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[ "BMC", "Evolutionary", "Biology", "Research", "article", "Sequence", "and", "organization", "of", "coelacanth", "neurohypophysial", "hormone", "genes:", "evolutionary", "history", "of", "the", "vertebrate", "neurohypophysial", "hormone", "gene", "locus", "Pai-Chung", "Gwee1,", "Chris", "T", "Amemiya2,", "Sydney", "Brenner1", "and", "Byrappa", "Venkatesh*1", "BioMed", "Central", "Open", "Access", "Address:", "1Institute", "of", "Molecular", "and", "Cell", "Biology,", "A*STAR", "(Agency", "for", "Science,", "Technology", "and", "Research),", "Biopolis,", "138673,", "Singapore", "and", "2Benaroya", "Research", "Institute", "at", "Virginia", "Mason,", "Seattle,", "Washington", "98101,", "USA", "Email:", "Pai-Chung", "Gwee", "-", "pcgwee@imcb.a-star.edu.sg;", "Chris", "T", "Amemiya", "-", "camemiya@benaroyaresearch.org;", "Sydney", "Brenner", "-", "sydney_brenner@a-star.edu.sg;", "Byrappa", "Venkatesh*", "-", "mcbbv@imcb.a-star.edu.sg", "*", "Corresponding", "author", "Published:", "26", "March", "2008", "BMC", "Evolutionary", "Biology", "2008,", "8:93", "doi:10.1186/1471-2148-8-93", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1471-2148/8/93", "Received:", "11", "January", "2008", "Accepted:", "26", "March", "2008", "©", "2008", "Gwee", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "The", "mammalian", "neurohypophysial", "hormones,", "vasopressin", "and", "oxytocin", "are", "involved", "in", "osmoregulation", "and", "uterine", "smooth", "muscle", "contraction", "respectively.", "All", "jawed", "vertebrates", "contain", "at", "least", "one", "homolog", "each", "of", "vasopressin", "and", "oxytocin", "whereas", "jawless", "vertebrates", "contain", "a", "single", "neurohypophysial", "hormone", "called", "vasotocin.", "The", "vasopressin", "homolog", "in", "non-mammalian", "vertebrates", "is", "vasotocin;", "and", "the", "oxytocin", "homolog", "is", "mesotocin", "in", "non-eutherian", "tetrapods,", "mesotocin", "and", "[Phe2]mesotocin", "in", "lungfishes,", "and", "isotocin", "in", "ray-finned", "fishes.", "The", "genes", "encoding", "vasopressin", "and", "oxytocin", "genes", "are", "closely", "linked", "in", "the", "human", "and", "rodent", "genomes", "in", "a", "tail-to-tail", "orientation.", "In", "contrast,", "their", "pufferfish", "homologs", "(vasotocin", "and", "isotocin)", "are", "located", "on", "the", "same", "strand", "of", "DNA", "with", "isotocin", "gene", "located", "upstream", "of", "vasotocin", "gene", "separated", "by", "five", "genes,", "suggesting", "that", "this", "locus", "has", "experienced", "rearrangements", "in", "either", "mammalian", "or", "ray-finned", "fish", "lineage,", "or", "in", "both", "lineages.", "The", "coelacanths", "occupy", "a", "unique", "phylogenetic", "position", "close", "to", "the", "divergence", "of", "the", "mammalian", "and", "ray-finned", "fish", "lineages.", "Results:", "We", "have", "sequenced", "a", "coelacanth", "(Latimeria", "menadoensis)", "BAC", "clone", "encompassing", "the", "neurohypophysial", "hormone", "genes", "and", "investigated", "the", "evolutionary", "history", "of", "the", "vertebrate", "neurohypophysial", "hormone", "gene", "locus", "within", "a", "comparative", "genomics", "framework.", "The", "coelacanth", "contains", "vasotocin", "and", "mesotocin", "genes", "like", "non-mammalian", "tetrapods.", "The", "coelacanth", "genes", "are", "present", "on", "the", "same", "strand", "of", "DNA", "with", "no", "intervening", "genes,", "with", "the", "vasotocin", "gene", "located", "upstream", "of", "the", "mesotocin", "gene.", "Nucleotide", "sequences", "of", "the", "second", "exons", "of", "the", "two", "genes", "are", "under", "purifying", "selection", "implying", "a", "regulatory", "function.", "We", "have", "also", "analyzed", "the", "neurohypophysial", "hormone", "gene", "locus", "in", "the", "genomes", "of", "opossum,", "chicken", "and", "Xenopus", "tropicalis.", "The", "opossum", "contains", "two", "tandem", "copies", "of", "vasopressin", "and", "mesotocin", "genes.", "The", "vasotocin", "and", "mesotocin", "genes", "in", "chicken", "and", "Xenopus,", "and", "the", "vasopressin", "and", "mesotocin", "genes", "in", "opossum", "are", "linked", "tail-to-", "head", "similar", "to", "their", "orthologs", "in", "coelacanth", "and", "unlike", "their", "homologs", "in", "human", "and", "rodents.", "Conclusion:", "Our", "results", "indicate", "that", "the", "neurohypophysial", "hormone", "gene", "locus", "has", "experienced", "independent", "rearrangements", "in", "both", "placental", "mammals", "and", "teleost", "fishes.", "The", "coelacanth", "genome", "appears", "to", "be", "more", "stable", "than", "mammalian", "and", "teleost", "fish", "genomes.", "As", "such,", "it", "serves", "as", "a", "valuable", "outgroup", "for", "studying", "the", "evolution", "of", "mammalian", "and", "teleost", "fish", "genomes.", "Page", "1", "of", "12", "(page", "number", "not", "for", "citation", "purposes)" ]

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[ "Law", "et", "al.", "BMC", "Health", "Services", "Research", "2010,", "10:313", "http://www.biomedcentral.com/1472-6963/10/313", "S", "T", "U", "D", "Y", "P", "R", "O", "T", "O", "C", "O", "L", "Open", "Access", "Effects", "of", "prescription", "adaptation", "by", "pharmacists", "Michael", "R", "Law1*,", "Steven", "G", "Morgan2,", "Sumit", "R", "Majumdar3,", "Larry", "D", "Lynd4,", "Carlo", "A", "Marra4", "Abstract", "Background:", "Granting", "dispensing", "pharmacists", "the", "authority", "to", "prescribe", "has", "significant", "implications", "for", "pharmaceutical", "and", "health", "human", "resources", "policy,", "and", "quality", "of", "care.", "Despite", "the", "growing", "number", "of", "jurisdictions", "that", "have", "given", "pharmacists", "such", "privileges,", "there", "are", "few", "rigorous", "evaluations", "of", "these", "policy", "changes.", "This", "study", "will", "examine", "a", "January", "2009", "policy", "change", "in", "British", "Columbia", "(BC),", "Canada", "that", "allowed", "pharmacists", "to", "independently", "adapt", "and", "renew", "prescriptions.", "We", "hypothesize", "this", "policy", "increased", "drug", "utilization", "and", "drug", "costs,", "increased", "patient", "adherence", "to", "medication,", "and", "reduced", "total", "healthcare", "resource", "use.", "Methods/Design:", "We", "will", "study", "a", "population-based", "cohort", "of", "approximately", "4", "million", "BC", "residents", "from", "2004", "through", "2010.", "We", "will", "use", "data", "from", "BC", "PharmaNet", "on", "all", "of", "the", "prescriptions", "obtained", "by", "this", "cohort", "during", "the", "study", "period,", "and", "link", "it", "to", "administrative", "billings", "from", "physicians", "and", "hospital", "discharges.", "Using", "interrupted", "time", "series", "analysis,", "we", "will", "study", "longitudinal", "changes", "in", "drug", "utilization", "and", "costs,", "medication", "adherence,", "and", "short-", "term", "health", "care", "use.", "Further,", "using", "hierarchical", "modelling,", "we", "will", "examine", "the", "factors", "at", "the", "regional,", "pharmacy,", "patient,", "and", "prescription", "levels", "that", "are", "associated", "with", "prescription", "adaptations", "and", "renewals.", "Discussion:", "In", "a", "recent", "survey", "of", "Canadian", "policymakers,", "many", "respondents", "ranked", "the", "issue", "of", "prescribing", "privileges", "as", "one", "of", "their", "most", "pressing", "policy", "questions.", "No", "matter", "the", "results", "of", "our", "study,", "they", "will", "be", "important", "for", "policymakers,", "as", "our", "data", "will", "make", "policy", "decisions", "surrounding", "pharmacist", "prescribing", "more", "evidence-based.", "Background", "Context", "Access", "to", "primary", "care", "is", "an", "important", "concern", "for", "patients", "in", "almost", "every", "jurisdiction", "examined.", "In", "Canada,", "nearly", "4", "million", "individuals", "report", "not", "having", "a", "regular", "physician", "and", "over", "2", "million", "report", "difficulties", "in", "accessing", "routine", "or", "ongoing", "care", "[1].", "For", "at", "least", "some", "of", "these", "individuals,", "and", "for", "certain", "components", "of", "pri-", "mary", "health", "care,", "non-physician", "health", "professionals", "may", "represent", "high-quality", "alternatives.", "There", "is", "some", "research", "evidence", "on", "the", "potential", "of", "deploying", "pharma-", "cists", "in", "primary", "care", "[2];", "that", "literature,", "and", "practical", "experience", "in", "other", "jurisdictions", "points", "to", "a", "considerable", "amount", "of", "untapped", "pharmacist", "human", "resources", "[3-7].", "Expanding", "the", "scope", "of", "pharmacy", "practice", "may", "be", "a", "cost-effective", "way", "to", "enhance", "patient", "access", "and", "adher-", "ence", "to", "medicines,", "and", "to", "reduce", "the", "clinical", "burden", "on", "primary", "care", "physicians.", "*", "Correspondence:", "mlaw@chspr.ubc.ca", "1Centre", "for", "Health", "Services", "and", "Policy", "Research,", "School", "of", "Population", "and", "Public", "Health,", "The", "University", "of", "British", "Columbia.", "201-2206", "East", "Mall,", "Vancouver,", "BC,", "V6T", "1Z3,", "Canada", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "Around", "53%", "of", "Canadians", "fill", "one", "or", "more", "prescrip-", "tions", "each", "year,", "and", "at", "least", "half", "of", "these", "represent", "chronic", "medications", "used", "to", "manage", "cardiovascular", "risk", "factors", "[8,9].", "However,", "rates", "of", "continuous", "use", "of", "medi-", "cines", "for", "chronic", "conditions", "are", "often", "sub-optimal", "[10].", "But", "with", "prescription", "lengths", "limited", "to", "approximately", "3", "months", "in", "most", "provinces", "(with", "up", "to", "4", "refills", "if", "they", "are", "provided),", "access", "to", "primary", "care", "doctors", "for", "the", "purpose", "of", "prescription", "renewal", "may", "be", "a", "barrier", "to", "continuous", "adherence", "to", "long-term", "drug", "therapies.", "Thus,", "granting", "pharmacists", "prescribing", "authority", "may", "increase", "Canadians’", "access", "to", "medications.", "Though", "pharmacists", "are", "highly", "trained", "in", "matters", "related", "to", "the", "effects,", "interactions,", "and", "appropriate", "use", "of", "medicines,", "their", "expertise", "is", "seldom", "called", "upon", "as", "a", "first-line", "pri-", "mary", "health", "care", "provider", "in", "community", "settings.", "Recently,", "numerous", "Canadian", "provinces", "have", "imple-", "mented", "programs", "designed", "to", "expand", "the", "scope", "of", "phar-", "macy", "practice.", "The", "first", "province", "to", "move", "in", "this", "direction", "was", "Alberta,", "which", "implemented", "a", "program", "in", "2007", "that", "allows", "pharmacists", "to", "prescribe", "medications", "and", "adapt", "existing", "prescriptions", "[3].", "One", "year", "later,", "three-quarters", "of", "pharmacists", "in", "the", "province", "reported", "©", "2010", "Law", "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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[ "CytoJournal", "Research", "Scope", "of", "FNAC", "in", "the", "diagnosis", "of", "soft", "tissue", "tumors-A", "study", "from", "a", "tertiary", "cancer", "referral", "center", "in", "India", "Bharat", "Rekhi*1,", "Biru", "D", "Gorad1,", "Anagha", "C", "Kakade2", "and", "RF", "Chinoy1", "BioMed", "Central", "Open", "Access", "Address:", "1Dept", "of", "Pathology,", "Tata", "Memorial", "Centre,", "Dr", "E.", "B.", "Road,", "Parel,", "Mumbai,", "400012,", "India", "and", "2Clinical", "Trials", "Coordinator,", "Epidemiology", "&", "Clinical", "Trials", "Unit", "(ECTU),", "Advanced", "Centre", "for", "Treatment,", "Research", "&", "Education", "in", "cancer", "(ACTREC),", "Tata", "Memorial", "Centre,", "Khargar,", "Navi", "Mumbai,", "India", "Email:", "Bharat", "Rekhi*", "-", "rekhi.bharat@gmail.com;", "Biru", "D", "Gorad", "-", "drbdev@yahoo.com;", "Anagha", "C", "Kakade", "-", "akakade@actrec.gov.in;", "RF", "Chinoy", "-", "roshchinoy@gmail.com", "*", "Corresponding", "author", "Published:", "31", "October", "2007", "CytoJournal", "2007,", "4:20", "doi:10.1186/1742-6413-4-20", "This", "article", "is", "available", "from:", "http://www.cytojournal.com/content/4/1/20", "Received:", "7", "August", "2007", "Accepted:", "31", "October", "2007", "©", "2007", "Rekhi", "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:", "Fine", "needle", "aspiration", "cytology", "(FNAC)", "forms", "one", "of", "the", "first", "diagnostic", "tools", "in", "the", "evaluation", "of", "tumors.", "Its", "role", "in", "diagnosing", "soft", "tissue", "tumors", "(STT)", "has", "been", "fairly", "documented,", "as", "well", "as", "debated.", "Present", "study", "was", "aimed", "at", "evaluating", "its", "scope", "in", "diagnosing", "127", "cases", "of", "soft", "tissue", "tumors.", "Methods:", "Conventional", "Pap", "and", "MGG", "staining", "was", "available", "in", "all", "the", "cases.", "Immunocytochemistry", "(ICC)", "was", "performed", "in", "15", "cases.", "Histopathological", "details", "were", "available", "in", "115", "cases.", "Results:", "50%", "cases", "were", "referred", "for", "a", "primary", "diagnosis,", "while", "26.8%", "&", "22.8%", "cases", "were", "evaluated", "for", "recurrent", "and", "metastatic", "lesions,", "respectively.", "Extremities", "were", "the", "commonest", "sites.", "On", "FNAC,", "101", "cases", "(79.5%)", "were", "labeled", "as", "malignant,", "whereas", "10", "cases", "(7.9%)", "were", "labeled", "as", "benign.", "The", "remaining", "16", "cases", "(11%)", "were", "not", "categorized", "and", "were", "labeled", "as", "'unsure/not", "specified'.", "Histopathological", "confirmation", "in", "115", "cases,", "gave", "a", "diagnostic", "accuracy", "of", "98%,", "with", "a", "positive", "predictive", "value", "of", "98%", "in", "malignant", "cases", "and", "a", "negative", "predictive", "value", "of", "100%", "in", "benign", "cases.", "Two", "cases", "were", "false", "positive.", "Among", "the", "various", "cytological", "categories,", "60", "cases", "(47.2%)", "were", "of", "spindle", "cell", "type,", "followed", "by", "32", "(25.2%)", "of", "round", "cell", "type", "and", "14", "cases", "(11%)", "of", "lipomatous", "type.", "Other", "12", "cases", "(9.4%)", "were", "of", "pleomorphic", "type;", "7", "(5.5%)", "cases", "of", "epithelioid", "type", "and", "remaining", "2", "cases", "were", "of", "myxoid", "type.", "All", "the", "round", "cell,", "pleomorphic", "and", "myxoid", "type", "of", "tumors", "were", "sarcomas,", "whereas", "73.3%", "cases", "of", "spindle", "cell", "type", "were", "labeled", "as", "'malignant'.", "Exact", "cytological", "sub", "typing", "was", "offered", "in", "58", "cases,", "with", "rhabdomyosarcoma", "(RMS)", "as", "the", "most", "frequently", "sub", "typed", "tumor.", "The", "two", "false", "positive", "malignant", "cases", "were", "of", "fibromatosis", "and", "a", "pigmented", "schwannoma,", "on", "biopsy.", "Out", "of", "28", "metastatic", "lesions,", "lymph", "nodes", "were", "the", "commonest", "site", "for", "metastasis,", "with", "epithelioid", "tumors", "that", "formed", "highest", "percentage", "of", "metastatic", "cases.", "Conclusion:", "FNAC", "is", "fairly", "specific", "and", "sensitive", "in", "STT", "diagnoses", "for", "primary,", "recurrent", "and", "metastatic", "lesions.", "The", "cytological", "types,", "especially", "round", "cell", "and", "pleomorphic", "sarcomas,", "can", "be", "quickly", "identified.", "Clinicopathological", "correlation", "with", "ICC", "as", "an", "adjunct,", "are", "valuable", "in", "exact", "sub", "typing.", "Page", "1", "of", "10", "(page", "number", "not", "for", "citation", "purposes)" ]

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[ "Abreu", "et", "al.", "Nanoscale", "Research", "Letters", "2011,", "6:482", "http://www.nanoscalereslett.com/content/6/1/482", "N", "A", "N", "O", "E", "X", "P", "R", "E", "S", "S", "Open", "Access", "Nanoliposomes", "for", "encapsulation", "and", "delivery", "of", "the", "potential", "antitumoral", "methyl", "6-methoxy-3-(4-", "methoxyphenyl)-1H-indole-2-carboxylate", "Ana", "S", "Abreu1,2*,", "Elisabete", "MS", "Castanheira1,", "Maria-João", "RP", "Queiroz2,", "Paula", "MT", "Ferreira2,", "Luís", "A", "Vale-Silva3", "and", "Eugénia", "Pinto3", "Abstract", "A", "potential", "antitumoral", "fluorescent", "indole", "derivative,", "methyl", "6-methoxy-3-(4-methoxyphenyl)-1H-indole-2-", "carboxylate,", "was", "evaluated", "for", "the", "in", "vitro", "cell", "growth", "inhibition", "on", "three", "human", "tumor", "cell", "lines,", "MCF-7", "(breast", "adenocarcinoma),", "A375-C5", "(melanoma),", "and", "NCI-H460", "(non-small", "cell", "lung", "cancer),", "after", "a", "continuous", "exposure", "of", "48", "h,", "exhibiting", "very", "low", "GI50", "values", "for", "all", "the", "cell", "lines", "tested", "(0.25", "to", "0.33", "μM).", "This", "compound", "was", "encapsulated", "in", "different", "nanosized", "liposome", "formulations,", "containing", "egg", "lecithin", "(Egg-PC),", "dipalmitoyl", "phosphatidylcholine", "(DPPC),", "dipalmitoyl", "phosphatidylglycerol", "(DPPG),", "DSPC,", "cholesterol,", "dihexadecyl", "phosphate,", "and", "DSPE-PEG.", "Dynamic", "light", "scattering", "measurements", "showed", "that", "nanoliposomes", "with", "the", "encapsulated", "compound", "are", "generally", "monodisperse", "and", "with", "hydrodynamic", "diameters", "lower", "than", "120", "nm,", "good", "stability", "and", "zeta", "potential", "values", "lower", "than", "-18", "mV.", "Dialysis", "experiments", "allowed", "to", "monitor", "compound", "diffusion", "through", "the", "lipid", "membrane,", "from", "DPPC/DPPG", "donor", "liposomes", "to", "NBD-labelled", "lipid/DPPC/DPPG", "acceptor", "liposomes.", "Introduction", "Anticancer", "drugs", "are", "crucial", "agents", "in", "the", "global", "approach", "to", "fight", "cancer.", "Drug-loaded", "nanoparticles", "provide", "a", "per-", "fect", "solution", "to", "afford", "higher", "therapeutic", "efficacy", "and/or", "reducing", "toxicity", "and", "the", "possibility", "of", "targeting", "cancer", "tis-", "sues.", "Nanoliposomes", "are", "one", "of", "the", "best", "drug", "delivery", "sys-", "tems", "for", "low", "molecular", "weight", "drugs,", "imaging", "agents,", "peptides,", "proteins,", "and", "nucleic", "acids.", "Nanoliposomes", "are", "able", "to", "enhance", "the", "performance", "of", "bioactive", "agents", "by", "improving", "their", "bioavailability,", "in", "vitro", "and", "in", "vivo", "stability,", "as", "well", "as", "preventing", "their", "unwanted", "interactions", "with", "other", "molecules", "[1-3].", "It", "is", "believed", "that", "the", "efficient", "anti-", "tumor", "activity", "can", "be", "attributed", "to", "the", "selective", "delivery", "and", "the", "preferential", "accumulation", "of", "the", "liposome", "nano-", "carrier", "in", "the", "tumor", "tissue", "via", "the", "enhanced", "permeability", "and", "retention", "effect", "[4-6].", "Nanoliposomes", "may", "contain,", "in", "addition", "to", "phospholi-", "pids,", "other", "molecules", "such", "as", "cholesterol", "(Ch)", "which", "is", "an", "important", "component", "of", "most", "natural", "membranes.", "*", "Correspondence:", "anabreu@quimica.uminho.pt", "1Centre", "of", "Physics", "(CFUM),", "University", "of", "Minho,", "Campus", "de", "Gualtar,", "4710-", "057", "Braga,", "Portugal", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "The", "incorporation", "of", "Ch", "can", "increase", "stability", "by", "modu-", "lating", "the", "fluidity", "of", "the", "lipid", "bilayer", "preventing", "crystalli-", "zation", "of", "the", "phospholipid", "acyl", "chains", "and", "providing", "steric", "hindrance", "to", "their", "movement.", "Further", "advances", "in", "liposome", "research", "found", "that", "surface", "modification", "with", "polyethylene", "glycol", "(PEG),", "which", "is", "inert", "in", "the", "body,", "generally", "reduces", "the", "clearance", "of", "liposome", "by", "RES,", "and", "therefore", "allows", "longer", "circulatory", "life", "of", "the", "drug", "deliv-", "ery", "system", "in", "the", "blood", "[3].", "Pegylated", "liposomal", "doxoru-", "bicin", "has", "shown", "great", "prolonged", "circulation", "and", "substantial", "efficacy", "in", "breast", "cancer", "treatment", "[7].", "The", "net", "charge", "of", "nanoliposomes", "is", "also", "an", "important", "factor", "and", "generally", "anionic", "and", "neutral", "liposomes", "survive", "longer", "than", "cationic", "liposomes", "in", "the", "blood", "circulation", "after", "intravenous", "injection", "[8,9].", "In", "the", 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"provided", "the", "original", "work", "is", "properly", "cited." ]

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[ "Hindawi", "Publishing", "Corporation", "PPAR", "Research", "Volume", "2009,", "Article", "ID", "373524,", "15", "pages", "doi:10.1155/2009/373524", "Review", "Article", "The", "Effects", "of", "Thiazolidinediones", "on", "Metabolic", "Complications", "and", "Lipodystrophy", "in", "HIV-Infected", "Patients", "Jussi", "Sutinen", "Division", "of", "Infectious", "Diseases", "and", "Division", "of", "Diabetes,", "Department", "of", "Medicine,", "Helsinki", "University", "Central", "Hospital,", "00029", "HUS,", "Helsinki,", "Finland", "Correspondence", "should", "be", "addressed", "to", "Jussi", "Sutinen,", "jussi.sutinen@hus.fi", "Received", "18", "March", "2008;", "Accepted", "25", "August", "2008", "Recommended", "by", "Jacqueline", "Capeau", "Highly", "active", "antiretroviral", "therapy", "(HAART)-associated", "metabolic", "complications", "include", "lipoatrophy", "(loss", "of", "subcutaneous", "adipose", "tissue", "(SAT))", "and", "insulin", "resistance.", "Thiazolidinediones", "are", "insulin-sensitizing", "antidiabetic", "agents", "which—as", "an", "untoward", "side", "effect", "in", "obese", "diabetic", "patients—increase", "SAT.", "Furthermore,", "troglitazone", "has", "improved", "lipoatrophy", "and", "glycemic", "control", "in", "non-HIV", "patients", "with", "various", "forms", "of", "lipodystrophy.", "These", "data", "have", "led", "to", "14", "clinical", "trials", "to", "examine", "whether", "thiazolidinediones", "could", "be", "useful", "in", "the", "treatment", "of", "HAART-associated", "metabolic", "complications.", "The", "results", "of", "these", "studies", "indicate", "very", "modest,", "if", "any,", "effect", "on", "lipoatrophic", "SAT,", "probably", "due", "to", "ongoing", "HAART", "negating", "the", "beneficial", "effect.", "The", "benefit", "might", "be", "more", "prominent", "in", "patients", "not", "taking", "thymidine", "analoges.", "Despite", "the", "poor", "effect", "on", "lipoatrophy,", "thiazolidin-", "ediones", "improved", "insulin", "sensitivity.", "However,", "especially", "rosiglitazone", "induced", "harmful", "effects", "on", "blood", "lipids.", "Current", "data", "do", "not", "provide", "evidence", "for", "the", "use", "of", "thiazolidinediones", "in", "the", "treatment", "of", "HAART-associated", "lipoatrophy,", "but", "treatment", "of", "lipoatrophy-associated", "diabetes", "may", "be", "warranted.", "The", "role", "of", "thiazolidinediones", "for", "novel", "indications,", "such", "as", "hepatosteatosis,", "should", "be", "studied", "in", "these", "patients.", "Copyright", "©", "2009", "Jussi", "Sutinen.", "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.", "1.", "Introduction", "The", "prognosis", "of", "HIV-infection", "has", "drastically", "changed", "after", "the", "introduction", "of", "combination", "antiretroviral", "therapy", "[1]", "often", "referred", "to", "as", "highly", "active", "antiretroviral", "therapy", "(HAART).", "Since", "the", "eradication", "of", "the", "virus", "is", "impossible", "with", "current", "medicines", "[2]", "and", "since", "periodic", "treatment", "with", "HAART", "can", "be", "harmful", "when", "compared", "to", "continuous", "ther-", "apy", "[3],", "patients", "need", "to", "continue", "therapy", "uninterruptedly", "and", "permanently.", "Lifelong", "exposure", "to", "HAART", "puts", "patients", "at", "a", "signif-", "icant", "risk", "for", "long-term", "metabolic", "adverse", "effects", "includ-", "ing", "lipodystrophy,", "insulin", "resistance,", "hyperlipidemia,", "and", "increased", "cardiovascular", "morbidity", "[4,", "5].", "The", "most", "char-", "acteristic", "component", "of", "HAART-associated", "lipodystrophy", "is", "the", "loss", "of", "subcutaneous", "adipose", "tissue", "[6]", "which", "has", "proven", "to", "be", "very", "difficult", "to", "treat", "(Figure", "1).", "Thiazolidinediones", "(glitazones)", "are", "oral", "insulin-sensiti-", "zing", "antidiabetic", "agents.", "As", "an", "untoward", "side", "effect,", "gli-", "tazones", "increase", "subcutaneous", "fat", "mass", "in", "patients", "with", "type", "2", "diabetes", "[7–9].", "Additionally,", "in", "non-HIV", "infected", "patients", "with", "various", "forms", "of", "lipodystrophy,", "troglitazone", "has", "improved", "metabolic", "control", "and", "subcutaneous", "lipoatro-", "phy", "[10].", "These", "insulin-sensitizing", "and", "fat-inducing", "effects", "of", "glitazones", "have", "lead", "to", "several", "clinical", "trials", "examining", "whether", "these", "drugs", "could", "reverse", "lipoatrophy", "and", "insulin", "resistance", "in", "patients", "with", "HAART-associated", "lipodystrophy.", "The", "ensuing", "review", "is", "focused", "on", "summarizing", "the", "currently", "available", "clinical", "data", "on", "the", "use", "of", "glitazones", "in", "patients", "with", "HAART-associated", "lipodystrophy", "2.", "Thiazolidinediones", "Thiazolidinediones", "are", "synthetic", "ligands", "for", "peroxisome", "proliferator-activated", "receptor", "gamma", "(PPARγ).", "PPARγ", "is", "a", "nuclear", "receptor", "which", "alters", "expression", "of", "multiple", "genes", "including", "those", "regulating", "lipid", "and", "glucose", "metabolism", "[11].", "PPARγ", "is", "expressed", "mainly", "in", "adipose", "tissue", "and", "is", "also", "found", "in", "pancreatic", "beta", "cells,", "vascular", "endothelium,", "and", "macrophages,", "and", "in", "low", "quantities", "in", "other", "tissues", "such" ]

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[ "Korkontzelos", "et", "al.", "BMC", "Medical", "Informatics", "and", "Decision", "Making", "2012,", "12(Suppl", "1):S3", "http://www.biomedcentral.com/1472-6947/12/S1/S3", "P", "R", "O", "C", "E", "E", "D", "I", "N", "G", "S", "Open", "Access", "ASCOT:", "a", "text", "mining-based", "web-service", "for", "efficient", "search", "and", "assisted", "creation", "of", "clinical", "trials", "Ioannis", "Korkontzelos*,", "Tingting", "Mu,", "Sophia", "Ananiadou", "From", "ACM", "Fifth", "International", "Workshop", "on", "Data", "and", "Text", "Mining", "in", "Biomedical", "Informatics", "(DTMBio", "2011)", "Glasgow,", "UK.", "24", "October", "2011", "Abstract", "Clinical", "trials", "are", "mandatory", "protocols", "describing", "medical", "research", "on", "humans", "and", "among", "the", "most", "valuable", "sources", "of", "medical", "practice", "evidence.", "Searching", "for", "trials", "relevant", "to", "some", "query", "is", "laborious", "due", "to", "the", "immense", "number", "of", "existing", "protocols.", "Apart", "from", "search,", "writing", "new", "trials", "includes", "composing", "detailed", "eligibility", "criteria,", "which", "might", "be", "time-consuming,", "especially", "for", "new", "researchers.", "In", "this", "paper", "we", "present", "ASCOT,", "an", "efficient", "search", "application", "customised", "for", "clinical", "trials.", "ASCOT", "uses", "text", "mining", "and", "data", "mining", "methods", "to", "enrich", "clinical", "trials", "with", "metadata,", "that", "in", "turn", "serve", "as", "effective", "tools", "to", "narrow", "down", "search.", "In", "addition,", "ASCOT", "integrates", "a", "component", "for", "recommending", "eligibility", "criteria", "based", "on", "a", "set", "of", "selected", "protocols.", "Introduction", "Clinical", "trials", "are", "health-related", "research", "studies", "on", "humans.", "A", "description", "of", "a", "clinical", "trial", "follows", "a", "pre-", "defined", "protocol", "and", "contains", "various", "information", "about", "the", "study:", "its", "title,", "the", "condition", "under", "inspection,", "the", "target,", "the", "characteristics", "of", "patients", "that", "can", "participate,", "details", "about", "the", "institutions", "that", "accomplished", "the", "study,", "etc.", "Clinical", "trials", "are", "among", "the", "most", "valuable", "sources", "for", "guiding", "evidence-based", "medical", "practice", "and", "designing", "new", "trials.", "However,", "the", "vast", "and", "rapidly", "growing", "number", "of", "existing", "trails", "hinders", "the", "effective", "use", "of", "this", "information.", "Significant", "effort", "has", "been", "devoted", "to", "efficient", "search", "applications", "for", "clinical", "trials,", "mainly", "by", "various", "registries,", "e.g.", "the", "UK", "Clinical", "Trials", "Gateway", "http://www.ukctg.nihr.ac.uk,", "Free", "International", "Standard", "Randomised", "Controlled", "Trials", "(http://isrctn.", "org)", "and", "http://controlled-trials.com.", "However,", "none", "has", "attempted", "to", "enrich", "the", "free", "text", "descriptions", "with", "structured", "metadata", "able", "to", "provide", "search", "with", "extra", "discriminative", "powers", "needed", "for", "customised", "search.", "One", "of", "the", "most", "difficult", "parts", "of", "creating", "a", "new", "clinical", "trial", "is", "listing", "the", "eligibility", "criteria,", "i.e.", "the", "characteristics", "*", "Correspondence:", "Ioannis.Korkontzelos@manchester.ac.uk", "National", "Centre", "for", "Text", "Mining", "&", "School", "of", "Computer", "Science,", "The", "University", "of", "Manchester,", "Manchester,", "M1", "7DN,", "UK", "of", "participants.", "At", "the", "same", "time,", "eligibility", "criteria", "can", "directly", "affect", "the", "quality", "of", "the", "experiment", "and", "its", "out-", "come.", "Although", "for", "experienced", "researchers", "composing", "the", "eligibility", "section", "of", "a", "trial", "might", "be", "straightforward,", "for", "inexperienced", "ones", "it", "would", "be", "time-consuming.", "It", "would", "imply", "searching", "for", "relevant", "trials", "and", "literature", "and", "then", "processing", "them.", "In", "this", "paper", "we", "present", "ASCOT", "(Assisting", "Search", "and", "Creation", "Of", "clinical", "Trials),", "an", "efficient", "search", "applica-", "tion", "customised", "to", "clinical", "trials", "that", "aims", "to", "address", "the", "information", "overload", "problem", "and", "to", "assist", "the", "creation", "of", "new", "protocols.", "ASCOT", "employs", "state-of-the-art", "text", "mining", "technologies,", "clustering", "and", "term", "extraction", "algo-", "rithms", "applied", "on", "large", "clinical", "trial", "collections.", "It", "is", "available", "at:", "http://www.nactem.ac.uk/clinical_trials.", "In", "more", "detail,", "search", "begins", "with", "a", "textual", "query.", "Then,", "it", "can", "be", "narrowed", "down", "in", "a", "multitude", "of", "ways:", "-", "by", "selecting", "values", "for", "properties", "that", "correspond", "to", "XML", "fields", "of", "the", "clinical", "trial", "protocols.", "-", "by", "selecting", "one", "of", "the", "automatically", "induced", "and", "labelled", "clusters", "of", "clinical", "trial", "protocols.", "-", "by", "selecting", "a", "UMLS", "or", "SNOMED", "CT", "concept", "to", "occur", "in", "the", "(inclusion", "or", "exclusion)", "eligibility", "cri-", "teria", "of", "the", "clinical", "trial", "protocols.", "©", "2012", "Korkontzelos", "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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542, 749, 556 ], [ 752, 542, 783, 556 ], [ 556, 556, 601, 570 ], [ 604, 556, 677, 570 ], [ 680, 556, 726, 570 ], [ 730, 556, 783, 570 ], [ 556, 571, 575, 585 ], [ 579, 571, 605, 585 ], [ 608, 571, 619, 585 ], [ 623, 571, 641, 585 ], [ 644, 571, 655, 585 ], [ 659, 571, 707, 585 ], [ 710, 571, 783, 585 ], [ 556, 585, 589, 599 ], [ 591, 585, 637, 599 ], [ 640, 585, 659, 599 ], [ 661, 585, 716, 599 ], [ 719, 585, 761, 599 ], [ 764, 585, 784, 599 ], [ 556, 600, 573, 614 ], [ 576, 600, 588, 614 ], [ 591, 600, 613, 614 ], [ 617, 600, 627, 614 ], [ 631, 600, 663, 614 ], [ 666, 600, 709, 614 ], [ 712, 600, 723, 614 ], [ 726, 600, 784, 614 ], [ 556, 615, 583, 629 ], [ 587, 615, 656, 629 ], [ 660, 615, 683, 629 ], [ 686, 615, 696, 629 ], [ 700, 615, 729, 629 ], [ 732, 615, 751, 629 ], [ 755, 615, 783, 629 ], [ 556, 629, 607, 643 ], [ 609, 629, 618, 643 ], [ 620, 629, 632, 643 ], [ 634, 629, 666, 643 ], [ 575, 644, 587, 658 ], [ 592, 644, 621, 658 ], [ 626, 644, 644, 658 ], [ 649, 644, 681, 658 ], 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[ "Research", "Fish", "Consumption", "and", "Advisory", "Awareness", "in", "the", "Great", "Lakes", "Basin", "Pamela", "Imm,", "Lynda", "Knobeloch,", "Henry", "A.", "Anderson,", "and", "the", "Great", "Lakes", "Sport", "Fish", "Consortium", "Division", "of", "Public", "Health,", "Wisconsin", "Department", "of", "Health", "and", "Family", "Services,", "Madison,", "Wisconsin,", "USA", "More", "than", "61", "million", "adults", "live", "in", "the", "eight", "U.S.", "states", "bordering", "the", "Great", "Lakes.", "Between", "June", "2001", "and", "June", "2002,", "a", "population-based,", "random-digit-dial", "telephone", "survey", "of", "adults", "residing", "in", "Great", "Lakes", "(GL)", "states", "was", "conducted", "to", "assess", "consumption", "of", "commercial", "and", "sport-caught", "fish", "and", "awareness", "of", "state-issued", "consumption", "advisories", "for", "GL", "fish.", "On", "the", "basis", "of", "the", "weighted", "sur-", "vey", "data,", "approximately", "84%", "of", "the", "adults", "living", "in", "these", "states", "included", "fish", "in", "their", "diets.", "Seven", "percent", "(an", "estimated", "4.2", "million", "adults)", "consumed", "fish", "caught", "from", "the", "Great", "Lakes.", "The", "percent-", "age", "of", "residents", "who", "had", "consumed", "sport-caught", "fish", "(from", "any", "water", "source)", "varied", "regionally", "and", "was", "highest", "among", "those", "who", "lived", "in", "Minnesota", "(44%)", "and", "Wisconsin", "(39%).", "Consumption", "of", "GL", "sport", "fish", "was", "highest", "among", "residents", "of", "Michigan", "(16%)", "and", "Ohio", "(12%).", "Among", "residents", "who", "had", "eaten", "GL", "fish,", "awareness", "of", "consumption", "advisories", "varied", "by", "gender", "and", "race", "and", "was", "lowest", "among", "women", "(30%)", "and", "black", "residents", "(15%).", "However,", "70%", "of", "those", "who", "consumed", "GL", "sport-caught", "fish", "twice", "a", "month", "or", "more", "(an", "estimated", "509,000", "adults", "across", "all", "eight", "states)", "were", "aware", "of", "the", "advisories.", "Findings", "from", "this", "survey", "indicate", "that", "exposure", "to", "persistent", "contam-", "inants", "found", "in", "GL", "fish", "is", "likely", "limited", "to", "a", "relatively", "small", "subpopulation", "of", "avid", "sport-fish", "con-", "sumers.", "Results", "also", "underscore", "the", "public", "health", "importance", "of", "advisories", "for", "commercial", "fish", "because", "an", "estimated", "2.9", "million", "adults", "living", "in", "these", "states", "consume", "more", "than", "104", "fish", "meals", "per", "year", "and", "may", "be", "at", "risk", "of", "exceeding", "the", "reference", "doses", "for", "methylmercury,", "polychlorinated", "biphenyls,", "and", "other", "bioaccumulative", "contaminants.", "Key", "words:", "advisory,", "awareness,", "fish,", "Great", "Lakes,", "sport", "fish.", "Environ", "Health", "Perspect", "113:1325–1329", "(2005).", "doi:10.1289/ehp.7980", "available", "via", "http://dx.doi.org/", "[Online", "13", "June", "2005]", "Consumption", "advisories", "for", "sport-caught", "fish", "were", "first", "issued", "by", "Great", "Lakes", "(GL)", "states", "during", "the", "1970s.", "These", "advisories", "were", "based", "on", "findings", "from", "investigations", "of", "the", "methyl-", "mercury", "poisonings", "that", "had", "occurred", "in", "Minamata,", "Japan,", "and", "on", "fish", "tissue", "analysis.", "Since", "that", "time,", "researchers", "have", "discovered", "that", "a", "variety", "of", "other", "persistent", "environmental", "contaminants,", "including", "PCBs", "(polychlori-", "nated", "biphenyls),", "DDT", "(dichlorodiphenyl-", "trichloroethane),", "and", "polybrominated", "diphenyl", "ethers,", "had", "found", "their", "way", "into", "the", "aquatic", "food", "chain", "and", "might", "pose", "a", "risk", "to", "frequent", "consumers", "of", "large,", "predatory", "fish.", "Currently,", "health", "departments", "and/or", "state", "environmental", "agencies", "in", "48", "states", "issue", "consumption", "guide-", "lines", "for", "local", "sport-caught", "fish—fish", "that", "is", "caught", "and", "not", "purchased.", "The", "recent", "methylmercury", "reference", "dose", "revision", "from", "0.5", "gµ/kg/day", "to", "0.1", "gµ/kg/day", "triggered", "states", "to", "review", "their", "sport-fish", "advi-", "sories", "and", "federal", "agencies", "to", "assess", "the", "need", "for", "a", "commercial", "fish", "advisory.", "In", "2004", "the", "U.S.", "Environmental", "Protection", "Agency", "(EPA)", "and", "the", "U.S.", "Food", "and", "Drug", "Administration", "(FDA)", "jointly", "issued", "consumption", "advice", "for", "commercial", "fish", "that", "was", "intended", "to", "protect", "women", "of", "childbearing", "age", "and", "young", "chil-", "dren", "against", "the", "neurodevelopmental", "effects", "of", "methylmercury.", "It", "became", "apparent", "to", "some", "states", "that", "there", "was", "a", "need", "for", "a", "holistic", "methylmercury", "fish", "consumption", "advisory", "that", "combined", "advice", "forlocal", "sport-caught", "fish", "and", "commercial", "fish.", "Up", "until", "this", "time", "sport-caught", "fish", "advisories", "largely", "ignored", "exposures", "from", "commercial", "fish.", "Current", "advisories", "are", "intended", "to", "assist", "anglers", "and", "consumers", "of", "commercial", "fish", "in", "selecting", "fish", "low", "in", "chemical", "contaminants", "as", "part", "of", "a", "healthy,", "balanced", "diet.", "In", "2001", "an", "estimated", "1.85", "million", "fisher-", "men", "purchased", "licenses", "to", "fish", "on", "the", "Great", "Lakes", "(U.S.", "Department", "of", "the", "Interior", "2002).", "Although", "this", "figure", "reflects", "an", "almost", "30%", "decline", "from", "2.55", "million", "in", "1991,", "GL", "sport", "fishing", "continues", "to", "be", "a", "popular", "recreational", "activity", "for", "many", "families.", "Frequent", "ingestion", "of", "fish", "from", "these", "lakes", "has", "been", "associated", "with", "higher", "body", "burdens", "of", "PCBs,", "DDT,", "and", "DDE", "(dichlorodiphenyldichloroethylene)", "(Anderson", "et", "al.", "1998;", "Fiore", "et", "al.", "1989;", "Humphrey", "1983;", "Schwartz", "e", "al.", "1983;", "Sonzogni", "et", "al.", "1991;", "Tilden", "et", "al.", "1997).", "These", "persistent", "contaminants", "accumulate", "in", "the", "body", "over", "time", "and", "increase", "the", "risk", "of", "a", "variety", "of", "health", "problems", "such", "as", "liver", "disease", "(Yu", "et", "al.", "1997),", "reproductive", "(Dar", "et", "al.", "1992;", "Weisskopf", "et", "al.", "2003)", "and", "neurologic", "prob-", "lems", "(Rogan", "and", "Gladen", "1992),", "endocrine", "changes", "(Braathen", "et", "al.", "2004;", "Persky", "et", "al.", "2001),", "and", "developmental", "delays", "(Jacobson", "et", "al.", "1990;", "Jacobson", "et", "al.", "1986;", "Kimbrough", "and", "Krouskas", "2003;", "Longnecker", "et", "al.", "1997;", "Tilson", "and", "Kodavanti", "1998).", "PCBs,", "DDT,", "and", "DDE", "have", "been", "classified", "as", "probable", "human", "carcinogens", "by", "the", "U.S.", "EPA,", "and", "sport-fish", "consumption", "has", "recently", "been", "associated", "with", "an", "increased", "risk", "of", "breast", "can-", "cer", "among", "young,", "premenopausal", "women", "(McElroy", "et", "al.", "2004).", "Environmental", "Health", "Perspectives", "•", "VOLUME", "113", "|", "NUMBER", "10", "|", "October", "2005", "Prenatal", "exposure", "to", "methylmercury", "has", "been", "associated", "with", "subtle", "learning", "delays", "and", "blood", "pressure", "changes", "(Grandjean", "et", "al.", "1998;", "Sorenson", "et", "al.", "1999).", "Methylmercury", "exposure", "during", "adulthood", "has", "recently", "been", "linked", "to", "higher", "rates", "of", "cardiovascular", "disease", "and", "acute", "myocardial", "infarction", "(Guallar", "et", "al.", "2002;", "Salonen", "et", "al.", "1995).", "Until", "the", "early", "1990s", "sport-fish", "consump-", "tion", "advisories", "were", "developed", "independently", "by", "each", "state.", "Development", "of", "these", "advisories", "may", "have", "been", "based", "on", "policy", "considerations", "as", "well", "as", "science.", "This", "led", "to", "confusion", "because", "neighboring", "states", "often", "provided", "dif-", "ferent", "advice", "for", "the", "same,", "shared", "body", "of", "water.", "This", "situation", "was", "confusing", "for", "anglers", "and", "may", "have", "reduced", "confidence", "in", "the", "advi-", "sories.", "At", "the", "direction", "of", "the", "Council", "of", "Great", "Lakes", "Governors,", "the", "states", "that", "border", "the", "Great", "Lakes", "(Illinois,", "Indiana,", "Michigan,", "Minnesota,", "New", "York,", "Ohio,", "Pennsylvania,", "and", "Wisconsin)", "developed", "a", "protocol", "for", "a", "Uniform", "Great", "Lakes", "Sport", "Fish", "Consumption", "Advisory", "(Anderson", "et", "al.", "1993).", "That", "1993", "advisory", "protocol", "provides", "information", "on", "the", "health", "benefits", "of", "fish;", "adverse", "effects", "of", "conta-", "minants;", "recommended", "quantity,", "frequency,", "and", "types", "of", "fish", "to", "consume;", "recommended", "fishing", "locations;", "and", "preparation", "methods", "that", "can", "be", "used", "to", "reduce", "exposure", "to", "bioaccumu-", "lative", "contaminants", "such", "as", "PCBs", "and", "DDE", "(Anderson", "et", "al.", "1993).", "In", "1991", "the", "Great", "Lakes", "Sport", "Fish", "Consortium", "of", "health", "departments", "in", "six", "of", "the", "eight", "GL", "states", "(Michigan", "and", "Pennsylvania", "were", "not", "members", "of", "the", "original", "consortium)", "was", "formed", "and", "received", "competitive", "funding", "from", "the", "Agency", "for", "Toxic", "Substances", "and", "Disease", "Registries.", "In", "1993–1994", "the", "consor-", "tium", "conducted", "a", "random-digit-dial", "telephone", "survey", "of", "8,306", "residents", "of", "the", "eight", "GL", "states", "to", "evaluate", "their", "total", "fish", "and", "GL", "sport-fish", "consumption", "habits,", "define", "at-risk", "subpopula-", "tions,", "and", "assess", "the", "effectiveness", "of", "state-issued", "consumption", "advisories.", "Households", "were", "selected", "by", "a", "computerized", "random-digit-dial", "system,", "and", "an", "adult", "was", "then", "randomly", "Address", "correspondence", "to", "P.", "Imm,", "Department", "of", "Health", "and", "Family", "Services,", "1", "West", "Wilson", "St.,", "Room", "150,", "Madison,", "WI", "53703", "USA.", "Telephone:", "(608)", "267-3565.", "Fax:", "(608)", "267-4853.", "E-mail:", "immpb@dhfs.state.wi.us", "This", "work", "was", "funded", "by", "U.S.", "Public", "Health", "Service", "Agency", "for", "Toxic", "Substances", "and", "Diseases", "Registry", "grant", "75/ATH598322-03.", "The", "authors", "declare", "they", "have", "no", "competing", "finan-", "cial", "interests.", "Received", "31", "January", "2005;", "accepted", "13", "June", "2005.", "1325" ]

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[ "Sironen", "et", "al.", "BMC", "Genomics", "2010,", "11:699", "http://www.biomedcentral.com/1471-2164/11/699", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Knobbed", "acrosome", "defect", "is", "associated", "with", "a", "region", "containing", "the", "genes", "STK17b", "and", "HECW2", "on", "porcine", "chromosome", "15", "Anu", "Sironen1*,", "Pekka", "Uimari1,", "Szabolcs", "Nagy2,", "Sándor", "Paku3,", "Magnus", "Andersson4,", "Johanna", "Vilkki1", "Abstract", "Background:", "Male", "infertility", "is", "an", "increasing", "problem", "in", "all", "domestic", "species", "including", "man.", "Localization", "and", "identification", "of", "genes", "involved", "in", "defects", "causing", "male", "infertility", "provide", "valuable", "information", "of", "specific", "events", "in", "sperm", "development.", "Correct", "condensation", "of", "the", "sperm", "head", "and", "development", "of", "the", "acrosome", "are", "required", "for", "fertile", "sperm.", "In", "the", "Finnish", "Yorkshire", "pig", "population", "a", "knobbed", "acrosome", "defect", "(KAD)", "has", "been", "reported", "which", "appears", "to", "be", "of", "genetic", "origin.", "In", "previous", "studies", "we", "have", "shown", "that", "a", "large", "number", "of", "affected", "spermatozoa", "have", "a", "cystic", "swelling", "anterior", "to", "the", "apical", "part", "of", "the", "acrosome.", "Results:", "Characterization", "of", "the", "knobbed", "acrosome", "affected", "sperm", "revealed", "that", "both", "the", "acrosomal", "granules", "and", "chromatin", "are", "affected.", "This", "type", "of", "KAD", "appears", "to", "be", "a", "previously", "unknown", "and", "serious", "form", "of", "the", "defect.", "A", "genome", "wide", "scan", "with", "PorcineSNP60", "Genotyping", "BeadChip", "defined", "the", "KAD", "associated", "region", "within", "0.7", "Mbp", "on", "porcine", "chromosome", "15.", "Two", "genes,", "STK17b", "and", "HECW2,", "located", "within", "this", "region", "were", "sequenced.", "The", "expression", "of", "these", "genes", "appeared", "comparable", "in", "KA-affected", "and", "control", "boars.", "The", "known", "function", "of", "HECW2", "in", "acrosome", "development", "highlighted", "this", "gene", "as", "a", "good", "candidate", "responsible", "for", "the", "KAD.", "One", "nonsynonymous", "SNP", "was", "identified", "within", "the", "HECW2", "gene.", "However,", "as", "this", "mutation", "was", "found", "in", "homozygous", "state", "in", "individuals", "with", "normal", "sperm,", "this", "is", "not", "likely", "to", "be", "the", "causal", "mutation.", "Conclusions:", "In", "this", "study", "we", "identified", "two", "candidate", "genes", "for", "a", "severe", "defect", "affecting", "both", "the", "sperm", "acrosome", "and", "chromatin", "that", "causes", "infertility.", "One", "of", "these", "genes,", "HECW2,", "plays", "an", "important", "role", "in", "ubiquitination,", "a", "prerequisite", "for", "chromatin", "remodelling", "and", "acrosome", "formation,", "highlighting", "the", "involvement", "of", "this", "gene", "in", "the", "knobbed", "acrosome", "defect", "and", "male", "infertility.", "Background", "Male", "infertility", "is", "becoming", "increasingly", "prevalent", "partly", "due", "to", "environmental", "factors,", "but", "many", "defects", "in", "sperm", "development", "arise", "from", "a", "genetic", "cause.", "Problems", "in", "the", "production", "and", "maturation", "of", "sperm", "are", "the", "most", "common", "causes", "of", "male", "infertility", "resulting", "in", "low", "sperm", "numbers,", "morphologically", "abnormal", "sperm", "or", "low", "sperm", "motility", "[1-3].", "Despite", "efforts", "to", "reveal", "the", "genes", "and", "their", "functions", "in", "spermatogenesis,", "little", "is", "known", "about", "the", "underlying", "causes", "of", "male", "infertility.", "Therefore,", "the", "localization", "and", "identification", "of", "muta-", "tions", "specifically", "affecting", "spermatogenesis", "provide", "*", "Correspondence:", "anu.sironen@mtt.fi", "1Agrifood", "Research", "Finland,", "MTT,", "Biotechnology", "and", "Food", "Research,", "Genomics,", "FI-36100", "Jokioinen,", "Finland", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "invaluable", "information", "for", "investigating", "the", "causes", "of", "male", "infertility.", "Mammalian", "spermatogenesis", "is", "a", "complex", "process,", "where", "diploid", "spermatogonia", "develop", "into", "haploid,", "highly", "specialized", "spermatozoa.", "Spermatogenesis", "includes", "many", "testis-specific", "processes", "that", "are", "controlled", "by", "complex", "regulatory", "mechanisms", "[4,5].", "During", "spermiogenesis,", "hap-", "loid", "round", "spermatids", "undergo", "dramatic", "biochemical", "and", "morphological", "changes", "that", "are", "governed", "by", "specialized", "gene", "expression", "and", "interactions", "between", "various", "genes", "and", "their", "protein", "products", "[6].", "Identification", "of", "genes", "involved", "in", "sperm", "development", "is", "a", "prerequisite", "to", "under-", "standing", "the", "molecular", "mechanisms", "of", "spermatogenesis.", "Sperm", "development", "is", "known", "to", "be", "disrupted", "during", "spermiogenesis", "in", "several", "acrosomal", "defects;", "e.g.", "globo-", "zoospermia", "in", "humans,", "where", "spermatozoa", "lack", "an", "©", "2010", "Sironen", "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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[ "Technical", "Note", "Polyhexanide", "and", "hydrogen", "peroxide", "inhibit", "proteoglycan", "synthesis", "of", "human", "chondrocytes", "Eric", "Ro¨hner1,", "Paula", "Hoff2,", "Tobias", "Winkler1,", "Philipp", "von", "Roth", "1", ",", "Jo¨rn", "Bengt", "Seeger1,", "Carsten", "Perka", "1", ",", "Georg", "Matziolis1", "1Department", "of", "Traumatology", "and", "Orthopaedics,", "and", "2Department", "of", "Rheumatology", "and", "Clinical", "Immunology,", "Charite´", "-", "Universita¨tsmedizin,", "Berlin,", "Germany", "The", "use", "of", "local", "antiseptics", "is", "a", "common", "method", "in", "septic", "joint", "surgery.", "We", "tested", "polyhexanide", "and", "hydrogen", "peroxide,", "two", "of", "the", "most", "frequently", "used", "antiseptics", "with", "high", "efficacy", "and", "low", "toxicity.", "The", "purpose", "of", "this", "study", "was", "to", "evaluate", "the", "effects", "of", "both", "antiseptics", "on", "the", "extracellular", "cartilaginous", "matrix", "synthesis", "of", "human", "chondrocytes.", "Chondrocytes", "were", "isolated", "from", "donated", "human", "knee", "joints,", "embedded", "in", "alginate", "beads,", "and", "incubated", "for", "10", "and", "30", "minutes", "with", "polyhexanide", "(0.04%),", "hydrogen", "peroxide", "(3%),", "or", "phosphate-buffered", "saline", "(PBS)", "for", "control.", "Cartilaginous", "matrix", "production", "was", "quantified", "through", "light", "microscopic", "analysis", "of", "Alcian", "blue", "staining.", "Cell", "number", "and", "morphology", "were", "detected", "by", "histological", "analysis.", "Chondrocytes", "showed", "a", "decreased", "intensity", "of", "blue", "colouring", "after", "antiseptic", "treatment", "versus", "PBS.", "In", "contrast", "to", "that,", "neither", "the", "cell", "number", "per", "view", "field", "nor", "the", "cell", "morphology", "differed", "between", "the", "groups.", "Polyhexanide", "has", "more", "toxic", "potential", "than", "hydrogen", "peroxide.", "Based", "on", "the", "fact", "that", "the", "cell", "number", "and", "morphology", "was", "not", "altered", "by", "the", "substances", "at", "the", "examined", "concentrations,", "the", "lower", "intensity", "of", "Alcian", "blue", "staining", "of", "treated", "chondrocytes", "indicates", "a", "decreased", "cartilage-specific", "matrix", "synthesis", "by", "polyhexanide", "more", "than", "by", "hydrogen", "peroxide", "and", "control.", "Keywords:", "Antiseptics,", "Human", "chondrocytes,", "Hydrogen", "peroxide,", "Polyhexanide,", "Proteoglycans", "Introduction", "Different", "studies", "showed", "that", "shoulder", "and", "knee", "joint", "infections", "often", "result", "from", "infiltrations", "with", "local", "anaesthetics,", "glucocorticoids,", "or", "hyaluronic", "acid", "con-", "trary", "to", "hip", "joint", "infections", "which", "are", "rarely", "infiltrated", "for", "diagnostic", "or", "therapeutic", "reasons.1–3", "In", "addition", "to", "arthroscopic", "or", "open", "debridement,", "the", "application", "of", "local", "antiseptics", "is", "a", "standard", "procedure", "in", "the", "treatment", "of", "joint", "infections.", "The", "most", "frequently", "used", "antiseptics", "of", "local", "joint", "and", "wound", "infections", "are", "polyhexanide,", "and", "hydrogen", "peroxide.", "In", "contrast", "to", "antibiotic", "substances,", "they", "do", "not", "differ", "between", "procariontic", "and", "eukaryontic", "cells.", "Therefore,", "the", "tissue", "toxicity", "of", "antiseptic", "substances", "has", "to", "be", "determined", "for", "every", "tissue", "coming", "into", "contact.", "There", "is", "an", "ongoing", "discussion", "between", "elimination", "of", "bacteria", "and", "toxicity", "against", "chondrocytes.4,5", "It", "should", "be", "assumed", "that", "the", "time", "of", "chondrocytes", "Correspondence", "to:", "Eric", "Ro¨hner,", "Center", "for", "Musculoskeletal", "Surgery,", "Orthopaedic", "Department,", "Charite´", "University", "Hospital,", "Berlin,", "Charite´platz", "1,", "10117", "Berlin,", "Germany.", "Email:", "eric.roehner@charite.de", "contact", "with", "local", "antiseptics", "should", "be", "between", "10", "and", "30", "minutes", "to", "eliminate", "most", "colonies", "of", "bacteria", "and", "though", "to", "limit", "chondrocyte", "toxicity.", "The", "most", "frequent", "bacteria,", "which", "are", "responsible", "for", "wound", "and", "joint", "infections,", "are", "staphylococci,", "streptococci,", "and", "Gram-negative", "bacteria.1,6–8", "Be-", "sides", "inducing", "cell", "death,", "antiseptic", "substances", "may", "alter", "the", "cartilage-specific", "synthesis", "of", "proteoglycan", "in", "chondrocytes", "and", "thereby", "affect", "the", "cartilage", "tissue.", "The", "undisturbed", "interaction", "between", "the", "chondrocytes", "and", "extracellular", "matrix", "plays", "an", "im-", "portant", "role", "for", "the", "regulation", "of", "chondrocyte", "homeostasis,", "which", "is", "important", "for", "the", "mainte-", "nance,", "the", "development,", "and", "the", "stabilisation", "of", "chondrocyte", "phenotype.9–12", "Consequently,", "an", "inter-", "ruption", "of", "proteoglycan", "synthesis", "results", "in", "cartilage", "damage", "with", "the", "loss", "of", "chondrocytes.9,13", "Two", "of", "the", "most", "commonly", "used", "antiseptics", "in", "septic", "joint", "surgery", "are", "polyhexanide", "and", "hydrogen", "peroxide.", "Literature", "reviews", "show", "insufficient", "data", "about", "the", "effects", "of", "antiseptics", "on", "human", "cartilage.", "2011", "National", "Society", "for", "Histotechnology", "MORE", "OpenChoice", "articles", "are", "open", "access", "and", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "3.0", "DOI", "10.1179/014788811X12949268296121", "Journal", "of", "Histotechnology", "2011", "VOL", "34", "NO", "1", "35" ]

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[ "Available", "online", "http://arthritis-research.com/content/6/6/R557", "Research", "article", "Vol6No6", "Analysis", "of", "HLA", "DR,", "HLA", "DQ,", "C4A,", "FcγRIIa,", "FcγRIIIa,", "MBL,", "and", "IL-1Ra", "allelic", "variants", "in", "Caucasian", "systemic", "lupus", "erythematosus", "patients", "suggests", "an", "effect", "of", "the", "combined", "FcγRIIa", "R/R", "and", "IL-1Ra", "2/2", "genotypes", "on", "disease", "susceptibility", "Open", "Access", "Andreas", "Jönsen1,", "Anders", "A", "Bengtsson1,", "Gunnar", "Sturfelt1", "and", "Lennart", "Truedsson2", "1Department", "of", "Rheumatology,", "Lund", "University", "Hospital,", "Lund,", "Sweden", "2Department", "of", "Laboratory", "Medicine,", "Section", "of", "Microbiology,", "Immunology", "and", "Glycobiology,", "Lund", "University,", "Lund,", "Sweden", "Corresponding", "author:", "Lennart", "Truedsson,", "lennart.truedsson@skane.se", "Received:", "22", "Dec", "2003", "Revisions", "requested:", "12", "Jan", "2004", "Revisions", "received:", "16", "Jun", "2004", "Accepted:", "16", "Jul", "2004", "Published:", "23", "Sep", "2004", "Arthritis", "Res", "Ther", "2004,", "6:R557-R562", "(DOI", "10.1186/ar1224)htp:/arthrits-research.com/content/6/6/R557", "©", "2004", "Jönsen", "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", "cited.", "Keywords:", "Fcγ", "receptor,", "HLA,", "interleukin-1", "receptor", "antagonist,", "mannan-binding", "lectin,", "systemic", "lupus", "erythematosus", "Abstract", "Dysfunction", "in", "various", "parts", "of", "immune", "defence,", "such", "as", "immune", "response,", "immune", "complex", "clearance,", "and", "inflammation,", "has", "an", "impact", "on", "pathogenesis", "in", "systemic", "lupus", "erythematosus", "(SLE).", "We", "hypothesised", "that", "combinations", "of", "common", "variants", "of", "genes", "involved", "in", "these", "immune", "functions", "are", "associated", "with", "susceptibility", "to", "SLE.", "The", "following", "variants", "were", "analysed:", "HLA", "DR3,", "HLA", "DQ2,", "C4AQ0,", "Fcγ", "receptor", "IIa", "(FcγRIIa)", "genotype", "R/R,", "Fcγ", "receptor", "IIIa", "(FcRγIIIa)", "genotype", "F/", "F,", "mannan-binding", "lectin", "(MBL)", "genotype", "conferring", "a", "low", "serum", "concentration", "of", "MBL", "(MBL-low),", "and", "interleukin-1", "receptor", "antagonist", "(IL-1Ra)", "genotype", "2/2.", "Polymorphisms", "were", "analysed", "in", "143", "Caucasian", "patients", "with", "SLE", "and", "200", "healthy", "controls.", "HLA", "DR3", "in", "SLE", "patients", "was", "in", "90%", "part", "of", "Introduction", "The", "genetic", "contribution", "to", "the", "aetiology", "of", "systemic", "lupus", "erythematosus", "(SLE)", "is", "high,", "as", "is", "indicated", "by", "familial", "aggregation", "and", "a", "higher", "concordance", "rate", "in", "monozygotic", "than", "dizygotic", "twins", "[1].", "The", "major", "histocompatibility", "com-", "plex", "(MHC)", "haplotype", "HLA", "DR3-DQ2-C4AQ0", "is", "strongly", "associated", "with", "SLE", "in", "Caucasians", "[2,3].", "The", "IgG", "Fc", "receptors", "appear", "to", "be", "important", "in", "the", "pathogenesis", "of", "SLE,", "as", "recently", "reviewed", "by", "Salmon", "and", "Pricop", "[4].", "With", "the", "allelic", "variant", "of", "R", "(arginine)", "instead", "of", "H", "(histidine)", "on", "amino", "acid", "position", "131,", "the", "ability", "of", "Fcγ", "receptor", "IIa", "(FcγRIIa)", "to", "bind", "IgG2", "is", "diminished", "[5].", "Similarly,", "an", "amino", "acid", "substitution", "in", "position", "158", "(phenylalanine", "[F]", "instead", "of", "valine", "[V])", "in", "the", "Fcγ", "receptor", "IIIa", "(FcγRIIIa)", "reduces", "the", "the", "haplotype", "HLA", "DR3-DQ2-C4AQ0,", "which", "was", "strongly", "associated", "with", "SLE", "(odds", "ratio", "[OR]", "2.8,", "95%", "CI", "1.7–4.5).", "Analysis", "of", "combinations", "of", "gene", "variants", "revealed", "that", "the", "strong", "association", "with", "SLE", "for", "HLA", "DR3-DQ2-C4AQ0", "remained", "after", "combination", "with", "FcγRIIa", "R/R,", "FcγRIIIa", "F/F,", "and", "MBL-low", "(OR>2).", "Furthermore,", "the", "combination", "of", "the", "FcγRIIa", "R/R", "and", "IL-1Ra", "2/2", "genotypes", "yielded", "a", "strong", "correlation", "with", "SLE", "(OR", "11.8,", "95%", "CI", "1.5–95.4).", "This", "study", "demonstrates", "that", "certain", "combinations", "of", "gene", "variants", "may", "increase", "susceptibility", "to", "SLE,", "suggesting", "this", "approach", "for", "future", "studies.", "It", "also", "confirms", "earlier", "findings", "regarding", "the", "HLA", "DR3-", "DQ2-C4AQ0", "haplotype.", "IgG1-,", "IgG3-,", "and", "IgG4-binding", "capacity", "of", "the", "receptor", "[6].", "These", "variants", "can", "result", "in", "suboptimal", "clearance", "of", "immune", "complexes", "from", "the", "circulation,", "which", "might", "con-", "tribute", "to", "the", "pathogenesis", "of", "immune-complex-mediated", "manifestations", "[7].", "Mannan-binding", "lectin", "(MBL)", "is", "structurally", "similar", "to", "C1q", "and", "has", "the", "ability", "to", "activate", "the", "complement", "cascade", "through", "the", "lectin", "pathway.", "Point", "mutations", "are", "found", "in", "the", "structural", "gene", "that", "affect", "the", "MBL", "serum", "concentration", "and", "the", "stability", "of", "MBL", "complex", "formation", "required", "for", "effi-", "cient", "complement", "activation", "[8].", "In", "the", "promoter", "regions,", "there", "are", "two", "polymorphisms", "that", "influence", "serum", "concen-", "tration,", "with", "LX", "conferring", "the", "lowest", "MBL", "level,", "LY", "a", "medium", "level,", "and", "HY", "the", "highest", "[8-11].", "MBL", "variant", "alle-", "ACR", "=", "American", "College", "of", "Rheumatology;", "F", "=", "phenylalanine;", "FcγRIIa", "=", "Fcγ", "receptor", "IIa;", "FcγRIIIa", "=", "Fcγ", "receptor", "IIIa;", "H", "=", "histidine;", "IL-1Ra", "=", "inter-", "leukin-1", "receptor", "antagonist;", "MBL", "=", "mannan-binding", "lectin;", "MBL-low/-intermediate/-high", "=", "MBL", "genotype", "conferring", "a", "low/intermediate/high", "serum", "concentration", "of", "MBL;", "MHC", "=", "major", "histocompatibility", "complex;", "OR", "=", "odds", "ratio;", "PCR", "=", "polymerase", "chain", "reaction;", "R", "=", "arginine;", "RERI", "=", "relative", "excess", "risk", "due", "to", "interaction;", "SLE", "=", "systemic", "lupus", "erythematosus;", "V", "=", "valine.", "R557" ]

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[ "BMC", "Infectious", "Diseases", "Research", "article", "Impact", "of", "Empiric", "Antimicrobial", "Therapy", "on", "Outcomes", "in", "Patients", "with", "Escherichia", "coli", "and", "Klebsiella", "pneumoniae", "Bacteremia:", "A", "Cohort", "Study", "Kerri", "A", "Thom*1,", "Marin", "L", "Schweizer1,", "Regina", "B", "Osih2,", "Jessina", "C", "McGregor3,", "Jon", "P", "Furuno1,", "Eli", "N", "Perencevich4,1", "and", "Anthony", "D", "Harris1", "BioMed", "Central", "Open", "Access", "Address:", "1Department", "of", "Epidemiology", "and", "Preventive", "Medicine,", "University", "of", "Maryland", "School", "of", "Medicine,", "Baltimore,", "MD,", "USA,", "2Department", "of", "Medicine,", "Centre", "Hospitalier", "Universitaire", "Vaudois", "and", "University", "of", "Lausanne,", "Lausanne,", "Switzerland,", "3College", "of", "Pharmacy,", "Oregon", "State", "University,", "Portland,", "OR,", "USA", "and", "4Vetrans", "Affairs", "Maryland", "Health", "Care", "System,", "Baltimore,", "MD,", "USA", "Email:", "Kerri", "A", "Thom*", "-", "kthoms@medicine.umaryland.edu;", "Marin", "L", "Schweizer", "-", "mschweiz@epi.umaryland.edu;", "Regina", "B", "Osih", "-", "regina_osih@yahoo.com;", "Jessina", "C", "McGregor", "-", "mcgregoj@ohsu.edu;", "Jon", "P", "Furuno", "-", "jfuruno@epi.umaryland.edu;", "Eli", "N", "Perencevich", "-", "eperence@epi.umaryland.edu;", "Anthony", "D", "Harris", "-", "aharris@epi.umaryland.edu", "*", "Corresponding", "author", "Published:", "15", "September", "2008", "BMC", "Infectious", "Diseases", "2008,", "8:116", "doi:10.1186/1471-2334-8-116", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1471-2334/8/116", "Received:", "12", "February", "2008", "Accepted:", "15", "September", "2008", "©", "2008", "Thom", "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:", "It", "is", "unclear", "whether", "appropriate", "empiric", "antimicrobial", "therapy", "improves", "outcomes", "in", "patients", "with", "bacteremia", "due", "to", "Escherichia", "coli", "or", "Klebsiella.", "The", "objective", "of", "this", "study", "is", "to", "assess", "the", "impact", "of", "appropriate", "empiric", "antimicrobial", "therapy", "on", "in-hospital", "mortality", "and", "post-infection", "length", "of", "stay", "in", "patients", "with", "Escherichia", "coli", "or", "Klebsiella", "bacteremia", "while", "adjusting", "for", "important", "confounding", "variables.", "Methods:", "We", "performed", "a", "retrospective", "cohort", "study", "of", "adult", "patients", "with", "a", "positive", "blood", "culture", "for", "E.", "coli", "or", "Klebsiella", "between", "January", "1,", "2001", "and", "June", "8,", "2005", "and", "compared", "in-hospital", "mortality", "and", "post-infection", "length", "of", "stay", "between", "subjects", "who", "received", "appropriate", "and", "inappropriate", "empiric", "antimicrobial", "therapy.", "Empiric", "therapy", "was", "defined", "as", "the", "receipt", "of", "an", "antimicrobial", "agent", "between", "8", "hours", "before", "and", "24", "hours", "after", "the", "index", "blood", "culture", "was", "drawn", "and", "was", "considered", "appropriate", "if", "it", "included", "antimicrobials", "to", "which", "the", "specific", "isolate", "displayed", "in", "vitro", "susceptibility.", "Data", "were", "collected", "electronically", "and", "through", "chart", "review.", "Survival", "analysis", "was", "used", "to", "statistically", "assess", "the", "association", "between", "empiric", "antimicrobial", "therapy", "and", "outcome", "(mortality", "or", "length", "of", "stay).", "Multivariable", "Cox", "proportional", "hazards", "models", "were", "used", "to", "calculate", "hazard", "ratios", "(HR)", "and", "95%", "confidence", "intervals", "(CI).", "Results:", "Among", "416", "episodes", "of", "bacteremia,", "305", "(73.3%)", "patients", "received", "appropriate", "empiric", "antimicrobial", "therapy.", "Seventy-one", "(17%)", "patients", "died", "before", "discharge", "from", "the", "hospital.", "The", "receipt", "of", "appropriate", "antimicrobial", "agents", "was", "more", "common", "in", "hospital", "survivors", "than", "in", "those", "who", "died", "(p", "=", "0.04).", "After", "controlling", "for", "confounding", "variables,", "there", "was", "no", "association", "between", "the", "receipt", "of", "appropriate", "empiric", "antimicrobial", "therapy", "and", "in-hospital", "mortality", "(HR,", "1.03;", "95%", "CI,", "0.60", "to", "1.78).", "The", "median", "post-infection", "length", "of", "stay", "was", "7", "days.", "The", "receipt", "of", "appropriate", "antimicrobial", "agents", "was", "not", "associated", "with", "shortened", "post-infection", "length", "of", "stay,", "even", "after", "controlling", "for", "confounding", "(HR,", "1.11;", "95%", "CI", "0.86", "to", "1.44).", "Conclusion:", "Appropriate", "empiric", "antimicrobial", "therapy", "for", "E.", "coli", "and", "Klebsiella", "bacteremia", "is", "not", "associated", "with", "lower", "in-hospital", "mortality", "or", "shortened", "post-infection", "length", "of", "stay.", "This", "suggests", "that", "the", "choice", "of", "empiric", "antimicrobial", "agents", "may", "not", "improve", "outcomes", "and", "also", "provides", "data", "to", "support", "a", "randomized", "trial", "to", "test", "the", "hypothesis", "that", "use", "(and", "overuse)", "of", "broad-spectrum", "antibiotics", "prior", "to", "the", "availability", "of", "culture", "results", "is", "not", "warranted.", "Page", "1", "of", "9", "(page", "number", "not", "for", "citation", "purposes)" ]

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[ "Hindawi", "Publishing", "Corporation", "Experimental", "Diabetes", "Research", "Volume", "2008,", "Article", "ID", "312060,", "9", "pages", "doi:10.1155/2008/312060", "Methodology", "Report", "GeneSpeed", "Beta", "Cell:", "An", "Online", "Genomics", "Data", "Repository", "and", "Analysis", "Resource", "Tailored", "for", "the", "Islet", "Cell", "Biologist", "Nayeem", "Quayum,1", "Alecksandr", "Kutchma,1", "Suparna", "A.", "Sarkar,1", "Kirstine", "Juhl,1", "Gerard", "Gradwohl,2", "Georg", "Mellitzer,2", "John", "C.", "Hutton,1", "and", "Jan", "Jensen1,", "3", "1", "Barbara", "Davis", "Center", "for", "Childhood", "Diabetes,", "University", "of", "Colorado,", "HSC.,", "1775", "Ursula", "Street,", "B140,", "Aurora,", "CO", "80045,", "USA", "2", "Development", "and", "Physiopathology", "of", "the", "Intestine", "and", "Pancreas,", "Inserm-ULP", "Unit", "682,", "3", "avenue", "Moli`ere,", "Strasbourg", "67200,", "France", "3", "Lerner", "Research", "Institute,", "Department", "of", "Stem", "Cell", "and", "Regenerative", "medicine", "Cleveland", "Clinic,", "9500", "Euclid", "avenue,", "Cleveland,", "OH", "44195,", "USA", "Correspondence", "should", "be", "addressed", "to", "Jan", "Jensen,", "jensenj2@ccf.org", "Received", "29", "November", "2007;", "Accepted", "9", "July", "2008", "Recommended", "by", "Ulf", "Eriksson", "Objective.", "We", "here", "describe", "the", "development", "of", "a", "freely", "available", "online", "database", "resource,", "GeneSpeed", "Beta", "Cell,", "which", "has", "been", "created", "for", "the", "pancreatic", "islet", "and", "pancreatic", "developmental", "biology", "investigator", "community.", "Research", "Design", "and", "Methods.", "We", "have", "developed", "GeneSpeed", "Beta", "Cell", "as", "a", "separate", "component", "of", "the", "GeneSpeed", "database,", "providing", "a", "genomics-type", "data", "repository", "of", "pancreas", "and", "islet-relevant", "datasets", "interlinked", "with", "the", "domain-oriented", "GeneSpeed", "database.", "Results.", "GeneSpeed", "Beta", "Cell", "allows", "the", "query", "of", "multiple", "published", "and", "unpublished", "select", "genomics", "datasets", "in", "a", "simultaneous", "fashion", "(multiexperiment", "viewing)", "and", "is", "capable", "of", "defining", "intersection", "results", "from", "precomputed", "analysis", "of", "such", "datasets", "(multidimensional", "querying).", "Combined", "with", "the", "protein-domain", "categorization/assembly", "toolbox", "provided", "by", "the", "GeneSpeed", "database,", "the", "user", "is", "able", "to", "define", "spatial", "expression", "constraints", "of", "select", "gene", "lists", "in", "a", "relatively", "rigid", "fashion", "within", "the", "pancreatic", "expression", "space.", "We", "provide", "several", "demonstration", "case", "studies", "of", "relevance", "to", "islet", "cell", "biology", "and", "development", "of", "the", "pancreas", "that", "provide", "novel", "insight", "into", "islet", "biology.", "Conclusions.", "The", "combination", "of", "an", "exhaustive", "domain-based", "compilation", "of", "the", "transcriptome", "with", "gene", "array", "data", "of", "interest", "to", "the", "islet", "biologist", "affords", "novel", "methods", "for", "multidimensional", "querying", "between", "individual", "datasets", "in", "a", "rapid", "fashion,", "presently", "not", "available", "elsewhere.", "Copyright", "©", "2008", "Nayeem", "Quayum", "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.", "1.", "INTRODUCTION", "Genomics", "is", "playing", "a", "growing", "role", "in", "almost", "any", "biological", "experimentation.", "Based", "on", "presently", "available", "commer-", "cial", "expression", "array", "technologies,", "an", "investigator", "is", "given", "almost", "full-genome", "coverage", "of", "transcriptional", "changes", "that", "provides", "for", "novel", "methods", "for", "gene", "identification", "and", "validation.", "However,", "exhaustive", "data", "mining", "from", "genomics", "datasets", "is", "cumbersome,", "and", "to", "a", "large", "extent", "is", "outside", "the", "expertise", "of", "the", "individual", "experimenter.", "The", "greatest", "strength", "in", "genomics", "data", "analysis", "stems", "from", "multidimen-", "sional", "analysis,", "as", "such", "orthogonal", "comparison", "can", "bring", "out", "biologically", "relevant", "information", "not", "extractable", "from", "the", "individual", "datasets", "alone.", "However,", "such", "multidimensional", "querying", "is", "often", "advised", "against,", "as", "individual", "genomics", "experiments", "are", "performed", "in", "different", "laboratories,", "using", "dissimilar", "methodologies.", "Such", "array", "data", "should", "not", "be", "uploaded", "and", "analyzed", "concomitantly", "in", "the", "available", "software", "data", "analysis", "programs", "commonly", "used.", "Prudent", "analysis", "of", "multiexperimental", "results", "would", "therefore", "call", "for", "individual", "data", "analysis", "of", "experimental", "sets,", "and", "only", "parse", "for", "intersections/exclusions", "within", "the", "resulting", "gene", "lists.", "This", "is", "possible", "through", "genomics", "analysis", "platforms", "using", "separate", "gene", "list", "saving.", "However,", "the", "process", "is", "burdened", "by", "the", "fact", "that", "the", "analysis", "of", "a", "relevant", "dataset", "for", "orthogonal", "querying", "requires", "the", "identification", "of", "the", "existence", "of", "the", "data,", "upload,", "normalization,", "and", "scaling", "of", "individual", "DNA", "chip", "scan", "files", "and", "thereafter", "selecting", "and", "executing", "a", "valid", "analysis", "for", "the", "particular", "dataset,", "followed", "by", "results", "storage.", "In", "practice,", "this", "is", "time", "consuming,", "and", "too", "overwhelming,", "for", "most", "biologists.", "In", "the", "islet", "and", "islet", "developmental", "biology", "research", "fields,", "a", "continuously", "growing", "set", "of", "public", "genomics", "data", "is", "becoming", "available.", "Also,", "initial", "problems", "in", "both", "genomics" ]

