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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"Cell", "Tissue", "Res", "(2012)", "349:517–525", "DOI", "10.1007/s00441-012-1426-4", "REGULAR", "ARTICLE", "Proliferation", "pattern", "during", "rostrum", "regeneration", "of", "the", "symbiotic", "flatworm", "Paracatenula", "galateia:", "a", "pulse-chase-pulse", "analysis", "Ulrich", "Dirks", "&", "Harald", "R.", "Gruber-Vodicka", "&", "Bernhard", "Egger", "&", "Jörg", "A.", "Ott", "Received:", "22", "November", "2011", "/", "Accepted:", "30", "March", "2012", "/", "Published", "online:", "22", "May", "2012", "#", "The", "Author(s)", "2012.", "This", "article", "is", "published", "with", "open", "access", "at", "Springerlink.com", "Abstract", "The", "remarkable", "totipotent", "stem-cell-based", "regener-", "ation", "capacities", "of", "the", "Platyhelminthes", "have", "brought", "them", "into", "the", "focus", "of", "stem", "cell", "and", "regeneration", "research.", "Although", "selected", "platyhelminth", "groups", "are", "among", "the", "best-studied", "invertebrates,", "our", "data", "provide", "new", "insights", "into", "regenerative", "processes", "in", "the", "most", "basally", "branching", "group", "of", "the", "Platyhel-", "minthes,", "the", "Catenulida.", "The", "mouth-", "and", "gutless", "free-living", "catenulid", "flatworm", "Paracatenula", "galateia", "harbors", "intracellular", "bacterial", "symbionts", "in", "its", "posterior", "body", "region,", "the", "tropho-", "some", "region,", "accounting", "for", "up", "to", "50%", "of", "the", "volume.", "Follow-", "ing", "decapitation", "of", "this", "flatworm,", "we", "have", "analyzed", "the", "behavior", "of", "the", "amputated", "fragments", "and", "any", "anterior", "and", "posterior", "regeneration.", "Using", "an", "EdU-pulse-chase/BrdU-pulse", "thymidine", "analog", "double-labeling", "approach", "combined", "with", "immunohistochemistry,", "we", "show", "that", "neoblasts", "are", "the", "main", "drivers", "of", "the", "regeneration", "processes.", "During", "anterior", "(rostrum)", "regeneration,", "EdU-pulse-chase-labeled", "cells", "aggregate", "inside", "the", "regenerating", "rostrum,", "whereas", "BrdU", "pulse-labeling", "before", "fixation", "indicates", "clusters", "of", "S-phase", "neoblasts", "at", "the", "same", "position.", "In", "parallel,", "serotonergic", "nerves", "reorganize", "and", "the", "U.", "Dirks", "(*)", ":", "H.", "R.", "Gruber-Vodicka", ":", "J.", "A.", "Ott", "Department", "of", "Marine", "Biology,", "University", "of", "Vienna,", "Althanstrasse", "14,", "1090", "Vienna,", "Austria", "e-mail:", "Uli.Dirks@gmx.de", "B.", "Egger", "Ultrastructural", "Research", "and", "Evolutionary", "Biology,", "Institute", "of", "Zoology,", "University", "of", "Innsbruck,", "Technikerstrasse", "25,", "6020", "Innsbruck,", "Austria", "B.", "Egger", "Department", "of", "Genetics,", "Evolution", "and", "Environment,", "University", "College", "London,", "Gower", "Street,", "Darwin", "Building,", "WC1E", "6BT", "London,", "UK", "brain", "regenerates.", "In", "completely", "regenerated", "animals,", "the", "orig-", "inal", "condition", "with", "S-phase", "neoblasts", "being", "restricted", "to", "the", "body", "region", "posterior", "to", "the", "brain", "is", "restored.", "In", "contrast,", "no", "posterior", "regeneration", "or", "growth", "of", "the", "trophosome", "region", "in", "anterior", "fragments", "cut", "a", "short", "distance", "posterior", "to", "the", "brain", "has", "been", "observed.", "Our", "data", "thus", "reveal", "interesting", "aspects", "of", "the", "cellular", "processes", "underlying", "the", "regeneration", "of", "the", "emerging", "catenulid-bacteria", "symbiosis", "model", "P.", "galateia", "and", "show", "that", "a", "neoblast", "stem", "cell", "system", "is", "indeed", "a", "plesiomorphic", "feature", "of", "basal", "platyhelminths.", "Keywords", "Morphallaxis", ".", "Epimorphosis", ".", "Bacteriocyte", ".", "Paratomy", ".", "Blastema", ".", "Neoblast", "Introduction", "From", "the", "human", "point", 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"Institute,", "New", "York", "University", "School", "of", "Medicine,", "550", "First", "Avenue,", "New", "York,", "NY", "10016", "Corresponding", "author:", "Naoko", "Tanese,", "tanesn01@med.nyu.edu", "Received:", "14", "Oct", "2008", "Revisions", "requested:", "4", "Nov", "2008", "Revisions", "received:", "31", "May", "2009", "Accepted:", "30", "Jun", "2009", "Published:", "30", "Jun", "2009", "Breast", "Cancer", "Research", "2009,", "11:R42", "(doi:10.1186/bcr2329)", "This", "article", "is", "online", "at:", "http://breast-cancer-research.com/content/11/3/R42", "©", "2009", "Lieberthal", "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", "Introduction", "Heterochromatin", "protein", "1", "(HP1)", "associates", "with", "chromatin", "by", "binding", "to", "histone", "H3", "and", "contributes", "to", "gene", "silencing.", "There", "are", "three", "isoforms", "of", "HP1", "in", "mammals:", "HP1α,", "β,", "and", "γ.", "Studies", "have", "shown", "that", "the", "level", "of", "HP1α", "is", "reduced", "in", "invasive", "human", "breast", "cancer", "cell", "lines", "such", "as", "MDA-MB-231", "and", "HS578T", "compared", "with", "non-invasive", "cell", "lines", "such", "as", "MCF7", "and", "T47D.", "It", "is", "hypothesized", "that", "reduced", "HP1α", "expression", "may", "lead", "to", "impaired", "epigenetic", "silencing", "of", "genes", "that", "are", "important", "in", "the", "acquisition", "of", "an", "invasive", "phenotype.", "We", "set", "out", "to", "determine", "whether", "reduced", "expression", "of", "HP1α", "in", "invasive", "breast", "cancer", "cell", "lines", "occurs", "at", "the", "level", "of", "transcription.", "Methods", "We", "used", "transient", "transfection", "assays", "to", "investigate", "the", "mechanism", "of", "differential", "transcriptional", "activity", "of", "the", "human", "HP1α", "gene", "promoter", "in", "different", "cell", "lines.", "Mutational", "analysis", "of", "putative", "transcription", "factor", "binding", "sites", "in", "an", "HP1α", "gene", "reporter", "construct", "was", "performed", "to", "identify", "transcription", "factors", "responsible", "for", "the", "differential", "activity.", "SiRNA-mediated", "knockdown", "and", "chromatin", "immunoprecipitation", "experiments", "Introduction", "Heterochromatin", "protein", "1", "(HP1)", "was", "first", "identified", "in", "Dro-", "sophila", "as", "a", "non-histone", "component", "of", "chromatin", "[1].", "Muta-", "tions", "in", "the", "HP1", "gene", "resulted", "in", "suppression", "of", "position-", "effect", "variegation,", "a", "result", "that", "implicated", "HP1", "in", "chromatin", "structure", "and", "gene", "expression", "[2].", "Mutation", "of", "the", "gene", "encoding", "HP1", "in", "Drosophila", "resulted", "in", "larval", "lethality", "[3].", "Examination", "of", "HP1", "mutant", "embryos", "revealed", "defects", "in", "chro-", "mosome", "segregation", "and", "telomere", "maintenance", "[4,5].", "There-", "fore,", "HP1", "is", "thought", "to", "play", "an", "essential", "role", "in", "heterochromatin-dependent", "processes", "in", "Drosophila.", "HP1", "were", "performed", "to", "determine", "the", "role", "of", "a", "specific", "transcription", "factor", "in", "regulating", "the", "HP1α", "gene.", "Results", "The", "transcription", "factor", "yin", "yang", "1", "(YY1)", "was", "found", "to", "play", "a", "role", "in", "differential", "transcriptional", "activity", "of", "the", "HP1α", "gene.", "Examination", "of", "the", "YY1", "protein", "and", "mRNA", "levels", "revealed", "that", "both", "were", "reduced", "in", "the", "invasive", "cell", "line", "HS578T", "compared", "with", "MCF7", "cells.", "YY1", "knockdown", "in", "MCF7", "cells", "resulted", "in", "a", "decreased", "level", "of", "HP1α", "mRNA,", "indicating", "that", "YY1", "positively", "regulates", "HP1α", "expression.", "Chromatin", "immunoprecipitation", "experiments", "verified", "YY1", "occupancy", "at", "the", "HP1α", "gene", "promoter", "in", "MCF7", "cells", "but", "not", "HS578T", "cells.", "Overexpression", "of", "YY1", "in", "HS578T", "cells", "decreased", "cell", "migration", "in", "a", "manner", "independent", "of", "HP1α", "overexpression.", "Conclusions", "Our", "data", "suggests", "that", "a", "reduction", "of", "YY1", "expression", "in", "breast", "cancer", "cells", "could", "contribute", "to", "the", "acquisition", "of", "an", "invasive", "phenotype", "through", "increased", "cell", "migration", "as", "well", "as", "by", "reduced", "expression", "of", "HP1α.", "can", "also", "be", "found", "in", "certain", "euchromatic", "loci,", "implying", "its", "role", "in", "euchromatic", "regions", "[6,7].", "HP1", "homologues", "have", "been", "identified", "in", "a", "variety", "of", "organ-", "isms", "including", "yeast,", "nematodes,", "insects,", "chickens,", "frogs,", "and", "mammals", "[8].", "There", "are", "three", "HP1", "isoforms", "in", "mammals:", "HP1α,", "β", "and", "γ", "[9,10].", "Each", "HP1", "isoform", "has", "a", "different", "chro-", "mosomal", "distribution.", "HP1α", "is", "located", "mainly", "in", "heterochro-", "matic", "regions,", "HP1β", "is", "found", "in", "both", "heterochromatic", "and", "euchromatic", "regions,", "and", "HP1γ", "is", "located", "almost", "exclusively", "in", "euchromatic", "regions", "[11-13].", "The", "localization", "of", "HP1", "isoforms", "to", "different", "regions", "of", "chromatin", "implies", "that", "each", "isoform", "BSA:", "bovine", "serum", "albumin;", "CD:", "chromodomain;", "ChIP:", "chromatin", "immunoprecipitation;", "CSD:", "chromoshadow", "domain;", "DMEM:", "Dulbecco's", "Modified", "Eagle", "Medium;", "HNRPA1:", "heterogeneous", "nuclear", "ribonucleoprotein", "A1;", "HP1:", "heterochromatin", "protein", "1;", "NRF-1:", "nuclear", "respiratory", "factor-1;", "PBS:", "phosphate-buffered", "saline;", "RT-PCR:", "reverse", "transcription", "polymerase", "chain", "reaction;", "YY1:", "ying", "yang", "1.", "Page", "1", "of", "11", "(page", "number", "not", "for", "citation", "purposes)" ]	[ 0, 0, 0, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 9, 9, 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, 6, 6, 6, 6, 6, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 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, 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, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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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1032 ], [ 415, 1020, 452, 1032 ], [ 454, 1020, 474, 1032 ], [ 477, 1020, 485, 1032 ], [ 487, 1020, 515, 1032 ], [ 517, 1020, 557, 1032 ], [ 560, 1020, 590, 1032 ], [ 716, 1058, 741, 1070 ], [ 744, 1058, 751, 1070 ], [ 753, 1058, 763, 1070 ], [ 765, 1058, 772, 1070 ], [ 605, 1072, 630, 1082 ], [ 632, 1072, 664, 1082 ], [ 667, 1072, 681, 1082 ], [ 683, 1072, 694, 1082 ], [ 697, 1072, 727, 1082 ], [ 729, 1072, 772, 1082 ] ]	[ "Available", "online", "http://arthritis-research.com/content/11/3/114", "Editorial", "Stress", "of", "different", "types", "increases", "the", "proinflammatory", "load", "in", "rheumatoid", "arthritis", "Rainer", "H", "Straub1", "and", "Joachim", "R", "Kalden2", "1Laboratory", "of", "Experimental", "Rheumatology", "and", "Neuroendocrino-Immunology,", "Division", "of", "Rheumatology,", "Department", "of", "Internal", "Medicine", "I,", "University", "Hospital,", "93042", "Regensburg,", "Germany", "2Department", "of", "Medicine", "3,", "University", "of", "Erlangen–Nuremberg,", "Nikolaus-Fiebiger-Center,", "91054", "Erlangen,", "Germany", "Corresponding", "author:", "Rainer", "H", "Straub,", "rainer.straub@klinik.uni-regensburg.de", "Published:", "17", "June", "2009", "This", "article", "is", "online", "at", "http://arthritis-research.com/content/11/3/114", "©", "2009", "BioMed", "Central", "Ltd", "See", "related", "research", "by", "Edwards", "et", "al.,", "http://arthritis-research.com/content/11/3/R61", "Arthritis", "Research", "&", "Therapy", "2009,", "11:114", "(doi:10.1186/ar2712)", "Abstract", "Stress", "in", "patients", "with", "chronic", "inflammatory", "diseases", "such", "as", "rheumatoid", "arthritis", "(RA)", "stimulates", "proinflammatory", "mechanisms", "due", "to", "the", "defect", "of", "stress", "response", "systems", "(for", "example,", "the", "sympathetic", "nervous", "system", "and", "the", "hypothalamic–pituitary–", "adrenal", "axis).", "Among", "other", "mechanisms,", "the", "loss", "of", "sympathetic", "nerve", "fibers", "in", "inflamed", "tissue", "and", "inadequate", "cortisol", "secretion", "in", "relation", "to", "inflammation", "lead", "to", "an", "enhanced", "proinflammatory", "load", "in", "RA.", "Stress", "and", "the", "subsequent", "stimulation", "of", "inflammation", "(systemic", "and", "local)", "lead", "to", "increased", "sensitization", "of", "pain", "and", "further", "defects", "of", "stress", "response", "systems", "(vicious", "cycle", "of", "stress,", "pain,", "and", "inflammation).", "In", "1937", "Hans", "Selye", "called", "the", "activation", "of", "stress", "systems", "an", "‘alarm", "reaction’,", "which", "is", "the", "reaction", "of", "an", "organism", "‘when", "first", "confronted", "with", "a", "stimulus", "to", "which", "it", "is", "quantitatively", "or", "qualitatively", "not", "adapted’.", "Until", "the", "beginning", "of", "the", "1980s,", "the", "stress", "systems", "including", "the", "sympathetic", "nervous", "system", "(SNS)", "and", "the", "hypothalamic–pituitary–adrenal", "axis", "were", "thought", "to", "play", "a", "proinflammatory", "role", "by", "supporting", "the", "immune", "response.", "This", "view", "was", "markedly", "changed", "in", "the", "years", "thereafter,", "when", "targeted", "experiments", "with", "specific", "immune", "cells", "involving", "hormones", "of", "the", "SNS", "and", "hypo-", "thalamic–pituitary–adrenal", "axis", "were", "carried", "out", "using", "cell", "culture.", "These", "results", "demonstrated", "that", "noradrenaline", "(via", "β2-adrenoceptors", "at", "10–6", "M)", "and", "cortisol", "(via", "glucocorticoid", "receptor", "α)", "exert", "many", "anti-inflammatory", "effects.", "Today", "we", "know", "that", "both", "proinflammatory", "and", "anti-inflammatory", "effects", "can", "appear", "under", "stressful", "conditions,", "which", "depend", "on", "the", "duration", "of", "the", "stress,", "the", "intensity", "of", "stress,", "the", "perception", "of", "stress", "(whether", "positive", "or", "negative),", "the", "environmental", "milieu", "within", "the", "body", "of", "the", "stressed", "person", "(whether", "acutely", "ill", "or", "chronically", "ill),", "and", "the", "time", "point", "of", "stress", "in", "relation", "to", "the", "outbreak", "of", "a", "chronic", "inflammatory", "disease", "(whether", "before", "outbreak", "or", "in", "later", "phases", "of", "the", "symptomatic", "disease).", "Knowledge", "in", "the", "stress", "field", "steadily", "increases,", "and", "today", "we", "can", "say", "that", "patients", "with", "chronic", "inflammatory", "diseases", "such", "as", "rheumatoid", "arthritis", "(RA)", "show", "abnormal", "stress", "responses", "leading", "to", "proinflammatory", "consequences.", "Stress", "can", "be", "induced", "by", "pain", "tests,", "which", "was", "recently", "demonstrated", "by", "Edwards", "and", "colleagues", "[1].", "In", "this", "study", "the", "authors", "used", "several", "pain", "tests,", "such", "as", "the", "pressure", "pain", "threshold,", "the", "heat", "pain", "threshold,", "and", "the", "cold", "pressor", "task.", "The", "patients", "with", "RA,", "compared", "with", "healthy", "control", "individuals,", "had", "lower", "mechanical", "pain", "thresholds,", "lower", "heat", "pain", "thresholds,", "and", "lower", "cold", "pain", "tolerance,", "all", "of", "which", "are", "expected", "in", "a", "situation", "with", "peripheral", "sensitization", "to", "noxious", "stimuli", "[2].", "Indeed,", "peripheral", "sensitization", "has", "been", "demonstrated", "several", "times", "in", "RA", "patients", "[2].", "The", "important", "and", "original", "aspect", "of", "the", "work", "of", "Edwards", "and", "colleagues", "is", "the", "fact", "that", "pain", "testing", "increased", "serum", "levels", "of", "TNF,", "which", "was", "not", "demonstrated", "in", "healthy", "control", "individuals.", "The", "increase", "was", "slow", "over", "the", "entire", "observation", "time", "without", "decline.", "A", "similar", "trend", "was", "observed", "for", "serum", "IL-6", "[1].", "This", "effect", "is", "interpreted", "as", "an", "unwanted", "deleterious", "effect", "that", "can", "shape", "the", "long-term", "symptomatology", "in", "RA.", "Edwards", "and", "colleagues’", "paper", "adds", "nicely", "to", "existing", "literature", "where,", "after", "stress", "testing,", "other", "groups", "demon-", "strated", "a", "very", "similar", "effect", "on", "serum", "or", "supernatant", "levels", "(in", "cell", "culture", "experiments)", "of", "proinflammatory", "cytokines", "(Table", "1).", "Since", "stress", "in", "healthy", "subjects", "can", "lead", "to", "an", "increase", "of", "serum", "cytokines", "[3],", "a", "comparison", "of", "patients", "with", "RA", "and", "healthy", "control", "individuals", "is", "mandatory.", "The", "important", "aspect", "in", "the", "studies", "demonstrated", "in", "Table", "1", "is", "the", "fact", "that", "respective", "control", "groups", "did", "not", 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473, 1018 ], [ 479, 1005, 492, 1018 ], [ 498, 1005, 534, 1018 ], [ 541, 1005, 576, 1018 ], [ 582, 1005, 592, 1018 ], [ 598, 1005, 722, 1018 ], [ 728, 1005, 769, 1018 ], [ 80, 1047, 105, 1059 ], [ 108, 1047, 129, 1059 ], [ 134, 1047, 137, 1059 ], [ 142, 1047, 225, 1059 ], [ 422, 1047, 428, 1059 ], [ 544, 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 ] ]	[ "Evidence", "for", "a", "Developmental", "Role", "for", "TLR4", "in", "Learning", "and", "Memory", "Eitan", "Okun1,", "Boaz", "Barak2,", "Ravit", "Saada-Madar1,", "Sarah", "M.", "Rothman3,", "Kathleen", "J.", "Griffioen3,", "Nicholas", "Roberts3,", "Kamilah", "Castro3,", "Mohamed", "R.", "Mughal3,", "Mario", "A.", "Pita3,", "Alexis", "M.", "Stranahan4,", "Thiruma", "V.", "Arumugam5,", "Mark", "P.", "Mattson3,6", "1", "The", "Mina", "and", "Everard", "Goodman", "Faculty", "of", "Life", "Sciences,", "The", "Leslie", "and", "Susan", "Gonda", "Multidisciplinary", "Brain", "Research", "Center,", "Bar-Ilan", "University,", "Ramat", "Gan,", "Israel,", "2", "Department", "of", "Neurobiology,", "Life", "Sciences", "Faculty", "and", "the", "Sagol", "School", "of", "Neuroscience,", "Tel", "Aviv", "University,", "Tel", "Aviv,", "Israel,", "3", "Laboratory", "of", "Neurosciences,", "National", "Institute", "on", "Aging", "Intramural", "Research", "Program,", "Baltimore,", "Maryland,", "United", "States", "of", "America,", "4", "Department", "of", "Physiology,", "Georgia", "Health", "Sciences", "University,", "Augusta,", "Georgia,", "United", "States", "of", "America,", "5", "School", "of", "Biomedical", "Sciences,", "The", "University", "of", "Queensland,", "Queensland,", "Australia,", "6", "Department", "of", "Neuroscience,", "Johns", "Hopkins", "University", "School", "of", "Medicine,", "Baltimore,", "Maryland,", "United", "States", "of", "America", "Abstract", "Toll-like", "receptors", "(TLRs)", "play", "essential", "roles", "in", "innate", "immunity", "and", "increasing", "evidence", "indicates", "that", "these", "receptors", "are", "expressed", "in", "neurons,", "astrocytes", "and", "microglia", "in", "the", "brain", "where", "they", "mediate", "responses", "to", "infection,", "stress", "and", "injury.", "Very", "little", "is", "known", "about", "the", "roles", "of", "TLRs", "in", "cognition.", "To", "test", "the", "hypothesis", "that", "TLR4", "has", "a", "role", "in", "hippocampus-", "dependent", "spatial", "learning", "and", "memory,", "we", "used", "mice", "deficient", "for", "TLR4", "and", "mice", "receiving", "chronic", "TLR4", "antagonist", "infusion", "to", "the", "lateral", "ventricles", "in", "the", "brain.", "We", "found", "that", "developmental", "TLR4", "deficiency", "enhances", "spatial", "reference", "memory", "acquisition", "and", "memory", "retention,", "impairs", "contextual", "fear-learning", "and", "enhances", "motor", "functions,", "traits", "that", "were", "correlated", "with", "CREB", "up-regulation", "in", "the", "hippocampus.", "TLR4", "antagonist", "infusion", "into", "the", "cerebral", "ventricles", "of", "adult", "mice", "did", "not", "affect", "cognitive", "behavior,", "but", "instead", "affected", "anxiety", "responses.", "Our", "findings", "indicate", "a", "developmental", "role", "for", "TLR4", "in", "shaping", "spatial", "reference", "memory,", "and", "fear", "learning", "and", "memory.", "Moreover,", "we", "show", "that", "central", "TLR4", "inhibition", "using", "a", "TLR4", "antagonist", "has", "no", "discernible", "physiological", "role", "in", "regulating", "spatial", "and", "contextual", "hippocampus-dependent", "cognitive", "behavior.", "Citation:", "Okun", "E,", "Barak", "B,", "Saada-Madar", "R,", "Rothman", "SM,", "Griffioen", "KJ,", "et", "al.", "(2012)", "Evidence", "for", "a", "Developmental", "Role", "for", "TLR4", "in", "Learning", "and", "Memory.", "PLoS", "ONE", "7(10):", "e47522.", "doi:10.1371/journal.pone.0047522", "Editor:", "Lena", "Alexopoulou,", "Centre", "d’Immunologie", "de", "Marseille-Luminy,", "CNRS-Inserm,", "France", "Received", "May", "9,", "2012;", "Accepted", "September", "12,", "2012;", "Published", "October", "11,", "2012", "This", "is", "an", "open-access", "article,", "free", "of", "all", "copyright,", "and", "may", "be", "freely", "reproduced,", "distributed,", "transmitted,", "modified,", "built", "upon,", "or", "otherwise", "used", "by", "anyone", "for", "any", "lawful", "purpose.", "The", "work", "is", "made", "available", "under", "the", "Creative", "Commons", "CC0", "public", "domain", "dedication.", "Funding:", "This", "study", "was", "supported", "in", "part", "by", "the", "Intramural", "Research", "Program", "of", "the", "National", "Institute", "on", "Aging", "and", "in", "part", "by", "the", "Gonda", "Multidisciplinary", "Center", "for", "Brain", "Research", "and", "the", "Mina", "and", "Everard", "Goodman", "Faculty", "of", "Life", "Sciences,", "Bar", "Ilan", "University.", "No", "additional", "external", "funding", "was", "received", "for", "this", "study.", "The", "funders", "had", "no", "role", "in", "study", "design,", "data", "collection", "and", "analysis,", "decision", "to", "publish,", "or", "preparation", "of", "the", "manuscript.", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "", "E-mail:", "eitan.okun@biu.ac.il", "Introduction", "Toll", "like", "receptors", "(TLRs)", "are", "type-I", "trans-membrane", "receptors", "that", "are", "best", "known", "as", "sensors", "of", "microbe-associated", "molecular", "patterns", "(MAMPs)", "by", "cells", "of", "the", "innate", "immune", "system", "[1].", "In", "addition,", "TLRs", "recognize", "damage-associated", "molecular", "patterns", "(DAMPs),", "also", "termed", "‘endogenous", "ligands’,", "generated", "in", "response", "to", "traumatic", "tissue", "injury", "or", "as", "a", "by-product", "of", "inflammation", "[2].", "Binding", "of", "MAMPs", "or", "DAMPs", "to", "TLRs", "typically", "activates", "signaling", "cascades", "that", "result", "in", "production", "of", "inflammatory", "cytokines/chemokines", "by", "effector", "cells,", "and", "may", "also", "stimulate", "a", "peripheral", "immune", "response", "[3].", "TLR4,", "a", "widely", "studied", "TLR,", "is", "activated", "by", "bacterial", "lipopolysaccharide", "(LPS),", "a", "constituent", "of", "the", "outer", "membrane", "of", "gram-negative", "bacteria.", "Central", "activation", "of", "TLR4", "by", "LPS", "has", "been", "thoroughly", "studied", "and", "was", "shown", "to", "reduce", "hippocampal", "pyramidal", "neuron", "dendrite", "length", "and", "to", "impair", "hippocampal-dependent", "spatial", "reference", "memory", "in", "an", "inflammation-dependent", "manner", "implying", "a", "neuroinflammatory", "role", "for", "TLR4", "following", "activation", "with", "bacterial-derived", "ligands", "[4,5].", "Increasing", "evidence", "indicates", "that", "TLRs", "located", "in", "the", "central", "nervous", "system", "are", "involved", "in", "developmental", "and", "adult", "neuroplasticity", "even", "in", "the", "absence", "of", "activation", "by", "infectious", "agents", "or", "tissue", "damage", "[6].", "TLR3", "for", "example,", "is", "a", "negative", "regulator", "of", "embryonic", "neural", "progenitor", "cell", "(NPC)", "proliferation", "[7].", "TLR2", "and", "TLR4", "are", "expressed", "in", "adult", "NPCs", "[8]", "and", "have", "distinct", "and", "opposing", "functions", "in", "NPC", "proliferation", "and", "differentiation;", "TLR2", "deficiency", "impairs", "hippocampal", "neurogen-", "esis,", "whereas", "TLR4", "deficiency", "enhances", "proliferation", "and", "neuronal", "differentiation", "[8].", "Further,", "TLRs", "2,", "3", "and", "4", "are", "expressed", "in", "hippocampal", "neurons", "[9],", "and", "we", "showed", "recently", "that", "TLR3-deficient", "mice", "exhibit", "enhanced", "hippocampus-de-", "pendent", "working", "(but", "not", "reference)", "memory,", "coupled", "with", "extended", "retention", "of", "spatial", "reference", "memory", "[10].", "In", "contrast,", "TLR3-deficient", "mice", "demonstrate", "impaired", "amygdala-", "and", "anxiety-related", "behavior", "[10].", "Because", "TLR3", "is", "involved", "in", "neurogenesis,", "NPC", "proliferation", "and", "cognitive", "learning", "and", "memory,", "we", "sought", "to", "determine", "the", "involvement", "of", "TLR4", "in", "these", "processes.", "The", "hippocampus,", "which", "possesses", "a", "well-defined", "neuroanato-", "my,", "is", "involved", "in", "various", "types", "of", "learning,", "which", "are", "governed", "by", "different", "strategies", "[11,12].", "While", "TLR4", "is", "involved", "in", "CNS", "plasticity", "processes", "such", "as", "NPC", "proliferation,", "the", "impact", "of", "TLR4s", "on", 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"Robert", "Galloway", "and", "Marie", "Healy", "BioMed", "Central", "Open", "Access", "Address:", "Department", "of", "Anaesthesia", "and", "Intensive", "care,", "The", "Royal", "London", "Hospital,", "Whitechapel,", "E1", "1BB,", "UK", "Email:", "Peter", "B", "Sherren", "-", "Petersherren@gmail.com;", "Robert", "Galloway", "-", "drrobgalloway@gmail.com;", "Marie", "Healy", "-", "marie.healy@bartsandthelondon.nhs.uk", "*", "Corresponding", "author", "Published:", "15", "December", "2009", "Scandinavian", "Journal", "of", "Trauma,", "Resuscitation", "and", "Emergency", "Medicine", "2009,", "17:64", "doi:10.1186/1757-7241-", "Accepted:", "15", "December", "2009", "17-64", "Received:", "9", "November", "2009", "This", "article", "is", "available", "from:", "http://www.sjtrem.com/content/17/1/64", "©", "2009", "Sherren", "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:", "Blunt", "Traumatic", "Pericardial", "Rupture", "(BTPR)", "with", "resulting", "cardiac", "herniation", "following", "chest", "trauma", "is", "an", "unusual", "and", "often", "fatal", "condition.", "Although", "there", "has", "been", "a", "multitude", "of", "case", "reports", "of", "this", "condition", "in", "past", "literature,", "the", "recurring", "theme", "is", "that", "of", "a", "missed", "injury.", "Its", "occurrence", "in", "severe", "blunt", "trauma", "is", "in", "the", "order", "of", "0.4%.", "It", "is", "an", "injury", "that", "frequently", "results", "in", "pre/early", "hospital", "death", "and", "diagnosis", "at", "autopsy,", "probably", "owing", "to", "a", "combination", "of", "diagnostic", "difficulties,", "lack", "of", "familiarity", "and", "associated", "polytrauma.", "Of", "the", "patients", "who", "survive", "to", "hospital", "attendance,", "the", "mortality", "rate", "is", "in", "the", "order", "of", "57-64%.", "Methods:", "We", "present", "two", "survivors", "of", "BTPR", "and", "cardiac", "herniation,", "one", "with", "a", "delayed", "penetrating", "cardiac", "injury", "secondary", "to", "rib", "fractures.", "With", "these", "two", "cases", "and", "literature", "review,", "we", "hope", "to", "provide", "a", "greater", "awareness", "of", "this", "injury", "Conclusion:", "BTPR", "and", "cardiac", "herniation", "is", "a", "complex", "and", "often", "fatal", "injury", "that", "usually", "presents", "under", "the", "umbrella", "of", "polytrauma.", "Clinicians", "must", "maintain", "a", "high", "index", "of", "suspicion", "for", "BTPR", "but,", "even", "then,", "the", "diagnosis", "is", "fraught", "with", "difficulty.", "In", "blunt", "chest", "trauma,", "patients", "should", "be", "considered", "high", "risk", "for", "BTPR", "when", "presenting", "with:", "Cardiovascular", "instability", "with", "no", "obvious", "cause", "Prominent", "or", "displaced", "cardiac", "silhouette", "and", "asymmetrical", "large", "volume", "pneumopericardium", "Potentially,", "with", "increasing", "awareness", "of", "the", "injury", "and", "improved", "use", "and", "availability", "of", "imaging", "modalities,", "the", "survival", "rates", "will", "improve", "and", "cardiac", "Herniation", "could", "even", "be", "considered", "the", "5th", "H", "of", "reversible", "causes", "of", "blunt", "traumatic", "PEA", "arrest.", "Background", "Cardiac", "herniation", "is", "a", "significant", "and", "potentially", "fatal", "complication", "of", "BTPR.", "This", "is", "by", "no", "means", "a", "new", "problem", "[1,2]", "and", "its", "occurrence", "in", "severe", "blunt", "trauma", "is", "in", "the", "order", "of", "0.4%", "[3,4].", "Despite", "literature", "experience", "dating", "back", "to", "1864", "[5],", "it", "is", "an", "injury", "that", "frequently", "results", "in", "pre/early", "hospital", "death", "and", "diagnosis", "at", "autopsy,", "proba-", "bly", "owing", "to", "a", "combination", "of", "diagnostic", "difficulties,", "lack", "of", "familiarity", "and", "associated", "polytrauma", "[3,6].", "Of", "those", "who", "make", "it", "to", "hospital,", "and", "are", "later", "diagnosed", "with", "Page", "1", "of", "7", "(page", "number", "not", "for", "citation", "purposes)" ]	[ 0, 0, 0, 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, 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, 13, 13, 13, 13, 7, 7, 7, 7, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 7, 7, 7, 7, 1, 1, 1, 1, 1, 1, 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, 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"Research", "Center,", "Louisiana", "State", "University", "System,", "Baton", "Rouge,", "Louisiana,", "United", "States", "of", "America,", "2", "Department", "of", "Cardiology,", "Ochsner", "Health", "System,", "New", "Orleans,", "Louisiana,", "United", "States", "of", "America,", "3", "Department", "of", "Exercise", "Science,", "Arnold", "School", "of", "Public", "Health,", "University", "of", "South", "Carolina,", "Columbia,", "South", "Carolina,", "United", "States", "of", "America,", "4", "The", "University", "of", "North", "Texas,", "Denton,", "Texas,", "United", "States", "of", "America", "Abstract", "Background:", "Decreased", "heart", "rate", "variability", "(HRV)", "is", "associated", "with", "a", "higher", "risk", "of", "mortality.", "Overall,", "postmenopausal", "women", "have", "lower", "levels", "of", "HRV", "than", "premenopausal", "women,", "which", "may", "be", "additionally", "complicated", "by", "lifestyle", "related", "behaviors", "such", "as", "physical", "inactivity", "and", "obesity.", "Though", "cardiorespiratory", "exercise", "training", "increases", "HRV,", "little", "is", "known", "regarding", "the", "exercise", "dose", "necessary", "to", "promote", "this", "improvement.", "Methodology/Principal", "Findings:", "Our", "primary", "aim", "was", "to", "measure", "HRV", "in", "post-menopausal", "women", "following", "6-months", "of", "exercise", "training.", "We", "examined", "supine", "resting", "HRV", "in", "373", "post-menopausal", "women", "(45–75", "y)", "after", "6-months", "of", "randomly", "assigned", "and", "double-blinded", "administered", "exercise", "training", "exercise", "training", "at", "50%,", "100%", "and", "150%", "of", "the", "NIH", "Consensus", "Development", "Panel’s", "recommended", "minimal", "physical", "activity", "level.", "This", "corresponded", "to", "4,", "8,", "or", "12", "kcal/kg", "per", "week", "(KKW)", "of", "energy", "expenditure.", "At", "baseline,", "we", "observed", "no", "significant", "differences", "in", "HRV", "or", "hormone", "replacement", "use", "between", "treatment", "groups.", "However,", "we", "did", "observe", "that", "Caucasian", "women", "and", "those", "taking", "antidepressant", "medications", "had", "lower", "levels", "of", "baseline", "HRV.", "After", "6-months", "of", "exercise", "intervention,", "we", "observed", "a", "dose", "dependent", "increase", "in", "all", "parasympathetically", "derived", "time", "and", "frequency", "domain", "measurements", "across", "exercise", "groups", "after", "adjustment", "for", "age,", "ethnicity,", "antidepressants,", "and", "baseline", "rMSSD", "(all,", "P,0.001).", "For", "example,", "the", "parasympathetic", "index", "rMSSD", "was", "greater", "than", "control", "(23.1961.0)", "for", "the", "4-KKW", "(25.9860.8;", "P", "=", "0.14),", "8-KKW", "(27.6661.0;", "P,0.05),", "and", "12-KKW", "(27.4060.0;", "P,0.05)", "groups", "at", "follow-up.", "Conclusions/Significance:", "Moderate", "intensity", "exercise", "training", "exercise", "is", "sufficient", "to", "improve", "HRV", "in", "previously", "sedentary", "postmenopausal", "women", "in", "a", "dose-dependent", "manner,", "as", "4-KKW", "is", "insufficient", "to", "improve", "parasympathetic", "indices", "of", "HRV,", "while", "12-KKW", "conferred", "no", "greater", "improvement", "than", "8-KKW.", "Trial", "Registration:", "Clinicaltrials.gov", "NCT", "00011193", "Citation:", "Earnest", "CP,", "Lavie", "CJ,", "Blair", "SN,", "Church", "TS", "(2008)", "Heart", "Rate", "Variability", "Characteristics", "in", "Sedentary", "Postmenopausal", "Women", "Following", "Six", "Months", "of", "Exercise", "Training:", "The", "DREW", "Study.", "PLoS", "ONE", "3(6):", "e2288.", "doi:10.1371/journal.pone.0002288", "Editor:", "Jose", "AL", "Calbet,", "University", "of", "Las", "Palmas", "de", "Gran", "Canaria,", "Spain", "Received", "March", "4,", "2008;", "Accepted", "April", "16,", "2008;", "Published", "June", "4,", "2008", "Copyright:", "2008", "Earnest", "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", "DREW", "study", "as", "financially", "supported", "by", "in", "part", "by", "American", "Heart", "Association", "Texas", "Affiliate", "award", "02651404;", "the", "National", "Institutes", "of", "Health", "grant", "HL-66262", "and", "an", "exercise", "equipment", "donation", "from", "Life", "Fitness", "(Schiller", "Park,", "IL).", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "", "E-mail:", "conrad.earnest@pbrc.edu", "Introduction", "Menopause", "represents", "a", "key", "transition", "period", "in", "a", "woman’s", "health.", "A", "fundamental", "etiology", "associated", "with", "menopause", "is", "the", "intricate", "link", "between", "estrogen", "metabolism", "and", "the", "autonomic", "nervous", "system.", "Autonomic", "nervous", "system", "balance", "can", "be", "assessed", "non-invasively", "via", "the", "use", "of", "heart", "rate", "variability", "(HRV).", "While", "a", "thorough", "review", "of", "HRV", "can", "be", "obtained", "elsewhere,[1]", "HRV", "is", "clinically", "useful", "because", "reduced", "HRV", "is", "associated", "with", "an", "increased", "risk", "of", "CV", "disease,", "type", "II", "diabetes", "and", "insulin", "resistance", "and", "has", "been", "shown", "to", "be", "reduced", "in", "postmenopausal", "women", "as", "compared", "with", "premenopausal", "women", "[2,3,4,5].", "Equally,", "the", "assessment", "of", "HRV", "in", "postmenopause", "is", "important", "because", "cardiovascular", "(CV)", "disease", "typically", "occurs", "later", "in", "women", "than", "in", "men;", "yet,", "the", "fact", "remains", "that", "CV", "disease", "is", "one", "of", "the", "two", "leading", "causes", "of", "death", "in", "women", "[6,7].", "A", "lifestyle", "behavior", "that", "has", "a", "significant", "affect", "on", "the", "metabolic", "processes", "surrounding", "CV", "disease", "is", "cardiorespiratory", "exercise", "training.", "Current", "recommendations", "from", "the", "National", "Institutes", "of", "Health", "(NIH)", "Consensus", "Development", "Panel", "recommend", "that", "women", "attain", "a", "minimal", "level", "of", "moderate", "intensity", "activity", "such", "as", "walking", "briskly", "for", "30", "minutes", "[8].", "In", "a", "recent", "report,", "we", "observed", "significant", "improvements", "in", "peak", "aerobic", "power", "for", "varying", "doses", "of", "exercise", "in", "postmenopausal", "women", "obtaining", ",50%,", "100%,", "and", "150%", "of", "the", "NIH", "recommendation", "[9].", "Cross-", "sectional", "reports,", "as", "well", "as", "reports", "in", 