id
int64 37.5k
3.5M
| image
unknown | bboxes
sequence | tokens
sequence | ner_tags
sequence |
---|---|---|---|---|
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552,
964
],
[
556,
950,
596,
964
],
[
599,
950,
610,
964
],
[
613,
950,
638,
964
],
[
641,
950,
679,
964
],
[
681,
950,
695,
964
],
[
698,
950,
738,
964
],
[
742,
950,
762,
964
],
[
427,
967,
476,
981
],
[
478,
967,
494,
981
],
[
496,
967,
551,
981
],
[
554,
967,
560,
981
],
[
563,
967,
617,
981
],
[
619,
967,
672,
981
],
[
675,
967,
686,
981
],
[
688,
967,
740,
981
],
[
743,
967,
762,
981
],
[
427,
984,
461,
998
],
[
463,
984,
510,
998
],
[
513,
984,
524,
998
],
[
527,
984,
574,
998
],
[
576,
984,
601,
998
],
[
603,
984,
631,
998
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[
633,
984,
692,
998
],
[
695,
984,
705,
998
],
[
707,
984,
724,
998
],
[
727,
984,
762,
998
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[
750,
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774,
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[
784,
1054,
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] | [
"JCB:",
"ARTICLE",
"Spatial",
"codes",
"in",
"dendritic",
"BC1",
"RNA",
"Ilham",
"A.",
"Muslimov,1",
"Anna",
"Iacoangeli,1",
"Jürgen",
"Brosius,3",
"and",
"Henri",
"Tiedge1,2",
"1Department",
"of",
"Physiology",
"and",
"Pharmacology",
"and",
"2Department",
"of",
"Neurology,",
"The",
"Robert",
"F.",
"Furchgott",
"Center",
"for",
"Neural",
"and",
"Behavioral",
"Science,",
"State",
"University",
"of",
"New",
"York",
"Health",
"Science",
"Center",
"at",
"Brooklyn,",
"Brooklyn,",
"NY",
"11203",
"3Institute",
"of",
"Experimental",
"Pathology,",
"Center",
"for",
"Molecular",
"Biology",
"of",
"Inflammation,",
"University",
"of",
"Münster,",
"D-48149",
"Münster,",
"Germany",
"B",
"been",
"implicated",
"in",
"local",
"translational",
"control",
"mech-",
"C1",
"RNA",
"is",
"a",
"dendritic",
"untranslated",
"RNA",
"that",
"has",
"anisms",
"in",
"neurons.",
"Prerequisite",
"for",
"a",
"functional",
"role",
"of",
"the",
"RNA",
"in",
"synaptodendritic",
"domains",
"is",
"its",
"targeted",
"delivery",
"along",
"the",
"dendritic",
"extent.",
"We",
"report",
"here",
"that",
"the",
"targeting-competent",
"5′",
"BC1",
"domain",
"carries",
"two",
"dendritic",
"targeting",
"codes.",
"One",
"code,",
"specifying",
"somatic",
"export,",
"is",
"located",
"in",
"the",
"medial-basal",
"region",
"of",
"the",
"5′",
"BC1",
"stem-loop",
"structure.",
"It",
"is",
"defined",
"by",
"an",
"export-determinant",
"stem-bulge",
"motif.",
"The",
"second",
"code,",
"specifying",
"long-range",
"dendritic",
"delivery,",
"is",
"located",
"in",
"the",
"apical",
"part",
"of",
"the",
"5′",
"stem-loop",
"domain.",
"This",
"element",
"features",
"a",
"GA",
"kink-turn",
"(KT)",
"motif",
"that",
"is",
"indispensable",
"for",
"distal",
"targeting.",
"It",
"spe-",
"cifically",
"interacts",
"with",
"heterogeneous",
"nuclear",
"ribonucleo-",
"protein",
"A2,",
"a",
"trans-acting",
"targeting",
"factor",
"that",
"has",
"previously",
"been",
"implicated",
"in",
"the",
"transport",
"of",
"MBP",
"mRNA",
"in",
"oligodendrocytes",
"and",
"neurons.",
"Our",
"work",
"suggests",
"that",
"a",
"BC1",
"KT",
"motif",
"encodes",
"distal",
"targeting",
"via",
"the",
"A2",
"pathway",
"and",
"that",
"architectural",
"RNA",
"elements,",
"such",
"as",
"KT",
"motifs,",
"may",
"function",
"as",
"spatial",
"codes",
"in",
"neural",
"cells.",
"Y",
"G",
"O",
"L",
"O",
"I",
"B",
"L",
"L",
"E",
"C",
"F",
"O",
"L",
"A",
"N",
"R",
"U",
"O",
"J",
"E",
"H",
"T",
"Introduction",
"The",
"targeted",
"delivery",
"of",
"select",
"RNAs",
"to",
"synaptodendritic",
"do-",
"mains",
"in",
"neurons",
"is",
"an",
"elemental",
"mechanism",
"in",
"the",
"spatiotemporal",
"regulation",
"of",
"postsynaptic",
"gene",
"expression",
"(for",
"reviews",
"see",
"Smith,",
"2004;",
"Kindler",
"et",
"al.,",
"2005).",
"Activity-dependent",
"on-site",
"control",
"of",
"protein",
"synthesis",
"is",
"now",
"seen",
"as",
"one",
"of",
"the",
"key",
"under-",
"pinnings",
"of",
"input-specific",
"long-term",
"synaptic",
"plasticity,",
"with",
"dendritic",
"RNA",
"transport",
"in",
"turn",
"serving",
"as",
"a",
"functional",
"prerequi-",
"site",
"for",
"the",
"local",
"translation",
"of",
"mRNAs",
"at",
"the",
"synapse",
"(Wells",
"et",
"al.,",
"2000;",
"Job",
"and",
"Eberwine,",
"2001;",
"Richter,",
"2001;",
"Richter",
"and",
"Lorenz,",
"2002;",
"Steward",
"and",
"Schuman,",
"2003;",
"Smith,",
"2004;",
"Kindler",
"et",
"al.,",
"2005).",
"For",
"these",
"reasons,",
"structural",
"and",
"functional",
"determinants",
"of",
"dendritic",
"RNA",
"transport",
"are",
"of",
"considerable",
"interest",
"to",
"students",
"of",
"neuronal",
"plasticity",
"(Smith,",
"2004).",
"The",
"number",
"of",
"RNAs",
"that",
"have",
"been",
"identified",
"in",
"dendrites",
"has",
"steadily",
"increased",
"over",
"the",
"past",
"few",
"years,",
"and",
"the",
"total",
"number",
"of",
"dendritic",
"RNAs",
"has",
"been",
"estimated",
"at",
"several",
"hundred",
"(Eberwine",
"et",
"al.,",
"2001).",
"Dendritic",
"RNAs",
"form",
"a",
"diverse",
"and",
"complex",
"group.",
"They",
"include",
"mRNAs",
"that",
"encode",
"various",
"types",
"of",
"synaptodendritic",
"proteins",
"(such",
"as",
"receptors,",
"kinases,",
"cytoskeletal",
"components,",
"etc.),",
"as",
"well",
"as",
"untranslated",
"RNAs",
"(Brosius",
"and",
"Tiedge,",
"2004),",
"such",
"as",
"ribosomal",
"RNAs",
"(rRNAs),",
"Correspondence",
"to",
"Henri",
"Tiedge:",
"htiedge@downstate.edu",
"Abbreviations",
"used",
"in",
"this",
"paper:",
"ANOVA,",
"analysis",
"of",
"variance;",
"CaMKIIα,",
"Ca2+/calmodulin-dependent",
"kinase",
"II",
"α",
"subunit;",
"DTE,",
"dendritic",
"targeting",
"ele-",
"ment;",
"EMSA,",
"electrophoretic",
"mobility",
"shift",
"assay;",
"hnRNP,",
"heterogeneous",
"nuclear",
"ribonucleoprotein;",
"KT,",
"kink-turn;",
"MBP,",
"myelin",
"basic",
"protein;",
"PKMζ,",
"protein",
"kinase",
"M",
"ζ;",
"RRM,",
"RNA",
"recognition",
"motif;",
"rRNA,",
"ribosomal",
"RNA;",
"WC,",
"Watson–Crick.",
"©",
"The",
"Rockefeller",
"University",
"Press",
"$8.00",
"The",
"Journal",
"of",
"Cell",
"Biology,",
"Vol.",
"175,",
"No.",
"3,",
"November",
"6,",
"2006",
"427–439",
"http://www.jcb.org/cgi/doi/10.1083/jcb.200607008",
"tRNAs,",
"micro",
"RNAs,",
"and",
"small",
"brain-specific",
"cytoplasmic",
"(BC)",
"RNAs",
"(Kindler",
"et",
"al.,",
"2005;",
"Cao",
"et",
"al.,",
"2006).",
"A",
"further",
"layer",
"of",
"complexity",
"is",
"introduced",
"by",
"the",
"fact",
"that",
"dendritic",
"RNAs",
"are",
"nonhomogeneously",
"distributed",
"along",
"the",
"dendritic",
"extent",
"and",
"differentially",
"localized",
"to",
"their",
"individual",
"destination",
"sites",
"within",
"the",
"dendritic",
"arborization",
"(Paradies",
"and",
"Steward,",
"1997;",
"Kindler",
"et",
"al.,",
"2005).",
"Another",
"subset",
"of",
"neuronal",
"RNAs,",
"only",
"partially",
"overlapping",
"with",
"dendritic",
"RNAs,",
"is",
"targeted",
"to",
"the",
"axonal",
"domain,",
"in",
"particular",
"during",
"periods",
"of",
"developmental",
"or",
"regenerative",
"growth",
"(for",
"review",
"see",
"Giuditta",
"et",
"al.,",
"2002).",
"The",
"complexities",
"of",
"neuronal",
"RNA",
"transport",
"raise",
"impor-",
"tant",
"questions.",
"On",
"the",
"most",
"fundamental",
"level,",
"spatial",
"codes",
"that",
"are",
"used",
"by",
"localized",
"neuronal",
"RNAs",
"to",
"specify",
"their",
"respective",
"subcellular",
"destinations",
"remain",
"poorly",
"understood.",
"Dendritic",
"targeting",
"elements",
"(DTEs),",
"which",
"are",
"cis-acting",
"elements",
"that",
"contain",
"codes",
"to",
"direct",
"neuronal",
"RNAs",
"to",
"or",
"along",
"dendrites,",
"have",
"been",
"identified",
"in",
"several",
"dendritic",
"RNAs",
"(Kindler",
"et",
"al.,",
"2005).",
"Frequently,",
"however,",
"the",
"functional",
"description",
"of",
"DTEs",
"has",
"been",
"rudimentary,",
"and",
"code-carrying",
"RNA",
"motifs",
"have",
"not",
"yet",
"been",
"deciphered",
"(Smith,",
"2004).",
"Considerable",
"progress",
"has",
"been",
"made",
"in",
"recent",
"years",
"in",
"the",
"elucidation",
"of",
"structure-function",
"relationships",
"in",
"RNAs",
"(for",
"review",
"see",
"Noller,",
"2005).",
"There",
"has",
"been",
"growing",
"awareness",
"of",
"the",
"functional",
"relevance",
"of",
"3D",
"RNA",
"motifs,",
"and",
"the",
"question",
"is",
"thus",
"raised",
"whether",
"dendritic",
"targeting",
"codes",
"may",
"find",
"expres-",
"sion",
"in",
"the",
"architectural",
"designs",
"of",
"such",
"motifs.",
"To",
"address",
"this",
"question,",
"we",
"performed",
"a",
"functional",
"dissection",
"of",
"cis-acting",
"tar-",
"geting",
"elements",
"in",
"neuronal",
"BC1",
"RNA",
"(Muslimov",
"et",
"al.,",
"1997).",
"JCB",
"427"
] | [
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1,
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1,
1,
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1,
1,
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1,
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1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
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] | [
"Tumor",
"Necrosis",
"Factor",
"Induces",
"Hyperphosphorylation",
"of",
"Kinesin",
"Light",
"Chain",
"and",
"Inhibits",
"Kinesin-mediated",
"Transport",
"of",
"Mitochondria",
"Kurt",
"De",
"Vos,*",
"Fedor",
"Severin,‡§",
"Franky",
"Van",
"Herreweghe,*",
"Katia",
"Vancompernolle,*",
"Vera",
"Goossens,*",
"Anthony",
"Hyman,‡§",
"and",
"Johan",
"Grooten*",
"*Department",
"of",
"Molecular",
"Biology,",
"Flanders",
"Interuniversity",
"Institute",
"for",
"Biotechnology",
"and",
"Ghent",
"University,",
"B-9000",
"Ghent,",
"Belgium;",
"and",
"‡Cell",
"Biology",
"Program,",
"European",
"Molecular",
"Biology",
"Laboratory,",
"D-69012",
"Heidelberg,",
"Germany;",
"and",
"§Max-Planck",
"Institute",
"for",
"Cell",
"Biology",
"and",
"Genetics,",
"D-01307",
"Dresden,",
"Germany",
"Abstract.",
"The",
"molecular",
"motor",
"kinesin",
"is",
"an",
"ATPase",
"that",
"mediates",
"plus",
"end-directed",
"transport",
"of",
"organelles",
"along",
"microtubules.",
"Although",
"the",
"biochemical",
"properties",
"of",
"kinesin",
"are",
"extensively",
"studied,",
"conclusive",
"data",
"on",
"regu-",
"lation",
"of",
"kinesin-mediated",
"transport",
"are",
"largely",
"lacking.",
"Previously,",
"we",
"showed",
"that",
"the",
"proinflammatory",
"cytokine",
"tumor",
"necrosis",
"factor",
"induces",
"perinuclear",
"clustering",
"of",
"mitochondria.",
"Here,",
"we",
"show",
"that",
"tumor",
"necrosis",
"factor",
"impairs",
"kinesin",
"motor",
"activity",
"and",
"hyperphosphorylates",
"kinesin",
"light",
"chain",
"through",
"activation",
"of",
"two",
"putative",
"kinesin",
"light",
"chain",
"kinases.",
"Inactivation",
"of",
"kinesin,",
"hyper-",
"phosphorylation",
"of",
"kinesin",
"light",
"chain,",
"and",
"perinuclear",
"clustering",
"of",
"mitochondria",
"exhibit",
"the",
"same",
"p38",
"mitogen-",
"activated",
"kinase",
"dependence,",
"indicating",
"their",
"functional",
"relationship.",
"These",
"data",
"provide",
"evidence",
"for",
"direct",
"regu-",
"lation",
"of",
"kinesin-mediated",
"organelle",
"transport",
"by",
"extra-",
"cellular",
"stimuli",
"via",
"cytokine",
"receptor",
"signaling",
"pathways.",
"Key",
"words:",
"microtubule",
"•",
"organelle",
"•",
"okadaic",
"acid",
"•",
"mitogen-activated",
"protein",
"kinase",
"•",
"phosphorylation",
"Introduction",
"Conventional",
"kinesin",
"(KIF5),",
"originally",
"discovered",
"in",
"1985",
"(Brady,",
"1985;",
"Vale",
"et",
"al.,",
"1985),",
"is",
"a",
"tetramer",
"of",
"two",
"kine-",
"sin",
"heavy",
"chains",
"(KHCs)1",
"and",
"two",
"kinesin",
"light",
"chains",
"(KLCs).",
"Three",
"domains",
"compose",
"KHC:",
"an",
"NH2-terminal",
"motor",
"domain",
"containing",
"the",
"ATPase",
"activity",
"and",
"the",
"mi-",
"crotubule",
"(MT)-binding",
"sites",
"(Yang",
"et",
"al.,",
"1989);",
"a",
"central",
"a-helical",
"coiled-coil",
"involved",
"in",
"dimerization",
"(de",
"Cuevas",
"et",
"al.,",
"1992);",
"and",
"a",
"COOH-terminal",
"tail,",
"which",
"binds",
"KLC",
"(Diefenbach",
"et",
"al.,",
"1998).",
"The",
"KHC-tail:KLC",
"complex",
"ap-",
"pears",
"to",
"be",
"a",
"crucial",
"regulatory",
"target,",
"involved",
"in",
"interac-",
"tion",
"with",
"cargo",
"(Brady",
"and",
"Pfister,",
"1991;",
"Stenoien",
"and",
"Brady,",
"1997;",
"Khodjakov",
"et",
"al.,",
"1998)",
"and",
"controlling",
"the",
"motor",
"activity",
"of",
"the",
"motor",
"protein",
"(Hackney",
"et",
"al.,",
"1991;",
"Verhey",
"et",
"al.,",
"1998;",
"Coy",
"et",
"al.,",
"1999;",
"Friedman",
"and",
"Vale,",
"1999;",
"Rahman",
"et",
"al.,",
"1999;",
"Stock",
"et",
"al.,",
"1999).",
"Address",
"correspondence",
"to",
"Johan",
"Grooten,",
"Department",
"of",
"Molecular",
"Bi-",
"ology,",
"Flanders",
"Interuniversity",
"Institute",
"for",
"Biotechnology",
"and",
"Ghent",
"University,",
"K.",
"L.",
"Ledeganckstraat",
"35,",
"B-9000",
"Ghent,",
"Belgium.",
"Tel.:",
"32",
"9",
"264",
"5310.",
"Fax:",
"32",
"9",
"264",
"5348.",
"E-mail:",
"johan.grooten@dmb.rug.ac.be",
"Kurt",
"De",
"Vos’",
"present",
"address",
"is",
"Department",
"of",
"Biological",
"Sciences,",
"Columbia",
"University,",
"New",
"York,",
"NY",
"10027.",
"1Abbreviations",
"used",
"in",
"this",
"paper:",
"2-DE,",
"two-dimensional",
"gel",
"electro-",
"phoresis;",
"Ab,",
"antibody;",
"KHC,",
"kinesin",
"heavy",
"chain;",
"KLC,",
"kinesin",
"light",
"chain;",
"MAP,",
"microtubule-associated",
"protein;",
"MAPK,",
"mitogen-activated",
"protein",
"kinase;",
"MT,",
"microtubule;",
"OA,",
"okadaic",
"acid;",
"PKA,",
"protein",
"kinase",
"A;",
"TNF,",
"tumor",
"necrosis",
"factor.",
"KHC",
"and",
"KLC",
"are",
"reversibly",
"phosphorylated",
"on",
"serine",
"residues",
"in",
"vivo,",
"suggesting",
"that",
"phosphorylation",
"is",
"in-",
"volved",
"in",
"kinesin",
"regulation.",
"Indeed,",
"KHC",
"of",
"membrane-",
"bound,",
"presumably",
"active",
"kinesin",
"is",
"hyperphosphorylated",
"in",
"vivo",
"(Lee",
"and",
"Hollenbeck,",
"1995)",
"and",
"kinesin",
"phosphor-",
"ylation",
"by",
"protein",
"kinase",
"A",
"(PKA)",
"in",
"vitro",
"increased",
"kine-",
"sin",
"ATPase",
"activity",
"and",
"thus",
"may",
"stimulate",
"transport",
"(Matthies",
"et",
"al.,",
"1993).",
"However,",
"phosphorylation",
"by",
"PKA",
"also",
"reduced",
"binding",
"of",
"kinesin",
"to",
"synaptic",
"vesicles",
"sug-",
"gesting",
"to",
"the",
"contrary",
"decreased",
"vesicle",
"transport",
"(Sato-",
"Yoshitake",
"et",
"al.,",
"1992).",
"In",
"a",
"different",
"approach,",
"using",
"oka-",
"daic",
"acid",
"(OA)",
"to",
"drive",
"hyperphosphorylation",
"of",
"kinesin",
"in",
"cytosolic",
"extracts,",
"McIlvain",
"et",
"al.",
"(1994)",
"showed",
"hyper-",
"phosphorylation",
"of",
"three",
"components",
"of",
"the",
"kinesin",
"com-",
"plex,",
"but",
"not",
"of",
"KHC",
"in",
"correlation",
"with",
"increased",
"kinesin",
"activity",
"in",
"vitro.",
"One",
"of",
"these",
"associated",
"proteins",
"was",
"re-",
"cently",
"identified",
"as",
"KLC,",
"and",
"hyperphosphorylation",
"of",
"this",
"KLC",
"isoform",
"was",
"sufficient",
"to",
"increase",
"kinesin",
"activity",
"in",
"vitro",
"(Lindesmith",
"et",
"al.,",
"1997).",
"Similarly",
"increased",
"vesicle",
"motility",
"was",
"observed",
"in",
"OA-treated",
"CV-1",
"cells",
"(Hamm-Alvarez",
"et",
"al.,",
"1993).",
"However,",
"in",
"these",
"cells",
"no",
"hyperphosphorylation",
"of",
"kinesin-associated",
"proteins",
"could",
"be",
"demonstrated,",
"suggesting",
"an",
"indirect",
"effect",
"of",
"OA",
"on",
"kinesin",
"activity",
"(McIlvain",
"et",
"al.,",
"1994).",
"Also,",
"in",
"melano-",
"phores,",
"melanocyte",
"stimulating",
"hormone-induced",
"disper-",
"sion",
"of",
"melanosomes",
"by",
"kinesin-II",
"was",
"dependent",
"on",
"PKA",
"ª",
"The",
"Rockefeller",
"University",
"Press,",
"0021-9525/2000/06/1207/8",
"$5.00",
"The",
"Journal",
"of",
"Cell",
"Biology,",
"Volume",
"149,",
"Number",
"6,",
"June",
"12,",
"2000",
"1207–1214",
"http://www.jcb.org",
"1207"
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] | [
"Int.",
"J.",
"Biol.",
"Sci.",
"2007,",
"3",
"Review",
"420",
"International",
"Journal",
"of",
"Biological",
"Sciences",
"ISSN",
"1449-2288",
"www.biolsci.org",
"2007",
"3(7):420-427",
"©Ivyspring",
"International",
"Publisher.",
"All",
"rights",
"reserved",
"Candidate",
"Gene",
"Identification",
"Approach:",
"Progress",
"and",
"Challenges",
"Mengjin",
"Zhu",
"and",
"Shuhong",
"Zhao",
"Key",
"Laboratory",
"of",
"Agricultural",
"Animal",
"Genetics,",
"Breeding",
"and",
"Reproduction",
"of",
"Ministry",
"of",
"Education,",
"Huazhong",
"Agricultural",
"University,",
"Wuhan",
"430070,",
"P.",
"R.",
"China",
"Correspondence",
"to:",
"Shuhong",
"Zhao,",
"Key",
"Laboratory",
"of",
"Agricultural",
"Animal",
"Genetics,",
"Breeding",
"and",
"Reproduction",
"of",
"Ministry",
"of",
"Education,",
"Huazhong",
"Agricultural",
"University,",
"Wuhan",
"430070,",
"P.",
"R.",
"China.",
"Tel:",
"+86-27-87281306;",
"Fax:",
"+86-27-87280408;",
"E-mail:",
"shzhao@mail.hzau.edu.cn",
"Received:",
"2007.08.26;",
"Accepted:",
"2007.10.24;",
"Published:",
"2007.10.25",
"Although",
"it",
"has",
"been",
"widely",
"applied",
"in",
"identification",
"of",
"genes",
"responsible",
"for",
"biomedically,",
"economically,",
"or",
"even",
"evolutionarily",
"important",
"complex",
"and",
"quantitative",
"traits,",
"traditional",
"candidate",
"gene",
"approach",
"is",
"largely",
"limited",
"by",
"its",
"reliance",
"on",
"the",
"priori",
"knowledge",
"about",
"the",
"physiological,",
"biochemical",
"or",
"functional",
"aspects",
"of",
"possible",
"candidates.",
"Such",
"limitation",
"results",
"in",
"a",
"fatal",
"information",
"bottleneck,",
"which",
"has",
"apparently",
"become",
"an",
"obstacle",
"for",
"further",
"applications",
"of",
"traditional",
"candidate",
"gene",
"approach",
"on",
"many",
"occasions.",
"While",
"the",
"identification",
"of",
"candidate",
"genes",
"involved",
"in",
"genetic",
"traits",
"of",
"specific",
"interest",
"remains",
"a",
"challenge,",
"significant",
"progress",
"in",
"this",
"subject",
"has",
"been",
"achieved",
"in",
"the",
"last",
"few",
"years.",
"Several",
"strategies",
"have",
"been",
"developed,",
"or",
"being",
"developed,",
"to",
"break",
"the",
"barrier",
"of",
"information",
"bottleneck.",
"Recently,",
"being",
"a",
"new",
"developing",
"method",
"of",
"candidate",
"gene",
"approach,",
"digital",
"candidate",
"gene",
"approach",
"(DigiCGA)",
"has",
"emerged",
"and",
"been",
"primarily",
"applied",
"to",
"identify",
"potential",
"candidate",
"genes",
"in",
"some",
"studies.",
"This",
"review",
"summarizes",
"the",
"progress,",
"application",
"software,",
"online",
"tools,",
"and",
"challenges",
"related",
"to",
"this",
"approach.",
"Key",
"words:",
"candidate",
"gene",
"approach;",
"information",
"bottleneck;",
"digital",
"candidate",
"gene",
"approach",
"1.",
"Introduction",
"Based",
"on",
"the",
"polygenic",
"hypothesis,",
"classical",
"quantitative",
"genetics",
"considers",
"a",
"black",
"box",
"to",
"reveal",
"the",
"holistic",
"status",
"of",
"all",
"genes",
"associated",
"with",
"variation",
"of",
"complex",
"and",
"quantitative",
"traits",
"by",
"complicated",
"statistical",
"methods.",
"Such",
"strategy",
"could",
"not",
"independently",
"decompose",
"individual",
"genes,",
"which",
"usually",
"follow",
"the",
"Mendel's",
"law,",
"from",
"the",
"polygenic",
"system",
"of",
"the",
"investigated",
"traits.",
"Advances",
"in",
"molecular",
"methods",
"and",
"quantitative",
"techniques",
"have",
"clearly",
"changed",
"this",
"status,",
"which",
"are",
"able",
"to",
"look",
"inside",
"the",
"black",
"box",
"of",
"polygenic",
"control",
"for",
"complex",
"and",
"quantitative",
"traits",
"with",
"a",
"more",
"accurate",
"description",
"of",
"how",
"genes",
"act",
"to",
"determine",
"the",
"phenotypic",
"variation.",
"More",
"recently,",
"major",
"progress",
"has",
"been",
"made",
"in",
"this",
"field",
"with",
"the",
"advent",
"of",
"genomics",
"and",
"its",
"potential",
"contribution",
"to",
"development",
"of",
"quantitative",
"genetics.",
"One",
"of",
"the",
"hot",
"interests",
"of",
"current",
"quantitative",
"genetics",
"is",
"systematically",
"exploring",
"an",
"exact",
"genetic",
"architecture",
"of",
"the",
"number,",
"distribution",
"and",
"interaction",
"of",
"loci",
"affecting",
"the",
"variations",
"of",
"biomedically,",
"economically,",
"and",
"evolutionarily",
"important",
"complex",
"and",
"quantitative",
"traits.",
"There",
"are",
"two",
"approaches",
"for",
"genetic",
"dissections",
"of",
"complex",
"and",
"quantitative",
"traits,",
"i.e.,",
"genome-wide",
"scanning",
"and",
"candidate",
"gene",
"approach,",
"which",
"each",
"has",
"specific",
"advantages",
"and",
"disadvantages.",
"Genome-wide",
"scanning",
"usually",
"proceeds",
"without",
"any",
"presuppositions",
"regarding",
"the",
"importance",
"of",
"specific",
"functional",
"features",
"of",
"the",
"investigated",
"traits,",
"but",
"of",
"which",
"the",
"principal",
"disadvantage",
"is",
"expensive",
"and",
"resource",
"intensive.",
"In",
"general,",
"genome-wide",
"scanning",
"only",
"locates",
"the",
"glancing",
"chromosomal",
"regions",
"of",
"quantitative",
"trait",
"loci",
"(QTLs)",
"at",
"cM-level",
"with",
"the",
"aid",
"of",
"DNA",
"markers",
"under",
"family-based",
"or",
"population-based",
"experimental",
"designs,",
"which",
"usually",
"embed",
"a",
"large",
"number",
"of",
"candidate",
"genes.",
"In",
"comparison,",
"the",
"alternative",
"candidate",
"gene",
"approach",
"has",
"been",
"proven",
"to",
"be",
"extremely",
"powerful",
"for",
"studying",
"the",
"genetic",
"architecture",
"of",
"complex",
"traits,",
"which",
"is",
"a",
"far",
"more",
"effective",
"and",
"economical",
"method",
"for",
"direct",
"gene",
"discovery.",
"Nevertheless,",
"the",
"practicability",
"of",
"traditional",
"candidate",
"gene",
"approach",
"is",
"largely",
"limited",
"by",
"its",
"reliance",
"on",
"existing",
"knowledge",
"about",
"the",
"known",
"or",
"presumed",
"biology",
"of",
"the",
"phenotype",
"under",
"investigation,",
"and",
"unfortunately",
"the",
"detailed",
"molecular",
"anatomy",
"of",
"most",
"biological",
"traits",
"remains",
"unknown.",
"It",
"is",
"quite",
"necessary",
"to",
"develop",
"new",
"strategies",
"to",
"break",
"the",
"restriction",
"of",
"information",
"bottleneck,",
"although",
"considerable",
"candidate",
"genes",
"have",
"already",
"been",
"identified.",
"In",
"this",
"article,",
"we",
"review",
"and",
"summarize",
"the",
"main",
"research",
"advances",
"in",
"the",
"subject,",
"including",
"the",
"outline",
"of",
"candidate",
"gene",
"approach",
"and",
"the",
"extended",
"strategies",
"for",
"breaking",
"the",
"information",
"bottleneck",
"of",
"traditional",
"candidate",
"gene",
"approach.",
"Finally,",
"as",
"a",
"new",
"development",
"of",
"candidate",
"gene",
"approach,",
"digital",
"candidate",
"gene",
"approach",
"(DigiCGA)",
"was",
"discussed",
"and",
"some",
"research",
"outlooks",
"were",
"given",
"to",
"further",
"promote",
"this",
"valuable",
"research",
"subject."
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] | [
"Original",
"Article",
"Influence",
"of",
"Connector",
"Width",
"on",
"the",
"Stress",
"Distribution",
"of",
"Posterior",
"Bridges",
"under",
"Loading",
"S.",
"Mir",
"Mohammad",
"Rezaei",
"1,",
"H.",
"Heidarifar",
"2,",
"F.",
"Fallahi",
"Arezodar",
"2,",
"A.",
"Azary",
"3,",
"S.",
"Mokhtarykhoee",
"4",
"1Associate",
"Professor,",
"Department",
"of",
"Prosthodontics,",
"School",
"of",
"Dentistry,",
"Tehran",
"University",
"of",
"Medical",
"Sciences,",
"Tehran,",
"Iran",
"2Mechanical",
"Engineer,",
"Private",
"Sector",
"3Assistant",
"Professor,",
"Department",
"of",
"Prosthodontics,",
"School",
"of",
"Dentistry,",
"Tehran",
"University",
"of",
"Medical",
"Sciences,",
"Tehran,",
"Iran",
"4Dentist,",
"Private",
"Practice",
"Abstract:",
"Objective:",
"In",
"all",
"ceramic",
"fixed",
"partial",
"dentures",
"the",
"connector",
"area",
"is",
"a",
"common",
"fracture",
"location.",
"The",
"survival",
"time",
"of",
"three-unit",
"fixed",
"partial",
"dentures",
"may",
"be",
"improved",
"by",
"alter-",
"ing",
"the",
"connector",
"design",
"in",
"regions",
"of",
"maximum",
"tension.",
"The",
"purpose",
"of",
"this",
"study",
"was",
"to",
"determine",
"the",
"effect",
"of",
"buccolingual",
"increase",
"of",
"the",
"connector",
"width",
"on",
"the",
"stress",
"distribu-",
"tion",
"in",
"posterior",
"fixed",
"partial",
"dentures",
"made",
"of",
"IPS",
"Empress",
"2.",
"To",
"simulate",
"the",
"anatomical",
"condition,",
"we",
"used",
"three-dimensional",
"finite",
"element",
"analysis",
"to",
"generate.",
"Materials",
"and",
"Methods:",
"Three",
"models",
"of",
"three-unit",
"bridges",
"replacing",
"the",
"first",
"molar",
"were",
"prepared.",
"The",
"buccolingual",
"connector",
"width",
"varied",
"from",
"3.0",
"to",
"5.0",
"mm.",
"Bridges",
"were",
"vertically",
"loaded",
"with",
"600",
"N",
"at",
"one",
"point",
"on",
"the",
"central",
"fossa",
"of",
"the",
"pontic,",
"at",
"12",
"points",
"along",
"the",
"cusp-fossa",
"contact",
"(50",
"N",
"each),",
"or",
"at",
"eight",
"points",
"along",
"the",
"cusp-marginal",
"ridge",
"contact",
"(75",
"N",
"each).",
"Alternatively,",
"a",
"load",
"of",
"225",
"N",
"was",
"applied",
"at",
"a",
"45º",
"angle",
"from",
"the",
"lingual",
"side.",
"Results:",
"Stress",
"concentrations",
"were",
"observed",
"within",
"or",
"near",
"the",
"connectors.",
"The",
"von",
"Mis-",
"es",
"stress",
"decreased",
"by",
"increasing",
"connector",
"width,",
"regardless",
"of",
"whether",
"the",
"loading",
"was",
"",
"Corresponding",
"author:",
"applied",
"vertically",
"or",
"at",
"an",
"angle.",
"F.",
"Fallahi",
"Arezodar,",
"Mechanical",
"Conclusion:",
"Within",
"the",
"limitations",
"of",
"this",
"study,",
"we",
"conclude",
"that",
"increasing",
"the",
"connect-",
"Engineer,",
"Private",
"Sector,",
"Tehran,",
"or",
"width",
"decreases",
"the",
"failure",
"probability",
"when",
"a",
"vertical",
"or",
"angled",
"load",
"is",
"applied.",
"Iran.",
"f.fallahi.a@gmail.com",
"Key",
"Words:",
"Ceramics;",
"Finite",
"Element",
"Analysis;",
"Denture,",
"Partial,",
"Fixed",
"Journal",
"of",
"Dentistry,",
"Tehran",
"University",
"of",
"Medical",
"Sciences,",
"Tehran,",
"Iran",
"(2011;",
"Vol.",
"8,",
"No.2)",
"Received:",
"Accepted:",
"INTRODUCTION",
"Clinical",
"stress",
"distribution",
"in",
"ceramic",
"dental",
"restorations",
"may",
"be",
"quite",
"complex.",
"Several",
"factors",
"are",
"associated",
"with",
"crack",
"initiation",
"and",
"propagation,",
"including",
"the",
"shape",
"of",
"the",
"resto-",
"ration,",
"micro",
"structural",
"nonhomogeneities,",
"the",
"size",
"and",
"distribution",
"of",
"surface",
"flaws,",
"residual",
"stresses",
"and",
"stress",
"gradients",
"induced",
"by",
"polish-",
"ing",
"and/or",
"thermal",
"processing,",
"the",
"environ-",
"ment",
"in",
"contact",
"with",
"the",
"restoration,",
"ceram-",
"ic/cement",
"interfacial",
"features,",
"thickness",
"and",
"thickness",
"variation",
"of",
"the",
"restoration,",
"different",
"2011;",
"Vol.",
"8,",
"No.",
"2",
"elastic",
"modules",
"of",
"the",
"restoration",
"components",
"and",
"the",
"magnitude",
"and",
"orientation",
"of",
"the",
"ap-",
"plied",
"load",
"[1].",
"Failure",
"may",
"be",
"a",
"mixed",
"pattern",
"of",
"compressive,",
"tensile,",
"and/or",
"shear",
"failures",
"[2].",
"However,",
"brittle",
"materials",
"(e.g.,",
"dental",
"ce-",
"ramics)",
"usually",
"demonstrate",
"the",
"least",
"strength",
"when",
"exposed",
"to",
"tensile",
"stress.",
"Thus,",
"tensile",
"stress",
"is",
"useful",
"for",
"assessing",
"the",
"service",
"time",
"of",
"ceramic",
"materials,",
"especially",
"when",
"flaws",
"are",
"present.",
"The",
"long-term",
"mechanical",
"behavior",
"of",
"the",
"restoration",
"is",
"also",
"critical,",
"since",
"ceramics",
"exhibit",
"a",
"time-dependent",
"strength",
"decrease",
"due",
"67"
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] | [
"Int.",
"J.",
"Environ.",
"Res.",
"Public",
"Health",
"2009,",
"6,",
"1268-1281;",
"doi:10.3390/ijerph6031268",
"OPEN",
"ACCESS",
"International",
"Journal",
"of",
"Environmental",
"Research",
"and",
"Public",
"Health",
"ISSN",
"1660-4601",
"www.mdpi.com/journal/ijerph",
"Article",
"Parents’",
"and",
"Teachers’",
"Opinions",
"about",
"the",
"School",
"Food",
"Policy",
"in",
"Belgian",
"Flemish",
"Nursery",
"Schools",
"Carine",
"Vereecken",
"1,2,*,",
"Hilde",
"van",
"Houte",
"3,4,",
"Veerle",
"Martens",
"3,4,",
"Isabelle",
"Wittebroodt",
"3",
"and",
"Lea",
"Maes",
"1",
"1",
"Department",
"of",
"Public",
"Health,",
"Ghent",
"University,",
"University",
"Hospital",
"BlokA,",
"2nd",
"floor,",
"De",
"Pintelaan",
"185,",
"9000",
"Gent,",
"Belgium;",
"E-Mail:",
"Lea.Maes@UGent.Be",
"2",
"Research",
"Foundation",
"Flanders",
"(FWO)",
"3",
"Department",
"of",
"early",
"childhood",
"education,",
"University",
"College",
"„Arteveldehogeschool‟,",
"Gent",
"9040,",
"Belgium;",
"E-Mails:",
"hilde.vanhoute@arteveldehs.be",
"(H-V.V.);",
"veerle.martens@arteveldehs.be",
"(V.M.);",
"isabelle.wittebroodt@arteveldehs.be",
"(I.W.)",
"4",
"Ghent",
"University",
"*",
"Author",
"to",
"whom",
"correspondence",
"should",
"be",
"addressed;",
"E-Mail:",
"Carine.Vereecken@UGent.Be;",
"Tel.:",
"+32-(0)9-3322081;",
"Fax:",
"+32-(0)9-3324994",
"Received:",
"24",
"February",
"2009",
"/",
"Accepted:",
"19",
"March",
"2009",
"/",
"Published:",
"24",
"March",
"2009",
"Abstract:",
"The",
"partnership",
"of",
"parents,",
"teachers,",
"and",
"schools",
"is",
"necessary",
"to",
"develop",
"effective",
"school",
"food",
"interventions.",
"To",
"gather",
"parents‟",
"and",
"teachers‟",
"opinions",
"and",
"perceptions",
"about",
"the",
"school",
"food",
"policy,",
"884",
"parents",
"and",
"70",
"teachers",
"of",
"preschoolers",
"completed",
"a",
"questionnaire.",
"School",
"food",
"policy",
"is",
"an",
"issue",
"of",
"importance",
"for",
"parents",
"and",
"teachers:",
"the",
"majority",
"agrees",
"that",
"schools",
"should",
"restrict",
"the",
"availability",
"of",
"snacks",
"and",
"soft",
"drinks;",
"however,",
"to",
"replace",
"fruit",
"juice",
"and",
"sugared",
"milk",
"drinks",
"with",
"sugarless",
"alternatives",
"will",
"take",
"special",
"effort.",
"Fruit",
"is",
"not",
"always",
"available",
"at",
"school,",
"although",
"parents",
"would",
"appreciate",
"it.",
"Parents",
"of",
"lower",
"educational",
"level",
"are",
"in",
"general",
"more",
"permissive.",
"Keywords:",
"Preschool;",
"school",
"food",
"policy;",
"parents;",
"teachers."
] | [
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",",
"Vinh",
"N.",
"Tran",
"2",
",",
"George",
"W.",
"Sundin1,2,3*",
"1",
"Program",
"in",
"Genetics,",
"Michigan",
"State",
"University,",
"East",
"Lansing,",
"Michigan,",
"United",
"States",
"of",
"America,",
"2",
"Department",
"of",
"Plant",
"Pathology,",
"Michigan",
"State",
"University,",
"East",
"Lansing,",
"Michigan,",
"United",
"States",
"of",
"America,",
"3",
"Centers",
"for",
"Microbial",
"Ecology",
"and",
"Pathogenesis,",
"Michigan",
"State",
"University,",
"East",
"Lansing,",
"Michigan,",
"United",
"States",
"of",
"America",
"Abstract",
"Background:",
"Mutagenic",
"DNA",
"repair",
"(MDR)",
"transiently",
"increases",
"mutation",
"rate",
"through",
"the",
"activation",
"of",
"low-fidelity",
"repair",
"polymerases",
"in",
"response",
"to",
"specific,",
"DNA-damaging",
"environmental",
"stress",
"conditions",
"such",
"as",
"ultraviolet",
"radiation",
"(UVR)",
"exposure.",
"These",
"repair",
"polymerases",
"also",
"confer",
"UVR",
"tolerance,",
"intimately",
"linking",
"mutability",
"and",
"survival",
"in",
"bacteria",
"that",
"colone",
"habitats",
"subject",
"to",
"regular",
"UVR",
"exposure.",
"Methodology/Principal",
"Findings:",
"Here,",
"we",
"investigate",
"adaptive",
"specificity",
"in",
"experimental",
"lineages",
"of",
"the",
"highly",
"UVR-",
"mutable",
"epiphytic",
"plant",
"pathogen",
"Pseudomonas",
"cichorii",
"302959.",
"Relative",
"fitness",
"measurements",
"of",
"isolates",
"and",
"population",
"samples",
"from",
"replicate",
"lineages",
"indicated",
"that",
"adaptive",
"improvements",
"emerged",
"early",
"in",
"all",
"lineages",
"of",
"our",
"evolution",
"experiment",
"and",
"specific",
"increases",
"in",
"relative",
"fitness",
"correlated",
"with",
"distinct",
"improvements",
"in",
"doubling",
"and",
"lag",
"times.",
"Adaptive",
"improvements",
"gained",
"under",
"UVR",
"and",
"non-UVR",
"conditions",
"were",
"acquired",
"preferentially,",
"and",
"differentially",
"contributed",
"to",
"relative",
"fitness",
"under",
"varied",
"growth",
"conditions.",
"Conclusions:",
"These",
"results",
"support",
"our",
"earlier",
"observations",
"that",
"MDR",
"activation",
"may",
"contribute",
"to",
"gains",
"in",
"relative",
"fitness",
"without",
"impeding",
"normal",
"patterns",
"of",
"adaptive",
"specificity",
"in",
"P.",
"cichorii",
"302959.",
"Citation:",
"Weigand",
"MR,",
"Tran",
"VN,",
"Sundin",
"GW",
"(2011)",
"Growth",
"Parameter",
"Components",
"of",
"Adaptive",
"Specificity",
"during",
"Experimental",
"Evolution",
"of",
"the",
"UVR-Inducible",
"Mutator",
"Pseudomonas",
"cichorii",
"302959.",
"PLoS",
"ONE",
"6(1):",
"e15975.",
"doi:10.1371/journal.pone.0015975",
"Editor:",
"Michael",
"Otto,",
"Laboratory",
"of",
"Human",
"Bacterial",
"Pathogenesis,",
"National",
"Institutes",
"of",
"Health,",
"United",
"States",
"of",
"America",
"Received",
"September",
"21,",
"2010;",
"Accepted",
"December",
"7,",
"2010;",
"Published",
"January",
"14,",
"2011",
"Copyright:",
"2011",
"Weigand",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"This",
"work",
"was",
"funded",
"by",
"the",
"Michigan",
"Agricultural",
"Experiment",
"Station.",
"The",
"funders",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript.",
"Competing",
"Interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"*",
"E-mail:",
"sundin@msu.edu",
"Introduction",
"Mutation",
"is",
"the",
"most",
"fundamental",
"source",
"of",
"variation",
"on",
"which",
"natural",
"selection",
"may",
"drive",
"evolution.",
"However,",
"the",
"predomi-",
"nantly",
"deleterious",
"nature",
"of",
"mutation",
"maintains",
"selection",
"pressure",
"in",
"favor",
"of",
"lower",
"mutation",
"rates",
"as",
"evidenced",
"by",
"the",
"conservation",
"of",
"multiple",
"DNA",
"error-avoidance",
"and",
"error-repair",
"processes",
"[1].",
"Yet",
"hypermutator",
"(or",
"mutator)",
"strains",
"of",
"bacteria",
"have",
"been",
"observed",
"in",
"a",
"variety",
"of",
"clinical,",
"environmental,",
"and",
"laboratory",
"populations",
"with",
"mutation",
"rates",
"100-1000",
"times",
"greater",
"than",
"wild-",
"type",
"due",
"to",
"defects",
"in",
"DNA",
"proofreading",
"and",
"repair",
"machinery",
"[2].",
"The",
"widespread",
"existence",
"of",
"both",
"constitutive",
"and",
"inducible",
"mutator",
"genotypes",
"suggests",
"that",
"evolutionary",
"strategies",
"of",
"bacteria",
"include",
"mechanisms",
"for",
"increasing",
"mutability",
"[3,4].",
"These",
"mutator",
"genotypes",
"have",
"not",
"been",
"shown",
"to",
"confer",
"an",
"intrinsic",
"fitness",
"advantage",
"and",
"their",
"abundance",
"within",
"natural",
"populations",
"likely",
"results",
"from",
"hitchhiking",
"with",
"secondary,",
"beneficial",
"mutations",
"which",
"counterbalance",
"the",
"cost",
"of",
"accumulating",
"deleterious",
"mutations",
"[5,6].",
"Inducible",
"mutability",
"in",
"the",
"form",
"of",
"mutagenic",
"DNA",
"repair",
"(MDR)",
"transiently",
"increases",
"mutation",
"rate",
"through",
"the",
"activation",
"of",
"low-fidelity",
"repair",
"polymerases",
"in",
"response",
"to",
"specific",
"environ-",
"mental",
"stress",
"conditions",
"such",
"as",
"ultraviolet",
"radiation",
"(UVR)",
"exposure.",
"UVR",
"directly",
"damages",
"DNA",
"causing",
"lesions,",
"including",
"cyclobutane",
"pyrimidine",
"dimers",
"and",
"6-4",
"photoproducts,",
"that",
"distort",
"the",
"helical",
"structure,",
"interrupting",
"replication",
"fork",
"progression",
"and",
"inducing",
"the",
"SOS",
"response.",
"The",
"SOS",
"regulon",
"coordinates",
"the",
"control",
"of",
"more",
"than",
"40",
"unlinked",
"genes",
"involved",
"in",
"DNA",
"repair,",
"recombination,",
"and",
"cell",
"cycle",
"control",
"[7,8].",
"Among",
"these,",
"the",
"Y",
"family",
"DNA",
"polymerases",
"polIV",
"(Escherichia",
"coli",
"DinB)",
"and",
"polV",
"(E.",
"coli",
"UmuDC)",
"rescue",
"stalled",
"replication",
"forks",
"and",
"permit",
"DNA",
"synthesis",
"across",
"damaged",
"regions",
"of",
"DNA",
"in",
"a",
"template-",
"independent",
"manner",
"by",
"nature",
"of",
"their",
"high",
"processivity",
"and",
"low",
"fidelity",
"[9].",
"Secondary",
"mutations",
"caused",
"by",
"these",
"error-prone",
"polymerases",
"comprise",
"the",
"majority",
"of",
"sequence",
"alterations",
"derived",
"from",
"UVR",
"exposure",
"and",
"define",
"the",
"inducible",
"mutator",
"phenotype.",
"This",
"translesion",
"DNA",
"synthesis",
"activity",
"confers",
"both",
"UVR",
"tolerance",
"and",
"inducible",
"mutability,",
"intimately",
"linking",
"survival",
"and",
"mutation",
"in",
"habitats",
"subject",
"to",
"regular",
"UVR",
"exposure.",
"MDR-mediated",
"UVR",
"tolerance",
"provides",
"a",
"critical",
"ecological",
"advantage",
"to",
"epiphytic",
"plant",
"pathogens",
"harboring",
"Y",
"family",
"polymerases",
"that",
"reside",
"in",
"habitats",
"optimized",
"for",
"solar",
"UVR",
"exposure",
"[10,11].",
"We",
"have",
"previously",
"reported",
"our",
"studies",
"of",
"experimental",
"evolution",
"with",
"the",
"highly",
"UVR-mutable",
"celery",
"pathogen",
"Pseudomonas",
"cichorii",
"302959",
"[12].",
"The",
"major",
"contributor",
"of",
"UVR-induced",
"mutability",
"in",
"this",
"strain",
"is",
"rulAB,",
"a",
"homolog",
"of",
"PLoS",
"ONE",
"|",
"www.plosone.org",
"1",
"January",
"2011",
"|",
"Volume",
"6",
"|",
"Issue",
"1",
"|",
"e15975"
] | [
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] | [
"BMC",
"Bioinformatics",
"Methodology",
"article",
"The",
"ontology",
"of",
"biological",
"sequences",
"Robert",
"Hoehndorf*1,2,3,",
"Janet",
"Kelso2",
"and",
"Heinrich",
"Herre1,3",
"BioMed",
"Central",
"Open",
"Access",
"Address:",
"1Research",
"Group",
"Ontologies",
"in",
"Medicine,",
"Institute",
"for",
"Medical",
"Informatics,",
"Statistics",
"and",
"Epidemiology,",
"University",
"of",
"Leipzig,",
"Haertelstrasse",
"16-18,",
"04107",
"Leipzig,",
"Germany,",
"2Department",
"of",
"Evolutionary",
"Genetics,",
"Max",
"Planck",
"Institute",
"for",
"Evolutionary",
"Anthropology,",
"Deutscher",
"Platz",
"6,",
"04103",
"Leipzig,",
"Germany",
"and",
"3Department",
"of",
"Computer",
"Science,",
"University",
"of",
"Leipzig,",
"Johannesgasse",
"26,",
"04103",
"Leipzig,",
"Germany",
"Email:",
"Robert",
"Hoehndorf*",
"-",
"leechuck@leechuck.de;",
"Janet",
"Kelso",
"-",
"kelso@eva.mpg.de;",
"Heinrich",
"Herre",
"-",
"heinrich.herre@imise.uni-leipzig.de",
"*",
"Corresponding",
"author",
"Published:",
"18",
"November",
"2009",
"BMC",
"Bioinformatics",
"2009,",
"10:377",
"doi:10.1186/1471-2105-10-377",
"This",
"article",
"is",
"available",
"from:",
"http://www.biomedcentral.com/1471-2105/10/377",
"Received:",
"18",
"August",
"2009",
"Accepted:",
"18",
"November",
"2009",
"©",
"2009",
"Hoehndorf",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Abstract",
"Background:",
"Biological",
"sequences",
"play",
"a",
"major",
"role",
"in",
"molecular",
"and",
"computational",
"biology.",
"They",
"are",
"studied",
"as",
"information-bearing",
"entities",
"that",
"make",
"up",
"DNA,",
"RNA",
"or",
"proteins.",
"The",
"Sequence",
"Ontology,",
"which",
"is",
"part",
"of",
"the",
"OBO",
"Foundry,",
"contains",
"descriptions",
"and",
"definitions",
"of",
"sequences",
"and",
"their",
"properties.",
"Yet",
"the",
"most",
"basic",
"question",
"about",
"sequences",
"remains",
"unanswered:",
"what",
"kind",
"of",
"entity",
"is",
"a",
"biological",
"sequence?",
"An",
"answer",
"to",
"this",
"question",
"benefits",
"formal",
"ontologies",
"that",
"use",
"the",
"notion",
"of",
"biological",
"sequences",
"and",
"analyses",
"in",
"computational",
"biology",
"alike.",
"Results:",
"We",
"provide",
"both",
"an",
"ontological",
"analysis",
"of",
"biological",
"sequences",
"and",
"a",
"formal",
"representation",
"that",
"can",
"be",
"used",
"in",
"knowledge-based",
"applications",
"and",
"other",
"ontologies.",
"We",
"distinguish",
"three",
"distinct",
"kinds",
"of",
"entities",
"that",
"can",
"be",
"referred",
"to",
"as",
"\"biological",
"sequence\":",
"chains",
"of",
"molecules,",
"syntactic",
"representations",
"such",
"as",
"those",
"in",
"biological",
"databases,",
"and",
"the",
"abstract",
"information-bearing",
"entities.",
"For",
"use",
"in",
"knowledge-based",
"applications",
"and",
"inclusion",
"in",
"biomedical",
"ontologies,",
"we",
"implemented",
"the",
"developed",
"axiom",
"system",
"for",
"use",
"in",
"automated",
"theorem",
"proving.",
"Conclusion:",
"Axioms",
"are",
"necessary",
"to",
"achieve",
"the",
"main",
"goal",
"of",
"ontologies:",
"to",
"formally",
"specify",
"the",
"meaning",
"of",
"terms",
"used",
"within",
"a",
"domain.",
"The",
"axiom",
"system",
"for",
"the",
"ontology",
"of",
"biological",
"sequences",
"is",
"the",
"first",
"elaborate",
"axiom",
"system",
"for",
"an",
"OBO",
"Foundry",
"ontology",
"and",
"can",
"serve",
"as",
"starting",
"point",
"for",
"the",
"development",
"of",
"more",
"formal",
"ontologies",
"and",
"ultimately",
"of",
"knowledge-based",
"applications.",
"Background",
"Biological",
"sequences",
"play",
"a",
"major",
"role",
"in",
"genetics",
"and",
"bio-",
"informatics",
"research.",
"They",
"are",
"important",
"in",
"the",
"descrip-",
"tion",
"of",
"DNA,",
"RNA",
"and",
"proteins,",
"and",
"are",
"among",
"the",
"basic",
"entities",
"studied",
"in",
"molecular",
"and",
"computational",
"biology.",
"In",
"the",
"realm",
"of",
"biological",
"ontologies,",
"the",
"Sequence",
"Ontol-",
"ogy",
"(SO)",
"[1]",
"was",
"developed",
"to",
"describe",
"sequences",
"and",
"their",
"features",
"semantically.",
"Although",
"many",
"formal",
"defini-",
"tions",
"are",
"available",
"for",
"the",
"SO",
"categories,",
"several",
"categories",
"remain",
"defined",
"using",
"natural",
"language.",
"Formal",
"ontologies",
"are",
"intended",
"to",
"formally",
"specify",
"a",
"con-",
"ceptualization",
"of",
"a",
"domain",
"[2],",
"and",
"therefore",
"provide",
"the",
"foundation",
"for",
"data",
"and",
"information",
"integration",
"and",
"exchange.",
"Definitions",
"alone",
"are",
"insufficient",
"to",
"achieve",
"this",
"goal.",
"Axioms",
"are",
"required",
"to",
"provide",
"meaning",
"for",
"primi-",
"tive,",
"undefined",
"categories",
"and",
"relations.",
"To",
"provide",
"an",
"ontological",
"analysis",
"of",
"\"biological",
"sequence\"",
"and",
"to",
"for-",
"malize",
"the",
"basic",
"categories",
"used",
"in",
"the",
"SO,",
"several",
"onto-",
"logical",
"questions",
"about",
"sequences",
"must",
"be",
"answered,",
"among",
"them:",
"what",
"kind",
"of",
"entity",
"is",
"a",
"biological",
"sequence?",
"Page",
"1",
"of",
"11",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
] | [
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] | [
"JCB",
"Report",
"Golgi",
"matrix",
"proteins",
"interact",
"with",
"p24",
"cargo",
"receptors",
"and",
"aid",
"their",
"efficient",
"retention",
"in",
"the",
"Golgi",
"apparatus",
"Francis",
"A.",
"Barr,",
"Christian",
"Preisinger,",
"Robert",
"Kopajtich,",
"and",
"Roman",
"Körner",
"Department",
"of",
"Cell",
"Biology,",
"Max-Planck-Institute",
"of",
"Biochemistry,",
"82152",
"Martinsried,",
"Germany",
"T",
"comprised",
"of",
"a",
"stack",
"of",
"cisternal",
"membranes",
"on",
"the",
"he",
"Golgi",
"apparatus",
"is",
"a",
"highly",
"complex",
"organelle",
"secretory",
"pathway",
"from",
"the",
"ER",
"to",
"the",
"cell",
"surface.",
"This",
"structure",
"is",
"maintained",
"by",
"an",
"exoskeleton",
"or",
"Golgi",
"matrix",
"constructed",
"from",
"a",
"family",
"of",
"coiled-coil",
"proteins,",
"the",
"golgins,",
"and",
"other",
"peripheral",
"membrane",
"components",
"such",
"as",
"GRASP55",
"and",
"GRASP65.",
"Here",
"we",
"find",
"that",
"TMP21,",
"p24a,",
"and",
"gp25L,",
"members",
"of",
"the",
"p24",
"cargo",
"receptor",
"family,",
"are",
"present",
"in",
"complexes",
"with",
"GRASP55",
"and",
"GRASP65",
"Introduction",
"The",
"Golgi",
"apparatus",
"is",
"an",
"organelle",
"on",
"the",
"secretory",
"pathway",
"required",
"for",
"the",
"processing",
"of",
"complex",
"sugar",
"structures",
"on",
"many",
"proteins",
"and",
"lipids,",
"and",
"for",
"the",
"sorting",
"of",
"these",
"proteins",
"and",
"lipids",
"to",
"their",
"correct",
"subcellular",
"destinations",
"(Farquhar",
"and",
"Palade,",
"1998).",
"It",
"is",
"comprised",
"of",
"a",
"series",
"of",
"cisternal",
"membranes",
"organized",
"into",
"a",
"stacked",
"structure,",
"the",
"first",
"or",
"cis-face",
"receives",
"material",
"from",
"the",
"ER,",
"whereas",
"the",
"final",
"or",
"trans-cisternae",
"packages",
"it",
"for",
"delivery",
"to",
"the",
"plasma",
"membrane",
"and",
"endocytic",
"pathways",
"(Farquhar",
"and",
"Palade,",
"1998).",
"This",
"structure",
"is",
"maintained",
"by",
"an",
"exoskeleton",
"or",
"Golgi",
"matrix",
"which",
"has",
"been",
"proposed",
"to",
"be",
"required",
"for",
"linking",
"cisternae",
"together",
"into",
"the",
"characteristic",
"Golgi",
"stack",
"structure,",
"and",
"also",
"for",
"vesicle",
"recognition",
"during",
"membrane",
"traffic",
"(Warren",
"and",
"Malhotra,",
"1998;",
"Seeman",
"et",
"al.,",
"2000).",
"The",
"most",
"studied",
"components",
"of",
"the",
"Golgi",
"matrix",
"are",
"p115,",
"the",
"GRASP65–GM130",
"complex,",
"and",
"an",
"integral",
"membrane",
"protein,",
"giantin",
"(Linstedt",
"and",
"Hauri,",
"1993;",
"Nakamura",
"et",
"al.,",
"1995;",
"Sapperstein",
"et",
"al.,",
"1995;",
"Barr",
"et",
"al.,",
"1997;",
"Shorter",
"and",
"Warren,",
"1999).",
"GRASP65",
"was",
"identified",
"in",
"a",
"screen",
"for",
"factors",
"involved",
"in",
"the",
"stacking",
"of",
"cisternae,",
"and",
"later",
"shown",
"to",
"be",
"a",
"specific",
"binding",
"partner",
"of",
"GM130",
"Address",
"correspondence",
"to",
"Francis",
"Barr,",
"Dept.",
"of",
"Cell",
"Biology,",
"Max-",
"Planck-Institute",
"of",
"Biochemistry,",
"Am",
"Klopferspitz",
"18a,",
"82152",
"Martinsried,",
"Germany.",
"Tel.:",
"49-89-8578-3135.",
"Fax:",
"49-89-8578-3102.",
"E-mail:",
"barr@biochem.mpg.de",
"Key",
"words:",
"GRASPs;",
"p24",
"proteins;",
"Golgi",
"matrix;",
"protein",
"transport;",
"cargo",
"receptors",
"",
"The",
"Rockefeller",
"University",
"Press,",
"0021-9525/2001/12/885/7",
"$5.00",
"The",
"Journal",
"of",
"Cell",
"Biology,",
"Volume",
"155,",
"Number",
"6,",
"December",
"10,",
"2001",
"885–891",
"http://www.jcb.org/cgi/doi/10.1083/jcb.200108102",
"in",
"vivo.",
"GRASPs",
"interact",
"directly",
"with",
"the",
"cytoplasmic",
"domains",
"of",
"specific",
"p24",
"cargo",
"receptors",
"depending",
"on",
"their",
"oligomeric",
"state,",
"and",
"mutation",
"of",
"the",
"GRASP",
"binding",
"site",
"in",
"the",
"cytoplasmic",
"tail",
"of",
"one",
"of",
"these,",
"p24a,",
"results",
"in",
"it",
"being",
"transported",
"to",
"the",
"cell",
"surface.",
"These",
"results",
"suggest",
"that",
"one",
"function",
"of",
"the",
"Golgi",
"matrix",
"is",
"to",
"aid",
"efficient",
"retention",
"or",
"sequestration",
"of",
"p24",
"cargo",
"receptors",
"and",
"other",
"membrane",
"proteins",
"in",
"the",
"Golgi",
"apparatus.",
"required",
"to",
"target",
"it",
"to",
"the",
"Golgi",
"(Barr",
"et",
"al.,",
"1998).",
"GM130",
"in",
"turn",
"is",
"a",
"receptor",
"for",
"p115,",
"required",
"for",
"tethering",
"vesicles",
"to",
"their",
"target",
"membrane",
"(Barroso",
"et",
"al.,",
"1995;",
"Nakamura",
"et",
"al.,",
"1997).",
"More",
"recently,",
"the",
"formation",
"of",
"Golgi",
"stacks",
"from",
"cisternae",
"in",
"vitro",
"was",
"found",
"to",
"require",
"p115,",
"discrete",
"from",
"its",
"membrane",
"fusion",
"function,",
"and",
"giantin",
"(Shorter",
"and",
"Warren,",
"1999).",
"GM130",
"and",
"p115",
"also",
"make",
"interactions",
"with",
"giantin",
"during",
"vesicle",
"docking,",
"and",
"potentially",
"during",
"cisternal",
"stacking",
"(Shorter",
"and",
"Warren,",
"1999;",
"Dirac-Svejstrup",
"et",
"al.,",
"2000;",
"Lesa",
"et",
"al.,",
"2000).",
"The",
"network",
"of",
"interactions",
"between",
"these",
"proteins",
"may",
"be",
"regulated",
"by",
"the",
"rab",
"GTPases,",
"as",
"both",
"p115",
"and",
"GM130",
"have",
"been",
"shown",
"to",
"interact",
"with",
"the",
"active",
"or",
"GTP",
"form",
"of",
"rab1",
"(Allan",
"et",
"al.,",
"2000;",
"Moyer",
"et",
"al.,",
"2001;",
"Weide",
"et",
"al.,",
"2001).",
"Recruitment",
"of",
"p115",
"to",
"vesicles",
"destined",
"to",
"fuse",
"with",
"the",
"cis-Golgi",
"is",
"mediated",
"via",
"the",
"interaction",
"with",
"rab1",
"(Allan",
"et",
"al.,",
"2000),",
"whereas",
"the",
"consequences",
"of",
"rab1",
"binding",
"to",
"GM130",
"are",
"unknown.",
"A",
"second",
"GRASP",
"complex,",
"containing",
"GRASP55",
"and",
"the",
"coiled-coil",
"protein",
"golgin-45,",
"exists",
"in",
"Golgi",
"membranes",
"(Shorter",
"et",
"al.,",
"1999;",
"Short",
"et",
"al.,",
"2001).",
"Like",
"the",
"GRASP65–",
"GM130",
"complex,",
"this",
"complex",
"also",
"binds",
"a",
"rab",
"GTPase",
"and",
"is",
"required",
"for",
"the",
"maintenance",
"of",
"normal",
"Golgi",
"structure",
"and",
"protein",
"transport",
"(Short",
"et",
"al.,",
"2001).",
"In",
"addition",
"to",
"the",
"Golgi",
"matrix",
"proteins",
"discussed",
"above,",
"some",
"membrane",
"proteins",
"are",
"of",
"potential",
"importance",
"to",
"Golgi",
"structure.",
"One",
"such",
"group",
"is",
"the",
"medial-Golgi",
"enzymes,",
"found",
"to",
"specifically",
"bind",
"to",
"the",
"Golgi",
"matrix",
"although",
"the",
"mechanism",
"remains",
"uncharacterized",
"(Slusarewicz",
"et",
"al.,",
"885"
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"Paxton-Aiken",
"et",
"al.",
"International",
"Journal",
"of",
"Behavioral",
"Nutrition",
"and",
"Physical",
"Activity",
"2012,",
"9:30",
"http://www.ijbnpa.org/content/9/1/30",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"Open",
"Access",
"How",
"accurate",
"are",
"parental",
"responses",
"concerning",
"their",
"fourth-grade",
"children’s",
"school-meal",
"participation,",
"and",
"what",
"is",
"the",
"relationship",
"between",
"children’s",
"body",
"mass",
"index",
"and",
"school-",
"meal",
"participation",
"based",
"on",
"parental",
"responses?",
"Amy",
"E",
"Paxton-Aiken1*†,",
"Suzanne",
"Domel",
"Baxter1†,",
"Joshua",
"M",
"Tebbs2,",
"Christopher",
"J",
"Finney1,",
"Caroline",
"H",
"Guinn1",
"and",
"Julie",
"A",
"Royer1",
"Abstract",
"Background:",
"This",
"article",
"investigated",
"(1)",
"parental",
"response",
"accuracy",
"of",
"fourth-grade",
"children’s",
"school-meal",
"participation",
"and",
"whether",
"accuracy",
"differed",
"by",
"children’s",
"body",
"mass",
"index",
"(BMI),",
"sex,",
"and",
"race,",
"and",
"(2)",
"the",
"relationship",
"between",
"BMI",
"and",
"school-meal",
"participation",
"(based",
"on",
"parental",
"responses).",
"Methods:",
"Data",
"were",
"from",
"four",
"cross-sectional",
"studies",
"conducted",
"from",
"fall",
"1999",
"to",
"spring",
"2003",
"with",
"fourth-grade",
"children",
"from",
"13",
"schools",
"total.",
"Consent",
"forms",
"asked",
"parents",
"to",
"report",
"children’s",
"usual",
"school-meal",
"participation.",
"As",
"two",
"studies’",
"consent",
"forms",
"did",
"not",
"ask",
"about",
"lunch",
"participation,",
"complete",
"data",
"were",
"available",
"for",
"breakfast",
"on",
"1,496",
"children",
"(51%",
"Black;",
"49%",
"boys)",
"and",
"for",
"lunch",
"on",
"785",
"children",
"(46%",
"Black;",
"48%",
"boys).",
"Researchers",
"compiled",
"nametag",
"records",
"(during",
"meal",
"observations)",
"of",
"meal",
"participation",
"on",
"randomly",
"selected",
"days",
"during",
"children’s",
"fourth-grade",
"school",
"year",
"for",
"breakfast",
"(average",
"nametag",
"days",
"across",
"studies:",
"7-35)",
"and",
"for",
"lunch",
"(average",
"nametag",
"days",
"across",
"studies:",
"4-10)",
"and",
"categorized",
"participation",
"as",
"“usually”",
"(≥",
"50%",
"of",
"days)",
"or",
"“not",
"usually”",
"(<",
"50%",
"of",
"days).",
"Weight",
"and",
"height",
"were",
"measured.",
"Concerning",
"parental",
"response",
"accuracy,",
"marginal",
"regression",
"was",
"used",
"with",
"agreement",
"between",
"parental",
"responses",
"and",
"nametag",
"records",
"as",
"the",
"dependent",
"variable;",
"independent",
"variables",
"were",
"BMI,",
"age,",
"sex,",
"race,",
"and",
"study.",
"Concerning",
"a",
"relationship",
"between",
"BMI",
"and",
"school-meal",
"participation,",
"marginal",
"regression",
"was",
"used",
"with",
"BMI",
"as",
"the",
"dependent",
"variable;",
"independent",
"variables",
"were",
"breakfast",
"participation,",
"lunch",
"participation,",
"age,",
"sex,",
"race,",
"and",
"study.",
"Results:",
"Concerning",
"breakfast",
"participation",
"and",
"lunch",
"participation,",
"74%",
"and",
"92%",
"of",
"parents",
"provided",
"accurate",
"responses,",
"respectively.",
"Parental",
"response",
"accuracy",
"was",
"better",
"for",
"older",
"children",
"for",
"breakfast",
"and",
"lunch",
"participation,",
"and",
"for",
"Black",
"than",
"White",
"children",
"for",
"lunch",
"participation.",
"Usual",
"school-meal",
"participation",
"was",
"significantly",
"related",
"to",
"children’s",
"BMI",
"but",
"in",
"opposite",
"directions",
"–",
"positively",
"for",
"breakfast",
"and",
"inversely",
"for",
"lunch.",
"Conclusions:",
"Parental",
"response",
"accuracy",
"of",
"children’s",
"school-meal",
"participation",
"was",
"moderately",
"high;",
"however,",
"disparate",
"effects",
"for",
"children’s",
"age",
"and",
"race",
"warrant",
"caution",
"when",
"relying",
"on",
"parental",
"responses.",
"The",
"BMI",
"results,",
"which",
"showed",
"a",
"relationship",
"between",
"school-meal",
"participation",
"(based",
"on",
"parental",
"responses)",
"and",
"childhood",
"obesity,",
"conflict",
"with",
"results",
"from",
"a",
"recent",
"article",
"that",
"used",
"data",
"from",
"the",
"same",
"four",
"studies",
"and",
"found",
"no",
"significant",
"relationship",
"when",
"participation",
"was",
"based",
"on",
"nametag",
"records",
"compiled",
"for",
"meal",
"observations.",
"Keywords:",
"Children,",
"School,",
"Obesity,",
"School-meal",
"participation,",
"Parental",
"response",
"accuracy",
"*",
"Correspondence:",
"paxtonae@mailbox.sc.edu",
"†",
"Contributed",
"equally",
"1Institute",
"for",
"Families",
"in",
"Society,",
"University",
"of",
"South",
"Carolina,",
"1600",
"Hampton",
"Street,",
"Suite",
"507,",
"Columbia,",
"SC",
"29208,",
"USA",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"©",
"2012",
"Paxton-Aiken",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
] | [
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] | [
"Correspondence",
"The",
"Human",
"Gene",
"Mutation",
"Database:",
"2008",
"update",
"Peter",
"D",
"Stenson,",
"Matthew",
"Mort,",
"Edward",
"V",
"Ball,",
"Katy",
"Howells,",
"Andrew",
"D",
"Phillips,",
"Nick",
"ST",
"Thomas",
"and",
"David",
"N",
"Cooper",
"Address:",
"Institute",
"of",
"Medical",
"Genetics,",
"Cardiff",
"University,",
"Heath",
"Park,",
"Cardiff",
"CF14",
"4XN,",
"UK.",
"Correspondence:",
"David",
"N",
"Cooper.",
"Email:",
"cooperdn@cardiff.ac.uk",
"Published:",
"22",
"January",
"2009",
"Genome",
"Medicine",
"2009,",
"1:13",
"(doi:10.1186/gm13)",
"The",
"electronic",
"version",
"of",
"this",
"article",
"is",
"the",
"complete",
"one",
"and",
"can",
"be",
"found",
"online",
"at",
"http://genomemedicine.com/content/1/1/13",
"©",
"2009",
"BioMed",
"Central",
"Ltd",
"Abstract",
"The",
"Human",
"Gene",
"Mutation",
"Database",
"(HGMD®)",
"is",
"a",
"comprehensive",
"core",
"collection",
"of",
"germline",
"mutations",
"in",
"nuclear",
"genes",
"that",
"underlie",
"or",
"are",
"associated",
"with",
"human",
"inherited",
"disease.",
"Here,",
"we",
"summarize",
"the",
"history",
"of",
"the",
"database",
"and",
"its",
"current",
"resources.",
"By",
"December",
"2008,",
"the",
"database",
"contained",
"over",
"85,000",
"different",
"lesions",
"detected",
"in",
"3,253",
"different",
"genes,",
"with",
"new",
"entries",
"currently",
"accumulating",
"at",
"a",
"rate",
"exceeding",
"9,000",
"per",
"annum.",
"Although",
"originally",
"established",
"for",
"the",
"scientific",
"study",
"of",
"mutational",
"mechanisms",
"in",
"human",
"genes,",
"HGMD",
"has",
"since",
"acquired",
"a",
"much",
"broader",
"utility",
"for",
"researchers,",
"physicians,",
"clinicians",
"and",
"genetic",
"counselors",
"as",
"well",
"as",
"for",
"companies",
"specializing",
"in",
"biopharmaceuticals,",
"bioinformatics",
"and",
"personalized",
"genomics.",
"HGMD",
"was",
"first",
"made",
"publicly",
"available",
"in",
"April",
"1996,",
"and",
"a",
"collaboration",
"was",
"initiated",
"in",
"2006",
"between",
"HGMD",
"and",
"BIOBASE",
"GmbH.",
"This",
"cooperative",
"agreement",
"covers",
"the",
"exclusive",
"worldwide",
"marketing",
"of",
"the",
"most",
"up-to-date",
"(subscription)",
"version",
"of",
"HGMD,",
"HGMD",
"Professional,",
"to",
"academic,",
"clinical",
"and",
"commercial",
"users.",
"The",
"Human",
"Gene",
"Mutation",
"Database",
"(HGMD®)",
"[1]",
"records",
"the",
"first",
"report",
"of",
"a",
"disease-causing",
"mutation",
"or",
"disease-",
"associated/functional",
"polymorphism",
"and",
"provides",
"these",
"data",
"in",
"a",
"readily",
"accessible",
"form",
"to",
"all",
"interested",
"parties,",
"whether",
"they",
"are",
"from",
"an",
"academic,",
"a",
"clinical",
"or",
"a",
"commercial",
"background.",
"HGMD",
"has",
"become",
"the",
"de",
"facto",
"central",
"disease-associated",
"mutation",
"database",
"available",
"to",
"the",
"scientific",
"community.",
"The",
"data",
"comprise",
"single",
"base-pair",
"substitutions",
"in",
"coding,",
"regulatory",
"and",
"splicing-relevant",
"regions",
"of",
"human",
"nuclear",
"genes,",
"micro-deletions",
"and",
"micro-",
"insertions,",
"combined",
"insertions/deletions",
"(indels),",
"repeat",
"expansions,",
"gross",
"lesions",
"(deletions,",
"insertions",
"and",
"duplica-",
"tions)",
"and",
"complex",
"rearrangements",
"(including",
"inversions).",
"These",
"categories",
"of",
"mutation",
"data",
"are",
"summarized",
"in",
"Table",
"1.",
"Mutation",
"and",
"polymorphism",
"data",
"are",
"obtained",
"by",
"means",
"of",
"a",
"combination",
"of",
"manual",
"and",
"computerized",
"search",
"proce-",
"dures.",
"Thus,",
"online",
"library",
"screening,",
"the",
"PubMed",
"database",
"and",
"publicly",
"available",
"locus-specific",
"mutation",
"databases",
"(LSDBs)",
"are",
"all",
"used",
"to",
"optimize",
"data",
"acquisition.",
"Each",
"mutation",
"or",
"disease-associated/functional",
"polymorphism",
"is",
"entered",
"into",
"HGMD",
"only",
"once",
"under",
"its",
"earliest",
"literature",
"citation.",
"Silent",
"mutations",
"within",
"the",
"coding",
"region",
"that",
"do",
"not",
"alter",
"the",
"encoded",
"amino",
"acid",
"are",
"not",
"recorded",
"unless",
"there",
"is",
"clear",
"evidence",
"of",
"altered",
"splicing",
"and/or",
"a",
"direct",
"disease",
"association.",
"Mutations",
"that",
"have",
"not",
"been",
"ade-",
"quately",
"or",
"unambiguously",
"described",
"in",
"the",
"corresponding",
"literature",
"report",
"are",
"also",
"excluded",
"unless",
"full",
"details",
"can",
"sub-",
"sequently",
"be",
"obtained",
"from",
"the",
"authors.",
"Disease-associated/",
"functional",
"polymorphisms",
"(see",
"below)",
"are",
"excluded",
"if",
"the",
"published",
"data",
"are",
"deemed",
"to",
"be",
"of",
"insufficient",
"quality",
"(either",
"because",
"of",
"the",
"description",
"provided",
"or",
"because",
"of",
"a",
"tenuous/",
"non-significant",
"association",
"with",
"a",
"clinical",
"or",
"laboratory",
"phenotype).",
"HGMD",
"does",
"not",
"include",
"somatic",
"lesions",
"or",
"mitochondrial",
"genome",
"mutations.",
"These",
"are",
"well",
"covered",
"by",
"COSMIC",
"[2]",
"and",
"MITOMAP",
"[3],",
"respectively.",
"Mutation",
"data",
"are",
"viewable",
"on",
"a",
"gene-wise",
"basis",
"and",
"access",
"to",
"the",
"subcategorized",
"mutation",
"data",
"is",
"available",
"via",
"hyper-",
"text",
"link",
"from",
"each",
"gene",
"page.",
"Additional",
"links",
"to",
"Genome",
"Medicine",
"2009,",
"1:13"
] | [
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"D.",
"Amponsah",
"Æ",
"S.",
"A.",
"Dulchavsky",
"Published",
"online:",
"7",
"January",
"2009",
"The",
"Author(s)",
"2008.",
"This",
"article",
"is",
"published",
"with",
"open",
"access",
"at",
"Springerlink.com",
"Abstract",
"Snowboarding",
"has",
"become",
"a",
"popular",
"recrea-",
"tional",
"and",
"professional",
"sport.",
"Participants",
"suffer",
"a",
"variety",
"of",
"injuries,",
"especially",
"of",
"the",
"extremities,",
"that",
"require",
"medical",
"evaluation.",
"This",
"article",
"reviews",
"the",
"reported",
"inju-",
"ries",
"to",
"both",
"leisure",
"and",
"elite",
"athletes.",
"To",
"many,",
"an",
"injured",
"extremity",
"requires",
"travel",
"to",
"a",
"medical",
"facility",
"for",
"accurate",
"evaluation.",
"Musculoskeletal",