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[ "Yang", "et", "al.", "Diagnostic", "Pathology", "2011,", "6:77", "http://www.diagnosticpathology.org/content/6/1/77", "R", "E", "S", "E", "A", "R", "C", "H", "Open", "Access", "Subtype", "distribution", "of", "lymphomas", "in", "Southwest", "China:", "Analysis", "of", "6,382", "cases", "using", "WHO", "classification", "in", "a", "single", "institution", "Qun-Pei", "Yang,", "Wen-Yan", "Zhang,", "Jian-Bo", "Yu,", "Sha", "Zhao,", "Huan", "Xu,", "Wei-Ya", "Wang,", "Cheng-Feng", "Bi,", "Zhuo", "Zuo,", "Xiao-Qing", "Wang,", "Juan", "Huang,", "Lin", "Dai", "and", "Wei-Ping", "Liu*", "Abstract", "Background:", "The", "subtype", "distribution", "of", "lymphoid", "neoplasms", "in", "Southwest", "China", "was", "analyzed", "according", "to", "WHO", "classifications.", "This", "study", "aims", "to", "analyze", "subtype", "distribution", "of", "lymphomas", "in", "southwest", "China.", "Methods:", "Lymphoid", "neoplasms", "diagnosed", "within", "9", "years", "in", "a", "single", "institution", "in", "Southwest", "China", "were", "analyzed", "according", "to", "the", "WHO", "classification.", "Results:", "From", "January", "2000", "to", "December", "2008,", "a", "total", "number", "of", "6,382", "patients", "with", "lymphoma", "were", "established,", "of", "which", "mature", "B-cell", "neoplasms", "accounted", "for", "56%,", "mature", "T-", "and", "NK-cell", "neoplasms", "occupied", "26%,", "and", "precursor", "lymphoid", "neoplasms", "and", "Hodgkin", "lymphomas", "were", "5%", "and", "13%,", "respectively.", "Mixed", "cellularity", "(76%)", "was", "the", "major", "subtype", "of", "classical", "Hodgkin", "lymphoma;", "and", "the", "bimodal", "age", "distribution", "was", "not", "observed.", "The", "top", "six", "subtypes", "of", "non-Hodgkin", "lymphoma", "were", "as", "follows:", "diffuse", "large", "B-cell", "lymphoma,", "extranodal", "NK/T-cell", "lymphoma,", "nasal", "type,", "extranodal", "marginal", "zone", "lymphoma", "of", "mucosa", "associated", "lymphoid", "tissue,", "follicular", "lymphoma,", "precursor", "lymphoid", "neoplasms,", "and", "chronic", "lymphocytic", "leukemia/small", "lymphocytic", "lymphoma.", "Extranodal", "lymphomas", "comprised", "about", "half", "of", "all", "cases,", "and", "most", "frequently", "involved", "Waldeyer’s", "ring,", "gastrointestinal", "tract,", "sinonasal", "region", "and", "skin.", "Conclusions:", "The", "lymphoid", "neoplasms", "of", "Southwest", "China", "displayed", "some", "epidemiologic", "features", "similar", "to", "those", "reported", "in", "literature", "from", "western", "and", "Asian", "countries,", "as", "well", "as", "other", "regions", "of", "China,", "whereas", "some", "subtypes", "showed", "distinct", "features.", "The", "high", "frequency", "of", "mature", "T/NK", "cell", "neoplasms", "and", "extranodal", "lymphomas,", "especially", "for", "extranodal", "NK/T-cell", "lymphoma,", "nasal", "type,", "is", "the", "most", "outstanding", "characteristic", "of", "this", "series.", "Keywords:", "Distribution,", "Lymphoma,", "Subtype,", "WHO", "classification", "Background", "Lymphoid", "neoplasms", "are", "a", "diverse", "group", "of", "malignancy", "that", "originate", "from", "either", "B,", "T", "or", "NK", "cell,", "representing", "about", "4%", "of", "the", "new", "cases", "of", "cancer", "diagnosed", "in", "China", "each", "year,", "making", "them", "the", "ninth", "most", "common", "cancer", "and", "the", "tenth", "leading", "cause", "of", "cancer", "death", "[1].", "Previous", "epidemiologic", "studies", "have", "shown", "remarkable", "differ-", "ences", "in", "the", "distribution", "of", "lymphoma", "subtypes", "between", "Asian", "and", "western", "populations", "[2-4].", "However,", "the", "pos-", "sible", "reasons", "of", "geographic", "differences", "in", "the", "spectrum", "of", "lymphoma", "remain", "unknown,", "mainly", "because", "the", "*", "Correspondence:", "liuweiping2001@vip.sina.com", "Department", "of", "Pathology,", "West", "China", "Hospital", "of", "Sichuan", "University,", "Chengdu,", "China", "etiology", "of", "lymphoma", "is", "largely", "unknown,", "even", "though", "some", "risk", "factors", "have", "been", "documented", "recently,", "including", "genetic", "factors,", "abnormality", "of", "immunity,", "indi-", "vidual", "susceptibilities,", "lifestyles,", "environmental", "expo-", "sures,", "as", "well", "as", "various", "kinds", "of", "infections", "caused", "by", "bacteria,", "viruses,", "mycoplasma", "and", "chlamydia", "[5].", "Major", "progression", "has", "been", "made", "in", "understanding", "the", "pathobiology", "of", "these", "diseases", "in", "the", "last", "two", "dec-", "ades,", "leading", "to", "the", "development", "of", "the", "internationally", "adopted", "WHO", "classification", "system", "and", "its", "updated", "ver-", "sion", "[5,6].", "From", "then", "on,", "many", "studies", "on", "lymphoma", "incidence", "patterns", "or", "distributions", "were", "reported", "all", "over", "the", "world.", "However,", "research", "on", "distribution", "of", "lymphoma", "in", "Mainland", "China", "was", "still", "limited,", "and", "the", "©", "2011", "Yang", "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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[ "Reduced", "Serotonin", "Reuptake", "Transporter", "(SERT)", "Function", "Causes", "Insulin", "Resistance", "and", "Hepatic", "Steatosis", "Independent", "of", "Food", "Intake", "Xiaoning", "Chen", "1", ",", "Kara", "J.", "Margolis3,", "Michael", "D.", "Gershon", "3", ",", "Gary", "J.", "Schwartz2,", "Ji", "Y.", "Sze1*", "1", "Department", "of", "Molecular", "Pharmacology,", "Albert", "Einstein", "College", "of", "Medicine,", "Bronx,", "New", "York,", "United", "States", "of", "America,", "2", "Department", "of", "Medicine", "and", "Neuroscience,", "Albert", "Einstein", "College", "of", "Medicine,", "Bronx,", "New", "York,", "United", "States", "of", "America,", "3", "Department", "of", "Pathology", "and", "Cell", "Biology,", "Columbia", "University,", "New", "York,", "New", "York,", "United", "States", "of", "America", "Abstract", "Serotonin", "reuptake", "transporter", "(SERT)", "is", "a", "key", "regulator", "of", "serotonin", "neurotransmission", "and", "a", "major", "target", "of", "antidepressants.", "Antidepressants,", "such", "as", "selectively", "serotonin", "reuptake", "inhibitors", "(SSRIs),", "that", "block", "SERT", "function", "are", "known", "to", "affect", "food", "intake", "and", "body", "weight.", "Here,", "we", "provide", "genetic", "evidence", "that", "food", "intake", "and", "metabolism", "are", "regulated", "by", "separable", "mechanisms", "of", "SERT", "function.", "SERT-deficient", "mice", "ate", "less", "during", "both", "normal", "diet", "and", "high", "fat", "diet", "feeding.", "The", "reduced", "food", "intake", "was", "accompanied", "with", "markedly", "elevated", "plasma", "leptin", "levels.", "Despite", "reduced", "food", "intake,", "SERT-deficient", "mice", "exhibited", "glucose", "intolerance", "and", "insulin", "resistance,", "and", "progressively", "developed", "obesity", "and", "hepatic", "steatosis.", "Several", "lines", "of", "evidence", "indicate", "that", "the", "metabolic", "deficits", "of", "SERT-deficient", "mice", "are", "attributable", "to", "reduced", "insulin-sensitivity", "in", "peripheral", "tissues.", "First,", "SERT-deficient", "mice", "exhibited", "beta-cell", "hyperplasia", "and", "islet-mass", "expansion.", "Second,", "biochemical", "analyses", "revealed", "constitutively", "elevated", "JNK", "activity", "and", "diminished", "insulin-induced", "AKT", "activation", "in", "the", "liver", "of", "SERT-deficient", "mice.", "SERT-deficient", "mice", "exhibited", "hyper-JNK", "activity", "and", "hyperinsulinemia", "prior", "to", "the", "development", "of", "obesity.", "Third,", "enhancing", "AKT", "signaling", "by", "PTEN", "deficiency", "corrected", "glucose", "tolerance", "in", "SERT-", "deficient", "mice.", "These", "findings", "have", "potential", "implications", "for", "designing", "selective", "SERT", "drugs", "for", "weight", "control", "and", "the", "treatment", "of", "metabolic", "syndromes.", "Citation:", "Chen", "X,", "Margolis", "KJ,", "Gershon", "MD,", "Schwartz", "GJ,", "Sze", "JY", "(2012)", "Reduced", "Serotonin", "Reuptake", "Transporter", "(SERT)", "Function", "Causes", "Insulin", "Resistance", "and", "Hepatic", "Steatosis", "Independent", "of", "Food", "Intake.", "PLoS", "ONE", "7(3):", "e32511.", "doi:10.1371/journal.pone.0032511", "Editor:", "Giorgio", "Sesti,", "Universita", "Magna-Graecia", "di", "Catanzaro,", "Italy", "Received", "September", "13,", "2011;", "Accepted", "January", "27,", "2012;", "Published", "March", "8,", "2012", "Copyright:", "2012", "Chen", "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", "Institutes", "of", "Health", "(MH083982)(JS),", "NIH", "DK", "020541", "DK", "026687(GJS).", "The", "funder", "had", "no", "role", "in", "study", "design,", "data", "collection", "and", "analysis,", "decision", "to", "publish,", "or", "preparation", "of", "the", "manuscript.", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "*", "E-mail:", "jiying.sze@einstein.yu.edu", "Introduction", "Disturbances", "in", "glucose", "homeostasis", "among", "psychiatric", "popu-", "lations", "have", "been", "documented", "extensively", "[1,2].", "The", "mechanisms", "for", "this", "comorbidity", "are", "currently", "unknown,", "and", "are", "likely", "to", "involve", "diverse", "genetic,", "behavioral", "and", "environmental", "factors.", "Therefore,", "identifying", "the", "regulation", "of", "metabolic", "homeostasis", "by", "genes", "implicated", "in", "anxiety-related", "disorders", "may", "reveal", "insights", "into", "the", "pathophysiology", "of", "both", "mental", "and", "metabolic", "disorders.", "The", "serotonin", "reuptake", "transporter", "(SERT)", "is", "a", "major", "target", "of", "antidepressants.", "Selective", "serotonin", "reuptake", "inhibitors", "(SSRIs)", "are", "believed", "to", "exert", "antidepressant", "effects", "by", "blocking", "SERT", "uptaking", "serotonin", "(5-HT)", "from", "extracellular", "space,", "thereby", "enhancing", "5-HT", "signaling", "[3].", "In", "this", "study,", "we", "focused", "on", "the", "impact", "of", "constitutive", "SERT", "deficiency", "on", "energy", "balance", "and", "glucose", "homeostasis", "in", "mice.", "Pharmacological", "studies", "have", "long", "implicated", "5-HT", "in", "reducing", "food", "intake", "and", "body", "weight", "[4,5,6].", "Subsequent", "genetic", "analyses", "in", "rodents", "demonstrated", "that", "hypothalamic", "5-HT", "signaling", "controls", "food", "intake.", "For", "example,", "the", "5-HT", "receptor", "5HTR2C", "is", "highly", "expressed", "in", "the", "hypothalamus", "and", "5HTR2C", "knockout", "mice", "develop", "hyperphagia,", "obesity", "and", "insulin", "resistance", "[7,8].", "In", "addition,", "the", "5-HT", "receptor", "5-HTR1B", "modulates", "the", "activity", "of", "melanocortin", "neurons", "to", "influence", "food", "intake", "[9].", "By", "contrast,", "the", "impact", "of", "SSRIs", "on", "metabolism", "is", "less", "clear.", "Meta-analyses", "of", "clinical", "trials", "reported", "significant", "weight", "loss", "in", "subjects", "treated", "with", "fluoxetine", "[10,11].", "The", "effect", "of", "SSRIs", "on", "weight", "loss", "is,", "however,", "short", "term,", "and", "individuals", "regain", "or", "increase", "weight,", "despite", "continued", "SSRIs", "treatments", "[12,13].", "In", "some", "cases,", "SSRI", "treatments", "yielded", "hyperglycemia", "and", "a", "trend", "towards", "diabetes", "[13,14,15].", "Accumulating", "evidence", "suggests", "that", "the", "effects", "of", "SSRIs", "on", "metabolisms", "are", "not", "merely", "secondary", "to", "improvement", "in", "affective", "states,", "but", "that", "5-HT", "may", "act", "at", "both", "the", "brain", "and", "peripheral", "tissues", "to", "influence", "metabolism", "[16,17,18,19].", "However,", "the", "impact", "of", "SERT", "inactivation", "on", "glucose", "homeostasis", "and", "insulin", "signaling", "has", "not", "been", "systemat-", "ically", "analyzed", "to", "date.", "The", "purpose", "of", "this", "study", "was", "to", "test", "whether", "mice", "lacking", "SERT", "gene", "Slc6a4", "function", "(SERT2/2)", "exhibit", "reduced", "food", "intake,", "thereby", "protecting", "them", "against", "obesity", "and", "diabetes.", "To", "circumvent", "potential", "complications", "of", "reproductive", "hormone", "cycles", "in", "females,", "we", "focused", "on", "male", "mice.", "As", "expected,", "we", "found", "SERT2/2", "mice", "ate", "less.", "However,", "contrary", "to", "our", "expectations,", "SERT", "deficient", "mice", "exhibited", "glucose", "intolerance", "and", "insulin", "resistance,", "and", "progressively", "developed", "obesity", "and", "liver", "steatosis.", "We", "found", "that", "SERT2/2", "mice", "were", "hyperlepti-", "nemic,", "hyperglycemic", "and", "hyperinsulinemic", "prior", "to", "exhibiting", "a", "measurable", "increase", "in", "body", "fat", "content.", "We", "identified", "that", "C-Jun-", "PLoS", "ONE", "|", "www.plosone.org", "1", "March", "2012", "|", "Volume", "7", "|", "Issue", "3", "|", "e32511" ]

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[ "Research", "A", "Prospective", "Study", "of", "Organochlorines", "in", "Adipose", "Tissue", "and", "Risk", "of", "Non‑Hodgkin", "Lymphoma", "Elvira", "Vaclavik", "Bräuner,1", "Mette", "Sørensen,1", "Eric", "Gaudreau,2", "Alain", "LeBlanc,2", "Kirsten", "Thorup", "Eriksen,1", "Anne", "Tjønneland,1", "Kim", "Overvad,3", "and", "Ole", "Raaschou-Nielsen1", "1Institute", "of", "Cancer", "Epidemiology,", "Danish", "Cancer", "Society,", "Copenhagen,", "Denmark;", "2Centre", "de", "toxicologie", "du", "Québec,", "Institut", "National", "de", "Santé", "Publique", "du", "Québec,", "Quebec", "City,", "Quebec,", "Canada;", "3Department", "of", "Epidemiology,", "School", "of", "Public", "Health,", "Aarhus", "University,", "Aarhus,", "Denmark", "Background", ":", "Exposure", "to", "organochlorines", "has", "been", "examined", "as", "a", "potential", "risk", "factor", "for", "non-Hodgkin", "lymphoma", "(NHL),", "with", "inconsistent", "results", "that", "may", "be", "related", "to", "limited", "statistical", "power", "or", "to", "imprecise", "exposure", "measurements.", "o", "Bjectiv", ":", "Our", "purpose", "was", "to", "examine", "associations", "between", "organochlorine", "concentrations", "in", "prediagnostic", "adipose", "tissue", "samples", "and", "the", "risk", "of", "NHL.", "Methods", ":", "We", "conducted", "a", "case–cohort", "study", "using", "a", "prospective", "Danish", "cohort", "of", "57,053", "persons", "enrolled", "between", "1993", "and", "1997.", "Within", "the", "cohort", "we", "identified", "256", "persons", "diagnosed", "with", "NHL", "in", "the", "population-based", "nationwide", "Danish", "Cancer", "Registry", "and", "randomly", "selected", "256", "sub-", "cohort", "persons.", "We", "measured", "concentrations", "of", "8", "pesticides", "and", "10", "polychlorinated", "biphenyl", "(PCB)", "congeners", "in", "adipose", "tissue", "collected", "upon", "enrollment.", "Associations", "between", "the", "18", "organochlorines", "and", "NHL", "were", "analyzed", "in", "Cox", "regression", "models,", "adjusting", "for", "body", "mass", "index.", "r", "esult", ":", "Incidence", "rate", "ratios", "and", "confidence", "intervals", "(CIs)", "for", "interquartile", "range", "increases", "in", "concentrations", "of", "dichlorodiphenyltrichlorethane", "(DDT),", "cis-nonachlor,", "and", "oxychlordane", "were", "1.35", "(95%", "CI:", "1.10,", "1.66),", "1.13", "(95%", "CI:", "0.94,", "1.36),", "and", "1.11", "(95%", "CI:", "0.89,", "1.38),", "respectively,", "with", "monotonic", "dose–response", "trends", "for", "DDT", "and", "cis-nonachlor", "based", "on", "categorical", "models.", "The", "relative", "risk", "estimates", "were", "higher", "for", "men", "than", "for", "women.", "In", "contrast,", "no", "clear", "association", "was", "found", "between", "NHL", "and", "PCBs.", "c", "onclusi", ":", "We", "found", "a", "higher", "risk", "of", "NHL", "in", "association", "with", "higher", "adipose", "tissue", "levels", "of", "DDT,", "cis-nonachlor,", "and", "oxychlordane,", "but", "no", "association", "with", "PCBs.", "This", "is", "the", "first", "study", "of", "organochlorines", "and", "NHL", "using", "prediagnostic", "adipose", "tissue", "samples", "in", "the", "exposure", "assessment", "and", "provides", "new", "environmental", "health", "evidence", "that", "these", "organochlorines", "contribute", "to", "NHL", "risk.", "k", "ey", "words", ":", "adipose", "tissue,", "case–cohort,", "non-Hodgkin", "lymphoma,", "organochlorines.", "Environ", "Health", "Perspect", "120:105–111", "(2012).", "http://dx.doi.org/10.1289/ehp.1103573", "[Online", "26", "August", "2011]", "Non-Hodgkin", "lymphomas", "(NHLs)", "are", "a", "het-", "erogeneous", "group", "of", "B-", "and", "T-cell", "neoplasms", "arising", "primarily", "in", "the", "lymph", "nodes.", "Incidence", "rates", "have", "nearly", "doubled", "in", "Western", "countries", "since", "the", "1970s,", "although", "no", "further", "rise", "has", "been", "observed", "since", "the", "mid-1990s", "(Dreiher", "and", "Kordysh", "2006).", "Established", "risk", "factors", "include", "genetic", "susceptibility", "and", "previous", "his-", "tory", "of", "malignant", "disease", "(Wang", "et", "al.", "2007).", "Immunological", "conditions", "are", "also", "related", "to", "this", "group", "of", "cancers,", "as", "evidenced", "by", "a", "more", "than", "100-fold", "increased", "risk", "of", "NHL", "among", "organ", "transplant", "recipients", "receiving", "immuno-", "suppressive", "therapy", "(Fisher", "and", "Fisher", "2004)", "and", "an", "increased", "incidence", "among", "subjects", "with", "primary", "immunodeficiency", "and", "autoimmune", "diseases", "(Vineis", "et", "al.", "2000).", "However,", "these", "factors,", "in", "combination", "with", "longer", "life", "spans", "and", "changes", "in", "diagnostic", "patterns,", "cannot", "explain", "all", "cases,", "and", "many", "researchers", "specu-", "late", "that", "the", "increase", "is", "partly", "due", "to", "exposure", "to", "environmental", "agents,", "including", "organo-", "chlorines", "(Hardell", "and", "Axelson", "1998).", "Dichlorodiphenyltrichlorethane", "(DDT)", "and", "other", "organochlorines", "are", "carcinogenic", "in", "animals", "(International", "Agency", "for", "Research", "on", "Cancer", "1987),", "and", "the", "production", "and", "environmental", "release", "of", "these", "compounds", "with", "subsequent", "bioaccumulation", "accelerated", "during", "the", "decades", "after", "1945", "(World", "Resources", "Institute", "1990),", "coinciding", "with", "increasing", "incidence", "rates", "for", "NHL", "in", "Western", "populations.", "Organochlorines", "are", "ubiquitously", "present", "as", "a", "mixture", "of", "mother", "compounds", "and", "metabolites", "in", "the", "environment", "and", "are", "characterized", "by", "high", "lipid", "solubility,", "environ-", "mental", "persistence,", "bioaccumulation", "(Agency", "for", "Toxic", "Substances", "and", "Disease", "Registry", "1993),", "and", "long", "biological", "half-lives", "in", "human", "tissue", "(Wolff", "et", "al.", "2000).", "Several", "studies", "have", "described", "immunotoxicity", "of", "selected", "organo-", "chlorines", "(Heilmann", "et", "al.", "2006;", "Reed", "et", "al.", "2004;", "Tryphonas", "et", "al.", "2003).", "The", "evidence", "relating", "organochlorines", "to", "NHL", "risk", "has", "been", "reviewed", "(Dreiher", "and", "Kordysh", "2006)", "and", "the", "association", "remains", "unclear,", "with", "some", "studies", "reporting", "associa-", "tions", "and", "others", "finding", "none.", "Reasons", "for", "these", "discrepancies", "may", "include", "low", "statis-", "tical", "power", "or", "imprecise", "exposure", "measure-", "ments,", "such", "as", "surrogate", "measures", "including", "occupation", "or", "self-reported", "questionnaires", "gathered", "after", "diagnosis.", "More", "recent", "studies", "have", "evaluated", "biological", "exposure", "measure-", "ments", "and", "have", "more", "consistently", "reported", "associations", "between", "NHL", "risk", "and", "various", "organochlorine", "pesticides", "and", "polychlorinated", "biphenyl", "(PCB)", "congeners", "(Bertrand", "et", "al.", "Environmental", "Health", "Perspectives", "•", "volume", "120", "|", "number", "1", "|", "January", "2012", "2010;", "Cantor", "et", "al.", "2003;", "De", "Roos", "et", "al.", "2005;", "Engel", "et", "al.", "2007;", "Laden", "et", "al.", "2010;", "Quintana", "et", "al.", "2004;", "Spinelli", "et", "al.", "2007).", "However,", "the", "specific", "compounds", "identified", "were", "not", "con-", "sistent", "among", "the", "studies,", "and", "different", "bio-", "logical", "media", "were", "used.", "Questions", "pertaining", "to", "the", "best", "quantification", "of", "biological", "expo-", "sure", "have", "been", "raised", "(Aronson", "et", "al.", "2000;", "Whitcomb", "et", "al.", "2005),", "and", "adipose", "tissue", "samples", "have", "been", "regarded", "by", "various", "authors", "(Allam", "and", "Lucena", "2001;", "Hardell", "et", "al.", "1996;", "Quintana", "et", "al.", "2004)", "as", "the", "preferred", "indica-", "tor", "of", "human", "exposure", "because", "organochlorine", "levels", "are", "known", "to", "be", "higher", "in", "adipose", "tissue", "and", "more", "representative", "of", "the", "cumulative", "internal", "exposure.", "However,", "only", "two", "studies", "have", "previously", "measured", "organochlorines", "in", "adipose", "tissue", "(Hardell", "et", "al.", "1996;", "Quintana", "et", "al.", "2004),", "and", "in", "both", "studies", "the", "adipose", "tissue", "was", "sampled", "after", "the", "diagnosis,", "render-", "ing", "results", "difficult", "to", "interpret", "because", "treat-", "ment", "may", "affect", "subsequent", "organochlorine", "concentrations", "(Gammon", "et", "al.", "1996;", "Morgan", "and", "Roan", "1971).", "In", "the", "present", "study,", "we", "investigated", "the", "hypothesis", "that", "organochlorines", "are", "related", "to", "an", "increased", "NHL", "risk,", "and", "we", "are", "the", "first", "to", "use", "adipose", "tissue", "sampled", "before", "the", "NHL", "diagnosis", "to", "assess", "organochlorine", "exposures", "in", "a", "population-based", "setting.", "Materials", "and", "Methods", "Between", "December", "1993", "and", "May", "1997,", "160,725", "persons", "50–64", "years", "of", "age", "were", "invited", "to", "participate", "in", "the", "prospective", "Diet,", "Cancer", "and", "Health", "study.", "The", "participants", "had", "to", "be", "born", "in", "Denmark,", "live", "in", "Copenhagen", "Address", "correspondence", "to", "O.", "Raaschou-Nielsen,", "Institute", "of", "Cancer", "Epidemiology,", "Danish", "Cancer", "Society,", "Copenhagen", "2100,", "Denmark.", "Telephone:", "45", "35257617.", "Fax:", "0045", "35257731.", "E-mail:ole@", "cancer.dk", "Supplemental", "Material", "is", "available", "online", "(http://", "dx.doi.org/10.1289/ehp.1103573).", "E.V.B.", "was", "supported", "by", "the", "Danish", "Medical", "Research", "Council,", "Danish", "Cancer", "Society,", "Aase", "and", "Ejnar", "Danielsens,", "King", "Christian", "the", "10th,", "A.P.", "Møller,", "the", "Hartmann", "Brothers,", "the", "Foundation", "of", "1870,", "Snedker", "Jacobsen", "and", "hustru", "Astrid", "Jacobsen,", "Architect", "Holger", "Hjortenberg", "and", "hustru", "Dagmar", "Hjortenberg,", "Civil", "Engineer", "Frode", "V.", "Nyegaard,", "and", "Simon", "Spies.", "The", "authors", "declare", "they", "have", "no", "actual", "or", "potential", "competing", "financial", "interests.", "Received", "14", "February", "2011;", "accepted", "26", "August", "2011.", "105" ]

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[ "Available", "online", "http://arthritis-research.com/content/4/5/E007", "Correspondence", "To", "keep", "the", "catch", "–", "that", "is", "the", "question:", "a", "personal", "account", "of", "the", "3rd", "Annual", "EULAR", "Congress,", "Stockholm", "Frank", "A", "Wollheim", "Department", "of", "Rheumatology,", "Lund", "University", "Hospital,", "Lund,", "Sweden", "Corresponding", "author:", "Frank", "A", "Wollheim", "(e-mail:", "Frank.Wollheim@reum.lu.se)", "Received:", "8", "July", "2002", "Accepted:", "9", "July", "2002", "Published:", "18", "July", "2002", "Arthritis", "Res", "2002,", "4:E007", "©", "2002", "BioMed", "Central", "Ltd", "(Print", "ISSN", "1465-9905;", "Online", "ISSN", "1465-9913)", "Abstract", "The", "3rd", "Annual", "EULAR", "Congress,", "held", "in", "Stockholm", "on", "12–15", "June", "2002,", "had", "a", "turnout", "of", "8300", "delegates,", "almost", "identical", "to", "last", "year’s", "record", "attendance", "level", "in", "Prague.", "The", "venue", "was", "close", "to", "ideal,", "allowing", "ample", "space", "for", "poster", "sessions", "in", "the", "exhibition", "hall.", "The", "manned", "poster", "sessions", "were", "well", "attended,", "even", "on", "the", "last", "day", "of", "the", "Congress.", "The", "numerous", "invited", "speakers", "represented", "the", "world’s", "elite,", "allowing", "the", "staging", "of", "excellent", "state-of-the-art", "podium", "sessions.", "The", "aim", "of", "attracting", "the", "young", "scientific", "community", "was", "partly", "achieved,", "but", "individual", "delegates’", "dependence", "on", "industry", "sponsorship", "poses", "potential", "problems.", "The", "organization", "was", "a", "big", "improvement", "compared", "to", "that", "of", "the", "two", "previous", "congresses.", "Approximately", "1800", "abstracts", "were", "submitted,", "an", "increase", "of", "50%,", "resulting", "in", "a", "higher", "quality", "of", "accepted", "abstracts.", "The", "satellite", "symposia", "held", "every", "morning", "and", "late", "afternoon", "were", "well", "attended;", "thus,", "industry", "exposure", "of", "new", "products,", "both", "in", "podium", "sessions", "and", "at", "the", "exhibitions,", "was", "well", "accommodated.", "The", "Annual", "EULAR", "Congress", "consolidates", "its", "position", "as", "one", "of", "the", "two", "most", "important", "annual", "congresses", "of", "rheumatology,", "but", "EULAR", "economy", "and", "commercial", "aspects", "are", "still", "too", "dominant", "in", "relation", "to", "science.", "Keywords:", "ACR,", "EULAR,", "poster", "sessions,", "rheumatology", "congress,", "satellite", "symposia", "Introduction", "A", "year", "ago", "I", "wrote", "a", "personal", "critique", "of", "the", "2nd", "Annual", "EULAR", "Congress", "in", "Prague", "for", "this", "journal", "[1].", "This", "year,", "I", "was", "asked", "for", "a", "similar", "article", "on", "the", "3rd", "EULAR", "Congress", "in", "Stockholm,", "and", "although", "playing", "a", "small", "part", "in", "the", "local", "organizing", "committee", "I", "felt", "unbiased", "enough", "to", "accept", "the", "challenge.", "This", "will", "not", "be", "a", "normal", "meeting", "report;", "I", "will", "not", "even", "attempt", "to", "summarize", "the", "sessions", "and", "activities", "I", "was", "obliged", "or", "allowed", "to", "attend.", "Realizing", "that", "this", "is", "the", "most", "important", "rheumatologic", "meeting", "outside", "the", "USA,", "I", "will", "attempt", "to", "convey", "positive", "and", "negative", "experi-", "ences,", "fully", "aware", "of", "the", "constraints", "under", "which", "EULAR", "strives", "to", "achieve", "a", "number", "of", "goals,", "political,", "economic,", "educational,", "scientific", "and", "social.", "All", "are", "important", "but", "dif-", "ficult", "to", "achieve", "simultaneously.", "A", "gigantic", "meeting", "The", "number", "of", "delegates", "registered", "(8,300", "—", "almost", "the", "same", "number", "that", "attended", "the", "Congress", "in", "Prague", "in", "2001)", "was", "no", "match", "for", "the", "EULAR", "congress", "organizer", "CMI", "in", "Geneva", "and", "its", "local", "partner", "in", "Stockholm.", "Hotel", "rooms", "were", "found", "for", "all", "the", "delegates,", "although", "those", "arriving", "without", "previous", "reservations", "had", "to", "accept", "less", "than", "classy", "accommodation.", "Volvo", "provided", "limousine", "transport", "for", "some", "VIPs,", "the", "invited", "speakers", "had", "a", "shuttle", "bus", "service", "from", "hotel", "to", "congress", "center,", "and", "the", "ordi-", "nary", "delegates", "were", "provided", "with", "a", "pass", "for", "public", "trans-", "port,", "which", "took", "them", "to", "the", "central", "station", "in", "11", "minutes.", "The", "venue", "was", "excellent,", "not", "least", "the", "big", "central", "exhibi-", "tion", "hall", "which", "housed", "nonprofit", "exhibitors,", "industry", "exhibi-", "tions", "and", "scientific", "posters.", "It", "was", "easy", "to", "get", "oriented", "by", "reading", "the", "program", "book,", "which", "compensated", "for", "the", "almost", "complete", "absence", "of", "signs.", "One", "would", "have", "wished", "for", "signs", "at", "the", "meeting", "room", "entrances,", "at", "least,", "indicating", "which", "session", "was", "in", "progress.", "It", "was", "nice", "to", "encounter", "a", "large", "number", "of", "non-European", "attendees,", "although", "some", "voices", "said", "that", "this", "made", "ACR", "ACR", "=", "American", "College", "of", "Rheumatology;", "EULAR", "=", "European", "League", "Against", "Rheumatism;", "VIP", "=", "very", "important", "person." ]

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[ "Nanoscale", "Res", "Lett", "(2009)", "4:420–430", "DOI", "10.1007/s11671-009-9262-5", "N", "A", "N", "O", "E", "X", "P", "R", "E", "S", "S", "Influence", "of", "Nanogels", "on", "Mechanical,", "Dynamic", "Mechanical,", "and", "Thermal", "Properties", "of", "Elastomers", "Suman", "Mitra", "Æ", "Santanu", "Chattopadhyay", "Æ", "Anil", "K.", "Bhowmick", "Received:", "6", "October", "2008", "/", "Accepted:", "27", "January", "2009", "/", "Published", "online:", "13", "February", "2009", "to", "the", "authors", "2009", "Abstract", "Use", "of", "sulfur", "crosslinked", "nanogels", "to", "improve", "various", "properties", "of", "virgin", "elastomers", "was", "investigated", "for", "the", "first", "time.", "Natural", "rubber", "(NR)", "and", "styrene", "butadiene", "rubber", "(SBR)", "nanogels", "were", "prepared", "by", "prevulcanization", "of", "the", "respective", "rubber", "lattices.", "These", "nanogels", "were", "characterized", "by", "dynamic", "light", "scattering,", "atomic", "force", "microscopy", "(AFM),", "solvent", "swelling,", "mechanical,", "and", "dynamic", "mechanical", "property", "measurements.", "Intermixing", "of", "gel", "and", "matrix", "at", "various", "ratios", "was", "carried", "out.", "Addition", "of", "NR", "gels", "greatly", "improved", "the", "green", "strength", "of", "SBR,", "whereas", "presence", "of", "SBR", "nanogels", "induced", "greater", "thermal", "stability", "in", "NR.", "For", "example,", "addition", "of", "16", "phr", "of", "NR", "gel", "increased", "the", "maximum", "tensile", "stress", "value", "of", "neat", "SBR", "by", "more", "than", "48%.", "Noticeable", "increase", "in", "glass", "transition", "temperature", "of", "the", "gel", "filled", "systems", "was", "also", "observed.", "Morphology", "of", "these", "gel", "filled", "elastomers", "was", "studied", "by", "a", "combination", "of", "energy", "dispersive", "X-ray", "mapping,", "trans-", "mission", "electron", "microscopy,", "and", "AFM", "techniques.", "Particulate", "filler", "composite", "reinforcement", "models", "were", "used", "to", "understand", "the", "reinforcement", "mechanism", "of", "these", "nanogels.", "Keywords", "Nanogels", "Mechanical", "properties", "Elastomers", "Gels", "Thermal", "properties", "Electronic", "supplementary", "material", "The", "online", "version", "of", "this", "article", "(doi:10.1007/s11671-009-9262-5)", "contains", "supplementary", "material,", "which", "is", "available", "to", "authorized", "users.", "S.", "Mitra", "S.", "Chattopadhyay", "A.", "K.", "Bhowmick", "(&)", "Rubber", "Technology", "Centre,", "Indian", "Institute", "of", "Technology,", "Kharagpur", "721302,", "India", "e-mail:", "anilkb@rtc.iitkgp.ernet.in", "123", "Introduction", "Virgin", "polymers,", "especially", "elastomers", "have", "inherently", "low", "stiffness", "and", "strength.", "In", "order", "to", "overcome", "these", "obvious", "limitations", "and", "to", "expand", "their", "applications", "in", "different", "fields,", "particulate", "fillers,", "such", "as", "carbon", "black,", "silica,", "glass,", "calcium", "carbonates,", "carbon", "nanotubes,", "nano", "clays", "etc.", "are", "often", "added", "to", "polymer.", "Particulate", "fillers", "modify", "physical", "and", "mechanical", "properties", "of", "polymers", "in", "many", "ways.", "Use", "of", "carbon", "black", "for", "improving", "reinforcement", "properties", "of", "an", "elastomer", "has", "been", "studied", "extensively", "in", "numerous", "investigations", "[1,", "2].", "Amongst", "the", "nonblack", "fillers,", "mostly", "silica", "provides", "the", "best", "reinforcing", "properties", "[3].", "In", "the", "last", "decade,", "it", "has", "been", "shown", "that", "dramatic", "improvements", "in", "mechanical", "and", "other", "properties", "can", "be", "achieved", "by", "incorporation", "of", "a", "few", "weight", "percentages", "(wt%)", "of", "inor-", "ganic", "exfoliated", "clay", "minerals", "consisting", "of", "mostly", "layered", "silicates", "in", "polymer", "matrices", "[4–10].", "These", "are", "better", "known", "as", "polymer", "nanocomposites.", "Similar", "enhancements", "in", "various", "properties", "have", "also", "been", "reported", "with", "other", "types", "of", "nanofillers", "e.g.", "multiwalled", "carbon", "nanotubes", "and", "layered", "double", "hydroxides", "[11,", "12].", "Although", "not", "strictly", "categorized", "as", "filler,", "use", "of", "gels", "to", "improve", "various", "physical", "properties", "of", "elastomers,", "with", "an", "added", "advantage", "of", "superior", "processability,", "can", "be", "found", "in", "the", "prevailing", "literature", "[13–15].", "Kawahara", "et", "al.", "[16]", "have", "reported", "the", "effect", "of", "gel", "on", "green", "strength", "of", "natural", "rubber.", "In", "most", "of", "the", "above", "work,", "the", "authors", "have", "used", "physically", "crosslinked", "or", "entangled", "network", "gels.", "How-", "ever,", "our", "recent", "preliminary", "work", "with", "chemically", "crosslinked", "nanogels", "and", "quasi-nanogels", "has", "revealed", "that", "addition", "of", "these", "gels", "leads", "to", "a", "considerable", "improvement", "in", "processability,", "mechanical,", "and", "dynamic", "mechanical", "properties", "of", "virgin", "natural", "rubber", "(NR)", "and", "styrene", "buta-", "diene", "rubber", "(SBR)", "[17–19].", "Optimization", "of", "these" ]

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[ "A", "R", "T", "I", "C", "L", "E", "State-independent", "Block", "of", "BK", "Channels", "by", "an", "Intracellular", "Quaternary", "Ammonium", "Christina", "M.", "Wilkens", "and", "Richard", "W.", "Aldrich", "Department", "of", "Molecular", "and", "Cellular", "Physiology,", "Stanford", "University,", "Stanford,", "CA", "94305", "Section", "of", "Neurobiology,", "University", "of", "Texas", "at", "Austin,", "Austin,", "TX", "78705", "Intracellular", "blockade", "by", "quaternary", "ammonium", "(QA)", "molecules", "of", "many", "potassium", "channels", "is", "state", "dependent,", "where", "the", "requirement", "for", "channel", "opening", "is", "evidenced", "by", "a", "time-dependent", "component", "of", "block", "in", "the", "macro-", "scopic", "record.", "Whether", "this", "is", "the", "case", "for", "Ca2+-", "and", "voltage-activated", "potassium", "(BK)", "channels,", "however,", "remains", "unclear.", "Previous", "work", "(Li,", "W.,", "and", "R.W.", "Aldrich.", "2004.", "J.", "Gen.", "Physiol.", "124:43–57)", "tentatively", "proposed", "a", "state-", "dependent,", "trapping", "model,", "but", "left", "open", "the", "possibility", "of", "state-independent", "block.", "Here,", "we", "found", "BK", "channel", "blockade", "by", "a", "novel", "QA", "derivative,", "bbTBA,", "was", "time", "dependent,", "raising", "the", "possibility", "of", "state-dependent,", "open", "channel", "block.", "Alternatively,", "the", "observed", "voltage", "dependence", "of", "block", "could", "be", "sufficient", "to", "explain", "time-dependent", "block.", "We", "have", "used", "steady-state", "and", "kinetic", "measurements", "of", "bbTBA", "blockade", "in", "order", "to", "discriminate", "between", "these", "two", "possibilities.", "bbTBA", "did", "not", "significantly", "slow", "deactivation", "kinetics", "at", "potentials", "between", "−200", "and", "−100", "mV,", "suggesting", "that", "channels", "can", "close", "unhindered", "by", "bound", "bbTBA.", "We", "further", "find", "no", "evidence", "that", "bbTBA", "is", "trapped", "inside", "BK", "channels", "after", "closing.", "Measurements", "of", "steady", "state", "fractional", "block", "at", "+40", "mV", "revealed", "a", "1.3-fold", "change", "in", "apparent", "affinity", "for", "a", "33-fold", "change", "in", "Po,", "in", "striking", "contrast", "to", "the", "31-fold", "change", "predicted", "by", "state-", "dependent", "block.", "Finally,", "the", "appearance", "of", "a", "third", "kinetic", "component", "of", "bbTBA", "blockade", "at", "high", "concentrations", "is", "incompatible", "with", "state-dependent", "block.", "Our", "results", "suggest", "that", "access", "of", "intracellular", "bbTBA", "to", "the", "BK", "chan-", "nel", "cavity", "is", "not", "strictly", "gated", "by", "channel", "opening", "and", "closing,", "and", "imply", "that", "the", "permeation", "gate", "for", "BK", "channels", "may", "not", "be", "intracellular.", "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", "mechanism", "of", "ion", "channel", "opening", "and", "closing", "is", "widely", "thought", "of", "in", "terms", "of", "a", "gate", "that", "permits", "or", "re-", "stricts", "access", "to", "the", "inner", "pore", "via", "a", "reversible", "confor-", "mational", "change.", "Much", "attention", "has", "been", "focused", "on", "locating", "the", "gate", "of", "K+", "channels,", "as", "a", "first", "step", "toward", "understanding", "the", "conformational", "changes", "that", "under-", "lie", "the", "gating", "process.", "Clay", "Armstrong’s", "innovative", "use", "of", "intracellular", "organic", "blockers", "that", "could", "block", "K+", "channels", "only", "when", "they", "were", "open", "(Armstrong,", "1966,", "1969,", "1971)", "produced", "the", "first", "strong", "evidence", "for", "an", "intracellular", "activation", "gate.", "The", "classic", "features", "of", "state-", "dependent", "(open", "channel)", "block", "defined", "in", "this", "work", "(Armstrong,", "1971)", "include", "(a)", "time-dependent", "block", "of", "macroscopic", "current,", "where", "steady-state", "block", "reaches", "equilibrium", "only", "after", "open", "probability", "is", "sufficiently", "high,", "(b)", "a", "“foot", "in", "the", "door”", "effect", "of", "blocker", "on", "chan-", "nel", "closing,", "where", "internally", "bound", "quaternary", "ammo-", "nium", "(QA)", "ions", "of", "a", "sufficient", "size", "were", "found", "to", "delay", "closure", "of", "the", "activation", "gate,", "and", "(c)", "“trapping”", "of", "a", "blocker", "molecule", "inside", "the", "channel", "pore", "after", "closure", "of", "the", "activation", "gate.", "These", "observations", "strongly", "sug-", "gested", "that", "intracellular", "blockers", "required", "channel", "opening", "in", "order", "to", "access", "(and", "exit)", "the", "pore,", "and", "im-", "plied", "that", "the", "gating", "structure", "regulating", "access", "of", "the", "blocker", "to", "the", "pore", "must", "be", "located", "on", "the", "intracellular", "Correspondence", "to", "Richard", "W.", "Aldrich:", "raldrich@mail.utexas.edu", "J.", "Gen.", "Physiol.", "©", "The", "Rockefeller", "University", "Press", "$8.00", "Volume", "128", "Number", "3", "September", "2006", "347–364", "http://www.jgp.org/cgi/doi/10.1085/jgp.200609579", "face", "of", "the", "channel.", "Numerous", "functional", "studies", "of", "K+", "channels", "(Armstrong", "and", "Hille,", "1972;", "MacKinnon", "and", "Miller,", "1989;", "MacKinnon", "and", "Yellen,", "1990;", "MacKinnon", "et", "al.,", "1990;", "Yellen", "et", "al.,", "1991;", "Heginbotham", "et", "al.,", "1992;", "Liu", "et", "al.,", "1997;", "Shin", "et", "al.,", "2001)", "and", "structural", "studies", "of", "bacterial", "(Doyle", "et", "al.,", "1998;", "Jiang", "et", "al.,", "2002a;", "Jiang", "et", "al.,", "2003;", "Kuo", "et", "al.,", "2003)", "and", "mammalian", "(Long", "et", "al.,", "2005)", "K+", "channels", "have", "confirmed", "Armstrong’s", "original", "hypothesis.", "The", "structure", "of", "the", "mammalian", "voltage-gated", "K+", "channel", "Kv", "1.2", "(Long", "et", "al.,", "2005)", "exemplifies", "the", "de-", "tailed", "organization", "of", "an", "archetypal", "K+", "channel", "pore.", "The", "S5", "and", "S6", "transmembrane", "domains", "from", "each", "of", "four", "subunits", "define", "the", "central", "pore,", "a", "large", "water-", "filled", "cavity", "constrained", "at", "the", "extracellular", "end", "by", "the", "narrow", "selectivity", "filter,", "and", "at", "the", "intracellular", "end", "by", "the", "“bundle", "crossing,”", "where", "the", "S6", "helices", "come", "into", "close", "apposition.", "For", "the", "majority", "of", "K+", "channels,", "per-", "meation", "of", "K+", "ions", "appears", "to", "be", "governed", "by", "constric-", "tion", "and", "enlargement", "of", "the", "S6", "aperture.", "On", "the", "other", "hand,", "it", "is", "clear", "that", "some", "related", "ion", "channels", "employ", "a", "different", "gating", "mechanism.", "The", "case", "for", "cyclic", "Abbreviations", "used", "in", "this", "paper:", "bbTBA,", "N-(4-[benzoyl]benyl)-", "N,N,N-tributylammonium", "bromide;", "BK,", "large-conductance", "Ca2+-", "and", "voltage-activated", "potassium;", "C10,", "decyltriethylammonium;", "CNG,", "cyclic", "nucleotide-gated;", "Po,", "open", "probability;", "QA,", "quaternary", "ammo-", "nium;", "TBA,", "tetrabutylammonium.", "347" ]

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[ "Available", "online", "http://ccforum.com/content/12/6/R146", "Research", "Vol12No6", "Recombinant", "human", "activated", "protein", "C", "ameliorates", "oleic", "acid-induced", "lung", "injury", "in", "awake", "sheep", "Kristine", "Waerhaug1,", "Mikhail", "Y", "Kirov1,2,", "Vsevolod", "V", "Kuzkov1,2,", "Vladimir", "N", "Kuklin1", "and", "Lars", "J", "Bjertnaes1", "Open", "Access", "1Department", "of", "Anesthesiology,", "Institute", "of", "Clinical", "Medicine,", "Faculty", "of", "Medicine,", "University", "of", "Tromsø,", "9037", "Tromsø,", "Norway", "2Department", "of", "Anesthesiology,", "Northern", "State", "Medical", "University,", "Troitzky", "avenue", "51,", "163000", "Arkhangelsk,", "Russian", "Federation", "Corresponding", "author:", "Lars", "J", "Bjertnaes,", "lars.bjertnaes@fagmed.uit.no", "Received:", "7", "Oct", "2008", "Revisions", "requested:", "25", "Oct", "2008", "Revisions", "received:", "7", "Nov", "2008", "Accepted:", "20", "Nov", "2008", "Published:", "20", "Nov", "2008", "Critical", "Care", "2008,", "12:R146", "(doi:10.1186/cc7128)", "This", "article", "is", "online", "at:", "http://ccforum.com/content/12/6/R146", "©", "2008", "Waerhaug", "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", "Acute", "lung", "injury", "(ALI)", "may", "arise", "both", "after", "sepsis", "and", "non-septic", "inflammatory", "conditions", "and", "is", "often", "associated", "with", "the", "release", "of", "fatty", "acids,", "including", "oleic", "acid", "(OA).", "Infusion", "of", "OA", "has", "been", "used", "extensively", "to", "mimic", "ALI.", "Recent", "research", "has", "revealed", "that", "intravenously", "administered", "recombinant", "human", "activated", "protein", "C", "(rhAPC)", "is", "able", "to", "counteract", "ALI.", "Our", "aim", "was", "to", "find", "out", "whether", "rhAPC", "dampens", "OA-induced", "ALI", "in", "sheep.", "Methods", "Twenty-two", "yearling", "sheep", "underwent", "instrumentation.", "After", "2", "days", "of", "recovery,", "animals", "were", "randomly", "assigned", "to", "one", "of", "three", "groups:", "(a)", "an", "OA+rhAPC", "group", "(n", "=", "8)", "receiving", "OA", "0.06", "mL/kg", "infused", "over", "the", "course", "of", "30", "minutes", "in", "parallel", "with", "an", "intravenous", "infusion", "of", "rhAPC", "24", "mg/kg", "per", "hour", "over", "the", "course", "of", "2", "hours,", "(b)", "an", "OA", "group", "(n", "=", "8)", "receiving", "OA", "as", "above,", "or", "(c)", "a", "sham-operated", "group", "(n", "=", "6).", "After", "2", "hours,", "sheep", "were", "sacrificed.", "Hemodynamics", "was", "assessed", "by", "catheters", "in", "the", "pulmonary", "artery", "and", "the", "aorta,", "and", "extravascular", "lung", "water", "index", "(EVLWI)", "was", "Introduction", "Mortality", "from", "acute", "lung", "injury", "(ALI)", "still", "remains", "between", "30%", "and", "40%", "[1].", "Patients", "with", "acute", "respiratory", "distress", "syndrome", "(ARDS),", "the", "most", "severe", "form", "of", "ALI,", "present", "with", "elevated", "plasma", "concentrations", "of", "oleic", "acid", "(OA),", "which", "is", "one", "of", "the", "most", "abundantly", "occurring", "fatty", "acids", "in", "human", "plasma", "[2].", "The", "proportion", "of", "OA", "increases", "in", "the", "bronchoal-", "veolar", "lavage", "fluid", "of", "patients", "with", "pneumonia", "and", "ARDS", "[3].", "In", "combination", "with", "sepsis,", "an", "enhanced", "plasma", "level", "of", "OA", "determined", "with", "the", "single", "transpulmonary", "thermodilution", "technique.", "Gas", "exchange", "was", "evaluated", "at", "baseline", "and", "at", "cessation", "of", "the", "experiment.", "Data", "were", "analyzed", "by", "analysis", "of", "variance;", "a", "P", "value", "of", "less", "than", "0.05", "was", "regarded", "as", "statistically", "significant.", "Results", "OA", "induced", "profound", "hypoxemia,", "increased", "right", "atrial", "and", "pulmonary", "artery", "pressures", "and", "EVLWI", "markedly,", "and", "decreased", "cardiac", "index.", "rhAPC", "counteracted", "the", "OA-induced", "changes", "in", "EVLWI", "and", "arterial", "oxygenation", "and", "reduced", "the", "OA-induced", "increments", "in", "right", "atrial", "and", "pulmonary", "artery", "pressures.", "Conclusions", "In", "ovine", "OA-induced", "lung", "injury,", "rhAPC", "dampens", "the", "increase", "in", "pulmonary", "artery", "pressure", "and", "counteracts", "the", "development", "of", "lung", "edema", "and", "the", "derangement", "of", "arterial", "oxygenation.", "adds", "to", "the", "risk", "of", "contracting", "ARDS", "[4].", "However,", "independ-", "ent", "of", "whether", "a", "high", "plasma", "concentration", "of", "OA", "contributes", "to", "ARDS", "or", "not,", "infusion", "of", "OA", "has", "been", "widely", "used", "to", "mimic", "non-septic", "lung", "injury", "in", "experimental", "settings.", "Administered", "to", "animals,", "OA", "increases", "pulmonary", "vascular", "pressure", "and", "per-", "meability,", "resulting", "in", "the", "development", "of", "lung", "edema", "and", "arte-", "rial", "hypoxemia", "that", "are", "typical", "for", "this", "condition", "[5].", "AaPO2:", "alveolar-arterial", "oxygen", "tension", "difference;", "ALI:", "acute", "lung", "injury;", "APC:", "activated", "protein", "C;", "ARDS:", "acute", "respiratory", "distress", "syndrome;", "CI:", "cardiac", "index;", "EVLWI:", "extravascular", "lung", "water", "index;", "HR:", "heart", "rate;", "IL:", "interleukin;", "iNOS:", "inducible", "nitric-oxide", "synthase;", "LVSWI:", "left", "ventricular", "stroke", "work", "index;", "MAP:", "mean", "systemic", "arterial", "pressure;", "OA:", "oleic", "acid;", "PaO2:", "partial", "tension", "of", "oxygen", "in", "arterial", "blood;", "PAOP:", "pulmonary", "arterial", "occlusion", "pressure;", "PAP:", "pulmonary", "arterial", "pressure;", "Pmo:", "pulmonary", "capillary", "micro-occlusion", "pressure;", "PVRI:", "pulmonary", "vascular", "resistance", "index;", "Qs/Qt:", "venous", "admixture;", "RAP:", "right", "atrial", "pressure;", "rhAPC:", "recombinant", "human", "activated", "protein", "C;", "RVSWI:", "right", "ventricular", "stroke", "work", "index;", "SaO2:", "arterial", "oxygen", "saturation;", "SVRI:", "systemic", "vascular", "resistance", "index.", "Page", "1", "of", "8", "(page", "number", "not", "for", "citation", "purposes)" ]

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[ "Molecular", "Cancer", "Research", "Blockade", "of", "Wnt-1", "signaling", "leads", "to", "anti-tumor", "effects", "in", "hepatocellular", "carcinoma", "cells", "Wei", "Wei1,", "Mei-Sze", "Chua*1,", "Susan", "Grepper2", "and", "Samuel", "K", "So1", "BioMed", "Central", "Open", "Access", "Address:", "1Asian", "Liver", "Center,", "Department", "of", "Surgery,", "Stanford", "University", "School", "of", "Medicine,", "Stanford,", "CA", "94305,", "USA", "and", "2CellzDirect/", "Invitrogen,", "4301", "Emperor", "Blvd,", "Durham,", "NC", "27703,", "USA", "Email:", "Wei", "Wei", "-", "weiwei25@stanford.edu;", "Mei-Sze", "Chua*", "-", "mchua@stanford.edu;", "Susan", "Grepper", "-", "sue.grepper@lifetech.com;", "Samuel", "K", "So", "-", "samso@stanford.edu", "*", "Corresponding", "author", "Published:", "24", "September", "2009", "Molecular", "Cancer", "2009,", "8:76", "doi:10.1186/1476-4598-8-76", "This", "article", "is", "available", "from:", "http://www.molecular-cancer.com/content/8/1/76", "Received:", "6", "August", "2009", "Accepted:", "24", "September", "2009", "©", "2009", "Wei", "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:", "Hepatocellular", "carcinoma", "(HCC)", "is", "an", "aggressive", "cancer,", "and", "is", "the", "third", "leading", "cause", "of", "cancer", "death", "worldwide.", "Standard", "therapy", "is", "ineffective", "partly", "because", "HCC", "is", "intrinsically", "resistant", "to", "conventional", "chemotherapy.", "Its", "poor", "prognosis", "and", "limited", "treatment", "options", "make", "it", "critical", "to", "develop", "novel", "and", "selective", "chemotherapeutic", "agents.", "Since", "the", "Wnt/β-catenin", "pathway", "is", "essential", "in", "HCC", "carcinogenesis,", "we", "studied", "the", "inhibition", "of", "Wnt-1-mediated", "signaling", "as", "a", "potential", "molecular", "target", "in", "HCC.", "Results:", "We", "demonstrated", "that", "Wnt-1", "is", "highly", "expressed", "in", "human", "hepatoma", "cell", "lines", "and", "a", "subgroup", "of", "human", "HCC", "tissues", "compared", "to", "paired", "adjacent", "non-tumor", "tissues.", "An", "anti-Wnt-1", "antibody", "dose-dependently", "decreased", "viability", "and", "proliferation", "of", "Huh7", "and", "Hep40", "cells", "over-", "expressing", "Wnt-1", "and", "harboring", "wild", "type", "β-catenin,", "but", "did", "not", "affect", "normal", "hepatocytes", "with", "undetectable", "Wnt-1", "expression.", "Apoptosis", "was", "also", "observed", "in", "Huh7", "and", "Hep40", "cells", "after", "treatment", "with", "anti-Wnt-1", "antibody.", "In", "these", "two", "cell", "lines,", "the", "anti-Wnt-1", "antibody", "decreased", "β-", "catenin/Tcf4", "transcriptional", "activities,", "which", "were", "associated", "with", "down-regulation", "of", "the", "endogenous", "β-catenin/Tcf4", "target", "genes", "c-Myc,", "cyclin", "D1,", "and", "survivin.", "Intratumoral", "injection", "of", "anti-Wnt-1", "antibody", "suppressed", "in", "vivo", "tumor", "growth", "in", "a", "Huh7", "xenograft", "model,", "which", "was", "also", "associated", "with", "apoptosis", "and", "reduced", "c-Myc,", "cyclin", "D1,", "and", "survivin", "expressions.", "Conclusion:", "Our", "results", "suggest", "that", "Wnt-1", "is", "a", "survival", "factor", "for", "HCC", "cells,", "and", "that", "the", "blockade", "of", "Wnt-1-mediated", "signaling", "may", "offer", "a", "potential", "pathway-specific", "therapeutic", "strategy", "for", "the", "treatment", "of", "a", "subgroup", "of", "HCC", "that", "over-expresses", "Wnt-1.", "Background", "Hepatocellular", "carcinoma", "(HCC)", "is", "the", "primary", "form", "of", "human", "adult", "liver", "cancer.", "It", "is", "the", "fifth", "most", "common", "can-", "cer", "worldwide,", "with", "about", "one", "million", "new", "cases", "diag-", "nosed", "annually,", "and", "almost", "an", "equal", "number", "of", "deaths.", "It", "is", "predominant", "in", "China,", "most", "parts", "of", "South", "East", "Asia,", "and", "South", "Africa,", "where", "hepatitis", "B", "virus", "(HBV)", "infection", "is", "endemic", "[1].", "The", "last", "decade", "has", "seen", "no", "major", "advances", "in", "the", "treatment", "of", "HCC.", "Approximately", "10-", "25%", "of", "HCC", "patients", "are", "candidates", "for", "surgical", "resection", "and", "liver", "transplantation;", "the", "majority", "of", "patients", "have", "limited", "treatment", "options", "due", "to", "the", "lack", "of", "effective", "chemotherapy", "against", "this", "intrinsically", "resistant", "tumor", "[2-", "4].", "New", "pharmacological", "interventions", "that", "offer", "even", "Page", "1", "of", "10", "(page", "number", "not", "for", "citation", "purposes)" ]

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[ "Mammalian", "Comparative", "Sequence", "Analysis", "of", "the", "Agrp", "Locus", "Christopher", "B.", "Kaelin1,", "Gregory", "M.", "Cooper2,", "Arend", "Sidow1,3,", "Gregory", "S.", "Barsh1,4*", "1", "Department", "of", "Genetics,", "Stanford", "University,", "Stanford,", "California,", "United", "States", "of", "America,", "2", "Department", "of", "Genome", "Sciences,", "University", "of", "Washington,", "Seattle,", "Washington,", "United", "States", "of", "America,", "3", "Department", "of", "Pathology,", "Stanford", "University,", "Stanford,", "California,", "United", "States", "of", "America,", "4", "Department", "of", "Pediatrics,", "Stanford", "University,", "Stanford,", "California,", "United", "States", "of", "America", "Agouti-related", "protein", "encodes", "a", "neuropeptide", "that", "stimulates", "food", "intake.", "Agrp", "expression", "in", "the", "brain", "is", "restricted", "to", "neurons", "in", "the", "arcuate", "nucleus", "of", "the", "hypothalamus", "and", "is", "elevated", "by", "states", "of", "negative", "energy", "balance.", "The", "molecular", "mechanisms", "underlying", "Agrp", "regulation,", "however,", "remain", "poorly", "defined.", "Using", "a", "combination", "of", "transgenic", "and", "comparative", "sequence", "analysis,", "we", "have", "previously", "identified", "a", "760", "bp", "conserved", "region", "upstream", "of", "Agrp", "which", "contains", "STAT", "binding", "elements", "that", "participate", "in", "Agrp", "transcriptional", "regulation.", "In", "this", "study,", "we", "attempt", "to", "improve", "the", "specificity", "for", "detecting", "conserved", "elements", "in", "this", "region", "by", "comparing", "genomic", "sequences", "from", "10", "mammalian", "species.", "Our", "analysis", "reveals", "a", "symmetrical", "organization", "of", "conserved", "sequences", "upstream", "of", "Agrp,", "which", "cluster", "into", "two", "inverted", "repeat", "elements.", "Conserved", "sequences", "within", "these", "elements", "suggest", "a", "role", "for", "homeodomain", "proteins", "in", "the", "regulation", "of", "Agrp", "and", "provide", "additional", "targets", "for", "functional", "evaluation.", "Citation:", "Kaelin", "CB,", "Cooper", "GM,", "Sidow", "A,", "Barsh", "GS", "(2007)", "Mammalian", "Comparative", "Sequence", "Analysis", "of", "the", "Agrp", "Locus.", "PLoS", "ONE", "2(8):", "e702.", "doi:10.1371/journal.pone.0000702", "INTRODUCTION", "AGRP", "is", "an", "orexigenic,", "hypothalamic", "peptide", "whose", "role", "in", "energy", "homeostasis", "has", "been", "conserved", "during", "vertebrate", "evolution.", "In", "a", "wide", "range", "of", "species,", "including", "mammals", "[1,2],", "birds", "[3,4],", "and", "fish", "[5],", "neuronal", "Agrp", "expression", "is", "restricted", "to", "a", "discrete", "population", "of", "neurons", "that", "sense", "the", "levels", "of", "peripheral", "energy", "stores,", "and", "is", "dramatically", "elevated", "by", "deficits", "in", "energy", "balance.", "AGRP", "neurons", "directly", "receive", "information", "about", "energy", "stores", "from", "leptin,", "an", "adipocyte-derived", "hormone", "that", "circulates", "at", "levels", "proportional", "to", "fat", "mass.", "Diminished", "levels", "of", "circulating", "leptin", "correspond", "to", "increased", "Agrp", "mRNA", "levels", "[6].", "Leptin", "receptor", "occupancy", "on", "AGRP", "neurons", "results", "in", "the", "phosphorylation", "of", "two", "transcription", "factors,", "FoxO1", "[7]", "and", "STAT3", "[8],", "inducing", "the", "cytoplasmic", "localization", "of", "FoxO1", "and", "the", "nuclear", "localization", "of", "STAT3.", "A", "recent", "study", "by", "Kitamura", "and", "colleagues", "[7]", "implicates", "a", "direct,", "reciprocal", "role", "for", "both", "STAT3", "and", "FoxO1", "in", "Agrp", "regulation,", "where", "STAT3", "represses", "and", "FoxO1", "stimulates", "Agrp", "transcription.", "However,", "conserved", "STAT", "binding", "sites", "in", "the", "Agrp", "promoter", "region", "do", "not", "function", "as", "simple", "repressor", "elements", "and,", "paradoxically,", "are", "required", "for", "fasting", "induced", "stimulation", "of", "Agrp", "transcription", "[9],", "suggesting", "a", "more", "complex", "mechanism", "of", "regulation", "involving", "additional", "cofactors.", "Support", "for", "this", "also", "stems", "from", "the", "observation", "that", "peripheral", "energy", "signals", "other", "than", "leptin", "regulate", "Agrp", "expression.", "For", "example,", "AGRP", "neurons", "directly", "mediate", "the", "orexigenic", "effects", "of", "glucocorticoids", "[10,11]", "and", "ghrelin", "[12].", "Central", "administration", "of", "either", "elevates", "Agrp", "mRNA", "levels", "[13,14],", "and", "intact", "glucocorti-", "coid", "signaling", "is", "required", "for", "fasting", "induced", "increases", "in", "Agrp", "expression", "[14].", "Neither", "STAT3", "nor", "FoxO1", "is", "a", "known", "target", "of", "glucocorticoid", "or", "ghrelin", "signaling.", "Cross-species", "comparative", "sequence", "analysis", "has", "facilitated", "the", "detection", "of", "functional", "elements", "that", "participate", "in", "transcriptional", "regulation", "[15].", "Previously,", "we", "identified", "mouse", "BAC", "clones", "that", "recapitulate", "Agrp", "expression", "in", "transgenic", "mice", "and", "that", "contain", "regions", "of", "high", "sequence", "conservation", "between", "mouse", "and", "human,", "including", "a", "760", "bp", "region", "located", "immediately", "upstream", "of", "Agrp", "[16].", "While", "we", "could", "identify", "candidate", "binding", "elements", "in", "this", "region", "based", "on", "biological", "inference", "[9],", "the", "level", "of", "resolution", "provided", "by", "mouse/human", "sequence", "comparison", "did", "not", "permit", "us", "to", "predict", "putative", "binding", "elements", "based", "solely", "on", "sequence", "conservation.", "The", "inclusion", "of", "sequences", "from", "multiple,", "divergent", "species", "sharing", "a", "commonly", "derived", "phenotype", "improves", "the", "resolution", "of", "comparative", "sequence", "analysis.", "The", "conserved", "nature", "of", "Agrp", "expression", "in", "vertebrates", "suggests", "that", "sequence", "comparisons", "of", "disparate", "vertebrate", "species", "provide", "an", "appropriate", "evolutionary", "scope", "for", "identifying", "Agrp", "regulatory", "elements.", "However,", "Agrp", "genomic", "sequences", "from", "distantly", "related", "vertebrate", "species", "have", "diverged", "to", "the", "extent", "that", "regional", "conservation", "is", "no", "longer", "detectable", "using", "traditional", "alignment", "methodologies", "[9].", "Here,", "we", "describe", "a", "comparative", "sequence", "analysis", "of", "an", "Agrp", "genomic", "region", "from", "ten", "mammalian", "species,", "representing", "several", "different", "orders", "and", "all", "three", "subclasses", "of", "mammalia.", "Our", "analysis", "reveals", "a", "symmetrical", "organization", "of", "conserved", "sequences", "upstream", "of", "Agrp,", "which", "cluster", "into", "two", "inverted", "repeat", "elements", "(IREs).", "The", "proximity", "of", "the", "elements", "to", "Agrp", "and", "the", "nearly", "perfect", "evolutionary", "conservation", "of", "their", "specific", "constituent", "sequences", "in", "all", "ten", "mammalian", "species", "and", "in", "chickens", "suggest", "a", "role", "in", "Agrp", "regulation.", "In", "addition,", "the", "resolution", "of", "the", "conserved", "elements", "provided", "by", "this", "approach", "allows", "general", "predictions", "concerning", "putative", "trans-regulatory", "factors.", "METHODS", "Matrix", "comparisons", "of", "Agrp", "genomic", "regions", "Genomic", "sequence", "surrounding", "the", "Agrp", "locus", "for", "chimpanzee", "(Pan", "troglodytes),", "human", "(Homo", "sapiens),", "dog", "(Canis", "familiaris),", "mouse", "(Mus", "Academic", 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"|", "Issue", "8", "|", "e702" ]

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[ "Yi", "et", "al.", "BMC", "Cancer", "2010,", "10:527", "http://www.biomedcentral.com/1471-2407/10/527", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Favorable", "response", "to", "doxorubicin", "combination", "chemotherapy", "does", "not", "yield", "good", "clinical", "outcome", "in", "patients", "with", "metastatic", "breast", "cancer", "with", "triple-negative", "phenotype", "Seong", "Yoon", "Yi1,", "Jin", "Seok", "Ahn1*,", "Ji", "Eun", "Uhm1,", "Do", "Hyoung", "Lim1,", "Sang", "Hoon", "Ji1,", "Hyun", "Jung", "Jun1,", "Kyoung", "Ha", "Kim1,", "Myung", "Hee", "Chang1,", "Min", "Jae", "Park1,", "Eun", "Yoon", "Cho2,", "Yoon", "La", "Choi2,", "Yeon", "Hee", "Park1,", "Young-Hyuck", "Im1", "Abstract", "Background:", "We", "analyzed", "the", "responses", "to", "first", "line", "treatment", "and", "clinical", "outcomes", "of", "metastatic", "breast", "cancer", "patients", "treated", "with", "palliative", "doxorubicin/cyclophosphamide", "(AC)", "according", "to", "molecular", "cancer", "subtype.", "Methods:", "A", "retrospective", "analysis", "was", "performed", "for", "110", "metastatic", "breast", "cancer", "patients", "selected", "on", "the", "basis", "of", "palliative", "AC", "treatment", "and", "the", "availability", "of", "immunohistochemical", "data", "for", "estrogen", "receptor", "(ER),", "progesterone", "receptor", "(PR),", "and", "human", "epidermal", "growth", "factor", "receptor-2", "(HER-2/neu)", "status.", "Results:", "Of", "the", "110", "patients", "analyzed,", "71", "(64.5%)", "were", "hormone", "receptor", "positive", "(HR+),", "14", "(12.7%)", "were", "HER2+,", "and", "25", "(22.7%)", "were", "triple", "negative", "(TN).", "There", "were", "no", "differences", "in", "age,", "stage", "at", "diagnosis,", "total", "number", "of", "cycles", "of", "palliative", "chemotherapy,", "incidence", "of", "visceral", "metastasis,", "and", "metastatic", "sites", "with", "the", "exception", "of", "liver", "among", "breast", "cancer", "subtypes.", "The", "overall", "response", "rates", "to", "AC", "were", "55.9%", "for", "the", "HR+", "subgroup,", "42.9%", "for", "the", "HER2+", "subgroup,", "and", "56.5%", "for", "the", "TN", "subgroup.", "The", "progression-free", "survival", "(PFS)", "in", "patients", "with", "HER2+", "and", "TN", "were", "significantly", "shorter", "than", "in", "the", "HR+", "(median", "PFS,", "9.1", "vs", "8.1", "vs", "11.5", "months,", "respectively;", "p", "=", "0.0002).", "The", "overall", "survival", "(OS)", "was", "25.4", "months", "in", "the", "TN", "subgroup", "and", "27.3", "months", "in", "HER2+", "subgroup.", "The", "median", "OS", "for", "these", "two", "groups", "was", "significantly", "shorter", "than", "for", "patients", "in", "the", "HR+", "subgroup", "(median,", "38.5", "months;", "95%", "CI,", "30.1-46.9", "months;", "p", "<", "0.0001).", "Conclusions:", "The", "response", "to", "palliative", "AC", "chemotherapy", "did", "not", "differ", "among", "breast", "cancer", "subtypes.", "Despite", "chemosensitivity", "for", "palliative", "AC,", "the", "TN", "subtype", "has", "a", "shorter", "overall", "survival", "than", "non-TN", "subtypes.", "Innovative", "treatment", "strategies", "should", "be", "developed", "to", "slow", "the", "course", "of", "disease.", "Background", "Breast", "cancer", "encompasses", "a", "heterogeneous", "group", "of", "diseases", "at", "the", "molecular", "level", "[1-4],", "and", "can", "be", "classi-", "fied", "into", "at", "least", "five", "distinct", "subtypes", "by", "gene", "expres-", "sion", "profiling:", "luminal", "A,", "luminal", "B,", "normal", "breast-like,", "ERBB2,", "and", "basal", "like", "[5-10].", "Basal", "cell-like", "tumors", "typi-", "cally", "show", "low", "or", "no", "expression", "of", "HER2", "and", "estrogen", "receptor", "(ER),", "and", "high", "expression", "of", "genes", "characteris-", "tic", "of", "basal", "epithelial", "cells", "[1,4,11-13].", "These", "tumors", "*", "Correspondence:", "ajis@skku.edu", "1Division", "of", "Hematology-Oncology,", "Department", "of", "Medicine,", "Samsung", "Medical", "Center,", "Sungkyunkwan", "University", "School", "of", "Medicine,", "50", "Irwon-", "dong", "Gangnam-gu,", "Seoul", "135-710", "Korea", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "may", "share", "clinical", "and", "biologic", "properties", "with", "triple", "negative", "breast", "cancers", "(TNBCs)", "that", "lack", "expression", "of", "ER,", "progesterone", "receptor", "(PgR)", "and", "HER2", "[5-8].", "There", "is", "increasing", "evidence", "that", "breast", "cancer", "molecular", "sub-", "types", "differ", "in", "their", "responses", "to", "therapeutic", "agents.", "TNBC", "is", "considered", "a", "high-risk", "subtype", "because", "of", "its", "typically", "younger", "patient", "age,", "poorly", "differentiated", "tumor", "characteristics,", "and", "shortened", "survival", "of", "patients", "who", "often", "do", "not", "benefit", "from", "targeted", "therapies", "[11-19].", "Because", "there", "is", "insufficient", "data", "on", "which", "to", "base", "treatment", "selection,", "no", "specific", "systemic", "treatment", "strategy", "is", "currently", "recommended", "for", "the", "treatment", "of", "TNBC.", "©", "2010", "Yi", "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", "Biology", "Research", "article", "A", "mutation", "in", "the", "centriole-associated", "protein", "centrin", "causes", "genomic", "instability", "via", "increased", "chromosome", "loss", "in", "Chlamydomonas", "reinhardtii", "Ivan", "Zamora", "and", "Wallace", "F", "Marshall*", "BioMed", "Central", "Open", "Access", "Address:", "Dept.", "of", "Biochemistry", "&", "Biophysics,", "University", "of", "California,", "San", "Francisco,", "600", "16th", "St.,", "San", "Francisco,", "California,", "9414,", "USA", "Email:", "Ivan", "Zamora", "-", "dsjiz@itsa.ucsf.edu;", "Wallace", "F", "Marshall*", "-", "wmarshall@biochem.ucsf.edu", "*", "Corresponding", "author", "Published:", "31", "May", "2005", "BMC", "Biology", "2005,", "3:15", "doi:10.1186/1741-7007-3-15", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1741-7007/3/15", "Received:", "15", "April", "2005", "Accepted:", "31", "May", "2005", "©", "2005", "Zamora", "and", "Marshall;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "The", "role", "of", "centrioles", "in", "mitotic", "spindle", "function", "remains", "unclear.", "One", "approach", "to", "investigate", "mitotic", "centriole", "function", "is", "to", "ask", "whether", "mutation", "of", "centriole-associated", "proteins", "can", "cause", "genomic", "instability.", "Results:", "We", "addressed", "the", "role", "of", "the", "centriole-associated", "EF-hand", "protein", "centrin", "in", "genomic", "stability", "using", "a", "Chlamydomonas", "reinhardtii", "centrin", "mutant", "that", "forms", "acentriolar", "bipolar", "spindles", "and", "lacks", "the", "centrin-based", "rhizoplast", "structures", "that", "join", "centrioles", "to", "the", "nucleus.", "Using", "a", "genetic", "assay", "for", "loss", "of", "heterozygosity,", "we", "found", "that", "this", "centrin", "mutant", "showed", "increased", "genomic", "instability", "compared", "to", "wild-type", "cells,", "and", "we", "determined", "that", "the", "increase", "in", "genomic", "instability", "was", "due", "to", "a", "100-fold", "increase", "in", "chromosome", "loss", "rates", "compared", "to", "wild", "type.", "Live", "cell", "imaging", "reveals", "an", "increased", "rate", "in", "cell", "death", "during", "G1", "in", "haploid", "cells", "that", "is", "consistent", "with", "an", "elevated", "rate", "of", "chromosome", "loss,", "and", "analysis", "of", "cell", "death", "versus", "centriole", "copy", "number", "argues", "against", "a", "role", "for", "multipolar", "spindles", "in", "this", "process.", "Conclusion:", "The", "increased", "chromosome", "loss", "rates", "observed", "in", "a", "centrin", "mutant", "that", "forms", "acentriolar", "spindles", "suggests", "a", "role", "for", "centrin", "protein,", "and", "possibly", "centrioles,", "in", "mitotic", "fidelity.", "Background", "Centrioles", "are", "cylindrical", "structures", "located", "within", "the", "core", "of", "the", "centrosome.", "Although", "the", "localization", "of", "cen-", "trioles", "within", "the", "centrosome", "together", "with", "their", "precise", "duplication", "prior", "to", "mitosis", "has", "suggested", "a", "role", "in", "bipolar", "spindle", "assembly", "or", "function,", "the", "actual", "role", "of", "centrioles", "in", "cell", "division", "remains", "unclear", "and", "controversial.", "Cells", "from", "which", "centrioles", "and", "centrosomes", "are", "ablated", "can", "still", "form", "bipolar", "spindles", "via", "a", "centrosome-independent", "self-organization", "process,", "but", "the", "effectiveness", "of", "such", "spindles", "in", "terms", "of", "chromosome", "segregation", "has", "not", "been", "carefully", "measured.", "Based", "on", "the", "circumstantial", "evi-", "dence", "that", "tumor", "cells", "which", "display", "genomic", "instability", "also", "frequently", "show", "aberrations", "in", "centriole", "structure", "or", "copy", "number", "[1,2],", "it", "has", "been", "proposed", "that", "centrioles", "may", "participate", "in", "the", "maintenance", "of", "genomic", "stability.", "If", "centrioles", "play", "a", "role", "in", "chromosome", "segregation,", "then", "mutations", "in", "genes", "encoding", "centriolar", "proteins", "would", "be", "expected", "to", "result", "in", "genomic", "instability.", "The", "EF-hand", "protein", "centrin", "[3]", "is", "one", "of", "the", "few", "identi-", "fied", "centriolar", "proteins.", "Centrin", "is", "found", "in", "all", "eukaryotes,", "and", "is", "localized", "to", "centrioles", "in", "vertebrate", "cells", "[4],", "basal", "bodies", "in", "green", "algae", "[5],", "and", "spindle", "pole", "bodies", "(SPBs)", "Page", "1", "of", "7", "(page", "number", "not", "for", "citation", "purposes)" ]

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[ "Available", "online", "http://respiratory-research.com/content/3/1/11", "Review", "Autocrine", "regulation", "of", "asthmatic", "airway", "inflammation:", "role", "of", "airway", "smooth", "muscle", "Sue", "McKay", "and", "Hari", "S", "Sharma", "Department", "of", "Pharmacology,", "Erasmus", "University", "Medical", "Centre,", "Rotterdam,", "The", "Netherlands", "Correspondence:", "Hari", "S", "Sharma,", "MPhil,", "PhD,", "Cardiopulmonary", "and", "Molecular", "Biology", "Laboratory,", "Institute", "of", "Pharmacology,", "Erasmus", "University", "Medical", "Center,", "Dr", "Molewaterplein", "50,", "3015", "GE", "Rotterdam,", "The", "Netherlands.", "Tel:", "+31", "10", "4087963;", "fax:", "+31", "10", "408", "9458;", "e-mail:", "sharma@farma.fgg.eur.nl", "Received:", "26", "March", "2001", "Revisions", "requested:", "3", "May", "2001", "Revisions", "received:", "18", "October", "2001", "Accepted:", "23", "October", "2001", "Published:", "28", "November", "2001", "Respir", "Res", "2002,", "3:11", "This", "article", "may", "contain", "supplementary", "data", "which", "can", "only", "be", "found", "online", "at", "http://respiratory-research.com/content/2/X", "©", "2002", "BioMed", "Central", "Ltd", "(Print", "ISSN", "1465-9921;", "Online", "ISSN", "1465-993X)", "Abstract", "Chronic", "airway", "inflammation", "is", "one", "of", "the", "main", "features", "of", "asthma.", "Release", "of", "mediators", "from", "infiltrating", "inflammatory", "cells", "in", "the", "airway", "mucosa", "has", "been", "proposed", "to", "contribute", "directly", "or", "indirectly", "to", "changes", "in", "airway", "structure", "and", "function.", "The", "airway", "smooth", "muscle,", "which", "has", "been", "regarded", "as", "a", "contractile", "component", "of", "the", "airways", "responding", "to", "various", "mediators", "and", "neurotransmitters,", "has", "recently", "been", "recognised", "as", "a", "rich", "source", "of", "pro-inflammatory", "cytokines,", "chemokines", "and", "growth", "factors.", "In", "this", "review,", "we", "discuss", "the", "role", "of", "airway", "smooth", "muscle", "cells", "in", "the", "regulation", "and", "perpetuation", "of", "airway", "inflammation", "that", "contribute", "to", "the", "pathogenesis", "of", "asthma.", "Keywords:", "airway", "smooth", "muscle,", "chemokine,", "cytokine,", "growth", "factor,", "inflammation", "Introduction", "Inflammation", "of", "the", "airway", "wall", "is", "a", "central", "characteristic", "of", "asthma", "[1].", "Airborne", "allergens", "often", "lead", "to", "an", "accumula-", "tion", "of", "eosinophils,", "lymphocytes", "(predominantly", "CD4", "type),", "mast", "cells", "and", "macrophages,", "resulting", "in", "an", "inflam-", "matory", "reaction", "in", "the", "mucosa.", "Neutrophil", "numbers", "can", "increase", "during", "an", "exacerbation.", "The", "release", "of", "mediators", "from", "these", "inflammatory", "cells", "has", "been", "proposed", "to", "con-", "tribute", "directly", "or", "indirectly", "to", "changes", "in", "airway", "structure", "and", "function.", "Important", "structural", "changes", "of", "inflamed", "airways", "include", "epithelial", "cell", "shedding,", "basement", "membrane", "thickening,", "goblet", "cell", "hyperplasia", "(increase", "in", "cell", "number)", "and", "hypertrophy", "(increase", "in", "cell", "size),", "as", "well", "as", "an", "increase", "in", "airway", "smooth", "muscle", "(ASM)", "content", "[2].", "These", "struc-", "tural", "changes", "consequently", "form", "the", "basis", "for", "airway", "remodelling,", "a", "phenomenon", "believed", "to", "have", "profound", "consequences", "for", "airway", "function", "[3].", "Bronchial", "vascular", "remodelling,", "with", "an", "increase", "in", "size", "and", "number", "of", "blood", "vessels", "as", "well", "as", "vascular", "hyperaemia", "have", "been", "pro-", "posed", "as", "contributing", "factors", "in", "airway", "wall", "remodelling", "in", "patients", "with", "chronic", "asthma.", "The", "ASM", "has", "been", "typically", "described", "as", "a", "contractile", "tissue,", "responding", "to", "pro-inflammatory", "mediators", "and", "neurotransmitters", "by", "contracting,", "and", "responding", "to", "bronchodilators", "by", "relaxing.", "It", "has", "recently", "been", "recognised,", "however,", "that", "the", "synthetic", "function", "of", "ASM", "cells", "may", "be", "related", "to", "the", "perpetuation", "and", "intensity", "of", "airway", "wall", "inflammation.", "A", "number", "of", "recent", "studies", "have", "shown", "that", "ASM", "cells", "are", "also", "a", "rich", "source", "of", "biologically", "active", "ASM", "=", "airway", "smooth", "muscle;", "BAL", "=", "bronchoalveolar", "lavage;", "COX", "=", "cyclooxygenase;", "ECM", "=", "extracellular", "matrix;", "FGF", "=", "fibroblast", "growth", "factor;", "GM-CSF", "=", "granulocyte/macrophage-colony", "stimulating", "factor;", "IFN", "=", "interferon;", "IGF", "=", "insulin-like", "growth", "factor;", "IL", "=", "interleukin;", "LIF", "=", "leukaemia", "inhibitory", "factor;", "5-LO", "=", "5-lipoxygenase;", "LT", "=", "leukotriene;", "MCP", "=", "monocyte", "chemotactic", "protein;", "MHC", "=", "major", "histocompatibility", "complex;", "NO", "=", "nitric", "oxide;", "PDGF", "=", "platelet-derived", "growth", "factor;", "PG", "=", "prostaglandin;", "RANTES", "=", "regulated", "on", "activation,", "normal", "T", "cell", "expressed", "and", "secreted;", "TGF", "=", "transforming", "growth", "factor;", "Th", "=", "T", "helper", "cells;", "TNF-α", "=", "tumour", "necrosis", "factor-α;", "TX", "=", "thromboxane.", "Page", "1", "of", "13", "(page", "number", "not", "for", "citation", "purposes)" ]

