "automated", "eGFR", "reporting", "for", "each", "facility", "and", "the", "time", "to", "actual", "implementation", "from", "the", "date", "the", "VHA", "adopted", "its", "policy", "for", "automated", "eGFR", "reporting.", "Using", "survey", "and", "administrative", "data,", "we", "assessed", "facility", "organizational", "characteristics", "associated", "with", "implementation", "of", "automated", "eGFR", "reporting", "via", "bivariate", "analyses.", "Results:", "Of", "104", "VHA", "laboratories,", "88%", "implemented", "automated", "eGFR", "reporting", "in", "existing", "laboratory", "IT", "systems", "by", "the", "end", "of", "the", "study", "period.", "Time", "to", "initial", "implementation", "ranged", "from", "0.2", "to", "4.0", "years", "with", "a", "median", "of", "1.8", "years.", "All", "VHA", "facilities", "with", "on-site", "dialysis", "units", "implemented", "the", "eGFR", "software", "(52%,", "p<0.001).", "Other", "organizational", "characteristics", "were", "not", "statistically", "significant.", "Conclusions:", "The", "VHA", "did", "not", "have", "uniform", "implementation", "of", "automated", "eGFR", "reporting", "across", "its", "facilities.", "Facility-level", "organizational", "characteristics", "were", "not", "associated", "with", "implementation,", "and", "this", "suggests", "that", "decisions", "for", "implementation", "of", "this", "software", "are", "not", "related", "to", "facility-level", "quality", "improvement", "measures.", "Additional", "studies", "on", "implementation", "of", "laboratory", "IT,", "such", "as", "automated", "eGFR", "reporting,", "could", "identify", "factors", "that", "are", "related", "to", "more", "timely", "implementation", "and", "lead", "to", "better", "healthcare", "delivery.", "Background", "Since", "its", "development,", "automated", "laboratory", "reporting", "of", "estimated", "glomerular", "filtration", "rate", "(eGFR)", "has", "facilitated", "diagnosis", "and", "management", "of", "chronic", "kidney", "disease", "*", "Correspondence:", "uptal.patel@dm.duke.edu", "1Center", "for", "Health", "Services", "Research", "in", "Primary", "Care,", "Veterans", "Affairs", "Health", "Services", "Research", "&", "Development,", "Durham,", "NC,", "USA", "2Department", "of", "Medicine,", "Duke", "University", "School", "of", "Medicine,", "Durham,", "NC,", "USA", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "(CKD)", "[1].", "To", "report", "eGFR,", "clinical", "laboratories", "imple-", "ment", "software", "that", "calculates", "eGFR", "from", "equations", "based", "on", "serum", "creatinine", "and", "demographic", "variables.", "As", "a", "result,", "clinicians", "who", "receive", "laboratory", "reports", "of", "eGFR", "in", "addition", "to", "serum", "creatinine", "may", "make", "more", "informed", "clinical", "decisions.", "The", "importance", "of", "auto-", "mated", "eGFR", "reporting", "was", "established", "by", "National", "Kid-", "ney", "Foundation", "clinical", "guidelines", "in", "2002,", "and,", "later,", "endorsed", "by", "the", "National", "Kidney", "Disease", "Education", "©", "2012", "Hall", "et", "al.;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

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2,795,934

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[ "J", "Korean", "Med", "Sci", "2010;", "25:", "647-50", "ISSN", "1011-8934", "DOI:", "10.3346/jkms.2010.25.4.647", "Acute", "Shunt", "Malfunction", "after", "Cesarean", "Section", "Delivery:", "A", "Case", "Report", "Shunt", "malfunctions", "that", "require", "surgical", "intervention", "during", "pregnancy", "and", "the", "postpartum", "period", "are", "rare.", "Furthermore,", "no", "study", "has", "reported", "on", "an", "acute", "shunt", "malfunction", "immediately", "after", "cesarean", "section.", "Here,", "we", "describe", "the", "case", "of", "a", "32-yr-old", "woman", "who", "became", "drowsy", "12", "hr", "after", "cesarean", "section", "delivery", "of", "her", "second", "child.", "She", "had", "a", "ventriculoperitoneal", "shunt", "placed", "to", "treat", "hydrocephalus", "associated", "with", "meningitis", "at", "26", "yr", "of", "age.", "Marked", "ventriculomegaly", "was", "seen", "on", "brain", "computed", "tomography", "and", "her", "consciousness", "recovered", "temporarily", "after", "aspirating", "cerebrospinal", "fluid", "from", "the", "flushing", "device.", "At", "surgery,", "the", "distal", "catheter", "tip", "was", "plugged", "by", "a", "blood", "clot.", "We", "believe", "that", "the", "blood", "spilled", "over", "during", "the", "cesarean", "section.", "The", "clogged", "catheter", "end", "was", "simply", "cut", "off", "and", "the", "remaining", "catheter", "was", "repositioned", "in", "the", "peritoneal", "cavity.", "Her", "consciousness", "recovered", "fully.", "Key", "Words", ":", "Ventriculoperitoneal", "Shunt;", "Prosthesis", "Failure;", "Hydrocephalus;", "Cesarean", "Section", "ⓒ", "2010", "The", "Korean", "Academy", "of", "Medical", "Sciences.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "Non-Commercial", "License", "(http://creativecommons.org/licenses/by-nc/3.0)", "which", "permits", "unrestricted", "non-commercial", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Sun-Chul", "Hwang1,", "Tae-Hee", "Kim2,", "Bum-Tae", "Kim1,", "Soo-Bin", "Im1,", "and", "Won-Han", "Shin1", "Department", "of", "Neurosurgery1,", "and", "Obstetrics", "and", "Gynecology2,", "Soonchunhyang", "University", "Bucheon", "Hospital,", "Bucheon,", "Korea", "Received", ":", "25", "June", "2008", "Accepted", ":", "20", "January", "2009", "Address", "for", "Correspondence", "Sun-Chul", "Hwang,", "M.D.", "Department", "of", "Neurosurgery,", "Soonchunhyang", "University", "Bucheon", "Hospital,", "1174", "Jung-dong,", "Wonmi-gu,", "Bucheon", "420-747,", "Korea", "Tel", ":", "+82.32-621-5291,", "Fax", ":", "+82.32-621-5016", "E-mail", ":", "sunchulh@sch.ac.kr", "INTRODUCTION", "Cerebrospinal", "fluid", "(CSF)", "shunts", "are", "a", "definite", "treatment", "for", "hydrocephalus.", "As", "increasing", "numbers", "of", "women", "have", "CSF", "shunts", "placed", "to", "treat", "hydrocephalus,", "more", "shunt-depen-", "dent", "women", "are", "becoming", "pregnant", "(1,", "2).", "Although", "the", "maternal", "and", "fetal", "outcome", "in", "patients", "with", "ventriculoperi-", "toneal", "(VP)", "shunts", "is", "uniformly", "excellent,", "the", "changes", "in", "the", "abdominal", "cavity,", "such", "as", "the", "enlargement", "of", "the", "uterus", "and", "increased", "abdominal", "pressure,", "could", "cause", "shunt", "failure", "(1,", "3-5).", "The", "distal", "shunt", "catheter", "is", "frequently", "obstructed", "in", "pregnancy,", "especially", "during", "the", "third", "trimester", "when", "the", "intra-abdominal", "pressure", "is", "thought", "to", "be", "highest", "(3,", "4).", "Post-", "partum", "shunt", "complications", "are", "rare", "(1,", "4,", "6,", "7),", "and", "shunt", "obstruction", "immediately", "after", "a", "cesarean", "section", "had", "not", "been", "reported.", "We", "present", "a", "patient", "with", "a", "VP", "shunt", "who", "had", "reduced", "consciousness", "due", "to", "obstruction", "of", "the", "abdominal", "shunt", "catheter", "immediately", "after", "a", "cesarean", "section", "delivery.", "CASE", "REPORT", "A", "32-yr-old", "woman,", "G2P2A0L2,", "came", "to", "the", "emergency", "department", "complaining", "that", "she", "felt", "drowsy.", "She", "had", "under-", "gone", "a", "cesarean", "section", "delivery", "of", "a", "full-term", "healthy", "baby", "647", "(3,200", "gm)", "the", "day", "before.", "At", "the", "age", "of", "26", "yr,", "she", "had", "a", "VP", "shunt", "placed", "to", "treat", "hydrocephalus", "associated", "with", "menin-", "gitis.", "She", "underwent", "a", "shunt", "revision", "when", "she", "was", "29", "yr", "old.", "At", "that", "time,", "she", "was", "in", "the", "sixth", "month", "of", "her", "first", "preg-", "nancy", "and", "complained", "of", "drowsiness", "and", "headache.", "Her", "hus-", "band", "said", "that", "the", "reason", "for", "the", "shunt", "malfunction", "had", "not", "been", "determined", "and", "the", "malfunctioning", "VP", "shunt", "had", "been", "replaced", "with", "a", "new", "device.", "The", "revision", "surgery", "had", "success-", "fully", "relieved", "her", "symptoms.", "At", "full", "term,", "she", "underwent", "a", "lower", "segment", "cesarean", "section", "because", "of", "fetal", "distress", "and", "gave", "birth", "to", "her", "first", "child,", "who", "weighed", "3,580", "g.", "The", "post-", "partum", "course", "was", "unremarkable", "after", "the", "birth", "of", "her", "first", "child.", "At", "31", "yr", "of", "age,", "she", "became", "pregnant", "with", "her", "second", "child.", "She", "had", "no", "symptoms", "related", "to", "shunt", "malfunction", "during", "gestation.", "A", "repeated", "cesarean", "section", "was", "performed", "at", "the", "same", "private", "obstetrics", "clinic", "and", "a", "healthy", "baby", "was", "deliv-", "ered.", "The", "peritoneal", "cavity", "was", "not", "irrigated", "and", "the", "shunt", "tube", "was", "not", "observed", "at", "surgery.", "She", "began", "to", "complain", "of", "a", "headache", "12", "hr", "after", "the", "cesarean", "section.", "Her", "consciousness", "deteriorated", "gradually", "and", "she", "became", "drowsy.", "She", "was", "trans-", "ferred", "to", "our", "hospital", "24", "hr", "postoperatively.", "In", "the", "emergency", "room,", "she", "did", "not", "open", "her", "eyes", "spontaneously", "and", "her", "ver-", "bal", "response", "was", "very", "slow", "and", "inappropriate.", "Ventriculome-", "galy", "with", "a", "bifrontal", "index", "of", "41%", "was", "seen", "on", "brain", "com-" ]

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[ "doi:10.1093/brain/awn184", "Brain", "(2008),", "131,", "2783^2797", "Correlation", "of", "passivity", "symptoms", "and", "dysfunctional", "visuomotor", "action", "monitoring", "in", "psychosis", "Knut", "Schnell,1", "Karsten", "Heekeren,2,3", "J", "o«rg", "Daumann,2", "Thomas", "Schnell,2", "Ralph", "Schnitker,4", "Walter", "M", "o«ller-Hartmann5", "and", "Euphrosyne", "Gouzoulis-Mayfrank2", "1Department", "of", "Psychiatry", "and", "Psychotherapy,", "Division", "of", "Medical", "Psychology,", "University", "Hospital", "of", "Bonn,", "2Department", "of", "Psychiatry", "and", "Psychotherapy,", "University", "Hospital", "of", "Cologne,", "Germany,", "3Psychiatric", "University", "Hospital,", "Zu«", "rich,", "Switzerland,", "4Interdisciplinary", "Center", "for", "Clinical", "Research", "(ICCR),", "Functional", "Neuroimaging", "Unit,", "RWTH", "Aachen", "and", "5Department", "of", "Radiology,", "University", "Hospital", "of", "Cologne,", "Germany", "Correspondence", "to:", "Dr", "Knut", "Schnell,", "Abteilung", "f", "u«r", "Medizinische", "Psychologie,", "Zentrum", "f", "u«r", "Nervenheilkunde,", "Universita«", "tsklinikum", "Bonn,", "Sigmund-Freud-Strasse", "25,", "53105", "Bonn,", "Germany", "E-mail:", "knut.schnell@ukb.uni-bonn.de", "Passivity", "experiences", "are", "hallmark", "symptoms", "of", "schizophrenia", "that", "can", "be", "characterized", "by", "the", "belief", "that", "one’s", "thoughts", "or", "actions", "are", "controlled", "by", "an", "external", "agent.", "It", "has", "recently", "been", "suggested", "that", "these", "psychotic", "experiences", "result", "from", "defective", "monitoring", "of", "one’s", "own", "actions,", "i.e.", "disturbed", "comparison", "of", "actions", "and", "perceived", "outcomes.", "In", "this", "study,", "we", "examined", "the", "function", "of", "the", "previously", "characterized", "action", "monitoring", "network", "of", "the", "inferior", "parietal", "lobule", "(IPL),", "medial", "(mPFC)", "and", "lateral", "prefrontal", "cortices", "in", "patients", "with", "different", "levels", "of", "passivity", "symptoms", "with", "an", "fMRI", "task.The", "visuomotor", "fMRI", "task", "demanded", "control", "of", "visually", "perceived", "object", "movements", "by", "alternating", "button", "presses", "with", "the", "left", "and", "the", "right", "index", "finger.", "In", "the", "monitoring", "condition", "of", "this", "task", "subjects", "stopped", "their", "actions", "whenever", "they", "detected", "visuomotor", "incongru-", "ence.", "fMRI", "and", "behavioural", "data", "from", "15", "patients", "were", "tested", "for", "correlation", "with", "passivity", "symptoms", "using", "standardized", "Scale", "for", "Assessment", "of", "Positive", "Symptoms", "(SAPS)-", "and", "AMDP-", "passivity", "symptom", "ratings.", "Both", "types", "of", "data", "were", "tested", "for", "differences", "between", "the", "patients", "group", "and", "15", "healthy", "controls.", "In", "the", "patient", "group", "we", "found", "the", "expected", "correlation", "of", "passivity", "symptoms", "and", "visuomotor", "monitoring", "performance.There", "was", "a", "significant", "positive", "correlation", "of", "passivity", "symptoms", "with", "increased", "latency", "of", "incongruence", "detection", "and", "a", "negative", "correlation", "of", "SAPS-passivity", "with", "the", "number", "of", "detected", "events.", "fMRI", "data", "revealed", "correla-", "tions", "of", "passivity", "symptoms", "with", "activation", "in", "bilateral", "IPL,", "primary", "motor", "and", "sensory", "cortices", "in", "the", "action", "monitoring", "condition.", "A", "correlation", "of", "passivity", "symptoms", "with", "the", "main", "experimental", "effect", "(actions", "with", "^", "actions", "without", "monitoring)", "was", "found", "in", "the", "posterior", "cingulate", "cortex", "(PCC)", "and", "in", "the", "left", "IPL.", "No", "group", "differences", "or", "group", "by", "task", "interactions", "were", "found", "within", "the", "visuomotor-action-monitoring", "network.", "Our", "results", "demonstrate", "the", "association", "between", "passivity", "symptoms", "and", "the", "dysfunction", "of", "visuomotor", "action", "monitoring", "and", "support", "the", "idea", "that", "psychotic", "passivity", "experiences", "result", "from", "dysfunctions", "of", "central", "action", "monitoring", "mechanisms:", "According", "to", "pre-existing", "concepts", "of", "parietal", "cortex", "function,", "IPL-hyperactivation", "may", "represent", "an", "increase", "in", "false", "detections", "of", "visuomotor", "incongruence", "while", "the", "correlation", "between", "passiv-", "ity", "and", "the", "differential", "effect", "of", "monitoring", "on", "PCC-activation", "assumedly", "represents", "greater", "self-monitoring", "effort", "in", "passivity", "experiences.", "Keywords:", "action", "monitoring;", "visuomotor;", "schizophrenia;", "functional", "magnetic", "resonance", "imaging;", "parietal", "lobe", "Abbreviations:", "AIMS", "=", "Abnormal", "Involuntary", "Movement", "Scale;", "BA", "=", "Brodmann", "area;", "CC", "=", "control", "condition;", "EPI", "=", "echoplanar", "imaging;", "EPS", "=", "Extrapyramidal", "Motor", "Side", "Effects", "Scale;", "FDR", "=", "false", "discovery", "rate;", "HRF", "=", "hemodynamic", "response", "function;", "IPL", "=", "inferior", "parietal", "lobule;", "MC", "=", "monitoring", "condition;", "mPFC", "=", "medial", "prefrontal", "cortex;", "PCC", "=", "posterior", "cingulate", "cortex;", "SANS", "=", "Scale", "for", "Assessment", "of", "Negative", "Symptoms;", "SAPS", "=", "Scale", "for", "Assessment", "of", "Positive", "Symptoms;", "SCID", "=", "Structured", "Clinical", "Interview", "for", "DSM-IV", "Axis", "I", "Disorders;", "SPM", "=", "Statistical", "Parametric", "Mapping", "Received", "February", "25,", "2008.", "Revised", "July", "7,", "2008.", "Accepted", "July", "21,", "2008.", "Advance", "Access", "publication", "August", "19,", "2008", "2008", "The", "Author(s)", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "Non-Commercial", "License", "(http://creativecommons.org/licenses/by-nc/2.0/uk/)", "which", "permits", "unrestricted", "non-commercial", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

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2,193,133

null

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[ "Brief", "Deﬁnitive", "Report", "Entry", "of", "B", "Cell", "Receptor", "into", "Signaling", "Domains", "Is", "Inhibited", "in", "Tolerant", "B", "Cells", "By", "Bennett", "C.Weintraub,*", "Jesse", "Eunsuk", "Jun,*", "Anthony", "C.", "Bishop,‡", "Kevan", "M.", "Shokat,‡", "Matthew", "L.", "Thomas,†", "and", "Christopher", "C.", "Goodnow*", "From", "the", "*Australian", "Cancer", "Research", "Foundation", "Genetics", "Laboratory,", "Medical", "Genome", "Centre,", "John", "Curtin", "School", "of", "Medical", "Research,", "Canberra", "2601,Australia;", "the", "‡Department", "of", "Chemistry,", "Princeton", "University,", "Princeton,", "New", "Jersey", "08544;", "and", "the", "†Howard", "Hughes", "Medical", "Institute", "and", "Department", "of", "Pathology,Washington", "University", "School", "of", "Medicine,", "St.", "Louis,", "Missouri", "63110", "Abstract", "Signal", "transduction", "through", "the", "B", "cell", "antigen", "receptor", "(BCR)", "is", "altered", "in", "B", "cells", "that", "express", "a", "receptor", "that", "recognizes", "self-antigen.", "To", "understand", "the", "molecular", "basis", "for", "the", "change", "in", "sig-", "naling", "in", "autoreactive", "B", "cells,", "a", "transgenic", "model", "was", "used", "to", "isolate", "a", "homogeneous", "popula-", "tion", "of", "tolerant", "B", "lymphocytes.", "These", "cells", "were", "compared", "with", "a", "similar", "population", "of", "naive", "B", "lymphocytes.", "We", "show", "that", "the", "BCR", "from", "naive", "B", "cells", "enters", "a", "detergent-insoluble", "domain", "of", "the", "cell", "within", "6", "s", "after", "antigen", "binding,", "before", "a", "detectable", "increase", "in", "BCR", "phosphoryla-", "tion.", "This", "fraction", "appears", "to", "be", "important", "for", "signaling", "because", "it", "is", "enriched", "for", "lyn", "kinase", "but", "lacks", "CD45", "tyrosine", "phosphatase", "and", "because", "the", "BCR", "that", "moves", "into", "this", "domain", "becomes", "more", "highly", "phosphorylated.", "Partitioning", "of", "the", "BCR", "into", "this", "fraction", "is", "unaffected", "by", "src", "family", "kinase", "inhibition.", "Tolerant", "B", "cells", "do", "not", "efficiently", "partition", "the", "BCR", "into", "the", "deter-", "gent-insoluble", "domain,", "providing", "an", "explanation", "for", "their", "reduced", "tyrosine", "kinase", "activation", "and", "calcium", "flux", "in", "response", "to", "antigen.", "These", "results", "identify", "an", "early,", "regulated", "step", "in", "anti-", "gen", "receptor", "signaling", "and", "self-tolerance.", "Key", "words:", "B", "cell", "antigen", "receptor", "signaling", "•", "tyrosine", "phosphorylation", "•", "membrane", "raft", "•", "self-tolerance", "•", "anergy", "Introduction", "Mice", "expressing", "transgenes", "for", "anti–hen", "egg", "lysozyme", "(HEL)", "IgM/IgD", "B", "cell", "antigen", "receptor", "(BCR)", "contain", "large", "homogeneous", "populations", "of", "B", "cells", "that", "are", "func-", "tionally", "naive.", "When", "anti-HEL", "transgenic", "mice", "are", "crossed", "to", "transgenic", "mice", "expressing", "soluble", "HEL,", "the", "B", "cells", "in", "the", "double-transgenic", "offspring", "are", "constantly", "ex-", "posed", "to", "low", "levels", "of", "antigenic", "stimulation", "and", "become", "functionally", "tolerant", "(anergic).", "The", "tolerant", "cells", "lose", "some", "responses", "to", "antigen,", "notably", "BCR-induced", "proliferation,", "but", "retain", "other", "responses,", "including", "BCR-induced", "apop-", "tosis,", "changes", "in", "follicular", "homing,", "and", "inhibition", "of", "plas-", "macyte", "differentiation", "(1–3).", "Binding", "of", "HEL", "to", "the", "BCR", "on", "these", "cells", "results", "in", "only", "a", "subset", "of", "the", "biochemical", "re-", "sponses", "that", "are", "triggered", "by", "HEL", "in", "naive", "anti-HEL", "trans-", "genic", "B", "cells.", "For", "example,", "the", "BCR", "on", "tolerant", "B", "cells", "Address", "correspondence", "to", "Christopher", "C.", "Goodnow,", "Medical", "Genome", "Centre,", "John", "Curtin", "School", "of", "Medical", "Research,", "ANU,", "Mills", "Rd.,", "Can-", "berra", "2601", "ACT,", "Australia.", "Phone:", "61-2-6249-3621;", "Fax:", "61-2-6279-", "8512;", "E-mail:", "Chris.Goodnow@anu.edu.au", "continually", "activates", "low", "intracellular", "calcium", "oscillations", "and", "extracellular", "signal–regulated", "kinase", "(ERK),", "and", "nu-", "clear", "factor", "of", "activated", "T", "cells", "(NFAT)c", "pathways", "but", "does", "not", "produce", "high", "calcium", "elevations", "or", "activate", "the", "c-Jun", "NH2-terminal", "kinase", "(JNK)", "and", "nuclear", "factor", "(NF)-kB", "pathways", "(4).", "How", "the", "BCR", "is", "selectively", "uncoupled", "from", "some", "sig-", "naling", "pathways", "but", "not", "others", "is", "unclear.", "Antigen-induced", "protein", "tyrosine", "phosphorylation", "of", "the", "BCR", "and", "other", "molecules", "is", "greatly", "reduced", "in", "HEL-tolerant", "B", "cells", "(5).", "However,", "tolerant", "B", "cells", "express", "at", "normal", "levels", "and", "with", "normal", "basal", "activity", "proteins", "important", "for", "BCR-induced", "signal", "transduction,", "such", "as", "syk,", "lyn,", "CD45,", "and", "Src", "homol-", "ogy", "2", "domain–containing", "protein", "tyrosine", "phosphatase", "(SHP)-1.", "Here", "we", "present", "evidence", "for", "an", "early,", "regulated", "step", "in", "BCR", "signaling", "that", "may", "resolve", "this", "paradox.", "We", "find", "that", "in", "naive", "cells,", "the", "stimulated", "BCR", "becomes", "associated", "with", "a", "detergent-insoluble", "fraction", "containing", "lyn,", "and", "that", "in", "tolerant", "cells,", "the", "BCR", "does", "not", "efficiently", "associate", "with", "1443", "J.", "Exp.", "Med.", "The", "Rockefeller", "University", "Press", "•", "0022-1007/2000/04/1443/06", "$5.00", "Volume", "191,", "Number", "8,", "April", "17,", "2000", "1443–1448", "http://www.jem.org/cgi/current/full/191/8/1443" ]

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3,429,903

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[ "Original", "Article", "Radiat", "Oncol", "J", "2011;29(3):199-205", "http://dx.doi.org/10.3857/roj.2011.29.3.199", "pISSN", "2234-1900", "·", "eISSN", "2234-3156", "A", "comparison", "of", "preplan", "MRI", "and", "preplan", "CT-based", "prostate", "volume", "with", "intraoperative", "ultrasound-based", "prostate", "volume", "in", "real-time", "permanent", "brachytherapy", "Hyeli", "Park,", "MD1,", "Ja", "Young", "Kim,", "MD1,", "Bo", "Mi", "Lee,", "MD1,", "Sei", "Kyung", "Chang,", "MD1,", "Seung", "Young", "Ko,", "BS1,", "Sung", "Jun", "Kim,", "MS1,", "Dong", "Soo", "Park,", "MD2,", "Hyun", "Soo", "Shin,", "MD1", "Departments", "of", "1Radiation", "Oncology,", "2Urology,", "CHA", "Bundang", "Medical", "Center,", "CHA", "University,", "Seougnam,", "Korea", "Purpose:", "The", "present", "study", "compared", "the", "difference", "between", "intraoperative", "transrectal", "ultrasound", "(iTRUS)-based", "prostate", "volume", "and", "preplan", "computed", "tomography", "(CT),", "preplan", "magnetic", "resonance", "imaging", "(MRI)-based", "prostate", "volume", "to", "estimate", "the", "number", "of", "seeds", "needed", "for", "appropriate", "dose", "coverage", "in", "permanent", "brachytherapy", "for", "prostate", "cancer.", "Materials", "and", "Methods:", "Between", "March", "2007", "and", "March", "2011,", "among", "112", "patients", "who", "underwent", "permanent", "brachytherapy", "with", "125I,", "60", "image", "scans", "of", "56", "patients", "who", "underwent", "preplan", "CT", "(pCT)", "or", "preplan", "MRI", "(pMRI)", "within", "2", "months", "before", "brachytherapy", "were", "retrospectively", "reviewed.", "Twenty-four", "cases", "among", "30", "cases", "with", "pCT", "and", "26", "cases", "among", "30", "cases", "with", "pMRI", "received", "neoadjuvant", "hormone", "therapy", "(NHT).", "In", "34", "cases,", "NHT", "started", "after", "acquisition", "of", "preplan", "image.", "The", "median", "duration", "of", "NHT", "after", "preplan", "image", "acquisition", "was", "17", "and", "21", "days", "for", "cases", "with", "pCT", "and", "pMRI,", "respectively.", "The", "prostate", "volume", "calculated", "by", "different", "modalities", "was", "compared.", "And", "retrospective", "planning", "with", "iTRUS", "image", "was", "performed", "to", "estimate", "the", "number", "of", "125I", "seed", "required", "to", "obtain", "recommended", "dose", "distribution", "according", "to", "prostate", "volume.", "Results:", "The", "mean", "difference", "in", "prostate", "volume", "was", "9.05", "mL", "between", "the", "pCT", "and", "iTRUS", "and", "6.84", "mL", "between", "the", "pMRI", "and", "iTRUS.", "The", "prostate", "volume", "was", "roughly", "overestimated", "by", "1.36", "times", "with", "pCT", "and", "by", "1.33", "times", "with", "pMRI.", "For", "34", "cases", "which", "received", "NHT", "after", "image", "acquisition,", "the", "prostate", "volume", "was", "roughly", "overestimated", "by", "1.45", "times", "with", "pCT", "and", "by", "1.37", "times", "with", "pMRI.", "A", "statistically", "signiﬁcant", "difference", "was", "found", "between", "preplan", "image-based", "volume", "and", "iTRUS-based", "volume", "(p", "<", "0.001).", "The", "median", "number", "of", "wasted", "seeds", "is", "approximately", "13,", "when", "the", "pCT", "or", "pMRI", "volume", "was", "accepted", "without", "modiﬁcation", "to", "assess", "the", "required", "number", "of", "seeds", "for", "brachytherapy.", "Conclusion:", "pCT-based", "volume", "and", "pMRI-based", "volume", "tended", "to", "overestimate", "prostate", "volume", "in", "comparison", "to", "iTRUS-based", "volume.", "To", "reduce", "wasted", "seeds", "and", "cost", "of", "the", "brachytherapy,", "we", "should", "take", "the", "volume", "discrepancy", "into", "account", "when", "we", "estimate", "the", "number", "of", "125I", "seeds", "for", "permanent", "brachytherapy.", "Keywords:", "Brachytherapy,", "Prostate", "cancer,", "Prostate", "volume", "Received", "25", "May", "2011,", "Revised", "5", "July", "2011,", "Accepted", "13", "July", "2011.", "Correspondence:", "Hyun", "Soo", "Shin,", "MD,", "Department", "of", "Radiation", "Oncology,", "CHA", "Bundang", "Medical", "Center,", "Yatap-dong,", "Bundang-gu,", "Seongnam", "463-712,", "Korea.", "Tel:", "+82-31-780-5426,", "Fax:", "+82-31-780-5420,", "E-mail:", "shin029@chamc.co.kr", "CC", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "Non-Commercial", "License", "(http://creativecommons.org/", "licenses/by-nc/3.0/)", "which", "permits", "unrestricted", "non-commercial", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "www.e-roj.org", "Copyright", "©", "2011.", "The", "Korean", "Society", "for", "Therapeutic", "Radiology", "and", "Oncology", "199" ]

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3,170,353

null

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[ "Pan", "et", "al.", "Journal", "of", "Medical", "Case", "Reports", "2011,", "5:377", "http://www.jmedicalcasereports.com/content/5/1/377", "C", "A", "S", "E", "R", "E", "P", "O", "R", "T", "JOURNAL", "OF", "MEDICAL", "CASE", "REPORTS", "Open", "Access", "Lobar", "pneumonia", "caused", "by", "Ralstonia", "pickettii", "in", "a", "sixty-five-year-old", "Han", "Chinese", "man:", "a", "case", "report", "Wensen", "Pan1,", "Zhiming", "Zhao2*", "and", "Mei", "Dong3", "Abstract", "Introduction:", "Ralstonia", "pickettii", "is", "a", "gram-negative,", "oxidase-positive", "bacillus", "and", "is", "an", "emerging", "pathogen", "found", "in", "infections", "described", "in", "hospital", "settings.", "The", "cases", "reported", "in", "the", "literature", "mostly", "are", "nosocomial", "infections", "due", "to", "contaminated", "blood", "products,", "sterile", "water,", "saline,", "treatment", "fluids", "and", "venous", "catheters.", "Human", "infection", "unrelated", "to", "contaminated", "solutions", "is", "rare.", "We", "report", "a", "case", "of", "lobar", "pneumonia", "and", "pulmonary", "abscess", "caused", "by", "Ralstonia", "pickettii", "in", "an", "older", "patient.", "Case", "presentation:", "A", "sixty-five-year", "old", "Han", "Chinese", "man", "presented", "having", "had", "cough,", "expectoration,", "chest", "pain", "and", "fever", "lasting", "for", "twenty", "days.", "His", "medical", "history", "was", "notable", "for", "hypertension", "over", "the", "previous", "ten", "years,", "and", "the", "habit", "of", "smoking", "for", "forty", "years.", "A", "thoracic", "computed", "tomography", "scan", "supported", "the", "diagnosis", "of", "right-", "sided", "lobar", "pneumonia.", "A", "lung", "biopsy", "was", "done", "and", "pathological", "analysis", "confirmed", "lobar", "pneumonia.", "Two", "lung", "biopsy", "specimens", "from", "separate", "sites", "grew", "Ralstonia", "pickettii.", "After", "six", "days,", "a", "repeat", "thoracic", "scan", "revealed", "a", "right-", "sided", "abscess.", "A", "thoracentesis", "was", "performed", "and", "the", "purulent", "fluid", "grew", "Ralstonia", "pickettii.", "The", "chest", "tube", "remained", "inserted", "to", "rinse", "the", "cavity", "with", "sterile", "sodium", "chloride.", "He", "received", "an", "antibiotic", "course", "of", "intravenous", "cefoperazone", "sodium-sulbactam", "sodium", "for", "eighteen", "days", "and", "imipenem-cilastatin", "for", "twelve", "days.", "A", "repeat", "chest", "X-ray", "revealed", "resolution", "of", "the", "pulmonary", "abscess", "and", "improvement", "of", "pneumonia.", "He", "remained", "afebrile", "and", "free", "of", "respiratory", "symptoms", "after", "treatments.", "Conclusion:", "This", "case", "demonstrates", "a", "Ralstonia", "pickettii", "infection", "in", "the", "absence", "of", "an", "obvious", "nosocomial", "source.", "It", "is", "possible", "that", "such", "cases", "will", "become", "common", "in", "the", "future.", "Therefore,", "further", "studies", "are", "needed", "to", "evaluate", "its", "sensitivity", "to", "common", "antibiotics.", "Introduction", "Ralstonia", "pickettii", "(R.", "pickettii)", "is", "an", "emerging", "pathogen.", "It", "is", "ubiquitous", "in", "nature", "and", "is", "found", "naturally", "in", "soil", "and", "groundwater.", "R.", "pickettii", "was", "first", "isolated", "in", "1973", "and", "included", "in", "the", "genus", "Pseudomonas", "[1].", "The", "rod-", "shaped", "organism", "was", "reclassified", "in", "the", "Burkholderia", "and", "then", "the", "Ralstonia", "genera,", "receiving", "its", "current", "name", "in", "1995", "[2].", "R.", "pickettii", "is", "often", "confused", "with", "other", "similar", "bacteria,", "increasing", "the", "difficulty", "of", "classi-", "fying", "and", "treating", "this", "pathogen.", "R.", "pickettii", "can", "be", "isolated", "from", "various", "clinical", "speci-", "mens,", "such", "as", "sputum,", "blood,", "infected", "wounds,", "urine,", "*", "Correspondence:", "pwszzmxx@sina.com.cn", "2Department", "of", "Reproductive", "Medicine,", "the", "Second", "Hospital", "of", "Hebei", "Medical", "University,", "Shijiazhuang,", "China", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "ear,", "nose", "swabs,", "and", "cerebrospinal", "fluid.", "It", "is", "also", "com-", "monly", "found", "in", "the", "respiratory", "tract", "secretions", "of", "cystic", "fibrosis", "patients.", "Most", "infections", "with", "R.", "pickettii", "are", "seen", "in", "the", "hospital", "setting", "resulting", "in", "bacteremia", "and/", "or", "septicemia", "and", "respiratory", "infections", "and/or", "pneumo-", "nia", "[3].", "The", "cases", "reported", "in", "the", "literature", "are", "mostly", "nosocomial", "infections", "due", "to", "contaminated", "solutions", "including", "blood", "products,", "sterile", "water,", "saline,", "chlorhexi-", "dine", "solution,", "treatment", "fluids", 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[ "Hindawi", "Publishing", "Corporation", "Journal", "of", "Pregnancy", "Volume", "2012,", "Article", "ID", "681306,", "9", "pages", "doi:10.1155/2012/681306", "Review", "Article", "Adrenocortical", "and", "Adipose", "Responses", "to", "High-Altitude-Induced,", "Long-Term", "Hypoxia", "in", "the", "Ovine", "Fetus", "Dean", "A.", "Myers1", "and", "Charles", "A.", "Ducsay2", "1", "Department", "of", "Obstetrics", "and", "Gynecology,", "University", "of", "Oklahoma", "Health", "Sciences", "Center,", "Oklahoma", "City,", "OK", "73104,", "USA", "2", "Center", "for", "Perinatal", "Biology,", "Loma", "Linda", "University", "School", "of", "Medicine,", "Loma", "Linda,", "CA", "92350,", "USA", "Correspondence", "should", "be", "addressed", "to", "Dean", "A.", "Myers,", "dean-myers@ouhsc.edu", "Received", "7", "February", "2012;", "Accepted", "2", "March", "2012", "Academic", "Editor:", "Timothy", "Regnault", "Copyright", "©", "2012", "D.", "A.", "Myers", "and", "C.", "A.", "Ducsay.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "By", "late", "gestation,", "the", "maturing", "hypothalamo-pituitary-adrenal", "(HPA)", "axis", "aids", "the", "fetus", "in", "responding", "to", "stress.", "Hypoxia", "represents", "a", "signiﬁcant", "threat", "to", "the", "fetus", "accompanying", "situations", "such", "as", "preeclampsia,", "smoking,", "high", "altitude,", "and", "preterm", "labor.", "We", "developed", "a", "model", "of", "high-altitude", "(3,820", "m),", "long-term", "hypoxia", "(LTH)", "in", "pregnant", "sheep.", "We", "describe", "the", "impact", "of", "LTH", "on", "the", "fetal", "HPA", "axis", "at", "the", "level", "of", "the", "hypothalamic", "paraventricular", "nucleus", "(PVN),", "anterior", "pituitary", "corticotrope,", "and", "adrenal", "cortex.", "At", "the", "PVN", "and", "anterior", "pituitary,", "the", "responses", "to", "LTH", "are", "consistent", "with", "hypoxia", "being", "a", "potent", "activator", "of", "the", "HPA", "axis", "and", "potentially", "maladaptive,", "while", "the", "adrenocortical", "response", "to", "LTH", "appears", "to", "be", "primarily", "adaptive.", "We", "discuss", "mechanisms", "involved", "in", "the", "delicate", "balance", "between", "these", "seemingly", "opposing", "responses", "that", "preserve", "the", "normal", "ontogenic", "rise", "in", "fetal", "plasma", "cortisol", "essential", "for", "organ", "maturation", "and", "in", "this", "species,", "birth.", "Further,", "we", "examine", "the", "response", "to,", "and", "ramiﬁcations", "of,", "an", "acute", "secondary", "stressor", "in", "the", "LTH", "fetus.", "We", "provide", "an", "integrative", "model", "on", "the", "potential", "role", "of", "adipose", "in", "modulating", "these", "responses", "to", "LTH.", "Integration", "of", "these", "adaptive", "responses", "to", "LTH", "plays", "a", "key", "role", "in", "promoting", "normal", "fetal", "growth", "and", "development", "under", "conditions", "of", "a", "chronic", "stress.", "1.", "Introduction", "Hypoxia", "represents", "a", "major", "threat", "to", "the", "developing", "fetus", "and", "often", "accompanies", "situations", "of", "preeclampsia,", "preterm", "labor,", "smoking,", "and", "high", "altitude.", "The", "impact", "that", "hypoxia", "has", "on", "the", "fetus", "depends", "on", "a", "variety", "of", "factors", "such", "as", "stage", "of", "gestation,", "severity", "of", "the", "hypoxic", "episode,", "duration", "of", "hypoxia,", "and", "the", "association", "with", "other", "confounders", "such", "as", "acidemia", "and", "hypercapnia.", "Severe", "hypoxic", "events", "can", "lead", "to", "fetal", "death", "or", "exert", "major", "deleterious", "impacts", "on", "develop-", "ment", "and", "function", "on", "fetal", "organs,", "including", "major", "damage", "of", "the", "CNS.", "However,", "fetuses", "are", "often", "and", "perhaps", "routinely", "exposed", "to", "less", "severe", "hypoxic", "episodes.", "While", "these", "hypoxic", "conditions", "may", "impact", "fetal", "growth,", "eﬀects", "on", "other", "organ", "systems", "are", "less", "clear.", "Due", "to", "its", "long", "gestational", "length,", "similarity", "of", "endocrine", "and", "physiological", "systems,", "and", "relative", "ease", "of", "fetal", "and", "maternal", "instrumentation,", "the", "sheep", "has", "emerged", "as", "a", "ma-", "jor", "animal", "model", "for", "studying", "the", "impact", "of", "hypoxia", "on", "the", "developing", "fetus.", "These", "studies", "have", "largely", "focused", "on", "so-called", "acute", "hypoxia", "in", "which", "a", "moderate-to-severe", "hypoxia", "(a", "decrease", "in", "fetal", "PO2", "of", "50%", "or", "greater)", "is", "induced", "for", "times", "ranging", "from", "minutes", "to", "several", "hours", "or", "chronic", "hypoxia", "in", "which", "the", "fetus", "is", "made", "hypoxic", "for", "one", "to", "several", "days.", "Experimentally,", "acute", "fetal", "hypoxia", "can", "be", "induced", "by", "maternal", "hypoxia", "[1–3],", "restricting", "blood", "ﬂow", "to", "the", "uterus", "and", "placenta", "on", "the", "maternal", "side", "[4],", "or", "reducing", "umbilical", "blood", "ﬂow", "by", "cord", "compression", "[5–", "7].", "More", "prolonged", "fetal", "hypoxemia", "can", "also", "be", "initiated", "by", "repeated", "umbilical", "cord", "compression", "[7–9],", "as", "well", "as", "placental", "embolization", "[10,", "11]", "and", "restriction", "of", "uterine", "blood", "ﬂow", "[12].", "These", "methods", "induce", "either", "a", "rather", "pure", "hypoxic", "episode", "or", "hypoxia", "accompanied", "with", "acidemia", "or", "hypoglycemia.", "Longer", "duration", "hypoxic", "situations", "(months)", "have", "been", "created", "in", "sheep", "by", "maternal", "carunclectomy,", "reducing", "the", "placentation", "area", "of", "the", "uterus", "[13].", "However,", "the", "hypoxia", "in", "this", "model", "is", "secondary", "to", "nutrient", "restric-", "tion." ]

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[ "Cases", "Journal", "Case", "Report", "Endometrial", "Cancer", "Presenting", "as", "Acute", "Urinary", "Retention", ":", "a", "Case", "Report", "and", "Review", "of", "The", "Literature", "Samer", "R", "Tannus*", "and", "Ilan", "Atlas", "Address:", "Department", "of", "Obstetrics", "&", "Gynecology,", "The", "Baruch", "Padeh", "Medical", "Center,", "Poriya,", "Lower", "Galilee", "15208.", "Israel", "Email:", "Samer", "R", "Tannus*", "-", "stannus@bezeqint.net;", "Ilan", "Atlas", "-", "ilanatlas@gmail.com", "*", "Corresponding", "author", "BioMed", "Central", "Open", "Access", "Published:", "22", "December", "2009", "Cases", "Journal", "2009,", "2:9382", "doi:10.1186/1757-1626-2-9382", "This", "article", "is", "available", "from:", "http://www.casesjournal.com/content/2/1/9382", "Received:", "29", "November", "2009", "Accepted:", "22", "December", "2009", "©", "2009", "Tannus", "and", "Atlas;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Introduction:", "Endometrial", "cancer", "is", "the", "most", "common", "gynecologic", "malignancy.", "Most", "women", "present", "with", "abnormal", "vaginal", "bleeding.", "Cervical", "stenosis", "can", "prevent", "early", "uterine", "bleeding", "leading", "to", "delayed", "diagnosis", "of", "the", "disease.", "Case", "presentation:", "A", "67", "years", "old", "Caucasian", "woman", "presented", "with", "three", "days", "history", "of", "right", "flank", "pain", "and", "difficulty", "in", "urination.", "Her", "medical", "history", "included", "cervical", "cautery", "due", "to", "ectropion", "15", "years", "previously.", "In", "physical", "exam", "a", "huge", "cystic", "mass", "that", "proved", "to", "be", "a", "large", "hematocervix", "was", "bulging", "in", "the", "vagina.", "Computed", "tomography", "of", "the", "abdomen", "revealed", "a", "distended", "cervix", "adjacent", "to", "distended", "urinary", "bladder", "secondary", "to", "endometrial", "cancer.", "Conclusion:", "To", "our", "knowledge", "this", "is", "the", "first", "case", "report", "describing", "acute", "urinary", "retention", "secondary", "to", "hematocervix.", "Cervical", "stenosis", "is", "common", "in", "elderly", "postmenopausal", "women", "and", "can", "prevent", "early", "manifestation", "of", "endometrial", "pathology", "and", "can", "be", "associated", "with", "local", "complications.", "Introduction", "Endometrial", "cancer", "is", "the", "most", "common", "gynecologic", "malignancy", "and", "the", "fourth", "most", "common", "cancer", "in", "women", "[1].", "It", "has", "a", "high", "cure", "rate", "as", "92", "percent", "of", "women", "are", "detected", "in", "stage", "I", "and", "II", "of", "the", "disease", "and", "most", "present", "with", "vaginal", "bleeding", "as", "the", "chief", "complaint.", "Cer-", "vical", "stenosis", "is", "a", "common", "occurrence", "in", "elderly", "women", "and", "can", "prevent", "early", "uterine", "bleeding", "of", "endometrial", "cancer", "and", "delays", "the", "diagnosis.", "We", "describe", "an", "unusual", "manifestation", "of", "low", "grade", "endometrial", "cancer", "diagnosed", "in", "advanced", "stage", "presenting", "as", "acute", "urinary", "retention", "secondary", "to", "hematocervix.", "A", "case", "report", "and", "review", "of", "the", "literature", "are", "presented.", "Case", "A", "67", "years", "old", "Caucasian", "woman", "gravida", "3,", "para", "1", "pre-", "sented", "with", "three", "days", "history", "of", "right", "flank", "pain", "and", "dif-", "ficulty", "in", "urination.", "Her", "medical", "history", "was", "significant", "for", "obesity,", "hypertension", "and", "previous", "salpingectomy", "due", "to", "ectopic", "pregnancy.", "15", "years", "previously", "a", "cervical", "cau-", "tery", "was", "performed", "due", "to", "cervical", "ectropion.", "On", "admission", "her", "vital", "signs", "were", "stable.", "Physical", "exami-", "nation", "revealed", "tenderness", "in", "both", "costovertebral", "angles", "and", "fullness", "in", "the", "lower", "abdomen.", "In", "gynecologic", "exam", "a", "huge", "soft", "cystic", "mass", "was", "bulging", "in", "the", "vagina", "to", "the", "level", "of", "the", "hymen.", "It", "was", "suspected", "to", "be", "a", "distended", "cer-", "vix.", "The", "external", "cervical", "os", "was", "not", "identified.", "Page", "1", "of", "3", "(page", "number", "not", "for", "citation", "purposes)" ]

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2,925,909

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[ "Molecular", "Vision", "2010;", "16:1453-1466", "<http://www.molvis.org/molvis/v16/a159>", "Received", "15", "June", "2010", "|", "Accepted", "23", "July", "2010", "|", "Published", "31", "July", "2010", "©", "2010", "Molecular", "Vision", "Abnormal", "fiber", "end", "migration", "in", "Royal", "College", "of", "Surgeons", "rats", "during", "posterior", "subcapsular", "cataract", "formation", "Anita", "Joy,1", "Tabraiz", "A.", "Mohammed,1", "Kristin", "J.", "Al-Ghoul1,2", "1Department", "of", "Anatomy", "&", "Cell", "Biology,", "Rush", "University", "Medical", "Center,", "Chicago,", "IL;", "2Department", "of", "Ophthalmology,", "Rush", "University", "Medical", "Center,", "Chicago,", "IL", "Purpose:", "Prior", "structural", "studies", "of", "posterior", "subcapsular", "cataract", "(PSC)", "development", "in", "Royal", "College", "of", "Surgeons", "(RCS)", "rats", "suggest", "that", "migration", "of", "basal", "fiber", "ends", "was", "disrupted,", "ultimately", "resulting", "in", "a", "PSC.", "Therefore", "the", "goal", "of", "this", "study", "was", "to", "assess", "the", "overall", "migration", "patterns", "as", "well", "as", "changes", "to", "the", "structure", "and", "cytoskeleton", "of", "basal", "fiber", "ends", "during", "PSC", "development.", "Methods:", "Lenses", "from", "48", "RCS", "dystrophic", "rats", "(RCS/Lav)", "and", "24", "genetically", "matched", "control", "animals", "(RCS-rdy+/Lav)", "from", "2", "to", "8", "weeks", "old", "were", "examined.", "Equatorial", "diameters", "were", "measured", "and", "suture", "patterns", "were", "photographed", "immediately", "following", "enucleation/dissection.", "Right", "eye", "lenses", "were", "fixed", "and", "processed", "to", "visualize", "the", "actin", "cytoskeleton", "via", "laser", "scanning", "confocal", "microcopy", "(LSCM),", "left", "eye", "lenses", "were", "decapsulated,", "fixed", "and", "processed", "for", "scanning", "electron", "microscopy", "(SEM).", "Scaled", "3D-computer", "assisted", "drawings", "(CADs)", "and", "animations", "were", "constructed", "from", "the", "data", "to", "depict", "the", "changes", "in", "suture", "patterns", "and", "fiber", "end", "architecture.", "Results:", "At", "2", "weeks,", "dystrophic", "lenses", "displayed", "an", "inverted", "Y", "suture", "on", "the", "posterior,", "and", "by", "3", "weeks", "most", "lenses", "had", "at", "least", "one", "sub-branch.", "Additional", "sub-branches", "were", "observed", "with", "time,", "opacities", "being", "visible", "as", "early", "as", "4", "weeks", "and", "progressing", "into", "PSC", "plaques", "by", "6", "weeks.", "Control", "lenses", "displayed", "inverted", "Y", "sutures", "at", "all", "ages", "and", "were", "transparent.", "SEM", "of", "dystrophic", "lenses", "revealed", "fiber", "ends", "with", "normal", "size,", "shape,", "arrangement,", "and", "filopodia", "at", "2", "weeks;", "scattered", "areas", "of", "dome-shaped", "fiber", "ends", "and", "small", "filopodia", "were", "present", "at", "3", "weeks.", "At", "4", "weeks", "the", "irregularly", "arranged", "domed", "fiber", "ends", "had", "extremely", "long", "filopodia", "with", "‘boutons’", "at", "their", "tips.", "By", "6", "weeks", "all", "fiber", "ends", "within", "plaques", "displayed", "rounded", "or", "domed", "basal", "membranes", "and", "lacked", "filopodial", "extensions.", "Control", "lenses", "at", "all", "time", "points", "had", "comparable", "ultrastructure", "to", "the", "2", "week", "old", "dystrophic", "lenses.", "F-actin", "arrangement", "within", "the", "basal", "membrane", "complex", "(BMC)", "of", "control", "lenses", "showed", "the", "expected", "peripheral", "pattern", "of", "labeling", "at", "all", "ages.", "Dystrophic", "RCS", "lenses", "at", "2", "weeks", "were", "comparable", "to", "controls,", "however", "by", "3–4", "weeks", "they", "displayed", "scattered", "foci", "of", "F-actin", "within", "the", "BMC.", "At", "all", "time", "points", "thereafter,", "F-actin", "was", "rearranged", "into", "a", "‘rosette’", "pattern", "of", "prominent", "foci", "at", "cell", "vertices.", "Conclusions:", "The", "data", "are", "consistent", "with", "the", "hypothesis", "that", "migration", "of", "basal", "fiber", "ends", "is", "altered", "in", "a", "two", "stage", "process", "wherein", "initially,", "migration", "patterns", "undergo", "a", "rapid", "shift", "resulting", "in", "abnormal", "suture", "sub-branch", "formation.", "Subsequent", "cytological", "alterations", "are", "consistent", "with", "an", "eventual", "cessation", "of", "migration,", "precluding", "proper", "targeting", "of", "basal", "ends", "to", "their", "sutural", "destinations", "and", "leading", "to", "cataract", "plaque", "formation.", "Congenital", "retinal", "dystrophy", "in", "the", "Royal", "College", "of", "Surgeons", "(RCS)", "rat", "is", "a", "recessively", "inherited", "anomaly", "that", "results", "in", "the", "progressive", "degeneration", "of", "photoreceptor", "cells", "in", "the", "retina", "during", "the", "later", "stages", "of", "retinal", "development", "(third", "week", "postnatal)", "[1-3].", "One", "of", "the", "many", "deleterious", "effects", "of", "this", "disease", "includes", "the", "formation", "of", "a", "secondary", "cataract,", "specifically", "a", "posterior", "subcapsular", "cataract", "(PSC).", "Although", "the", "cataract", "was", "the", "first", "feature", "noted", "and", "described", "in", "the", "RCS", "rat", "[4],", "this", "animal", "model", "has", "been", "extensively", "used", "to", "study", "retinal", "degeneration.", "Since", "the", "first", "description", "of", "the", "genetic", "abnormality", "responsible", "for", "the", "retinal", "Correspondence", "to:", "Kristin", "J.", "Al-Ghoul,", "Ph.D.,", "Department", "of", "Anatomy", "and", "Cell", "Biology,", "Rush", "University", "Medical", "Center,", "600", "S.", "Paulina", "St.,", "Ste", "507,", "Chicago,", "IL,", "60612;", "Phone:", "(312)", "563-2672;", "FAX:", "(312)", "942-5744;", "email:", "kristin_j_al-ghoul@rush.edu", "Dr.", "Mohammed", "is", "currently", "at", "the", "Department", "of", "Medicine,", "University", "of", "Wisconsin", "Hospitals", "and", "Clinics,", "Madison,", "WI", "dystrophy", "by", "Bourne", "et", "al.", "[2,5],", "the", "early", "initiation,", "rapid", "progression,", "and", "the", "resultant", "PSC", "formation", "in", "these", "animals", "have", "also", "been", "well", "documented.", "Similarities", "between", "the", "rodent", "disease", "and", "retinitis", "pigmentosa", "in", "humans", "have", "been", "established", "[5-8],", "and", "the", "RCS", "rat", "is", "therefore", "an", "excellent", "model", "to", "study", "both", "autosomal", "recessive", "retinitis", "pigmentosa", "(ARRP)", "and", "PSCs.", "In", "the", "retina,", "the", "first", "damage", "occurs", "approximately", "12", "days", "postnatal", "in", "the", "rod", "outer", "segments", "and", "by", "18", "days", "postnatal,", "the", "outer", "segment", "layer", "is", "twice", "as", "thick", "when", "compared", "to", "normal.", "There", "is", "also", "the", "presence", "of", "outer", "segment", "debris", "within", "this", "thickened", "layer.", "At", "about", "4", "weeks", "postnatal,", "this", "layer", "reaches", "its", "maximum", "thickness", "and", "both", "the", "inner", "segments", "as", "well", "as", "the", "photoreceptor", "nuclei", "begin", "to", "degenerate.", "By", "about", "40", "days", "postnatal,", "both", "inner", "and", "outer", "rod", "segments", "have", "completely", "disintegrated", "[3,9-11].", "The", "temporal", "sequence", "of", "events", "that", "mark", "the", "maximal", "accumulation", "of", "outer", "segment", "debris", "and", "retinal", "breakdown", "closely", "mirror", "the", "changes", "that", "occur", "at", "the", "posterior", "surface", "1453" ]

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2,556,395

null

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[ "Symphysiotomy", "in", "Zimbabwe;", "Postoperative", "Outcome,", "Width", "of", "the", "Symphysis", "Joint,", "and", "Knowledge,", "Attitudes", "and", "Practice", "among", "Doctors", "and", "Midwives", "Hege", "Langli", "Ersdal1*,", "Douwe", "A.", "A.", "Verkuyl2,", "Kenneth", "Bjo¨", "rklund{1,", "Staffan", "Bergstro¨", "m1", "1", "Division", "of", "International", "Health", "(IHCAR),", "Karolinska", "Institutet,", "Stockholm,", "Sweden,", "2", "Department", "of", "Obstetrics", "and", "Gynaecology,", "United", "Bulawayo", "Hospital,", "Bulawayo,", "Zimbabwe", "Abstract", "Background:", "Obstructed", "labour", "remains", "one", "of", "the", "leading", "causes", "of", "maternal", "and", "foetal", "death", "and", "morbidity", "in", "poorly", "resourced", "areas", "of", "the", "world,", "where", "the", "24", "hours", "availability", "of", "a", "caesarean", "section", "(CS)", "cannot", "be", "guaranteed,", "and", "the", "CS", "related", "mortality", "rate", "is", "still", "high.", "In", "these", "settings,", "reinstatement", "of", "symphysiotomy", "has", "been", "advocated.", "The", "objectives", "were,", "in1994;", "to", "study", "perioperative", "and", "long-term", "complications", "of", "symphysiotomy", "and", "compare", "them", "to", "those", "related", "to", "CS", "for", "similar", "indications,", "in", "1996;", "to", "measure", "the", "symphyseal", "width", "after", "symphysiotomy", "and", "compare", "it", "to", "that", "after", "normal", "vaginal", "delivery,", "and,", "in", "1998;", "to", "assess", "knowledge,", "attitudes", "and", "practice", "related", "to", "symphysiotomy", "among", "doctors", "and", "midwives", "in", "Zimbabwe.", "Methods", "and", "Findings:", "Thirty-four", "women", "who", "had", "undergone", "symphysiotomy", "and", "29", "women", "who", "had", "undergone", "a", "CS", "for", "obstructed", "labour", "were", "interviewed.", "The", "symphyseal", "widths", "of", "19", "women", "with", "a", "previous", "symphysiotomy", "were", "compared", "to", "that", "of", "92", "women", "with", "previous", "normal", "vaginal", "deliveries,", "using", "ultrasound", "technique.", "Forty-one", "doctors", "and", "39", "midwives,", "in", "three", "central", "hospitals", "and", "seven", "district", "hospitals", "in", "Zimbabwe,", "were", "interviewed", "about", "symphysiotomy.", "None", "of", "the", "34", "women", "reported", "serious", "soft", "tissue", "injuries", "or", "infections", "post", "symphysiotomy.", "Long-term", "complications", "after", "symphysiotomy", "do", "not", "differ", "notably", "from", "those", "after", "CS", "for", "similar", "indications.", "The", "intra-articular", "width", "of", "the", "symphysis", "pubis", "is", "increased", "after", "a", "symphysiotomy.", "Seventy-nine", "of", "the", "80", "interviewed", "health", "care", "workers", "knew", "about", "symphysiotomy.", "One", "obstetrician", "had", "performed", "symphysiotomies.", "Two-thirds", "of", "the", "participants", "considered", "symphysiotomy", "an", "obsolete", "and", "second-class", "operation,", "but", "lifesaving", "and", "appropriate", "in", "remote", "areas", "of", "Zimbabwe.", "Ten", "of", "13", "midwives", "in", "remote", "areas", "wanted", "to", "carry", "out", "symphysiotomies", "themselves.", "Conclusions:", "No", "severe", "complications", "due", "to", "symphysiotomy", "were", "revealed", "in", "this", "study.", "The", "results", "suggest", "that", "a", "modest", "permanent", "enlargement", "of", "the", "pelvis", "post", "symphysiotomy", "(together", "with", "the", "absence", "of", "a", "scarred", "uterus)", "may", "facilitate", "subsequent", "vaginal", "delivery.", "Doctors", "and", "midwives", "working", "in", "district", "hospitals", "have", "a", "more", "positive", "attitude", "to", "symphysiotomies", "than", "the", "colleagues", "in", "central", "hospitals.", "Obstetricians", "(who", "would", "have", "to", "do", "the", "teaching),", "working", "in", "the", "large", "urban", "hospitals", "almost", "exclude", "symphysiotomy", "as", "an", "alternative", "management", "in", "Zimbabwe.", "Citation:", "Ersdal", "HL,", "Verkuyl", "DAA,", "Bj", "o¨rklund", "K,", "Bergstro¨", "m", "S", "(2008)", "Symphysiotomy", "in", "Zimbabwe;", "Postoperative", "Outcome,", "Width", "of", "the", "Symphysis", "Joint,", "and", "Knowledge,", "Attitudes", "and", "Practice", "among", "Doctors", "and", "Midwives.", "PLoS", "ONE", "3(10):", "e3317.", "doi:10.1371/journal.pone.0003317", "Editor:", "Landon", "Myer,", "University", "of", "Cape", "Town,", "South", "Africa", "Received", "May", "9,", "2008;", "Accepted", "September", "12,", "2008;", "Published", "October", "10,", "2008", "Copyright:", "2008", "Ersdal", "et", "al.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Funding:", "The", "work", "presented", "is", "partly", "financed", "by", "The", "Research", "Council", "of", "Norway", "(student", "scholarship", "for", "the", "first", "auther", "HLE).", "The", "funder", "had", "no", "role", "in", "study", "design,", "data", "collection", "and", "analysis,", "decision", "to", "publish,", "or", "preparation", "of", "the", "manuscript", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "*", "E-mail:", "hege@ersdal.com", "{", "Deceased.", "Introduction", "Symphysiotomy", "was", "developed", "in", "Europe", "late", "in", "the", "18th", "century", "as", "a", "means", "to", "save", "the", "lives", "of", "mother", "and", "child", "in", "obstructed", "labour.", "In", "the", "early", "days", "the", "separation", "of", "the", "bones", "was", "performed", "after", "exposing", "the", "symphysis.", "With", "the", "introduc-", "tion", "of", "aseptic", "techniques", "in", "the", "mid", "19th", "century", "and", "the", "subcutaneous", "symphysiotomy", "by", "Frank", "[1],", "using", "local", "anaesthet-", "ics,", "the", "operation", "gained", "acceptance", "and", "became", "part", "of", "the", "obstetric", "arsenal", "in", "many", "parts", "of", "Europe", "[2–5].", "The", "technique", "was", "further", "refined", "by", "Za´rate", "in", "Argentina", "[6],", "and", "symphysiot-", "omy", "was", "extensively", "practised", "in", "Latin", "America", "and", "Ireland", "up", "to", "the", "mid", "20th", "century", "[4,7,8].", "Seedat", "and", "Crichton", "in", "Durban,", "South", "Africa,", "further", "developed", "the", "technique", "[9]", "and", "symphy-", "siotomy", "came", "to", "be", "used", "in", "Africa", "for", "the", "ensuing", "decades", "[9–12].", "Currently,", "outside", "Africa,", "symphysiotomies", "are", "still", "performed", "in", "Papua", "New", "Guinea", "[13].", "Mechanical", "obstruction", "in", "the", "second", "stage", "complicates", "1–2%", "of", "labours", "[14].", "In", "developing", "countries", "this", "percentage", "might", "be", "higher", "because", "women", "often", "do", "not", "attain", "their", "(pelvic)", "growth", "potential", "due", "to", "stunting.", "The", "facilities", "and", "staffing", "level", "of", "non-", "private", "hospitals", "in", "developing", "countries", "make", "it", "often", "inevitable", "that", "CSs", "are", "associated", "with", "an", "appreciable", "mortality", "rate.", "In", "addition,", "there", "is", "no", "guarantee", "that", "a", "woman", "with", "a", "scar", "in", "the", "uterus", "can,", "or", "even", "would", "like", "to,", "reach", "in", "time", "a", "(still", "adequately", "staffed)", "hospital", "for", "the", "next", "delivery.", "The", "World", "Health", "Organization", "(WHO)", "PLoS", "ONE", "|", "www.plosone.org", "1", "October", "2008", "|", "Volume", "3", "|", "Issue", "10", "|", "e3317" ]