"ultrasound",
"is",
"an",
"accurate",
"and",
"portable",
"technology",
"that",
"can",
"be",
"used",
"for",
"real",
"time,",
"moun-",
"tainside",
"diagnoses",
"of",
"these",
"injuries.",
"Keywords",
"Mountainside",
"ultrasound",
"Remote",
"guidance",
"ultrasound",
"Snowboarding",
"injuries",
"Diagnostic",
"ultrasound",
"Mountainside",
"diagnostics",
"M.",
"R.",
"Nowak",
"(&)",
"Departments",
"of",
"Emergency",
"Medicine",
"and",
"Surgery,",
"Henry",
"Ford",
"Hospital,",
"Detroit,",
"MI,",
"USA",
"e-mail:",
"mnowak2@hfhs.org",
"A.",
"W.",
"Kirkpatrick",
"Regional",
"Trauma",
"Services,",
"Foothills",
"Medical",
"Center,",
"Calgary,",
"AB,",
"Canada",
"J.",
"A.",
"Bouffard",
"Department",
"of",
"Radiology,",
"Henry",
"Ford",
"Hospital,",
"Detroit,",
"MI,",
"USA",
"D.",
"Amponsah",
"Department",
"of",
"Emergency",
"Medicine,",
"Henry",
"Ford",
"Hospital,",
"Detroit,",
"MI,",
"USA",
"S.",
"A.",
"Dulchavsky",
"Department",
"of",
"Surgery,",
"Henry",
"Ford",
"Hospital,",
"Detroit,",
"MI,",
"USA",
"Introduction",
"Snowboarding",
"has",
"experienced",
"a",
"tremendous",
"growth",
"as",
"a",
"sport",
"over",
"the",
"years.",
"The",
"National",
"Sporting",
"Goods",
"Asso-",
"ciation",
"reported",
"6.6",
"million",
"snowboarders",
"participating",
"in",
"this",
"sport",
"in",
"2004.",
"To-date",
"there",
"has",
"not",
"been",
"a",
"careful",
"overall",
"review",
"of",
"the",
"medical",
"literature",
"to",
"summarize",
"the",
"injuries",
"sustained",
"by",
"these",
"individuals.",
"Snowboarding",
"is",
"physically",
"demanding",
"and",
"is",
"often",
"conducted",
"in",
"a",
"chal-",
"lenging",
"physical",
"environment",
"such",
"that",
"the",
"risks",
"of",
"serious",
"injury",
"or",
"even",
"death",
"are",
"real.",
"Reviews",
"of",
"snowboarding",
"injuries",
"from",
"around",
"the",
"world",
"have",
"demonstrated",
"head,",
"abdominal,",
"spinal,",
"and",
"extremity",
"trauma",
"to",
"be",
"the",
"most",
"frequent",
"serious,",
"and",
"occasionally",
"fatal,",
"injuries",
"sustained",
"[1–4].",
"Fortunately,",
"most",
"snow-boarding",
"injuries",
"are",
"not",
"life-threatening,",
"but",
"when",
"a",
"professional",
"or",
"leisure",
"snow-",
"boarder",
"suffers",
"a",
"potential",
"traumatic",
"injury,",
"it",
"can",
"be",
"extremely",
"challenging",
"for",
"a",
"non-physician",
"on-mountain",
"care-provider",
"to",
"make",
"the",
"correct",
"diagnosis.",
"This",
"is",
"because",
"of",
"the",
"limited",
"medical",
"knowledge",
"of",
"the",
"mountain",
"patrol",
"or",
"sports",
"trainers",
"and",
"the",
"lack",
"of",
"radiological",
"imaging",
"support.",
"Often",
"the",
"snowboarder",
"must",
"be",
"trans-",
"ported",
"to",
"a",
"local",
"hospital",
"or",
"to",
"a",
"specialty",
"clinic",
"for",
"additional",
"medical",
"assessments",
"[5].",
"Generally,",
"conditions",
"in",
"which",
"snowboarders",
"are",
"injured",
"preclude",
"the",
"ability",
"to",
"quickly",
"assess",
"injuries",
"using",
"imaging",
"techniques",
"such",
"as",
"magnetic",
"resonance",
"imaging",
"(MRI),",
"CAT",
"scans,",
"and",
"even",
"plain",
"radiographs.",
"As",
"many",
"snow-",
"boarding",
"facilities",
"are",
"located",
"in",
"relatively",
"remote",
"locations,",
"an",
"initial",
"accurate",
"diagnostic",
"assessment",
"would",
"be",
"critical",
"to",
"maximize",
"the",
"recovery",
"of",
"a",
"patient.",
"For",
"example,",
"in",
"the",
"case",
"of",
"an",
"individual",
"who",
"suffers",
"a",
"potential",
"joint",
"injury",
"of",
"unknown",
"severity,",
"the",
"decision",
"must",
"be",
"made",
"to",
"apply",
"first",
"aid",
"principles",
"(the",
"application",
"of",
"cold",
"and",
"elevation",
"to",
"the",
"affected",
"area,",
"anti-inflammatory",
"medications,",
"and",
"rest",
"for",
"a"
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] | [
"Hindawi",
"Publishing",
"Corporation",
"Mediators",
"of",
"Inflammation",
"Volume",
"2010,",
"Article",
"ID",
"498980,",
"9",
"pages",
"doi:10.1155/2010/498980",
"Review",
"Article",
"Targeting",
"Toll-Like",
"Receptors",
"for",
"Treatment",
"of",
"SLE",
"Christopher",
"G.",
"Horton,1,",
"2",
"Zi-jian",
"Pan,2",
"and",
"A.",
"Darise",
"Farris1,",
"2",
"1",
"Department",
"of",
"Microbiology",
"and",
"Immunology,",
"University",
"of",
"Oklahoma",
"Health",
"Sciences",
"Center,",
"Oklahoma",
"City,",
"OK",
"73104,",
"USA",
"2",
"Arthritis",
"and",
"Immunology",
"Program,",
"Oklahoma",
"Medical",
"Research",
"Foundation,",
"825",
"NE",
"13th",
"Street,",
"Oklahoma",
"City,",
"OK",
"73104,",
"USA",
"Correspondence",
"should",
"be",
"addressed",
"to",
"A.",
"Darise",
"Farris,",
"farrisd@omrf.org",
"Received",
"10",
"December",
"2009;",
"Accepted",
"24",
"August",
"2010",
"Academic",
"Editor:",
"Kathy",
"Triantafilou",
"Copyright",
"©",
"2010",
"Christopher",
"G.",
"Horton",
"et",
"al.",
"This",
"is",
"an",
"open",
"access",
"article",
"distributed",
"under",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Toll-like",
"receptors",
"(TLRs)",
"are",
"important",
"innate",
"immune",
"receptors",
"for",
"the",
"identification",
"and",
"clearance",
"of",
"invading",
"pathogens.",
"Twelve",
"TLRs",
"that",
"recognize",
"various",
"conserved",
"components",
"of",
"microorganisms",
"are",
"currently",
"known.",
"Among",
"these,",
"the",
"endosomal",
"TLRs",
"3,",
"7/8,",
"and",
"9",
"recognize",
"dsRNA,",
"ssRNA,",
"and",
"CpG",
"DNA,",
"respectively.",
"Nucleic",
"acid-sensing",
"TLRs,",
"TLR",
"7",
"in",
"particular,",
"have",
"been",
"implicated",
"in",
"systemic",
"lupus",
"erythematosus",
"(SLE)",
"and",
"are",
"thought",
"to",
"exacerbate",
"disease",
"pathology.",
"Activation",
"of",
"these",
"TLRs",
"results",
"in",
"the",
"production",
"of",
"inflammatory",
"cytokines",
"and",
"type",
"I",
"interferon.",
"Genome-wide",
"association",
"studies,",
"single",
"nucleotide",
"polymorphism",
"analyses",
"as",
"well",
"as",
"experimental",
"mouse",
"models",
"have",
"provided",
"evidence",
"of",
"TLR",
"signaling",
"involvement",
"in",
"SLE",
"and",
"other",
"autoimmune",
"diseases.",
"Since",
"activation",
"of",
"these",
"receptor",
"pathways",
"promotes",
"autoimmune",
"phenotypes,",
"inhibitory",
"drugs",
"that",
"target",
"these",
"pathways",
"constitute",
"important",
"new",
"therapeutic",
"strategies",
"for",
"the",
"treatment",
"of",
"systemic",
"autoimmunity.",
"1.",
"Introduction",
"Toll-like",
"receptors",
"(TLRs)",
"are",
"pattern",
"recognition",
"recep-",
"tors",
"of",
"the",
"innate",
"immune",
"system",
"that",
"recognize",
"specific",
"pathogen-associated",
"molecular",
"patterns",
"(PAMPs)",
"conserved",
"among",
"microorganisms.",
"There",
"are",
"currently",
"twelve",
"known",
"TLRs",
"in",
"mammals,",
"which",
"identify",
"common",
"constituents",
"of",
"invading",
"pathogens",
"including",
"double-stranded",
"and",
"single-stranded",
"RNA,",
"unmethylated",
"CpG",
"DNA,",
"bacterial",
"lipopolysaccharide",
"(LPS),",
"lipoproteins,",
"and",
"flagellin",
"[1].",
"Upon",
"interaction",
"with",
"their",
"ligands,",
"TLRs",
"signal",
"through",
"adapter",
"proteins,",
"most",
"commonly",
"Myeloid",
"Differentia-",
"tion",
"Primary",
"Response",
"Gene",
"88",
"(MyD88),",
"though",
"TLR",
"3",
"alternatively",
"signals",
"via",
"the",
"TIR-Domain",
"Containing",
"Adaptor",
"Inducing",
"Interferon-β",
"(TRIF)",
"adapter",
"[2].",
"These",
"adapters",
"recruit",
"other",
"molecules",
"to",
"initiate",
"signaling",
"cascades",
"ultimately",
"leading",
"to",
"the",
"production",
"of",
"proinflammatory",
"cytokines",
"and",
"type",
"I",
"IFN",
"[3].",
"These",
"TLR",
"responses",
"are",
"important",
"in",
"the",
"functioning",
"of",
"both",
"the",
"innate",
"and",
"adaptive",
"arms",
"of",
"immunity",
"[4,",
"5].",
"Although",
"TLRs",
"are",
"important",
"for",
"antimicrobial",
"immu-",
"nity,",
"they",
"have",
"also",
"been",
"implicated",
"in",
"the",
"pathogenesis",
"of",
"autoimmune",
"diseases.",
"For",
"example,",
"TLRs",
"2",
"and",
"4",
"have",
"been",
"identified",
"as",
"factors",
"involved",
"in",
"the",
"onset",
"of",
"type",
"I",
"diabetes",
"mellitus",
"[6–9],",
"and",
"TLRs",
"1–6",
"are",
"expressed",
"by",
"rheumatoid",
"arthritis",
"(RA)",
"synovial",
"fibroblasts",
"and",
"are",
"thought",
"to",
"provoke",
"joint",
"inflammation",
"in",
"RA",
"[10,",
"11].",
"Moreover,",
"the",
"nucleic",
"acid",
"binding",
"TLRs",
"7",
"and",
"9",
"have",
"been",
"connected",
"to",
"both",
"human",
"and",
"mouse",
"models",
"of",
"systemic",
"lupus",
"erythematosus",
"(SLE)",
"[12–17].",
"Because",
"of",
"these",
"links",
"between",
"TLRs",
"and",
"autoimmunity,",
"a",
"great",
"deal",
"of",
"work",
"has",
"been",
"directed",
"toward",
"understanding",
"how",
"these",
"receptors",
"act",
"in",
"disease",
"progression.",
"Two",
"major",
"possibilities",
"arise",
"in",
"describing",
"how",
"TLRs",
"might",
"work",
"in",
"autoimmunity;",
"either",
"they",
"are",
"stimulated",
"by",
"exogenous",
"antigens,",
"like",
"viral",
"ssRNA,",
"which",
"then",
"stimulate",
"resident",
"immune",
"cells,",
"or",
"the",
"TLRs",
"recognize",
"endogenous",
"self-antigens",
"to",
"initiate",
"and",
"propagate",
"inflammation",
"and",
"autoimmunity.",
"The",
"accumulation",
"of",
"evidence",
"pointing",
"towards",
"TLRs",
"in",
"autoimmunity",
"has",
"opened",
"the",
"door",
"for",
"potential",
"therapeutic",
"interventions",
"directed",
"towards",
"the",
"modulation",
"of",
"Toll-like",
"receptors",
"and",
"their",
"signaling",
"pathways.",
"Since",
"TLRs",
"are",
"normally",
"responsive",
"to",
"microbial",
"pathogens,",
"there",
"has",
"been",
"some",
"speculation",
"as",
"to",
"the",
"application",
"of",
"TLR",
"agonists",
"as",
"vaccine",
"adjuvants",
"to",
"stimulate",
"more",
"robust",
"immune",
"responses",
"[18,",
"19].",
"On",
"the",
"other",
"side",
"of",
"the",
"spectrum,",
"for",
"autoimmunity,",
"disease",
"can",
"result",
"from",
"aberrant",
"hyperac-",
"tive",
"signaling;",
"therefore,",
"the",
"application",
"of",
"inhibitory,",
"or"
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] | [
"Hematology",
"Reports",
"2012;",
"volume",
"4:e3",
"Immunophenotyping",
"of",
"chronic",
"B-cell",
"neoplasms:",
"flow",
"cytometry",
"versus",
"immunohistochemistry",
"Afaf",
"Abdel-Aziz",
"Abdel-Ghafar,",
"Manal",
"Ahmed",
"Shams",
"El",
"Din",
"El",
"Telbany,",
"Hanan",
"Mohamed",
"Mahmoud,",
"Yasmin",
"Nabil",
"El-Sakhawy",
"Clinical",
"and",
"Chemical",
"Pathology,",
"Faculty",
"of",
"Medicine,",
"Ain",
"Shams",
"University,",
"Cairo,",
"Egypt",
"Abstract",
"Morphological",
"differentiation",
"between",
"benign",
"and",
"malignant",
"lymphoproliferative",
"disorders",
"(LPDs)",
"can",
"be",
"challenging.",
"Immunophenotyping",
"(IPT)",
"by",
"either",
"technique,",
"flow",
"cytometry",
"or",
"immunohistochemistry",
"(IHC),",
"is",
"an",
"important",
"step",
"in",
"solving",
"such",
"difficulty.",
"Thirty-five",
"newly",
"diagnosed",
"patients",
"with",
"chronic",
"B-cell",
"neo-",
"plasms",
"(11",
"chronic",
"lymphocytic",
"leukemia,",
"22",
"non",
"Hodgkin",
"lymphoma",
"and",
"2",
"hairy",
"cell",
"leukemia)",
"were",
"included",
"in",
"this",
"study",
"with",
"age",
"range",
"from",
"20",
"to",
"70",
"years.",
"Monoclonal",
"antibodies",
"surface",
"expression",
"using",
"lymphoproliferative",
"disorders",
"panel",
"(CD45,",
"CD19,",
"CD5,",
"CD10,",
"CD11c,",
"CD20,",
"CD22,",
"CD23,",
"CD38,",
"CD79b,",
"FMC7,",
"CD103,",
"CD25,",
"kappa",
"and",
"lambda",
"light",
"chains)",
"by",
"flow",
"cytometry",
"was",
"done",
"on",
"bone",
"marrow",
"samples.",
"CD20,",
"CD5,",
"CD23,",
"Bcl-2,",
"Bcl-6,",
"kappa",
"and",
"lambda",
"light",
"chain",
"immunostaining",
"were",
"performed",
"on",
"fixed",
"bone",
"marrow",
"trephine",
"biopsy",
"specimen.",
"The",
"sensitiv-",
"ity",
"of",
"IHC",
"was",
"81.8%",
"in",
"chronic",
"lymphocytic",
"leukemia",
"(CLL)",
"and",
"100%",
"in",
"non",
"Hodgkin",
"lym-",
"phoma",
"(NHL)",
"as",
"regards",
"CD20,",
"100%",
"in",
"both",
"groups",
"as",
"regards",
"CD5,",
"46%",
"in",
"CLL",
"and",
"66.7%",
"in",
"NHL",
"as",
"regards",
"CD23,",
"33.3%",
"in",
"CLL",
"and",
"50%",
"in",
"NHL",
"as",
"regards",
"kappa",
"chain,",
"20%",
"in",
"CLL",
"and",
"33.3%",
"in",
"NHL",
"as",
"regards",
"lambda",
"chain.",
"We",
"found",
"that",
"IHC",
"and",
"flow",
"cytometry",
"are",
"equally",
"effective",
"in",
"diagnosing",
"CLL;",
"however,",
"IHC",
"might",
"be",
"slight-",
"ly",
"more",
"sensitive",
"than",
"flow",
"cytometry",
"in",
"detect-",
"ing",
"bone",
"marrow",
"infiltration",
"in",
"NHL",
"and",
"hairy",
"cell",
"leukemia",
"(HCL).",
"Introduction",
"Distinguishing",
"benign",
"and",
"malignant",
"lympho-",
"proliferative",
"disorders",
"(LPDs)",
"by",
"purely",
"morpho-",
"logic",
"criteria",
"can",
"be",
"difficult.",
"Immunophenotypic",
"analysis",
"is",
"a",
"useful",
"adjunct",
"to",
"the",
"morphologic",
"evaluation",
"of",
"LPDs",
"and",
"is",
"of",
"considerable",
"assis-",
"tance",
"in",
"resolving",
"difficult",
"diagnostic",
"dilemmas.",
"The",
"advent",
"of",
"immunophenotyping",
"(IPT)",
"of",
"sam-",
"ples",
"from",
"patients",
"with",
"LPDs",
"has",
"added",
"much",
"for",
"[page",
"6]",
"proper",
"diagnosis",
"and",
"classification",
"and",
"for",
"better",
"understanding",
"of",
"the",
"pathogenetic",
"mechanisms",
"underlying",
"the",
"development",
"of",
"these",
"disorders.1",
"There",
"are",
"several",
"ways",
"for",
"testing",
"cell",
"mark-",
"ers,",
"such",
"as",
"flow",
"cytometry",
"in",
"which",
"suspensions",
"of",
"viable",
"or",
"fixed",
"cells",
"are",
"tested,",
"and",
"immuno-",
"histochemistry",
"which",
"studies",
"cells",
"in",
"frozen",
"or",
"paraffin-embedded",
"sections",
"from",
"bone",
"marrow",
"biopsy",
"specimens",
"or",
"other",
"hemopoietic",
"tissues.2",
"In",
"immunohistochemistry",
"(IHC),",
"morphology",
"and",
"antigen",
"label",
"can",
"be",
"visualized",
"simultane-",
"ously",
"by",
"light",
"microscopy",
"which",
"is",
"not",
"the",
"case",
"in",
"flow",
"cytometry,",
"enabling",
"accurate",
"identification",
"of",
"the",
"cells",
"or",
"region",
"of",
"interest.3",
"It",
"is",
"considered",
"more",
"suitable",
"in",
"the",
"detection",
"of",
"partial",
"or",
"focal",
"involvement",
"by",
"neoplastic",
"cells",
"and",
"it",
"is",
"also",
"more",
"beneficial",
"in",
"nuclear",
"antigen",
"assessment.4",
"Another",
"privilege",
"of",
"IHC",
"is",
"the",
"long-term",
"preser-",
"vation",
"of",
"the",
"biological",
"specimen",
"after",
"process-",
"ing",
"and",
"the",
"ability",
"to",
"re-examine",
"it",
"at",
"any",
"time.5",
"The",
"aim",
"of",
"this",
"study",
"was",
"to",
"to",
"identify",
"the",
"diagnostic",
"role",
"of",
"IHC",
"in",
"chronic",
"B-cell",
"neo-",
"plasms",
"using",
"a",
"selected",
"panel",
"of",
"monoclonal",
"antibodies",
"and",
"to",
"compare",
"this",
"role",
"to",
"that",
"of",
"flow",
"cytometry.",
"Materials",
"and",
"Methods",
"Subjects",
"This",
"study",
"comprised",
"35",
"newly",
"diagnosed",
"chronic",
"B-cell",
"neoplasms",
"adult",
"patients",
"attend-",
"ing",
"the",
"hematological",
"unit",
"of",
"clinical",
"pathology",
"department,",
"Ain",
"Shams",
"University,",
"Cairo,",
"Egypt.",
"Patients",
"were",
"recruited",
"to",
"the",
"study",
"on",
"the",
"basis",
"of",
"clinical,",
"laboratory,",
"bone",
"marrow",
"aspirate",
"and",
"trephine",
"biopsy",
"findings",
"and",
"immunophenotypic",
"criteria",
"of",
"chronic",
"B-cell",
"neoplasms.",
"Sometimes",
"lymph",
"nodes",
"biopsy",
"results",
"were",
"provided",
"to",
"con-",
"firm",
"the",
"diagnosis.",
"They",
"were",
"22",
"males",
"and",
"13",
"females",
"with",
"a",
"male",
"to",
"female",
"ratio",
"1.7:1.0.",
"Their",
"ages",
"ranged",
"from",
"20",
"to",
"70",
"years",
"old",
"with",
"mean",
"of",
"51",
"±",
"15.2",
"years.",
"The",
"35",
"patients",
"were",
"divided",
"into",
"3",
"groups:",
"chronic",
"lymphocytic",
"leukemia",
"(CLL)",
"group",
"(11",
"patients),",
"non",
"Hodgkin",
"lymphoma",
"(NHL)",
"group",
"(22",
"patients)",
"and",
"hairy",
"cell",
"leukemia",
"(HCL)",
"group",
"(2",
"patients).",
"The",
"22",
"NHL",
"cases",
"comprised",
"8",
"mantle",
"cell",
"lymphomas,",
"6",
"follicular",
"lymphomas,",
"5",
"diffuse",
"large",
"B-cell",
"lymphomas",
"and",
"3",
"Burkitt’s",
"lymphomas.",
"Patients",
"were",
"subjected",
"to",
"clinical",
"sheet",
"details",
"(with",
"special",
"concern",
"to",
"organomegaly,",
"lymphadenopathy,",
"fever",
"and",
"weight",
"loss),",
"com-",
"plete",
"blood",
"count",
"with",
"examination",
"of",
"peripheral",
"blood",
"smears",
"stained",
"with",
"Leishman",
"stain,",
"bone",
"marrow",
"aspiration,",
"bone",
"marrow",
"trephine",
"biop-",
"sy,",
"flow",
"cytometric",
"immunophenotyping",
"for",
"cases",
"in",
"leukemic",
"phase",
"using",
"lymphoproliferative",
"dis-",
"orders",
"panel",
"(CD45,",
"CD19,",
"CD5,",
"CD10,",
"CD11c,",
"CD20,",
"CD22,",
"CD23,",
"CD38,",
"CD79b,",
"FMC7,",
"CD103,",
"CD25,",
"kappa",
"and",
"lambda",
"light",
"chains).",
"CD20,",
"CD5,",
"CD23,",
"Bcl-2,",
"Bcl-6,",
"kappa",
"and",
"lambda",
"light",
"[Hematology",
"Reports",
"2012;",
"4:e3]",
"Correspondence:",
"Yasmin",
"Nabil,",
"Clinical",
"and",
"Chemical",
"Pathology,",
"Faculty",
"of",
"Medicine,",
"Ain",
"Shams",
"University,",
"El",
"Abbassia",
"Square,",
"Cairo,",
"Egypt.",
"Tel.",
"+20.224.845.802",
"-",
"Fax:",
"+20.224.845.802.",
"E-mail:",
"yasminnabil@hotmail.com",
"Key",
"words:",
"chronic",
"B-",
"LPD,",
"immunohistochem-",
"istry,",
"immunophenotyping.",
"Received",
"for",
"publication:",
"26",
"August",
"2011.",
"Revision",
"received:",
"4",
"November",
"2011.",
"Accepted",
"for",
"publication:",
"22",
"December",
"2011.",
"This",
"work",
"is",
"licensed",
"under",
"a",
"Creative",
"Commons",
"Attribution",
"NonCommercial",
"3.0",
"License",
"(CC",
"BY-",
"NC",
"3.0).",
"©Copyright",
"A.A.A.",
"Abdel-Ghafar",
"et",
"al.,",
"2012",
"Licensee",
"PAGEPress,",
"Italy",
"Hematology",
"Reports",
"2012;",
"4:e3",
"doi:10.4081/hr.2012.e3",
"chain",
"immunostaining",
"was",
"performed",
"on",
"fixed",
"bone",
"marrow",
"trephine",
"biopsy",
"specimen.",
"Specimens",
"Two",
"milliliters",
"peripheral",
"blood",
"samples",
"were",
"collected",
"in",
"a",
"sterile",
"ethylene-diamine-tetra-",
"acetic",
"acid",
"(EDTA)",
"containing",
"vaccutainers",
"for",
"CBC.",
"Bone",
"marrow",
"(BM)",
"aspiration",
"was",
"with-",
"drawn;",
"the",
"first",
"few",
"drops",
"were",
"spread",
"on",
"glass",
"slides",
"for",
"morphological",
"examination",
"and",
"1",
"mL",
"into",
"sterile",
"EDTA",
"containing",
"vacutainers",
"for",
"IPT.",
"For",
"IPT",
"by",
"flow",
"cytometry",
"samples",
"were",
"processed",
"within",
"24",
"hours.",
"BM",
"trephine",
"core",
"biopsy",
"was",
"obtained",
"and",
"transferred",
"immediate-",
"ly",
"in",
"a",
"sterile",
"plastic",
"cup",
"containing",
"aldehyde",
"solution",
"as",
"a",
"fixative.",
"Methods",
"Flow",
"cytometry",
"Samples",
"were",
"processed",
"using",
"whole",
"blood",
"lysis",
"method",
"and",
"analysis",
"was",
"done",
"using",
"4",
"colour",
"flow",
"cytometric",
"analyzer",
"(Coulter",
"EPICS-",
"XL",
"flow",
"cytometer",
"with",
"system",
"II",
"software)",
"USA.",
"FCM",
"quality",
"control",
"including",
"alignment,",
"calibra-",
"tion,",
"and",
"color",
"compensation",
"was",
"performed",
"before",
"sample",
"acquisition",
"according",
"to",
"manufac-",
"turer’s",
"instructional",
"manual.",
"Samples",
"were",
"dilut-",
"ed",
"1:1",
"with",
"phosphate",
"buffered-saline",
"(PBS),",
"pH",
"7.4",
"(Sigma",
"Chemicals,",
"St",
"Louis).",
"The",
"final",
"cell",
"count",
"suspension",
"was",
"adjusted",
"between",
"5",
"and",
"10¥109/L:",
"50",
"uL",
"of",
"each",
"sample",
"was",
"pipetted",
"in",
"two",
"tubes",
"(one",
"test",
"tube",
"and",
"one",
"control",
"tube);",
"5",
"uL",
"of",
"MoAbs",
"fluorescin",
"isothiocyanate",
"(FITC),",
"or",
"phycoerythrin",
"(PE)",
"labeled",
"(Provided",
"by",
"Coulter",
"electronics,",
"USA)",
"were",
"added",
"to",
"the",
"test",
"tube",
"while",
"5",
"uL",
"of",
"isotype",
"matched",
"conjugated",
"Igs",
"to",
"determine",
"the",
"non",
"specific",
"binding",
"were",
"added",
"to",
"the",
"control",
"tube.",
"Tubes",
"were",
"gently",
"vortexed",
"and",
"incubated",
"15",
"min",
"at",
"room",
"temperature",
"in",
"the",
"dark.",
"One",
"mL",
"lysing",
"solution",
"was",
"added",
"to",
"each"
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926
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] | [
"Szatmári",
"et",
"al.",
"Critical",
"Care",
"2010,",
"14:R50",
"http://ccforum.com/content/14/2/R50",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"Open",
"Access",
"IRmeseaprcahired",
"cerebrovascular",
"reactivity",
"in",
"sepsis-associated",
"encephalopathy",
"studied",
"by",
"acetazolamide",
"test",
"Szilárd",
"Szatmári1,",
"Tamás",
"Végh1,",
"Ákos",
"Csomós2,",
"Judit",
"Hallay1,",
"István",
"Takács3,",
"Csilla",
"Molnár1",
"and",
"Béla",
"Fülesdi*1",
"Abstract",
"Introduction:",
"The",
"pathophysiology",
"of",
"sepsis-associated",
"encephalopathy",
"(SAE)",
"is",
"not",
"entirely",
"clear.",
"One",
"of",
"the",
"possible",
"underlying",
"mechanisms",
"is",
"the",
"alteration",
"of",
"the",
"cerebral",
"microvascular",
"function",
"induced",
"by",
"the",
"systemic",
"inflammation.",
"The",
"aim",
"of",
"the",
"present",
"work",
"was",
"to",
"test",
"whether",
"cerebral",
"vasomotor-reactivity",
"is",
"impaired",
"in",
"patients",
"with",
"SAE.",
"Methods:",
"Patients",
"fulfilling",
"the",
"criteria",
"of",
"clinical",
"sepsis",
"and",
"showing",
"disturbance",
"of",
"consciousness",
"of",
"any",
"severity",
"were",
"included",
"(n",
"=",
"14).",
"Non-septic",
"persons",
"whithout",
"previous",
"diseases",
"affecting",
"cerebral",
"vasoreactivity",
"served",
"as",
"controls",
"(n",
"=",
"20).",
"Transcranial",
"Doppler",
"blood",
"flow",
"velocities",
"were",
"measured",
"at",
"rest",
"and",
"at",
"5,",
"10,",
"15",
"and",
"20",
"minutes",
"after",
"intravenous",
"administration",
"of",
"15",
"mg/kgBW",
"acetazolamide.",
"The",
"time",
"course",
"of",
"the",
"acetazolamide",
"effect",
"on",
"cerebral",
"blood",
"flow",
"velocity",
"(cerebrovascular",
"reactivity,",
"CVR)",
"and",
"the",
"maximal",
"vasodilatory",
"effect",
"of",
"acetazolemide",
"(cerebrovascular",
"reserve",
"capacity,",
"CRC)",
"were",
"compared",
"among",
"the",
"groups.",
"Results:",
"Absolute",
"blood",
"flow",
"velocities",
"after",
"adminsitration",
"of",
"the",
"vasodilator",
"drug",
"were",
"higher",
"among",
"control",
"subjects",
"than",
"in",
"SAE.",
"Assessment",
"of",
"the",
"time-course",
"of",
"the",
"vasomotor",
"reaction",
"showed",
"that",
"patients",
"with",
"SAE",
"reacted",
"slower",
"to",
"the",
"vasodilatory",
"stimulus",
"than",
"control",
"persons.",
"When",
"assessing",
"the",
"maximal",
"vasodilatory",
"ability",
"of",
"the",
"cerebral",
"arterioles",
"to",
"acetazolamide",
"during",
"vasomotor",
"testing,",
"we",
"found",
"that",
"patients",
"with",
"SAE",
"reacted",
"to",
"a",
"lesser",
"extent",
"to",
"the",
"drug",
"than",
"did",
"control",
"subjects",
"(CRC",
"controls:46.2",
"±",
"15.9%,",
"CRC",
"SAE:",
"31,5",
"±",
"15.8%,",
"P",
"<",
"0.01).",
"Conclusions:",
"We",
"conclude",
"that",
"cerebrovascular",
"reactivity",
"is",
"impaired",
"in",
"patients",
"with",
"SAE.",
"The",
"clinical",
"significance",
"of",
"this",
"pathophysiological",
"finding",
"has",
"to",
"be",
"assessed",
"in",
"further",
"studies.",
"Introduction",
"Sepsis-associated",
"encephalopathy",
"is",
"defined",
"as",
"a",
"diffuse",
"cerebral",
"dysfunction",
"induced",
"by",
"the",
"systemic",
"response",
"to",
"the",
"infection",
"without",
"clinical",
"or",
"laboratory",
"evidence",
"of",
"direct",
"infectious",
"involvement",
"of",
"the",
"central",
"nervous",
"sys-",
"tem",
"[1].",
"Previous",
"clinical",
"observations",
"have",
"shown",
"that",
"the",
"brain",
"is",
"often",
"the",
"first",
"organ",
"to",
"be",
"affected",
"by",
"sepsis,",
"preceeding",
"the",
"clinical",
"symptoms",
"of",
"other",
"organ",
"manifes-",
"tations.",
"According",
"to",
"the",
"studies",
"of",
"Wilson",
"and",
"col-",
"leagues",
"and",
"Young",
"and",
"colleagues,",
"electroencephalogram",
"(EEG)",
"may",
"be",
"abnormal",
"in",
"87%",
"of",
"patients",
"with",
"bacteri-",
"emia.",
"They",
"diagnosed",
"70%",
"with",
"disturbance",
"of",
"con-",
"sciousness",
"of",
"differing",
"severity",
"ranging",
"from",
"somnolence",
"*",
"Correspondence:",
"fulesdi@dote.hu",
"1",
"Department",
"of",
"Anesthesiology",
"and",
"Intensive",
"Care,",
"University",
"of",
"Debrecen,",
"Health",
"and",
"Medical",
"Science",
"Center,",
"H-4032.",
"Debrecen,",
"Nagyerdei",
"krt.",
"98,",
"Hungary",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"to",
"coma",
"[1-3].",
"Ebersoldt",
"and",
"colleagues,",
"reviewing",
"sepsis-",
"associated",
"delirium,",
"reported",
"on",
"a",
"prevalence",
"ranging",
"from",
"9",
"to",
"71%",
"[4].",
"The",
"exact",
"pathomechanism",
"involved",
"is",
"not",
"yet",
"fully",
"understood.",
"It",
"is",
"believed",
"that",
"microcircula-",
"tory",
"alterations,",
"disturbance",
"of",
"cerebral",
"autoregulation,",
"damage",
"of",
"the",
"blood-brain",
"barrier,",
"branched",
"chain/aro-",
"matic",
"amino",
"acid",
"inbalance",
"and",
"the",
"direct",
"effect",
"of",
"the",
"inflammatory",
"process",
"(e.g.",
"free",
"radicals,",
"oxydative",
"stress,",
"cytokines,",
"excitotoxicity",
"apoptosis)",
"on",
"glial",
"cells",
"may",
"play",
"a",
"decisive",
"role.",
"Sepsis-related",
"encephalopathy",
"is",
"most",
"likely",
"to",
"be",
"a",
"multifactorially",
"determined",
"syndrome",
"[5].",
"When",
"assessing",
"cerebral",
"microvascular",
"contributing",
"factors,",
"in",
"previous",
"human",
"investigations",
"Matta",
"and",
"Stow",
"[6]",
"found",
"cerebral",
"autoregulation",
"and",
"carbon",
"dioxide",
"reactivity",
"to",
"be",
"normal",
"in",
"patients",
"with",
"sepsis,",
"whereas",
"Terborg",
"and",
"colleagues",
"reported",
"on",
"severely",
"disturbed",
"vasomotor",
"reactivity",
"(VMR)",
"[7].",
"In",
"the",
"past",
"two",
"decades,",
"©",
"2010",
"Szatmári",
"et",
"al.;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"open",
"access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"BioMed",
"Central",
"Attribution",
"License",
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] | [
"Lünsdorf",
"et",
"al.",
"Microbial",
"Cell",
"Factories",
"2011,",
"10:48",
"http://www.microbialcellfactories.com/content/10/1/48",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"Open",
"Access",
"Virus-like",
"particle",
"production",
"with",
"yeast:",
"ultrastructural",
"and",
"immunocytochemical",
"insights",
"into",
"Pichia",
"pastoris",
"producing",
"high",
"levels",
"of",
"the",
"Hepatitis",
"B",
"surface",
"antigen",
"Heinrich",
"Lünsdorf1,",
"Chandrasekhar",
"Gurramkonda2,3,",
"Ahmad",
"Adnan2,4,",
"Navin",
"Khanna3",
"and",
"Ursula",
"Rinas2,5*",
"Abstract",
"Background:",
"A",
"protective",
"immune",
"response",
"against",
"Hepatitis",
"B",
"infection",
"can",
"be",
"obtained",
"through",
"the",
"administration",
"of",
"a",
"single",
"viral",
"polypeptide,",
"the",
"Hepatitis",
"B",
"surface",
"antigen",
"(HBsAg).",
"Thus,",
"the",
"Hepatitis",
"B",
"vaccine",
"is",
"generated",
"through",
"the",
"utilization",
"of",
"recombinant",
"DNA",
"technology,",
"preferentially",
"by",
"using",
"yeast-based",
"expression",
"systems.",
"However,",
"the",
"polypeptide",
"needs",
"to",
"assemble",
"into",
"spherical",
"particles,",
"so-called",
"virus-like",
"particles",
"(VLPs),",
"to",
"elicit",
"the",
"required",
"protective",
"immune",
"response.",
"So",
"far,",
"no",
"clear",
"evidence",
"has",
"been",
"presented",
"showing",
"whether",
"HBsAg",
"assembles",
"in",
"vivo",
"inside",
"the",
"yeast",
"cell",
"into",
"VLPs",
"or",
"later",
"in",
"vitro",
"during",
"down-stream",
"processing",
"and",
"purification.",
"Results:",
"High",
"level",
"production",
"of",
"HBsAg",
"was",
"carried",
"out",
"with",
"recombinant",
"Pichia",
"pastoris",
"using",
"the",
"methanol",
"inducible",
"AOX1",
"expression",
"system.",
"The",
"recombinant",
"vaccine",
"was",
"isolated",
"in",
"form",
"of",
"VLPs",
"after",
"several",
"down-",
"stream",
"steps",
"from",
"detergent-treated",
"cell",
"lysates.",
"Search",
"for",
"the",
"intracellular",
"localization",
"of",
"the",
"antigen",
"using",
"electron",
"microscopic",
"studies",
"in",
"combination",
"with",
"immunogold",
"labeling",
"revealed",
"the",
"presence",
"of",
"HBsAg",
"in",
"an",
"extended",
"endoplasmic",
"reticulum",
"where",
"it",
"was",
"found",
"to",
"assemble",
"into",
"defined",
"multi-layered,",
"lamellar",
"structures.",
"The",
"distance",
"between",
"two",
"layers",
"was",
"determined",
"as",
"~6",
"nm",
"indicating",
"that",
"these",
"lamellas",
"represent",
"monolayers",
"of",
"well-ordered",
"HBsAg",
"subunits.",
"We",
"did",
"not",
"find",
"any",
"evidence",
"for",
"the",
"presence",
"of",
"VLPs",
"within",
"the",
"endoplasmic",
"reticulum",
"or",
"other",
"parts",
"of",
"the",
"yeast",
"cell.",
"Conclusions:",
"It",
"is",
"concluded",
"that",
"high",
"level",
"production",
"and",
"intrinsic",
"slow",
"HBsAg",
"VLP",
"assembly",
"kinetics",
"are",
"leading",
"to",
"retention",
"and",
"accumulation",
"of",
"the",
"antigen",
"in",
"the",
"endoplasmic",
"reticulum",
"where",
"it",
"assembles",
"at",
"least",
"partly",
"into",
"defined",
"lamellar",
"structures.",
"Further",
"transport",
"of",
"HBsAg",
"to",
"the",
"Golgi",
"apparatus",
"is",
"impaired",
"thus",
"leading",
"to",
"secretory",
"pathway",
"disfunction",
"and",
"the",
"formation",
"of",
"an",
"extended",
"endoplasmic",
"reticulum",
"which",
"bulges",
"into",
"irregular",
"cloud-",
"shaped",
"formations.",
"As",
"VLPs",
"were",
"not",
"found",
"within",
"the",
"cells",
"it",
"is",
"concluded",
"that",
"the",
"VLP",
"assembly",
"process",
"must",
"take",
"place",
"during",
"down-stream",
"processing",
"after",
"detergent-mediated",
"disassembly",
"of",
"HBsAg",
"lamellas",
"and",
"subsequent",
"reassembly",
"of",
"HBsAg",
"into",
"spherical",
"VLPs.",
"Background",
"Unlike",
"many",
"other",
"vaccines",
"against",
"virus-caused",
"diseases,",
"a",
"single",
"viral",
"polypeptide",
"is",
"sufficient",
"to",
"elicit",
"a",
"protecting",
"immune",
"response",
"against",
"Hepatitis",
"B",
"infection",
"[1].",
"However,",
"the",
"polypeptide",
"needs",
"to",
"assemble",
"into",
"spherical",
"particles,",
"so-called",
"virus-like",
"particles",
"(VLPs),",
"*",
"Correspondence:",
"Ursula.Rinas@helmholtz-hzi.de",
"2Helmholtz",
"Centre",
"for",
"Infection",
"Research",
"(SB),",
"Braunschweig,",
"Germany",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"to",
"initiate",
"the",
"required",
"protective",
"immune",
"response",
"[2].",
"In",
"HBV",
"infected",
"individuals,",
"viral",
"surface",
"proteins",
"are",
"produced",
"in",
"large",
"excess",
"in",
"liver",
"cells",
"over",
"the",
"amount",
"needed",
"for",
"virus",
"assembly",
"and",
"are",
"secreted",
"as",
"a",
"mixture",
"of",
"spherical",
"particles",
"and",
"tubular",
"forms.",
"Thus,",
"in",
"the",
"serum",
"of",
"HBV",
"infected",
"patients,",
"intact",
"viruses",
"(Dane",
"particles)",
"but",
"also",
"“empty”",
"spherical",
"particles",
"and",
"tubu-",
"lar",
"forms",
"consisting",
"of",
"the",
"surface",
"proteins",
"of",
"the",
"Hepa-",
"titis",
"B",
"virus",
"are",
"found",
"[3,4].",
"©",
"2011",
"Lünsdorf",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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] | [
"BMC",
"Medical",
"Education",
"Research",
"article",
"An",
"interactive",
"course",
"to",
"enhance",
"self-efficacy",
"of",
"family",
"practitioners",
"to",
"treat",
"obesity",
"Sara",
"Katz*1,",
"Amiel",
"Feigenbaum2,",
"Shmuel",
"Pasternak3",
"and",
"Shlomo",
"Vinker2",
"Address:",
"1Technion",
"–",
"Israel",
"Institute",
"of",
"Technology",
"–",
"Faculty",
"of",
"Medicine,",
"Haifa,",
"Israel,",
"2Department",
"of",
"Family",
"Medicine,",
"Sackler",
"School",
"of",
"Medicine,",
"Tel",
"Aviv",
"University,",
"Israel",
"and",
"3General",
"Health",
"Services,",
"Holon,",
"Israel",
"Email:",
"Sara",
"Katz*",
"-",
"sara1@tx.technion.ac.il;",
"Amiel",
"Feigenbaum",
"-",
"amielfe@netvision.net.il;",
"Shmuel",
"Pasternak",
"-",
"amielfe@netvision.net.il;",
"Shlomo",
"Vinker",
"-",
"vinker01@zahav.net.il",
"*",
"Corresponding",
"author",
"BioMed",
"Central",
"Open",
"Access",
"Published:",
"29",
"January",
"2005",
"BMC",
"Medical",
"Education",
"2005,",
"5:4",
"doi:10.1186/1472-6920-5-4",
"This",
"article",
"is",
"available",
"from:",
"http://www.biomedcentral.com/1472-6920/5/4",
"Received:",
"05",
"July",
"2004",
"Accepted:",
"29",
"January",
"2005",
"©",
"2005",
"Katz",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Abstract",
"Background:",
"Physicians'",
"awareness",
"of",
"their",
"important",
"role",
"in",
"defusing",
"the",
"obesity",
"epidemic",
"has",
"increased.",
"However,",
"the",
"number",
"of",
"family",
"practitioners",
"who",
"treat",
"obesity",
"problems",
"continues",
"to",
"be",
"low.",
"Self-efficacy",
"refers",
"to",
"the",
"belief",
"in",
"one's",
"ability",
"to",
"organize",
"and",
"execute",
"the",
"courses",
"of",
"action",
"required",
"to",
"produce",
"given",
"attainments.",
"Thus,",
"practitioners",
"who",
"judge",
"themselves",
"incapable",
"of",
"managing",
"obesity",
"do",
"not",
"even",
"try.",
"We",
"hypothesized",
"that",
"practitioners'",
"self-efficacy",
"and",
"motivation",
"would",
"be",
"enhanced",
"as",
"a",
"result",
"of",
"participating",
"in",
"an",
"interactive",
"course",
"designed",
"to",
"enrich",
"their",
"knowledge",
"of",
"obesity",
"management.",
"Methods:",
"Twenty-nine",
"family",
"practitioners",
"participated",
"in",
"the",
"course,",
"which",
"was",
"accompanied",
"by",
"qualitative",
"interviews.",
"The",
"difference",
"between",
"the",
"physicians'",
"pre-course",
"and",
"post-course",
"appraisals",
"was",
"tested",
"by",
"paired",
"t-test.",
"The",
"interviews",
"were",
"analyzed",
"by",
"qualitative",
"methods.",
"Results:",
"Post-course",
"efficacy",
"appraisals",
"were",
"significantly",
"higher",
"than",
"pre-course",
"appraisals",
"(p",
"<",
"0.0005).",
"A",
"deeper",
"insight",
"on",
"the",
"practitioners'",
"self-efficacy",
"processes",
"was",
"gained",
"through",
"reflection",
"of",
"the",
"practitioners",
"on",
"their",
"self-efficacy",
"during",
"the",
"interviews.",
"Conclusions:",
"Up-to-date",
"information",
"and",
"workshops",
"where",
"skills,",
"attitudes",
"and",
"social",
"support",
"were",
"addressed",
"were",
"important",
"in",
"making",
"the",
"program",
"effective.",
"Background",
"Obesity",
"is",
"becoming",
"increasingly",
"common",
"and",
"is",
"recog-",
"nized",
"as",
"a",
"major",
"public",
"health",
"problem",
"worldwide",
"[1-3].",
"In",
"the",
"UK,",
"the",
"overweight",
"and",
"obese",
"population",
"increased",
"by",
"almost",
"15%",
"between",
"1980",
"and",
"1992.",
"Similar",
"increases",
"have",
"been",
"noted",
"in",
"many",
"countries,",
"including",
"the",
"USA",
"[4],",
"Sweden",
"[5]",
"and",
"the",
"Netherlands",
"[6].",
"In",
"Israel,",
"55%",
"of",
"females",
"and",
"58%",
"of",
"males",
"aged",
"25–64",
"were",
"reported",
"to",
"be",
"overweight",
"or",
"obese",
"(Body",
"Mass",
"Index",
">25",
"kg/m2)",
"in",
"a",
"Mabat",
"survey",
"[7]",
"in",
"2000.",
"Guidelines",
"published",
"in",
"1996",
"for",
"the",
"management",
"of",
"obesity",
"recommended",
"setting",
"a",
"modest",
"weight",
"loss",
"and",
"weight",
"maintenance,",
"rather",
"than",
"a",
"targeted",
"ideal",
"weight,",
"as",
"goals",
"[8].",
"Lately,",
"pharmacological",
"therapies",
"have",
"been",
"proposed",
"as",
"adjuncts",
"to",
"diet",
"and",
"lifestyle",
"changes",
"to",
"improve",
"long-term",
"weight",
"loss",
"[9].",
"The",
"World",
"Health",
"Organization",
"declared",
"obesity",
"an",
"epidemic",
"in",
"developed",
"countries.",
"Awareness",
"of",
"physicians",
"of",
"their",
"important",
"role",
"in",
"defusing",
"the",
"obesity",
"epidemic",
"has",
"increased.",
"Yet,",
"the",
"number",
"of",
"family",
"practitioners",
"(FP)",
"treating",
"obesity",
"prob-",
"lems",
"continues",
"to",
"be",
"low",
"[10].",
"Page",
"1",
"of",
"8",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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] | [
"Int.",
"J.",
"Biol.",
"Sci.",
"2006,",
"2",
"Research",
"paper",
"32",
"International",
"Journal",
"of",
"Biological",
"Sciences",
"ISSN",
"1449-2288",
"www.biolsci.org",
"2006",
"2(2):32-37",
"©2006",
"Ivyspring",
"International",
"Publisher.",
"All",
"rights",
"reserved",
"Metaphylogeny",
"of",
"82",
"gene",
"families",
"sheds",
"a",
"new",
"light",
"on",
"chordate",
"evolution",
"Alexandre",
"Vienne",
"and",
"Pierre",
"Pontarotti",
"Phylogenomics",
"Laboratory,",
"EA",
"3781",
"Evolution",
"Biologique,",
"Université",
"de",
"Provence,",
"13331",
"MARSEILLE",
"CEDEX",
"03,",
"FRANCE",
"Corresponding",
"to:",
"Alexandre",
"Vienne,",
"Phylogenomics",
"Laboratory,",
"EA",
"3781",
"Evolution",
"Biologique,",
"Place",
"V.",
"HUGO,",
"Université",
"de",
"Provence,",
"13331",
"MARSEILLE",
"CEDEX",
"03,",
"France.",
"Email:",
"avienne@up.univ-mrs.fr.",
"Phone:",
"(33)",
"4",
"91",
"10",
"64",
"89",
"Received:",
"2006.01.15;",
"Accepted:",
"2006.03.31;",
"Published:",
"2006.04.10",
"Achieving",
"a",
"better",
"comprehension",
"of",
"the",
"evolution",
"of",
"species",
"has",
"always",
"been",
"an",
"important",
"matter",
"for",
"evolutionary",
"biologists.",
"The",
"deuterostome",
"phylogeny",
"has",
"been",
"described",
"for",
"many",
"years,",
"and",
"three",
"phyla",
"are",
"distinguishable:",
"Echinodermata",
"(including",
"sea",
"stars,",
"sea",
"urchins,",
"etc…),",
"Hemichordata",
"(including",
"acorn",
"worms",
"and",
"pterobranchs),",
"and",
"Chordata",
"(including",
"urochordates,",
"cephalochordates",
"and",
"extant",
"vertebrates).",
"Inside",
"the",
"Chordata",
"phylum,",
"the",
"position",
"of",
"vertebrate",
"species",
"is",
"quite",
"unanimously",
"accepted.",
"Nonetheless,",
"the",
"position",
"of",
"urochordates",
"in",
"regard",
"with",
"vertebrates",
"is",
"still",
"the",
"subject",
"of",
"debate,",
"and",
"has",
"even",
"been",
"suggested",
"by",
"some",
"authors",
"to",
"be",
"a",
"separate",
"phylum",
"from",
"cephalochordates",
"and",
"vertebrates.",
"It",
"was",
"also",
"the",
"case",
"for",
"agnathans",
"species",
"–myxines",
"and",
"hagfish–",
"for",
"which",
"phylogenetic",
"evidence",
"was",
"recently",
"given",
"for",
"a",
"controversial",
"monophyly.",
"This",
"raises",
"the",
"following",
"question:",
"which",
"one",
"of",
"the",
"cephalochordata",
"or",
"urochordata",
"is",
"the",
"sister",
"group",
"of",
"vertebrates",
"and",
"what",
"are",
"their",
"relationships?",
"In",
"the",
"present",
"work,",
"we",
"analyzed",
"82",
"protein",
"families",
"presenting",
"homologs",
"between",
"urochordata",
"and",
"other",
"deuterostomes",
"and",
"focused",
"on",
"two",
"points:",
"1)",
"testing",
"accurately",
"the",
"position",
"of",
"urochordata",
"and",
"cephalochordata",
"phyla",
"in",
"regard",
"with",
"vertebrates",
"as",
"well",
"as",
"chordates",
"monophyly,",
"2)",
"performing",
"an",
"estimation",
"of",
"the",
"rate",
"of",
"gene",
"loss",
"in",
"the",
"Ciona",
"intestinalis",
"genome.",
"We",
"showed",
"that",
"the",
"urochordate",
"phyla",
"is",
"the",
"vertebrate",
"sister",
"group",
"and",
"that",
"gene",
"loss",
"played",
"a",
"major",
"role",
"in",
"structuring",
"the",
"urochordate",
"genome.",
"Keywords:",
"chordate",
"monophyly,",
"evolution,",
"cephalochordate,",
"urochordate,",
"gene",
"loss",
"1.",
"INTRODUCTION",
"The",
"positioning",
"of",
"species",
"among",
"the",
"deuterostome",
"phylum",
"and",
"the",
"evolution",
"of",
"metazoans",
"has",
"fascinated",
"researchers",
"for",
"decades,",
"and",
"has",
"been",
"the",
"purpose",
"of",
"strong",
"debates.",
"Using",
"for",
"comparisons",
"the",
"morphological",
"as",
"well",
"as",
"the",
"molecular",
"data",
"that",
"are",
"nowadays",
"abundant",
"and",
"available",
"through",
"large",
"number",
"of",
"databases,",
"they",
"all",
"tried",
"to",
"describe",
"as",
"accurately",
"as",
"possible",
"the",
"reality",
"of",
"species",
"evolutionary",
"history.",
"Inside",
"deuterostomians,",
"three",
"major",
"groups",
"are",
"quiet",
"unanimously",
"defined",
"(Figure",
"1):",
"Echinodermata",
"(including",
"starfish,",
"sea",
"urchins,",
"etc…),",
"Hemichordata",
"(including",
"acorn",
"worms",
"and",
"pterobranchs),",
"and",
"Chordata",
"(including",
"three",
"subphyla:",
"urochordates",
"–composed",
"of",
"more",
"than",
"3.000",
"species—,",
"cephalochordates",
"–composed",
"of",
"approximately",
"29",
"species—,",
"and",
"the",
"extant",
"vertebrates",
"including",
"hagfishes,",
"lampreys,",
"and",
"jawed",
"vertebrates",
"–composed",
"of",
"approximately",
"53.000",
"species—)",
"[1].",
"The",
"analysis",
"of",
"anatomical",
"data",
"has",
"led",
"to",
"several",
"hypotheses",
"regarding",
"deuterostome",
"phylogeny",
"[2]",
"and",
"the",
"relationships",
"inter",
"and",
"intra-",
"groups",
"are",
"still",
"subject",
"to",
"debates.",
"One",
"of",
"the",
"specificity",
"of",
"chordates",
"is",
"their",
"morphological",
"synapomorphic.",
"These",
"particularities",
"shared",
"between",
"urochordates,",
"cephalochordates",
"and",
"vertebrates",
"are",
"quiet",
"well",
"known–as",
"for",
"example",
"the",
"notochord,",
"the",
"dorsal",
"hollow",
"nerve",
"cord,",
"the",
"tail",
"extending",
"behind",
"the",
"visceral",
"cavity,",
"the",
"thyroid",
"gland",
"(endostyle),",
"and",
"some",
"other",
"features",
"[3].",
"Nonetheless,",
"controversy",
"is",
"common",
"among",
"evolutionary",
"biologists",
"regarding",
"the",
"kind",
"of",
"data",
"analysed,",
"those",
"data",
"being",
"tested",
"as",
"nucleic",
"or",
"protein",
"sequences,",
"considering",
"them",
"as",
"fast",
"or",
"slow-evolving",
"genes",
"or",
"parts",
"of",
"genes",
"[4].",
"These",
"latter",
"will",
"give",
"more",
"or",
"less",
"phylogenetic",
"signals",
"from",
"the",
"data",
"sets",
"for",
"recent",
"or",
"deeper",
"events",
"during",
"evolution.",
"Recent",
"studies",
"have",
"led",
"to",
"the",
"re-examination",
"of",
"some",
"species",
"relationships,",
"and",
"echinoderms",
"+",
"hemichordates",
"were",
"shown",
"to",
"constitute",
"a",
"monophyletic",
"group.",
"More",
"recently,",
"relationships",
"of",
"agnathans",
"species",
"–myxine",
"and",
"hagfish—were",
"revisited",
"[5],",
"and",
"this",
"example",
"is",
"the",
"best",
"illustration",
"of",
"discussions.",
"Indeed,",
"strong",
"support",
"was",
"given",
"for",
"the",
"monophyly",
"of",
"jawless",
"vertebrates",
"which",
"are",
"the",
"most",
"basal",
"group",
"of",
"vertebrates,",
"by",
"the",
"analysis",
"of",
"35",
"protein",
"coding",
"gene",
"families",
"after",
"years",
"of",
"controversial",
"debates.",
"The",
"concatenation",
"of",
"the",
"different",
"topologies",
"obtained",
"led",
"to",
"the",
"assessment",
"of",
"a",
"monophyletic",
"group.",
"This",
"work",
"can",
"be",
"extended",
"to",
"the",
"present",
"purpose",
"concerning",
"the",
"existing",
"relationships",
"between",
"cephalochordates",
"and",
"urochordates,",
"leading",
"to",
"the",
"following",
"question:",
"which",
"one",
"of",
"cephalochordata",
"or",
"urochordata",
"correspond",
"to",
"the",
"sister",
"group",
"of",
"vertebrates?"
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459,
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473,
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884,
509,
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536,
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627,
898
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630,
884,
641,
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700,
898
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703,
884,
764,
898
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421,
900,
441,
914
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444,
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481,
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517,
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558,
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468,
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630,
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633,
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647,
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650,
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727,
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730,
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490,
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] | [
"Olangirhcaser",
"elcitra",
"published:",
"31",
"January",
"2011",
"doi:",
"10.3389/fpsyg.2010.00246",
"Childhood",
"trauma",
"and",
"chronic",
"illness",
"in",
"adulthood:",
"mental",
"health",
"and",
"socioeconomic",
"status",
"as",
"explanatory",
"factors",
"and",
"buffers",
"Steven",
"E.",
"Mock*",
"and",
"Susan",
"M.",
"Arai",
"Department",
"of",
"Recreation",
"and",
"Leisure",
"Studies,",
"Department",
"of",
"Health",
"Studies",
"and",
"Gerontology,",
"University",
"of",
"Waterloo,",
"Waterloo,",
"ON,",
"Canada",
"Edited",
"by:",
"Elysia",
"Davis,",
"University",
"of",
"California",
"at",
"Irvine,",
"USA",
"Reviewed",
"by:",
"Nadine",
"Fink,",
"Harvard",
"Medical",
"School,",
"USA",
"Kerry-Ann",
"Grant,",
"Macquarie",
"University,",
"Australia",
"*Correspondence:",
"Steven",
"E.",
"Mock,",
"Department",
"of",
"Recreation",
"and",
"Leisure",
"Studies,",
"Department",
"of",
"Health",
"Studies",
"and",
"Gerontology,",
"University",
"of",
"Waterloo,",
"200",
"University",
"Avenue",
"West,",
"Waterloo,",
"ON,",
"Canada",
"N2L",
"3G1.",
"e-mail:",
"smock@uwaterloo.ca",
"Experiences",
"of",
"traumatic",
"events",
"in",
"childhood",
"have",
"been",
"shown",
"to",
"have",
"long-term",
"consequences",
"for",
"health",
"in",
"adulthood.",
"With",
"data",
"from",
"the",
"2005",
"Canadian",
"Community",
"Health",
"Survey",
"we",
"take",
"a",
"life",
"course",
"perspective",
"of",
"cumulative",
"disadvantage",
"and",
"examine",
"the",
"potential",
"role",
"of",
"mental",
"health",
"and",
"socioeconomic",
"status",
"in",
"adulthood",
"as",
"multiple",
"mediators",
"of",
"the",
"link",
"between",
"childhood",
"trauma",
"and",
"chronic",
"illness",
"in",
"adulthood.",
"Mental",
"health",
"and",
"socioeconomic",
"status",
"are",
"also",
"tested",
"as",
"buffers",
"against",
"the",
"typically",
"adverse",
"consequences",
"of",
"childhood",
"trauma.",
"The",
"results",
"suggest",
"mental",
"health",
"and",
"socioeconomic",
"status",
"partially",
"explain",
"the",
"association",
"of",
"childhood",
"trauma",
"with",
"chronic",
"illness",
"in",
"adulthood,",
"with",
"mental",
"health",
"showing",
"a",
"stronger",
"effect.",
"In",
"addition,",
"an",
"analysis",
"of",
"the",
"interactions",
"suggested",
"higher",
"socioeconomic",
"status",
"is",
"a",
"potential",
"protective",
"factor",
"for",
"those",
"with",
"a",
"history",
"of",
"trauma.",
"Results",
"also",
"suggest",
"cumulative",
"disadvantage",
"following",
"trauma",
"may",
"lead",
"to",
"chronic",
"illness",
"and",
"suggest",
"the",
"need",
"for",
"public",
"health",
"expenditures",
"on",
"resources",
"such",
"as",
"counseling",
"and",
"income",
"supports",
"to",
"prevent",
"or",
"reduce",
"psychological",
"harm",
"and",
"chronic",
"illness",
"resulting",
"from",
"traumatic",
"events.",
"Keywords:",
"childhood",
"trauma,",
"chronic",
"illness,",
"mental",
"health,",
"socioeconomic",
"status,",
"cumulative",
"disadvantage",
"IIcudortnno",
"The",
"experience",
"of",
"traumatic",
"events",
"in",
"childhood",
"has",
"consequences",
"for",
"health",
"in",
"adulthood.",
"A",
"broad",
"range",
"of",
"traumatic",
"events",
"expe-",
"rienced",
"in",
"childhood",
"including",
"physical",
"abuse,",
"sexual",
"abuse,",
"pro-",
"longed",
"hospitalization,",
"and",
"family",
"instability",
"such",
"as",
"parental",
"unemployment",
"or",
"substance",
"abuse",
"have",
"been",
"linked",
"to",
"chronic",
"illness",
"in",
"adulthood",
"stemming",
"from",
"poor",
"immune",
"functioning",
"or",
"poor",
"cardiovascular",
"health",
"(Springer",
"et",
"al.,",
"2003;",
"Mulvihill,",
"2005;",
"O’Rand",
"and",
"Hamil-Luker,",
"2005;",
"Wickrama",
"et",
"al.,",
"2005).",
"According",
"to",
"a",
"life",
"course",
"perspective,",
"there",
"are",
"multiple",
"potential",
"pathways",
"that",
"may",
"contribute",
"to",
"a",
"process",
"of",
"cumulative",
"disadvantage",
"fol-",
"lowing",
"traumatic",
"childhood",
"events",
"(Dannefer,",
"2003;",
"Pearlin",
"et",
"al.,",
"2005).",
"One",
"potential",
"pathway",
"is",
"through",
"the",
"negative",
"mental",
"health",
"consequences",
"in",
"adulthood",
"of",
"trauma",
"experienced",
"in",
"childhood",
"(Turner",
"and",
"Lloyd,",
"1995;",
"Paolucci",
"et",
"al.,",
"2001;",
"Briere",
"and",
"Jordan,",
"2009).",
"Recent",
"work",
"also",
"suggests",
"that",
"there",
"are",
"socioeconomic",
"dis-",
"advantages",
"in",
"adulthood",
"resulting",
"from",
"trauma",
"early",
"in",
"life",
"that",
"may",
"contribute",
"to",
"chronic",
"illness",
"(Hyman,",
"2000;",
"Zielinski,",
"2009;",
"Currie",
"and",
"Spatz",
"Widom,",
"2010).",
"In",
"addition",
"to",
"being",
"potential",
"explanatory",
"factors",
"for",
"the",
"link",
"between",
"childhood",
"trauma",
"and",
"chronic",
"illness,",
"adult",
"mental",
"health",
"and",
"socioeconomic",
"status",
"(SES)",
"are",
"plausible",
"buffers",
"of",
"the",
"negative",
"effects",
"of",
"trauma",
"on",
"health",
"(Melchior",
"et",
"al.,",
"2007;",
"Wethington",
"et",
"al.,",
"2008).",
"A",
"traumatic",
"experience",
"is",
"one",
"that",
"threatens",
"death",
"or",
"injury",
"to",
"self",
"or",
"others",
"and",
"elicits",
"intense",
"feelings",
"of",
"fear,",
"helplessness,",
"or",
"horror",
"(American",
"Psychiatric",
"Association,",
"2000).",
"Examples",
"of",
"traumatic",
"events",
"include",
"physical",
"abuse,",
"sexual",
"abuse,",
"combat,",
"wit-",
"nessing",
"violence",
"or",
"disaster,",
"or",
"the",
"sudden",
"death",
"of",
"a",
"loved",
"one.",
"Over",
"a",
"lifetime",
"most",
"people",
"experience",
"at",
"least",
"one",
"potentially",
"traumatic",
"event",
"(Klein",
"and",
"Alexander,",
"2009).",
"In",
"a",
"community-level",
"study",
"in",
"the",
"United",
"States,",
"it",
"was",
"found",
"that",
"74.2%",
"of",
"women",
"and",
"81.3%",
"of",
"men",
"reported",
"experiencing",
"at",
"least",
"one",
"traumatic",
"event",
"in",
"their",
"lifetime",
"(Stein",
"et",
"al.,",
"1997).",
"A",
"community",
"study",
"(Breslau,",
"2009;",
"Breslau",
"et",
"al.,",
"1999)",
"reported",
"similar",
"findings,",
"78.1%",
"for",
"women",
"and",
"92.2%",
"among",
"men,",
"for",
"lifetime",
"prevalence",
"of",
"exposure",
"to",
"traumatic",
"events.",
"Results",
"from",
"a",
"national",
"study",
"in",
"the",
"United",
"States",
"indicate",
"overall",
"rates",
"of",
"child",
"maltreatment",
"at",
"13.8%",
"(8.0%",
"having",
"experi-",
"enced",
"sexual",
"abuse,",
"6.7%",
"physical",
"abuse,",
"2.9%",
"severe",
"neglect,",
"and",
"3.2%",
"reporting",
"multiple",
"forms",
"of",
"child",
"maltreatment",
"experienced;",
"Zielinski,",
"2009).",
"Goodwin",
"et",
"al.",
"(2003)",
"reported",
"physical",
"abuse",
"by",
"parents",
"at",
"a",
"rate",
"of",
"15.8%",
"and",
"similar",
"rates",
"have",
"been",
"reported",
"in",
"Canadian",
"research",
"(MacMillan",
"et",
"al.,",
"1997).",
"In",
"a",
"community-level",
"study",
"of",
"traumatic",
"experiences",
"in",
"childhood",
"(Turner",
"and",
"Lloyd,",
"1995)",
"19.5%",
"reported",
"major",
"illness",
"or",
"accident,",
"9.6%",
"parental",
"divorce,",
"17.7%",
"repeating",
"a",
"year",
"of",
"school,",
"9.4%",
"parent",
"unemploy-",
"ment,",
"26.5%",
"experience",
"of",
"a",
"significant",
"scare,",
"2.6%",
"being",
"sent",
"away",
"from",
"home,",
"8.2%",
"parent",
"alcohol",
"or",
"drug",
"use,",
"and",
"3.8%",
"physical",
"abuse.",
"The",
"experience",
"of",
"traumatic",
"events",
"in",
"childhood",
"is",
"associated",
"with",
"long-term",
"health",
"effects.",
"In",
"a",
"study",
"of",
"the",
"impact",
"of",
"child-",
"hood",
"trauma",
"on",
"health",
"in",
"adulthood,",
"those",
"who",
"reported",
"child-",
"hood",
"psychological",
"or",
"physical",
"victimization",
"had",
"worse",
"health",
"than",
"those",
"who",
"did",
"not",
"and",
"also",
"experienced",
"significantly",
"more",
"decline",
"in",
"health",
"over",
"a",
"10-year",
"period",
"in",
"adulthood",
"(Greenfield",
"and",
"Marks,",
"2009).",
"This",
"is",
"consistent",
"with",
"research",
"that",
"shows",
"the",
"negative",
"impact",
"of",
"childhood",
"adversity",
"on",
"cardiovascular",
"health",
"(O’Rand",
"and",
"Hamil-Luker,",
"2005)",
"and",
"recent",
"reviews",
"documenting",
"a",
"consistent",
"association",
"between",
"childhood",
"trauma",
"and",
"negative",
"health",
"consequences",
"in",
"adulthood",
"including",
"pain,",
"unexplained",
"somatic",
"symptoms,",
"stress-related",
"illnesses,",
"and",
"illnesses",
"related",
"to",
"www.frontiersin.org",
"January",
"2011",
"|",
"Volume",
"1",
"|",
"Article",
"246",
"|",
"1"
] | [
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] | [
"Flexor",
"Tenorrhaphy",
"Using",
"Absorbable",
"Suture",
"Materials",
"Hyung",
"Joo",
"Kang,",
"Dong",
"Chul",
"Lee,",
"Jin",
"Soo",
"Kim,",
"Sae",
"Hwi",
"Ki,",
"Si",
"Young",
"Roh,",
"Jae",
"Won",
"Yang",
"Department",
"of",
"Plastic",
"and",
"Reconstructive",
"Surgery,",
"Kwang-Myung",
"Sung-Ae",
"General",
"Hospital,",
"Gwangmyeong",
",",
"Korea",
"Background ",
"Nonabsorbable",
" ",
"sutures ",
"are ",
"favorable ",
"for ",
"repairing ",
"flexor ",
"tendons. ",
"However, ",
"absorbable ",
"sutures ",
"have ",
"performed ",
"favorably ",
"in ",
"an ",
"animal ",
"model.",
"Methods ",
"Two-strand",
" ",
"sutures ",
"using ",
"the ",
"interlocking ",
"modified ",
"Kessler ",
"method ",
"with ",
"polydioxanone ",
"absorbable ",
"sutures ",
"4-0 ",
"were ",
"used ",
"to ",
"repair ",
"completely ",
"ruptured ",
"flexor ",
"tendons ",
"in ",
"55 ",
"fingers ",
"from ",
"41 ",
"consecutive ",
"patients. ",
"The ",
"medical ",
"records ",
"of ",
"average ",
"42 ",
"follow ",
"up ",
"weeks ",
"were ",
"analyzed ",
"retrospectively. ",
"The ",
"data ",
"analyzed ",
"using ",
"the ",
"chi-squared ",
"test, ",
"and ",
"Fisher’s ",
"exact ",
"test ",
"was ",
"used ",
"for ",
"postoperative ",
"complications. ",
"The ",
"results ",
"were ",
"compared ",
"with ",
"those ",
"of ",
"other ",
"studies.",
"Results ",
"Among",
" ",
"the ",
"index, ",
"middle, ",
"ring, ",
"and ",
"little ",
"fingers ",
"were ",
"injured ",
"in ",
"9, ",
"17, ",
"16, ",
"and ",
"13 ",
"fingers, ",
"respectively. ",
"The ",
"injury ",
"levels ",
"varied ",
"from ",
"zone ",
"1 ",
"to ",
"5. ",
"Of ",
"the ",
"55 ",
"digits ",
"in ",
"our ",
"study, ",
"there ",
"were ",
"26 ",
"(47%) ",
"isolated ",
"flexor ",
"digitorum ",
"profundus ",
"(FDP) ",
"injuries ",
"and ",
"29 ",
"(53%) ",
"combined ",
"FDP ",
"and ",
"with ",
"flexor ",
"digitorum ",
"superficialis ",
"injuries. ",
"Pulley ",
"repair ",
"was ",
"also ",
"conducted. ",
"Concomitant ",
"injuries ",
"of ",
"blood ",
"vessels ",
"and ",
"nerves ",
"were ",
"found ",
"in ",
"17 ",
"patients ",
"(23 ",
"fingers); ",
"nerve ",
"injuries ",
"occurred ",
"in ",
"5 ",
"patients ",
"(10 ",
"fingers). ",
"Two ",
"patients ",
"had ",
"ruptures ",
"(3.6%), ",
"and ",
"one ",
"patient ",
"had ",
"two ",
"adhesions ",
"(3.6%). ",
"Using ",
"the ",
"original ",
"Strickland ",
"criteria, ",
"all ",
"the ",
"patients ",
"were ",
"assessed ",
"to ",
"be ",
"excellent ",
"or ",
"good. ",
"Also, ",
"fibrosis ",
"and ",
"long-term ",
"foreign ",
"body ",
"tissue ",
"reactions ",
"such ",
"as ",
"stitch ",
"granuloma ",
"were ",
"less ",
"likely ",
"occurred ",
"in ",
"our ",
"study. ",
"Compared ",
"to ",
"the ",
"Cullen’s ",
"report ",
"that ",
"used ",
"nonabsorbable ",
"sutures, ",
"there ",
"was ",
"no ",
"significant ",
"difference ",
"in ",
"the ",
"rupture ",
"or ",
"adhesion ",
"rates.",
"Conclusions ",
"Therefore,",
" ",
"this ",
"study ",
"suggests ",
"that ",
"appropriate ",
"absorbable ",
"core ",
"sutures ",
"can ",
"be ",
"used ",
"safely ",
"for ",
"flexor ",
"tendon ",
"repairs.",
"Keywords ",
"Hand",
" ",
"/ ",
"Polydioxanone ",
"/ ",
"Rupture ",
"/ ",
"Tendon ",
"Injuries",
"Received:",
"8",
"Mar",
"2012",
"•",
"Revised:",
"23",
"May",
"2012",
"•",
"Accepted:",
"23",
"May",
"2012",
"pISSN: 2234-6163 ",
"• eISSN: 2234-6171 ",
"• http://dx.doi.org/10.5999/aps.2012.39.4.397 ",
"• Arch Plast Surg 2012;39:397-403",
"Correspondence:",
"Dong",
"Chul",
"Lee",
"Department",
"of",
"Plastic",
"and",
"Reconstructive",
"Surgery,",
"Kwang-Myung",
"Sung-Ae",
"General",
"Hospital,",
"36",
"Digital-ro,",
"Gwangmyeong",
"423-711,",
"Korea",
"Tel:",
"+82-2-2680-7238",
"Fax:",
"+82-2-2615-7218",
"E-mail:",
"ophand@gmail.com",
"O",
"r",
"i",
"g",
"i",
"n",
"a",
"l",
"A",
"r",
"t",
"i",
"c",
"l",
"e",
"This",
"article",
"was",
"presented",
"at",
"the",
"Research",
"and",
"Reconstructive",
"Forum",
"on",
"May",
"12-13,",
"2011",
"in",
"Daejeon,",
"Korea.",
"No",
"potential",
"conflict",
"of",
"interest",
"relevant",
"to",
"this",
"article",
"was",
"reported",
"INTRODUCTION",
"been",
"performed",
"since",
"the",
"beginning",
"of",
"the",
"20th",
"century.",
"Since",
"Kleinert",
"et",
"al.",
"[1]",
"conducted",
"primary",
"repair",
"for",
"a",
"flexor",
"tendon",
"Various",
"sutures",
"can",
"be",
"used",
"to",
"repair",
"a",
"ruptured",
"flexor",
"tendon.",
"rupture",
"in",
"the",
"no",
"man’s",
"land,",
"tendon",
"repair",
"has",
"been",
"commonly",
"Since",
"Avicenna",
"first",
"performed",
"a",
"tendon",
"repair",
"procedure,",
"pri-",
"performed",
"on",
"flexor",
"tendon",
"ruptures",
"of",
"the",
"fingers;",
"studies",
"on",
"mary",
"tendon",
"repair",
"has",
"rarely",
"been",
"performed",
"because",
"primary",
"the",
"repair",
"of",
"the",
"flexor",
"tendon",
"have",
"been",
"also",
"conducted.",
"Suture",
"tenorrhaphy",
"is",
"a",
"controversial",
"procedure",
"[1].",
"Until",
"the",
"mid-20th",
"materials",
"used",
"for",
"tendon",
"repair",
"have",
"been",
"developed",
"over",
"time.",
"century,",
"using",
"a",
"tendon",
"graft",
"had",
"been",
"preferred",
"over",
"tendon",
"Many",
"surgeons",
"prefer",
"sutures",
"made",
"of",
"nonabsorbable",
"materials",
"repair",
"for",
"treating",
"the",
"“no",
"man’s",
"land”",
"section",
"of",
"the",
"hand.",
"Stud-",
"such",
"as",
"nylon,",
"braided",
"polyester,",
"and",
"polypropylene",
"[2].",
"How-",
"ies",
"on",
"flexor",
"tendon",
"healing",
"of",
"the",
"digital",
"sheath,",
"however,",
"have",
"ever,",
"Trail",
"et",
"al.",
"[3]",
"reported",
"that",
"using",
"sutures",
"made",
"of",
"nonab-",
"Copyright",
"©",
"2012",
"The",
"Korean",
"Society",
"of",
"Plastic",
"and",
"Reconstructive",
"Surgeons",
"This",
"is",
"an",
"OpenAccess",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"CommonsAttribution",
"Non-Commercial",
"License",
"(http://creativecommons.org/",
"licenses/by-nc/3.0/)",
"which",
"permits",
"unrestricted",
"non-commercial",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"www.e-aps.org",
"397"
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] | [
"International",
"Journal",
"for",
"Equity",
"in",
"Health",
"Research",
"Musculo-skeletal",
"pain",
"among",
"40-",
"and",
"45-year",
"olds",
"in",
"Oslo:",
"differences",
"between",
"two",
"socioeconomically",
"contrasting",
"areas,",
"and",
"their",
"possible",
"explanations",
"Mette",
"Brekke*1",
"and",
"Per",
"Hjortdahl2",
"Address:",
"1Department",
"of",
"General",
"Practice",
"and",
"Community",
"Medicine,",
"University",
"of",
"Oslo,",
"Box",
"1130",
"Blindern,",
"N-0317",
"Oslo,",
"Norway",
"and",
"2Per",
"Hjortdahl,",
"Department",
"of",
"General",
"Practice",
"and",
"Community",
"Medicine,",
"University",
"of",
"Oslo,",
"Box",
"1130",
"Blindern,",
"N-0317",
"Oslo,",
"Norway",
"Email:",
"Mette",
"Brekke*",
"-",
"mette.brekke@medisin.uio.no;",
"Per",
"Hjortdahl",
"-",
"per.hjortdahl@medisin.uio.no",
"*",
"Corresponding",
"author",
"BioMed",
"Central",
"Open",
"Access",
"Published:",
"19",
"October",
"2004",
"International",
"Journal",
"for",
"Equity",
"in",
"Health",
"2004,",
"3:10",
"doi:10.1186/1475-9276-3-10",
"This",
"article",
"is",
"available",
"from:",
"http://www.equityhealthj.com/content/3/1/10",
"Received:",
"27",
"May",
"2004",
"Accepted:",
"19",
"October",
"2004",
"©",
"2004",
"Brekke",
"and",
"Hjortdahl;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"population",
"surveysocial",
"inequalities",
"in",
"healthmuskulo-skeletal",
"disordersmental",
"healthimmigrants",
"Abstract",
"Background:",
"The",
"objective",
"of",
"the",
"study",
"was",
"to",
"compare",
"the",
"prevalence",
"and",
"severity",
"of",
"musculo-",
"skeletal",
"pain",
"between",
"two",
"socioeconomically",
"contrasting",
"areas",
"in",
"Oslo,",
"Norway,",
"and",
"to",
"explore",
"possible",
"explanatory",
"factors.",
"Methods:",
"Questionnaire",