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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", "Shimon", "Sakaguchi:", "shimon@frontier.kyoto-u.ac.jp", "Abbreviations", "used:", "CP,", "cyclo-", "phosphamide;", "ITS1,", "internal", "transcriber", "spacer", "1;", "poly(I:C),", "polyinosinic-polycytidylic", "acid;", "PTX,", "pertussis", "toxin;", "RA,", "rheu-", "matoid", "arthritis;", "SPF,", "specific", "pathogen-free;", "TLR,", "Toll-like", "receptor.", "A", "R", "T", "I", "C", "L", "E", "A", "role", "for", "fungal", "-glucans", "and", "their", "receptor", "Dectin-1", "in", "the", "induction", "of", "autoimmune", "arthr", "itis", "in", "genetically", "susceptible", "mice", "Hiroyuki", "Yoshitomi,1,2", "Noriko", "Sakaguchi,1,3", "Katsuya", "Kobayashi,4", "Gordon", "D.", "Brown,5", "Tomoyuki", "Tagami,1", "Toshiko", "Sakihama,1", "Keiji", "Hirota,1", "Satoshi", "Tanaka,1", "Takashi", "Nomura,1", "Ichiro", "Miki,4", "Siamon", "Gordon,6", "Shizuo", "Akira,7", "Takashi", "Nakamura,2", "and", "Shimon", "Sakaguchi1,3,8", "1Department", "of", "Experimental", "Pathology,", "Institute", "for", "Frontier", "Medical", "Sciences,", "Kyoto", "University", "and", "2Department", "of", "Orthopedic", "Surgery,", "Kyoto", "University", "Graduate", "School", "of", "Medicine,", "Kyoto", "606-8507,", "Japan", "3Laboratory", "for", "Immunopathology,", "Research", "Center", "for", "Allergy", "and", "Immunology,", "Institute", "of", "Physical", "and", "Chemical", "Research,", "Yokohama", "230-0045,", "Japan", "4Department", "of", "Allergy,", "Pharmaceutical", "Research", "Center,", "Kyowa", "Hakko,", "Ltd.,", "Shizuoka", "411-8731,", "Japan", "5Institute", "of", "Infectious", "Disease", "and", "Molecular", "Medicine,", "University", "of", "Cape", "Town,", "Cape", "Town", "7925,", "South", "Africa", "6Sir", "William", "Dunn", "School", "of", "Pathology,", "University", "of", "Oxford,", "Oxford", "OX1", "3RE,", "England,", "UK", "7Department", "of", "Host", "Defense,", "Research", "Institute", "for", "Microbial", "Diseases,", "Osaka", "University,", "Osaka", "565-0871,", "Japan", "8Core", "Research", "for", "Evolutional", "Science", "and", "Technology,", "Science", "and", "Technology", "Agency", "of", "Japan,", "Kawaguchi", "332-0012,", "Japan", "A", "combination", "of", "genetic", "and", "environmental", "factors", "can", "cause", "autoimmune", "disease", "in", "animals.", "SKG", "mice,", "which", "are", "genetically", "prone", "to", "develop", "autoimmune", "arthritis,", "fail", "to", "develop", "the", "disease", "under", "a", "microbially", "clean", "condition,", "despite", "active", "thymic", "production", "of", "arthritogenic", "autoimmune", "T", "cells", "and", "their", "persistence", "in", "the", "periphery.", "However,", "in", "the", "clean", "environment,", "a", "single", "intraperitoneal", "injection", "of", "zymosan,", "a", "crude", "fungal", "-glucan,", "or", "purified", "-glucans", "such", "as", "curdlan", "and", "laminarin", "can", "trigger", "severe", "chronic", "arthritis", "in", "SKG", "mice,", "but", "only", "transient", "arthritis", "in", "normal", "mice.", "Blockade", "of", "Dectin-1,", "a", "major", "-glucan", "receptor,", "can", "prevent", "SKG", "arthritis", "triggered", "by", "-glucans,", "which", "strongly", "activate", "dendritic", "cells", "in", "vitro", "in", "a", "Dectin-1–dependent", "but", "Toll-like", "receptor-independent", "manner.", "Furthermore,", "antibiotic", "treatment", "against", "fungi", "can", "prevent", "SKG", "arthritis", "in", "an", "arthritis-", "prone", "microbial", "environment.", "Multiple", "injections", "of", "polyinosinic-polycytidylic", "acid", "double-", "stranded", "RNA", "also", "elicit", "mild", "arthritis", "in", "SKG", "mice.", "Thus,", "specific", "microbes,", "including", "fungi", "and", "viruses,", "may", "evoke", "autoimmune", "arthritis", "such", "as", "rheumatoid", "arthritis", "by", "stimulating", "innate", "immunity", "in", "individuals", "who", "harbor", "potentially", "arthritogenic", "autoimmune", "T", "cells", "as", "a", "result", "of", "genetic", "anomalies", "or", "variations.", "Both", "genetic", "and", "environmental", "factors", "con-", "tribute", "to", "the", "development", "of", "common", "au-", "toimmune", "diseases,", "such", "as", "rheumatoid", "arthritis", "(RA)", "and", "type", "1", "diabetes", "(1,", "2).", "However,", "it", "remains", "obscure", "how", "each", "factor", "is", "arranged", "into", "a", "causal", "chain", "of", "pathogenesis.", "Given", "that", "H.", "Yoshitomi", "and", "N.", "Sakaguchi", "contributed", "equally", "to", "this", "work.", "T.", "Tagami’s", "present", "address", "is", "Ajinomoto", "Co.,", "Inc.,", "Kawasaki", "210-8681,", "Japan.", "T.", "Sakihama’s", "present", "address", "is", "Laboratory", "for", "Systems", "Biol-", "ogy", "and", "Medicine,", "Research", "Center", "for", "Advanced", "Science", "and", "Technology,", "University", "of", "Tokyo,", "Tokyo", "153-8904,", "Japan.", "The", "online", "version", "of", "this", "article", "contains", "supplemental", "material.", "T", "cells", "are", "the", "main", "mediators", "of", "many", "au-", "toimmune", "diseases,", "one", "of", "the", "key", "issues", "for", "elucidating", "the", "mechanism", "of", "autoimmune", "disease", "would", "be", "to", "understand", "how", "genetic", "and", "environmental", "factors", "affect", "the", "control", "of", "the", "generation,", "activation,", "and", "expansion", "of", "pathogenic", "self-reactive", "T", "cells.", "RA", "is", "a", "chronic", "systemic", "inflammatory", "dis-", "ease", "that", "primarily", "affects", "the", "synovial", "mem-", "branes", "of", "multiple", "joints", "(1).", "Both", "genetic", "and", "environmental", "factors", "are", "involved", "in", "the", "pathogenesis", "(1,", "3,", "4).", "For", "example,", "MHC", "and", "non-MHC", "genes", "play", "significant", "roles", "in", "de-", "termining", "the", "genetic", "susceptibility", "to", "RA", "JEM", "©", "The", "Rockefeller", "University", "Press", "$8.00", "Vol.", "201,", "No.", "6,", "March", "21,", "2005", "949–960", "www.jem.org/cgi/doi/10.1084/jem.20041758", "949" ]

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[ "Cleavage", "by", "Granzyme", "B", "Is", "Strongly", "Predictive", "of", "Autoantigen", "Status:", "Implications", "for", "Initiation", "of", "Autoimmunity", "By", "Livia", "Casciola-Rosen,*§", "Felipe", "Andrade,‡i", "Danielle", "Ulanet,‡i", "Wes", "Bang", "Wong,‡i", "and", "Antony", "Rosen‡§i", "From", "the", "*Department", "of", "Dermatology,", "the", "‡Department", "of", "Medicine,", "the", "§Department", "of", "Cell", "Biology", "and", "Anatomy,", "and", "the", "iGraduate", "Program", "in", "Immunology,", "Johns", "Hopkins", "University", "School", "of", "Medicine,", "Baltimore,", "Maryland", "21205", "Summary", "Systemic", "autoimmune", "diseases", "are", "a", "genetically", "complex,", "heterogeneous", "group", "of", "disorders", "in", "which", "the", "immune", "system", "targets", "a", "diverse", "but", "highly", "specific", "group", "of", "intracellular", "autoanti-", "gens.", "The", "molecules", "targeted", "are", "not", "unified", "by", "common", "structure,", "function,", "or", "distribution", "in", "control", "cells", "but", "become", "clustered", "and", "concentrated", "in", "surface", "blebs", "when", "cells", "undergo", "apop-", "tosis.", "We", "show", "here", "that", "the", "majority", "of", "autoantigens", "targeted", "across", "the", "spectrum", "of", "human", "systemic", "autoimmune", "diseases", "are", "efficiently", "cleaved", "by", "granzyme", "B", "in", "vitro", "and", "during", "cyto-", "toxic", "lymphocyte", "granule–induced", "death,", "generating", "unique", "fragments", "not", "observed", "during", "any", "other", "form", "of", "apoptosis.", "These", "molecules", "are", "not", "cleaved", "by", "caspase-8,", "although", "this", "pro-", "tease", "has", "a", "very", "similar", "specificity", "to", "granzyme", "B.", "The", "granzyme", "B", "cleavage", "sites", "in", "autoanti-", "gens", "contain", "amino", "acids", "in", "the", "P2", "and", "P3", "positions", "that", "are", "preferred", "by", "granzyme", "B", "but", "are", "not", "tolerated", "by", "caspase-8.", "In", "contrast", "to", "autoantigens,", "nonautoantigens", "are", "either", "not", "cleaved", "by", "granzyme", "B", "or", "are", "cleaved", "to", "generate", "fragments", "identical", "to", "those", "formed", "in", "other", "forms", "of", "apoptosis.", "The", "striking", "ability", "of", "granzyme", "B", "to", "generate", "unique", "fragments", "is", "therefore", "an", "ex-", "clusive", "property", "of", "autoantigens", "and", "unifies", "the", "majority", "of", "molecules", "targeted", "in", "this", "spectrum", "of", "diseases.", "These", "results", "focus", "attention", "on", "the", "role", "of", "the", "cytotoxic", "lymphocyte", "granule–induced", "death", "pathway", "in", "the", "initiation", "and", "propagation", "of", "systemic", "autoimmunity.", "Key", "words:", "apoptosis", "•", "cytotoxic", "T", "lymphocyte", "•", "protease", "•", "caspase", "Tautoimmune", "diseases", "generally", "predicts", "the", "biologic", "he", "highly", "specific", "autoantibody", "response", "in", "systemic", "phenotype", "of", "the", "disease,", "making", "autoantibodies", "diagnosti-", "cally", "useful", "(1,", "2).", "Although", "molecules", "targeted", "by", "the", "im-", "mune", "system", "in", "these", "diseases", "are", "exceptionally", "diverse", "in", "terms", "of", "structure,", "function,", "and", "subcellular", "distribution", "in", "healthy", "cells,", "they", "are", "strikingly", "redistributed", "in", "apoptotic", "cells,", "becoming", "clustered", "and", "concentrated", "in", "two", "popula-", "tions", "of", "surface", "structures", "on", "the", "dying", "cell", "(3).", "It", "has", "been", "proposed", "that", "cleavage", "of", "proteins", "might", "play", "a", "role", "in", "se-", "lecting", "molecules", "as", "autoantigens,", "perhaps", "by", "cleavage-", "induced", "revelation", "of", "cryptic", "epitopes", "(4,", "5).", "In", "this", "regard,", "several", "of", "the", "clustered", "antigens", "are", "substrates", "for", "caspases", "during", "apoptosis.", "These", "include", "poly", "(ADP-ribose)", "poly-", "merase", "(PARP),1", "U1-70kD,", "the", "catalytic", "subunit", "of", "DNA-", "1Abbreviations", "used", "in", "this", "paper:", "CENP,", "centromere", "protein;", "CrmA,", "cy-", "tokine", "response", "modifier", "1;", "DTT,", "dithiothreitol;", "GC,", "granule", "contents;", "FMK,", "fluoromethylketone;", "IAA,", "iodoacetamide;", "NuMA,", "nuclear", "mitotic", "apparatus", "protein;", "NOR,", "nucleolus", "organizer", "region;", "PARP,", "poly", "(ADP-", "ribose)", "polymerase;", "SRP,", "signal", "recognition", "particle.", "dependent", "protein", "kinase", "(DNA-PKcs),", "the", "nuclear", "mitotic", "apparatus", "protein", "(NuMA),", "nucleolus", "organizer", "region", "(NOR)-90,", "fodrin,", "topoisomerase", "I,", "signal", "recognition", "par-", "ticle", "(SRP)-72,", "and", "lamin", "B", "(6–10).", "However,", "the", "autoan-", "tigen", "fragments", "produced", "by", "caspases", "during", "all", "forms", "of", "apoptotic", "death", "described", "to", "date", "(including", "thymocyte", "ap-", "optosis)", "are", "all", "identical,", "making", "it", "likely", "that", "caspase-", "derived", "fragments", "have", "previously", "been", "generated", "during", "apoptosis", "and", "tolerized", "centrally", "and", "peripherally", "(11,", "12).", "Furthermore,", "there", "are", "several", "autoantigens", "(fibrillarin,", "centromere", "protein", "(CENP)-B,", "Ku,", "Ro,", "and", "La)", "that", "are", "not", "cleaved", "by", "caspases", "during", "apoptosis,", "indicating", "that", "susceptibility", "to", "cleavage", "by", "caspases", "is", "not", "a", "general", "feature", "of", "autoantigens", "(for", "review", "see", "reference", "13).", "Granzyme", "B", "is", "a", "serine", "protease", "found", "in", "the", "cytoplasmic", "granules", "of", "CTLs", "and", "NK", "cells", "that", "plays", "an", "important", "role", "in", "inducing", "apoptotic", "changes", "in", "target", "cells", "during", "granule", "exocytosis–induced", "cytotoxicity", "(14–16).", "This", "function", "is", "achieved", "partly", "by", "catalyzing", "the", "cleavage", "and", "activation", "of", "several", "caspases,", "as", "well", "as", "through", "caspase-independent", "pathways", "(17–20).", "We", "recently", "demonstrated", "that", "gran-", "815", "J.", "Exp.", "Med.", "The", "Rockefeller", "University", "Press", "•", "0022-1007/99/09/815/14", "$5.00", "Volume", "190,", "Number", "6,", "September", "20,", "1999", "815–825", "http://www.jem.org" ]

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[ "Journal", "of", "Geriatric", "Cardiology", "(2011)", "8:", "3134", "©2011", "IGC", "All", "rights", "reserved;", "www.jgc301.com", "Research", "Articles", "Medical", "comorbidities", "at", "admission", "is", "predictive", "for", "30-day", "in-hospital", "mortality", "in", "patients", "with", "acute", "myocardial", "infarction:", "analysis", "of", "5161", "cases", "", "Open", "Access", "", "Xue-Dong", "Yang,", "Yu-Sheng", "Zhao,", "Yu-Feng", "Li,", "Xin-Hong", "Guo", "Institute", "of", "Geriatric", "Cardiology,", "Chinese", "PLA", "General", "Hospital,", "Beijing", "100853,", "China", "Abstract", "Background", "The", "present", "study", "investigated", "the", "prognostic", "value", "of", "medical", "comorbidities", "at", "admission", "for", "30-day", "in-hospital", "mortality", "in", "patients", "with", "acute", "myocardial", "infarction", "(AMI).", "Methods", "A", "total", "of", "5161", "patients", "with", "AMI", "were", "admitted", "in", "Chinese", "PLA", "General", "Hospital", "between", "January", "1,", "1993", "and", "December", "31,", "2007.", "Medical", "comorbidities", "including", "hypertension,", "diabetes", "mellitus,", "previous", "myocardial", "infarction,", "valvular", "heart", "disease,", "chronic", "obstructive", "pulmonary", "disease", "(COPD),", "renal", "insufficiency,", "previous", "stroke,", "atrial", "fibrillation", "and", "anemia,", "were", "identified", "at", "admission.", "The", "patients", "were", "divided", "into", "4", "groups", "based", "on", "the", "number", "of", "medical", "comorbidities", "at", "admission", "(0,", "1,", "2,", "and", "≥", "3).", "Cox", "regression", "analysis", "was", "used", "to", "calculate", "relative", "risk", "(RR)", "and", "95%", "confidence", "intervals", "(CI),", "with", "adjustment", "for", "age,", "sex,", "heart", "failure", "and", "percutaneous", "coronary", "intervention", "(PCI).", "Results", "The", "mean", "age", "of", "the", "studied", "population", "was", "63.9", "±", "13.6", "years,", "and", "80.1%", "of", "the", "patients", "were", "male.", "In", "74.6%", "of", "the", "patients", "at", "least", "one", "comorbidity", "were", "identified.", "Hypertension", "(50.7%),", "diabetes", "mellitus", "(24.0%)", "and", "previous", "myocardial", "infarction", "(12%)", "were", "the", "leading", "common", "comorbidities", "at", "admission.", "The", "30-day", "in-hospital", "mortality", "in", "patients", "with", "0,", "1,", "2,", "and", "≥", "3", "comorbidities", "at", "admission", "(7.2%)", "was", "4.9%,", "7.2%,", "11.1%,", "and", "20.3%,", "respectively.", "The", "presence", "of", "2", "or", "more", "comorbidities", "was", "associated", "with", "higher", "30-day", "in-hospital", "mortality", "compared", "with", "patients", "without", "comorbidity", "(RR:", "1.41,", "95%", "CI:", "1.13-1.77,", "P", "=", "0.003,", "and", "RR:", "1.95,", "95%", "CI:", "1.59-2.39,", "P", "=", "0.000,", "respectively).", "Conclusions", "Medical", "comorbidities", "were", "frequently", "found", "in", "patients", "with", "AMI.", "AMI", "patients", "with", "more", "comorbidities", "had", "a", "higher", "30-day", "in-hospital", "mortality", "might", "be", "predictive", "of", "early", "poor", "outcome", "in", "patients", "with", "AMI.", "J", "Geriatr", "Cardiol", "2011;", "8:", "3134.", "doi:", "10.3724/SP.J.1263.2011.00031", "Keywords:", "acute", "myocardial", "infarction;", "comorbidity;", "mortality", "1", "Introduction", "In", "the", "past", "five", "decades,", "we", "have", "witnessed", "major", "breakthroughs", "in", "the", "management", "of", "acute", "myocardial", "infarction", "(AMI).[1]", "However,", "AMI", "remains", "a", "leading", "cause", "of", "death", "worldwide,", "and", "the", "mortality", "rate", "from", "AMI", "is", "still", "unacceptably", "high.[2,3]", "Many", "challenges", "remain", "in", "the", "risk", "stratification", "and", "management", "of", "patients", "with", "AMI,", "such", "as", "optimal", "risk", "stratification", "of", "patients,", "with", "comorbidities.", "Comorbidities", "may", "affect", "multiple", "clinical", "outcomes,", "including", "mortality,", "quality", "of", "life,", "and", "cost.[4]", "Comorbidities", "in", "patients", "with", "AMI,", "such", "as", "renal", "insufficiency,", "diabetes", "mellitus", "and", "stroke,", "may", "reduce", "the", "patient’s", "physiologic", "reserve", "and", "thereby", "increase", "the", "risk", "of", "adverse", "outcome.", "Therefore", "the", "assessment", "of", "comorbidity", "is", "important", "for", "Correspondence", "to:", "Yu-Sheng", "Zhao,", "MD,", "Institute", "of", "Geriatric", "Cardiology,", "Chinese", "PLA", "General", "Hospital,", "Fuxing", "Road", "28,", "Beijing", "100853,", "China.", "E-mail:", "zys3012002@yahoo.com", "Telephone:", "+86-10-55499139", "Fax:", "+86-10-68188906", "Received:", "September", "5,", "2010", "Revised:", "March", "17,", "2011", "Accepted:", "March", "24,", "2011", "Published", "online:", "March", "28,", "2011", "risk", "stratification", "of", "AMI.", "To", "date,", "little", "information", "is", "available", "on", "the", "effects", "of", "patients’", "comorbidity", "on", "the", "outcome", "of", "patients", "with", "AMI.", "In", "the", "present", "study,", "we", "investigated", "whether", "medical", "comorbidities", "at", "admission", "might", "be", "predictive", "for", "the", "30-day", "in-hospital", "mortality", "of", "patients", "with", "AMI", "hospitalized", "in", "a", "single", "medical", "center.", "2", "2.1", "Methods", "Data", "sources", "Since", "1992", "a", "computerized", "medical", "record", "database", "has", "been", "established", "in", "the", "Chinese", "PLA", "General", "Hospital,", "with", "the", "diagnostic", "codes", "based", "on", "the", "ninth", "revision", "of", "the", "International", "Classification", "of", "Diseases", "developed", "by", "the", "World", "Health", "Organization,", "commonly", "referred", "to", "as", "ICD9.", "The", "medical", "records", "of", "the", "patients", "with", "a", "primary", "diagnosis", "of", "AMI", "who", "were", "admitted", "between", "January", "1,", "1993", "and", "December", "31,", "2007", "were", "identified", "through", "discharge", "diagnosis", "of", "ICD9", "code", "410.", "A", "total", "of", "5161", "patients", "were", "identified,", "and", "the", "medical", "records", "of", "these", "patients", "were", "then", "reviewed,", "with", "emphasis", "on", "age,", "gender,", "medical", "http://www.jgc301.com;", "jgc@mail.sciencep.com", "|", "Journal", "of", "Geriatric", "Cardiology" ]

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[ "Hindawi", "Publishing", "Corporation", "Journal", "of", "Nutrition", "and", "Metabolism", "Volume", "2012,", "Article", "ID", "134202,", "8", "pages", "doi:10.1155/2012/134202", "Review", "Article", "Childhood", "Obesity", "and", "Obstructive", "Sleep", "Apnea", "Indra", "Narang", "and", "Joseph", "L.", "Mathew", "Division", "of", "Respiratory", "Medicine,", "The", "Hospital", "For", "Sick", "Children,", "555", "University", "Avenue,", "Toronto,", "ON,", "Canada", "M5G", "1X8", "Correspondence", "should", "be", "addressed", "to", "Indra", "Narang,", "indra.narang@sickkids.ca", "Received", "29", "May", "2012;", "Accepted", "31", "July", "2012", "Academic", "Editor:", "Dominique", "Bougle´", "Copyright", "©", "2012", "I.", "Narang", "and", "J.", "L.", "Mathew.", "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", "global", "epidemic", "of", "childhood", "and", "adolescent", "obesity", "and", "its", "immediate", "as", "well", "as", "long-term", "consequences", "for", "obese", "individuals", "and", "society", "as", "a", "whole", "cannot", "be", "overemphasized.", "Obesity", "in", "childhood", "and", "adolescence", "is", "associated", "with", "an", "increased", "risk", "of", "adult", "obesity", "and", "clinically", "significant", "consequences", "affecting", "the", "cardiovascular", "and", "metabolic", "systems.", "Importantly,", "obesity", "is", "additionally", "complicated", "by", "obstructive", "sleep", "apnea", "(OSA),", "occurring", "in", "up", "to", "60%", "of", "obese", "children.", "OSA,", "which", "is", "diagnosed", "using", "the", "gold", "standard", "polysomnogram", "(PSG),", "is", "characterised", "by", "snoring,", "recurrent", "partial", "(hypopneas)", "or", "complete", "(apneas)", "obstruction", "of", "the", "upper", "airway.", "OSA", "is", "frequently", "associated", "with", "intermittent", "oxyhemoglobin", "desaturations,", "sleep", "disruption,", "and", "sleep", "fragmentation.", "There", "is", "emerging", "data", "that", "OSA", "is", "associated", "with", "cardiovascular", "burden", "including", "systemic", "hypertension,", "changes", "in", "ventricular", "structure", "and", "function,", "arterial", "stiffness,", "and", "metabolic", "syndromes.", "Thus,", "OSA", "in", "the", "context", "of", "obesity", "may", "independently", "or", "synergistically", "magnify", "the", "underlying", "cardiovascular", "and", "metabolic", "burden.", "This", "is", "of", "importance", "as", "early", "recognition", "and", "treatment", "of", "OSA", "in", "obese", "children", "are", "likely", "to", "result", "in", "the", "reduction", "of", "cardiometabolic", "burden", "in", "obese", "children.", "This", "paper", "summarizes", "the", "current", "state", "of", "understanding", "of", "obesity-related", "OSA.", "Specifically,", "this", "paper", "will", "discuss", "epidemiology,", "pathophysiology,", "cardiometabolic", "burden,", "and", "management", "of", "obese", "children", "and", "adolescents", "with", "OSA.", "1.", "Introduction", "The", "epidemic", "of", "pediatric", "obesity", "has", "caused", "serious", "concern", "all", "over", "the", "world", "as", "the", "prevalence", "has", "increased", "alarmingly", "over", "time,", "not", "only", "in", "developed", "countries", "but", "also", "in", "developing", "countries", "[1,", "2].", "Furthermore,", "there", "is", "increasing", "recognition", "that", "childhood", "obesity", "is", "occurring", "at", "progres-", "sively", "younger", "ages", "[3].", "Recent", "publications", "have", "highlighted", "the", "challenge", "of", "defining", "childhood", "obesity", "in", "a", "manner", "that", "is", "both", "evidence", "based", "as", "well", "as", "uniformly", "applicable", "across", "different", "settings", "[4].", "In", "general,", "a", "statistical", "definition", "using", "BMI", "for", "age", "is", "used", "wherein", ">85th", "percentile", "is", "defined", "as", "overweight", "and", ">95th", "percentile", "as", "obesity", "[5].", "In", "contrast,", "the", "WHO", "defines", "obesity", "as", "BMI", "for", "age", "Z-score", ">3", "and", "overweight", "as", "Z-score", ">2.", "A", "large-scale", "multicentric", "study", "calculated", "BMI", "in", "children", "and", "adolescents", "and", "extrapolated", "the", "cut-off", "values", "for", "adult", "obesity", "(BMI", ">", "30)", "and", "over-", "weight", "(BMI", ">", "25),", "to", "the", "corresponding", "values", "in", "childhood", "and", "adolescence.", "Based", "on", "this,", "they", "were", "able", "to", "tabulate", "age-", "and", "gender-specific", "cut-off", "values", "for", "children", "and", "ado-", "lescents", "[6].", "At", "the", "present", "time,", "waist", "circumference", "is", "not", "used", "routinely", "to", "define", "obesity", "in", "children", "and", "adolescents.", "The", "high", "prevalence", "of", "obesity", "is", "believed", "to", "be", "a", "complex", "interplay", "of", "genetic,", "environmental", "(life-style),", "socioeco-", "nomic,", "cultural,", "and", "psychological", "factors", "which", "are", "beyond", "the", "scope", "of", "this", "paper.", "However,", "interestingly", "the", "pattern", "of", "in", "utero", "growth", "may", "program", "the", "pattern", "of", "subsequent", "body", "fat", "deposition", "and", "neuroendocrine", "interactions", "that", "promote", "eating", "behavior.", "Specifically,", "there", "is", "an", "observed", "increase", "in", "childhood", "obesity", "with", "increasing", "birth", "weight", "[7].", "Counterintuitively,", "infants", "with", "low", "birth", "weight", "and", "an", "early", "adiposity", "rebound", "are", "also", "predisposed", "to", "higher", "rates", "of", "obesity", "in", "later", "childhood", "[8].", "There", "are", "several", "well-documented", "adverse", "consequences", "of", "childhood", "obesity.", "Specific", "morbidities", "associated", "with", "obesity", "include", "hypertension,", "left", "ventricular", "abnormalities,", "insulin", "resistance,", "type", "2", "diabetes,", "dyslipidemia,", "nonalco-", "holic", "fatty", "liver", "disease,", "and", "obstructive", "sleep", "apnea", "[9].", "Further,", "in", "obese", "individuals,", "the", "clustering", "of", "dyslipidemia,", "hypertension,", "and", "impaired", "glucose", "tolerance/insulin", "resis-", "tance", "is", "referred", "to", "as", "the", "Metabolic", "Syndrome", "(MetS),", "which", "further", "increases", "the", "risk", "of", "atherosclerotic", "heart", "disease", "[10].", "In", "a", "followup", "of", "over", "200,000", "Norwegian", "adolescents,", "the", "relative", "risk", "of", "death", "due", "to", "ischaemic", "heart", "disease", "for", "those" ]

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[ "Biochem.", "J.", "(2012)", "445,", "237–246", "(Printed", "in", "Great", "Britain)", "doi:10.1042/BJ20111978", "237", "Different", "molecular", "bases", "underlie", "the", "mitochondrial", "respiratory", "activity", "in", "the", "homoeothermic", "spadices", "of", "Symplocarpus", "renifolius", "and", "the", "transiently", "thermogenic", "appendices", "of", "Arum", "maculatum", "Yusuke", "KAKIZAKI*,", "Anthony", "L.", "MOORE†", "and", "Kikukatsu", "ITO‡1", "*The", "United", "Graduate", "School", "of", "Agricultural", "Sciences,", "Iwate", "University,", "3-18-8", "Ueda,", "Morioka,", "Iwate,", "020-8550,", "Japan,", "†Department", "of", "Biochemistry", "and", "Molecular", "Biology,", "School", "of", "Life", "Sciences,", "University", "of", "Sussex,", "Falmer,", "Brighton,", "BN1", "9QG,", "U.K.,", "and", "‡Cryobiofrontier", "Research", "Center,", "Faculty", "of", "Agriculture,", "Iwate", "University,", "3-18-8", "Ueda,", "Morioka,", "Iwate,", "020-8550,", "Japan", "Symplocarpus", "renifolius", "and", "Arum", "maculatum", "are", "known", "to", "produce", "significant", "heat", "during", "the", "course", "of", "their", "floral", "development,", "but", "they", "use", "different", "regulatory", "mechanisms,", "i.e.", "homoeothermic", "compared", "with", "transient", "thermogenesis.", "To", "further", "clarify", "the", "molecular", "basis", "of", "species-specific", "thermogenesis", "in", "plants,", "in", "the", "present", "study", "we", "have", "analysed", "the", "native", "structures", "and", "expression", "patterns", "of", "the", "mitochondrial", "respiratory", "components", "in", "S.", "renifolius", "and", "A.", "maculatum.", "Our", "comparative", "analysis", "using", "Blue", "native", "PAGE", "combined", "with", "nano", "LC", "(liquid", "chromatography)-MS/MS", "(tandem", "MS)", "has", "revealed", "that", "the", "constituents", "of", "the", "respiratory", "complexes", "in", "both", "plants", "were", "basically", "similar,", "but", "that", "several", "mitochondrial", "components", "appeared", "to", "be", "differently", "expressed", "in", "their", "thermogenic", "organs.", "Namely,", "complex", "II", "in", "S.", "renifolius", "was", "detected", "as", "a", "340", "kDa", "product,", "suggesting", "an", "oligomeric", "or", "supramolecular", "structure", "in", "vivo.", "Moreover,", "the", "expression", "of", "an", "external", "NAD(P)H", "dehydrogenase", "was", "found", "to", "be", "higher", "in", "A.", "maculatum", "than", "in", "S.", "renifolius,", "whereas", "an", "internal", "NAD(P)H", "dehydrogenase", "was", "expressed", "at", "a", "similar", "level", "in", "both", "species.", "Alternative", "oxidase", "was", "detected", "as", "smear-like", "signals", "that", "were", "elongated", "on", "the", "first", "dimension", "with", "a", "peak", "at", "around", "200", "kDa", "in", "both", "species.", "The", "significance", "and", "implication", "of", "these", "data", "are", "discussed", "in", "terms", "of", "thermoregulation", "in", "plants.", "Key", "words:", "alternative", "oxidase", "(AOX),", "Blue", "native", "PAGE,", "mitochondrial", "respiratory", "chain,", "thermogenic", "plants,", "type", "II", "NAD(P)H", "dehydrogenase.", "INTRODUCTION", "Organ-specific", "thermogenesis", "associated", "with", "floral", "development", "has", "been", "well", "documented", "in", "plants", "from", "a", "diverse", "range", "of", "families,", "including", "the", "monocotyledonous", "Araceae", "[1],", "dicotyledonous", "Nelumbonaceae", "[2]", "and", "gymnospermous", "Cycadaceae", "[3].", "Most", "thermogenic", "activities", "in", "these", "plants", "can", "be", "categorized", "into", "two", "types,", "in", "accordance", "with", "the", "transition", "patterns", "of", "their", "tissue", "temperature.", "Transient", "heat", "production", "has", "been", "observed", "in", "the", "majority", "of", "thermogenic", "plants", "analysed,", "where", "the", "temperature", "of", "a", "thermogenic", "organ", "rises", "discontinuously", "over", "one", "or", "two", "events.", "This", "type", "of", "thermogenesis", "has", "been", "well", "studied", "in", "Arum", "species", "since", "Jean-", "Baptiste", "Lamarck", "first", "documented", "the", "thermogenic", "activity", "of", "plants", "in", "the", "European", "arum", "lily", "[4].", "For", "instance,", "it", "is", "now", "widely", "known", "that", "appendices", "of", "Arum", "maculatum", "can", "be", "hotter", "than", "30", "◦C", "at", "the", "peak", "of", "their", "transient", "thermogenesis,", "when", "the", "ambient", "temperature", "is", "between", "7–22", "◦C", "[5,6,7].", "On", "the", "other", "hand,", "homoeothermic", "heat", "production", "has", "also", "been", "reported", "in", "a", "limited", "number", "of", "species,", "such", "as", "sacred", "lotus", "(Nelumbo", "nucifera)", "and", "skunk", "cabbage", "(Symplocarpus", "species)", "[2,8,9].", "In", "these", "plants,", "the", "thermogenic", "organ", "remains", "at", "a", "constant", "temperature", "for", "several", "days", "with", "remarkable", "precision.", "For", "example,", "the", "spadices", "of", "S.", "renifolius", "are", "reported", "to", "maintain", "their", "tissue", "temperature", "at", "a", "relatively", "stable", "21", "+", "2.4", "◦C,", "although", "the", "−", "ambient", "temperature", "varies", "over", "a", "wide", "range", "[8].", "Surprisingly,", "this", "plant", "can", "produce", "heat", "that", "is", "sufficient", "to", "melt", "the", "surrounding", "snow", "in", "its", "natural", "environment", "[10].", "The", "molecular", "basis", "of", "thermogenesis", "in", "plants", "has", "long", "been", "associated", "with", "the", "expression", "of", "cyanide-resistant", "respiration", "[4].", "Such", "respiration", "is", "attributed", "to", "the", "activity", "of", "AOX", "(alternative", "oxidase),", "which", "is", "located", "on", "the", "matrix", "surface", "of", "the", "inner", "mitochondrial", "membrane", "and", "catalyses", "the", "oxidation", "of", "ubiquinol", "and", "the", "reduction", "of", "molecular", "oxygen", "to", "water", "[11].", "AOX", "is", "an", "energy-dissipative", "enzyme,", "since", "it", "does", "not", "contribute", "to", "the", "formation", "of", "a", "proton", "electrochemical", "gradient", "across", "the", "inner", "membrane", "and,", "as", "a", "consequence,", "to", "ATP", "synthesis.", "The", "drastic", "change", "in", "free", "energy", "which", "is", "accompanied", "by", "the", "reaction", "catalysed", "by", "AOX", "is", "believed", "to", "be", "liberated", "as", "heat", "in", "thermogenic", "plants.", "In", "fact,", "a", "large", "cyanide-resistant", "respiration", "capacity", "has", "been", "observed", "to", "be", "associated", "with", "thermogenesis", "in", "plants,", "regardless", "of", "whether", "it", "is", "transient", "or", "homoeothermic", "[12,13].", "Although", "a", "large", "quantity", "of", "AOX", "protein", "has", "been", "shown", "to", "accumulate", "in", "mitochondria", "following", "the", "onset", "of", "thermogenesis", "in", "some", "species", "[13,14],", "this", "is", "not", "the", "prerequisite", "for", "a", "considerable", "cyanide-resistant", "respiration", "capacity", "as", "previously", "demonstrated", "in", "A.", "maculatum", "[12].", "BN-PAGE", "(Blue", "native", "PAGE)", "has", "become", "a", "major", "technique", "in", "the", "analysis", "of", "multiprotein", "complexes,", "particularly", "those", "localized", "to", "membranes", "[15].", "This", "method", "is", "especially", "effective", "when", "combined", "with", "2D", "(two-dimensional)", "SDS/PAGE", "and", "MS,", "as", "it", "is", "then", "possible", "to", "identify", "the", "constitutive", "subunits", "of", "a", "complex.", "All", "of", "the", "typical", "plant", "mitochondrial", "respiratory", "complexes", "have", "been", "characterized", "using", "this", "technique", "[16,17],", "the", "major", "findings", "of", "which", "have", "revealed", "that", "there", "are", "distinct", "differences", "between", "plant", "and", "mammalian", "mitochondria,", "such", "Abbreviations", "used:", "1D,", "one-dimensional;", "2D,", "two-dimensional;", "AOX,", "alternative", "oxidase;", "BCA,", "bicinchoninic", "acid;", "BN-PAGE,", "Blue", "native", "PAGE;", "COX,", "cytochrome", "c", "oxidase;", "Fp,", "flavoprotein;", "MS/MS,", "tandem", "MS;", "RACE,", "rapid", "amplification", "of", "cDNA", "ends;", "RT,", "reverse", "transcription;", "TCA,", "tricarboxylic", "acid;", "UTR,", "untranslated", "region.", "1", "To", "whom", "correspondence", "should", "be", "addressed", "(email", "kikuito@iwate-u.ac.jp).", "©", "2012", "The", "Author(s)", "c", "The", "Authors", "Journal", "compilation", "c", "2012", "Biochemical", "Society", "The", "author(s)", "has", "paid", "for", "this", "article", "to", "be", "freely", "available", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "Non-Commercial", "Licence", "(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.", ".", "j", "i", ".", "l", "l", "i", "i" ]

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[ "Primates", "(2011)", "52:373–383", "DOI", "10.1007/s10329-011-0258-2", "O", "R", "I", "G", "I", "N", "A", "L", "A", "R", "T", "I", "C", "L", "E", "Copulation", "patterns", "in", "captive", "hamadryas", "baboons:", "a", "quantitative", "analysis", "Florian", "Nitsch", "•", "Sabine", "Stueckle", "•", "Daniel", "Stahl", "•", "Dietmar", "Zinner", "Received:", "22", "November", "2010", "/", "Accepted:", "6", "June", "2011", "/", "Published", "online:", "28", "June", "2011", "Japan", "Monkey", "Centre", "and", "Springer", "2011", "Abstract", "For", "primates,", "as", "for", "many", "other", "vertebrates,", "copulation", "which", "results", "in", "ejaculation", "is", "a", "prerequisite", "for", "reproduction.", "The", "probability", "of", "ejaculation", "is", "affected", "by", "various", "physiological", "and", "social", "factors,", "for", "example", "reproductive", "state", "of", "male", "and", "female", "and", "operational", "sex-", "ratio.", "In", "this", "paper,", "we", "present", "quantitative", "and", "qualitative", "data", "on", "patterns", "of", "sexual", "behaviour", "in", "a", "captive", "group", "of", "hamadryas", "baboons", "(Papio", "hamadryas),", "a", "species", "with", "a", "polygynous–monandric", "mating", "system.", "We", "observed", "more", "than", "700", "copulations", "and", "analysed", "factors", "that", "can", "affect", "the", "probability", "of", "ejaculation.", "Multilevel", "logistic", "regression", "analysis", "and", "Akaike’s", "information", "criterion", "(AIC)", "model", "selection", "procedures", "revealed", "that", "the", "probability", "of", "suc-", "cessful", "copulation", "increased", "as", "the", "size", "of", "female", "sexual", "swellings", "increased,", "indicating", "increased", "probability", "of", "ovulation,", "and", "as", "the", "number", "of", "females", "per", "one-male", "unit", "(OMU)", "decreased.", "In", "contrast,", "occurrence", "of", "female", "F.", "Nitsch", "S.", "Stueckle", "D.", "Zinner", "(&)", "Cognitive", "Ethology", "Laboratory,", "German", "Primate", "Center,", "Kellnerweg", "4,", "37077", "Go¨ttingen,", "Germany", "e-mail:", "dzinner@gwdg.de", "F.", "Nitsch", "Department", "of", "Animal", "Behaviour,", "University", "of", "Bielefeld,", "Bielefeld,", "Germany", "D.", "Stahl", "Department", "of", "Biostatistics,", "King’s", "College", "London,", "Institute", "of", "Psychiatry,", "London,", "UK", "Present", "Address:", "S.", "Stueckle", "Department", "of", "Microsystems", "Engineering,", "University", "of", "Freiburg,", "Freiburg,", "Germany", "copulation", "calls,", "sex", "of", "the", "copulation", "initiator,", "and", "pre-", "vious", "male", "aggression", "toward", "females", "did", "not", "affect", "the", "probability", "of", "ejaculation.", "Synchrony", "of", "oestrus", "cycles", "also", "had", "no", "effect", "(most", "likely", "because", "the", "sample", "size", "was", "too", "small).", "We", "also", "observed", "29", "extra-group", "copulations", "by", "two", "non-adult", "males.", "Our", "results", "indicate", "that", "male", "hamadryas", "baboons", "copulated", "more", "successfully", "around", "the", "time", "of", "ovulation", "and", "that", "males", "in", "large", "OMUs", "with", "many", "females", "may", "be", "confronted", "by", "time", "or", "energy-allo-", "cation", "problems.", "Keywords", "Sexual", "behaviour", "Copulation", "pattern", "Papio", "hamadryas", "Akaike’s", "Information", "Criterion", "Introduction", "Effective", "copulation", "that", "leads", "to", "conception", "is", "crucial", "for", "successful", "reproduction", "and", "hence", "for", "fitness.", "Successful", "copulation", "is", "affected", "by", "a", "number", "of", "factors,", "for", "example", "the", "quality", "and", "quantity", "of", "sperm", "(Birkhead", "and", "Fletcher", "1995;", "Parker", "1998)", "and", "timing", "in", "relation", "to", "ovulation", "(Hrdy", "and", "Whitten", "1987;", "Dixson", "1998).", "In", "primates,", "as", "in", "other", "mammals,", "copulation", "comprises", "mounting", "and", "intromission,", "at", "least", "(Dixson", "1998).", "In", "any", "case,", "one", "decisive", "prerequisite", "for", "copulation", "to", "be", "effective", "is", "the", "occurrence", "of", "ejaculation.", "The", "ability", "of", "a", "male", "to", "provide", "sperm", "during", "copulation", "depends", "both", "on", "his", "own", "repro-", "ductive", "physiology", "and", "behaviour", "and", "on", "the", "reproductive", "status", "and", "behaviour", "of", "his", "mating", "partner.", "Most", "primate", "males", "can", "only", "copulate", "when", "females", "cooperate", "(Strum", "1982;", "Bercovitch", "1995).", "Copulation", "success", "can", "also", "be", "affected", "by", "the", "frequency", "with", "which", "males", "copulate", "given", "that", "sperm", "can", "be", "a", "limited", "resource", "in", "some", "circum-", "stances,", "as", "proposed", "by", "Small", "(1988).", "Such", "a", "situation", "may", "123" ]

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[ "Journal", "of", "Synchrotron", "Radiation", "ISSN", "0909-0495", "Received", "9", "August", "2010", "Accepted", "7", "February", "2011", "research", "papers", "Development", "of", "a", "hard", "X-ray", "delay", "line", "for", "X-ray", "photon", "correlation", "spectroscopy", "and", "jitter-free", "pump–probe", "experiments", "at", "X-ray", "free-electron", "laser", "sources", "Wojciech", "Roseker,a*", "Hermann", "Franz,a", "Horst", "Schulte-Schrepping,a", "Anita", "Ehnes,a", "Olaf", "Leupold,a", "Federico", "Zontone,b", "Sooheyong", "Lee,a,c", "Aymeric", "Robertc", "and", "Gerhard", "Gru¨bela", "aHamburger", "Synchrotronstrahlungslabor", "am", "Deutschen", "Elektronen", "Synchrotron", "(DESY),", "Notkestrasse", "85,", "D-22603", "Hamburg,", "Germany,", "bEuropean", "Synchrotron", "Radiation", "Facility,", "6", "rue", "Jules", "Horowitz,", "BP", "220,", "38043", "Grenoble", "Cedex", "09,", "France,", "and", "cSLAC", "National", "Accelerator", "Laboratory,", "2575", "Sand", "Hill", "Road,", "Menlo", "Park,", "CA", "94025,", "USA.", "E-mail:", "wojciech.roseker@desy.de", "A", "hard", "X-ray", "delay", "line", "capable", "of", "splitting", "and", "delaying", "single", "X-ray", "pulses", "has", "been", "developed", "with", "the", "aim", "of", "performing", "X-ray", "photon", "correlation", "spectroscopy", "(XPCS)", "and", "X-ray", "pump–probe", "experiments", "at", "hard", "X-ray", "free-", "electron", "laser", "sources.", "The", "performance", "of", "the", "device", "was", "tested", "with", "8.39", "keV", "synchrotron", "radiation.", "Time", "delays", "up", "to", "2.95", "ns", "have", "been", "demonstrated.", "The", "feasibility", "of", "the", "device", "for", "performing", "XPCS", "studies", "was", "tested", "by", "recording", "static", "speckle", "patterns.", "The", "achieved", "speckle", "contrast", "of", "56%", "indicates", "the", "possibility", "of", "performing", "ultra-fast", "XPCS", "studies", "with", "the", "delay", "line.", "Keywords:", "delay", "line;", "XPCS;", "pump–probe;", "X-ray", "optics.", "1.", "Introduction", "Probing", "matter", "on", "time", "scales", "ranging", "from", "femtoseconds", "to", "nanoseconds", "is", "one", "of", "the", "key", "attributes", "offered", "by", "X-ray", "free-", "electron", "lasers", "(XFELs)", "(Altarelli", "et", "al.,", "2006;", "Patterson", "et", "al.,", "2010;", "Shintake", "et", "al.,", "2008).", "These", "new", "X-ray", "sources", "provide", "ultra-short", "and", "coherent", "pulses", "that", "carry", "more", "than", "1012", "photons", "per", "pulse.", "Apart", "from", "the", "extremely", "high", "peak", "brightness", "and", "coherence,", "the", "most", "prominent", "feature", "of", "the", "XFEL", "machines", "is", "their", "time", "structure.", "The", "European", "XFEL", "will", "deliver", "sub-100", "fs-long", "pulses", "separated", "by", "200", "ns", "in", "bunch", "trains", "arriving", "with", "a", "repetition", "rate", "of", "10", "Hz", "(Altarelli", "et", "al.,", "2006).", "The", "Linac", "Coherent", "Light", "Source", "(LCLS)", "will", "provide", "sub-100", "fs", "pulses", "at", "a", "repetition", "rate", "up", "to", "120", "Hz", "(Emma", "et", "al.,", "2010).", "Such", "capabilities", "of", "the", "new", "light", "sources", "will", "enable", "new", "types", "of", "experiments", "currently", "not", "feasible", "with", "third-", "generation", "storage", "rings.", "However,", "the", "intrinsic", "time", "structure", "of", "the", "machines", "and", "the", "timing", "jitter", "between", "pump", "and", "probe", "beams", "need", "to", "be", "addressed", "to", "fully", "utilize", "the", "ultra-short", "pulse", "duration.", "For", "instance,", "in", "X-ray", "pump–X-ray", "probe", "or", "X-ray", "photon", "correlation", "spectroscopy", "(XPCS)", "experiments", "(Sutton", "et", "al.,", "1991;", "Gru¨", "bel", "&", "Zontone,", "2004)", "the", "shortest", "time", "scale", "that", "can", "be", "measured", "is", "set", "by", "the", "minimum", "pulse", "spacing", "and", "the", "pulse", "duration", "of", "the", "source.", "Therefore,", "employing", "the", "intrinsic", "time", "structure", "of", "the", "XFEL", "source", "in", "J.", "Synchrotron", "Rad.", "(2011).", "18,", "481–491", "XPCS", "or", "X-ray", "pump–X-ray", "pump", "experiments", "will", "limit", "the", "access", "to", "time", "scales", "shorter", "than", "200", "ns", "at", "the", "European", "XFEL", "or", "8.3", "ms", "at", "LCLS.", "Adapting", "the", "time", "structure", "of", "the", "XFEL", "source", "to", "the", "needs", "of", "the", "aforementioned", "experiments", "can", "be", "achieved", "by", "split", "pulse", "and", "delay", "techniques", "(i.e.", "usage", "of", "a", "delay", "line).", "Moreover,", "the", "pulses", "provided", "by", "a", "delay", "line", "(i.e.", "the", "main", "pulse", "and", "its", "delayed", "replica)", "originate", "from", "the", "same", "electron", "bunch", "and", "thus", "give", "an", "intrinsic", "synchronization", "to", "the", "X-ray", "source.", "Furthermore,", "the", "time", "resolution", "of", "the", "pump–probe", "experiment", "is", "determined", "not", "by", "a", "detector", "but", "the", "delay", "line", "itself.", "In", "ultra-fast", "XPCS", "experiments", "(Gru¨", "bel", "et", "al.,", "2007;", "Gutt", "et", "al.,", "2007)", "it", "provides", "an", "intrinsic", "normalization", "of", "the", "measured", "speckle", "pattern", "contrast.", "In", "this", "case,", "any", "bunch-to-", "bunch", "instabilities", "(e.g.", "change", "of", "intensity", "or", "coherence", "properties", "of", "pulses)", "coming", "from", "the", "XFEL", "source", "will", "not", "affect", "the", "experiment.", "In", "addition,", "the", "use", "of", "a", "delay", "line", "in", "XPCS", "puts", "less", "demands", "on", "the", "detector", "performance.", "The", "time", "resolution", "of", "the", "detector", "used", "in", "the", "experiment", "must", "be", "only", "better", "than", "the", "minimum", "pulse", "spacing", "of", "the", "X-ray", "source.", "Existing", "delay", "lines", "operate", "in", "the", "spectral", "range", "from", "visible", "radiation", "to", "soft", "X-rays", "(Mitzner", "et", "al.,", "2005;", "Sorgenfrei", "et", "al.,", "2010).", "Equivalent", "devices", "for", "hard", "X-rays", "have", "been", "discussed", "for", "many", "years", "and", "several", "beam", "geometries", "have", "been", "proposed", "(Altarelli", "et", "al.,", "2006;", "Arthur", "et", "al.,", "2002;", "doi:10.1107/S0909049511004511", "481" ]

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[ "J", "Gastrointest", "Surg", "(2009)", "13:1550–1553", "DOI", "10.1007/s11605-009-0852-4", "GI", "IMAGE", "Primary", "Hepatic", "Osteosarcoma", "Atta", "Nawabi", "&", "Sidhartha", "Rath", "&", "Nicholas", "Nissen", "&", "Charles", "Forscher", "&", "Steven", "Colquhoun", "&", "Joseph", "Lee", "&", "Stephen", "Geller", "&", "Anna", "Wong", "&", "Andrew", "S.", "Klein", "Received:", "30", "September", "2008", "/", "Accepted:", "26", "February", "2009", "/", "Published", "online:", "18", "March", "2009", "#", "2009", "The", "Author(s).", "This", "article", "is", "published", "with", "open", "access", "at", "Springerlink.com", "Keywords", "Osteosarcoma", ".", "Hepatic", "neoplasm", ".", "Hepatic", "malignancy", "Extraskeletal", "osteosarcoma", "(EOS)", "is", "a", "rare", "entity.", "Most", "human", "cases", "have", "been", "described", "in", "the", "soft", "tissues", "of", "the", "limb.1", "Primary", "hepatic", "osteosarcoma", "is", "extremely", "uncom-", "mon", "with", "only", "seven", "cases", "reported", "in", "the", "world’s", "literature.", "Of", "these", "cases,", "no", "patient", "survived", "more", "than", "8", "weeks", "from", "the", "time", "of", "diagnosis.", "We", "describe", "a", "young", "patient", "with", "a", "symptomatic", "primary", "hepatic", "osteosarcoma", "that", "was", "suc-", "cessfully", "treated", "by", "surgical", "resection", "and", "adjuvant", "chemo-", "therapy.", "She", "is", "alive", "and", "tumor", "free", "3", "years", "after", "surgery.", "Case", "Report", "A", "healthy,", "athletic", "19-year-old", "African", "American", "woman", "presented", "for", "a", "surgical", "evaluation", "of", "a", "newly", "diagnosed", "hepatic", "mass.", "The", "patient", "reported", "approximately", "18", "months", "of", "occasional", "and", "intermittent", "episodes", "of", "epigastric", "discomfort.", "Recently,", "she", "had", "developed", "symptoms", "of", "early", "satiety", "and", "anorexia.", "On", "physical", "exam,", "she", "had", "vague", "diffuse", "upper", "abdominal", "tenderness", "and", "a", "firm,", "palpable", "mass", "in", "the", "left", "upper", "quadrant", "extending", "to", "the", "midline.", "A", "calcified", "left", "upper", "quadrant", "mass", "was", "seen", "on", "abdominal", "X-ray", "taken", "during", "an", "emergency", "room", "visit.", "Laboratory", "A.", "Nawabi", ":", "S.", "Rath", ":", "N.", "Nissen", ":", "C.", "Forscher", ":", "S.", "Colquhoun", ":", "J.", "Lee", ":", "S.", "Geller", ":", "A.", "Wong", ":", "A.", "S.", "Klein", "(*)", "Department", "of", "Surgery,", "Cedars-Sinai", "Medical", "Center,", "8635", "W.", "3rd", "Street,", "590", "West,", "Los", "Angeles,", "CA", "90048,", "USA", "e-mail:", "kleinas@cshs.org", "evaluation", "was", "remarkable", "for", "moderate", "elevations", "of", "alkaline", "phosphatase", "and", "alpha", "fetoprotein.", "To", "further", "evaluate", "the", "mass,", "a", "CT", "scan", "of", "the", "chest,", "abdomen,", "and", "pelvis", "was", "performed", "(Fig.", "1),", "which", "showed", "a", "large", "heterogeneous", "mass", "occupying", "the", "left", "lobe", "of", "the", "liver", "with", "a", "5-cm", "area", "of", "calcification", "in", "the", "anterior", "aspect.", "MRI", "demonstrated", "a", "single", "heterogeneously", "enhancing", "15×", "10", "×13.8", "cm", "lobulated", "mass", "inseparable", "from", "the", "left", "lobe", "of", "the", "liver", "(Fig.", "2).", "The", "left", "portal", "vein", "was", "not", "visualized", "and", "there", "was", "no", "biliary", "dilatation.", "T1-", "and", "T2-weighted", "sequences", "showed", "a", "5-cm", "area", "of", "signal", "hypointensity", "with", "multiple", "hypointense", "non-enhancing", "linear", "areas", "throughout", "the", "mass", "consistent", "with", "areas", "of", "calcification.", "A", "small", "amount", "of", "intraperitoneal", "free", "fluid", "was", "present.", "Staging", "chest", "and", "brain", "CT", "demonstrated", "no", "evidence", "for", "metastatic", "disease.", "Whole", "body", "Tc-99m", "MDP", "bone", "scan", "demonstrated", "no", "evidence", "of", "skeletal", "metastatic", "disease.", "The", "radiologic", "differential", "diagnosis", "includes", "sarcoma,", "including", "metastatic", "osteosarcoma,", "and", "fibrolamellar", "hepa-", "tocellular", "carcinoma.", "At", "operation,", "a", "large,", "scarred", "lesion", "replacing", "the", "left", "hepatic", "lobe", "was", "immediately", "identified.", "The", "lesion", "extended", "across", "the", "falciform", "ligament", "into", "segment", "4", "of", "the", "liver.", "It", "was", "also", "adherent", "to,", "but", "did", "not", "invade,", "the", "stomach.", "The", "abdominal", "cavity", "was", "examined", "and", "no", "metastatic", "deposits", "were", "noted.", "The", "right", "hepatic", "lobe", "was", "examined", "with", "both", "palpation", "and", "intraoperative", "ultra-", "sound,", "and", "was", "free", "of", "tumor.", "A", "left", "hepatic", "lobectomy", "was", "performed", "with", "en-bloc", "cholecystectomy", "using", "a", "combina-", "tion", "of", "electrocautery", "and", "hydrojet", "dissection.", "The", "middle", "hepatic", "vein", "was", "not", "involved", "in", "the", "mass", "and", "was", "left", "in-", "situ.", "Her", "post-operative", "recovery", "was", "uneventful.", "She", "was", "discharged", "on", "the", "fifth", "post-operative", "day." ]

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[ "organic", "compounds", "Acta", "Crystallographica", "Section", "E", "Structure", "Reports", "Online", "ISSN", "1600-5368", "Cyclo(L-tyrosyl-L-tryptophanyl)", "dimethyl-", "formamide", "solvate", "Carl", "Henrik", "Go¨rbitz*", "and", "Lars", "Male", "Hartviksen", "Department", "of", "Chemistry,", "University", "of", "Oslo,", "PO", "Box", "1033", "Blindern,", "N-0315", "Oslo,", "Norway", "Correspondence", "e-mail:", "c.h.gorbitz@kjemi.uio.no", "Received", "3", "December", "2007;", "accepted", "8", "January", "2008", "Key", "indicators:", "single-crystal", "X-ray", "study;", "T", "=", "105", "K;", "mean", "(C–C)", "=", "0.004", "A˚;", "R", "factor", "=", "0.046;", "wR", "factor", "=", "0.123;", "data-to-parameter", "ratio", "=", "9.4.", "The", "structure", "of", "the", "title", "compound", "[systematic", "name:", "(3S,6S)-", "3-(4-hydroxybenzyl)-6-(1H-indol-3-ylmethyl)piperazine-2,5-", "dione", "dimethylformamide", "solvate],", "C20H19N3O3", "C3H7NO,", "contains", "hydrogen-bonded", "tapes", "typical", "for", "diketopipera-", "zines.", "The", "structure", "is", "stabilized", "by", "strong", "intermolecular", "interactions", "of", "the", "types", "O—H", "O", "and", "N—H", "O", "involving", "the", "dipeptide", "and", "the", "solvent", "molecules.", "The", "absolute", "configuration", "was", "known", "from", "the", "starting", "materials.", "Related", "literature", "For", "related", "structures,", "see:", "Morris", "et", "al.", "(1974);", "Grant", "et", "al.", "(1999);", "Suguna", "et", "al.", "(1984);", "Lin", "&", "Webb", "(1973);", "Razak", "et", "al.,", "(2000);", "Luo", "&", "Palmore", "(2002);", "Go¨", "rbitz", "(1987);", "Go¨", "rbitz", "&", "Hartviksen", "(2006).", "Solvent", "inclusion:", "Go¨", "rbitz", "&", "Hersleth", "(2000).", "Cambridge", "Structural", "Database:", "Allen", "(2002).", "Experimental", "Crystal", "data", "C20H19N3O3", "C3H7NO", "Mr", "=", "422.48", "Monoclinic,", "P21", "a", "=", "6.1923", "(2)", "A˚", "b", "=", "15.3873", "(5)", "A˚", "c", "=", "11.3780", "(3)", "A˚", "=", "96.661", "(1)", "V", "=", "1076.81", "(6)", "A˚", "3", "Z", "=", "2", "Mo", "K", "radiation", "=", "0.09", "mm", "1", "T", "=", "105", "(2)", "K", "0.80", "0.65", "0.20", "mm", "Data", "collection", "Siemens", "SMART", "CCD", "diffractometer", "Absorption", "correction:", "multi-scan", "(SADABS;", "Sheldrick,", "1996)", "Tmin", "=", "0.800,", "Tmax", "=", "0.982", "Refinement", "R[F", "2", ">", "2", "(F", "2)]", "=", "0.045", "wR(F", "2)", "=", "0.122", "S", "=", "1.15", "2786", "reflections", "297", "parameters", "1", "restraint", "Table", "1", "Hydrogen-bond", "geometry", "(A˚", ",", ").", "D—H", "A", "N1—H1", "N2—H2", "N3—H3", "O2—H4", "O1i", "O3ii", "O1iii", "O1D", "D—H", "0.96", "(3)", "0.87", "(3)", "0.81", "(4)", "1.04", "(5)", "9514", "measured", "reflections", "2786", "independent", "reflections", "2454", "reflections", "with", "I", ">", "2", "(I)", "Rint", "=", "0.038", "H", "atoms", "treated", "by", "a", "mixture", "of", "independent", "and", "constrained", "refinement", "max", "=", "0.23", "e", "A˚", "3", "min", "=", "0.27", "e", "A˚", "3", "H", "A", "1.94", "(3)", "2.01", "(3)", "2.16", "(4)", "1.59", "(5)", "D", "A", "2.902", "(3)", "2.884", "(3)", "2.851", "(3)", "2.606", "(3)", "D—H", "A", "174", "(3)", "178", "(3)", "144", "(3)", "163", "(4)", "Symmetry", "codes:", "(i)", "x", "þ", "1;", "y;", "z;", "(ii)", "x", "1;", "y;", "z;", "(iii)", "x;", "y", "þ", "12;", "z", "þ", "1.", "Data", "collection:", "SMART", "(Bruker,", "1998);", "cell", "refinement:", "SAINT-", "Plus", "(Bruker,", "2001);", "data", "reduction:", "SAINT-Plus;", "program(s)", "used", "to", "solve", "structure:", "SHELXS97", "(Sheldrick,", "2008);", "program(s)", "used", "to", "refine", "structure:", "SHELXTL", "(Bruker,", "2000);", "molecular", "graphics:", "SHELXTL;", "software", "used", "to", "prepare", "material", "for", "publication:", "SHELXTL.", "The", "purchase", "of", "the", "diffractometer", "was", "made", "possible", "through", "support", "from", "the", "Research", "Council", "of", "Norway", "(NFR).", "Supplementary", "data", "and", "figures", "for", "this", "paper", "are", "available", "from", "the", "IUCr", "electronic", "archives", "(Reference:", "PV2058).", "References", "Allen,", "F.", "H.", "(2002).", "Acta", "Cryst.", "B58,", "380–388.", "Bruker", "(1998).", "SMART.", "Version", "5.054.", "Bruker", "AXS", "Inc.,", "Madison,", "Wisconsin,", "USA.", "Bruker", "(2000).", "SHELXTL.", "Version", "6.10.", "Bruker", "AXS", "Inc.,", "Madison,", "Wisconsin,", "USA.", "Bruker", "(2001).", "SAINT-Plus.", "Version", "6.22.", "Bruker", "AXS", "Inc.,", "Madison,", "Wisconsin,", "USA.", "Go¨", "rbitz,", "C.", "H.", "(1987).", "Acta", "Chem.", "Scand.", "B,", "41,", "83–86.", "Go¨", "rbitz,", "C.", "H.", "&", "Hartviksen,", "L.", "M.", "(2006).", "Acta", "Cryst.", "E62,", "o2358–o2360.", "Go¨", "rbitz,", "C.", "H.", "&", "Hersleth,", "H.-P.", "(2000).", "Acta", "Cryst.", "B56,", "1094–1102.", "Grant,", "G.", "D.,", "Hunt,", "A.", "L.,", "Milne,", "P.", "J.,", "Roos,", "H.", "M.", "&", "Joubert,", "J.", "A.", "(1999).", "J.", "Chem.", "Crystallogr.", "29,", "435–447.", "Lin,", "C.-F.", "&", "Webb,", "L.", "E.", "(1973).", "J.", "Am.", "Chem.", "Soc.", "95,", "6803–6811.", "Luo,", "T.-J.", "M.", "&", "Palmore,", "G.", "T.", "R.", "(2002).", "Cryst.", "Growth", "Des.", "2,", "337–350.", "Morris,", "A.", "J.,", "Geddes,", "A.", "J.", "&", "Sheldrick,", "B.", "(1974).", "Cryst.", "Struct.", "Commun.", "3,", "345–349.", "Razak,", "I.", "A.,", "Shanmuga", "Sundara", "Raj,", "S.,", "Fun,", "H.-K.,", "Chen,", "Z.-F.,", "Zhang,", "J.,", "Xiong,", "R.-G.", "&", "You,", "X.-Z.", "(2000).", "Acta", "Cryst.", "C56,", "e341–e342.", "Sheldrick,", "G.", "M.", "(1996).", "SADABS.", "University", "of", "Go¨", "ttingen,", "Germany.", "Sheldrick,", "G.", "M.", "(2008).", "Acta", "Cryst.", "A64,", "112–122.", "Suguna,", "K.,", "Ramakumar,", "S.", "&", "Kopple,", "K.", "D.", "(1984).", "Acta", "Cryst.", "C40,", "2053–", "2056.", "o436", "G", "o¨rbitz", "and", "Hartviksen", "doi:10.1107/S1600536808000640", "Acta", "Cryst.", "(2008).", "E64,", "o436" ]

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[ "Merzenich", "et", "al:", "BMC", "Public", "Health", "2010,", "10:24", "http://www.biomedcentral.com/1471-2458/10/24", "D", "E", "B", "A", "T", "E", "Open", "Access", "DDebeatcereasing", "sperm", "quality:", "a", "global", "problem?", "Hiltrud", "Merzenich*,", "Hajo", "Zeeb", "and", "Maria", "Blettner", "Abstract", "Background:", "Carlsen", "and", "coworkers", "(1992)", "reviewed", "61", "heterogeneous", "observational", "studies", "on", "semen", "quality", "published", "between", "1938", "and", "1990.", "This", "review", "indicates", "that", "mean", "sperm", "density", "decreased", "significantly", "between", "1940", "and", "1990.", "An", "extended", "meta-analysis", "with", "101", "studies", "confirmed", "a", "decline", "in", "sperm", "density", "for", "the", "period", "from", "1934", "to", "1996", "(2000).", "The", "key", "message", "of", "the", "meta-analyses", "is", "that", "sperm", "counts", "have", "decreased", "globally", "by", "about", "50%", "over", "the", "past", "decades.", "This", "assessment", "has", "been", "questioned.", "Discussion:", "A", "major", "methodological", "problem", "of", "the", "meta-analysis", "is", "the", "use", "of", "data", "collected", "in", "different", "countries,", "at", "different", "times,", "on", "different", "populations", "and", "with", "different", "methods", "of", "semen", "analysis.", "Furthermore,", "the", "results", "of", "studies", "concerning", "semen", "analysis", "are", "frequently", "biased", "e.g.", "by", "selection", "criteria", "of", "volunteers.", "In", "most", "studies", "on", "human", "semen", "characteristics", "the", "populations", "under", "study", "are", "insufficiently", "defined", "and", "the", "study", "participants", "are", "not", "a", "representative", "population", "sample.", "The", "incidence", "of", "testicular", "cancer", "has", "increased", "in", "Caucasian", "men", "worldwide.", "The", "investigation", "of", "common", "risk", "factors", "for", "male", "reproductive", "disorders", "requires", "well", "designed", "epidemiological", "studies", "and", "the", "collection", "of", "individual", "data.", "Summary:", "Former", "meta-analyses", "of", "sperm", "count", "data", "show", "a", "global", "downward", "trend.", "This", "conclusion", "should", "be", "interpreted", "with", "caution.", "The", "included", "studies", "are", "of", "great", "heterogeneity", "due", "to", "geographical", "and/or", "ethnical", "variation,", "different", "study", "designs", "and", "different", "methodological", "standards.", "Population-based", "prospective", "studies", "are", "needed", "to", "investigate", "secular", "trends", "in", "male", "reproductive", "disorders.", "Background", "Analyses", "of", "sperm", "count", "data", "suggest", "a", "global", "downward", "trend", "but", "the", "results", "are", "inconclusive.", "An", "increase", "in", "male", "reproductive", "disorders", "like", "cryptorchidism", "and", "tes-", "ticular", "cancer", "raise", "the", "question", "of", "common", "risk", "factors.", "Data", "on", "testicular", "cancer", "trends", "are", "usually", "based", "on", "population-based", "cancer", "registries", "with", "good", "validity.", "The", "corresponding", "data", "from", "fertility", "studies", "need", "care-", "ful", "consideration", "in", "terms", "of", "methods", "and", "results.", "Carlsen", "et", "al.", "[1]", "reviewed", "studies", "on", "human", "sperm", "quality.", "Publications", "were", "excluded", "if", "they", "included", "men", "from", "infertile", "couples", "or", "those", "referred", "for", "oligozoo-", "spermia", "or", "some", "genital", "abnormality.", "Furthermore,", "pub-", "lications", "were", "excluded", "if", "they", "included", "men", "selected", "for", "either", "high", "or", "low", "sperm", "count", "and", "if", "counting", "of", "sperm", "cells", "had", "been", "performed", "with", "non-manual", "methods.", "A", "total", "of", "61", "studies", "has", "been", "included", "covering", "results", "published", "between", "1938", "and", "1990", "without", "any", "geograph-", "ical", "restriction.", "The", "data", "were", "analyzed", "by", "linear", "regres-", "*", "Correspondence:", "merzenich@imbei.uni-mainz.de", "1Institute", "of", "Medical", "Biostatistics,", "Epidemiology", "and", "Informatics,", "University", "Medical", "Center", "of", "the", "Johannes", "Gutenberg", "University,", "Mainz", "sion", "in", "which", "the", "weight", "of", "each", "study", "was", "dependent", "on", "the", "number", "of", "men", "included", "in", "the", "study.", "The", "results", "of", "this", "meta-analysis", "indicate", "that", "mean", "sperm", "density", "decreased", "from", "113", "×", "106/ml", "in", "1940", "to", "66", "×", "106/ml", "in", "1990,", "and", "seminal", "volume", "decreased", "from", "3.40", "ml", "to", "2.75", "ml", "during", "the", "same", "period.", "These", "results", "caused", "consid-", "erable", "attention.", "Swan", "et", "al.", "[2]", "excluded", "from", "Carlsens'", "meta-analysis", 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[ "Advance", "Publication", "Acta", "Histochem.", "Cytochem.", "40", "(2):", "61–67,", "2007", "doi:10.1267/ahc.07008", "J01TRAa03oecHp.4kgt1aaC47yu2n-0olH65aS7,7r98io0Js/90Aatc0o10phi8recacttihn.yc0el7meo0fi0cH8aisetoCchyetomcihsetrmyiacnad", "Cytochemistry", "Promoting", "Effects", "of", "Milk", "on", "the", "Development", "of", "7,12-dimethylbenz(a)anthracene", "(DMBA)-induced", "Mammary", "Tumors", "in", "Rats", "De-Fu", "Ma1,2,", "Ryohei", "Katoh2,", "Hong", "Zhou1", "and", "Pei-Yu", "Wang1", "1Department", "of", "Social", "Medicine", "&", "Health", "Education,", "School", "of", "Public", "Health,", "Peking", "University,", "Beijing,", "100083,", "China", "and", "2Department", "of", "Human", "Pathology,", "University", "of", "Yamanashi", "Interdisciplinary", "Graduate", "School", "of", "Medicine", "and", "Engineering,", "Yamanashi", "409–3898,", "Japan", "00", "Received", "February", "19,", "2007;", "accepted", "March", "20,", "2007;", "published", "online", "May", "10,", "2007", "CopyrTigoht", "a©ss2e00s7s", "AtHheC", "effect", "of", "milk", "on", "the", "development", "of", "7,12-dimethylbenz(a)anthracene", "(DMBA)-induced", "mammary", "tumors,", "48", "female", "Sprague-Dawley", "rats", "treated", "with", "DMBA", "were", "divided", "into", "3", "groups", "and", "given", "1", "of", "3", "test", "solutions", "for", "20", "weeks", "as", "their", "drinking", "liquid:", "milk,", "estrone", "sulfate", "solution", "or", "tap", "water.", "The", "milk", "group", "showed", "a", "significantly", "great", "incidence", "(75%)", "in", "tumor", "development", "compared", "with", "the", "water", "group", "(38%)", "and", "was", "com-", "parable", "to", "the", "estrone", "sulfate", "group", "(69%).", "Mean", "tumor", "number", "per", "rat", "in", "the", "milk", "group", "was", "significantly", "higher", "than", "that", "in", "the", "water", "group", "(p=0.009).", "We", "classified", "the", "mammary", "tumors", "into", "three", "histological", "types:", "intraductal", "papilloma,", "fibroadenoma,", "and", "adenocarci-", "noma.", "Although", "the", "percent", "of", "intraductal", "papilloma", "and", "fibroadenoma", "was", "almost", "same", "among", "the", "three", "groups,", "malignant", "tumor", "was", "found", "only", "in", "the", "milk", "and", "estrone", "sulfate", "groups.", "In", "conclusion,", "our", "results", "indicate", "that", "milk", "as", "well", "as", "estrone", "sulfate", "promotes", "the", "development", "of", "DMBA-induced", "mammary", "tumors", "in", "rat", "and", "could", "be", "associated", "with", "the", "occurrence", "of", "adenocarcinoma.", "Key", "words:", "mammary", "tumor,", "milk,", "smooth", "muscle", "actin,", "proliferating", "cell", "nuclear", "antigen,", "estrogen", "receptor", "I.", "Introduction", "Breast", "cancer", "is", "the", "most", "common", "malignant", "neoplasm,", "and", "is", "the", "number", "one", "cause", "of", "cancer-related", "deaths", "in", "nonsmoking", "women", "[3].", "The", "incidence", "of", "breast", "cancer", "has", "been", "increasing", "in", "both", "developed", "and", "developing", "countries", "[4].", "Although", "epidemiological", "studies", "have", "identified", "vari-", "ous", "risk", "factors,", "including", "obesity,", "menarche", "at", "young", "age,", "and", "late", "menopause,", "these", "known", "risk", "factors", "seem", "to", "ac-", "count", "for", "only", "a", "third", "of", "the", "breast", "cancer", "cases", "[10,", "23].", "Recently,", "an", "epidemiological", "analysis", "revealed", "that", "the", "in-", "cidence", "of", "breast", "cancer", "in", "42", "countries", "is", "highly", "correlated", "(r=0.79)", "with", "the", "consumption", "of", "milk", "and", "dairy", "products", "Correspondence", "to:", "Ryohei", "Katoh,", "Department", "of", "Human", "Pathology,", "University", "of", "Yamanashi", "Interdisciplinary", "Graduate", "School", "of", "Medicine", "and", "Engineering,", "1110", "Shimokato,", "Chuo,", "Yamanashi", "409–3898,", "Japan.", "E-mail:", "rkatoh@yamanashi.ac.jp", "Pei-Yu", "Wang,", "Department", "of", "Social", "Medicine", "&", "Health", "Education,", "School", "of", "Public", "Health,", "Peking", "University,", "Beijing,", "100083,", "China.", "E-mail:", "wpeiyu@bjmu.edu.cn", "[22].", "The", "positive", "association", "between", "milk", "and", "breast", "can-", "cer", "has", "been", "proved", "by", "some", "case-control", "studies", "and", "cohort", "studies", "[18,", "26].", "Recently,", "Qin", "et", "al.", "reported", "that", "low-fat", "milk", "pro-", "moted", "the", "development", "of", "7,12-dimethylbenz(a)anthracene", "(DMBA)-induced", "mammary", "tumors", "in", "rats", "[17].", "But", "they", "did", "not", "thoroughly", "observe", "their", "natural", "history", "and", "mor-", "phology,", "or", "perform", "pathological", "classification", "for", "experi-", "mental", "tumors", "to", "assess", "the", "effects", "of", "milk", "on", "morphology", "and", "pathology", "of", "tumors.", "It", "is", "possible", "to", "evaluate", "tumori-", "genic", "response", "by", "palpable", "tumors,", "but", "the", "true", "nature", "of", "palpable", "lesions", "can", "be", "determined", "only", "through", "histo-", "logical", "examination", "[21].", "Moreover,", "the", "classification", "of", "tumors", "is", "very", "useful", "for", "the", "further", "interpretation", "of", "ex-", "perimental", "data", "[21].", "In", "the", "present", "study,", "we", "performed", "haematoxylin-eosin", "staining", "(HE)", "and", "carefully", "implement-", "ed", "pathological", "classification", "for", "all", "experimental", "tumors.", "Since", "the", "presence", "of", "myoepithelial", "cells", "is", "commonly", "regarded", "as", "the", "hallmark", "of", "benignity", "for", "human", "tumors", "[2,", "14]", "and", "proliferating", "cell", "nuclear", "antigen", "(PCNA)", "is", "sensi-", "©", "2007", "The", "Japan", "Society", "of", "Histochemistry", "and", "Cytochemistry" ]

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[ "BMC", "Research", "Notes", "Short", "Report", "Epiblast-specific", "Snai1", "deletion", "results", "in", "embryonic", "lethality", "due", "to", "multiple", "vascular", "defects", "Hilda", "Lomelí1,", "Christa", "Starling2", "and", "Thomas", "Gridley*2", "BioMed", "Central", "Open", "Access", "Address:", "1Departamento", "de", "Genética", "del", "Desarrollo", "y", "Fisiología", "Molecular,", "Instituto", "de", "Biotecnología,", "Universidad", "Nacional", "Autónoma", "de", "México,", "Cuernavaca,", "Morelos,", "México", "and", "2The", "Jackson", "Laboratory,", "Bar", "Harbor,", "ME", "04609,", "USA", "Email:", "Hilda", "Lomelí", "-", "hilda@ibt.unam.mx;", "Christa", "Starling", "-", "christa.starling@jax.org;", "Thomas", "Gridley*", "-", "tom.gridley@jax.org", "*", "Corresponding", "author", "Published:", "6", "February", "2009", "BMC", "Research", "Notes", "2009,", "2:22", "doi:10.1186/1756-0500-2-22", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1756-0500/2/22", "Received:", "6", "December", "2008", "Accepted:", "6", "February", "2009", "©", "2009", "Gridley", "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:", "Members", "of", "the", "Snail", "gene", "family,", "which", "encode", "zinc", "finger", "proteins", "that", "function", "as", "transcriptional", "repressors,", "play", "essential", "roles", "during", "embryonic", "development", "in", "vertebrates.", "Mouse", "embryos", "with", "conditional", "deletion", "of", "the", "Snail1", "(Snai1)", "gene", "in", "the", "epiblast,", "but", "not", "in", "most", "extraembryonic", "membranes,", "exhibit", "defects", "in", "left-right", "asymmetry", "specification", "and", "migration", "of", "mesoderm", "cells", "through", "the", "posterior", "primitive", "streak.", "Here", "we", "describe", "phenotypic", "defects", "that", "result", "in", "death", "of", "the", "mutant", "embryos", "by", "9.5", "days", "of", "gestation.", "Findings:", "Endothelial", "cells", "differentiated", "in", "epiblast-specific", "Snai1-deficient", "embryos,", "but", "formation", "of", "an", "interconnected", "vascular", "network", "was", "abnormal.", "To", "determine", "whether", "the", "observed", "vascular", "defects", "were", "dependent", "on", "disruption", "of", "blood", "flow,", "we", "analyzed", "vascular", "remodeling", "in", "cultured", "allantois", "explants", "from", "the", "mutant", "embryos.", "Similar", "vascular", "defects", "were", "observed", "in", "the", "mutant", "allantois", "explants.", "Conclusion:", "These", "studies", "demonstrate", "that", "lethality", "in", "the", "Snai1-conditional", "mutant", "embryos", "is", "caused", "by", "multiple", "defects", "in", "the", "cardiovascular", "system.", "Background", "In", "mammals,", "there", "are", "three", "Snail", "family", "genes:", "Snai1", "(formerly", "Snail),", "Snai2", "(formerly", "Slug),", "and", "Snai3", "(reviewed", "in", "[1,2]).", "We", "have", "shown", "that", "mouse", "embryos", "homozygous", "for", "a", "Snai1", "null", "mutation", "(Snai1-/-", "embryos)", "exhibit", "defects", "in", "mesoderm", "formation", "and", "die", "shortly", "after", "embryonic", "day", "(E)", "7.5", "[3],", "likely", "due", "to", "defects", "in", "the", "extraembryonic", "membranes.", "In", "contrast,", "mouse", "embryos", "(Meox2-Cre;", "Snai1flox/-", "embryos)", "with", "deletion", "of", "the", "Snai1", "gene", "specifically", "in", "the", "epiblast", "(i.e.,", "the", "embryo", "proper", "plus", "extraembryonic", "mesoderm)", "survive", "past", "the", "period", "of", "lethality", "at", "E7.5.", "These", "embryos", "exhibit", "defects", "in", "left-", "right", "asymmetry", "specification", "and", "delayed", "progression", "of", "mesoderm", "cells", "through", "the", "posterior", "primitive", "streak", "[4].", "Here", "we", "describe", "phenotypic", "defects", "in", "Meox2-Cre;", "Snai1flox/-", "(hereafter", "designated", "Snai1-cko)", "embryos", "that", "result", "in", "death", "of", "the", "mutant", "embryos", "by", "approximately", "E9-E10.", "Methods", "Mice", "The", "targeted", "null", "allele", "of", "the", "Snai1", "gene", "[3]", "and", "the", "Snai1flox", "conditional", "allele", "[5]", "have", "been", "described.", "Snail1flox/flox", "mice", "were", "maintained", "as", "homozygotes.", "Meox2-Cre", "mice", "[6]", "were", "obtained", "from", "the", "Jackson", "Labo-", "ratory.", "For", "the", "experiments", "described", "here,", "male", "mice", "het-", "erozygous", "for", "both", "the", "Meox2-Cre", "allele", "and", "the", "Snai1", "null", "allele", "(Snai1+/-)", "were", "crossed", "to", "Snai1flox/flox", "females,", "and", "Page", "1", "of", "6", "(page", "number", "not", "for", "citation", "purposes)" ]