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3,413,157

null

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[ "6774–6786", "Nucleic", "Acids", "Research,", "2012,", "Vol.", "40,", "No.", "14", "doi:10.1093/nar/gks388", "Published", "online", "7", "May", "2012", "Biochemical", "analyses", "indicate", "that", "binding", "and", "cleavage", "specificities", "define", "the", "ordered", "processing", "of", "human", "Okazaki", "fragments", "by", "Dna2", "and", "FEN1", "Jason", "W.", "Gloor1,", "Lata", "Balakrishnan", "1", ",", "Judith", "L.", "Campbell2", "and", "Robert", "A.", "Bambara1,*", "1Department", "of", "Microbiology", "and", "Immunology,", "University", "of", "Rochester", "School", "of", "Medicine", "and", "Dentistry,", "Rochester,", "NY", "14642", "and", "2Braun", "Laboratories,", "California", "Institute", "of", "Technology,", "Pasadena,", "CA", "91125,", "USA", "Received", "March", "12,", "2012;", "Revised", "April", "5,", "2012;", "Accepted", "April", "13,", "2012", "ABSTRACT", "In", "eukaryotic", "Okazaki", "fragment", "processing,", "the", "RNA", "primer", "is", "displaced", "into", "a", "single-stranded", "flap", "prior", "to", "removal.", "Evidence", "suggests", "that", "some", "flaps", "become", "long", "before", "they", "are", "cleaved,", "and", "that", "this", "cleavage", "involves", "the", "sequential", "action", "of", "two", "nucleases.", "Strand", "displacement", "characteristics", "of", "the", "polymerase", "show", "that", "a", "short", "gap", "precedes", "the", "flap", "during", "synthesis.", "Using", "biochemical", "tech-", "niques,", "binding", "and", "cleavage", "assays", "presented", "here", "indicate", "that", "when", "the", "flap", "is", "30", "nt", "long", "the", "nuclease", "Dna2", "can", "bind", "with", "high", "affinity", "to", "the", "flap", "and", "downstream", "double", "strand", "and", "begin", "cleavage.", "When", "the", "polymerase", "idles", "or", "dissociates", "the", "Dna2", "can", "reorient", "for", "additional", "contacts", "with", "the", "upstream", "primer", "region,", "allowing", "the", "nuclease", "to", "remain", "stably", "bound", "as", "the", "flap", "is", "further", "shortened.", "The", "DNA", "can", "then", "equilibrate", "to", "a", "double", "flap", "that", "can", "bind", "Dna2", "and", "flap", "endonucle-", "ase", "(FEN1)", "simultaneously.", "When", "Dna2", "shortens", "the", "flap", "even", "more,", "FEN1", "can", "displace", "the", "Dna2", "and", "cleave", "at", "the", "flap", "base", "to", "make", "a", "nick", "for", "ligation.", "INTRODUCTION", "In", "both", "prokaryotic", "and", "eukaryotic", "DNA", "replication,", "one", "strand", "of", "DNA,", "called", "lagging,", "is", "initially", "made", "in", "discon-", "tinuous", "segments", "termed", "Okazaki", "fragments.", "In", "humans,", "each", "fragment", "is", "initiated", "by", "an", "RNA", "primer", "8–10", "nt", "in", "length", "and", "extended", "150–200", "nt", "with", "DNA", "(1).", "The", "fragments", "need", "to", "be", "joined", "to", "make", "a", "continuous", "strand.", "This", "involves", "strand", "displacement", "synthesis", "from", "one", "fragment", "to", "raise", "the", "RNA", "primer", "region", "of", "the", "adjacent", "fragment", "into", "a", "ﬂap.", "Genetic", "experiments", "and", "reconstitutions", "in", "vitro", "suggest", "that", "ﬂap", "creation", "and", "removal", "occurs", "via", "two", "pathways.", "One", "employs", "the", "ﬂap", "endonuclease", "(FEN1),", "which", "removes", "the", "ﬂap", "containing", "the", "initiator", "RNA", "leaving", "a", "nick", "for", "ligation.", "If", "a", "ﬂap", "escapes", "FEN1", "to", "grow", "long", "enough", "to", "acquire", "the", "eukary-", "otic", "DNA-binding", "protein", "(RPA),", "nucleolytic", "cleavage", "will", "be", "blocked.", "If", "so,", "the", "ﬂap", "is", "processed", "by", "the", "second", "pathway", "in", "which", "the", "nuclease/helicase", "Dna2", "displaces", "the", "RPA.", "Dna2", "then", "successively", "cleaves", "the", "ﬂap", "until", "it", "is", "too", "short", "to", "bind", "RPA", "and", "becomes", "a", "substrate", "for", "FEN1", "(2,3).", "Biochemical", "analyses", "have", "demonstrated", "that", "both", "FEN1", "(4–13)", "and", "Dna2", "(14)", "employ", "a", "threading", "mechan-", "ism", "for", "binding", "and", "cleavage", "of", "the", "ﬂap", "substrate.", "Recent", "results", "show", "that", "both", "nucleases", "recognize", "and", "bind", "to", "the", "base", "of", "the", "ﬂap", "and", "then", "thread", "the", "50", "end", "of", "the", "ﬂap", "through", "the", "protein", "(15–17).", "Dna2", "cleaves", "periodically", "during", "the", "threading", "(18,19),", "and", "FEN1", "cleaves", "speciﬁc-", "ally", "at", "the", "base", "(4,20,21).", "Previous", "analyses", "with", "puriﬁed", "proteins", "from", "Saccharo-", "myces", "cerevisiae", "clariﬁed", "how", "these", "proteins", "act", "in", "succes-", "sion", "to", "process", "Okazaki", "fragments", "(8,22–25).", "On", "a", "long", "ﬂap", "substrate,", "S.", "cerevisiae", "Dna2", "(scDna2)", "was", "shown", "to", "displace", "bound", "scRPA", "in", "a", "reaction", "that", "did", "not", "require", "cleavage", "(26).", "scFEN1", "was", "shown", "to", "displace", "the", "scDna2,", "so", "that", "it", "could", "have", "access", "to", "its", "cleavage", "site", "at", "the", "ﬂap", "base", "(17).", "In", "addition", "to", "the", "role", "it", "plays", "in", "Okazaki", "fragment", "pro-", "cessing,", "Dna2", "functions", "in", "conjunction", "with", "30–50", "helicases", "and", "RPA", "to", "resect", "the", "50", "end", "of", "DNA", "during", "double-strand", "break", "(DSB)", "repair", "and", "telomere", "maintenance", "(27).", "Human", "and", "yeast", "systems", "employ", "redundant", "pathways", "during", "these", "processes,", "one", "of", "which", "utilizes", "Dna2", "(28–30).", "Once", "recruited", "to", "the", "DSB,", "a", "30–50", "helicase", "separ-", "ates", "the", "two", "strands", "of", "the", "DNA", "creating", "a", "pseudo-Y", "struc-", "ture", "consisting", "of", "a", "30", "single-stranded", "(ss)", "DNA", "tail,", "a", "50", "ssDNA", "tail", "and", "a", "double-stranded", "region.", "These", "single-", "stranded", "tails", "can", "then", "be", "coated", "by", "RPA.", "Similar", "to", "its", "role", "in", "the", "long", "ﬂap", "Okazaki", "fragment", "pathway,", "Dna2", "cleaves", "the", "50-ssDNA.", "Surprisingly,", "even", "though", "Dna2", "possesses", "a", "30", "nuclease", "activity,", "RPA", "prevents", "cleavage", "of", "the", "30-ssDNA", "(30,31).", "Dna2", "interacts", "with", "the", "RPA1", "(70", "kDa)", "subunit", "of", "RPA", "(22).", "The", "N", "terminus", "of", "RPA1", "*To", "whom", "correspondence", "should", "be", "addressed.", "Tel:", "+1", "585", "275", "3269;", "Fax:", "+1", "585", "275", "6007;", "Email:", "robert_bambara@urmc.rochester.edu", "The", "Author(s)", "2012.", "Published", "by", "Oxford", "University", "Press.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "Non-Commercial", "License", "(http://creativecommons.org/licenses/", "by-nc/3.0),", "which", "permits", "unrestricted", "non-commercial", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

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1,087,827

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[ "BMC", "Bioinformatics", "Research", "article", "Evolutionary", "distance", "estimation", "and", "fidelity", "of", "pair", "wise", "sequence", "alignment", "Michael", "S", "Rosenberg*", "Address:", "Center", "for", "Evolutionary", "Functional", "Genomics,", "The", "Biodesign", "Institute,", "and", "the", "School", "of", "Life", "Sciences,", "Arizona", "State", "University,", "Tempe,", "AZ", "84287-4501,", "USA", "Email:", "Michael", "S", "Rosenberg*", "-", "msr@asu.edu", "*", "Corresponding", "author", "BioMed", "Central", "Open", "Access", "Published:", "19", "April", "2005", "BMC", "Bioinformatics", "2005,", "6:102", "doi:10.1186/1471-2105-6-102", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1471-2105/6/102", "Received:", "16", "December", "2004", "Accepted:", "19", "April", "2005", "©", "2005", "Rosenberg;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "Evolutionary", "distances", "are", "a", "critical", "measure", "in", "comparative", "genomics", "and", "molecular", "evolutionary", "biology.", "A", "simulation", "study", "was", "used", "to", "examine", "the", "effect", "of", "alignment", "accuracy", "of", "DNA", "sequences", "on", "evolutionary", "distance", "estimation.", "Results:", "Under", "the", "studied", "conditions,", "distance", "estimation", "was", "relatively", "unaffected", "by", "alignment", "error", "(50%", "or", "more", "of", "the", "sites", "incorrectly", "aligned)", "as", "long", "as", "50%", "or", "more", "of", "the", "sites", "were", "identical", "among", "the", "sequences", "(observed", "P-distance", "<", "0.5).", "Beyond", "this", "threshold,", "the", "alignment", "procedure", "artificially", "inflates", "the", "apparent", "sequence", "identity,", "skewing", "distance", "estimates,", "and", "creating", "alignments", "that", "are", "essentially", "indistinguishable", "from", "random", "data.", "This", "general", "result", "was", "independent", "of", "substitution", "model,", "sequence", "length,", "and", "insertion", "and", "deletion", "size", "and", "rate.", "Conclusion:", "Examination", "of", "the", "estimated", "sequence", "identity", "may", "yield", "some", "guidance", "as", "to", "the", "accuracy", "of", "the", "alignment.", "Inaccurate", "alignments", "are", "expected", "to", "have", "large", "effects", "on", "analyses", "dependent", "on", "site", "specificity,", "but", "analyses", "that", "depend", "on", "evolutionary", "distance", "may", "be", "somewhat", "robust", "to", "alignment", "error", "as", "long", "as", "fewer", "than", "half", "of", "the", "sites", "have", "diverged.", "Background", "Evolutionary", "distance,", "the", "number", "of", "substitutions", "per", "site", "separating", "a", "pair", "of", "homologous", "sequences", "since", "they", "diverged", "from", "their", "common", "ancestral", "sequence,", "is", "an", "extremely", "important", "measure", "in", "molecular", "evolution", "and", "comparative", "genomics.", "It", "is", "used", "for", "a", "wide", "variety", "of", "pur-", "poses,", "ranging", "from", "phylogenetic", "analysis", "[1,2],", "to", "esti-", "mating", "times", "of", "divergence", "[3,4],", "the", "tempo", "and", "mode", "of", "evolutionary", "change", "[5],", "and", "functional", "constraints", "[6,7].", "Evolutionary", "distance", "estimation", "is", "often", "one", "of", "the", "first", "steps", "in", "high-throughput", "sequence", "analysis;", "errors", "in", "these", "estimates", "may", "have", "wide-ranging", "consequences", "on", "downstream", "analyses", "and", "conclusions.", "There", "are", "many", "ways", "to", "estimate", "evolutionary", "distance;", "accuracy", "of", "various", "methods", "tends", "to", "be", "dependent", "on", "proper", "specification", "of", "the", "substitution", "model", "and", "sequence", "length", "[8,9].", "One", "factor", "that", "has", "not", "been", "well", "examined", "with", "respect", "to", "evolutionary", "distance", "estima-", "tion,", "however,", "is", "alignment", "(although", "see", "[10-12]).", "Sequence", "alignment", "is", "an", "extremely", "common", "analytical", "tool", "used", "in", "comparative", "genomics.", "The", "purpose", "of", "align-", "ment", "is", "to", "identify", "positions", "in", "homologous", "sequences", "that", "are", "descended", "from", "a", "common", "ancestor.", "Because", "alignment", "is", "the", "first", "step", "in", "many", "complex,", "high-", "throughput", "studies", "[13],", "it", "is", "often", "forgotten", "that", "align-", "ment", "algorithms", "produce", "a", "hypothesis", "of", "homology", "(just", "as", "a", "phylogenetic", "tree", "is", "a", "hypothesis", "of", "evolutionary", "Page", "1", "of", "9", "(page", "number", "not", "for", "citation", "purposes)" ]

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[ "Hamzaoui", "et", "al.", "International", "Archives", "of", "Medicine", "2011,", "4:9", "http://www.intarchmed.com/content/4/1/9", "C", "A", "S", "E", "R", "E", "P", "O", "R", "T", "Open", "Access", "Co-existing", "sarcoidosis", "and", "Takayasu", "arteritis:", "report", "of", "a", "case", "Amira", "Hamzaoui1*,", "Randa", "Salem2,", "Rim", "Klii1,", "Olfa", "Harzallah1,", "Olfa", "Berriche1,", "Mondher", "Golli2,", "Silvia", "Mahjoub1", "Abstract", "Introduction:", "Takayasu", "arteritis", "(TA)", "is", "a", "chronic", "vasculitis", "of", "unknown", "origin,", "affecting", "mainly", "the", "aorta", "and", "its", "main", "branches.", "As", "a", "result", "of", "the", "inflammation,", "stenosis,", "occlusion", "or", "dilatation", "of", "the", "involved", "vessels", "may", "occur", "and", "cause", "a", "wide", "range", "of", "symptoms.", "It", "has", "been", "described", "in", "association", "with", "various", "auto-immune", "disorders", "(mainly", "inflammatory", "digestive", "tract", "diseases).", "However,", "only", "few", "cases", "of", "TA", "associated", "with", "sarcoidosis", "have", "been", "reported,", "raising", "the", "question", "of", "an", "association", "by", "chance.", "Case", "report:", "We", "report", "a", "case", "of", "a", "34", "year-old", "woman,", "with", "one", "year", "history", "of", "sarcoidosis,", "who", "presented", "with", "asymmetric", "high", "hypertension", "revealing", "inflammatory", "humeral,", "axillary", "and", "subclavian", "arteritis", "related", "to", "TA,", "successfully", "treated", "by", "steroid", "and", "immunosuppressive", "therapy(MethotrexateR).", "Conclusion:", "TA", "and", "sarcoidosis", "may", "be", "related,", "rising", "the", "hypothesis", "that", "TA", "or", "Takayasu", "arteritis-like", "granulomatous", "vasculitis", "may", "be,", "in", "fact,", "a", "complication", "of", "sarcoidosis.", "Introduction", "Takayasu", "arteritis", "(TA)", "is", "a", "chronic", "inflammatory", "dis-", "ease", "of", "large", "arteries", "which", "progressively", "develop", "steno-", "sis,", "occlusion", "or", "aneurismal", "degeneration.", "The", "clinical", "presentation", "is", "characterised", "by", "an", "acute", "phase", "with", "constitutional", "symptoms,", "followed,", "months", "or", "years", "later,", "by", "a", "chronic", "phase", "in", "which", "symptoms", "relate", "to", "fibrosis", "or", "occlusion", "of", "vessels.", "Angiography", "is", "the", "gold", "standard", "for", "diagnosis", "and", "for", "topographical", "classifica-", "tion", "and", "it", "correlates", "with", "symptoms", "and", "prognosis.", "Proinflammatory", "cytokines", "and,", "among", "these,", "tumor", "necrosis", "factor-alpha", "(TNF-alpha)", "are", "increased", "and", "play", "a", "pathogenetic", "role", "in", "the", "development", "of", "disease.", "Laboratory", "findings", "are", "non-specific.", "Treatment", "of", "active", "disease", "is", "primarily", "based", "on", "corticosteroids", "but", "other", "immunosuppressive", "drugs", "are", "frequently", "needed.", "Anti-platelets", "agents,", "statins", "and", "antihypertensive", "drugs", "are", "frequently", "considered", "[1].", "Sarcoidosis,", "too,", "is", "a", "systemic", "inflammatory", "disease", "which", "can", "affect", "virtually", "any", "organ", "system.", "The", "lungs", "are", "most", "commonly", "affected,", "but", "often", "there", "is", "also", "affection", "of", "the", "musculoskeletal", "system,", "the", "cutaneous", "*", "Correspondence:", "hamzaoui.amira@yahoo.fr", "1Department", "of", "Internal", "Medicine-", "Fattouma", "Bourguiba", "Hospital-", "Monastir-", "Tunisia", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "and", "central", "nervous", "systems,", "and", "the", "heart.", "Histology", "shows", "granulomas", "consisting", "of", "a", "central", "zone", "with", "macrophages,", "epithelioid", "cells,", "and", "multinucleated", "giant", "cells", "in", "addition", "to", "activated", "CD4", "lymphocytes,", "and", "a", "peripheral", "zone", "with", "macrophages,", "fibroblasts,", "and", "CD4", "and", "CD8", "lymphocytes.", "Inclusion", "bodies", "are", "commonly", "found.", "Vasculitis", "may", "be", "found", "occasionally", "in", "patients", "with", "sarcoidosis.", "It", "has", "not", "been", "confirmed,", "however,", "whether", "vasculitis", "is", "a", "true", "manifestation", "of", "the", "disease", "or", "an", "occasional,", "incidentally", "concurring", "abnormality.", "Concurrence", "of", "sarcoidosis", "and", "TA", "were", "reported", "in", "few", "cases.", "Case", "Report", "A", "34", "year", "old", "woman", "was", "admitted", "to", "the", "hospital", "with", "dyspnea,", "submandubular", "gland", "tumefaction", "and", "parotid", "swelling.", "On", "physical", "examination,", "we", "found", "the", "tumefaction", "of", "the", "parotid", "and", "the", "submandibular", "gland.", "The", "respira-", "tory", "frequency", "was", "24", "cycles", "per", "minute.", "The", "rest", "of", "the", "clinical", "examination", "was", "without", "abnormalities.", "Laboratory", "results", "were", "as", "follows:", "Haemoglobin", "10", "g/dl,", "white", "blood", "cell", "count", "(WBC)", "11", "200/mm3,", "platelets", "450", "000/mm3,", "erythrocyte", "sedimentation", "rate", "(ESR)", "76", "mm/h,", "calcium", "12", "mg/dl", "(normal:", "9-11", "mg/dl", ").", "Muscle", "©", "2011", "Hamzaoui", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

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2,789,965

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[ "접수번호:", "2009-045", "Korean", "Journal", "of", "Ophthalm", "ology", "2009;23:329-331", "ISSN", ":", "1011-8942", "DOI", ":", "10.3341/kjo.2009.23.4.329", "A", "Case", "of", "Pseudo-Duane’s", "Retraction", "Syndrome", "With", "Old", "Medial", "Orbital", "Wall", "Fracture", "Seung", "Hee", "Lee,", "MD,", "Jae", "Hyung", "Lee,", "MD,", "Soo", "Yoon", "Lee,", "MD,", "Sook", "Young", "Kim,", "MD", "Department", "of", "Ophthalmology,", "Daegu", "Catholic", "University", "College", "of", "Medicine,", "Daegu,", "Korea", "We", "report", "a", "case", "of", "pseudo-Duane’s", "retraction", "syndrome", "with", "entrapment", "of", "the", "medial", "rectus", "muscle", "in", "an", "old", "medial", "orbital", "wall", "fracture", "presenting", "identical", "clinical", "symptoms", "as", "Duane’s", "retraction", "syndrome.", "A15-year-old", "boy", "presented", "with", "persistent", "limited", "right", "eye", "movement", "since", "a", "young", "age.", "Examination", "showed", "marked", "limited", "abduction,", "mildly", "limited", "adduction,", "and", "globe", "retraction", "accompanied", "by", "narrowing", "of", "the", "palpebral", "fissure", "during", "attempted", "adduction", "in", "the", "right", "eye.", "He", "showed", "a", "right", "esotropia", "of", "16", "prism", "diopters", "and", "his", "head", "turned", "slightly", "to", "the", "right.", "A", "slight", "enophthalmos", "was", "noted", "in", "his", "right", "eye.", "A", "computed", "tomography", "scan", "demonstrated", "entrapment", "of", "the", "medial", "rectus", "muscle", "and", "surrounding", "tissues", "in", "an", "old", "medial", "orbital", "wall", "fracture.", "A", "forced", "duction", "test", "revealed", "a", "marked", "restriction", "of", "abduction", "in", "the", "right", "eye.", "A", "5", "mm", "recession", "of", "the", "right", "medial", "rectus", "muscle", "was", "performed.", "Post-", "operatively,", "the", "patient’s", "head", "turn", "and", "esotropia", "in", "the", "primary", "position", "were", "successfully", "corrected,", "but", "there", "was", "still", "some", "limitations", "to", "his", "ocular", "movement.", "The", "importance", "of", "several", "tests", "such", "as", "the", "forced", "duction", "test", "and", "an", "imaging", "study", "should", "be", "emphasized", "in", "making", "a", "diagnosis", "for", "limitation", "of", "eye", "movement.", "Korean", "J", "Ophthalmol", "2009;23:329-331", "ⓒ", "2009", "by", "the", "Korean", "Ophthalmological", "Society.", "Key", "Words:", "Duane’s", "retraction", "syndrome,", "Medial", "orbital", "wall", "fracture,", "Pseudo-Duane’s", "retraction", "syndrome", "Since", "Alexander", "Duane", "published", "a", "paper", "in", "1905", "des-", "cribing", "what", "has", "come", "to", "be", "known", "as", "Duane’s", "retraction", "syndrome,", "Thomas", "Duane", "reported", "a", "similar,", "yet", "different", "set", "of", "symptoms", "and", "signs", "as", "‘pseudo-Duane’s", "retraction", "syndrome’", "in", "1976.1", "In", "the", "most", "common", "type", "of", "Duane’s", "retraction", "syndrome,", "there", "is", "markedly", "restricted", "abduction", "with", "eyeball", "retraction", "and", "narrowing", "of", "the", "palpebral", "fissure", "on", "adduction.2", "In", "pseudo-Duane’s", "retraction", "syndrome,", "how-", "ever,", "abduction", "of", "the", "affected", "eye", "is", "possible", "to", "some", "extent,", "and", "the", "globe", "retraction", "occurs", "on", "abduction", "accompanied", "by", "narrowing", "of", "the", "palpebral", "fissure", "presenting", "the", "opposite", "features", "as", "those", "of", "classic", "Duane’s", "retraction", "syndrome.", "The", "etiology", "is", "also", "completely", "different", "from", "those", "of", "Duane’s", "retraction", "syndrome.", "Pseudo-Duane’s", "retraction", "syndrome", "has", "been", "reported", "as", "being", "caused", "by", "acquired", "or", "congenital", "factors", "that", "affect", "the", "medial", "rectus", "muscle.", "Entrapment", "of", "the", "medial", "rectus", "muscle", "in", "a", "medial", "orbital", "wall", "fracture", "has", "been", "known", "to", "be", "the", "most", "common", "cause.3", "We", "report", "a", "case", "of", "pseudo-Duane’s", "retraction", "syndrome", "with", "entrapment", "of", "the", "medial", "rectus", "muscle", "in", "an", "old", "medial", "orbital", "wall", "fracture,", "presenting", "very", "similar", "clinical", "features", "as", "those", "of", "classic", "Duane’s", "retraction", "syndrome.", "The", "pre-", "Received:", "April", "22,", "2009", "Accepted:", "October", "29,", "2009", "Reprint", "requests", "to", "Sook", "Young", "Kim,", "MD.", "Department", "of", "Ophthalmology,", "Daegu", "Catholic", "University", "College", "of", "Medicine,", "#3056-6", "Daemyeong", "4-dong,", "Nam-gu,", "Daegu", "705-718,", "Korea.", "Tel:", "82-53-650-4728,", "E-mail:", "kimsy@cu.ac.kr", "sentation", "is", "contradictory", "to", "previous", "reports", "of", "pseudo-", "Duane’s", "retraction", "syndrome.", "Case", "Repo", "rt", "A", "15-year-old", "boy", "had", "complained", "of", "motility", "limitation", "in", "the", "right", "eye", "since", "a", "young", "age.", "His", "visual", "acuity", "was", "20/20", "in", "each", "eye,", "although", "an", "ocular", "motility", "examination", "revealed", "markedly", "limited", "abduction", "and", "mildly", "limited", "adduction", "in", "his", "right", "eye", "(Fig.", "1).", "On", "attempted", "adduction", "of", "the", "right", "eye,", "globe", "retraction", "(Fig.", "2)", "with", "narrowing", "of", "the", "palpebral", "fissure", "was", "observed,", "and", "there", "mild", "upshoot", "and", "downshoot", "were", "also", "observed", "(Fig.", "1).", "The", "palpebral", "fissure", "of", "the", "right", "eye", "was", "slightly", "widened", "on", "attempted", "abduction.", "An", "alternate", "prism", "cover", "test", "revealed", "a", "16", "prism", "diopters", "(PD)", "right", "esotropia", "(ET)", "in", "the", "primary", "position,", "25", "PD", "ET", "in", "right", "gaze,", "10", "PD", "ET", "in", "left", "gaze", "at", "dist-", "ance", "fixation,", "and", "4", "PD", "ET", "at", "near", "fixation.", "He", "assumed", "a", "compensatory", "face", "turn", "to", "the", "right", "and", "did", "not", "comp-", "lain", "of", "diplopia.", "No", "living", "member", "on", "either", "the", "paternal", "or", "maternal", "side", "had", "a", "squint.", "Duane’s", "retraction", "syndrome", "was", "inferred", "as", "the", "diagnosis", "until", "we", "noted", "that", "the", "patient’s", "right", "eye", "had", "slight", "enophthalmos.", "Hertel’s", "exophthalmo-", "metry", "revealed", "a", "1.5", "mm", "difference", "between", "both", "eyes", "and", "the", "margin", "reflex", "distance", "1", "was", "0.5", "mm", "in", "the", "right", "eye.", "Computed", "tomography", "of", "the", "orbits", "was", "performed", "and", "demonstrated", "an", "old", "medial", "orbital", "wall", "fracture", "with", "entrapment", "of", "the", "medial", "rectus", "muscle", "and", "surrounding", "tissues", "(Fig.", "3).", "However,", "there", "was", "no", "history", "of", "trauma", "329" ]

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2,731,100

null

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[ "BMC", "Public", "Health", "Research", "article", "Rubella", "seroprevalence", "among", "primary", "and", "pre-", "primary", "school", "pupils", "at", "Moi's", "Bridge", "location,", "Uasin", "Gishu", "District,", "Kenya", "Janeth", "J", "Kombich*,", "Paul", "C", "Muchai,", "Peter", "Tukei", "and", "Peter", "K", "Borus", "BioMed", "Central", "Open", "Access", "Address:", "Centre", "for", "Virus", "Research,", "Kenya", "Medical", "Research", "Institute,", "Nairobi,", "Kenya", "Email:", "Janeth", "J", "Kombich*", "-", "jkombich@kemri.org;", "Paul", "C", "Muchai", "-", "pmuchai@kemri.org;", "Peter", "Tukei", "-", "ptukei@kemri.org;", "Peter", "K", "Borus", "-", "pborus@kemri.org", "*", "Corresponding", "author", "Published:", "29", "July", "2009", "BMC", "Public", "Health", "2009,", "9:269", "doi:10.1186/1471-2458-9-269", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1471-2458/9/269", "Received:", "19", "August", "2008", "Accepted:", "29", "July", "2009", "©", "2009", "Kombich", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "Rubella", "is", "an", "infectious", "and", "generally", "mild", "childhood", "viral", "disease.", "The", "disease", "is", "of", "public", "health", "importance", "because", "infection", "acquired", "during", "early", "pregnancy", "often", "results", "in", "foetal", "abnormalities", "that", "are", "classified", "as", "congenital", "rubella", "syndrome", "(CRS).", "The", "burden", "of", "rubella", "infection", "in", "most", "developing", "countries", "in", "not", "well", "documented", "because", "of", "limited", "epidemiological", "data.", "However,", "availability", "of", "an", "effective", "vaccine", "has", "made", "it", "necessary", "to", "have", "all", "the", "countries", "with", "no", "routine", "vaccination", "schedule", "to", "evaluate", "the", "burden", "of", "disease", "in", "order", "to", "make", "informed", "decisions", "on", "rubella", "vaccination", "and", "strategy.", "To", "address", "this", "gap", "we", "conducted", "a", "study", "to", "determine", "age-specific", "rubella", "seroprevalence", "rates", "and", "related", "risk", "factors", "among", "primary", "and", "pre-primary", "school", "children", "in", "Uasin", "Gishu", "district,", "Moi's", "Bridge", "location", "of", "Kenya.", "Methods:", "Subjects", "of", "the", "study", "were", "498", "pupils", "from", "seven", "primary", "schools", "aged", "4–20", "years.", "Questionnaire", "surveys", "with", "blood", "sampling", "were", "conducted", "between", "January", "to", "July", "2005.", "Samples", "were", "tested", "for", "rubella", "specific", "IgG", "antibody", "using", "ELISA", "test", "kit", "(Enzygnost®", "Behring,", "Germany).", "Results:", "Overall,", "rubella", "seropositivity", "rate", "was", "80%", "and", "it", "increased", "with", "age", "from", "59%", "(among", "ages", "4–6", "years)", "to", "94%", "(ages", "14–20", "years).", "Multivariate", "logistic", "regression", "analysis", "model,", "showed", "that", "age", "of", "child", "and", "ownership", "of", "a", "television", "set", "which", "is", "a", "proxy", "measure", "of", "socio-economic", "status", "of", "family", "were", "significantly", "associated", "with", "rubella", "seropositivity.", "The", "odds", "of", "rubella", "seropositivity", "in", "a", "child", "older", "than", "13", "years", "was", "more", "than", "that", "in", "children", "younger", "than", "7", "years", "(OR", "=", "3.8", "95%", "CI", "2.56–5.78).", "The", "odds", "of", "rubella", "seropositivity", "in", "a", "child", "whose", "family", "did", "not", "own", "a", "television", "set", "was", "3", "times", "higher", "than", "that", "of", "child", "whose", "family", "owned", "a", "set", "(OR", "3.06,", "95%", "CI", "1.17–7.97).", "Conclusion:", "The", "study", "provides", "important", "and", "highly", "useful", "information", "on", "rubella", "age", "specific", "seroprevalence", "rates", "in", "Kenya.", "Advancing", "age", "was", "found", "to", "be", "associated", "with", "increased", "risk", "of", "rubella.", "Low", "socio-economic", "factors", "suggest", "an", "increased", "risk", "of", "infection", "in", "certain", "categories", "of", "society,", "and", "control", "measures", "need", "to", "target", "this.", "Overall,", "the", "findings", "can", "also", "be", "used", "by", "policy", "makers", "to", "model", "introduction", "of", "routine", "rubella", "vaccination", "in", "the", "country", "and", "also", "other", "developing", "countries", "facing", "similar", "challenges.", "More", "than", "half", "of", "the", "children", "got", "infected", "in", "pre-", "primary", "and", "efforts", "to", "control", "rubella", "should", "target", "pre-school", "children.", "These", "data", "provides", "pre-", "vaccination", "information", "that", "can", "be", "used", "to", "guide", "immunization", "strategy", "as", "well", "as", "to", "determine", "success", "of", "an", "immunization", "programme.", "Page", "1", "of", "5", "(page", "number", "not", "for", "citation", "purposes)" ]

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[ "Hindawi", "Publishing", "Corporation", "Journal", "of", "Biomedicine", "and", "Biotechnology", "Volume", "2010,", "Article", "ID", "130265,", "6", "pages", "doi:10.1155/2010/130265", "Research", "Article", "Monocyte", "Chemoattractant", "Protein-1", "−2518", "A/G", "Single", "Nucleotide", "Polymorphism", "Might", "Be", "Associated", "with", "Renal", "Disease", "and", "Thrombocytopenia", "of", "SLE", "Piotr", "Piotrowski,1,", "2", "Margarita", "Lianeri,1", "Robert", "Gasik,1,", "3", "Andrzej", "Roszak,1,", "4", "Marzena", "Olesi", "n´ska,3", "and", "Paweł", "P.", "Jagodzi", "n´ski1", "1", "Department", "of", "Biochemistry", "and", "Molecular", "Biology,", "Poznan´", "University", "of", "Medical", "Sciences,", "6", "S´wi¸ecickiego", "St.,", "60-781", "Poznan´,", "Poland", "2", "Medical", "Research", "Centre,", "Polish", "Academy", "of", "Sciences,", "Warsaw,", "Poland", "3", "Institute", "of", "Rheumatology,", "Warsaw,", "Poland", "4", "Department", "of", "Radiotherapy", "and", "Gynecological", "Oncology,", "Greater", "Poland", "Cancer", "Centre,", "15", "Garbary", "St.,", "61-866", "Poznan,", "Poland", "Correspondence", "should", "be", "addressed", "to", "Paweł", "P.", "Jagodzi", "n´ski,", "pjagodzi@am.poznan.pl", "Received", "30", "November", "2009;", "Revised", "13", "February", "2010;", "Accepted", "14", "March", "2010", "Academic", "Editor:", "Timothy", "B.", "Niewold", "Copyright", "©", "2010", "Piotr", "Piotrowski", "et", "al.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "There", "is", "conﬂicting", "evidence", "on", "the", "contribution", "of", "the", "MCP-1", "−2518", "A>G", "(rs", "1024611)", "polymorphism", "to", "SLE", "incidence", "and", "clinical", "manifestations.", "We", "examined", "the", "prevalence", "of", "the", "MCP-1", "−2518", "A>G", "polymorphism", "in", "SLE", "patients", "(n", "=", "199)", "and", "controls", "(n", "=", "250)", "in", "Poland.", "We", "did", "not", "observe", "a", "signiﬁcant", "diﬀerence", "in", "the", "distribution", "of", "MCP-1", "−2518", "A>G", "polymorphic", "variants", "in", "patients", "with", "SLE", "and", "healthy", "individuals.", "However,", "we", "found", "an", "association", "between", "the", "GG", "versus", "AG", "and", "AA", "genotypes", "as", "well", "as", "the", "AG", "and", "GG", "versus", "AA", "genotypes", "with", "renal", "manifestations", "of", "SLE", "OR", "=", "3.614", "(1.123–11.631,", "P", "=", "0.0345)", "and", "OR", "=", "2.297", "(1.301–4.057,", "P", "=", "0.0046),", "respectively.", "We", "also", "observed", "that", "the", "MCP-1", "AG", "and", "GG", "-genotypes", "contribute", "to", "the", "occurrence", "of", "thrombocytopenia", "in", "SLE", "patients", "OR", "=", "2.618", "(1.280–5.352,", "P", "=", "0.0089).", "Our", "observations", "indicate", "that", "either", "MCP-1", "−2518", "G", "variant", "can", "be", "associated", "with", "some", "clinical", "ﬁndings", "in", "patients", "with", "SLE.", "1.", "Introduction", "Systemic", "lupus", "erythematosus", "(SLE)", "is", "a", "chronic", "and", "pro-", "gressive", "multisystem", "autoimmune", "connective", "tissue", "disorder,", "which", "is", "characterized", "by", "immune-mediated", "host", "tissue", "destruction", "[1].", "Occupational", "exposure,", "chemicals,", "drugs,", "food,", "as", "well", "as", "viral", "and", "bacterial", "infectious", "agents", "can", "contribute", "signiﬁcantly", "to", "changes", "in", "the", "immune", "system", "[2,", "3].", "Immune", "cells", "from", "patients", "with", "SLE", "exhibit", "various", "defects", "including", "skewed", "cytokine", "production,", "a", "decrease", "in", "cytotoxic", "T", "cell", "function,", "and", "an", "increase", "in", "the", "humoral", "response", "[4–7].", "The", "defective", "function", "of", "CD4+", "T", "cells", "asso-", "ciated", "with", "abnormal", "stimulation", "of", "B", "cells", "causes", "abundant", "autoantibody", "production", "[4,", "6].", "These", "autoantibodies", "form", "immune", "complexes", "with", "antigens", "on", "the", "patient’s", "own", "cells", "and", "are", "accumulated", "in", "the", "skin,", "synovium,", "lungs,", "renal", "glomeruli,", "and", "other", "organs", "and", "tissues.", "This", "results", "in", "the", "clinical", "presentation", "of", "SLE", "[1,", "8].", "The", "pathogenesis", "of", "SLE", "remains", "unclear,", "though", "there", "is", "much", "evidence", "demonstrating", "the", "involvement", "of", "genetic", "factors", "in", "the", "incidence", "of", "this", "autoimmune", "disease", "[9–13].", "The", "genetic", "background", "contributing", "to", "SLE", "development", "includes,", "in", "particular,", "genes", "encoding", "disparate", "proteins", "that", "control", "immune", "system", "pathways", "[9,", "10,", "13].", "The", "monocyte", "chemoattractant", "protein", "1", "(MCP-1),", "cur-", "rently", "also", "designated", "CCL2,", "belongs", "to", "the", "family", "of", "chemo-", "tactic", "cytokines.", "MCP-1", "functions", "as", "a", "potent", "agonist", "for", "monocytes,", "memory", "T", "cells,", "and", "basophils", "[14].", "Evidence", "in", "animal", "and", "human", "studies", "suggests", "a", "signiﬁcant", "role", "of", "MCP-", "1", "in", "the", "progression", "of", "glomerular", "and", "tubulointerstitial", "injuries", "and", "glomerulonephriti", "in", "patients", "with", "SLE", "[15–19].", "It", "has", "been", "demonstrated", "that", "the", "MCP-1", "–2518", "A>G", "(rs", "1024611)", "transition", "in", "the", "promoter", "region", "may", "modulate" ]

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3,104,169

null

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[ "pISSN", "1229-845X,", "eISSN", "1976-555X", "J.", "Vet.", "Sci.", "(2011),", "12(2),", "151-157", "DOI:", "10.4142/jvs.2011.12.2.151", "Received:", "07", "Apr.", "2010,", "Accepted:", "26", "Jul.", "2010", "Original", "Article", "J", "O", "U", "R", "N", "A", "L", "O", "F", "Veterinary", "Science", "The", "stress", "of", "weaning", "influences", "serum", "levels", "of", "acute-phase", "proteins,", "iron-binding", "proteins,", "inflammatory", "cytokines,", "cortisol,", "and", "leukocyte", "subsets", "in", "Holstein", "calves", "Myung-Hoo", "Kim1,†,", "Ji-Young", "Yang1,†,", "Santi", "Devi", "Upadhaya1,", "Hyun-Jun", "Lee2,", "Cheol-Heui", "Yun1,", "Jong", "K.", "Ha1,*", "1Department", "of", "Agricultural", "Biotechnology", "and", "Research", "Institute", "for", "Agriculture", "and", "Life", "Sciences,", "College", "of", "Agriculture", "and", "Life", "Sciences,", "Seoul", "National", "University,", "Seoul", "151-742,", "Korea", "2Dairy", "Science", "Division,", "National", "Institute", "of", "Animal", "Science,", "Cheonan", "330-801,", "Korea", "The", "purpose", "of", "our", "study", "was", "to", "investigate", "changes", "in", "immunological", "parameters", "induced", "by", "weaning", "stress", "(including", "milk", "restriction)", "in", "calves.", "Fifteen", "Holstein", "calves", "were", "subjected", "to", "weaning", "at", "6", "weeks", "of", "age.", "Blood", "samples", "were", "collected", "at", "−14,", "−7,", "−2,", "1,", "3,", "and", "5", "days", "post-weaning", "(DPW;", "0", "DPW", "=", "42", "days).", "Weaning", "caused", "significant", "(p", "＜", "0.01)", "increases", "in", "the", "neutrophil", "(NE):lymphocyte", "(LY)", "ratio", "at", "5", "DPW", "with", "a", "significant", "(p", "＜", "0.05)", "reduction", "of", "LYs.", "The", "concentration", "of", "acute-phase", "proteins", "(haptoglobin", "and", "serum", "amyloid", "A)", "also", "increased", "significantly", "(p", "＜", "0.05)", "at", "3", "and", "5", "DPW", "compared", "to", "−2", "DPW.", "Levels", "of", "the", "iron-binding", "protein", "lactoferrin", "decreased", "significantly", "(p", "＜", "0.05)", "after", "weaning.", "Serum", "tumor", "necrosis", "factor-α", "and", "cortisol", "levels", "were", "elevated", "(p", "＜", "0.05)", "at", "3", "DPW,", "while", "those", "of", "serum", "interferon-γ", "decreased", "(p", "＜", "0.05)", "at", "1", "and", "3", "DPW", "compared", "to", "levels", "observed", "before", "weaning.", "Weaning", "significantly", "(p", "＜", "0.05)", "decreased", "the", "percentage", "of", "CD25+", "T", "cells", "in", "the", "peripheral", "blood.", "In", "conclusion,", "weaning", "stress", "affected", "the", "NE:LY", "ratio", "along", "with", "the", "levels", "of", "acute", "phase", "proteins,", "lactoferrin,", "cortisol,", "and", "inflammatory", "cytokines", "in", "the", "peripheral", "blood", "of", "calves.", "Weaning", "stress", "may", "induce", "an", "acute", "phase", "response", "possibly", "through", "the", "elevation", "of", "cortisol", "production", "and", "modulation", "of", "inflammatory", "cytokines.", "Keywords:", "acute", "phase", "protein,", "immune", "inflammatory", "cytokines,", "stress,", "weaning", "response,", "Introduction", "Stress", "can", "be", "defined", "as", "the", "biological", "response", "elicited", "*Corresponding", "author", "Tel:", "+82-2-880-4809;", "Fax:", "+82-2-785-8710", "E-mail:", "jongha@snu.ac.kr", "†The", "first", "two", "authors", "contributed", "equally", "to", "this", "work.", "when", "a", "threat", "to", "homeostasis", "is", "perceived.", "The", "effects", "of", "several", "types", "of", "stressors,", "such", "as", "transportation,", "heat,", "and", "weaning,", "have", "been", "studied", "in", "various", "animals", "[2,10,", "11,30].", "Stress", "is", "an", "important", "factor", "in", "the", "animal", "industry", "because", "it", "has", "been", "directly", "linked", "to", "growth,", "reproduction,", "meat", "quality,", "animal", "welfare,", "and", "disease", "susceptibility", "[27,28,37],", "thereby", "giving", "it", "the", "potential", "for", "making", "a", "substantial", "economic", "impact", "[8].", "Weaning", "and", "transportation", "are", "regarded", "as", "the", "top", "stressors", "that", "calves", "may", "experience", "[14,27].", "Although", "the", "effects", "of", "all", "stages", "of", "transportation", "on", "cattle", "are", "well-documented", "in", "the", "literature,", "there", "has", "been", "limited", "research", "on", "the", "effects", "of", "weaning", "alone", "or", "weaning", "and", "grouping", "on", "calves.", "The", "majority", "of", "reports", "focus", "on", "weaning", "and", "transportation", "together", "since", "both", "of", "these", "stressors", "often", "occur", "at", "the", "same", "time", "in", "agriculture", "[11].", "Previous", "studies", "have", "found", "that", "weaning", "stress", "alters", "the", "concentration", "of", "plasma", "acute", "phase", "protein", "(APP)", "[24]", "and", "the", "neutrophil", "(NE):", "lymphocyte", "(LY)", "ratio,", "and", "increases", "norepinephrine", "and", "cortisol", "levels", "[6,8,12].", "Lactoferrin", "(Lf)", "and", "transferrin", "(Tf),", "two", "iron-binding", "proteins,", "play", "many", "physiological", "roles", "including", "regulation", "of", "iron", "metabolism,", "protection", "against", "microbial", "infection,", "and", "regulation", "of", "immune", "functions", "[33].", "The", "acute", "phase", "response", "is", "considered", "to", "be", "an", "exclusive", "biomarker", "of", "inflammation", "and/or", "infection", "[20].", "Accordingly,", "the", "concentration", "of", "APPs", "is", "a", "useful", "indicator", "of", "stress", "response", "in", "calves.", "The", "elevation", "of", "APPs", "by", "transportation", "and", "weaning", "stress", "has", "already", "been", "reported", "[2,21,25].", "Triggered", "by", "inflammatory", "signals", "(predominantly", "cytokines),", "the", "circulating", "concentrations", "of", "APPs", "are", "elevated", "in", "a", "nonspecific", "manner", "in", "animals", "[32].", "In", "particular,", "inflammatory", "cytokines", "including", "interleukin", "(IL)-1,", "IL-6,", "tumor", "necrosis", "factor-α", "(TNF-α),", "and", "interferon-γ", "(IFN-γ)", "are", "considered", "to", "be", "the", "mediators", "of", "immunological", "and", "pathological", "responses", "to", "stress", "and", "infection", "[15,35].", "The", "goal", "of", "this", "study", "was", "to", "elucidate", "the", "interaction" ]

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[ "Human", "Resources", "for", "Health", "Research", "Mid-level", "providers", "in", "emergency", "obstetric", "and", "newborn", "health", "care:", "factors", "affecting", "their", "performance", "and", "retention", "within", "the", "Malawian", "health", "system", "Susan", "Bradley*", "and", "Eilish", "McAuliffe", "Address:", "Centre", "for", "Global", "Health,", "Trinity", "College", "Dublin,", "3-4", "Foster", "Place,", "Dublin", "2,", "Ireland", "Email:", "Susan", "Bradley*", "-", "susan.bradley@tcd.ie;", "Eilish", "McAuliffe", "-", "eilish.mcauliffe@tcd.ie", "*", "Corresponding", "author", "BioMed", "Central", "Open", "Access", "Published:", "19", "February", "2009", "Human", "Resources", "for", "Health", "2009,", "7:14", "doi:10.1186/1478-4491-7-14", "This", "article", "is", "available", "from:", "http://www.human-resources-health.com/content/7/1/14", "Received:", "5", "May", "2008", "Accepted:", "19", "February", "2009", "©", "2009", "Bradley", "and", "McAuliffe;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "Malawi", "has", "a", "chronic", "shortage", "of", "human", "resources", "for", "health.", "This", "has", "a", "significant", "impact", "on", "maternal", "health,", "with", "mortality", "rates", "amongst", "the", "highest", "in", "the", "world.", "Mid-level", "cadres", "of", "health", "workers", "provide", "the", "bulk", "of", "emergency", "obstetric", "and", "neonatal", "care.", "In", "this", "context", "these", "cadres", "are", "defined", "as", "those", "who", "undertake", "roles", "and", "tasks", "that", "are", "more", "usually", "the", "province", "of", "internationally", "recognised", "cadres,", "such", "as", "doctors", "and", "nurses.", "While", "there", "have", "been", "several", "studies", "addressing", "retention", "factors", "for", "doctors", "and", "registered", "nurses,", "data", "and", "studies", "addressing", "the", "perceptions", "of", "these", "mid-level", "cadres", "on", "the", "factors", "that", "influence", "their", "performance", "and", "retention", "within", "health", "care", "systems", "are", "scarce.", "Methods:", "This", "exploratory", "qualitative", "study", "took", "place", "in", "four", "rural", "mission", "hospitals", "in", "Malawi.", "The", "study", "population", "was", "mid-level", "providers", "of", "emergency", "obstetric", "and", "neonatal", "care.", "Focus", "group", "discussions", "took", "place", "with", "nursing", "and", "medical", "cadres.", "Semi-structured", "interviews", "with", "key", "human", "resources,", "training", "and", "administrative", "personnel", "were", "used", "to", "provide", "context", "and", "background.", "Data", "were", "analysed", "using", "a", "framework", "analysis.", "Results:", "Participants", "confirmed", "the", "difficulties", "of", "their", "working", "conditions", "and", "the", "clear", "commitment", "they", "have", "to", "serving", "the", "rural", "Malawian", "population.", "Although", "insufficient", "financial", "remuneration", "had", "a", "negative", "impact", "on", "retention", "and", "performance,", "the", "main", "factors", "identified", "were", "limited", "opportunities", "for", "career", "development", "and", "further", "education", "(particularly", "for", "clinical", "officers)", "and", "inadequate", "or", "non-existent", "human", "resources", "management", "systems.", "The", "lack", "of", "performance-related", "rewards", "and", "recognition", "were", "perceived", "to", "be", "particularly", "demotivating.", "Conclusion:", "Mid-level", "cadres", "are", "being", "used", "to", "stem", "Africa's", "brain", "drain.", "It", "is", "in", "the", "interests", "of", "both", "the", "government", "and", "mission", "organizations", "to", "protect", "their", "investment", "in", "these", "workers.", "For", "optimal", "performance", "and", "quality", "of", "care", "they", "need", "to", "be", "supported", "and", "properly", "motivated.", "A", "structured", "system", "of", "continuing", "professional", "development", "and", "functioning", "human", "resources", "management", "would", "show", "commitment", "to", "these", "cadres", "and", "support", "them", "as", "professionals.", "Action", "needs", "to", "be", "taken", "to", "prevent", "staff", "members", "from", "leaving", "the", "health", "sector", "for", "less", "stressful,", "more", "financially", "rewarding", "alternatives.", "Page", "1", "of", "8", "(page", "number", "not", "for", "citation", "purposes)" ]

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2,978,096

null

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[ "Amyloid-b", "Oligomer", "Specificity", "Mediated", "by", "the", "IgM", "Isotype", "–", "Implications", "for", "a", "Specific", "Protective", "Mechanism", "Exerted", "by", "Endogenous", "Auto-Antibodies", "Malin", "Lindhagen-Persson", "1", ",", "Kristoffer", "Bra¨", "nnstro¨", "m1,", "Monika", "Vestling", "1", ",", "Michael", "Steinitz2,", "Anders", "1", "Olofsson", "*", "1", "Department", "of", "Medical", "Biochemistry", "and", "Biophysics,", "Umea˚", "University,", "Umea˚,", "Sweden,", "2", "Department", "of", "Pathology,", "Hebrew", "University", "Hadassah", "Medical", "School,", "Jerusalem,", "Israel", "Abstract", "Background:", "Alzheimers", "disease", "(AD)", "has", "been", "strongly", "linked", "to", "an", "anomalous", "self-assembly", "of", "the", "amyloid-b", "peptide", "(Ab).", "The", "correlation", "between", "clinical", "symptoms", "of", "AD", "and", "Ab", "depositions", "is,", "however,", "weak.", "Instead", "small", "and", "soluble", "Ab", "oligomers", "are", "suggested", "to", "exert", "the", "major", "pathological", "effects.", "In", "strong", "support", "of", "this", "notion,", "immunological", "targeting", "of", "Ab", "oligomers", "in", "AD", "mice-models", "shows", "that", "memory", "impairments", "can", "be", "restored", "without", "affecting", "the", "total", "burden", "of", "Ab", "deposits.", "Consequently", "a", "specific", "immunological", "targeting", "of", "Ab", "oligomers", "is", "of", "high", "therapeutic", "interest.", "Methodology/Principal", "Findings:", "Previously", "the", "generation", "of", "conformational-dependent", "oligomer", "specific", "anti-Ab", "antibodies", "has", "been", "described.", "However,", "to", "avoid", "the", "difficult", "task", "of", "identifying", "a", "molecular", "architecture", "only", "present", "on", "oligomers,", "we", "have", "focused", "on", "a", "more", "general", "approach", "based", "on", "the", "hypothesis", "that", "all", "oligomers", "expose", "multiple", "identical", "epitopes", "and", "therefore", "would", "have", "an", "increased", "binding", "to", "a", "multivalent", "receptor.", "Using", "the", "polyvalent", "IgM", "immunoglobulin", "we", "have", "developed", "a", "monoclonal", "anti-Ab", "antibody", "(OMAB).", "OMAB", "only", "demonstrates", "a", "weak", "interaction", "with", "Ab", "monomers", "and", "dimers", "having", "fast", "on", "and", "off-rate", "kinetics.", "However,", "as", "an", "effect", "of", "avidity,", "its", "interaction", "with", "Ab-", "oligomers", "results", "in", "a", "strong", "complex", "with", "an", "exceptionally", "slow", "off-rate.", "Through", "this", "mechanism", "a", "selectivity", "towards", "Ab", "oligomers", "is", "acquired", "and", "OMAB", "fully", "inhibits", "the", "cytotoxic", "effect", "exerted", "by", "Ab(1-42)", "at", "highly", "substoichiometric", "ratios.", "Anti-Ab", "auto-antibodies", "of", "IgM", "isotype", "are", "frequently", "present", "in", "the", "sera", "of", "humans.", "Through", "a", "screen", "of", "endogenous", "anti-", "Ab", "IgM", "auto-antibodies", "from", "a", "group", "of", "healthy", "individuals", "we", "show", "that", "all", "displays", "a", "preference", "for", "oligomeric", "Ab.", "Conclusions/Significance:", "Taken", "together", "we", "provide", "a", "simple", "and", "general", "mechanism", "for", "targeting", "of", "oligomers", "without", "the", "requirement", "of", "conformational-dependent", "epitopes.", "In", "addition,", "our", "results", "suggest", "that", "IgM", "anti-Ab", "auto-antibodies", "may", "exert", "a", "more", "specific", "protective", "mechanism", "in", "vivo", "than", "previously", "anticipated.", "Citation:", "Lindhagen-Persson", "M,", "Bra¨nnstro¨", "m", "K,", "Vestling", "M,", "Steinitz", "M,", "Olofsson", "A", "(2010)", "Amyloid-b", "Oligomer", "Specificity", "Mediated", "by", "the", "IgM", "Isotype", "–", "Implications", "for", "a", "Specific", "Protective", "Mechanism", "Exerted", "by", "Endogenous", "Auto-Antibodies.", "PLoS", "ONE", "5(11):", "e13928.", "doi:10.1371/journal.pone.0013928", "Editor:", "Ashley", "I.", "Bush,", "Mental", "Health", "Research", "Institute", "of", "Victoria,", "Australia", "Received", "July", "5,", "2010;", "Accepted", "October", "18,", "2010;", "Published", "November", "10,", "2010", "Copyright:", "2010", "Lindhagen-Persson", "et", "al.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Funding:", "This", "work", "was", "supported", "by", "Ernst", "and", "Lili", "Rosenhain", "fund,", "Bruxelles,", "Belgium,", "J.", "C.", "Kempe,", "the", "Swedish", "research", "council,", "Socialstyrelsen,", "FAMY", "and", "the", "Medical", "Faculty", "of", "Umea˚", "University.", "The", "funders", "had", "no", "role", "in", "study", "design,", "data", "collection", "and", "analysis,", "decision", "to", "publish,", "or", "preparation", "of", "the", "manuscript.", "Competing", "Interests:", "The", "monoclonal", "antibody", "OMAB", "presented", "in", "this", "investigation", "is", "fully", "own", "by", "Alexo-Tech", "AB", "(www.alexotech.com).", "A.O.", "is", "a", "shareholder", "of", "Alexo-Tech", "AB.", "Alexo-Tech", "AB", "had", "no", "role", "in", "study", "design,", "data", "collection", "and", "analysis,", "decision", "to", "publish,", "or", "preparation", "of", "the", "manuscript", "and", "does", "not", "in", "any", "other", "way", "interfere", "with", "the", "study.", "This", "does", "not", "alter", "the", "authors’", "adherence", "to", "all", "the", "PLoS", "ONE", "policies", "on", "sharing", "data", "and", "materials.", "*", "E-mail:", "anders.olofsson@medchem.umu.se", "Introduction", "Amyloid", "is", "today", "linked", "to", "more", "than", "twenty-five", "different", "syndromes,", "of", "which", "the", "neurodegenerative", "disorder", "Alzheimer’s", "disease", "(AD)", "represents", "the", "most", "prominent", "example.", "Amyloid", "depositions", "in", "AD", "patients", "are", "largely", "composed", "of", "the", "Ab-", "peptide,", "derived", "from", "the", "proteolytic", "cleavage", "of", "the", "amyloid", "precursor", "protein", "(APP).", "Ab", "peptides", "of", "39–43", "residues", "all", "have", "clinical", "relevance,", "but", "Ab(1–40)", "and", "Ab(1–42)", "represent", "the", "most", "abundant", "variants.", "Ab(1–42),", "in", "particular,", "has", "a", "significantly", "higher", "propensity", "to", "aggregate,", "and", "has", "been", "strongly", "implicated", "in", "the", "etiology", "of", "AD", "[1].", "Although", "the", "histopathological", "features", "of", "Ab", "depositions", "(plaques)", "are", "striking,", "the", "correlation", "between", "Ab", "depositions", "and", "the", "clinical", "symptoms", "of", "AD", "is", "weak", "[2].", "Small", "and", "soluble", "Ab", "assemblies,", "known", "as", "Ab", "oligomers,", "correlate", "better", "with", "negative", "clinical", "status", "and", "have", "been", "suggested", "to", "be", "the", "Ab", "species", "primarily", "responsible", "for", "cytotoxicity.", "The", "structural", "features", "of", "Ab", "oligomers", "are", "largely", "unknown.", "Ab-targeting", "immunization,", "both", "passive", "and", "active,", "has", "been", "studied", "in", "AD", "mouse", "models", "and", "both", "types", "of", "immunizations", "have", "shown", "a", "dramatic", "improvement", "regarding", "memory", "and", "behavior", "[3,4,5,6,7,8].", "Interestingly,", "passive", "Ab", "vaccination", "improved", "cognitive", "performance", "within", "days,", "without", "reducing", "plaque", "burden,", "suggesting", "that", "the", "removal", "of", "soluble", "Ab", "is", "an", "adequate", "treatment", "to", "restore", "cognitive", "function", "[6].", "Ab", "and", "its", "precursor", "APP", "has", "both", "been", "suggested", "to", "have", "important", "roles", "concerning", "neuroprotection", "and", "neurotrophicity", "[9,10,11].", "Therefore,", "to", "avoid", "interfering", "with", "the", "homeostatic", "functions", "of", "amyloid", "proteins,", "a", "therapeutic", "approach", "focused", "on", "clearance", "of", "Ab", "should", "preferentially", "target", "Ab", "oligomers", "while", "PLoS", "ONE", "|", "www.plosone.org", "1", "November", "2010", "|", "Volume", "5", "|", "Issue", "11", "|", "e13928" ]