"survey,",
"carried",
"out",
"as",
"part",
"of",
"The",
"Oslo",
"Health",
"Study",
"in",
"2000–2001.",
"Data",
"from",
"821",
"persons",
"(40",
"and",
"45",
"year",
"old)",
"living",
"in",
"a",
"less",
"affluent",
"inner",
"city",
"area",
"(called",
"east)",
"were",
"compared",
"with",
"854",
"persons",
"living",
"in",
"an",
"affluent",
"area",
"of",
"the",
"city",
"(called",
"west).",
"Bivariate",
"comparisons",
"(chi",
"square",
"test)",
"and",
"multiple",
"regression",
"analyses",
"were",
"performed",
"to",
"investigate",
"differences",
"between",
"the",
"samples.",
"Results:",
"61",
"%",
"in",
"east",
"and",
"56",
"%",
"in",
"west",
"(p",
"<",
"0.05)",
"reported",
"pain/stiffness",
"in",
"muscles/joints",
"during",
"the",
"last",
"four",
"weeks.",
"30",
"%",
"in",
"east",
"versus",
"19",
"%",
"in",
"west",
"(p",
"<",
"0.001)",
"reported",
"extensive",
"pain.",
"The",
"between",
"area",
"difference",
"in",
"extensive",
"pain",
"was",
"partially",
"explained",
"by",
"physical",
"inactivity,",
"mental",
"health",
"problems",
"and",
"being",
"of",
"non-Western",
"origin.",
"Conclusion:",
"Musculo-skeletal",
"pain",
"is",
"reported",
"by",
"55–60",
"%",
"of",
"middle",
"aged",
"persons",
"in",
"Oslo",
"during",
"a",
"four",
"week",
"period,",
"and",
"must",
"be",
"considered",
"a",
"normal",
"phenomenon.",
"Poor",
"social",
"conditions,",
"inactivity,",
"mental",
"health",
"problems",
"and",
"being",
"an",
"immigrant",
"imply",
"increased",
"risk",
"of",
"more",
"severe",
"symptoms",
"with",
"a",
"concomitant",
"demand",
"of",
"health",
"care.",
"Background",
"In",
"affluent",
"societies",
"like",
"Norway,",
"living",
"conditions",
"as",
"well",
"as",
"general",
"health",
"status",
"have",
"improved",
"during",
"the",
"last",
"dec-",
"ades.",
"In",
"spite",
"of",
"this,",
"social",
"health",
"inequities",
"still",
"exist,",
"and",
"recent",
"analyses",
"from",
"Oslo",
"even",
"indicate",
"an",
"increase",
"during",
"the",
"last",
"30",
"years",
"[1].",
"Life",
"expectancy",
"for",
"men",
"living",
"in",
"the",
"least",
"affluent",
"city",
"area",
"is",
"69",
"years,",
"compared",
"to",
"76",
"for",
"men",
"in",
"the",
"most",
"affluent",
"area",
"[2].",
"Well-known",
"risk",
"factors",
"like",
"smoking,",
"physical",
"inactivity",
"and",
"overweight,",
"as",
"well",
"as",
"the",
"incidence",
"of",
"atherosclerotic",
"disease",
"and",
"several",
"forms",
"of",
"cancer",
"show",
"similar",
"correlation",
"[3].",
"Page",
"1",
"of",
"5",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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] | [
"Int.",
"J.",
"Mol.",
"Sci.",
"2009,",
"10,",
"4428-4434;",
"doi:10.3390/ijms10104428",
"OPEN",
"ACCESS",
"International",
"Journal",
"of",
"Molecular",
"Sciences",
"ISSN",
"1422-0067",
"www.mdpi.com/journal/ijms",
"Review",
"Role",
"of",
"the",
"Ubiquitin",
"Proteasome",
"System",
"in",
"Regulating",
"Skin",
"Pigmentation",
"Hideya",
"Ando",
"1,2,",
"Masamitsu",
"Ichihashi",
"1,2",
"and",
"Vincent",
"J.",
"Hearing",
"3,*",
"1",
"Skin",
"Aging",
"and",
"Photo-aging",
"Research",
"Center,",
"Doshisha",
"University,",
"Kizugawa,",
"Kyoto",
"619-0225,",
"Japan;",
"E-Mails:",
"hideyaando@aol.com",
"(H.A.);",
"mm_ichihashi@hotmail.com",
"(M.I.)",
"2",
"Kobe",
"Skin",
"Research",
"Institute,",
"Kobe,",
"Hyogo",
"650-0047,",
"Japan",
"3",
"Laboratory",
"of",
"Cell",
"Biology,",
"National",
"Cancer",
"Institute,",
"National",
"Institutes",
"of",
"Health,",
"Bethesda,",
"MD",
"20892,",
"USA",
"*",
"Author",
"to",
"whom",
"correspondence",
"should",
"be",
"addressed;",
"E-Mail:",
"hearingv@nih.gov;",
"Tel.:",
"+1-301-496-1564;",
"Fax:",
"+1-301-402-8787.",
"Received:",
"3",
"September",
"2009;",
"in",
"revised",
"form:",
"29",
"September",
"2009",
"/",
"Accepted:",
"9",
"October",
"2009",
"/",
"Published:",
"15",
"October",
"2009",
"Abstract:",
"Pigmentation",
"of",
"the",
"skin,",
"hair",
"and",
"eyes",
"is",
"regulated",
"by",
"tyrosinase,",
"the",
"critical",
"rate-limiting",
"enzyme",
"in",
"melanin",
"synthesis",
"by",
"melanocytes.",
"Tyrosinase",
"is",
"degraded",
"endogenously,",
"at",
"least",
"in",
"part,",
"by",
"the",
"ubiquitin",
"proteasome",
"system",
"(UPS).",
"Several",
"types",
"of",
"inherited",
"hypopigmentary",
"diseases,",
"such",
"as",
"oculocutaneous",
"albinism",
"and",
"Hermansky-",
"Pudlak",
"syndrome,",
"involve",
"the",
"aberrant",
"processing",
"and/or",
"trafficking",
"of",
"tyrosinase",
"and",
"its",
"subsequent",
"degradation",
"which",
"can",
"occur",
"due",
"to",
"the",
"quality-control",
"machinery.",
"Studies",
"on",
"carbohydrate",
"modifications",
"have",
"revealed",
"that",
"tyrosinase",
"in",
"the",
"endoplasmic",
"reticulum",
"(ER)",
"is",
"proteolyzed",
"via",
"ER-associated",
"protein",
"degradation",
"and",
"that",
"tyrosinase",
"degradation",
"can",
"also",
"occur",
"following",
"its",
"complete",
"maturation",
"in",
"the",
"Golgi.",
"Among",
"intrinsic",
"factors",
"that",
"regulate",
"the",
"UPS,",
"fatty",
"acids",
"have",
"been",
"shown",
"to",
"modulate",
"tyrosinase",
"degradation",
"in",
"contrasting",
"manners",
"through",
"increased",
"or",
"decreased",
"amounts",
"of",
"ubiquitinated",
"tyrosinase",
"that",
"leads",
"to",
"its",
"accelerated",
"or",
"decelerated",
"degradation",
"by",
"proteasomes.",
"Keywords:",
"fatty",
"acid;",
"melanin;",
"melanocyte;",
"tyrosinase;",
"skin;",
"pigmentation"
] | [
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] | [
"HD",
"Jung,",
"et",
"al",
"Ann",
"Dermatol",
"Vol.",
"23,",
"Suppl.",
"2,",
"2011",
"CASE",
"REPORT",
"http://dx.doi.org/10.5021/ad.2011.23.S2.S270",
"Multiple",
"Granulocytic",
"Sarcomas",
"in",
"a",
"Patient",
"with",
"Longstanding",
"Complete",
"Remission",
"of",
"Acute",
"Myelogenous",
"Leukemia",
"Hee-Dam",
"Jung,",
"M.D.,",
"Hei-Sung",
"Kim,",
"M.D.,",
"Young-Min",
"Park,",
"M.D.,",
"Hyung-Ok",
"Kim,",
"M.D.,",
"Jun-Young",
"Lee,",
"M.D.",
"Department",
"of",
"Dermatology,",
"Seoul",
"St.",
"Mary’s",
"Hospital,",
"College",
"of",
"Medicine,",
"The",
"Catholic",
"University",
"of",
"Korea,",
"Seoul,",
"Korea",
"Granulocytic",
"sarcoma",
"is",
"an",
"extramedullary",
"tumor",
"composed",
"of",
"granulocytic",
"precursor",
"cells.",
"It",
"usually",
"presents",
"as",
"a",
"nodular",
"mass",
"in",
"the",
"course",
"of",
"acute",
"myelogenous",
"leukemia.",
"Rarely,",
"the",
"tumor",
"develops",
"in",
"non-hematological",
"conditions",
"or",
"in",
"a",
"patient",
"with",
"complete",
"remission",
"from",
"the",
"acute",
"myelogenous",
"leukemia.",
"In",
"such",
"cases,",
"aleukemic",
"granulo-",
"cytic",
"sarcoma",
"can",
"be",
"a",
"preceding",
"sign",
"of",
"systemic",
"leukemia",
"or",
"a",
"first",
"sign",
"of",
"hematologic",
"relapse",
"of",
"leukemia.",
"We",
"present",
"an",
"unusual",
"case",
"of",
"multiple",
"granulocytic",
"sarcomas",
"develo-",
"ped",
"in",
"a",
"patient",
"with",
"longstanding",
"complete",
"remission",
"of",
"acute",
"myelogenous",
"leukemia,",
"who",
"has",
"not",
"had",
"bone",
"marrow",
"and",
"peripheral",
"blood",
"involvement",
"for",
"a",
"long",
"time.",
"(Ann",
"Dermatol",
"23(S2)",
"S270∼S273,",
"2011)",
"-Keywords-",
"Aleukemic",
"leukemia",
"cutis,",
"AML",
"M1,",
"Granulocytic",
"sarco-",
"ma",
"INTRODUCTION",
"Granulocytic",
"sarcomas",
"usually",
"occur",
"during",
"the",
"course",
"of",
"Received",
"March",
"23,",
"2011,",
"Revised",
"July",
"12,",
"2011,",
"Accepted",
"for",
"publication",
"August",
"12,",
"2011",
"Corresponding",
"author:",
"Jun-Young",
"Lee,",
"M.D.,",
"Department",
"of",
"Der-",
"matology,",
"Seoul",
"St.",
"Mary’s",
"Hospital,",
"College",
"of",
"Medicine,",
"The",
"Catholic",
"University",
"of",
"Korea,",
"505",
"Banpo-dong,",
"Seocho-gu,",
"Seoul",
"137-040,",
"Korea.",
"Tel:",
"82-2-2258-1386,",
"Fax:",
"82-2-594-3255,",
"E-mail:",
"jylee@catholic.ac.kr",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"Non-Commercial",
"License",
"(http://",
"creativecommons.org/licenses/by-nc/3.0)",
"which",
"permits",
"unrestricted",
"non-commercial",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"S270",
"Ann",
"Dermatol",
"acute",
"myelogenous",
"leukemia",
"(AML)",
"and",
"antecede",
"blastic",
"cirisis",
"in",
"myeloproliferative",
"disease",
"or",
"myelodysplastic",
"syndromes.",
"However,",
"the",
"tumor",
"can",
"also",
"develop",
"in",
"patients",
"who",
"have",
"either",
"no",
"prior",
"history",
"of",
"hematological",
"disease",
"or",
"have",
"shown",
"complete",
"remission",
"from",
"acute",
"myelogenous",
"leukemia.",
"Herein,",
"we",
"describe",
"a",
"patient",
"who",
"has",
"shown",
"an",
"unusual",
"clinical",
"course",
"in",
"that",
"she",
"was",
"in",
"complete",
"remission",
"from",
"AML",
"for",
"a",
"long",
"time",
"and",
"that",
"there",
"were",
"no",
"signs",
"of",
"peripheral",
"blood",
"and",
"bone",
"marrow",
"relapse",
"for",
"a",
"long",
"time",
"following",
"the",
"development",
"of",
"granulocytic",
"sarcoma.",
"CASE",
"REPORT",
"A",
"72-year-old",
"Korean",
"woman",
"presented",
"with",
"a",
"1-month",
"history",
"of",
"rapidly",
"growing",
"multiple",
"cutaneous",
"nodules",
"on",
"the",
"whole",
"body.",
"Physical",
"examination",
"revealed",
"wide-",
"spread",
"well-demarcated",
"variable-sized",
"greenish",
"firm",
"cutaneous",
"nodules",
"over",
"the",
"face,",
"trunk",
"and",
"extremities",
"(Fig.",
"1).",
"She",
"had",
"a",
"history",
"of",
"acute",
"myeloblastic",
"leukemia",
"without",
"maturation",
"(AML",
"M1),",
"and",
"achieved",
"complete",
"remission",
"after",
"the",
"3rd",
"consolidation",
"chemotherapy,",
"ten",
"years",
"ago.",
"The",
"patient",
"remained",
"asymptomatic",
"for",
"nine",
"years",
"and",
"then",
"visited",
"the",
"hospital",
"presenting",
"with",
"an",
"asymptomatic",
"solitary",
"firm",
"mass",
"on",
"the",
"left",
"upper",
"eyelid",
"in",
"September",
"2009.",
"An",
"excisional",
"biopsy",
"of",
"the",
"lesion",
"was",
"performed",
"and",
"histopathologic",
"findings",
"were",
"consistent",
"with",
"a",
"granulocytic",
"sarcoma.",
"Bone",
"marrow",
"biopsy",
"showed",
"normocellular",
"bone",
"marrow",
"without",
"leukemic",
"cell",
"involvement",
"and",
"peripheral",
"blood",
"also",
"revealed",
"normal",
"findings.",
"In",
"April",
"2010,",
"she",
"complained",
"of",
"nasal",
"stuffiness,",
"bloody",
"nasal",
"discharge",
"and",
"hoarseness.",
"Neck",
"computed",
"tomography",
"and",
"magnetic",
"resonance",
"imaging",
"findings"
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"access",
"and",
"availability",
"for",
"local",
"consumers,",
"is",
"unclear.",
"This",
"article",
"presents",
"a",
"conceptual",
"framework",
"that",
"outlines",
"the",
"policy",
"implications",
"of",
"medical",
"tourism’s",
"growth",
"for",
"health",
"systems,",
"drawing",
"on",
"the",
"cases",
"of",
"Thailand,",
"Singapore",
"and",
"Malaysia,",
"three",
"regional",
"hubs",
"for",
"medical",
"tourism,",
"via",
"an",
"extensive",
"review",
"of",
"academic",
"and",
"grey",
"literature.",
"Variables",
"for",
"further",
"analysis",
"of",
"the",
"potential",
"impact",
"of",
"medical",
"tourism",
"on",
"health",
"systems",
"are",
"also",
"identified.",
"The",
"framework",
"can",
"provide",
"a",
"basis",
"for",
"empirical,",
"in",
"country",
"studies",
"weighing",
"the",
"benefits",
"and",
"disadvantages",
"of",
"medical",
"tourism",
"for",
"health",
"systems.",
"The",
"policy",
"implications",
"described",
"are",
"of",
"particular",
"relevance",
"for",
"policymakers",
"and",
"industry",
"practitioners",
"in",
"other",
"Southeast",
"Asian",
"countries",
"with",
"similar",
"health",
"systems",
"where",
"governments",
"have",
"expressed",
"interest",
"in",
"facilitating",
"the",
"growth",
"of",
"the",
"medical",
"tourist",
"industry.",
"This",
"article",
"calls",
"for",
"a",
"universal",
"definition",
"of",
"medical",
"tourism",
"and",
"medical",
"tourists",
"to",
"be",
"enunciated,",
"as",
"well",
"as",
"concerted",
"data",
"collection",
"efforts,",
"to",
"be",
"undertaken",
"prior",
"to",
"any",
"meaningful",
"empirical",
"analysis",
"of",
"medical",
"tourism’s",
"impact",
"on",
"health",
"systems.",
"Introduction",
"Growing",
"demand",
"for",
"health",
"services",
"is",
"a",
"global",
"phenom-",
"enon,",
"linked",
"to",
"economic",
"development",
"that",
"generates",
"ris-",
"ing",
"incomes",
"and",
"education.",
"Demographic",
"change,",
"especially",
"population",
"ageing",
"and",
"older",
"people’s",
"require-",
"ments",
"for",
"more",
"medical",
"services,",
"coupled",
"with",
"epidemiolo-",
"gical",
"change,",
"i.e.",
"rising",
"incidence",
"of",
"chronic",
"conditions,",
"also",
"fuel",
"demand",
"for",
"more",
"and",
"better",
"health",
"services.",
"Wait-",
"ing",
"times",
"and/or",
"the",
"increasing",
"cost",
"of",
"health",
"services",
"at",
"home,",
"coupled",
"with",
"the",
"availability",
"of",
"cheaper",
"alternatives",
"in",
"developing",
"countries,",
"has",
"lead",
"new",
"healthcare",
"consu-",
"mers,",
"or",
"medical",
"tourists,",
"to",
"seek",
"treatment",
"overseas",
"[1].",
"The",
"correspondent",
"growth",
"in",
"the",
"global",
"health",
"service",
"sec-",
"tor",
"reflects",
"this",
"demand.",
"The",
"globalisation",
"of",
"healthcare",
"is",
"marked",
"by",
"increasing",
"international",
"trade",
"in",
"health",
"products",
"and",
"services,",
"strikingly",
"via",
"cross",
"border",
"patient",
"flows.",
"*",
"Correspondence:",
"sppnp@nus.edu.sg",
"Lee",
"Kuan",
"Yew",
"School",
"of",
"Public",
"Policy,",
"National",
"University",
"of",
"Singapore,",
"469C",
"Bukit",
"Timah",
"Road,",
"OTH",
"Building,",
"Singapore",
"259772,",
"Singapore",
"In",
"Southeast",
"Asia,",
"the",
"health",
"sector",
"is",
"expanding",
"rapidly,",
"attributable",
"to",
"rapid",
"growth",
"of",
"the",
"private",
"sector",
"and",
"notably,",
"medical",
"tourism,",
"which",
"is",
"emerging",
"as",
"a",
"lucrative",
"business",
"opportunity.",
"Countries",
"here",
"are",
"capita-",
"lising",
"on",
"their",
"popularity",
"as",
"tourist",
"destinations",
"by",
"com-",
"bining",
"high",
"quality",
"medical",
"services",
"at",
"competitive",
"prices",
"with",
"tourist",
"packages.",
"Some",
"countries",
"are",
"establishing",
"comparative",
"advantages",
"in",
"service",
"provision",
"based",
"on",
"their",
"health",
"system’s",
"organizational",
"structure",
"(table",
"1).",
"Thailand",
"has",
"established",
"a",
"niche",
"for",
"cosmetic",
"surgery",
"and",
"sex",
"change",
"operations,",
"whilst",
"Singapore",
"is",
"attracting",
"patients",
"at",
"the",
"high",
"end",
"of",
"the",
"market",
"for",
"advanced",
"treat-",
"ments",
"like",
"cardiovascular,",
"neurological",
"surgery",
"and",
"stem",
"cell",
"therapy",
"[2].",
"In",
"Singapore,",
"Malaysia",
"and",
"Thailand",
"alone,",
"an",
"estimated",
"2",
"million",
"medical",
"travellers",
"visited",
"in",
"2006",
"-",
"7,",
"earning",
"these",
"countries",
"over",
"US$",
"3",
"billion",
"in",
"treatment",
"costs",
"(table",
"2).",
"Carrera",
"and",
"Bridges",
"(2006)",
"define",
"medical",
"tourism",
"as",
"“the",
"organized",
"travel",
"outside",
"one’s",
"natural",
"healthcare",
"©",
"2011",
"Pocock",
"and",
"Phua;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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] | [
"Hall",
"et",
"al.",
"BMC",
"Medical",
"Informatics",
"and",
"Decision",
"Making",
"2012,",
"12:69",
"http://www.biomedcentral.com/1472-6947/12/69",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"Implementation",
"of",
"automated",
"reporting",
"of",
"estimated",
"glomerular",
"filtration",
"rate",
"among",
"Veterans",
"Affairs",
"laboratories:",
"a",
"retrospective",
"study",
"Rasheeda",
"K",
"Hall1,2,",
"Virginia",
"Wang1,2,",
"George",
"L",
"Jackson1,2,",
"Bradley",
"G",
"Hammill2,",
"Matthew",
"L",
"Maciejewski1,2,",
"Elizabeth",
"M",
"Yano3,4,",
"Laura",
"P",
"Svetkey2,5",
"and",
"Uptal",
"D",
"Patel1,2,6*",
"Abstract",
"Background:",
"Automated",
"reporting",
"of",
"estimated",
"glomerular",
"filtration",
"rate",
"(eGFR)",
"is",
"a",
"recent",
"advance",
"in",
"laboratory",
"information",
"technology",
"(IT)",
"that",
"generates",
"a",
"measure",
"of",
"kidney",
"function",
"with",
"chemistry",
"laboratory",
"results",
"to",
"aid",
"early",
"detection",
"of",
"chronic",
"kidney",
"disease",
"(CKD).",
"Because",
"accurate",
"diagnosis",
"of",
"CKD",
"is",
"critical",
"to",
"optimal",
"medical",
"decision-making,",
"several",
"clinical",
"practice",
"guidelines",
"have",
"recommended",
"the",
"use",
"of",
"automated",
"eGFR",
"reporting.",
"Since",
"its",
"introduction,",
"automated",
"eGFR",
"reporting",
"has",
"not",
"been",
"uniformly",
"implemented",
"by",
"U.",
"S.",
"laboratories",
"despite",
"the",
"growing",
"prevalence",
"of",
"CKD.",
"CKD",
"is",
"highly",
"prevalent",
"within",
"the",
"Veterans",
"Health",
"Administration",
"(VHA),",
"and",
"implementation",
"of",
"automated",
"eGFR",
"reporting",
"within",
"this",
"integrated",
"healthcare",
"system",
"has",
"the",
"potential",
"to",
"improve",
"care.",
"In",
"July",
"2004,",
"the",
"VHA",
"adopted",
"automated",
"eGFR",
"reporting",
"through",
"a",
"system-wide",
"mandate",
"for",
"software",
"implementation",
"by",
"individual",
"VHA",
"laboratories.",
"This",
"study",
"examines",
"the",
"timing",
"of",
"software",
"implementation",
"by",
"individual",
"VHA",
"laboratories",
"and",
"factors",
"associated",
"with",
"implementation.",
"Methods:",
"We",
"performed",
"a",
"retrospective",
"observational",
"study",
"of",
"laboratories",
"in",
"VHA",
"facilities",
"from",
"July",
"2004",
"to",
"September",
"2009.",
"Using",
"laboratory",
"data,",
"we",
"identified",
"the",
"status",
"of",
"implementation",
"of",
"automated",
"eGFR",
"reporting",
"for",
"each",
"facility",
"and",
"the",
"time",
"to",
"actual",
"implementation",
"from",
"the",
"date",
"the",
"VHA",
"adopted",
"its",
"policy",
"for",
"automated",
"eGFR",
"reporting.",
"Using",
"survey",
"and",
"administrative",
"data,",
"we",
"assessed",
"facility",
"organizational",
"characteristics",
"associated",
"with",
"implementation",
"of",
"automated",
"eGFR",
"reporting",
"via",
"bivariate",
"analyses.",
"Results:",
"Of",
"104",
"VHA",
"laboratories,",
"88%",
"implemented",
"automated",
"eGFR",
"reporting",
"in",
"existing",
"laboratory",
"IT",
"systems",
"by",
"the",
"end",
"of",
"the",
"study",
"period.",
"Time",
"to",
"initial",
"implementation",
"ranged",
"from",
"0.2",
"to",
"4.0",
"years",
"with",
"a",
"median",
"of",
"1.8",
"years.",
"All",
"VHA",
"facilities",
"with",
"on-site",
"dialysis",
"units",
"implemented",
"the",
"eGFR",
"software",
"(52%,",
"p<0.001).",
"Other",
"organizational",
"characteristics",
"were",
"not",
"statistically",
"significant.",
"Conclusions:",
"The",
"VHA",
"did",
"not",
"have",
"uniform",
"implementation",
"of",
"automated",
"eGFR",
"reporting",
"across",
"its",
"facilities.",
"Facility-level",
"organizational",
"characteristics",
"were",
"not",
"associated",
"with",
"implementation,",
"and",
"this",
"suggests",
"that",
"decisions",
"for",
"implementation",
"of",
"this",
"software",
"are",
"not",
"related",
"to",
"facility-level",
"quality",
"improvement",
"measures.",
"Additional",
"studies",
"on",
"implementation",
"of",
"laboratory",
"IT,",
"such",
"as",
"automated",
"eGFR",
"reporting,",
"could",
"identify",
"factors",
"that",
"are",
"related",
"to",
"more",
"timely",
"implementation",
"and",
"lead",
"to",
"better",
"healthcare",
"delivery.",
"Background",
"Since",
"its",
"development,",
"automated",
"laboratory",
"reporting",
"of",
"estimated",
"glomerular",
"filtration",
"rate",
"(eGFR)",
"has",
"facilitated",
"diagnosis",
"and",
"management",
"of",
"chronic",
"kidney",
"disease",
"*",
"Correspondence:",
"uptal.patel@dm.duke.edu",
"1Center",
"for",
"Health",
"Services",
"Research",
"in",
"Primary",
"Care,",
"Veterans",
"Affairs",
"Health",
"Services",
"Research",
"&",
"Development,",
"Durham,",
"NC,",
"USA",
"2Department",
"of",
"Medicine,",
"Duke",
"University",
"School",
"of",
"Medicine,",
"Durham,",
"NC,",
"USA",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"(CKD)",
"[1].",
"To",
"report",
"eGFR,",
"clinical",
"laboratories",
"imple-",
"ment",
"software",
"that",
"calculates",
"eGFR",
"from",
"equations",
"based",
"on",
"serum",
"creatinine",
"and",
"demographic",
"variables.",
"As",
"a",
"result,",
"clinicians",
"who",
"receive",
"laboratory",
"reports",
"of",
"eGFR",
"in",
"addition",
"to",
"serum",
"creatinine",
"may",
"make",
"more",
"informed",
"clinical",
"decisions.",
"The",
"importance",
"of",
"auto-",
"mated",
"eGFR",
"reporting",
"was",
"established",
"by",
"National",
"Kid-",
"ney",
"Foundation",
"clinical",
"guidelines",
"in",
"2002,",
"and,",
"later,",
"endorsed",
"by",
"the",
"National",
"Kidney",
"Disease",
"Education",
"©",
"2012",
"Hall",
"et",
"al.;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
] | [
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"rheumatoid",
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"Kimberly",
"E",
"Taylor",
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"Lindsey",
"A",
"Criswell*",
"Address:",
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"Medical",
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"University",
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"374",
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"San",
"Francisco,",
"California",
"94143",
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"E-mail:",
"Kimberly",
"E",
"Taylor",
"-",
"kim.taylor@ucsf.edu;",
"Lindsey",
"A",
"Criswell*",
"-",
"lindsey.criswell@ucsf.edu",
"*Corresponding",
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"BioMed",
"Central",
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"Genetic",
"Analysis",
"Workshop",
"16",
"St",
"Louis,",
"MO,",
"USA",
"17-20",
"September",
"2009",
"Published:",
"15",
"December",
"2009",
"BMC",
"Proceedings",
"2009,",
"3(Suppl",
"7):S36",
"doi:",
"10.1186/1753-6561-3-S7-S36",
"This",
"article",
"is",
"available",
"from:",
"http://www.biomedcentral.com/1753-6561/3/S7/S36",
"©",
"2009",
"Taylor",
"and",
"Criswell;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"open",
"access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Abstract",
"We",
"performed",
"a",
"whole-genome",
"association",
"study",
"of",
"rheumatoid",
"arthritis",
"susceptibility",
"using",
"Illumina",
"550k",
"single-nucleotide",
"polymorphism",
"(SNP)",
"genotypes",
"of",
"868",
"cases",
"and",
"1194",
"controls",
"from",
"the",
"North",
"American",
"Rheumatoid",
"Arthritis",
"Consortium",
"(NARAC).",
"Structured",
"association",
"analysis",
"with",
"adjustment",
"for",
"potential",
"population",
"stratification",
"yielded",
"200",
"SNPs",
"with",
"p",
"<",
"1",
"×",
"10-8",
"for",
"association",
"with",
"RA,",
"all",
"of",
"which",
"were",
"on",
"chromosome",
"6",
"in",
"a",
"2.7-Mb",
"region",
"of",
"the",
"major",
"histocompatibility",
"complex",
"(MHC).",
"Given",
"the",
"extensive",
"linkage",
"equilibrium",
"in",
"the",
"region",
"and",
"known",
"risk",
"of",
"HLA-DRB1",
"alleles,",
"we",
"then",
"applied",
"conditional",
"analyses",
"to",
"ascertain",
"independent",
"signals",
"for",
"RA",
"susceptibility",
"among",
"these",
"200",
"candidate",
"SNPs.",
"Conditional",
"analyses",
"incorporating",
"risk",
"categories",
"of",
"the",
"HLA-DRB1",
"\"shared",
"epitope”",
"revealed",
"three",
"SNPs",
"having",
"independent",
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"with",
"RA",
"(conditional",
"p",
"<",
"0.001).",
"This",
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"MHC",
"in",
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"is",
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"systemic",
"auto-",
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"characterized",
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"damage",
"to",
"synovial",
"joints",
"as",
"well",
"as",
"extraarticular",
"manifestations.",
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"strongest",
"known",
"genetic",
"risk",
"factor",
"is",
"the",
"HLA-DRB1",
"gene",
"on",
"chromosome",
"6,",
"namely",
"a",
"set",
"of",
"alleles",
"sharing",
"a",
"common",
"sequence",
"known",
"as",
"the",
"shared",
"epitope",
"(SE)",
"[1].",
"Recent",
"whole-genome",
"association",
"studies",
"have",
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"new",
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"genes",
"outside",
"of",
"the",
"HLA",
"region",
"[2-4],",
"and",
"some",
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"additional",
"influences",
"from",
"the",
"HLA",
"class",
"III",
"and",
"class",
"I",
"regions",
"[5,6].",
"In",
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"RA",
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"alleles",
"throughout",
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"genome,",
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"histocompatibility",
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"(MHC)",
"in",
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"550k",
"genotyping",
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"from",
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"whole-genome",
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"study",
"by",
"North",
"American",
"Rheumatoid",
"Arthritis",
"Consortium",
"(NARAC)",
"[3]",
"was",
"used",
"for",
"this",
"study",
"as",
"part",
"of",
"the",
"Genetic",
"Analysis",
"Workshop",
"16;",
"duplicated",
"and",
"contaminated",
"samples",
"had",
"been",
"removed",
"previously.",
"Using",
"the",
"computer",
"program",
"Page",
"1",
"of",
"5",
"(page",
"number",
"not",
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] | [
"J",
"Korean",
"Med",
"Sci",
"2010;",
"25:",
"647-50",
"ISSN",
"1011-8934",
"DOI:",
"10.3346/jkms.2010.25.4.647",
"Acute",
"Shunt",
"Malfunction",
"after",
"Cesarean",
"Section",
"Delivery:",
"A",
"Case",
"Report",
"Shunt",
"malfunctions",
"that",
"require",
"surgical",
"intervention",
"during",
"pregnancy",
"and",
"the",
"postpartum",
"period",
"are",
"rare.",
"Furthermore,",
"no",
"study",
"has",
"reported",
"on",
"an",
"acute",
"shunt",
"malfunction",
"immediately",
"after",
"cesarean",
"section.",
"Here,",
"we",
"describe",
"the",
"case",
"of",
"a",
"32-yr-old",
"woman",
"who",
"became",
"drowsy",
"12",
"hr",
"after",
"cesarean",
"section",
"delivery",
"of",
"her",
"second",
"child.",
"She",
"had",
"a",
"ventriculoperitoneal",
"shunt",
"placed",
"to",
"treat",
"hydrocephalus",
"associated",
"with",
"meningitis",
"at",
"26",
"yr",
"of",
"age.",
"Marked",
"ventriculomegaly",
"was",
"seen",
"on",
"brain",
"computed",
"tomography",
"and",
"her",
"consciousness",
"recovered",
"temporarily",
"after",
"aspirating",
"cerebrospinal",
"fluid",
"from",
"the",
"flushing",
"device.",
"At",
"surgery,",
"the",
"distal",
"catheter",
"tip",
"was",
"plugged",
"by",
"a",
"blood",
"clot.",
"We",
"believe",
"that",
"the",
"blood",
"spilled",
"over",
"during",
"the",
"cesarean",
"section.",
"The",
"clogged",
"catheter",
"end",
"was",
"simply",
"cut",
"off",
"and",
"the",
"remaining",
"catheter",
"was",
"repositioned",
"in",
"the",
"peritoneal",
"cavity.",
"Her",
"consciousness",
"recovered",
"fully.",
"Key",
"Words",
":",
"Ventriculoperitoneal",
"Shunt;",
"Prosthesis",
"Failure;",
"Hydrocephalus;",
"Cesarean",
"Section",
"ⓒ",
"2010",
"The",
"Korean",
"Academy",
"of",
"Medical",
"Sciences.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"Non-Commercial",
"License",
"(http://creativecommons.org/licenses/by-nc/3.0)",
"which",
"permits",
"unrestricted",
"non-commercial",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Sun-Chul",
"Hwang1,",
"Tae-Hee",
"Kim2,",
"Bum-Tae",
"Kim1,",
"Soo-Bin",
"Im1,",
"and",
"Won-Han",
"Shin1",
"Department",
"of",
"Neurosurgery1,",
"and",
"Obstetrics",
"and",
"Gynecology2,",
"Soonchunhyang",
"University",
"Bucheon",
"Hospital,",
"Bucheon,",
"Korea",
"Received",
":",
"25",
"June",
"2008",
"Accepted",
":",
"20",
"January",
"2009",
"Address",
"for",
"Correspondence",
"Sun-Chul",
"Hwang,",
"M.D.",
"Department",
"of",
"Neurosurgery,",
"Soonchunhyang",
"University",
"Bucheon",
"Hospital,",
"1174",
"Jung-dong,",
"Wonmi-gu,",
"Bucheon",
"420-747,",
"Korea",
"Tel",
":",
"+82.32-621-5291,",
"Fax",
":",
"+82.32-621-5016",
"E-mail",
":",
"sunchulh@sch.ac.kr",
"INTRODUCTION",
"Cerebrospinal",
"fluid",
"(CSF)",
"shunts",
"are",
"a",
"definite",
"treatment",
"for",
"hydrocephalus.",
"As",
"increasing",
"numbers",
"of",
"women",
"have",
"CSF",
"shunts",
"placed",
"to",
"treat",
"hydrocephalus,",
"more",
"shunt-depen-",
"dent",
"women",
"are",
"becoming",
"pregnant",
"(1,",
"2).",
"Although",
"the",
"maternal",
"and",
"fetal",
"outcome",
"in",
"patients",
"with",
"ventriculoperi-",
"toneal",
"(VP)",
"shunts",
"is",
"uniformly",
"excellent,",
"the",
"changes",
"in",
"the",
"abdominal",
"cavity,",
"such",
"as",
"the",
"enlargement",
"of",
"the",
"uterus",
"and",
"increased",
"abdominal",
"pressure,",
"could",
"cause",
"shunt",
"failure",
"(1,",
"3-5).",
"The",
"distal",
"shunt",
"catheter",
"is",
"frequently",
"obstructed",
"in",
"pregnancy,",
"especially",
"during",
"the",
"third",
"trimester",
"when",
"the",
"intra-abdominal",
"pressure",
"is",
"thought",
"to",
"be",
"highest",
"(3,",
"4).",
"Post-",
"partum",
"shunt",
"complications",
"are",
"rare",
"(1,",
"4,",
"6,",
"7),",
"and",
"shunt",
"obstruction",
"immediately",
"after",
"a",
"cesarean",
"section",
"had",
"not",
"been",
"reported.",
"We",
"present",
"a",
"patient",
"with",
"a",
"VP",
"shunt",
"who",
"had",
"reduced",
"consciousness",
"due",
"to",
"obstruction",
"of",
"the",
"abdominal",
"shunt",
"catheter",
"immediately",
"after",
"a",
"cesarean",
"section",
"delivery.",
"CASE",
"REPORT",
"A",
"32-yr-old",
"woman,",
"G2P2A0L2,",
"came",
"to",
"the",
"emergency",
"department",
"complaining",
"that",
"she",
"felt",
"drowsy.",
"She",
"had",
"under-",
"gone",
"a",
"cesarean",
"section",
"delivery",
"of",
"a",
"full-term",
"healthy",
"baby",
"647",
"(3,200",
"gm)",
"the",
"day",
"before.",
"At",
"the",
"age",
"of",
"26",
"yr,",
"she",
"had",
"a",
"VP",
"shunt",
"placed",
"to",
"treat",
"hydrocephalus",
"associated",
"with",
"menin-",
"gitis.",
"She",
"underwent",
"a",
"shunt",
"revision",
"when",
"she",
"was",
"29",
"yr",
"old.",
"At",
"that",
"time,",
"she",
"was",
"in",
"the",
"sixth",
"month",
"of",
"her",
"first",
"preg-",
"nancy",
"and",
"complained",
"of",
"drowsiness",
"and",
"headache.",
"Her",
"hus-",
"band",
"said",
"that",
"the",
"reason",
"for",
"the",
"shunt",
"malfunction",
"had",
"not",
"been",
"determined",
"and",
"the",
"malfunctioning",
"VP",
"shunt",
"had",
"been",
"replaced",
"with",
"a",
"new",
"device.",
"The",
"revision",
"surgery",
"had",
"success-",
"fully",
"relieved",
"her",
"symptoms.",
"At",
"full",
"term,",
"she",
"underwent",
"a",
"lower",
"segment",
"cesarean",
"section",
"because",
"of",
"fetal",
"distress",
"and",
"gave",
"birth",
"to",
"her",
"first",
"child,",
"who",
"weighed",
"3,580",
"g.",
"The",
"post-",
"partum",
"course",
"was",
"unremarkable",
"after",
"the",
"birth",
"of",
"her",
"first",
"child.",
"At",
"31",
"yr",
"of",
"age,",
"she",
"became",
"pregnant",
"with",
"her",
"second",
"child.",
"She",
"had",
"no",
"symptoms",
"related",
"to",
"shunt",
"malfunction",
"during",
"gestation.",
"A",
"repeated",
"cesarean",
"section",
"was",
"performed",
"at",
"the",
"same",
"private",
"obstetrics",
"clinic",
"and",
"a",
"healthy",
"baby",
"was",
"deliv-",
"ered.",
"The",
"peritoneal",
"cavity",
"was",
"not",
"irrigated",
"and",
"the",
"shunt",
"tube",
"was",
"not",
"observed",
"at",
"surgery.",
"She",
"began",
"to",
"complain",
"of",
"a",
"headache",
"12",
"hr",
"after",
"the",
"cesarean",
"section.",
"Her",
"consciousness",
"deteriorated",
"gradually",
"and",
"she",
"became",
"drowsy.",
"She",
"was",
"trans-",
"ferred",
"to",
"our",
"hospital",
"24",
"hr",
"postoperatively.",
"In",
"the",
"emergency",
"room,",
"she",
"did",
"not",
"open",
"her",
"eyes",
"spontaneously",
"and",
"her",
"ver-",
"bal",
"response",
"was",
"very",
"slow",
"and",
"inappropriate.",
"Ventriculome-",
"galy",
"with",
"a",
"bifrontal",
"index",
"of",
"41%",
"was",
"seen",
"on",
"brain",
"com-"
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] | [
"doi:10.1093/brain/awn184",
"Brain",
"(2008),",
"131,",
"2783^2797",
"Correlation",
"of",
"passivity",
"symptoms",
"and",
"dysfunctional",
"visuomotor",
"action",
"monitoring",
"in",
"psychosis",
"Knut",
"Schnell,1",
"Karsten",
"Heekeren,2,3",
"J",
"o«rg",
"Daumann,2",
"Thomas",
"Schnell,2",
"Ralph",
"Schnitker,4",
"Walter",
"M",
"o«ller-Hartmann5",
"and",
"Euphrosyne",
"Gouzoulis-Mayfrank2",
"1Department",
"of",
"Psychiatry",
"and",
"Psychotherapy,",
"Division",
"of",
"Medical",
"Psychology,",
"University",
"Hospital",
"of",
"Bonn,",
"2Department",
"of",
"Psychiatry",
"and",
"Psychotherapy,",
"University",
"Hospital",
"of",
"Cologne,",
"Germany,",
"3Psychiatric",
"University",
"Hospital,",
"Zu«",
"rich,",
"Switzerland,",
"4Interdisciplinary",
"Center",
"for",
"Clinical",
"Research",
"(ICCR),",
"Functional",
"Neuroimaging",
"Unit,",
"RWTH",
"Aachen",
"and",
"5Department",
"of",
"Radiology,",
"University",
"Hospital",
"of",
"Cologne,",
"Germany",
"Correspondence",
"to:",
"Dr",
"Knut",
"Schnell,",
"Abteilung",
"f",
"u«r",
"Medizinische",
"Psychologie,",
"Zentrum",
"f",
"u«r",
"Nervenheilkunde,",
"Universita«",
"tsklinikum",
"Bonn,",
"Sigmund-Freud-Strasse",
"25,",
"53105",
"Bonn,",
"Germany",
"E-mail:",
"knut.schnell@ukb.uni-bonn.de",
"Passivity",
"experiences",
"are",
"hallmark",
"symptoms",
"of",
"schizophrenia",
"that",
"can",
"be",
"characterized",
"by",
"the",
"belief",
"that",
"one’s",
"thoughts",
"or",
"actions",
"are",
"controlled",
"by",
"an",
"external",
"agent.",
"It",
"has",
"recently",
"been",
"suggested",
"that",
"these",
"psychotic",
"experiences",
"result",
"from",
"defective",
"monitoring",
"of",
"one’s",
"own",
"actions,",
"i.e.",
"disturbed",
"comparison",
"of",
"actions",
"and",
"perceived",
"outcomes.",
"In",
"this",
"study,",
"we",
"examined",
"the",
"function",
"of",
"the",
"previously",
"characterized",
"action",
"monitoring",
"network",
"of",
"the",
"inferior",
"parietal",
"lobule",
"(IPL),",
"medial",
"(mPFC)",
"and",
"lateral",
"prefrontal",
"cortices",
"in",
"patients",
"with",
"different",
"levels",
"of",
"passivity",
"symptoms",
"with",
"an",
"fMRI",
"task.The",
"visuomotor",
"fMRI",
"task",
"demanded",
"control",
"of",
"visually",
"perceived",
"object",
"movements",
"by",
"alternating",
"button",
"presses",
"with",
"the",
"left",
"and",
"the",
"right",
"index",
"finger.",
"In",
"the",
"monitoring",
"condition",
"of",
"this",
"task",
"subjects",
"stopped",
"their",
"actions",
"whenever",
"they",
"detected",
"visuomotor",
"incongru-",
"ence.",
"fMRI",
"and",
"behavioural",
"data",
"from",
"15",
"patients",
"were",
"tested",
"for",
"correlation",
"with",
"passivity",
"symptoms",
"using",
"standardized",
"Scale",
"for",
"Assessment",
"of",
"Positive",
"Symptoms",
"(SAPS)-",
"and",
"AMDP-",
"passivity",
"symptom",
"ratings.",
"Both",
"types",
"of",
"data",
"were",
"tested",
"for",
"differences",
"between",
"the",
"patients",
"group",
"and",
"15",
"healthy",
"controls.",
"In",
"the",
"patient",
"group",
"we",
"found",
"the",
"expected",
"correlation",
"of",
"passivity",
"symptoms",
"and",
"visuomotor",
"monitoring",
"performance.There",
"was",
"a",
"significant",
"positive",
"correlation",
"of",
"passivity",
"symptoms",
"with",
"increased",
"latency",
"of",
"incongruence",
"detection",
"and",
"a",
"negative",
"correlation",
"of",
"SAPS-passivity",
"with",
"the",
"number",
"of",
"detected",
"events.",
"fMRI",
"data",
"revealed",
"correla-",
"tions",
"of",
"passivity",
"symptoms",
"with",
"activation",
"in",
"bilateral",
"IPL,",
"primary",
"motor",
"and",
"sensory",
"cortices",
"in",
"the",
"action",
"monitoring",
"condition.",
"A",
"correlation",
"of",
"passivity",
"symptoms",
"with",
"the",
"main",
"experimental",
"effect",
"(actions",
"with",
"^",
"actions",
"without",
"monitoring)",
"was",
"found",
"in",
"the",
"posterior",
"cingulate",
"cortex",
"(PCC)",
"and",
"in",
"the",
"left",
"IPL.",
"No",
"group",
"differences",
"or",
"group",
"by",
"task",
"interactions",
"were",
"found",
"within",
"the",
"visuomotor-action-monitoring",
"network.",
"Our",
"results",
"demonstrate",
"the",
"association",
"between",
"passivity",
"symptoms",
"and",
"the",
"dysfunction",
"of",
"visuomotor",
"action",
"monitoring",
"and",
"support",
"the",
"idea",
"that",
"psychotic",
"passivity",
"experiences",
"result",
"from",
"dysfunctions",
"of",
"central",
"action",
"monitoring",
"mechanisms:",
"According",
"to",
"pre-existing",
"concepts",
"of",
"parietal",
"cortex",
"function,",
"IPL-hyperactivation",
"may",
"represent",
"an",
"increase",
"in",
"false",
"detections",
"of",
"visuomotor",
"incongruence",
"while",
"the",
"correlation",
"between",
"passiv-",
"ity",
"and",
"the",
"differential",
"effect",
"of",
"monitoring",
"on",
"PCC-activation",
"assumedly",
"represents",
"greater",
"self-monitoring",
"effort",
"in",
"passivity",
"experiences.",
"Keywords:",
"action",
"monitoring;",
"visuomotor;",
"schizophrenia;",
"functional",
"magnetic",
"resonance",
"imaging;",
"parietal",
"lobe",
"Abbreviations:",
"AIMS",
"=",
"Abnormal",
"Involuntary",
"Movement",
"Scale;",
"BA",
"=",
"Brodmann",
"area;",
"CC",
"=",
"control",
"condition;",
"EPI",
"=",
"echoplanar",
"imaging;",
"EPS",
"=",
"Extrapyramidal",
"Motor",
"Side",
"Effects",
"Scale;",
"FDR",
"=",
"false",
"discovery",
"rate;",
"HRF",
"=",
"hemodynamic",
"response",
"function;",
"IPL",
"=",
"inferior",
"parietal",
"lobule;",
"MC",
"=",
"monitoring",
"condition;",
"mPFC",
"=",
"medial",
"prefrontal",
"cortex;",
"PCC",
"=",
"posterior",
"cingulate",
"cortex;",
"SANS",
"=",
"Scale",
"for",
"Assessment",
"of",
"Negative",
"Symptoms;",
"SAPS",
"=",
"Scale",
"for",
"Assessment",
"of",
"Positive",
"Symptoms;",
"SCID",
"=",
"Structured",
"Clinical",
"Interview",
"for",
"DSM-IV",
"Axis",
"I",
"Disorders;",
"SPM",
"=",
"Statistical",
"Parametric",
"Mapping",
"Received",
"February",
"25,",
"2008.",
"Revised",
"July",
"7,",
"2008.",
"Accepted",
"July",
"21,",
"2008.",
"Advance",
"Access",
"publication",
"August",
"19,",
"2008",
"2008",
"The",
"Author(s)",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"Non-Commercial",
"License",
"(http://creativecommons.org/licenses/by-nc/2.0/uk/)",
"which",
"permits",
"unrestricted",
"non-commercial",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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] | [
"Brief",
"Definitive",
"Report",
"Entry",
"of",
"B",
"Cell",
"Receptor",
"into",
"Signaling",
"Domains",
"Is",
"Inhibited",
"in",
"Tolerant",
"B",
"Cells",
"By",
"Bennett",
"C.Weintraub,*",
"Jesse",
"Eunsuk",
"Jun,*",
"Anthony",
"C.",
"Bishop,‡",
"Kevan",
"M.",
"Shokat,‡",
"Matthew",
"L.",
"Thomas,†",
"and",
"Christopher",
"C.",
"Goodnow*",
"From",
"the",
"*Australian",
"Cancer",
"Research",
"Foundation",
"Genetics",
"Laboratory,",
"Medical",
"Genome",
"Centre,",
"John",
"Curtin",
"School",
"of",
"Medical",
"Research,",
"Canberra",
"2601,Australia;",
"the",
"‡Department",
"of",
"Chemistry,",
"Princeton",
"University,",
"Princeton,",
"New",
"Jersey",
"08544;",
"and",
"the",
"†Howard",
"Hughes",
"Medical",
"Institute",
"and",
"Department",
"of",
"Pathology,Washington",
"University",
"School",
"of",
"Medicine,",
"St.",
"Louis,",
"Missouri",
"63110",
"Abstract",
"Signal",
"transduction",
"through",
"the",
"B",
"cell",
"antigen",
"receptor",
"(BCR)",
"is",
"altered",
"in",
"B",
"cells",
"that",
"express",
"a",
"receptor",
"that",
"recognizes",
"self-antigen.",
"To",
"understand",
"the",
"molecular",
"basis",
"for",
"the",
"change",
"in",
"sig-",
"naling",
"in",
"autoreactive",
"B",
"cells,",
"a",
"transgenic",
"model",
"was",
"used",
"to",
"isolate",
"a",
"homogeneous",
"popula-",
"tion",
"of",
"tolerant",
"B",
"lymphocytes.",
"These",
"cells",
"were",
"compared",
"with",
"a",
"similar",
"population",
"of",
"naive",
"B",
"lymphocytes.",
"We",
"show",
"that",
"the",
"BCR",
"from",
"naive",
"B",
"cells",
"enters",
"a",
"detergent-insoluble",
"domain",
"of",
"the",
"cell",
"within",
"6",
"s",
"after",
"antigen",
"binding,",
"before",
"a",
"detectable",
"increase",
"in",
"BCR",
"phosphoryla-",
"tion.",
"This",
"fraction",
"appears",
"to",
"be",
"important",
"for",
"signaling",
"because",
"it",
"is",
"enriched",
"for",
"lyn",
"kinase",
"but",
"lacks",
"CD45",
"tyrosine",
"phosphatase",
"and",
"because",
"the",
"BCR",
"that",
"moves",
"into",
"this",
"domain",
"becomes",
"more",
"highly",
"phosphorylated.",
"Partitioning",
"of",
"the",
"BCR",
"into",
"this",
"fraction",
"is",
"unaffected",
"by",
"src",
"family",
"kinase",
"inhibition.",
"Tolerant",
"B",
"cells",
"do",
"not",
"efficiently",
"partition",
"the",
"BCR",
"into",
"the",
"deter-",
"gent-insoluble",
"domain,",
"providing",
"an",
"explanation",
"for",
"their",
"reduced",
"tyrosine",
"kinase",
"activation",
"and",
"calcium",
"flux",
"in",
"response",
"to",
"antigen.",
"These",
"results",
"identify",
"an",
"early,",
"regulated",
"step",
"in",
"anti-",
"gen",
"receptor",
"signaling",
"and",
"self-tolerance.",
"Key",
"words:",
"B",
"cell",
"antigen",
"receptor",
"signaling",
"•",
"tyrosine",
"phosphorylation",
"•",
"membrane",
"raft",
"•",
"self-tolerance",
"•",
"anergy",
"Introduction",
"Mice",
"expressing",
"transgenes",
"for",
"anti–hen",
"egg",
"lysozyme",
"(HEL)",
"IgM/IgD",
"B",
"cell",
"antigen",
"receptor",
"(BCR)",
"contain",
"large",
"homogeneous",
"populations",
"of",
"B",
"cells",
"that",
"are",
"func-",
"tionally",
"naive.",
"When",
"anti-HEL",
"transgenic",
"mice",
"are",
"crossed",
"to",
"transgenic",
"mice",
"expressing",
"soluble",
"HEL,",
"the",
"B",
"cells",
"in",
"the",
"double-transgenic",
"offspring",
"are",
"constantly",
"ex-",
"posed",
"to",
"low",
"levels",
"of",
"antigenic",
"stimulation",
"and",
"become",
"functionally",
"tolerant",
"(anergic).",
"The",
"tolerant",
"cells",
"lose",
"some",
"responses",
"to",
"antigen,",
"notably",
"BCR-induced",
"proliferation,",
"but",
"retain",
"other",
"responses,",
"including",
"BCR-induced",
"apop-",
"tosis,",
"changes",
"in",
"follicular",
"homing,",
"and",
"inhibition",
"of",
"plas-",
"macyte",
"differentiation",
"(1–3).",
"Binding",
"of",
"HEL",
"to",
"the",
"BCR",
"on",
"these",
"cells",
"results",
"in",
"only",
"a",
"subset",
"of",
"the",
"biochemical",
"re-",
"sponses",
"that",
"are",
"triggered",
"by",
"HEL",
"in",
"naive",
"anti-HEL",
"trans-",
"genic",
"B",
"cells.",
"For",
"example,",
"the",
"BCR",
"on",
"tolerant",
"B",
"cells",
"Address",
"correspondence",
"to",
"Christopher",
"C.",
"Goodnow,",
"Medical",
"Genome",
"Centre,",
"John",
"Curtin",
"School",
"of",
"Medical",
"Research,",
"ANU,",
"Mills",
"Rd.,",
"Can-",
"berra",
"2601",
"ACT,",
"Australia.",
"Phone:",
"61-2-6249-3621;",
"Fax:",
"61-2-6279-",
"8512;",
"E-mail:",
"Chris.Goodnow@anu.edu.au",
"continually",
"activates",
"low",
"intracellular",
"calcium",
"oscillations",
"and",
"extracellular",
"signal–regulated",
"kinase",
"(ERK),",
"and",
"nu-",
"clear",
"factor",
"of",
"activated",
"T",
"cells",
"(NFAT)c",
"pathways",
"but",
"does",
"not",
"produce",
"high",
"calcium",
"elevations",
"or",
"activate",
"the",
"c-Jun",
"NH2-terminal",
"kinase",
"(JNK)",
"and",
"nuclear",
"factor",
"(NF)-kB",
"pathways",
"(4).",
"How",
"the",
"BCR",
"is",
"selectively",
"uncoupled",
"from",
"some",
"sig-",
"naling",
"pathways",
"but",
"not",
"others",
"is",
"unclear.",
"Antigen-induced",
"protein",
"tyrosine",
"phosphorylation",
"of",
"the",
"BCR",
"and",
"other",
"molecules",
"is",
"greatly",
"reduced",
"in",
"HEL-tolerant",
"B",
"cells",
"(5).",
"However,",
"tolerant",
"B",
"cells",
"express",
"at",
"normal",
"levels",
"and",
"with",
"normal",
"basal",
"activity",
"proteins",
"important",
"for",
"BCR-induced",
"signal",
"transduction,",
"such",
"as",
"syk,",
"lyn,",
"CD45,",
"and",
"Src",
"homol-",
"ogy",
"2",
"domain–containing",
"protein",
"tyrosine",
"phosphatase",
"(SHP)-1.",
"Here",
"we",
"present",
"evidence",
"for",
"an",
"early,",
"regulated",
"step",
"in",
"BCR",
"signaling",
"that",
"may",
"resolve",
"this",
"paradox.",
"We",
"find",
"that",
"in",
"naive",
"cells,",
"the",
"stimulated",
"BCR",
"becomes",
"associated",
"with",
"a",
"detergent-insoluble",
"fraction",
"containing",
"lyn,",
"and",
"that",
"in",
"tolerant",
"cells,",
"the",
"BCR",
"does",
"not",
"efficiently",
"associate",
"with",
"1443",
"J.",
"Exp.",
"Med.",
"The",
"Rockefeller",
"University",
"Press",
"•",
"0022-1007/2000/04/1443/06",
"$5.00",
"Volume",
"191,",
"Number",
"8,",
"April",
"17,",
"2000",
"1443–1448",
"http://www.jem.org/cgi/current/full/191/8/1443"
] | [
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] | [
"Original",
"Article",
"Radiat",
"Oncol",
"J",
"2011;29(3):199-205",
"http://dx.doi.org/10.3857/roj.2011.29.3.199",
"pISSN",
"2234-1900",
"·",
"eISSN",
"2234-3156",
"A",
"comparison",
"of",
"preplan",
"MRI",
"and",
"preplan",
"CT-based",
"prostate",
"volume",
"with",
"intraoperative",
"ultrasound-based",
"prostate",
"volume",
"in",
"real-time",
"permanent",
"brachytherapy",
"Hyeli",
"Park,",
"MD1,",
"Ja",
"Young",
"Kim,",
"MD1,",
"Bo",
"Mi",
"Lee,",
"MD1,",
"Sei",
"Kyung",
"Chang,",
"MD1,",
"Seung",
"Young",
"Ko,",
"BS1,",
"Sung",
"Jun",
"Kim,",
"MS1,",
"Dong",
"Soo",
"Park,",
"MD2,",
"Hyun",
"Soo",
"Shin,",
"MD1",
"Departments",
"of",
"1Radiation",
"Oncology,",
"2Urology,",
"CHA",
"Bundang",
"Medical",
"Center,",
"CHA",
"University,",
"Seougnam,",
"Korea",
"Purpose:",
"The",
"present",
"study",
"compared",
"the",
"difference",
"between",
"intraoperative",
"transrectal",
"ultrasound",
"(iTRUS)-based",
"prostate",
"volume",
"and",
"preplan",
"computed",
"tomography",
"(CT),",
"preplan",
"magnetic",
"resonance",
"imaging",
"(MRI)-based",
"prostate",
"volume",
"to",
"estimate",
"the",
"number",
"of",
"seeds",
"needed",
"for",
"appropriate",
"dose",
"coverage",
"in",
"permanent",
"brachytherapy",
"for",
"prostate",
"cancer.",
"Materials",
"and",
"Methods:",
"Between",
"March",
"2007",
"and",
"March",
"2011,",
"among",
"112",
"patients",
"who",
"underwent",
"permanent",
"brachytherapy",
"with",
"125I,",
"60",
"image",
"scans",
"of",
"56",
"patients",
"who",
"underwent",
"preplan",
"CT",
"(pCT)",
"or",
"preplan",
"MRI",
"(pMRI)",
"within",
"2",
"months",
"before",
"brachytherapy",
"were",
"retrospectively",
"reviewed.",
"Twenty-four",
"cases",
"among",
"30",
"cases",
"with",
"pCT",
"and",
"26",
"cases",
"among",
"30",
"cases",
"with",
"pMRI",
"received",
"neoadjuvant",
"hormone",
"therapy",
"(NHT).",
"In",
"34",
"cases,",
"NHT",
"started",
"after",
"acquisition",
"of",
"preplan",
"image.",
"The",
"median",
"duration",
"of",
"NHT",
"after",
"preplan",
"image",
"acquisition",
"was",
"17",
"and",
"21",
"days",
"for",
"cases",
"with",
"pCT",
"and",
"pMRI,",
"respectively.",
"The",
"prostate",
"volume",
"calculated",
"by",
"different",
"modalities",
"was",
"compared.",
"And",
"retrospective",
"planning",
"with",
"iTRUS",
"image",
"was",
"performed",
"to",
"estimate",
"the",
"number",
"of",
"125I",
"seed",
"required",
"to",
"obtain",
"recommended",
"dose",
"distribution",
"according",
"to",
"prostate",
"volume.",
"Results:",
"The",
"mean",
"difference",
"in",
"prostate",
"volume",
"was",
"9.05",
"mL",
"between",
"the",
"pCT",
"and",
"iTRUS",
"and",
"6.84",
"mL",
"between",
"the",
"pMRI",
"and",
"iTRUS.",
"The",
"prostate",
"volume",
"was",
"roughly",
"overestimated",
"by",
"1.36",
"times",
"with",
"pCT",
"and",
"by",
"1.33",
"times",
"with",
"pMRI.",
"For",
"34",
"cases",
"which",
"received",
"NHT",
"after",
"image",
"acquisition,",
"the",
"prostate",
"volume",
"was",
"roughly",
"overestimated",
"by",
"1.45",
"times",
"with",
"pCT",
"and",
"by",
"1.37",
"times",
"with",
"pMRI.",
"A",
"statistically",
"significant",
"difference",
"was",
"found",
"between",
"preplan",
"image-based",
"volume",
"and",
"iTRUS-based",
"volume",
"(p",
"<",
"0.001).",
"The",
"median",
"number",
"of",
"wasted",
"seeds",
"is",
"approximately",
"13,",
"when",
"the",
"pCT",
"or",
"pMRI",
"volume",
"was",
"accepted",
"without",
"modification",
"to",
"assess",
"the",
"required",
"number",
"of",
"seeds",
"for",
"brachytherapy.",
"Conclusion:",
"pCT-based",
"volume",
"and",
"pMRI-based",
"volume",
"tended",
"to",
"overestimate",
"prostate",
"volume",
"in",
"comparison",
"to",
"iTRUS-based",
"volume.",
"To",
"reduce",
"wasted",
"seeds",
"and",
"cost",
"of",
"the",
"brachytherapy,",
"we",
"should",
"take",
"the",
"volume",
"discrepancy",
"into",
"account",
"when",
"we",
"estimate",
"the",
"number",
"of",
"125I",
"seeds",
"for",
"permanent",
"brachytherapy.",
"Keywords:",
"Brachytherapy,",
"Prostate",
"cancer,",
"Prostate",
"volume",
"Received",
"25",
"May",
"2011,",
"Revised",
"5",
"July",
"2011,",
"Accepted",
"13",
"July",
"2011.",
"Correspondence:",
"Hyun",
"Soo",
"Shin,",
"MD,",
"Department",
"of",
"Radiation",
"Oncology,",
"CHA",
"Bundang",
"Medical",
"Center,",
"Yatap-dong,",
"Bundang-gu,",
"Seongnam",
"463-712,",
"Korea.",
"Tel:",
"+82-31-780-5426,",
"Fax:",
"+82-31-780-5420,",
"E-mail:",
"shin029@chamc.co.kr",
"CC",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"Non-Commercial",
"License",
"(http://creativecommons.org/",
"licenses/by-nc/3.0/)",
"which",
"permits",
"unrestricted",
"non-commercial",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"www.e-roj.org",
"Copyright",
"©",
"2011.",
"The",
"Korean",
"Society",
"for",
"Therapeutic",
"Radiology",
"and",
"Oncology",
"199"
] | [
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] | [
"Pan",
"et",
"al.",
"Journal",
"of",
"Medical",
"Case",
"Reports",
"2011,",
"5:377",
"http://www.jmedicalcasereports.com/content/5/1/377",
"C",
"A",
"S",
"E",
"R",
"E",
"P",
"O",
"R",
"T",
"JOURNAL",
"OF",
"MEDICAL",
"CASE",
"REPORTS",
"Open",
"Access",
"Lobar",
"pneumonia",
"caused",
"by",
"Ralstonia",
"pickettii",
"in",
"a",
"sixty-five-year-old",
"Han",
"Chinese",
"man:",
"a",
"case",
"report",
"Wensen",
"Pan1,",
"Zhiming",
"Zhao2*",
"and",
"Mei",
"Dong3",
"Abstract",
"Introduction:",
"Ralstonia",
"pickettii",
"is",
"a",
"gram-negative,",
"oxidase-positive",
"bacillus",
"and",
"is",
"an",
"emerging",
"pathogen",
"found",
"in",
"infections",
"described",
"in",
"hospital",
"settings.",
"The",
"cases",
"reported",
"in",
"the",
"literature",
"mostly",
"are",
"nosocomial",
"infections",
"due",
"to",
"contaminated",
"blood",
"products,",
"sterile",
"water,",
"saline,",
"treatment",
"fluids",
"and",
"venous",
"catheters.",
"Human",
"infection",
"unrelated",
"to",
"contaminated",
"solutions",
"is",
"rare.",
"We",
"report",
"a",
"case",
"of",
"lobar",
"pneumonia",
"and",
"pulmonary",
"abscess",
"caused",
"by",
"Ralstonia",
"pickettii",
"in",
"an",
"older",
"patient.",
"Case",
"presentation:",
"A",
"sixty-five-year",
"old",
"Han",
"Chinese",
"man",
"presented",
"having",
"had",
"cough,",
"expectoration,",
"chest",
"pain",
"and",
"fever",
"lasting",
"for",
"twenty",
"days.",
"His",
"medical",
"history",
"was",
"notable",
"for",
"hypertension",
"over",
"the",
"previous",
"ten",
"years,",
"and",
"the",
"habit",
"of",
"smoking",
"for",
"forty",
"years.",
"A",
"thoracic",
"computed",
"tomography",
"scan",
"supported",
"the",
"diagnosis",
"of",
"right-",
"sided",
"lobar",
"pneumonia.",
"A",
"lung",
"biopsy",
"was",
"done",
"and",
"pathological",
"analysis",
"confirmed",
"lobar",
"pneumonia.",
"Two",
"lung",
"biopsy",
"specimens",
"from",
"separate",
"sites",
"grew",
"Ralstonia",
"pickettii.",
"After",
"six",
"days,",
"a",
"repeat",
"thoracic",
"scan",
"revealed",
"a",
"right-",
"sided",
"abscess.",
"A",
"thoracentesis",
"was",
"performed",
"and",
"the",
"purulent",
"fluid",
"grew",
"Ralstonia",
"pickettii.",
"The",
"chest",
"tube",
"remained",
"inserted",
"to",
"rinse",
"the",
"cavity",
"with",
"sterile",
"sodium",
"chloride.",
"He",
"received",
"an",
"antibiotic",
"course",
"of",
"intravenous",
"cefoperazone",
"sodium-sulbactam",
"sodium",
"for",
"eighteen",
"days",
"and",
"imipenem-cilastatin",
"for",
"twelve",
"days.",
"A",
"repeat",
"chest",
"X-ray",
"revealed",
"resolution",
"of",
"the",
"pulmonary",
"abscess",
"and",
"improvement",
"of",
"pneumonia.",
"He",
"remained",
"afebrile",
"and",
"free",
"of",
"respiratory",
"symptoms",
"after",
"treatments.",
"Conclusion:",
"This",
"case",
"demonstrates",
"a",
"Ralstonia",
"pickettii",
"infection",
"in",
"the",
"absence",
"of",
"an",
"obvious",
"nosocomial",
"source.",
"It",
"is",
"possible",
"that",
"such",
"cases",
"will",
"become",
"common",
"in",
"the",
"future.",
"Therefore,",
"further",
"studies",
"are",
"needed",
"to",
"evaluate",
"its",
"sensitivity",
"to",
"common",
"antibiotics.",
"Introduction",
"Ralstonia",
"pickettii",
"(R.",
"pickettii)",
"is",
"an",
"emerging",
"pathogen.",
"It",
"is",
"ubiquitous",
"in",
"nature",
"and",
"is",
"found",
"naturally",
"in",
"soil",
"and",
"groundwater.",
"R.",
"pickettii",
"was",
"first",
"isolated",
"in",
"1973",
"and",
"included",
"in",
"the",
"genus",
"Pseudomonas",
"[1].",
"The",
"rod-",
"shaped",
"organism",
"was",
"reclassified",
"in",
"the",
"Burkholderia",
"and",
"then",
"the",
"Ralstonia",
"genera,",
"receiving",
"its",
"current",
"name",
"in",
"1995",
"[2].",
"R.",
"pickettii",
"is",
"often",
"confused",
"with",
"other",
"similar",
"bacteria,",
"increasing",
"the",
"difficulty",
"of",
"classi-",
"fying",
"and",
"treating",
"this",
"pathogen.",
"R.",
"pickettii",
"can",
"be",
"isolated",
"from",
"various",
"clinical",
"speci-",
"mens,",
"such",
"as",
"sputum,",
"blood,",
"infected",
"wounds,",
"urine,",
"*",
"Correspondence:",
"pwszzmxx@sina.com.cn",
"2Department",
"of",
"Reproductive",
"Medicine,",
"the",
"Second",
"Hospital",
"of",
"Hebei",
"Medical",
"University,",
"Shijiazhuang,",
"China",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"ear,",
"nose",
"swabs,",
"and",
"cerebrospinal",
"fluid.",
"It",
"is",
"also",
"com-",
"monly",
"found",
"in",
"the",
"respiratory",
"tract",
"secretions",
"of",
"cystic",
"fibrosis",
"patients.",
"Most",
"infections",
"with",
"R.",
"pickettii",
"are",
"seen",
"in",
"the",
"hospital",
"setting",
"resulting",
"in",
"bacteremia",
"and/",
"or",
"septicemia",
"and",
"respiratory",
"infections",
"and/or",
"pneumo-",
"nia",
"[3].",
"The",
"cases",
"reported",
"in",
"the",
"literature",
"are",
"mostly",
"nosocomial",
"infections",
"due",
"to",
"contaminated",
"solutions",
"including",
"blood",
"products,",
"sterile",
"water,",
"saline,",
"chlorhexi-",
"dine",
"solution,",
"treatment",
"fluids",
"for",
"the",
"respiratory",
"tract,",
"and",
"contaminated",
"venous",
"catheters",
"[4-7].",
"Human",
"infec-",
"tion",
"unrelated",
"to",
"contaminated",
"solutions",
"is",
"rare.",
"There",
"is",
"only",
"one",
"documented",
"case",
"of",
"an",
"empyema",
"caused",
"by",
"R.",
"pickettii,",
"and",
"our",
"case",
"is",
"similar",
"in",
"some",
"respects",
"[8].",
"Our",
"case",
"is",
"perhaps",
"the",
"first",
"one",
"reported",
"of",
"a",
"lobar",
"pneumonia",
"and",
"pulmonary",
"abscess",
"caused",
"by",
"R.",
"pickettii.",
"©",
"2011",
"Pan",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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] | [
"Hindawi",
"Publishing",
"Corporation",
"Journal",
"of",
"Pregnancy",
"Volume",
"2012,",
"Article",
"ID",
"681306,",
"9",
"pages",
"doi:10.1155/2012/681306",
"Review",
"Article",
"Adrenocortical",
"and",
"Adipose",
"Responses",
"to",
"High-Altitude-Induced,",
"Long-Term",
"Hypoxia",
"in",
"the",
"Ovine",
"Fetus",
"Dean",
"A.",
"Myers1",
"and",
"Charles",
"A.",
"Ducsay2",
"1",
"Department",
"of",
"Obstetrics",
"and",
"Gynecology,",
"University",
"of",
"Oklahoma",
"Health",
"Sciences",
"Center,",
"Oklahoma",
"City,",
"OK",
"73104,",
"USA",
"2",
"Center",
"for",
"Perinatal",
"Biology,",
"Loma",
"Linda",
"University",
"School",
"of",
"Medicine,",
"Loma",
"Linda,",
"CA",
"92350,",
"USA",
"Correspondence",
"should",
"be",
"addressed",
"to",
"Dean",
"A.",
"Myers,",
"dean-myers@ouhsc.edu",
"Received",
"7",
"February",
"2012;",
"Accepted",
"2",
"March",
"2012",
"Academic",
"Editor:",
"Timothy",
"Regnault",
"Copyright",
"©",
"2012",
"D.",
"A.",
"Myers",
"and",
"C.",
"A.",
"Ducsay.",
"This",
"is",
"an",
"open",
"access",
"article",
"distributed",
"under",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"By",
"late",
"gestation,",
"the",
"maturing",
"hypothalamo-pituitary-adrenal",
"(HPA)",
"axis",
"aids",
"the",
"fetus",
"in",
"responding",
"to",
"stress.",
"Hypoxia",
"represents",
"a",
"significant",
"threat",
"to",
"the",
"fetus",
"accompanying",
"situations",
"such",
"as",
"preeclampsia,",
"smoking,",
"high",
"altitude,",
"and",
"preterm",
"labor.",
"We",
"developed",
"a",
"model",
"of",
"high-altitude",
"(3,820",
"m),",
"long-term",
"hypoxia",
"(LTH)",
"in",
"pregnant",
"sheep.",
"We",
"describe",
"the",
"impact",
"of",
"LTH",
"on",
"the",
"fetal",
"HPA",
"axis",
"at",
"the",
"level",
"of",
"the",
"hypothalamic",
"paraventricular",
"nucleus",
"(PVN),",
"anterior",
"pituitary",
"corticotrope,",
"and",
"adrenal",
"cortex.",
"At",
"the",
"PVN",
"and",
"anterior",
"pituitary,",
"the",
"responses",
"to",
"LTH",
"are",
"consistent",
"with",
"hypoxia",
"being",
"a",
"potent",
"activator",
"of",
"the",
"HPA",
"axis",
"and",
"potentially",
"maladaptive,",
"while",
"the",
"adrenocortical",
"response",
"to",
"LTH",
"appears",
"to",
"be",
"primarily",
"adaptive.",
"We",
"discuss",
"mechanisms",
"involved",
"in",
"the",
"delicate",
"balance",
"between",
"these",
"seemingly",
"opposing",
"responses",
"that",
"preserve",
"the",
"normal",
"ontogenic",
"rise",
"in",
"fetal",
"plasma",
"cortisol",
"essential",
"for",
"organ",
"maturation",
"and",
"in",
"this",
"species,",
"birth.",
"Further,",
"we",
"examine",
"the",
"response",
"to,",
"and",
"ramifications",
"of,",
"an",
"acute",
"secondary",
"stressor",
"in",
"the",
"LTH",
"fetus.",
"We",
"provide",
"an",
"integrative",
"model",
"on",
"the",
"potential",
"role",
"of",
"adipose",
"in",
"modulating",
"these",
"responses",
"to",
"LTH.",
"Integration",
"of",
"these",
"adaptive",
"responses",
"to",
"LTH",
"plays",
"a",
"key",
"role",
"in",
"promoting",
"normal",
"fetal",
"growth",
"and",
"development",
"under",
"conditions",
"of",
"a",
"chronic",
"stress.",
"1.",
"Introduction",
"Hypoxia",
"represents",
"a",
"major",
"threat",
"to",
"the",
"developing",
"fetus",
"and",
"often",
"accompanies",
"situations",
"of",
"preeclampsia,",
"preterm",
"labor,",
"smoking,",
"and",
"high",
"altitude.",
"The",
"impact",
"that",
"hypoxia",
"has",
"on",
"the",
"fetus",
"depends",
"on",
"a",
"variety",
"of",
"factors",
"such",
"as",
"stage",
"of",
"gestation,",
"severity",
"of",
"the",
"hypoxic",
"episode,",
"duration",
"of",
"hypoxia,",
"and",
"the",
"association",
"with",
"other",
"confounders",
"such",
"as",
"acidemia",
"and",
"hypercapnia.",
"Severe",
"hypoxic",
"events",
"can",
"lead",
"to",
"fetal",
"death",
"or",
"exert",
"major",
"deleterious",
"impacts",
"on",
"develop-",
"ment",
"and",
"function",
"on",
"fetal",
"organs,",
"including",
"major",
"damage",
"of",
"the",
"CNS.",
"However,",
"fetuses",
"are",
"often",
"and",
"perhaps",
"routinely",
"exposed",
"to",
"less",
"severe",
"hypoxic",
"episodes.",
"While",
"these",
"hypoxic",
"conditions",
"may",
"impact",
"fetal",
"growth,",
"effects",
"on",
"other",
"organ",
"systems",
"are",
"less",
"clear.",
"Due",
"to",
"its",
"long",
"gestational",
"length,",
"similarity",
"of",
"endocrine",
"and",
"physiological",
"systems,",
"and",
"relative",
"ease",
"of",
"fetal",
"and",
"maternal",
"instrumentation,",
"the",
"sheep",
"has",
"emerged",
"as",
"a",
"ma-",
"jor",
"animal",
"model",
"for",
"studying",
"the",
"impact",
"of",
"hypoxia",
"on",
"the",
"developing",
"fetus.",
"These",
"studies",
"have",
"largely",
"focused",
"on",
"so-called",
"acute",
"hypoxia",
"in",
"which",
"a",
"moderate-to-severe",
"hypoxia",
"(a",
"decrease",
"in",
"fetal",
"PO2",
"of",
"50%",
"or",
"greater)",
"is",
"induced",
"for",
"times",
"ranging",
"from",
"minutes",
"to",
"several",
"hours",
"or",
"chronic",
"hypoxia",
"in",
"which",
"the",
"fetus",
"is",
"made",
"hypoxic",
"for",
"one",
"to",
"several",
"days.",
"Experimentally,",
"acute",
"fetal",
"hypoxia",
"can",
"be",
"induced",
"by",
"maternal",
"hypoxia",
"[1–3],",
"restricting",
"blood",
"flow",
"to",
"the",
"uterus",
"and",
"placenta",
"on",
"the",
"maternal",
"side",
"[4],",
"or",
"reducing",
"umbilical",
"blood",
"flow",
"by",
"cord",
"compression",
"[5–",
"7].",
"More",
"prolonged",
"fetal",
"hypoxemia",
"can",
"also",
"be",
"initiated",
"by",
"repeated",
"umbilical",
"cord",
"compression",
"[7–9],",
"as",
"well",
"as",
"placental",
"embolization",
"[10,",
"11]",
"and",
"restriction",
"of",
"uterine",
"blood",
"flow",
"[12].",
"These",
"methods",
"induce",
"either",
"a",
"rather",
"pure",
"hypoxic",
"episode",
"or",
"hypoxia",
"accompanied",
"with",
"acidemia",
"or",
"hypoglycemia.",
"Longer",
"duration",
"hypoxic",
"situations",
"(months)",
"have",
"been",
"created",
"in",
"sheep",
"by",
"maternal",
"carunclectomy,",
"reducing",
"the",
"placentation",
"area",
"of",
"the",
"uterus",
"[13].",
"However,",
"the",
"hypoxia",
"in",
"this",
"model",
"is",
"secondary",
"to",
"nutrient",
"restric-",
"tion."
