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SotiriosKastanas

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try_groto_new

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[ "Germinal", "Center", "Initiation,Variable", "Gene", "Region", "Hypermutation,", "and", "Mutant", "B", "Cell", "Selection", "without", "Detectable", "Immune", "Complexes", "on", "Follicular", "Dendritic", "Cells", "By", "Lynn", "G.", "Hannum,*", "Ann", "M.", "Haberman,*", "Shannon", "M.", "Anderson,*", "and", "Mark", "J.", "Shlomchik‡", "From", "the", "*Section", "of", "Immunobiology", "and", "the", "‡Department", "of", "Laboratory", "Medicine,Yale", "University", "School", "of", "Medicine,", "New", "Haven,", "Connecticut", "06510", "Abstract", "Serum", "antibody", "(Ab)", "can", "play", "several", "roles", "during", "B", "cell", "immune", "responses.", "Among", "these", "is", "to", "promote", "the", "deposition", "of", "immune", "complexes", "(ICs)", "on", "follicular", "dendritic", "cells", "(FDCs).", "ICs", "on", "FDCs", "are", "generally", "thought", "to", "be", "critical", "for", "normal", "germinal", "center", "(GC)", "formation", "and", "the", "development", "and", "selection", "of", "memory", "B", "cells.", "However,", "it", "has", "been", "very", "difficult", "to", "test", "these", "ideas.", "To", "determine", "directly", "whether", "FDC-bound", "complexes", "do", "indeed", "function", "in", "these", "roles,", "we", "have", "developed", "a", "transgenic", "(Tg)", "mouse", "in", "which", "all", "B", "lymphocytes", "produce", "only", "the", "membrane-bound", "form", "of", "immunoglobulin", "M.", "Immune", "Tg", "mice", "have", "10,000-fold", "less", "specific", "Ab", "than", "wild-type", "mice", "and", "lack", "detectable", "ICs", "on", "FDCs.", "Nonetheless,", "primary", "im-", "mune", "responses", "and", "the", "GC", "reaction", "in", "these", "mice", "are", "robust,", "suggesting", "that", "ICs", "on", "FDCs", "do", "not", "play", "critical", "roles", "in", "immune", "response", "initiation", "and", "GC", "formation.", "Moreover,", "as", "indicated", "by", "the", "presence", "and", "pattern", "of", "somatic", "mutations,", "memory", "cell", "formation", "and", "selection", "appear", "normal", "in", "these", "IC-deficient", "GCs.", "Key", "words:", "B", "lymphocyte", "•", "transgenic", "mouse", "•", "surface", "immunoglobulin", "•", "lambda", "light", "chain", "•", "immunological", "memory", "Introduction", "Immune", "responses", "in", "the", "spleen", "begin", "with", "proliferating", "B", "and", "T", "cells", "at", "the", "interface", "of", "the", "T", "and", "B", "cell", "zones", "(1,", "2).", "Within", "a", "few", "days,", "early", "Ab-forming", "cells", "(AFCs)1", "are", "seen,", "which", "provide", "the", "first", "sources", "of", "serum", "Ab.", "The", "B", "cells", "that", "participate", "in", "the", "early", "extrafollicular", "reaction", "are", "gen-", "erally", "of", "low", "affinity", "(3).", "By", "day", "6", "after", "immunization,", "the", "first", "signs", "of", "the", "germinal", "center", "(GC)", "reaction", "are", "evident.", "Over", "the", "next", "10", "d,", "the", "GC", "reaction", "peaks,", "culminating", "in", "the", "selection", "of", "higher", "affinity", "mutants", "and", "the", "differentia-", "tion", "of", "both", "memory", "cells", "and", "plasma", "cells.", "Follicular", "dendritic", "cells", "(FDCs)", "are", "thought", "to", "play", "a", "key", "role", "in", "the", "formation", "of", "GCs,", "as", "well", "as", "in", "selection,", "L.G.", "Hannum’s", "present", "address", "is", "University", "of", "Southern", "Maine/", "Lewiston-Auburn", "College,", "51", "Westminster", "St.,", "Lewiston,", "ME", "04240.", "Address", "correspondence", "to", "Mark", "J.", "Shlomchik,", "Department", "of", "Labora-", "tory", "Medicine,", "Yale", "University", "School", "of", "Medicine,", "P.O.", "Box", "208035,", "330", "Cedar", "St.,", "New", "Haven,", "CT", "06520-8035.", "Phone:", "203-688-2089;", "Fax:", "203-688-2748;", "E-mail:", "mark.shlomchik@yale.edu", "1Abbreviations", "used", "in", "this", "paper:", "AFC,", "Ab-forming", "cell;", "BCR,", "B", "cell", "re-", "ceptor;", "CGG,", "chicken", "gamma", "globulin;", "CR,", "complement", "receptor;", "FDC,", "follicular", "dendritic", "cell;", "GC,", "germinal", "center;", "HSA,", "human", "serum", "albumin;", "IC,", "immune", "complex;", "JhD,", "Jh", "knockout", "strain;", "LT,", "lympho-", "toxin;", "mIg,", "membrane", "Ig;", "MZ,", "marginal", "zone;", "PNA-HRP,", "peanut", "ag-", "glutinin–horseradish", "peroxidase;", "Tg,", "transgenic", "or", "transgene.", "differentiation,", "and", "maintenance", "of", "memory", "B", "cells.", "FDCs", "are", "dendritiform,", "nonphagocytic", "cells", "found", "in", "the", "follicles", "of", "secondary", "lymphoid", "organs", "(4).", "A", "striking", "characteristic", "of", "FDCs", "is", "their", "ability", "to", "retain", "native", "immune", "complexes", "(ICs)", "on", "their", "surface", "for", "long", "periods", "of", "time", "(5).", "The", "half-life", "of", "radiolabeled", "Ags", "on", "FDCs", "is", "months,", "if", "not", "years", "(6).", "Complement", "receptors", "(CRs)", "provide", "the", "main", "mechanism", "for", "ICs", "trapping", "on", "FDCs.", "C3", "fragments", "bound", "to", "ICs", "bind", "CR1", "(CD35)", "and", "CR2", "(CD21),", "which", "are", "highly", "expressed", "on", "FDCs", "(7,", "8).", "Depletion", "of", "C3", "by", "cobra", "venom", "factor", "inhibits", "Ag", "localization", "to", "FDCs", "(9),", "as", "does", "treatment", "with", "anti-C3", "(10)", "or", "anti-CR1/2", "(11).", "ICs", "also", "bind", "Fc", "receptors", "on", "FDCs,", "particularly", "during", "the", "GC", "response", "(11).", "Hence,", "except", "for", "certain", "Ags", "that", "might", "fix", "sufficient", "complement", "autonomously,", "both", "mechanisms", "for", "Ag", "retention", "by", "FDCs", "require", "that", "Ag", "be", "complexed", "with", "Ab.", "Several", "important", "functions", "have", "been", "postulated", "for", "the", "ICs", "that", "deposit", "on", "FDCs.", "It", "has", "been", "hypothesized", "that", "the", "initial", "localization", "of", "ICs", "on", "FDCs", "nucleates", "the", "GC", "re-", "sponse", "and", "provides", "the", "Ag", "to", "which", "GC", "B", "cells", "respond", "(6,", "12).", "This", "idea", "provides", "an", "explanation", "for", "the", "delayed", "appearance", "of", "GCs,", "since", "several", "days", "would", "be", "needed", "to", "931", "J.", "Exp.", "Med.", "The", "Rockefeller", "University", "Press", "•", "0022-1007/2000/10/931/12", "$5.00", "Volume", "192,", "Number", "7,", "October", "2,", "2000", "931–942", "http://www.jem.org/cgi/content/full/192/7/931" ]

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[ "BMC", "Immunology", "Research", "article", "Thymus-derived", "glucocorticoids", "are", "insufficient", "for", "normal", "thymus", "homeostasis", "in", "the", "adult", "mouse", "Stephen", "B", "Pruett*1", "and", "Eric", "L", "Padgett1,2", "BioMed", "Central", "Open", "Access", "Address:", "1Department", "of", "Cellular", "Biology", "and", "Anatomy,", "Louisiana", "State", "University", "Health", "Sciences", "Center,", "1501", "Kings", "Highway,", "Shreveport,", "LA,", "USA", "and", "2Wil", "Research", "Labs,", "1407", "George", "Road,", "Ashland,", "OH,", "USA", "Email:", "Stephen", "B", "Pruett*", "-", "spruet@LSUHSC.edu;", "Eric", "L", "Padgett", "-", "padgett@wilresearch.com", "*", "Corresponding", "author", "Published:", "02", "November", "2004", "BMC", "Immunology", "2004,", "5:24", "doi:10.1186/1471-2172-5-24", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1471-2172/5/24", "Received:", "29", "August", "2004", "Accepted:", "02", "November", "2004", "©", "2004", "Pruett", "and", "Padgett;", "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:", "It", "is", "unclear", "if", "thymus-derived", "glucocorticoids", "reach", "sufficient", "local", "concentrations", "to", "support", "normal", "thymus", "homeostasis,", "or", "if", "adrenal-derived", "glucocorticoids", "from", "the", "circulation", "are", "required.", "Modern", "approaches", "to", "this", "issue", "(transgenic", "mice", "that", "under", "or", "over", "express", "glucocorticoid", "receptor", "in", "the", "thymus)", "have", "yielded", "irreconcilably", "contradictory", "results,", "suggesting", "fundamental", "problems", "with", "one", "or", "more", "the", "transgenic", "mouse", "strains", "used.", "In", "the", "present", "study,", "a", "more", "direct", "approach", "was", "used,", "in", "which", "mice", "were", "adrenalectomized", "with", "or", "without", "restoration", "of", "circulating", "corticosterone", "using", "timed", "release", "pellets.", "Reversal", "of", "the", "increased", "number", "of", "thymocytes", "caused", "by", "adrenalectomy", "following", "restoration", "of", "physiological", "corticosterone", "concentrations", "would", "indicate", "that", "corticosterone", "is", "the", "major", "adrenal", "product", "involved", "in", "thymic", "homeostasis.", "Results:", "A", "clear", "relationship", "was", "observed", "between", "systemic", "corticosterone", "concentration,", "thymus", "cell", "number,", "and", "percentage", "of", "apoptotic", "thymocytes.", "Physiological", "concentrations", "of", "corticosterone", "in", "adrenalectomized", "mice", "restored", "thymus", "cell", "number", "to", "normal", "values", "and", "revealed", "differential", "sensitivity", "of", "thymocyte", "subpopulations", "to", "physiological", "and", "stress-inducible", "corticosterone", "concentrations.", "Conclusion:", "This", "indicates", "that", "thymus-derived", "glucocorticoids", "are", "not", "sufficient", "to", "maintain", "normal", "levels", "of", "death", "by", "neglect", "in", "the", "thymus,", "but", "that", "apoptosis", "and", "possibly", "other", "mechanisms", "induced", "by", "physiological,", "non", "stress-induced", "levels", "of", "adrenal-derived", "corticosterone", "are", "responsible", "for", "keeping", "the", "total", "number", "of", "thymocytes", "within", "the", "normal", "range.", "Background", "Although", "it", "is", "clear", "that", "elevated", "concentrations", "of", "endog-", "enous", "glucocorticoids", "can", "cause", "apoptosis", "in", "the", "thymus", "[1-3],", "the", "role", "of", "normal", "concentrations", "of", "glucocorticoids", "in", "thymic", "homeostasis", "remains", "controversial", "[4-7].", "Results", "reported", "by", "Ashwell", "and", "colleagues", "suggest", "gluco-", "corticoids", "are", "essential", "at", "very", "low", "concentrations", "for", "early", "development", "and", "survival", "of", "thymocytes", "and", "that", "gluco-", "corticoids", "can", "alter", "the", "sensitivity", "of", "more", "mature", "thymo-", "cytes", "to", "positive", "selection,", "thereby", "influencing", "the", "T", "cell", "receptor", "repertoire", "[5].", "In", "addition,", "there", "is", "convincing", "evidence", "that", "corticosterone", "is", "produced", "in", "the", "thymus", "and", "that", "it", "acts", "locally", "to", "affect", "thymocyte", "development", "[8,9].", "Therefore,", "it", "was", "surprising", "when", "normal", "cellular", "development", "(including", "repertoire)", "was", "observed", "until", "the", "time", "of", "birth", "in", "glucocorticoid", "receptor", "knockout", "mice", "Page", "1", "of", "14", "(page", "number", "not", "for", "citation", "purposes)" ]

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[ "WNT5A", "Signaling", "Contributes", "to", "Ab-Induced", "Neuroinflammation", "and", "Neurotoxicity", "Bei", "Li1,2.,", "Ling", "Zhong2.,", "Xiangling", "Yang2,", "Tommy", "Andersson", "3", ",", "Min", "Huang2,", "Shao-Jun", "Tang", "1", "*", "1", "Department", "of", "Neuroscience", "and", "Cell", "Biology,", "University", "of", "Texas", "Medical", "Branch,", "Galveston,", "Texas,", "United", "States", "of", "America,", "2", "School", "of", "Pharmaceutical", "Sciences,", "Sun", "Yat-Sen", "University,", "Guangzhou,", "People’s", "Republic", "of", "China,", "3", "Department", "of", "Laboratory", "Medicine,", "Lund", "University,", "Clinical", "Research", "Centre,", "Ska˚ne", "University", "Hospital,", "Malmo¨", ",", "Sweden", "Abstract", "Neurodegenration", "is", "a", "pathological", "hallmark", "of", "Alzheimer’s", "disease", "(AD),", "but", "the", "underlying", "molecular", "mechanism", "remains", "elusive.", "Here,", "we", "present", "evidence", "that", "reveals", "a", "crucial", "role", "of", "Wnt5a", "signaling", "in", "this", "process.", "We", "showed", "that", "Wnt5a", "and", "its", "receptor", "Frizzled-5", "(Fz5)", "were", "up-regulated", "in", "the", "AD", "mouse", "brain,", "and", "that", "beta-amyloid", "peptide", "(Ab),", "a", "major", "constituent", "of", "amyloid", "plaques,", "stimulated", "Wnt5a", "and", "Fz5", "expression", "in", "primary", "cortical", "cultures;", "these", "observations", "indicate", "that", "Wnt5a", "signaling", "could", "be", "aberrantly", "activated", "during", "AD", "pathogenesis.", "In", "support", "of", "such", "a", "possibility,", "we", "observed", "that", "inhibition", "of", "Wnt5a", "signaling", "attenuated", "while", "activation", "of", "Wnt5a", "signaling", "enhanced", "Ab-evoked", "neurotoxicity,", "suggesting", "a", "role", "of", "Wnt5a", "signaling", "in", "AD-related", "neurodegeneration.", "Furthermore,", "we", "also", "demonstrated", "that", "Ab-induced", "neurotoxicity", "depends", "on", "inflammatory", "processes,", "and", "that", "activation", "of", "Wnt5a", "signaling", "elicited", "the", "expression", "of", "proinflammatory", "cytokines", "IL-1b", "and", "TNF-a", "whereas", "inhibition", "of", "Wnt5a", "signaling", "attenuated", "the", "Ab-induced", "expression", "of", "the", "cytokines", "in", "cortical", "cultures.", "Our", "findings", "collectively", "suggest", "that", "aberrantly", "up-regulated", "Wnt5a", "signaling", "is", "a", "crucial", "pathological", "step", "that", "contributes", "to", "AD-related", "neurodegeneration", "by", "regulating", "neuroinflammation.", "Citation:", "Li", "B,", "Zhong", "L,", "Yang", "X,", "Andersson", "T,", "Huang", "M,", "et", "al.", "(2011)", "WNT5A", "Signaling", "Contributes", "to", "Ab-Induced", "Neuroinflammation", "and", "Neurotoxicity.", "PLoS", "ONE", "6(8):", "e22920.", "doi:10.1371/journal.pone.0022920", "Editor:", "Colin", "Combs,", "University", "of", "North", "Dakota,", "United", "States", "of", "America", "Received", "February", "8,", "2011;", "Accepted", "July", "7,", "2011;", "Published", "August", "17,", "2011", "Copyright:", "2011", "Li", "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", "the", "start-up", "funds", "from", "the", "University", "of", "Texas", "Medical", "Branch", "to", "S-JT", "and", "by", "grant", "No.", "30873457", "from", "the", "National", "Natural", "Science", "Foundation", "of", "China", "and", "No.", "2008A060202010", "and", "2010B050700019", "from", "the", "Scientific", "Technology", "Project", "of", "Guangdong", "Province", "of", "China", "to", "LZ.", "BL", "is", "a", "Ph.D.", "student", "fellow", "supported", "by", "China", "Scholarship", "Council.", "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:", "shtang@utmb.edu", ".", "These", "authors", "contributed", "equally", "to", "this", "work.", "Introduction", "Beta-Amyloid", "(Ab)", "peptide", "is", "a", "dominant", "candidate", "of", "the", "causative", "agents", "for", "Alzheimer’s", "disease", "(AD)", "[1,2].", "According", "to", "the", "widely-held", "amyloid", "hypothesis", "of", "AD,", "Ab", "initiates", "an", "array", "of", "molecular", "and", "cellular", "cascades", "that", "eventually", "lead", "to", "progressive", "neuronal", "dysfunction", "and", "degeneration", "[1,2].", "However,", "mecha-", "nistic", "molecular", "processes", "that", "link", "Ab", "and", "neurodegeneration", "remain", "to", "be", "firmly", "established.", "Chronic", "neuroinflammation", "associated", "with", "persistent", "glial", "activation", "is", "a", "major", "disease", "process", "evoked", "by", "Ab", "and", "intimately", "associated", "with", "the", "progress", "of", "AD", "pathologies", "[3,4].", "Previous", "studies", "suggest", "that", "neuroinflammation", "contributes", "to", "the", "development", "of", "neurodegenerative", "hallmarks", "in", "AD", "brains,", "including", "Ab", "plaques", "[4]", "and", "tau", "tangles", "[5,6,7].", "AD", "therapeutic", "approaches", "that", "target", "neuroinflammation", "are", "under", "develop-", "ment", "[8,9,10,11].", "AD", "neuroinflammation", "is", "likely", "triggered", "by", "Ab-mediated", "activation", "of", "microglia", "and", "astrocytes", "[3,4,", "12,13,14].", "It", "was", "reported", "that", "Ab", "induces", "the", "expression", "of", "cytokines", "(including", "IL-1b,", "TNF-a,", "IL-6,", "and", "IL-8)", "in", "cultured", "astrocytes", "and", "microglia", "[15,16,17,18].", "Mounting", "evidence", "suggests", "that", "Ab", "may", "activate", "glial", "cells", "via", "specific", "sensor", "receptors", "such", "as", "toll-like", "receptors", "(TLR),", "receptors", "for", "advanced", "glycoxidation", "end-products", "(RAGE)", "and", "NOD-like", "receptors", "(NLR)", "[4].", "Despite", "the", "significant", "understandings", "on", "the", "induction", "of", "AD", "neuroinflammation,", "the", "downstream", "molecular", "processes", "that", "are", "elicited", "by", "Ab", "and", "regulate", "the", "inflammation", "remain", "poorly", "understood.", "Wnts", "are", "secreted", "signaling", "proteins", "that", "play", "important", "roles", "in", "neural", "development", "and", "plasticity", "[19,20,21,22].", "Multiple", "lines", "of", "evidence", "indicate", "a", "critical", "role", "of", "Wnt", "signaling", "in", "AD", "[22].", "b-", "catenin,", "a", "key", "downstream", "effector", "protein", "in", "the", "canonical", "Wnt", "signaling", "pathway,", "interacts", "with", "and", "is", "regulated", "by", "presenilin", "[23,24,25].", "Glycogen", "synthase", "kinase", "(GSK)-3,", "a", "central", "serine/", "threnine", "kinase", "in", "the", "canonical", "Wnt", "signaling", "pathway,", "plays", "a", "critical", "role", "in", "the", "regulation", "of", "Ab", "production", "[26]", "and", "aggregation", "[27]", "and", "in", "tau", "phosphorylation", "[28].", "Genetic", "studies", "revealed", "that", "LRP6", "polymorphisms", "are", "causally", "linked", "to", "AD", "[29].", "In", "AD", "brains,", "canonical", "Wnt", "signaling", "is", "impaired", "[30],", "and", "DKK1,", "an", "antagonist", "of", "Wnt", "signaling,", "is", "upregulated", "[31,32].", "Importantly,", "Ab", "was", "reported", "to", "inhibit", "Wnt", "signaling", "by", "directly", "binding", "to", "the", "Frizzled", "receptors", "[33].", "The", "impairment", "of", "canonical", "Wnt", "signaling", "is", "likely", "etiologically", "significant,", "because", "forced", "up-regulation", "of", "the", "canonical", "Wnt", "signaling", "pathway", "has", "rescuing", "effects", "on", "the", "development", "of", "AD-related", "phenotypes", "in", "both", "neuron", "cultures", "and", "animal", "models", "[27,30,34,35].", "In", "contrast", "to", "the", "canonical", "pathway,", "the", "involvement", "of", "non-canonical", "Wnt", "signaling", "pathways", "in", "the", "regulation", "of", "AD", "pathogenesis", "is", "less", "clear.", "A", "recent", "study", "indicates", "that", "Wnt5a-activated", "non-canonical", "Wnt", "signaling", "antagonizes", "Ab", "synaptotoxicity", "[36].", "PLoS", "ONE", "|", "www.plosone.org", "1", "August", "2011", "|", "Volume", "6", "|", "Issue", "8", "|", "e22920" ]

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[ "W652–W656", "Nucleic", "Acids", "Research,", "2010,", "Vol.", "38,", "Web", "Server", "issue", "doi:10.1093/nar/gkq367", "Published", "online", "11", "May", "2010", "SIMCOMP/SUBCOMP:", "chemical", "structure", "search", "servers", "for", "network", "analyses", "Masahiro", "Hattori,", "Nobuya", "Tanaka,", "Minoru", "Kanehisa", "and", "Susumu", "Goto*", "Bioinformatics", "Center,", "Institute", "for", "Chemical", "Research,", "Kyoto", "University,", "Uji,", "Kyoto", "611-0011,", "Japan", "Received", "January", "31,", "2010;", "Revised", "April", "8,", "2010;", "Accepted", "April", "24,", "2010", "ABSTRACT", "One", "of", "the", "greatest", "challenges", "in", "bioinformatics", "is", "to", "shed", "light", "on", "the", "relationship", "between", "genomic", "and", "chemical", "significances", "of", "metabolic", "pathways.", "Here,", "we", "demonstrate", "two", "types", "of", "chemical", "struc-", "ture", "search", "servers:", "SIMCOMP", "(http://www", ".genome.jp/tools/simcomp/)", "for", "the", "chemical", "simi-", "larity", "search", "and", "SUBCOMP", "(http://www.genome", ".jp/tools/subcomp/)", "for", "the", "chemical", "substructure", "search,", "where", "both", "servers", "provide", "links", "to", "the", "KEGG", "PATHWAY", "and", "BRITE", "databases.", "The", "SIMCOMP", "is", "a", "graph-based", "method", "for", "searching", "the", "maximal", "common", "subgraph", "isomorphism", "by", "finding", "the", "maximal", "cliques", "in", "the", "association", "graph.", "In", "contrast,", "the", "SUBCOMP", "is", "an", "extended", "method", "for", "solving", "the", "subgraph", "isomorphism", "problem.", "The", "obtained", "links", "to", "PATHWAY", "or", "BRITE", "databases", "can", "be", "used", "to", "interpret", "as", "the", "biological", "meanings", "of", "chemical", "structures", "from", "the", "viewpoint", "of", "the", "various", "biological", "functions", "including", "meta-", "bolic", "networks.", "INTRODUCTION", "To", "understand", "the", "complex", "system", "of", "life", "it", "is", "required", "to", "investigate", "the", "characteristics", "of", "biomolecular", "network", "consisting", "of", "not", "only", "proteins", "or", "nucleic", "acids", "but", "also", "small", "chemical", "compounds", "(1,2).", "In", "spite", "of", "a", "number", "of", "sequence", "comparison", "servers,", "there", "are", "few", "servers", "to", "compare", "chemical", "structures", "for", "metabolic", "pathway", "analyses.", "In", "addition,", "almost", "all", "servers", "for", "chemical", "struc-", "ture", "comparisons", "commonly", "use", "the", "bit-string", "method", "(3),", "and", "there", "had", "been", "no", "server", "based", "on", "the", "graph", "compari-", "son", "method,", "which", "is", "considered", "more", "accurate.", "In", "this", "context,", "we", "have", "developed", "two", "types", "of", "chemical", "struc-", "ture", "search", "servers", "as", "parts", "of", "the", "GenomeNet", "computa-", "tion", "services,", "aiming", "at", "the", "better", "comprehension", "of", "the", "relationship", "between", "genomic", "and", "chemical", "implications", "of", "metabolic", "pathways.", "One", "is", "the", "SIMCOMP", "(4,5)", "server", "for", "the", "chemical", "similarity", "search", "and", "the", "other", "is", "the", "SUBCOMP", "for", "the", "chemical", "substructure", "search,", "where", "both", "servers", "provide", "links", "to", "the", "KEGG", "PATHWAY", "and", "BRITE", "databases", "(6).", "SIMCOMP", "(SIMilar", "COMPound)", "has", "originally", "been", "developed", "as", "a", "graph-based", "method", "for", "comparing", "chemical", "structures,", "which", "searches", "for", "the", "maximal", "cliques", "in", "the", "association", "graph", "as", "the", "maximum", "common", "induced", "subgraph", "(MCIS).", "However,", "the", "current", "version", "of", "SIMCOMP", "can", "also", "compute", "the", "maximum", "common", "edge", "subgraph", "(MCES),", "which", "is", "faster", "because", "of", "the", "small", "number", "of", "nodes", "in", "an", "associ-", "ation", "graph.", "Moreover,", "we", "have", "now", "added", "further", "com-", "putation", "features", "to", "SIMCOMP,", "including", "chirality", "check", "and", "PATHWAY/BRITE", "mapping.", "In", "contrast,", "SUBCOMP", "(SUBstructure", "matching", "of", "COMPounds)", "is", "an", "extended", "method", "based", "on", "the", "bit-vector", "representa-", "tion", "for", "searching", "chemical", "substructures,", "which", "is", "often", "used", "as", "a", "rapid", "alternative", "to", "more", "time-consuming", "(but", "more", "accurate)", "SIMCOMP.", "The", "notable", "features", "of", "the", "SIMCOMP", "and", "SUBCOMP", "servers", "are", "as", "follows:", "(i)", "After", "obtaining", "the", "list", "of", "similar", "compounds,", "users", "can", "map", "the", "selected", "entries", "onto", "the", "KEGG", "PATHWAY", "or", "KEGG", "BRITE", "databases.", "This", "feature", "may", "help", "us", "to", "investigate", "biological", "roles", "of", "those", "chemical", "compounds", "as", "well", "as", "a", "query", "compound.", "(ii)", "Both", "SIMCOMP", "and", "SUBCOMP", "can", "dis-", "criminate", "the", "isomeric", "structures,", "including", "the", "R", "/S", "chirality", "found", "at", "asymmetrical", "carbons", "and", "the", "cis–trans", "isomerism", "around", "the", "carbon–carbon", "double", "bonds.", "(iii)", "Various", "matching", "conditions", "are", "now", "available", "in", "the", "SUBCOMP", "computation.", "‘Charge’", "and", "‘Valence’", "options", "will", "distinguish", "ionized", "atoms", "from", "normal", "atoms", "and", "the", "valence", "of", "each", "atom,", "in", "other", "words,", "the", "oxidation", "state", "of", "each", "atom,", "respectively.", "‘Coordinate", "bond’", "option", "can", "be", "used", "to", "consider", "the", "coordinate", "bond", "formed", "between", "anion–cation", "single", "bond.", "(iv)", "The", "superstructure", "search", "is", "also", "available", "for", "searching", "chemical", "compounds", "that", "are", "included", "in", "the", "query", "struc-", "ture,", "in", "the", "SUBCOMP.", "*To", "whom", "correspondence", "should", "be", "addressed.", "Tel:", "+81", "774", "38", "3271;", "Fax:", "+81", "774", "38", "3269;", "Email:", "goto@kuicr.kyoto-u.ac.jp", "Present", "address:", "Nobuya", "Tanaka,", "Intellectual", "Property", "Division,", "Research", "&", "Development", "Management", "Headquarters,", "FUJIFILM", "Co.,", "Minamiashigara,", "Kanagawa,", "250-0193,", "Japan.", "The", "Author(s)", "2010.", "Published", "by", "Oxford", "University", "Press.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "Non-Commercial", "License", "(http://creativecommons.org/licenses/", "by-nc/2.5),", "which", "permits", "unrestricted", "non-commercial", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

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[ "e", "n", "i", "c", "i", "d", "e", "M", "l", "a", "t", "n", "e", "m", "i", "r", "e", "p", "x", "E", "f", "o", "l", "a", "n", "r", "u", "o", "J", "e", "h", "T", "CORRESPONDENCE", "Steven", "L.", "Reiner:", "sreiner@mail.med.upenn.edu", "Abbreviation", "used:", "LCMV,", "lym-", "phocytic", "choriomeningitis", "virus.", "JEM", "©", "The", "Rockefeller", "University", "Press", "$30.00", "Vol.", "204,", "No.", "9,", "September", "3,", "2007", "2015-2021", "www.jem.org/cgi/doi/10.1084/jem.20070841", "B", "R", "I", "E", "F", "D", "E", "F", "I", "N", "I", "T", "I", "V", "E", "R", "E", "P", "O", "RT", "Requirement", "for", "T-bet", "in", "the", "aberrant", "differentiation", "of", "unhelped", "memory", "CD8", "T", "cells", "Andrew", "M.", "Intlekofer,1,2", "Naofumi", "Takemoto,1,2", "Charlly", "Kao,4", "Arnob", "Banerjee,1,2", "Felix", "Schambach,1,2", "John", "K.", "Northrop,3", "Hao", "Shen,3", "E.", "John", "Wherry,4", "and", "Steven", "L.", "Reiner1,2", "1Abramson", "Family", "Cancer", "Research", "Institute,", "2Department", "of", "Medicine,", "and", "3Department", "of", "Microbiology,", "University", "of", "Pennsylvania,", "Philadelphia,", "PA", "19104", "4Immunology", "Program,", "The", "Wistar", "Institute,", "Philadelphia,", "PA", "19104", "Immunity", "to", "intracellular", "pathogens", "requires", "dynamic", "balance", "between", "terminal", "differen-", "tiation", "of", "short-lived,", "cytotoxic", "effector", "CD8", "T", "cells", "and", "self-renewal", "of", "central–memory", "CD8", "T", "cells.", "We", "now", "show", "that", "T-bet", "represses", "transcription", "of", "IL-7R", "and", "drives", "differ-", "entiation", "of", "effector", "and", "effector–memory", "CD8", "T", "cells", "at", "the", "expense", "of", "central–memory", "cells.", "We", "also", "found", "T-bet", "to", "be", "overexpressed", "in", "CD8", "T", "cells", "that", "differentiated", "in", "the", "absence", "of", "CD4", "T", "cell", "help,", "a", "condition", "that", "is", "associated", "with", "defective", "central–memory", "formation.", "Finally,", "deletion", "of", "T-bet", "corrected", "the", "abnormal", "phenotypic", "and", "functional", "properties", "of", "“unhelped”", "memory", "CD8", "T", "cells.", "T-bet,", "thus,", "appears", "to", "function", "as", "a", "molecular", "switch", "between", "central–", "and", "effector–memory", "cell", "differentiation.", "Antagonism", "of", "T-bet", "may,", "therefore,", "represent", "a", "novel", "strategy", "to", "offset", "dysfunctional", "programming", "of", "memory", "CD8", "T", "cells.", "When", "a", "naive", "CD8", "T", "cell", "encounters", "antigen,", "it", "undergoes", "vigorous", "clonal", "expansion", "and", "dif-", "ferentiation", "into", "a", "population", "comprised", "primar-", "ily", "of", "short-lived,", "cytotoxic", "effectors", "that", "undergo", "cell", "death", "after", "pathogen", "is", "cleared", "(1).", "The", "elimination", "of", "the", "antigen-experienced", "progeny", "of", "a", "selected", "T", "cell", "clone,", "however,", "is", "generally", "incomplete,", "ensuring", "preservation", "of", "a", "portion", "of", "daughter", "cells", "to", "provide", "a", "“memory”", "of", "the", "pathogen", "encounter.", "At", "least", "two", "functionally", "distinct", "classes", "of", "memory", "cells", "have", "been", "de-", "scribed,", "based", "on", "their", "pattern", "of", "tissue", "homing", "in", "the", "absence", "of", "antigen.", "Effector–memory", "CD8", "T", "cells", "provide", "protection", "against", "rein-", "fection", "by", "patrolling", "peripheral", "tissues,", "but", "have", "a", "poor", "capacity", "for", "homeostatic", "renewal", "and", "secondary", "proliferation.", "Central–memory", "CD8", "T", "cells,", "in", "contrast,", "recapitulate", "the", "surveil-", "lance", "behavior", "of", "their", "naive", "predecessor", "by", "migrating", "through", "secondary", "lymphoid", "organs;", "they", "are", "distinguished", "by", "efficient", "homeostatic", "re-", "newal", "and", "rapid", "secondary", "proliferative", "responses", "to", "generate", "cytotoxic", "effectors", "upon", "reencoun-", "ter", "with", "pathogen", "(2,", "3).", "It", "remains", "controver-", "sial", "whether", "commitment", "to", "the", "self-renewing,", "The", "online", "version", "of", "this", "article", "contains", "supplemental", "material.", "central–memory", "lineage", "occurs", "before", "or", "after", "adoption", "of", "the", "effector", "fate", "(3–6).", "The", "intrinsic", "molecular", "program", "that", "directs", "commitment", "to", "the", "effector–", "versus", "central–", "memory", "CD8", "T", "cell", "lineage", "is", "not", "fully", "under-", "stood.Wefoundthatdeficiencyofthetranscription", "factor", "T-bet", "resulted", "in", "defective", "generation", "of", "effector–memory", "CD8", "T", "cells", "and", "excessive", "generation", "of", "central–memory", "CD8", "T", "cells.", "The", "enhanced", "central–memory", "formation", "result-", "ing", "from", "T-bet", "deficiency", "directly", "contrasted", "with", "the", "defective", "central–memory", "formation", "oc-", "curring", "in", "the", "absence", "of", "CD4", "T", "cell", "help.", "Dele-", "tion", "of", "T-bet", "prevented", "the", "defective", "phenotypic", "and", "functional", "characteristics", "of", "unhelped", "CD8", "T", "cells.", "These", "results", "suggest", "that", "T-bet", "may", "rep-", "resent", "a", "novel", "target", "for", "manipulating", "the", "balance", "between", "terminal", "differentiation", "and", "self-renewal", "of", "pathogen-specific", "CD8", "T", "cells.", "RESULTS", "AND", "DISCUSSION", "T-bet", "represses", "IL-7R", "in", "effector", "CD8", "T", "cells", "During", "the", "acute", "phase", "of", "an", "infection,", "repres-", "sion", "of", "IL-7R", "marks", "pathogen-specific", "CD8", "T", "cells", "destined", "for", "elimination,", "whereas", "the", "cells", "that", "will", "give", "rise", "to", "self-renewing", "memory", "2015" ]

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[ "laboratory", "notes", "Journal", "of", "Applied", "Crystallography", "ISSN", "0021-8898", "Received", "19", "October", "2011", "Accepted", "6", "December", "2011", "A", "manual", "low-cost", "protein-crystallization", "plate", "jig", "for", "in", "situ", "diffraction", "in", "the", "home", "laboratory", "David", "Hargreaves", "AstraZeneca,", "Alderley", "Park,", "Alderley", "Edge,", "Cheshire", "SK10", "4TF,", "England.", "Correspondence", "e-mail:", "david.hargreaves@astrazeneca.com", "A", "prototype", "jig", "to", "attach", "a", "protein", "crystallization", "plate", "to", "a", "standard", "X-ray", "goniometer", "has", "been", "designed", "and", "constructed", "in", "partnership", "with", "an", "engineering", "firm.", "This", "allows", "a", "low-cost", "implementation", "of", "in", "situ", "diffraction", "using", "the", "available", "home-laboratory", "X-ray", "source.", "1.", "Introduction", "Testing", "the", "diffraction", "properties", "of", "crystals", "is", "routine", "in", "the", "protein", "structure", "determination", "process.", "Early", "testing", "of", "multiple", "hits", "from", "crystallization", "screening", "allows", "the", "selection", "and", "optimization", "of", "protein", "crystals", "based", "on", "diffraction", "quality", "rather", "than", "aesthetics.", "Even", "after", "optimization,", "it", "may", "be", "necessary", "to", "screen", "crystals", "in", "order", "to", "select", "those", "with", "the", "best", "resolution,", "lowest", "mosaicity", "or", "lowest", "anisotropy,", "or", "those", "with", "desirable", "cell", "and", "lattice", "parameters", "for", "further", "experiments.", "In", "situ", "diffraction", "testing", "(irradiating", "crystals", "while", "they", "are", "still", "in", "the", "crystallization", "plate)", "remains", "the", "least", "invasive", "technique", "for", "determining", "macromolecular", "crystal", "characteristics", "that", "influence", "decision", "making", "in", "crystal", "screening", "and", "optimization", "cycles", "of", "crystal", "growth.", "Compared", "to", "the", "usual", "practice", "of", "fishing", "a", "crystal", "from", "the", "mother", "liquor", "with", "a", "loop,", "and", "then", "cryoprotecting", "and", "flash-freezing", "it", "prior", "to", "X-ray", "diffraction", "testing,", "this", "technique", "offers", "two", "main", "advantages:", "(1)", "it", "avoids", "the", "damaging", "effects", "of", "crystal", "manipulation", "and", "(2)", "a", "room-temperature", "diffraction-quality", "baseline", "is", "established", "against", "which", "the", "effects", "of", "cryoprotectants", "and", "other", "soaking", "tech-", "niques", "can", "be", "compared.", "The", "in", "situ", "diffraction", "devices", "that", "are", "currently", "available", "tend", "to", "be", "highly", "automated", "both", "for", "synchrotron", "and", "for", "home", "X-ray", "sources.", "Synchrotron", "beamlines", "typically", "have", "robotic", "systems", "that", "allow", "accurate", "positioning", "and", "manipulation", "of", "the", "plate", "in", "the", "X-ray", "beam", "and", "allow", "a", "limited", "rotation", "range", "for", "data", "collection", "(Bingel-", "Erlenmeyer", "et", "al.,", "2011;", "Jacquamet", "et", "al.,", "2004;", "http://www.natx-ray.", "com/products/flyer_G-Rob.pdf).", "Many", "synchrotrons", "have", "installed", "or", "are", "currently", "installing", "in", "situ", "equipped", "beamlines", "offering", "the", "possibility", "of", "merging", "data", "sets", "collected", "from", "many", "small", "crystals", "in", "situ", "as", "well", "as", "simple", "diffraction", "screening.", "The", "ability", "to", "collect", "data", "from", "multiple", "crystals", "may", "open", "up", "new", "possibilities,", "particularly", "from", "a", "drug", "discovery", "perspective,", "where", "rapid", "in", "situ", "techniques", "to", "detect", "bound", "ligands", "(le", "Maire", "et", "al.,", "2011)", "could", "simplify", "the", "experi-", "mental", "process", "of", "iterative", "ligand-bound", "structure", "determination.", "Oxford", "Diffraction", "(now", "Agilent)", "has", "developed", "the", "PX", "scanner", "(http://www.chem.agilent.com),", "which", "provides", "an", "integrated", "stand-", "alone", "solution", "for", "in", "situ", "diffraction", "including", "a", "sealed-tube", "X-ray", "source,", "X-ray", "optics", "and", "CCD", "detector", "for", "use", "in", "the", "home", "labora-", "tory.", "The", "system", "allows", "the", "user", "to", "capture", "photographic", "images", "of", "crystals", "prior", "to", "automated", "X-ray", "screening,", "which", "is", "useful", "for", "correlating", "crystal", "morphology", "with", "diffraction", "quality.", "Diffraction", "images", "are", "processed", "using", "an", "algorithm", "that", "subtracts", "the", "scatter", "derived", "from", "the", "solvent", "and", "crystallization", "plate,", "resulting", "in", "an", "image", "that", "is", "easier", "to", "interpret.", "Lastly,", "as", "the", "system", "is", "fully", "inte-", "grated", "it", "is", "easily", "placed", "in", "any", "laboratory.", "138", "doi:10.1107/S0021889811052654", "Recent", "interest", "in", "in", "situ", "screening", "and", "data", "collection", "has", "prompted", "crystallization", "plate", "manufacturers", "to", "offer", "standard", "format", "plates", "with", "improved", "X-ray", "absorption", "characteristics", "(e.g.", "CrystalQuickX;", "http://www.greinerbioone.com/UserFiles/File/PRODUCTS/", "Poster_CrystalQuickX_PSDI%202010.pdf).", "Better", "choices", "of", "plastic", "and", "careful", "positioning", "and", "design", "of", "the", "crystal", "wells", "have", "led", "to", "significant", "improvements", "in", "the", "overall", "intensity", "and", "angle", "of", "scat-", "tered", "X-rays.", "Innovative", "approaches", "to", "protein", "crystallization", "have", "led", "to", "a", "number", "of", "new", "devices", "on", "the", "market", "based", "on", "free", "interface", "diffusion", "or", "counter", "diffusion", "techniques.", "Many", "of", "these", "devices", "have", "been", "designed", "with", "in", "situ", "use", "in", "mind", "[CrystalHarp", "(http://www.", "swissci.com/downloads/Crystal_Harp_News271010.pdf),", "TOPAZ", "1.96", "diffraction", "capable", "chip", "(http://www.fluidigm.com/home/fluidigm/", "docs/Datasheet_1.96DC.pdf),", "MPCS", "Plug", "Maker", "(http://www.", "emeraldbiosystems.com/c-331-mpcs-plug-maker.aspx)].", "Furthermore,", "bespoke", "apparatus", "has", "been", "developed", "in", "some", "home", "laboratories", "to", "satisfy", "the", "need", "for", "in", "situ", "testing", "(Watanabe", "et", "al.,", "2002;", "McPherson,", "2000;", "Agirre", "et", "al.,", "2008).", "Given", "the", "above", "advantages,", "we", "wanted", "to", "access", "in", "situ", "screening", "in", "our", "home", "laboratory", "cheaply", "using", "our", "existing", "X-ray", "equipment", "and", "crystallization", "plate", "format.", "Hence,", "we", "devised", "a", "simple,", "manual,", "low-cost", "jig", "that", "allows", "attachment", "of", "a", "crystallization", "plate", "onto", "our", "Rigaku", "AFC-11", "X-ray", "goniometer.", "2.", "Description", "of", "jig", "The", "jig", "is", "a", "prototype", "plate", "holder", "that", "allows", "manual", "translation", "of", "a", "standard", "crystallization", "plate", "in", "the", "X-ray", "beam", "(Figs.", "1a", "and", "1b).", "The", "jig", "comprises", "two", "main", "parts:", "the", "plate", "holder", "and", "the", "base", "assembly", "with", "coarse", "and", "fine", "translation", "slides.", "A", "crystallization", "plate", "is", "clipped", "into", "place", "on", "the", "plate", "holder,", "which", "is", "then", "slid", "into", "the", "base", "assembly", "previously", "mounted", "on", "the", "goniometer.", "A", "simple", "scale", "derived", "from", "the", "crystallization", "plate", "dimensions", "allows", "coarse", "positioning", "of", "the", "well", "of", "interest,", "while", "x,", "y,", "z", "micrometer", "adjustment", "screws", "allow", "accurate", "positioning", "of", "the", "crystal", "in", "the", "beam.", "Owing", "to", "the", "geometry", "of", "the", "Rigaku", "AFC-11", "goniometer,", "it", "is", "only", "possible", "to", "access", "the", "bottom", "four", "rows", "of", "a", "plate", "held", "in", "landscape,", "so", "the", "jig", "allows", "the", "user", "to", "invert", "the", "plate", "and", "use", "a", "second", "scale", "to", "access", "the", "top", "four", "rows.", "Crystal", "centring", "exploits", "the", "existing", "Rigaku", "camera", "microscope", "and", "CameraMan", "software", "(http://www.rigaku.com/).", "The", "cold", "light", "source", "on", "the", "Rigaku", "system", "was", "supplemented", "by", "a", "second", "light", "source", "to", "improve", "the", "image", "and", "help", "locate", "crystals", "in", "drops.", "When", "the", "jig", "is", "mounted", "on", "the", "goniometer,", "the", "cryostream", "is", "moved", "out", "of", "the", "way", "and", "the", "Rigaku", "beam", "stop", "is", "replaced", "with", "a", "J.", "Appl.", "Cryst.", "(2012).", "45,", "138–140" ]

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[ "Research", "Low-Level", "Environmental", "Cadmium", "Exposure", "Is", "Associated", "with", "DNA", "Hypomethylation", "in", "Argentinean", "Women", "Mohammad", "Bakhtiar", "Hossain,1,2", "Marie", "Vahter,3", "Gabriela", "Concha,4", "and", "Karin", "Broberg", "1", "1Department", "of", "Laboratory", "Medicine,", "Division", "of", "Occupational", "and", "Environmental", "Medicine,", "Lund", "University,", "Lund,", "Sweden;", "2International", "Centre", "for", "Diarrhoeal", "Disease", "Research,", "Bangladesh,", "Dhaka,", "Bangladesh;", "3Institute", "of", "Environmental", "Medicine,", "Karolinska", "Institutet,", "Stockholm,", "Sweden;", "4Risk", "and", "Benefit", "Assessment", "Department,", "National", "Food", "Agency,", "Uppsala,", "Sweden", "Background", ":", "Cadmium,", "a", "common", "food", "pollutant,", "alters", "DNA", "methylation", "in", "vitro.", "Epigenetic", "effects", "might", "therefore", "partly", "explain", "cadmium’s", "toxicity,", "including", "its", "carcinogenicity;", "however,", "human", "data", "on", "epigenetic", "effects", "are", "lacking.", "o", "Bjectiv", ":", "We", "evaluated", "the", "effects", "of", "dietary", "cadmium", "exposure", "on", "DNA", "methylation,", "consider­", "ing", "other", "environmental", "exposures,", "genetic", "predisposition,", "and", "gene", "expression.", "Methods", ":", "Concentrations", "of", "cadmium,", "arsenic,", "selenium,", "and", "zinc", "in", "blood", "and", "urine", "of", "non­", "smoking", "women", "(n", "=", "202)", "from", "the", "northern", "Argentinean", "Andes", "were", "measured", "by", "inductively", "coupled", "mass", "spectrometry.", "Methylation", "in", "CpG", "islands", "of", "LINE-1", "(long", "interspersed", "nuclear", "element­1;", "a", "proxy", "for", "global", "DNA", "methylation)", "and", "promoter", "regions", "of", "p16", "[cyclin­dependent", "kinase", "inhibitor", "2A", "(CDKN2A)]", "and", "MLH1", "(mutL", "homolog", "1)", "in", "peripheral", "blood", "were", "measured", "by", "bisulfite", "polymerase", "chain", "reaction", "pyrosequencing.", "Genotyping", "(n", "=", "172)", "for", "the", "DNA", "(cytosine­", "5)­m­ethyltransferase", "1", "gene", "(", "DNMT1", "rs10854076", "and", "rs2228611)", "and", "DNA", "(cytosine5­)­m­ethyl­", "transferase", "3", "beta", "gene", "(DNMT3B", "rs2424913", "and", "rs2424932)", "was", "performed", "with", "Sequenom", "iPLEX", "GOLD", "SNP", "genotyping;", "and", "gene", "expression", "(n", "=", "90),", "with", "DirectHyb", "HumanHT­12", "(version", "3.0).", "r", "esult", ":", "Cadmium", "exposure", "was", "low:", "median", "concentrations", "in", "blood", "and", "urine", "were", "0.36", "and", "0.23", "µg/L,", "respectively.", "Urinary", "cadmium", "(natural", "log", "transformed)", "was", "inversely", "associated", "with", "LINE-1", "methylation", "(β", "=", "–0.50,", "p", "=", "0.0070;", "β", "=", "–0.44,", "p", "=", "0.026,", "adjusted", "for", "age", "and", "coca", "chew­", "ing)", "but", "not", "with", "p16", "or", "MLH1", "methylation.", "Both", "DNMT1", "rs10854076", "and", "DNMT1", "rs2228611", "polymorphisms", "modified", "associations", "between", "urinary", "cadmium", "and", "LINE-1", "(pv­alues", "for", "interaction", "in", "adjusted", "models", "were", "0.045", "and", "0.064,", "respectively).", "The", "rare", "genotypes", "demonstrated", "stronger", "hypomethylation", "with", "increasing", "urinary", "cadmium", "concentrations.", "Cadmium", "was", "inversely", "associated", "with", "DNMT3B", "(rS", "=", "–0.28,", "p", "=", "0.0086)", "but", "not", "with", "DNMT1", "expression", "(rS", "=", "–0.075,", "p", "=", "0.48).", "c", "onclusi", ":", "Environmental", "cadmium", "exposure", "was", "associated", "with", "DNA", "hypomethylation", "in", "peripheral", "blood,", "and", "DNMT1", "genotypes", "modified", "this", "association.", "The", "role", "of", "epigenetic", "modifica­", "tions", "in", "cadmiuma­ssociated", "diseases", "needs", "clarification.", "k", "ey", "w", "ords", ":", "cadmium,", "DNMT1,", "DNMT3B,", "epigenetic,", "genotype,", "LINE-1,", "MLH1,", "p16,", "pyro­", "sequencing.", "Environ", "Health", "Perspect", "120:879–884", "(2012).", "http://dx.doi.org/10.1289/ehp.1104600", "[Online", "1", "March", "2012]", "Cadmium", "is", "a", "widespread", "environmental", "pollutant", "associated", "with", "adverse", "health", "effects,", "including", "cancer,", "kidney", "damage,", "low", "bone-mineral", "density,", "bone", "fractures,", "and", "probably", "impaired", "early-life", "development", "(Engström", "A", "et", "al.", "2011;", "Järup", "and", "Åkesson", "2009;", "Kippler", "et", "al.", "2011).", "The", "general", "popu-", "lation", "is", "exposed", "to", "cadmium", "mainly", "through", "the", "diet,", "in", "particular,", "through", "cereals", "and", "vegetables,", "and", "through", "smoking.", "Potential", "mechanisms", "of", "cadmium", "toxicity", "described", "so", "far", "include", "interactions", "with", "sulfhydryl", "groups", "and", "endocrine", "disruption,", "as", "well", "as", "oxidative", "stress", "(Hartwig", "2010;", "Johnson", "et", "al.", "2003;", "Monroe", "and", "Halvorsen", "2006;", "Xu", "et", "al.", "2011;", "Yu", "et", "al.", "2010).", "DNA", "methylation", "is", "essential", "for", "embryo-", "genesis", "and", "for", "maintaining", "cell-lineage–", "specific", "gene", "expression", "throughout", "life.", "Dysregulation", "of", "epigenetic", "processes,", "such", "as", "DNA", "methylation,", "may", "lead", "to", "impaired", "child-", "hood", "development", "or", "chronic", "diseases", "later", "in", "life,", "including", "cancer", "(Faulk", "and", "Dolinoy", "2011;", "Feinberg", "2007;", "Robins", "et", "al.", "2011).", "In", "carcinogenesis,", "global", "DNA", "methylation", "is", "generally", "decreased,", "whereas", "specific", "regions", "of", "DNA", "that", "contain", "tumor", "suppressor", "genes", "often", "show", "hypermethylation", "(Chalitchagorn", "et", "al.", "2004;", "Deng", "et", "al.", "2006;", "Gaudet", "et", "al.", "2003;", "Robertson", "and", "Jones", "2000).", "In", "vitro", "studies", "have", "indicated", "that", "cadmium", "may", "interfere", "with", "epigenetic", "processes:", "Both", "gene-", "specific", "DNA", "hypermethylation", "with", "gene", "silencing", "of", "p16INK4a", "[CDKN2A", "(cyclin-", "dependent", "kinase", "inhibitor", "2A)],", "RASSF1", "[Ras", "association", "(RalGDS/AF-6)", "domain", "family", "member", "1],", "and", "MT1", "(metallothionein", "1)", "genes,", "and", "global", "DNA", "hypomethylation", "have", "been", "reported", "(Benbrahim-Tallaa", "et", "al.", "2007;", "Huang", "et", "al.", "2008;", "Jiang", "et", "al.", "2008;", "Martinez-Zamudio", "and", "Ha", "2011;", "Takiguchi", "et", "al.", "2003).", "However,", "there", "are", "no", "reports", "on", "the", "epigenetic", "effects", "of", "cadmium", "exposure", "in", "humans.", "The", "aim", "of", "this", "study", "was", "to", "evaluate", "whether", "environmental", "cadmium", "exposure,", "mainly", "through", "the", "normal", "diet,", "may", "affect", "DNA", "methylation,", "both", "of", "repetitive", "genetic", "Environmental", "Health", "Perspectives", "•", "volume", "120", "|", "number", "6", "|", "June", "2012", "elements", "(as", "a", "proxy", "for", "global", "methylation)", "and", "of", "specific", "genes.", "Materials", "and", "Methods", "Participants.", "We", "studied", "202", "women", "living", "in", "the", "Andean", "plateau", "(3,800", "m", "above", "sea", "level)", "in", "northern", "Argentina,", "an", "area", "that", "has", "minimal", "industrial", "or", "vehicle-derived", "pollu-", "tion.", "Most", "of", "the", "study", "participants", "(161)", "were", "from", "the", "village", "of", "San", "Antonio", "de", "los", "Cobres,", "which", "has", "about", "5,000", "inhabitants.", "The", "41", "remaining", "participants", "were", "from", "small", "surrounding", "villages.", "The", "study", "area", "is", "known", "to", "have", "elevated", "concentrations", "of", "arsenic", "(Vahter", "et", "al.", "1995),", "but", "not", "cadmium", "(Concha", "et", "al.", "2010),", "in", "the", "drinking", "water.", "The", "study", "individuals", "were", "recruited", "with", "the", "assistance", "of", "local", "medical", "personnel,", "except", "in", "the", "small", "mining", "village", "of", "Tolar", "Grande,", "where", "we", "went", "from", "house", "to", "house", "to", "explain", "the", "study", "and", "invited", "the", "adults", "to", "participate.", "We", "included", "only", "women", "because", "men", "were", "often", "away", "from", "home", "for", "longer", "periods", "for", "work", "and", "were", "therefore", "likely", "to", "be", "exposed", "to", "a", "different", "variety", "of", "environmental", "hazards.", "Furthermore,", "women", "may", "be", "more", "susceptible", "to", "cadmium", "exposure", "than", "are", "men", "because", "of", "their", "increased", "gastrointestinal", "cadmium", "absorption", "when", "iron", "stores", "are", "low", "(Berglund", "et", "al.", "1994),", "as", "is", "common", "in", "women", "of", "child-", "bearing", "age.", "Only", "four", "study", "participants", "smoked", "cigarettes,", "and", "one", "reported", "drinking", "alcohol,", "but", "almost", "half", "(46.5%)", "reported", "that", "they", "chewed", "coca", "leaves.", "As", "reported", "before,", "interviews", "with", "the", "study", "participants", "revealed", "that", "almost", "all", "women", "drank", "exclusively", "public", "water", "and", "that", "their", "diets", "consisted", "mainly", "of", "corn,", "beans,", "chicken,", "and", "pork", "(Broberg", "et", "al.", "2011).", "Only", "three", "women", "reported", "taking", "Address", "correspondence", "to", "K.", "Broberg,", "Department", "of", "Laboratory", "Medicine,", "Division", "of", "Occupational", "and", "Environmental", "Medicine,", "Lund", "University,", "Klinikgatan", "21,", "SE-22185", "Lund,", "Sweden.", "Telephone:", "46046173819.", "Fax:", "46046143207.", "E-mail:", "karin.", "broberg_palmgren@med.lu.se", "Supplemental", "Material", "is", "available", "online", "(http://", "dx.doi.org/10.1289/ehp.1104600).", "We", "thank", "the", "Department", "of", "Oncology,", "Lund", "University,", "for", "technical", "assistance.", "This", "research", "was", "supported", "by", "the", "Swedish", "Council", "for", "Working", "Life", "and", "Social", "Research,", "Karolinska", "Institutet,", "and", "Kungliga", "fysiografiska", "sällskapet,", "European", "Union", "(FP6;", "“PHIME”", "FOOD-CT-2006-", "016253).", "The", "authors", "declare", "they", "have", "no", "actual", "or", "potential", "competing", "financial", "interests.", "Received", "10", "October", "2011;", "accepted", "1", "March", "2012.", "879" ]

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189, 784, 248, 797 ], [ 253, 784, 284, 797 ], [ 289, 784, 299, 797 ], [ 304, 784, 340, 797 ], [ 345, 784, 364, 797 ], [ 369, 784, 412, 797 ], [ 80, 799, 109, 812 ], [ 113, 799, 119, 812 ], [ 123, 799, 168, 812 ], [ 171, 799, 232, 812 ], [ 236, 799, 304, 812 ], [ 308, 799, 318, 812 ], [ 321, 799, 342, 812 ], [ 346, 799, 413, 812 ], [ 80, 814, 88, 827 ], [ 91, 814, 126, 827 ], [ 130, 814, 140, 827 ], [ 143, 814, 159, 827 ], [ 163, 814, 227, 827 ], [ 230, 814, 240, 827 ], [ 244, 814, 262, 827 ], [ 265, 814, 300, 827 ], [ 304, 814, 322, 827 ], [ 326, 814, 356, 827 ], [ 360, 814, 400, 827 ], [ 403, 814, 413, 827 ], [ 80, 829, 98, 842 ], [ 101, 829, 121, 842 ], [ 124, 829, 146, 842 ], [ 149, 829, 157, 842 ], [ 160, 829, 181, 842 ], [ 184, 829, 194, 842 ], [ 197, 829, 229, 842 ], [ 232, 829, 247, 842 ], [ 250, 829, 293, 842 ], [ 295, 829, 344, 842 ], [ 347, 829, 353, 842 ], [ 357, 829, 389, 842 ], [ 392, 829, 413, 842 ], [ 80, 843, 127, 856 ], [ 130, 843, 172, 856 ], [ 174, 843, 218, 856 ], [ 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[ "NOD2,", "RIP2", "and", "IRF5", "Play", "a", "Critical", "Role", "in", "the", "Type", "I", "Interferon", "Response", "to", "Mycobacterium", "tuberculosis", "Amit", "K.", "Pandey1.,", "Yibin", "Yang2.,", "Zhaozhao", "Jiang3,", "Sarah", "M.", "Fortune4,", "Francois", "Coulombe5,", "Marcel", "A.", "Behr5,", "Katherine", "A.", "Fitzgerald3,", "Christopher", "M.", "Sassetti1*,", "Michelle", "A.", "Kelliher2*", "1", "Department", "of", "Molecular", "Genetics", "and", "Microbiology,", "University", "of", "Massachusetts", "Medical", "School,", "Worcester,", "Massachusetts,", "United", "States", "of", "America,", "2", "Department", "of", "Cancer", "Biology", "and", "the", "Immunology", "and", "Virology", "Program,", "University", "of", "Massachusetts", "Medical", "School,", "Worcester,", "Massachusetts,", "United", "States", "of", "America,", "3", "Department", "of", "Medicine", "and", "the", "Immunology", "and", "Virology", "Program,", "University", "of", "Massachusetts", "Medical", "School,", "Worcester,", "Massachusetts,", "United", "States", "of", "America,", "4", "Department", "of", "Immunology", "and", "Infectious", "Diseases,", "Harvard", "School", "of", "Public", "Health,", "Boston,", "Massachusetts,", "United", "States", "of", "America,", "5", "Department", "of", "Medicine,", "McGill", "University", "Health", "Centre,", "Montreal,", "Quebec,", "Canada", "Abstract", "While", "the", "recognition", "of", "microbial", "infection", "often", "occurs", "at", "the", "cell", "surface", "via", "Toll-like", "receptors,", "the", "cytosol", "of", "the", "cell", "is", "also", "under", "surveillance", "for", "microbial", "products", "that", "breach", "the", "cell", "membrane.", "An", "important", "outcome", "of", "cytosolic", "recognition", "is", "the", "induction", "of", "IFNa", "and", "IFNb,", "which", "are", "critical", "mediators", "of", "immunity", "against", "both", "bacteria", "and", "viruses.", "Like", "many", "intracellular", "pathogens,", "a", "significant", "fraction", "of", "the", "transcriptional", "response", "to", "Mycobacterium", "tuberculosis", "infection", "depends", "on", "these", "type", "I", "interferons,", "but", "the", "recognition", "pathways", "responsible", "remain", "elusive.", "In", "this", "work,", "we", "demonstrate", "that", "intraphagosomal", "M.", "tuberculosis", "stimulates", "the", "cytosolic", "Nod2", "pathway", "that", "responds", "to", "bacterial", "peptidoglycan,", "and", "this", "event", "requires", "membrane", "damage", "that", "is", "actively", "inflicted", "by", "the", "bacterium.", "Unexpectedly,", "this", "recognition", "triggers", "the", "expression", "of", "type", "I", "interferons", "in", "a", "Tbk1-", "and", "Irf5-dependent", "manner.", "This", "response", "is", "only", "partially", "impaired", "by", "the", "loss", "of", "Irf3", "and", "therefore,", "differs", "fundamentally", "from", "those", "stimulated", "by", "bacterial", "DNA,", "which", "depend", "entirely", "on", "this", "transcription", "factor.", "This", "difference", "appears", "to", "result", "from", "the", "unusual", "peptidoglycan", "produced", "by", "mycobacteria,", "which", "we", "show", "is", "a", "uniquely", "potent", "agonist", "of", "the", "Nod2/Rip2/Irf5", "pathway.", "Thus,", "the", "Nod2", "system", "is", "specialized", "to", "recognize", "bacteria", "that", "actively", "perturb", "host", "membranes", "and", "is", "remarkably", "sensitive", "to", "mycobacteria,", "perhaps", "reflecting", "the", "strong", "evolutionary", "pressure", "exerted", "by", "these", "pathogens", "on", "the", "mammalian", "immune", "system.", "Citation:", "Pandey", "AK,", "Yang", "Y,", "Jiang", "Z,", "Fortune", "SM,", "Coulombe", "F,", "et", "al.", "(2009)", "NOD2,", "RIP2", "and", "IRF5", "Play", "a", "Critical", "Role", "in", "the", "Type", "I", "Interferon", "Response", "to", "Mycobacterium", "tuberculosis.", "PLoS", "Pathog", "5(7):", "e1000500.", "doi:10.1371/journal.ppat.1000500", "Editor:", "Pascale", "Cossart,", "Institut", "Pasteur,", "France", "Received", "October", "17,", "2008;", "Accepted", "June", "5,", "2009;", "Published", "July", "3,", "2009", "Copyright:", "2009", "Pandey", "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", "NIH/AI", "RO1", "AI075118", "grant", "to", "MAK,", "NIH", "RO1", "AI064282", "to", "CMS", "and", "NIH", "RO1", "AI067497", "to", "KAF.", "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:", "christopher.sassetti@umassmed.edu", "(CMS);", "michelle.kelliher@umassmed.edu", "(MAK)", ".", "These", "authors", "contributed", "equally", "to", "this", "work.", "Introduction", "Mycobacterium", "tuberculosis", "(Mtb),", "the", "causative", "agent", "of", "human", "tuberculosis,", "is", "an", "exquisitely", "adapted", "obligate", "human", "pathogen", "that", "is", "thought", "to", "persist", "within", "as", "many", "as", "one", "billion", "individuals", "worldwide", "[1].", "This", "bacterium’s", "ability", "to", "survive", "and", "replicate", "inside", "a", "modified", "phagosomal", "compartment", "of", "host", "macrophages", "is", "central", "to", "the", "pathogenesis", "of", "this", "disease", "[2].", "While", "residing", "at", "this", "site,", "Mtb", "is", "able", "to", "persist", "for", "decades.", "However,", "a", "robust", "cell-", "mediated", "immune", "response", "effectively", "inhibits", "bacterial", "replication", "in", "approximately", "90%", "of", "otherwise", "healthy", "individuals,", "and", "the", "infection", "can", "be", "controlled", "indefinitely.", "Deficits", "in", "this", "immune", "response", "result", "in", "progressive", "bacterial", "replication,", "necrosis", "of", "infected", "lung", "tissue,", "and", "spread", "to", "other", "individuals.", "Thus,", "like", "many", "other", "pathogens", "that", "cause", "chronic", "infections,", "the", "long-term", "survival", "of", "Mtb,", "depends", "on", "a", "delicate", "balance", "between", "bacterial", "virulence", "and", "host", "immunity.", "Immunity", "to", "tuberculosis", "depends", "on", "both", "the", "innate", "and", "adaptive", "responses", "of", "the", "host.", "Initial", "recognition", "of", "the", "bacterium", "is", "mediated", "by", "pattern", "recognition", "receptors", "(PRR)", "such", "as", "Toll-", "like", "receptors", "(TLRs)", "[3,4]", "or", "nucleotide", "binding", "oligomerization", "domain", "(NOD)-like", "receptors", "(NLRs)", "[5,6],", "both", "of", "which", "recognize", "conserved", "microbial", "structures", "known", "as", "pathogen", "associated", "molecular", "patterns", "(PAMPs).", "TLRs", "monitor", "the", "extracellular", "environment", "and", "endosomal", "compartments,", "and", "recognize", "a", "variety", "of", "microbial", "components", "including", "bacterial", "lipoprotein,", "peptidoglycan,", "CpG", "DNA,", "and", "double-", "and", "single-", "stranded", "RNA", "[4].", "NLRs", "constitute", "a", "more", "diverse", "family", "of", "approximately", "25", "proteins,", "including", "the", "caspase-recruiting", "domain", "(CARD)-containing", "Nod1,", "Nod2", "and", "NLRCs,", "the", "pyrin", "(PYR)", "domain-containing", "NLRPs", "and", "the", "baculovirus-inhibitor-", "of-apoptosis-repeats", "(BIRs)-containing", "NLRBs.", "Nod1", "and", "Nod2", "reside", "in", "the", "cytosol", "and", "recognize", "microbial", "products", "in", "this", "compartment", "[7].", "While", "the", "functions", "of", "most", "NLR’s", "remain", "undefined,", "the", "Nod1", "and", "Nod2", "proteins", "have", "been", "shown", "to", "respond", "to", "bacterial", "cell", "wall", "fragments.", "The", "Nod1", "protein", "recognizes", "a", "fragment", "of", "peptidoglycan", "(PGN)", "containing", "the", "dipeptide", "c-d-glutamyl-meso-diaminopimelic", "acid", "(iE-DAP)", "pro-", "duced", "by", "Gram-negative", "and", "some", "Gram-positive", "bacteria.", "Nod2", "recognizes", "muramyl", "dipeptide", "(MDP)", "present", "on", "most", "types", "of", "PGN", "[8,9,10,11].", "While", "the", "recognition", "of", "these", "common", "forms", "of", "peptidoglycan", "have", "been", "extensively", "studied,", "bacteria", "modify", "their", "PLoS", "Pathogens", "|", "www.plospathogens.org", "1", "July", "2009", "|", "Volume", "5", "|", "Issue", "7", "|", "e1000500" ]

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[ "Nutrition", "Research", "and", "Practice", "(Nutr", "Res", "Pract)", "2012;6(3):221-225", "http://dx.doi.org/10.4162/nrp.2012.6.3.221", "pISSN", "1976-1457", "eISSN", "2005-6168", "Effect", "of", "zinc", "supplementation", "on", "insulin", "resistance", "and", "metabolic", "risk", "factors", "in", "obese", "Korean", "women", "Jihye", "Kim§", "and", "Sunju", "Lee", "Department", "of", "Food", "and", "Nutrition,", "Daegu", "University,", "Jillyang,", "Gyeongsan,", "Gyeongbuk", "712-714,", "Korea", "Abstract", "Zinc", "deficiency", "is", "known", "to", "be", "associated", "with", "insulin", "resistance", "in", "obese", "individuals.", "This", "study", "was", "performed", "to", "evaluate", "the", "effect", "of", "zinc", "supplementation", "on", "insulin", "resistance", "and", "metabolic", "risk", "factors", "in", "obese", "Korean", "women.", "Forty", "obese", "women", "(body", "mass", "index", "(BMI)", "≥", "25", "kg/m2)", "aged", "19-28", "years", "were", "recruited", "for", "this", "study.", "Twenty", "women", "of", "the", "study", "group", "took", "30", "mg/day", "of", "supplemental", "zinc", "as", "zinc", "gluconate", "for", "8", "weeks", "and", "20", "women", "of", "control", "group", "took", "placebo.", "Usual", "dietary", "zinc", "intake", "was", "estimated", "from", "3-day", "diet", "records.", "Insulin", "resistances", "were", "measured", "using", "Homeostasis", "model", "assessment", "(HOMA)", "indices,", "and", "insulin", "sensitivities", "Matsuda", "indices,", "which", "were", "calculated", "using", "oral", "glucose", "tolerance", "test", "data.", "Metabolic", "risk", "factors,", "such", "as", "waist", "circumference,", "blood", "pressure,", "fasting", "glucose,", "triglyceride,", "high", "density", "lipoprotein", "(HDL)", "cholesterol,", "and", "adipocyte", "hormones", "such", "as", "leptin,", "and", "adiponectin", "were", "also", "measured.", "At", "the", "beginning", "of", "study,", "dietary", "zinc", "averaged", "7.31", "mg/day", "and", "serum", "zinc", "averaged", "12.98", "μmol/L", "in", "the", "study", "group.", "Zinc", "supplementation", "increased", "serum", "zinc", "by", "15%", "and", "urinary", "zinc", "by", "56%", "(P", "<", "0.05).", "HOMA", "values", "tended", "to", "decrease", "and", "insulin", "sensitivity", "increased", "slightly", "in", "the", "study", "group,", "but", "not", "significantly", "so.", "BMI,", "waist", "circumference,", "blood", "pressure,", "blood", "glucose,", "triglyceride,", "HDL", "cholesterol,", "and", "adipocyte", "hormones", "did", "not", "change", "in", "either", "the", "study", "or", "control", "group.", "These", "results", "suggest", "that", "zinc", "status", "may", "not", "affect", "insulin", "resistance", "and", "metabolic", "risk", "factors", "in", "obese", "Korean", "women.", "Further", "research", "is", "required", "on", "a", "larger", "cohort", "with", "a", "longer", "follow-up", "to", "determine", "the", "effects", "of", "zinc", "status", "on", "insulin", "resistance", "and", "metabolic", "variables.", "Key", "Words:", "Supplemental", "zinc,", "insulin", "resistance,", "serum", "zinc,", "metabolic", "risk", "factors,", "obese", "women", "Introduction6)", "Zinc", "is", "known", "to", "be", "an", "essential", "trace", "element", "and", "a", "component", "of", "hundreds", "of", "enzymes", "[1],", "and", "is", "involved", "in", "the", "synthesis,", "storage,", "and", "release", "of", "insulin.", "Many", "studies", "have", "documented", "that", "plasma", "zinc", "levels", "are", "lower", "in", "obese", "individuals", "[2,3].", "Furthermore,", "zinc", "deficiency", "may", "predispose", "glucose", "intolerance", "and", "insulin", "resistance,", "diabetes", "mellitus,", "and", "coronary", "artery", "disease", "[4-6].", "Recent", "studies", "have", "revealed", "that", "zinc", "had", "beneficial", "effects", "on", "insulin", "resistance", "and", "on", "glucose", "and", "lipid", "profiles", "in", "patients", "with", "diabetes", "or", "metabolic", "syndrome", "[7-10].", "For", "example,", "a", "prospective", "study", "demonstrated", "that", "higher", "zinc", "intakesare", "associated", "with", "a", "lower", "risk", "of", "type", "2", "diabetes", "in", "U.S.", "women", "[10],", "and", "other", "studies", "have", "shown", "that", "zinc", "supplementation", "increases", "high", "density", "lipoprotein", "(HDL)", "cholesterol", "and", "reduces", "triglyceride", "(TG)", "in", "type", "2", "diabetes", "patients", "[7,8].", "Furthermore,", "in", "a", "randomized", "cross-over", "trial,", "supplemental", "zinc", "(20", "mg", "per", "day)", "significantly", "decreased", "insulin", "resistance", "in", "obese", "children", "with", "metabolic", "syndrome", "[9].", "However,", "relationships", "between", "zinc", "status", "and", "insulin", "resistance/metabolic", "risk", "factors", "are", "more", "controversial", "among", "non-diabetic", "obese", "and", "non-obese", "subjects.", "Marreiro", "et", "al.", "[11]", "found", "that", "insulin", "sensitivity", "improved,", "without", "changes", "in", "leptin", "levels,", "in", "non-diabetic", "obese", "subjects", "on", "zinc", "supplementation.", "Whereas", "Obeid", "et", "al.", "[12]", "reported", "that", "lower", "plasma", "zinc", "concentrations", "were", "not", "related", "to", "glycemic", "status", "or", "components", "of", "metabolic", "syndrome", "in", "Lebanese", "adults.", "Insulin", "resistance", "plays", "an", "important", "role", "in", "the", "pathophy-", "siology", "of", "obesity", "and", "metabolic", "syndrome", "[13],", "the", "prevalence", "of", "which", "are", "rapidly", "increasing", "in", "the", "Korean", "population.", "According", "to", "Korean", "National", "Health", "and", "Nutrition", "Examination", "Survey", "III", "data,", "an", "estimated", "32%", "and", "30%", "of", "Korean", "adults", "are", "obese", "or", "have", "metabolic", "syndrome,", "respectively", "[14].", "Thus,", "it", "is", "critical", "that", "the", "relationship", "between", "zinc", "status", "and", "insulin", "resistance", "or", "its", "related", "metabolic", "risk", "factors", "be", "determined", "in", "obese", "subjects,", "because", "this", "could", "allow", "us", "to", "consider", "zinc", "intervention", "for", "the", "treatment", "or", "prevention", "of", "metabolic", "disease", "related", "to", "insulin", "resistance.", "Therefore,", "in", "this", "study,", "we", "evaluated", "the", "effects", "of", "zinc", "supplementation", "at", "30", "mg/day", "for", "8", "weeks", "on", "insulin", "resistance", "and", "metabolic", "risk", "factors,", "such", "as,", "obesity,", "blood", "glucose,", "and", "lipid", "profiles", "in", "obese", "Korean", "women.", "This", "research", "was", "supported", "by", "the", "Basic", "Science", "Research", "Program", "of", "the", "National", "Research", "Foundation", "of", "Korea", "(NRF)", "funded", "by", "the", "Ministry", "of", "Education,", "Science,", "and", "Technology", "(grant", "no.", "NRF-2009-0068869).", "§", "Corresponding", "Author:", "Jihye", "Kim,", "Tel.", "82-53-850-6832,", "Fax.", "82-53-850-6839,", "Email.", "kjhye76@daegu.ac.kr", "Received:", "January", "5,", "2012,", "Revised:", "March", "7,", "2012,", "Accepted:", "March", "19,", "2012", "ⓒ2012", "The", "Korean", "Nutrition", "Society", "and", "the", "Korean", "Society", "of", "Community", "Nutrition", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "Non-Commercial", "License", "(http://creativecommons.org/licenses/by-nc/3.0/)", "which", "permits", "unrestricted", "non-commercial", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

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[ "The", "INT6", "Cancer", "Gene", "and", "MEK", "Signaling", "Pathways", "Converge", "during", "Zebrafish", "Development", "Michal", "Grzmil1,", "Danny", "Whiting1,", "John", "Maule2,", "Corina", "Anastasaki2,", "James", "F.", "Amatruda3,", "Robert", "N.", "Kelsh4,", "Chris", "J.", "Norbury1,", "E.", "Elizabeth", "Patton1,2*", "1", "Sir", "William", "Dunn", "School", "of", "Pathology,", "University", "of", "Oxford,", "Oxford,", "United", "Kingdom,", "2", "MRC", "Human", "Genetics", "Unit", "and", "University", "of", "Edinburgh", "Cancer", "Research", "Centre,", "Western", "General", "Hospital,", "Edinburgh,", "United", "Kingdom,", "3", "Departments", "of", "Pediatrics,", "Internal", "Medicine", "and", "Molecular", "Biology,", "University", "of", "Texas", "Southwestern", "Medical", "Center,", "Dallas,", "Texas,", "United", "States", "of", "America,", "4", "Centre", "for", "Regenerative", "Medicine,", "Developmental", "Biology", "Programme,", "Department", "of", "Biology", "and", "Biochemistry,", "University", "of", "Bath,", "Bath,", "United", "Kingdom", "Background.", "Int-6", "(integration", "site", "6)", "was", "identified", "as", "an", "oncogene", "in", "a", "screen", "of", "tumorigenic", "mouse", "mammary", "tumor", "virus", "(MMTV)", "insertions.", "INT6", "expression", "is", "altered", "in", "human", "cancers,", "but", "the", "precise", "role", "of", "disrupted", "INT6", "in", "tumorigenesis", "remains", "unclear,", "and", "an", "animal", "model", "to", "study", "Int-6", "physiological", "function", "has", "been", "lacking.", "Principal", "Findings.", "Here,", "we", "create", "an", "in", "vivo", "model", "of", "Int6", "function", "in", "zebrafish,", "and", "through", "genetic", "and", "chemical-genetic", "approaches", "implicate", "Int6", "as", "a", "tissue-specific", "modulator", "of", "MEK-ERK", "signaling.", "We", "find", "that", "Int6", "is", "required", "for", "normal", "expression", "of", "MEK1", "protein", "in", "human", "cells,", "and", "for", "Erk", "signaling", "in", "zebrafish", "embryos.", "Loss", "of", "either", "Int6", "or", "Mek", "signaling", "causes", "defects", "in", "craniofacial", "development,", "and", "Int6", "and", "Erk-signaling", "have", "overlapping", "domains", "of", "tissue", "expression.", "Significance.", "Our", "results", "provide", "new", "insight", "into", "the", "physiological", "role", "of", "vertebrate", "Int6,", "and", "have", "implications", "for", "the", "treatment", "of", "human", "tumors", "displaying", "altered", "INT6", "expression.", "Citation:", "Grzmil", "M,", "Whiting", "D,", "Maule", "J,", "Anastasaki", "C,", "Amatruda", "JF,", "et", "al", "(2007)", "The", "INT6", "Cancer", "Gene", "and", "MEK", "Signaling", "Pathways", "Converge", "during", "Zebrafish", "Development.", "PLoS", "ONE", "2(9):", "e959.", "doi:10.1371/journal.pone.0000959", "INTRODUCTION", "Embryonic", "development", "and", "tumour", "development", "often", "share", "underlying", "molecular", "mechanisms–a", "concept", "illustrated", "by", "the", "identification", "of", "genes", "disrupted", "by", "the", "mouse", "mammary", "tumor", "virus", "(MMTV)", "in", "mammary", "cancers", "[1].", "An", "important", "example,", "the", "Int-1", "gene", "which", "is", "a", "common", "integration", "site", "for", "MMTV", "in", "mammary", "tumours,", "encodes", "the", "homologue", "of", "the", "Drosophila", "wingless", "gene", "[2,3]", "and", "was", "subsequently", "named", "Wnt1", "(wingless/", "Int)", "in", "recognition", "of", "this", "conserved", "function.", "Wnt", "signaling", "is", "now", "known", "to", "be", "disrupted", "in", "many", "human", "tumor", "types,", "especially", "colon", "cancer", "[4].", "Other", "Int", "genes,", "such", "as", "Int-2", "and", "4", "(Fgf3,", "4),", "and", "Int-3", "(Notch4),", "encode", "mitogens", "and", "regulators", "of", "development", "that", "are", "also", "misactivated", "in", "many", "cancers", "[1,5].", "In", "the", "majority", "of", "cases,", "MMTV", "activates", "Int", "gene", "expression", "as", "a", "result", "of", "proviral", "integration", "upstream", "of", "the", "promoter", "region.", "Remarkably,", "all", "three", "MMTV", "insertions", "found", "in", "Int-6,", "which", "encodes", "a", "component", "of", "the", "eukaryotic", "translation", "initation", "factor", "3", "(eIF3),", "were", "found", "to", "lie", "within", "introns,", "and", "in", "the", "opposite", "transcriptional", "orientation", "to", "the", "Int-6", "gene,", "creating", "a", "truncated", "Int-6", "mRNA", "[1,6].", "Ectopic", "expression", "of", "equivalently", "truncated", "Int-6", "can", "transform", "cell", "cultures", "[7,8],", "and", "promote", "persistent", "mammary", "alveolar", "hyperplasia", "and", "tumorigenesis", "in", "transgenic", "mice", "[9].", "Despite", "important", "evidence", "in", "favor", "of", "a", "role", "for", "INT6", "in", "human", "tumourigenesis", "[10–12],", "the", "molecular", "basis", "for", "INT6", "in", "cancer", "development", "remains", "unresolved.", "Highly", "conserved", "in", "eukaryotes,", "INT6", "contains", "a", "PCI", "domain,", "found", "in", "proteins", "of", "the", "19S", "regulatory", "lid", "of", "the", "proteasome,", "the", "COP9", "signalosome", "(CSN),", "and", "the", "eIF3", "translation", "initiation", "complex;", "all", "three", "complexes", "share", "overall", "structural", "similarity,", "and", "INT6", "has", "been", "found", "associated", "with", "each", "[13].", "When", "over-", "expressed", "in", "yeast,", "Int6", "induces", "multi-drug", "resistance", "by", "activating", "an", "AP-1", "transcription", "factor", "[14,15],", "and", "in", "human", "cells,", "the", "range", "of", "INT6", "function", "includes", "orderly", "progression", "through", "mitosis", "[16],", "regulation", "of", "the", "proteasome-dependent", "stability", "of", "MCM7", "[17]", "and", "HIF2a", "[18],", "and", "nonsense", "mediated", "mRNA", "decay", "[19].", "With", "no", "animal", "model", "for", "Int6", "loss-of-function", "available,", "we", "reasoned", "that", "an", "understanding", "of", "INT6", "during", "development", "would", "provide", "novel", "insight", "into", "INT6", "function", "in", "normal", "vertebrate", "cells,", "thereby", "providing", "a", "new", "perspective", "on", "INT6", "function", "in", "cancer", "formation.", "Here,", "using", "zebrafish", "and", "mammalian", "cells,", "we", "describe", "the", "first", "Int6", "loss-of-function", "phenotype", "in", "an", "animal,", "and", "link", "Int6", "with", "a", "signaling", "pathway,", "that", "like", "those", "effected", "by", "other", "Int", "genes,", "is", "critical", "for", "both", "development", "and", "cancer.", "RESULTS", "Int6", "is", "essential", "for", "zebrafish", "embryogenesis", "We", "chose", "to", "study", "the", "physiological", "role", "of", "zebrafish", "Int6", "during", "development,", "using", "morpholino", "oligonucleotides", "(MOs)", "to", "reduce", "Int6", "protein,", "as", "well", "as", "an", "int6hi2470", "insertional", "mutant", "line", "(kindly", "provided", "by", "N.", "Hopkins,", "A.", "Amsterdam", "and", "S.", "Farrington.", "M.I.T.).", "Zebrafish", "Int6", "is", "over", "90%", "identical", "in", "its", "amino", "acid", "sequence", "to", "human", "INT6", "(Ensembl", "ENSDARG00000002549)", "and", "using", "an", "Int6", "antibody", "raised", "against", "the", "N-terminus", "of", "the", "human", "Academic", "Editor:", "Thomas", "Zwaka,", "Baylor", "College", "of", "Medicine,", "United", "States", "of", "America", "Received", "August", "3,", "2007;", "Accepted", "September", "2,", "2007;", "Published", "September", "26,", "2007", "Copyright:", "2007", "Grzmil", "et", "al.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Funding:", "This", "work", "was", "funded", "by", "a", "MRC", "grant", "to", "EEP,", "and", "by", "grants", "from", "CRUK", "and", "the", "AICR", "to", "CJN.", "Funders", "had", "no", "role", "in", "the", "design", "or", "conduct", "of", "the", "study,", "in", "the", "collection,", "analysis,", "or", "interpretation", "of", "the", "data,", "or", "in", "the", "preparation,", "review,", "or", "approval", "of", "the", "manuscript.", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "*", "To", "whom", "correspondence", "should", "be", "addressed.", "E-mail:", "epatton@staffmail.ed.", "ac.uk", "PLoS", "ONE", "|", "www.plosone.org", "1", "September", "2007", "|", "Issue", "9", "|", "e959" ]