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3,369,548

null

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[ "Image", "patterned", "molecular", "delivery", "into", "live", "cells", "using", "gold", "particle", "coated", "substrates", "Ting-Hsiang", "Wu,1", "Sheraz", "Kalim,2", "Caitlin", "Callahan,2", "Michael", "A.", "Teitell,2,*", "and", "Pei-Yu", "Chiou", "3,*", "1Department", "of", "Electrical", "Engineering,", "University", "of", "California,", "Los", "Angeles", "(UCLA),", "420", "Westwood", "Plaza,", "48-121", "Engineering", "IV,", "Los", "Angeles,", "CA", "90095-1597,", "USA", "2Departments", "of", "Pathology", "and", "Pediatrics,", "UCLA,", "675", "Charles", "E.", "Young", "Drive", "South,", "MRL", "4-762,", "Los", "Angeles,", "CA", "90095-1732,", "USA", "3Department", "of", "Mechanical", "and", "Aerospace", "Engineering,", "UCLA,", "420", "Westwood", "Plaza,", "48-121", "Engineering", "IV,", "Los", "Angeles,", "CA", "90095-1597,", "USA", "*pychiou@seas.ucla.edu", "Abstract:", "An", "image-patterned", "molecular", "delivery", "system", "for", "mammalian", "cells", "is", "demonstrated", "by", "pulsed", "laser", "irradiation", "of", "gold", "particles", "immobilized", "on", "a", "substrate", "below", "a", "cell", "monolayer.", "Patterned", "cavitation", "bubble", "nucleation", "was", "captured", "using", "a", "time-resolved", "imaging", "system", "and", "molecular", "delivery", "verified", "by", "observing", "the", "uptake", "of", "a", "membrane-", "impermeable", "fluorescent", "dye,", "calcein.", "Delivery", "efficiency", "as", "high", "as", "90%", "was", "observed", "and", "multiplexed,", "patterned", "dye", "delivery", "was", "demonstrated.", "©2009", "Optical", "Society", "of", "America", "OCIS", "codes:", "(140.3540)", "Lasers,", "Q-switched;", "(170.1420)", "Biology;", "(170.1530)", "Cell", "analysis.", "References", "and", "links", "1.", "A.", "Vogel,", "J.", "Noack,", "G.", "Hő", "ttman,", "and", "G.", "Paltauf,", "“Mechanisms", "of", "femtosecond", "laser", "nanosurgery", "of", "cells", "and", "tissues,”", "Appl.", "Phys.", "B", "81(8),", "1015–1047", "(2005).", "2.", "U.", "K.", "Tirlapur,", "and", "K.", "König,", "“Targeted", "transfection", "by", "femtosecond", "laser,”", "Nature", "418(6895),", "290–291", "(2002).", "3.", "C.", "M.", "Pitsillides,", "E.", "K.", "Joe,", "X.", "Wei,", "R.", "R.", "Anderson,", "and", "C.", "P.", "Lin,", "“Selective", "cell", "targeting", "with", "light-absorbing", "microparticles", "and", "nanoparticles,”", "Biophys.", "J.", "84(6),", "4023–4032", "(2003).", "4.", "C.", "Yao,", "R.", "Rahmanzadeh,", "E.", "Endl,", "Z.", "Zhang,", "J.", "Gerdes,", "and", "G.", "Hüttmann,", "“Elevation", "of", "plasma", "membrane", "permeability", "by", "laser", "irradiation", "of", "selectively", "bound", "nanoparticles,”", "J.", "Biomed.", "Opt.", "10(6),", "064012", "(2005).", "5.", "V.", "Kotaidis,", "C.", "Dahmen,", "G.", "von", "Plessen,", "F.", "Springer,", "and", "A.", "Plech,", "“Excitation", "of", "nanoscale", "vapor", "bubbles", "at", "the", "surface", "of", "gold", "nanoparticles", "in", "water,”", "J.", "Chem.", "Phys.", "124(18),", "184702", "(2006).", "6.", "S.", "J.", "Henley,", "J.", "D.", "Carey,", "and", "S.", "R.", "P.", "Silva,", "“Pulsed-laser-induced", "nanoscale", "island", "formation", "in", "thin", "metal-on-", "oxide", "films,”", "Phys.", "Rev.", "B", "72(19),", "195408", "(2005).", "7.", "J.", "Trice,", "D.", "Thomas,", "C.", "Favazza,", "R.", "Rureshkumar,", "and", "R.", "Kalyanaraman,", "“Pulsed-laser-induced", "dewetting", "in", "nanoscopic", "metal", "films:", "Theory", "and", "experiments,”", "Phys.", "Rev.", "B", "75(23),", "235439", "(2007).", "8.", "E.", "D.", "Tsagarakis,", "C.", "Lew,", "M.", "O.", "Thompson,", "and", "E.", "P.", "Giannelis,", "“Nanocrystalline", "barium", "titanate", "films", "on", "flexible", "plastic", "substrates", "via", "pulsed", "laser", "annealing,”", "Appl.", "Phys.", "Lett.", "89(20),", "20910", "(2006).", "9.", "C.", "F.", "Bohren,", "and", "D.", "R.", "Huffman,", "Absorption", "and", "Scattering", "of", "Light", "by", "Small", "Particles", "(Wiley,", "New", "York,", "1983).", "10.", "P.", "Mulvaney,", "“Surface", "plasmon", "spectroscopy", "of", "nanosized", "metal", "particles,”", "Langmuir", "12(3),", "788–800", "(1996).", "11.", "C.", "E.", "Brennen,", "“Phase", "change,", "nucleation", "and", "cavitation,”", "in", "Cavitation", "and", "Bubble", "Dynamics,", "(Oxford", "University", "Press,", "New", "York,", "2005).", "12.", "G.", "Mie,", "“Articles", "on", "the", "optical", "characteristics", "of", "turbid", "tubes,", "especially", "colloidal", "metal", "solutions,”", "Ann.", "Phys.", "(Leipzig)", "25,", "377", "(1908).", "13.", "P.", "K.", "Jain,", "K.", "S.", "Lee,", "I.", "H.", "El-Sayed,", "and", "M.", "A.", "El-Sayed,", "“Calculated", "absorption", "and", "scattering", "properties", "of", "gold", "nanoparticles", "of", "different", "size,", "shape,", "and", "composition:", "applications", "in", "biological", "imaging", "and", "biomedicine,”", "J.", "Phys.", "Chem.", "B", "110(14),", "7238–7248", "(2006).", "14.", "P.", "B.", "Johnson,", "and", "R.", "W.", "Christy,", "“Optical", "constants", "of", "the", "noble", "metals,”", "Phys.", "Rev.", "B", "6(12),", "4370–4379", "(1972).", "15.", "H.", "Goldenberg,", "and", "C.", "J.", "Tranter,", "“Heat", "flow", "in", "an", "infinite", "medium", "heated", "by", "a", "sphere,”", "Br.", "J.", "Appl.", "Phys.", "3(9),", "296–298", "(1952).", "16.", "D.", "O.", "Lapotko,", "E.", "Lukianova,", "and", "A.", "A.", "Oraevsky,", "“Selective", "laser", "nano-thermolysis", "of", "human", "leukemia", "cells", "with", "microbubbles", "generated", "around", "clusters", "of", "gold", "nanoparticles,”", "Lasers", "Surg.", "Med.", "38(6),", "631–642", "(2006).", "17.", "I.", "B.", "Clark,", "E.", "G.", "Hanania,", "J.", "Stevens,", "M.", "Gallina,", "A.", "Fieck,", "R.", "Brandes,", "B.", "O.", "Palsson,", "and", "M.", "R.", "Koller,", "“Optoinjection", "for", "efficient", "targeted", "delivery", "of", "a", "broad", "range", "of", "compounds", "and", "macromolecules", "into", "diverse", "cell", "types,”", "J.", "Biomed.", "Opt.", "11(1),", "014034", "(2006).", "#116246", "-", "$15.00", "USD", "Received", "4", "Sep", "2009;", "revised", "30", "Oct", "2009;", "accepted", "4", "Nov", "2009;", "published", "7", "Jan", "2010", "(C)", "2010", "OSA", "18", "January", "2010", "/", "Vol.", "18,", "No.", "2", "/", "OPTICS", "EXPRESS", "938" ]

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[ "Wang", "et", "al.", "Molecular", "Brain", "2012,", "5:21", "http://www.molecularbrain.com/content/5/1/21", "R", "E", "S", "E", "A", "R", "C", "H", "Open", "Access", "Activation", "of", "c-jun", "N-terminal", "kinase", "in", "spinal", "cord", "contributes", "to", "breast", "cancer", "induced", "bone", "pain", "in", "rats", "Xiao-Wei", "Wang,", "Shan", "Hu,", "Qi-Liang", "Mao-Ying,", "Qian", "Li,", "Chang-Jiang", "Yang,", "Hui", "Zhang,", "Wen-Li", "Mi,", "Gen-Cheng", "Wu", "and", "Yan-Qing", "Wang*", "Abstract", "Background:", "The", "most", "frequent", "pain", "in", "patients", "with", "metastatic", "breast", "and", "prostate", "cancer", "is", "bone", "pain,", "which", "can", "be", "severe", "and", "difficult", "to", "treat.", "The", "mechanisms", "underlying", "this", "pain", "remain", "unclear.", "Here", "we", "investigated", "the", "role", "of", "c-jun", "N-terminal", "kinase", "(JNK)", "pathway", "in", "the", "spinal", "cord", "in", "cancer-induced", "bone", "pain", "(CIBP).", "Results:", "In", "this", "study,", "we", "used", "an", "established", "rat", "CIBP", "model", "to", "investigate", "the", "possible", "role", "of", "JNK", "activation", "in", "the", "spinal", "cord.", "After", "intra-tibial", "inoculation", "with", "Walker", "256", "rat", "mammary", "gland", "carcinoma", "cells,", "the", "rats", "displayed", "mechanical", "allodynia", "on", "day", "5,", "which", "lasted", "to", "day", "16.", "The", "activation", "of", "JNK", "in", "neurons", "and", "astrocytes", "in", "the", "spinal", "cord", "was", "found", "on", "day", "12", "and", "day", "16", "after", "intra-tibial", "inoculation", "with", "carcinoma", "cells.", "A", "single", "intrathecal", "injection", "with", "JNK", "inhibitor", "SP600125", "by", "lumbar", "puncture", "attenuated", "mechanical", "allodynia", "on", "day", "12,", "and", "repeated", "intrathecal", "injection", "of", "SP600126", "from", "day", "10", "to", "day", "14", "had", "a", "cumulative", "analgesic", "effect", "on", "CIBP.", "Conclusions:", "Taken", "together,", "our", "results", "demonstrated", "for", "the", "first", "time", "that", "JNK", "activation", "in", "the", "spinal", "cord", "is", "required", "in", "the", "maintenance", "of", "CIBP.", "Inhibition", "of", "the", "spinal", "JNK", "pathway", "may", "provide", "a", "new", "therapy", "for", "CIBP", "management.", "Keywords:", "c-Jun", "N-terminal", "kinase,", "Cancer-induced", "bone", "pain,", "Spinal", "cord,", "Rats", "Background", "The", "c-jun", "N-terminal", "kinase", "(JNK)", "is", "an", "evolutionarily", "conserved", "sub-group", "of", "mitogen-activated", "protein", "kinases", "(MAPK)", "that", "participates", "in", "survival", "signaling,", "apoptosis", "and", "pain", "[1-3].", "The", "JNK", "family", "is", "encoded", "by", "three", "genes:", "jnk1,", "jnk2", "and", "jnk3.", "Recent", "studies", "have", "demonstrated", "that", "JNK1", "and", "JNK2", "activation", "play", "important", "roles", "in", "the", "development", "and", "maintenance", "of", "chronic", "pain", "[4];", "JNK3", "has", "different", "functions", "from", "JNK1", "and", "JNK2", "and", "has", "been", "reported", "to", "participate", "in", "apoptosis", "in", "the", "brain.", "JNK", "acti-", "vation", "is", "mediated", "by", "the", "dual", "phosphorylation", "on", "Thr", "and", "Tyr", "by", "two", "MAPK", "kinases", "(MKK4/7),", "and", "several", "transcriptional", "factors", "can", "be", "regulated", "by", "JNK", "activation", "[5].", "JNK1/2", "was", "shown", "to", "be", "activated", "in", "the", "spinal", "cord", "at", "6", "h", "after", "intra-plantar", "injection", "of", "complete", "Freund’s", "*", "Correspondence:", "wangyanqing@shmu.edu.cn", "Department", "of", "Integrative", "Medicine", "and", "Neurobiology,", "State", "Key", "Laboratory", "of", "Medical", "Neurobiology,", "Shanghai", "Medical", "College;", "Institute", "of", "Acupuncture", "Research", "(WHO", "Collaborating", "Center", "for", "Traditional", "Medicine),", "Fudan", "University,", "P.O.", "Box", "291138", "Yi", "Xue", "Yuan", "Road,", "Shanghai,", "200032,", "China", "adjuvant", "(CFA)", "[6]", "and", "at", "day", "3", "after", "spinal", "nerve", "ligation", "(SNL)", "[7].", "Moreover,", "intrathecal", "injection", "of", "JNK", "inhibitor", "SP600125", "decreased", "pain", "behavior", "in", "animals", "with", "inflam-", "matory", "pain,", "neuropathic", "pain", "and", "skin", "cancer", "pain", "[8-10].", "Cancer-induced", "bone", "pain", "(CIBP)", "is", "a", "severe", "problem", "for", "patients", "with", "end-stage", "cancer.", "The", "preferential", "metas-", "tasis", "of", "cancer", "cells", "to", "bone", "disrupts", "the", "process", "of", "bone", "remodeling", "and", "results", "in", "lesions", "that", "cause", "significant", "pain", "[11].", "The", "model", "of", "bone", "cancer", "induced", "by", "intrame-", "dullary", "inoculation", "with", "tumor", "cells", "has", "been", "the", "most", "frequently", "encountered", "type", "of", "cancer-induced", "pain", "in", "cancer", "patients", "with", "bone", "metastasis", "[12].", "Several", "animal", "models", "of", "CIBP", "have", "been", "developed", "recently,", "and", "these", "models", "contributed", "to", "our", "understanding", "of", "CIBP", "[13-15].", "A", "widely", "used", "model", "of", "CIBP", "is", "induced", "by", "intra-tibial", "in-", "oculation", "with", "Walker", "256", "rat", "mammary", "gland", "carcinoma", "cells", "[16-18].", "Rats", "inoculated", "with", "carcinoma", "cells", "devel-", "oped", "mechanical", "allodynia", "from", "day", "5", "as", "indicated", "by", "decreased", "paw", "withdrawal", "thresholds", "for", "the", "ipsilateral", "©", "2012", "Wang", "et", "al.;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

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1,062,873

null

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[ "Nucleic", "Acids", "Research,", "2005,", "Vol.", "33,", "No.", "5", "1435–1444", "doi:10.1093/nar/gki281", "Regulated", "chromatin", "domain", "comprising", "cluster", "of", "co-expressed", "genes", "in", "Drosophila", "melanogaster", "1", "Alla", "I.", "Kalmykova,", "Dmitry", "I.", "Nurminsky", ",", "Dmirty", "V.", "Ryzhov", "and", "Yuri", "Y.", "Shevelyov*", "Department", "of", "Molecular", "Genetics", "of", "Cell,", "Institute", "of", "Molecular", "Genetics,", "Russian", "Academy", "of", "Sciences,", "Moscow", "123182,", "Russia", "and", "1Department", "of", "Anatomy", "and", "Cell", "Biology,", "Tufts", "University", "School", "of", "Medicine,", "Boston,", "MA", "02111,", "USA", "Received", "September", "7,", "2004;", "Revised", "January", "24,", "2005;", "Accepted", "February", "15,", "2005", "DDBJ/EMBL/GenBank", "accession", "nos+", "ABSTRACT", "Recently,", "the", "phenomenon", "of", "clustering", "of", "co-expressed", "genes", "on", "chromosomes", "was", "dis-", "covered", "in", "eukaryotes.", "To", "explore", "the", "hypothesis", "that", "genes", "within", "clusters", "occupy", "shared", "chroma-", "tin", "domains,", "we", "performed", "a", "detailed", "analysis", "of", "transcription", "pattern", "and", "chromatin", "structure", "of", "a", "cluster", "of", "co-expressed", "genes.", "We", "found", "that", "five", "non-homologous", "genes", "(Crtp,", "Yu,", "CK2btes,", "Pros28.1B", "and", "CG13581)", "are", "expressed", "exclusively", "in", "Drosophila", "melanogaster", "male", "germ-line", "and", "form", "a", "non-interrupted", "cluster", "in", "the", "15", "kb", "region", "of", "chromosome", "2.", "The", "cluster", "is", "surrounded", "by", "genes", "with", "broader", "transcription", "patterns.", "Analysis", "of", "DNase", "I", "sensitivity", "revealed", "‘open’", "chromatin", "conformation", "in", "the", "cluster", "and", "adjacent", "regions", "in", "the", "male", "germ-line", "cells,", "where", "all", "studied", "genes", "are", "transcribed.", "In", "contrast,", "in", "somatic", "tissues", "where", "the", "cluster", "genes", "are", "silent,", "the", "domain", "of", "repressed", "chromatin", "encompassed", "four", "out", "of", "five", "cluster", "genes", "and", "an", "adjacent", "non-cluster", "gene", "CG13589", "that", "is", "also", "silent", "in", "analyzed", "somatic", "tissues.", "The", "fifth", "cluster", "gene", "(CG13581)", "appears", "to", "be", "excluded", "from", "the", "chromatin", "domain", "occupied", "by", "the", "other", "four", "genes.", "Our", "results", "suggest", "that", "extensive", "clustering", "of", "co-expressed", "genes", "in", "eukaryotic", "genomes", "does", "in", "general", "reflect", "the", "domain", "organization", "of", "chro-", "matin,", "although", "domain", "borders", "may", "not", "exactly", "correspond", "to", "the", "margins", "of", "gene", "clusters.", "INTRODUCTION", "It", "has", "been", "suggested", "that", "eukaryotic", "genome", "is", "functionally", "divided", "into", "domains", "that", "contain", "all", "regulatory", "elements", "necessary", "for", "full,", "correct", "and", "positionally", "independent", "expression", "of", "resident", "gene(s)", "(1,2).", "These", "domains", "are", "evident", "at", "the", "level", "of", "local", "chromatin", "structure,", "where", "tran-", "scriptionally", "active", "genes", "are", "associated", "with", "‘open’", "and", "acetylated", "chromatin,", "whereas", "silent", "genes", "are", "embedded", "in", "compacted", "and", "hypermethylated", "chromatin", "[reviewed", "in", "(3–5)].", "The", "assumption", "that", "not", "only", "single", "genes", "such", "as", "chicken", "glyceraldehyde-3-phosphate", "dehydrogenase", "(6),", "human", "apoB", "(7),", "and", "chicken", "lysozyme", "(8,9)", "genes,", "but", "also", "multigenic", "loci", "may", "be", "regulated", "at", "the", "level", "of", "common", "chromatin", "domains,", "originated", "from", "the", "data", "obtained", "on", "sev-", "eral", "intensively", "studied", "gene", "clusters.", "The", "examples", "include,", "but", "are", "not", "limited", "to,", "the", "cluster", "of", "b-globin", "genes", "in", "chicken,", "mouse", "and", "human", "(10–17);", "growth", "hormone", "genes", "(18,19),", "IL-4/IL-13", "genes", "(20)", "and", "PRM1-PRM2-TNP", "genes", "in", "human", "(21);", "ovalbumin", "genes", "in", "chicken", "(22);", "and", "heat-shock", "genes", "in", "Drosophila", "(23).", "All", "these", "clusters", "comprise", "paralogous", "genes", "that", "most", "likely", "have", "originated", "from", "ancestral", "genes", "through", "local", "duplications.", "It", "is", "not", "clear", "whether", "the", "infer-", "ences", "from", "the", "studies", "on", "these", "models", "can", "be", "extrapolated", "to", "the", "organization", "of", "entire", "genome,", "where", "clusters", "of", "para-", "logous", "genes", "occur", "rather", "rarely.", "Recently,", "a", "number", "of", "reports", "have", "demonstrated", "non-", "random", "clustering", "of", "co-expressed", "genes", "on", "chromosomes.", "First", "observations", "of", "this", "phenomenon,", "that", "we", "are", "aware", "of,", "date", "back", "to", "1991", "(24),", "but", "in", "2002", "an", "inﬂux", "of", "publications", "based", "on", "the", "analysis", "of", "whole-genome", "transcription", "data", "from", "different", "organisms", "indicated", "that", "mechanisms", "of", "transcrip-", "tional", "co-regulation,", "that", "operate", "with", "chromatin", "domains,", "are", "common", "from", "yeast", "to", "higher", "eukaryotes", "[reviewed", "in", "(25)].", "Moreover,", "according", "to", "the", "data", "of", "Spellman", "and", "Rubin", "(26)", "over", "20%", "of", "all", "Drosophila", "genes", "are", "clustered", "on", "chromo-", "somes", "according", "to", "their", "expression", "patterns", "and", "thus", "may", "share", "common", "chromatin", "domains.", "However,", "direct", "evidence", "that", "would", "link", "the", "observed", "gene", "clusters", "to", "the", "chromatin", "domains", "was", "still", "missing.", "To", "address", "this", "issue,", "we", "thoroughly", "characterized", "the", "cluster", "of", "non-homologous", "testes-speciﬁc", "*To", "whom", "correspondence", "should", "be", "addressed.", "Tel:", "+7", "095", "1960809;", "Fax:", "+7", "095", "1960221;", "Email:", "shevelev@img.ras.ru", "+AF197938,", "AY078076", "and", "AY078077", "ª", "The", "Author", "2005.", "Published", "by", "Oxford", "University", "Press.", "All", "rights", "reserved.", "The", "online", "version", "of", "this", "article", "has", "been", "published", "under", "an", "open", "access", "model.", "Users", "are", "entitled", "to", "use,", "reproduce,", "disseminate,", "or", "display", "the", "open", "access", "version", "of", "this", "article", "for", "non-commercial", "purposes", "provided", "that:", "the", "original", "authorship", "is", "properly", "and", "fully", "attributed;", "the", "Journal", "and", "Oxford", "University", "Press", "are", "attributed", "as", "the", "original", "place", "of", "publication", "with", "the", "correct", "citation", "details", "given;", "if", "an", "article", "is", "subsequently", "reproduced", "or", "disseminated", "not", "in", "its", "entirety", "but", "only", "in", "part", "or", "as", "a", "derivative", "work", "this", "must", "be", "clearly", "indicated.", "For", "commercial", "re-use,", "please", "contact", "journals.permissions@oupjournals.org" ]

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2,972,450

null

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[ "Indian", "J.", "PsychiaL,", "1994,36(1),", "25-29.", "PLEA", "OF", "INSANITY", "AS", "A", "DEFENSE", "IN", "CRIMINAL", "CASES:", "AN", "UPDATE", "SAYEED", "AKHTAR,", "TUSHAR", "JAGAWAT", "Mc'Naughten", "Rule", "is", "die", "commonest", "formulation", "for", "plea", "of", "insanity", "in", "most", "countries.", "Althougjk", "assessment", "of", "the", "mental", "state", "at", "thetimeofoffence", "is", "difficult,", "few", "instruments", "have", "been", "devised", "for", "this", "purpose.", "In", "the", "USA.,", "efforts", "are", "being", "made", "to", "abolish", "the", "insanity", "defense", "and", "in", "the", "United", "Kingdom,", "amendments", "in", "the", "provisions", "of", "insanity", "defense", "have", "been", "proposed.", "The", "authors", "have", "stressed", "the", "need", "for", "some", "changes", "in", "the", "relevant", "sections", "of", "Indian", "Penal", "Code", "to", "increase", "the", "credibility", "ofPsychiatric", "testimony", "in", "such", "cases.", "INTRODUCTION", "Plea", "of", "insanity", "is", "used", "as", "a", "defense", "in", "criminal", "cases", "and", "when", "successful", "the", "accused", "is", "acquitted", "of", "the", "charge", "on", "the", "ground", "of", "insanity.", "The", "term", "'insanity'", "is", "not", "a", "medical", "term", "but", "a", "legal", "concept", "meaning", "that", "degree", "of", "mental", "disorder", "that", "relieves", "toe", "offender", "of", "the", "criminal", "responsibility", "for", "his", "action.", "In", "the", "Western", "countries,", "it", "is", "estimated", "that", "plea", "of", "insanity", "is", "used", "as", "a", "defense", "in", "1-2%", "of", "the", "criminal", "cases", "(Pasewik", "&", "Craig,", "1980).", "Not", "Guilty", "By", "Reason", "of", "Insanity", "(NGBRI)", "defendants", "tend", "to", "be", "older,", "married", "and", "un", "employed", "at", "the", "time", "of", "commission", "of", "the", "crime.", "Most", "of", "them", "have", "a", "prior", "psychiatric", "treatment", "history", "and", "there", "is", "a", "history", "of", "drug", "and", "alcohol", "abuse", "(Roger,", "1987).", "Acquitees", "differed", "from", "those", "convicted,", "in", "being", "female", "(Roger,", "1984),", "older", "and", "more", "educated,", "and", "more", "likely", "to", "be", "schizophrenic", "(Somasundaram,", "1960", "&", "1974;", "Benezech", "et", "aL", "1984).", "Li", "a", "study", "of", "187", "men", "found", "NGBRI", "(Taylor", "&", "London,", "1982),", "34%", "of", "the", "defendants", "using", "the", "insanity", "plea", "were", "patients", "with", "Bipolar", "Affective", "Disorder.", "A", "high", "concordance", "rate", "(88%)", "was", "found", "between", "psychiatric", "evaluation", "of", "insanity", "and", "the", "verdict", "of", "the", "court.", "It", "reflects", "the", "influence", "of", "the", "psychiatrist's", "recommendations", "in", "the", "court's", "decision", "of", "insanity", "plea.", "HISTORICAL", "BACKGROUND", "The", "defence", "of", "insanity", "has", "been", "recognized", "in", "English", "courts", "for", "over", "700", "years", "beginning", "from", "the", "reign", "of", "Edward", "HI", "in", "the", "fourteenth", "century,", "when", "complete", "madness", "was", "considered", "as", "a", "defense", "to", "a", "criminal", "charge", "(Simon,", "1967).", "By", "1518,", "it", "was", "well", "established", "that", "the", "lack", "of", "guilty", "mind", "and", "intellect", "meant", "a", "lack", "of", "criminal", "responsibility.", "Some", "250", "years", "ago", "an", "English", "judge,", "in", "the", "trial", "of", "Edward", "Arnold", "said,", "\"in", "order", "to", "avail", "oneself", "of", "defense", "of", "insanity,", "a", "man", "must", "be", "totally", "deprived", "of", "under", "standing", "and", "memory", "that", "be", "is", "not", "to", "know", "what", "i", "x", "was", "doing,", "not", "more", "than", "an", "infant,", "brute", "or", "a", "wild", "beast", "(Simon,", "1983).", "The", "\"wild-beast\"", "test", "along", "with", "determination", "of", "ability", "to", "distinguish", "between", "right", "and", "wrong", "remained", "the", "standard", "of", "judging", "criminal", "responsibility", "until", "the", "year", "1800", "A", "D", ".", ",", "when", "the", "landmark", "trial", "of", "Hadfield", "set", "a", "new", "stand", "ard", "(Whitlock,", "1963).", "A", "former", "soldier.", "James", "Hadfield", "attempted", "as", "sassination", "of", "reigning", "English", "monarch,", "George", "m", "with", "the", "belief", "that", "be", "was", "the", "savior", "of", "mankind.", "He", "thought", "that", "in", "order", "to", "become", "popular", "he", "should", "sacrifice", "his", "life", "like", "Jesus", "Christ", "and", "for", "this", "he", "chose", "to", "carry", "out", "an", "act", "for", "which", "he", "would", "be", "hanged.", "The", "prosecution", "argued", "that", "the", "defendant's", "behavior", "(purchase", "of", "gunpowder,", "concealment", "of", "pistol", "etc.)", "clearly", "indicated", "that", "he", "was", "neither", "an", "idiot", "nor", "a", "madman,", "so", "\"afflicted", "by", "absolute", "priva", "tion", "of", "reason\".", "The", "jury", "acquitted", "him", "because", "he", "was", "insane", "at", "the", "time", "of", "commission", "of", "the", "crime.", "This", "decision", "was", "a", "landmark", "because", "it", "rejected", "two", "concepts", "previously", "held", "by", "the", "court.", "First,", "it", "is", "not", "necessary", "for", "acquittal", "on", "the", "ground", "of", "insanity", "that", "be", "must", "be", "completely", "deprived", "of", "his", "mental", "faculties;", "second,", "it", "severed", "the", "tie", "between", "insanity", "and", "ability", "to", "distinguish", "between", "right", "and", "wrong,", "MC'NAUGHTEN", "RULE", "Daniel", "Mc'Naughten", "was", "a", "Scottish", "woodcutter", "who", "assassinated", "Edward", "Drummond", "who", "was", "secretary", "to", "the", "Prime", "Minister", "Sir", "Robert", "Peel,", "in", "the", "mistaken", "belief", "that", "Drummond", "was", "the", "Prime", "Minister.", "Mc'Naughten", "was", "described", "by", "nine", "medical", "witnesses", "as", "'an", "extreme", "paranoiac", "en", "tangled", "in", "an", "elaborate", "system", "of", "delusions'", "and", "be", "believed,", "albeit", "falsely,", "that", "the", "Prime", "Minister", "was", "responsible", "for", "all", "his", "financial", "and", "personal", "misfor", "tunes.", "His", "trial,", "acquittal", "and", "reference", "to", "the", "House", "of", "Lords", "led", "to", "the", "formulation", "of", "a", "popular", "set", "of", "rules", "for", "criminal", "responsibility", "which", "have", "come", "to", "»" ]

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[ "Identification", "of", "a", "Novel", "Type", "of", "Spacer", "Element", "Required", "for", "Imprinting", "in", "Fission", "Yeast", "Suha", "Sayrac,", "Sonya", "Vengrova,", "Emma", "L.", "Godfrey,", "Jacob", "Z.", "Dalgaard*", "Clinical", "Sciences", "Research", "Institute,", "Gibbet", "Hill", "Campus,", "University", "of", "Warwick,", "Coventry,", "United", "Kingdom", "Abstract", "Asymmetrical", "segregation", "of", "differentiated", "sister", "chromatids", "is", "thought", "to", "be", "important", "for", "cellular", "differentiation", "in", "higher", "eukaryotes.", "Similarly,", "in", "fission", "yeast,", "cellular", "differentiation", "involves", "the", "asymmetrical", "segregation", "of", "a", "chromosomal", "imprint.", "This", "imprint", "has", "been", "shown", "to", "consist", "of", "two", "ribonucleotides", "that", "are", "incorporated", "into", "the", "DNA", "during", "lagging-", "strand", "synthesis", "in", "response", "to", "a", "replication", "pause,", "but", "the", "underlying", "mechanism", "remains", "unknown.", "Here", "we", "present", "key", "novel", "discoveries", "important", "for", "unravelling", "this", "process.", "Our", "data", "show", "that", "cis-acting", "sequences", "within", "the", "mat1", "cassette", "mediate", "pausing", "of", "replication", "forks", "at", "the", "proximity", "of", "the", "imprinting", "site,", "and", "the", "results", "suggest", "that", "this", "pause", "dictates", "specific", "priming", "at", "the", "position", "of", "imprinting", "in", "a", "sequence-independent", "manner.", "Also,", "we", "identify", "a", "novel", "type", "of", "cis-acting", "spacer", "region", "important", "for", "the", "imprinting", "process", "that", "affects", "where", "subsequent", "primers", "are", "put", "down", "after", "the", "replication", "fork", "is", "released", "from", "the", "pause.", "Thus,", "our", "data", "suggest", "that", "the", "imprint", "is", "formed", "by", "ligation", "of", "a", "not-fully-", "processed", "Okazaki", "fragment", "to", "the", "subsequent", "fragment.", "The", "presented", "work", "addresses", "how", "differentiated", "sister", "chromatids", "are", "established", "during", "DNA", "replication", "through", "the", "involvement", "of", "replication", "barriers.", "Citation:", "Sayrac", "S,", "Vengrova", "S,", "Godfrey", "EL,", "Dalgaard", "JZ", "(2011)", "Identification", "of", "a", "Novel", "Type", "of", "Spacer", "Element", "Required", "for", "Imprinting", "in", "Fission", "Yeast.", "PLoS", "Genet", "7(3):", "e1001328.", "doi:10.1371/journal.pgen.1001328", "Editor:", "James", "E.", "Haber,", "Brandeis", "University,", "United", "States", "of", "America", "Received", "July", "15,", "2010;", "Accepted", "February", "7,", "2011;", "Published", "March", "10,", "2011", "Copyright:", "2011", "Sayrac", "et", "al.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Funding:", "This", "work", "was", "supported", "by", "a", "grant", "from", "Marie", "Curie", "Cancer", "Care.", "The", "funders", "had", "no", "role", "in", "study", "design,", "data", "collection", "and", "analysis,", "decision", "to", "publish,", "or", "preparation", "of", "the", "manuscript.", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "*", "E-mail:", "j.z.dalgaard@warwick.ac.uk", "Introduction", "Differentiated", "sister", "chromatids,", "coupled", "with", "non-random", "segregation,", "have", "been", "proposed", "to", "control", "cell", "fate", "during", "the", "development", "and", "differentiation", "of", "multicellular", "organisms", "[1].", "Similarly,", "cellular", "differentiation", "in", "the", "fission", "yeast", "Schizosacchar-", "omyces", "pombe", "involves", "the", "establishment", "of", "differentiated", "chromatids", "and", "their", "asymmetrical", "segregation.", "The", "nature", "of", "this", "epigenetic", "mark", "or", "imprint", "that", "acts", "to", "discriminate", "the", "chromatids", "has", "been", "defined,", "however,", "the", "mechanism", "that", "leads", "to", "its", "introduction", "remains", "unknown.", "Fission", "yeast", "cells", "exhibit", "two", "different", "mating-", "types", "denoted", "as", "M", "and", "P.", "Homothallic", "strains", "are", "able", "to", "switch", "between", "mating-types", "in", "a", "pattern", "where", "only", "one", "granddaughter", "of", "a", "newly", "switched", "cell", "will", "have", "switched", "mating-type", "(Figure", "1A)", "[2–6].", "The", "mating-type", "of", "a", "cell", "is", "determined", "by", "the", "transcriptionally", "expressed", "mat1", "locus", "located", "on", "chromosome", "II,", "which", "encodes", "either", "an", "M-", "or", "a", "P-specific", "gene", "cassette", "(Figure", "1B)", "[7,8].", "Switching", "between", "the", "two", "mating-types", "occurs", "through", "a", "recombination", "event", "that", "replaces", "the", "cassette", "present", "at", "mat1", "with", "that", "of", "the", "opposite", "mating-type,", "using", "one", "of", "the", "two", "transcriptionally", "silenced", "loci,", "mat2P", "and", "mat3M,", "as", "a", "donor", "of", "the", "information.", "The", "molecular", "mechanism", "underlying", "mating-type", "switching", "is", "tightly", "linked", "to", "DNA", "replication,", "and", "the", "asymmetrical", "pattern", "of", "switching", "reflects", "the", "asymmetry", "of", "the", "replication", "process.", "The", "mat1", "locus", "is", "replicated", "unidirectionally", "in", "the", "centromere-", "proximal", "direction", "(see", "below).", "An", "imprint,", "which", "marks", "the", "mat1", "locus", "of", "switchable", "cells", "(Figure", "1B,", "1C),", "is", "introduced", "during", "lagging-strand", "synthesis", "of", "the", "mat1", "DNA", "in", "only", "one", "of", "the", "two", "sister", "chromatids", "formed", "in", "S", "phase", "[9,10].", "This", "imprint", "is", "maintained", "for", "one", "cell", "cycle,", "then", "during", "the", "next", "S", "phase,", "the", "imprint", "acts", "as", "a", "barrier", "for", "leading-strand", "replication,", "resulting", "in", "the", "replication-coupled", "recombination", "event", "that", "underlies", "mating-type", "switching", "[11–13].", "The", "recombination", "event", "pro-", "gresses", "by", "the", "‘‘synthesis", "dependent", "single-strand", "annealing", "mechanism’’", "where", "only", "one", "DNA", "strand", "at", "the", "donor", "locus", "provides", "the", "genetic", "information", "that", "is", "transferred", "to", "mat1", "[14].", "The", "homology", "needed", "for", "both", "the", "initiation", "and", "resolution", "of", "this", "recombination", "event", "is", "provided", "by", "short", "homology", "domains,", "named", "H1", "and", "H2,", "that", "flank", "both", "the", "mat1", "locus", "and", "each", "of", "the", "two", "donor", "loci,", "mat2P", "and", "mat3M", "(Figure", "1B)", "[8,15].", "As", "a", "result", "of", "this", "recombination", "event,", "the", "mating-type", "cassette", "of", "only", "one", "of", "the", "two", "sister", "chromatids", "is", "replaced", "by", "a", "cassette", "containing", "the", "opposite", "mating-type", "information,", "such", "that", "the", "subsequent", "cell", "division", "gives", "rise", "to", "two", "cells", "with", "opposite", "mating-types.", "The", "imprint", "was", "first", "identified", "genetically", "as", "a", "strand-specific,", "chromosomally", "inherited", "mark", "that", "is", "linked", "to", "the", "mat1", "locus", "and", "is", "required", "for", "the", "induction", "of", "switching", "[4–6,16].", "Subsequently", "it", "was", "shown", "that", "the", "imprint", "consists", "of", "two", "ribonucleotides", "that", "are", "incorporated", "into", "the", "DNA", "duplex", "in", "a", "strand-", "and", "site-specific", "manner", "([12]", "and", "reviewed", "in", "[17]).", "These", "two", "ribonucleotides", "are", "located", "at", "the", "junction", "between", "the", "mating-type", "cassette", "and", "the", "homology", "domain", "H1", "(Figure", "1B)", "[18].", "The", "bonds", "of", "the", "RNA-", "DNA", "hybrid", "at", "the", "imprint", "site", "appear", "to", "be", "efficiently", "hydrolyzed", "by", "cellular", "enzymes,", "making", "purification", "of", "intact", "imprinted", "DNA", "difficult.", "During", "standard", "purification", "methods,", "the", "imprint", "is", "converted", "into", "a", "double-stranded", "break", "that", "can", "be", "detected", "by", "Southern", "analysis", "[10,19].", "However,", "we", "have", "managed", "to", "purify", "PLoS", "Genetics", "|", "www.plosgenetics.org", "1", "March", "2011", "|", "Volume", "7", "|", "Issue", "3", "|", "e1001328" ]

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2,841,176

null

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[ "Teut", "et", "al.", "BMC", "Geriatrics", "2010,", "10:10", "http://www.biomedcentral.com/1471-2318/10/10", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Homeopathic", "treatment", "of", "elderly", "patients", "-", "a", "prospective", "observational", "study", "with", "follow-up", "over", "a", "two", "year", "period", "Michael", "Teut1*,", "Rainer", "Lüdtke2,", "Katharina", "Schnabel1,", "Stefan", "N", "Willich1,", "Claudia", "M", "Witt1", "Abstract", "Background:", "Very", "little", "is", "known", "about", "the", "range", "of", "diagnoses,", "course", "of", "treatment", "and", "long-term", "outcome", "in", "elderly", "patients", "who", "choose", "to", "receive", "homeopathic", "medical", "treatment.", "We", "investigated", "homeopathic", "practice", "in", "an", "industrialised", "country", "under", "everyday", "conditions.", "The", "aim", "of", "the", "study", "was", "to", "determine", "the", "spectrum", "of", "diagnoses", "and", "treatments,", "as", "well", "as", "to", "describe", "the", "course", "of", "illness", "over", "time", "among", "older", "patients", "who", "chose", "to", "receive", "homeopathic", "treatment.", "Methods:", "In", "this", "subgroup", "analysis", "of", "a", "prospective,", "multicentre", "cohort", "study", "totally", "including", "3981", "patients", "treated", "by", "homeopathic", "physicians", "in", "primary", "care", "practices", "in", "Germany", "and", "Switzerland,", "data", "was", "analysed", "from", "all", "patients", ">", "70", "years", "consulting", "the", "physician", "for", "the", "first", "time.", "The", "main", "outcome", "measures", "were:", "assessment", "by", "patient", "of", "the", "severity", "of", "complaints", "(numeric", "rating", "scales)", "and", "quality", "of", "life", "(SF-36)", "and", "by", "the", "physician", "of", "the", "severity", "of", "diagnoses", "(numeric", "rating", "scales)", "at", "baseline,", "and", "after", "3,", "12,", "and", "24", "months.", "Results:", "A", "total", "of", "83", "patients", "were", "included", "in", "the", "subgroup", "analysis", "(41%", "men,", "mean", "age", "73.2", "±", "(SD)", "3.1", "years;", "59%", "women,", "74.3", "±", "3.8", "years).", "98.6", "percent", "of", "all", "diagnoses", "were", "chronic", "with", "an", "average", "duration", "of", "11.5", "±", "11.5", "years.", "82", "percent", "of", "the", "patients", "were", "taking", "medication", "at", "baseline.", "The", "most", "frequent", "diagnoses", "were", "hypertension", "(20.5%,", "11.1", "±", "7.5", "years)", "and", "sleep", "disturbances", "(15.7%,", "22.1", "±", "25.8", "years).", "The", "severity", "of", "complaints", "decreased", "significantly", "between", "baseline", "and", "24", "months", "in", "both", "patients", "(from", "6.3", "(95%", "CI:", "5.7-6.8)", "to", "4.6", "(4.0-5.1),", "p", "<", "0.001)", "and", "physicians’", "assessments", "(from", "6.6", "(6.0-7.1)", "to", "3.7", "(3.2-4.3),", "p", "<", "0.001);", "qual-", "ity", "of", "life", "(SF", "36)", "and", "the", "number", "of", "medicines", "taken", "did", "not", "significantly", "change.", "Conclusion:", "The", "severity", "of", "disease", "showed", "marked", "and", "sustained", "improvements", "under", "homeopathic", "treatment,", "but", "this", "did", "not", "lead", "to", "an", "improvement", "of", "quality", "of", "life.", "Our", "findings", "might", "indicate", "that", "homeopathic", "medical", "therapy", "may", "play", "a", "beneficial", "role", "in", "the", "long-term", "care", "of", "older", "adults", "with", "chronic", "diseases", "and", "studies", "on", "comparative", "effectiveness", "are", "needed", "to", "evaluate", "this", "hypothesis.", "Background", "Homeopathy", "is", "one", "of", "the", "most", "frequently", "used", "but", "con-", "troversial", "forms", "of", "complementary", "and", "alternative", "medi-", "cine", "(CAM).", "It", "is", "based", "on", "the", "ancient", "‘principle", "of", "similars’.", "Highly", "diluted", "preparations", "of", "substances", "that", "cause", "symptoms", "in", "healthy", "individuals", "are", "used", "to", "stimu-", "late", "healing", "reactions", "in", "patients", "who", "display", "similar", "*", "Correspondence:", "michael.teut@charite.de", "1Institute", "for", "Social", "Medicine,", "Epidemiology", "and", "Health", "Economics,", "Charité", "University", "Medical", "Center,", "Luisenstr.", "57,", "D-10017", "Berlin,", "Germany", "symptoms", "when", "ill", "[1].", "In", "classical", "homeopathy", "a", "single", "homeopathic", "remedy", "is", "selected,", "based", "on", "a", "patient’s", "total", "spectrum", "of", "symptoms", "[2].", "The", "proportion", "of", "patients", "obtaining", "homeopathic", "care", "has", "quadrupled", "in", "the", "last", "seven", "years", "according", "to", "a", "US", "survey", "[3].", "For", "Germany", "a", "recent", "survey", "demonstrated", "that", "approxi-", "mately", "10%", "of", "men", "and", "20%", "of", "women", "in", "the", "general", "population", "used", "homeopathic", "medicines", "during", "the", "pre-", "vious", "year", "[4].", "To", "date,", "few", "studies", "have", "evaluated", "the", "use", "of", "complementary", "therapies", "in", "geriatric", "patients", "[5].", "In", "Germany,", "73%", "of", "adults", "over", "60", "years", "of", "age", "use", "©", "2010", "Teut", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

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2,684,152

null

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[ "Curr", "Rev", "Musculoskelet", "Med", "(2008)", "1:39–47", "DOI", "10.1007/s12178-007-9004-1", "Yoga", "and", "pilates", "in", "the", "management", "of", "low", "back", "pain", "Susan", "Sorosky", "Æ", "Sonja", "Stilp", "Æ", "Venu", "Akuthota", "Published", "online:", "6", "November", "2007", "Humana", "Press", "2007", "Abstract", "Many", "interventions", "for", "the", "management", "of", "low", "back", "pain", "exist,", "however", "most", "have", "modest", "efﬁcacy", "at", "best,", "and", "there", "are", "few", "with", "clearly", "demonstrated", "beneﬁts", "once", "pain", "becomes", "chronic.", "Therapeutic", "exercise,", "on", "the", "other", "hand,", "does", "appear", "to", "have", "signiﬁcant", "beneﬁts", "for", "managing", "patients", "with", "chronic", "low", "back", "pain", "(CLBP)", "in", "terms", "of", "decreasing", "pain", "and", "improving", "function.", "In", "addition,", "because", "chronic", "pain", "is", "complex", "and", "does", "not", "ﬁt", "a", "simple", "model,", "there", "have", "also", "been", "numerous", "trials", "investigating", "and", "demonstrating", "the", "efﬁcacy", "of", "multidisciplinary", "pain", "programs", "for", "CLBP.", "It", "follows", "that", "interventions", "that", "treat", "more", "than", "one", "aspect", "of", "LBP", "would", "have", "signiﬁcant", "ben-", "eﬁts", "for", "this", "patient", "population.", "Yoga", "and", "Pilates", "which", "have,", "both", "been", "gaining", "in", "popularity", "over", "the", "last", "decade", "are", "two", "mind–body", "exercise", "interventions", "that", "address", "both", "the", "physical", "and", "mental", "aspects", "of", "pain", "with", "core", "strengthening,", "ﬂexibility,", "and", "relaxation.", "There", "has", "been", "a", "slow", "evolution", "of", "these", "nontraditional", "exercise", "regimens", "into", "treatment", "paradigms", "for", "LBP,", "although", "few", "studies", "S.", "Sorosky", "(&)", "Desert", "Pain", "Institute,", "Phoenix,", "AZ,", "USA", "e-mail:", "ssorosky@cox.net", "S.", "Sorosky", "Midwestern", "University,", "Glendale,", "AZ,", "USA", "S.", "Stilp", "Boulder", "Orthopedics,", "Boulder,", "CO,", "USA", "S.", "Stilp", "V.", "Akuthota", "Department", "of", "Physical", "Medicine", "and", "Rehabilitation,", "University", "of", "Colorado", "School", "of", "Medicine,", "New", "York,", "USA", "V.", "Akuthota", "The", "Spine", "Center", "at", "the", "University", "of", "Colorado", "Hospital,", "Aurora,", "CO,", "USA", "examining", "their", "effects", "have", "been", "published.", "The", "following", "article", "will", "focus", "on", "the", "scientiﬁc", "and", "theoretical", "basis", "of", "using", "yoga", "and", "Pilates", "in", "the", "management", "of", "CLBP.", "Keywords", "Low", "back", "pain", "Yoga", "Pilates", "Therapeutic", "exercise", "Core", "strengthening", "Rehabilitation", "Many", "interventions", "for", "the", "management", "of", "low", "back", "pain", "exist,", "however", "most", "have", "modest", "efﬁcacy", "at", "best,", "and", "there", "are", "few", "with", "clearly", "demonstrated", "beneﬁts", "once", "pain", "becomes", "chronic.", "Therapeutic", "exercise,", "on", "the", "other", "hand,", "does", "appear", "to", "have", "signiﬁcant", "beneﬁts", "for", "managing", "patients", "with", "chronic", "low", "back", "pain", "(CLBP).", "In", "a", "system-", "atic", "review", "of", "the", "literature", "evaluating", "exercise", "therapy", "for", "non-speciﬁc", "CLBP,", "the", "authors", "concluded", "therapeutic", "exercise", "is", "effective", "in", "decreasing", "pain", "and", "improving", "function", "in", "this", "patient", "population", "[1].", "Studies", "examining", "speciﬁc", "exercise", "techniques", "for", "LBP", "including", "core", "strengthening", "have", "reported", "even", "more", "promising", "results.", "In", "addition,", "because", "chronic", "pain", "presents", "with", "many", "facets", "and", "does", "not", "ﬁt", "a", "simple", "model,", "there", "have", "also", "been", "numerous", "trials", "investigating", "and", "demonstrating", "the", "efﬁ-", "cacy", "of", "multidisciplinary", "pain", "programs", "for", "CLBP.", "It", "follows", "that", "interventions", "that", "treat", "more", "than", "one", "aspect", "of", "LBP", "would", "have", "signiﬁcant", "beneﬁts", "for", "this", "patient", "pop-", "ulation.", "Yoga", "and", "Pilates", "which", "have", "both", "been", "gaining", "in", "popularity", "over", "the", "last", "decade", "are", "two", "mind–body", "exercise", "interventions", "that", "address", "both", "the", "physical", "and", "mental", "aspects", "of", "pain", "with", "core", "strengthening,", "ﬂexibility", "and", "relaxation.", "There", "has", "been", "a", "slow", "evolution", "of", "these", "non-", "traditional", "exercise", "regimens", "into", "treatment", "paradigms", "for", "LBP,", "although", "few", "studies", "examining", "their", "effects", "have", "been", "published.", "The", "following", "article", "will", "focus", "on", "the" ]

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[ "Cytotoxic", "Effect", "of", "Poly-Dispersed", "Single", "Walled", "Carbon", "Nanotubes", "on", "Erythrocytes", "In", "Vitro", "and", "In", "Vivo", "Sumedha", "Sachar,", "Rajiv", "K.", "Saxena*", "School", "of", "Life", "Sciences,", "Jawaharlal", "Nehru", "University,", "New", "Delhi,", "India", "Abstract", "Single", "wall", "Carbon", "Nanotubes", "(SWCNTs)", "are", "hydrophobic", "and", "do", "not", "disperse", "in", "aqueous", "solvents.", "Acid", "functionalization", "of", "SWCNTs", "results", "in", "attachment", "of", "carboxy", "and", "sulfonate", "groups", "to", "carbon", "atoms", "and", "the", "resulting", "acid", "functionalized", "product", "(AF-SWCNTs)", "is", "negatively", "charged", "and", "disperses", "easily", "in", "water", "and", "buffers.", "In", "the", "present", "study,", "effect", "of", "AF-", "SWCNTs", "on", "blood", "erythrocytes", "was", "examined.", "Incubation", "of", "mouse", "erythrocytes", "with", "AF-SWCNTs", "and", "not", "with", "control", "SWCNTs,", "resulted", "in", "a", "dose", "and", "time", "dependent", "lysis", "of", "erythrocyte.", "Using", "fluorescence", "tagged", "AF-SWCNTs,", "binding", "of", "AF-", "SWCNTs", "with", "erythrocytes", "could", "be", "demonstrated.", "Confocal", "microscopy", "results", "indicated", "that", "AF-SWCNTs", "could", "enter", "the", "erythrocytes.", "Treatment", "with", "AF-SWCNTs", "resulted", "in", "exposure", "of", "hydrophobic", "patches", "on", "erythrocyte", "membrane", "that", "is", "indicative", "of", "membrane", "damage.", "A", "time", "and", "dose", "dependent", "increase", "in", "externalization", "of", "phosphatidylserine", "on", "erythrocyte", "membrane", "bilayer", "was", "also", "found.", "Administration", "of", "AF-SWCNTs", "through", "intravenous", "route", "resulted", "in", "a", "transient", "anemia", "as", "seen", "by", "a", "sharp", "decline", "in", "blood", "erythrocyte", "count", "accompanied", "with", "a", "significant", "drop", "in", "blood", "haemoglobin", "level.", "Administration", "of", "AF-SWCNTs", "through", "intratracheal", "administration", "also", "showed", "significant", "decline", "in", "RBC", "count", "while", "administration", "through", "other", "routes", "(gavage", "and", "intra-peritoneal)", "was", "not", "effective.", "By", "using", "a", "recently", "developed", "technique", "of", "a", "two", "step", "in", "vivo", "biotinylation", "of", "erythrocytes", "that", "enables", "simultaneous", "enumeration", "of", "young", "(age", ",10", "days)", "and", "old", "(age.40", "days)", "erythrocytes", "in", "mouse", "blood,", "it", "was", "found", "that", "the", "in", "vivo", "toxic", "effect", "of", "AF-SWCNTs", "was", "more", "pronounced", "on", "older", "subpopulation", "of", "erythrocytes.", "Subpopulation", "of", "old", "erythrocytes", "fell", "after", "treatment", "with", "AF-SWCNTs", "but", "recovered", "by", "third", "day", "after", "the", "intravenous", "administration", "of", "AF-SWCNTs.", "Taken", "together", "our", "results", "indicate", "that", "treatment", "with", "AF-SWCNTs", "results", "in", "acute", "membrane", "damage", "and", "eventual", "lysis", "of", "erythrocytes.", "Intravenous", "administration", "of", "AF-SWCNTs", "resulted", "in", "a", "transient", "anemia", "in", "which", "older", "erythrocytes", "are", "preferably", "lysed.", "Citation:", "Sachar", "S,", "Saxena", "RK", "(2011)", "Cytotoxic", "Effect", "of", "Poly-Dispersed", "Single", "Walled", "Carbon", "Nanotubes", "on", "Erythrocytes", "In", "Vitro", "and", "In", "Vivo.", "PLoS", "ONE", "6(7):", "e22032.", "doi:10.1371/journal.pone.0022032", "Editor:", "David", "L.", "McCormick,", "IIT", "Research", "Institute,", "United", "States", "of", "America", "Received", "March", "11,", "2011;", "Accepted", "June", "13,", "2011;", "Published", "July", "19,", "2011", "Copyright:", "2011", "Sachar,", "Saxena.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Funding:", "This", "study", "was", "supported", "by", "a", "Department", "of", "Science", "and", "Technology", "(DST)", "grant", "(SR/SO/HS-133/2007)", "to", "RKS,", "and", "a", "fellowship", "from", "DBT", "to", "SS.", "The", "funders", "had", "no", "role", "in", "study", "design,", "data", "collection", "and", "analysis,", "decision", "to", "publish,", "or", "preparation", "of", "the", "manuscript.", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "*", "E-mail:", "rajivksaxena@hotmail.com", "Introduction", "Nano-sized", "particles", "are", "finding", "increasing", "practical", "applica-", "tions", "and", "commercial", "use.", "Consequently,", "the", "possibility", "of", "occupational", "exposure", "to", "nano-particles", "has", "increased.", "Further-", "more,", "as", "the", "use", "of", "nanoparticles", "increases,", "they", "may", "diffuse", "and", "accumulate", "in", "environment", "increasing", "the", "risk", "of", "environmental", "exposure.", "Health", "effects", "of", "exposure", "to", "nanoparticles", "are", "now", "under", "investigation", "by", "many", "researchers", "[1],", "[2],", "[3].", "Nanopar-", "ticles", "have", "a", "tendency", "to", "agglomerate", "into", "particles", "of", "larger", "size", "that", "may", "not", "have", "the", "same", "biological", "effects", "as", "non-agglomerated", "nanoparticles.", "For", "studying", "the", "biological", "effects", "therefore", "it", "is", "necessary", "to", "test", "non-agglomerated", "forms", "of", "nanoparticles.", "For", "Single", "walled", "Carbon", "Nanotubes", "(SWCNTs)", "disaggregation", "can", "be", "achieved", "by", "acid", "functionalization", "that", "introduces", "negative", "charge,", "without", "changing", "the", "essential", "structural", "features", "of", "SWCNTs", "[4],", "[5].", "We", "have", "previously", "reported", "cytostatic", "and", "toxic", "effects", "of", "acid", "functionalized", "SWCNTs", "(AF-SWCNTs)", "on", "LA4", "lung", "epithelial", "cell", "line", "[5].", "We", "also", "found", "that", "the", "administration", "of", "AF-SWCNTs", "intratracheally", "resulted", "in", "cardiac", "damage", "in", "mice", "[6].", "Since", "AF-SWCNTs", "were", "toxic", "to", "some", "types", "of", "nucleated", "cells", "that", "are", "capable", "of", "self", "repair,", "we", "hypothesized", "that", "the", "AF-", "SWCNTs", "may", "have", "a", "more", "aggravated", "toxic", "effect", "on", "erythrocytes", "that", "have", "no", "nucleus", "and", "lack", "substantial", "cellular", "repair", "mechanisms.", "This", "proposition", "was", "examined", "in", "the", "present", "study.", "Our", "results", "indicate", "that", "unlike", "pristine", "SWCNTs,", "AF-", "SWCNTs", "are", "significantly", "toxic", "to", "mouse", "blood", "derived", "erythrocytes", "in", "vitro", "as", "well", "as", "in", "vivo.", "AF-SWCNTs", "were", "found", "to", "bind", "with", "erythrocytes", "and", "cause", "significant", "membrane", "damage", "as", "well", "as", "externalization", "of", "phosphatidylserine.", "Administration", "of", "AF-SWCNTs", "intravenously", "induced", "a", "significant", "though", "transient", "anemia", "in", "mice.", "Older", "as", "compared", "to", "the", "younger", "subpopulation", "of", "erythrocyte", "in", "blood", "circulation,", "was", "more", "susceptible", "to", "the", "toxic", "effect", "of", "AF-SWCNTs.", "Taken", "together", "our", "results", "show", "that", "non-agglomerated", "form", "of", "SWCNTs", "may", "exert", "significant", "and", "rapid", "toxic", "effects", "on", "blood", "erythrocytes.", "Materials", "and", "Methods", "Experimental", "model", "Inbred", "Swiss", "and", "C57BL/6", "female", "mice", "(6–12", "weeks", "old,", "20–25", "g", "body", "weight)", "were", "used", "throughout", "this", "study.", "Animals", "were", "bred", "and", "maintained", "in", "the", "animal", "house", "facility", "at", "JNU,", "New", "Delhi", "or", "obtained", "from", "the", "National", "Institute", "of", "Nutrition,", "Hyderabad.", "The", "animals", "were", "housed", "in", "positive-pressure", "air", "PLoS", "ONE", "|", "www.plosone.org", "1", "July", "2011", "|", "Volume", "6", "|", "Issue", "7", "|", "e22032" ]

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2,676,305

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[ "BMC", "Genomics", "Research", "article", "Small", "noncoding", "RNA", "GcvB", "is", "a", "novel", "regulator", "of", "acid", "resistance", "in", "Escherichia", "coli", "Ye", "Jin1,", "Rory", "M", "Watt2,", "Antoine", "Danchin3", "and", "Jian-dong", "Huang*1", "BioMed", "Central", "Open", "Access", "Address:", "1Department", "of", "Biochemistry,", "Li", "Ka", "Shing", "Faculty", "of", "Medicine,", "University", "of", "Hong", "Kong,", "Pok", "Fu", "Lam,", "Hong", "Kong", "SAR,", "PR", "China,", "2Oral", "Biosciences,", "Faculty", "of", "Dentistry,", "University", "of", "Hong", "Kong,", "Pok", "Fu", "Lam,", "Hong", "Kong", "SAR,", "PR", "China", "and", "3Genetics", "of", "Bacterial", "Genomes,", "CNRS", "URA2171,", "Institut", "Pasteur,", "28,", "rue", "du", "Docteur", "Roux,", "Paris", "Cedex", "15,", "75724,", "France", "Email:", "Ye", "Jin", "-", "yejin@hkucc.hku.hk;", "Rory", "M", "Watt", "-", "rmwatt@hku.hk;", "Antoine", "Danchin", "-", "antoine.danchin@normalesup.org;", "Jian-", "dong", "Huang*", "-", "jdhuang@hkucc.hku.hk", "*", "Corresponding", "author", "Published:", "20", "April", "2009", "BMC", "Genomics", "2009,", "10:165", "doi:10.1186/1471-2164-10-165", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1471-2164/10/165", "Received:", "26", "January", "2009", "Accepted:", "20", "April", "2009", "©", "2009", "Jin", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "The", "low", "pH", "environment", "of", "the", "human", "stomach", "is", "lethal", "for", "most", "microorganisms;", "but", "not", "Escherichia", "coli,", "which", "can", "tolerate", "extreme", "acid", "stress.", "Acid", "resistance", "in", "E.", "coli", "is", "hierarchically", "controlled", "by", "numerous", "regulators", "among", "which", "are", "small", "noncoding", "RNAs", "(sncRNA).", "Results:", "In", "this", "study,", "we", "individually", "deleted", "seventy-nine", "sncRNA", "genes", "from", "the", "E.", "coli", "K12-", "MG1655", "chromosome,", "and", "established", "a", "single-sncRNA", "gene", "knockout", "library.", "By", "systematically", "screening", "the", "sncRNA", "mutant", "library,", "we", "show", "that", "the", "sncRNA", "GcvB", "is", "a", "novel", "regulator", "of", "acid", "resistance", "in", "E.", "coli.", "We", "demonstrate", "that", "GcvB", "enhances", "the", "ability", "of", "E.", "coli", "to", "survive", "low", "pH", "by", "upregulating", "the", "levels", "of", "the", "alternate", "sigma", "factor", "RpoS.", "Conclusion:", "GcvB", "positively", "regulates", "acid", "resistance", "by", "affecting", "RpoS", "expression.", "These", "data", "advance", "our", "understanding", "of", "the", "sncRNA", "regulatory", "network", "involved", "in", "modulating", "acid", "resistance", "in", "E.", "coli.", "Background", "The", "ability", "to", "survive", "the", "extremely", "low", "pH", "environment", "present", "within", "the", "stomach", "(pH", "values", "<", "2.5)", "is", "essential", "for", "colonization", "of", "the", "intestine", "by", "commensals", "and", "for", "the", "pathogenesis", "of", "enteric", "bacteria.", "Three", "distinct", "acid", "resistance", "(AR)", "systems", "are", "responsible", "for", "protecting", "bac-", "terial", "cells", "from", "acid", "shock", "[1-3].", "AR", "system", "1", "is", "a", "glucose-", "repressed", "system", "and", "does", "not", "require", "any", "external", "amino", "acids", "to", "function", "at", "low", "pH", "[1].", "Unidentified", "components", "of", "this", "system", "are", "controlled", "by", "the", "alternate", "sigma", "factor", "RpoS,", "with", "the", "underlying", "mechanism", "remaining", "unclear", "[1].", "In", "contrast,", "AR", "systems", "2", "and", "3", "provide", "AR", "by", "con-", "suming", "intracellular", "protons", "via", "the", "glutamate", "(AR2)", "and", "arginine", "(AR3)", "decarboxylation", "reactions", "[2,3].", "AR2", "is", "the", "most", "efficient", "AR", "system.", "It", "involves", "two", "isozymes", "of", "glutamate", "decarboxylase,", "encoded", "by", "genes", "gadA", "and", "gadB,", "and", "a", "membrane-associated", "antiporter", "(GadC)", "that", "exchanges", "external", "glutamate", "for", "the", "intracellular", "decar-", "boxylation", "product", "γ-aminobutyric", "acid", "(GABA)", "[2].", "AR2", "is", "hierarchically", "regulated", "by", "multiple", "regulators,", "which", "include", "small", "noncoding", "RNAs", "(sncRNA)", "DsrA", "and", "possibly", "GadY.", "DsrA", "activates", "the", "expression", "of", "rpoS", "[4]", "and", "several", "AR", "genes", "including", "hdeAB,", "gadAX,", "and", "gadBC", "[5].", "GadY,", "whose", "effects", "on", "AR", "have", "yet", "to", "be", "determined,", "controls", "the", "synthesis", "of", "GadX", "and", "GadW,", "which", "are", "reg-", "Page", "1", "of", "7", "(page", "number", "not", "for", "citation", "purposes)" ]