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] | [
"Cases",
"Journal",
"Case",
"Report",
"Endometrial",
"Cancer",
"Presenting",
"as",
"Acute",
"Urinary",
"Retention",
":",
"a",
"Case",
"Report",
"and",
"Review",
"of",
"The",
"Literature",
"Samer",
"R",
"Tannus*",
"and",
"Ilan",
"Atlas",
"Address:",
"Department",
"of",
"Obstetrics",
"&",
"Gynecology,",
"The",
"Baruch",
"Padeh",
"Medical",
"Center,",
"Poriya,",
"Lower",
"Galilee",
"15208.",
"Israel",
"Email:",
"Samer",
"R",
"Tannus*",
"-",
"stannus@bezeqint.net;",
"Ilan",
"Atlas",
"-",
"ilanatlas@gmail.com",
"*",
"Corresponding",
"author",
"BioMed",
"Central",
"Open",
"Access",
"Published:",
"22",
"December",
"2009",
"Cases",
"Journal",
"2009,",
"2:9382",
"doi:10.1186/1757-1626-2-9382",
"This",
"article",
"is",
"available",
"from:",
"http://www.casesjournal.com/content/2/1/9382",
"Received:",
"29",
"November",
"2009",
"Accepted:",
"22",
"December",
"2009",
"©",
"2009",
"Tannus",
"and",
"Atlas;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Abstract",
"Introduction:",
"Endometrial",
"cancer",
"is",
"the",
"most",
"common",
"gynecologic",
"malignancy.",
"Most",
"women",
"present",
"with",
"abnormal",
"vaginal",
"bleeding.",
"Cervical",
"stenosis",
"can",
"prevent",
"early",
"uterine",
"bleeding",
"leading",
"to",
"delayed",
"diagnosis",
"of",
"the",
"disease.",
"Case",
"presentation:",
"A",
"67",
"years",
"old",
"Caucasian",
"woman",
"presented",
"with",
"three",
"days",
"history",
"of",
"right",
"flank",
"pain",
"and",
"difficulty",
"in",
"urination.",
"Her",
"medical",
"history",
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"cautery",
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"15",
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"a",
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"a",
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"cervix",
"adjacent",
"to",
"distended",
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"cancer.",
"Conclusion:",
"To",
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"knowledge",
"this",
"is",
"the",
"first",
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"describing",
"acute",
"urinary",
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"women",
"and",
"can",
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"Endometrial",
"cancer",
"is",
"the",
"most",
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"gynecologic",
"malignancy",
"and",
"the",
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"most",
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"[1].",
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"urinary",
"retention",
"secondary",
"to",
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"A",
"case",
"report",
"and",
"review",
"of",
"the",
"literature",
"are",
"presented.",
"Case",
"A",
"67",
"years",
"old",
"Caucasian",
"woman",
"gravida",
"3,",
"para",
"1",
"pre-",
"sented",
"with",
"three",
"days",
"history",
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"flank",
"pain",
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"ficulty",
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"Her",
"medical",
"history",
"was",
"significant",
"for",
"obesity,",
"hypertension",
"and",
"previous",
"salpingectomy",
"due",
"to",
"ectopic",
"pregnancy.",
"15",
"years",
"previously",
"a",
"cervical",
"cau-",
"tery",
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"due",
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"cervical",
"ectropion.",
"On",
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"vital",
"signs",
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"Physical",
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"the",
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"abdomen.",
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"exam",
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"mass",
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"bulging",
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"vagina",
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"a",
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"cer-",
"vix.",
"The",
"external",
"cervical",
"os",
"was",
"not",
"identified.",
"Page",
"1",
"of",
"3",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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] | [
"Molecular",
"Vision",
"2010;",
"16:1453-1466",
"<http://www.molvis.org/molvis/v16/a159>",
"Received",
"15",
"June",
"2010",
"|",
"Accepted",
"23",
"July",
"2010",
"|",
"Published",
"31",
"July",
"2010",
"©",
"2010",
"Molecular",
"Vision",
"Abnormal",
"fiber",
"end",
"migration",
"in",
"Royal",
"College",
"of",
"Surgeons",
"rats",
"during",
"posterior",
"subcapsular",
"cataract",
"formation",
"Anita",
"Joy,1",
"Tabraiz",
"A.",
"Mohammed,1",
"Kristin",
"J.",
"Al-Ghoul1,2",
"1Department",
"of",
"Anatomy",
"&",
"Cell",
"Biology,",
"Rush",
"University",
"Medical",
"Center,",
"Chicago,",
"IL;",
"2Department",
"of",
"Ophthalmology,",
"Rush",
"University",
"Medical",
"Center,",
"Chicago,",
"IL",
"Purpose:",
"Prior",
"structural",
"studies",
"of",
"posterior",
"subcapsular",
"cataract",
"(PSC)",
"development",
"in",
"Royal",
"College",
"of",
"Surgeons",
"(RCS)",
"rats",
"suggest",
"that",
"migration",
"of",
"basal",
"fiber",
"ends",
"was",
"disrupted,",
"ultimately",
"resulting",
"in",
"a",
"PSC.",
"Therefore",
"the",
"goal",
"of",
"this",
"study",
"was",
"to",
"assess",
"the",
"overall",
"migration",
"patterns",
"as",
"well",
"as",
"changes",
"to",
"the",
"structure",
"and",
"cytoskeleton",
"of",
"basal",
"fiber",
"ends",
"during",
"PSC",
"development.",
"Methods:",
"Lenses",
"from",
"48",
"RCS",
"dystrophic",
"rats",
"(RCS/Lav)",
"and",
"24",
"genetically",
"matched",
"control",
"animals",
"(RCS-rdy+/Lav)",
"from",
"2",
"to",
"8",
"weeks",
"old",
"were",
"examined.",
"Equatorial",
"diameters",
"were",
"measured",
"and",
"suture",
"patterns",
"were",
"photographed",
"immediately",
"following",
"enucleation/dissection.",
"Right",
"eye",
"lenses",
"were",
"fixed",
"and",
"processed",
"to",
"visualize",
"the",
"actin",
"cytoskeleton",
"via",
"laser",
"scanning",
"confocal",
"microcopy",
"(LSCM),",
"left",
"eye",
"lenses",
"were",
"decapsulated,",
"fixed",
"and",
"processed",
"for",
"scanning",
"electron",
"microscopy",
"(SEM).",
"Scaled",
"3D-computer",
"assisted",
"drawings",
"(CADs)",
"and",
"animations",
"were",
"constructed",
"from",
"the",
"data",
"to",
"depict",
"the",
"changes",
"in",
"suture",
"patterns",
"and",
"fiber",
"end",
"architecture.",
"Results:",
"At",
"2",
"weeks,",
"dystrophic",
"lenses",
"displayed",
"an",
"inverted",
"Y",
"suture",
"on",
"the",
"posterior,",
"and",
"by",
"3",
"weeks",
"most",
"lenses",
"had",
"at",
"least",
"one",
"sub-branch.",
"Additional",
"sub-branches",
"were",
"observed",
"with",
"time,",
"opacities",
"being",
"visible",
"as",
"early",
"as",
"4",
"weeks",
"and",
"progressing",
"into",
"PSC",
"plaques",
"by",
"6",
"weeks.",
"Control",
"lenses",
"displayed",
"inverted",
"Y",
"sutures",
"at",
"all",
"ages",
"and",
"were",
"transparent.",
"SEM",
"of",
"dystrophic",
"lenses",
"revealed",
"fiber",
"ends",
"with",
"normal",
"size,",
"shape,",
"arrangement,",
"and",
"filopodia",
"at",
"2",
"weeks;",
"scattered",
"areas",
"of",
"dome-shaped",
"fiber",
"ends",
"and",
"small",
"filopodia",
"were",
"present",
"at",
"3",
"weeks.",
"At",
"4",
"weeks",
"the",
"irregularly",
"arranged",
"domed",
"fiber",
"ends",
"had",
"extremely",
"long",
"filopodia",
"with",
"‘boutons’",
"at",
"their",
"tips.",
"By",
"6",
"weeks",
"all",
"fiber",
"ends",
"within",
"plaques",
"displayed",
"rounded",
"or",
"domed",
"basal",
"membranes",
"and",
"lacked",
"filopodial",
"extensions.",
"Control",
"lenses",
"at",
"all",
"time",
"points",
"had",
"comparable",
"ultrastructure",
"to",
"the",
"2",
"week",
"old",
"dystrophic",
"lenses.",
"F-actin",
"arrangement",
"within",
"the",
"basal",
"membrane",
"complex",
"(BMC)",
"of",
"control",
"lenses",
"showed",
"the",
"expected",
"peripheral",
"pattern",
"of",
"labeling",
"at",
"all",
"ages.",
"Dystrophic",
"RCS",
"lenses",
"at",
"2",
"weeks",
"were",
"comparable",
"to",
"controls,",
"however",
"by",
"3–4",
"weeks",
"they",
"displayed",
"scattered",
"foci",
"of",
"F-actin",
"within",
"the",
"BMC.",
"At",
"all",
"time",
"points",
"thereafter,",
"F-actin",
"was",
"rearranged",
"into",
"a",
"‘rosette’",
"pattern",
"of",
"prominent",
"foci",
"at",
"cell",
"vertices.",
"Conclusions:",
"The",
"data",
"are",
"consistent",
"with",
"the",
"hypothesis",
"that",
"migration",
"of",
"basal",
"fiber",
"ends",
"is",
"altered",
"in",
"a",
"two",
"stage",
"process",
"wherein",
"initially,",
"migration",
"patterns",
"undergo",
"a",
"rapid",
"shift",
"resulting",
"in",
"abnormal",
"suture",
"sub-branch",
"formation.",
"Subsequent",
"cytological",
"alterations",
"are",
"consistent",
"with",
"an",
"eventual",
"cessation",
"of",
"migration,",
"precluding",
"proper",
"targeting",
"of",
"basal",
"ends",
"to",
"their",
"sutural",
"destinations",
"and",
"leading",
"to",
"cataract",
"plaque",
"formation.",
"Congenital",
"retinal",
"dystrophy",
"in",
"the",
"Royal",
"College",
"of",
"Surgeons",
"(RCS)",
"rat",
"is",
"a",
"recessively",
"inherited",
"anomaly",
"that",
"results",
"in",
"the",
"progressive",
"degeneration",
"of",
"photoreceptor",
"cells",
"in",
"the",
"retina",
"during",
"the",
"later",
"stages",
"of",
"retinal",
"development",
"(third",
"week",
"postnatal)",
"[1-3].",
"One",
"of",
"the",
"many",
"deleterious",
"effects",
"of",
"this",
"disease",
"includes",
"the",
"formation",
"of",
"a",
"secondary",
"cataract,",
"specifically",
"a",
"posterior",
"subcapsular",
"cataract",
"(PSC).",
"Although",
"the",
"cataract",
"was",
"the",
"first",
"feature",
"noted",
"and",
"described",
"in",
"the",
"RCS",
"rat",
"[4],",
"this",
"animal",
"model",
"has",
"been",
"extensively",
"used",
"to",
"study",
"retinal",
"degeneration.",
"Since",
"the",
"first",
"description",
"of",
"the",
"genetic",
"abnormality",
"responsible",
"for",
"the",
"retinal",
"Correspondence",
"to:",
"Kristin",
"J.",
"Al-Ghoul,",
"Ph.D.,",
"Department",
"of",
"Anatomy",
"and",
"Cell",
"Biology,",
"Rush",
"University",
"Medical",
"Center,",
"600",
"S.",
"Paulina",
"St.,",
"Ste",
"507,",
"Chicago,",
"IL,",
"60612;",
"Phone:",
"(312)",
"563-2672;",
"FAX:",
"(312)",
"942-5744;",
"email:",
"kristin_j_al-ghoul@rush.edu",
"Dr.",
"Mohammed",
"is",
"currently",
"at",
"the",
"Department",
"of",
"Medicine,",
"University",
"of",
"Wisconsin",
"Hospitals",
"and",
"Clinics,",
"Madison,",
"WI",
"dystrophy",
"by",
"Bourne",
"et",
"al.",
"[2,5],",
"the",
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"rapid",
"progression,",
"and",
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"in",
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"have",
"also",
"been",
"well",
"documented.",
"Similarities",
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"the",
"rodent",
"disease",
"and",
"retinitis",
"pigmentosa",
"in",
"humans",
"have",
"been",
"established",
"[5-8],",
"and",
"the",
"RCS",
"rat",
"is",
"therefore",
"an",
"excellent",
"model",
"to",
"study",
"both",
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"recessive",
"retinitis",
"pigmentosa",
"(ARRP)",
"and",
"PSCs.",
"In",
"the",
"retina,",
"the",
"first",
"damage",
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"12",
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"postnatal",
"in",
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"rod",
"outer",
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"and",
"by",
"18",
"days",
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"the",
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"is",
"twice",
"as",
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"when",
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"as",
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"days",
"postnatal,",
"both",
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"and",
"outer",
"rod",
"segments",
"have",
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"[3,9-11].",
"The",
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"sequence",
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"mark",
"the",
"maximal",
"accumulation",
"of",
"outer",
"segment",
"debris",
"and",
"retinal",
"breakdown",
"closely",
"mirror",
"the",
"changes",
"that",
"occur",
"at",
"the",
"posterior",
"surface",
"1453"
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] | [
"Symphysiotomy",
"in",
"Zimbabwe;",
"Postoperative",
"Outcome,",
"Width",
"of",
"the",
"Symphysis",
"Joint,",
"and",
"Knowledge,",
"Attitudes",
"and",
"Practice",
"among",
"Doctors",
"and",
"Midwives",
"Hege",
"Langli",
"Ersdal1*,",
"Douwe",
"A.",
"A.",
"Verkuyl2,",
"Kenneth",
"Bjo¨",
"rklund{1,",
"Staffan",
"Bergstro¨",
"m1",
"1",
"Division",
"of",
"International",
"Health",
"(IHCAR),",
"Karolinska",
"Institutet,",
"Stockholm,",
"Sweden,",
"2",
"Department",
"of",
"Obstetrics",
"and",
"Gynaecology,",
"United",
"Bulawayo",
"Hospital,",
"Bulawayo,",
"Zimbabwe",
"Abstract",
"Background:",
"Obstructed",
"labour",
"remains",
"one",
"of",
"the",
"leading",
"causes",
"of",
"maternal",
"and",
"foetal",
"death",
"and",
"morbidity",
"in",
"poorly",
"resourced",
"areas",
"of",
"the",
"world,",
"where",
"the",
"24",
"hours",
"availability",
"of",
"a",
"caesarean",
"section",
"(CS)",
"cannot",
"be",
"guaranteed,",
"and",
"the",
"CS",
"related",
"mortality",
"rate",
"is",
"still",
"high.",
"In",
"these",
"settings,",
"reinstatement",
"of",
"symphysiotomy",
"has",
"been",
"advocated.",
"The",
"objectives",
"were,",
"in1994;",
"to",
"study",
"perioperative",
"and",
"long-term",
"complications",
"of",
"symphysiotomy",
"and",
"compare",
"them",
"to",
"those",
"related",
"to",
"CS",
"for",
"similar",
"indications,",
"in",
"1996;",
"to",
"measure",
"the",
"symphyseal",
"width",
"after",
"symphysiotomy",
"and",
"compare",
"it",
"to",
"that",
"after",
"normal",
"vaginal",
"delivery,",
"and,",
"in",
"1998;",
"to",
"assess",
"knowledge,",
"attitudes",
"and",
"practice",
"related",
"to",
"symphysiotomy",
"among",
"doctors",
"and",
"midwives",
"in",
"Zimbabwe.",
"Methods",
"and",
"Findings:",
"Thirty-four",
"women",
"who",
"had",
"undergone",
"symphysiotomy",
"and",
"29",
"women",
"who",
"had",
"undergone",
"a",
"CS",
"for",
"obstructed",
"labour",
"were",
"interviewed.",
"The",
"symphyseal",
"widths",
"of",
"19",
"women",
"with",
"a",
"previous",
"symphysiotomy",
"were",
"compared",
"to",
"that",
"of",
"92",
"women",
"with",
"previous",
"normal",
"vaginal",
"deliveries,",
"using",
"ultrasound",
"technique.",
"Forty-one",
"doctors",
"and",
"39",
"midwives,",
"in",
"three",
"central",
"hospitals",
"and",
"seven",
"district",
"hospitals",
"in",
"Zimbabwe,",
"were",
"interviewed",
"about",
"symphysiotomy.",
"None",
"of",
"the",
"34",
"women",
"reported",
"serious",
"soft",
"tissue",
"injuries",
"or",
"infections",
"post",
"symphysiotomy.",
"Long-term",
"complications",
"after",
"symphysiotomy",
"do",
"not",
"differ",
"notably",
"from",
"those",
"after",
"CS",
"for",
"similar",
"indications.",
"The",
"intra-articular",
"width",
"of",
"the",
"symphysis",
"pubis",
"is",
"increased",
"after",
"a",
"symphysiotomy.",
"Seventy-nine",
"of",
"the",
"80",
"interviewed",
"health",
"care",
"workers",
"knew",
"about",
"symphysiotomy.",
"One",
"obstetrician",
"had",
"performed",
"symphysiotomies.",
"Two-thirds",
"of",
"the",
"participants",
"considered",
"symphysiotomy",
"an",
"obsolete",
"and",
"second-class",
"operation,",
"but",
"lifesaving",
"and",
"appropriate",
"in",
"remote",
"areas",
"of",
"Zimbabwe.",
"Ten",
"of",
"13",
"midwives",
"in",
"remote",
"areas",
"wanted",
"to",
"carry",
"out",
"symphysiotomies",
"themselves.",
"Conclusions:",
"No",
"severe",
"complications",
"due",
"to",
"symphysiotomy",
"were",
"revealed",
"in",
"this",
"study.",
"The",
"results",
"suggest",
"that",
"a",
"modest",
"permanent",
"enlargement",
"of",
"the",
"pelvis",
"post",
"symphysiotomy",
"(together",
"with",
"the",
"absence",
"of",
"a",
"scarred",
"uterus)",
"may",
"facilitate",
"subsequent",
"vaginal",
"delivery.",
"Doctors",
"and",
"midwives",
"working",
"in",
"district",
"hospitals",
"have",
"a",
"more",
"positive",
"attitude",
"to",
"symphysiotomies",
"than",
"the",
"colleagues",
"in",
"central",
"hospitals.",
"Obstetricians",
"(who",
"would",
"have",
"to",
"do",
"the",
"teaching),",
"working",
"in",
"the",
"large",
"urban",
"hospitals",
"almost",
"exclude",
"symphysiotomy",
"as",
"an",
"alternative",
"management",
"in",
"Zimbabwe.",
"Citation:",
"Ersdal",
"HL,",
"Verkuyl",
"DAA,",
"Bj",
"o¨rklund",
"K,",
"Bergstro¨",
"m",
"S",
"(2008)",
"Symphysiotomy",
"in",
"Zimbabwe;",
"Postoperative",
"Outcome,",
"Width",
"of",
"the",
"Symphysis",
"Joint,",
"and",
"Knowledge,",
"Attitudes",
"and",
"Practice",
"among",
"Doctors",
"and",
"Midwives.",
"PLoS",
"ONE",
"3(10):",
"e3317.",
"doi:10.1371/journal.pone.0003317",
"Editor:",
"Landon",
"Myer,",
"University",
"of",
"Cape",
"Town,",
"South",
"Africa",
"Received",
"May",
"9,",
"2008;",
"Accepted",
"September",
"12,",
"2008;",
"Published",
"October",
"10,",
"2008",
"Copyright:",
"2008",
"Ersdal",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"The",
"work",
"presented",
"is",
"partly",
"financed",
"by",
"The",
"Research",
"Council",
"of",
"Norway",
"(student",
"scholarship",
"for",
"the",
"first",
"auther",
"HLE).",
"The",
"funder",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript",
"Competing",
"Interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"*",
"E-mail:",
"hege@ersdal.com",
"{",
"Deceased.",
"Introduction",
"Symphysiotomy",
"was",
"developed",
"in",
"Europe",
"late",
"in",
"the",
"18th",
"century",
"as",
"a",
"means",
"to",
"save",
"the",
"lives",
"of",
"mother",
"and",
"child",
"in",
"obstructed",
"labour.",
"In",
"the",
"early",
"days",
"the",
"separation",
"of",
"the",
"bones",
"was",
"performed",
"after",
"exposing",
"the",
"symphysis.",
"With",
"the",
"introduc-",
"tion",
"of",
"aseptic",
"techniques",
"in",
"the",
"mid",
"19th",
"century",
"and",
"the",
"subcutaneous",
"symphysiotomy",
"by",
"Frank",
"[1],",
"using",
"local",
"anaesthet-",
"ics,",
"the",
"operation",
"gained",
"acceptance",
"and",
"became",
"part",
"of",
"the",
"obstetric",
"arsenal",
"in",
"many",
"parts",
"of",
"Europe",
"[2–5].",
"The",
"technique",
"was",
"further",
"refined",
"by",
"Za´rate",
"in",
"Argentina",
"[6],",
"and",
"symphysiot-",
"omy",
"was",
"extensively",
"practised",
"in",
"Latin",
"America",
"and",
"Ireland",
"up",
"to",
"the",
"mid",
"20th",
"century",
"[4,7,8].",
"Seedat",
"and",
"Crichton",
"in",
"Durban,",
"South",
"Africa,",
"further",
"developed",
"the",
"technique",
"[9]",
"and",
"symphy-",
"siotomy",
"came",
"to",
"be",
"used",
"in",
"Africa",
"for",
"the",
"ensuing",
"decades",
"[9–12].",
"Currently,",
"outside",
"Africa,",
"symphysiotomies",
"are",
"still",
"performed",
"in",
"Papua",
"New",
"Guinea",
"[13].",
"Mechanical",
"obstruction",
"in",
"the",
"second",
"stage",
"complicates",
"1–2%",
"of",
"labours",
"[14].",
"In",
"developing",
"countries",
"this",
"percentage",
"might",
"be",
"higher",
"because",
"women",
"often",
"do",
"not",
"attain",
"their",
"(pelvic)",
"growth",
"potential",
"due",
"to",
"stunting.",
"The",
"facilities",
"and",
"staffing",
"level",
"of",
"non-",
"private",
"hospitals",
"in",
"developing",
"countries",
"make",
"it",
"often",
"inevitable",
"that",
"CSs",
"are",
"associated",
"with",
"an",
"appreciable",
"mortality",
"rate.",
"In",
"addition,",
"there",
"is",
"no",
"guarantee",
"that",
"a",
"woman",
"with",
"a",
"scar",
"in",
"the",
"uterus",
"can,",
"or",
"even",
"would",
"like",
"to,",
"reach",
"in",
"time",
"a",
"(still",
"adequately",
"staffed)",
"hospital",
"for",
"the",
"next",
"delivery.",
"The",
"World",
"Health",
"Organization",
"(WHO)",
"PLoS",
"ONE",
"|",
"www.plosone.org",
"1",
"October",
"2008",
"|",
"Volume",
"3",
"|",
"Issue",
"10",
"|",
"e3317"
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] | [
"6774–6786",
"Nucleic",
"Acids",
"Research,",
"2012,",
"Vol.",
"40,",
"No.",
"14",
"doi:10.1093/nar/gks388",
"Published",
"online",
"7",
"May",
"2012",
"Biochemical",
"analyses",
"indicate",
"that",
"binding",
"and",
"cleavage",
"specificities",
"define",
"the",
"ordered",
"processing",
"of",
"human",
"Okazaki",
"fragments",
"by",
"Dna2",
"and",
"FEN1",
"Jason",
"W.",
"Gloor1,",
"Lata",
"Balakrishnan",
"1",
",",
"Judith",
"L.",
"Campbell2",
"and",
"Robert",
"A.",
"Bambara1,*",
"1Department",
"of",
"Microbiology",
"and",
"Immunology,",
"University",
"of",
"Rochester",
"School",
"of",
"Medicine",
"and",
"Dentistry,",
"Rochester,",
"NY",
"14642",
"and",
"2Braun",
"Laboratories,",
"California",
"Institute",
"of",
"Technology,",
"Pasadena,",
"CA",
"91125,",
"USA",
"Received",
"March",
"12,",
"2012;",
"Revised",
"April",
"5,",
"2012;",
"Accepted",
"April",
"13,",
"2012",
"ABSTRACT",
"In",
"eukaryotic",
"Okazaki",
"fragment",
"processing,",
"the",
"RNA",
"primer",
"is",
"displaced",
"into",
"a",
"single-stranded",
"flap",
"prior",
"to",
"removal.",
"Evidence",
"suggests",
"that",
"some",
"flaps",
"become",
"long",
"before",
"they",
"are",
"cleaved,",
"and",
"that",
"this",
"cleavage",
"involves",
"the",
"sequential",
"action",
"of",
"two",
"nucleases.",
"Strand",
"displacement",
"characteristics",
"of",
"the",
"polymerase",
"show",
"that",
"a",
"short",
"gap",
"precedes",
"the",
"flap",
"during",
"synthesis.",
"Using",
"biochemical",
"tech-",
"niques,",
"binding",
"and",
"cleavage",
"assays",
"presented",
"here",
"indicate",
"that",
"when",
"the",
"flap",
"is",
"30",
"nt",
"long",
"the",
"nuclease",
"Dna2",
"can",
"bind",
"with",
"high",
"affinity",
"to",
"the",
"flap",
"and",
"downstream",
"double",
"strand",
"and",
"begin",
"cleavage.",
"When",
"the",
"polymerase",
"idles",
"or",
"dissociates",
"the",
"Dna2",
"can",
"reorient",
"for",
"additional",
"contacts",
"with",
"the",
"upstream",
"primer",
"region,",
"allowing",
"the",
"nuclease",
"to",
"remain",
"stably",
"bound",
"as",
"the",
"flap",
"is",
"further",
"shortened.",
"The",
"DNA",
"can",
"then",
"equilibrate",
"to",
"a",
"double",
"flap",
"that",
"can",
"bind",
"Dna2",
"and",
"flap",
"endonucle-",
"ase",
"(FEN1)",
"simultaneously.",
"When",
"Dna2",
"shortens",
"the",
"flap",
"even",
"more,",
"FEN1",
"can",
"displace",
"the",
"Dna2",
"and",
"cleave",
"at",
"the",
"flap",
"base",
"to",
"make",
"a",
"nick",
"for",
"ligation.",
"INTRODUCTION",
"In",
"both",
"prokaryotic",
"and",
"eukaryotic",
"DNA",
"replication,",
"one",
"strand",
"of",
"DNA,",
"called",
"lagging,",
"is",
"initially",
"made",
"in",
"discon-",
"tinuous",
"segments",
"termed",
"Okazaki",
"fragments.",
"In",
"humans,",
"each",
"fragment",
"is",
"initiated",
"by",
"an",
"RNA",
"primer",
"8–10",
"nt",
"in",
"length",
"and",
"extended",
"150–200",
"nt",
"with",
"DNA",
"(1).",
"The",
"fragments",
"need",
"to",
"be",
"joined",
"to",
"make",
"a",
"continuous",
"strand.",
"This",
"involves",
"strand",
"displacement",
"synthesis",
"from",
"one",
"fragment",
"to",
"raise",
"the",
"RNA",
"primer",
"region",
"of",
"the",
"adjacent",
"fragment",
"into",
"a",
"flap.",
"Genetic",
"experiments",
"and",
"reconstitutions",
"in",
"vitro",
"suggest",
"that",
"flap",
"creation",
"and",
"removal",
"occurs",
"via",
"two",
"pathways.",
"One",
"employs",
"the",
"flap",
"endonuclease",
"(FEN1),",
"which",
"removes",
"the",
"flap",
"containing",
"the",
"initiator",
"RNA",
"leaving",
"a",
"nick",
"for",
"ligation.",
"If",
"a",
"flap",
"escapes",
"FEN1",
"to",
"grow",
"long",
"enough",
"to",
"acquire",
"the",
"eukary-",
"otic",
"DNA-binding",
"protein",
"(RPA),",
"nucleolytic",
"cleavage",
"will",
"be",
"blocked.",
"If",
"so,",
"the",
"flap",
"is",
"processed",
"by",
"the",
"second",
"pathway",
"in",
"which",
"the",
"nuclease/helicase",
"Dna2",
"displaces",
"the",
"RPA.",
"Dna2",
"then",
"successively",
"cleaves",
"the",
"flap",
"until",
"it",
"is",
"too",
"short",
"to",
"bind",
"RPA",
"and",
"becomes",
"a",
"substrate",
"for",
"FEN1",
"(2,3).",
"Biochemical",
"analyses",
"have",
"demonstrated",
"that",
"both",
"FEN1",
"(4–13)",
"and",
"Dna2",
"(14)",
"employ",
"a",
"threading",
"mechan-",
"ism",
"for",
"binding",
"and",
"cleavage",
"of",
"the",
"flap",
"substrate.",
"Recent",
"results",
"show",
"that",
"both",
"nucleases",
"recognize",
"and",
"bind",
"to",
"the",
"base",
"of",
"the",
"flap",
"and",
"then",
"thread",
"the",
"50",
"end",
"of",
"the",
"flap",
"through",
"the",
"protein",
"(15–17).",
"Dna2",
"cleaves",
"periodically",
"during",
"the",
"threading",
"(18,19),",
"and",
"FEN1",
"cleaves",
"specific-",
"ally",
"at",
"the",
"base",
"(4,20,21).",
"Previous",
"analyses",
"with",
"purified",
"proteins",
"from",
"Saccharo-",
"myces",
"cerevisiae",
"clarified",
"how",
"these",
"proteins",
"act",
"in",
"succes-",
"sion",
"to",
"process",
"Okazaki",
"fragments",
"(8,22–25).",
"On",
"a",
"long",
"flap",
"substrate,",
"S.",
"cerevisiae",
"Dna2",
"(scDna2)",
"was",
"shown",
"to",
"displace",
"bound",
"scRPA",
"in",
"a",
"reaction",
"that",
"did",
"not",
"require",
"cleavage",
"(26).",
"scFEN1",
"was",
"shown",
"to",
"displace",
"the",
"scDna2,",
"so",
"that",
"it",
"could",
"have",
"access",
"to",
"its",
"cleavage",
"site",
"at",
"the",
"flap",
"base",
"(17).",
"In",
"addition",
"to",
"the",
"role",
"it",
"plays",
"in",
"Okazaki",
"fragment",
"pro-",
"cessing,",
"Dna2",
"functions",
"in",
"conjunction",
"with",
"30–50",
"helicases",
"and",
"RPA",
"to",
"resect",
"the",
"50",
"end",
"of",
"DNA",
"during",
"double-strand",
"break",
"(DSB)",
"repair",
"and",
"telomere",
"maintenance",
"(27).",
"Human",
"and",
"yeast",
"systems",
"employ",
"redundant",
"pathways",
"during",
"these",
"processes,",
"one",
"of",
"which",
"utilizes",
"Dna2",
"(28–30).",
"Once",
"recruited",
"to",
"the",
"DSB,",
"a",
"30–50",
"helicase",
"separ-",
"ates",
"the",
"two",
"strands",
"of",
"the",
"DNA",
"creating",
"a",
"pseudo-Y",
"struc-",
"ture",
"consisting",
"of",
"a",
"30",
"single-stranded",
"(ss)",
"DNA",
"tail,",
"a",
"50",
"ssDNA",
"tail",
"and",
"a",
"double-stranded",
"region.",
"These",
"single-",
"stranded",
"tails",
"can",
"then",
"be",
"coated",
"by",
"RPA.",
"Similar",
"to",
"its",
"role",
"in",
"the",
"long",
"flap",
"Okazaki",
"fragment",
"pathway,",
"Dna2",
"cleaves",
"the",
"50-ssDNA.",
"Surprisingly,",
"even",
"though",
"Dna2",
"possesses",
"a",
"30",
"nuclease",
"activity,",
"RPA",
"prevents",
"cleavage",
"of",
"the",
"30-ssDNA",
"(30,31).",
"Dna2",
"interacts",
"with",
"the",
"RPA1",
"(70",
"kDa)",
"subunit",
"of",
"RPA",
"(22).",
"The",
"N",
"terminus",
"of",
"RPA1",
"*To",
"whom",
"correspondence",
"should",
"be",
"addressed.",
"Tel:",
"+1",
"585",
"275",
"3269;",
"Fax:",
"+1",
"585",
"275",
"6007;",
"Email:",
"robert_bambara@urmc.rochester.edu",
"The",
"Author(s)",
"2012.",
"Published",
"by",
"Oxford",
"University",
"Press.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"Non-Commercial",
"License",
"(http://creativecommons.org/licenses/",
"by-nc/3.0),",
"which",
"permits",
"unrestricted",
"non-commercial",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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] | [
"BMC",
"Bioinformatics",
"Research",
"article",
"Evolutionary",
"distance",
"estimation",
"and",
"fidelity",
"of",
"pair",
"wise",
"sequence",
"alignment",
"Michael",
"S",
"Rosenberg*",
"Address:",
"Center",
"for",
"Evolutionary",
"Functional",
"Genomics,",
"The",
"Biodesign",
"Institute,",
"and",
"the",
"School",
"of",
"Life",
"Sciences,",
"Arizona",
"State",
"University,",
"Tempe,",
"AZ",
"84287-4501,",
"USA",
"Email:",
"Michael",
"S",
"Rosenberg*",
"-",
"msr@asu.edu",
"*",
"Corresponding",
"author",
"BioMed",
"Central",
"Open",
"Access",
"Published:",
"19",
"April",
"2005",
"BMC",
"Bioinformatics",
"2005,",
"6:102",
"doi:10.1186/1471-2105-6-102",
"This",
"article",
"is",
"available",
"from:",
"http://www.biomedcentral.com/1471-2105/6/102",
"Received:",
"16",
"December",
"2004",
"Accepted:",
"19",
"April",
"2005",
"©",
"2005",
"Rosenberg;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Abstract",
"Background:",
"Evolutionary",
"distances",
"are",
"a",
"critical",
"measure",
"in",
"comparative",
"genomics",
"and",
"molecular",
"evolutionary",
"biology.",
"A",
"simulation",
"study",
"was",
"used",
"to",
"examine",
"the",
"effect",
"of",
"alignment",
"accuracy",
"of",
"DNA",
"sequences",
"on",
"evolutionary",
"distance",
"estimation.",
"Results:",
"Under",
"the",
"studied",
"conditions,",
"distance",
"estimation",
"was",
"relatively",
"unaffected",
"by",
"alignment",
"error",
"(50%",
"or",
"more",
"of",
"the",
"sites",
"incorrectly",
"aligned)",
"as",
"long",
"as",
"50%",
"or",
"more",
"of",
"the",
"sites",
"were",
"identical",
"among",
"the",
"sequences",
"(observed",
"P-distance",
"<",
"0.5).",
"Beyond",
"this",
"threshold,",
"the",
"alignment",
"procedure",
"artificially",
"inflates",
"the",
"apparent",
"sequence",
"identity,",
"skewing",
"distance",
"estimates,",
"and",
"creating",
"alignments",
"that",
"are",
"essentially",
"indistinguishable",
"from",
"random",
"data.",
"This",
"general",
"result",
"was",
"independent",
"of",
"substitution",
"model,",
"sequence",
"length,",
"and",
"insertion",
"and",
"deletion",
"size",
"and",
"rate.",
"Conclusion:",
"Examination",
"of",
"the",
"estimated",
"sequence",
"identity",
"may",
"yield",
"some",
"guidance",
"as",
"to",
"the",
"accuracy",
"of",
"the",
"alignment.",
"Inaccurate",
"alignments",
"are",
"expected",
"to",
"have",
"large",
"effects",
"on",
"analyses",
"dependent",
"on",
"site",
"specificity,",
"but",
"analyses",
"that",
"depend",
"on",
"evolutionary",
"distance",
"may",
"be",
"somewhat",
"robust",
"to",
"alignment",
"error",
"as",
"long",
"as",
"fewer",
"than",
"half",
"of",
"the",
"sites",
"have",
"diverged.",
"Background",
"Evolutionary",
"distance,",
"the",
"number",
"of",
"substitutions",
"per",
"site",
"separating",
"a",
"pair",
"of",
"homologous",
"sequences",
"since",
"they",
"diverged",
"from",
"their",
"common",
"ancestral",
"sequence,",
"is",
"an",
"extremely",
"important",
"measure",
"in",
"molecular",
"evolution",
"and",
"comparative",
"genomics.",
"It",
"is",
"used",
"for",
"a",
"wide",
"variety",
"of",
"pur-",
"poses,",
"ranging",
"from",
"phylogenetic",
"analysis",
"[1,2],",
"to",
"esti-",
"mating",
"times",
"of",
"divergence",
"[3,4],",
"the",
"tempo",
"and",
"mode",
"of",
"evolutionary",
"change",
"[5],",
"and",
"functional",
"constraints",
"[6,7].",
"Evolutionary",
"distance",
"estimation",
"is",
"often",
"one",
"of",
"the",
"first",
"steps",
"in",
"high-throughput",
"sequence",
"analysis;",
"errors",
"in",
"these",
"estimates",
"may",
"have",
"wide-ranging",
"consequences",
"on",
"downstream",
"analyses",
"and",
"conclusions.",
"There",
"are",
"many",
"ways",
"to",
"estimate",
"evolutionary",
"distance;",
"accuracy",
"of",
"various",
"methods",
"tends",
"to",
"be",
"dependent",
"on",
"proper",
"specification",
"of",
"the",
"substitution",
"model",
"and",
"sequence",
"length",
"[8,9].",
"One",
"factor",
"that",
"has",
"not",
"been",
"well",
"examined",
"with",
"respect",
"to",
"evolutionary",
"distance",
"estima-",
"tion,",
"however,",
"is",
"alignment",
"(although",
"see",
"[10-12]).",
"Sequence",
"alignment",
"is",
"an",
"extremely",
"common",
"analytical",
"tool",
"used",
"in",
"comparative",
"genomics.",
"The",
"purpose",
"of",
"align-",
"ment",
"is",
"to",
"identify",
"positions",
"in",
"homologous",
"sequences",
"that",
"are",
"descended",
"from",
"a",
"common",
"ancestor.",
"Because",
"alignment",
"is",
"the",
"first",
"step",
"in",
"many",
"complex,",
"high-",
"throughput",
"studies",
"[13],",
"it",
"is",
"often",
"forgotten",
"that",
"align-",
"ment",
"algorithms",
"produce",
"a",
"hypothesis",
"of",
"homology",
"(just",
"as",
"a",
"phylogenetic",
"tree",
"is",
"a",
"hypothesis",
"of",
"evolutionary",
"Page",
"1",
"of",
"9",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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"Hamzaoui",
"et",
"al.",
"International",
"Archives",
"of",
"Medicine",
"2011,",
"4:9",
"http://www.intarchmed.com/content/4/1/9",
"C",
"A",
"S",
"E",
"R",
"E",
"P",
"O",
"R",
"T",
"Open",
"Access",
"Co-existing",
"sarcoidosis",
"and",
"Takayasu",
"arteritis:",
"report",
"of",
"a",
"case",
"Amira",
"Hamzaoui1*,",
"Randa",
"Salem2,",
"Rim",
"Klii1,",
"Olfa",
"Harzallah1,",
"Olfa",
"Berriche1,",
"Mondher",
"Golli2,",
"Silvia",
"Mahjoub1",
"Abstract",
"Introduction:",
"Takayasu",
"arteritis",
"(TA)",
"is",
"a",
"chronic",
"vasculitis",
"of",
"unknown",
"origin,",
"affecting",
"mainly",
"the",
"aorta",
"and",
"its",
"main",
"branches.",
"As",
"a",
"result",
"of",
"the",
"inflammation,",
"stenosis,",
"occlusion",
"or",
"dilatation",
"of",
"the",
"involved",
"vessels",
"may",
"occur",
"and",
"cause",
"a",
"wide",
"range",
"of",
"symptoms.",
"It",
"has",
"been",
"described",
"in",
"association",
"with",
"various",
"auto-immune",
"disorders",
"(mainly",
"inflammatory",
"digestive",
"tract",
"diseases).",
"However,",
"only",
"few",
"cases",
"of",
"TA",
"associated",
"with",
"sarcoidosis",
"have",
"been",
"reported,",
"raising",
"the",
"question",
"of",
"an",
"association",
"by",
"chance.",
"Case",
"report:",
"We",
"report",
"a",
"case",
"of",
"a",
"34",
"year-old",
"woman,",
"with",
"one",
"year",
"history",
"of",
"sarcoidosis,",
"who",
"presented",
"with",
"asymmetric",
"high",
"hypertension",
"revealing",
"inflammatory",
"humeral,",
"axillary",
"and",
"subclavian",
"arteritis",
"related",
"to",
"TA,",
"successfully",
"treated",
"by",
"steroid",
"and",
"immunosuppressive",
"therapy(MethotrexateR).",
"Conclusion:",
"TA",
"and",
"sarcoidosis",
"may",
"be",
"related,",
"rising",
"the",
"hypothesis",
"that",
"TA",
"or",
"Takayasu",
"arteritis-like",
"granulomatous",
"vasculitis",
"may",
"be,",
"in",
"fact,",
"a",
"complication",
"of",
"sarcoidosis.",
"Introduction",
"Takayasu",
"arteritis",
"(TA)",
"is",
"a",
"chronic",
"inflammatory",
"dis-",
"ease",
"of",
"large",
"arteries",
"which",
"progressively",
"develop",
"steno-",
"sis,",
"occlusion",
"or",
"aneurismal",
"degeneration.",
"The",
"clinical",
"presentation",
"is",
"characterised",
"by",
"an",
"acute",
"phase",
"with",
"constitutional",
"symptoms,",
"followed,",
"months",
"or",
"years",
"later,",
"by",
"a",
"chronic",
"phase",
"in",
"which",
"symptoms",
"relate",
"to",
"fibrosis",
"or",
"occlusion",
"of",
"vessels.",
"Angiography",
"is",
"the",
"gold",
"standard",
"for",
"diagnosis",
"and",
"for",
"topographical",
"classifica-",
"tion",
"and",
"it",
"correlates",
"with",
"symptoms",
"and",
"prognosis.",
"Proinflammatory",
"cytokines",
"and,",
"among",
"these,",
"tumor",
"necrosis",
"factor-alpha",
"(TNF-alpha)",
"are",
"increased",
"and",
"play",
"a",
"pathogenetic",
"role",
"in",
"the",
"development",
"of",
"disease.",
"Laboratory",
"findings",
"are",
"non-specific.",
"Treatment",
"of",
"active",
"disease",
"is",
"primarily",
"based",
"on",
"corticosteroids",
"but",
"other",
"immunosuppressive",
"drugs",
"are",
"frequently",
"needed.",
"Anti-platelets",
"agents,",
"statins",
"and",
"antihypertensive",
"drugs",
"are",
"frequently",
"considered",
"[1].",
"Sarcoidosis,",
"too,",
"is",
"a",
"systemic",
"inflammatory",
"disease",
"which",
"can",
"affect",
"virtually",
"any",
"organ",
"system.",
"The",
"lungs",
"are",
"most",
"commonly",
"affected,",
"but",
"often",
"there",
"is",
"also",
"affection",
"of",
"the",
"musculoskeletal",
"system,",
"the",
"cutaneous",
"*",
"Correspondence:",
"hamzaoui.amira@yahoo.fr",
"1Department",
"of",
"Internal",
"Medicine-",
"Fattouma",
"Bourguiba",
"Hospital-",
"Monastir-",
"Tunisia",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"and",
"central",
"nervous",
"systems,",
"and",
"the",
"heart.",
"Histology",
"shows",
"granulomas",
"consisting",
"of",
"a",
"central",
"zone",
"with",
"macrophages,",
"epithelioid",
"cells,",
"and",
"multinucleated",
"giant",
"cells",
"in",
"addition",
"to",
"activated",
"CD4",
"lymphocytes,",
"and",
"a",
"peripheral",
"zone",
"with",
"macrophages,",
"fibroblasts,",
"and",
"CD4",
"and",
"CD8",
"lymphocytes.",
"Inclusion",
"bodies",
"are",
"commonly",
"found.",
"Vasculitis",
"may",
"be",
"found",
"occasionally",
"in",
"patients",
"with",
"sarcoidosis.",
"It",
"has",
"not",
"been",
"confirmed,",
"however,",
"whether",
"vasculitis",
"is",
"a",
"true",
"manifestation",
"of",
"the",
"disease",
"or",
"an",
"occasional,",
"incidentally",
"concurring",
"abnormality.",
"Concurrence",
"of",
"sarcoidosis",
"and",
"TA",
"were",
"reported",
"in",
"few",
"cases.",
"Case",
"Report",
"A",
"34",
"year",
"old",
"woman",
"was",
"admitted",
"to",
"the",
"hospital",
"with",
"dyspnea,",
"submandubular",
"gland",
"tumefaction",
"and",
"parotid",
"swelling.",
"On",
"physical",
"examination,",
"we",
"found",
"the",
"tumefaction",
"of",
"the",
"parotid",
"and",
"the",
"submandibular",
"gland.",
"The",
"respira-",
"tory",
"frequency",
"was",
"24",
"cycles",
"per",
"minute.",
"The",
"rest",
"of",
"the",
"clinical",
"examination",
"was",
"without",
"abnormalities.",
"Laboratory",
"results",
"were",
"as",
"follows:",
"Haemoglobin",
"10",
"g/dl,",
"white",
"blood",
"cell",
"count",
"(WBC)",
"11",
"200/mm3,",
"platelets",
"450",
"000/mm3,",
"erythrocyte",
"sedimentation",
"rate",
"(ESR)",
"76",
"mm/h,",
"calcium",
"12",
"mg/dl",
"(normal:",
"9-11",
"mg/dl",
").",
"Muscle",
"©",
"2011",
"Hamzaoui",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
] | [
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] | [
"접수번호:",
"2009-045",
"Korean",
"Journal",
"of",
"Ophthalm",
"ology",
"2009;23:329-331",
"ISSN",
":",
"1011-8942",
"DOI",
":",
"10.3341/kjo.2009.23.4.329",
"A",
"Case",
"of",
"Pseudo-Duane’s",
"Retraction",
"Syndrome",
"With",
"Old",
"Medial",
"Orbital",
"Wall",
"Fracture",
"Seung",
"Hee",
"Lee,",
"MD,",
"Jae",
"Hyung",
"Lee,",
"MD,",
"Soo",
"Yoon",
"Lee,",
"MD,",
"Sook",
"Young",
"Kim,",
"MD",
"Department",
"of",
"Ophthalmology,",
"Daegu",
"Catholic",
"University",
"College",
"of",
"Medicine,",
"Daegu,",
"Korea",
"We",
"report",
"a",
"case",
"of",
"pseudo-Duane’s",
"retraction",
"syndrome",
"with",
"entrapment",
"of",
"the",
"medial",
"rectus",
"muscle",
"in",
"an",
"old",
"medial",
"orbital",
"wall",
"fracture",
"presenting",
"identical",
"clinical",
"symptoms",
"as",
"Duane’s",
"retraction",
"syndrome.",
"A15-year-old",
"boy",
"presented",
"with",
"persistent",
"limited",
"right",
"eye",
"movement",
"since",
"a",
"young",
"age.",
"Examination",
"showed",
"marked",
"limited",
"abduction,",
"mildly",
"limited",
"adduction,",
"and",
"globe",
"retraction",
"accompanied",
"by",
"narrowing",
"of",
"the",
"palpebral",
"fissure",
"during",
"attempted",
"adduction",
"in",
"the",
"right",
"eye.",
"He",
"showed",
"a",
"right",
"esotropia",
"of",
"16",
"prism",
"diopters",
"and",
"his",
"head",
"turned",
"slightly",
"to",
"the",
"right.",
"A",
"slight",
"enophthalmos",
"was",
"noted",
"in",
"his",
"right",
"eye.",
"A",
"computed",
"tomography",
"scan",
"demonstrated",
"entrapment",
"of",
"the",
"medial",
"rectus",
"muscle",
"and",
"surrounding",
"tissues",
"in",
"an",
"old",
"medial",
"orbital",
"wall",
"fracture.",
"A",
"forced",
"duction",
"test",
"revealed",
"a",
"marked",
"restriction",
"of",
"abduction",
"in",
"the",
"right",
"eye.",
"A",
"5",
"mm",
"recession",
"of",
"the",
"right",
"medial",
"rectus",
"muscle",
"was",
"performed.",
"Post-",
"operatively,",
"the",
"patient’s",
"head",
"turn",
"and",
"esotropia",
"in",
"the",
"primary",
"position",
"were",
"successfully",
"corrected,",
"but",
"there",
"was",
"still",
"some",
"limitations",
"to",
"his",
"ocular",
"movement.",
"The",
"importance",
"of",
"several",
"tests",
"such",
"as",
"the",
"forced",
"duction",
"test",
"and",
"an",
"imaging",
"study",
"should",
"be",
"emphasized",
"in",
"making",
"a",
"diagnosis",
"for",
"limitation",
"of",
"eye",
"movement.",
"Korean",
"J",
"Ophthalmol",
"2009;23:329-331",
"ⓒ",
"2009",
"by",
"the",
"Korean",
"Ophthalmological",
"Society.",
"Key",
"Words:",
"Duane’s",
"retraction",
"syndrome,",
"Medial",
"orbital",
"wall",
"fracture,",
"Pseudo-Duane’s",
"retraction",
"syndrome",
"Since",
"Alexander",
"Duane",
"published",
"a",
"paper",
"in",
"1905",
"des-",
"cribing",
"what",
"has",
"come",
"to",
"be",
"known",
"as",
"Duane’s",
"retraction",
"syndrome,",
"Thomas",
"Duane",
"reported",
"a",
"similar,",
"yet",
"different",
"set",
"of",
"symptoms",
"and",
"signs",
"as",
"‘pseudo-Duane’s",
"retraction",
"syndrome’",
"in",
"1976.1",
"In",
"the",
"most",
"common",
"type",
"of",
"Duane’s",
"retraction",
"syndrome,",
"there",
"is",
"markedly",
"restricted",
"abduction",
"with",
"eyeball",
"retraction",
"and",
"narrowing",
"of",
"the",
"palpebral",
"fissure",
"on",
"adduction.2",
"In",
"pseudo-Duane’s",
"retraction",
"syndrome,",
"how-",
"ever,",
"abduction",
"of",
"the",
"affected",
"eye",
"is",
"possible",
"to",
"some",
"extent,",
"and",
"the",
"globe",
"retraction",
"occurs",
"on",
"abduction",
"accompanied",
"by",
"narrowing",
"of",
"the",
"palpebral",
"fissure",
"presenting",
"the",
"opposite",
"features",
"as",
"those",
"of",
"classic",
"Duane’s",
"retraction",
"syndrome.",
"The",
"etiology",
"is",
"also",
"completely",
"different",
"from",
"those",
"of",
"Duane’s",
"retraction",
"syndrome.",
"Pseudo-Duane’s",
"retraction",
"syndrome",
"has",
"been",
"reported",
"as",
"being",
"caused",
"by",
"acquired",
"or",
"congenital",
"factors",
"that",
"affect",
"the",
"medial",
"rectus",
"muscle.",
"Entrapment",
"of",
"the",
"medial",
"rectus",
"muscle",
"in",
"a",
"medial",
"orbital",
"wall",
"fracture",
"has",
"been",
"known",
"to",
"be",
"the",
"most",
"common",
"cause.3",
"We",
"report",
"a",
"case",
"of",
"pseudo-Duane’s",
"retraction",
"syndrome",
"with",
"entrapment",
"of",
"the",
"medial",
"rectus",
"muscle",
"in",
"an",
"old",
"medial",
"orbital",
"wall",
"fracture,",
"presenting",
"very",
"similar",
"clinical",
"features",
"as",
"those",
"of",
"classic",
"Duane’s",
"retraction",
"syndrome.",
"The",
"pre-",
"Received:",
"April",
"22,",
"2009",
"Accepted:",
"October",
"29,",
"2009",
"Reprint",
"requests",
"to",
"Sook",
"Young",
"Kim,",
"MD.",
"Department",
"of",
"Ophthalmology,",
"Daegu",
"Catholic",
"University",
"College",
"of",
"Medicine,",
"#3056-6",
"Daemyeong",
"4-dong,",
"Nam-gu,",
"Daegu",
"705-718,",
"Korea.",
"Tel:",
"82-53-650-4728,",
"E-mail:",
"kimsy@cu.ac.kr",
"sentation",
"is",
"contradictory",
"to",
"previous",
"reports",
"of",
"pseudo-",
"Duane’s",
"retraction",
"syndrome.",
"Case",
"Repo",
"rt",
"A",
"15-year-old",
"boy",
"had",
"complained",
"of",
"motility",
"limitation",
"in",
"the",
"right",
"eye",
"since",
"a",
"young",
"age.",
"His",
"visual",
"acuity",
"was",
"20/20",
"in",
"each",
"eye,",
"although",
"an",
"ocular",
"motility",
"examination",
"revealed",
"markedly",
"limited",
"abduction",
"and",
"mildly",
"limited",
"adduction",
"in",
"his",
"right",
"eye",
"(Fig.",
"1).",
"On",
"attempted",
"adduction",
"of",
"the",
"right",
"eye,",
"globe",
"retraction",
"(Fig.",
"2)",
"with",
"narrowing",
"of",
"the",
"palpebral",
"fissure",
"was",
"observed,",
"and",
"there",
"mild",
"upshoot",
"and",
"downshoot",
"were",
"also",
"observed",
"(Fig.",
"1).",
"The",
"palpebral",
"fissure",
"of",
"the",
"right",
"eye",
"was",
"slightly",
"widened",
"on",
"attempted",
"abduction.",
"An",
"alternate",
"prism",
"cover",
"test",
"revealed",
"a",
"16",
"prism",
"diopters",
"(PD)",
"right",
"esotropia",
"(ET)",
"in",
"the",
"primary",
"position,",
"25",
"PD",
"ET",
"in",
"right",
"gaze,",
"10",
"PD",
"ET",
"in",
"left",
"gaze",
"at",
"dist-",
"ance",
"fixation,",
"and",
"4",
"PD",
"ET",
"at",
"near",
"fixation.",
"He",
"assumed",
"a",
"compensatory",
"face",
"turn",
"to",
"the",
"right",
"and",
"did",
"not",
"comp-",
"lain",
"of",
"diplopia.",
"No",
"living",
"member",
"on",
"either",
"the",
"paternal",
"or",
"maternal",
"side",
"had",
"a",
"squint.",
"Duane’s",
"retraction",
"syndrome",
"was",
"inferred",
"as",
"the",
"diagnosis",
"until",
"we",
"noted",
"that",
"the",
"patient’s",
"right",
"eye",
"had",
"slight",
"enophthalmos.",
"Hertel’s",
"exophthalmo-",
"metry",
"revealed",
"a",
"1.5",
"mm",
"difference",
"between",
"both",
"eyes",
"and",
"the",
"margin",
"reflex",
"distance",
"1",
"was",
"0.5",
"mm",
"in",
"the",
"right",
"eye.",
"Computed",
"tomography",
"of",
"the",
"orbits",
"was",
"performed",
"and",
"demonstrated",
"an",
"old",
"medial",
"orbital",
"wall",
"fracture",
"with",
"entrapment",
"of",
"the",
"medial",
"rectus",
"muscle",
"and",
"surrounding",
"tissues",
"(Fig.",
"3).",
"However,",
"there",
"was",
"no",
"history",
"of",
"trauma",
"329"
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"BMC",
"Public",
"Health",
"Research",
"article",
"Rubella",
"seroprevalence",
"among",
"primary",
"and",
"pre-",
"primary",
"school",
"pupils",
"at",
"Moi's",
"Bridge",
"location,",
"Uasin",
"Gishu",
"District,",
"Kenya",
"Janeth",
"J",
"Kombich*,",
"Paul",
"C",
"Muchai,",
"Peter",
"Tukei",
"and",
"Peter",
"K",
"Borus",
"BioMed",
"Central",
"Open",
"Access",
"Address:",
"Centre",
"for",
"Virus",
"Research,",
"Kenya",
"Medical",
"Research",
"Institute,",
"Nairobi,",
"Kenya",
"Email:",
"Janeth",
"J",
"Kombich*",
"-",
"jkombich@kemri.org;",
"Paul",
"C",
"Muchai",
"-",
"pmuchai@kemri.org;",
"Peter",
"Tukei",
"-",
"ptukei@kemri.org;",
"Peter",
"K",
"Borus",
"-",
"pborus@kemri.org",
"*",
"Corresponding",
"author",
"Published:",
"29",
"July",
"2009",
"BMC",
"Public",
"Health",
"2009,",
"9:269",
"doi:10.1186/1471-2458-9-269",
"This",
"article",
"is",
"available",
"from:",
"http://www.biomedcentral.com/1471-2458/9/269",
"Received:",
"19",
"August",
"2008",
"Accepted:",
"29",
"July",
"2009",
"©",
"2009",
"Kombich",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Abstract",
"Background:",
"Rubella",
"is",
"an",
"infectious",
"and",
"generally",
"mild",
"childhood",
"viral",
"disease.",
"The",
"disease",
"is",
"of",
"public",
"health",
"importance",
"because",
"infection",
"acquired",
"during",
"early",
"pregnancy",
"often",
"results",
"in",
"foetal",
"abnormalities",
"that",
"are",
"classified",
"as",
"congenital",
"rubella",
"syndrome",
"(CRS).",
"The",
"burden",
"of",
"rubella",
"infection",
"in",
"most",
"developing",
"countries",
"in",
"not",
"well",
"documented",
"because",
"of",
"limited",
"epidemiological",
"data.",
"However,",
"availability",
"of",
"an",
"effective",
"vaccine",
"has",
"made",
"it",
"necessary",
"to",
"have",
"all",
"the",
"countries",
"with",
"no",
"routine",
"vaccination",
"schedule",
"to",
"evaluate",
"the",
"burden",
"of",
"disease",
"in",
"order",
"to",
"make",
"informed",
"decisions",
"on",
"rubella",
"vaccination",
"and",
"strategy.",
"To",
"address",
"this",
"gap",
"we",
"conducted",
"a",
"study",
"to",
"determine",
"age-specific",
"rubella",
"seroprevalence",
"rates",
"and",
"related",
"risk",
"factors",
"among",
"primary",
"and",
"pre-primary",
"school",
"children",
"in",
"Uasin",
"Gishu",
"district,",
"Moi's",
"Bridge",
"location",
"of",
"Kenya.",
"Methods:",
"Subjects",
"of",
"the",
"study",
"were",
"498",
"pupils",
"from",
"seven",
"primary",
"schools",
"aged",
"4–20",
"years.",
"Questionnaire",
"surveys",
"with",
"blood",
"sampling",
"were",
"conducted",
"between",
"January",
"to",
"July",
"2005.",
"Samples",
"were",
"tested",
"for",
"rubella",
"specific",
"IgG",
"antibody",
"using",
"ELISA",
"test",
"kit",
"(Enzygnost®",
"Behring,",
"Germany).",
"Results:",
"Overall,",
"rubella",
"seropositivity",
"rate",
"was",
"80%",
"and",
"it",
"increased",
"with",
"age",
"from",
"59%",
"(among",
"ages",
"4–6",
"years)",
"to",
"94%",
"(ages",
"14–20",
"years).",
"Multivariate",
"logistic",
"regression",
"analysis",
"model,",
"showed",
"that",
"age",
"of",
"child",
"and",
"ownership",
"of",
"a",
"television",
"set",
"which",
"is",
"a",
"proxy",
"measure",
"of",
"socio-economic",
"status",
"of",
"family",
"were",
"significantly",
"associated",
"with",
"rubella",
"seropositivity.",
"The",
"odds",
"of",
"rubella",
"seropositivity",
"in",
"a",
"child",
"older",
"than",
"13",
"years",
"was",
"more",
"than",
"that",
"in",
"children",
"younger",
"than",
"7",
"years",
"(OR",
"=",
"3.8",
"95%",
"CI",
"2.56–5.78).",
"The",
"odds",
"of",
"rubella",
"seropositivity",
"in",
"a",
"child",
"whose",
"family",
"did",
"not",
"own",
"a",
"television",
"set",
"was",
"3",
"times",
"higher",
"than",
"that",
"of",
"child",
"whose",
"family",
"owned",
"a",
"set",
"(OR",
"3.06,",
"95%",
"CI",
"1.17–7.97).",
"Conclusion:",
"The",
"study",
"provides",
"important",
"and",
"highly",
"useful",
"information",
"on",
"rubella",
"age",
"specific",
"seroprevalence",
"rates",
"in",
"Kenya.",
"Advancing",
"age",
"was",
"found",
"to",
"be",
"associated",
"with",
"increased",
"risk",
"of",
"rubella.",
"Low",
"socio-economic",
"factors",
"suggest",
"an",
"increased",
"risk",
"of",
"infection",
"in",
"certain",
"categories",
"of",
"society,",
"and",
"control",
"measures",
"need",
"to",
"target",
"this.",
"Overall,",
"the",
"findings",
"can",
"also",
"be",
"used",
"by",
"policy",
"makers",
"to",
"model",
"introduction",
"of",
"routine",
"rubella",
"vaccination",
"in",
"the",
"country",
"and",
"also",
"other",
"developing",
"countries",
"facing",
"similar",
"challenges.",
"More",
"than",
"half",
"of",
"the",
"children",
"got",
"infected",
"in",
"pre-",
"primary",
"and",
"efforts",
"to",
"control",
"rubella",
"should",
"target",
"pre-school",
"children.",
"These",
"data",
"provides",
"pre-",
"vaccination",
"information",
"that",
"can",
"be",
"used",
"to",
"guide",
"immunization",
"strategy",
"as",
"well",
"as",
"to",
"determine",
"success",
"of",
"an",
"immunization",
"programme.",
"Page",
"1",
"of",
"5",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
] | [
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] | [
"Hindawi",
"Publishing",
"Corporation",
"Journal",
"of",
"Biomedicine",
"and",
"Biotechnology",
"Volume",
"2010,",
"Article",
"ID",
"130265,",
"6",
"pages",
"doi:10.1155/2010/130265",
"Research",
"Article",
"Monocyte",
"Chemoattractant",
"Protein-1",
"−2518",
"A/G",
"Single",
"Nucleotide",
"Polymorphism",
"Might",
"Be",
"Associated",
"with",
"Renal",
"Disease",
"and",
"Thrombocytopenia",
"of",
"SLE",
"Piotr",
"Piotrowski,1,",
"2",
"Margarita",
"Lianeri,1",
"Robert",
"Gasik,1,",
"3",
"Andrzej",
"Roszak,1,",
"4",
"Marzena",
"Olesi",
"n´ska,3",
"and",
"Paweł",
"P.",
"Jagodzi",
"n´ski1",
"1",
"Department",
"of",
"Biochemistry",
"and",
"Molecular",
"Biology,",
"Poznan´",
"University",
"of",
"Medical",
"Sciences,",
"6",
"S´wi¸ecickiego",
"St.,",
"60-781",
"Poznan´,",
"Poland",
"2",
"Medical",
"Research",
"Centre,",
"Polish",
"Academy",
"of",
"Sciences,",
"Warsaw,",
"Poland",
"3",
"Institute",
"of",
"Rheumatology,",
"Warsaw,",
"Poland",
"4",
"Department",
"of",
"Radiotherapy",
"and",
"Gynecological",
"Oncology,",
"Greater",
"Poland",
"Cancer",
"Centre,",
"15",
"Garbary",
"St.,",
"61-866",
"Poznan,",
"Poland",
"Correspondence",
"should",
"be",
"addressed",
"to",
"Paweł",
"P.",
"Jagodzi",
"n´ski,",
"pjagodzi@am.poznan.pl",
"Received",
"30",
"November",
"2009;",
"Revised",
"13",
"February",
"2010;",
"Accepted",
"14",
"March",
"2010",
"Academic",
"Editor:",
"Timothy",
"B.",
"Niewold",
"Copyright",
"©",
"2010",
"Piotr",
"Piotrowski",
"et",
"al.",
"This",
"is",
"an",
"open",
"access",
"article",
"distributed",
"under",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"There",
"is",
"conflicting",
"evidence",
"on",
"the",
"contribution",
"of",
"the",
"MCP-1",
"−2518",
"A>G",
"(rs",
"1024611)",
"polymorphism",
"to",
"SLE",
"incidence",
"and",
"clinical",
"manifestations.",
"We",
"examined",
"the",
"prevalence",
"of",
"the",
"MCP-1",
"−2518",
"A>G",
"polymorphism",
"in",
"SLE",
"patients",
"(n",
"=",
"199)",
"and",
"controls",
"(n",
"=",
"250)",
"in",
"Poland.",
"We",
"did",
"not",
"observe",
"a",
"significant",
"difference",
"in",
"the",
"distribution",
"of",
"MCP-1",
"−2518",
"A>G",
"polymorphic",
"variants",
"in",
"patients",
"with",
"SLE",
"and",
"healthy",
"individuals.",
"However,",
"we",
"found",
"an",
"association",
"between",
"the",
"GG",
"versus",
"AG",
"and",
"AA",
"genotypes",
"as",
"well",
"as",
"the",
"AG",
"and",
"GG",
"versus",
"AA",
"genotypes",
"with",
"renal",
"manifestations",
"of",
"SLE",
"OR",
"=",
"3.614",
"(1.123–11.631,",
"P",
"=",
"0.0345)",
"and",
"OR",
"=",
"2.297",
"(1.301–4.057,",
"P",
"=",
"0.0046),",
"respectively.",
"We",
"also",
"observed",
"that",
"the",
"MCP-1",
"AG",
"and",
"GG",
"-genotypes",
"contribute",
"to",
"the",
"occurrence",
"of",
"thrombocytopenia",
"in",
"SLE",
"patients",
"OR",
"=",
"2.618",
"(1.280–5.352,",
"P",
"=",
"0.0089).",
"Our",
"observations",
"indicate",
"that",
"either",
"MCP-1",
"−2518",
"G",
"variant",
"can",
"be",
"associated",
"with",
"some",
"clinical",
"findings",
"in",
"patients",
"with",
"SLE.",
"1.",
"Introduction",
"Systemic",
"lupus",
"erythematosus",
"(SLE)",
"is",
"a",
"chronic",
"and",
"pro-",
"gressive",
"multisystem",
"autoimmune",
"connective",
"tissue",
"disorder,",
"which",
"is",
"characterized",
"by",
"immune-mediated",
"host",
"tissue",
"destruction",
"[1].",
"Occupational",
"exposure,",
"chemicals,",
"drugs,",
"food,",
"as",
"well",
"as",
"viral",
"and",
"bacterial",
"infectious",
"agents",
"can",
"contribute",
"significantly",
"to",
"changes",
"in",
"the",
"immune",
"system",
"[2,",
"3].",
"Immune",
"cells",
"from",
"patients",
"with",
"SLE",
"exhibit",
"various",
"defects",
"including",
"skewed",
"cytokine",
"production,",
"a",
"decrease",
"in",
"cytotoxic",
"T",
"cell",
"function,",
"and",
"an",
"increase",
"in",
"the",
"humoral",
"response",
"[4–7].",
"The",
"defective",
"function",
"of",
"CD4+",
"T",
"cells",
"asso-",
"ciated",
"with",
"abnormal",
"stimulation",
"of",
"B",
"cells",
"causes",
"abundant",
"autoantibody",
"production",
"[4,",
"6].",
"These",
"autoantibodies",
"form",
"immune",
"complexes",
"with",
"antigens",
"on",
"the",
"patient’s",
"own",
"cells",
"and",
"are",
"accumulated",
"in",
"the",
"skin,",
"synovium,",
"lungs,",
"renal",
"glomeruli,",
"and",
"other",
"organs",
"and",
"tissues.",
"This",
"results",
"in",
"the",
"clinical",
"presentation",
"of",
"SLE",
"[1,",
"8].",
"The",
"pathogenesis",
"of",
"SLE",
"remains",
"unclear,",
"though",
"there",
"is",
"much",
"evidence",
"demonstrating",
"the",
"involvement",
"of",
"genetic",
"factors",
"in",
"the",
"incidence",
"of",
"this",
"autoimmune",
"disease",
"[9–13].",
"The",
"genetic",
"background",
"contributing",
"to",
"SLE",
"development",
"includes,",
"in",
"particular,",
"genes",
"encoding",
"disparate",
"proteins",
"that",
"control",
"immune",
"system",
"pathways",
"[9,",
"10,",
"13].",
"The",
"monocyte",
"chemoattractant",
"protein",
"1",
"(MCP-1),",
"cur-",
"rently",
"also",
"designated",
"CCL2,",
"belongs",
"to",
"the",
"family",
"of",
"chemo-",
"tactic",
"cytokines.",
"MCP-1",
"functions",
"as",
"a",
"potent",
"agonist",
"for",
"monocytes,",
"memory",
"T",
"cells,",
"and",
"basophils",
"[14].",
"Evidence",
"in",
"animal",
"and",
"human",
"studies",
"suggests",
"a",
"significant",
"role",
"of",
"MCP-",
"1",
"in",
"the",
"progression",
"of",
"glomerular",
"and",
"tubulointerstitial",
"injuries",
"and",
"glomerulonephriti",
"in",
"patients",
"with",
"SLE",
"[15–19].",
"It",
"has",
"been",
"demonstrated",
"that",
"the",
"MCP-1",
"–2518",
"A>G",
"(rs",
"1024611)",
"transition",
"in",
"the",
"promoter",
"region",
"may",
"modulate"
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] | [
"pISSN",
"1229-845X,",
"eISSN",
"1976-555X",
"J.",
"Vet.",
"Sci.",
"(2011),",
"12(2),",
"151-157",
"DOI:",
"10.4142/jvs.2011.12.2.151",
"Received:",
"07",
"Apr.",
"2010,",
"Accepted:",
"26",
"Jul.",
"2010",
"Original",
"Article",
"J",
"O",
"U",
"R",
"N",
"A",
"L",
"O",
"F",
"Veterinary",
"Science",
"The",
"stress",
"of",
"weaning",
"influences",
"serum",
"levels",
"of",
"acute-phase",
"proteins,",
"iron-binding",
"proteins,",
"inflammatory",
"cytokines,",
"cortisol,",
"and",
"leukocyte",
"subsets",
"in",
"Holstein",
"calves",
"Myung-Hoo",
"Kim1,†,",
"Ji-Young",
"Yang1,†,",
"Santi",
"Devi",
"Upadhaya1,",
"Hyun-Jun",
"Lee2,",
"Cheol-Heui",
"Yun1,",
"Jong",
"K.",
"Ha1,*",
"1Department",
"of",
"Agricultural",
"Biotechnology",
"and",
"Research",
"Institute",
"for",
"Agriculture",
"and",
"Life",
"Sciences,",
"College",
"of",
"Agriculture",
"and",
"Life",
"Sciences,",
"Seoul",
"National",
"University,",
"Seoul",
"151-742,",
"Korea",
"2Dairy",
"Science",
"Division,",
"National",
"Institute",
"of",
"Animal",
"Science,",
"Cheonan",
"330-801,",
"Korea",
"The",
"purpose",
"of",
"our",
"study",
"was",
"to",
"investigate",
"changes",
"in",
"immunological",
"parameters",
"induced",
"by",
"weaning",
"stress",
"(including",
"milk",
"restriction)",
"in",
"calves.",
"Fifteen",
"Holstein",
"calves",
"were",
"subjected",
"to",
"weaning",
"at",
"6",
"weeks",
"of",
"age.",
"Blood",
"samples",
"were",
"collected",
"at",
"−14,",
"−7,",
"−2,",
"1,",
"3,",
"and",
"5",
"days",
"post-weaning",
"(DPW;",
"0",
"DPW",
"=",
"42",
"days).",
"Weaning",
"caused",
"significant",
"(p",
"<",
"0.01)",
"increases",
"in",
"the",
"neutrophil",
"(NE):lymphocyte",
"(LY)",
"ratio",
"at",
"5",
"DPW",
"with",
"a",
"significant",
"(p",
"<",
"0.05)",
"reduction",
"of",
"LYs.",
"The",
"concentration",
"of",
"acute-phase",
"proteins",
"(haptoglobin",
"and",
"serum",
"amyloid",
"A)",
"also",
"increased",
"significantly",
"(p",
"<",
"0.05)",
"at",
"3",
"and",
"5",
"DPW",
"compared",
"to",
"−2",
"DPW.",
"Levels",
"of",
"the",
"iron-binding",
"protein",
"lactoferrin",
"decreased",
"significantly",
"(p",
"<",
"0.05)",
"after",
"weaning.",
"Serum",
"tumor",
"necrosis",
"factor-α",
"and",
"cortisol",
"levels",
"were",
"elevated",
"(p",
"<",
"0.05)",
"at",
"3",
"DPW,",
"while",
"those",
"of",
"serum",
"interferon-γ",
"decreased",
"(p",
"<",
"0.05)",
"at",
"1",
"and",
"3",
"DPW",
"compared",
"to",
"levels",
"observed",
"before",
"weaning.",
"Weaning",
"significantly",
"(p",
"<",
"0.05)",
"decreased",
"the",
"percentage",
"of",
"CD25+",
"T",
"cells",
"in",
"the",
"peripheral",
"blood.",
"In",
"conclusion,",
"weaning",
"stress",
"affected",
"the",
"NE:LY",
"ratio",
"along",
"with",
"the",
"levels",
"of",
"acute",
"phase",
"proteins,",
"lactoferrin,",
"cortisol,",
"and",
"inflammatory",
"cytokines",
"in",
"the",
"peripheral",
"blood",
"of",
"calves.",
"Weaning",
"stress",
"may",
"induce",
"an",
"acute",
"phase",
"response",
"possibly",
"through",
"the",
"elevation",
"of",
"cortisol",
"production",
"and",
"modulation",
"of",
"inflammatory",
"cytokines.",
"Keywords:",
"acute",
"phase",
"protein,",
"immune",
"inflammatory",
"cytokines,",
"stress,",
"weaning",
"response,",
"Introduction",
"Stress",
"can",
"be",
"defined",
"as",
"the",
"biological",
"response",
"elicited",
"*Corresponding",
"author",
"Tel:",
"+82-2-880-4809;",
"Fax:",
"+82-2-785-8710",
"E-mail:",
"jongha@snu.ac.kr",
"†The",
"first",
"two",
"authors",
"contributed",
"equally",
"to",
"this",
"work.",
"when",
"a",
"threat",
"to",
"homeostasis",
"is",
"perceived.",
"The",
"effects",
"of",
"several",
"types",
"of",
"stressors,",
"such",
"as",
"transportation,",
"heat,",
"and",
"weaning,",
"have",
"been",
"studied",
"in",
"various",
"animals",
"[2,10,",
"11,30].",
"Stress",
"is",
"an",
"important",
"factor",
"in",
"the",
"animal",
"industry",
"because",
"it",
"has",
"been",
"directly",
"linked",
"to",
"growth,",
"reproduction,",
"meat",
"quality,",
"animal",
"welfare,",
"and",
"disease",
"susceptibility",
"[27,28,37],",
"thereby",
"giving",
"it",
"the",
"potential",
"for",
"making",
"a",
"substantial",
"economic",
"impact",
"[8].",
"Weaning",
"and",
"transportation",
"are",
"regarded",
"as",
"the",
"top",
"stressors",
"that",
"calves",
"may",
"experience",
"[14,27].",
"Although",
"the",
"effects",
"of",
"all",
"stages",
"of",
"transportation",
"on",
"cattle",
"are",
"well-documented",
"in",
"the",
"literature,",
"there",
"has",
"been",
"limited",
"research",
"on",
"the",
"effects",
"of",
"weaning",
"alone",
"or",
"weaning",
"and",
"grouping",
"on",
"calves.",
"The",
"majority",
"of",
"reports",
"focus",
"on",
"weaning",
"and",
"transportation",
"together",
"since",
"both",
"of",
"these",
"stressors",
"often",
"occur",
"at",
"the",
"same",
"time",
"in",
"agriculture",
"[11].",
"Previous",
"studies",
"have",
"found",
"that",
"weaning",
"stress",
"alters",
"the",
"concentration",
"of",
"plasma",
"acute",
"phase",
"protein",
"(APP)",
"[24]",
"and",
"the",
"neutrophil",
"(NE):",
"lymphocyte",
"(LY)",
"ratio,",
"and",
"increases",
"norepinephrine",
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"Lactoferrin",
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"[32].",
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"factor-α",
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"and",
"pathological",
"responses",
"to",
"stress",
"and",
"infection",
"[15,35].",
"The",
"goal",
"of",
"this",
"study",
"was",
"to",
"elucidate",
"the",
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] | [
"Human",
"Resources",
"for",
"Health",
"Research",
"Mid-level",
"providers",
"in",
"emergency",
"obstetric",
"and",
"newborn",
"health",
"care:",
"factors",
"affecting",
"their",
"performance",
"and",
"retention",
"within",
"the",
"Malawian",
"health",
"system",
"Susan",
"Bradley*",
"and",
"Eilish",
"McAuliffe",
"Address:",
"Centre",
"for",
"Global",
"Health,",
"Trinity",
"College",
"Dublin,",
"3-4",
"Foster",
"Place,",
"Dublin",
"2,",
"Ireland",
"Email:",
"Susan",
"Bradley*",
"-",
"susan.bradley@tcd.ie;",
"Eilish",
"McAuliffe",
"-",
"eilish.mcauliffe@tcd.ie",
"*",
"Corresponding",
"author",
"BioMed",
"Central",
"Open",
"Access",
"Published:",
"19",
"February",
"2009",
"Human",
"Resources",
"for",
"Health",
"2009,",
"7:14",
"doi:10.1186/1478-4491-7-14",
"This",
"article",
"is",
"available",
"from:",
"http://www.human-resources-health.com/content/7/1/14",
"Received:",
"5",
"May",
"2008",
"Accepted:",
"19",
"February",
"2009",
"©",
"2009",
"Bradley",
"and",
"McAuliffe;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Abstract",
"Background:",
"Malawi",
"has",
"a",
"chronic",
"shortage",
"of",
"human",
"resources",
"for",
"health.",
"This",
"has",
"a",
"significant",
"impact",
"on",
"maternal",
"health,",
"with",
"mortality",
"rates",
"amongst",
"the",
"highest",
"in",
"the",
"world.",
"Mid-level",
"cadres",
"of",
"health",
"workers",
"provide",
"the",
"bulk",
"of",
"emergency",
"obstetric",
"and",
"neonatal",
"care.",
"In",
"this",
"context",
"these",
"cadres",
"are",
"defined",
"as",
"those",
"who",
"undertake",
"roles",
"and",
"tasks",
"that",
"are",
"more",
"usually",
"the",
"province",
"of",
"internationally",
"recognised",
"cadres,",
"such",
"as",
"doctors",
"and",
"nurses.",
"While",
"there",
"have",
"been",
"several",
"studies",
"addressing",
"retention",
"factors",
"for",
"doctors",
"and",
"registered",
"nurses,",
"data",
"and",
"studies",
"addressing",
"the",
"perceptions",
"of",
"these",
"mid-level",
"cadres",
"on",
"the",
"factors",
"that",
"influence",
"their",
"performance",
"and",
"retention",
"within",
"health",
"care",
"systems",
"are",
"scarce.",
"Methods:",
"This",
"exploratory",
"qualitative",
"study",
"took",
"place",
"in",
"four",
"rural",
"mission",
"hospitals",
"in",
"Malawi.",
"The",
"study",
"population",
"was",
"mid-level",
"providers",
"of",
"emergency",
"obstetric",
"and",
"neonatal",
"care.",
"Focus",
"group",
"discussions",
"took",
"place",
"with",
"nursing",
"and",
"medical",
"cadres.",
"Semi-structured",
"interviews",
"with",
"key",
"human",
"resources,",
"training",
"and",
"administrative",
"personnel",
"were",
"used",
"to",
"provide",
"context",
"and",
"background.",
"Data",
"were",
"analysed",
"using",
"a",
"framework",
"analysis.",
"Results:",
"Participants",
"confirmed",
"the",
"difficulties",
"of",
"their",
"working",
"conditions",
"and",
"the",
"clear",
"commitment",
"they",
"have",
"to",
"serving",
"the",
"rural",
"Malawian",
"population.",
"Although",
"insufficient",
"financial",
"remuneration",
"had",
"a",
"negative",
"impact",
"on",
"retention",
"and",
"performance,",
"the",
"main",
"factors",
"identified",
"were",
"limited",
"opportunities",
"for",
"career",
"development",
"and",
"further",
"education",
"(particularly",
"for",
"clinical",
"officers)",
"and",
"inadequate",
"or",
"non-existent",
"human",
"resources",
"management",
"systems.",
"The",
"lack",
"of",
"performance-related",
"rewards",
"and",
"recognition",
"were",
"perceived",
"to",
"be",
"particularly",
"demotivating.",
"Conclusion:",
"Mid-level",
"cadres",
"are",
"being",
"used",
"to",
"stem",
"Africa's",
"brain",
"drain.",
"It",
"is",
"in",
"the",
"interests",
"of",
"both",
"the",
"government",
"and",
"mission",
"organizations",
"to",
"protect",
"their",
"investment",
"in",
"these",
"workers.",
"For",
"optimal",
"performance",
"and",
"quality",
"of",
"care",
"they",
"need",
"to",
"be",
"supported",
"and",
"properly",
"motivated.",
"A",
"structured",
"system",
"of",
"continuing",
"professional",
"development",
"and",
"functioning",
"human",
"resources",
"management",
"would",
"show",
"commitment",
"to",
"these",
"cadres",
"and",
"support",
"them",
"as",
"professionals.",
"Action",
"needs",
"to",
"be",
"taken",
"to",
"prevent",
"staff",
"members",
"from",
"leaving",
"the",
"health",
"sector",
"for",
"less",
"stressful,",
"more",
"financially",
"rewarding",
"alternatives.",
"Page",
"1",
"of",
"8",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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] | [
"Amyloid-b",
"Oligomer",
"Specificity",
"Mediated",
"by",
"the",
"IgM",
"Isotype",
"–",
"Implications",
"for",
"a",
"Specific",
"Protective",
"Mechanism",
"Exerted",
"by",
"Endogenous",
"Auto-Antibodies",
"Malin",
"Lindhagen-Persson",
"1",
",",
"Kristoffer",
"Bra¨",
"nnstro¨",
"m1,",
"Monika",
"Vestling",
"1",
",",
"Michael",
"Steinitz2,",
"Anders",
"1",
"Olofsson",
"*",
"1",
"Department",
"of",
"Medical",
"Biochemistry",
"and",
"Biophysics,",
"Umea˚",
"University,",
"Umea˚,",
"Sweden,",
"2",
"Department",
"of",
"Pathology,",
"Hebrew",
"University",
"Hadassah",
"Medical",
"School,",
"Jerusalem,",
"Israel",
"Abstract",
"Background:",
"Alzheimers",
"disease",
"(AD)",
"has",
"been",
"strongly",
"linked",
"to",
"an",
"anomalous",
"self-assembly",
"of",
"the",
"amyloid-b",
"peptide",
"(Ab).",
"The",
"correlation",
"between",
"clinical",
"symptoms",
"of",
"AD",
"and",
"Ab",
"depositions",
"is,",
"however,",
"weak.",
"Instead",
"small",
"and",
"soluble",
"Ab",
"oligomers",
"are",
"suggested",
"to",
"exert",
"the",
"major",
"pathological",
"effects.",
"In",
"strong",
"support",
"of",
"this",
"notion,",
"immunological",
"targeting",
"of",
"Ab",
"oligomers",
"in",
"AD",
"mice-models",
"shows",
"that",
"memory",
"impairments",
"can",
"be",
"restored",
"without",
"affecting",
"the",
"total",
"burden",
"of",
"Ab",
"deposits.",
"Consequently",
"a",
"specific",
"immunological",
"targeting",
"of",
"Ab",
"oligomers",
"is",
"of",
"high",
"therapeutic",
"interest.",
"Methodology/Principal",
"Findings:",
"Previously",
"the",
"generation",
"of",
"conformational-dependent",
"oligomer",
"specific",
"anti-Ab",
"antibodies",
"has",
"been",
"described.",
"However,",
"to",
"avoid",
"the",
"difficult",
"task",
"of",
"identifying",
"a",
"molecular",
"architecture",
"only",
"present",
"on",
"oligomers,",
"we",
"have",
"focused",
"on",
"a",
"more",
"general",
"approach",
"based",
"on",
"the",
"hypothesis",
"that",
"all",
"oligomers",
"expose",
"multiple",
"identical",
"epitopes",
"and",
"therefore",
"would",
"have",
"an",
"increased",
"binding",
"to",
"a",
"multivalent",
"receptor.",
"Using",
"the",
"polyvalent",
"IgM",
"immunoglobulin",
"we",
"have",
"developed",
"a",
"monoclonal",
"anti-Ab",
"antibody",
"(OMAB).",
"OMAB",
"only",
"demonstrates",
"a",
"weak",
"interaction",
"with",
"Ab",
"monomers",
"and",
"dimers",
"having",
"fast",
"on",
"and",
"off-rate",
"kinetics.",
"However,",
"as",
"an",
"effect",
"of",
"avidity,",
"its",
"interaction",
"with",
"Ab-",
"oligomers",
"results",
"in",
"a",
"strong",
"complex",
"with",
"an",
"exceptionally",
"slow",
"off-rate.",
"Through",
"this",
"mechanism",
"a",
"selectivity",
"towards",
"Ab",
"oligomers",
"is",
"acquired",
"and",
"OMAB",
"fully",
"inhibits",
"the",
"cytotoxic",
"effect",
"exerted",
"by",
"Ab(1-42)",
"at",
"highly",
"substoichiometric",
"ratios.",
"Anti-Ab",
"auto-antibodies",
"of",
"IgM",
"isotype",
"are",
"frequently",
"present",
"in",
"the",
"sera",
"of",
"humans.",
"Through",
"a",
"screen",
"of",
"endogenous",
"anti-",
"Ab",
"IgM",
"auto-antibodies",
"from",
"a",
"group",
"of",
"healthy",
"individuals",
"we",
"show",
"that",
"all",
"displays",
"a",
"preference",
"for",
"oligomeric",
"Ab.",
"Conclusions/Significance:",
"Taken",
"together",
"we",
"provide",
"a",
"simple",
"and",
"general",
"mechanism",
"for",
"targeting",
"of",
"oligomers",
"without",
"the",
"requirement",
"of",
"conformational-dependent",
"epitopes.",
"In",
"addition,",
"our",
"results",
"suggest",
"that",
"IgM",
"anti-Ab",
"auto-antibodies",
"may",
"exert",
"a",
"more",
"specific",
"protective",
"mechanism",
"in",
"vivo",
"than",
"previously",
"anticipated.",
"Citation:",
"Lindhagen-Persson",
"M,",
"Bra¨nnstro¨",
"m",
"K,",
"Vestling",
"M,",
"Steinitz",
"M,",
"Olofsson",
"A",
"(2010)",
"Amyloid-b",
"Oligomer",
"Specificity",
"Mediated",
"by",
"the",
"IgM",
"Isotype",
"–",
"Implications",
"for",
"a",
"Specific",
"Protective",
"Mechanism",
"Exerted",
"by",
"Endogenous",
"Auto-Antibodies.",
"PLoS",
"ONE",
"5(11):",
"e13928.",
"doi:10.1371/journal.pone.0013928",
"Editor:",
"Ashley",
"I.",
"Bush,",
"Mental",
"Health",
"Research",
"Institute",
"of",
"Victoria,",
"Australia",
"Received",
"July",
"5,",
"2010;",
"Accepted",
"October",
"18,",
"2010;",
"Published",
"November",
"10,",
"2010",
"Copyright:",
"2010",
"Lindhagen-Persson",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"This",
"work",
"was",
"supported",
"by",
"Ernst",
"and",
"Lili",
"Rosenhain",
"fund,",
"Bruxelles,",
"Belgium,",
"J.",
"C.",
"Kempe,",
"the",
"Swedish",
"research",
"council,",
"Socialstyrelsen,",
"FAMY",
"and",
"the",
"Medical",
"Faculty",
"of",
"Umea˚",
"University.",
"The",
"funders",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript.",
"Competing",
"Interests:",
"The",
"monoclonal",
"antibody",
"OMAB",
"presented",
"in",
"this",
"investigation",
"is",
"fully",
"own",
"by",
"Alexo-Tech",
"AB",
"(www.alexotech.com).",
"A.O.",
"is",
"a",
"shareholder",
"of",
"Alexo-Tech",
"AB.",
"Alexo-Tech",
"AB",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript",
"and",
"does",
"not",
"in",
"any",
"other",
"way",
"interfere",
"with",
"the",
"study.",
"This",
"does",
"not",
"alter",
"the",
"authors’",
"adherence",
"to",
"all",
"the",
"PLoS",
"ONE",
"policies",
"on",
"sharing",
"data",
"and",
"materials.",
"*",
"E-mail:",
"anders.olofsson@medchem.umu.se",
"Introduction",
"Amyloid",
"is",
"today",
"linked",
"to",
"more",
"than",
"twenty-five",
"different",
"syndromes,",
"of",
"which",
"the",
"neurodegenerative",
"disorder",
"Alzheimer’s",
"disease",
"(AD)",
"represents",
"the",
"most",
"prominent",
"example.",
"Amyloid",
"depositions",
"in",
"AD",
"patients",
"are",
"largely",
"composed",
"of",
"the",
"Ab-",
"peptide,",
"derived",
"from",
"the",
"proteolytic",
"cleavage",
"of",
"the",
"amyloid",
"precursor",
"protein",
"(APP).",
"Ab",
"peptides",
"of",
"39–43",
"residues",
"all",
"have",
"clinical",
"relevance,",
"but",
"Ab(1–40)",
"and",
"Ab(1–42)",
"represent",
"the",
"most",
"abundant",
"variants.",
"Ab(1–42),",
"in",
"particular,",
"has",
"a",
"significantly",
"higher",
"propensity",
"to",
"aggregate,",
"and",
"has",
"been",
"strongly",
"implicated",
"in",
"the",
"etiology",
"of",
"AD",
"[1].",
"Although",
"the",
"histopathological",
"features",
"of",
"Ab",
"depositions",
"(plaques)",
"are",
"striking,",
"the",
"correlation",
"between",
"Ab",
"depositions",
"and",
"the",
"clinical",
"symptoms",
"of",
"AD",
"is",
"weak",
"[2].",
"Small",
"and",
"soluble",
"Ab",
"assemblies,",
"known",
"as",
"Ab",
"oligomers,",
"correlate",
"better",
"with",
"negative",
"clinical",
"status",
"and",
"have",
"been",
"suggested",
"to",
"be",
"the",
"Ab",
"species",
"primarily",
"responsible",
"for",
"cytotoxicity.",
"The",
"structural",
"features",
"of",
"Ab",
"oligomers",
"are",
"largely",
"unknown.",
"Ab-targeting",
"immunization,",
"both",
"passive",
"and",
"active,",
"has",
"been",
"studied",
"in",
"AD",
"mouse",
"models",
"and",
"both",
"types",
"of",
"immunizations",
"have",
"shown",
"a",
"dramatic",
"improvement",
"regarding",
"memory",
"and",
"behavior",
"[3,4,5,6,7,8].",
"Interestingly,",
"passive",
"Ab",
"vaccination",
"improved",
"cognitive",
"performance",
"within",
"days,",
"without",
"reducing",
"plaque",
"burden,",
"suggesting",
"that",
"the",
"removal",
"of",
"soluble",
"Ab",
"is",
"an",
"adequate",
"treatment",
"to",
"restore",
"cognitive",
"function",
"[6].",
"Ab",
"and",
"its",
"precursor",
"APP",
"has",
"both",
"been",
"suggested",
"to",
"have",
"important",
"roles",
"concerning",
"neuroprotection",
"and",
"neurotrophicity",
"[9,10,11].",
"Therefore,",
"to",
"avoid",
"interfering",
"with",
"the",
"homeostatic",
"functions",
"of",
"amyloid",
"proteins,",
"a",
"therapeutic",
"approach",
"focused",
"on",
"clearance",
"of",
"Ab",
"should",
"preferentially",
"target",
"Ab",
"oligomers",
"while",
"PLoS",
"ONE",
"|",
"www.plosone.org",
"1",
"November",
"2010",
"|",
"Volume",
"5",
"|",
"Issue",
"11",
"|",
"e13928"
] | [
8,
8,
8,
8,
8,
8,
8,
8,
8,
8,
8,
8,
8,
8,
8,
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] | [
"Image",
"patterned",
"molecular",
"delivery",
"into",
"live",
"cells",
"using",
"gold",
"particle",
"coated",
"substrates",
"Ting-Hsiang",
"Wu,1",
"Sheraz",
"Kalim,2",
"Caitlin",
"Callahan,2",
"Michael",
"A.",
"Teitell,2,*",
"and",
"Pei-Yu",
"Chiou",
"3,*",
"1Department",
"of",
"Electrical",
"Engineering,",
"University",
"of",
"California,",
"Los",
"Angeles",
"(UCLA),",
"420",
"Westwood",
"Plaza,",
"48-121",
"Engineering",
"IV,",
"Los",
"Angeles,",
"CA",
"90095-1597,",
"USA",
"2Departments",
"of",
"Pathology",
"and",
"Pediatrics,",
"UCLA,",
"675",
"Charles",
"E.",
"Young",
"Drive",
"South,",
"MRL",
"4-762,",
"Los",
"Angeles,",
"CA",
"90095-1732,",
"USA",
"3Department",
"of",
"Mechanical",
"and",
"Aerospace",
"Engineering,",
"UCLA,",
"420",
"Westwood",
"Plaza,",
"48-121",
"Engineering",
"IV,",
"Los",
"Angeles,",
"CA",
"90095-1597,",
"USA",
"*pychiou@seas.ucla.edu",
"Abstract:",
"An",
"image-patterned",
"molecular",
"delivery",
"system",
"for",
"mammalian",
"cells",
"is",
"demonstrated",
"by",
"pulsed",
"laser",
"irradiation",
"of",
"gold",
"particles",
"immobilized",
"on",
"a",
"substrate",
"below",
"a",
"cell",
"monolayer.",
"Patterned",
"cavitation",
"bubble",
"nucleation",
"was",
"captured",
"using",
"a",
"time-resolved",
"imaging",
"system",
"and",
"molecular",
"delivery",
"verified",
"by",
"observing",
"the",
"uptake",
"of",
"a",
"membrane-",
"impermeable",
"fluorescent",
"dye,",
"calcein.",
"Delivery",
"efficiency",
"as",
"high",
"as",
"90%",
"was",
"observed",
"and",
"multiplexed,",
"patterned",
"dye",
"delivery",
"was",
"demonstrated.",
"©2009",
"Optical",
"Society",
"of",
"America",
"OCIS",
"codes:",
"(140.3540)",
"Lasers,",
"Q-switched;",
"(170.1420)",
"Biology;",
"(170.1530)",
"Cell",
"analysis.",
"References",
"and",
"links",
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"cell",
"targeting",
"with",
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"and",
"nanoparticles,”",
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"“Excitation",
"of",
"nanoscale",
"vapor",
"bubbles",
"at",
"the",
"surface",
"of",
"gold",
"nanoparticles",
"in",
"water,”",
"J.",
"Chem.",
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"island",
"formation",
"in",
"thin",
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"oxide",
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"in",
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"Tsagarakis,",
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"of",
"gold",
"nanoparticles",
"of",
"different",
"size,",
"shape,",
"and",
"composition:",
"applications",
"in",
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"biomedicine,”",
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"6(12),",
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"(1972).",
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"flow",
"in",