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[ "Hindawi", "Publishing", "Corporation", "Clinical", "and", "Developmental", "Immunology", "Volume", "2011,", "Article", "ID", "439752,", "7", "pages", "doi:10.1155/2011/439752", "Review", "Article", "The", "Confluence", "of", "Stereotactic", "Ablative", "Radiotherapy", "and", "Tumor", "Immunology", "Steven", "Eric", "Finkelstein,1", "Robert", "Timmerman,2", "William", "H.", "McBride,3", "Do¨rthe", "Schaue,3", "Sarah", "E.", "Hoffe,4", "Constantine", "A.", "Mantz,1", "and", "George", "D.", "Wilson5", "1", "21st", "Century", "Oncology", "Translational", "Research", "Consortium,", "Scottsdale,", "AZ", "85251,", "USA", "2", "Department", "of", "Radiation", "Oncology", "and", "Neurologic", "Surgery,", "University", "of", "Texas", "Southwestern", "Medical", "Center,", "Dallas,", "TX", "75391,", "USA", "3", "Department", "of", "Radiation", "Oncology,", "David", "Geffen", "School", "of", "Medicine", "at", "UCLA,", "Los", "Angeles,", "CA", "90095,", "USA", "4", "Department", "of", "Radiation", "Oncology,", "Moffitt", "International,", "Tampa,", "FL", "33612,", "USA", "5", "Division", "of", "Radiation", "Biology,", "William", "Beaumont", "Hospital,", "Royal", "Oak,", "MI", "48073,", "USA", "Correspondence", "should", "be", "addressed", "to", "Steven", "Eric", "Finkelstein,", "sfinkels@rtsx.com", "Received", "25", "August", "2011;", "Accepted", "5", "September", "2011", "Academic", "Editor:", "Luca", "Gattinoni", "Copyright", "©", "2011", "Steven", "Eric", "Finkelstein", "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.", "Stereotactic", "radiation", "approaches", "are", "gaining", "more", "popularity", "for", "the", "treatment", "of", "intracranial", "as", "well", "as", "extracranial", "tumors", "in", "organs", "such", "as", "the", "liver", "and", "lung.", "Technology,", "rather", "than", "biology,", "is", "driving", "the", "rapid", "adoption", "of", "stereotactic", "body", "radiation", "therapy", "(SBRT),", "also", "known", "as", "stereotactic", "ablative", "radiotherapy", "(SABR),", "in", "the", "clinic", "due", "to", "advances", "in", "precise", "positioning", "and", "targeting.", "Dramatic", "improvements", "in", "tumor", "control", "have", "been", "demonstrated;", "however,", "our", "knowledge", "of", "normal", "tissue", "biology", "response", "mechanisms", "to", "large", "fraction", "sizes", "is", "lacking.", "Herein,", "we", "will", "discuss", "how", "SABR", "can", "induce", "cellular", "expression", "of", "MHC", "I,", "adhesion", "molecules,", "costimulatory", "molecules,", "heat", "shock", "proteins,", "inflammatory", "mediators,", "immunomodulatory", "cytokines,", "and", "death", "receptors", "to", "enhance", "antitumor", "immune", "responses.", "1.", "Introduction", "Stereotactic", "radiosurgery", "(SRS)", "was", "originally", "developed", "for", "the", "treatment", "of", "intracranial", "tumors", "and", "has", "demonstrated", "clinical", "effectiveness", "in", "treating", "a", "variety", "of", "benign", "and", "malignant", "conditions.", "Its", "extracranial", "counterpart,", "stereotac-", "tic", "body", "radiation", "therapy", "(SBRT),", "also", "known", "as", "stereotactic", "ablative", "radiotherapy", "(SABR),", "has", "more", "recently", "shown", "efficacy", "for", "the", "treatment", "of", "tumors", "in", "organs", "such", "as", "the", "liver", "and", "lung.", "The", "potential", "for", "using", "SABR", "is", "likely", "greater", "than", "for", "SRS", "given", "the", "larger", "volume", "of", "potential", "indications", "outside", "the", "central", "nervous", "system.", "Technology,", "rather", "than", "biology,", "is", "driving", "the", "rapid", "adoption", "of", "SABR", "in", "the", "clinic", "due", "to", "advances", "in", "precise", "positioning,", "motion", "control,", "dosimetry,", "and", "precise", "targeting", "with", "image", "guid-", "ance.", "Dramatic", "improvements", "in", "tumor", "control", "have", "been", "demonstrated", "in", "several", "studies", "due", "to", "the", "demonstration", "that", "very", "potent", "dose", "can", "be", "delivered", "by", "use", "of", "the", "mentioned", "technology.", "However,", "our", "knowledge", "of", "normal", "tissue", "biology", "response", "mechanisms", "to", "large", "fraction", "sizes", "is", "relatively", "lacking", "compared", "to", "conventional", "fractionation.", "2.", "Radiobiologic", "Considerations", "A", "fundamental", "issue", "in", "SABR", "is", "whether", "classical", "radiobi-", "ologic", "modeling", "with", "the", "linear-quadratic", "(LQ)", "model", "is", "a", "valid", "method", "to", "assess", "the", "biologically", "effective", "dose", "at", "the", "high", "doses", "typically", "encountered", "in", "radiosurgery.", "This", "point", "was", "debated", "in", "back-to-back", "papers", "in", "seminars", "in", "radiation", "oncology", "[1,", "2],", "where", "Brenner", "argued", "that", "LQ", "formalism", "was", "appropriate", "whilst", "Kirkpatrick", "and", "colleagues", "suggested", "it", "was", "inappropriate.", "Brenner’s", "argument", "is", "based", "on", "the", "robustness", "of", "the", "LQ", "model", "to", "predict", "fractionation", "and", "dose-rate", "effects", "in", "experimental", "models", "in", "vitro", "and", "in", "vivo", "at", "doses", "up", "to", "10", "Gy.", "This", "conclusion", "is", "based", "on", "the", "premise", "that", "cell", "killing", "is", "the", "dominant", "process", "mediating", "the", "radiotherapeutic", "response", "for", "both", "early", "and", "late", "effects", "including", "vascular", "effects.", "Brenner", "argued", "that,", "to", "date,", "there" ]

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[ "6116–6125", "Nucleic", "Acids", "Research,", "2006,", "Vol.", "34,", "No.", "21", "doi:10.1093/nar/gkl862", "Published", "online", "3", "November", "2006", "Role", "of", "metal", "ions", "in", "catalysis", "by", "HIV", "integrase", "analyzed", "using", "a", "quantitative", "PCR", "disintegration", "assay", "Tracy", "L.", "Diamond", "and", "Frederic", "D.", "Bushman*", "Department", "of", "Microbiology,", "University", "of", "Pennsylvania", "School", "of", "Medicine,", "3610", "Hamilton", "Walk", "Philadelphia,", "PA", "19104-6076,", "USA", "Received", "July", "27,", "2006;", "Revised", "September", "29,", "2006;", "Accepted", "October", "3,", "2006", "ABSTRACT", "Paired", "metal", "ions", "have", "been", "proposed", "to", "be", "central", "to", "the", "catalytic", "mechanisms", "of", "RNase", "H", "nucleases,", "bacterial", "transposases,", "Holliday", "junction", "resolvases,", "retroviral", "integrases", "and", "many", "other", "enzymes.", "Here", "we", "present", "a", "sensitive", "assay", "for", "DNA", "transesterifi-", "cation", "in", "which", "catalysis", "by", "human", "immunodefi-", "ciency", "virus-type", "1", "(HIV-1)", "integrase", "(IN)", "connects", "two", "DNA", "strands", "(disintegration", "reaction),", "allowing", "detection", "using", "quantitative", "PCR", "(qPCR).", "We", "present", "evidence", "suggesting", "that", "the", "three", "acidic", "residues", "of", "the", "IN", "active", "site", "function", "through", "metal", "binding", "using", "metal", "rescue.", "In", "this", "method,", "the", "catalytic", "acidic", "residues", "were", "each", "substituted", "with", "cys-", "teines.", "Mn21", "binds", "tightly", "to", "the", "sulfur", "atoms", "of", "the", "cysteine", "residues,", "but", "Mg21", "does", "not.", "We", "found", "that", "Mn21,", "but", "not", "Mg21,", "could", "rescue", "catalysis", "of", "each", "cysteine-substituted", "enzyme,", "providing", "evidence", "for", "functionally", "important", "metal", "binding", "by", "all", "three", "residues.", "We", "also", "used", "the", "PCR-boosted", "assay", "to", "show", "that", "HIV-1", "IN", "could", "carry", "out", "transesterification", "reactions", "involving", "DNA", "50", "hydroxyl", "groups", "as", "well", "as", "30", "hydroxyls", "as", "nucleophiles.", "Lastly,", "we", "show", "that", "Mn21", "by", "itself", "(i.e.", "without", "enzyme)", "can", "catalyze", "formation", "of", "a", "low", "level", "of", "PCR-amplifiable", "product", "under", "extreme", "conditions,", "allowing", "us", "to", "estimate", "the", "rate", "enhancement", "due", "to", "the", "IN-protein", "scaffold", "as", "at", "least", "60", "million-fold.", "INTRODUCTION", "Divalent", "metal", "ions", "are", "required", "for", "catalysis", "by", "many", "enzymes", "that", "carry", "out", "nucleic", "acid", "phosphoryl-transfer", "reac-", "tions.", "It", "has", "been", "proposed", "for", "many", "such", "enzymes", "that", "rate", "enhancement", "is", "mostly", "due", "to", "metal–nucleic", "acid", "interactions", "in", "the", "transition", "state,", "and", "the", "role", "of", "the", "protein", "scaffold", "is", "mainly", "to", "bind", "and", "position", "the", "metal", "ions", "and", "substrates", "(1,2).", "This", "may", "explain", "the", "ability", "of", "dissimilar", "metal", "binding", "protein", "and", "RNA", "enzymes", "to", "carry", "out", "related", "chemical", "reac-", "tions", "(3–5).", "The", "role", "of", "bound", "metals", "has", "been", "studied", "extensively", "for", "members", "of", "the", "ribonuclease", "H", "(RNase", "H)-like", "enzyme", "superfamily,", "which", "includes", "RuvC", "resolvase,", "bacterial", "and", "retroviral", "RNase", "Hs,", "bacterial", "transposases", "and", "retroviral", "integrases,", "all", "of", "which", "carry", "out", "polynucleotide", "phosphoryl-", "transferase", "reactions.", "These", "enzymes", "have", "similar", "secondary", "structures", "within", "their", "catalytic", "domains.", "The", "protein", "folds", "bring", "together", "three", "or", "four", "conserved", "acidic", "residues", "that", "are", "thought", "to", "be", "involved", "in", "metal", "coordination", "(4–7).", "These", "enzymes", "can", "utilize", "Mn2+", "and/or", "Mg2+", "for", "catalysis,", "though", "other", "metal", "ions", "can", "bind", "and", "for", "some", "enzymes", "support", "partial", "function", "(8–12).", "Three", "hypotheses", "for", "metal", "binding", "by", "RNase", "H-like", "enzymes", "have", "been", "proposed.", "Several", "RNase", "H", "enzyme", "structures", "determined", "by", "X-ray", "crystallography", "have", "been", "shown", "to", "contain", "two", "metal", "atoms", "bound", "at", "the", "active", "site", "(12–14),", "but", "the", "majority", "of", "structures", "have", "only", "one", "bound", "metal", "(9,15–19).", "The", "latter", "observation", "supports", "the", "second", "hypothesis", "that", "only", "one", "metal", "is", "involved", "catalytically", "(16,20,21).", "However,", "observation", "of", "a", "single", "bound", "metal", "in", "the", "absence", "of", "substrate", "could", "reflect", "the", "need", "for", "nucleic", "acid", "substrate", "binding", "to", "stabilize", "metal", "binding", "at", "the", "second", "site.", "As", "a", "third", "possibility,", "it", "has", "also", "been", "proposed", "that", "two", "metals", "bind,", "with", "the", "first", "activating", "catalysis", "and", "the", "second", "inhibiting", "(22).", "The", "human", "immunodeficiency", "virus", "(HIV)", "integrase", "(IN)", "is", "a", "member", "of", "the", "RNase", "H-like", "superfamily", "and", "has", "been", "extensively", "studied", "for", "metal", "binding", "at", "the", "D,DX35E", "motif", "(composed", "of", "D64,", "D116", "and", "E152).", "Several", "structural", "stud-", "ies", "of", "retroviral", "INs", "in", "the", "absence", "of", "DNA", "substrate", "have", "reported", "binding", "of", "a", "single", "Mg2+", "ion", "between", "the", "two", "aspar-", "tate", "residues", "(8,17,18),", "but", "none", "have", "shown", "Mg2+", "binding", "at", "the", "second", "site", "between", "residues", "D64", "and", "E152.", "Crystal", "structures", "of", "the", "avian", "sarcoma", "virus", "(ASV)", "IN", "in", "the", "pres-", "ence", "of", "Cd2+", "or", "Zn2+", "ions", "revealed", "two", "bound", "metals", "at", "the", "catalytic", "triad", "(8).", "However,", "these", "complexes", "did", "not", "retain", "normal", "catalytic", "activity,", "complicating", "interpretation.", "*To", "whom", "correspondence", "should", "be", "addressed.", "Tel:", "+1", "215", "573", "8732;", "Fax:", "+1", "215", "573", "4856;", "Email:", "bushman@mail.med.upenn.edu", "2006", "The", "Author(s).", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "Non-Commercial", "License", "(http://creativecommons.org/licenses/", "by-nc/2.0/uk/)", "which", "permits", "unrestricted", "non-commercial", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

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[ "Trophoblast", "Class", "I", "Major", "Histocompatibility", "Complex", "(MHC)", "Products", "Are", "Resistant", "to", "Rapid", "Degradation", "Imposed", "by", "the", "Human", "Cytomegalovirus", "(HCMV)", "Gene", "Products", "US2", "and", "US11", "By", "Danny", "J.", "Schust,*", "Domenico", "Tortorella,*", "Jörg", "Seebach,‡", "Cindy", "Phan,*", "and", "Hidde", "L.", "Ploegh*", "From", "the", "*Department", "of", "Pathology,", "Harvard", "Medical", "School,", "Boston,", "Massachusetts", "02115;", "and", "the", "‡Transplantation", "Biology", "Research", "Center,", "Massachusetts", "General", "Hospital,", "Boston,", "Massachusetts", "02119", "Summary", "US11", "and", "US2", "encode", "gene", "products", "expressed", "early", "in", "the", "replicative", "cycle", "of", "human", "cy-", "tomegalovirus", "(HCMV),", "which", "cause", "dislocation", "of", "human", "and", "murine", "major", "histocompatibil-", "ity", "complex", "(MHC)", "class", "I", "molecules", "from", "the", "lumen", "of", "the", "endoplasmic", "reticulum", "to", "the", "cy-", "tosol,", "where", "the", "class", "I", "heavy", "chains", "are", "rapidly", "degraded.", "Human", "histocompatibility", "leukocyte", "antigens", "(HLA)-C", "and", "HLA-G", "are", "uniquely", "resistant", "to", "the", "effects", "of", "both", "US11", "and", "US2", "in", "a", "human", "trophoblast", "cell", "line", "as", "well", "as", "in", "porcine", "endothelial", "cells", "stably", "transfected", "with", "human", "class", "I", "genes.", "Dislocation", "and", "degradation", "of", "MHC", "class", "I", "heavy", "chains", "do", "not", "appear", "to", "in-", "volve", "cell", "type–specific", "factors,", "as", "US11", "and", "US2", "are", "fully", "active", "in", "this", "xenogeneic", "model.", "Im-", "portantly,", "trophoblasts", "HLA-G", "and", "HLA-C", "possess", "unique", "characteristics", "that", "allow", "their", "es-", "cape", "from", "HCMV-associated", "MHC", "class", "I", "degradation.", "Trophoblast", "class", "I", "molecules", "could", "serve", "not", "only", "to", "block", "recognition", "by", "natural", "killer", "cells,", "but", "also", "to", "guide", "virus-specific", "HLA-C–", "and", "possibly", "HLA-G–restricted", "cytotoxic", "T-lymphocytes", "to", "their", "targets.", "Key", "words:", "trophoblast", "•", "cytomegalovirus", "•", "human", "•", "MHC", "class", "I", "•", "HLA-G", "Daurreingexhpuomsedan", "dpirreecgtnlyantcoy,", "malalotegrennailc", "imtrompuhnoeblaesftfeccetollrs", "cells.", "For", "many", "years,", "the", "absence", "of", "MHC-restricted", "re-", "jection", "of", "the", "implanting", "trophoblast", "was", "attributed", "to", "the", "lack", "of", "class", "I", "MHC", "expression", "on", "these", "cells.", "It", "is", "now", "clear", "that", "trophoblast", "cells", "express", "both", "classical", "(HLA-C;", "references", "1–4)", "and", "nonclassical", "(HLA-G;", "references", "5–9)", "class", "I", "products.", "To", "date,", "the", "function", "of", "these", "molecules", "and", "their", "involvement", "in", "creating", "an", "immunologically", "privileged", "site", "at", "the", "maternal–fetal", "interface", "remains", "elu-", "sive.", "Sequence", "similarity", "of", "HLA-G", "to", "HLA-A", "and", "-B", "molecules", "suggests", "that", "HLA-G", "(7)", "may", "function", "in", "a", "man-", "ner", "analogous", "to", "its", "classical", "counterparts:", "HLA-G", "may", "have", "a", "role", "in", "antigen", "presentation", "(10–12)", "and/or", "in", "evad-", "ing", "NK", "cell–mediated", "lysis", "(13,", "14),", "although", "the", "existence", "of", "HLA-G–restricted", "T", "cells", "in", "vivo", "remains", "to", "be", "estab-", "lished.", "Trophoblast", "HLA-C", "locus", "products", "might", "have", "a", "complementary", "or", "overlapping", "purpose.", "However,", "the", "unique", "and", "limited", "localization", "of", "HLA-G", "(15–18),", "its", "re-", "stricted", "polymorphism", "(19–23),", "and", "the", "known", "reduced", "surface", "stability", "of", "HLA-C", "locus", "products", "(24–27)", "suggest", "that", "human", "trophoblast", "MHC", "class", "I", "molecules", "may", "possess", "attributes", "that", "allow", "a", "unique", "function", "at", "the", "maternal–fetal", "interface.", "Human", "cytomegalovirus", "(HCMV)1", "is", "a", "common", "human", "pathogen", "that", "typically", "causes", "morbidity", "only", "in", "the", "immu-", "nocompromised", "host", "or", "when", "infection", "occurs", "during", "pregnancy.", "HCMV", "infects", "trophoblast", "(28),", "it", "is", "a", "known", "teratogen,", "and", "HCMV", "infection", "during", "pregnancy", "has", "been", "linked", "to", "spontaneous", "pregnancy", "loss", "(29,", "30).", "HCMV", "has", "proven", "interesting", "from", "an", "immunologic", "viewpoint,", "as", "the", "virus", "has", "developed", "a", "number", "of", "strategies", "that", "enable", "it", "to", "evade", "immune", "detection", "(31,", "32).", "Of", "interest", "for", "this", "re-", "port,", "HCMV-infected", "cells", "synthesize", "two", "gene", "products", "early", "in", "the", "HCMV", "infectious", "cycle,", "US2", "and", "US11,", "which", "cause", "the", "dislocation", "of", "newly", "synthesized", "class", "I", "heavy", "chain", "from", "the", "endoplasmic", "reticulum", "(ER)", "to", "the", "cytosol.", "Cytosolic", "class", "I", "heavy", "chains", "are", "deglycosylated", "by", "1Abbreviations", "used", "in", "this", "paper:", "CM,", "complete", "medium;", "ER,", "endoplasmic", "reticulum;", "HCMV,", "human", "cytomegalovirus;", "MOI,", "multiplicity", "of", "infec-", "tion.", "497", "J.", "Exp.", "Med.", "The", "Rockefeller", "University", "Press", "•", "0022-1007/98/08/497/07", "$2.00", "Volume", "188,", "Number", "3,", "August", "3,", "1998", "497–503", "http://www.jem.org" ]

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[ "The", "Open", "Rheumatology", "Journal,", "2008,", "2,", "33-37", "33", "Open", "Access", "Cigarette", "Smoking,", "Birthweight", "and", "Osteoporosis", "in", "Adulthood:", "Results", "from", "the", "Hertfordshire", "Cohort", "Study", "M.M.", "Moinuddin,", "K.A.", "Jameson,", "H.E.", "Syddall,", "A.", "Aihie", "Sayer,", "H.J.", "Martin,", "S.", "Robinson,", "C.", "Cooper", "and", "E.M.", "Dennison*", "MRC", "Resource", "Centre,", "University", "of", "Southampton,", "Southampton", "General", "Hospital,", "Southampton", "SO16", "6YD,", "UK", "Abstract:", "We", "looked", "for", "interaction", "between", "early", "environment", "and", "adult", "lifestyle", "in", "determination", "of", "bone", "mineral", "con-", "tent", "(BMC)", "and", "bone", "mineral", "density", "(BMD)", "among", "498", "men", "and", "468", "women", "for", "whom", "birth", "records", "were", "available.", "Participants", "completed", "a", "health", "questionnaire,", "and", "bone", "densitometry", "(DXA)", "of", "the", "lumbar", "spine", "and", "femoral", "neck", "per-", "formed.", "We", "found", "no", "relationships", "between", "cigarette", "and", "alcohol", "consumption,", "physical", "activity", "and", "either", "BMC", "or", "BMD", "after", "adjustment", "for", "age,", "body", "mass", "index,", "dietary", "calcium,", "social", "class,", "HRT", "use", "and", "years", "since", "menopause.", "However,", "male", "current", "smokers", "in", "the", "lowest", "third", "of", "birth", "weight", "had", "lower", "femoral", "neck", "BMD", "than", "ex-", "or", "never", "smokers", "from", "the", "low-", "est", "birth", "weight", "third", "(p", "value", "for", "interaction", "term", "=", "0.04).", "Similar", "trends", "were", "seen", "with", "femoral", "neck", "BMC", "and", "lumber", "spine", "BMC.", "Individuals", "of", "lower", "birth", "weight", "may", "be", "particularly", "vulnerable", "to", "the", "effects", "of", "bone", "noxious", "stimuli", "such", "as", "cigarette", "smoking.", "INTRODUCTION", "Epidemiological", "studies", "have", "shown", "that", "individuals", "of", "low", "birthweight", "may", "be", "at", "increased", "risk", "of", "osteoporosis", "in", "adult", "life", "[1-6].", "Lifestyle", "factors", "in", "adulthood", "also", "affect", "bone", "mineral", "content", "(BMC)", "and", "bone", "mineral", "density", "(BMD)", "although", "the", "extent", "of", "this", "influence", "may", "vary", "be-", "tween", "individuals;", "previous", "studies", "have", "suggested", "that", "the", "early", "environment", "may", "interact", "with", "adult", "lifestyle", "to", "deter-", "mine", "risk", "factors", "for", "common", "diseases.", "In", "one", "recent", "study", "by", "Robinson", "et", "al.", "individuals", "of", "low", "birth", "weight", "were", "par-", "ticularly", "susceptible", "to", "the", "effect", "of", "high", "dietary", "fat", "intakes", "when", "blood", "cholesterol", "levels", "were", "measured", "[7].", "To", "inves-", "tigate", "whether", "a", "similar", "interaction", "might", "operate", "between", "later", "lifestyle", "factors", "and", "growth", "in", "early", "life", "to", "determine", "the", "risk", "of", "adult", "osteoporosis,", "we", "examined", "the", "relationships", "between", "birth", "weight,", "lifestyle", "factors", "and", "adult", "BMD", "and", "BMC", "in", "a", "cohort", "of", "men", "and", "women", "from", "Hertfordshire,", "UK.", "MATERIALS", "AND", "METHODS", "Four", "hundred", "and", "ninety", "eight", "men", "and", "468", "women", "aged", "59-71", "years", "were", "recruited", "to", "this", "study,", "which", "was", "designed", "to", "examine", "the", "relationship", "between", "growth", "in", "infancy", "and", "the", "subsequent", "risk", "of", "osteoporosis.", "The", "selection", "procedure", "for", "these", "individuals", "was", "as", "follows:", "in", "brief,", "with", "the", "help", "of", "the", "National", "Health", "Service", "Central", "Registry", "at", "Southport,", "and", "Hertfordshire", "Family", "Health", "Service", "Association,", "we", "traced", "men", "and", "women", "who", "were", "born", "during", "1931-39", "in", "Hertfordshire,", "and", "still", "lived", "there", "during", "the", "period", "1998-", "*Address", "correspondence", "to", "this", "author", "at", "the", "MRC", "Resource", "Centre,", "Uni-", "versity", "of", "Southampton,", "Southampton", "General", "Hospital,", "Southampton", "SO16", "6YD,", "UK;", "Tel:", "+44", "(0)23", "8077", "7624;", "Fax:", "+44", "(0)23", "8070", "4021;", "E-mail:", "emd@mrc.soton.ac.uk", "2003.", "After", "obtaining", "written", "permission", "from", "each", "subject’s", "General", "Practitioner,", "we", "approached", "each", "person", "by", "letter,", "to", "ask", "them", "if", "they", "would", "be", "willing", "to", "be", "contacted", "by", "one", "of", "our", "research", "nurses.", "If", "they", "agreed,", "a", "research", "nurse", "per-", "formed", "a", "home", "visit,", "where", "they", "administered", "a", "structured", "questionnaire.", "This", "included", "information", "on", "socioeconomic", "status,", "medical", "history,", "cigarette", "smoking,", "alcohol", "consump-", "tion", "and", "dietary", "calcium", "intake.", "Physical", "activity", "was", "as-", "sessed", "by", "a", "previously", "validated", "questionnaire", "[8].", "The", "sub-", "ject", "was", "then", "invited", "to", "attend", "a", "local", "clinic.", "Height", "was", "measured", "to", "the", "nearest", "0.1cm", "using", "a", "Har-", "penden", "pocket", "stadiometer", "(Chasmors", "Ltd.,", "London,", "UK)", "and", "weight", "to", "the", "nearest", "0.1kg", "on", "a", "SECA", "floor", "scale", "(Chasmors", "Ltd.,", "London,", "UK).", "Body", "mass", "index", "(BMI)", "was", "calculated", "as", "weight", "divided", "by", "height", "2", "(kg/m2).", "Bone", "mineral", "density", "and", "bone", "mineral", "content", "were", "measured", "in", "each", "subject,", "by", "dual", "energy", "X-ray", "absorptiome-", "try", "at", "the", "lumbar", "spine", "and", "proximal", "femur", "(neck,", "total,", "in-", "tertrochanteric", "and", "trochanteric", "regions,", "Wards", "triangle)", "us-", "ing", "a", "Hologic", "QDR", "4500", "instrument.", "Measurement", "precision", "error,", "expressed", "as", "coefficient", "of", "variation,", "was", "1.55%", "for", "lumbar", "spine", "BMD,", "1.45%", "for", "total", "femur", "and", "1.83%", "for", "femoral", "neck", "BMD", "for", "the", "Hologic", "QDR", "4500;", "these", "figures", "were", "obtained", "by", "twenty", "five", "volunteers", "who", "were", "not", "part", "of", "the", "study", "undergoing", "two", "scans", "on", "the", "same", "day,", "getting", "on", "and", "off", "the", "table", "between", "examinations.", "Short-term", "(two", "month)", "precision", "error", "for", "the", "QDR", "4500", "was", "less", "than", "1%", "for", "both", "sites", "(manufacturers", "figures).", "Individuals", "taking", "drugs", "known", "to", "alter", "bone", "metabolism", "(such", "as", "bisphospho-", "nates)", "were", "excluded", "from", "this", "part", "of", "the", "study,", "although", "women", "taking", "hormone", "replacement", "therapy", "(HRT)", "were", "allowed", "to", "participate,", "due", "to", "the", "large", "numbers", "of", "women", "taking", "this", "medication", "(with", "appropriate", "adjustment", "in", "all", "analyses).", "There", "were", "no", "other", "exclusion", "criteria", "to", "this", "part", "1874-3129/08", "2008", "Bentham", "Open" ]

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"Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Uterine", "prolapse", "is", "a", "condition", "that", "has", "likely", "affected", "women", "for", "all", "of", "time", "as", "it", "is", "documented", "in", "the", "oldest", "medical", "literature.", "By", "looking", "at", "the", "watershed", "moments", "in", "its", "recorded", "history", "we", "are", "able", "to", "appreciate", "the", "evolution", "of", "urogynecology", "and", "to", "gain", "perspective", "on", "the", "challenges", "faced", "by", "today’s", "female", "pelvic", "medicine", "and", "reconstructive", "surgeons", "in", "their", "attempts", "to", "treat", "uterine", "and", "vaginal", "vault", "prolapse.", "“He", "who", "cannot", "render", "an", "account", "to", "himself", "of", "at", "least", "three", "thousand", "years", "of", "time,", "will", "always", "grope", "in", 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[ "Journal", "of", "Multidisciplinary", "Healthcare", "Open", "Access", "Full", "Text", "Article", "Let’s", "move", "our", "next", "generation", "of", "patients", "toward", "healthy", "behaviors", "Dovepress", "open", "access", "to", "scientific", "and", "medical", "research", "P", "E", "R", "S", "P", "E", "C", "T", "I", "v", "E", "S", "Phyllis", "A", "Nsiah-Kumi1,2", "Lydia", "Y", "Kang1", "Jennifer", "R", "Parker1,2", "1General", "Internal", "Medicine,", "2Internal", "Medicine-Pediatrics", "Program,", "University", "of", "Nebraska", "Medical", "Center,", "Omaha,", "NE,", "USA", "Correspondence:", "Phyllis", "A", "Nsiah-Kumi", "Internal", "Medicine-Pediatrics,", "University", "of", "Nebraska", "Medical", "Center,", "984085", "Nebraska", "Medical", "Center,", "Omaha,", "NE", "68198-4085,", "USA", "Tel", "+1", "402", "559", "6946", "Fax", "+1", "402", "559", "6113", "Email", "pnkumi@unmc.edu", "submit", "your", "manuscript", "|", "www.dovepress.com", "Dovepress", "http://dx.doi.org/10.2147/JMDH.S23578", "Abstract:", "Health", "care", "professionals", "in", "all", "disciplines", "who", "care", "for", "adults", "have", "the", "opportunity", "to", "improve", "the", "health", "of", "the", "next", "generation.", "The", "prevalence", "of", "overweight", "and", "obesity", "continues", "to", "rise", "in", "children", "and", "adults", "around", "the", "world.", "As", "providers", "caring", "for", "adults,", "our", "primary", "goal", "is", "to", "address", "the", "health", "needs", "of", "our", "patients.", "However,", "it", "is", "important", "to", "recognize", "that", "counsel-", "ing", "our", "patients", "who", "have", "children", "can", "lead", "them", "to", "adopt", "model", "behaviors", "that", "will", "be", "imitated", "by", "their", "children", "(and", "therefore", "improve", "the", "weight", "status", "and", "reduce", "health", "risks", "for", "their", "children).", "Additionally,", "many", "patients", "are", "more", "motivated", "to", "adopt", "behavior", "changes", "for", "the", "sake", "of", "their", "children", "than", "for", "their", "own", "health.", "All", "of", "2012’s", "11-year-old", "children", "may", "be", "our", "adult", "patients", "in", "10", "years", "–", "especially", "if", "they", "have", "already", "developed", "weight-related", "health", "problems.", "Anything", "we", "do", "to", "address", "childhood", "obesity", "is", "an", "investment", "in", "the", "health", "of", "our", "patient", "panels,", "both", "now", "and", "in", "the", "future.", "While", "counseling", "may", "feel", "futile", "at", "times,", "there", "is", "strong", "evidence", "for", "the", "power", "of", "counseling", "to", "shape", "patient", "behavior.", "Counseling", "adult", "patients", "about", "healthy", "behaviors", "will", "benefit", "not", "only", "our", "patients", "today", "but", "our", "patients", "in", "the", "future", "as", "well.", "Keywords:", "obesity,", "counseling,", "provider,", "lifestyle", "change,", "parental", "modeling,", "self-efficacy", "Introduction", "On", "February", "9,", "2010,", "Michelle", "Obama,", "the", "First", "Lady", "of", "the", "United", "States,", "declared", "war", "on", "childhood", "obesity.", "The", "Let’s", "Move!", "Campaign", "is", "an", "ambitious", "national", "initia-", "tive", "to", "eliminate", "childhood", "obesity", "within", "a", "generation.", "While", "childhood", "obesity", "may", "seem", "like", "a", "pediatrician", "or", "primary", "care", "practitioner’s", "challenge,", "it", "is,", "in", "fact,", "a", "public", "health", "problem", "that", "providers", "caring", "for", "adults", "can", "tackle", "in", "their", "patient", "encounters", "as", "well.1", "In", "fact,", "several", "US", "organizations", "represent-", "ing", "the", "community", "of", "health", "care", "providers", "pledged", "their", "support", "to", "this", "initiative", "when", "it", "began", "two", "years", "ago.2–7", "The", "statistics", "are", "sobering", "with", "one", "in", "three", "adults", "and", "half", "of", "children", "in", "the", "US", "being", "overweight", "or", "obese,", "no", "matter", "the", "health", "care", "discipline,", "we", "have", "our", "work", "cut", "out", "for", "us.8,9", "In", "the", "US,", "up", "to", "50%", "of", "obese", "6", "year", "olds", "and", "80%", "of", "obese", "10–14", "year", "olds", "who", "have", "an", "obese", "parent", "will", "become", "obese", "young", "adults.10", "For", "young", "children", "with", "an", "obese", "parent,", "the", "risk", "of", "being", "obese", "as", "an", "adult", "is", "increased", "threefold.", "If", "both", "parents", "are", "obese,", "a", "child’s", "risk", "of", "obesity", "in", "adulthood", "is", "increased", "tenfold.", "Prepregnancy", "obesity", "and", "excess", "pregnancy", "weight", "gain", "are", "also", "associated", "with", "childhood", "obesity", "and", "obesity", "later", "in", "life.11", "Childhood", "obesity", "is", "an", "important", "risk", "factor", "for", "significant", "adult", "morbidity", "and", "premature", "mortality,", "and", "the", "importance", "of", "addressing", "it", "cannot", "be", "underestimated.12–14", "Journal", "of", "Multidisciplinary", "Healthcare", "2012:5", "115–119", "115", "©", "2012", "Nsiah-Kumi", "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." ]

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[ "Hepat", "Mon.", "2011;11(2):128-129", "Journal", "home", "page:", "www.HepatMon.ir", "KOWSAR", "Occult", "hepatitis", "B", "infection", "in", "chronic", "hemodialysis", "patients:", "Comparison", "of", "results", "and", "concepts", "Amitis", "Ramezani", "1,", "Mohammad", "Banifazl", "2,", "Arezoo", "Aghakhani", "1*", "1", "Clinical", "Research", "Department,", "Pasteur", "Institute", "of", "Iran,", "Tehran,", "IR", "Iran", "2", "Iranian", "Society", "for", "Support", "Patients", "with", "Infectious", "Diseases,", "Tehran,", "IR", "Iran", "A", "R", "T", "I", "C", "L", "E", "I", "N", "F", "O", "Article", "Type:", "Letter", "to", "Editor", "Article", "history:", "Received:", "14", "Sep", "2010", "Revised:", "19", "Sep", "2010", "Accepted:", "21", "Dec", "2010", "Keywords:", "Occult", "hepatitia", "B", "infection", "Hemodialysis", "Dear", "Editor,", "We", "greatly", "enjoyed", "reading", "the", "excellent", "review", "by", "Hol-", "linger", "and", "colleagues", "on", "occult", "hepatitis", "B", "infection", "in", "chronic", "hemodialysis", "(HD)", "patients", "(1).", "As", "Hollinger", "et", "al.", "mentioned", "in", "their", "review,", "few", "studies", "have", "shown", "the", "prevalence", "of", "occult", "hepatitis", "B", "virus", "(HBV)", "infection", "in", "HD", "patients.", "Due", "to", "the", "parenteral", "transmission", "of", "HBV,", "HD", "pa-", "tients", "are", "at", "high", "risk", "of", "acquiring", "this", "virus", "because", "they", "need", "frequent", "blood", "transfusions", "and", "undergo", "medical", "procedures", "that", "accompany", "bleeding", "(2).", "The", "prevalence", "of", "occult", "HBV", "infection", "in", "these", "patients", "is", "between", "0", "to", "58%", "(3-5).", "The", "different", "frequencies", "of", "occult", "HBV", "infection", "in", "HD", "patients", "may", "be", "due", "to", "variation", "in", "the", "prevalence", "of", "HBV", "infection", "among", "countries,", "sensitivity", "of", "molecular", "tech-", "niques,", "and", "the", "size", "and", "virological", "features", "of", "the", "study", "groups.", "In", "one", "study,", "we", "determined", "the", "rate", "of", "occult", "HBV", "infection", "in", "Iranian", "HD", "patients", "with", "isolated", "hepatitis", "B", "core", "antibody", "(anti-HBc)", "(6).", "Of", "289", "patients", "enrolled", "in", "this", "study,", "18", "subjects", "had", "isolated", "anti-HBc", "and", "HBV-DNA", "was", "de-", "tected", "in", "50%", "of", "patients", "who", "had", "isolated", "anti-HBc.", "Plasma", "HBV-DNA", "load", "was", "less", "than", "50", "IU/ml", "in", "each", "patient.", "Our", "in-", "vestigation", "showed", "that", "occult", "HBV", "infection", "was", "common", "in", "HD", "patients", "with", "isolated", "anti-HBc", "regardless", "of", "age,", "sex,", "aminotransferases", "levels,", "or", "length", "of", "time", "on", "dialysis", "(6).", "Our", "data", "is", "in", "agreement", "with", "the", "results", "of", "hollinger", "et", "al.", "*", "Corresponding", "author", "at:", "Arezoo", "Aghakhani,", "Clinical", "Research", "Department,", "Pas-", "teur", "Institute", "of", "Iran,", "No", "69,", "Pasteur", "Ave.,", "Tehran,", "IR", "Iran.", "Tel:", "+98-2166465147,", "Fax:", "+98-2166465147.", "E-mail", "address:", "aaghakhani@pasteur.ac.ir,", "araghakhani@hotmail.com", "c", "2011", "Kowsar", "M.P.Co.", "All", "rights", "reserved.", "Please", "cite", "this", "paper", "as:", "Ramezani", "A,", "Banifazl", "M,", "Aghakhani", "A.", "Occult", "hepatitis", "B", "infection", "in", "chronic", "hemodialysis", "patients:", "Comparison", "of", "results", "and", "concepts.", "Hepat", "Mon.", "2011;11(2):128-129.", "c", "2011", "Kowsar", "M.P.Co.", "All", "rights", "reserved.", "(1)", "and", "suggests", "a", "relatively", "high", "prevalence", "of", "occult", "HBV", "infection", "in", "hemodialysis", "patients.", "Our", "study", "showed", "that", "detection", "of", "isolated", "anti-HBc", "could", "reflect", "unrecognized", "occult", "HBV", "infection", "in", "HD", "patients", "which", "is", "in", "concordance", "with", "the", "conclusions", "of", "Hollinger", "et", "al.", "The", "majority", "of", "these", "infections", "were", "associated", "with", "low", "viral", "loads", "(6).", "In", "anoth-", "er", "study,", "we", "determined", "the", "genotype", "and", "surface", "gene", "mu-", "tations", "of", "HBV", "in", "HD", "patients", "with", "occult", "HBV", "infection.", "All", "HBV", "isolates", "belonged", "to", "genotype", "D.", "The", "most", "important", "mutations", "were", "the", "insertion", "of", "a", "single", "nucleotide,", "prema-", "ture", "stop", "codons", "at", "Leu15,", "and", "Gly10", "and", "S207N", "mutations.", "No", "“a”", "determinant", "mutations", "were", "found.", "Our", "study", "sug-", "gested", "that", "“a”", "regionmutations", "do", "not", "play", "a", "major", "role", "in", "HBsAg", "detection", "(7).", "This", "review", "provides", "important", "infor-", "mation", "about", "the", "current", "concepts", "and", "strategy", "in", "occult", "HBV", "infection", "in", "chronic", "HD", "patients.", "Our", "study", "is", "limited", "in", "that", "we", "report", "no", "data", "on", "liver", "histopathology", "or", "outcome", "measurements;", "these", "should", "be", "investigated", "in", "the", "future.", "References", "1.", "Hollinger", "FB,", "Habibollahi", "P,", "Daneshmand", "A,", "Alavian", "SM.", "Occult", "Hepa-", "titis", "B", "Infection", "in", "Chronic", "Hemodialysis", "Patients:", "Current", "Concepts", "and", "Strategy.", "Hepat", "Mon.", "2010;", "10(3):199-204.", "2.", "Eslamifar", "A,", "Hamkar", "R,", "Ramezani", "A,", "Ahmadi", "F,", "Gachkar", "L,", "Jalilvand", "S,", "et", "al.", "Hepatitis", "G", "virus", "exposure", "in", "dialysis", "staff.", "Ther", "Apher", "Dial.", "2007;", "11(5):370-4.", "3.", "Minuk", "GY,", "Sun", "DF,", "Greenberg", "R,", "Zhang", "M,", "Hawkins", "K,", "Uhanova", "J,", "et", "al.", "Occult", "hepatitis", "B", "virus", "infection", "in", "a", "North", "American", "adult", "hemodi-", "alysis", "patient", "population.", "Hepatology.", "2004;", "40(5):1072-7.", "4.", "Cabrerizo", "M,", "Bartolome", "J,", "Caramelo", "C,", "Barril", "G,", "Carreno", "V.", "Molecu-", "lar", "analysis", "of", "hepatitis", "B", "virus", "DNA", "in", "serum", "and", "peripheral", "blood", "mononuclear", "cells", "from", "hepatitis", "B", "surface", "antigen-negative", "cases.", "Hepatology.", "2000;", "32(1):116-23.", "5.", "Fabrizi", "F,", "Messa", "PG,", "Lunghi", "G,", "Aucella", "F,", "Bisegna", "S,", "Mangano", "S,", "et", "al." ]

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[ "Makis", "et", "al.", "Journal", "of", "Medical", "Case", "Reports", "2010,", "4:281", "http://www.jmedicalcasereports.com/content/4/1/281", "C", "A", "S", "E", "R", "E", "P", "O", "R", "T", "JOURNAL", "OF", "MEDICAL", "CASE", "REPORTS", "Open", "Access", "Acute", "febrile", "neutrophilic", "dermatosis", "(Sweet’s", "syndrome)", "in", "a", "child,", "associated", "with", "a", "rotavirus", "infection:", "a", "case", "report", "Alexandros", "Makis1*,", "Stavros", "Stavrou1,", "Nikolaos", "Chaliasos1,", "Aikaterini", "Zioga2,", "Antonios", "P", "Vlahos1,", "Georgios", "Gaitanis3,", "Antigone", "Siamopoulou1,", "Ioannis", "D", "Bassukas3", "Abstract", "Introduction:", "Sweet’s", "syndrome", "characterized", "by", "fever,", "blood", "neutrophilia", "and", "inflammatory", "skin", "lesions,", "is", "rarely", "diagnosed", "in", "children.", "It", "presents", "in", "three", "clinical", "settings:", "classical", "Sweet’s", "syndrome,", "usually", "after", "a", "respiratory", "tract", "infection;", "malignancy-associated,", "frequently", "related", "to", "acute", "myelogeneous", "leukemia;", "and", "drug-induced.", "We", "present,", "to", "the", "best", "of", "our", "knowledge,", "the", "first", "case", "of", "a", "rotavirus", "-infection-related", "Sweet’s", "syndrome.", "Case", "presentation:", "An", "18-month-old", "boy", "of", "Hellenic", "origin", "was", "referred", "to", "us", "with", "diarrhea,", "fever,", "neutrophilia,", "typical", "skin", "lesions,", "asymmetrical", "hip", "arthritis", "and", "oropharyngeal", "involvement.", "A", "skin", "biopsy", "confirmed", "the", "diagnosis.", "Thorough", "screening", "did", "not", "reveal", "any", "underlying", "systemic", "illness,", "except", "for", "the", "confirmation", "of", "an", "overt", "rotavirus", "infection.", "The", "syndrome", "responded", "promptly", "upon", "corticosteroid", "administration;", "no", "recurrence", "was", "observed.", "Conclusion:", "Besides", "describing", "the", "connection", "of", "Sweet’s", "syndrome", "to", "a", "rotavirus", "infection,", "this", "case", "report", "is", "also", "a", "reminder", "that", "in", "a", "child", "presenting", "with", "a", "febrile", "papulo-nodular", "rash", "with", "neutrophilia", "Sweet’s", "syndrome", "should", "be", "included", "in", "the", "differential.", "Introduction", "Sweet’s", "syndrome", "(acute", "febrile", "neutrophilic", "dermatosis)", "is", "characterized", "by", "a", "constellation", "of", "clinical", "symptoms", "and", "physical", "findings,", "which", "include", "fever,", "blood", "and", "tissue", "neutrophilia,", "leading", "to", "the", "development", "of", "ten-", "der,", "erythematous", "inflammatory", "skin", "lesions", "(papules,", "nodules,", "plaques),", "histopathologically", "characterized", "by", "the", "presence", "of", "abundant", "mature", "neutrophils", "[1].", "It", "pre-", "sents", "in", "three", "clinical", "settings:", "‘classical’", "(’para-infec-", "tious’)", "Sweet’s", "syndrome,", "representing", "a", "hypersensitivity", "reaction", "preceding", "infection;", "malignancy-associated", "(’para-neoplastic’)", "Sweet’s", "syndrome", "(in", "children", "usually", "associated", "with", "acute", "myelogenous", "leukemia);", "and", "less", "frequently", "as", "an", "adverse", "drug", "reaction,", "sometimes", "in", "connection", "with", "certain", "underlying", "diseases", "(drug-", "induced", "Sweet’s", "syndrome)", "[2].", "Irrespective", "of", "its", "cause,", "clinical", "and", "laboratory", "signs", "in", "Sweet’s", "syndrome", "*", "Correspondence:", "amakis@cc.uoi.gr", "1Child", "Health", "Department,", "University", "of", "Ioannina", "Medical", "School,", "P.O.", "Box", "1187,", "GR-45110", "Ioannina,", "Greece", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "respond", "promptly", "to", "systemic", "corticosteroids.", "Sponta-", "neous", "resolution", "is", "possible,", "although", "a", "persisting", "recur-", "rent", "course", "over", "months", "is", "the", "rule", "[3].", "Sweet’s", "syndrome", "is", "rarely", "diagnosed", "in", "children", "[4].", "Here,", "on", "the", "occasion", "of", "a", "child", "with", "classical,", "“para-", "infectious”", "Sweet’s", "syndrome", "we", "present,", "to", "the", "best", "of", "our", "knowledge", "for", "the", "first", "time", "in", "the", "accessible", "literature,", "the", "association", "of", "this", "syndrome", "to", "a", "rota-", "virus", "infection.", "The", "current", "report", "appends", "rotavirus", "to", "the", "list", "of", "infectious", "agents", "associated", "with", "Sweet’s", "syndrome,", "thus", "expanding", "the", "pertinent", "diagnostic", "cri-", "teria", "[5].", "Case", "presentation", "An", "18-month-old", "boy", "of", "Hellenic", "origin", "was", "initially", "admitted", "to", "another", "hospital", "because", "of", "fever", "up", "to", "39.9°C", "lasting", "for", "five", "days,", "a", "mild", "cough,", "one", "to", "two", "vomits", "and", "two", "to", "three", "yellowish", "diarrheas", "per", "day.", "On", "examination,", "apart", "from", "fever", "(38.8°C)", "no", "other", "patholo-", "gical", "findings", "were", "present.", "Laboratory", "evaluation", "revealed", "leukocytosis", "(26,500/μl)", "with", "47%", "neutrophils", "©", "2010", "Makis", "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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[ "Sports", "Medicine,", "Arthroscopy,", "Rehabilitation,", "Therapy", "&", "Technology", "Case", "report", "Partial", "isolated", "rupture", "of", "the", "popliteus", "tendon", "in", "a", "professional", "soccer", "player:", "a", "case", "report", "Pier", "Paolo", "Mariani*", "and", "Fabrizio", "Margheritini", "BioMed", "Central", "Open", "Access", "Address:", "Department", "of", "Health", "Sciences,", "Unit", "of", "Sports", "Traumatology,", "Piazza", "L.", "de", "Bosis", "6,", "University", "of", "Rome", "\"Foro", "Italico\",", "I-00135", "Rome,", "Italy", "Email:", "Pier", "Paolo", "Mariani*", "-", "ppmariani@virgilio.it;", "Fabrizio", "Margheritini", "-", "fab.mar@iol.it", "*", "Corresponding", "author", "Published:", "31", "July", "2009", "Sports", "Medicine,", "Arthroscopy,", "Rehabilitation,", "Therapy", "&", "Technology", "2009,", "1:18", "doi:10.1186/1758-2555-1-18", "This", "article", "is", "available", "from:", "http://www.smarttjournal.com/content/1/1/18", "Received:", "29", "May", "2009", "Accepted:", "31", "July", "2009", "©", "2009", "Mariani", "and", "Margheritini;", "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", "The", "complete", "isolated", "rupture", "of", "the", "popliteus", "tendon", "has", "been", "described", "as", "a", "rare", "injury", "and", "this", "report", "describes", "the", "case", "of", "a", "31-year-old", "soccer", "player", "who", "sustained", "a", "partial", "rupture", "of", "the", "popliteus", "tendon", "during", "a", "game.", "The", "injury", "was", "suspected", "clinically", "and", "at", "MRI", "but", "confirmed", "only", "by", "the", "arthroscopic", "examination.", "The", "treatment", "consisted", "in", "open", "debridment", "with", "no", "tendon", "repair", "or", "augmentation.", "Seven", "weeks", "post-operation", "the", "patient", "was", "symptom-free", "and", "returned", "to", "competitive", "professional", "soccer", "at", "the", "same", "preinjury", "level.", "The", "clinical", "and", "arthroscopic", "findings", "of", "the", "case", "reported", "suggest", "a", "possible", "overuse", "disease", "with", "degenerative", "expression.", "Introduction", "The", "popliteus", "muscle", "functions", "as", "a", "dynamic", "internal", "rotator", "of", "the", "tibia.", "For", "this", "reason", "rupture", "of", "the", "popli-", "teus", "muscle", "is", "usually", "associated", "with", "acute", "or", "chronic", "posterolateral", "instability", "of", "the", "knee.", "The", "isolated", "rupture", "of", "the", "popliteus", "tendon", "is", "a", "very", "rare", "injury", "and", "it", "has", "been", "rarely", "reported", "in", "the", "literature", "as", "a", "cause", "of", "knee", "hemar-", "throsis", "and", "functional", "disabilities.", "While", "most", "of", "the", "reported", "cases", "deal", "with", "tendon", "avulsions", "[1-6]", "or", "intra-", "substance", "ruptures", "[7,8],", "partial", "rupture", "has", "never", "been", "reported", "previously.", "The", "purpose", "of", "this", "article", "is", "to", "report", "one", "case", "of", "partial", "rupture", "of", "the", "popliteus", "tendon", "in", "a", "professional", "soccer", "player", "treated", "by", "debridment", "and", "to", "discuss", "the", "pathological", "findings", "of", "this", "lesion", "that", "could", "suggest", "an", "overuse", "disease", "of", "the", "tendon", "in", "a", "athlete.", "Case", "presentation", "A", "31-year-old", "professional", "first", "division", "goalkeeper", "injured", "his", "right", "knee", "hitting", "the", "ground", "with", "the", "lateral", "side", "of", "the", "knee", "after", "making", "a", "save", "during", "a", "game.", "No", "previous", "similar", "injuries", "were", "sustained", "by", "the", "player,", "while", "he", "wasn't", "able", "to", "identify", "the", "exact", "moment", "of", "the", "trauma.", "He", "referred", "immediately", "only", "minimal", "discom-", "fort", "and", "no", "apparent", "effusion", "and", "he", "continued", "to", "play", "on.", "After", "2", "weeks,", "the", "discomfort", "progressed", "despite", "phys-", "iotherapy.", "An", "orthopaedic", "referral", "was", "made", "for", "persistent", "pain", "located", "at", "knee", "lateral", "aspect", "only", "during", "his", "sports", "activity.", "The", "first", "orthopaedic", "surgeon", "made", "a", "clinical", "diagnosis", "of", "a", "lateral", "meniscal", "tear", "and", "requested", "an", "MRI", "examination", "that", "was", "judged", "negative.", "At", "that", "time", "the", "patient", "came", "to", "our", "institution", "without", "any", "further", "treat-", "ment", "carried", "on.", "Clinical", "examination", "revealed", "absence", "of", "effusion", "and", "non-specific", "lateral", "joint-line", "tenderness", "with", "full", "extension", "and", "flexion.", "It", "was", "possible", "to", "elicit", "sharp", "pain", "palpating", "the", "popliteus", "tendon", "at", "femoral", "groove.", "The", "suspicion", "of", "other", "diseases,", "such", "as", "popliteus", "tendon", "snapping", "or", "popliteomeniscal", "fascicle", "tear", "were", "ruled", "out", "with", "the", "figure-four", "test", "and", "the", "Cabot", "test", "that", "Page", "1", "of", "4", "(page", "number", "not", "for", "citation", "purposes)" ]

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[ "Maric", "et", "al.", "Molecular", "Cytogenetics", "2011,", "4:26", "http://www.molecularcytogenetics.org/content/4/1/26", "R", "E", "S", "E", "A", "R", "C", "H", "Open", "Access", "Centrosomal", "and", "mitotic", "abnormalities", "in", "cell", "lines", "derived", "from", "papillary", "thyroid", "cancer", "harboring", "specific", "gene", "alterations", "Irena", "Maric1,2†,", "Silvia", "Viaggi1,2†,", "Paola", "Caria3,", "Daniela", "V", "Frau3,", "Paolo", "Degan2", "and", "Roberta", "Vanni3*", "Abstract", "Background:", "Differentiated", "thyroid", "carcinoma", "offers", "a", "good", "model", "to", "investigate", "the", "possible", "correlation", "between", "specific", "gene", "mutations", "and", "chromosome", "instability.", "Papillary", "thyroid", "neoplasms", "are", "characterized", "by", "different", "mutually", "exclusive", "genetic", "alterations,", "some", "of", "which", "are", "associated", "with", "aneuploidy", "and", "aggressive", "phenotype.", "Results:", "We", "investigated", "the", "centrosome", "status", "and", "mitotic", "abnormalities", "in", "three", "thyroid", "carcinoma-derived", "cell", "lines,", "each", "maintaining", "the", "specific,", "biologically", "relevant", "gene", "alteration", "harbored", "by", "the", "parental", "tumors:", "RET/PTC1", "rearrangement", "in", "TPC1;", "heterozygous", "and", "homozygous", "BRAFV600E", "mutation", "in", "K1", "and", "in", "B-CPAP,", "respectively.", "B-", "CPAP", "cells", "showed", "a", "statistically", "significant", "(P", "<", "0.01)", "higher", "frequency", "of", "abnormal", "mitotic", "figures", "compared", "to", "TPC1", "and", "K1", "cells.", "Conclusions:", "Our", "data", "indicate", "that", "RET/PTC1", "oncogenic", "activity", "is", "not", "related", "to", "mitotic", "chromosome", "impairment", "and", "missegregation", "whereas,", "based", "on", "the", "consistent", "difference", "in", "types/frequencies", "of", "centrosome", "and", "spindle", "abnormalities", "observed", "between", "K1", "and", "B-CPAP", "cells,", "the", "hetero/homozygous", "allelic", "status", "of", "BRAFV600E", "mutation", "seems", "to", "be", "not", "irrelevant", "in", "respect", "to", "chromosomal", "instability", "development.", "Keywords:", "thyroid", "carcinoma,", "centrosome,", "mitotic", "spindle,", "RET/PTC,", "BRAF", "Background", "Chromosomal", "instability", "(CIN),", "a", "genetic", "condition", "that", "promotes", "a", "high", "rate", "of", "chromosome", "missegregation", "during", "mitosis,", "is", "a", "shared", "feature", "of", "most", "cancers.", "Aneuploidy", "is", "a", "distinctive", "trait", "of", "most", "human", "cancers", "and", "has", "been", "linked", "to", "high", "tumour", "grade,", "advanced", "stage,", "and", "poor", "prognosis;", "however,", "its", "role", "in", "neoplastic", "transformation", "and", "the", "relationship", "with", "CIN", "are", "some-", "what", "unclear", "[1].", "A", "variety", "of", "alterations", "have", "been", "pro-", "posed", "as", "being", "responsible", "for", "CIN,", "including", "defects", "in", "the", "spindle", "checkpoint,", "defective", "sister-chromatid", "cohe-", "sion,", "kinetochore", "assembly,", "upregulation", "of", "cyclins,", "ero-", "sion", "of", "telomeres", "and", "centrosome", "abnormalities", "[2].", "The", "normal", "function", "and", "numeral", "integrity", "of", "centrosomes", "can", "be", "affected", "directly", "by", "the", "mutated", "products", "of", "cer-", "tain", "proto-oncogenes", "and", "tumour-suppressor", "genes", "*", "Correspondence:", "vanni@unica.it", "†", "Contributed", "equally", "3Dipartimento", "di", "Scienze", "e", "Tecnologie", "Biomediche,", "Università", "di", "Cagliari,", "09042,", "Italy", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "[3,4].", "In", "particular,", "centrosome", "amplification", "(the", "pre-", "sence", "in", "the", "cell", "of", "more", "than", "two", "centrosomes)", "seems", "to", "be", "an", "early", "event", "in", "tumourigenesis", "[5],", "and", "it", "may", "affect", "CIN", "in", "different", "ways,", "depending", "on", "the", "capacity", "to", "maintain", "a", "correct", "bipolar", "chromosome", "segregation", "in", "the", "presence", "of", "multipolar", "spindles.", "In", "addition", "to", "amplification,", "structural", "and", "functional", "defects", "of", "cen-", "trosomes", "may", "influence", "CIN", "[4].", "Papillary", "thyroid", "carcinoma", "(PTC),", "accounting", "for", "approximately", "80%", "of", "differentiated", "thyroid", "carcinoma", "(DTC),", "has", "a", "number", "of", "variants", "with", "specific", "histologi-", "cal", "characteristics.", "The", "classical", "form", "of", "PTC", "may", "show", "activation", "of", "the", "BRAF", "gene", "or", "RET/PTC", "variants,", "in", "40-45%", "and", "10-20%", "of", "cases,", "respectively", "[6].", "The", "two", "alterations", "are", "usually", "mutually", "exclusive.", "In", "different", "PTC-derived", "cell", "lines,", "the", "alternative", "presence", "of", "either", "BRAF", "mutation", "or", "RET/PTC", "rearrangement", "has", "been", "confirmed", "[7],", "reinforcing", "the", "hypothesis", "that", "RET", "and", "BRAF", "changes", "are", "alternative", "oncogenic", "events.", "The", "majority", "of", "papillary", "thyroid", "carcinoma", "shows", "stable", "©", "2011", "Maric", "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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[ "BIOINFORMATICS", "APPLICATIONS", "NOTE", "Vol.", "26", "no.", "15", "2010,", "pages", "1903–1904", "doi:10.1093/bioinformatics/btq304", "Sequence", "analysis", "Cloud-Coffee:", "implementation", "of", "a", "parallel", "consistency-based", "multiple", "alignment", "algorithm", "in", "the", "T-Coffee", "package", "and", "its", "benchmarking", "on", "the", "Amazon", "Elastic-Cloud", "1", "2", "2", "2", "Paolo", "Di", "Tommaso", ",", "Miquel", "Orobitg", ",", "Fernando", "Guirado", ",", "Fernado", "Cores", ",", "Toni", "Espinosa3", "and", "Cedric", "Notredame1,∗", "1Centre", "For", "Genomic", "Regulation", "(Pompeu", "Fabra", "University),", "Carrer", "del", "Doctor", "Aiguader", "88,", "08003", "Barcelona,", "2Department", "of", "Computer", "Science", "and", "Industrial", "Engineering,", "University", "of", "Lleida,", "Campus", "de", "Cappont,", "C.", "de", "Jaume", "II", "69,", "E-25001", "Lleida", "and", "3Department", "of", "Computer", "Architecture", "and", "Operating", "Systems,", "Universitad", "Autonoma", "de", "Barcelona,", "Campus", "UAB,", "Edifici", "Q,", "08193", "Bellaterra", "(Barcelona),", "Spain", "Associate", "Editor:", "Burkhard", "Rost", "ABSTRACT", "Summary:", "We", "present", "the", "first", "parallel", "implementation", "of", "the", "T-Coffee", "consistency-based", "multiple", "aligner.", "We", "benchmark", "it", "on", "the", "Amazon", "Elastic", "Cloud", "(EC2)", "and", "show", "that", "the", "parallelization", "procedure", "is", "reasonably", "effective.", "We", "also", "conclude", "that", "for", "a", "web", "server", "with", "moderate", "usage", "(10K", "hits/month)", "the", "cloud", "provides", "a", "cost-effective", "alternative", "to", "in-house", "deployment.", "Availability:", "T-Coffee", "is", "a", "freeware", "open", "source", "package", "available", "from", "http://www.tcoffee.org/homepage.html", "Contact:", "cedric.notredame@crg.es", "Received", "on", "March", "30,", "2010;", "revised", "on", "May", "18,", "2010;", "accepted", "on", "June", "2,", "2010", "1", "INTRODUCTION", "T-Coffee", "was", "the", "first", "package", "featuring", "an", "implementation", "of", "the", "consistency-based", "progressive", "alignment", "algorithm", "(for", "Reviews", "see", "Edgar", "and", "Batzoglou,", "2006).", "While", "the", "use", "of", "consistency", "is", "widely", "recognized", "as", "an", "important", "development", "in", "the", "field", "of", "multiple", "sequence", "alignment,", "this", "improvement", "comes", "at", "a", "cost.", "Consistency-", "based", "methods", "have", "increased", "CPU", "and", "memory", "consumption", "proportional", "to", "the", "number", "of", "sequences", "being", "processed.", "This", "over-", "head", "is", "incompatible", "with", "the", "size", "of", "the", "datasets", "being", "generated", "by", "next", "generation", "sequencing", "technologies.", "Heuristic", "solutions", "have", "been", "proposed", "(Pei", "et", "al.,", "2003)", "that", "rely", "on", "a", "pre-clustering", "of", "the", "sequences,", "but", "no", "effort", "had", "yet", "been", "reported", "to", "extensively", "parallelize", "consistency", "based", "algorithm", "and", "benefit", "from", "the", "widely", "available", "multi-core", "CPUs.", "To", "our", "knowledge", "this", "report", "is", "the", "first", "one", "describing", "a", "parallelization", "of", "all", "steps", "involving", "consistency-", "based", "alignments.", "The", "new", "implementation", "is", "available", "from", "version", "8.00", "and", "higher", "of", "T-Coffee.", "In", "practice,", "its", "usage", "is", "transparent", "to", "the", "user,", "with", "the", "package", "automatically", "and", "explicitly", "switching", "to", "parallel", "mode", "whenever", "multi-core", "processors", "are", "available.", "The", "procedure", "supports", "all", "modes", "of", "T-Coffee", "for", "aligning", "protein", "(O’Sullivan", "et", "al.,", "2004)", "or", "RNA", "(Wilm", "et", "al.,", "2008)", "sequences.", "It", "runs", "on", "all", "the", "platforms", "where", "the", "standard", "T-Coffee", "can", "be", "compiled", "and", "installed", "(Windows,", "MacOSX,", "Linux,", "UNIX,", "etc.).", "∗To", "whom", "correspondence", "should", "be", "addressed.", "We", "benchmarked", "this", "new", "implementation", "on", "the", "Amazon", "Elastic", "Cloud", "(EC2)", "in", "order", "to", "estimate", "its", "efficiency", "and", "also", "measure", "the", "cost", "associated", "with", "running", "this", "type", "of", "application", "on", "a", "cloud-environment.", "Cloud", "computation", "is", "providing", "the", "community", "with", "an", "increasingly", "popular", "alternative", "to", "in-house", "computational", "resources.", "It", "is", "therefore", "becoming", "an", "important", "question", "to", "determine", "the", "relative", "cost", "of", "these", "new", "environments", "when", "comparing", "them", "with", "more", "traditional", "infrastructures.", "2", "METHOD", "Parallelization", "is", "controlled", "with", "the", "flag", "-multi_core=", "templates_jobs_relax_msa,", "where", "the", "flag", "value", "is", "composed", "by", "four", "different", "keywords,", "each", "controlling", "a", "specific", "alignment", "step.", "These", "are", "templates:", "template", "selection;", "jobs:", "library", "computation;", "relax:", "library", "relaxation;", "msa:", "progressive", "alignment.", "Parallelization", "can", "be", "switched", "off", "(e.g.", "-multi_core=no)", "or", "customized", "(e.g.", "-multi_core=jobs).", "(1)", "Template", "selection.", "In", "T-Coffee", "most", "advanced", "modes", "[R-Coffee,", "3D-", "Coffee", "and", "PSI-Coffee", "(Kemena", "and", "Notredame,", "2009)],", "structural", "templates", "are", "automatically", "associated", "with", "user-provided", "sequences.", "Templates", "can", "either", "be", "identified", "by", "running", "a", "BLAST", "against", "an", "appropriate", "database", "or", "produced", "by", "modeling", "(i.e.", "RNA", "secondary", "structure", "prediction).", "This", "simple", "process,", "iterated", "on", "the", "list", "of", "user", "provided", "sequences", "can", "be", "computationally", "intensive", "and", "constitutes", "a", "natural", "and", "trivial", "target", "for", "parallelization.", "(2)", "Library", "computation.", "Library", "computation", "involves", "computing", "pairwise", "(or", "multiple)", "alignments", "using", "some", "pre-defined", "method.", "Release", "8.00", "of", "T-Coffee", "can", "use", "21", "external", "sequence", "and", "structure", "aligners.", "Parallelization", "is", "achieved", "by", "grouping", "the", "alignment", "tasks", "into", "a", "number", "of", "individual", "jobs", "equal", "to", "the", "number", "of", "available", "processors.", "Jobs", "are", "then", "submitted", "simultaneously,", "and", "their", "output", "merged", "into", "a", "single", "library", "by", "the", "master", "process.", "(3)", "Library", "extension.", "The", "library", "extension", "[named", "relaxation", "in", "ProbCons", "(Do", "et", "al.,", "2005)]", "involves", "re-evaluating", "the", "score", "for", "aligning", "every", "residue", "pair.", "This", "operation", "is", "achieved", "by", "considering", "in", "turn", "every", "pair", "of", "sequences", "and", "subsequently", "updating", "the", "library.", "It", "can", "therefore", "be", "parallelized", "using", "the", "library", "computation", "strategy.", "(4)", "Progressive", "alignment.", "The", "progressive", "alignment", "stage", "involves", "aligning", "sequences", "(or", "profiles)", "two", "by", "two,", "while", "following", "the", "order", "indicated", "by", "a", "binary", "guide", "tree.", "In", "practice,", "going", "from", "leaf", "to", "tip,", "one", "uses", "dynamic", "programming", "(Needleman", "and", "Wunsch,", "1970)", "to", "align", "the", "two", "child", "sequences/profiles", "associated", "with", "each", "node.", "Parallelization", "is", "achieved", "by", "separately", "processing", "all", "the", "independent", "nodes,", "with", "optimal", "©", "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.", "[16:45", "30/6/2010", "Bioinformatics-btq304.tex]", "Page:", "1903", "1903–1904" ]

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[ "Hindawi", "Publishing", "Corporation", "Experimental", "Diabetes", "Research", "Volume", "2012,", "Article", "ID", "519784,", "5", "pages", "doi:10.1155/2012/519784", "Review", "Article", "Bone:", "Incretin", "Hormones", "Perceiver", "or", "Receiver?", "Ilaria", "Dicembrini,1", "Edoardo", "Mannucci,2", "and", "Carlo", "Maria", "Rotella1", "1", "Section", "of", "Endocrinology,", "Department", "of", "Clinical", "Pathophysiology,", "Careggi", "Teaching", "Hospital,", "University", "of", "Florence", "and", "Obesity", "Agency,", "50127", "Florence,", "Italy", "2", "Careggi", "Teaching", "Hospital,", "Diabetes", "Agency,", "50127", "Florence,", "Italy", "Correspondence", "should", "be", "addressed", "to", "Carlo", "Maria", "Rotella,", "c.rotella@dfc.unifi.it", "Received", "6", "March", "2012;", "Accepted", "9", "May", "2012", "Academic", "Editor:", "Giovanni", "Di", "Pasquale", "Copyright", "©", "2012", "Ilaria", "Dicembrini", "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.", "Novel", "incretin-based", "drugs,", "such", "as", "glucagon-like", "peptide-1", "receptor", "agonists", "(GLP-1", "RA)", "and", "dipeptidyl", "peptidase-4", "inhibitors", "(DPP-4i),", "have", "been", "last", "introduced", "in", "the", "pharmacological", "treatment", "of", "type", "2", "diabetes.", "In", "the", "last", "few", "years,", "the", "interest", "on", "the", "relationship", "of", "gut", "hormones", "with", "bone", "metabolism", "in", "diabetes", "has", "been", "increasing.", "The", "aim", "of", "present", "paper", "is", "to", "examine", "in", "vitro", "and", "in", "vivo", "evidence", "on", "the", "connections", "between", "incretin", "hormones", "and", "bone", "metabolism.", "We", "also", "discuss", "results", "of", "clinical", "trials", "and", "metaanalysis,", "explore", "the", "effects", "of", "incretin", "drugs", "in", "vitro", "on", "osteogenic", "cells", "and", "osteoclasts,", "and", "speculate", "on", "the", "possibility", "of", "different", "effects", "of", "GLP-1", "RA", "and", "DPP-4i", "on", "the", "risk", "of", "bone", "fractures", "risk", "in", "humans.", "Although", "existing", "preliminary", "evidence", "suggests", "a", "protective", "effect", "on", "the", "bone,", "at", "least", "for", "DPP-4i,", "further", "controlled,", "long-term", "studies", "with", "measurement", "of", "bone", "markers,", "bone", "density,", "and", "clinical", "fractures", "rates", "are", "needed", "to", "substantiate", "and", "confirm", "those", "findings.", "1.", "Introduction", "Glucose,", "protein,", "and", "fat", "and", "mixed", "meal", "ingestion", "is", "associated", "with", "a", "significant", "reduction", "in", "markers", "of", "bone", "resorption,", "detectable", "by", "twenty", "minutes", "after", "feeding", "[1].", "Bone", "formation", "is", "also", "influenced,", "but", "it", "seems", "to", "be", "less", "responsive", "to", "nutrients", "than", "resorption", "[2].", "Biochemical", "assessment", "of", "bone", "turnover", "demonstrates", "that", "food", "intake", "is", "the", "major", "cause", "of", "the", "reduced", "bone", "turnover", "during", "daytime,", "which", "is", "followed", "by", "a", "nocturnal", "increase", "[3].", "In", "addition,", "the", "observation", "that", "parenteral", "feeding", "is", "related", "to", "bone", "mass", "reduction", "[4]", "suggests", "a", "functional", "link", "between", "gut", "and", "bone", "metabolism", "through", "hormones", "responding", "to", "nutrients", "absorption,", "such", "as,", "incretins.", "The", "concept", "of", "incretins", "has", "been", "introduced", "to", "define", "gastrointestinal", "hormones", "released", "after", "meal", "ingestion,", "which", "modulate", "glucose", "homeostasis,", "mainly", "through", "both", "glucose-induced", "enhancement", "of", "insulin", "secretion", "and", "inhibition", "of", "glucagon", "release,", "such", "as", "glucagon-like", "peptide-1", "(GLP-1).", "Beneficial", "extraglycemic", "actions", "on", "body", "weight,", "blood", "pressure,", "dyslipidemia,", "cardiac", "and", "endothelial", "function", "are", "further", "reported.", "Novel", "drugs", "based", "on", "the", "incretin", "system,", "such", "as,", "glucagon-like", "peptide-1", "receptor", "agonists", "(GLP-1", "RA)", "and", "dipeptidyl", "peptidase-4", "inhibitors", "(DPP-4i),", "have", "been", "approved", "for", "the", "therapy", "of", "type", "2", "diabetes", "[5].", "In", "the", "last", "few", "years,", "the", "interest", "on", "the", "relationship", "of", "gut", "hormones", "with", "bone", "formation", "and", "turnover", "in", "diabetes", "has", "been", "increasing,", "with", "preliminary", "data", "suggesting", "the", "possibility", "of", "positive", "effects", "of", "GLP-1", "RA", "and", "DPP-4i", "on", "bone", "health.", "The", "aim", "of", "present", "paper", "is", "to", "examine", "in", "vitro", "and", "in", "vivo", "evidences", "on", "the", "connections", "between", "incretin", "hormones", "and", "bone", "metabolism.", "We", "also", "discuss", "results", "of", "clinical", "trials", "and", "meta-analysis,", "thus", "explore", "investigating", "the", "in", "vitro", "effects", "of", "incretin", "drugs", "in", "vitro", "on", "osteoblasts", "and", "osteoclasts,", "and", "speculate", "on", "the", "cells", "and", "presenting", "the", "possibility", "of", "different", "effects", "of", "GLP-1", "RA", "and", "DPP-4i", "effects", "on", "the", "risk", "of", "bone", "fractures", "risk", "in", "humans", "clinical", "studies.", "2.", "The", "Gut-Brain-Bone", "Axis", "and", "Diabetes", "The", "regulation", "of", "bone", "turnover", "in", "response", "to", "feeding", "is", "complex", "with", "probable", "involvement", "of", "several", "mediators.", "The", "most", "important", "mediators", "identified", "are", "intestinal", "(GLP-1,", "GLP-2,", "Glucose-dependent", "Insulinotropic", "Peptide", "or", "GIP,", "and", "Peptide", "YY)", "and", "pancreatic", "beta", "cell", "(insulin," ]

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[ "A", "Novel", "MMP-2", "Inhibitor", "3-azidowithaferin", "A", "(3-", "azidoWA)", "Abrogates", "Cancer", "Cell", "Invasion", "and", "Angiogenesis", "by", "Modulating", "Extracellular", "Par-4", "Bilal", "Rah", "1", ",", "Hina", "Amin1,", "Khalid", "Yousuf2,", "Sheema", "Khan", "1", ",", "Gayatri", "Jamwal1,", "Debaraj", "Mukherjee2,", "Anindya", "Goswami1*", "1", "Molecular", "Signal", "Transduction", "Laboratory,", "Cancer", "Pharmacology", "Division,", "Indian", "Institute", "of", "Integrative", "Medicine", "(CSIR),", "Jammu", "Tawi,", "India,", "2", "Nautral", "Product", "Chemistry,", "Indian", "Institute", "of", "Integrative", "Medicine", "(CSIR),", "Jammu", "Tawi,", "India", "Abstract", "Background:", "Withaferin", "A,", "which", "is", "a", "naturally", "derived", "steroidal", "lactone,", "has", "been", "found", "to", "prevent", "angiogenesis", "and", "metastasis", "in", "diverse", "tumor", "models.", "It", "has", "also", "been", "recognized", "by", "different", "groups", "for", "prominent", "anti-carcinogenic", "roles.", "However,", "in", "spite", "of", "these", "studies", "on", "withanolides,", "their", "detailed", "anti-metastatic", "mechanism", "of", "action", "remained", "unknown.", "The", "current", "study", "has", "poised", "to", "address", "the", "machinery", "involved", "in", "invasion", "regulation", "by", "stable", "derivative", "of", "Withaferin", "A,", "3-azido", "Withaferin", "A", "(3-azidoWA)", "in", "human", "cervical", "HeLa", "and", "prostate", "PC-3", "cells.", "Methods", "and", "Principal", "Findings:", "Sub-toxic", "concentration", "of", "3-azidowithaferin", "A", "(3-azido", "WA)", "inhibited", "cancer", "cell", "motility", "and", "invasion", "in", "wound", "healing", "and", "Boyden", "chamber", "invasion", "by", "suppressing", "MMP-2", "activity", "in", "gelatin", "zymography", "and", "its", "expression", "has", "proved", "to", "be", "a", "major", "obstacle", "in", "chemo-sensitivity.", "We", "have", "uncovered", "a", "novel", "mechanism", "of", "3-azidoWA", "induced", "extracellular", "pro-apoptotic", "candidate", "tumor", "suppressor", "Par-4", "protein", "stimulation", "in", "conditioned", "media", "and", "also", "noticed", "a", "concomitant", "marked", "reduction", "in", "pAkt", "and", "pERK", "signaling", "by", "immunoblot", "analysis.", "Furthermore,", "our", "zymography", "results", "suggest", "3-azidoWA", "induced", "MMP-2", "inhibition", "was", "mediated", "through", "secretory", "Par-4.", "The", "inhibition", "of", "apoptosis", "by", "3-azidoWA", "could", "not", "restore", "MMP-2", "gelatinase", "activity.", "In", "addition", "to", "this,", "our", "in", "vivo", "animal", "experiments", "data", "showed", "3-azidoWA", "abrogated", "neovascularisation", "in", "dose", "dependent", "manner", "in", "mouse", "Matrigel", "plug", "assay.", "Conclusion/Significance:", "For", "this", "report,", "we", "found", "that", "3-azidoWA", "suppressed", "motility", "and", "invasion", "of", "HeLa", "and", "PC-3", "cells", "in", "MMP-2", "dependent", "manner.", "Our", "in", "vitro", "result", "strongly", "suggests", "that", "sub-toxic", "doses", "of", "3-azidoWA", "enhanced", "the", "secretion", "of", "extracellular", "Par-4", "that", "abolished", "secretory", "MMP-2", "expression", "and", "activity.", "Depletion", "of", "secretory", "Par-4", "restored", "MMP-2", "expression", "and", "invasion", "capability", "of", "HeLa", "and", "PC-3", "cells.", "Further,", "our", "findings", "implied", "that", "3-azidoWA", "attenuated", "internal", "phospho-ERK", "and", "phospho-Akt", "expression", "in", "a", "dose", "dependent", "manner", "might", "play", "a", "key", "role", "in", "inhibition", "of", "mouse", "angiogenesis", "by", "3-azidoWA.", "Citation:", "Rah", "B,", "Amin", "H,", "Yousuf", "K,", "Khan", "S,", "Jamwal", "G,", "et", "al.", "(2012)", "A", "Novel", "MMP-2", "Inhibitor", "3-azidowithaferin", "A", "(3-azidoWA)", "Abrogates", "Cancer", "Cell", "Invasion", "and", "Angiogenesis", "by", "Modulating", "Extracellular", "Par-4.", "PLoS", "ONE", "7(9):", "e44039.", "doi:10.1371/journal.pone.0044039", "Editor:", "Daotai", "Nie,", "Southern", "Illinois", "University", "School", "of", "Medicine,", "United", "States", "of", "America", "Received", "May", "23,", "2012;", "Accepted", "August", "1,", "2012;", "Published", "September", "4,", "2012", "Copyright:", "2012", "Rah", "et", "al.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Funding:", "The", "authors", "have", "no", "support", "or", "funding", "to", "report.", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "*", "E-mail:", "agoswami@iiim.ac.in", "Introduction", "Extracellular", "secretory", "pathways", "are", "considered", "to", "play", "pivotal", "role", "in", "human", "physiology.", "Body’s", "vital", "hormones", "and", "growth", "factors", "are", "secreted", "and", "they", "control", "the", "development", "and", "differentiation", "of", "organs", "in", "normal", "physiological", "condition.", "Likewise,", "systemic", "(extracellular)", "proteins", "attribute", "major", "in", "vivo", "function", "during", "tissue", "growth", "and", "apoptosis", "[1].", "Prostate", "apoptotic", "response", "4", "(Par-4)", "is", "ubiquitously", "expressed", "and", "evolutionary", "conserved", "pro-apoptotic", "protein", "whose", "expression", "was", "mainly", "correlated", "with", "the", "cells", "that", "undergo", "apoptosis", "due", "to", "exogenous", "insults", "[2].", "Apart", "from", "its", "intracellular", "function,", "the", "new", "perspective", "of", "extracellular", "secretion", "in", "different", "cancer", "cells", "has", "augmented", "the", "therapeutic", "potential", "of", "Par-4", "[3].", "Recently,", "Burikhanov", "et", "al.", "have", "shown", "that", "mammalian", "cells", "in", "general", "caused", "secretion", "of", "Par-4.", "However,", "the", "apoptotic", "induction", "by", "extracellular", "Par-4", "occurring", "via", "cell-", "surface", "GRP-78", "was", "found", "to", "promote", "cell", "invasion", "and", "tumorigenesis", "[3].", "The", "stabilization", "of", "pro-angiogenic", "GRP-78", "by", "Par-4", "has", "been", "designated", "an", "anti-", "invasive", "role", "of", "extracellular", "Par-4.", "Metastasis", "is", "a", "multi-step", "process", "involving", "cell", "migration", "and", "pericellular", "proteolysis", "of", "ECM", "that", "mediates", "cancer", "cells", "protrusion", "[4].", "Matrix", "metalloproteinases", "(MMP’s)", "are", "responsible", "for", "the", "degradation", "of", "environmental", "barriers,", "such", "as", "the", "extracellular", "matrix", "and", "basement", "membrane", "[5,6].", "Amongst", "the", "MMP", "family", "members,", "MMP-2", "and", "-9", "are", "generally", "considered", "to", "be", "the", "malignancy", "of", "various", "tumors", "as", "well", "as", "poor", "prognosis", "of", "many", "cancers", "[6].", "Thus,", "MMP’s", "are", "capable", "of", "cleaving", "type", "IV", "basement", "membrane", "collagen", "(MMP-2", "and", "-9)", "and", "add", "value", "for", "drug", "development.", "Compelling", "preclinical", "studies", "from", "diverse", "laboratories", "have", "provided", "overwhelming", "support", "for", "direct", "relationship", "between", "MMP-2", "over", "expression", "PLOS", "ONE", "|", "www.plosone.org", "1", "September", "2012", "|", "Volume", "7", "|", "Issue", "9", "|", "e44039" ]