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[ "BMC", "Family", "Practice", "Research", "article", "Development", "of", "a", "questionnaire", "weighted", "scoring", "system", "to", "target", "diagnostic", "examinations", "for", "asthma", "in", "adults:", "a", "modelling", "study", "Sybil", "Hirsch*1,", "Timothy", "L", "Frank1,", "Jonathan", "L", "Shapiro2,", "Michelle", "L", "Hazell1", "and", "Peter", "I", "Frank1", "BioMed", "Central", "Open", "Access", "Address:", "1General", "Practice", "Research", "Unit,", "North", "West", "Lung", "Research", "Centre,", "Wythenshawe", "Hospital,", "Manchester,", "M23", "9LT,", "UK", "and", "2Department", "of", "Computer", "Science,", "University", "of", "Manchester,", "Oxford", "Road,", "Manchester", "M13", "9PL,", "UK", "Email:", "Sybil", "Hirsch*", "-", "gpresearchunit@yahoo.co.uk;", "Timothy", "L", "Frank", "-", "gpresearchunit@yahoo.co.uk;", "Jonathan", "L", "Shapiro", "-", "jls@cs.man.ac.uk;", "Michelle", "L", "Hazell", "-", "gpresearchunit@yahoo.co.uk;", "Peter", "I", "Frank", "-", "gpresearchunit@yahoo.co.uk", "*", "Corresponding", "author", "Published:", "17", "December", "2004", "BMC", "Family", "Practice", "2004,", "5:30", "doi:10.1186/1471-2296-5-30", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1471-2296/5/30", "Received:", "14", "July", "2004", "Accepted:", "17", "December", "2004", "©", "2004", "Hirsch", "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:", "Identification", "and", "treatment", "of", "unrecognised", "asthmatics", "in", "the", "community", "is", "important", "for", "improving", "the", "health", "of", "the", "individual", "and", "minimising", "cost", "and", "quality", "of", "life", "burden.", "It", "is", "not", "practical", "to", "offer", "clinical", "diagnostic", "assessment", "to", "whole", "communities,", "and", "a", "simple", "tool", "such", "as", "a", "questionnaire", "is", "required", "to", "identify", "a", "smaller", "target", "group.", "Conventional", "questionnaire", "screening", "methods", "which", "separate", "individuals", "into", "positive", "and", "negative", "categories", "have", "resulted", "in", "large", "numbers", "of", "individuals", "requiring", "clinical", "assessment.", "This", "study", "has", "therefore", "developed", "and", "tested", "a", "weighted", "scoring", "system", "that", "prioritises", "those", "most", "urgently", "in", "need,", "based", "on", "their", "questionnaire", "responses.", "Methods:", "A", "stratified", "random", "sample", "of", "adult", "respondents", "to", "a", "general", "practice", "postal", "questionnaire", "survey", "were", "categorised", "'asthmatic'", "or", "'non-asthmatic'", "according", "to", "three", "expert", "physicians'", "opinions.", "Based", "on", "this", "categorisation,", "logistic", "regression", "was", "used", "to", "derive", "weights", "reflecting", "the", "relative", "importance", "of", "each", "question", "in", "predicting", "asthma,", "allowing", "calculation", "of", "weighted", "scores", "reflecting", "likelihood", "of", "asthma.", "Respondents", "scoring", "higher", "than", "a", "chosen", "threshold", "would", "be", "offered", "diagnostic", "examination.", "Results:", "Age", "and", "presence", "of", "wheeze", "were", "most", "influential", "(weight", "3)", "and", "overall", "weighted", "scores", "ranged", "from", "-1", "to", "13.", "Positive", "predictive", "values", "(PPV)", "were", "estimated.", "For", "example,", "setting", "the", "threshold", "score", "at", "nine", "gave", "an", "estimated", "PPV", "for", "asthma", "diagnosis", "of", "93.5%,", "a", "threshold", "score", "of", "seven", "corresponded", "to", "PPV", "78.8%.", "PPV", "estimates", "were", "supported", "by", "examining", "145", "individuals", "from", "a", "new", "survey.", "Conclusion:", "Weighted", "scoring", "of", "questionnaire", "responses", "provides", "a", "method", "for", "evaluating", "the", "priority", "level", "of", "an", "individual", "'at", "a", "glance',", "minimising", "the", "resource", "wastage", "of", "examining", "false", "positives.", "Background", "There", "are", "individuals", "in", "the", "community", "who", "are", "asth-", "matic", "but", "are", "not", "receiving", "treatment", "because", "they", "are", "unknown", "to", "the", "medical", "services", "[1-5].", "Detecting", "these", "Page", "1", "of", "9", "(page", "number", "not", "for", "citation", "purposes)" ]

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[ "R", "E", "V", "I", "E", "W", "Anecor", "tave", "acetate", "in", "the", "treatment", "of", "age-related", "macular", "degeneration", "Albert", "Augustin", "Department", "of", "Ophthalmology,", "Moltkestrasse", "90,", "76133", "Karlsruhe,", "Germany", "Correspondence:Albert", "Augustin", "Department", "of", "Ophthalmology,", "Moltkestrasse", "90,", "76133", "Karlsruhe,", "Germany", "Tel", "+49", "721", "9742001", "Fax", "+49", "721", "9742009", "Email", "106020.560@compuserve.com", "Abstract:", "RETAANE®", "15mg", "(anecortave", "acetate", "suspension)", "is", "under", "investigation", "to", "treat", "exudative", "age-related", "macular", "degeneration", "(AMD),", "the", "single", "largest", "cause", "of", "blindness", "in", "the", "Western", "world,", "affecting", "over", "15", "million", "people", "in", "the", "USA.", "RETAANE", "suspension", "is", "a", "unique", "synthetic", "cortisene", "and", "has", "antiangiogenic", "properties", "that", "were", "established", "in", "multiple", "experimental", "models", "of", "angiogenesis.", "The", "molecule", "acts", "at", "multiple", "sites", "of", "the", "angiogenic", "cascade.", "Clinical", "trials", "in", "patients", "with", "exudative", "AMD", "have", "demonstrated", "the", "excellent", "safety", "record", "of", "both", "the", "drug", "anecortave", "acetate", "and", "the", "posterior", "juxtascleral", "depot", "(PJD)", "administration", "procedure.", "A", "pivotal", "study", "comparing", "RETAANE", "suspension", "with", "placebo", "showed", "a", "significantly", "higher", "chance", "of", "maintaining", "vision", "in", "the", "treatment", "(73%)", "as", "compared", "with", "placebo", "(47%).", "Another", "study", "compared", "RETAANE", "suspension", "with", "Visudyne®", "photodynamic", "therapy,", "revealing", "no", "statistically", "significant", "differences", "between", "the", "two", "treatments", "over", "24", "months.", "AMD", "is", "a", "multi-faceted", "disease", "and", "therefore", "a", "molecule", "such", "as", "RETAANE", "suspension", "with", "a", "unique", "mechanism", "of", "action,", "demonstrated", "clinical", "efficacy,", "and", "retreatment", "every", "six", "months", "is", "an", "important", "potential", "treatment", "option", "which", "should", "be", "further", "investigated", "both", "as", "a", "monotherapy", "or", "in", "combination", "with", "other", "treatment", "strategies.", "Keywords:", "age-related", "macular", "degeneration", "(AMD),", "anecortave", "acetate,", "RETAANE", "suspension,", "exudative", "AMD,", "progression", "of", "dry", "AMD", "Introduction", "–", "current", "treatment", "options", "Age-related", "macular", "degeneration", "(AMD)", "is", "the", "most", "serious", "threat", "to", "the", "vision", "of", "the", "elderly.", "It", "is", "the", "leading", "cause", "of", "severe", "and", "permanent", "central", "vision", "loss", "amongst", "those", "over", "50", "(Swann", "and", "Lovie-Kitchin", "1990).", "About", "10%", "of", "the", "population", "over", "the", "age", "of", "52", "and", "up", "to", "33%", "of", "those", "over", "75", "present", "with", "any", "signs", "of", "AMD.", "Over", "15", "million", "Americans", "are", "already", "afflicted", "with", "a", "form", "of", "the", "disease", "and", "the", "number", "is", "rising", "at", "the", "rate", "of", "2", "million", "new", "cases", "every", "year.", "According", "to", "the", "European", "office", "of", "AMD", "Alliance", "International,", "an", "estimated", "2.8", "million", "cases", "of", "wet", "AMD", "will", "be", "diagnosed", "in", "the", "25", "European", "countries", "within", "the", "next", "decade.", "With", "such", "an", "imminent", "threat", "to", "the", "vision", "of", "the", "elderly,", "significant", "research", "and", "development", "efforts", "are", "being", "devoted", "to", "finding", "effective", "treatment", "methods", "for", "wet", "AMD.", "Currently", "available", "treatments", "include", "laser", "photocoagulation,", "verteporfin", "photodynamic", "therapy", "(PDT)", "(Visudyne®,", "Novartis", "AG,", "Basel,", "Switzerland),", "pegaptanib", "sodium", "injection", "(Macugen®,", "Eyetech", "Pharmaceuticals/Pfizer),", "and", "anecortave", "acetate", "(RETAANE®", "suspension,", "Alcon", "Laboratories,", "Inc.,", "Fort", "Worth,", "Texas,", "USA).", "In", "addition,", "modified", "PDT", "treatments", "such", "as", "the", "combination", "of", "PDT", "with", "intravitreal", "triamcinolone", "became", "very", "popular", "within", "the", "last", "year", "(Augustin", "and", "Schmidt-Erfurth", "2006).", "Anecortave", "acetate", "is", "a", "promising", "new", "treatment", "option", "that", "is", "being", "clinically", "tested", "and", "recently", "approved", "in", "Australia", "for", "treating", "AMD", "patients", "with", "classic", "containing", "lesions.", "Until", "2000,", "laser", "photocoagulation", "was", "the", "only", "approved", "Clinical", "Interventions", "in", "Aging", "2006:1(3)", "237–246", "2006", "Dove", "Medical", "Press", "Limited.", "All", "rights", "reserved", "237" ]

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

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[ "Hindawi", "Publishing", "Corporation", "International", "Journal", "of", "Peptides", "Volume", "2011,", "Article", "ID", "708710,", "3", "pages", "doi:10.1155/2011/708710", "Research", "Article", "Activity", "of", "Cathelicidin", "Peptides", "against", "Simkania", "negevensis", "Manuela", "Donati,1", "Antonietta", "Di", "Francesco,2", "Maria", "Di", "Paolo,1", "Natascia", "Fiani,1", "Monica", "Benincasa,3", "Renato", "Gennaro,3", "Paola", "Nardini,1", "Claudio", "Foschi,1", "and", "Roberto", "Cevenini1", "1", "Section", "of", "Microbiology", "DESOS,", "Policlinico", "S.", "Orsola,", "University", "of", "Bologna,", "40138", "Bologna,", "Italy", "2", "Department", "of", "Veterinary", "Medical", "Sciences,", "University", "of", "Bologna,", "40064", "Ozzano", "dell’Emilia,", "Italy", "3", "Department", "of", "Life", "Sciences,", "University", "of", "Trieste,", "34127,", "Trieste,", "Italy", "Correspondence", "should", "be", "addressed", "to", "Antonietta", "Di", "Francesco,", "antoniet.difrancesco@unibo.it", "Received", "10", "December", "2010;", "Accepted", "30", "January", "2011", "Academic", "Editor:", "Peter", "Bergman", "Copyright", "©", "2011", "Manuela", "Donati", "et", "al.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "The", "in", "vitro", "activity", "of", "six", "cathelicidin", "peptides", "against", "the", "reference", "strain", "Z", "of", "Simkania", "negevensis", "was", "investigated.", "Five", "peptides—PG-1,", "Bac7,", "SMAP-29,", "BMAP-27,", "and", "BMAP-28—proved", "to", "be", "active", "at", "very", "low", "concentrations", "(1", "to", "0.1", "µg/mL),", "while", "LL-37", "cathelicidin", "was", "ineffective", "even", "at", "a", "concentration", "of", "100", "µg/mL.", "In", "comparison", "to", "chlamydiae,", "S.", "negevensis", "proved", "to", "be", "more", "susceptible", "to", "the", "antimicrobial", "peptides", "tested.", "1.", "Introduction", "Simkania", "negevensis", "is", "an", "obligate", "intracellular", "Gram-nega-", "tive", "bacterium", "belonging", "to", "the", "family", "of", "Simkaniaceae", "in", "the", "order", "Chlamydiales", "[1],", "discovered", "as", "a", "contaminant", "in", "a", "variety", "of", "cell", "cultures", "[2],", "and", "is", "able", "to", "grow", "also", "in", "various", "environmental", "free-living", "amoebae", "such", "as", "Acanthamoeba", "poliphaga", "[3].", "Epidemiologic", "studies", "have", "reported", "a", "human", "widesp-", "read", "exposure", "to", "this", "bacterium", "[4,", "5],", "both", "in", "healthy", "sub-", "jects", "and", "in", "association", "with", "respiratory", "diseases", "in", "infants", "and", "adults", "[6–10].", "Coinfections", "with", "other", "pathogens", "have", "been", "described,", "such", "as", "respiratory", "syncytial", "virus", "in", "children", "and", "influenza", "virus", "and", "other", "bacterial", "species", "in", "adults", "[7,", "8,", "11].", "A", "possible", "association", "between", "S.", "negevensis", "and", "acute", "rejection", "in", "lung", "transplant", "recipients", "has", "been", "suggested", "[12].", "S.", "negevensis", "DNA", "has", "also", "been", "amplified", "from", "an", "aortic", "aneurysm", "[13,", "14].", "Previous", "investigations", "reported", "S.", "negevensis", "in", "vitro", "sus-", "ceptibility", "to", "azithromycin,", "minocycline,", "erithromycin,", "dox-", "ycycline,", "and", "ofloxacin", "like", "chlamydiae", "[15]", "and", "the", "lack", "of", "susceptibility", "to", "ampicillin,", "penicillin", "G,", "bacitracin,", "cycl-", "osporine,", "and", "fluoroquinolones", "[2,", "15,", "16].", "Several", "studies", "[17–20]", "demonstrated", "the", "in", "vitro", "antich-", "lamydial", "activity", "of", "peptides,", "such", "as", "cathelicidins,", "stored", "by", "mammalian", "leucocytes", "and", "show", "an", "antimicrobial", "activity", "against", "bacteria,", "fungi,", "protozoa,", "and", "enveloped", "viruses.", "With", "regard", "to", "the", "mode", "of", "action", "of", "these", "peptides", "against", "chlamydiae,", "previous", "investigations", "on", "the", "activity", "of", "prote-", "grins", "[21]", "suggested", "an", "initial", "binding", "to", "lipopolysaccharide", "followed", "by", "insertion", "into", "the", "membrane", "that", "results", "in", "permeabilization.", "Yasin", "et", "al.", "[22]", "demonstrated", "that", "the", "antichlamydial", "activity", "of", "protegrins", "resided", "especially", "in", "residues", "5", "to", "15", "of", "native", "protegrin-1", "and", "required", "both", "intramolecular", "disulfide", "bonds.", "In", "the", "present", "study,", "we", "investigate", "the", "in", "vitro", "activity", "of", "six", "antimicrobial", "peptides", "against", "the", "reference", "strain", "Z", "of", "S.", "negevensis.", "2.", "Materials", "and", "Methods", "The", "cathelicidin", "peptides—PG-1", "from", "pig,", "Bac7", "(1–35)", "from", "cattle,", "SMAP-29", "from", "sheep,", "LL-37", "from", "human,", "BMAP-", "27,", "and", "BMAP-28", "from", "cattle—were", "chemically", "synthesized,", "purified,", "characterized,", "and", "provided", "as", "lyophilized", "peptide,", "as", "previously", "reported", "[19].", "The", "reference", "strain", "Z", "of", "S.", "negevensis", "(American", "Type", "Culture", "Collection", "VR-1471)", "was", "grown", "in", "LLC-MK2", "cells", "[23]", "in", "6-large", "well", "plates", "and", "elementary", "bodies", "(EBs)", "were", "purified", "by", "use", "of", "sucrose", "gradients", "[24],", "resuspended", "in", "sucrose-phosphate-glutamic" ]

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[ "Pearls", "A", "Population", "Genomics", "Perspective", "on", "the", "Emergence", "and", "Adaptation", "of", "New", "Plant", "Pathogens", "in", "Agro-", "Ecosystems", "Eva", "H.", "Stukenbrock1*,", "Thomas", "Bataillon2", "1", "Max", "Planck", "Institute", "for", "Terrestrial", "Microbiology,", "Marburg,", "Germany,", "2", "Bioinformatics", "Research", "Center,", "Aarhus", "University,", "Aarhus", "C,", "Denmark", "Plants", "and", "pathogens", "evolve", "in", "response", "to", "each", "other.", "This", "co-", "evolutionary", "arms", "race", "is", "fueled", "by", "genetic", "variation", "underlying", "the", "recognition", "of", "pathogen", "proteins", "by", "the", "host", "and", "the", "defeat", "of", "host", "defenses", "by", "the", "pathogen.", "Together", "with", "new", "mutations,", "genetic", "diversity", "in", "populations", "of", "both", "the", "host", "and", "pathogen", "represent", "a", "pool", "of", "possible", "variants", "to", "maintain", "adaptation", "via", "natural", "selection.", "Drastic", "changes", "in", "genetic", "diversity", "in", "crop", "species", "have", "occurred", "as", "a", "consequence", "of", "domestication.", "Whether", "changes", "in", "the", "genetic", "composition", "of", "these", "host", "populations", "also", "have", "affected", "genetic", "diversity", "in", "pathogen", "species", "is,", "so", "far,", "poorly", "understood.", "Advances", "in", "comparative", "genomics", "and", "population", "genomic", "approaches", "open", "new", "avenues", "to", "study", "adaptive", "processes", "in", "plant", "pathogens", "and", "to", "infer", "the", "impact", "of", "agro-ecosystems", "on", "the", "evolution", "of", "pathogen", "populations.", "Here", "we", "summarize", "new", "insights", "gained", "from", "comparative", "genome", "studies", "and", "population", "genomics", "in", "host-pathogen", "systems.", "1.", "What", "Are", "the", "Evolutionary", "Consequences", "of", "Domestication", "in", "Crop", "Species?", "In", "the", "process", "of", "domestication,", "crop", "species", "have", "undergone", "striking", "changes", "in", "both", "morphology", "and", "physiology.", "At", "the", "genetic", "level,", "these", "phenotypic", "changes", "have", "been", "brought", "by", "strong", "directional", "selection", "on", "a", "few", "genes", "[1].", "Genome-wide", "analyses", "of", "domesticated", "crop", "species", "and", "their", "wild", "relatives", "have", "provided", "new", "insights", "into", "the", "evolutionary", "consequences", "of", "domestication.", "While", "only", "a", "modest,", "yet", "growing,", "number", "of", "genes", "associated", "with", "domestication", "have", "been", "identified", "[2–4],", "genome-", "wide", "‘‘footprints’’", "of", "domestication", "are", "well", "documented", "in", "several", "crop", "species", "[5–8].", "Most", "notably", "the", "level", "of", "genetic", "variation", "has", "been", "dramatically", "reduced", "in", "many", "domesticated", "species", "relative", "to", "their", "wild", "ancestors", "[1].", "This", "is", "best", "explained", "by", "intense", "selection", "on", "a", "small", "subset", "of", "genotypes", "exhibiting", "desirable", "phenotypes.", "Such", "strong", "directional", "selection", "also", "entails", "a", "number", "of", "important", "evolutionary", "side", "effects.", "First,", "genetic", "diversity", "can", "be", "swept", "away", "in", "genomic", "regions", "flanking", "strongly", "selected", "domestication", "genes", "[9].", "Second,", "strong", "selection", "on", "one", "gene", "can", "reduce", "the", "efficacy", "of", "selection", "at", "neighboring", "loci,", "which,", "in", "return,", "may", "lead", "to", "an", "accumulation", "of", "slightly", "deleterious", "mutations.", "This", "process", "was", "first", "documented", "as", "an", "accumulation", "of", "non-synonymous", "mutations", "in", "Asian", "rice", "[5]", "and", "has", "since", "been", "termed", "the", "‘‘cost’’", "of", "domestication", "(see,", "e.g.,", "[1,10]).", "The", "loss", "of", "variation", "and", "the", "cost", "of", "domestication", "in", "genomes", "of", "crop", "species", "may", "compromise", "the", "level", "of", "natural", "defenses", "against", "pathogens", "and", "render", "them", "more", "susceptible", "than", "their", "wild", "relatives.", "2.", "How", "Does", "the", "Agro-Ecosystem", "Affect", "Evolution", "of", "Plant", "Pathogens?", "Agro-ecosystems", "brought", "by", "domestication", "have", "favored", "the", "emergence", "and", "specialization", "of", "new", "pathogen", "species", "by", "providing", "a", "new", "ecological", "niche.", "High", "densities", "of", "host", "individuals,", "genetic", "homogeneity", "of", "host", "populations,", "and", "recently", "the", "facilitated", "long", "distance", "dispersal", "of", "propagules", "by", "anthropo-", "genic", "activities", "are", "factors", "that", "are", "greatly", "conducive", "for", "the", "propagation", "of", "pathogens", "in", "agro-ecosystems", "[11].", "However,", "successful", "propagation", "in", "the", "field", "also", "poses", "challenges", "for", "pathogens:", "the", "new", "agricultural", "environment", "imposes", "strong", "directional", "selection", "on", "the", "pathogen", "genome,", "notably", "on", "genes", "controlling", "the", "defeat", "of", "crop", "resistance", "genes", "and", "resistance", "towards", "pesticides.", "Speciation", "in", "an", "agricultural", "environment", "can", "also", "have", "drastic", "implications", "for", "the", "population", "biology", "of", "pathogens", "as", "exemplified", "by", "the", "potato", "late", "blight", "pathogen", "Phythophthora", "infestans", "[12],", "the", "rice", "blast", "pathogen", "Magnaporthe", "oryzae", "[13],", "and", "the", "yellow", "rust", "pathogen", "Puccinia", "striiformis", "[14].", "The", "emergence", "of", "these", "three", "species", "was", "associated", "with", "a", "strong", "reduction", "in", "sexual", "recombination", "and", "the", "spread", "of", "only", "few", "specialized", "clonal", "lineages.", "Notably,", "genetic", "diversity", "among", "‘‘domesticated’’", "asexual", "pathogen", "lineages", "was", "significantly", "reduced", "compared", "to", "their", "wild", "relatives.", "However,", "even", "when", "sexual", "recombination", "is", "maintained", "in", "the", "pathogen,", "the", "transition", "to", "an", "agricultural", "host", "can", "entail", "founder", "events", "where", "substantial", "genetic", "variation", "is", "lost.", "Comparisons", "of", "levels", "of", "genetic", "diversity", "in", "pathogens", "occurring", "on", "domesticated", "versus", "non-cultivated", "hosts", "have", "confirmed", "this", "hypothesis", "[15,16].", "Substantial", "loss", "of", "genetic", "diversity", "is", "often", "associated", "with", "speciation", "and", "speciali-", "zation", "to", "a", "crop", "host,", "yet", "several", "studies", "report", "rapid", "emergence", "and", "adaptation", "of", "plant", "pathogens", "to", "crop", "species", "[17].", "This", "states", "the", "paradox", "that", "despite", "relatively", "modest", "levels", "of", "genetic", "variation,", "pathogen", "populations", "can", "readily", "adapt", "to", "agro-", "ecosystems", "and", "rapidly", "respond", "to", "new", "introduced", "resistance", "genes,", "fungicides,", "and", "other", "disease", "control", "agents.", "3.", "How", "Have", "Plant", "Pathogens", "Emerged", "in", "Agro-", "Ecosystems?", "Comparative", "genomics", "and", "population", "genomic", "analyses", "have", "provided", "new", "insights", "into", "genome", "evolution,", "speciation,", "and", "the", "Citation:", "Stukenbrock", "EH,", "Bataillon", "T", "(2012)", "A", "Population", "Genomics", "Perspective", "on", "the", "Emergence", "and", "Adaptation", "of", "New", "Plant", "Pathogens", "in", "Agro-", "Ecosystems.", "PLoS", "Pathog", "8(9):", "e1002893.", "doi:10.1371/journal.ppat.1002893", "Editor:", "Joseph", "Heitman,", "Duke", "University", "Medical", "Center,", "United", "States", "of", "America", "Published", "September", "27,", "2012", "Copyright:", "2012", "Stukenbrock,", "Bataillon.", "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", "authors", "received", "no", "specific", "funding", "for", "this", "study.", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "*", "E-mail:", "eva.stukenbrock@mpi-marburg.mpg.de", "PLOS", "Pathogens", "|", "www.plospathogens.org", "1", "September", "2012", "|", "Volume", "8", "|", "Issue", "9", "|", "e1002893" ]

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[ "Research", "Creatinine,", "Diet,", "Micronutrients,", "and", "Arsenic", "Methylation", "in", "West", "Bengal,", "India", "Arin", "Basu,1,2", "Soma", "Mitra,3", "Joyce", "Chung,1,4", "D.N.", "Guha", "Mazumder,5", "Nilima", "Ghosh,5", "David", "Kalman,6", "Ondine", "S.", "von", "Ehrenstein,1,7", "Craig", "Steinmaus,1,8", "Jane", "Liaw,1", "and", "Allan", "H.", "Smith1", "1Arsenic", "Health", "Effects", "Research", "Group,", "School", "of", "Public", "Health,", "University", "of", "California,", "Berkeley,", "California,", "USA;", "2Health", "Sciences", "Centre,", "University", "of", "Canterbury,", "Christchurch,", "New", "Zealand;", "3School", "of", "Human", "Sciences,", "London", "Metropolitan", "University,", "London,", "United", "Kingdom;", "4Veteran’s", "Administration,", "Palo", "Alto", "Health", "Care", "System,", "Palo", "Alto,", "California,", "USA;", "5Department", "of", "Gastroenterology,", "Institute", "of", "Post", "Graduate", "Medical", "Education", "and", "Research,", "Kolkata,", "India;", "6Department", "of", "Environmental", "Health,", "University", "of", "Washington,", "Seattle,", "Washington,", "USA;", "7School", "of", "Public", "Health,", "University", "of", "California,", "Los", "Angeles,", "California,", "USA;", "8Office", "of", "Environmental", "Health", "Hazard", "Assessment,", "California", "Environmental", "Protection", "Agency,", "Oakland,", "California,", "USA", "Background", ":", "Ingested", "inorganic", "arsenic", "(InAs)", "is", "methylated", "to", "monomethylated", "(MMA)", "and", "dimethylated", "metabolites", "(DMA).", "Methylation", "may", "have", "an", "important", "role", "in", "arsenic", "toxicity,", "because", "the", "monomethylated", "trivalent", "metabolite", "[MMA(III)]", "is", "highly", "toxic.", "o", "Bjectivs", ":", "We", "assessed", "the", "relationship", "of", "creatinine", "and", "nutrition—using", "dietary", "intake", "and", "blood", "concentrations", "of", "micronutrients—with", "arsenic", "metabolism,", "as", "reflected", "in", "the", "proportions", "of", "InAS,", "MMA,", "and", "DMA", "in", "urine,", "in", "the", "first", "study", "that", "incorporated", "both", "dietary", "and", "micro­", "nutrient", "data.", "Methods", ":", "We", "studied", "methylation", "patterns", "and", "nutritional", "factors", "in", "405", "persons", "who", "were", "selected", "from", "a", "cross­sectional", "survey", "of", "7", ",638", "people", "in", "an", "arsenic­exposed", "population", "in", "West", "Bengal,", "India.", "We", "assessed", "associations", "of", "urine", "creatinine", "and", "nutritional", "factors", "(19", "dietary", "intake", "variables", "and", "16", "blood", "micronutrients)", "with", "arsenic", "metabolites", "in", "urine.", "r", "esult", ":", "Urinary", "creatinine", "had", "the", "strongest", "relationship", "with", "overall", "arsenic", "methylation", "to", "DMA.", "Those", "with", "the", "highest", "urinary", "creatinine", "concentrations", "had", "7.2%", "more", "arsenic", "as", "DMA", "compared", "with", "those", "with", "low", "creatinine", "(p", "<", "0.001).", "Animal", "fat", "intake", "had", "the", "strongest", "relation­", "ship", "with", "MMA%", "(highest", "tertile", "animal", "fat", "intake", "had", "2.3%", "more", "arsenic", "as", "MMA,", "p", "<", "0.001).", "Low", "serum", "selenium", "and", "low", "folate", "were", "also", "associated", "with", "increased", "MMA%.", "c", "onclusion", ":", "Urine", "creatinine", "concentration", "was", "the", "strongest", "biological", "marker", "of", "arsenic", "methylation", "efficiency,", "and", "therefore", "should", "not", "be", "used", "to", "adjust", "for", "urine", "concentration", "in", "arsenic", "studies.", "hTe", "new", "finding", "that", "animal", "fat", "intake", "has", "a", "positive", "relationship", "with", "MMA%", "warrants", "further", "assessment", "in", "other", "studies.", "Increased", "MMA%", "was", "also", "associated,", "to", "a", "lesser", "extent,", "with", "low", "serum", "selenium", "and", "folate.", "k", "ey", "words", ":", "arsenic,", "creatinine,", "diet,", "India,", "methylation,", "micronutrients,", "West", "Bengal.", "Environ", "Health", "Perspect", "119:1308–1313", "(2011).", "http://dx.doi.org/10.1289/ehp.1003393", "[Online", "7", "June", "2011]", "to", "DMA(V)", "in", "a", "second", "methylation", "step", "then", "reduces", "toxicity.", "Epidemiological", "stud-", "ies", "have", "found", "evidence", "of", "increased", "risks", "of", "skin", "and", "bladder", "cancer", "among", "persons", "with", "higher", "proportions", "of", "MMA", "in", "their", "urine", "(Steinmaus", "et", "al.", "2003).", "Therefore,", "factors", "that", "influence", "arsenic", "methylation", "may", "be", "important", "determinants", "of", "susceptibility", "to", "health", "effects", "resulting", "from", "exposure", "to", "InAs", "in", "drinking", "water.", "We", "were", "also", "interested", "in", "urine", "creatinine,", "because", "it", "is", "frequently", "used", "to", "adjust", "for", "the", "concentration", "of", "urine,", "something", "that", "would", "introduce", "bias", "if", "creati-", "nine", "were", "related", "to", "arsenic", "methylation.", "Methods", "Study", "participants.", "This", "study", "involved", "405", "participants", "selected", "from", "a", "study", "base", "of", "7,683", "individuals", "living", "in", "the", "South", "24-Parganas", "district", "of", "West", "Bengal,", "India,", "who", "were", "identified", "in", "a", "1995", "through", "1996", "cross-sectional", "survey", "(Guha", "Mazumder", "et", "al.", "1998).", "Participants", "had", "been", "selected", "for", "a", "case–control", "study", "of", "skin", "lesions", "caused", "by", "arsenic", "involving", "192", "cases", "and", "213", "controls", "(Haque", "et", "al.", "2003),", "whose", "primary", "sources", "of", "drinking", "water", "contained", "<", "500", "µg/L", "InAs", "[n", "=", "4,185", "(2,160", "females", "and", "2,025", "males)].", "Cases", "had", "positive", "skin-lesion", "classifica-", "tions,", "with", "either", "hyperpigmentation", "(mot-", "tled,", "dark-brown", "pigmentation", "bilaterally", "distributed", "on", "the", "trunk),", "keratoses", "(diffuse", "thickening", "of", "palms", "or", "soles,", "with", "or", "with-", "out", "nodules),", "or", "both", "conditions", "at", "the", "time", "of", "the", "survey.", "Of", "the", "7,683", "individuals", "in", "the", "base", "population,", "we", "randomly", "selected", "controls", "from", "a", "subset", "of", "4,185", "individuals,", "with", "drinking", "water", "concentrations", "of", "arsenic", "<", "500", "µg/L;", "controls", "were", "matched", "to", "cases", "Address", "correspondence", "to", "A.H.", "Smith,", "Arsenic", "Health", "Effects", "Research", "Group,", "School", "of", "Public", "Health,", "University", "of", "California,", "Berkeley,", "50", "University", "Hall,", "MC", "7360,", "Berkeley,", "CA", "94720", "USA.", "Telephone:", "(510)", "843-1736.", "E-mail:", "ahsmith@", "berkeley.edu", "The", "authors", "gratefully", "acknowledge", "the", "assistance", "of", "C.", "Alston", "in", "preparation", "of", "this", "paper.", "United", "This", "work", "was", "supported", "by", "National", "Institutes", "of", "Health", "grants", "P42-ES04705", "and", "D43-TW000815", "and", "Nations", "Children’s", "Fund", "SSA/", "INDQ/2001/00003082-1.", "The", "authors", "declare", "they", "have", "no", "actual", "or", "potential", "competing", "financial", "interests.", "Received", "28", "December", "2010;", "accepted", "7", "June", "2011.", "ovlume", "119", "|", "number", "9", "|", "September", "2011", "•", "Environmental", "Health", "Perspectives", "Arsenic", "in", "drinking", "water", "is", "a", "major", "public", "health", "problem", "in", "the", "Bengal", "delta,", "affecting", "millions", "of", "people", "in", "the", "West", "Bengal", "state", "of", "India", "and", "adjoining", "areas", "in", "Bangladesh.", "In", "view", "of", "widespread", "poor", "nutrition", "prevalent", "in", "West", "Bengal", "and", "Bangladesh,", "it", "is", "important", "to", "identify", "dietary", "factors", "that", "might", "increase", "arse-", "nic", "toxicity", "or", "metabolism.", "We", "have", "already", "reported", "on", "the", "relationship", "of", "dietary", "constit-", "uents", "and", "blood", "micronutrients", "with", "arsenic-", "caused", "skin", "lesions", "in", "West", "Bengal", "(Chung", "et", "al.", "2006;", "Mitra", "et", "al.", "2004).", "Here,", "we", "report", "the", "findings", "concerning", "19", "dietary", "intake", "con-", "stituents,", "16", "blood", "micronutrients,", "and", "urine", "creatinine", "with", "arsenic", "methylation", "patterns", "in", "urine,", "in", "what", "we", "believe", "is", "the", "first", "com-", "prehensive", "joint", "assessment", "of", "dietary", "intake", "and", "micronutrients.", "For", "brevity,", "we", "refer", "to", "the", "dietary", "intake", "factors,", "along", "with", "the", "blood", "micronutrients,", "as", "“nutritional", "factors.”", "Nutritional", "factors", "may", "play", "important", "roles", "in", "methylation", "of", "inorganic", "arsenic", "(InAs),", "and", "the", "results", "of", "numerous", "studies", "have", "shown", "that", "methylation", "affects", "the", "toxicity", "of", "ingested", "InAs.", "In", "drinking", "water,", "InAs", "exists", "in", "trivalent", "[As(III)]", "and", "pentavalent", "[As(V)]", "forms.", "After", "ingestion,", "As(V)", "is", "reduced", "to", "1308", "As(III),", "followed", "by", "sequential", "methylation", "and", "reduction", "reaction", "steps", "resulting", "in", "for-", "mation", "of", "trivalent", "and", "pentavalent", "methylated", "arsenicals—first", "monomethyl", "acids", "[MMA(III)", "and", "MMA(V)]", "and", "subsequently", "trivalent", "and", "pentavalent", "dimethyl", "acids", "[DMA(III)", "and", "DMA(V),", "respectively.", "However,", "this", "process", "is", "incomplete,", "and", "populations", "show", "variations", "in", "the", "proportions", "of", "urinary", "InAs", "and", "the", "methylated", "arsenical", "compounds", "(Aposhian", "1997;", "Concha", "et", "al.", "2002;", "Drobna", "et", "al.", "2004;", "Healy", "et", "al.", "1997;", "Hopenhayn-Rich", "et", "al.", "1996a,", "1996b;", "Hopenhayn", "et", "al.", "2003;", "Hughes", "2002).", "I", "s", "o", "l", "a", "t", "i", "o", "n", "a", "n", "d", "c", "h", "a", "r", "a", "c", "t", "e", "r", "i", "z", "a", "t", "i", "o", "n", "o", "f", "MMA(III)", "indicates", "that", "the", "first", "step", "of", "methylation", "that", "produces", "MMA", "should", "be", "considered", "an", "activation", "step.", "Laboratory", "studies", "have", "shown", "that", "the", "trivalent", "forms", "of", "MMA", "and", "DMA", "are", "much", "more", "toxic", "than", "the", "pentavalent", "forms,", "and", "in", "vitro", "evidence", "suggests", "that", "MMA(III),", "in", "particular,", "may", "be", "more", "toxic", "than", "trivalent", "InAs", "[InAs(III)]", "(Cullen", "and", "Reimer", "1989;", "Lin", "et", "al.", "1999,", "2001;", "Mass", "et", "al.", "2001;", "Petrick", "et", "al.", "2000;", "Styblo", "et", "al.", "1999,", "2000;", "Styblo", "and", "Thomas", "1997).", "The", "conversion", "of", "MMA(III)" ]

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[ "Streptococcus", "pneumoniae", "in", "Biofilms", "Are", "Unable", "to", "Cause", "Invasive", "Disease", "Due", "to", "Altered", "Virulence", "Determinant", "Production", "Carlos", "J.", "Sanchez1,", "Nikhil", "Kumar2,", "Anel", "Lizcano", "1", ",", "Pooja", "Shivshankar1,", "Julie", "C.", "Dunning", "Hotopp", "2", ",", "James", "H.", "Jorgensen1,3,", "Herve´", "Tettelin2,", "Carlos", "J.", "Orihuela1*", "1", "Department", "of", "Microbiology", "and", "Immunology,", "The", "University", "of", "Texas", "Health", "Science", "Center", "at", "San", "Antonio,", "San", "Antonio,", "Texas,", "United", "States", "of", "America,", "2", "Department", "of", "Microbiology", "and", "Immunology,", "Institute", "for", "Genome", "Sciences,", "University", "of", "Maryland", "School", "of", "Medicine,", "Baltimore,", "Maryland,", "United", "States", "of", "America,", "3", "Department", "of", "Pathology,", "The", "University", "of", "Texas", "Health", "Science", "Center", "at", "San", "Antonio,", "San", "Antonio,", "Texas,", "United", "States", "of", "America", "Abstract", "It", "is", "unclear", "whether", "Streptococcus", "pneumoniae", "in", "biofilms", "are", "virulent", "and", "contribute", "to", "development", "of", "invasive", "pneumococcal", "disease", "(IPD).", "Using", "electron", "microscopy", "we", "confirmed", "the", "development", "of", "mature", "pneumococcal", "biofilms", "in", "a", "continuous-flow-through", "line", "model", "and", "determined", "that", "biofilm", "formation", "occurred", "in", "discrete", "stages", "with", "mature", "biofilms", "composed", "primarily", "of", "dead", "pneumococci.", "Challenge", "of", "mice", "with", "equal", "colony", "forming", "units", "of", "biofilm", "and", "planktonic", "pneumococci", "determined", "that", "biofilm", "bacteria", "were", "highly", "attenuated", "for", "invasive", "disease", "but", "not", "nasopharyngeal", "colonization.", "Biofilm", "pneumococci", "of", "numerous", "serotypes", "were", "hyper-adhesive", "and", "bound", "to", "A549", "type", "II", "pneumocytes", "and", "Detroit", "562", "pharyngeal", "epithelial", "cells", "at", "levels", "2", "to", "11-fold", "greater", "than", "planktonic", "counterparts.", "Using", "genomic", "microarrays", "we", "examined", "the", "pneumococcal", "transcriptome", "and", "determined", "that", "during", "biofilm", "formation", "S.", "pneumoniae", "down-regulated", "genes", "involved", "in", "protein", "synthesis,", "energy", "production,", "metabolism,", "capsular", "polysaccharide", "(CPS)", "production,", "and", "virulence.", "We", "confirmed", "these", "changes", "by", "measuring", "CPS", "by", "ELISA", "and", "immunoblotting", "for", "the", "toxin", "pneumolysin", "and", "the", "bacterial", "adhesins", "phosphorylcholine", "(ChoP),", "choline-binding", "protein", "A", "(CbpA),", "and", "Pneumococcal", "serine-rich", "repeat", "protein", "(PsrP).", "We", "conclude", "that", "biofilm", "pneumococci", "were", "avirulent", "due", "to", "reduced", "CPS", "and", "pneumolysin", "production", "along", "with", "increased", "ChoP,", "which", "is", "known", "to", "bind", "C-reactive", "protein", "and", "is", "opsonizing.", "Likewise,", "biofilm", "pneumococci", "were", "hyper-adhesive", "due", "to", "selection", "for", "the", "transparent", "phase", "variant,", "reduced", "CPS,", "and", "enhanced", "production", "of", "PsrP,", "CbpA,", "and", "ChoP.", "These", "studies", "suggest", "that", "biofilms", "do", "not", "directly", "contribute", "to", "development", "of", "IPD", "and", "may", "instead", "confer", "a", "quiescent", "mode", "of", "growth", "during", "colonization.", "Citation:", "Sanchez", "CJ,", "Kumar", "N,", "Lizcano", "A,", "Shivshankar", "P,", "Dunning", "Hotopp", "JC,", "et", "al.", "(2011)", "Streptococcus", "pneumoniae", "in", "Biofilms", "Are", "Unable", "to", "Cause", "Invasive", "Disease", "Due", "to", "Altered", "Virulence", "Determinant", "Production.", "PLoS", "ONE", "6(12):", "e28738.", "doi:10.1371/journal.pone.0028738", "Editor:", "Indranil", "Biswas,", "University", "of", "Kansas", "Medical", "Center,", "United", "States", "of", "America", "Received", "June", "8,", "2011;", "Accepted", "November", "14,", "2011;", "Published", "December", "8,", "2011", "Copyright:", "2011", "Sanchez", "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", "National", "Institutes", "of", "Health", "grants", "DE14318", "to", "CJS", "and", "AI078972", "to", "CJO.", "Work", "completed", "by", "NK,", "JCDH", "and", "HT", "was", "supported", "by", "University", "of", "Maryland", "internal", "funds.", "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:", "orihuela@uthscsa.edu", "Introduction", "Streptococcus", "pneumoniae", "(the", "pneumococcus)", "is", "a", "leading", "cause", "of", "otitis", "media,", "community-acquired", "pneumonia,", "sepsis", "and", "menin-", "gitis.", "S.", "pneumoniae", "typically", "colonizes", "the", "human", "nasopharynx", "asymptomatically", "with", "invasive", "pneumococcal", "disease", "(IPD)", "occurring", "as", "a", "result", "of", "dissemination", "to,", "and", "bacterial", "replication", "at,", "normally", "sterile", "sites", "including", "the", "middle", "ear,", "lungs,", "and", "bloodstream.", "IPD", "is", "opportunistic", "in", "nature", "and", "primarily", "occurs", "in", "infants,", "the", "elderly,", "and", "those", "with", "underlying", "medical", "conditions", "[1,2,3,4].", "Worldwide", "the", "pneumococcus", "is", "responsible", "for", "more", "than", "14.5", "million", "episodes", "of", "IPD", "annually", "and", "up", "to", "11%", "of", "all", "deaths", "in", "children", "[5,6].", "Notably,", "in", "individuals", ".65", "years", "of", "age", "the", "case-fatality", "rate", "for", "IPD", "can", "be", "as", "high", "as", "30%", "[7].", "Thus", "pneumococcal", "infections", "are", "a", "major", "medical", "problem", "for", "both", "children", "and", "the", "elderly.", "S.", "pneumoniae", "biofilm", "formation", "has", "been", "shown", "to", "occur", "in", "humans", "during", "nasopharyngeal", "colonization", "and", "recurrent", "otitis", "media.", "Pneumococcal", "biofilms", "have", "been", "detected", "in", "human", "sinus", "mucosa", "biopsies,", "resected", "adenoids", "from", "individuals", "with", "tonsil-", "litis,", "and", "biofilms", "have", "been", "observed", "within", "tympanostomy", "tubes", "collected", "from", "children", "with", "chronic", "otitis", "media", "[8,9].", "Fulfilling", "Koch’s", "postulates,", "biofilms", "and", "biofilm-like", "pneumococcal", "aggre-", "gates", "have", "been", "observed", "in", "the", "middle", "ears", "of", "experimentally", "infected", "chinchillas", "as", "well", "as", "bronchial", "and", "nasal", "lavage", "fluids", "taken", "from", "the", "nasopharynx", "of", "infected", "mice,", "respectively", "[10,11].", "Thus", "biofilm", "formation", "is", "a", "naturally", "occurring,", "if", "not", "yet", "fully", "understood,", "biological", "mechanism", "for", "S.", "pneumoniae.", "During", "the", "past", "10", "years", "considerable", "effort", "has", "gone", "towards", "dissecting", "the", "molecular", "mechanisms", "underlying", "biofilm", "develop-", "ment", "in", "vitro", "and", "its", "recalcitrance", "to", "antimicrobial", "therapy", "in", "vivo", "[12,13,14,15,16].", "Importantly,", "and", "despite", "these", "considerable", "findings,", "whether", "biofilm", "formation", "contributes", "towards", "the", "development", "of", "IPD", "remains", "unclear.", "For", "example,", "studies", "by", "Munoz-Elisa", "et", "al.,", "Parker", "et", "al.,", "and", "Trappetti", "et", "al.,", "indicate", "that", "genes", "required", "for", "robust", "biofilm", "formation", "in", "vitro", "are", "important", "for", "nasopharyngeal", "colonization", "and", "in", "some", "instances", "progression", "towards", "lung", "disease", "[15,17,18,19].", "In", "contrast,", "studies", "by", "PLoS", "ONE", "|", "www.plosone.org", "1", "December", "2011", "|", "Volume", "6", "|", "Issue", "12", "|", "e28738" ]

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[ "e", "n", "i", "c", "i", "d", "e", "M", "l", "a", "t", "n", "e", "m", "i", "r", "e", "p", "x", "E", "f", "o", "l", "a", "n", "r", "u", "o", "J", "e", "h", "T", "B", "R", "I", "E", "F", "D", "E", "F", "I", "N", "I", "T", "I", "V", "E", "R", "E", "P", "O", "RT", "Visualizing", "B", "cell", "capture", "of", "cognate", "antigen", "from", "follicular", "dendr", "itic", "cells", "Kazuhiro", "Suzuki,", "Irina", "Grigorova,", "Tri", "Giang", "Phan,", "Lisa", "M.", "Kelly,", "and", "Jason", "G.", "Cyster", "Howard", "Hughes", "Medical", "Institute", "and", "Department", "of", "Microbiology", "and", "Immunology,", "University", "of", "California,", "San", "Francisco,", "San", "Francisco,", "CA", "94143", "The", "prominent", "display", "of", "opsonized", "antigen", "by", "follicular", "dendritic", "cells", "(FDCs)", "has", "long", "favored", "the", "view", "that", "they", "serve", "as", "antigen-presenting", "cells", "for", "B", "cells.", "Surprisingly,", "how-", "ever,", "although", "B", "cell", "capture", "of", "antigen", "from", "macrophages", "and", "dendritic", "cells", "has", "been", "visualized,", "acquisition", "from", "FDCs", "has", "not", "been", "directly", "observed.", "Using", "two-photon", "micros-", "copy,", "we", "visualized", "B", "cell", "capture", "of", "cognate", "antigen", "from", "FDCs.", "B", "cell", "CXCR5", "expression", "was", "required,", "and", "encounter", "with", "FDC-associated", "antigen", "could", "be", "detected", "for", ">1", "wk", "after", "immunization.", "B", "cell–FDC", "contact", "times", "were", "often", "brief", "but", "occasionally", "persisted", "for", ">30", "min,", "and", "B", "cells", "sometimes", "acquired", "antigen", "together", "with", "FDC", "surface", "proteins.", "These", "observations", "establish", "that", "FDCs", "can", "serve", "as", "sites", "of", "B", "cell", "antigen", "capture,", "with", "their", "prolonged", "display", "time", "ensuring", "that", "even", "rare", "B", "cells", "have", "the", "chance", "of", "antigen", "encounter,", "and", "they", "suggest", "possible", "information", "transfer", "from", "antigen-presenting", "cell", "to", "B", "cell.", "CORRESPONDENCE", "Jason", "G.", "Cyster:", "Jason.Cyster@ucsf.edu", "Abbreviations:", "CFP,", "cyan", "fluo-", "rescent", "protein;", "CR,", "comple-", "ment", "receptor;", "DEL,", "duck", "egg", "lysozyme;", "FDC,", "follicular", "den-", "dritic", "cell;", "GC,", "germinal", "center;", "HEL,", "hen", "egg", "lysozyme;", "IC,", "immune", "complex;", "SA,", "strepta-", "vidin;", "SCS,", "subcapsular", "sinus", "macrophage;", "tg,", "transgenic.", "The", "Rockefeller", "University", "Press", "$30.00", "J.", "Exp.", "Med.", "Vol.", "206", "No.", "7", "1485-1493", "www.jem.org/cgi/doi/10.1084/jem.20090209", "B", "cells", "must", "encounter", "intact", "antigen", "to", "mount", "humoral", "immune", "responses.", "At", "any", "one", "time,", "most", "B", "cells", "in", "the", "body", "are", "situated", "inside", "lym-", "phoid", "follicles", "of", "spleen,", "LNs,", "and", "mucosal", "lym-", "phoid", "tissues,", "sites", "which", "are", "shielded", "from", "direct", "access", "to", "most", "fluid-borne", "antigens.", "Some", "40", "yr", "ago,", "antigen-tracking", "studies", "showed", "that", "opsonized", "antigens", "became", "distributed", "inside", "lymphoid", "follicles", "in", "a", "reticular", "fashion,", "and", "this", "led", "to", "studies", "identifying", "and", "characterizing", "follicular", "dendritic", "cells", "(FDCs)", "as", "the", "special-", "ized", "antigen-trapping", "cells", "within", "follicles", "(Nossal", "et", "al.,", "1964;", "Szakal", "et", "al.,", "1989).", "FDCs", "express-", "ing", "complement", "receptor", "(CR)", "1", "and", "CR2", "are", "present", "within", "primary", "follicles,", "whereas", "the", "FDCs", "within", "germinal", "center", "(GC)", "light", "zones", "express", "additional", "surface", "markers", "including", "FcRIIb", "(Szakal", "et", "al.,", "1989;", "Allen", "and", "Cyster,", "2008).", "FDCs", "also", "express", "the", "integrin", "ligands", "ICAM-1,", "VCAM-1,", "and", "MAdCAM-1", "(Szakal", "et", "al.,", "1989;", "Allen", "and", "Cyster,", "2008).", "Follicular", "stromal", "cells,", "including", "FDCs,", "are", "a", "source", "of", "the", "chemokine", "CXCL13,", "and", "migration", "of", "B", "cells", "into", "lymphoid", "follicles", "depends", "on", "expression", "of", "the", "CXCL13", "receptor", "CXCR5", "(Allen", "and", "Cyster,", "2008).", "Despite", "the", "long", "period", "of", "study,", "the", "sites", "of", "first", "encounter", "between", "B", "cells", "and", "antigen", "have", "only", "recently", "been", "visualized.", "Three", "studies", "T.G.", "Phan’s", "present", "address", "is", "Garvan", "Institute", "of", "Medical", "Research,", "Sydney", "NSW", "2010,", "Australia", "identified", "subcapsular", "sinus", "macrophages", "(SCSs)", "in", "LNs", "as", "an", "important", "site", "of", "cognate", "encoun-", "ter", "with", "particulate", "antigen", "in", "the", "first", "hours", "of", "the", "response", "(Carrasco", "and", "Batista,", "2007;", "Junt", "et", "al.,", "2007;", "Phan", "et", "al.,", "2007).", "It", "was", "also", "shown", "that", "noncognate", "B", "cells", "could", "capture", "opsonized", "antigen", "via", "CR1/2,", "and", "these", "cells", "delivered", "the", "antigen", "to", "FDCs", "(Phan", "et", "al.,", "2007).", "Another", "study", "used", "a", "model", "system", "to", "demonstrate", "B", "cell", "antigen", "capture", "from", "T", "zone", "dendritic", "cells", "dur-", "ing", "entry", "into", "LNs", "(Qi", "et", "al.,", "2006).", "In", "two", "fur-", "ther", "studies,", "follicular", "B", "cell", "antigen", "encounter", "with", "a", "small", "(14", "kD)", "soluble", "protein", "antigen", "appeared", "to", "occur", "by", "free", "diffusion", "of", "the", "anti-", "gen", "into", "the", "follicle", "(Pape", "et", "al.,", "2007)", "or", "after", "traveling", "via", "follicular", "conduits", "(Roozendaal", "et", "al.,", "2009).", "Given", "these", "advances,", "the", "lack", "of", "in", "vivo", "data", "on", "B", "cell", "antigen", "capture", "from", "FDCs", "is", "a", "notable", "omission.", "In", "vitro", "studies", "demonstrated", "that", "B", "cell", "activation", "by", "immune", "complexes", "(ICs)", "is", "enhanced", "when", "they", "are", "encountered", "in", "the", "presence", "of", "FDCs", "(Wu", "et", "al.,", "2008).", "Two-", "photon", "microscopy", "of", "GCs", "showed", "B", "cell", "mi-", "gration", "in", "close", "association", "with", "GC", "FDCs,", "but", "these", "studies", "did", "not", "use", "fluorescently", "labeled", "antigens", "and", "could", "not", "track", "antigen", "capture", "©", "2009", "Suzuki", "et", "al.", "This", "article", "is", "distributed", "under", "the", "terms", "of", "an", "Attribu-", "tion–Noncommercial–Share", "Alike–No", "Mirror", "Sites", "license", "for", "the", "first", "six", "months", "after", "the", 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[ "Stress", "Activated", "Protein", "Kinase", "Pathway", "Modulates", "Homologous", "Recombination", "in", "Fission", "Yeast", "Angela", "Bellini1,2,", "Pierre-Marie", "Girard1,2,", "Sarah", "Lambert1,2,", "Ludovic", "Tessier1,2,", "Evelyne", "Sage1,2,", "Stefania", "Francesconi1,2*", "1", "Institut", "Curie,", "Centre", "de", "Recherche,", "Orsay,", "France,", "2", "CNRS", "UMR", "3348,", "Centre", "Universitaire,", "Orsay,", "France", "Abstract", "Rad52", "is", "a", "key", "player", "in", "homologous", "recombination", "(HR),", "a", "DNA", "repair", "pathway", "that", "is", "dedicated", "to", "double", "strand", "breaks", "repair", "and", "recovery", "of", "perturbed", "replication", "forks.", "Here", "we", "show", "that", "fission", "yeast", "Rad52", "homologue", "is", "phosphorylated", "when", "S", "phase", "cells", "are", "exposed", "to", "ROS", "inducers", "such", "as", "ultraviolet", "A", "radiation", "or", "hydrogen", "peroxide,", "but", "not", "to", "ultraviolet", "C", "or", "camptothecin.", "Phosphorylation", "does", "not", "depend", "on", "kinases", "Chk1,", "Rad3,", "Tel1", "or", "Cdc2,", "but", "depends", "on", "a", "functional", "stress", "activated", "protein", "kinase", "(SAPK)", "pathway", "and", "can", "be", "partially", "prevented", "by", "anti-oxidant", "treatment.", "Indeed,", "cells", "lacking", "Sty1,", "the", "major", "fission", "yeast", "MAP", "kinase", "of", "the", "SAPK", "pathway,", "do", "not", "display", "Rad52", "phosphorylation", "and", "have", "UVA", "induced", "Rad52", "foci", "that", "persist", "longer", "if", "compared", "to", "wild", "type", "cells.", "In", "addition,", "spontaneous", "intrachromosomal", "HR", "is", "diminished", "in", "cells", "lacking", "Sty1", "and,", "more", "precisely,", "gene", "conversion", "is", "affected.", "Moreover,", "HR", "induced", "by", "site-specific", "arrest", "of", "replication", "forks", "is", "twice", "less", "efficient", "in", "cells", "that", "do", "not", "express", "Sty1.", "Importantly,", "impairing", "HR", "by", "deletion", "of", "the", "gene", "encoding", "the", "recombinase", "Rhp51", "leads", "to", "Sty1", "dependent", "Rad52", "phosphorylation.", "Thus,", "SAPK", "pathway", "impinges", "on", "early", "step", "of", "HR", "through", "phosphorylation", "of", "Rad52", "in", "cells", "challenged", "by", "oxidative", "stress", "or", "lacking", "Rhp51", "and", "is", "required", "to", "promote", "spontaneous", "gene", "conversion", "and", "recovery", "from", "blocked", "replication", "forks.", "Citation:", "Bellini", "A,", "Girard", "P-M,", "Lambert", "S,", "Tessier", "L,", "Sage", "E,", "et", "al.", "(2012)", "Stress", "Activated", "Protein", "Kinase", "Pathway", "Modulates", "Homologous", "Recombination", "in", "Fission", "Yeast.", "PLoS", "ONE", "7(10):", "e47987.", "doi:10.1371/journal.pone.0047987", "Editor:", "Marco", "Muzi-Falconi,", "Universita’", "di", "Milano,", "Italy", "Received", "June", "13,", "2012;", "Accepted", "September", "19,", "2012;", "Published", "October", "31,", "2012", "Copyright:", "2012", "Bellini", "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", "‘‘Centre", "National", "de", "la", "Recherche", "Scientifique’’", "and", "Curie", "Institute.", "A.", "Bellini", "was", "supported", "by", "PhD", "fellowships", "from", "Curie", "Institute", "and", "‘‘Association", "pour", "la", "Recherche", "sur", "le", "Cancer’’.", "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:", "stefania.francesconi@curie.fr", "Introduction", "UVA", "radiation", "is", "the", "most", "abundant", "solar", "UV", "radiation", "that", "reaches", "earth’s", "surface.", "UVA", "is", "able", "to", "penetrate", "human", "skin", "deeper", "than", "UVB", "and", "reaches", "the", "basal", "layer", "of", "skin", "where", "actively", "replicating", "keratinocytes", "are", "present.", "Different", "from", "UVB,", "UVA", "is", "weakly", "absorbed", "by", "DNA", "and", "mainly", "acts", "through", "interaction", "with", "endogenous", "photosensitizers", "resulting", "in", "genera-", "tion", "of", "reactive", "oxygen", "species", "(ROS),", "predominantly", "singlet", "oxygen,", "which", "can", "damage", "all", "cellular", "components", "[1,2,3].", "UVA", "induced", "ROS", "have", "been", "linked", "to", "skin", "photoaging", "[4]", "and", "increasing", "evidence", "suggest", "contribution", "to", "skin", "carcinogenesis", "[5].", "More", "generally,", "ROS-induced", "cellular", "damage", "is", "linked", "to", "pathological", "conditions", "such", "as", "cancer,", "diabetes,", "atherosclerosis,", "neurodegenerative", "diseases", "and", "premature", "aging", "[6,7,8,9,10].", "Because", "UVA", "induced", "biological", "effects", "are", "oxygen", "dependent,", "UVA", "is", "an", "inducer", "of", "oxidative", "stress", "and", "thus,", "cellular", "response", "to", "this", "radiation", "is", "complex.", "As", "many", "stresses,", "UVA-induced", "oxidative", "stress", "activates", "the", "SAPK", "pathways", "that", "are", "character-", "ized", "by", "a", "cascade", "of", "kinases", "highly", "conserved:", "MAPK", "(mitogen", "activated", "protein", "kinase)", "kinase", "kinases", "(MAPKKK),", "MAPK", "kinases", "(MAPKK)", "and", "MAPKs.", "Eventually,", "activation", "of", "SAPK", "pathways", "results", "in", "protection", "of", "cells", "from", "injuries", "through", "appropriate", "regulation", "of", "gene", "expression", "and", "protein", "translation", "[11,12].", "In", "human", "keratinocytes", "the", "p38", "MAP", "kinase", "and", "JNK", "(c-", "Jun", "N-terminal", "kinase)", "pathways", "are", "activated", "by", "UVA", "radiation", "[13].", "In", "Schizosaccharomyces", "pombe", "(S.", "pombe),", "Sty1/Spc1", "is", "the", "principal", "MAPK,", "mainly", "related", "to", "human", "p38,", "which", "is", "activated", "by", "phosphorylation", "following", "a", "variety", "of", "stresses", "including", "high", "osmolarity,", "oxidative", "stress,", "UVC", "exposure", "[14,15]", "and", "metabolic", "inputs", "such", "as", "calorie", "restriction", "and", "histidine", "starvation,", "two", "situations", "generating", "endogenous", "oxidative", "stress", "[16,17].", "Sty1", "is", "also", "required", "for", "sexual", "differentiation", "by", "regulating", "Ste11", "expression,", "the", "major", "transcription", "factor", "required", "to", "induce", "meiotic", "genes", "[18].", "Activation", "of", "Sty1", "results", "in", "its", "nuclear", "localization", "and", "induction", "of", "gene", "expression", "mainly", "through", "the", "Atf1", "transcription", "factor.", "Such", "modulation", "of", "the", "gene", "expression", "program", "will", "provide", "cells", "with", "the", "necessary", "to", "face", "stress", "[19].", "Furthermore,", "Sty1,", "but", "not", "its", "major", "target", "Atf1,", "controls", "mitotic", "entry", "upon", "nutritional", "stress", "[20,21].", "However,", "different", "degrees", "of", "Sty1", "activation", "impact", "on", "mitotic", "commitment", "in", "opposite", "ways:", "basal", "level", "of", "Sty1", "activity", "promotes", "mitotic", "onset", "while", "high", "level", "of", "Sty1", "activity", "delays", "mitotic", "entry", "[22].", "This", "function", "is", "also", "conserved", "in", "mammals", "where", "the", "extracellular", "signal-related", "kinase", "(ERK)", "is", "required", "for", "mitotic", "entry", "and", "p38", "activation", "by", "stress", "is", "required", "for", "mitotic", "delay", "[23,24,25].", "In", "addition,", "different", "ways", "of", "Sty1", "activation", "according", "to", "the", "stimulus", "applied", "have", "been", "reported,", "implying", "that", "Sty1,", "similarly", "to", "mammalian", "SAPKs,", "is", "finely", "tuned", "in", "the", "cell", "[26,27,28].", "Nowadays,", "it", "is", "well", "established", "that", "UVA", "solar", "radiation", "is", "a", "biological", "relevant", "genotoxic", "agent", "[29].", "At", "the", "DNA", "level", "UVA", "induces", "formation", "of", "oxidized", "bases,", "mainly", "8-oxoguanine", "(8-", "PLOS", "ONE", "|", "www.plosone.org", "1", "October", "2012", "|", "Volume", "7", "|", "Issue", "10", "|", "e47987" ]

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[ "Hindawi", "Publishing", "Corporation", "Cardiology", "Research", "and", "Practice", "Volume", "2012,", "Article", "ID", "823193,", "11", "pages", "doi:10.1155/2012/823193", "Review", "Article", "Targeting", "the", "ACE2", "and", "Apelin", "Pathways", "Are", "Novel", "Therapies", "for", "Heart", "Failure:", "Opportunities", "and", "Challenges", "Seyyed", "M.", "R.", "Kazemi-Bajestani,1,", "2", "Vaibhav", "B.", "Patel,1,", "3", "Wang", "Wang,1,", "2", "and", "Gavin", "Y.", "Oudit1,", "2,", "3", "1", "Mazankowski", "Alberta", "Heart", "Institute,", "University", "of", "Alberta,", "Edmonton,", "AB,", "Canada", "T6G", "2S2", "2", "Department", "of", "Physiology,", "University", "of", "Alberta,", "Edmonton,", "AB,", "Canada", "T6G", "2H7", "3", "Division", "of", "Cardiology,", "Department", "of", "Medicine,", "University", "of", "Alberta,", "Edmonton,", "AB,", "Canada", "T6G", "2G3", "Correspondence", "should", "be", "addressed", "to", "Gavin", "Y.", "Oudit,", "gavin.oudit@ualberta.ca", "Received", "12", "December", "2011;", "Accepted", "21", "February", "2012", "Academic", "Editor:", "Gregory", "Giamouzis", "Copyright", "©", "2012", "Seyyed", "M.", "R.", "Kazemi-Bajestani", "et", "al.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Angiotensin-converting", "enzyme", "2", "(ACE2)/Ang", "II/Ang", "1–7", "and", "the", "apelin/APJ", "are", "two", "important", "peptide", "systems", "which", "exert", "diverse", "effects", "on", "the", "cardiovascular", "system.", "ACE2", "is", "a", "key", "negative", "regulator", "of", "the", "renin-angiotensin", "system", "(RAS)", "where", "it", "metab-", "olizes", "angiotensin", "(Ang)", "II", "into", "Ang", "1–7,", "an", "endogenous", "antagonist", "of", "Ang", "II.", "Both", "the", "prolonged", "activation", "of", "RAS", "and", "the", "loss", "of", "ACE2", "can", "be", "detrimental", "as", "they", "lead", "to", "functional", "deterioration", "of", "the", "heart", "and", "progression", "of", "cardiac,", "renal,", "and", "vascular", "dis-", "eases.", "Recombinant", "human", "ACE2", "in", "an", "animal", "model", "of", "ACE2", "knockout", "mice", "lowers", "Ang", "II.", "These", "interactions", "neutralize", "the", "pres-", "sor", "and", "subpressor", "pathologic", "effects", "of", "Ang", "II", "by", "producing", "Ang", "1–7", "levels", "in", "vivo,", "that", "might", "be", "cardiovascular", "protective.", "ACE2", "hydrolyzes", "apelin", "to", "Ang", "II", "and,", "therefore,", "is", "responsible", "for", "the", "degradation", "of", "both", "peptides.", "Apelin", "has", "emerged", "as", "a", "promising", "peptide", "biomarker", "of", "heart", "failure.", "The", "serum", "level", "of", "apelin", "in", "cardiovascular", "diseases", "tends", "to", "be", "decreased.", "Apelin", "is", "recognized", "as", "an", "imperative", "controller", "of", "systemic", "blood", "pressure", "and", "myocardium", "contractility.", "Dysregulation", "of", "the", "apelin/APJ", "system", "may", "be", "involved", "in", "the", "predisposition", "to", "cardiovascular", "diseases,", "and", "enhancing", "apelin", "action", "may", "have", "important", "therapeutic", "effects.", "1.", "Introduction", "Angiotensin-converting", "enzyme", "2", "(ACE2)/Ang", "II/Ang", "1–7", "and", "apelin/APJ", "are", "two", "important", "peptide", "systems", "with", "diverse", "and", "fundamental", "cardiovascular", "protective", "effects", "that", "may", "prevent", "or", "reverse", "a", "variety", "of", "vascular", "and", "cardiac", "disorders", "[1–3].", "ACE2", "is", "a", "monocarboxypeptidase", "which", "effectively", "plays", "a", "key", "role", "as", "the", "central", "negative", "regulator", "of", "the", "renin-angiotensin", "system", "(RAS).", "ACE2", "is", "of", "particular", "interest", "because", "it", "is", "an", "essential", "component", "of", "RAS", "which", "is", "possibly", "implicated", "in", "metabolizing", "angiotensin", "(Ang)", "II", "into", "Ang", "1–7", "[4].", "These", "interactions", "counteract", "the", "pathologic", "effects", "of", "Ang", "II", "by", "producing", "Ang", "1–7,", "that", "is", "known", "to", "be", "cardiovascular", "protective.", "Ang", "II", "impairs", "cardiovascular", "function", "and", "enhances", "pressor", "and", "subpressor", "pathologic", "consequences,", "and", "hence", "Ang", "1–7", "protects", "against", "these", "pathological", "processes", "[1,", "2].", "Apelin", "is", "an", "endogenous", "peptide", "that", "is", "widely", "expressed", "in", "various", "organs", "as", "a", "77", "amino", "acid", "preproapelin.", "Several", "active", "fragments", "of", "apelin", "have", "been", "known", "(apelin-36,", "apelin-19,", "apelin-17,", "apelin-16,", "apelin-13,", "and", "apelin-12)", "which", "relatively", "share", "similar", "biological", "activities.", "In", "addition", "to", "the", "possibility", "of", "application", "of", "apelin", "as", "a", "heart", "failure", "(HF)", "biomarker,", "apelin", "also", "has", "direct", "biological", "effects", "including", "vasodilatory", "and", "inotropic", "effects", "[5].", "Several", "previous", "studies", "have", "shown", "the", "cardioprotective", "effect", "of", "ACE2", "and", "apelin", "in", "all", "three", "steps", "of", "primary,", "secondary", "and", "tertiary", "prevention", "of", "HF", "(Figures", "1", "and", "2).", "In", "this", "paper", "we", "summarize", "the", "current", "literature", "regarding", "the", "cardiovascu-", "lar", "effects", "of", "ACE2", "and", "apelin", "and", "their", "possible", "therapeutic", "applications.", "2.", "Role", "of", "ACE2", "and", "Apelin", "in", "Systemic", "and", "Pulmonary", "Hypertension", "Several", "previous", "studies", "demonstrated", "that", "ACE2", "can", "mod-", "ulate", "blood", "pressure.", "Daily", "infusion", "of", "recombinant", "human" ]

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[ "Ito", "et", "al.", "World", "Journal", "of", "Surgical", "Oncology", "2011,", "9:102", "http://www.wjso.com/content/9/1/102", "R", "E", "S", "E", "A", "R", "C", "H", "WORLD", "JOURNAL", "OF", "SURGICAL", "ONCOLOGY", "Open", "Access", "The", "impact", "of", "surgical", "outcome", "after", "pancreaticoduodenectomy", "in", "elderly", "patients", "Yasuhiro", "Ito1*,", "Takeshi", "Kenmochi1,", "Tomoyuki", "Irino1,", "Tomohisa", "Egawa1,", "Shinobu", "Hayashi1,", "Atsushi", "Nagashima1", "and", "Yuko", "Kitagawa2", "Abstract", "Background:", "The", "elderly", "population", "has", "increased", "in", "many", "countries.", "Indications", "for", "cancer", "treatment", "in", "elderly", "patients", "have", "expanded,", "because", "surgical", "techniques", "and", "medical", "management", "have", "improved", "remarkably.", "Pancreaticoduodenectomy", "(PD)", "requires", "high-quality", "techniques", "and", "perioperative", "management", "methods.", "If", "it", "is", "possible", "for", "elderly", "patients", "to", "withstand", "an", "aggressive", "surgery,", "age", "should", "not", "be", "considered", "a", "contraindication", "for", "PD.", "Appropriate", "preoperative", "evaluation", "of", "elderly", "patients", "will", "lead", "to", "their", "safer", "management.", "The", "purpose", "of", "the", "present", "study", "was", "to", "evaluate", "the", "safety", "of", "PD", "in", "patients", "older", "than", "75", "years", "and", "to", "show", "the", "influence", "of", "advanced", "age", "on", "the", "morbidity", "and", "mortality", "associated", "with", "this", "operation.", "Patients", "and", "methods:", "Subjects", "were", "98", "patients", "who", "underwent", "PD", "during", "the", "time", "period", "from", "April", "2005", "to", "April", "2011.", "During", "this", "study,", "31", "patients", "were", "75", "years", "of", "age", "or", "older", "(group", "A),", "and", "the", "other", "67", "patients", "were", "less", "than", "75", "years", "old", "(group", "B).", "Preoperative", "demographic", "and", "clinical", "data,", "surgical", "procedure,", "pathologic", "diagnosis,", "postoperative", "course", "and", "complication", "details", "were", "collected", "prospectively", "and", "they", "were", "analyzed", "in", "two", "group.", "Results:", "There", "was", "no", "statistical", "difference", "between", "patient", "groups", "in", "terms", "of", "gender,", "comorbidity,", "preoperative", "drainage,", "diagnosis,", "or", "laboratory", "data.", "Preoperative", "albumin", "values", "were", "lower", "in", "group", "A", "(P", "=", "0.04).", "The", "mean", "surgical", "time", "in", "group", "A", "was", "408.1", "±", "73.47", "min.", "Blood", "loss", "and", "blood", "transfusion", "were", "not", "significantly", "different", "between", "both", "groups.", "There", "was", "no", "statistical", "differences", "in", "mortality", "rate", "(P", "=", "0.14),", "morbidity", "rate", "(P", "=", "0.43),", "and", "mean", "length", "of", "hospital", "stay", "(P", "=", "0.22)", "between", "both", "groups.", "Long-term", "survival", "was", "also", "no", "statistically", "significant", "difference", "between", "the", "two", "groups", "using", "the", "log-rank", "test", "(P", "=", "0.10).", "Conclusion:", "It", "cannot", "be", "ignored", "that", "the", "elderly", "population", "is", "getting", "larger.", "We", "must", "investigate", "the", "management", "of", "elderly", "patients", "after", "PD", "and", "prepare", "further", "for", "more", "experiences", "of", "PD.", "If", "appropriate", "surgical", "management", "is", "provided", "to", "elderly", "patients,", "we", "suggest", "that", "PD", "will", "lead", "to", "no", "adverse", "effects", "after", "surgery,", "and", "PD", "can", "be", "performed", "safely", "in", "elderly", "patients.", "We", "conclude", "that", "age", "should", "not", "be", "a", "contraindication", "to", "PD.", "Keywords:", "Pancreaticoduodenectomy,", "Elderly", "patients,", "Outcome", "Background", "The", "elderly", "population", "has", "increased", "in", "many", "countries.", "Indications", "for", "cancer", "treatment", "in", "elderly", "patients", "have", "expanded,", "because", "surgical", "techniques", "and", "medical", "man-", "agement", "have", "improved", "remarkably.", "However,", "given", "that", "the", "morbidity", "and", "mortality", "associated", "with", "surgical", "*", "Correspondence:", "yasuito@ca3.so-net.ne.jp", "1Department", "of", "Surgery,", "Saiseikai", "Yokohamashi", "Tobu", "Hospital,", "3-6-1", "Shimosueyoshi,", "Tsurumi-ku,", "Yokohama-shi,", "Kanagawa,", "230-0012", "Japan", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "procedures", "are", "poorly", "defined", "in", "this", "population,", "the", "decision", "to", "perform", "an", "operation", "in", "an", "elderly", "patient", "can", "be", "difficult", "[1].", "Therefore,", "surgeons", "must", "give", "this", "decision", "careful", "consideration.", "Pancreaticoduodenectomy", "(PD),", "which", "may", "cause", "considerable", "complications,", "including", "pancreatic", "fistula,", "intra-abdominal", "bleeding,", "intra-abdominal", "abscess,", "sepsis", "and", "organ", "failure,", "requires", "high-quality", "techniques", "and", "perioperative", "man-", "agement", "methods.", "Though", "PD", "is", "performed", "in", "many", "hospitals,", "its", "associated", "morbidity", "and", "mortality", "rates", "are", "©", "2011", "Ito", "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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[ "Pflugers", "Arch", "-", "Eur", "J", "Physiol", "(2010)", "459:569–577", "DOI", "10.1007/s00424-009-0748-x", "CARDIOVASCULAR", "PHYSIOLOGY", "Impaired", "Ca2+-handling", "in", "HIF-1α+/−", "of", "pressure", "overload", "Monique", "Silter", "&", "Harald", "Kögler", "&", "Anke", "Zieseniss", "&", "Jörg", "Wilting", "&", "Katrin", "Schäfer", "&", "Karl", "Toischer", "&", "Adam", "G.", "Rokita", "&", "Gerhard", "Breves", "&", "Lars", "S.", "Maier", "&", "Dörthe", "M.", "Katschinski", "mice", "as", "a", "consequence", "Received:", "28", "July", "2009", "/", "Revised:", "7", "October", "2009", "/", "Accepted:", "13", "October", "2009", "/", "Published", "online:", "8", "November", "2009", "#", "The", "Author(s)", "2009.", "This", "article", "is", "published", "with", "open", "access", "at", "Springerlink.com", "Abstract", "The", "hypoxia-inducible", "factor", "(HIF)-1", "is", "critically", "involved", "in", "the", "cellular", "adaptation", "to", "a", "decrease", "in", "oxygen", "availability.", "The", "influence", "of", "HIF-1α", "for", "the", "development", "of", "cardiac", "hypertrophy", "and", "cardiac", "function", "that", "occurs", "in", "response", "to", "sustained", "pressure", "overload", "has", "been", "mainly", "attributed", "to", "a", "challenged", "cardiac", "angiogenesis", "and", "cardiac", "hypertrophy", "up", "to", "now.", "Hif-1α+/+", "and", "Hif-1α+/−", "mice", "were", "studied", "regarding", "left", "ventricular", "hypertrophy", "and", "cardiac", "function", "after", "being", "subjected", "to", "transverse", "aortic", "constriction", "(TAC).", "After", "TAC,", "both", "Hif-1α+/+", "and", "Hif-1α+/−", "mice", "developed", "left", "ventricular", "hypertrophy", "with", "increased", "poste-", "Electronic", "supplementary", "material", "The", "online", "version", "of", "this", "article", "(doi:10.1007/s00424-009-0748-x)", "contains", "supplementary", "material,", "which", "is", "available", "to", "authorized", "users.", "M.", "Silter", ":", "A.", "Zieseniss", ":", "D.", "M.", "Katschinski", "(*)", "Department", "of", "Cardiovascular", "Physiology,", "Heart", "Center", "Georg-August", "University", "Göttingen,", "Humboldtallee", "23,", "37073", "Göttingen,", "Germany", "e-mail:", "katschinski@physiol.med.uni-goettingen.de", "H.", "Kögler", ":", "K.", "Schäfer", ":", "K.", "Toischer", ":", "A.", "G.", "Rokita", ":", "L.", "S.", "Maier", "Department", "of", "Cardiology", "and", "Pneumology,", "Heart", "Center", "Georg-August", "University", "Göttingen,", "Robert-Koch", "Str.", "40,", "37075", "Göttingen,", "Germany", "J.", "Wilting", "Department", "of", "Anatomy", "and", "Cell", "Biology,", "Georg-August", "University", "Göttingen,", "Kreuzbergring", "36,", "37075", "Göttingen,", "Germany", "G.", "Breves", "Department", "of", "Physiology,", "University", "of", "Veterinary", "Medicine", "Hannover,", "Bischofsholer", "Damm", "15/102,", "30173", "Hannover,", "Germany", "rior", "wall", "thickness,", "septum", "thickness", "and", "increased", "left", "ventricular", "weight", "to", "a", "similar", "extent.", "No", "significant", "difference", "in", "cardiac", "vessel", "density", "was", "observed", "between", "Hif-1α+/+", "and", "Hif-1α+/−", "mice.", "However,", "only", "the", "Hif-1α+/−", "mice", "developed", "severe", "heart", "failure", "as", "revealed", "by", "a", "significantly", "reduced", "fractional", "shortening", "mostly", "due", "to", "increased", "end-systolic", "left", "ventricular", "diameter.", "On", "the", "single", "cell", "level", "this", "correlated", "with", "reduced", "myocyte", "shortenings,", "decreased", "intracellular", "Ca2+-transients", "and", "SR-Ca2+", "content", "in", "myocytes", "of", "Hif-1a+/−", "mice.", "Thus,", "HIF-1α", "can", "be", "critically", "involved", "in", "the", "preservation", "of", "cardiac", "function", "after", "chronic", "pressure", "overload", "without", "affecting", "cardiac", "hypertrophy.", "This", "effect", "is", "mediated", "via", "HIF-dependent", "modulation", "of", "cardiac", "calcium", "handling", "and", "contractility.", "Keywords", "Hypoxia", ".", "Transverse", "aortic", "constriction", ".", "Cardiac", "hypertrophy", ".", "Hypoxia-inducible", "factor", ".", "Heart", "failure", "Introduction", "An", "intact", "oxygen", "homeostasis", "in", "the", "heart", "is", "important", "not", "only", "for", "cardiac", "development", "but", "also", "for", "adaptation", "of", "the", "adult", "myocardium", "to", "a", "decrease", "in", "oxygen", "supply", "[18,", "21].", "Hypoxia", "affects", "cardiac", "vessel", "density", "and", "cell", "fate", "of", "cardiomyocytes", "[10].", "Like", "in", "other", "tissues,", "hypoxia", "initiates", "a", "hypoxia-inducible", "gene", "expression", "programme,", "including", "genes", "regulating", "angiogenesis,", "anaerobic", "glycolysis,", "etc.,", "in", "the", "heart", "[14].", "The", "hypoxia-inducible", "factor", "(HIF)-1", "is", "the", "transcriptional", "master", "regulator", "for", "these", "hypoxia-inducible", "genes", "[36].", "At", "the", "molecular", "level,", "hypoxia", "is", "sensed", "by", "three", "oxygen-,", "iron-", "and", "2-oxoglutarate-dependent", "prolyl-4-", "hydroxylase", "domain", "(PHD)", "enzymes.", "The", "basis", "for", "the", "hypoxia-induced", "stability", "and", "activity", "of", "HIF-1", "is", "the", "oxygen-dependent,", "PHD-mediated", "hydroxylation", "of", "distinct" ]