"an",
"infinite",
"medium",
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"by",
"a",
"sphere,”",
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"Appl.",
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"D.",
"O.",
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"E.",
"Lukianova,",
"and",
"A.",
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"Oraevsky,",
"“Selective",
"laser",
"nano-thermolysis",
"of",
"human",
"leukemia",
"cells",
"with",
"microbubbles",
"generated",
"around",
"clusters",
"of",
"gold",
"nanoparticles,”",
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"Surg.",
"Med.",
"38(6),",
"631–642",
"(2006).",
"17.",
"I.",
"B.",
"Clark,",
"E.",
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"Hanania,",
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"Stevens,",
"M.",
"Gallina,",
"A.",
"Fieck,",
"R.",
"Brandes,",
"B.",
"O.",
"Palsson,",
"and",
"M.",
"R.",
"Koller,",
"“Optoinjection",
"for",
"efficient",
"targeted",
"delivery",
"of",
"a",
"broad",
"range",
"of",
"compounds",
"and",
"macromolecules",
"into",
"diverse",
"cell",
"types,”",
"J.",
"Biomed.",
"Opt.",
"11(1),",
"014034",
"(2006).",
"#116246",
"-",
"$15.00",
"USD",
"Received",
"4",
"Sep",
"2009;",
"revised",
"30",
"Oct",
"2009;",
"accepted",
"4",
"Nov",
"2009;",
"published",
"7",
"Jan",
"2010",
"(C)",
"2010",
"OSA",
"18",
"January",
"2010",
"/",
"Vol.",
"18,",
"No.",
"2",
"/",
"OPTICS",
"EXPRESS",
"938"
] | [
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] | [
"Wang",
"et",
"al.",
"Molecular",
"Brain",
"2012,",
"5:21",
"http://www.molecularbrain.com/content/5/1/21",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"Open",
"Access",
"Activation",
"of",
"c-jun",
"N-terminal",
"kinase",
"in",
"spinal",
"cord",
"contributes",
"to",
"breast",
"cancer",
"induced",
"bone",
"pain",
"in",
"rats",
"Xiao-Wei",
"Wang,",
"Shan",
"Hu,",
"Qi-Liang",
"Mao-Ying,",
"Qian",
"Li,",
"Chang-Jiang",
"Yang,",
"Hui",
"Zhang,",
"Wen-Li",
"Mi,",
"Gen-Cheng",
"Wu",
"and",
"Yan-Qing",
"Wang*",
"Abstract",
"Background:",
"The",
"most",
"frequent",
"pain",
"in",
"patients",
"with",
"metastatic",
"breast",
"and",
"prostate",
"cancer",
"is",
"bone",
"pain,",
"which",
"can",
"be",
"severe",
"and",
"difficult",
"to",
"treat.",
"The",
"mechanisms",
"underlying",
"this",
"pain",
"remain",
"unclear.",
"Here",
"we",
"investigated",
"the",
"role",
"of",
"c-jun",
"N-terminal",
"kinase",
"(JNK)",
"pathway",
"in",
"the",
"spinal",
"cord",
"in",
"cancer-induced",
"bone",
"pain",
"(CIBP).",
"Results:",
"In",
"this",
"study,",
"we",
"used",
"an",
"established",
"rat",
"CIBP",
"model",
"to",
"investigate",
"the",
"possible",
"role",
"of",
"JNK",
"activation",
"in",
"the",
"spinal",
"cord.",
"After",
"intra-tibial",
"inoculation",
"with",
"Walker",
"256",
"rat",
"mammary",
"gland",
"carcinoma",
"cells,",
"the",
"rats",
"displayed",
"mechanical",
"allodynia",
"on",
"day",
"5,",
"which",
"lasted",
"to",
"day",
"16.",
"The",
"activation",
"of",
"JNK",
"in",
"neurons",
"and",
"astrocytes",
"in",
"the",
"spinal",
"cord",
"was",
"found",
"on",
"day",
"12",
"and",
"day",
"16",
"after",
"intra-tibial",
"inoculation",
"with",
"carcinoma",
"cells.",
"A",
"single",
"intrathecal",
"injection",
"with",
"JNK",
"inhibitor",
"SP600125",
"by",
"lumbar",
"puncture",
"attenuated",
"mechanical",
"allodynia",
"on",
"day",
"12,",
"and",
"repeated",
"intrathecal",
"injection",
"of",
"SP600126",
"from",
"day",
"10",
"to",
"day",
"14",
"had",
"a",
"cumulative",
"analgesic",
"effect",
"on",
"CIBP.",
"Conclusions:",
"Taken",
"together,",
"our",
"results",
"demonstrated",
"for",
"the",
"first",
"time",
"that",
"JNK",
"activation",
"in",
"the",
"spinal",
"cord",
"is",
"required",
"in",
"the",
"maintenance",
"of",
"CIBP.",
"Inhibition",
"of",
"the",
"spinal",
"JNK",
"pathway",
"may",
"provide",
"a",
"new",
"therapy",
"for",
"CIBP",
"management.",
"Keywords:",
"c-Jun",
"N-terminal",
"kinase,",
"Cancer-induced",
"bone",
"pain,",
"Spinal",
"cord,",
"Rats",
"Background",
"The",
"c-jun",
"N-terminal",
"kinase",
"(JNK)",
"is",
"an",
"evolutionarily",
"conserved",
"sub-group",
"of",
"mitogen-activated",
"protein",
"kinases",
"(MAPK)",
"that",
"participates",
"in",
"survival",
"signaling,",
"apoptosis",
"and",
"pain",
"[1-3].",
"The",
"JNK",
"family",
"is",
"encoded",
"by",
"three",
"genes:",
"jnk1,",
"jnk2",
"and",
"jnk3.",
"Recent",
"studies",
"have",
"demonstrated",
"that",
"JNK1",
"and",
"JNK2",
"activation",
"play",
"important",
"roles",
"in",
"the",
"development",
"and",
"maintenance",
"of",
"chronic",
"pain",
"[4];",
"JNK3",
"has",
"different",
"functions",
"from",
"JNK1",
"and",
"JNK2",
"and",
"has",
"been",
"reported",
"to",
"participate",
"in",
"apoptosis",
"in",
"the",
"brain.",
"JNK",
"acti-",
"vation",
"is",
"mediated",
"by",
"the",
"dual",
"phosphorylation",
"on",
"Thr",
"and",
"Tyr",
"by",
"two",
"MAPK",
"kinases",
"(MKK4/7),",
"and",
"several",
"transcriptional",
"factors",
"can",
"be",
"regulated",
"by",
"JNK",
"activation",
"[5].",
"JNK1/2",
"was",
"shown",
"to",
"be",
"activated",
"in",
"the",
"spinal",
"cord",
"at",
"6",
"h",
"after",
"intra-plantar",
"injection",
"of",
"complete",
"Freund’s",
"*",
"Correspondence:",
"wangyanqing@shmu.edu.cn",
"Department",
"of",
"Integrative",
"Medicine",
"and",
"Neurobiology,",
"State",
"Key",
"Laboratory",
"of",
"Medical",
"Neurobiology,",
"Shanghai",
"Medical",
"College;",
"Institute",
"of",
"Acupuncture",
"Research",
"(WHO",
"Collaborating",
"Center",
"for",
"Traditional",
"Medicine),",
"Fudan",
"University,",
"P.O.",
"Box",
"291138",
"Yi",
"Xue",
"Yuan",
"Road,",
"Shanghai,",
"200032,",
"China",
"adjuvant",
"(CFA)",
"[6]",
"and",
"at",
"day",
"3",
"after",
"spinal",
"nerve",
"ligation",
"(SNL)",
"[7].",
"Moreover,",
"intrathecal",
"injection",
"of",
"JNK",
"inhibitor",
"SP600125",
"decreased",
"pain",
"behavior",
"in",
"animals",
"with",
"inflam-",
"matory",
"pain,",
"neuropathic",
"pain",
"and",
"skin",
"cancer",
"pain",
"[8-10].",
"Cancer-induced",
"bone",
"pain",
"(CIBP)",
"is",
"a",
"severe",
"problem",
"for",
"patients",
"with",
"end-stage",
"cancer.",
"The",
"preferential",
"metas-",
"tasis",
"of",
"cancer",
"cells",
"to",
"bone",
"disrupts",
"the",
"process",
"of",
"bone",
"remodeling",
"and",
"results",
"in",
"lesions",
"that",
"cause",
"significant",
"pain",
"[11].",
"The",
"model",
"of",
"bone",
"cancer",
"induced",
"by",
"intrame-",
"dullary",
"inoculation",
"with",
"tumor",
"cells",
"has",
"been",
"the",
"most",
"frequently",
"encountered",
"type",
"of",
"cancer-induced",
"pain",
"in",
"cancer",
"patients",
"with",
"bone",
"metastasis",
"[12].",
"Several",
"animal",
"models",
"of",
"CIBP",
"have",
"been",
"developed",
"recently,",
"and",
"these",
"models",
"contributed",
"to",
"our",
"understanding",
"of",
"CIBP",
"[13-15].",
"A",
"widely",
"used",
"model",
"of",
"CIBP",
"is",
"induced",
"by",
"intra-tibial",
"in-",
"oculation",
"with",
"Walker",
"256",
"rat",
"mammary",
"gland",
"carcinoma",
"cells",
"[16-18].",
"Rats",
"inoculated",
"with",
"carcinoma",
"cells",
"devel-",
"oped",
"mechanical",
"allodynia",
"from",
"day",
"5",
"as",
"indicated",
"by",
"decreased",
"paw",
"withdrawal",
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] | [
"Nucleic",
"Acids",
"Research,",
"2005,",
"Vol.",
"33,",
"No.",
"5",
"1435–1444",
"doi:10.1093/nar/gki281",
"Regulated",
"chromatin",
"domain",
"comprising",
"cluster",
"of",
"co-expressed",
"genes",
"in",
"Drosophila",
"melanogaster",
"1",
"Alla",
"I.",
"Kalmykova,",
"Dmitry",
"I.",
"Nurminsky",
",",
"Dmirty",
"V.",
"Ryzhov",
"and",
"Yuri",
"Y.",
"Shevelyov*",
"Department",
"of",
"Molecular",
"Genetics",
"of",
"Cell,",
"Institute",
"of",
"Molecular",
"Genetics,",
"Russian",
"Academy",
"of",
"Sciences,",
"Moscow",
"123182,",
"Russia",
"and",
"1Department",
"of",
"Anatomy",
"and",
"Cell",
"Biology,",
"Tufts",
"University",
"School",
"of",
"Medicine,",
"Boston,",
"MA",
"02111,",
"USA",
"Received",
"September",
"7,",
"2004;",
"Revised",
"January",
"24,",
"2005;",
"Accepted",
"February",
"15,",
"2005",
"DDBJ/EMBL/GenBank",
"accession",
"nos+",
"ABSTRACT",
"Recently,",
"the",
"phenomenon",
"of",
"clustering",
"of",
"co-expressed",
"genes",
"on",
"chromosomes",
"was",
"dis-",
"covered",
"in",
"eukaryotes.",
"To",
"explore",
"the",
"hypothesis",
"that",
"genes",
"within",
"clusters",
"occupy",
"shared",
"chroma-",
"tin",
"domains,",
"we",
"performed",
"a",
"detailed",
"analysis",
"of",
"transcription",
"pattern",
"and",
"chromatin",
"structure",
"of",
"a",
"cluster",
"of",
"co-expressed",
"genes.",
"We",
"found",
"that",
"five",
"non-homologous",
"genes",
"(Crtp,",
"Yu,",
"CK2btes,",
"Pros28.1B",
"and",
"CG13581)",
"are",
"expressed",
"exclusively",
"in",
"Drosophila",
"melanogaster",
"male",
"germ-line",
"and",
"form",
"a",
"non-interrupted",
"cluster",
"in",
"the",
"15",
"kb",
"region",
"of",
"chromosome",
"2.",
"The",
"cluster",
"is",
"surrounded",
"by",
"genes",
"with",
"broader",
"transcription",
"patterns.",
"Analysis",
"of",
"DNase",
"I",
"sensitivity",
"revealed",
"‘open’",
"chromatin",
"conformation",
"in",
"the",
"cluster",
"and",
"adjacent",
"regions",
"in",
"the",
"male",
"germ-line",
"cells,",
"where",
"all",
"studied",
"genes",
"are",
"transcribed.",
"In",
"contrast,",
"in",
"somatic",
"tissues",
"where",
"the",
"cluster",
"genes",
"are",
"silent,",
"the",
"domain",
"of",
"repressed",
"chromatin",
"encompassed",
"four",
"out",
"of",
"five",
"cluster",
"genes",
"and",
"an",
"adjacent",
"non-cluster",
"gene",
"CG13589",
"that",
"is",
"also",
"silent",
"in",
"analyzed",
"somatic",
"tissues.",
"The",
"fifth",
"cluster",
"gene",
"(CG13581)",
"appears",
"to",
"be",
"excluded",
"from",
"the",
"chromatin",
"domain",
"occupied",
"by",
"the",
"other",
"four",
"genes.",
"Our",
"results",
"suggest",
"that",
"extensive",
"clustering",
"of",
"co-expressed",
"genes",
"in",
"eukaryotic",
"genomes",
"does",
"in",
"general",
"reflect",
"the",
"domain",
"organization",
"of",
"chro-",
"matin,",
"although",
"domain",
"borders",
"may",
"not",
"exactly",
"correspond",
"to",
"the",
"margins",
"of",
"gene",
"clusters.",
"INTRODUCTION",
"It",
"has",
"been",
"suggested",
"that",
"eukaryotic",
"genome",
"is",
"functionally",
"divided",
"into",
"domains",
"that",
"contain",
"all",
"regulatory",
"elements",
"necessary",
"for",
"full,",
"correct",
"and",
"positionally",
"independent",
"expression",
"of",
"resident",
"gene(s)",
"(1,2).",
"These",
"domains",
"are",
"evident",
"at",
"the",
"level",
"of",
"local",
"chromatin",
"structure,",
"where",
"tran-",
"scriptionally",
"active",
"genes",
"are",
"associated",
"with",
"‘open’",
"and",
"acetylated",
"chromatin,",
"whereas",
"silent",
"genes",
"are",
"embedded",
"in",
"compacted",
"and",
"hypermethylated",
"chromatin",
"[reviewed",
"in",
"(3–5)].",
"The",
"assumption",
"that",
"not",
"only",
"single",
"genes",
"such",
"as",
"chicken",
"glyceraldehyde-3-phosphate",
"dehydrogenase",
"(6),",
"human",
"apoB",
"(7),",
"and",
"chicken",
"lysozyme",
"(8,9)",
"genes,",
"but",
"also",
"multigenic",
"loci",
"may",
"be",
"regulated",
"at",
"the",
"level",
"of",
"common",
"chromatin",
"domains,",
"originated",
"from",
"the",
"data",
"obtained",
"on",
"sev-",
"eral",
"intensively",
"studied",
"gene",
"clusters.",
"The",
"examples",
"include,",
"but",
"are",
"not",
"limited",
"to,",
"the",
"cluster",
"of",
"b-globin",
"genes",
"in",
"chicken,",
"mouse",
"and",
"human",
"(10–17);",
"growth",
"hormone",
"genes",
"(18,19),",
"IL-4/IL-13",
"genes",
"(20)",
"and",
"PRM1-PRM2-TNP",
"genes",
"in",
"human",
"(21);",
"ovalbumin",
"genes",
"in",
"chicken",
"(22);",
"and",
"heat-shock",
"genes",
"in",
"Drosophila",
"(23).",
"All",
"these",
"clusters",
"comprise",
"paralogous",
"genes",
"that",
"most",
"likely",
"have",
"originated",
"from",
"ancestral",
"genes",
"through",
"local",
"duplications.",
"It",
"is",
"not",
"clear",
"whether",
"the",
"infer-",
"ences",
"from",
"the",
"studies",
"on",
"these",
"models",
"can",
"be",
"extrapolated",
"to",
"the",
"organization",
"of",
"entire",
"genome,",
"where",
"clusters",
"of",
"para-",
"logous",
"genes",
"occur",
"rather",
"rarely.",
"Recently,",
"a",
"number",
"of",
"reports",
"have",
"demonstrated",
"non-",
"random",
"clustering",
"of",
"co-expressed",
"genes",
"on",
"chromosomes.",
"First",
"observations",
"of",
"this",
"phenomenon,",
"that",
"we",
"are",
"aware",
"of,",
"date",
"back",
"to",
"1991",
"(24),",
"but",
"in",
"2002",
"an",
"influx",
"of",
"publications",
"based",
"on",
"the",
"analysis",
"of",
"whole-genome",
"transcription",
"data",
"from",
"different",
"organisms",
"indicated",
"that",
"mechanisms",
"of",
"transcrip-",
"tional",
"co-regulation,",
"that",
"operate",
"with",
"chromatin",
"domains,",
"are",
"common",
"from",
"yeast",
"to",
"higher",
"eukaryotes",
"[reviewed",
"in",
"(25)].",
"Moreover,",
"according",
"to",
"the",
"data",
"of",
"Spellman",
"and",
"Rubin",
"(26)",
"over",
"20%",
"of",
"all",
"Drosophila",
"genes",
"are",
"clustered",
"on",
"chromo-",
"somes",
"according",
"to",
"their",
"expression",
"patterns",
"and",
"thus",
"may",
"share",
"common",
"chromatin",
"domains.",
"However,",
"direct",
"evidence",
"that",
"would",
"link",
"the",
"observed",
"gene",
"clusters",
"to",
"the",
"chromatin",
"domains",
"was",
"still",
"missing.",
"To",
"address",
"this",
"issue,",
"we",
"thoroughly",
"characterized",
"the",
"cluster",
"of",
"non-homologous",
"testes-specific",
"*To",
"whom",
"correspondence",
"should",
"be",
"addressed.",
"Tel:",
"+7",
"095",
"1960809;",
"Fax:",
"+7",
"095",
"1960221;",
"Email:",
"shevelev@img.ras.ru",
"+AF197938,",
"AY078076",
"and",
"AY078077",
"ª",
"The",
"Author",
"2005.",
"Published",
"by",
"Oxford",
"University",
"Press.",
"All",
"rights",
"reserved.",
"The",
"online",
"version",
"of",
"this",
"article",
"has",
"been",
"published",
"under",
"an",
"open",
"access",
"model.",
"Users",
"are",
"entitled",
"to",
"use,",
"reproduce,",
"disseminate,",
"or",
"display",
"the",
"open",
"access",
"version",
"of",
"this",
"article",
"for",
"non-commercial",
"purposes",
"provided",
"that:",
"the",
"original",
"authorship",
"is",
"properly",
"and",
"fully",
"attributed;",
"the",
"Journal",
"and",
"Oxford",
"University",
"Press",
"are",
"attributed",
"as",
"the",
"original",
"place",
"of",
"publication",
"with",
"the",
"correct",
"citation",
"details",
"given;",
"if",
"an",
"article",
"is",
"subsequently",
"reproduced",
"or",
"disseminated",
"not",
"in",
"its",
"entirety",
"but",
"only",
"in",
"part",
"or",
"as",
"a",
"derivative",
"work",
"this",
"must",
"be",
"clearly",
"indicated.",
"For",
"commercial",
"re-use,",
"please",
"contact",
"journals.permissions@oupjournals.org"
] | [
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] | [
"Indian",
"J.",
"PsychiaL,",
"1994,36(1),",
"25-29.",
"PLEA",
"OF",
"INSANITY",
"AS",
"A",
"DEFENSE",
"IN",
"CRIMINAL",
"CASES:",
"AN",
"UPDATE",
"SAYEED",
"AKHTAR,",
"TUSHAR",
"JAGAWAT",
"Mc'Naughten",
"Rule",
"is",
"die",
"commonest",
"formulation",
"for",
"plea",
"of",
"insanity",
"in",
"most",
"countries.",
"Althougjk",
"assessment",
"of",
"the",
"mental",
"state",
"at",
"thetimeofoffence",
"is",
"difficult,",
"few",
"instruments",
"have",
"been",
"devised",
"for",
"this",
"purpose.",
"In",
"the",
"USA.,",
"efforts",
"are",
"being",
"made",
"to",
"abolish",
"the",
"insanity",
"defense",
"and",
"in",
"the",
"United",
"Kingdom,",
"amendments",
"in",
"the",
"provisions",
"of",
"insanity",
"defense",
"have",
"been",
"proposed.",
"The",
"authors",
"have",
"stressed",
"the",
"need",
"for",
"some",
"changes",
"in",
"the",
"relevant",
"sections",
"of",
"Indian",
"Penal",
"Code",
"to",
"increase",
"the",
"credibility",
"ofPsychiatric",
"testimony",
"in",
"such",
"cases.",
"INTRODUCTION",
"Plea",
"of",
"insanity",
"is",
"used",
"as",
"a",
"defense",
"in",
"criminal",
"cases",
"and",
"when",
"successful",
"the",
"accused",
"is",
"acquitted",
"of",
"the",
"charge",
"on",
"the",
"ground",
"of",
"insanity.",
"The",
"term",
"'insanity'",
"is",
"not",
"a",
"medical",
"term",
"but",
"a",
"legal",
"concept",
"meaning",
"that",
"degree",
"of",
"mental",
"disorder",
"that",
"relieves",
"toe",
"offender",
"of",
"the",
"criminal",
"responsibility",
"for",
"his",
"action.",
"In",
"the",
"Western",
"countries,",
"it",
"is",
"estimated",
"that",
"plea",
"of",
"insanity",
"is",
"used",
"as",
"a",
"defense",
"in",
"1-2%",
"of",
"the",
"criminal",
"cases",
"(Pasewik",
"&",
"Craig,",
"1980).",
"Not",
"Guilty",
"By",
"Reason",
"of",
"Insanity",
"(NGBRI)",
"defendants",
"tend",
"to",
"be",
"older,",
"married",
"and",
"un",
"employed",
"at",
"the",
"time",
"of",
"commission",
"of",
"the",
"crime.",
"Most",
"of",
"them",
"have",
"a",
"prior",
"psychiatric",
"treatment",
"history",
"and",
"there",
"is",
"a",
"history",
"of",
"drug",
"and",
"alcohol",
"abuse",
"(Roger,",
"1987).",
"Acquitees",
"differed",
"from",
"those",
"convicted,",
"in",
"being",
"female",
"(Roger,",
"1984),",
"older",
"and",
"more",
"educated,",
"and",
"more",
"likely",
"to",
"be",
"schizophrenic",
"(Somasundaram,",
"1960",
"&",
"1974;",
"Benezech",
"et",
"aL",
"1984).",
"Li",
"a",
"study",
"of",
"187",
"men",
"found",
"NGBRI",
"(Taylor",
"&",
"London,",
"1982),",
"34%",
"of",
"the",
"defendants",
"using",
"the",
"insanity",
"plea",
"were",
"patients",
"with",
"Bipolar",
"Affective",
"Disorder.",
"A",
"high",
"concordance",
"rate",
"(88%)",
"was",
"found",
"between",
"psychiatric",
"evaluation",
"of",
"insanity",
"and",
"the",
"verdict",
"of",
"the",
"court.",
"It",
"reflects",
"the",
"influence",
"of",
"the",
"psychiatrist's",
"recommendations",
"in",
"the",
"court's",
"decision",
"of",
"insanity",
"plea.",
"HISTORICAL",
"BACKGROUND",
"The",
"defence",
"of",
"insanity",
"has",
"been",
"recognized",
"in",
"English",
"courts",
"for",
"over",
"700",
"years",
"beginning",
"from",
"the",
"reign",
"of",
"Edward",
"HI",
"in",
"the",
"fourteenth",
"century,",
"when",
"complete",
"madness",
"was",
"considered",
"as",
"a",
"defense",
"to",
"a",
"criminal",
"charge",
"(Simon,",
"1967).",
"By",
"1518,",
"it",
"was",
"well",
"established",
"that",
"the",
"lack",
"of",
"guilty",
"mind",
"and",
"intellect",
"meant",
"a",
"lack",
"of",
"criminal",
"responsibility.",
"Some",
"250",
"years",
"ago",
"an",
"English",
"judge,",
"in",
"the",
"trial",
"of",
"Edward",
"Arnold",
"said,",
"\"in",
"order",
"to",
"avail",
"oneself",
"of",
"defense",
"of",
"insanity,",
"a",
"man",
"must",
"be",
"totally",
"deprived",
"of",
"under",
"standing",
"and",
"memory",
"that",
"be",
"is",
"not",
"to",
"know",
"what",
"i",
"x",
"was",
"doing,",
"not",
"more",
"than",
"an",
"infant,",
"brute",
"or",
"a",
"wild",
"beast",
"(Simon,",
"1983).",
"The",
"\"wild-beast\"",
"test",
"along",
"with",
"determination",
"of",
"ability",
"to",
"distinguish",
"between",
"right",
"and",
"wrong",
"remained",
"the",
"standard",
"of",
"judging",
"criminal",
"responsibility",
"until",
"the",
"year",
"1800",
"A",
"D",
".",
",",
"when",
"the",
"landmark",
"trial",
"of",
"Hadfield",
"set",
"a",
"new",
"stand",
"ard",
"(Whitlock,",
"1963).",
"A",
"former",
"soldier.",
"James",
"Hadfield",
"attempted",
"as",
"sassination",
"of",
"reigning",
"English",
"monarch,",
"George",
"m",
"with",
"the",
"belief",
"that",
"be",
"was",
"the",
"savior",
"of",
"mankind.",
"He",
"thought",
"that",
"in",
"order",
"to",
"become",
"popular",
"he",
"should",
"sacrifice",
"his",
"life",
"like",
"Jesus",
"Christ",
"and",
"for",
"this",
"he",
"chose",
"to",
"carry",
"out",
"an",
"act",
"for",
"which",
"he",
"would",
"be",
"hanged.",
"The",
"prosecution",
"argued",
"that",
"the",
"defendant's",
"behavior",
"(purchase",
"of",
"gunpowder,",
"concealment",
"of",
"pistol",
"etc.)",
"clearly",
"indicated",
"that",
"he",
"was",
"neither",
"an",
"idiot",
"nor",
"a",
"madman,",
"so",
"\"afflicted",
"by",
"absolute",
"priva",
"tion",
"of",
"reason\".",
"The",
"jury",
"acquitted",
"him",
"because",
"he",
"was",
"insane",
"at",
"the",
"time",
"of",
"commission",
"of",
"the",
"crime.",
"This",
"decision",
"was",
"a",
"landmark",
"because",
"it",
"rejected",
"two",
"concepts",
"previously",
"held",
"by",
"the",
"court.",
"First,",
"it",
"is",
"not",
"necessary",
"for",
"acquittal",
"on",
"the",
"ground",
"of",
"insanity",
"that",
"be",
"must",
"be",
"completely",
"deprived",
"of",
"his",
"mental",
"faculties;",
"second,",
"it",
"severed",
"the",
"tie",
"between",
"insanity",
"and",
"ability",
"to",
"distinguish",
"between",
"right",
"and",
"wrong,",
"MC'NAUGHTEN",
"RULE",
"Daniel",
"Mc'Naughten",
"was",
"a",
"Scottish",
"woodcutter",
"who",
"assassinated",
"Edward",
"Drummond",
"who",
"was",
"secretary",
"to",
"the",
"Prime",
"Minister",
"Sir",
"Robert",
"Peel,",
"in",
"the",
"mistaken",
"belief",
"that",
"Drummond",
"was",
"the",
"Prime",
"Minister.",
"Mc'Naughten",
"was",
"described",
"by",
"nine",
"medical",
"witnesses",
"as",
"'an",
"extreme",
"paranoiac",
"en",
"tangled",
"in",
"an",
"elaborate",
"system",
"of",
"delusions'",
"and",
"be",
"believed,",
"albeit",
"falsely,",
"that",
"the",
"Prime",
"Minister",
"was",
"responsible",
"for",
"all",
"his",
"financial",
"and",
"personal",
"misfor",
"tunes.",
"His",
"trial,",
"acquittal",
"and",
"reference",
"to",
"the",
"House",
"of",
"Lords",
"led",
"to",
"the",
"formulation",
"of",
"a",
"popular",
"set",
"of",
"rules",
"for",
"criminal",
"responsibility",
"which",
"have",
"come",
"to",
"»"
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722,
845,
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845,
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858
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445,
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491,
873
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508,
873
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873
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693,
860,
760,
873
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[
762,
860,
769,
873
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[
437,
875,
456,
888
],
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459,
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492,
888
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494,
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514,
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533,
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547,
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552,
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580,
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584,
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618,
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[
623,
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633,
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[
638,
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644,
902
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[
649,
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685,
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[
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708,
902
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[
713,
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770,
902
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[
437,
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477,
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479,
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504,
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506,
904,
525,
917
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573,
917
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586,
917
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[
589,
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617,
917
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619,
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650,
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[
653,
904,
672,
917
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751,
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769,
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931
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] | [
"Identification",
"of",
"a",
"Novel",
"Type",
"of",
"Spacer",
"Element",
"Required",
"for",
"Imprinting",
"in",
"Fission",
"Yeast",
"Suha",
"Sayrac,",
"Sonya",
"Vengrova,",
"Emma",
"L.",
"Godfrey,",
"Jacob",
"Z.",
"Dalgaard*",
"Clinical",
"Sciences",
"Research",
"Institute,",
"Gibbet",
"Hill",
"Campus,",
"University",
"of",
"Warwick,",
"Coventry,",
"United",
"Kingdom",
"Abstract",
"Asymmetrical",
"segregation",
"of",
"differentiated",
"sister",
"chromatids",
"is",
"thought",
"to",
"be",
"important",
"for",
"cellular",
"differentiation",
"in",
"higher",
"eukaryotes.",
"Similarly,",
"in",
"fission",
"yeast,",
"cellular",
"differentiation",
"involves",
"the",
"asymmetrical",
"segregation",
"of",
"a",
"chromosomal",
"imprint.",
"This",
"imprint",
"has",
"been",
"shown",
"to",
"consist",
"of",
"two",
"ribonucleotides",
"that",
"are",
"incorporated",
"into",
"the",
"DNA",
"during",
"lagging-",
"strand",
"synthesis",
"in",
"response",
"to",
"a",
"replication",
"pause,",
"but",
"the",
"underlying",
"mechanism",
"remains",
"unknown.",
"Here",
"we",
"present",
"key",
"novel",
"discoveries",
"important",
"for",
"unravelling",
"this",
"process.",
"Our",
"data",
"show",
"that",
"cis-acting",
"sequences",
"within",
"the",
"mat1",
"cassette",
"mediate",
"pausing",
"of",
"replication",
"forks",
"at",
"the",
"proximity",
"of",
"the",
"imprinting",
"site,",
"and",
"the",
"results",
"suggest",
"that",
"this",
"pause",
"dictates",
"specific",
"priming",
"at",
"the",
"position",
"of",
"imprinting",
"in",
"a",
"sequence-independent",
"manner.",
"Also,",
"we",
"identify",
"a",
"novel",
"type",
"of",
"cis-acting",
"spacer",
"region",
"important",
"for",
"the",
"imprinting",
"process",
"that",
"affects",
"where",
"subsequent",
"primers",
"are",
"put",
"down",
"after",
"the",
"replication",
"fork",
"is",
"released",
"from",
"the",
"pause.",
"Thus,",
"our",
"data",
"suggest",
"that",
"the",
"imprint",
"is",
"formed",
"by",
"ligation",
"of",
"a",
"not-fully-",
"processed",
"Okazaki",
"fragment",
"to",
"the",
"subsequent",
"fragment.",
"The",
"presented",
"work",
"addresses",
"how",
"differentiated",
"sister",
"chromatids",
"are",
"established",
"during",
"DNA",
"replication",
"through",
"the",
"involvement",
"of",
"replication",
"barriers.",
"Citation:",
"Sayrac",
"S,",
"Vengrova",
"S,",
"Godfrey",
"EL,",
"Dalgaard",
"JZ",
"(2011)",
"Identification",
"of",
"a",
"Novel",
"Type",
"of",
"Spacer",
"Element",
"Required",
"for",
"Imprinting",
"in",
"Fission",
"Yeast.",
"PLoS",
"Genet",
"7(3):",
"e1001328.",
"doi:10.1371/journal.pgen.1001328",
"Editor:",
"James",
"E.",
"Haber,",
"Brandeis",
"University,",
"United",
"States",
"of",
"America",
"Received",
"July",
"15,",
"2010;",
"Accepted",
"February",
"7,",
"2011;",
"Published",
"March",
"10,",
"2011",
"Copyright:",
"2011",
"Sayrac",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"This",
"work",
"was",
"supported",
"by",
"a",
"grant",
"from",
"Marie",
"Curie",
"Cancer",
"Care.",
"The",
"funders",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript.",
"Competing",
"Interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"*",
"E-mail:",
"j.z.dalgaard@warwick.ac.uk",
"Introduction",
"Differentiated",
"sister",
"chromatids,",
"coupled",
"with",
"non-random",
"segregation,",
"have",
"been",
"proposed",
"to",
"control",
"cell",
"fate",
"during",
"the",
"development",
"and",
"differentiation",
"of",
"multicellular",
"organisms",
"[1].",
"Similarly,",
"cellular",
"differentiation",
"in",
"the",
"fission",
"yeast",
"Schizosacchar-",
"omyces",
"pombe",
"involves",
"the",
"establishment",
"of",
"differentiated",
"chromatids",
"and",
"their",
"asymmetrical",
"segregation.",
"The",
"nature",
"of",
"this",
"epigenetic",
"mark",
"or",
"imprint",
"that",
"acts",
"to",
"discriminate",
"the",
"chromatids",
"has",
"been",
"defined,",
"however,",
"the",
"mechanism",
"that",
"leads",
"to",
"its",
"introduction",
"remains",
"unknown.",
"Fission",
"yeast",
"cells",
"exhibit",
"two",
"different",
"mating-",
"types",
"denoted",
"as",
"M",
"and",
"P.",
"Homothallic",
"strains",
"are",
"able",
"to",
"switch",
"between",
"mating-types",
"in",
"a",
"pattern",
"where",
"only",
"one",
"granddaughter",
"of",
"a",
"newly",
"switched",
"cell",
"will",
"have",
"switched",
"mating-type",
"(Figure",
"1A)",
"[2–6].",
"The",
"mating-type",
"of",
"a",
"cell",
"is",
"determined",
"by",
"the",
"transcriptionally",
"expressed",
"mat1",
"locus",
"located",
"on",
"chromosome",
"II,",
"which",
"encodes",
"either",
"an",
"M-",
"or",
"a",
"P-specific",
"gene",
"cassette",
"(Figure",
"1B)",
"[7,8].",
"Switching",
"between",
"the",
"two",
"mating-types",
"occurs",
"through",
"a",
"recombination",
"event",
"that",
"replaces",
"the",
"cassette",
"present",
"at",
"mat1",
"with",
"that",
"of",
"the",
"opposite",
"mating-type,",
"using",
"one",
"of",
"the",
"two",
"transcriptionally",
"silenced",
"loci,",
"mat2P",
"and",
"mat3M,",
"as",
"a",
"donor",
"of",
"the",
"information.",
"The",
"molecular",
"mechanism",
"underlying",
"mating-type",
"switching",
"is",
"tightly",
"linked",
"to",
"DNA",
"replication,",
"and",
"the",
"asymmetrical",
"pattern",
"of",
"switching",
"reflects",
"the",
"asymmetry",
"of",
"the",
"replication",
"process.",
"The",
"mat1",
"locus",
"is",
"replicated",
"unidirectionally",
"in",
"the",
"centromere-",
"proximal",
"direction",
"(see",
"below).",
"An",
"imprint,",
"which",
"marks",
"the",
"mat1",
"locus",
"of",
"switchable",
"cells",
"(Figure",
"1B,",
"1C),",
"is",
"introduced",
"during",
"lagging-strand",
"synthesis",
"of",
"the",
"mat1",
"DNA",
"in",
"only",
"one",
"of",
"the",
"two",
"sister",
"chromatids",
"formed",
"in",
"S",
"phase",
"[9,10].",
"This",
"imprint",
"is",
"maintained",
"for",
"one",
"cell",
"cycle,",
"then",
"during",
"the",
"next",
"S",
"phase,",
"the",
"imprint",
"acts",
"as",
"a",
"barrier",
"for",
"leading-strand",
"replication,",
"resulting",
"in",
"the",
"replication-coupled",
"recombination",
"event",
"that",
"underlies",
"mating-type",
"switching",
"[11–13].",
"The",
"recombination",
"event",
"pro-",
"gresses",
"by",
"the",
"‘‘synthesis",
"dependent",
"single-strand",
"annealing",
"mechanism’’",
"where",
"only",
"one",
"DNA",
"strand",
"at",
"the",
"donor",
"locus",
"provides",
"the",
"genetic",
"information",
"that",
"is",
"transferred",
"to",
"mat1",
"[14].",
"The",
"homology",
"needed",
"for",
"both",
"the",
"initiation",
"and",
"resolution",
"of",
"this",
"recombination",
"event",
"is",
"provided",
"by",
"short",
"homology",
"domains,",
"named",
"H1",
"and",
"H2,",
"that",
"flank",
"both",
"the",
"mat1",
"locus",
"and",
"each",
"of",
"the",
"two",
"donor",
"loci,",
"mat2P",
"and",
"mat3M",
"(Figure",
"1B)",
"[8,15].",
"As",
"a",
"result",
"of",
"this",
"recombination",
"event,",
"the",
"mating-type",
"cassette",
"of",
"only",
"one",
"of",
"the",
"two",
"sister",
"chromatids",
"is",
"replaced",
"by",
"a",
"cassette",
"containing",
"the",
"opposite",
"mating-type",
"information,",
"such",
"that",
"the",
"subsequent",
"cell",
"division",
"gives",
"rise",
"to",
"two",
"cells",
"with",
"opposite",
"mating-types.",
"The",
"imprint",
"was",
"first",
"identified",
"genetically",
"as",
"a",
"strand-specific,",
"chromosomally",
"inherited",
"mark",
"that",
"is",
"linked",
"to",
"the",
"mat1",
"locus",
"and",
"is",
"required",
"for",
"the",
"induction",
"of",
"switching",
"[4–6,16].",
"Subsequently",
"it",
"was",
"shown",
"that",
"the",
"imprint",
"consists",
"of",
"two",
"ribonucleotides",
"that",
"are",
"incorporated",
"into",
"the",
"DNA",
"duplex",
"in",
"a",
"strand-",
"and",
"site-specific",
"manner",
"([12]",
"and",
"reviewed",
"in",
"[17]).",
"These",
"two",
"ribonucleotides",
"are",
"located",
"at",
"the",
"junction",
"between",
"the",
"mating-type",
"cassette",
"and",
"the",
"homology",
"domain",
"H1",
"(Figure",
"1B)",
"[18].",
"The",
"bonds",
"of",
"the",
"RNA-",
"DNA",
"hybrid",
"at",
"the",
"imprint",
"site",
"appear",
"to",
"be",
"efficiently",
"hydrolyzed",
"by",
"cellular",
"enzymes,",
"making",
"purification",
"of",
"intact",
"imprinted",
"DNA",
"difficult.",
"During",
"standard",
"purification",
"methods,",
"the",
"imprint",
"is",
"converted",
"into",
"a",
"double-stranded",
"break",
"that",
"can",
"be",
"detected",
"by",
"Southern",
"analysis",
"[10,19].",
"However,",
"we",
"have",
"managed",
"to",
"purify",
"PLoS",
"Genetics",
"|",
"www.plosgenetics.org",
"1",
"March",
"2011",
"|",
"Volume",
"7",
"|",
"Issue",
"3",
"|",
"e1001328"
] | [
8,
8,
8,
8,
8,
8,
8,
8,
8,
8,
8,
8,
8,
8,
6,
6,
6,
6,
6,
6,
6,
6,
6,
6,
3,
3,
3,
3,
3,
3,
3,
3,
3,
3,
3,
3,
3,
5,
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] | [
"Teut",
"et",
"al.",
"BMC",
"Geriatrics",
"2010,",
"10:10",
"http://www.biomedcentral.com/1471-2318/10/10",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"Homeopathic",
"treatment",
"of",
"elderly",
"patients",
"-",
"a",
"prospective",
"observational",
"study",
"with",
"follow-up",
"over",
"a",
"two",
"year",
"period",
"Michael",
"Teut1*,",
"Rainer",
"Lüdtke2,",
"Katharina",
"Schnabel1,",
"Stefan",
"N",
"Willich1,",
"Claudia",
"M",
"Witt1",
"Abstract",
"Background:",
"Very",
"little",
"is",
"known",
"about",
"the",
"range",
"of",
"diagnoses,",
"course",
"of",
"treatment",
"and",
"long-term",
"outcome",
"in",
"elderly",
"patients",
"who",
"choose",
"to",
"receive",
"homeopathic",
"medical",
"treatment.",
"We",
"investigated",
"homeopathic",
"practice",
"in",
"an",
"industrialised",
"country",
"under",
"everyday",
"conditions.",
"The",
"aim",
"of",
"the",
"study",
"was",
"to",
"determine",
"the",
"spectrum",
"of",
"diagnoses",
"and",
"treatments,",
"as",
"well",
"as",
"to",
"describe",
"the",
"course",
"of",
"illness",
"over",
"time",
"among",
"older",
"patients",
"who",
"chose",
"to",
"receive",
"homeopathic",
"treatment.",
"Methods:",
"In",
"this",
"subgroup",
"analysis",
"of",
"a",
"prospective,",
"multicentre",
"cohort",
"study",
"totally",
"including",
"3981",
"patients",
"treated",
"by",
"homeopathic",
"physicians",
"in",
"primary",
"care",
"practices",
"in",
"Germany",
"and",
"Switzerland,",
"data",
"was",
"analysed",
"from",
"all",
"patients",
">",
"70",
"years",
"consulting",
"the",
"physician",
"for",
"the",
"first",
"time.",
"The",
"main",
"outcome",
"measures",
"were:",
"assessment",
"by",
"patient",
"of",
"the",
"severity",
"of",
"complaints",
"(numeric",
"rating",
"scales)",
"and",
"quality",
"of",
"life",
"(SF-36)",
"and",
"by",
"the",
"physician",
"of",
"the",
"severity",
"of",
"diagnoses",
"(numeric",
"rating",
"scales)",
"at",
"baseline,",
"and",
"after",
"3,",
"12,",
"and",
"24",
"months.",
"Results:",
"A",
"total",
"of",
"83",
"patients",
"were",
"included",
"in",
"the",
"subgroup",
"analysis",
"(41%",
"men,",
"mean",
"age",
"73.2",
"±",
"(SD)",
"3.1",
"years;",
"59%",
"women,",
"74.3",
"±",
"3.8",
"years).",
"98.6",
"percent",
"of",
"all",
"diagnoses",
"were",
"chronic",
"with",
"an",
"average",
"duration",
"of",
"11.5",
"±",
"11.5",
"years.",
"82",
"percent",
"of",
"the",
"patients",
"were",
"taking",
"medication",
"at",
"baseline.",
"The",
"most",
"frequent",
"diagnoses",
"were",
"hypertension",
"(20.5%,",
"11.1",
"±",
"7.5",
"years)",
"and",
"sleep",
"disturbances",
"(15.7%,",
"22.1",
"±",
"25.8",
"years).",
"The",
"severity",
"of",
"complaints",
"decreased",
"significantly",
"between",
"baseline",
"and",
"24",
"months",
"in",
"both",
"patients",
"(from",
"6.3",
"(95%",
"CI:",
"5.7-6.8)",
"to",
"4.6",
"(4.0-5.1),",
"p",
"<",
"0.001)",
"and",
"physicians’",
"assessments",
"(from",
"6.6",
"(6.0-7.1)",
"to",
"3.7",
"(3.2-4.3),",
"p",
"<",
"0.001);",
"qual-",
"ity",
"of",
"life",
"(SF",
"36)",
"and",
"the",
"number",
"of",
"medicines",
"taken",
"did",
"not",
"significantly",
"change.",
"Conclusion:",
"The",
"severity",
"of",
"disease",
"showed",
"marked",
"and",
"sustained",
"improvements",
"under",
"homeopathic",
"treatment,",
"but",
"this",
"did",
"not",
"lead",
"to",
"an",
"improvement",
"of",
"quality",
"of",
"life.",
"Our",
"findings",
"might",
"indicate",
"that",
"homeopathic",
"medical",
"therapy",
"may",
"play",
"a",
"beneficial",
"role",
"in",
"the",
"long-term",
"care",
"of",
"older",
"adults",
"with",
"chronic",
"diseases",
"and",
"studies",
"on",
"comparative",
"effectiveness",
"are",
"needed",
"to",
"evaluate",
"this",
"hypothesis.",
"Background",
"Homeopathy",
"is",
"one",
"of",
"the",
"most",
"frequently",
"used",
"but",
"con-",
"troversial",
"forms",
"of",
"complementary",
"and",
"alternative",
"medi-",
"cine",
"(CAM).",
"It",
"is",
"based",
"on",
"the",
"ancient",
"‘principle",
"of",
"similars’.",
"Highly",
"diluted",
"preparations",
"of",
"substances",
"that",
"cause",
"symptoms",
"in",
"healthy",
"individuals",
"are",
"used",
"to",
"stimu-",
"late",
"healing",
"reactions",
"in",
"patients",
"who",
"display",
"similar",
"*",
"Correspondence:",
"michael.teut@charite.de",
"1Institute",
"for",
"Social",
"Medicine,",
"Epidemiology",
"and",
"Health",
"Economics,",
"Charité",
"University",
"Medical",
"Center,",
"Luisenstr.",
"57,",
"D-10017",
"Berlin,",
"Germany",
"symptoms",
"when",
"ill",
"[1].",
"In",
"classical",
"homeopathy",
"a",
"single",
"homeopathic",
"remedy",
"is",
"selected,",
"based",
"on",
"a",
"patient’s",
"total",
"spectrum",
"of",
"symptoms",
"[2].",
"The",
"proportion",
"of",
"patients",
"obtaining",
"homeopathic",
"care",
"has",
"quadrupled",
"in",
"the",
"last",
"seven",
"years",
"according",
"to",
"a",
"US",
"survey",
"[3].",
"For",
"Germany",
"a",
"recent",
"survey",
"demonstrated",
"that",
"approxi-",
"mately",
"10%",
"of",
"men",
"and",
"20%",
"of",
"women",
"in",
"the",
"general",
"population",
"used",
"homeopathic",
"medicines",
"during",
"the",
"pre-",
"vious",
"year",
"[4].",
"To",
"date,",
"few",
"studies",
"have",
"evaluated",
"the",
"use",
"of",
"complementary",
"therapies",
"in",
"geriatric",
"patients",
"[5].",
"In",
"Germany,",
"73%",
"of",
"adults",
"over",
"60",
"years",
"of",
"age",
"use",
"©",
"2010",
"Teut",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
] | [
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"Curr",
"Rev",
"Musculoskelet",
"Med",
"(2008)",
"1:39–47",
"DOI",
"10.1007/s12178-007-9004-1",
"Yoga",
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"pain",
"Susan",
"Sorosky",
"Æ",
"Sonja",
"Stilp",
"Æ",
"Venu",
"Akuthota",
"Published",
"online:",
"6",
"November",
"2007",
"Humana",
"Press",
"2007",
"Abstract",
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"low",
"back",
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"model,",
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"demonstrating",
"the",
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"of",
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"for",
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"that",
"treat",
"more",
"than",
"one",
"aspect",
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"LBP",
"would",
"have",
"significant",
"ben-",
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"for",
"this",
"patient",
"population.",
"Yoga",
"and",
"Pilates",
"which",
"have,",
"both",
"been",
"gaining",
"in",
"popularity",
"over",
"the",
"last",
"decade",
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"two",
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"exercise",
"interventions",
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"address",
"both",
"the",
"physical",
"and",
"mental",
"aspects",
"of",
"pain",
"with",
"core",
"strengthening,",
"flexibility,",
"and",
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"nontraditional",
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"regimens",
"into",
"treatment",
"paradigms",
"for",
"LBP,",
"although",
"few",
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"S.",
"Sorosky",
"(&)",
"Desert",
"Pain",
"Institute,",
"Phoenix,",
"AZ,",
"USA",
"e-mail:",
"ssorosky@cox.net",
"S.",
"Sorosky",
"Midwestern",
"University,",
"Glendale,",
"AZ,",
"USA",
"S.",
"Stilp",
"Boulder",
"Orthopedics,",
"Boulder,",
"CO,",
"USA",
"S.",
"Stilp",
"V.",
"Akuthota",
"Department",
"of",
"Physical",
"Medicine",
"and",
"Rehabilitation,",
"University",
"of",
"Colorado",
"School",
"of",
"Medicine,",
"New",
"York,",
"USA",
"V.",
"Akuthota",
"The",
"Spine",
"Center",
"at",
"the",
"University",
"of",
"Colorado",
"Hospital,",
"Aurora,",
"CO,",
"USA",
"examining",
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] | [
"Cytotoxic",
"Effect",
"of",
"Poly-Dispersed",
"Single",
"Walled",
"Carbon",
"Nanotubes",
"on",
"Erythrocytes",
"In",
"Vitro",
"and",
"In",
"Vivo",
"Sumedha",
"Sachar,",
"Rajiv",
"K.",
"Saxena*",
"School",
"of",
"Life",
"Sciences,",
"Jawaharlal",
"Nehru",
"University,",
"New",
"Delhi,",
"India",
"Abstract",
"Single",
"wall",
"Carbon",
"Nanotubes",
"(SWCNTs)",
"are",
"hydrophobic",
"and",
"do",
"not",
"disperse",
"in",
"aqueous",
"solvents.",
"Acid",
"functionalization",
"of",
"SWCNTs",
"results",
"in",
"attachment",
"of",
"carboxy",
"and",
"sulfonate",
"groups",
"to",
"carbon",
"atoms",
"and",
"the",
"resulting",
"acid",
"functionalized",
"product",
"(AF-SWCNTs)",
"is",
"negatively",
"charged",
"and",
"disperses",
"easily",
"in",
"water",
"and",
"buffers.",
"In",
"the",
"present",
"study,",
"effect",
"of",
"AF-",
"SWCNTs",
"on",
"blood",
"erythrocytes",
"was",
"examined.",
"Incubation",
"of",
"mouse",
"erythrocytes",
"with",
"AF-SWCNTs",
"and",
"not",
"with",
"control",
"SWCNTs,",
"resulted",
"in",
"a",
"dose",
"and",
"time",
"dependent",
"lysis",
"of",
"erythrocyte.",
"Using",
"fluorescence",
"tagged",
"AF-SWCNTs,",
"binding",
"of",
"AF-",
"SWCNTs",
"with",
"erythrocytes",
"could",
"be",
"demonstrated.",
"Confocal",
"microscopy",
"results",
"indicated",
"that",
"AF-SWCNTs",
"could",
"enter",
"the",
"erythrocytes.",
"Treatment",
"with",
"AF-SWCNTs",
"resulted",
"in",
"exposure",
"of",
"hydrophobic",
"patches",
"on",
"erythrocyte",
"membrane",
"that",
"is",
"indicative",
"of",
"membrane",
"damage.",
"A",
"time",
"and",
"dose",
"dependent",
"increase",
"in",
"externalization",
"of",
"phosphatidylserine",
"on",
"erythrocyte",
"membrane",
"bilayer",
"was",
"also",
"found.",
"Administration",
"of",
"AF-SWCNTs",
"through",
"intravenous",
"route",
"resulted",
"in",
"a",
"transient",
"anemia",
"as",
"seen",
"by",
"a",
"sharp",
"decline",
"in",
"blood",
"erythrocyte",
"count",
"accompanied",
"with",
"a",
"significant",
"drop",
"in",
"blood",
"haemoglobin",
"level.",
"Administration",
"of",
"AF-SWCNTs",
"through",
"intratracheal",
"administration",
"also",
"showed",
"significant",
"decline",
"in",
"RBC",
"count",
"while",
"administration",
"through",
"other",
"routes",
"(gavage",
"and",
"intra-peritoneal)",
"was",
"not",
"effective.",
"By",
"using",
"a",
"recently",
"developed",
"technique",
"of",
"a",
"two",
"step",
"in",
"vivo",
"biotinylation",
"of",
"erythrocytes",
"that",
"enables",
"simultaneous",
"enumeration",
"of",
"young",
"(age",
",10",
"days)",
"and",
"old",
"(age.40",
"days)",
"erythrocytes",
"in",
"mouse",
"blood,",
"it",
"was",
"found",
"that",
"the",
"in",
"vivo",
"toxic",
"effect",
"of",
"AF-SWCNTs",
"was",
"more",
"pronounced",
"on",
"older",
"subpopulation",
"of",
"erythrocytes.",
"Subpopulation",
"of",
"old",
"erythrocytes",
"fell",
"after",
"treatment",
"with",
"AF-SWCNTs",
"but",
"recovered",
"by",
"third",
"day",
"after",
"the",
"intravenous",
"administration",
"of",
"AF-SWCNTs.",
"Taken",
"together",
"our",
"results",
"indicate",
"that",
"treatment",
"with",
"AF-SWCNTs",
"results",
"in",
"acute",
"membrane",
"damage",
"and",
"eventual",
"lysis",
"of",
"erythrocytes.",
"Intravenous",
"administration",
"of",
"AF-SWCNTs",
"resulted",
"in",
"a",
"transient",
"anemia",
"in",
"which",
"older",
"erythrocytes",
"are",
"preferably",
"lysed.",
"Citation:",
"Sachar",
"S,",
"Saxena",
"RK",
"(2011)",
"Cytotoxic",
"Effect",
"of",
"Poly-Dispersed",
"Single",
"Walled",
"Carbon",
"Nanotubes",
"on",
"Erythrocytes",
"In",
"Vitro",
"and",
"In",
"Vivo.",
"PLoS",
"ONE",
"6(7):",
"e22032.",
"doi:10.1371/journal.pone.0022032",
"Editor:",
"David",
"L.",
"McCormick,",
"IIT",
"Research",
"Institute,",
"United",
"States",
"of",
"America",
"Received",
"March",
"11,",
"2011;",
"Accepted",
"June",
"13,",
"2011;",
"Published",
"July",
"19,",
"2011",
"Copyright:",
"2011",
"Sachar,",
"Saxena.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"This",
"study",
"was",
"supported",
"by",
"a",
"Department",
"of",
"Science",
"and",
"Technology",
"(DST)",
"grant",
"(SR/SO/HS-133/2007)",
"to",
"RKS,",
"and",
"a",
"fellowship",
"from",
"DBT",
"to",
"SS.",
"The",
"funders",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript.",
"Competing",
"Interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"*",
"E-mail:",
"rajivksaxena@hotmail.com",
"Introduction",
"Nano-sized",
"particles",
"are",
"finding",
"increasing",
"practical",
"applica-",
"tions",
"and",
"commercial",
"use.",
"Consequently,",
"the",
"possibility",
"of",
"occupational",
"exposure",
"to",
"nano-particles",
"has",
"increased.",
"Further-",
"more,",
"as",
"the",
"use",
"of",
"nanoparticles",
"increases,",
"they",
"may",
"diffuse",
"and",
"accumulate",
"in",
"environment",
"increasing",
"the",
"risk",
"of",
"environmental",
"exposure.",
"Health",
"effects",
"of",
"exposure",
"to",
"nanoparticles",
"are",
"now",
"under",
"investigation",
"by",
"many",
"researchers",
"[1],",
"[2],",
"[3].",
"Nanopar-",
"ticles",
"have",
"a",
"tendency",
"to",
"agglomerate",
"into",
"particles",
"of",
"larger",
"size",
"that",
"may",
"not",
"have",
"the",
"same",
"biological",
"effects",
"as",
"non-agglomerated",
"nanoparticles.",
"For",
"studying",
"the",
"biological",
"effects",
"therefore",
"it",
"is",
"necessary",
"to",
"test",
"non-agglomerated",
"forms",
"of",
"nanoparticles.",
"For",
"Single",
"walled",
"Carbon",
"Nanotubes",
"(SWCNTs)",
"disaggregation",
"can",
"be",
"achieved",
"by",
"acid",
"functionalization",
"that",
"introduces",
"negative",
"charge,",
"without",
"changing",
"the",
"essential",
"structural",
"features",
"of",
"SWCNTs",
"[4],",
"[5].",
"We",
"have",
"previously",
"reported",
"cytostatic",
"and",
"toxic",
"effects",
"of",
"acid",
"functionalized",
"SWCNTs",
"(AF-SWCNTs)",
"on",
"LA4",
"lung",
"epithelial",
"cell",
"line",
"[5].",
"We",
"also",
"found",
"that",
"the",
"administration",
"of",
"AF-SWCNTs",
"intratracheally",
"resulted",
"in",
"cardiac",
"damage",
"in",
"mice",
"[6].",
"Since",
"AF-SWCNTs",
"were",
"toxic",
"to",
"some",
"types",
"of",
"nucleated",
"cells",
"that",
"are",
"capable",
"of",
"self",
"repair,",
"we",
"hypothesized",
"that",
"the",
"AF-",
"SWCNTs",
"may",
"have",
"a",
"more",
"aggravated",
"toxic",
"effect",
"on",
"erythrocytes",
"that",
"have",
"no",
"nucleus",
"and",
"lack",
"substantial",
"cellular",
"repair",
"mechanisms.",
"This",
"proposition",
"was",
"examined",
"in",
"the",
"present",
"study.",
"Our",
"results",
"indicate",
"that",
"unlike",
"pristine",
"SWCNTs,",
"AF-",
"SWCNTs",
"are",
"significantly",
"toxic",
"to",
"mouse",
"blood",
"derived",
"erythrocytes",
"in",
"vitro",
"as",
"well",
"as",
"in",
"vivo.",
"AF-SWCNTs",
"were",
"found",
"to",
"bind",
"with",
"erythrocytes",
"and",
"cause",
"significant",
"membrane",
"damage",
"as",
"well",
"as",
"externalization",
"of",
"phosphatidylserine.",
"Administration",
"of",
"AF-SWCNTs",
"intravenously",
"induced",
"a",
"significant",
"though",
"transient",
"anemia",
"in",
"mice.",
"Older",
"as",
"compared",
"to",
"the",
"younger",
"subpopulation",
"of",
"erythrocyte",
"in",
"blood",
"circulation,",
"was",
"more",
"susceptible",
"to",
"the",
"toxic",
"effect",
"of",
"AF-SWCNTs.",
"Taken",
"together",
"our",
"results",
"show",
"that",
"non-agglomerated",
"form",
"of",
"SWCNTs",
"may",
"exert",
"significant",
"and",
"rapid",
"toxic",
"effects",
"on",
"blood",
"erythrocytes.",
"Materials",
"and",
"Methods",
"Experimental",
"model",
"Inbred",
"Swiss",
"and",
"C57BL/6",
"female",
"mice",
"(6–12",
"weeks",
"old,",
"20–25",
"g",
"body",
"weight)",
"were",
"used",
"throughout",
"this",
"study.",
"Animals",
"were",
"bred",
"and",
"maintained",
"in",
"the",
"animal",
"house",
"facility",
"at",
"JNU,",
"New",
"Delhi",
"or",
"obtained",
"from",
"the",
"National",
"Institute",
"of",
"Nutrition,",
"Hyderabad.",
"The",
"animals",
"were",
"housed",
"in",
"positive-pressure",
"air",
"PLoS",
"ONE",
"|",
"www.plosone.org",
"1",
"July",
"2011",
"|",
"Volume",
"6",
"|",
"Issue",
"7",
"|",
"e22032"
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] | [
"BMC",
"Genomics",
"Research",
"article",
"Small",
"noncoding",
"RNA",
"GcvB",
"is",
"a",
"novel",
"regulator",
"of",
"acid",
"resistance",
"in",
"Escherichia",
"coli",
"Ye",
"Jin1,",
"Rory",
"M",
"Watt2,",
"Antoine",
"Danchin3",
"and",
"Jian-dong",
"Huang*1",
"BioMed",
"Central",
"Open",
"Access",
"Address:",
"1Department",
"of",
"Biochemistry,",
"Li",
"Ka",
"Shing",
"Faculty",
"of",
"Medicine,",
"University",
"of",
"Hong",
"Kong,",
"Pok",
"Fu",
"Lam,",
"Hong",
"Kong",
"SAR,",
"PR",
"China,",
"2Oral",
"Biosciences,",
"Faculty",
"of",
"Dentistry,",
"University",
"of",
"Hong",
"Kong,",
"Pok",
"Fu",
"Lam,",
"Hong",
"Kong",
"SAR,",
"PR",
"China",
"and",
"3Genetics",
"of",
"Bacterial",
"Genomes,",
"CNRS",
"URA2171,",
"Institut",
"Pasteur,",
"28,",
"rue",
"du",
"Docteur",
"Roux,",
"Paris",
"Cedex",
"15,",
"75724,",
"France",
"Email:",
"Ye",
"Jin",
"-",
"yejin@hkucc.hku.hk;",
"Rory",
"M",
"Watt",
"-",
"rmwatt@hku.hk;",
"Antoine",
"Danchin",
"-",
"antoine.danchin@normalesup.org;",
"Jian-",
"dong",
"Huang*",
"-",
"jdhuang@hkucc.hku.hk",
"*",
"Corresponding",
"author",
"Published:",
"20",
"April",
"2009",
"BMC",
"Genomics",
"2009,",
"10:165",
"doi:10.1186/1471-2164-10-165",
"This",
"article",
"is",
"available",
"from:",
"http://www.biomedcentral.com/1471-2164/10/165",
"Received:",
"26",
"January",
"2009",
"Accepted:",
"20",
"April",
"2009",
"©",
"2009",
"Jin",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Abstract",
"Background:",
"The",
"low",
"pH",
"environment",
"of",
"the",
"human",
"stomach",
"is",
"lethal",
"for",
"most",
"microorganisms;",
"but",
"not",
"Escherichia",
"coli,",
"which",
"can",
"tolerate",
"extreme",
"acid",
"stress.",
"Acid",
"resistance",
"in",
"E.",
"coli",
"is",
"hierarchically",
"controlled",
"by",
"numerous",
"regulators",
"among",
"which",
"are",
"small",
"noncoding",
"RNAs",
"(sncRNA).",
"Results:",
"In",
"this",
"study,",
"we",
"individually",
"deleted",
"seventy-nine",
"sncRNA",
"genes",
"from",
"the",
"E.",
"coli",
"K12-",
"MG1655",
"chromosome,",
"and",
"established",
"a",
"single-sncRNA",
"gene",
"knockout",
"library.",
"By",
"systematically",
"screening",
"the",
"sncRNA",
"mutant",
"library,",
"we",
"show",
"that",
"the",
"sncRNA",
"GcvB",
"is",
"a",
"novel",
"regulator",
"of",
"acid",
"resistance",
"in",
"E.",
"coli.",
"We",
"demonstrate",
"that",
"GcvB",
"enhances",
"the",
"ability",
"of",
"E.",
"coli",
"to",
"survive",
"low",
"pH",
"by",
"upregulating",
"the",
"levels",
"of",
"the",
"alternate",
"sigma",
"factor",
"RpoS.",
"Conclusion:",
"GcvB",
"positively",
"regulates",
"acid",
"resistance",
"by",
"affecting",
"RpoS",
"expression.",
"These",
"data",
"advance",
"our",
"understanding",
"of",
"the",
"sncRNA",
"regulatory",
"network",
"involved",
"in",
"modulating",
"acid",
"resistance",
"in",
"E.",
"coli.",
"Background",
"The",
"ability",
"to",
"survive",
"the",
"extremely",
"low",
"pH",
"environment",
"present",
"within",
"the",
"stomach",
"(pH",
"values",
"<",
"2.5)",
"is",
"essential",
"for",
"colonization",
"of",
"the",
"intestine",
"by",
"commensals",
"and",
"for",
"the",
"pathogenesis",
"of",
"enteric",
"bacteria.",
"Three",
"distinct",
"acid",
"resistance",
"(AR)",
"systems",
"are",
"responsible",
"for",
"protecting",
"bac-",
"terial",
"cells",
"from",
"acid",
"shock",
"[1-3].",
"AR",
"system",
"1",
"is",
"a",
"glucose-",
"repressed",
"system",
"and",
"does",
"not",
"require",
"any",
"external",
"amino",
"acids",
"to",
"function",
"at",
"low",
"pH",
"[1].",
"Unidentified",
"components",
"of",
"this",
"system",
"are",
"controlled",
"by",
"the",
"alternate",
"sigma",
"factor",
"RpoS,",
"with",
"the",
"underlying",
"mechanism",
"remaining",
"unclear",
"[1].",
"In",
"contrast,",
"AR",
"systems",
"2",
"and",
"3",
"provide",
"AR",
"by",
"con-",
"suming",
"intracellular",
"protons",
"via",
"the",
"glutamate",
"(AR2)",
"and",
"arginine",
"(AR3)",
"decarboxylation",
"reactions",
"[2,3].",
"AR2",
"is",
"the",
"most",
"efficient",
"AR",
"system.",
"It",
"involves",
"two",
"isozymes",
"of",
"glutamate",
"decarboxylase,",
"encoded",
"by",
"genes",
"gadA",
"and",
"gadB,",
"and",
"a",
"membrane-associated",
"antiporter",
"(GadC)",
"that",
"exchanges",
"external",
"glutamate",
"for",
"the",
"intracellular",
"decar-",
"boxylation",
"product",
"γ-aminobutyric",
"acid",
"(GABA)",
"[2].",
"AR2",
"is",
"hierarchically",
"regulated",
"by",
"multiple",
"regulators,",
"which",
"include",
"small",
"noncoding",
"RNAs",
"(sncRNA)",
"DsrA",
"and",
"possibly",
"GadY.",
"DsrA",
"activates",
"the",
"expression",
"of",
"rpoS",
"[4]",
"and",
"several",
"AR",
"genes",
"including",
"hdeAB,",
"gadAX,",
"and",
"gadBC",
"[5].",
"GadY,",
"whose",
"effects",
"on",
"AR",
"have",
"yet",
"to",
"be",
"determined,",
"controls",
"the",
"synthesis",
"of",
"GadX",
"and",
"GadW,",
"which",
"are",
"reg-",
"Page",
"1",
"of",
"7",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
] | [
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] | [
"Fluch",
"et",
"al.",
"BMC",
"Research",
"Notes",
"2011,",
"4:401",
"http://www.biomedcentral.com/1756-0500/4/401",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"Characterization",
"of",
"variable",
"EST",
"SSR",
"markers",
"for",
"Norway",
"spruce",
"(Picea",
"abies",
"L.)",
"Silvia",
"Fluch1*,",
"Agnes",
"Burg1,",
"Dieter",
"Kopecky1,",
"Andreas",
"Homolka1,",
"Nadine",
"Spiess1",
"and",
"Giovanni",
"G",
"Vendramin2",
"Abstract",
"Background:",
"Norway",
"spruce",
"is",
"widely",
"distributed",
"across",
"Europe",
"and",
"the",
"predominant",
"tree",
"of",
"the",
"Alpine",
"region.",
"Fast",
"growth",
"and",
"the",
"fact",
"that",
"timber",
"can",
"be",
"harvested",
"cost-effectively",
"in",
"relatively",
"young",
"populations",
"define",
"its",
"status",
"as",
"one",
"of",
"the",
"economically",
"most",
"important",
"tree",
"species",
"of",
"Northern",
"Europe.",
"In",
"this",
"study,",
"EST",
"derived",
"simple",
"sequence",
"repeat",
"(SSR)",
"markers",
"were",
"developed",
"for",
"the",
"assessment",
"of",
"putative",
"functional",
"diversity",
"in",
"Austrian",
"Norway",
"spruce",
"stands.",
"Results:",
"SSR",
"sequences",
"were",
"identified",
"by",
"analyzing",
"14,022",
"publicly",
"available",
"EST",
"sequences.",
"Tri-nucleotide",
"repeat",
"motifs",
"were",
"most",
"abundant",
"in",
"the",
"data",
"set",
"followed",
"by",
"penta-",
"and",
"hexa-nucleotide",
"repeats.",
"Specific",
"primer",
"pairs",
"were",
"designed",
"for",
"sixty",
"loci.",
"Among",
"these,",
"27",
"displayed",
"polymorphism",
"in",
"a",
"testing",
"population",
"of",
"16",
"P.",
"abies",
"individuals",
"sampled",
"across",
"Austria",
"and",
"in",
"an",
"additional",
"screening",
"population",
"of",
"96",
"P.",
"abies",
"individuals",
"from",
"two",
"geographically",
"distinct",
"Austrian",
"populations.",
"Allele",
"numbers",
"per",
"locus",
"ranged",
"from",
"two",
"to",
"17",
"with",
"observed",
"heterozygosity",
"ranging",
"from",
"0.075",
"to",
"0.99.",
"Conclusions:",
"We",
"have",
"characterized",
"variable",
"EST",
"SSR",
"markers",
"for",
"Norway",
"spruce",
"detected",
"in",
"expressed",
"genes.",
"Due",
"to",
"their",
"moderate",
"to",
"high",
"degree",
"of",
"variability",
"in",
"the",
"two",
"tested",
"screening",
"populations,",
"these",
"newly",
"developed",
"SSR",
"markers",
"are",
"well",
"suited",
"for",
"the",
"analysis",
"of",
"stress",
"related",
"functional",
"variation",
"present",
"in",
"Norway",
"spruce",
"populations.",
"Background",
"Natural",
"populations",
"of",
"Picea",
"abies",
"L.",
"(Norway",
"spruce)",
"are",
"found",
"from",
"north-western",
"Europe",
"outside",
"perma-",
"frost",
"areas",
"down",
"to",
"northern",
"Greece,",
"westwards",
"to",
"the",
"Massif",
"Central",
"(France)",
"and",
"east",
"to",
"the",
"Ural",
"Mountains.",
"Picea",
"abies",
"is",
"growing",
"above",
"400-500",
"m",
"and",
"ascends",
"close",
"to",
"2000",
"m",
"in",
"the",
"Alps.",
"Studies",
"on",
"genetic",
"variation",
"based",
"on",
"allozymes",
"have",
"shown",
"that",
"Picea",
"abies",
"genetic",
"differentiation",
"among",
"populations",
"is",
"rather",
"low",
"over",
"its",
"whole",
"distribution",
"range",
"[1,2].",
"Previous",
"studies",
"on",
"the",
"genetic",
"structure",
"of",
"P.",
"abies",
"using",
"organelle",
"markers",
"showed",
"pronounced",
"differentiation",
"between",
"north-east",
"boreal",
"origins",
"and",
"areas",
"in",
"the",
"central",
"European",
"moun-",
"tains",
"[3,4],",
"supporting",
"the",
"hypothesis",
"of",
"two",
"distinct",
"main",
"glacial",
"refugia",
"as",
"postulated",
"from",
"pollen",
"data",
"[5].",
"Initial",
"reports",
"on",
"the",
"occurrence",
"of",
"SSRs",
"in",
"conifers",
"such",
"as",
"Pinus",
"radiata",
"[6],",
"Pinus",
"sylvestris",
"[7]",
"or",
"Picea",
"*",
"Correspondence:",
"silvia.fluch@ait.ac.at",
"1AIT",
"Austrian",
"Institute",
"of",
"Technology",
"GmbH,",
"Health",
"&",
"Environment",
"Department,",
"Bioresources,",
"3430",
"Tulln,",
"Austria",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"abies",
"[8]",
"have",
"shown",
"that",
"marker",
"development",
"for",
"such",
"complex",
"genomes",
"is",
"difficult.",
"Frequently",
"several",
"DNA",
"fragments",
"in",
"addition",
"to",
"the",
"expected",
"ones",
"are",
"amplified",
"when",
"using",
"primers",
"flanking",
"putative",
"SSR",
"regions.",
"This",
"can",
"be",
"attributed",
"to",
"the",
"very",
"large",
"size",
"of",
"the",
"conifer",
"genomes,",
"with",
"Norway",
"spruce",
"having",
"39.140",
"Mb",
"in",
"the",
"diploid",
"genome",
"(2n",
"=",
"24)",
"as",
"well",
"as",
"the",
"high",
"proportion",
"of",
"repetitive",
"DNA",
"in",
"the",
"conifer",
"genomes",
"[9].",
"These",
"repetitive",
"elements",
"as",
"well",
"as",
"pseudogenes",
"frequently",
"produce",
"complex",
"amplification",
"products",
"from",
"multiple",
"loci",
"[10,11].",
"To",
"overcome",
"this",
"problem,",
"Scotti",
"et",
"al.",
"[12]",
"showed",
"that",
"by",
"isolating",
"di-nucleotide",
"SSRs",
"from",
"cDNA",
"libraries",
"of",
"conifer",
"species",
"this",
"problem",
"can",
"be",
"over-",
"come",
"relying",
"on",
"the",
"fact",
"that",
"expressed",
"genes",
"are",
"less",
"likely",
"to",
"be",
"of",
"repetitive",
"nature",
"in",
"the",
"genome.",
"Following",
"this",
"line",
"of",
"exploiting",
"the",
"advantages",
"of",
"publicly",
"available",
"data",
"on",
"expressed",
"sequences",
"(ESTs)",
"as",
"source",
"for",
"marker",
"development",
"[13]",
"as",
"described",
"also",
"by",
"Rungis",
"et",
"al.",
"[14]",
"for",
"conifers,",
"we",
"used",
"Norway",
"spruce",
"EST",
"sequences",
"from",
"NCBI",
"for",
"in",
"silico",
"identification",
"of",
"SSR",
"regions",
"which",
"could",
"serve",
"for",
"marker",
"development.",
"©",
"2011",
"Fluch",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"open",
"access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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] | [
"SAGE-Hindawi",
"Access",
"to",
"Research",
"Cardiology",
"Research",
"and",
"Practice",
"Volume",
"2011,",
"Article",
"ID",
"714515,",
"10",
"pages",
"doi:10.4061/2011/714515",
"Review",
"Article",
"Local",
"Bone",
"Marrow",
"Renin-Angiotensin",
"System",
"and",
"Atherosclerosis",
"Yavuz",
"Beyazit,1",
"Tugrul",
"Purnak,2",
"Gulay",
"Sain",
"Guven,3",
"and",
"Ibrahim",
"C.",
"Haznedaroglu1",
"1",
"Department",
"of",
"Gastroenterology,",
"Turkiye",
"Yuksek",
"Ihtisas",
"Teaching",
"and",
"Research",
"Hospital,",
"06100",
"Ankara,",
"Turkey",
"2",
"Department",
"of",
"Gastroenterology,",
"Ankara",
"Numune",
"Education",
"and",
"Research",
"Hospital,",
"06100",
"Ankara,",
"Turkey",
"3",
"Department",
"of",
"Internal",
"Medicine,",
"Faculty",
"of",
"Medicine,",
"Hacettepe",
"University,",
"06100",
"Ankara,",
"Turkey",
"Correspondence",
"should",
"be",
"addressed",
"to",
"Yavuz",
"Beyazit,",
"yavuzbeyaz@yahoo.com",
"Received",
"28",
"September",
"2010;",
"Revised",
"14",
"October",
"2010;",
"Accepted",
"23",
"October",
"2010",
"Academic",
"Editor:",
"Masaki",
"Mogi",
"Copyright",
"©",
"2011",
"Yavuz",
"Beyazit",
"et",
"al.",
"This",
"is",
"an",
"open",
"access",
"article",
"distributed",
"under",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Local",
"hematopoietic",
"bone",
"marrow",
"(BM)",
"renin-angiotensin",
"system",
"(RAS)",
"affects",
"the",
"growth,",
"production,",
"proliferation",
"differentiation,",
"and",
"function",
"of",
"hematopoietic",
"cells.",
"Angiotensin",
"II",
"(Ang",
"II),",
"the",
"dominant",
"effector",
"peptide",
"of",
"the",
"RAS,",
"regulates",
"cellular",
"growth",
"in",
"a",
"wide",
"variety",
"of",
"tissues",
"in",
"pathobiological",
"states.",
"RAS,",
"especially",
"Ang",
"II",
"and",
"Ang",
"II",
"type",
"1",
"receptor",
"(AT1R),",
"has",
"considerable",
"proinflammatory",
"and",
"proatherogenic",
"effects",
"on",
"the",
"vessel",
"wall,",
"causing",
"progression",
"of",
"atherosclerosis.",
"Recent",
"investigations,",
"by",
"analyzing",
"several",
"BM",
"chimeric",
"mice",
"whose",
"BM",
"cells",
"were",
"positive",
"or",
"negative",
"for",
"AT1R,",
"disclosed",
"that",
"AT1R",
"in",
"BM",
"cells",
"participates",
"in",
"the",
"pathogenesis",
"of",
"atherosclerosis.",
"Therefore,",
"AT1R",
"blocking",
"not",
"only",
"in",
"vascular",
"cells",
"but",
"also",
"in",
"the",
"BM",
"could",
"be",
"an",
"important",
"therapeutic",
"approach",
"to",
"prevent",
"atherosclerosis.",
"The",
"aim",
"of",
"this",
"paper",
"is",
"to",
"review",
"the",
"function",
"of",
"local",
"BM",
"RAS",
"in",
"the",
"pathogenesis",
"of",
"atherosclerosis.",
"1.",
"Introduction",
"The",
"renin-angiotensin",
"system",
"(RAS)",
"plays",
"a",
"crucial",
"role",
"in",
"the",
"control",
"of",
"blood",
"pressure,",
"blood",
"flow,",
"fluid",
"volume,",
"and",
"electrolyte",
"balance,",
"and",
"overactivity",
"of",
"this",
"system",
"contributes",
"to",
"the",
"pathogenesis",
"of",
"a",
"variety",
"of",
"clinical",
"conditions,",
"including",
"onset,",
"progression,",
"and",
"outcome",
"of",
"atherosclerosis",
"[1–3].",
"Angiotensinogen",
"(AGT)",
"produced",
"in",
"the",
"liver",
"is",
"the",
"precursor",
"of",
"angiotensin",
"I",
"(Ang",
"I),",
"an",
"inactive",
"decapeptide",
"that",
"is",
"converted",
"into",
"Ang",
"II,",
"the",
"main",
"effector",
"of",
"the",
"RAS.",
"Its",
"only",
"role",
"known",
"is",
"as",
"a",
"substrate",
"for",
"renin,",
"a",
"highly",
"specific",
"aspartyl",
"protease.",
"Renin",
"that",
"is",
"secreted",
"from",
"juxtaglomerular",
"apparatus",
"of",
"the",
"kidney",
"cleaves",
"the",
"N-",
"terminal",
"end",
"of",
"AGT",
"to",
"generate",
"Ang",
"I.",
"Ang",
"I",
"is",
"then",
"activated",
"to",
"the",
"Ang",
"II",
"by",
"angiotensin",
"converting",
"enzyme",
"(ACE),",
"which",
"is",
"predominantly",
"expressed",
"in",
"high",
"concentrations",
"on",
"the",
"surface",
"of",
"endothelial",
"cells",
"in",
"the",
"pulmonary",
"circulation",
"[4].",
"Ang",
"II",
"plays",
"a",
"main",
"role",
"in",
"the",
"RAS",
"mediated",
"mainly",
"by",
"two",
"seven",
"transmembrane",
"domain",
"receptors",
"termed",
"Ang",
"II",
"type",
"1",
"receptor",
"(AT1R)",
"and",
"Ang",
"II",
"type",
"2",
"receptor",
"(AT2R)",
"showing",
"a",
"complex",
"pattern",
"of",
"regulation",
"and",
"function",
"[5].",
"Most",
"of",
"the",
"well-known",
"actions",
"of",
"Ang",
"II-AT1R",
"interaction",
"causes",
"vasoconstriction",
"and",
"aldosterone",
"release",
"from",
"the",
"adrenal",
"gland.",
"This",
"classical",
"description",
"of",
"the",
"RAS",
"has",
"been",
"expanded",
"by",
"recent",
"findings",
"that",
"RAS",
"is",
"activated",
"locally,",
"particularly",
"in",
"the",
"vessel",
"wall,",
"heart,",
"the",
"kidney,",
"and",
"the",
"brain",
"[6–14].",
"Ang",
"II",
"was",
"also",
"described",
"to",
"be",
"produced",
"by",
"other",
"enzymes",
"such",
"as",
"chymase,",
"an",
"efficient",
"Ang",
"II-forming",
"serine",
"protease",
"[15].",
"It",
"is",
"not",
"affected",
"by",
"ACE",
"inhibition",
"and",
"has",
"been",
"suggested",
"as",
"relevant",
"for",
"alternative",
"pathways",
"of",
"Ang",
"II",
"generation",
"[16–18].",
"Although",
"several",
"other",
"alternative",
"enzymes",
"involved",
"in",
"Ang",
"II",
"formation",
"such",
"as",
"tonin",
"and",
"cathepsins,",
"chymase",
"deserves",
"special",
"attention",
"due",
"to",
"its",
"high",
"substrate",
"specificity.",
"The",
"enzyme",
"is",
"also",
"expressed",
"in",
"the",
"vascular",
"wall,",
"where",
"it",
"has",
"been",
"suggested",
"as",
"a",
"possible",
"player",
"in",
"Ang",
"II-mediated",
"arteriosclerosis",
"[15].",
"Inflammatory",
"cells",
"detected",
"in",
"atherosclerotic",
"lesions",
"are",
"mainly",
"originated",
"from",
"bone",
"marrow",
"(BM).",
"The",
"presence",
"of",
"a",
"locally",
"activated",
"bone",
"marrow",
"(BM)",
"RAS",
"affecting",
"the",
"growth,",
"production,",
"proliferation,",
"and",
"differentiation",
"of",
"hematopoietic",
"cells",
"was",
"suggested",
"in",
"1996",
"[19].",
"Other",
"than",
"a",
"wide",
"variety",
"of",
"evidences",
"disclosed",
"the",
"existence",
"of",
"a",
"functional",
"local",
"BM",
"RAS.",
"Angiotensin",
"II,",
"through",
"interacting"
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] | [
"BioPsychoSocial",
"Medicine",
"Research",
"General",
"practitioners'",
"responses",
"to",
"the",
"initial",
"presentation",
"of",
"medically",
"unexplained",
"symptoms:",
"a",
"quantitative",
"analysis",
"Teus",
"Kappen",
"and",
"Sandra",
"van",
"Dulmen*",
"BioMed",
"Central",
"Open",
"Access",
"Address:",
"NIVEL",
"(Netherlands",
"Institute",
"for",
"Health",
"Services",
"Research),",
"P.O.Box",
"1568,",
"3500",
"BN",
"Utrecht,",
"The",
"Netherlands",
"Email:",
"Teus",
"Kappen",
"-",
"t.kappen@umcutrecht.nl;",
"Sandra",
"van",
"Dulmen*",
"-",
"s.vandulmen@nivel.nl",
"*",
"Corresponding",
"author",
"Published:",
"17",
"November",
"2008",
"BioPsychoSocial",
"Medicine",
"2008,",
"2:22",
"doi:10.1186/1751-0759-2-22",
"This",
"article",
"is",
"available",
"from:",
"http://www.bpsmedicine.com/content/2/1/22",
"Received:",
"27",
"June",
"2008",
"Accepted:",
"17",
"November",
"2008",
"©",
"2008",
"Kappen",
"and",
"van",
"Dulmen;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Abstract",
"Background:",
"Physicians",
"in",
"primary",
"and",
"secondary",
"care",
"are",
"frequently",
"confronted",
"with",
"patients",
"with",
"medically",
"unexplained",
"symptoms",
"(MUS).",
"In",
"order",
"to",
"solve",
"their",
"patients'",
"problems",
"and",
"out",
"of",
"a",
"fear",
"of",
"overlooking",
"a",
"serious",
"disease,",
"many",
"physicians",
"give",
"their",
"patients",
"full",
"physical",
"examinations",
"and",
"interventions,",
"thereby",
"incorrectly",
"confirming",
"the",
"somatic",
"nature",
"of",
"their",
"condition.",
"Preventing",
"somatization",
"could",
"be",
"achieved",
"by",
"examining",
"the",
"patient's",
"symptom",
"presentation",
"for",
"clues",
"to",
"underlying",
"psychosocial",
"issues",
"and",
"by",
"an",
"appropriate",
"physician",
"response.",
"Methods:",
"Ninety-seven",
"videotaped",
"medical",
"visits",
"from",
"primary",
"care",
"patients",
"presenting",
"MUS",
"for",
"the",
"first",
"time",
"were",
"analyzed.",
"Patients'",
"presentations",
"were",
"categorized",
"in:",
"(1)",
"symptoms",
"only;",
"(2)",
"symptoms",
"with",
"a",
"clue",
"to",
"an",
"underlying",
"concern;",
"or",
"(3)",
"symptoms",
"with",
"an",
"explicit",
"concern.",
"General",
"practitioners'",
"(GPs')",
"responses",
"to",
"patients'",
"presentation",
"were",
"classified",
"into",
"ignoring",
"or",
"more",
"or",
"less",
"exploring",
"responses.",
"Exploring",
"responses",
"were",
"further",
"subdivided",
"in",
"non-directional",
"explorations,",
"clue",
"explorations",
"and",
"medical",
"explorations.",
"Results:",
"Results",
"show",
"that",
"most",
"patients",
"presented",
"their",
"symptoms",
"together",
"with",
"a",
"reference",
"to",
"an",
"underlying",
"concern.",
"Yet,",
"most",
"of",
"them",
"did",
"so",
"in",
"an",
"implicit",
"way.",
"GPs",
"usually",
"explored",
"the",
"concern",
"presented",
"by",
"the",
"patients,",
"but",
"most",
"often",
"in",
"a",
"medical",
"way",
"only.",
"Conclusion:",
"To",
"address",
"the",
"potential",
"psychological",
"basis",
"of",
"patients'",
"medically",
"unexplained",
"symptoms,",
"GPs",
"should",
"pay",
"more",
"attention",
"to",
"the",
"specific",
"clues",
"patients",
"present",
"to",
"them.",
"Likewise,",
"in",
"order",
"to",
"receive",
"full",
"attention,",
"patients",
"should",
"try",
"to",
"present",
"their",
"concerns",
"more",
"explicitly.",
"Background",
"In",
"primary",
"as",
"well",
"as",
"secondary",
"care",
"a",
"large",
"number",
"of",
"patients",
"commonly",
"present",
"with",
"persistent",
"physical",
"symp-",
"toms",
"for",
"which",
"no",
"somatic",
"origin",
"can",
"be",
"found.",
"The",
"major",
"issue",
"in",
"these",
"medically",
"unexplained",
"symptoms",
"(MUS)",
"is",
"that",
"there",
"is",
"a",
"delicate",
"balance",
"between",
"diagnosing",
"MUS",
"and",
"the",
"physician",
"missing",
"a",
"somatic",
"disease.",
"Because",
"phy-",
"sicians",
"take",
"responsibility",
"for",
"solving",
"their",
"patients'",
"prob-",
"lems",
"and",
"because",
"they",
"are",
"afraid",
"of",
"overlooking",
"serious",
"diseases,",
"many",
"patients",
"receive",
"a",
"whole",
"spectrum",
"of",
"phys-",
"ical",
"examinations,",
"interventions",
"and",
"referrals,",
"to",
"exclude",
"potential",
"somatic",
"causes.",
"This",
"contributes",
"to",
"their",
"beliefs",
"that",
"the",
"presented",
"symptoms",
"are",
"indeed",
"of",
"physical",
"ori-",
"gin,",
"which",
"was",
"described",
"by",
"Quill",
"[1]",
"and",
"others",
"as",
"a",
"path-",
"ologic",
"intervention",
"cycle,",
"suggesting",
"the",
"chronic",
"nature",
"of",
"these",
"symptoms",
"to",
"be",
"of",
"iatrogenic",
"origin.",
"Page",
"1",
"of",
"8",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
] | [
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] | [
"Hindawi",
"Publishing",
"Corporation",
"Clinical",
"and",
"Developmental",
"Immunology",
"Volume",
"2011,",
"Article",
"ID",
"235142,",
"6",
"pages",
"doi:10.1155/2011/235142",
"Review",
"Article",
"Adaptive",
"Immune",
"Responses",
"in",
"Primary",
"Cutaneous",
"Sarcoidosis",
"Matteo",
"Bordignon,1",
"Paola",
"Rottoli,2",
"Carlo",
"Agostini,3",
"and",
"Mauro",
"Alaibac1",
"1",
"Unit",
"of",
"Dermatology,",
"University",
"of",
"Padua,",
"Via",
"Cesare",
"Battisti",
"206,",
"35128",
"Padua,",
"Italy",
"2",
"Respiratory",
"Diseases",
"Section,",
"Department",
"of",
"Clinical",
"Medicine",
"and",
"Immunological",
"Sciences,",
"Siena",
"University,",
"53100",
"Siena,",
"Italy",
"3",
"Department",
"of",
"Clinical",
"and",
"Experimental",
"Medicine,",
"University",
"of",
"Padua,",
"Via",
"Cesare",
"Battisti",
"206,",
"35128",
"Padua,",
"Italy",
"Correspondence",
"should",
"be",
"addressed",
"to",
"Mauro",
"Alaibac,",
"mauro.alaibac@unipd.it",
"Received",
"31",
"July",
"2010;",
"Accepted",
"27",
"January",
"2011",
"Academic",
"Editor:",
"E.",
"Shevach",
"Copyright",
"©",
"2011",
"Matteo",
"Bordignon",
"et",
"al.",
"This",
"is",
"an",
"open",
"access",
"article",
"distributed",
"under",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Sarcoidosis",
"is",
"a",
"multisystemic",
"inflammatory",
"disorder",
"with",
"cutaneous",
"lesions",
"present",
"in",
"about",
"one-quarter",
"of",
"the",
"patients.",
"Cutaneous",
"lesions",
"have",
"been",
"classified",
"as",
"specific",
"and",
"nonspecific,",
"depending",
"on",
"the",
"presence",
"of",
"nonnecrotizing",
"epithelial",
"cell",
"granulomas",
"on",
"histologic",
"studies.",
"The",
"development",
"and",
"progression",
"of",
"specific",
"cutaneous",
"sarcoidosis",
"involves",
"a",
"complex",
"interaction",
"between",
"cells",
"of",
"the",
"adaptive",
"immune",
"systems,",
"notably",
"T-lymphocytes",
"and",
"dendritic",
"cells.",
"In",
"this",
"paper,",
"we",
"will",
"discuss",
"the",
"role",
"of",
"T-cells",
"and",
"skin",
"dendritic",
"cells",
"in",
"the",
"development",
"of",
"primary",
"cutaneous",
"sarcoidosis",
"and",
"comment",
"on",
"the",
"potential",
"antigenic",
"stimuli",
"that",
"may",
"account",
"for",
"the",
"development",
"of",
"the",
"immunological",
"response.",
"We",
"will",
"further",
"explore",
"the",
"contributions",
"of",
"selected",
"cytokines",
"to",
"the",
"immunopathological",
"process.",
"The",
"knowledge",
"of",
"the",
"adaptive",
"immunological",
"mechanisms",
"operative",
"in",
"cutaneous",
"sarcoidosis",
"may",
"subsequently",
"be",
"useful",
"for",
"identifying",
"prevention",
"and",
"treatment",
"strategies",
"of",
"systemic",
"sarcoidosis.",
"1.",
"Introduction",
"Sarcoidosis",
"is",
"a",
"multisystemic",
"inflammatory",
"disorder",
"charac-",
"terized",
"by",
"the",
"accumulation",
"of",
"mononuclear",
"phagocytes",
"with",
"the",
"formation",
"of",
"nonnecrotizing",
"epithelial",
"cell",
"granulomas.",
"Multiple",
"organs",
"may",
"be",
"involved,",
"including",
"lungs,",
"mediasti-",
"nal",
"and",
"peripheral",
"lymph",
"nodes,",
"liver,",
"spleen,",
"skin,",
"eyes,",
"and",
"parotid",
"glands;",
"central",
"nervous",
"system,",
"heart,",
"upper",
"respir-",
"atory",
"tract,",
"bones,",
"and",
"joints",
"are",
"less",
"frequently",
"but",
"usually",
"more",
"severely",
"involved",
"[1,",
"2].",
"Sarcoidosis",
"is",
"characterized",
"by",
"local",
"immune",
"hyperacti-",
"vation",
"associated",
"with",
"clinical",
"anergy",
"[3].",
"The",
"pathogenesis",
"of",
"sarcoidosis",
"is",
"suspected",
"to",
"be",
"a",
"host",
"immunologic",
"response",
"to",
"an",
"antigenic",
"exposure",
"[4].",
"The",
"role",
"of",
"T-lymphocytes",
"in",
"the",
"recognition",
"of",
"specific",
"antigens",
"and",
"in",
"the",
"amplification",
"of",
"inflammatory",
"responses",
"has",
"been",
"well",
"established",
"[5].",
"In",
"addition,",
"dendritic",
"cells",
"have",
"recently",
"been",
"shown",
"to",
"have",
"a",
"prominent",
"role",
"in",
"the",
"immunopathological",
"processes",
"op-",
"erating",
"in",
"this",
"condition",
"[6,",
"7].",
"Cutaneous",
"involvement",
"in",
"sarcoidosis",
"occurs",
"in",
"about",
"one-quarter",
"of",
"the",
"patients",
"and",
"is",
"generally",
"observed",
"at",
"the",
"onset",
"of",
"the",
"disease",
"process",
"although",
"it",
"may",
"occur",
"coincident",
"with",
"or",
"after",
"systemic",
"involvement",
"[8,",
"9].",
"Therefore,",
"cuta-",
"neous",
"lesions",
"can",
"be",
"an",
"initial",
"presentation",
"and",
"are",
"probably",
"an",
"important",
"factor",
"in",
"the",
"investigation",
"of",
"the",
"etiology",
"of",
"sarcoidosis.",
"Skin",
"lesions",
"may",
"be",
"classified",
"in",
"specific,",
"when",
"histology",
"shows",
"typical",
"noncaseating",
"granulomatous",
"inflammation,",
"or",
"non",
"specific,",
"in",
"presence",
"of",
"reactive",
"process",
"without",
"granu-",
"lomas.",
"2.",
"Clinical",
"Aspects",
"of",
"Primary",
"Cutaneous",
"Sarcoidosis",
"The",
"frequency",
"of",
"specific",
"skin",
"involvement",
"ranges",
"from",
"9%",
"to",
"37%",
"[10].",
"All",
"specific",
"cutaneous",
"lesions",
"exhibit",
"non-",
"caseating",
"granulomas",
"on",
"biopsy.",
"Histological",
"findings",
"in",
"specific",
"sarcoid",
"lesions",
"show",
"aggregates",
"of",
"epithelioid",
"histi-",
"ocytes",
"with",
"occasional",
"Langhans",
"giant",
"cells",
"and",
"few",
"or",
"no",
"other",
"inflammatory",
"cells,",
"the",
"so-called",
"naked",
"or",
"sarcoidal",
"noncaseating",
"granulomas.",
"Frequently,",
"there",
"are",
"inclusion",
"bodies",
"in",
"giant",
"cells",
"[11].",
"The",
"centre",
"of",
"granulomas",
"is",
"typically",
"surrounded",
"by",
"CD4+",
"lymphocytes,",
"rare",
"CD8+",
"lymphocytes",
"and",
"mature",
"macrophages.",
"Despite",
"the",
"same",
"histologic",
"appearance,",
"clinical",
"manifestations",
"of",
"primary",
"cutaneous",
"sarcoidosis",
"may",
"be",
"variable."