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[ "Available", "online", "http://breast-cancer-research.com/content/8/6/R67", "Research", "article", "Vol8No6", "Comprehensive", "analysis", "of", "the", "ATM,", "CHEK2", "and", "ERBB2", "genes", "in", "relation", "to", "breast", "tumour", "characteristics", "and", "survival:", "a", "population-based", "case-control", "and", "follow-up", "study", "Open", "Access", "Kristjana", "Einarsdóttir1,", "Lena", "U", "Rosenberg1,", "Keith", "Humphreys1,", "Carine", "Bonnard2,", "Juni", "Palmgren1,3,", "Yuqing", "Li2,", "Yi", "Li4,", "Kee", "S", "Chia5,", "Edison", "T", "Liu2,", "Per", "Hall1,", "Jianjun", "Liu2", "and", "Sara", "Wedrén1", "1Department", "of", "Medical", "Epidemiology", "and", "Biostatistics,", "Karolinska", "Institute,", "Nobels", "väg", "12A,", "171", "77", "Solna,", "Sweden", "2Population", "Genetics,", "Genome", "Institute", "of", "Singapore,", "60", "Biopolis", "Street,", "Genome", "#02-01,", "Singapore", "138672", "3Department", "of", "Mathematics,", "Stockholm", "University,", "Roslagsvägen", "101,", "106", "91", "Stockholm,", "Sweden", "4Information", "and", "Mathematical", "Sciences,", "Genome", "Institute", "of", "Singapore,", "60", "Biopolis", "Street,", "Genome", "#02-01,", "Singapore", "138672", "5Centre", "for", "Molecular", "Epidemiology,", "Department", "of", "Community,", "Occupational", "and", "Family", "Medicine,", "National", "University", "of", "Singapore,", "16", "Medical", "Drive,", "Singapore", "117597", "Corresponding", "author:", "Kristjana", "Einarsdóttir,", "Kristjana.Einarsdottir@ki.se", "Received:", "3", "Oct", "2006", "Revisions", "requested:", "13", "Nov", "2006", "Revisions", "received:", "16", "Nov", "2006", "Accepted:", "28", "Nov", "2006", "Published:", "28", "Nov", "2006", "Breast", "Cancer", "Research", "2006,", "8:R67", "(doi:10.1186/bcr1623)", "This", "article", "is", "online", "at:", "http://breast-cancer-research.com/content/8/6/R67", "©", "2006", "Einarsdóttir", "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", "Mutations", "in", "the", "ataxia-telangiectasia", "mutated", "(ATM)", "and", "checkpoint", "kinase", "2", "(CHEK2)", "genes", "and", "amplification", "of", "the", "v-erb-b2", "avian", "erythroblastic", "leukemia", "viral", "oncogene", "homolog", "2", "(ERBB2)", "gene", "have", "been", "suggested", "to", "have", "an", "important", "role", "in", "breast", "cancer", "aetiology.", "However,", "whether", "common", "variation", "in", "these", "genes", "has", "a", "role", "in", "the", "development", "of", "breast", "cancer", "or", "breast", "cancer", "survival", "in", "humans", "is", "still", "not", "clear.", "Methods", "We", "performed", "a", "comprehensive", "haplotype", "analysis", "of", "the", "ATM,", "CHEK2", "and", "ERBB2", "genes", "in", "a", "Swedish", "population-", "based", "study,", "which", "included", "1,579", "breast", "cancer", "cases", "and", "1,516", "controls.", "We", "followed", "the", "cases", "for", "8.5", "years,", "on", "average,", "and", "retrieved", "information", "on", "the", "date", "and", "cause", "of", "death", "during", "that", "period", "from", "the", "nationwide", "Swedish", "causes", "of", "death", "registry.", "We", "selected", "seven", "haplotype-tagging", "SNPs", "(tagSNPs)", "in", "the", "ATM", "gene,", "six", "tagSNPs", "in", "the", "CHEK2", "gene", "and", "seven", "tagSNPs", "in", "the", "ERBB2", "gene", "that", "predicted", "both", "haplotypic", "and", "single", "locus", "variations", "in", "the", "respective", "genes", "with", "R2", "values", "≥", "0.8.", "These", "tagSNPs", "were", "genotyped", "in", "the", "complete", "set", "of", "cases", "and", "controls.", "We", "computed", "expected", "haplotype", "dosages", "of", "the", "tagSNP", "haplotypes", "and", "included", "the", "dosages", "as", "explanatory", "variables", "in", "Cox", "proportional", "hazards", "or", "logistic", "regression", "models.", "Results", "We", "found", "no", "association", "between", "any", "genetic", "variation", "in", "the", "ATM,", "CHEK2", "or", "ERBB2", "genes", "and", "breast", "cancer", "survival", "or", "the", "risk", "of", "developing", "tumours", "with", "certain", "characteristics.", "Conclusion", "Our", "results", "indicate", "that", "common", "variants", "in", "the", "ATM,", "CHEK2", "or", "ERBB2", "genes", "are", "not", "involved", "in", "modifying", "breast", "cancer", "survival", "or", "the", "risk", "of", "tumour-characteristic-", "defined", "breast", "cancer.", "Introduction", "Twin", "and", "family", "studies", "consistently", "indicate", "that", "the", "risk", "of", "breast", "cancer", "is", "influenced,", "in", "part,", "by", "hereditary", "factors,", "but", "high-risk", "mutations", "seem", "to", "account", "for", "only", "1–2%", "of", "all", "breast", "cancer", "cases", "in", "the", "general", "population", "[1].", "A", "polygenic", "model", "has", "been", "proposed", "to", "account", "for", "the", "residual", "familial", "risk", "[2],", "which", "anticipates", "small", "effects", "of", "several", "low-pene-", "trance", "genetic", "risk", "variants", "in", "combination", "with", "environmental", "influence.", "Although", "no", "human", "data", "exist", "for", "the", "affect", "of", "germ-", "line", "polymorphisms", "on", "tumour", "outcome,", "there", "is", "strong", "evi-", "dence", "that", "strain", "background", "is", "a", "significant", "determinant", "of", "the", "clinical", "behaviour", "of", "experimental", "mammary", "carcinomas", "in", "mice", "[3-5].", "We", "thus", "set", "out", "to", "study", "the", "role", "of", "common", "vari-", "ation", "in", "key", "breast", "cancer", "candidate", "genes", "in", "relation", "to", "breast", "cancer", "aetiology,", "survival", "and", "tumour", "characteristics.", "The", "ataxia-telangiectasia", "mutated", "(ATM;", "MIM", "607585),", "checkpoint", "kinase", "2", "(CHEK2;", "MIM", "604373)", "and", "v-erb-b2", "A-T", "=", "ataxia-telangiectasia;", "ATM", "=", "ataxia-telangiectasia", "mutated;", "CHEK2", "=", "checkpoint", "kinase", "2;", "CI", "=", "confidence", "interval;", "dbSNP", "=", "Single", "Nucle-", "otide", "Polymorphism", "database;", "ERBB2", "=", "v-erb-b2", "avian", "erythroblastic", "leukemia", "viral", "oncogene", "homolog", "2;", "HWE", "=", "Hardy–Weinberg", "equilibrium;", "kb", "=", "kilobase;", "LD", "=", "linkage", "disequilibrium;", "OR", "=", "odds", "ratio;", "SNP", "=", "single", "nucleotide", "polymorphism;", "tagSNP", "=", "haplotype-tagging", "SNP.", "Page", "1", "of", "12", "(page", "number", "not", "for", "citation", "purposes)" ]

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[ "Ku", "Regulates", "the", "Non-Homologous", "End", "Joining", "Pathway", "Choice", "of", "DNA", "Double-Strand", "Break", "Repair", "in", "Human", "Somatic", "Cells", "Farjana", "Fattah¤a,", "Eu", "Han", "Lee,", "Natalie", "Weisensel¤b,", "Yongbao", "Wang,", "Natalie", "Lichter,", "Eric", "A.", "Hendrickson*", "Department", "of", "Biochemistry,", "Molecular", "Biology,", "and", "Biophysics,", "University", "of", "Minnesota", "Medical", "School,", "Minneapolis,", "Minnesota,", "United", "States", "of", "America", "Abstract", "The", "repair", "of", "DNA", "double-strand", "breaks", "(DSBs)", "is", "critical", "for", "the", "maintenance", "of", "genomic", "integrity", "and", "viability", "for", "all", "organisms.", "Mammals", "have", "evolved", "at", "least", "two", "genetically", "discrete", "ways", "to", "mediate", "DNA", "DSB", "repair:", "homologous", "recombination", "(HR)", "and", "non-homologous", "end", "joining", "(NHEJ).", "In", "mammalian", "cells,", "most", "DSBs", "are", "preferentially", "repaired", "by", "NHEJ.", "Recent", "work", "has", "demonstrated", "that", "NHEJ", "consists", "of", "at", "least", "two", "sub-pathways—the", "main", "Ku", "heterodimer-", "dependent", "or", "‘‘classic’’", "NHEJ", "(C-NHEJ)", "pathway", "and", "an", "‘‘alternative’’", "NHEJ", "(A-NHEJ)", "pathway,", "which", "usually", "generates", "microhomology-mediated", "signatures", "at", "repair", "junctions.", "In", "our", "study,", "recombinant", "adeno-associated", "virus", "knockout", "vectors", "were", "utilized", "to", "construct", "a", "series", "of", "isogenic", "human", "somatic", "cell", "lines", "deficient", "in", "the", "core", "C-NHEJ", "factors", "(Ku,", "DNA-PKcs,", "XLF,", "and", "LIGIV),", "and", "the", "resulting", "cell", "lines", "were", "characterized", "for", "their", "ability", "to", "carry", "out", "DNA", "DSB", "repair.", "The", "absence", "of", "DNA-PKcs,", "XLF,", "or", "LIGIV", "resulted", "in", "cell", "lines", "that", "were", "profoundly", "impaired", "in", "DNA", "DSB", "repair", "activity.", "Unexpectedly,", "Ku86-", "null", "cells", "showed", "wild-type", "levels", "of", "DNA", "DSB", "repair", "activity", "that", "was", "dominated", "by", "microhomology", "joining", "events", "indicative", "of", "A-NHEJ.", "Importantly,", "A-NHEJ", "DNA", "DSB", "repair", "activity", "could", "also", "be", "efficiently", "de-repressed", "in", "LIGIV-null", "and", "DNA-PKcs-null", "cells", "by", "subsequently", "reducing", "the", "level", "of", "Ku70.", "These", "studies", "demonstrate", "that", "in", "human", "cells", "C-NHEJ", "is", "the", "major", "DNA", "DSB", "repair", "pathway", "and", "they", "show", "that", "Ku", "is", "the", "critical", "C-NHEJ", "factor", "that", "regulates", "DNA", "NHEJ", "DSB", "pathway", "choice.", "Citation:", "Fattah", "F,", "Lee", "EH,", "Weisensel", "N,", "Wang", "Y,", "Lichter", "N,", "et", "al.", "(2010)", "Ku", "Regulates", "the", "Non-Homologous", "End", "Joining", "Pathway", "Choice", "of", "DNA", "Double-Strand", "Break", "Repair", "in", "Human", "Somatic", "Cells.", "PLoS", "Genet", "6(2):", "e1000855.", "doi:10.1371/journal.pgen.1000855", "Editor:", "Christopher", "E.", "Pearson,", "The", "Hospital", "for", "Sick", "Children", "and", "University", "of", "Toronto,", "Canada", "Received", "July", "31,", "2009;", "Accepted", "January", "23,", "2010;", "Published", "February", "26,", "2010", "Copyright:", "2010", "Fattah", "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", "NIH", "awards", "GM069576", "and", "HL079559", "to", "EAH.", "We", "would", "like", "to", "acknowledge", "the", "assistance", "of", "the", "Flow", "Cytometry", "Core", "Facility", "of", "the", "Masonic", "Cancer", "Center,", "a", "comprehensive", "cancer", "center", "designated", "by", "the", "National", "Cancer", "Institute,", "supported", "in", "part", "by", "P30", "CA77598.", "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:", "hendr064@umn.edu", "¤a", "Current", "address:", "Department", "of", "Pharmacology,", "Howard", "Hughes", "Medical", "Institute,", "University", "of", "Texas", "Southwestern", "Medical", "Center,", "Dallas,", "Texas,", "United", "States", "of", "America", "¤b", "Current", "address:", "School", "of", "Medicine", "and", "Public", "Health,", "University", "of", "Wisconsin,", "Madison,", "Wisconsin,", "United", "States", "of", "America", "Introduction", "One", "of", "the", "most", "harmful", "lesions", "a", "cell", "can", "encounter", "is", "a", "DNA", "double-strand", "break", "(DSB).", "In", "all", "organisms,", "efficient", "repair", "of", "these", "DSBs", "is", "critical", "for", "the", "maintenance", "of", "genomic", "integrity", "and", "viability", "[1].", "Unfortunately,", "DSBs", "are", "frequently", "generated", "endogenously", "during", "normal", "cellular", "processes", "such", "as", "DNA", "replication,", "lymphoid", "V(D)J", "or", "class-switch", "recombination", "and", "are", "induced", "exogenously", "by", "the", "exposure", "to", "a", "variety", "of", "genotoxic", "agents", "such", "as", "ionizing", "radiation", "or", "chemotherapeutics", "[2].", "Cells", "have", "conspired", "to", "meet", "this", "demand", "on", "their", "genetic", "material", "with", "the", "evolution", "of", "two", "mechanistically", "distinct", "pathways", "to", "repair", "DSBs:", "homologous", "recombination", "(HR),", "which", "takes", "advantage", "of", "either", "a", "homologous", "chromosome", "or", "a", "sister", "chromatid", "to", "join", "the", "broken", "DNA", "ends", "[3]", "and", "non-homologous", "end", "joining", "(NHEJ),", "a", "process", "that", "directly", "joins", "the", "DSB", "with", "little", "or", "no", "sequence", "homology", "between", "the", "broken", "ends", "[2].", "In", "bacteria", "and", "lower", "eukaryotes,", "HR", "dominates", "the", "DNA", "DSB", "repair", "events", "whereas", "in", "higher", "eukaryotes,", "and", "especially", "in", "mammals,", "NHEJ", "is", "the", "preferred", "pathway", "for", "DNA", "DSB", "repair.", "NHEJ", "consists", "of", "at", "least", "two", "genetically", "and", "biochemically", "distinct", "sub-pathways:", "a", "main—", "‘‘classic’’—end-joining", "pathway", "(C-NHEJ)", "and", "one", "interchange-", "ably", "referred", "to", "as", "microhomology-mediated", "end", "joining", "(MMEJ)", "[4],", "alternative", "NHEJ", "(A-NHEJ),", "or", "backup", "NHEJ", "(B-NHEJ)", "[5,6]", "(hereafter", "referred", "to", "as", "A-NHEJ).", "C-NHEJ,", "while", "by", "no", "means", "precise,", "results", "in", "minimal", "DNA", "end", "processing,", "whereas", "A-NHEJ", "mechanistically", "results", "in", "deletions", "per", "force", "that", "are", "often", "accompanied", "by", "microhomology", "at", "the", "repair", "junction", "{[7,8];", "reviewed", "by", "[6,9]}.", "There", "are", "at", "least", "seven", "proteins", "required", "for", "C-NHEJ:", "Ku70,", "Ku86,", "the", "DNA", "dependent", "protein", "kinase", "catalytic", "subunit", "(DNA-", "PKcs),", "Artemis,", "X-ray", "cross", "complementing", "4", "(XRCC4),", "XRCC4-", "like", "factor", "(XLF)", "and", "DNA", "ligase", "IV", "(LIGIV)", "{reviewed", "by", "[10]}.", "The", "basic", "mechanism", "of", "C-NHEJ", "has", "been", "worked", "out", "in", "great", "detail.", "Ku70", "and", "Ku86", "form", "a", "heterodimer", "(Ku)", "that", "contains", "an", "internal", "cavity,", "which", "Ku", "uses", "to", "bind", "to", "and", "encircle", "broken", "DNA", "ends", "[11].", "Ku,", "besides", "protecting", "DNA", "ends", "from", "exonucleolytic", "attack,", "also", "recruits", "DNA-PKcs,", "a", "phosphoinositol-3-like", "family", "serine/threonine", "protein", "kinase", "[12].", "Together,", "Ku70,", "Ku86", "and", "DNA-PKcs", "form", "the", "DNA-dependent", "protein", "kinase", "complex", "(DNA-PK)", "and", "the", "assembly", "of", "this", "trimeric", "complex", "on", "the", "ends", "of", "double-stranded", "DNA", "activates", "the", "kinase", "activity", "of", "DNA-", "PLoS", "Genetics", "|", "www.plosgenetics.org", "1", "February", "2010", "|", "Volume", "6", "|", "Issue", "2", "|", "e1000855" ]

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[ "Auvinet", "et", "al.", "BMC", "Musculoskeletal", "Disorders", "2011,", "12:258", "http://www.biomedcentral.com/1471-2474/12/258", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "The", "interest", "of", "gait", "markers", "in", "the", "identification", "of", "subgroups", "among", "fibromyalgia", "patients", "Bernard", "Auvinet1*,", "Denis", "Chaleil2,", "Jean", "Cabane3,", "Anne", "Dumolard4,", "Pierre", "Hatron5,", "Robert", "Juvin4,", "Michel", "Lanteri-Minet6,", "Yves", "Mainguy7,", "Laurence", "Negre-Pages8,", "Fabien", "Pillard9,", "Daniel", "Riviere9", "and", "Yves-Michel", "Maugars10", "Abstract", "Background:", "Fibromyalgia", "(FM)", "is", "a", "heterogeneous", "syndrome", "and", "its", "classification", "into", "subgroups", "calls", "for", "broad-", "based", "discussion.", "FM", "subgrouping,", "which", "aims", "to", "adapt", "treatment", "according", "to", "different", "subgroups,", "relies", "in", "part,", "on", "psychological", "and", "cognitive", "dysfunctions.", "Since", "motor", "control", "of", "gait", "is", "closely", "related", "to", "cognitive", "function,", "we", "hypothesized", "that", "gait", "markers", "could", "be", "of", "interest", "in", "the", "identification", "of", "FM", "patients’", "subgroups.", "This", "controlled", "study", "aimed", "at", "characterizing", "gait", "disorders", "in", "FM,", "and", "subgrouping", "FM", "patients", "according", "to", "gait", "markers", "such", "as", "stride", "frequency", "(SF),", "stride", "regularity", "(SR),", "and", "cranio-caudal", "power", "(CCP)", "which", "measures", "kinesia.", "Methods:", "A", "multicentre,", "observational", "open", "trial", "enrolled", "patients", "with", "primary", "FM", "(44.1", "±", "8.1", "y),", "and", "matched", "controls", "(44.1", "±", "7.3", "y).", "Outcome", "measurements", "and", "gait", "analyses", "were", "available", "for", "52", "pairs.", "A", "3-step", "statistical", "analysis", "was", "carried", "out.", "A", "preliminary", "single", "blind", "analysis", "using", "k-means", "cluster", "was", "performed", "as", "an", "initial", "validation", "of", "gait", "markers.", "Then", "in", "order", "to", "quantify", "FM", "patients", "according", "to", "psychometric", "and", "gait", "variables", "an", "open", "descriptive", "analysis", "comparing", "patients", "and", "controls", "were", "made,", "and", "correlations", "between", "gait", "variables", "and", "main", "outcomes", "were", "calculated.", "Finally", "using", "cluster", "analysis,", "we", "described", "subgroups", "for", "each", "gait", "variable", "and", "looked", "for", "significant", "differences", "in", "self-reported", "assessments.", "Results:", "SF", "was", "the", "most", "discriminating", "gait", "variable", "(73%", "of", "patients", "and", "controls).", "SF,", "SR,", "and", "CCP", "were", "different", "between", "patients", "and", "controls.", "There", "was", "a", "non-significant", "association", "between", "SF,", "FIQ", "and", "physical", "components", "from", "Short-Form", "36", "(p", "=", "0.06).", "SR", "was", "correlated", "to", "FIQ", "(p", "=", "0.01)", "and", "catastrophizing", "(p", "=", "0.05)", "while", "CCP", "was", "correlated", "to", "pain", "(p", "=", "0.01).", "The", "SF", "cluster", "identified", "3", "subgroups", "with", "a", "particular", "one", "characterized", "by", "normal", "SF,", "low", "pain,", "high", "activity", "and", "hyperkinesia.", "The", "SR", "cluster", "identified", "2", "distinct", "subgroups:", "the", "one", "with", "a", "reduced", "SR", "was", "distinguished", "by", "high", "FIQ,", "poor", "coping", "and", "altered", "affective", "status.", "Conclusion:", "Gait", "analysis", "may", "provide", "additional", "information", "in", "the", "identification", "of", "subgroups", "among", "fibromyalgia", "patients.", "Gait", "analysis", "provided", "relevant", "information", "about", "physical", "and", "cognitive", "status,", "and", "pain", "behavior.", "Further", "studies", "are", "needed", "to", "better", "understand", "gait", "analysis", "implications", "in", "FM.", "Background", "In", "clinical", "trials", "and", "observational", "research", "studies,", "fibromyalgia", "(FM)", "is", "usually", "diagnosed", "according", "to", "American", "College", "of", "Rheumatology", "(ACR)", "1990", "criteria", "[1].", "However,", "patients", "fulfilling", "the", "ACR", "classification", "criteria", "for", "FM", "do", "not", "constitute", "a", "homogeneous", "group", "and", "the", "classification", "of", "FM", "into", "different", "subgroups", "calls", "for", "broad-based", "discussion.", "Strazt", "et", "al", "[2]", "sought", "*", "Correspondence:", "bernard.auvinet@gmail.com", "1Locomotion", "Research", "Unit,", "Laval", "Hospital,", "53015", "Laval,", "France", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "to", "identify", "different", "FM", "subgroups", "by", "distinguishing", "between", "FM", "with", "and", "without", "depression.", "Turk", "et", "al", "[3]", "showed", "that", "subgroups", "identified", "by", "cluster", "analysis,", "based", "on", "the", "Multidimensional", "Pain", "Inventory", "(MPI),", "could", "be", "applicable", "to", "FM", "patients;", "this", "subgrouping", "was", "based", "on", "psychosocial", "and", "cognitive", "characteristics.", "Giesecke", "et", "al", "[4]", "showed", "that", "the", "combination", "of", "these", "two", "features", "and", "pain", "sensitivity", "indices", "best", "distin-", "guished", "subgroups", "of", "FM", "patients.", "Using", "the", "MPI,", "Thieme", "et", "al", "[5]", "identified", "three", "subgroups", "of", "FM", "patients", "on", "the", "basis", "of", "anxiety", "and", "psychiatric", "©", "2011", "Auvinet", "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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[ "Castañeda", "et", "al.", "BMC", "Complementary", "and", "Alternative", "Medicine", "2012,", "12:38", "http://www.biomedcentral.com/1472-6882/12/38", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "A", "gallotannin-rich", "fraction", "from", "Caesalpinia", "spinosa", "(Molina)", "Kuntze", "displays", "cytotoxic", "activity", "and", "raises", "sensitivity", "to", "doxorubicin", "in", "a", "leukemia", "cell", "line", "Diana", "M", "Castañeda1†,", "Luis", "Miguel", "Pombo2†,", "Claudia", "Patricia", "Urueña1,", "John", "Fredy", "Hernandez1", "and", "Susana", "Fiorentino1*", "Abstract", "Background:", "Enhancement", "of", "tumor", "cell", "sensitivity", "may", "help", "facilitate", "a", "reduction", "in", "drug", "dosage", "using", "conventional", "chemotherapies.", "Consequently,", "it", "is", "worthwhile", "to", "search", "for", "adjuvants", "with", "the", "potential", "of", "increasing", "chemotherapeutic", "drug", "effectiveness", "and", "improving", "patient", "quality", "of", "life.", "Natural", "products", "are", "a", "very", "good", "source", "of", "such", "adjuvants.", "Methods:", "The", "biological", "activity", "of", "a", "fraction", "enriched", "in", "hydrolysable", "polyphenols", "(P2Et)", "obtained", "from", "Caesalpinia", "spinosa", "was", "evaluated", "using", "the", "hematopoietic", "cell", "line", "K562.", "This", "fraction", "was", "tested", "alone", "or", "in", "combination", "with", "the", "conventional", "chemotherapeutic", "drugs", "doxorubicin,", "vincristine,", "etoposide,", "camptothecin", "and", "taxol.", "The", "parameters", "evaluated", "were", "mitochondrial", "depolarization,", "caspase", "3", "activation,", "chromatin", "condensation", "and", "clonogenic", "activity.", "Results:", "We", "found", "that", "the", "P2Et", "fraction", "induced", "mitochondrial", "depolarization,", "activated", "caspase", "3,", "induced", "chromatin", "condensation", "and", "decreased", "the", "clonogenic", "capacity", "of", "the", "K562", "cell", "line.", "When", "the", "P2Et", "fraction", "was", "used", "in", "combination", "with", "chemotherapeutic", "drugs", "at", "sub-lethal", "concentrations,", "a", "fourfold", "reduction", "in", "doxorubicin", "inhibitory", "concentration", "50", "(IC50)", "was", "seen", "in", "the", "K562", "cell", "line.", "This", "finding", "suggested", "that", "P2Et", "fraction", "activity", "is", "specific", "for", "the", "molecular", "target", "of", "doxorubicin.", "Conclusions:", "Our", "results", "suggest", "that", "a", "natural", "fraction", "extracted", "from", "Caesalpinia", "spinosa", "in", "combination", "with", "conventional", "chemotherapy", "in", "combination", "with", "natural", "products", "on", "leukemia", "cells", "may", "increase", "therapeutic", "effectiveness", "in", "relation", "to", "leukemia.", "Keywords:", "Adjuvants,", "Gallotannins,", "C.spinosa,", "Tumor,", "Leukemia", "Background", "Caesalpinia", "spinosa", "is", "a", "shrub", "commonly", "named", "divi-", "divi.", "It", "is", "acknowledged", "to", "have", "antimicrobial", "and", "anti-", "oxidant", "activity,", "and", "is", "traditionally", "known", "for", "its", "antitumor", "activity", "[1].", "An", "ethanol", "extract", "from", "the", "fruit", "of", "C.spinosa", "has", "been", "proven", "to", "have", "antimicrobial", "*", "Correspondence:", "susana.fiorentino@javeriana.edu.co", "†", "Contributed", "equally", "1Grupo", "de", "Inmunobiología", "y", "Biología", "Celular,", "Facultad", "de", "Ciencias,", "Pontificia", "Universidad", "Javeriana,", "Bogotá,", "Colombia,", "Carrera", "7", "N.", "43-82", "Building", "52,", "Office", "608", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "activity", "against", "gram-positive", "and", "gram-negative", "bac-", "teria,", "probably", "due", "to", "the", "presence", "of", "hydrolysable", "tan-", "nins", "in", "the", "fruits", "[2].", "Hydrolysable", "tannins", "are", "a", "group", "of", "gallic", "acid", "esters", "associated", "with", "polyols", "(glucose,", "glu-", "citol,", "shikimic", "acid,", "quinic", "acid", "and", "quercitol,", "among", "others),", "where", "the", "galloyl", "groups", "can", "be", "further", "cross-", "linked", "by", "etherification", "or", "oxidation", "to", "form", "complex", "structures.", "The", "gallotannins", "(gallic", "acid", "esters)", "are", "the", "simplest", "hydrolysable", "tannins,", "were", "1,2,3,4,6-penta-O-", "galloyl-b-D-glucose", "(pentagalloyl", "glucose", "[PGG])", "is", "the", "prototype", "and", "central", "compound", "of", "the", "biosynthetic", "pathway", "[3].", "The", "presence", "of", "PGG,", "as", "well", "as", "©", "2012", "Castañeda", "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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[ "open", "access", "www.bioinformation.net", "Volume", "6(4)", "Hypothesis", "Insights", "of", "interaction", "between", "small", "and", "large", "subunits", "of", "ADP-glucose", "pyrophosphorylase", "from", "bread", "wheat", "(Triticum", "aestivum", "L.)", "Mohd", "Danishuddin,", "Ravish", "Chatrath,", "Rajender", "Singh*", "Directorate", "of", "Wheat", "Research,", "Post", "Box", "158,", "Karnal", "-", "132001,", "India;", "Rajender", "Singh", "-", "Email:", "rajenderkhokhar@yahoo.com;", "*Corresponding", "author", "Received", "July", "26,", "2010,", "Accepted", "January", "29,", "2011;", "Published", "May", "07,", "2011", "Abstract:", "Lack", "of", "knowledge", "of", "three", "dimensional", "structures", "of", "small", "and", "large", "subunits", "of", "ADP-", "glucose", "pyrophosphorylase", "(AGPase)", "in", "wheat", "has", "hindered", "efforts", "to", "understand", "the", "binding", "specifities", "of", "substrate", "and", "catalytic", "mechanism.", "Thus,", "to", "understand", "the", "structure", "activity", "relationship,", "3D", "structures", "were", "built", "by", "homology", "modelling", "based", "on", "crystal", "structure", "of", "potato", "tuber", "ADP-glucose", "pyrophosphorylase.", "Selected", "models", "were", "refined", "by", "energy", "minimization", "and", "further", "validated", "by", "Procheck", "and", "Prosa-web", "analysis.", "Ramachandran", "plot", "showed", "that", "overall", "main", "chain", "and", "side", "chain", "parameters", "are", "favourable.", "Moreover,", "Z-score", "of", "the", "models", "from", "Prosa-web", "analysis", "gave", "the", "conformation", "that", "they", "are", "in", "the", "range", "of", "the", "template.", "Interaction", "analysis", "depicts", "the", "involvement", "of", "six", "amino", "acids", "in", "hydrogen", "bonding", "(AGP-SThr422-AGP-LMet138,", "AGP-", "SArg420-AGP-LGly47,", "AGP-SSer259-AGP-LSer306,", "AGP-SGlu241-AGP-LIle311,", "AGP-", "SGln113-AGP-LGlu286", "and", "AGP-SGln70-AGP-LLys291).", "Fifteen", "amino", "acids", "of", "small", "subunit", "were", "able", "to", "make", "hydrophobic", "contacts", "with", "seventeen", "amino", "acids", "of", "large", "subunit.", "Furthermore,", "decrease", "in", "the", "solvent", "accessible", "surface", "area", "in", "the", "amino", "acids", "involved", "in", "interaction", "were", "also", "reported.", "All", "the", "distances", "were", "formed", "in", "between", "2.27", "to", "3.78Å.", "The", "present", "study", "focussed", "on", "heterodimeric", "structure", "of", "(AGPase).", "This", "predicted", "complex", "not", "only", "enhance", "our", "understanding", "of", "the", "interaction", "mechanism", "between", "these", "subunits", "(AGP-L", "and", "AGP-S)", "but", "also", "enable", "to", "further", "study", "to", "obtain", "better", "variants", "of", "this", "enzyme", "for", "the", "improvement", "of", "the", "plant", "yield.", "Keywords:", "AGPase,", "ADP-glucose", "pyrophosphorylase,", "AGP-S,", "AGP-L,", "modelling,", "molecular", "docking,", "hydrogen", "bonding,", "hydrophobic", "contacts,", "accessible", "surface", "area.", "Background:", "Wheat", "(Triticum", "aestivum", "L.)", "is", "one", "of", "the", "most", "important", "staple", "crops", "worldwide,", "with", "a", "total", "production", "of", "over", "600", "million", "tonnes", "annually.", "The", "seed", "number", "and", "seed", "weight", "are", "critical", "yield", "components", "of", "wheat.", "Starch,", "which", "accounts", "65-75%", "of", "wheat", "seed", "weight,", "is", "a", "major", "determinant", "wheat", "yield.", "Starch", "is", "known", "to", "be", "an", "important", "carbohydrate", "and", "the", "primary", "energy", "source", "for", "plants,", "having", "numerous", "industrial", "applications", "[1,", "2].", "It", "is", "generally", "accepted", "that", "four", "enzymes", "may", "play", "a", "key", "role", "in", "starch", "biosynthesis:", "ADP-", "glucose", "pyrophosphorylase,", "starch", "synthase,", "starch", "branching", "enzyme", "and", "starch", "debranching", "enzyme", "[3].", "ADP-glucose", "pyrophosphorylase", "(AGPase)", "is", "regarded", "as", "rate-", "limiting", "enzyme", "in", "starch", "biosynthesis.", "This", "enzyme", "plays", "a", "key", "role", "in", "the", "modulation", "of", "photosynthetic", "efficiency", "in", "source", "tissues", "and", "also", "determines", "the", "level", "of", "storage", "starch", "in", "sink", "tissues,", "thus", "influencing", "overall", "crop", "yield", "potential.", "It", "catalyzes", "the", "first", "step", "of", "starch", "biosynthesis", "by", "generating", "the", "sugar", "nucleotide", "ADP-glucose", "and", "inorganic", "pyrophosphate", "(Pi)", "from", "glucose-1-phosphate", "and", "ATP.", "ADP-glucose", "functions", "as", "the", "glucosyl", "donor", "for", "glucan", "synthesis", "by", "starch", "synthase.", "AGPase", "from", "higher", "plants", "is", "heterotetrameric,", "consisting", "of", "two", "large", "subunits", "(AGP-L)", "and", "two", "small", "subunits", "(AGP-S)", "encoded", "by", "two", "distinct", "genes", "[4].", "Seed", "yield", "and", "plant", "biomass", "increases", "are", "conferred", "by", "deregulation", "of", "endosperm", "AGPase", "and", "thus,", "AGPase", "has", "attracted", "wide", "interest", "for", "potential", "crop", "improvements", "[5].", "In", "the", "present", "study", "the", "3D", "structures", "of", "the", "subunits", "(large", "and", "small)", "from", "wheat", "were", "modelled", "by", "the", "in", "silico", "homology", "techniques", "using", "the", "crystal", "structure", "of", "small", "subunit", "from", "potato", "tuber", "as", "a", "template.", "Moreover,", "molecular", "docking", "between", "these", "subunits", "was", "also", "performed", "to", "gain", "the", "insight", "of", "interaction.", "Methodology:", "Amino", "acids", "sequences", "of", "large", "subunit", "(P12299)", "and", "small", "subunit", "(P30523)", "were", "retrieved", "from", "Swiss-Prot", "database", "[6].", "Template", "was", "searched", "by", "BLAST-P", "analysis", "against", "PDB", "database.", "The", "crystal", "structure", "of", "potato", "AGPase", "(1YP2)", "available", "at", "PDB", "was", "used", "as", "template", "for", "modelling.", "Sequence", "alignment", "between", "the", "model", "sequence", "and", "template", "was", "done", "with", "ClustalW", "[7].", "Homology", "models", "of", "large", "and", "small", "subunits", "were", "built", "by", "Modeller", "[8]", "version", "9v7.", "One", "model", "from", "each", "subunit", "was", "selected", "using", "PROCHECK", "[9]", "and", "Prosa-web", "[10].", "Further,", "models", "were", "subjected", "to", "energy", "minimization", "using", "GROMOS96", "implemented", "via", "Swiss-pdb", "viewer", "[11].", "RMSD", "of", "the", "model", "structures", "of", "AGP-L", "and", "AGP-S", "were", "evaluated", "form", "its", "template", "using", "the", "SUPERPOSE", "[12].", "Docking", "of", "model", "structure", "was", "performed", "by", "GRAMM-X", "[13].", "Model", "structure", "was", "further", "evaluated", "by", "Patchdock", "[14].", "Best", "docked", "structure", "based", "on", "RMSD", "and", "Patchdock", "score", "was", "chosen", "for", "further", "analysis.", "Hydrogen", "and", "hydrophobic", "interactions", "between", "these", "subunits", "were", "analyzed", "by", "Ligplot", "[15].", "Figures", "representation", "was", "generated", "with", "Discovery", "studio", "visualizer", "programme", "[16].", "Accessible", "surface", "area", "was", "calculated", "by", "Mark", "Gerstein’s", "calc-surface", "programme", "implemented", "in", "Chimera", "[17].", "ISSN", "0973-2063", "(online)", "0973-8894", "(print)", "Bioinformation", "6(4):", "144-148", "(2011)", " ", "144", "©", "2011", "Biomedical", "Informatics" ]

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[ "Malaria", "Journal", "Research", "Willingness", "and", "ability", "to", "pay", "for", "artemisinin-based", "combination", "therapy", "in", "rural", "Tanzania", "Eleonor", "C", "Saulo1,", "Birger", "C", "Forsberg*2,", "Zul", "Premji3,", "Scott", "M", "Montgomery4", "and", "Anders", "Björkman1", "BioMed", "Central", "Open", "Access", "Address:", "1Malaria", "Research", "Unit", "(M9),", "Division", "of", "Infectious", "Diseases,", "Department", "of", "Medicine,", "Karolinska", "University", "Hospital,", "171", "76", "Stockholm,", "Sweden,", "2Division", "of", "International", "Health", "(IHCAR),", "Department", "of", "Public", "Health", "Sciences,", "Karolinska", "Institutet,", "171", "77", "Stockholm,", "Sweden,", "3Department", "of", "Parasitology", "and", "Entomology,", "Muhimbili", "University", "College", "of", "Health", "Sciences,", "PO", "Box", "65001,", "Dar", "es", "Salaam,", "United", "Republic", "of", "Tanzania", "and", "4Clinical", "Epidemiology", "Unit,", "Department", "of", "Medicine,", "Karolinska", "University", "Hospital,", "Karolinska", "Institutet,", "171", "76", "Stockholm,", "Sweden", "Email:", "Eleonor", "C", "Saulo", "-", "eleonor76@yahoo.com;", "Birger", "C", "Forsberg*", "-", "birger.forsberg@ki.se;", "Zul", "Premji", "-", "zpremji@muchs.ac.tz;", "Scott", "M", "Montgomery", "-", "scott.montgomery@ki.se;", "Anders", "Björkman", "-", "anders.bjorkman@karolinska.se", "*", "Corresponding", "author", "Published:", "31", "October", "2008", "Malaria", "Journal", "2008,", "7:227", "doi:10.1186/1475-2875-7-227", "This", "article", "is", "available", "from:", "http://www.malariajournal.com/content/7/1/227", "Received:", "3", "April", "2008", "Accepted:", "31", "October", "2008", "©", "2008", "Saulo", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "The", "aim", "of", "this", "study", "was", "to", "analyse", "willingness", "to", "pay", "(WTP)", "and", "ability", "to", "pay", "(ATP)", "for", "ACT", "for", "children", "below", "five", "years", "of", "age", "in", "a", "rural", "setting", "in", "Tanzania", "before", "the", "introduction", "of", "artemisinin-based", "combination", "therapy", "(ACT)", "as", "first-line", "treatment", "for", "uncomplicated", "malaria.", "Socio-economic", "factors", "associated", "with", "WTP", "and", "expectations", "on", "anti-malaria", "drugs,", "including", "ACT,", "were", "also", "explored.", "Methods:", "Structured", "interviews", "and", "focus", "group", "discussions", "were", "held", "with", "mothers,", "household", "heads,", "health-", "care", "workers", "and", "village", "leaders", "in", "Ishozi,", "Gera", "and", "Ishunju", "wards", "in", "north-west", "Tanzania", "in", "2004.", "Contingent", "valuation", "method", "(CVM)", "was", "used", "with", "\"take-it-or-leave-it\"", "as", "the", "eliciting", "method,", "expressed", "as", "WTP", "for", "a", "full", "course", "of", "ACT", "for", "a", "child", "and", "households'", "opportunity", "cost", "of", "ACT", "was", "used", "to", "assess", "ATP.", "The", "study", "included", "descriptive", "analyses", "with", "multivariate", "adjustment", "for", "potential", "confounding", "factors.", "Results:", "Among", "265", "mothers", "and", "household", "heads,", "244", "(92%,", "CI", "=", "88%–95%)", "were", "willing", "to", "pay", "Tanzanian", "Shillings", "(TSh)", "500", "(US$", "0.46)", "for", "a", "child's", "dose", "of", "ACT,", "but", "only", "55%", "(49%–61%)", "were", "willing", "to", "pay", "more", "than", "TSh", "500.", "Mothers", "were", "more", "often", "willing", "to", "pay", "than", "male", "household", "heads", "(adjusted", "odds", "ratio", "=", "2.1,", "CI", "=", "1.2–3.6).", "Socio-economic", "status", "had", "no", "significant", "effect", "on", "WTP.", "The", "median", "annual", "non-subsidized", "ACT", "cost", "for", "clinical", "malaria", "episodes", "in", "an", "average", "household", "was", "calculated", "as", "US$", "6.0,", "which", "would", "represent", "0.9%", "of", "the", "average", "total", "consumption", "expenditures", "as", "estimated", "from", "official", "data", "in", "2001.", "The", "cost", "of", "non-subsidized", "ACT", "represented", "7.0%", "of", "reported", "total", "annual", "expenditure", "on", "food", "and", "33.0%", "of", "total", "annual", "expenditure", "on", "health", "care.", "\"Rapid", "effect,\"", "\"no", "adverse", "effect\"", "and", "\"inexpensive\"", "were", "the", "most", "desired", "features", "of", "an", "anti-malarial", "drug.", "Conclusion:", "WTP", "for", "ACT", "in", "this", "study", "was", "less", "than", "its", "real", "cost", "and", "a", "subsidy", "is,", "therefore,", "needed", "to", "enable", "its", "equitable", "affordability.", "The", "decision", "taken", "in", "Tanzania", "to", "subsidize", "Coartem®", "fully", "at", "governmental", "health", "care", "facilities", "and", "at", "a", "consumer", "price", "of", "TSh", "300–500", "(US$", "0.28–0.46)", "at", "special", "designated", "shops", "through", "the", "programme", "of", "Accredited", "Drug", "Dispensing", "Outlets", "(ADDOs)", "appears", "to", "be", "well", "founded.", "Page", "1", "of", "10", "(page", "number", "not", "for", "citation", "purposes)" ]

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[ "Research", "|", "Children’s", "Health", "Organophosphate", "Pesticide", "Exposure", "and", "Attention", "in", "Young", "Mexican-American", "Children:", "The", "CHAMACOS", "Study", "Amy", "R.", "Marks,1", "Kim", "Harley,1", "Asa", "Bradman,1", "Katherine", "Kogut,1", "Dana", "Boyd", "Barr,2", "Caroline", "Johnson,1", "Norma", "Calderon,3", "and", "Brenda", "Eskenazi", "1", "1Center", "for", "Children’s", "Environmental", "Health", "Research,", "School", "of", "Public", "Health,", "University", "of", "California,", "Berkeley,", "Berkeley,", "California,", "USA;", "2Emory", "University,", "Rollins", "School", "of", "Public", "Health,", "Atlanta,", "Georgia,", "USA;", "3Center", "for", "the", "Health", "Assessment", "of", "Mothers", "and", "Children", "of", "Salinas,", "Clinica", "de", "Salud", "del", "Valle", "de", "Salinas,", "Salinas,", "California,", "USA", "Background", ":", "Exposure", "to", "organophosphate", "(OP)", "pesticides,", "wellk‑nown", "neurotoxicants,", "has", "been", "associated", "with", "neurobehavioral", "deficits", "in", "children.", "o", "Bjectivs", ":", "We", "investigated", "whether", "OP", "exposure,", "as", "measured", "by", "urinary", "dialkyl", "phosphate", "(DAP)", "metabolites", "in", "pregnant", "women", "and", "their", "children,", "was", "associated", "with", "attention‑related", "outcomes", "among", "MexicanA‑merican", "children", "living", "in", "an", "agricultural", "region", "of", "California.", "Methods", ":", "Children", "were", "assessed", "at", "ages", "3.5", "years", "(n", "=", "331)", "and", "5", "years", "(n", "=", "323).", "Mothers", "com‑", "pleted", "the", "Child", "Behavior", "Checklist", "(CBCL).", "We", "administered", "the", "NEPSYI‑I", "visual", "attention", "sub", "‑", "test", "to", "children", "at", "3.5", "years", "and", "Conners’", "Kiddie", "Continuous", "Performance", "Test", "(KC‑PT)", "at", "5", "years.", "The", "K‑", "CPT", "yielded", "a", "standardized", "attention", "deficit/hyperactivity", "disorder", "(ADHD)", "Confidence", "Index", "score.", "Psychometricians", "scored", "behavior", "of", "the", "5y‑earo‑lds", "during", "testing", "using", "the", "Hillside", "Behavior", "Rating", "Scale.", "r", "esult", ":", "Prenatal", "DAPs", "(nanomoles", "per", "liter)", "were", "nonsignificantly", "associated", "with", "maternal", "report", "of", "attention", "problems", "and", "ADHD", "at", "age", "3.5", "years", "but", "were", "significantly", "related", "at", "age", "5", "years", "[CBCL", "attention", "problems:", "β", "=", "0.7", "points;", "95%", "confidence", "interval", "(CI),", "0.2–1.2;", "ADHD:", "β", "=", "1.3;", "95%", "CI,", "0.4–2.1].", "Prenatal", "DAPs", "were", "associated", "with", "scores", "on", "the", "KC‑PT", "ADHD", "Confidence", "Index", ">", "70th", "percentile", "[odds", "ratio", "(OR)", "=", "5.1;", "95%", "CI,", "1.7–15.7]", "and", "with", "a", "composite", "ADHD", "indicator", "of", "the", "various", "measures", "(OR", "=", "3.5;", "95%", "CI,", "1.1–10.7).", "Some", "outcomes", "exhibited", "evidence", "of", "effect", "modification", "by", "sex,", "with", "associations", "found", "only", "among", "boys.", "There", "was", "also", "limited", "ev", "i‑", "dence", "of", "associations", "between", "child", "DAPs", "and", "attention.", "c", "onclusi", ":", "In", "utero", "DAPs", "and,", "to", "a", "lesser", "extent,", "postnatal", "DAPs", "were", "associated", "adversely", "with", "attention", "as", "assessed", "by", "maternal", "report,", "psychometrician", "observation,", "and", "direct", "assessment.", "These", "associations", "were", "somewhat", "stronger", "at", "5", "years", "than", "at", "3.5", "years", "and", "were", "stronger", "in", "boys.", "k", "ey", "words", ":", "ADHD,", "attention,", "Child", "Behavior", "Checklist,", "DAPs,", "farmworker,", "Mexican", "Americans,", "neurobehavior,", "organophosphates,", "pesticides.", "Environ", "Health", "Perspect", "118:1768–1774", "(2010).", "doi:10.1289/ehp.1002056", "[Online", "19", "August", "2010]", "mothers’", "report", "of", "symptoms", "consistent", "with", "pervasive", "developmental", "disorder", "(PDD)", "as", "well", "as", "of", "attention", "deficit/hyperactivity", "disor-", "der", "(ADHD)", "or", "attention", "problems.", "A", "recent", "cross-sectional", "study", "also", "reported", "associations", "between", "child", "OP", "metabolite", "concentrations", "and", "ADHD", "in", "8-", "to", "15-year-olds", "representa-", "tive", "of", "the", "U.S.", "population", "(Bouchard", "et", "al.", "2010).", "Although", "we", "previously", "reported", "that", "prenatal", "OP", "metabolite", "concentrations", "were", "associated", "with", "mothers’", "report", "of", "PDD", "symptoms", "in", "2-year-olds", "living", "in", "the", "agri-", "cultural", "Salinas", "Valley", "of", "California,", "we", "did", "not", "find", "an", "association", "between", "maternal", "or", "child", "dialkyl", "phosphates", "(DAPs)", "and", "meas-", "ures", "of", "attention", "at", "2", "years", "of", "age", "(Eskenazi", "et", "al.", "2007).", "However,", "the", "children", "in", "our", "study", "were", "younger—potentially", "too", "young", "at", "2", "years", "of", "age", "to", "manifest", "attention", "prob-", "lems", "or", "for", "mothers", "to", "detect", "them.", "Although", "ADHD,", "characterized", "by", "inattention,", "impul-", "sivity,", "and/or", "hyperactivity,", "is", "occasionally", "diagnosed", "in", "children", "as", "young", "as", "2", "or", "3", "years,", "it", "is", "more", "apparent", "after", "children", "begin", "school", "and", "is", "more", "commonly", "reported", "in", "boys", "than", "Address", "correspondence", "to", "B.", "Eskenazi,", "Center", "for", "Children’s", "Environmental", "Health", "Research,", "School", "of", "Public", "Health,", "UC", "Berkeley,", "1995", "University", "Ave.,", "Suite", "265,", "Berkeley,", "CA", "94720", "USA.", "Telephone:", "(510)", "643-1337.", "Fax:", "(510)", "642-9083.", "E-mail:", "eskenazi@berkeley.edu", "Supplemental", "Material", "is", "available", "online", "(doi:10.1289/ehp.1002056", "via", "http://dx.doi.org/).", "We", "acknowledge", "the", "CHAMACOS", "staff,", "students,", "community", "partners,", "and", "participants", "and", "families,", "without", "whom", "this", "study", "would", "not", "be", "possible.", "We", "would", "specifically", "like", "to", "thank", "the", "CHAMACOS", "Field", "Office", "staff", "as", "well", "as", "N.", "Holland", "for", "her", "assis-", "tance", "in", "specimen", "management", "and", "R.", "Klein", "for", "advice", "on", "attention", "measurements.", "This", "publication", "was", "made", "possible", "by", "research", "supported", "by", "grants", "RD", "83171001", "from", "the", "U.S.", "Environmental", "Protection", "Agency", "(EPA),", "PO1", "ES009605", "from", "the", "National", "Institute", "of", "Environmental", "Health", "Sciences", "(NIEHS),", "and", "RO1", "OH007400", "from", "the", "National", "Institute", "for", "Occupational", "Safety", "and", "Health", "(NIOSH).", "The", "contents", "are", "solely", "the", "responsibility", "of", "the", "authors", "and", "do", "not", "necessarily", "represent", "the", "official", "views", "of", "the", "NIEHS,", "NIOSH,", "National", "Institutes", "of", "Health,", "or", "U.S.", "EPA.", "Since", "this", "paper", "was", "written,", "B.E.", "worked", "as", "an", "expert", "witness", "in", "a", "pesticide", "poisoning", "case.", "The", "authors", "declare", "they", "have", "no", "actual", "or", "potential", "com-", "peting", "financial", "interests.", "Received", "12", "February", "2010;", "accepted", "29", "March", "2010.", "ovlume", "118", "|", "number", "12", "|", "December", "2010", "•", "Environmental", "Health", "Perspectives", "Organophosphate", "(OP)", "pesticides", "are", "potent", "toxicants", "that", "target", "the", "nervous", "systems", "of", "insects", "and", "other", "pests", "(Jokanovic", "2009).", "OPs", "operate", "primarily", "through", "the", "inhibition", "of", "acetylcholinesterase,", "an", "enzyme", "that", "degrades", "the", "neurotransmitter", "acetylcholine,", "resulting", "in", "a", "buildup", "of", "acetylcholine", "in", "the", "neuronal", "junction", "(Jeyaratnam", "and", "Maroni", "1994).", "However,", "cholinergic", "inhibition", "may", "not", "be", "the", "sole", "mechanism", "of", "effect,", "particularly", "in", "cases", "of", "low-level", "exposure", "(Costa", "2006;", "Ray", "and", "Richards", "2001;", "Timofeeva", "et", "al.", "2008).", "Although", "accounts", "of", "human", "poisoning", "with", "these", "compounds", "have", "reported", "symptoms", "such", "as", "impaired", "concentration,", "slowed", "infor-", "mation", "processing", "and", "motor", "function,", "anxi-", "ety,", "confusion,", "tremors,", "seizure,", "and", "death", "(Jeyaratnam", "and", "Maroni", "1994;", "Levin", "and", "Rodnitzky", "1976),", "few", "studies", "have", "investi-", "gated", "the", "health", "effects", "in", "humans", "of", "low-", "level", "chronic", "exposure", "to", "OP", "pesticides.", "The", "potential", "effects", "of", "such", "low-level", "exposures", "on", "neurobehavioral", "functioning", "are", "particu-", "larly", "relevant", "for", "fetuses", "and", "young", "children,", "who", "may", "be", "especially", "vulnerable", "to", "neuro-", "toxicants", "because", "of", "their", "immature", "nervous", "systems,", "their", "rapid", "rate", "of", "brain", "growth", "and", "1768", "development", "in", "utero", "and", "during", "early", "child-", "hood,", "and", "their", "low", "levels", "of", "the", "enzymes", "involved", "in", "the", "metabolism", "and", "detoxifica-", "tion", "of", "OP", "pesticides", "(Eskenazi", "et", "al.", "1999;", "Huen", "et", "al.", "2009).", "Animal", "studies", "have", "found", "adverse", "effects", "of", "OP", "exposure", "during", "the", "pre-", "natal", "and", "early", "postnatal", "periods", "(Costa", "2006;", "Eskenazi", "et", "al.", "1999).", "Although", "research", "is", "limited,", "a", "few", "recent", "epidemiologic", "studies", "have", "reported", "asso-", "ciations", "between", "in", "utero", "OP", "exposure", "and", "adverse", "effects", "on", "neurobehavioral", "devel-", "opment", "(Engel", "et", "al.", "2007;", "Eskenazi", "et", "al.", "2007;", "Rauh", "et", "al.", "2006;", "Young", "et", "al.", "2005).", "These", "studies", "have", "found", "that", "biomarkers", "of", "prenatal", "OP", "exposure", "are", "associated", "with", "an", "increased", "number", "of", "abnormal", "neonatal", "reflexes,", "as", "measured", "by", "the", "Brazelton", "Scales", "of", "Neonatal", "Development", "(Engel", "et", "al.", "2007;", "Young", "et", "al.", "2005),", "and", "poorer", "mental", "devel-", "opment", "in", "early", "childhood,", "as", "measured", "on", "the", "Bayley", "Scales", "of", "Infant", "Development", "(Eskenazi", "et", "al.", "2007;", "Rauh", "et", "al.", "2006).", "Rauh", "et", "al.", "(2006)", "also", "found", "in", "a", "cohort", "of", "3-year-olds", "living", "in", "New", "York", "City", "that", "con-", "centrations", "of", "the", "OP", "pesticide", "chlorpyrifos", "in", "maternal", "serum", "were", "associated", "with", "the" ]

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[ "Sensors", "2011,", "11,", "7749-7762;", "doi:10.3390/s110807749", "OPEN", "ACCESS", "sensors", "ISSN", "1424-8220", "www.mdpi.com/journal/sensors", "Article", "A", "Renewable", "and", "Ultrasensitive", "Electrochemiluminescence", "Immunosenor", "Based", "on", "Magnetic", "RuL@SiO2-Au~RuL-Ab2", "Sandwich-Type", "Nano-Immunocomplexes", "Ning", "Gan", "*,", "Jianguo", "Hou,", "Futao", "Hu,", "Yuting", "Cao,", "Tianhua", "Li,", "Zhiyong", "Guo", "and", "Jun", "Wang", "The", "State", "key", "Laboratory", "of", "Novel", "Functional", "Materials", "and", "Preparation", "Science,", "Faculty", "of", "Material", "Science", "and", "Chemical", "Engineering,", "Ningbo", "University,", "Ningbo", "315211,", "China;", "E-Mails:", "aaaguolong@gmail.com", "(J.H.);", "hufutao@nbu.edu.cn", "(F.H.);", "caoyuting001@126.com", "(Y.C.);", "litianhua@nbu.edu.cn", "(T.L.);", "guozhiyong@nbu.edu.cn", "(Z.G.)", "*", "Author", "to", "whom", "correspondence", "should", "be", "addressed;", "E-Mail:ganning@nbu.edu.cn;", "Tel:", "+86-574-8760-9933.", "Fax:", "+86-574-8760-0734.", "Received:", "23", "June", "2011;", "in", "revised", "form:", "20", "July", "2011", "/", "Accepted:", "21", "July", "2011", "/", "Published:", "5", "August", "2011", "Abstract:", "An", "ultrasensitive", "and", "renewable", "electrochemiluminescence", "(ECL)", "immunosensor", "was", "developed", "for", "the", "detection", "of", "tumor", "markers", "by", "combining", "a", "newly", "designed", "trace", "tag", "and", "streptavidin-coated", "magnetic", "particles", "(SCMPs).", "The", "trace", "tag", "(RuL@SiO2-Au~RuL-Ab2)", "was", "prepared", "by", "loading", "Ru(bpy)32+(RuL)-conjuged", "secondary", "antibodies", "(RuL-Ab2)", "on", "RuL@SiO2", "(RuL-doped", "SiO2)", "doped", "Au", "(RuL@SiO2-Au).", "To", "fabricate", "the", "immunosensor,", "SCMPs", "were", "mixed", "with", "biotinylated", "AFP", "primary", "antibody", "(Biotin-Ab1),", "AFP,", "and", "RuL@SiO2-Au~RuL-Ab2", "complexes,", "then", "the", "resulting", "SCMP/Biotin-Ab1/AFP/RuL@SiO2-Au~RuL-Ab2", "(SBAR)", "sandwich-type", "immunocomplexes", "were", "absorbed", "on", "screen", "printed", "carbon", "electrode", "(SPCE)", "for", "detection.", "The", "immunocomplexes", "can", "be", "easily", "washed", "away", "from", "the", "surface", "of", "the", "SPCE", "when", "the", "magnetic", "field", "was", "removed,", "which", "made", "the", "immunosensor", "reusable.", "The", "present", "immunosensor", "showed", "a", "wide", "linear", "range", "of", "0.05–100", "ng", "mL–1", "for", "detecting", "AFP,", "with", "a", "low", "detection", "limit", "of", "0.02", "ng", "mL–1", "(defined", "as", "S/N", "=", "3).", "The", "method", "takes", "advantage", "of", "three", "properties", "of", "the", "immunosensor:", "firstly,", "the", "RuL@SiO2-Au~RuL-Ab2", "composite", "exhibited", "dual", "amplification", "since", "SiO2", "could", "load", "large", "amount", "of", "reporter", "molecules", "(RuL)", "for", "signal", "amplification.", "Gold", "particles", "could", "provide", "a", "large", "active", "surface", "to", "load", "more", "reporter", "molecules", "(RuL-Ab2).", "Accordingly,", "through", "the", "ECL", "response", "of", "RuL", "and", "tripropylamine", "(TPA),", "a", "strong", "ECL", "signal", "was", "obtained", "and", "an", "amplification", "analysis", "of" ]

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[ "Camporota", "et", "al.", "Critical", "Care", "2012,", "16:114", "http://ccforum.com/content/16/1/114", "C", "O", "M", "M", "E", "N", "TA", "R", "Y", "Extravascular", "lung", "water", "in", "acute", "respiratory", "distress", "syndrome:", "potential", "clinical", "value,", "assumptions", "and", "limitations", "Luigi", "Camporota*,", "Mark", "De", "Neef", "and", "Richard", "Beale", "See", "related", "research", "by", "Chew", "et", "al.,", "http://ccforum.com/content/16/1/R1", "Abstract", "Extravascular", "lung", "water", "has", "been", "proposed", "as", "a", "marker", "of", "disease", "severity,", "response", "to", "treatment", "and", "mortality", "in", "patients", "with", "acute", "respiratory", "distress", "syndrome.", "Here,", "we", "discuss", "its", "potential", "value", "and", "limitations", "in", "clinical", "practice.", "Acute", "respiratory", "distress", "syndrome", "(ARDS)", "is", "charac-", "terised", "by", "diffuse", "alveolar", "damage", "and", "increased", "extra-", "vascular", "lung", "water", "(EVLW),", "clinically", "measured", "by", "the", "trans-pulmonary", "single-indicator", "thermo-dilution", "method.", "Although", "not", "part", "of", "the", "diagnostic", "criteria", "for", "ARDS,", "increased", "EVLW", "is", "central", "to", "the", "pathophysiology", "of", "the", "syndrome", "and", "correlates", "with", "the", "severity", "of", "lung", "injury,", "response", "to", "treatment", "and", "clinical", "outcome.", "In", "this", "issue", "of", "Critical", "Care,", "Chew", "and", "colleagues", "[1],", "in", "an", "obser-", "vational", "study", "involving", "an", "heterogeneous", "population", "of", "patients", "with", "shock,", "report", "the", "role", "of", "EVLW", "in", "the", "context", "of", "two", "themes:", "its", "ability", "to", "predict", "disease", "severity", "and", "outcome", "and", "its", "added", "value", "as", "a", "diagnostic", "criterion", "of", "ARDS.", "On", "the", "first", "theme,", "Chew", "and", "colleagues", "[1]", "report", "that", "patients", "with", "higher", "EVLW", "indices", "(EVLWIs)", "had", "more", "severe", "disease", "with", "greater", "Lung", "Injury", "Score,", "and", "were", "less", "likely", "to", "survive", "ICU", "[1].", "These", "findings", "are", "in", "accor-", "dance", "with", "the", "available", "literature", "[2-4],", "which", "suggests", "that", "EVLW", "is", "a", "good", "predictor", "of", "mortality", "with", "an", "odds", "ratio", "of", "8.8", "[5].", "However,", "there", "is", "still", "no", "firm", "consensus", "on", "its", "range", "of", "normal", "values", "and", "the", "best", "indexing", "parameter", "(for", "example,", "actual", "or", "predicted", "body", "weight", "*Correspondence:", "luigi.camporota@gstt.nhs.uk", "Department", "of", "Adult", "Critical", "Care", "-", "Guy’s", "and", "St", "Thomas’", "NHS", "Foundation", "Trust,", "St", "Thomas’", "Hospital,", "1st", "Floor", "East", "Wing,", "Lambeth", "Palace", "Road,", "London,", "SE1", "7EH,", "United", "Kingdom", "©", "2010", "BioMed", "Central", "Ltd", "©", "2012", "BioMed", "Central", "Ltd", "or", "pulmonary", "blood", "volume)", "against", "which", "EVLW", "should", "be", "normalised.", "Chew", "and", "colleagues", "[1]", "found", "that", "EVLW", "indexed", "to", "absolute", "body", "weight", "resulted", "in", "a", "stronger", "association", "with", "outcome.", "This", "result", "differs", "from", "previous", "clinical", "studies", "showing", "that", "EVLW", "indexed", "to", "predicted", "body", "weight", "(PBW)", "is", "a", "superior", "predictor", "of", "mortality", "[6],", "of", "developing", "multiple", "organ", "failure", "[2]", "and", "for", "the", "diagnosis", "of", "ARDS", "[4,6-8].", "The", "physiologic", "rationale", "for", "using", "predicted", "body", "weight", "is", "that", "lung", "size", "and", "lung", "weight", "depend", "on", "height", "and", "gender", "-", "and", "therefore", "predicted", "body", "weight", "-", "whereas", "adjusting", "EVLW", "for", "absolute", "body", "weight", "may", "lead", "to", "erroneous", "estimations", "of", "EVLW", "in", "obese", "patients.", "How-", "ever,", "obesity", "may", "be", "an", "explanatory", "variable", "rather", "than", "a", "confounding", "one.", "Obesity", "may", "directly", "affect", "EVLW", "-", "for", "example,", "by", "decreasing", "the", "intra-thoracic", "blood", "volume", "(ITBV)", "or", "the", "lymphatic", "clearance", "of", "EVLW", "through", "increased", "intra-abdominal", "and", "pleural", "pressures.", "As", "EVLW", "is", "calculated", "as", "the", "difference", "between", "the", "intra-", "thoracic", "thermal", "volume", "and", "ITBV,", "any", "change", "in", "pulmonary", "perfusion", "and", "ITBV", "will", "affect", "EVLW.", "In", "addition,", "the", "relationship", "between", "EVLW", "and", "disease", "severity,", "and", "EVLW", "and", "outcome,", "may", "reflect", "three", "independent", "but", "concurrent", "possibilities.", "First,", "EVLWI", "may", "measure", "the", "amount", "of", "inflammatory", "oedema", "(high", "permeability).", "The", "ratio", "of", "EVLW", "to", "the", "pulmonary", "blood", "volume", "has", "been", "used", "as", "an", "indirect", "index", "of", "pulmonary", "vascular", "permeability", "in", "critically", "ill", "patients", "with,", "or", "at", "risk", "of,", "ARDS", "[9],", "with", "normal", "ratios", "helping", "to", "exclude", "high", "pulmonary", "permeability", "[10].", "Chew", "and", "colleagues", "[1]", "show", "that", "this", "ratio", "seems", "a", "better", "marker", "of", "disease", "severity", "in", "patients", "with", "a", "Lung", "Injury", "Score", ">2.5,", "perhaps", "implying", "that", "patients", "with", "severe", "ARDS", "have", "greater", "lung", "oedema,", "possibly", "due", "to", "greater", "pulmonary", "permeability,", "and", "greater", "mortality.", "Computed", "tomography", "studies", "of", "patients", "with", "ARDS", "have", "suggested", "that", "patients", "with", "severe", "ARDS", "have", "greater", "inflammatory", "oedema", "and", "lung", "weight,", "a", "greater", "response", "to", "lung", "recruitment", "and", "higher", "positive" ]

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[ "JCB", "Article", "Laminin", "1", "is", "critical", "for", "Schwann", "cell", "differentiation,", "axon", "myelination,", "and", "regeneration", "in", "the", "peripheral", "nerve", "Zu-Lin", "Chen", "and", "Sidney", "Strickland", "Laboratory", "of", "Neurobiology", "and", "Genetics,", "The", "Rockefeller", "University,", "New", "York,", "NY", "10021", "y", "g", "o", "l", "o", "i", "B", "l", "l", "e", "C", "f", "o", "l", "a", "n", "r", "u", "o", "J", "e", "h", "T", "Lthat", "regulate", "cell", "viability", "and", "function.", "Laminin-2,", "aminins", "are", "heterotrimeric", "extracellular", "matrix", "proteins", "composed", "of", "2,", "1,", "and", "1", "chains,", "is", "a", "major", "ma-", "trix", "component", "of", "the", "peripheral", "nervous", "system", "(PNS).", "To", "investigate", "the", "role", "of", "laminin", "in", "the", "PNS,", "we", "used", "the", "Cre–loxP", "system", "to", "disrupt", "the", "laminin", "1", "gene", "in", "Schwann", "cells.", "These", "mice", "have", "dramatically", "reduced", "ex-", "pression", "of", "laminin", "1", "in", "Schwann", "cells,", "which", "results", "in", "a", "similar", "reduction", "in", "laminin", "2", "and", "1", "chains.", "These", "mice", "exhibit", "motor", "defects", "which", "lead", "to", "hind", "leg", "paralysis", "Introduction", "Myelination", "of", "nerves", "is", "essential", "for", "proper", "function", "of", "the", "nervous", "system,", "predominantly", "by", "allowing", "faster", "conduction", "velocity", "of", "action", "potentials.", "In", "the", "peripheral", "nervous", "system", "(PNS),", "bundles", "of", "axons", "are", "assembled", "during", "embryonic", "development.", "After", "birth,", "premyelinating", "Schwann", "cells", "separate", "these", "bundles", "by", "extending", "processes", "between", "the", "axons.", "Myelinating", "Schwann", "cells", "establish", "a", "1:1", "ratio", "with", "axons,", "and", "envelop", "them", "in", "a", "myelin", "sheath.", "Nonmyelinating", "Schwann", "cells", "extend", "cytoplasmic", "processes", "between", "axons", "and", "separate", "them,", "but", "do", "not", "form", "a", "myelin", "sheath", "(Mirsky", "and", "Jessen,", "1999).", "The", "ECM", "has", "been", "implicated", "in", "myelination", "in", "the", "PNS", "(R.", "Bunge,", "1993),", "and", "laminins", "are", "components", "of", "the", "ECM", "that", "appear", "to", "be", "especially", "important.", "Studies", "in", "cell", "culture", "have", "suggested", "that", "laminin", "plays", "a", "critical", "role", "in", "myelination", "(Doyu", "et", "al.,", "1993;", "Fernandez-Valle", "et", "al.,", "1993;", "Fernandez-Valle", "et", "al.,", "1994;", "Podratz", "et", "al.,", "2001;", "Tsiper", "and", "Yurchenco,", "2002).", "In", "vivo", "studies", "have", "also", "suggested", "that", "laminin", "is", "important.", "Mutations", "in", "the", "laminin", "2", "gene", "in", "mice", "(dy/dy", "and", "dy2J/dy2J;", "Xu", "et", "al.,", "1994;", "Sunada", "Address", "correspondence", "to", "Sidney", "Strickland,", "Laboratory", "of", "Neurobiology", "and", "Genetics,", "The", "Rockefeller", "University,", "1230", "York", "Ave.,", "New", "York,", "NY", "10021.", "Tel.:", "(212)", "327-8705.", "Fax:", "(212)", "327-8774.", "email:", "strickland@rockefeller.edu", "Key", "words:", "paralysis;", "axon", "sorting;", "Cre-loxP;", "extracellular", "matrix", "", "The", "Rockefeller", "University", "Press,", "0021-9525/2003/11/889/11", "$8.00", "The", "Journal", "of", "Cell", "Biology,", "Volume", "163,", "Number", "4,", "November", "24,", "2003", "889–899", "http://www.jcb.org/cgi/doi/10.1083/jcb.200307068", "and", "tremor.", "During", "development,", "Schwann", "cells", "that", "lack", "laminin", "1", "were", "present", "in", "peripheral", "nerves,", "and", "prolif-", "erated", "and", "underwent", "apoptosis", "similar", "to", "control", "mice.", "However,", "they", "were", "unable", "to", "differentiate", "and", "synthesize", "myelin", "proteins,", "and", "therefore", "unable", "to", "sort", "and", "myelinate", "axons.", "In", "mutant", "mice,", "after", "sciatic", "nerve", "crush,", "the", "axons", "showed", "impaired", "regeneration.", "These", "experiments", "demon-", "strate", "that", "laminin", "is", "an", "essential", "component", "for", "axon", "my-", "elination", "and", "regeneration", "in", "the", "PNS.", "et", "al.,", "1995)", "or", "humans", "(CMD;", "Helbling-Leclerc", "et", "al.,", "1995)", "result", "in", "muscular", "dystrophy", "and", "a", "minor", "peripheral", "myelination", "defect", "(Bradley", "and", "Jenkison,", "1973;", "Madrid", "et", "al.,", "1975;", "Perkins", "et", "al.,", "1981).", "In", "this", "case,", "because", "the", "mutations", "also", "affect", "the", "muscle,", "the", "phenotype", "is", "a", "combi-", "nation", "of", "effects", "on", "the", "nerve", "and", "the", "muscle", "(Kuang", "et", "al.,", "1998).", "Other", "evidence", "suggesting", "a", "possible", "role", "for", "laminin", "in", "myelination", "stems", "from", "the", "observation", "that", "1", "integrin,", "a", "component", "of", "many", "laminin", "receptors,", "is", "necessary", "for", "proper", "myelination", "of", "peripheral", "nerves", "(Feltri", "et", "al.,", "2002).", "These", "results", "suggest", "that", "laminin", "might", "be", "important", "for", "myelination", "of", "peripheral", "nerves,", "but", "the", "mechanism", "for", "laminin", "action", "in", "vivo", "has", "not", "been", "elucidated.", "Laminins", "are", "heterotrimeric", "proteins", "composed", "of", "an", ",", ",", "and", "chain.", "At", "present,", "five", "chains,", "three", "chains,", "and", "three", "chains", "have", "been", "identified,", "and", "of", "the", "possible", "45", "potential", "trimeric", "mole-", "cules", "that", "could", "be", "generated", "from", "these", "chains,", "15", "have", "been", "observed", "(Colognato", "and", "Yurchenco,", "2000;", "Grimpe", "et", "al.,", "2002).", "Laminin", "1", "chain", "is", "one", "of", "the", "most", "abundant", "chains", "and", "is", "present", "in", "all", "known", "laminin", "isoforms", "except", "laminin-5", "and", "laminins", "12–15", "(Grimpe", "et", "al.,", "2002).", "Previous", "studies", "have", "shown", "that", "global", "disruption", "of", "laminin", "1", "gene", "leads", "to", "early", "(E5.5)", "embryonic", "lethality", "(Smyth", "et", "al.,", "1999).", "Abbreviations", "used", "in", "this", "paper:", "CaMKII", ",", "calcium/calmodulin-depen-", "dent", "protein", "kinase", "II", ";", "MBP,", "myelin", "basic", "protein;", "neoR,", "neomycin", "re-", "sistance;", "PNS,", "peripheral", "nervous", "system.", "889" ]

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[ "CMV", "Infection", "Attenuates", "the", "Disease", "Course", "in", "a", "Murine", "Model", "of", "Multiple", "Sclerosis", "Istvan", "Pirko1*,", "Rhonda", "Cardin2,", "Yi", "Chen", "3", ",", "Anne", "K.", "Lohrey3,", "Diana", "M.", "Lindquist4,", "R.", "Scott", "Dunn4,", "Robert", "Zivadinov5,", "Aaron", "J.", "Johnson3", "1", "Department", "of", "Neurology,", "Mayo", "Clinic,", "Rochester,", "Minnesota,", "United", "States", "of", "America,", "2", "Division", "of", "Infectious", "Diseases,", "Cincinnati", "Children’s", "Hospital", "Medical", "Center,", "Cincinnati,", "Ohio,", "United", "States", "of", "America,", "3", "Department", "of", "Neurology", "and", "Immunology,", "Mayo", "Clinic,", "Rochester,", "Minnesota,", "United", "States", "of", "America,", "4", "Imaging", "Research", "Center,", "Cincinnati", "Children’s", "Hospital", "Medical", "Center,", "Cincinnati,", "Ohio,", "United", "States", "of", "America,", "5", "Department", "of", "Neurology", "and", "Buffalo", "Neuroimaging", "Analysis", "Center,", "University", "of", "Buffalo,", "Buffalo,", "New", "York,", "United", "States", "of", "America", "Abstract", "Recent", "evidence", "in", "multiple", "sclerosis", "(MS)", "suggests", "that", "active", "CMV", "infection", "may", "result", "in", "more", "benign", "clinical", "disease.", "The", "goal", "of", "this", "pilot", "study", "was", "to", "determine", "whether", "underlying", "murine", "CMV", "(MCMV)", "infection", "affects", "the", "course", "of", "the", "Theiler’s", "murine", "encephalitis", "virus", "(TMEV)", "induced", "murine", "model", "of", "MS.", "A", "group", "of", "eight", "TMEV-infected", "mice", "were", "co-", "infected", "with", "MCMV", "at", "2", "weeks", "prior", "to", "TMEV", "infection", "while", "a", "second", "group", "of", "TMEV-infected", "mice", "received", "MCMV", "two", "weeks", "post", "TMEV.", "We", "also", "used", "2", "control", "groups,", "where", "at", "the", "above", "time", "points", "MCMV", "was", "replaced", "with", "PBS.", "Outcome", "measures", "included", "(1)", "monthly", "monitoring", "of", "disability", "via", "rotarod", "for", "8", "months;", "(2)", "in", "vivo", "MRI", "for", "brain", "atrophy", "studies", "and", "(3)", "FACS", "analysis", "of", "brain", "infiltrating", "lymphocytes", "at", "8", "months", "post", "TMEV", "infection.", "Co-infection", "with", "MCMV", "influenced", "the", "disease", "course", "in", "mice", "infected", "prior", "to", "TMEV", "infection.", "In", "this", "group,", "rotarod", "detectable", "motor", "performance", "was", "significantly", "improved", "starting", "3", "months", "post-infection", "and", "beyond", "(p#0.024).", "In", "addition,", "their", "brain", "atrophy", "was", "close", "to", "30%", "reduced", "at", "8", "months,", "but", "this", "was", "only", "present", "as", "a", "trend", "due", "to", "low", "power", "(p", "=", "0.19).", "A", "significant", "reduction", "in", "the", "proportion", "of", "brain", "infiltrating", "CD3+", "cells", "was", "detected", "in", "this", "group", "(p", "=", "0.026),", "while", "the", "proportion", "of", "CD45+", "Mac1+", "cells", "significantly", "increased", "(p", "=", "0.003).", "There", "was", "also", "a", "strong", "trend", "for", "a", "reduced", "proportion", "of", "CD4+", "cells", "(p", "=", "0.17)", "while", "CD8", "and", "B220+", "cell", "proportion", "did", "not", "change.", "These", "findings", "support", "an", "immunomodulatory", "effect", "of", "MCMV", "infection", "in", "this", "MS", "model.", "Future", "studies", "in", "this", "co-infection", "model", "will", "provide", "insight", "into", "mechanisms", "which", "modulate", "the", "development", "of", "demyelination", "and", "may", "be", "utilized", "for", "the", "development", "of", "novel", "therapeutic", "strategies.", "Citation:", "Pirko", "I,", "Cardin", "R,", "Chen", "Y,", "Lohrey", "AK,", "Lindquist", "DM,", "et", "al.", "(2012)", "CMV", "Infection", "Attenuates", "the", "Disease", "Course", "in", "a", "Murine", "Model", "of", "Multiple", "Sclerosis.", "PLoS", "ONE", "7(2):", "e32767.", "doi:10.1371/journal.pone.0032767", "Editor:", "Steven", "Jacobson,", "National", "Institutes", "of", "Health,", "United", "States", "of", "America", "Received", "September", "19,", "2011;", "Accepted", "January", "30,", "2012;", "Published", "February", "29,", "2012", "Copyright:", "2012", "Pirko", "et", "al.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Funding:", "This", "study", "was", "funded", "by", "the", "National", "MS", "Society,", "by", "intramural", "funds", "at", "the", "University", "of", "Cincinnati’s", "Waddell", "Center", "for", "Multiple", "Sclerosis,", "and", "by", "the", "National", "Institutes", "of", "Heatlh", "(NINDS", "R01", "NS058698).", "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:", "Pirko@mayo.edu", "Introduction", "Multiple", "sclerosis", "(MS)", "is", "the", "most", "common", "inflammatory", "demyelinating", "disease", "of", "the", "central", "nervous", "system", "(CNS).", "MS", "is", "the", "leading", "cause", "of", "non-traumatic", "disability", "among", "young", "adults", "in", "their", "most", "productive", "years", "[1].", "Although", "the", "exact", "cause", "of", "MS", "remains", "elusive,", "it", "is", "widely", "accepted", "that", "the", "pathology", "of", "MS", "is", "mediated", "by", "the", "immune", "system", "in", "genetically", "susceptible", "hosts", "[2].", "In", "addition", "to", "genetic", "risk", "factors,", "which", "determine", "the", "susceptibility", "and", "may", "influence", "disease", "severity,", "environmental", "factors", "are", "also", "suspected", "to", "contribute", "as", "disease", "initiating", "events", "[3].", "Infections,", "especially", "of", "viral", "etiology,", "have", "long", "been", "suspected", "as", "environmental", "factors", "that", "may", "contribute", "to", "the", "development", "of", "MS", "in", "addition", "to", "environmental", "variables", "including", "vitamin-D", "deficiency", "[4].", "Several", "viruses", "have", "been", "suspected", "as", "MS", "triggers.", "Currently,", "the", "most", "commonly", "studied", "virus", "which", "appears", "to", "be", "associated", "with", "MS", "is", "Epstein-Barr", "Virus", "(EBV),", "a", "member", "of", "the", "Herpesviridae", "family", "[5].", "EBV", "establishes", "a", "persistent", "infection", "in", "B", "cells.", "Interestingly,", "EBV", "is", "also", "suspected", "to", "play", "a", "role", "in", "the", "pathogenesis", "of", "several", "classic", "autoimmune", "diseases,", "including", "polymyositis,", "SLE,", "anti-phospho-", "lipid", "antibody", "syndrome,", "rheumatoid", "arthritis,", "pemphigus", "vul-", "garis,", "giant", "cell", "arthritis,", "Wegener’s", "granulomatosis,", "and", "polyar-", "teritis", "nodosa", "[6].", "A", "second", "herpes", "virus,", "human", "cytomegalovirus", "(HCMV),", "has", "also", "been", "proposed", "as", "a", "potential", "MS", "trigger", "[7].", "However,", "more", "recent", "studies", "with", "extensive", "case", "ascertainment", "failed", "to", "demonstrate", "such", "an", "association", "[5].", "Among", "systemic", "autoimmune", "conditions,", "elevated", "HCMV", "IgG", "titers", "were", "observed", "only", "in", "the", "sera", "of", "SLE", "patients", "[6].", "In", "a", "recent", "study", "analyzing", "the", "role", "of", "active", "HCMV", "infection", "in", "MS", "cases,", "multiple", "analyses", "demonstrated", "a", "clear", "association", "between", "antibody", "positivity", "against", "HCMV", "and", "better", "clinical", "and", "MRI", "outcomes", "[8].", "These", "analyses", "indicated", "that", "patients", "positive", "for", "antibodies", "against", "HCMV", "had", "significantly", "older", "age", "of", "disease", "onset,", "lower", "lifetime", "relapse", "rate,", "higher", "brain", "parenchymal", "fraction", "(BPF)on", "volumetric", "MRI,", "suggesting", "less", "brain", "atrophy.", "HCMV-positive", "patients", "who", "had", "higher", "antibody", "titer", "presented", "with", "lower", "T2", "weighted", "lesion", "load", "and", "higher", "BPF", "compared", "to", "patients", "with", "lower", "levels.", "Of", "note,", "this", "doesn’t", "mean", "that", "the", "antibody", "itself", "would", "be", "responsible", "for", "the", "protective", "effect;", "instead,", "it", "implies", "that", "recent", "active", "infection", "overall", "has", "a", "protective", "role,", "via", "a", "mechanism", "that", "can’t", "be", "directly", "clarified", "in", "PLoS", "ONE", "|", "www.plosone.org", "1", "February", "2012", "|", "Volume", "7", "|", "Issue", "2", "|", "e32767" ]