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3,199,268

null

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[ "Fluch", "et", "al.", "BMC", "Research", "Notes", "2011,", "4:401", "http://www.biomedcentral.com/1756-0500/4/401", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Characterization", "of", "variable", "EST", "SSR", "markers", "for", "Norway", "spruce", "(Picea", "abies", "L.)", "Silvia", "Fluch1*,", "Agnes", "Burg1,", "Dieter", "Kopecky1,", "Andreas", "Homolka1,", "Nadine", "Spiess1", "and", "Giovanni", "G", "Vendramin2", "Abstract", "Background:", "Norway", "spruce", "is", "widely", "distributed", "across", "Europe", "and", "the", "predominant", "tree", "of", "the", "Alpine", "region.", "Fast", "growth", "and", "the", "fact", "that", "timber", "can", "be", "harvested", "cost-effectively", "in", "relatively", "young", "populations", "define", "its", "status", "as", "one", "of", "the", "economically", "most", "important", "tree", "species", "of", "Northern", "Europe.", "In", "this", "study,", "EST", "derived", "simple", "sequence", "repeat", "(SSR)", "markers", "were", "developed", "for", "the", "assessment", "of", "putative", "functional", "diversity", "in", "Austrian", "Norway", "spruce", "stands.", "Results:", "SSR", "sequences", "were", "identified", "by", "analyzing", "14,022", "publicly", "available", "EST", "sequences.", "Tri-nucleotide", "repeat", "motifs", "were", "most", "abundant", "in", "the", "data", "set", "followed", "by", "penta-", "and", "hexa-nucleotide", "repeats.", "Specific", "primer", "pairs", "were", "designed", "for", "sixty", "loci.", "Among", "these,", "27", "displayed", "polymorphism", "in", "a", "testing", "population", "of", "16", "P.", "abies", "individuals", "sampled", "across", "Austria", "and", "in", "an", "additional", "screening", "population", "of", "96", "P.", "abies", "individuals", "from", "two", "geographically", "distinct", "Austrian", "populations.", "Allele", "numbers", "per", "locus", "ranged", "from", "two", "to", "17", "with", "observed", "heterozygosity", "ranging", "from", "0.075", "to", "0.99.", "Conclusions:", "We", "have", "characterized", "variable", "EST", "SSR", "markers", "for", "Norway", "spruce", "detected", "in", "expressed", "genes.", "Due", "to", "their", "moderate", "to", "high", "degree", "of", "variability", "in", "the", "two", "tested", "screening", "populations,", "these", "newly", "developed", "SSR", "markers", "are", "well", "suited", "for", "the", "analysis", "of", "stress", "related", "functional", "variation", "present", "in", "Norway", "spruce", "populations.", "Background", "Natural", "populations", "of", "Picea", "abies", "L.", "(Norway", "spruce)", "are", "found", "from", "north-western", "Europe", "outside", "perma-", "frost", "areas", "down", "to", "northern", "Greece,", "westwards", "to", "the", "Massif", "Central", "(France)", "and", "east", "to", "the", "Ural", "Mountains.", "Picea", "abies", "is", "growing", "above", "400-500", "m", "and", "ascends", "close", "to", "2000", "m", "in", "the", "Alps.", "Studies", "on", "genetic", "variation", "based", "on", "allozymes", "have", "shown", "that", "Picea", "abies", "genetic", "differentiation", "among", "populations", "is", "rather", "low", "over", "its", "whole", "distribution", "range", "[1,2].", "Previous", "studies", "on", "the", "genetic", "structure", "of", "P.", "abies", "using", "organelle", "markers", "showed", "pronounced", "differentiation", "between", "north-east", "boreal", "origins", "and", "areas", "in", "the", "central", "European", "moun-", "tains", "[3,4],", "supporting", "the", "hypothesis", "of", "two", "distinct", "main", "glacial", "refugia", "as", "postulated", "from", "pollen", "data", "[5].", "Initial", "reports", "on", "the", "occurrence", "of", "SSRs", "in", "conifers", "such", "as", "Pinus", "radiata", "[6],", "Pinus", "sylvestris", "[7]", "or", "Picea", "*", "Correspondence:", "silvia.fluch@ait.ac.at", "1AIT", "Austrian", "Institute", "of", "Technology", "GmbH,", "Health", "&", "Environment", "Department,", "Bioresources,", "3430", "Tulln,", "Austria", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "abies", "[8]", "have", "shown", "that", "marker", "development", "for", "such", "complex", "genomes", "is", "difficult.", "Frequently", "several", "DNA", "fragments", "in", "addition", "to", "the", "expected", "ones", "are", "amplified", "when", "using", "primers", "flanking", "putative", "SSR", "regions.", "This", "can", "be", "attributed", "to", "the", "very", "large", "size", "of", "the", "conifer", "genomes,", "with", "Norway", "spruce", "having", "39.140", "Mb", "in", "the", "diploid", "genome", "(2n", "=", "24)", "as", "well", "as", "the", "high", "proportion", "of", "repetitive", "DNA", "in", "the", "conifer", "genomes", "[9].", "These", "repetitive", "elements", "as", "well", "as", "pseudogenes", "frequently", "produce", "complex", "amplification", "products", "from", "multiple", "loci", "[10,11].", "To", "overcome", "this", "problem,", "Scotti", "et", "al.", "[12]", "showed", "that", "by", "isolating", "di-nucleotide", "SSRs", "from", "cDNA", "libraries", "of", "conifer", "species", "this", "problem", "can", "be", "over-", "come", "relying", "on", "the", "fact", "that", "expressed", "genes", "are", "less", "likely", "to", "be", "of", "repetitive", "nature", "in", "the", "genome.", "Following", "this", "line", "of", "exploiting", "the", "advantages", "of", "publicly", "available", "data", "on", "expressed", "sequences", "(ESTs)", "as", "source", "for", "marker", "development", "[13]", "as", "described", "also", "by", "Rungis", "et", "al.", "[14]", "for", "conifers,", "we", "used", "Norway", "spruce", "EST", "sequences", "from", "NCBI", "for", "in", "silico", "identification", "of", "SSR", "regions", "which", "could", "serve", "for", "marker", "development.", "©", "2011", "Fluch", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

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3,014,698

null

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[ "SAGE-Hindawi", "Access", "to", "Research", "Cardiology", "Research", "and", "Practice", "Volume", "2011,", "Article", "ID", "714515,", "10", "pages", "doi:10.4061/2011/714515", "Review", "Article", "Local", "Bone", "Marrow", "Renin-Angiotensin", "System", "and", "Atherosclerosis", "Yavuz", "Beyazit,1", "Tugrul", "Purnak,2", "Gulay", "Sain", "Guven,3", "and", "Ibrahim", "C.", "Haznedaroglu1", "1", "Department", "of", "Gastroenterology,", "Turkiye", "Yuksek", "Ihtisas", "Teaching", "and", "Research", "Hospital,", "06100", "Ankara,", "Turkey", "2", "Department", "of", "Gastroenterology,", "Ankara", "Numune", "Education", "and", "Research", "Hospital,", "06100", "Ankara,", "Turkey", "3", "Department", "of", "Internal", "Medicine,", "Faculty", "of", "Medicine,", "Hacettepe", "University,", "06100", "Ankara,", "Turkey", "Correspondence", "should", "be", "addressed", "to", "Yavuz", "Beyazit,", "yavuzbeyaz@yahoo.com", "Received", "28", "September", "2010;", "Revised", "14", "October", "2010;", "Accepted", "23", "October", "2010", "Academic", "Editor:", "Masaki", "Mogi", "Copyright", "©", "2011", "Yavuz", "Beyazit", "et", "al.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Local", "hematopoietic", "bone", "marrow", "(BM)", "renin-angiotensin", "system", "(RAS)", "aﬀects", "the", "growth,", "production,", "proliferation", "diﬀerentiation,", "and", "function", "of", "hematopoietic", "cells.", "Angiotensin", "II", "(Ang", "II),", "the", "dominant", "eﬀector", "peptide", "of", "the", "RAS,", "regulates", "cellular", "growth", "in", "a", "wide", "variety", "of", "tissues", "in", "pathobiological", "states.", "RAS,", "especially", "Ang", "II", "and", "Ang", "II", "type", "1", "receptor", "(AT1R),", "has", "considerable", "proinﬂammatory", "and", "proatherogenic", "eﬀects", "on", "the", "vessel", "wall,", "causing", "progression", "of", "atherosclerosis.", "Recent", "investigations,", "by", "analyzing", "several", "BM", "chimeric", "mice", "whose", "BM", "cells", "were", "positive", "or", "negative", "for", "AT1R,", "disclosed", "that", "AT1R", "in", "BM", "cells", "participates", "in", "the", "pathogenesis", "of", "atherosclerosis.", "Therefore,", "AT1R", "blocking", "not", "only", "in", "vascular", "cells", "but", "also", "in", "the", "BM", "could", "be", "an", "important", "therapeutic", "approach", "to", "prevent", "atherosclerosis.", "The", "aim", "of", "this", "paper", "is", "to", "review", "the", "function", "of", "local", "BM", "RAS", "in", "the", "pathogenesis", "of", "atherosclerosis.", "1.", "Introduction", "The", "renin-angiotensin", "system", "(RAS)", "plays", "a", "crucial", "role", "in", "the", "control", "of", "blood", "pressure,", "blood", "ﬂow,", "ﬂuid", "volume,", "and", "electrolyte", "balance,", "and", "overactivity", "of", "this", "system", "contributes", "to", "the", "pathogenesis", "of", "a", "variety", "of", "clinical", "conditions,", "including", "onset,", "progression,", "and", "outcome", "of", "atherosclerosis", "[1–3].", "Angiotensinogen", "(AGT)", "produced", "in", "the", "liver", "is", "the", "precursor", "of", "angiotensin", "I", "(Ang", "I),", "an", "inactive", "decapeptide", "that", "is", "converted", "into", "Ang", "II,", "the", "main", "eﬀector", "of", "the", "RAS.", "Its", "only", "role", "known", "is", "as", "a", "substrate", "for", "renin,", "a", "highly", "speciﬁc", "aspartyl", "protease.", "Renin", "that", "is", "secreted", "from", "juxtaglomerular", "apparatus", "of", "the", "kidney", "cleaves", "the", "N-", "terminal", "end", "of", "AGT", "to", "generate", "Ang", "I.", "Ang", "I", "is", "then", "activated", "to", "the", "Ang", "II", "by", "angiotensin", "converting", "enzyme", "(ACE),", "which", "is", "predominantly", "expressed", "in", "high", "concentrations", "on", "the", "surface", "of", "endothelial", "cells", "in", "the", "pulmonary", "circulation", "[4].", "Ang", "II", "plays", "a", "main", "role", "in", "the", "RAS", "mediated", "mainly", "by", "two", "seven", "transmembrane", "domain", "receptors", "termed", "Ang", "II", "type", "1", "receptor", "(AT1R)", "and", "Ang", "II", "type", "2", "receptor", "(AT2R)", "showing", "a", "complex", "pattern", "of", "regulation", "and", "function", "[5].", "Most", "of", "the", "well-known", "actions", "of", "Ang", "II-AT1R", "interaction", "causes", "vasoconstriction", "and", "aldosterone", "release", "from", "the", "adrenal", "gland.", "This", "classical", "description", "of", "the", "RAS", "has", "been", "expanded", "by", "recent", "ﬁndings", "that", "RAS", "is", "activated", "locally,", "particularly", "in", "the", "vessel", "wall,", "heart,", "the", "kidney,", "and", "the", "brain", "[6–14].", "Ang", "II", "was", "also", "described", "to", "be", "produced", "by", "other", "enzymes", "such", "as", "chymase,", "an", "eﬃcient", "Ang", "II-forming", "serine", "protease", "[15].", "It", "is", "not", "aﬀected", "by", "ACE", "inhibition", "and", "has", "been", "suggested", "as", "relevant", "for", "alternative", "pathways", "of", "Ang", "II", "generation", "[16–18].", "Although", "several", "other", "alternative", "enzymes", "involved", "in", "Ang", "II", "formation", "such", "as", "tonin", "and", "cathepsins,", "chymase", "deserves", "special", "attention", "due", "to", "its", "high", "substrate", "speciﬁcity.", "The", "enzyme", "is", "also", "expressed", "in", "the", "vascular", "wall,", "where", "it", "has", "been", "suggested", "as", "a", "possible", "player", "in", "Ang", "II-mediated", "arteriosclerosis", "[15].", "Inﬂammatory", "cells", "detected", "in", "atherosclerotic", "lesions", "are", "mainly", "originated", "from", "bone", "marrow", "(BM).", "The", "presence", "of", "a", "locally", "activated", "bone", "marrow", "(BM)", "RAS", "aﬀecting", "the", "growth,", "production,", "proliferation,", "and", "diﬀerentiation", "of", "hematopoietic", "cells", "was", "suggested", "in", "1996", "[19].", "Other", "than", "a", "wide", "variety", "of", "evidences", "disclosed", "the", "existence", "of", "a", "functional", "local", "BM", "RAS.", "Angiotensin", "II,", "through", "interacting" ]

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2,596,168

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[ "BioPsychoSocial", "Medicine", "Research", "General", "practitioners'", "responses", "to", "the", "initial", "presentation", "of", "medically", "unexplained", "symptoms:", "a", "quantitative", "analysis", "Teus", "Kappen", "and", "Sandra", "van", "Dulmen*", "BioMed", "Central", "Open", "Access", "Address:", "NIVEL", "(Netherlands", "Institute", "for", "Health", "Services", "Research),", "P.O.Box", "1568,", "3500", "BN", "Utrecht,", "The", "Netherlands", "Email:", "Teus", "Kappen", "-", "t.kappen@umcutrecht.nl;", "Sandra", "van", "Dulmen*", "-", "s.vandulmen@nivel.nl", "*", "Corresponding", "author", "Published:", "17", "November", "2008", "BioPsychoSocial", "Medicine", "2008,", "2:22", "doi:10.1186/1751-0759-2-22", "This", "article", "is", "available", "from:", "http://www.bpsmedicine.com/content/2/1/22", "Received:", "27", "June", "2008", "Accepted:", "17", "November", "2008", "©", "2008", "Kappen", "and", "van", "Dulmen;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "Physicians", "in", "primary", "and", "secondary", "care", "are", "frequently", "confronted", "with", "patients", "with", "medically", "unexplained", "symptoms", "(MUS).", "In", "order", "to", "solve", "their", "patients'", "problems", "and", "out", "of", "a", "fear", "of", "overlooking", "a", "serious", "disease,", "many", "physicians", "give", "their", "patients", "full", "physical", "examinations", "and", "interventions,", "thereby", "incorrectly", "confirming", "the", "somatic", "nature", "of", "their", "condition.", "Preventing", "somatization", "could", "be", "achieved", "by", "examining", "the", "patient's", "symptom", "presentation", "for", "clues", "to", "underlying", "psychosocial", "issues", "and", "by", "an", "appropriate", "physician", "response.", "Methods:", "Ninety-seven", "videotaped", "medical", "visits", "from", "primary", "care", "patients", "presenting", "MUS", "for", "the", "first", "time", "were", "analyzed.", "Patients'", "presentations", "were", "categorized", "in:", "(1)", "symptoms", "only;", "(2)", "symptoms", "with", "a", "clue", "to", "an", "underlying", "concern;", "or", "(3)", "symptoms", "with", "an", "explicit", "concern.", "General", "practitioners'", "(GPs')", "responses", "to", "patients'", "presentation", "were", "classified", "into", "ignoring", "or", "more", "or", "less", "exploring", "responses.", "Exploring", "responses", "were", "further", "subdivided", "in", "non-directional", "explorations,", "clue", "explorations", "and", "medical", "explorations.", "Results:", "Results", "show", "that", "most", "patients", "presented", "their", "symptoms", "together", "with", "a", "reference", "to", "an", "underlying", "concern.", "Yet,", "most", "of", "them", "did", "so", "in", "an", "implicit", "way.", "GPs", "usually", "explored", "the", "concern", "presented", "by", "the", "patients,", "but", "most", "often", "in", "a", "medical", "way", "only.", "Conclusion:", "To", "address", "the", "potential", "psychological", "basis", "of", "patients'", "medically", "unexplained", "symptoms,", "GPs", "should", "pay", "more", "attention", "to", "the", "specific", "clues", "patients", "present", "to", "them.", "Likewise,", "in", "order", "to", "receive", "full", "attention,", "patients", "should", "try", "to", "present", "their", "concerns", "more", "explicitly.", "Background", "In", "primary", "as", "well", "as", "secondary", "care", "a", "large", "number", "of", "patients", "commonly", "present", "with", "persistent", "physical", "symp-", "toms", "for", "which", "no", "somatic", "origin", "can", "be", "found.", "The", "major", "issue", "in", "these", "medically", "unexplained", "symptoms", "(MUS)", "is", "that", "there", "is", "a", "delicate", "balance", "between", "diagnosing", "MUS", "and", "the", "physician", "missing", "a", "somatic", "disease.", "Because", "phy-", "sicians", "take", "responsibility", "for", "solving", "their", "patients'", "prob-", "lems", "and", "because", "they", "are", "afraid", "of", "overlooking", "serious", "diseases,", "many", "patients", "receive", "a", "whole", "spectrum", "of", "phys-", "ical", "examinations,", "interventions", "and", "referrals,", "to", "exclude", "potential", "somatic", "causes.", "This", "contributes", "to", "their", "beliefs", "that", "the", "presented", "symptoms", "are", "indeed", "of", "physical", "ori-", "gin,", "which", "was", "described", "by", "Quill", "[1]", "and", "others", "as", "a", "path-", "ologic", "intervention", "cycle,", "suggesting", "the", "chronic", "nature", "of", "these", "symptoms", "to", "be", "of", "iatrogenic", "origin.", "Page", "1", "of", "8", "(page", "number", "not", "for", "citation", "purposes)" ]

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3,095,245

null

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[ "Hindawi", "Publishing", "Corporation", "Clinical", "and", "Developmental", "Immunology", "Volume", "2011,", "Article", "ID", "235142,", "6", "pages", "doi:10.1155/2011/235142", "Review", "Article", "Adaptive", "Immune", "Responses", "in", "Primary", "Cutaneous", "Sarcoidosis", "Matteo", "Bordignon,1", "Paola", "Rottoli,2", "Carlo", "Agostini,3", "and", "Mauro", "Alaibac1", "1", "Unit", "of", "Dermatology,", "University", "of", "Padua,", "Via", "Cesare", "Battisti", "206,", "35128", "Padua,", "Italy", "2", "Respiratory", "Diseases", "Section,", "Department", "of", "Clinical", "Medicine", "and", "Immunological", "Sciences,", "Siena", "University,", "53100", "Siena,", "Italy", "3", "Department", "of", "Clinical", "and", "Experimental", "Medicine,", "University", "of", "Padua,", "Via", "Cesare", "Battisti", "206,", "35128", "Padua,", "Italy", "Correspondence", "should", "be", "addressed", "to", "Mauro", "Alaibac,", "mauro.alaibac@unipd.it", "Received", "31", "July", "2010;", "Accepted", "27", "January", "2011", "Academic", "Editor:", "E.", "Shevach", "Copyright", "©", "2011", "Matteo", "Bordignon", "et", "al.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Sarcoidosis", "is", "a", "multisystemic", "inﬂammatory", "disorder", "with", "cutaneous", "lesions", "present", "in", "about", "one-quarter", "of", "the", "patients.", "Cutaneous", "lesions", "have", "been", "classiﬁed", "as", "speciﬁc", "and", "nonspeciﬁc,", "depending", "on", "the", "presence", "of", "nonnecrotizing", "epithelial", "cell", "granulomas", "on", "histologic", "studies.", "The", "development", "and", "progression", "of", "speciﬁc", "cutaneous", "sarcoidosis", "involves", "a", "complex", "interaction", "between", "cells", "of", "the", "adaptive", "immune", "systems,", "notably", "T-lymphocytes", "and", "dendritic", "cells.", "In", "this", "paper,", "we", "will", "discuss", "the", "role", "of", "T-cells", "and", "skin", "dendritic", "cells", "in", "the", "development", "of", "primary", "cutaneous", "sarcoidosis", "and", "comment", "on", "the", "potential", "antigenic", "stimuli", "that", "may", "account", "for", "the", "development", "of", "the", "immunological", "response.", "We", "will", "further", "explore", "the", "contributions", "of", "selected", "cytokines", "to", "the", "immunopathological", "process.", "The", "knowledge", "of", "the", "adaptive", "immunological", "mechanisms", "operative", "in", "cutaneous", "sarcoidosis", "may", "subsequently", "be", "useful", "for", "identifying", "prevention", "and", "treatment", "strategies", "of", "systemic", "sarcoidosis.", "1.", "Introduction", "Sarcoidosis", "is", "a", "multisystemic", "inﬂammatory", "disorder", "charac-", "terized", "by", "the", "accumulation", "of", "mononuclear", "phagocytes", "with", "the", "formation", "of", "nonnecrotizing", "epithelial", "cell", "granulomas.", "Multiple", "organs", "may", "be", "involved,", "including", "lungs,", "mediasti-", "nal", "and", "peripheral", "lymph", "nodes,", "liver,", "spleen,", "skin,", "eyes,", "and", "parotid", "glands;", "central", "nervous", "system,", "heart,", "upper", "respir-", "atory", "tract,", "bones,", "and", "joints", "are", "less", "frequently", "but", "usually", "more", "severely", "involved", "[1,", "2].", "Sarcoidosis", "is", "characterized", "by", "local", "immune", "hyperacti-", "vation", "associated", "with", "clinical", "anergy", "[3].", "The", "pathogenesis", "of", "sarcoidosis", "is", "suspected", "to", "be", "a", "host", "immunologic", "response", "to", "an", "antigenic", "exposure", "[4].", "The", "role", "of", "T-lymphocytes", "in", "the", "recognition", "of", "speciﬁc", "antigens", "and", "in", "the", "ampliﬁcation", "of", "inﬂammatory", "responses", "has", "been", "well", "established", "[5].", "In", "addition,", "dendritic", "cells", "have", "recently", "been", "shown", "to", "have", "a", "prominent", "role", "in", "the", "immunopathological", "processes", "op-", "erating", "in", "this", "condition", "[6,", "7].", "Cutaneous", "involvement", "in", "sarcoidosis", "occurs", "in", "about", "one-quarter", "of", "the", "patients", "and", "is", "generally", "observed", "at", "the", "onset", "of", "the", "disease", "process", "although", "it", "may", "occur", "coincident", "with", "or", "after", "systemic", "involvement", "[8,", "9].", "Therefore,", "cuta-", "neous", "lesions", "can", "be", "an", "initial", "presentation", "and", "are", "probably", "an", "important", "factor", "in", "the", "investigation", "of", "the", "etiology", "of", "sarcoidosis.", "Skin", "lesions", "may", "be", "classiﬁed", "in", "speciﬁc,", "when", "histology", "shows", "typical", "noncaseating", "granulomatous", "inﬂammation,", "or", "non", "speciﬁc,", "in", "presence", "of", "reactive", "process", "without", "granu-", "lomas.", "2.", "Clinical", "Aspects", "of", "Primary", "Cutaneous", "Sarcoidosis", "The", "frequency", "of", "speciﬁc", "skin", "involvement", "ranges", "from", "9%", "to", "37%", "[10].", "All", "speciﬁc", "cutaneous", "lesions", "exhibit", "non-", "caseating", "granulomas", "on", "biopsy.", "Histological", "ﬁndings", "in", "speciﬁc", "sarcoid", "lesions", "show", "aggregates", "of", "epithelioid", "histi-", "ocytes", "with", "occasional", "Langhans", "giant", "cells", "and", "few", "or", "no", "other", "inﬂammatory", "cells,", "the", "so-called", "naked", "or", "sarcoidal", "noncaseating", "granulomas.", "Frequently,", "there", "are", "inclusion", "bodies", "in", "giant", "cells", "[11].", "The", "centre", "of", "granulomas", "is", "typically", "surrounded", "by", "CD4+", "lymphocytes,", "rare", "CD8+", "lymphocytes", "and", "mature", "macrophages.", "Despite", "the", "same", "histologic", "appearance,", "clinical", "manifestations", "of", "primary", "cutaneous", "sarcoidosis", "may", "be", "variable." ]

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[ "Erbudak", "and", "Erzan", "Theoretical", "Biology", "and", "Medical", "Modelling", "2010,", "7:30", "http://www.tbiomed.com/content/7/1/30", "R", "E", "S", "E", "A", "R", "C", "H", "Open", "Access", "Tracking", "tumor", "evolution", "via", "prostate-specific", "antigen:", "an", "individual", "post-operative", "study", "Mehmet", "Erbudak1*,", "Ayşe", "Erzan2", "*", "Correspondence:", "erbudak@phys.", "ethz.ch", "1Laboratory", "for", "Solid", "State", "Physics,", "ETH", "Zurich,", "CH-8093", "Zurich,", "Switzerland", "Abstract", "Background:", "The", "progress", "of", "the", "prostate-specific", "antigen", "(PSA)", "level", "after", "radical", "prostatectomy", "is", "observed", "for", "a", "patient", "in", "order", "to", "extract", "information", "about", "the", "mode", "of", "tumor", "cell", "growth.", "Although", "PSA", "values", "are", "determined", "routinely", "to", "find", "the", "doubling", "time", "of", "the", "prostate", "marker,", "to", "our", "knowledge,", "this", "analysis", "is", "the", "first", "in", "the", "literature.", "Results:", "The", "prostate", "tumor", "marker", "values", "were", "determined", "regularly", "after", "the", "surgery", "and", "plotted", "on", "a", "logarithmic", "scale", "against", "time.", "An", "initial", "rapid-growth", "mode", "changed", "to", "a", "slower", "power-law", "regime", "within", "two", "years", "of", "surgery.", "Our", "analysis", "associates", "this", "observation", "with", "a", "transition", "in", "the", "growth", "mode", "from", "unrestricted", "growth", "of", "dispersed", "cells", "to", "their", "clumping", "into", "macroscopic", "structures.", "Conclusions:", "Such", "studies", "may", "help", "determine", "the", "appropriate", "time", "window", "for", "postoperative", "therapies", "in", "order", "to", "increase", "the", "life", "expectancy", "of", "the", "patient.", "Background", "Cancer", "of", "the", "prostate", "gland", "is", "one", "of", "the", "most", "frequently", "diagnosed", "male", "illnesses", "and", "may", "lead", "to", "death", "of", "the", "patient.", "The", "carcinoma", "is", "routinely", "detected", "by", "a", "straight-", "forward", "blood", "test", "that", "measures", "a", "glycoprotein", "called", "prostate-specific", "antigen", "(PSA).", "At", "an", "early", "stage", "of", "cancer", "growth", "with", "a", "localized", "tumor,", "radical", "removal", "of", "the", "pros-", "tate", "gland", "has", "proved", "to", "be", "the", "optimum", "treatment.", "If", "the", "PSA", "value", "rises", "after", "radical", "prostatectomy,", "different", "alternatives", "for", "treatment", "are", "currently", "under", "debate.", "The", "doubling", "time", "(DT)", "of", "the", "PSA", "value", "is", "accepted", "as", "a", "strong", "prognostic", "factor", "for", "the", "risk", "of", "cancer", "death.", "In", "a", "group", "of", "379", "patients,", "almost", "no", "prostate", "cancer", "deaths", "were", "recorded", "within", "approximately", "4", "years", "of", "prostate", "removal", "for", "3", "<", "DT", "<", "8.9", "months,", "while", "some", "patients", "with", "DT", "<", "3", "months", "died", "within", "1.5", "years", "[1].", "It", "is", "therefore", "rea-", "sonable", "to", "infer", "that", "findings", "during", "the", "last", "few", "years", "based", "on", "long-term", "statistics", "suggest", "a", "longer", "life", "expectancy", "for", "patients", "with", "postoperative", "radiotherapy", "that", "fol-", "lows", "(within", "6", "months", "of)", "radical", "prostate", "surgery", "[2].", "Transdermal", "radiotherapy", "is", "commonly", "applied", "after", "the", "PSA", "level", "reaches", "a", "threshold", "value.", "However,", "a", "wait-and-", "watch", "method", "may", "cost", "valuable", "time", "and", "the", "relevant", "moment", "for", "action", "may", "be", "missed", "regardless", "of", "how", "low", "the", "threshold", "value", "is", "set.", "Many", "authors", "have", "already", "suggested", "[3-5]", "that", "the", "entire", "course", "of", "tumor", "growth", "offers", "important", "information", "regarding", "the", "clinical", "strategies", "to", "be", "followed.", "©", "2010", "Erbudak", "and", "Erzan;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

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[ "BMC", "Musculoskeletal", "Disorders", "BioMed", "Central", "3BR2M0e0Cs2eM,ausrccuhlosakerltetiacllDeisorders", "x", "Correlation", "of", "the", "score", "for", "subjective", "pain", "with", "physical", "disability,", "clinical", "and", "radiographic", "scores", "in", "recent", "onset", "rheumatoid", "arthritis", "Piercarlo", "Sarzi-Puttini*1,", "Tania", "Fiorini2,", "Benedetta", "Panni1,", "Maurizio", "Turiel2,", "Marco", "Cazzola1", "and", "Fabiola", "Atzeni1", "Address:", "1Rheumatology", "Unit,", "University", "Hospital", "L.", "Sacco,", "Milan,", "Italy", "and", "2Istituto", "di", "Scienze", "Biomediche,", "Università", "di", "Milano,", "Italy", "E-mail:", "Piercarlo", "Sarzi-Puttini*", "-", "sarzi@tiscalinet.it;", "Tania", "Fiorini", "-", "tania@posta.statfac.unibo.it;", "Benedetta", "Panni", "-", "benedetta_p@virgilio.it;", "Maurizio", "Turiel", "-", "maurizio.turiel@unimi.it;", "Marco", "Cazzola", "-", "marco.cazzola@tiscalinet.it;", "Fabiola", "Atzeni", "-", "atzenifabiola@hotmail.com", "*Corresponding", "author", "Published:", "19", "July", "2002", "BMC", "Musculoskeletal", "Disorders", "2002,", "3:18", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1471-2474/3/18", "Received:", "12", "December", "2001", "Accepted:", "19", "July", "2002", "©", "2002", "Sarzi-Puttini", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "Verbatim", "copying", "and", "redistribution", "of", "this", "article", "are", "permitted", "in", "any", "medium", "for", "any", "purpose,", "provided", "this", "notice", "is", "preserved", "along", "with", "the", "article's", "original", "URL.", "Keywords:", "Rheumatoid", "arthritis,", "pain,", "pain", "measurement", "Abstract", "Background:", "To", "analyse", "the", "relationship", "between", "subjective", "pain", "score", "and", "other", "measures", "of", "clinical,", "radiographic", "and", "functional", "status;", "in", "particular", "Larsen", "radiographic", "scores", "and", "Health", "Assessment", "Questionnaire", "(HAQ);", "in", "patients", "with", "severe", "rheumatoid", "arthritis", "(RA)", "with", "a", "disease", "duration", "of", "less", "than", "3", "years.", "Methods:", "In", "this", "cross", "sectional", "study", "of", "105", "patients", "with", "RA", "(76", "women,", "29", "men:", "mean", "age", "50.93;", "mean", "disease", "duration", "15.86", "months;", "71%", "rheumatoid", "factor", "positive)", "subjective", "pain", "was", "assessed", "according", "to", "the", "Visual", "Analog", "Scale", "(VAS).", "Correlation", "coefficients", "between", "pain", "score", "and", "disease", "activity", "measures", "(patients'", "global", "assessment", "of", "disease", "by", "VAS,", "number", "of", "tender", "and", "swollen", "joints,", "morning", "stiffness,", "erythrocyte", "sedimentation", "rate", "[ESR],", "C-reactive", "protein", "[CRP]", "and", "titre", "of", "rheumatoid", "factor,", "radiographic", "evaluations", "(Larsen-Dale", "scores", "for", "radiographic", "damage", "of", "the", "small", "joints", "of", "the", "hands,", "wrist", "and", "feet),", "disability", "measures", "(health", "assessment", "questionnaire", "[HAQ]),", "and", "demographic", "variables", "were", "calculated;", "hierarchical", "regression", "analysis", "was", "done", "with", "subjective", "pain", "score", "as", "the", "dependent", "variable.", "Results:", "The", "Spearman's", "correlation", "coefficient", "comparing", "subjective", "pain", "and", "HAQ", "was", "0.421", "(p", "<", "0.001),", "between", "subjective", "pain", "and", "global", "assessment", "of", "disease", "and", "morning", "stiffness", "was", "0.573", "(p", "<", "0.001)", "and", "0.427", "(p", "<", "0.001)", "respectively,", "and", "between", "pain", "and", "number", "of", "tender", "and", "swollen", "joints", "0.037", "and", "0.050", "respectively", "(p", ">", "0.05).", "In", "regression", "analysis,", "global", "assessment", "of", "disease", "by", "patients", "explained", "32.8%", "of", "the", "variation", "in", "pain", "intensity", "score,", "morning", "stiffness", "10.7%,", "CRP", "4.0%,", "HAQ", "3.8%", "and", "Larsen-Dale", "scores", "explained", "2.1%;", "other", "variables", "were", "not", "significant", "in", "the", "model.", "Conclusions:", "Pain", "scores", "of", "patients", "with", "early", "severe", "rheumatoid", "arthritis", "are", "correlated", "at", "higher", "levels", "with", "patients'", "global", "assessment", "of", "disease", "and", "with", "morning", "stiffness", "rather", "than", "with", "radiographic", "or", "other", "clinical", "variables", "such", "as", "number", "of", "tender", "and", "swollen", "joints.", "Page", "1", "of", "4", "(page", "number", "not", "for", "citation", "purposes)" ]

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2,483,984

null

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[ "BMC", "Infectious", "Diseases", "Research", "article", "Childhood", "TB", "epidemiology", "and", "treatment", "outcomes", "in", "Thailand:", "a", "TB", "active", "surveillance", "network,", "2004", "to", "2006", "Rangsima", "Lolekha1,", "Amornrat", "Anuwatnonthakate2,", "Sriprapa", "Nateniyom3,", "Surin", "Sumnapun4,", "Norio", "Yamada5,", "Wanpen", "Wattanaamornkiat6,", "Wanchai", "Sattayawuthipong7,", "Pricha", "Charusuntonsri8,", "Natpatou", "Sanguanwongse9,", "Charles", "D", "Wells10", "and", "Jay", "K", "Varma*2,10", "Address:", "1Global", "AIDS", "Program,", "Thailand", "MOPH", "–", "U.S.", "CDC", "Collaboration,", "Nonthaburi,", "Thailand,", "2TB", "Program,", "Thailand", "MOPH", "–", "U.S.", "CDC", "Collaboration,", "Nonthaburi,", "Thailand,", "3Bureau", "of", "TB,", "Thailand", "Ministry", "of", "Public", "Health,", "Nonthaburi,", "Thailand,", "4Chiang", "Rai", "Provincial", "Public", "Health", "Office,", "Chiang", "Rai,", "Thailand,", "5Research", "Institute", "of", "Tuberculosis", "(Japan),", "Chiang", "Rai,", "Thailand,", "6AIDS,", "TB,", "STI", "and", "Leprosy", "Section,", "Office", "of", "Disease", "Prevention", "and", "Control", "7,", "Ubon-ratchathani,", "Thailand,", "7Phuket", "Provincial", "Public", "Health", "Office,", "Phuket,", "Thailand,", "8Health", "Center", "41,", "Bangkok", "Metropolitan", "Health", "Administration,", "Bangkok,", "Thailand,", "9Medicine", "Department,", "Bamrasnaradura", "Institute,", "Nonthaburi,", "Thailand", "and", "10Division", "of", "TB", "Elimination,", "U.S.", "Centers", "for", "Disease", "Control", "and", "Prevention,", "Atlanta,", "USA", "Email:", "Rangsima", "Lolekha", "-", "rangsimaL@th.cdc.gov;", "Amornrat", "Anuwatnonthakate", "-", "AmornratA@th.cdc.gov;", "Sriprapa", "Nateniyom", "-", "nateniyoms@yahoo.com;", "Surin", "Sumnapun", "-", "angvcr@hotmail.com;", "Norio", "Yamada", "-", "nyamada@jata.or.jp;", "Wanpen", "Wattanaamornkiat", "-", "Wanpen_wa@yahoo.com;", "Wanchai", "Sattayawuthipong", "-", "wanchaig@health.moph.go.th;", "Pricha", "Charusuntonsri", "-", "pcharu@gmail.com;", "Natpatou", "Sanguanwongse", "-", "natpatou@yahoo.com;", "Charles", "D", "Wells", "-", "cdwells6@bellsouth.net;", "Jay", "K", "Varma*", "-", "jvarma@cdc.gov", "BioMed", "Central", "Open", "Access", "*", "Corresponding", "author", "Published:", "18", "July", "2008", "BMC", "Infectious", "Diseases", "2008,", "8:94", "doi:10.1186/1471-2334-8-94", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1471-2334/8/94", "Received:", "26", "December", "2007", "Accepted:", "18", "July", "2008", "©", "2008", "Lolekha", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "Of", "the", "9.2", "million", "new", "TB", "cases", "occurring", "each", "year,", "about", "10%", "are", "in", "children.", "Because", "childhood", "TB", "is", "usually", "non-infectious", "and", "non-fatal,", "national", "programs", "do", "not", "prioritize", "childhood", "TB", "diagnosis", "and", "treatment.", "We", "reviewed", "data", "from", "a", "demonstration", "project", "to", "learn", "more", "about", "the", "epidemiology", "of", "childhood", "TB", "in", "Thailand.", "Methods:", "In", "four", "Thai", "provinces", "and", "one", "national", "hospital,", "we", "contacted", "healthcare", "facilities", "monthly", "to", "record", "data", "about", "persons", "diagnosed", "with", "TB,", "assist", "with", "patient", "care,", "provide", "HIV", "counseling", "and", "testing,", "and", "obtain", "sputum", "for", "culture", "and", "susceptibility", "testing.", "We", "analyzed", "clinical", "and", "treatment", "outcome", "data", "for", "patients", "age", "<", "15", "years", "old", "registered", "in", "2005", "and", "2006.", "Results:", "Only", "279", "(2%)", "of", "14,487", "total", "cases", "occurred", "in", "children.", "The", "median", "age", "of", "children", "was", "8", "years", "(range:", "4", "months,", "14", "years).", "Of", "197", "children", "with", "pulmonary", "TB,", "63", "(32%)", "were", "bacteriologically-confirmed:", "56", "(28%)", "were", "smear-positive", "and", "7", "(4%)", "were", "smear-negative,", "but", "culture-positive.", "One", "was", "diagnosed", "with", "multi-drug", "resistant", "TB.", "HIV", "infection", "was", "documented", "in", "75", "(27%).", "Thirteen", "(17%)", "of", "75", "HIV-infected", "children", "died", "during", "TB", "treatment", "compared", "with", "4", "(2%)", "of", "204", "not", "known", "to", "be", "HIV-infected", "(p", "<", "0.01).", "Conclusion:", "Childhood", "TB", "is", "infrequently", "diagnosed", "in", "Thailand.", "Understanding", "whether", "this", "is", "due", "to", "absence", "of", "disease", "or", "diagnostic", "effort", "requires", "further", "research.", "HIV", "contributes", "substantially", "to", "the", "childhood", "TB", "burden", "in", "Thailand", "and", "is", "associated", "with", "high", "mortality.", "Page", "1", "of", "9", "(page", "number", "not", "for", "citation", "purposes)" ]

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2,699,955

null

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[ "R", "E", "V", "I", "E", "W", "Defect", "of", "alveolar", "regeneration", "in", "pulmonary", "emphysema:", "Role", "of", "lung", "ﬁbroblasts", "Laurent", "Plantier1,2", "Jorge", "Boczkowski1,3", "Bruno", "Crestani1,4", "1INSERM,", "U700,", "Faculté", "Xavier", "Bichat,", "Paris,", "France;", "2Assistance", "Publique-", "Hôpitaux", "de", "Paris,", "Hôpital", "Bichat,", "Service", "de", "Pneumologie", "B,", "Paris,", "France;", "3Assistance", "Publique-Hôpitaux", "de", "Paris,", "Hôpital", "Bichat,", "CIC", "07,", "Paris,", "France;", "4Assistance", "Publique-Hôpitaux", "de", "Paris,", "Hôpital", "Bichat,", "Service", "de", "Pneumologie", "A,", "Paris,", "France", "Correspondence:", "Bruno", "Crestani", "Service", "de", "Pneumologie", "A,", "Hôpital", "Bichat,", "16", "rue", "Henri", "Huchard,", "75877,", "Paris", "Cedex", "18,", "France", "Tel", "+33", "1", "40256800", "Fax", "+33", "1", "40258818", "Email", "bruno.crestani@bch.aphp.fr", "Abstract:", "Pulmonary", "emphysema", "is", "characterized", "by", "the", "irreversible", "loss", "of", "pulmonary", "alveoli.", "Despite", "recent", "advances", "in", "the", "understanding", "this", "disease,", "its", "treatment", "remains", "palliative.", "In", "this", "review,", "we", "will", "successively", "review", "the", "data", "suggesting", "(1)", "that", "alveolar", "regeneration", "systems", "are", "functional", "in", "the", "mammalian", "lung", "and", "have", "the", "potential", "to", "regrow", "lost", "alveoli,", "(2)", "that", "cigarette", "smoke,", "the", "main", "etiologic", "factor", "of", "emphysema,", "inhibits", "those", "systems", "under", "experimental", "conditions,", "and", "(3)", "that", "alveolar", "regeneration", "systems", "are", "dysfunctional", "in", "the", "human", "emphysematous", "lung", "and", "may", "be", "a", "target", "for", "therapeutic", "intervention", "in", "this", "disease.", "Special", "emphasis", "will", "be", "put", "on", "the", "role", "of", "alveolar", "ﬁbroblasts", "in", "those", "processes.", "Keywords:", "emphysema,", "repair,", "regeneration,", "HGF,", "ﬁbroblasts", "Introduction", "Pulmonary", "emphysema", "is", "characterized", "by", "the", "progressive", "destruction", "of", "pulmonary", "alveoli.", "It", "is", "one", "of", "the", "most", "common", "diseases", "worldwide", "(Halbert", "et", "al", "2006)", "and", "its", "incidence", "keeps", "growing", "along", "with", "the", "large", "diffusion", "of", "its", "main", "etiologic", "factor,", "tobacco", "smoking.", "The", "ever-increasing", "use", "of", "tobacco", "in", "the", "developing", "world", "allows", "for", "the", "prediction", "of", "a", "huge", "increase", "in", "the", "number", "of", "cases", "in", "the", "near", "and", "distant", "future.", "The", "prognosis", "of", "pulmonary", "emphysema", "is", "poor,", "with", "airﬂow", "limitation", "progressing", "to", "chronic", "respiratory", "insufﬁciency,", "disability", "and", "premature", "death.", "To", "this", "day,", "therapeutic", "options", "for", "pulmonary", "emphysema", "are", "few", "and", "scarcely", "effective.", "Patients", "who", "stop", "smoking", "do", "beneﬁt", "in", "terms", "of", "lung", "function", "and", "survival,", "but", "the", "decline", "in", "lung", "function", "is", "not", "reversed,", "merely", "slowed.", "Apart", "from", "long-term", "oxygen", "therapy,", "pharmacological", "intervention", "is", "unsatisfactory", "and", "is", "mainly", "limited", "to", "the", "control", "of", "symptoms", "related", "to", "frequently-associated", "chronic", "bronchitis", "(Sutherland", "and", "Cherniack", "2004).", "Lung", "volume", "reduction", "surgery", "can", "be", "of", "interest", "in", "selected", "patients", "(Fishman", "et", "al", "2003)", "as", "may", "be", "the", "implantation", "of", "endobronchial", "one-way", "valves", "(Wood", "et", "al", "2007)", "but", "those", "techniques", "do", "not", "remedy", "the", "underlying", "condition.", "Lung", "transplantation,", "while", "beneﬁcial", "in", "terms", "of", "symptoms-related", "quality", "of", "life,", "does", "not", "improve", "survival", "in", "patients", "with", "pulmonary", "emphysema", "(Hosenpud", "et", "al", "1998).", "Overall,", "treatment", "of", "pulmonary", "emphysema", "is", "palliative.", "Most", "studies", "of", "the", "pathogenesis", "of", "emphysema", "focused", "on", "the", "mechanisms", "involved", "in", "chronic", "injury", "induced", "by", "cigarette", "smoke", "to", "the", "pulmonary", "parenchyma.", "In", "particular,", "the", "role", "of", "protease-antiprotease", "imbalance,", "persistent", "inﬂammation,", "oxi-", "dative", "stress", "and", "excessive", "apoptosis", "of", "alveolar", "cells", "was", "demonstrated", "(Barnes", "et", "al", "2003).", "However,", "while", "great", "advances", "were", "made", "towards", "the", "comprehension", "of", "those", "phenomenons,", "they", "have", "not", "translated", "into", "new", "therapeutic", "prospects", "until", "now.", "Alveolar", "regeneration", "systems", "may", "be", "important", "actors", "in", "the", "course", "of", "emphysema.", "On", "the", "one", "hand,", "alterations", "or", "defects", "in", "those", "systems", "may", "account", "for", "the", "deﬁciency", "in", "tissue", "repair", "which", "is", "observed", "in", "the", "emphysematous", "lung.", "On", "the", "other", "hand,", "the", "induction", "of", "alveolar", "regeneration", "would", "be", "an", "interesting", "therapeutic", "target", "in", "International", "Journal", "of", "COPD", "2007:2(4)", "463–469", "©", "2007", "Dove", "Medical", "Press", "Limited.", "All", "rights", "reserved", "463" ]

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3,033,130

null

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[ "MEDITERRANEAN", "JOURNAL", "OF", "HEMATOLOGY", "AND", "INFECTIOUS", "DISEASES", "www.mjhid.org", "ISSN", "2035-3006", "Original", "Article", "Poor", "Hematopoietic", "Stem", "Institution", "Experience.", "Cell", "Mobilizers", "in", "Multiple", "Myeloma:", "a", "Single", "Guillermo", "J.", "Ruiz-Delgado,1,2,3", "Avril", "López-Otero,1,3", "Ana", "Hernandez-Arizpe,1,3", "Aura", "Ramirez-Medina1", "and", "Guillermo", "J.", "Ruiz-Argüelles.1,2,3", "1", "Centro", "de", "Hematología", "y", "Medicina", "Interna", "de", "Puebla.", "Puebla,", "MEXICO.", "2", "Laboratorios", "Clínicos", "de", "Puebla.", "Puebla,", "MEXICO.", "3", "Universidad", "Popular", "Autónoma", "del", "Estado", "de", "Puebla.", "Correspondence", "to:", "Guillermo", "J.", "Ruiz-Delgado", "MD,", "Centro", "de", "Hematología", "y", "Medicina,", "Interna", "de", "Puebla,", "8B", "Sur", "3710,", "72530", "Puebla,", "Pue.", "Mexico.", "Teléfono:", "+", "52", "(222)", "243", "8100,", "Telefax:", "+", "52", "(222)", "243", "8428.", "E-mail:", "gruiz2@clinicaruiz.com", "Competing", "interests:", "The", "author", "have", "declared", "that", "no", "competing", "interests", "exist.", "Published:", "Jume", "21,", "2010", "Received:", "May", "31,", "2010", "Accepted:", "June", "19,", "2010", "Medit", "J", "Hemat", "Infect", "Dis", "2010,", "2(2):", "e2010016,", "DOI", "10.4084/MJHID.2010.016", "This", "article", "is", "available", "from:", "http://www.mjhid.org/article/view/6020", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited", "Abstract", "In", "a", "single", "institution,", "in", "a", "group", "of", "28", "myeloma", "patients", "deemed", "eligible", "for", "autologous", "transplant,", "stem", "cell", "mobilization", "was", "attempted", "using", "filgrastim:", "26", "individuals", "were", "given", "31", "autografts", "employing", "1-4", "(median", "three)", "apheresis", "sessions,", "to", "obtain", "a", "target", "stem", "cell", "dose", "of", "1", "x", "106", "CD34", "+ve", "viable", "cells", "/", "Kg", "of", "the", "recipient.", "The", "median", "number", "of", "grafted", "CD34", "cells", "was", "7.56", "x", "106", "/", "Kg", "of", "the", "recipient;", "the", "range", "being", "0.92", "to", "14.8.", "By", "defining", "as", "poor", "mobilizers", "individuals", "in", "which", "a", "cell", "collection", "of", "<", "1", "x", "106", "CD34", "viable", "cells", "/", "Kg", "was", "obtained,", "a", "subset", "of", "eight", "poor", "mobilizers", "was", "identified;", "in", "two", "patients", "the", "autograft", "was", "aborted", "because", "of", "an", "extremely", "poor", "CD34", "+ve", "cell", "yield", "(<", "0.2", "x", "106", "CD34", "+ve", "viable", "cells", "/", "Kg", "of", "the", "recipient)", "after", "four", "apheresis", "sessions.", "The", "long-term", "overall", "survival", "of", "the", "patients", "grafted", "with", ">", "1", "x", "106", "CD34", "+ve", "viable", "cells", "/", "Kg", "was", "better", "(80%", "at", "80", "months)", "than", "those", "grafted", "with", "<", "1", "x", "106", "CD34", "+ve", "viable", "cells", "/", "Kg", "(67%", "at", "76", "months).", "Methods", "to", "improve", "stem", "cell", "mobilization", "are", "needed", "and", "may", "result", "in", "obtaining", "better", "results", "when", "autografting", "multiple", "myeloma", "patients.", "Introduction:", "High-dose", "chemotherapy", "followed", "by", "autologous", "stem", "cell", "transplantation", "(SCT)", "is", "considered", "standard", "of", "care", "for", "patients", "with", "multiple", "myeloma", "(MM).1,2", "In", "this", "setting,", "autologous", "peripheral", "blood", "stem", "cells", "(PBSC)", "have", "largely", "replaced", "autologous", "bone", "marrow", "as", "the", "source", "of", "stem", "cells.", "Advantages", "of", "autologous", "PBSC", "grafts", "over", "bone", "marrow", "grafts", "include", "faster", "Medit", "J", "Hemat", "Infect", "Dis", "2010;", "2(2);", "Open", "Journal", "System", "engrafment", "after", "high-dose", "chemotherapy,", "reduced", "contamination", "with", "tumor", "cells3", "and", "lower", "morbidity", "and", "mortality.3-5", "Hematopoietic", "stem", "cell", "mobilization", "is", "generally", "accomplished", "by", "administration", "of", "hematopoietic", "growth", "factors", "like", "granulocyte", "colony", "stimulating", "factor", "(G-CSF)1-5", "or", "a", "combination", "of", "myelosuppressive", "chemotherapy" ]

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[ "JCB:", "REPORT", "ESCRT", "ubiquitin-binding", "domains", "function", "cooperatively", "during", "MVB", "cargo", "sorting", "S.", "Brookhart", "Shields,1", "Andrea", "J.", "Oestreich,2", "Stanley", "Winistorfer,1", "Doris", "Nguyen,2", "Johanna", "A.", "Payne,2", "David", "J.", "Katzmann,2", "and", "Robert", "Piper1", "1Department", "of", "Molecular", "Physiology", "and", "Biophysics,", "University", "of", "Iowa,", "Iowa", "City,", "IA", "52240", "2Department", "of", "Biochemistry", "and", "Molecular", "Biology,", "Mayo", "Clinic", "College", "of", "Medicine,", "Rochester,", "MN", "55905", "U", "geting", "of", "ubiquitinated", "membrane", "proteins", "into", "biquitin", "(Ub)", "sorting", "receptors", "facilitate", "the", "tar-", "multivesicular", "bodies", "(MVBs).", "Ub-binding", "do-", "mains", "(UBDs)", "have", "been", "described", "in", "several", "endosomal", "sorting", "complexes", "required", "for", "transport", "(ESCRT).", "Using", "available", "structural", "information,", "we", "have", "investigated", "the", "role", "of", "the", "multiple", "UBDs", "within", "ESCRTs", "during", "MVB", "cargo", "selection.", "We", "found", "a", "novel", "UBD", "within", "ESCRT-I", "and", "show", "that", "it", "contributes", "to", "MVB", "sorting", "in", "concert", "with", "the", "known", "UBDs", "within", "the", "ESCRT", "complexes.", "These", "experiments", "reveal", "an", "unexpected", "level", "of", "coordination", "among", "the", "ESCRT", "UBDs,", "suggesting", "that", "they", "collectively", "recognize", "a", "diverse", "set", "of", "cargo", "rather", "than", "act", "sequen-", "tially", "at", "discrete", "steps.", "Y", "G", "O", "L", "O", "I", "B", "L", "L", "E", "C", "F", "O", "L", "A", "N", "R", "U", "O", "J", "E", "H", "T", "Introduction", "Many", "integral", "membrane", "proteins", "targeted", "for", "lysosomal", "degra-", "dation", "are", "ubiquitinated", "and", "sorted", "into", "vesicles", "that", "bud", "from", "the", "limiting", "membrane", "into", "the", "lumen", "of", "endosomes", "during", "the", "biogenesis", "of", "multivesicular", "bodies", "(MVBs;", "Piper", "and", "Katzmann,", "2007).", "Cargo", "selection", "during", "MVB", "sorting", "is", "dependent", "on", "several", "endosomal", "protein", "complexes", "known", "as", "endosomal", "sorting", "complexes", "required", "for", "transport", "(ESCRT).", "Several", "ESCRT", "components", "contain", "ubiquitin", "(Ub)-binding", "do-", "mains", "(UBDs)", "that", "may", "act", "as", "receptors", "for", "ubiquitinated", "mem-", "brane", "proteins.", "For", "instance,", "ESCRT-0,", "comprised", "of", "yeast", "Vps27", "and", "Hse1", "or", "mammalian", "Hrs", "and", "STAM", "(signal", "trans-", "ducing", "adaptor", "molecule),", "contains", "Ub-interacting", "motifs", "(UIMs)", "required", "for", "MVB", "sorting", "of", "ubiquitinated", "cargo", "(Bilodeau", "et", "al.,", "2002;", "Shih", "et", "al.,", "2002;", "Piper", "and", "Katzmann,", "2007).", "The", "Ub", "E2", "variant", "(UEV)", "domain", "in", "Vps23/TSG101,", "an", "ESCRT-I", "component", "in", "yeast/mammalian", "cells,", "and", "the", "GLUE", "(GRAM-like", "Ub", "binding", "in", "EAP45)", "or", "Npl4", "zinc", "finger", "(NZF)", "domains", "of", "Vps36,", "an", "ESCRT-II", "component,", "also", "contain", "UBDs", "that", "have", "been", "implicated", "in", "MVB", "cargo", "selection", "(Katzmann", "et", "al.,", "2001;", "Alam", "et", "al.,", "2004;", "Slagsvold", "et", "al.,", "2005).", "This", "had", "led", "to", "a", "model", "in", "which", "Ub", "cargo", "is", "passed", "sequentially", "from", "S.B.", "Shields", "and", "A.J.", "Oestreich", "contributed", "equally", "to", "this", "paper.", "Correspondence", "to", "David", "J.", "Katzmann:", "katzmann.david@mayo.edu;", "or", "Robert", "Piper:", "Robert-piper@uiowa.edu", "Abbreviations", "used", "in", "this", "paper:", "CPY,", "carboxypeptidase", "Y;", "ESCRT,", "endosomal", "sorting", "complexes", "required", "for", "transport;", "DIC,", "differential", "interference", "contrast;", "HSQC,", "heteronuclear", "single", "quantum", "coherence;", "MVB,", "multivesicular", "body;", "NMR,", "nuclear", "magnetic", "resonance;", "NZF,", "Npl4", "zinc", "finger;", "TAP,", "tandem", "affinity", "purification;", "Ub,", "ubiquitin;", "UBD,", "Ub-binding", "domain;", "UEV,", "Ub", "E2", "variant;", "UIM,", "Ub-interacting", "motif.", "The", "Rockefeller", "University", "Press", "$30.00", "J.", "Cell", "Biol.", "Vol.", "185", "No.", "2", "213–224", "www.jcb.org/cgi/doi/10.1083/jcb.200811130", "ESCRT-0", "to", "ESCRT-I", "and", "to", "ESCRT-II", "for", "final", "deposit", "into", "the", "forming", "lumenal", "vesicles", "(Katzmann", "et", "al.,", "2002;", "Gruenberg", "and", "Stenmark,", "2004;", "Hurley,", "2008).", "Previous", "studies", "have", "indi-", "cated", "the", "importance", "of", "these", "UBDs", "during", "MVB", "sorting;", "how-", "ever,", "recent", "high", "resolution", "structures", "that", "detail", "Ub", "interactions", "have", "enabled", "a", "more", "precise", "approach", "to", "dissect", "the", "contri-", "butions", "of", "these", "UBDs", "to", "MVB", "sorting", "(Alam", "et", "al.,", "2004,", "2006;", "Sundquist", "et", "al.,", "2004;", "Teo", "et", "al.,", "2004;", "Hirano", "et", "al.,", "2006).", "Surprisingly,", "we", "found", "that", "mutant", "forms", "of", "Vps23", "and", "Vps36", "unable", "to", "bind", "Ub", "had", "no", "defects", "in", "MVB", "sorting,", "even", "in", "combi-", "nation.", "This", "led", "us", "to", "search", "for", "additional", "UBDs", "within", "ESCRT-I", "and", "resulted", "in", "the", "discovery", "of", "a", "novel", "UBD", "within", "Mvb12.", "The", "UBD", "of", "Mvb12", "works", "in", "concert", "with", "the", "UBDs", "of", "the", "ESCRTs", "to", "promote", "cargo", "recognition", "and", "MVB", "sorting.", "Results", "and", "discussion", "Mutants", "of", "Vps23", "and", "Vps36", "defective", "for", "Ub", "binding", "Cocrystal", "structures", "of", "Ub", "with", "the", "UEV", "domains", "of", "Vps23", "and", "TSG101", "were", "used", "to", "guide", "mutagenesis", "experiments", "rendering", "Vps23", "unable", "to", "bind", "Ub", "(Sundquist", "et", "al.,", "2004;", "Teo", "et", "al.", "2004).", "The", "structures", "show", "that", "the", "UEV", "domains", "bind", "to", "Ub", "via", "a", "", "hairpin", "tongue", "and", "a", "lip", "(Fig.", "1", "A).", "The", "structure", "of", "the", "©", "2009", "Shields", "et", "al.", "This", "article", "is", "distributed", "under", "the", "terms", "of", "an", "Attribution–", "Noncommercial–Share", "Alike–No", "Mirror", "Sites", "license", "for", "the", "first", "six", "months", "after", "the", "publica-", "tion", "date", "(see", "http://www.jcb.org/misc/terms.shtml).", "After", "six", "months", "it", "is", "available", "under", "a", "Creative", "Commons", "License", "(Attribution–Noncommercial–Share", "Alike", "3.0", "Unported", "license,", "as", "described", "at", "http://creativecommons.org/licenses/by-nc-sa/3.0/).", "JCB", "213" ]

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3,312,864

null

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[ "Ngan", "et", "al.", "BMC", "Pulmonary", "Medicine", "2012,", "12:3", "http://www.biomedcentral.com/1471-2466/12/3", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "The", "relationship", "of", "systemic", "inflammation", "to", "prior", "hospitalization", "in", "adult", "patients", "with", "cystic", "fibrosis", "David", "A", "Ngan,", "Pearce", "G", "Wilcox,", "May", "Aldaabil,", "Yuexin", "Li,", "Jonathon", "A", "Leipsic,", "Don", "D", "Sin", "and", "SF", "Paul", "Man*", "Abstract", "Background:", "In", "cystic", "fibrosis", "(CF)", "patients,", "it", "has", "been", "suggested", "that", "systemic", "inflammation", "may", "be", "an", "important", "risk", "factor", "for", "poor", "health", "outcomes.", "The", "relationship", "of", "plasma", "inflammatory", "biomarkers", "to", "lung", "function", "and", "hospitalization", "history", "remains", "largely", "unexplored.", "Methods:", "This", "cross-sectional", "study", "included", "58", "consecutive,", "clinically", "stable", "adults", "from", "the", "CF", "Clinic", "at", "St.", "Paul’s", "Hospital", "(Vancouver,", "Canada).", "Blood", "levels", "of", "interleukin", "(IL)-6,", "IL-1b,", "C-reactive", "protein", "(CRP),", "interleukin", "(IL)-6,", "IL-", "1b,", "granzyme", "B", "(GzmB),", "chemokine", "C-C", "motif", "ligand", "18", "(CCL18/PARC),", "surfactant", "protein", "D", "(SP-D),", "lipopolysaccharide", "(LPS)-binding", "protein,", "and", "soluble", "cluster", "of", "differentiation", "14", "(sCD14)", "were", "measured", "using", "enzyme-linked", "immunosorbent", "assays,", "and", "LPS", "levels", "were", "measured", "using", "a", "Limulus", "amebocyte", "lysate", "assay.", "Spirometry", "was", "also", "performed.", "Multivariable", "linear", "regression", "analysis", "was", "used", "to", "assess", "relationships", "of", "the", "blood", "biomarkers", "to", "lung", "function.", "Results:", "Lung", "function", "impairment", "was", "independently", "associated", "with", "elevated", "plasma", "levels", "of", "CRP", "(P", "<", "0.01),", "IL-", "6", "(P", "=", "0.04),", "IL-1b", "(P", "<", "0.01),", "and", "LBP", "(P", "<", "0.01).", "Increasing", "age", "(P", "<", "0.01),", "reduced", "body", "mass", "index", "(P", "=", "0.02),", "prior", "hospitalizations", "(P", "=", "0.03),", "and", "presence", "of", "Pseudomonas", "aeruginosa", "in", "sputum", "cultures", "(P", "<", "0.01)", "were", "also", "associated", "with", "reduced", "lung", "function.", "Elevated", "concentrations", "of", "LPS", "in", "plasma", "were", "associated", "with", "a", "previous", "history", "of", "hospitalization", "(P", "<", "0.05).", "There", "was", "a", "trend", "towards", "an", "increase", "in", "plasma", "IL-6", "(P", "=", "0.07)", "and", "IL-1b", "(P", "=", "0.06)", "levels", "in", "patients", "who", "were", "previously", "hospitalized.", "Conclusions:", "IL-6", "and", "IL-1b", "are", "promising", "systemic", "biomarkers", "for", "lung", "function", "impairment", "and", "history", "of", "hospitalization", "in", "adult", "patients", "with", "CF.", "Background", "Cystic", "fibrosis", "(CF)", "is", "a", "progressive,", "debilitating", "disease", "that", "affects", "nearly", "30,000", "Americans", "and", "occurs", "with", "a", "frequency", "of", "about", "1", "in", "3500", "births", "[1].", "It", "is", "character-", "ized", "by", "persistent", "lung", "infection", "and", "lung", "function", "impairment.", "It", "also", "affects", "other", "organs", "including", "the", "sinuses,", "gastrointestinal", "tract,", "endocrine", "glands,", "and", "the", "bone", "[2-5].", "Although", "all", "CF", "cases", "are", "caused", "by", "a", "muta-", "tion", "in", "the", "gene", "for", "the", "CF", "transmembrane", "conductance", "regulator,", "there", "is", "considerable", "heterogeneity", "in", "the", "rate", "at", "which", "the", "disease", "progresses", "[6].", "The", "traditional", "risk", "factors", "for", "rapid", "progression", "include", "reduced", "body", "mass", "*", "Correspondence:", "pman@providencehealth.bc.ca", "UBC", "James", "Hogg", "Research", "Centre,", "Institute", "for", "Heart", "+", "Lung", "Health", "at", "St.", "Paul’s", "Hospital", "and", "Department", "of", "Medicine,", "University", "of", "British", "Columbia,", "Vancouver,", "BC,", "Canada", "index,", "colonization", "of", "the", "airways", "with", "pathogenic", "bac-", "teria", "such", "as", "Pseudomonas", "aeruginosa,", "and", "female", "sex", "[7-9].", "More", "recently,", "some", "have", "suggested", "that", "systemic", "inflammation", "may", "be", "another", "important", "risk", "factor", "for", "poor", "health", "outcomes", "in", "CF", "independent", "of", "these", "tradi-", "tional", "risk", "factors", "[3,8,10,11].", "However,", "the", "studies", "that", "have", "evaluated", "this", "issue", "have", "produced", "inconsistent", "results", "and", "have", "measured", "different", "components", "of", "the", "immune", "system,", "making", "cross", "comparisons", "difficult.", "Moreover,", "none", "of", "these", "studies", "have", "evaluated", "these", "biomarkers", "on", "hard", "clinical", "outcomes", "such", "as", "exacerba-", "tions", "or", "hospitalizations,", "which", "are", "important", "endpoints", "in", "CF.", "In", "this", "study,", "we", "determined", "the", "relationship", "of", "plasma", "inflammatory", "biomarkers", "to", "lung", "function", "and", "hospitalization", "history", "in", "adult", "patients", "with", "CF.", "The", "plasma", "biomarkers", "were", "carefully", "chosen", "to", "represent", "©", "2012", "Ngan", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