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[ "Original", "Article", "Elmer", "Press", "J", "Clin", "Med", "Res", "•", "2009;1(4):226-229", "Management", "of", "Giant", "Ventral", "Hernia", "by", "Polypropylene", "Mesh", "and", "Host", "Tissue", "Barrier:", "Trial", "of", "Simplification", "Samir", "A.", "Ammar", "Abstract", "Background:", "Surgical", "management", "of", "giant", "ventral", "hernias", "is", "a", "surgical", "challenge", "due", "to", "limited", "abdominal", "cavity.", "This", "study", "evaluates", "management", "of", "giant", "ventral", "hernias", "using", "polypropylene", "mesh", "and", "host", "tissue", "barrier", "after", "suitable", "preoperative", "preparation.", "Methods:", "In", "the", "period", "from", "January", "2005", "and", "January", "2007,", "35", "patients", "with", "giant", "ventral", "hernias", "underwent", "hernia", "repair.", "After", "careful", "preoperative", "preparation,", "repair", "was", "done", "using", "polypropyl-", "ene", "mesh.", "The", "mesh", "was", "separated", "from", "the", "viscera", "by", "a", "small", "part", "of", "the", "hernia", "sac", "and", "the", "greater", "omentum.", "Results:", "The", "average", "age", "of", "the", "patients", "was", "52.", "Twenty", "patients", "had", "post-operative", "incisional", "and", "15", "had", "para-umbilical", "hernias.", "The", "mean", "hernia", "defect", "size", "was", "16.8", "cm.", "Mean", "body", "mass", "index", "was", "33.", "Follow", "up", "ranged", "from", "18-36", "months.", "No", "patient", "required", "ventilation", "after", "operation.", "Recurrent", "seroma,", "which", "responded", "to", "repeated", "aspiration,", "was", "experienced", "in", "4", "patients.", "Minor", "wound", "infection", "was", "observed", "in", "5", "patients.", "Small", "hernia", "recurrence", "oc-", "curred", "in", "one", "patient.", "Conclusions:", "The", "use", "of", "polypropylene", "and", "host", "tissue", "barrier", "af-", "ter", "suitable", "preoperative", "preparation", "is", "relatively", "simple,", "safe,", "and", "reliable", "surgical", "solution", "to", "the", "problem", "of", "giant", "ventral", "hernia.", "Keywords:", "Hernia", "repair;", "Giant", "ventral", "hernia;", "Polypropylene", "mesh", "Introduction", "The", "management", "of", "giant", "hernia", "with", "loss", "of", "abdomi-", "Manuscript", "accepted", "for", "publication", "September", "8,", "2009", "Surgery", "Department,", "Assiut", "University", "Hospitals,", "El", "Gamma", "Street,", "Assiut,", "Egypt.", "Email:", "microsurg1@gmail.com", "doi:10.4021/jocmr2009.10.1268", "nal", "domain", "remains", "a", "surgical", "challenge.", "Loss", "of", "abdomi-", "nal", "domain", "occurs", "when", "the", "intra-abdominal", "contents", "can", "no", "longer", "lie", "within", "the", "abdominal", "cavity", "[1].", "Giant", "ventral", "hernias", "are", "considered", "in", "cases", "where", "the", "hernia", "orifice", "is", "greater", "than", "10", "cm", "[2].", "Huge", "hernias", "are", "more", "liable", "to", "com-", "plications", "and", "poorly", "controlled", "by", "external", "support.", "There", "are", "many", "problems", "associated", "with", "the", "management", "of", "such", "giant", "hernias.", "Firstly", "reduction", "of", "the", "contents", "is", "difficult.", "Postoperative", "disorders", "in", "the", "cardiovascular", "system,", "tissue", "oxygenation,", "increased", "intra–abdominal", "pressure,", "and", "pul-", "monary", "embolism", "expose", "the", "patient", "to", "severe", "risks", "[3,", "4].", "As", "the", "hernia", "is", "large,", "the", "risk", "of", "recurrence", "is", "high.", "Lastly", "the", "residual", "skin", "needs", "excision", "for", "cosmetic", "reasons.", "The", "objective", "of", "this", "study", "is", "to", "evaluate", "management", "of", "giant", "ventral", "hernia", "using", "polypropylene", "mesh", "and", "host", "tissue", "barrier", "after", "appropriate", "preoperative", "preparation.", "For", "tension", "free", "closure,", "no", "attempt", "at", "approximation", "of", "the", "muscle", "to", "close", "the", "defect", "was", "done.", "The", "mesh", "was", "separated", "from", "the", "viscera", "by", "a", "host", "tissue", "barrier", "composed", "of", "a", "small", "part", "of", "the", "hernia", "sac", "and", "the", "greater", "omentum.", "Patients", "and", "Methods", "This", "study", "is", "a", "prospective", "study", "included", "35", "patients", "treated", "at", "surgery", "department", "Assiut", "University", "Hospital", "in", "the", "period", "from", "January", "2005", "and", "January", "2007.", "Patients", "booked", "for", "elective", "repair", "of", "giant", "ventral", "hernia", "had", "complete", "preoperative", "fitness.", "All", "patients", "gave", "written", "informed", "consent,", "and", "the", "local", "ethics", "committee", "approved", "the", "study.", "The", "exclusion", "criteria", "were", "as", "follows:", "strangulated", "or", "obstructed", "hernia,", "major", "co-morbidities", "as", "severe", "cardiac,", "renal", "or", "respiratory", "disease,", "and", "intra-oper-", "ative", "musculoaponeurotic", "defect", "10", "cm", "or", "less", "in", "diameter.", "Two", "days", "before", "surgery,", "the", "patients", "kept", "on", "a", "low", "residue", "diet", "that", "changed", "to", "full", "liquid", "diet", "the", "day", "before", "operation.", "The", "patients", "underwent", "colonic", "washing", "out", "using", "Sodium", "Phosphate", "enema", "to", "deflate", "the", "bowel", "the", "day", "before", "surgery.", "All", "procedures", "were", "done", "under", "general", "endotracheal", "anesthesia.", "At", "the", "onset", "of", "anesthesia,", "a", "cephalosporin", "was", "administered", "intravenously.", "A", "nasogastric", "tube", "and", "Foley’s", "catheter", "were", "introduced", "after", "induction", "of", "anesthesia.", "An", "226", "Articles", "©", "The", "authors,", "Journal", "compilation", "©", "J", "Clin", "Med", "Res", "and", "Elmer", "Press™,", "www.jocmr.org" ]

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[ "Review", "Abstract", "Clinical", "applications", "of", "fractional", "flow", "reserve", "in", "bifurcation", "lesions", "Sang", "Hyun", "Park,", "Bon-Kwon", "Koo", "Seoul", "National", "University", "College", "of", "Medicine,", "101", "Daehang-ro,", "Chongno-gu,", "Seoul", "110-744,", "South", "Korea", "Journal", "of", "Geriatric", "Cardiology", "(2012)", "9:", "278−284", "©2012", "JGC", "All", "rights", "reserved;", "www.jgc301.com", "•", "Open", "Access", "•", "Percutaneous", "coronary", "intervention", "(PCI)", "for", "coronary", "bifurcation", "lesions", "has", "been", "associated", "with", "lower", "procedural", "success", "rates", "and", "worse", "clinical", "outcomes", "compared", "with", "PCI", "for", "simple", "coronary", "lesions.", "Angiographic", "evaluation", "alone", "is", "sometimes", "inaccurate", "and", "does", "not", "reflect", "the", "functional", "significance", "of", "bifurcation", "lesions.", "The", "fractional", "flow", "reserve", "(FFR)", "is", "an", "easily", "obtainable,", "reliable,", "and", "reproducible", "physiologic", "parameter.", "This", "parameter", "is", "epicardial", "lesion", "specific", "and", "reflects", "both", "degree", "of", "stenosis", "and", "the", "myocardial", "territory", "supplied", "by", "the", "specific", "artery.", "Recent", "studies", "have", "shown", "that", "FFR-guided", "provisional", "side", "branch", "intervention", "strategy", "for", "bifurcation", "lesions", "is", "feasible", "and", "effective", "and", "can", "reduce", "unnecessary", "complex", "interventions", "and", "related", "complications.", "However,", "an", "adequate", "understanding", "of", "coronary", "physiology", "and", "the", "pitfalls", "of", "FFR", "is", "essential", "to", "properly", "use", "FFR", "for", "PCI", "of", "complex", "bifurcation", "lesions.", "J", "Geriatr", "Cardiol", "2012;", "9:", "278−284.", "doi:", "10.3724/SP.J.1263.2012.05091", "Keywords:", "Coronary", "stenosis;", "Bifurcation", "lesion;", "Physiology;", "Fractional", "flow", "reserve", "1", "Introduction", "Coronary", "bifurcation", "lesions", "have", "been", "one", "of", "the", "most", "challenging", "lesion", "subsets", "in", "the", "field", "of", "percutaneous", "coronary", "intervention", "(PCI).", "Bifurcation", "intervention", "is", "asso-", "ciated", "with", "higher", "procedural", "cost,", "higher", "complication", "rate,", "higher", "restenosis", "rate", "and", "worse", "outcomes", "when", "compared", "with", "PCI", "of", "simple", "coronary", "artery", "lesions.[1–4]", "The", "provi-", "sional", "side", "branch", "(SB)", "interventional", "strategy", "is", "preferred", "for", "most", "bifurcation", "lesions", "as", "most", "previous", "studies", "have", "failed", "to", "show", "the", "benefit", "of", "systematic", "two", "stenting", "over", "this", "strategy.[3–7]", "Though", "there", "have", "been", "many", "studies", "about", "how", "to", "treat", "bifurcation", "lesions,", "it", "is", "still", "not", "clear", "which", "SB", "should", "be", "treated", "and", "how", "the", "functional", "significance", "of", "these", "lesions", "ought", "to", "be", "assessed.", "Although", "various", "angiographic", "or", "flow", "criteria", "are", "currently", "used", "for", "the", "decision", "of", "SB", "intervention,", "there", "is", "no", "validated", "criteria", "yet.", "Furthermore,", "angiographic", "assessment", "of", "bifurcation", "lesions", "is", "sometimes", "inaccurate", "because", "of", "the", "innate", "limitations", "of", "angiography.", "Therefore,", "a", "more", "physiologic", "and", "standardized", "measurement", "modality", "is", "required", "for", "better", "evaluation", "in", "the", "treatment", "of", "bifurcation", "lesions.", "Correspondence", "to:", "Bon-Kwon", "Koo,", "MD,", "PhD,", "Seoul", "National", "University", "College", "of", "Medicine,", "101", "Daehang-ro,", "Chongno-gu,", "Seoul", "110-744,", "South", "Korea.", "E-mail:", "bkkoo@snu.ac.kr", "Telephone:", "+82-2-2072-2062", "Fax:", "+82-2-3675-0805", "Received:", "May", "9,", "2012", "Revised:", "July", "10,", "2012", "Accepted:", "July", "11,", "2012", "Published", "online:", "August", "14,", "2012", "http://www.jgc301.com;", "jgc@jgc301.com", "|", "Journal", "of", "Geriatric", "Cardiology", "2", "What", "is", "fractional", "flow", "reserve", "(FFR)?", "FFR", "is", "a", "parameter", "that", "defines", "the", "physiologic", "signi-", "ficance", "of", "a", "coronary", "artery", "stenosis", "and", "is", "the", "ratio", "of", "maximal", "blood", "flow", "in", "a", "stenotic", "artery", "to", "normal", "maximal", "flow.[8]", "Since", "the", "resistance", "is", "minimal", "under", "maximal", "hyperemia", "and", "the", "venous", "pressure", "is", "negligible", "compared", "to", "coronary", "arterial", "pressure,", "FFR", "can", "be", "simply", "calculated", "as", "the", "ratio", "of", "distal", "coronary", "pressure", "(Pd)", "to", "proximal", "aortic", "pressure", "(Pa)", "(Figure", "1).", "It", "can", "be", "easily", "determined", "during", "coronary", "angiography", "by", "calculating", "the", "fraction", "of", "distal", "coronary", "pressure", "measured", "with", "a", "coronary", "pressure", "wire", "to", "aortic", "pressure", "measured", "simultaneously", "with", "the", "guide", "catheter", "as", "shown", "in", "Figure", "1.", "FFR", "is", "an", "epicardial", "lesion-specific", "physiologic", "parameter", "reflecting", "both", "the", "degree", "of", "stenosis", "and", "the", "myocardial", "territory", "supplied", "by", "the", "specific", "artery.[8–12]", "This", "parameter", "is", "nearly", "independent", "of", "hemodynamic", "conditions", "such", "as", "heart", "rate,", "blood", "pressure,", "and", "myocardial", "contractility.[11]", "In", "a", "study", "by", "Pijls", "et", "al.,[8]", "an", "FFR", "value", "of", "0.75", "or", "less", "almost", "invariably", "identified", "ischemia-causing", "coronary", "artery", "stenoses", "with", "high", "sensitivity", "(88%),", "specificity", "(100%),", "positive", "predictive", "value", "(100%),", "and", "overall", "accuracy", "(93%).", "Considering", "the", "presence", "of", "a", "grey", "zone", "(0.75−0.80)", "and", "the", "results", "of", "the", "FAME", "study,[13]", "an", "FFR", "cutoff", "value", "of", "0.8", "has", "become", "more", "popular", "in", "recent", "days.", "An", "FFR-guided", "revascularization", "strategy", "has", "been", "validated", "in", "various", "lesion", "subsets.", "In", "the", "DEFER", "study,", "the", "rate", "of", "cardiac", "death", "or", "myocardial", "infarction", "in", "the", "DEFER", "group", "according", "to" ]

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"lentiform", "nucleus,", "and", "thalamus.", "Methods", "We", "studied", "18", "healthy", "control", "subjects,", "20", "patients", "with", "a", "unilateral", "asymptomatic", "ICA", "stenosis,", "and", "15", "patients", "with", "a", "recently", "symptomatic", "unilateral", "ICA", "stenosis.", "The", "contribution", "of", "the", "ICAs", "and", "the", "basilar", "artery", "to", "the", "perfusion", "of", "the", "deep", "brain", "structures", "was", "assessed", "by", "perfusion", "territory", "selective", "arterial", "spin", "labeling", "(ASL)", "MRI.", "Differences", "were", "tested", "with", "a", "two-tailed", "Fishers’", "exact", "test.", "Results", "The", "caudate", "nucleus", "was", "predominantly", "supplied", "with", "blood", "by", "the", "ipsilateral", "ICA", "in", "all", "groups.", "In", "4", "of", "the", "15", "(27%)", "the", "symptomatic", "patients,", "the", "caudate", "nucleus", "partially", "received", "blood", "from", "the", "contralateral", "ICA,", "compared", "to", "none", "of", "the", "18", "healthy", "control", "subjects", "(p", "=", "0.03).", "The", "lentiform", "nucleus", "and", "the", "thalamus", "were", "predominantly", "supplied", "with", "blood", "by", "the", "ipsilateral", "ICA", "and", "basilar", "artery", "respectively", "in", "all", "groups.", "N.", "S.", "Hartkamp", "(*)", ":", "R.", "P.", "H.", "Bokkers", ":", "J.", "Hendrikse", "Department", "of", "Radiology,", "University", "Medical", "Center", "Utrecht,", "PO", "Box", "85500,", "3508", "GA", "Utrecht,", "The", "Netherlands", "e-mail:", "n.s.hartkamp@umcutrecht.nl", "H.", "B.", "van", "der", "Worp", ":", "L.", "J.", "Kappelle", "Department", "of", "Neurology,", "Rudolf", "Magnus", "Institute", "of", "Neuroscience,", "University", "Medical", "Center", "Utrecht,", "Utrecht,", "The", "Netherlands", "M.", "J.", "P.", "van", "Osch", "Department", "of", "Radiology,", "C.J.", "Gorter", "Institute", "of", "High", "Field", "MRI,", "Leiden", "University", "Medical", "Center,", "Leiden,", "The", "Netherlands", "Conclusion", "In", "patients", "with", "a", "symptomatic", "ICA", "stenosis,", "the", "caudate", "nucleus", "may", "be", "supplied", "with", "blood", "by", "the", "contralateral", "ICA", "more", "often", "than", "in", "healthy", "controls.", "Keywords", "Magnetic", "resonance", "imaging", ".", "Cerebral", "hemodynamics", ".", "Perfusion", ".", "Basal", "ganglia", ".", "Carotid", "artery", "stenosis", "Introduction", "There", "is", "wide", "variation", "in", "the", "perfusion", "territories", "of", "the", "brain-feeding", "arteries,", "which", "is", "most", "pronounced", "in", "those", "supplying", "the", "deep", "brain", "structures", "[1–3].", "The", "caudate", "nucleus,", "lentiform", "nucleus,", "and", "thalamus", "are", "supplied", "with", "blood", "from", "groups", "of", "different", "perforating", "arteries", "that", "branch", "either", "from", "the", "anterior,", "middle", "and", "posterior", "cerebral", "artery", "or", "from", "the", "posterior", "communicating", "artery", "[2,", "4–7].", "In", "addition", "to", "the", "normal", "variability,", "there", "may", "be", "a", "shift", "in", "the", "perfusion", "territories", "of", "the", "brain-feeding", "arteries", "in", "patients", "with", "steno-occlusive", "disease", "of", "the", "ICA,", "due", "to", "the", "recruitment", "of", "collateral", "blood", "pathways", "[8,", "9].", "Perfusion", "territory", "selective", "arterial", "spin", "labeling", "magnetic", "resonance", "imaging", "(ASL-MRI)", "has", "recently", "been", "intro-", "duced", "to", "visualize", "the", "perfusion", "territories", "of", "the", "individual", "brain-feeding", "arteries", "[10,", "11].", "ASL-MRI", "is", "a", "non-invasive", "technique", "for", "imaging", "whole-brain", "cerebral", "perfusion", "that", "uses", "radiofrequency", "pulses", "to", "magnetically", "label", "blood", "and", "does", "not", "require", "gadolinium-based", "contrast", "agents.", "The", "aim", "of", "our", "study", "was", "to", "investigate", "the", "influence", "of", "ICA", "stenosis", "on", "the", "distribution", "of", "cerebral", "blood", "flow", "to", "the", "caudate", "nucleus,", "lentiform", "nucleus", "and", "thalamus", "with", "perfusion", "territory", "selective", "ASL-MRI", "in", "patients", "with" ]

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[ "Case", "Report", "DOI", "10.3349/ymj.2010.51.5.784", "pISSN:", "0513-5796,", "eISSN:", "1976-2437", "Yonsei", "Med", "J", "51(5):784-786,", "2010", "Kawasaki", "Disease", "Mimicking", "Retropharyngeal", "Abscess", "Ramaswamy", "Ganesh,1", "Vazhkudai", "Sridharan", "Srividhya,1", "Thiruvengadam", "Vasanthi,1", "and", "Somu", "Shivbalan2", "1Department", "of", "Pediatrics,", "Kanchi", "Kamakoti", "Childs", "Trust", "Hospital,", "Chennai;", "2Pediatrician", "and", "Pulmonologist,", "Sundaram", "Medical", "Foundation", "and", "Dr", "Rangarajan", "Memorial", "Hospital,", "Chennai,", "India.", "Received:", "March", "31,", "2008", "Revised:", "May", "21,", "2008", "Accepted:", "June", "3,", "2008", "Corresponding", "author:", "Dr.", "Ramaswamy", "Ganesh,", "Department", "of", "Pediatrics,", "Kanchi", "Kamakoti", "Childs", "Trust", "Hospital,", "12-", "A,", "Nageswara", "road,", "Nungambakkam,", "Chennai-600034,", "TamilNadu,", "India.", "Tel:", "91-44-42001800,", "Fax:", "91-44-28259633", "E-mail:", "ganeped79@rediffmail.com", "∙The", "authors", "have", "no", "financial", "conflicts", "of", "interest.", "©", "Copyright:", "Yonsei", "University", "College", "of", "Medicine", "2010", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "Non-", "Commercial", "License", "(http://creativecommons.org/", "licenses/by-nc/3.0)", "which", "permits", "unrestricted", "non-", "commercial", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Kawasaki", "disease", "is", "an", "acute,", "self-limiting", "febrile", "mucocutaneous", "vasculitis", "of", "infants", "and", "young", "children.", "Retropharyngeal", "lymphadenopathy", "is", "a", "rare", "presentation", "of", "Kawasaki", "disease.", "We", "present", "a", "case", "of", "Kawasaki", "disease", "mimicking", "a", "retro-", "pharyngeal", "abscess,", "with", "upper", "airway", "obstruction", "resulting", "in", "delayed", "diagnosis.", "Key", "Words:", "Kawasaki", "disease,", "retropharyngeal", "abscess", "INTRODUCTION", "Kawasaki", "disease", "(KD)", "is", "an", "acute,", "self-limiting", "febrile", "mucocutaneous", "vasculitis", "of", "infants", "and", "children.", "Diagnosis", "of", "KD", "is", "clinical", "and", "is", "based", "on", "the", "presence", "of", "fever", "with", "other", "features", "suggestive", "of", "KD,", "lymphadenopathy", "being", "the", "least", "common.", "Retropharyngeal", "abscess", "mimicking", "KD", "has", "been", "rarely", "reported", "from", "India.", "We", "discuss", "an", "8-year-old", "boy", "presenting", "initially", "with", "a", "retropharyngeal", "abscess", "and", "upper", "airway", "obstruction,", "later", "developing", "a", "full-blown", "KD,", "thus", "resulting", "in", "a", "delayed", "diagnosis", "of", "KD.", "CASE", "REPORT", "An", "8-year-old", "boy", "presented", "with", "fever,", "pain", "on", "the", "left", "side", "of", "the", "neck", "asso-", "ciated", "with", "restricted", "neck", "movements,", "and", "trismus", "for", "1", "day.", "He", "also", "had", "difficulty", "in", "swallowing", "and", "breathing.", "On", "examination", "he", "was", "febrile", "(104˚F),", "toxic,", "anxious,", "irritable,", "and", "a", "throat", "examination", "revealed", "a", "4×5", "cm", "swelling", "in", "the", "posterior", "pharyngeal", "wall", "to", "the", "left", "of", "the", "midline.", "He", "also", "had", "upper", "deep", "left", "cervical", "lymphadenopathy", "and", "there", "was", "no", "cyanosis.", "His", "respiratory", "rate", "was", "48/min,", "and", "he", "had", "suprasternal", "indrawing", "and", "stridor.", "His", "systemic", "examination", "was", "normal.", "Investigations", "revealed", "a", "total", "white", "blood", "count", "(WBC)", "count:", "20,800/mm3,", "polymorphs:", "80%,", "platelet", "count:", "3.5", "lacs/mm3,", "erythrocyte", "sedimen-", "tation", "rate", "(ESR):", "55", "mm/hr,", "and", "a", "C", "reactive", "protein", "(CRP)", "of", "48", "mg/dL.", "Blood", "cultures", "showed", "no", "growth.", "A", "lateral", "neck", "X-ray", "revealed", "widening", "of", "the", "retropharyngeal", "space", "and", "narrowing", "of", "the", "upper", "airway.", "Computed", "tomography", "(CT)", "of", "the", "neck", "revealed", "ill-defined", "hypodense", "lesion", "extending", "from", "the", "C2-C6", "vertebral", "level", "in", "the", "posterior", "pharyngeal", "space", "with", "no", "contrast", "enhancement", "compatible", "with", "a", "diagnosis", "of", "retropharyngeal", "abscess", "(Fig.", "1).", "In", "light", "of", "the", "high", "fever", "and", "toxemia,", "he", "was", "started", "on", "antibiotics", "(Cefotaxim", "100", "mg/kg/day)", "and", "surgical", "aspiration", "was", "undertaken", "within", "24", "hours", "of", "the", "antibiotics", "and", "yielded", "784", "Yonsei", "Med", "J", "http://www.eymj.org", "Volume", "51", "Number", "5", "September", "2010" ]

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[ "Regulation", "of", "Vascular", "Endothelial", "Cell", "Polarization", "and", "Migration", "by", "Hsp70/Hsp90-Organizing", "Protein", "Jingyu", "Li1.,", "Xiaodong", "Sun1.,", "Zaizhu", "Wang1,", "Li", "Chen1,", "Dengwen", "Li1,", "Jun", "Zhou", "1", ",", "Min", "Liu2*", "1", "State", "Key", "Laboratory", "of", "Medicinal", "Chemical", "Biology,", "College", "of", "Life", "Sciences,", "Nankai", "University,", "Tianjin,", "China,", "2", "Key", "Laboratory", "of", "Immune", "Microenvironment", "and", "Disease", "of", "the", "Ministry", "of", "Education,", "Basic", "Medical", "College,", "Tianjin", "Medical", "University,", "Tianjin,", "China", "Abstract", "Hsp70/Hsp90-organizing", "protein", "(HOP)", "is", "a", "member", "of", "the", "co-chaperone", "family,", "which", "directly", "binds", "to", "chaperones", "to", "regulate", "their", "activities.", "The", "participation", "of", "HOP", "in", "cell", "motility", "and", "endothelial", "cell", "functions", "remains", "largely", "unknown.", "In", "this", "study,", "we", "demonstrate", "that", "HOP", "is", "critically", "involved", "in", "endothelial", "cell", "migration", "and", "angiogenesis.", "Tube", "formation", "and", "capillary", "sprouting", "experiments", "reveal", "that", "depletion", "of", "HOP", "expression", "significantly", "inhibits", "vessel", "formation", "from", "endothelial", "cells.", "Wound", "healing", "and", "transwell", "migration", "assays", "show", "that", "HOP", "is", "important", "for", "endothelial", "cell", "migration.", "By", "examination", "of", "centrosome", "reorientation", "and", "membrane", "ruffle", "dynamics,", "we", "find", "that", "HOP", "plays", "a", "crucial", "role", "in", "the", "establishment", "of", "cell", "polarity", "in", "response", "to", "migratory", "stimulus.", "Furthermore,", "our", "data", "show", "that", "HOP", "interacts", "with", "tubulin", "and", "colocalizes", "with", "microtubules", "in", "endothelial", "cells.", "These", "findings", "indicate", "HOP", "as", "a", "novel", "regulator", "of", "angiogenesis", "that", "functions", "through", "promoting", "vascular", "endothelial", "cell", "polarization", "and", "migration.", "Citation:", "Li", "J,", "Sun", "X,", "Wang", "Z,", "Chen", "L,", "Li", "D,", "et", "al.", "(2012)", "Regulation", "of", "Vascular", "Endothelial", "Cell", "Polarization", "and", "Migration", "by", "Hsp70/Hsp90-Organizing", "Protein.", "PLoS", "ONE", "7(4):", "e36389.", "doi:10.1371/journal.pone.0036389", "Editor:", "Paolo", "Madeddu,", "Bristol", "Heart", "Institute,", "University", "of", "Bristol,", "United", "Kingdom", "Received", "January", "4,", "2012;", "Accepted", "March", "31,", "2012;", "Published", "April", "30,", "2012", "Copyright:", "2012", "Li", "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", "grants", "from", "the", "National", "Basic", "Research", "Program", "of", "China", "(2012CB945002", "and", "2010CB912204)", "and", "the", "National", "Natural", "Science", "Foundation", "of", "China", "(30825022).", "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:", "minliu@tijmu.edu.cn", ".", "These", "authors", "contributed", "equally", "to", "this", "work.", "Introduction", "Hsp70/Hsp90-organizing", "protein", "(HOP)", "is", "a", "co-chaperone", "protein", "that", "could", "directly", "bind", "to", "the", "major", "chaperones,", "Hsp70", "and", "Hsp90,", "and", "modulate", "their", "ATPase", "activities", "[1–4].", "HOP", "also", "belongs", "to", "the", "stress-inducible", "protein", "1", "(STI1)", "family,", "which", "contains", "various", "vertebrate", "and", "invertebrate", "homologs", "of", "HOP", "[5].", "Human", "HOP", "has", "three", "tetratricopeptide", "repeat", "(TPR)", "domains,", "including", "TPR1,", "TPR2a,", "and", "TPR2b", "[6].", "TPR", "domains", "are", "responsible", "for", "the", "interaction", "of", "HOP", "with", "Hsp70/Hsp90,", "with", "TPR1", "for", "HOP", "binding", "to", "Hsp70", "and", "TPR2a", "for", "HOP", "binding", "to", "Hsp90", "[7,8].", "However,", "no", "specific", "ligands", "for", "the", "TPR2b", "domain", "have", "been", "found.", "HOP", "also", "has", "non-TPR", "domains,", "including", "a", "DP", "repeat", "region", "and", "two", "nuclear", "localization", "signals,", "which", "render", "HOP", "to", "dynamically", "translocate", "between", "the", "cytoplasm", "and", "the", "nucleus", "[9,10].", "In", "addition,", "HOP", "has", "been", "found", "in", "a", "number", "of", "Hsp90-independent", "complexes,", "including", "prion", "protein", "complex", "and", "nuclear", "transcription", "complex", "[11–14].", "Hsp70", "and", "Hsp90", "have", "been", "shown", "to", "be", "overexpressed", "in", "several", "tumor", "types,", "and", "inhibition", "of", "Hsp70/Hsp90", "has", "been", "reported", "to", "induce", "tumor", "cell-specific", "apoptosis", "[15].", "However,", "whether", "HOP", "is", "involved", "in", "cancer", "development", "remains", "unclear.", "In", "addition,", "it", "is", "unknown", "whether", "HOP", "plays", "a", "role", "in", "angiogenesis,a", "process", "that", "refers", "to", "the", "generation", "of", "new", "blood", "vessels", "from", "pre-existing", "ones", "and", "relies", "largely", "on", "vascular", "endothelial", "cell", "proliferation", "and", "migration", "[16].", "The", "angiogenic", "process", "is", "also", "critical", "for", "tumor", "growth,", "progression,", "and", "metastasis", "[17,18],", "and", "anti-angiogenesis", "strategy", "has", "been", "proven", "useful", "for", "cancer", "treatment", "[19–22].", "Given", "that", "HOP", "harbors", "multiple", "structural", "motifs", "and", "interacts", "with", "various", "proteins,", "we", "hypothesized", "that", "HOP", "might", "participate", "in", "cell", "motility", "and", "endothelial", "cell", "functions.", "This", "study", "was", "designed", "to", "test", "this", "hypothesis", "directly,", "and", "our", "data", "demonstrate", "that", "HOP", "is", "important", "for", "angiogenesis", "through", "modulating", "endothelial", "cell", "polarization", "and", "migration.", "Materials", "and", "Methods", "Materials", "Antibodies", "against", "b-actin,", "a-tubulin,", "c-tubulin,", "and", "GST", "were", "purchased", "from", "Sigma-Aldrich.", "Antibodies", "against", "GFP,", "RhoA,", "Cdc42,", "and", "Rac1", "were", "from", "Cell", "Signaling.", "Antibodies", "against", "HOP,", "Akt,", "and", "HDAC6", "were", "from", "Santa", "Cruz", "Biotechnology.", "Anti-GFP", "antibody-conjugated", "agarose", "beads", "(MBL", "Internation-", "al),", "glutathione-conjugated", "agarose", "beads", "(Sigma-Aldrich),", "horse-", "radish", "peroxidase-conjugated", "secondary", "antibodies", "(Amersham", "Biosciences),", "and", "fluorescein-", "or", "rhodamine-conjugated", "secondary", "antibodies", "(Jackson", "Immuno", "Research", "Laboratories)", "were", "ob-", "tained", "from", "the", "indicated", "sources.", "Matrigel", "and", "mouse", "collagen", "IV", "were", "from", "BD", "Biosciences.", "Plasmids", "Mammalian", "expression", "plasmids", "of", "GFP-HOP", "and", "GFP-tagged", "mutant", "forms", "of", "HOP", "were", "constructed", "using", "the", "pEGFPC1", "vector.", "Bacterial", "expression", "plasmid", "of", "GST-HOP", "was", "cloned", "using", "the", "pGEX6P3", "vector,", "and", "GST-HOP", "fusion", "protein", "was", "PLoS", "ONE", "|", "www.plosone.org", "1", "April", "2012", "|", "Volume", "7", "|", "Issue", "4", "|", "e36389" ]

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[ "Replicative", "Age", "Induces", "Mitotic", "Recombination", "in", "the", "Ribosomal", "RNA", "Gene", "Cluster", "of", "Saccharomyces", "cerevisiae", "Derek", "L.", "Lindstrom,", "Christina", "K.", "Leverich,", "Kiersten", "A.", "Henderson,", "Daniel", "E.", "Gottschling*", "Division", "of", "Basic", "Sciences,", "Fred", "Hutchinson", "Cancer", "Research", "Center,", "Seattle,", "Washington,", "United", "States", "of", "America", "Abstract", "Somatic", "mutations", "contribute", "to", "the", "development", "of", "age-associated", "disease.", "In", "earlier", "work,", "we", "found", "that,", "at", "high", "frequency,", "aging", "Saccharomyces", "cerevisiae", "diploid", "cells", "produce", "daughters", "without", "mitochondrial", "DNA,", "leading", "to", "loss", "of", "respiration", "competence", "and", "increased", "loss", "of", "heterozygosity", "(LOH)", "in", "the", "nuclear", "genome.", "Here", "we", "used", "the", "recently", "developed", "Mother", "Enrichment", "Program", "to", "ask", "whether", "aging", "cells", "that", "maintain", "the", "ability", "to", "produce", "respiration-", "competent", "daughters", "also", "experience", "increased", "genomic", "instability.", "We", "discovered", "that", "this", "population", "exhibits", "a", "distinct", "genomic", "instability", "phenotype", "that", "primarily", "affects", "the", "repeated", "ribosomal", "RNA", "gene", "array", "(rDNA", "array).", "As", "diploid", "cells", "passed", "their", "median", "replicative", "life", "span,", "recombination", "rates", "between", "rDNA", "arrays", "on", "homologous", "chromosomes", "progressively", "increased,", "resulting", "in", "mutational", "events", "that", "generated", "LOH", "at", ".300", "contiguous", "open", "reading", "frames", "on", "the", "right", "arm", "of", "chromosome", "XII.", "We", "show", "that,", "while", "these", "recombination", "events", "were", "dependent", "on", "the", "replication", "fork", "block", "protein", "Fob1,", "the", "aging", "process", "that", "underlies", "this", "phenotype", "is", "Fob1-independent.", "Furthermore,", "we", "provide", "evidence", "that", "this", "aging", "process", "is", "not", "driven", "by", "mechanisms", "that", "modulate", "rDNA", "recombination", "in", "young", "cells,", "including", "loss", "of", "cohesion", "within", "the", "rDNA", "array", "or", "loss", "of", "Sir2", "function.", "Instead,", "we", "suggest", "that", "the", "age-associated", "increase", "in", "rDNA", "recombination", "is", "a", "response", "to", "increasing", "DNA", "replication", "stress", "generated", "in", "aging", "cells.", "Citation:", "Lindstrom", "DL,", "Leverich", "CK,", "Henderson", "KA,", "Gottschling", "DE", "(2011)", "Replicative", "Age", "Induces", "Mitotic", "Recombination", "in", "the", "Ribosomal", "RNA", "Gene", "Cluster", "of", "Saccharomyces", "cerevisiae.", "PLoS", "Genet", "7(3):", "e1002015.", "doi:10.1371/journal.pgen.1002015", "Editor:", "Jasper", "Rine,", "University", "of", "California", "Berkeley,", "United", "States", "of", "America", "Received", "November", "24,", "2010;", "Accepted", "January", "13,", "2011;", "Published", "March", "17,", "2011", "Copyright:", "2011", "Lindstrom", "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", "in", "part", "by", "postdoctoral", "fellowship", "#PF-04-041-01-GMC", "from", "the", "American", "Cancer", "Society", "(http://www.cancer.org)", "to", "DLL,", "a", "Fellow’s", "Career", "Development", "Program", "Award", "from", "The", "Leukemia", "and", "Lymphoma", "Society", "(http://www.leukemia-lymphoma.org/hm_lls)", "to", "KAH,", "National", "Institutes", "of", "Health", "(http://www.nih.gov/)", "grant", "AG023779", "and", "a", "Glenn", "Award", "for", "Research", "in", "Biological", "Mechanisms", "of", "Aging", "(http://glennfoundation.org/)", "to", "DEG,", "and", "National", "Cancer", "Institute", "(http://www.cancer.gov/)", "grant", "T32", "CA09657.", "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:", "dgottsch@fhcrc.org", "Introduction", "One", "of", "the", "greatest", "risk", "factors", "associated", "with", "carcinogenesis", "is", "age.", "Cancer", "risk", "increases", "exponentially", "toward", "the", "end", "of", "life", "in", "humans", "and", "other", "mammalian", "species", "[1].", "Somatic", "genetic", "changes", "contribute", "significantly", "to", "the", "development", "of", "most", "tumors.", "However,", "the", "rate", "at", "which", "spontaneous", "mutations", "arise", "in", "normal", "adult", "cells", "has", "been", "hypothesized", "to", "be", "too", "low", "to", "generate", "all", "the", "genetic", "changes", "necessary", "to", "produce", "tumors", "at", "the", "observed", "rates", "[2–3].", "Consequently,", "Loeb", "et", "al.", "developed", "the", "mutator", "hypothesis,", "which", "postulates", "an", "increased", "mutation", "rate", "in", "precancerous", "cells", "[3].", "A", "variety", "of", "mechanisms", "could", "lead", "to", "such", "an", "increase,", "but", "a", "favored", "model", "is", "that", "sporadic", "mutations", "in,", "or", "epigenetic", "silencing", "of,", "genes", "responsible", "for", "maintaining", "genome", "integrity", "lead", "to", "increased", "rates", "of", "mutation.", "Once", "acquired,", "this", "mutator", "phenotype", "may", "serve", "as", "the", "driving", "force", "toward", "carcinogenesis", "as", "individuals", "age.", "When", "genomes", "of", "tumors", "are", "examined,", "loss", "of", "heterozygosity", "(LOH)", "is", "observed", "as", "a", "common", "mechanism", "in", "which", "the", "sole", "functional", "allele", "of", "a", "tumor", "suppressor", "gene", "is", "inactivated", "by", "somatic", "mutation", "[4–5].", "LOH", "can", "be", "generated", "by", "many", "different", "mutational", "events,", "including", "point", "mutations,", "small", "deletions", "or", "inversions,", "mitotic", "recombination", "or", "chromosome", "loss.", "Recent", "advances", "in", "high-", "resolution", "single-nucleotide", "polymorphism", "arrays", "(SNP", "arrays)", "have", "revealed", "that", "a", "surprising", "number", "of", "tumors", "contain", "long", "tracts", "of", "homozygosity", "that", "are", "not", "accompanied", "by", "a", "change", "in", "gene", "copy", "number.", "This", "type", "of", "LOH", "arises", "from", "somatic", "mitotic", "recombina-", "tion", "events", "and", "is", "referred", "to", "as", "partial", "(or", "acquired)", "uniparental", "disomy", "(UPD)", "[6].", "Importantly,", "UPD", "can", "alter", "the", "genotype", "for", "hundreds", "of", "genes", "following", "a", "single", "event,", "thereby", "amplifying", "its", "potential", "to", "contribute", "to", "cancer", "development", "[7].", "Within", "any", "genome,", "there", "are", "regions", "that", "exhibit", "higher", "rates", "of", "mitotic", "recombination", "than", "the", "genomic", "average", "as", "the", "result", "of", "their", "proximity", "to", "hotspots", "or", "common", "fragile", "sites", "[8].", "These", "regions", "typically", "represent", "slow-replicating", "sequences,", "and", "agents", "that", "generate", "DNA", "replication", "stress", "often", "reveal", "their", "fragility.", "These", "regions", "are", "also", "often", "associated", "with", "non-histone", "protein", "complexes", "that", "inhibit", "DNA", "replication", "fork", "progression.", "This", "generates", "DNA", "replication", "stress", "that", "may", "lead", "to", "an", "increased", "frequency", "of", "DNA", "damage", "due", "to", "replication", "fork", "collapse", "[9–10].", "While", "conservative", "repair", "of", "this", "DNA", "damage", "would", "have", "no", "genetic", "consequence,", "the", "higher", "incidence", "of", "damage", "results", "in", "a", "greater", "chance", "that", "an", "alternative", "repair", "pathway", "will", "be", "utilized", "that", "does", "confer", "a", "genotypic", "change.", "Previously,", "we", "found", "evidence", "for", "a", "mutator", "phenotype", "associated", "with", "advancing", "replicative", "age", "in", "a", "common", "lab", "strain", "PLoS", "Genetics", "|", "www.plosgenetics.org", "1", "March", "2011", "|", "Volume", "7", "|", "Issue", "3", "|", "e1002015" ]

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[ "Acta", "Crystallographica", "Section", "D", "Biological", "Crystallography", "ISSN", "0907-4449", "Talat", "Jabeen,‡", "Philip", "Leonard,§", "Haryati", "Jamaluddin}", "and", "K.", "Ravi", "Acharya*", "Department", "of", "Biology", "and", "Biochemistry,", "University", "of", "Bath,", "Claverton", "Down,", "Bath", "BA2", "7AY,", "England", "‡", "Present", "address:", "School", "of", "Biosciences,", "University", "of", "Birmingham,", "Edgbaston,", "Birmingham", "B15", "2TT,", "England.", "§", "Present", "address:", "Sareum", "Ltd,", "2", "Iconix", "Park,", "Pampisford,", "Cambridge", "CB22", "3EG,", "England.", "}", "Present", "address:", "Faculty", "of", "Biosciences", "and", "Engineering,", "Universiti", "Teknologi", "Malaysia,", "81310", "Skudai,", "Johor,", "Malaysia.", "Correspondence", "e-mail:", "bsskra@bath.ac.uk", "research", "papers", "Structure", "of", "mouse", "IP-10,", "a", "chemokine", "Interferon-", "-inducible", "protein", "(IP-10)", "belongs", "to", "the", "CXC", "class", "of", "chemokines", "and", "plays", "a", "significant", "role", "in", "the", "pathophysiology", "of", "various", "immune", "and", "inflammatory", "responses.", "It", "is", "also", "a", "potent", "angiostatic", "factor", "with", "antifibrotic", "properties.", "The", "biological", "activities", "of", "IP-10", "are", "exerted", "by", "interactions", "with", "the", "G-protein-coupled", "receptor", "CXCR3", "expressed", "on", "Th1", "lymphocytes.", "IP-10", "thus", "forms", "an", "attractive", "target", "for", "structure-based", "rational", "drug", "design", "of", "anti-", "inflammatory", "molecules.", "The", "crystal", "structure", "of", "mouse", "IP-10", "has", "been", "determined", "and", "reveals", "a", "novel", "tetrameric", "association.", "In", "the", "tetramer,", "two", "conventional", "CXC", "chemo-", "kine", "dimers", "are", "associated", "through", "their", "N-terminal", "regions", "to", "form", "a", "12-stranded", "elongated", "-sheet", "of", "90", "A˚", "in", "length.", "This", "association", "differs", "significantly", "from", "the", "previously", "studied", "tetramers", "of", "human", "IP-10,", "platelet", "factor", "4", "and", "neutrophil-", "activating", "peptide-2.", "In", "addition,", "heparin-", "and", "receptor-", "binding", "residues", "were", "mapped", "on", "the", "surface", "of", "IP-10", "tetramer.", "Two", "heparin-binding", "sites", "were", "observed", "on", "the", "surface", "and", "were", "present", "at", "the", "interface", "of", "each", "of", "the", "two", "-sheet", "dimers.", "The", "structure", "supports", "the", "formation", "of", "higher", "order", "oligomers", "of", "IP-10,", "as", "observed", "in", "recent", "in", "vivo", "studies", "with", "mouse", "IP-10,", "which", "will", "have", "functional", "relevance.", "1.", "Introduction", "Chemokines", "are", "involved", "in", "chemotaxis", "and", "activation", "of", "leukocytes", "in", "immune", "and", "inflammatory", "responses", "by", "inter-", "acting", "with", "their", "specific", "G-protein-coupled", "receptors", "(Moser", "&", "Loetscher,", "2001)", "and", "have", "been", "divided", "into", "C,", "CC,", "CXC", "and", "CX3C", "subfamilies", "on", "the", "basis", "of", "their", "N-terminal", "cysteine", "positions", "(Zlotnik", "&", "Yoshie,", "2000;", "Ottonello,", "2006).", "Interferon-", "-inducible", "protein", "(IP-10;", "CXCL10;", "10", "kDa)", "belongs", "to", "the", "CXC", "family", "of", "chemokines", "and", "is", "secreted", "by", "a", "variety", "of", "cell", "types", "(Baggiolini", "et", "al.,", "1997).", "IP-10", "acts", "as", "an", "immunoinflammatory", "mediator", "in", "Th1-type", "inflammatory", "diseases", "(Papadakis", "et", "al.,", "2004),", "rheumatoid", "arthritis", "(Ruschpler", "et", "al.,", "2003),", "cardiac", "allograft", "rejection", "(Zhao", "et", "al.,", "2002),", "multiple", "sclerosis", "(Sorensen,", "2004),", "atherosclerosis", "(Heller", "et", "al.,", "2006),", "sarcoidosis", "(Sugiyama", "et", "al.,", "2006)", "and", "prostate", "cancer", "(Nagpal", "et", "al.,", "2006).", "The", "receptor", "for", "IP-10", "has", "been", "recognized", "as", "CXCR3", "(Loetscher", "et", "al.,", "1996),", "which", "is", "predominantly", "expressed", "on", "activated", "T", "lymphocytes", "(Th1;", "Sallusto", "et", "al.,", "1998)", "in", "addition", "to", "other", "cell", "types", "including", "NK", "cells,", "dendritic", "cells,", "macrophages", "and", "B", "cells", "(Loetscher", "et", "al.,", "1998;", "Qin", "et", "al.,", "1998).", "Two", "other", "physiological", "ligands", "for", "CXCR3", "are", "monokine", "induced", "by", "interferon-", "(Mig;", "CXCL9;", "Loetscher", "et", "al.,", "1996)", "and", "interferon-inducible", "T-cell", "chemoattractant", "(I-TAC;", "CXCL11;", "Cole", "et", "al.,", "1998).", "Received", "16", "October", "2007", "Accepted", "13", "March", "2008", "PDB", "Reference:", "mouse", "IP-10,", "2r3z,", "r2r3zsf.", "Acta", "Cryst.", "(2008).", "D64,", "611–619", "doi:10.1107/S0907444908007026", "611" ]

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[ "Ma", "et", "al.", "Molecular", "Cancer", "2010,", "9:190", "http://www.molecular-cancer.com/content/9/1/190", "R", "E", "S", "E", "A", "R", "C", "H", "Open", "Access", "Extensive", "analysis", "of", "D7S486", "in", "primary", "gastric", "cancer", "supports", "TESTIN", "as", "a", "candidate", "tumor", "suppressor", "gene", "Haiqing", "Ma1†,", "Desheng", "Weng1†,", "Yibing", "Chen1,", "Wei", "Huang1,", "Ke", "Pan1,", "Hui", "Wang1,", "Jiancong", "Sun1,", "Qijing", "Wang1,", "Zhiwei", "Zhou2,", "Huiyun", "Wang1*,", "Jianchuan", "Xia1*", "Abstract", "Background:", "High", "frequency", "of", "loss", "of", "heterozygosity", "(LOH)", "was", "found", "at", "D7S486", "in", "primary", "gastric", "cancer", "(GC).", "And", "we", "found", "a", "high", "frequency", "of", "LOH", "region", "on", "7q31", "in", "primary", "GC", "from", "China,", "and", "identified", "D7S486", "to", "be", "the", "most", "frequent", "LOH", "locus.", "This", "study", "was", "aimed", "to", "determine", "what", "genes", "were", "affected", "by", "the", "LOH", "and", "served", "as", "tumor", "suppressor", "genes", "(TSGs)", "in", "this", "region.", "Here,", "a", "high-throughput", "single", "nucleotide", "polymorphisms", "(SNPs)", "microarray", "fabricated", "in-house", "was", "used", "to", "analyze", "the", "LOH", "status", "around", "D7S486", "on", "7q31", "in", "75", "patients", "with", "primary", "GC.", "Western", "blot,", "immunohistochemistry,", "and", "RT-PCR", "were", "used", "to", "assess", "the", "protein", "and", "mRNA", "expression", "of", "TESTIN", "(TES)", "in", "50", "and", "140", "primary", "GC", "samples,", "respectively.", "MTS", "assay", "was", "used", "to", "investigate", "the", "effect", "of", "TES", "overexpression", "on", "the", "proliferation", "of", "GC", "cell", "lines.", "Mutation", "and", "methylation", "analysis", "were", "performed", "to", "explore", "possible", "mechanisms", "of", "TES", "inactivation", "in", "GC.", "Results:", "LOH", "analysis", "discovered", "five", "candidate", "genes", "(ST7,", "FOXP2,", "MDFIC,", "TES", "and", "CAV1)", "whose", "frequencies", "of", "LOH", "were", "higher", "than", "30%.", "However,", "only", "TES", "showed", "the", "potential", "to", "be", "a", "TSG", "associated", "with", "GC.", "Among", "140", "pairs", "of", "GC", "samples,", "decreased", "TES", "mRNA", "level", "was", "found", "in", "96", "(68.6%)", "tumor", "tissues", "when", "compared", "with", "matched", "non-tumor", "tissues", "(p", "<", "0.001).", "Also,", "reduced", "TES", "protein", "level", "was", "detected", "in", "36", "(72.0%)", "of", "all", "50", "tumor", "tissues", "by", "Western", "blot", "(p", "=", "0.001).", "In", "addition,", "immunohistochemical", "staining", "result", "was", "in", "agreement", "with", "that", "of", "RT-PCR", "and", "Western", "blot.", "Down", "regulation", "of", "TES", "was", "shown", "to", "be", "correlated", "with", "tumor", "differentiation", "(p", "=", "0.035)", "and", "prognosis", "(p", "=", "0.035,", "log-rank", "test).", "Its", "overexpression", "inhibited", "the", "growth", "of", "three", "GC", "cell", "lines.", "Hypermethylation", "of", "TES", "promoter", "was", "a", "frequent", "event", "in", "primary", "GC", "and", "GC", "cell", "lines.", "However,", "no", "specific", "gene", "mutation", "was", "observed", "in", "the", "coding", "region", "of", "the", "TES", "gene.", "Conclusions:", "Collectively,", "all", "results", "support", "the", "role", "of", "TES", "as", "a", "TSG", "in", "gastric", "carcinogenesis", "and", "that", "TES", "is", "inactivated", "primarily", "by", "LOH", "and", "CpG", "island", "methylation.", "Background", "Gastric", "cancer", "(GC)", "is", "one", "of", "the", "leading", "causes", "of", "cancer", "mortality", "in", "the", "world,", "particularly", "in", "East", "Asian", "coun-", "tries", "such", "as", "China,", "Japan", "and", "Korea,", "as", "well", "as", "other", "developing", "countries.", "Over", "the", "past", "decades,", "the", "overall", "survival", "for", "GC", "has", "not", "significantly", "improved", "in", "spite", "of", "improvement", "in", "surgical", "technique", "and", "significant", "advancement", "of", "chemotherapy", "and", "radiotherapy", "options", "*", "Correspondence:", "wanghyun@mail.sysu.edu.cn;", "xiajch@mail.sysu.edu.cn", "†", "Contributed", "equally", "1State", "Key", "Laboratory", "of", "Oncology", "in", "Southern", "China", "and", "Department", "of", "Experimental", "Research,", "Sun", "Yat-sen", "University", "Cancer", "Center,", "651", "Dongfeng", "Road", "East,", "Guangzhou", "510060,", "P.", "R.", "China", "[1].", "Therefore,", "it", "is", "important", "to", "understand", "the", "molecu-", "lar", "mechanisms", "involved", "in", "the", "carcinogenesis", "of", "GC.", "Loss", "of", "heterozygosity", "(LOH)", "at", "specific", "sites", "of", "the", "cancer", "genome", "is", "considered", "to", "embody", "tumor", "suppres-", "sor", "genes", "(TSGs).", "Frequent", "LOH", "at", "7q31.1/2", "has", "been", "detected", "in", "many", "human", "malignancies", "including", "GC", "[2].", "Recently,", "we", "found", "a", "high", "frequency", "of", "LOH", "region", "on", "7q31", "in", "primary", "GC", "from", "China,", "and", "identified", "D7S486", "to", "be", "the", "most", "frequent", "LOH", "locus", "[3].", "This", "study", "was", "designed", "to", "explore", "what", "TSGs", "associated", "with", "GC", "were", "located", "around", "D7S486", "in", "this", "region.", "Using", "microarray", "technology,", "a", "high-throughput", "single", "nucleotide", "polymorphisms", "(SNP)", "genotyping", "system", "was", "©", "2010", "Ma", "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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[ "Retrovirology", "Research", "Induction", "of", "the", "HIV-1", "Tat", "co-factor", "cyclin", "T1", "during", "monocyte", "differentiation", "is", "required", "for", "the", "regulated", "expression", "of", "a", "large", "portion", "of", "cellular", "mRNAs", "Wendong", "Yu1,", "Yan", "Wang1,", "Chad", "A", "Shaw2,", "Xiao-Feng", "Qin3", "and", "Andrew", "P", "Rice*1", "BioMed", "Central", "Open", "Access", "Address:", "1Department", "of", "Molecular", "Virology", "and", "Microbiology,", "Baylor", "College", "of", "Medicine,", "Houston,", "Texas", "77030,", "USA,", "2Department", "of", "Human", "and", "Molecular", "Genetics,", "Baylor", "College", "of", "Medicine,", "Houston,", "Texas,", "USA", "and", "3Center", "for", "Cancer", "Immunology", "Research,", "Department", "of", "Immunology,", "The", "University", "of", "Texas", "M.D.", "Anderson", "Cancer", "Center,", "Houston,", "Texas,", "USA", "Email:", "Wendong", "Yu", "-", "wy132177@bcm.tmc.edu;", "Yan", "Wang", "-", "yw135452@bcm.tmc.edu;", "Chad", "A", "Shaw", "-", "cashaw@bcm.tmc.edu;", "Xiao-", "Feng", "Qin", "-", "fqin@mdanderson.org;", "Andrew", "P", "Rice*", "-", "arice@bcm.tmc.edu", "*", "Corresponding", "author", "Published:", "09", "June", "2006", "Retrovirology", "2006,", "3:32", "doi:10.1186/1742-4690-3-32", "This", "article", "is", "available", "from:", "http://www.retrovirology.com/content/3/1/32", "Received:", "27", "April", "2006", "Accepted:", "09", "June", "2006", "©", "2006", "Yu", "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:", "P-TEFb,", "a", "general", "RNA", "polymerase", "II", "elongation", "factor,", "is", "composed", "of", "CDK9", "(cyclin-dependent", "kinase", "9)", "as", "a", "catalytic", "unit", "and", "either", "cyclin", "T1,", "T2", "or", "K", "as", "a", "regulatory", "subunit.", "The", "cyclin", "T1/P-TEFb", "complex", "is", "targeted", "by", "HIV", "to", "mediate", "Tat", "transactivation.", "Cyclin", "T1", "protein", "expression", "is", "induced", "during", "early", "macrophage", "differentiation,", "suggesting", "a", "role", "in", "regulation", "of", "mRNA", "expression", "during", "the", "differentiation", "process.", "To", "study", "the", "functional", "significance", "of", "cyclin", "T1", "induction", "during", "differentiation,", "we", "utilized", "the", "human", "Mono", "Mac", "6", "(MM6)", "monocytic", "cell", "line.", "Results:", "We", "found", "that", "cyclin", "T1", "protein", "expression", "is", "induced", "by", "a", "post-transcriptional", "mechanism", "following", "PMA", "treatment", "of", "MM6", "cells,", "similar", "to", "its", "induction", "in", "primary", "monocytes", "and", "macrophages.", "Also", "in", "agreement", "with", "findings", "in", "primary", "cells,", "cyclin", "T2a", "is", "present", "at", "relatively", "high", "levels", "in", "MM6", "cells", "and", "is", "not", "induced", "by", "PMA.", "Although", "the", "knock-down", "of", "cyclin", "T1", "in", "MM6", "cells", "by", "shRNA", "inhibited", "HIV-1", "Tat", "transactivation,", "MM6", "cell", "growth", "was", "not", "affected", "by", "the", "depletion", "of", "cyclin", "T1.", "Using", "DNA", "microarray", "technology,", "we", "found", "that", "more", "than", "20%", "of", "genes", "induced", "by", "PMA", "require", "cyclin", "T1", "for", "their", "normal", "level", "of", "induction,", "and", "approximately", "15%", "of", "genes", "repressed", "by", "PMA", "require", "cyclin", "T1", "for", "their", "normal", "level", "of", "repression.", "Gene", "ontology", "analysis", "indicates", "that", "many", "of", "these", "cyclin", "T1-dependent", "genes", "are", "related", "to", "immune", "response", "and", "signal", "transduction.", "Conclusion:", "These", "results", "suggest", "that", "cyclin", "T1", "serves", "a", "critical", "role", "in", "the", "program", "of", "macrophage", "differentiation,", "and", "this", "raises", "questions", "about", "the", "feasibility", "of", "cyclin", "T1", "serving", "as", "an", "antiviral", "therapeutic", "target.", "Background", "Mammalian", "RNA", "polymerase", "II", "transcription", "(RNAP", "II)", "is", "a", "complex", "and", "coordinated", "process", "and", "its", "regulation", "is", "involved", "in", "many", "important", "cellular", "events", "such", "as", "differ-", "entiation,", "activation,", "and", "stress", "response.", "While", "the", "regu-", "lation", "of", "transcription", "initiation", "has", "been", "an", "actively", "Page", "1", "of", "16", "(page", "number", "not", "for", "citation", "purposes)" ]

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[ "International", "Seminars", "in", "Surgical", "Oncology", "Case", "report", "Tattoo", "pigment", "in", "an", "axillary", "lymph", "node", "simulating", "metastatic", "malignant", "melanoma", "CM", "Jack,", "A", "Adwani*", "and", "H", "Krishnan", "BioMed", "Central", "Open", "Access", "Address:", "Breast", "Unit", "and", "Pathology", "Department", "Mayday", "University", "Hospital,", "London", "Road,", "Croydon,", "CR7", "7YE,", "Surrey", "UK", "Email:", "CM", "Jack", "-", "chrisjack@doctors.org.uk;", "A", "Adwani*", "-", "ashaadwani@doctors.org.uk;", "H", "Krishnan", "-", "hari.krishnan@mayday.nhs.uk", "*", "Corresponding", "author", "Published:", "01", "December", "2005", "International", "Seminars", "in", "Surgical", "Oncology", "2005,", "2:28", "doi:10.1186/1477-7800-2-28", "This", "article", "is", "available", "from:", "http://www.issoonline.com/content/2/1/28", "Received:", "28", "August", "2005", "Accepted:", "01", "December", "2005", "©", "2005", "Jack", "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.", "Tattoo", "PigmentLymphadenopathyMalignant", "Melanoma", "Abstract", "We", "report", "a", "case", "of", "axillary", "lymphadenopathy", "thirty", "years", "after", "a", "decorative", "tattoo", "clinically", "mimicking", "metastatic", "melanoma.", "The", "importance", "of", "relying", "on", "histological", "confirmation", "of", "metastatic", "disease", "before", "altering", "extent", "of", "surgery", "is", "discussed.", "The", "importance", "of", "recording", "presence", "of", "decorative", "tattoos", "is", "stressed.", "Background", "The", "presence", "of", "lymphadenopathy", "requires", "further", "inves-", "tigation.", "Often", "its", "presence", "is", "explained", "by", "a", "simple", "viral", "illness", "or", "trauma.", "Rarer", "causes", "are", "often", "made", "apparent", "by", "thorough", "history", "taking", "and", "examination.", "The", "need", "for", "a", "biopsy", "is", "controversial.", "We", "report", "a", "case", "where", "the", "answer", "may", "have", "been", "staring", "us", "in", "the", "face", "if", "we", "knew", "where", "to", "look.", "The", "fact", "that", "a", "tattoo", "causes", "lymphadenopathy", "is", "well", "known", "in", "the", "acute", "phase.", "This", "is", "thought", "to", "be", "due", "to", "local", "inflammation", "from", "the", "initial", "insult.", "However,", "to", "our", "knowledge", "there", "have", "been", "no", "reports", "of", "a", "palpable", "node", "after", "time", "delay", "this", "long.", "Case", "report", "A", "54", "year", "old", "man", "presented", "with", "a", "lump", "in", "the", "right", "axilla", "of", "six", "months", "duration.", "The", "lump", "was", "non", "tender", "and", "had", "not", "changed", "in", "size.", "He", "complained", "of", "weight", "loss", "of", "5", "kg", "over", "the", "past", "two", "months.", "He", "denied", "foreign", "travel,", "night", "sweats,", "recent", "injury,", "cough,", "or", "the", "presence", "of", "any", "other", "lumps.", "His", "past", "medical", "history", "was", "unre-", "markable.", "There", "was", "no", "family", "history", "of", "breast", "or", "bowel", "cancer.", "The", "lump", "was", "clinically", "palpable", "and", "measured", "3", "cm.", "It", "was", "firm,", "non", "tender,", "not", "attached", "to", "the", "skin", "or", "deep", "tissues", "and", "was", "consistent", "with", "a", "clinical", "diagnosis", "of", "axillary", "lymphadenopathy.", "The", "left", "axilla", "and", "supraclavic-", "ular", "fossae", "were", "normal.", "There", "was", "no", "skin", "lesion", "in", "the", "drainage", "area", "of", "the", "axilla.", "Examination", "of", "the", "breasts,", "chest", "and", "abdomen", "were", "unremarkable.", "Haematology,", "Biochemistry", "and", "Chest", "X-rays", "were", "normal.", "Ultrasound", "confirmed", "a", "benign", "appearing", "lymph", "node", "with", "a", "fatty", "centre.", "In", "view", "of", "the", "size", "and", "longstanding", "nature", "of", "the", "lymph", "node,", "an", "excision", "biopsy", "was", "performed.", "At", "sur-", "gery", "the", "node", "was", "firm,", "suspicious", "and", "black", "in", "colour.", "On", "histology,", "the", "specimen", "of", "the", "lymph", "node", "with", "attached", "fatty", "tissue", "measured", "3", "×", "2", "×", "0.8", "cms.", "Black", "dis-", "colouration", "was", "present", "on", "the", "cut", "surface.", "Microscopic", "examination", "of", "the", "routine", "haematoxylin", "and", "eosin", "sections", "of", "the", "lymph", "node", "showed", "preserva-", "tion", "of", "architecture", "with", "follicular", "hyperplasia.", "Black", "car-", "bon", "like", "pigment", "was", "seen", "lying", "within", "the", "macrophages", "and", "dispersed", "outside", "them", "in", "the", "sinuses.", "There", "was", "asso-", "Page", "1", "of", "3", "(page", "number", "not", "for", "citation", "purposes)" ]

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[ "EPMA", "Journal", "(2010)", "1:421–437", "DOI", "10.1007/s13167-010-0044-z", "REVIEW", "ARTICLE", "Prediction", "and", "prognosis:", "impact", "of", "gene", "expression", "profiling", "in", "personalized", "treatment", "of", "breast", "cancer", "patients", "Michael", "R.", "Mallmann", "&", "Andrea", "Staratschek-Jox", "&", "Christian", "Rudlowski", "&", "Michael", "Braun", "&", "Andrea", "Gaarz", "&", "Matthias", "Wolfgarten", "&", "Walther", "Kuhn", "&", "Joachim", "L.", "Schultze", "Received:", "17", "June", "2010", "/", "Accepted:", "12", "July", "2010", "/", "Published", "online:", "20", "August", "2010", "#", "European", "Association", "for", "Predictive,", "Preventive", "and", "Personalised", "Medicine", "2010", "Abstract", "Breast", "cancer", "is", "a", "complex", "disease,", "whose", "heterogeneity", "is", "increasingly", "recognized.", "Despite", "consider-", "able", "improvement", "in", "breast", "cancer", "treatment", "and", "survival,", "a", "significant", "proportion", "of", "patients", "seems", "to", "be", "over-", "or", "undertreated.", "To", "date,", "single", "clinicopathological", "parameters", "show", "limited", "success", "in", "predicting", "the", "likelihood", "of", "survival", "or", "response", "to", "endocrine", "therapy", "and", "chemother-", "apy.", "Consequently,", "new", "gene", "expression", "based", "prognostic", "and", "predictive", "tests", "are", "emerging", "that", "promise", "an", "improve-", "ment", "in", "predicting", "survival", "and", "therapy", "response.", "Initial", "evidence", "has", "emerged", "that", "this", "leads", "to", "allocation", "of", "fewer", "patients", "into", "high-risk", "groups", "allowing", "a", "reduction", "of", "chemotherapy", "treatment.", "Moreover,", "pattern-based", "approaches", "have", "also", "been", "developed", "to", "predict", "response", "to", "endocrine", "therapy", "or", "particular", "chemotherapy", "regimens.", "Irrespective", "of", "current", "pitfalls", "such", "as", "lack", "of", "validation", "and", "standardization,", "these", "pattern-based", "biomarkers", "will", "prove", "useful", "for", "clinical", "decision", "making", "in", "the", "near", "future,", "especially", "if", "more", "patients", "get", "access", "to", "this", "form", "of", "personalized", "medicine.", "Keywords", "Gene", "expression", "profile", ".", "Microarray", ".", "Breast", "cancer", ".", "Prediction", ".", "Prognosis", ".", "Pattern-based", "biomarkers", "M.", "R.", "Mallmann", "(*)", ":", "C.", "Rudlowski", ":", "M.", "Braun", ":", "M.", "Wolfgarten", ":", "W.", "Kuhn", "Department", "of", "Obstetrics", "&", "Gynecology,", "Center", "for", "Integrated", "Oncology,", "University", "Hospital", "of", "Bonn,", "Sigmund-Freud-Strasse", "25,", "53105", "Bonn,", "Germany", "e-mail:", "michael.mallmann@ukb.uni-bonn.de", "M.", "R.", "Mallmann", ":", "A.", "Staratschek-Jox", ":", "A.", "Gaarz", ":", "J.", "L.", "Schultze", "LIMES", "(Life", "and", "Medical", "Sciences", "Bonn)", "Institute,", "Genomics", "and", "Immunoregulation,", "University", "Bonn,", "Carl-Troll-Strasse", "31,", "53115", "Bonn,", "Germany", "Introduction", "Breast", "cancer", "is", "the", "most", "common", "cancer", "of", "women", "in", "the", "western", "world.", "The", "overall", "death", "rate", "has", "been", "significantly", "reduced", "in", "the", "last", "decades,", "but", "depending", "on", "subtype", "and", "stage,", "still", "a", "significant", "portion", "of", "patients", "will", "suffer", "from", "relapse", "or", "even", "die", "of", "the", "disease", "[1,", "2].", "While", "up", "to", "70%", "of", "patients", "with", "breast", "cancer", "can", "be", "cured", "nowadays,", "a", "significant", "proportion", "of", "these", "patients", "is", "overtreated.", "It", "remains", "a", "challenge", "to", "identify", "those", "patients", "who", "will", "indeed", "profit", "from", "current", "treatment", "strategies", "and", "also", "to", "develop", "innovative", "concepts", "for", "patients", "currently", "at", "high-", "risk", "for", "relapse", "after", "treatment.", "For", "this", "reason,", "the", "identification", "of", "reliable", "prognostic", "biomarkers", "together", "with", "the", "development", "of", "clinically", "efficient", "therapies", "is", "urgently", "needed", "[3].", "Today,", "the", "prognostic", "clustering", "of", "breast", "cancer", "in", "daily", "routine", "relies", "on", "the", "determination", "of", "a", "limited", "set", "of", "molecular", "markers", "(e.g.", "estrogen", "receptor", "(ER),", "progesterone", "receptor", "(PR)", "and", "epidermal-growth-factor", "receptor", "2", "(HER2,", "also", "referred", "to", "as", "Her2/neu,", "ErbB-2))", "mostly", "by", "semi-quantitative", "assays", "e.g.", "by", "immunohistochemistry", "(Fig.", "1).", "Clearly,", "some", "of", "these", "markers", "are", "first", "examples", "of", "personalized", "medicine", "and", "targeted", "treatment", "since", "for", "instance", "only", "the", "determination", "of", "ER-expression", "by", "immunohistochemistry", "allows", "for", "a", "directed", "anti-hormonal", "therapy", "with", "receptor", "blockade", "or", "inhibition,", "or", "both.", "[4].", "Moreover", "HER2-overexpression", "has", "paved", "the", "way", "for", "anti-", "HER2", "treatment", "with", "the", "humanized", "monoclonal", "antibody", "trastuzumab", "[5–7]", "or", "the", "small-molecule", "inhibitor", "of", "the", "tyrosine", "kinase", "domains", "of", "HER1", "and", "HER2,", "lapatinib", "[8–", "10].", "The", "best", "HER2-targeted", "treatment", "option", "together", "with", "chemotherapy", "in", "patients", "with", "metastasized", "but", "operable", "breast", "cancer", "is", "currently", "assessed", "in", "clinical", "trials", "[11].", "In", "addition", "to", "tissue", "based", "markers", "that", "have", "prognostic", "and", "predictive", "value,", "blood-based", "proteomic", "tests", "for", "early" ]

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[ "International", "Scholarly", "Research", "Network", "ISRN", "Neurology", "Volume", "2012,", "Article", "ID", "427102,", "6", "pages", "doi:10.5402/2012/427102", "Review", "Article", "Depression", "in", "Multiple", "Sclerosis:", "A", "Review", "of", "Assessment", "and", "Treatment", "Approaches", "in", "Adult", "and", "Pediatric", "Populations", "Maria", "Skokou,", "Evanthia", "Soubasi,", "and", "Philippos", "Gourzis", "Department", "of", "Psychiatry,", "School", "of", "Medicine", "and", "University", "Hospital", "of", "Patras,", "University", "of", "Patras,", "Rio,", "26504", "Patras,", "Greece", "Correspondence", "should", "be", "addressed", "to", "Philippos", "Gourzis,", "pgourzis@upatras.gr", "Received", "26", "August", "2012;", "Accepted", "17", "September", "2012", "Academic", "Editors:", "M.", "G.", "Grasso", "and", "Y.", "Wang", "Copyright", "©", "2012", "Maria", "Skokou", "et", "al.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Multiple", "sclerosis", "is", "a", "chronic", "demyelinating", "disease", "affecting", "one", "million", "people", "worldwide,", "with", "a", "significant", "burden", "of", "psychiatric", "comorbidity.", "Depression", "is", "the", "commonest", "psychiatric", "manifestation", "but", "still", "remains", "largely", "underdiagnosed", "and", "undertreated.", "The", "present", "work", "reviews", "current", "knowledge", "on", "diagnosis,", "assessment,", "and", "somatic", "and", "psychotherapeutic", "treatment", "interventions", "for", "depression", "in", "adult", "and", "pediatric", "populations", "of", "patients", "with", "multiple", "sclerosis.", "1.", "Introduction", "Multiple", "sclerosis", "is", "a", "chronic", "demyelinating", "disease", "of", "the", "central", "nervous", "system,", "affecting", "any", "part", "of", "the", "CNS,", "but", "mostly", "white", "matter", "tracts", "in", "the", "cerebral", "hemispheres,", "optic", "nerves,", "brainstem,", "cerebellum,", "and", "spinal", "cord", "[1].", "The", "prevalence", "of", "the", "disorder", "ranges", "between", "2", "and", "150/100,000", "depending", "on", "the", "country", "or", "specific", "population", "[2],", "affect-", "ing", "approximately", "1", "million", "people", "worldwide", "[3].", "Pediatric-", "onset", "cases", "comprise", "2–5%", "of", "total", "multiple", "sclerosis", "patients", "[4].", "Psychiatric", "symptoms", "in", "the", "context", "of", "MS", "were", "first", "noted", "by", "Charcot,", "who", "described", "mania,", "hallucinations,", "and", "depression", "among", "other", "manifestations", "of", "the", "disease", "[5].", "Lifetime", "prevalence", "of", "major", "depression", "ranges", "from", "19", "to", "54%,", "depending", "on", "the", "population", "sample", "and", "diagnostic", "criteria", "used", "[6–8].", "Annual", "prevalence", "is", "estimated", "at", "16%", "[9],", "and", "point", "prevalence", "of", "clinically", "significant", "depressive", "symptoms", "is", "as", "high", "as", "50%", "[10].", "The", "rate", "of", "depressive", "disorders", "in", "a", "pediatric", "population", "with", "demyelinating", "dis-", "ease", "has", "been", "estimated", "at", "27%", "[11].", "Evidently,", "prevalence", "is", "considerably", "higher", "than", "in", "the", "general", "population", "or", "among", "patients", "with", "general", "medical", "conditions", "other", "than", "MS", "[8].", "Etiologic", "factors", "seem", "to", "be", "both", "biological", "and", "psychosocial", "[12],", "and", "risk", "factors", "have", "been", "reported", "to", "be", "female", "sex,", "age", "<35", "years,", "family", "history", "of", "major", "depression,", "and", "a", "high", "level", "of", "stress", "[13].", "Disease-modifying", "agents,", "interferon", "beta", "in", "particular,", "have", "also", "been", "suspected", "to", "induce", "depressive", "symptomatology", "[14,", "15].", "However,", "subsequent", "well-designed", "studies", "failed", "to", "prove", "a", "depressogenic", "effect,", "and", "pretreatment", "depressed", "mood", "was", "found", "to", "be", "the", "best", "predictor", "of", "subsequent", "depression", "[16,", "17].", "The", "importance", "of", "this", "clinical", "issue", "cannot", "be", "underestimated,", "given", "its", "high", "frequency,", "the", "possible", "adverse", "effects", "of", "depression", "on", "disease", "course", "[18],", "cognitive", "functioning", "[19],", "treatment", "adherence", "[20],", "deleterious", "consequences", "on", "quality", "of", "life", "[21],", "and", "increased", "risk", "of", "suicide", "[22,", "23].", "Unfortunately,", "mental", "comorbidity", "and", "depression", "in", "particular", "are", "frequently", "underdiagnosed", "and", "undertreated,", "with", "reported", "rates", "of", "missed", "diagnosis", "around", "23–30%", "[6,", "24]", "and", "rates", "of", "inadequate", "treatment", "around", "20%–36%", "of", "those", "reporting", "depression", "[6,", "25].", "In", "a", "cross-section-", "al", "community", "study", "of", "patients", "with", "MS", "by", "Cetin", "et", "al.", "[26],", "59%", "of", "the", "patients", "who", "had", "significant", "symptoms", "of", "depression", "were", "not", "taking", "medication,", "possibly", "due", "to", "missed", "diagnosis,", "denial", "of", "symptoms,", "or", "false", "reporting,", "whereas", "the", "rest", "41%", "received", "inadequate", "treatment.", "In", "the", "whole", "sample", "(n", "=", "542),", "28%", "of", "the", "patients", "were", "adequately", "treated", "for", "depression", "and", "therefore", "had", "achieved", "remission.", "In", "another", "study", "by", "Mohr", "et", "al.", "[27],", "65.6%", "of", "depressed", "patients", "did", "not", "receive", "medication,", "4,7%", "received", "subthreshold", "treatment,", "26,6%", "received", "threshold,", "and", "only" ]