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[ "BMC", "Surgery", "Case", "report", "Splenectomy", "and", "proximal", "lieno-renal", "shunt", "in", "a", "factor", "five", "deficient", "patient", "with", "extra-hepatic", "portal", "vein", "obstruction", "Srinivas", "Prabhu", "Chava*1,", "Sujoy", "Pal1,", "Supriyo", "Ghatak1,", "Rajat", "Kumar2,", "Peush", "Sahni1", "and", "Tushar", "Kanti", "Chattopadhyay1", "BioMed", "Central", "Open", "Access", "Address:", "1Department", "of", "G.I.", "Surgery,", "All", "India", "Institute", "of", "Medical", "Sciences,", "New", "Delhi,", "110029,", "India", "and", "2Department", "of", "Hematology,", "All", "India", "Institute", "of", "Medical", "Sciences,", "New", "Delhi,", "110029,", "India", "Email:", "Srinivas", "Prabhu", "Chava*", "-", "spchava@yahoo.com;", "Sujoy", "Pal", "-", "sujoypal@hotmail.com;", "Supriyo", "Ghatak", "-", "drsupriyo@yahoo.co.in;", "Rajat", "Kumar", "-", "rajatkumar@hotmail.com;", "Peush", "Sahni", "-", "peush_sahni@hotmail.com;", "Tushar", "Kanti", "Chattopadhyay", "-", "tkc46@hotmail.com", "*", "Corresponding", "author", "Published:", "19", "May", "2006", "BMC", "Surgery", "2006,", "6:7", "doi:10.1186/1471-2482-6-7", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1471-2482/6/7", "Received:", "20", "September", "2005", "Accepted:", "19", "May", "2006", "©", "2006", "Chava", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "The", "clinico-surgical", "implication", "and", "successful", "management", "of", "a", "rare", "case", "of", "factor", "five", "(V)", "deficiency", "with", "portal", "hypertension", "and", "hypersplenism", "due", "to", "idiopathic", "extra-hepatic", "portal", "venous", "obstruction", "is", "presented.", "Case", "presentation:", "A", "16-year", "old", "boy", "had", "gastro-esophageal", "variceal", "bleeding,", "splenomegaly", "and", "hypersplenism.", "During", "preoperative", "workup", "prolonged", "prothrombin", "time", "and", "activated", "partial", "thromboplastin", "time", "were", "detected,", "which", "on", "further", "evaluation", "turned", "out", "to", "be", "due", "to", "factor", "V", "deficiency.", "Proximal", "lieno-renal", "shunt", "and", "splenectomy", "were", "successfully", "performed", "with", "transfusion", "of", "fresh", "frozen", "plasma", "during", "and", "after", "the", "surgical", "procedure.", "At", "surgery", "there", "was", "no", "excessive", "bleeding.", "The", "perioperative", "course", "was", "uneventful", "and", "the", "patient", "is", "doing", "well", "on", "follow", "up.", "Conclusion:", "Surgical", "portal", "decompressive", "procedures", "can", "be", "safely", "undertaken", "in", "clotting", "factor", "deficient", "patients", "with", "portal", "hypertension", "if", "meticulous", "surgical", "hemostasis", "is", "achieved", "at", "operation", "and", "the", "deficient", "factor", "is", "adequately", "replaced", "in", "the", "perioperative", "period.", "Background", "Congenital", "deficiency", "of", "factor", "V", "(parahemophilia)", "is", "a", "rare", "inherited", "disorder", "of", "coagulation", "which", "appears", "to", "follow", "an", "autosomal", "recessive", "or", "partially", "dominant", "pat-", "tern", "[1-4].", "Although", "the", "clinical", "features", "are", "rather", "mild", "compared", "with", "hemophilia,", "any", "surgical", "procedure", "undertaken", "without", "replacement", "therapy", "is", "uniformly", "complicated", "by", "excessive", "hemorrhage", "[1,2,5].", "As", "factor", "V", "concentrate", "is", "not", "available,", "fresh", "frozen", "plasma", "(FFP)", "is", "the", "only", "available", "source", "of", "factor", "V", "at", "the", "present", "time.", "We", "report", "a", "boy", "with", "extra-hepatic", "portal", "venous", "obstruc-", "tion", "(EHPVO),", "portal", "hypertension", "and", "upper", "gastroin-", "testinal", "(UGI)", "hemorrhage", "who", "also", "had", "factor", "V", "deficiency.", "Although", "many", "congenital", "anomalies", "such", "as", "cleft", "palate,", "mental", "retardation,", "short", "stature,", "syndactyly,", "atrial", "septal", "defect,", "ventricular", "septal", "defect,", "coarctation", "of", "aorta,", "duplication", "of", "the", "genitourinary", "collecting", "system", "have", "been", "associated", "with", "congenital", "deficiency", "of", "factor", "V", "[1-4],", "the", "simultaneous", "occurrence", "of", "factor", "V", "deficiency", "with", "EHPVO", "has", "not", "been", "described", "till", "date.", "EHPVO", "is", "a", "relatively", "common", "cause", "of", "portal", "hypertension", "in", "India,", "especially", "in", "the", "younger", "age", "group", "[6,7].", "Many", "causes,", "Page", "1", "of", "5", "(page", "number", "not", "for", "citation", "purposes)" ]

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[ "REVIEW", "ARTICLE", "published:", "31", "August", "2012", "doi:", "10.3389/fphys.2012.00346", "Induced", "pluripotent", "stem", "cell", "derived", "cardiomyocytes", "as", "models", "for", "cardiac", "arrhythmias", "Maaike", "Hoekstra", "1*,", "Christine", "L.", "Mummery", "2,", "Arthur", "A.", "M.", "Wilde", "1,", "Connie", "R.", "Bezzina", "1", "and", "Arie", "O.", "Verkerk", "3", "1", "Department", "of", "Clinical", "and", "Experimental", "Cardiology,", "Heart", "Failure", "Research", "Center,", "Academic", "Medical", "Center,", "University", "of", "Amsterdam,", "Amsterdam,", "Netherlands", "2", "Department", "of", "Anatomy", "and", "Embryology,", "Leiden", "University", "Medical", "Center,", "Leiden,", "Netherlands", "3", "Department", "of", "Anatomy,", "Embryology,", "and", "Physiology,", "Heart", "Failure", "Research", "Center,", "Academic", "Medical", "Center,", "University", "of", "Amsterdam,", "Amsterdam,", "Netherlands", "Edited", "by:", "Carol", "Ann", "Remme,", "University", "of", "Amsterdam,", "Netherlands", "Reviewed", "by:", "Teun", "P.", "De", "Boer,", "University", "Medical", "Center", "Utrecht,", "Netherlands", "Isabelle", "Baro,", "CNRS,", "France", "*Correspondence:", "Maaike", "Hoekstra,", "Department", "of", "Clinical", "and", "Experimental", "Cardiology,", "Heart", "Failure", "Research", "Center,", "Academic", "Medical", "Center,", "University", "of", "Amsterdam,", "room", "K2-113,", "Meibergdreef", "15,", "PO", "Box", "22700,", "1100", "DE", "Amsterdam,", "Netherlands.", "e-mail:", "m.hoekstra@amc.uva.nl", "Cardiac", "arrhythmias", "are", "a", "major", "cause", "of", "morbidity", "and", "mortality.", "In", "younger", "patients,", "the", "majority", "of", "sudden", "cardiac", "deaths", "have", "an", "underlying", "Mendelian", "genetic", "cause.", "Over", "the", "last", "15", "years,", "enormous", "progress", "has", "been", "made", "in", "identifying", "the", "distinct", "clinical", "phenotypes", "and", "in", "studying", "the", "basic", "cellular", "and", "genetic", "mechanisms", "associated", "with", "the", "primary", "Mendelian", "(monogenic)", "arrhythmia", "syndromes.", "Investigation", "of", "the", "electrophysiological", "consequences", "of", "an", "ion", "channel", "mutation", "is", "ideally", "done", "in", "the", "native", "cardiomyocyte", "(CM)", "environment.", "However,", "the", "majority", "of", "such", "studies", "so", "far", "have", "relied", "on", "heterologous", "expression", "systems", "in", "which", "single", "ion", "channel", "genes", "are", "expressed", "in", "non-cardiac", "cells.", "In", "some", "cases,", "transgenic", "mouse", "models", "have", "been", "generated,", "but", "these", "also", "have", "significant", "shortcomings,", "primarily", "related", "to", "species", "differences.", "The", "discovery", "that", "somatic", "cells", "can", "be", "reprogrammed", "to", "pluripotency", "as", "induced", "pluripotent", "stem", "cells", "(iPSC)", "has", "generated", "much", "interest", "since", "it", "presents", "an", "opportunity", "to", "generate", "patient-", "and", "disease-specific", "cell", "lines", "from", "which", "normal", "and", "diseased", "human", "CMs", "can", "be", "obtained", "These", "genetically", "diverse", "human", "model", "systems", "can", "be", "studied", "in", "vitro", "and", "used", "to", "decipher", "mechanisms", "of", "disease", "and", "identify", "strategies", "and", "reagents", "for", "new", "therapies.", "Here,", "we", "review", "the", "present", "state", "of", "the", "art", "with", "respect", "to", "cardiac", "disease", "models", "already", "generated", "using", "IPSC", "technology", "and", "which", "have", "been", "(partially)", "characterized.", "Human", "iPSC", "(hiPSC)", "models", "have", "been", "described", "for", "the", "cardiac", "arrhythmia", "syndromes,", "including", "LQT1,", "LQT2,", "LQT3-Brugada", "Syndrome,", "LQT8/Timothy", "syndrome", "and", "catecholaminergic", "polymorphic", "ventricular", "tachycardia", "(CPVT).", "In", "most", "cases,", "the", "hiPSC-derived", "cardiomyoctes", "recapitulate", "the", "disease", "phenotype", "and", "have", "already", "provided", "opportunities", "for", "novel", "insight", "into", "cardiac", "pathophysiology.", "It", "is", "expected", "that", "the", "lines", "will", "be", "useful", "in", "the", "development", "of", "pharmacological", "agents", "for", "the", "management", "of", "these", "disorders.", "Keywords:", "induced", "pluripotent", "stem", "cells,", "cardiac", "arrhythmia", "syndromes,", "electrophysiology,", "cardiomyocytes,", "human,", "iPS,", "heart", "INTRODUCTION", "Cardiac", "arrhythmias", "can", "be", "life", "threatening", "and", "are", "a", "major", "cause", "of", "morbidity", "and", "mortality", "in", "developed", "nations", "(Wolf", "and", "Berul,", "2008).", "In", "older", "patients,", "most", "arrhythmic", "sudden", "deaths", "occur", "in", "the", "setting", "of", "acute", "ischemia", "or", "coronary", "artery", "dis-", "eases", "(Zipes", "and", "Wellens,", "1998).", "In", "younger", "patients,", "the", "great", "majority", "of", "sudden", "arrhythmic", "deaths", "have", "an", "underlying", "genetic", "cause", "(Wilde", "and", "Bezzina,", "2005).", "These", "can", "be", "broadly", "subdi-", "vided", "into", "those", "associated", "with", "structural", "heart", "disease", "(such", "as", "hypertrophic", "cardiomyopathy)", "and", "those", "associated", "with", "elec-", "trical", "disease", "in", "the", "structurally", "normal", "heart", "(Wolf", "and", "Berul,", "2008).", "Over", "the", "last", "15", "years,", "much", "progress", "has", "been", "made", "in", "identifying", "the", "clinical", "phenotypes", "and", "cellular", "and", "genetic", "mech-", "anisms", "underlying", "the", "various", "primary", "Mendelian", "arrhythmia", "syndromes,", "including", "the", "Long", "QT", "syndrome", "(LQTS),", "Brugada", "Syndrome", "(BrS),", "and", "catecholaminergic", "polymorphic", "ventric-", "ular", "tachycardia", "(CPVT)", "(Wilde", "and", "Bezzina,", "2005).", "This", "has", "provided", "important", "insights", "into", "these", "disorders", "and", "as", "a", "con-", "sequence", "improved", "the", "management", "of", "affected", "patients.", "The", "availability", "of", "genetic", "tests", "has", "added", "an", "important", "diagnostic", "tool", "permitting", "early", "(presymptomatic)", "identification", "of", "patients", "at", "risk", "and", "allowing", "for", "the", "timely", "implementation", "of", "preven-", "tive", "strategies", "(Hofman", "et", "al.,", "2010).", "Studies", "into", "genotype–", "phenotype", "relationships", "have", "uncovered", "important", "gene-specific", "aspects", "of", "disease", "and", "indicated", "that", "patient", "management", "must", "take", "the", "nature", "of", "the", "gene", "affected", "into", "consideration", "(Priori,", "2004).", "However,", "there", "is", "considerable", "variation", "in", "phenotypic", "expression", "of", "arrhythmia", "syndromes", "even", "within", "families", "carry-", "ing", "the", "same", "mutation", "(Scicluna", "et", "al.,", "2008).", "Studying", "the", "electrophysiological", "and", "molecular", "consequences", "of", "a", "mutation", "associated", "with", "cardiac", "arrhythmia", "is", "ideally", "www.frontiersin.org", "August", "2012", "|", "Volume", "3", "|", "Article", "346", "|", "1" ]

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[ "Published", "online", "29", "September", "2010", "Nucleic", "Acids", "Research,", "2011,", "Vol.", "39,", "No.", "3", "1165–1175", "doi:10.1093/nar/gkq855", "Photosensitized", "[2+2]", "cycloaddition", "of", "N-acetylated", "cytosine", "affords", "stereoselective", "formation", "of", "cyclobutane", "pyrimidine", "dimer", "Junpei", "Yamamoto1,", "Kosuke", "Nishiguchi1,", "Koichiro", "Manabe", "1", ",", "Chikahide", "Masutani2,", "Fumio", "Hanaoka3", "and", "Shigenori", "Iwai1,*", "1Division", "of", "Chemistry,", "Graduate", "School", "of", "Engineering", "Science,", "Osaka", "University,", "1-3", "Machikaneyama,", "Toyonaka,", "Osaka", "560-8531,", "2Graduate", "School", "of", "Frontier", "Biosciences,", "Osaka", "University,", "1-3", "Yamada-oka,", "Suita,", "Osaka", "565-0871", "and", "3Faculty", "of", "Science,", "Gakushuin", "University,", "1-5-1", "Mejiro,", "Toshima-ku,", "Tokyo", "171-8588,", "Japan", "Received", "August", "12,", "2010;", "Revised", "September", "9,", "2010;", "Accepted", "September", "10,", "2010", "ABSTRACT", "Photocycloaddition", "between", "two", "adjacent", "bases", "in", "DNA", "produces", "a", "cyclobutane", "pyrimidine", "dimer", "(CPD),", "which", "is", "one", "of", "the", "major", "UV-induced", "DNA", "lesions,", "with", "either", "the", "cis-syn", "or", "trans-syn", "structure.", "In", "this", "study,", "we", "investigated", "the", "photosensitized", "intramolecular", "cycloaddition", "of", "partially-protected", "thymidylyl-(30!50)-N4-acetyl-20-", "deoxy-5-methylcytidine,", "to", "clarify", "the", "effect", "of", "the", "base", "modification", "on", "the", "cycloaddition", "reaction.", "The", "reaction", "resulted", "in", "the", "stereoselective", "forma-", "tion", "of", "the", "trans-syn", "CPD,", "followed", "by", "hydrolysis", "of", "the", "acetylamino", "group.", "The", "same", "result", "was", "obtained", "for", "the", "photocycloaddition", "of", "thymidylyl-", "(30!50)-N4-acetyl-20-deoxycytidine,", "whereas", "both", "the", "cis-syn", "and", "trans-syn", "CPDs", "were", "formed", "from", "thymidylyl-(30!50)-thymidine.", "Kinetic", "analyses", "revealed", "that", "the", "activation", "energy", "of", "the", "acid-", "catalyzed", "hydrolysis", "is", "comparable", "to", "that", "reported", "for", "the", "thymine-cytosine", "CPD.", "These", "findings", "provided", "a", "new", "strategy", "for", "the", "synthesis", "of", "oligonucleotides", "containing", "the", "trans-syn", "CPD.", "Using", "the", "synthesized", "oligonucleotide,", "translesion", "synthesis", "by", "human", "DNA", "polymerase", "g", "was", "analyzed.", "INTRODUCTION", "In", "the", "field", "of", "organic", "synthesis,", "cycloaddition", "reactions", "are", "versatile", "and", "well-studied", "methods", "to", "form", "carbon–", "carbon", "covalent", "bonds.", "They", "include", "the", "[2+2]", "cycloadd-", "ition", "by", "light", "irradiation,", "the", "Diels–Alder", "reaction", "by", "heating,", "and", "the", "1,3-dipolar", "cycloaddition", "using", "metal", "catalysts.", "Among", "such", "reactions,", "the", "[2+2]", "cycloaddition,", "in", "which", "4p", "electrons", "of", "two", "double", "bonds", "participate", "in", "the", "formation", "of", "a", "four-membered", "ring,", "is", "widely", "used", "for", "the", "construction", "of", "the", "core", "four-membered", "ring", "in", "natural", "products", "and", "for", "the", "introduction", "of", "functional", "groups", "by", "rearrangement", "via", "the", "heterolytic", "opening", "of", "the", "strained", "four-membered", "ring", "(1–5).", "DNA", "is", "an", "organic", "molecule", "that", "undergoes", "the", "[2+2]", "cycloaddition", "reaction", "as", "well", "as", "other", "chemical", "reactions.", "The", "major", "reaction", "occurs", "between", "the", "C5–C6", "double", "bonds", "of", "adjacent", "pyrimidine", "bases", "when", "they", "are", "exposed", "to", "environmental", "ultraviolet", "light,", "which", "results", "in", "the", "formation", "of", "cyclobutane", "pyrimidine", "dimers", "(CPDs),", "a", "major", "type", "of", "UV-induced", "lesions.", "The", "struc-", "ture", "of", "the", "CPD", "can", "be", "categorized", "into", "four", "types,", "namely", "cis-syn,", "trans-syn,", "cis-anti", "and", "trans-anti,", "depend-", "ing", "on", "the", "spatial", "alignment", "of", "the", "two", "bases", "(Figure", "1A).", "Among", "these", "four", "structures,", "the", "cis-syn", "CPD", "is", "predom-", "inantly", "formed", "in", "double-stranded", "DNA,", "due", "to", "geometric", "constraints", "(6,7).", "The", "trans-syn", "CPD,", "which", "is", "formed", "by", "UVB", "and", "UVC", "at", "partially", "distorted", "regions", "within", "DNA", "(8–11),", "is", "the", "second", "major", "stereoisomer", "of", "this", "photo-", "product.", "This", "type", "of", "CPD", "is", "reportedly", "recognized", "by", "proteins", "(12–14).", "The", "trans-syn", "CPD", "is", "a", "substrate", "for", "DNA", "repair", "enzymes,", "such", "as", "DNA", "photolyase", "(12)", "and", "T4", "endonuclease", "V", "(13),", "although", "the", "repair", "efficiency", "was", "much", "lower", "than", "that", "for", "the", "cis-syn", "CPD.", "UvrA", "and", "XPE,", "which", "are", "the", "prokaryotic", "and", "human", "proteins", "involved", "in", "nucleotide", "excision", "repair,", "respectively,", "bound", "to", "this", "CPD", "with", "an", "affinity", "comparable", "to", "that", "for", "other", "UV", "lesions", "(14).", "Other", "types", "of", "CPD", "structures", "are", "reportedly", "formed", "between", "non-adjacent", "bases", "(15,16).", "UV", "irradiation", "of", "a", "single-stranded", "oligonucleotide", "in", "an", "acidic", "solution", "and", "the", "telomeric", "G-quadruplex", "structure", "*To", "whom", "correspondence", "should", "be", "addressed.", "Tel:", "+81", "6", "6850", "6250;", "Fax:", "+81", "6", "6850", "6240;", "Email:", "iwai@chem.es.osaka-u.ac.jp", "Present", "address:", "Chikahide", "Masutani,", "Research", "Institute", "of", "Environmental", "Medicine,", "Nagoya", "University,", "Furo-cho,", "Chikusa-ku,", "Nagoya", "464-8601,", "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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"heat", "and", "cold", "tolerance.", "To", "test", "the", "hypothesis", "that", "climate", "shaped", "variation", "in", "metabolism", "genes", "in", "humans,", "we", "used", "a", "bioinformatics", "approach", "based", "on", "network", "theory", "to", "select", "82", "candidate", "genes", "for", "common", "metabolic", "disorders.", "We", "genotyped", "873", "tag", "SNPs", "in", "these", "genes", "in", "54", "worldwide", "populations", "(including", "the", "52", "in", "the", "Human", "Genome", "Diversity", "Project", "panel)", "and", "found", "correlations", "with", "climate", "variables", "using", "rank", "correlation", "analysis", "and", "a", "newly", "developed", "method", "termed", "Bayesian", "geographic", "analysis.", "In", "addition,", "we", "genotyped", "210", "carefully", "matched", "control", "SNPs", "to", "provide", "an", "empirical", "null", "distribution", "for", "spatial", "patterns", "of", "allele", "frequency", "due", "to", "population", "history", "alone.", "For", "nearly", "all", "climate", "variables,", "we", "found", "an", "excess", "of", "genic", "SNPs", "in", "the", "tail", "of", "the", "distributions", "of", "the", "test", "statistics", "compared", "to", "the", "control", "SNPs,", "implying", "that", "metabolic", "genes", "as", "a", "group", "show", "signals", "of", "spatially", "varying", "selection.", "Among", "our", "strongest", "signals", "were", "several", "SNPs", "(e.g.,", "LEPR", "R109K,", "FABP2", "A54T)", "that", "had", "previously", "been", "associated", "with", "phenotypes", "directly", "related", "to", "cold", "tolerance.", "Since", "variation", "in", "climate", "may", "be", "correlated", "with", "other", "aspects", "of", "environmental", "variation,", "it", "is", "possible", "that", "some", "of", "the", "signals", "that", "we", "detected", "reflect", "selective", "pressures", "other", "than", "climate.", "Nevertheless,", "our", "results", "are", "consistent", "with", "the", "idea", "that", "climate", "has", "been", "an", "important", "selective", "pressure", "acting", "on", "candidate", "genes", "for", "common", "metabolic", "disorders.", "Citation:", "Hancock", "AM,", "Witonsky", "DB,", "Gordon", "AS,", "Eshel", "G,", "Pritchard", "JK,", "et", "al.", "(2008)", "Adaptations", "to", "climate", "in", "candidate", "genes", "for", "common", "metabolic", "disorders.", "PLoS", "Genet", "4(2):", "e32.", "doi:10.1371/journal.pgen.0040032", "Introduction", "The", "ability", "to", "cope", "with", "heat", "and", "cold", "stress", "is", "important", "for", "survival", "and", "reproduction", "of", "organisms", "in", "general,", "and", "especially", "for", "those", "exposed", "to", "extreme", "temperatures", "[1].", "If", "phenotypes", "that", "increase", "heat", "or", "cold", "tolerance", "were", "acted", "upon", "by", "natural", "selection,", "the", "genes", "responsible", "for", "these", "phenotypes", "would", "be", "expected", "to", "carry", "detectable", "signatures", "of", "selection", "in", "the", "spatial", "distribution", "of", "genetic", "variation.", "Indeed,", "latitudinal", "clines", "of", "allele", "frequencies", "have", "been", "observed", "for", "several", "polymorphisms", "in", "humans", "(e.g.", "[2,3])", "as", "well", "as", "in", "natural", "populations", "of", "model", "organisms,", "including", "Drosophila", "melanogaster", "(e.g.", "[4–8]),", "and", "Arabidopsis", "thaliana", "([9–", "11]).", "Interestingly,", "many", "of", "the", "variants", "with", "latitudinal", "clines", "in", "Drosophila", "reside", "in", "genes", "involved", "in", "energy", "metabolism.", "Adaptations", "to", "spatially", "varying", "selective", "pressures,", "such", "as", "climates,", "may", "be", "particularly", "important", "in", "human", "popula-", "tions.", "Because", "the", "human", "species", "first", "arose", "in", "equatorial", "Africa,", "the", "ability", "to", "tolerate", "high", "temperatures", "was", "likely", "under", "strong", "long-term", "selection", "in", "ancestral", "human", "pop-", "ulations.", "As", "humans", "spread", "out", "of", "equatorial", "Africa", "to", "regions", "at", "higher", "latitudes,", "cold", "temperatures", "likely", "became", "important", "selective", "forces.", "As", "a", "consequence,", "traits", "under", "stabilizing", "selection", "at", "near-equatorial", "latitudes", "may", "have", "become", "deleterious", "at", "higher", "latitudes.", "In", "addition", "to", "thermal", "stress,", "this", "scenario", "is", "likely", "to", "apply", "to", "a", "range", "of", "selective", "pressures,", "e.g.", "exposure", "to", "UV", "radiation", "and", "to", "different", "pathogens,", "which", "may", "be", "directly", "influenced", "by", "and", "partly", "correlated", "with", "climate.", "A", "striking", "example", "of", "adaptation", "to", "an", "environmental", "variable", "is", "variation", "in", "skin", "pigmentation,", "a", "phenotype", "known", "to", "vary", "worldwide", "as", "a", "function", "of", "UV", "radiation", "[12].", "Consistent", "with", "the", "notion", "that", "variation", "in", "skin", "pigmentation", "is", "adaptive,", "genome-wide", "scans", "for", "selection", "have", "detected", "strong", "signals", "at", "candidate", "genes", "for", "melanin", "production", "and", "melanocyte", "function", "[13–18].", "An-", "other", "possible", "example", "of", "spatial", "variation", "in", "selective", "pressures", "is", "sodium", "homeostasis.", "It", "was", "proposed", "that", "climate-related", "selection", "acted", "on", "the", "genes", "influencing", "salt", "and", "water", "retention", "and", "that", "variation", "in", "the", "intensity", "of", "selection", "partly", "accounts", "for", "the", "large", "inter-ethnic", "differ-", "ences", "in", "the", "prevalence", "of", "salt-sensitive", "hypertension", "[19,20].", "In", "support", "of", "this", "hypothesis,", "two", "recent", "studies", "reported", "a", "strong", "correlation", "between", "the", "frequencies", "of", "candidate", "risk", "variants", "for", "hypertension", "and", "latitude;", "this", "correlation", "was", "significant", "also", "when", "compared", "to", "that", "observed", "for", "a", "genome-wide", "set", "of", "random", "markers", "[21,22].", "In", "addition", "to", "skin", "pigmentation", "and", "sodium", "homeostasis,", "human", "body", "shape", "and", "size", "also", "show", "clines", "with", "climate", "variables,", "suggesting", "that", "humans", "conform", "to", "the", "classical", "Editor:", "Dmitri", "A.", "Petrov,", "Stanford", "University,", "United", "States", "of", "America", "Received", "November", "5,", "2007;", "Accepted", "December", "26,", "2007;", "Published", "February", "15,", "2008", "Copyright:", "2008", "Hancock", "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:", "HGDP,", "Human", "Genome", "Diversity", "Project;", "T2D,", "type", "2", "diabetes", "*", "To", "whom", "correspondence", "should", "be", "addressed.", "E-mail:", "dirienzo@genetics.", "uchicago.edu", "¤", "Current", "address:", "Division", "of", "Science,", "Mathematics", "and", "Computing,", "Bard", "College", "at", "Simon’s", "Rock,", "Great", "Barrington,", "Massachusetts,", "United", "States", "of", "America", "PLoS", "Genetics", "|", "www.plosgenetics.org", "0001", "February", "2008", "|", "Volume", "4", "|", "Issue", "2", "|", "e32" ]

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[ "Jia", "et", "al.", "BMC", "Cancer", "2010,", "10:446", "http://www.biomedcentral.com/1471-2407/10/446", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Traditional", "Cantonese", "diet", "and", "nasopharyngeal", "carcinoma", "risk:", "a", "large-scale", "case-control", "study", "in", "Guangdong,", "China", "Wei-Hua", "Jia1,2,3*†,", "Xiang-Yu", "Luo1,2†,", "Bing-Jian", "Feng4†,", "Hong-Lian", "Ruan1,3,", "Jin-Xin", "Bei1,2,", "Wen-Sheng", "Liu1,2,", "Hai-De", "Qin1,2,", "Qi-Sheng", "Feng1,2,", "Li-Zhen", "Chen1,2,", "Shugart", "Yin", "Yao5,", "Yi-Xin", "Zeng1,2", "Abstract", "Background:", "Nasopharyngeal", "carcinoma", "(NPC)", "is", "rare", "in", "most", "parts", "of", "the", "world", "but", "is", "a", "common", "malignancy", "in", "southern", "China,", "especially", "in", "Guangdong.", "Dietary", "habit", "is", "regarded", "as", "an", "important", "modifier", "of", "NPC", "risk", "in", "several", "endemic", "areas", "and", "may", "partially", "explain", "the", "geographic", "distribution", "of", "NPC", "incidence.", "In", "China,", "rapid", "economic", "development", "during", "the", "past", "few", "decades", "has", "changed", "the", "predominant", "lifestyle", "and", "dietary", "habits", "of", "the", "Chinese", "considerably,", "requiring", "a", "reassessment", "of", "diet", "and", "its", "potential", "influence", "on", "NPC", "risk", "in", "this", "NPC-endemic", "area.", "Methods:", "To", "evaluate", "the", "association", "between", "dietary", "factors", "and", "NPC", "risk", "in", "Guangdong,", "China,", "a", "large-scale,", "hospital-based", "case-control", "study", "was", "conducted.", "1387", "eligible", "cases", "and", "1459", "frequency", "matched", "controls", "were", "recruited.", "Odds", "ratios", "(ORs)", "and", "the", "corresponding", "95%", "confidence", "intervals", "(CIs)", "were", "estimated", "using", "a", "logistic", "regression", "model,", "adjusting", "for", "age,", "sex,", "education,", "dialect,", "and", "habitation", "household", "type.", "Results:", "Observations", "made", "include", "the", "following:", "1)", "consumption", "of", "canton-style", "salted", "fish,", "preserved", "vegetables", "and", "preserved/cured", "meat", "were", "significantly", "associated", "with", "increased", "risk", "of", "NPC,", "with", "enhanced", "odds", "ratios", "(OR)", "of", "2.45", "(95%", "CI:", "2.03-2.94),", "3.17(95%", "CI:", "2.68-3.77)", "and", "2.09", "(95%", "CI:", "1.22-3.60)", "respectively", "in", "the", "highest", "intake", "frequency", "stratum", "during", "childhood;", "2)", "consumption", "of", "fresh", "fruit", "was", "associated", "with", "reduced", "risk", "with", "a", "dose-", "dependent", "relationship", "(p", "=", "0.001);", "and", "3)", "consumption", "of", "Canton-style", "herbal", "tea", "and", "herbal", "slow-cooked", "soup", "was", "associated", "with", "decreased", "risk,", "with", "ORs", "of", "0.84", "(95%", "CI:", "0.68-1.03)", "and", "0.58", "(95%", "CI:", "0.47-0.72)", "respectively", "in", "the", "highest", "intake", "frequency", "stratum.", "In", "multivariate", "analyses,", "these", "associations", "remained", "significant.", "Conclusions:", "It", "can", "be", "inferred", "that", "previously", "established", "dietary", "risk", "factors", "in", "the", "Cantonese", "population", "are", "still", "stable", "and", "have", "contributed", "to", "the", "incidence", "of", "NPC.", "Background", "Although", "rare", "in", "most", "parts", "of", "the", "world,", "nasopharyn-", "geal", "carcinoma", "(NPC)", "is", "a", "common", "malignancy", "in", "southern", "China,", "especially", "in", "the", "Guangdong", "province", "[1,2].", "The", "incidence", "rate", "for", "males", "is", "more", "than", "20", "per", "100,000", "person-years", "and", "is", "as", "high", "as", "25", "to", "40", "per", "100,000", "person-years", "in", "some", "areas", "bordering", "the", "Xijiang", "River", "and", "the", "Pearl", "River", "[1-4].", "Within", "China,", "the", "incidence", "of", "NPC", "varies", "up", "to", "50-fold", "between", "*", "Correspondence:", "jiaweih@mail.sysu.edu.cn", "†", "Contributed", "equally", "1State", "Key", "Laboratory", "of", "Oncology", "in", "Southern", "China,", "Guangzhou,", "510060,", "China", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "regions,", "with", "rates", "generally", "increasing", "from", "northern", "China", "(e.g.,", "Beijing", "and", "Tianjin)", "to", "southern", "China;", "the", "rates", "in", "Chinese", "men", "in", "the", "most", "northern", "provinces", "are", "no", "higher", "than", "3", "per", "100,000", "person-years", "[1,2].", "Reports", "indicate", "that", "southern", "Chinese", "who", "migrate", "to", "intermediate-risk", "areas,", "such", "as", "Southeast", "Asia,", "or", "to", "low-risk", "areas,", "such", "as", "the", "United", "Kingdom,", "Australia", "and", "the", "United", "States,", "continue", "to", "have", "a", "high", "incidence", "of", "NPC", "[1,5-10].", "However,", "those", "who", "reside", "for", "a", "longer", "period", "of", "time", "in", "low-risk", "areas", "and", "their", "succeeding", "generations", "born", "in", "the", "West,", "have", "a", "decreased", "risk", "for", "NPC", "[8-10].", "These", "results", "suggest", "that", "environmental", "factors", "inherent", "in", "the", "traditional", "southern", "Chinese", "©", "2010", "Jia", "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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[ "3550–3560", "Nucleic", "Acids", "Research,", "2005,", "Vol.", "33,", "No.", "11", "doi:10.1093/nar/gki657", "Thermolytic", "CpG-containing", "DNA", "oligonucleotides", "as", "potential", "immunotherapeutic", "prodrugs", "1", "1", "Andrzej", "Grajkowski,", "Joao", "Pedras-Vasconcelos", ",", "Vivian", "Wang", ",", "Cristina", "Aus´ın,", "Sonja", "Hess2,", "Daniela", "Verthelyi1", "and", "Serge", "L.", "Beaucage*", "Laboratory", "of", "Chemistry", "and", "1Laboratory", "of", "Immunology,", "Division", "of", "Therapeutic", "Proteins,", "Center", "for", "Drug", "Evaluation", "and", "Research,", "Food", "and", "Drug", "Administration,", "8800", "Rockville", "Pike,", "Bethesda,", "MD", "20892,", "USA", "and", "2Laboratory", "of", "Bioorganic", "Chemistry,", "National", "Institute", "of", "Diabetes", "and", "Digestive", "and", "Kidney", "Diseases,", "The", "National", "Institutes", "of", "Health,", "9000", "Rockville", "Pike,", "Bethesda,", "MD", "20892,", "USA", "Received", "February", "14,", "2005;", "Revised", "May", "9,", "2005;", "Accepted", "May", "26,", "2005", "ABSTRACT", "A", "CpG-containing", "DNA", "oligonucleotide", "functional-", "ized", "with", "the", "2-(N-formyl-N-methyl)aminoethyl", "thio-", "phosphate", "protecting", "group", "(CpG", "ODN", "fma1555)", "was", "prepared", "from", "phosphoramidites", "1a–d", "using", "solid-phase", "techniques.", "The", "oligonucleotide", "beha-", "ved", "as", "a", "prodrug", "by", "virtue", "of", "its", "conversion", "to", "the", "well-studied", "immunomodulatory", "CpG", "ODN", "1555", "through", "thermolytic", "cleavage", "of", "the", "2-(N-formyl-N-", "methyl)aminoethyl", "thiophosphate", "protecting", "group.", "Such", "a", "conversion", "occurred", "at", "37", "C", "with", "a", "half-", "time", "of", "73", "h.", "The", "immunostimulatory", "properties", "of", "CpG", "ODN", "fma1555", "were", "evaluated", "in", "two", "in", "vivo", "assays,", "one", "of", "which", "consisted", "of", "mice", "challenged", "in", "the", "ear", "with", "live", "Leishmania", "major", "metacyclic", "promastigotes.", "Local", "intradermal", "administration", "of", "CpG", "ODN", "fma1555", "was", "as", "effective", "as", "that", "of", "CpG", "ODN", "1555", "in", "reducing", "the", "size", "of", "Leishmania", "lesions", "over", "time.", "In", "a", "different", "infectious", "model,", "CpG", "ODN", "1555", "prevented", "the", "death", "of", "Tacaribe-", "infected", "mice", "(43%", "survival)", "when", "administered", "between", "day", "0", "and", "3", "post", "infection.", "Administration", "of", "CpG", "ODN", "fma1555", "three", "days", "before", "infection", "resulted", "in", "improved", "immunoprotection", "(60–70%", "survival).", "Moreover,", "co-administration", "of", "CpG", "ODN", "fma1555", "and", "CpG", "ODN", "1555", "in", "this", "model", "increa-", "sed", "the", "window", "for", "therapeutic", "treatment", "against", "Tacaribe", "virus", "infection,", "and", "thus", "supports", "the", "use", "of", "thermolytic", "oligonucleotides", "as", "prodrugs", "in", "the", "effective", "treatment", "of", "infectious", "diseases.", "INTRODUCTION", "Over", "the", "last", "few", "years,", "our", "research", "efforts", "have", "focused", "on", "the", "design", "and", "development", "of", "thermolytic", "groups", "for", "50-hydroxyl", "(1)", "and", "phosphate", "(2–7)", "protection", "in", "an", "attempt", "to", "implement", "a", "‘heat-driven’", "process", "(8)", "for", "the", "synthesis", "of", "DNA", "oligonucleotides", "on", "microarrays.", "In", "sharp", "contrast", "to", "the", "current", "methods", "employed", "for", "oligonucleotide", "synthesis,", "such", "a", "process", "would", "involve", "rapid", "and", "efficient", "thermal", "removal", "of", "protecting", "groups", "from", "oligonucleotides", "under", "neutral", "conditions", "throughout", "chain", "assembly", "and", "final", "depro-", "tection.", "Specifically,", "heat-sensitive", "phosphate/thiophosphate", "protecting", "groups", "exhibiting", "unique", "thermolytic", "properties", "have", "been", "incorporated", "into", "oligonucleotides", "via", "phosphor-", "amidites", "1–6", "(Scheme", "1)", "employing", "solid-phase", "techniques.", "The", "deprotection", "mechanism", "of", "each", "thermolytic", "phosphate", "protecting", "group", "is", "consistent", "with", "a", "well-studied", "intramole-", "cular", "cyclodeesterification", "reaction", "(9–12),", "which", "has", "also", "been", "observed", "by", "others", "(13–16).", "Given", "the", "relatively", "rapid", "phosphate", "deprotection", "kinetics", "of", "DNA", "oligonucleotides", "that", "have", "been", "prepared", "using", "phosphoramidites", "4,", "5", "and", "6", "(6,7),", "the", "thermolytic", "3-(2-pyridyl)-1-propyl,", "2-[N-methyl-N-", "(2-pyridyl)]aminoethyl,", "and", "4-methythio-1-butyl", "groups", "for", "phosphate", "protection", "may", "indeed", "find", "application", "in", "the", "synthesis", "of", "oligonucleotides", "on", "microarrays", "considering", "the", "mildness", "of", "the", "deprotection", "conditions", "used", "for", "each", "group.", "However,", "oligonucleotides", "functionalized", "with", "the", "2-(N-formyl-N-methyl)aminoethyl", "group", "for", "phosphate/", "thiophosphate", "protection", "require", "a", "much", "higher", "temperature", "(90", "C)", "over", "a", "considerably", "longer", "period", "of", "time", "(", "3", "h)", "to", "complete", "the", "thermolytic", "cleavage", "of", "this", "protecting", "group.", "Although", "these", "conditions", "are", "not", "optimal", "for", "the", "preparation", "of", "diagnostic", "oligonucleotide", "microarrays,", "oligonucleotides", "functionalized", "with", "the", "2-(N-formyl-N-methyl)aminoethyl", "*To", "whom", "correspondence", "should", "be", "addressed.", "Tel:", "+1", "301", "827", "5162;", "Fax:", "+1", "301", "480", "3256;", "Email:", "beaucage@cber.fda.gov", "This", "paper", "is", "dedicated", "to", "Professor", "Wojciech", "J.", "Stec", "on", "the", "occasion", "of", "his", "65th", "birthday.", "The", "authors", "wish", "it", "to", "be", "known", "that,", "in", "their", "opinion,", "the", "first", "two", "authors", "should", "be", "regarded", "as", "joint", "First", "Authors", "The", "Author", "2005.", "Published", "by", "Oxford", "University", "Press.", "All", "rights", "reserved.", "The", "online", "version", "of", "this", "article", "has", "been", "published", "under", "an", "open", "access", "model.", "Users", "are", "entitled", "to", "use,", "reproduce,", "disseminate,", "or", "display", "the", "open", "access", "version", "of", "this", "article", "for", "non-commercial", "purposes", "provided", "that:", "the", "original", "authorship", "is", "properly", "and", "fully", "attributed;", "the", "Journal", "and", "Oxford", "University", "Press", "are", "attributed", "as", "the", "original", "place", "of", "publication", "with", "the", "correct", "citation", "details", "given;", "if", "an", "article", "is", "subsequently", "reproduced", "or", "disseminated", "not", "in", "its", "entirety", "but", "only", "in", "part", "or", "as", "a", "derivative", "work", "this", "must", "be", "clearly", "indicated.", "For", "commercial", "re-use,", "please", "contact", "journals.permissions@oupjournals.org" ]

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[ "Stark", "et", "al.", "BMC", "Health", "Services", "Research", "2011,", "11:9", "http://www.biomedcentral.com/1472-6963/11/9", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Health", "care", "use", "and", "costs", "of", "adverse", "drug", "events", "emerging", "from", "outpatient", "treatment", "in", "Germany:", "A", "modelling", "approach", "Renee", "G", "Stark1*,", "Jürgen", "John1,", "Reiner", "Leidl", "1,2", "Abstract", "Background:", "This", "study’s", "aim", "was", "to", "develop", "a", "first", "quantification", "of", "the", "frequency", "and", "costs", "of", "adverse", "drug", "events", "(ADEs)", "originating", "in", "ambulatory", "medical", "practice", "in", "Germany.", "Methods:", "The", "frequencies", "and", "costs", "of", "ADEs", "were", "quantified", "for", "a", "base", "case,", "building", "on", "an", "existing", "cost-of-", "illness", "model", "for", "ADEs.", "The", "model", "originates", "from", "the", "U.S.", "health", "care", "system,", "its", "structure", "of", "treatment", "probabilities", "linked", "to", "ADEs", "was", "transferred", "to", "Germany.", "Sensitivity", "analyses", "based", "on", "values", "determined", "from", "a", "literature", "review", "were", "used", "to", "test", "the", "postulated", "results.", "Results:", "For", "Germany,", "the", "base", "case", "postulated", "that", "about", "2", "million", "adults", "ingesting", "medications", "have", "will", "have", "an", "ADE", "in", "2007.", "Health", "care", "costs", "related", "to", "ADEs", "in", "this", "base", "case", "totalled", "816", "million", "Euros,", "mean", "costs", "per", "case", "were", "381", "Euros.", "About", "58%", "of", "costs", "resulted", "from", "hospitalisations,", "11%", "from", "emergency", "department", "visits", "and", "21%", "from", "long-term", "care.", "Base", "case", "estimates", "of", "frequency", "and", "costs", "of", "ADEs", "were", "lower", "than", "all", "estimates", "of", "the", "sensitivity", "analyses.", "Discussion:", "The", "postulated", "frequency", "and", "costs", "of", "ADEs", "illustrate", "the", "possible", "size", "of", "the", "health", "problems", "and", "economic", "burden", "related", "to", "ADEs", "in", "Germany.", "The", "validity", "of", "the", "U.S.", "treatment", "structure", "used", "remains", "to", "be", "determined", "for", "Germany.", "The", "sensitivity", "analysis", "used", "assumptions", "from", "different", "studies", "and", "thus", "further", "quantified", "the", "information", "gap", "in", "Germany", "regarding", "ADEs.", "Conclusions:", "This", "study", "found", "costs", "of", "ADEs", "in", "the", "ambulatory", "setting", "in", "Germany", "to", "be", "significant.", "Due", "to", "data", "scarcity,", "results", "are", "only", "a", "rough", "indication.", "Background", "Medications", "are", "used", "to", "cure", "or", "slow", "disease", "processes,", "to", "reduce", "symptoms", "and", "to", "improve", "quality", "of", "life", "[1].", "However,", "all", "medications", "may", "have", "disadvantageous", "effects,", "which", "may", "be", "reported", "as", "drug", "related", "problems", "(DRPs)", "or", "adverse", "drug", "events", "(ADEs).", "Studies", "of", "DRPs", "report", "actual", "or", "potential", "problems", "which", "interfere", "with", "the", "desired", "health", "outcome,", "a", "spectrum", "ranging", "from", "adverse", "consequences", "(such", "as", "side", "effects)", "to", "lack", "of", "effectiveness", "[2].", "In", "contrast,", "studies", "of", "ADEs", "report", "injuries", "due", "to", "the", "use", "of", "a", "drug", "[3].", "ADEs", "may", "be", "due", "to:", "1)", "medication", "errors;", "2)", "adverse", "drug", "reactions", "*", "Correspondence:", "r.stark@helmholtz-muenchen.de", "1Institute", "for", "Health", "Economics", "and", "Health", "Care", "Management,", "Helmholtz", "Zentrum", "München", "-", "German", "Research", "Center", "for", "Environmental", "Health,", "Ingolstädter", "Landstraße", "1,", "Neuherberg,", "85764,", "Germany", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "(ADRs),", "i.e.", "unintended", "reactions", "occurring", "at", "usual", "doses", "[4];", "3)", "interactions", "with", "other", "drugs,", "underlying", "diseases", "or", "the", "patient", "(idiosyncratic", "reactions", "and", "aller-", "gies)", "or", "4)", "errors", "in", "prescribing,", "dispensing,", "adhering", "to", "and", "monitoring", "medications", "[1,5].", "Literature", "reviews", "regarding", "the", "number", "of", "hospital", "admissions", "due", "to", "ADRs", "have", "reported", "various", "results.", "One", "review", "in", "2002", "reported", "that", "ADRs", "account", "for", "4.9%", "of", "hospital", "admissions", "[6]", "whereas", "another", "review", "in", "1997", "reported", "that", "5.8%", "of", "all", "admissions", "to", "medical", "departments", "[4]", "were", "drug-related.", "Only", "2", "studies", "have", "reported", "drug-related", "hospitalisations", "to", "internal", "medi-", "cine", "wards", "in", "Germany.", "Dormann", "[7]", "reported", "that", "3.8%", "of", "medical", "admissions", "were", "drug-related,", "while", "Schnee-", "weiss", "reported", "that", "2.4%", "of", "all", "medical", "admissions", "over", "30", "months", "were", "drug-related", "[8].", "©", "2011", "Stark", "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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[ "E", "X", "T", "R", "A", "Dement", "Geriatr", "Cogn", "Disord", "Extra", "2012;2:1–9", "DOI:", "10.1159/000335494", "©", "2012", "S.", "Karger", "AG,", "Basel", "Published", "online:", "January", "19,", "2012", "www.karger.com/dee", "This", "is", "an", "Open", "Access", "article", "licensed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution-", "NonCommercial-NoDerivs", "3.0", "License", "(www.karger.com/OA-license),", "applicable", "to", "the", "online", "version", "of", "the", "article", "only.", "Distribution", "for", "non-commercial", "purposes", "only.", "1", "Lack", "of", "Association", "between", "Apolipoprotein", "E", "Polymorphism", "with", "Age", "at", "Onset", "of", "Subcortical", "Vascular", "Dementia", "Hye", "Guk", "Ryua", "Sung-Won", "Younb", "Oh", "Dae", "Kwonc", "aDepartment", "of", "Biological", "Science,", "College", "of", "Natural", "Sciences,", "Daegu", "University,", "Departments", "of", "bRadiology", "and", "cNeurology,", "School", "of", "Medicine,", "Catholic", "University", "of", "Daegu,", "Daegu,", "South", "Korea", "Key", "Words", "Subcortical", "vascular", "dementia", "Alzheimer’s", "disease", "Age", "at", "onset", "Apolipoprotein", "E", "Risk", "factors", "White", "matter", "lesions", "Abstract", "Background", "and", "Purpose:", "The", "relationship", "between", "apolipoprotein", "E", "(ApoE)", "and", "onset", "of", "vas-", "cular", "dementia", "remains", "controversial.", "The", "aim", "of", "this", "study", "was", "to", "evaluate", "the", "relationship", "between", "ApoE", "polymorphism", "and", "the", "onset", "of", "subcortical", "vascular", "dementia", "(SVaD)", "compared", "to", "Alzheimer’s", "disease", "(AD)", "and", "normal", "controls.", "Methods:", "The", "study", "was", "comprised", "of", "61", "pa-", "tients", "with", "SVaD", "(42", "Binswanger", "type,", "19", "lacunar", "type)", "and", "112", "patients", "with", "AD", "(16", "early-onset", "AD,", "96", "late-onset", "AD)", "as", "well", "as", "284", "age-,", "gender-", "and", "education-matched", "normal", "controls.", "The", "diagnosis", "of", "SVaD", "was", "based", "on", "modified", "NINDS-AIREN", "criteria,", "and", "the", "diagnosis", "of", "AD", "was", "based", "on", "NINCDS-ADRDA", "criteria.", "ApoE", "polymorphism", "was", "genotyped", "in", "all", "participants.", "Re-", "sults:", "None", "of", "the", "three", "ApoE", "alleles", "was", "more", "prevalent", "in", "SVaD", "patients", "compared", "to", "normal", "controls,", "which", "was", "the", "case", "when", "both", "Binswanger", "and", "lacunar", "types", "were", "analyzed", "sepa-", "rately.", "ApoE", "4", "did", "not", "accelerate", "the", "onset", "of", "SVaD", "(OR", "1.66,", "95%", "CI:", "0.8–3.4),", "in", "contrast", "to", "a", "significant", "relation", "with", "late-onset", "AD", "(OR", "3.78,", "95%", "CI:", "2.2–6.5).", "Conclusion:", "Our", "results", "sug-", "gest", "that", "ApoE", "polymorphism", "is", "not", "associated", "with", "the", "onset", "of", "SVaD", "and", "that", "the", "two", "sub-", "types", "of", "SVaD", "may", "share", "similar", "pathophysiologies.", "Copyright", "©", "2012", "S.", "Karger", "AG,", "Basel", "Dr.", "Oh", "Dae", "Kwon", "Department", "of", "Neurology,", "Daegu", "Catholic", "University", "Medical", "Center", "Catholic", "University", "of", "Daegu", "3056-6,", "Daemyung", "4-dong,", "Namgu,", "Daegu", "(South", "Korea)", "Tel.", "+82", "53", "650", "4298,", "E-Mail", "dolbaeke@cu.ac.kr" ]

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[ "International", "Journal", "of", "Mental", "Health", "Systems", "Research", "BioMed", "Central", "Open", "Access", "Attitude", "of", "young", "psychiatrists", "toward", "coercive", "measures", "in", "psychiatry:", "a", "case", "vignette", "study", "in", "Japan", "Masaru", "Tateno*1,", "Kanna", "Sugiura2,", "Kumi", "Uehara3,", "Daisuke", "Fujisawa4,", "Yueren", "Zhao5,", "Naoki", "Hashimoto6,", "Hidehiko", "Takahashi7,", "Naofumi", "Yoshida8,", "Takahiro", "Kato9,", "Wakako", "Nakano10,", "Yosuke", "Wake11,", "Tomohiro", "Shirasaka1,", "Seiju", "Kobayashi1", "and", "Soichiro", "Sato12", "Address:", "1Department", "of", "Neuropsychiatry,", "School", "of", "Medicine,", "Sapporo", "Medical", "University,", "South-1,", "West-16,", "Chuo-ku,", "Sapporo,", "Japan", "0608543,", "2Department", "of", "Psychiatry,", "Yokohama", "City", "University,", "Yokohama,", "Japan,", "3Department", "of", "Psychiatry,", "Kanagawa", "Psychiatric", "Center", "Serigaya", "Hospital,", "Yokohama,", "Japan,", "4Department", "of", "Psychiatry,", "School", "of", "Medicine,", "Keio", "University,", "Tokyo,", "Japan,", "5Department", "of", "Psychiatry,", "Meisei", "Hospital,", "Kumamoto,", "Japan,", "6Department", "of", "Psychiatry,", "Hokkaido", "University", "Graduate", "School", "of", "Medicine,", "Sapporo,", "Japan,", "7Department", "of", "Molecular", "Neuroimaging,", "Clinical", "Neuroimaging", "Section,", "National", "Institute", "of", "Radiological", "Sciences,", "Chiba,", "Japan,", "8Department", "of", "Neuropsychiatry,", "Toho", "University,", "School", "of", "Medicine,", "Tokyo,", "Japan,", "9Department", "of", "Neuropsychiatry,", "Graduate", "school", "of", "Medical", "Sciences,", "Kyushu", "University,", "Fukuoka,", "Japan,", "10Department", "of", "Psychiatry,", "University", "of", "Occupational", "and", "Environmental", "Health,", "Kitakyushu,", "Japan,", "11Department", "of", "Neuropsychiatry,", "Okayama", "University", "Graduate", "School", "of", "Medicine,", "Dentistry", "and", "Pharmaceutical", "Sciences,", "Okayama,", "Japan", "and", "12Department", "of", "Psychiatry,", "Zikei", "Hospital,", "Okayama,", "Japan", "Email:", "Masaru", "Tateno*", "-", "tatema@sapmed.ac.jp;", "Kanna", "Sugiura", "-", "kannas@fb3.so-net.ne.jp;", "Kumi", "Uehara", "-", "kums@ballade.plala.or.jp;", "Daisuke", "Fujisawa", "-", "fujisawa@sc.itc.keio.ac.jp;", "Yueren", "Zhao", "-", "taipeeyen@ybb.ne.jp;", "Naoki", "Hashimoto", "-", "hashinao@vega.ocn.ne.jp;", "Hidehiko", "Takahashi", "-", "hidehiko@nirs.go.jp;", "Naofumi", "Yoshida", "-", "nao234@med.toho-u.ac.jp;", "Takahiro", "Kato", "-", "med@jap.com;", "Wakako", "Nakano", "-", "wakako-u@med.uoeh-u.ac.jp;", "Yosuke", "Wake", "-", "yosukewake@yahoo.co.jp;", "Tomohiro", "Shirasaka", "-", "shirasaka.t@sapmed.ac.jp;", "Seiju", "Kobayashi", "-", "seij@pastel.ocn.ne.jp;", "Soichiro", "Sato", "-", "soichiro@ja2.so-net.ne.jp", "*", "Corresponding", "author", "Published:", "22", "September", "2009", "International", "Journal", "of", "Mental", "Health", "Systems", "2009,", "3:20", "doi:10.1186/1752-4458-3-20", "This", "article", "is", "available", "from:", "http://www.ijmhs.com/content/3/1/20", "Received:", "20", "May", "2009", "Accepted:", "22", "September", "2009", "©", "2009", "Tateno", "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:", "Every", "psychiatrist", "must", "pay", "careful", "attention", "to", "avoid", "violating", "human", "rights", "when", "initiating", "coercive", "treatments", "such", "as", "seclusion", "and", "restraint.", "However,", "these", "interventions", "are", "indispensable", "in", "clinical", "psychiatry,", "and", "they", "are", "often", "used", "as", "strategies", "to", "treat", "agitated", "patients.", "In", "this", "study,", "we", "investigated", "young", "psychiatrists'", "attitudes", "toward", "psychiatric", "coercive", "measures.", "Methods:", "A", "total", "of", "183", "young", "psychiatrists", "participated", "as", "subjects", "in", "our", "study.", "A", "questionnaire", "with", "a", "case", "vignette", "describing", "a", "patient", "with", "acute", "psychosis", "was", "sent", "to", "the", "study", "subjects", "via", "the", "Internet", "or", "by", "mail.", "This", "questionnaire", "included", "scoring", "the", "necessity", "for", "hospitalization,", "and", "the", "likelihood", "of", "prescribing", "seclusion", "and/or", "restraint,", "on", "a", "9-point", "Likert", "scale", "(with", "9", "indicating", "strong", "agreement).", "Results:", "There", "was", "general", "agreement", "among", "the", "study", "subjects", "that", "the", "case", "should", "be", "admitted", "to", "a", "hospital", "(8.91", "±", "0.3)", "and", "secluded", "(8.43", "±", "1.0).", "The", "estimated", "length", "of", "hospitalization", "was", "13.53", "±", "6.4", "weeks.", "Regarding", "the", "likelihood", "of", "prescribing", "restraint,", "results", "showed", "great", "diversity", "(5.14", "±", "2.5", "on", "9-point", "scale);", "psychiatrists", "working", "at", "general", "hospitals", "scored", "significantly", "higher", "(6.25", "±", "2.5)", "than", "those", "working", "at", "university", "hospitals", "(5.02", "±", "2.3)", "or", "psychiatric", "hospitals", "(4.15", "±", "2.6).", "A", "two-group", "comparison", "of", "the", "length", "of", "inpatient", "care", "revealed", "a", "significant", "difference", "Page", "1", "of", "7", "(page", "number", "not", "for", "citation", "purposes)" ]

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[ "Interfacial", "integrity", "of", "bonded", "restorations", "with", "self-etching", "adhesives:", "Water", "storage", "and", "thermo-mechanical", "cycling", "Gislaine", "Cristine", "Martins1", "Alfonso", "Sánchez-Ayala2", "Paulo", "Henrique", "Perlatti", "D’Alpino3", "Abraham", "Lincoln", "Calixto4", "João", "Carlos", "Gomes4", "Osnara", "Maria", "Mongruel", "Gomes4", "AbstrA", "tc", "Objectives:", "Objective:", "To", "evaluate", "the", "effect", "of", "thermo-mechanical", "cycling", "(TMC)", "on", "the", "microle-", "akage", "(µL)", "and", "axial", "gap", "width", "(AG)", "of", "Class", "V", "bonded", "restorations", "in", "premolars", "using", "self-etching", "adhesive", "systems.", "The", "bond", "strength", "of", "composite", "restorations", "to", "dentin", "(µTBS)", "using", "the", "same", "adhesives", "was", "also", "evaluated", "in", "third", "molars", "after", "water", "storage:", "24", "h", "and", "6", "months.", "The", "research", "hypotheses", "were", "tested", "for", "the", "results", "of", "two", "self-etching", "adhesives", "in", "comparison", "when", "a", "conven-", "tional", "two-step", "adhesive", "was", "used:", "(1)", "the", "µL", "and", "AG", "would", "be", "lower,", "regardless", "of", "TMC;", "(2)", "the", "µTBS", "of", "self-etching", "adhesives", "would", "be", "higher,", "irrespective", "of", "evaluation", "times.", "Methods:", "Sixty", "Class", "V", "composite", "restorations", "were", "made", "in", "30", "premolars", "and", "bonded", "with", "Ad-", "per", "Single", "Bond", "2", "(ASB2),", "AdheSE", "(ASE),", "and", "Adper", "Prompt", "L-Pop", "(APL-P)", "(n=20).", "Dentin", "µL", "and", "AG", "were", "immediately", "measured", "for", "half", "of", "the", "sample.", "The", "other", "half", "was", "evaluated", "after", "TMC.", "Eighteen", "third", "molars", "were", "also", "selected", "and", "bonded", "using", "the", "same", "adhesives", "to", "test", "the", "µTBS", "to", "dentin.", "Specimens", "were", "evaluated", "after", "24", "h", "and", "6", "months", "of", "water", "storage.", "Results:", "No", "differences", "in", "µL", "and", "AG", "were", "found", "among", "the", "groups", "(P>.05).", "The", "µTBS", "mean", "val-", "ues", "were:", "ASB2>ASE>APL-P", "(P<.05);", "only", "Adper", "Single", "Bond", "2", "presented", "a", "significantly", "lower", "µTBS", "after", "water", "storage", "(P<.05).", "Conclusions:", "The", "bonding", "approach", "does", "not", "influence", "the", "microleakage", "and", "interfacial", "gap", "ex-", "tension.", "Despite", "the", "decrease", "in", "the", "mean", "values,", "the", "bond", "strength", "to", "dentin", "of", "the", "conventional,", "two-step", "adhesive", "remains", "high", "after", "6", "months", "of", "water", "storage.", "(Eur", "J", "Dent", "2012;6:169-177)", "Key", "words:", "Dentin-bonding", "agents;", "bond", "strength;", "durability;", "microleakage.", "1", "Departament", "of", "Restorative", "Dentistry,", "State", "University", "of", "Ponta", "Grossa,", "Ponta", "Grossa,", "Paraná,", "BRASIL", "2", "Post", "Graduate", "Program", "in", "Department", "of", "Prosthetics", "Dentistry,", "School", "of", "Dentistry,", "University", "of", "Campinas,", "BRAZIL", "3", "Biomaterials", "Research", "Group,", "Anhanguera-Uniban", "University", "BRAZIL", "April", "2012", "-", "Vol.6", "4", "Dentistry", "Post", "Graduate", "Program,", "Department", "of", "Dentistry,", "State", "University", "of", "Ponta", "Grossa,", "BRAZIL", "Corresponding", "author:", "Dr.", "Gislaine", "Cristine", "Martins", "Rua:", "Comendador", "Miró,", "711", "–", "Centro,", "CEP:", "84010-160,", "Ponta", "Grossa,", "Paraná,", "BRASIL", "Tel:", "+55", "42", "3224", "5306", "Email:", "gislainecmartins@yahoo.com.br", "169", "European", "Journal", "of", "Dentistry" ]

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[ "Parasites", "&", "Vectors", "Research", "Communities", "of", "gastrointestinal", "helminths", "of", "fish", "in", "historically", "connected", "habitats:", "habitat", "fragmentation", "effect", "in", "a", "carnivorous", "catfish", "Pelteobagrus", "fulvidraco", "from", "seven", "lakes", "in", "flood", "plain", "of", "the", "Yangtze", "River,", "China", "Wen", "X", "Li,", "Pin", "Nie*,", "Gui", "T", "Wang", "and", "Wei", "J", "Yao", "BioMed", "Central", "Open", "Access", "Address:", "State", "Key", "Laboratory", "of", "Freshwater", "Ecology", "and", "Biotechnology,", "Institute", "of", "Hydrobiology,", "Chinese", "Academy", "of", "Sciences,", "Wuhan,", "Hubei", "Province", "430072,", "PR", "China", "Email:", "Wen", "X", "Li", "-", "liwx@ihb.ac.cn;", "Pin", "Nie*", "-", "pinnie@ihb.ac.cn;", "Gui", "T", "Wang", "-", "gtwang@ihb.ac.cn;", "Wei", "J", "Yao", "-", "wjyao@ihb.ac.cn", "*", "Corresponding", "author", "Published:", "27", "April", "2009", "Parasites", "&", "Vectors", "2009,", "2:22", "doi:10.1186/1756-3305-2-22", "This", "article", "is", "available", "from:", "http://www.parasitesandvectors.com/content/2/1/22", "Received:", "4", "February", "2009", "Accepted:", "27", "April", "2009", "©", "2009", "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:", "Habitat", "fragmentation", "may", "result", "in", "the", "reduction", "of", "diversity", "of", "parasite", "communities", "by", "affecting", "population", "size", "and", "dispersal", "pattern", "of", "species.", "In", "the", "flood", "plain", "of", "the", "Yangtze", "River", "in", "China,", "many", "lakes,", "which", "were", "once", "connected", "with", "the", "river,", "have", "become", "isolated", "since", "the", "1950s", "from", "the", "river", "by", "the", "construction", "of", "dams", "and", "sluices,", "with", "many", "larger", "lakes", "subdivided", "into", "smaller", "ones", "by", "road", "embankments.", "These", "artificial", "barriers", "have", "inevitably", "obstructed", "the", "migration", "of", "fish", "between", "the", "river", "and", "lakes", "and", "also", "among", "lakes.", "In", "this", "study,", "the", "gastrointestinal", "helminth", "communities", "were", "investigated", "in", "a", "carnivorous", "fish,", "the", "yellowhead", "catfish", "Pelteobagrus", "fulvidraco,", "from", "two", "connected", "and", "five", "isolated", "lakes", "in", "the", "flood", "plain", "in", "order", "to", "detect", "the", "effect", "of", "lake", "fragmentation", "on", "the", "parasite", "communities.", "Results:", "A", "total", "of", "11", "species", "of", "helminths", "were", "recorded", "in", "the", "stomach", "and", "intestine", "of", "P.", "fulvidraco", "from", "seven", "lakes,", "including", "two", "lakes", "connected", "with", "the", "Yangtze", "River,", "i.e.", "Poyang", "and", "Dongting", "lakes,", "and", "five", "isolated", "lakes,", "i.e.", "Honghu,", "Liangzi,", "Tangxun,", "Niushan", "and", "Baoan", "lakes.", "Mean", "helminth", "individuals", "and", "diversity", "of", "helminth", "communities", "in", "Honghu", "and", "Dongting", "lakes", "was", "lower", "than", "in", "the", "other", "five", "lakes.", "The", "nematode", "Procamallanus", "fulvidraconis", "was", "the", "dominant", "species", "of", "communities", "in", "all", "the", "seven", "lakes.", "No", "significant", "difference", "in", "the", "Shannon-Wiener", "index", "was", "detected", "between", "connected", "lakes", "(0.48)", "and", "isolated", "lakes", "(0.50).", "The", "similarity", "of", "helminth", "communities", "between", "Niushan", "and", "Baoan", "lakes", "was", "the", "highest", "(0.6708),", "and", "the", "lowest", "was", "between", "Tangxun", "and", "Dongting", "lakes", "(0.1807).", "The", "similarity", "was", "low", "between", "Dongting", "and", "the", "other", "lakes,", "and", "the", "similarity", "decreased", "with", "the", "geographic", "distance", "among", "these", "lakes.", "The", "helminth", "community", "in", "one", "connected", "lake,", "Poyang", "Lake", "was", "clustered", "with", "isolated", "lakes,", "but", "the", "community", "in", "Dongting", "Lake", "was", "separated", "in", "the", "tree.", "Conclusion:", "The", "similarity", "in", "the", "helminth", "communities", "of", "this", "fish", "in", "the", "flood-plain", "lakes", "may", "be", "attributed", "to", "the", "historical", "connection", "of", "these", "habitats", "and", "to", "the", "completion", "of", "the", "life-cycles", "of", "this", "fish", "as", "well", "as", "the", "helminth", "species", "within", "the", "investigated", "habitats.", "The", "diversity", "and", "the", "digenean", "majority", "in", "the", "helminth", "communities", "can", "be", "related", "to", "the", "diet", "of", "this", "fish,", "and", "to", "the", "lacustrine", "and", "macrophytic", "characters", "of", "the", "habitats.", "The", "lake", "isolation", "from", "the", "river", "had", "little", "detectable", "effect", "on", "the", "helminth", "communities", "of", "the", "catfish", "in", "flood-plain", "lakes", "of", "the", "Yangtze", "River.", "The", "low", "similarities", "in", "helminth", "communities", "between", "the", "Dongting", "Lake", "and", "others", "may", "just", "be", "a", "reflection", "of", "its", "unique", "water", "environment", "and", "anthropogenic", "alterations", "or", "fragmentation", "in", "this", "lake.", "Page", "1", "of", "7", "(page", "number", "not", "for", "citation", "purposes)" ]

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[ "J.", "Vet.", "Sci.", "(2009),", "10(4),", "365?", "367", "DOI:", "10.4142/jvs.2009.10.4.365", "Case", "Report", "J", "O", "U", "R", "N", "A", "L", "O", "F", "Veterinary", "Science", "Syringomyelia", "in", "three", "small", "breed", "dogs", "secondary", "to", "Chiari-like", "malformation:", "clinical", "and", "diagnostic", "findings", "Chul", "Park1,", "Byeong-Teck", "Kang2,", "Jong-Hyun", "Yoo2,", "Hee-Myung", "Park2,*", "1Department", "of", "Medicine", "and", "Epidemiology,", "School", "of", "Veterinary", "Medicine,", "University", "of", "California,", "Davis,", "CA", "95616,", "USA", "2BK21", "Basic", "&", "Diagnostic", "Veterinary", "Specialist", "Program", "for", "Animal", "Diseases", "and", "Department", "of", "Veterinary", "Internal", "Medicine,", "College", "of", "Veterinary", "Medicine,", "Konkuk", "University,", "Seoul", "143-701,", "Korea", "Three", "small", "breed", "dogs", "were", "referred", "for", "the", "evaluation", "of", "neurologic", "deficits.", "Upon", "physical", "and", "neurologic", "examination,", "all", "dogs", "displayed", "hyperesthesia,", "pain,", "and", "neck", "stiffness.", "Magnetic", "resonance", "imaging", "was", "performed", "on", "the", "brain", "and", "spinal", "cord,", "and", "all", "three", "dogs", "presented", "Chiari-", "like", "malformations", "and", "syringomyelia.", "These", "dogs", "were", "treated", "with", "prednisolone", "and", "furosemide,", "and", "showed", "rapid", "improvement", "of", "clinical", "signs.", "Chiari", "malformations", "and", "syringomyelia", "were", "not", "improved", "because", "of", "congenital", "disorders.", "This", "case", "report", "demonstrates", "the", "clinical", "and", "diagnostic", "features", "of", "Chiari-like", "malformations", "and", "syringomyelia", "in", "three", "small", "breed", "dogs.", "Keywords:", "canine,", "Chiari-like", "malformation,", "syringomyelia", "Syringomyelia", "(SM)", "of", "unknown", "etiology", "is", "a", "condition", "in", "which", "fluid", "containing", "cavities", "develop", "within", "the", "spinal", "cord", "parenchyma", "[9].", "Although", "the", "cause", "of", "SM", "is", "unknown,", "the", "condition", "may", "result", "from", "venous", "obstruction", "or", "distension,", "or", "may", "be", "due", "to", "mechanical", "disruption", "or", "shearing", "of", "spinal", "cord", "tissue", "planes", "[9].", "Cervical", "pain", "is", "a", "predominant", "clinical", "sign", "of", "this", "disease,", "which", "is", "reported", "in", "approximately", "80%", "of", "affected", "humans", "and", "35%", "of", "affected", "dogs", "[7,10],", "although", "there", "is", "some", "controversy", "as", "to", "how", "this", "disease", "results", "in", "pain.", "In", "addition", "to", "pain,", "dogs", "with", "SM", "often", "scratch", "at", "one", "area", "of", "the", "shoulder,", "ear,", "neck", "or", "sternum,", "and", "may", "have", "other", "neurological", "deficits", "such", "as", "cervical", "scoliosis,", "thoracic", "limb", "weakness,", "and", "pelvic", "limb", "ataxia", "[6].", "Medical", "treatment", "can", "help,", "but", "typically", "does", "not", "resolve", "the", "clinical", "signs.", "Non-steroidal", "anti-inflammatory", "drugs,", "corticosteroids,", "gabapentin,", "and", "oral", "opioids", "can", "be", "used", "for", "the", "treatment", "of", "SM", "[10].", "The", "most", "common", "procedure", "performed", "is", "foramen", "magnum", "decompression,", "where", "the", "*Corresponding", "author", "Tel:", "+82-2-450-4140;", "Fax:", "+82-2-444-4396", "E-mail:", "parkhee@konkuk.ac.kr", "hypoplastic", "occipital", "bone", "and", "sometimes", "the", "cranial", "dorsal", "laminae", "of", "the", "atlas", "are", "removed", "(with", "or", "without", "a", "durotomy)", "to", "decompress", "the", "foramen", "magnum", "[1,3].", "This", "case", "report", "demonstrates", "SM/Chiari-like", "malformation", "(CM)", "in", "three", "small", "breed", "dogs", "primarily", "showing", "hyperesthesia,", "pain,", "and", "neck", "stiffness", "based", "on", "clinical", "and", "diagnostic", "findings.", "Case", "No.", "1:", "A", "6-year-old,", "spayed", "female", "Poodle", "dog", "weighing", "4.1", "kg", "was", "presented", "with", "neck", "stiffness,", "hyperesthesia", "and", "hind", "limb", "ataxia.", "Uncoordinated", "gait", "of", "hind", "limb", "was", "acutely", "presented", "3", "days", "ago", "and", "had", "maintained", "steadily", "until", "the", "admission", "day.", "No", "abnormalities", "on", "the", "complete", "blood", "count", "(CBC)", "and", "serum", "biochemical", "profile", "were", "detected.", "Neurological", "examination", "revealed", "decreased", "postural", "reactions", "in", "both", "hind", "limbs,", "though", "cranial", "nerves", "and", "spinal", "reflexes", "were", "normal.", "Based", "on", "the", "examination,", "myelopathy", "or", "cerebellar", "diseases", "were", "suspected.", "Magnetic", "resonance", "imaging", "(MRI)", "scan", "of", "the", "brain", "and", "spinal", "cord", "was", "obtained", "using", "a", "0.2", "Tesla", "(E-Scan;", "Esaote,", "Italy)", "in", "transverse,", "sagittal,", "and", "dorsal,", "T1-", "and", "T2-weighted", "images.", "Caudal", "cerebellar", "herniation", "through", "the", "foramen", "magnum", "and", "syrinx", "in", "the", "spinal", "cord", "between", "second", "and", "fourth", "cervical", "vertebrae", "were", "noted", "(Fig.", "1).", "Based", "on", "these", "findings,", "the", "dog", "was", "diagnosed", "with", "Chiari-like", "malformations", "and", "syringomyelia", "(CM/SM).", "The", "dog", "was", "treated", "with", "furosemide", "(Lasix,", "2", "mg/kg,", "PO,", "BID;", "Handok", "Pham,", "Korea)", "and", "prednisolone", "(Prednisolone,", "1", "mg/kg,", "PO,", "BID;", "Korea", "Pharma,", "Korea).", "The", "ataxia", "mildly", "improved", "on", "the", "third", "day", "and", "completely", "disappeared", "by", "the", "second", "week.", "Medication", "had", "been", "tapered", "off", "over", "2", "months.", "There", "was", "no", "relapse", "for", "6", "months", "until", "last", "follow-ups.", "Case", "No.", "2:", "A", "3-year-old,", "intact", "male", "Maltese", "dog", "weighing", "4.16", "kg", "was", "presented", "with", "the", "neck", "pain,", "stiffness,", "and", "weakness", "in", "the", "hindlimbs", "for", "7", "days.", "The", "owners", "also", "reported", "that", "the", "dog", "had", "a", "mild", "tendency", "to", "scratch", "at", "its", "mid-cervical", "area", "and", "was", "becoming", "more" ]