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1,993,944

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[ "Acta", "Crystallographica", "Section", "E", "Structure", "Reports", "Online", "ISSN", "1600-5368", "3-Oxo-18a-olean-28,13b-olide", "R.", "C.", "Santos,a", "R.", "M.", "A.", "Pinto,a", "A.", "Matos", "Beja,b", "J.", "A.", "R.", "Salvadora", "and", "J.", "A.", "Paix˜aob*", "aLaborato´", "rio", "de", "Qu´ımica", "Farmaceˆutica,", "Faculdade", "de", "Farma´cia,", "Universidade", "de", "Coimbra,", "Po´", "lo", "das", "Cieˆncias", "da", "Sau´", "de,", "Azinhaga", "de", "Santa", "Comba,", "P-3000-548", "Coimbra,", "Portugal,", "and", "bCEMDRX,", "Departamento", "de", "F´ısica,", "Faculdade", "de", "Cieˆncias", "e", "Tecnologia,", "Universidade", "de", "Coimbra,", "P-3004-516", "Coimbra,", "Portugal", "Correspondence", "e-mail:", "jap@pollux.fis.uc.pt", "Received", "15", "July", "2010;", "accepted", "20", "July", "2010", "Key", "indicators:", "single-crystal", "X-ray", "study;", "T", "=", "295", "K;", "mean", "(C–C)", "=", "0.005", "A˚;", "R", "factor", "=", "0.042;", "wR", "factor", "=", "0.100;", "data-to-parameter", "ratio", "=", "8.3.", "The", "title", "terpene,", "C30H46O3,", "is", "a", "28,13", "-lactone", "of", "oleanolic", "acid", "prepared", "with", "bismuth", "triﬂuoromethanesulfonate", "(OTf),", "Bi(OTf)3", "xH2O.", "All", "rings", "are", "trans-fused.", "The", "X-ray", "study", "shows", "the", "inversion", "of", "the", "orientation", "of", "18-H", "in", "the", "lactonization", "reaction.", "A", "quantum", "chemical", "ab-initio", "Roothaan", "Hartree–Fock", "calculation", "of", "the", "equilibrium", "geometry", "of", "the", "isolated", "molecule", "gives", "values", "for", "bond", "lengths", "and", "valency", "angles", "in", "close", "agreement", "with", "experi-", "mental", "values.", "The", "calculation", "also", "reproduces", "the", "observed", "molecular", "conformation,", "with", "puckering", "parameters", "that", "agree", "well", "with", "those", "determined", "from", "the", "crystallographic", "study.", "Related", "literature", "For", "general", "background", "to", "the", "use", "of", "natural", "products", "as", "sources", "of", "anticancer", "drugs,", "see:", "Koehn", "&", "Carter", "(2005).", "For", "the", "biological", "activity", "of", "oleanolic", "acid,", "see:", "Ringbom", "et", "al.", "(1998);", "Ma", "et", "al.", "(2000);", "Tokuda", "et", "al.", "(1986);", "Horiuchi", "et", "al.", "(2007);", "Lee", "et", "al.", "(1994);", "Sohn", "et", "al.", "(1995).", "For", "the", "biosyn-", "thesis", "of", "pentacyclic", "triterpenoids,", "see:", "Gershenzon", "&", "Dudareva", "(2007);", "Salvador", "(2010);", "Dzubak", "et", "al.", "(2006).", "For", "the", "lactonization", "reaction", "of", "oleanane-type", "triterpenoids,", "see:", "Cheriti", "et", "al.", "(1994).", "For", "the", "synthesis", "of", "the", "title", "compound,", "see:", "Salvador", "et", "al.", "(2009).", "For", "related", "structures,", "see:", "Eggle-", "ston", "(1987);", "Chang", "et", "al.", "(1982);", "Sutthivaiyakit", "et", "al.", "(2001);", "Wang", "et", "al.", "(2006).", "For", "puckering", "and", "asymmetry", "parameters,", "see:", "Cremer", "&", "Pople", "(1975);", "Duax", "&", "Norton", "(1975).", "The", "quantum", "chemical", "calculations", "were", "performed", "with", "the", "computer", "program", "GAMESS", "(Schmidt", "et", "al.,", "1993).", "organic", "compounds", "Experimental", "Crystal", "data", "C30H46O3", "Mr", "=", "454.67", "Monoclinic,", "P21", "a", "=", "6.7789", "(3)", "A˚", "b", "=", "12.3122", "(6)", "A˚", "c", "=", "15.4524", "(7)", "A˚", "=", "99.644", "(2)", "Data", "collection", "Bruker", "APEXII", "CCD", "area-detector", "diffractometer", "Absorption", "correction:", "multi-scan", "(SADABS;", "Sheldrick,", "2000)", "Tmin", "=", "0.746,", "Tmax", "=", "1.0", "Reﬁnement", "R[F", "2", ">", "2", "(F", "2)]", "=", "0.042", "wR(F", "2)", "=", "0.100", "S", "=", "1.08", "2536", "reﬂections", "305", "parameters", "V", "=", "1271.48", "(10)", "A˚3", "Z", "=", "2", "Mo", "K", "radiation", "=", "0.07", "mm", "1", "T", "=", "295", "K", "0.45", "0.17", "0.04", "mm", "16467", "measured", "reﬂections", "2536", "independent", "reﬂections", "1805", "reﬂections", "with", "I", ">", "2", "(I)", "Rint", "=", "0.057", "1", "restraint", "H-atom", "parameters", "constrained", "max", "=", "0.14", "e", "A˚", "3", "min", "=", "0.17", "e", "A˚", "3", "Data", "collection:", "APEX2", "(Bruker,", "2006);", "cell", "reﬁnement:", "SAINT", "(Bruker,", "2006);", "data", "reduction:", "SAINT;", "program(s)", "used", "to", "solve", "structure:", "SHELXS97", "(Sheldrick,", "2008);", "program(s)", "used", "to", "reﬁne", "structure:", "SHELXL97", "(Sheldrick,", "2008);", "molecular", "graphics:", "PLATON", "(Spek,", "2009);", "software", "used", "to", "prepare", "material", "for", "publication:", "SHELXL97.", "This", "work", "was", "supported", "by", "the", "Fundac¸a˜", "o", "para", "a", "Ci", "eˆncia", "e", "Tecnologia.", "RCS", "(SFRH/BD/23700/2005)", "and", "RMAP", "(SFRH/", "BD/18013/2004)", "thank", "the", "FCT", "for", "grants.", "We", "gratefully", "acknowledge", "LCA–UC", "for", "the", "grant", "of", "computer", "time", "in", "the", "Milipeia", "cluster", "and", "Mr", "Carlos", "Pereira", "for", "help", "in", "the", "analysis", "of", "the", "output", "of", "the", "GAMESS", "code.", "Supplementary", "data", "and", "ﬁgures", "for", "this", "paper", "are", "available", "from", "the", "IUCr", "electronic", "archives", "(Reference:", "RK2222).", "References", "Bruker", "(2006).", "APEX2", "and", "SAINT.", "Bruker", "AXS", "Inc.,", "Madison,", "Wisconsin,", "USA.", "Chang,", "H.-M.,", "Chiang,", "T.-C.", "&", "Mak,", "T.", "C.", "W.", "(1982).", "Chem.", "Commun.", "pp.", "1197–1198.", "Cheriti,", "A.,", "Babadjamian,", "A.", "&", "Balansard,", "G.", "(1994).", "J.", "Nat.", "Prod.", "57,", "1160–", "1163.", "Acta", "Cryst.", "(2010).", "E66,", "o2139–o2140", "doi:10.1107/S160053681002903X", "Santos", "et", "al.", "o2139" ]

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[ "JCB:", "ARTICLE", "Neural", "crest", "stem", "cell", "maintenance", "by", "combinatorial", "Wnt", "and", "BMP", "signaling", "Maurice", "Kléber,1", "Hye-Youn", "Lee,1", "Heiko", "Wurdak,1", "Johanna", "Buchstaller,1", "Martin", "M.", "Riccomagno,2", "Lars", "M.", "Ittner,3", "Ueli", "Suter,1", "Douglas", "J.", "Epstein,2", "and", "Lukas", "Sommer1", "1Institute", "of", "Cell", "Biology,", "Department", "of", "Biology,", "Swiss", "Federal", "Institute", "of", "Technology,", "ETH-Hönggerberg,", "CH-8093", "Zurich,", "Switzerland", "2Department", "of", "Genetics,", "University", "of", "Pennsylvania", "School", "of", "Medicine,", "Philadelphia,", "PA", "19104", "3Research", "Laboratory", "for", "Calcium", "Metabolism,", "University", "Hospital", "Balgrist,", "University", "of", "Zurich,", "CH-8008", "Zurich,", "Switzerland", "Y", "G", "O", "L", "O", "I", "B", "L", "L", "E", "C", "F", "O", "L", "A", "N", "R", "U", "O", "J", "E", "H", "T", "C", "sensory", "anonical", "neurogenesis", "Wnt", "signaling", "in", "early", "instructively", "neural", "crest", "promotes", "stem", "cells", "(eNCSCs)", "(Lee,", "H.Y.,", "M.", "Kléber,", "L.", "Hari,", "V.", "Brault,", "U.", "Suter,", "M.M.", "Taketo,", "R.", "Kemler,", "and", "L.", "Sommer.", "2004.", "Science.", "303:1020–1023).", "However,", "during", "nor-", "mal", "development", "Wnt", "signaling", "induces", "a", "sensory", "fate", "only", "in", "a", "subpopulation", "of", "eNCSCs", "while", "other", "cells", "maintain", "their", "stem", "cell", "features,", "despite", "the", "presence", "of", "Wnt", "activity.", "Hence,", "factors", "counteracting", "Wnt", "signaling", "must", "exist.", "Here,", "we", "show", "that", "bone", "morphogenic", "protein", "Introduction", "Because", "of", "its", "broad", "developmental", "potential,", "the", "neural", "crest", "represents", "an", "ideal", "model", "system", "to", "study", "stem", "cell", "biology.", "Neural", "crest", "cells", "delaminate", "from", "the", "developing", "dorsal", "neural", "tube,", "migrate", "to", "various", "locations", "within", "the", "embryo,", "and", "gen-", "erate", "multiple", "neural", "cell", "types", "of", "the", "vertebrate", "peripheral", "ner-", "vous", "system", "(PNS)", "as", "well", "as", "several", "nonneural", "tissues", "(Le", "Douarin", "and", "Dupin,", "2003).", "At", "least", "some", "neural", "crest", "cells", "are", "multipotent,", "giving", "rise", "to", "neuronal,", "glial,", "and", "nonneural", "deriv-", "atives,", "as", "has", "been", "shown", "by", "clonal", "analysis", "in", "culture", "and", "in", "vivo.", "Moreover,", "some", "crest", "cells", "have", "features", "of", "stem", "cells", "with", "the", "capacity", "to", "self-renew.", "Both", "in", "migrating", "neural", "crest", "and", "in", "crest-derived", "tissues,", "such", "multipotent", "stem", "and", "progen-", "itor", "cells", "coexist", "with", "cells", "that", "display", "more", "restricted", "devel-", "opmental", "potential.", "Recently", "we", "have", "described", "an", "early", "population", "of", "neural", "crest", "stem", "cells", "(eNCSCs)", "that", "is", "highly", "homogeneous", "with", "respect", "to", "marker", "expression", "and", "the", "potential", "to", "generate", "au-", "tonomic", "and", "sensory", "neurons,", "glia,", "and", "smooth", "muscle", "cells", "(Lee", "et", "al.,", "2004).", "Clonal", "cell", "culture", "experiments", "revealed", "the", "responsiveness", "of", "these", "cells", "to", "several", "instructive", "growth", "Correspondence", "to", "Lukas", "Sommer:", "sommer@cell.biol.ethz.ch", "Abbreviations", "used", "in", "this", "paper:", "BMP,", "bone", "morphogenic", "protein;", "DRG,", "dorsal", "root", "ganglia;", "eNCSC,", "early", "neural", "crest", "stem", "cell;", "GFAP,", "glial", "fibrillary", "acidic", "protein;", "NCSC,", "neural", "crest", "stem", "cell;", "NF,", "neurofilament;", "NRG,", "neuregulin;", "PNS,", "peripheral", "nervous", "system;", "SMA,", "smooth", "muscle", "actin.", "©", "The", "Rockefeller", "University", "Press", "$8.00", "The", "Journal", "of", "Cell", "Biology,", "Vol.", "169,", "No.", "2,", "April", "25,", "2005", "309–320", "http://www.jcb.org/cgi/doi/10.1083/jcb.200411095", "(BMP)", "signaling", "antagonizes", "the", "sensory", "fate-inducing", "activity", "of", "Wnt/", "-catenin.", "Intriguingly,", "Wnt", "and", "BMP", "act", "synergistically", "to", "suppress", "differentiation", "and", "to", "maintain", "NCSC", "marker", "expression", "and", "multipotency.", "Similar", "to", "NCSCs", "in", "vivo,", "NCSCs", "maintained", "in", "culture", "alter", "their", "responsiveness", "to", "instructive", "growth", "factors", "with", "time.", "Thus,", "stem", "cell", "development", "is", "regulated", "by", "combinatorial", "growth", "factor", "activities", "that", "interact", "with", "changing", "cell-", "intrinsic", "cues.", "factors", "that", "promote", "the", "generation", "of", "specific", "cell", "fates", "at", "the", "expense", "of", "other", "possible", "fates.", "These", "factors", "include", "members", "of", "the", "TGF", "factor", "family", "that", "promote", "autonomic", "neuro-", "genesis", "and", "the", "development", "of", "smooth", "muscle–like", "cells,", "neuregulin1", "(NRG1)", "isoforms", "that", "induce", "the", "generation", "of", "pe-", "ripheral", "glia,", "and", "Wnt", "signaling", "that", "promotes", "sensory", "neuro-", "genesis", "in", "a", "-catenin–dependent", "manner", "(Le", "Douarin", "and", "Dupin,", "2003;", "Kléber", "and", "Sommer,", "2004).", "In", "vivo", "and", "in", "cell", "cul-", "ture,", "eNCSCs", "that", "lack", "the", "Wnt", "signaling", "component", "-catenin", "fail", "to", "generate", "sensory", "neurons", "(Hari", "et", "al.,", "2002).", "Comple-", "mentary", "to", "this,", "embryos", "that", "express", "a", "constitutively", "active", "form", "of", "-catenin", "specifically", "in", "NCSCs", "generate", "almost", "ex-", "clusively", "sensory", "neural", "cells", "at", "the", "expense", "of", "other", "possible", "neural", "crest–derived", "lineages", "(Lee", "et", "al.,", "2004).", "Thus,", "unlike", "in", "other", "stem", "cell", "types,", "canonical", "Wnt", "signaling", "on", "its", "own", "does", "not", "support", "stem", "cell", "expansion", "in", "NCSCs,", "but", "rather", "promotes", "sensory", "neurogenesis.", "So", "far,", "the", "signals", "supporting", "NCSC", "maintenance", "and", "self-renewal", "have", "not", "been", "identified,", "al-", "though", "it", "has", "been", "possible", "to", "passage", "both", "migratory", "and", "postmigratory", "NCSCs", "for", "some", "generations", "in", "a", "nondefined", "medium", "(Stemple", "and", "Anderson,", "1992;", "Bixby", "et", "al.,", "2002).", "Given", "the", "expression", "of", "Wnts", "in", "the", "dorsal", "neural", "tube", "at", "the", "time", "of", "neural", "crest", "emigration", "and", "the", "sensitivity", "of", "almost", "all", "eNCSCs", "to", "Wnt", "signaling", "(Parr", "et", "al.,", "1993;", "Lee", "et", "al.,", "2004),", "the", "question", "arises", "as", "to", "why", "during", "normal", "development", "only", "JCB", "309" ]

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3,091,748

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[ "Natarajan", "et", "al.", "BMC", "Genomics", "2010,", "11:606", "http://www.biomedcentral.com/1471-2164/11/606", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Gene", "discovery", "from", "Jatropha", "curcas", "by", "sequencing", "of", "ESTs", "from", "normalized", "and", "full-length", "enriched", "cDNA", "library", "from", "developing", "seeds", "Purushothaman", "Natarajan,", "Deepa", "Kanagasabapathy,", "Gnanasekaran", "Gunadayalan,", "Jasintha", "Panchalingam,", "Noopur", "shree,", "Priyanka", "Annabel", "Sugantham,", "Kavita", "Kumari", "Singh,", "Parani", "Madasamy*", "Abstract", "Background:", "Jatropha", "curcas", "L.", "is", "promoted", "as", "an", "important", "non-edible", "biodiesel", "crop", "worldwide.", "Jatropha", "oil,", "which", "is", "a", "triacylglycerol,", "can", "be", "directly", "blended", "with", "petro-diesel", "or", "transesterified", "with", "methanol", "and", "used", "as", "biodiesel.", "Genetic", "improvement", "in", "jatropha", "is", "needed", "to", "increase", "the", "seed", "yield,", "oil", "content,", "drought", "and", "pest", "resistance,", "and", "to", "modify", "oil", "composition", "so", "that", "it", "becomes", "a", "technically", "and", "economically", "preferred", "source", "for", "biodiesel", "production.", "However,", "genetic", "improvement", "efforts", "in", "jatropha", "could", "not", "take", "advantage", "of", "genetic", "engineering", "methods", "due", "to", "lack", "of", "cloned", "genes", "from", "this", "species.", "To", "overcome", "this", "hurdle,", "the", "current", "gene", "discovery", "project", "was", "initiated", "with", "an", "objective", "of", "isolating", "as", "many", "functional", "genes", "as", "possible", "from", "J.", "curcas", "by", "large", "scale", "sequencing", "of", "expressed", "sequence", "tags", "(ESTs).", "Results:", "A", "normalized", "and", "full-length", "enriched", "cDNA", "library", "was", "constructed", "from", "developing", "seeds", "of", "J.", "curcas.", "The", "cDNA", "library", "contained", "about", "1", "×", "106", "clones", "and", "average", "insert", "size", "of", "the", "clones", "was", "2.1", "kb.", "Totally", "12,084", "ESTs", "were", "sequenced", "to", "average", "high", "quality", "read", "length", "of", "576", "bp.", "Contig", "analysis", "revealed", "2258", "contigs", "and", "4751", "singletons.", "Contig", "size", "ranged", "from", "2-23", "and", "there", "were", "7333", "ESTs", "in", "the", "contigs.", "This", "resulted", "in", "7009", "unigenes", "which", "were", "annotated", "by", "BLASTX.", "It", "showed", "3982", "unigenes", "with", "significant", "similarity", "to", "known", "genes", "and", "2836", "unigenes", "with", "significant", "similarity", "to", "genes", "of", "unknown,", "hypothetical", "and", "putative", "proteins.", "The", "remaining", "191", "unigenes", "which", "did", "not", "show", "similarity", "with", "any", "genes", "in", "the", "public", "database", "may", "encode", "for", "unique", "genes.", "Functional", "classification", "revealed", "unigenes", "related", "to", "broad", "range", "of", "cellular,", "molecular", "and", "biological", "functions.", "Among", "the", "7009", "unigenes,", "6233", "unigenes", "were", "identified", "to", "be", "potential", "full-length", "genes.", "Conclusions:", "The", "high", "quality", "normalized", "cDNA", "library", "was", "constructed", "from", "developing", "seeds", "of", "J.", "curcas", "for", "the", "first", "time", "and", "7009", "unigenes", "coding", "for", "diverse", "biological", "functions", "including", "oil", "biosynthesis", "were", "identified.", "These", "genes", "will", "serve", "as", "invaluable", "genetic", "resource", "for", "crop", "improvement", "in", "jatropha", "to", "make", "it", "an", "ideal", "and", "profitable", "crop", "for", "biodiesel", "production.", "Background", "Jatropha", "curcas", "L.,", "one", "of", "the", "175", "species", "in", "genus", "Jatropha", "of", "the", "family", 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"production", "of", "food", "crops.", "It", "reduces", "the", "dependence", "on", "fossil", "fuel", "which", "is", "often", "imported", "by", "using", "precious", "foreign", "currency.", "Its", "decentralized", "production", "will", "provide", "income", "for", "a", "large", "number", "of", "small", "and", "marginal", "farmers.", "Biodiesel", "is", "also", "less", "harm-", "ful", "to", "the", "environment", "in", "that", "its", "production", "and", "com-", "bustion", "reduces", "emission", "of", "greenhouse", "gases", "by", "41%", "relative", "to", "fossil", "fuel", "[2].", "It", "is", "reported", "that", "biodiesel", "©", "2010", "Natarajan", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

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[ "Brief", "Report", "nSec1", "Binds", "a", "Closed", "Conformation", "of", "Syntaxin1A", "Bin", "Yang,", "Martin", "Steegmaier,", "Lino", "C.", "Gonzalez,", "Jr.,", "and", "Richard", "H.", "Scheller", "Howard", "Hughes", "Medical", "Institute,", "Department", "of", "Molecular", "and", "Cellular", "Physiology,", "Stanford", "University", "School", "of", "Medicine,", "Stanford,", "California", "94305-5428", "Abstract.", "The", "Sec1", "family", "of", "proteins", "is", "proposed", "to", "function", "in", "vesicle", "trafﬁcking", "by", "forming", "complexes", "with", "target", "membrane", "SNAREs", "(soluble", "N-ethylmale-", "imide-sensitive", "factor", "[NSF]", "attachment", "protein", "[SNAP]", "receptors)", "of", "the", "syntaxin", "family.", "Here,", "we", "demonstrate,", "by", "using", "in", "vitro", "binding", "assays,", "nondena-", "turing", "gel", "electrophoresis,", "and", "speciﬁc", "neurotoxin", "treat-", "ment,", "that", "the", "interaction", "of", "syntaxin1A", "with", "the", "core", "SNARE", "components,", "SNAP-25", "(synaptosome-associ-", "ated", "protein", "of", "25", "kD)", "and", "VAMP2", "(vesicle-associated", "membrane", "protein", "2),", "precludes", "the", "interaction", "with", "nSec1", "(also", "called", "Munc18", "and", "rbSec1).", "Inversely,", "asso-", "ciation", "of", "nSec1", "and", "syntaxin1A", "prevents", "assembly", "of", "the", "ternary", "SNARE", "complex.", "Furthermore,", "using", "chemical", "cross-linking", "of", "rat", "brain", "membranes,", "we", "iden-", "tiﬁed", "nSec1", "complexes", "containing", "syntaxin1A,", "but", "not", "SNAP-25", "or", "VAMP2.", "These", "results", "support", "the", "hypoth-", "esis", "that", "Sec1", "proteins", "function", "as", "syntaxin", "chaperons", "during", "vesicle", "docking,", "priming,", "and", "membrane", "fusion.", "Key", "words:", "membrane", "fusion", "•", "synaptic", "vesicles", "•", "exocytosis", "•", "SNARE", "•", "synapse", "Introduction", "Two", "of", "the", "most", "intensively", "studied", "membrane", "transport", "processes", "are", "the", "fusion", "of", "Golgi", "apparatus-derived", "vesi-", "cles", "with", "the", "plasma", "membrane", "in", "yeast", "and", "the", "secretion", "of", "neurotransmitter", "from", "the", "mammalian", "presynaptic", "nerve", "terminal", "(Bennett", "and", "Scheller,", "1994;", "Jahn", "and", "Süd-", "hof,", "1994;", "Rothman,", "1994).", "These", "membrane", "fusion", "events", "are", "mediated", "by", "a", "set", "of", "structurally", "and", "likely", "functionally", "related", "proteins", "called", "SNAREs1", "(soluble", "N-ethylmale-", "imide-sensitive", "factor", "[NSF]", "attachment", "protein", "[SNAP]", "receptors;", "Bennett,", "1995).", "These", "proteins", "include", "vesicle-", "associated", "membrane", "proteins", "(VAMP)", "1", "and", "2", "(synap-", "tobrevin),", "a", "synaptosome-associated", "protein", "of", "25", "kD", "(SNAP-25),", "and", "syntaxin1A", "and", "B", "in", "mammals;", "and", "their", "yeast", "orthologues", "Snc1", "and", "2,", "Sec9,", "and", "Sso1", "and", "2,", "re-", "spectively", "(Bennett", "and", "Scheller,", "1994;", "Brennwald", "et", "al.,", "Address", "correspondence", "to", "Richard", "H.", "Scheller,", "Howard", "Hughes", "Medical", "Institute,", "Department", "of", "Molecular", "and", "Cellular", "Physiology,", "Stanford", "University", "School", "of", "Medicine,", "Stanford,", "CA", "94305-5428.", "Tel.:", "650-723-", "9075.", "Fax:", "650-725-4436.", "E-mail:", "scheller@cmgm.stanford.edu", "1Abbreviations", "used", "in", "this", "paper:", "DSS,", "disuccinimidyl", "suberate;", "GST,", "glutathione", "S-transferase;", "NSF,", "N-ethylmaleimide-sensitive", "factor;", "SNAP,", "soluble", "NSF", "attachment", "protein;", "SNAP-25,", "synaptosome-associated", "pro-", "tein", "of", "25", "kD;", "SNARE,", "SNAP", "receptor;", "VAMP,", "vesicle-associated", "mem-", "brane", "protein.", "1994).", "The", "pairing", "of", "SNAREs", "across", "membranes", "to", "form", "four-stranded", "helical", "bundles", "is", "a", "late", "event", "in", "the", "fusion", "process,", "perhaps", "driving", "the", "actual", "mixing", "of", "the", "lipid", "bi-", "layers", "(Poirier", "et", "al.,", "1998;", "Sutton", "et", "al.,", "1998;", "Weber", "et", "al.,", "1998;", "Chen", "et", "al.,", "1999).", "In", "addition", "to", "SNAREs,", "a", "critical", "component", "of", "the", "fu-", "sion", "process", "is", "the", "Sec1p", "protein,", "known", "in", "mammals", "as", "munc18,", "nSec1,", "or", "rbSec1", "(Hata", "et", "al.,", "1993;", "Garcia", "et", "al.,", "1994;", "Pevsner", "et", "al.,", "1994b).", "This", "soluble", "protein", "is", "critical", "for", "vesicle", "trafficking", "in", "yeast", "and", "is", "proposed", "to", "play", "an", "important", "role", "in", "the", "exocytosis", "process.", "Loss", "of", "Sec1", "function", "results", "in", "an", "accumulation", "of", "vesicles", "at", "specific", "steps", "in", "secretion", "(Novick", "and", "Scheckman,", "1979;", "Ossig", "et", "al.,", "1991;", "Cowles", "et", "al.,", "1994),", "and", "overexpression", "of", "Sec1", "in", "Drosophila", "melanogaster", "results", "in", "a", "reduction", "of", "synap-", "tic", "transmission", "(Schulze", "et", "al.,", "1994;", "Wu", "et", "al.,", "1998).", "Bio-", "chemical", "studies", "conducted", "with", "the", "mammalian", "proteins", "showed", "that", "nSec1", "from", "brain", "extracts,", "bacterially", "ex-", "pressed", "recombinant,", "or", "in", "vitro", "translated", "nSec1,", "binds", "directly", "to", "syntaxin", "(Hata", "et", "al.,", "1993;", "Garcia", "et", "al.,", "1994;", "Hodel", "et", "al.,", "1994;", "Pevsner", "et", "al.,", "1994b).", "Further", "investi-", "gations", "demonstrated", "that", "when", "syntaxin", "is", "bound", "to", "nSec1,", "the", "binding", "to", "either", "VAMP", "or", "SNAP-25", "is", "inhib-", "ited", "(Pevsner", "et", "al.,", "1994a).", "A", "model", "for", "Sec1/syntaxin", "function", "was", "suggested", "from", "an", "early", "study", "demonstrating", "that", "binding", "of", "the", "NH2-ter-", "ª", "The", "Rockefeller", "University", "Press,", "0021-9525/2000/01/247/6", "$5.00", "The", "Journal", "of", "Cell", "Biology,", "Volume", "148,", "Number", "2,", "January", "24,", "2000", "247–252", "http://www.jcb.org", "247" ]

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[ "ORIGINAL", "RESEARCH", "ARTICLE", "published:", "25", "June", "2012", "doi:", "10.3389/fnins.2012.00093", "Stress", "transiently", "affects", "Pavlovian-to-instrumental", "transfer", "Pedro", "Morgado1,2,", "Miguel", "Silva1,2,", "Nuno", "Sousa1,2", "and", "João", "J.", "Cerqueira1,2*", "1", "Life", "and", "Health", "Sciences", "Research", "Institute,", "School", "of", "Health", "Sciences,", "University", "of", "Minho,", "Braga,", "Portugal", "2", "ICVS-3Bs", "PT", "Government", "Associate", "Laboratory,", "Braga/Guimarães,", "Portugal", "Edited", "by:", "Scott", "A.", "Huettel,", "Duke", "University,", "USA", "Reviewed", "by:", "Jack", "Van", "Honk,", "Utrecht", "University,", "Netherlands", "Mauricio", "R.", "Delgado,", "Rutgers-Newark:", "The", "State", "University", "of", "New", "Jersey,", "USA", "*Correspondence:", "João", "J.", "Cerqueira,", "Life", "and", "Health", "Sciences", "Research", "Institute,", "School", "of", "Health", "Sciences,", "University", "of", "Minho,", "Campus", "de", "Gualtar,", "4710-057", "Braga,", "Portugal.", "e-mail:", "jcerqueira@ecsaude.uminho.pt", "Stress", "has", "a", "strong", "impact", "in", "the", "brain,", "impairing", "decision-making", "processes", "as", "a", "result", "of", "changes", "in", "circuits", "involving", "the", "prefrontal", "and", "orbitofrontal", "cortices", "and", "the", "striatum.", "Given", "that", "these", "same", "circuits", "are", "key", "for", "action", "control", "and", "outcome", "encoding,", "we", "hypothesized", "that", "adaptive", "responses", "to", "which", "these", "are", "essential", "functions,", "could", "also", "be", "targeted", "by", "stress.", "To", "test", "this", "hypothesis", "we", "herein", "assessed", "the", "impact", "of", "chronic", "stress", "in", "a", "Pavlovian-to-instrumental", "transfer", "(PIT)", "paradigm,", "a", "model", "of", "an", "adaptive", "response", "in", "which", "a", "previously", "conditioned", "cue", "biases", "an", "instrumental", "goal-directed", "action.", "Data", "reveals", "that", "rats", "submitted", "to", "chronic", "unpredictable", "stress", "did", "not", "display", "deﬁcits", "in", "pavlovian", "condition-", "ing", "nor", "on", "the", "learning", "of", "the", "instrumental", "task,", "but", "were", "impaired", "in", "PIT;", "importantly,", "after", "a", "stress-free", "period", "the", "PIT", "deﬁcits", "were", "no", "longer", "observed.", "These", "results", "are", "relevant", "to", "understand", "how", "stress", "biases", "multiple", "incentive", "processes", "that", "contribute", "to", "instrumental", "performance.", "Keywords:", "stress,", "conditioning,", "pavlovian-to-instrumental", "transfer,", "choices", "INTRODUCTION", "Exposure", "to", "a", "stressful", "stimulus", "activates", "a", "physiological", "response", "intended", "to", "restore", "the", "organism’s", "homeostasis.", "However,", "when", "stressors", "are", "maintained", "for", "long", "periods", "of", "time,", "this", "response", "becomes", "maladaptive", "and", "results", "in", "several", "disruptions", "at", "the", "level", "of", "the", "regulatory", "systems,", "of", "which", "the", "brain", "is", "a", "key", "element.", "Thus,", "it", "is", "not", "surprising", "that", "chronic", "stress", "exposure", "is", "associated", "with", "signiﬁcant", "behavioral", "impairments", "such", "as", "deﬁcits", "in", "spatial", "reference", "and", "working", "memory", "(Mizoguchi", "et", "al.,", "2000;", "Cerqueira", "et", "al.,", "2007),", "behavioral", "ﬂexibility", "(Cerqueira", "et", "al.,", "2007),", "anxiety", "(Pêgo", "et", "al.,", "2006),", "and", "mood", "(Bessa", "et", "al.,", "2009).", "Such", "func-", "tional", "deﬁcits", "are", "paralleled", "by", "structural", "changes", "in", "several", "brain", "regions", "(Sousa", "and", "Almeida,", "2002),", "that", "render", "chronic", "stress", "as", "an", "important", "risk-factor", "for", "the", "development", "of", "several", "neuropsychi-", "atric", "disorders.", "Importantly,", "several", "studies", "have", "also", "shown", "that", "the", "behavioral", "and", "structural", "effects", "of", "stress", "are", "transient,", "and", "important", "plastic", "phenomena", "take", "place", "after", "the", "removal", "of", "the", "stressful", "stimuli", "(Sousa", "et", "al.,", "2000;", "Bloss", "et", "al.,", "2010).", "Recent", "studies", "from", "our", "laboratory", "show", "that", "chronic", "stress", "bias", "decision-making", "processes,", "by", "favoring", "the", "shift", "from", "goal-", "directed", "actions", "to", "habit", "based", "behaviors", "(Dias-Ferreira", "et", "al.,", "2009).", "These", "alterations", "in", "instrumental", "behavior", "are", "correlated", "with", "changes", "in", "neuronal", "circuits", "involving", "different", "areas", "of", "the", "prefrontal", "cortex", "(PFC)", "[including", "the", "medial", "PFC", "(mPFC)", "and", "orbitofrontal", "cortex", "(OFC)]", "and", "dorsal", "striatum", "(Dias-Ferreira", "et", "al.,", "2009).", "Given", "that", "these", "regions", "are", "implicated", "in", "action", "control", "(Balleine", "and", "O’Doherty,", "2010)", "and", "outcome", "encoding", "necessary", "for", "adaptive", "responses", "(Chudasama", "and", "Robbins,", "2003;", "Hornak", "et", "al.,", "2004),", "we", "hypothesized", "that", "stress-induced", "changes", "in", "neuronal", "circuits", "involving", "the", "PFC", "and", "the", "striatum", "could", "lead", "to", "outcome", "encoding", "deﬁcits", "and", "to", "changes", "in", "the", "multiple", "incentive", "processes", "that", "contribute", "to", "instrumental", "performance.", "One", "of", "these", "processes", "is", "Pavlovian-to-instrumental", "transfer", "(PIT;", "Estes,", "1948;", "Colwill", "and", "Rescorla,", "1986).", "PIT", "encompasses", "three", "distinct", "components:(1)", "Pavlovian", "learning,", "in", "which", "stim-", "uli", "are", "associated", "with", "rewards;", "(2)", "instrumental", "conditioning,", "in", "which", "associations", "between", "actions", "and", "out", "comes", "are", "learned;", "and", "(3)", "a", "test", "phase,", "in", "which", "the", "impact", "of", "previous", "cues", "on", "instrumental", "response", "is", "assessed.", "The", "associative", "value", "of", "cue", "and", "its", "motivational", "signiﬁcance", "are", "determinants", "found", "crucial", "to", "proper", "transfer,", "a", "phenomenon", "which", "resembles", "cue-mediated", "increased", "drive", "seeking", "for", "drugs", "seen", "in", "drug", "abusers", "(Dickinson", "et", "al.,", "2000;", "Corbit", "and", "Janak,", "2007).", "Because", "of", "that,", "PIT", "has", "been", "used", "as", "a", "useful", "model", "of", "maladaptive", "learning", "observed", "in", "several", "conditions,", "namely", "addictive", "disorders.", "The", "neural", "basis", "of", "PIT", "is", "not", "completely", "established", "but", "sev-", "eral", "studies", "implicate", "regions", "associated", "with", "emotional", "processing", "[amygdala", "and", "nucleus", "accumbens", "(NAc)],", "executive", "commands", "(dorsal", "striatum),", "and", "their", "integration", "(mPFC", "and", "OFC);", "impor-", "tantly,", "it", "is", "known", "that", "key", "regions", "involved", "in", "PIT", "operate", "in", "parallel.", "In", "fact,", "lesion", "studies", "in", "the", "amygdala", "and", "NAc", "have", "demonstrated", "that", "these", "brain", "regions", "are", "necessary", "for", "the", "behav-", "ioral", "expression", "of", "PIT", "(Corbit", "et", "al.,", "2001;", "Hall", "et", "al.,", "2001;", "de", "Borchgrave", "et", "al.,", "2002;", "Holland", "and", "Gallagher,", "2004).", "Moreover,", "it", "is", "relevant", "to", "note", "that", "different", "regions", "of", "the", "amygdala", "and", "NAc", "display", "different", "roles", "in", "this", "process.", "While", "the", "amygdala", "baso-", "lateral", "nucleus", "(BLA)", "mediates", "the", "association", "between", "speciﬁc", "sensory", "and", "emotional", "features", "of", "stimulus", "and", "the", "responses", "that", "are", "elicited", "by", "each", "one", "(consummatory", "conditioning),", "the", "central", "nucleus", "(CN)", "mediates", "the", "association", "between", "cues", "and", "affective", "properties", "of", "stimuli", "(preparatory", "conditioning;", "Killcross", "et", "al.,", "1997;", "Balleine", "and", "Killcross,", "2006).", "In", "what", "concerns", "the", "NAc,", "the", "core", "mediates", "the", "general", "excitatory", "effects", "of", "reward-related", "cues,", "whereas", "the", "shell", "mediates", "the", "effect", "of", "outcome-speciﬁc", "reward", "www.frontiersin.org", "June", "2012", "|", "Volume", "6", "|", "Article", "93", "|", "1" ]

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"we", "present", "thermodynamic", "analysis", "of", "several", "GOF", "mutants", "to", "clarify", "the", "nature", "and", "position", "of", "low-conducting", "conformations", "in", "the", "transition", "pathway.", "Unlike", "wild-type", "(WT)", "MscL,", "which", "predominantly", "occupies", "the", "closed", "and", "fully", "open", "states", "with", "very", "brief", "substates,", "the", "mild", "V23T", "GOF", "mutant", "frequently", "visits", "a", "multitude", "of", "short-lived", "subconducting", "states.", "Severe", "mutants", "V23D", "and", "G22N", "open", "in", "sequence:", "closed", "(C)", "→", "low-conducting", "substate", "(S)", "→", "open", "(O),", "with", "the", "ﬁrst", "subtransition", "occurring", "at", "lower", "tensions.", "Analyses", "of", "equilibrium", "state", "occupancies", "as", "functions", "of", "membrane", "tension", "show", "that", "the", "C→S", "subtransition", "in", "WT", "MscL", "is", "associated", "with", "only", "a", "minor", "conductance", "increment,", "but", "the", "largest", "in-plane", "expansion", "and", "free", "energy", "change.", "The", "GOF", "substitutions", "strongly", "affect", "the", "ﬁrst", "subtransition", "by", "reducing", "area", "(", "A)", "and", "energy", "(", "E)", "changes", "between", "C", "and", "S", "states", "commensurably", "with", "the", "severity", "of", "mutation.", "GOF", "mutants", "also", "exhibited", "a", "considerably", "larger", "E", "associated", "with", "the", "second", "(S→O)", "subtransition,", "but", "a", "A", "similar", "to", "WT.", "The", "area", "changes", "indicate", "that", "closed", "conformations", "of", "GOF", "mutants", "are", "physically", "preexpanded.", "The", "tension", "dependencies", "of", "rate", "constants", "for", "channel", "closure", "(koff)", "predict", "different", "positions", "of", "rate-limiting", "barriers", "on", "the", "energy-area", "proﬁles", "for", "WT", "and", "GOF", "MscL.", "The", "data", "support", "the", "two-gate", "mechanism", "in", "which", "the", "ﬁrst", "subtransition", "(C→S)", "can", "be", "viewed", "as", "opening", "of", "the", "central", "(M1)", "gate,", "resulting", "in", "an", "expanded", "water-ﬁlled", "“leaky”", "conformation.", "Strong", "facilitation", "of", "this", "step", "by", "polar", "GOF", "substitutions", "suggests", "that", "separation", "of", "M1", "helices", "associated", "with", "hydration", "of", "the", "pore", "in", "WT", "MscL", "is", "the", "major", "energetic", "barrier", "for", "opening.", "Mutants", "with", "a", "stabilized", "S1", "gate", "demonstrate", "impeded", "transitions", "from", "low-conducting", "substates", "to", "the", "fully", "open", "state,", "whereas", "extensions", "of", "S1–M1", "linkers", "result", "in", "a", "much", "higher", "probability", "of", "reverse", "O→S", "transitions.", "These", "data", "strongly", "suggest", "that", "the", "bulk", "of", "conductance", "gain", "in", "the", "second", "subtransition", "(S→O)", "occurs", "through", "the", "opening", "of", "the", "NH2-terminal", "(S1)", "gate", "and", "the", "linkers", "are", "coupling", "elements", "between", "the", "M1", "and", "S1", "gates.", "k", "e", "y", "w", "o", "r", "d", "s", ":", "mechanosensitive", "channel", "•", "tension", "•", "thermodynamics", "•", "subconducting", "states", "•", "hydration", "I", "N", "T", "R", "O", "D", "U", "C", "T", "I", "O", "N", "Uniﬁed", "mainly", "by", "function,", "mechanosensitive", "ion", "chan-", "nels", "form", "a", "diverse", "group", "of", "sensory", "receptors,", "com-", "prising", "members", "of", "structurally", "unrelated", "channel", "fam-", "ilies", "(for", "review", "see", "Sukharev", "and", "Corey,", "2004).", "The", "multiplicity", "of", "mechanoreceptor", "types", "suggests", "that", "similar", "functions", "can", "be", "implemented", "with", "different", "se-", "quences", "and", "structural", "designs,", "thus", "emphasizing", "the", "importance", "of", "unifying", "biophysical", "principles", "of", "gating", "by", "mechanical", "force.", "Bacterial", "mechanosensitive", "channels", "are", "convenient", "model", "systems", "for", "the", "basic", "channel", "biophysics.", "They", "fulﬁll", "the", "role", "of", "turgor", "pressure", "regulators", "in", "small", "prokaryotic", "cells,", "which", "in", "the", "wild", "are", "subjected", "to", "a", "constantly", "changing", "environment.", "Three", "bacterial", "mechanosensitive", "channels", "have", "been", "identiﬁed", "in", "Escherichia", "coli:", "MscL,", "MscS,", "and", "MscK", "(Sukharev", "et", "al.,", "1994;", "Levina", "et", "al.,", "1999;", "Pivetti", "et", "al.,", "2003).", "Two", "of", "A.", "Anishkin", "and", "C.-S.", "Chiang", "contributed", "equally", "to", "this", "work.", "Correspondence", "to", "Sergei", "Sukharev:", "sukharev@umd.edu", "them,", "MscL", "and", "MscS,", "were", "isolated,", "reconstituted,", "and", "shown", "to", "be", "gated", "directly", "by", "tension", "in", "the", "lipid", "bilayer", "(Hase", "et", "al.,", "1995;", "Blount", "et", "al.,", "1996a;", "Okada", "et", "al.,", "2002;", "Sukharev,", "2002).", "Successful", "efforts", "in", "crystallization", "of", "MscS", "from", "E.", "coli", "(Bass", "et", "al.,", "2002)", "and", "the", "MscL", "homologue", "from", "M.", "tuberculosis", "(Chang", "et", "al.,", "1998)", "(TbMscL)", "have", "opened", "rich", "opportunities", "for", "detailed", "structure-based", "studies", "of", "their", "gating", "mechanisms.", "Since", "then,", "MscL", "has", "been", "the", "best", "understood", "“simple”", "chan-", "nel", "gated", "by", "membrane", "stretch", "(Blount,", "2003;", "Perozo", "and", "Rees,", "2003;", "Sukharev", "and", "Anishkin,", "2004).", "Identiﬁcation", "of", "the", "main", "gate", "region", "in", "randomly", "generated", "gain-of-function", "mutants", "of", "MscL", "(Ou", "et", "al.,", "1998)", "corroborated", "extremely", "well", "with", "the", "crystal", "structure.", "The", "separation", "of", "the", "tightly", "packed", "M1", "helices", "in", "the", "core", "of", "the", "complex", "was", "inferred", "to", "be", "the", "central", "step", "in", "the", "gating", "process", "(Chang", "et", "al.,", "1998;", "Yoshimura", "et", "al.,", "1999;", "Batiza", "et", "al.,", "1999;", "Suk-", "harev", "et", "al.,", "2001a).", "The", "“iris”", "model", "of", "the", "MscL", "barrel", "Abbreviations", "used", "in", "this", "paper:", "GOF,", "gain-of-function;", "WT,", "wild", "type.", "155", "J.", "Gen.", "Physiol.", "©", "The", "Rockefeller", "University", "Press", "•", "0022-1295/2005/02/155/16", "$8.00", "Volume", "125", "February", "2005", "155–170", "http://www.jgp.org/cgi/doi/10.1085/jgp.200409118" ]

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2,330,072

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[ "Promoter-Wide", "Hypermethylation", "of", "the", "Ribosomal", "RNA", "Gene", "Promoter", "in", "the", "Suicide", "Brain", "Patrick", "O.", "McGowan1,2,3,", "Aya", "Sasaki1,2,3,", "Tony", "C.", "T.", "Huang3,4,", "Alexander", "Unterberger3,4,", "Matthew", "Suderman3,5,", "Carl", "Ernst1,6,", "Michael", "J.", "Meaney1,2,3,", "Gustavo", "Turecki1,6*,", "Moshe", "Szyf3,4*", "1", "Department", "of", "Psychiatry,", "Douglas", "Mental", "Health", "University", "Institute,", "Montreal,", "Quebec,", "Canada,", "2", "Department", "of", "Neurology", "and", "Neurosurgery,", "McGill", "Program", "for", "the", "Study", "of", "Behaviour,", "Genes", "and", "Environment,", "McGill", "University,", "Montreal,", "Quebec,", "Canada,", "3", "Sackler", "Program", "for", "Epigenetics", "&", "Psychobiology,", "McGill", "University,", "Montreal,", "Quebec,", "Canada,", "4", "Department", "of", "Pharmacology", "and", "Therapeutics,", "McGill", "University,", "Montreal,", "Quebec,", "Canada,", "5", "McGill", "Centre", "for", "Bioinformatics,", "McGill", "University,", "Montreal,", "Quebec,", "Canada,", "6", "McGill", "Group", "for", "Suicide", "Studies,", "Douglas", "Mental", "Health", "University", "Institute,", "Montreal,", "Quebec,", "Canada", "Abstract", "Background:", "Alterations", "in", "gene", "expression", "in", "the", "suicide", "brain", "have", "been", "reported", "and", "for", "several", "genes", "DNA", "methylation", "as", "an", "epigenetic", "regulator", "is", "thought", "to", "play", "a", "role.", "rRNA", "genes,", "that", "encode", "ribosomal", "RNA,", "are", "the", "backbone", "of", "the", "protein", "synthesis", "machinery", "and", "levels", "of", "rRNA", "gene", "promoter", "methylation", "determine", "rRNA", "transcription.", "Methodology/Principal", "Findings:", "We", "test", "here", "by", "sodium", "bisulfite", "mapping", "of", "the", "rRNA", "promoter", "and", "quantitative", "real-", "time", "PCR", "of", "rRNA", "expression", "the", "hypothesis", "that", "epigenetic", "differences", "in", "critical", "loci", "in", "the", "brain", "are", "involved", "in", "the", "pathophysiology", "of", "suicide.", "Suicide", "subjects", "in", "this", "study", "were", "selected", "for", "a", "history", "of", "early", "childhood", "neglect/abuse,", "which", "is", "associated", "with", "decreased", "hippocampal", "volume", "and", "cognitive", "impairments.", "rRNA", "was", "significantly", "hypermethylated", "throughout", "the", "promoter", "and", "59", "regulatory", "region", "in", "the", "brain", "of", "suicide", "subjects,", "consistent", "with", "reduced", "rRNA", "expression", "in", "the", "hippocampus.", "This", "difference", "in", "rRNA", "methylation", "was", "not", "evident", "in", "the", "cerebellum", "and", "occurred", "in", "the", "absence", "of", "genome-wide", "changes", "in", "methylation,", "as", "assessed", "by", "nearest", "neighbor.", "Conclusions/Significance:", "This", "is", "the", "first", "study", "to", "show", "aberrant", "regulation", "of", "the", "protein", "synthesis", "machinery", "in", "the", "suicide", "brain.", "The", "data", "implicate", "the", "epigenetic", "modulation", "of", "rRNA", "in", "the", "pathophysiology", "of", "suicide.", "Citation:", "McGowan", "PO,", "Sasaki", "A,", "Huang", "TCT,", "Unterberger", "A,", "Suderman", "M,", "et", "al.", "(2008)", "Promoter-Wide", "Hypermethylation", "of", "the", "Ribosomal", "RNA", "Gene", "Promoter", "in", "the", "Suicide", "Brain.", "PLoS", "ONE", "3(5):", "e2085.", "doi:10.1371/journal.pone.0002085", "Editor:", "Jo¨", "rg", "Hoheisel,", "Deutsches", "Krebsforschungszentrum,", "Germany", "Received", "October", "28,", "2007;", "Accepted", "March", "20,", "2008;", "Published", "May", "7,", "2008", "Copyright:", "2008", "McGowan", "et", "al.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Funding:", "This", "work", "was", "funded", "by", "a", "grant", "from", "the", "National", "Cancer", "Institute", "to", "MS,", "NICHD", "to", "MJM", "and", "MS,", "HSFP", "to", "MJM", "and", "MS,", "the", "Maternal", "Adversity,", "Vulnerability", "and", "Neurodevelopment", "Project", "grant", "from", "the", "Canadian", "Institutes", "for", "Health", "Research", "(CIHR)", "to", "MJM", "and", "MS,", "as", "well", "as", "grants", "from", "CIHR", "to", "GT.", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "*", "E-mail:", "gustvao.turecki@mcgill.ca", "(GT);", "moshe.szyf@mcgill.ca", "(MS)", "Introduction", "Suicide", "is", "a", "leading", "cause", "of", "death,", "particularly", "in", "males", "[1,2].", "Although", "many", "suicide", "subjects", "have", "a", "diagnosable", "psychiatric", "illness,", "most", "persons", "with", "a", "psychiatric", "disorder", "never", "attempt", "suicide", "[2].", "Suicidal", "behavior", "aggregates", "in", "families", "[1],", "and", "studies", "of", "twins", "show", "that", "monozygotic", "individuals", "have", "a", "greater", "concordance", "for", "suicide", "completion", "and", "suicide", "attempts", "com-", "pared", "to", "dizygotic", "individuals", "[2–4].", "Non-genetic", "familial", "factors,", "including", "a", "history", "of", "abuse", "or", "neglect", "during", "childhood,", "are", "also", "risk", "factors", "for", "suicidal", "behavior", "[5,6].", "Similarly,", "childhood", "abuse", "is", "associated", "with", "an", "increased", "risk", "for", "psychopathology", "[7,8]", "and", "altered", "neural", "development", "[9].", "Several", "lines", "of", "evidence", "suggest", "that", "changes", "in", "gene", "expression", "in", "the", "brain", "occur", "in", "the", "context", "of", "psychiatric", "disorders", "and", "suicide", "[10–15].", "Alterations", "in", "gene", "regulation", "can", "be", "caused", "by", "epigenetic", "programming", "of", "gene", "expression", "in", "response", "to", "environmental", "exposure,", "including", "social", "and", "physical", "adversity", "[16].", "The", "genome", "is", "epigenetically", "programmed", "by", "changes", "in", "the", "chromatin", "state", "and", "by", "a", "pattern", "of", "modification", "of", "the", "DNA", "molecule", "itself", "through", "methylation", "[17].", "DNA", "methylation", "is", "a", "stable", "epigenetic", "mark", "associated", "with", "long-lasting", "silencing", "of", "gene", "expression", "[18].", "In", "rodents,", "genes", "responsive", "to", "differences", "in", "the", "quality", "of", "maternal", "care", "early", "in", "life", "are", "altered", "through", "epigenetic", "mechanisms", "[19,20].", "In", "the", "human", "brain,", "aberrant", "DNA", "methylation", "of", "specific", "genes", "also", "occurs", "in", "the", "context", "of", "psychiatric", "disorders", "[21–26].", "Decreased", "expression", "of", "ribosomal", "RNA", "(rRNA),", "a", "bottleneck", "gene", "for", "protein", "production", "in", "the", "cell,", "occurs", "in", "patients", "with", "mild", "cognitive", "impairment", "and", "early", "Alzheimer’s", "disease", "[27,28].", "DNA", "methylation", "can", "regulate", "gene", "expression", "in", "two", "ways.", "One", "is", "site-specific", "methylation,", "involving", "direct", "interference", "with", "the", "binding", "of", "transcription", "factors", "[29].", "The", "second", "is", "site-", "independent", "promoter-wide", "methylation,", "attracting", "methylated", "DNA", "binding", "proteins", "and", "leading", "to", "an", "inactive", "chromatin", "structure.", "In", "the", "latter", "case,", "the", "density", "of", "methylated", "CpGs", "determines", "the", "extent", "of", "gene", "silencing", "[30].", "Both", "mechanisms", "can", "regulate", "rRNA", "expression.", "Previous", "work", "in", "cultured", "mouse", "cells", "indicated", "that", "rRNA", "is", "regulated", "by", "methylation", "of", "a", "single", "CpG", "dinucleotide", "at", "position", "2133", "residing", "at", "the", "upstream", "control", "element", "(UCE)", "[31].", "In", "human", "cell", "culture,", "the", "transcriptionally", "active", "fraction", "of", "rRNA", "promoters", "associated", "with", "RNA", "polymerase", "I", "(pol", "I)", "is", "completely", "unmethylated", "whereas", "the", "fraction", "not", "associated", "with", "pol", "I", "is", "almost", "completely", "methylated", "[32],", "thus", "determining", "transcription", "by", "defining", "the", "fraction", "of", "unmethylated", "rRNA.", "Mouse", "and", "human", "rRNA", "promoters", "show", "PLoS", "ONE", "|", "www.plosone.org", "1", "May", "2008", "|", "Volume", "3", "|", "Issue", "5", "|", "e2085" ]

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3,405,457

null

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[ "Harris", "et", "al.", "Pediatric", "Rheumatology", "2012,", "10:9", "http://www.ped-rheum.com/content/10/1/9", "C", "A", "S", "E", "R", "E", "P", "O", "R", "T", "Asymptomatic", "intracardiac", "mass", "in", "a", "14-year-old", "girl", "with", "granulomatosis", "with", "polyangiitis:", "Case", "report", "Julia", "G", "Harris1,4*,", "David", "M", "Salvay2,5", "and", "Marisa", "S", "Klein-Gitelman3,6", "Open", "Access", "Abstract", "Granulomatosis", "with", "polyangiitis", "(GPA;", "Wegener’s", "granulomatosis)", "is", "a", "systemic", "necrotizing", "vasculitis", "of", "unknown", "etiology", "that", "commonly", "involves", "the", "upper", "airways,", "lungs,", "and", "kidneys.", "Cardiac", "involvement", "with", "an", "intracardiac", "mass", "is", "an", "exceedingly", "rare", "manifestation", "of", "this", "disease,", "especially", "in", "the", "pediatric", "population", "where,", "to", "our", "knowledge,", "only", "one", "article", "exists", "to", "date", "that", "has", "described", "such", "a", "finding.", "In", "this", "report,", "we", "present", "the", "case", "of", "an", "adolescent", "female", "who", "initially", "presented", "with", "renal", "failure", "and", "an", "intracardiac", "mass.", "Subsequent", "work-up", "led", "to", "a", "diagnosis", "of", "granulomatosis", "with", "polyangiitis", "(GPA).", "Cardiac", "manifestations", "in", "pediatric", "GPA", "are", "not", "common;", "however,", "they", "may", "be", "more", "prevalent", "than", "reported", "given", "recent", "adult", "literature", "and", "concern", "for", "clinically", "silent", "abnormalities.", "Keywords:", "Granulomatosis", "with", "polyangiitis,", "Wegener’s", "granulomatosis,", "Intracardiac", "mass", "Background", "Granulomatosis", "with", "polyangiitis", "(GPA;", "Wegener’s", "granulo-", "matosis)", "is", "a", "systemic", "vasculitis", "characterized", "by", "acute", "nec-", "rotizing", "granulomas", "of", "the", "upper", "respiratory", "tract", "and", "lungs,", "necrotizing", "or", "granulomatous", "vasculitis", "affecting", "small", "to", "medium-sized", "vessels", "and", "pauci-immune,", "necrotiz-", "ing,", "and", "crescentic", "glomerulonephritis;", "however,", "this", "disease", "can", "affect", "virtually", "any", "organ", "system", "[1-7].", "In", "this", "report,", "we", "describe", "a", "case", "of", "GPA", "presenting", "as", "renal", "failure", "with", "discovery", "of", "an", "intracardiac", "mass", "in", "an", "adolescent", "patient.", "We", "will", "discuss", "the", "significance", "of", "this", "finding", "in", "light", "of", "re-", "cent", "literature.", "Case", "Presentation", "A", "14-year-old", "girl", "presented", "with", "a", "6-week", "history", "of", "fa-", "tigue,", "persistent", "rhinorrhea,", "and", "intermittent", "epistaxis.", "Her", "history", "was", "also", "significant", "for", "recurrent", "sinusitis,", "rash,", "decreased", "urine", "output,", "and", "myalgias.", "The", "patient", "was", "seen", "by", "her", "pediatrician", "with", "concerns", "that", "her", "nose", "was", "“col-", "lapsing.”", "Past", "medical", "history", "includes", "atopic", "dermatitis", "as", "a", "child", "and", "allergic", "rhinitis.", "*", "Correspondence:", "jgharris@mcw.edu", "1Medical", "College", "of", "Wisconsin,", "Children’s", "Hospital", "of", "Wisconsin,", "Milwaukee,", "WI,", "USA", "4Children’s", "Hospital", "of", "Wisconsin,", "9000", "West", "Wisconsin", "Avenue,", "Wauwatosa,", "WI", "53226,", "USA", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "On", "admission", "to", "our", "hospital,", "the", "patient’s", "physical", "exam", "was", "remarkable", "for", "pallor,", "saddle", "nose,", "dried", "nasal", "secretions,", "oral", "ulcers,", "synovial", "swelling", "around", "multiple", "joints,", "and", "palpable", "purpura", "on", "her", "distal", "extremities.", "Ini-", "tial", "laboratory", "tests", "showed", "that", "the", "patient", "was", "in", "acute", "renal", "failure", "with", "a", "BUN", "of", "131", "mg/dL", "and", "creatinine", "of", "11.14", "mg/dL.", "She", "also", "had", "elevated", "inflammatory", "markers", "(ESR", "82", "mm/hr,", "CRP", "19.2", "mg/dL),", "normocytic", "anemia", "(hemoglobin", "8.7", "g/dL,", "MCV", "79.7", "fL),", "leukocytosis", "(white", "blood", "cells", "29", "×", "103/mm", "3", ",", "absolute", "eosinophil", "count", "615/uL),", "thrombocytosis", "(platelets", "661", "×", "103/mm", "3", "),", "and", "proteinuria", "and", "hematuria", "on", "urinalysis", "(specific", "gravity", "1.015,", "pH", "6.0,", "large", "occult", "blood,", "RBC", "21–30/hpf,", "protein", "100", "mg/dL,", "trace", "leukocytes,", "WBC", "0–2/hpf,", "epithelial", "cells", "6–10/hpf;", "negative", "nitrite,", "bilirubin,", "ketones,", "and", "glucose).", "Initial", "imaging", "studies", "showed", "a", "left", "lower", "lobe", "infiltrate", "via", "chest", "x-ray", "and", "renal", "ultrasound", "demonstrated", "large,", "echogenic", "kidneys", "with", "absent", "corticomedullary", "junction", "differentiation.", "Given", "her", "vasculitic", "rash,", "nasal", "cartilage", "destruction,", "and", "apparent", "sinusitis—signs", "consistent", "with", "GPA—the", "patient", "was", "started", "on", "methylprednisolone", "(30", "mg/kg/day)", "and", "cyclophosphamide", "(1", "mg/kg/day)", "with", "decreased", "dosing", "secondary", "to", "renal", "failure.", "Additional", "laboratory", "results", "showed", "a", "positive", "ANCA", "with", "a", "cytoplasmic", "pattern", "by", "indirect", "immunofluorescence", "screening", "and", "an", "anti-", "©", "2012", "Harris", "et", "al.;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