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[ "Vacuolar", "Storage", "Proteins", "Are", "Sorted", "in", "the", "cis-Cisternae", "of", "the", "Pea", "Cotyledon", "Golgi", "Apparatus", "Stefan", "Hillmer,", "Ali", "Movafeghi,", "David", "G.", "Robinson,", "and", "Giselbert", "Hinz", "Department", "of", "Structural", "Cell", "Physiology,", "Albrecht-von-Haller", "Institute", "for", "Plant", "Sciences,", "University", "of", "Göttingen,", "37073", "Göttingen,", "Germany", "Abstract.", "Developing", "pea", "cotyledons", "contain", "function-", "ally", "different", "vacuoles,", "a", "protein", "storage", "vacuole", "and", "a", "lytic", "vacuole.", "Lumenal", "as", "well", "as", "membrane", "proteins", "of", "the", "protein", "storage", "vacuole", "exit", "the", "Golgi", "apparatus", "in", "dense", "vesicles", "rather", "than", "in", "clathrin-coated", "vesicles", "(CCVs).", "Although", "the", "sorting", "receptor", "for", "vacuolar", "hy-", "drolases", "BP-80", "is", "present", "in", "CCVs,", "it", "is", "not", "detectable", "in", "dense", "vesicles.", "To", "localize", "these", "different", "vacuolar", "sorting", "events", "in", "the", "Golgi,", "we", "have", "compared", "the", "dis-", "tribution", "of", "vacuolar", "storage", "proteins", "and", "of", "a-TIP,", "a", "membrane", "protein", "of", "the", "protein", "storage", "vacuole,", "with", "the", "distribution", "of", "the", "vacuolar", "sorting", "receptor", "BP-80", "across", "the", "Golgi", "stack.", "Analysis", "of", "immunogold", "label-", "ing", "from", "cryosections", "and", "from", "high", "pressure", "frozen", "Introduction", "It", "is", "now", "well", "established", "that", "plants", "are", "unique", "in", "harbor-", "ing", "functionally", "different", "vacuoles", "in", "a", "single", "cell", "(Hoh", "et", "al.,", "1995;", "Paris", "et", "al.,", "1996;", "Di", "Sansebastiano", "et", "al.,", "1998;", "Swanson", "et", "al.,", "1998).", "These", "vacuoles", "are", "characterized", "by", "the", "presence", "of", "distinct", "aquaporins,", "members", "of", "the", "family", "of", "major", "intrinsic", "proteins", "(MIPs;", "Weig", "et", "al.,", "1997;", "Jauh", "et", "al.,", "1998,", "1999)", "in", "their", "membranes,", "and", "by", "the", "differential", "distribution", "of", "hydrolases", "and", "storage", "proteins", "in", "their", "lu-", "men", "(Hara-Nishimura", "and", "Maeshima,", "2000).", "Lumenal", "vacuolar", "proteins", "appear", "to", "reach", "the", "protein", "storage", "vac-", "uole", "(PSV)1", "in", "one", "of", "three", "ways.", "The", "first", "route", "is", "through", "autophagy", "of", "ER-released", "storage", "protein", "aggre-", "gates", "(Levanony", "et", "al.,", "1992).", "The", "second", "route,", "which", "also", "bypasses", "the", "Golgi", "apparatus,", "entails", "the", "release", "of", "vesicles", "from", "the", "ER.", "This", "happens", "with", "storage", "proteins", "during", "PSV", "formation", "in", "pumpkin", "cotyledons.", "Here,", "200-", "Address", "correspondence", "to", "Giselbert", "Hinz,", "Abteilung", "für", "Strukturelle", "Zellphysiologie,", "Albrecht-von-Haller", "Institut", "für", "Pflanzenwissenschaften,", "Georg-August", "Universität,", "Untere", "Karspüle", "2,", "37073-Göttingen,", "Ger-", "many.", "Tel.:", "49-551-397862.", "Fax.:", "49-551-397833.", "E-mail:", "ghinz@gwdg.de", "S.", "Hillmer,", "A.", "Movafeghi,", "and", "D.", "Robinson’s", "present", "address", "is", "Zellen-", "lehre,", "Universität", "Heidelberg,", "Im", "Neuenheimer", "Feld", "230,", "69120", "Heidel-", "berg,", "Germany.", "1Abbreviations", "used", "in", "this", "paper:", "AtALEU,", "Arabidopsis", "thaliana", "Aleu;", "AtELP,", "Arabidopsis", "thaliana", "Elp;", "bF1,", "b-fructosidase;", "CCV,", "clathrin-", "coated", "vesicle;", "DV,", "dense", "vesicle;", "HPF,", "high", "pressure", "frozen;", "MPR,", "man-", "nosyl", "6-phosphate", "receptor;", "PSV,", "protein", "storage", "vacuole;", "VSR,", "vacuolar", "sorting", "receptor.", "samples", "has", "revealed", "a", "steep", "gradient", "in", "the", "distribu-", "tion", "of", "the", "storage", "proteins", "within", "the", "Golgi", "stack.", "In-", "tense", "labeling", "for", "storage", "proteins", "was", "registered", "for", "the", "cis-cisternae,", "contrasting", "with", "very", "low", "labeling", "for", "these", "antigens", "in", "the", "trans-cisternae.", "The", "distribution", "of", "BP-80", "was", "the", "reverse,", "showing", "a", "peak", "in", "the", "trans-", "Golgi", "network", "with", "very", "low", "labeling", "of", "the", "cis-cister-", "nae.", "These", "results", "indicate", "a", "spatial", "separation", "of", "differ-", "ent", "vacuolar", "sorting", "events", "in", "the", "Golgi", "apparatus", "of", "developing", "pea", "cotyledons.", "Key", "words:", "Golgi", "apparatus", "•", "clathrin-coated", "vesicle", "•", "dense", "vesicles", "•", "storage", "protein", "•", "vacuolar", "sorting", "re-", "ceptor", "nm", "diameter", "so-called", "precursor-accumulating", "vesicles", "are", "formed,", "which", "also", "receive", "an", "additional", "vesicular", "contri-", "bution", "from", "the", "Golgi", "apparatus", "en", "route", "to", "the", "PSV", "(Hara-Nishimura", "et", "al.,", "1998).", "It", "can", "also", "occur", "with", "pro-", "teinases", "during", "PSV", "to", "lytic", "vacuole", "transformation", "in", "ger-", "minating", "seeds", "(Toyooka", "et", "al.,", "2000).", "The", "third", "route", "in-", "cludes", "transport", "through", "the", "Golgi", "apparatus", "where", "they", "become", "sorted", "from", "other", "proteins", "of", "the", "secretory", "path-", "way.", "This", "is", "typical", "of", "proteins", "stored", "in", "legumes", "(Robin-", "son", "and", "Hinz,", "1999).", "Receptor-mediated", "sorting", "of", "lysomal/vacuolar", "acid", "hy-", "drolases", "in", "the", "Golgi", "apparatus", "of", "mammalian/yeast", "cells", "occurs", "in", "a", "late", "Golgi", "compartment", "and", "culminates", "in", "their", "packaging", "into", "clathrin-coated", "vesicles", "(CCVs)", "(for", "reviews", "see", "Conibear", "and", "Stevens,", "1998;", "Le", "Borgne", "and", "Hoflack,", "1998).", "Recently,", "a", "family", "of", "vacuolar", "sorting", "receptor", "(VSR)", "proteins", "has", "been", "identified", "from", "widely", "differing", "plant", "species", "(Kirsch", "et", "al.,", "1994;", "Paris", "and", "Rogers,", "1996;", "Ahmed", "et", "al.,", "1997;", "Paris", "et", "al.,", "1997;", "Shimada", "et", "al.,", "1997;", "Laval", "et", "al.,", "1999;", "Miller", "et", "al.,", "1999).", "Both", "the", "pea", "and", "the", "Arabidopsis", "homologues", "localize", "to", "the", "CCV", "(Ahmed", "et", "al.,", "1997;", "Robinson", "et", "al.,", "1998b;", "Sanderfoot", "et", "al.,", "1998;", "Hinz", "et", "al.,", "1999),", "and", "it", "has", "been", "shown", "that", "their", "cytoplas-", "mic", "domains", "bind", "to", "mammalian", "Golgi", "AP-1", "adaptins", "(Robinson", "et", "al.,", "1998b;", "Sanderfoot", "et", "al.,", "1998).", "Thus,", "it", "would", "seem", "that", "receptor–CCV", "adaptin", "interactions", "are", "common", "to", "the", "Golgi", "apparatus", "of", "all", "eukaryotic", "cells.", "ª", "The", "Rockefeller", "University", "Press,", "0021-9525/2001/01/41/10", "$5.00", "The", "Journal", "of", "Cell", "Biology,", "Volume", "152,", "Number", "1,", "January", "8,", "2001", "41–50", "http://www.jcb.org/cgi/content/full/152/1/41", "41" ]

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[ "Acta", "Crystallographica", "Section", "E", "Structure", "Reports", "Online", "ISSN", "1600-5368", "Ethyl", "3-(4-methylbenzylidene)carbazate", "Yu-Feng", "Li,a", "Wen-Hai", "Shengb", "and", "Fang-Fang", "Jianc*", "aMicroscale", "Science", "Institute,", "Department", "of", "Chemistry", "and", "Chemical", "Engineering,", "Weifang", "University,", "Weifang", "261061,", "People’s", "Republic", "of", "China,", "bDepartment", "of", "Chemistry", "and", "Chemical", "Engineering,", "Weifang", "University,", "Weifang", "261061,", "People’s", "Republic", "of", "China,", "and", "cMicroscale", "Science", "Institute,", "Weifang", "University,", "Weifang", "261061,", "People’s", "Republic", "of", "China", "Correspondence", "e-mail:", "liyufeng8111@163.com", "Received", "26", "May", "2010;", "accepted", "31", "May", "2010", "Key", "indicators:", "single-crystal", "X-ray", "study;", "T", "=", "293", "K;", "mean", "(C–C)", "=", "0.002", "A˚;", "R", "factor", "=", "0.055;", "wR", "factor", "=", "0.185;", "data-to-parameter", "ratio", "=", "18.9.", "There", "are", "two", "molecules", "in", "the", "asymmetric", "unit", "of", "the", "title", "compound,", "C11H14N2O2,", "which", "have", "similar", "conformations.", "In", "the", "crystal,", "the", "molecules", "are", "linked", "by", "N—H", "O", "hydrogen", "bonds,", "generating", "C(4)", "chains", "propagating", "in", "[001].", "Related", "literature", "For", "background", "to", "Schiff", "bases", "with", "additional", "donor", "groups,", "see:", "Borisova", "et", "al.", "(2007);", "Gradinaru", "et", "al.", "(2007).", "For", "a", "related", "structure,", "see:", "Li", "et", "al.", "(2009).", "Experimental", "Crystal", "data", "C11H14N2O2", "Mr", "=", "206.24", "Monoclinic,", "P21=c", "a", "=", "15.251", "(3)", "A˚", "b", "=", "8.2853", "(17)", "A˚", "c", "=", "18.139", "(4)", "A˚", "=", "101.85", "(3)", "V", "=", "2243.3", "(8)", "A˚", "3", "Data", "collection", "Bruker", "SMART", "CCD", "diffractometer", "21172", "measured", "reflections", "Refinement", "R[F", "2", ">", "2", "(F", "2)]", "=", "0.055", "wR(F", "2)", "=", "0.185", "S", "=", "1.08", "5128", "reflections", "Table", "1", "Hydrogen-bond", "geometry", "(A˚", ",", ").", "D—H", "A", "N1B—H1BA", "N1A—H1AA", "O1A", "O1Bi", "Symmetry", "code:", "(i)", "x;", "y", "þ", "32;", "z", "þ", "12.", "D—H", "0.86", "0.86", "organic", "compounds", "Z", "=", "8", "Mo", "K", "radiation", "=", "0.09", "mm", "1", "T", "=", "293", "K", "0.22", "0.21", "0.20", "mm", "5128", "independent", "reflections", "3927", "reflections", "with", "I", ">", "2", "(I)", "Rint", "=", "0.037", "272", "parameters", "H-atom", "parameters", "constrained", "max", "=", "0.24", "e", "A˚", "3", "min", "=", "0.30", "e", "A˚", "3", "H", "2.03", "2.13", "A", "D", "A", "2.8747", "(17)", "2.9383", "(17)", "D—H", "A", "165", "157", "Data", "collection:", "SMART", "(Bruker,", "1997);", "cell", "refinement:", "SAINT", "(Bruker,", "1997);", "data", "reduction:", "SAINT;", "program(s)", "used", "to", "solve", "structure:", "SHELXS97", "(Sheldrick,", "2008);", "program(s)", "used", "to", "refine", "structure:", "SHELXL97", "(Sheldrick,", "2008);", "molecular", "graphics:", "SHELXTL", "(Sheldrick,", "2008);", "software", "used", "to", "prepare", "material", "for", "publication:", "SHELXTL.", "Supplementary", "data", "and", "figures", "for", "this", "paper", "are", "available", "from", "the", "IUCr", "electronic", "archives", "(Reference:", "HB5473).", "References", "Borisova,", "N.", "E.,", "Reshetova,", "M.", "D.", "&", "Ustynyuk,", "Y.", "A.", "(2007).", "Chem.", "Rev.", "107,", "46–79.", "Bruker", "(1997).", "SMART", "and", "SAINT", "Bruker", "AXS", "Inc.,", "Madison,", "Wisconsin,", "USA.", "Gradinaru,", "J.,", "Forni,", "A.", "&", "Druta,", "V.", "(2007).", "Inorg.", "Chem.", "46,", "884–895.", "Li,", "Y.-F.,", "Liu,", "H.-X.", "&", "Jian,", "F.-F.", "(2009).", "Acta", "Cryst.", "E65,", "o2959.", "Sheldrick,", "G.", "M.", "(2008).", "Acta", "Cryst.", "A64,", "112–122.", "Acta", "Cryst.", "(2010).", "E66,", "o1565", "doi:10.1107/S1600536810020623", "Li", "et", "al.", "o1565" ]

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[ "European", "Journal", "of", "Histochemistry", "2012;", "volume", "56:e9", "PARP-1", "protein", "expression", "in", "glioblastoma", "multiforme", "A.", "Galia,1", "A.E.", "Calogero,2", "R.A.", "Condorelli,2", "F.", "Fraggetta,1", "C.", "La", "Corte,1", "F.", "Ridolfo,3", "P.", "Bosco,4", "R.", "Castiglione,2", "M.", "Salemi4", "1Unit", "of", "Pathology,", "Cannizzaro", "Hospital,", "Catania;", "2Section", "of", "Endocrinology,", "Andrology", "and", "Internal", "Medicine,", "Department", "of", "Internal", "Medicine", "and", "Systemic", "Diseases,", "University", "of", "Catania;", "3Post-graduate", "School", "in", "Clinical", "Biochemistry,", "University", "of", "Milan;", "4Laboratory", "of", "Cytogenetics,", "Oasi", "Institute", "for", "Research", "on", "Mental", "Retardation", "and", "Brain", "Aging,", "Troina,", "Italy", "Abstract", "One", "of", "the", "most", "common", "type", "of", "primary", "brain", "tumors", "in", "adults", "is", "the", "glioblastoma", "mul-", "tiforme", "(GBM)", "(World", "Health", "Organization", "grade", "IV", "astrocytoma).", "It", "is", "the", "most", "common", "malignant", "and", "aggressive", "form", "of", "glioma", "and", "it", "is", "among", "the", "most", "lethal", "ones.", "Poly", "(ADP-", "ribose)", "polymerase", "1", "(PARP-1)", "gene,", "located", "to", "1q42,", "plays", "an", "important", "role", "for", "the", "efficient", "maintenance", "of", "genome", "integrity.", "PARP-1", "pro-", "tein", "is", "required", "for", "the", "apoptosis-inducing", "fac-", "tor", "(AIF)", "translocation", "from", "the", "mitochondria", "to", "the", "nucleus.", "PARP-1", "is", "proteolytically", "cleaved", "at", "the", "onset", "of", "apoptosis", "by", "caspase-3.", "Microarray", "analysis", "of", "PARP-1", "gene", "expression", "in", "more", "than", "8000", "samples", "revealed", "that", "PARP-1", "is", "more", "highly", "expressed", "in", "several", "types", "of", "cancer", "compared", "with", "the", "equivalent", "normal", "tissues.", "Overall,", "the", "most", "differences", "in", "PARP-1", "gene", "expression", "have", "been", "observed", "in", "breast,", "ovarian,", "endometrial,", "lung,", "and", "skin", "cancers,", "and", "non-Hodgkin’s", "lymphoma.", "We", "evaluated", "the", "expression", "of", "PARP-1", "protein", "in", "normal", "brain", "tissues", "and", "primary", "GBM", "by", "immunohistochemistry.", "Positive", "nuclear", "PARP-1", "staining", "was", "found", "in", "all", "samples", "with", "GBM,", "but", "not", "in", "normal", "neurons", "from", "controls", "(n=4)", "and", "GBM", "patients", "(n=27).", "No", "cytoplas-", "mic", "staining", "was", "observed", "in", "any", "sample.", "In", "conclusion,", "PARP-1", "gene", "is", "expressed", "in", "GBM.", "This", "finding", "may", "be", "envisioned", "as", "an", "attempt", "to", "trigger", "apoptosis", "in", "this", "tumor,", "as", "well", "as", "in", "many", "other", "malignancies.", "The", "presence", "of", "the", "protein", "exclusively", "at", "the", "nucleus", "further", "sup-", "port", "the", "function", "played", "by", "this", "gene", "in", "genome", "integrity", "maintenance", "and", "apoptosis.", "Finally,", "PARP-1", "staining", "may", "be", "used", "as", "GBM", "cell", "marker.", "Introduction", "Glioblastoma", "multiforme", "(GBM),", "or", "World", "Health", "Organization", "(WHO)", "grade", "IV", "astrocy-", "toma,", "is", "the", "most", "common", "type", "of", "primary", "brain", "tumor", "in", "adults.", "In", "addition,", "it", "is", "the", "most", "malignant", "and", "aggressive", "form", "of", "glioma", "and", "among", "the", "most", "lethal", "ones", "because", "of", "its", "highly", "invasive", "potential", "and", "least", "effective", "treatment", "available", "among", "solid", "tumors.1", "Various", "genetic", "alterations", "lead", "to", "the", "develop-", "ment", "of", "malignant", "phenotype", "expression", "in", "human", "GBM.2,3", "Heterogeneous", "pathological", "features", "associated", "with", "complex", "molecular", "heterogeneity", "are", "the", "major", "problems", "for", "the", "development", "of", "effective", "drug", "targets.4,5", "GBMs", "can", "arise", "either", "de", "novo", "(primary)", "or", "progress", "to", "GBM", "from", "low", "grade", "gliomas", "(sec-", "ondary)", "with", "two", "distinct", "molecular", "pathways.3", "Significant", "indicators", "of", "anaplasia", "in", "gliomas", "include:", "atypia", "(coarse", "nuclear", "chromatin,", "nuclear", "pleomorphism,", "multinucleation),", "mitotic", "activity,", "cellularity,", "microvascular", "pro-", "liferation,", "and", "necrosis.", "Necrosis", "with", "the", "microvascular", "or", "endothelial", "cell", "proliferations", "is", "a", "histological", "hallmark", "of", "glioblastoma.3-5", "Poly", "(ADP-ribose)", "polymerase", "1", "(PARP-1)", "gene,", "located", "to", "1q42,", "is", "43", "kb-long", "and", "divided", "into", "23", "exons", "(OMIM", "173870).", "Grube", "and", "Burkle6", "suggested", "that", "a", "higher", "PARP-1", "action", "capacity", "may", "contribute", "to", "an", "efficient", "mainte-", "nance", "of", "genome", "integrity.", "Yu", "et", "al.7", "showed", "that", "PARP-1", "activation", "is", "required", "for", "translo-", "cation", "of", "apoptosis-inducing", "factor", "(AIF)", "from", "the", "mitochondria", "to", "the", "nucleus.", "PARP-1", "pro-", "tein", "is", "then", "proteolytically", "cleaved", "at", "the", "onset", "of", "apoptosis", "by", "caspase-3;8", "furthermore,", "PARP-", "1", "activity", "and", "poly", "(ADP-ribose)", "(PAR)", "poly-", "mer,", "mediate", "PARP-1-induced", "cell", "death.8,9", "Genetic", "and", "pharmacological", "studies", "found", "that", "overexpression", "of", "PARP-1", "is", "a", "key", "media-", "tor", "of", "programmed-necrotic", "cell", "death", "in", "vivo.", "In", "addition,", "PARP-1", "appears", "to", "be", "also", "involved", "in", "programmed", "cell", "death", "processes,", "such", "as", "apoptosis", "or", "macroautophagocytotic", "cell", "death.10", "Microarray", "analysis", "showed", "that", "PARP-1", "mRNA", "expression", "in", "histologically", "nor-", "mal", "tissues", "is", "low", "and", "uniform", "across", "a", "wide", "variety", "of", "tissues.11", "Furthermore,", "microarray", "analysis", "of", "PARP-1", "gene", "expression", "in", "more", "than", "8000", "samples", "revealed", "that", "PARP-1", "is", "more", "highly", "expressed", "in", "several", "types", "of", "tumors", "compared", "with", "the", "equivalent", "normal", "tissue.", "Overall,", "the", "most", "striking", "differences", "in", "PARP-1", "gene", "expression", "have", "been", "observed", "in", "breast,", "ovarian,", "endometrial,", "lung,", "skin", "can-", "cers,", "and", "non-Hodgkin’s", "lymphoma.11", "The", "present", "study", "was", "undertaken", "to", "evalu-", "ate", "the", "expression", "of", "PARP-1", "protein", "in", "normal", "brain", "tissues", "and", "primary", "glioblastomas", "(grade", "IV", "WHO)", "with", "immunohistochemistry.", "Correspondence:", "Prof.", "Aldo", "E.", "Calogero,", "Section", "of", "Endocrinology,", "Andrology", "and", "Internal", "Medicine,", "Department", "of", "Internal", "Medicine", "and", "Systemic", "Diseases,", "University", "of", "Catania,", "via", "S.", "Sofia", "78,", "95123", "Catania,", "Italy.", "E-mail:", "acaloger@unict.it", "Key", "words:", "Glioblastoma", "multiforme,", "brain,", "immunohistochemistry,", "PARP-1", "gene.", "Received", "for", "publication:", "26", "November", "2011.", "Accepted", "for", "publication:", "26", "January", "2012.", "This", "work", "is", "licensed", "under", "a", "Creative", "Commons", "Attribution", "NonCommercial", "3.0", "License", "(CC", "BY-", "NC", "3.0).", "©Copyright", "A.", "Galia", "et", "al.,", "2012", "Licensee", "PAGEPress,", "Italy", "European", "Journal", "of", "Histochemistry", "2012;", "56:e9", "doi:10.4081/ejh.2012.e9", "Materials", "and", "Methods", "Patient", "and", "control", "brain", "samples", "The", "comparison", "has", "been", "made", "between:", "i)", "4", "normal", "tissues", "brain", "removed", "with", "post", "mortem", "autopsy", "by", "normal", "donors", "(2", "males", "and", "2", "females);", "ii)", "27", "non-tumor", "peripheral", "tissues", "brain", "removed", "during", "surgical", "resec-", "tion", "on", "patients", "with", "GBM", "and", "27", "tumor", "tis-", "sues", "WHO", "grade", "IV", "GBM,", "specifically,", "by", "14", "male", "patients", "(58.3±10.0", "years)", "and", "13", "female", "patients", "(58.3±12.6", "years)", "(Table", "1).", "Diagnoses", "of", "GBM", "were", "made", "on", "histologi-", "cal", "sections", "stained", "with", "hematoxylin-eosin", "and", "the", "sections", "were", "evaluated", "by", "at", "least", "two", "operators.", "The", "protocol", "was", "approved", "by", "the", "internal", "Institutional", "Review", "Board", "and", "an", "informed", "written", "consent", "was", "obtained", "from", "each", "patient", "with", "GBM", "or,", "if", "deceased,", "by", "his/her", "relatives.", "Immunohistochemical", "staining", "Brain", "sections", "(4", "μm", "thick)", "were", "obtained", "from", "all", "normal", "donors", "and", "GMB", "patients.", "Brain", "sections", "from", "GBM", "patients", "included", "both", "GBM", "and", "normal", "tissue", "(Table", "1).", "All", "sec-", "tions", "were", "formalin-fixed", "and", "paraffin-embed-", "ded", "following", "standard", "methods.", "PARP-(F-2),", "a", "mouse", "monoclonal", "antibody", "raised", "against", "PARP-1", "protein,", "was", "used", "for", "immunohistochemistry", "(Santa", "Cruz", "Biotechnology,", "Inc.,", "Heidelberg,", "Germany)", "PARP-1", "(F-2):", "sc-8007).", "As", "indicated", "by", "the", "manufacturer", "instructions,", "this", "antibody,", "at", "the", "dilution", "of", "1:300,", "has", "been", "shown", "to", "reli-", "ably", "recognize", "PARP-1", "proteins", "in", "glioblas-", "tomas", "and", "normal", "brain", "by", "immunohistochem-", "istry.", "Slides", "were", "deparaffinized,", "rehydrated,", "subjected", "to", "three", "5-min", "cycles", "in", "a", "microwave", "at", "360", "W", "in", "citrate", "buffer,", "preincubated", "in", "3%", "[European", "Journal", "of", "Histochemistry", "2012;", "56:e9]", "[page", "45]" ]

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[ "Editorial", "Ten", "Simple", "Rules", "for", "Getting", "Help", "from", "Online", "Scientific", "Communities", "Giovanni", "M.", "Dall’Olio1*,", "Jacopo", "Marino", "2", ",", "Michael", "Schubert3,", "Kevin", "L.", "Keys1,", "Melanie", "I.", "Stefan4,", "Colin", "S.", "Gillespie5,", "Pierre", "Poulain6,7,8,", "Khader", "Shameer9,10,", "Robert", "Sugar3,", "Brandon", "M.", "Invergo1,", "Lars", "J.", "Jensen11,", "Jaume", "Bertranpetit1,", "Hafid", "Laayouni1", "1", "Institute", "of", "Evolutionary", "Biology", "(UPF-CSIC),", "Departament", "de", "Cie`ncies", "Experimentals", "i", "de", "la", "Salut,", "Barcelona,", "Spain,", "2", "Institute", "of", "Organic", "Chemistry", "Universita¨t", "Zurich,", "Zurich,", "Switzerland,", "3", "EMBL-EBI,", "Wellcome-Trust", "Genome", "Campus,", "Hinxton,", "United", "Kingdom,", "4", "California", "Institute", "of", "Technology,", "Biology", "Division,", "Pasadena,", "California,", "United", "States", "of", "America,", "5", "School", "of", "Mathematics", "&", "Statistics,", "Newcastle", "University,", "Newcastle", "upon", "Tyne,", "United", "Kingdom,", "6", "DSIMB,", "INSERM,", "U665,", "Paris,", "France,", "7", "Univ", "Paris", "Diderot,", "Sorbonne", "Paris", "Cite´,", "UMR-S665,", "Paris,", "France,", "8", "Institut", "National", "de", "la", "Transfusion", "Sanguine,", "Paris,", "France,", "9", "Division", "of", "Cardiovascular", "Diseases,", "Mayo", "Clinic,", "Rochester,", "Minnesota,", "United", "States", "of", "America,", "10", "National", "Centre", "for", "Biological", "Sciences", "(TIFR),", "GKVK", "Campus,", "Bangalore,", "India,", "11", "NNF", "Center", "for", "Protein", "Research,", "Faculty", "of", "Health", "Sciences,", "University", "of", "Copenhagen,", "Copenhagen,", "Denmark", "Introduction", "The", "increasing", "complexity", "of", "research", "requires", "scientists", "to", "work", "at", "the", "intersection", "of", "multiple", "fields", "and", "to", "face", "problems", "for", "which", "their", "formal", "education", "has", "not", "prepared", "them.", "For", "example,", "biologists", "with", "no", "or", "little", "background", "in", "programming", "are", "now", "often", "using", "complex", "scripts", "to", "handle", "the", "results", "from", "their", "experiments;", "vice", "versa,", "programmers", "wishing", "to", "enter", "the", "world", "of", "bioinformatics", "must", "know", "about", "biochemistry,", "genetics,", "and", "other", "fields.", "In", "this", "context,", "communication", "tools", "such", "as", "mailing", "lists,", "web", "forums,", "and", "online", "communities", "acquire", "increasing", "importance.", "These", "tools", "permit", "scientists", "to", "quickly", "contact", "people", "skilled", "in", "a", "specialized", "field.", "A", "question", "posed", "properly", "to", "the", "right", "online", "scientific", "community", "can", "help", "in", "solving", "difficult", "problems,", "often", "faster", "than", "screening", "literature", "or", "writing", "to", "publication", "authors.", "The", "growth", "of", "active", "online", "scientific", "communities,", "such", "as", "those", "listed", "in", "Table", "S1,", "demonstrates", "how", "these", "tools", "are", "becoming", "an", "important", "source", "of", "support", "for", "an", "increasing", "number", "of", "researchers.", "Nevertheless,", "making", "proper", "use", "of", "these", "resources", "is", "not", "easy.", "Adhering", "to", "the", "social", "norms", "of", "World", "Wide", "Web", "communica-", "tion—loosely", "termed", "‘‘netiquette’’—is", "both", "important", "and", "non-trivial.", "In", "this", "article,", "we", "take", "inspiration", "from", "our", "experience", "on", "Internet-shared", "scien-", "tific", "knowledge,", "and", "from", "similar", "docu-", "ments", "such", "as", "‘‘Asking", "the", "Questions", "the", "Smart", "Way’’", "[1]", "and", "‘‘Getting", "Answers’’", "[2],", "to", "provide", "guidelines", "and", "suggestions", "on", "how", "to", "use", "online", "communities", "to", "solve", "scientific", "problems.", "Rule", "1.", "Do", "Not", "Be", "Afraid", "to", "Ask", "a", "Question", "Some", "people", "are", "afraid", "of", "asking", "a", "question", "in", "public,", "for", "fear", "of", "appearing", "ignorant", "or", "foolish.", "Other", "people", "worry", "about", "their", "ability", "to", "express", "the", "question", "proficiently", "or", "with", "the", "correct", "grammar.", "Actually,", "asking", "a", "question", "in", "a", "public", "website", "is", "a", "good", "thing.", "First,", "the", "process", "of", "composing", "a", "message", "to", "explain", "a", "problem", "is", "itself", "a", "great", "exercise.", "Second,", "it", "is", "a", "great", "way", "to", "learn", "faster,", "and", "to", "enter", "into", "contact", "with", "people", "from", "different", "fields.", "Third,", "and", "more", "impor-", "tantly,", "your", "career", "will", "be", "difficult", "if", "you", "do", "not", "learn", "how", "to", "get", "help", "from", "other", "people.", "As", "Albert", "Einstein", "once", "said,", "‘‘The", "important", "thing", "is", "not", "to", "stop", "questioning.", "Curiosity", "has", "its", "own", "reason", "for", "existing’’", "[3].", "Asking", "the", "right", "questions", "should", "always", "be", "a", "priority", "in", "science,", "and", "online", "communities", "are", "a", "good", "place", "to", "practice.", "Rule", "2.", "State", "the", "Question", "Clearly", "The", "key", "to", "getting", "a", "good", "answer", "is", "to", "ask", "the", "question", "in", "a", "clear", "and", "concise", "way.", "If", "your", "question", "is", "too", "long,", "many", "people", "simply", "will", "not", "read", "it.", "On", "the", "contrary,", "if", "your", "question", "is", "too", "short,", "people", "may", "interpret", "it", "incorrectly", "and", "give", "you", "an", "erroneous", "answer.", "A", "way", "to", "keep", "your", "questions", "short", "and", "concise", "is", "to", "systematically", "break", "down", "the", "problem", "into", "smaller", "parts.", "This", "can", "help", "you", "to", "decide", "where", "to", "seek", "help,", "and", "how", "much", "to", "seek.", "If", "you", "feel", "your", "problem", "is", "composed", "of", "multiple", "questions,", "then", "post", "as", "many", "messages", "as", "needed.", "You", "should", "start", "a", "separate", "discussion", "thread", "for", "each", "of", "the", "problems", "you", "want", "to", "solve,", "avoiding", "mixing", "messages", "about", "different", "topics", "together.", "On", "the", "other", "hand,", "you", "should", "provide", "enough", "details", "so", "that", "people", "can", "answer", "you", "without", "having", "to", "ask", "you", "for", "additional", "explanations.", "Read", "the", "message", "you", "wrote", "carefully,", "and", "think", "about", "which", "details", "you", "forgot", "to", "include.", "A", "reader", "should", "be", "able", "to", "answer", "you", "just", "by", "reading", "your", "initial", "message,", "without", "having", "to", "look", "at", "the", "rest", "of", "the", "discussion,", "or", "at", "what", "other", "people", "already", "have", "said", "in", "response.", "Some", "examples", "of", "non-concise", "ques-", "tions", "and", "how", "to", "improve", "them", "are", "shown", "in", "Text", "S1.", "Spend", "as", "much", "time", "as", "you", "need", "in", "preparing", "your", "initial", "message:", "this", "will", "save", "time", "later", "and", "will", "lead", "you", "to", "find", "the", "best", "solution", "more", "easily.", "Many", "people", "are", "surprised", "to", "see", "how", "some-", "Citation:", "Dall’Olio", "GM,", "Marino", "J,", "Schubert", "M,", "Keys", "KL,", "Stefan", "MI,", "et", "al.", "(2011)", "Ten", "Simple", "Rules", "for", "Getting", "Help", "from", "Online", "Scientific", "Communities.", "PLoS", "Comput", "Biol", "7(9):", "e1002202.", "doi:10.1371/journal.pcbi.1002202", "Editor:", "Philip", "E.", "Bourne,", "University", "of", "California", "San", "Diego,", "United", "States", "of", "America", "Published", "September", "29,", "2011", "Copyright:", "2011", "Dall’Olio", "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:", "GMD", "is", "supported", "by", "grants", "SAF-2007-63171", "and", "BFU2010-19443", "(subprogram", "BMC)", "awarded", "by", "Ministerio", "de", "Educaci", "o´n", "y", "Ciencia", "(Spain),", "the", "Direccio´", "General", "de", "Recerca,", "Generalitat", "de", "Catalunya", "(Grup", "de", "Recerca", "Consolidat", "2009", "SGR", "1101)", "to", "JB.", "KLK", "is", "supported", "by", "a", "2010–2011", "Fulbright", "student", "research", "grant", "to", "Spain.", "LJJ", "is", "supported", "by", "a", "donation", "from", "the", "Novo", "Nordisk", "Foundation.", "JM", "is", "supported", "by", "funding", "from", "the", "University", "of", "Zurich.", "MIS", "is", "supported", "by", "a", "long-term", "fellowship", "from", "EMBO.", "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:", "giovanni.dallolio@upf.edu", "PLoS", "Computational", "Biology", "|", "www.ploscompbiol.org", "1", "September", "2011", "|", "Volume", "7", "|", "Issue", "9", "|", "e1002202" ]

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[ "Viruses", "2010,", "2,", "413-434;", "doi:10.3390/v2020413", "OPEN", "ACCESS", "viruses", "ISSN", "1999-4915", "www.mdpi.com/journal/viruses", "Review", "Gert", "Zimmer", "RNA", "Replicons", "-", "A", "New", "Approach", "for", "Influenza", "Virus", "Immunoprophylaxis", "Institute", "of", "Virology", "and", "Immunoprophylaxis", "(IVI),", "Sensemattstrasse", "293,", "CH-3147", "Mittelhäusern,", "Switzerland;", "E-Mail:", "gert.zimmer@ivi.admin.ch;", "Tel.:", "+41-31-848-9211;", "Fax:", "+41-31-848-9222", "Received:", "31", "August", "2009;", "in", "revised", "form:", "25", "January", "2010", "/", "Accepted:", "27", "January", "2010", "/", "Published:", "29", "January", "2010", "Abstract:", "RNA", "replicons", "are", "derived", "from", "either", "positive-", "or", "negative-strand", "RNA", "viruses.", "They", "represent", "disabled", "virus", "vectors", "that", "are", "not", "only", "avirulent,", "but", "also", "unable", "to", "revert", "to", "virulence.", "Due", "to", "autonomous", "RNA", "replication,", "RNA", "replicons", "are", "able", "to", "drive", "high", "level,", "cytosolic", "expression", "of", "recombinant", "antigens", "stimulating", "both", "the", "humoral", "and", "the", "cellular", "branch", "of", "the", "immune", "system.", "This", "review", "provides", "an", "update", "on", "the", "available", "literature", "covering", "influenza", "virus", "vaccines", "based", "on", "RNA", "replicons.", "The", "pros", "and", "cons", "of", "these", "vaccine", "strategies", "will", "be", "discussed", "and", "future", "perspectives", "disclosed.", "Keywords:", "RNA", "replicon;", "vaccine;", "biosafety;", "cellular", "immunity;", "mucosal", "immunity;", "heterosubtypic", "immunity;", "alphavirus;", "vesicular", "stomatitis", "virus", "1.", "Introduction", "Influenza", "viruses", "are", "highly", "contagious,", "rapidly", "evolving", "respiratory", "pathogens", "with", "established", "lineages", "in", "avian", "and", "mammalian", "species.", "Human", "influenza", "viruses", "circulate", "worldwide,", "causing", "annual", "epidemics", "associated", "with", "three", "to", "five", "million", "cases", "of", "severe", "illness", "and", "250,000", "to", "500,000", "deaths", "(www.who.int/mediacentre/factsheets/fs211/en).", "In", "temperate", "regions,", "annual", "influenza", "epidemics", "usually", "start", "in", "November", "and", "last", "until", "March.", "Influenza", "viruses", "can", "affect", "persons", "at", "any", "age,", "but", "the", "elderly", "(>65", "years),", "young", "children", "(<2", "years)", "and", "persons", "with", "underlying", "chronic", "diseases", "or", "weakened", "immune", "systems", "are", "particularly", "susceptible", "to", "severe", "and", "sometimes", "fatal", "respiratory", "distress", "symptoms", "[1]." ]

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[ "Acta", "Crystallographica", "Section", "E", "Structure", "Reports", "Online", "ISSN", "1600-5368", "4,6-Bis(diphenylphosphanyl)dibenzo-", "[b,d]furan", "Thashree", "Marimuthu,", "Holger", "B.", "Friedrich", "and", "Muhammad", "D.", "Bala*", "School", "of", "Chemistry,", "University", "of", "KwaZulu-Natal,", "Westville", "Campus,", "Private", "Bag", "X54001,", "Durban", "4000,", "South", "Africa", "Correspondence", "e-mail:", "bala@ukzn.ac.za", "Received", "4", "November", "2011;", "accepted", "10", "November", "2011", "Key", "indicators:", "single-crystal", "X-ray", "study;", "T", "=", "173", "K;", "mean", "(C–C)", "=", "0.003", "A˚;", "R", "factor", "=", "0.041;", "wR", "factor", "=", "0.100;", "data-to-parameter", "ratio", "=", "17.6.", "The", "asymmetric", "unit", "of", "the", "title", "compound,", "C36H26OP2,", "comprises", "two", "molecules", "which", "have", "slightly", "different", "conformations", "of", "the", "phenyl", "ring", "substituents.", "In", "both", "molecules,", "the", "dibenzofuran", "unit", "is", "close", "to", "being", "planar,", "with", "dihedral", "angles", "of", "3.20", "(3)", "and", "1.86", "(2)", "for", "the", "two", "molecules.", "Its", "planarity", "affects", "the", "intramolecular", "distances", "between", "P", "atoms,", "with", "P", "P", "distances", "of", "5.574", "(2)", "and", "5.485", "(2)", "A˚", "for", "the", "two", "molecules.", "Related", "literature", "For", "related", "syntheses,", "see:", "Kranenburg", "et", "al.", "(1995);", "Hilleb-", "rand", "et", "al.", "(1995).", "For", "related", "structures,", "see:", "Vogl", "et", "al.", "(1996);", "Marimuthu", "et", "al.", "(2008a,b).", "For", "structures", "containing", "the", "dibenzofuran", "unit,", "see:", "Dideberg", "et", "al.", "(1972);", "Banerjee", "(1973);", "Reppart", "et", "al.,", "(1984).", "Experimental", "Crystal", "data", "C36H26OP2", "Mr", "=", "536.51", "Triclinic,", "P1", "a", "=", "11.7463", "(2)", "A˚", "b", "=", "14.7238", "(3)", "A˚", "c", "=", "16.7140", "(4)", "A˚", "=", "96.821", "(2)", "=", "96.351", "(5)", "Data", "collection", "Bruker", "APEXII", "CCD", "diffractometer", "28406", "measured", "reflections", "Refinement", "R[F", "2", ">", "2", "(F", "2)]", "=", "0.041", "wR(F", "2)", "=", "0.100", "S", "=", "0.90", "12363", "reflections", "organic", "compounds", "=", "95.240", "(2)", "V", "=", "2836.58", "(10)", "A˚3", "Z", "=", "4", "Mo", "K", "radiation", "=", "0.18", "mm", "1", "T", "=", "173", "K", "0.40", "0.22", "0.18", "mm", "12364", "independent", "reflections", "8323", "reflections", "with", "I", ">", "2", "(I)", "Rint", "=", "0.052", "703", "parameters", "H-atom", "parameters", "constrained", "max", "=", "0.29", "e", "A˚", "3", "min", "=", "0.30", "e", "A˚", "3", "Data", "collection:", "APEX2", "(Bruker,", "2005);", "cell", "refinement:", "SAINT-", "Plus", "(Bruker,", "2005);", "data", "reduction:", "SAINT-Plus;", "program(s)", "used", "to", "solve", "structure:", "SHELXS97", "(Sheldrick,", "2008);", "program(s)", "used", "to", "refine", "structure:", "SHELXL97", "(Sheldrick,", "2008);", "molecular", "graphics:", "SHELXTL", "(Sheldrick,", "2008);", "software", "used", "to", "prepare", "material", "for", "publication:", "SHELXTL.", "We", "thank", "Dr", "Manuel", "Fernandes", "for", "the", "data", "collection", "and", "SASOL,", "THRIP", "and", "the", "University", "of", "KwaZulu-Natal", "for", "financial", "support.", "Supplementary", "data", "and", "figures", "for", "this", "paper", "are", "available", "from", "the", "IUCr", "electronic", "archives", "(Reference:", "KP2367).", "References", "Banerjee,", "A.", "(1973).", "Acta", "Cryst.", "B29,", "2070–2074.", "Bruker", "(2005).", "APEX2", "and", "SAINT-Plus.", "Bruker", "AXS", "Inc.,", "Madison,", "Wisconsin,", "USA.", "Dideberg,", "O.,", "Dupont,", "L.", "&", "Andr", "e´,", "J.", "M.", "(1972).", "Acta", "Cryst.", "B28,", "1002–1007.", "Hillebrand,", "S.,", "Bruckmann,", "J.,", "Kruger,", "C.", "&", "Haenel,", "M.", "W.", "(1995).", "Tetrahedron", "Lett.", "36,", "75–78.", "Kranenburg,", "M.,", "Vanderburgt,", "Y.", "E.", "M.,", "Kamer,", "P.", "C.", "J.,", "van", "Leeuwen,", "P.", "W.", "N.", "M.,", "Goubitz,", "K.", "&", "Fraanje,", "J.", "(1995).", "Organometallics,", "14,", "3081–", "3089.", "Marimuthu,", "T.,", "Bala,", "M.", "D.", "&", "Friedrich,", "H.", "B.", "(2008a).", "Acta", "Cryst.", "E64,", "o711.", "Marimuthu,", "T.,", "Bala,", "M.", "D.", "&", "Friedrich,", "H.", "B.", "(2008b).", "Acta", "Cryst.", "E64,", "o772.", "Reppart,", "W.", "J.,", "Gallucci,", "J.", "C.,", "Lundstedt,", "A.", "P.", "&", "Gerkin,", "R.", "E.", "(1984).", "Acta", "Cryst.", "C40,", "1572–1576.", "Sheldrick,", "G.", "M.", "(2008).", "Acta", "Cryst.", "A64,", "112–122.", "Vogl,", "E.", "M.,", "Bruckmann,", "J.,", "Kru¨", "ger,", "C.", "&", "Haenel,", "M.", "W.", "(1996).", "J.", "Organomet.", "Chem.", "520,", "249–252.", "Acta", "Cryst.", "(2011).", "E67,", "o3319", "doi:10.1107/S1600536811047787", "Marimuthu", "et", "al.", "o3319" ]

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[ "Hindawi", "Publishing", "Corporation", "Clinical", "and", "Developmental", "Immunology", "Volume", "2011,", "Article", "ID", "593863,", "15", "pages", "doi:10.1155/2011/593863", "Review", "Article", "Oxidative", "Stress", "and", "Redox", "Modulation", "Potential", "in", "Type", "1", "Diabetes", "Meghan", "M.", "Delmastro1,", "2", "and", "Jon", "D.", "Piganelli1,", "2,", "3", "1", "Diabetes", "Institute,", "Division", "of", "Immunogenetics,", "Department", "of", "Pediatrics,", "Children’s", "Hospital", "of", "Pittsburgh,", "University", "of", "Pittsburgh", "School", "of", "Medicine,", "Pittsburgh,", "PA", "15224,", "USA", "2", "Department", "of", "Immunology,", "University", "of", "Pittsburgh", "School", "of", "Medicine,", "Pittsburgh,", "PA", "15224,", "USA", "3", "Rangos", "Research", "Center,", "Department", "of", "Pediatrics,", "Children’s", "Hospital", "of", "Pittsburgh", "of", "UPMC,", "4401", "Penn", "Avenue,", "Pittsburgh,", "PA", "15224,", "USA", "Correspondence", "should", "be", "addressed", "to", "Jon", "D.", "Piganelli,", "jdp51@pitt.edu", "Received", "18", "January", "2011;", "Accepted", "9", "March", "2011", "Academic", "Editor:", "Nick", "Giannoukakis", "Copyright", "©", "2011", "M.", "M.", "Delmastro", "and", "J.", "D.", "Piganelli.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Redox", "reactions", "are", "imperative", "to", "preserving", "cellular", "metabolism", "yet", "must", "be", "strictly", "regulated.", "Imbalances", "between", "reactive", "oxygen", "species", "(ROS)", "and", "antioxidants", "can", "initiate", "oxidative", "stress,", "which", "without", "proper", "resolve,", "can", "manifest", "into", "disease.", "In", "type", "1", "diabetes", "(T1D),", "T-cell-mediated", "autoimmune", "destruction", "of", "pancreatic", "β-cells", "is", "secondary", "to", "the", "primary", "invasion", "of", "macrophages", "and", "dendritic", "cells", "(DCs)", "into", "the", "islets.", "Macrophages/DCs,", "however,", "are", "activated", "by", "intercellular", "ROS", "from", "resident", "pancreatic", "phagocytes", "and", "intracellular", "ROS", "formed", "after", "receptor-ligand", "interactions", "via", "redox-dependent", "transcription", "factors", "such", "as", "NF-κB.", "Activated", "macrophages/DCs", "ferry", "β-cell", "antigens", "specifically", "to", "pancreatic", "lymph", "nodes,", "where", "they", "trigger", "reactive", "T", "cells", "through", "synapse", "formation", "and", "secretion", "of", "proinflammatory", "cytokines", "and", "more", "ROS.", "ROS", "generation,", "therefore,", "is", "pivotal", "in", "formulating", "both", "innate", "and", "adaptive", "immune", "responses", "accountable", "for", "islet", "cell", "autoimmunity.", "The", "importance", "of", "ROS/oxidative", "stress", "as", "well", "as", "potential", "for", "redox", "modulation", "in", "the", "context", "of", "T1D", "will", "be", "discussed.", "1.", "Introduction", "Oxidation-reduction", "or", "redox", "reactions", "are", "pivotal", "to", "main-", "taining", "life", "through", "respiration,", "metabolism,", "and", "energy", "sup-", "ply.", "Mitochondria,", "which", "are", "known", "to", "be", "the", "powerhouses", "of", "the", "cell,", "possess", "the", "ability", "to", "utilize", "nutrients", "to", "generate", "energy", "(redox", "potential)", "via", "the", "electron", "transport", "chain,", "which", "donates", "electrons", "to", "oxygen", "to", "yield", "ATP", "and", "H2O", "[1,", "2].", "Consequently,", "oxygen", "free", "radicals,", "known", "as", "superox-", "ide", "(O2−),", "are", "nonenzymatically", "leaked", "from", "the", "mitochon-", "dria", "and", "react", "with", "other", "molecules", "to", "create", "reactive", "oxygen", "species", "(ROS)", "such", "as", "hydrogen", "peroxide", "(H2O2),", "peroxyni-", "trite", "(ONOO−),", "and", "hydroxyl", "radical", "(OH−),", "all", "of", "which", "can", "alter", "DNA,", "proteins,", "carbohydrates,", "and", "nucleic", "acids", "[3–5]", "and", "may", "eventually", "lead", "to", "irreversible", "damage.", "The", "inability", "of", "a", "cell’s", "antioxidant", "defenses", "to", "overcome", "oxidative", "injury", "and", "accretion", "of", "severe", "ROS-mediated", "damage", "over", "time", "will", "eventually", "lead", "to", "cell", "death", "[5–7].", "In", "order", "to", "maintain", "a", "reduced", "environment,", "several", "cellular", "antioxidant", "defenses", "are", "in", "place,", "including", "glutathione,", "glutathione", "peroxidase,", "catalase,", "and", "three", "different", "superoxide", "dismutase", "(SOD)", "enzymes:", "SOD1,", "2,", "and", "3,", "located", "in", "different", "subcellular", "and", "extracellular", "locations.", "A", "basal", "level", "of", "“accidental”", "superoxide", "is", "accumulated", "in", "healthy", "individuals", "[1,", "8],", "which", "has", "been", "widely", "hypothesized", "to", "be", "responsible", "for", "aging", "and", "the", "associated", "pathologies", "[9–11].", "However,", "oxidative", "stress", "occurs", "from", "an", "imbalance", "between", "ROS", "and", "antioxidant", "actions.", "During", "chronic", "oxidative", "stress", "caused", "by", "environmental", "factors", "(i.e.,", "UV", "light,", "ionizing", "radiation,", "toxic", "substances),", "infections,", "or", "lack", "of", "dietary", "antioxidants,", "an", "inequity", "of", "cellular", "reducing", "equivalents", "capable", "of", "detoxifying", "the", "increased", "burden", "of", "ROS", "has", "marked", "effects", "on", "normal", "cellular", "processes.", "However,", "in", "times", "of", "oxidative", "stress,", "normal", "cellular", "respiration", "is", "also", "still", "functioning,", "resulting", "in", "dysregulated", "mitochondrial", "free", "radical", "produc-", "tion", "and", "disparity", "between", "ROS", "generation", "and", "antioxidant" ]

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[ "Congpuong", "et", "al.", "Malaria", "Journal", "2012,", "11:288", "http://www.malariajournal.com/content/11/1/288", "R", "E", "S", "E", "A", "R", "C", "H", "Open", "Access", "Mass", "blood", "survey", "for", "malaria:", "pooling", "and", "real-", "time", "PCR", "combined", "with", "expert", "microscopy", "in", "north-west", "Thailand", "Kanungnit", "Congpuong1,4*,", "Aungkana", "SaeJeng2,", "Rungniran", "Sug-aram1,", "Supannee", "Aruncharus1,", "Ampai", "Darakapong1,", "Steven", "R", "Meshnick3", "and", "Wichai", "Satimai1", "Abstract", "Background:", "Asymptomatic", "carriage", "of", "Plasmodium", "falciparum", "and", "Plasmodium", "vivax", "is", "common", "in", "both", "low-and", "high-transmission", "settings", "and", "represents", "an", "important", "reservoir", "of", "infection", "that", "needs", "to", "be", "targeted", "if", "malaria", "elimination", "is", "to", "succeed.", "Methods:", "Mass", "blood", "examinations", "(475", "individuals)", "were", "conducted", "in", "two", "villages", "in", "Mae", "Hong", "Son,", "an", "area", "of", "endemic", "but", "low-transmission", "malaria", "in", "the", "north-west", "of", "Thailand.", "The", "microscopist", "at", "the", "local", "malaria", "clinic", "did", "not", "detect", "any", "infections.", "Pools", "of", "four", "samples", "were", "screened", "by", "real-time", "PCR;", "individual", "members", "of", "all", "of", "the", "positive", "pools", "were", "then", "re-examined", "by", "expert", "microscopy", "and", "by", "a", "second", "species-specific", "PCR", "reaction.", "Results:", "Eight", "subjects", "were", "found", "to", "be", "positive", "by", "both", "PCR", "and", "expert", "microscopy", "and", "one", "was", "found", "to", "be", "positive", "by", "PCR", "alone.", "The", "slides", "contained", "asexual", "stage", "parasites", "of", "P.", "vivax,", "P.", "falciparum", "and", "Plasmodium", "malariae,", "but", "no", "gametocytes.", "The", "local", "clinic", "was", "notified", "within", "two", "to", "eight", "days", "of", "the", "survey.", "Conclusion:", "A", "combination", "of", "pooling,", "real-time", "PCR", "and", "expert", "microscopy", "provides", "a", "feasible", "approach", "to", "identifying", "and", "treating", "asymptomatic", "malaria", "infections", "in", "a", "timely", "manner.", "Background", "Active", "case", "detection", "(ACD)", "is", "a", "key", "component", "of", "mal-", "aria", "surveillance", "programmes.", "As", "early", "as", "1848,", "active", "surveillance", "for", "splenomegaly", "was", "used", "as", "an", "indicator", "of", "malaria", "prevalence", "[1].", "ACD", "programmes", "now", "em-", "ploy", "microscopy", "and/or", "rapid", "diagnostic", "tests.", "In", "Thai-", "land,", "three", "types", "of", "ACD", "are", "used:", "contact", "tracing", "(“Case", "Investigation", "Survey”),", "high-risk", "group", "screening", "(“Special", "Case", "Detection”),", "and", "mass", "blood", "examination.", "ACD", "may", "have", "an", "even", "greater", "impact", "using", "PCR,", "which", "detect", "large", "numbers", "of", "infections", "that", "were", "previ-", "ously", "undetected", "by", "microscopy", "(“submicroscopic", "infec-", "tions”)", "[2-10].", "Asymptomatic", "carriers", "could", "represent", "an", "important", "reservoir", "[3,9,11]", "and", "thus", "be", "of", "particular", "rele-", "vance", "to", "elimination", "efforts", "[12].", "Historically,", "infections", "*", "Correspondence:", "kanungnitcongpuong@ymail.com", "1Bureau", "of", "Vector-Borne", "Diseases,", "Ministry", "of", "Public", "Health,", "Nonthaburi,", "Thailand", "4Faculty", "of", "Science", "&", "Technology,", "Bansomdejchaopraya", "Rajabhat", "University,", "Bangkok,", "Thailand", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "were", "identified", "by", "microscopy,", "however,", "a", "myriad", "of", "stud-", "ies", "has", "shown", "that", "PCR", "is", "much", "more", "sensitive.", "A", "high-throughput", "real-time", "PCR", "protocol", "for", "detect-", "ing", "parasites", "and", "determining", "their", "species", "was", "previ-", "ously", "reported", "[7,13].", "Pools", "of", "four", "samples", "were", "screened", "first", "using", "PCR", "primers", "that", "recognize", "all", "mal-", "aria", "species;", "individuals", "in", "positive", "pools", "were", "then", "screened", "with", "species-specific", "primers.", "Pooling", "led", "to", "substantial", "reductions", "in", "cost", "and", "effort", "for", "a", "Case", "In-", "vestigation", "Survey/Special", "Case", "Detection", "study", "in", "Bo", "Rai", "District,", "Trat", "Province,", "Thailand", "[7].", "PCR", "detected", "four", "infections", "while", "the", "local", "microscopist", "detected", "none.", "Three", "of", "the", "four", "PCR-positive", "cases", "were", "later", "confirmed", "by", "an", "expert", "microscopist.", "The", "current", "paper", "shows", "that", "pooled", "real-time", "PCR", "coupled", "with", "expert", "microscopy", "enhances", "sensitivity", "of", "detection", "in", "mass", "blood", "examinations.", "Methods", "Two", "villages", "in", "Mae", "Hong", "Son", "were", "selected", "for", "mass", "blood", "examinations.", "Mae", "Hong", "Son", "is", "in", "north-west", "©", "2012", "Congpuong", "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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[ "Acta", "Crystallographica", "Section", "E", "Structure", "Reports", "Online", "ISSN", "1600-5368", "(N-Benzoyl-N0,N0-diphenylthioureato-", "2", "4", "j", "S,O)(g", "-cycloocta-1,5-diene)-", "rhodium(I)", "Stefan", "Warsink*", "and", "Andreas", "Roodt", "Department", "of", "Chemistry,", "University", "of", "the", "Free", "State,", "PO", "Box", "339,", "Bloemfontein", "9300,", "South", "Africa", "Correspondence", "e-mail:", "2011009426@ufs4life.ac.za", "Received", "27", "June", "2012;", "accepted", "29", "June", "2012", "Key", "indicators:", "single-crystal", "X-ray", "study;", "T", "=", "100", "K;", "mean", "(C–C)", "=", "0.003", "A˚;", "R", "factor", "=", "0.028;", "wR", "factor", "=", "0.070;", "data-to-parameter", "ratio", "=", "18.7.", "The", "title", "complex,", "[Rh(C20H15N2OS)(C8H12)],", "exhibits", "an", "essentially", "square-planar", "coordination", "environment", "around", "the", "RhI", "atom,", "which", "bears", "a", "bidentate", "cyclooctadiene", "ligand", "as", "well", "as", "a", "monoanionic", "bidentate", "benzoylthioureate", "ligand.", "The", "RhI", "atom,", "the", "S-", "and", "O-donor", "atoms", "and", "the", "alkene", "centroids", "of", "the", "cyclooctadiene", "ligand", "do", "not", "deviate", "by", "more", "than", "0.031", "A˚", "from", "their", "least", "mean-squares", "plane.", "Related", "literature", "For", "rhodium", "complexes", "containing", "related", "monoanionic", "bidentate", "ligands,", "see:", "Trzeciak", "et", "al.", "(2004);", "Roodt", "et", "al.", "(2011);", "Crous", "et", "al.", "(2005);", "Guiseppe", "et", "al.", "(2011);", "Venter", "et", "al.", "(2009).", "For", "bidentate", "thioureato", "ligands,", "see:", "Sacht", "et", "al.", "(2000a,b);", "Kemp", "et", "al.", "(1997).", "For", "RhI", "complexes", "bearing", "cyclooctadiene", "and", "S,O-bidentate", "ligands,", "see:", "Grim", "et", "al.", "(1991);", "Hesp", "et", "al.", "(2007).", "For", "RhI", "complexes", "bearing", "a", "thio-", "urea", "ligand", "and", "cyclooctadiene,", "see:", "Kotze", "et", "al.", "(2010);", "Cauzzi", "et", "al.", "(1995).", "For", "trisubstituted", "thiourea", "ligands,", "see:", "Hernandez", "et", "al.", "(2003);", "Arslan", "et", "al.", "(2003).", "Experimental", "Crystal", "data", "[Rh(C20H15N2OS)(C8H12)]", "Mr", "=", "542.50", "Triclinic,", "P1", "a", "=", "9.8028", "(4)", "A˚", "metal-organic", "compounds", "Z", "=", "2", "Mo", "K", "radiation", "=", "0.84", "mm", "1", "T", "=", "100", "K", "0.22", "0.17", "0.09", "mm", "12388", "measured", "reflections", "5583", "independent", "reflections", "5014", "reflections", "with", "I", ">", "2", "(I)", "Rint", "=", "0.025", "298", "parameters", "H-atom", "parameters", "constrained", "max", "=", "0.66", "e", "A˚", "3", "min", "=", "1.01", "e", "A˚", "3", "b", "=", "11.2293", "(5)", "A˚", "c", "=", "11.5316", "(5)", "A˚", "=", "90.408", "(2)", "=", "91.684", "(2)", "=", "112.1831", "(18)", "V", "=", "1174.69", "(9)", "A˚3", "Data", "collection", "Bruker", "X8", "APEXII", "4K", "KappaCCD", "diffractometer", "Absorption", "correction:", "multi-scan", "(SADABS;", "Bruker,", "2007)", "Tmin", "=", "0.843,", "Tmax", "=", "0.927", "Refinement", "R[F", "2", ">", "2", "(F", "2)]", "=", "0.028", "wR(F", "2)", "=", "0.07", "S", "=", "1.04", "5583", "reflections", "Table", "1", "Selected", "bond", "lengths", "(A˚", ").", "Rh1—O5", "Rh1—C21", "Rh1—C22", "Rh1—C25", "Rh1—C26", "2.0537", "(16)", "2.116", "(2)", "2.131", "(2)", "2.148", "(2)", "2.155", "(2)", "Rh1—S1", "C01—O5", "C01—N1", "C02—N1", "C02—S1", "2.2942", "(10)", "1.263", "(2)", "1.330", "(3)", "1.346", "(3)", "1.726", "(2)", "Data", "collection:", "APEX2", "(Bruker,", "2007);", "cell", "refinement:", "SAINT-", "Plus", "(Bruker,", "2007);", "data", "reduction:", "SAINT-Plus;", "program(s)", "used", "to", "solve", "structure:", "SHELXS97", "(Sheldrick,", "2008);", "program(s)", "used", "to", "refine", "structure:", "SHELXL97", "(Sheldrick,", "2008);", "molecular", "graphics:", "Mercury", "(Macrae", "et", "al.,", "2008);", "software", "used", "to", "prepare", "material", "for", "publication:", "WinGX", "(Farrugia,", "1999).", "The", "authors", "thank", "SASOL,", "the", "South", "African", "NRF", "and", "THRIP,", "the", "University", "of", "the", "Free", "State", "Research", "Fund", "and", "the", "UFS", "Materials", "and", "Nanosciences", "SStrategic", "Research", "Cluster", "initiative", "for", "financial", "support.", "The", "views", "expressed", "do", "not", "necessarily", "represent", "those", "of", "the", "NRF.", "Supplementary", "data", "and", "figures", "for", "this", "paper", "are", "available", "from", "the", "IUCr", "electronic", "archives", "(Reference:", "WM2654).", "References", "Arslan,", "H.,", "Flo¨", "rke,", "U.", "&", "Ku¨", "lcu¨", ",", "N.", "(2003).", "Acta", "Cryst.", "E59,", "o641–o642.", "Bruker", "(2007).", "APEX2,", "SAINT-Plus", "and", "SADABS.", "Bruker", "AXS", "Inc.,", "Madison,", "Wisconsin,", "USA.", "Cauzzi,", "D.,", "Lanfranchi,", "M.,", "Marzolini,", "G.,", "Predieri,", "G.,", "Tiripicchio,", "A.,", "Costa,", "M.", "&", "Zanoni,", "R.", "(1995).", "J.", "Organomet.", "Chem.", "488,", "115–125.", "Crous,", "R.,", "Datt,", "M.,", "Foster,", "D.,", "Bennie,", "L.,", "Steenkamp,", "C.,", "Huyser,", "J.,", "Kirsten,", "L.,", "Steyl,", "G.", "&", "Roodt,", "A.", "(2005).", "Dalton", "Trans.", "pp.", "1108–1116.", "Farrugia,", "L.", "J.", "(1999).", "J.", "Appl.", "Cryst.", "32,", "837–838.", "Grim,", "S.", "O.,", "Kettler,", "P.", "B.", "&", "Thoden,", "J.", "B.", "(1991).", "Organometallics,", "10,", "2399–", "2403.", "Guiseppe,", "A.", "D.,", "Casterlenas,", "R.,", "Perez-Torrente,", "J.", "J.,", "Lahoz,", "F.", "H.,", "Polo,", "V.", "&", "Oro,", "L.", "A.", "(2011).", "Angew.", "Chem.", "Int.", "Ed.", "50,", "3938–3942.", "Hernandez,", "W.,", "Spodine,", "E.,", "Munoz,", "J.", "C.,", "Beyer,", "L.,", "Schroder,", "U.,", "Ferreira,", "J.", "&", "Pavani,", "M.", "(2003).", "Bioinorg.", "Chem.", "Appl.", "1,", "271–284.", "Hesp,", "K.", "D.,", "Wechsler,", "D.,", "Cipot,", "J.,", "Myers,", "A.,", "McDonald,", "R.,", "Ferguson,", "M.", "J.,", "Schatte,", "G.", "&", "Stradiotto,", "M.", "(2007).", "Organometallics,", "26,", "5430–5437.", "Kemp,", "G.,", "Purcell,", "W.,", "Roodt,", "A.", "&", "Koch,", "K.", "R.", "(1997).", "J.", "Chem.", "Soc.", "Dalton", "Trans.", "pp.", "4481–4483.", "Kotze,", "P.", "D.", "R.,", "Roodt,", "A.,", "Venter,", "J.", "A.", "&", "Otto,", "S.", "(2010).", "Acta", "Cryst.", "E66,", "m1028–m1029.", "Acta", "Cryst.", "(2012).", "E68,", "m1053–m1054", "doi:10.1107/S1600536812029753", "Warsink", "and", "Roodt", "m1053" ]

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[ "J", "Appl", "Genetics", "(2011)", "52:313–318", "DOI", "10.1007/s13353-011-0049-x", "PLANT", "GENETICS", "∙", "SHORT", "COMMUNICATION", "DArT", "markers", "tightly", "linked", "with", "the", "Rfc1", "gene", "controlling", "restoration", "of", "male", "fertility", "in", "the", "CMS-C", "system", "in", "cultivated", "rye", "(Secale", "cereale", "L.)", "Stefan", "Andrzej", "Stojałowski", "&", "Paweł", "Milczarski", "&", "Monika", "Hanek", "&", "Hanna", "Bolibok-Brągoszewska", "&", "Beata", "Myśków", "&", "Andrzej", "Kilian", "&", "Monika", "Rakoczy-Trojanowska", "Received:", "19", "December", "2010", "/", "Revised:", "7", "April", "2011", "/", "Accepted:", "13", "April", "2011", "/", "Published", "online:", "11", "May", "2011", "#", "The", "Author(s)", "2011.", "This", "article", "is", "published", "with", "open", "access", "at", "SpringerLink.com", "Abstract", "The", "Rfc1", "gene", "controls", "restoration", "of", "male", "fertility", "in", "rye", "(Secale", "cereale", "L.)", "with", "sterility-inducing", "cytoplasm", "CMS-C.", "Two", "populations", "of", "recombinant", "inbred", "lines", "(RIL)", "were", "used", "in", "this", "study", "to", "identify", "DArT", "markers", "located", "on", "the", "4RL", "chromosome,", "in", "the", "close", "vicinity", "of", "the", "Rfc1", "gene.", "In", "the", "population", "developed", "from", "the", "541×2020LM", "inter-", "cross,", "numerous", "markers", "tightly", "linked", "with", "the", "restorer", "gene", "were", "identified.", "This", "group", "contained", "91", "DArT", "markers", "and", "three", "SCARs", "additionally", "analyzed", "in", "the", "study.", "All", "these", "markers", "were", "mapped", "in", "the", "distance", "not", "exceeding", "6", "cM", "from", "the", "gene", "of", "interest.", "In", "the", "second", "mapping", "population", "(541×Ot1-3", "intercross),", "only", "9", "DArT", "markers", "located", "closely", "to", "the", "Rfc1", "gene", "were", "identified.", "Five", "of", "these", "DArT", "markers", "were", "polymorphic", "in", "both", "populations.", "Keywords", "Cytoplasmic", "male", "sterility", ".", "Genetic", "mapping", ".", "Restorer", "gene", ".", "Rye", "Rye", "(Secale", "cereale", "L.)", "is", "a", "crop", "of", "a", "great", "importance", "in", "the", "north-east", "part", "of", "Europe", "due", "to", "its", "tolerance", "to", "low", "temperatures", "in", "winter,", "aluminum", "ions", "in", "the", "soil", "and", "other", "S.", "A.", "Stojałowski", "(*)", ":", "P.", "Milczarski", ":", "M.", "Hanek", ":", "B.", "Myśków", "Department", "of", "Plant", "Genetics,", "Breeding", "and", "Biotechnology,", "West-Pomeranian", "University", "of", "Technology,", "Szczecin,", "Poland", "e-mail:", "sstojalowski@zut.edu.pl", "H.", "Bolibok-Brągoszewska", ":", "M.", "Rakoczy-Trojanowska", "Department", "of", "Plant", "Genetics,", "Breeding", "and", "Biotechnology,", "Warsaw", "University", "of", "Life", "Sciences,", "Warsaw,", "Poland", "A.", "Kilian", "Diversity", "Arrays", "Technology", 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[ "A", "R", "T", "I", "C", "L", "E", "Novel", "Insights", "Regarding", "the", "Operational", "Characteristics", "and", "Teleological", "Purpose", "of", "the", "Renal", "Na", "-K", "-Cl", "Cotransporter", "(NKCC2s)", "Splice", "Variants", "Geneviève", "M.", "Brunet,", "Edith", "Gagnon,", "Charles", "F.", "Simard,", "Nikolas", "D.", "Daigle,", "Luc", "Caron,", "Micheline", "Noël,", "Marie-Hélène", "Lefoll,", "Marc", "J.", "Bergeron,", "and", "Paul", "Isenring", "Nephrology", "Group,", "L’Hôtel-Dieu", "de", "Québec", "Research", "Center,", "Department", "of", "Medicine,", "Faculty", "of", "Medicine,", "Laval", "University,", "Québec,", "Canada", "G1R2J6", "The", "absorptive", "Na", "-K", "-Cl", "cotransporter", "(NKCC2)", "is", "a", "polytopic", "protein", "that", "forms", "homooligomeric", "complexes", "in", "the", "apical", "membrane", "of", "the", "thick", "ascending", "loop", "of", "Henle", "(TAL).", "It", "occurs", "in", "at", "least", "four", "splice", "variants", "(called", "B,", "A,", "F,", "and", "AF)", "that", "are", "identical", "to", "one", "another", "except", "for", "a", "short", "region", "in", "the", "membrane-associated", "domain.", "Although", "each", "of", "these", "variants", "exhibits", "unique", "functional", "properties", "and", "distributions", "along", "the", "TAL,", "their", "teleological", "purpose", "and", "structural", "organization", "remain", "poorly", "defined.", "In", "the", "current", "work,", "we", "provide", "additional", "insight", "in", "these", "regards", "by", "showing", "in", "mouse", "that", "the", "administration", "of", "either", "furosemide", "or", "an", "H2O-", "rich", "diet,", "which", "are", "predicted", "to", "alter", "NKCC2", "expression", "in", "the", "TAL,", "exerts", "differential", "effects", "on", "mRNA", "levels", "for", "the", "variants,", "increasing", "those", "of", "A", "(furosemide)", "but", "decreasing", "those", "of", "F", "and", "AF", "(furosemide", "or", "H2O).", "Based", "on", "a", "yeast", "two-hybrid", "mapping", "analysis,", "we", "also", "show", "that", "the", "formation", "of", "homooligomeric", "complexes", "is", "mediated", "by", "two", "self-interacting", "domains", "in", "the", "COOH", "terminus", "(residues", "671", "to", "816", "and", "910", "to", "1098),", "and", "that", "these", "complexes", "could", "probably", "include", "more", "than", "one", "type", "of", "variant.", "Taken", "together,", "the", "data", "reported", "here", "suggest", "that", "A,", "F,", "and", "AF", "each", "play", "unique", "roles", "that", "are", "adapted", "to", "specific", "physiological", "needs,", "and", "that", "the", "accomplishment", "of", "such", "roles", "is", "coordinated", "through", "the", "splicing", "machinery", "as", "well", "as", "complex", "NKCC2–NKCC2", "interactions.", "y", "g", "o", "l", "o", "i", "s", "y", "h", "P", "l", "a", "r", "e", "n", "e", "G", "f", "o", "l", "a", "n", "r", "u", "o", "J", "e", "h", "T", "I", "N", "T", "R", "O", "D", "U", "C", "T", "I", "O", "N", "The", "second", "isoform", "of", "the", "Na", "-K", "-Cl", "cotransporter", "(NKCC2)", "is", "restricted", "in", "its", "localization", "to", "the", "apical", "membrane", "of", "the", "thick", "ascending", "loop", "of", "Henle", "(TAL;", "see", "Payne", "and", "Forbush,", "1994;", "Kaplan", "et", "al.,", "1996;", "Yang", "et", "al.,", "1996).", "It", "plays", "a", "critical", "role", "in", "salt", "reabsorption", "along", "this", "nephron", "segment,", "thereby", "participating", "in", "the", "maintenance", "of", "extracellular", "fluid", "volumes", "and", "excretion", "of", "free", "H2O", "(Greger,", "1985;", "Gimenez", "and", "Forbush,", "2003;", "Fernandez-Llama", "et", "al.,", "2005).", "The", "physiological", "importance", "of", "NKCC2", "in", "mammals", "is", "suggested", "by", "the", "occurrence", "of", "salt", "wasting,", "uncom-", "pensated", "polyuria,", "or", "systemic", "hypertension", "when", "the", "transporter", "is", "functionally", "impaired", "(Simon", "et", "al.,", "1996;", "Bartter", "et", "al.,", "1998;", "Takahashi", "et", "al.,", "2000;", "Alvarez-", "Guerra", "and", "Garay,", "2002).", "NKCC2", "belongs", "to", "the", "cation-Cl", "cotransporter", "(CCC)", "family,", "which", "is", "comprised", "of", "several", "isoforms", "that", "mediate", "cell", "surface", "Cl", "-dependent", "Na", "and/or", "K", "cotransport.", "Members", "within", "this", "family", "are", "very", "homologous", "to", "one", "another,", "possessing", "12", "transmem-", "brane", "domains", "(tm)", "flanked", "by", "cytosolic", "termini", "(see", "model", "of", "NKCC2", "in", "Fig.", "1).", "Previous", "studies", "have", "re-", "vealed", "that", "a", "number", "of", "CCC", "isoforms", "also", "occur", "in", "splice", "variants", "(Payne", "and", "Forbush,", "1994,", "Igarashi", "et", "al.,", "1995;", "Race", "et", "al.,", "1999;", "Plata", "et", "al.,", "2001;", "Gagnon", "Correspondence", "to", "Paul", "Isenring:", "paul.isenring@crhdq.ulaval.ca", "J.", "Gen.", "Physiol.", "©", "The", "Rockefeller", "University", "Press", "$8.00", "Volume", "126", "Number", "4", "October", "2005", "325–337", "http://www.jgp.org/cgi/doi/10.1085/jgp.200509334", "et", "al.,", "2002;", "Hebert", "et", "al.,", "2004).", "Among", "terrestrial", "vertebrates,", "e.g.,", "at", "least", "four", "types", "of", "NKCC2s", "have", "been", "described:", "NKCC2F,", "A,", "and", "B,", "which", "are", "identical", "to", "one", "another", "except", "for", "a", "96-bp", "exon", "that", "encodes", "the", "second", "tm", "and", "part", "of", "the", "following", "connecting", "segment,", "and", "NKCC2AF,", "which", "possesses", "both", "the", "A", "and", "F", "exons", "in", "tandem", "(Payne", "and", "Forbush,", "1994;", "Igarashi", "et", "al.,", "1995;", "Plata", "et", "al.,", "2001;", "Gagnon", "et", "al.,", "2002).", "In", "situ", "hybridization", "studies", "in", "lagomorphs", "have", "revealed", "that", "the", "NKCC2", "variants", "are", "differentially", "distributed", "along", "the", "TAL", "but", "with", "some", "degree", "of", "overlap", "in", "their", "site", "of", "expression;", "A", "is", "to", "a", "large", "extent", "in", "the", "outer", "stripe", "of", "the", "outer", "medulla", "(OM)", "and", "cortex,", "and", "F", "in", "the", "inner", "stripe", "of", "the", "OM", "(Payne", "and", "Forbush,", "1994;", "Igarashi", "et", "al.,", "1995).", "These", "studies", "have", "also", "demonstrated", "that", "A", "and", "F", "are", "not", "produced", "in", "equal", "proportions", "within", "the", "diluting", "segment.", "For", "instance,", "F", "is", "the", "most", "abundant", "transcript", "whereas", "B", "is", "the", "least", "abundant.", "As", "for", "AF,", "indirect", "evidence", "sug-", "gests", "that", "this", "variant", "is", "present", "in", "the", "OM", "(Payne", "and", "Forbush,", "1994;", "Gagnon", "et", "al.,", "2002,", "2003),", "and", "that", "it", "Abbreviations", "used", "in", "this", "paper:", "CCC,", "cation-Cl", "cotransporter;", "Ct,", "COOH", "terminus;", "ctl,", "control;", "EIR,", "essential", "interacting", "region;", "hu,", "human;", "ms,", "mouse;", "NKCC2,", "Na", "-K", "-Cl", "cotransporter;", "OM,", "outer", "medulla;", "RT-PCR,", "reverse", "transcriptase", "PCR;", "sa,", "shark;", "TAL,", "thick", "ascending", "loop", "of", "Henle.", "325" ]

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[ "Selection", "of", "Target", "Sites", "for", "Mobile", "DNA", "Integration", "in", "the", "Human", "Genome", "Charles", "Berry1,", "Sridhar", "Hannenhalli2,", "Jeremy", "Leipzig3,", "Frederic", "D.", "Bushman3*", "1", "Department", "of", "Family", "and", "Preventive", "Medicine,", "School", "of", "Medicine,", "University", "of", "California", "San", "Diego,", "La", "Jolla,", "California,", "United", "States", "of", "America,", "2", "Department", "of", "Genetics,", "University", "of", "Pennsylvania", "School", "of", "Medicine,", "Philadelphia,", "Pennsylvania,", "United", "States", "of", "America,", "3", "Department", "of", "Microbiology,", "University", "of", "Pennsylvania", "School", "of", "Medicine,", "Philadelphia,", "Pennsylvania,", "United", "States", "of", "America", "DNA", "sequences", "from", "retroviruses,", "retrotransposons,", "DNA", "transposons,", "and", "parvoviruses", "can", "all", "become", "integrated", "into", "the", "human", "genome.", "Accumulation", "of", "such", "sequences", "accounts", "for", "at", "least", "40%", "of", "our", "genome", "today.", "These", "integrating", "elements", "are", "also", "of", "interest", "as", "gene-delivery", "vectors", "for", "human", "gene", "therapy.", "Here", "we", "present", "a", "comprehensive", "bioinformatic", "analysis", "of", "integration", "targeting", "by", "HIV,", "MLV,", "ASLV,", "SFV,", "L1,", "SB,", "and", "AAV.", "We", "used", "a", "mathematical", "method", "which", "allowed", "annotation", "of", "each", "base", "pair", "in", "the", "human", "genome", "for", "its", "likelihood", "of", "hosting", "an", "integration", "event", "by", "each", "type", "of", "element,", "taking", "advantage", "of", "more", "than", "200", "types", "of", "genomic", "annotation.", "This", "bioinformatic", "resource", "documents", "a", "wealth", "of", "new", "associations", "between", "genomic", "features", "and", "integration", "targeting.", "The", "study", "also", "revealed", "that", "the", "length", "of", "genomic", "intervals", "analyzed", "strongly", "affected", "the", "conclusions", "drawn—thus,", "answering", "the", "question", "‘‘What", "genomic", "features", "affect", "integration?’’", "requires", "carefully", "specifying", "the", "length", "scale", "of", "interest.", "Citation:", "Berry", "C,", "Hannenhalli", "S,", "Leipzig", "J,", "Bushman", "FD", "(2006)", "Selection", "of", "target", "sites", "for", "mobile", "DNA", "integration", "in", "the", "human", "genome.", "PLoS", "Comput", "Biol", "2(11):", "e157.", "doi:10.1371/journal.pcbi.0020157", "Introduction", "The", "exons", "of", "human", "genes", "comprise", "only", "about", "1.5%", "of", "the", "total", "genome", "sequence", "[1,2].", "Fragments", "of", "genomic", "parasites—integrating", "viruses", "and", "transposons—comprise", "a", "much", "larger", "fraction,", "at", "least", "40%.", "These", "elements", "are", "also", "highly", "dynamic—new", "elements", "insert", "and", "occasionally", "excise,", "and", "repeated", "sequences", "provide", "portable", "regions", "of", "sequence", "homology", "that", "act", "as", "substrates", "for", "homologous", "recombina-", "tion.", "Integration", "of", "new", "DNA", "can", "result", "in", "changes", "in", "gene", "activity", "or", "formation", "of", "new", "genes", "[3,4].", "Integrating", "DNA", "elements", "are", "also", "important", "in", "human", "gene", "therapy", "as", "delivery", "vehicles", "for", "new", "sequences.", "Recent", "setbacks", "in", "gene", "therapy,", "however,", "emphasize", "the", "importance", "of", "integration", "target", "site", "selection.", "In", "an", "otherwise", "quite", "successful", "gene", "therapy", "trial", "treating", "human", "X-SCID,", "the", "gene", "therapy", "vector", "used", "integrated", "near", "a", "proto-oncogene", "and", "caused", "leukemia", "in", "three", "of", "the", "patients", "treated", "[5,6].", "Here", "we", "present", "a", "detailed", "bioinformatic", "analysis", "of", "integration", "targeting", "in", "the", "human", "genome", "by", "seven", "types", "of", "integrating", "elements,", "taking", "advantage", "of", "the", "extensive", "sequence", "data", "available", "on", "de", "novo", "sites", "of", "integration", "[7].", "For", "the", "retroviruses,", "published", "genome-wide", "surveys", "of", "integration", "target", "sites", "have", "shown", "that", "human", "immunode-", "ficiency", "virus", "(HIV),", "murine", "leukemia", "virus", "(MLV),", "avian", "sarcoma–leukosis", "virus", "(ASLV),", "and", "simian", "foamy", "virus", "(SFV)", "all", "show", "different", "patterns", "of", "favored", "integration", "sites.", "HIV", "favors", "integration", "in", "active", "transcription", "units", "(TUs)", "[8–16],", "while", "MLV", "favored", "integration", "near", "gene", "59", "ends", "[9,16].", "ASLV", "shows", "the", "most", "random", "target", "site", "distribution,", "favoring", "TUs", "only", "slightly", "[10,17].", "SFV", "integration", "sites", "are", "also", "relatively", "randomly", "distributed,", "though", "a", "favoring", "of", "integration", "near", "CpG", "islands", "could", "be", "detected", "[18].", "Long", "interspersed", "nuclear", "elements", "(LINEs)", "are", "non-LTR", "retrotransposons", "that", "replicate", "via", "transcription,", "then", "re-", "verse", "transcription", "primed", "by", "a", "nick", "in", "the", "genomic", "target", "DNA", "[3,4,19,20].", "LINE-related", "sequences", "comprise", "fully", "20%", "of", "the", "human", "DNA", "[1,2].", "LINEs", "are", "the", "only", "known", "class", "of", "human", "transposons", "that", "are", "active", "for", "transposition,", "the", "others", "being", "inactive", "molecular", "fossils.", "Two", "previous", "surveys", "of", "integration", "targeting", "by", "engineered", "human", "L1", "LINEs", "emphasized", "that", "the", "integration", "reaction", "often", "rearranges", "the", "target", "site", "DNA", "as", "a", "consequence", "of", "the", "coupled", "reverse", "transcription–integration", "mechanism", "[21,22].", "The", "published", "studies", "reached", "different", "conclusions", "on", "whether", "or", "not", "TUs", "were", "favored", "integration", "targets.", "Another", "class", "of", "transposons", "is", "exemplified", "by", "Sleeping", "Beauty", "(SB).", "This", "element", "transposes", "via", "a", "‘‘cut-and-paste’’", "mechanism,", "involving", "excision", "of", "the", "SB", "DNA", "from", "the", "genome", "and", "reintegration", "at", "a", "new", "site", "[3,4].", "SB", "integration", "site", "selection", "in", "vivo", "has", "been", "studied", "by", "two", "groups,", "revealing", "that", "integration", "sites", "were", "nearly", "randomly", "dis-", "tributed", "in", "the", "genome,", "showing", "only", "a", "weak", "favoring", "of", "TUs", "[23,24].", "The", "last", "integrating", "element", "studied", "is", "the", "parvovirus", "adeno-associated", "virus", "(AAV).", "AAV", "does", "not", "integrate", "as", "a", "normal", "step", "in", "its", "life", "cycle,", "but", "under", "certain", "growth", "conditions", "a", "portion", "of", "the", "viral", "DNA", "can", "become", "integrated", "in", "the", "host", "cell", "chromosome.", "In", "infections", "with", "wild-type", "Editor:", "Jonathan", "Eisen,", "University", "of", "California", "Davis,", "United", "States", "of", "America", "Received", "August", "17,", "2006;", "Accepted", "October", "4,", "2006;", "Published", "November", "24,", "2006", "Copyright:", "2006", "Berry", "et", "al.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Abbreviations:", "AAV,", "adeno-associated", "virus;", "ASLV,", "avian", "sarcoma–leukosis", "virus;", "BMA,", "Bayes", "model", "averaging;", "LINEs,", "long", "interspersed", "nuclear", "elements;", "MLV,", "murine", "leukemia", "virus;", "PWM,", "positional", "weight", "matrix;", "ROC,", "receiver", "operator", "characteristic;", "SB,", "Sleeping", "Beauty;", "SFV,", "simian", "foamy", "virus;", "TU,", "transcriptional", "unit", "*", "To", "whom", "correspondence", "should", "be", "addressed.", "E-mail:", "bushman@mail.med.", "upenn.edu", "PLoS", "Computational", "Biology", "|", "www.ploscompbiol.org", "1450", "November", "2006", "|", "Volume", "2", "|", "Issue", "11", "|", "e157" ]