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"among", "children", "in", "the", "United", "States", "with", "congenital", "hypothyroidism:", "findings", "from", "health", "insurance", "claims", "data", "Alex", "R", "Kemper1,", "Lijing", "Ouyang2,", "Scott", "D", "Grosse2", "Abstract", "Background:", "Thyroid", "hormone", "treatment", "in", "children", "with", "congenital", "hypothyroidism", "can", "prevent", "intellectual", "disability.", "Guidelines", "recommend", "that", "children", "diagnosed", "with", "congenital", "hypothyroidism", "through", "newborn", "screening", "remain", "on", "treatment", "to", "at", "least", "3", "years", "of", "age,", "after", "which", "a", "trial", "off", "therapy", "can", "determine", "which", "children", "have", "transient", "hypothyroidism.", "The", "purpose", "of", "this", "study", "was", "to", "describe", "the", "rate", "at", "which", "children", "with", "congenital", "hypothyroidism", "in", "the", "United", "States", "discontinue", "thyroid", "hormone", "treatment", "in", "early", "childhood.", "Methods:", "Retrospective", "analysis", "of", "the", "2002-2006", "MarketScan®", "Commercial", "Claims", "and", "Encounters", "research", "databases", "and", "the", "2001-2005", "MarketScan", "Multi-State", "Medicaid", "databases.", "Children", "were", "classified", "as", "having", "congenital", "hypothyroidism", "based", "on", "billing", "codes", "and", "having", "filled", "a", "prescription", "for", "thyroid", "hormone", "treatment.", "Kaplan-Meier", "curve", "analysis", "was", "used", "to", "determine", "discontinuation", "rates.", "Results:", "There", "were", "a", "total", "of", "412", "Medicaid-enrolled", "children", "and", "292", "privately-insured", "children", "with", "presumed", "congenital", "hypothyroidism", "included", "in", "this", "study.", "The", "overall", "birth", "prevalence", "of", "congenital", "hypothyroidism", "across", "both", "datasets", "was", "about", "1", "per", "2,300.", "By", "36", "months,", "the", "percentage", "who", "had", "discontinued", "thyroid", "replacement", "treatment", "was", "38%", "(95%", "Confidence", "Interval:", "32%-44%).", "Medicaid-enrolled", "children", "had", "a", "more", "rapid", "decline", "in", "the", "first", "24", "months", "of", "treatment", "compared", "to", "those", "with", "private", "insurance", "(P", "=", "0.02).", "Conclusions:", "More", "than", "one-third", "of", "children", "treated", "for", "congenital", "hypothyroidism", "discontinued", "treatment", "within", "36", "months,", "which", "is", "inconsistent", "with", "current", "guidelines.", "It", "is", "not", "known", "how", "many", "of", "these", "children", "required", "continued", "treatment", "or", "experience", "adverse", "effects", "from", "discontinuation.", "These", "findings", "emphasize", "the", "critical", "need", "for", "follow-up", "systems", "to", "monitor", "the", "outcome", "of", "newborn", "screening.", "Background", "Although", "there", "has", "been", "dramatic", "expansion", "in", "the", "con-", "ditions", "identified", "by", "newborn", "screening,", "few", "data", "are", "available", "regarding", "the", "care", "that", "children", "receive", "after", "they", "are", "diagnosed", "through", "newborn", "screening.", "Appro-", "priate", "delivery", "of", "health", "care", "services", "is", "necessary", "to", "assure", "the", "benefit", "of", "early", "diagnosis.", "We", "chose", "to", "focus", "on", "congenital", "hypothyroidism", "(CH)", "because", "of", "its", "rela-", "tively", "high", "prevalence", "compared", "to", "other", "conditions", "", "Correspondence:", "alex.kemper@duke.edu", "1Program", "on", "Pediatric", "Health", "Services", "Research,", "Department", "of", "Pediatrics,", "Duke", "University", "Medical", "Center,", "Durham,", "NC,", "USA", "included", "in", "newborn", "screening", "and", "because", "treatment", "is", "among", "the", "most", "straight-forward.", "Newborn", "screening", "for", "CH", "followed", "by", "the", "early", "initiation", "of", "thyroid", "hormone", "treatment", "to", "normalize", "thyroxin", "(T4)", "concentrations", "has", "been", "shown", "to", "prevent", "intellectual", "disability", "(i.e.,", "mental", "retardation)", "[1-3].", "Among", "population-based", "studies", "of", "children", "born", "prior", "to", "the", "introduction", "of", "newborn", "screening", "for", "CH", "in", "the", "late", "1970s,", "8%", "to", "29%", "of", "children", "with", "clinically", "diag-", "nosed", "CH", "received", "special", "education", "services", "for", "intel-", "lectual", "disability", "[4-6].", "Despite", "the", "unquestioned", "public", "health", "success", "from", "newborn", "screening", "and", "the", "management", "of", "CH,", "there", "©", "2010", "Kemper", "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, 8, 8, 8, 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, 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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 ] ]	[ "Onwujekwe", "et", "al.", "BMC", "Health", "Services", "Research", "2010,", "10:67", "http://www.biomedcentral.com/1472-6963/10/67", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Investigating", "determinants", "of", "out-of-pocket", "spending", "and", "strategies", "for", "coping", "with", "payments", "for", "healthcare", "in", "southeast", "Nigeria", "Obinna", "E", "Onwujekwe1,2,", "Benjamin", "SC", "Uzochukwu2,3,", "Eric", "N", "Obikeze1,2,", "Ijeoma", "Okoronkwo2,4,", "Ogbonnia", "G", "Ochonma1,", "Chima", "A", "Onoka1,2,3,", "Grace", "Madubuko2,4,", "Chijioke", "Okoli2", "Abstract", "Background:", "Out-of-pocket", "spending", "(OOPS)", "is", "the", "major", "payment", "strategy", "for", "healthcare", "in", "Nigeria.", "Hence,", "the", "paper", "assessed", "the", "determinants", "socio-economic", "status", "(SES)", "of", "OOPS", "and", "strategies", "for", "coping", "with", "payments", "for", "healthcare", "in", "urban,", "semi-urban", "and", "rural", "areas", "of", "southeast", "Nigeria.", "This", "paper", "provides", "information", "that", "would", "be", "required", "to", "improve", "financial", "accessibility", "and", "equity", "in", "financing", "within", "the", "public", "health", "care", "system.", "Methods:", "The", "study", "areas", "were", "three", "rural", "and", "three", "urban", "areas", "from", "Ebonyi", "and", "Enugu", "states", "in", "South-east", "Nigeria.", "Cross-sectional", "survey", "using", "interviewer-administered", "questionnaires", "to", "randomly", "selected", "householders", "was", "the", "study", "tool.", "A", "socio-economic", "status", "(SES)", "index", "that", "was", "developed", "using", "principal", "components", "analysis", "was", "used", "to", "examine", "levels", "of", "inequity", "in", "OOPS", "and", "regression", "analysis", "was", "used", "to", "examine", "the", "determinants", "of", "use", "of", "OOPS.", "Results:", "All", "the", "SES", "groups", "equally", "sought", "healthcare", "when", "they", "needed", "to.", "However,", "the", "poorest", "households", "were", "most", "likely", "to", "use", "low", "level", "and", "informal", "providers", "such", "as", "traditional", "healers,", "whilst", "the", "least", "poor", "households", "were", "more", "likely", "to", "use", "the", "services", "of", "higher", "level", "and", "formal", "providers", "such", "as", "health", "centres", "and", "hospitals.", "The", "better-off", "SES", "more", "than", "worse-off", "SES", "groups", "used", "OOPS", "to", "pay", "for", "healthcare.", "The", "use", "of", "own", "money", "was", "the", "commonest", "payment-coping", "mechanism", "in", "the", "three", "communities.", "The", "sales", "of", "movable", "household", "assets", "or", "land", "were", "not", "commonly", "used", "as", "payment-coping", "mechanisms.", "Decreasing", "SES", "was", "associated", "with", "increased", "sale", "of", "household", "assets", "to", "cope", "with", "payment", "for", "healthcare", "in", "one", "of", "the", "communities.", "Fee", "exemptions", "and", "subsidies", "were", "almost", "non-existent", "as", "coping", "mechanisms", "in", "this", "study", "Conclusions:", "There", "is", "the", "need", "to", "reduce", "OOPS", "and", "channel", "and", "improve", "equity", "in", "healthcare", "financing", "by", "designing", "and", "implementing", "payment", "strategies", "that", "will", "assure", "financial", "risk", "protection", "of", "the", "poor", "such", "pre-payment", "mechanisms", "with", "government", "paying", "for", "the", "poor.", "Background", "Out-of-pocket", "spending", "(OOPS)", "is", "the", "major", "payment", "strategy", "for", "healthcare", "in", "Nigeria.", "The", "real", "challenge", "of", "health", "care", "financing", "in", "Nigeria", "as", "in", "many", "countries", "in", "sub-Saharan", "Africa", "(SSA)", "lies", "not", "primarily", "in", "the", "acute", "scarcity", "of", "resources,", "but", "in", "the", "absence", "of", "intermedia-", "tion", "and", "insurance", "mechanisms", "to", "manage", "risk,", "and", "inefficient", "resource", "allocation", "and", "purchasing", "practices", "[1].", "User", "fees", "fall", "within", "the", "broader", "concept", "of", "“cost-", "", "Correspondence:", "ericobikeze@mail.com", "1Department", "of", "Health", "Administration", "and", "Management,", "College", "of", "Medicine,", "University", "of", "Nigeria,", "Enugu,", "Nigeria", "sharing”,", "a", "practice", "whereby", "beneficiaries", "contribute", "towards", "the", "cost", "of", "a", "public", "service", "and", "they", "are", "defined", "as", "payment", "of", "out-of-pocket", "charges", "at", "the", "time", "of", "use", "of", "services", "[2].", "OOPS", "for", "healthcare", "increased", "with", "the", "introduction", "of", "user", "fees", "in", "the", "health", "sector", "and", "like", "most", "African", "countries,", "Nigeria", "introduced", "user", "fees", "as", "a", "mode", "of", "financing", "government", "health", "services", "within", "the", "frame-", "work", "of", "the", "Bamako", "Initiative", "revolving", "drug", "funds", "[3].", "It", "is", "however", "noted", "that", "user", "fees", "and", "revolving", "drug", "funds", "are", "interlinked.", "The", "introduction", "of", "user", "fees", "was", "arguably", "in", "response", "to", "the", "severe", "problems", "in", "financing", "©", "2010", "Onwujekwe", "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, 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, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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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961 ], [ 623, 947, 665, 961 ], [ 669, 947, 689, 961 ], [ 693, 947, 710, 961 ], [ 714, 947, 757, 961 ], [ 426, 964, 475, 978 ], [ 479, 964, 491, 978 ], [ 495, 964, 512, 978 ], [ 516, 964, 558, 978 ], [ 562, 964, 602, 978 ], [ 606, 964, 653, 978 ], [ 657, 964, 674, 978 ], [ 679, 964, 727, 978 ], [ 731, 964, 757, 978 ], [ 426, 981, 437, 995 ], [ 442, 981, 459, 995 ], [ 465, 981, 504, 995 ], [ 509, 981, 526, 995 ], [ 531, 981, 582, 995 ], [ 588, 981, 613, 995 ], [ 618, 981, 665, 995 ], [ 671, 981, 730, 995 ], [ 736, 981, 757, 995 ] ]	[ "Clin", "Rheumatol", "(2009)", "28:923–929", "DOI", "10.1007/s10067-009-1176-1", "ORIGINAL", "ARTICLE", "The", "feasibility", "and", "efficacy", "of", "a", "multidisciplinary", "intervention", "with", "aftercare", "meetings", "for", "fibromyalgia", "Mariëlle", "Kroese", "&", "Guy", "Schulpen", "&", "Monique", "Bessems", "&", "Frans", "Nijhuis", "&", "Johan", "Severens", "&", "Robert", "Landewé", "Received:", "28", "October", "2008", "/", "Revised:", "11", "March", "2009", "/", "Accepted:", "27", "March", "2009", "/", "Published", "online:", "5", "May", "2009", "#", "The", "Author(s)", "2009.", "This", "article", "is", "published", "with", "open", "access", "at", "Springerlink.com", "Abstract", "The", "objective", "of", "this", "study", "is", "to", "examine", "the", "feasibility", "and", "long-term", "results", "of", "a", "12-week", "multidisci-", "plinary", "part-time", "daycare", "intervention", "with", "five", "aftercare", "meetings", "in", "fibromyalgia", "(FM)", "patients.", "One", "hundred", "and", "five", "patients", "diagnosed", "with", "FM", "started", "with", "a", "multidisci-", "plinary", "intervention", "and", "were", "assessed", "for", "feasibility,", "func-", "tional", "status", "(Fibromyalgia", "Impact", "Questionnaire", "[FIQ]),", "and", "quality", "of", "life", "(EuroQol-5D", "[EQ-5D])", "until", "9", "months", "after", "completion.", "The", "program", "consisted", "of", "sociotherapy,", "physiotherapy,", "psychotherapy,", "and", "creative", "arts", "therapy.", "Drop-out", "rate", "was", "4.8%.", "The", "attendance", "rate", "of", "100", "patients", "who", "completed", "the", "12-week", "program", "and", "five", "aftercare", "meetings", "was", "high", "(97.4%),", "just", "like", "patient", "and", "therapist", "satisfaction", "(8.2", "on", "a", "10", "points", "scale).", "After", "the", "12-week", "program,", "statistically", "significant", "improvement", "was", "seen", "in", "both", "FIQ", "and", "EQ-5D.", "This", "improvement", "was", "maintained", "after", "9", "months", "of", "follow-up.", "On", "average,", "moderate", "im-", "provements", "were", "observed.", "Our", "12-week", "multidisciplinary", "M.", "Kroese", "(*)", ":", "G.", "Schulpen", ":", "M.", "Bessems", "Department", "of", "Integrated", "Care,", "University", "Hospital", "Maastricht,", "PO", "Box", "5800,", "6202", "AZ", "Maastricht,", "The", "Netherlands", "e-mail:", "marielle.kroese@mumc.nl", "F.", "Nijhuis", ":", "J.", "Severens", "Department", "of", "Health", "Organization,", "Policy,", "and", "Economics,", "University", "of", "Maastricht,", "Maastricht,", "The", "Netherlands", "J.", "Severens", "Department", "of", "Clinical", "Epidemiology", "and", "Medical", "Technology", "Assessment,", "University", "Hospital", "Maastricht,", "Maastricht,", "The", "Netherlands", "R.", "Landewé", "Department", "of", "Internal", "Medicine,", "Division", "of", "Rheumatology,", "University", "Hospital", "Maastricht,", "Maastricht,", "The", "Netherlands", "part-time", "daycare", "intervention", "with", "five", "aftercare", "meetings", "for", "FM", "patients", "is", "feasible", "and", "it", "is", "indicated", "that", "it", "can", "lead", "to", "sustained", "improvement", "in", "functional", "status", "and", "quality", "of", "life.", "Keywords", "Feasibility", ".", "Fibromyalgia", ".", "Multidisciplinary", "intervention", "Introduction", "Fibromyalgia", "(FM)", "is", "a", "common", "chronic", "pain", "condition,", "characterized", "by", "generalized", "pain,", "stiffness,", "fatigue,", "dis-", "turbed", "sleep,", "psychological", "distress,", "and", "impaired", "cognitive", "function", "[1,", "2].", "The", "cause", "of", "and", "pathologic", "mechanisms", "underlying", "FM", "are", "unknown,", "but", "FM", "may", "lead", "to", "disability", "and", "reduced", "quality", "of", "life", "[3].", "Increasingly,", "FM", "is", "considered", "as", "a", "combination", "of", "physical,", "psychological,", "and", "social", "disabilities,", "the", "biopsy-", "chosocial", "model", "[4,", "5].", "In", "this", "model,", "physical", "treatment", "is", "combined", "with", "psychological,", "behavioral,", "and/or", "educa-", "tional", "interventions", "[6].", "The", "studies", "that", "have", "systematically", "compared", "monotherapies", "with", "treatment", "combinations", "that", "include", "both", "physical", "and", "psychosocial", "components", "have", "fairly", "consistently", "shown", "that", "for", "chronic", "pain", "combined", "treatments", "result", "in", "better", "outcomes", "than", "single", "therapies", "[7].", "Rossy", "et", "al.", "concluded", "in", "their", "meta-analysis", "that", "the", "optimal", "intervention", "for", "FM", "would", "include", "exercise", "and", "cognitive-behavioral", "therapy", "[8].", "A", "number", "of", "studies", "have", "investigated", "the", "effect", "of", "multimodal", "or", "multidisciplinary", "therapy", "for", "FM,", "but", "the", "systematic", "reviews", "performed", "in", "this", "area", "concluded", "that", "the", "evidence", "is", "scarce", "because", "of", "few", "studies,", "the", "low", "quality", "of", "the", "studies,", "and", "the", "varying", "elements", "of", "the", "therapy", "[9–11].", "Besides,", "the", "drop-out", "rates", "in", "the", "studies", "are", "generally", "high", "[12–17],", "suggesting", "that" ]	[ 0, 0, 0, 0, 0, 0, 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, 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], [ 463, 992, 474, 1006 ], [ 477, 992, 496, 1006 ], [ 499, 992, 543, 1006 ], [ 545, 992, 572, 1006 ], [ 576, 992, 588, 1006 ], [ 591, 992, 648, 1006 ], [ 651, 992, 677, 1006 ], [ 680, 992, 712, 1006 ], [ 698, 1052, 728, 1065 ], [ 731, 1052, 738, 1065 ], [ 741, 1052, 752, 1065 ], [ 755, 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", "Cell", "Biology", "Research", "article", "Arf6", "recruits", "the", "Rac", "GEF", "Kalirin", "to", "the", "plasma", "membrane", "facilitating", "Rac", "activation", "Tae", "Hyeon", "Koo1,", "Betty", "A", "Eipper2", "and", "Julie", "G", "Donaldson1", "Address:", "1Laboratory", "of", "Cell", "Biology,", "NHLBI,", "NIH,", "Building", "50,", "Rm", "2503,", "Bethesda,", "MD", "20892,", "USA", "and", "2Department", "of", "Neuroscience,", "University", "of", "Connecticut", "Health", "Center,", "Farmington,", "CT", "06030,", "USA", "Email:", "Tae", "Hyeon", "Koo", "-", "gutae@kfda.go.kr;", "Betty", "A", "Eipper", "-", "Eipper@uchc.edu;", "Julie", "G", "Donaldson", "-", "jdonalds@helix.nih.gov", "*", "Corresponding", "author", "BioMed", "Central", "Open", "Access", "Published:", "18", "July", "2007", "BMC", "Cell", "Biology", "2007,", "8:29", "doi:10.1186/1471-2121-8-29", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1471-2121/8/29", "Received:", "2", "March", "2007", "Accepted:", "18", "July", "2007", "©", "2007", "Koo", "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:", "Many", "studies", "implicate", "Arf6", "activity", "in", "Rac-mediated", "membrane", "ruffling", "and", "cytoskeletal", "reorganization.", "Although", "Arf6", "facilitates", "the", "trafficking", "of", "Rac1", "to", "the", "plasma", "membrane", "and", "in", "many", "cases", "Arf6", "activation", "leads", "to", "the", "activation", "of", "Rac1,", "the", "details", "of", "how", "Arf6", "influences", "Rac", "function", "remain", "to", "be", "elucidated.", "Results:", "We", "demonstrate", "in", "binding", "assays", "and", "by", "co-immunoprecipitation", "that", "GDP-bound", "Arf6", "binds", "to", "Kalirin5,", "a", "Rho", "family", "guanine", "nucleotide", "exchange", "factor,", "through", "interaction", "with", "the", "spectrin", "repeat", "region.", "In", "cells,", "expression", "of", "wild", "type", "Arf6", "recruits", "spectrin", "repeat", "5", "and", "Kalirin", "to", "the", "plasma", "membrane", "and", "leads", "to", "enhanced", "Kalirin5-induced", "ruffling.", "By", "contrast,", "expression", "of", "an", "Arf6", "mutant", "that", "cannot", "become", "activated,", "Arf6", "T27N,", "still", "recruits", "spectrin", "repeat", "5", "and", "Kalirin", "to", "membranes", "but", "inhibits", "Kalirin5-induced", "ruffling", "in", "HeLa", "cells.", "Kalirin5-induced", "Rac1", "activation", "is", "increased", "by", "the", "expression", "of", "wild", "type", "Arf6", "and", "decreased", "by", "Arf6T27N.", "Furthermore,", "expression", "of", "a", "catalytically-inactive", "mutant", "of", "Kalirin5", "inhibits", "cytoskeletal", "changes", "observed", "in", "cells", "expressing", "EFA6,", "an", "Arf6", "guanine", "nucleotide", "exchange", "factor", "that", "leads", "to", "activation", "of", "Rac.", "Conclusion:", "We", "show", "here", "with", "over-expressed", "proteins", "that", "the", "GDP-bound", "form", "of", "Arf6", "can", "bind", "to", "the", "spectrin", "repeat", "regions", "in", "Kalirin", "Rho", "family", "GEFs", "thereby", "recruiting", "Kalirin", "to", "membranes.", "Although", "Kalirin", "is", "recruited", "onto", "membranes", "by", "Arf6-GDP,", "subsequent", "Rac", "activation", "and", "membrane", "ruffling", "requires", "Arf6", "activation.", "From", "these", "results,", "we", "suggest", "that", "Arf6", "can", "regulate", "through", "its", "GTPase", "cycle", "the", "activation", "of", "Rac.", "Background", "Arfs", "are", "small,", "ubiquitous,", "Ras-related", "GTPases", "that", "play", "an", "essential", "role", "in", "membrane", "traffic", "and", "structure.", "Among", "the", "6", "mammalian", "Arf", "proteins,", "Arf6", "has", "been", "implicated", "in", "the", "regulation", "of", "endocytic", "membrane", "traf-", "fic", "and", "cortical", "actin", "structure", "at", "the", "plasma", "membrane", "(PM)", "[1,2].", "The", "small", "GTPases", "of", "the", "Rho", "subfamily", "are", "also", "known", "to", "be", "important", "regulators", "of", "the", "actin", "cytoskeleton.", "To", "date,", "at", "least", "25", "Rho", "family", "proteins", "have", "been", "identified", "and", "of", "these,", "RhoA,", "Rac1", "and", "Cdc42", "have", "been", "the", "most", "widely", "studied", "for", "their", "effects", "on", "actin", "organization.", "In", "particular,", "Rac1", "controls", "the", "formation", "of", "lamellipodia", "and", "membrane", "ruffles,", "the", "sites", "of", "protrusive", "actin", "polymerization", "and", "early", "adhesion", "formation", "initi-", "ated", "at", "the", "leading", "edge", "of", "migrating", "cells", "[3,4].", "Page", "1", "of", "10", "(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, 3, 3, 3, 3, 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, 0, 0, 9, 9, 7, 7, 7, 7, 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, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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, 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"Correspondence:", "Jung", "Jin", "Kim,", "MD,", "PhD", "Department", "of", "Psychiatry,", "The", "Catholic", "University", "of", "Korea", "College", "of", "Medicine,", "Seoul", "St.", "Mary’s", "Hospital,", "505", "Banpo-dong,", "Seocho-gu,", "Seoul", "137-701,", "Korea", "Tel:", "+82-2-2258-6084,", "Fax:", "+82-2-594-3870,", "E-mail:", "jjean@catholic.ac.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", "reproduc-", "tion", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "224", "Copyright", "©", "2010", "Korean", "Neuropsychiatric", "Association", "structure", "important", "for", "the", "regulation", "of", "emotions,", "cognition", "and", "behavior.5-8", "The", "fact", 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"Medicine", "and", "Biomedical", "Sciences,", "University", "at", "Buffalo,", "State", "University", "of", "New", "York,", "Buffalo,", "New", "York,", "USA", "Corresponding", "author:", "Sarah", "L", "Gaffen,", "sgaffen@buffalo.edu", "Published:", "8", "October", "2004", "Arthritis", "Res", "Ther", "2004,", "6:240-247", "(DOI", "10.1186/ar1444)", "©", "2004", "BioMed", "Central", "Ltd", "Abstract", "IL-17", "and", "its", "receptor", "are", "founding", "members", "of", "an", "emerging", "family", "of", "cytokines", "and", "receptors", "with", "many", "unique", "characteristics.", "IL-17", "is", "produced", "primarily", "by", "T", "cells,", "particularly", "those", "of", "the", "memory", "compartment.", "In", "contrast,", "IL-17", "receptor", "is", "ubiquitously", "expressed,", "making", "nearly", "all", "cells", "potential", "targets", "of", "IL-17.", "Although", "it", "has", "only", "limited", "homology", "to", "other", "cytokines,", "IL-17", "exhibits", "proinflammatory", "properties", "similar", "to", "those", "of", "tumor", "necrosis", "factor-α,", "particularly", "with", "respect", "to", "induction", "of", "other", "inflammatory", "effectors.", "In", "addition,", "IL-17", "synergizes", "potently", "with", "other", "cytokines,", "placing", "it", "in", "the", "center", "of", "the", "inflammatory", "network.", "Strikingly,", "IL-17", "has", "been", "associated", "with", "several", "bone", "pathologies,", "most", "notably", "rheumatoid", "arthritis.", "Keywords:", "bone,", "cytokines,", "interleukin-17,", "inflammation,", "synergy", "Introduction", "The", "cytokine", "IL-17,", "originally", "termed", "CTLA-8,", "was", "isolated", "as", "a", "CD4-specific", "transcript", "from", "a", "rodent", "cDNA", "library", "[1].", "Shortly", "thereafter,", "IL-17", "was", "discovered", "in", "humans,", "and", "its", "receptor", "(IL-17R)", "was", "cloned", "and", "characterized", "[2–4].", "The", "most", "striking", "feature", "of", "both", "IL-17", "and", "IL-17R", "is", "that", "they", "are", "distinct", "in", "sequence", "from", "previously", "described", "cytokine/receptor", "families.", "However,", "they", "are", "highly", "homologous", "among", "mice,", "rats,", "and", "humans.", "In", "addition,", "an", "IL-17R", "homolog", "in", "zebrafish", "(termed", "SEF", "[similar", "expression", "of", "FGF", "genes])", "has", "been", "described", "that", "functions", "in", "embryonic", "development", "[5],", "and", "mammalian", "homologs", "of", "SEF", "were", "also", "recently", "identified", "[6,7].", "Consequently,", "IL-17", "and", "IL-17R", "are", "now", "recognized", "to", "be", "the", "founding", "members", "of", "an", "emerging", "new", "family", "that,", "in", "mammals,", "contains", "at", "least", "six", "cytokines", "and", "five", "receptors", "(Table", "1", "[8,9]).", "This", "review", "focuses", "primarily", "on", "the", "original", "IL-17", "cytokine", "(also", "known", "as", "IL-17A),", "because", "its", "roles", "in", "bone", "physiology", "and", "arthritis", "are", "most", "clearly", "defined,", "but", "the", "biology", "of", "the", "remaining", "family", "members", "promises", "to", "be", "a", "fascinating", "emerging", "story", "within", "the", "field", "of", "‘high", "numbered’", "cytokines.", "Interleukin-17", "and", "interleukin-17", "receptor", "structure", "Even", "though", "IL-17", "and", "IL-17R", "have", "been", "recognized", "for", "many", "years,", "there", "is", "still", "much", "to", "learn", "about", "their", "respective", "structures", "and", "functions.", "IL-17", "is", "secreted", "primarily", "by", "CD4+", "T", "cells", "in", "a", "mix", "of", "both", "nonglycosylated", "and", "N-glycosylated", "forms,", "which", "migrate", "in", "SDS-PAGE", "at", "28", "kDa", "and", "33", "kDa,", "respectively", "[2].", "Secreted", "IL-17", "apparently", "exists", "as", "a", "homodimer,", "but", "the", "specific", "contact", "points", "between", "IL-17", "subunits", "or", "between", "IL-17", "and", "IL-17R", "have", "never", "been", "defined", "[2,10].", "IL-17B", "and", "IL-17F", "also", "exist", "as", "dimers", "[10,11].", "While", "the", "amino", "acid", "sequence", "of", "IL-17", "did", "not", "permit", "it", "to", "be", "classified", "as", "a", "240", "CCL", "=", "CC", "chemokine", "ligand;", "C/EBP", "=", "CCAAT/enhancer", "binding", "protein;", "CIA", "=", "collagen", "induced", "arthritis;", "CXCL", "=", "CXC", "chemokine", "ligand;", "DC", "=", "dendritic", "cell;", "IFN", "=", "interferon;", "IL", "=", "interleukin;", "IL-17R", "=", "IL-17", "receptor;", "MAPK", "=", "mitogen-activated", "protein", "kinase;", "NF-κB", "=", "nuclear", "factor-κB;", "OPG", "=", "osteoprotegerin;", "RA", "=", "rheumatoid", "arthritis;", "RANKL", "=", "receptor", "activator", "of", "nuclear", "factor-κB", "ligand;", "TNF", "=", "tumor", "necrosis", "factor;", "TRAF", "=", "tumor", "necrosis", "factor", "receptor-associated", "factor." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 6, 19, 19, 19, 19, 19, 19, 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"cells", "transiently", "transfected", "with", "wild-type", "or", "mutant", "Na+", "channels", "revealed", "significant", "changes", "in", "channel", "biophysics,", "all", "contributing", "to", "the", "proband’s", "phenotype", "as", "predicted", "by", "in", "silico", "modeling.", "Furthermore,", "subtle", "differences", "in", "drug", "action", "were", "detected", "in", "correcting", "mutant", "channel", "activity", "that,", "together", "with", "both", "the", "known", "genetic", "background", "and", "age", "of", "the", "patient,", "contribute", "to", "the", "distinct", "therapeutic", "responses", "observed", "clinically.", "Significance.", "The", "results", "of", "our", "study", "provide", "further", "evidence", "of", "the", "grave", "vulnerability", "of", "newborns", "to", "Na+", "channel", "defects", "and", "suggest", "that", "both", "genetic", "background", "and", "age", "are", "particularly", "important", "in", "developing", "a", "mutation-", "specific", "therapeutic", "personalized", "approach", "to", "manage", "disorders", "in", "the", "young.", "Citation:", "Bankston", "JR,", "Yue", "M,", "Chung", "W,", "Spyres", "M,", "Pass", "RH,", "et", "al", "(2007)", "A", "Novel", "and", "Lethal", "De", "Novo", "LQT-3", "Mutation", "in", "a", "Newborn", "with", "Distinct", "Molecular", "Pharmacology", "and", "Therapeutic", "Response.", "PLoS", "ONE", "2(12):", "e1258.", "doi:10.1371/journal.pone.0001258", "INTRODUCTION", "The", "long", "QT", "syndrome", "(LQTS),", "a", "relatively", "uncommon", "(1", "in", "2500)", "genetic", "disorder", "associated", "with", "life-threatening", "arrhyth-", "mias,", "is", "an", "example", "of", "a", "channelopathy", "that", "has", "provided", "a", "wealth", "of", "information", "about", "fundamental", "mechanisms", "underlying", "human", "cardiac", "electrophysiology[1].", "LQTS", "is", "currently", "associated", "with", "mutations", "in", "10", "different", "genes[1–3].", "LQT", "variant", "3", "(LQT-3)", "is", "caused", "by", "mutations", "in", "SCN5A,", "the", "gene", "coding", "for", "the", "alpha", "subunit", "(NaV1.5)", "of", "the", "primary", "cardiac", "voltage-gated", "Na+", "channel", "in", "the", "human", "heart.", "Despite", "a", "relatively", "common", "phenotype", "(delayed", "repolarization", "reflected", "in", "QT", "prolongation),", "therapeutic", "strategies", "have", "been", "developed", "that", "are", "dictated", "by", "molecular", "etiology.", "Na+", "channel", "blockers", "such", "as", "mexiletine", "and", "flecainide", "are", "effective", "in", "treating", "LQT-3", "patients", "due", "to", "preferential", "inhibition", "of", "mutant", "Na+", "channel", "activity[4,5].", "Furthermore,", "current", "evidence", "suggests", "that", "mutations", "in", "ion", "channels", "may", "also", "contribute", "to", "sudden", "infant", "death", "syndrome", "(SIDS)", "and", "other", "cardiac", "arrhythmias", "in", "newborns,", "and", "that", "the", "frequency,", "severity,", "and", "treatment", "of", "SCN5A", "mutations", "may", "be", "distinct", "in", "infants", "compared", "with", "adults[6,7,8–11]", "Here", "we", "report", "investigation", "of", "a", "de", "novo", "SCN5A", "mutation", "discovered", "in", "a", "newborn", "who", "had", "presented", "with", "extreme", "QT", "prolongation", "(approximately", "800", "ms);", "2:1", "heart", "block;", "and", "differen-", "tial", "responses", "to", "the", "Na+", "channel", "blockers", "lidocaine,", "mexiletine,", "and", "flecainide.", "Also", "found", "in", "the", "proband", "was", "common", "polymorphism", "(K897T)", "in", "KCNH2,", "the", "gene", "coding", "for", "the", "HERG", "potassium", "channel", "which", "contributes", "to", "control", "of", "ventricular", "repolarization.", "Our", "results", "reveal", "multiple", "biophysical", "changes", "in", "Na+", "channel", "gating", "induced", "by", "the", "F1473C", "mutation", "that", "all", "contribute", "to", "delayed", "repolarization", "of", "cellular", "action", "potentials", "and", "are", "consistent", "with", "the", "pronounced", "phenotype", "of", "the", "patient.", "Furthermore", "our", "data", "suggest", "an", "important", "role", "of", "the", "KCNH2", "polymorphism", "and", "developmentally-related", "expression", "of", "background", "ion", "channels", "in", "both", "the", "therapeutic", "response", "and", "disease", "phenotype", "of", "the", "proband.", "RESULTS", "Clinical", "profile", "The", "proband", "was", "a", "full", "term", "newborn", "infant", "boy", "with", "a", "prenatal", "history", "significant", "for", "fetal", "bradycardia", "of", "unclear", "etiology", "with", "Academic", "Editor:", "Arnold", "Schwartz,", "University", "of", "Cincinnati,", "United", "States", "of", "America", "Received", "October", "5,", "2007;", "Accepted", "November", "10,", "2007;", "Published", "December", "5,", "2007", "Copyright:", "2007", "Bankston", "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", "the", "NIH", "(1R01", "HL-56810-10", "to", "RSK).", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "", "To", "whom", "correspondence", "should", "be", "addressed.", "E-mail:", "rsk20@columbia.edu", ".", "These", "authors", "contributed", "equally", "to", "this", "work.", "PLoS", "ONE", "\|", "www.plosone.org", "1", "December", "2007", "\|", "Issue", "12", "\|", "e1258" ]	[ 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, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 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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[ 520, 962, 582, 976 ], [ 585, 962, 599, 976 ], [ 603, 962, 614, 976 ], [ 617, 962, 643, 976 ], [ 646, 962, 668, 976 ], [ 672, 962, 683, 976 ], [ 686, 962, 714, 976 ], [ 718, 962, 756, 976 ], [ 425, 979, 450, 993 ], [ 454, 979, 494, 993 ], [ 498, 979, 518, 993 ], [ 523, 979, 596, 993 ], [ 600, 979, 636, 993 ], [ 640, 979, 667, 993 ], [ 672, 979, 727, 993 ], [ 731, 979, 756, 993 ] ]	[ "J", "Cachexia", "Sarcopenia", "Muscle", "(2011)", "2:181–188", "DOI", "10.1007/s13539-011-0037-3", "ORIGINAL", "ARTICLE", "Decreased", "NADPH", "oxidase", "expression", "and", "antioxidant", "activity", "in", "cachectic", "skeletal", "muscle", "Melanie", "J.", "Sullivan-Gunn", "&", "Siun", "P.", "Campbell-O’Sullivan", "&", "Michael", "J.", "Tisdale", "&", "Paul", "A.", "Lewandowski", "Received:", "22", "February", "2011", "/", "Accepted:", "27", "July", "2011", "/", "Published", "online:", "11", "August", "2011", "#", "The", "Author(s)", "2011.", "This", "article", "is", "published", "with", "open", "access", "at", "Springerlink.com", "Abstract", "Background", "Cancer", "cachexia", "is", "the", "progressive", "loss", "of", "skeletal", "muscle", "protein", "that", "contributes", "significantly", "to", "cancer", "morbidity", "and", "mortality.", "Evidence", "of", "antioxidant", "attenuation", "and", "the", "presence", "of", "oxidised", "proteins", "in", "patients", "with", "cancer", "cachexia", "indicate", "a", "role", "for", "oxidative", "stress.", "The", "level", "of", "oxidative", "stress", "in", "tissues", "is", "determined", "by", "an", "imbalance", "between", "reactive", "oxygen", "species", "production", "and", "antioxidant", "activity.", "This", "study", "aimed", "to", "investigate", "the", "superoxide", "generating", "NADPH", "oxidase", "(NOX)", "enzyme", "and", "antioxidant", "enzyme", "systems", "in", "murine", "adenocarcinoma", "tumour-bearing", "cachectic", "mice.", "Methods", "Superoxide", "levels,", "mRNA", "levels", "of", "NOX", "enzyme", "subunits", "and", "the", "antioxidant", "enzymes", "superoxide", "dismutase", "(SOD),", "glutathione", "peroxidise", "(GPx)", "and", "catalase", "was", "measured", "in", "the", "skeletal", "muscle", "of", "mice", "with", "cancer", "and", "cancer", "cachexia.", "Protein", "expression", "levels", "of", "NOX", "enzyme", "subunits", "and", "antioxidant", "enzyme", "activity", "was", "also", "mea-", "sured", "in", "the", "same", "muscle", "samples.", "Results", "Superoxide", "levels", "increased", "1.4-fold", "in", "the", "muscle", "of", "mice", "with", "cancer", "cachexia,", "and", "this", "was", "associated", "with", "M.", "J.", "Sullivan-Gunn", ":", "P.", "A.", "Lewandowski", "(*)", "School", "of", "Medicine,", "Deakin", "University,", "Geelong", "Campus,", "Geelong,", "VIC", "3217,", "Australia", "e-mail:", "paul.lewandowski@deakin.edu.au", "S.", "P.", "Campbell-O’Sullivan", "School", "of", "Biomedical", "Sciences,", "Victoria", "University,", "Centre", "for", "Aging,", "Rehabilitation,", "Exercise", "and", "Sport,", "PO", "Box", "14428,", "Melbourne", "8001,", "Australia", "M.", "J.", "Tisdale", "School", "of", "Life", "Sciences,", "Aston", "University,", "Aston", "Triangle,", "Birmingham", "B4", "7ET,", "UK", "a", "decrease", "in", "mRNA", "of", "NOX", "enzyme", "subunits,", "NOX2,", "p40phox", "and", "p67phox", "along", "with", "the", "antioxidant", "enzymes", "SOD1,", "SOD2", "and", "GPx.", "Cancer", "cachexia", "was", "also", "associated", "with", "a", "1.3-fold", "decrease", "in", "SOD1", "and", "2.0-fold", "decrease", "in", "GPx", "enzyme", "activity.", "Conclusion", "Despite", "increased", "superoxide", "levels", "in", "cachectic", "skeletal", "muscle,", "NOX", "enzyme", "subunits,", "NOX2,", "p40phox", "and", "p67phox,", "were", "downregulated", "along", "with", "the", "expression", "and", "activity", "of", "the", "antioxidant", "enzymes.", "Therefore,", "the", "increased", "superoxide", "levels", "in", "cachectic", "skeletal", "muscle", "may", "be", "attributed", "to", "the", "reduction", "in", "the", "activity", "of", "endogenous", "antioxidant", "enzymes.", "Keywords", "Cancer", "cachexia", ".", "NADPH", "oxidase", ".", "ROS", ".", "O2−", ".", "Antioxidant", ".", "SOD", "1", "Introduction", "Cancer", "cachexia", "is", "a", "condition", "of", "progressive", "muscle", "wasting", "that", "develops", "as", "a", "secondary", "condition", "in", "response", "to", "tumour", "growth", "[1].", "While", "cachexia", "develops", "in", "a", "wide", "range", "of", "pathologies", "including", "anorexia", "nervosa,", "acquired", "immunodeficiency", "syndrome,", "amyotrophic", "lateral", "sclerosis,", "congestive", "heart", "failure", "and", "various", "malignant", "cancers,", "cancer", "cachexia", "has", "been", "reported", "to", "develop", "at", "a", "faster", "rate", "than", "any", "other", "cachectic", "condition", "[1].", "Approximately", "half", "of", "all", "patients", "with", "cancer", "experience", "cachexia", "and", "almost", "a", "third", "of", "mortalities", "are", "estimated", "to", "result", "from", "cachexia", "[2].", "Tumour", "growth", "induces", "a", "specific", "catabolic", "response", "in", "skeletal", "muscle", "that", "causes", "the", "accelerated", "loss", "of", "protein,", "characterised", "by", "the", "significant", "loss", "of", "body", "weight", "[3].", "Animal", "tumour", "models", "have", "been", "used", "to", "investigate", "cancer", "cachexia,", "developing", "up", "to", "30%", "loss", "in", "body", "weight", "after", "tumour", "cell", "implantation.", "NMRI", "mice", "implanted", "with" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 