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] | [
"Erbudak",
"and",
"Erzan",
"Theoretical",
"Biology",
"and",
"Medical",
"Modelling",
"2010,",
"7:30",
"http://www.tbiomed.com/content/7/1/30",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"Open",
"Access",
"Tracking",
"tumor",
"evolution",
"via",
"prostate-specific",
"antigen:",
"an",
"individual",
"post-operative",
"study",
"Mehmet",
"Erbudak1*,",
"Ayşe",
"Erzan2",
"*",
"Correspondence:",
"erbudak@phys.",
"ethz.ch",
"1Laboratory",
"for",
"Solid",
"State",
"Physics,",
"ETH",
"Zurich,",
"CH-8093",
"Zurich,",
"Switzerland",
"Abstract",
"Background:",
"The",
"progress",
"of",
"the",
"prostate-specific",
"antigen",
"(PSA)",
"level",
"after",
"radical",
"prostatectomy",
"is",
"observed",
"for",
"a",
"patient",
"in",
"order",
"to",
"extract",
"information",
"about",
"the",
"mode",
"of",
"tumor",
"cell",
"growth.",
"Although",
"PSA",
"values",
"are",
"determined",
"routinely",
"to",
"find",
"the",
"doubling",
"time",
"of",
"the",
"prostate",
"marker,",
"to",
"our",
"knowledge,",
"this",
"analysis",
"is",
"the",
"first",
"in",
"the",
"literature.",
"Results:",
"The",
"prostate",
"tumor",
"marker",
"values",
"were",
"determined",
"regularly",
"after",
"the",
"surgery",
"and",
"plotted",
"on",
"a",
"logarithmic",
"scale",
"against",
"time.",
"An",
"initial",
"rapid-growth",
"mode",
"changed",
"to",
"a",
"slower",
"power-law",
"regime",
"within",
"two",
"years",
"of",
"surgery.",
"Our",
"analysis",
"associates",
"this",
"observation",
"with",
"a",
"transition",
"in",
"the",
"growth",
"mode",
"from",
"unrestricted",
"growth",
"of",
"dispersed",
"cells",
"to",
"their",
"clumping",
"into",
"macroscopic",
"structures.",
"Conclusions:",
"Such",
"studies",
"may",
"help",
"determine",
"the",
"appropriate",
"time",
"window",
"for",
"postoperative",
"therapies",
"in",
"order",
"to",
"increase",
"the",
"life",
"expectancy",
"of",
"the",
"patient.",
"Background",
"Cancer",
"of",
"the",
"prostate",
"gland",
"is",
"one",
"of",
"the",
"most",
"frequently",
"diagnosed",
"male",
"illnesses",
"and",
"may",
"lead",
"to",
"death",
"of",
"the",
"patient.",
"The",
"carcinoma",
"is",
"routinely",
"detected",
"by",
"a",
"straight-",
"forward",
"blood",
"test",
"that",
"measures",
"a",
"glycoprotein",
"called",
"prostate-specific",
"antigen",
"(PSA).",
"At",
"an",
"early",
"stage",
"of",
"cancer",
"growth",
"with",
"a",
"localized",
"tumor,",
"radical",
"removal",
"of",
"the",
"pros-",
"tate",
"gland",
"has",
"proved",
"to",
"be",
"the",
"optimum",
"treatment.",
"If",
"the",
"PSA",
"value",
"rises",
"after",
"radical",
"prostatectomy,",
"different",
"alternatives",
"for",
"treatment",
"are",
"currently",
"under",
"debate.",
"The",
"doubling",
"time",
"(DT)",
"of",
"the",
"PSA",
"value",
"is",
"accepted",
"as",
"a",
"strong",
"prognostic",
"factor",
"for",
"the",
"risk",
"of",
"cancer",
"death.",
"In",
"a",
"group",
"of",
"379",
"patients,",
"almost",
"no",
"prostate",
"cancer",
"deaths",
"were",
"recorded",
"within",
"approximately",
"4",
"years",
"of",
"prostate",
"removal",
"for",
"3",
"<",
"DT",
"<",
"8.9",
"months,",
"while",
"some",
"patients",
"with",
"DT",
"<",
"3",
"months",
"died",
"within",
"1.5",
"years",
"[1].",
"It",
"is",
"therefore",
"rea-",
"sonable",
"to",
"infer",
"that",
"findings",
"during",
"the",
"last",
"few",
"years",
"based",
"on",
"long-term",
"statistics",
"suggest",
"a",
"longer",
"life",
"expectancy",
"for",
"patients",
"with",
"postoperative",
"radiotherapy",
"that",
"fol-",
"lows",
"(within",
"6",
"months",
"of)",
"radical",
"prostate",
"surgery",
"[2].",
"Transdermal",
"radiotherapy",
"is",
"commonly",
"applied",
"after",
"the",
"PSA",
"level",
"reaches",
"a",
"threshold",
"value.",
"However,",
"a",
"wait-and-",
"watch",
"method",
"may",
"cost",
"valuable",
"time",
"and",
"the",
"relevant",
"moment",
"for",
"action",
"may",
"be",
"missed",
"regardless",
"of",
"how",
"low",
"the",
"threshold",
"value",
"is",
"set.",
"Many",
"authors",
"have",
"already",
"suggested",
"[3-5]",
"that",
"the",
"entire",
"course",
"of",
"tumor",
"growth",
"offers",
"important",
"information",
"regarding",
"the",
"clinical",
"strategies",
"to",
"be",
"followed.",
"©",
"2010",
"Erbudak",
"and",
"Erzan;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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] | [
"BMC",
"Musculoskeletal",
"Disorders",
"BioMed",
"Central",
"3BR2M0e0Cs2eM,ausrccuhlosakerltetiacllDeisorders",
"x",
"Correlation",
"of",
"the",
"score",
"for",
"subjective",
"pain",
"with",
"physical",
"disability,",
"clinical",
"and",
"radiographic",
"scores",
"in",
"recent",
"onset",
"rheumatoid",
"arthritis",
"Piercarlo",
"Sarzi-Puttini*1,",
"Tania",
"Fiorini2,",
"Benedetta",
"Panni1,",
"Maurizio",
"Turiel2,",
"Marco",
"Cazzola1",
"and",
"Fabiola",
"Atzeni1",
"Address:",
"1Rheumatology",
"Unit,",
"University",
"Hospital",
"L.",
"Sacco,",
"Milan,",
"Italy",
"and",
"2Istituto",
"di",
"Scienze",
"Biomediche,",
"Università",
"di",
"Milano,",
"Italy",
"E-mail:",
"Piercarlo",
"Sarzi-Puttini*",
"-",
"sarzi@tiscalinet.it;",
"Tania",
"Fiorini",
"-",
"tania@posta.statfac.unibo.it;",
"Benedetta",
"Panni",
"-",
"benedetta_p@virgilio.it;",
"Maurizio",
"Turiel",
"-",
"maurizio.turiel@unimi.it;",
"Marco",
"Cazzola",
"-",
"marco.cazzola@tiscalinet.it;",
"Fabiola",
"Atzeni",
"-",
"atzenifabiola@hotmail.com",
"*Corresponding",
"author",
"Published:",
"19",
"July",
"2002",
"BMC",
"Musculoskeletal",
"Disorders",
"2002,",
"3:18",
"This",
"article",
"is",
"available",
"from:",
"http://www.biomedcentral.com/1471-2474/3/18",
"Received:",
"12",
"December",
"2001",
"Accepted:",
"19",
"July",
"2002",
"©",
"2002",
"Sarzi-Puttini",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"Verbatim",
"copying",
"and",
"redistribution",
"of",
"this",
"article",
"are",
"permitted",
"in",
"any",
"medium",
"for",
"any",
"purpose,",
"provided",
"this",
"notice",
"is",
"preserved",
"along",
"with",
"the",
"article's",
"original",
"URL.",
"Keywords:",
"Rheumatoid",
"arthritis,",
"pain,",
"pain",
"measurement",
"Abstract",
"Background:",
"To",
"analyse",
"the",
"relationship",
"between",
"subjective",
"pain",
"score",
"and",
"other",
"measures",
"of",
"clinical,",
"radiographic",
"and",
"functional",
"status;",
"in",
"particular",
"Larsen",
"radiographic",
"scores",
"and",
"Health",
"Assessment",
"Questionnaire",
"(HAQ);",
"in",
"patients",
"with",
"severe",
"rheumatoid",
"arthritis",
"(RA)",
"with",
"a",
"disease",
"duration",
"of",
"less",
"than",
"3",
"years.",
"Methods:",
"In",
"this",
"cross",
"sectional",
"study",
"of",
"105",
"patients",
"with",
"RA",
"(76",
"women,",
"29",
"men:",
"mean",
"age",
"50.93;",
"mean",
"disease",
"duration",
"15.86",
"months;",
"71%",
"rheumatoid",
"factor",
"positive)",
"subjective",
"pain",
"was",
"assessed",
"according",
"to",
"the",
"Visual",
"Analog",
"Scale",
"(VAS).",
"Correlation",
"coefficients",
"between",
"pain",
"score",
"and",
"disease",
"activity",
"measures",
"(patients'",
"global",
"assessment",
"of",
"disease",
"by",
"VAS,",
"number",
"of",
"tender",
"and",
"swollen",
"joints,",
"morning",
"stiffness,",
"erythrocyte",
"sedimentation",
"rate",
"[ESR],",
"C-reactive",
"protein",
"[CRP]",
"and",
"titre",
"of",
"rheumatoid",
"factor,",
"radiographic",
"evaluations",
"(Larsen-Dale",
"scores",
"for",
"radiographic",
"damage",
"of",
"the",
"small",
"joints",
"of",
"the",
"hands,",
"wrist",
"and",
"feet),",
"disability",
"measures",
"(health",
"assessment",
"questionnaire",
"[HAQ]),",
"and",
"demographic",
"variables",
"were",
"calculated;",
"hierarchical",
"regression",
"analysis",
"was",
"done",
"with",
"subjective",
"pain",
"score",
"as",
"the",
"dependent",
"variable.",
"Results:",
"The",
"Spearman's",
"correlation",
"coefficient",
"comparing",
"subjective",
"pain",
"and",
"HAQ",
"was",
"0.421",
"(p",
"<",
"0.001),",
"between",
"subjective",
"pain",
"and",
"global",
"assessment",
"of",
"disease",
"and",
"morning",
"stiffness",
"was",
"0.573",
"(p",
"<",
"0.001)",
"and",
"0.427",
"(p",
"<",
"0.001)",
"respectively,",
"and",
"between",
"pain",
"and",
"number",
"of",
"tender",
"and",
"swollen",
"joints",
"0.037",
"and",
"0.050",
"respectively",
"(p",
">",
"0.05).",
"In",
"regression",
"analysis,",
"global",
"assessment",
"of",
"disease",
"by",
"patients",
"explained",
"32.8%",
"of",
"the",
"variation",
"in",
"pain",
"intensity",
"score,",
"morning",
"stiffness",
"10.7%,",
"CRP",
"4.0%,",
"HAQ",
"3.8%",
"and",
"Larsen-Dale",
"scores",
"explained",
"2.1%;",
"other",
"variables",
"were",
"not",
"significant",
"in",
"the",
"model.",
"Conclusions:",
"Pain",
"scores",
"of",
"patients",
"with",
"early",
"severe",
"rheumatoid",
"arthritis",
"are",
"correlated",
"at",
"higher",
"levels",
"with",
"patients'",
"global",
"assessment",
"of",
"disease",
"and",
"with",
"morning",
"stiffness",
"rather",
"than",
"with",
"radiographic",
"or",
"other",
"clinical",
"variables",
"such",
"as",
"number",
"of",
"tender",
"and",
"swollen",
"joints.",
"Page",
"1",
"of",
"4",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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"BMC",
"Infectious",
"Diseases",
"Research",
"article",
"Childhood",
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"Anuwatnonthakate2,",
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"Norio",
"Yamada5,",
"Wanpen",
"Wattanaamornkiat6,",
"Wanchai",
"Sattayawuthipong7,",
"Pricha",
"Charusuntonsri8,",
"Natpatou",
"Sanguanwongse9,",
"Charles",
"D",
"Wells10",
"and",
"Jay",
"K",
"Varma*2,10",
"Address:",
"1Global",
"AIDS",
"Program,",
"Thailand",
"MOPH",
"–",
"U.S.",
"CDC",
"Collaboration,",
"Nonthaburi,",
"Thailand,",
"2TB",
"Program,",
"Thailand",
"MOPH",
"–",
"U.S.",
"CDC",
"Collaboration,",
"Nonthaburi,",
"Thailand,",
"3Bureau",
"of",
"TB,",
"Thailand",
"Ministry",
"of",
"Public",
"Health,",
"Nonthaburi,",
"Thailand,",
"4Chiang",
"Rai",
"Provincial",
"Public",
"Health",
"Office,",
"Chiang",
"Rai,",
"Thailand,",
"5Research",
"Institute",
"of",
"Tuberculosis",
"(Japan),",
"Chiang",
"Rai,",
"Thailand,",
"6AIDS,",
"TB,",
"STI",
"and",
"Leprosy",
"Section,",
"Office",
"of",
"Disease",
"Prevention",
"and",
"Control",
"7,",
"Ubon-ratchathani,",
"Thailand,",
"7Phuket",
"Provincial",
"Public",
"Health",
"Office,",
"Phuket,",
"Thailand,",
"8Health",
"Center",
"41,",
"Bangkok",
"Metropolitan",
"Health",
"Administration,",
"Bangkok,",
"Thailand,",
"9Medicine",
"Department,",
"Bamrasnaradura",
"Institute,",
"Nonthaburi,",
"Thailand",
"and",
"10Division",
"of",
"TB",
"Elimination,",
"U.S.",
"Centers",
"for",
"Disease",
"Control",
"and",
"Prevention,",
"Atlanta,",
"USA",
"Email:",
"Rangsima",
"Lolekha",
"-",
"rangsimaL@th.cdc.gov;",
"Amornrat",
"Anuwatnonthakate",
"-",
"AmornratA@th.cdc.gov;",
"Sriprapa",
"Nateniyom",
"-",
"nateniyoms@yahoo.com;",
"Surin",
"Sumnapun",
"-",
"angvcr@hotmail.com;",
"Norio",
"Yamada",
"-",
"nyamada@jata.or.jp;",
"Wanpen",
"Wattanaamornkiat",
"-",
"Wanpen_wa@yahoo.com;",
"Wanchai",
"Sattayawuthipong",
"-",
"wanchaig@health.moph.go.th;",
"Pricha",
"Charusuntonsri",
"-",
"pcharu@gmail.com;",
"Natpatou",
"Sanguanwongse",
"-",
"natpatou@yahoo.com;",
"Charles",
"D",
"Wells",
"-",
"cdwells6@bellsouth.net;",
"Jay",
"K",
"Varma*",
"-",
"jvarma@cdc.gov",
"BioMed",
"Central",
"Open",
"Access",
"*",
"Corresponding",
"author",
"Published:",
"18",
"July",
"2008",
"BMC",
"Infectious",
"Diseases",
"2008,",
"8:94",
"doi:10.1186/1471-2334-8-94",
"This",
"article",
"is",
"available",
"from:",
"http://www.biomedcentral.com/1471-2334/8/94",
"Received:",
"26",
"December",
"2007",
"Accepted:",
"18",
"July",
"2008",
"©",
"2008",
"Lolekha",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Abstract",
"Background:",
"Of",
"the",
"9.2",
"million",
"new",
"TB",
"cases",
"occurring",
"each",
"year,",
"about",
"10%",
"are",
"in",
"children.",
"Because",
"childhood",
"TB",
"is",
"usually",
"non-infectious",
"and",
"non-fatal,",
"national",
"programs",
"do",
"not",
"prioritize",
"childhood",
"TB",
"diagnosis",
"and",
"treatment.",
"We",
"reviewed",
"data",
"from",
"a",
"demonstration",
"project",
"to",
"learn",
"more",
"about",
"the",
"epidemiology",
"of",
"childhood",
"TB",
"in",
"Thailand.",
"Methods:",
"In",
"four",
"Thai",
"provinces",
"and",
"one",
"national",
"hospital,",
"we",
"contacted",
"healthcare",
"facilities",
"monthly",
"to",
"record",
"data",
"about",
"persons",
"diagnosed",
"with",
"TB,",
"assist",
"with",
"patient",
"care,",
"provide",
"HIV",
"counseling",
"and",
"testing,",
"and",
"obtain",
"sputum",
"for",
"culture",
"and",
"susceptibility",
"testing.",
"We",
"analyzed",
"clinical",
"and",
"treatment",
"outcome",
"data",
"for",
"patients",
"age",
"<",
"15",
"years",
"old",
"registered",
"in",
"2005",
"and",
"2006.",
"Results:",
"Only",
"279",
"(2%)",
"of",
"14,487",
"total",
"cases",
"occurred",
"in",
"children.",
"The",
"median",
"age",
"of",
"children",
"was",
"8",
"years",
"(range:",
"4",
"months,",
"14",
"years).",
"Of",
"197",
"children",
"with",
"pulmonary",
"TB,",
"63",
"(32%)",
"were",
"bacteriologically-confirmed:",
"56",
"(28%)",
"were",
"smear-positive",
"and",
"7",
"(4%)",
"were",
"smear-negative,",
"but",
"culture-positive.",
"One",
"was",
"diagnosed",
"with",
"multi-drug",
"resistant",
"TB.",
"HIV",
"infection",
"was",
"documented",
"in",
"75",
"(27%).",
"Thirteen",
"(17%)",
"of",
"75",
"HIV-infected",
"children",
"died",
"during",
"TB",
"treatment",
"compared",
"with",
"4",
"(2%)",
"of",
"204",
"not",
"known",
"to",
"be",
"HIV-infected",
"(p",
"<",
"0.01).",
"Conclusion:",
"Childhood",
"TB",
"is",
"infrequently",
"diagnosed",
"in",
"Thailand.",
"Understanding",
"whether",
"this",
"is",
"due",
"to",
"absence",
"of",
"disease",
"or",
"diagnostic",
"effort",
"requires",
"further",
"research.",
"HIV",
"contributes",
"substantially",
"to",
"the",
"childhood",
"TB",
"burden",
"in",
"Thailand",
"and",
"is",
"associated",
"with",
"high",
"mortality.",
"Page",
"1",
"of",
"9",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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] | [
"R",
"E",
"V",
"I",
"E",
"W",
"Defect",
"of",
"alveolar",
"regeneration",
"in",
"pulmonary",
"emphysema:",
"Role",
"of",
"lung",
"fibroblasts",
"Laurent",
"Plantier1,2",
"Jorge",
"Boczkowski1,3",
"Bruno",
"Crestani1,4",
"1INSERM,",
"U700,",
"Faculté",
"Xavier",
"Bichat,",
"Paris,",
"France;",
"2Assistance",
"Publique-",
"Hôpitaux",
"de",
"Paris,",
"Hôpital",
"Bichat,",
"Service",
"de",
"Pneumologie",
"B,",
"Paris,",
"France;",
"3Assistance",
"Publique-Hôpitaux",
"de",
"Paris,",
"Hôpital",
"Bichat,",
"CIC",
"07,",
"Paris,",
"France;",
"4Assistance",
"Publique-Hôpitaux",
"de",
"Paris,",
"Hôpital",
"Bichat,",
"Service",
"de",
"Pneumologie",
"A,",
"Paris,",
"France",
"Correspondence:",
"Bruno",
"Crestani",
"Service",
"de",
"Pneumologie",
"A,",
"Hôpital",
"Bichat,",
"16",
"rue",
"Henri",
"Huchard,",
"75877,",
"Paris",
"Cedex",
"18,",
"France",
"Tel",
"+33",
"1",
"40256800",
"Fax",
"+33",
"1",
"40258818",
"Email",
"bruno.crestani@bch.aphp.fr",
"Abstract:",
"Pulmonary",
"emphysema",
"is",
"characterized",
"by",
"the",
"irreversible",
"loss",
"of",
"pulmonary",
"alveoli.",
"Despite",
"recent",
"advances",
"in",
"the",
"understanding",
"this",
"disease,",
"its",
"treatment",
"remains",
"palliative.",
"In",
"this",
"review,",
"we",
"will",
"successively",
"review",
"the",
"data",
"suggesting",
"(1)",
"that",
"alveolar",
"regeneration",
"systems",
"are",
"functional",
"in",
"the",
"mammalian",
"lung",
"and",
"have",
"the",
"potential",
"to",
"regrow",
"lost",
"alveoli,",
"(2)",
"that",
"cigarette",
"smoke,",
"the",
"main",
"etiologic",
"factor",
"of",
"emphysema,",
"inhibits",
"those",
"systems",
"under",
"experimental",
"conditions,",
"and",
"(3)",
"that",
"alveolar",
"regeneration",
"systems",
"are",
"dysfunctional",
"in",
"the",
"human",
"emphysematous",
"lung",
"and",
"may",
"be",
"a",
"target",
"for",
"therapeutic",
"intervention",
"in",
"this",
"disease.",
"Special",
"emphasis",
"will",
"be",
"put",
"on",
"the",
"role",
"of",
"alveolar",
"fibroblasts",
"in",
"those",
"processes.",
"Keywords:",
"emphysema,",
"repair,",
"regeneration,",
"HGF,",
"fibroblasts",
"Introduction",
"Pulmonary",
"emphysema",
"is",
"characterized",
"by",
"the",
"progressive",
"destruction",
"of",
"pulmonary",
"alveoli.",
"It",
"is",
"one",
"of",
"the",
"most",
"common",
"diseases",
"worldwide",
"(Halbert",
"et",
"al",
"2006)",
"and",
"its",
"incidence",
"keeps",
"growing",
"along",
"with",
"the",
"large",
"diffusion",
"of",
"its",
"main",
"etiologic",
"factor,",
"tobacco",
"smoking.",
"The",
"ever-increasing",
"use",
"of",
"tobacco",
"in",
"the",
"developing",
"world",
"allows",
"for",
"the",
"prediction",
"of",
"a",
"huge",
"increase",
"in",
"the",
"number",
"of",
"cases",
"in",
"the",
"near",
"and",
"distant",
"future.",
"The",
"prognosis",
"of",
"pulmonary",
"emphysema",
"is",
"poor,",
"with",
"airflow",
"limitation",
"progressing",
"to",
"chronic",
"respiratory",
"insufficiency,",
"disability",
"and",
"premature",
"death.",
"To",
"this",
"day,",
"therapeutic",
"options",
"for",
"pulmonary",
"emphysema",
"are",
"few",
"and",
"scarcely",
"effective.",
"Patients",
"who",
"stop",
"smoking",
"do",
"benefit",
"in",
"terms",
"of",
"lung",
"function",
"and",
"survival,",
"but",
"the",
"decline",
"in",
"lung",
"function",
"is",
"not",
"reversed,",
"merely",
"slowed.",
"Apart",
"from",
"long-term",
"oxygen",
"therapy,",
"pharmacological",
"intervention",
"is",
"unsatisfactory",
"and",
"is",
"mainly",
"limited",
"to",
"the",
"control",
"of",
"symptoms",
"related",
"to",
"frequently-associated",
"chronic",
"bronchitis",
"(Sutherland",
"and",
"Cherniack",
"2004).",
"Lung",
"volume",
"reduction",
"surgery",
"can",
"be",
"of",
"interest",
"in",
"selected",
"patients",
"(Fishman",
"et",
"al",
"2003)",
"as",
"may",
"be",
"the",
"implantation",
"of",
"endobronchial",
"one-way",
"valves",
"(Wood",
"et",
"al",
"2007)",
"but",
"those",
"techniques",
"do",
"not",
"remedy",
"the",
"underlying",
"condition.",
"Lung",
"transplantation,",
"while",
"beneficial",
"in",
"terms",
"of",
"symptoms-related",
"quality",
"of",
"life,",
"does",
"not",
"improve",
"survival",
"in",
"patients",
"with",
"pulmonary",
"emphysema",
"(Hosenpud",
"et",
"al",
"1998).",
"Overall,",
"treatment",
"of",
"pulmonary",
"emphysema",
"is",
"palliative.",
"Most",
"studies",
"of",
"the",
"pathogenesis",
"of",
"emphysema",
"focused",
"on",
"the",
"mechanisms",
"involved",
"in",
"chronic",
"injury",
"induced",
"by",
"cigarette",
"smoke",
"to",
"the",
"pulmonary",
"parenchyma.",
"In",
"particular,",
"the",
"role",
"of",
"protease-antiprotease",
"imbalance,",
"persistent",
"inflammation,",
"oxi-",
"dative",
"stress",
"and",
"excessive",
"apoptosis",
"of",
"alveolar",
"cells",
"was",
"demonstrated",
"(Barnes",
"et",
"al",
"2003).",
"However,",
"while",
"great",
"advances",
"were",
"made",
"towards",
"the",
"comprehension",
"of",
"those",
"phenomenons,",
"they",
"have",
"not",
"translated",
"into",
"new",
"therapeutic",
"prospects",
"until",
"now.",
"Alveolar",
"regeneration",
"systems",
"may",
"be",
"important",
"actors",
"in",
"the",
"course",
"of",
"emphysema.",
"On",
"the",
"one",
"hand,",
"alterations",
"or",
"defects",
"in",
"those",
"systems",
"may",
"account",
"for",
"the",
"deficiency",
"in",
"tissue",
"repair",
"which",
"is",
"observed",
"in",
"the",
"emphysematous",
"lung.",
"On",
"the",
"other",
"hand,",
"the",
"induction",
"of",
"alveolar",
"regeneration",
"would",
"be",
"an",
"interesting",
"therapeutic",
"target",
"in",
"International",
"Journal",
"of",
"COPD",
"2007:2(4)",
"463–469",
"©",
"2007",
"Dove",
"Medical",
"Press",
"Limited.",
"All",
"rights",
"reserved",
"463"
] | [
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"MEDITERRANEAN",
"JOURNAL",
"OF",
"HEMATOLOGY",
"AND",
"INFECTIOUS",
"DISEASES",
"www.mjhid.org",
"ISSN",
"2035-3006",
"Original",
"Article",
"Poor",
"Hematopoietic",
"Stem",
"Institution",
"Experience.",
"Cell",
"Mobilizers",
"in",
"Multiple",
"Myeloma:",
"a",
"Single",
"Guillermo",
"J.",
"Ruiz-Delgado,1,2,3",
"Avril",
"López-Otero,1,3",
"Ana",
"Hernandez-Arizpe,1,3",
"Aura",
"Ramirez-Medina1",
"and",
"Guillermo",
"J.",
"Ruiz-Argüelles.1,2,3",
"1",
"Centro",
"de",
"Hematología",
"y",
"Medicina",
"Interna",
"de",
"Puebla.",
"Puebla,",
"MEXICO.",
"2",
"Laboratorios",
"Clínicos",
"de",
"Puebla.",
"Puebla,",
"MEXICO.",
"3",
"Universidad",
"Popular",
"Autónoma",
"del",
"Estado",
"de",
"Puebla.",
"Correspondence",
"to:",
"Guillermo",
"J.",
"Ruiz-Delgado",
"MD,",
"Centro",
"de",
"Hematología",
"y",
"Medicina,",
"Interna",
"de",
"Puebla,",
"8B",
"Sur",
"3710,",
"72530",
"Puebla,",
"Pue.",
"Mexico.",
"Teléfono:",
"+",
"52",
"(222)",
"243",
"8100,",
"Telefax:",
"+",
"52",
"(222)",
"243",
"8428.",
"E-mail:",
"gruiz2@clinicaruiz.com",
"Competing",
"interests:",
"The",
"author",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"Published:",
"Jume",
"21,",
"2010",
"Received:",
"May",
"31,",
"2010",
"Accepted:",
"June",
"19,",
"2010",
"Medit",
"J",
"Hemat",
"Infect",
"Dis",
"2010,",
"2(2):",
"e2010016,",
"DOI",
"10.4084/MJHID.2010.016",
"This",
"article",
"is",
"available",
"from:",
"http://www.mjhid.org/article/view/6020",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited",
"Abstract",
"In",
"a",
"single",
"institution,",
"in",
"a",
"group",
"of",
"28",
"myeloma",
"patients",
"deemed",
"eligible",
"for",
"autologous",
"transplant,",
"stem",
"cell",
"mobilization",
"was",
"attempted",
"using",
"filgrastim:",
"26",
"individuals",
"were",
"given",
"31",
"autografts",
"employing",
"1-4",
"(median",
"three)",
"apheresis",
"sessions,",
"to",
"obtain",
"a",
"target",
"stem",
"cell",
"dose",
"of",
"1",
"x",
"106",
"CD34",
"+ve",
"viable",
"cells",
"/",
"Kg",
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"the",
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"grafted",
"CD34",
"cells",
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"7.56",
"x",
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"/",
"Kg",
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"individuals",
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"those",
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"x",
"106",
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"+ve",
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"cells",
"/",
"Kg",
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"76",
"months).",
"Methods",
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"stem",
"cell",
"mobilization",
"are",
"needed",
"and",
"may",
"result",
"in",
"obtaining",
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"results",
"when",
"autografting",
"multiple",
"myeloma",
"patients.",
"Introduction:",
"High-dose",
"chemotherapy",
"followed",
"by",
"autologous",
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"cell",
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"include",
"faster",
"Medit",
"J",
"Hemat",
"Infect",
"Dis",
"2010;",
"2(2);",
"Open",
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"System",
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650,
641,
687,
655
],
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691,
641,
701,
655
],
[
706,
641,
723,
655
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727,
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762,
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614,
724,
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738
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427,
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556,
741,
586,
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589,
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649,
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652,
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704,
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708,
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427,
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514,
795
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523,
778,
563,
795
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571,
778,
690,
795
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427,
810,
493,
822
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498,
810,
513,
822
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518,
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570,
822
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576,
810,
603,
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608,
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822
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666,
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734,
822
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427,
826,
450,
838
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455,
826,
476,
838
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481,
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535,
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427,
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855
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481,
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535,
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546,
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549,
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594,
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613,
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691,
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427,
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530,
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427,
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467,
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523,
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745,
891,
762,
905
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427,
907,
444,
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447,
907,
453,
921
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456,
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545,
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] | [
"JCB:",
"REPORT",
"ESCRT",
"ubiquitin-binding",
"domains",
"function",
"cooperatively",
"during",
"MVB",
"cargo",
"sorting",
"S.",
"Brookhart",
"Shields,1",
"Andrea",
"J.",
"Oestreich,2",
"Stanley",
"Winistorfer,1",
"Doris",
"Nguyen,2",
"Johanna",
"A.",
"Payne,2",
"David",
"J.",
"Katzmann,2",
"and",
"Robert",
"Piper1",
"1Department",
"of",
"Molecular",
"Physiology",
"and",
"Biophysics,",
"University",
"of",
"Iowa,",
"Iowa",
"City,",
"IA",
"52240",
"2Department",
"of",
"Biochemistry",
"and",
"Molecular",
"Biology,",
"Mayo",
"Clinic",
"College",
"of",
"Medicine,",
"Rochester,",
"MN",
"55905",
"U",
"geting",
"of",
"ubiquitinated",
"membrane",
"proteins",
"into",
"biquitin",
"(Ub)",
"sorting",
"receptors",
"facilitate",
"the",
"tar-",
"multivesicular",
"bodies",
"(MVBs).",
"Ub-binding",
"do-",
"mains",
"(UBDs)",
"have",
"been",
"described",
"in",
"several",
"endosomal",
"sorting",
"complexes",
"required",
"for",
"transport",
"(ESCRT).",
"Using",
"available",
"structural",
"information,",
"we",
"have",
"investigated",
"the",
"role",
"of",
"the",
"multiple",
"UBDs",
"within",
"ESCRTs",
"during",
"MVB",
"cargo",
"selection.",
"We",
"found",
"a",
"novel",
"UBD",
"within",
"ESCRT-I",
"and",
"show",
"that",
"it",
"contributes",
"to",
"MVB",
"sorting",
"in",
"concert",
"with",
"the",
"known",
"UBDs",
"within",
"the",
"ESCRT",
"complexes.",
"These",
"experiments",
"reveal",
"an",
"unexpected",
"level",
"of",
"coordination",
"among",
"the",
"ESCRT",
"UBDs,",
"suggesting",
"that",
"they",
"collectively",
"recognize",
"a",
"diverse",
"set",
"of",
"cargo",
"rather",
"than",
"act",
"sequen-",
"tially",
"at",
"discrete",
"steps.",
"Y",
"G",
"O",
"L",
"O",
"I",
"B",
"L",
"L",
"E",
"C",
"F",
"O",
"L",
"A",
"N",
"R",
"U",
"O",
"J",
"E",
"H",
"T",
"Introduction",
"Many",
"integral",
"membrane",
"proteins",
"targeted",
"for",
"lysosomal",
"degra-",
"dation",
"are",
"ubiquitinated",
"and",
"sorted",
"into",
"vesicles",
"that",
"bud",
"from",
"the",
"limiting",
"membrane",
"into",
"the",
"lumen",
"of",
"endosomes",
"during",
"the",
"biogenesis",
"of",
"multivesicular",
"bodies",
"(MVBs;",
"Piper",
"and",
"Katzmann,",
"2007).",
"Cargo",
"selection",
"during",
"MVB",
"sorting",
"is",
"dependent",
"on",
"several",
"endosomal",
"protein",
"complexes",
"known",
"as",
"endosomal",
"sorting",
"complexes",
"required",
"for",
"transport",
"(ESCRT).",
"Several",
"ESCRT",
"components",
"contain",
"ubiquitin",
"(Ub)-binding",
"do-",
"mains",
"(UBDs)",
"that",
"may",
"act",
"as",
"receptors",
"for",
"ubiquitinated",
"mem-",
"brane",
"proteins.",
"For",
"instance,",
"ESCRT-0,",
"comprised",
"of",
"yeast",
"Vps27",
"and",
"Hse1",
"or",
"mammalian",
"Hrs",
"and",
"STAM",
"(signal",
"trans-",
"ducing",
"adaptor",
"molecule),",
"contains",
"Ub-interacting",
"motifs",
"(UIMs)",
"required",
"for",
"MVB",
"sorting",
"of",
"ubiquitinated",
"cargo",
"(Bilodeau",
"et",
"al.,",
"2002;",
"Shih",
"et",
"al.,",
"2002;",
"Piper",
"and",
"Katzmann,",
"2007).",
"The",
"Ub",
"E2",
"variant",
"(UEV)",
"domain",
"in",
"Vps23/TSG101,",
"an",
"ESCRT-I",
"component",
"in",
"yeast/mammalian",
"cells,",
"and",
"the",
"GLUE",
"(GRAM-like",
"Ub",
"binding",
"in",
"EAP45)",
"or",
"Npl4",
"zinc",
"finger",
"(NZF)",
"domains",
"of",
"Vps36,",
"an",
"ESCRT-II",
"component,",
"also",
"contain",
"UBDs",
"that",
"have",
"been",
"implicated",
"in",
"MVB",
"cargo",
"selection",
"(Katzmann",
"et",
"al.,",
"2001;",
"Alam",
"et",
"al.,",
"2004;",
"Slagsvold",
"et",
"al.,",
"2005).",
"This",
"had",
"led",
"to",
"a",
"model",
"in",
"which",
"Ub",
"cargo",
"is",
"passed",
"sequentially",
"from",
"S.B.",
"Shields",
"and",
"A.J.",
"Oestreich",
"contributed",
"equally",
"to",
"this",
"paper.",
"Correspondence",
"to",
"David",
"J.",
"Katzmann:",
"katzmann.david@mayo.edu;",
"or",
"Robert",
"Piper:",
"Robert-piper@uiowa.edu",
"Abbreviations",
"used",
"in",
"this",
"paper:",
"CPY,",
"carboxypeptidase",
"Y;",
"ESCRT,",
"endosomal",
"sorting",
"complexes",
"required",
"for",
"transport;",
"DIC,",
"differential",
"interference",
"contrast;",
"HSQC,",
"heteronuclear",
"single",
"quantum",
"coherence;",
"MVB,",
"multivesicular",
"body;",
"NMR,",
"nuclear",
"magnetic",
"resonance;",
"NZF,",
"Npl4",
"zinc",
"finger;",
"TAP,",
"tandem",
"affinity",
"purification;",
"Ub,",
"ubiquitin;",
"UBD,",
"Ub-binding",
"domain;",
"UEV,",
"Ub",
"E2",
"variant;",
"UIM,",
"Ub-interacting",
"motif.",
"The",
"Rockefeller",
"University",
"Press",
"$30.00",
"J.",
"Cell",
"Biol.",
"Vol.",
"185",
"No.",
"2",
"213–224",
"www.jcb.org/cgi/doi/10.1083/jcb.200811130",
"ESCRT-0",
"to",
"ESCRT-I",
"and",
"to",
"ESCRT-II",
"for",
"final",
"deposit",
"into",
"the",
"forming",
"lumenal",
"vesicles",
"(Katzmann",
"et",
"al.,",
"2002;",
"Gruenberg",
"and",
"Stenmark,",
"2004;",
"Hurley,",
"2008).",
"Previous",
"studies",
"have",
"indi-",
"cated",
"the",
"importance",
"of",
"these",
"UBDs",
"during",
"MVB",
"sorting;",
"how-",
"ever,",
"recent",
"high",
"resolution",
"structures",
"that",
"detail",
"Ub",
"interactions",
"have",
"enabled",
"a",
"more",
"precise",
"approach",
"to",
"dissect",
"the",
"contri-",
"butions",
"of",
"these",
"UBDs",
"to",
"MVB",
"sorting",
"(Alam",
"et",
"al.,",
"2004,",
"2006;",
"Sundquist",
"et",
"al.,",
"2004;",
"Teo",
"et",
"al.,",
"2004;",
"Hirano",
"et",
"al.,",
"2006).",
"Surprisingly,",
"we",
"found",
"that",
"mutant",
"forms",
"of",
"Vps23",
"and",
"Vps36",
"unable",
"to",
"bind",
"Ub",
"had",
"no",
"defects",
"in",
"MVB",
"sorting,",
"even",
"in",
"combi-",
"nation.",
"This",
"led",
"us",
"to",
"search",
"for",
"additional",
"UBDs",
"within",
"ESCRT-I",
"and",
"resulted",
"in",
"the",
"discovery",
"of",
"a",
"novel",
"UBD",
"within",
"Mvb12.",
"The",
"UBD",
"of",
"Mvb12",
"works",
"in",
"concert",
"with",
"the",
"UBDs",
"of",
"the",
"ESCRTs",
"to",
"promote",
"cargo",
"recognition",
"and",
"MVB",
"sorting.",
"Results",
"and",
"discussion",
"Mutants",
"of",
"Vps23",
"and",
"Vps36",
"defective",
"for",
"Ub",
"binding",
"Cocrystal",
"structures",
"of",
"Ub",
"with",
"the",
"UEV",
"domains",
"of",
"Vps23",
"and",
"TSG101",
"were",
"used",
"to",
"guide",
"mutagenesis",
"experiments",
"rendering",
"Vps23",
"unable",
"to",
"bind",
"Ub",
"(Sundquist",
"et",
"al.,",
"2004;",
"Teo",
"et",
"al.",
"2004).",
"The",
"structures",
"show",
"that",
"the",
"UEV",
"domains",
"bind",
"to",
"Ub",
"via",
"a",
"",
"hairpin",
"tongue",
"and",
"a",
"lip",
"(Fig.",
"1",
"A).",
"The",
"structure",
"of",
"the",
"©",
"2009",
"Shields",
"et",
"al.",
"This",
"article",
"is",
"distributed",
"under",
"the",
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] | [
"Ngan",
"et",
"al.",
"BMC",
"Pulmonary",
"Medicine",
"2012,",
"12:3",
"http://www.biomedcentral.com/1471-2466/12/3",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"The",
"relationship",
"of",
"systemic",
"inflammation",
"to",
"prior",
"hospitalization",
"in",
"adult",
"patients",
"with",
"cystic",
"fibrosis",
"David",
"A",
"Ngan,",
"Pearce",
"G",
"Wilcox,",
"May",
"Aldaabil,",
"Yuexin",
"Li,",
"Jonathon",
"A",
"Leipsic,",
"Don",
"D",
"Sin",
"and",
"SF",
"Paul",
"Man*",
"Abstract",
"Background:",
"In",
"cystic",
"fibrosis",
"(CF)",
"patients,",
"it",
"has",
"been",
"suggested",
"that",
"systemic",
"inflammation",
"may",
"be",
"an",
"important",
"risk",
"factor",
"for",
"poor",
"health",
"outcomes.",
"The",
"relationship",
"of",
"plasma",
"inflammatory",
"biomarkers",
"to",
"lung",
"function",
"and",
"hospitalization",
"history",
"remains",
"largely",
"unexplored.",
"Methods:",
"This",
"cross-sectional",
"study",
"included",
"58",
"consecutive,",
"clinically",
"stable",
"adults",
"from",
"the",
"CF",
"Clinic",
"at",
"St.",
"Paul’s",
"Hospital",
"(Vancouver,",
"Canada).",
"Blood",
"levels",
"of",
"interleukin",
"(IL)-6,",
"IL-1b,",
"C-reactive",
"protein",
"(CRP),",
"interleukin",
"(IL)-6,",
"IL-",
"1b,",
"granzyme",
"B",
"(GzmB),",
"chemokine",
"C-C",
"motif",
"ligand",
"18",
"(CCL18/PARC),",
"surfactant",
"protein",
"D",
"(SP-D),",
"lipopolysaccharide",
"(LPS)-binding",
"protein,",
"and",
"soluble",
"cluster",
"of",
"differentiation",
"14",
"(sCD14)",
"were",
"measured",
"using",
"enzyme-linked",
"immunosorbent",
"assays,",
"and",
"LPS",
"levels",
"were",
"measured",
"using",
"a",
"Limulus",
"amebocyte",
"lysate",
"assay.",
"Spirometry",
"was",
"also",
"performed.",
"Multivariable",
"linear",
"regression",
"analysis",
"was",
"used",
"to",
"assess",
"relationships",
"of",
"the",
"blood",
"biomarkers",
"to",
"lung",
"function.",
"Results:",
"Lung",
"function",
"impairment",
"was",
"independently",
"associated",
"with",
"elevated",
"plasma",
"levels",
"of",
"CRP",
"(P",
"<",
"0.01),",
"IL-",
"6",
"(P",
"=",
"0.04),",
"IL-1b",
"(P",
"<",
"0.01),",
"and",
"LBP",
"(P",
"<",
"0.01).",
"Increasing",
"age",
"(P",
"<",
"0.01),",
"reduced",
"body",
"mass",
"index",
"(P",
"=",
"0.02),",
"prior",
"hospitalizations",
"(P",
"=",
"0.03),",
"and",
"presence",
"of",
"Pseudomonas",
"aeruginosa",
"in",
"sputum",
"cultures",
"(P",
"<",
"0.01)",
"were",
"also",
"associated",
"with",
"reduced",
"lung",
"function.",
"Elevated",
"concentrations",
"of",
"LPS",
"in",
"plasma",
"were",
"associated",
"with",
"a",
"previous",
"history",
"of",
"hospitalization",
"(P",
"<",
"0.05).",
"There",
"was",
"a",
"trend",
"towards",
"an",
"increase",
"in",
"plasma",
"IL-6",
"(P",
"=",
"0.07)",
"and",
"IL-1b",
"(P",
"=",
"0.06)",
"levels",
"in",
"patients",
"who",
"were",
"previously",
"hospitalized.",
"Conclusions:",
"IL-6",
"and",
"IL-1b",
"are",
"promising",
"systemic",
"biomarkers",
"for",
"lung",
"function",
"impairment",
"and",
"history",
"of",
"hospitalization",
"in",
"adult",
"patients",
"with",
"CF.",
"Background",
"Cystic",
"fibrosis",
"(CF)",
"is",
"a",
"progressive,",
"debilitating",
"disease",
"that",
"affects",
"nearly",
"30,000",
"Americans",
"and",
"occurs",
"with",
"a",
"frequency",
"of",
"about",
"1",
"in",
"3500",
"births",
"[1].",
"It",
"is",
"character-",
"ized",
"by",
"persistent",
"lung",
"infection",
"and",
"lung",
"function",
"impairment.",
"It",
"also",
"affects",
"other",
"organs",
"including",
"the",
"sinuses,",
"gastrointestinal",
"tract,",
"endocrine",
"glands,",
"and",
"the",
"bone",
"[2-5].",
"Although",
"all",
"CF",
"cases",
"are",
"caused",
"by",
"a",
"muta-",
"tion",
"in",
"the",
"gene",
"for",
"the",
"CF",
"transmembrane",
"conductance",
"regulator,",
"there",
"is",
"considerable",
"heterogeneity",
"in",
"the",
"rate",
"at",
"which",
"the",
"disease",
"progresses",
"[6].",
"The",
"traditional",
"risk",
"factors",
"for",
"rapid",
"progression",
"include",
"reduced",
"body",
"mass",
"*",
"Correspondence:",
"pman@providencehealth.bc.ca",
"UBC",
"James",
"Hogg",
"Research",
"Centre,",
"Institute",
"for",
"Heart",
"+",
"Lung",
"Health",
"at",
"St.",
"Paul’s",
"Hospital",
"and",
"Department",
"of",
"Medicine,",
"University",
"of",
"British",
"Columbia,",
"Vancouver,",
"BC,",
"Canada",
"index,",
"colonization",
"of",
"the",
"airways",
"with",
"pathogenic",
"bac-",
"teria",
"such",
"as",
"Pseudomonas",
"aeruginosa,",
"and",
"female",
"sex",
"[7-9].",
"More",
"recently,",
"some",
"have",
"suggested",
"that",
"systemic",
"inflammation",
"may",
"be",
"another",
"important",
"risk",
"factor",
"for",
"poor",
"health",
"outcomes",
"in",
"CF",
"independent",
"of",
"these",
"tradi-",
"tional",
"risk",
"factors",
"[3,8,10,11].",
"However,",
"the",
"studies",
"that",
"have",
"evaluated",
"this",
"issue",
"have",
"produced",
"inconsistent",
"results",
"and",
"have",
"measured",
"different",
"components",
"of",
"the",
"immune",
"system,",
"making",
"cross",
"comparisons",
"difficult.",
"Moreover,",
"none",
"of",
"these",
"studies",
"have",
"evaluated",
"these",
"biomarkers",
"on",
"hard",
"clinical",
"outcomes",
"such",
"as",
"exacerba-",
"tions",
"or",
"hospitalizations,",
"which",
"are",
"important",
"endpoints",
"in",
"CF.",
"In",
"this",
"study,",
"we",
"determined",
"the",
"relationship",
"of",
"plasma",
"inflammatory",
"biomarkers",
"to",
"lung",
"function",
"and",
"hospitalization",
"history",
"in",
"adult",
"patients",
"with",
"CF.",
"The",
"plasma",
"biomarkers",
"were",
"carefully",
"chosen",
"to",
"represent",
"©",
"2012",
"Ngan",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
] | [
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] | [
"R",
"E",
"V",
"I",
"E",
"W",
"Carotid",
"ultrasound",
"assessment",
"of",
"patients",
"with",
"coronar",
"y",
"ar",
"ter",
"y",
"disease:",
"a",
"useful",
"index",
"for",
"risk",
"stratification",
"Roman",
"Komorovsky",
"Alessandro",
"Desideri",
"Cardiovascular",
"Research",
"Foundation,",
"S",
"Giacomo",
"Hospital,",
"Castelfranco",
"Veneto,",
"Italy",
"Correspondence:",
"Roman",
"Komorovsky",
"Cardiovascular",
"Research",
"Foundation,",
"Ospedale",
"S",
"Giacomo,",
"31033",
"Castelfranco",
"Veneto",
"(TV),",
"Italy",
"Tel",
"+39",
"0423",
"732",
"306",
"Fax",
"+39",
"0423",
"732",
"301",
"Email",
"roman_komor@yahoo.com",
"Abstract:",
"Carotid",
"disease",
"is",
"a",
"common",
"finding",
"in",
"patients",
"with",
"coronary",
"artery",
"disease",
"(CAD)",
"and",
"its",
"presence",
"is",
"associated",
"with",
"worse",
"clinical",
"outcomes.",
"Intima-media",
"thickness",
"provides",
"incremental",
"value",
"over",
"traditional",
"risk",
"factors",
"in",
"predicting",
"cardiovascular",
"events;",
"however,",
"it",
"does",
"not",
"predict",
"the",
"absence",
"of",
"CAD",
"or",
"its",
"extent",
"and",
"severity.",
"The",
"presence",
"of",
"carotid",
"plaques",
"is",
"associated",
"with",
"an",
"increased",
"risk",
"of",
"cardiovascular",
"events",
"in",
"patients",
"with",
"CAD",
"regardless",
"of",
"the",
"treatment",
"strategy",
"(medical",
"therapy",
"alone",
"or",
"myocardial",
"revascularization).",
"Hence,",
"we",
"advocate",
"the",
"screening",
"of",
"patients",
"with",
"diagnosed",
"CAD",
"for",
"carotid",
"atherosclerosis.",
"The",
"prognostic",
"impact",
"of",
"ultrasound",
"characteristics",
"of",
"carotid",
"plaques",
"on",
"cardiovascular",
"outcomes",
"of",
"patients",
"with",
"CAD",
"remains",
"controversial.",
"Keywords:",
"intima-media",
"thickness,",
"carotid",
"plaques,",
"coronary",
"artery",
"disease,",
"ultrasound",
"Introduction",
"The",
"coexistence",
"of",
"carotid",
"and",
"coronary",
"artery",
"disease",
"(CAD)",
"is",
"a",
"challenge",
"to",
"cardiologists,",
"vascular",
"and",
"cardiothoracic",
"surgeons,",
"and",
"neurologists.",
"Patients",
"with",
"coexistent",
"narrowing",
"of",
"carotid",
"and",
"coronary",
"arteries",
"represent",
"a",
"particularly",
"high-",
"risk",
"group",
"and",
"to",
"date",
"there",
"has",
"been",
"no",
"consensus",
"with",
"regard",
"to",
"their",
"management.",
"Carotid",
"endarterectomy",
"in",
"these",
"patients",
"is",
"associated",
"with",
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"2004;",
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"al",
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"al",
"2000).",
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"and",
"an",
"increased",
"risk",
"of",
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"events.",
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"and",
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"Management",
"2005:1(2)",
"131–136",
"©",
"2005",
"Dove",
"Medical",
"Press",
"Limited.",
"All",
"rights",
"reserved",
"131"
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"aLaborato´",
"rio",
"de",
"Qu´ımica",
"Farmaceˆutica,",
"Faculdade",
"de",
"Farma´cia,",
"Universidade",
"de",
"Coimbra,",
"Po´",
"lo",
"das",
"Cieˆncias",
"da",
"Sau´",
"de,",
"Azinhaga",
"de",
"Santa",
"Comba,",
"P-3000-548",
"Coimbra,",
"Portugal,",
"and",
"bCEMDRX,",
"Departamento",
"de",
"F´ısica,",
"Faculdade",
"de",
"Cieˆncias",
"e",
"Tecnologia,",
"Universidade",
"de",
"Coimbra,",
"P-3004-516",
"Coimbra,",
"Portugal",
"Correspondence",
"e-mail:",
"jap@pollux.fis.uc.pt",
"Received",
"15",
"July",
"2010;",
"accepted",
"20",
"July",
"2010",
"Key",
"indicators:",
"single-crystal",
"X-ray",
"study;",
"T",
"=",
"295",
"K;",
"mean",
"(C–C)",
"=",
"0.005",
"A˚;",
"R",
"factor",
"=",
"0.042;",
"wR",
"factor",
"=",
"0.100;",
"data-to-parameter",
"ratio",
"=",
"8.3.",
"The",
"title",
"terpene,",
"C30H46O3,",
"is",
"a",
"28,13",
"-lactone",
"of",
"oleanolic",
"acid",
"prepared",
"with",
"bismuth",
"trifluoromethanesulfonate",
"(OTf),",
"Bi(OTf)3",
"xH2O.",
"All",
"rings",
"are",
"trans-fused.",
"The",
"X-ray",
"study",
"shows",
"the",
"inversion",
"of",
"the",
"orientation",
"of",
"18-H",
"in",
"the",
"lactonization",
"reaction.",
"A",
"quantum",
"chemical",
"ab-initio",
"Roothaan",
"Hartree–Fock",
"calculation",
"of",
"the",
"equilibrium",
"geometry",
"of",
"the",
"isolated",
"molecule",
"gives",
"values",
"for",
"bond",
"lengths",
"and",
"valency",
"angles",
"in",
"close",
"agreement",
"with",
"experi-",
"mental",
"values.",
"The",
"calculation",
"also",
"reproduces",
"the",
"observed",
"molecular",
"conformation,",
"with",
"puckering",
"parameters",
"that",
"agree",
"well",
"with",
"those",
"determined",
"from",
"the",
"crystallographic",
"study.",
"Related",
"literature",
"For",
"general",
"background",
"to",
"the",
"use",
"of",
"natural",
"products",
"as",
"sources",
"of",
"anticancer",
"drugs,",
"see:",
"Koehn",
"&",
"Carter",
"(2005).",
"For",
"the",
"biological",
"activity",
"of",
"oleanolic",
"acid,",
"see:",
"Ringbom",
"et",
"al.",
"(1998);",
"Ma",
"et",
"al.",
"(2000);",
"Tokuda",
"et",
"al.",
"(1986);",
"Horiuchi",
"et",
"al.",
"(2007);",
"Lee",
"et",
"al.",
"(1994);",
"Sohn",
"et",
"al.",
"(1995).",
"For",
"the",
"biosyn-",
"thesis",
"of",
"pentacyclic",
"triterpenoids,",
"see:",
"Gershenzon",
"&",
"Dudareva",
"(2007);",
"Salvador",
"(2010);",
"Dzubak",
"et",
"al.",
"(2006).",
"For",
"the",
"lactonization",
"reaction",
"of",
"oleanane-type",
"triterpenoids,",
"see:",
"Cheriti",
"et",
"al.",
"(1994).",
"For",
"the",
"synthesis",
"of",
"the",
"title",
"compound,",
"see:",
"Salvador",
"et",
"al.",
"(2009).",
"For",
"related",
"structures,",
"see:",
"Eggle-",
"ston",
"(1987);",
"Chang",
"et",
"al.",
"(1982);",
"Sutthivaiyakit",
"et",
"al.",
"(2001);",
"Wang",
"et",
"al.",
"(2006).",
"For",
"puckering",
"and",
"asymmetry",
"parameters,",
"see:",
"Cremer",
"&",
"Pople",
"(1975);",
"Duax",
"&",
"Norton",
"(1975).",
"The",
"quantum",
"chemical",
"calculations",
"were",
"performed",
"with",
"the",
"computer",
"program",
"GAMESS",
"(Schmidt",
"et",
"al.,",
"1993).",
"organic",
"compounds",
"Experimental",
"Crystal",
"data",
"C30H46O3",
"Mr",
"=",
"454.67",
"Monoclinic,",
"P21",
"a",
"=",
"6.7789",
"(3)",
"A˚",
"b",
"=",
"12.3122",
"(6)",
"A˚",
"c",
"=",
"15.4524",
"(7)",
"A˚",
"=",
"99.644",
"(2)",
"Data",
"collection",
"Bruker",
"APEXII",
"CCD",
"area-detector",
"diffractometer",
"Absorption",
"correction:",
"multi-scan",
"(SADABS;",
"Sheldrick,",
"2000)",
"Tmin",
"=",
"0.746,",
"Tmax",
"=",
"1.0",
"Refinement",
"R[F",
"2",
">",
"2",
"(F",
"2)]",
"=",
"0.042",
"wR(F",
"2)",
"=",
"0.100",
"S",
"=",
"1.08",
"2536",
"reflections",
"305",
"parameters",
"V",
"=",
"1271.48",
"(10)",
"A˚3",
"Z",
"=",
"2",
"Mo",
"K",
"radiation",
"=",
"0.07",
"mm",
"1",
"T",
"=",
"295",
"K",
"0.45",
"0.17",
"0.04",
"mm",
"16467",
"measured",
"reflections",
"2536",
"independent",
"reflections",
"1805",
"reflections",
"with",
"I",
">",
"2",
"(I)",
"Rint",
"=",
"0.057",
"1",
"restraint",
"H-atom",
"parameters",
"constrained",
"max",
"=",
"0.14",
"e",
"A˚",
"3",
"min",
"=",
"0.17",
"e",
"A˚",
"3",
"Data",
"collection:",
"APEX2",
"(Bruker,",
"2006);",
"cell",
"refinement:",
"SAINT",
"(Bruker,",
"2006);",
"data",
"reduction:",
"SAINT;",
"program(s)",
"used",
"to",
"solve",
"structure:",
"SHELXS97",
"(Sheldrick,",
"2008);",
"program(s)",
"used",
"to",
"refine",
"structure:",
"SHELXL97",
"(Sheldrick,",
"2008);",
"molecular",
"graphics:",
"PLATON",
"(Spek,",
"2009);",
"software",
"used",
"to",
"prepare",
"material",
"for",
"publication:",
"SHELXL97.",
"This",
"work",
"was",
"supported",
"by",
"the",
"Fundac¸a˜",
"o",
"para",
"a",
"Ci",
"eˆncia",
"e",
"Tecnologia.",
"RCS",
"(SFRH/BD/23700/2005)",
"and",
"RMAP",
"(SFRH/",
"BD/18013/2004)",
"thank",
"the",
"FCT",
"for",
"grants.",
"We",
"gratefully",
"acknowledge",
"LCA–UC",
"for",
"the",
"grant",
"of",
"computer",
"time",
"in",
"the",
"Milipeia",
"cluster",
"and",
"Mr",
"Carlos",
"Pereira",
"for",
"help",
"in",
"the",
"analysis",
"of",
"the",
"output",
"of",
"the",
"GAMESS",
"code.",
"Supplementary",
"data",
"and",
"figures",
"for",
"this",
"paper",
"are",
"available",
"from",
"the",
"IUCr",
"electronic",
"archives",
"(Reference:",
"RK2222).",
"References",
"Bruker",
"(2006).",
"APEX2",
"and",
"SAINT.",
"Bruker",
"AXS",
"Inc.,",
"Madison,",
"Wisconsin,",
"USA.",
"Chang,",
"H.-M.,",
"Chiang,",
"T.-C.",
"&",
"Mak,",
"T.",
"C.",
"W.",
"(1982).",
"Chem.",
"Commun.",
"pp.",
"1197–1198.",
"Cheriti,",
"A.,",
"Babadjamian,",
"A.",
"&",
"Balansard,",
"G.",
"(1994).",
"J.",
"Nat.",
"Prod.",
"57,",
"1160–",
"1163.",
"Acta",
"Cryst.",
"(2010).",
"E66,",
"o2139–o2140",
"doi:10.1107/S160053681002903X",
"Santos",
"et",
"al.",
"o2139"
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] | [
"JCB:",
"ARTICLE",
"Neural",
"crest",
"stem",
"cell",
"maintenance",
"by",
"combinatorial",
"Wnt",
"and",
"BMP",
"signaling",
"Maurice",
"Kléber,1",
"Hye-Youn",
"Lee,1",
"Heiko",
"Wurdak,1",
"Johanna",
"Buchstaller,1",
"Martin",
"M.",
"Riccomagno,2",
"Lars",
"M.",
"Ittner,3",
"Ueli",
"Suter,1",
"Douglas",
"J.",
"Epstein,2",
"and",
"Lukas",
"Sommer1",
"1Institute",
"of",
"Cell",
"Biology,",
"Department",
"of",
"Biology,",
"Swiss",
"Federal",
"Institute",
"of",
"Technology,",
"ETH-Hönggerberg,",
"CH-8093",
"Zurich,",
"Switzerland",
"2Department",
"of",
"Genetics,",
"University",
"of",
"Pennsylvania",
"School",
"of",
"Medicine,",
"Philadelphia,",
"PA",
"19104",
"3Research",
"Laboratory",
"for",
"Calcium",
"Metabolism,",
"University",
"Hospital",
"Balgrist,",
"University",
"of",
"Zurich,",
"CH-8008",
"Zurich,",
"Switzerland",
"Y",
"G",
"O",
"L",
"O",
"I",
"B",
"L",
"L",
"E",
"C",
"F",
"O",
"L",
"A",
"N",
"R",
"U",
"O",
"J",
"E",
"H",
"T",
"C",
"sensory",
"anonical",
"neurogenesis",
"Wnt",
"signaling",
"in",
"early",
"instructively",
"neural",
"crest",
"promotes",
"stem",
"cells",
"(eNCSCs)",
"(Lee,",
"H.Y.,",
"M.",
"Kléber,",
"L.",
"Hari,",
"V.",
"Brault,",
"U.",
"Suter,",
"M.M.",
"Taketo,",
"R.",
"Kemler,",
"and",
"L.",
"Sommer.",
"2004.",
"Science.",
"303:1020–1023).",
"However,",
"during",
"nor-",
"mal",
"development",
"Wnt",
"signaling",
"induces",
"a",
"sensory",
"fate",
"only",
"in",
"a",
"subpopulation",
"of",
"eNCSCs",
"while",
"other",
"cells",
"maintain",
"their",
"stem",
"cell",
"features,",
"despite",
"the",
"presence",
"of",
"Wnt",
"activity.",
"Hence,",
"factors",
"counteracting",
"Wnt",
"signaling",
"must",
"exist.",
"Here,",
"we",
"show",
"that",
"bone",
"morphogenic",
"protein",
"Introduction",
"Because",
"of",
"its",
"broad",
"developmental",
"potential,",
"the",
"neural",
"crest",
"represents",
"an",
"ideal",
"model",
"system",
"to",
"study",
"stem",
"cell",
"biology.",
"Neural",
"crest",
"cells",
"delaminate",
"from",
"the",
"developing",
"dorsal",
"neural",
"tube,",
"migrate",
"to",
"various",
"locations",
"within",
"the",
"embryo,",
"and",
"gen-",
"erate",
"multiple",
"neural",
"cell",
"types",
"of",
"the",
"vertebrate",
"peripheral",
"ner-",
"vous",
"system",
"(PNS)",
"as",
"well",
"as",
"several",
"nonneural",
"tissues",
"(Le",
"Douarin",
"and",
"Dupin,",
"2003).",
"At",
"least",
"some",
"neural",
"crest",
"cells",
"are",
"multipotent,",
"giving",
"rise",
"to",
"neuronal,",
"glial,",
"and",
"nonneural",
"deriv-",
"atives,",
"as",
"has",
"been",
"shown",
"by",
"clonal",
"analysis",
"in",
"culture",
"and",
"in",
"vivo.",
"Moreover,",
"some",
"crest",
"cells",
"have",
"features",
"of",
"stem",
"cells",
"with",
"the",
"capacity",
"to",
"self-renew.",
"Both",
"in",
"migrating",
"neural",
"crest",
"and",
"in",
"crest-derived",
"tissues,",
"such",
"multipotent",
"stem",
"and",
"progen-",
"itor",
"cells",
"coexist",
"with",
"cells",
"that",
"display",
"more",
"restricted",
"devel-",
"opmental",
"potential.",
"Recently",
"we",
"have",
"described",
"an",
"early",
"population",
"of",
"neural",
"crest",
"stem",
"cells",
"(eNCSCs)",
"that",
"is",
"highly",
"homogeneous",
"with",
"respect",
"to",
"marker",
"expression",
"and",
"the",
"potential",
"to",
"generate",
"au-",
"tonomic",
"and",
"sensory",
"neurons,",
"glia,",
"and",
"smooth",
"muscle",
"cells",
"(Lee",
"et",
"al.,",
"2004).",
"Clonal",
"cell",
"culture",
"experiments",
"revealed",
"the",
"responsiveness",
"of",
"these",
"cells",
"to",
"several",
"instructive",
"growth",
"Correspondence",
"to",
"Lukas",
"Sommer:",
"sommer@cell.biol.ethz.ch",
"Abbreviations",
"used",
"in",
"this",
"paper:",
"BMP,",
"bone",
"morphogenic",
"protein;",
"DRG,",
"dorsal",
"root",
"ganglia;",
"eNCSC,",
"early",
"neural",
"crest",
"stem",
"cell;",
"GFAP,",
"glial",
"fibrillary",
"acidic",
"protein;",
"NCSC,",
"neural",
"crest",
"stem",
"cell;",
"NF,",
"neurofilament;",
"NRG,",
"neuregulin;",
"PNS,",
"peripheral",
"nervous",
"system;",
"SMA,",
"smooth",
"muscle",
"actin.",
"©",
"The",
"Rockefeller",
"University",
"Press",
"$8.00",
"The",
"Journal",
"of",
"Cell",
"Biology,",
"Vol.",
"169,",
"No.",
"2,",
"April",
"25,",
"2005",
"309–320",
"http://www.jcb.org/cgi/doi/10.1083/jcb.200411095",
"(BMP)",
"signaling",
"antagonizes",
"the",
"sensory",
"fate-inducing",
"activity",
"of",
"Wnt/",
"-catenin.",
"Intriguingly,",
"Wnt",
"and",
"BMP",
"act",
"synergistically",
"to",
"suppress",
"differentiation",
"and",
"to",
"maintain",
"NCSC",
"marker",
"expression",
"and",
"multipotency.",
"Similar",
"to",
"NCSCs",
"in",
"vivo,",
"NCSCs",
"maintained",
"in",
"culture",
"alter",
"their",
"responsiveness",
"to",
"instructive",
"growth",
"factors",
"with",
"time.",
"Thus,",
"stem",
"cell",
"development",
"is",
"regulated",
"by",
"combinatorial",
"growth",
"factor",
"activities",
"that",
"interact",
"with",
"changing",
"cell-",
"intrinsic",
"cues.",
"factors",
"that",
"promote",
"the",
"generation",
"of",
"specific",
"cell",
"fates",
"at",
"the",
"expense",
"of",
"other",
"possible",
"fates.",
"These",
"factors",
"include",
"members",
"of",
"the",
"TGF",
"factor",
"family",
"that",
"promote",
"autonomic",
"neuro-",
"genesis",
"and",
"the",
"development",
"of",
"smooth",
"muscle–like",
"cells,",
"neuregulin1",
"(NRG1)",
"isoforms",
"that",
"induce",
"the",
"generation",
"of",
"pe-",
"ripheral",
"glia,",
"and",
"Wnt",
"signaling",
"that",
"promotes",
"sensory",
"neuro-",
"genesis",
"in",
"a",
"-catenin–dependent",
"manner",
"(Le",
"Douarin",
"and",
"Dupin,",
"2003;",
"Kléber",
"and",
"Sommer,",
"2004).",
"In",
"vivo",
"and",
"in",
"cell",
"cul-",
"ture,",
"eNCSCs",
"that",
"lack",
"the",
"Wnt",
"signaling",
"component",
"-catenin",
"fail",
"to",
"generate",
"sensory",
"neurons",
"(Hari",
"et",
"al.,",
"2002).",
"Comple-",
"mentary",
"to",
"this,",
"embryos",
"that",
"express",
"a",
"constitutively",
"active",
"form",
"of",
"-catenin",
"specifically",
"in",
"NCSCs",
"generate",
"almost",
"ex-",
"clusively",
"sensory",
"neural",
"cells",
"at",
"the",
"expense",
"of",
"other",
"possible",
"neural",
"crest–derived",
"lineages",
"(Lee",
"et",
"al.,",
"2004).",
"Thus,",
"unlike",
"in",
"other",
"stem",
"cell",
"types,",
"canonical",
"Wnt",
"signaling",
"on",
"its",
"own",
"does",
"not",
"support",
"stem",
"cell",
"expansion",
"in",
"NCSCs,",
"but",
"rather",
"promotes",
"sensory",
"neurogenesis.",
"So",
"far,",
"the",
"signals",
"supporting",
"NCSC",
"maintenance",
"and",
"self-renewal",
"have",
"not",
"been",
"identified,",
"al-",
"though",
"it",
"has",
"been",
"possible",
"to",
"passage",
"both",
"migratory",
"and",
"postmigratory",
"NCSCs",
"for",
"some",
"generations",
"in",
"a",
"nondefined",
"medium",
"(Stemple",
"and",
"Anderson,",
"1992;",
"Bixby",
"et",
"al.,",
"2002).",
"Given",
"the",
"expression",
"of",
"Wnts",
"in",
"the",
"dorsal",
"neural",
"tube",
"at",
"the",
"time",
"of",
"neural",
"crest",
"emigration",
"and",
"the",
"sensitivity",
"of",
"almost",
"all",
"eNCSCs",
"to",
"Wnt",
"signaling",
"(Parr",
"et",
"al.,",
"1993;",
"Lee",
"et",
"al.,",
"2004),",
"the",
"question",
"arises",
"as",
"to",
"why",
"during",
"normal",
"development",
"only",
"JCB",
"309"
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] | [
"Natarajan",
"et",
"al.",
"BMC",
"Genomics",
"2010,",
"11:606",
"http://www.biomedcentral.com/1471-2164/11/606",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"Gene",
"discovery",
"from",
"Jatropha",
"curcas",
"by",
"sequencing",
"of",
"ESTs",
"from",
"normalized",
"and",
"full-length",
"enriched",
"cDNA",
"library",
"from",
"developing",
"seeds",
"Purushothaman",
"Natarajan,",
"Deepa",
"Kanagasabapathy,",
"Gnanasekaran",
"Gunadayalan,",
"Jasintha",
"Panchalingam,",
"Noopur",
"shree,",
"Priyanka",
"Annabel",
"Sugantham,",
"Kavita",
"Kumari",
"Singh,",
"Parani",
"Madasamy*",
"Abstract",
"Background:",
"Jatropha",
"curcas",
"L.",
"is",
"promoted",
"as",
"an",
"important",
"non-edible",
"biodiesel",
"crop",
"worldwide.",
"Jatropha",
"oil,",
"which",
"is",
"a",
"triacylglycerol,",
"can",
"be",
"directly",
"blended",
"with",
"petro-diesel",
"or",
"transesterified",
"with",
"methanol",
"and",
"used",
"as",
"biodiesel.",
"Genetic",
"improvement",
"in",
"jatropha",
"is",
"needed",
"to",
"increase",
"the",
"seed",
"yield,",
"oil",
"content,",
"drought",
"and",
"pest",
"resistance,",
"and",
"to",
"modify",
"oil",
"composition",
"so",
"that",
"it",
"becomes",
"a",
"technically",
"and",
"economically",
"preferred",
"source",
"for",
"biodiesel",
"production.",
"However,",
"genetic",
"improvement",
"efforts",
"in",
"jatropha",
"could",
"not",
"take",
"advantage",
"of",
"genetic",
"engineering",
"methods",
"due",
"to",
"lack",
"of",
"cloned",
"genes",
"from",
"this",
"species.",
"To",
"overcome",
"this",
"hurdle,",
"the",
"current",
"gene",
"discovery",
"project",
"was",
"initiated",
"with",
"an",
"objective",
"of",
"isolating",
"as",
"many",
"functional",
"genes",
"as",
"possible",
"from",
"J.",
"curcas",
"by",
"large",
"scale",
"sequencing",
"of",
"expressed",
"sequence",
"tags",
"(ESTs).",
"Results:",
"A",
"normalized",
"and",
"full-length",
"enriched",
"cDNA",
"library",
"was",
"constructed",
"from",
"developing",
"seeds",
"of",
"J.",
"curcas.",
"The",
"cDNA",
"library",
"contained",
"about",
"1",
"×",
"106",
"clones",
"and",
"average",
"insert",
"size",
"of",
"the",
"clones",
"was",
"2.1",
"kb.",
"Totally",
"12,084",
"ESTs",
"were",
"sequenced",
"to",
"average",
"high",
"quality",
"read",
"length",
"of",
"576",
"bp.",
"Contig",
"analysis",
"revealed",
"2258",
"contigs",
"and",
"4751",
"singletons.",
"Contig",
"size",
"ranged",
"from",
"2-23",
"and",
"there",
"were",
"7333",
"ESTs",
"in",
"the",
"contigs.",
"This",
"resulted",
"in",
"7009",
"unigenes",
"which",
"were",
"annotated",
"by",
"BLASTX.",
"It",
"showed",
"3982",
"unigenes",
"with",
"significant",
"similarity",
"to",
"known",
"genes",
"and",
"2836",
"unigenes",
"with",
"significant",
"similarity",
"to",
"genes",
"of",
"unknown,",
"hypothetical",
"and",
"putative",
"proteins.",
"The",
"remaining",
"191",
"unigenes",
"which",
"did",
"not",
"show",
"similarity",
"with",
"any",
"genes",
"in",
"the",
"public",
"database",
"may",
"encode",
"for",
"unique",
"genes.",
"Functional",
"classification",
"revealed",
"unigenes",
"related",
"to",
"broad",
"range",
"of",
"cellular,",
"molecular",
"and",
"biological",
"functions.",
"Among",
"the",
"7009",
"unigenes,",
"6233",
"unigenes",
"were",
"identified",
"to",
"be",
"potential",
"full-length",
"genes.",
"Conclusions:",
"The",
"high",
"quality",
"normalized",
"cDNA",
"library",
"was",
"constructed",
"from",
"developing",
"seeds",
"of",
"J.",