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[ "A", "Modular", "Library", "of", "Small", "Molecule", "Signals", "Regulates", "Social", "Behaviors", "in", "Caenorhabditis", "elegans", "Jagan", "Srinivasan1.,", "Stephan", "H.", "von", "Reuss2.,", "Neelanjan", "Bose2,", "Alon", "Zaslaver1,", "Parag", "Mahanti2,", "Margaret", "C.", "Ho", "1", ",", "Oran", "G.", "O’Doherty2,", "Arthur", "S.", "Edison", "3", ",", "Paul", "W.", "Sternberg1*,", "Frank", "C.", "Schroeder2*", "1", "Howard", "Hughes", "Medical", "Institute", "and", "Division", "of", "Biology,", "California", "Institute", "of", "Technology,", "Pasadena,", "California,", "United", "States", "of", "America,", "2", "Boyce", "Thompson", "Institute", "and", "Department", "of", "Chemistry", "and", "Chemical", "Biology,", "Cornell", "University,", "Ithaca,", "New", "York,", "United", "States", "of", "America,", "3", "Department", "of", "Biochemistry", "and", "Molecular", "Biology,", "and", "National", "High", "Magnetic", "Field", "Laboratory,", "University", "of", "Florida,", "Gainesville,", "Florida,", "United", "States", "of", "America", "Abstract", "The", "nematode", "C.", "elegans", "is", "an", "important", "model", "for", "the", "study", "of", "social", "behaviors.", "Recent", "investigations", "have", "shown", "that", "a", "family", "of", "small", "molecule", "signals,", "the", "ascarosides,", "controls", "population", "density", "sensing", "and", "mating", "behavior.", "However,", "despite", "extensive", "studies", "of", "C.", "elegans", "aggregation", "behaviors,", "no", "intraspecific", "signals", "promoting", "attraction", "or", "aggregation", "of", "wild-type", "hermaphrodites", "have", "been", "identified.", "Using", "comparative", "metabolomics,", "we", "show", "that", "the", "known", "ascarosides", "are", "accompanied", "by", "a", "series", "of", "derivatives", "featuring", "a", "tryptophan-derived", "indole", "moiety.", "Behavioral", "assays", "demonstrate", "that", "these", "indole", "ascarosides", "serve", "as", "potent", "intraspecific", "attraction", "and", "aggregation", "signals", "for", "hermaphrodites,", "in", "contrast", "to", "ascarosides", "lacking", "the", "indole", "group,", "which", "are", "repulsive.", "Hermaphrodite", "attraction", "to", "indole", "ascarosides", "depends", "on", "the", "ASK", "amphid", "sensory", "neurons.", "Downstream", "of", "the", "ASK", "sensory", "neuron,", "the", "interneuron", "AIA", "is", "required", "for", "mediating", "attraction", "to", "indole", "ascarosides", "instead", "of", "the", "RMG", "interneurons,", "which", "previous", "studies", "have", "shown", "to", "integrate", "attraction", "and", "aggregation", "signals", "from", "ASK", "and", "other", "sensory", "neurons.", "The", "role", "of", "the", "RMG", "interneuron", "in", "mediating", "aggregation", "and", "attraction", "is", "thought", "to", "depend", "on", "the", "neuropeptide", "Y-like", "receptor", "NPR-1,", "because", "solitary", "and", "social", "C.", "elegans", "strains", "are", "distinguished", "by", "different", "npr-1", "variants.", "We", "show", "that", "indole", "ascarosides", "promote", "attraction", "and", "aggregation", "in", "both", "solitary", "and", "social", "C.", "elegans", "strains.", "The", "identification", "of", "indole", "ascarosides", "as", "aggregation", "signals", "reveals", "unexpected", "complexity", "of", "social", "signaling", "in", "C.", "elegans,", "which", "appears", "to", "be", "based", "on", "a", "modular", "library", "of", "ascarosides", "integrating", "building", "blocks", "derived", "from", "lipid", "b-oxidation", "and", "amino-acid", "metabolism.", "Variation", "of", "modules", "results", "in", "strongly", "altered", "signaling", "content,", "as", "addition", "of", "a", "tryptophan-derived", "indole", "unit", "to", "repellent", "ascarosides", "produces", "strongly", "attractive", "indole", "ascarosides.", "Our", "findings", "show", "that", "the", "library", "of", "ascarosides", "represents", "a", "highly", "developed", "chemical", "language", "integrating", "different", "neurophysiological", "pathways", "to", "mediate", "social", "communication", "in", "C.", "elegans.", "Citation:", "Srinivasan", "J,", "von", "Reuss", "SH,", "Bose", "N,", "Zaslaver", "A,", "Mahanti", "P,", "et", "al.", "(2012)", "A", "Modular", "Library", "of", "Small", "Molecule", "Signals", "Regulates", "Social", "Behaviors", "in", "Caenorhabditis", "elegans.", "PLoS", "Biol", "10(1):", "e1001237.", "doi:10.1371/journal.pbio.1001237", "Academic", "Editor:", "Piali", "Sengupta,", "Brandeis,", "United", "States", "of", "America", "Received", "August", "22,", "2011;", "Accepted", "November", "22,", "2011;", "Published", "January", "10,", "2012", "Copyright:", "2012", "Srinivasan", "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", "in", "part", "by", "a", "National", "Institutes", "of", "Health", "grant", "(GM088290", "to", "FCS", "and", "GM085285", "to", "ASE,", "FCS,", "and", "PWS),", "and", "the", "Howard", "Hughes", "Medical", "Institute,", "with", "which", "PWS", "is", "an", "Investigator.", "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.", "Abbreviations:", "ascr,", "non-indole", "ascaroside;", "ASK,", "amphid", "single-ciliated", "sensory", "neurons", "type", "K;", "CeMM,", "C.", "elegans", "Maintenance", "Medium;", "DANS,", "Differential", "Analysis", "of", "two-dimensional", "NMR", "spectra;", "fM,", "femtomolar;", "icas,", "indole", "ascarosides;", "MS,", "mass", "spectrometric;", "NGM,", "nematode", "growth", "medium;", "TGF–b,", "transforming", "growth", "factor–b", "*", "E-mail:", "pws@caltech.edu", "(PWS);", "schroeder@cornell.edu", "(FCS)", ".", "These", "authors", "contributed", "equally", "to", "this", "work.", "Introduction", "Communication", "among", "individuals", "of", "a", "species", "relies", "on", "a", "number", "of", "different", "sensory", "inputs", "including", "chemical,", "mechan-", "ical,", "auditory,", "or", "visual", "cues", "[1].", "Chemical", "signaling", "is", "perhaps", "the", "most", "ancient", "form", "of", "interorganismal", "communication", "[1,2],", "and", "analysis", "of", "the", "chemical", "signals", "and", "the", "behaviors", "they", "mediate", "is", "of", "great", "significance", "for", "understanding", "the", "ecological", "and", "evolutionary", "dynamics", "of", "intra-", "and", "inter-specific", "interactions.", "The", "free-living", "nematode", "C.", "elegans", "is", "used", "extensively", "as", "a", "model", "system", "for", "social", "behaviors", "such", "as", "foraging,", "population", "density", "sensing,", "mating,", "and", "aggregation", "(http://www.wormbook.org;", "[3]).", "Recent", "investigations", "have", "shown", "that", "a", "family", "of", "small", "molecules,", "the", "ascarosides,", "play", "important", "roles", "as", "chemical", "signals", "regulating", "several", "different", "aspects", "of", "C.", "elegans", "behavior", "(Figure", "1A)", "[4–8].", "The", "ascarosides", "ascr#1,", "ascr#2,", "and", "ascr#3", "were", "originally", "identified", "as", "major", "components", "of", "the", "dauer", "phero-", "mone,", "a", "population-density", "signal", "that", "promotes", "entry", "into", "an", "alternate", "larval", "stage,", "the", "non-feeding", "and", "highly", "persistent", "dauer", "stage", "[4–7].", "Additional", "work", "showed", "that", "at", "concentrations", "far", "below", "those", "required", "for", "dauer", "formation,", "synergistic", "mixtures", "of", "ascarosides", "act", "as", "strong", "male-specific", "attractants,", "and", "that", "male", "attraction", "to", "ascarosides", "requires", "the", "amphid", "sensory", "neurons", "ASK", "and", "the", "cephalic", "sensory", "neurons", "CEM", "[6,7].", "Wild-type", "(N2)", "hermaphrodites", "do", "not", "respond", "to", "low", "concentrations", "of", "ascaro-", "sides", "and", "show", "repulsion", "at", "dauer-inducing", "concentrations", "[4].", "However,", "a", "recent", "study", "showed", "that", "mutation", "of", "the", "neuropep-", "tide-Y", "receptor", "homolog", "NPR-1", "strongly", "affects", "hermaphrodite", "response", "to", "ascarosides", "[9].", "The", "strong", "loss-of-function", "mutant", "npr-", "1(ad609)", "showed", "attraction", "or", "reduced", "repulsion", "to", "specific", "PLoS", "Biology", "|", "www.plosbiology.org", "1", "January", "2012", "|", "Volume", "10", "|", "Issue", "1", "|", "e1001237" ]

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[ "Advance", "Access", "Publication", "31", "August", "2009", "Meeting", "Report", "Dana", "Ullman", "Homeopathic", "Educational", "Services,", "Berkely,", "California,", "USA", "A", "Review", "of", "a", "Historical", "Summit", "on", "Integrative", "Medicine", "eCAM", "2010;7(4)511–514", "doi:10.1093/ecam/nep128", "The", "US", "Institute", "of", "Medical", "sponsors", "a", "‘‘Summit", "on", "Integrative", "Medicine", "and", "the", "Health", "of", "the", "Public’’", "on", "February", "25–27,", "2009.", "A", "prestigious", "body", "of", "speakers", "and", "attendees", "created", "a", "dynamic", "conference", "in", "which", "the", "content", "and", "discussions", "provided", "vital", "information", "for", "trans-", "forming", "the", "US", "health", "care", "system.", "Topics", "included:", "patient-centered", "care,", "the", "scientific", "basis", "of", "integrative", "medicine,", "health", "care", "financing", "reform", "and", "value-driven", "care,", "and", "mind-body", "relationships", "and", "health.", "Keywords:", "mind/body", "medicine", "–", "healing", "–", "patient-centered", "care", "–", "health", "care", "reform", "–", "cost-effectiveness", "–", "wellness", "The", "Institute", "of", "Medicine", "(IOM)", "is", "considered", "America’s", "preeminent", "body", "of", "physicians,", "scientists", "and", "academi-", "cians", "interested", "in", "health", "and", "medical", "issues.", "It", "is", "a", "part", "of", "the", "United", "States", "National", "Academies,", "which", "also", "includes", "the", "National", "Academy", "of", "Sciences.", "The", "IOM", "produces", "independent", "recommendations", "and", "policy", "reports", "by", "enlisting", "various", "experts", "to", "address", "the", "scientific", "and", "technical", "aspects", "of", "some", "of", "society’s", "health", "problems.", "On", "February", "25–27,", "2009,", "the", "IOM", "convened", "a", "‘Summit", "on", "Integrative", "Medicine", "and", "the", "Health", "of", "the", "Public’", "at", "its", "headquarters", "in", "Washington,", "DC.", "Approxi-", "mately", "600", "people", "participated", "in", "this", "historic", "meeting", "which", "included", "a", "wide", "variety", "of", "experts", "in", "integra-", "tive", "medicine", "as", "well", "as", "people", "in", "leading", "positions", "in", "government,", "industry", "and", "academia.", "This", "summit", "was", "co-sponsored", "by", "the", "Bravewell", "Collaboration,", "a", "founda-", "tion", "composed", "of", "leading", "philanthropists", "dedicated", "to", "transforming", "the", "culture", "and", "delivery", "of", "health", "care.", "The", "summit", "content", "and", "discussions", "provided", "vital", "information", "for", "transforming", "the", "US", "health", "care", "system.", "Topics", "included:", "patient-centered", "care,", "the", "scien-", "tific", "basis", "of", "integrative", "medicine,", "health", "care", "financing", "reform", "and", "value-driven", "care", "and", "mind–body", "For", "reprint", "and", "all", "correspondence:", "Dana", "Ullman,", "MPH,", "President,", "Homeopathic", "Educational", "Services,", "2124", "Kittredge", "St.", "#Q,", "Berkeley,", "CA,", "94704.", "Tel:", "+1-510-649-0294;", "Fax:", "+1-510-649-1955;", "E-mail:", "dana@homeopathic.com", "relationships", "and", "health.", "Prior", "to", "the", "conference,", "the", "IOM", "commissioned", "several", "papers", "to", "provide", "back-", "ground", "information", "on", "integrative", "medicine’s", "perfor-", "mance", "in", "prevention", "and", "wellness,", "patient-centered", "care,", "research,", "public", "education,", "professional", "education", "and", "economics", "and", "policy.", "The", "Players", "The", "speakers", "at", "this", "summit", "included", "many", "of", "the", "move-", "ment’s", "high", "profile", "leaders,", "including", "Dean", "Ornish,", "Mehmet", "Oz", "and", "Kenneth", "Pelletier.", "Evidence", "of", "the", "inter-", "est", "in", "the", "broad", "field", "of", "integrative", "medicine", "was", "the", "inclusion", "of", "the", "program", "of", "Thomas", "Donahue", "(the", "CEO", "of", "the", "US", "Chamber", "of", "Commerce),", "George", "Halvorson", "(chairman", "and", "CEO,", "Kaiser", "Foundation", "Health", "Plan),", "Senator", "Tom", "Harkin", "(Iowa),", "Bill", "Novelli", "(CEO,", "AARP),", "and", "Reed", "Tuckson", "[Chief", "of", "Medical", "Affairs,", "United", "Health", "Group,", "a", "major", "health", "maintenance", "organization", "(HMO)", "and", "former", "Senior", "Vice", "President,", "AMA].", "Other", "speakers", "included", "Mimi", "Guarneri,", "(cardiologist", "and", "medical", "director", "of", "the", "Scripps", "Center", "for", "Integrative", "Medicine),", "David", "Katz", "(internist", "and", "founder", "of", "Yale’s", "Prevention", "Research", "Center),", "Victor", "Sierpina", "(University", "of", "Texas),", "Victoria", "Maizes", "(University", "of", "Arizona),", "Tracy", "Gaudet", "(Duke", "University)", "and", "Josephine", "Briggs", "(Director,", "NIH’s", "National", "Center", "for", "Complementary", "and", "Alternative", "Medicine).", "The", "chairperson", "of", "the", "The", "Author", "2009.", "Published", "by", "Oxford", "University", "Press.", "All", "rights", "reserved.", "For", "permissions,", "please", "email:", "journals.permissions@oxfordjournals.org" ]

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[ "Ponsuksili", "et", "al.", "BMC", "Genomics", "2010,", "11:572", "http://www.biomedcentral.com/1471-2164/11/572", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Identification", "of", "expression", "QTL", "(eQTL)", "of", "genes", "expressed", "in", "porcine", "M.", "longissimus", "dorsi", "and", "associated", "with", "meat", "quality", "traits", "Siriluck", "Ponsuksili1,", "Eduard", "Murani2,", "Manfred", "Schwerin1,", "Karl", "Schellander3,", "Klaus", "Wimmers2*", "Abstract", "Background:", "Genetic", "analysis", "of", "transcriptional", "profiles", "is", "a", "promising", "approach", "for", "identifying", "and", "dissecting", "the", "genetics", "of", "complex", "traits", "like", "meat", "performance.", "Accordingly,", "expression", "levels", "obtained", "by", "microarray", "analysis", "were", "taken", "as", "phenotypes", "in", "a", "linkage", "analysis", "to", "map", "eQTL.", "Moreover,", "expression", "levels", "were", "correlated", "with", "traits", "related", "to", "meat", "quality", "and", "principle", "components", "with", "high", "loadings", "of", "these", "traits.", "By", "using", "an", "up-to-date", "annotation", "and", "localization", "of", "the", "respective", "probe-sets,", "the", "integration", "of", "eQTL", "mapping", "data", "and", "information", "of", "trait", "correlated", "expression", "finally", "served", "to", "point", "to", "candidate", "genes", "for", "meat", "quality", "traits.", "Results:", "Genome-wide", "transcriptional", "profiles", "of", "M.", "longissimus", "dorsi", "RNAs", "samples", "of", "74", "F2", "animals", "of", "a", "pig", "resource", "population", "revealed", "11,457", "probe-sets", "representing", "genes", "expressed", "in", "the", "muscle.", "Linkage", "analysis", "of", "expression", "levels", "of", "these", "probe-sets", "provided", "9,180", "eQTL", "at", "the", "suggestive", "significance", "threshold", "of", "LOD", ">", "2.", "We", "mapped", "653", "eQTL", "on", "the", "same", "chromosome", "as", "the", "corresponding", "gene", "and", "these", "were", "designated", "as", "‘putative", "cis-eQTL’.", "In", "order", "to", "link", "eQTL", "to", "the", "traits", "of", "interest,", "probe-sets", "were", "addressed", "with", "relative", "transcript", "abundances", "that", "showed", "correlation", "with", "meat", "quality", "traits", "at", "p", "≤", "0.05.", "Out", "of", "the", "653", "‘putative", "cis-eQTL’,", "262", "transcripts", "were", "correlated", "with", "at", "least", "one", "meat", "quality", "trait.", "Furthermore,", "association", "of", "expression", "levels", "with", "composite", "traits", "with", "high", "loadings", "for", "meat", "quality", "traits", "generated", "by", "principle", "component", "analysis", "were", "taken", "into", "account", "leading", "to", "a", "list", "of", "85", "genes", "exhibiting", "cis-eQTL", "and", "trait", "dependent", "expression.", "Conclusion:", "Holistic", "expression", "profiling", "was", "integrated", "with", "QTL", "analysis", "for", "meat", "quality", "traits.", "Correlations", "between", "transcript", "abundance", "and", "meat", "quality", "traits,", "combined", "with", "genetic", "positional", "information", "of", "eQTL", "allowed", "us", "to", "prioritise", "candidate", "genes", "for", "further", "study.", "Background", "Genetical", "genomics", "as", "a", "new", "approach", "which", "combines", "gene-expression", "data", "and", "marker", "genotypes", "in", "a", "segre-", "gating", "population,", "offers", "great", "perspectives", "to", "make", "a", "major", "contribution", "to", "the", "dissection", "of", "complex", "traits", "[1,2].", "Genetical", "genomics", "aims", "at", "detecting", "genomic", "loci", "that", "control", "variation", "in", "gene", "expression,", "so-called", "expression", "QTL", "(eQTL;", "to", "distinguish", "them", "from", "func-", "tional", "QTL", "that", "affect", "traits", "at", "the", "whole-organism", "level,", "subsequently", "termed", "pheneQTL(pQTL)).", "The", "detected", "eQTL", "can", "represent", "a", "locus", "that", "lies", "close", "to", "the", "gene", "that", "is", "being", "controlled", "(cis-acting)", "or", "one", "or", "more", "loci", "*", "Correspondence:", "wimmers@fbn-dummerstorf.de", "2Leibniz", "Institute", "for", "Farm", "Animal", "Biology,", "Research", "Unit", "Molecular", "Biology,", "Wilhelm-Stahl-Allee", "2,", "18196", "Dummerstorf,", "Germany", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "that", "are", "unlinked", "to", "the", "gene", "that", "is", "being", "controlled", "(trans-acting)", "[1].", "Expression-QTL", "for", "genes", "showing", "high", "correlation", "with", "the", "phenotype", "may", "provide", "the", "necessary", "information", "required", "for", "identifying", "genes", "that", "control", "quantitative", "phenotypes.", "Those", "cis-eQTLs", "resulting", "from", "the", "correlation", "of", "expression", "profiles", "with", "phenotypic", "measurements", "represent", "candidate", "genes", "for", "the", "genetic", "regulation", "underlying", "the", "variation", "of", "the", "physiological", "traits", "[3,4].", "We", "have", "previously", "reported", "on", "the", "identification", "of", "eQTL", "of", "genes", "showing", "expression", "levels", "correlated", "with", "waterholding", "capacity", "of", "meat", "measured", "as", "drip", "loss", "[5].", "Here", "in", "this", "study,", "we", "expand", "and", "up-dated", "the", "analysis", "towards", "global", "eQTL", "mapping", "of", "transcripts", "showing", "variable", "abundance", "in", "porcine", "muscle", "and", "using", "annotation", "and", "localisation", "data", "of", "Affymetrix", "©", "2010", "Ponsuksili", "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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[ "Heider", "et", "al.", "BMC", "Bioinformatics", "2010,", "11:37", "http://www.biomedcentral.com/1471-2105/11/37", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Predicting", "Bevirimat", "resistance", "of", "HIV-1", "from", "genotype", "Dominik", "Heider1*,", "Jens", "Verheyen2,", "Daniel", "Hoffmann1", "Abstract", "Background:", "Maturation", "inhibitors", "are", "a", "new", "class", "of", "antiretroviral", "drugs.", "Bevirimat", "(BVM)", "was", "the", "first", "substance", "in", "this", "class", "of", "inhibitors", "entering", "clinical", "trials.", "While", "the", "inhibitory", "function", "of", "BVM", "is", "well", "established,", "the", "molecular", "mechanisms", "of", "action", "and", "resistance", "are", "not", "well", "understood.", "It", "is", "known", "that", "mutations", "in", "the", "regions", "CS", "p24/p2", "and", "p2", "can", "cause", "phenotypic", "resistance", "to", "BVM.", "We", "have", "investigated", "a", "set", "of", "p24/p2", "sequences", "of", "HIV-1", "of", "known", "phenotypic", "resistance", "to", "BVM", "to", "test", "whether", "BVM", "resistance", "can", "be", "predicted", "from", "sequence,", "and", "to", "identify", "possible", "molecular", "mechanisms", "of", "BVM", "resistance", "in", "HIV-1.", "Results:", "We", "used", "artificial", "neural", "networks", "and", "random", "forests", "with", "different", "descriptors", "for", "the", "prediction", "of", "BVM", "resistance.", "Random", "forests", "with", "hydrophobicity", "as", "descriptor", "performed", "best", "and", "classified", "the", "sequences", "with", "an", "area", "under", "the", "Receiver", "Operating", "Characteristics", "(ROC)", "curve", "of", "0.93", "±", "0.001.", "For", "the", "collected", "data", "we", "find", "that", "p2", "sequence", "positions", "369", "to", "376", "have", "the", "highest", "impact", "on", "resistance,", "with", "positions", "370", "and", "372", "being", "particularly", "important.", "These", "findings", "are", "in", "partial", "agreement", "with", "other", "recent", "studies.", "Apart", "from", "the", "complex", "machine", "learning", "models", "we", "derived", "a", "number", "of", "simple", "rules", "that", "predict", "BVM", "resistance", "from", "sequence", "with", "surprising", "accuracy.", "According", "to", "computational", "predictions", "based", "on", "the", "data", "set", "used,", "cleavage", "sites", "are", "usually", "not", "shifted", "by", "resistance", "mutations.", "However,", "we", "found", "that", "resistance", "mutations", "could", "shorten", "and", "weaken", "the", "a-helix", "in", "p2,", "which", "hints", "at", "a", "possible", "resistance", "mechanism.", "Conclusions:", "We", "found", "that", "BVM", "resistance", "of", "HIV-1", "can", "be", "predicted", "well", "from", "the", "sequence", "of", "the", "p2", "peptide,", "which", "may", "prove", "useful", "for", "personalized", "therapy", "if", "maturation", "inhibitors", "reach", "clinical", "practice.", "Results", "of", "secondary", "structure", "analysis", "are", "compatible", "with", "a", "possible", "route", "to", "BVM", "resistance", "in", "which", "mutations", "weaken", "a", "six-helix", "bundle", "discovered", "in", "recent", "experiments,", "and", "thus", "ease", "Gag", "cleavage", "by", "the", "retroviral", "protease.", "Background", "HIV", "and", "Bevirimat", "Bevirimat", "(BVM)", "[1]", "belongs", "to", "a", "new", "class", "of", "anti-HIV", "substances", "that", "inhibit", "maturation", "of", "virus", "particles", "by", "preventing", "cleavage", "of", "precursor", "polyprotein", "by", "the", "ret-", "roviral", "protease", "(PR).", "BVM", "prevents", "the", "final", "cleavage", "of", "precursor", "protein", "p25", "to", "p24", "and", "p2,", "hence", "p25", "pro-", "teins", "are", "accumulating", "in", "the", "immature", "virions.", "These", "immature", "viral", "particles", "are", "not", "capable", "of", "transforming", "to", "an", "infectious", "stage,", "and", "the", "viral", "replication", "cycle", "is", "interrupted.", "A", "first", "set", "of", "mutations", "conferring", "resis-", "tance", "to", "BVM", "were", "found", "in", "selection", "experiments", "with", "BVM", "and", "were", "located", "at", "CS", "p24/p2", "[1-4].", "In", "clinical", "phase", "II", "trials,", "polymorphisms", "in", "the", "QVT-motif", "of", "p2", "*", "Correspondence:", "dominik.heider@uni-due.de", "1Department", "of", "Bioinformatics,", "Center", "of", "Medical", "Biotechnology,", "University", "of", "Duisburg-Essen,", "Universitaetsstr.", "2,", "45117", "Essen,", "Germany", "were", "found", "to", "prevent", "antiretroviral", "activity", "of", "BVM", "and", "were", "extensively", "studied", "in", "phenotypic", "resistance", "assays", "[5-7].", "Machine", "learning", "The", "notion", "of", "a", "resistance", "mutation", "is", "often", "useful", "as", "a", "first,", "simple", "approximation", "to", "describe", "relations", "between", "point", "mutations", "and", "resistance", "phenotypes.", "However,", "it", "is", "often", "observed", "that", "the", "more", "data", "become", "available", "the", "more", "complex", "are", "the", "relations", "between", "genotype", "and", "phenotype", "that", "show", "up.", "For", "instance,", "it", "has", "been", "observed", "that", "mutations", "in", "the", "QVT", "motif", "(wild", "type", "sequence", "369-371)", "are", "preferentially", "associated", "with", "resistance", "to", "BVM", "[8].", "However,", "as", "the", "data", "analyzed", "in", "the", "current", "study", "shows,", "the", "same", "set", "of", "mutations", "of", "QVT", "to", "QAS", "can", "be", "associated", "with", "BVM", "resistance", "[5]", "or", "susceptibility", "[6],", "depending", "on", "the", "mutational", "©", "2010", "Heider", "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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[ "Case", "Report", "Iran", "J", "Pediatr", "Dec", "2010;", "Vol", "20", "(No", "4),", "Pp:", "483-486", "Coincidence", "of", "Niemann-Pick", "Disease", "and", "beta-Thalassemia;", "a", "Case", "Report", "Fatemeh", "Farahmand1,2,", "MD;", "Vajiheh", "Modaresi*2,", "MD;", "Mina", "Izadyar1,2,", "MD,", "and", "Fatemeh", "Mahjob3,", "MD", "1.", "Department", "of", "Pediatric,", "Tehran", "University", "of", "Medical", "Sciences,", "Tehran,", "IR", "Iran", "2.", "Center", "of", "Excellence", "for", "Pediatrics.", "Children's", "Medical", "Center,", "Tehran", "University", "of", "Medical", "Sciences,", "Tehran,", "IR", "Iran", "3.", "Department", "of", "Pathology,", "Tehran", "University", "of", "Medical", "Sciences,", "Tehran,", "IR", "Iran", "Received:", "Jan", "09,", "2010;", "Final", "Revision:", "Jun", "09,", "2010;", "Accepted:", "Jul", "30,", "2010", "Abstract", "Background:", "Niemann-Pick", "disease", "and", "-thalassemia", "are", "distinct", "conditions", "with", "specific", "clinical", "and", "morphological", "manifestations.", "-thalassemia", "is", "the", "most", "common", "inherited", "blood", "disorder", "in", "Iran", "whereas", "Niemann-Pick", "disease,", "a", "lysosomal", "storage", "disorder,", "is", "rarely", "found", "in", "this", "country.", "Case", "Presentation:", "This", "5-month", "old", "girl,", "a", "known", "case", "of", "-thalassemia", "major", "was", "hospitalized", "for", "failure", "to", "thrive", "and", "hepathosplenomegaly.", "Because", "of", "unusual", "splenomegaly", "and", "liver", "enzymes", "disturbance", "that", "was", "not", "compatible", "with", "the", "first", "diagnosis,", "further", "evaluation", "revealed", "cherry", "red", "spot", "and", "high", "lipid", "profile", "suggestive", "of", "lysosomal", "storage", "disease.", "Foamy", "cells", "in", "the", "bone", "marrow", "and", "low", "activity", "of", "the", "specific", "enzyme", "led", "to", "the", "diagnosis", "of", "Niemann-Pick", "disease.", "Conclusion:", "This", "unique", "case", "illustrates", "the", "importance", "of", "looking", "for", "a", "second", "pathological", "condition", "in", "a", "patient", "whose", "clinical", "profile", "does", "not", "support", "the", "first", "diagnosis", "in", "its", "entirety.", "Iranian", "Journal", "of", "Pediatrics,", "Volume", "20", "(Number", "4),", "December", "2010,", "Pages:", "483-486", "Key", "Words:", "Niemann-Pick", "disease;", "Beta-Thalassemia;", "Liver", "enzyme;", "Lipidosis;", "Hemolytic", "anemia", "Introduction", "Niemann-Pick", "disease[1]", "and", "-thalassemia[2]", "are", "distinct", "conditions", "with", "specific", "clinical", "and", "morphological", "manifestations.", "Beta-thalassemia", "major", "(BTM)", "is", "the", "term", "applied", "to", "patients", "who", "have", "either", "no", "effective", "production", "(as", "in", "homozygous", "/0", "thalassemia)", "or", "severely", "limited", "production", "of", "beta", "globin.", "These", "hemoglobinopathies", "are", "relatively", "common", "in", "Iran,", "since", "Iran", "is", "located", "on", "the", "\"thalassemia", "belt\",", "with", "estimated", "three", "million", "carriers", "in", "population[3,4].", "For", "this", "reason", "all", "patients", "could", "be", "recognized", "early", "in", "life", "and", "usually", "receive", "appropriate", "supportive", "*", "Corresponding", "Author;", "Address:", "Gastroenterology", "Division,", "Children's", "Medical", "Center", "Hospital,No", "62,", "Dr.Gharib", "Street,", "Keshavarz", "Blvd,", "Tehran,", "IR", "Iran", "E-mail:", "drmodarressi@gmail.com", "©", "2010", "by", "Pediatrics", "Center", "of", "Excellence,", "Childrens", "Medical", "Center,", "Tehran", "University", "of", "Medical", "Sciences,", "All", "rights", "reserved." ]

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[ "Int.", "J.", "Environ.", "Res.", "Public", "Health", "2010,", "7,", "1076-1092;", "doi:10.3390/ijerph7031076", "OPEN", "ACCESS", "International", "Journal", "of", "Environmental", "Research", "and", "Public", "Health", "ISSN", "1660-4601", "www.mdpi.com/journal/ijerph", "Review", "A", "New", "View", "of", "Alcohol", "Metabolism", "and", "Alcoholism—Role", "of", "the", "High-Km", "Class", "Ⅲ", "Alcohol", "Dehydrogenase", "(ADH3)", "Takeshi", "Haseba", "*", "and", "Youkichi", "Ohno", "Department", "of", "Legal", "Medicine,", "Nippon", "Medical", "School,", "1-1-5", "Sendagi,", "Bunkyo-ku,", "Tokyo", "113-8602,", "Japan;", "E-Mail:", "ohno@nms.ac.jp", "*", "Author", "to", "whom", "correspondence", "should", "be", "addressed:", "E-Mail:", "hasebat@nms.ac.jp;", "Tel.:", "+81-03-3822;", "Fax:", "+81-03-5814-5680.", "Received:", "4", "January", "2010;", "in", "revised", "form:", "12", "February", "2010", "/", "Accepted:", "22", "February", "2010", "/", "Published:", "15", "March", "2010", "Abstract:", "The", "conventional", "view", "is", "that", "alcohol", "metabolism", "is", "carried", "out", "by", "ADH1", "(Class", "I)", "in", "the", "liver.", "However,", "it", "has", "been", "suggested", "that", "another", "pathway", "plays", "an", "important", "role", "in", "alcohol", "metabolism,", "especially", "when", "the", "level", "of", "blood", "ethanol", "is", "high", "or", "when", "drinking", "is", "chronic.", "Over", "the", "past", "three", "decades,", "vigorous", "attempts", "to", "identify", "the", "enzyme", "responsible", "for", "the", "non-ADH1", "pathway", "have", "focused", "on", "the", "microsomal", "ethanol", "oxidizing", "system", "(MEOS)", "and", "catalase,", "but", "have", "failed", "to", "clarify", "their", "roles", "in", "systemic", "alcohol", "metabolism.", "Recently,", "using", "ADH3-null", "mutant", "mice,", "we", "demonstrated", "that", "ADH3", "(Class", "III),", "which", "has", "a", "high", "Km", "and", "is", "a", "ubiquitous", "enzyme", "of", "ancient", "origin,", "contributes", "to", "systemic", "alcohol", "metabolism", "in", "a", "dose-dependent", "manner,", "thereby", "diminishing", "acute", "alcohol", "intoxication.", "Although", "the", "activity", "of", "ADH3", "toward", "ethanol", "is", "usually", "low", "in", "vitro", "due", "to", "its", "very", "high", "Km,", "the", "catalytic", "efficiency", "(kcat/Km)", "is", "markedly", "enhanced", "when", "the", "solution", "hydrophobicity", "of", "the", "reaction", "medium", "increases.", "Activation", "of", "ADH3", "by", "increasing", "hydrophobicity", "should", "also", "occur", "in", "liver", "cells;", "a", "cytoplasmic", "solution", "of", "mouse", "liver", "cells", "was", "shown", "to", "be", "much", "more", "hydrophobic", "than", "a", "buffer", "solution", "when", "using", "Nile", "red", "as", "a", "hydrophobicity", "probe.", "When", "various", "doses", "of", "ethanol", "are", "administered", "to", "mice,", "liver", "ADH3", "activity", "is", "dynamically", "regulated", "through", "induction", "or", "kinetic", "activation,", "while", "ADH1", "activity", "is", "markedly", "lower", "at", "high", "doses", "(3–5", "g/kg).", "These", "data", "suggest", "that", "ADH3", "plays", "a", "dynamic", "role", "in", "alcohol", "metabolism,", "either", "collaborating", "with", "ADH1", "or", "compensating", "for", "the", "reduced", "role", "of", "ADH1.", "A", "complex", "two-ADH", "model", "that", "ascribes" ]

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[ "Linard", "et", "al.", "International", "Journal", "of", "Health", "Geographics", "2010,", "9:45", "http://www.ij-healthgeographics.com/content/9/1/45", "R", "E", "S", "E", "A", "R", "C", "H", "INTERNATIONAL", "JOURNAL", "OF", "HEALTH", "GEOGRAPHICS", "Open", "Access", "A", "high", "resolution", "spatial", "population", "database", "of", "Somalia", "for", "disease", "risk", "mapping", "Catherine", "Linard1,2*,", "Victor", "A", "Alegana3,", "Abdisalan", "M", "Noor3,4,", "Robert", "W", "Snow3,4,", "Andrew", "J", "Tatem5,6,7", "Abstract", "Background:", "Millions", "of", "Somali", "have", "been", "deprived", "of", "basic", "health", "services", "due", "to", "the", "unstable", "political", "situation", "of", "their", "country.", "Attempts", "are", "being", "made", "to", "reconstruct", "the", "health", "sector,", "in", "particular", "to", "estimate", "the", "extent", "of", "infectious", "disease", "burden.", "However,", "any", "approach", "that", "requires", "the", "use", "of", "modelled", "disease", "rates", "requires", "reasonable", "information", "on", "population", "distribution.", "In", "a", "low-income", "country", "such", "as", "Somalia,", "population", "data", "are", "lacking,", "are", "of", "poor", "quality,", "or", "become", "outdated", "rapidly.", "Modelling", "methods", "are", "therefore", "needed", "for", "the", "production", "of", "contemporary", "and", "spatially", "detailed", "population", "data.", "Results:", "Here", "land", "cover", "information", "derived", "from", "satellite", "imagery", "and", "existing", "settlement", "point", "datasets", "were", "used", "for", "the", "spatial", "reallocation", "of", "populations", "within", "census", "units.", "We", "used", "simple", "and", "semi-automated", "methods", "that", "can", "be", "implemented", "with", "free", "image", "processing", "software", "to", "produce", "an", "easily", "updatable", "gridded", "population", "dataset", "at", "100", "×", "100", "meters", "spatial", "resolution.", "The", "2010", "population", "dataset", "was", "matched", "to", "administrative", "population", "totals", "projected", "by", "the", "UN.", "Comparison", "tests", "between", "the", "new", "dataset", "and", "existing", "population", "datasets", "revealed", "important", "differences", "in", "population", "size", "distributions,", "and", "in", "population", "at", "risk", "of", "malaria", "estimates.", "These", "differences", "are", "particularly", "important", "in", "more", "densely", "populated", "areas", "and", "strongly", "depend", "on", "the", "settlement", "data", "used", "in", "the", "modelling", "approach.", "Conclusions:", "The", "results", "show", "that", "it", "is", "possible", "to", "produce", "detailed,", "contemporary", "and", "easily", "updatable", "settlement", "and", "population", "distribution", "datasets", "of", "Somalia", "using", "existing", "data.", "The", "2010", "population", "dataset", "produced", "is", "freely", "available", "as", "a", "product", "of", "the", "AfriPop", "Project", "and", "can", "be", "downloaded", "from:", "http://www.afripop.", "org.", "Background", "Since", "the", "fall", "of", "the", "central", "government", "in", "1989,", "Soma-", "lia", "has", "been", "suffering", "from", "18", "years", "of", "conflict", "and", "civil", "war", "that", "has", "resulted", "in", "a", "series", "of", "humanitarian", "disas-", "ters.", "Thousands", "of", "Somali", "have", "been", "externally", "and", "internally", "displaced", "and", "millions", "have", "been", "deprived", "of", "basic", "health", "and", "social", "services", "[1].", "Attempts", "are", "being", "made", "to", "reconstruct", "the", "health", "sector", "but", "with", "the", "exception", "of", "the", "relatively", "peaceful", "northern", "region,", "the", "current", "political", "situation", "in", "Somalia", "poses", "a", "major", "obstacle", "for", "the", "establishment", "of", "a", "comprehensive", "health", "care", "system.", "The", "situation", "has", "inevitably", "resulted", "in", "an", "*", "Correspondence:", "catherine.linard@zoo.ox.ac.uk", "1Spatial", "Ecology", "and", "Epidemiology", "Group,", "Department", "of", "Zoology,", "University", "of", "Oxford,", "Tinbergen", "Building,", "South", "Parks", "Road,", "Oxford,", "OX1", "3PS,", "UK", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "almost", "complete", "lack", "of", "any", "systematic,", "comprehensive", "nationwide", "systems", "of", "vital", "or", "health", "information.", "Defining", "the", "extent", "of", "infectious", "diseases", "as", "a", "public", "health", "burden", "and", "their", "distribution", "in", "time", "and", "space", "are", "critical", "to", "scoping", "the", "financial", "requirements,", "setting", "a", "control", "agenda", "and", "monitoring", "[2].", "However,", "any", "approach", "that", "requires", "the", "use", "of", "modelled", "disease", "rates", "requires", "reasonable", "information", "on", "the", "resident", "popula-", "tion", "for", "the", "years", "one", "is", "intending", "to", "estimate", "risk.", "Where", "risks", "of", "disease", "are", "over-distributed", "in", "space,", "such", "as", "is", "the", "case", "for", "most", "vector", "borne", "diseases,", "popu-", "lation", "distributions", "and", "counts", "must", "be", "resolved", "to", "higher", "levels", "of", "spatial", "detail", "than", "large", "regional", "esti-", "mates.", "Detailed", "and", "spatially", "disaggregated", "population", "data", "are", "essential", "resources", "in", "the", "assessment", "of", "the", "number", "of", "impacted", "people", "for", "planning", "health", "service", "delivery", "and", "for", "decision-making", "processes", "related", "to", "developmental", "or", "health", "issues", "[3-6].", "©", "2010", "Linard", "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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[ "Research", "Meeting", "Report:", "Knowledge", "and", "Gaps", "in", "Developing", "Microbial", "Criteria", "for", "Inland", "Recreational", "Waters", "Samuel", "Dorevitch,1", "Nicholas", "J.", "Ashbolt,2", "Christobel", "M.", "Ferguson,3,4", "Roger", "Fujioka,5", "Charles", "D.", "McGee,6", "Jeffrey", "A.", "Soller,7", "and", "Richard", "L.", "Whitman", "8", "1University", "of", "Illinois", "at", "Chicago", "School", "of", "Public", "Health,", "Chicago,", "Illinois,", "USA;", "2Office", "of", "Research", "and", "Development,", "U.S.", "Environmental", "Protection", "Agency,", "Cincinnati,", "Ohio,", "USA;", "3Ecowise", "Environmental,", "Penrith,", "New", "South", "Wales,", "Australia;", "4Australian", "National", "University,", "Canberra,", "Australian", "Capitol", "Territory,", "Australia;", "5University", "of", "Hawaii,", "Water", "Resources", "Research", "Center,", "Honolulu,", "Hawaii,", "USA;", "6Orange", "County", "Sanitation", "District,", "Fountain", "Valley,", "California,", "USA;", "7Soller", "Environmental,", "Berkeley,", "California,", "USA;", "8U.S.", "Geological", "Survey,", "Lake", "Michigan", "Ecological", "Research", "Station,", "Porter,", "Indiana,", "USA", "The", "U.S.", "Environmental", "Protection", "Agency", "(EPA)", "has", "committed", "to", "issuing", "in", "2012", "new", "or", "revised", "criteria", "designed", "to", "protect", "the", "health", "of", "those", "who", "use", "surface", "waters", "for", "recreation.", "For", "this", "purpose,", "the", "U.S.", "EPA", "has", "been", "conducting", "epidemiologic", "studies", "to", "establish", "relationships", "between", "microbial", "measures", "of", "water", "quality", "and", "adverse", "health", "outcomes", "among", "swimmers.", "New", "methods", "for", "testing", "water", "quality", "that", "would", "provide", "same-day", "results", "will", "likely", "be", "elements", "of", "the", "new", "criteria.", "Although", "the", "epidemiologic", "studies", "upon", "which", "the", "criteria", "will", "be", "based", "were", "conducted", "at", "Great", "Lakes", "and", "marine", "beaches,", "the", "new", "water", "quality", "criteria", "may", "be", "extended", "to", "inland", "waters", "(IWs).", "Similarities", "and", "important", "differences", "between", "coastal", "waters", "(CWs)", "and", "IWs", "that", "should", "be", "considered", "when", "developing", "criteria", "for", "IWs", "were", "the", "focus", "of", "an", "expert", "workshop.", "Here,", "we", "summarize", "the", "state", "of", "knowledge", "and", "research", "needed", "to", "base", "IWs", "microbial", "criteria", "on", "sound", "science.", "Two", "key", "differences", "between", "CWs", "and", "IWs", "are", "the", "sources", "of", "indicator", "bacteria,", "which", "may", "modify", "the", "relationship", "between", "indicator", "microbes", "and", "health", "risk,", "and", "the", "relation-", "ship", "between", "indicators", "and", "pathogens,", "which", "also", "may", "vary", "within", "IWs.", "Monitoring", "using", "rapid", "molecular", "methods", "will", "require", "the", "standardization", "and", "simplification", "of", "analytical", "methods,", "as", "well", "as", "greater", "clarity", "about", "their", "interpretation.", "Research", "needs", "for", "the", "short", "term", "and", "longer", "term", "are", "described.", "Key", "words:", "Clean", "Water", "Act,", "environmental", "epidemiology,", "environmental", "microbiology,", "indica-", "tor", "bacteria,", "inland", "waters,", "predictive", "modeling,", "waterborne", "pathogens,", "water", "recreation.", "Environ", "Health", "Perspect", "118:871–876", "(2010).", "doi:10.1289/ehp.0901627", "[Online", "25", "January", "2010]", "Recreational", "Water", "Quality", "Criteria", "Ambient", "water", "quality", "criteria.", "Viral,", "bacterial,", "and", "protozoan", "pathogens", "are", "responsible", "for", "infectious", "disease", "outbreaks", "among", "recreators", "at", "coastal", "and", "inland", "sur-", "face", "waters", "(Yoder", "et", "al.", "2008).", "To", "protect", "the", "public", "from", "recreational", "waterborne", "illness,", "the", "U.S.", "Environmental", "Protection", "Agency", "(EPA)", "established", "ambient", "water", "quality", "crite-", "ria", "(AWQC;", "U.S.", "EPA", "1986).", "The", "epidemio-", "logic", "studies", "on", "which", "the", "current", "AWQC", "are", "based", "suggest", "that", "at", "freshwater", "beaches,", "the", "rate", "of", "acute", "gastrointestinal", "illness", "attribut-", "able", "to", "swimming", "should", "be", "about", "8", "cases", "per", "1,000", "swimmers", "when", "monthly", "geo-", "metric", "mean", "(GM)", "density", "(concentration)", "of", "Escherichia", "coli", "is", "<", "126", "colony-forming", "units", "(CFU)/100", "mL),", "or", "if", "the", "monthly", "GM", "density", "of", "enterococci", "is", "<", "33", "CFU/100", "mL", "(EPA", "1984).", "For", "marine", "waters,", "the", "gastro-", "intestinal", "illness", "rate", "should", "be", "about", "19", "per", "1,000", "swimmers", "when", "monthly", "GM", "entero-", "cocci", "densities", "do", "not", "exceed", "35", "CFU/100", "mL", "(U.S.", "EPA", "1983).", "Additionally,", "single-sample", "maximum", "values", "were", "established", "to", "aid", "in", "day-to-day", "beach", "management.", "For", "freshwater", "beaches,", "these", "maxima", "are", "235", "CFU/100", "mL", "for", "E.", "coli", "or", "61", "CFU/100", "mL", "for", "enterococci;", "for", "marine", "beaches,", "the", "single", "sample", "maxi-", "mum", "for", "enterococci", "is", "104", "CFU/100", "mL.", "Nonetheless,", "final", "implementation", "guide-", "lines", "for", "the", "1986", "AWQC", "were", "never", "issued,", "and", "prior", "to", "the", "passage", "of", "the", "Beaches", "Environmental", "Assessment", "and", "Coastal", "Health", "Act", "(BEACH", "Act", "2000),", "only", "11", "states", "applied", "the", "criteria", "to", "their", "marine", "or", "Great", "Lakes", "recreational", "waters", "[herein", "referred", "to", "collectively", "as", "coastal", "waters", "(CWs)]", "(U.S.", "EPA", "2006).", "Indicators", "and", "their", "limitations.", "Fecal", "indicator", "bacteria", "(FIB),", "such", "as", "enterococci", "and", "E.", "coli,", "are", "measured", "because", "they", "are", "thought", "to", "indicate", "the", "presence", "of", "fecal", "matter,", "and", "potentially", "pathogens,", "in", "sur-", "face", "waters.", "Compared", "with", "the", "pathogens", "that", "cause", "recreational", "waterborne", "infections,", "FIB", "are", "easier", "to", "detect", "and", "enumerate", "using", "well-established", "and", "inexpensive", "methods.", "Epidemiologic", "studies", "support", "the", "use", "of", "FIB", "as", "predictors", "of", "illness", "rates", "among", "swimmers", "(Wade", "et", "al.", "2003).", "Culture", "techniques", "for", "FIB", "require", "a", "min-", "imum", "of", "18–24", "hr", "to", "perform.", "Thus,", "beach", "managers", "evaluate", "information", "that", "is,", "at", "best,", "1", "day", "old", "when", "deciding", "to", "issue", "swimming", "bans", "or", "advisories.", "By", "the", "time", "FIB", "results", "become", "available,", "the", "microbial", "water", "qual-", "ity", "may", "have", "changed", "substantially", "(Boehm", "2007;", "Hou", "et", "al.", "2006;", "Whitman", "et", "al.", "2004).", "Illness", "rates", "at", "beaches", "that", "are", "impacted", "by", "human", "sewage", "are", "related", "to", "FIB,", "which", "are", "Environmental", "Health", "Perspectives", "•", "volume", "118", "|", "number", "6", "|", "June", "2010", "measured", "by", "culture", "(U.S.", "EPA", "1983,", "1984)", "or", "by", "rapid", "molecular", "methods", "(Wade", "et", "al.", "2006,", "2008),", "but", "at", "beaches", "without", "point", "sources", "of", "human", "fecal", "pollution,", "this", "may", "not", "be", "true", "(Calderon", "et", "al.", "1991;", "Colford", "et", "al.", "2007).", "If", "the", "environmental", "sources", "and", "persistence", "of", "FIB", "were", "similar", "to", "those", "of", "pathogens,", "FIB", "should", "be", "good", "predictors", "of", "human", "illness.", "However,", "FIB", "may", "per-", "sist", "or", "even", "regrow", "in", "soil,", "plants,", "sand,", "and", "sediments", "(Byappanahalli", "and", "Fujioka", "2004;", "Byappanahalli", "et", "al.", "2006;", "Davies", "et", "al.", "1995;", "Desmarais", "et", "al.", "2002)—environments", "that,", "without", "a", "suitable", "host", "organism,", "do", "not", "sup-", "port", "the", "replication", "of", "human", "viral", "or", "proto-", "zoan", "pathogens.", "Boehm", "et", "al.", "(2009)", "recently", "reviewed", "these", "and", "other", "limitations", "of", "FIB", "as", "indicators.", "Inland", "water", "recreation,", "risk,", "and", "regu-", "lation.", "Inland", "flowing", "(riverine)", "waters", "are", "surface", "waters", "with", "a", "net", "directional", "current", "and", "are", "confined", "by", "banks", "and", "stream", "beds.", "Lacustrine", "waters", "are", "freshwater", "bodies", "gener-", "ally", "confined", "to", "a", "basin", "(lakes).", "According", "to", "the", "U.S.", "EPA", "ATTAINS", "database", "(2009),", "the", "United", "States", "has", ">", "3.5", "million", "miles", "of", "inland", "flowing", "waters", "and", "more", "than", "41", "mil-", "lion", "acres", "of", "inland", "waters", "(IWs).", "The", "1986", "AWQC", "were", "based", "almost", "entirely", "on", "epidemiologic", "studies", "conducted", "at", "coastal", "beaches,", "with", "a", "small", "portion", "of", "Address", "correspondence", "to", "S.", "Dorevitch,", "UIC", "School", "of", "Public", "Health,", "2121", "W.", "Taylor,", "M/C", "923,", "Chicago,", "IL", "60612", "USA.", "Telephone:", "(312)", "355-3629.", "Fax:", "(312)", "413-9898.", "E-mail:", "sdorevit@uic.edu", "We", "acknowledge", "all", "workshop", "participants", "for", "their", "efforts.", "Many", "thanks", "to", "S.", "Briggs,", "Michigan", "Department", "of", "Environmental", "Quality,", "for", "her", "com-", "ments.", "We", "acknowledge", "the", "Water", "Environment", "Research", "Foundation", "(WERF)", "and", "the", "U.S.", "EPA", "for", "organizing", "the", "expert", "workshop.", "R.L.W.:", "Contribution", "1583", "of", "the", "U.S.", "Geological", "Survey", "Great", "Lakes", "Science", "Center.", "This", "manuscript", "has", "been", "reviewed", "by", "the", "U.S.", "Environmental", "Protection", "Agency", "(EPA)", "and", "by", "the", "U.S.", "Geological", "Survey", "(USGS).", "The", "views", "expressed", "by", "the", "authors", "are", "not", "necessarily", "policy", "nor", "the", "views", "of", "U.S.", "EPA", "or", "the", "USGS.", "S.D.", "currently", "receives", "research", "support", "from", "the", "WERF", "and", "the", "Metropolitan", "Water", "Reclamation", "District", "of", "Greater", "Chicago.", "J.A.S.", "is", "employed", "by", "Soller", "Environmental,", "Berkeley,", "CA.", "The", "remaining", "authors", "declare", "they", "have", "no", "actual", "or", "potential", "com-", "peting", "financial", "interests.", "Received", "26", "October", "2009;", "accepted", "25", "January", "2010.", "871" ]

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[ "Amino", "Acids", "(2010)", "38:923–928", "DOI", "10.1007/s00726-009-0300-5", "O", "R", "I", "G", "I", "N", "A", "L", "A", "R", "T", "I", "C", "L", "E", "Plasma", "levels", "of", "nitric", "oxide", "related", "amino", "acids", "in", "demented", "subjects", "with", "Down", "syndrome", "are", "related", "to", "neopterin", "concentrations", "A.", "M.", "W.", "Coppus", "Æ", "D.", "Fekkes", "Æ", "W.", "M.", "A.", "Verhoeven", "Æ", "S.", "Tuinier", "Æ", "C.", "M.", "van", "Duijn", "Received:", "19", "April", "2009", "/", "Accepted:", "21", "April", "2009", "/", "Published", "online:", "20", "May", "2009", "The", "Author(s)", "2009.", "This", "article", "is", "published", "with", "open", "access", "at", "Springerlink.com", "Abstract", "Subjects", "with", "Down", "syndrome", "(DS)", "have", "abnormalities", "in", "virtually", "all", "aspects", "of", "the", "immune", "system", "and", "almost", "all", "will", "be", "affected", "with", "Alzheimer’s", "disease", "(AD).", "It", "is", "thought", "that", "nitric", "oxide", "(NO)", "is", "involved", "in", "the", "pathophysiology", "of", "AD.", "In", "the", "present", "study,", "including", "a", "total", "of", "401", "elderly", "DS", "subjects,", "the", "spectrum", "of", "plasma", "amino", "acids", "and", "neopterin", "was", "investigated", "and", "related", "to", "development", "of", "AD.", "Concentrations", "of", "nearly", "all", "amino", "acids", "in", "DS", "subjects", "differed", "significantly", "from", "those", "of", "healthy", "controls.", "Neopterin", "was", "increased", "in", "DS", "subjects,", "especially", "in", "dementia.", "The", "production", "of", "NO", "as", "reflected", "by", "an", "increased", "citrulline/arginine", "ratio", "(Cit/Arg", "ratio)", "was", "enhanced", "during", "development", "of", "clinical", "dementia.", "Neop-", "terin", "concentrations", "correlated", "to", "the", "Cit/Arg", "ratio", "only", "in", "the", "group", "of", "prevalent", "demented", "subjects", "(q", "=", "0.48,", "A.", "M.", "W.", "Coppus", "(&)", "Centre", "for", "the", "Intellectually", "Disabled,", "Dichterbij,", "Gennep,", "The", "Netherlands", "e-mail:", "a.coppus@erasmusmc.nl", "A.", "M.", "W.", "Coppus", "C.", "M.", "van", "Duijn", "Department", "of", "Epidemiology,", "Erasmus", "University", "Medical", "Centre,", "Rotterdam,", "The", "Netherlands", "D.", "Fekkes", "Department", "of", "Neuroscience,", "Erasmus", "University", "Medical", "Centre,", "Rotterdam,", "The", "Netherlands", "W.", "M.", "A.", "Verhoeven", "S.", "Tuinier", "Vincent", "van", "Gogh", "Institute", "for", "Psychiatry,", "Venray,", "The", "Netherlands", "D.", "Fekkes", "W.", "M.", "A.", "Verhoeven", "Department", "of", "Psychiatry,", "Erasmus", "University", "Medical", "Centre,", "Rotterdam,", "The", "Netherlands", "P", "=", "0.006).", "The", "results", "of", "this", "study", "are", "suggestive", "for", "an", "increase", "in", "oxidative", "processes", "in", "DS", "subjects", "with", "AD.", "Keywords", "Nitric", "oxide", "Amino", "acids", "Down", "syndrome", "Neopterin", "Branched", "chain", "amino", "acids", "Introduction", "Down", "syndrome", "(DS)", "is", "a", "common", "genetic", "disorder", "with", "a", "prevalence", "of", "1:750", "and", "is", "caused", "by", "a", "complete", "or", "occa-", "sionally", "partial", "triplication", "of", "chromosome", "21.", "Its", "preva-", "lence", "is", "highly", "dependent", "on", "maternal", "age", "at", "gestation.", "It", "is", "well", "known", "that", "individuals", "with", "DS", "have", "an", "increased", "rate", "of", "congenital", "and", "acquired", "medical", "complications", "includ-", "ing", "among", "others", "thyroid", "gland", "dysfunction.", "Abnormalities", "have", "been", "reported", "in", "virtually", "all", "aspects", "of", "the", "immune", "system", "resulting", "in", "a", "greater", "susceptibility", "to", "infectious", "disease.", "Finally,", "they", "have", "a", "higher", "risk", "for", "hematological", "malignancies,", "particularly", "leukemia’s,", "and", "virtually", "all", "show", "the", "neuropathological", "changes", "of", "Alzheimer’s", "dis-", "ease", "(AD)", "by", "the", "age", "of", "35–40", "years.", "This", "may", "be", "due", "to", "an", "increased", "production", "of", "the", "amyloid", "precursor", "protein", "(Cheon", "et", "al.", "2008;", "Lockstone", "et", "al.", "2007).", "Onset", "of", "clin-", "ical", "dementia", "is", "in", "general", "in", "the", "first", "half", "of", "the", "sixth", "decade.", "With", "respect", "to", "psychopathology,", "depression", "is", "frequently", "diagnosed", "and", "shows", "an", "age", "related", "increase", "(Hunter", "2005).", "A", "growing", "body", "of", "evidence", "indicates", "that", "there", "is", "an", "increased", "oxidative", "stress", "in", "AD", "brains", "and", "it", "is", "hypothe-", "sized", "that", "nitric", "oxide", "(NO)", "can", "be", "related", "to", "many", "of", "the", "pathophysiological", "mechanisms", "of", "AD", "(Akomolafe", "et", "al.", "2006;", "Moreira", "et", "al.", "2008).", "The", "presence", "of", "any", "stimulant", "that", "leads", "to", "an", "overproduction", "of", "NO", "will", "probably", "cause", "neuronal", "damage", "(Akyol", "et", "al.", "2004).", "The", "biologically", "123" ]

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[ "Sun", "et", "al.", "AMB", "Express", "2012,", "2:21", "http://www.amb-express.com/content/2/1/21", "O", "R", "I", "G", "I", "N", "A", "L", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Microbial", "community", "analysis", "in", "biocathode", "microbial", "fuel", "cells", "packed", "with", "different", "materials", "Yanmei", "Sun,", "Jincheng", "Wei,", "Peng", "Liang", "and", "Xia", "Huang*", "Abstract", "Biocathode", "MFCs", "using", "microorganisms", "as", "catalysts", "have", "important", "advantages", "in", "lowering", "cost", "and", "improving", "sustainability.", "Electrode", "materials", "and", "microbial", "synergy", "determines", "biocathode", "MFCs", "performance.", "In", "this", "study,", "four", "materials,", "granular", "activated", "carbon", "(GAC),", "granular", "semicoke", "(GS),", "granular", "graphite", "(GG)", "and", "carbon", "felt", "cube", "(CFC)", "were", "used", "as", "packed", "cathodic", "materials.", "The", "microbial", "composition", "on", "each", "material", "and", "its", "correlation", "with", "the", "electricity", "generation", "performance", "of", "MFCs", "were", "investigated.", "Results", "showed", "that", "different", "biocathode", "materials", "had", "an", "important", "effect", "on", "the", "type", "of", "microbial", "species", "in", "biocathode", "MFCs.", "The", "microbes", "belonging", "to", "Bacteroidetes", "and", "Proteobacteria", "were", "the", "dominant", "phyla", "in", "the", "four", "materials", "packed", "biocathode", "MFCs.", "Comamonas", "of", "Betaproteobacteria", "might", "play", "significant", "roles", "in", "electron", "transfer", "process", "of", "GAC,", "GS", "and", "CFC", "packed", "biocathode", "MFCs,", "while", "in", "GG", "packed", "MFC", "Acidovorax", "may", "be", "correlated", "with", "power", "generation.", "The", "biocathode", "materials", "also", "had", "influence", "on", "the", "microbial", "diversity", "and", "evenness,", "but", "the", "differences", "in", "them", "were", "not", "positively", "related", "to", "the", "power", "production.", "Keywords:", "Biocathode", "microbial", "fuel", "cell,", "Cathodic", "materials,", "Electricity", "generation,", "Microbial", "community", "Introduction", "Microbial", "fuel", "cells", "(MFCs)", "utilize", "microorganisms", "as", "catalysts,", "which", "can", "promote", "biodegradation", "of", "organic", "matters", "and", "simultaneously", "produce", "an", "electrical", "cur-", "rent", "(Bond", "et", "al.", "2002).", "In", "the", "past", "few", "years,", "research-", "ers", "generally", "use", "chemical", "cathode", "MFC", "to", "remove", "the", "organic", "carbon", "in", "wastewater,", "but", "the", "cost", "of", "chemical", "cathode", "is", "high", "and", "it", "is", "easily", "lead", "to", "pollution.", "Cur-", "rently,", "biocathode", "MFCs", "using", "microorganisms", "instead", "of", "common", "Pt", "as", "catalysts", "have", "important", "advantages", "in", "lowering", "cost,", "expanding", "function", "and", "improving", "sus-", "tainability.", "Therefore,", "biocathode", "MFCs", "as", "a", "new", "eco-", "nomical", "and", "environmentally", "friendly", "wastewater", "treatment", "technology", "has", "drawn", "more", "and", "more", "atten-", "tions", "(Huang", "et", "al.", "2011).", "Although", "biocathode", "MFCs", "have", "many", "advantages,", "the", "current", "studies", "are", "still", "at", "laboratory", "level.", "The", "main", "challenge", "for", "their", "large-scale", "application", "is", "low", "power", "generation", "capability.", "Microor-", "ganisms", "are", "the", "core", "of", "biocathode", "MFCs.", "In", "the", "anode,", "*", "Correspondence:", "xhuang@tsinghua.edu.cn", "State", "Key", "Joint", "Laboratory", "of", "Environment", "Simulation", "and", "Pollution", "Control,", "School", "of", "Environment,", "Tsinghua", "University,", "Beijing", "100084,", "P.", "R.", "China", "microorganisms", "attaching", "on", "the", "electrode", "material", "and", "forming", "biofilm", "play", "an", "essential", "role", "in", "MFC", "generating", "electricity", "(Rabaey", "and", "Rozendal", "2010),", "and", "in", "the", "cath-", "ode,", "the", "microbial", "catalytic", "efficiency", "plays", "a", "key", "role", "to", "improve", "the", "cathode", "potential", "and", "power", "output", "(Osman", "et", "al.", "2010).", "Therefore,", "better", "understanding", "of", "the", "ecology", "of", "the", "microbial", "communities", "in", "the", "differ-", "ent", "reactors", "will", "be", "helpful", "to", "improve", "MFCs", "power", "production.", "At", "present,", "the", "anodic", "microbes", "get", "more", "attention,", "including", "the", "electricity-producing", "bacteria", "species", "(Holmes", "et", "al.", "2004Xia", "et", "al.", "2010),", "anodic", "microbial", "community", "composition", "(Cárcer", "et", "al.", "2011Jung", "and", "Regan", "2010Kim", "et", "al.", "2011Zhang", "et", "al.", "2011),", "the", "mechanism", "of", "extracellular", "electron", "transfer", "(Carmona-", "Martinez", "et", "al.", "2011Strycharz", "et", "al.", "2011)", "and", "so", "on.", "In", "contrast,", "the", "researches", "on", "the", "microbes", "of", "biocathode", "MFCs", "are", "very", "limited,", "and", "mainly", "focused", "on", "the", "role", "of", "pure", "bacteria", "in", "biocathode", "MFCs.", "For", "instance,", "Car-", "bajosa", "et", "al.", "(2010)", "found", "that", "an", "acidophilic", "Acidithio-", "bacillus", "ferrooxidans", "could", "promote", "oxygen", "reduction", "in", "biocathode", "MFCs.", "Mao", "et", "al.", "(2010)", "reported", "that", "the", "©", "2012", "Sun", "et", "al;", "licensee", "Springer.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

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[ "Kang", "et", "al.", "BMC", "Plant", "Biology", "2010,", "10:210", "http://www.biomedcentral.com/1471-2229/10/210", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Distribution", "of", "polycyclic", "aromatic", "hydrocarbons", "in", "subcellular", "root", "tissues", "of", "ryegrass", "(Lolium", "multiflorum", "Lam.)", "Fuxing", "Kang,", "Dongsheng", "Chen,", "Yanzheng", "Gao*,", "Yi", "Zhang", "Abstract", "Background:", "Because", "of", "the", "increasing", "quantity", "and", "high", "toxicity", "to", "humans", "of", "polycyclic", "aromatic", "hydrocarbons", "(PAHs)", "in", "the", "environment,", "several", "bioremediation", "mechanisms", "and", "protocols", "have", "been", "investigated", "to", "restore", "PAH-contaminated", "sites.", "The", "transport", "of", "organic", "contaminants", "among", "plant", "cells", "via", "tissues", "and", "their", "partition", "in", "roots,", "stalks,", "and", "leaves", "resulting", "from", "transpiration", "and", "lipid", "content", "have", "been", "extensively", "investigated.", "However,", "information", "about", "PAH", "distributions", "in", "intracellular", "tissues", "is", "lacking,", "thus", "limiting", "the", "further", "development", "of", "a", "mechanism-based", "phytoremediation", "strategy", "to", "improve", "treatment", "efficiency.", "Results:", "Pyrene", "exhibited", "higher", "uptake", "and", "was", "more", "recalcitrant", "to", "metabolism", "in", "ryegrass", "roots", "than", "was", "phenanthrene.", "The", "kinetic", "processes", "of", "uptake", "from", "ryegrass", "culture", "medium", "revealed", "that", "these", "two", "PAHs", "were", "first", "adsorbed", "onto", "root", "cell", "walls,", "and", "they", "then", "penetrated", "cell", "membranes", "and", "were", "distributed", "in", "intracellular", "organelle", "fractions.", "At", "the", "beginning", "of", "uptake", "(<", "50", "h),", "adsorption", "to", "cell", "walls", "dominated", "the", "subcellular", "partitioning", "of", "the", "PAHs.", "After", "96", "h", "of", "uptake,", "the", "subcellular", "partition", "of", "PAHs", "approached", "a", "stable", "state", "in", "the", "plant", "water", "system,", "with", "the", "proportion", "of", "PAH", "distributed", "in", "subcellular", "fractions", "being", "controlled", "by", "the", "lipid", "contents", "of", "each", "component.", "Phenanthrene", "and", "pyrene", "primarily", "accumulated", "in", "plant", "root", "cell", "walls", "and", "organelles,", "with", "about", "45%", "of", "PAHs", "in", "each", "of", "these", "two", "fractions,", "and", "the", "remainder", "was", "retained", "in", "the", "dissolved", "fraction", "of", "the", "cells.", "Because", "of", "its", "higher", "lipophilicity,", "pyrene", "displayed", "greater", "accumulation", "factors", "in", "subcellular", "walls", "and", "organelle", "fractions", "than", "did", "phenanthrene.", "Conclusions:", "Transpiration", "and", "the", "lipid", "content", "of", "root", "cell", "fractions", "are", "the", "main", "drivers", "of", "the", "subcellular", "partition", "of", "PAHs", "in", "roots.", "Initially,", "PAHs", "adsorb", "to", "plant", "cell", "walls,", "and", "they", "then", "gradually", "diffuse", "into", "subcellular", "fractions", "of", "tissues.", "The", "lipid", "content", "of", "intracellular", "components", "determines", "the", "accumulation", "of", "lipophilic", "compounds,", "and", "the", "diffusion", "rate", "is", "related", "to", "the", "concentration", "gradient", "established", "between", "cell", "walls", "and", "cell", "organelles.", "Our", "results", "offer", "insights", "into", "the", "transport", "mechanisms", "of", "PAHs", "in", "ryegrass", "roots", "and", "their", "diffusion", "in", "root", "cells.", "Background", "Polycyclic", "aromatic", "hydrocarbons", "(PAHs)", "are", "a", "group", "of", "persistent", "organic", "contaminants", "(POPs)", "that", "are", "ubiqui-", "tous", "in", "the", "environment", "[1-3].", "Their", "toxicity", "(e.g.,", "muta-", "genic,", "carcinogenic)", "and", "potential", "of", "accumulation", "in", "biota", "have", "led", "to", "concern", "about", "their", "fate", "and", "transport", "in", "the", "environment", "[4-6].", "The", "major", "sources", "of", "PAHs", "in", "the", "environment", "include", "incomplete", "combustion", "of", "*", "Correspondence:", "gaoyanzheng@njau.edu.cn", "Institute", "of", "Organic", "Contaminant", "Control", "and", "Soil", "Remediation,", "College", "of", "Resource", "and", "Environment", "Science,", "Nanjing", "Agricultural", "University,", "Nanjing", "210095,", "China", "organic", "residues", "(polymerization", "of", "benzene", "rings", "at", "high", "temperature),", "petroleum", "production,", "volcanic", "erup-", "tions,", "and", "enzymatic", "polymerization", "of", "the", "benzene", "ring", "from", "plant", "exudates", "to", "the", "soil", "[7,8].", "Although", "these", "contaminants", "are", "mainly", "metabolized", "and", "decomposed", "via", "environmental", "biotic", "and", "abiotic", "processes", "[9,10],", "PAHs", "in", "the", "environment", "have", "gradually", "increased", "over", "the", "past", "several", "decades.", "For", "example,", "in", "Daya", "Bay,", "South", "China,", "before", "1955,", "the", "temporal", "distribution", "of", "PAH", "concentrations", "in", "sediments", "was", "below", "150", "μg·kg-1", "(dry", "weight),", "but", "by", "1995,", "concentrations", "had", "risen", "to", "300", "μg·kg-1", "[11].", "This", "increased", "PAH", "accumulation", "in", "©", "2010", "Kang", "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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"SHELXL97.", "We", "thank", "the", "Analysis", "and", "Testing", "Foundation", "of", "Northeast", "Normal", "University", "for", "support.", "Supplementary", "data", "and", "figures", "for", "this", "paper", "are", "available", "from", "the", "IUCr", "electronic", "archives", "(Reference:", "PV2108).", "References", "Choi,", "H.", "J.", "&", "Suh,", "M.", "P.", "(1999).", "Inorg.", "Chem.", "38,", "6309–6312.", "Higashi,", "T.", "(1995).", "ABSCOR.", "Rigaku", "Corporation,", "Tokyo,", "Japan.", "Jiang,", "L.,", "Feng,", "X.-F.", "&", "Lu,", "T.-B.", "(2005).", "Cryst.", "Growth", "Des.", "5,", "1469–1475.", "Massoud,", "S.", "S.,", "Mautner,", "F.", "A.,", "Vicente,", "R.", "&", "Rodrigue,", "B.", "M.", "(2006).", "Inorg.", "Chem.", "Acta,", "359,", "3321–3329.", "Ray,", "A.,", "Mijanuddin,", "M.,", "Chatterjee,", "R.,", "Marek,", "J.,", "Mondal,", "S.", "&", "Ali,", "M.", "(2006).", "Inorg.", "Chem.", "Commun.", "9,", "167–170.", "Rigaku", "(1998).", "PROCESS-AUTO.", "Rigaku", "Corporation,", "Tokyo,", "Japan.", "Sheldrick,", "G.", "M.", "(2008).", "Acta", "Cryst.", "A64,", "112–122.", "Acta", "Cryst.", "(2008).", "E64,", "m1431", "doi:10.1107/S160053680803314X", "Meng", "et", "al.", "m1431" ]

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[ "BMC", "Medicine", "Commentary", "Can", "we", "improve", "outcomes", "in", "AF", "patients", "by", "early", "therapy?", "Paulus", "Kirchhof1,2", "BioMed", "Central", "Open", "Access", "Address:", "1Department", "of", "Cardiology", "and", "Angiology,", "University", "Hospital", "Münster,", "Germany", "and", "2German", "Atrial", "Fibrillation", "competence", "NETwork", "(AFNET)", "Email:", "Paulus", "Kirchhof", "-", "kirchhp@uni-muenster.de", "Published:", "26", "November", "2009", "BMC", "Medicine", "2009,", "7:72", "doi:10.1186/1741-7015-7-72", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1741-7015/7/72", "Received:", "26", "October", "2009", "Accepted:", "26", "November", "2009", "©", "2009", "Kirchhof;", "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", "Atrial", "fibrillation", "affects", "at", "least", "1%", "of", "the", "population", "and", "causes", "marked", "society-wide", "morbidity", "and", "mortality.", "Current", "management", "of", "atrial", "fibrillation", "including", "antithrombotic", "therapy", "and", "management", "of", "concomitant", "conditions", "in", "all", "patients,", "rate", "control", "therapy", "in", "most", "patients,", "and", "rhythm", "control", "therapy", "in", "patients", "with", "severe", "atrial", "fibrillation-related", "symptoms", "can", "alleviate", "atrial", "fibrillation-related", "symptoms", "but", "can", "neither", "effectively", "prevent", "recurrent", "atrial", "fibrillation", "nor", "suppress", "atrial", "fibrillation-related", "complications.", "Hence,", "there", "is", "a", "need", "for", "better", "therapy", "of", "atrial", "fibrillation.", "The", "etiology", "of", "atrial", "fibrillation", "is", "complex.", "Most", "of", "the", "causes", "of", "atrial", "fibrillation", "which", "are", "known", "at", "present", "perpetuate", "themselves", "in", "vicious", "circles,", "and", "presence", "of", "the", "arrhythmia", "by", "itself", "causes", "marked", "damage", "of", "atrial", "myocardium.", "These", "pathophysiological", "insights", "suggest", "that", "early", "diagnosis", "and", "comprehensive", "therapy", "of", "atrial", "fibrillation,", "including", "adequate", "therapy", "of", "all", "atrial", "fibrillation-", "causing", "conditions,", "rate", "control,", "and", "rhythm", "control", "therapy,", "could", "help", "to", "prevent", "progression", "of", "atrial", "fibrillation", "and", "reduce", "atrial", "fibrillation-related", "complications.", "Such", "a", "therapy", "should", "make", "use", "of", "safe", "and", "effective", "therapeutic", "modalities,", "some", "of", "which", "have", "become", "available", "recently", "or", "will", "become", "available", "in", "the", "near", "future.", "The", "hypothesis", "that", "early", "diagnosis", "and", "early,", "comprehensive", "therapy", "of", "atrial", "fibrillation", "can", "improve", "outcomes", "requires", "formal", "testing", "in", "controlled", "trials.", "Commentary", "Atrial", "fibrillation", "(AF)", "is", "the", "most", "common", "sustained", "arrhythmia", "and", "affects", "at", "least", "1%", "of", "the", "population,", "amounting", "to", "5.5", "to", "7", "million", "patients", "with", "AF", "in", "Europe", "[1,2].", "AF", "is", "characterized", "by", "very", "rapid,", "irregular", "electrical", "activation", "of", "the", "atria", "(350", "to", "400", "bpm),", "resulting", "in", "1)", "loss", "of", "coordinated", "contraction", "and", "transport", "function", "in", "the", "atria", "and", "2)", "irregular", "ventricular", "rate", "and", "loss", "of", "ven-", "tricular", "rate", "adaptation", "to", "increased", "demands", "(arrhythmia", "absoluta).", "In", "an", "ageing", "population,", "the", "prevalence", "and", "incidence", "of", "AF", "will", "increase", "dramatically", "in", "the", "next", "dec-", "ades", "[2,3].", "Unlike", "most", "other", "supraventricular", "tachyar-", "rhythmias,", "atrial", "fibrillation", "can", "usually", "not", "be", "cured", "[4,5].", "Rather,", "most", "patients", "progress", "from", "paroxysmal", "AF,", "that", "is,", "AF", "that", "alternates", "with", "periods", "of", "sinus", "rhythm,", "to", "sustained", "forms", "(Figure", "1),", "even", "when", "currently", "available", "therapeutic", "options", "are", "applied.", "This", "sobering", "finding", "is", "aggravated", "by", "the", "dramatic", "consequences", "that", "AF", "implies", "in", "affected", "individuals", "and", "for", "society", "(Table", "1).", "One", "of", "the", "reasons", "why", "AF", "is", "so", "difficult", "to", "cure", "is", "proba-", "bly", "the", "complex", "etiology", "of", "the", "arrhythmia", "as", "recently", "outlined", "in", "two", "consensus", "conferences", "on", "AF", "[6,7]:", "AF", "can", "be", "caused", "by", "atrial", "structural", "damage", "conferred", "by", "cardiac", "or", "extracardiac", "disease", "and", "rapid", "irregular", "ventricular", "rate", "[8,9],", "a", "sign", "of", "natural", "ageing", "of", "the", "heart,", "and", "an", "electrical", "Page", "1", "of", "6", "(page", "number", "not", "for", "citation", "purposes)" ]