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, 7, 7, 7, 7, 7, 7, 7, 7, 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, 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"http://www.biomedcentral.com/1471-2164/12/277", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Song", "exposure", "regulates", "known", "and", "novel", "microRNAs", "in", "the", "zebra", "finch", "auditory", "forebrain", "Preethi", "H", "Gunaratne1,2,3†,", "Ya-Chi", "Lin4†,", "Ashley", "L", "Benham1,", "Jenny", "Drnevich5,", "Cristian", "Coarfa11,", "Jayantha", "B", "Tennakoon1,", "Chad", "J", "Creighton6,", "Jong", "H", "Kim1,", "Aleksandar", "Milosavljevic11,", "Michael", "Watson7,", "Sam", "Griffiths-Jones8", "and", "David", "F", "Clayton4,9,10", "Abstract", "Background:", "In", "an", "important", "model", "for", "neuroscience,", "songbirds", "learn", "to", "discriminate", "songs", "they", "hear", "during", "tape-recorded", "playbacks,", "as", "demonstrated", "by", "song-specific", "habituation", "of", "both", "behavioral", "and", "neurogenomic", "responses", "in", "the", "auditory", "forebrain.", "We", "hypothesized", "that", "microRNAs", "(miRNAs", "or", "miRs)", "may", "participate", "in", "the", "changing", "pattern", "of", "gene", "expression", "induced", "by", "song", "exposure.", "To", "test", "this,", "we", "used", "massively", "parallel", "Illumina", "sequencing", "to", "analyse", "small", "RNAs", "from", "auditory", "forebrain", "of", "adult", "zebra", "finches", "exposed", "to", "tape-recorded", "birdsong", "or", "silence.", "Results:", "In", "the", "auditory", "forebrain,", "we", "identified", "121", "known", "miRNAs", "conserved", "in", "other", "vertebrates.", "We", "also", "identified", "34", "novel", "miRNAs", "that", "do", "not", "align", "to", "human", "or", "chicken", "genomes.", "Five", "conserved", "miRNAs", "showed", "significant", "and", "consistent", "changes", "in", "copy", "number", "after", "song", "exposure", "across", "three", "biological", "replications", "of", "the", "song-silence", "comparison,", "with", "two", "increasing", "(tgu-miR-25,", "tgu-miR-192)", "and", "three", "decreasing", "(tgu-miR-92,", "tgu-", "miR-124,", "tgu-miR-129-5p).", "We", "also", "detected", "a", "locus", "on", "the", "Z", "sex", "chromosome", "that", "produces", "three", "different", "novel", "miRNAs,", "with", "supporting", "evidence", "from", "Northern", "blot", "and", "TaqMan", "qPCR", "assays", "for", "differential", "expression", "in", "males", "and", "females", "and", "in", "response", "to", "song", "playbacks.", "One", "of", "these,", "tgu-miR-2954-3p,", "is", "predicted", "(by", "TargetScan)", "to", "regulate", "eight", "song-responsive", "mRNAs", "that", "all", "have", "functions", "in", "cellular", "proliferation", "and", "neuronal", "differentiation.", "Conclusions:", "The", "experience", "of", "hearing", "another", "bird", "singing", "alters", "the", "profile", "of", "miRNAs", "in", "the", "auditory", "forebrain", "of", "zebra", "finches.", "The", "response", "involves", "both", "known", "conserved", "miRNAs", "and", "novel", "miRNAs", "described", "so", "far", "only", "in", "the", "zebra", "finch,", "including", "a", "novel", "sex-linked,", "song-responsive", "miRNA.", "These", "results", "indicate", "that", "miRNAs", "are", "likely", "to", "contribute", "to", "the", "unique", "behavioural", "biology", "of", "learned", "song", "communication", "in", "songbirds.", "Background", "Songbirds", "are", "important", "models", "for", "exploring", "the", "neural", "and", "genomic", "mechanisms", "underlying", "vocal", "communica-", "tion,", "social", "experience", "and", "learning", "(reviewed", "in", "[1]).", "Songbirds", "communicate", "using", "both", "innate", "calls", "and", "learned", "vocalizations", "(songs),", "and", "unique", "specializations", "of", "the", "brain", "evolved", "to", "support", "this", "behavior", "(reviewed", "in", "[2]).", "In", "the", "zebra", "finch,", "only", "the", "male", "produces", "songs,", "although", "both", "sexes", "process", "and", "discriminate", "specific", "songs", "[3-6].", "The", "genome", "is", "actively", "engaged", "by", "song", "communication,", "as", "first", "shown", "in", "an", "early", "", "Correspondence:", "dclayton@uiuc.edu", "†", "Contributed", "equally", "4Department", "of", "Cell", "and", "Developmental", "Biology,", "University", "of", "Illinois,", "Urbana-Champaign,", "IL", "61801,", "USA", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "demonstration", "of", "how", "gene", "responses", "in", "the", "brain", "dis-", "criminate", "among", "different", "song", "stimuli", "[7].", "The", "genomic", "response", "is", "not", "a", "simple", "correlate", "of", "neural", "activity", "and", "it", "can", "vary", "significantly", "according", "to", "the", "salience", "and", "behavioral", "context", "of", "the", "experience", "[8-13].", "Recent", "stu-", "dies", "using", "microarray", "technology", "have", "now", "shown", "that", "song", "exposure", "affects", "the", "expression", "of", "thousands", "of", "genes", "in", "the", "auditory", "forebrain", "[14,15].", "Repeated", "expo-", "sure", "to", "one", "song", "leads", "to", "an", "altered", "gene", "expression", "profile,", "correlated", "with", "habituation", "of", "both", "the", "beha-", "vioral", "and", "immediate", "genomic", "responses", "to", "that", "specific", "song.", "These", "observations", "suggest", "the", "involvement", "of", "large", "and", "dynamic", "transcriptional", "network", "in", "the", "recog-", "nition", "and", "memory", "of", "complex", "vocal", "signals", "[14].", "MicroRNAs", "(miRNAs", "or", "miRs)", "are", "emerging", "as", "potential", "control", "points", "in", "transcriptional", "networks,", "and", "©", "2011", "Gunaratne", "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", 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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 ] ]	[ "Dieter", "and", "Estus", "Molecular", "Neurodegeneration", "2010,", "5:34", "http://www.molecularneurodegeneration.com/content/5/1/34", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Isoform", "of", "APOE", "with", "retained", "intron", "3;", "quantitation", "and", "identification", "of", "an", "associated", "single", "nucleotide", "polymorphism", "Laura", "S", "Dieter,", "Steven", "Estus", "Abstract", "Background:", "Alleles", "of", "apolipoprotein", "E", "(APOE)", "are", "the", "major", "genetic", "risk", "factor", "for", "late", "onset", "Alzheimer’s", "Disease", "(LOAD).", "Recently,", "an", "APOE", "splice", "variant", "that", "retains", "intron", "3", "(APOE-I3)", "was", "identified.", "To", "gain", "insight", "into", "the", "possible", "role", "of", "this", "isoform", "in", "LOAD,", "we", "quantified", "its", "expression", "in", "a", "cohort", "of", "56", "human", "brain", "specimens", "by", "using", "quantitative", "RT-PCR.", "Results:", "We", "found", "that", "APOE-I3", "generally", "represents", "a", "low", "percentage", "(<", "0.5%)", "of", "overall", "APOE", "expression.", "However,", "in", "one", "specimen,", "the", "proportion", "of", "APOE-I3", "was", "increased", "about", "~13", "fold.", "This", "specimen", "was", "unique", "in", "the", "cohort", "for", "possessing", "the", "minor", "allele", "of", "an", "intron", "3", "single", "nucleotide", "polymorphism", "(SNP),", "rs12982192.", "Additionally,", "an", "allelic", "expression", "imbalance", "study", "indicated", "that", "the", "rs12982192", "minor", "allele", "was", "associated", "with", "increased", "APOE-I3", "expression.", "Conclusions:", "Overall,", "we", "interpret", "our", "results", "as", "suggesting", "that", "APOE-I3", "represents", "a", "minor", "portion", "of", "APOE", "expression", "and", "that", "rs12982192", "is", "associated", "with", "APOE", "intron", "3", "retention.", "Since", "the", "minor", "allele", "of", "this", "SNP", "is", "on", "the", "same", "haplotype", "as", "the", "minor", "allele", "of", "rs429358,", "which", "defines", "the", "APOE4", "allele,", "we", "speculate", "that", "rs12982192", "may", "reflect", "a", "modest", "loss", "of", "mRNA", "encoding", "functional", "APOE4.", "Background", "APOE", "variants", "are", "the", "single", "largest", "genetic", "factors", "impacting", "late", "onset", "Alzheimer", "Disease", "(LOAD),", "the", "most", "common", "neurodegenerative", "disease.", "In", "particular,", "the", "APOE4", "allele", "confers", "increased", "risk,", "being", "present", "at", "a", "~15%", "frequency", "in", "the", "general", "population", "and", "at", "50%", "in", "LOAD", "[1,2].", "APOE", "consists", "of", "4", "exons", "and", "3", "introns", "encoding", "a", "total", "of", "317", "amino", "acids.", "After", "cleavage", "of", "the", "signal", "peptide,", "the", "mature", "APOE", "protein", "is", "299", "amino", "acids.", "Protein", "translation", "begins", "in", "exon", "2", "and", "ends", "in", "exon", "4.", "In", "the", "brain,", "APOE", "transports", "choles-", "terol", "and", "modulates", "Aß", "clearance", "[1,2].", "APOE", "is", "pri-", "marily", "secreted", "by", "astrocytes", "[3,4]", "with", "microglia", "[5]", "and,", "possibly,", "stressed", "neurons", "also", "contributing", "to", "APOE", "production", "[6].", "Overall,", "insights", "into", "APOE", "expression", "will", "provide", "further", "information", "on", "AD", "risk.", "Recently,", "Xu", "et", "al", "reported", "an", "APOE", "isoform", "that", "retained", "intron", "3", "(APOE-I3)", "and", "was", "increased", "with", "", "Correspondence:", "steve.estus@uky.edu", "Department", "of", "Physiology", "and", "Sanders-Brown", "Center", "on", "Aging,", "University", "of", "Kentucky,", "Lexington,", "KY,", "USA", "neuronal", "stress", "in", "murine", "models", "[7].", "To", "gain", "insights", "into", "this", "novel", "APOE", "isoform", "in", "humans,", "we", "quantified", "APOE-I3", "as", "well", "as", "the", "normal", "length", "APOE", "(APOE-NL)", "in", "a", "cohort", "of", "56", "AD", "and", "non-AD", "brain", "samples.", "We", "report", "that", "APOE-I3", "represents", "a", "low", "proportion", "of", "over-", "all", "APOE", "expression.", "In", "addition,", "we", "identified", "an", "indivi-", "dual", "with", "significantly", "increased", "expression", "of", "the", "APOE-", "I3", "isoform.", "Further", "analysis", "revealed", "that", "this", "individual", "was", "unique", "in", "the", "cohort", "for", "an", "intron", "3", "single", "nucleotide", "polymorphism", "(SNP),", "rs12982192.", "Moreover,", "APOE-I3", "was", "in", "allelic", "expression", "imbalance", "(AEI)", "in", "this", "indivi-", "dual", "such", "that", "the", "minor", "allele", "of", "rs12982192", "correlated", "with", "increased", "expression", "of", "the", "APOE-I3", "isoform.", "Over-", "all,", "we", "interpret", "our", "results", "as", "suggesting", "that", "APOE-I3", "represents", "a", "minor", "portion", "of", "APOE", "expression", "and", "that", "rs12982192", "is", "associated", "with", "APOE", "intron", "3", "retention.", "Materials", "and", "methods", "Human", "autopsy", "tissue", "The", "human", "autopsy", "tissue", "specimens", "used", "here", "have", "been", "described", "elsewhere", "[8,9].", "Briefly,", "anterior", "cingulate", "tissue", "©", "2010", "Dieter", "and", "Estus;", "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, 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, 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"\"the", "arm", "test\"", "and", "other", "inaccurate", "procedures", "Walter", "H", "Schmitt", "Jr", "and", "Scott", "C", "Cuthbert", "BioMed", "Central", "Open", "Access", "Address:", "Chiropractic", "Health", "Center,", "255", "West", "Abriendo", "Avenue,", "Pueblo,", "CO", "81004,", "USA", "Email:", "Walter", "H", "Schmitt", "-", "wallys@mindspring.com;", "Scott", "C", "Cuthbert", "-", "cranialdc@hotmail.com", "*", "Corresponding", "author", "Published:", "19", "December", "2008", "Chiropractic", "&", "Osteopathy", "2008,", "16:16", "doi:10.1186/1746-1340-16-16", "This", "article", "is", "available", "from:", "http://www.chiroandosteo.com/content/16/1/16", "Received:", "2", "June", "2008", "Accepted:", "19", "December", "2008", "©", "2008", "Schmitt", "and", "Cuthbert;", "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", "manual", "muscle", "test", "(MMT)", "has", "been", "offered", "as", "a", "chiropractic", "assessment", "tool", "that", "may", "help", "diagnose", "neuromusculoskeletal", "dysfunction.", "We", "contend", "that", "due", "to", "the", "number", "of", "manipulative", "practitioners", "using", "this", "test", "as", "part", "of", "the", "assessment", "of", "patients,", "clinical", "guidelines", "for", "the", "MMT", "are", "required", "to", "heighten", "the", "accuracy", "in", "the", "use", "of", "this", "tool.", "Objective:", "To", "present", "essential", "operational", "definitions", "of", "the", "MMT", "for", "chiropractors", "and", "other", "clinicians", "that", "should", "improve", "the", "reliability", "of", "the", "MMT", "as", "a", "diagnostic", "test.", "Controversy", "about", "the", "usefulness", "and", "reliability", "of", "the", "MMT", "for", "chiropractic", "diagnosis", "is", "ongoing,", "and", "clinical", "guidelines", "about", "the", "MMT", "are", "needed", "to", "resolve", "confusion", "regarding", "the", "MMT", "as", "used", "in", "clinical", "practice", "as", "well", "as", "the", "evaluation", "of", "experimental", "evidence", "concerning", "its", "use.", "Discussion:", "We", "expect", "that", "the", "resistance", "to", "accept", "the", "MMT", "as", "a", "reliable", "and", "valid", "diagnostic", "tool", "will", "continue", "within", "some", "portions", "of", "the", "manipulative", "professions", "if", "clinical", "guidelines", "for", "the", "use", "of", "MMT", "methods", "are", "not", "established", "and", "accepted.", "Unreliable", "assessments", "of", "this", "method", "of", "diagnosis", "will", "continue", "when", "non-standard", "MMT", "research", "papers", "are", "considered", "representative", "of", "the", "methods", "used", "by", "properly", "trained", "clinicians.", "Conclusion:", "Practitioners", "who", "employ", "the", "MMT", "should", "use", "these", "clinical", "guidelines", "for", "improving", "their", "use", "of", "the", "MMT", "in", "their", "assessments", "of", "muscle", "dysfunction", "in", "patients", "with", "musculoskeletal", "pain.", "Background", "Since", "Goodheart", "introduced", "applied", "kinesiology", "(AK)", "as", "a", "chiropractic", "clinical", "concept", "in", "1964", "[1],", "the", "use", "of", "man-", "ual", "muscle", "testing", "(MMT)", "has", "become", "widespread", "throughout", "the", "chiropractic", "profession", "and", "has", "spilled", "over", "into", "the", "medical,", "dental", "and", "other", "health", "professions", "as", "a", "mode", "of", "analysis", "of", "nervous", "system", "function", "[2-17].", "The", "MMT", "is", "used", "in", "the", "chiropractic,", "orthopedic,", "neuro-", "logical,", "medical,", "dental,", "homeopathic,", "and", "physical", "ther-", "apy", "arenas", "to", "assess", "locomotor", "system", "dysfunction", "and", "to", "determine", "a", "patient's", "progress", "during", "therapy.", "In", "the", "words", "of", "the", "cliché,", "\"Imitation", "is", "the", "sincerest", "form", "of", "flattery.\"", "In", "the", "practice", "of", "muscle", "testing,", "however,", "imi-", "tation", "has", "proven", "to", "be", "an", "embarcadero", "for", "inconsistency.", "All", "too", "many", "well-meaning", "clinical", "investigators", "observed", "the", "phenomena", "of", "muscles", "strengthening", "and", "weakening", "during", "standard", "AK", "and", "MMT", "procedures,", "and", "have", "Page", "1", "of", "14", "(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, 0, 0, 9, 9, 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, 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, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4 ]
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1047, 683, 1059 ], [ 688, 1047, 712, 1059 ], [ 716, 1047, 722, 1059 ], [ 727, 1047, 730, 1059 ], [ 736, 1047, 770, 1059 ] ]	[ "Co-Administration", "of", "IL-1+IL-6+TNF-a", "with", "Mycobacterium", "tuberculosis", "Infected", "Macrophages", "Vaccine", "Induces", "Better", "Protective", "T", "Cell", "Memory", "than", "BCG", "Vijender", "Singh", "1", ",", "Shweta", "Jain1,", "Uthaman", "Gowthaman", "1", ",", "Pankaj", "Parihar1,", "Pushpa", "Gupta2,", "Umesh", "D.", "Gupta2,", "Javed", "N.", "Agrewala1", "1", "Immunology", "Laboratory,", "Institute", "of", "Microbial", "Technology,", "Chandigarh,", "India,", "2", "National", "JALMA", "Institute", "for", "Leprosy", "and", "Other", "Mycobacterial", "Diseases,", "Agra,", "India", "Abstract", "BCG", "has", "been", "administered", "globally", "for", "more", "than", "75", "years,", "yet", "tuberculosis", "(TB)", "continues", "to", "kill", "more", "than", "2", "million", "people", "annually.", "Further,", "BCG", "protects", "childhood", "TB", "but", "is", "quite", "inefficient", "in", "adults.", "This", "indicates", "that", "BCG", "fails", "to", "induce", "long-term", "protection.", "Hence", "there", "is", "a", "need", "to", "explore", "alternative", "vaccination", "strategies", "that", "can", "stimulate", "enduring", "T", "cell", "memory", "response.", "Dendritic", "cell", "based", "vaccination", "has", "attained", "extensive", "popularity", "following", "their", "success", "in", "various", "malignancies.", "In", "our", "previous", "study,", "we", "have", "established", "a", "novel", "and", "unique", "vaccination", "strategy", "against", "Mycobacterium", "tuberculosis", "(M.", "tb)", "and", "Salmonella", "typhimurium", "by", "utilizing", "infected", "macrophages", "(IM).", "In", "short-term", "experiments", "(30", "days),", "substantial", "degree", "of", "protection", "was", "observed.", "However,", "remarkable", "difference", "was", "not", "observed", "in", "long-term", "studies", "(240", "days)", "due", "to", "failure", "of", "the", "vaccine", "to", "generate", "long-lasting", "memory", "T", "cells.", "Hence,", "in", "the", "present", "study", "we", "employed", "T", "cell", "memory", "augmenting", "cytokines", "IL-1+IL-6+TNF-a", "and", "IL-7+IL-15", "for", "the", "induction", "of", "the", "enhancement", "of", "long-term", "protection", "by", "the", "vaccine.", "We", "co-administered", "the", "M.", "tb", "infected", "macrophages", "vaccine", "with", "IL-1+IL-6+TNF-a", "(IM-1.6.a)", "and", "IL-7+IL-15", "(IM-7.15).", "The", "mice", "were", "then", "rested", "for", "a", "reasonably", "large", "period", "(240", "days)", "to", "study", "the", "bona", "fide", "T", "cell", "memory", "response", "before", "exposing", "them", "to", "aerosolized", "M.", "tb.", "IM-1.6.a", "but", "not", "IM-7.15", "significantly", "improved", "memory", "T", "cell", "response", "against", "M.", "tb,", "as", "evidenced", "by", "recall", "responses", "of", "memory", "T", "cells,", "expansion", "of", "both", "central", "as", "well", "as", "effector", "memory", "CD4", "and", "CD8", "T", "cell", "pools,", "elicitation", "of", "mainly", "Th1", "memory", "response,", "reduction", "in", "the", "mycobacterial", "load", "and", "alleviated", "lung", "pathology.", "Importantly,", "the", "protection", "induced", "by", "IM-1.6.a", "was", "significantly", "better", "than", "BCG.", "Thus,", "this", "study", "demonstrates", "that", "not", "only", "antigen-pulsed", "DCs", "can", "be", "successfully", "employed", "as", "vaccines", "against", "cancer", "and", "infectious", "diseases", "but", "also", "macrophages", "infected", "with", "M.", "tb", "can", "be", "utilized", "with", "great", "efficacy", "especially", "in", "protection", "against", "TB.", "Citation:", "Singh", "V,", "Jain", "S,", "Gowthaman", "U,", "Parihar", "P,", "Gupta", "P,", "et", "al.", "(2011)", "Co-Administration", "of", "IL-1+IL-6+TNF-a", "with", "Mycobacterium", "tuberculosis", "Infected", "Macrophages", "Vaccine", "Induces", "Better", "Protective", "T", "Cell", "Memory", "than", "BCG.", "PLoS", "ONE", "6(1):", "e16097.", "doi:10.1371/journal.pone.0016097", "Editor:", "Leonardo", "A.", "Sechi,", "Universita", "di", "Sassari,", "Italy", "Received", "November", "30,", "2010;", "Accepted", "December", "10,", "2010;", "Published", "January", "19,", "2011", "Copyright:", "2011", "Singh", "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", "is", "supported", "by", "the", "Indian", "Council", "of", "Medical", "Research", "(Grant", "Reference", "No.", "5/8/5/6/2005-ECD-I)", "and", "Department", "of", "Biotechnology", "(Grant", "Reference", "No.", "BT/PR6219/Med/14/762/2005),", "New", "Delhi,", "India.", "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:", "javed@imtech.res.in", "Introduction", "In", "1992,", "nearly", "100", "million", "children", "received", "BCG", "[1].", "Despite", "the", "reality", "that", "more", "people", "have", "been", "immunized", "with", "BCG", "than", "any", "other", "vaccine,", "TB", "continues", "to", "kill", "some", "2", "million", "people", "annually", "and", "2", "billion", "people", "worldwide", "are", "infected", "with", "M.", "tb", "[2].", "Hence,", "the", "protective", "efficacy", "of", "the", "BCG", "vaccine", "remains", "doubtful.", "The", "wide", "spread", "of", "TB", "has", "been", "further", "aggravated", "by", "the", "emergence", "of", "multidrug-resistant", "(MDR)", "strains", "of", "mycobac-", "teria", "and", "the", "AIDS-pandemic", "[3].", "Therefore,", "there", "is", "a", "serious", "need", "and", "challenge", "for", "scientific", "community", "to", "develop", "alternative", "vaccines", "for", "the", "control", "of", "the", "disease.", "Approximately", "one-third", "of", "the", "world", "population", "is", "infected", "with", "M.", "tb,", "but", "only", "5%–10%", "contract", "active", "disease", "while", "remaining", "develop", "effective", "immunity", "[2].", "Further,", "mice", "cleared", "of", "TB", "infection", "respond", "vigorously", "upon", "re-exposure", "to", "mycobacteria", "and", "remain", "protected", "[4].", "This", "suggests", "that", "infection", "with", "viable", "mycobacteria", "develop", "effective", "and", "long-lasting", "protective", "immu-", "nity.", "There", "may", "exist", "a", "possibility", "that", "growing", "bacilli", "express", "discrete", "molecules", "inside", "the", "macrophage", "[5],", "that", "may", "act", "as", "protective", "antigens", "necessary", "for", "the", "generation", "of", "effector", "and", "memory", "T", "cells", "responsible", "for", "protective", "immunity.", "Whether", "such", "protective", "antigens", "of", "M.", "tb", "that", "can", "be", "exploited", "as", "vaccines,", "still", "remains", "to", "be", "identified.", "[4,5].", "Incidentally,", "the", "antigens", "isolated", "from", "in", "vitro", "cultures", "have", "failed", "to", "generate", "considerable", "protective", "immunity,", "corroborating", "to", "the", "above", "mentioned", "hypothesis", "[6,7].", "In", "the", "past", "few", "decades,", "a", "number", "of", "new", "vaccine", "approaches", "like", "naked", "DNA", "vaccines,", "live", "attenuated", "vaccines", "and", "subunit", "vaccines", "have", "been", "elucidated.", "Unfortunately,", "none", "of", "them", "worked", "successfully", "against", "TB", "since", "they", "failed", "to", "generate", "long-", "lasting", "memory", "cells", "[8].", "This", "indicates", "that", "novel", "and", "unique", "vaccination", "strategies", "still", "need", "to", "be", "explored", "for", "TB.", "Recently,", "many", "studies", "have", "highlighted", "the", "role", "of", "cell-based", "vaccines", "viz.", "antigen-loaded", "DCs", "to", "evoke", "protective", "T", "cell", "PLoS", "ONE", "\|", "www.plosone.org", "1", "January", "2011", "\|", "Volume", "6", "\|", "Issue", "1", "\|", "e16097" ]	[ 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, 1, 1, 1, 1, 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, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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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1074 ], [ 760, 1062, 785, 1074 ] ]	[ "organic", "compounds", "Acta", "Crystallographica", "Section", "E", "Structure", "Reports", "Online", "ISSN", "1600-5368", "Dihalogenated", "trichodermin", "(4b-", "acetoxy-9,10-dibromo-12,13-epoxytri-", "chothec)", "Jin-Hao", "Zhao,a", "Yong", "Zhou,b", "Jian-Gong", "Zhang,a", "Jing-Li", "Chenga", "and", "Fu-Cheng", "Linc*", "aInstitute", "of", "Pesticide", "and", "Environmental", "Toxicology,", "Zhejiang", "University,", "Hangzhou", "310029,", "People’s", "Republic", "of", "China,", "bCollege", "of", "Chemical", "Engineering", "and", "Materials", "Science,", "Zhejiang", "University", "Of", "Technology,", "Hangzhou", "310032,", "People’s", "Republic", "of", "China,", "and", "cInstitute", "of", "Biotechnology,", "Zhejiang", "University,", "Hangzhou", "310029,", "People’s", "Republic", "of", "China", "Correspondence", "e-mail:", "fuchenglin@zj.com", "Received", "30", "November", "2009;", "accepted", "15", "December", "2009", "Key", "indicators:", "single-crystal", "X-ray", "study;", "T", "=", "296", "K;", "mean", "(C–C)", "=", "0.007", "A˚;", "R", "factor", "=", "0.032;", "wR", "factor", "=", "0.095;", "data-to-parameter", "ratio", "=", "17.2.", "In", "the", "title", "dihalogenated", "trichodermin", "molecule,", "C17H24Br2O4", "(systematic", "name:", "9,10-dibromo-12,13-epoxy-", "trichothec-9-en-4", "-yl", "acetate),", "the", "ﬁve-membered", "ring", "displays", "an", "envelope", "conformation,", "whereas", "the", "two", "six-", "membered", "rings", "show", "the", "same", "conformation,", "viz.", "chair.", "As", "for", "the", "seven-membered", "ring,", "the", "dihedral", "angle", "between", "the", "mean", "planes", "formed", "by", "the", "four", "C", "atoms", "of", "the", "envelope", "unit", "and", "the", "three", "C", "and", "one", "O", "atoms", "of", "the", "six-membered", "chair", "is", "69.08", "(4)", ";", "these", "two", "mean", "planes", "are", "nearly", "perpendicular", "to", "the", "epoxy", "ring", "with", "angles", "of", "87.53", "(4)", "and", "88.67", "(4)", ",", "respectively.", "Related", "literature", "For", "the", "fungicidal", "activity", "of", "trichodermin,", "see:", "Zhang", "et", "al.", "(2007).", "Trichodermin", "is", "a", "member", "of", "the", "4", "-aceoxy-12,13-", "epoxytrichothecene", "family,", "see:", "Nielsen", "et", "al.", "(2005).", "For", "the", "structure", "of", "trichodermin,", "see:", "Chen", "et", "al.", "(2008)", "and", "for", "the", "structure", "of", "a", "trichodermin", "derivative,", "see:", "Cheng", "et", "al.", "(2009).", "Experimental", "Crystal", "data", "C17H24Br2O4", "Mr", "=", "452.18", "Monoclinic,", "P21", "a", "=", "10.0120", "(4)", "A˚", "b", "=", "8.3397", "(4)", "A˚", "c", "=", "11.1235", "(6)", "A˚", "=", "106.6220", "(10)", "Data", "collection", "Rigaku", "R-AXIS", "RAPID", "diffractometer", "Absorption", "correction:", "multi-scan", "(ABSCOR:", "Higashi,", "1995)", "Tmin", "=", "0.323,", "Tmax", "=", "0.633", "Reﬁnement", "R[F", "2", ">", "2", "(F", "2)]", "=", "0.032", "wR(F", "2)", "=", "0.095", "S", "=", "1.00", "3667", "reﬂections", "213", "parameters", "1", "restraint", "V", "=", "889.97", "(7)", "A˚", "3", "Z", "=", "2", "Mo", "K", "radiation", "=", "4.57", "mm", "1", "T", "=", "296", "K", "0.26", "0.20", "0.10", "mm", "8698", "measured", "reﬂections", "3667", "independent", "reﬂections", "2752", "reﬂections", "with", "I", ">", "2", "(I)", "Rint", "=", "0.032", "H-atom", "parameters", "constrained", "max", "=", "0.67", "e", "A˚", "3", "min", "=", "0.65", "e", "A˚", "3", "Absolute", "structure:", "Flack", "(1983),", "1506", "Friedel", "pairs", "Flack", "parameter:", "0.000", "(15)", "Data", "collection:", "PROCESS-AUTO", "(Rigaku,", "2006);", "cell", "reﬁne-", "ment:", "PROCESS-AUTO;", "data", "reduction:", "CrystalStructure", "(Rigaku,", "2007);", "program(s)", "used", "to", "solve", "structure:", "SHELXS97", "(Sheldrick,", "2008);", "program(s)", "used", "to", "reﬁne", "structure:", "SHELXL97", "(Sheldrick,", "2008);", "molecular", "graphics:", "ORTEP-3", "for", "Windows", "(Farrugia,", "1997);", "software", "used", "to", "prepare", "material", "for", "publication:", "WinGX", "(Farrugia,", "1999)", "and", "PLATON", "(Spek,", "2009).", "The", "work", "was", "supported", "by", "the", "National", "Natural", "Science", "Foundation", "of", "China", "(No.", "30700532)", "and", "the", "Science", "and", "Technology", "Project", "of", "Zhejiang", "Province", "(No.", "2009", "C21014).", "The", "authors", "are", "grateful", "to", "Professor", "Jianming", "Gu", "for", "the", "crystal", "structure", "analysis.", "Supplementary", "data", "and", "ﬁgures", "for", "this", "paper", "are", "available", "from", "the", "IUCr", "electronic", "archives", "(Reference:", "SI2228).", "References", "Chen,", "S.-Y.,", "Zhang,", "C.-L.,", "Chen,", "Y.-Z.", "&", "Lin,", "F.-C.", "(2008).", "Acta", "Cryst.", "E64,", "o702.", "Cheng,", "J.-L.,", "Zhou,", "Y.,", "Lin,", "F.-C.,", "Zhao,", "J.-H.", "&", "Zhu,", "G.-N.", "(2009).", "Acta", "Cryst.", "E65,", "o2879.", "Farrugia,", "L.", "J.", "(1997).", "J.", "Appl.", "Cryst.", "30,", "565.", "Farrugia,", "L.", "J.", "(1999).", "J.", "Appl.", "Cryst.", "32,", "837–838.", "Flack,", "H.", "D.", "(1983).", "Acta", "Cryst.", "A39,", "876–881.", "Higashi,", "T.", "(1995).", "ABSCOR.", "Rigaku", "Corporation,", "Tokyo,", "Japan.", "Nielsen,", "K.", "F.,", "Grafenhan,", "T.,", "Zafari,", "D.", "&", "Thrane,", "U.", "(2005).", "J.", "Agric.", "Food", "Chem.", "53,", "8190–8196.", "Rigaku", "(2006).", "PROCESS-AUTO.", "Rigaku", "Corporation,", "Tokyo,", "Japan.", "Rigaku", "(2007).", "CrystalStructure.", "Rigaku", "Corporation,", "Tokyo,", "Japan.", "Sheldrick,", "G.", "M.", "(2008).", "Acta", "Cryst.", "A64,", "112–122.", "Spek,", "A.", "L.", "(2009).", "Acta", "Cryst.", "D65,", "148–155.", "Zhang,", "C.,", "Liu,", "S.,", "Lin,", "F.,", "Kubicek,", "C.", "P.", "&", "Druzhinina,", "I.", "S.", "(2007).", "Microbiology", "Lett.", "270,", "90–96.", "o210", "Zhao", "et", "al.", "doi:10.1107/S1600536809054178", "Acta", "Cryst.", "(2010).", "E66,", "o210" ]	[ 16, 16, 0, 0, 0, 0, 0, 0, 0, 0, 0, 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, 3, 3, 3, 7, 7, 7, 7, 7, 7, 7, 7, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 9, 14, 5, 8, 8, 8, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 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, 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1053, 149, 1063 ], [ 427, 1053, 444, 1063 ] ]	[ "A", "Cell-free", "Assay", "System", "for", "b-Catenin", "Signaling", "that", "Recapitulates", "Direct", "Inductive", "Events", "in", "the", "Early", "Xenopus", "laevis", "Embryo", "Richard", "W.", "Nelson", "and", "Barry", "M.", "Gumbiner", "Cellular", "Biochemistry", "and", "Biophysics", "Program,", "Memorial", "Sloan-Kettering", "Cancer", "Center,", "New", "York,", "New", "York", "10021", "Abstract.", "In", "vertebrate", "embryos,", "signaling", "via", "the", "b-catenin", "protein", "is", "known", "to", "play", "an", "essential", "role", "in", "the", "induction", "of", "the", "dorsal", "axis.", "In", "its", "signaling", "capacity,", "b-catenin", "acts", "directly", "to", "affect", "target", "gene", "transcrip-", "tion,", "in", "concert", "with", "transcription", "factors", "of", "the", "TCF/", "LEF", "family.", "We", "have", "developed", "a", "cell-free", "in", "vitro", "as-", "say", "for", "b-catenin", "signaling", "activity", "that", "utilizes", "tran-", "scriptionally", "active", "nuclei", "and", "cytoplasm", "from", "cleavage-", "blocked", "Xenopus", "laevis", "embryos.", "Under", "these", "assay", "conditions,", "we", "demonstrate", "that", "either", "addition", "of", "b-catenin", "protein", "or", "upstream", "activation", "of", "the", "b-cate-", "nin", "signaling", "pathway", "can", "induce", "the", "expression", "of", "de-", "velopmentally", "relevant", "target", "genes.", "Addition", "of", "exoge-", "nous", "b-catenin", "protein", "induced", "expression", "of", "Siamois,", "XTwin,", "Xnr3,", "and", "Cerberus", "mRNAs", "in", "a", "protein", "syn-", "thesis", "independent", "manner,", "whereas", "a", "panel", "of", "other", "Spemann", "organizer-speciﬁc", "genes", "did", "not", "respond", "to", "b-catenin.", "Lithium", "induction", "of", "the", "b-catenin", "signaling", "A", "S", "a", "b-catenin", "key", "intermediate", "and", "its", "homologues", "in", "the", "Wnt", "signaling", "are", "known", "pathway,", "to", "play", "important", "roles", "in", "numerous", "developmental", "pro-", "cesses,", "including", "segmentation", "in", "Drosophila", "melanogaster", "(Peifer", "et", "al.,", "1991),", "cell", "fate", "determinations", "in", "Caenorhab-", "ditis", "elegans", "(Thorpe", "et", "al.,", "1997;", "Giarre", "et", "al.,", "1998),", "and", "dorsal", "axis", "formation", "in", "vertebrates", "(McCrea", "et", "al.,", "1993;", "Heasman", "et", "al.,", "1994;", "Funayama", "et", "al.,", "1995).", "In", "addition", "to", "its", "role", "in", "developmental", "events,", "the", "loss", "of", "control", "of", "b-catenin", "signaling", "has", "been", "shown", "to", "be", "an", "essential", "step", "in", "the", "progression", "of", "cancer", "in", "certain", "differentiated", "tis-", "sues", "(for", "review,", "see", "Gumbiner,", "1997;", "Bullions", "and", "Le-", "vine,", "1998).", "As", "a", "central", "component", "of", "the", "cadherin", "adhesion", "com-", "plex,", "b-catenin", "is", "expressed", "widely", "in", "the", "cells", "of", "verte-", "brates.", "However,", "this", "cadherin-bound", "pool", "of", "b-catenin", "is", "not", "thought", "to", "directly", "participate", "in", "signaling.", "Rather,", "a", "Address", "correspondence", "to", "Barry", "M.", "Gumbiner,", "Cellular", "Biochemistry", "and", "Biophysics", "Program,", "Memorial", "Sloan-Kettering", "Cancer", "Center,", "New", "York,", "NY", "10021.", "Tel.:", "(212)", "639-6146.", "E-mail:", "b-gumbiner@ski.mskcc.org", "Richard", "W.", "Nelson’s", "current", "address", "is", "Biology", "Department,", "Wabash", "College,", "Crawfordsville,", "IN", "47933.", "pathway,", "which", "is", "thought", "to", "cause", "b-catenin", "accumula-", "tion", "by", "inhibiting", "its", "proteasome-dependent", "degrada-", "tion,", "caused", "increased", "expression", "of", "Siamois", "in", "a", "pro-", "tein", "synthesis", "independent", "fashion.", "This", "result", "suggests", "that", "b-catenin", "derived", "from", "a", "preexisting", "pool", "can", "be", "activated", "to", "signal,", "and", "that", "accumulation", "of", "this", "acti-", "vated", "form", "does", "not", "require", "ongoing", "synthesis.", "Further-", "more,", "activation", "of", "the", "signaling", "pathway", "with", "lithium", "did", "not", "detectably", "alter", "cytoplasmic", "b-catenin", "levels", "and", "was", "insensitive", "to", "inhibition", "of", "the", "proteasome-", "dependent", "degradation", "pathway.", "Taken", "together,", "these", "results", "suggest", "that", "activation", "of", "b-catenin", "signaling", "by", "lithium", "in", "this", "system", "may", "occur", "through", "a", "distinct", "acti-", "vation", "mechanism", "that", "does", "not", "require", "modulation", "of", "levels", "through", "regulation", "of", "proteasomal", "degradation.", "Key", "words:", "b-catenin", "•", "Xenopus", "laevis", "•", "Siamois", "•", "signaling", "•", "assay", "pool", "of", "free", "b-catenin", "(not", "bound", "to", "cadherins)", "enters", "the", "nucleus", "(Fagotto", "et", "al.,", "1998)", "and,", "through", "direct", "interac-", "tion", "with", "transcription", "factors", "of", "the", "TCF/LEF", "family,", "af-", "fects", "transcriptional", "activation", "at", "target", "gene", "promoters", "(Behrens", "et", "al.,", "1996;", "Huber", "et", "al.,", "1996;", "Molenaar", "et", "al.,", "1996).", "Therefore,", "modulation", "of", "the", "levels", "or", "activity", "of", "these", "noncadherin", "bound", "pool(s)", "of", "b-catenin", "is", "likely", "to", "be", "crucial", "for", "effective", "control", "of", "the", "signaling", "pathway.", "Maintenance", "of", "low", "levels", "of", "cytoplasmic", "b-catenin", "is", "brought", "about", "by", "ubiquitin-dependent", "degradation", "(Ab-", "erle", "et", "al.,", "1997;", "Orford", "et", "al.,", "1997;", "Jiang", "and", "Struhl,", "1998;", "Marikawa", "and", "Elinson,", "1998;", "for", "review,", "see", "Maniatis,", "1999).", "In", "cell", "culture", "systems,", "ubiquitin-dependent", "degra-", "dation", "of", "b-catenin", "is", "facilitated", "by", "the", "interaction", "of", "b-catenin", "with", "a", "number", "of", "proteins,", "including", "axin/conduc-", "tin", "(Zeng", "et", "al.,", "1997;", "Behrens", "et", "al.,", "1998;", "Hart", "et", "al.,", "1998;", "Ikeda", "et", "al.,", "1998;", "Itoh", "et", "al.,", "1998;", "Kishida", "et", "al.,", "1998;", "Na-", "kamura", "et", "al.,", "1998;", "Yamamoto", "et", "al.,", "1998),", "the", "adenoma-", "tous", "polyposis", "coli", "(APC)1", "protein", "(Rubinfeld", "et", "al.,", "1993;", "1.", "Abbreviations", "used", "in", "this", "paper:", "APC,", "adenomatous", "polyposis", "coli;", "GSK-3,", "glycogen", "synthase", "kinase", "3;", "RT,", "reverse", "transcriptase.", "ª", "The", "Rockefeller", "University", "Press,", "0021-9525/99/10/367/8", "$5.00", "The", "Journal", "of", "Cell", "Biology,", "Volume", "147,", "Number", "2,", "October", "18,", "1999", "367–374", "http://www.jcb.org", "367" ]	[ 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, 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, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 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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3,414,702