"curcas",
"for",
"the",
"first",
"time",
"and",
"7009",
"unigenes",
"coding",
"for",
"diverse",
"biological",
"functions",
"including",
"oil",
"biosynthesis",
"were",
"identified.",
"These",
"genes",
"will",
"serve",
"as",
"invaluable",
"genetic",
"resource",
"for",
"crop",
"improvement",
"in",
"jatropha",
"to",
"make",
"it",
"an",
"ideal",
"and",
"profitable",
"crop",
"for",
"biodiesel",
"production.",
"Background",
"Jatropha",
"curcas",
"L.,",
"one",
"of",
"the",
"175",
"species",
"in",
"genus",
"Jatropha",
"of",
"the",
"family",
"Euphorbiaceae",
"is",
"a",
"perennial",
"small",
"tree",
"or",
"large",
"shrub",
"native",
"to",
"tropical",
"America",
"and",
"is",
"distributed",
"throughout",
"the",
"tropics",
"and",
"subtropics",
"of",
"Asia",
"and",
"Africa",
"[1].",
"Recently,",
"jatropha",
"oil",
"is",
"promoted",
"as",
"alternative",
"transport",
"fuel",
"which",
"can",
"be",
"directly",
"blended",
"with",
"petro-diesel",
"or",
"transesterified",
"with",
"*",
"Correspondence:",
"hod.gn@ktr.srmuniv.ac.in",
"Genomics",
"Laboratory,",
"Department",
"of",
"Genetic",
"Engineering,",
"SRM",
"University,",
"Chennai,",
"Tamil",
"Nadu,",
"603",
"203",
"India",
"methanol",
"and",
"used",
"as",
"biodiesel.",
"From",
"a",
"global",
"food",
"security",
"point",
"of",
"view,",
"jatropha",
"being",
"a",
"non-edible",
"crop",
"which",
"can",
"be",
"grown",
"in",
"areas",
"not",
"suitable",
"for",
"agriculture,",
"is",
"a",
"preferred",
"source",
"for",
"biodiesel",
"feedstock",
"as",
"it",
"does",
"not",
"compete",
"with",
"production",
"of",
"food",
"crops.",
"It",
"reduces",
"the",
"dependence",
"on",
"fossil",
"fuel",
"which",
"is",
"often",
"imported",
"by",
"using",
"precious",
"foreign",
"currency.",
"Its",
"decentralized",
"production",
"will",
"provide",
"income",
"for",
"a",
"large",
"number",
"of",
"small",
"and",
"marginal",
"farmers.",
"Biodiesel",
"is",
"also",
"less",
"harm-",
"ful",
"to",
"the",
"environment",
"in",
"that",
"its",
"production",
"and",
"com-",
"bustion",
"reduces",
"emission",
"of",
"greenhouse",
"gases",
"by",
"41%",
"relative",
"to",
"fossil",
"fuel",
"[2].",
"It",
"is",
"reported",
"that",
"biodiesel",
"©",
"2010",
"Natarajan",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
] | [
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] | [
"Brief",
"Report",
"nSec1",
"Binds",
"a",
"Closed",
"Conformation",
"of",
"Syntaxin1A",
"Bin",
"Yang,",
"Martin",
"Steegmaier,",
"Lino",
"C.",
"Gonzalez,",
"Jr.,",
"and",
"Richard",
"H.",
"Scheller",
"Howard",
"Hughes",
"Medical",
"Institute,",
"Department",
"of",
"Molecular",
"and",
"Cellular",
"Physiology,",
"Stanford",
"University",
"School",
"of",
"Medicine,",
"Stanford,",
"California",
"94305-5428",
"Abstract.",
"The",
"Sec1",
"family",
"of",
"proteins",
"is",
"proposed",
"to",
"function",
"in",
"vesicle",
"trafficking",
"by",
"forming",
"complexes",
"with",
"target",
"membrane",
"SNAREs",
"(soluble",
"N-ethylmale-",
"imide-sensitive",
"factor",
"[NSF]",
"attachment",
"protein",
"[SNAP]",
"receptors)",
"of",
"the",
"syntaxin",
"family.",
"Here,",
"we",
"demonstrate,",
"by",
"using",
"in",
"vitro",
"binding",
"assays,",
"nondena-",
"turing",
"gel",
"electrophoresis,",
"and",
"specific",
"neurotoxin",
"treat-",
"ment,",
"that",
"the",
"interaction",
"of",
"syntaxin1A",
"with",
"the",
"core",
"SNARE",
"components,",
"SNAP-25",
"(synaptosome-associ-",
"ated",
"protein",
"of",
"25",
"kD)",
"and",
"VAMP2",
"(vesicle-associated",
"membrane",
"protein",
"2),",
"precludes",
"the",
"interaction",
"with",
"nSec1",
"(also",
"called",
"Munc18",
"and",
"rbSec1).",
"Inversely,",
"asso-",
"ciation",
"of",
"nSec1",
"and",
"syntaxin1A",
"prevents",
"assembly",
"of",
"the",
"ternary",
"SNARE",
"complex.",
"Furthermore,",
"using",
"chemical",
"cross-linking",
"of",
"rat",
"brain",
"membranes,",
"we",
"iden-",
"tified",
"nSec1",
"complexes",
"containing",
"syntaxin1A,",
"but",
"not",
"SNAP-25",
"or",
"VAMP2.",
"These",
"results",
"support",
"the",
"hypoth-",
"esis",
"that",
"Sec1",
"proteins",
"function",
"as",
"syntaxin",
"chaperons",
"during",
"vesicle",
"docking,",
"priming,",
"and",
"membrane",
"fusion.",
"Key",
"words:",
"membrane",
"fusion",
"•",
"synaptic",
"vesicles",
"•",
"exocytosis",
"•",
"SNARE",
"•",
"synapse",
"Introduction",
"Two",
"of",
"the",
"most",
"intensively",
"studied",
"membrane",
"transport",
"processes",
"are",
"the",
"fusion",
"of",
"Golgi",
"apparatus-derived",
"vesi-",
"cles",
"with",
"the",
"plasma",
"membrane",
"in",
"yeast",
"and",
"the",
"secretion",
"of",
"neurotransmitter",
"from",
"the",
"mammalian",
"presynaptic",
"nerve",
"terminal",
"(Bennett",
"and",
"Scheller,",
"1994;",
"Jahn",
"and",
"Süd-",
"hof,",
"1994;",
"Rothman,",
"1994).",
"These",
"membrane",
"fusion",
"events",
"are",
"mediated",
"by",
"a",
"set",
"of",
"structurally",
"and",
"likely",
"functionally",
"related",
"proteins",
"called",
"SNAREs1",
"(soluble",
"N-ethylmale-",
"imide-sensitive",
"factor",
"[NSF]",
"attachment",
"protein",
"[SNAP]",
"receptors;",
"Bennett,",
"1995).",
"These",
"proteins",
"include",
"vesicle-",
"associated",
"membrane",
"proteins",
"(VAMP)",
"1",
"and",
"2",
"(synap-",
"tobrevin),",
"a",
"synaptosome-associated",
"protein",
"of",
"25",
"kD",
"(SNAP-25),",
"and",
"syntaxin1A",
"and",
"B",
"in",
"mammals;",
"and",
"their",
"yeast",
"orthologues",
"Snc1",
"and",
"2,",
"Sec9,",
"and",
"Sso1",
"and",
"2,",
"re-",
"spectively",
"(Bennett",
"and",
"Scheller,",
"1994;",
"Brennwald",
"et",
"al.,",
"Address",
"correspondence",
"to",
"Richard",
"H.",
"Scheller,",
"Howard",
"Hughes",
"Medical",
"Institute,",
"Department",
"of",
"Molecular",
"and",
"Cellular",
"Physiology,",
"Stanford",
"University",
"School",
"of",
"Medicine,",
"Stanford,",
"CA",
"94305-5428.",
"Tel.:",
"650-723-",
"9075.",
"Fax:",
"650-725-4436.",
"E-mail:",
"scheller@cmgm.stanford.edu",
"1Abbreviations",
"used",
"in",
"this",
"paper:",
"DSS,",
"disuccinimidyl",
"suberate;",
"GST,",
"glutathione",
"S-transferase;",
"NSF,",
"N-ethylmaleimide-sensitive",
"factor;",
"SNAP,",
"soluble",
"NSF",
"attachment",
"protein;",
"SNAP-25,",
"synaptosome-associated",
"pro-",
"tein",
"of",
"25",
"kD;",
"SNARE,",
"SNAP",
"receptor;",
"VAMP,",
"vesicle-associated",
"mem-",
"brane",
"protein.",
"1994).",
"The",
"pairing",
"of",
"SNAREs",
"across",
"membranes",
"to",
"form",
"four-stranded",
"helical",
"bundles",
"is",
"a",
"late",
"event",
"in",
"the",
"fusion",
"process,",
"perhaps",
"driving",
"the",
"actual",
"mixing",
"of",
"the",
"lipid",
"bi-",
"layers",
"(Poirier",
"et",
"al.,",
"1998;",
"Sutton",
"et",
"al.,",
"1998;",
"Weber",
"et",
"al.,",
"1998;",
"Chen",
"et",
"al.,",
"1999).",
"In",
"addition",
"to",
"SNAREs,",
"a",
"critical",
"component",
"of",
"the",
"fu-",
"sion",
"process",
"is",
"the",
"Sec1p",
"protein,",
"known",
"in",
"mammals",
"as",
"munc18,",
"nSec1,",
"or",
"rbSec1",
"(Hata",
"et",
"al.,",
"1993;",
"Garcia",
"et",
"al.,",
"1994;",
"Pevsner",
"et",
"al.,",
"1994b).",
"This",
"soluble",
"protein",
"is",
"critical",
"for",
"vesicle",
"trafficking",
"in",
"yeast",
"and",
"is",
"proposed",
"to",
"play",
"an",
"important",
"role",
"in",
"the",
"exocytosis",
"process.",
"Loss",
"of",
"Sec1",
"function",
"results",
"in",
"an",
"accumulation",
"of",
"vesicles",
"at",
"specific",
"steps",
"in",
"secretion",
"(Novick",
"and",
"Scheckman,",
"1979;",
"Ossig",
"et",
"al.,",
"1991;",
"Cowles",
"et",
"al.,",
"1994),",
"and",
"overexpression",
"of",
"Sec1",
"in",
"Drosophila",
"melanogaster",
"results",
"in",
"a",
"reduction",
"of",
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"tic",
"transmission",
"(Schulze",
"et",
"al.,",
"1994;",
"Wu",
"et",
"al.,",
"1998).",
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"et",
"al.,",
"1993;",
"Garcia",
"et",
"al.,",
"1994;",
"Hodel",
"et",
"al.,",
"1994;",
"Pevsner",
"et",
"al.,",
"1994b).",
"Further",
"investi-",
"gations",
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"when",
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"et",
"al.,",
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"early",
"study",
"demonstrating",
"that",
"binding",
"of",
"the",
"NH2-ter-",
"ª",
"The",
"Rockefeller",
"University",
"Press,",
"0021-9525/2000/01/247/6",
"$5.00",
"The",
"Journal",
"of",
"Cell",
"Biology,",
"Volume",
"148,",
"Number",
"2,",
"January",
"24,",
"2000",
"247–252",
"http://www.jcb.org",
"247"
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] | [
"ORIGINAL",
"RESEARCH",
"ARTICLE",
"published:",
"25",
"June",
"2012",
"doi:",
"10.3389/fnins.2012.00093",
"Stress",
"transiently",
"affects",
"Pavlovian-to-instrumental",
"transfer",
"Pedro",
"Morgado1,2,",
"Miguel",
"Silva1,2,",
"Nuno",
"Sousa1,2",
"and",
"João",
"J.",
"Cerqueira1,2*",
"1",
"Life",
"and",
"Health",
"Sciences",
"Research",
"Institute,",
"School",
"of",
"Health",
"Sciences,",
"University",
"of",
"Minho,",
"Braga,",
"Portugal",
"2",
"ICVS-3Bs",
"PT",
"Government",
"Associate",
"Laboratory,",
"Braga/Guimarães,",
"Portugal",
"Edited",
"by:",
"Scott",
"A.",
"Huettel,",
"Duke",
"University,",
"USA",
"Reviewed",
"by:",
"Jack",
"Van",
"Honk,",
"Utrecht",
"University,",
"Netherlands",
"Mauricio",
"R.",
"Delgado,",
"Rutgers-Newark:",
"The",
"State",
"University",
"of",
"New",
"Jersey,",
"USA",
"*Correspondence:",
"João",
"J.",
"Cerqueira,",
"Life",
"and",
"Health",
"Sciences",
"Research",
"Institute,",
"School",
"of",
"Health",
"Sciences,",
"University",
"of",
"Minho,",
"Campus",
"de",
"Gualtar,",
"4710-057",
"Braga,",
"Portugal.",
"e-mail:",
"jcerqueira@ecsaude.uminho.pt",
"Stress",
"has",
"a",
"strong",
"impact",
"in",
"the",
"brain,",
"impairing",
"decision-making",
"processes",
"as",
"a",
"result",
"of",
"changes",
"in",
"circuits",
"involving",
"the",
"prefrontal",
"and",
"orbitofrontal",
"cortices",
"and",
"the",
"striatum.",
"Given",
"that",
"these",
"same",
"circuits",
"are",
"key",
"for",
"action",
"control",
"and",
"outcome",
"encoding,",
"we",
"hypothesized",
"that",
"adaptive",
"responses",
"to",
"which",
"these",
"are",
"essential",
"functions,",
"could",
"also",
"be",
"targeted",
"by",
"stress.",
"To",
"test",
"this",
"hypothesis",
"we",
"herein",
"assessed",
"the",
"impact",
"of",
"chronic",
"stress",
"in",
"a",
"Pavlovian-to-instrumental",
"transfer",
"(PIT)",
"paradigm,",
"a",
"model",
"of",
"an",
"adaptive",
"response",
"in",
"which",
"a",
"previously",
"conditioned",
"cue",
"biases",
"an",
"instrumental",
"goal-directed",
"action.",
"Data",
"reveals",
"that",
"rats",
"submitted",
"to",
"chronic",
"unpredictable",
"stress",
"did",
"not",
"display",
"deficits",
"in",
"pavlovian",
"condition-",
"ing",
"nor",
"on",
"the",
"learning",
"of",
"the",
"instrumental",
"task,",
"but",
"were",
"impaired",
"in",
"PIT;",
"importantly,",
"after",
"a",
"stress-free",
"period",
"the",
"PIT",
"deficits",
"were",
"no",
"longer",
"observed.",
"These",
"results",
"are",
"relevant",
"to",
"understand",
"how",
"stress",
"biases",
"multiple",
"incentive",
"processes",
"that",
"contribute",
"to",
"instrumental",
"performance.",
"Keywords:",
"stress,",
"conditioning,",
"pavlovian-to-instrumental",
"transfer,",
"choices",
"INTRODUCTION",
"Exposure",
"to",
"a",
"stressful",
"stimulus",
"activates",
"a",
"physiological",
"response",
"intended",
"to",
"restore",
"the",
"organism’s",
"homeostasis.",
"However,",
"when",
"stressors",
"are",
"maintained",
"for",
"long",
"periods",
"of",
"time,",
"this",
"response",
"becomes",
"maladaptive",
"and",
"results",
"in",
"several",
"disruptions",
"at",
"the",
"level",
"of",
"the",
"regulatory",
"systems,",
"of",
"which",
"the",
"brain",
"is",
"a",
"key",
"element.",
"Thus,",
"it",
"is",
"not",
"surprising",
"that",
"chronic",
"stress",
"exposure",
"is",
"associated",
"with",
"significant",
"behavioral",
"impairments",
"such",
"as",
"deficits",
"in",
"spatial",
"reference",
"and",
"working",
"memory",
"(Mizoguchi",
"et",
"al.,",
"2000;",
"Cerqueira",
"et",
"al.,",
"2007),",
"behavioral",
"flexibility",
"(Cerqueira",
"et",
"al.,",
"2007),",
"anxiety",
"(Pêgo",
"et",
"al.,",
"2006),",
"and",
"mood",
"(Bessa",
"et",
"al.,",
"2009).",
"Such",
"func-",
"tional",
"deficits",
"are",
"paralleled",
"by",
"structural",
"changes",
"in",
"several",
"brain",
"regions",
"(Sousa",
"and",
"Almeida,",
"2002),",
"that",
"render",
"chronic",
"stress",
"as",
"an",
"important",
"risk-factor",
"for",
"the",
"development",
"of",
"several",
"neuropsychi-",
"atric",
"disorders.",
"Importantly,",
"several",
"studies",
"have",
"also",
"shown",
"that",
"the",
"behavioral",
"and",
"structural",
"effects",
"of",
"stress",
"are",
"transient,",
"and",
"important",
"plastic",
"phenomena",
"take",
"place",
"after",
"the",
"removal",
"of",
"the",
"stressful",
"stimuli",
"(Sousa",
"et",
"al.,",
"2000;",
"Bloss",
"et",
"al.,",
"2010).",
"Recent",
"studies",
"from",
"our",
"laboratory",
"show",
"that",
"chronic",
"stress",
"bias",
"decision-making",
"processes,",
"by",
"favoring",
"the",
"shift",
"from",
"goal-",
"directed",
"actions",
"to",
"habit",
"based",
"behaviors",
"(Dias-Ferreira",
"et",
"al.,",
"2009).",
"These",
"alterations",
"in",
"instrumental",
"behavior",
"are",
"correlated",
"with",
"changes",
"in",
"neuronal",
"circuits",
"involving",
"different",
"areas",
"of",
"the",
"prefrontal",
"cortex",
"(PFC)",
"[including",
"the",
"medial",
"PFC",
"(mPFC)",
"and",
"orbitofrontal",
"cortex",
"(OFC)]",
"and",
"dorsal",
"striatum",
"(Dias-Ferreira",
"et",
"al.,",
"2009).",
"Given",
"that",
"these",
"regions",
"are",
"implicated",
"in",
"action",
"control",
"(Balleine",
"and",
"O’Doherty,",
"2010)",
"and",
"outcome",
"encoding",
"necessary",
"for",
"adaptive",
"responses",
"(Chudasama",
"and",
"Robbins,",
"2003;",
"Hornak",
"et",
"al.,",
"2004),",
"we",
"hypothesized",
"that",
"stress-induced",
"changes",
"in",
"neuronal",
"circuits",
"involving",
"the",
"PFC",
"and",
"the",
"striatum",
"could",
"lead",
"to",
"outcome",
"encoding",
"deficits",
"and",
"to",
"changes",
"in",
"the",
"multiple",
"incentive",
"processes",
"that",
"contribute",
"to",
"instrumental",
"performance.",
"One",
"of",
"these",
"processes",
"is",
"Pavlovian-to-instrumental",
"transfer",
"(PIT;",
"Estes,",
"1948;",
"Colwill",
"and",
"Rescorla,",
"1986).",
"PIT",
"encompasses",
"three",
"distinct",
"components:(1)",
"Pavlovian",
"learning,",
"in",
"which",
"stim-",
"uli",
"are",
"associated",
"with",
"rewards;",
"(2)",
"instrumental",
"conditioning,",
"in",
"which",
"associations",
"between",
"actions",
"and",
"out",
"comes",
"are",
"learned;",
"and",
"(3)",
"a",
"test",
"phase,",
"in",
"which",
"the",
"impact",
"of",
"previous",
"cues",
"on",
"instrumental",
"response",
"is",
"assessed.",
"The",
"associative",
"value",
"of",
"cue",
"and",
"its",
"motivational",
"significance",
"are",
"determinants",
"found",
"crucial",
"to",
"proper",
"transfer,",
"a",
"phenomenon",
"which",
"resembles",
"cue-mediated",
"increased",
"drive",
"seeking",
"for",
"drugs",
"seen",
"in",
"drug",
"abusers",
"(Dickinson",
"et",
"al.,",
"2000;",
"Corbit",
"and",
"Janak,",
"2007).",
"Because",
"of",
"that,",
"PIT",
"has",
"been",
"used",
"as",
"a",
"useful",
"model",
"of",
"maladaptive",
"learning",
"observed",
"in",
"several",
"conditions,",
"namely",
"addictive",
"disorders.",
"The",
"neural",
"basis",
"of",
"PIT",
"is",
"not",
"completely",
"established",
"but",
"sev-",
"eral",
"studies",
"implicate",
"regions",
"associated",
"with",
"emotional",
"processing",
"[amygdala",
"and",
"nucleus",
"accumbens",
"(NAc)],",
"executive",
"commands",
"(dorsal",
"striatum),",
"and",
"their",
"integration",
"(mPFC",
"and",
"OFC);",
"impor-",
"tantly,",
"it",
"is",
"known",
"that",
"key",
"regions",
"involved",
"in",
"PIT",
"operate",
"in",
"parallel.",
"In",
"fact,",
"lesion",
"studies",
"in",
"the",
"amygdala",
"and",
"NAc",
"have",
"demonstrated",
"that",
"these",
"brain",
"regions",
"are",
"necessary",
"for",
"the",
"behav-",
"ioral",
"expression",
"of",
"PIT",
"(Corbit",
"et",
"al.,",
"2001;",
"Hall",
"et",
"al.,",
"2001;",
"de",
"Borchgrave",
"et",
"al.,",
"2002;",
"Holland",
"and",
"Gallagher,",
"2004).",
"Moreover,",
"it",
"is",
"relevant",
"to",
"note",
"that",
"different",
"regions",
"of",
"the",
"amygdala",
"and",
"NAc",
"display",
"different",
"roles",
"in",
"this",
"process.",
"While",
"the",
"amygdala",
"baso-",
"lateral",
"nucleus",
"(BLA)",
"mediates",
"the",
"association",
"between",
"specific",
"sensory",
"and",
"emotional",
"features",
"of",
"stimulus",
"and",
"the",
"responses",
"that",
"are",
"elicited",
"by",
"each",
"one",
"(consummatory",
"conditioning),",
"the",
"central",
"nucleus",
"(CN)",
"mediates",
"the",
"association",
"between",
"cues",
"and",
"affective",
"properties",
"of",
"stimuli",
"(preparatory",
"conditioning;",
"Killcross",
"et",
"al.,",
"1997;",
"Balleine",
"and",
"Killcross,",
"2006).",
"In",
"what",
"concerns",
"the",
"NAc,",
"the",
"core",
"mediates",
"the",
"general",
"excitatory",
"effects",
"of",
"reward-related",
"cues,",
"whereas",
"the",
"shell",
"mediates",
"the",
"effect",
"of",
"outcome-specific",
"reward",
"www.frontiersin.org",
"June",
"2012",
"|",
"Volume",
"6",
"|",
"Article",
"93",
"|",
"1"
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] | [
"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",
"Gain-of-function",
"Mutations",
"Reveal",
"Expanded",
"Intermediate",
"States",
"and",
"a",
"Sequential",
"Action",
"of",
"Two",
"Gates",
"in",
"MscL",
"Andriy",
"Anishkin,",
"Chien-Sung",
"Chiang,",
"and",
"Sergei",
"Sukharev",
"Department",
"of",
"Biology,",
"University",
"of",
"Maryland,",
"College",
"Park,",
"MD",
"20742",
"a",
"b",
"s",
"t",
"r",
"a",
"c",
"t",
"The",
"tension-driven",
"gating",
"transition",
"in",
"the",
"large",
"mechanosensitive",
"channel",
"MscL",
"proceeds",
"through",
"detectable",
"states",
"of",
"intermediate",
"conductance.",
"Gain-of-function",
"(GOF)",
"mutants",
"with",
"polar",
"or",
"charged",
"substitutions",
"in",
"the",
"main",
"hydrophobic",
"gate",
"display",
"altered",
"patterns",
"of",
"subconducting",
"states,",
"providing",
"valuable",
"information",
"about",
"gating",
"intermediates.",
"Here",
"we",
"present",
"thermodynamic",
"analysis",
"of",
"several",
"GOF",
"mutants",
"to",
"clarify",
"the",
"nature",
"and",
"position",
"of",
"low-conducting",
"conformations",
"in",
"the",
"transition",
"pathway.",
"Unlike",
"wild-type",
"(WT)",
"MscL,",
"which",
"predominantly",
"occupies",
"the",
"closed",
"and",
"fully",
"open",
"states",
"with",
"very",
"brief",
"substates,",
"the",
"mild",
"V23T",
"GOF",
"mutant",
"frequently",
"visits",
"a",
"multitude",
"of",
"short-lived",
"subconducting",
"states.",
"Severe",
"mutants",
"V23D",
"and",
"G22N",
"open",
"in",
"sequence:",
"closed",
"(C)",
"→",
"low-conducting",
"substate",
"(S)",
"→",
"open",
"(O),",
"with",
"the",
"first",
"subtransition",
"occurring",
"at",
"lower",
"tensions.",
"Analyses",
"of",
"equilibrium",
"state",
"occupancies",
"as",
"functions",
"of",
"membrane",
"tension",
"show",
"that",
"the",
"C→S",
"subtransition",
"in",
"WT",
"MscL",
"is",
"associated",
"with",
"only",
"a",
"minor",
"conductance",
"increment,",
"but",
"the",
"largest",
"in-plane",
"expansion",
"and",
"free",
"energy",
"change.",
"The",
"GOF",
"substitutions",
"strongly",
"affect",
"the",
"first",
"subtransition",
"by",
"reducing",
"area",
"(",
"A)",
"and",
"energy",
"(",
"E)",
"changes",
"between",
"C",
"and",
"S",
"states",
"commensurably",
"with",
"the",
"severity",
"of",
"mutation.",
"GOF",
"mutants",
"also",
"exhibited",
"a",
"considerably",
"larger",
"E",
"associated",
"with",
"the",
"second",
"(S→O)",
"subtransition,",
"but",
"a",
"A",
"similar",
"to",
"WT.",
"The",
"area",
"changes",
"indicate",
"that",
"closed",
"conformations",
"of",
"GOF",
"mutants",
"are",
"physically",
"preexpanded.",
"The",
"tension",
"dependencies",
"of",
"rate",
"constants",
"for",
"channel",
"closure",
"(koff)",
"predict",
"different",
"positions",
"of",
"rate-limiting",
"barriers",
"on",
"the",
"energy-area",
"profiles",
"for",
"WT",
"and",
"GOF",
"MscL.",
"The",
"data",
"support",
"the",
"two-gate",
"mechanism",
"in",
"which",
"the",
"first",
"subtransition",
"(C→S)",
"can",
"be",
"viewed",
"as",
"opening",
"of",
"the",
"central",
"(M1)",
"gate,",
"resulting",
"in",
"an",
"expanded",
"water-filled",
"“leaky”",
"conformation.",
"Strong",
"facilitation",
"of",
"this",
"step",
"by",
"polar",
"GOF",
"substitutions",
"suggests",
"that",
"separation",
"of",
"M1",
"helices",
"associated",
"with",
"hydration",
"of",
"the",
"pore",
"in",
"WT",
"MscL",
"is",
"the",
"major",
"energetic",
"barrier",
"for",
"opening.",
"Mutants",
"with",
"a",
"stabilized",
"S1",
"gate",
"demonstrate",
"impeded",
"transitions",
"from",
"low-conducting",
"substates",
"to",
"the",
"fully",
"open",
"state,",
"whereas",
"extensions",
"of",
"S1–M1",
"linkers",
"result",
"in",
"a",
"much",
"higher",
"probability",
"of",
"reverse",
"O→S",
"transitions.",
"These",
"data",
"strongly",
"suggest",
"that",
"the",
"bulk",
"of",
"conductance",
"gain",
"in",
"the",
"second",
"subtransition",
"(S→O)",
"occurs",
"through",
"the",
"opening",
"of",
"the",
"NH2-terminal",
"(S1)",
"gate",
"and",
"the",
"linkers",
"are",
"coupling",
"elements",
"between",
"the",
"M1",
"and",
"S1",
"gates.",
"k",
"e",
"y",
"w",
"o",
"r",
"d",
"s",
":",
"mechanosensitive",
"channel",
"•",
"tension",
"•",
"thermodynamics",
"•",
"subconducting",
"states",
"•",
"hydration",
"I",
"N",
"T",
"R",
"O",
"D",
"U",
"C",
"T",
"I",
"O",
"N",
"Unified",
"mainly",
"by",
"function,",
"mechanosensitive",
"ion",
"chan-",
"nels",
"form",
"a",
"diverse",
"group",
"of",
"sensory",
"receptors,",
"com-",
"prising",
"members",
"of",
"structurally",
"unrelated",
"channel",
"fam-",
"ilies",
"(for",
"review",
"see",
"Sukharev",
"and",
"Corey,",
"2004).",
"The",
"multiplicity",
"of",
"mechanoreceptor",
"types",
"suggests",
"that",
"similar",
"functions",
"can",
"be",
"implemented",
"with",
"different",
"se-",
"quences",
"and",
"structural",
"designs,",
"thus",
"emphasizing",
"the",
"importance",
"of",
"unifying",
"biophysical",
"principles",
"of",
"gating",
"by",
"mechanical",
"force.",
"Bacterial",
"mechanosensitive",
"channels",
"are",
"convenient",
"model",
"systems",
"for",
"the",
"basic",
"channel",
"biophysics.",
"They",
"fulfill",
"the",
"role",
"of",
"turgor",
"pressure",
"regulators",
"in",
"small",
"prokaryotic",
"cells,",
"which",
"in",
"the",
"wild",
"are",
"subjected",
"to",
"a",
"constantly",
"changing",
"environment.",
"Three",
"bacterial",
"mechanosensitive",
"channels",
"have",
"been",
"identified",
"in",
"Escherichia",
"coli:",
"MscL,",
"MscS,",
"and",
"MscK",
"(Sukharev",
"et",
"al.,",
"1994;",
"Levina",
"et",
"al.,",
"1999;",
"Pivetti",
"et",
"al.,",
"2003).",
"Two",
"of",
"A.",
"Anishkin",
"and",
"C.-S.",
"Chiang",
"contributed",
"equally",
"to",
"this",
"work.",
"Correspondence",
"to",
"Sergei",
"Sukharev:",
"sukharev@umd.edu",
"them,",
"MscL",
"and",
"MscS,",
"were",
"isolated,",
"reconstituted,",
"and",
"shown",
"to",
"be",
"gated",
"directly",
"by",
"tension",
"in",
"the",
"lipid",
"bilayer",
"(Hase",
"et",
"al.,",
"1995;",
"Blount",
"et",
"al.,",
"1996a;",
"Okada",
"et",
"al.,",
"2002;",
"Sukharev,",
"2002).",
"Successful",
"efforts",
"in",
"crystallization",
"of",
"MscS",
"from",
"E.",
"coli",
"(Bass",
"et",
"al.,",
"2002)",
"and",
"the",
"MscL",
"homologue",
"from",
"M.",
"tuberculosis",
"(Chang",
"et",
"al.,",
"1998)",
"(TbMscL)",
"have",
"opened",
"rich",
"opportunities",
"for",
"detailed",
"structure-based",
"studies",
"of",
"their",
"gating",
"mechanisms.",
"Since",
"then,",
"MscL",
"has",
"been",
"the",
"best",
"understood",
"“simple”",
"chan-",
"nel",
"gated",
"by",
"membrane",
"stretch",
"(Blount,",
"2003;",
"Perozo",
"and",
"Rees,",
"2003;",
"Sukharev",
"and",
"Anishkin,",
"2004).",
"Identification",
"of",
"the",
"main",
"gate",
"region",
"in",
"randomly",
"generated",
"gain-of-function",
"mutants",
"of",
"MscL",
"(Ou",
"et",
"al.,",
"1998)",
"corroborated",
"extremely",
"well",
"with",
"the",
"crystal",
"structure.",
"The",
"separation",
"of",
"the",
"tightly",
"packed",
"M1",
"helices",
"in",
"the",
"core",
"of",
"the",
"complex",
"was",
"inferred",
"to",
"be",
"the",
"central",
"step",
"in",
"the",
"gating",
"process",
"(Chang",
"et",
"al.,",
"1998;",
"Yoshimura",
"et",
"al.,",
"1999;",
"Batiza",
"et",
"al.,",
"1999;",
"Suk-",
"harev",
"et",
"al.,",
"2001a).",
"The",
"“iris”",
"model",
"of",
"the",
"MscL",
"barrel",
"Abbreviations",
"used",
"in",
"this",
"paper:",
"GOF,",
"gain-of-function;",
"WT,",
"wild",
"type.",
"155",
"J.",
"Gen.",
"Physiol.",
"©",
"The",
"Rockefeller",
"University",
"Press",
"•",
"0022-1295/2005/02/155/16",
"$8.00",
"Volume",
"125",
"February",
"2005",
"155–170",
"http://www.jgp.org/cgi/doi/10.1085/jgp.200409118"
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] | [
"Promoter-Wide",
"Hypermethylation",
"of",
"the",
"Ribosomal",
"RNA",
"Gene",
"Promoter",
"in",
"the",
"Suicide",
"Brain",
"Patrick",
"O.",
"McGowan1,2,3,",
"Aya",
"Sasaki1,2,3,",
"Tony",
"C.",
"T.",
"Huang3,4,",
"Alexander",
"Unterberger3,4,",
"Matthew",
"Suderman3,5,",
"Carl",
"Ernst1,6,",
"Michael",
"J.",
"Meaney1,2,3,",
"Gustavo",
"Turecki1,6*,",
"Moshe",
"Szyf3,4*",
"1",
"Department",
"of",
"Psychiatry,",
"Douglas",
"Mental",
"Health",
"University",
"Institute,",
"Montreal,",
"Quebec,",
"Canada,",
"2",
"Department",
"of",
"Neurology",
"and",
"Neurosurgery,",
"McGill",
"Program",
"for",
"the",
"Study",
"of",
"Behaviour,",
"Genes",
"and",
"Environment,",
"McGill",
"University,",
"Montreal,",
"Quebec,",
"Canada,",
"3",
"Sackler",
"Program",
"for",
"Epigenetics",
"&",
"Psychobiology,",
"McGill",
"University,",
"Montreal,",
"Quebec,",
"Canada,",
"4",
"Department",
"of",
"Pharmacology",
"and",
"Therapeutics,",
"McGill",
"University,",
"Montreal,",
"Quebec,",
"Canada,",
"5",
"McGill",
"Centre",
"for",
"Bioinformatics,",
"McGill",
"University,",
"Montreal,",
"Quebec,",
"Canada,",
"6",
"McGill",
"Group",
"for",
"Suicide",
"Studies,",
"Douglas",
"Mental",
"Health",
"University",
"Institute,",
"Montreal,",
"Quebec,",
"Canada",
"Abstract",
"Background:",
"Alterations",
"in",
"gene",
"expression",
"in",
"the",
"suicide",
"brain",
"have",
"been",
"reported",
"and",
"for",
"several",
"genes",
"DNA",
"methylation",
"as",
"an",
"epigenetic",
"regulator",
"is",
"thought",
"to",
"play",
"a",
"role.",
"rRNA",
"genes,",
"that",
"encode",
"ribosomal",
"RNA,",
"are",
"the",
"backbone",
"of",
"the",
"protein",
"synthesis",
"machinery",
"and",
"levels",
"of",
"rRNA",
"gene",
"promoter",
"methylation",
"determine",
"rRNA",
"transcription.",
"Methodology/Principal",
"Findings:",
"We",
"test",
"here",
"by",
"sodium",
"bisulfite",
"mapping",
"of",
"the",
"rRNA",
"promoter",
"and",
"quantitative",
"real-",
"time",
"PCR",
"of",
"rRNA",
"expression",
"the",
"hypothesis",
"that",
"epigenetic",
"differences",
"in",
"critical",
"loci",
"in",
"the",
"brain",
"are",
"involved",
"in",
"the",
"pathophysiology",
"of",
"suicide.",
"Suicide",
"subjects",
"in",
"this",
"study",
"were",
"selected",
"for",
"a",
"history",
"of",
"early",
"childhood",
"neglect/abuse,",
"which",
"is",
"associated",
"with",
"decreased",
"hippocampal",
"volume",
"and",
"cognitive",
"impairments.",
"rRNA",
"was",
"significantly",
"hypermethylated",
"throughout",
"the",
"promoter",
"and",
"59",
"regulatory",
"region",
"in",
"the",
"brain",
"of",
"suicide",
"subjects,",
"consistent",
"with",
"reduced",
"rRNA",
"expression",
"in",
"the",
"hippocampus.",
"This",
"difference",
"in",
"rRNA",
"methylation",
"was",
"not",
"evident",
"in",
"the",
"cerebellum",
"and",
"occurred",
"in",
"the",
"absence",
"of",
"genome-wide",
"changes",
"in",
"methylation,",
"as",
"assessed",
"by",
"nearest",
"neighbor.",
"Conclusions/Significance:",
"This",
"is",
"the",
"first",
"study",
"to",
"show",
"aberrant",
"regulation",
"of",
"the",
"protein",
"synthesis",
"machinery",
"in",
"the",
"suicide",
"brain.",
"The",
"data",
"implicate",
"the",
"epigenetic",
"modulation",
"of",
"rRNA",
"in",
"the",
"pathophysiology",
"of",
"suicide.",
"Citation:",
"McGowan",
"PO,",
"Sasaki",
"A,",
"Huang",
"TCT,",
"Unterberger",
"A,",
"Suderman",
"M,",
"et",
"al.",
"(2008)",
"Promoter-Wide",
"Hypermethylation",
"of",
"the",
"Ribosomal",
"RNA",
"Gene",
"Promoter",
"in",
"the",
"Suicide",
"Brain.",
"PLoS",
"ONE",
"3(5):",
"e2085.",
"doi:10.1371/journal.pone.0002085",
"Editor:",
"Jo¨",
"rg",
"Hoheisel,",
"Deutsches",
"Krebsforschungszentrum,",
"Germany",
"Received",
"October",
"28,",
"2007;",
"Accepted",
"March",
"20,",
"2008;",
"Published",
"May",
"7,",
"2008",
"Copyright:",
"2008",
"McGowan",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"This",
"work",
"was",
"funded",
"by",
"a",
"grant",
"from",
"the",
"National",
"Cancer",
"Institute",
"to",
"MS,",
"NICHD",
"to",
"MJM",
"and",
"MS,",
"HSFP",
"to",
"MJM",
"and",
"MS,",
"the",
"Maternal",
"Adversity,",
"Vulnerability",
"and",
"Neurodevelopment",
"Project",
"grant",
"from",
"the",
"Canadian",
"Institutes",
"for",
"Health",
"Research",
"(CIHR)",
"to",
"MJM",
"and",
"MS,",
"as",
"well",
"as",
"grants",
"from",
"CIHR",
"to",
"GT.",
"Competing",
"Interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"*",
"E-mail:",
"gustvao.turecki@mcgill.ca",
"(GT);",
"moshe.szyf@mcgill.ca",
"(MS)",
"Introduction",
"Suicide",
"is",
"a",
"leading",
"cause",
"of",
"death,",
"particularly",
"in",
"males",
"[1,2].",
"Although",
"many",
"suicide",
"subjects",
"have",
"a",
"diagnosable",
"psychiatric",
"illness,",
"most",
"persons",
"with",
"a",
"psychiatric",
"disorder",
"never",
"attempt",
"suicide",
"[2].",
"Suicidal",
"behavior",
"aggregates",
"in",
"families",
"[1],",
"and",
"studies",
"of",
"twins",
"show",
"that",
"monozygotic",
"individuals",
"have",
"a",
"greater",
"concordance",
"for",
"suicide",
"completion",
"and",
"suicide",
"attempts",
"com-",
"pared",
"to",
"dizygotic",
"individuals",
"[2–4].",
"Non-genetic",
"familial",
"factors,",
"including",
"a",
"history",
"of",
"abuse",
"or",
"neglect",
"during",
"childhood,",
"are",
"also",
"risk",
"factors",
"for",
"suicidal",
"behavior",
"[5,6].",
"Similarly,",
"childhood",
"abuse",
"is",
"associated",
"with",
"an",
"increased",
"risk",
"for",
"psychopathology",
"[7,8]",
"and",
"altered",
"neural",
"development",
"[9].",
"Several",
"lines",
"of",
"evidence",
"suggest",
"that",
"changes",
"in",
"gene",
"expression",
"in",
"the",
"brain",
"occur",
"in",
"the",
"context",
"of",
"psychiatric",
"disorders",
"and",
"suicide",
"[10–15].",
"Alterations",
"in",
"gene",
"regulation",
"can",
"be",
"caused",
"by",
"epigenetic",
"programming",
"of",
"gene",
"expression",
"in",
"response",
"to",
"environmental",
"exposure,",
"including",
"social",
"and",
"physical",
"adversity",
"[16].",
"The",
"genome",
"is",
"epigenetically",
"programmed",
"by",
"changes",
"in",
"the",
"chromatin",
"state",
"and",
"by",
"a",
"pattern",
"of",
"modification",
"of",
"the",
"DNA",
"molecule",
"itself",
"through",
"methylation",
"[17].",
"DNA",
"methylation",
"is",
"a",
"stable",
"epigenetic",
"mark",
"associated",
"with",
"long-lasting",
"silencing",
"of",
"gene",
"expression",
"[18].",
"In",
"rodents,",
"genes",
"responsive",
"to",
"differences",
"in",
"the",
"quality",
"of",
"maternal",
"care",
"early",
"in",
"life",
"are",
"altered",
"through",
"epigenetic",
"mechanisms",
"[19,20].",
"In",
"the",
"human",
"brain,",
"aberrant",
"DNA",
"methylation",
"of",
"specific",
"genes",
"also",
"occurs",
"in",
"the",
"context",
"of",
"psychiatric",
"disorders",
"[21–26].",
"Decreased",
"expression",
"of",
"ribosomal",
"RNA",
"(rRNA),",
"a",
"bottleneck",
"gene",
"for",
"protein",
"production",
"in",
"the",
"cell,",
"occurs",
"in",
"patients",
"with",
"mild",
"cognitive",
"impairment",
"and",
"early",
"Alzheimer’s",
"disease",
"[27,28].",
"DNA",
"methylation",
"can",
"regulate",
"gene",
"expression",
"in",
"two",
"ways.",
"One",
"is",
"site-specific",
"methylation,",
"involving",
"direct",
"interference",
"with",
"the",
"binding",
"of",
"transcription",
"factors",
"[29].",
"The",
"second",
"is",
"site-",
"independent",
"promoter-wide",
"methylation,",
"attracting",
"methylated",
"DNA",
"binding",
"proteins",
"and",
"leading",
"to",
"an",
"inactive",
"chromatin",
"structure.",
"In",
"the",
"latter",
"case,",
"the",
"density",
"of",
"methylated",
"CpGs",
"determines",
"the",
"extent",
"of",
"gene",
"silencing",
"[30].",
"Both",
"mechanisms",
"can",
"regulate",
"rRNA",
"expression.",
"Previous",
"work",
"in",
"cultured",
"mouse",
"cells",
"indicated",
"that",
"rRNA",
"is",
"regulated",
"by",
"methylation",
"of",
"a",
"single",
"CpG",
"dinucleotide",
"at",
"position",
"2133",
"residing",
"at",
"the",
"upstream",
"control",
"element",
"(UCE)",
"[31].",
"In",
"human",
"cell",
"culture,",
"the",
"transcriptionally",
"active",
"fraction",
"of",
"rRNA",
"promoters",
"associated",
"with",
"RNA",
"polymerase",
"I",
"(pol",
"I)",
"is",
"completely",
"unmethylated",
"whereas",
"the",
"fraction",
"not",
"associated",
"with",
"pol",
"I",
"is",
"almost",
"completely",
"methylated",
"[32],",
"thus",
"determining",
"transcription",
"by",
"defining",
"the",
"fraction",
"of",
"unmethylated",
"rRNA.",
"Mouse",
"and",
"human",
"rRNA",
"promoters",
"show",
"PLoS",
"ONE",
"|",
"www.plosone.org",
"1",
"May",
"2008",
"|",
"Volume",
"3",
"|",
"Issue",
"5",
"|",
"e2085"
] | [
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] | [
"Harris",
"et",
"al.",
"Pediatric",
"Rheumatology",
"2012,",
"10:9",
"http://www.ped-rheum.com/content/10/1/9",
"C",
"A",
"S",
"E",
"R",
"E",
"P",
"O",
"R",
"T",
"Asymptomatic",
"intracardiac",
"mass",
"in",
"a",
"14-year-old",
"girl",
"with",
"granulomatosis",
"with",
"polyangiitis:",
"Case",
"report",
"Julia",
"G",
"Harris1,4*,",
"David",
"M",
"Salvay2,5",
"and",
"Marisa",
"S",
"Klein-Gitelman3,6",
"Open",
"Access",
"Abstract",
"Granulomatosis",
"with",
"polyangiitis",
"(GPA;",
"Wegener’s",
"granulomatosis)",
"is",
"a",
"systemic",
"necrotizing",
"vasculitis",
"of",
"unknown",
"etiology",
"that",
"commonly",
"involves",
"the",
"upper",
"airways,",
"lungs,",
"and",
"kidneys.",
"Cardiac",
"involvement",
"with",
"an",
"intracardiac",
"mass",
"is",
"an",
"exceedingly",
"rare",
"manifestation",
"of",
"this",
"disease,",
"especially",
"in",
"the",
"pediatric",
"population",
"where,",
"to",
"our",
"knowledge,",
"only",
"one",
"article",
"exists",
"to",
"date",
"that",
"has",
"described",
"such",
"a",
"finding.",
"In",
"this",
"report,",
"we",
"present",
"the",
"case",
"of",
"an",
"adolescent",
"female",
"who",
"initially",
"presented",
"with",
"renal",
"failure",
"and",
"an",
"intracardiac",
"mass.",
"Subsequent",
"work-up",
"led",
"to",
"a",
"diagnosis",
"of",
"granulomatosis",
"with",
"polyangiitis",
"(GPA).",
"Cardiac",
"manifestations",
"in",
"pediatric",
"GPA",
"are",
"not",
"common;",
"however,",
"they",
"may",
"be",
"more",
"prevalent",
"than",
"reported",
"given",
"recent",
"adult",
"literature",
"and",
"concern",
"for",
"clinically",
"silent",
"abnormalities.",
"Keywords:",
"Granulomatosis",
"with",
"polyangiitis,",
"Wegener’s",
"granulomatosis,",
"Intracardiac",
"mass",
"Background",
"Granulomatosis",
"with",
"polyangiitis",
"(GPA;",
"Wegener’s",
"granulo-",
"matosis)",
"is",
"a",
"systemic",
"vasculitis",
"characterized",
"by",
"acute",
"nec-",
"rotizing",
"granulomas",
"of",
"the",
"upper",
"respiratory",
"tract",
"and",
"lungs,",
"necrotizing",
"or",
"granulomatous",
"vasculitis",
"affecting",
"small",
"to",
"medium-sized",
"vessels",
"and",
"pauci-immune,",
"necrotiz-",
"ing,",
"and",
"crescentic",
"glomerulonephritis;",
"however,",
"this",
"disease",
"can",
"affect",
"virtually",
"any",
"organ",
"system",
"[1-7].",
"In",
"this",
"report,",
"we",
"describe",
"a",
"case",
"of",
"GPA",
"presenting",
"as",
"renal",
"failure",
"with",
"discovery",
"of",
"an",
"intracardiac",
"mass",
"in",
"an",
"adolescent",
"patient.",
"We",
"will",
"discuss",
"the",
"significance",
"of",
"this",
"finding",
"in",
"light",
"of",
"re-",
"cent",
"literature.",
"Case",
"Presentation",
"A",
"14-year-old",
"girl",
"presented",
"with",
"a",
"6-week",
"history",
"of",
"fa-",
"tigue,",
"persistent",
"rhinorrhea,",
"and",
"intermittent",
"epistaxis.",
"Her",
"history",
"was",
"also",
"significant",
"for",
"recurrent",
"sinusitis,",
"rash,",
"decreased",
"urine",
"output,",
"and",
"myalgias.",
"The",
"patient",
"was",
"seen",
"by",
"her",
"pediatrician",
"with",
"concerns",
"that",
"her",
"nose",
"was",
"“col-",
"lapsing.”",
"Past",
"medical",
"history",
"includes",
"atopic",
"dermatitis",
"as",
"a",
"child",
"and",
"allergic",
"rhinitis.",
"*",
"Correspondence:",
"jgharris@mcw.edu",
"1Medical",
"College",
"of",
"Wisconsin,",
"Children’s",
"Hospital",
"of",
"Wisconsin,",
"Milwaukee,",
"WI,",
"USA",
"4Children’s",
"Hospital",
"of",
"Wisconsin,",
"9000",
"West",
"Wisconsin",
"Avenue,",
"Wauwatosa,",
"WI",
"53226,",
"USA",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"On",
"admission",
"to",
"our",
"hospital,",
"the",
"patient’s",
"physical",
"exam",
"was",
"remarkable",
"for",
"pallor,",
"saddle",
"nose,",
"dried",
"nasal",
"secretions,",
"oral",
"ulcers,",
"synovial",
"swelling",
"around",
"multiple",
"joints,",
"and",
"palpable",
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"©",
"2012",
"Harris",
"et",
"al.;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
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"under",
"the",
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"of",
"the",
"Creative",
"Commons",
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"License",
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"and",
"reproduction",
"in",
"any",
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] | [
"Roberts",
"et",
"al.",
"Journal",
"of",
"Foot",
"and",
"Ankle",
"Research",
"2011,",
"4:1",
"http://www.jfootankleres.com/content/4/1/1",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"JOURNAL",
"OF",
"FOOT",
"AND",
"ANKLE",
"RESEARCH",
"Open",
"Access",
"Comparison",
"of",
"ankle",
"and",
"subtalar",
"joint",
"complex",
"range",
"of",
"motion",
"during",
"barefoot",
"walking",
"and",
"walking",
"in",
"Masai",
"Barefoot",
"Technology",
"sandals",
"Sophie",
"Roberts1*,",
"Ivan",
"Birch2,",
"Simon",
"Otter3*",
"Abstract",
"Background:",
"Masai",
"Barefoot",
"Technology",
"(MBT,",
"Switzerland)",
"produce",
"footwear",
"which",
"they",
"claim",
"simulate",
"walking",
"barefoot",
"on",
"soft",
"undulating",
"ground.",
"This",
"paper",
"reports",
"an",
"investigation",
"into",
"the",
"effect",
"of",
"MBT",
"sandals",
"on",
"the",
"motion",
"of",
"the",
"ankle",
"and",
"subtalar",
"joint",
"complex",
"during",
"walking.",
"Methods:",
"Range",
"of",
"motion",
"data",
"was",
"collected",
"in",
"the",
"sagittal,",
"frontal",
"and",
"transverse",
"plane",
"from",
"the",
"ankle",
"and",
"subtalar",
"joint",
"complex",
"from",
"32",
"asymptomatic",
"subjects",
"using",
"the",
"CODA",
"MPX30",
"motion",
"analysis",
"system",
"during",
"both",
"barefoot",
"walking",
"and",
"walking",
"in",
"the",
"MBT",
"sandal.",
"Shod",
"and",
"un-shod",
"data",
"were",
"compared",
"using",
"the",
"Wilcoxon",
"signed",
"ranks",
"test.",
"Results:",
"A",
"significantly",
"greater",
"range",
"of",
"motion",
"in",
"the",
"frontal",
"and",
"sagittal",
"planes",
"was",
"recorded",
"when",
"walking",
"in",
"the",
"MBT",
"sandal",
"(p",
"=",
"0.031,",
"and",
"p",
"=",
"0.015",
"respectively).",
"In",
"the",
"transverse",
"plane,",
"no",
"significant",
"difference",
"was",
"found",
"(p",
"=",
"0.470).",
"Conclusions:",
"MBT",
"sandals",
"increase",
"the",
"range",
"of",
"motion",
"of",
"the",
"ankle",
"and",
"subtalar",
"joint",
"complex",
"in",
"the",
"frontal",
"and",
"sagittal",
"planes.",
"MBT",
"footwear",
"could",
"therefore",
"have",
"a",
"role",
"to",
"play",
"in",
"the",
"management",
"of",
"musculoskeletal",
"disorders",
"where",
"an",
"increase",
"in",
"frontal",
"and",
"sagittal",
"plane",
"range",
"of",
"motion",
"is",
"desirable.",
"Background",
"With",
"the",
"growth",
"in",
"the",
"health",
"and",
"fitness",
"industry,",
"sports",
"footwear",
"has",
"shown",
"technological",
"advances",
"and",
"diversification.",
"The",
"introduction",
"of",
"footwear",
"such",
"as",
"the",
"MBT",
"shoe",
"(manufactured",
"by",
"Masai",
"Barefoot",
"Technolo-",
"gies)",
"is",
"an",
"example",
"of",
"this",
"diversification.",
"MBT",
"have",
"based",
"their",
"shoe",
"design",
"on",
"observations",
"of",
"the",
"Masai,",
"a",
"semi-nomadic",
"tribe",
"from",
"Africa",
"who",
"are",
"well",
"known",
"for",
"their",
"posture",
"and",
"for",
"walking",
"long",
"distances",
"on",
"uneven",
"terrain.",
"The",
"MBT",
"shoe",
"construction",
"is",
"based",
"on",
"a",
"mid-",
"sole",
"pivot",
"with",
"a",
"rounded",
"sole",
"in",
"the",
"anterior-posterior",
"direction,",
"and",
"a",
"soft",
"heel",
"pad.",
"It",
"is",
"claimed",
"that",
"the",
"effect",
"of",
"the",
"angled",
"soft",
"sole",
"not",
"only",
"creates",
"anterior/",
"posterior",
"facilitation",
"of",
"movement,",
"by",
"purposefully",
"creating",
"medial",
"and",
"lateral",
"instability",
"in",
"the",
"shoe",
"[1].",
"*",
"Correspondence:",
"sophieroberts@thegaitlab.co.uk;",
"s.otter@brighton.ac.uk",
"1Outpatients",
"Department,",
"Parkside",
"Hospital,",
"53",
"Parkside,",
"London,",
"SW19",
"5NX,",
"UK",
"3University",
"of",
"Brighton,",
"School",
"of",
"Health",
"Sciences,",
"49",
"Darley",
"Rd,",
"Eastbourne,",
"BN20",
"7UR,",
"UK",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"According",
"to",
"Romkes",
"et",
"al",
"[2],",
"MBT",
"shoes",
"have",
"been",
"used",
"to",
"treat",
"foot",
"problems",
"such",
"as",
"hallux",
"valgus,",
"pes",
"planus,",
"heel",
"and",
"tendo-achilles",
"pain",
"as",
"well",
"as",
"circula-",
"tory",
"problems.",
"Nigg",
"et",
"al",
"[3]",
"found",
"that",
"MBT",
"shoes",
"may",
"be",
"useful",
"as",
"a",
"training",
"device",
"for",
"stability",
"and",
"mus-",
"cle",
"strengthening",
"adding",
"another",
"dimension",
"to",
"their",
"use.",
"However,",
"New",
"et",
"al",
"[4]",
"and",
"Nigg",
"et",
"al",
"[3]",
"found",
"that",
"subjects",
"from",
"many",
"of",
"the",
"studies",
"conducted",
"using",
"MBT",
"shoes",
"received",
"an",
"instruction",
"session",
"in",
"which",
"they",
"were",
"taught",
"how",
"to",
"use",
"the",
"shoes",
"correctly",
"by",
"a",
"qualified",
"instructor",
"and",
"given",
"a",
"long",
"training",
"period",
"to",
"acclimatise",
"to",
"the",
"shoes.",
"As",
"such",
"there",
"remains",
"debate",
"as",
"to",
"whether",
"the",
"reported",
"changes",
"in",
"gait",
"were",
"as",
"a",
"result",
"of",
"the",
"MBT",
"shoe",
"or",
"the",
"professional",
"instruction",
"in",
"gait",
"and",
"posture",
"the",
"subjects",
"received",
"and",
"the",
"train-",
"ing",
"period",
"they",
"had",
"[4].",
"Nigg",
"et",
"al",
"[3]",
"described",
"that",
"an",
"increase",
"in",
"the",
"angle",
"of",
"ankle",
"dorsiflexion",
"in",
"MBT",
"shoes",
"was",
"evident",
"com-",
"pared",
"to",
"a",
"standard",
"training",
"shoe.",
"Vernon",
"et",
"al",
"[5]",
"also",
"reported",
"subjects",
"exhibited",
"significantly",
"higher",
"maxi-",
"mum",
"dorsiflexion",
"angle",
"at",
"the",
"ankle",
"joint",
"when",
"wearing",
"©",
"2011",
"Roberts",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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] | [
"J",
"Korean",
"Med",
"Sci",
"2008;",
"23:",
"146-8",
"ISSN",
"1011-8934",
"DOI:",
"10.3346/jkms.2008.23.1.146",
"Copyright",
"The",
"Korean",
"Academy",
"of",
"Medical",
"Sciences",
"Unrelated",
"Bone",
"Marrow",
"Transplantation",
"with",
"a",
"Reduced",
"Toxicity",
"Myeloablative",
"Conditioning",
"Regimen",
"in",
"Wiskott-Aldrich",
"Syndrome",
"Wiskott-Aldrich",
"syndrome",
"(WAS)",
"is",
"an",
"X-linked",
"congenital",
"immune-deficiency",
"syn-",
"drome,",
"and",
"bone",
"marrow",
"transplantation",
"(BMT)",
"has",
"become",
"a",
"curative",
"modality.",
"However,",
"the",
"transplant",
"with",
"the",
"alternative",
"donor",
"needed",
"more",
"intensive",
"condi-",
"tioning",
"with",
"increased",
"treatment-related",
"toxicities.",
"Recently,",
"fludarabine-based",
"reduc-",
"ed",
"toxicity",
"myeloablative",
"conditioning",
"regimens",
"have",
"been",
"developed",
"for",
"adult",
"myeloid",
"malignancies",
"with",
"promising",
"results",
"of",
"good",
"engraftment",
"and",
"low",
"treatment-relat-",
"ed",
"toxicities.",
"To",
"increase",
"the",
"engraftment",
"potential",
"without",
"serious",
"complications,",
"a",
"boy",
"with",
"WAS",
"received",
"successful",
"unrelated",
"BMT",
"with",
"a",
"reduced",
"toxicity",
"myeloab-",
"lative",
"conditioning",
"regimen",
"composed",
"of",
"fludarabine",
"(40",
"mg/m2",
"on",
"days",
"-8,",
"-7,",
"-6,",
"-5,",
"-4,",
"-3),",
"busulfan",
"(0.8",
"mg/kg",
"i.",
"v.",
"q",
"6",
"hr",
"on",
"days",
"-6,",
"-5,",
"-4,",
"-3),",
"and",
"thymoglobulin",
"(2.5",
"mg/kg",
"on",
"days",
"-4,",
"-3,",
"-2).",
"This",
"novel",
"conditioning",
"regimen",
"could",
"improve",
"the",
"outcome",
"of",
"allogeneic",
"transplantation",
"for",
"other",
"non-malignant",
"diseases",
"such",
"as",
"congenital",
"immune-deficiency",
"syndromes",
"or",
"metabolic",
"storage",
"diseases.",
"Key",
"Words",
":",
"Wiskott-Aldrich",
"Syndrome;",
"Bone",
"Marrow",
"Transplantation;",
"Busulfan;",
"Fludarabine",
"Hyoung",
"Jin",
"Kang,",
"Hee",
"Young",
"Shin,",
"Sun",
"Hie",
"Ko,",
"Jeong",
"Ah",
"Park,",
"Eun",
"Kyung",
"Kim,",
"Jung",
"Woo",
"Rhim,",
"Joong",
"Gon",
"Kim,",
"Hyo",
"Seop",
"Ahn",
"Department",
"of",
"Pediatrics,",
"Cancer",
"Research",
"Institute,",
"Seoul",
"National",
"University",
"College",
"of",
"Medicine,",
"Seoul,",
"Korea",
"Received",
":",
"8",
"January",
"2007",
"Accepted",
":",
"21",
"February",
"2007",
"Address",
"for",
"correspondence",
"Hyo",
"Seop",
"Ahn,",
"M.D.",
"Department",
"of",
"Pediatrics,",
"Cancer",
"Research",
"Institute,",
"Seoul",
"National",
"University",
"College",
"of",
"Medicine,",
"28",
"Yeongeon-dong,",
"Jongno-gu,",
"Seoul",
"110-744,",
"Korea",
"Tel",
":",
"+82.2-2072-3625,",
"Fax",
":",
"+82.2-743-3455",
"E-mail",
":",
"hsahn@snu.ac.kr",
"*This",
"study",
"was",
"supported",
"by",
"grant",
"of",
"the",
"Korea",
"Health",
"21",
"R&D",
"Project,",
"Ministry",
"of",
"Health",
"&",
"Welfare,",
"Republic",
"of",
"Korea",
"(A050089).",
"INTRODUCTION",
"Wiskott-Aldrich",
"syndrome",
"(WAS)",
"is",
"an",
"X-linked",
"congen-",
"ital",
"immune-deficiency",
"syndrome",
"characterized",
"by",
"the",
"triad",
"of",
"recurrent",
"infection,",
"eczema,",
"and",
"thrombocytopenia,",
"and",
"bone",
"marrow",
"transplantation",
"(BMT)",
"from",
"an",
"HLA-matched",
"related",
"donor",
"is",
"an",
"effective",
"treatment",
"(1,",
"2).",
"Patients",
"with-",
"out",
"an",
"appropriate",
"related",
"donor",
"could",
"receive",
"an",
"alternative",
"stem",
"cell",
"source",
"such",
"as",
"matched",
"unrelated",
"donor",
"or",
"cord",
"blood.",
"However,",
"the",
"transplant",
"with",
"the",
"alternative",
"donor",
"needed",
"more",
"intensive",
"conditioning",
"to",
"overcome",
"the",
"hema-",
"tologic",
"and",
"immunologic",
"barrier",
"with",
"increased",
"treatment-",
"related",
"toxicity.",
"Recently,",
"fludarabine-based",
"reduced",
"toxici-",
"ty",
"myeloablative",
"conditioning",
"regimens",
"have",
"been",
"develop-",
"ed",
"for",
"adult",
"myeloid",
"malignancies",
"with",
"promising",
"results",
"of",
"good",
"engraftment",
"and",
"low",
"treatment",
"related",
"toxicities",
"(3-5).",
"To",
"increase",
"the",
"engraftment",
"potential",
"without",
"serious",
"com-",
"plications,",
"a",
"boy",
"with",
"WAS",
"received",
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] | [
"Int.",
"J.",
"Mol.",
"Sci.",
"2011,",
"12,",
"4975-4990;",
"doi:10.3390/ijms12084975",
"OPEN",
"ACCESS",
"International",
"Journal",
"of",
"Molecular",
"Sciences",
"ISSN",
"1422-0067",
"www.mdpi.com/journal/ijms",
"Article",
"Transient",
"Co-Expression",
"of",
"Post-Transcriptional",
"Gene",
"Silencing",
"Suppressors",
"for",
"Increased",
"in",
"Planta",
"Expression",
"of",
"a",
"Recombinant",
"Anthrax",
"Receptor",
"Fusion",
"Protein",
"Lucas",
"Arzola",
"1,",
"Junxing",
"Chen",
"1,",
"Kittipong",
"Rattanaporn",
"1,",
"James",
"M.",
"Maclean",
"2",
"and",
"Karen",
"A.",
"McDonald",
"1,*",
"1",
"Department",
"of",
"Chemical",
"Engineering",
"and",
"Materials",
"Science,",
"University",
"of",
"California,",
"Davis,",
"One",
"Shields",
"Ave,",
"Davis,",
"CA",
"95616,",
"USA;",
"E-Mails:",
"larzola@ucdavis.edu",
"(L.A.);",
"cicchen@ucdavis.edu",
"(J.C.);",
"krattanaporn@ucdavis.edu",
"(K.R.)",
"2",
"Planet",
"Biotechnology",
"Inc.,",
"25571",
"Clawiter",
"Road,",
"Hayward,",
"CA",
"94545,",
"USA;",
"E-Mail:",
"jmaclean@planetbiotechnology.com",
"*",
"Author",
"to",
"whom",
"correspondence",
"should",
"be",
"addressed;",
"E-Mail:",
"kamcdonald@ucdavis.edu;",
"Tel.:",
"+1-530-752-1979;",
"Fax:",
"+1-530-752-8058.",
"Received:",
"1",
"April",
"2011;",
"in",
"revised",
"form:",
"18",
"June",
"2011",
"/",
"Accepted:",
"20",
"July",
"2011",
"/",
"Published:",
"5",
"August",
"2011",
"Abstract:",
"Potential",
"epidemics",
"of",
"infectious",
"diseases",
"and",
"the",
"constant",
"threat",
"of",
"bioterrorism",
"demand",
"rapid,",
"scalable,",
"and",
"cost-efficient",
"manufacturing",
"of",
"therapeutic",
"proteins.",
"Molecular",
"farming",
"of",
"tobacco",
"plants",
"provides",
"an",
"alternative",
"for",
"the",
"recombinant",
"production",
"of",
"therapeutics.",
"We",
"have",
"developed",
"a",
"transient",
"production",
"platform",
"that",
"uses",
"Agrobacterium",
"infiltration",
"of",
"Nicotiana",
"benthamiana",
"plants",
"to",
"express",
"a",
"novel",
"anthrax",
"receptor",
"decoy",
"protein",
"(immunoadhesin),",
"CMG2-Fc.",
"This",
"chimeric",
"fusion",
"protein,",
"designed",
"to",
"protect",
"against",
"the",
"deadly",
"anthrax",
"toxins,",
"is",
"composed",
"of",
"the",
"von",
"Willebrand",
"factor",
"A",
"(VWA)",
"domain",
"of",
"human",
"capillary",
"morphogenesis",
"2",
"(CMG2),",
"an",
"effective",
"anthrax",
"toxin",
"receptor,",
"and",
"the",
"Fc",
"region",
"of",
"human",
"immunoglobulin",
"G",
"(IgG).",
"We",
"evaluated,",
"in",
"N.",
"benthamiana",
"intact",
"plants",
"and",
"detached",
"leaves,",
"the",
"expression",
"of",
"CMG2-Fc",
"under",
"the",
"control",
"of",
"the",
"constitutive",
"CaMV",
"35S",
"promoter,",
"and",
"the",
"co-expression",
"of",
"CMG2-Fc",
"with",
"nine",
"different",
"viral",
"suppressors",
"of",
"post-transcriptional",
"gene",
"silencing",
"(PTGS):",
"p1,",
"p10,",
"p19,",
"p21,",
"p24,",
"p25,",
"p38,",
"2b,",
"and",
"HCPro.",
"Overall,",
"transient",
"CMG2-Fc",
"expression",
"was",
"higher",
"on",
"intact",
"plants",
"than",
"detached",
"leaves.",
"Maximum",
"expression",
"was",
"observed",
"with",
"p1",
"co-expression",
"at",
"3.5",
"days",
"post-infiltration",
"(DPI),",
"with",
"a",
"level",
"of",
"0.56",
"g",
"CMG2-Fc",
"per",
"kg",
"of",
"leaf",
"fresh",
"weight",
"and",
"1.5%",
"of",
"the",
"total",
"soluble",
"protein,",
"a",
"ten-fold",
"increase",
"in",
"expression",
"when",
"compared",
"to"
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] | [
"A",
"Mouse",
"Model",
"for",
"Chikungunya:",
"Young",
"Age",
"and",
"Inefficient",
"Type-I",
"Interferon",
"Signaling",
"Are",
"Risk",
"Factors",
"for",
"Severe",
"Disease",
"The´",
"r",
"e`se",
"Couderc1,2[,",
"Fabrice",
"Chre´",
"tien3,4,5,6[,",
"Cl",
"e´mentine",
"Schilte7,8[,",
"Olivier",
"Disson1,2,9,",
"Madly",
"Brigitte4,5,6,",
"Florence",
"Guivel-Benhassine1,2,",
"Yasmina",
"Touret10,",
"Georges",
"Barau10,",
"Nade`",
"ge",
"Cayet11,",
"Isabelle",
"Schuffenecker12,",
"Philippe",
"Despr",
"e`s13,",
"Fernando",
"Arenzana-Seisdedos14,15,",
"Alain",
"Michault16,",
"Matthew",
"L.",
"Albert7,8[,",
"Marc",
"Lecuit1,2,9,17[*",
"1",
"Groupe",
"‘‘Microorganismes",
"et",
"Barrie`res",
"de",
"l’Hoˆte’’,",
"Institut",
"Pasteur,",
"Paris,",
"France,",
"2",
"E´quipe",
"Avenir",
"INSERM",
"U604",
"Paris,",
"France,",
"3",
"Unite´",
"‘‘Cellules",
"Souches",
"et",
"De´veloppement’’,",
"CNRS",
"URA",
"2578,",
"Institut",
"Pasteur,",
"Paris,",
"France,",
"4",
"INSERM,",
"U841,",
"Team",
"10,",
"Cre´teil,",
"France,",
"5",
"AP-HP,",
"Groupe",
"Hospitalier",
"Albert",
"Chenevier-Henri",
"Mondor,",
"De´partement",
"de",
"Pathologie,",
"Cre´teil,",
"France,",
"6",
"Universite´",
"Paris",
"XII,",
"Faculte´",
"de",
"Me´decine,",
"Cre´teil,",
"France,",
"7",
"Groupe",
"‘‘Immunobiologie",
"des",
"Cellules",
"Dendritiques’’,",
"Institut",
"Pasteur,",
"Paris,",
"France,",
"8",
"INSERM",
"U818,",
"Paris,",
"France,",
"9",
"Unite´",
"‘‘Interactions",
"Bacte´ries-Cellules’’,",
"Institut",
"Pasteur,",
"Paris,",
"France,",
"10",
"De´partement",
"de",
"Gyne´cologie",
"et",
"Obste´trique,",
"Groupe",
"Hospitalier",
"Sud-Re´union,",
"Saint-Pierre,",
"La",
"Re´union,",
"France,",
"11",
"Plateforme",
"de",
"Microscopie",
"Ultrastructurale,",
"Institut",
"Pasteur,",
"Paris,",
"France,",
"12",
"Centre",
"National",
"de",
"Re´fe´rence",
"des",
"Arbovirus,",
"Institut",
"Pasteur",
"Lyon,",
"France,",
"13",
"Unite´",
"‘‘Interactions",
"Mole´culaires",
"Flavivirus-Hoˆtes’’,",
"Institut",
"Pasteur,",
"Paris,",
"France,",
"14",
"Laboratoire",
"‘‘Pathoge´nie",
"Virale",
"Mole´culaire’’,",
"Institut",
"Pasteur,",
"Paris,",
"France,",
"15",
"CNRS",
"URA",
"3015,",
"Paris,",
"France,",
"16",
"Laboratoire",
"de",
"Microbiologie,",
"Groupe",
"Hospitalier",
"Sud-Re´union,",
"Saint-Pierre,",
"Ile",
"de",
"la",
"Re´union,",
"France,",
"17",
"Centre",
"d’Infectiologie",
"Necker-Pasteur,",
"Hoˆ",
"pital",
"Necker-Enfants",
"malades,",
"Assistance",
"Publique-Hoˆpitaux",
"de",
"Paris,",
"Universite´",
"Paris",
"Descartes,",
"Paris,",
"France",
"Chikungunya",
"virus",
"(CHIKV)",
"is",
"a",
"re-emerging",
"arbovirus",
"responsible",
"for",
"a",
"massive",
"outbreak",
"currently",
"afflicting",
"the",
"Indian",
"Ocean",
"region",
"and",
"India.",
"Infection",
"from",
"CHIKV",
"typically",
"induces",
"a",
"mild",
"disease",
"in",
"humans,",
"characterized",
"by",
"fever,",
"myalgia,",
"arthralgia,",
"and",
"rash.",
"Cases",
"of",
"severe",
"CHIKV",
"infection",
"involving",
"the",
"central",
"nervous",
"system",
"(CNS)",
"have",
"recently",
"been",
"described",
"in",
"neonates",
"as",
"well",
"as",
"in",
"adults",
"with",
"underlying",
"conditions.",
"The",
"pathophysiology",
"of",
"CHIKV",
"infection",
"and",
"the",
"basis",
"for",
"disease",
"severity",
"are",
"unknown.",
"To",
"address",
"these",
"critical",
"issues,",
"we",
"have",
"developed",
"an",
"animal",
"model",
"of",
"CHIKV",
"infection.",
"We",
"show",
"here",
"that",
"whereas",
"wild",
"type",
"(WT)",
"adult",
"mice",
"are",
"resistant",
"to",
"CHIKV",
"infection,",
"WT",
"mouse",
"neonates",
"are",
"susceptible",
"and",
"neonatal",
"disease",
"severity",
"is",
"age-dependent.",
"Adult",
"mice",
"with",
"a",
"partially",
"(IFN-a/bRþ/",
")",
"or",
"totally",
"(IFN-a/bR",
"/",
")",
"abrogated",
"type-I",
"IFN",
"pathway",
"develop",
"a",
"mild",
"or",
"severe",
"infection,",
"respectively.",
"In",
"mice",
"with",
"a",
"mild",
"infection,",
"after",
"a",
"burst",
"of",
"viral",
"replication",
"in",
"the",
"liver,",
"CHIKV",
"primarily",
"targets",
"muscle,",
"joint,",
"and",
"skin",
"fibroblasts,",
"a",
"cell",
"and",
"tissue",
"tropism",
"similar",
"to",
"that",
"observed",
"in",
"biopsy",
"samples",
"of",
"CHIKV-infected",
"humans.",
"In",
"case",
"of",
"severe",
"infections,",
"CHIKV",
"also",
"disseminates",
"to",
"other",
"tissues",
"including",
"the",
"CNS,",
"where",
"it",
"specifically",
"targets",
"the",
"choroid",
"plexuses",
"and",
"the",
"leptomeninges.",
"Together,",
"these",
"data",
"indicate",
"that",
"CHIKV-associated",
"symptoms",
"match",
"viral",
"tissue",
"and",
"cell",
"tropisms,",
"and",
"demonstrate",
"that",
"the",
"fibroblast",
"is",
"a",
"predominant",
"target",
"cell",
"of",
"CHIKV.",
"These",
"data",
"also",
"identify",
"the",
"neonatal",
"phase",
"and",
"inefficient",
"type-I",
"IFN",
"signaling",
"as",
"risk",
"factors",
"for",
"severe",
"CHIKV-associated",
"disease.",
"The",
"development",
"of",
"a",
"permissive",
"small",
"animal",
"model",
"will",
"expedite",
"the",
"testing",
"of",
"future",
"vaccines",
"and",
"therapeutic",
"candidates.",
"Citation:",
"Couderc",
"T,",
"Chre´tien",
"F,",
"Schilte",
"C,",
"Disson",
"O,",
"Brigitte",
"M,",
"et",
"al.",
"(2008)",
"A",
"mouse",
"model",
"for",
"Chikungunya:",
"young",
"age",
"and",
"inefficient",
"type-I",
"interferon",
"signaling",
"are",
"risk",
"factors",
"for",
"severe",
"disease.",
"PLoS",
"Pathog",
"4(2):",
"e29.",
"doi:10.1371/journal.ppat.0040029",
"Introduction",
"Chikungunya",
"virus",
"(CHIKV)",
"was",
"first",
"isolated",
"in",
"Tanzania",
"in",
"1953",
"[1],",
"and",
"has",
"recently",
"emerged",
"in",
"islands",
"of",
"the",
"Indian",
"Ocean",
"in",
"2005,",
"and",
"engendered",
"the",
"largest",
"Chikungunya",
"fever",
"epidemic",
"on",
"record",
"[2].",
"The",
"most",
"affected",
"region",
"was",
"the",
"island",
"of",
"La",
"Re´",
"union,",
"where",
"CHIKV",
"infected",
"approx-",
"imately",
"a",
"third",
"of",
"the",
"island’s",
"inhabitants",
"(i.e.,",
";300,000)",
"[3–",
"5].",
"The",
"outbreak,",
"which",
"now",
"also",
"involves",
"India",
"with",
"an",
"estimated",
"1.3",
"million",
"cases",
"[6–8],",
"has",
"a",
"significant",
"potential",
"to",
"spread",
"globally",
"given",
"the",
"wide",
"distribution",
"of",
"its",
"arthropod",
"vector",
"[9,10].",
"CHIKV",
"is",
"a",
"member",
"of",
"the",
"genus",
"Alphavirus",
"in",
"the",
"family",
"of",
"Togaviridae.",
"Alphaviruses",
"are",
"small,",
"enveloped",
"viruses",
"with",
"a",
"message-sense",
"RNA",
"genome",
"that",
"encodes",
"four",
"non-structural",
"proteins",
"(nsP1–4)",
"and",
"three",
"structural",
"proteins",
"(C,",
"E1–2).",
"This",
"arbovirus",
"is",
"maintained",
"in",
"nature",
"by",
"uninterrupted",