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[ "BMC", "Public", "Health", "Research", "Evaluation", "of", "the", "use", "of", "Global", "Youth", "Tobacco", "Survey", "(GYTS)", "data", "for", "developing", "evidence-based", "tobacco", "control", "policies", "in", "Turkey", "Toker", "Erguder*1,", "Banu", "Çakir2,", "Dilek", "Aslan2,", "Charles", "W", "Warren3,", "Nathan", "R", "Jones3", "and", "Samira", "Asma3", "Open", "Access", "Address:", "1World", "Health", "Organization", "Country", "Office,", "Birlik", "Mahallesi", "2.", "Cadde", "No:", "11,", "Cankaya,", "Ankara,", "06610", "Turkey,", "2Department", "of", "Public", "Health,", "Hacettepe", "University", "Faculty", "of", "Medicine,", "Sihhiye,", "Ankara,", "06100", "Turkey,", "3Office", "on", "Smoking", "and", "Health,", "Centers", "for", "Disease", "Control", "and", "Prevention,", "4770", "Buford", "Highway", "NE", "Mailstop", "K-50,", "Atlanta,", "Georgia,", "33041,", "USA", "Email:", "Toker", "Erguder*", "-", "ergudert@euro.who.int;", "Banu", "Cakir", "-", "cakir@tr.net;", "Dilek", "Aslan", "-", "daslan@hacettepe.edu.tr;", "Charles", "W", "Warren", "-", "wcw1@cdc.gov;", "Nathan", "R", "Jones", "-", "njones@uwccc.wisc.edu;", "Samira", "Asma", "-", "sea5@cdc.gov", "*", "Corresponding", "author", "Published:", "15", "December", "2008", "BMC", "Public", "Health", "2008,", "8(Suppl", "1):S4", "doi:10.1186/1471-2458-8-S1-S4", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1471-2458/8/S1/S4", "©", "2008", "Erguder", "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:", "The", "tobacco", "control", "effort", "in", "Turkey", "has", "made", "significant", "progress", "in", "recent", "years.", "Turkey", "initiated", "its", "tobacco", "control", "effort", "with", "the", "passing", "of", "Law", "4207", "(The", "Prevention", "of", "Harmful", "Effects", "of", "Tobacco", "Products)", "in", "1996", "and", "ratified", "the", "World", "Health", "Organization", "(WHO)", "Framework", "Convention", "on", "Tobacco", "Control", "(FCTC)", "in", "2004.", "It", "is", "important", "to", "base", "policy", "decisions", "on", "valid", "and", "reliable", "evidence", "from", "population-based,", "representative", "studies", "that", "are", "periodically", "repeated", "to", "enable", "policy", "makers", "to", "monitor", "the", "results", "of", "their", "interventions", "and", "to", "appropriately", "tailor", "anti-tobacco", "activities", "towards", "future", "needs.", "Methods:", "The", "Global", "Youth", "Tobacco", "Survey", "(GYTS)", "was", "developed", "to", "track", "tobacco", "use", "among", "young", "people", "and", "enhance", "the", "capacity", "of", "countries", "to", "design,", "implement,", "and", "evaluate", "tobacco", "control", "and", "prevention", "programs.", "Turkey", "conducted", "the", "GYTS", "in", "2003", "and", "data", "from", "this", "survey", "can", "be", "used", "as", "baseline", "measures", "for", "evaluation", "of", "the", "tobacco", "control", "programs", "implemented", "by", "the", "Ministry", "of", "Health", "(MOH)", "of", "the", "Turkish", "government.", "Results:", "The", "GYTS", "was", "conducted", "in", "2003", "on", "a", "representative", "sample", "of", "students", "aged", "13", "to", "15", "years.", "It", "indicated", "that", "almost", "3", "in", "10", "students", "in", "Turkey", "had", "ever", "smoked", "cigarettes,", "with", "significantly", "higher", "rates", "among", "boys.", "Current", "cigarette", "smoking", "rates", "were", "lower,", "at", "9%", "for", "boys", "and", "4%", "for", "girls.", "The", "prevalence", "of", "current", "use", "of", "other", "tobacco", "products", "was", "about", "half", "these", "figures", "for", "each", "gender.", "About", "80%", "were", "exposed", "to", "secondhand", "smoke.", "Exposure", "to", "pro-smoking", "media", "messages", "was", "not", "rare.Almost", "half", "of", "the", "smokers", "‘usually’", "bought", "their", "tobacco", "from", "a", "store,", "despite", "the", "law", "prohibiting", "this.", "Exposure", "to", "teaching", "against", "smoking", "in", "schools", "was", "not", "universal.", "Conclusion:", "Findings", "from", "the", "GYTS,", "with", "periodic", "repeats", "of", "the", "survey,", "can", "be", "used", "to", "monitor", "the", "impact", "of", "enforcing", "various", "provisions", "of", "the", "present", "law", "(No:", "4207),", "the", "progress", "made", "in", "achieving", "the", "goals", "of", "the", "WHO", "FCTC,", "and", "the", "effectiveness", "of", "various", "preventive", "interventions", "against", "smoking.", "Such", "data", "would", "inform", "and", "help", "in", "the", "development", "of", "public", "health", "strategy.", "Page", "1", "of", "7", "(page", "number", "not", "for", "citation", "puroposes)" ]

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[ "Molecular", "Vision", "2009;", "15:187-199", "<http://www.molvis.org/molvis/v15/a18>", "Received", "31", "May", "2008", "|", "Accepted", "1", "January", "2009", "|", "Published", "23", "January", "2009", "©", "2009", "Molecular", "Vision", "Generation", "of", "immature", "retinal", "neurons", "from", "proliferating", "cells", "in", "the", "pars", "plana", "after", "retinal", "histogenesis", "in", "mice", "with", "retinal", "degeneration", "Koji", "M.", "Nishiguchi,", "Hiroki", "Kaneko,", "Makoto", "Nakamura,", "Shu", "Kachi,", "Hiroko", "Terasaki", "Nagoya", "University", "Graduate", "School", "of", "Medicine,", "Department", "of", "Ophthalmology,", "Showa-ku,", "Japan", "Purpose:", "To", "study", "the", "differentiation", "of", "immature", "retinal", "neurons/retinal", "precursors", "in", "the", "ciliary", "epithelium", "after", "retinal", "histogenesis", "in", "mice", "with", "inherited", "or", "acquired", "retinal", "degeneration.", "Methods:", "Immunoreactivity", "to", "anti-recoverin,", "rhodopsin,", "and", "Pax6", "antibodies", "and", "binding", "to", "peanut", "agglutinin", "were", "analyzed", "histologically.", "The", "distribution", "and", "differentiation", "of", "immature", "retinal", "neurons/retinal", "precursors", "in", "the", "ciliary", "epithelium", "of", "mice", "with", "inherited", "(C3H/HeJ)", "and", "acquired", "(C57BL", "mice", "injected", "with", "60", "mg/kg", "N-methyl-N-nitrosourea)", "retinal", "degeneration", "were", "assessed.", "Proliferating", "retinal", "progenitors", "were", "labeled", "with", "bromodeoxyuridine", "(BrdU),", "and", "they", "were", "studied", "histologically", "using", "retinal", "markers.", "Results:", "Many", "cells", "of", "rod", "and", "cone", "photoreceptor", "lineage", "were", "identified", "within", "the", "ciliary", "epithelium", "of", "the", "pars", "plana", "in", "adult", "mice", "with", "inherited", "retinal", "degeneration.", "Tracking", "experiments", "using", "BrdU", "indicated", "that", "some", "of", "recoverin-", "positive", "cells", "in", "the", "pars", "plana", "(approximately", "3%)", "were", "generated", "after", "retinal", "histogenesis,", "and", "few", "were", "produced", "at", "or", "after", "postnatal", "day", "24", "(P24).", "The", "induction", "of", "acquired", "retinal", "degeneration", "in", "adult", "wild-type", "mice", "(P30)", "increased", "the", "number", "of", "BrdU-positve", "cells", "by", "roughly", "fourfold", "and", "recoverin-positive", "cells", "by", "approximately", "17-fold", "in", "the", "pars", "plana.", "Moreover,", "some", "(approximately", "1.5%)", "of", "the", "recoverin-positive", "cells", "were", "newly", "generated", "from", "dividing", "retinal", "progenitors", "in", "the", "adult", "pars", "plana.", "Conclusions:", "In", "response", "to", "retinal", "damage,", "an", "increased", "number", "of", "immature", "retinal", "neurons/retinal", "precursors", "was", "observed", "in", "the", "pars", "plana", "of", "mice", "with", "acquired", "and", "inherited", "retinal", "degeneration.", "Some", "of", "these", "cells", "differentiated", "from", "proliferating", "cells", "even", "after", "retinal", "histogenesis.", "In", "fishes", "and", "amphibians,", "a", "circumferential", "zone", "in", "the", "retinal", "margin,", "called", "the", "ciliary", "marginal", "zone", "(CMZ),", "produces", "all", "types", "of", "retinal", "neurons,", "and", "thereby", "continuously", "regenerates", "the", "retina", "throughout", "life", "[1-3].", "While", "the", "CMZ", "increases", "its", "production", "of", "new", "neurons", "in", "response", "to", "retinal", "injury,", "neurogenesis", "by", "the", "intrinsic", "stem", "cells", "within", "the", "mature", "retina", "in", "fishes", "or", "neural", "transdifferentiation", "of", "the", "retinal", "pigment", "epithelium", "in", "most", "amphibians", "can", "also", "take", "place", "to", "promote", "the", "regeneration", "of", "the", "retina", "[1-3].", "However,", "in", "mammals,", "despite", "the", "identification", "of", "adult", "germinal", "zones", "for", "neural", "regeneration", "of", "areas", "in", "the", "central", "nervous", "system", "[4,5],", "such", "as", "the", "subgranular", "zone", "for", "the", "olfactory", "bulb", "[6,7]", "and", "the", "utricular", "sensory", "epithelium", "for", "the", "inner", "ear", "[8],", "a", "zone", "for", "retinal", "regeneration", "capable", "of", "replacing", "lost", "neurons", "has", "not", "been", "defined.", "There", "is", "evidence", "suggesting", "that", "the", "adult", "ciliary", "epithelium", "contains", "stem", "cells", "that", "have", "the", "potential", "to", "proliferate", "and", "express", "markers", "specific", "to", "retinal", "neurons", "in", "mammals", "[9-14],", "including", "humans", "[15].", "However,", "the", "in", "situ", "Correspondence", "to:", "Koji", "M.", "Nishiguchi,", "Department", "of", "Ophthalmology,", "Nagoya", "University", "Graduate", "School", "of", "Medicine,", "65", "Tsuruma,", "Showa-ku,", "Nagoya", "466-8550,", "Japan;", "Phone:", "+81", "52", "744", "2275;", "FAX:", "+81", "52", "744", "2278;", "email:", "kojinish@med.nagoya-u.ac.jp", "distributions", "or", "roles", "of", "these", "cells", "are", "still", "unclear.", "Recently,", "we", "found", "that", "the", "neuroblast", "layer,", "a", "retinal", "layer", "composed", "of", "retinal", "progenitor", "cells", "seen", "only", "during", "retinal", "development,", "extended", "into", "the", "ciliary", "epithelium", "of", "the", "pars", "plana", "during", "ocular", "development", "in", "wild-type", "mice", "[16].", "In", "addition,", "many", "cone", "and", "rod", "photoreceptor", "precursors", "(termed", "immature", "photoreceptors/photoreceptor", "precursors", "in", "the", "current", "study)", "in", "various", "stages", "of", "morphological", "differentiation", "were", "identified", "in", "the", "pars", "plana", "during", "retinal", "histogenesis.", "However,", "once", "the", "gross", "development", "of", "the", "retina", "was", "complete,", "such", "precursors", "were", "rare", "in", "the", "ciliary", "epithelium.", "Nonetheless,", "these", "observations", "suggested", "that", "the", "ciliary", "epithelium", "of", "the", "pars", "plana", "may", "play", "an", "important", "role", "in", "the", "generation", "of", "retinal", "neurons.", "In", "the", "brain,", "it", "is", "well", "known", "that", "neural", "stem", "cells", "proliferate", "in", "response", "to", "neural", "damage", "even", "in", "adult", "mammals", "[17-19].", "Consistent", "with", "these", "reports,", "we", "have", "also", "reported", "an", "increased", "number", "of", "cells", "immunopositive", "for", "a", "retinal", "marker", "in", "the", "adult", "pars", "plana", "after", "toxin-induced", "retinal", "degeneration", "[16].", "However,", "it", "is", "not", "known", "whether", "these", "cells", "were", "generated", "from", "dividing", "cells", "or", "differentiated", "from", "post-mitotic", "cells.", "In", "this", "study,", "we", "examined", "two", "mouse", "models", "with", "retinal", "degeneration,", "inherited", "and", "acquired,", "and", "found", "that", "a", "small", "fraction", "of", "immature", "retinal", "neurons/retinal", "187" ]

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[ "Cell", "Tissue", "Res", "(2012)", "348:189–197", "DOI", "10.1007/s00441-012-1340-9", "REGULAR", "ARTICLE", "Human", "first-trimester", "chorionic", "villi", "have", "a", "myogenic", "potential", "Reiko", "Arakawa", "&", "Ryoko", "Aoki", "&", "Masayuki", "Arakawa", "&", "Kayoko", "Saito", "Received:", "27", "June", "2011", "/", "Accepted:", "18", "January", "2012", "/", "Published", "online:", "28", "February", "2012", "#", "The", "Author(s)", "2012.", "This", "article", "is", "published", "with", "open", "access", "at", "Springerlink.com", "Abstract", "First-trimester", "chorionic-villi-derived", "cells", "(FTCVs)", "are", "the", "earliest", "fetal", "material", "that", "can", "be", "obtained", "for", "prenatal", "diagnosis", "of", "fetal", "disorders", "such", "as", "Duchenne", "muscular", "dystro-", "phy", "(DMD).", "DMD", "is", "a", "devastating", "X-linked", "disorder", "charac-", "terized", "by", "the", "absence", "of", "dystrophin", "at", "the", "sarcolemma", "of", "muscle", "fibers.", "Currently,", "a", "limited", "number", "of", "treatment", "options", "are", "available", "for", "DMD,", "although", "cell", "therapy", "is", "a", "promising", "treatment", "strategy", "for", "muscle", "degeneration", "in", "DMD", "patients.", "A", "novel", "candidate", "source", "of", "cells", "for", "this", "approach", "is", "FTCVs", "Electronic", "supplementary", "material", "The", "online", "version", "of", "this", "article", "(doi:10.1007/s00441-012-1340-9)", "contains", "supplementary", "material,", "which", "is", "available", "to", "authorized", "users.", "This", "work", "was", "supported", "by", "a", "Research", "Grant", "(20B-13-03)", "for", "Nervous", "and", "Mental", "Disorders", "from", "the", "Ministry", "of", "Health,", "Labour", "and", "Welfare;", "Grants-in-Aid", "from", "the", "Research", "Committee", "of", "Spinal", "Muscular", "Atrophy", "(SMA)", "from", "the", "Ministry", "of", "Health,", "Labour", "and", "Welfare", "of", "Japan;", "and", "the", "Global", "COE", "program,", "Multidisciplinary", "Education", "and", "Research", "Center", "for", "Regenerative", "Medicine", "(MERCREM)", "from", "the", "Ministry", "of", "Education,", "Culture,", "Sports", "Science,", "and", "Technology", "(MEXT),", "Japan.", "R.", "Arakawa", ":", "K.", "Saito", "Affiliated", "Field", "of", "Medical", "Genetics,", "Division", "of", "Biomedical", "Engineering", "and", "Science,", "Graduate", "Course", "of", "Medicine,", "Graduate", "School", "of", "Tokyo", "Women’s", "Medical", "University,", "10-22", "Kawadacho,", "Shinjyuku,", "Tokyo", "162-0054,", "Japan", "R.", "Arakawa", ":", "R.", "Aoki", ":", "K.", "Saito", "(*)", "Institute", "of", "Medical", "Genetics,", "Tokyo", "Women’s", "Medical", "University,", "10-22", "Kawadacho,", "Shinjyuku,", "Tokyo", "162-0054,", "Japan", "e-mail:", "saito@img.twmu.ac.jp", "M.", "Arakawa", "Institute", "of", "Microbial", "Chemistry,", "Microbial", "Chemistry", "Research", "Foundation,", "3-14-23", "Kamiosaki,", "Shinagawa,", "Tokyo", "141-0021,", "Japan", "taken", "between", "the", "9th", "and", "11th", "weeks", "of", "gestation.", "FTCVs", "might", "have", "a", "higher", "undifferentiated", "potential", "than", "any", "other", "tissue-derived", "cells", "because", "they", "are", "the", "earliest", "fetal", "material.", "We", "examined", "the", "expression", "of", "mesenchymal", "stem", "cell", "and", "pluripotent", "stem", "cell", "markers", "in", "FTCVs,", "in", "addition", "to", "their", "myogenic", "potential.", "FTCVs", "expressed", "mesenchymal", "stem", "cell", "markers", "and", "Nanog", "and", "Sox2", "transcription", "factors", "as", "pluripo-", "tent", "stem", "cell", "markers.", "These", "cells", "efficiently", "differentiated", "into", "myotubes", "after", "myogenic", "induction,", "at", "which", "point", "Nanog", "and", "Sox2", "were", "down-regulated,", "whereas", "MyoD,", "myo-", "genin,", "desmin", "and", "dystrophin", "were", "up-regulated.", "To", "our", "knowledge,", "this", "is", "the", "first", "demonstration", "that", "FTCVs", "can", "be", "efficiently", "directed", "to", "differentiate", "in", "vitro", "into", "skeletal", "muscle", "cells", "that", "express", "dystrophin", "as", "the", "last", "stage", "marker", "of", "myo-", "genic", "differentiation.", "The", "myogenic", "potential", "of", "FTCVs", "reveals", "their", "promise", "for", "use", "in", "cell", "therapy", "for", "DMD,", "for", "which", "no", "effective", "treatment", "presently", "exists.", "Keywords", "Duchenne", "muscular", "dystrophy", ".", "First-trimester", "chorionic", "villi", ".", "Myogenic", "differentiation", ".", "Dystrophin", ".", "Cell", "therapy", "Introduction", "In", "the", "early", "1980s,", "prenatal", "diagnosis", "by", "using", "chorionic", "villus", "sampling", "(CVS)", "was", "introduced;", "this", "method", "has", "advanced", "the", "diagnosis", "of", "fetal", "genetic", "disorders", "such", "as", "Duchenne", "muscular", "dystrophy", "(DMD)", "in", "the", "first-trimester", "of", "pregnancy.", "The", "numerous", "advances", "in", "prenatal", "diagnosis", "and", "molecular", "genetic", "testing", "of", "DMD", "have", "permitted", "the", "accurate", "and", "early", "diagnosis", "of", "carrier", "women.", "During", "human", "development,", "the", "morula", "constitutes", "the", "inner", "cell", "mass", "and", "the", "outer", "cell", "mass.", "The", "outer", "cell", "mass", "forms", "the", "trophoblasts,", "which", "later", "contribute", "to", "the", "formation" ]

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[ "Acta", "Orthopaedica", "2009;", "80", "(4):", "445–450", "445", "Impact", "of", "instrumentation", "in", "lumbar", "spinal", "fusion", "in", "elderly", "patients", "71", "patients", "followed", "for", "2–7", "years", "Thomas", "Andersen,", "Finn", "B", "Christensen,", "Bent", "Niedermann,", "Peter", "Helmig,", "Kristian", "Høy,", "Ebbe", "S", "Hansen,", "and", "Cody", "Bünger", "Spine", "Unit,", "Department", "of", "Orthopaedics", "E,", "Aarhus", "University", "Hospital,", "Aarhus,", "Denmark", "Correspondence", "TA:", "tba@dadlnet.dk", "Submitted", "08-11-17.", "Accepted", "09-04-20", "Background", "and", "purpose", "An", "increasing", "number", "of", "lumbar", "fusions", "are", "performed", "using", "allograft", "to", "avoid", "donor-site", "pain.", "In", "elderly", "patients,", "fusion", "potential", "is", "reduced", "and", "the", "patient", "may", "need", "supplementary", "stability", "to", "achieve", "a", "solid", "fusion", "if", "allograft", "is", "used.", "We", "investigated", "the", "effect", "of", "instrumentation", "in", "lumbar", "spinal", "fusion", "performed", "with", "fresh", "frozen", "allograft", "in", "elderly", "patients.", "Methods", "94", "patients,", "mean", "age", "70", "(60–88)", "years,", "who", "underwent", "posterolateral", "spinal", "fusion", "either", "non-instrumented", "(51", "patients)", "or", "instrumented", "(43", "patients)", "were", "followed", "for", "2–7", "years.", "Func-", "tional", "outcome", "was", "assessed", "with", "the", "Dallas", "pain", "questionnaire", "(DPQ),", "the", "low", "back", "pain", "rating", "scale", "pain", "index", "(LBPRS),", "and", "SF-36.", "Fusion", "was", "assessed", "using", "plain", "radiographs.", "Results", "Instrumented", "patients", "had", "statistically", "significantly", "better", "outcome", "scores", "in", "6", "of", "7", "parameters.", "Fusion", "rate", "was", "higher", "in", "the", "instrumented", "group", "(81%", "vs.", "68%,", "p", "=", "0.1).", "Solid", "fusion", "was", "associated", "with", "a", "better", "functional", "outcome", "at", "follow-up", "(sig-", "nificant", "in", "2", "of", "7", "parameters).", "15", "patients", "(6", "in", "the", "non-instru-", "mented", "group", "and", "9", "in", "the", "instrumented", "group)", "had", "repeated", "lumbar", "surgery", "after", "their", "initial", "fusion", "procedure.", "Functional", "outcome", "was", "poorer", "in", "the", "group", "with", "additional", "spine", "surgeries", "(significant", "in", "4", "of", "7", "parameters).", "Interpretation", "Superior", "outcomes", "after", "lumbar", "spinal", "fusion", "in", "elderly", "patients", "can", "be", "achieved", "by", "use", "of", "instrumentation", "in", "selected", "patients.", "Outcome", "was", "better", "in", "patients", "in", "which", "a", "solid", "fusion", "was", "obtained.", "Instrumentation", "was", "associated", "with", "a", "larger", "number", "of", "additional", "surgeries,", "which", "resulted", "in", "a", "lesser", "degree", "of", "improvement.", "Instrumentation", "should", "not", "be", "discarded", "just", "because", "of", "the", "age", "of", "the", "patient.", "", "Instrumented", "spinal", "fusion", "in", "elderly", "patients", "has", "been", "prob-", "lematized", "due", "to", "the", "risk", "of", "screw", "loosening", "and", "comorbidity", "(Hu", "1997,", "Okuyama", "et", "al.", "2001,", "Okuda", "et", "al.", "2006,", "Cho", "et", "al.", "2007),", "leaving", "uninstrumented", "fusion", "as", "an", "obvious", "alterna-", "tive.", "Spinal", "instrumentation", "has", "only", "been", "shown", "to", "increase", "fusion", "rates", "compared", "to", "uninstrumented", "fusion;", "the", "effect", "on", "functional", "outcome", "has", "been", "insignificant", "(Gibson", "and", "Wad-", "dell", "2005).", "These", "studies", "have,", "however,", "all", "been", "performed", "using", "autograft", "as", "fusion", "material", "and", "also", "mostly", "in", "younger", "patients.", "The", "use", "of", "autograft", "has", "been", "problematized", "due", "to", "increased", "concern", "about", "the", "amount", "and", "extent", "of", "pain", "aris-", "ing", "from", "the", "donor", "site", "(Arrington", "et", "al.", "1996,", "Robertson", "and", "Wray", "2001,", "Sasso", "et", "al.", "2005).", "In", "order", "to", "overcome", "the", "prob-", "lems", "of", "donor", "site", "pain,", "allograft", "and", "bone", "substitutes", "have", "gained", "increasing", "interest", "(Sandhu", "et", "al.", "1999,", "Ehrler", "and", "Vaccaro", "2000).", "Fresh", "frozen", "allograft", "has", "been", "one", "of", "the", "most", "widely", "used.", "One", "randomized", "study", "has", "shown", "that", "it", "gives", "similar", "outcomes", "compared", "to", "autograft", "in", "instrumented", "posterolateral", "fusion", "(Gibson", "et", "al.", "2002);", "however,", "most", "sur-", "geons", "still", "believe", "that", "autograft", "has", "superior", "qualities", "(An", "et", "al.", "1995,", "Sandhu", "et", "al.", "1999,", "Ehrler", "and", "Vaccaro", "2000).", "The", "use", "of", "allografts", "in", "the", "older", "patient", "population", "may", "be", "prob-", "lematic", "due", "to", "reduced", "fusion", "potential", "(Lohmann", "et", "al.", "2001,", "Laursen", "et", "al.", "2003).", "One", "long-term", "study", "in", "an", "elderly", "popu-", "lation", "has", "shown", "significantly", "better", "outcomes", "in", "patients", "in", "which", "a", "solid", "fusion", "was", "obtained", "compared", "to", "those", "without", "(Kornblum", "et", "al.", "2004).", "Thus,", "the", "beneficial", "effect", "of", "instru-", "mentation", "in", "lumbar", "spinal", "fusion", "might", "be", "more", "pronounced", "in", "an", "older", "patient", "population", "fused", "with", "allograft.", "The", "aim", "of", "this", "study", "was", "to", "compare", "instrumented", "and", "non-instrumented", "lumbar", "spinal", "fusion", "performed", "using", "fresh", "frozen", "allograft", "in", "patients", "older", "than", "60", "years", "with", "regard", "to", "functional", "outcome", "and", "fusion", "rates.", "Open", "Access", "-", "This", "article", "is", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "Noncommercial", "License", "which", "permits", "any", "noncommercial", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "source", "is", "credited.", "DOI", "10.3109/17453670903170505" ]

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[ "ORIGINAL", "RESEARCH", "ARTICLE", "published:", "29", "March", "2012", "doi:", "10.3389/fpls.2012.00060", "The", "rice", "diacylglycerol", "kinase", "family:", "functional", "analysis", "using", "transient", "RNA", "interference", "Hongliang", "Ge,", "Chu", "Chen,", "Wen", "Jing,", "Qun", "Zhang,", "Hong", "Wang,", "Rong", "Wang", "and", "Wenhua", "Zhang*", "State", "Key", "Laboratory", "of", "Crop", "Genetics", "and", "Germplasm", "Enhancement,", "College", "of", "Life", "Sciences,", "Nanjing", "Agricultural", "University,", "Nanjing,", "China", "Edited", "by:", "Kent", "D.", "Chapman,", "University", "of", "North", "Texas,", "USA", "Reviewed", "by:", "Shan", "Lu,", "Nanjing", "University,", "China", "Yueyun", "Hong,", "Huazhong", "Agricultural", "University,", "China", "*Correspondence:", "Wenhua", "Zhang,", "State", "Key", "Laboratory", "of", "Crop", "Genetics", "and", "Germplasm", "Enhancement,", "College", "of", "Life", "Sciences,", "Nanjing", "Agricultural", "University,", "Nanjing", "210095,", "China.", "e-mail:", "whzhang@njau.edu.cn", "Diacylglycerol", "kinase", "(DGK)", "is", "a", "pivotal", "enzyme", "that", "phosphorylates", "diacylglycerol", "(DAG)", "to", "form", "phosphatidic", "acid", "(PA).", "The", "production", "of", "PA", "from", "phospholipase", "D", "(PLD)", "and", "the", "coupled", "phospholipase", "C/DGK", "route", "is", "an", "important", "signaling", "process", "in", "animal", "and", "plant", "cells.", "In", "this", "study,", "we", "report", "a", "genomic", "analysis", "of", "eight", "putative", "rice", "DGKs", "encoded", "by", "a", "gene", "family", "(OsDGKs)", "grouped", "into", "three", "clusters.", "To", "further", "investigate", "the", "func-", "tions", "of", "the", "OsDGKs,", "a", "double-stranded", "RNA", "(dsRNA)-induced", "RNA", "silencing", "method", "was", "established.", "Introduction", "of", "in", "vitro-synthesized", "dsRNAs", "corresponding", "to", "a", "unique", "or", "con-", "served", "region", "of", "OsDGKs", "into", "rice", "protoplasts", "abolished", "or", "diminished", "the", "expression", "of", "individual", "or", "multiple", "OsDGK", "genes.", "Suppressing", "the", "expression", "of", "OsDGKs", "resulted", "in", "a", "distinct", "depletion", "of", "the", "transcripts", "of", "the", "defense", "gene", "OsNPR1", "and", "the", "salt-responsive", "gene", "OsCIPK15.", "Our", "primary", "results", "suggest", "that", "OsDGKs", "are", "involved", "in", "the", "signaling", "of", "stress", "responses.", "Keywords:", "diacylglycerol", "kinase,", "double-stranded", "RNA,", "rice,", "RNA", "interference", "INTRODUCTION", "Phospholipase", "C", "(PLC)", "catalyzes", "the", "hydrolysis", "of", "phosphatidyli-", "nositol", "4,5-bisphosphate", "[PtdIns(4,5)P2]", "to", "produce", "diacylglyc-", "erol", "(DAG),", "which", "is", "phosphorylated", "to", "phosphatidic", "acid", "(PA)", "by", "diacylglycerol", "kinases", "(DGKs;", "Arisz", "et", "al.,", "2009).", "In", "animal", "cells,", "DAG", "and", "PA", "are", "important", "signaling", "molecules.", "DGK", "is", "thought", "to", "act", "as", "a", "conversional", "switch", "with", "two", "functional", "implications:", "the", "termination", "of", "DAG", "signaling", "and", "the", "initiation", "of", "PA", "sig-", "naling", "(Frere", "and", "Paolo,", "2009).", "However,", "no", "direct", "DAG", "target", "(such", "as", "PKC", "in", "animal", "cells)", "has", "been", "found", "in", "plants,", "and", "the", "role", "for", "DAG", "as", "a", "plant", "signaling", "molecule", "has", "yet", "to", "been", "con-", "firmed", "(Munnik", "and", "Testerink,", "2009).", "In", "contrast,", "PA", "generated", "from", "both", "the", "PLD", "and", "PLC/DGK", "pathways", "is", "emerging", "as", "a", "stress", "signal", "molecule", "in", "plants", "(Munnik", "and", "Testerink,", "2009;", "Hong", "et", "al.,", "2010;", "Zhang", "et", "al.,", "2010).", "PLD-derived", "PA", "has", "been", "found", "to", "regu-", "late", "a", "series", "of", "developmental", "and", "environmental", "responses", "via", "its", "downstream", "targets", "(Li", "et", "al.,", "2009;", "Zhang", "et", "al.,", "2010).", "Relatively", "little", "genetic", "evidence", "for", "PA", "from", "PLC-coupled", "DGK", "regulating", "signaling", "in", "plant", "cells", "has", "been", "found", "(Munnik", "and", "Testerink,", "2009).", "Diacylglycerol", "kinase", "activity", "has", "been", "reported", "in", "several", "plant", "species,", "including", "tobacco,", "wheat,", "tomato,", "and", "Arabidop-", "sis", "(Kamada", "and", "Muto,", "1991;", "Lundberg", "and", "Sommarin,", "1992;", "Wissing", "and", "Wagner,", "1992;", "Katagiri", "et", "al.,", "1996;", "Snedden", "and", "Blumwald,", "2000).", "Recently,", "multiple", "DGK-encoding", "genes", "have", "been", "isolated", "from", "plants", "(Snedden", "and", "Blumwald,", "2000;", "Gómez-", "Merino", "et", "al.,", "2005;", "Chen", "et", "al.,", "2007).", "In", "Arabidopsis,", "AtDGK2", "and", "AtDGK7", "have", "been", "biochemically", "characterized", "(Gómez-Merino", "et", "al.,", "2004,", "2005).", "A", "hydrophobic", "segment", "at", "the", "N-termini", "of", "AtDGK1", "and", "AtDGK2", "is", "necessary", "to", "target", "the", "resulting", "proteins", "to", "endoplasmic", "reticulum", "(ER)", "membranes", "(Vaultier", "et", "al.,", "2008).", "In", "rice,", "pharmacological", "evidence", "indicates", "that", "PLC/DGK-", "mediated", "signaling", "is", "required", "for", "a", "benzothiadiazole-induced", "oxidative", "burst", "and", "hypersensitive", "cell", "death,", "and", "the", "tran-", "scription", "of", "one", "OsDGK", "is", "induced", "during", "this", "process", "(Chen", "et", "al.,", "2007).", "No", "genomic", "analysis", "of", "the", "rice", "DGK", "family", "has", "been", "reported.", "In", "this", "study,", "we", "report", "that", "OsDGKs", "are", "grouped", "into", "three", "clusters", "(I,", "II,", "and", "III)", "based", "on", "gene", "archi-", "tecture,", "evolutionary", "relationships,", "and", "sequence", "identity.", "The", "transcription", "of", "OsDGKs", "was", "characterized", "using", "RT-PCR", "and", "real-time", "PCR,", "and", "their", "expression", "levels", "following", "treatment", "with", "xylanase", "or", "salt", "were", "analyzed.", "We", "established", "a", "transient", "double-stranded", "RNA", "(dsRNA)-induced", "RNA", "silencing", "assay", "that", "was", "used", "for", "rapid", "analysis", "of", "OsDGK", "functions", "in", "stress", "responses.", "MATERIALS", "AND", "METHODS", "SUSPENSION", "CELL", "CULTURES", "AND", "TREATMENTS", "Rice", "(Oryza", "sativa", "L.", "Nipponbare", "ssp.", "japonica)", "suspension", "cells", "were", "initiated", "from", "embryogenic", "calli", "induced", "from", "mature", "rice", "scutella.", "The", "cells", "were", "grown", "in", "100-ml", "conical", "flasks", "contain-", "ing", "Murashige", "and", "Skoog", "liquid", "medium", "supplemented", "with", "3%", "sucrose", "and", "2", "mg/l", "2,4-D,", "and", "incubated", "on", "a", "rotary", "shaker", "(100–120", "rpm)", "at", "26", "±", "2˚C", "in", "darkness.", "The", "suspension", "cells", "were", "subcultured", "every", "7", "day.", "Fresh", "suspension", "cells", "were", "collected", "by", "centrifugation", "after", "subculture", "for", "4", "to", "5", "day,", "and", "then", "treated", "with", "200", "μg/ml", "xylanase", "(Trichoderma", "viride;", "Fluka", "Bio-Chemika).", "RICE", "SEEDLING", "GROWTH", "AND", "PROTOPLAST", "ISOLATION", "Rice", "seedlings", "were", "grown", "in", "a", "growth", "room", "at", "27˚C", "for", "2–3", "weeks.", "Seedlings", "of", "5–8", "high", "were", "used", "for", "protoplast", "isolation", "accord-", "ing", "to", "the", "method", "of", "Sheen", "(2001)", "with", "modifications.", "Stems,", "including", "the", "sheaths", "of", "young", "seedlings,", "were", "cut", "into", "∼0.5–", "1.0", "mm", "segments", "using", "a", "razor", "blade,", "and", "immediately", "placed", "in", "a", "Petri", "dish", "containing", "K3", "medium", "(see", "Table", "A1", "in", "Appendix)", "www.frontiersin.org", "March", "2012", "|", "Volume", "3", "|", "Article", "60", "|", "1" ]

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"the", "Arp2/3", "complex.", "We", "now", "report", "that", "the", "Arp2/3", "com-", "plex", "must", "be", "phosphorylated", "on", "either", "threonine", "or", "tyro-", "sine", "residues", "to", "be", "activated", "by", "NPFs.", "Phosphorylation", "of", "the", "Arp2/3", "complex", "is", "not", "necessary", "to", "bind", "NPFs", "or", "the", "sides", "of", "actin", "filaments", "but", "is", "critical", "for", "binding", "the", "pointed", "end", "of", "actin", "filaments", "and", "nucleating", "actin", "filaments.", "Introduction", "Eukaryotic", "cells", "change", "shape", "and", "move", "by", "assembling", "ordered", "networks", "of", "actin", "filaments", "at", "their", "leading", "edges", "(Pollard", "et", "al.,", "2001).", "The", "heart", "of", "this", "actin-based", "motility", "engine", "is", "the", "actin-", "related", "protein", "2/3", "(Arp2/3)", "complex,", "a", "seven-subunit", "protein", "complex", "that", "builds", "cross-linked", "filament", "arrays", "by", "nucleating", "new", "filaments", "from", "the", "sides", "of", "preexisting", "filaments", "(Goley", "and", "Welch,", "2006).", "Actin-nucleating", "and", "cross-linking", "activities", "of", "the", "Arp2/3", "complex", "are", "required", "to", "build", "many", "cellular", "structures,", "including", "lamellipodia", "and", "phagocytic", "cups,", "and", "to", "move", "endosomes", "and", "intracellular", "pathogens", "through", "the", "cytoplasm", "(Pollard", "and", "Borisy,", "2003).", "The", "Arp2/3", "complex,", "which", "is", "composed", "of", "two", "actin-", "related", "proteins", "(Arp2", "and", "Arp3)", "and", "five", "accessory", "proteins,", "nu-", "cleates", "a", "new", "actin", "filament", "by", "first", "binding", "to", "the", "side", "of", "a", "preexisting", "filament.", "Next,", "the", "Arp2", "and", "Arp3", "subunits", "form", "a", "protonucleus", "that", "mimics", "a", "new", "fast-growing", "barbed", "end", "of", "an", "ac-", "tin", "filament", "(Robinson", "et", "al.,", "2001;", "Goley", "et", "al.,", "2004;", "Nolen", "et", "al.,", "2004).", "Actin", "monomers", "polymerize", "at", "this", "barbed", "end,", "elongating", "rapidly", "toward", "the", "plasma", "membrane,", "whereas", "the", "Arp2/3", "complex", "Correspondence", "to", "Diane", "L.", "Barber:", "diane.barber@ucsf.edu", "M.", "Baumgartner’s", "present", "address", "is", "Vetsuisse", "Faculty,", "Department", "of", "Clinical", "Research", "and", "Veterinary", "Public", "Health,", "Section", "of", "Molecular", "Pathobiology,", "University", "of", "Bern,", "Bern", "CH-3012,", "Switzerland.", "Abbreviations", "used", "in", "this", "paper:", "AP,", "Antarctic", "phosphatase;", "Arp,", "actin-", "related", "protein;", "NPF,", "nucleation-promoting", "factor;", "PP2C", ",", "protein", "phosphatase", "2C", ";", "pThr,", "phosphothreonine;", "pTyr,", "phosphotyrosine;", "WASP,", "Wiskott-Aldrich", "syndrome", "protein.", "The", "online", "version", "of", "this", "article", "contains", "supplemental", "material.", "The", "Rockefeller", "University", "Press", "$30.00", "J.", "Cell", "Biol.", "Vol.", "182", "No.", "4", "647–654", "www.jcb.org/cgi/doi/10.1083/jcb.200802145", "Mass", "spectrometry", "revealed", "phosphorylated", "Thr237", "and", "Thr238", "in", "Arp2,", "which", "are", "evolutionarily", "conserved", "resi-", "dues.", "In", "cells,", "phosphorylation", "of", "only", "the", "Arp2", "subunit", "increases", "in", "response", "to", "growth", "factors,", "and", "alanine", "sub-", "stitutions", "of", "Arp2", "T237", "and", "T238", "or", "Y202", "inhibits", "mem-", "brane", "protrusion.", "These", "findings", "reveal", "an", "additional", "level", "of", "regulation", "of", "actin", "filament", "assembly", "independent", "of", "WASP", "proteins,", "and", "show", "that", "phosphorylation", "of", "the", "Arp2/3", "complex", "provides", "a", "logical", "“or", "gate”", "capable", "integrating", "diverse", "upstream", "signals.", "remains", "bound", "to", "the", "slow-growing", "pointed", "end,", "thereby", "cross-", "linking", "the", "new", "filament", "to", "the", "mother", "filament", "(Mullins", "et", "al.,", "1998).", "Arp2", "and", "Arp3", "subunits", "of", "the", "complex", "bind", "ATP.", "Although", "ATP", "hydrolysis", "is", "not", "necessary", "for", "actin", "nucleation,", "it", "is", "thought", "to", "be", "necessary", "for", "debranching", "of", "Arp2/3-branched", "actin", "filaments", "(Martin", "et", "al.,", "2006).", "Wiskott-Aldrich", "syndrome", "protein", "(WASP)", "family", "proteins", "are", "the", "predominant", "activators", "of", "the", "Arp2/3", "com-", "plex.", "However,", "in", "addition", "to", "regulation", "by", "WASP", "proteins,", "recent", "evidence", "indicates", "the", "Arp2/3", "complex", "is", "phosphorylated", "by", "serine/threonine", "kinases.", "The", "p21-activated", "kinase", "(PAK)", "phos-", "phorylates", "Thr21", "in", "the", "ARPC1", "subunit", "(Vadlamudi", "et", "al.,", "2004),", "and", "the", "MAPK-activated", "protein", "kinase", "2", "phosphorylates", "Ser77", "in", "the", "ARPC5", "subunit", "(Singh", "et", "al.,", "2003).", "Although", "phosphorylation", "of", "the", "Arp2/3", "complex", "is", "suggested", "to", "increase", "cell", "motility,", "whether", "phosphorylation", "directly", "regulates", "actin", "nu-", "cleating", "activity", "of", "the", "Arp2/3", "complex", "has", "not", "been", "reported.", "Results", "and", "discussion", "Purified", "Arp2/3", "complex", "is", "phosphorylated", "We", "found", "that", "several", "subunits", "of", "the", "Arp2/3", "complex", "are", "phosphorylated", "in", "cells.", "Using", "2D", "electrophoresis", "of", "purified", "©", "2008", "LeClaire", "et", "al.", "This", "article", "is", "distributed", "under", "the", "terms", "of", "an", "Attribution–", "Noncommercial–Share", "Alike–No", "Mirror", "Sites", "license", "for", "the", "first", "six", "months", "after", "the", "publica-", "tion", "date", "(see", "http://www.jcb.org/misc/terms.shtml).", "After", "six", "months", "it", "is", "available", "under", "a", "Creative", "Commons", "License", "(Attribution–Noncommercial–Share", "Alike", "3.0", "Unported", "license,", "as", "described", "at", "http://creativecommons.org/licenses/by-nc-sa/3.0/).", "JCB", "647" ]

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[ "Zintl", "et", "al.", "Veterinary", "Research", "2011,", "42:7", "http://www.veterinaryresearch.org/content/42/1/7", "R", "E", "S", "E", "A", "R", "C", "H", "VETERINARY", "RESEARCH", "Open", "Access", "Babesias", "of", "red", "deer", "(Cervus", "elaphus)", "in", "Ireland", "Annetta", "Zintl1,", "Eugene", "J", "Finnerty2,", "Thomas", "M", "Murphy3,", "Theo", "de", "Waal1,", "Jeremy", "S", "Gray2*", "Abstract", "Blood", "samples", "were", "obtained", "from", "38", "wild", "red", "deer", "(Cervus", "elaphus)", "at", "two", "sites", "in", "Ireland", "and", "subjected", "to", "PCR", "analysis", "of", "the", "18S", "rRNA", "gene", "followed", "by", "sequencing.", "Two", "fragments", "of", "the", "18S", "rRNA", "gene", "were", "generated", "by", "two", "different", "PCR", "protocols", "and", "subsequent", "sequencing", "suggested", "that", "at", "least", "six", "of", "the", "deer", "were", "infected", "by", "a", "babesia", "that,", "in", "those", "loci,", "is", "indistinguishable", "from", "Babesia", "divergens,", "an", "important", "tick-borne", "pathogen", "of", "cattle", "and", "of", "zoonotic", "significance.", "Additionally,", "a", "B.", "odocoilei-like", "parasite", "was", "detected", "in", "three", "samples", "and", "a", "babesia", "that", "did", "not", "match", "any", "sequences", "in", "the", "GenBank", "database", "was", "found", "in", "five", "samples.", "Neither", "B.", "capreoli", "nor", "B.", "venatorum", "(EU1)", "were", "found.", "There", "have", "been", "several", "reports", "of", "B.", "divergens", "occurring", "in", "deer", "species,", "including", "red", "deer,", "roe", "deer", "(Capreolus", "capreolus)", "and", "reindeer", "(Rangifer", "tarandus).", "However,", "in", "view", "of", "recent", "re-sequencing", "of", "bovine-origin", "samples", "deposited", "previously", "in", "GenBank,", "it", "is", "unlikely", "that", "any", "of", "these", "sequences", "from", "deer", "are", "B.", "divergens.", "The", "present", "study", "describes", "the", "only", "deer", "piroplasm", "detected", "so", "far", "that", "shows", "complete", "identity", "with", "B.", "divergens,", "in", "just", "over", "half", "of", "the", "18S", "rRNA", "gene.", "The", "entire", "gene", "of", "this", "deer", "parasite", "should", "be", "analysed", "and", "transmission", "experiments", "undertaken", "before", "the", "infectivity", "of", "B.", "divergens", "for", "red", "deer", "can", "be", "confirmed.", "Introduction", "There", "has", "been", "considerable", "recent", "interest", "in", "the", "iden-", "tity", "of", "Babesia", "spp.", "in", "deer,", "because", "of", "concerns", "about", "the", "health", "of", "endangered", "host", "species", "such", "as", "chamois", "(Rupicapra", "r.", "rupicapra)", "[1]", "and", "also", "because", "of", "the", "possibility", "of", "deer", "acting", "as", "reservoirs", "for", "important", "cat-", "tle", "parasites", "such", "as", "Babesia", "divergens", "[2].", "Earlier", "stu-", "dies", "on", "red", "(Cervus", "elaphus)", "and", "sika", "(C.", "nippon)", "deer", "babesias", "in", "Europe", "suggested", "that", "they", "were", "morpholo-", "gically", "and", "antigenically", "indistinguishable", "from", "B.", "diver-", "gens,", "but", "were", "not", "transmissible", "to", "splenectomised", "calves.", "They", "were", "therefore", "tentatively", "identified", "as", "B.", "capreoli", "[3,4],", "which", "was", "first", "observed", "in", "roe", "deer", "(Capreolus", "capreolus)", "[5].", "With", "the", "advent", "of", "molecular", "taxonomy", "based", "on", "analysis", "of", "DNA", "sequences,", "several", "authors", "described", "parasites", "in", "roe,", "red", "or", "reindeer", "as", "B.", "divergens", "or", "B.", "divergens-like", "[2,6-12].", "These", "authors", "based", "their", "conclusions", "on", "18S", "rRNA", "gene", "sequence", "alignment,", "but", "none", "of", "their", "samples", "showed", "100%", "simi-", "larity", "with", "B.", "divergens", "sequences", "of", "bovine", "origin", "in", "GenBank.", "Resequencing", "of", "the", "18S", "rRNA", "gene", "from", "the", "same", "strains", "of", "B.", "divergens", "originally", "deposited", "in", "Gen-", "Bank", "showed", "that", "all", "were", "in", "fact", "identical", "and", "that", "*", "Correspondence:", "Jeremy.gray@ucd.ie", "2UCD", "School", "of", "Biology", "and", "Environmental", "Science,", "University", "College", "Dublin,", "Ireland", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "there", "were", "errors", "in", "the", "original", "sequences", "(Slemenda", "et", "al.,", "unpublished,", "cited", "in", "[13]).", "This", "suggests", "that", "parasites", "showing", "less", "than", "100%", "similarity", "for", "this", "gene", "should", "not", "be", "designated", "B.", "divergens", "and", "to", "date", "there", "are", "no", "studies", "showing", "that", "B.", "divergens", "occurs", "naturally", "in", "ruminant", "hosts", "other", "than", "cattle.", "An", 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[ "Standards", "in", "Genomic", "Sciences", "(2011)", "5:371-378", "DOI:10.4056/sigs.2425302", "Complete", "genome", "sequence", "of", "Desulfurispirillum", "indicum", "strain", "S5T", "Elisabetta", "Bini1*,", "Ines", "Rauschenbach1,", "Priya", "Narasingarao1,6,", "Valentin", "Starovoytov2,", "Lauren", "Hauser3,", "Cynthia", "D.", "Jeffries3,", "Miriam", "Land3,", "David", "Bruce4,", "Chris", "Detter4,", "Lynne", "Goodwin4,", "Shunsheng", "Han4,", "Brittany", "Held4,", "Roxanne", "Tapia4,", "Alex", "Copeland5,", "Natalia", "Ivanova5,", "Natalia", "Mikhailova5,", "Matt", "Nolan5,", "Amrita", "Pati5,", "Len", "Pennacchio5,", "Sam", "Pitluck5,", "Tanja", "Woyke5,", "and", "Max", "Häggblom1", "1Rutgers,", "The", "State", "University", "of", "New", "Jersey,", "Department", "of", "Biochemistry", "and", "Microbiology,", "School", "of", "Environmental", "and", "Biological", "Sciences,", "New", "Brunswick,", "New", "Jersey,", "USA", "2Rutgers,", "The", "State", "University", "of", "New", "Jersey,", "Department", "of", "Cell", "Biology", "and", "Neuroscience,", "Piscataway,", "NJ,", "USA", "3Oak", "Ridge", "National", "Laboratory,", "Oak", "Ridge,", "Tennessee,", "USA", "4Los", "Alamos", "National", "Laboratory,", "Los", "Alamos,", "New", "Mexico,", "USA", "5Joint", "Genome", "Institute,", "Walnut", "Creek,", "USA", "6Current", "address:", "Scripps", "Institution", "of", "Oceanography,", "San", "Diego,", "CA,", "USA", "*Corresponding", "author:", "Elisabetta", "Bini,", "bini@aesop.rutgers.edu", "Keywords:", "Desulfurispirillum", "indicum", "S5,", "Chrysiogenetes,", "arsenate,", "selenate,", "anaerobe,", "free-", "living", "Desulfurispirillum", "indicum", "strain", "S5T", "is", "a", "strictly", "anaerobic", "bacterium", "isolated", "from", "river", "se-", "diment", "in", "Chennai,", "India.", "D.", "indicum", "belongs", "to", "the", "deep", "branching", "phylum", "of", "Chrysioge-", "netes,", "which", "currently", "only", "includes", "three", "other", "cultured", "species.", "Strain", "S5T", "is", "the", "type", "strain", "of", "the", "species", "and", "it", "is", "capable", "of", "growth", "using", "selenate,", "selenite,", "arsenate,", "nitrate", "or", "nitrite", "as", "terminal", "electron", "acceptors.", "The", "2,928,377", "bp", "genome", "encodes", "2,619", "proteins", "and", "49", "RNA", "genes,", "and", "the", "information", "gained", "from", "its", "sequence", "will", "be", "relevant", "to", "the", "elucidation", "of", "mi-", "crobially-mediated", "transformations", "of", "arsenic", "and", "selenium,", "in", "addition", "to", "deepening", "our", "knowledge", "of", "the", "underrepresented", "phylum", "of", "Chrysiogenetes.", "Introduction", "Desulfurispirillum", "indicum", "type", "strain", "S5T", "(=DSM", "22839T", "=ATCC", "BAA-1389T)", "was", "isolated", "from", "an", "estuarine", "sediment", "for", "its", "ability", "to", "grow", "on", "sele-", "nate", "[1].", "D.", "indicum", "belongs", "to", "the", "Chrysiogenetes,", "a", "deeply", "branching", "phylum", "that", "includes", "three", "other", "cultured", "species:", "Chrysiogenes", "arsenatis", "[2],", "Desul-", "furispirillum", "alkaliphilum", "[3],", "and", "Desulfurispira", "natronophila", "[4].", "The", "four", "microorganisms", "are", "all", "strict", "anaerobes", "and", "are", "capable", "of", "using", "a", "variety", "of", "terminal", "electron", "acceptors", "and", "a", "few", "short-", "chain", "fatty", "acids", "as", "electron", "donors", "and", "sources", "of", "carbon.", "Specifically,", "D.", "alkaliphilum", "can", "respire", "sul-", "fur,", "fumarate,", "nitrate,", "nitrite", "and", "chromate,", "while", "C.", "arsenatis", "can", "grow", "using", "arsenate,", "nitrate", "and", "ni-", "trite.", "Desulfurispira", "natronophila", "can", "grow", "under", "moderate", "haloalkaline", "conditions,", "respiring", "sulfur", "or", "arsenate.", "Thus,", "D.", "indicum", "is", "the", "only", "characte-", "rized", "Chrysiogenetes", "that", "is", "capable", "of", "dissimilatory", "reduction", "of", "both", "arsenate", "and", "selenate,", "in", "addition", "to", "nitrate", "and", "nitrite", "respiration.", "This", "feature", "makes", "it", "an", "ideal", "system", "to", "identify", "and", "elucidate", "the", "pathways", "for", "selenate", "and", "arsenate", "oxyanions", "respiration", "and", "their", "regulation.", "Here", "we", "summar-", "ize", "the", "features", "of", "D.", "indicum", "and", "present", "a", "descrip-", "tion", "of", "its", "sequenced", "genome,", "which", "is", "the", "first", "se-", "quenced", "genome", "of", "a", "member", "of", "the", "phylum", "Chry-", "siogenetes.", "Organism", "information", "D.", "indicum", "forms", "a", "deeply", "branching", "clade", "related", "to", "Chrysiogenes", "arsenatis,", "an", "arsenate", "respiring", "bacte-", "rium", "that", "cannot", "use", "selenate", "as", "electron", "acceptor,", "and", "Desulfurispira", "natronophila", "that", "only", "uses", "sulfur", "or", "arsenate", "as", "terminal", "electron", "acceptor", "(Table", "1).", "Interestingly,", "its", "closest", "relative", "D.", "alkaliphilum,", "with", "a", "16S", "rRNA", "gene", "identity", "of", "99.8%,", "is", "not", "capable", "of", "either", "arsenate", "or", "selenate", "respiration.", "The", "phylo-", "genetic", "position", "of", "D.", "indicum", "relative", "to", "its", "closest", "relatives", "is", "shown", "in", "Figure", "1.", "This", "Gram-negative", "bacterium", "is", "spiral-shaped", "and", "accumulates", "elec-", "tron-dense", "granules", "when", "grown", "in", "the", "presence", "of", "selenium", "(Figure", "2).", "The", "Genomic", "Standards", "Consortium" ]

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[ "Clinical", "research", "Understanding", "the", "expression", "of", "Toll-like", "receptors", "in", "Asian", "Indians", "predisposed", "to", "coronary", "artery", "disease", "Arindam", "Maitra1,", "Jayashree", "Shanker1,", "Debabrata", "Dash1,", "Prathima", "Arvind1,", "Vijay", "V.", "Kakkar1,2", "1Thrombosis", "Research", "Institute,", "India", "2Thrombosis", "Research", "Institute,", "London,", "United", "Kingdom", "Submitted:", "5", "May", "2010", "Accepted:", "12", "July", "2010", "Arch", "Med", "Sci", "2011;", "7,", "5:", "781-787", "DOI:", "10.5114/aoms.2011.25552", "Copyright", "©", "2011", "Termedia", "&", "Banach", "A", "b", "s", "t", "r", "a", "c", "t", "Introduction:", "Toll-like", "receptors", "(TLRs)", "are", "an", "important", "link", "between", "innate", "and", "adaptive", "immunity.", "Material", "and", "methods:", "Expression", "of", "TLR-2,", "TLR-4,", "and", "TLR-9", "genes", "was", "assessed", "in", "60", "coronary", "artery", "disease", "(CAD)", "patients", "and", "79", "controls", "by", "SYBR", "Green", "1", "based", "real", "time", "PCR", "assay.", "Results:", "Expression", "of", "the", "TLR-2", "gene", "was", "found", "to", "be", "significantly", "elevated", "in", "cases", "(1.295", "±0.09)", "compared", "to", "the", "controls", "(1.033", "±0.08)", "(p", "=", "0.015)", "whereas", "expression", "of", "the", "TLR-9", "gene", "was", "significantly", "lower", "in", "cases", "(1.522", "±0.18)", "than", "in", "the", "controls", "(2.165", "±0.16)", "(p", "=", "0.032).", "There", "was", "no", "difference", "in", "TLR-4", "expression", "levels", "(p", "=", "0.174).", "A", "significant", "correlation", "of", "TLR-2", "was", "observed", "with", "TLR-4", "(r", "=", "0.803,", "p", "<", "0.0001)", "and", "TLR-9", "(r", "=", "0.264,", "p", "=", "0.003)", "as", "well", "as", "between", "TLR-4", "and", "TLR-9", "(r", "=", "0.303,", "p", "=", "0.001).", "A", "significant", "association", "was", "seen", "between", "TLR", "2", "(OR", "3.94,", "95%", "CI", "1.73-8.99,", "p", "=", "0.001)", "and", "TLR-9", "(OR", "0.297,", "95%", "CI", "0.131-0.672,", "p", "=", "0.004)", "with", "CAD", "after", "adjustment", "for", "age", "and", "gender.", "Statins", "did", "not", "affect", "TLR", "gene", "expression.", "Conclusions:", "The", "TLR-2,", "TLR-4", "and", "TLR-9", "genes", "exhibit", "a", "differential", "pattern", "of", "expression", "between", "CAD", "patients", "and", "controls", "in", "this", "Asian", "Indian", "cohort.", "This", "observation", "warrants", "further", "investigation,", "keeping", "in", "mind", "the", "infectious", "and", "inflammatory", "elements", "in", "perspective,", "in", "order", "to", "understand", "the", "true", "implications", "of", "TLR", "in", "the", "aetiopathology", "of", "CAD", "and", "consequent", "therapeutic", "implications.", "Key", "words:", "Toll-like", "receptors,", "gene", "expression,", "coronary", "artery", "disease,", "Asian", "Indians.", "Introduction", "Atherosclerosis", "is", "considered", "to", "be", "an", "immunomodulatory", "disease,", "wherein", "infections", "by", "common", "pathogens", "and", "the", "ensuing", "inflammatory", "and", "immune", "response", "mechanisms", "play", "a", "significant", "role", "in", "the", "regulation", "of", "disease", "progression", "[1,", "2].", "Toll-like", "receptors", "(TLRs)", "are", "a", "family", "of", "pattern", "recognition", "receptors", "that", "serve", "as", "the", "first", "line", "of", "defence", "against", "invading", "microbes", "and/or", "tissue", "injury", "[3].", "Endothelial", "cells,", "macrophages,", "adventitious", "fibroblasts", "and", "dendritic", "cells", "express", "TLRs", "in", "the", "atherosclerotic", "vessel", "wall.", "Twelve", "different", "families", "of", "TLRs", "have", "been", "discovered", "to", "date,", "of", "which", "TLR-1,", "TLR-2,", "TLR-4", "and", "TLR-9", "are", "key", "receptors", "implicated", "in", "the", "development", "and", "progression", "of", "coronary", "artery", "disease", "(CAD)", "[4,", "5].", "The", "TLRs", "recognize", "a", "variety", "of", "bacterial", "and", "fungal", "Corresponding", "author:", "Dr.", "Jayashree", "Shanker", "Thrombosis", "Research", "Institute", "258/A,", "Bommasandra", "Industrial", "Area", "Anekal", "Taluk", "Bangalore", "560099,", "India", "Phone:", "91-80-27835303,", "91-80-27835302", "E-mail:", "jayashreeshanker@triindia.org.in" ]

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[ "The", "Journal", "of", "Nutrition", "Nutrient", "Physiology,", "Metabolism,", "and", "Nutrient-Nutrient", "Interactions", "Resistant", "Starches", "Protect", "against", "Colonic", "DNA", "Damage", "and", "Alter", "Microbiota", "and", "Gene", "1–3", "Expression", "in", "Rats", "Fed", "a", "Western", "Diet", "Michael", "A.", "Conlon,4–6", "Caroline", "A.", "Kerr,4,7", "Christopher", "S.", "McSweeney,4,8", "Robert", "A.", "Dunne,4,9", "Janet", "M.", "Shaw,4,7", "Seungha", "Kang,4,8", "Anthony", "R.", "Bird,4–6", "Matthew", "K.", "Morell,5,10", "Trevor", "J.", "Lockett,4,7", "Peter", "L.", "Molloy,4,7", "Ahmed", "Regina,5,10", "Shusuke", "Toden,4–6", "Julie", "M.", "Clarke,4,6", "and", "David", "L.", "Topping4–6*", "4CSIRO", "Preventative", "Health,", "5Food", "Futures", "National", "Research", "Flagships,", "and", "6CSIRO", "Food", "and", "Nutritional", "Sciences,", "Adelaide,", "South", "Australia,", "Australia;", "7CSIRO", "Food", "and", "Nutritional", "Sciences,", "North", "Ryde,", "New", "South", "Wales,", "Australia;", "8CSIRO", "Livestock", "Industries,", "St", "Lucia,", "Queensland,", "Australia;", "9CSIRO", "Mathematics,", "Informatics", "and", "Statistics,", "Glen", "Osmond,", "South", "Australia,", "Australia;", "and", "10CSIRO", "Plant", "Industry,", "Black", "Mountain,", "Australian", "Capital", "Territory,", "Australia", "Abstract", "Resistant", "starch", "(RS),", "fed", "as", "high", "amylose", "maize", "starch", "(HAMS)", "or", "butyrylated", "HAMS", "(HAMSB),", "opposes", "dietary", "protein-", "induced", "colonocyte", "DNA", "damage", "in", "rats.", "In", "this", "study,", "rats", "were", "fed", "Western-type", "diets", "moderate", "in", "fat", "(19%)", "and", "protein", "(20%)", "containing", "digestible", "starches", "[low", "amylose", "maize", "starch", "(LAMS)", "or", "low", "amylose", "whole", "wheat", "(LAW)]", "or", "RS", "[HAMS,", "HAMSB,", "or", "a", "whole", "high", "amylose", "wheat", "(HAW)", "generated", "by", "RNA", "interference]", "for", "11", "wk", "(n", "=", "10/group).", "A", "control", "diet", "included", "7%", "fat,", "13%", "protein,", "and", "LAMS.", "Colonocyte", "DNA", "single-strand", "breaks", "(SSB)", "were", "significantly", "higher", "(by", "70%)", "in", "rats", "fed", "the", "Western", "diet", "containing", "LAMS", "relative", "to", "controls.", "Dietary", "HAW,", "HAMS,", "and", "HAMSB", "opposed", "this", "effect", "while", "raising", "digesta", "levels", "of", "SCFA", "and", "lowering", "ammonia", "and", "phenol", "levels.", "SSB", "correlated", "inversely", "with", "total", "large", "bowel", "SCFA,", "including", "colonic", "butyrate", "concentration", "(R2", "=", "0.40;", "P", "=", "0.009),", "and", "positively", "with", "colonic", "ammonia", "concentration", "(R2", "=", "0.40;", "P", "=", "0.014).", "Analysis", "of", "gut", "microbiota", "populations", "using", "a", "phylogenetic", "microarray", "revealed", "profiles", "that", "fell", "into", "3", "distinct", "groups:", "control", "and", "LAMS;", "HAMS", "and", "HAMSB;", "and", "LAW", "and", "HAW.", "The", "expression", "of", "colonic", "genes", "associated", "with", "the", "maintenance", "of", "genomic", "integrity", "(notably", "Mdm2,", "Top1,", "Msh3,", "Ung,", "Rere,", "Cebpa,", "Gmnn,", "and", "Parg)", "was", "altered", "and", "varied", "with", "RS", "source.", "HAW", "is", "as", "effective", "as", "HAMS", "and", "HAMSB", "in", "opposing", "diet-induced", "colonic", "DNA", "damage", "in", "rats,", "but", "their", "effects", "on", "the", "large", "bowel", "microbiota", "and", "colonocyte", "gene", "expression", "differ,", "possibly", "due", "to", "the", "presence", "of", "other", "fiber", "components", "in", "HAW.", "J.", "Nutr.", "142:", "832–840,", "2012.", "ã", "2012", "American", "Society", "for", "Nutrition.", "Manuscript", "received", "July", "7,", "2011.", "Initial", "review", "completed", "August", "24,", "2011.", "Revision", "accepted", "February", "1,", "2012.", "First", "published", "online", "March", "28,", "2012;", "doi:10.3945/jn.111.147660.", "Introduction", "Colorectal", "cancer", "(CRC)11", "is", "a", "major", "cause", "of", "premature", "morbidity", "and", "mortality", "in", "westernized", "industrial", "countries", "and", "is", "appearing", "1", "Supported", "by", "CSIRO.", "CSIRO", "receives", "support", "from", "a", "joint", "venture", "with", "Arista,", "which", "indirectly", "provides", "assistance", "to", "CSIRO", "researchers.", "2", "Author", "disclosures:", "M.", "A.", "Conlon,", "C.", "A.", "Kerr,", "C.", "S.", "McSweeney,", "R.", "A.", "Dunne,", "J.", "M.", "Shaw,", "S.", "Kang,", "A.", "R.", "Bird,", "M.", "K.", "Morell,", "T.", "J.", "Lockett,", "P.", "L.", "Molloy,", "A.", "Regina,", "S.", "Toden,", "J.", "M.", "Clarke,", "and", "D.", "L.", "Topping,", "no", "conflicts;", "the", "research", "was", "carried", "out", "as", "part", "of", "the", "authors’", "normal", "duties", "at", "CSIRO.", "3", "Supplemental", "Tables", "1–3,", "Supplemental", "Figures", "1–3,", "and", "Supplemental", "Text", "are", "available", "from", "the", "“Online", "Supporting", "Material”", "link", "in", "the", "online", "posting", "of", "the", "article", "and", "from", "the", "same", "link", "in", "the", "online", "table", "of", "contents", "at", "http://jn.nutrition.org.", "11", "Abbreviations", "used:", "C-LAMS,", "control", "diet", "containing", "low", "amylose", "maize", "starch;", "CRC,", "colorectal", "cancer;", "cRNA,", "single-stranded", "RNA;", "EPIC,", "European", "Prospective", "Investigation", "into", "Cancer", "and", "Nutrition;", "HAMS,", "high", "amylose", "maize", "starch;", "HAMSB,", "butyrylated", "high", "amylose", "maize", "starch;", "HAW,", "high", "amylose", "wheat", "flour;", "LAMS,", "low", "amylose", "maize", "starch;", "LAW,", "low", "amylose", "wheat", "flour;", "NSP,", "nonstarch", "polysaccharide;", "PCA,", "principal", "components", "analysis;", "RS,", "resistant", "starch;", "SSB,", "single-strand", "break;", "W-HAMS,", "Western", "diet", "containing", "high", "amylose", "maize", "starch;", "W-HAMSB,", "Western", "diet", "containing", "butyrylated", "high", "amylose", "maize", "starch;", "W-HAW,", "Western", "diet", "containing", "high", "amylose", "wheat", "flour;", "W-LAMS,", "Western", "diet", "containing", "low", "amylose", "maize", "starch;", "W-LAW,", "Western", "diet", "containing", "low", "amylose", "wheat", "flour.", "*", "To", "whom", "correspondence", "should", "be", "addressed.", "E-mail:", "david.topping@csiro.au.", "832", "rapidly", "in", "developing", "economies", "with", "greater", "affluence", "(1).", "This", "time", "trend", "supports", "the", "importance", "of", "environmental", "influences", "in", "its", "etiology", "whereas", "genetic", "factors", "are", "thought", "to", "contribute", "#30%", "of", "new", "cases,", "strengthening", "the", "case", "for", "control", "through", "prevention", "(2).", "A", "study", "by", "the", "European", "Prospective", "Investiga-", "tion", "into", "Cancer", "and", "Nutrition", "(EPIC)", "showed", "that", "dietary", "fiber", "dose-dependently", "lowered", "CRC", "risk", "(3),", "whereas", "an", "earlier", "international", "comparison", "of", "population", "studies", "found", "that", "greater", "dietary", "protein", "intakes", "increase", "risk", "(4).", "Further", "analysis", "of", "the", "EPIC", "data", "showed", "that", "consumption", "of", "red", "and", "processed", "meat", "increased", "CRC", "risk", "(5).", "Unrepaired", "DNA", "damage", "is", "a", "prerequisite", "for", "carcinogenesis", "and", "we", "showed", "that", "feeding", "high-", "protein", "diets", "substantially", "increased", "the", "number", "of", "colonic", "DNA", "strand", "breaks", "in", "rats", "(6–8).", "Significantly", "greater", "damage", "was", "seen", "with", "some", "protein", "sources,", "including", "red", "meat", "and", "casein,", "than", "with", "others,", "such", "as", "chicken,", "which", "is", "consistent", "with", "prospective", "population", "studies.", "Damage", "was", "dose-dependently", "opposed", "by", "dietary", "RS", "(resistant", "starch)", "fed", "as", "high", "amylose", "maize", "starch", "(HAMS)", "(6–8)", "or", "butyrylated", "HAMS", "(HAMSB)", "(9).", "Resistant", "starch", "(RS),", "the", "starch", "and", "the", "products", "of", "its", "digestion,", "escapes", "from", "the", "small", "intestine", "and", "enters", "the", "large" ]

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[ "Suppression", "and", "Regression", "of", "Choroidal", "Neovascularization", "in", "Mice", "by", "a", "Novel", "CCR2", "Antagonist,", "INCB3344", "Ping", "Xie,", "Motohiro", "Kamei*,", "Mihoko", "Suzuki,", "Nagakazu", "Matsumura,", "Kentaro", "Nishida,", "Susumu", "Sakimoto,", "Hirokazu", "Sakaguchi,", "Kohji", "Nishida", "Department", "of", "Ophthalmology,", "Graduate", "School", "of", "Medicine,", "Osaka", "University,", "Suita,", "Osaka,", "Japan", "Abstract", "Purpose:", "To", "investigate", "the", "effect", "of", "an", "intravitreally", "administered", "CCR2", "antagonist,", "INCB3344,", "on", "a", "mouse", "model", "of", "choroidal", "neovascularization", "(CNV).", "Methods:", "CNV", "was", "induced", "by", "laser", "photocoagulation", "on", "Day", "0", "in", "wild", "type", "mice.", "INCB3344", "or", "vehicle", "was", "administered", "intravitreally", "immediately", "after", "laser", "application.", "On", "Day", "14,", "CNV", "areas", "were", "measured", "on", "retinal", "pigment", "epithelium", "(RPE)-", "choroid", "flat", "mounts", "and", "histopathologic", "examination", "was", "performed", "on", "7", "mm-thick", "sections.", "Macrophage", "infiltration", "was", "evaluated", "by", "immunohistochemistry", "on", "RPE-choroid", "flat", "mounts", "and", "quantified", "by", "flow", "cytometry", "on", "Day", "3.", "Expression", "of", "vascular", "endothelial", "growth", "factor", "(VEGF)", "protein", "in", "RPE-choroid", "tissue", "was", "examined", "by", "immunohistochemistry", "and", "ELISA,", "VEGF", "mRNA", "in", "sorted", "macrophages", "in", "RPE-choroid", "tissue", "was", "examine", "by", "real-time", "PCR", "and", "expression", "of", "phosphorylated", "extracellular", "signal-regulated", "kinase", "(p-ERK", "1/2)", "in", "RPE-choroid", "tissue", "was", "measured", "by", "Western", "blot", "analysis", "on", "Day", "3.", "We", "also", "evaluated", "the", "efficacy", "of", "intravitreal", "INCB3344", "to", "spontaneous", "CNV", "detected", "in", "Cu,", "Zn-superoxide", "dismutase", "(SOD1)", "deficient", "mice.", "Changes", "in", "CNV", "size", "were", "assessed", "between", "pre-", "and", "1week", "post-INCB3344", "or", "vehicle", "administration", "in", "fundus", "photography", "and", "fluorescence", "angiography", "(FA).", "Results:", "The", "mean", "CNV", "area", "in", "INCB3344-treated", "mice", "decreased", "by", "42.4%", "compared", "with", "the", "vehicle-treated", "control", "mice", "(p,0.001).", "INCB3344", "treatment", "significantly", "inhibited", "macrophage", "infiltration", "into", "the", "laser-irradiated", "area", "(p,0.001),", "and", "suppressed", "the", "expression", "of", "VEGF", "protein", "(p", "=", "0.012),", "VEGF", "mRNA", "in", "infiltrating", "macrophages", "(p,0.001)", "and", "the", "phosphorylation", "of", "ERK1/2", "(p,0.001).", "The", "area", "of", "spontaneous", "CNV", "in", "Sod12/2", "mice", "regressed", "by", "70.35%", "in", "INCB3344-", "treated", "animals", "while", "no", "change", "was", "detected", "in", "vehicle-treated", "control", "mice", "(p,0.001).", "Conclusions:", "INCB3344", "both", "inhibits", "newly", "forming", "CNV", "and", "regresses", "established", "CNV.", "Controlling", "inflammation", "by", "suppressing", "macrophage", "infiltration", "and", "angiogenic", "ability", "via", "the", "CCR-2/MCP-1", "signal", "may", "be", "a", "useful", "therapeutic", "strategy", "for", "treating", "CNV", "associated", "with", "age-related", "macular", "degeneration.", "Citation:", "Xie", "P,", "Kamei", "M,", "Suzuki", "M,", "Matsumura", "N,", "Nishida", "K,", "et", "al.", "(2011)", "Suppression", "and", "Regression", "of", "Choroidal", "Neovascularization", "in", "Mice", "by", "a", "Novel", "CCR2", "Antagonist,", "INCB3344.", "PLoS", "ONE", "6(12):", "e28933.", "doi:10.1371/journal.pone.0028933", "Editor:", "Paul", "Proost,", "University", "of", "Leuven,", "Rega", "Institute,", "Belgium", "Received", "August", "9,", "2011;", "Accepted", "November", "17,", "2011;", "Published", "December", "19,", "2011", "Copyright:", "2011", "Xie", "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-in-Aid", "for", "Scientific", "Research", "(#15591853)", "from", "the", "Ministry", "of", "Education,", "Science", "and", "Culture", "of", "Japan.", "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:", "mkamei@ophthal.med.osaka-u.ac.jp", "Introduction", "Age-related", "macular", "degeneration", "(AMD)", "is", "the", "leading", "cause", "of", "legal", "blindness", "among", "elderly", "people", "in", "developed", "countries", "[1].", "The", "majority", "of", "these", "patients", "with", "severe", "vision", "loss", "have", "retinal", "damage", "by", "choroidal", "neovascularization", "(CNV)", "[2],", "which", "is", "the", "hallmark", "of", "wet", "AMD", "and", "is", "defined", "as", "new", "blood", "vessels", "arising", "from", "choriocapillaris", "and", "extending", "into", "the", "sub-retinal", "pigment", "epithelium", "(sub-RPE)", "[3],", "sub-retinal", "space,", "or", "both.", "Although", "the", "pathogenesis", "of", "CNV", "is", "not", "completely", "understood,", "inflammatory", "processes,", "especially", "the", "infiltration", "of", "inflammatory", "cells,", "are", "recognized", "as", "an", "important", "mediator", "of", "CNV", "formation", "[4].", "Macrophage", "accumulation", "in", "the", "CNV", "area", "and", "expression", "of", "angiogenic", "cytokines,", "such", "as", "vascular", "endothelial", "growth", "factor", "(VEGF)", "are", "involved", "in", "CNV", "formation", "[5–10].", "Moreover,", "in", "mice", "depleted", "of", "macrophages,", "CNV", "is", "reduced", "and", "VEGF", "production", "is", "decreased", "[11],", "[12],", "which", "suggests", "a", "role", "for", "macrophages", "as", "producers", "and", "regulators", "of", "angiogenic", "factors", "in", "the", "pathogenesis", "of", "CNV.", "The", "chemokine", "receptor", "CCR2", "and", "its", "ligand,", "monocyte", "chemoattractant", "protein-1", "(MCP-1;", "also", "known", "as", "CCL2)", "represent", "a", "critical", "signaling", "pathway", "responsible", "for", "the", "recruitment", "of", "monocyte-macrophages", "[13–16].", "MCP-1", "expres-", "sion", "is", "not", "detectable", "[2],", "[17]", "or", "very", "low", "[18]", "in", "healthy", "young", "adult", "mice,", "but", "is", "found", "in", "high", "concentrations", "in", "the", "eyes", "of", "CNV", "bearing", "mice", "with", "the", "infiltration", "of", "macrophages", "[2],", "[17],", "[19],", "[20].", "Recent", "studies", "also", "demonstrate", "an", "association", "between", "elevated", "urinary", "MCP-1", "level", "and", "AMD", "[21],", "and", "the", "intraocular", "PLoS", "ONE", "|", "www.plosone.org", "1", "December", "2011", "|", "Volume", "6", "|", "Issue", "12", "|", "e28933" ]