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[ "Bussmann", "and", "Glenn", "Journal", "of", "Ethnobiology", "and", "Ethnomedicine", "2010,", "6:30", "http://www.ethnobiomed.com/content/6/1/30", "R", "E", "S", "E", "A", "R", "C", "H", "Medicinal", "plants", "used", "in", "Northern", "Peru", "for", "reproductive", "problems", "and", "female", "health", "Rainer", "W", "Bussmann*,", "Ashley", "Glenn", "JOURNAL", "OF", "ETHNOBIOLOGY", "AND", "ETHNOMEDICINE", "Open", "Access", "Abstract", "Infections", "of", "the", "reproductive", "tract,", "complications", "after", "childbirth,", "and", "reproductive", "problems", "continue", "to", "be", "a", "major", "health", "challenge", "worldwide.", "An", "impressive", "number", "of", "plant", "species", "is", "traditionally", "used", "to", "remedy", "such", "afflictions,", "and", "some", "have", "been", "investigated", "for", "their", "efficacy", "with", "positive", "results.", "A", "total", "of", "105", "plant", "species", "belonging", "to", "91", "genera", "and", "62", "families", "were", "documented", "and", "identified", "as", "herbal", "remedies", "for", "reproductive", "problems", "in", "Northern", "Peru.", "Most", "species", "used", "were", "Asteraceae", "(9.52%),", "followed", "by", "Lamiaceae", "and", "Fabaceae", "(8.57%", "and", "6.67%).", "The", "most", "important", "families", "are", "clearly", "represented", "very", "similarly", "to", "their", "overall", "importance", "in", "the", "local", "pharmacopoeia.", "The", "majority", "of", "herbal", "preparations", "for", "reproductive", "afflictions", "were", "prepared", "from", "the", "leaves", "of", "plants", "(22.72%),", "the", "whole", "plant", "(21.97%),", "and", "stems", "(21.21%),", "while", "other", "plant", "parts", "were", "used", "less", "frequently.", "More", "than", "60%", "of", "the", "cases", "fresh", "plant", "material", "was", "used", "to", "prepare", "remedies.", "Over", "70%", "of", "the", "remedies", "were", "applied", "orally,", "while", "the", "remaining", "ones", "were", "applied", "topically.", "Many", "remedies", "were", "prepared", "as", "mixtures", "of", "multiple", "ingredients.", "Little", "scientific", "evidence", "exists", "to", "prove", "the", "efficacy", "of", "the", "species", "employed", "as", "reproductive", "disorder", "remedies", "in", "Northern", "Peru.", "Only", "34%", "of", "the", "plants", "found", "or", "their", "congeners", "have", "been", "studied", "at", "all", "for", "their", "medicinal", "properties.", "The", "information", "gained", "on", "frequently", "used", "traditional", "remedies", "might", "give", "some", "leads", "for", "future", "targets", "for", "further", "analysis", "in", "order", "to", "develop", "new", "drugs.", "Background", "According", "to", "1999", "WHO", "estimates", "reproductive", "pro-", "blems,", "including,", "340", "million", "new", "cases", "of", "curable", "Sexu-", "ally", "Transmitted", "Diseases", "(STIs;", "syphilis,", "gonorrhoea,", "chlamydia", "and", "trichomoniasis)", "occur", "annually", "through-", "out", "the", "world", "in", "adults", "aged", "15-49", "years.", "In", "developing", "countries,", "STIs", "and", "their", "complications", "rank", "in", "the", "top", "five", "disease", "categories", "for", "which", "adults", "seek", "health", "care.", "Infection", "with", "STIs", "can", "lead", "to", "acute", "symptoms,", "chronic", "infection", "and", "serious", "delayed", "consequences", "such", "as", "infer-", "tility,", "ectopic", "pregnancy,", "cervical", "cancer", "and", "the", "untimely", "death", "of", "infants", "and", "adults", "[1].", "Traditional", "Medicine", "(TM)", "is", "used", "globally", "and", "is", "rapidly", "growing", "in", "economic", "importance.", "In", "developing", "countries,", "TM", "is", "often", "the", "only", "accessible", "and", "affordable", "treatment", "available.", "The", "WHO", "reports", "that", "TM", "is", "the", "primary", "health", "care", "system", "for", "80%", "of", "the", "population", "in", "developing", "countries.", "In", "Latin", "America,", "the", "WHO", "Regio-", "nal", "Office", "for", "the", "Americas", "(AMRO/PAHO)", "reports", "that", "*", "Correspondence:", "rainer.bussmann@mobot.org", "William", "L.", "Brown", "Center,", "Missouri", "Botanical", "Garden,", "P.O.", "Box", "299,", "St.", "Louis,", "MO", "63166-0299,", "USA", "71%", "of", "the", "population", "in", "Chile", "and", "40%", "of", "the", "population", "in", "Colombia", "have", "used", "TM.", "The", "WHO", "indicates", "that", "in", "many", "Asian", "countries", "TM", "is", "widely", "used,", "even", "though", "Western", "medicine", "is", "often", "readily", "available,", "and", "in", "Japan,", "60-70%", "of", "allopathic", "doctors", "prescribe", "TMs", "for", "their", "patients", "[2].", "Complementary", "Alternative", "Medicine", "(CAM)", "is", "gain-", "ing", "popularity", "in", "many", "developed", "countries.", "Forty-two", "percent", "of", "the", "population", "in", "the", "US", "have", "used", "CAM", "at", "least", "once", "[3],", "and", "the", "use", "of", "at", "least", "one", "of", "16", "alternative", "therapies", "increased", "from", "34%", "in", "1990", "to", "42%", "in", "1997", "[4].", "The", "number", "of", "visits", "to", "providers", "of", "CAM", "now", "exceeds", "by", "far", "the", "number", "of", "visits", "to", "all", "primary", "care", "physicians", "in", "the", "US", "[5,6].", "The", "expenses", "for", "the", "use", "of", "TM", "and", "CAM", "are", "exponentially", "growing", "in", "many", "parts", "of", "the", "world.", "The", "1997", "out-of-pocket", "CAM", "expenditure", "was", "estimated", "at", "US$", "2,7", "billion", "in", "the", "USA,", "and", "the", "world", "market", "for", "herbal", "medicines", "based", "on", "traditional", "knowl-", "edge", "is", "now", "estimated", "at", "US$", "60", "billion", "[7].", "Northern", "Peru", "is", "believed", "to", "be", "the", "center", "of", "the", "Cen-", "tral", "Andean", "Health", "Axis", "[8],", "and", "traditional", "medicinal", "practices", "in", "this", "region", "remain", "an", "important", "component", "©", "2010", "Bussmann", "and", "Glenn;", "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", "Stem", "Cells", "International", "Volume", "2012,", "Article", "ID", "141624,", "8", "pages", "doi:10.1155/2012/141624", "Review", "Article", "Bench", "to", "Bedside", "of", "Neural", "Stem", "Cell", "in", "Traumatic", "Brain", "Injury", "Solomon", "O.", "Ugoya", "and", "Jian", "Tu", "Australian", "School", "of", "Advanced", "Medicine,", "Macquarie", "University,", "2", "Technology", "Place,", "North", "Ryde,", "Sydney,", "NSW", "2109,", "Australia", "Correspondence", "should", "be", "addressed", "to", "Jian", "Tu,", "james.tu@mq.edu.au", "Received", "1", "June", "2012;", "Revised", "10", "August", "2012;", "Accepted", "21", "August", "2012", "Academic", "Editor:", "Rocio", "E.", "Gonzalez-Castaneda", "Copyright", "©", "2012", "S.", "O.", "Ugoya", "and", "J.", "Tu.", "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.", "Traumatic", "brain", "injury", "(TBI)", "is", "one", "of", "the", "leading", "causes", "of", "major", "disability", "and", "death", "worldwide.", "Neural", "stem", "cells", "(NSCs)", "have", "recently", "been", "shown", "to", "contribute", "to", "the", "cellular", "remodelling", "that", "occurs", "following", "TBI", "and", "attention", "has", "been", "drawn", "to", "the", "area", "of", "neural", "stem", "cell", "as", "possible", "therapy", "for", "TBI.", "The", "NSCs", "may", "play", "an", "important", "role", "in", "the", "treatment", "of", "TBI", "by", "replacing", "the", "damaged", "cells", "and", "eventual", "remyelination.", "This", "paper", "summarized", "a", "critical", "assessment", "of", "recent", "data", "and", "developed", "a", "view", "comprising", "of", "six", "points", "to", "possible", "quality", "translation", "of", "NSCs", "in", "TBI.", "1.", "Introduction", "Traumatic", "brain", "injury", "(TBI)", "has", "remained", "a", "major", "cause", "of", "mortality,", "morbidity", "and", "leading", "cause", "of", "large-scale", "dis-", "abilities", "worldwide.", "TBI", "results", "in", "a", "large", "number", "of", "deaths", "and", "a", "cause", "of", "permanent", "disabilities", "with", "enormous", "losses", "to", "individuals,", "families,", "and", "communities", "[1].", "World", "Health", "Organization", "(WHO),", "in", "2004,", "has", "estimated", "that", "25%", "of", "road", "traffic", "collisions", "requiring", "admission", "to", "a", "hospital", "suf-", "fered", "TBI", "[1–3].", "Moreover,", "WHO", "has", "introduced", "the", "new", "metric", "tool,", "the", "disability-adjusted", "life", "year", "(DALY),", "which", "quantifies", "the", "burden", "of", "diseases,", "injuries", "and", "risk", "factors.", "The", "worldwide", "leading", "causes", "of", "TBI", "include", "road", "traffic", "accidents", "that", "were", "estimated", "being", "41.2", "million", "DALYs", "in", "2008,", "violence", "being", "responsible", "for", "21.7", "million", "DALYs,", "and", "self-inflicted", "injuries", "being", "19.6", "million", "DALYs,", "respectively.", "All", "these", "will", "leave", "disability", "associated", "with", "TBI", "in", "survivors", "[2,", "3].", "However,", "no", "effective", "therapy", "or", "program", "is", "available", "for", "treatment", "of", "individuals", "with", "TBI;", "nonetheless,", "researchers", "had", "tried", "some", "therapeutic", "agents", "like", "levodopa/carbidopa", "and", "some", "neurotrophic", "factors", "in", "brain", "injury", "with", "persistent", "vegetative", "state", "with", "the", "aim", "of", "augmenting", "and", "slowing", "the", "progression", "from", "persistent", "vegetative", "state", "into", "some", "degree", "of", "consciousness.", "This", "still", "needs", "experimentation", "to", "confirm", "if", "these", "dopamine", "precursors", "and", "other", "neurotrophic", "factors", "have", "any", "role", "in", "TBI.", "Several", "other", "therapeutic", "agents", "like", "cannabinoid", "dexanabinol,", "erythropoietin,", "and", "gamma-", "glutamylcysteine", "ethyl", "ester", "have", "all", "shown", "to", "have", "neuropro-", "tective", "effect", "in", "human", "at", "experimental", "stage", "with", "remarkable", "improvement", "in", "post-TBI", "outcome", "[4–8].", "Recently,", "more", "attention", "has", "been", "drawn", "to", "the", "area", "of", "stem", "cell", "therapy,", "largely", "due", "to", "advanced", "knowledge", "about", "stem", "cells.", "The", "stem", "cells", "may", "play", "an", "important", "role", "in", "the", "treatment", "of", "TBI", "by", "replacing", "damaged", "cells,", "and", "helping", "functional", "recovery.", "The", "search", "for", "stem", "cell", "therapy", "for", "TBI", "is", "progressing.", "Since", "the", "pathophysiology", "of", "TBI", "is", "largely", "unknown,", "it", "makes", "a", "search", "for", "an", "effective", "stem", "cell", "therapy", "difficult.", "This", "is", "because", "multiple", "cell", "types", "like", "neuronal", "cells,", "glial,", "and", "endothelial", "cells", "are", "usually", "involved", "in", "TBI.", "Furthermore,", "cerebral", "vasculature,", "especially", "the", "blood", "brain", "barrier", "(BBB),", "may", "be", "affected", "in", "TBI;", "this", "injury", "may", "be", "focal", "or", "diffuse", "axonal", "injury", "(DAI).", "Taming", "these", "burgeon-", "ing", "effects", "of", "TBI", "will", "require", "NSCs", "which", "can", "differentiate", "into", "neurons", "and", "glial", "cells.", "It", "has", "been", "reported", "that", "progenitor", "cells", "differentiated", "into", "neurons", "and", "glial", "in", "adult", "brain,", "and", "an", "increase", "in", "astrocytic", "progeny", "is", "forming", "reactive", "astrocytes", "to", "primarily", "limit", "cyst", "enlargement", "in", "posttraumatic", "syringomyelia", "[9–12].", "This", "review", "is", "an", 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[ "Dysregulation", "of", "MicroRNA-34a", "Expression", "in", "Head", "and", "Neck", "Squamous", "Cell", "Carcinoma", "Promotes", "Tumor", "Growth", "and", "Tumor", "Angiogenesis", "Bhavna", "Kumar1,2,", "Arti", "Yadav2,", "James", "Lang1,2,", "Theodoros", "N.", "Teknos1,2,", "Pawan", "Kumar1,2*", "1", "Department", "of", "Otolaryngology-Head", "and", "Neck", "Surgery,", "The", "Ohio", "State", "University,", "Columbus,", "Ohio,", "United", "States", "of", "America,", "2", "The", "Ohio", "State", "University", "Comprehensive", "Cancer", "Center,", "The", "Ohio", "State", "University,", "Columbus,", "Ohio,", "United", "States", "of", "America", "Abstract", "Background:", "MicroRNAs", "(miRs)", "are", "small", "non-coding", "RNAs", "that", "play", "an", "important", "role", "in", "cancer", "development", "where", "they", "can", "act", "as", "oncogenes", "or", "as", "tumor-suppressors.", "miR-34a", "is", "a", "tumor-suppressor", "that", "is", "frequently", "downregulated", "in", "a", "number", "of", "tumor", "types.", "However,", "little", "is", "known", "about", "the", "role", "of", "miR-34a", "in", "head", "and", "neck", "squamous", "cell", "carcinoma", "(HNSCC).", "Methods", "and", "Results:", "miR-34a", "expression", "in", "tumor", "samples,", "HNSCC", "cell", "lines", "and", "endothelial", "cells", "was", "examined", "by", "real", "time", "PCR.", "Lipofectamine-2000", "was", "used", "to", "transfect", "miR-34a", "in", "HNSCC", "cell", "lines", "and", "human", "endothelial", "cells.", "Cell-", "proliferation,", "migration", "and", "clonogenic", "survival", "was", "examined", "by", "MTT,", "Xcelligence", "system,", "scratch", "assay", "and", "colony", "formation", "assay.", "miR-34a", "effect", "on", "tumor", "growth", "and", "tumor", "angiogenesis", "was", "examined", "by", "in", "vivo", "SCID", "mouse", "xenograft", "model.", "Our", "results", "demonstrate", "that", "miR-34a", "is", "significantly", "downregulated", "in", "HNSCC", "tumors", "and", "cell", "lines.", "Ectopic", "expression", "of", "miR-34a", "in", "HNSCC", "cell", "lines", "significantly", "inhibited", "tumor", "cell", "proliferation,", "colony", "formation", "and", "migration.", "miR-34a", "overexpression", "also", "markedly", "downregulated", "E2F3", "and", "survivin", "levels.", "Rescue", "experiments", "using", "microRNA", "resistant", "E2F3", "isoforms", "suggest", "that", "miR-34a-mediated", "inhibition", "of", "cell", "proliferation", "and", "colony", "formation", "is", "predominantly", "mediated", "by", "E2F3a", "isoform.", "In", "addition,", "tumor", "samples", "from", "HNSCC", "patients", "showed", "an", "inverse", "relationship", "between", "miR-34a", "and", "survivin", "as", "well", "as", "miR-34a", "and", "E2F3", "levels.", "Overexpression", "of", "E2F3a", "completely", "rescued", "survivin", "expression", "in", "miR-34a", "expressing", "cells,", "thereby", "suggesting", "that", "miR-34a", "may", "be", "regulating", "survivin", "expression", "via", "E2F3a.", "Ectopic", "expression", "of", "miR-34a", "also", "significantly", "inhibited", "tumor", "growth", "and", "tumor", "angiogenesis", "in", "a", "SCID", "mouse", "xenograft", "model.", "Interestingly,", "miR-34a", "inhibited", "tumor", "angiogenesis", "by", "blocking", "VEGF", "production", "by", "tumor", "cells", "as", "well", "as", "directly", "inhibiting", "endothelial", "cell", "functions.", "Conclusions:", "Taken", "together,", "these", "findings", "suggest", "that", "dysregulation", "of", "miR-34a", "expression", "is", "common", "in", "HNSCC", "and", "modulation", "of", "miR34a", "activity", "might", "represent", "a", "novel", "therapeutic", "strategy", "for", "the", "treatment", "of", "HNSCC.", "Citation:", "Kumar", "B,", "Yadav", "A,", "Lang", "J,", "Teknos", "TN,", "Kumar", "P", "(2012)", "Dysregulation", "of", "MicroRNA-34a", "Expression", "in", "Head", "and", "Neck", "Squamous", "Cell", "Carcinoma", "Promotes", "Tumor", "Growth", "and", "Tumor", "Angiogenesis.", "PLoS", "ONE", "7(5):", "e37601.", "doi:10.1371/journal.pone.0037601", "Editor:", "Irina", "V.", "Lebedeva,", "Enzo", "Life", "Sciences,", "Inc.,", "United", "States", "of", "America", "Received", "August", "16,", "2011;", "Accepted", "April", "26,", "2012;", "Published", "May", "22,", "2012", "Copyright:", "2012", "Kumar", "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", "National", "Institutes", "of", "Health/National", "Cancer", "Institute", "grant", "CA133250", "(PK)", "and", "Joan’s", "Fund", "Research", "Grant", "(BK", "and", "PK).", "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:", "pawan.kumar@osumc.edu", "Introduction", "Head", "and", "neck", "squamous", "cell", "carcinoma", "(HNSCC),", "which", "includes", "cancers", "of", "oral", "cavity,", "oropharynx,", "larynx,", "and", "hypo-", "pharynx", "accounts", "for", "approximately", "600,000", "new", "cases", "every", "year", "and", "is", "sixth", "leading", "cancer", "by", "incidence", "worldwide", "[1].", "The", "most", "important", "risk", "factors", "identified", "so", "far", "are", "tobacco", "use", "and", "alcohol", "consumption,", "which", "seem", "to", "have", "a", "synergistic", "effect", "[2].", "In", "recent", "years,", "the", "incidence", "of", "oropharyngeal", "cancers,", "particularly", "in", "the", "western", "world,", "has", "markedly", "increased,", "which", "may", "be", "related", "to", "increase", "in", "oral", "and", "oropharyngeal", "human", "papillomavirus", "(HPV)", "infections", "[3].", "Despite", "advancements", "in", "surgical", "and", "other", "therapeutic", "regimens,", "5", "year", "survival", "rates", "for", "head", "and", "neck", "patients", "have", "stayed", "around", "50%", "during", "the", "last", "two", "decades", "[4].", "Patients", "that", "survive", "with", "surgery", "and/or", "chemo-radiation", "treatment", "(CRT)", "often", "live", "with", "significant", "cosmetic", "and", "functional", "defects.", "The", "limited", "information", "available", "on", "the", "molecular", "carcinogenesis", "of", "HNSCC", "and", "the", "genetic", "and", "biological", "heterogeneity", "of", "the", "disease", "has", "hampered", "the", "development", "of", "novel", "therapeutic", "strategies.", "Cancer", "is", "a", "complex", "genetic", "disease", "in", "which", "deregulated", "cell", "growth", "arises", "due", "to", "defects", "in", "major", "pathways", "that", "are", "fundamental", "for", "normal", "homeostasis", "[1].", "Evidence", "is", "emerging", "that", "alterations", "in", "the", "expression", "of", "microRNAs", "(miRs)", "may", "play", "a", "key", "role", "in", "cancer", "development", "and", "progression", "[5].", "MicroRNAs", "(miRs),", "first", "described", "about", "18", "years", "ago", "in", "Caenorhabditis", "elegans", "[6],", "are", "small", "non-coding", "RNAs", "that", "act", "in", "concert", "to", "regulate", "expression", "of", "myriad", "target", "Proteins.", "Today", "more", "than", "17000", "microRNA’s", "in", "over", "153", "species", "have", "been", "identified", "(miRBase", "Sequence", "Database", "-", "Release", "17;", "www.", "miRbase.org),", "of", "which", "around", "1400", "are", "in", "humans.", "Most", "miRs", "are", "evolutionarily", "conserved", "and", "often", "found", "in", "clusters", "[7].", "In", "mammals,", "mature", "miRs", "are", "recognized", "by", "specific", "proteins", "to", "form", "RNA-inducing", "silencing", "complex", "(RISC)", "and", "associate", "PLoS", "ONE", "|", "www.plosone.org", "1", "May", "2012", "|", "Volume", "7", "|", "Issue", "5", "|", "e37601" ]

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[ "The", "Quorum", "Sensing", "Volatile", "Molecule", "2-Amino", "Acetophenon", "Modulates", "Host", "Immune", "Responses", "in", "a", "Manner", "that", "Promotes", "Life", "with", "Unwanted", "Guests", "Arunava", "Bandyopadhaya1,2,3.,", "Meenu", "Kesarwani1,2,3.¤,", "Yok-Ai", "Que1,2,3,", "Jianxin", "He1,2,3,", "Katie", "Padfield1,3,", "Ronald", "Tompkins1,3,", "Laurence", "G.", "Rahme1,2,3*", "1", "Department", "of", "Surgery,", "Harvard", "Medical", "School", "and", "Massachusetts", "General", "Hospital,", "Boston,", "Massachusetts,", "United", "States", "of", "America,", "2", "Department", "of", "Microbiology", "and", "Immunobiology,", "Harvard", "Medical", "School,", "Boston,", "Massachusetts,", "United", "States", "of", "America,", "3", "Shriners", "Hospitals", "for", "Children", "Boston,", "Boston,", "Massachusetts,", "United", "States", "of", "America", "Abstract", "Increasing", "evidence", "indicates", "that", "bacterial", "quorum", "sensing", "(QS)", "signals", "are", "important", "mediators", "of", "immunomodulation.", "However,", "whether", "microbes", "utilize", "these", "immunomodulatory", "signals", "to", "maintain", "infection", "remain", "unclear.", "Here,", "we", "show", "that", "the", "Pseudomonas", "aeruginosa", "QS-regulated", "molecule", "2-amino", "acetophenone", "(2-AA)", "modulates", "host", "immune", "responses", "in", "a", "manner", "that", "increases", "host", "ability", "to", "cope", "with", "this", "pathogen.", "Mice", "treated", "with", "2-AA", "prior", "to", "infection", "had", "a", "90%", "survival", "compared", "to", "10%", "survival", "rate", "observed", "in", "the", "non-pretreated", "infected", "mice.", "Whilst", "2-AA", "stimulation", "activates", "key", "innate", "immune", "response", "pathways", "involving", "mitogen-activated", "protein", "kinases", "(MAPKs),", "nuclear", "factor", "(NF)-kB,", "and", "pro-", "inflammatory", "cytokines,", "it", "attenuates", "immune", "response", "activation", "upon", "pretreatment,", "most", "likely", "by", "upregulating", "anti-", "inflammatory", "cytokines.", "2-AA", "host", "pretreatment", "is", "characterized", "by", "a", "transcriptionally", "regulated", "block", "of", "c-JUN", "N-terminal", "kinase", "(JNK)", "and", "NF-kB", "activation,", "with", "relatively", "preserved", "activation", "of", "extracellular", "regulated", "kinase", "(ERK)", "1/2.", "These", "kinase", "changes", "lead", "to", "CCAAT/enhancer-binding", "protein-b", "(c/EBPb)", "activation", "and", "formation", "of", "the", "c/EBPb-p65", "complex", "that", "prevents", "NF-kB", "activation.", "2-AA’s", "aptitude", "for", "dampening", "the", "inflammatory", "processes", "while", "increasing", "host", "survival", "and", "pathogen", "persistence", "concurs", "with", "its", "ability", "to", "signal", "bacteria", "to", "switch", "to", "a", "chronic", "infection", "mode.", "Our", "results", "reveal", "a", "QS", "immunomodulatory", "signal", "that", "promotes", "original", "aspects", "of", "interkingdom", "communication.", "We", "propose", "that", "this", "communication", "facilitates", "pathogen", "persistence,", "while", "enabling", "host", "tolerance", "to", "infection.", "Citation:", "Bandyopadhaya", "A,", "Kesarwani", "M,", "Que", "Y-A,", "He", "J,", "Padfield", "K,", "et", "al.", "(2012)", "The", "Quorum", "Sensing", "Volatile", "Molecule", "2-Amino", "Acetophenon", "Modulates", "Host", "Immune", "Responses", "in", "a", "Manner", "that", "Promotes", "Life", "with", "Unwanted", "Guests.", "PLoS", "Pathog", "8(11):", "e1003024.", "doi:10.1371/journal.ppat.1003024", "Editor:", "Barbara", "I.", "Kazmierczak,", "Yale", "University,", "United", "States", "of", "America", "Received", "May", "21,", "2012;", "Accepted", "September", "26,", "2012;", "Published", "November", "15,", "2012", "Copyright:", "2012", "Bandyopadhaya", "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", "Shriners", "research", "grant", "#87100", "to", "LGR.", "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:", "rahme@molbio.mgh.harvard.edu", "¤", "Current", "address:", "Cincinnati", "Children’s", "Hospital", "and", "Medical", "Center,", "Cincinnati,", "Ohio,", "United", "States", "of", "America.", ".", "These", "authors", "contributed", "equally", "to", "this", "work.", "Introduction", "Host-pathogen", "interactions", "are", "characterized", "by", "an", "antagonistic", "interplay", "between", "bacterial", "and", "host", "factors.", "The", "overall", "success", "of", "a", "pathogen", "depends", "on", "the", "efficacy", "of", "its", "virulence", "factors,", "anti-", "immune", "weapons,", "and", "the", "immune", "status", "of", "the", "host.", "Secreted", "microbial", "products,", "which", "include", "many", "virulence", "factors,", "play", "a", "critical", "role", "in", "the", "outcome", "of", "this", "antagonistic", "interaction.", "Bacterial", "quorum", "sensing", "(QS)", "regulates", "many", "of", "these", "products", "[1],", "[2].", "QS", "is", "a", "communication", "system", "widely", "utilized", "by", "bacteria", "to", "perceive", "and", "promote", "collective", "behaviors", "that", "depend", "on", "population", "density", "signaling.", "This", "cell", "density-dependent", "commu-", "nication", "system", "is", "achieved", "through", "the", "production", "and", "regulation", "of", "low-molecular-weight,", "excreted", "signal", "molecules", "[1],", "[3]", "as", "a", "means", "for", "pathogens", "to", "activate", "virulence", "factors", "[4]", "critical", "for", "infecting", "mammals", "[4–6].", "Several", "such", "signal", "molecules", "are", "becoming", "more", "appreciated", "recently", "as", "important", "anti-immune", "weapons", "and", "mediators", "of", "inter-kingdom", "antagonistic", "relations", "[7].", "One", "of", "the", "best", "characterized", "QS", "systems", "is", "that", "of", "the", "recalcitrant", "Gram-negative", "bacterium", "Pseudomonas", "aeruginosa", "[8],", "[9].", "This", "opportunistic", "pathogen", "defies", "eradication", "by", "antibiotics", "and", "is", "an", "exemplar", "of", "bacteria", "that", "produce", "clinically", "problematic", "acute", "and", "chronic", "infections.", "It", "causes", "particularly", "difficult", "to", "treat", "infections", "in", "people", "with", "cystic", "fibrosis", "(CF),", "burn", "wounds,", "trauma,", "and", "compromised", "immune", "systems", "[10],", "[11].", "P.", "aeruginosa", "controls", "the", "gene", "expression", "of", "many", "virulence", "factors", "through", "three", "QS", "systems:", "LasR,", "RhlR,", "and", "MvfR", "(PqsR)", "[9].", "LasR", "and", "RhlR", "are", "activated", "by", "the", "N-acyl-homoserine", "lactone", "(AHL)", "signaling", "molecules", "N-3-oxododecanoyl", "homoserine", "lactone", "(3-oxo-C12-", "HSL)", "and", "N-3-butanoyl-DL-homoserine", "lactone", "(C4-HSL)", "[9].", "Meanwhile,", "MvfR", "(PqsR)", "is", "activated", "by", "the", "4-hydroxy-2-", "alkylquinolines", "(HAQs)", "signaling", "molecules", "PQS", "(2-heptyl-3,4-", "dihydroxyquinoline", "(Pseudomonas", "Quinolone", "Signal)", "and", "HHQ", "(4-hydroxy-2-heptylquinoline)", "[5],", "[6],", "[8],", "[12].", "In", "addition", "to", "their", "role", "as", "QS", "signal", "molecules,", "AHLs", "and", "HAQs", "also", "modulate", "inflammation", "and", "immune", "responses", "in", "mammals", "[7],", "[13].", "The", "3-oxo-C12-HSL", "signal", "molecule", "inhibits", "dendritic", "cell", "and", "T-cell", "PLOS", "Pathogens", "|", "www.plospathogens.org", "1", "November", "2012", "|", "Volume", "8", "|", "Issue", "11", "|", "e1003024" ]

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[ "Zheng", "et", "al.", "Journal", "of", "Hematology", "&", "Oncology", "2011,", "4:21", "http://www.jhoonline.org/content/4/1/21", "S", "H", "O", "R", "T", "R", "E", "P", "O", "R", "T", "JOURNAL", "OF", "HEMATOLOGY", "&", "ONCOLOGY", "Open", "Access", "Expression", "and", "distribution", "of", "PPP2R5C", "gene", "in", "leukemia", "Haitao", "Zheng1†,", "Yu", "Chen1,2†,", "Shaohua", "Chen1,", "Yuzhe", "Niu1,2,", "Lijian", "Yang1,", "Bo", "Li1,", "Yuhong", "Lu1,", "Suxia", "Geng3,", "Xin", "Du3", "and", "Yangqiu", "Li1,2*", "Abstract", "Background:", "Recently,", "we", "clarified", "at", "the", "molecular", "level", "novel", "chromosomal", "translocation", "t(14;14)(q11;q32)", "in", "a", "case", "of", "Sézary", "syndrome,", "which", "caused", "a", "rearrangement", "from", "TRAJ7", "to", "the", "PPP2R5C", "gene.", "PPP2R5C", "is", "one", "of", "the", "regulatory", "B", "subunits", "of", "protein", "phosphatase", "2A", "(PP2A).", "It", "plays", "a", "crucial", "role", "in", "cell", "proliferation,", "differentiation,", "and", "transformation.", "To", "characterize", "the", "expression", "and", "distribution", "of", "five", "different", "transcript", "variants", "of", "the", "PPP2R5C", "gene", "in", "leukemia,", "we", "analyzed", "the", "expression", "level", "of", "PPP2R5C", "in", "peripheral", "blood", "mononuclear", "cells", "from", "77", "patients", "with", "de", "novo", "leukemia,", "26", "patients", "with", "leukemia", "in", "complete", "remission", "(CR),", "and", "20", "healthy", "individuals", "by", "real-time", "PCR", "and", "identified", "the", "different", "variants", "of", "PPP2R5C", "by", "RT-PCR.", "Findings:", "Significantly", "higher", "expression", "of", "PPP2R5C", "was", "found", "in", "AML,", "CML,", "T-ALL,", "and", "B-CLL", "groups", "in", "comparison", "with", "healthy", "controls.", "High", "expression", "of", "PPP2R5C", "was", "detected", "in", "the", "B-ALL", "group;", "however,", "no", "significant", "difference", "was", "found", "compared", "with", "the", "healthy", "group.", "The", "expression", "level", "of", "PPP2R5C", "in", "the", "CML-CR", "group", "decreased", "significantly", "compared", "with", "that", "in", "the", "de", "novo", "CML", "group", "and", "was", "not", "significantly", "different", "from", "the", "level", "in", "the", "healthy", "group.", "By", "using", "different", "primer", "pairs", "that", "covered", "different", "exons,", "five", "transcript", "variants", "of", "PPP2R5C", "could", "be", "identified.", "All", "variants", "could", "be", "detected", "in", "healthy", "samples", "as", "well", "as", "in", "all", "the", "leukemia", "samples,", "and", "similar", "frequencies", "and", "distributions", "of", "PPP2R5C", "were", "indicated.", "Conclusions:", "Overexpression", "of", "PPP2R5C", "in", "T-cell", "malignancy", "as", "well", "as", "in", "myeloid", "leukemia", "cells", "might", "relate", "to", "its", "proliferation", "and", "differentiation.", "Investigation", "of", "the", "effect", "of", "target", "inhibition", "of", "this", "gene", "might", "be", "beneficial", "to", "further", "characterization", "of", "molecular", "mechanisms", "and", "targeted", "therapy", "in", "leukemia.", "Keywords:", "PPP2R5C", "leukemia,", "gene", "expression,", "transcript", "variant", "Background", "Molecular", "genetic", "aberrations", "could", "provide", "the", "basis", "for", "assays", "that", "can", "predict", "prognosis", "of", "individual", "patients", "as", "well", "as", "potential", "molecular", "targets", "for", "novel", "therapies", "[1-3].", "The", "process", "of", "malignant", "transformation", "in", "leukemia", "is", "complex,", "and", "many", "factors", "such", "as", "abnormal", "gene", "expression", "and", "mutation,", "chromosomal", "aberrations,", "deregulation", "of", "various", "cellular", "signaling", "pathways,", "and", "deregulation", "of", "epigenetic", "regulation", "are", "involved", "in", "the", "development", "of", "leukemia", "[1].", "Therefore,", "new", "data", "regarding", "molecular", "genetic", "aberrations", "in", "*", "Correspondence:", "yangqiuli@hotmail.com", "†", "Contributed", "equally", "1Institute", "of", "Hematology,", "Medical", "College,", "Jinan", "University,", "Guangzhou,", "P.R.", "China", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "different", "types", "of", "leukemia", "are", "needed", "for", "further", "characterization.", "PPP2R5C", "is", "one", "of", "the", "regulatory", "B", "subunits", "of", "protein", "phosphatase", "2A", "(PP2A),", "which", "is", "a", "major", "cellu-", "lar", "serine/threonine", "phosphatase", "that", "affects", "the", "phos-", "phorylation", "status", "of", "many", "proteins", "[4].", "The", "PPP2R5C", "gene", "encodes", "five", "differentially", "spliced", "variants:", "B56g1,", "B56g2,", "B56g3,", "B56g5,", "and", "B56g6", "(Figure", "1),", "whereas", "B56g4", "is", "identified", "only", "in", "mice.", "The", "functional", "PPP2R5C", "gene", "locus", "resides", "at", "14q32.2,", "whereas", "a", "non-", "functional", "B56g1", "pseudogene", "PPP2R5C", "is", "present", "at", "3p21.3", "[4,5].", "PPP2R5C", "plays", "a", "crucial", "role", "in", "cell", "prolif-", "eration,", "differentiation,", "and", "transformation,", "based", "on", "its", "induction", "of", "dephosphorylation", "of", "P53", "at", "various", "resi-", "dues", "[6].", "It", "has", "been", "reported", "that", "the", "dynamic", "nuclear", "distribution", "of", "the", "B56g3", "regulatory", "subunit", "controls", "©", "2011", "Zheng", "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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[ "Sensors", "2012,", "12,", "905-922;", "doi:10.3390/s120100905", "OPEN", "ACCESS", "sensors", "ISSN", "1424-8220", "www.mdpi.com/journal/sensors", "Article", "Sheathless", "Size-Based", "Acoustic", "Particle", "Separation", "Rasim", "Guldiken", "1,*,", "Myeong", "Chan", "Jo", "1,", "Nathan", "D.", "Gallant", "1,", "Utkan", "Demirci", "2,3", "and", "Jiang", "Zhe", "4,*", "1", "2", "3", "4", "Department", "of", "Mechanical", "Engineering,", "University", "of", "South", "Florida,", "Tampa,", "FL", "33620,", "USA;", "E-Mails:", "mjo@mail.usf.edu", "(M.C.J.);", "ngallant@usf.edu", "(N.D.G.)", "Center", "for", "Biomedical", "Engineering,", "Department", "of", "Medicine,", "Brigham", "and", "Women’s", "Hospital,", "Harvard", "Medical", "School,", "Boston,", "MA", "02115,", "USA;", "E-Mail:", "utkan@mit.edu", "Harvard-MIT", "Health", "Sciences", "and", "Technology,", "Cambridge,", "MA", "02139,", "USA", "Department", "of", "Mechanical", "Engineering,", "University", "of", "Akron,", "Akron,", "OH", "44325,", "USA", "*", "Authors", "to", "whom", "correspondence", "should", "be", "addressed;", "E-Mails:", "guldiken@usf.edu", "(R.G.);", "jzhe@uakron.edu", "(J.Z.);", "Tel.:", "+1-813-974-5628", "(R.G.);", "Fax:", "+1-813-974-3539", "(R.G.);", "Tel.:", "+1-330-972-7737", "(J.Z.);", "Fax:", "+1-330-972-6027", "(J.Z.).", "Received:", "23", "November", "2011;", "in", "revised", "form:", "4", "January", "2012", "/", "Accepted:", "14", "January", "2012", "/", "Published:", "16", "January", "2012", "Abstract:", "Particle", "separation", "is", "of", "great", "interest", "in", "many", "biological", "and", "biomedical", "applications.", "Flow-based", "methods", "have", "been", "used", "to", "sort", "particles", "and", "cells.", "However,", "the", "main", "challenge", "with", "flow", "based", "particle", "separation", "systems", "is", "the", "need", "for", "a", "sheath", "flow", "for", "successful", "operation.", "Existence", "of", "the", "sheath", "liquid", "dilutes", "the", "analyte,", "necessitates", "precise", "flow", "control", "between", "sample", "and", "sheath", "flow,", "requires", "a", "complicated", "design", "to", "create", "sheath", "flow", "and", "separation", "efficiency", "depends", "on", "the", "sheath", "liquid", "composition.", "In", "this", "paper,", "we", "present", "a", "microfluidic", "platform", "for", "sheathless", "particle", "separation", "using", "standing", "surface", "acoustic", "waves.", "In", "this", "platform,", "particles", "are", "first", "lined", "up", "at", "the", "center", "of", "the", "channel", "without", "introducing", "any", "external", "sheath", "flow.", "The", "particles", "are", "then", "entered", "into", "the", "second", "stage", "where", "particles", "are", "driven", "towards", "the", "off-center", "pressure", "nodes", "for", "size", "based", "separation.", "The", "larger", "particles", "are", "exposed", "to", "more", "lateral", "displacement", "in", "the", "channel", "due", "to", "the", "acoustic", "force", "differences.", "Consequently,", "different-size", "particles", "are", "separated", "into", "multiple", "collection", "outlets.", "The", "prominent", "feature", "of", "the", "present", "microfluidic", "platform", "is", "that", "the", "device", "does", "not", "require", "the", "use", "of", "the", "sheath", "flow", "for", "positioning", "and", "aligning", "of", "particles.", "Instead,", "the", "sheathless", "flow", "focusing", "and", "separation", "are", "integrated", "within", "a", "single", "microfluidic", "device", "and", "accomplished", "simultaneously.", "In", "this", "paper,", "we", "demonstrated", "two", "different", "particle", "size-resolution", "separations;", "(1)", "3", "µm", "and", "10", "µm", "and", "(2)", "3", "µm", "and", "5", "µm.", "Also,", "the", "effects", "of", "the", "input", "power,", "the", "flow", "rate,", "and", "particle" ]

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[ "Distributed", "Fading", "Memory", "for", "Stimulus", "Properties", "in", "the", "Primary", "Visual", "Cortex", "Danko", "Nikolic´", "1,2.*,", "Stefan", "Ha¨", "usler3.,", "Wolf", "Singer1,2,", "Wolfgang", "Maass2,3", "1", "Department", "of", "Neurophysiology,", "Max-Planck-Institute", "for", "Brain", "Research,", "Frankfurt,", "Germany,", "2", "Frankfurt", "Institute", "for", "Advanced", "Studies", "(FIAS),", "Johann", "Wolfgang", "Goethe", "University,", "Frankfurt,", "Germany,", "3", "Institute", "for", "Theoretical", "Computer", "Science,", "Graz", "University", "of", "Technology,", "Graz,", "Austria", "Abstract", "It", "is", "currently", "not", "known", "how", "distributed", "neuronal", "responses", "in", "early", "visual", "areas", "carry", "stimulus-related", "information.", "We", "made", "multielectrode", "recordings", "from", "cat", "primary", "visual", "cortex", "and", "applied", "methods", "from", "machine", "learning", "in", "order", "to", "analyze", "the", "temporal", "evolution", "of", "stimulus-related", "information", "in", "the", "spiking", "activity", "of", "large", "ensembles", "of", "around", "100", "neurons.", "We", "used", "sequences", "of", "up", "to", "three", "different", "visual", "stimuli", "(letters", "of", "the", "alphabet)", "presented", "for", "100", "ms", "and", "with", "intervals", "of", "100", "ms", "or", "larger.", "Most", "of", "the", "information", "about", "visual", "stimuli", "extractable", "by", "sophisticated", "methods", "of", "machine", "learning,", "i.e.,", "support", "vector", "machines", "with", "nonlinear", "kernel", "functions,", "was", "also", "extractable", "by", "simple", "linear", "classification", "such", "as", "can", "be", "achieved", "by", "individual", "neurons.", "New", "stimuli", "did", "not", "erase", "information", "about", "previous", "stimuli.", "The", "responses", "to", "the", "most", "recent", "stimulus", "contained", "about", "equal", "amounts", "of", "information", "about", "both", "this", "and", "the", "preceding", "stimulus.", "This", "information", "was", "encoded", "both", "in", "the", "discharge", "rates", "(response", "amplitudes)", "of", "the", "ensemble", "of", "neurons", "and,", "when", "using", "short", "time", "constants", "for", "integration", "(e.g.,", "20", "ms),", "in", "the", "precise", "timing", "of", "individual", "spikes", "(#,20", "ms),", "and", "persisted", "for", "several", "100", "ms", "beyond", "the", "offset", "of", "stimuli.", "The", "results", "indicate", "that", "the", "network", "from", "which", "we", "recorded", "is", "endowed", "with", "fading", "memory", "and", "is", "capable", "of", "performing", "online", "computations", "utilizing", "information", "about", "temporally", "sequential", "stimuli.", "This", "result", "challenges", "models", "assuming", "frame-by-frame", "analyses", "of", "sequential", "inputs.", "Citation:", "Nikolic´", "D,", "Ha¨usler", "S,", "Singer", "W,", "Maass", "W", "(2009)", "Distributed", "Fading", "Memory", "for", "Stimulus", "Properties", "in", "the", "Primary", "Visual", "Cortex.", "PLoS", "Biol", "7(12):", "e1000260.", "doi:10.1371/journal.pbio.1000260", "Academic", "Editor:", "Jonathan", "D.", "Victor,", "Weill", "Cornell", "Medical", "College,", "United", "States", "of", "America", "Received", "June", "22,", "2009;", "Accepted", "November", "10,", "2009;", "Published", "December", "22,", "2009", "Copyright:", "2009", "Nikolic", "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", "Deutsche", "Forschungsgemeinschaft", "(NI", "708/2-1),", "by", "the", "German", "Federal", "Ministry", "of", "Education", "and", "Research", "(BMBF)", "within", "the", "‘‘Bernstein", "Focus:", "Neurotechnology’’,", "through", "research", "grant", "01GQ0840,", "Alexander", "von", "Humboldt", "Stiftung,", "and", "Hertie", "Stiftung.", "Additional", "partial", "support", "was", "obtained", "also", "from", "the", "Austrian", "Science", "Fund", "FWF", "#", "S9102-N13", "and", "project", "#", "FP6-015879", "(FACETS),", "project", "#", "FP7-216593", "(SECO),", "and", "project", "#", "FP7-506778", "(PASCAL2)", "of", "the", "European", "Union.", "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:", "AUC,", "area", "under", "receiver-operating", "characteristics;", "I&F,", "integrate-and-fire;", "ISI,", "interspike", "interval;", "IT,", "inferotemporal;", "Mfr,", "mean", "firing", "rate;", "PSTH,", "peristimulus", "time", "histogram;", "RBF,", "radial", "basis", "function;", "RF,", "receptive", "field;", "SD,", "standard", "deviation;", "SVM,", "support", "vector", "machine;", "XOR,", "exclusive", "OR", "*", "E-mail:", "danko.nikolic@gmail.com", ".", "These", "authors", "contributed", "equally", "to", "this", "work.", "Introduction", "A", "number", "of", "analysis", "methods", "have", "been", "designed", "to", "investigate", "how", "neuronal", "spiking", "activity", "correlates", "to", "sensory", "stimulation", "or", "behavior", "and,", "as", "expected,", "many", "relations", "have", "been", "found.", "All", "of", "the", "following", "variables—firing", "rates", "[1–4]", "and", "the", "synchronization", "[4–7]", "and", "the", "differential", "timing", "of", "spiking", "activity", "[8–10]—have", "been", "reported", "to", "correlate,", "one", "way", "or", "another,", "with", "stimuli", "and/", "or", "with", "behavior.", "Most", "of", "the", "efforts", "to", "distinguish", "between", "relevant", "and", "epiphenomenal", "variables", "face", "the", "problem", "that", "they", "have", "to", "rely", "on", "correlative", "rather", "than", "causal", "evidence.", "In", "the", "absence", "of", "direct", "access", "to", "the", "information", "of", "causal", "nature,", "one", "way", "to", "begin", "addressing", "this", "issue", "is", "to", "complement", "the", "highly", "specialized", "statistical", "methods", "that", "have", "been", "developed", "to", "detect", "specific", "stimulus-related", "changes", "in", "responses", "[9,11–18]", "with", "analyses", "that", "make", "minimal", "assumptions", "about", "putative", "codes", "[19–21],", "and", "examine", "how", "much", "information", "can", "be", "extracted", "by", "a", "single", "cortical", "neuron", "from", "the", "joint", "responses", "of", "its", "presynaptic", "neurons", "and", "then", "find", "out", "which", "variables", "were", "carrying", "the", "relevant", "information", "[22,23].", "To", "adjust", "to", "the", "conditions", "under", "which", "these", "cortical", "‘‘readout’’", "neurons", "are", "likely", "to", "operate,", "the", "data", "must", "be", "presented", "to", "the", "readout", "units", "in", "parallel,", "i.e.,", "the", "responses", "of", "the", "putative", "feeding", "neurons", "must", "be", "recorded", "simultaneously.", "Also,", "analysis", "and", "classification", "of", "data", "should", "correspond", "to", "that", "conducted", "in", "real", "time.", "Thus,", "the", "results", "should", "be", "available", "with", "short", "delays.", "Hence,", "the", "analysis", "method", "should", "be", "allowed", "no", "more", "time", "for", "accumulating", "evidence", "than", "is", "available", "for", "cortical", "neurons", "to", "accomplish", "their", "task.", "To", "fulfill", "these", "requirements,", "readout", "neurons", "need", "to", "be", "simulated", "on", "a", "computer", "and", "fed", "with", "data", "obtained", "in", "parallel", "recordings", "from", "a", "large", "number", "of", "cortical", "neurons,", "the", "assumption", "being", "that", "a", "certain", "fraction", "of", "these", "neurons", "provides", "input", "to", "neuronal", "classification.", "The", "present", "study", "was", "designed", "to", "fulfill", "these", "premises.", "Applying", "multielectrode", "technology,", "we", "recorded", "simultaneously", "from", "a", "large", "number", "of", "neurons", "in", "area", "17", "of", "lightly", "anesthetized", "cats", "and", "evoked", "responses", "with", "brief", "sequences", "of", "different,", "stationary", "flashed", "stimuli", "(letters", "of", "the", "alphabet).", "These", "responses", "were", "then", "fed", "as", "inputs", "to", "artificial", "readout", "neurons", "simulated", "on", "a", "computer", "(also", "referred", "to", "as", "classifiers).", "We", "first", "trained", "the", "artificial", "neurons", "to", "classify", "the", "visual", "stimuli", "that", "have", "generated", "the", "responses,", "and", "once", "the", "classification", "had", "reached", "criterion,", "we", "PLoS", "Biology", "|", "www.plosbiology.org", "1", "December", "2009", "|", "Volume", "7", "|", "Issue", "12", "|", "e1000260" ]

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[ "Effect", "of", "Different", "Ammonia", "Concentrations", "on", "Community", "Succession", "of", "Ammonia-oxidizing", "Microorganisms", "in", "a", "Simulated", "Paddy", "Soil", "Column", "Hu", "Baolan,", "Liu", "Shuai,", "Shen", "Lidong,", "Zheng", "Ping,", "Xu", "Xiangyang,", "Lou", "Liping*", "Department", "of", "Environmental", "Engineering,", "Zhejiang", "University,", "Hangzhou,", "Zhejiang,", "China", "Abstract", "Ammonia", "oxidation", "is", "performed", "by", "both", "ammonia-oxidizing", "bacteria", "(AOB)", "and", "ammonia-oxidizing", "archaea", "(AOA).", "To", "explore", "the", "effect", "of", "ammonia", "concentration", "on", "the", "population", "dynamic", "changes", "of", "ammonia-oxidizing", "microorganisms,", "we", "examined", "changes", "in", "the", "abundance", "and", "community", "composition", "of", "AOA", "and", "AOB", "in", "different", "layers.", "Most", "of", "the", "archaeal", "amoA", "sequences", "were", "Nitrosotalea-related", "and", "the", "proportion", "that", "Nitrosotalea", "cluster", "occupied", "decreased", "in", "the", "surface", "layer", "and", "increased", "in", "the", "deep", "layer", "during", "the", "cultivation", "process.", "Nitrosopumilus-related", "sequences", "were", "only", "detected", "in", "the", "deep", "layer", "in", "the", "first", "stage", "and", "disappeared", "later.", "Both", "phylogenetic", "and", "quantitative", "analysis", "showed", "that", "there", "were", "increased", "Nitrosomonas-related", "sequences", "appeared", "in", "the", "surface", "layer", "where", "the", "ammonia", "concentration", "was", "the", "highest.", "Both", "AOA", "and", "AOB", "OTU", "numbers", "in", "different", "layers", "decreased", "under", "selective", "pressure", "and", "then", "recovered.", "The", "potential", "nitrification", "rates", "were", "25.06", "mg?N?L21?g21", "dry", "soil?h21", "in", "the", "mid", "layer", "which", "was", "higher", "than", "the", "other", "two", "layers.", "In", "general,", "obvious", "population", "dynamic", "changes", "were", "found", "for", "both", "AOA", "and", "AOB", "under", "the", "selective", "pressure", "of", "exogenous", "ammonia", "and", "the", "changes", "were", "different", "in", "three", "layers", "of", "the", "soil", "column.", "Citation:", "Baolan", "H,", "Shuai", "L,", "Lidong", "S,", "Ping", "Z,", "Xiangyang", "X,", "et", "al.", "(2012)", "Effect", "of", "Different", "Ammonia", "Concentrations", "on", "Community", "Succession", "of", "Ammonia-", "oxidizing", "Microorganisms", "in", "a", "Simulated", "Paddy", "Soil", "Column.", "PLoS", "ONE", "7(8):", "e44122.", "doi:10.1371/journal.pone.0044122", "Editor:", "Matthias", "Horn,", "University", "of", "Vienna,", "Austria", "Received", "February", "15,", "2012;", "Accepted", "July", "30,", "2012;", "Published", "August", "31,", "2012", "Copyright:", "2012", "Baolan", "et", "al.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Funding:", "The", "authors", "wish", "to", "thank", "the", "National", "Natural", "Science", "Foundation", "of", "China", "(40801198),", "National", "Key", "Technologies", "Research", "and", "Development", "program", "of", "China", "(2012BAJ25B00)", "and", "the", "Natural", "Science", "Foundation", "of", "Zhejiang", "province", "(Y507227).", "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:", "baolanhz@hotmail.com", "Introduction", "Nitrification", "is", "critical", "in", "the", "global", "nitrogen", "cycle", "and", "is", "a", "unique", "pathway", "linking", "reduced", "inorganic", "nitrogen", "with", "oxidised", "inorganic", "nitrogen", "in", "nature", "[1].", "Ammonia", "oxidation", "is", "the", "first", "and", "rate-limiting", "step", "of", "nitrification.", "It", "was", "assumed", "that", "all", "ammonia", "oxidisers", "were", "bacteria", "until", "ammonia-oxidizing", "archaea", "were", "found.", "The", "findings", "of", "Venter", "et", "al.", "[2]", "and", "Treusch", "et", "al.", "[3]", "indicated", "the", "posibility", "of", "archaea", "involving", "in", "ammonia", "oxidation", "and", "the", "exist", "of", "ammonia-oxidation", "archaea", "was", "finally", "certified", "by", "the", "enrichments", "and", "pure", "cultures", "of", "several", "strains", "of", "AOA", "[4–", "10].", "Recent", "research", "has", "demonstrated", "that", "ammonia-oxidizing", "archaea", "may", "form", "a", "separate", "and", "deep-branching", "phylum,", "the", "Thaumarchaeota", "[11–13].", "Molecular", "biological", "research", "based", "on", "the", "functional", "gene", "amoA", "and", "the", "16SrRNA", "gene", "has", "revealed", "a", "widespread", "distribution", "of", "AOA", "[14–17].", "Quantitative", "PCR", "analyses", "found", "that", "AOA", "normally", "outnumbered", "their", "substrate", "competitors,", "such", "as", "AOB,", "in", "both", "soil", "[17]", "and", "water", "[18],", "but", "the", "relative", "contributions", "of", "AOA", "and", "AOB", "in", "the", "soil", "nitrogen", "cycle", "remained", "undetermined.", "Some", "researchers", "believed", "that", "AOB", "played", "a", "more", "important", "role", "than", "AOA", "in", "soil", "nitrification.", "Jia", "and", "Conrad", "[19]", "found", "that", "changes", "in", "potential", "nitrification", "rates", "were", "only", "correlated", "with", "the", "number", "of", "AOB", "amoA", "genes", "when", "they", "added", "substrate", "(NH3)", "or", "inhibitor", "(C2H2)", "of", "ammonia", "oxidation", "to", "the", "soil.", "Subsequently,", "Di", "et", "al.", "[20]", "discovered", "the", "same", "phenomenon", "in", "New", "Zealand", "grassland.", "In", "contrast,", "other", "researchers", "regarded", "AOA", "as", "the", "main", "drivers", "of", "ammonia", "oxidation", "in", "soil.", "Gubry-Rangin", "et", "al.", "[21]", "reported", "that", "the", "potential", "nitrification", "rates", "were", "positively", "correlated", "with", "the", "number", "and", "transcriptional", "activity", "of", "AOA", "amoA", "genes.", "Zhang", "et", "al.", "[22]", "confirmed", "the", "dominant", "role", "of", "AOA", "in", "soil", "nitrification", "by", "means", "of", "stable", "isotope", "probe", "and", "the", "quantitative", "analysis", "of", "archaral", "amoA", "genes.", "Offre", "et", "al.", "[23]", "also", "demonstrated", "that", "the", "growth", "of", "only", "archaeal", "but", "not", "bacterial", "ammonia", "oxidizers", "occurred", "in", "microcosms", "with", "active", "nitrification.", "Differences", "in", "cell", "size,", "specific", "cell", "activity", "and", "other", "physiological", "characteristics", "may", "explain", "the", "different", "contributions", "of", "AOA", "and", "AOB", "to", "soil", "nitrification.", "In", "addition,", "AOA", "and", "AOB", "may", "compete", "mutually", "or", "exhibit", "functional", "redundancy", "under", "some", "conditions,", "whereas", "under", "other", "conditions", "the", "fundamental", "physiological", "differences", "between", "these", "organisms", "may", "lead", "to", "niche", "separation", "of", "AOA", "and", "AOB", "[24].", "Therefore,", "environmental", "factors", "are", "important", "in", "determining", "the", "different", "nitrification", "activities", "and", "relative", "contributions", "of", "AOA", "and", "AOB.", "Among", "all", "environmental", "factors,", "ammonia", "is", "the", "substrate", "of", "ammonia", "oxidation", "for", "which", "concentrations", "will", "directly", "affect", "nitrification", "activity.", "It", "was", "found", "that", "AOA", "were", "able", "to", "grow", "well", "and", "the", "growth", "of", "AOA", "was", "coupled", "with", "soil", "nitrification", "when", "the", "concentration", "of", "ammonia", "was", "relatively", "low", "or", "the", "supply", "of", "ammonia", "was", "through", "the", "mineralization", "of", "organic", "matter;", "however,", "AOB", "were", "more", "competitive", "in", "soil", "nitrification", "and", "the", "number", "of", "AOB", "amoA", "gene", "copies", "was", "greater", "than", "that", "of", "AOA", "PLOS", "ONE", "|", "www.plosone.org", "1", "August", "2012", "|", "Volume", "7", "|", "Issue", "8", "|", "e44122" ]

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[ "Martinsen", "et", "al.", "BMC", "Evolutionary", "Biology", "2010,", "10:3", "http://www.biomedcentral.com/1471-2148/10/3", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Phylogenetic", "footprinting", "of", "non-coding", "RNA:", "hammerhead", "ribozyme", "sequences", "in", "a", "satellite", "DNA", "family", "of", "Dolichopoda", "cave", "crickets", "(Orthoptera,", "Rhaphidophoridae)", "Lene", "Martinsen1,", "Arild", "Johnsen1,", "Federica", "Venanzetti2,", "Lutz", "Bachmann1*", "Abstract", "Background:", "The", "great", "variety", "in", "sequence,", "length,", "complexity,", "and", "abundance", "of", "satellite", "DNA", "has", "made", "it", "difficult", "to", "ascribe", "any", "function", "to", "this", "genome", "component.", "Recent", "studies", "have", "shown", "that", "satellite", "DNA", "can", "be", "transcribed", "and", "be", "involved", "in", "regulation", "of", "chromatin", "structure", "and", "gene", "expression.", "Some", "satellite", "DNAs,", "such", "as", "the", "pDo500", "sequence", "family", "in", "Dolichopoda", "cave", "crickets,", "have", "a", "catalytic", "hammerhead", "(HH)", "ribozyme", "structure", "and", "activity", "embedded", "within", "each", "repeat.", "Results:", "We", "assessed", "the", "phylogenetic", "footprints", "of", "the", "HH", "ribozyme", "within", "the", "pDo500", "sequences", "from", "38", "different", "populations", "representing", "12", "species", "of", "Dolichopoda.", "The", "HH", "region", "was", "significantly", "more", "conserved", "than", "the", "non-hammerhead", "(NHH)", "region", "of", "the", "pDo500", "repeat.", "In", "addition,", "stems", "were", "more", "conserved", "than", "loops.", "In", "stems,", "several", "compensatory", "mutations", "were", "detected", "that", "maintain", "base", "pairing.", "The", "core", "region", "of", "the", "HH", "ribozyme", "was", "affected", "by", "very", "few", "nucleotide", "substitutions", "and", "the", "cleavage", "position", "was", "altered", "only", "once", "among", "198", "sequences.", "RNA", "folding", "of", "the", "HH", "sequences", "revealed", "that", "a", "potentially", "active", "HH", "ribozyme", "can", "be", "found", "in", "most", "of", "the", "Dolichopoda", "populations", "and", "species.", "Conclusions:", "The", "phylogenetic", "footprints", "suggest", "that", "the", "HH", "region", "of", "the", "pDo500", "sequence", "family", "is", "selected", "for", "function", "in", "Dolichopoda", "cave", "crickets.", "However,", "the", "functional", "role", "of", "HH", "ribozymes", "in", "eukaryotic", "organisms", "is", "unclear.", "The", "possible", "functions", "have", "been", "related", "to", "trans", "cleavage", "of", "an", "RNA", "target", "by", "a", "ribonucleoprotein", "and", "regulation", "of", "gene", "expression.", "Whether", "the", "HH", "ribozyme", "in", "Dolichopoda", "is", "involved", "in", "similar", "functions", "remains", "to", "be", "investigated.", "Future", "studies", "need", "to", "demonstrate", "how", "the", "observed", "nucleotide", "changes", "and", "evolutionary", "constraint", "have", "affected", "the", "catalytic", "efficiency", "of", "the", "hammerhead.", "Background", "Noncoding", "tandem-repetitive", "satellite", "DNA", "(satDNA)", "has", "long", "been", "known", "to", "constitute", "a", "large", "portion", "of", "any", "eukaryotic", "genome", "[1].", "Recent", "studies", "in", "Drosophila", "through", "underreplication", "documented", "a", "strong", "positive", "correlation", "between", "genome", "size", "and", "the", "amount", "of", "satDNA", "[2].", "SatDNA", "is", "usually", "located", "in", "the", "hetero-", "chromatic", "parts", "of", "the", "chromosomes", "close", "to", "the", "centromeres", "and", "telomeres.", "The", "high", "evolutionary", "turn-", "over", "of", "satDNA", "and", "the", "frequent", "species-specific", "*", "Correspondence:", "lutz.bachmann@nhm.uio.no", "1Natural", "History", "Museum,", "Department", "for", "Research", "and", "Collections,", "University", "of", "Oslo,", "0318", "Oslo,", "Norway", "patterns", "have", "puzzled", "researchers", "for", "many", "years.", "Such", "data", "challenge", "the", "hypothesis", "that", "there", "is", "a", "general", "bio-", "logical", "function", "of", "satDNA.", "The", "enormous", "diversity", "of", "satDNA", "in", "nucleotide", "sequence,", "length", "of", "repeats,", "com-", "plexity,", "and", "genomic", "abundance,", "instead", "suggest", "that", "a", "specific", "function", "cannot", "be", "ascribed", "to", "satDNA.", "However,", "transcription", "of", "satDNA", "and", "other", "non-cod-", "ing", "DNA", "has", "been", "found", "in", "many", "species", "(e.g.", "[3-10]).", "The", "function", "of", "the", "vast", "majority", "of", "these", "transcripts", "is", "unclear,", "but", "recent", "studies", "using", "RNA", "interference", "have", "documented", "the", "role", "of", "non-coding", "RNAs", "in", "regulation", "of", "gene", "expression,", "chromatin", "organization,", "and", "genome", "functioning", "(for", "a", "review,", "see", "[11]).", "For", "example,", "it", "has", "been", "demonstrated", "that", "small", "non-coding", "RNAs", "can", "©", "2010", "Martinsen", "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", "(Z)-3-(9-Anthryl)-1-(4-chlorophenyl)-2-", "(4-nitro-1H-imidazol-1-yl)prop-2-en-1-", "one", "Guang-zhou", "Wang,", "Yi-hui", "Lu,", "Cheng-he", "Zhou*", "and", "Yi-yi", "Zhang", "School", "of", "Chemistry", "and", "Chemical", "Engineering,", "Southwest", "University,", "Chongqing", "400715,", "People’s", "Republic", "of", "China", "Correspondence", "e-mail:", "zhouch@swu.edu.cn", "Received", "10", "April", "2009;", "accepted", "20", "April", "2009", "Key", "indicators:", "single-crystal", "X-ray", "study;", "T", "=", "292", "K;", "mean", "(C–C)", "=", "0.003", "A˚;", "R", "factor", "=", "0.044;", "wR", "factor", "=", "0.113;", "data-to-parameter", "ratio", "=", "13.6.", "In", "the", "title", "compound,", "C26H16ClN3O3,", "the", "dihedral", "angle", "between", "the", "anthracene", "mean", "plane", "and", "imidazole", "ring", "is", "64.75", "(2)", ".", "In", "the", "crystal,", "–", "interactions", "between", "anthracene", "fragments", "lead", "to", "the", "formation", "of", "stacks", "of", "molecules", "propagating", "in", "[100].", "The", "short", "distance", "between", "the", "carbonyl", "groups", "of", "symmetry-related", "molecules", "[C", "O", "=", "2.985", "(2)", "A˚", "]", "indicates", "the", "existence", "of", "dipole–dipole", "interactions.", "The", "crystal", "packing", "also", "exhibits", "short", "intermolecular", "contacts", "between", "the", "nitro", "groups", "and", "Cl", "atoms", "[Cl", "O", "=", "3.181", "(2)", "A˚", "].", "Related", "literature", "For", "general", "background,", "see:", "Corr", "eˆa", "et", "al.", "(2001);", "Daskiewicz", "et", "al.", "(2005);", "Sivakumar", "et", "al.", "(2009);", "Vogel", "et", "al.", "(2008).", "The", "synthesis", "was", "described", "by", "Erhardt", "et", "al.", "(1985).", "Experimental", "Crystal", "data", "C26H16ClN3O3", "Mr", "=", "453.87", "Triclinic,", "P1", "a", "=", "8.0511", "(9)", "A˚", "organic", "compounds", "b", "=", "11.0406", "(12)", "A˚", "c", "=", "12.9274", "(14)", "A˚", "=", "76.065", "(2)", "=", "85.974", "(2)", "=", "71.258", "(2)", "V", "=", "1056.1", "(2)", "A˚", "3", "Data", "collection", "Bruker", "SMART", "APEX", "CCD", "area-", "detector", "diffractometer", "Absorption", "correction:", "multi-scan", "(SADABS;", "Sheldrick,", "1997)", "Tmin", "=", "0.956,", "Tmax", "=", "0.979", "Refinement", "R[F", "2", ">", "2", "(F", "2)]", "=", "0.044", "wR(F", "2)", "=", "0.113", "S", "=", "1.04", "4070", "reflections", "Z", "=", "2", "Mo", "K", "radiation", "=", "0.22", "mm", "1", "T", "=", "292", "K", "0.16", "0.12", "0.10", "mm", "6168", "measured", "reflections", "4070", "independent", "reflections", "3354", "reflections", "with", "I", ">", "2", "(I)", "Rint", "=", "0.014", "299", "parameters", "H-atom", "parameters", "constrained", "max", "=", "0.56", "e", "A˚", "3", "min", "=", "0.50", "e", "A˚", "3", "3.746", "(7)", "3.863", "(8)", "Table", "1", "Selected", "interatomic", "distances", "(", "A˚).", "C17", "Cl1", "O1i", "O3ii", "2.985", "(2)", "3.181", "(3)", "Cg1", "Cg2", "Cg2iii", "Cg2iv", "Symmetry", "codes:", "(i)", "x", "þ", "1;", "y", "þ", "2;", "z;", "(ii)", "x", "þ", "1;", "y", "þ", "1;", "z;", "(iii)", "x", "þ", "1;", "y", "þ", "2;", "z", "þ", "1;", "(iv)", "x;", "y", "þ", "2;", "z", "þ", "1.", "Cg1", "and", "Cg2", "are", "the", "centroids", "of", "atoms", "C1/C2/C14/C7–C9", "and", "C2–C7,", "respectively.", "Data", "collection:", "SMART", "(Bruker,", "2001);", "cell", "refinement:", "SAINT", "(Bruker,", "2001);", "data", "reduction:", "SAINT;", "program(s)", "used", "to", "solve", "structure:", "SHELXS97", "(Sheldrick,", "2008);", "program(s)", "used", "to", "refine", "structure:", "SHELXL97", "(Sheldrick,", "2008);", "molecular", "graphics:", "PLATON", "(Spek,", "2009);", "software", "used", "to", "prepare", "material", "for", "publication:", "PLATON.", "We", "thank", "Southwest", "University", "(grant", "Nos.", "SWUB2006018,", "XSGX0602", "and", "SWUF2007023)", "and", "the", "Natural", "Science", "Foundation", "of", "Chongqing", "(grant", "No.", "2007BB5369)", "for", "finan-", "cial", "support.", "Supplementary", "data", "and", "figures", "for", "this", "paper", "are", "available", "from", "the", "IUCr", "electronic", "archives", "(Reference:", "CV2548).", "References", "Bruker", "(2001).", "SAINT-Plus", "and", "SMART.", "Bruker", "AXS", "Inc.,", "Madison,", "Wisconsin,", "USA.", "Correˆ", "a,", "R.,", "Pereira,", "M.", "A.", "S.,", "Santos,", "L.", "D.,", "Filho,", "V.", "C.,", "Santos,", "A.", "R.", "S.", "&", "Nunes,", "R.", "J.", "(2001).", "Arch.", "Pharm.", "Pharm.", "Med.", "Chem.", "334,", "332–334.", "Daskiewicz,", "J.", "B.,", "Depeint,", "F.,", "Viornery,", "L.,", "Bayet,", "C.,", "Sarrazin,", "G.", "C.,", "Comte,", "G.,", "Gee,", "J.", "M.,", "Johnson,", "I.", "T.,", "Ndjoko,", "K.,", "Hostettmann,", "K.", "&", "Barron,", "D.", "(2005).", "J.", "Med.", "Chem.", "48,", "2790–2804.", "Erhardt,", "H.,", "Mildenberger,", "H.,", "Handte,", "R.,", "Sachse,", "B.,", "Hartz,", "P.", "&", "Bu¨", "rstell,", "H.", "(1985).", "German", "Patent", "No.", "DE3406908.", "Sheldrick,", "G.", "M.", "(1997).", "SADABS.", "Bruker", "AXS", "Inc.,", "Madison,", "Wisconsin,", "USA.", "Sheldrick,", "G.", "M.", "(2008).", "Acta", "Cryst.", "A64,", "112–122.", "Sivakumar,", "P.", "M.,", "Priya,", "S.", "&", "Doble,", "M.", "(2009).", "Chem.", "Biol.", "Drug", "Des.", "73,", "403–", "415.", "Spek,", "A.", "L.", "(2009).", "Acta", "Cryst.", "D65,", "148–155.", "Vogel,", "S.,", "Ohmayer,", "S.,", "Brunner,", "G.", "&", "Heilmann,", "J.", "(2008).", "Bioorg.", "Med.", "Chem.", "16,", "4286–4293.", "Acta", "Cryst.", "(2009).", "E65,", "o1113", "doi:10.1107/S1600536809014676", "Wang", "et", "al.", "o1113" ]

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[ "Force-Induced", "Unfolding", "Simulations", "of", "the", "Human", "Notch1", "Negative", "Regulatory", "Region:", "Possible", "Roles", "of", "the", "Heterodimerization", "Domain", "in", "Mechanosensing", "Jianhan", "Chen*,", "Anna", "Zolkiewska*", "Department", "of", "Biochemistry,", "Kansas", "State", "University,", "Manhattan,", "Kansas,", "United", "States", "of", "America", "Abstract", "Notch", "receptors", "are", "core", "components", "of", "the", "Notch", "signaling", "pathway", "and", "play", "a", "central", "role", "in", "cell", "fate", "decisions", "during", "development", "as", "well", "as", "tissue", "homeostasis.", "Upon", "ligand", "binding,", "Notch", "is", "sequentially", "cleaved", "at", "the", "S2", "site", "by", "an", "ADAM", "protease", "and", "at", "the", "S3", "site", "by", "the", "c-secretase", "complex.", "Recent", "X-ray", "structures", "of", "the", "negative", "regulatory", "region", "(NRR)", "of", "the", "Notch", "receptor", "reveal", "an", "auto-inhibited", "fold", "where", "three", "protective", "Lin12/Notch", "repeats", "(LNR)", "of", "the", "NRR", "shield", "the", "S2", "cleavage", "site", "housed", "in", "the", "heterodimerization", "(HD)", "domain.", "One", "of", "the", "models", "explaining", "how", "ligand", "binding", "drives", "the", "NRR", "conformation", "from", "a", "protease-resistant", "state", "to", "a", "protease-sensitive", "one", "invokes", "a", "mechanical", "force", "exerted", "on", "the", "NRR", "upon", "ligand", "endocytosis.", "Here,", "we", "combined", "physics-based", "atomistic", "simulations", "and", "topology-based", "coarse-grained", "modeling", "to", "investigate", "the", "intrinsic", "and", "force-induced", "folding", "and", "unfolding", "mechanisms", "of", "the", "human", "Notch1", "NRR.", "The", "simulations", "support", "that", "external", "force", "applied", "to", "the", "termini", "of", "the", "NRR", "disengages", "the", "LNR", "modules", "from", "the", "heterodimerization", "(HD)", "domain", "in", "a", "well-defined,", "largely", "sequential", "manner.", "Importantly,", "the", "mechanical", "force", "can", "further", "drive", "local", "unfolding", "of", "the", "HD", "domain", "in", "a", "functionally", "relevant", "fashion", "that", "would", "provide", "full", "proteolytic", "access", "to", "the", "S2", "site", "prior", "to", "heterodimer", "disassociation.", "We", "further", "analyzed", "local", "structural", "features,", "intrinsic", "folding", "free", "energy", "surfaces,", "and", "correlated", "motions", "of", "the", "HD", "domain.", "The", "results", "are", "consistent", "with", "a", "model", "in", "which", "the", "HD", "domain", "possesses", "inherent", "mechanosensing", "characteristics", "that", "could", "be", "utilized", "during", "Notch", "activation.", "This", "potential", "role", "of", "the", "HD", "domain", "in", "ligand-dependent", "Notch", "activation", "may", "have", "implications", "for", "understanding", "normal", "and", "aberrant", "Notch", "signaling.", "Citation:", "Chen", "J,", "Zolkiewska", "A", "(2011)", "Force-Induced", "Unfolding", "Simulations", "of", "the", "Human", "Notch1", "Negative", "Regulatory", "Region:", "Possible", "Roles", "of", "the", "Heterodimerization", "Domain", "in", "Mechanosensing.", "PLoS", "ONE", "6(7):", "e22837.", "doi:10.1371/journal.pone.0022837", "Editor:", "Markus", "J.", "Buehler,", "Massachusetts", "Institute", "of", "Technology,", "United", "States", "of", "America", "Received", "February", "14,", "2011;", "Accepted", "June", "30,", "2011;", "Published", "July", "28,", "2011", "Copyright:", "2011", "Chen,", "Zolkiewska.", "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", "NSF", "through", "a", "CAREER", "Award", "(MCB", "0952514)", "to", "JC", "and", "by", "the", "National", "Institutes", "of", "Health", "through", "an", "R15", "Award", "(CA151065)", "to", "AZ.", "This", "work", "is", "contribution", "11-225-J", "from", "the", "Kansas", "Agricultural", "Experiment", "Station.", "The", "funders", "had", "no", "role", "in", "study", "design,", "data", "collection", "and", "analysis,", "decision", "to", "publish,", "or", "preparation", "of", "the", "manuscript.", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "*", "E-mail:", "jianhanc@ksu.edu", "(JC);", "zolkiea@ksu.edu", "(AZ)", "Introduction", "Notch", "signaling", "is", "a", "highly", "conserved", "inter-cellular", "communi-", "cation", "pathway", "that", "plays", "critical", "roles", "in", "embryonic", "development", "and", "in", "tissue", "homeostasis", "[1–3].", "Abnormal", "Notch", "signaling", "is", "frequently", "associated", "with", "a", "number", "of", "human", "diseases,", "including", "T-cell", "acute", "lymphocytic", "leukemia", "(T-ALL)", "and", "solid", "tumors", "[4,5].", "At", "the", "heart", "of", "Notch", "signaling", "are", "the", "Notch", "receptors,", "a", "family", "of", "highly", "modular,", "single-pass", "transmembrane", "proteins", "[6,7].", "There", "are", "four", "Notch", "receptors", "in", "mammals,", "designated", "as", "Notch1–4.", "All", "Notch", "receptors", "have", "a", "similar", "modular", "architecture,", "as", "illustrated", "in", "Fig.", "1a", "for", "human", "Notch1.", "During", "maturation,", "the", "Notch", "receptor", "is", "cleaved", "at", "the", "S1", "site", "by", "a", "furin-like", "protease,", "which", "yields", "a", "heterodimer", "with", "non-covalently", "associated", "extracellular", "and", "transmembrane", "subunits", "[8,9].", "Canonical", "Notch", "activation", "is", "initiated", "by", "binding", "of", "a", "transmembrane", "ligand", "of", "the", "Delta/", "Serrate/LAG-2", "(DSL)", "family", "on", "the", "signal-sending", "cell", "to", "a", "Notch", "receptor", "on", "the", "surface", "of", "the", "signal", "receiving", "cell", "[2,6,7].", "Through", "mechanisms", "yet", "to", "be", "precisely", "determined,", "ligand", "engagement", "triggers", "regulated", "intra-membrane", "proteolysis", "where", "the", "Notch", "receptor", "is", "first", "cleaved", "at", "a", "juxtamembrane", "extracellular", "site", "S2", "by", "ADAM10", "or", "ADAM17", "metalloproteases", "[10–14].", "After", "the", "S2", "cleavage,", "the", "Notch", "receptor", "is", "further", "cleaved", "at", "an", "intra-", "membrane", "S3", "site", "by", "the", "c-secretase", "complex", "[15–17].", "The", "S3", "cleavage", "releases", "the", "intracellular", "portion", "of", "Notch", "(ICN)", "and", "allows", "it", "to", "translocate", "to", "the", "nucleus", "and", "participate", "in", "tran-", "scription", "regulation", "in", "a", "context", "and", "gene", "dose", "dependent", "manner", "[18,19].", "Important", "progresses", "have", "been", "made", "towards", "understanding", "a", "structural", "basis", "of", "Notch", "signaling", "and", "regulation", "[7,20].", "One", "of", "the", "key", "advances", "is", "the", "recent", "determination", "of", "high-resolution", "X-", "ray", "structures", "of", "the", "negative", "regulatory", "regions", "(NRR)", "of", "human", "Notch1", "and", "Notch2", "[21,22].", "The", "NRR", "consists", "of", "three", "Lin12/", "Notch", "repeats", "(LNR)", "and", "the", "heterodimerization", "(HD)", "domain.", "The", "later", "contains", "both", "the", "S1", "and", "S2", "sites", "near", "the", "middle", "and", "the", "C-terminus,", "respectively", "(Fig.", "1).", "The", "X-ray", "structure", "(Fig.", "1b)", "reveals", "that", "the", "NRR", "maintains", "an", "auto-inhibited,", "compact", "fold", "where", "the", "LNR", "modules", "wrap", "around", "the", "HD", "domain", "and", "shield", "the", "S2", "site", "from", "metalloprotease", "access.", "Clearly,", "large-scale", "conformational", "movements", "involving", "a", "displacement", "of", "LNR-A,", "the", "LNR-AB", "linker,", "and", "LNR-B", "from", "the", "HD", "domain", "are", "necessary", "for", "an", "ADAM", "protease", "to", "gain", "access", "to", "the", "S2", "site.", "Several", "models", "have", "been", "proposed", "to", "explain", "how", "ligand", "binding", "might", "facilitate", "large", "conformational", "changes", "within", "the", "NRR,", "PLoS", "ONE", "|", "www.plosone.org", "1", "July", "2011", "|", "Volume", "6", "|", "Issue", "7", "|", "e22837" ]

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[ "Hindawi", "Publishing", "Corporation", "Evidence-Based", "Complementary", "and", "Alternative", "Medicine", "Volume", "2011,", "Article", "ID", "790784,", "6", "pages", "doi:10.1093/ecam/nen060", "Original", "Article", "A", "Chinese", "Herbal", "Preparation", "Containing", "Radix", "Salviae", "Miltiorrhizae,", "Radix", "Notoginseng", "and", "Borneolum", "Syntheticum", "Reduces", "Circulating", "Adhesion", "Molecules", "Kylie", "A.", "O’Brien,1,", "2", "Shanhong", "Ling,1", "Estelle", "Abbas,1", "Aozhi", "Dai,1", "Jiansheng", "Zhang,3", "Wen", "Cheng", "Wang,4", "Alan", "Bensoussan,5", "Ruizhi", "Luo,6", "Zhi-Xin", "Guo,6", "and", "Paul", "A.", "Komesaroff1", "1", "Monash", "University", "Department", "of", "Medicine,", "Alfred", "Hospital,", "Melbourne,", "Australia", "2", "Faculty", "of", "Health,", "Engineering", "and", "Science,", "Victoria", "University,", "P.O.", "Box", "14428,", "Melbourne,", "VIC", "8001,", "Australia", "3", "Division", "of", "Chinese", "Medicine,", "School", "of", "Health", "Sciences,", "RMIT", "University,", "Melbourne,", "Australia", "4", "Registered", "Chinese", "medicine", "practitioner", "in", "private", "practice,", "Prahran,", "VIC,", "Australia", "5", "National", "Institute", "of", "Complementary", "Medicine,", "University", "of", "Western", "Sydney,", "Sydney,", "Australia", "6", "Institute", "of", "Research", "and", "Development,", "Tianjin", "Tasly", "Pharmaceutical", "Corporation,", "Tianjin,", "China", "Correspondence", "should", "be", "addressed", "to", "Kylie", "A.", "O’Brien,", "kylie.obrien@vu.edu.au", "Received", "13", "December", "2007;", "Accepted", "21", "August", "2008", "Copyright", "©", "2011", "Kylie", "A.", "O’Brien", "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.", "Circulating", "adhesion", "molecules", "(CAMs),", "surface", "proteins", "expressed", "in", "the", "vascular", "endothelium,", "have", "emerged", "as", "risk", "factors", "for", "cardiovascular", "disease", "(CVD).", "CAMs", "are", "involved", "in", "intercellular", "communication", "that", "are", "believed", "to", "play", "a", "role", "in", "atherosclerosis.", "A", "Chinese", "medicine,", "the", "“Dantonic", "Pill”", "(DP)", "(also", "known", "as", "the", "“Cardiotonic", "Pill”),", "containing", "three", "Chinese", "herbal", "material", "medica,", "Radix", "Salviae", "Miltiorrhizae,", "Radix", "Notoginseng", "and", "Borneolum", "Syntheticum,", "has", "been", "used", "in", "China", "for", "the", "prevention", "and", "management", "of", "CVD.", "Previous", "laboratory", "and", "animal", "studies", "have", "suggested", "that", "this", "preparation", "reduces", "both", "atherogenesis", "and", "adhesion", "molecule", "expression.", "A", "parallel", "double", "blind", "randomized", "placebo-controlled", "study", "was", "conducted", "to", "assess", "the", "effects", "of", "the", "DP", "on", "three", "species", "of", "CAM", "(intercellular", "cell", "adhesion", "molecule-1", "(ICAM-1),", "vascular", "cell", "adhesion", "molecule-1", "and", "endothelial", "cell", "selectin", "(E-selectin))", "in", "participants", "with", "mild-moderate", "hypercholesterolemia.", "Secondary", "endpoints", "included", "biochemical", "and", "hematological", "variables", "and", "clinical", "effects.", "Forty", "participants", "were", "randomized", "to", "either", "treatment", "or", "control", "for", "12", "weeks.", "Treatment", "with", "DP", "was", "associated", "with", "a", "statistically", "significant", "decrease", "in", "ICAM-1", "(9%", "decrease,", "P", "=", ".03)", "and", "E-Selectin", "(15%", "decrease,", "P", "=", ".004).", "There", "was", "no", "significant", "change", "in", "renal", "function", "tests,", "liver", "function", "tests,", "glucose,", "lipids", "or", "C-reactive", "protein", "levels", "and", "clinical", "adverse", "effects", "did", "not", "differ", "between", "the", "active", "and", "the", "control", "groups.", "There", "were", "no", "relevant", "changes", "in", "participants", "receiving", "placebo.", "These", "results", "suggest", "that", "this", "herbal", "medicine", "may", "contribute", "to", "the", "development", "of", "a", "novel", "approach", "to", "cardiovascular", "risk", "reduction.", "1.", "Introduction", "Circulating", "adhesion", "molecules", "(CAMs)", "are", "proteins", "ex-", "pressed", "by", "the", "vascular", "endothelium", "involved", "in", "intercellular", "communication", "that", "are", "believed", "to", "play", "a", "role", "in", "the", "initiation", "of", "the", "atherosclerotic", "process.", "There", "are", "several", "families", "of", "CAMs,", "including", "integrins,", "cadherins,", "selectins", "and", "immunoglobulin", "superfamily", "members", "[1].", "The", "most", "important", "adhesion", "molecules", "involved", "in", "atherosclerosis", "appear", "to", "be", "intercellular", "cell", "adhesion", "molecule-1", "(ICAM-", "1),", "endothelial", "cell", "selectin", "(E-selectin)", "and", "vascular", "cell", "adhesion", "molecule-1", "(VCAM-1).", "Raised", "levels", "of", "ICAM-", "1", "have", "been", "found", "to", "be", "predictive", "of", "increased", "risk", "of", "cardiovascular", "events", "[2,", "3],", "including", "in", "healthy", "individuals", "[4].", "Levels", "of", "P-selectin", "and", "E-selectin", "have", "been", "found", "to", "predict", "cardiovascular", "disease", "(CVD)", "risk", "in", "healthy", "women", "[5],", "and", "in", "patients", "with", "stable", "coronary", "artery", "disease", "plasma", "levels", "of", "E-selectin", "appear", "to", "reflect", "the", "severity", "of", "systemic", "atherosclerosis", "[6].", "VCAM-1", "may", "be", "a", "more", "specific", "marker", "for", "advanced", "atherosclerosis,", "since", "it", "is", "usually", "expressed", "in", "atherosclerotic", "plaques", "[7]", "and", "higher", "levels", "are", "associated", "with", "increased", "risk", "of", "coronary", "events" ]