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3,024,926

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[ "Roberts", "et", "al.", "Journal", "of", "Foot", "and", "Ankle", "Research", "2011,", "4:1", "http://www.jfootankleres.com/content/4/1/1", "R", "E", "S", "E", "A", "R", "C", "H", "JOURNAL", "OF", "FOOT", "AND", "ANKLE", "RESEARCH", "Open", "Access", "Comparison", "of", "ankle", "and", "subtalar", "joint", "complex", "range", "of", "motion", "during", "barefoot", "walking", "and", "walking", "in", "Masai", "Barefoot", "Technology", "sandals", "Sophie", "Roberts1*,", "Ivan", "Birch2,", "Simon", "Otter3*", "Abstract", "Background:", "Masai", "Barefoot", "Technology", "(MBT,", "Switzerland)", "produce", "footwear", "which", "they", "claim", "simulate", "walking", "barefoot", "on", "soft", "undulating", "ground.", "This", "paper", "reports", "an", "investigation", "into", "the", "effect", "of", "MBT", "sandals", "on", "the", "motion", "of", "the", "ankle", "and", "subtalar", "joint", "complex", "during", "walking.", "Methods:", "Range", "of", "motion", "data", "was", "collected", "in", "the", "sagittal,", "frontal", "and", "transverse", "plane", "from", "the", "ankle", "and", "subtalar", "joint", "complex", "from", "32", "asymptomatic", "subjects", "using", "the", "CODA", "MPX30", "motion", "analysis", "system", "during", "both", "barefoot", "walking", "and", "walking", "in", "the", "MBT", "sandal.", "Shod", "and", "un-shod", "data", "were", "compared", "using", "the", "Wilcoxon", "signed", "ranks", "test.", "Results:", "A", "significantly", "greater", "range", "of", "motion", "in", "the", "frontal", "and", "sagittal", "planes", "was", "recorded", "when", "walking", "in", "the", "MBT", "sandal", "(p", "=", "0.031,", "and", "p", "=", "0.015", "respectively).", "In", "the", "transverse", "plane,", "no", "significant", "difference", "was", "found", "(p", "=", "0.470).", "Conclusions:", "MBT", "sandals", "increase", "the", "range", "of", "motion", "of", "the", "ankle", "and", "subtalar", "joint", "complex", "in", "the", "frontal", "and", "sagittal", "planes.", "MBT", "footwear", "could", "therefore", "have", "a", "role", "to", "play", "in", "the", "management", "of", "musculoskeletal", "disorders", "where", "an", "increase", "in", "frontal", "and", "sagittal", "plane", "range", "of", "motion", "is", "desirable.", "Background", "With", "the", "growth", "in", "the", "health", "and", "fitness", "industry,", "sports", "footwear", "has", "shown", "technological", "advances", "and", "diversification.", "The", "introduction", "of", "footwear", "such", "as", "the", "MBT", "shoe", "(manufactured", "by", "Masai", "Barefoot", "Technolo-", "gies)", "is", "an", "example", "of", "this", "diversification.", "MBT", "have", "based", "their", "shoe", "design", "on", "observations", "of", "the", "Masai,", "a", "semi-nomadic", "tribe", "from", "Africa", "who", "are", "well", "known", "for", "their", "posture", "and", "for", "walking", "long", "distances", "on", "uneven", "terrain.", "The", "MBT", "shoe", "construction", "is", "based", "on", "a", "mid-", "sole", "pivot", "with", "a", "rounded", "sole", "in", "the", "anterior-posterior", "direction,", "and", "a", "soft", "heel", "pad.", "It", "is", "claimed", "that", "the", "effect", "of", "the", "angled", "soft", "sole", "not", "only", "creates", "anterior/", "posterior", "facilitation", "of", "movement,", "by", "purposefully", "creating", "medial", "and", "lateral", "instability", "in", "the", "shoe", "[1].", "*", "Correspondence:", "sophieroberts@thegaitlab.co.uk;", "s.otter@brighton.ac.uk", "1Outpatients", "Department,", "Parkside", "Hospital,", "53", "Parkside,", "London,", "SW19", "5NX,", "UK", "3University", "of", "Brighton,", "School", "of", "Health", "Sciences,", "49", "Darley", "Rd,", "Eastbourne,", "BN20", "7UR,", "UK", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "According", "to", "Romkes", "et", "al", "[2],", "MBT", "shoes", "have", "been", "used", "to", "treat", "foot", "problems", "such", "as", "hallux", "valgus,", "pes", "planus,", "heel", "and", "tendo-achilles", "pain", "as", "well", "as", "circula-", "tory", "problems.", "Nigg", "et", "al", "[3]", "found", "that", "MBT", "shoes", "may", "be", "useful", "as", "a", "training", "device", "for", "stability", "and", "mus-", "cle", "strengthening", "adding", "another", "dimension", "to", "their", "use.", "However,", "New", "et", "al", "[4]", "and", "Nigg", "et", "al", "[3]", "found", "that", "subjects", "from", "many", "of", "the", "studies", "conducted", "using", "MBT", "shoes", "received", "an", "instruction", "session", "in", "which", "they", "were", "taught", "how", "to", "use", "the", "shoes", "correctly", "by", "a", "qualified", "instructor", "and", "given", "a", "long", "training", "period", "to", "acclimatise", "to", "the", "shoes.", "As", "such", "there", "remains", "debate", "as", "to", "whether", "the", "reported", "changes", "in", "gait", "were", "as", "a", "result", "of", "the", "MBT", "shoe", "or", "the", "professional", "instruction", "in", "gait", "and", "posture", "the", "subjects", "received", "and", "the", "train-", "ing", "period", "they", "had", "[4].", "Nigg", "et", "al", "[3]", "described", "that", "an", "increase", "in", "the", "angle", "of", "ankle", "dorsiflexion", "in", "MBT", "shoes", "was", "evident", "com-", "pared", "to", "a", "standard", "training", "shoe.", "Vernon", "et", "al", "[5]", "also", "reported", "subjects", "exhibited", "significantly", "higher", "maxi-", "mum", "dorsiflexion", "angle", "at", "the", "ankle", "joint", "when", "wearing", "©", "2011", "Roberts", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

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2,526,489

null

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[ "J", "Korean", "Med", "Sci", "2008;", "23:", "146-8", "ISSN", "1011-8934", "DOI:", "10.3346/jkms.2008.23.1.146", "Copyright", "The", "Korean", "Academy", "of", "Medical", "Sciences", "Unrelated", "Bone", "Marrow", "Transplantation", "with", "a", "Reduced", "Toxicity", "Myeloablative", "Conditioning", "Regimen", "in", "Wiskott-Aldrich", "Syndrome", "Wiskott-Aldrich", "syndrome", "(WAS)", "is", "an", "X-linked", "congenital", "immune-deficiency", "syn-", "drome,", "and", "bone", "marrow", "transplantation", "(BMT)", "has", "become", "a", "curative", "modality.", "However,", "the", "transplant", "with", "the", "alternative", "donor", "needed", "more", "intensive", "condi-", "tioning", "with", "increased", "treatment-related", "toxicities.", "Recently,", "fludarabine-based", "reduc-", "ed", "toxicity", "myeloablative", "conditioning", "regimens", "have", "been", "developed", "for", "adult", "myeloid", "malignancies", "with", "promising", "results", "of", "good", "engraftment", "and", "low", "treatment-relat-", "ed", "toxicities.", "To", "increase", "the", "engraftment", "potential", "without", "serious", "complications,", "a", "boy", "with", "WAS", "received", "successful", "unrelated", "BMT", "with", "a", "reduced", "toxicity", "myeloab-", "lative", "conditioning", "regimen", "composed", "of", "fludarabine", "(40", "mg/m2", "on", "days", "-8,", "-7,", "-6,", "-5,", "-4,", "-3),", "busulfan", "(0.8", "mg/kg", "i.", "v.", "q", "6", "hr", "on", "days", "-6,", "-5,", "-4,", "-3),", "and", "thymoglobulin", "(2.5", "mg/kg", "on", "days", "-4,", "-3,", "-2).", "This", "novel", "conditioning", "regimen", "could", "improve", "the", "outcome", "of", "allogeneic", "transplantation", "for", "other", "non-malignant", "diseases", "such", "as", "congenital", "immune-deficiency", "syndromes", "or", "metabolic", "storage", "diseases.", "Key", "Words", ":", "Wiskott-Aldrich", "Syndrome;", "Bone", "Marrow", "Transplantation;", "Busulfan;", "Fludarabine", "Hyoung", "Jin", "Kang,", "Hee", "Young", "Shin,", "Sun", "Hie", "Ko,", "Jeong", "Ah", "Park,", "Eun", "Kyung", "Kim,", "Jung", "Woo", "Rhim,", "Joong", "Gon", "Kim,", "Hyo", "Seop", "Ahn", "Department", "of", "Pediatrics,", "Cancer", "Research", "Institute,", "Seoul", "National", "University", "College", "of", "Medicine,", "Seoul,", "Korea", "Received", ":", "8", "January", "2007", "Accepted", ":", "21", "February", "2007", "Address", "for", "correspondence", "Hyo", "Seop", "Ahn,", "M.D.", "Department", "of", "Pediatrics,", "Cancer", "Research", "Institute,", "Seoul", "National", "University", "College", "of", "Medicine,", "28", "Yeongeon-dong,", "Jongno-gu,", "Seoul", "110-744,", "Korea", "Tel", ":", "+82.2-2072-3625,", "Fax", ":", "+82.2-743-3455", "E-mail", ":", "hsahn@snu.ac.kr", "*This", "study", "was", "supported", "by", "grant", "of", "the", "Korea", "Health", "21", "R&D", "Project,", "Ministry", "of", "Health", "&", "Welfare,", "Republic", "of", "Korea", "(A050089).", "INTRODUCTION", "Wiskott-Aldrich", "syndrome", "(WAS)", "is", "an", "X-linked", "congen-", "ital", "immune-deficiency", "syndrome", "characterized", "by", "the", "triad", "of", "recurrent", "infection,", "eczema,", "and", "thrombocytopenia,", "and", "bone", "marrow", "transplantation", "(BMT)", "from", "an", "HLA-matched", "related", "donor", "is", "an", "effective", "treatment", "(1,", "2).", "Patients", "with-", "out", "an", "appropriate", "related", "donor", "could", "receive", "an", "alternative", "stem", "cell", "source", "such", "as", "matched", "unrelated", "donor", "or", "cord", "blood.", "However,", "the", "transplant", "with", "the", "alternative", "donor", "needed", "more", "intensive", "conditioning", "to", "overcome", "the", "hema-", "tologic", "and", "immunologic", "barrier", "with", "increased", "treatment-", "related", "toxicity.", "Recently,", "fludarabine-based", "reduced", "toxici-", "ty", "myeloablative", "conditioning", "regimens", "have", "been", "develop-", "ed", "for", "adult", "myeloid", "malignancies", "with", "promising", "results", "of", "good", "engraftment", "and", "low", "treatment", "related", "toxicities", "(3-5).", "To", "increase", "the", "engraftment", "potential", "without", "serious", "com-", "plications,", "a", "boy", "with", "WAS", "received", "BMT", "from", "a", "matched", "unrelated", "donor", "with", "a", "reduced", "toxicity", "myeloablative", "con-", "ditioning", "regimen.", "CASE", "REPORT", "A", "3-yr-old", "boy", "was", "admitted", "because", "of", "eczema,", "recurrent", "146", "infection,", "and", "thrombocytopenia", "with", "a", "platelet", "count", "less", "than", "10×109/L", "and", "was", "diagnosed", "as", "having", "WAS", "with", "a", "large", "deletion", "in", "the", "exon", "1", "to", "11", "of", "the", "WAS", "gene", "(Fig.", "1).", "For", "the", "detection", "of", "mutation,", "the", "following", "primers", "were", "used;", "exon", "1", "forward", "5′-GGT", "TTT", "TTG", "CAT", "TTC", "CTG", "TTC-", "3′and", "exon", "1", "reverse", "5′-AGG", "AAG", "AGG", "AAG", "AAA", "CGG", "TG-3′,", "exon", "2", "forward", "5′-CCT", "GAC", "CAG", "ACT", "CCA", "CTG", "AC-3′and", "exon", "2", "reverse", "5′-CTT", "GAA", "GCT", "ATG", "GAC", "ACA", "TAT", "G-3′,", "exon", "3", "forward", "5′CCT", "CAG", "TGC", "CAC", "TGT", "GCC", "TC3′and", "exon", "3", "reverse", "5′-TTC", "CCA", "TCT", "CCT", "CTC", "CAC", "AC-3′,", "exon", "4", "forward", "5′-GTG", "TGG", "AGA", "GGA", "GAT", "GGG", "AA-3′and", "exon", "4", "reverse", "5′-CAC", "TCA", "CCT", "CTG", "CCC", "AAC", "TT-3′,", "exon", "5", "forward", "5′-AAG", "TTG", "GGC", "AGA", "GGT", "GAG", "TG-3′and", "exon", "5", "reverse", "5′-AGA", "GAG", "TTA", "TCA", "CAG", "CCC", "TG-3′,", "exon", "6", "forward", "5′-GGC", "TGT", "GAT", "AAC", "TCT", "CTA", "CA-3′and", "exon", "6", "reverse", "5′-CCA", "TCC", "ATC", "CAG", "AGA", "CAC", "AG-3′,", "exon", "7", "forward", "5′-TGG", "TAA", "GTG", "GGT", "CAA", "TGA", "GC-3′and", "exon", "7", "reverse", "5′-", "CAG", "CTG", "TCC", "ACT", "TGT", "TCA", "TG-3′,", "exon", "8", "forward", "5′-AAG", "GAA", "GGG", "CAG", "TGA", "GGA", "TT-3′and", "exon", "8", "reverse", "5′-GGT", "GGA", "AGT", "TTA", "GTG", "GAG", "TC-3′,", "exon", "9", "forward", "5′-CGC", "CTT", "ATT", "CCT", "CTA", "CTC", "CT-3′and", "exon", "9", "reverse", "5′-GAC", "TGA", "GTG", "ACT", "TAG", "TGC", "GT-3′,", "exon", "10-1", "forward", "5′-TCA", "GTC", "AGG", "AGT", "TGG", "TCA", "GT-3′and", "exon", "10-1", "reverse", "5′-GTC", "CAG", "AAC", "GTC", "CAG" ]

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[ "Int.", "J.", "Mol.", "Sci.", "2011,", "12,", "4975-4990;", "doi:10.3390/ijms12084975", "OPEN", "ACCESS", "International", "Journal", "of", "Molecular", "Sciences", "ISSN", "1422-0067", "www.mdpi.com/journal/ijms", "Article", "Transient", "Co-Expression", "of", "Post-Transcriptional", "Gene", "Silencing", "Suppressors", "for", "Increased", "in", "Planta", "Expression", "of", "a", "Recombinant", "Anthrax", "Receptor", "Fusion", "Protein", "Lucas", "Arzola", "1,", "Junxing", "Chen", "1,", "Kittipong", "Rattanaporn", "1,", "James", "M.", "Maclean", "2", "and", "Karen", "A.", "McDonald", "1,*", "1", "Department", "of", "Chemical", "Engineering", "and", "Materials", "Science,", "University", "of", "California,", "Davis,", "One", "Shields", "Ave,", "Davis,", "CA", "95616,", "USA;", "E-Mails:", "larzola@ucdavis.edu", "(L.A.);", "cicchen@ucdavis.edu", "(J.C.);", "krattanaporn@ucdavis.edu", "(K.R.)", "2", "Planet", "Biotechnology", "Inc.,", "25571", "Clawiter", "Road,", "Hayward,", "CA", "94545,", "USA;", "E-Mail:", "jmaclean@planetbiotechnology.com", "*", "Author", "to", "whom", "correspondence", "should", "be", "addressed;", "E-Mail:", "kamcdonald@ucdavis.edu;", "Tel.:", "+1-530-752-1979;", "Fax:", "+1-530-752-8058.", "Received:", "1", "April", "2011;", "in", "revised", "form:", "18", "June", "2011", "/", "Accepted:", "20", "July", "2011", "/", "Published:", "5", "August", "2011", "Abstract:", "Potential", "epidemics", "of", "infectious", "diseases", "and", "the", "constant", "threat", "of", "bioterrorism", "demand", "rapid,", "scalable,", "and", "cost-efficient", "manufacturing", "of", "therapeutic", "proteins.", "Molecular", "farming", "of", "tobacco", "plants", "provides", "an", "alternative", "for", "the", "recombinant", "production", "of", "therapeutics.", "We", "have", "developed", "a", "transient", "production", "platform", "that", "uses", "Agrobacterium", "infiltration", "of", "Nicotiana", "benthamiana", "plants", "to", "express", "a", "novel", "anthrax", "receptor", "decoy", "protein", "(immunoadhesin),", "CMG2-Fc.", "This", "chimeric", "fusion", "protein,", "designed", "to", "protect", "against", "the", "deadly", "anthrax", "toxins,", "is", "composed", "of", "the", "von", "Willebrand", "factor", "A", "(VWA)", "domain", "of", "human", "capillary", "morphogenesis", "2", "(CMG2),", "an", "effective", "anthrax", "toxin", "receptor,", "and", "the", "Fc", "region", "of", "human", "immunoglobulin", "G", "(IgG).", "We", "evaluated,", "in", "N.", "benthamiana", "intact", "plants", "and", "detached", "leaves,", "the", "expression", "of", "CMG2-Fc", "under", "the", "control", "of", "the", "constitutive", "CaMV", "35S", "promoter,", "and", "the", "co-expression", "of", "CMG2-Fc", "with", "nine", "different", "viral", "suppressors", "of", "post-transcriptional", "gene", "silencing", "(PTGS):", "p1,", "p10,", "p19,", "p21,", "p24,", "p25,", "p38,", "2b,", "and", "HCPro.", "Overall,", "transient", "CMG2-Fc", "expression", "was", "higher", "on", "intact", "plants", "than", "detached", "leaves.", "Maximum", "expression", "was", "observed", "with", "p1", "co-expression", "at", "3.5", "days", "post-infiltration", "(DPI),", "with", "a", "level", "of", "0.56", "g", "CMG2-Fc", "per", "kg", "of", "leaf", "fresh", "weight", "and", "1.5%", "of", "the", "total", "soluble", "protein,", "a", "ten-fold", "increase", "in", "expression", "when", "compared", "to" ]

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[ "A", "Mouse", "Model", "for", "Chikungunya:", "Young", "Age", "and", "Inefficient", "Type-I", "Interferon", "Signaling", "Are", "Risk", "Factors", "for", "Severe", "Disease", "The´", "r", "e`se", "Couderc1,2[,", "Fabrice", "Chre´", "tien3,4,5,6[,", "Cl", "e´mentine", "Schilte7,8[,", "Olivier", "Disson1,2,9,", "Madly", "Brigitte4,5,6,", "Florence", "Guivel-Benhassine1,2,", "Yasmina", "Touret10,", "Georges", "Barau10,", "Nade`", "ge", "Cayet11,", "Isabelle", "Schuffenecker12,", "Philippe", "Despr", "e`s13,", "Fernando", "Arenzana-Seisdedos14,15,", "Alain", "Michault16,", "Matthew", "L.", "Albert7,8[,", "Marc", "Lecuit1,2,9,17[*", "1", "Groupe", "‘‘Microorganismes", "et", "Barrie`res", "de", "l’Hoˆte’’,", "Institut", "Pasteur,", "Paris,", "France,", "2", "E´quipe", "Avenir", "INSERM", "U604", "Paris,", "France,", "3", "Unite´", "‘‘Cellules", "Souches", "et", "De´veloppement’’,", "CNRS", "URA", "2578,", "Institut", "Pasteur,", "Paris,", "France,", "4", "INSERM,", "U841,", "Team", "10,", "Cre´teil,", "France,", "5", "AP-HP,", "Groupe", "Hospitalier", "Albert", "Chenevier-Henri", "Mondor,", "De´partement", "de", "Pathologie,", "Cre´teil,", "France,", "6", "Universite´", "Paris", "XII,", "Faculte´", "de", "Me´decine,", "Cre´teil,", "France,", "7", "Groupe", "‘‘Immunobiologie", "des", "Cellules", "Dendritiques’’,", "Institut", "Pasteur,", "Paris,", "France,", "8", "INSERM", "U818,", "Paris,", "France,", "9", "Unite´", "‘‘Interactions", "Bacte´ries-Cellules’’,", "Institut", "Pasteur,", "Paris,", "France,", "10", "De´partement", "de", "Gyne´cologie", "et", "Obste´trique,", "Groupe", "Hospitalier", "Sud-Re´union,", "Saint-Pierre,", "La", "Re´union,", "France,", "11", "Plateforme", "de", "Microscopie", "Ultrastructurale,", "Institut", "Pasteur,", "Paris,", "France,", "12", "Centre", "National", "de", "Re´fe´rence", "des", "Arbovirus,", "Institut", "Pasteur", "Lyon,", "France,", "13", "Unite´", "‘‘Interactions", "Mole´culaires", "Flavivirus-Hoˆtes’’,", "Institut", "Pasteur,", "Paris,", "France,", "14", "Laboratoire", "‘‘Pathoge´nie", "Virale", "Mole´culaire’’,", "Institut", "Pasteur,", "Paris,", "France,", "15", "CNRS", "URA", "3015,", "Paris,", "France,", "16", "Laboratoire", "de", "Microbiologie,", "Groupe", "Hospitalier", "Sud-Re´union,", "Saint-Pierre,", "Ile", "de", "la", "Re´union,", "France,", "17", "Centre", "d’Infectiologie", "Necker-Pasteur,", "Hoˆ", "pital", "Necker-Enfants", "malades,", "Assistance", "Publique-Hoˆpitaux", "de", "Paris,", "Universite´", "Paris", "Descartes,", "Paris,", "France", "Chikungunya", "virus", "(CHIKV)", "is", "a", "re-emerging", "arbovirus", "responsible", "for", "a", "massive", "outbreak", "currently", "afflicting", "the", "Indian", "Ocean", "region", "and", "India.", "Infection", "from", "CHIKV", "typically", "induces", "a", "mild", "disease", "in", "humans,", "characterized", "by", "fever,", "myalgia,", "arthralgia,", "and", "rash.", "Cases", "of", "severe", "CHIKV", "infection", "involving", "the", "central", "nervous", "system", "(CNS)", "have", "recently", "been", "described", "in", "neonates", "as", "well", "as", "in", "adults", "with", "underlying", "conditions.", "The", "pathophysiology", "of", "CHIKV", "infection", "and", "the", "basis", "for", "disease", "severity", "are", "unknown.", "To", "address", "these", "critical", "issues,", "we", "have", "developed", "an", "animal", "model", "of", "CHIKV", "infection.", "We", "show", "here", "that", "whereas", "wild", "type", "(WT)", "adult", "mice", "are", "resistant", "to", "CHIKV", "infection,", "WT", "mouse", "neonates", "are", "susceptible", "and", "neonatal", "disease", "severity", "is", "age-dependent.", "Adult", "mice", "with", "a", "partially", "(IFN-a/bRþ/", ")", "or", "totally", "(IFN-a/bR", "/", ")", "abrogated", "type-I", "IFN", "pathway", "develop", "a", "mild", "or", "severe", "infection,", "respectively.", "In", "mice", "with", "a", "mild", "infection,", "after", "a", "burst", "of", "viral", "replication", "in", "the", "liver,", "CHIKV", "primarily", "targets", "muscle,", "joint,", "and", "skin", "fibroblasts,", "a", "cell", "and", "tissue", "tropism", "similar", "to", "that", "observed", "in", "biopsy", "samples", "of", "CHIKV-infected", "humans.", "In", "case", "of", "severe", "infections,", "CHIKV", "also", "disseminates", "to", "other", "tissues", "including", "the", "CNS,", "where", "it", "specifically", "targets", "the", "choroid", "plexuses", "and", "the", "leptomeninges.", "Together,", "these", "data", "indicate", "that", "CHIKV-associated", "symptoms", "match", "viral", "tissue", "and", "cell", "tropisms,", "and", "demonstrate", "that", "the", "fibroblast", "is", "a", "predominant", "target", "cell", "of", "CHIKV.", "These", "data", "also", "identify", "the", "neonatal", "phase", "and", "inefficient", "type-I", "IFN", "signaling", "as", "risk", "factors", "for", "severe", "CHIKV-associated", "disease.", "The", "development", "of", "a", "permissive", "small", "animal", "model", "will", "expedite", "the", "testing", "of", "future", "vaccines", "and", "therapeutic", "candidates.", "Citation:", "Couderc", "T,", "Chre´tien", "F,", "Schilte", "C,", "Disson", "O,", "Brigitte", "M,", "et", "al.", "(2008)", "A", "mouse", "model", "for", "Chikungunya:", "young", "age", "and", "inefficient", "type-I", "interferon", "signaling", "are", "risk", "factors", "for", "severe", "disease.", "PLoS", "Pathog", "4(2):", "e29.", "doi:10.1371/journal.ppat.0040029", "Introduction", "Chikungunya", "virus", "(CHIKV)", "was", "ﬁrst", "isolated", "in", "Tanzania", "in", "1953", "[1],", "and", "has", "recently", "emerged", "in", "islands", "of", "the", "Indian", "Ocean", "in", "2005,", "and", "engendered", "the", "largest", "Chikungunya", "fever", "epidemic", "on", "record", "[2].", "The", "most", "affected", "region", "was", "the", "island", "of", "La", "Re´", "union,", "where", "CHIKV", "infected", "approx-", "imately", "a", "third", "of", "the", "island’s", "inhabitants", "(i.e.,", ";300,000)", "[3–", "5].", "The", "outbreak,", "which", "now", "also", "involves", "India", "with", "an", "estimated", "1.3", "million", "cases", "[6–8],", "has", "a", "signiﬁcant", "potential", "to", "spread", "globally", "given", "the", "wide", "distribution", "of", "its", "arthropod", "vector", "[9,10].", "CHIKV", "is", "a", "member", "of", "the", "genus", "Alphavirus", "in", "the", "family", "of", "Togaviridae.", "Alphaviruses", "are", "small,", "enveloped", "viruses", "with", "a", "message-sense", "RNA", "genome", "that", "encodes", "four", "non-structural", "proteins", "(nsP1–4)", "and", "three", "structural", "proteins", "(C,", "E1–2).", "This", "arbovirus", "is", "maintained", "in", "nature", "by", "uninterrupted", "cycles", "of", "transmission", "between", "mosquitoes", "and", "vertebrate", "hosts", "such", "as", "macaques", "[11–13].", "Several", "alphaviruses", "cause", "disease", "in", "humans,", "primarily", "as", "a", "result", "of", "epizootic", "infections.", "These", "include", "the", "American", "encephalitic", "alphavi-", "ruses", "and", "several", "species", "in", "the", "Semliki", "Forest", "Virus", "group,", "principally", "the", "Afro-Asian", "CHIKV,", "the", "African", "O’Nyong-", "Nyong", "virus,", "as", "well", "as", "the", "Australasian", "Barmah", "Forest", "virus", "and", "Ross", "River", "virus", "[14].", "CHIKV", "infection", "is", "characterized", "by", "fever,", "arthralgia,", "myalgia,", "rash", "and", "headache.", "During", "the", "La", "R", "e´union", "Island", "outbreak,", "previously", "unreported", "severe", "forms", "of", "Chikungunya", "infection", "were", "observed", "in", "adults,", "compli-", "Editor:", "Michael", "J.", "Buchmeier,", "The", "Scripps", "Research", "Institute,", "United", "States", "of", "America", "Received", "August", "24,", "2007;", "Accepted", "December", "28,", "2007;", "Published", "February", "15,", "2008", "Copyright:", "2008", "Couderc", "et", "al.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Abbreviations:", "BBB,", "blood-brain", "barrier;", "CNS,", "central", "nervous", "system;", "CSF,", "cerebrospinal", "fluid;", "D,", "day;", "DAB,", "diaminobenzidine;", "HRP,", "horseradish-peroxidase;", "ID,", "intra-dermal;", "IFN-a/bR,", "IFN-a/b", "receptor;", "LD50,", "lethal", "dose", "50;", "MOI,", "multiplicity", "of", "infection;", "pi,", "post", "infection;", "TCID50,", "tissue", "cytopathic", "infectious", "dose", "50", "*", "To", "whom", "correspondence", "should", "be", "addressed.", "E-mail:", "mlecuit@pasteur.fr", "[", "These", "authors", "contributed", "equally", "to", "this", "work.", "PLoS", "Pathogens", "|", "www.plospathogens.org", "0001", "February", "2008", "|", "Volume", "4", "|", "Issue", "2", "|", "e29" ]

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2,835,711

null

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[ "Ratnapalan", "et", "al.", "BMC", "Medical", "Ethics", "2010,", "11:1", "http://www.biomedcentral.com/1472-6939/11/1", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Documentation", "of", "best", "interest", "by", "intensivists:", "a", "retrospective", "study", "in", "an", "Ontario", "critical", "care", "unit", "Mohana", "Ratnapalan1,", "Andrew", "B", "Cooper2,3*,", "Damon", "C", "Scales3,4,", "Ruxandra", "Pinto4", "Abstract", "Background:", "Intensive", "care", "physicians", "often", "must", "rely", "on", "substitute", "decision", "makers", "to", "address", "all", "dimensions", "of", "the", "construct", "of", "“best", "interest”", "for", "incapable,", "critically", "ill", "patients.", "This", "task", "involves", "identifying", "prior", "wishes", "and", "to", "facilitate", "the", "substitute", "decision", "maker’s", "understanding", "of", "the", "incapable", "patient’s", "condition", "and", "their", "likely", "response", "to", "treatment.", "We", "sought", "to", "determine", "how", "well", "such", "discussions", "are", "documented", "in", "a", "typical", "intensive", "care", "unit.", "Methods:", "Using", "a", "quality", "of", "communication", "instrument", "developed", "from", "a", "literature", "search", "and", "expert", "opinion,", "2", "investigators", "transcribed", "and", "analyzed", "260", "handwritten", "communications", "for", "105", "critically", "ill", "patients", "who", "died", "in", "the", "intensive", "care", "unit", "between", "January", "and", "June", "2006.", "Cohen’s", "kappa", "was", "calculated", "before", "analysis", "and", "then", "disagreements", "were", "resolved", "by", "consensus.", "We", "report", "results", "on", "a", "per-patient", "basis", "to", "represent", "documented", "communication", "as", "a", "process", "leading", "up", "to", "the", "time", "of", "death", "in", "the", "ICU.", "We", "report", "frequencies", "and", "percentages", "for", "discrete", "data,", "median", "(m)", "and", "interquartile", "range", "(IQR)", "for", "continuous", "data.", "Results:", "Our", "cohort", "was", "elderly", "(m", "72,", "IQR", "58-81", "years)", "and", "had", "high", "APACHE", "II", "scores", "predictive", "of", "a", "high", "probability", "of", "death", "(m", "28,", "IQR", "23-36).", "Length", "of", "stay", "in", "the", "intensive", "care", "unit", "prior", "to", "death", "was", "short", "(m", "2,", "IQR", "1-5", "days),", "and", "withdrawal", "of", "life", "support", "preceded", "death", "for", "more", "than", "half", "(n", "57,", "54%).", "Brain", "death", "criteria", "were", "present", "for", "18", "patients", "(17%).", "Although", "intensivists’", "communications", "were", "timely", "(median", "17", "h", "from", "admission", "to", "critical", "care),", "the", "person", "consenting", "on", "behalf", "of", "the", "incapable", "patient", "was", "explicitly", "documented", "for", "only", "10%", "of", "patients.", "Life", "support", "strategies", "at", "the", "time", "of", "communication", "were", "noted", "in", "45%", "of", "charts,", "and", "options", "for", "their", "future", "use", "were", "presented", "in", "88%.", "Considerations", "relevant", "to", "determining", "the", "patient’s", "best", "interest", "in", "relation", "to", "the", "treatment", "plan", "were", "not", "well", "documented.", "While", "explicit", "survival", "estimates", "were", "noted", "in", "50%", "of", "charts,", "physicians", "infrequently", "documented", "their", "own", "predictions", "of", "the", "patient’s", "functional", "status", "(20%),", "anticipated", "need", "for", "chronic", "care", "(0%),", "or", "post", "ICU", "quality", "of", "life", "(3%).", "Similarly,", "documentation", "of", "the", "patient’s", "own", "perspectives", "on", "these", "ranged", "from", "2-18%.", "Conclusions:", "Intensivists’", "documentation", "of", "their", "communication", "with", "substitute", "decision", "makers", "frequently", "outlined", "the", "proposed", "plan", "of", "treatment,", "but", "often", "lacked", "evidence", "of", "discussion", "relevant", "to", "whether", "the", "treatment", "plan", "was", "expected", "to", "improve", "the", "patient’s", "condition.", "Legislative", "standards", "for", "determination", "of", "best", "interest,", "such", "as", "the", "Health", "Care", "Consent", "Act", "in", "Ontario,", "Canada,", "may", "provide", "guidance", "for", "intensivists", "to", "optimally", "document", "the", "rationales", "for", "proposed", "treatment", "plans.", "Background", "The", "appropriate", "use", "of", "scarce", "critical", "care", "resources", "is", "an", "important", "target", "for", "quality", "improvement", "in", "our", "health", "care", "system.", "For", "example,", "the", "final", "report", "of", "the", "Ontario", "Critical", "Care", "Strategy", "states", "“considerable", "*", "Correspondence:", "andrew.cooper@williamoslerhs.ca", "2Department", "of", "Critical", "Care", "Medicine,", "William", "Osler", "Health", "System,", "Brampton", "Civic", "Hospital,", "2100", "Bovaird", "Drive", "East,", "Brampton,", "Ontario", "L6R", "3J7,", "Canada", "anecdotal", "evidence", "exists", "that", "Critical", "Care", "in", "Ontario", "is", "often", "provided", "to", "patients", "who", "do", "not,", "or", "can", "no", "longer", "benefit", "from", "this", "level", "of", "care”[1].", "In", "a", "grounded", "theory", "investigation,", "senior", "intensive", "care", "staff", "at", "16", "Ontario", "intensive", "care", "units", "defined", "medically", "futile", "care", "as", "“the", "use", "of", "considerable", "resources", "without", "a", "reasonable", "hope", "that", "the", "patient", "might", "recover", "to", "a", "state", "of", "relative", "inde-", "pendence,", "or", "to", "be", "interactive", "with", "the", "environment”[2].", "Providers", "identified", "family", "demands", "and", "a", "lack", "of", "timely", "©", "2010", "Ratnapalan", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

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[ "Molecular", "Networks", "in", "FGF", "Signaling:", "Flotillin-1", "and", "Cbl-", "Associated", "Protein", "Compete", "for", "the", "Binding", "to", "Fibroblast", "Growth", "Factor", "Receptor", "Substrate", "2", "Ana", "Tomasovic1,2,", "Stephanie", "Traub2¤,", "Ritva", "Tikkanen1,2*", "1", "Institute", "of", "Biochemistry,", "University", "of", "Giessen,", "Giessen,", "Germany,", "2", "Institute", "of", "Biochemistry", "II,", "University", "Clinic", "of", "Frankfurt,", "Frankfurt", "am", "Main,", "Germany", "Abstract", "Fibroblast", "growth", "factor", "receptor", "substrate", "2", "(FRS2a)", "is", "a", "signaling", "adaptor", "protein", "that", "regulates", "downstream", "signaling", "of", "many", "receptor", "tyrosine", "kinases.", "During", "signal", "transduction,", "FRS2", "can", "be", "both", "tyrosine", "and", "threonine", "phosphorylated", "and", "forms", "signaling", "complexes", "with", "other", "adaptor", "proteins", "and", "tyrosine", "phosphatases.", "We", "have", "here", "identified", "flotillin-1", "and", "the", "cbl-associated", "protein/ponsin", "(CAP)", "as", "novel", "interaction", "partners", "of", "FRS2.", "Flotillin-1", "binds", "to", "the", "phosphotyrosine", "binding", "domain", "(PTB)", "of", "FRS2", "and", "competes", "for", "the", "binding", "with", "the", "fibroblast", "growth", "factor", "receptor.", "Flotillin-1", "knockdown", "results", "in", "increased", "Tyr", "phosphorylation", "of", "FRS2,", "in", "line", "with", "the", "inhibition", "of", "ERK", "activity", "in", "the", "absence", "of", "flotillin-1.", "CAP", "directly", "interacts", "with", "FRS2", "by", "means", "of", "its", "sorbin", "homology", "(SoHo)", "domain,", "which", "has", "previously", "been", "shown", "to", "interact", "with", "flotillin-1.", "In", "addition,", "the", "third", "SH3", "domain", "in", "CAP", "binds", "to", "FRS2.", "Due", "to", "the", "overlapping", "binding", "domains,", "CAP", "and", "flotillin-1", "appear", "to", "compete", "for", "the", "binding", "to", "FRS2.", "Thus,", "our", "results", "reveal", "a", "novel", "signaling", "network", "containing", "FRS2,", "CAP", "and", "flotillin-1,", "whose", "successive", "interactions", "are", "most", "likely", "required", "to", "regulate", "receptor", "tyrosine", "kinase", "signaling,", "especially", "the", "mitogen", "activated", "protein", "kinase", "pathway.", "Citation:", "Tomasovic", "A,", "Traub", "S,", "Tikkanen", "R", "(2012)", "Molecular", "Networks", "in", "FGF", "Signaling:", "Flotillin-1", "and", "Cbl-Associated", "Protein", "Compete", "for", "the", "Binding", "to", "Fibroblast", "Growth", "Factor", "Receptor", "Substrate", "2.", "PLoS", "ONE", "7(1):", "e29739.", "doi:10.1371/journal.pone.0029739", "Editor:", "Henning", "Ulrich,", "University", "of", "Sa˜o", "Paulo,", "Brazil", "Received", "July", "12,", "2011;", "Accepted", "December", "4,", "2011;", "Published", "January", "3,", "2012", "Copyright:", "2012", "Tomasovic", "et", "al.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Funding:", "Funds", "were", "received", "from", "Deutsche", "Forschungsgemeinschaft", "DFG", "(www.dfg.de),", "personal", "grant", "to", "RT", "(Ti", "291/6-1).", "The", "funders", "had", "no", "role", "in", "study", "design,", "data", "collection", "and", "analysis,", "decision", "to", "publish,", "or", "preparation", "of", "the", "manuscript.", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "*", "E-mail:", "Ritva.Tikkanen@biochemie.med.uni-giessen.de", "¤", "Current", "address:", "Dermatology,", "University", "Clinic", "of", "Cologne,", "Cologne,", "Germany", "Introduction", "Fibroblast", "growth", "factor", "receptor", "substrate", "2", "(FRS2/FRS2a/", "SNT1)", "is", "a", "membrane", "linked", "docking", "protein", "originally", "identified", "as", "a", "protein", "that", "becomes", "tyrosine", "phosphorylated", "upon", "nerve", "growth", "factor", "(NGF)", "or", "fibroblast", "growth", "factor", "(FGF)", "stimulation", "in", "PC12", "cells", "[1,2,3].", "Together", "with", "FGF", "receptor", "substrate", "3", "(FRS3/FRS2b/SNT2),", "it", "belongs", "to", "the", "FRS", "adaptor", "protein", "family", "[4].", "In", "this", "paper,", "we", "will", "use", "the", "name", "FRS2", "for", "FRS2a/", "SNT1,", "and", "FRS3", "for", "FRS2b/SNT2", "for", "the", "sake", "of", "clarity.", "FRS2", "and", "FRS3", "share", "a", "similar", "structure", "and", "48%", "of", "amino", "acid", "sequence", "identity.", "In", "the", "N-terminus,", "they", "contain", "a", "consensus", "myristoylation", "sequence", "which", "is", "important", "for", "the", "membrane", "localization", "[1].", "This", "sequence", "is", "followed", "by", "a", "phosphotyrosine", "binding", "(PTB)", "domain", "that", "is", "highly", "similar", "between", "the", "two", "proteins.", "The", "PTB", "domain", "binds", "specific", "peptides", "of", "certain", "receptor", "tyrosine", "kinases", "(RTKs)", "with", "or", "without", "tyrosine", "phosphorylated", "residues", "[5,6].", "FRS2", "is", "ubiquitously", "expressed", "with", "the", "highest", "expression", "in", "brain,", "kidney,", "lung,", "ovary", "and", "testis", "and", "can", "be", "detected", "at", "all", "developmental", "stages", "of", "a", "mouse", "[7].", "FRS2", "knockout", "mice", "show", "embryonic", "lethality", "due", "to", "severe", "problems", "in", "gastrulation", "[8,9],", "demonstrating", "how", "crucial", "FGF", "signaling", "is", "in", "animal", "development.", "In", "contrast", "to", "FRS2,", "the", "expression", "of", "FRS3", "protein", "begins", "around", "day", "9", "and", "is", "restricted", "to", "tissues", "of", "neuronal", "origin", "[7,10].", "When", "exogenously", "expressed", "in", "FRS2-null", "mouse", "embryonic", "fibroblasts,", "FRS3", "compensates", "for", "the", "loss", "of", "FRS2", "by", "stimulating", "FGF", "induced", "activation", "of", "extracellularly", "regulated", "kinase", "(ERK),", "a", "member", "of", "the", "mitogen", "activated", "protein", "(MAP)", "kinase", "family", "[10].", "Both", "FRS2", "and", "FRS3", "are", "tyrosine", "phosphorylated", "in", "response", "to", "NGF,", "FGF", "[9,11]", "and", "glial", "derived", "neurotrophic", "factor", "(GDNF)", "[12,13],", "but", "only", "FRS2", "is", "threonine", "phosphorylated.", "Phosphor-", "ylation", "of", "8", "threonine", "residues", "in", "FRS2", "occurs", "as", "a", "response", "to", "stimulation", "with", "FGF,", "epidermal", "growth", "factor", "(EGF),", "insulin", "and", "platelet", "derived", "growth", "factor", "(PDGF).", "This", "represents", "a", "negative", "feedback", "mechanism", "in", "which", "activated", "ERK", "inhibits", "further", "tyrosine", "phosphorylation", "of", "FRS2", "by", "phosphorylating", "its", "threo-", "nine", "residues", "[14,15].", "FRS2", "plays", "an", "important", "role", "in", "FGF", "dependent", "proliferation", "and", "migration", "of", "the", "cells", "[1]", "and", "in", "differentiation", "of", "PC12", "cells", "by", "regulating", "sustained", "ERK", "activity", "upon", "FGF", "or", "NGF", "stimuli", "[1,16,17].", "It", "is", "tyrosine", "phosphorylated", "upon", "insulin", "treatment,", "but", "its", "precise", "role", "in", "insulin", "signaling", "pathway", "remains", "largely", "unknown", "[18].", "The", "C-terminus", "of", "FRS", "proteins", "bears", "multiple", "tyrosine", "phosphorylation", "sites", "(6", "Tyr", "in", "FRS2),", "which,", "when", "phosphory-", "lated", "by", "specific", "RTKs,", "recruit", "SH2-domain", "containing", "proteins", "such", "as", "adaptor", "protein", "Grb2", "(4", "Tyr", "in", "FRS2)", "and", "protein", "tyrosine", "phosphatase", "Shp2", "(2", "Tyr", "in", "FRS2)", "[1,19].", "The", "recruitment", "of", "Grb2", "eventually", "results", "in", "a", "strong", "activation", "of", "PI3-kinase", "signaling", "and", "moderate", "activation", "of", "ERK", "pathway", "[9,20],", "while", "phosphorylation", "and", "subsequent", "activation", "of", "Shp2", "will", "result", "in", "a", "strong", "activation", "of", "ERK", "signaling", "[9].", "PLoS", "ONE", "|", "www.plosone.org", "1", "January", "2012", "|", "Volume", "7", "|", "Issue", "1", "|", "e29739" ]

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[ "Hermsdorff", "et", "al.", "Nutrition", "&", "Metabolism", "2010,", "7:42", "http://www.nutritionandmetabolism.com/content/7/1/42", "R", "E", "S", "E", "A", "R", "C", "H", "Open", "Access", "RFerseuaricth", "and", "vegetable", "consumption", "and", "proinflammatory", "gene", "expression", "from", "peripheral", "blood", "mononuclear", "cells", "in", "young", "adults:", "a", "translational", "study", "Helen", "Hermana", "M", "Hermsdorff,", "María", "Ángeles", "Zulet,", "Blanca", "Puchau", "and", "José", "Alfredo", "Martínez*", "Abstract", "Background:", "Fruits", "and", "vegetables", "are", "important", "sources", "of", "fiber", "and", "nutrients", "with", "a", "recognized", "antioxidant", "capacity,", "which", "could", "have", "beneficial", "effects", "on", "the", "proinflammatory", "status", "as", "well", "as", "some", "metabolic", "syndrome", "and", "cardiovascular", "disease", "features.", "The", "current", "study", "assessed", "the", "potential", "relationships", "of", "fruit", "and", "vegetable", "consumption", "with", "the", "plasma", "concentrations", "and", "mRNA", "expression", "values", "of", "some", "proinflammatory", "markers", "in", "young", "adults.", "Methods:", "One-hundred", "and", "twenty", "healthy", "subjects", "(50", "men/70", "women;", "20.8", "±", "2.6", "y;", "22.3", "±", "2.8", "kg/m2)", "were", "enrolled.", "Experimental", "determinations", "included", "anthropometry,", "blood", "pressure", "and", "lifestyle", "features", "as", "well", "as", "blood", "biochemical", "and", "inflammatory", "measurements.", "The", "mRNA", "was", "isolated", "from", "peripheral", "blood", "mononuclear", "cells", "(PBMC)", "and", "the", "gene", "expression", "concerning", "selected", "inflammatory", "markers", "was", "assessed", "by", "quantitative", "real-time", "PCR.", "Nutritional", "intakes", "were", "estimated", "by", "a", "validated", "semi-quantitative", "food-frequency", "questionnaire.", "Results:", "The", "highest", "tertile", "of", "energy-adjusted", "fruit", "and", "vegetable", "consumption", "(>660", "g/d)", "was", "associated", "with", "lower", "plasma", "concentrations", "of", "C-reactive", "protein", "(CRP)", "and", "homocysteine", "and", "with", "lower", "ICAM1,", "IL1R1,", "IL6,", "TNFα", "and", "NFκB1", "gene", "expression", "in", "PBMC", "(P", "for", "trend", "<", "0.05),", "independently", "of", "gender,", "age,", "energy", "intake,", "physical", "activity,", "smoking,", "body", "mass", "index,", "systolic", "blood", "pressure", "and", "circulating", "non-esterified", "fatty", "acids.", "In", "addition,", "plasma", "CRP,", "homocysteine", "and", "TNFα", "concentrations", "and", "ICAM1,", "TNFα", "and", "NFκB1", "gene", "expression", "in", "PBMC", "showed", "a", "descending", "trend", "as", "increased", "fiber", "intake", "(>19.5", "g/d)", "from", "fruits", "and", "vegetables", "(P", "for", "trend", "<", "0.05).", "Furthermore,", "the", "participants", "within", "the", "higher", "tertile", "(>11.8", "mmol/d)", "of", "dietary", "total", "antioxidant", "capacity", "showed", "lower", "plasma", "CRP", "and", "mRNA", "values", "of", "ICAM1,", "IL1R1,", "IL6,", "TNFα", "and", "NFκB1", "genes", "(P", "for", "trend", "<", "0.05).", "The", "inverse", "association", "between", "fruit", "and", "vegetable", "consumption", "and", "study", "proinflammatory", "markers", "followed", "the", "same", "trend", "and", "remained", "statistically", "significant,", "after", "the", "inclusion", "of", "other", "foods/nutrients", "in", "the", "linear", "regression", "models.", "Conclusion:", "A", "higher", "fruit", "and", "vegetable", "consumption", "was", "independently", "associated", "not", "only", "with", "reduced", "CRP", "and", "homocysteine", "concentrations", "but", "also", "with", "a", "lower", "mRNA", "expression", "in", "PBMC", "of", "some", "relevant", "proinflammatory", "markers", "in", "healthy", "young", "adults.", "Background", "A", "low-chronic", "inflammatory", "status", "is", "a", "recognized", "link", "between", "excessive", "adiposity", "and", "metabolic", "syndrome", "fea-", "tures,", "diabetes,", "and", "atherosclerosis", "[1,2].", "In", "fact,", "a", "num-", "ber", "of", "studies", "has", "demonstrated", "an", "increased", "expression", "*", "Correspondence:", "jalfmtz@unav.es", "1", "Department", "of", "Nutrition,", "Food", "Science,", "Physiology", "and", "Toxicology,", "University", "of", "Navarra,", "Pamplona,", "Spain", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "of", "transcription", "nuclear", "factors", "such", "as", "nuclear-factor-", "kappa-B", "(NFκB)", "as", "well", "as", "of", "interleukins", "(IL)", "and", "tumor", "necrosis", "factor-alpha", "(TNFα)", "in", "obese", "subjects", "[1,3].", "These", "changes", "appear", "to", "involve", "a", "higher", "production", "of", "proinflammatory", "and", "pro-atherogenic", "molecules", "such", "as", "C-reactive", "protein", "(CRP),", "homocysteine,", "selectins", "and", "adhesion", "molecules", "as", "well", "as", "some", "cytokines", "[1,3].", "Fur-", "thermore,", "circulating", "peripheral", "blood", "mononuclear", "cells", "©", "2010", "Hermsdorff", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Com-", "BioMed", "Central", "mons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduc-", "tion", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

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2,981,878

null

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[ "IMMUNOME", "RESEARCH", "Open", "Access", "EL-Manzalawy", "and", "Honavar", "Immunome", "Research", "2010,", "6(Suppl", "2):S2", "http://www.immunome-research.com/content/6/S2/S2", "R", "E", "V", "I", "E", "W", "Abstract", "Recent", "advances", "in", "B-cell", "epitope", "prediction", "methods", "Yasser", "EL-Manzalawy1,2*,", "Vasant", "Honavar2*", "Identification", "of", "epitopes", "that", "invoke", "strong", "responses", "from", "B-cells", "is", "one", "of", "the", "key", "steps", "in", "designing", "effective", "vaccines", "against", "pathogens.", "Because", "experimental", "determination", "of", "epitopes", "is", "expensive", "in", "terms", "of", "cost,", "time,", "and", "effort", "involved,", "there", "is", "an", "urgent", "need", "for", "computational", "methods", "for", "reliable", "identification", "of", "B-cell", "epitopes.", "Although", "several", "computational", "tools", "for", "predicting", "B-cell", "epitopes", "have", "become", "available", "in", "recent", "years,", "the", "pre-", "dictive", "performance", "of", "existing", "tools", "remains", "far", "from", "ideal.", "We", "review", "recent", "advances", "in", "computational", "methods", "for", "B-cell", "epitope", "prediction,", "identify", "some", "gaps", "in", "the", "current", "state", "of", "the", "art,", "and", "outline", "some", "promising", "direc-", "tions", "for", "improving", "the", "reliability", "of", "such", "methods.", "Review", "Antigen-antibody", "interactions", "play", "a", "pivotal", "role", "in", "the", "humoral", "immune", "response.", "Antibodies", "bind", "to", "antigens", "at", "specific", "sites", "which", "correspond", "to", "the", "antigenic", "deter-", "minants", "or", "B-cell", "epitopes.", "Identification", "and", "characteri-", "zation", "of", "B-cell", "epitopes", "in", "target", "antigens", "is", "one", "of", "the", "key", "steps", "in", "epitope-driven", "vaccine", "design,", "immunodiag-", "nostic", "tests,", "and", "antibody", "production.", "B-cell", "epitopes", "typically", "belong", "to", "one", "of", "two", "classes:", "linear", "(continuous", "or", "sequential)", "epitopes", "or", "conformational", "(discontinu-", "ous)", "epitopes.", "Linear", "epitopes", "are", "short", "peptides", "that", "correspond", "to", "a", "contiguous", "amino", "acid", "sequence", "frag-", "ment", "of", "a", "protein", "[1,2].", "Linear", "epitopes", "are", "usually", "iden-", "tified", "using", "assays", "such", "as", "PEPSCAN.", "Consequently,", "current", "experimental", "methods", "offer", "little", "direct", "evidence", "indicating", "that", "each", "residue", "in", "the", "epitope", "does", "in", "fact", "make", "contact", "with", "one", "or", "more", "residues", "in", "the", "paratope", "(the", "part", "in", "the", "antibody", "that", "binds", "to", "the", "antigen)", "[3].", "Conformational", "epitopes", "are", "composed", "of", "amino", "acids", "that", "although", "not", "contiguous", "in", "primary", "sequence,", "are", "brought", "into", "close", "proximity", "within", "the", "folded", "3-dimen-", "sional", "protein", "structure.", "Most", "B-cell", "epitopes,", "although", "they", "are", "composed", "of", "short", "linear", "peptides,", "appear", "to", "be", "conformational", "epitopes.", "*", "Correspondence:", "yasser@iastate.edu;", "honavar@iastate.edu", "1Department", "of", "Systems", "and", "Computer", "Engineering,", "Al-Azhar", "University,", "Egypt", "2Department", "of", "Computer", "Science,", "Artificial", "Intelligence", "Research", "Laboratory,", "Center", "for", "Computational", "Intelligence,", "Learning,", "and", "Discovery,", "Iowa", "State", "University,", "USA", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "Several", "experimental", "techniques", "are", "currently", "available", "for", "experimental", "mapping", "of", "B-cell", "epitopes", "[4].", "How-", "ever,", "the", "high", "cost", "and", "effort", "involved", "makes", "them", "impractical", "for", "application", "on", "a", "genomic", "scale.", "Compu-", "tational", "techniques", "offer", "a", "fast,", "scalable,", "and", "cost-effec-", "tive", "approach", "for", "predicting", "B-cell", "epitopes,", "for", "focusing", "experimental", "investigations", "and", "for", "improving", "our", "understanding", "of", "antigen-antibody", "interactions.", "Hence,", "there", "is", "a", "growing", "interest", "in", "the", "development", "of", "sophis-", "ticated", "computational", "tools", "for", "reliable", "prediction", "of", "B-cell", "epitopes.", "Several", "computational", "methods", "for", "B-cell", "epitope", "pre-", "diction", "have", "been", "developed", "in", "recent", "years", "(e.g.,", "[5-14]).", "However,", "the", "predictive", "performance", "of", "current", "methods", "is", "far", "from", "ideal", "[15].", "To", "complicate", "matters,", "immunogenicity", "of", "proteins", "is", "poorly", "understood", "[16]", "and", "whether", "B-cell", "epitopes", "could", "be", "deciphered", "as", "an", "intrinsic", "features", "of", "the", "protein", "remains", "an", "open", "ques-", "tion", "[17].", "Recent", "studies", "have", "pointed", "out", "some", "of", "the", "limitations", "of", "current", "epitope", "prediction", "methods", "[6,17,18].", "Hence,", "increasing", "the", "reliability", "of", "computa-", "tional", "methods", "for", "B-cell", "epitope", "prediction", "remains", "a", "major", "challenge", "in", "computational", "vaccinology", "[19].", "In", "2007,", "the", "National", "Institute", "of", "Allergy", "and", "Infectious", "Diseases", "(NIAID)", "sponsored", "a", "workshop", "and", "a", "meeting", "of", "a", "panel", "of", "immunologists", "and", "bioinformaticians", "in", "order", "to", "assess", "the", "current", "state", "of", "the", "art", "in", "epitope", "prediction", "and", "to", "identify", "some", "areas", "for", "further", "research", "[15].", "One", "of", "the", "key", "goals", "of", "the", "workshop", "was", "to", "facilitate", "and", "expedite", "the", "development", "of", "improved", "©", "2010", "EL-Manzalawy", "and", "Honavar;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