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[ "Skrzypulec-Plinta", "et", "al.", "Reproductive", "Biology", "and", "Endocrinology", "2010,", "8:141", "http://www.rbej.com/content/8/1/141", "R", "E", "S", "E", "A", "R", "C", "H", "Open", "Access", "The", "complexity", "of", "premenstrual", "dysphoric", "disorder", "-", "risk", "factors", "in", "the", "population", "of", "Polish", "women", "Violetta", "Skrzypulec-Plinta1,", "Agnieszka", "Drosdzol1*,", "Krzysztof", "Nowosielski1,", "Ryszard", "Plinta2", "Abstract", "Background:", "Premenstrual", "dysphoric", "disorder", "has", "multiple", "determinants", "in", "the", "biological,", "psychological", "and", "socio-cultural", "domains.", "The", "aim", "of", "the", "study", "was", "to", "evaluate", "the", "risk", "factors", "for", "premenstrual", "dysphoric", "disorder", "in", "Polish", "women,", "considering", "their", "reproductive", "history,", "socio-economic", "factors,", "as", "well", "as", "lifestyle", "and", "health-related", "factors.", "Methods:", "2,500", "females,", "aged", "18", "to", "45,", "from", "the", "Upper", "Silesian", "region", "of", "Poland", "were", "eligible", "for", "the", "prospective", "population", "study.", "The", "final", "study", "sample", "was", "1,540", "individuals.", "The", "research", "was", "based", "on", "a", "questionnaire", "containing", "socio-economic", "status,", "general", "health,", "lifestyle,", "medical", "and", "reproductive", "history,", "premenstrual", "symptoms", "based", "on", "the", "American", "Psychiatric", "Association’s", "criteria", "for", "diagnosing", "premenstrual", "dysphoric", "disorder,", "and", "patient", "prospective", "daily", "ratings", "of", "symptoms.", "The", "Statistica", "8.0", "computer", "software", "was", "used", "for", "statistical", "analysis.", "The", "value", "of", "p", "<", "0.05", "was", "adopted", "as", "the", "level", "of", "statistical", "significance.", "Results:", "The", "mean", "age", "of", "the", "studied", "population", "was", "31.9", "+/-", "7.3", "years.", "The", "majority", "of", "the", "studied", "women", "were", "married", "(57.9%),", "lived", "in", "large", "cities", "(42.0%)", "and", "had", "tertiary", "education", "(43.2%).", "The", "results", "of", "the", "study", "indicated", "that", "the", "prevalence", "of", "premenstrual", "dysphoric", "disorder", "was", "2.1%.", "The", "final", "statistical", "analysis", "revealed", "that", "only", "tertiary", "education", "decreased", "the", "risk", "of", "premenstrual", "dysphoric", "disorder", "(OR", "=", "0.08;", "p", "<", "0.05).", "Conclusions:", "Our", "research", "showed", "that", "women", "with", "tertiary", "education", "are", "less", "vulnerable", "to", "premenstrual", "dysphoric", "disorder", "than", "women", "with", "a", "lower", "level", "of", "education.", "Reproductive", "and", "lifestyle", "factors", "seem", "to", "be", "play", "a", "lesser", "role.", "Background", "Most", "women", "experience", "a", "variety", "of", "physical,", "behavioral", "and", "emotional", "symptoms", "during", "the", "luteal", "phase", "of", "the", "menstrual", "cycle.", "The", "symptoms", "include", "lethargy,", "persis-", "tent", "irritability,", "mood", "swings,", "changes", "in", "appetite,", "bloat-", "ing,", "acne", "and", "breast", "tenderness", "[1,2].", "Up", "to", "70%", "of", "women", "are", "affected", "by", "menstrual", "disorders", "each", "year", "[2,3].", "However,", "a", "definitive", "etiology", "has", "not", "yet", "been", "established", "[2,3].", "Fluctuations", "in", "estrogen", "and", "progester-", "one,", "as", "well", "as", "genetic", "(estrogen", "receptor", "1", "variation)", "or", "neurobiological", "factors", "are", "believed", "to", "play", "an", "important", "role", "in", "premenstrual", "symptomatology", "[2-5].", "Premenstrual", "symptoms", "are", "characterized", "in", "terms", "of", "their", "type,", "severity,", "and", "timing", "[6].", "They", "may", "be", "limited", "to", "a", "mild", "discomfort", "or", "extend", "to", "the", "premenstrual", "*", "Correspondence:", "cor111@poczta.onet.pl", "1Department", "of", "Womens’", "Disease", "Control", "and", "Prevention,", "the", "Medical", "University", "of", "Silesia,", "ul.", "Medyków", "12;", "40-752", "Katowice,", "Poland", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "syndrome", "(PMS).", "Depending", "on", "the", "degree", "of", "emotional", "and", "somatic", "impairment,", "they", "may", "even", "involve", "the", "most", "severe", "premenstrual", "dysphoric", "disorder", "(PMDD)", "[1,2,6,7].", "The", "criteria", "for", "PMS", "and", "PMDD", "were", "estab-", "lished", "relatively", "recently", "(in", "2000)", "by", "the", "American", "Col-", "lege", "of", "Obstetricians", "and", "Gynecologists", "(PMS)", "and", "the", "American", "Psychiatric", "Association", "(PMDD)", "[6,8].", "PMS", "is", "a", "common", "pathology", "experienced", "by", "up", "to", "50%", "of", "women", "of", "reproductive", "age", "[9,10].", "By", "contrast,", "the", "prevalence", "of", "PMDD,", "i.e.", "where", "premenstrual", "symp-", "toms", "reach", "a", "level", "of", "severity", "that", "interferes", "with", "perso-", "nal,", "social", "and", "professional", "functioning,", "is", "much", "lower:", "3%", "to", "8%", "[9,10].", "PMDD,", "most", "likely,", "has", "multiple", "determinants", "in", "the", "biological,", "psychological", "and", "socio-cultural", "domains.", "Some", "of", "the", "currently", "investigated", "potential", "risk", "factors", "for", "PMDD", "are:", "the", "quality", "of", "interpersonal", "relationships", "and", "cooperation,", "self-esteem,", "expectation", "and", "perception", "of", "premenstrual", "symptoms,", "stress,", "socio-economic", "©", "2010", "Skrzypulec-Plinta", "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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[ "Hindawi", "Publishing", "Corporation", "Case", "Reports", "in", "Medicine", "Volume", "2012,", "Article", "ID", "473732,", "3", "pages", "doi:10.1155/2012/473732", "Case", "Report", "Giant", "Aortic", "Pseudoaneurysm", "with", "Stanford", "Type", "A", "Aortic", "Dissection", "after", "Aortic", "Valve", "Replacement", "Mertay", "Boran,1", "Ali", "I˙hsan", "Parlar,2", "and", "Ertay", "Boran3", "1", "Department", "of", "Thoracic", "Surgery,", "Cankiri", "State", "Hospital,", "Cankiri", "18100,", "Turkey", "2", "Department", "of", "Cardiovascular", "Surgery,", "Trabzon", "Ahi", "Evren", "Training", "and", "Research", "Hospital,", "Trabzon", "61040,", "Turkey", "3", "1st", "Department", "of", "Anesthesiology", "and", "Reanimation,", "Izmir", "Ataturk", "Training", "and", "Research", "Hospital,", "Izmir", "35150,", "Turkey", "Correspondence", "should", "be", "addressed", "to", "Mertay", "Boran,", "mertayboran@yahoo.com", "Received", "27", "September", "2011;", "Accepted", "20", "December", "2011", "Academic", "Editor:", "Frank", "A.", "Pigula", "Copyright", "©", "2012", "Mertay", "Boran", "et", "al.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Giant", "pseudoaneurysm", "of", "the", "ascending", "aorta", "is", "a", "rare", "but", "dreadful", "complication", "occurring", "several", "months", "or", "years", "after", "aortic", "surgery.", "Thoracic", "aortic", "aneurysms", "tend", "to", "be", "asymptomatic", "and", "were", "previously", "often", "diagnosed", "only", "after", "a", "complication", "such", "as", "dissection", "or", "rupture.", "We", "present", "a", "rare", "case", "of", "giant", "ascending", "aneurysm", "with", "Stanford", "type", "A", "aortic", "dissection", "occurring", "6", "years", "after", "aortic", "valve", "replacement", "and", "also", "illustrate", "the", "potential", "dimensions", "the", "ascending", "aorta", "may", "reach", "by", "a", "pseudoaneurysm", "and", "dissection", "after", "AVR.", "1.", "Introduction", "Giant", "pseudoaneurysm", "of", "the", "ascending", "aorta", "after", "aortic", "valve", "replacement", "(AVR)", "is", "a", "rare", "and", "dreadful", "complication,", "which", "may", "occur", "several", "months", "or", "years", "after", "aortic", "surgery", "[1–3].", "These", "aneurysms", "tend", "to", "be", "asymptomatic", "and", "are", "often", "diagnosed", "only", "after", "a", "complication", "such", "as", "dissection", "or", "rupture", "[3,", "4].", "We", "present", "a", "case", "of", "giant", "ascending", "pseudoaneurysm", "with", "Stanford", "type", "A", "aortic", "dissection", "occurring", "6", "years", "after", "aortic", "valve", "replacement.", "The", "case", "also", "illustrates", "the", "potential", "dimensions", "the", "ascending", "aorta", "may", "reach", "by", "a", "pseudoaneurysm", "and", "dissection", "after", "AVR.", "2.", "Case", "Presentation", "A", "71-year-old", "man,", "with", "increasing", "interscapular", "and", "back", "pain", "complaint", "that", "started", "3", "days", "before,", "was", "taken", "to", "emergency", "department", "after", "a", "syncope", "episode.", "He", "had", "a", "history", "of", "aortic", "valve", "(bileaflet", "mechanical", "heart", "valve)", "replacement", "surgery", "performed", "6", "years", "ago.", "The", "patient’s", "physical", "exam", "revealed", "a", "well-healed", "median", "sternotomy", "incision,", "100/60", "mmHg", "of", "blood", "pressure,", "86", "beats/min", "of", "heart", "rate,", "equal", "blood", "pressures", "in", "all", "extremities,", "and", "diminished", "lung", "sounds", "at", "the", "right", "lower", "hemithorax.", "The", "laboratory", "showed", "only", "elevated", "creatinin", "kinase", "levels", "while", "hemoglobin", "and", "hematocrit", "levels", "were", "in", "normal", "limits.", "Chest", "X-ray", "revealed", "sternal", "closure", "sutures", "and", "enlargement", "of", "mediastinum", "and", "opacities", "of", "prosthetic", "aortic", "valve", "(Figure", "1).", "CT", "scan", "of", "the", "chest", "demonstrated", "an", "intimal", "flap", "separating", "the", "true", "and", "false", "lumen,", "aneurysm", "of", "the", "ascend-", "ing", "thoracic", "aorta", "approximately", "11", "cm", "in", "diameter,", "large", "thrombus", "surrounding", "the", "aorta,", "bilateral", "pleural", "effusion,", "more", "at", "the", "right", "(Figure", "2)", "and", "minimal", "at", "the", "left", "hemitho-", "rax", "and", "prosthetic", "aortic", "valve", "(Figure", "3).", "Transthoracic", "echocardiography", "showed", "a", "markedly", "enlarged", "ascending", "aorta,", "intimal", "flap", "in", "the", "aorta,", "normal", "prosthetic", "valve", "function", "and", "50%", "ventricular", "ejection", "fraction.", "The", "patient’s", "previous", "outpatient", 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[ "Joly", "et", "al.", "BMC", "Genomics", "2010,", "11:422", "http://www.biomedcentral.com/1471-2164/11/422", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Comparative", "analysis", "of", "secreted", "protein", "evolution", "using", "expressed", "sequence", "tags", "from", "four", "poplar", "leaf", "rusts", "(Melampsora", "spp.)", "David", "L", "Joly1,", "Nicolas", "Feau1,3,", "Philippe", "Tanguay1,", "Richard", "C", "Hamelin1,2*", "Abstract", "Background:", "Obligate", "biotrophs", "such", "as", "rust", "fungi", "are", "believed", "to", "establish", "long-term", "relationships", "by", "modulating", "plant", "defenses", "through", "a", "plethora", "of", "effector", "proteins,", "whose", "most", "recognizable", "feature", "is", "the", "presence", "of", "a", "signal", "peptide", "for", "secretion.", "Since", "the", "phenotypes", "of", "these", "effectors", "extend", "to", "host", "cells,", "their", "genes", "are", "expected", "to", "be", "under", "accelerated", "evolution", "stimulated", "by", "host-pathogen", "coevolutionary", "arms", "races.", "Recently,", "whole", "genome", "sequence", "data", "has", "allowed", "the", "prediction", "of", "secretomes,", "facilitating", "the", "identification", "of", "putative", "effectors.", "Results:", "We", "generated", "cDNA", "libraries", "from", "four", "poplar", "leaf", "rust", "pathogens", "(Melampsora", "spp.)", "and", "used", "computational", "approaches", "to", "identify", "and", "annotate", "putative", "secreted", "proteins", "with", "the", "aim", "of", "uncovering", "new", "knowledge", "about", "the", "nature", "and", "evolution", "of", "the", "rust", "secretome.", "While", "more", "than", "half", "of", "the", "predicted", "secretome", "members", "encoded", "lineage-specific", "proteins,", "similarities", "with", "experimentally", "characterized", "fungal", "effectors", "were", "also", "identified.", "A", "SAGE", "analysis", "indicated", "a", "strong", "stage-specific", "regulation", "of", "transcripts", "encoding", "secreted", "proteins.", "The", "average", "sequence", "identity", "of", "putative", "secreted", "proteins", "to", "their", "closest", "orthologs", "in", "the", "wheat", "stem", "rust", "Puccinia", "graminis", "f.", "sp.", "tritici", "was", "dramatically", "reduced", "compared", "with", "non-secreted", "ones.", "A", "comparative", "genomics", "approach", "based", "on", "homologous", "gene", "groups", "unravelled", "positive", "selection", "in", "putative", "members", "of", "the", "secretome.", "Conclusion:", "We", "uncovered", "robust", "evidence", "that", "different", "evolutionary", "constraints", "are", "acting", "on", "the", "rust", "secretome", "when", "compared", "to", "the", "rest", "of", "the", "genome.", "These", "results", "are", "consistent", "with", "the", "view", "that", "these", "genes", "are", "more", "likely", "to", "exhibit", "an", "effector", "activity", "and", "be", "involved", "in", "coevolutionary", "arms", "races", "with", "host", "factors.", "Background", "Rust", "fungi", "or", "Pucciniales", "(=", "Uredinales)", "represent", "the", "largest", "group", "of", "fungal", "plant", "pathogens,", "including", "more", "than", "7000", "species", "that", "possess", "the", "most", "complex", "life", "cycles", "in", "the", "Kingdom", "Fungi", "[1].", "Some", "of", "these", "obligate", "biotrophs", "have", "been", "of", "long", "standing", "concern", "for", "agri-", "culture", "and", "forestry", "while", "others", "have", "emerged", "in", "recent", "epidemics.", "For", "instance,", "poplar", "leaf", "rusts", "belonging", "to", "the", "genus", "Melampsora", "are", "considered", "as", "the", "world’s", "most", "important", "disease", "of", "poplars", "[2].", "Selection", "for", "dur-", "able", "resistance", "to", "these", "pathogens", "is", "thus", "an", "important", "challenge", "for", "poplar", "breeders", "[3].", "Although", "poplar", "breeding", "programs", "have", "been", "in", "place", "for", "decades", "in", "*", "Correspondence:", "richard.hamelin@ubc.ca", "1Natural", "Resources", "Canada,", "Canadian", "Forest", "Service,", "Laurentian", "Forestry", "Centre,", "1055", "du", "PEPS,", "P.O.", "Box", "10380,", "Stn.", "Sainte-Foy,", "Québec,", "QC,", "G1V", "4C7,", "Canada", "Europe,", "clones", "selected", "for", "complete", "resistance", "against", "rust", "have", "increasingly", "succumbed", "in", "time", "to", "new", "races", "of", "Melampsora", "larici-populina", "[4].", "Sustainability", "of", "newly", "selected", "resistance", "clearly", "requires", "a", "better", "understanding", "of", "the", "molecular", "mechanisms", "involved", "in", "Populus-", "Melampsora", "interactions.", "Prokaryotic", "and", "eukaryotic", "plant", "pathogens", "have", "evolved", "highly", "advanced", "strategies", "to", "engage", "their", "hosts", "in", "intimate", "contacts", "and", "deliver", "suites", "of", "effector", "pro-", "teins", "to", "modulate", "plants’", "innate", "immunity", "and", "enable", "parasitic", "colonization", "[5-12].", "Understanding", "the", "translo-", "cation", "mechanisms", "of", "bacterial", "pathogen", "effectors", "inside", "host", "cells", "has", "been", "an", "outstanding", "breakthrough", "with", "the", "characterization", "of", "the", "type", "III", "secretion", "system.", "This", "export", "apparatus", "enables", "a", "bacterium", "to", "manipu-", "late", "host", "cellular", "processes", "by", "injecting", "effector", "proteins", "into", "the", "host", "cytoplasm", "[7].", "Similarly,", "plant-parasitic", "©", "2010", "Joly", "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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[ "Research", "|", "Children’s", "Health", "Prenatal", "Exposure", "to", "Organophosphates,", "Paraoxonase", "1,", "and", "Cognitive", "Development", "in", "Childhood", "Stephanie", "M.", "Engel,1", "James", "Wetmur,2,3", "Jia", "Chen,1", "Chenbo", "Zhu,1", "Dana", "Boyd", "Barr,4", "Richard", "L.", "Canfield,5", "and", "Mary", "S.", "Wolff", "1", "1Department", "of", "Preventive", "Medicine,", "2Department", "of", "Microbiology,", "and", "3Department", "of", "Genetics", "and", "Genomic", "Sciences,", "Mount", "Sinai", "School", "of", "Medicine,", "New", "York,", "New", "York,", "USA;", "4School", "of", "Public", "Health,", "Emory", "University,", "Atlanta,", "Georgia,", "USA;", "5Division", "of", "Nutritional", "Sciences,", "College", "of", "Human", "Ecology,", "Cornell", "University,", "Ithaca,", "New", "York,", "USA", "Background", ":", "Prenatal", "exposure", "to", "organophosphate", "pesticides", "has", "been", "shown", "to", "negatively", "affect", "child", "neurobehavioral", "development.", "Paraoxonase", "1", "(PON1)", "is", "a", "key", "enzyme", "in", "the", "metabolism", "of", "organophosphates.", "o", "Bjectiv", ":", "We", "examined", "the", "relationship", "between", "biomarkers", "of", "organophosphate", "exposure,", "PON1,", "and", "cognitive", "development", "at", "ages", "12", "and", "24", "months", "and", "6–9", "years.", "Methods", ":", "hTe", "Mount", "Sinai", "Children’s", "Environmental", "Health", "Study", "enrolled", "a", "multiethnic", "prena", "-", "tal", "population", "in", "New", "York", "City", "between", "1998", "and", "2002", "(n", "=", "404).", "hTird-", "trimester", "maternal", "urine", "samples", "were", "collected", "and", "analyzed", "for", "organophosphate", "metabolites", "(n", "=", "360).", "Prenatal", "maternal", "blood", "was", "analyzed", "for", "PON1", "activity", "and", "genotype.", "Children", "returned", "for", "neurodevelopment", "assessments", "ages", "12", "months", "(n", "=", "200),", "24", "months", "(n", "=", "276),", "and", "6–9", "(n", "=", "169)", "years", "of", "age.", "r", "esult", ":", "Prenatal", "total", "dialkylphosphate", "metabolite", "level", "was", "associated", "with", "a", "decrement", "in", "mental", "development", "at", "12", "months", "among", "blacks", "and", "Hispanics.", "hTese", "associations", "appeared", "to", "be", "enhanced", "among", "children", "of", "mothers", "who", "carried", "the", "PON1", "Q192R", "QR/RR", "genotype.", "In", "later", "childhood,", "increasing", "prenatal", "total", "dialkyl-", "and", "dimethylphosphate", "metabolites", "were", "associated", "with", "decrements", "in", "perceptual", "reasoning", "in", "the", "maternal", "PON1", "Q192R", "QQ", "genotype,", "which", "imparts", "slow", "catalytic", "activity", "for", "chlorpyrifos", "oxon,", "with", "a", "monotonic", "trend", "consistent", "with", "greater", "decrements", "with", "increasing", "prenatal", "exposure.", "words", "c", "onclusion", ":", "Our", "findings", "suggest", "that", "prenatal", "exposure", "to", "organophosphates", "is", "negatively", "associated", "with", "cognitive", "development,", "particularly", "perceptual", "reasoning,", "with", "evidence", "of", "effects", "beginning", "at", "12", "months", "and", "continuing", "through", "early", "childhood.", "PON1", "may", "be", "an", "important", "sus-", "ceptibility", "factor", "for", "these", "deleterious", "effects.", "k", "ey", ":", "environmental", "exposures,", "IQ,", "mental", "development,", "organophosphates,", "pesticides.", "Environ", "Health", "Perspect", "119:1182–1188", "(2011).", "doi:10.1289/ehp.1003183", "[Online", "21", "April", "2011]", "Before", "2001,", "residential", "exposure", "to", "organo-", "phosphate", "pesticides,", "including", "chlorpyri-", "fos", "and", "diazinon,", "was", "common,", "even", "in", "an", "urban", "setting.", "Insecticides", "are", "used", "in", "mul-", "tiunit,", "inner-city", "dwellings", "to", "control", "insect", "and", "rodent", "infestations", "within", "apartments,", "in", "common", "spaces,", "and", "around", "building", "exte-", "riors.", "Despite", "the", "voluntary", "cancellation", "of", "residential", "use", "registrations", "of", "chlorpyrifos", "and", "diazinon", "in", "2001", "and", "2004,", "respectively,", "between", "June", "2005", "and", "March", "2006,", "78%", "of", "randomly", "selected", "nationally", "representative", "U.S.", "homes", "had", "measurable", "levels", "of", "chlorpy-", "rifos,", "and", "35%", "had", "measurable", "levels", "of", "diazi-", "non,", "suggesting", "ongoing", "residential", "exposure", "(Stout", "et", "al.", "2009).", "Additionally,", "exposure", "to", "organophosphate", "pesticides", "or", "their", "residues", "may", "occur", "via", "consumption", "of", "conventionally", "grown", "fruits", "and", "vegetables", "(Lu", "et", "al.", "2008).", "Neurodevelopmental", "consequences", "of", "human", "exposure", "to", "organophosphate", "pes-", "ticides", "have", "been", "demonstrated", "in", "urban", "(Bouchard", "et", "al.", "2010;", "Engel", "et", "al.", "2007;", "Rauh", "et", "al.", "2006),", "rural", "(Eskenazi", "et", "al.", "2007,", "2010;", "Young", "et", "al.", "2005),", "and", "occupational", "settings", "(Handal", "et", "al.", "2008;", "Roldan-Tapia", "et", "al.", "2006),", "some", "of", "which", "specifically", "involve", "prenatal", "exposure", "(Engel", "et", "al.", "2007;", "Eskenazi", "et", "al.", "2007,", "2010;", "Marks", "et", "al.", "2010;", "1182", "Rauh", "et", "al.", "2006;", "Young", "et", "al.", "2005).", "We", "have", "previously", "reported", "that", "prenatal", "pes-", "ticide", "exposure", "was", "associated", "with", "smaller", "head", "circumference", "(Berkowitz", "et", "al.", "2004)", "and", "more", "abnormal", "primitive", "reflexes", "(Engel", "et", "al.", "2007),", "particularly", "among", "children", "of", "mothers", "with", "low", "paraoxonase", "1", "(PON1)", "activity.", "PON1", "is", "a", "key", "enzyme", "in", "the", "metab-", "olism", "of", "organophosphate", "pesticides", "(Costa", "et", "al.", "1999)", "and", "has", "been", "shown", "to", "be", "a", "bio-", "marker", "of", "susceptibility", "to", "the", "toxic", "effects", "of", "organophophate", "pesticides,", "both", "in", "animals", "(Costa", "et", "al.", "2003)", "and", "in", "humans", "(Engel", "et", "al.", "2007;", "Eskenazi", "et", "al.", "2010;", "Lee", "et", "al.", "2003;", "Nielsen", "et", "al.", "2010).", "We", "undertook", "an", "investigation", "of", "the", "impact", "of", "prenatal", "organophosphate", "metabo-", "lite", "biomarker", "levels", "in", "relation", "to", "cognitive", "development", "at", "multiple", "times", "in", "childhood,", "while", "considering", "the", "modifying", "influence", "of", "maternal", "and", "child", "PON1", "genotype", "and", "enzymatic", "activity.", "Methods", "The", "Mount", "Sinai", "Children’s", "Environmental", "Health", "Cohort", "study", "is", "a", "prospective", "multieth-", "nic", "cohort", "that", "enrolled", "primiparous", "women", "who", "presented", "for", "prenatal", "care", "with", "single-", "ton", "pregnancies", "at", "the", "Mount", "Sinai", "prenatal", "clinic", "and", "two", "private", "practices", "and", "were", "sub-", "sequently", "delivered", "at", "Mount", "Sinai", "Hospital", "between", "May", "1998", "and", "July", "2001.", "The", "target", "population", "was", "healthy,", "first-born", "infants", "with", "no", "underlying", "health", "conditions", "that", "might", "independently", "result", "in", "serious", "neurodevelop-", "mental", "impairment.", "Therefore,", "women", "were", "considered", "eligible", "if", "they", "were", "primiparous", "with", "singleton", "pregnancies,", "had", "no", "underlying", "health", "conditions", "that", "might", "predispose", "them", "to", "have", "serious", "complications", "of", "pregnancy", "that", "might", "result", "in", "an", "at-risk", "infant,", "and", "ultimately", "delivered", "infants", "that", "were", "neither", "extremely", "preterm", "nor", "very", "low", "birth", "weight.", "(Berkowitz", "et", "al.", "2003,", "2004).", "Mother–infant", "pairs", "were", "recruited", "early", "in", "pregnancy", "(n", "=", "479).", "In", "brief,", "subsequent", "to", "delivery,", "75", "women", "were", "excluded", "because", "of", "medical", "complications,", "very", "premature", "births", "(delivery", "before", "32", "com-", "pleted", "weeks", "or", "birth", "weight", "<", "1,500", "g),", "deliv-", "ery", "of", "an", "infant", "with", "a", "birth", "defect,", "inability", "to", "collect", "biologic", "specimens", "before", "birth,", "change", "of", "hospital", "or", "residence", "outside", "New", "York", "City,", "or", "refusal", "to", "continue", "to", "participate,", "leav-", "ing", "404", "women–infant", "pairs", "in", "the", "final", "cohort", "(Berkowitz", "et", "al.", "2004).", "We", "administered", "a", "questionnaire", "to", "par-", "ticipants", "during", "their", "third", "trimester", "of", "preg-", "nancy", "to", "obtain", "information", "on", "environmental", "exposures,", "sociodemographic", "characteristics,", "Address", "correspondence", "to", "S.", "Engel,", "Department", "of", "Epidemiology,", "Gillings", "School", "of", "Global", "Public", "Health,", "University", "of", "North", "Carolina–Chapel", "Hill,", "2104C", "McGavran-Greenberg,", "Box", "7435,", "Chapel", "Hill,", "NC", "27599-7435", "USA.", "Telephone:", "(919)", "966-", "7435.", "Fax:", "(919)", "966-2089.", "E-mail:", "Stephanie.", "Engel@unc.edu", "Supplemental", "Material", "is", "available", "online", "(doi:10.1289/ehp.1003183", "via", "http://dx.doi.org/).", "We", "gratefully", "acknowledge", "the", "tremendous", "contri-", "butions", "of", "G.", "Berkowitz", "in", "developing", "the", "New", "York", "Children’s", "Environmental", "Health", "cohort.", "We", "also", "thank", "M.", "Lievano,", "S.", "Meisel,", "K.", "Ireland,", "Z.", "Liu,", "and", "K.", "Nichols", "for", "valuable", "assistance.", "This", "research", "was", "supported", "by", "National", "Institute", "for", "Environmental", "Health", "Sciences/U.S.", "Environmental", "Protection", "Agency", "Children’s", "Center", "grants", "ES09584", "and", "R827039,", "the", "New", "York", "Community", "Trust,", "and", "the", "Agency", "for", "Toxic", "Substances", "and", "Disease", "Registry/", "Centers", "for", "Disease", "Control", "and", "Prevention", "(CDC)/", "Association", "of", "Teachers", "of", "Preventive", "Medicine.", "The", "findings", "and", "conclusions", "in", "this", "report", "are", "those", "of", "the", "authors", "and", "do", "not", "necessarily", "represent", "the", "views", "of", "the", "CDC.", "The", "authors", "declare", "they", "have", "no", "actual", "or", "potential", "competing", "financial", "interests.", "Received", "7", "November", "2010;", "accepted", "5", "April", "2011.", "ovlume", "119", "|", "number", "8", "|", "August", "2011", "•", "Environmental", "Health", "Perspectives" ]

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[ "Greggi", "et", "al.", "Scoliosis", "2010,", "5:24", "http://www.scoliosisjournal.com/content/5/1/24", "C", "A", "S", "E", "R", "E", "P", "O", "R", "T", "Open", "Access", "Surgical", "treatment", "of", "scoliosis", "in", "a", "rare", "disease:", "arthrogryposis", "Tiziana", "Greggi1*,", "Konstantinos", "Martikos1,", "Emanuela", "Pipitone1,", "Francesco", "Lolli1,", "Francesco", "Vommaro1,", "Elena", "Maredi1", ",", "Stefano", "Cervellati2,", "Mario", "Di", "Silvestre1", "Abstract", "Background:", "The", "reported", "incidence", "of", "scoliosis", "in", "arthrogryposis", "varies", "from", "30%", "to", "67%", "and,", "in", "most", "cases,", "the", "curves", "progress", "rapidly", "and", "become", "stiff", "from", "early", "age.", "The", "authors", "report", "six", "cases", "of", "scoliosis", "in", "arthrogryposis", "to", "assess", "the", "role", "of", "surgical", "treatment.", "Methods:", "Six", "cases", "(3", "males,", "3", "females;", "mean", "age", "at", "surgery", "13.2", "years)", "with", "arthrogryposis", "multiplex", "congenita", "associated", "with", "the", "characteristic", "amyoplasia", "were", "reviewed:", "they", "were", "operated", "on", "for", "scoliosis", "at", "the", "authors’", "Spine", "Surgery", "Department", "between", "1987", "and", "2008.", "Surgery", "was", "performed", "using", "the", "Harrington-Luque", "instrumentation", "(2", "cases),", "the", "Luque", "system", "(1),", "a", "hybrid", "segmental", "technique", "with", "hooks", "and", "screws", "(1)", "and", "spinal", "anchoring", "with", "pedicle", "screws", "(2).", "Results:", "The", "patients", "were", "clinically", "and", "radiologically", "reviewed", "at", "a", "mean", "follow-up", "of", "4.2", "years,", "±", "2.7", "(range,", "1", "to", "9", "years).", "Three", "minor", "postoperative", "complications", "were", "encountered;", "a", "long-term", "pulmonary", "complication", "was", "seen", "in", "one", "case", "after", "reintervention", "and", "was", "successfully", "resolved", "after", "10", "days.", "Surgery", "was", "successful", "in", "the", "other", "5", "cases,", "where", "solid", "arthrodesis", "was", "achieved", "and", "no", "significant", "curve", "progression", "was", "observed", "at", "follow-", "up.", "Conclusions:", "The", "experience", "acquired", "with", "the", "present", "case", "series", "leads", "the", "authors", "to", "assert", "that", "prompt", "action", "should", "be", "taken", "when", "treating", "such", "aggressive", "forms", "of", "scoliosis.", "In", "case", "of", "mild", "spinal", "deformities", "in", "arthrogryposis,", "brace", "treatment", "should", "be", "attempted,", "the", "evolution", "of", "the", "curves", "being", "unpredictable;", "however,", "when", "the", "curve", "exceeds", "40°", "and", "presents", "with", "marked", "hyperkyphosis,", "hyperlordosis", "or", "pelvic", "obliquity,", "surgery", "should", "not", "be", "delayed.", "Introduction", "The", "term", "“arthrogryposis”", "was", "first", "used", "by", "Stern", "early", "in", "1923", "[1]", "to", "define", "the", "characteristic", "clinical", "appear-", "ance", "of", "three", "children", "affected", "with", "multiple", "congenital", "contractures", "(MCC)", "that", "produced", "symmetrical", "motion", "limitation", "of", "proximal", "and", "distal", "joints.", "The", "syndrome", "was", "first", "described", "by", "Otto", "in", "1841,", "under", "the", "term", "“congenital", "myodystrophy”.", "In", "1982", "Hall", "et", "al", "intro-", "duced", "the", "term", "“amyoplasia”,", "which", "describes", "the", "most", "common", "type", "of", "arthrogryposis,", "characterized", "by", "quadri-", "melic", "involvement", "and", "replacement", "of", "skeletal", "muscle", "by", "dense", "fibrous", "tissue", "and", "fat", "[2].", "At", "present", "at", "least", "nine", "different", "types", "of", "amyoplasia", "are", "recognized.", "*", "Correspondence:", "tiziana.greggi@ior.it", "1Spine", "Surgery", "Division,", "Rizzoli", "Orthopaedic", "Institute,", "Bologna,", "Italy", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "Nowadays", "the", "term", "arthrogryposis", "is", "commonly", "used", "as", "a", "generic", "expression", "to", "describe", "the", "typical", "clinical", "appearance", "of", "children", "with", "congenital", "non", "progressive", "MCCs;", "however,", "it", "does", "not", "define", "a", "specific", "pathologi-", "cal", "entity,", "since", "it", "represents", "the", "phenotypical", "manifesta-", "tion", "of", "more", "than", "150", "distinct", "entities", "[3],", "such", "as", "myelomeningocele,", "Larsen", "syndrome,", "multiple", "ptery-", "gium", "syndrome", "(Escobar", "syndrome),", "Freeman-Sheldon", "syndrome", "(whistling", "face", "syndrome),", "Beals", "contractural", "arachnodactyly,", "sacral", "agenesis,", "diastrophic", "dysplasia,", "metatropic", "dysplasia,", "thrombocytopenia-absent", "radius", "(TAR)", "syndrome,", "Steinert", "myotonic", "dystrophy,", 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"biochemical", "implications", "has", "been", "diminished", "and", "often", "eliminated", "from", "the", "pre-", "and", "post-doctoral", "programs.", "Interpretations", "and", "conclusions", "of", "alterations", "in", "cellular", "enzyme", "activity", "and", "associated", "metabolic", "pathways", "based", "on", "genetic/proteomic", "changes", "can", "and", "will", "result", "in", "misrepresentation", "of", "important", "metabolic", "implications", "in", "malignancy", "and", "other", "diseases.", "It", "is", "essential", "that", "the", "genetic/proteomic", "studies", "be", "coupled", "to", "biochemical/metabolic", "cellular", "events", "to", "satisfy", "the", "axiom:", "\"genetic", "transformations", "and", "proteomic", "alterations", "will", "have", "little", "relevancy", "to", "disease", "processes", "if", "the", "genetic/proteomic", "alterations", "are", "not", "manifested", "in", "altered", "and", "impaired", "cellular", "and", "metabolic", "function\".", "The", "appropriate", "marriage", "of", "molecular", "genetics/proteomics", "with", "the", "regulation", "of", "cellular", "intermediary", "metabolism", "will", "provide", "new", "revelations", "and", "understanding", "of", "malignancy", "that", "could", "not", "be", "achieved", "in", "earlier", "generations.", "Background", "Metabolic", "transformations", "of", "malignant", "cells", "are", "essential", "to", "the", "development", "and", "progression", "of", "all", "cancers.", "That", "tumor", "cells", "exhibit", "metabolic", "characteristics", "that", "are", "markedly", "different", "from", "their", "precursor", "sane", "cells", "has", "been", "well", "established", "since", "the", "original", "classic", "studies", "of", "Warburg", "et", "al", "reported", "in", "1926", "[1].", "While", "an", "altered", "metabolism", "is", "not", "the", "cause", "of", "malignancy,", "without", "the", "required", "metabolic", "transformation,", "the", "neoplastic", "cell", "cannot", "successfully", "elicit", "its", "malignant", "capabilities.", "The", "Page", "1", "of", "5", "(page", "number", "not", "for", "citation", "purposes)" ]

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[ "JCB:", "ARTICLE", "Y", "G", "O", "L", "O", "I", "B", "L", "L", "E", "C", "F", "O", "L", "A", "N", "R", "U", "O", "J", "E", "H", "T", "Spectrin", "functions", "upstream", "of", "ankyrin", "in", "a", "spectrin", "cytoskeleton", "assembly", "pathway", "Amlan", "Das,", "Christine", "Base,", "Srilakshmi", "Dhulipala,", "and", "Ronald", "R.", "Dubreuil", "Program", "in", "Cell", "&", "Developmental", "Biology,", "Department", "of", "Biological", "Sciences,", "University", "of", "Illinois", "at", "Chicago,", "Chicago,", "IL", "60607", "P", "ankyrin", "in", "a", "pathway", "of", "assembly", "and", "function", "in", "revailing", "models", "place", "spectrin", "downstream", "of", "polarized", "cells.", "We", "used", "a", "transgene", "rescue", "strat-", "egy", "in", "Drosophila", "melanogaster", "to", "test", "contributions", "of", "four", "specific", "functional", "sites", "in", "β", "spectrin", "to", "its", "assembly", "and", "function.", "(1)", "Removal", "of", "the", "pleckstrin", "homology", "domain", "blocked", "polarized", "spectrin", "assembly", "in", "midgut", "epithelial", "cells", "and", "was", "usually", "lethal.", "(2)", "A", "point", "mutation", "in", "the", "tetramer", "formation", "site,", "modeled", "after", "a", "hereditary", "elliptocytosis", "mutation", "in", "human", "erythrocyte", "spectrin,", "had", "no", "detectable", "effect", "on", "function.", "(3)", "Replacement", "of", "repetitive", "segments", "4–11", "of", "β", "spectrin", "with", "repeats", "2–9", "of", "α", "spectrin", "abolished", "function", "but", "did", "not", "prevent", "polarized", "assembly.", "(4)", "Removal", "of", "the", "putative", "ankyrin-", "binding", "site", "had", "an", "unexpectedly", "mild", "phenotype", "with", "no", "detectable", "effect", "on", "spectrin", "targeting", "to", "the", "plasma", "membrane.", "The", "results", "suggest", "an", "alternate", "pathway", "in", "which", "spectrin", "directs", "ankyrin", "assembly", "and", "in", "which", "some", "important", "functions", "of", "spectrin", "are", "independent", "of", "ankyrin.", "Introduction", "The", "protein", "spectrin", "is", "the", "defining", "element", "of", "a", "nearly", "ubiqui-", "tous", "submembrane", "protein", "network", "in", "animal", "cells.", "The", "spectrin", "supergene", "family", "includes", "a", "diverse", "set", "of", "proteins", "that", "share", "two", "main", "structural", "features:", "the", "spectrin", "repeat", "and", "a", "calponin-", "homology", "actin-binding", "domain", "(for", "review", "see", "Roper", "et", "al.,", "2002).", "The", "“immediate", "family”", "of", "the", "founding", "member", "spec-", "trin", "includes", "a", "group", "of", "closely", "related", "gene", "products", "that", "as-", "semble", "as", "tetramers", "of", "α", "and", "β", "subunits,", "that", "associate", "with", "specific", "subdomains", "of", "the", "plasma", "membrane", "in", "many", "cells,", "and", "that", "share", "the", "ability", "to", "form", "cross-linked", "arrays", "with", "actin.", "Most,", "but", "not", "all,", "of", "these", "family", "members", "are", "linked", "to", "plasma", "membrane", "proteins", "via", "the", "adaptor", "ankyrin", "(for", "review", "see", "Bennett", "and", "Baines,", "2001).", "The", "functions", "of", "several", "spectrins", "and", "ankyrins", "have", "been", "tested", "in", "gene", "knockout", "experiments.", "One", "consistently", "observed", "effect", "is", "that", "loss", "of", "spectrin", "or", "ankyrin", "leads", "to", "a", "failure", "of", "in-", "teracting", "membrane", "proteins", "to", "accumulate", "at", "the", "appropriate", "site.", "In", "the", "most", "extreme", "case,", "RNAi", "knockdown", "of", "ankyrin-G", "in", "cultured", "bronchial", "epithelial", "cells", "led", "to", "the", "loss", "of", "an", "entire", "domain", "of", "the", "plasma", "membrane", "(Kizhatil", "and", "Bennett,", "2004).", "However,", "in", "other", "knockout", "studies,", "loss", "of", "spectrin", "or", "ankyrin", "led", "to", "more", "subtle", "effects", "in", "which", "specific", "interacting", "mem-", "Correspondence", "to", "Ronald", "R.", "Dubreuil:", "ron@uic.edu", "Abbreviations", "used", "in", "this", "paper:", "HS,", "heat", "shock;", "PH,", "pleckstrin", "homology;", "PtdIns,", "phosphatidylinositol.", "The", "online", "version", "of", "this", "article", "contains", "supplemental", "material.", "©", "The", "Rockefeller", "University", "Press", "$8.00", "The", "Journal", "of", "Cell", "Biology,", "Vol.", "175,", "No.", "2,", "October", "23,", "2006", "325–335", "http://www.jcb.org/cgi/doi/10.1083/jcb.200602095", "brane", "proteins", "were", "lost", "from", "the", "domain", "normally", "occupied", "by", "the", "spectrin", "cytoskeleton.", "For", "example,", "loss", "of", "β", "spectrin", "in", "Drosophila", "melanogaster", "led", "to", "loss", "of", "Na,K", "ATPase", "from", "the", "basolateral", "domain", "of", "epithelial", "cells", "(Dubreuil", "et", "al.,", "2000);", "loss", "of", "βIV", "spectrin", "in", "mouse", "brain", "led", "to", "loss", "of", "voltage-", "dependent", "sodium", "channels", "from", "axon", "initial", "segments", "and", "the", "node", "of", "Ranvier", "(Komada", "and", "Soriano,", "2002);", "knockouts", "of", "ankyrin-G", "and", "-B", "in", "mouse", "brain", "led", "to", "reduced", "levels", "of", "voltage-dependent", "sodium", "channels", "and", "L1", "family", "cell", "adhe-", "sion", "molecules", "(Scotland", "et", "al.,", "1998;", "Zhou", "et", "al.,", "1998;", "Jenkins", "and", "Bennett,", "2001).", "Recent", "studies", "also", "indicate", "an", "important", "role", "for", "the", "spectrin", "cytoskeleton", "in", "muscle", "(for", "review", "see", "Mohler", "and", "Bennett,", "2005).", "Defects", "in", "ankyrin-B", "are", "associated", "with", "human", "cardiac", "arryhthmia", "and", "sudden", "cardiac", "death", "(Mohler", "et", "al.,", "2003).", "Loss", "of", "ankyrin-B", "leads", "to", "a", "concomitant", "loss", "of", "Na,K", "ATPase,", "Na,Ca", "exchangers", "and", "inositol", "triphosphate", "receptors", "and", "perhaps", "other", "proteins", "from", "their", "normal", "cellular", "sites", "(Mohler", "et", "al.,", "2004b).", "A", "similar", "cardiac", "defect", "in", "humans", "re-", "sults", "from", "a", "mutation", "of", "the", "voltage-dependent", "sodium", "channel", "in", "its", "ankyrin-G–binding", "site", "(Mohler", "et", "al.,", "2004a).", "Although", "the", "consequences", "of", "loss", "of", "function", "are", "becom-", "ing", "clear,", "the", "cues", "that", "trigger", "assembly", "of", "the", "spectrin", "cytoskel-", "eton", "within", "specialized", "membrane", "domains", "remain", "unknown.", "Evidence", "placing", "ankyrin", "upstream", "of", "spectrin", "in", "the", "assembly", "pathway", "has", "come", "from", "studies", "of", "cultured", "cardiac", "myocytes", "from", "ankyrin-B", "knockout", "mice.", "An", "engineered", "ankyrin-B", "JCB", "325" ]

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[ "Kim", "et", "al.", "Lipids", "in", "Health", "and", "Disease", "2012,", "11:43", "http://www.lipidworld.com/content/11/1/43", "R", "E", "S", "E", "A", "R", "C", "H", "Open", "Access", "Omega-3", "index", "and", "smoking", "in", "patients", "with", "acute", "ST-elevation", "myocardial", "infarction", "taking", "statins:", "a", "case-control", "study", "in", "Korea", "Young", "Joo", "Kim1†,", "Dong", "Wook", "Jeong2†,", "Jeong", "Gyu", "Lee1†,", "Han", "Cheol", "Lee3,", "Sang", "Yeoup", "Lee2,4,6*,", "Yun", "Jin", "Kim1,", "Yu", "Hyeon", "Yi1,", "Yong", "Soon", "Park5,", "Young", "Hye", "Cho2,", "Mi", "Jin", "Bae1", "and", "Eun", "Jung", "Choi2", "Abstract", "Background:", "n-3", "fatty", "acids", "and", "lifestyle", "also", "are", "closely", "related", "to", "risk", "of", "CVD.", "Most", "Koreans", "have", "higher", "fish", "consumption", "than", "people", "of", "Western", "populations.", "However,", "little", "is", "known", "about", "the", "recommended", "value", "of", "omega-3", "index", "in", "Korean", "patients", "with", "acute", "ST-elevation", "myocardial", "infarction", "(STEMI)", "taking", "statins.", "Here,", "we", "tested", "the", "hypothesis", "that", "lower", "omega-3", "fatty", "acids", "and/or", "smoking", "are", "associated", "with", "acute", "STEMI,", "even", "though", "patients", "with", "dyslipidemia", "who", "were", "taking", "statins", "and", "who", "attained", "their", "LDL-C", "goals.", "Methods:", "We", "conducted", "a", "case-control", "study", "in", "which", "omega-3", "fatty", "acids", "and", "lifestyle", "factors", "were", "determined", "in", "24", "consecutive", "Korean", "patients", "taking", "statins", "with", "angiographically", "confirmed", "acute", "STEMI", "and", "68", "healthy", "controls", "without", "acute", "STEMI.", "The", "omega-3", "index", "was", "calculated", "by", "the", "sum", "of", "eicosapentaenoic", "acid", "and", "docosahexaenoic", "acid", "in", "erythrocyte", "membranes.", "Multivariable", "adjusted", "regression", "analysis", "was", "used", "to", "assess", "independent", "associations", "between", "acute", "STEMI,", "omega-3", "index,", "and", "lifestyle", "factors", "after", "adjusting", "for", "age,", "sex,", "and", "body", "mass", "index", "(BMI).", "Results:", "The", "mean", "age", "of", "total", "subjects", "was", "59.9", "years,", "and", "57.6%", "of", "the", "subjects", "were", "male.", "The", "omega-3", "index", "was", "significantly", "lower", "in", "cases", "(8.83%)", "than", "controls", "(11.13%;", "P", "<", "0.001);", "however,", "total", "trans-fatty", "acids", "were", "not", "different", "between", "the", "two", "groups.", "The", "omega-3", "index", "was", "inversely", "associated", "with", "odds", "for", "being", "a", "case", "(OR", "0.16", "(95%", "CI", "0.03-1.14);", "P", "=", "0.047),", "while", "smoking", "was", "positively", "associated", "with", "odds", "for", "being", "a", "case", "(OR", "6.67", "(95%", "CI", "1.77-25.23);", "P", "=", "0.005)", "after", "adjusting", "for", "all", "confounding", "variables.", "Conclusion:", "This", "study", "shows", "that", "relative", "to", "controls,", "acute", "STEMI", "cases", "are", "more", "likely", "to", "be", "smokers", "and", "to", "have", "a", "lower", "omega-3", "index,", "even", "though", "the", "cases", "were", "taking", "statins.", "An", "omega-3", "index", "of", "at", "least", "11%", "and", "abstinence", "from", "smoking", "are", "associated", "with", "cardioprotection", "for", "Koreans.", "Keywords:", "Omega-3", "index,", "Smoking,", "Myocardial", "infarction,", "Fatty", "acid,", "Fish", "oil", "Background", "Cardiovascular", "disease", "(CVD)", "is", "one", "of", "the", "most", "com-", "mon", "causes", "of", "mortality", "and", "morbidity", "across", "the", "globe", "[1].", "Studies", "that", "have", "focused", "on", "the", "prevention", "of", "cor-", "onary", "heart", "disease", "(CHD)", "have", "reported", "that", "lifestyle", "modifications", "such", "as", "smoking", "cessation,", "adequate", "alco-", "hol", "consumption,", "exercise,", "stress", "reduction,", "weight", "*", "Correspondence:", "saylee@pnu.edu", "†", "Contributed", "equally", "2Family", "Medicine", "Clinic", "and", "Research", "Institute", "of", "Convergence", "of", "Biomedical", "Science", "and", "Technology,", "Pusan", "National", "University", "Yangsan", "Hospital,", "Yangsan,", "South", "Korea", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "control,", "and", "diet", "are", "preventable", "factors", "of", "CVD", "[2-5].", "Dietary", "n-3", "polyunsaturated", "fatty", "acids", "(PUFA)", "such", "as", "eicosapentaenoic", "acid", "(EPA)", "and", "docosahexaenoic", "acid", "(DHA),", "which", "are", "found", "in", "fish", "meat", "and", "fish", "oil,", "have", "also", "been", "shown", "to", "protect", "against", "CVD", "during", "the", "past", "three", "decades", "[6].", "Since", "the", "first", "observation", "of", "Green-", "land", "Eskimos", "in", "1970,", "epidemiologic", "studies", "have", "sug-", "gested", "that", "n-3", "PUFA", "may", "play", "a", "role", "in", "the", "prevention", "of", "CVD", "[7].", "Several", "large-scale", "intervention", "studies", "have", "reported", "that", "n-3", "PUFA", "from", "fish", "or", "fish-oil", "supple-", "ments", "reduces", "the", "rates", "of", "all-cause", "mortality,", "cardiac", "and", "sudden", "death,", "and", "possibly", "stroke", "[8].", "In", "addition,", "©", "2012", "Kim", "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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[ "REVIEW", "ARTICLE", "published:", "27", "July", "2011", "doi:", "10.3389/fphys.2011.00041", "Similar", "structures", "but", "different", "roles", "–", "an", "updated", "perspective", "on", "TLR", "structures", "Balachandran", "Manavalan,", "Shaherin", "Basith", "and", "Sangdun", "Choi*", "Department", "of", "Molecular", "Science", "and", "Technology,", "Ajou", "University,", "Suwon,", "South", "Korea", "Edited", "by:", "Masa", "Tsuchiya,", "Keio", "University,", "Japan", "Reviewed", "by:", "Vladimir", "N.", "Uversky,", "University", "of", "South", "Florida,", "USA", "Tiandi", "Wei,", "Shandong", "University,", "China", "*Correspondence:", "Sangdun", "Choi,", "Department", "of", "Molecular", "Science", "and", "Technology,", "Ajou", "University,", "Suwon", "443-749,", "South", "Korea.", "e-mail:", "sangdunchoi@ajou.ac.kr", "Toll-like", "receptors", "(TLRs)", "are", "pattern", "recognition", "receptors", "that", "recognize", "conserved", "struc-", "tures", "in", "pathogens,", "trigger", "innate", "immune", "responses,", "and", "prime", "antigen-specific", "adaptive", "immunity.", "Elucidation", "of", "crystal", "structures", "of", "TLRs", "interacting", "with", "their", "ligands", "such", "as", "TLR1-2", "with", "triacylated", "lipopeptide,", "TLR2-6", "with", "diacylated", "lipopeptide,", "TLR4–MD-2", "with", "LPS,", "and", "TLR3", "with", "double-stranded", "RNA", "(dsRNA)", "have", "enabled", "an", "understanding", "of", "the", "initiation", "of", "TLR", "signaling.", "Agonistic", "ligands", "such", "as", "LPS,", "dsRNA,", "and", "lipopeptides", "induce", "“m”", "shaped", "TLR", "dimers", "in", "which", "C-termini", "converge", "at", "the", "center.", "Such", "central", "conver-", "gence", "is", "necessary", "to", "bring", "the", "two", "intracellular", "receptor", "TIR", "domains", "closer", "together", "and", "promote", "their", "dimerization,", "which", "serves", "as", "an", "essential", "step", "in", "downstream", "signaling.", "In", "this", "review,", "we", "summarize", "TLR", "ECD", "structures", "that", "have", "been", "reported", "to", "date", "with", "special", "emphasis", "on", "ligand", "recognition", "and", "activation", "mechanism.", "Keywords:", "innate", "immunity,", "ligand,", "myeloid", "differentiation", "factor", "88,Toll-like", "receptor", "INTRODUCTION", "The", "Toll-like", "receptor", "(TLR)", "protein", "family", "plays", "an", "important", "role", "in", "the", "innate", "immune", "system", "by", "recognizing", "common", "struc-", "tural", "patterns", "in", "diverse", "microbial", "molecules", "(Gay", "and", "Gangloff,", "2007).", "TLRs", "are", "type", "I", "transmembrane", "glycoproteins", "character-", "ized", "by", "the", "presence", "of", "an", "extracellular", "domain", "(ectodomain;", "ECD)", "containing", "leucine", "rich", "repeats", "(LRRs),", "which", "is", "primarily", "responsible", "for", "mediating", "ligand", "recognition,", "followed", "by", "a", "single", "transmembrane", "helix", "and", "an", "intracellular", "Toll-like/interleukin-1", "(IL-1)", "receptor", "(TIR)", "domain", "that", "is", "responsible", "for", "downstream", "signaling.", "To", "date,", "10", "and", "12", "functional", "TLRs", "have", "been", "iden-", "tified", "in", "humans", "and", "mice,", "respectively.", "TLR1-9", "is", "conserved", "in", "both", "species;", "however,", "mouse", "TLR10", "is", "not", "functional", "because", "of", "a", "retrovirus", "insertion,", "and", "TLR11-13", "have", "been", "lost", "from", "the", "human", "genome", "(Kawai", "and", "Akira,", "2010).", "“Toll”", "was", "first", "identi-", "fied", "as", "a", "protein", "important", "in", "the", "early", "stages", "of", "development", "in", "Drosophila.", "Later,", "it", "was", "discovered", "that", "Toll", "signals", "to", "Dorsal", "(like", "mammalian", "NF-κB)", "and", "is", "involved", "in", "the", "coordination", "of", "anti-", "fungal", "and", "antibacterial", "responses", "(Rosetto", "et", "al.,", "1995;", "Lemaitre", "et", "al.,", "1996).", "The", "TLR", "family", "can", "be", "largely", "divided", "into", "two", "subgroups,", "extracellular", "and", "intracellular,", "depending", "on", "their", "cellular", "local-", "ization.", "TLR1,", "2,", "4,", "5,", "6,", "and", "10", "are", "largely", "localized", "on", "the", "cell", "surface", "to", "recognize", "PAMPs.", "Conversely,", "TLR3,", "7,", "8,", "and", "9", "are", "localized", "in", "intracellular", "organelles", "such", "as", "endosomal/lysosomal", "compartments", "and", "the", "endoplasmic", "reticulum", "(ER).", "Among", "the", "TLRs,", "the", "ligand", "(lipopolysaccharide;", "LPS)", "of", "TLR4", "was", "first", "iden-", "tified", "by", "genetic", "studies", "(Lemaitre", "et", "al.,", "1996).", "Lipopeptides", "or", "lipoproteins", "are", "recognized", "by", "TLR2", "in", "complex", "with", "TLR1", "or", "6,", "while", "viral", "double-stranded", "RNA", "(dsRNA)", "is", "recognized", "by", "TLR3,", "flagellin", "is", "recognized", "by", "TLR5,", "single-stranded", "RNA", "is", "recognized", "by", "TLR7", "and", "8,", "and", "host-", "or", "pathogen-derived", "DNA", "is", "recog-", "nized", "by", "TLR9.", "In", "addition", "to", "known", "pathogen/microbial", "derived", "ligands,", "TLR", "also", "recognizes", "the", "endogenous", "ligands", "(produced", "by", "stressed", "or", "damaged", "cells)", "and", "synthetic", "ligands", "listed", "in", "Table", "1.", "The", "common", "mechanism", "of", "TLR", "signaling", "is", "that", "interaction", "of", "an", "agonist", "with", "the", "ECD", "either", "induces", "the", "formation", "of", "a", "recep-", "tor", "dimer,", "or", "changes", "the", "conformation", "of", "a", "pre-existing", "dimer", "(Latz", "et", "al.,", "2007;", "Zhu", "et", "al.,", "2009)", "in", "such", "a", "way", "that", "it", "brings", "two", "intracellular", "TIR", "domains", "of", "the", "TLRs", "to", "interact", "physically.", "This", "simple", "rearrangement", "serves", "as", "a", "nucleating", "act", "for", "the", "recruitment", "of", "downstream", "signaling", "adapter", "proteins", "(Jin", "and", "Lee,", "2008).", "Sig-", "naling", "cascades", "via", "the", "intracellular", "TIR", "domains", "are", "mediated", "by", "specific", "adaptor", "molecules", "such", "as", "Myd88", "(Myeloid", "differentiation", "factor", "88),", "Mal", "(Myd88", "adaptor", "like),", "TRIF", "(TIR", "domain", "con-", "taining", "adaptor", "inducing", "interferon-β),", "and", "TRAM", "(TRIF", "related", "adaptor", "molecule).", "These", "adaptor", "proteins", "also", "contain", "TIR", "domains", "that", "mediate", "TIR–TIR", "interactions", "between", "TLR", "recep-", "tors,", "receptor–adaptor,", "and", "adaptor–adaptor", "interactions", "that", "are", "critical", "for", "signaling", "(Palsson-Mcdermott", "and", "O’Neill,", "2007).", "In", "general,", "intracellular", "TIR", "domain", "of", "adaptor", "proteins", "are", "com-", "posed", "of", "approximately", "160", "amino", "acid", "residues", "and", "the", "primary", "sequences", "of", "TIR", "domains", "are", "characterized", "by", "three", "conserved", "sequence", "boxes", "designated", "Box", "1,", "2,", "and", "3.", "Box", "1", "is", "considered", "to", "be", "the", "signature", "sequence", "of", "the", "family,", "whereas", "boxes", "2", "and", "3", "contain", "functionally", "important", "residues", "involved", "in", "signaling", "(Carpenter", "and", "O’Neill,", "2009).", "These", "processes", "result", "in", "the", "for-", "mation", "of", "a", "large", "multimer", "complex,", "or", "“signaling", "platform,”", "that", "propagates", "downstream", "signaling,", "eventually", "leading", "to", "changes", "in", "the", "expression", "of", "several", "hundred", "primary", "immune", "response", "genes.", "However,", "the", "architecture", "of", "the", "TLR", "signaling", "complexes", "is", "poorly", "understood", "at", "this", "time", "due", "to", "a", "lack", "of", "reliable", "meth-", "ods", "to", "study", "such", "interactions", "as", "well", "as", "the", "inherent", "weaknesses", "of", "individual", "inter-", "and", "intra-protein", "interactions", "in", "transitory", "complexes.", "www.frontiersin.org", "July", "2011", "|", "Volume", "2", "|", "Article", "41", "|", "1" ]

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[ "Piwil2", "Suppresses", "P53", "by", "Inducing", "Phosphorylation", "of", "Signal", "Transducer", "and", "Activator", "of", "Transcription", "3", "in", "Tumor", "Cells", "Yilu", "Lu", ".", ",", "Kun", "Zhang", ".", ",", "Chao", "Li.,", "Youlin", "Yao,", "Dachang", "Tao,", "Yunqiang", "Liu,", "Sizong", "Zhang,", "Yongxin", "Ma*", "State", "Key", "Laboratory", "of", "Biotherapy,", "Division", "of", "Morbid", "Genomics,", "Department", "of", "Medical", "Genetics,", "West", "China", "Hospital,", "Sichuan", "University,", "Chengdu,", "China", "Abstract", "Piwi", "proteins", "have", "been", "implicated", "in", "germ", "cell", "proliferation,", "differentiation,", "germline", "stem", "cell", "maintenance", "and", "transposon", "control", "in", "germline", "from", "Drosophila", "to", "mammals.", "The", "Piwi-like2", "(piwil2)", "gene", "is", "mainly", "expressed", "in", "testis", "or", "embryonic", "cells", "among", "normal", "tissues", "but", "widely", "expressed", "in", "tumors.", "However,", "it", "remains", "to", "be", "fully", "determined", "through", "which", "mechanism", "piwil2", "is", "involved", "in", "tumorigenesis.", "Here", "we", "report", "that", "Human", "piwil2,", "or", "Hili", "represses", "the", "tumor", "suppressor", "P53", "in", "human", "cancer", "cells.", "Immunoprecipitation", "analysis", "shows", "that", "Piwil2", "can", "directly", "associate", "with", "Signal", "Transducer", "and", "Activator", "of", "Transcription", "3", "(STAT3)", "protein", "via", "its", "PAZ", "domain", "and", "form", "a", "Piwil2/STAT3/c-Src", "triple", "protein-", "protein", "complex.", "Furthermore,", "STAT3", "is", "phosphorylated", "by", "c-Src", "and", "translocated", "to", "nucleus,", "then", "binds", "to", "P53", "promoter", "and", "represses", "its", "transcription.", "The", "present", "study", "demonstrated", "that", "Piwil2", "plays", "a", "role", "in", "anti-apoptosis", "in", "tumor", "cells", "possessing", "P53", "as", "a", "positive", "regulator", "of", "STAT3", "signaling", "pathway,", "providing", "novel", "sights", "into", "roles", "of", "Piwil2", "in", "tumorigenesis.", "Citation:", "Lu", "Y,", "Zhang", "K,", "Li", "C,", "Yao", "Y,", "Tao", "D,", "et", "al.", "(2012)", "Piwil2", "Suppresses", "P53", "by", "Inducing", "Phosphorylation", "of", "Signal", "Transducer", "and", "Activator", "of", "Transcription", "3", "in", "Tumor", "Cells.", "PLoS", "ONE", "7(1):", "e30999.", "doi:10.1371/journal.pone.0030999", "Editor:", "Kevin", "D.", "Bunting,", "Emory", "University,", "United", "States", "of", "America", "Received", "September", "29,", "2011;", "Accepted", "December", "29,", "2011;", "Published", "January", "27,", "2012", "Copyright:", "2012", "Lu", "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", "is", "supported", "by", "the", "National", "Natural", "Science", "Foundation", "of", "China", "(90919006", "and", "31070676),", "Trans-Century", "Training", "Programme", "Foundation", "for", "the", "Talents", "by", "the", "Ministry", "of", "Education", "of", "China", "(grant", "no.", "NCET-07-0580)", "and", "Spring", "Sunshine", "Programme", "by", "the", "Ministry", "of", "Education", "of", "China", "(grant", "no.", "Z2009-1-61003).", "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:", "mayongxin@gmail.com", ".", "These", "authors", "contributed", "equally", "to", "this", "work.", "Introduction", "The", "Argonaute", "gene", "family", "which", "encode", "basic", "proteins", "that", "contain", "both", "PAZ", "and", "Piwi", "conserved", "domains,", "have", "been", "reported", "to", "induce", "histone", "and", "DNA", "methylation,", "mRNA", "breakdown", "and", "inhibition", "of", "translation", "[1,2].", "As", "a", "predominantly", "germline", "specific", "clade", "of", "Argonaute", "gene", "family,", "Piwi", "subfamily", "are", "found", "in", "all", "animals", "tested", "so", "far", "and", "play", "essential", "roles", "in", "stem-cell", "self-renewal,", "gametogenesis", "and", "RNA", "silencing", "in", "diverse", "organisms", "[3–8].", "Mutations", "of", "three", "Piwi", "homologs", "in", "mice", "(miwi,", "mili", "and", "miwi2)", "respectively", "cause", "arrestment", "of", "spermatogenesis", "and", "male", "sterility", "[9–11].", "The", "piwil2", "gene,", "alias", "mili", "in", "mouse", "or", "Hili", "in", "human,", "is", "mainly", "expressed", "in", "testis", "or", "embryonic", "cells", "among", "normal", "tissues", "but", "widely", "expressed", "in", "tumors,", "suggesting", "that", "Piwil2", "may", "disturb", "cell", "division,", "inhibit", "apoptosis", "and", "play", "a", "role", "as", "dose-dependent", "oncogenic", "fate", "determinants.", "However,", "the", "underlying", "mechanism", "through", "which", "Piwil2", "involved", "in", "tumorigenesis", "remains", "largely", "unknown", "yet", "[12,13].", "The", "tumor", "suppressor", "p53", "which", "involved", "in", "a", "number", "of", "cellular", "signaling", "pathways", "is", "known", "to", "play", "an", "essential", "role", "in", "regulating", "apoptosis.", "Loss", "of", "P53", "function", "is", "a", "common", "feature", "of", "many", "human", "cancers", "[14–16].", "Though", "deletions", "or", "mutations", "of", "P53", "have", "been", "observed", "in", "a", "great", "number", "of", "tumors,", "the", "HeLa", "cell", "line", "possesses", "wild-type", "P53", "alleles", "detectable", "in", "both", "mRNA", "and", "protein", "level", "[17].", "Interestingly,", "Lin", "et", "al.", "reported", "that", "in", "prostate", "cancer", "cell", "lines", "wild-type", "but", "not", "mutant", "P53", "can", "significantly", "inhibit", "STAT3", "activity,", "whereas", "it", "has", "also", "been", "reported", "that", "STAT3", "can", "bind", "to", "P53", "promoter", "and", "inhibit", "the", "P53", "gene", "transcription", "rate", "[18,19].", "STAT", "signaling", "pathways", "activated", "in", "response", "to", "cytokines", "and", "growth", "factors", "have", "been", "reported", "to", "constitutively", "express", "in", "varied", "tumor-derived", "cell", "lines", "and", "tumor", "tissues", "[20].", "STAT3", "activation", "can", "resist", "apoptotic", "machinery", "relied", "anti-tumor", "therapies,", "and", "also", "enhance", "the", "growth", "of", "tumor", "cell", "[18].", "Because", "its", "activation", "can", "mediate", "oncogenic", "transformation", "in", "cultured", "cells", "and", "tumor", "formation", "in", "nude", "mice,", "Stat3", "has", "been", "classified", "as", "an", "oncogene", "[21].", "Here", "we", "present", "that", "human", "piwil2", "gene", "suppresses", "apoptosis", "by", "phosphorylating", "STAT3", "along", "with", "c-Src", "and", "initiating", "transcriptional", "silencing", "of", "P53.", "Results", "Piwil2", "inhibits", "P53", "involved", "apoptosis", "in", "HeLa", "Cells", "Previous", "studies", "have", "reported", "that", "Piwil2", "is", "expressed", "in", "various", "tumors", "and", "inhibits", "apoptosis", "when", "transfected", "into", "embryo", "fibroblast", "cells", "[13].", "To", "investigate", "the", "role", "which", "human", "piwil2", "protein,", "alias", "HILI", "plays", "in", "tumorigenesis", "and", "apoptosis", "in", "cancer", "cells,", "expression", "vectors", "and", "siRNAs", "were", "transfected", "into", "HeLa", "Cells.", "Real-time", "qPCR", "and", "Western", "blot", "analysis", "revealed", "that", "there", "was", "a", "significant", "decrease", "in", "P53", "expression", "following", "the", "over-expression", "of", "Piwil2", "in", "both", "mRNA", "and", "protein", "level,", "while", "its", "counterpart,", "Piwil2-knockdowned", "HeLa", "cells", "express", "a", "higher", "level", "of", "P53", "(Fig.", "1A).", "We", "also", "examined", "several", "other", "PLoS", "ONE", "|", "www.plosone.org", "1", "January", "2012", "|", "Volume", "7", "|", "Issue", "1", "|", "e30999" ]

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[ "Martínez", "et", "al.", "BMC", "Neurology", "2010,", "10:71", "http://www.biomedcentral.com/1471-2377/10/71", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Two", "common", "nonsynonymous", "paraoxonase", "1", "(PON1)", "gene", "polymorphisms", "and", "brain", "astrocytoma", "and", "meningioma", "Carmen", "Martínez1,", "José", "A", "Molina2,", "Hortensia", "Alonso-Navarro3,4,", "Félix", "J", "Jiménez-Jiménez3,", "José", "AG", "Agúndez1,", "Elena", "García-Martín5*", "Abstract", "Background:", "Human", "serum", "paraoxonase", "1", "(PON1)", "plays", "a", "major", "role", "in", "the", "metabolism", "of", "several", "organophosphorus", "compounds.", "The", "enzyme", "is", "encoded", "by", "the", "polymorphic", "gene", "PON1,", "located", "on", "chromosome", "7q21.3.", "Aiming", "to", "identify", "genetic", "variations", "related", "to", "the", "risk", "of", "developing", "brain", "tumors,", "we", "investigated", "the", "putative", "association", "between", "common", "nonsynonymous", "PON1", "polymorphisms", "and", "the", "risk", "of", "developing", "astrocytoma", "and", "meningioma.", "Methods:", "Seventy", "one", "consecutive", "patients", "with", "brain", "tumors", "(43", "with", "astrocytoma", "grade", "II/III", "and", "28", "with", "meningioma)", "with", "ages", "ranging", "21", "to", "76", "years,", "and", "220", "healthy", "controls", "subjects", "were", "analyzed", "for", "the", "frequency", "of", "the", "nonsynonymous", "PON1", "genotypes", "L55M", "rs854560", "and", "Q192R", "rs662.", "All", "participants", "were", "adult", "Caucasian", "individuals", "recruited", "in", "the", "central", "area", "of", "Spain.", "Results:", "The", "frequencies", "of", "the", "PON1", "genotypes", "and", "allelic", "variants", "of", "the", "polymorphisms", "PON1", "L55M", "and", "PON1", "Q192R", "did", "not", "differ", "significantly", "between", "patients", "with", "astrocytoma", "and", "meningioma", "and", "controls.", "The", "minor", "allele", "frequencies", "were", "as", "follows:", "PON1", "55L,", "0.398,", "0.328", "and", "0.286", "for", "patients", "with", "astrocytoma,", "meningioma", "and", "control", "individuals,", "respectively;", "PON1", "192R,", "0.341,", "0.362", "and", "0.302", "for", "patients", "with", "astrocytoma,", "meningioma", "and", "control", "individuals,", "respectively.", "Correction", "for", "age,", "gender,", "or", "education,", "made", "no", "difference", "in", "odds", "ratios", "and", "the", "p", "values", "remained", "non-significant.", "Haplotype", "association", "analyses", "did", "not", "identify", "any", "significant", "association", "with", "the", "risk", "of", "developing", "astrocytoma", "or", "meningioma.", "Conclusions:", "Common", "nonsynonymous", "PON1", "polymorphisms", "are", "not", "related", "with", "the", "risk", "of", "developing", "astrocytoma", "and", "meningioma.", "Background", "Primary", "cancers", "of", "the", "brain", "and", "nervous", "system", "glob-", "ally", "account", "for", "nearly", "200,000", "new", "cases", "per", "year,", "the", "highest", "rates", "being", "observed", "in", "developed", "areas", "[1].", "The", "two", "most", "common", "histologic", "types", "of", "brain", "tumors", "in", "adults", "are", "gliomas", "and", "meningiomas,", "and", "data", "suggest", "that", "gliomas", "are", "more", "common", "in", "men,", "while", "meningio-", "mas", "occur", "more", "often", "in", "women", "[2].", "The", "etiology", "of", "brain", "tumors", "is", "still", "poorly", "under-", "stood.", "Despite", "some", "studies", "suggested", "a", "possible", "*", "Correspondence:", "elenag@unex.es", "5Department", "of", "Biochemistry", "and", "Molecular", "Biology", "and", "Genetics,", "University", "of", "Extremadura,", "Avda", "de", "Elvas", "s/n,", "06071,", "Badajoz,", "Spain", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "relationship", "between", "the", "risk", "for", "brain", "tumors", "and", "sev-", "eral", "occupational", "and", "environmental", "exposures,", "includ-", "ing", "farming", "[3-5]", "and", "pesticides", "and/or", "herbicides", "[2,5-10],", "others", "failed", "to", "show", "this", "association", "[11-13].", "A", "recent", "multicenter", "case-control", "study", "examining", "inci-", "dent", "glioma", "and", "meningioma", "risk", "associated", "with", "occu-", "pational", "exposure", "to", "insecticides", "and", "herbicides", "showed", "increased", "risk", "for", "meningioma", "in", "women", "who", "reported", "ever", "using", "pesticides,", "with", "a", "trend", "of", "increasing", "risk", "with", "increasing", "years", "of", "herbicide", "exposure", "[14].", "Inter-", "estingly,", "it", "has", "been", "reported", "that,", "in", "experimental", "mod-", "els,", "organophosphorus", "insecticides", "and", "their", "oxons", "can", "affect", "astroglial", "cell", "proliferation", "in", "cultures", "of", "astro-", "cytoma-glioma", "cell", "lines", "or", "primary", "astrocytes", "[15,16].", "©", "2010", "Martínez", "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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[ "Microbial", "Cell", "Factories", "Research", "Molecular", "cloning", "and", "characterization", "of", "a", "novel", "pyrethroid-hydrolyzing", "esterase", "originating", "from", "the", "Metagenome", "Gang", "Li†,", "Kui", "Wang†", "and", "Yu", "Huan", "Liu*", "Address:", "State", "Key", "Laboratory", "of", "Biocontrol,", "School", "of", "Life", "sciences,", "Sun", "Yat-sen", "University,", "Guangzhou,", "510275,", "PR", "China", "Email:", "Gang", "Li", "-", "lsslig@mail.sysu.edu.cn;", "Kui", "Wang", "-", "uk0829@126.com;", "Yu", "Huan", "Liu*", "-", "lsslyh@mail.sysu.edu.cn", "*", "Corresponding", "author", "†Equal", "contributors", "BioMed", "Central", "Open", "Access", "Published:", "30", "December", "2008", "Microbial", "Cell", "Factories", "2008,", "7:38", "doi:10.1186/1475-2859-7-38", "This", "article", "is", "available", "from:", "http://www.microbialcellfactories.com/content/7/1/38", "Received:", "27", "October", "2008", "Accepted:", "30", "December", "2008", "©", "2008", "Li", "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:", "Pyrethroids", "and", "pyrethrins", "are", "widely", "used", "insecticides.", "Extensive", "applications", "not", "only", "result", "in", "pest", "resistance", "to", "these", "insecticides,", "but", "also", "may", "lead", "to", "environmental", "issues", "and", "human", "exposure.", "Numerous", "studies", "have", "shown", "that", "very", "high", "exposure", "to", "pyrethroids", "might", "cause", "potential", "problems", "to", "man", "and", "aquatic", "organisms.", "Therefore,", "it", "is", "important", "to", "develop", "a", "rapid", "and", "efficient", "disposal", "process", "to", "eliminate", "or", "minimize", "contamination", "of", "surface", "water,", "groundwater", "and", "agricultural", "products", "by", "pyrethroid", "insecticides.", "Bioremediation", "is", "considered", "to", "be", "a", "reliable", "and", "cost-effective", "technique", "for", "pesticides", "abatement", "and", "a", "major", "factor", "determining", "the", "fate", "of", "pyrethroid", "pesticides", "in", "the", "environment,", "and", "suitable", "esterase", "is", "expected", "to", "be", "useful", "for", "potential", "application", "for", "detoxification", "of", "pyrethroid", "residues.", "Soil", "is", "a", "complex", "environment", "considered", "as", "one", "of", "the", "main", "reservoirs", "of", "microbial", "diversity", "on", "the", "planet.", "However,", "most", "of", "the", "microorganisms", "in", "nature", "are", "inaccessible", "as", "they", "are", "uncultivable", "in", "the", "laboratory.", "Metagenomic", "approaches", "provide", "a", "powerful", "tool", "for", "accessing", "novel", "valuable", "genetic", "resources", "(novel", "enzymes)", "and", "developing", "various", "biotechnological", "applications.", "Results:", "The", "pyrethroid", "pesticides", "residues", "on", "foods", "and", "the", "environmental", "contamination", "are", "a", "public", "safety", "concern.", "Pretreatment", "with", "pyrethroid-hydrolyzing", "esterase", "has", "the", "potential", "to", "alleviate", "the", "conditions.", "To", "this", "end,", "a", "pyrethroid-", "hydrolyzing", "esterase", "gene", "was", "successfully", "cloned", "using", "metagenomic", "DNA", "combined", "with", "activity-based", "functional", "screening", "from", "soil,", "sequence", "analysis", "of", "the", "DNA", "responsible", "for", "the", "pye3", "gene", "revealed", "an", "open", "reading", "frame", "of", "819", "bp", "encoding", "for", "a", "protein", "of", "272", "amino", "acid", "residues.", "Extensive", "multiple", "sequence", "alignments", "of", "the", "deduced", "amino", "acid", "of", "Pye3", "with", "the", "most", "homologous", "carboxylesterases", "revealed", "moderate", "identity", "(45–49%).", "The", "recombinant", "Pye3", "was", "heterologously", "expressed", "in", "E.", "coli", "BL21(DE3),", "purified", "and", "characterized.", "The", "molecular", "mass", "of", "the", "native", "enzyme", "was", "approximately", "31", "kDa", "as", "determined", "by", "gel", "filtration.", "The", "results", "of", "sodium", "dodecyl", "sulfate-polyacrylamide", "gel", "electrophoresis", "and", "the", "deduced", "amino", "acid", "sequence", "of", "the", "Pye3", "indicated", "molecular", "mass", "of", "31", "kDa", "and", "31.5", "kDa,", "respectively,", "suggesting", "that", "the", "Pye3", "is", "a", "monomer.", "The", "purified", "Pye3", "not", "only", "degraded", "all", "pyrethroid", "pesticides", "tested,", "but", "also", "hydrolyzed", "ρ-nitrophenyl", "esters", "of", "medium-short", "chain", "fatty", "acids,", "indicating", "that", "the", "Pye3", "is", "an", "esterase", "with", "broader", "specificity.", "The", "Km", "values", "for", "trans-Permethrin", "and", "cis-permethrin", "are", "0.10", "μM", "and", "0.18", "μM,", "respectively,", "and", "these", "catalytic", "properties", "were", "superior", "to", "carboxylesterases", "from", "resistant", "insects", "and", "mammals.", "The", "catalytic", "activity", "of", "the", "Pye3", "was", "strongly", "inhibited", "by", "Hg2+,", "Ag+,", "ρ-chloromercuribenzoate,", "whereas", "less", "pronounced", "effect", "was", "observed", "in", "the", "presence", "of", "divalent", "cations,", "the", "chelating", "agent", "EDTA", "and", "phenanthroline.", "Conclusion:", "A", "novel", "pyrethroid-hydrolyzing", "esterase", "gene", "was", "successfully", "cloned", "using", "metagenomic", "DNA", "combined", "with", "activity-based", "functional", "screening", "from", "soil,", "the", "broader", "substrate", "specificities", "and", "higher", "activity", "of", "the", "pyrethroid-hydrolyzing", "esterase", "(Pye3)", "make", "it", "an", "ideal", "candidate", "for", "in", "situ", "for", "detoxification", "of", "pyrethroids", "where", "they", "cause", "environmental", "contamination", "problems.", "Consequently,", "metagenomic", "DNA", "clone", "library", "offers", "possibilities", "to", "discover", "novel", "bio-molecules", "through", "the", "expression", "of", "genes", "from", "uncultivated", "bacteria.", "Page", "1", "of", "10", "(page", "number", "not", "for", "citation", "purposes)" ]

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[ "Journal", "of", "Inflammation", "Research", "Young", "adult", "obese", "subjects", "with", "and", "without", "insulin", "resistance:", "what", "is", "the", "role", "of", "chronic", "inflammation", "and", "how", "to", "weigh", "it", "non-invasively?", "Giovanni", "Tarantino*1,", "Patrizia", "Colicchio1,", "Paolo", "Conca1,", "Carmine", "Finelli1,", "Matteo", "Nicola", "Dario", "Di", "Minno1,", "Marianna", "Tarantino2,", "Domenico", "Capone3", "and", "Fabrizio", "Pasanisi1", "BioMed", "Central", "Open", "Access", "Address:", "1Department", "of", "Clinical", "and", "Experimental", "Medicine,", "Federico", "II", "University", "Medical", "School", "of", "Naples,", "Italy,", "2Department", "of", "Biomorphological", "and", "Functional", "Sciences,", "Federico", "II", "University", "Medical", "School", "of", "Naples,", "Italy", "and", "3Department", "of", "Neurosciences,", "Unit", "of", "Clinical", "Pharmacology,", "Federico", "II", "University", "Medical", "School", "of", "Naples,", "Italy", "Email:", "Giovanni", "Tarantino*", "-", "tarantin@unina.it;", "Patrizia", "Colicchio", "-", "dottpatty@libero.it;", "Paolo", "Conca", "-", "paoloconca@unina.it;", "Carmine", "Finelli", "-", "pasanisi@unina.it;", "Matteo", "Nicola", "Dario", "Di", "Minno", "-", "diminno@unina.it;", "Marianna", "Tarantino", "-", "tarantin@unina.it;", "Domenico", "Capone", "-", "docapone@unina.it;", "Fabrizio", "Pasanisi", "-", "pasanisi@unina.it", "*", "Corresponding", "author", "Published:", "16", "March", "2009", "Journal", "of", "Inflammation", "2009,", "6:6", "doi:10.1186/1476-9255-6-6", "This", "article", "is", "available", "from:", "http://www.journal-inflammation.com/content/6/1/6", "Received:", "14", "January", "2009", "Accepted:", "16", "March", "2009", "©", "2009", "Tarantino", "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:", "Obesity", "is", "a", "leading", "risk", "factor", "for", "metabolic", "syndrome", "whose", "further", "expression", "is", "non-alcoholic", "fatty", "liver", "disease.", "Metabolic", "syndrome", "is", "associated", "with", "a", "proinflammatory", "state", "that", "contributes", "to", "insulin", "resistance.", "Finally,", "a", "\"metabolically", "benign", "obesity\"", "that", "is", "not", "accompanied", "by", "insulin", "resistance", "has", "recently", "been", "postulated", "to", "exist.", "Aim:", "To", "find", "whether", "any", "inflammation", "markers", "were", "independently", "associated", "with", "the", "presence", "of", "insulin", "resistance,", "evaluating", "specific", "anthropometric,", "ultrasonographic", "and", "laboratory", "parameters", "in", "a", "population", "of", "young", "adult", "obese", "subjects.", "Methods:", "Of", "forty", "two", "young", "individuals,", "divided", "into", "two", "groups", "(with", "or", "without", "insulin", "resistance),", "were", "studied", "serum", "C-reactive", "protein", "and", "fibrinogen", "as", "indexes", "of", "chronic", "pro-inflammatory", "status.", "Body", "mass", "index,", "waist", "circumference", "and", "metabolic", "syndrome", "presence", "were", "assessed", "as", "part", "of", "the", "metabolic", "evaluation.", "Ultrasonography", "weighted", "visceral", "and", "subcutaneous", "abdominal", "fat", "thickness,", "spleen", "size", "as", "longitudinal", "diameter", "and", "liver", "hyperechogenicity.", "Results", "and", "Discussion:", "Serum", "C-reactive", "protein", "and", "fibrinogen", "as", "well", "as", "spleen", "longitudinal", "diameter", "were", "significantly", "increased", "in", "the", "obese", "young", "with", "insulin", "resistance", "compared", "to", "non-insulin", "resistance", "group.", "Insulin", "resistance", "was", "significantly", "associated", "with", "hepatic", "steatosis", "score", "at", "sonography", "(r", "=", "0.33,", "P", "=", "0.03),", "spleen", "longitudinal", "diameter", "(r", "=", "0.35,", "P", "=", "0.02)", "and", "C-reactive", "protein", "(r", "=", "0.38,", "P", "=", "0.01),", "but", "not", "with", "body", "mass", "index,", "visceral", "or", "subcutaneous", "abdominal", "adipose", "tissue,", "waist", "circumference", "and", "fibrinogen", "(P", "=", "0.18,", "0.46,", "0.33,", "0.37", "and", "0.4,", "respectively).", "Steatosis", "score", "at", "sonography", "was", "well", "associated", "with", "spleen", "volume", "(rho", "=", "0.40,", "P", "=", "0.01)", "and", "C-reactive", "protein", "levels", "(rho", "=", "0.49,", "P", "=", "0.002).", "Metabolic", "syndrome", "was", "much", "more", "frequent", "in", "obese", "patients", "with", "insulin", "resistance.", "These", "findings", "show", "that", "in", "young", "adults", "the", "only", "abdominal", "adiposity", "without", "insulin", "resistance,", "plays", "a", "scarce", "role", "in", "determining", "hepatic", "steatosis", "as", "well", "as", "metabolic", "syndrome.", "Conclusion:", "Increases", "in", "spleen", "size", "and", "CRP", "levels", "represent", "a", "reliable", "tool", "in", "diagnosing", "insulin", "resistance.", "Page", "1", "of", "6", "(page", "number", "not", "for", "citation", "purposes)" ]

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[ "SAGE-Hindawi", "Access", "to", "Research", "International", "Journal", "of", "Hypertension", "Volume", "2011,", "Article", "ID", "595791,", "3", "pages", "doi:10.4061/2011/595791", "Review", "Article", "Management", "of", "High", "Blood", "Pressure", "in", "Those", "without", "Overt", "Cardiovascular", "Disease", "Utilising", "Absolute", "Risk", "Scores", "Mark", "R.", "Nelson", "Discipline", "of", "General", "Practice,", "Menzies", "Research", "Institute,", "Private", "Bag", "23,", "Hobart,", "TAS", "7001,", "Australia", "Correspondence", "should", "be", "addressed", "to", "Mark", "R.", "Nelson,", "Mark.Nelson@utas.edu.au", "Received", "22", "January", "2011;", "Accepted", "31", "March", "2011", "Academic", "Editor:", "Samy", "I.", "McFarlane", "Copyright", "©", "2011", "Mark", "R.", "Nelson.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Increasing", "blood", "pressure", "has", "a", "continuum", "of", "adverse", "risk", "for", "cardiovascular", "events.", "Traditionally", "this", "single", "measure", "was", "used", "to", "determine", "who", "to", "treat", "and", "how", "vigorously.", "However,", "estimating", "absolute", "risk", "rather", "than", "measurement", "of", "a", "single", "risk", "factor", "such", "as", "blood", "pressure", "is", "a", "superior", "method", "to", "identify", "who", "is", "most", "at", "risk", "of", "having", "an", "adverse", "cardiovascular", "event", "such", "as", "stroke", "or", "myocardial", "infarction,", "and", "therefore", "who", "would", "most", "likely", "benefit", "from", "therapeutic", "intervention.", "Cardiovascular", "disease", "(CVD)", "risk", "calculators", "must", "be", "used", "to", "estimate", "absolute", "risk", "in", "those", "without", "overt", "CVD", "as", "physician", "estimation", "is", "unreliable.", "Incorporation", "into", "usual", "practice", "and", "limitations", "of", "the", "strategy", "are", "discussed.", "1.", "Introduction", "Physicians", "treat", "diseases.", "For", "this", "reason", "when", "increasing", "blood", "pressure", "was", "recognized", "as", "a", "risk", "factor", "for", "coronary", "artery", "disease", "and", "stroke,", "it", "was", "dichotomized", "into", "a", "disease", "state", "“hypertension”", "and", "a", "nondisease", "state", "“normotension”", "by", "creating", "an", "arbitrary", "cut", "point.", "This", "cut", "point", "has", "gen-", "erally", "become", "lower", "over", "time", "as", "evidence", "of", "benefit", "in", "treating", "blood", "pressure", "levels", "lower", "than", "the", "contemporary", "accepted", "cut", "points", "accumulated.", "Recognition", "of", "other", "risk", "factors", "such", "as", "dyslipidemia,", "higher", "risk", "groups", "such", "as", "the", "aged", "[1,", "2],", "and", "those", "with", "comorbid", "conditions", "such", "as", "diabetes", "[3]", "has", "led", "to", "differential", "treatment", "thresholds", "and", "target", "blood", "pressures", "resulting", "in", "confusing", "or", "conflicting", "guideline", "recommendations,", "depending", "on", "which", "peak", "body", "produced", "them.", "Is", "there", "a", "simpler", "way", "to", "identify", "those", "most", "likely", "to", "have", "a", "major", "adverse", "cardiovascular", "event", "who", "do", "not", "have", "overt", "disease,", "and", "therefore", "who", "needs", "rigorous", "therapeutic", "intervention", "for", "their", "blood", "pressure", "and", "other", "CVD", "risk", "factors?", "2.", "Absolute", "Cardiovascular", "Risk", "Increasing", "blood", "pressure", "has", "a", "log-linear", "relationship", "with", "adverse", "risk", "for", "cardiovascular", "events", "[4].", "Using", "this", "figure", "alone", "in", "clinical", "decision", "making", "risks", "overtreatment", "(“med-", "icalization”", "where", "medication", "adverse", "events", "likely", "to", "exceed", "benefit,", "and", "adverse", "cost-effectiveness)", "and", "undertreatment", "(failure", "to", "act", "where", "medication", "benefit", "is", "likely", "to", "exceed", "adverse", "events", "and", "be", "cost", "effective).", "Estimating", "absolute", "risk,", "the", "risk", "of", "having", "an", "adverse", "cardiovascular", "event", "over", "a", "specified", "period", "of", "time", "(usually", "5", "or", "10", "years),", "is", "a", "superior", "method", "to", "measurement", "of", "blood", "pressure", "alone", "to", "identify", "who", "is", "most", "at", "risk", "of", "having", "a", "cardiovascular", "event", "and", "therefore", "who", "would", "most", "likely", "benefit", "from", "intervention", "[5,", "6].", "It", "does", "this", "because", "the", "figure", "derived", "is", "more", "holistic,", "incorporating", "other", "CVD", "risk", "factors", "that", "explain", "almost", "all", "risk", "including", "blood", "pressure,", "and", "directly", "estimates", "why", "we", "treat", "blood", "pressure", "in", "any", "population", "without", "CVD,", "to", "prevent", "its", "onset", "and", "complications.", "Guidelines", "are", "increasingly", "recognizing", "the", "benefit", "of", "utilizing", "absolute", "risk", "scores", "rather", "than", "blood", "pressure", "measurements", "alone", "[7–", "12].", "3.", "Cardiovascular", "Disease", "Risk", "Calculators", "CVD", "risk", "calculators", "are", "based", "on", "algorithms", "derived", "from", "observational", "prospective", "cohort", "studies", "such", "as", "the", "Fram-", "ingham", "study", "[13,", "14].", "CVD", "risk", "calculators", "must", "be", "used", "to", "estimate", "absolute", "risk", "in", "those", "without", "prior", "CVD", "events" ]