null

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[ "Cell", "Tissue", "Res", "(2012)", "349:517–525", "DOI", "10.1007/s00441-012-1426-4", "REGULAR", "ARTICLE", "Proliferation", "pattern", "during", "rostrum", "regeneration", "of", "the", "symbiotic", "flatworm", "Paracatenula", "galateia:", "a", "pulse-chase-pulse", "analysis", "Ulrich", "Dirks", "&", "Harald", "R.", "Gruber-Vodicka", "&", "Bernhard", "Egger", "&", "Jörg", "A.", "Ott", "Received:", "22", "November", "2011", "/", "Accepted:", "30", "March", "2012", "/", "Published", "online:", "22", "May", "2012", "#", "The", "Author(s)", "2012.", "This", "article", "is", "published", "with", "open", "access", "at", "Springerlink.com", "Abstract", "The", "remarkable", "totipotent", "stem-cell-based", "regener-", "ation", "capacities", "of", "the", "Platyhelminthes", "have", "brought", "them", "into", "the", "focus", "of", "stem", "cell", "and", "regeneration", "research.", "Although", "selected", "platyhelminth", "groups", "are", "among", "the", "best-studied", "invertebrates,", "our", "data", "provide", "new", "insights", "into", "regenerative", "processes", "in", "the", "most", "basally", "branching", "group", "of", "the", "Platyhel-", "minthes,", "the", "Catenulida.", "The", "mouth-", "and", "gutless", "free-living", "catenulid", "flatworm", "Paracatenula", "galateia", "harbors", "intracellular", "bacterial", "symbionts", "in", "its", "posterior", "body", "region,", "the", "tropho-", "some", "region,", "accounting", "for", "up", "to", "50%", "of", "the", "volume.", "Follow-", "ing", "decapitation", "of", "this", "flatworm,", "we", "have", "analyzed", "the", "behavior", "of", "the", "amputated", "fragments", "and", "any", "anterior", "and", "posterior", "regeneration.", "Using", "an", "EdU-pulse-chase/BrdU-pulse", "thymidine", "analog", "double-labeling", "approach", "combined", "with", "immunohistochemistry,", "we", "show", "that", "neoblasts", "are", "the", "main", "drivers", "of", "the", "regeneration", "processes.", "During", "anterior", "(rostrum)", "regeneration,", "EdU-pulse-chase-labeled", "cells", "aggregate", "inside", "the", "regenerating", "rostrum,", "whereas", "BrdU", "pulse-labeling", "before", "fixation", "indicates", "clusters", "of", "S-phase", "neoblasts", "at", "the", "same", "position.", "In", "parallel,", "serotonergic", "nerves", "reorganize", "and", "the", "U.", "Dirks", "(*)", ":", "H.", "R.", "Gruber-Vodicka", ":", "J.", "A.", "Ott", "Department", "of", "Marine", "Biology,", "University", "of", "Vienna,", "Althanstrasse", "14,", "1090", "Vienna,", "Austria", "e-mail:", "Uli.Dirks@gmx.de", "B.", "Egger", "Ultrastructural", "Research", "and", "Evolutionary", "Biology,", "Institute", "of", "Zoology,", "University", "of", "Innsbruck,", "Technikerstrasse", "25,", "6020", "Innsbruck,", "Austria", "B.", "Egger", "Department", "of", "Genetics,", "Evolution", "and", "Environment,", "University", "College", "London,", "Gower", "Street,", "Darwin", "Building,", "WC1E", "6BT", "London,", "UK", "brain", "regenerates.", "In", "completely", "regenerated", "animals,", "the", "orig-", "inal", "condition", "with", "S-phase", "neoblasts", "being", "restricted", "to", "the", "body", "region", "posterior", "to", "the", "brain", "is", "restored.", "In", "contrast,", "no", "posterior", "regeneration", "or", "growth", "of", "the", "trophosome", "region", "in", "anterior", "fragments", "cut", "a", "short", "distance", "posterior", "to", "the", "brain", "has", "been", "observed.", "Our", "data", "thus", "reveal", "interesting", "aspects", "of", "the", "cellular", "processes", "underlying", "the", "regeneration", "of", "the", "emerging", "catenulid-bacteria", "symbiosis", "model", "P.", "galateia", "and", "show", "that", "a", "neoblast", "stem", "cell", "system", "is", "indeed", "a", "plesiomorphic", "feature", "of", "basal", "platyhelminths.", "Keywords", "Morphallaxis", ".", "Epimorphosis", ".", "Bacteriocyte", ".", "Paratomy", ".", "Blastema", ".", "Neoblast", "Introduction", "From", "the", "human", "point", "of", "view,", "the", "capability", "to", "regenerate", "lost", "body", "parts", "is", "a", "fascinating", "phenomenon.", "Indeed,", "among", "many", "invertebrates,", "regeneration", "is", "a", "common", "feature,", "which", "is,", "in", "many", "cases,", "also", "connected", "with", "asexual", "repro-", "duction.", "For", "more", "than", "100", "years,", "Platyhelminthes", "have", "acted", "as", "famous", "model", "systems", "for", "studying", "the", "principles", "underlying", "the", "regeneration", "of", "lost", "body", "parts.", "Because", "of", "their", "extraordinary", "regeneration", "capacity,", "some", "flatworms", "have", "been", "called", "“almost", "immortal", "under", "the", "edge", "of", "the", "knife”", "(Dalyell", "1814).", "Today,", "we", "know", "of", "the", "huge", "variety", "of", "regenerative", "powers", "exhibited", "by", "the", "various", "flatworm", "taxa", "and", "researchers", "have", "tried", "to", "categorize", "and", "to", "deter-", "mine", "a", "pattern", "explaining", "why", "some", "species", "can", "regenerate", "lost", "body", "parts", "and", "others", "cannot", "(for", "a", "review,", "see", "Egger", "et", "al.", "2007).", "Comparative", "data", "suggest", "a", "link", "between", "asexual", "reproduction", "and", "regenerative", "capabilities,", "as", "these", "process-", "es", "co-occur", "and", "show", "strong", "parallels", "in", "their", "progression", "pattern.", "Therefore,", "the", "use", "of", "the", "term", "“pregeneration”", "has" ]