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[ "7188–7196", "Nucleic", "Acids", "Research,", "2007,", "Vol.", "35,", "No.", "21", "doi:10.1093/nar/gkm864", "Published", "online", "18", "October", "2007", "SILVA:", "a", "comprehensive", "online", "resource", "for", "quality", "checked", "and", "aligned", "ribosomal", "RNA", "sequence", "data", "compatible", "with", "ARB", "Elmar", "Pruesse1,2,", "Christian", "Quast1,3,", "Katrin", "Knittel4,", "Bernhard", "M.", "Fuchs4,", "Wolfgang", "Ludwig5,", "Jo¨", "rg", "Peplies6", "and", "Frank", "Oliver", "Glo¨", "ckner1,3,*", "1Microbial", "Genomics", "Group,", "Max", "Planck", "Institute", "for", "Marine", "Microbiology,", "2University", "Bremen,", "Center", "for", "Computing", "Technologies,", "D-28359,", "3Jacobs", "University", "Bremen", "gGmbH,", "D-28759,", "4Department", "of", "Molecular", "Ecology,", "Max", "Planck", "Institute", "for", "Marine", "Microbiology,", "D-28359", "Bremen,", "5Department", "for", "Microbiology,", "Technical", "University", "Munich,", "D-85354", "Freising", "and", "6Ribocon", "GmbH,", "D-28359", "Bremen", "Received", "May", "26,", "2007;", "Revised", "August", "18,", "2007;", "Accepted", "September", "14,", "2007", "ABSTRACT", "Sequencing", "ribosomal", "RNA", "(rRNA)", "genes", "is", "cur-", "rently", "the", "method", "of", "choice", "for", "phylogenetic", "reconstruction,", "nucleic", "acid", "based", "detection", "and", "quantification", "of", "microbial", "diversity.", "The", "ARB", "soft-", "ware", "suite", "with", "its", "corresponding", "rRNA", "datasets", "has", "been", "accepted", "by", "researchers", "worldwide", "as", "a", "standard", "tool", "for", "large", "scale", "rRNA", "analysis.", "However,", "the", "rapid", "increase", "of", "publicly", "available", "rRNA", "sequence", "data", "has", "recently", "hampered", "the", "maintenance", "of", "comprehensive", "and", "curated", "rRNA", "knowledge", "databases.", "A", "new", "system,", "SILVA", "(from", "Latin", "silva,", "forest),", "was", "implemented", "to", "provide", "a", "central", "comprehensive", "web", "resource", "for", "up", "to", "date,", "quality", "controlled", "databases", "of", "aligned", "rRNA", "sequences", "from", "the", "Bacteria,", "Archaea", "and", "Eukarya", "domains.", "All", "sequences", "are", "checked", "for", "anomalies,", "carry", "a", "rich", "set", "of", "sequence", "associated", "contextual", "information,", "have", "multiple", "taxonomic", "classifications,", "and", "the", "latest", "validly", "described", "nomenclature.", "Furthermore,", "two", "precompiled", "sequence", "datasets", "compatible", "with", "ARB", "are", "offered", "for", "download", "on", "the", "SILVA", "website:", "(i)", "the", "reference", "(Ref)", "datasets,", "comprising", "only", "high", "quality,", "nearly", "full", "length", "sequences", "suitable", "for", "in-depth", "phyloge-", "netic", "analysis", "and", "probe", "design", "and", "(ii)", "the", "comprehensive", "Parc", "datasets", "with", "all", "publicly", "available", "rRNA", "sequences", "longer", "than", "300", "nucleo-", "tides", "suitable", "for", "biodiversity", "analyses.", "The", "latest", "publicly", "available", "database", "release", "91", "(August", "2007)", "hosts", "547", "521", "sequences", "split", "into", "461", "823", "small", "subunit", "and", "85", "689", "large", "subunit", "rRNAs.", "INTRODUCTION", "Initiated", "by", "the", "pioneering", "studies", "of", "Fox", "and", "Woese", "(1)", "30", "years", "ago", "and", "later", "on", "pursued", "by", "Pace,", "Olsen,", "Giovannoni,", "and", "Ward", "(2–5),", "the", "ribosomal", "RNA", "(rRNA)", "molecule", "has", "been", "established", "as", "the", "‘gold-", "standard’", "for", "the", "investigation", "of", "the", "phylogeny", "and", "ecology", "of", "microorganisms", "(6,7).", "Today", "the", "more", "than", "500", "000", "publicly", "available", "small", "and", "large", "subunit", "(SSU", "and", "LSU)", "rRNA", "sequences", "ask", "for", "specialized", "quality", "controlled", "databases", "and", "appropriate", "software", "tools.", "In", "anticipation", "of", "this", "impending", "deluge", "of", "rRNA", "data,", "the", "development", "of", "the", "ARB", "software", "suite", "and", "the", "curation", "of", "its", "associated", "databases", "began", "more", "than", "12", "years", "ago", "(8).", "The", "software", "suite", "offers", "a", "graphical", "user", "interface", "and", "a", "wide", "variety", "of", "interacting", "software", "tools", "built", "around", "a", "common", "database.", "Furthermore,", "the", "ARB", "project", "provides", "structured,", "integrative", "knowledge", "data-", "bases", "for", "small", "and", "large", "subunit", "rRNAs.", "Based", "on", "regularly", "offered", "international", "workshops", "and", "the", "ARB", "mailing", "list", "it", "is", "currently", "estimated", "that", "the", "ARB", "software", "suite", "and", "its", "databases", "are", "employed", "worldwide", "by", "several", "thousand", "users", "from", "academia", "and", "industry.", "In", "addition", "to", "the", "ARB", "approach,", "there", "are", "currently", "three", "projects", "offering", "access", "to", "a", "set", "of", "curated", "ribosomal", "RNA", "sequence", "and", "alignment", "databases:", "the", "European", "rRNA", "databank", "at", "the", "University", "of", "Gent", "(http://www.psb.", "ugent.be/rRNA/)", "(9),", "the", "Ribosomal", "Database", "Project", "II", "(http://rdp.cme.msu.edu/)", "at", "Michigan", "State", "University", "in", "East", "Lansing,", "MI", "(10,11),", "and", "the", "greengenes", "project", "(http://greengenes.lbl.gov/)", "maintained", "by", "the", "Lawrence", "Berkeley", "National", "Laboratory", "in", "Berkeley,", "CA", "(12).", "All", "four", "projects", "offer", "at", "least", "one", "16S", "rRNA", "dataset,", "but", "vary", "in", "the", "amount", "of", "sequences,", "quality", "checks,", "alignments,", "and", "update", "procedures.", "However,", "the", "ARB", "project", "is", "the", "*To", "whom", "correspondence", "should", "be", "addressed.", "Tel:", "+49", "421", "2028970;", "Fax:", "+49", "421", "2028580;", "Email:", "fog@mpi-bremen.de", "The", "authors", "wish", "it", "to", "be", "known", "that,", "in", "their", "opinion,", "the", "first", "two", "authors", "should", "be", "regarded", "as", "joint", "First", "Authors.", "2007", "The", "Author(s)", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "Non-Commercial", "License", "(http://creativecommons.org/licenses/", "by-nc/2.0/uk/)", "which", "permits", "unrestricted", "non-commercial", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

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[ "Sensors", "2010,", "10,", "10752-10777;", "doi:10.3390/s101210752", "OPEN", "ACCESS", "sensors", "ISSN", "1424-8220", "www.mdpi.com/journal/sensors", "Article", "Study", "of", "the", "Ubiquitous", "Hog", "Farm", "System", "Using", "Wireless", "Sensor", "Networks", "for", "Environmental", "Monitoring", "and", "Facilities", "Control", "Jeonghwan", "Hwang", "and", "Hyun", "Yoe", "*", "School", "of", "Information", "and", "Communication", "Engineering,", "Sunchon", "National", "University,", "Maegok-dong,", "Suncheon-si,", "Jeollanam-do,", "Korea;", "E-Mail:", "jhwang@sunchon.ac.kr", "*", "Author", "to", "whom", "correspondence", "should", "be", "addressed;", "E-Mail:", "yhyun@sunchon.ac.kr;", "Tel.:", "+82-61-750-3591;", "Fax:", "+82-61-750-3590.", "Received:", "2", "November", "2010;", "in", "revised", "form:", "16", "November", "2010", "/", "Accepted:", "26", "November", "2010", "/", "Published:", "2", "December", "2010", "Abstract:", "Many", "hog", "farmers", "are", "now", "suffering", "from", "high", "pig", "mortality", "rates", "due", "to", "various", "wasting", "diseases", "and", "increased", "breeding", "costs,", "etc.", "It", "is", "therefore", "necessary", "for", "hog", "farms", "to", "implement", "systematic", "and", "scientific", "pig", "production", "technology", "to", "increase", "productivity", "and", "produce", "high", "quality", "pork", "in", "order", "to", "solve", "these", "problems.", "In", "this", "study,", "we", "describe", "such", "a", "technology", "by", "suggesting", "a", "ubiquitous", "hog", "farm", "system", "which", "applies", "WSN", "(Wireless", "Sensor", "Network)", "technology", "to", "the", "pig", "industry.", "We", "suggest", "that", "a", "WSN", "and", "CCTV", "(Closed-circuit", "television)", "should", "be", "installed", "on", "hog", "farms", "to", "collect", "environmental", "and", "image", "information", "which", "shall", "then", "help", "producers", "not", "only", "in", "monitoring", "the", "hog", "farm", "via", "the", "Web", "from", "outside", "the", "farm,", "but", "also", "facilitate", "the", "control", "of", "hog", "farm", "facilities", "in", "remote", "locations.", "In", "addition,", "facilities", "can", "be", "automatically", "controlled", "based", "on", "breeding", "environment", "parameters", "which", "are", "already", "set", "up", "and", "a", "SMS", "notice", "service", "to", "notify", "of", "deviations", "shall", "provide", "users", "with", "convenience.", "Hog", "farmers", "may", "increase", "production", "and", "improve", "pork", "quality", "through", "this", "ubiquitous", "hog", "farm", "system", "and", "prepare", "a", "database", "with", "information", "collected", "from", "environmental", "factors", "and", "the", "hog", "farm", "control", "devices,", "which", "is", "expected", "to", "provide", "information", "needed", "to", "design", "and", "implement", "suitable", "control", "strategies", "for", "hog", "farm", "operation.", "Keywords:", "WSN;", "ubiquitous;", "agriculture;", "pig;", "hog", "farm" ]

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[ "Morissette", "et", "al.", "Respiratory", "Research", "2011,", "12:105", "http://respiratory-research.com/content/12/1/105", "R", "E", "S", "E", "A", "R", "C", "H", "Open", "Access", "The", "emphysematous", "lung", "is", "abnormally", "sensitive", "to", "TRAIL-mediated", "apoptosis", "Mathieu", "C", "Morissette,", "Julie", "Parent", "and", "Julie", "Milot*", "Abstract", "Background:", "Alveolar", "apoptosis", "is", "increased", "in", "the", "emphysematous", "lung.", "However,", "mechanisms", "involved", "are", "not", "fully", "understood.", "Recently,", "we", "demonstrated", "that", "levels", "of", "TRAIL", "receptor", "1", "and", "2,", "levels", "of", "p53,", "and", "Bax/Bcl-xL", "ratio", "were", "elevated", "in", "the", "lung", "of", "subjects", "with", "emphysema,", "despite", "smoking", "cessation.", "Thus,", "we", "postulate", "that", "due", "to", "chronic", "pulmonary", "oxidative", "stress,", "the", "emphysematous", "lung", "would", "be", "abnormally", "sensitive", "to", "TRAIL-", "mediated", "apoptosis.", "Methodology:", "A549", "cells", "were", "exposed", "to", "rTRAIL,", "cigarette", "smoke", "extract,", "and/or", "H2O2", "prior", "to", "caspase-3", "activity", "measurement", "and", "annexin", "V", "staining", "assessment.", "In", "addition,", "freshly", "resected", "lung", "samples", "were", "obtained", "from", "non-emphysematous", "and", "emphysematous", "subjects", "and", "exposed", "ex", "vivo", "to", "rTRAIL", "for", "up", "to", "18", "hours.", "Lung", "samples", "were", "harvested", "and", "levels", "of", "active", "caspase-3", "and", "caspase-8", "were", "measured", "from", "tissue", "lysates.", "Results:", "Both", "cigarette", "smoke", "extract", "and", "H2O2", "were", "able", "to", "sensitize", "A549", "cells", "to", "TRAIL-mediated", "apoptosis.", "Moreover,", "following", "exposure", "to", "rTRAIL,", "caspase-3", "and", "-8", "were", "activated", "in", "lung", "explants", "from", "emphysematous", "subjects", "while", "being", "decreased", "in", "lung", "explants", "from", "non-emphysematous", "subjects.", "Significance", "of", "the", "study:", "Alveolar", "sensitivity", "to", "TRAIL-mediated", "apoptosis", "is", "strongly", "increased", "in", "the", "emphysematous", "lung", "due", "to", "the", "presence", "of", "oxidative", "stress.", "This", "might", "be", "a", "new", "mechanism", "leading", "to", "increased", "alveolar", "apoptosis", "and", "persistent", "alveolar", "destruction", "following", "smoking", "cessation.", "Keywords:", "Apoptosis,", "COPD,", "oxidative", "stress,", "p53,", "TRAIL", "Introduction", "Emphysema,", "largely", "caused", "by", "cigarette", "smoking,", "is", "mainly", "characterized", "by", "a", "loss", "of", "alveolar", "integrity", "lead-", "ing", "to", "poor", "gas", "exchange", "between", "the", "alveolar", "space", "and", "pulmonary", "capillaries", "[1].", "Moreover,", "the", "emphyse-", "matous", "lung", "is", "an", "inflamed", "tissue", "in", "which", "activated", "neutrophils,", "alveolar", "macrophages", "and", "lymphocytes", "are", "found", "in", "large", "numbers", "[2].", "In", "addition", "to", "proteases", "and", "inflammatory", "mediators,", "neutrophils", "and", "macrophages", "generate", "reactive", "oxygen", "species", "(ROS)", "[3,4].", "This", "adds", "to", "oxidative", "stress", "aggression", "induced", "by", "primary", "cigar-", "ette", "smoke", "exposure", "and", "is", "responsible", "for", "the", "persis-", "tence", "of", "oxidative", "stress", "after", "smoking", "cessation", "[5].", "High", "oxidative", "stress", "can", "damage", "cell", "lipids,", "proteins,", "and", "nucleic", "acids", "[6].", "If", "too", "severe,", "such", "damage", "will", "force", "cells", "to", "activate", "their", "programmed", "cell", "death", "*", "Correspondence:", "Julie.milot@criucpq.ulaval.ca", "Centre", "de", "recherche", "de", "l’Institut", "universitaire", "de", "cardiologie", "et", "de", "pneumologie", "de", "Québec", "(CRIUCPQ),", "Québec,", "Canada", "(apoptosis)", "[7].", "Exposure", "to", "exogenous", "ROS", "acts", "on", "sev-", "eral", "apoptosis/survival-related", "signaling", "pathways", "such", "as", "MAPK,", "AKT,", "JAK/STAT,", "NF-", "B", "and", "the", "DNA", "damage", "checkpoint", "involving", "p53", "[7].", "The", "transcription", "factor", "p53", "is", "an", "important", "member", "of", "the", "cellular", "response", "to", "DNA", "damage.", "Depending", "on", "the", "severity", "of", "the", "DNA", "injuries,", "p53", "will", "transcribe", "genes", "that", "will", "stop", "the", "cell", "cycle", "(i.e.", "p21,", "14-3-3s)", "and", "allow", "DNA", "repair.", "However,", "p53", "can", "also", "promote", "the", "transcription", "of", "pro-apoptotic", "genes", "(i.e.", "Bax,", "PUMA,", "NOXA,", "Fas,", "TRAIL-receptors", "1", "and", "2)", "that", "will", "activate", "apoptosis", "and", "lead", "to", "cell", "death", "[8].", "It", "is", "now", "well", "accepted", "that", "apoptosis", "is", "increased", "in", "the", "emphysematous", "lung", "[9-12],", "however,", "the", "cause", "is", "not", "fully", "understood.", "Our", "laboratory", "has", "previously", "demonstrated", "that", "a", "sub-lethal", "dose", "of", "hydrogen", "perox-", "ide", "(H2O2)", "activates", "p53", "and", "up-regulates", "Bax", "and", "pro-", "apoptotic", "TRAIL-receptors", "(TRAIL-Rs)", "1", "and", "2", "in", "lung", "adenocarcinoma", "cells", "A549", "[13].", "These", "apoptotic", "factors", "©", "2011", "Morissette", "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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[ "Journal", "of", "Translational", "Medicine", "Research", "Melanoma-restricted", "genes", "Ena", "Wang1,", "Monica", "C", "Panelli1,", "Katia", "Zavaglia1,", "Susanna", "Mandruzzato2,", "Nan", "Hu3,", "Phil", "R", "Taylor3,", "Barbara", "Seliger4,", "Paola", "Zanovello2,", "Ralph", "S", "Freedman5", "and", "Francesco", "M", "Marincola*1", "BioMed", "Central", "Open", "Access", "Address:", "1Immunogenetics", "Section,", "Department", "of", "Transfusion", "Medicine,", "Clinical", "Center,", "National", "Institutes", "of", "Health,", "Bethesda,", "Maryland", "20892,", "USA,", "2Department", "of", "Oncology", "and", "Surgical", "Sciences,", "Oncology", "Section,", "University", "of", "Padova,", "Padova,", "Italy,", "3Cancer", "Prevention", "Studies", "Branch,", "Center", "for", "Cancer", "Research,", "National", "Cancer", "Institute,", "National", "Institutes", "of", "Health,", "Bethesda,", "MD", "20892,", "USA,", "4Institute", "of", "Medical", "Immunology,", "Martin", "Luther", "University", "Halle-Wittenberg,", "06112", "Halle,", "Germany", "and", "5Department", "of", "Gynecologic", "Oncology,", "The", "University", "of", "Texas,", "MD", "Anderson", "Cancer", "Center,", "Houston,", "TX,", "USA", "Email:", "Ena", "Wang", "-", "ewang@mail.cc.nih.gov;", "Monica", "C", "Panelli", "-", "MPanelli@mail.cc.nih.gov;", "Katia", "Zavaglia", "-", "kzavaglia@cc.nih.gov;", "Susanna", "Mandruzzato", "-", "susanna.mandruzzato@unipd.it;", "Nan", "Hu", "-", "hun@dcpcepn.nci.nih.gov;", "Phil", "R", "Taylor", "-", "taylorp@dcpcepn.nci.nih.gov;", "Barbara", "Seliger", "-", "barbara.seliger@medizin.uni-halle.de;", "Paola", "Zanovello", "-", "paola.zanovello@unipd.it;", "Ralph", "S", "Freedman", "-", "rfreedma@mdanderson.org;", "Francesco", "M", "Marincola*", "-", "FMarincola@cc.nih.gov", "*", "Corresponding", "author", "Published:", "15", "October", "2004", "Journal", "of", "Translational", "Medicine", "2004,", "2:34", "doi:10.1186/1479-5876-2-34", "Received:", "16", "September", "2004", "Accepted:", "15", "October", "2004", "This", "article", "is", "available", "from:", "http://www.translational-medicine.com/content/2/1/34", "©", "2004", "Wang", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Human", "metastatic", "cutaneous", "melanoma", "has", "gained", "a", "well", "deserved", "reputation", "for", "its", "immune", "responsiveness.", "The", "reason(s)", "remain(s)", "unknown.", "We", "attempted", "previously", "to", "characterize", "several", "variables", "that", "may", "affect", "the", "relationship", "between", "tumor", "and", "host", "immune", "cells", "but,", "taken", "one", "at", "the", "time,", "none", "yielded", "a", "convincing", "explanation.", "With", "explorative", "purposes,", "high-", "throughput", "technology", "was", "applied", "here", "to", "portray", "transcriptional", "characteristics", "unique", "to", "metastatic", "cutaneous", "melanoma", "that", "may", "or", "may", "not", "be", "relevant", "to", "its", "immunogenic", "potential.", "Several", "functional", "signatures", "could", "be", "identified", "descriptive", "of", "immune", "or", "other", "biological", "functions.", "In", "addition,", "the", "transcriptional", "profile", "of", "metastatic", "melanoma", "was", "compared", "with", "that", "of", "primary", "renal", "cell", "cancers", "(RCC)", "identifying", "several", "genes", "co-coordinately", "expressed", "by", "the", "two", "tumor", "types.", "Since", "RCC", "is", "another", "immune", "responsive", "tumor,", "commonalities", "between", "RCC", "and", "melanoma", "may", "help", "untangle", "the", "enigma", "of", "their", "potential", "immune", "responsiveness.", "This", "purely", "descriptive", "study", "provides,", "therefore,", "a", "map", "for", "the", "investigation", "of", "metastatic", "melanoma", "in", "future", "clinical", "trials", "and", "at", "the", "same", "time", "may", "invite", "consideration", "of", "novel", "therapeutic", "targets.", "Background", "Human", "metastatic", "cutaneous", "melanoma", "relative", "to", "other", "common", "solid", "tumors", "shares", "with", "renal", "cell", "cancer", "(RCC)", "the", "well", "deserved", "reputation", "of", "being", "responsive", "to", "immune", "manipulation", "[1,2].", "However,", "the", "reason(s)", "for", "this", "phenomenon", "remain(s)", "largely", "unknown", "[3].", "Possi-", "bly,", "metastatic", "cutaneous", "melanoma", "is", "endowed", "com-", "pared", "to", "other", "tumors", "with", "a", "wealth", "of", "\"tumor", "rejection\"", "antigens", "of", "unique", "immunogenic", "potential.", "Indeed,", "the", "ease", "in", "which", "tumor", "infiltrating", "lymphocytes", "recognizing", "autologous", "tumor", "cells", "can", "be", "isolated", "from", "melanoma", "metastases", "suggests", "an", "extraordinary", "ability", "of", "melanoma", "cells", "to", "elicit", "cognitive", "T", "cell", "responses", "[4].", "In", "addition,", "the", "broad", "repertoire", "of", "melanoma-associated", "antigens", "so", "far", "discovered", "largely", "outnumbers", "that", "of", "other", "tumors", "sug-", "gesting", "a", "stronger", "immunogenicity", "of", "this", "cancer", "[5-7].", "Page", "1", "of", "14", "(page", "number", "not", "for", "citation", "purposes)" ]

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[ "Gut", "and", "Liver,", "Vol.", "5,", "No.", "2,", "June", "2011,", "pp.", "181-186", "ORiginal", "Article", "Clinical", "Characteristics", "of", "Microscopic", "Colitis", "in", "Korea:", "Prospective", "Multicenter", "Study", "by", "KASID", "Young", "Sook", "Park*,∥∥,", "Dae", "Hyun", "Baek*,", "Won", "Ho", "Kim†,∥∥,", "Joo", "Sung", "Kim‡,∥∥,", "Suk-Kyun", "Yang§,∥∥,", "Sung-Ae", "Jung∥,∥∥,", "Byung", "Ik", "Jang¶,∥∥,", "Chnag", "Hwan", "Choi#,∥∥,", "Dong", "Soo", "Han**,∥∥,", "Young-Ho", "Kim††,∥∥,", "Yong", "Woo", "Chung‡‡,∥∥,", "Sang", "Woo", "Kim‡‡,∥∥,", "and", "You", "Sun", "Kim§§,∥∥", "Departments", "of", "Internal", "Medicine,", "*Eulji", "University", "College", "of", "Medicine,", "Yonsei", "University", "College", "of", "Medicine,", "Seoul", "National", "University", "College", "of", "Medicine,", "§University", "of", "Ulsan", "College", "of", "Medicine,", "∥Ehwa", "Womans", "University", "School", "of", "Medicine,", "¶Yeungnam", "University", "College", "of", "Medicine,", "#Chung", "Ang", "University", "College", "of", "Medicine,", "**Hanyang", "University", "College", "of", "Medicine,", "Sungkyunkwan", "University", "School", "of", "Medicine,", "Hallym", "University", "College", "of", "Medine,", "§§Inje", "University", "College", "of", "Medicine,", "and", "∥∥Korean", "Association", "for", "the", "Study", "of", "the", "Intestinal", "Disease", "(KASID),", "Korea", "Background/Aims:", "Microscopic", "colitis", "(MC)", "encompasses", "collagenous", "and", "lymphocytic", "colitis", "and", "is", "characterized", "by", "chronic", "diarrhea.", "In", "cases", "of", "MC,", "colonic", "mucosae", "are", "macroscopically", "normal,", "and", "diagnostic", "histopathological", "features", "are", "observed", "only", "upon", "microscopic", "examination.", "We", "designed", "a", "prospective", "multicenter", "study", "to", "determine", "the", "clinical", "features,", "pathological", "distribution", "in", "the", "colon", "and", "prevalence", "of", "MC", "in", "Korea.", "Methods:", "We", "prospectively", "enrolled", "patients", "having", "watery", "diarrhea", "no", "more", "than", "3", "times", "a", "day", "between", "March", "2008", "and", "February", "2009.", "We", "obtained", "patient", "histories", "and", "performed", "colonoscopies", "with", "random", "biopsies", "at", "each", "colon", "segment.", "Results:", "A", "total", "of", "100", "patients", "with", "chronic", "diarrhea", "were", "enrolled", "for", "a", "nor-", "mal", "colonoscopy", "and", "stool", "exam.", "MC", "was", "observed", "in", "22", "pa-", "tients", "(22%)", "(M:F", "1.2:1;", "mean", "age,", "47.5", "years).", "Of", "those", "22", "patients,", "18", "had", "lymphocytic", "colitis", "and", "4", "had", "collagenous", "colitis.", "The", "entire", "colon", "was", "affected", "in", "only", "3", "cases", "(13.6%),", "the", "ascending", "colon", "in", "6", "cases", "(27.2%),", "the", "transverse", "colon", "in", "3", "cases", "(13.6%),", "and", "the", "left", "colon", "in", "3", "cases", "(13.6%).", "More", "than", "2", "segments", "were", "affected", "in", "7", "cases", "(31.8%).", "Nonsteroidal", "anti-inflammatory", "drug-associated", "MCs", "were", "observed", "in", "4", "cases", "(18.2%),", "3", "of", "which", "showed", "improved", "diarrhea", "symptoms", "following", "discontinuation", "of", "the", "medica-", "tion.", "Frequently", "associated", "symptoms", "were", "abdominal", "pain", "and", "weight", "loss.", "Autoimmune", "diseases", "were", "observed", "in", "4", "cases", "(18.2%).", "Half", "of", "the", "22", "patients", "with", "MC", "improved", "with", "conservative", "care", "by", "loperamide", "or", "probiotics.", "Conclu-", "sions:", "In", "a", "prospective", "multicenter", "study", "of", "Korean", "patients", "with", "chronic", "diarrhea,", "the", "frequency", "of", "MC", "was", "found", "to", "be", "approximately", "20%,", "similar", "to", "the", "percentage", "observed", "in", "Western", "countries.", "Therefore,", "the", "identification", "of", "MC", "is", "important", "for", "the", "adequate", "management", "of", "Korean", "patients", "with", "chronic", "diarrhea.", "(Gut", "Liver", "2011;5:181-186)", "Key", "Words:", "Chronic", "diarrhea;", "Microscopic", "colitis;", "Collag-", "enous", "colitis;", "Lymphocytic", "colitis", "INTRODUCTION", "The", "main", "symptom", "of", "microscopic", "colitis", "is", "chronic", "watery", "diarrhea.", "Despite", "the", "grossly", "normal", "mucosa,", "it", "displays", "typical", "histologic", "abnormalities.", "Microscopic", "colitis", "is", "classified", "as", "col-", "lagenous", "colitis,", "in", "which", "subepithelial", "collagen", "layer", "thickens", "around", "10", "to", "100", "μm", "and", "lymphocytic", "colitis,", "characterized", "by", "the", "presence", "of", "a", "lymphocytes", "more", "than", "20", "in", "100", "epithelial", "cells.1", "In", "Western", "countries,", "it", "has", "become", "apparent", "that", "microscop-", "ic", "colitis", "is", "a", "common", "cause", "of", "diarrhea,", "particularly", "in", "middle-", "aged", "or", "elderly", "patients.2", "Its", "etiology", "and", "pathophysiology", "has", "not", "been", "proven", "yet,", "but", "it", "seems", "to", "associate", "with", "using", "of", "various", "medication", "such", "as", "lansoprazole", "and", "non-steroidal", "anti", "inflammatory", "drugs", "(NSAIDs).3,4", "Also", "many", "reports", "shows", "microscopic", "colitis", "is", "associated", "with", "celiac", "disease", "and", "autoim-", "mune", "diseases,", "such", "as", "Type", "I", "diabetes", "and", "thyroid", "disease.2", "There", "has", "been", "a", "rapid", "increase", "in", "researches", "and", "publica-", "tions", "on", "this", "disease", "entity.", "In", "Korea,", "interest", "about", "microscopic", "colitis", "has", "been", "increasing,", "and", "some", "clinical", "reports", "by", "single", "center", "are", "available.", "Therefore,", "Korean", "Association", "for", "the", "Study", "Correspondence", "to:", "Young", "Sook", "Park", "Department", "of", "Internal", "Medicine,", "Eulji", "Medical", "Center,", "Eulji", "University", "College", "of", "Medicine,", "14", "Hangeulbiseok-gil,", "Nowon-gu,", "Seoul", "139-872,", "Korea", "Tel:", "+82-2-970-8207,", "Fax:", "+82-2-970-8621,", "E-mail:", "Pys1109@eulji.ac.kr", "Received", "on", "July", "23,", "2010.", "Accepted", "on", "January", "3,", "2011.", "pISSN", "1976-2283", "eISSN", "2005-1212", "DOI:", "10.5009/gnl.2011.5.2.181", "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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[ "Bassareo", "et", "al.", "BMC", "Cardiovascular", "Disorders", "2010,", "10:48", "http://www.biomedcentral.com/1471-2261/10/48", "C", "A", "S", "E", "R", "E", "P", "O", "R", "T", "Open", "Access", "Ventricular", "septal", "defect", "in", "a", "child", "with", "Alport", "syndrome:", "a", "case", "report", "Pier", "Paolo", "Bassareo1*,", "Andrea", "Raffaele", "Marras2,", "Giuseppe", "Mercuro1", "Abstract", "Background:", "Alport", "syndrome", "(AS)", "is", "a", "rare", "inherited", "disorder", "characterized", "by", "an", "inflammation", "of", "the", "kidneys", "and", "damage", "to", "the", "glomerular", "capillaries,", "ultimately", "leading", "to", "renal", "failure", "at", "an", "early", "age.", "To", "date,", "rare", "reports", "of", "cardiac", "involvement", "in", "AS", "have", "been", "described,", "due", "in", "the", "majority", "of", "cases", "to", "the", "higher", "risk", "of", "heart", "conduction", "abnormalities", "in", "these", "patients,", "at", "times", "requiring", "implantation", "of", "a", "transcutaneous", "pacemaker.", "An", "increased", "risk", "of", "hypertension", "is", "likewise", "commonly", "featured.", "Case", "presentation:", "We", "report", "the", "case", "of", "a", "17-year-old", "female", "affected", "by", "a", "very", "severe", "early", "form", "of", "AS.", "A", "previously", "unreported", "association", "of", "the", "syndrome", "with", "congenital", "heart", "disease", "(CHD),", "(in", "this", "case", "membranous", "ventricular", "septal", "defect),", "is", "also", "reported.", "A", "possible", "pathophysiological", "mechanism", "underlying", "the", "concomitant", "manifestation", "of", "these", "two", "disorders", "is", "suggested.", "Complications", "implicated", "in", "surgical", "treatment", "of", "CHD", "are", "described.", "Clinical", "and", "therapeutic", "management", "of", "AS", "with", "cardiovascular", "involvement", "are", "discussed,", "and", "a", "short", "literature", "review", "performed.", "Conclusions:", "This", "first", "report", "of", "a", "cardiovascular", "association", "highlights", "the", "possible", "involvement", "of", "collagen", "mutations", "in", "the", "two", "pathologies.", "Even", "when", "drug-resistance", "appears", "to", "be", "responsible", "for", "the", "failure", "to", "control", "secondary", "hypertension", "in", "AS,", "clonidine", "may", "represent", "a", "safe,", "effective", "option", "in", "the", "normalization", "of", "high", "blood", "pressure.", "Background", "Alport", "syndrome", "(AS),", "first", "described", "by", "Cecil", "A.", "Alport", "in", "1927,", "is", "a", "rare", "inherited", "form", "of", "progressive", "kidney", "inflammation", "(0.3", "-", "2.3%", "of", "patients", "presenting", "with", "end-stage", "renal", "disease)", "affecting", "predominantly", "males.", "The", "disorder", "is", "caused", "by", "defects", "in", "the", "genes", "encoding", "a", "connective", "tissue", "protein,", "one", "of", "the", "several", "subunits", "of", "collagen", "(particularly", "type", "IV),", "and", "a", "major", "compo-", "nent", "of", "the", "renal", "glomerular", "basal", "membrane", "[1-5].", "Various", "mutations", "lead", "to", "a", "broad", "spectrum", "of", "signifi-", "cantly", "different", "disease", "phenotypes,", "ranging", "from", "benign", "mild", "renal", "insufficiency", "to", "end-stage", "renal", "disease.", "AS", "is", "inherited", "by", "the", "majority", "of", "patients", "(approx", "85%)", "as", "an", "X-linked", "trait,", "although", "some", "patients", "display", "an", "autoso-", "mal", "recessive", "(10-15%)", "or", "autosomal", "dominant", "(rare)", "genetic", "transmission", "[6].", "As", "a", "general", "rule,", "severity", "of", "the", "disease", "is", "greater", "in", "males", "with", "X-linked", "AS,", "being", "*", "Correspondence:", "piercard@inwind.it", "1Department", "of", "Cardiovascular", "and", "Neurological", "Sciences,", "University", "of", "Cagliari,", "Cagliari,", "Italy", "Full", "list", "of", 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"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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[ "Arias", "et", "al.", "BMC", "Genomics", "2011,", "12:390", "http://www.biomedcentral.com/1471-2164/12/390", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Genome-wide", "survey", "of", "yeast", "mutations", "leading", "to", "activation", "of", "the", "yeast", "cell", "integrity", "MAPK", "pathway:", "Novel", "insights", "into", "diverse", "MAPK", "outcomes", "Patricia", "Arias,", "Sonia", "Díez-Muñiz,", "Raúl", "García,", "César", "Nombela,", "José", "M", "Rodríguez-Peña*", "and", "Javier", "Arroyo", "Abstract", "Background:", "The", "yeast", "cell", "wall", "integrity", "mitogen-activated", "protein", "kinase", "(CWI-MAPK)", "pathway", "is", "the", "main", "regulator", "of", "adaptation", "responses", "to", "cell", "wall", "stress", "in", "yeast.", "Here,", "we", "adopt", "a", "genomic", "approach", "to", "shed", "light", "on", "two", "aspects", "that", "are", "only", "partially", "understood,", "namely,", "the", "characterization", "of", "the", "gene", "functional", "catalog", "associated", "with", "CWI", "pathway", "activation", "and", "the", "extent", "to", "which", "MAPK", "activation", "correlates", "with", "transcriptional", "outcomes.", "Results:", "A", "systematic", "yeast", "mutant", "deletion", "library", "was", "screened", "for", "constitutive", "transcriptional", "activation", "of", "the", "CWI-", "related", "reporter", "gene", "MLP1.", "Monitoring", "phospho-Slt2/Mpk1", "levels", "in", "the", "identified", "mutants", "revealed", "sixty-four", "deletants", "with", "high", "levels", "of", "phosphorylation", "of", "this", "MAPK,", "including", "mainly", "genes", "related", "to", "cell", "wall", "construction", "and", "morphogenesis,", "signaling,", "and", "those", "with", "unknown", "function.", "Phenotypic", "analysis", "of", "the", "last", "group", "of", "mutants", "suggests", "their", "involvement", "in", "cell", "wall", "homeostasis.", "A", "good", "correlation", "between", "levels", "of", "Slt2", "phosphorylation", "and", "the", "magnitude", "of", "the", "transcriptional", "response", "was", "found", "in", "most", "cases.", "However,", "the", "expression", "of", "CWI", "pathway-related", "genes", "was", "enhanced", "in", "some", "mutants", "in", "the", "absence", "of", "significant", "Slt2", "phosphorylation,", "despite", "the", "fact", "that", "functional", "MAPK", "signaling", "through", "the", "pathway", "was", "required.", "CWI", "pathway", "activation", "was", "associated", "to", "increased", "deposition", "of", "chitin", "in", "the", "cell", "wall", "-", "a", "known", "survival", "compensatory", "mechanism", "-", "in", "about", "30%", "of", "the", "mutants", "identified.", "Conclusion:", "We", "provide", "new", "insights", "into", "yeast", "genes", "related", "to", "the", "CWI", "pathway", "and", "into", "how", "the", "state", "of", "activation", "of", "the", "Slt2", "MAPK", "leads", "to", "different", "outcomes,", "discovering", "the", "versatility", "of", "this", "kind", "of", "signaling", "pathways.", "These", "findings", "potentially", "have", "broad", "implications", "for", "understanding", "the", "functioning", "of", "other", "eukaryotic", "MAPKs.", "Background", "The", "capacity", "to", "respond", "properly", "to", "external", "stimuli", "or", "environmental", "conditions", "is", "essential", "for", "homeostasis", "in", "eukaryotes.", "Signaling", "pathways,", "in", "particular", "those", "mediated", "by", "mitogen-activated", "protein", "kinases", "(MAPKs),", "play", "a", "key", "role", "in", "these", "processes.", "A", "significant", "amount", "of", "research", "has", "been", "conducted", "in", "recent", "years", "to", "charac-", "terize", "these", "signal", "transduction", "pathways,", "based", "largely", "on", "the", "model", "yeast", "Saccharomyces", "cerevisiae", "(also", "known", "as", "baker’s", "or", "budding", "yeast).", "Since", "MAPK", "pathways", "are", "evolutionarily", "conserved,", "insights", "gained", "from", "yeast", "con-", "tribute", "to", "a", "better", "understanding", "of", "orthologous", "path-", "ways", "in", "higher", "organisms.", "The", "basic", "assembly", "of", "MAPK", "*", "Correspondence:", "josemanu@farm.ucm.es", "Departamento", "de", "Microbiología", "II,", "Facultad", "de", "Farmacia,", "Universidad", "Complutense", "de", "Madrid,", "IRYCIS,", "28040", "Madrid,", "Spain", "pathways", "is", "a", "three-component", "module", "conserved", "from", "yeast", "to", "humans,", "consisting", "of", "three", "kinases", "that", "establish", "a", "sequential", "activation", "pathway", "by", "means", "of", "phosphoryla-", "tion", "events", "[1].", "The", "regulation", "of", "MAPK", "signal", "transduc-", "tion", "depends", "on", "a", "variety", "of", "mechanisms", "including", "scaffold", "proteins,", "subcellular", "localization", "of", "different", "ele-", "ments", "and", "the", "action", "of", "protein", "phosphatases", "[2].", "In", "yeast,", "six", "MAPK", "cascades", "have", "been", "identified", "that", "mediate", "the", "response", "to", "different", "stimuli:", "(i)", "pheromones", "(pheromone", "response", "pathway);", "(ii)", "nitrogen", "starvation", "(filamentous", "growth", "pathway);", "(iii)", "hyperosmolarity", "(high", "osmolarity/glycerol", "pathway);", "(iv)", "STE", "vegetative", "growth", "pathway", "(SVG)", "[3];", "(v)", "nutrient", "starvation", "(spore", "wall", "assembly", "pathway);", "and", "(vi)", "cell", "wall", "stress", "(CWI:", "cell", "wall", "integrity", "pathway)", "(see", "an", "extensive", "review", "of", "MAPK", "path-", "ways", "in", "[2]).", "The", "CWI", "pathway", "is", "essential", "for", "maintaining", "©", "2011", "Arias", "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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[ "ORIGINAL", "ARTICLE", "JBMR", "Antiepileptic", "Drug", "Use,", "Falls,", "Fractures,", "and", "BMD", "in", "Postmenopausal", "Women:", "Findings", "From", "the", "Women’s", "Health", "Initiative", "(WHI)", "Laura", "D", "Carbone", ",1,2", "Karen", "C", "Johnson", ",3", "John", "Robbins", ",4", "Joseph", "C", "Larson", ",5", "J", "David", "Curb", ",6", "Kathleen", "Watson", ",7", "Margery", "Gass", ",8", "and", "Andrea", "Z", "LaCroix5", "1Department", "of", "Veterans", "Affairs", "Medical", "Center,", "Memphis,", "TN,", "USA", "2Department", "of", "Medicine,", "University", "of", "Tennessee", "Health", "Science", "Center,", "Memphis,", "TN,", "USA", "3Department", "of", "Preventive", "Medicine,", "University", "of", "Tennessee", "Health", "Science", "Center,", "Memphis,", "TN,", "USA", "4Department", "of", "Medicine,", "University", "of", "California,", "Davis,", "CA,", "USA", "5Fred", "Hutchinson", "Cancer", "Research", "Center,", "Seattle,", "WA,", "USA", "6Department", "of", "Geriatric", "Medicine,", "John", "A", "Burns", "School", "of", "Medicine,", "University", "of", "Hawaii,", "Honolulu,", "HI,", "USA", "7University", "of", "Washington,", "Seattle,", "WA,", "USA", "8University", "of", "Cincinnati,", "Cincinnati,", "OH,", "USA", "ABSTRACT", "Antiepileptic", "drugs", "(AEDs)", "are", "used", "increasingly", "in", "clinical", "practice", "to", "treat", "a", "number", "of", "conditions.", "However,", "the", "relationship", "between", "the", "use", "of", "these", "medications,", "particularly", "the", "newer", "AEDs,", "and", "fracture", "risk", "has", "not", "been", "well", "characterized.", "We", "used", "data", "from", "the", "Women’s", "Health", "Initiative", "(WHI)", "to", "determine", "the", "relationship", "bewteen", "the", "use", "of", "AEDs", "and", "falls,", "fractures,", "and", "bone", "mineral", "density", "(BMD)", "over", "an", "average", "of", "7.7", "years", "of", "follow-up.", "We", "included", "138,667", "women", "(1,385", "users", "of", "AEDs", "and", "137,282", "nonusers)", "aged", "50", "to", "79", "years", "in", "this", "longitudinal", "cohort", "analyses.", "After", "adjustment", "for", "covariates,", "use", "of", "AEDs", "was", "positively", "associated", "with", "total", "fractures", "[hazard", "ratio", "(HR)", "¼", "1.44,", "95%", "confidence", "interval", "(CI)", "1.30–1.61],", "all", "site-specific", "fractures", "including", "the", "hip", "(HR", "¼", "1.51,", "95%", "CI", "1.05–2.17),", "clinical", "vertebral", "fractures", "(HR", "¼", "1.60,", "95%", "CI", "1.20–2.12),", "lower", "arm", "or", "wrist", "fractures", "(HR", "¼", "1.40,", "95%", "CI", "1.11–1.76),", "and", "other", "clinical", "fractures", "(HR", "¼", "1.46,", "95%", "CI", "1.29–1.65)", "and", "two", "or", "more", "falls", "(HR", "¼", "1.62,", "95%", "CI", "1.50–1.74)", "but", "not", "with", "baseline", "BMD", "or", "changes", "in", "BMD", "(", "p", ".064", "for", "all", "sites).", "Use", "of", "more", "than", "one", "and", "use", "of", "enzyme-inducing", "AEDs", "were", "significantly", "associated", "with", "total", "fractures", "(HR", "¼", "1.55,", "95%", "CI", "1.15–2.09", "and", "HR", "¼", "1.36,", "95%", "CI", "1.09–1.69,", "respectively).", "We", "conclude", "that", "in", "clinical", "practice,", "postmenopausal", "women", "who", "use", "AEDs", "should", "be", "considered", "at", "increased", "risk", "for", "fracture,", "and", "attention", "to", "fall", "prevention", "may", "be", "particularly", "important", "in", "these", "women.", "2010", "American", "Society", "for", "Bone", "and", "Mineral", "Research.", "KEY", "WORDS:", "POPULATION", "STUDIES;", "AGING;", "MENOPAUSE", "Introduction", "Wmajority", "use", "antiepileptic", "drugs", "(AEDs).(1)", "However,", "orldwide,", "50", "million", "people", "suffer", "from", "epilepsy,", "and", "the", "increasingly,", "even", "among", "those", "without", "epilepsy,", "use", "of", "AEDs", "is", "becoming", "more", "prevalent.(2,3)", "Therefore,", "the", "relationship", "of", "AED", "use", "to", "osteoporosis", "is", "of", "interest.", "The", "relationship", "of", "AED", "use", "to", "fractures", "is", "controversial,", "with", "some,(4,5)", "although", "not", "all,(6)", "studies", "suggesting", "that", "fracture", "risk", "is", "increased.", "However,", "these", "reports", "are", "limited", "by", "sample", "size,", "selection", "of", "controls,", "and", "most", "important,", "the", "failure", "to", "take", "into", "account", "potential", "confounding", "factors.(4,5)", "Even", "a", "large", "pharmac-", "oepidemiologic", "database", "that", "examined", "the", "relationship", "of", "AED", "use", "and", "fractures", "was", "unable", "to", "control", "for", "important", "potential", "confounders,", "including", "family", "history", "of", "fractures,", "smoking", "history,", "and", "calcium/vitamin", "D", "intake,(7)", "which", "are", "available", "in", "the", "Women’s", "Health", "Initiative", "(WHI).", "In", "addition,", "most", "studies", "of", "the", "relationship", "of", "AED", "use", "and", "fractures", "have", "excluded", "racial", "groups", "other", "than", "Caucasians.(6,8)", "However,", "epilepsy", "does", "not", "have", "a", "particular", "racial", "predilection.(9)", "Few", "studies", "have", "included", "the", "non-enzyme-inducing", "category", "of", "these", "drugs,(7,10,11)", "whose", "use", "is", "increasing", "rapidly,", "including", "for", "indications", "other", "than", "Received", "in", "original", "form", "June", "16,", "2009;", "revised", "form", "September", "14,", "2009;", "accepted", "October", "15,", "2009.", "Published", "online", "October", "17,", "2009.", "Address", "correspondence", "to:", "Laura", "D", "Carbone,", "MD,", "MS,", "University", "of", "Tennessee", "Health", "Science", "Center,", "956", "Court", "Aveenue,", "Memphis,", "TN", "38163,", "USA.", "E-mail:", "lcarbone@uthsc.edu", "Journal", "of", "Bone", "and", "Mineral", "Research,", "Vol.", "25,", "No.", "4,", "April", "2010,", "pp", "873–881", "DOI:", "10.1359/jbmr.091027", "2010", "American", "Society", "for", "Bone", "and", "Mineral", "Research", "873" ]

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[ "Tumor", "Biol.", "(2011)", "32:769–776", "DOI", "10.1007/s13277-011-0179-0", "RESEARCH", "ARTICLE", "Major", "regulators", "of", "microRNAs", "biogenesis", "Dicer", "and", "Drosha", "are", "down-regulated", "in", "endometrial", "cancer", "Anna", "Torres", "&", "Kamil", "Torres", "&", "Tomasz", "Paszkowski", "&", "Barbara", "Jodłowska-Jędrych", "&", "Tomasz", "Radomański", "&", "Andrzej", "Książek", "&", "Ryszard", "Maciejewski", "Received:", "28", "February", "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", "Alterations", "in", "microRNAs", "expression", "have", "been", "proposed", "to", "play", "role", "in", "endometrial", "cancer", "pathogenesis.", "Dicer", "and", "Drosha", "are", "main", "regulators", "of", "microRNA", "biogenesis", "and", "deregulation", "of", "their", "expression", "has", "been", "indicated", "as", "a", "possible", "cause", "of", "microRNAs", "alterations", "observed", "in", "various", "cancers.", "The", "objective", "of", "this", "study", "was", "to", "investigate", "Dicer", "and", "Drosha", "genes", "expression", "in", "endometrial", "cancer", "and", "to", "analyze", "the", "impact", "of", "clinico-", "pathological", "characteristics", "on", "their", "expression.", "Fresh", "tissue", "Electronic", "supplementary", "material", "The", "online", "version", "of", "this", "article", "(doi:10.1007/s13277-011-0179-0)", "contains", "supplementary", "material,", "which", "is", "available", "to", "authorized", "users.", "A.", "Torres", ":", "K.", "Torres", ":", "R.", "Maciejewski", "Laboratory", "of", "Biostructure,", "Department", "of", "Human", "Anatomy,", "Medical", "University", "of", "Lublin,", "ul.", "Jaczewskiego", "4,", "20–094", "Lublin,", "Poland", "A.", "Torres", ":", "T.", "Paszkowski", ":", "T.", "Radomański", "III", "Department", "of", "Gynecology,", "Medical", "University", "of", "Lublin,", "ul.", "Jaczewskiego", "8,", "20–094", "Lublin,", "Poland", "K.", "Torres", "General", "and", "Oncologic", "Surgery", "Department,", "Lublin", "County", "Specialist", "Hospital,", "ul.", "Kraśnicka", "100,", "Lublin,", "Poland", "B.", "Jodłowska-Jędrych", "Department", "of", "Histology", "and", "Embryology", "with", "Experimental", "Cytology", "Unit,", "Medical", "University", "of", "Lublin,", "ul.", "Radziwiłłowska", "11,", "20–080", "Lublin,", "Poland", "A.", "Książek", "Department", "of", "Nephrology,", "Medical", "University", "of", "Lublin,", "ul.", "Jaczewskiego", "8,", "20-094", "Lublin,", "Poland", "samples", "were", "collected", "from", "44", "patients", "(26", "endometroid", "endometrial", "carcinoma", "and", "18", "controls).", "Clinical", "and", "pathological", "data", "were", "acquired", "from", "medical", "documenta-", "tion.", "Dicer", "and", "Drosha", "genes", "expressions", "were", "assessed", "by", "qRT-PCR", "using", "validated", "reference", "genes.", "Dicer", "and", "Drosha", "expression", "levels", "were", "significantly", "lower", "in", "endometrial", "cancer", "samples", "comparing", "to", "controls.", "Dicer", "was", "down-regulated", "by", "the", "factor", "of", "1.54", "(p", "=", "0.009)", "and", "Drosha", "gene", "mean", "expression", "value", "was", "1.4", "times", "lower", "in", "R.", "Maciejewski", "II", "Department", "of", "Surgery,", "Medical", "University", "of", "Lublin,", "ul.", "Staszica", "16,", "20-081", "Lublin,", "Poland", "R.", "Maciejewski", "Medical", "Emergency", "Department,", "UlTM", "in", "Rzeszów,", "ul.", "Sucharskiego", "2,", "35-225", "Rzeszów,", "Poland", "A.", "Torres", "(*)", "Katedra", "i", "Zakład", "Anatomii", "Prawidłowej", "Człowieka,", "Uniwersytet", "Medyczny", "w", "Lublinie,", "ul.", "Jaczewskiego", "4,", "20-094", "Lublin,", "Poland", "e-mail:", "anna.torres@wp.pl", "A.", "Torres", "e-mail:", "anna.torres@umlub.pl" ]

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[ "Gating", "Kinetics", "of", "Single", "Large-Conductance", "Ca21-activated", "K1", "Channels", "in", "High", "Ca21", "Suggest", "a", "Two-Tiered", "Allosteric", "Gating", "MechanismJ", "Brad", "S.", "Rothberg", "and", "Karl", "L.", "Magleby", "From", "the", "Department", "of", "Physiology", "and", "Biophysics,", "University", "of", "Miami", "School", "of", "Medicine,", "Miami,", "Florida", "33101-6430", "a", "b", "s", "t", "r", "a", "c", "t", "The", "Ca21-dependent", "gating", "mechanism", "of", "large-conductance", "calcium-activated", "K1", "(BK)", "channels", "from", "cultured", "rat", "skeletal", "muscle", "was", "examined", "from", "low", "(4", "mM)", "to", "high", "(1,024", "mM)", "intracellular", "concentrations", "of", "calcium", "(Ca21", ")", "using", "single-channel", "recording.", "Open", "probability", "(Po)", "increased", "with", "increasing", "Ca21i", "(K0.5", "i", "11.2", "6", "0.3", "mM", "at", "130", "mV,", "Hill", "coefficient", "of", "3.5", "6", "0.3),", "reaching", "a", "maximum", "of", "z0.97", "for", "Ca21i", "z", "100", "mM.", "In-", "creasing", "Ca21i", "further", "to", "1,024", "mM", "had", "little", "additional", "effect", "on", "either", "Po", "or", "the", "single-channel", "kinetics.", "The", "channels", "gated", "among", "at", "least", "three", "to", "four", "open", "and", "four", "to", "five", "closed", "states", "at", "high", "levels", "of", "Ca21i", "(.100", "mM),", "compared", "with", "three", "to", "four", "open", "and", "five", "to", "seven", "closed", "states", "at", "lower", "Ca21i.", "The", "ability", "of", "kinetic", "schemes", "to", "account", "for", "the", "single-channel", "kinetics", "was", "examined", "with", "simultaneous", "maximum", "likelihood", "fitting", "of", "two-", "dimensional", "(2-D)", "dwell-time", "distributions", "obtained", "from", "low", "to", "high", "Ca21i.", "Kinetic", "schemes", "drawn", "from", "the", "10-", "state", "Monod-Wyman-Changeux", "model", "could", "not", "describe", "the", "dwell-time", "distributions", "from", "low", "to", "high", "Ca21i.", "Ki-", "netic", "schemes", "drawn", "from", "Eigen’s", "general", "model", "for", "a", "ligand-activated", "tetrameric", "protein", "could", "approximate", "the", "dwell-time", "distributions", "but", "not", "the", "dependency", "(correlations)", "between", "adjacent", "intervals", "at", "high", "Ca21i.", "However,", "models", "drawn", "from", "a", "general", "50", "state", "two-tiered", "scheme,", "in", "which", "there", "were", "25", "closed", "states", "on", "the", "upper", "tier", "and", "25", "open", "states", "on", "the", "lower", "tier,", "could", "approximate", "both", "the", "dwell-time", "distributions", "and", "the", "dependency", "from", "low", "to", "high", "Ca21i.", "In", "the", "two-tiered", "model,", "the", "BK", "channel", "can", "open", "directly", "from", "each", "closed", "state,", "and", "a", "minimum", "of", "five", "open", "and", "five", "closed", "states", "are", "available", "for", "gating", "at", "any", "given", "Ca21i.", "A", "model", "that", "assumed", "that", "the", "apparent", "Ca21-binding", "steps", "can", "reach", "a", "maximum", "rate", "at", "high", "Ca21i", "could", "also", "approximate", "the", "gating", "from", "low", "to", "high", "Ca21i.", "The", "considered", "models", "can", "serve", "as", "working", "hypotheses", "for", "the", "gating", "of", "BK", "channels.", "k", "e", "y", "w", "o", "r", "d", "s", ":", "BK", "channel", "•", "KCa", "channel", "•", "Monod-Wyman-Changeux", "•", "Eigen", "•", "Markov", "i", "n", "t", "r", "o", "d", "u", "c", "t", "i", "o", "n", "Large-conductance", "Ca21-activated", "K1", "(BK)1", "channels,", "which", "are", "activated", "by", "micromolar", "concentrations", "of", "intracellular", "Ca21", "(Ca21i)", "and", "by", "depolarization", "(Bar-", "rett", "et", "al.,", "1982)", "are", "present", "in", "a", "wide", "variety", "of", "tissues", "(reviewed", "by", "Rudy,", "1988;", "Marty,", "1989;", "McManus,", "1991;", "Latorre,", "1994;", "Conly,", "1996).", "Activated", "BK", "channels", "re-", "duce", "membrane", "excitability", "by", "allowing", "K1", "efflux", "through", "their", "opened", "pores,", "which", "drives", "the", "mem-", "brane", "potential", "more", "negative.", "Hence,", "BK", "channels", "form", "a", "link", "in", "a", "negative", "feed-back", "loop", "that", "decreases", "excitability", "in", "response", "to", "both", "increased", "Ca21i", "and", "de-", "polarization.", "Information", "about", "the", "gating", "mechanism", "of", "BK", "chan-", "nels", "has", "accumulated", "from", "kinetic", "studies", "on", "native", "and", "heterologously", "expressed", "channels.", "BK", "channels", "are", "Address", "correspondence", "to", "Dr.", "Karl", "L.", "Magleby,", "Dept.", "of", "Physiology", "and", "Biophysics", "(R-430),", "University", "of", "Miami", "School", "of", "Medicine,", "Miami,", "FL", "33101-6430.", "Fax:", "305-243-6898;", "E-mail:", "kmagleby@", "miami.edu", "J", "The", "online", "version", "of", "this", "article", "contains", "supplemental", "material.", "1Abbreviations", "used", "in", "this", "paper:", "1-D,", "1-dimensional;", "BK", "channel,", "large-conductance", "calcium-activated", "K1", "channel;", "MWC,", "Monod-", "Wyman-Changeux;", "NLR1000,", "normalized", "likelihood", "ratio.", "homotetramers,", "formed", "from", "four", "alpha", "subunits", "(Shen", "et", "al.,", "1994),", "with", "one", "or", "more", "Ca21-binding", "sites", "per", "subunit", "(Schreiber", "and", "Salkoff,", "1997).", "BK", "channels", "typically", "display", "a", "steep", "relation", "between", "Ca21i", "and", "open", "probability,", "Po,", "with", "Hill", "coefficients", "usually", "in", "the", "range", "of", "2–4", "(Barrett", "et", "al.", "1982;", "Wong", "et", "al.,", "1982;", "Golowasch", "et", "al.,", "1986;", "Oberhauser", "et", "al.,", "1988;", "Rein-", "hart", "et", "al.,", "1989;", "McManus", "and", "Magleby,", "1991;", "Art", "et", "al.,", "1995;", "DiChiara", "and", "Reinhart,", "1995;", "Cui", "et", "al.,", "1997).", "Hill", "coefficients", ".1", "suggest", "a", "cooperative", "action", "of", "Ca21", "on", "P", ",", "and", "are", "often", "associated", "with", "allosteric", "o", "modulation", "of", "activity", "(Colquhoun", "1973;", "Fersht", "1985).", "Models", "drawn", "from", "the", "Monod-Wyman-Changeux", "(MWC)", "model", "(Monod", "et", "al.,", "1965)", "describing", "the", "transitions", "of", "tetrameric", "allosteric", "proteins", "have", "often", "been", "used", "to", "describe", "the", "Ca21-dependent", "gating", "of", "BK", "channels.", "For", "example,", "McManus", "and", "Magleby", "(1991)", "found", "that", "a", "model", "with", "three", "open", "and", "five", "closed", "states", "drawn", "from", "the", "MWC", "model", "could", "account", "for", "many", "of", "the", "basic", "features", "of", "the", "Ca21", "dependence", "of", "the", "single-channel", "gating", "kinetics", "from", "low", "to", "interme-", "diate", "levels", "of", "activity,", "and", "Cox", "et", "al.", "(1997b)", "found", "that", "the", "full", "10-state", "MWC", "model", "(and", "also", "an", "extended", "12-", "state", "model)", "could", "account", "for", "macroscopic", "conduc-", "tance–voltage", "relations", "over", "a", "wide", "range", "of", "Ca21i.", "93", "J.", "Gen.", "Physiol.", "©", "The", "Rockefeller", "University", "Press", "•", "0022-1295/99/07/93/32", "$5.00", "Volume", "114", "July", "1999", "93–124", "http://www.jgp.org" ]

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[ "Toxins", "2010,", "2,", "2663-2679;", "doi:10.3390/toxins2112663", "OPEN", "ACCESS", "toxins", "ISSN", "2072-6651", "www.mdpi.com/journal/toxins", "Article", "β-N-Methylamino-L-Alanine", "Induces", "Neurological", "Deficits", "and", "Shortened", "Life", "Span", "in", "Drosophila", "Xianchong", "Zhou", "1,", "Wilfredo", "Escala", "2,", "Spyridon", "Papapetropoulos", "3", "and", "R.", "Grace", "Zhai", "1,*", "1", "2", "3", "Department", "of", "Molecular", "and", "Cellular", "Pharmacology,", "Miller", "School", "of", "Medicine,", "University", "of", "Miami,", "Miami,", "Florida", "33136,", "USA;", "E-Mail:", "zhouxchong@gmail.com", "University", "of", "Miami", "Bridges", "to", "the", "Future", "Program,", "Miami", "Dade", "Honors", "College,", "Miami,", "Florida", "33132,", "USA;", "E-Mail:", "wilfredo.escala@gmail.com", "Department", "of", "Neurology,", "Miller", "School", "of", "Medicine,", "University", "of", "Miami,", "Miami,", "Florida", "33136,", "USA;", "E-Mail:", "spapapetropoulos@med.miami.edu", "*", "Author", "to", "whom", "correspondence", "should", "be", "addressed;", "E-Mail:", "gzhai@med.miami.edu;", "Tel.:", "+1-305-243-6316;", "Fax:", "+1-305-243-4555.", "Received:", "29", "September", "2010;", "in", "revised", "form:", "28", "October", "2010", "/", "Accepted:", "1", "November", "2010", "/", "Published:", "3", "November", "2010", "Abstract:", "The", "neurotoxic", "non-protein", "amino", "acid,", "β-N-methylamino-L-alanine", "(BMAA),", "was", "first", "associated", "with", "the", "high", "incidence", "of", "Amyotrophic", "Lateral", "Sclerosis/Parkinsonism", "Dementia", "Complex", "(ALS/PDC)", "in", "Guam.", "Recently,", "BMAA", "has", "been", "implicated", "as", "a", "fierce", "environmental", "factor", "that", "contributes", "to", "the", "etiology", "of", "Alzheimer’s", "and", "Parkinson’s", "diseases,", "in", "addition", "to", "ALS.", "However,", "the", "toxicity", "of", "BMAA", "in", "vivo", "has", "not", "been", "clearly", "demonstrated.", "Here", "we", "report", "our", "investigation", "of", "the", "neurotoxicity", "of", "BMAA", "in", "Drosophila.", "We", "found", "that", "dietary", "intake", "of", "BMAA", "reduced", "life", "span,", "locomotor", "functions,", "and", "learning", "and", "memory", "abilities", "in", "flies.", "The", "severity", "of", "the", "alterations", "in", "phenotype", "is", "correlated", "with", "the", "concentration", "of", "BMAA", "detected", "in", "flies.", "Interestingly,", "developmental", "exposure", "to", "BMAA", "had", "limited", "impact", "on", "survival", "rate,", "but", "reduced", "fertility", "in", "females,", "and", "caused", "delayed", "neurological", "impairment", "in", "aged", "adults.", "Our", "studies", "indicate", "that", "BMAA", "exposure", "causes", "chronic", "neurotoxicity,", "and", "that", "Drosophila", "serves", "as", "a", "useful", "model", "in", "dissecting", "the", "pathogenesis", "of", "ALS/PDC.", "Keywords:", "Amyotrophic", "Lateral", "Sclerosis;", "dementia;", "neurodegeneration" ]

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[ "Hindawi", "Publishing", "Corporation", "PPAR", "Research", "Volume", "2007,", "Article", "ID", "23812,", "12", "pages", "doi:10.1155/2007/23812", "Review", "Article", "PPARs", "in", "Alveolar", "Macrophage", "Biology", "Monica", "R.", "Smith,", "Theodore", "J.", "Standiford,", "and", "Raju", "C.", "Reddy", "Division", "of", "Pulmonary", "and", "Critical", "Care", "Medicine,", "Department", "of", "Internal", "Medicine,", "University", "of", "Michigan", "Medical", "Center,", "Ann", "Arbor,", "MI", "48109-2200,", "USA", "Correspondence", "should", "be", "addressed", "to", "Raju", "C.", "Reddy,", "rajuc@umich.edu", "Received", "13", "March", "2007;", "Accepted", "18", "May", "2007", "Recommended", "by", "Jesse", "Roman", "PPARs,", "most", "notably", "PPAR-γ,", "play", "a", "crucial", "role", "in", "regulating", "the", "activation", "of", "alveolar", "macrophages,", "which", "in", "turn", "occupy", "a", "pivotal", "place", "in", "the", "immune", "response", "to", "pathogens", "and", "particulates", "drawn", "in", "with", "inspired", "air.", "In", "this", "review,", "we", "describe", "the", "dual", "role", "of", "the", "alveolar", "macrophage", "as", "both", "a", "first-line", "defender", "through", "its", "phagocytotic", "activity", "and", "a", "regulator", "of", "the", "immune", "re-", "sponse.", "Depending", "on", "its", "state", "of", "activation,", "the", "alveolar", "macrophage", "may", "either", "enhance", "or", "suppress", "different", "aspects", "of", "immune", "function", "in", "the", "lung.", "We", "then", "review", "the", "role", "of", "PPAR-γ", "and", "its", "ligands", "in", "deactivating", "alveolar", "macrophages—thus", "limiting", "the", "inflammatory", "response", "that,", "if", "unchecked,", "could", "threaten", "the", "essential", "respiratory", "function", "of", "the", "alveolus—while", "upregulating", "the", "cell’s", "phagocytotic", "activity.", "Finally,", "we", "examine", "the", "role", "that", "inadequate", "or", "inappropriate", "PPAR-γ", "responses", "play", "in", "specific", "lung", "diseases.", "Copyright", "©", "2007", "Monica", "R.", "Smith", "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.", "1.", "INTRODUCTION", "Peroxisome", "proliferator-activated", "receptors", "(PPARs)", "are", "members", "of", "the", "nuclear-receptor", "superfamily.", "Their", "name", "derives", "from", "the", "first-discovered", "member", "of", "the", "class,", "PPAR-", "α,", "whose", "activation", "induces", "proliferation", "of", "peroxisomes", "in", "the", "liver;", "no", "similar", "effect", "is", "seen", "with", "other", "members", "of", "the", "class,", "however.", "These", "receptors", "act", "as", "transcription", "fac-", "tors,", "forming", "heterodimers", "with", "the", "retinoid", "X", "receptor", "and", "then", "binding", "to", "specific", "response", "elements", "(PPREs)", "in", "the", "promoter", "regions", "of", "the", "genes", "they", "regulate.", "When", "activated", "by", "appropriate", "ligands,", "PPARs", "undergo", "a", "conformational", "change", "that", "leads", "to", "release", "of", "corepressors", "and", "binding", "of", "coactivator", "molecules,", "with", "consequent", "increases", "in", "tran-", "scription", "of", "the", "genes", "involved.", "Some", "evidence", "suggests", "that", "in", "the", "absence", "of", "activating", "ligands,", "PPARs", "may", "bind", "core-", "pressors", "and", "downregulate", "expression", "of", "genes", "with", "PPRE-", "containing", "promoters", "[1].", "There", "are", "three", "PPAR", "isoforms:", "PPAR-α,", "PPAR-γ,", "and", "PPAR-β/δ.", "Each", "of", "the", "isoforms", "is", "the", "product", "of", "a", "differ-", "ent", "gene.", "PPAR-β/δ", "is", "expressed", "in", "almost", "every", "tissue", "of", "the", "body.", "PPAR-α", "is", "most", "commonly", "thought", "of", "in", "connection", "with", "hepatocytes", "and", "PPAR-γ", "with", "adipocytes,", "but", "in", "fact", "both", "are", "expressed", "in", "a", "variety", "of", "cells", "and", "tissues.", "Broadly", "speaking,", "PPAR-α", "regulates", "lipid", "metabolism,", "lipoprotein", "formation", "and", "transport", "as", "well", "as", "lipid", "catabolism,", "whereas", "PPAR-β/δ", "promotes", "lipid", "oxidation,", "and", "PPAR-γ", "promotes", "adipogenesis", "[2].", "Each", "has", "other", "functions", "in", "specific", "tis-", "sues,", "however.", "For", "example,", "PPAR-α", "inhibits", "proliferation", "of", "vascular", "smooth", "muscle", "cells", "in", "response", "to", "injury", "[3]", "and", "antagonizes", "the", "effects", "of", "angiotensin", "II", "on", "the", "vas-", "cular", "wall", "[4].", "In", "skin,", "PPAR-β/δ", "induces", "terminal", "differ-", "entiation", "of", "keratinocytes", "[5].", "Activation", "of", "PPAR-γ", "in", "en-", "dothelial", "and", "vascular", "smooth", "muscle", "cells", "likewise", "inhibits", "expression", "of", "the", "angiotensin", "II", "receptor", "[6]", "and", "lowers", "blood", "pressure", "in", "hypertensive", "mice", "[7].", "PPAR-γ", "agonists", "have", "also", "been", "shown", "to", "exert", "antiproliferative", "effects", "on", "a", "variety", "of", "cancer", "cells", "[8].", "This", "has", "led", "to", "widespread", "discussion", "of", "their", "possible", "usefulness", "in", "cancer", "therapy", "(e.g.,", "for", "breast", "cancer", "[9])", "and", "even", "to", "a", "few", "early", "clinical", "trials.", "All", "three", "PPARs", "have", "significant", "anti-inflammatory", "roles", "in", "cells", "of", "the", "immune", "system.", "PPAR-γ", "has", "been", "found", "in", "monocytes/macrophages", "[10,", "11],", "neutrophils", "[12],", "dendritic", "cells", "[13],", "B", "[14]", "and", "T", "[15–17]", "lymphocytes,", "eosinophils", "[18],", "natural", "killer", "cells", "[19],", "and", "mast", "cells", "[20].", "PPAR-γ", "downregulates", "expression", "of", "a", "number", "of", "proinflammatory", "mediators", "while", "upregulating", "expression", "of", "anti-inflammatory", "mediators", "(reviewed", "in", "[21]).", "PPAR-", "α", "is", "found", "in", "essentially", "all", "the", "same", "cells", "as", "PPAR-γ", "with" ]

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[ "Parasite", "Immunology,", "2008,", "30,", "515–524", "DOI:", "10.1111/j.1365-3024.2008.01051.x", "SBOIplRaecInkGniwcINeclhAaPLnugbAeliRsflhnTiIvnCigscLeErtadSllaeishmaniamsismation", "and", "structural", "changes", "of", "splenic", "lymphoid", "tissue", "in", "visceral", "leishmaniasis:", "A", "study", "on", "naturally", "infected", "dogs", "C.", "C.", "SANTANA,1", "J.", "VASSALLO,2", "L.", "A.", "R.", "DE", "FREITAS,1", "G.", "G.", "S.", "OLIVEIRA,1", "L.", "C.", "PONTES-DE-CARVALHO1", "&", "W.", "L.", "C.", "DOS-SANTOS1", "1Centro", "de", "Pesquisas", "Gonçalo", "Moniz,", "Fundação", "Oswaldo", "Cruz,", "Fundação", "Oswaldo", "Cruz,", "Candeal,", "Salvador,", "Bahia,", "Brazil,", "2Faculdade", "de", "Ciências", "Médicas,", "Universidade", "de", "Campinas,", "Cidade", "Universitária", "‘Zeferino", "Vaz’,", "Campinas,", "São", "Paulo,", "Brazil", "SUMMARY", "The", "aim", "of", "this", "study", "was", "to", "identify", "splenic", "immuno-inflammatory", "patterns", "associated", "with", "natural", "infection", "by", "Leishmania", "chagasi.", "Spleen", "samples", "were", "obtained", "from", "72", "stray", "dogs", "from", "an", "endemic", "area", "of", "visceral", "leishmaniasis.", "The", "animals", "were", "grouped", "into", "four", "categories", "as", "follows:", "(i)", "potentially", "resistant", "to", "visceral", "leishmaniasis,", "with", "a", "positive", "leishmanin", "skin", "test", "result,", "and", "negative", "splenic", "culture", "for", "Leishmania", "parasites", "(ii)", "potentially", "susceptible", "to", "visceral", "leishmaniasis,", "with", "a", "negative", "leishmanin", "skin", "test", "and", "positive", "splenic", "culture", "for", "Leishmania", "(iii)", "infected", "with", "undefined", "susceptibility", "status,", "with", "a", "positive", "leishmanin", "skin", "test", "and", "positive", "splenic", "culture", "for", "Leishmania,", "and", "(iv)", "noninfected,", "with", "a", "negative", "leishmanin", "skin", "test,", "negative", "splenic", "culture", "for", "Leishmania,", "and", "negative", "serology", "for", "anti-Leishmania", "antibodies.", "Histopathological", "analyses", "showed", "that", "there", "was", "a", "higher", "frequency", "of", "perisplenitis", "(18/25,", "P", "<", "0·0001),", "granuloma", "(7/25,", "P", "=", "0·0102),", "structural", "disorganization", "(14/25,", "P", "<", "0·0001),", "and", "atrophy", "of", "the", "lymphoid", "follicles", "(20/25,", "P", "=", "0·0036)", "and", "of", "the", "marginal", "zone", "(15/25,", "P", "=", "0·0025)", "in", "the", "potentially", "susceptible", "group", "than", "in", "the", "other", "groups.", "The", "data", "presented", "here", "show", "changes", "in", "the", "white", "pulp", "of", "the", "spleen", "that", "are", "associated", "with", "naturally", "acquired", "visceral", "leishmaniasis.", "Keywords", "canine", "visceral", "leishmaniasis,", "Leishmania", "chagasi,", "Leishmania", "infantum,", "lymphoid", "tissue,", "Spleen", "Correspondence:", "WLC", "Dos-Santos", "Washington", "LC", "dos-Santos,", "Centro", "de", "Pesquisas", "Gonçalo", "Moniz-FIOCRUZ,", "Rua", "Waldemar", "Falcão", "121,", "Candeal,", "40·296–710,", "Salvador,", "Bahia,", "Brazil", "(e-mail:", "wluis@bahia.fiocruz.br).", "Re-use", "of", "this", "article", "is", "permitted", "in", "accordance", "with", "the", "Creative", "Commons", "Deed,", "Attribution", "2·5,", "which", "does", "not", "permit", "commercial", "exploitation.", "Received:", "10", "March", "2008", "Accepted", "for", "publication:", "28", "May", "2008", "©", "2008", "The", "Authors", "Journal", "compilation", "©", "2008", "Blackwell", "Publishing", "Ltd", "INTRODUCTION", "Visceral", "leishmaniasis", "is", "used", "to", "describe", "two", "clinically,", "parasitologically", "and", "epidemiologically", "different", "diseases:", "antroponotic", "visceral", "leishmaniasis,", "caused", "by", "Leishmania", "donovani,", "and", "zoonotic", "visceral", "leishmaniasis", "(VL),", "caused", "by", "L.", "chagasi/L.", "infantum.", "The", "latter", "disease", "is", "endemic", "in", "Mediterranean", "countries", "and", "the", "American", "continent,", "and", "its", "causal", "agents", "are", "transmitted", "to", "mammalian", "hosts", "by", "sand", "flies", "of", "the", "Phlebotomus", "and", "Lutzomyia", "genera", "(1).", "Leishmania", "chagasi/L.", "infantum", "infection", "does", "not", "always", "lead", "to", "VL", "(2).", "Most", "infected", "humans", "(2,3)", "and", "at", "least", "a", "proportion", "of", "infected", "dogs", "(4,5)", "remain", "asymptomatic", "or", "develop", "a", "mild", "disease,", "which", "is", "spontaneously", "cured.", "Occasionally,", "dogs", "and", "humans", "develop", "a", "severe", "form", "of", "VL", "(2,6)", "that", "is", "usually", "lethal", "if", "left", "untreated.", "In", "this", "report,", "we", "use", "the", "term", "VL", "to", "refer", "to", "this", "severe", "form", "of", "the", "disease.", "In", "both", "humans", "and", "dogs,", "the", "disease", "proceeds", "with", "emaciation,", "enlargement", "of", "the", "liver", "and", "spleen,", "fever,", "anaemia,", "and", "an", "increased", "predisposition", "to", "bacterial", "infection", "(2,7–10).", "In", "dogs,", "such", "signs", "of", "disease", "are", "further", "accompanied", "by", "a", "variety", "of", "skin", "and", "ocular", "lesions", "(9).", "Much", "that", "is", "known", "about", "the", "immune", "response", "to", "Leishmania", "parasites,", "and", "even", "the", "immune", "response", "in", "general", "has", "come", "from", "studies", "in", "murine", "models", "of", "leishmaniases", "(11–13).", "Most", "of", "these", "models,", "however,", "are", "intrinsically", "compromised", "by", "the", "artificial", "nature", "of", "the", "infective", "inocula.", "Instead", "of", "consisting", "only", "of", "naturally", "infective,", "metacyclic", "promastigotes,", "these", "inocula", "usually", "contain", "(i)", "either", "relatively", "large", "number", "of", "complement-", "fixing,", "noninfective", "procyclic", "promastigotes", "(usually", "constitut-", "ing", "more", "than", "70%", "of", "the", "inoculum)", "(14)", "or", "(ii)", "amastigotes,", "which", "are", "not", "the", "usual", "infectious", "form", "of", "the", "parasite.", "Canine", "VL,", "arising", "from", "natural", "infection", "by", "L.", "chagasi,", "is", "a", "disease", "worthy", "not", "only", "of", "study", "in", "its", "own", "right", "for", "veterinary", "and", "epidemiological", "reasons", "(15),", "but", "also", "for", "consideration", "as", "an", "attractive", "animal", "model", "for", "the", "human", "disease,", "because", "515" ]

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[ "van", "Eijk", "et", "al.", "BMC", "Bioinformatics", "2010,", "11:67", "http://www.biomedcentral.com/1471-2105/11/67", "S", "O", "F", "T", "W", "A", "R", "E", "Open", "Access", "MLPAinter", "for", "MLPA", "interpretation:", "an", "integrated", "approach", "for", "the", "analysis,", "visualisation", "and", "data", "management", "of", "Multiplex", "Ligation-dependent", "Probe", "Amplification", "Ronald", "van", "Eijk1,", "Paul", "HC", "Eilers2,", "Remco", "Natté1,", "Anne-Marie", "Cleton-Jansen1,", "Hans", "Morreau1,", "Tom", "van", "Wezel,", "Jan", "Oosting1*", "Abstract", "Background:", "Multiplex", "Ligation-Dependent", "Probe", "Amplification", "(MLPA)", "is", "an", "application", "that", "can", "be", "used", "for", "the", "detection", "of", "multiple", "chromosomal", "aberrations", "in", "a", "single", "experiment.", "In", "one", "reaction,", "up", "to", "50", "different", "genomic", "sequences", "can", "be", "analysed.", "For", "a", "reliable", "work-flow,", "tools", "are", "needed", "for", "administrative", "support,", "data", "management,", "normalisation,", "visualisation,", "reporting", "and", "interpretation.", "Results:", "Here,", "we", "developed", "a", "data", "management", "system,", "MLPAInter", "for", "MLPA", "interpretation,", "that", "is", "windows", "executable", "and", "has", "a", "stand-alone", "database", "for", "monitoring", "and", "interpreting", "the", "MLPA", "data", "stream", "that", "is", "generated", "from", "the", "experimental", "setup", "to", "analysis,", "quality", "control", "and", "visualisation.", "A", "statistical", "approach", "is", "applied", "for", "the", "normalisation", "and", "analysis", "of", "large", "series", "of", "MLPA", "traces,", "making", "use", "of", "multiple", "control", "samples", "and", "internal", "controls.", "Conclusions:", "MLPAinter", "visualises", "MLPA", "data", "in", "plots", "with", "information", "about", "sample", "replicates,", "normalisation", "settings,", "and", "sample", "characteristics.", "This", "integrated", "approach", "helps", "in", "the", "automated", "handling", "of", "large", "series", "of", "MLPA", "data", "and", "guarantees", "a", "quick", "and", "streamlined", "dataflow", "from", "the", "beginning", "of", "an", "experiment", "to", "an", "authorised", "report.", "Background", "In", "medical", "research,", "knowledge", "of", "chromosomal", "dele-", "tions", "or", "amplifications", "is", "of", "great", "importance.", "For", "exam-", "ple,", "it", "can", "help", "us", "better", "understand", "the", "genetic", "causes", "of", "certain", "diseases", "and", "as", "a", "consequence,", "improve", "the", "treatment", "and", "prognosis", "of", "individual", "patients.", "Classic", "techniques", "for", "the", "detection", "of", "chromosomal", "abnormal-", "ities", "include", "karyotyping,", "Southern", "blotting,", "Fluorescent", "In", "Situ", "Hybridisation", "(FISH),", "CA-repeat", "analysis", "and", "quantitative", "micro", "satellite", "analysis", "by", "real-time", "PCR", "[1-4].", "In", "recent", "years,", "high-throughput", "methods", "based", "on", "BAC", "arrays,", "SNP", "arrays", "and", "related", "techniques", "have", "gained", "prominence", "[5,6].", "Although", "these", "are", "excellent", "tools", "for", "whole", "genome", "analysis,", "these", "techniques", "are", "*", "Correspondence:", "j.oosting@lumc.nl", "1Department", "of", "Pathology,", "Leiden", "University", "Medical", "Center,", "Leiden,", "The", "Netherlands", "laborious,", "time-consuming,", "difficult", "to", "implement,", "expensive", "and", "generate", "large", "data", "sets.", "The", "management", "and", "interpretation", "of", "such", "voluminous", "data", "is", "not", "a", "light", "task.", "Multiplex", "Ligation-dependent", "Probe", "Amplification", "(MLPA)", "[7]", "has", "been", "introduced", "as", "a", "relatively", "cheap", "and", "fast", "method", "to", "perform", "quantitative", "chromosomal", "analysis", "of", "up", "to", "about", "50", "genomic", "DNA", "or", "RNA", "sequences,", "which", "is", "able", "to", "distinguish", "sequences", "differ-", "ing", "in", "only", "one", "nucleotide.", "This", "technique", "fills", "the", "gap", "between", "the", "methods", "that", "investigate", "a", "single", "locus", "and", "the", "techniques", "that", "interrogate", "thousands", "of", "loci.", "MLPA", "is", "a", "quick", "and", "cost", "effective", "approach", "to", "testing", "for", "the", "presence", "of", "gene", "deletions", "or", "obtaining", "tumour", "profiles", "on", "multiple", "loci", "in", "a", "single", "tube,", "which", "can", "easily", "be", "applied", "in", "molecular", "pathology.", "Furthermore,", "MLPA", "only", "requires", "small", "amounts", "of", "DNA.", "Moreover,", "DNA", "obtained", "from", "formalin", "fixed", "paraffin", "embedded", "material", "can", "be", "used.", "Currently,", "MLPA", "is", "used", "for", "the", "©", "2010", "van", "Eijk", "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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