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[ "Toranza", "and", "Arim", "BMC", "Ecology", "2010,", "10:18", "http://www.biomedcentral.com/1472-6785/10/18", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Carolina", "Toranza1*,", "Matías", "Arim2,3", "Abstract", "Cross-taxon", "congruence", "and", "environmental", "conditions", "Open", "Access", "Background:", "Diversity", "patterns", "of", "different", "taxa", "typically", "covary", "in", "space,", "a", "phenomenon", "called", "cross-taxon", "congruence.", "This", "pattern", "has", "been", "explained", "by", "the", "effect", "of", "one", "taxon", "diversity", "on", "taxon", "diversity,", "shared", "biogeographic", "histories", "of", "different", "taxa,", "and/or", "common", "responses", "to", "environmental", "conditions.", "A", "meta-analysis", "of", "the", "association", "between", "environment", "and", "diversity", "patterns", "found", "that", "in", "83", "out", "of", "85", "studies,", "more", "than", "60%", "of", "the", "spatial", "variability", "in", "species", "richness", "was", "related", "to", "variables", "representing", "energy,", "water", "or", "their", "interaction.", "The", "role", "of", "the", "environment", "determining", "taxa", "diversity", "patterns", "leads", "us", "to", "hypothesize", "that", "this", "would", "explain", "the", "observed", "cross-taxon", "congruence.", "However,", "recent", "analyses", "reported", "the", "persistence", "of", "cross-taxon", "congruence", "when", "environmental", "effect", "was", "statistically", "removed.", "Here", "we", "evaluate", "this", "hypothesis,", "analyzing", "the", "cross-taxon", "congruence", "between", "birds", "and", "mammals", "in", "the", "Brazilian", "Cerrado,", "and", "assess", "the", "environmental", "role", "on", "the", "spatial", "covariation", "in", "diversity", "patterns.", "Results:", "We", "found", "a", "positive", "association", "between", "avian", "and", "mammal", "richness", "and", "a", "positive", "latitudinal", "trend", "for", "both", "groups", "in", "the", "Brazilian", "Cerrado.", "Regression", "analyses", "indicated", "an", "effect", "of", "latitude,", "PET,", "and", "mean", "temperature", "over", "both", "biological", "groups.", "In", "addition,", "we", "show", "that", "NDVI", "was", "only", "associated", "with", "avian", "diversity;", "while", "the", "annual", "relative", "humidity,", "was", "only", "correlated", "with", "mammal", "diversity.", "We", "determined", "the", "environmental", "effects", "on", "diversity", "in", "a", "path", "analysis", "that", "accounted", "for", "73%", "and", "76%", "of", "the", "spatial", "variation", "in", "avian", "and", "mammal", "richness.", "However,", "an", "association", "between", "avian", "and", "mammal", "diversity", "remains", "significant.", "Indeed,", "the", "importance", "of", "this", "link", "between", "bird", "and", "mammal", "diversity", "was", "also", "supported", "by", "a", "significant", "association", "between", "birds", "and", "mammal", "spatial", "autoregressive", "model", "residuals.", "Conclusion:", "Our", "study", "corroborates", "the", "main", "role", "of", "environmental", "conditions", "on", "diversity", "patterns,", "but", "suggests", "that", "other", "important", "mechanisms,", "which", "have", "not", "been", "properly", "evaluated,", "are", "involved", "in", "the", "observed", "cross-", "taxon", "congruence.", "The", "approaches", "introduced", "here", "indicate", "that", "the", "prevalence", "of", "a", "significant", "association", "among", "taxa,", "after", "considering", "the", "environmental", "determinant,", "could", "indicate", "both", "the", "need", "to", "incorporate", "additional", "processes", "(e.g.", "biogeographic", "and", "evolutionary", "history", "or", "trophic", "interactions)", "and/or", "the", "existence", "of", "a", "shared", "trend", "in", "detection", "biases", "among", "taxa", "and", "regions.", "Background", "Spatial", "concordance", "in", "diversity", "of", "different", "taxa", "is", "a", "recurrent", "feature", "in", "nature", "[1-3].", "The", "strength", "of", "this", "association,", "known", "as", "cross-taxon", "congruence,", "depends", "on", "the", "studied", "taxonomic", "groups", "and", "the", "scale", "of", "analy-", "sis", "[4].", "This", "is", "because", "the", "spatial", "association", "in", "diversity", "patterns", "of", "related", "taxa", "is", "typically", "larger", "than", "that", "observed", "between", "weakly", "related", "taxa", "[5]", "and", "is", "more", "*", "Correspondence:", "ctoranza@gmail.com", "1Instituto", "de", "Ecología", "y", "Ciencias", "Ambientales,", "Facultad", "de", "Ciencias,", "Universidad", "de", "la", "República,", "Uruguay,", "Iguá", "4225", "Piso", "8", "Sur,", "Montevideo,", "Uruguay", "common", "over", "large", "geographic", "scales", "[6].", "This", "scale", "dependence", "in", "the", "strength", "of", "spatial", "taxonomic", "covaria-", "tion", "would", "be", "associated", "with", "changes", "in", "the", "factors", "determining", "species", "richness", 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[ "Gresback", "et", "al.", "Nanoscale", "Research", "Letters", "2011,", "6:68", "http://www.nanoscalereslett.com/content/6/1/68", "N", "A", "N", "O", "E", "X", "P", "R", "E", "S", "S", "Open", "Access", "Combined", "plasma", "gas-phase", "synthesis", "and", "colloidal", "processing", "of", "InP/ZnS", "core/shell", "nanocrystals", "Ryan", "Gresback1,", "Ryan", "Hue2,", "Wayne", "L", "Gladfelter2,", "Uwe", "R", "Kortshagen1*", "Abstract", "Indium", "phosphide", "nanocrystals", "(InP", "NCs)", "with", "diameters", "ranging", "from", "2", "to", "5", "nm", "were", "synthesized", "with", "a", "scalable,", "flow-through,", "nonthermal", "plasma", "process", "at", "a", "rate", "ranging", "from", "10", "to", "40", "mg/h.", "The", "NC", "size", "is", "controlled", "through", "the", "plasma", "operating", "parameters,", "with", "the", "residence", "time", "of", "the", "gas", "in", "the", "plasma", "region", "strongly", "influencing", "the", "NC", "size.", "The", "NC", "size", "distribution", "is", "narrow", "with", "the", "standard", "deviation", "being", "less", "than", "20%", "of", "the", "mean", "NC", "size.", "Zinc", "sulfide", "(ZnS)", "shells", "were", "grown", "around", "the", "plasma-synthesized", "InP", "NCs", "in", "a", "liquid", "phase", "reaction.", "Photoluminescence", "with", "quantum", "yields", "as", "high", "as", "15%", "were", "observed", "for", "the", "InP/ZnS", "core-shell", "NCs.", "Introduction", "Over", "the", "last", "two", "decades,", "semiconductor", "nanocrystals", "(NCs)", "have", "attracted", "significant", "attention", "because", "of", "their", "various", "unique", "properties.", "Semiconductor", "NCs", "provide", "size-tunable", "optical", "and", "electrical", "properties,", "based", "on", "quantum", "confinement", "of", "charge", "carriers", "within", "them,", "high", "surface-to-volume", "ratios,", "and", "other", "attributes", "that", "have", "led", "to", "the", "development", "of", "a", "new", "generation", "of", "materials", "and", "devices", "[1,2].", "A", "significant", "amount", "of", "study", "has", "focused", "on", "compound", "semiconduc-", "tor", "NCs", "of", "the", "II-VI", "and", "IV-VI", "systems", "because", "of", "the", "relative", "ease", "of", "synthesizing", "high", "quality", "materials", "using", "colloidal", "techniques", "[3,4].", "While", "synthesis", "and", "surface", "functionalization", "methods", "for", "these", "NC", "materials", "are", "well", "established", "and", "NCs", "have", "shown", "impressive", "optical", "and", "electronic", "properties,", "there", "exists", "considerable", "inter-", "est", "to", "produce", "systems", "consisting", "of", "NCs", "of", "other", "mate-", "rials", "whose", "constituent", "elements", "pose", "less", "of", "an", "environmental", "concern,", "which", "are", "more", "radiation", "resis-", "tant,", "and", "less", "prone", "to", "photo-oxidation.", "Compound", "semiconductor", "NCs", "of", "the", "III-V", "systems", "may", "offer", "some", "of", "these", "desirable", "attributes.", "While", "III-V", "semiconductors", "are", "known", "to", "be", "“radiation-hard,”", "they", "also", "are", "direct", "bandgap", "semiconductors,", "which", "is", "a", "big", "advantage", "for", "optical", "applications", "compared", "to,", "for", "*", "Correspondence:", "kortshagen@umn.edu", "1Department", "of", "Mechanical", "Engineering,", "University", "of", "Minnesota,", "Minneapolis,", "MN,", "USA", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "instance,", "group", "IV", "NC", "materials", "[5].", "Hence,", "there", "has", "been", "considerable", "interest", "in", "the", "synthesis", "of", "high", "qual-", "ity", "III-V", "compound", "NCs,", "such", "as", "indium", "phosphide", "(InP).", "While", "synthesizing", "methods", "similar", "to", "those", "of", "II-", "VI", "semiconductor", "NCs", "can", "be", "applied", "to", "InP", "NCs,", "these", "have", "turned", "out", "to", "be", "very", "difficult", "and", "time", "consuming,", "often", "requiring", "days", "to", "produce", "NCs", "of", "high", "quality", "[6,7].", "More", "recently,", "synthesis", "of", "high", "quality", "InP", "NCs", "has", "been", "achieved", "with", "non-coordinating", "solvents", "[8]", "and", "weak-coordinating", "solvents", "[9].", "However,", "as", "these", "synthesizing", "methods", "require", "organic", "surfactants", "to", "sta-", "bilize", "NCs", "in", "solution", "during", "synthesis,", "they", "provide", "challenges", "for", "applications", "of", "the", "synthesized", "NCs", "in", "devices", "because", "of", "the", "often", "electrically", "insulating", "nature", "of", "the", "ligands.", "Synthesis", "of", "NCs", "using", "nonthermal", "plasmas", "has", "become", "a", "viable", "method", "even", "for", "materials,", "which", "need", "to", "be", "produced", "in", "crystalline", "form", "requiring", "high", "tem-", "peratures,", "such", "as", "Si", "[10,11]", "and", "Ge", "[12].", "An", "added", "advantage", "of", "plasma", "synthesis", "as", "compared", "to", "liquid", "phase", "routes", "is", "that", "the", "resulting", "material", "is", "free", "of", "ligands", "or", "surfactants,", "and", "that", "the", "ligands", "can", "be", "added", "later", "depending", "on", "the", "targeted", "application.", "This", "makes", "integration", "of", "plasma-produced", "NCs", "into", "devices", "easier,", "as", "it", "eliminates", "intermediate", "steps", "of", "ligand", "exchanges", "often", "required", "for", "II-VI", "and", "IV-VI", "NCs.", "In", "this", "article,", "we", "propose", "a", "method", "to", "synthesize", "InP", "NCs", "with", "a", "nonthermal", "plasma.", "In", "addition,", "we", "show", "that", "solution", "chemistry", "routes", "can", "be", "used", "for", "post-synthesis", "©", "2011", "Gresback", "et", "al;", "licensee", "Springer.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

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3,257,463

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[ "CASE", "REPORT", "http://dx.doi.org/10.4070/kcj.2011.41.12.763", "Print", "ISSN", "1738-5520", "/", "On-line", "ISSN", "1738-5555", "Copyright", "©", "2011", "The", "Korean", "Society", "of", "Cardiology", "Open", "Access", "ABSTRACT", "Stent", "Fracture", "at", "the", "Proximal", "Shaft", "of", "the", "Left", "Main", "Stem", "Jae", "Ho", "Lee,", "MD1,", "Suk", "Min", "Seo,", "MD1,2,", "Eun", "Oh", "Kim,", "MD1,", "Hyo", "Jun", "Ahn,", "MD1,", "Yang", "Won", "Lee,", "MD1,", "Yul-Hee", "Cho,", "MD1,", "Inwoon", "Baek,", "MD1,", "You", "Suk", "Oh,", "MD1,", "Jihyun", "Yu,", "MD1,", "and", "Ki-Bae", "Seung,", "MD1,2", "1Department", "of", "Internal", "Medicine", "and", "2Cardiovascular", "Center", "and", "Cardiology", "Division,", "Seoul", "St.", "Mary’s", "Hospital,", "College", "of", "Medicine,", "The", "Catholic", "University", "of", "Korea,", "Seoul,", "Korea", "Stent", "fracture", "is", "likely", "to", "be", "caused", "due", "to", "mechanical", "stress", "at", "the", "hinge", "point", "or", "kinking", "movement", "at", "the", "point", "of", "aneurysm", "formation", "with", "stent", "malapposition.", "To", "our", "knowledge,", "this", "is", "the", "first", "published", "report", "of", "stent", "fracture", "at", "the", "proximal", "shaft", "of", "the", "left", "main", "stem", "in", "a", "patient", "with", "acute", "myocardial", "infarction.", "(Korean", "Circ", "J", "2011;41:763-765)", "KEY", "WORDS:", "Stent", "fracture;", "Left", "main", "stem;", "Acute", "myocardial", "infarction.", "Introduction", "The", "suggested", "predisposing", "factors", "associated", "with", "frac-", "tures", "of", "coronary", "stent", "are", "sites", "of", "increased", "vessel", "movement,", "lengthy", "coronary", "stents,", "right", "coronary", "artery", "stents,", "overlapp-", "ing", "stents,", "sirolimus-eluting", "stents", "(SES),", "and", "saphenous", "vein", "graft", "stents.1)2)", "In", "addition,", "stent", "fracture", "is", "likely", "to", "be", "caused", "due", "to", "bending", "movement", "such", "as", "torsion,", "flexion,", "and", "rotation", "at", "the", "hinge", "point", "or", "kinking", "movement", "at", "the", "point", "of", "aneu-", "rysm", "formation", "with", "stent", "malapposition.3)", "We", "report", "the", "first", "case", "of", "stent", "fracture", "at", "the", "proximal", "shaft", "of", "the", "left", "main", "stem", "(LMS).", "Case", "A", "55-year-old", "man", "visited", "our", "hospital", "for", "follow-up", "coron-", "ary", "angiography.", "He", "had", "no", "particular", "symptoms", "prior", "to", "ad-", "mission,", "but", "he", "wanted", "to", "undergo", "coronary", "angiography.", "Sm-", "oking", "was", "the", "only", "cardiovascular", "risk", "factor.", "Received:", "February", "10,", "2011", "Revision", "Received:", "March", "8,", "2011", "Accepted:", "March", "22,", "2011", "Correspondence:", "Ki-Bae", "Seung,", "MD,", "Department", "of", "Internal", "Medicine", "and", "Cardiovascular", "Center", "and", "Cardiology", "Division,", "Seoul", "St.", "Mary’s", "Hos-", "pital,", "College", "of", "Medicine,", "The", "Catholic", "University", "of", "Korea,", "222", "Banpo-", "daero,", "Seocho-gu,", "Seoul", "137-701,", "Korea", "Tel:", "82-2-2258-1134,", "Fax:", "82-2-591-1506", "E-mail:", "kbseung@catholic.ac.kr", "•", "The", "authors", "have", "no", "financial", "conflicts", "of", "interest.", "cc", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Cre-", "ative", "Commons", "Attribution", "Non-Commercial", "License", "(http://creativecom-", "mons.org/licenses/by-nc/3.0)", "which", "permits", "unrestricted", "non-commer-", "cial", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "origi-", "nal", "work", "is", "properly", "cited.", "763", "Twenty-one", "months", "ago,", "primary", "percutaneous", "coronary", "intervention", "was", "performed", "because", "of", "symptoms", "of", "progres-", "sive", "angina", "and", "ST-segment", "elevation", "on", "the", "electrocardio-", "gram.", "He", "was", "diagnosed", "with", "acute", "myocardial", "infarction", "(AMI)", "with", "the", "culprit", "lesion", "being", "a", "long", "stenotic", "lesion", "in-", "volving", "the", "segment", "from", "the", "ostium", "of", "the", "LMS", "to", "the", "mid", "left", "anterior", "descending", "coronary", "artery", "(LAD)", "(Fig.", "1A).", "We", "implanted", "SES", "(Cypher®,", "Cordis,", "3.5×23", "mm)", "from", "the", "ostium", "of", "the", "LMS", "to", "the", "proximal", "LAD", "and", "then", "overlapped", "paclitaxel-eluting", "stent", "(Taxus®,", "Boston,", "3.0×32", "mm)", "at", "the", "proximal", "to", "mid-LAD.", "Additional", "ballooning", "was", "also", "per-", "formed,", "using", "high-pressure", "balloon", "(Quantum®,", "Schneider,", "4.0×12", "mm)", "up", "to", "10", "atm", "for", "15", "seconds", "(Fig.", "1B).", "Intravas-", "cular", "ultrasound", "(IVUS;", "42", "mHz,", "Clear", "View,", "MA,", "Boston,", "USA)", "confirmed", "well-positioned", "stents.", "Follow-up", "coronary", "angiography", "showed", "stent", "fracture", "at", "the", "proximal", "shaft", "of", "the", "LMS", "with", "minimal", "luminal", "narrow-", "ing", "(Fig.", "2A", "and", "B).", "IVUS", "revealed", "the", "absence", "of", "the", "stent", "strut", "corresponding", "to", "stent", "fracture", "and", "ectatic", "change", "with", "malapposition", "of", "stent", "around", "the", "site", "of", "stent", "fracture", "(Fig.", "2C,", "D", "and", "E).", "Based", "on", "these", "findings,", "the", "lesion", "was", "redi-", "lated", "up", "to", "16", "atm", "for", "15", "seconds", "with", "high-pressure", "balloon", "(Quantum®,", "Schneider,", "4.0×12", "mm).", "Finally,", "IVUS", "confirm-", "ed", "well-apposite", "struts.", "Discussion", "The", "suggested", "predisposing", "factors", "associated", "with", "stent", "fracture", "are", "sites", "of", "increased", "vessel", "movement,", "lengthy", "cor-", "onary", "stents,", "right", "coronary", "artery", "stents,", "overlapping", "stents,", "SES,", "and", "saphenous", "vein", "graft", "stents.1)2)", "Fractures", "occur", "as", "a" ]

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[ "Lu", "et", "al.", "Journal", "of", "Neuroinflammation", "2010,", "7:46", "http://www.jneuroinflammation.com/content/7/1/46", "R", "E", "S", "E", "A", "R", "C", "H", "JOURNAL", "OF", "NEUROINFLAMMATION", "Open", "Access", "Resveratrol", "differentially", "modulates", "inflammatory", "responses", "of", "microglia", "and", "astrocytes", "Xiaofeng", "Lu1†,", "Lili", "Ma1†,", "Lingfei", "Ruan1,2,", "Yan", "Kong1,2,", "Haiwei", "Mou1,2,", "Zhijie", "Zhang1,", "Zhijun", "Wang4,", "Ji", "Ming", "Wang3,", "Yingying", "Le1,2*", "Abstract", "Background:", "Inflammatory", "responses", "in", "the", "CNS", "mediated", "by", "activated", "glial", "cells", "play", "an", "important", "role", "in", "host-", "defense", "but", "are", "also", "involved", "in", "the", "development", "of", "neurodegenerative", "diseases.", "Resveratrol", "is", "a", "natural", "polyphenolic", "compound", "that", "has", "cardioprotective,", "anticancer", "and", "anti-inflammatory", "properties.", "We", "investigated", "the", "capacity", "of", "resveratrol", "to", "protect", "microglia", "and", "astrocyte", "from", "inflammatory", "insults", "and", "explored", "mechanisms", "underlying", "different", "inhibitory", "effects", "of", "resveratrol", "on", "microglia", "and", "astrocytes.", "Methods:", "A", "murine", "microglia", "cell", "line", "(N9),", "primary", "microglia,", "or", "astrocytes", "were", "stimulated", "by", "LPS", "with", "or", "without", "different", "concentrations", "of", "resveratrol.", "The", "expression", "and", "release", "of", "proinflammatory", "cytokines", "(TNF-a,", "IL-", "1b,", "IL-6,", "MCP-1)", "and", "iNOS/NO", "by", "the", "cells", "were", "measured", "by", "PCR/real-time", "PCR", "and", "ELISA,", "respectively.", "The", "phosphorylation", "of", "the", "MAP", "kinase", "superfamily", "was", "analyzed", "by", "western", "blotting,", "and", "activation", "of", "NF-", "B", "and", "AP-", "1", "was", "measured", "by", "luciferase", "reporter", "assay", "and/or", "electrophoretic", "mobility", "shift", "assay.", "Results:", "We", "found", "that", "LPS", "stimulated", "the", "expression", "of", "TNF-a,", "IL-1b,", "IL-6,", "MCP-1", "and", "iNOS", "in", "murine", "microglia", "and", "astrocytes", "in", "which", "MAP", "kinases,", "NF-", "B", "and", "AP-1", "were", "differentially", "involved.", "Resveratrol", "inhibited", "LPS-", "induced", "expression", "and", "release", "of", "TNF-a,", "IL-6,", "MCP-1,", "and", "iNOS/NO", "in", "both", "cell", "types", "with", "more", "potency", "in", "microglia,", "and", "inhibited", "LPS-induced", "expression", "of", "IL-1b", "in", "microglia", "but", "not", "astrocytes.", "Resveratrol", "had", "no", "effect", "on", "LPS-stimulated", "phosphorylation", "of", "ERK1/2", "and", "p38", "in", "microglia", "and", "astrocytes,", "but", "slightly", "inhibited", "LPS-", "stimulated", "phosphorylation", "of", "JNK", "in", "astrocytes.", "Resveratrol", "inhibited", "LPS-induced", "NF-", "B", "activation", "in", "both", "cell", "types,", "but", "inhibited", "AP-1", "activation", "only", "in", "microglia.", "Conclusion:", "These", "results", "suggest", "that", "murine", "microglia", "and", "astrocytes", "produce", "proinflammatory", "cytokines", "and", "NO", "in", "response", "to", "LPS", "in", "a", "similar", "pattern", "with", "some", "differences", "in", "signaling", "molecules", "involved,", "and", "further", "suggest", "that", "resveratrol", "exerts", "anti-inflammatory", "effects", "in", "microglia", "and", "astrocytes", "by", "inhibiting", "different", "proinflammatory", "cytokines", "and", "key", "signaling", "molecules.", "Background", "Microglia,", "the", "resident", "macrophage-like", "cells", "in", "the", "brain,", "play", "an", "important", "role", "in", "host", "defense", "and", "tissue", "repair", "in", "CNS", "[1,2].", "Activated", "microglia", "produce", "a", "vari-", "ety", "of", "pro-inflammatory", "mediators,", "including", "tumor", "necrosis", "factor", "a", "(TNF-a),", "interleukin-1b", "(IL-1b),", "IL-6,", "monocyte", "chemotactic", "protein", "1", "(MCP-1,", "CCL2),", "nitric", "oxide", "(NO),", "and", "reactive", "oxygen", "species", "(ROS).", "*", "Correspondence:", "yyle@sibs.ac.cn", "†", "Contributed", "equally", "1Key", "laboratory", "of", "Nutrition", "and", "Metabolism,", "Institute", "for", "Nutritional", "Sciences,", "Shanghai", "Institutes", "for", "Biological", "Sciences;", "Chinese", "Academy", "of", "Sciences,", "Shanghai", "200031,", "China", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "Activated", "microglia", "serve", "immune", "surveillance", "functions", "by", "removing", "foreign", "microorganisms,", "but", "may", "also", "result", "in", "excessive", "inflammatory", "responses", "in", "the", "CNS", "[1,2].", "Astrocytes", "are", "the", "main", "glial", "cell", "type", "in", "the", "brain", "involved", "in", "maintaining", "CNS", "homeostasis.", "They", "also", "respond", "promptly", "to", "injury", "and", "regulate", "neuroinflam-", "matory", "events", "[2-4].", "Both", "in", "vitro", "and", "in", "vivo", "studies", "have", "documented", "the", "ability", "of", "astrocytes", "to", "produce", "a", "variety", "of", "cytokines,", "including", "IL-1,", "IL-6,", "IL-10,", "inter-", "feron-a", "(INF-a),", "IFN-b,", "TNF-a,", "TNF-b;", "and", "chemo-", "kines,", "including", "RANTES", "(CCL5),", "IL-8", "(CXCL8)", "and", "MCP-1", "[3].", "Over-activation", "of", "glial", "cells", "and", "release", "of", "proinflammatory", "cytokines", "may", "lead", "to", "neuronal", "death", "[5-7],", "causing", "neuropathological", "changes", "in", "CNS", "©", "2010", "Lu", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

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3,259,139

null

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[ "|", "Case", "Report", "|", "Korean", "J", "Pain", "2012", "January;", "Vol.", "25,", "No.", "1:", "52-54", "pISSN", "2005-9159", "eISSN", "2093-0569", "http://dx.doi.org/10.3344/kjp.2012.25.1.52", "Treatment", "Experience", "of", "Pulsed", "Radiofrequency", "Under", "Ultrasound", "Guided", "to", "the", "Trapezius", "Muscle", "at", "Myofascial", "Pain", "Syndrome", "-A", "Case", "Report-", "Department", "of", "Anesthesiology", "and", "Pain", "Medicine,", "Yonsei", "University", "College", "of", "Medicine,", "Seoul,", "Korea", "Chung", "Hoon", "Park,", "MD,", "Yoon", "Woo", "Lee,", "MD,", "Yong", "Chan", "Kim,", "MD,", "Joo", "Hwa", "Moon,", "MD,", "and", "Jong", "Bum", "Choi,", "MD", "Trigger", "point", "injection", "treatment", "is", "an", "effective", "and", "widely", "applied", "treatment", "for", "myofascial", "pain", "syndrome.", "The", "trapezius", "muscle", "frequently", "causes", "myofascial", "pain", "in", "neck", "area.", "We", "herein", "report", "a", "case", "in", "which", "direct", "pulsed", "radiofrequency", "(RF)", "treatment", "was", "applied", "to", "the", "trapezius", "muscle.", "We", "observed", "that", "the", "RF", "treatment", "produced", "continuous", "pain", "relief", "when", "the", "effective", "duration", "of", "trigger", "point", "injection", "was", "temporary", "in", "myofascial", "pain.", "(Korean", "J", "Pain", "2012;", "25:", "52-54)", "Key", "Words:", "myofascial", "pain,", "pulsed", "RF", "(radiofrequency),", "trigger", "point", "injection.", "Myofascial", "pain", "syndrome", "is", "a", "common", "disease.", "The", "rary", "treatment", "method.", "Therefore,", "we", "report", "on", "a", "my-", "main", "treatment", "includes", "injection", "therapy", "at", "the", "trigger", "ofascial", "pain", "syndrome", "case", "where", "direct", "pulsed", "radio-", "point", "and", "medication", "in", "which", "an", "analgesic", "anti-inflam-", "frequency", "treatment", "was", "applied", "to", "the", "trapezius", "muscle", "matory", "agent", "and", "muscle", "relaxant", "are", "administrated", "on", "which", "TPI", "had", "been", "sufficiently", "effective", "but", "of", "short", "together.", "Trigger", "point", "injection", "(TPI)", "is", "widely", "applied", "duration.", "Moreover,", "the", "analgesic", "effect", "of", "the", "pulsed", "RF", "since", "it", "is", "effective", "in", "most", "cases", "and", "easily", "performed", "on", "treatment", "was", "maintained", "for", "a", "considerable", "duration.", "outpatients.", "However,", "the", "duration", "of", "pain", "relief", "may,", "in", "some", "cases,", "be", "short.", "Hence,", "many", "patients", "return", "to", "the", "clinic", "as", "outpatients", "when", "the", "analgesic", "effect", "diminishes.", "TPI", "may", "be", "used", "many", "times,", "but", "repetitive", "TPI", "may", "be", "CASE", "REPORT", "A", "47-year", "old", "female", "patient", "visited", "our", "clinic", "with", "the", "rejected", "because", "of", "its", "cost", "and", "the", "fact", "that", "it", "relies", "on", "main", "complaint", "of", "neck", "pain", "that", "had", "become", "severe", "over", "a", "needle", "injection.", "Some", "patients", "consider", "TPI", "as", "a", "tempo-", "the", "past", "year.", "The", "medical", "history", "showed", "that", "the", "patient", "Received", "September", "30,", "2011.", "Revised", "November", "15,", "2011.", "Accepted", "November", "15,", "2011.", "Correspondence", "to:", "Jong", "Bum", "Choi,", "MD", "Department", "of", "Anesthesioligy", "and", "Pain", "Medicine,", "Gangnam", "Severance", "Hospital,", "712,", "Eonju-ro,", "Gangnam-gu,", "Seoul", "135-720,", "Korea", "Tel:", "＋82-2-2019-3520,", "Fax:", "＋82-2-3463-0940,", "E-mail:", "romeojb@yuhs.ac", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "Non-Commercial", "License", "(http://", "creativecommons.org/licenses/by-nc/3.0/),", "which", "permits", "unrestricted", "non-commercial", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Copyright", "ⓒ", "The", "Korean", "Pain", "Society,", "2012" ]

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3,051,743

null

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[ "organic", "compounds", "Acta", "Crystallographica", "Section", "E", "Structure", "Reports", "Online", "ISSN", "1600-5368", "4-(5-Amino-1H-1,2,4-triazol-3-yl)-", "pyridinium", "chloride", "monohydrate", "Victor", "M.", "Chernyshev,a", "Elena", "V.", "Tarasova,a", "Anna", "V.", "Chernyshevaa", "and", "Victor", "B.", "Rybakovb*", "aSouth-Russia", "State", "Technical", "University,", "346428", "Novocherkassk,", "Russian", "Federation,", "and", "bDepartment", "of", "Chemistry,", "Moscow", "State", "University,", "119992", "Moscow,", "Russian", "Federation", "Correspondence", "e-mail:", "rybakov20021@yandex.ru", "Received", "8", "January", "2011;", "accepted", "17", "January", "2011", "Key", "indicators:", "single-crystal", "X-ray", "study;", "T", "=", "295", "K;", "mean", "(C–C)", "=", "0.003", "A˚;", "R", "factor", "=", "0.042;", "wR", "factor", "=", "0.109;", "data-to-parameter", "ratio", "=", "15.8.", "In", "the", "cation", "of", "the", "title", "compound,", "C7H8N5+", "Cl", "H2O,", "the", "mean", "planes", "of", "the", "pyridine", "and", "1,2,4-triazole", "rings", "form", "a", "dihedral", "angle", "of", "2.3", "(1)", ".", "The", "N", "atom", "of", "the", "amino", "group", "adopts", "a", "trigonal–pyramidal", "conﬁguration.", "The", "N", "atom", "of", "the", "pyridine", "ring", "is", "protonated,", "forming", "a", "chloride", "salt.", "In", "the", "crystal,", "intermolecular", "N—H", "O,", "N—H", "N,", "N—H", "Cl", "and", "O—H", "Cl", "hydrogen", "bonds", "link", "the", "cations,", "anions", "and", "water", "molecules", "into", "layers", "parallel", "to", "the", "(1,", "0,", "12)", "plane.", "Related", "literature", "For", "the", "use", "of", "3-pyridyl-substituted", "5-amino-1,2,4-triazoles", "in", "the", "synthesis", "of", "biologically", "active", "compounds,", "see:", "Lipinski", "(1983);", "Ram", "(1988);", "Akahoshi", "et", "al.", "(1998);", "Young", "et", "al.", "(2001);", "Ouyang", "et", "al.", "(2005);", "Dolzhenko", "et", "al.", "(2007).", "For", "metal", "complexes", "of", "3-pyridyl-substituted", "5-amino-1,2,4-tri-", "azoles,", "see:", "Mishra", "et", "al.", "(1989);", "Ferrer", "et", "al.", "(2004);", "Castineiras", "&", "Garcia-Santos", "(2008).", "For", "a", "theoretical", "investigation", "of", "the", "protonation", "of", "C-amino-1,2,4-triazoles,", "see:", "Anders", "et", "al.", "(1997).", "For", "the", "crystal", "structures", "of", "protonated", "C-amino-1,2,4-", "triazoles,", "see:", "Lynch", "et", "al.", "(1999);", "Baouab", "et", "al.", "(2000);", "Bichay", "et", "al.", "(2006);", "Guerfel", "et", "al.", "(2007);", "Matulkova´", "et", "al.", "(2007).", "For", "the", "ionization", "constants", "(pK", ")", "of", "3-substituted", "5-amino-1H-", "1,2,4-triazoles,", "see:", "Voronkov", "et", "al.", "(1976).", "For", "the", "1H", "and", "13C", "NMR", "spectra", "of", "3-pyridyl-substituted", "5-amino-1,2,4-triazoles,", "see:", "Dolzhenko", "et", "al.", "(2009a).", "For", "typical", "NMR", "chemical", "shifts", "of", "3-substituted", "5-amino-1,2,4-triazoles", "and", "their", "salts,", "see:", "Chernyshev", "et", "al.", "(2010).", "For", "the", "crystal", "structures", "of", "3-", "substituted", "5-amino-1H-1,2,4-triazoles,", "see:", "Rusinov", "et", "al.", "(1991);", "Daro", "et", "al.", "(2000);", "Boechat", "et", "al.", "(2004);", "Dolzhenko", "et", "al.", "(2009b,c).", "For", "the", "crystal", "structures", "of", "3(5)-pyridyl-substi-", "tuted", "1,2,4-triazoles", "protonated", "at", "the", "pyridine", "ring,", "see:", "Ren", "&", "Jian", "(2008);", "Xie", "et", "al.", "(2009);", "Du", "et", "al.", "(2009).", "For", "values", "of", "bond", "lengths", "in", "organic", "compounds,", "see:", "Allen", "et", "al.", "(1987).", "For", "the", "correlation", "of", "bond", "lengths", "with", "bond", "orders", "between", "sp2-hybridized", "C", "and", "N", "atoms,", "see:", "Burke-Laing", "&", "Laing", "(1976).", "Experimental", "Crystal", "data", "C7H8N5+", "Cl", "H2O", "Mr", "=", "215.65", "Monoclinic,", 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[ "Upsala", "Journal", "of", "Medical", "Sciences.", "2012;", "117:", "99–112", "REVIEW", "ARTICLE", "PDGF", "and", "PDGF", "receptors", "in", "glioma", "INGA", "NAZARENKO1,", "SANNA-MARIA", "HEDE1,3,", "XIAOBING", "HE", "1", ",", "ANNA", "HEDRÉN1,", "JAMES", "THOMPSON1,2,", "MIKAEL", "S.", "LINDSTRÖM1", "&", "MONICA", "NISTÉR1,2", "1Department", "of", "Oncology-Pathology,", "Karolinska", "Institutet,", "CCK", "R8:04,", "Karolinska", "University", "Hospital", "Solna,", "SE-17176", "Stockholm,", "Sweden,", "2Karolinska", "Healthcare", "Research", "Biobank", "(KHRBB),", "Clinical", "Pathology/Cytology,", "Karolinska", "University", "Hospital,", "SE-17176", "Stockholm,", "Sweden,", "and", "3(currently)", "Uppsala", "University,", "Rudbeck", "Laboratory,", "Department", "of", "Immunology,", "Genetics", "and", "Pathology,", "SE-751", "85", "Uppsala,", "Sweden", "Abstract", "The", "family", "of", "platelet-derived", "growth", "factors", "(PDGFs)", "plays", "a", "number", "of", "critical", "roles", "in", "normal", "embryonic", "development,", "cellular", "differentiation,", "and", "response", "to", "tissue", "damage.", "Not", "surprisingly,", "as", "it", "is", "a", "multi-faceted", "regulatory", "system,", "numerous", "pathological", "conditions", "are", "associated", "with", "aberrant", "activity", "of", "the", "PDGFs", "and", "their", "receptors.", "As", "we", "and", "others", "have", "shown,", "human", "gliomas,", "especially", "glioblastoma,", "express", "all", "PDGF", "ligands", "and", "both", "the", "two", "cell", "surface", "receptors,", "PDGFR-a", "and", "-b.", "The", "cellular", "distribution", "of", "these", "proteins", "in", "tumors", "indicates", "that", "glial", "tumor", "cells", "are", "stimulated", "via", "PDGF/PDGFR-a", "autocrine", "and", "paracrine", "loops,", "while", "tumor", "vessels", "are", "stimulated", "via", "the", "PDGFR-b.", "Here", "we", "summarize", "the", "initial", "discoveries", "on", "the", "role", "of", "PDGF", "and", "PDGF", "receptors", "in", "gliomas", "and", "provide", "a", "brief", "overview", "of", "what", "is", "known", "in", "this", "ﬁeld.", "Key", "words:", "Animal", "tumor", "model,", "brain", "tumor,", "cancer", "stem", "cell,", "glioma,", "neural", "stem", "cell,", "platelet-derived", "growth", "factor", "(PDGF),", "PDGF", "receptor", "Introduction", "Gliomas", "are", "the", "most", "common", "form", "of", "primary", "malignancies", "of", "the", "central", "nervous", "system", "(CNS)", "mainly", "affecting", "adults.", "These", "tumors", "have", "a", "histo-", "logical", "resemblance", "to", "different", "types", "of", "glial", "cells", "and", "are", "categorized", "into", "astrocytomas,", "oligodendroglio-", "mas,", "oligoastrocytomas,", "and", "ependymomas,", "based", "on", "the", "predominant", "cell", "type(s)", "in", "the", "respective", "tumor", "(1).", "Initial", "discovery", "and", "extensive", "studies", "of", "the", "epi-", "dermal", "growth", "factor", "(EGF)", "and", "transforming", "growth", "factor", "alpha", "(TGF-a),", "as", "well", "as", "the", "platelet-", "derived", "growth", "factor", "(PDGF)", "family,", "revealed", "their", "presence", "in", "glioblastoma", "cell", "cultures", "and", "tissues.", "These", "growth", "factors,", "by", "signaling", "via", "their", "cell", "sur-", "face", "tyrosine", "kinase", "receptors,", "EGFR", "and", "PDGFR-a", "and", "-b,", "were", "able", "not", "only", "to", "induce", "normal", "mitogenic", "and", "migratory", "responses,", "but", "when", "aberrantly", "activated", "they", "were", "also", "able", "to", "transform", "cells.", "Knowledge", "gained", "from", "in", "vitro", "experiments", "was", "transferred", "to", "in", "vivo", "systems,", "and", "several", "mouse", "models", "were", "created", "showing", "that", "gliomas", "can", "be", "induced", "by", "forced", "expression", "of", "PDGF-B", "in", "the", "brain.", "However,", "treatment", "with", "single", "tyrosine", "kinase", "inhibitors", "(TKIs)", "given", "to", "glioma", "patients", "has", "gener-", "ally", "not", "been", "successful.", "Ever", "since", "the", "initial", "discoveries,", "investigations", "on", "the", "molecular", "mechanisms", "and", "signaling", "pathways", "involved", "in", "glioma", "have", "provided", "a", "more", "detailed", "insight", "into", "the", "key", "events", "behind", "brain", "tumor", "initi-", "ation,", "maintenance,", "and", "progression", "and", "have", "resulted", "in", "signiﬁcantly", "improved", "cancer", "drug", "discov-", "eries.", "However,", "the", "prognosis", "for", "patients", "with", "aggres-", "sive", "brain", "tumors", "is", "still", "very", "poor.", "One", "intriguing", "hypothesis", "is", "that", "glioblastoma", "resistance", "to", "therapy", "and", "its", "rapid", "recurrence", "is", "due", "to", "the", "presence", "of", "a", "subpopulation", "of", "tumor", "cells", "displaying", "stem", "cell", "Correspondence:", "Monica", "Nistér", "MD", "PhD,", "Department", "of", "Oncology-Pathology,", "Karolinska", "Institutet,", "CCK", "R8:04,", "Karolinska", "University", "Hospital", "Solna,", "SE-17176", "Stockholm,", "Sweden.", "E-mail:", "Monica.Nister@ki.se", "(Received", "24", "January", "2012;", "accepted", "6", "February", "2012)", "ISSN", "0300-9734", "print/ISSN", "2000-1967", "online", "2012", "Informa", "Healthcare", "DOI:", "10.3109/03009734.2012.665097" ]

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[ "R", "E", "V", "I", "E", "W", "Treatment", "of", "Lennox-Gastaut", "syndrome:", "overview", "and", "recent", "f", "indings", "Kenou", "van", "Rijckevorsel", "Reference", "Centre", "of", "Refractory", "Epilepsy,", "Cliniques", "Universitaires", "St", "Luc,", "Université", "Catholique", "de", "Louvain,", "Brussels,", "Belgium", "Correspondence:", "Kenou", "van", "Rijckevorsel", "Reference", "Centre", "for", "Refractory", "Epilepsy,", "Cliniques", "Universitaires", "St", "Luc,Avenue", "Hippocrate,", "10,", "B-1200", "Brussels,", "Belgium", "Tel", "+32", "2", "7643308", "Fax", "+32", "2", "7642142", "Email", "vanrijckevorsel@nops.ucl.ac.be", "Abstract:", "Lennox-Gastaut", "syndrome", "(LGS)", "is", "a", "rare,", "age-related", "syndrome,", "characterized", "by", "multiple", "seizure", "types,", "a", "speciﬁc", "electro-encephalographic", "pattern,", "and", "mental", "regression.", "However,", "published", "data", "on", "the", "etiology,", "evolution,", "and", "therapeutic", "approach", "of", "LGS", "are", "contradictory,", "partly", "because", "the", "precise", "deﬁnition", "of", "LGS", "used", "in", "the", "literature", "varies.", "In", "the", "most", "recent", "classiﬁcation,", "LGS", "belongs", "to", "the", "epileptic", "encephalopathies", "and", "is", "highly", "refractory", "to", "all", "antiepileptic", "drugs.", "Numerous", "treatments,", "medical", "and", "non-medical,", "have", "been", "proposed", "and", "results", "mostly", "from", "open", "studies", "or", "case", "series", "have", "been", "published.", "Sometimes,", "patients", "with", "LGS", "are", "included", "in", "a", "more", "global", "group", "of", "patients", "with", "refractory", "epilepsy.", "Only", "6", "randomized", "double-blind", "controlled", "trials", "of", "medical", "treatments,", "which", "included", "patients", "with", "LGS,", "have", "been", "published.", "Overall,", "treatment", "is", "rarely", "effective", "and", "the", "ﬁnal", "prognosis", "remains", "poor", "in", "spite", "of", "new", "therapeutic", "strategies.", "Co-morbidities", "need", "speciﬁc", "treatment.", "This", "paper", "summarizes", "the", "deﬁnition,", "diagnosis", "and", "therapeutic", "approach", "to", "LGS,", "including", "not", "only", "recognized", "antiepileptic", "drugs,", "but", "also", "“off", "label”", "medications,", "immune", "therapy,", "diet,", "surgery", "and", "some", "perspectives", "for", "the", "future.", "Keywords:", "Lennox-Gastaut", "syndrome,", "treatment,", "VNS,", "surgery,", "epileptic", "encephalopathies,", "LGS,", "refractory", "Introduction", "The", "term", "Lennox-Gastaut", "syndrome", "(LGS)", "appeared", "in", "the", "literature", "for", "the", "ﬁrst", "time", "in", "1969", "(Niedermeyer", "1969),", "but", "this", "syndrome", "was", "actually", "ﬁrst", "described", "by", "Lennox", "and", "Davis", "in", "1950", "and", "by", "Gastaut", "et", "al", "in", "1966.", "The", "International", "League", "Against", "Epilepsy", "(ILAE)", "Commission", "(Classiﬁcation", "Epilepsia", "1989)", "classiﬁed", "LGS", "among", "the", "cryptogenic", "or", "symptomatic", "generalized", "epilepsies,", "but,", "more", "recently,", "the", "ILAE", "Task", "Force", "classiﬁed", "it", "among", "the", "age-related", "epileptic", "encephalopathies", "(Engel", "2001).", "LGS", "comprises", "atypical", "absences", "with", "slow", "spike-and-wave", "(SW)", "complexes,", "tonic", "seizures", "that", "are", "mostly", "sleep-related,", "and", "cognitive", "deterioration", "(ILAE).", "However,", "LGS", "has", "also", "been", "deﬁned", "as", "diffuse", "SW", "pattern", "on", "electroencephalogram", "(EEG),", "mental", "retardation,", "and", "multiple", "types", "of", "seizures", "without", "reference", "to", "age", "or", "to", "nocturnal", "tonic", "seizures", "(French", "et", "al", "2004).", "This", "broader", "deﬁnition,", "mostly", "used", "in", "the", "US,", "may", "include", "for", "example,", "Dravet", "syndrome,", "Doose", "syndrome,", "or", "focal", "cryptogenic", "epilepsies,", "especially", "of", "frontal", "lobe", "origin.", "According", "to", "Genton", "et", "al", "(2000),", "EEG", "criteria", "should", "include", "not", "only", "bilateral", "slow", "SW", "but", "also", "10–20", "Hz", "epileptic", "fast", "rhythms,", "predominantly", "in", "sleep.", "Furthermore,", "this", "syndrome", "belongs", "to", "the", "age-related", "epileptic", "encephalopathies", "and", "starts", "during", "childhood.", "When", "using", "these", "full", "criteria,", "LGS", "appears", "to", "be", "rare.", "Largely", "as", "a", "result", "of", "the", "different", "deﬁnitions,", "the", "literature", "presents,", "or", "seems", "to", "present,", "contradictory", "data", "about", "the", "frequency", "of", "seizure", "types,", "epidemiology,", "treatment", "options,", "prognosis,", "and", "long", "term", "evolution", "of", "LGS.", "Furthermore,", "results", "of", "clinical", "studies", "are", "difﬁcult", "to", "compare", "in", "terms", "of", "efﬁcacy", "and", "most", "of", "them,", "especially", "randomized", "studies,", "do", "not", "cover", "more", "than", "a", "few", "weeks", "(Hancock", "and", "Cross", "2003).", "Neuropsychiatric", "Disease", "and", "Treatment", "2008:4(6)", "1001–1019", "©", "2008", "Dove", "Medical", "Press", "Limited.", "All", "rights", "reserved", "1001" ]

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2,195,607

null

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[ "Endothelial", "Cells", "Modify", "the", "Costimulatory", "Capacity", "of", "Transmigrating", "Leukocytes", "and", "Promote", "CD28-mediated", "CD41", "T", "Cell", "Alloactivation", "By", "Mark", "D.", "Denton,*‡", "Christopher", "S.", "Geehan,*", "Steve", "I.", "Alexander,*", "Mohamed", "H.", "Sayegh,‡", "and", "David", "M.", "Briscoe*", "From", "the", "*Division", "of", "Nephrology,", "Department", "of", "Medicine,", "Children’s", "Hospital,", "and", "the", "‡Laboratory", "of", "Immunogenetics", "and", "Transplantation,", "Renal", "Division,", "Department", "of", "Medicine,", "Brigham", "and", "Women’s", "Hospital,", "and", "Harvard", "Medical", "School,", "Boston,", "Massachusetts", "02115", "Summary", "Activated", "vascular", "endothelial", "cells", "(ECs)", "express", "major", "histocompatibility", "complex", "(MHC)", "class", "II", "molecules", "in", "vitro", "and", "in", "vivo", "in", "acute", "and", "chronic", "allograft", "rejection.", "However,", "hu-", "man", "ECs", "may", "be", "limited", "in", "their", "ability", "to", "effectively", "activate", "CD41", "T", "cells,", "because", "they", "do", "not", "express", "members", "of", "the", "B7", "family", "(CD80", "and", "CD86)", "of", "costimulatory", "molecules.", "In", "this", "study,", "we", "show", "that", "ECs", "promote", "the", "full", "activation", "of", "CD41", "T", "cells", "via", "trans-costimulatory", "interactions.", "By", "reverse", "transcriptase", "polymerase", "chain", "reaction,", "Western", "blot,", "and", "FACS®", "analysis,", "we", "could", "not", "detect", "the", "expression", "of", "CD80", "and", "CD86", "on", "activated", "ECs", "and", "found", "minimal", "expression", "on", "purified", "CD41", "T", "cells.", "In", "contrast,", "both", "CD80", "and", "CD86", "were", "ex-", "pressed", "in", "allogeneic", "CD41", "T", "cell–EC", "cocultures.", "Expression", "of", "CD86", "peaked", "at", "early", "times", "between", "12", "and", "24", "h", "after", "coculture,", "whereas", "CD80", "was", "not", "expressed", "until", "72", "h.", "Addition", "of", "anti-CD86", "but", "not", "anti-CD80", "monoclonal", "antibodies", "to", "cocultures", "inhibited", "IL-2", "production", "and", "the", "proliferation", "of", "CD41", "T", "cells", "to", "allogeneic", "donor", "human", "umbilical", "vein", "ECs", "(HU-", "VECs),", "as", "well", "as", "to", "skin", "and", "lung", "microvascular", "ECs.", "Furthermore,", "we", "found", "that", "interferon", "g–activated", "ECs", "but", "not", "untreated", "ECs", "induced", "mRNA", "and", "cell", "surface", "expression", "of", "CD80", "and", "CD86", "on", "CD41", "T", "cells,", "and", "these", "T", "cells", "were", "functional", "to", "provide", "a", "trans-costimulatory", "signal", "to", "autologous", "CD41", "T", "cells.", "Blockade", "of", "MHC", "class", "II", "and", "lymphocyte", "function–associ-", "ated", "antigen", "3", "but", "not", "other", "EC", "cell", "surface", "molecules", "on", "IFN-g–activated", "ECs", "inhibited", "the", "induction", "of", "CD86", "on", "CD41", "T", "cells.", "Transmigration", "of", "purified", "populations", "of", "monocytes", "across", "EC", "monolayers", "similarly", "resulted", "in", "the", "induction", "of", "functional", "CD86,", "but", "also", "induced", "the", "de", "novo", "expression", "of", "the", "cytokines", "interleukin", "(IL)-1a", "and", "IL-12.", "In", "addition,", "EC-modi-", "fied", "monocytes", "supported", "enhanced", "proliferation", "of", "allogeneic", "and", "autologous", "CD41", "T", "cells.", "Taken", "together,", "these", "data", "define", "the", "ability", "of", "the", "endothelium", "to", "modify", "CD41", "T", "cells", "and", "monocytes", "for", "trans-costimulatory", "events.", "This", "unique", "function", "of", "the", "endothelium", "in", "alloim-", "mune", "T", "cell", "activation", "has", "functional", "consequences", "for", "the", "direct", "and", "the", "indirect", "pathways", "of", "allorecognition.", "Key", "words:", "endothelium", "•", "T", "lymphocyte", "•", "monocyte", "•", "allorecognition", "•", "transplantation", "Rtocompatibility", "antigens)", "by", "CD41", "T", "cells", "is", "the", "ini-", "ecognition", "of", "alloantigen", "(donor", "major", "or", "minor", "his-", "tiating", "event", "that", "ultimately", "leads", "to", "graft", "rejection.", "Recip-", "ient", "CD41", "T", "cells", "may", "recognize", "either", "intact", "allo-MHC", "class", "II", "molecules", "on", "donor", "cells", "(known", "as", "direct", "allorec-", "ognition)", "or", "peptides", "derived", "from", "allo-MHC", "molecules,", "shed", "from", "the", "allograft", "and", "subsequently", "processed", "and", "pre-", "sented", "bound", "to", "MHC", "class", "II", "on", "recipient", "APCs", "(known", "as", "indirect", "allorecognition)", "(1).", "Irrespective", "of", "the", "pathway", "of", "allorecognition,", "full", "activation", "of", "naive", "or", "previously", "ac-", "tivated", "CD41", "T", "cells", "requires", "a", "second", "signal", "that", "may", "be", "provided", "by", "soluble", "factors", "such", "as", "cytokines,", "but", "more", "of-", "ten", "is", "provided", "by", "cell", "surface", "costimulatory", "molecules", "such", "as", "B7-1", "(CD80)", "and", "B7-2", "(CD86)", "(2,", "3).", "These", "molecules", "are", "expressed", "by", "professional", "APCs", "and", "bind", "the", "counter-", "receptors", "CD28", "and", "cytolytic", "T", "lymphocyte–associated", "an-", "tigen", "(CTLA)41", "expressed", "by", "CD41", "T", "cells.", "Ligation", "of", "1Abbreviations", "used", "in", "this", "paper:", "CHO,", "Chinese", "hamster", "ovary;", "CTLA4,", "cytolytic", "T", "lymphocyte–associated", "antigen", "4;", "EC,", "endothelial", "cell;", "HU-", "VEC,", "human", "umbilical", "vein", "EC;", "ICAM-1,", "intercellular", "adhesion", "mole-", "cule", "1;", "LFA-3,", "lymphocyte", "function–associated", "antigen", "3;", "U,", "abbitor", "units.", "555", "J.", "Exp.", "Med.", "The", "Rockefeller", "University", "Press", "•", "0022-1007/99/08/555/12", "$5.00", "Volume", "190,", "Number", "4,", "August", "16,", "1999", "555–566", "http://www.jem.org" ]

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2,634,755

null

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[ "Annals", "of", "Clinical", "Microbiology", "and", "Antimicrobials", "BioMed", "Central", "Research", "Open", "Access", "Minor", "contribution", "of", "mutations", "at", "iniA", "codon", "501", "and", "embC-embA", "intergenic", "region", "in", "ethambutol-resistant", "clinical", "Mycobacterium", "tuberculosis", "isolates", "in", "Kuwait", "Al-Anoud", "Jaber,", "Suhail", "Ahmad*", "and", "Eiman", "Mokaddas", "Address:", "Department", "of", "Microbiology,", "Faculty", "of", "Medicine,", "Kuwait", "University,", "Kuwait", "City,", "Kuwait", "Email:", "Al-Anoud", "Jaber", "-", "Gad1978@hotmail.com;", "Suhail", "Ahmad*", "-", "suhail_ah@hsc.edu.kw;", "Eiman", "Mokaddas", "-", "e.mokaddas@hsc.edu.kw", "*", "Corresponding", "author", "Published:", "15", "January", "2009", "Annals", "of", "Clinical", "Microbiology", "and", "Antimicrobials", "2009,", "8:2", "doi:10.1186/1476-0711-8-2", "This", "article", "is", "available", "from:", "http://www.ann-clinmicrob.com/content/8/1/2", "Received:", "2", "November", "2008", "Accepted:", "15", "January", "2009", "©", "2009", "Jaber", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "Ethambutol", "(EMB)", "is", "a", "first-line", "drug", "for", "the", "treatment", "of", "tuberculosis", "(TB).", "Resistance", "to", "EMB", "in", "Mycobacterium", "tuberculosis", "isolates", "is", "mediated", "by", "mutations", "in", "several", "genes", "involved", "in", "arabinan", "synthesis", "notably", "three", "emb", "(arabinosyl", "transferase)", "and", "iniA", "(isoniazid-", "inducible)", "genes.", "Most", "epidemiologically", "unrelated", "EMB-resistant", "M.", "tuberculosis", "strains", "contain", "mutations", "at", "embB", "codons", "306,", "406", "and", "497,", "embC-embA", "intergenic", "region", "(IGR)", "and", "iniA", "codon", "501", "(iniA501).", "Objective:", "To", "develop", "a", "more", "comprehensive", "molecular", "screen", "for", "EMB-resistance", "detectioamong", "epidemiologically", "unrelated", "EMB-resistant", "M.", "tuberculosis", "strains", "previously", "analyzed", "for", "embB", "codon", "306,", "406", "and", "497", "mutations", "by", "including", "analysis", "of", "mutations", "at", "iniA501", "and", "in", "embC-embA", "IGR.", "Methods:", "Fifty", "consecutive", "and", "phenotypically", "documented", "EMB-resistant", "and", "25", "pansusceptible", "M.", "tuberculosis", "strains", "isolated", "from", "75", "different", "TB", "patients", "over", "a", "four-year", "period", "in", "Kuwait", "were", "analyzed.", "Mutations", "at", "iniA501", "were", "detected", "by", "PCR", "amplification", "followed", "by", "restriction", "fragment", "length", "polymorphism", "(RFLP)", "patterns", "generated", "with", "Hpy", "99", "I.", "Direct", "DNA", "sequencing", "was", "used", "to", "confirm", "RFLP", "results", "and", "for", "detecting", "mutations", "in", "embC-embA", "IGR.", "Results:", "Nearly", "same", "number", "of", "EMB-resistant", "M.", "tuberculosis", "strains", "were", "resistant", "to", "EMB", "alone", "and", "EMB", "together", "with", "additional", "resistance", "to", "rifampicin", "and", "isoniazid", "(9", "of", "50,", "18%", "and", "11", "of", "50,", "22%,", "respectively).", "All", "the", "25", "pansusceptible", "strains", "contained", "wild-type", "sequences", "at", "iniA501", "and", "in", "embC-embA", "IGR.", "The", "analysis", "of", "50", "EMB-resistant", "M.", "tuberculosis", "isolates", "showed", "that", "only", "one", "strain", "contained", "a", "mutated", "iniA501", "while", "no", "mutation", "was", "detected", "in", "embC-embA", "IGR", "in", "any", "of", "the", "isolate.", "Conclusion:", "Analysis", "of", "iniA501", "and", "embC-embA", "IGR", "in", "epidemiologically", "unrelated", "EMB-resistant", "M.", "tuberculosis", "isolates", "in", "Kuwait", "indicate", "that", "mutations", "at", "these", "locations", "occur", "very", "infrequently", "and", "their", "inclusion", "for", "the", "development", "of", "a", "comprehensive", "molecular", "screen", "will", "make", "only", "minor", "contribution", "towards", "rapid", "EMB", "resistance", "detection.", "Page", "1", "of", "9", "(page", "number", "not", "for", "citation", "purposes)" ]

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3,145,015

null

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[ "DATABASES", "Human", "Mutation", "dbNSFP:", "A", "Lightweight", "Database", "of", "Human", "Nonsynonymous", "SNPs", "and", "Their", "Functional", "Predictions", "Xiaoming", "Liu,", "Xueqiu", "Jian,", "and", "Eric", "Boerwinkle", "Human", "Genetics", "Center,", "School", "of", "Public", "Health,", "The", "University", "of", "Texas", "Health", "Science", "Center", "at", "Houston,", "Houston,", "Texas", "Communicated", "by", "George", "Patrinos", "Received", "23", "February", "2011;", "accepted", "revised", "manuscript", "13", "April", "2011.", "Published", "online", "21", "April", "2011", "in", "Wiley", "Online", "Library", "(www.wiley.com/humanmutation).", "DOI", "10.1002/humu.21517", "OFFICIAL", "JOURNAL", "www.hgvs.org", "ABSTRACT:", "With", "the", "advance", "of", "sequencing", "technologies,", "whole", "exome", "sequencing", "has", "increasingly", "been", "used", "to", "identify", "mutations", "that", "cause", "human", "diseases,", "especially", "rare", "Mendelian", "diseases.", "Among", "the", "analysis", "steps,", "functional", "prediction", "(of", "being", "deleterious)", "plays", "an", "important", "role", "in", "filtering", "or", "prioritizing", "nonsynonymous", "SNP", "(NS)", "for", "further", "analysis.", "Unfortunately,", "different", "prediction", "algorithms", "use", "different", "information", "and", "each", "has", "its", "own", "strength", "and", "weakness.", "It", "has", "been", "suggested", "that", "investigators", "should", "use", "predictions", "from", "multiple", "algorithms", "instead", "of", "relying", "on", "a", "single", "one.", "However,", "querying", "predictions", "from", "different", "databases/Web-servers", "for", "different", "algorithms", "is", "both", "tedious", "and", "time", "consum-", "ing,", "especially", "when", "dealing", "with", "a", "huge", "number", "of", "NSs", "identified", "by", "exome", "sequencing.", "To", "facilitate", "the", "process,", "we", "developed", "dbNSFP", "(database", "for", "nonsynonymous", "SNPs’", "functional", "predictions).", "It", "compiles", "prediction", "scores", "from", "four", "new", "and", "popular", "algorithms", "(SIFT,", "Polyphen2,", "LRT,", "and", "MutationTaster),", "along", "with", "a", "conservation", "score", "(PhyloP)", "and", "other", "related", "information,", "for", "every", "potential", "NS", "in", "the", "human", "genome", "(a", "total", "of", "75,931,005).", "It", "is", "the", "first", "integrated", "database", "of", "functional", "predictions", "from", "multiple", "algorithms", "for", "the", "comprehensive", "collection", "of", "human", "NSs.", "dbNSFP", "is", "freely", "available", "for", "download", "at", "http://sites.google.com/site/jpopgen/dbNSFP.", "Hum", "Mutat", "32:894–899,", "2011.", "&", "2011", "Wiley-Liss,", "Inc.", "KEY", "WORDS:", "dbNSFP;", "functional", "prediction;", "database;", "SIFT;", "Polyphen2;", "LRT;", "MutationTaster;", "PhyloP", "Introduction", "A", "nonsynonymous", "SNP", "(NS)", "is", "a", "single", "nucleotide", "variant", "that", "causes", "an", "amino", "acid", "change", "of", "its", "corresponding", "protein.", "Because", "of", "their", "direct", "link", "to", "protein", "changes,", "NSs", "are", "believed", "to", "be", "the", "major", "contributor", "to", "heritable", "human", "diseases", "among", "all", "types", "of", "variants", "in", "the", "human", "genome.", "As", "evidence,", "NSs", "constitute", "more", "than", "half", "of", "the", "entries", "of", "disease-causing", "genetic", "changes", "in", "the", "Human", "Gene", "Mutation", "Database", "(HGMD)", "[Stenson", "et", "al.,", "2009].", "Additional", "Supporting", "Information", "may", "be", "found", "in", "the", "online", "version", "of", "this", "article.", "Correspondence", "to:", "Xiaoming", "Liu,", "Human", "Genetics", "Center,", "School", "of", "Public", "Health,", "The", "University", "of", "Texas", "Health", "Science", "Center", "at", "Houston,", "1200", "Herman", "Pressler", "Drive,", "E529,", "Houston,", "Texas", "77030.", "E-mail:", "xiaoming.liu@uth.tmc.edu", "Contract", "grant", "sponsor:", "The", "National", "Institutes", "of", "Health;", "Contract", "grant", "numbers:", "RC2-HL02419-01;", "RC2", "HL103010-01;", "1U01HG005728-01.", "Based", "on", "current", "technologies,", "it", "is", "too", "costly", "and", "time-", "consuming", "to", "investigate", "the", "functional", "effect", "of", "every", "NS", "experimentally.", "Fortunately,", "there", "are", "algorithms", "available", "to", "help", "to", "predict", "the", "potential", "of", "a", "NS", "being", "functional", "or", "deleterious.", "Functional", "prediction", "algorithms", "for", "NS", "have", "been", "developed", "in", "recent", "years", "with", "the", "advance", "of", "phylogenetics,", "structure", "biology,", "bioinformatics", "and", "population", "genetics", "(see", "reviews", "by", "[Horner", "et", "al.,", "2010;", "Karchin,", "2009;", "Ng", "and", "Henikoff,", "2006;", "Thusberg", "and", "Vihinen,", "2009]).", "Usually,", "the", "algorithms", "output", "a", "score", "measuring", "how", "likely", "an", "NS", "is", "deleterious,", "along", "with", "its", "binary", "prediction.", "Functional", "predictions", "play", "an", "important", "role", "in", "sequencing", "based", "genotype–phenotype", "association", "analyses.", "Prediction", "scores", "have", "been", "used", "to", "weight", "different", "NSs", "in", "order", "to", "increase", "the", "power", "of", "detecting", "genes", "influencing", "a", "trait", "[Price", "et", "al.,", "2010].", "More", "importantly,", "functional", "prediction", "has", "become", "an", "indispensable", "step", "in", "identifying", "genes", "causing", "rare", "Mendelian", "diseases", "using", "an", "exome-sequencing", "approach", "[Cooper", "et", "al.,", "2010;", "Ng", "et", "al.,", "2010a,b,c].", "Functional", "predictions", "or", "conservation", "information", "are", "used", "to", "filter", "or", "prioritize", "the", "novel", "NSs", "for", "further", "analysis", "or", "confirmation", "[Ng", "et", "al.,", "2010].", "Because", "different", "algorithms", "use", "different", "information", "and", "are", "based", "on", "different", "training", "data,", "each", "has", "its", "own", "strength", "and", "weakness.", "It", "has", "been", "suggested", "to", "use", "the", "outputs", "from", "multiple", "algorithms", "to", "make", "a", "more", "reliable", "prediction", "for", "a", "NS", "(e.g.,", "by", "using", "consensus", "prediction", "or", "majority", "vote)", "[Chun", "and", "Fay,", "2009].", "Because", "querying", "predictions", "from", "different", "databases/Web-", "servers", "for", "different", "algorithms", "is", "both", "tedious", "and", "time", "consuming,", "we", "developed", "dbNSFP", "(database", "for", "nonsynonymous", "SNPs’", "functional", "predictions)", "to", "facilitate", "the", "process.", "We", "first", "compiled", "a", "collection", "of", "all", "possible", "NSs", "in", "the", "human", "genome", "(a", "total", "of", "75,931,005)", "based", "on", "the", "annotation", 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[ "Available", "online", "http://respiratory-research.com/content/3/1/12", "Meeting", "report", "First", "Siena", "International", "Conference", "on", "Animal", "Models", "of", "Chronic", "Obstructive", "Pulmonary", "Disease,", "Certosa", "di", "Pontignano,", "University", "of", "Siena,", "Italy,", "September", "30–October", "2,", "2001", "David", "Hele", "Respiratory", "Pharmacology", "Group,", "Cardiothoracic", "Surgery,", "Faculty", "of", "Medicine,", "Imperial", "College,", "National", "Heart", "and", "Lung", "Institute,", "London,", "UK", "Correspondence:", "David", "Hele,", "Respiratory", "Pharmacology", "Group,", "Cardiothoracic", "Surgery,", "Faculty", "of", "Medicine,", "Imperial", "College,", "National", "Heart", "and", "Lung", "Institute,", "Dovehouse", "Street,", "London", "SW3", "6LY,", "UK.", "Tel:", "+44", "0207", "352", "8121", "ext.", "3042;", "fax:", "+44", "0207", "351", "8126;", "e-mail:", "d.hele@ic.ac.uk", "Received:", "9", "October", "2001", "Accepted:", "25", "October", "2001", "Published:", "28", "November", "2001", "Respir", "Res", "2002,", "3:12", "©", "2002", "BioMed", "Central", "Ltd", "(Print", "ISSN", "1465-9921;", "Online", "ISSN", "1465-993X)", "Abstract", "The", "meeting", "proved", "of", "great", "interest", "to", "those", "developing", "an", "animal", "model", "of", "chronic", "obstructive", "pulmonary", "disease", "(COPD).", "COPD", "is", "caused", "by", "cigarette", "smoking,", "evidenced", "by", "deterioration", "in", "lung", "function.", "Lung", "function", "is", "only", "rarely", "assessed", "in", "animal", "models.", "A", "cigarette", "smoke", "driven", "pathology", "should", "provide", "the", "best", "in", "vivo", "model", "for", "COPD.", "However,", "as", "lesions", "produced", "this", "way", "take", "8–12", "months", "to", "develop", "other", "strategies", "have", "to", "be", "employed.", "Emphysematous", "lesions", "were", "also", "achieved", "by", "treatment", "with", "elastase,", "lipopolysaccharide,", "ozone", "and", "other", "inducers.", "Several", "studies", "described", "treatments", "that", "have", "shown", "activity", "in", "these", "models.", "Transgenic", "models", "were", "discussed,", "as", "was", "the", "importance", "of", "species", "and", "strain", "selection.", "Keywords:", "animal", "models,", "COPD,", "cigarette", "smoke,", "elastase,", "lung", "function", "Introduction", "The", "meeting", "was", "attended", "by", "approximately", "80", "people", "and", "was", "designed", "to", "bring", "together", "an", "international", "group", "of", "academic", "investigators", "and", "industrial", "scientists", "in", "a", "forum", "that", "would", "foster", "discussion", "and", "exchange", "of", "ideas.", "The", "purpose", "of", "the", "meeting", "was", "to", "assess", "current", "animal", "models", "of", "emphysema", "and", "COPD,", "and", "to", "promote", "the", "use", "of", "new", "technologies.", "The", "immediate", "goal", "was", "to", "accelerate", "the", "translation", "of", "information", "gained", "from", "the", "development", "of", "animal", "models", "to", "improvements", "in", "patient", "care.", "Specifically,", "the", "formal", "presentations", "and", "informal", "discussions", "held", "during", "the", "conference", "addressed", "aetiological", "factors", "in", "COPD,", "and", "emphasized", "transgenic", "technologies", "and", "naturally", "occur-", "ring", "genetic", "variants.", "The", "objectives", "of", "the", "programme", "were", "to", "consolidate", "our", "present", "understanding", "of", "lung", "and", "airway", "inflammation,", "and", "its", "involvement", "in", "the", "COPD=chronic", "obstructive", "pulmonary", "disease.", "pathogenesis", "of", "COPD", "caused", "by", "cigarette", "smoking,", "ageing", "and", "genetic", "predisposition;", "and", "to", "promote", "further", "imaginative", "investigations.", "Lung", "physiology", "and", "lung", "function", "Dr", "A.", "Ten", "Have-Opbroek", "(Leiden", "University,", "Leiden,", "The", "Netherlands)", "presented", "an", "overview", "of", "lung", "development,", "stating", "that", "animal", "models", "may", "contribute", "to", "our", "insight", "into", "the", "pathogenesis", "of", "human", "COPD", "because", "there", "are", "major", "similarities", "in", "lung", "development", "and", "lung", "structure", "between", "mammals.", "Many", "attendees", "presented", "data", "at", "the", "meeting", "on", "the", "pathogenesis", "of", "emphysema/COPD,", "whereas", "little", "was", "presented", "regarding", "function", "of", "the", "lungs.", "The", "use", "of", "pathology", "to", "establish", "the", "presence", "of", "disease", "allied", "to", "an", "assessment", "of", "lung", "mechanics", "may", "provide", "a", "more", "meaningful", "assessment", "in", "the", "animal", "model", "of", "choice.", "Page", "1", "of", "3", "(page", "number", "not", "for", "citation", "purposes)" ]