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[ "Available", "online", "http://breast-cancer-research.com/content/11/3/R42", "Research", "article", "Vol11No3", "The", "role", "of", "YY1", "in", "reduced", "HP1α", "gene", "expression", "in", "invasive", "human", "breast", "cancer", "cells", "Open", "Access", "Jason", "G", "Lieberthal,", "Marissa", "Kaminsky,", "Christopher", "N", "Parkhurst", "and", "Naoko", "Tanese", "Department", "of", "Microbiology", "and", "NYU", "Cancer", "Institute,", "New", "York", "University", "School", "of", "Medicine,", "550", "First", "Avenue,", "New", "York,", "NY", "10016", "Corresponding", "author:", "Naoko", "Tanese,", "tanesn01@med.nyu.edu", "Received:", "14", "Oct", "2008", "Revisions", "requested:", "4", "Nov", "2008", "Revisions", "received:", "31", "May", "2009", "Accepted:", "30", "Jun", "2009", "Published:", "30", "Jun", "2009", "Breast", "Cancer", "Research", "2009,", "11:R42", "(doi:10.1186/bcr2329)", "This", "article", "is", "online", "at:", "http://breast-cancer-research.com/content/11/3/R42", "©", "2009", "Lieberthal", "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", "Introduction", "Heterochromatin", "protein", "1", "(HP1)", "associates", "with", "chromatin", "by", "binding", "to", "histone", "H3", "and", "contributes", "to", "gene", "silencing.", "There", "are", "three", "isoforms", "of", "HP1", "in", "mammals:", "HP1α,", "β,", "and", "γ.", "Studies", "have", "shown", "that", "the", "level", "of", "HP1α", "is", "reduced", "in", "invasive", "human", "breast", "cancer", "cell", "lines", "such", "as", "MDA-MB-231", "and", "HS578T", "compared", "with", "non-invasive", "cell", "lines", "such", "as", "MCF7", "and", "T47D.", "It", "is", "hypothesized", "that", "reduced", "HP1α", "expression", "may", "lead", "to", "impaired", "epigenetic", "silencing", "of", "genes", "that", "are", "important", "in", "the", "acquisition", "of", "an", "invasive", "phenotype.", "We", "set", "out", "to", "determine", "whether", "reduced", "expression", "of", "HP1α", "in", "invasive", "breast", "cancer", "cell", "lines", "occurs", "at", "the", "level", "of", "transcription.", "Methods", "We", "used", "transient", "transfection", "assays", "to", "investigate", "the", "mechanism", "of", "differential", "transcriptional", "activity", "of", "the", "human", "HP1α", "gene", "promoter", "in", "different", "cell", "lines.", "Mutational", "analysis", "of", "putative", "transcription", "factor", "binding", "sites", "in", "an", "HP1α", "gene", "reporter", "construct", "was", "performed", "to", "identify", "transcription", "factors", "responsible", "for", "the", "differential", "activity.", "SiRNA-mediated", "knockdown", "and", "chromatin", "immunoprecipitation", "experiments", "Introduction", "Heterochromatin", "protein", "1", "(HP1)", "was", "first", "identified", "in", "Dro-", "sophila", "as", "a", "non-histone", "component", "of", "chromatin", "[1].", "Muta-", "tions", "in", "the", "HP1", "gene", "resulted", "in", "suppression", "of", "position-", "effect", "variegation,", "a", "result", "that", "implicated", "HP1", "in", "chromatin", "structure", "and", "gene", "expression", "[2].", "Mutation", "of", "the", "gene", "encoding", "HP1", "in", "Drosophila", "resulted", "in", "larval", "lethality", "[3].", "Examination", "of", "HP1", "mutant", "embryos", "revealed", "defects", "in", "chro-", "mosome", "segregation", "and", "telomere", "maintenance", "[4,5].", "There-", "fore,", "HP1", "is", "thought", "to", "play", "an", "essential", "role", "in", "heterochromatin-dependent", "processes", "in", "Drosophila.", "HP1", "were", "performed", "to", "determine", "the", "role", "of", "a", "specific", "transcription", "factor", "in", "regulating", "the", "HP1α", "gene.", "Results", "The", "transcription", "factor", "yin", "yang", "1", "(YY1)", "was", "found", "to", "play", "a", "role", "in", "differential", "transcriptional", "activity", "of", "the", "HP1α", "gene.", "Examination", "of", "the", "YY1", "protein", "and", "mRNA", "levels", "revealed", "that", "both", "were", "reduced", "in", "the", "invasive", "cell", "line", "HS578T", "compared", "with", "MCF7", "cells.", "YY1", "knockdown", "in", "MCF7", "cells", "resulted", "in", "a", "decreased", "level", "of", "HP1α", "mRNA,", "indicating", "that", "YY1", "positively", "regulates", "HP1α", "expression.", "Chromatin", "immunoprecipitation", "experiments", "verified", "YY1", "occupancy", "at", "the", "HP1α", "gene", "promoter", "in", "MCF7", "cells", "but", "not", "HS578T", "cells.", "Overexpression", "of", "YY1", "in", "HS578T", "cells", "decreased", "cell", "migration", "in", "a", "manner", "independent", "of", "HP1α", "overexpression.", "Conclusions", "Our", "data", "suggests", "that", "a", "reduction", "of", "YY1", "expression", "in", "breast", "cancer", "cells", "could", "contribute", "to", "the", "acquisition", "of", "an", "invasive", "phenotype", "through", "increased", "cell", "migration", "as", "well", "as", "by", "reduced", "expression", "of", "HP1α.", "can", "also", "be", "found", "in", "certain", "euchromatic", "loci,", "implying", "its", "role", "in", "euchromatic", "regions", "[6,7].", "HP1", "homologues", "have", "been", "identified", "in", "a", "variety", "of", "organ-", "isms", "including", "yeast,", "nematodes,", "insects,", "chickens,", "frogs,", "and", "mammals", "[8].", "There", "are", "three", "HP1", "isoforms", "in", "mammals:", "HP1α,", "β", "and", "γ", "[9,10].", "Each", "HP1", "isoform", "has", "a", "different", "chro-", "mosomal", "distribution.", "HP1α", "is", "located", "mainly", "in", "heterochro-", "matic", "regions,", "HP1β", "is", "found", "in", "both", "heterochromatic", "and", "euchromatic", "regions,", "and", "HP1γ", "is", "located", "almost", "exclusively", "in", "euchromatic", "regions", "[11-13].", "The", "localization", "of", "HP1", "isoforms", "to", "different", "regions", "of", "chromatin", "implies", "that", "each", "isoform", "BSA:", "bovine", "serum", "albumin;", "CD:", "chromodomain;", "ChIP:", "chromatin", "immunoprecipitation;", "CSD:", "chromoshadow", "domain;", "DMEM:", "Dulbecco's", "Modified", "Eagle", "Medium;", "HNRPA1:", "heterogeneous", "nuclear", "ribonucleoprotein", "A1;", "HP1:", "heterochromatin", "protein", "1;", "NRF-1:", "nuclear", "respiratory", "factor-1;", "PBS:", "phosphate-buffered", "saline;", "RT-PCR:", "reverse", "transcription", "polymerase", "chain", "reaction;", "YY1:", "ying", "yang", "1.", "Page", "1", "of", "11", "(page", "number", "not", "for", "citation", "purposes)" ]

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2,714,129

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[ "Available", "online", "http://arthritis-research.com/content/11/3/114", "Editorial", "Stress", "of", "different", "types", "increases", "the", "proinflammatory", "load", "in", "rheumatoid", "arthritis", "Rainer", "H", "Straub1", "and", "Joachim", "R", "Kalden2", "1Laboratory", "of", "Experimental", "Rheumatology", "and", "Neuroendocrino-Immunology,", "Division", "of", "Rheumatology,", "Department", "of", "Internal", "Medicine", "I,", "University", "Hospital,", "93042", "Regensburg,", "Germany", "2Department", "of", "Medicine", "3,", "University", "of", "Erlangen–Nuremberg,", "Nikolaus-Fiebiger-Center,", "91054", "Erlangen,", "Germany", "Corresponding", "author:", "Rainer", "H", "Straub,", "rainer.straub@klinik.uni-regensburg.de", "Published:", "17", "June", "2009", "This", "article", "is", "online", "at", "http://arthritis-research.com/content/11/3/114", "©", "2009", "BioMed", "Central", "Ltd", "See", "related", "research", "by", "Edwards", "et", "al.,", "http://arthritis-research.com/content/11/3/R61", "Arthritis", "Research", "&", "Therapy", "2009,", "11:114", "(doi:10.1186/ar2712)", "Abstract", "Stress", "in", "patients", "with", "chronic", "inflammatory", "diseases", "such", "as", "rheumatoid", "arthritis", "(RA)", "stimulates", "proinflammatory", "mechanisms", "due", "to", "the", "defect", "of", "stress", "response", "systems", "(for", "example,", "the", "sympathetic", "nervous", "system", "and", "the", "hypothalamic–pituitary–", "adrenal", "axis).", "Among", "other", "mechanisms,", "the", "loss", "of", "sympathetic", "nerve", "fibers", "in", "inflamed", "tissue", "and", "inadequate", "cortisol", "secretion", "in", "relation", "to", "inflammation", "lead", "to", "an", "enhanced", "proinflammatory", "load", "in", "RA.", "Stress", "and", "the", "subsequent", "stimulation", "of", "inflammation", "(systemic", "and", "local)", "lead", "to", "increased", "sensitization", "of", "pain", "and", "further", "defects", "of", "stress", "response", "systems", "(vicious", "cycle", "of", "stress,", "pain,", "and", "inflammation).", "In", "1937", "Hans", "Selye", "called", "the", "activation", "of", "stress", "systems", "an", "‘alarm", "reaction’,", "which", "is", "the", "reaction", "of", "an", "organism", "‘when", "first", "confronted", "with", "a", "stimulus", "to", "which", "it", "is", "quantitatively", "or", "qualitatively", "not", "adapted’.", "Until", "the", "beginning", "of", "the", "1980s,", "the", "stress", "systems", "including", "the", "sympathetic", "nervous", "system", "(SNS)", "and", "the", "hypothalamic–pituitary–adrenal", "axis", "were", "thought", "to", "play", "a", "proinflammatory", "role", "by", "supporting", "the", "immune", "response.", "This", "view", "was", "markedly", "changed", "in", "the", "years", "thereafter,", "when", "targeted", "experiments", "with", "specific", "immune", "cells", "involving", "hormones", "of", "the", "SNS", "and", "hypo-", "thalamic–pituitary–adrenal", "axis", "were", "carried", "out", "using", "cell", "culture.", "These", "results", "demonstrated", "that", "noradrenaline", "(via", "β2-adrenoceptors", "at", "10–6", "M)", "and", "cortisol", "(via", "glucocorticoid", "receptor", "α)", "exert", "many", "anti-inflammatory", "effects.", "Today", "we", "know", "that", "both", "proinflammatory", "and", "anti-inflammatory", "effects", "can", "appear", "under", "stressful", "conditions,", "which", "depend", "on", "the", "duration", "of", "the", "stress,", "the", "intensity", "of", "stress,", "the", "perception", "of", "stress", "(whether", "positive", "or", "negative),", "the", "environmental", "milieu", "within", "the", "body", "of", "the", "stressed", "person", "(whether", "acutely", "ill", "or", "chronically", "ill),", "and", "the", "time", "point", "of", "stress", "in", "relation", "to", "the", "outbreak", "of", "a", "chronic", "inflammatory", "disease", "(whether", "before", "outbreak", "or", "in", "later", "phases", "of", "the", "symptomatic", "disease).", "Knowledge", "in", "the", "stress", "field", "steadily", "increases,", "and", "today", "we", "can", "say", "that", "patients", "with", "chronic", "inflammatory", "diseases", "such", "as", "rheumatoid", "arthritis", "(RA)", "show", "abnormal", "stress", "responses", "leading", "to", "proinflammatory", "consequences.", "Stress", "can", "be", "induced", "by", "pain", "tests,", "which", "was", "recently", "demonstrated", "by", "Edwards", "and", "colleagues", "[1].", "In", "this", "study", "the", "authors", "used", "several", "pain", "tests,", "such", "as", "the", "pressure", "pain", "threshold,", "the", "heat", "pain", "threshold,", "and", "the", "cold", "pressor", "task.", "The", "patients", "with", "RA,", "compared", "with", "healthy", "control", "individuals,", "had", "lower", "mechanical", "pain", "thresholds,", "lower", "heat", "pain", "thresholds,", "and", "lower", "cold", "pain", "tolerance,", "all", "of", "which", "are", "expected", "in", "a", "situation", "with", "peripheral", "sensitization", "to", "noxious", "stimuli", "[2].", "Indeed,", "peripheral", "sensitization", "has", "been", "demonstrated", "several", "times", "in", "RA", "patients", "[2].", "The", "important", "and", "original", "aspect", "of", "the", "work", "of", "Edwards", "and", "colleagues", "is", "the", "fact", "that", "pain", "testing", "increased", "serum", "levels", "of", "TNF,", "which", "was", "not", "demonstrated", "in", "healthy", "control", "individuals.", "The", "increase", "was", "slow", "over", "the", "entire", "observation", "time", "without", "decline.", "A", "similar", "trend", "was", "observed", "for", "serum", "IL-6", "[1].", "This", "effect", "is", "interpreted", "as", "an", "unwanted", "deleterious", "effect", "that", "can", "shape", "the", "long-term", "symptomatology", "in", "RA.", "Edwards", "and", "colleagues’", "paper", "adds", "nicely", "to", "existing", "literature", "where,", "after", "stress", "testing,", "other", "groups", "demon-", "strated", "a", "very", "similar", "effect", "on", "serum", "or", "supernatant", "levels", "(in", "cell", "culture", "experiments)", "of", "proinflammatory", "cytokines", "(Table", "1).", "Since", "stress", "in", "healthy", "subjects", "can", "lead", "to", "an", "increase", "of", "serum", "cytokines", "[3],", "a", "comparison", "of", "patients", "with", "RA", "and", "healthy", "control", "individuals", "is", "mandatory.", "The", "important", "aspect", "in", "the", "studies", "demonstrated", "in", "Table", "1", "is", "the", "fact", "that", "respective", "control", "groups", "did", "not", "show", "a", "similar", "increase", "of", "inflammation", "markers.", "Form", "this", "point", "of", "view,", "the", "IL", "=", "interleukin;", "RA", "=", "rheumatoid", "arthritis;", "SNS", "=", "sympathetic", "nervous", "system;", "TNF", "=", "tumor", "necrosis", "factor.", "Page", "1", "of", "2", "(page", "number", "not", "for", "citation", "purposes)" ]

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[ "Evidence", "for", "a", "Developmental", "Role", "for", "TLR4", "in", "Learning", "and", "Memory", "Eitan", "Okun1*,", "Boaz", "Barak2,", "Ravit", "Saada-Madar1,", "Sarah", "M.", "Rothman3,", "Kathleen", "J.", "Griffioen3,", "Nicholas", "Roberts3,", "Kamilah", "Castro3,", "Mohamed", "R.", "Mughal3,", "Mario", "A.", "Pita3,", "Alexis", "M.", "Stranahan4,", "Thiruma", "V.", "Arumugam5,", "Mark", "P.", "Mattson3,6", "1", "The", "Mina", "and", "Everard", "Goodman", "Faculty", "of", "Life", "Sciences,", "The", "Leslie", "and", "Susan", "Gonda", "Multidisciplinary", "Brain", "Research", "Center,", "Bar-Ilan", "University,", "Ramat", "Gan,", "Israel,", "2", "Department", "of", "Neurobiology,", "Life", "Sciences", "Faculty", "and", "the", "Sagol", "School", "of", "Neuroscience,", "Tel", "Aviv", "University,", "Tel", "Aviv,", "Israel,", "3", "Laboratory", "of", "Neurosciences,", "National", "Institute", "on", "Aging", "Intramural", "Research", "Program,", "Baltimore,", "Maryland,", "United", "States", "of", "America,", "4", "Department", "of", "Physiology,", "Georgia", "Health", "Sciences", "University,", "Augusta,", "Georgia,", "United", "States", "of", "America,", "5", "School", "of", "Biomedical", "Sciences,", "The", "University", "of", "Queensland,", "Queensland,", "Australia,", "6", "Department", "of", "Neuroscience,", "Johns", "Hopkins", "University", "School", "of", "Medicine,", "Baltimore,", "Maryland,", "United", "States", "of", "America", "Abstract", "Toll-like", "receptors", "(TLRs)", "play", "essential", "roles", "in", "innate", "immunity", "and", "increasing", "evidence", "indicates", "that", "these", "receptors", "are", "expressed", "in", "neurons,", "astrocytes", "and", "microglia", "in", "the", "brain", "where", "they", "mediate", "responses", "to", "infection,", "stress", "and", "injury.", "Very", "little", "is", "known", "about", "the", "roles", "of", "TLRs", "in", "cognition.", "To", "test", "the", "hypothesis", "that", "TLR4", "has", "a", "role", "in", "hippocampus-", "dependent", "spatial", "learning", "and", "memory,", "we", "used", "mice", "deficient", "for", "TLR4", "and", "mice", "receiving", "chronic", "TLR4", "antagonist", "infusion", "to", "the", "lateral", "ventricles", "in", "the", "brain.", "We", "found", "that", "developmental", "TLR4", "deficiency", "enhances", "spatial", "reference", "memory", "acquisition", "and", "memory", "retention,", "impairs", "contextual", "fear-learning", "and", "enhances", "motor", "functions,", "traits", "that", "were", "correlated", "with", "CREB", "up-regulation", "in", "the", "hippocampus.", "TLR4", "antagonist", "infusion", "into", "the", "cerebral", "ventricles", "of", "adult", "mice", "did", "not", "affect", "cognitive", "behavior,", "but", "instead", "affected", "anxiety", "responses.", "Our", "findings", "indicate", "a", "developmental", "role", "for", "TLR4", "in", "shaping", "spatial", "reference", "memory,", "and", "fear", "learning", "and", "memory.", "Moreover,", "we", "show", "that", "central", "TLR4", "inhibition", "using", "a", "TLR4", "antagonist", "has", "no", "discernible", "physiological", "role", "in", "regulating", "spatial", "and", "contextual", "hippocampus-dependent", "cognitive", "behavior.", "Citation:", "Okun", "E,", "Barak", "B,", "Saada-Madar", "R,", "Rothman", "SM,", "Griffioen", "KJ,", "et", "al.", "(2012)", "Evidence", "for", "a", "Developmental", "Role", "for", "TLR4", "in", "Learning", "and", "Memory.", "PLoS", "ONE", "7(10):", "e47522.", "doi:10.1371/journal.pone.0047522", "Editor:", "Lena", "Alexopoulou,", "Centre", "d’Immunologie", "de", "Marseille-Luminy,", "CNRS-Inserm,", "France", "Received", "May", "9,", "2012;", "Accepted", "September", "12,", "2012;", "Published", "October", "11,", "2012", "This", "is", "an", "open-access", "article,", "free", "of", "all", "copyright,", "and", "may", "be", "freely", "reproduced,", "distributed,", "transmitted,", "modified,", "built", "upon,", "or", "otherwise", "used", "by", "anyone", "for", "any", "lawful", "purpose.", "The", "work", "is", "made", "available", "under", "the", "Creative", "Commons", "CC0", "public", "domain", "dedication.", "Funding:", "This", "study", "was", "supported", "in", "part", "by", "the", "Intramural", "Research", "Program", "of", "the", "National", "Institute", "on", "Aging", "and", "in", "part", "by", "the", "Gonda", "Multidisciplinary", "Center", "for", "Brain", "Research", "and", "the", "Mina", "and", "Everard", "Goodman", "Faculty", "of", "Life", "Sciences,", "Bar", "Ilan", "University.", "No", "additional", "external", "funding", "was", "received", "for", "this", "study.", "The", "funders", "had", "no", "role", "in", "study", "design,", "data", "collection", "and", "analysis,", "decision", "to", "publish,", "or", "preparation", "of", "the", "manuscript.", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "*", "E-mail:", "eitan.okun@biu.ac.il", "Introduction", "Toll", "like", "receptors", "(TLRs)", "are", "type-I", "trans-membrane", "receptors", "that", "are", "best", "known", "as", "sensors", "of", "microbe-associated", "molecular", "patterns", "(MAMPs)", "by", "cells", "of", "the", "innate", "immune", "system", "[1].", "In", "addition,", "TLRs", "recognize", "damage-associated", "molecular", "patterns", "(DAMPs),", "also", "termed", "‘endogenous", "ligands’,", "generated", "in", "response", "to", "traumatic", "tissue", "injury", "or", "as", "a", "by-product", "of", "inflammation", "[2].", "Binding", "of", "MAMPs", "or", "DAMPs", "to", "TLRs", "typically", "activates", "signaling", "cascades", "that", "result", "in", "production", "of", "inflammatory", "cytokines/chemokines", "by", "effector", "cells,", "and", "may", "also", "stimulate", "a", "peripheral", "immune", "response", "[3].", "TLR4,", "a", "widely", "studied", "TLR,", "is", "activated", "by", "bacterial", "lipopolysaccharide", "(LPS),", "a", "constituent", "of", "the", "outer", "membrane", "of", "gram-negative", "bacteria.", "Central", "activation", "of", "TLR4", "by", "LPS", "has", "been", "thoroughly", "studied", "and", "was", "shown", "to", "reduce", "hippocampal", "pyramidal", "neuron", "dendrite", "length", "and", "to", "impair", "hippocampal-dependent", "spatial", "reference", "memory", "in", "an", "inflammation-dependent", "manner", "implying", "a", "neuroinflammatory", "role", "for", "TLR4", "following", "activation", "with", "bacterial-derived", "ligands", "[4,5].", "Increasing", "evidence", "indicates", "that", "TLRs", "located", "in", "the", "central", "nervous", "system", "are", "involved", "in", "developmental", "and", "adult", "neuroplasticity", "even", "in", "the", "absence", "of", "activation", "by", "infectious", "agents", "or", "tissue", "damage", "[6].", "TLR3", "for", "example,", "is", "a", "negative", "regulator", "of", "embryonic", "neural", "progenitor", "cell", "(NPC)", "proliferation", "[7].", "TLR2", "and", "TLR4", "are", "expressed", "in", "adult", "NPCs", "[8]", "and", "have", "distinct", "and", "opposing", "functions", "in", "NPC", "proliferation", "and", "differentiation;", "TLR2", "deficiency", "impairs", "hippocampal", "neurogen-", "esis,", "whereas", "TLR4", "deficiency", "enhances", "proliferation", "and", "neuronal", "differentiation", "[8].", "Further,", "TLRs", "2,", "3", "and", "4", "are", "expressed", "in", "hippocampal", "neurons", "[9],", "and", "we", "showed", "recently", "that", "TLR3-deficient", "mice", "exhibit", "enhanced", "hippocampus-de-", "pendent", "working", "(but", "not", "reference)", "memory,", "coupled", "with", "extended", "retention", "of", "spatial", "reference", "memory", "[10].", "In", "contrast,", "TLR3-deficient", "mice", "demonstrate", "impaired", "amygdala-", "and", "anxiety-related", "behavior", "[10].", "Because", "TLR3", "is", "involved", "in", "neurogenesis,", "NPC", "proliferation", "and", "cognitive", "learning", "and", "memory,", "we", "sought", "to", "determine", "the", "involvement", "of", "TLR4", "in", "these", "processes.", "The", "hippocampus,", "which", "possesses", "a", "well-defined", "neuroanato-", "my,", "is", "involved", "in", "various", "types", "of", "learning,", "which", "are", "governed", "by", "different", "strategies", "[11,12].", "While", "TLR4", "is", "involved", "in", "CNS", "plasticity", "processes", "such", "as", "NPC", "proliferation,", "the", "impact", "of", "TLR4s", "on", "various", "aspects", "of", "hippocampus-dependent", "learning", "PLOS", "ONE", "|", "www.plosone.org", "1", "October", "2012", "|", "Volume", "7", "|", "Issue", "10", "|", "e47522" ]

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2,804,570

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[ "Scandinavian", "Journal", "of", "Trauma,", "Resuscitation", "and", "Emergency", "Medicine", "Case", "report", "Blunt", "traumatic", "pericardial", "rupture", "and", "cardiac", "herniation", "with", "a", "penetrating", "twist:", "two", "case", "reports", "Peter", "B", "Sherren*,", "Robert", "Galloway", "and", "Marie", "Healy", "BioMed", "Central", "Open", "Access", "Address:", "Department", "of", "Anaesthesia", "and", "Intensive", "care,", "The", "Royal", "London", "Hospital,", "Whitechapel,", "E1", "1BB,", "UK", "Email:", "Peter", "B", "Sherren*", "-", "Petersherren@gmail.com;", "Robert", "Galloway", "-", "drrobgalloway@gmail.com;", "Marie", "Healy", "-", "marie.healy@bartsandthelondon.nhs.uk", "*", "Corresponding", "author", "Published:", "15", "December", "2009", "Scandinavian", "Journal", "of", "Trauma,", "Resuscitation", "and", "Emergency", "Medicine", "2009,", "17:64", "doi:10.1186/1757-7241-", "Accepted:", "15", "December", "2009", "17-64", "Received:", "9", "November", "2009", "This", "article", "is", "available", "from:", "http://www.sjtrem.com/content/17/1/64", "©", "2009", "Sherren", "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:", "Blunt", "Traumatic", "Pericardial", "Rupture", "(BTPR)", "with", "resulting", "cardiac", "herniation", "following", "chest", "trauma", "is", "an", "unusual", "and", "often", "fatal", "condition.", "Although", "there", "has", "been", "a", "multitude", "of", "case", "reports", "of", "this", "condition", "in", "past", "literature,", "the", "recurring", "theme", "is", "that", "of", "a", "missed", "injury.", "Its", "occurrence", "in", "severe", "blunt", "trauma", "is", "in", "the", "order", "of", "0.4%.", "It", "is", "an", "injury", "that", "frequently", "results", "in", "pre/early", "hospital", "death", "and", "diagnosis", "at", "autopsy,", "probably", "owing", "to", "a", "combination", "of", "diagnostic", "difficulties,", "lack", "of", "familiarity", "and", "associated", "polytrauma.", "Of", "the", "patients", "who", "survive", "to", "hospital", "attendance,", "the", "mortality", "rate", "is", "in", "the", "order", "of", "57-64%.", "Methods:", "We", "present", "two", "survivors", "of", "BTPR", "and", "cardiac", "herniation,", "one", "with", "a", "delayed", "penetrating", "cardiac", "injury", "secondary", "to", "rib", "fractures.", "With", "these", "two", "cases", "and", "literature", "review,", "we", "hope", "to", "provide", "a", "greater", "awareness", "of", "this", "injury", "Conclusion:", "BTPR", "and", "cardiac", "herniation", "is", "a", "complex", "and", "often", "fatal", "injury", "that", "usually", "presents", "under", "the", "umbrella", "of", "polytrauma.", "Clinicians", "must", "maintain", "a", "high", "index", "of", "suspicion", "for", "BTPR", "but,", "even", "then,", "the", "diagnosis", "is", "fraught", "with", "difficulty.", "In", "blunt", "chest", "trauma,", "patients", "should", "be", "considered", "high", "risk", "for", "BTPR", "when", "presenting", "with:", "Cardiovascular", "instability", "with", "no", "obvious", "cause", "Prominent", "or", "displaced", "cardiac", "silhouette", "and", "asymmetrical", "large", "volume", "pneumopericardium", "Potentially,", "with", "increasing", "awareness", "of", "the", "injury", "and", "improved", "use", "and", "availability", "of", "imaging", "modalities,", "the", "survival", "rates", "will", "improve", "and", "cardiac", "Herniation", "could", "even", "be", "considered", "the", "5th", "H", "of", "reversible", "causes", "of", "blunt", "traumatic", "PEA", "arrest.", "Background", "Cardiac", "herniation", "is", "a", "significant", "and", "potentially", "fatal", "complication", "of", "BTPR.", "This", "is", "by", "no", "means", "a", "new", "problem", "[1,2]", "and", "its", "occurrence", "in", "severe", "blunt", "trauma", "is", "in", "the", "order", "of", "0.4%", "[3,4].", "Despite", "literature", "experience", "dating", "back", "to", "1864", "[5],", "it", "is", "an", "injury", "that", "frequently", "results", "in", "pre/early", "hospital", "death", "and", "diagnosis", "at", "autopsy,", "proba-", "bly", "owing", "to", "a", "combination", "of", "diagnostic", "difficulties,", "lack", "of", "familiarity", "and", "associated", "polytrauma", "[3,6].", "Of", "those", "who", "make", "it", "to", "hospital,", "and", "are", "later", "diagnosed", "with", "Page", "1", "of", "7", "(page", "number", "not", "for", "citation", "purposes)" ]