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[ "Iranian", "J", "Publ", "Health,", "Vol.", "41,", "No.5,", "May", "2012,", "pp.105-109", "Original", "Article", "Serum", "Selenium,", "Zinc,", "and", "Copper", "in", "Early", "Diagnosed", "Patients", "with", "Pemphigus", "Vulgaris", "MH", "Javanbakht", "1,", "M", "Daneshpazhooh", "2,", "C", "Chams-Davatchi", "2,", "MR", "Eshraghian", "3,", "M", "Zarei", "1,", "M", "Chamari", "1,", "*Djalali", "M", "1", "1.", "Dept.", "of", "Nutrition", "and", "Biochemistry,", "Faculty", "of", "Public", "Health,", "Tehran", "University", "of", "Medical", "Sciences,", "Te-", "hran,", "Iran", "2.", "Dept.", "of", "Dermatology,", "Razi", "hospital,", "Tehran", "University", "of", "Medical", "Sciences,", "Tehran,", "Iran", "3.", "Dept.", "of", "Biostatistics", "and", "Epidemiology,", "Faculty", "of", "Public", "Health,", "Tehran", "University", "of", "Medical", "Sciences,", "Tehran,", "Iran", "(Received", "19", "Jul", "2011;", "accepted", "25", "Feb", "2012)", "Abstract", "Background:", "Pemphigus", "vulgaris", "is", "a", "life", "threatening,", "blistering", "skin", "disease.", "It", "is", "an", "autoimmune", "abnormality.", "Due", "to", "involvement", "of", "oral", "cavity", "and", "pharynx,", "patients", "are", "at", "risk", "of", "nutrients", "deficiency.", "The", "aim", "of", "this", "study", "was", "to", "evaluate", "the", "status", "of", "selenium,", "copper,", "and", "zinc", "in", "these", "patients.", "Methods:", "In", "a", "case-control", "study,", "43", "newly", "diagnosed", "pemphigus", "vulgaris", "patients", "were", "compared", "with", "58", "healthy", "people", "from", "2009", "to", "2010.", "The", "severity", "of", "the", "disease", "was", "estimated", "according", "to", "Harman’s", "scores.", "Se-", "rum", "selenium", "was", "measured", "with", "atomic", "absorption", "but", "serum", "zinc", "and", "copper", "concentrations", "were", "determined", "spectrophotometrically.", "Data", "were", "compared", "with", "independent", "t", "test.", "Correlations", "were", "evaluated", "by", "Pearson", "correlation", "test.", "Results:", "Both", "groups", "were", "the", "same", "based", "on", "sex,", "age,", "and", "weight", "and", "body", "mass", "index.", "The", "mean", "duration", "of", "disease", "was", "5.6", "month.", "The", "oral", "and", "skin", "severities", "were", "1.79", "and", "2.3", "respectively,", "based", "on", "Harman’s", "scores.", "Serum", "selenium", "of", "pemphigus", "patients", "was", "significantly", "less", "than", "that", "of", "healthy", "people", "(P<0.001).", "Serum", "cop-", "per", "was", "negatively", "correlated", "with", "duration", "of", "disease", "in", "males", "(P=0.02,", "r=-0.5).", "Conclusions:", "Pemphigus", "vulgaris", "negatively", "affects", "on", "serum", "selenium,", "copper", "and", "zinc.", "It", "seems", "that", "serum", "selenium,", "copper", "and", "zinc", "decrease", "as", "the", "disease", "lasts", "longer.", "Keywords:", "Selenium,", "Zinc,", "Copper,", "Pemphigus", "vulgaris", "Introduction", "Pemphigus", "as", "a", "word", "originates", "from", "pemphix,", "a", "Greek", "word", "that", "means", "blister.", "Pemphigus", "is", "a", "life", "threatening", "skin", "disease", "(1).", "It", "possesses", "two", "sub-", "types,", "vulgaris,", "and", "foliaceus.", "Pemphigus", "vulgaris", "is", "the", "most", "common", "form", "of", "pemphigus", "in", "many", "territories.", "It", "is", "especially", "common", "among", "Jews", "and", "Mediterranean", "peoples.", "Nearly", "91.9%", "of", "all", "cases", "with", "pemphigus", "belong", "to", "pemphigus", "vul-", "garis", "(2).", "The", "incidence", "of", "pemphigus", "vulgaris", "var-", "ies", "from", "0.07", "to", "3.2", "cases", "per", "100000", "people", "per", "year,", "but", "it", "depends", "on", "geographical", "location", "and", "is", "nearly", "1", "per", "100000", "population", "in", "Iran", "(2).", "The", "mean", "age", "in", "which", "the", "disease", "starts", "is", "42", "years", "in", "Tehran", "(3).", "Pemphigus", "vulgaris", "affects", "females", "a", "bit", "more", "than", "males,", "therefore", "male", "to", "female", "ra-", "tio", "is", "1", "to", "1.5", "(3).", "Its", "mortality", "rate", "is", "5%", "to", "25%", "depending", "on", "the", "population", "under", "study", "(4).", "It", "is", "an", "autoimmune", "disorder,", "which", "causes", "painful", "*Corresponding", "Author:", "E-mail", "address:", "jalalimahmoud@hotmail.com" ]

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[ "Characterization", "of", "the", "p53", "Response", "to", "Oncogene-", "Induced", "Senescence", "Lidia", "Ruiz1.,", "Magali", "Traskine2.,", "Irene", "Ferrer1.,", "Estrella", "Castro1,", "Juan", "F.", "M.", "Leal1,", "Marcelline", "Kaufman", "2", ",", "Amancio", "Carnero1*", "1", "Experimental", "Therapeutics", "Programme,", "Centro", "Nacional", "De", "Investigaciones", "Oncolo´", "gicas", "(CNIO),", "Madrid,", "Spain,", "2", "Unit", "of", "Theoretical", "and", "Computational", "Biology,", "Faculte´", "des", "Sciences,", "Universite´", "Libre", "de", "Bruxelles", "(U.L.B.),", "Bruxelles,", "Belgium", "Abstract", "Background:", "P53", "activation", "can", "trigger", "various", "outcomes,", "among", "them", "reversible", "growth", "arrest", "or", "cellular", "senescence.", "It", "is", "a", "live", "debate", "whether", "these", "outcomes", "are", "influenced", "by", "quantitative", "or", "qualitative", "mechanisms.", "Furthermore,", "the", "relative", "contribution", "of", "p53", "to", "Ras-induced", "senescence", "is", "also", "matter", "of", "controversy.", "Methodology/Principal", "Findings:", "This", "study", "compared", "situations", "in", "which", "different", "signals", "drove", "senescence", "with", "increasing", "levels", "of", "p53", "activation.", "The", "study", "revealed", "that", "the", "levels", "of", "p53", "activation", "do", "not", "determine", "the", "outcome", "of", "the", "response.", "This", "is", "further", "confirmed", "by", "the", "clustering", "of", "transcriptional", "patterns", "into", "two", "broad", "groups:", "p53-activated", "or", "p53-", "inactivated,", "i.e.,", "growth", "and", "cellular", "arrest/senescence.", "Furthermore,", "while", "p53-dependent", "transcription", "decreases", "after", "24", "hrs", "in", "the", "presence", "of", "active", "p53,", "senescence", "continues.", "Maintaining", "cells", "in", "the", "arrested", "state", "for", "long", "periods", "does", "not", "switch", "reversible", "arrest", "to", "cellular", "senescence.", "Together,", "these", "data", "suggest", "that", "a", "Ras-dependent,", "p53-independent,", "second", "signal", "is", "necessary", "to", "induce", "senescence.", "This", "study", "tested", "whether", "PPP1CA", "(the", "catalytic", "subunit", "of", "PP1a),", "recently", "identified", "as", "contributing", "to", "Ras-induced", "senescence,", "might", "be", "this", "second", "signal.", "PPP1CA", "is", "induced", "by", "Ras;", "its", "inactivation", "inhibits", "Ras-induced", "senescence,", "presumably", "by", "inhibiting", "pRb", "dephosphorylation.", "Finally,", "PPP1CA", "seems", "to", "strongly", "co-", "localize", "with", "pRb", "only", "during", "senescence.", "Conclusions:", "The", "levels", "of", "p53", "activation", "do", "not", "determine", "the", "outcome", "of", "the", "response.", "Rather,", "p53", "activity", "seems", "to", "act", "as", "a", "necessary", "but", "not", "sufficient", "condition", "for", "senescence", "to", "arise.", "Maintaining", "cells", "in", "the", "arrested", "state", "for", "long", "periods", "does", "not", "switch", "reversible", "arrest", "to", "cellular", "senescence.", "PPP1CA", "is", "induced", "by", "Ras;", "its", "inactivation", "inhibits", "Ras-induced", "senescence,", "presumably", "by", "inhibiting", "pRb", "dephosphorylation.", "Finally,", "PPP1CA", "seems", "to", "strongly", "co-localize", "with", "pRb", "only", "during", "senescence,", "suggesting", "that", "PP1a", "activation", "during", "senescence", "may", "be", "the", "second", "signal", "contributing", "to", "the", "irreversibility", "of", "the", "senescent", "phenotype.", "Citation:", "Ruiz", "L,", "Traskine", "M,", "Ferrer", "I,", "Castro", "E,", "Leal", "JFM,", "et", "al.", "(2008)", "Characterization", "of", "the", "p53", "Response", "to", "Oncogene-Induced", "Senescence.", "PLoS", "ONE", "3(9):", "e3230.", "doi:10.1371/journal.pone.0003230", "Editor:", "Mikhail", "V.", "Blagosklonny,", "Ordway", "Research", "Institute,", "United", "States", "of", "America", "Received", "June", "30,", "2008;", "Accepted", "August", "24,", "2008;", "Published", "September", "18,", "2008", "Copyright:", "2008", "Ruiz", "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", "has", "been", "supported", "by", "grants", "from", "the", "Ministerio", "de", "Educacion", "y", "Ciencia", "(SAF2005-00944),", "Fundacio´", "n", "Mutua", "Madrilen˜", "a", "and", "the", "EU", "(from", "VI", "framework,", "Project", "COMBIO,", "Project", "NETSENSOR).", "IF", "is", "supported", "by", "a", "fellowship", "from", "the", "Ministerio", "de", "Educacion", "y", "Ciencia.", "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:", "acarnero@cnio.es", ".", "These", "authors", "contributed", "equally", "to", "this", "work.", "Introduction", "Among", "the", "different", "methods", "cells", "have", "to", "monitor", "external", "or", "internal", "stresses,", "the", "surveillance", "mechanism", "associated", "with", "the", "p53", "gene", "is", "central.", "Numerous", "molecular", "studies", "over", "the", "years", "have", "presented", "p53", "as", "an", "essential", "controller", "of", "cellular", "and", "genome", "integrity", "[1].", "p53", "is", "a", "master", "transcription", "factor,", "functionally", "inactive", "under", "normal", "conditions", "due", "to", "its", "rapid", "degradation", "by", "the", "ubiquitin", "ligase", "MDM2.", "A", "chain", "of", "events", "triggered", "in", "response", "to", "cellular", "stress", "upsets", "this", "precise", "balance,", "leading", "to", "the", "uncoupling", "of", "MDM2-driven", "degradation", "and", "to", "the", "ultimate", "accumulation", "and", "activation", "of", "p53", "[2].", "p53", "works", "mostly", "as", "a", "transcriptional", "activator,", "with", "few", "molecules", "in", "each", "cell", "[3].", "However,", "p53", "might", "also", "act", "as", "a", "repressor", "in", "some", "instances", "[4].", "The", "p53", "transcriptional", "program", "includes", "the", "activation", "of", "a", "number", "of", "cell", "cycle", "inhibitors", "and", "proapoptotic", "proteins,", "which", "results", "in", "apoptosis,", "reversible", "proliferative", "arrest", "or", "cellular", "senescence", "[5,6,7].", "In", "principle,", "the", "various", "outcomes", "of", "p53", "activation", "might", "be", "influenced", "by", "quantitative", "or", "qualitative", "mechanisms", "[8].", "Some", "studies", "suggest", "that", "the", "level", "of", "p53", "output", "determines", "whether", "cells", "will", "enter", "cell", "cycle", "arrest", "or", "apoptosis.", "Consistent", "with", "this", "view,", "only", "a", "subset", "of", "the", "genes", "induced", "by", "high", "p53", "levels", "are", "induced", "by", "lower", "p53", "levels", "[9].", "Introduction", "of", "high", "p53", "levels", "into", "tumor", "cell", "lines", "induces", "apoptosis,", "while", "the", "introduction", "of", "lower", "levels", "induces", "only", "cell", "cycle", "arrest", "[10].", "However,", "other", "studies", "suggest", "that", "the", "outcome", "of", "p53", "activation", "is", "determined", "by", "factors", "controlled", "by", "the", "tissue", "type", "or", "by", "the", "cell", "genotype.", "Oncogenic", "Ras", "can", "activate", "p53", "to", "promote", "cellular", "senescence,", "limiting", "the", "transforming", "potential", "of", "excessive", "signalling", "[11–16].", "This", "study", "and", "others", "have", "demonstrated", "that", "conditional", "activation", "of", "p53", "in", "mouse", "embryonic", "fibroblast", "cells", "(MEFs)", "PLoS", "ONE", "|", "www.plosone.org", "1", "September", "2008", "|", "Volume", "3", "|", "Issue", "9", "|", "e3230" ]

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[ "Gomes", "Sobrinho", "et", "al.", "Reproductive", "Biology", "and", "Endocrinology", "2011,", "9:143", "http://www.rbej.com/content/9/1/143", "R", "E", "V", "I", "E", "W", "Open", "Access", "IVF/ICSI", "outcomes", "after", "culture", "of", "human", "embryos", "at", "low", "oxygen", "tension:", "a", "meta-analysis", "David", "B", "Gomes", "Sobrinho1,", "Joao", "Batista", "A", "Oliveira1,2,3*,", "Claudia", "G", "Petersen1,2,3,", "Ana", "L", "Mauri2,3,", "Liliane", "FI", "Silva1,2,3,", "Fabiana", "C", "Massaro2,3,", "Ricardo", "LR", "Baruffi2,3,", "Mario", "Cavagna2,3,4", "and", "José", "G", "Franco", "Jr1,2,3", "Abstract", "Background:", "Improved", "pregnancy,", "implantation,", "and", "birth", "rates", "have", "been", "reported", "after", "the", "use", "of", "reduced", "O2", "concentration", "during", "embryo", "culture,", "mainly", "due", "to", "a", "reduction", "of", "the", "cumulative", "detrimental", "effects", "of", "reactive", "oxygen", "species.", "However,", "some", "studies", "have", "failed", "to", "report", "any", "positive", "effects.", "The", "objective", "of", "this", "meta-", "analysis", "was", "to", "evaluate", "the", "effect", "of", "a", "low-O2", "environment", "on", "IVF/intracytoplasmic", "sperm", "injection", "(ICSI)", "outcomes.", "Methods:", "All", "available", "published", "and", "ongoing", "randomised", "trials", "that", "compared", "the", "effects", "of", "low", "(~5%;", "OC~5)", "and", "atmospheric", "(~20%;", "OC~20)", "oxygen", "concentrations", "on", "IVF/ICSI", "outcomes", "were", "included.", "Search", "strategies", "included", "online", "surveys", "of", "databases", "from", "1980", "to", "2011.", "The", "outcomes", "measured", "were", "fertilisation", "rate,", "implantation", "rate", "and", "ongoing", "pregnancy", "rates.", "The", "fixed", "effects", "model", "was", "used", "to", "calculate", "the", "odds", "ratio.", "Results:", "Seven", "studies", "were", "included", "in", "this", "analysis.", "The", "pooled", "fertilisation", "rate", "did", "not", "differ", "significantly", "(P", "=", "0.54)", "between", "the", "group", "of", "oocytes", "cultured", "at", "low", "O2", "tension", "and", "the", "group", "at", "atmospheric", "O2", "tension.", "Concerning", "all", "cycles,", "the", "implantation", "(P", "=", "0.06)", "and", "ongoing", "pregnancy", "(P", "=", "0.051)", "rates", "were", "not", "significantly", "different", "between", "the", "group", "receiving", "transferred", "sets", "containing", "only", "OC~5", "embryos", "and", "the", "group", "receiving", "transferred", "sets", "with", "only", "OC~20", "embryos.", "In", "a", "meta-analysis", "performed", "for", "only", "those", "trials", "in", "which", "embryos", "were", "transferred", "on", "day", "2/3,", "implantation", "(P", "=", "0.63)", "and", "ongoing", "pregnancy", "(P", "=", "0.19)", "rates", "were", "not", "significantly", "different", "between", "the", "groups.", "In", "contrast,", "when", "a", "meta-analysis", "was", "performed", "using", "only", "trials", "in", "which", "embryos", "were", "transferred", "on", "days", "5", "and", "6", "(at", "the", "blastocyst", "stage),", "the", "group", "with", "transferred", "sets", "of", "only", "OC~5", "embryos", "showed", "a", "statistically", "significantly", "higher", "implantation", "rate", "(P", "=", "0.006)", "than", "the", "group", "receiving", "transferred", "sets", "with", "only", "OC~20", "embryos,", "although", "the", "ongoing", "pregnancy", "(P", "=", "0.19)", "rates", "were", "not", "significantly", "different", "between", "the", "groups.", "Conclusions:", "Despite", "some", "promising", "results,", "it", "seems", "too", "early", "to", "conclude", "that", "low", "O2", "culture", "has", "an", "effect", "on", "IVF", "outcome.", "Additional", "randomised", "controlled", "trials", "are", "necessary", "before", "evidence-based", "recommendations", "can", "be", "provided.", "It", "should", "be", "emphasised", "that", "the", "present", "meta-analysis", "does", "not", "provide", "any", "evidence", "that", "low", "oxygen", "concentration", "is", "unnecessary.", "Keywords:", "low", "oxygen,", "embryo", "culture,", "gas", "atmosphere,", "IVF/ICSI", "Background", "The", "role", "of", "oxygen", "tension", "during", "the", "culture", "of", "gametes", "and", "embryos", "has", "been", "the", "subject", "of", "study", "in", "both", "animal", "models", "and", "humans.", "Following", "protocols", "from", "somatic", "cell", "culture", "techniques,", "the", "embryos", "of", "humans", "and", "other", "mammals", "have", "traditionally", "been", "cultured", "under", "*", "Correspondence:", "joaobatista@crh.com.br", "1Department", "of", "Gynaecology", "and", "Obstetrics,", "Botucatu", "Medical", "School,", "São", "Paulo", "State", "University", "-", "UNESP,", "Botucatu,", "Brazil", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "atmospheric", "oxygen", "tension", "(~20%).", "However,", "experi-", "mental", "studies", "in", "various", "species", "of", "mammals", "have", "revealed", "that", "the", "concentration", "of", "O2", "inside", "the", "uterus", "and", "oviducts", "usually", "fluctuates", "in", "the", "range", "of", "2-8%", "[1-5].", "Culture", "at", "low", "levels", "of", "O2", "(5-7%)", "can", "improve", "embryo-", "nic", "development", "in", "several", "species,", "including", "mice", "[6-10],", "rats", "[11],", "hamsters", "[12],", "rabbits", "[13],", "pigs", "[14],", "goats", "[15],", "sheep", "[16,17],", "and", "cattle", "[16,18].", "In", "addition,", "culturing", "at", "a", "low", "O2", "concentration", "is", "associated", "with", "a", "reduced", "rate", "of", "aneuploidy", "in", "mouse", "embryos", "[19].", "©", "2011", "Gomes", "Sobrinho", "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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[ "Cases", "Journal", "Case", "Report", "Neurocysticercosis", "as", "a", "first", "presentation", "of", "tonic-clonic", "seizures:", "a", "case", "report", "Matthew", "J", "Booker*,", "Catherine", "Snelson", "and", "Louise", "Dodd", "BioMed", "Central", "Open", "Access", "Address:", "Intensive", "Care", "Department,", "City", "Hospital,", "Birmingham,", "UK", "Email:", "Matthew", "J", "Booker*", "-", "mattbooker@doctors.org.uk;", "Catherine", "Snelson", "-", "snelson.catherine@swbh.nhs.uk;", "Louise", "Dodd", "-", "dodd.louise@swbh.nhs.uk", "*", "Corresponding", "author", "Published:", "18", "August", "2008", "Cases", "Journal", "2008,", "1:104", "doi:10.1186/1757-1626-1-104", "This", "article", "is", "available", "from:", "http://www.casesjournal.com/content/1/1/104", "Received:", "31", "July", "2008", "Accepted:", "18", "August", "2008", "©", "2008", "Booker", "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", "We", "report", "the", "case", "of", "a", "28", "year-old", "immigrant", "Asian", "man", "from", "the", "Punjab", "region", "with", "a", "first", "presentation", "of", "seizures.", "This", "patient", "had", "no", "significant", "past", "medical", "history,", "but", "suffered", "several", "headaches", "in", "the", "preceding", "week", "and", "was", "pyrexial", "on", "presentation.", "A", "CT", "scan", "of", "his", "head", "showed", "a", "single", "area", "of", "subcortical", "low", "attenuation", "initially", "suggesting", "ischaemia.", "A", "lumbar", "puncture", "and", "CSF", "examination", "was", "unremarkable.", "Further", "investigation", "revealed", "discrete", "calcified", "gluteal", "lesions", "on", "pelvic", "X-ray,", "and", "serum", "immunology", "positive", "for", "cysticercosis.", "The", "diagnosis", "of", "neurocysticercosis", "was", "made,", "and", "the", "patient", "improved", "on", "dexamethasone", "and", "a", "short", "course", "of", "vermicide,", "to", "be", "discharged", "a", "week", "later.", "With", "increasing", "global", "migration,", "the", "prevalence", "of", "neurological", "parasitic", "infections", "seen", "in", "the", "UK", "is", "likely", "to", "rise.", "This", "case", "highlights", "the", "importance", "of", "careful", "interpretation", "of", "non-specific", "head", "CTs", "in", "the", "context", "of", "first", "presentation", "of", "seizures", "in", "a", "susceptible", "population.", "Background", "Cysticercosis", "is", "the", "commonest", "parasitic", "infestation", "of", "the", "central", "nervous", "system", "worldwide.", "It", "is", "caused", "by", "the", "ingestion", "of", "the", "eggs", "or", "larvae", "of", "the", "tapeworm", "Taenia", "solium,", "found", "in", "faecally", "contaminated", "water", "and", "under-", "cooked", "pork,", "affecting", "the", "gut", "initially", "and", "spreading", "hae-", "matogenously", "[1].", "Sufferers", "often", "experience", "a", "long", "asymptomatic", "period,", "and", "can", "present", "with", "a", "variety", "of", "neurological", "manifestations,", "including", "focal", "neurological", "deficits,", "migraines,", "visual", "hallucinations", "and", "seizures", "[2].", "The", "diagnosis", "of", "cysticercosis", "is", "often", "only", "made", "coinci-", "dentally", "on", "post-mortem", "examination.", "Extra-neurological", "manifestations", "include", "ocular", "deposition", "and", "skeletal", "muscle", "nodules.", "As", "such,", "careful", "fundoscopy", "and", "plain", "film", "radiology", "are", "mandatory", "for", "all", "in", "whom", "the", "diagno-", "sis", "is", "suspected.", "A", "single", "short", "course", "of", "the", "vermicidal", "albendazole", "is", "usually", "sufficient", "to", "clear", "an", "infestation.", "The", "patient", "will", "need", "repeat", "imaging", "after", "several", "months", "to", "ensure", "complete", "eradication.", "Even", "having", "achieved", "this,", "long-term", "neurological", "sequelae", "are", "not", "uncommon.", "Case", "presentation", "The", "patient,", "a", "28", "year-old", "Asian", "man,", "was", "admitted", "via", "ambulance", "to", "the", "Accident", "&", "Emergency", "department", "of", "City", "Hospital,", "Birmingham", "UK,", "following", "three", "successive", "witnessed", "tonic-clonic", "seizures.", "Each", "seizure", "lasted", "approximately", "6", "minutes,", "being", "separated", "by", "several", "min-", "utes", "of", "incomplete", "recovery.", "The", "patient", "had", "complained", "to", "relatives", "of", "minor", "headaches", "during", "the", "preceding", "week,", "settling", "with", "simple", "analgesia.", "He", "was", "otherwise", "fit", "and", "well,", "on", "no", "medication,", "with", "no", "significant", "past", "med-", "ical", "history", "of", "note", "and", "no", "history", "of", "head", "trauma.", "He", "moved", "to", "the", "UK", "from", "the", "Punjab", "region", "10", "years", "previ-", "ously,", "and", "has", "not", "been", "abroad", "since.", "Page", "1", "of", "2", "(page", "number", "not", "for", "citation", "purposes)" ]

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[ "Olivieri", "et", "al.", "Italian", "Journal", "of", "Pediatrics", "2010,", "36:72", "http://www.ijponline.net/content/36/1/72", "C", "A", "S", "E", "R", "E", "P", "O", "R", "T", "ITALIAN", "JOURNAL", "OF", "PEDIATRICS", "Open", "Access", "Refractory", "vasculitic", "ulcer", "of", "the", "toe", "in", "adolescent", "suffering", "from", "Systemic", "Lupus", "Erythematosus", "treated", "successfully", "with", "hyperbaric", "oxygen", "therapy", "Alma", "N", "Olivieri1*,", "Antonio", "Mellos1,", "Carlo", "Duilio2,", "Milena", "Di", "Meglio1,", "Angela", "Mauro1,", "Laura", "Perrone1", "Abstract", "Skin", "ulcers", "are", "a", "dangerous", "and", "uncommon", "complication", "of", "vasculitis.", "We", "describe", "the", "case", "of", "a", "teenager", "suffering", "from", "Systemic", "Lupus", "Erythematosus", "with", "digital", "ulcer", "resistant", "to", "conventional", "therapy,", "treated", "success-", "fully", "with", "Hyperbaric", "Oxygen", "Therapy.", "The", "application", "of", "hyperbaric", "oxygen,", "which", "is", "used", "for", "the", "treatment", "of", "ischemic", "ulcers,", "is", "an", "effective", "and", "safe", "therapeutic", "option", "in", "patients", "with", "ischemic", "vasculitic", "ulcers", "in", "combina-", "tion", "with", "immunosuppressive", "drugs.", "Further", "studies", "are", "needed", "to", "evaluate", "its", "role", "as", "primary", "therapy", "for", "this", "group", "of", "patients.", "Introduction", "Vasculitis", "is", "a", "heterogeneous", "group", "of", "diseases", "character-", "ized", "by", "inflammatory", "processes", "of", "the", "blood", "vessel", "wall", "resulting", "in", "the", "alteration", "of", "blood", "flow", "and", "vascular", "damage.", "The", "vessels", "involved", "are", "of", "different", "sizes", "(arteries,", "arterioles,", "venules,", "capillaries).", "Resulting", "syn-", "dromes", "are", "the", "consequence", "of", "tissue", "ischemia,", "vascular", "damage", "and", "systemic", "inflammation.", "Most", "vasculitis", "is", "mediated", "by", "the", "vascular", "deposition", "of", "immune", "com-", "plexes", "(IC),", "abnormal", "cell-mediated", "immune", "responses,", "antibodies", "against", "endothelial", "cells", "or", "against", "lysosomal", "enzymes", "of", "neutrophils.", "Vasculitis", "may", "be", "primary", "or", "secondary", "to", "connective", "tissue", "and", "intestinal", "diseases,", "medications,", "tumors", "or", "athopy.", "Vasculitic", "skin", "ulcers", "are", "clinical", "manifestations", "of", "ischemic", "injury,", "and", "are", "usually", "treated", "medically", "by", "controlling", "the", "underlying", "disease", "with", "immunosuppressants", "and", "systemic", "vasodilators", "[1].", "Hyperbaric", "oxygen", "therapy", "(HBOT)", "is", "used", "as", "primary", "or", "adjuvant", "therapy", "in", "various", "clinical", "conditions,", "including", "cutaneous", "vasculitic", "ulcers", "that", "are", "resistant", "to", "immuno-", "suppressive", "therapy", "[2].", "We", "present", "a", "case", "of", "refractory", "vasculitic", "ulcer", "responding", "to", "hyperbaric", "oxygen", "(HBO),", "which", "was", "used", "in", "combination", "with", "immunosuppressive", "therapy.", "We", "decided", "to", "treat", "the", "infected", "ulcer", "of", "the", "patient", "with", "HBOT", "not", "only", "because", "it", "improves", "the", "*", "Correspondence:", "alma.olivieri@unina2.it", "1Department", "of", "Pediatrics,", "Second", "University", "of", "Naples,", "Via", "L.", "De", "Crecchio", "2,", "80138", "Naples,", "Italy", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "oxygenation", "of", "ischemic", "tissues", "and", "exerts", "beneficial", "effects", "on", "vascular", "inflammatory", "response", "by", "regulating", "the", "chemotaxis", "of", "leukocytes,", "but", "also", "because", "it", "facili-", "tates", "the", "healing", "process", "of", "infected", "wounds", "promoting", "the", "deposition", "of", "collagen,", "angiogenesis,", "epithelialization", "and", "facilitating", "the", "oxygen-dependent", "killing", "by", "leukocytes.", "Case", "report", "In", "mid", "February", "2008", "a", "14", "year", "old", "girl", "came", "under", "our", "observation.", "She", "had", "been", "suffering", "for", "about", "3", "months", "from", "persistent", "fever", "(38", "°", "C),", "weight", "loss", "(9", "kilos),", "head-", "ache", "and", "asthenia", "and", "was", "previously", "treated", "with", "several", "courses", "of", "antibiotics", "and", "prednisone.", "Family", "history", "shows", "that", "her", "paternal", "grandmother", "suffers", "from", "sclero-", "derma,", "her", "paternal", "grandfather", "from", "rheumatoid", "arthritis,", "her", "maternal", "grandmother", "from", "autoimmune", "thrombocy-", "topenia,", "and", "her", "mother", "from", "thyroiditis.", "At", "admission,", "she", "had", "a", "body", "weight", "of", "45", "kg", "(10th", "-25th", "percentile)", "and", "a", "height", "of", "154", "cm", "(10th", "-25th", "percentile).", "Physical", "exami-", "nation", "revealed", "a", "rash", "on", "the", "face,", "livedo", "reticularis,", "acro-", "cyanosis", "at", "the", "first", "and", "second", "toe", "of", "the", "left", "foot,", "arthritis", "in", "knees", "and", "ankles.", "Blood", "tests", "showed:", "anemia", "(hemoglobin", "10.5", "gr/dl),", "leukocitopenia", "(3300/μl)", "with", "lymphopenia", "(30%),", "normal", "platelet", "count", "(289000/μl),", "increased", "inflammatory", "indexes", "(erythrocyte", "sedimenta-", "tion", "rate", "53", "mm/1", "hour;", "C-reactive", "protein", "1,44", "mg/dl);", "increased", "serum", "IgG", "(2270", "mg/dl),", "lengthening", "of", "prothrombin", "time", "(57.5", "seconds),", "reduced", "serum", "iron", "©", "2010", "Olivieri", "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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[ "BMC", "Molecular", "Biology", "Research", "article", "Selective", "control", "of", "primer", "usage", "in", "multiplex", "one-step", "reverse", "transcription", "PCR", "Elena", "Hidalgo", "Ashrafi,", "Joyclyn", "Yee", "and", "Natasha", "Paul*", "BioMed", "Central", "Open", "Access", "Address:", "Department", "of", "Research", "and", "Development,", "TriLink", "BioTechnologies,", "Inc.,", "9955", "Mesa", "Rim", "Road,", "San", "Diego,", "CA", "92121,", "USA", "Email:", "Elena", "Hidalgo", "Ashrafi", "-", "ehidalgo@trilinkbiotech.com;", "Joyclyn", "Yee", "-", "jyee@jcvi.org;", "Natasha", "Paul*", "-", "npaul@trilinkbiotech.com", "*", "Corresponding", "author", "Published:", "30", "December", "2009", "BMC", "Molecular", "Biology", "2009,", "10:113", "doi:10.1186/1471-2199-10-113", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1471-2199/10/113", "Received:", "11", "May", "2009", "Accepted:", "30", "December", "2009", "©", "2009", "Hidalgo", "Ashrafi", "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:", "Multiplex", "RT-PCR", "is", "a", "valuable", "technique", "used", "for", "pathogen", "identification,", "disease", "detection", "and", "relative", "quantification", "of", "gene", "expression.", "The", "simplification", "of", "this", "protocol", "into", "a", "one-step", "procedure", "saves", "time", "and", "reagents.", "However,", "intensive", "PCR", "optimization", "is", "often", "required", "to", "overcome", "competing", "undesired", "PCR", "primer", "extension", "during", "the", "RT", "step.", "Results:", "Herein,", "we", "report", "multiplex", "one-step", "RT-PCR", "experiments", "in", "which", "the", "PCR", "primers", "contain", "thermolabile", "phosphotriester", "modification", "groups.", "The", "presence", "of", "these", "groups", "minimizes", "PCR", "primer", "extension", "during", "the", "RT", "step", "and", "allows", "for", "control", "of", "PCR", "primer", "extension", "until", "the", "more", "stringent,", "elevated", "temperatures", "of", "PCR", "are", "reached.", "Results", "reveal", "that", "the", "use", "of", "primers", "whose", "extension", "can", "be", "controlled", "in", "a", "temperature-mediated", "way", "provides", "improved", "one-step", "RT-PCR", "specificity", "in", "both", "singleplex", "and", "multiplex", "reaction", "formats.", "Conclusions:", "The", "need", "for", "an", "accurate", "and", "sensitive", "technique", "to", "quantify", "mRNA", "expression", "levels", "makes", "the", "described", "modified", "primer", "technology", "a", "promising", "tool", "for", "use", "in", "multiplex", "one-", "step", "RT-PCR.", "A", "more", "accurate", "representation", "of", "the", "abundances", "in", "initial", "template", "sample", "is", "feasible", "with", "modified", "primers,", "as", "artifacts", "of", "biased", "PCR", "are", "reduced", "because", "of", "greater", "improvements", "in", "reaction", "specificity.", "Background", "Reverse", "transcription", "PCR", "(RT-PCR),", "a", "protocol", "widely", "used", "to", "produce", "DNA", "copies", "of", "an", "RNA", "strand", "of", "interest,", "involves", "a", "lower", "temperature", "reverse", "transcription", "step", "followed", "by", "an", "elevated", "temperature", "PCR", "step", "[1].", "RT-", "PCR", "reactions", "are", "typically", "separated", "into", "two", "separate", "steps.", "However,", "as", "the", "number", "of", "manipulations", "in", "a", "reac-", "tion", "protocol", "increases,", "so", "does", "the", "probability", "of", "con-", "tamination.", "Reduction", "of", "the", "two", "separate", "manipulation", "procedures", "into", "a", "one-step", "RT-PCR", "protocol", "provides", "a", "more", "streamlined,", "high-throughput", "technique", "that", "lowers", "the", "probability", "of", "contamination", "by", "minimizing", "the", "number", "of", "handling", "steps", "[2].", "However,", "one-step", "RT-PCR", "protocols", "are", "not", "without", "inherent", "limitations", "and", "have", "often", "been", "found", "to", "be", "less", "sensitive", "than", "the", "correspond-", "ing", "two-step", "protocols", "[3-5].", "One", "likely", "cause", "for", "this", "lower", "sensitivity", "is", "competing", "extension", "of", "PCR", "primers", "by", "reverse", "transcriptase", "[6]", "or", "DNA", "polymerase", "[7].", "At", "lower,", "less", "discriminatory", "temperatures", "of", "reverse", "tran-", "scription,", "PCR", "primer", "extension", "may", "result", "in", "off-target", "amplification", "products", "such", "as", "primer", "dimer", "and", "mispriming", "products.", "To", "improve", "the", "specificity", "of", "RT-", "PCR,", "it", "is", "necessary", "to", "block", "such", "primer", "extension", "at", "lower", "temperatures.", "Page", "1", "of", "13", "(page", "number", "not", "for", "citation", "purposes)" ]

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[ "Adaptation", "to", "larval", "crowding", "in", "Drosophila", "ananassae", "leads", "to", "the", "evolution", "of", "population", "stability", "Snigdhadip", "Dey,", "Joy", "Bose∗", "&", "Amitabh", "Joshi", "Evolutionary", "Biology", "Laboratory,", "Evolutionary", "and", "Organismal", "Biology", "Unit,", "Jawaharlal", "Nehru", "Centre", "for", "Advanced", "Scientific", "Research,", "Jakkur", "P.O.,", "Bangalore,", "560", "064,", "India", "Keywords", "α-Selection,", "competitive", "ability,", "constancy,", "density-dependent", "selection,", "K-selection,", "life-history", "evolution,", "persistence,", "population", "dynamics.", "Correspondence", "Amitabh", "Joshi,", "Evolutionary", "and", "Organismal", "Biology", "Unit,", "Jawaharlal", "Nehru", "Centre", "for", "Advanced", "Scientific", "Research,", "Jakkur", "P.O.,", "Bangalore", "560", "064,", "India.", "Tel:", "+91-80-22082802;", "Fax:", "+91–80-22082766;", "E-mail:", "ajoshi@jncasr.ac.in", "∗Current", "address:", "Department", "of", "Behavioural", "Biology,", "University", "of", "Osnabru¨", "ck,", "49076", "Osnabr", "u¨ck,", "Germany.", "Supported", "by", "funds", "from", "the", "Department", "of", "Science", "and", "Technology,", "Government", "of", "India.", "Received:", "14", "October", "2011;", "Revised:", "13", "January", "2012;", "Accepted:", "24", "January", "2012", "Ecology", "and", "Evolution", "2012;", "2(5):", "941–951", "doi:", "10.1002/ece3.227", "Abstract", "Density-dependent", "selection", "is", "expected", "to", "lead", "to", "population", "stability,", "especially", "if", "r", "and", "K", "tradeoff.", "Yet,", "there", "is", "no", "empirical", "evidence", "of", "adaptation", "to", "crowding", "leading", "to", "the", "evolution", "of", "stability.", "We", "show", "that", "populations", "of", "Drosophila", "ananassae", "selected", "for", "adaptation", "to", "larval", "crowding", "have", "higher", "K", "and", "lower", "r,", "and", "evolve", "greater", "stability", "than", "controls.", "We", "also", "show", "that", "increased", "population", "growth", "rates", "at", "high", "density", "can", "enhance", "stability,", "even", "in", "the", "absence", "of", "a", "decrease", "in", "r,", "by", "ensuring", "that", "the", "crowding", "adapted", "populations", "do", "not", "fall", "to", "very", "low", "sizes.", "We", "discuss", "our", "results", "in", "the", "context", "of", "traits", "known", "to", "have", "diverged", "between", "the", "selected", "and", "control", "populations,", "and", "compare", "our", "results", "with", "previous", "work", "on", "the", "evolution", "of", "stability", "in", "D.", "melanogaster.", "Overall,", "our", "results", "suggest", "that", "density-dependent", "selection", "may", "be", "an", "important", "factor", "promoting", "the", "evolution", "of", "relatively", "stable", "dynamics", "in", "natural", "populations.", "Introduction", "Though", "the", "connection", "between", "crowding", "and", "evolution", "was", "implicit", "in", "the", "conception", "of", "natural", "selection,", "the", "unifying", "interface", "between", "population", "dynamics", "and", "evolutionary", "ge-", "netics", "was", "largely", "unexplored", "by", "ecologists", "and", "evolutionists", "during", "the", "first", "half", "of", "the", "20th", "century", "(Mueller", "and", "Joshi", "2000).", "The", "first", "studies", "at", "this", "interface", "addressed", "the", "effect", "of", "ecology", "on", "evolution", "via", "density-dependent", "selection,", "or", "the", "notion", "that", "genotypic", "fitnesses", "could", "vary", "as", "a", "function", "of", "population", "density", "(MacArthur", "1962;", "MacArthur", "and", "Wilson", "1967;", "Gadgil", "and", "Bossert", "1970;", "Roughgarden", "1971;", "Clarke", "1972;", "Asmussen", "1983).", "Many", "of", "these", "studies", "assumed", "that", "life-history", "related", "traits", "affecting", "intrinsic", "growth", "rate", "(r)", "and", "carrying", "capacity", "(K", ")", "would", "tradeoff,", "and", "such", "a", "trade-", "off", "between", "realized", "per", "capita", "growth", "rates", "at", "low", "versus", "high", "densities", "was", "empirically", "demonstrated", "in", "Drosophila", "melanogaster", "by", "Mueller", "and", "Ayala", "(1981a).", "Around", "the", "same", "time,", "it", "was", "also", "realized", "that", "simple", "population", "growth", "mod-", "els", "could", "yield", "complex", "and", "unstable", "dynamics,", "especially", "if", "intrinsic", "per", "capita", "growth", "rates", "were", "high", "(May", "1974;", "May", "and", "Oster", "1976).", "Yet,", "a", "majority", "of", "wild", "and", "laboratory", "pop-", "ulations", "with", "high", "female", "fecundity", "were", "found", "to", "show", "rel-", "atively", "stable", "dynamics", "(Hassell", "et", "al.", "1976;", "Thomas", "et", "al.", "1980;", "Mueller", "and", "Ayala", "1981b)", "leading", "to", "an", "increasing", "in-", "terest", "in", "proximal", "and", "ultimate", "causes", "of", "population", "stability", "(reviewed", "by", "Mueller", "and", "Joshi", "2000).", "Among", "the", "suggested", "mechanisms", "for", "the", "evolution", "of", "population", "stability", "were", "group", "selection", "favoring", "popula-", "tions", "with", "stable", "dynamics", "(Thomas", "et", "al.", "1980;", "Berryman", "c", "2012", "The", "Authors.", "Published", "by", "Blackwell", "Publishing", "Ltd.", "This", "is", "an", "open", "access", "article", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "Non", "Commercial", "License,", "which", "permits", "use,", "distribution", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited", "and", "is", "not", "used", "for", "commercial", "purposes.", "941" ]

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[ "Zailong", "Cai1*", "Abstract", "Puerarin", "Suppresses", "Proliferation", "of", "Endometriotic", "Stromal", "Cells", "Partly", "via", "the", "MAPK", "Signaling", "Pathway", "Induced", "by", "17ß-estradiol-BSA", "Wen", "Cheng1.,", "Lizao", "Chen1.,", "Shengsheng", "Yang1.,", "Jie", "Han", "1", ",", "Dongxia", "Zhai1,", "Jian", "Ni2,", "Chaoqin", "Yu1*,", "1", "Department", "of", "Traditional", "Chinese", "Medicine,", "Changhai", "Hospital", "and", "Department", "of", "Biochemistry", "and", "Molecular", "Biology,", "Second", "Military", "Medical", "University,", "Shanghai,", "China,", "2", "Institute", "of", "Micro/Nano", "Science", "and", "Technology,", "Shanghai", "Jiaotong", "University,", "Shanghai,", "China", "Background:", "Puerarin", "is", "a", "major", "isoflavonoid", "compound", "extracted", "from", "Radix", "puerariae.", "It", "has", "a", "weak", "estrogenic", "action", "by", "binding", "to", "estrogen", "receptors", "(ERs).", "In", "our", "early", "clinical", "practice", "to", "treat", "endometriosis,", "a", "better", "therapeutic", "effect", "was", "achieved", "if", "the", "formula", "of", "traditional", "Chinese", "medicine", "included", "Radix", "puerariae.", "The", "genomic", "and", "non-genomic", "effects", "of", "puerarin", "were", "studied", "in", "our", "Lab.", "This", "study", "aims", "to", "investigate", "the", "ability", "of", "puerarin", "to", "bind", "competitively", "to", "ERs", "in", "human", "endometriotic", "stromal", "cells", "(ESCs),", "determine", "whether", "and", "how", "puerarin", "may", "influence", "phosphorylation", "of", "the", "non-", "genomic", "signaling", "pathway", "induced", "by", "17ß-estradiol", "conjugated", "to", "BSA", "(E2-BSA).", "Methodology:", "ESCs", "were", "successfully", "established.", "Binding", "of", "puerarin", "to", "ERs", "was", "assessed", "by", "a", "radioactive", "competitive", "binding", "assay", "in", "ESCs.", "Activation", "of", "the", "signaling", "pathway", "was", "screened", "by", "human", "phospho-kinase", "array,", "and", "was", "further", "confirmed", "by", "western", "blot.", "Cell", "proliferation", "was", "analyzed", "according", "to", "the", "protocol", "of", "CCK-8.", "The", "mRNA", "and", "protein", "levels", "of", "cyclin", "D1,", "Cox-2", "and", "Cyp19", "were", "determined", "by", "real-time", "PCR", "and", "western", "blotting.", "Inhibitor", "of", "MEK1/2", "or", "ER", "antagonist", "was", "used", "to", "confirm", "the", "involved", "signal", "pathway.", "Principal", "Findings:", "Our", "data", "demonstrated", "that", "the", "total", "binding", "ability", "of", "puerarin", "to", "ERs", "on", "viable", "cells", "is", "around", "1/3", "that", "of", "17ß-estradiol", "(E2).", "E2-BSA", "was", "able", "to", "trigger", "a", "rapid,", "non-genomic,", "membrane-mediated", "activation", "of", "ERK1/2", "in", "ESCs", "and", "this", "phenomenon", "was", "associated", "with", "an", "increased", "proliferation", "of", "ESCs.", "Treating", "ESCs", "with", "puerarin", "abrogated", "the", "phosphorylation", "of", "ERK", "and", "significantly", "decreased", "cell", "proliferation,", "as", "well", "as", "related", "gene", "expression", "levels", "enhanced", "by", "E2-BSA.", "Conclusions/Significance:", "Puerarin", "suppresses", "proliferation", "of", "ESCs", "induced", "by", "E2-BSA", "partly", "via", "impeding", "a", "rapid,", "non-", "genomic,", "membrane-initiated", "ERK", "pathway,", "and", "down-regulation", "of", "Cyclin", "D1,", "Cox-2", "and", "Cyp19", "are", "involved", "in", "the", "process.", "Our", "data", "further", "show", "that", "puerarin", "may", "be", "a", "new", "candidate", "to", "treat", "endometriosis.", "Citation:", "Cheng", "W,", "Chen", "L,", "Yang", "S,", "Han", "J,", "Zhai", "D,", "et", "al.", "(2012)", "Puerarin", "Suppresses", "Proliferation", "of", "Endometriotic", "Stromal", "Cells", "Partly", "via", "the", "MAPK", "Signaling", "Pathway", "Induced", "by", "17ß-estradiol-BSA.", "PLoS", "ONE", "7(9):", "e45529.", "doi:10.1371/journal.pone.0045529", "Editor:", "Luis", "Eduardo", "M.", "Quintas,", "Universidade", "Federal", "do", "Rio", "de", "Janeiro,", "Brazil", "Received", "April", "17,", "2012;", "Accepted", "August", "20,", "2012;", "Published", "September", "19,", "2012", "Copyright:", "2012", "Cheng", "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", "National", "Natural", "Science", "Foundation", "of", "China", "(Project", "No.", "30672742,", "30873353,", "30930113)", "and", "973", "project", "(2010CB933902).", "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:", "chqyu81@gmail.com", "(CY);", "czl8003@hotmail.com", "(ZC)", ".", "These", "authors", "contributed", "equally", "to", "this", "work.", "Introduction", "Endometriosis", "(EM)", "is", "an", "estrogen-dependent", "benign", "disease", "characterized", "by", "extra-uterine", "implantation", "and", "ectopic", "growth", "of", "endometrium.", "It", "affects", "10–20%", "of", "women", "in", "their", "reproductive", "years,", "causing", "chronic", "pelvic", "pain", "and", "infertility", "[1].", "Current", "treatments,", "based", "on", "hormonal", "therapy", "or", "surgery,", "are", "often", "insufficient", "[2–4].", "Therefore,", "exploring", "novel", "therapeutic", "strategies", "is", "necessary", "for", "improving", "the", "clinical", "management", "of", "patients", "with", "endometriosis.", "17ß-estradiol", "(E2),", "which", "can", "be", "locally", "and", "distantly", "secreted", "by", "endometriotic", "cells", "and", "ovary,", "plays", "a", "critical", "role", "in", "the", "development", "and", "progression", "of", "endometriosis,", "in", "which", "it", "acts", "as", "an", "important", "regulator", "of", "cell", "proliferation,", "survival", "and", "differentiation.", "Clinical", "and", "experimental", "data", "have", "clearly", "established", "that", "E2", "is", "the", "key", "factor", "leading", "to", "adhesion,", "aggression", "and", "angiogenesis", "in", "the", "pathological", "process", "of", "endometriosis", "[5].", "The", "predominant", "physiological", "effects", "of", "E2", "traditionally", "have", "been", "considered", "to", "be", "based", "on", "interaction", "of", "E2", "with", "estrogen", "receptors", "(ERa", "and", "ERß).", "The", "effects", "are", "brought", "about", "via", "the", "regulation", "of", "transcriptional", "processes,", "involving", "nuclear", "trans-", "location,", "binding", "to", "specific", "estrogen", "response", "elements", "(EREs)", "and", "ultimately", "regulation", "of", "gene", "expression", "[6].", "However,", "a", "number", "of", "studies", "have", "shown", "that", "steroid", "hormones,", "particularly", "E2,", "are", "able", "to", "elicit", "cellular", "responses", "that", "are", "too", "rapid", "to", "be", "mediated", "by", "the", "activation", "of", "transcription", "and", "PLOS", "ONE", "|", "www.plosone.org", "1", "September", "2012", "|", "Volume", "7", "|", "Issue", "9", "|", "e45529" ]

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[ "JNM", "J", "Neurogastroenterol", "Motil,", "Vol.", "16", "No.", "1", "January,", "2010", "DOI:", "10.5056/jnm.2010.16.1.35", "Journal", "of", "Neurogastroenterology", "and", "Motility", "Original", "Article", "Short", "Segment", "Hiatal", "Hernia:", "Is", "It", "a", "Clinically", "Significant", "Entity?", "Jong", "Jin", "Hyun,", "M.D.,", "Ji", "Hoon", "Kim,", "M.D.,", "Jong", "Eun", "Yeon,", "M.D.,", "Jong-Jae", "Park,", "M.D.,", "Jae", "Seon", "Kim,", "M.D.,", "Kwan", "Soo", "Byun,", "M.D.,", "and", "Young-Tae", "Bak,", "M.D.*", "Department", "of", "Gastroenterology,", "Korea", "University", "Guro", "Hospital,", "Seoul,", "Korea", "Introduction", "Hiatal", "hernia", "(HH)", "is", "a", "well-known", "contributory", "factor", "of", "gastroesophageal", "reflux", "disease", "(GERD).", "However,", "studies", "on", "the", "clin", "-", "ical", "significance", "of", "simple", "small", "HH", "are", "lacking.", "We", "conducted", "a", "study", "to", "clarify", "the", "clinical", "significance", "of", "short", "segment", "HH", "(SSHH)", "in", "relation", "to", "GERD.", "Methods", "4,592", "consecutive", "cases", "(male/female:", "2,076/2,516,", "median", "age:", "49", "years)", "examined", "with", "diagnostic", "esophagogastroduodeno", "-", "scopy", "for", "the", "first", "time", "were", "enrolled.", "During", "the", "insertion", "of", "endoscope,", "presence", "of", "HH", "was", "determined", "and", "the", "length", "was", "measured,", "if", "present.", "The", "relationships", "between", "gender,", "age,", "presence", "of", "erosive", "esophagitis,", "and", "columnar-lined", "esophagus", "(CLE)", "and", "the", "lengths", "of", "HH", "were", "analyzed.", "Results", "Among", "4,592", "cases,", "HH", "was", "present", "in", "428", "cases", "(9.3%);", "SSHH", "was", "found", "in", "255", "cases", "(5.6%)", "and", "long", "segment", "HH", "(LSHH)", "in", "173", "cases", "(3.8%).", "HH", "was", "more", "frequent", "among", "males", "and", "patients", "with", "LSHH", "tended", "to", "be", "older.", "Erosive", "esophagitis", "was", "observed", "in", "4.8%,", "22.0%,", "and", "37.0%", "of", "no", "HH,", "SSHH,", "and", "LSHH", "group,", "respectively", "(p", "＜", "0.05).", "CLE", "was", "observed", "in", "14.4%,", "36.5%,", "and", "24.3%", "of", "no", "HH,", "SSHH,", "and", "LSHH", "group,", "respectively", "(p", "＜", "0.05).", "Conclusions", "SSHH", "is", "not", "a", "clinically", "silent", "and", "“innocent", "entity,”", "but", "rather", "a", "condition", "with", "a", "significant", "pathologic", "significance", "similar", "to", "LSHH", "in", "regard", "to", "GERD.", "(J", "Neurogastroenterol", "M", "otil", "2010;16:35-39)", "Key", "Words", "Hiatal", "hernia,", "Gastroesophageal", "reflux", "disease,", "Erosive", "esophagitis,", "Columnar-lined", "esophagus", "In", "tro", "d", "u", "c", "tio", "n", "Sliding", "type", "hiatal", "hernia", "(HH)", "is", "a", "condition", "in", "which", "the", "gastroesophageal", "junction", "(GEJ)", "and", "some", "portion", "of", "the", "stom-", "ach", "are", "displaced", "above", "the", "diaphragm.1,2", "HH", "impairs", "lower", "esophageal", "sphincter", "(LES)", "function", "and", "esophageal", "acid", "clea-", "rance.1-6", "Therefore,", "it", "predisposes", "to", "gastroesophageal", "reflux", "dis-", "Received:", "November", "15th,", "2009", "Accepted:", "November", "26th,", "2009", "CC", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "Non-Commercial", "License", "(http://creativecommons.", "org/licenses/by-nc/3.0)", "which", "permits", "unrestricted", "non-commercial", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "*Correspondence:", "Young-Tae", "Bak,", "M.D.", "Department", "of", "Gastroenterology,", "Korea", "University", "Guro", "Hospital,", "97", "Gurodong-gil,", "Guro-gu,", "Seoul", "152-703,", "Korea", "Tel:", "+82-2-2626-1778,", "Fax:", "+82-505-115-1778,", "E-mail:", "drbakyt@korea.ac.kr", "Financial", "support:", "None.", "Conflicts", "of", "interest:", "None.", "ⓒ", "2010", "The", "Korean", "Society", "of", "Neurogastroenterology", "and", "Motility", "J", "Neurogastroenterol", "Motil,", "Vol.", "16", "No.", "1", "January,", "2010", "www.jnmjournal.org", "ㅋ", "35" ]

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[ "Hindawi", "Publishing", "Corporation", "Sarcoma", "Volume", "2011,", "Article", "ID", "756982,", "11", "pages", "doi:10.1155/2011/756982", "Review", "Article", "Receptor", "Tyrosine", "Kinases", "as", "Therapeutic", "Targets", "in", "Rhabdomyosarcoma", "Lisa", "E.", "S.", "Crose1", "and", "Corinne", "M.", "Linardic1,", "2", "1", "Department", "of", "Pediatrics,", "Duke", "University", "Medical", "Center,", "Durham,", "NC", "27710,", "USA", "2", "Department", "of", "Pharmacology", "and", "Cancer", "Biology,", "Duke", "University", "Medical", "Center,", "Durham,", "NC", "27710,", "USA", "Correspondence", "should", "be", "addressed", "to", "Corinne", "M.", "Linardic,", "linar001@mc.duke.edu", "Received", "15", "September", "2010;", "Accepted", "1", "November", "2010", "Academic", "Editor:", "Peter", "Houghton", "Copyright", "©", "2011", "L.", "E.", "S.", "Crose", "and", "C.", "M.", "Linardic.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Rhabdomyosarcomas", "(RMSs)", "are", "the", "most", "common", "soft", "tissue", "sarcomas", "of", "childhood", "and", "adolescence.", "To", "date,", "there", "are", "no", "effective", "treatments", "that", "target", "the", "genetic", "abnormalities", "in", "RMS,", "and", "current", "treatment", "options", "for", "high-risk", "groups", "are", "not", "adequate.", "Over", "the", "past", "two", "decades,", "research", "into", "the", "molecular", "mechanisms", "of", "RMS", "has", "identified", "key", "genes", "and", "signaling", "pathways", "involved", "in", "disease", "pathogenesis.", "In", "these", "studies,", "members", "of", "the", "receptor", "tyrosine", "kinase", "(RTK)", "family", "of", "cell", "surface", "receptors", "have", "been", "characterized", "as", "druggable", "targets", "for", "RMS.", "Through", "small", "molecule", "inhibitors,", "ligand-neutralizing", "agents,", "and", "monoclonal", "receptor-blocking", "antibodies,", "RTK", "activity", "can", "be", "manipulated", "to", "block", "oncogenic", "properties", "associated", "with", "RMS.", "Herein,", "we", "review", "the", "members", "of", "the", "RTK", "family", "that", "are", "implicated", "in", "RMS", "tumorigenesis", "and", "discuss", "both", "the", "problems", "and", "promise", "of", "targeting", "RTKs", "in", "RMS.", "1.", "Introduction", "The", "most", "common", "soft", "tissue", "sarcomas", "of", "childhood", "and", "adolescence", "are", "rhabdomyosarcomas", "(RMSs).", "These", "malig-", "nancies", "express", "skeletal", "muscle", "markers", "but", "are", "believed", "to", "be", "the", "result", "of", "dysregulated", "skeletal", "muscle", "differentiation", "of", "mesenchymal", "precursors.", "Like", "other", "sarcomas,", "RMS", "tumors", "are", "molecularly", "diverse;", "histological", "classification", "separates", "RMS", "into", "two", "major", "types,", "embryonal", "(eRMS)", "and", "alveolar", "rhabdomyosarcoma", "(aRMS).", "As", "the", "name", "implies,", "eRMS", "tumors", "consist", "of", "cells", "morphologically", "similar", "to", "embryonic", "muscle", "precursors.", "The", "histology", "of", "aRMS", "tumors", "is", "distinc-", "tive,", "with", "clusters", "of", "primitive,", "round", "cells", "and", "open", "spaces", "between", "cell", "sheets", "developing", "upon", "fixation", "in", "formalin,", "vaguely", "resembling", "lung", "alveoli", "[1].", "The", "eRMS", "and", "aRMS", "subtypes", "differ", "not", "only", "in", "histological", "appearance", "but", "also", "in", "prognosis.", "Patients", "with", "eRMS", "have", "a", "generally", "favor-", "able", "prognosis,", "while", "patients", "with", "aRMS", "do", "significantly", "worse,", "with", "a", "five-year", "survival", "rate", "of", "less", "than", "50%", "[2].", "Furthermore,", "aRMS", "can", "be", "specified", "by", "the", "presence", "of", "a", "chromosomal", "translocation", "resulting", "in", "a", "PAX3-FOXO1", "(or", "the", "less", "frequent", "PAX7-FOXO1,", "PAX3-NCOA1,", "or", "PAX3-", "NCOA2", "[3])", "gene", "product.", "When", "metastatic,", "PAX3-FOXO1-", "positive", "aRMS", "patients", "survive", "in", "fewer", "than", "10%", "of", "cases", "[4].", "Although", "staging", "of", "RMS", "still", "utilizes", "histology,", "recent", "gene", "profiling", "studies", "have", "suggested", "that", "a", "more", "accurate", "classification", "of", "RMS", "might", "be", "as", "fusion", "gene", "positive", "or", "negative", "[5,", "6].", "Thus,", "modified", "classification", "of", "RMS", "may", "lead", "to", "better", "risk", "stratification", "at", "diagnosis", "and", "direct", "appropriate", "therapy.", "Treatment", "for", "RMS", "has", "depended", "on", "a", "multimodal", "approach", "of", "surgery,", "chemotherapy,", "and", "radiation.", "This", "team", "strategy", "has", "resulted", "in", "an", "overall", "survival", "of", "RMS", "at", "about", "70%", "[7].", "But", "as", "described", "above,", "high-risk", "patients", "have", "a", "poor", "prognosis,", "and", "treatment", "options", "are", "limited.", "It", "is", "believed", "that", "without", "targeted", "therapies", "specific", "for", "genetic", "abnormalities", "associated", "with", "RMS,", "the", "survival", "rate", "will", "not", "improve.", "Over", "the", "past", "two", "decades,", "research", "into", "the", "molecular", "mechanisms", "of", "RMS", "has", "identified", "key", "genes", "and", "signaling", "pathways", "involved", "in", "disease", "pathogenesis.", "Opportunely,", "many", "groups", "have", "identified", "favorable", "molecular", "targets", "for" ]

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"Taichung,", "Taiwan;", "5Department", "of", "Physical", "Therapy,", "China", "Medical", "University,", "Taichung,", "Taiwan", "Correspondence:", "Li-Wei", "Chou", "Department", "of", "Physical", "Medicine", "and", "Rehabilitation,", "China", "Medical", "University", "Hospital,", "No", "2", "Yuh-Der", "Road,", "Taichung", "404,Taiwan", "Tel", "+88", "64", "2205", "2121", "ext", "2381", "Fax", "+88", "64", "2202", "6041", "Email", "chouliwe@tcts.seed.net.tw", "submit", "your", "manuscript", "|", "www.dovepress.com", "Dovepress", "http://dx.doi.org/10.2147/NDT.S31713", "Abstract:", "There", "are", "few", "reports", "in", "the", "literature", "of", "tuberculous", "brain", "abscess.", "Tuberculous", "brain", "abscess", "usually", "occurs", "in", "an", "immunocompromised", "host.", "Almost", "all", "previously", "documented", "cases", "have", "involved", "acquired", "immune", "deficiency", "syndrome.", "We", "encountered", "a", "53-year-old", "right-handed", "immunocompetent", "male", "who", "was", "initially", "suspected", "of", "having", "a", "cerebrovascular", "accident", "due", "to", "acute-onset", "right", "hemiparesis", "and", "paresthesia.", "A", "tentative", "diagnosis", "of", "brain", "tumor", "versus", "brain", "abscess", "was", "made", "on", "imaging", "studies.", "The", "patient", "was", "finally", "diagnosed", "with", "a", "tuberculous", "brain", "abscess", "based", "upon", "deterioration", "on", "imaging", "and", "a", "positive", "tuberculosis", "culture.", "The", "tuberculous", "brain", "abscess", "was", "located", "in", "the", "left", "parietal", "lobe,", "which", "resulted", "in", "Gerstmann’s", "syndrome", "and", "right-sided", "apraxia.", "Stereotactic", "surgery", "was", "performed.", "He", "was", "also", "given", "antituberculosis", "chemotherapy", "and", "comprehensive", "rehabilitation.", "Considerable", "improvement", "was", "noted", "after", "rehabilitation.", "The", "patient", "even", "returned", "to", "a", "normal", "life", "and", "work.", "Our", "case", "demonstrates", "that", "an", "aggressive", "intensive", "inpatient", "rehabilitation", "program", "combined", "with", "stereotactic", "surgery", "and", "effective", "antituberculosis", "therapy", "play", "an", "important", "role", "in", "improving", "the", "outcome", "for", "patients", "with", "tuberculous", "brain", "abscess,", "Gerstmann’s", "syndrome,", "and", "right-sided", "apraxia.", "Keywords:", "tuberculous", "brain", "abscess,", "Gerstmann’s", "syndrome,", "rehabilitation", "Introduction", "Tuberculosis", "(TB)", "most", "commonly", "affects", "the", "lungs,1", "with", "extrapulmonary", "TB", "observed", "in", "only", "20%", "of", "all", "cases.2", "TB", "of", "the", "central", "nervous", "system", "accounts", "for", "approximately", "1%", "of", "all", "TB", "cases.3", "Most", "cases", "of", "TB", "affecting", "the", "central", "nervous", "system", "develop", "in", "immunocompromised", "persons", "with", "pulmonary", "TB,4,5", "and", "com-", "monly", "manifests", "as", "meningitis", "or", "tuberculoma.6,7", "Tuberculous", "brain", "abscess", "is", "a", "very", "uncommon", "form", "of", "TB", "in", "the", "central", "nervous", "system.6,7", "Diagnosis", "of", "a", "tuberculous", "brain", "abscess", "may", "be", "very", "difficult", "in", "a", "person", "without", "a", "history", "of", "contact", "with", "TB", "or", "without", "pulmonary", "TB.", "Symptoms", "of", "tuberculous", "brain", "abscess", "also", "depend", "on", "the", "location", "of", "the", "lesion.", "A", "tuberculous", "brain", "abscess", "may", "mimic", "a", "cerebrovascular", "accident", "or", "a", "brain", "tumor.", "Lesions", "located", "in", "the", "left", "parietal", "lobe", "may", "result", "in", "Gerstmann’s", "syndrome.", "Here", "we", "present", "a", "case", "present-", "ing", "as", "Gerstmann’s", "syndrome", "secondary", "to", "a", "rare", "tuberculous", "brain", "abscess", "without", "primary", "pulmonary", "lesions", "or", "immunocompromise.", "Case", "report", "A", "53-year-old", "right-handed", "man", "complained", "of", "acute-onset", "right-sided", "weakness", "and", "paresthesia.", "He", "was", "reportedly", "healthy", "with", "no", "chronic", "or", "infectious", "diseases.", "Neuropsychiatric", "Disease", "and", "Treatment", "2012:8", "217–220", "©", "2012", "Kuo", "et", "al,", "publisher", "and", "licensee", "Dove", "Medical", "Press", "Ltd.", "This", "is", "an", "Open", "Access", "article", "which", "permits", "unrestricted", "noncommercial", "use,", "provided", "the", "original", "work", "is", "properly", "cited.", "217" ]

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[ "Cox-Singh", "et", "al.", "Malaria", "Journal", "2010,", "9:10", "http://www.malariajournal.com/content/9/1/10", "C", "A", "S", "E", "R", "E", "P", "O", "R", "T", "Open", "Access", "Severe", "malaria", "-", "a", "case", "of", "fatal", "Plasmodium", "knowlesi", "infection", "with", "post-mortem", "findings:", "a", "case", "report", "Janet", "Cox-Singh1,2*†,", "Jessie", "Hiu3†,", "Sebastian", "B", "Lucas4,", "Paul", "C", "Divis2,", "Mohammad", "Zulkarnaen2,", "Patricia", "Chandran5,", "Kum", "T", "Wong5,", "Patricia", "Adem6,", "Sherif", "R", "Zaki6,", "Balbir", "Singh2,", "Sanjeev", "Krishna1,2", "Abstract", "Background:", "Zoonotic", "malaria", "caused", "by", "Plasmodium", "knowlesi", "is", "an", "important,", "but", "newly", "recognized,", "human", "pathogen.", "For", "the", "first", "time,", "post-mortem", "findings", "from", "a", "fatal", "case", "of", "knowlesi", "malaria", "are", "reported", "here.", "Case", "presentation:", "A", "formerly", "healthy", "40", "year-old", "male", "became", "symptomatic", "10", "days", "after", "spending", "time", "in", "the", "jungle", "of", "North", "Borneo.", "Four", "days", "later,", "he", "presented", "to", "hospital", "in", "a", "state", "of", "collapse", "and", "died", "within", "two", "hours.", "He", "was", "hyponatraemic", "and", "had", "elevated", "blood", "urea,", "potassium,", "lactate", "dehydrogenase", "and", "amino", "transferase", "values;", "he", "was", "also", "thrombocytopenic", "and", "eosinophilic.", "Dengue", "haemorrhagic", "shock", "was", "suspected", "and", "a", "post-", "mortem", "examination", "performed.", "Investigations", "for", "dengue", "virus", "were", "negative.", "Blood", "for", "malaria", "parasites", "indicated", "hyperparasitaemia", "and", "single", "species", "P.", "knowlesi", "infection", "was", "confirmed", "by", "nested-PCR.", "Macroscopic", "pathology", "of", "the", "brain", "and", "endocardium", "showed", "multiple", "petechial", "haemorrhages,", "the", "liver", "and", "spleen", "were", "enlarged", "and", "lungs", "had", "features", "consistent", "with", "ARDS.", "Microscopic", "pathology", "showed", "sequestration", "of", "pigmented", "parasitized", "red", "blood", "cells", "in", "the", "vessels", "of", "the", "cerebrum,", "cerebellum,", "heart", "and", "kidney", "without", "evidence", "of", "chronic", "inflammatory", "reaction", "in", "the", "brain", "or", "any", "other", "organ", "examined.", "Brain", "sections", "were", "negative", "for", "intracellular", "adhesion", "molecule-1.", "The", "spleen", "and", "liver", "had", "abundant", "pigment", "containing", "macrophages", "and", "parasitized", "red", "blood", "cells.", "The", "kidney", "had", "evidence", "of", "acute", "tubular", "necrosis", "and", "endothelial", "cells", "in", "heart", "sections", "were", "prominent.", "Conclusions:", "The", "overall", "picture", "in", "this", "case", "was", "one", "of", "systemic", "malaria", "infection", "that", "fit", "the", "WHO", "classification", "for", "severe", "malaria.", "Post-mortem", "findings", "in", "this", "case", "were", "unexpectedly", "similar", "to", "those", "that", "define", "fatal", "falciparum", "malaria,", "including", "cerebral", "pathology.", "There", "were", "important", "differences", "including", "the", "absence", "of", "coma", "despite", "petechial", "haemorrhages", "and", "parasite", "sequestration", "in", "the", "brain.", "These", "results", "suggest", "that", "further", "study", "of", "knowlesi", "malaria", "will", "aid", "the", "interpretation", "of,", "often", "conflicting,", "information", "on", "malaria", "pathophysiology", "in", "humans.", "Background", "The", "underlying", "pathophysiology", "of", "malaria", "is", "not", "well", "understood", "despite", "considerable", "and", "prolonged", "interna-", "tional", "research", "effort.", "This", "effort", "is", "largely", "driven", "by", "the", "need", "to", "reduce", "the", "impact", "of", "Plasmodium", "falciparum", "on", "human", "life,", "particularly", "in", "African", "children", "[1,2].", "Part", "of", "the", "difficulty", "in", "studying", "the", "pathophysiology", "of", "P.", "falciparum", "malaria", "is", "the", "lack", "of", "a", "permissive", "animal", "model", "and", "a", "comparator", "disease", "in", "man.", "With", "the", "*", "Correspondence:", "coxsingh@gmail.com;", "coxsingh@gmail.com", "†", "Contributed", "equally", "1Division", "of", "Cellular", "and", "Molecular", "Medicine,", "Centre", "For", "Infection,", "St", "George’s", "University", "of", "London,", "Cranmer", "Terrace,", "London", "SW17", "0RE,", "UK", "recent", "discovery", "of", "severe", "malaria,", "caused", "by", "the", "zoono-", "tic", "parasite", "Plasmodium", "knowlesi", "in", "the", "human", "popula-", "tion", "of", "Southeast", "Asia", "[3,4],", "it", "is", "now", "possible", "to", "link", "findings", "in", "primates", "and", "humans", "through", "this", "common", "agent.", "In", "the", "natural", "primate", "hosts", "(long", "and", "pig-tailed", "macaques),", "P.", "knowlesi", "causes", "asymptomatic", "low-grade", "parasitism.", "In", "contrast,", "hyperparasitaemia", "and", "death", "ensue", "in", "the", "well-used", "Rhesus", "experimental", "model", "[5].", "Consequently,", "there", "is", "much", "information", "on", "experimen-", "tal", "P.", "knowlesi", "malaria,", "including", "organ", "pathology", "in", "various", "animal", "models", "[6-8].", "Natural", "P.", "knowlesi", "infec-", "tions", "of", "humans", "were", "formerly", "missed", "because", "of", "©", "2010", "Cox-Singh", "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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[ "J", "Korean", "Med", "Sci", "2009;", "24:", "166-9", "ISSN", "1011-8934", "DOI:", "10.3346/jkms.2009.24.1.166", "Copyright", "The", "Korean", "Academy", "of", "Medical", "Sciences", "Abdominal", "Aortic", "Aneurysm", "Repair", "in", "Patient", "with", "a", "Renal", "Allograft:", "A", "Case", "Report", "Renal", "transplant", "recipients", "requiring", "aortic", "reconstruction", "due", "to", "abdominal", "aortic", "aneurysm", "(AAA)", "pose", "a", "unique", "clinical", "problem.", "The", "concern", "during", "surgery", "is", "caus-", "ing", "ischemic", "injury", "to", "the", "renal", "allograft.", "A", "variety", "of", "strategies", "for", "protection", "of", "the", "renal", "allograft", "during", "AAA", "intervention", "have", "been", "described", "including", "a", "temporary", "shunt,", "cold", "renal", "perfusion,", "extracorporeal", "bypass,", "general", "hypothermia,", "and", "en-", "dovascular", "stent-grafting.", "In", "addition,", "some", "investigators", "have", "reported", "no", "remark-", "able", "complications", "of", "the", "renal", "allograft", "without", "any", "specific", "measures.", "We", "treated", "a", "case", "of", "AAA", "in", "a", "patient", "with", "a", "renal", "allograft", "using", "a", "temporary", "aortofemoral", "shunt", "with", "good", "result.", "Since", "this", "technique", "is", "safe", "and", "effective,", "it", "should", "be", "con-", "sidered", "in", "similar", "patients", "with", "AAA", "and", "previously", "placed", "renal", "allografts.", "Key", "Words", ":", "Aortic", "Aneurysm,", "Abdominal;", "Renal", "Allograft,", "Temporary", "Shunt", "INTRODUCTION", "Renal", "transplantation", "is", "a", "widely", "accepted", "treatment", "app-", "roach", "for", "an", "increasing", "number", "of", "patients", "with", "end-stage", "renal", "disease.", "Because", "of", "the", "improvement", "in", "immunosup-", "pressive", "therapy", "and", "management", "of", "patients", "after", "renal", "trans-", "plantation,", "long-term", "patient", "and", "renal", "allograft", "survival", "has", "improved.", "With", "the", "long-term", "renal", "allograft", "and", "patient", "survival,", "some", "patients", "develop", "secondary", "complications", "of", "systemic", "atherosclerosis,", "such", "as", "aortic", "aneurysmal", "or", "occlu-", "sive", "disease,", "necessitating", "operative", "intervention.", "In", "fact,", "many", "of", "these", "patients", "are", "at", "risk", "for", "accelerated", "atherogenesis", "due", "to", "their", "long-standing", "hypertension,", "uremia", "and", "other", "comor-", "bid", "factors.", "In", "renal", "allograft", "recipients,", "an", "abdominal", "aortic", "aneurysm", "(AAA)", "requiring", "surgical", "management", "may", "represent", "a", "truly", "life-threatening", "condition,", "and", "a", "more", "complicated", "repair.", "Aortic", "reconstruction", "with", "aortic", "cross-clamping", "places", "the", "renal", "allograft", "in", "the", "pelvis", "at", "risk", "for", "ischemic", "damage.", "To", "minimize", "this", "risk,", "several", "different", "operative", "strategies", "have", "been", "reported", "(1-8).", "We", "herein", "report", "our", "experience", "using", "a", "temporary", "shunt", "for", "AAA", "repair", "in", "a", "patient", "with", "a", "renal", "allograft.", "CASE", "REPORT", "A", "40-yr-old", "man", "developed", "end-stage", "renal", "disease", "secon-", "Hyung-Kee", "Kim,", "Jong-Pil", "Ryuk,", "Hyang", "Hee", "Choi,", "Sang-Hwy", "Kwon,", "and", "Seung", "Huh", "Division", "of", "Transplantation", "and", "Vascular", "Surgery,", "Department", "of", "Surgery,", "Kyungpook", "National", "University", "Hospital,", "Daegu,", "Korea", "Received", ":", "16", "October", "2007", "Accepted", ":", "19", "January", "2008", "Address", "for", "correspondence", "Seung", "Huh,", "M.D.", "Division", "of", "Transplantation", "and", "Vascular", "Surgery,", "Department", "of", "Surgery,", "Kyungpook", "National", "University", "Hospital,", "50", "Samdeok", "2-ga,", "Jung-gu,", "Daegu", "700-721,", "Korea", "Tel", ":", "+82.53-420-6520,", "Fax", ":", "+82.53-421-0510", "E-mail", ":", "shuh@mail.knu.ac.kr", "166", "dary", "to", "chronic", "glomerulonephritis", "that", "had", "been", "diagnosed", "18", "yr", "before.", "Thirteen", "years", "previously,", "he", "had", "undergone", "a", "living-related", "renal", "transplantation", "to", "the", "right", "iliac", "fossa", "without", "complications.", "The", "patient", "was", "maintained", "on", "pred-", "nisone", "and", "other", "immunosuppressants", "such", "as", "cyclosporine", "and", "mycophenolate", "mofetil.", "The", "transplanted", "kidney", "showed", "excellent", "function", "until", "the", "diagnosis", "of", "AAA.", "The", "serum", "creatinine", "level", "was", "within", "normal", "limits", "during", "the", "follow-", "up", "period.", "An", "abdominal", "ultrasound", "for", "the", "regular", "follow-", "up", "evaluation", "was", "performed", "in", "December", "2005.", "The", "scan", "revealed", "an", "AAA,", "and", "subsequent", "computed", "tomography", "(CT)", "angiography", "showed", "an", "infrarenal", "AAA", "measuring", "6.4", "cm", "in", "diameter", "(Fig.", "1).", "There", "was", "no", "radiographic", "evidence", "of", "leak", "or", "rupture.", "On", "preoperative", "evaluations,", "myocardial", "perfusion", "imag-", "ing", "at", "rest", "and", "under", "stress", "revealed", "an", "abnormal", "irreversible", "perfusion", "defect", "in", "the", "inferior", "and", "basal", "lateral", "wall.", "Coro-", "nary", "angiography", "showed", "a", "focal", "severe", "stenosis", "of", "the", "prox-", "imal", "left", "circumflex", "coronary", "artery.", "However,", "attempts", "to", "pass", "a", "balloon", "failed", "and", "he", "was", "maintained", "with", "medical", "treatment.", "After", "one", "month", "of", "medical", "management,", "he", "underwent", "an", "AAA", "repair", "with", "a", "tube", "prosthesis", "and", "a", "temporary", "aor-", "tofemoral", "shunt.", "Through", "a", "transperitoneal", "approach,", "the", "aorta", "was", "dissected", "up", "to", "the", "renal", "artery", "without", "renal", "vein", "division.", "A", "separate", "right", "groin", "incision", "was", "made", "to", "expose", "the", "common", "femoral", "artery.", "Because", "the", "proximal", "neck", "of", "his", "AAA", "was", "enough", "to", "place", "the", "temporary", "shunt,", "cannu-" ]

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