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[ "HUMAN", "NEUROSCIENCE", "Differential", "maturation", "of", "brain", "signal", "complexity", "in", "the", "human", "auditory", "and", "visual", "system", "Sarah", "Lippé1*,", "Natasa", "Kovacevic", "2", "and", "Anthony", "Randal", "McIntosh", "2", "1", "Centre", "de", "Recherche", "CHU", "Ste-Justine,", "University", "of", "Montreal,", "Montreal,", "Quebec,", "Canada", "2", "The", "Rotman", "Research", "Institute,", "University", "ofToronto,Toronto,", "Ontario,", "Canada", "REVIEW", "ARTICLE", "published:", "16", "November", "2009", "doi:", "10.3389/neuro.09.048.2009", "Edited", "by:", "Silvia", "A.", "Bunge,", "University", "of", "California,", "USA", "Reviewed", "by:", "Rick", "O.", "Gilmore,The", "Pennyslvania", "State", "University,", "USA", "*Correspondence:", "Sarah", "Lippé,", "Département", "de", "Psychologie", "Université", "de", "Montréal,", "C.P.", "6128,", "succursale", "Centre-Ville", "Montréal,", "Québec,", "H3C", "3J7,", "Canada.", "e-mail:", "sarah.lippe@umontreal.ca", "Brain", "development", "carries", "with", "it", "a", "large", "number", "of", "structural", "changes", "at", "the", "local", "level", "which", "impact", "on", "the", "functional", "interactions", "of", "distributed", "neuronal", "networks", "for", "perceptual", "processing.", "Such", "changes", "enhance", "information", "processing", "capacity,", "which", "can", "be", "indexed", "by", "estimation", "of", "neural", "signal", "complexity.", "Here,", "we", "show", "that", "during", "development,", "EEG", "signal", "complexity", "increases", "from", "one", "month", "to", "5", "years", "of", "age", "in", "response", "to", "auditory", "and", "visual", "stimulation.", "However,", "the", "rates", "of", "change", "in", "complexity", "were", "not", "equivalent", "for", "the", "two", "responses.", "Infants’", "signal", "complexity", "for", "the", "visual", "condition", "was", "greater", "than", "auditory", "signal", "complexity,", "whereas", "adults", "showed", "the", "same", "level", "of", "complexity", "to", "both", "types", "of", "stimuli.", "The", "differential", "rates", "of", "complexity", "change", "may", "reﬂect", "a", "combination", "of", "innate", "and", "experiential", "factors", "on", "the", "structure", "and", "function", "of", "the", "two", "sensory", "systems.", "Keywords:", "development,", "EEG,", "signal,", "entropy,", "complexity,", "vision,", "audition,", "infant", "INTRODUCTION", "Infancy", "is", "a", "time", "of", "enormous", "changes", "in", "brain", "structure", "and", "function.", "For", "example,", "glucose", "metabolism", "rises", "(Chugani,", "1998)", "and", "brain", "volume", "shows", "a", "4-fold", "increase", "during", "the", "ﬁrst", "4", "years", "of", "life", "(Courchesne", "et", "al.,", "2000).", "Increases", "in", "synaptic", "density", "are", "followed", "by", "a", "declining", "slope", "within", "this", "period", "(Huttenlocher", "and", "Dabholkar,", "1997),", "whereas", "myelination", "continues", "well", "into", "adolescence", "(Paus", "et", "al.,", "1999).", "The", "functional", "consequence", "of", "these", "changes", "should", "be", "reﬂected", "in", "the", "increasing", "processing", "capacities", "of", "the", "developing", "child.", "More", "precisely,", "the", "changes", "in", "functional", "responses", "are", "thought", "to", "represent", "an", "increase", "in", "the", "integration", "within", "local", "neural", "ensembles", "together", "with", "more", "precise", "re-entrant", "interactions", "between", "distal", "ensembles", "(Thatcher", "et", "al.,", "2007;", "Fair", "et", "al.,", "2009).", "The", "balance", "between", "local", "integration", "and", "distal", "segregation", "is", "a", "characteristic", "architecture", "for", "a", "complex", "system", "that", "has", "an", "optimal", "capacity", "for", "information", "inte-", "gration", "(Tononi", "et", "al.,", "1994).", "Thus,", "development", "can", "be", "conceived", "of", "as", "the", "movement", "of", "the", "brain", "towards", "a", "complex", "system.", "Measures", "of", "complexity", "may", "be", "a", "sensitive", "index", "of", "maturational", "changes", "in", "brain", "function.", "For", "example,", "a", "marked", "increase", "with", "age", "in", "complex-", "ity", "of", "the", "brain’s", "electrical", "resting", "state", "activity", "has", "been", "shown", "by", "(Meyer-Lindenberg,", "1996)", "using", "two", "measures", "of", "complexity,", "cor-", "relation", "dimensions", "and", "the", "Lyapunov", "coefﬁcient.", "A", "recent", "study", "by", "McIntosh", "et", "al.", "(2008)", "showed", "an", "increase", "in", "EEG", "signal", "complexity", "with", "maturation", "in", "pre-adolescent", "children.", "Critically,", "they", "showed", "that", "this", "increase", "in", "complexity", "was", "strongly", "correlated", "with", "more", "stable", "and", "accurate", "behavioural", "performance.", "There", "does", "appear", "to", "be", "a", "general", "increase", "in", "brain", "signal", "com-", "plexity", "with", "maturation.", "However,", "the", "maturational", "rates", "of", "different", "neural", "systems", "are", "not", "uniform.", "For", "example,", "rates", "of", "neuroana-", "tomical", "and", "functional", "development", "for", "the", "visual", "and", "the", "auditory", "systems", "are", "distinct.", "The", "subcortical", "auditory", "pathways", "seem", "to", "mature", "earlier", "compared", "to", "the", "visual", "subcortical", "system.", "Brainstem", "auditory", "evoked", "potential", "of", "a", "few", "milliseconds", "post", "stimulus", "can", "be", "measured", "from", "birth", "(Jiang", "et", "al.,", "2001).", "Conversely,", "at", "the", "thalamocortical", "level,", "the", "tendency", "may", "be", "reversed.", "The", "genicu-", "localcarine", "tract", "(visual", "thalamocortical", "pathway)", "shows", "relative", "maturity", "at", "5", "months", "of", "age,", "whereas", "the", "maturation", "of", "the", "tha-", "lamic", "projections", "to", "the", "auditory", "cortex", "continues", "until", "6", "years", "of", "age", "(Yakovlev", "and", "Lecours,", "1967;", "Moore", "and", "Linthicum,", "2007).", "In", "addition,", "myelination", "begins", "earlier", "in", "the", "occipital", "lobe", "than", "in", "the", "temporal", "lobe", "(Yakovlev", "and", "Lecours,", "1967).", "Synapse", "density", "shows", "a", "rapid", "increase", "in", "the", "occipital", "cortex", "until", "about", "8", "months", "of", "age", "that", "is", "followed", "by", "a", "decline", "(Huttenlocher", "and", "Dabholkar,", "1997),", "whereas", "the", "synaptic", "density", "of", "the", "auditory", "cortex", "increases", "until", "50", "months", "before", "connections", "are", "pruned", "(Huttenlocher", "and", "Dabholkar,", "1997).", "Even", "at", "later", "ages", "of", "childhood,", "the", "time", "course", "of", "grey", "matter", "thickness", "change", "differs", "across", "brain", "regions", "(Giedd", "et", "al.,", "2006).", "The", "differences", "in", "prenatal", "exposure", "of", "the", "sensory", "sys-", "tem", "to", "environmental", "stimulation", "may", "have", "an", "impact", "on", "the", "func-", "tional", "state.", "Human", "foetuses", "and", "newborns", "detect", "sound", "changes", "in", "frequencies", "(Draganova", "et", "al.,", "2005).", "Auditory", "abilities", "in", "the", "early", "post-natal", "months", "include", "discrimination", "of", "musical", "features", "(Leppanen", "and", "Lyytinen,", "1997;", "Ceponiene", "et", "al.,", "2002;", "Morr", "et", "al.,", "2002),", "phonemic", "identity", "(Cheour", "et", "al.,", "1998),", "and", "gap", "detection", "(Trehub", "et", "al.,", "1995).", "By", "8", "months", "of", "age,", "infants", "already", "discrimi-", "nate", "their", "native", "language", "better", "than", "any", "other", "languages", "(Kuhl,", "2000).", "On", "the", "contrary,", "intrauterine", "visual", "competences", "of", "the", "infant", "have", "not", "been", "well", "explored.", "Prematurely", "born", "infants", "show", "a", "visual", "evoked", "potential", "response", "that", "is", "not", "advanced", "after", "term", "compared", "to", "infants", "born", "at", "term", "(Roy", "et", "al.,", "1995).", "The", "development", "of", "visual", "capacities", "is", "rapid", "in", "the", "ﬁrst", "post-natal", "months.", "By", "4", "months", "of", "age,", "infants", "born", "at", "term", "show", "ﬁxation/orientation", "abilities,", "saccades,", "binocular", "vision,", "and", "the", "visual", "ﬁelds", "are", "enlarged", "(Speeg-Schatz,", "2007).", "Infants", "of", "4–6", "months", "of", "age", "and", "on", "can", "segment", "objects", "from", "texture", "orientations", "(Atkinson", "and", "Braddick,", "1992;", "Burkhalter,", "1993;", "Norcia", "et", "al.,", "2005),", "resulting", "in", "visuomotor", "behaviours", "devel-", "opment", "such", "as", "reaching", "and", "grasping", "capacities.", "Frontiers", "in", "Human", "Neuroscience", "www.frontiersin.org", "November", "2009", "|", "Volume", "3", "|", "Article", "48", "|", "1" ]

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2,041,965

null

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[ "Perspectives", "Computational", "Biology", "in", "Brazil", "Goran", "Neshich", "Introduction", "At", "the", "request", "of", "the", "PLoS", "Computational", "Biology", "Editor-in-", "Chief,", "I", "agreed", "to", "write", "about", "computational", "biology", "in", "Brazil", "(see", "author", "information", "in", "Box", "1).", "That", "meant", "describing:", "a)", "the", "history", "of", "the", "ﬁeld", "in", "our", "country", "(short", "as", "the", "history", "of", "the", "ﬁeld", "itself", "is", "short);", "b)", "the", "current", "state", "of", "the", "ﬁeld", "in", "Brazil;", "c)", "the", "inﬂuence", "of", "computational", "biology–related", "technologies", "on", "the", "development", "of", "the", "national", "economy;", "d)", "the", "entrepreneurship", "that", "is", "rising", "from", "already-established", "academic", "activities;", "and", "e)", "educational", "activities", "ongoing", "or", "planned", "which", "are", "deemed", "necessary", "to", "establish", "the", "required", "critical", "mass", "of", "well-trained", "specialists.", "Why", "is", "an", "article", "like", "this", "important", "now?", "It", "is", "estimated", "that", "Brazil", "combined", "with", "China,", "Russia,", "and", "India", "will", "have", "a", "larger", "gross", "national", "product", "(GNP)", "than", "the", "US,", "Japan,", "Germany,", "and", "the", "UK", "combined", "by", "2020.", "In", "short,", "we", "can", "expect", "Brazil", "to", "have", "signiﬁcant", "impact", "on", "the", "ﬁeld", "of", "computational", "biology", "in", "the", "years", "to", "come,", "and", "now", "is", "the", "time", "to", "explore", "that", "promise.", "Increased", "Economic", "Activity", "Boosted", "Research", "Investment", "Brazil", "is", "a", "country", "with", "almost", "190", "million", "inhabitants", "that", "occupies", "an", "area", "equal", "to", "81%", "of", "the", "area", "of", "Europe", "and", "115%", "of", "the", "area", "of", "the", "US,", "excluding", "Alaska", "and", "Hawaii.", "In", "the", "late", "1980s,", "Brazil", "left", "behind", "its", "mantle", "as", "a", "simple", "coffee", "producer", "with", "an", "agricultural", "boom,", "offering", "the", "world", "market", "major", "commodities", "such", "as", "soybeans,", "meat,", "poultry,", "and,", "more", "recently,", "fruit", "and", "ﬂour.", "The", "rise", "in", "agricultural", "production", "came", "via", "a", "well-constructed", "socioeconomic", "plan", "put", "together", "by", "the", "Brazilian", "government,", "including", "targeted", "investment", "in", "supporting", "science", "and", "technology.", "As", "a", "consequence,", "Brazil", "became,", "for", "example,", "one", "of", "the", "major", "exporters", "of", "medium-sized", "aircraft.", "Further,", "the", "Brazilian", "petroleum", "company,", "Petrobras,", "provides", "Brazil", "self-", "sufﬁciency", "in", "oil,", "and", "is", "a", "major", "catalyst", "for", "the", "widespread", "use", "of", "ethanol", "in", "automobiles.", "The", "increasing", "economic", "activity", "enabled", "the", "country", "to", "invest", "proportionally", "in", "its", "scientiﬁc", "research.", "Government", "Policies", "for", "Research", "and", "Development", "As", "part", "of", "this", "investment,", "the", "Brazilian", "government", "showed", "speciﬁc", "interest", "in", "biotechnology,", "and", "I", "would", "argue", "that", "the", "current", "favorable", "situation,", "in", "which", "computational", "biologists", "ﬁnd", "themselves,", "has", "deep", "roots", "in", "the", "long-term", "dedication", "of", "policymakers", "to", "biotechnology.", "In", "the", "1920s", "and", "1930s", "the", "ﬁrst", "Brazilian", "universities", "were", "established.", "The", "largest", "of", "them", "all,", "USP", "(University", "of", "Sa˜", "o", "Paulo),", "was", "started", "in", "1934.", "Today,", "USP", "is", "responsible", "for", "more", "than", "a", "quarter", "of", "the", "total", "publications", "in", "Brazil", "in", "almost", "every", "scientiﬁc", "area,", "even", "though", "there", "are", "more", "than", "100", "universities", "in", "Brazil", "now.", "In", "terms", "of", "productivity,", "three", "other", "universities", "closely", "follow:", "UNICAMP", "in", "Campinas,", "in", "the", "state", "of", "Sa˜", "o", "Paulo,", "UFRJ", "in", "Rio", "de", "Janeiro,", "and", "UFMG", "in", "Belo", "Horizonte.", "Notably,", "these", "four", "universities", "together", "with", "EMBRAPA", "(Brazilian", "enterprise", "for", "research", "in", "agriculture,", "a", "close", "equivalent", "to", "the", "US", "Department", "of", "Agriculture),", "Fiocruz,", "and", "Ludwig", "Institute,", "both", "of", "which", "are", "involved", "in", "human", "health", "related", "research,", "and", "the", "National", "Laboratory", "for", "Scientiﬁc", "Computation", "(LNCC),", "are", "responsible", "for", "most", "of", "the", "scientiﬁc", "publications", "in", "computational", "biology.", "To", "consolidate", "its", "efforts", "in", "building", "consistent", "policies", "for", "scientiﬁc", "growth", "and", "to", "create", "a", "critical", "mass", "of", "specialists", "in", "various", "areas", "of", "science,", "in", "1951", "the", "Brazilian", "government", "established", "the", "National", "Research", "Council", "(CNPq),", "and", "the", "National", "Agency", "for", "Scholarly", "Advancement", "in", "Scientiﬁc", "Research", "(CAPES).", "The", "former", "agency", "was", "focused", "on", "guiding", "national", "scientiﬁc", "advancement", "through", "ﬁnancing", "research", "projects", "and", "collaborations,", "while", "the", "latter", "provided", "scholarships", "to", "anyone", "who", "wanted", "to", "obtain", "higher", "degrees", "(Master’s,", "Ph.D.)", "and", "to", "undertake", "postdoctoral", "training,", "either", "here", "in", "Brazil", "or", "abroad.", "In", "parallel,", "Brazilian", "states", "initiated", "their", "own", "Scientiﬁc", "Research", "Agencies", "(FAP)", "and", "Sa˜", "o", "Paulo", "started", "with", "its", "own,", "FAPESP,", "in", "1958.", "As", "Sa˜", "o", "Paulo", "is", "the", "richest", "state", "in", "the", "Brazilian", "federation,", "the", "impact", "of", "FAPESP", "investments", "on", "science", "and", "technology", "in", "that", "particular", "region", "were,", "and", "are,", "substantial.", "The", "positive", "impact", "of", "FAPESP", "can", "be", "attributed", "to", "at", "least", "two", "factors.", "First,", "Sa˜", "o", "Paulo", "has", "a", "law", "stating", "that", "1%", "of", "the", "tax", "revenue", "collected", "by", "the", "state", "has", "to", "be", "given", "to", "FAPESP,", "and,", "second,", "the", "administrative", "costs", "of", "FAPESP", "are", "limited", "to", "not", "more", "than", "5%", "of", "its", "total", "budget.", "On", "the", "national", "level,", "in", "1981", "the", "Brazilian", "government", "initiated", "a", "broad", "program", "(PRONAB)", "for", "supporting", "scientiﬁc", "research", "in", "biotechnology.", "A", "further", "government", "program,", "PADCT,", "was", "initiated", "in", "1984.", "As", "a", "consequence", "of", "these", "national", "programs,", "Brazil", "has", "established", "a", "critical", "mass", "of", "well-trained", "specialists", "and", "equipped", "many", "laboratories,", "which", "were", "fully", "functional", "by", "the", "early", "1990s.", "These", "programs", "notwithstanding,", "Brazil", "remains", "below", "many", "countries", "with", "only", "12%", "of", "17-", "to", "25-year-olds", "studying", "at", "universities", "compared", "with", "approximately", "50%", "in", "the", "United", "States.", "Genomics", "and", "Bioinformatics", "In", "1997", "FAPESP", "began", "to", "invest", "both", "ﬁnancial", "and", "human", "resources", "in", "genome", "sequencing.", "No", "central", "sequencing", "Editor:", "Philip", "E.", "Bourne,", "University", "of", "California", "San", "Diego,", "United", "States", "of", "America", "Citation:", "Neshich", "G", "(2007)", "Computational", "Biology", "in", "Brazil.", "PLoS", "Comput", "Biol", "3(10):", "e185.", "doi:10.1371/journal.pcbi.0030185", "Copyright:", "2007", "Goran", "Neshich.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Goran", "Neshich", "is", "with", "the", "Embrapa", "Informa´tica", "Agropecua´ria,", "Campinas,", "Brazil.", "E-", "mail:", "neshich@cbi.cnptia.embrapa.br", "PLoS", "Computational", "Biology", "|", "www.ploscompbiol.org", "1845", "October", "2007", "|", "Volume", "3", "|", "Issue", "10", "|", "e185" ]

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3,359,245

null

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[ "Bisgin", "et", "al.", "BMC", "Cancer", "2012,", "12:58", "http://www.biomedcentral.com/1471-2407/12/58", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Increased", "serum", "sTRAIL", "levels", "were", "correlated", "with", "survival", "in", "bevacizumab-treated", "metastatic", "colon", "cancer", "Atil", "Bisgin1*,", "Aysegul", "Kargi2,", "Arzu", "D", "Yalcin3,", "Cigdem", "Aydin1,", "Deniz", "Ekinci2,", "Burhan", "Savas2", "and", "Salih", "Sanlioglu1", "Abstract", "Background:", "Colorectal", "cancer", "is", "the", "third", "most", "common", "cancer", "and", "the", "third", "leading", "cause", "of", "cancer-related", "death.", "Bevacizumab", "is", "a", "humanized", "monoclonal", "antibody", "developed", "against", "vascular", "endothelial", "growth", "factor", "(VEGF)", "for", "the", "treatment", "of", "metastatic", "cancer.", "The", "parameters", "of", "RECIST", "(Response", "Evaluation", "Criteria", "for", "Solid", "Tumors)", "are", "not", "adequate", "to", "detect", "important", "treatment", "effects", "and", "response.", "Our", "goal", "was", "to", "evaluate", "the", "possibility", "of", "using", "sTRAIL", "(serum-soluble", "TNF-related", "apoptosis-inducing", "ligand)", "and", "VEGF", "as", "markers", "of", "treatment", "efficacy", "and", "prognosis", "in", "patients", "with", "metastatic", "colon", "cancer.", "Methods:", "sTRAIL", "and", "VEGF", "levels", "were", "measured", "by", "ELISA", "in", "the", "sera", "of", "16", "bevacizumab-treated", "metastatic", "colon", "cancer", "patients", "and", "10", "presumably", "healthy", "age-matched", "controls.", "The", "measurements", "were", "taken", "before", "and", "after", "treatment", "for", "comparison", "purposes.", "Results:", "Elevated", "levels", "of", "sTRAIL", "were", "found", "in", "seven", "out", "of", "16", "patients", "after", "bevacizumab", "treatment.", "Although", "these", "patients", "had", "a", "median", "survival", "time", "of", "20.6", "months,", "the", "remaining", "bevacizumab-treated", "patients", "who", "did", "not", "show", "an", "increase", "in", "sTRAIL", "had", "a", "median", "survival", "time", "of", "9.4", "months.", "As", "expected,", "serum", "VEGF", "levels", "were", "decreased", "in", "all", "patients", "who", "received", "bevacizumab", "therapy", "and", "showed", "no", "correlation", "between", "serum", "VEGF", "levels", "and", "patient", "survival", "(data", "not", "shown).", "Conclusions:", "Serum", "sTRAIL", "levels", "might", "be", "a", "useful", "predictor", "of", "prognosis", "in", "metastatic", "colon", "cancer,", "in", "the", "early", "evaluation", "stages", "following", "bevacizumab", "treatment.", "Background", "Colorectal", "cancer", "is", "the", "third", "most", "common", "cancer", "and", "the", "second", "leading", "cause", "of", "cancer-related", "death", "[1].", "Overall,", "the", "5-year", "survival", "rate", "is", "<10%", "for", "stage", "IV", "cancer", "[2].", "The", "cure", "rate", "with", "surgery", "alone", "is", "very", "low", "and", "chemotherapy", "and", "radiotherapy", "are", "usually", "needed", "in", "patients", "with", "untreated", "metastatic", "colon", "cancer.", "The", "development", "of", "colorectal", "cancer", "is", "characterized", "by", "a", "sequence", "of", "events", "during", "which", "normal", "colonic", "epithe-", "lium", "gradually", "transforms", "to", "carcinoma", "tissue,", "in", "most", "cases,", "via", "the", "development", "of", "colorectal", "adenomas", "[3].", "This", "sequence", "of", "events", "is", "driven", "by", "an", "accumulation", "of", "molecular", "(epi)genetic", "alterations", "causing", "progressive", "disorders", "in", "cell", "growth,", "differentiation", "and", "apoptosis", "*", "Correspondence:", "atilbisgin@yahoo.co.uk", "1Human", "Gene", "and", "Cell", "Therapy", "Center", "of", "Akdeniz", "University", "Hospitals", "and", "Clinics,", "Department", "of", "Medical", "Genetics,", "Antalya,", "Turkey", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "[4,5].", "Apoptosis,", "or", "programmed", "cell", "death,", "plays", "an", "important", "role", "in", "the", "development", "and", "maintenance", "of", "tissue", "homeostasis", "but", "also", "represents", "an", "effective", "mechanism", "by", "which", "abnormal", "cells,", "such", "as", "tumor", "cells,", "can", "be", "eliminated", "[6-8].", "Abnormalities", "in", "apoptotic", "function", "or", "resistance", "to", "apoptosis", "have", "been", "identified", "as", "important", "events", "in", "the", "pathogenesis", "of", "colorectal", "cancer", "and", "its", "resistance", "to", "chemotherapeutic", "drugs", "and", "radiotherapy", "[9,10].", "In", "recent", "years,", "bevacizumab,", "a", "novel", "humanized", "monoclonal", "antibody", "directed", "against", "vascular", "endothe-", "lial", "growth", "factor", "(VEGF)", "has", "found", "widespread", "clinical", "use", "as", "an", "angiogenesis", "inhibitor", "for", "certain", "types", "of", "metastatic", "cancers", "[11].", "Treatment", "with", "bevacizumab", "with/without", "the", "combination", "of", "other", "chemotherapeu-", "tic", "agents", "inhibits", "VEGF", "receptor", "activation", "and", "vascular", "permeability,", "which", "eventually", "lead", "to", "tumor", "cell", "apop-", "tosis", "[12,13].", "Apoptosis", "can", "be", "induced", "passively,", "©", "2012", "Bisgin", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

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1,794,448

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[ "Available", "online", "http://ccforum.com/content/10/6/169", "Commentary", "Live", "and", "let", "die:", "asymmetric", "dimethylarginine", "and", "septic", "shock", "Rainer", "H", "Böger", "Clinical", "Pharmacology", "Unit,", "Institute", "of", "Experimental", "and", "Clinical", "Pharmacology,", "University", "Hospital", "Hamburg-Eppendorf,", "Germany", "Corresponding", "author:", "Rainer", "H", "Böger,", "boeger@uke.uni-hamburg.de", "Published:", "3", "November", "2006", "This", "article", "is", "online", "at", "http://ccforum.com/content/10/6/169", "©", "2006", "BioMed", "Central", "Ltd", "See", "related", "research", "by", "O’Dwyer", "et", "al.,", "http://ccforum.com/content/10/5/R139", "Critical", "Care", "2006,", "10:169", "(doi:10.1186/cc5076)", "Abstract", "Nitric", "oxide", "(NO)", "is", "an", "important", "mediator", "of", "host", "defence", "and", "of", "vascular", "tone.", "In", "septic", "shock,", "upregulation", "of", "inducible", "NO", "synthase", "leads", "to", "the", "production", "of", "vast", "amounts", "of", "NO,", "which", "contribute", "to", "pathogen", "elimination", "but", "also", "to", "inappropriate", "vaso-", "dilation", "and", "to", "loss", "of", "vascular", "resistance.", "Asymmetric", "dimethyl-", "arginine", "(ADMA)", "is", "an", "endogenous", "inhibitor", "of", "NO", "synthases", "shown", "to", "contribute", "to", "the", "regulation", "of", "vascular", "tone.", "ADMA", "was", "recently", "identified", "as", "a", "marker", "of", "organ", "dysfunction", "and", "mortality", "in", "intensive", "care", "patients", "and", "as", "a", "novel", "cardiovascular", "risk", "factor.", "In", "the", "present", "issue", "of", "Critical", "Care,", "a", "study", "by", "O’Dwyer", "and", "colleagues", "identifies", "ADMA", "as", "a", "potential", "regulator", "of", "NO", "production", "in", "septic", "shock.", "Being", "an", "inhibitor", "of", "NO", "production,", "ADMA", "may", "at", "least", "partly", "counteract", "pathological", "hypotension,", "but", "at", "the", "same", "time", "may", "impair", "the", "NO-dependent", "host", "defence.", "A", "mechanism", "is", "proposed", "by", "which", "the", "interplay", "between", "ADMA", "and", "inducible", "NO", "synthase", "activity", "is", "mediated.", "ADMA", "levels", "should", "be", "determined", "in", "future", "studies", "evaluating", "the", "regulation", "of", "NO", "in", "the", "intensive", "care", "setting.", "In", "the", "present", "issue", "of", "Critical", "Care,", "O’Dwyer", "and", "colleagues", "[1]", "report", "the", "results", "of", "a", "study", "in", "47", "patients", "with", "septic", "shock.", "Asymmetric", "dimethylarginine", "(ADMA)", "levels", "were", "elevated", "in", "these", "patients", "at", "the", "time", "of", "admission", "to", "the", "intensive", "care", "unit", "(ICU)", "as", "compared", "with", "a", "group", "of", "10", "healthy", "controls.", "ADMA", "levels", "in", "septic", "patients", "directly", "correlated", "with", "the", "Sequential", "Organ", "Failure", "Assessment", "scores,", "with", "the", "degree", "of", "acidaemia", "and", "lactaemia,", "and", "with", "vasopressor", "requirements.", "Interestingly", "enough,", "ADMA", "levels", "were", "higher", "in", "patients", "requiring", "vasoactive", "infusions", "than", "in", "those", "not", "requiring", "vasoactive", "infusions.", "ADMA", "levels", "further", "increased", "during", "the", "subsequent", "7", "days", "of", "ICU", "treatment.", "Nonsurvivors", "tended", "to", "have", "higher", "ADMA", "plasma", "levels", "on", "days", "1", "and", "7", "of", "ICU", "treatment", "as", "compared", "with", "survivors,", "although", "this", "trend", "was", "insignificant", "in", "the", "small", "patient", "group.", "The", "authors", "also", "demonstrated", "that", "a", "genetic", "polymorphism", "in", "the", "promoter", "region", "of", "the", "dimethylarginine", "dimethylaminohydrolase", "(DDAH)", "II", "gene", "was", "significantly", "associated", "with", "ADMA", "levels", "in", "these", "patients,", "suggesting", "that", "the", "genetically", "anchored", "dysfunction", "of", "the", "enzyme", "that", "metabolises", "ADMA", "may", "importantly", "regulate", "ADMA", "levels.", "Standard", "therapy", "for", "patients", "with", "sepsis", "includes", "ICU", "admission,", "careful", "selection", "of", "antibiotic", "therapy,", "and,", "if", "needed,", "haemodynamic", "and", "ventilatory", "support", "[2].", "Despite", "the", "use", "of", "these", "intensive", "therapies,", "however,", "mortality", "from", "sepsis", "has", "remained", "at", "levels", "between", "35%", "and", "50%", "[2].", "Nitric", "oxide", "(NO)", "is", "referred", "to", "as", "a", "key", "mediator", "of", "vasodilatation", "and", "catecholamine", "resistance", "in", "septic", "shock", "[3,4].", "Whereas", "in", "physiological", "conditions", "NO", "is", "mainly", "formed", "in", "the", "endothelium", "at", "low", "rates", "by", "the", "activity", "of", "the", "constitutive,", "endothelial", "isoform", "of", "the", "enzyme", "NO", "synthase,", "inflammatory", "stimuli", "such", "as", "bacterial", "lipopolysaccharides", "and", "cytokines", "released", "during", "sepsis", "result", "in", "a", "strong", "upregulation", "of", "an", "inducible", "isofom", "of", "NO", "synthase", "(iNOS).", "This", "isoform,", "once", "upregulated,", "releases", "huge", "amounts", "of", "NO", "during", "prolonged", "time", "intervals.", "The", "iNOS-derived", "NO", "contributes", "to", "pathogen", "elimination.", "NO-induced", "vaso-", "dilatation,", "however,", "also", "contributes", "to", "widespread", "vascular", "loss", "of", "tone", "and", "has", "been", "implicated", "in", "the", "cardiovascular", "failure", "in", "septic", "shock", "[5].", "There", "has", "been", "controversy", "about", "the", "pathophysiological", "roles", "of", "iNOS", "and", "NO", "in", "the", "development", "of", "septic", "shock", "after", "a", "phase", "III", "trial", "with", "NG-", "monomethyl-L-arginine,", "a", "nonselective", "NO", "synthase", "inhibitor,", "resulted", "in", "excess", "mortality", "[6].", "Indeed,", "experimental", "studies", "have", "suggested", "that", "iNOS-derived", "NO", "plays", "an", "important", "role", "in", "host", "defence", "and", "organ", "protection", "[7].", "During", "the", "past", "decade", "knowledge", "has", "accumulated", "of", "endogenous", "compounds", "that", "inhibit", "NO", "synthase", "activity,", "and", "thereby", "regulate", "NO-dependent", "vascular", "function.", "The", "major", "molecule", "endogenously", "present", "in", "the", "circulation", "at", "concentrations", "sufficiently", "high", "to", "exert", "inhibitory", "effects", "on", "ADMA", "=", "asymmetric", "dimethylarginine;", "DDAH", "=", "dimethylarginine", "dimethylaminohydrolase;", "ICU", "=", "intensive", "care", "unit;", "iNOS", "=", "inducible", "NO", "synthase;", "NO", "=", "nitric", "oxide.", "Page", "1", "of", "3", "(page", "number", "not", "for", "citation", "purposes)" ]

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3,407,204

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[ "PDHK-2", "Deficiency", "Is", "Associated", "with", "Attenuation", "of", "Lipase-Mediated", "Fat", "Consumption", "for", "the", "Increased", "Survival", "of", "Caenorhabditis", "elegans", "Dauers", "Sunhee", "Kim,", "E-Jin", "Shin,", "Jeong-Hoon", "Hahm,", "Pil-Jong", "Park,", "Ji-Eun", "Hwang,", "Young-Ki", "Paik*", "Department", "of", "Biochemistry", "and", "Integrated", "Omics", "for", "Biomedical", "Science,", "World", "Class", "University", "Program,", "College", "of", "Life", "Science", "and", "Biotechnology,", "Yonsei", "Proteome", "Research", "Center,", "Yonsei", "University,", "Seoul,", "Korea", "Abstract", "In", "Caenorhabditis", "elegans,", "slow", "fat", "consumption", "has", "been", "suggested", "to", "contribute", "to", "the", "extension", "of", "the", "survival", "rate", "during", "nutritionally", "adverse", "conditions.", "Here,", "we", "investigated", "the", "potential", "role", "of", "pyruvate", "dehydrogenase", "kinase", "(PDHK)-", "2,", "the", "C.", "elegans", "homolog", "of", "mammalian", "PDK,", "effects", "on", "fat", "metabolism", "under", "nutritional", "conditions.", "PDHK-2", "was", "expressed", "at", "low", "levels", "under", "well-fed", "conditions", "but", "was", "highly", "induced", "during", "long-term", "starvation", "and", "in", "the", "dauer", "state.", "This", "increase", "in", "pdhk-2", "expression", "was", "regulated", "by", "both", "DAF-16", "and", "NHR-49.", "Dauer-specific", "induction", "of", "PDHK-2", "was", "abolished", "upon", "entry", "into", "the", "post-dauer", "stage.", "Interestingly,", "in", "the", "long-term", "dauer", "state,", "stored", "fat", "levels", "were", "higher", "in", "daf-2(e1370);pdhk-2", "double", "mutants", "than", "in", "daf-2(e1370),", "suggesting", "a", "positive", "relationship", "between", "PDHK-2", "activity", "and", "fat", "consumption.", "PDHK-2", "deficiency", "has", "been", "shown", "to", "lead", "to", "greater", "preservation", "of", "residual", "fats,", "which", "would", "be", "predicted", "to", "contribute", "to", "survival", "during", "the", "dauer", "state.", "A", "test", "of", "this", "prediction", "showed", "that", "the", "survival", "rates", "of", "daf-2(e1370);pdhk-", "2(tm3075)", "and", "daf-2(e1370);pdhk-2(tm3086)", "double", "mutants", "were", "higher", "than", "that", "of", "daf-2(e1370),", "suggesting", "that", "loss", "of", "either", "the", "ATP-binding", "domain", "(tm3075)", "or", "branched", "chain", "keto-acid", "dehydrogenase", "kinase", "domain", "(tm3086)", "of", "PDHK-2", "leads", "to", "reduced", "fat", "consumption", "and", "thus", "favors", "increased", "dauer", "survival.", "This", "attenuated", "fat", "consumption", "in", "the", "long-", "term", "dauer", "state", "of", "C.", "elegans", "daf-2", "(e1370);pdhk-2", "mutants", "was", "associated", "with", "concomitant", "down-regulation", "of", "the", "lipases", "ATGL", "(adipose", "triglyceride", "lipase),", "HSL", "(hormone-sensitive", "lipase),", "and", "C07E3.9", "(phospholipase).", "In", "contrast,", "PDHK-2", "overexpression", "in", "wild-type", "starved", "worms", "induced", "lipase", "expression", "and", "promoted", "abnormal", "dauer", "formation.", "Thus,", "we", "propose", "that", "PDHK-2", "serves", "as", "a", "molecular", "bridge,", "connecting", "fat", "metabolism", "and", "survival", "under", "nutritionally", "adverse", "conditions", "in", "C.", "elegans.", "Citation:", "Kim", "S,", "Shin", "E-J,", "Hahm", "J-H,", "Park", "P-J,", "Hwang", "J-E,", "et", "al.", "(2012)", "PDHK-2", "Deficiency", "Is", "Associated", "with", "Attenuation", "of", "Lipase-Mediated", "Fat", "Consumption", "for", "the", "Increased", "Survival", "of", "Caenorhabditis", "elegans", "Dauers.", "PLoS", "ONE", "7(7):", "e41755.", "doi:10.1371/journal.pone.0041755", "Editor:", "Howard", "Riezman,", "University", "of", "Geneva,", "Switzerland", "Received", "June", "18,", "2012;", "Accepted", "June", "25,", "2012;", "Published", "July", "27,", "2012", "Copyright:", "2012", "Kim", "et", "al.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Funding:", "This", "study", "was", "supported", "by", "the", "National", "Research", "Foundation", "of", "Korea", "(NRF)", "grant", "(No.", "2011-0028112", "to", "YKP)", "and", "WCU", "Program", "(R31-2008-000-", "10086-0)", "funded", "by", "the", "Korean", "government", "(MEST),", "and", "the", "National", "Project", "for", "Personalized", "Genomic", "Medicine", "(A111218-11-CP01", "to", "YKP).", "The", "funders", "had", "no", "role", "in", "study", "design,", "data", "collection", "and", "analysis,", "decision", "to", "publish,", "or", "preparation", "of", "the", "manuscript.", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "*", "E-mail:", "paikyk@yonsei.ac.kr", "Introduction", "It", "has", "been", "well", "documented", "that", "a", "close", "relationship", "exists", "between", "energy", "metabolism", "and", "aging", "processes", "in", "animals,", "including", "the", "nematode", "Caenorhabditis", "elegans", "[1,2].", "In", "C.", "elegans,", "in", "particular,", "the", "critical", "role", "of", "insulin/insulin-like", "growth", "factor-1", "(IGF-1)", "signaling", "(IIS)", "in", "metabolism", "and", "the", "control", "of", "aging", "has", "been", "well", "established.", "For", "example,", "suppression", "of", "the", "IIS", "pathway", "has", "been", "shown", "to", "cause", "a", "substantial", "increase", "in", "both", "mean", "lifespan", "(MLS)", "and", "fat", "accumulation", "[1–3].", "This", "pathway", "also", "controls", "the", "dauer", "state,", "a", "non-aging", "condition", "that", "is", "important", "in", "determining", "the", "relationship", "between", "metabolism", "and", "aging", "[4,5].", "When", "C.", "elegans", "encounters", "unfavorable", "growth", "conditions", "(e.g.,", "lack", "of", "food", "or", "high", "temperatures)", "or", "high", "concentrations", "of", "dauer", "pheromones", "(daumones", "or", "ascarosides),", "it", "can", "enter", "the", "dauer", "state", "[5–10].", "Studies", "on", "dauer", "entry", "in", "C.", "elegans", "have", "suggested", "that", "this", "process", "is", "compartmentalized", "according", "to", "metabolic", "phase", "and", "growth", "time", "[11].", "When", "L2", "larvae", "prepare", "for", "dauer", "entry,", "nutritional", "adaptation", "accompanies", "intestinal", "and", "hypodermal", "fat", "accumulation,", "enabling", "C.", "elegans", "to", "survive", "an", "extended", "dormant", "period", "[12].", "The", "dauer", "state", "is", "controlled", "by", "an", "IIS", "mechanism", "in", "which", "DAF-16", "serves", "as", "a", "downstream", "effector", "[11–13].", "The", "dauer", "state", "is", "resistant", "to", "environmental", "stresses,", "such", "as", "heat", "and", "cold,", "as", "well", "as", "oxidative", "stress,", "and", "the", "metabolic", "activity", "of", "dauer", "larvae", "is", "generally", "reduced", "[12].", "Because", "dauer", "larvae", "do", "not", "feed,", "they", "use", "mostly", "stored", "triglycerides", "(TGs)", "as", "an", "energy", "source", "[12,13];", "TGs,", "in", "turn,", "are", "hydrolyzed", "to", "fatty", "acids", "by", "lipases", "[14].", "Additional", "macronutrients", "that", "are", "stored", "and", "metabolized", "in", "dauer", "larvae", "include", "glycogen", "and", "trehalose", "[15].", "Because", "their", "supply", "of", "stored", "nutrients", "is", "limited,", "dauers", "must", "suppress", "energy-consuming", "metabolic", "activities", "to", "survive", "[16].", "Microarray", "and", "SAGE", "(serial", "analysis", "of", "gene", "expression)", "assays", "of", "dauer", "larvae,", "recovered", "dauers,", "and", "mixed-stage", "populations", "have", "suggested", "that", "the", "expression", "of", "enzymes", "involved", "in", "b-oxidation", "of", "fatty", "acids,", "glycolysis,", "glyoxylate,", "and", "gluconeogenesis", "pathways", "are", "enhanced", "under", "nutritionally", "adverse", "conditions,", "indicating", "that", "TGs", "are", "degraded", "by", "lipases", "and", "converted", "into", "sugars", "that", "are", "used", "for", "survival", "[17–21].", "Slow", "energy", "release", "and", "tightly", "controlled", "energy", "consumption", "may", "be", "critical", "to", "long-term", "survival", "through", "diapause,", "hibernation,", "or", "long-term", "fasting", "in", "a", "PLoS", "ONE", "|", "www.plosone.org", "1", "July", "2012", "|", "Volume", "7", "|", "Issue", "7", "|", "e41755" ]

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[ "Rasul", "et", "al.", "Cardiovascular", "Diabetology", "2011,", "10:55", "http://www.cardiab.com/content/10/1/55", "O", "R", "I", "G", "I", "N", "A", "L", "I", "N", "V", "E", "S", "T", "I", "G", "A", "T", "I", "O", "N", "CARDIO", "VASCULAR", "DIABETOLOGY", "Open", "Access", "Circulating", "angiopoietin-2", "and", "soluble", "Tie-2", "in", "type", "2", "diabetes", "mellitus:", "a", "cross-sectional", "study", "Sazan", "Rasul1,", "Marie", "Helene", "Reiter2,", "Aysegul", "Ilhan3,", "Katharina", "Lampichler2,", "Ludwig", "Wagner3", "and", "Alexandra", "Kautzky-Willer1*", "Abstract", "Background:", "Type", "2", "diabetes", "is", "associated", "with", "increased", "levels", "of", "Angiopoietin-2", "(Ang-2)", "and", "soluble", "Tie-2", "(sTie-", "2),", "but", "its", "impact", "on", "vascular", "disease", "is", "still", "unknown.", "This", "study", "aimed", "to", "further", "explore", "the", "associations", "of", "Ang-2", "and", "sTie-2", "with", "metabolic", "control", "and", "diabetic", "complications.", "Methods:", "In", "a", "cross-sectional", "designed", "study,", "levels", "of", "Ang-2", "and", "sTie-2", "as", "well", "as", "their", "relationships", "to", "cardiometabolic", "parameters", "were", "determined", "in", "80", "type", "2", "diabetic", "subjects", "(age", "65", "±", "7", "years,", "female", "47.4%).", "Results:", "After", "controlling", "for", "age", "and", "BMI,", "Ang-2", "levels", "were", "associated", "with", "levels", "of", "sTie-2,", "diastolic", "blood", "pressure,", "plasma", "insulin,", "homeostasis", "model", "assessment", "of", "insulin", "resistance", "(HOMA-IR),", "creatinine,", "glomerular", "filtration", "rate", "(GFR),", "and", "gamma-glutamyl", "transferase", "(GGT)", "(all", "p", "<", "0.02).", "Presence", "of", "diabetic", "macrovascular", "complications,", "polyneuropathy", "and", "insulin", "therapy", "were", "associated", "with", "higher", "Ang-2", "levels", "(p", "<", "0.05).", "Conversely,", "sTie-2", "levels", "were", "associated", "with", "glycated", "hemoglobin", "(HbA1c),", "fasting", "plasma", "glucose", "and", "insulin,", "HOMA-IR,", "triglyceride,", "and", "liver", "function", "parameters", "(all", "p", "<", "0.03).", "Multiple", "linear", "regression", "analysis", "showed", "that", "Ang-2", "remained", "significantly", "associated", "only", "with", "levels", "of", "GGT", "(p", "<", "0.04),", "whereas", "sTie-2", "remained", "significantly", "associated", "with", "HbA1c,", "insulin", "levels,", "and", "HOMA-IR", "(p", "<", "0.03).", "No", "differences", "in", "Ang-2", "and", "sTie-2", "levels", "were", "observed", "with", "regard", "to", "gender", "of", "participants.", "Conclusions:", "Ang-2", "is", "independently", "associated", "with", "levels", "of", "GGT", "while", "sTie-2", "is", "independently", "associated", "with", "levels", "of", "HbA1c,", "plasma", "insulin", "and", "HOMA-IR", "in", "type", "2", "diabetic", "subjects.", "Therefore", "we", "suggest", "that", "the", "associations", "of", "Ang-2", "and", "sTie-2", "with", "type", "2", "diabetes", "are", "based", "on", "different", "patho-physiological", "mechanisms.", "Background", "Angiopoietins", "are", "growth", "factors", "that", "promote", "angiogen-", "esis", "together", "with", "vascular", "endothelial", "growth", "factor", "(VEGF).", "Among", "the", "four", "identified", "angiopoietins", "(1-4),", "Angiopoietin", "(Ang)-1", "and", "Ang-2", "are", "reported", "to", "be", "required", "for", "the", "formation", "of", "mature", "blood", "vessels,", "as", "demonstrated", "by", "mouse", "knock", "out", "studies", "[1,2].", "Ang-2", "is", "expressed", "primarily", "in", "the", "vascular", "endothelium", "at", "sites", "of", "vascular", "remodeling", "[3].", "Both", "Ang-1", "and", "Ang-2", "act", "by", "binding", "to", "the", "endothelium-specific", "receptor", "tyrosine", "kinase", "2", "(Tie-2).", "A", "soluble", "form", "of", "the", "Tie-2", "receptor", "can", "be", "detected", "in", "human", "biological", "fluids", "[4].", "The", "Ang/Tie", "system", "tightly", "controls", "the", "endothelial", "phenotype", "during", "*", "Correspondence:", "Alexandra.kautzky-willer@meduniwien.ac.at", "1Department", "of", "Internal", "Medicine", "III,", "Division", "of", "Endocrinology", "and", "Metabolism,", "Unit", "of", "Gender", "Medicine,", "Medical", "University", "of", "Vienna,", "Vienna,", "Austria", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "angiogenesis", "and", "vascular", "inflammation", "in", "a", "unique", "fash-", "ion.", "While", "Ang-1", "has", "an", "agonistic", "effect", "on", "Tie-2", "through", "induction", "of", "autophosphorylation", "of", "the", "receptor", "neces-", "sary", "for", "the", "stabilization", "of", "the", "blood", "vessels", "[5],", "Ang-2", "appears", "to", "have", "an", "antagonistic", "effect.", "It", "acts", "as", "a", "competi-", "tive", "inhibitor", "of", "Ang-1", "for", "Tie-2", "binding,", "thereby", "inhibit-", "ing", "Ang-1/Tie-2", "signaling", "[6].", "Consequently,", "the", "loss", "of", "Tie-2", "signaling", "destabilizes", "the", "endothelium", "and", "facilitates", "the", "angiogenic", "and", "inflammatory", "response", "to", "growth", "factors", "and", "cytokines", "[7].", "Ang-2", "promotes", "also", "VEGF", "induced", "neovascularization.", "Growing", "evidence", "suggests", "an", "involvement", "of", "Ang-2", "and", "its", "receptor", "Tie-2", "in", "the", "pathophysiology", "of", "differ-", "ent", "vascular", "and", "inflammatory", "diseases", "such", "as", "arterio-", "sclerosis", "[8],", "hypertension", "[9],", "idiopathic", "pulmonary", "arterial", "hypertension", "[10],", "chronic", "kidney", "disease", "[11],", "and", "rheumatoid", "arthritis", "[12].", "©", "2011", "Rasul", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

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3,121,618

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[ "Huo", "et", "al.", "BMC", "Neuroscience", "2011,", "12:49", "http://www.biomedcentral.com/1471-2202/12/49", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Dexamethasone", "inhibits", "the", "Nox-dependent", "ROS", "production", "via", "suppression", "of", "MKP-1-dependent", "MAPK", "pathways", "in", "activated", "microglia", "Yingqian", "Huo,", "Parakalan", "Rangarajan,", "Eng-Ang", "Ling", "and", "S", "Thameem", "Dheen*", "Abstract", "Background:", "Nox-2", "(also", "known", "as", "gp91phox),", "a", "subunit", "component", "of", "NADPH", "oxidases,", "generates", "reactive", "oxygen", "species", "(ROS).", "Nox-dependent", "ROS", "generation", "and", "nitric", "oxide", "(NO)", "release", "by", "microglia", "have", "been", "implicated", "in", "a", "variety", "of", "diseases", "in", "the", "central", "nervous", "system.", "Dexamethasone", "(Dex)", "has", "been", "shown", "to", "suppress", "the", "ROS", "production,", "NO", "release", "and", "inflammatory", "reaction", "of", "activated", "microglial", "cells.", "However,", "the", "underlying", "mechanisms", "remain", "unclear.", "Results:", "The", "present", "study", "showed", "that", "the", "increased", "ROS", "production", "and", "NO", "release", "in", "activated", "BV-2", "microglial", "cells", "by", "LPS", "were", "associated", "with", "increased", "expression", "of", "Nox-2", "and", "iNOS.", "Dex", "suppressed", "the", "upregulation", "of", "Nox-2", "and", "iNOS,", "as", "well", "as", "the", "subsequent", "ROS", "production", "and", "NO", "synthesis", "in", "activated", "BV-2", "cells.", "This", "inhibition", "caused", "by", "Dex", "appeared", "to", "be", "mediated", "by", "upregulation", "of", "MAPK", "phosphatase-1", "(MKP-1),", "which", "antagonizes", "the", "activity", "of", "mitogen-activated", "protein", "kinases", "(MAPKs).", "Dex", "induced-suppression", "of", "Nox-2", "and", "-upregulation", "of", "MKP-", "1", "was", "also", "evident", "in", "the", "activated", "microglia", "from", "corpus", "callosum", "of", "postnatal", "rat", "brains.", "The", "overexpression", "of", "MKP-1", "or", "inhibition", "of", "MAPKs", "(by", "specific", "inhibitors", "of", "JNK", "and", "p38", "MAPKs),", "were", "found", "to", "downregulate", "the", "expression", "of", "Nox-2", "and", "iNOS", "and", "thereby", "inhibit", "the", "synthesis", "of", "ROS", "and", "NO", "in", "activated", "BV-2", "cells.", "Moreover,", "Dex", "was", "unable", "to", "suppress", "the", "LPS-induced", "synthesis", "of", "ROS", "and", "NO", "in", "BV-2", "cells", "transfected", "with", "MKP-1", "siRNA.", "On", "the", "other", "hand,", "knockdown", "of", "Nox-2", "in", "BV-2", "cells", "suppressed", "the", "LPS-induced", "ROS", "production", "and", "NO", "release.", "Conclusion:", "In", "conclusion,", "it", "is", "suggested", "that", "downregulation", "of", "Nox-2", "and", "overexpression", "of", "MKP-1", "that", "regulate", "ROS", "and", "NO", "may", "form", "the", "potential", "therapeutic", "strategy", "for", "the", "treatment", "of", "neuroinflammation", "in", "neurodegenerative", "diseases.", "Keywords:", "microglia,", "Nox-2,", "MAPKs,", "ROS,", "dexamethasone", "Background", "An", "inflammatory", "process", "in", "the", "central", "nervous", "system", "(CNS)", "is", "considered", "to", "be", "a", "prominent", "feature", "in", "a", "num-", "ber", "of", "neurodegenerative", "diseases", "and", "is", "mediated", "by", "the", "activated", "microglia,", "the", "resident", "immune", "cells", "of", "the", "CNS.", "The", "microglia", "normally", "respond", "to", "neuronal", "damage", "and", "remove", "the", "damaged", "cells", "by", "phagocytosis", "[1].", "The", "chronic", "activation", "of", "these", "cells", "appears", "to", "cause", "neuronal", "damage", "through", "enhanced", "release", "of", "potentially", "cytotoxic", "molecules", "such", "as", "proinflammatory", "cytokines", "including", "tumor", "necrosis", "factor-a", "(TNF-a)", "and", "*", "Correspondence:", "antstd@nus.edu.sg", "Department", "of", "Anatomy", "Yong", "Loo", "Lin", "school", "of", "Medicine", "National", "University", "of", "Singapore,", "117597,", "Singapore", "interleukin-1b", "(IL-1b),", "nitric", "oxide", "(NO),", "reactive", "oxygen", "intermediates,", "proteinases", "and", "complement", "proteins", "[2-5].", "Moreover,", "microglia-derived", "free", "radicals", "as", "well", "as", "the", "reactive", "reaction", "products,", "hydrogen", "peroxide", "and", "peroxynitrite,", "have", "the", "potential", "to", "harm", "cells", "and", "have", "been", "implicated", "in", "contributing", "to", "oxidative", "damage", "and", "neurodegeneration", "in", "neurological", "diseases", "[6,7].", "There-", "fore,", "suppression", "of", "microglia-mediated", "inflammation", "has", "been", "considered", "as", "an", "important", "strategy", "in", "neurode-", "generative", "disease", "therapy.", "Nicotinamide", "adenine", "dinuceotide", "phosphate", "(NADPH)", "oxidase,", "a", "multi-component", "enzyme", "complex", "is", "an", "impor-", "tant", "source", "of", "reactive", "oxygen", "species", "(ROS)", "in", "respiratory", "oxidative", "stress", "and", "intracellular", "signaling", "pathways", "[8,9].", "©", "2011", "Huo", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

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3,097,780

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[ "Available", "online", "at", "http://www.biij.org/2009/3/e25", "doi:", "10.2349/biij.5.3.e25", "biij", "Biomedical", "Imaging", "and", "Intervention", "Journal", "TECHNICAL", "REPORT", "Third", "party", "EPID", "with", "IGRT", "capability", "retrofitted", "onto", "an", "existing", "medical", "linear", "accelerator", "DO", "Odero*,1,2,", "PhD,", "DS", "Shimm1,", "MD", "1", "Radiation", "Therapy,", "Raleigh", "Regional", "Cancer", "Center,", "Beckley,", "West", "Virginia,", "United", "States", "2", "Radiologic", "Technology,", "Mountain", "State", "University,", "Beckley,", "West", "Virginia", "United", "States", "Received", "30", "October", "2008;", "received", "in", "revised", "form", "4", "June", "2009,", "accepted", "23", "June", "2009", "ABSTRACT", "Radiation", "therapy", "requires", "precision", "to", "avoid", "unintended", "irradiation", "of", "normal", "organs.", "Electronic", "Portal", "Imaging", "Devices", "(EPIDs),", "can", "help", "with", "precise", "patient", "positioning", "for", "accurate", "treatment.", "EPIDs", "are", "now", "bundled", "with", "new", "linear", "accelerators,", "or", "they", "can", "be", "purchased", "from", "the", "Linac", "manufacturer", "for", "retrofit.", "Retrofitting", "a", "third", "party", "EPID", "to", "a", "linear", "accelerator", "can", "pose", "challenges.", "The", "authors", "describe", "a", "relatively", "inexpensive", "third", "party", "CCD", "camera-based", "EPID", "manufactured", "by", "TheraView", "(Cablon", "Medical", "B.V.),", "installed", "onto", "a", "Siemens", "Primus", "linear", "accelerator,", "and", "integrated", "with", "a", "Lantis", "record", "and", "verify", "system,", "an", "Oldelft", "simulator", "with", "Digital", "Therapy", "Imaging", "(DTI)", "unit,", "and", "a", "Philips", "ADAC", "Pinnacle", "treatment", "planning", "system", "(TPS).", "This", "system", "integrates", "well", "with", "existing", "equipment", "and", "its", "software", "can", "process", "DICOM", "images", "from", "other", "sources.", "The", "system", "provides", "a", "complete", "imaging", "system", "that", "eliminates", "the", "need", "for", "separate", "software", "for", "portal", "image", "viewing,", "interpretation,", "analysis,", "archiving,", "image", "guided", "radiation", "therapy", "and", "other", "image", "management", "applications.", "It", "can", "also", "be", "accessed", "remotely", "via", "safe", "VPN", "tunnels.", "TheraView", "EPID", "retrofit", "therefore", "presents", "an", "example", "of", "a", "less", "expensive", "alternative", "to", "linear", "accelerator", "manufacturers’", "proprietary", "EPIDs", "suitable", "for", "implementation", "in", "third", "world", "countries", "radiation", "therapy", "departments", "which", "are", "often", "faced", "with", "limited", "financial", "resources.", "©", "2009", "Biomedical", "Imaging", "and", "Intervention", "Journal.", "All", "rights", "reserved.", "Keywords:", "Portal", "Imaging;", "Simulation;", "EPID;", "IMRT;", "IGRT", "INTRODUCTION", "The", "aim", "of", "external", "beam", "radiotherapy", "is", "to", "deliver", "a", "tumoricidal", "radiation", "dose", "while", "minimizing", "dose", "to", "the", "surrounding", "normal", "tissues,", "which", "requires", "accurate", "and", "reproducible", "field", "placement.", "Verifying", "patient", "position", "and", "fields", "historically", "has", "been", "accomplished", "*", "Corresponding", "author.", "Present", "address:", "Raleigh", "Regional", "Cancer", "Center", "and", "Mountain", "State", "University,", "275", "Dry", "Hill", "Road,", "Beckley", "WV", "25801", "USA.", "E-mail:", "oderodan@netscape.net", "(Dan", "Odero).", "via", "exit", "radiation", "portal", "films.", "Ideally,", "films", "should", "be", "performed", "every", "day", "before", "the", "treatment", "[1-4],", "but", "this", "process", "ties", "up", "departmental", "personnel,", "the", "film", "processor,", "and", "the", "treatment", "machine", "for", "several", "minutes,", "while", "the", "patient", "must", "remain", "immobile", "on", "the", "treatment", "table.", "The", "electronic", "portal", "imaging", "device", "(EPID)", "[5]", "is", "a", "relatively", "new", "development", "in", "portal", "imaging.", "Boyer", "et", "al", "[6]", "and", "Munro", "[7]", "have", "written", "comprehensive", "reviews", "of", "EPIDs,", "and,", "briefly,", "they", "consist", "of", "an", "image", "acquisition", "unit", "fitted", "to", "the", "linear", "accelerator", "(Linac)," ]

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