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2,387,062

null

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[ "Heart", "Rate", "Variability", "Characteristics", "in", "Sedentary", "Postmenopausal", "Women", "Following", "Six", "Months", "of", "Exercise", "Training:", "The", "DREW", "Study", "Conrad", "P.", "Earnest1*,", "Carl", "J.", "Lavie2,", "Steven", "N.", "Blair3,4,", "Timothy", "S.", "Church1", "1", "Pennington", "Biomedical", "Research", "Center,", "Louisiana", "State", "University", "System,", "Baton", "Rouge,", "Louisiana,", "United", "States", "of", "America,", "2", "Department", "of", "Cardiology,", "Ochsner", "Health", "System,", "New", "Orleans,", "Louisiana,", "United", "States", "of", "America,", "3", "Department", "of", "Exercise", "Science,", "Arnold", "School", "of", "Public", "Health,", "University", "of", "South", "Carolina,", "Columbia,", "South", "Carolina,", "United", "States", "of", "America,", "4", "The", "University", "of", "North", "Texas,", "Denton,", "Texas,", "United", "States", "of", "America", "Abstract", "Background:", "Decreased", "heart", "rate", "variability", "(HRV)", "is", "associated", "with", "a", "higher", "risk", "of", "mortality.", "Overall,", "postmenopausal", "women", "have", "lower", "levels", "of", "HRV", "than", "premenopausal", "women,", "which", "may", "be", "additionally", "complicated", "by", "lifestyle", "related", "behaviors", "such", "as", "physical", "inactivity", "and", "obesity.", "Though", "cardiorespiratory", "exercise", "training", "increases", "HRV,", "little", "is", "known", "regarding", "the", "exercise", "dose", "necessary", "to", "promote", "this", "improvement.", "Methodology/Principal", "Findings:", "Our", "primary", "aim", "was", "to", "measure", "HRV", "in", "post-menopausal", "women", "following", "6-months", "of", "exercise", "training.", "We", "examined", "supine", "resting", "HRV", "in", "373", "post-menopausal", "women", "(45–75", "y)", "after", "6-months", "of", "randomly", "assigned", "and", "double-blinded", "administered", "exercise", "training", "exercise", "training", "at", "50%,", "100%", "and", "150%", "of", "the", "NIH", "Consensus", "Development", "Panel’s", "recommended", "minimal", "physical", "activity", "level.", "This", "corresponded", "to", "4,", "8,", "or", "12", "kcal/kg", "per", "week", "(KKW)", "of", "energy", "expenditure.", "At", "baseline,", "we", "observed", "no", "significant", "differences", "in", "HRV", "or", "hormone", "replacement", "use", "between", "treatment", "groups.", "However,", "we", "did", "observe", "that", "Caucasian", "women", "and", "those", "taking", "antidepressant", "medications", "had", "lower", "levels", "of", "baseline", "HRV.", "After", "6-months", "of", "exercise", "intervention,", "we", "observed", "a", "dose", "dependent", "increase", "in", "all", "parasympathetically", "derived", "time", "and", "frequency", "domain", "measurements", "across", "exercise", "groups", "after", "adjustment", "for", "age,", "ethnicity,", "antidepressants,", "and", "baseline", "rMSSD", "(all,", "P,0.001).", "For", "example,", "the", "parasympathetic", "index", "rMSSD", "was", "greater", "than", "control", "(23.1961.0)", "for", "the", "4-KKW", "(25.9860.8;", "P", "=", "0.14),", "8-KKW", "(27.6661.0;", "P,0.05),", "and", "12-KKW", "(27.4060.0;", "P,0.05)", "groups", "at", "follow-up.", "Conclusions/Significance:", "Moderate", "intensity", "exercise", "training", "exercise", "is", "sufficient", "to", "improve", "HRV", "in", "previously", "sedentary", "postmenopausal", "women", "in", "a", "dose-dependent", "manner,", "as", "4-KKW", "is", "insufficient", "to", "improve", "parasympathetic", "indices", "of", "HRV,", "while", "12-KKW", "conferred", "no", "greater", "improvement", "than", "8-KKW.", "Trial", "Registration:", "Clinicaltrials.gov", "NCT", "00011193", "Citation:", "Earnest", "CP,", "Lavie", "CJ,", "Blair", "SN,", "Church", "TS", "(2008)", "Heart", "Rate", "Variability", "Characteristics", "in", "Sedentary", "Postmenopausal", "Women", "Following", "Six", "Months", "of", "Exercise", "Training:", "The", "DREW", "Study.", "PLoS", "ONE", "3(6):", "e2288.", "doi:10.1371/journal.pone.0002288", "Editor:", "Jose", "AL", "Calbet,", "University", "of", "Las", "Palmas", "de", "Gran", "Canaria,", "Spain", "Received", "March", "4,", "2008;", "Accepted", "April", "16,", "2008;", "Published", "June", "4,", "2008", "Copyright:", "2008", "Earnest", "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", "DREW", "study", "as", "financially", "supported", "by", "in", "part", "by", "American", "Heart", "Association", "Texas", "Affiliate", "award", "02651404;", "the", "National", "Institutes", "of", "Health", "grant", "HL-66262", "and", "an", "exercise", "equipment", "donation", "from", "Life", "Fitness", "(Schiller", "Park,", "IL).", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "*", "E-mail:", "conrad.earnest@pbrc.edu", "Introduction", "Menopause", "represents", "a", "key", "transition", "period", "in", "a", "woman’s", "health.", "A", "fundamental", "etiology", "associated", "with", "menopause", "is", "the", "intricate", "link", "between", "estrogen", "metabolism", "and", "the", "autonomic", "nervous", "system.", "Autonomic", "nervous", "system", "balance", "can", "be", "assessed", "non-invasively", "via", "the", "use", "of", "heart", "rate", "variability", "(HRV).", "While", "a", "thorough", "review", "of", "HRV", "can", "be", "obtained", "elsewhere,[1]", "HRV", "is", "clinically", "useful", "because", "reduced", "HRV", "is", "associated", "with", "an", "increased", "risk", "of", "CV", "disease,", "type", "II", "diabetes", "and", "insulin", "resistance", "and", "has", "been", "shown", "to", "be", "reduced", "in", "postmenopausal", "women", "as", "compared", "with", "premenopausal", "women", "[2,3,4,5].", "Equally,", "the", "assessment", "of", "HRV", "in", "postmenopause", "is", "important", "because", "cardiovascular", "(CV)", "disease", "typically", "occurs", "later", "in", "women", "than", "in", "men;", "yet,", "the", "fact", "remains", "that", "CV", "disease", "is", "one", "of", "the", "two", "leading", "causes", "of", "death", "in", "women", "[6,7].", "A", "lifestyle", "behavior", "that", "has", "a", "significant", "affect", "on", "the", "metabolic", "processes", "surrounding", "CV", "disease", "is", "cardiorespiratory", "exercise", "training.", "Current", "recommendations", "from", "the", "National", "Institutes", "of", "Health", "(NIH)", "Consensus", "Development", "Panel", "recommend", "that", "women", "attain", "a", "minimal", "level", "of", "moderate", "intensity", "activity", "such", "as", "walking", "briskly", "for", "30", "minutes", "[8].", "In", "a", "recent", "report,", "we", "observed", "significant", "improvements", "in", "peak", "aerobic", "power", "for", "varying", "doses", "of", "exercise", "in", "postmenopausal", "women", "obtaining", ",50%,", "100%,", "and", "150%", "of", "the", "NIH", "recommendation", "[9].", "Cross-", "sectional", "reports,", "as", "well", "as", "reports", "in", "cardiac", "rehabilitation,[10]", "suggest", "that", "regular", "exercise", "training", "improves", "HRV;", "however,", "exercise", "training", "studies", "elaborating", "on", "the", "dose", "necessary", "to", "affect", "beneficial", "HRV", "changes", "are", "not", "clear", "[11,12,13,14].", "Limited", "exercise", "training", "studies", "conducted", "on", "postmenopausal", "women", "PLoS", "ONE", "|", "www.plosone.org", "1", "June", "2008", "|", "Volume", "3", "|", "Issue", "6", "|", "e2288" ]

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2,829,008

null

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[ "Kemper", "et", "al.", "BMC", "Pediatrics", "2010,", "10:9", "http://www.biomedcentral.com/1471-2431/10/9", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Discontinuation", "of", "thyroid", "hormone", "treatment", "among", "children", "in", "the", "United", "States", "with", "congenital", "hypothyroidism:", "findings", "from", "health", "insurance", "claims", "data", "Alex", "R", "Kemper1*,", "Lijing", "Ouyang2,", "Scott", "D", "Grosse2", "Abstract", "Background:", "Thyroid", "hormone", "treatment", "in", "children", "with", "congenital", "hypothyroidism", "can", "prevent", "intellectual", "disability.", "Guidelines", "recommend", "that", "children", "diagnosed", "with", "congenital", "hypothyroidism", "through", "newborn", "screening", "remain", "on", "treatment", "to", "at", "least", "3", "years", "of", "age,", "after", "which", "a", "trial", "off", "therapy", "can", "determine", "which", "children", "have", "transient", "hypothyroidism.", "The", "purpose", "of", "this", "study", "was", "to", "describe", "the", "rate", "at", "which", "children", "with", "congenital", "hypothyroidism", "in", "the", "United", "States", "discontinue", "thyroid", "hormone", "treatment", "in", "early", "childhood.", "Methods:", "Retrospective", "analysis", "of", "the", "2002-2006", "MarketScan®", "Commercial", "Claims", "and", "Encounters", "research", "databases", "and", "the", "2001-2005", "MarketScan", "Multi-State", "Medicaid", "databases.", "Children", "were", "classified", "as", "having", "congenital", "hypothyroidism", "based", "on", "billing", "codes", "and", "having", "filled", "a", "prescription", "for", "thyroid", "hormone", "treatment.", "Kaplan-Meier", "curve", "analysis", "was", "used", "to", "determine", "discontinuation", "rates.", "Results:", "There", "were", "a", "total", "of", "412", "Medicaid-enrolled", "children", "and", "292", "privately-insured", "children", "with", "presumed", "congenital", "hypothyroidism", "included", "in", "this", "study.", "The", "overall", "birth", "prevalence", "of", "congenital", "hypothyroidism", "across", "both", "datasets", "was", "about", "1", "per", "2,300.", "By", "36", "months,", "the", "percentage", "who", "had", "discontinued", "thyroid", "replacement", "treatment", "was", "38%", "(95%", "Confidence", "Interval:", "32%-44%).", "Medicaid-enrolled", "children", "had", "a", "more", "rapid", "decline", "in", "the", "first", "24", "months", "of", "treatment", "compared", "to", "those", "with", "private", "insurance", "(P", "=", "0.02).", "Conclusions:", "More", "than", "one-third", "of", "children", "treated", "for", "congenital", "hypothyroidism", "discontinued", "treatment", "within", "36", "months,", "which", "is", "inconsistent", "with", "current", "guidelines.", "It", "is", "not", "known", "how", "many", "of", "these", "children", "required", "continued", "treatment", "or", "experience", "adverse", "effects", "from", "discontinuation.", "These", "findings", "emphasize", "the", "critical", "need", "for", "follow-up", "systems", "to", "monitor", "the", "outcome", "of", "newborn", "screening.", "Background", "Although", "there", "has", "been", "dramatic", "expansion", "in", "the", "con-", "ditions", "identified", "by", "newborn", "screening,", "few", "data", "are", "available", "regarding", "the", "care", "that", "children", "receive", "after", "they", "are", "diagnosed", "through", "newborn", "screening.", "Appro-", "priate", "delivery", "of", "health", "care", "services", "is", "necessary", "to", "assure", "the", "benefit", "of", "early", "diagnosis.", "We", "chose", "to", "focus", "on", "congenital", "hypothyroidism", "(CH)", "because", "of", "its", "rela-", "tively", "high", "prevalence", "compared", "to", "other", "conditions", "*", "Correspondence:", "alex.kemper@duke.edu", "1Program", "on", "Pediatric", "Health", "Services", "Research,", "Department", "of", "Pediatrics,", "Duke", "University", "Medical", "Center,", "Durham,", "NC,", "USA", "included", "in", "newborn", "screening", "and", "because", "treatment", "is", "among", "the", "most", "straight-forward.", "Newborn", "screening", "for", "CH", "followed", "by", "the", "early", "initiation", "of", "thyroid", "hormone", "treatment", "to", "normalize", "thyroxin", "(T4)", "concentrations", "has", "been", "shown", "to", "prevent", "intellectual", "disability", "(i.e.,", "mental", "retardation)", "[1-3].", "Among", "population-based", "studies", "of", "children", "born", "prior", "to", "the", "introduction", "of", "newborn", "screening", "for", "CH", "in", "the", "late", "1970s,", "8%", "to", "29%", "of", "children", "with", "clinically", "diag-", "nosed", "CH", "received", "special", "education", "services", "for", "intel-", "lectual", "disability", "[4-6].", "Despite", "the", "unquestioned", "public", "health", "success", "from", "newborn", "screening", "and", "the", "management", "of", "CH,", "there", "©", "2010", "Kemper", "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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2,851,710

null

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[ "Onwujekwe", "et", "al.", "BMC", "Health", "Services", "Research", "2010,", "10:67", "http://www.biomedcentral.com/1472-6963/10/67", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Investigating", "determinants", "of", "out-of-pocket", "spending", "and", "strategies", "for", "coping", "with", "payments", "for", "healthcare", "in", "southeast", "Nigeria", "Obinna", "E", "Onwujekwe1,2,", "Benjamin", "SC", "Uzochukwu2,3,", "Eric", "N", "Obikeze1,2*,", "Ijeoma", "Okoronkwo2,4,", "Ogbonnia", "G", "Ochonma1,", "Chima", "A", "Onoka1,2,3,", "Grace", "Madubuko2,4,", "Chijioke", "Okoli2", "Abstract", "Background:", "Out-of-pocket", "spending", "(OOPS)", "is", "the", "major", "payment", "strategy", "for", "healthcare", "in", "Nigeria.", "Hence,", "the", "paper", "assessed", "the", "determinants", "socio-economic", "status", "(SES)", "of", "OOPS", "and", "strategies", "for", "coping", "with", "payments", "for", "healthcare", "in", "urban,", "semi-urban", "and", "rural", "areas", "of", "southeast", "Nigeria.", "This", "paper", "provides", "information", "that", "would", "be", "required", "to", "improve", "financial", "accessibility", "and", "equity", "in", "financing", "within", "the", "public", "health", "care", "system.", "Methods:", "The", "study", "areas", "were", "three", "rural", "and", "three", "urban", "areas", "from", "Ebonyi", "and", "Enugu", "states", "in", "South-east", "Nigeria.", "Cross-sectional", "survey", "using", "interviewer-administered", "questionnaires", "to", "randomly", "selected", "householders", "was", "the", "study", "tool.", "A", "socio-economic", "status", "(SES)", "index", "that", "was", "developed", "using", "principal", "components", "analysis", "was", "used", "to", "examine", "levels", "of", "inequity", "in", "OOPS", "and", "regression", "analysis", "was", "used", "to", "examine", "the", "determinants", "of", "use", "of", "OOPS.", "Results:", "All", "the", "SES", "groups", "equally", "sought", "healthcare", "when", "they", "needed", "to.", "However,", "the", "poorest", "households", "were", "most", "likely", "to", "use", "low", "level", "and", "informal", "providers", "such", "as", "traditional", "healers,", "whilst", "the", "least", "poor", "households", "were", "more", "likely", "to", "use", "the", "services", "of", "higher", "level", "and", "formal", "providers", "such", "as", "health", "centres", "and", "hospitals.", "The", "better-off", "SES", "more", "than", "worse-off", "SES", "groups", "used", "OOPS", "to", "pay", "for", "healthcare.", "The", "use", "of", "own", "money", "was", "the", "commonest", "payment-coping", "mechanism", "in", "the", "three", "communities.", "The", "sales", "of", "movable", "household", "assets", "or", "land", "were", "not", "commonly", "used", "as", "payment-coping", "mechanisms.", "Decreasing", "SES", "was", "associated", "with", "increased", "sale", "of", "household", "assets", "to", "cope", "with", "payment", "for", "healthcare", "in", "one", "of", "the", "communities.", "Fee", "exemptions", "and", "subsidies", "were", "almost", "non-existent", "as", "coping", "mechanisms", "in", "this", "study", "Conclusions:", "There", "is", "the", "need", "to", "reduce", "OOPS", "and", "channel", "and", "improve", "equity", "in", "healthcare", "financing", "by", "designing", "and", "implementing", "payment", "strategies", "that", "will", "assure", "financial", "risk", "protection", "of", "the", "poor", "such", "pre-payment", "mechanisms", "with", "government", "paying", "for", "the", "poor.", "Background", "Out-of-pocket", "spending", "(OOPS)", "is", "the", "major", "payment", "strategy", "for", "healthcare", "in", "Nigeria.", "The", "real", "challenge", "of", "health", "care", "financing", "in", "Nigeria", "as", "in", "many", "countries", "in", "sub-Saharan", "Africa", "(SSA)", "lies", "not", "primarily", "in", "the", "acute", "scarcity", "of", "resources,", "but", "in", "the", "absence", "of", "intermedia-", "tion", "and", "insurance", "mechanisms", "to", "manage", "risk,", "and", "inefficient", "resource", "allocation", "and", "purchasing", "practices", "[1].", "User", "fees", "fall", "within", "the", "broader", "concept", "of", "“cost-", "*", "Correspondence:", "ericobikeze@mail.com", "1Department", "of", "Health", "Administration", "and", "Management,", "College", "of", "Medicine,", "University", "of", "Nigeria,", "Enugu,", "Nigeria", "sharing”,", "a", "practice", "whereby", "beneficiaries", "contribute", "towards", "the", "cost", "of", "a", "public", "service", "and", "they", "are", "defined", "as", "payment", "of", "out-of-pocket", "charges", "at", "the", "time", "of", "use", "of", "services", "[2].", "OOPS", "for", "healthcare", "increased", "with", "the", "introduction", "of", "user", "fees", "in", "the", "health", "sector", "and", "like", "most", "African", "countries,", "Nigeria", "introduced", "user", "fees", "as", "a", "mode", "of", "financing", "government", "health", "services", "within", "the", "frame-", "work", "of", "the", "Bamako", "Initiative", "revolving", "drug", "funds", "[3].", "It", "is", "however", "noted", "that", "user", "fees", "and", "revolving", "drug", "funds", "are", "interlinked.", "The", "introduction", "of", "user", "fees", "was", "arguably", "in", "response", "to", "the", "severe", "problems", "in", "financing", "©", "2010", "Onwujekwe", "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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[ "Clin", "Rheumatol", "(2009)", "28:923–929", "DOI", "10.1007/s10067-009-1176-1", "ORIGINAL", "ARTICLE", "The", "feasibility", "and", "efficacy", "of", "a", "multidisciplinary", "intervention", "with", "aftercare", "meetings", "for", "fibromyalgia", "Mariëlle", "Kroese", "&", "Guy", "Schulpen", "&", "Monique", "Bessems", "&", "Frans", "Nijhuis", "&", "Johan", "Severens", "&", "Robert", "Landewé", "Received:", "28", "October", "2008", "/", "Revised:", "11", "March", "2009", "/", "Accepted:", "27", "March", "2009", "/", "Published", "online:", "5", "May", "2009", "#", "The", "Author(s)", "2009.", "This", "article", "is", "published", "with", "open", "access", "at", "Springerlink.com", "Abstract", "The", "objective", "of", "this", "study", "is", "to", "examine", "the", "feasibility", "and", "long-term", "results", "of", "a", "12-week", "multidisci-", "plinary", "part-time", "daycare", "intervention", "with", "five", "aftercare", "meetings", "in", "fibromyalgia", "(FM)", "patients.", "One", "hundred", "and", "five", "patients", "diagnosed", "with", "FM", "started", "with", "a", "multidisci-", "plinary", "intervention", "and", "were", "assessed", "for", "feasibility,", "func-", "tional", "status", "(Fibromyalgia", "Impact", "Questionnaire", "[FIQ]),", "and", "quality", "of", "life", "(EuroQol-5D", "[EQ-5D])", "until", "9", "months", "after", "completion.", "The", "program", "consisted", "of", "sociotherapy,", "physiotherapy,", "psychotherapy,", "and", "creative", "arts", "therapy.", "Drop-out", "rate", "was", "4.8%.", "The", "attendance", "rate", "of", "100", "patients", "who", "completed", "the", "12-week", "program", "and", "five", "aftercare", "meetings", "was", "high", "(97.4%),", "just", "like", "patient", "and", "therapist", "satisfaction", "(8.2", "on", "a", "10", "points", "scale).", "After", "the", "12-week", "program,", "statistically", "significant", "improvement", "was", "seen", "in", "both", "FIQ", "and", "EQ-5D.", "This", "improvement", "was", "maintained", "after", "9", "months", "of", "follow-up.", "On", "average,", "moderate", "im-", "provements", "were", "observed.", "Our", "12-week", "multidisciplinary", "M.", "Kroese", "(*)", ":", "G.", "Schulpen", ":", "M.", "Bessems", "Department", "of", "Integrated", "Care,", "University", "Hospital", "Maastricht,", "PO", "Box", "5800,", "6202", "AZ", "Maastricht,", "The", "Netherlands", "e-mail:", "marielle.kroese@mumc.nl", "F.", "Nijhuis", ":", "J.", "Severens", "Department", "of", "Health", "Organization,", "Policy,", "and", "Economics,", "University", "of", "Maastricht,", "Maastricht,", "The", "Netherlands", "J.", "Severens", "Department", "of", "Clinical", "Epidemiology", "and", "Medical", "Technology", "Assessment,", "University", "Hospital", "Maastricht,", "Maastricht,", "The", "Netherlands", "R.", "Landewé", "Department", "of", "Internal", "Medicine,", "Division", "of", "Rheumatology,", "University", "Hospital", "Maastricht,", "Maastricht,", "The", "Netherlands", "part-time", "daycare", "intervention", "with", "five", "aftercare", "meetings", "for", "FM", "patients", "is", "feasible", "and", "it", "is", "indicated", "that", "it", "can", "lead", "to", "sustained", "improvement", "in", "functional", "status", "and", "quality", "of", "life.", "Keywords", "Feasibility", ".", "Fibromyalgia", ".", "Multidisciplinary", "intervention", "Introduction", "Fibromyalgia", "(FM)", "is", "a", "common", "chronic", "pain", "condition,", "characterized", "by", "generalized", "pain,", "stiffness,", "fatigue,", "dis-", "turbed", "sleep,", "psychological", "distress,", "and", "impaired", "cognitive", "function", "[1,", "2].", "The", "cause", "of", "and", "pathologic", "mechanisms", "underlying", "FM", "are", "unknown,", "but", "FM", "may", "lead", "to", "disability", "and", "reduced", "quality", "of", "life", "[3].", "Increasingly,", "FM", "is", "considered", "as", "a", "combination", "of", "physical,", "psychological,", "and", "social", "disabilities,", "the", "biopsy-", "chosocial", "model", "[4,", "5].", "In", "this", "model,", "physical", "treatment", "is", "combined", "with", "psychological,", "behavioral,", "and/or", "educa-", "tional", "interventions", "[6].", "The", "studies", "that", "have", "systematically", "compared", "monotherapies", "with", "treatment", "combinations", "that", "include", "both", "physical", "and", "psychosocial", "components", "have", "fairly", "consistently", "shown", "that", "for", "chronic", "pain", "combined", "treatments", "result", "in", "better", "outcomes", "than", "single", "therapies", "[7].", "Rossy", "et", "al.", "concluded", "in", "their", "meta-analysis", "that", "the", "optimal", "intervention", "for", "FM", "would", "include", "exercise", "and", "cognitive-behavioral", "therapy", "[8].", "A", "number", "of", "studies", "have", "investigated", "the", "effect", "of", "multimodal", "or", "multidisciplinary", "therapy", "for", "FM,", "but", "the", "systematic", "reviews", "performed", "in", "this", "area", "concluded", "that", "the", "evidence", "is", "scarce", "because", "of", "few", "studies,", "the", "low", "quality", "of", "the", "studies,", "and", "the", "varying", "elements", "of", "the", "therapy", "[9–11].", "Besides,", "the", "drop-out", "rates", "in", "the", "studies", "are", "generally", "high", "[12–17],", "suggesting", "that" ]

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1,939,998

null

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[ "BMC", "Cell", "Biology", "Research", "article", "Arf6", "recruits", "the", "Rac", "GEF", "Kalirin", "to", "the", "plasma", "membrane", "facilitating", "Rac", "activation", "Tae", "Hyeon", "Koo1,", "Betty", "A", "Eipper2", "and", "Julie", "G", "Donaldson*1", "Address:", "1Laboratory", "of", "Cell", "Biology,", "NHLBI,", "NIH,", "Building", "50,", "Rm", "2503,", "Bethesda,", "MD", "20892,", "USA", "and", "2Department", "of", "Neuroscience,", "University", "of", "Connecticut", "Health", "Center,", "Farmington,", "CT", "06030,", "USA", "Email:", "Tae", "Hyeon", "Koo", "-", "gutae@kfda.go.kr;", "Betty", "A", "Eipper", "-", "Eipper@uchc.edu;", "Julie", "G", "Donaldson*", "-", "jdonalds@helix.nih.gov", "*", "Corresponding", "author", "BioMed", "Central", "Open", "Access", "Published:", "18", "July", "2007", "BMC", "Cell", "Biology", "2007,", "8:29", "doi:10.1186/1471-2121-8-29", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1471-2121/8/29", "Received:", "2", "March", "2007", "Accepted:", "18", "July", "2007", "©", "2007", "Koo", "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:", "Many", "studies", "implicate", "Arf6", "activity", "in", "Rac-mediated", "membrane", "ruffling", "and", "cytoskeletal", "reorganization.", "Although", "Arf6", "facilitates", "the", "trafficking", "of", "Rac1", "to", "the", "plasma", "membrane", "and", "in", "many", "cases", "Arf6", "activation", "leads", "to", "the", "activation", "of", "Rac1,", "the", "details", "of", "how", "Arf6", "influences", "Rac", "function", "remain", "to", "be", "elucidated.", "Results:", "We", "demonstrate", "in", "binding", "assays", "and", "by", "co-immunoprecipitation", "that", "GDP-bound", "Arf6", "binds", "to", "Kalirin5,", "a", "Rho", "family", "guanine", "nucleotide", "exchange", "factor,", "through", "interaction", "with", "the", "spectrin", "repeat", "region.", "In", "cells,", "expression", "of", "wild", "type", "Arf6", "recruits", "spectrin", "repeat", "5", "and", "Kalirin", "to", "the", "plasma", "membrane", "and", "leads", "to", "enhanced", "Kalirin5-induced", "ruffling.", "By", "contrast,", "expression", "of", "an", "Arf6", "mutant", "that", "cannot", "become", "activated,", "Arf6", "T27N,", "still", "recruits", "spectrin", "repeat", "5", "and", "Kalirin", "to", "membranes", "but", "inhibits", "Kalirin5-induced", "ruffling", "in", "HeLa", "cells.", "Kalirin5-induced", "Rac1", "activation", "is", "increased", "by", "the", "expression", "of", "wild", "type", "Arf6", "and", "decreased", "by", "Arf6T27N.", "Furthermore,", "expression", "of", "a", "catalytically-inactive", "mutant", "of", "Kalirin5", "inhibits", "cytoskeletal", "changes", "observed", "in", "cells", "expressing", "EFA6,", "an", "Arf6", "guanine", "nucleotide", "exchange", "factor", "that", "leads", "to", "activation", "of", "Rac.", "Conclusion:", "We", "show", "here", "with", "over-expressed", "proteins", "that", "the", "GDP-bound", "form", "of", "Arf6", "can", "bind", "to", "the", "spectrin", "repeat", "regions", "in", "Kalirin", "Rho", "family", "GEFs", "thereby", "recruiting", "Kalirin", "to", "membranes.", "Although", "Kalirin", "is", "recruited", "onto", "membranes", "by", "Arf6-GDP,", "subsequent", "Rac", "activation", "and", "membrane", "ruffling", "requires", "Arf6", "activation.", "From", "these", "results,", "we", "suggest", "that", "Arf6", "can", "regulate", "through", "its", "GTPase", "cycle", "the", "activation", "of", "Rac.", "Background", "Arfs", "are", "small,", "ubiquitous,", "Ras-related", "GTPases", "that", "play", "an", "essential", "role", "in", "membrane", "traffic", "and", "structure.", "Among", "the", "6", "mammalian", "Arf", "proteins,", "Arf6", "has", "been", "implicated", "in", "the", "regulation", "of", "endocytic", "membrane", "traf-", "fic", "and", "cortical", "actin", "structure", "at", "the", "plasma", "membrane", "(PM)", "[1,2].", "The", "small", "GTPases", "of", "the", "Rho", "subfamily", "are", "also", "known", "to", "be", "important", "regulators", "of", "the", "actin", "cytoskeleton.", "To", "date,", "at", "least", "25", "Rho", "family", "proteins", "have", "been", "identified", "and", "of", "these,", "RhoA,", "Rac1", "and", "Cdc42", "have", "been", "the", "most", "widely", "studied", "for", "their", "effects", "on", "actin", "organization.", "In", "particular,", "Rac1", "controls", "the", "formation", "of", "lamellipodia", "and", "membrane", "ruffles,", "the", "sites", "of", "protrusive", "actin", "polymerization", "and", "early", "adhesion", "formation", "initi-", "ated", "at", "the", "leading", "edge", "of", "migrating", "cells", "[3,4].", "Page", "1", "of", "10", "(page", "number", "not", "for", "citation", "purposes)" ]

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null

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[ "online", "©", "ML", "Comm", "BRIEF", "REPORT", "DOI", "10.4306/pi.2010.7.3.224", "Print", "ISSN", "1738-3684", "/", "On-line", "ISSN", "1976-3026", "OPEN", "ACCESS", "Association", "between", "Estrogen", "Receptor", "Gene", "Polymorphisms", "and", "Depression", "in", "Post-Menopausal", "Women:", "A", "Preliminary", "Study", "Jung", "Jin", "Kim1", ",", "Chi", "Un", "Pae1,", "Mi", "Ran", "Kim2,", "Jung", "Ah", "Min1,", "Kyung", "Hee", "Kim1,", "Chang", "Uk", "Lee1,", "Chul", "Lee1", "and", "In", "Ho", "Paik1", "1Departments", "of", "Psychiatry", "and", "2Gynecology,", "The", "Catholic", "University", "of", "Korea", "College", "of", "Medicine,", "Seoul", "St.", "Mary’s", "Hospital,", "Seoul,", "Korea", "Post-menopausal", "women", "experience", "variable", "biological", "and", "psychological", "changes.", "The", "effect", "of", "reduced", "levels", "of", "estrogen", "can", "effect", "on", "post-menopausal", "depression.", "Estrogen", "triggers", "physiological", "responses", "by", "binding", "to", "the", "estrogen", "receptor", "(ER).", "Two", "subtypes", "of", "ER,", "ERa", "and", "ERb", "are", "now", "known.", "We", "investigated", "the", "significance", "of", "ERa", "and", "ERb", "polymorphisms", "and", "post-menopasal", "depression", "in", "this", "study.", "Forty", "three", "women", "with", "post-menopausal", "depression", "and", "63", "post-menopausal", "women", "without", "depression", "as", "normal", "controls", "were", "recruited.", "Polymerase", "chain", "reaction-restriction", "fragment", "length", "polymorphism", "method", "was", "used", "to", "investigate", "genotypes", "of", "ERa", "and", "ERb", "polymorphisms.", "Genotypes", "of", "PvuII", "and", "XbaI", "polymorphism", "of", "ERa", "receptor", "were", "significantly", "different", "in", "patients", "with", "post-", "menopausal", "depression", "comparing", "with", "controls.", "Genotypes", "of", "ERb", "did", "not", "show", "association", "with", "post-menopausal", "depression.", "Our", "study", "showed", "that", "ERa", "receptor", "polymorphism", "had", "an", "association", "with", "depression", "in", "post-menopausal", "women.", "It", "suggests", "that", "investigation", "of", "ER", "genes", "and", "their", "functions", "might", "be", "important", "for", "understanding", "pathophysilogical", "mechanism", "of", "post-menopausal", "depression.", "Psychiatry", "Investig", "2010;7:224-227", "Key", "WordsaaMenopause,", "Depression,", "Estrogen,", "Receptor,", "Polymorphism.", "INTRODUCTION", "Women", "are", "vulnerable", "to", "depression", "especially", "along", "with", "menopause.1", "Women", "who", "had", "reproductive", "cycle", "event-relat-", "ed", "depression", "such", "as", "premenstrual", "dysphoric", "disorder,", "peri-", "menopausal", "depression", "and", "postpartum", "depression", "reported", "a", "stronger", "family", "history", "of", "mental", "illness", "than", "other", "depressed", "women.2", "It", "suggests", "unique", "characteristics", "and", "perhaps", "a", "more", "biologically", "driven", "illness", "for", "this", "subgroup", "of", "depressed", "women.2", "Post-menopausal", "women", "experience", "variable", "biological", "and", "psychological", "changes.", "The", "effect", "of", "reduced", "levels", "of", "es-", "trogen", "can", "effect", "on", "post-menopausal", "depression", "in", "suscep-", "tible", "women.3,4", "Estrogen", "passes", "the", "blood-brain", "barrier,", "and", "receptors", "for", "them", "are", "abundant", "in", "brain", "areas", "such", "as", "limbic", "Received:", "February", "26,", "2010", "Revised:", "May", "29,", "2010", "Accepted:", "June", "17,", "2010", "Available", "online:", "August", "13,", "2010", "", "Correspondence:", "Jung", "Jin", "Kim,", "MD,", "PhD", "Department", "of", "Psychiatry,", "The", "Catholic", "University", "of", "Korea", "College", "of", "Medicine,", "Seoul", "St.", "Mary’s", "Hospital,", "505", "Banpo-dong,", "Seocho-gu,", "Seoul", "137-701,", "Korea", "Tel:", "+82-2-2258-6084,", "Fax:", "+82-2-594-3870,", "E-mail:", "jjean@catholic.ac.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", "reproduc-", "tion", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "224", "Copyright", "©", "2010", "Korean", "Neuropsychiatric", "Association", "structure", "important", "for", "the", "regulation", "of", "emotions,", "cognition", "and", "behavior.5-8", "The", "fact", "that", "men", "and", "women", "differ", "with", "re-", "spect", "to", "the", "prevalence", "of", "depression", "may", "possibly", "also", "reflect", "an", "influence", "of", "estrogen", "on", "human", "behavior.6", "Estrogen", "triggers", "physiological", "responses", "by", "binding", "to", "a", "nu-", "clear", "receptor", "protein,", "the", "estrogen", "receptor", "(ER).", "ERs", "are", "nu-", "clear", "receptor", "proteins", "that", "have", "an", "estrogen", "binding", "domain", "and", "a", "deoxyribonucleic", "acid", "(DNA)", "binding", "domain.9", "The", "ER", "is", "classified", "as", "a", "class", "1", "member", "of", "the", "superfamily", "of", "nuclear", "hormone", "receptors.10", "Two", "subtypes", "of", "ER", "are", "now", "known,", "ERa", "and", "ERb.11", "The", "ERa", "gene", "is", "localized", "on", "chromosome", "6q25.1,12", "and", "the", "ERb", "gene", "is", "localized", "on", "chromosome", "14q22-24.13", "Recently,", "several", "genetic", "variants", "of", "Era", "and", "ERb", "gene", "were", "described.", "The", "association", "of", "genetic", "polymorphisms", "of", "ER", "and", "psy-", "chiatric", "disorders", "have", "been", "the", "subject", "of", "increasing", "interest.14", "However,", "given", "the", "important", "role", "of", "estrogen", "for", "brain", "func-", "tion", "and", "abrupt", "change", "of", "it", "in", "postmenopausal", "period,", "there", "are", "relatively", "few", "studies", "so", "far", "have", "addressed", "the", "possible", "in-", "fluence", "of", "ER", "polymorphism", "with", "respect", "to", "susceptibility", "to", "depression", "in", "postmenopausal", "women.15-18", "Therefore,", "we", "investigated", "the", "significance", "of", "ERa", "and", "ERb", "polymorphisms", "and", "post-menopasal", "depression", "in", "this", "study." ]

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1,064,872

null

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[ "Arthritis", "Research", "&", "Therapy", "Vol", "6", "No", "6", "Gaffen", "Review", "Biology", "of", "recently", "discovered", "cytokines:", "Interleukin-17", "–", "a", "unique", "inflammatory", "cytokine", "with", "roles", "in", "bone", "biology", "and", "arthritis", "Sarah", "L", "Gaffen", "Department", "of", "Oral", "Biology,", "School", "of", "Dental", "Medicine,", "University", "at", "Buffalo,", "State", "University", "of", "New", "York,", "and", "Department", "of", "Microbiology", "and", "Immunology,", "School", "of", "Medicine", "and", "Biomedical", "Sciences,", "University", "at", "Buffalo,", "State", "University", "of", "New", "York,", "Buffalo,", "New", "York,", "USA", "Corresponding", "author:", "Sarah", "L", "Gaffen,", "sgaffen@buffalo.edu", "Published:", "8", "October", "2004", "Arthritis", "Res", "Ther", "2004,", "6:240-247", "(DOI", "10.1186/ar1444)", "©", "2004", "BioMed", "Central", "Ltd", "Abstract", "IL-17", "and", "its", "receptor", "are", "founding", "members", "of", "an", "emerging", "family", "of", "cytokines", "and", "receptors", "with", "many", "unique", "characteristics.", "IL-17", "is", "produced", "primarily", "by", "T", "cells,", "particularly", "those", "of", "the", "memory", "compartment.", "In", "contrast,", "IL-17", "receptor", "is", "ubiquitously", "expressed,", "making", "nearly", "all", "cells", "potential", "targets", "of", "IL-17.", "Although", "it", "has", "only", "limited", "homology", "to", "other", "cytokines,", "IL-17", "exhibits", "proinflammatory", "properties", "similar", "to", "those", "of", "tumor", "necrosis", "factor-α,", "particularly", "with", "respect", "to", "induction", "of", "other", "inflammatory", "effectors.", "In", "addition,", "IL-17", "synergizes", "potently", "with", "other", "cytokines,", "placing", "it", "in", "the", "center", "of", "the", "inflammatory", "network.", "Strikingly,", "IL-17", "has", "been", "associated", "with", "several", "bone", "pathologies,", "most", "notably", "rheumatoid", "arthritis.", "Keywords:", "bone,", "cytokines,", "interleukin-17,", "inflammation,", "synergy", "Introduction", "The", "cytokine", "IL-17,", "originally", "termed", "CTLA-8,", "was", "isolated", "as", "a", "CD4-specific", "transcript", "from", "a", "rodent", "cDNA", "library", "[1].", "Shortly", "thereafter,", "IL-17", "was", "discovered", "in", "humans,", "and", "its", "receptor", "(IL-17R)", "was", "cloned", "and", "characterized", "[2–4].", "The", "most", "striking", "feature", "of", "both", "IL-17", "and", "IL-17R", "is", "that", "they", "are", "distinct", "in", "sequence", "from", "previously", "described", "cytokine/receptor", "families.", "However,", "they", "are", "highly", "homologous", "among", "mice,", "rats,", "and", "humans.", "In", "addition,", "an", "IL-17R", "homolog", "in", "zebrafish", "(termed", "SEF", "[similar", "expression", "of", "FGF", "genes])", "has", "been", "described", "that", "functions", "in", "embryonic", "development", "[5],", "and", "mammalian", "homologs", "of", "SEF", "were", "also", "recently", "identified", "[6,7].", "Consequently,", "IL-17", "and", "IL-17R", "are", "now", "recognized", "to", "be", "the", "founding", "members", "of", "an", "emerging", "new", "family", "that,", "in", "mammals,", "contains", "at", "least", "six", "cytokines", "and", "five", "receptors", "(Table", "1", "[8,9]).", "This", "review", "focuses", "primarily", "on", "the", "original", "IL-17", "cytokine", "(also", "known", "as", "IL-17A),", "because", "its", "roles", "in", "bone", "physiology", "and", "arthritis", "are", "most", "clearly", "defined,", "but", "the", "biology", "of", "the", "remaining", "family", "members", "promises", "to", "be", "a", "fascinating", "emerging", "story", "within", "the", "field", "of", "‘high", "numbered’", "cytokines.", "Interleukin-17", "and", "interleukin-17", "receptor", "structure", "Even", "though", "IL-17", "and", "IL-17R", "have", "been", "recognized", "for", "many", "years,", "there", "is", "still", "much", "to", "learn", "about", "their", "respective", "structures", "and", "functions.", "IL-17", "is", "secreted", "primarily", "by", "CD4+", "T", "cells", "in", "a", "mix", "of", "both", "nonglycosylated", "and", "N-glycosylated", "forms,", "which", "migrate", "in", "SDS-PAGE", "at", "28", "kDa", "and", "33", "kDa,", "respectively", "[2].", "Secreted", "IL-17", "apparently", "exists", "as", "a", "homodimer,", "but", "the", "specific", "contact", "points", "between", "IL-17", "subunits", "or", "between", "IL-17", "and", "IL-17R", "have", "never", "been", "defined", "[2,10].", "IL-17B", "and", "IL-17F", "also", "exist", "as", "dimers", "[10,11].", "While", "the", "amino", "acid", "sequence", "of", "IL-17", "did", "not", "permit", "it", "to", "be", "classified", "as", "a", "240", "CCL", "=", "CC", "chemokine", "ligand;", "C/EBP", "=", "CCAAT/enhancer", "binding", "protein;", "CIA", "=", "collagen", "induced", "arthritis;", "CXCL", "=", "CXC", "chemokine", "ligand;", "DC", "=", "dendritic", "cell;", "IFN", "=", "interferon;", "IL", "=", "interleukin;", "IL-17R", "=", "IL-17", "receptor;", "MAPK", "=", "mitogen-activated", "protein", "kinase;", "NF-κB", "=", "nuclear", "factor-κB;", "OPG", "=", "osteoprotegerin;", "RA", "=", "rheumatoid", "arthritis;", "RANKL", "=", "receptor", "activator", "of", "nuclear", "factor-κB", "ligand;", "TNF", "=", "tumor", "necrosis", "factor;", "TRAF", "=", "tumor", "necrosis", "factor", "receptor-associated", "factor." ]

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[ "A", "Novel", "and", "Lethal", "De", "Novo", "LQT-3", "Mutation", "in", "a", "Newborn", "with", "Distinct", "Molecular", "Pharmacology", "and", "Therapeutic", "Response", "John", "R.", "Bankston1.,", "Minerva", "Yue1.,", "Wendy", "Chung2,", "Meghan", "Spyres3,", "Robert", "H.", "Pass2,", "Eric", "Silver2,", "Kevin", "J.", "Sampson1,", "Robert", "S.", "Kass1*", "1", "Department", "of", "Pharmacology,", "College", "of", "Physicians", "and", "Surgeons,", "Columbia", "University", "Medical", "Center,", "New", "York,", "New", "York,", "United", "States", "of", "America,", "2", "Department", "of", "Pediatrics,", "College", "of", "Physicians", "and", "Surgeons,", "Columbia", "University", "Medical", "Center,", "New", "York,", "New", "York,", "United", "States", "of", "America,", "3", "College", "of", "Physicians", "and", "Surgeons,", "Columbia", "University", "Medical", "Center,", "New", "York,", "New", "York,", "United", "States", "of", "America", "Background.", "SCN5A", "encodes", "the", "a-subunit", "(Nav1.5)", "of", "the", "principle", "Na+", "channel", "in", "the", "human", "heart.", "Genetic", "lesions", "in", "SCN5A", "can", "cause", "congenital", "long", "QT", "syndrome", "(LQTS)", "variant", "3", "(LQT-3)", "in", "adults", "by", "disrupting", "inactivation", "of", "the", "Nav1.5", "channel.", "Pharmacological", "targeting", "of", "mutation-altered", "Na+", "channels", "has", "proven", "promising", "in", "developing", "a", "gene-specific", "therapeutic", "strategy", "to", "manage", "specifically", "this", "LQTS", "variant.", "SCN5A", "mutations", "that", "cause", "similar", "channel", "dysfunction", "may", "also", "contribute", "to", "sudden", "infant", "death", "syndrome", "(SIDS)", "and", "other", "arrhythmias", "in", "newborns,", "but", "the", "prevalence,", "impact,", "and", "therapeutic", "management", "of", "SCN5A", "mutations", "may", "be", "distinct", "in", "infants", "compared", "with", "adults.", "Methods", "and", "Results.", "Here,", "in", "a", "multidisciplinary", "approach,", "we", "report", "a", "de", "novo", "SCN5A", "mutation", "(F1473C)", "discovered", "in", "a", "newborn", "presenting", "with", "extreme", "QT", "prolongation", "and", "differential", "responses", "to", "the", "Na+", "channel", "blockers", "flecainide", "and", "mexiletine.", "Our", "goal", "was", "to", "determine", "the", "Na+", "channel", "phenotype", "caused", "by", "this", "severe", "mutation", "and", "to", "determine", "whether", "distinct", "effects", "of", "different", "Na+", "channel", "blockers", "on", "mutant", "channel", "activity", "provide", "a", "mechanistic", "understanding", "of", "the", "distinct", "therapeutic", "responsiveness", "of", "the", "mutation", "carrier.", "Sequence", "analysis", "of", "the", "proband", "revealed", "the", "novel", "missense", "SCN5A", "mutation", "(F1473C)", "and", "a", "common", "variant", "in", "KCNH2", "(K897T).", "Patch", "clamp", "analysis", "of", "HEK", "293", "cells", "transiently", "transfected", "with", "wild-type", "or", "mutant", "Na+", "channels", "revealed", "significant", "changes", "in", "channel", "biophysics,", "all", "contributing", "to", "the", "proband’s", "phenotype", "as", "predicted", "by", "in", "silico", "modeling.", "Furthermore,", "subtle", "differences", "in", "drug", "action", "were", "detected", "in", "correcting", "mutant", "channel", "activity", "that,", "together", "with", "both", "the", "known", "genetic", "background", "and", "age", "of", "the", "patient,", "contribute", "to", "the", "distinct", "therapeutic", "responses", "observed", "clinically.", "Significance.", "The", "results", "of", "our", "study", "provide", "further", "evidence", "of", "the", "grave", "vulnerability", "of", "newborns", "to", "Na+", "channel", "defects", "and", "suggest", "that", "both", "genetic", "background", "and", "age", "are", "particularly", "important", "in", "developing", "a", "mutation-", "specific", "therapeutic", "personalized", "approach", "to", "manage", "disorders", "in", "the", "young.", "Citation:", "Bankston", "JR,", "Yue", "M,", "Chung", "W,", "Spyres", "M,", "Pass", "RH,", "et", "al", "(2007)", "A", "Novel", "and", "Lethal", "De", "Novo", "LQT-3", "Mutation", "in", "a", "Newborn", "with", "Distinct", "Molecular", "Pharmacology", "and", "Therapeutic", "Response.", "PLoS", "ONE", "2(12):", "e1258.", "doi:10.1371/journal.pone.0001258", "INTRODUCTION", "The", "long", "QT", "syndrome", "(LQTS),", "a", "relatively", "uncommon", "(1", "in", "2500)", "genetic", "disorder", "associated", "with", "life-threatening", "arrhyth-", "mias,", "is", "an", "example", "of", "a", "channelopathy", "that", "has", "provided", "a", "wealth", "of", "information", "about", "fundamental", "mechanisms", "underlying", "human", "cardiac", "electrophysiology[1].", "LQTS", "is", "currently", "associated", "with", "mutations", "in", "10", "different", "genes[1–3].", "LQT", "variant", "3", "(LQT-3)", "is", "caused", "by", "mutations", "in", "SCN5A,", "the", "gene", "coding", "for", "the", "alpha", "subunit", "(NaV1.5)", "of", "the", "primary", "cardiac", "voltage-gated", "Na+", "channel", "in", "the", "human", "heart.", "Despite", "a", "relatively", "common", "phenotype", "(delayed", "repolarization", "reflected", "in", "QT", "prolongation),", "therapeutic", "strategies", "have", "been", "developed", "that", "are", "dictated", "by", "molecular", "etiology.", "Na+", "channel", "blockers", "such", "as", "mexiletine", "and", "flecainide", "are", "effective", "in", "treating", "LQT-3", "patients", "due", "to", "preferential", "inhibition", "of", "mutant", "Na+", "channel", "activity[4,5].", "Furthermore,", "current", "evidence", "suggests", "that", "mutations", "in", "ion", "channels", "may", "also", "contribute", "to", "sudden", "infant", "death", "syndrome", "(SIDS)", "and", "other", "cardiac", "arrhythmias", "in", "newborns,", "and", "that", "the", "frequency,", "severity,", "and", "treatment", "of", "SCN5A", "mutations", "may", "be", "distinct", "in", "infants", "compared", "with", "adults[6,7,8–11]", "Here", "we", "report", "investigation", "of", "a", "de", "novo", "SCN5A", "mutation", "discovered", "in", "a", "newborn", "who", "had", "presented", "with", "extreme", "QT", "prolongation", "(approximately", "800", "ms);", "2:1", "heart", "block;", "and", "differen-", "tial", "responses", "to", "the", "Na+", "channel", "blockers", "lidocaine,", "mexiletine,", "and", "flecainide.", "Also", "found", "in", "the", "proband", "was", "common", "polymorphism", "(K897T)", "in", "KCNH2,", "the", "gene", "coding", "for", "the", "HERG", "potassium", "channel", "which", "contributes", "to", "control", "of", "ventricular", "repolarization.", "Our", "results", "reveal", "multiple", "biophysical", "changes", "in", "Na+", "channel", "gating", "induced", "by", "the", "F1473C", "mutation", "that", "all", "contribute", "to", "delayed", "repolarization", "of", "cellular", "action", "potentials", "and", "are", "consistent", "with", "the", "pronounced", "phenotype", "of", "the", "patient.", "Furthermore", "our", "data", "suggest", "an", "important", "role", "of", "the", "KCNH2", "polymorphism", "and", "developmentally-related", "expression", "of", "background", "ion", "channels", "in", "both", "the", "therapeutic", "response", "and", "disease", "phenotype", "of", "the", "proband.", "RESULTS", "Clinical", "profile", "The", "proband", "was", "a", "full", "term", "newborn", "infant", "boy", "with", "a", "prenatal", "history", "significant", "for", "fetal", "bradycardia", "of", "unclear", "etiology", "with", "Academic", "Editor:", "Arnold", "Schwartz,", "University", "of", "Cincinnati,", "United", "States", "of", "America", "Received", "October", "5,", "2007;", "Accepted", "November", "10,", "2007;", "Published", "December", "5,", "2007", "Copyright:", "2007", "Bankston", "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", "the", "NIH", "(1R01", "HL-56810-10", "to", "RSK).", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "*", "To", "whom", "correspondence", "should", "be", "addressed.", "E-mail:", "rsk20@columbia.edu", ".", "These", "authors", "contributed", "equally", "to", "this", "work.", "PLoS", "ONE", "|", "www.plosone.org", "1", "December", "2007", "|", "Issue", "12", "|", "e1258" ]

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[ "J", "Cachexia", "Sarcopenia", "Muscle", "(2011)", "2:181–188", "DOI", "10.1007/s13539-011-0037-3", "ORIGINAL", "ARTICLE", "Decreased", "NADPH", "oxidase", "expression", "and", "antioxidant", "activity", "in", "cachectic", "skeletal", "muscle", "Melanie", "J.", "Sullivan-Gunn", "&", "Siun", "P.", "Campbell-O’Sullivan", "&", "Michael", "J.", "Tisdale", "&", "Paul", "A.", "Lewandowski", "Received:", "22", "February", "2011", "/", "Accepted:", "27", "July", "2011", "/", "Published", "online:", "11", "August", "2011", "#", "The", "Author(s)", "2011.", "This", "article", "is", "published", "with", "open", "access", "at", "Springerlink.com", "Abstract", "Background", "Cancer", "cachexia", "is", "the", "progressive", "loss", "of", "skeletal", "muscle", "protein", "that", "contributes", "significantly", "to", "cancer", "morbidity", "and", "mortality.", "Evidence", "of", "antioxidant", "attenuation", "and", "the", "presence", "of", "oxidised", "proteins", "in", "patients", "with", "cancer", "cachexia", "indicate", "a", "role", "for", "oxidative", "stress.", "The", "level", "of", "oxidative", "stress", "in", "tissues", "is", "determined", "by", "an", "imbalance", "between", "reactive", "oxygen", "species", "production", "and", "antioxidant", "activity.", "This", "study", "aimed", "to", "investigate", "the", "superoxide", "generating", "NADPH", "oxidase", "(NOX)", "enzyme", "and", "antioxidant", "enzyme", "systems", "in", "murine", "adenocarcinoma", "tumour-bearing", "cachectic", "mice.", "Methods", "Superoxide", "levels,", "mRNA", "levels", "of", "NOX", "enzyme", "subunits", "and", "the", "antioxidant", "enzymes", "superoxide", "dismutase", "(SOD),", "glutathione", "peroxidise", "(GPx)", "and", "catalase", "was", "measured", "in", "the", "skeletal", "muscle", "of", "mice", "with", "cancer", "and", "cancer", "cachexia.", "Protein", "expression", "levels", "of", "NOX", "enzyme", "subunits", "and", "antioxidant", "enzyme", "activity", "was", "also", "mea-", "sured", "in", "the", "same", "muscle", "samples.", "Results", "Superoxide", "levels", "increased", "1.4-fold", "in", "the", "muscle", "of", "mice", "with", "cancer", "cachexia,", "and", "this", "was", "associated", "with", "M.", "J.", "Sullivan-Gunn", ":", "P.", "A.", "Lewandowski", "(*)", "School", "of", "Medicine,", "Deakin", "University,", "Geelong", "Campus,", "Geelong,", "VIC", "3217,", "Australia", "e-mail:", "paul.lewandowski@deakin.edu.au", "S.", "P.", "Campbell-O’Sullivan", "School", "of", "Biomedical", "Sciences,", "Victoria", "University,", "Centre", "for", "Aging,", "Rehabilitation,", "Exercise", "and", "Sport,", "PO", "Box", "14428,", "Melbourne", "8001,", "Australia", "M.", "J.", "Tisdale", "School", "of", "Life", "Sciences,", "Aston", "University,", "Aston", "Triangle,", "Birmingham", "B4", "7ET,", "UK", "a", "decrease", "in", "mRNA", "of", "NOX", "enzyme", "subunits,", "NOX2,", "p40phox", "and", "p67phox", "along", "with", "the", "antioxidant", "enzymes", "SOD1,", "SOD2", "and", "GPx.", "Cancer", "cachexia", "was", "also", "associated", "with", "a", "1.3-fold", "decrease", "in", "SOD1", "and", "2.0-fold", "decrease", "in", "GPx", "enzyme", "activity.", "Conclusion", "Despite", "increased", "superoxide", "levels", "in", "cachectic", "skeletal", "muscle,", "NOX", "enzyme", "subunits,", "NOX2,", "p40phox", "and", "p67phox,", "were", "downregulated", "along", "with", "the", "expression", "and", "activity", "of", "the", "antioxidant", "enzymes.", "Therefore,", "the", "increased", "superoxide", "levels", "in", "cachectic", "skeletal", "muscle", "may", "be", "attributed", "to", "the", "reduction", "in", "the", "activity", "of", "endogenous", "antioxidant", "enzymes.", "Keywords", "Cancer", "cachexia", ".", "NADPH", "oxidase", ".", "ROS", ".", "O2−", ".", "Antioxidant", ".", "SOD", "1", "Introduction", "Cancer", "cachexia", "is", "a", "condition", "of", "progressive", "muscle", "wasting", "that", "develops", "as", "a", "secondary", "condition", "in", "response", "to", "tumour", "growth", "[1].", "While", "cachexia", "develops", "in", "a", "wide", "range", "of", "pathologies", "including", "anorexia", "nervosa,", "acquired", "immunodeficiency", "syndrome,", "amyotrophic", "lateral", "sclerosis,", "congestive", "heart", "failure", "and", "various", "malignant", "cancers,", "cancer", "cachexia", "has", "been", "reported", "to", "develop", "at", "a", "faster", "rate", "than", "any", "other", "cachectic", "condition", "[1].", "Approximately", "half", "of", "all", "patients", "with", "cancer", "experience", "cachexia", "and", "almost", "a", "third", "of", "mortalities", "are", "estimated", "to", "result", "from", "cachexia", "[2].", "Tumour", "growth", "induces", "a", "specific", "catabolic", "response", "in", "skeletal", "muscle", "that", "causes", "the", "accelerated", "loss", "of", "protein,", "characterised", "by", "the", "significant", "loss", "of", "body", "weight", "[3].", "Animal", "tumour", "models", "have", "been", "used", "to", "investigate", "cancer", "cachexia,", "developing", "up", "to", "30%", "loss", "in", "body", "weight", "after", "tumour", "cell", "implantation.", "NMRI", "mice", "implanted", "with" ]

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3,118,218

null

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[ "Gunaratne", "et", "al.", "BMC", "Genomics", "2011,", "12:277", "http://www.biomedcentral.com/1471-2164/12/277", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Song", "exposure", "regulates", "known", "and", "novel", "microRNAs", "in", "the", "zebra", "finch", "auditory", "forebrain", "Preethi", "H", "Gunaratne1,2,3†,", "Ya-Chi", "Lin4†,", "Ashley", "L", "Benham1,", "Jenny", "Drnevich5,", "Cristian", "Coarfa11,", "Jayantha", "B", "Tennakoon1,", "Chad", "J", "Creighton6,", "Jong", "H", "Kim1,", "Aleksandar", "Milosavljevic11,", "Michael", "Watson7,", "Sam", "Griffiths-Jones8", "and", "David", "F", "Clayton4,9,10*", "Abstract", "Background:", "In", "an", "important", "model", "for", "neuroscience,", "songbirds", "learn", "to", "discriminate", "songs", "they", "hear", "during", "tape-recorded", "playbacks,", "as", "demonstrated", "by", "song-specific", "habituation", "of", "both", "behavioral", "and", "neurogenomic", "responses", "in", "the", "auditory", "forebrain.", "We", "hypothesized", "that", "microRNAs", "(miRNAs", "or", "miRs)", "may", "participate", "in", "the", "changing", "pattern", "of", "gene", "expression", "induced", "by", "song", "exposure.", "To", "test", "this,", "we", "used", "massively", "parallel", "Illumina", "sequencing", "to", "analyse", "small", "RNAs", "from", "auditory", "forebrain", "of", "adult", "zebra", "finches", "exposed", "to", "tape-recorded", "birdsong", "or", "silence.", "Results:", "In", "the", "auditory", "forebrain,", "we", "identified", "121", "known", "miRNAs", "conserved", "in", "other", "vertebrates.", "We", "also", "identified", "34", "novel", "miRNAs", "that", "do", "not", "align", "to", "human", "or", "chicken", "genomes.", "Five", "conserved", "miRNAs", "showed", "significant", "and", "consistent", "changes", "in", "copy", "number", "after", "song", "exposure", "across", "three", "biological", "replications", "of", "the", "song-silence", "comparison,", "with", "two", "increasing", "(tgu-miR-25,", "tgu-miR-192)", "and", "three", "decreasing", "(tgu-miR-92,", "tgu-", "miR-124,", "tgu-miR-129-5p).", "We", "also", "detected", "a", "locus", "on", "the", "Z", "sex", "chromosome", "that", "produces", "three", "different", "novel", "miRNAs,", "with", "supporting", "evidence", "from", "Northern", "blot", "and", "TaqMan", "qPCR", "assays", "for", "differential", "expression", "in", "males", "and", "females", "and", "in", "response", "to", "song", "playbacks.", "One", "of", "these,", "tgu-miR-2954-3p,", "is", "predicted", "(by", "TargetScan)", "to", "regulate", "eight", "song-responsive", "mRNAs", "that", "all", "have", "functions", "in", "cellular", "proliferation", "and", "neuronal", "differentiation.", "Conclusions:", "The", "experience", "of", "hearing", "another", "bird", "singing", "alters", "the", "profile", "of", "miRNAs", "in", "the", "auditory", "forebrain", "of", "zebra", "finches.", "The", "response", "involves", "both", "known", "conserved", "miRNAs", "and", "novel", "miRNAs", "described", "so", "far", "only", "in", "the", "zebra", "finch,", "including", "a", "novel", "sex-linked,", "song-responsive", "miRNA.", "These", "results", "indicate", "that", "miRNAs", "are", "likely", "to", "contribute", "to", "the", "unique", "behavioural", "biology", "of", "learned", "song", "communication", "in", "songbirds.", "Background", "Songbirds", "are", "important", "models", "for", "exploring", "the", "neural", "and", "genomic", "mechanisms", "underlying", "vocal", "communica-", "tion,", "social", "experience", "and", "learning", "(reviewed", "in", "[1]).", "Songbirds", "communicate", "using", "both", "innate", "calls", "and", "learned", "vocalizations", "(songs),", "and", "unique", "specializations", "of", "the", "brain", "evolved", "to", "support", "this", "behavior", "(reviewed", "in", "[2]).", "In", "the", "zebra", "finch,", "only", "the", "male", "produces", "songs,", "although", "both", "sexes", "process", "and", "discriminate", "specific", "songs", "[3-6].", "The", "genome", "is", "actively", "engaged", "by", "song", "communication,", "as", "first", "shown", "in", "an", "early", "*", "Correspondence:", "dclayton@uiuc.edu", "†", "Contributed", "equally", "4Department", "of", "Cell", "and", "Developmental", "Biology,", "University", "of", "Illinois,", "Urbana-Champaign,", "IL", "61801,", "USA", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "demonstration", "of", "how", "gene", "responses", "in", "the", "brain", "dis-", "criminate", "among", "different", "song", "stimuli", "[7].", "The", "genomic", "response", "is", "not", "a", "simple", "correlate", "of", "neural", "activity", "and", "it", "can", "vary", "significantly", "according", "to", "the", "salience", "and", "behavioral", "context", "of", "the", "experience", "[8-13].", "Recent", "stu-", "dies", "using", "microarray", "technology", "have", "now", "shown", "that", "song", "exposure", "affects", "the", "expression", "of", "thousands", "of", "genes", "in", "the", "auditory", "forebrain", "[14,15].", "Repeated", "expo-", "sure", "to", "one", "song", "leads", "to", "an", "altered", "gene", "expression", "profile,", "correlated", "with", "habituation", "of", "both", "the", "beha-", "vioral", "and", "immediate", "genomic", "responses", "to", "that", "specific", "song.", "These", "observations", "suggest", "the", "involvement", "of", "large", "and", "dynamic", "transcriptional", "network", "in", "the", "recog-", "nition", "and", "memory", "of", "complex", "vocal", "signals", "[14].", "MicroRNAs", "(miRNAs", "or", "miRs)", "are", "emerging", "as", "potential", "control", "points", "in", "transcriptional", "networks,", "and", "©", "2011", "Gunaratne", "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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[ "Dieter", "and", "Estus", "Molecular", "Neurodegeneration", "2010,", "5:34", "http://www.molecularneurodegeneration.com/content/5/1/34", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Isoform", "of", "APOE", "with", "retained", "intron", "3;", "quantitation", "and", "identification", "of", "an", "associated", "single", "nucleotide", "polymorphism", "Laura", "S", "Dieter,", "Steven", "Estus*", "Abstract", "Background:", "Alleles", "of", "apolipoprotein", "E", "(APOE)", "are", "the", "major", "genetic", "risk", "factor", "for", "late", "onset", "Alzheimer’s", "Disease", "(LOAD).", "Recently,", "an", "APOE", "splice", "variant", "that", "retains", "intron", "3", "(APOE-I3)", "was", "identified.", "To", "gain", "insight", "into", "the", "possible", "role", "of", "this", "isoform", "in", "LOAD,", "we", "quantified", "its", "expression", "in", "a", "cohort", "of", "56", "human", "brain", "specimens", "by", "using", "quantitative", "RT-PCR.", "Results:", "We", "found", "that", "APOE-I3", "generally", "represents", "a", "low", "percentage", "(<", "0.5%)", "of", "overall", "APOE", "expression.", "However,", "in", "one", "specimen,", "the", "proportion", "of", "APOE-I3", "was", "increased", "about", "~13", "fold.", "This", "specimen", "was", "unique", "in", "the", "cohort", "for", "possessing", "the", "minor", "allele", "of", "an", "intron", "3", "single", "nucleotide", "polymorphism", "(SNP),", "rs12982192.", "Additionally,", "an", "allelic", "expression", "imbalance", "study", "indicated", "that", "the", "rs12982192", "minor", "allele", "was", "associated", "with", "increased", "APOE-I3", "expression.", "Conclusions:", "Overall,", "we", "interpret", "our", "results", "as", "suggesting", "that", "APOE-I3", "represents", "a", "minor", "portion", "of", "APOE", "expression", "and", "that", "rs12982192", "is", "associated", "with", "APOE", "intron", "3", "retention.", "Since", "the", "minor", "allele", "of", "this", "SNP", "is", "on", "the", "same", "haplotype", "as", "the", "minor", "allele", "of", "rs429358,", "which", "defines", "the", "APOE4", "allele,", "we", "speculate", "that", "rs12982192", "may", "reflect", "a", "modest", "loss", "of", "mRNA", "encoding", "functional", "APOE4.", "Background", "APOE", "variants", "are", "the", "single", "largest", "genetic", "factors", "impacting", "late", "onset", "Alzheimer", "Disease", "(LOAD),", "the", "most", "common", "neurodegenerative", "disease.", "In", "particular,", "the", "APOE4", "allele", "confers", "increased", "risk,", "being", "present", "at", "a", "~15%", "frequency", "in", "the", "general", "population", "and", "at", "50%", "in", "LOAD", "[1,2].", "APOE", "consists", "of", "4", "exons", "and", "3", "introns", "encoding", "a", "total", "of", "317", "amino", "acids.", "After", "cleavage", "of", "the", "signal", "peptide,", "the", "mature", "APOE", "protein", "is", "299", "amino", "acids.", "Protein", "translation", "begins", "in", "exon", "2", "and", "ends", "in", "exon", "4.", "In", "the", "brain,", "APOE", "transports", "choles-", "terol", "and", "modulates", "Aß", "clearance", "[1,2].", "APOE", "is", "pri-", "marily", "secreted", "by", "astrocytes", "[3,4]", "with", "microglia", "[5]", "and,", "possibly,", "stressed", "neurons", "also", "contributing", "to", "APOE", "production", "[6].", "Overall,", "insights", "into", "APOE", "expression", "will", "provide", "further", "information", "on", "AD", "risk.", "Recently,", "Xu", "et", "al", "reported", "an", "APOE", "isoform", "that", "retained", "intron", "3", "(APOE-I3)", "and", "was", "increased", "with", "*", "Correspondence:", "steve.estus@uky.edu", "Department", "of", "Physiology", "and", "Sanders-Brown", "Center", "on", "Aging,", "University", "of", "Kentucky,", "Lexington,", "KY,", "USA", "neuronal", "stress", "in", "murine", "models", "[7].", "To", "gain", "insights", "into", "this", "novel", "APOE", "isoform", "in", "humans,", "we", "quantified", "APOE-I3", "as", "well", "as", "the", "normal", "length", "APOE", "(APOE-NL)", "in", "a", "cohort", "of", "56", "AD", "and", "non-AD", "brain", "samples.", "We", "report", "that", "APOE-I3", "represents", "a", "low", "proportion", "of", "over-", "all", "APOE", "expression.", "In", "addition,", "we", "identified", "an", "indivi-", "dual", "with", "significantly", "increased", "expression", "of", "the", "APOE-", "I3", "isoform.", "Further", "analysis", "revealed", "that", "this", "individual", "was", "unique", "in", "the", "cohort", "for", "an", "intron", "3", "single", "nucleotide", "polymorphism", "(SNP),", "rs12982192.", "Moreover,", "APOE-I3", "was", "in", "allelic", "expression", "imbalance", "(AEI)", "in", "this", "indivi-", "dual", "such", "that", "the", "minor", "allele", "of", "rs12982192", "correlated", "with", "increased", "expression", "of", "the", "APOE-I3", "isoform.", "Over-", "all,", "we", "interpret", "our", "results", "as", "suggesting", "that", "APOE-I3", "represents", "a", "minor", "portion", "of", "APOE", "expression", "and", "that", "rs12982192", "is", "associated", "with", "APOE", "intron", "3", "retention.", "Materials", "and", "methods", "Human", "autopsy", "tissue", "The", "human", "autopsy", "tissue", "specimens", "used", "here", "have", "been", "described", "elsewhere", "[8,9].", "Briefly,", "anterior", "cingulate", "tissue", "©", "2010", "Dieter", "and", "Estus;", "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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2,628,341

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[ "Chiropractic", "&", "Osteopathy", "Commentary", "Common", "errors", "and", "clinical", "guidelines", "for", "manual", "muscle", "testing:", "\"the", "arm", "test\"", "and", "other", "inaccurate", "procedures", "Walter", "H", "Schmitt", "Jr*", "and", "Scott", "C", "Cuthbert", "BioMed", "Central", "Open", "Access", "Address:", "Chiropractic", "Health", "Center,", "255", "West", "Abriendo", "Avenue,", "Pueblo,", "CO", "81004,", "USA", "Email:", "Walter", "H", "Schmitt*", "-", "wallys@mindspring.com;", "Scott", "C", "Cuthbert", "-", "cranialdc@hotmail.com", "*", "Corresponding", "author", "Published:", "19", "December", "2008", "Chiropractic", "&", "Osteopathy", "2008,", "16:16", "doi:10.1186/1746-1340-16-16", "This", "article", "is", "available", "from:", "http://www.chiroandosteo.com/content/16/1/16", "Received:", "2", "June", "2008", "Accepted:", "19", "December", "2008", "©", "2008", "Schmitt", "and", "Cuthbert;", "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", "manual", "muscle", "test", "(MMT)", "has", "been", "offered", "as", "a", "chiropractic", "assessment", "tool", "that", "may", "help", "diagnose", "neuromusculoskeletal", "dysfunction.", "We", "contend", "that", "due", "to", "the", "number", "of", "manipulative", "practitioners", "using", "this", "test", "as", "part", "of", "the", "assessment", "of", "patients,", "clinical", "guidelines", "for", "the", "MMT", "are", "required", "to", "heighten", "the", "accuracy", "in", "the", "use", "of", "this", "tool.", "Objective:", "To", "present", "essential", "operational", "definitions", "of", "the", "MMT", "for", "chiropractors", "and", "other", "clinicians", "that", "should", "improve", "the", "reliability", "of", "the", "MMT", "as", "a", "diagnostic", "test.", "Controversy", "about", "the", "usefulness", "and", "reliability", "of", "the", "MMT", "for", "chiropractic", "diagnosis", "is", "ongoing,", "and", "clinical", "guidelines", "about", "the", "MMT", "are", "needed", "to", "resolve", "confusion", "regarding", "the", "MMT", "as", "used", "in", "clinical", "practice", "as", "well", "as", "the", "evaluation", "of", "experimental", "evidence", "concerning", "its", "use.", "Discussion:", "We", "expect", "that", "the", "resistance", "to", "accept", "the", "MMT", "as", "a", "reliable", "and", "valid", "diagnostic", "tool", "will", "continue", "within", "some", "portions", "of", "the", "manipulative", "professions", "if", "clinical", "guidelines", "for", "the", "use", "of", "MMT", "methods", "are", "not", "established", "and", "accepted.", "Unreliable", "assessments", "of", "this", "method", "of", "diagnosis", "will", "continue", "when", "non-standard", "MMT", "research", "papers", "are", "considered", "representative", "of", "the", "methods", "used", "by", "properly", "trained", "clinicians.", "Conclusion:", "Practitioners", "who", "employ", "the", "MMT", "should", "use", "these", "clinical", "guidelines", "for", "improving", "their", "use", "of", "the", "MMT", "in", "their", "assessments", "of", "muscle", "dysfunction", "in", "patients", "with", "musculoskeletal", "pain.", "Background", "Since", "Goodheart", "introduced", "applied", "kinesiology", "(AK)", "as", "a", "chiropractic", "clinical", "concept", "in", "1964", "[1],", "the", "use", "of", "man-", "ual", "muscle", "testing", "(MMT)", "has", "become", "widespread", "throughout", "the", "chiropractic", "profession", "and", "has", "spilled", "over", "into", "the", "medical,", "dental", "and", "other", "health", "professions", "as", "a", "mode", "of", "analysis", "of", "nervous", "system", "function", "[2-17].", "The", "MMT", "is", "used", "in", "the", "chiropractic,", "orthopedic,", "neuro-", "logical,", "medical,", "dental,", "homeopathic,", "and", "physical", "ther-", "apy", "arenas", "to", "assess", "locomotor", "system", "dysfunction", "and", "to", "determine", "a", "patient's", "progress", "during", "therapy.", "In", "the", "words", "of", "the", "cliché,", "\"Imitation", "is", "the", "sincerest", "form", "of", "flattery.\"", "In", "the", "practice", "of", "muscle", "testing,", "however,", "imi-", "tation", "has", "proven", "to", "be", "an", "embarcadero", "for", "inconsistency.", "All", "too", "many", "well-meaning", "clinical", "investigators", "observed", "the", "phenomena", "of", "muscles", "strengthening", "and", "weakening", "during", "standard", "AK", "and", "MMT", "procedures,", "and", "have", "Page", "1", "of", "14", "(page", "number", "not", "for", "citation", "purposes)" ]

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3,023,717

null

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[ "Co-Administration", "of", "IL-1+IL-6+TNF-a", "with", "Mycobacterium", "tuberculosis", "Infected", "Macrophages", "Vaccine", "Induces", "Better", "Protective", "T", "Cell", "Memory", "than", "BCG", "Vijender", "Singh", "1", ",", "Shweta", "Jain1,", "Uthaman", "Gowthaman", "1", ",", "Pankaj", "Parihar1,", "Pushpa", "Gupta2,", "Umesh", "D.", "Gupta2,", "Javed", "N.", "Agrewala1*", "1", "Immunology", "Laboratory,", "Institute", "of", "Microbial", "Technology,", "Chandigarh,", "India,", "2", "National", "JALMA", "Institute", "for", "Leprosy", "and", "Other", "Mycobacterial", "Diseases,", "Agra,", "India", "Abstract", "BCG", "has", "been", "administered", "globally", "for", "more", "than", "75", "years,", "yet", "tuberculosis", "(TB)", "continues", "to", "kill", "more", "than", "2", "million", "people", "annually.", "Further,", "BCG", "protects", "childhood", "TB", "but", "is", "quite", "inefficient", "in", "adults.", "This", "indicates", "that", "BCG", "fails", "to", "induce", "long-term", "protection.", "Hence", "there", "is", "a", "need", "to", "explore", "alternative", "vaccination", "strategies", "that", "can", "stimulate", "enduring", "T", "cell", "memory", "response.", "Dendritic", "cell", "based", "vaccination", "has", "attained", "extensive", "popularity", "following", "their", "success", "in", "various", "malignancies.", "In", "our", "previous", "study,", "we", "have", "established", "a", "novel", "and", "unique", "vaccination", "strategy", "against", "Mycobacterium", "tuberculosis", "(M.", "tb)", "and", "Salmonella", "typhimurium", "by", "utilizing", "infected", "macrophages", "(IM).", "In", "short-term", "experiments", "(30", "days),", "substantial", "degree", "of", "protection", "was", "observed.", "However,", "remarkable", "difference", "was", "not", "observed", "in", "long-term", "studies", "(240", "days)", "due", "to", "failure", "of", "the", "vaccine", "to", "generate", "long-lasting", "memory", "T", "cells.", "Hence,", "in", "the", "present", "study", "we", "employed", "T", "cell", "memory", "augmenting", "cytokines", "IL-1+IL-6+TNF-a", "and", "IL-7+IL-15", "for", "the", "induction", "of", "the", "enhancement", "of", "long-term", "protection", "by", "the", "vaccine.", "We", "co-administered", "the", "M.", "tb", "infected", "macrophages", "vaccine", "with", "IL-1+IL-6+TNF-a", "(IM-1.6.a)", "and", "IL-7+IL-15", "(IM-7.15).", "The", "mice", "were", "then", "rested", "for", "a", "reasonably", "large", "period", "(240", "days)", "to", "study", "the", "bona", "fide", "T", "cell", "memory", "response", "before", "exposing", "them", "to", "aerosolized", "M.", "tb.", "IM-1.6.a", "but", "not", "IM-7.15", "significantly", "improved", "memory", "T", "cell", "response", "against", "M.", "tb,", "as", "evidenced", "by", "recall", "responses", "of", "memory", "T", "cells,", "expansion", "of", "both", "central", "as", "well", "as", "effector", "memory", "CD4", "and", "CD8", "T", "cell", "pools,", "elicitation", "of", "mainly", "Th1", "memory", "response,", "reduction", "in", "the", "mycobacterial", "load", "and", "alleviated", "lung", "pathology.", "Importantly,", "the", "protection", "induced", "by", "IM-1.6.a", "was", "significantly", "better", "than", "BCG.", "Thus,", "this", "study", "demonstrates", "that", "not", "only", "antigen-pulsed", "DCs", "can", "be", "successfully", "employed", "as", "vaccines", "against", "cancer", "and", "infectious", "diseases", "but", "also", "macrophages", "infected", "with", "M.", "tb", "can", "be", "utilized", "with", "great", "efficacy", "especially", "in", "protection", "against", "TB.", "Citation:", "Singh", "V,", "Jain", "S,", "Gowthaman", "U,", "Parihar", "P,", "Gupta", "P,", "et", "al.", "(2011)", "Co-Administration", "of", "IL-1+IL-6+TNF-a", "with", "Mycobacterium", "tuberculosis", "Infected", "Macrophages", "Vaccine", "Induces", "Better", "Protective", "T", "Cell", "Memory", "than", "BCG.", "PLoS", "ONE", "6(1):", "e16097.", "doi:10.1371/journal.pone.0016097", "Editor:", "Leonardo", "A.", "Sechi,", "Universita", "di", "Sassari,", "Italy", "Received", "November", "30,", "2010;", "Accepted", "December", "10,", "2010;", "Published", "January", "19,", "2011", "Copyright:", "2011", "Singh", "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", "is", "supported", "by", "the", "Indian", "Council", "of", "Medical", "Research", "(Grant", "Reference", "No.", "5/8/5/6/2005-ECD-I)", "and", "Department", "of", "Biotechnology", "(Grant", "Reference", "No.", "BT/PR6219/Med/14/762/2005),", "New", "Delhi,", "India.", "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:", "javed@imtech.res.in", "Introduction", "In", "1992,", "nearly", "100", "million", "children", "received", "BCG", "[1].", "Despite", "the", "reality", "that", "more", "people", "have", "been", "immunized", "with", "BCG", "than", "any", "other", "vaccine,", "TB", "continues", "to", "kill", "some", "2", "million", "people", "annually", "and", "2", "billion", "people", "worldwide", "are", "infected", "with", "M.", "tb", "[2].", "Hence,", "the", "protective", "efficacy", "of", "the", "BCG", "vaccine", "remains", "doubtful.", "The", "wide", "spread", "of", "TB", "has", "been", "further", "aggravated", "by", "the", "emergence", "of", "multidrug-resistant", "(MDR)", "strains", "of", "mycobac-", "teria", "and", "the", "AIDS-pandemic", "[3].", "Therefore,", "there", "is", "a", "serious", "need", "and", "challenge", "for", "scientific", "community", "to", "develop", "alternative", "vaccines", "for", "the", "control", "of", "the", "disease.", "Approximately", "one-third", "of", "the", "world", "population", "is", "infected", "with", "M.", "tb,", "but", "only", "5%–10%", "contract", "active", "disease", "while", "remaining", "develop", "effective", "immunity", "[2].", "Further,", "mice", "cleared", "of", "TB", "infection", "respond", "vigorously", "upon", "re-exposure", "to", "mycobacteria", "and", "remain", "protected", "[4].", "This", "suggests", "that", "infection", "with", "viable", "mycobacteria", "develop", "effective", "and", "long-lasting", "protective", "immu-", "nity.", "There", "may", "exist", "a", "possibility", "that", "growing", "bacilli", "express", "discrete", "molecules", "inside", "the", "macrophage", "[5],", "that", "may", "act", "as", "protective", "antigens", "necessary", "for", "the", "generation", "of", "effector", "and", "memory", "T", "cells", "responsible", "for", "protective", "immunity.", "Whether", "such", "protective", "antigens", "of", "M.", "tb", "that", "can", "be", "exploited", "as", "vaccines,", "still", "remains", "to", "be", "identified.", "[4,5].", "Incidentally,", "the", "antigens", "isolated", "from", "in", "vitro", "cultures", "have", "failed", "to", "generate", "considerable", "protective", "immunity,", "corroborating", "to", "the", "above", "mentioned", "hypothesis", "[6,7].", "In", "the", "past", "few", "decades,", "a", "number", "of", "new", "vaccine", "approaches", "like", "naked", "DNA", "vaccines,", "live", "attenuated", "vaccines", "and", "subunit", "vaccines", "have", "been", "elucidated.", "Unfortunately,", "none", "of", "them", "worked", "successfully", "against", "TB", "since", "they", "failed", "to", "generate", "long-", "lasting", "memory", "cells", "[8].", "This", "indicates", "that", "novel", "and", "unique", "vaccination", "strategies", "still", "need", "to", "be", "explored", "for", "TB.", "Recently,", "many", "studies", "have", "highlighted", "the", "role", "of", "cell-based", "vaccines", "viz.", "antigen-loaded", "DCs", "to", "evoke", "protective", "T", "cell", "PLoS", "ONE", "|", "www.plosone.org", "1", "January", "2011", "|", "Volume", "6", "|", "Issue", "1", "|", "e16097" ]

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[ "organic", "compounds", "Acta", "Crystallographica", "Section", "E", "Structure", "Reports", "Online", "ISSN", "1600-5368", "Dihalogenated", "trichodermin", "(4b-", "acetoxy-9,10-dibromo-12,13-epoxytri-", "chothec)", "Jin-Hao", "Zhao,a", "Yong", "Zhou,b", "Jian-Gong", "Zhang,a", "Jing-Li", "Chenga", "and", "Fu-Cheng", "Linc*", "aInstitute", "of", "Pesticide", "and", "Environmental", "Toxicology,", "Zhejiang", "University,", "Hangzhou", "310029,", "People’s", "Republic", "of", "China,", "bCollege", "of", "Chemical", "Engineering", "and", "Materials", "Science,", "Zhejiang", "University", "Of", "Technology,", "Hangzhou", "310032,", "People’s", "Republic", "of", "China,", "and", "cInstitute", "of", "Biotechnology,", "Zhejiang", "University,", "Hangzhou", "310029,", "People’s", "Republic", "of", "China", "Correspondence", "e-mail:", "fuchenglin@zj.com", "Received", "30", "November", "2009;", "accepted", "15", "December", "2009", "Key", "indicators:", "single-crystal", "X-ray", "study;", "T", "=", "296", "K;", "mean", "(C–C)", "=", "0.007", "A˚;", "R", "factor", "=", "0.032;", "wR", "factor", "=", "0.095;", "data-to-parameter", "ratio", "=", "17.2.", "In", "the", "title", "dihalogenated", "trichodermin", "molecule,", "C17H24Br2O4", "(systematic", "name:", "9,10-dibromo-12,13-epoxy-", "trichothec-9-en-4", "-yl", "acetate),", "the", "ﬁve-membered", "ring", "displays", "an", "envelope", "conformation,", "whereas", "the", "two", "six-", "membered", "rings", "show", "the", "same", "conformation,", "viz.", "chair.", "As", "for", "the", "seven-membered", "ring,", "the", "dihedral", "angle", "between", "the", "mean", "planes", "formed", "by", "the", "four", "C", "atoms", "of", "the", "envelope", "unit", "and", "the", "three", "C", "and", "one", "O", "atoms", "of", "the", "six-membered", "chair", "is", "69.08", "(4)", ";", "these", "two", "mean", "planes", "are", "nearly", "perpendicular", "to", "the", "epoxy", "ring", "with", "angles", "of", "87.53", "(4)", "and", "88.67", "(4)", ",", "respectively.", "Related", "literature", "For", "the", "fungicidal", "activity", "of", "trichodermin,", "see:", "Zhang", "et", "al.", "(2007).", "Trichodermin", "is", "a", "member", "of", "the", "4", "-aceoxy-12,13-", "epoxytrichothecene", "family,", "see:", "Nielsen", "et", "al.", "(2005).", "For", "the", "structure", "of", "trichodermin,", "see:", "Chen", "et", "al.", "(2008)", "and", "for", "the", "structure", "of", "a", "trichodermin", "derivative,", "see:", "Cheng", "et", "al.", "(2009).", "Experimental", "Crystal", "data", "C17H24Br2O4", "Mr", "=", "452.18", "Monoclinic,", "P21", "a", "=", "10.0120", "(4)", "A˚", "b", "=", "8.3397", "(4)", "A˚", "c", "=", "11.1235", "(6)", "A˚", "=", "106.6220", "(10)", "Data", "collection", "Rigaku", "R-AXIS", "RAPID", "diffractometer", "Absorption", "correction:", "multi-scan", "(ABSCOR:", "Higashi,", "1995)", "Tmin", "=", "0.323,", "Tmax", "=", "0.633", "Reﬁnement", "R[F", "2", ">", "2", "(F", "2)]", "=", "0.032", "wR(F", "2)", "=", "0.095", "S", "=", "1.00", "3667", "reﬂections", "213", "parameters", "1", "restraint", "V", "=", "889.97", "(7)", "A˚", "3", "Z", "=", "2", "Mo", "K", "radiation", "=", "4.57", "mm", "1", "T", "=", "296", "K", "0.26", "0.20", "0.10", "mm", "8698", "measured", "reﬂections", "3667", "independent", "reﬂections", "2752", "reﬂections", "with", "I", ">", "2", "(I)", "Rint", "=", "0.032", "H-atom", "parameters", "constrained", "max", "=", "0.67", "e", "A˚", "3", "min", "=", "0.65", "e", "A˚", "3", "Absolute", "structure:", "Flack", "(1983),", "1506", "Friedel", "pairs", "Flack", "parameter:", "0.000", "(15)", "Data", "collection:", "PROCESS-AUTO", "(Rigaku,", "2006);", "cell", "reﬁne-", "ment:", "PROCESS-AUTO;", "data", "reduction:", "CrystalStructure", "(Rigaku,", "2007);", "program(s)", "used", "to", "solve", "structure:", "SHELXS97", "(Sheldrick,", "2008);", "program(s)", "used", "to", "reﬁne", "structure:", "SHELXL97", "(Sheldrick,", "2008);", "molecular", "graphics:", "ORTEP-3", "for", "Windows", "(Farrugia,", "1997);", "software", "used", "to", "prepare", "material", "for", "publication:", "WinGX", "(Farrugia,", "1999)", "and", "PLATON", "(Spek,", "2009).", "The", "work", "was", "supported", "by", "the", "National", "Natural", "Science", "Foundation", "of", "China", "(No.", "30700532)", "and", "the", "Science", "and", "Technology", "Project", "of", "Zhejiang", "Province", "(No.", "2009", "C21014).", "The", "authors", "are", "grateful", "to", "Professor", "Jianming", "Gu", "for", "the", "crystal", "structure", "analysis.", "Supplementary", "data", "and", "ﬁgures", "for", "this", "paper", "are", "available", "from", "the", "IUCr", "electronic", "archives", "(Reference:", "SI2228).", "References", "Chen,", "S.-Y.,", "Zhang,", "C.-L.,", "Chen,", "Y.-Z.", "&", "Lin,", "F.-C.", "(2008).", "Acta", "Cryst.", "E64,", "o702.", "Cheng,", "J.-L.,", "Zhou,", "Y.,", "Lin,", "F.-C.,", "Zhao,", "J.-H.", "&", "Zhu,", "G.-N.", "(2009).", "Acta", "Cryst.", "E65,", "o2879.", "Farrugia,", "L.", "J.", "(1997).", "J.", "Appl.", "Cryst.", "30,", "565.", "Farrugia,", "L.", "J.", "(1999).", "J.", "Appl.", "Cryst.", "32,", "837–838.", "Flack,", "H.", "D.", "(1983).", "Acta", "Cryst.", "A39,", "876–881.", "Higashi,", "T.", "(1995).", "ABSCOR.", "Rigaku", "Corporation,", "Tokyo,", "Japan.", "Nielsen,", "K.", "F.,", "Grafenhan,", "T.,", "Zafari,", "D.", "&", "Thrane,", "U.", "(2005).", "J.", "Agric.", "Food", "Chem.", "53,", "8190–8196.", "Rigaku", "(2006).", "PROCESS-AUTO.", "Rigaku", "Corporation,", "Tokyo,", "Japan.", "Rigaku", "(2007).", "CrystalStructure.", "Rigaku", "Corporation,", "Tokyo,", "Japan.", "Sheldrick,", "G.", "M.", "(2008).", "Acta", "Cryst.", "A64,", "112–122.", "Spek,", "A.", "L.", "(2009).", "Acta", "Cryst.", "D65,", "148–155.", "Zhang,", "C.,", "Liu,", "S.,", "Lin,", "F.,", "Kubicek,", "C.", "P.", "&", "Druzhinina,", "I.", "S.", "(2007).", "Microbiology", "Lett.", "270,", "90–96.", "o210", "Zhao", "et", "al.", "doi:10.1107/S1600536809054178", "Acta", "Cryst.", "(2010).", "E66,", "o210" ]

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"active", "nuclei", "and", "cytoplasm", "from", "cleavage-", "blocked", "Xenopus", "laevis", "embryos.", "Under", "these", "assay", "conditions,", "we", "demonstrate", "that", "either", "addition", "of", "b-catenin", "protein", "or", "upstream", "activation", "of", "the", "b-cate-", "nin", "signaling", "pathway", "can", "induce", "the", "expression", "of", "de-", "velopmentally", "relevant", "target", "genes.", "Addition", "of", "exoge-", "nous", "b-catenin", "protein", "induced", "expression", "of", "Siamois,", "XTwin,", "Xnr3,", "and", "Cerberus", "mRNAs", "in", "a", "protein", "syn-", "thesis", "independent", "manner,", "whereas", "a", "panel", "of", "other", "Spemann", "organizer-speciﬁc", "genes", "did", "not", "respond", "to", "b-catenin.", "Lithium", "induction", "of", "the", "b-catenin", "signaling", "A", "S", "a", "b-catenin", "key", "intermediate", "and", "its", "homologues", "in", "the", "Wnt", "signaling", "are", "known", "pathway,", "to", "play", "important", "roles", "in", "numerous", "developmental", "pro-", "cesses,", "including", "segmentation", "in", "Drosophila", "melanogaster", "(Peifer", "et", "al.,", "1991),", "cell", "fate", "determinations", "in", "Caenorhab-", "ditis", "elegans", "(Thorpe", "et", "al.,", "1997;", "Giarre", "et", "al.,", "1998),", "and", "dorsal", "axis", "formation", "in", "vertebrates", "(McCrea", "et", "al.,", "1993;", "Heasman", "et", "al.,", "1994;", "Funayama", "et", "al.,", "1995).", "In", "addition", "to", "its", "role", "in", "developmental", "events,", "the", "loss", "of", "control", "of", "b-catenin", "signaling", "has", "been", "shown", "to", "be", "an", "essential", "step", "in", "the", "progression", "of", "cancer", "in", "certain", "differentiated", "tis-", "sues", "(for", "review,", "see", "Gumbiner,", "1997;", "Bullions", "and", "Le-", "vine,", "1998).", "As", "a", "central", "component", "of", "the", "cadherin", "adhesion", "com-", "plex,", "b-catenin", "is", "expressed", "widely", "in", "the", "cells", "of", "verte-", "brates.", "However,", "this", "cadherin-bound", "pool", "of", "b-catenin", "is", "not", "thought", "to", "directly", "participate", "in", "signaling.", "Rather,", "a", "Address", "correspondence", "to", "Barry", "M.", "Gumbiner,", "Cellular", "Biochemistry", "and", "Biophysics", "Program,", "Memorial", "Sloan-Kettering", "Cancer", "Center,", "New", "York,", "NY", "10021.", "Tel.:", "(212)", "639-6146.", "E-mail:", "b-gumbiner@ski.mskcc.org", "Richard", "W.", "Nelson’s", "current", "address", "is", "Biology", "Department,", "Wabash", "College,", "Crawfordsville,", "IN", "47933.", "pathway,", "which", "is", "thought", "to", "cause", "b-catenin", "accumula-", "tion", "by", "inhibiting", "its", "proteasome-dependent", "degrada-", "tion,", "caused", "increased", "expression", "of", "Siamois", "in", "a", "pro-", "tein", "synthesis", "independent", "fashion.", "This", "result", "suggests", "that", "b-catenin", "derived", "from", "a", "preexisting", "pool", "can", "be", "activated", "to", "signal,", "and", "that", "accumulation", "of", "this", "acti-", "vated", "form", "does", "not", "require", "ongoing", "synthesis.", "Further-", "more,", "activation", "of", "the", "signaling", "pathway", "with", "lithium", "did", "not", "detectably", "alter", "cytoplasmic", "b-catenin", "levels", "and", "was", "insensitive", "to", "inhibition", "of", "the", "proteasome-", "dependent", "degradation", "pathway.", "Taken", "together,", "these", "results", "suggest", "that", "activation", "of", "b-catenin", "signaling", "by", "lithium", "in", "this", "system", "may", "occur", "through", "a", "distinct", "acti-", "vation", "mechanism", "that", "does", "not", "require", "modulation", "of", "levels", "through", "regulation", "of", "proteasomal", "degradation.", "Key", "words:", "b-catenin", "•", "Xenopus", "laevis", "•", "Siamois", "•", "signaling", "•", "assay", "pool", "of", "free", "b-catenin", "(not", "bound", "to", "cadherins)", "enters", "the", "nucleus", "(Fagotto", "et", "al.,", "1998)", "and,", "through", "direct", "interac-", "tion", "with", "transcription", "factors", "of", "the", "TCF/LEF", "family,", "af-", "fects", "transcriptional", "activation", "at", "target", "gene", "promoters", "(Behrens", "et", "al.,", "1996;", "Huber", "et", "al.,", "1996;", "Molenaar", "et", "al.,", "1996).", "Therefore,", "modulation", "of", "the", "levels", "or", "activity", "of", "these", "noncadherin", "bound", "pool(s)", "of", "b-catenin", "is", "likely", "to", "be", "crucial", "for", "effective", "control", "of", "the", "signaling", "pathway.", "Maintenance", "of", "low", "levels", "of", "cytoplasmic", "b-catenin", "is", "brought", "about", "by", "ubiquitin-dependent", "degradation", "(Ab-", "erle", "et", "al.,", "1997;", "Orford", "et", "al.,", "1997;", "Jiang", "and", "Struhl,", "1998;", "Marikawa", "and", "Elinson,", "1998;", "for", "review,", "see", "Maniatis,", "1999).", "In", "cell", "culture", "systems,", "ubiquitin-dependent", "degra-", "dation", "of", "b-catenin", "is", "facilitated", "by", "the", "interaction", "of", "b-catenin", "with", "a", "number", "of", "proteins,", "including", "axin/conduc-", "tin", "(Zeng", "et", "al.,", "1997;", "Behrens", "et", "al.,", "1998;", "Hart", "et", "al.,", "1998;", "Ikeda", "et", "al.,", "1998;", "Itoh", "et", "al.,", "1998;", "Kishida", "et", "al.,", "1998;", "Na-", "kamura", "et", "al.,", "1998;", "Yamamoto", "et", "al.,", "1998),", "the", "adenoma-", "tous", "polyposis", "coli", "(APC)1", "protein", "(Rubinfeld", "et", "al.,", "1993;", "1.", "Abbreviations", "used", "in", "this", "paper:", "APC,", "adenomatous", "polyposis", "coli;", "GSK-3,", "glycogen", "synthase", "kinase", "3;", "RT,", "reverse", "transcriptase.", "ª", "The", "Rockefeller", "University", "Press,", "0021-9525/99/10/367/8", "$5.00", "The", "Journal", "of", "Cell", "Biology,", "Volume", "147,", "Number", "2,", "October", "18,", "1999", "367–374", "http://www.jcb.org", "367" ]

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