"cycles",
"of",
"transmission",
"between",
"mosquitoes",
"and",
"vertebrate",
"hosts",
"such",
"as",
"macaques",
"[11–13].",
"Several",
"alphaviruses",
"cause",
"disease",
"in",
"humans,",
"primarily",
"as",
"a",
"result",
"of",
"epizootic",
"infections.",
"These",
"include",
"the",
"American",
"encephalitic",
"alphavi-",
"ruses",
"and",
"several",
"species",
"in",
"the",
"Semliki",
"Forest",
"Virus",
"group,",
"principally",
"the",
"Afro-Asian",
"CHIKV,",
"the",
"African",
"O’Nyong-",
"Nyong",
"virus,",
"as",
"well",
"as",
"the",
"Australasian",
"Barmah",
"Forest",
"virus",
"and",
"Ross",
"River",
"virus",
"[14].",
"CHIKV",
"infection",
"is",
"characterized",
"by",
"fever,",
"arthralgia,",
"myalgia,",
"rash",
"and",
"headache.",
"During",
"the",
"La",
"R",
"e´union",
"Island",
"outbreak,",
"previously",
"unreported",
"severe",
"forms",
"of",
"Chikungunya",
"infection",
"were",
"observed",
"in",
"adults,",
"compli-",
"Editor:",
"Michael",
"J.",
"Buchmeier,",
"The",
"Scripps",
"Research",
"Institute,",
"United",
"States",
"of",
"America",
"Received",
"August",
"24,",
"2007;",
"Accepted",
"December",
"28,",
"2007;",
"Published",
"February",
"15,",
"2008",
"Copyright:",
"2008",
"Couderc",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Abbreviations:",
"BBB,",
"blood-brain",
"barrier;",
"CNS,",
"central",
"nervous",
"system;",
"CSF,",
"cerebrospinal",
"fluid;",
"D,",
"day;",
"DAB,",
"diaminobenzidine;",
"HRP,",
"horseradish-peroxidase;",
"ID,",
"intra-dermal;",
"IFN-a/bR,",
"IFN-a/b",
"receptor;",
"LD50,",
"lethal",
"dose",
"50;",
"MOI,",
"multiplicity",
"of",
"infection;",
"pi,",
"post",
"infection;",
"TCID50,",
"tissue",
"cytopathic",
"infectious",
"dose",
"50",
"*",
"To",
"whom",
"correspondence",
"should",
"be",
"addressed.",
"E-mail:",
"mlecuit@pasteur.fr",
"[",
"These",
"authors",
"contributed",
"equally",
"to",
"this",
"work.",
"PLoS",
"Pathogens",
"|",
"www.plospathogens.org",
"0001",
"February",
"2008",
"|",
"Volume",
"4",
"|",
"Issue",
"2",
"|",
"e29"
] | [
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3,
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"their",
"likely",
"response",
"to",
"treatment.",
"We",
"sought",
"to",
"determine",
"how",
"well",
"such",
"discussions",
"are",
"documented",
"in",
"a",
"typical",
"intensive",
"care",
"unit.",
"Methods:",
"Using",
"a",
"quality",
"of",
"communication",
"instrument",
"developed",
"from",
"a",
"literature",
"search",
"and",
"expert",
"opinion,",
"2",
"investigators",
"transcribed",
"and",
"analyzed",
"260",
"handwritten",
"communications",
"for",
"105",
"critically",
"ill",
"patients",
"who",
"died",
"in",
"the",
"intensive",
"care",
"unit",
"between",
"January",
"and",
"June",
"2006.",
"Cohen’s",
"kappa",
"was",
"calculated",
"before",
"analysis",
"and",
"then",
"disagreements",
"were",
"resolved",
"by",
"consensus.",
"We",
"report",
"results",
"on",
"a",
"per-patient",
"basis",
"to",
"represent",
"documented",
"communication",
"as",
"a",
"process",
"leading",
"up",
"to",
"the",
"time",
"of",
"death",
"in",
"the",
"ICU.",
"We",
"report",
"frequencies",
"and",
"percentages",
"for",
"discrete",
"data,",
"median",
"(m)",
"and",
"interquartile",
"range",
"(IQR)",
"for",
"continuous",
"data.",
"Results:",
"Our",
"cohort",
"was",
"elderly",
"(m",
"72,",
"IQR",
"58-81",
"years)",
"and",
"had",
"high",
"APACHE",
"II",
"scores",
"predictive",
"of",
"a",
"high",
"probability",
"of",
"death",
"(m",
"28,",
"IQR",
"23-36).",
"Length",
"of",
"stay",
"in",
"the",
"intensive",
"care",
"unit",
"prior",
"to",
"death",
"was",
"short",
"(m",
"2,",
"IQR",
"1-5",
"days),",
"and",
"withdrawal",
"of",
"life",
"support",
"preceded",
"death",
"for",
"more",
"than",
"half",
"(n",
"57,",
"54%).",
"Brain",
"death",
"criteria",
"were",
"present",
"for",
"18",
"patients",
"(17%).",
"Although",
"intensivists’",
"communications",
"were",
"timely",
"(median",
"17",
"h",
"from",
"admission",
"to",
"critical",
"care),",
"the",
"person",
"consenting",
"on",
"behalf",
"of",
"the",
"incapable",
"patient",
"was",
"explicitly",
"documented",
"for",
"only",
"10%",
"of",
"patients.",
"Life",
"support",
"strategies",
"at",
"the",
"time",
"of",
"communication",
"were",
"noted",
"in",
"45%",
"of",
"charts,",
"and",
"options",
"for",
"their",
"future",
"use",
"were",
"presented",
"in",
"88%.",
"Considerations",
"relevant",
"to",
"determining",
"the",
"patient’s",
"best",
"interest",
"in",
"relation",
"to",
"the",
"treatment",
"plan",
"were",
"not",
"well",
"documented.",
"While",
"explicit",
"survival",
"estimates",
"were",
"noted",
"in",
"50%",
"of",
"charts,",
"physicians",
"infrequently",
"documented",
"their",
"own",
"predictions",
"of",
"the",
"patient’s",
"functional",
"status",
"(20%),",
"anticipated",
"need",
"for",
"chronic",
"care",
"(0%),",
"or",
"post",
"ICU",
"quality",
"of",
"life",
"(3%).",
"Similarly,",
"documentation",
"of",
"the",
"patient’s",
"own",
"perspectives",
"on",
"these",
"ranged",
"from",
"2-18%.",
"Conclusions:",
"Intensivists’",
"documentation",
"of",
"their",
"communication",
"with",
"substitute",
"decision",
"makers",
"frequently",
"outlined",
"the",
"proposed",
"plan",
"of",
"treatment,",
"but",
"often",
"lacked",
"evidence",
"of",
"discussion",
"relevant",
"to",
"whether",
"the",
"treatment",
"plan",
"was",
"expected",
"to",
"improve",
"the",
"patient’s",
"condition.",
"Legislative",
"standards",
"for",
"determination",
"of",
"best",
"interest,",
"such",
"as",
"the",
"Health",
"Care",
"Consent",
"Act",
"in",
"Ontario,",
"Canada,",
"may",
"provide",
"guidance",
"for",
"intensivists",
"to",
"optimally",
"document",
"the",
"rationales",
"for",
"proposed",
"treatment",
"plans.",
"Background",
"The",
"appropriate",
"use",
"of",
"scarce",
"critical",
"care",
"resources",
"is",
"an",
"important",
"target",
"for",
"quality",
"improvement",
"in",
"our",
"health",
"care",
"system.",
"For",
"example,",
"the",
"final",
"report",
"of",
"the",
"Ontario",
"Critical",
"Care",
"Strategy",
"states",
"“considerable",
"*",
"Correspondence:",
"andrew.cooper@williamoslerhs.ca",
"2Department",
"of",
"Critical",
"Care",
"Medicine,",
"William",
"Osler",
"Health",
"System,",
"Brampton",
"Civic",
"Hospital,",
"2100",
"Bovaird",
"Drive",
"East,",
"Brampton,",
"Ontario",
"L6R",
"3J7,",
"Canada",
"anecdotal",
"evidence",
"exists",
"that",
"Critical",
"Care",
"in",
"Ontario",
"is",
"often",
"provided",
"to",
"patients",
"who",
"do",
"not,",
"or",
"can",
"no",
"longer",
"benefit",
"from",
"this",
"level",
"of",
"care”[1].",
"In",
"a",
"grounded",
"theory",
"investigation,",
"senior",
"intensive",
"care",
"staff",
"at",
"16",
"Ontario",
"intensive",
"care",
"units",
"defined",
"medically",
"futile",
"care",
"as",
"“the",
"use",
"of",
"considerable",
"resources",
"without",
"a",
"reasonable",
"hope",
"that",
"the",
"patient",
"might",
"recover",
"to",
"a",
"state",
"of",
"relative",
"inde-",
"pendence,",
"or",
"to",
"be",
"interactive",
"with",
"the",
"environment”[2].",
"Providers",
"identified",
"family",
"demands",
"and",
"a",
"lack",
"of",
"timely",
"©",
"2010",
"Ratnapalan",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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"regulates",
"downstream",
"signaling",
"of",
"many",
"receptor",
"tyrosine",
"kinases.",
"During",
"signal",
"transduction,",
"FRS2",
"can",
"be",
"both",
"tyrosine",
"and",
"threonine",
"phosphorylated",
"and",
"forms",
"signaling",
"complexes",
"with",
"other",
"adaptor",
"proteins",
"and",
"tyrosine",
"phosphatases.",
"We",
"have",
"here",
"identified",
"flotillin-1",
"and",
"the",
"cbl-associated",
"protein/ponsin",
"(CAP)",
"as",
"novel",
"interaction",
"partners",
"of",
"FRS2.",
"Flotillin-1",
"binds",
"to",
"the",
"phosphotyrosine",
"binding",
"domain",
"(PTB)",
"of",
"FRS2",
"and",
"competes",
"for",
"the",
"binding",
"with",
"the",
"fibroblast",
"growth",
"factor",
"receptor.",
"Flotillin-1",
"knockdown",
"results",
"in",
"increased",
"Tyr",
"phosphorylation",
"of",
"FRS2,",
"in",
"line",
"with",
"the",
"inhibition",
"of",
"ERK",
"activity",
"in",
"the",
"absence",
"of",
"flotillin-1.",
"CAP",
"directly",
"interacts",
"with",
"FRS2",
"by",
"means",
"of",
"its",
"sorbin",
"homology",
"(SoHo)",
"domain,",
"which",
"has",
"previously",
"been",
"shown",
"to",
"interact",
"with",
"flotillin-1.",
"In",
"addition,",
"the",
"third",
"SH3",
"domain",
"in",
"CAP",
"binds",
"to",
"FRS2.",
"Due",
"to",
"the",
"overlapping",
"binding",
"domains,",
"CAP",
"and",
"flotillin-1",
"appear",
"to",
"compete",
"for",
"the",
"binding",
"to",
"FRS2.",
"Thus,",
"our",
"results",
"reveal",
"a",
"novel",
"signaling",
"network",
"containing",
"FRS2,",
"CAP",
"and",
"flotillin-1,",
"whose",
"successive",
"interactions",
"are",
"most",
"likely",
"required",
"to",
"regulate",
"receptor",
"tyrosine",
"kinase",
"signaling,",
"especially",
"the",
"mitogen",
"activated",
"protein",
"kinase",
"pathway.",
"Citation:",
"Tomasovic",
"A,",
"Traub",
"S,",
"Tikkanen",
"R",
"(2012)",
"Molecular",
"Networks",
"in",
"FGF",
"Signaling:",
"Flotillin-1",
"and",
"Cbl-Associated",
"Protein",
"Compete",
"for",
"the",
"Binding",
"to",
"Fibroblast",
"Growth",
"Factor",
"Receptor",
"Substrate",
"2.",
"PLoS",
"ONE",
"7(1):",
"e29739.",
"doi:10.1371/journal.pone.0029739",
"Editor:",
"Henning",
"Ulrich,",
"University",
"of",
"Sa˜o",
"Paulo,",
"Brazil",
"Received",
"July",
"12,",
"2011;",
"Accepted",
"December",
"4,",
"2011;",
"Published",
"January",
"3,",
"2012",
"Copyright:",
"2012",
"Tomasovic",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"Funds",
"were",
"received",
"from",
"Deutsche",
"Forschungsgemeinschaft",
"DFG",
"(www.dfg.de),",
"personal",
"grant",
"to",
"RT",
"(Ti",
"291/6-1).",
"The",
"funders",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript.",
"Competing",
"Interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"*",
"E-mail:",
"Ritva.Tikkanen@biochemie.med.uni-giessen.de",
"¤",
"Current",
"address:",
"Dermatology,",
"University",
"Clinic",
"of",
"Cologne,",
"Cologne,",
"Germany",
"Introduction",
"Fibroblast",
"growth",
"factor",
"receptor",
"substrate",
"2",
"(FRS2/FRS2a/",
"SNT1)",
"is",
"a",
"membrane",
"linked",
"docking",
"protein",
"originally",
"identified",
"as",
"a",
"protein",
"that",
"becomes",
"tyrosine",
"phosphorylated",
"upon",
"nerve",
"growth",
"factor",
"(NGF)",
"or",
"fibroblast",
"growth",
"factor",
"(FGF)",
"stimulation",
"in",
"PC12",
"cells",
"[1,2,3].",
"Together",
"with",
"FGF",
"receptor",
"substrate",
"3",
"(FRS3/FRS2b/SNT2),",
"it",
"belongs",
"to",
"the",
"FRS",
"adaptor",
"protein",
"family",
"[4].",
"In",
"this",
"paper,",
"we",
"will",
"use",
"the",
"name",
"FRS2",
"for",
"FRS2a/",
"SNT1,",
"and",
"FRS3",
"for",
"FRS2b/SNT2",
"for",
"the",
"sake",
"of",
"clarity.",
"FRS2",
"and",
"FRS3",
"share",
"a",
"similar",
"structure",
"and",
"48%",
"of",
"amino",
"acid",
"sequence",
"identity.",
"In",
"the",
"N-terminus,",
"they",
"contain",
"a",
"consensus",
"myristoylation",
"sequence",
"which",
"is",
"important",
"for",
"the",
"membrane",
"localization",
"[1].",
"This",
"sequence",
"is",
"followed",
"by",
"a",
"phosphotyrosine",
"binding",
"(PTB)",
"domain",
"that",
"is",
"highly",
"similar",
"between",
"the",
"two",
"proteins.",
"The",
"PTB",
"domain",
"binds",
"specific",
"peptides",
"of",
"certain",
"receptor",
"tyrosine",
"kinases",
"(RTKs)",
"with",
"or",
"without",
"tyrosine",
"phosphorylated",
"residues",
"[5,6].",
"FRS2",
"is",
"ubiquitously",
"expressed",
"with",
"the",
"highest",
"expression",
"in",
"brain,",
"kidney,",
"lung,",
"ovary",
"and",
"testis",
"and",
"can",
"be",
"detected",
"at",
"all",
"developmental",
"stages",
"of",
"a",
"mouse",
"[7].",
"FRS2",
"knockout",
"mice",
"show",
"embryonic",
"lethality",
"due",
"to",
"severe",
"problems",
"in",
"gastrulation",
"[8,9],",
"demonstrating",
"how",
"crucial",
"FGF",
"signaling",
"is",
"in",
"animal",
"development.",
"In",
"contrast",
"to",
"FRS2,",
"the",
"expression",
"of",
"FRS3",
"protein",
"begins",
"around",
"day",
"9",
"and",
"is",
"restricted",
"to",
"tissues",
"of",
"neuronal",
"origin",
"[7,10].",
"When",
"exogenously",
"expressed",
"in",
"FRS2-null",
"mouse",
"embryonic",
"fibroblasts,",
"FRS3",
"compensates",
"for",
"the",
"loss",
"of",
"FRS2",
"by",
"stimulating",
"FGF",
"induced",
"activation",
"of",
"extracellularly",
"regulated",
"kinase",
"(ERK),",
"a",
"member",
"of",
"the",
"mitogen",
"activated",
"protein",
"(MAP)",
"kinase",
"family",
"[10].",
"Both",
"FRS2",
"and",
"FRS3",
"are",
"tyrosine",
"phosphorylated",
"in",
"response",
"to",
"NGF,",
"FGF",
"[9,11]",
"and",
"glial",
"derived",
"neurotrophic",
"factor",
"(GDNF)",
"[12,13],",
"but",
"only",
"FRS2",
"is",
"threonine",
"phosphorylated.",
"Phosphor-",
"ylation",
"of",
"8",
"threonine",
"residues",
"in",
"FRS2",
"occurs",
"as",
"a",
"response",
"to",
"stimulation",
"with",
"FGF,",
"epidermal",
"growth",
"factor",
"(EGF),",
"insulin",
"and",
"platelet",
"derived",
"growth",
"factor",
"(PDGF).",
"This",
"represents",
"a",
"negative",
"feedback",
"mechanism",
"in",
"which",
"activated",
"ERK",
"inhibits",
"further",
"tyrosine",
"phosphorylation",
"of",
"FRS2",
"by",
"phosphorylating",
"its",
"threo-",
"nine",
"residues",
"[14,15].",
"FRS2",
"plays",
"an",
"important",
"role",
"in",
"FGF",
"dependent",
"proliferation",
"and",
"migration",
"of",
"the",
"cells",
"[1]",
"and",
"in",
"differentiation",
"of",
"PC12",
"cells",
"by",
"regulating",
"sustained",
"ERK",
"activity",
"upon",
"FGF",
"or",
"NGF",
"stimuli",
"[1,16,17].",
"It",
"is",
"tyrosine",
"phosphorylated",
"upon",
"insulin",
"treatment,",
"but",
"its",
"precise",
"role",
"in",
"insulin",
"signaling",
"pathway",
"remains",
"largely",
"unknown",
"[18].",
"The",
"C-terminus",
"of",
"FRS",
"proteins",
"bears",
"multiple",
"tyrosine",
"phosphorylation",
"sites",
"(6",
"Tyr",
"in",
"FRS2),",
"which,",
"when",
"phosphory-",
"lated",
"by",
"specific",
"RTKs,",
"recruit",
"SH2-domain",
"containing",
"proteins",
"such",
"as",
"adaptor",
"protein",
"Grb2",
"(4",
"Tyr",
"in",
"FRS2)",
"and",
"protein",
"tyrosine",
"phosphatase",
"Shp2",
"(2",
"Tyr",
"in",
"FRS2)",
"[1,19].",
"The",
"recruitment",
"of",
"Grb2",
"eventually",
"results",
"in",
"a",
"strong",
"activation",
"of",
"PI3-kinase",
"signaling",
"and",
"moderate",
"activation",
"of",
"ERK",
"pathway",
"[9,20],",
"while",
"phosphorylation",
"and",
"subsequent",
"activation",
"of",
"Shp2",
"will",
"result",
"in",
"a",
"strong",
"activation",
"of",
"ERK",
"signaling",
"[9].",
"PLoS",
"ONE",
"|",
"www.plosone.org",
"1",
"January",
"2012",
"|",
"Volume",
"7",
"|",
"Issue",
"1",
"|",
"e29739"
] | [
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] | [
"Hermsdorff",
"et",
"al.",
"Nutrition",
"&",
"Metabolism",
"2010,",
"7:42",
"http://www.nutritionandmetabolism.com/content/7/1/42",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"Open",
"Access",
"RFerseuaricth",
"and",
"vegetable",
"consumption",
"and",
"proinflammatory",
"gene",
"expression",
"from",
"peripheral",
"blood",
"mononuclear",
"cells",
"in",
"young",
"adults:",
"a",
"translational",
"study",
"Helen",
"Hermana",
"M",
"Hermsdorff,",
"María",
"Ángeles",
"Zulet,",
"Blanca",
"Puchau",
"and",
"José",
"Alfredo",
"Martínez*",
"Abstract",
"Background:",
"Fruits",
"and",
"vegetables",
"are",
"important",
"sources",
"of",
"fiber",
"and",
"nutrients",
"with",
"a",
"recognized",
"antioxidant",
"capacity,",
"which",
"could",
"have",
"beneficial",
"effects",
"on",
"the",
"proinflammatory",
"status",
"as",
"well",
"as",
"some",
"metabolic",
"syndrome",
"and",
"cardiovascular",
"disease",
"features.",
"The",
"current",
"study",
"assessed",
"the",
"potential",
"relationships",
"of",
"fruit",
"and",
"vegetable",
"consumption",
"with",
"the",
"plasma",
"concentrations",
"and",
"mRNA",
"expression",
"values",
"of",
"some",
"proinflammatory",
"markers",
"in",
"young",
"adults.",
"Methods:",
"One-hundred",
"and",
"twenty",
"healthy",
"subjects",
"(50",
"men/70",
"women;",
"20.8",
"±",
"2.6",
"y;",
"22.3",
"±",
"2.8",
"kg/m2)",
"were",
"enrolled.",
"Experimental",
"determinations",
"included",
"anthropometry,",
"blood",
"pressure",
"and",
"lifestyle",
"features",
"as",
"well",
"as",
"blood",
"biochemical",
"and",
"inflammatory",
"measurements.",
"The",
"mRNA",
"was",
"isolated",
"from",
"peripheral",
"blood",
"mononuclear",
"cells",
"(PBMC)",
"and",
"the",
"gene",
"expression",
"concerning",
"selected",
"inflammatory",
"markers",
"was",
"assessed",
"by",
"quantitative",
"real-time",
"PCR.",
"Nutritional",
"intakes",
"were",
"estimated",
"by",
"a",
"validated",
"semi-quantitative",
"food-frequency",
"questionnaire.",
"Results:",
"The",
"highest",
"tertile",
"of",
"energy-adjusted",
"fruit",
"and",
"vegetable",
"consumption",
"(>660",
"g/d)",
"was",
"associated",
"with",
"lower",
"plasma",
"concentrations",
"of",
"C-reactive",
"protein",
"(CRP)",
"and",
"homocysteine",
"and",
"with",
"lower",
"ICAM1,",
"IL1R1,",
"IL6,",
"TNFα",
"and",
"NFκB1",
"gene",
"expression",
"in",
"PBMC",
"(P",
"for",
"trend",
"<",
"0.05),",
"independently",
"of",
"gender,",
"age,",
"energy",
"intake,",
"physical",
"activity,",
"smoking,",
"body",
"mass",
"index,",
"systolic",
"blood",
"pressure",
"and",
"circulating",
"non-esterified",
"fatty",
"acids.",
"In",
"addition,",
"plasma",
"CRP,",
"homocysteine",
"and",
"TNFα",
"concentrations",
"and",
"ICAM1,",
"TNFα",
"and",
"NFκB1",
"gene",
"expression",
"in",
"PBMC",
"showed",
"a",
"descending",
"trend",
"as",
"increased",
"fiber",
"intake",
"(>19.5",
"g/d)",
"from",
"fruits",
"and",
"vegetables",
"(P",
"for",
"trend",
"<",
"0.05).",
"Furthermore,",
"the",
"participants",
"within",
"the",
"higher",
"tertile",
"(>11.8",
"mmol/d)",
"of",
"dietary",
"total",
"antioxidant",
"capacity",
"showed",
"lower",
"plasma",
"CRP",
"and",
"mRNA",
"values",
"of",
"ICAM1,",
"IL1R1,",
"IL6,",
"TNFα",
"and",
"NFκB1",
"genes",
"(P",
"for",
"trend",
"<",
"0.05).",
"The",
"inverse",
"association",
"between",
"fruit",
"and",
"vegetable",
"consumption",
"and",
"study",
"proinflammatory",
"markers",
"followed",
"the",
"same",
"trend",
"and",
"remained",
"statistically",
"significant,",
"after",
"the",
"inclusion",
"of",
"other",
"foods/nutrients",
"in",
"the",
"linear",
"regression",
"models.",
"Conclusion:",
"A",
"higher",
"fruit",
"and",
"vegetable",
"consumption",
"was",
"independently",
"associated",
"not",
"only",
"with",
"reduced",
"CRP",
"and",
"homocysteine",
"concentrations",
"but",
"also",
"with",
"a",
"lower",
"mRNA",
"expression",
"in",
"PBMC",
"of",
"some",
"relevant",
"proinflammatory",
"markers",
"in",
"healthy",
"young",
"adults.",
"Background",
"A",
"low-chronic",
"inflammatory",
"status",
"is",
"a",
"recognized",
"link",
"between",
"excessive",
"adiposity",
"and",
"metabolic",
"syndrome",
"fea-",
"tures,",
"diabetes,",
"and",
"atherosclerosis",
"[1,2].",
"In",
"fact,",
"a",
"num-",
"ber",
"of",
"studies",
"has",
"demonstrated",
"an",
"increased",
"expression",
"*",
"Correspondence:",
"jalfmtz@unav.es",
"1",
"Department",
"of",
"Nutrition,",
"Food",
"Science,",
"Physiology",
"and",
"Toxicology,",
"University",
"of",
"Navarra,",
"Pamplona,",
"Spain",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"of",
"transcription",
"nuclear",
"factors",
"such",
"as",
"nuclear-factor-",
"kappa-B",
"(NFκB)",
"as",
"well",
"as",
"of",
"interleukins",
"(IL)",
"and",
"tumor",
"necrosis",
"factor-alpha",
"(TNFα)",
"in",
"obese",
"subjects",
"[1,3].",
"These",
"changes",
"appear",
"to",
"involve",
"a",
"higher",
"production",
"of",
"proinflammatory",
"and",
"pro-atherogenic",
"molecules",
"such",
"as",
"C-reactive",
"protein",
"(CRP),",
"homocysteine,",
"selectins",
"and",
"adhesion",
"molecules",
"as",
"well",
"as",
"some",
"cytokines",
"[1,3].",
"Fur-",
"thermore,",
"circulating",
"peripheral",
"blood",
"mononuclear",
"cells",
"©",
"2010",
"Hermsdorff",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Com-",
"BioMed",
"Central",
"mons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduc-",
"tion",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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] | [
"IMMUNOME",
"RESEARCH",
"Open",
"Access",
"EL-Manzalawy",
"and",
"Honavar",
"Immunome",
"Research",
"2010,",
"6(Suppl",
"2):S2",
"http://www.immunome-research.com/content/6/S2/S2",
"R",
"E",
"V",
"I",
"E",
"W",
"Abstract",
"Recent",
"advances",
"in",
"B-cell",
"epitope",
"prediction",
"methods",
"Yasser",
"EL-Manzalawy1,2*,",
"Vasant",
"Honavar2*",
"Identification",
"of",
"epitopes",
"that",
"invoke",
"strong",
"responses",
"from",
"B-cells",
"is",
"one",
"of",
"the",
"key",
"steps",
"in",
"designing",
"effective",
"vaccines",
"against",
"pathogens.",
"Because",
"experimental",
"determination",
"of",
"epitopes",
"is",
"expensive",
"in",
"terms",
"of",
"cost,",
"time,",
"and",
"effort",
"involved,",
"there",
"is",
"an",
"urgent",
"need",
"for",
"computational",
"methods",
"for",
"reliable",
"identification",
"of",
"B-cell",
"epitopes.",
"Although",
"several",
"computational",
"tools",
"for",
"predicting",
"B-cell",
"epitopes",
"have",
"become",
"available",
"in",
"recent",
"years,",
"the",
"pre-",
"dictive",
"performance",
"of",
"existing",
"tools",
"remains",
"far",
"from",
"ideal.",
"We",
"review",
"recent",
"advances",
"in",
"computational",
"methods",
"for",
"B-cell",
"epitope",
"prediction,",
"identify",
"some",
"gaps",
"in",
"the",
"current",
"state",
"of",
"the",
"art,",
"and",
"outline",
"some",
"promising",
"direc-",
"tions",
"for",
"improving",
"the",
"reliability",
"of",
"such",
"methods.",
"Review",
"Antigen-antibody",
"interactions",
"play",
"a",
"pivotal",
"role",
"in",
"the",
"humoral",
"immune",
"response.",
"Antibodies",
"bind",
"to",
"antigens",
"at",
"specific",
"sites",
"which",
"correspond",
"to",
"the",
"antigenic",
"deter-",
"minants",
"or",
"B-cell",
"epitopes.",
"Identification",
"and",
"characteri-",
"zation",
"of",
"B-cell",
"epitopes",
"in",
"target",
"antigens",
"is",
"one",
"of",
"the",
"key",
"steps",
"in",
"epitope-driven",
"vaccine",
"design,",
"immunodiag-",
"nostic",
"tests,",
"and",
"antibody",
"production.",
"B-cell",
"epitopes",
"typically",
"belong",
"to",
"one",
"of",
"two",
"classes:",
"linear",
"(continuous",
"or",
"sequential)",
"epitopes",
"or",
"conformational",
"(discontinu-",
"ous)",
"epitopes.",
"Linear",
"epitopes",
"are",
"short",
"peptides",
"that",
"correspond",
"to",
"a",
"contiguous",
"amino",
"acid",
"sequence",
"frag-",
"ment",
"of",
"a",
"protein",
"[1,2].",
"Linear",
"epitopes",
"are",
"usually",
"iden-",
"tified",
"using",
"assays",
"such",
"as",
"PEPSCAN.",
"Consequently,",
"current",
"experimental",
"methods",
"offer",
"little",
"direct",
"evidence",
"indicating",
"that",
"each",
"residue",
"in",
"the",
"epitope",
"does",
"in",
"fact",
"make",
"contact",
"with",
"one",
"or",
"more",
"residues",
"in",
"the",
"paratope",
"(the",
"part",
"in",
"the",
"antibody",
"that",
"binds",
"to",
"the",
"antigen)",
"[3].",
"Conformational",
"epitopes",
"are",
"composed",
"of",
"amino",
"acids",
"that",
"although",
"not",
"contiguous",
"in",
"primary",
"sequence,",
"are",
"brought",
"into",
"close",
"proximity",
"within",
"the",
"folded",
"3-dimen-",
"sional",
"protein",
"structure.",
"Most",
"B-cell",
"epitopes,",
"although",
"they",
"are",
"composed",
"of",
"short",
"linear",
"peptides,",
"appear",
"to",
"be",
"conformational",
"epitopes.",
"*",
"Correspondence:",
"yasser@iastate.edu;",
"honavar@iastate.edu",
"1Department",
"of",
"Systems",
"and",
"Computer",
"Engineering,",
"Al-Azhar",
"University,",
"Egypt",
"2Department",
"of",
"Computer",
"Science,",
"Artificial",
"Intelligence",
"Research",
"Laboratory,",
"Center",
"for",
"Computational",
"Intelligence,",
"Learning,",
"and",
"Discovery,",
"Iowa",
"State",
"University,",
"USA",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"Several",
"experimental",
"techniques",
"are",
"currently",
"available",
"for",
"experimental",
"mapping",
"of",
"B-cell",
"epitopes",
"[4].",
"How-",
"ever,",
"the",
"high",
"cost",
"and",
"effort",
"involved",
"makes",
"them",
"impractical",
"for",
"application",
"on",
"a",
"genomic",
"scale.",
"Compu-",
"tational",
"techniques",
"offer",
"a",
"fast,",
"scalable,",
"and",
"cost-effec-",
"tive",
"approach",
"for",
"predicting",
"B-cell",
"epitopes,",
"for",
"focusing",
"experimental",
"investigations",
"and",
"for",
"improving",
"our",
"understanding",
"of",
"antigen-antibody",
"interactions.",
"Hence,",
"there",
"is",
"a",
"growing",
"interest",
"in",
"the",
"development",
"of",
"sophis-",
"ticated",
"computational",
"tools",
"for",
"reliable",
"prediction",
"of",
"B-cell",
"epitopes.",
"Several",
"computational",
"methods",
"for",
"B-cell",
"epitope",
"pre-",
"diction",
"have",
"been",
"developed",
"in",
"recent",
"years",
"(e.g.,",
"[5-14]).",
"However,",
"the",
"predictive",
"performance",
"of",
"current",
"methods",
"is",
"far",
"from",
"ideal",
"[15].",
"To",
"complicate",
"matters,",
"immunogenicity",
"of",
"proteins",
"is",
"poorly",
"understood",
"[16]",
"and",
"whether",
"B-cell",
"epitopes",
"could",
"be",
"deciphered",
"as",
"an",
"intrinsic",
"features",
"of",
"the",
"protein",
"remains",
"an",
"open",
"ques-",
"tion",
"[17].",
"Recent",
"studies",
"have",
"pointed",
"out",
"some",
"of",
"the",
"limitations",
"of",
"current",
"epitope",
"prediction",
"methods",
"[6,17,18].",
"Hence,",
"increasing",
"the",
"reliability",
"of",
"computa-",
"tional",
"methods",
"for",
"B-cell",
"epitope",
"prediction",
"remains",
"a",
"major",
"challenge",
"in",
"computational",
"vaccinology",
"[19].",
"In",
"2007,",
"the",
"National",
"Institute",
"of",
"Allergy",
"and",
"Infectious",
"Diseases",
"(NIAID)",
"sponsored",
"a",
"workshop",
"and",
"a",
"meeting",
"of",
"a",
"panel",
"of",
"immunologists",
"and",
"bioinformaticians",
"in",
"order",
"to",
"assess",
"the",
"current",
"state",
"of",
"the",
"art",
"in",
"epitope",
"prediction",
"and",
"to",
"identify",
"some",
"areas",
"for",
"further",
"research",
"[15].",
"One",
"of",
"the",
"key",
"goals",
"of",
"the",
"workshop",
"was",
"to",
"facilitate",
"and",
"expedite",
"the",
"development",
"of",
"improved",
"©",
"2010",
"EL-Manzalawy",
"and",
"Honavar;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"open",
"access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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] | [
"Toranza",
"and",
"Arim",
"BMC",
"Ecology",
"2010,",
"10:18",
"http://www.biomedcentral.com/1472-6785/10/18",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Carolina",
"Toranza1*,",
"Matías",
"Arim2,3",
"Abstract",
"Cross-taxon",
"congruence",
"and",
"environmental",
"conditions",
"Open",
"Access",
"Background:",
"Diversity",
"patterns",
"of",
"different",
"taxa",
"typically",
"covary",
"in",
"space,",
"a",
"phenomenon",
"called",
"cross-taxon",
"congruence.",
"This",
"pattern",
"has",
"been",
"explained",
"by",
"the",
"effect",
"of",
"one",
"taxon",
"diversity",
"on",
"taxon",
"diversity,",
"shared",
"biogeographic",
"histories",
"of",
"different",
"taxa,",
"and/or",
"common",
"responses",
"to",
"environmental",
"conditions.",
"A",
"meta-analysis",
"of",
"the",
"association",
"between",
"environment",
"and",
"diversity",
"patterns",
"found",
"that",
"in",
"83",
"out",
"of",
"85",
"studies,",
"more",
"than",
"60%",
"of",
"the",
"spatial",
"variability",
"in",
"species",
"richness",
"was",
"related",
"to",
"variables",
"representing",
"energy,",
"water",
"or",
"their",
"interaction.",
"The",
"role",
"of",
"the",
"environment",
"determining",
"taxa",
"diversity",
"patterns",
"leads",
"us",
"to",
"hypothesize",
"that",
"this",
"would",
"explain",
"the",
"observed",
"cross-taxon",
"congruence.",
"However,",
"recent",
"analyses",
"reported",
"the",
"persistence",
"of",
"cross-taxon",
"congruence",
"when",
"environmental",
"effect",
"was",
"statistically",
"removed.",
"Here",
"we",
"evaluate",
"this",
"hypothesis,",
"analyzing",
"the",
"cross-taxon",
"congruence",
"between",
"birds",
"and",
"mammals",
"in",
"the",
"Brazilian",
"Cerrado,",
"and",
"assess",
"the",
"environmental",
"role",
"on",
"the",
"spatial",
"covariation",
"in",
"diversity",
"patterns.",
"Results:",
"We",
"found",
"a",
"positive",
"association",
"between",
"avian",
"and",
"mammal",
"richness",
"and",
"a",
"positive",
"latitudinal",
"trend",
"for",
"both",
"groups",
"in",
"the",
"Brazilian",
"Cerrado.",
"Regression",
"analyses",
"indicated",
"an",
"effect",
"of",
"latitude,",
"PET,",
"and",
"mean",
"temperature",
"over",
"both",
"biological",
"groups.",
"In",
"addition,",
"we",
"show",
"that",
"NDVI",
"was",
"only",
"associated",
"with",
"avian",
"diversity;",
"while",
"the",
"annual",
"relative",
"humidity,",
"was",
"only",
"correlated",
"with",
"mammal",
"diversity.",
"We",
"determined",
"the",
"environmental",
"effects",
"on",
"diversity",
"in",
"a",
"path",
"analysis",
"that",
"accounted",
"for",
"73%",
"and",
"76%",
"of",
"the",
"spatial",
"variation",
"in",
"avian",
"and",
"mammal",
"richness.",
"However,",
"an",
"association",
"between",
"avian",
"and",
"mammal",
"diversity",
"remains",
"significant.",
"Indeed,",
"the",
"importance",
"of",
"this",
"link",
"between",
"bird",
"and",
"mammal",
"diversity",
"was",
"also",
"supported",
"by",
"a",
"significant",
"association",
"between",
"birds",
"and",
"mammal",
"spatial",
"autoregressive",
"model",
"residuals.",
"Conclusion:",
"Our",
"study",
"corroborates",
"the",
"main",
"role",
"of",
"environmental",
"conditions",
"on",
"diversity",
"patterns,",
"but",
"suggests",
"that",
"other",
"important",
"mechanisms,",
"which",
"have",
"not",
"been",
"properly",
"evaluated,",
"are",
"involved",
"in",
"the",
"observed",
"cross-",
"taxon",
"congruence.",
"The",
"approaches",
"introduced",
"here",
"indicate",
"that",
"the",
"prevalence",
"of",
"a",
"significant",
"association",
"among",
"taxa,",
"after",
"considering",
"the",
"environmental",
"determinant,",
"could",
"indicate",
"both",
"the",
"need",
"to",
"incorporate",
"additional",
"processes",
"(e.g.",
"biogeographic",
"and",
"evolutionary",
"history",
"or",
"trophic",
"interactions)",
"and/or",
"the",
"existence",
"of",
"a",
"shared",
"trend",
"in",
"detection",
"biases",
"among",
"taxa",
"and",
"regions.",
"Background",
"Spatial",
"concordance",
"in",
"diversity",
"of",
"different",
"taxa",
"is",
"a",
"recurrent",
"feature",
"in",
"nature",
"[1-3].",
"The",
"strength",
"of",
"this",
"association,",
"known",
"as",
"cross-taxon",
"congruence,",
"depends",
"on",
"the",
"studied",
"taxonomic",
"groups",
"and",
"the",
"scale",
"of",
"analy-",
"sis",
"[4].",
"This",
"is",
"because",
"the",
"spatial",
"association",
"in",
"diversity",
"patterns",
"of",
"related",
"taxa",
"is",
"typically",
"larger",
"than",
"that",
"observed",
"between",
"weakly",
"related",
"taxa",
"[5]",
"and",
"is",
"more",
"*",
"Correspondence:",
"ctoranza@gmail.com",
"1Instituto",
"de",
"Ecología",
"y",
"Ciencias",
"Ambientales,",
"Facultad",
"de",
"Ciencias,",
"Universidad",
"de",
"la",
"República,",
"Uruguay,",
"Iguá",
"4225",
"Piso",
"8",
"Sur,",
"Montevideo,",
"Uruguay",
"common",
"over",
"large",
"geographic",
"scales",
"[6].",
"This",
"scale",
"dependence",
"in",
"the",
"strength",
"of",
"spatial",
"taxonomic",
"covaria-",
"tion",
"would",
"be",
"associated",
"with",
"changes",
"in",
"the",
"factors",
"determining",
"species",
"richness",
"at",
"different",
"scales",
"[7-9].",
"A",
"finer",
"spatial",
"scale",
"would",
"increase",
"the",
"role",
"of",
"biological",
"interactions",
"like",
"competition",
"[10],",
"which",
"may",
"lessen",
"the",
"spatial",
"congruence",
"between",
"different",
"groups.",
"Several",
"hypotheses",
"have",
"been",
"proposed",
"to",
"explain",
"the",
"cross",
"cor-",
"relation",
"between",
"major",
"taxa",
"diversity.",
"These",
"can",
"be",
"grouped",
"into",
"those",
"that",
"focus",
"on",
"the",
"diversity",
"effect",
"of",
"one",
"taxon",
"on",
"another",
"taxon’s",
"diversity;",
"those",
"that",
"pro-",
"pose",
"that",
"the",
"diversity",
"patterns",
"of",
"different",
"taxa",
"are",
"©",
"2010",
"Toranza",
"and",
"Arim;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
] | [
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423,
609,
453,
623
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457,
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623
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494,
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549,
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602,
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606,
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622,
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653,
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481,
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483,
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547,
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808,
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423,
841,
467,
855
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841,
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492,
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564,
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] | [
"Gresback",
"et",
"al.",
"Nanoscale",
"Research",
"Letters",
"2011,",
"6:68",
"http://www.nanoscalereslett.com/content/6/1/68",
"N",
"A",
"N",
"O",
"E",
"X",
"P",
"R",
"E",
"S",
"S",
"Open",
"Access",
"Combined",
"plasma",
"gas-phase",
"synthesis",
"and",
"colloidal",
"processing",
"of",
"InP/ZnS",
"core/shell",
"nanocrystals",
"Ryan",
"Gresback1,",
"Ryan",
"Hue2,",
"Wayne",
"L",
"Gladfelter2,",
"Uwe",
"R",
"Kortshagen1*",
"Abstract",
"Indium",
"phosphide",
"nanocrystals",
"(InP",
"NCs)",
"with",
"diameters",
"ranging",
"from",
"2",
"to",
"5",
"nm",
"were",
"synthesized",
"with",
"a",
"scalable,",
"flow-through,",
"nonthermal",
"plasma",
"process",
"at",
"a",
"rate",
"ranging",
"from",
"10",
"to",
"40",
"mg/h.",
"The",
"NC",
"size",
"is",
"controlled",
"through",
"the",
"plasma",
"operating",
"parameters,",
"with",
"the",
"residence",
"time",
"of",
"the",
"gas",
"in",
"the",
"plasma",
"region",
"strongly",
"influencing",
"the",
"NC",
"size.",
"The",
"NC",
"size",
"distribution",
"is",
"narrow",
"with",
"the",
"standard",
"deviation",
"being",
"less",
"than",
"20%",
"of",
"the",
"mean",
"NC",
"size.",
"Zinc",
"sulfide",
"(ZnS)",
"shells",
"were",
"grown",
"around",
"the",
"plasma-synthesized",
"InP",
"NCs",
"in",
"a",
"liquid",
"phase",
"reaction.",
"Photoluminescence",
"with",
"quantum",
"yields",
"as",
"high",
"as",
"15%",
"were",
"observed",
"for",
"the",
"InP/ZnS",
"core-shell",
"NCs.",
"Introduction",
"Over",
"the",
"last",
"two",
"decades,",
"semiconductor",
"nanocrystals",
"(NCs)",
"have",
"attracted",
"significant",
"attention",
"because",
"of",
"their",
"various",
"unique",
"properties.",
"Semiconductor",
"NCs",
"provide",
"size-tunable",
"optical",
"and",
"electrical",
"properties,",
"based",
"on",
"quantum",
"confinement",
"of",
"charge",
"carriers",
"within",
"them,",
"high",
"surface-to-volume",
"ratios,",
"and",
"other",
"attributes",
"that",
"have",
"led",
"to",
"the",
"development",
"of",
"a",
"new",
"generation",
"of",
"materials",
"and",
"devices",
"[1,2].",
"A",
"significant",
"amount",
"of",
"study",
"has",
"focused",
"on",
"compound",
"semiconduc-",
"tor",
"NCs",
"of",
"the",
"II-VI",
"and",
"IV-VI",
"systems",
"because",
"of",
"the",
"relative",
"ease",
"of",
"synthesizing",
"high",
"quality",
"materials",
"using",
"colloidal",
"techniques",
"[3,4].",
"While",
"synthesis",
"and",
"surface",
"functionalization",
"methods",
"for",
"these",
"NC",
"materials",
"are",
"well",
"established",
"and",
"NCs",
"have",
"shown",
"impressive",
"optical",
"and",
"electronic",
"properties,",
"there",
"exists",
"considerable",
"inter-",
"est",
"to",
"produce",
"systems",
"consisting",
"of",
"NCs",
"of",
"other",
"mate-",
"rials",
"whose",
"constituent",
"elements",
"pose",
"less",
"of",
"an",
"environmental",
"concern,",
"which",
"are",
"more",
"radiation",
"resis-",
"tant,",
"and",
"less",
"prone",
"to",
"photo-oxidation.",
"Compound",
"semiconductor",
"NCs",
"of",
"the",
"III-V",
"systems",
"may",
"offer",
"some",
"of",
"these",
"desirable",
"attributes.",
"While",
"III-V",
"semiconductors",
"are",
"known",
"to",
"be",
"“radiation-hard,”",
"they",
"also",
"are",
"direct",
"bandgap",
"semiconductors,",
"which",
"is",
"a",
"big",
"advantage",
"for",
"optical",
"applications",
"compared",
"to,",
"for",
"*",
"Correspondence:",
"kortshagen@umn.edu",
"1Department",
"of",
"Mechanical",
"Engineering,",
"University",
"of",
"Minnesota,",
"Minneapolis,",
"MN,",
"USA",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"instance,",
"group",
"IV",
"NC",
"materials",
"[5].",
"Hence,",
"there",
"has",
"been",
"considerable",
"interest",
"in",
"the",
"synthesis",
"of",
"high",
"qual-",
"ity",
"III-V",
"compound",
"NCs,",
"such",
"as",
"indium",
"phosphide",
"(InP).",
"While",
"synthesizing",
"methods",
"similar",
"to",
"those",
"of",
"II-",
"VI",
"semiconductor",
"NCs",
"can",
"be",
"applied",
"to",
"InP",
"NCs,",
"these",
"have",
"turned",
"out",
"to",
"be",
"very",
"difficult",
"and",
"time",
"consuming,",
"often",
"requiring",
"days",
"to",
"produce",
"NCs",
"of",
"high",
"quality",
"[6,7].",
"More",
"recently,",
"synthesis",
"of",
"high",
"quality",
"InP",
"NCs",
"has",
"been",
"achieved",
"with",
"non-coordinating",
"solvents",
"[8]",
"and",
"weak-coordinating",
"solvents",
"[9].",
"However,",
"as",
"these",
"synthesizing",
"methods",
"require",
"organic",
"surfactants",
"to",
"sta-",
"bilize",
"NCs",
"in",
"solution",
"during",
"synthesis,",
"they",
"provide",
"challenges",
"for",
"applications",
"of",
"the",
"synthesized",
"NCs",
"in",
"devices",
"because",
"of",
"the",
"often",
"electrically",
"insulating",
"nature",
"of",
"the",
"ligands.",
"Synthesis",
"of",
"NCs",
"using",
"nonthermal",
"plasmas",
"has",
"become",
"a",
"viable",
"method",
"even",
"for",
"materials,",
"which",
"need",
"to",
"be",
"produced",
"in",
"crystalline",
"form",
"requiring",
"high",
"tem-",
"peratures,",
"such",
"as",
"Si",
"[10,11]",
"and",
"Ge",
"[12].",
"An",
"added",
"advantage",
"of",
"plasma",
"synthesis",
"as",
"compared",
"to",
"liquid",
"phase",
"routes",
"is",
"that",
"the",
"resulting",
"material",
"is",
"free",
"of",
"ligands",
"or",
"surfactants,",
"and",
"that",
"the",
"ligands",
"can",
"be",
"added",
"later",
"depending",
"on",
"the",
"targeted",
"application.",
"This",
"makes",
"integration",
"of",
"plasma-produced",
"NCs",
"into",
"devices",
"easier,",
"as",
"it",
"eliminates",
"intermediate",
"steps",
"of",
"ligand",
"exchanges",
"often",
"required",
"for",
"II-VI",
"and",
"IV-VI",
"NCs.",
"In",
"this",
"article,",
"we",
"propose",
"a",
"method",
"to",
"synthesize",
"InP",
"NCs",
"with",
"a",
"nonthermal",
"plasma.",
"In",
"addition,",
"we",
"show",
"that",
"solution",
"chemistry",
"routes",
"can",
"be",
"used",
"for",
"post-synthesis",
"©",
"2011",
"Gresback",
"et",
"al;",
"licensee",
"Springer.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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] | [
"CASE",
"REPORT",
"http://dx.doi.org/10.4070/kcj.2011.41.12.763",
"Print",
"ISSN",
"1738-5520",
"/",
"On-line",
"ISSN",
"1738-5555",
"Copyright",
"©",
"2011",
"The",
"Korean",
"Society",
"of",
"Cardiology",
"Open",
"Access",
"ABSTRACT",
"Stent",
"Fracture",
"at",
"the",
"Proximal",
"Shaft",
"of",
"the",
"Left",
"Main",
"Stem",
"Jae",
"Ho",
"Lee,",
"MD1,",
"Suk",
"Min",
"Seo,",
"MD1,2,",
"Eun",
"Oh",
"Kim,",
"MD1,",
"Hyo",
"Jun",
"Ahn,",
"MD1,",
"Yang",
"Won",
"Lee,",
"MD1,",
"Yul-Hee",
"Cho,",
"MD1,",
"Inwoon",
"Baek,",
"MD1,",
"You",
"Suk",
"Oh,",
"MD1,",
"Jihyun",
"Yu,",
"MD1,",
"and",
"Ki-Bae",
"Seung,",
"MD1,2",
"1Department",
"of",
"Internal",
"Medicine",
"and",
"2Cardiovascular",
"Center",
"and",
"Cardiology",
"Division,",
"Seoul",
"St.",
"Mary’s",
"Hospital,",
"College",
"of",
"Medicine,",
"The",
"Catholic",
"University",
"of",
"Korea,",
"Seoul,",
"Korea",
"Stent",
"fracture",
"is",
"likely",
"to",
"be",
"caused",
"due",
"to",
"mechanical",
"stress",
"at",
"the",
"hinge",
"point",
"or",
"kinking",
"movement",
"at",
"the",
"point",
"of",
"aneurysm",
"formation",
"with",
"stent",
"malapposition.",
"To",
"our",
"knowledge,",
"this",
"is",
"the",
"first",
"published",
"report",
"of",
"stent",
"fracture",
"at",
"the",
"proximal",
"shaft",
"of",
"the",
"left",
"main",
"stem",
"in",
"a",
"patient",
"with",
"acute",
"myocardial",
"infarction.",
"(Korean",
"Circ",
"J",
"2011;41:763-765)",
"KEY",
"WORDS:",
"Stent",
"fracture;",
"Left",
"main",
"stem;",
"Acute",
"myocardial",
"infarction.",
"Introduction",
"The",
"suggested",
"predisposing",
"factors",
"associated",
"with",
"frac-",
"tures",
"of",
"coronary",
"stent",
"are",
"sites",
"of",
"increased",
"vessel",
"movement,",
"lengthy",
"coronary",
"stents,",
"right",
"coronary",
"artery",
"stents,",
"overlapp-",
"ing",
"stents,",
"sirolimus-eluting",
"stents",
"(SES),",
"and",
"saphenous",
"vein",
"graft",
"stents.1)2)",
"In",
"addition,",
"stent",
"fracture",
"is",
"likely",
"to",
"be",
"caused",
"due",
"to",
"bending",
"movement",
"such",
"as",
"torsion,",
"flexion,",
"and",
"rotation",
"at",
"the",
"hinge",
"point",
"or",
"kinking",
"movement",
"at",
"the",
"point",
"of",
"aneu-",
"rysm",
"formation",
"with",
"stent",
"malapposition.3)",
"We",
"report",
"the",
"first",
"case",
"of",
"stent",
"fracture",
"at",
"the",
"proximal",
"shaft",
"of",
"the",
"left",
"main",
"stem",
"(LMS).",
"Case",
"A",
"55-year-old",
"man",
"visited",
"our",
"hospital",
"for",
"follow-up",
"coron-",
"ary",
"angiography.",
"He",
"had",
"no",
"particular",
"symptoms",
"prior",
"to",
"ad-",
"mission,",
"but",
"he",
"wanted",
"to",
"undergo",
"coronary",
"angiography.",
"Sm-",
"oking",
"was",
"the",
"only",
"cardiovascular",
"risk",
"factor.",
"Received:",
"February",
"10,",
"2011",
"Revision",
"Received:",
"March",
"8,",
"2011",
"Accepted:",
"March",
"22,",
"2011",
"Correspondence:",
"Ki-Bae",
"Seung,",
"MD,",
"Department",
"of",
"Internal",
"Medicine",
"and",
"Cardiovascular",
"Center",
"and",
"Cardiology",
"Division,",
"Seoul",
"St.",
"Mary’s",
"Hos-",
"pital,",
"College",
"of",
"Medicine,",
"The",
"Catholic",
"University",
"of",
"Korea,",
"222",
"Banpo-",
"daero,",
"Seocho-gu,",
"Seoul",
"137-701,",
"Korea",
"Tel:",
"82-2-2258-1134,",
"Fax:",
"82-2-591-1506",
"E-mail:",
"kbseung@catholic.ac.kr",
"•",
"The",
"authors",
"have",
"no",
"financial",
"conflicts",
"of",
"interest.",
"cc",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Cre-",
"ative",
"Commons",
"Attribution",
"Non-Commercial",
"License",
"(http://creativecom-",
"mons.org/licenses/by-nc/3.0)",
"which",
"permits",
"unrestricted",
"non-commer-",
"cial",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"origi-",
"nal",
"work",
"is",
"properly",
"cited.",
"763",
"Twenty-one",
"months",
"ago,",
"primary",
"percutaneous",
"coronary",
"intervention",
"was",
"performed",
"because",
"of",
"symptoms",
"of",
"progres-",
"sive",
"angina",
"and",
"ST-segment",
"elevation",
"on",
"the",
"electrocardio-",
"gram.",
"He",
"was",
"diagnosed",
"with",
"acute",
"myocardial",
"infarction",
"(AMI)",
"with",
"the",
"culprit",
"lesion",
"being",
"a",
"long",
"stenotic",
"lesion",
"in-",
"volving",
"the",
"segment",
"from",
"the",
"ostium",
"of",
"the",
"LMS",
"to",
"the",
"mid",
"left",
"anterior",
"descending",
"coronary",
"artery",
"(LAD)",
"(Fig.",
"1A).",
"We",
"implanted",
"SES",
"(Cypher®,",
"Cordis,",
"3.5×23",
"mm)",
"from",
"the",
"ostium",
"of",
"the",
"LMS",
"to",
"the",
"proximal",
"LAD",
"and",
"then",
"overlapped",
"paclitaxel-eluting",
"stent",
"(Taxus®,",
"Boston,",
"3.0×32",
"mm)",
"at",
"the",
"proximal",
"to",
"mid-LAD.",
"Additional",
"ballooning",
"was",
"also",
"per-",
"formed,",
"using",
"high-pressure",
"balloon",
"(Quantum®,",
"Schneider,",
"4.0×12",
"mm)",
"up",
"to",
"10",
"atm",
"for",
"15",
"seconds",
"(Fig.",
"1B).",
"Intravas-",
"cular",
"ultrasound",
"(IVUS;",
"42",
"mHz,",
"Clear",
"View,",
"MA,",
"Boston,",
"USA)",
"confirmed",
"well-positioned",
"stents.",
"Follow-up",
"coronary",
"angiography",
"showed",
"stent",
"fracture",
"at",
"the",
"proximal",
"shaft",
"of",
"the",
"LMS",
"with",
"minimal",
"luminal",
"narrow-",
"ing",
"(Fig.",
"2A",
"and",
"B).",
"IVUS",
"revealed",
"the",
"absence",
"of",
"the",
"stent",
"strut",
"corresponding",
"to",
"stent",
"fracture",
"and",
"ectatic",
"change",
"with",
"malapposition",
"of",
"stent",
"around",
"the",
"site",
"of",
"stent",
"fracture",
"(Fig.",
"2C,",
"D",
"and",
"E).",
"Based",
"on",
"these",
"findings,",
"the",
"lesion",
"was",
"redi-",
"lated",
"up",
"to",
"16",
"atm",
"for",
"15",
"seconds",
"with",
"high-pressure",
"balloon",
"(Quantum®,",
"Schneider,",
"4.0×12",
"mm).",
"Finally,",
"IVUS",
"confirm-",
"ed",
"well-apposite",
"struts.",
"Discussion",
"The",
"suggested",
"predisposing",
"factors",
"associated",
"with",
"stent",
"fracture",
"are",
"sites",
"of",
"increased",
"vessel",
"movement,",
"lengthy",
"cor-",
"onary",
"stents,",
"right",
"coronary",
"artery",
"stents,",
"overlapping",
"stents,",
"SES,",
"and",
"saphenous",
"vein",
"graft",
"stents.1)2)",
"Fractures",
"occur",
"as",
"a"
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] | [
"Lu",
"et",
"al.",
"Journal",
"of",
"Neuroinflammation",
"2010,",
"7:46",
"http://www.jneuroinflammation.com/content/7/1/46",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"JOURNAL",
"OF",
"NEUROINFLAMMATION",
"Open",
"Access",
"Resveratrol",
"differentially",
"modulates",
"inflammatory",
"responses",
"of",
"microglia",
"and",
"astrocytes",
"Xiaofeng",
"Lu1†,",
"Lili",
"Ma1†,",
"Lingfei",
"Ruan1,2,",
"Yan",
"Kong1,2,",
"Haiwei",
"Mou1,2,",
"Zhijie",
"Zhang1,",
"Zhijun",
"Wang4,",
"Ji",
"Ming",
"Wang3,",
"Yingying",
"Le1,2*",
"Abstract",
"Background:",
"Inflammatory",
"responses",
"in",
"the",
"CNS",
"mediated",
"by",
"activated",
"glial",
"cells",
"play",
"an",
"important",
"role",
"in",
"host-",
"defense",
"but",
"are",
"also",
"involved",
"in",
"the",
"development",
"of",
"neurodegenerative",
"diseases.",
"Resveratrol",
"is",
"a",
"natural",
"polyphenolic",
"compound",
"that",
"has",
"cardioprotective,",
"anticancer",
"and",
"anti-inflammatory",
"properties.",
"We",
"investigated",
"the",
"capacity",
"of",
"resveratrol",
"to",
"protect",
"microglia",
"and",
"astrocyte",
"from",
"inflammatory",
"insults",
"and",
"explored",
"mechanisms",
"underlying",
"different",
"inhibitory",
"effects",
"of",
"resveratrol",
"on",
"microglia",
"and",
"astrocytes.",
"Methods:",
"A",
"murine",
"microglia",
"cell",
"line",
"(N9),",
"primary",
"microglia,",
"or",
"astrocytes",
"were",
"stimulated",
"by",
"LPS",
"with",
"or",
"without",
"different",
"concentrations",
"of",
"resveratrol.",
"The",
"expression",
"and",
"release",
"of",
"proinflammatory",
"cytokines",
"(TNF-a,",
"IL-",
"1b,",
"IL-6,",
"MCP-1)",
"and",
"iNOS/NO",
"by",
"the",
"cells",
"were",
"measured",
"by",
"PCR/real-time",
"PCR",
"and",
"ELISA,",
"respectively.",
"The",
"phosphorylation",
"of",
"the",
"MAP",
"kinase",
"superfamily",
"was",
"analyzed",
"by",
"western",
"blotting,",
"and",
"activation",
"of",
"NF-",
"B",
"and",
"AP-",
"1",
"was",
"measured",
"by",
"luciferase",
"reporter",
"assay",
"and/or",
"electrophoretic",
"mobility",
"shift",
"assay.",
"Results:",
"We",
"found",
"that",
"LPS",
"stimulated",
"the",
"expression",
"of",
"TNF-a,",
"IL-1b,",
"IL-6,",
"MCP-1",
"and",
"iNOS",
"in",
"murine",
"microglia",
"and",
"astrocytes",
"in",
"which",
"MAP",
"kinases,",
"NF-",
"B",
"and",
"AP-1",
"were",
"differentially",
"involved.",
"Resveratrol",
"inhibited",
"LPS-",
"induced",
"expression",
"and",
"release",
"of",
"TNF-a,",
"IL-6,",
"MCP-1,",
"and",
"iNOS/NO",
"in",
"both",
"cell",
"types",
"with",
"more",
"potency",
"in",
"microglia,",
"and",
"inhibited",
"LPS-induced",
"expression",
"of",
"IL-1b",
"in",
"microglia",
"but",
"not",
"astrocytes.",
"Resveratrol",
"had",
"no",
"effect",
"on",
"LPS-stimulated",
"phosphorylation",
"of",
"ERK1/2",
"and",
"p38",
"in",
"microglia",
"and",
"astrocytes,",
"but",
"slightly",
"inhibited",
"LPS-",
"stimulated",
"phosphorylation",
"of",
"JNK",
"in",
"astrocytes.",
"Resveratrol",
"inhibited",
"LPS-induced",
"NF-",
"B",
"activation",
"in",
"both",
"cell",
"types,",
"but",
"inhibited",
"AP-1",
"activation",
"only",
"in",
"microglia.",
"Conclusion:",
"These",
"results",
"suggest",
"that",
"murine",
"microglia",
"and",
"astrocytes",
"produce",
"proinflammatory",
"cytokines",
"and",
"NO",
"in",
"response",
"to",
"LPS",
"in",
"a",
"similar",
"pattern",
"with",
"some",
"differences",
"in",
"signaling",
"molecules",
"involved,",
"and",
"further",
"suggest",
"that",
"resveratrol",
"exerts",
"anti-inflammatory",
"effects",
"in",
"microglia",
"and",
"astrocytes",
"by",
"inhibiting",
"different",
"proinflammatory",
"cytokines",
"and",
"key",
"signaling",
"molecules.",
"Background",
"Microglia,",
"the",
"resident",
"macrophage-like",
"cells",
"in",
"the",
"brain,",
"play",
"an",
"important",
"role",
"in",
"host",
"defense",
"and",
"tissue",
"repair",
"in",
"CNS",
"[1,2].",
"Activated",
"microglia",
"produce",
"a",
"vari-",
"ety",
"of",
"pro-inflammatory",
"mediators,",
"including",
"tumor",
"necrosis",
"factor",
"a",
"(TNF-a),",
"interleukin-1b",
"(IL-1b),",
"IL-6,",
"monocyte",
"chemotactic",
"protein",
"1",
"(MCP-1,",
"CCL2),",
"nitric",
"oxide",
"(NO),",
"and",
"reactive",
"oxygen",
"species",
"(ROS).",
"*",
"Correspondence:",
"yyle@sibs.ac.cn",
"†",
"Contributed",
"equally",
"1Key",
"laboratory",
"of",
"Nutrition",
"and",
"Metabolism,",
"Institute",
"for",
"Nutritional",
"Sciences,",
"Shanghai",
"Institutes",
"for",
"Biological",
"Sciences;",
"Chinese",
"Academy",
"of",
"Sciences,",
"Shanghai",
"200031,",
"China",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"Activated",
"microglia",
"serve",
"immune",
"surveillance",
"functions",
"by",
"removing",
"foreign",
"microorganisms,",
"but",
"may",
"also",
"result",
"in",
"excessive",
"inflammatory",
"responses",
"in",
"the",
"CNS",
"[1,2].",
"Astrocytes",
"are",
"the",
"main",
"glial",
"cell",
"type",
"in",
"the",
"brain",
"involved",
"in",
"maintaining",
"CNS",
"homeostasis.",
"They",
"also",
"respond",
"promptly",
"to",
"injury",
"and",
"regulate",
"neuroinflam-",
"matory",
"events",
"[2-4].",
"Both",
"in",
"vitro",
"and",
"in",
"vivo",
"studies",
"have",
"documented",
"the",
"ability",
"of",
"astrocytes",
"to",
"produce",
"a",
"variety",
"of",
"cytokines,",
"including",
"IL-1,",
"IL-6,",
"IL-10,",
"inter-",
"feron-a",
"(INF-a),",
"IFN-b,",
"TNF-a,",
"TNF-b;",
"and",
"chemo-",
"kines,",
"including",
"RANTES",
"(CCL5),",
"IL-8",
"(CXCL8)",
"and",
"MCP-1",
"[3].",
"Over-activation",
"of",
"glial",
"cells",
"and",
"release",
"of",
"proinflammatory",
"cytokines",
"may",
"lead",
"to",
"neuronal",
"death",
"[5-7],",
"causing",
"neuropathological",
"changes",
"in",
"CNS",
"©",
"2010",
"Lu",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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] | [
"|",
"Case",
"Report",
"|",
"Korean",
"J",
"Pain",
"2012",
"January;",
"Vol.",
"25,",
"No.",
"1:",
"52-54",
"pISSN",
"2005-9159",
"eISSN",
"2093-0569",
"http://dx.doi.org/10.3344/kjp.2012.25.1.52",
"Treatment",
"Experience",
"of",
"Pulsed",
"Radiofrequency",
"Under",
"Ultrasound",
"Guided",
"to",
"the",
"Trapezius",
"Muscle",
"at",
"Myofascial",
"Pain",
"Syndrome",
"-A",
"Case",
"Report-",
"Department",
"of",
"Anesthesiology",
"and",
"Pain",
"Medicine,",
"Yonsei",
"University",
"College",
"of",
"Medicine,",
"Seoul,",
"Korea",
"Chung",
"Hoon",
"Park,",
"MD,",
"Yoon",
"Woo",
"Lee,",
"MD,",
"Yong",
"Chan",
"Kim,",
"MD,",
"Joo",
"Hwa",
"Moon,",
"MD,",
"and",
"Jong",
"Bum",
"Choi,",
"MD",
"Trigger",
"point",
"injection",
"treatment",
"is",
"an",
"effective",
"and",
"widely",
"applied",
"treatment",
"for",
"myofascial",
"pain",
"syndrome.",
"The",
"trapezius",
"muscle",
"frequently",
"causes",
"myofascial",
"pain",
"in",
"neck",
"area.",
"We",
"herein",
"report",
"a",
"case",
"in",
"which",
"direct",
"pulsed",
"radiofrequency",
"(RF)",
"treatment",
"was",
"applied",
"to",
"the",
"trapezius",
"muscle.",
"We",
"observed",
"that",
"the",
"RF",
"treatment",
"produced",
"continuous",
"pain",
"relief",
"when",
"the",
"effective",
"duration",
"of",
"trigger",
"point",
"injection",
"was",
"temporary",
"in",
"myofascial",
"pain.",
"(Korean",
"J",
"Pain",
"2012;",
"25:",
"52-54)",
"Key",
"Words:",
"myofascial",
"pain,",
"pulsed",
"RF",
"(radiofrequency),",
"trigger",
"point",
"injection.",
"Myofascial",
"pain",
"syndrome",
"is",
"a",
"common",
"disease.",
"The",
"rary",
"treatment",
"method.",
"Therefore,",
"we",
"report",
"on",
"a",
"my-",
"main",
"treatment",
"includes",
"injection",
"therapy",
"at",
"the",
"trigger",
"ofascial",
"pain",
"syndrome",
"case",
"where",
"direct",
"pulsed",
"radio-",
"point",
"and",
"medication",
"in",
"which",
"an",
"analgesic",
"anti-inflam-",
"frequency",
"treatment",
"was",
"applied",
"to",
"the",
"trapezius",
"muscle",
"matory",
"agent",
"and",
"muscle",
"relaxant",
"are",
"administrated",
"on",
"which",
"TPI",
"had",
"been",
"sufficiently",
"effective",
"but",
"of",
"short",
"together.",
"Trigger",
"point",
"injection",
"(TPI)",
"is",
"widely",
"applied",
"duration.",
"Moreover,",
"the",
"analgesic",
"effect",
"of",
"the",
"pulsed",
"RF",
"since",
"it",
"is",
"effective",
"in",
"most",
"cases",
"and",
"easily",
"performed",
"on",
"treatment",
"was",
"maintained",
"for",
"a",
"considerable",
"duration.",
"outpatients.",
"However,",
"the",
"duration",
"of",
"pain",
"relief",
"may,",
"in",
"some",
"cases,",
"be",
"short.",
"Hence,",
"many",
"patients",
"return",
"to",
"the",
"clinic",
"as",
"outpatients",
"when",
"the",
"analgesic",
"effect",
"diminishes.",
"TPI",
"may",
"be",
"used",
"many",
"times,",
"but",
"repetitive",
"TPI",
"may",
"be",
"CASE",
"REPORT",
"A",
"47-year",
"old",
"female",
"patient",
"visited",
"our",
"clinic",
"with",
"the",
"rejected",
"because",
"of",
"its",
"cost",
"and",
"the",
"fact",
"that",
"it",
"relies",
"on",
"main",
"complaint",
"of",
"neck",
"pain",
"that",
"had",
"become",
"severe",
"over",
"a",
"needle",
"injection.",
"Some",
"patients",
"consider",
"TPI",
"as",
"a",
"tempo-",
"the",
"past",
"year.",
"The",
"medical",
"history",
"showed",
"that",
"the",
"patient",
"Received",
"September",
"30,",
"2011.",
"Revised",
"November",
"15,",
"2011.",
"Accepted",
"November",
"15,",
"2011.",
"Correspondence",
"to:",
"Jong",
"Bum",
"Choi,",
"MD",
"Department",
"of",
"Anesthesioligy",
"and",
"Pain",
"Medicine,",
"Gangnam",
"Severance",
"Hospital,",
"712,",
"Eonju-ro,",
"Gangnam-gu,",
"Seoul",
"135-720,",
"Korea",
"Tel:",
"+82-2-2019-3520,",
"Fax:",
"+82-2-3463-0940,",
"E-mail:",
"romeojb@yuhs.ac",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"Non-Commercial",
"License",
"(http://",
"creativecommons.org/licenses/by-nc/3.0/),",
"which",
"permits",
"unrestricted",
"non-commercial",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Copyright",
"ⓒ",
"The",
"Korean",
"Pain",
"Society,",
"2012"
] | [
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] | [
"organic",
"compounds",
"Acta",
"Crystallographica",
"Section",
"E",
"Structure",
"Reports",
"Online",
"ISSN",
"1600-5368",
"4-(5-Amino-1H-1,2,4-triazol-3-yl)-",
"pyridinium",
"chloride",
"monohydrate",
"Victor",
"M.",
"Chernyshev,a",
"Elena",
"V.",
"Tarasova,a",
"Anna",
"V.",
"Chernyshevaa",
"and",
"Victor",
"B.",
"Rybakovb*",
"aSouth-Russia",
"State",
"Technical",
"University,",
"346428",
"Novocherkassk,",
"Russian",
"Federation,",
"and",
"bDepartment",
"of",
"Chemistry,",
"Moscow",
"State",
"University,",
"119992",
"Moscow,",
"Russian",
"Federation",
"Correspondence",
"e-mail:",
"rybakov20021@yandex.ru",
"Received",
"8",
"January",
"2011;",
"accepted",
"17",
"January",
"2011",
"Key",
"indicators:",
"single-crystal",
"X-ray",
"study;",
"T",
"=",
"295",
"K;",
"mean",
"(C–C)",
"=",
"0.003",
"A˚;",
"R",
"factor",
"=",
"0.042;",
"wR",
"factor",
"=",
"0.109;",
"data-to-parameter",
"ratio",
"=",
"15.8.",
"In",
"the",
"cation",
"of",
"the",
"title",
"compound,",
"C7H8N5+",
"Cl",
"H2O,",
"the",
"mean",
"planes",
"of",
"the",
"pyridine",
"and",
"1,2,4-triazole",
"rings",
"form",
"a",
"dihedral",
"angle",
"of",
"2.3",
"(1)",
".",
"The",
"N",
"atom",
"of",
"the",
"amino",
"group",
"adopts",
"a",
"trigonal–pyramidal",
"configuration.",
"The",
"N",
"atom",
"of",
"the",
"pyridine",
"ring",
"is",
"protonated,",
"forming",
"a",
"chloride",
"salt.",
"In",
"the",
"crystal,",
"intermolecular",
"N—H",
"O,",
"N—H",
"N,",
"N—H",
"Cl",
"and",
"O—H",
"Cl",
"hydrogen",
"bonds",
"link",
"the",
"cations,",
"anions",
"and",
"water",
"molecules",
"into",
"layers",
"parallel",
"to",
"the",
"(1,",
"0,",
"12)",
"plane.",
"Related",
"literature",
"For",
"the",
"use",
"of",
"3-pyridyl-substituted",
"5-amino-1,2,4-triazoles",
"in",
"the",
"synthesis",
"of",
"biologically",
"active",
"compounds,",
"see:",
"Lipinski",
"(1983);",
"Ram",
"(1988);",
"Akahoshi",
"et",
"al.",
"(1998);",
"Young",
"et",
"al.",
"(2001);",
"Ouyang",
"et",
"al.",
"(2005);",
"Dolzhenko",
"et",
"al.",
"(2007).",
"For",
"metal",
"complexes",
"of",
"3-pyridyl-substituted",
"5-amino-1,2,4-tri-",
"azoles,",
"see:",
"Mishra",
"et",
"al.",
"(1989);",
"Ferrer",
"et",
"al.",
"(2004);",
"Castineiras",
"&",
"Garcia-Santos",
"(2008).",
"For",
"a",
"theoretical",
"investigation",
"of",
"the",
"protonation",
"of",
"C-amino-1,2,4-triazoles,",
"see:",
"Anders",
"et",
"al.",
"(1997).",
"For",
"the",
"crystal",
"structures",
"of",
"protonated",
"C-amino-1,2,4-",
"triazoles,",
"see:",
"Lynch",
"et",
"al.",
"(1999);",
"Baouab",
"et",
"al.",
"(2000);",
"Bichay",
"et",
"al.",
"(2006);",
"Guerfel",
"et",
"al.",
"(2007);",
"Matulkova´",
"et",
"al.",
"(2007).",
"For",
"the",
"ionization",
"constants",
"(pK",
")",
"of",
"3-substituted",
"5-amino-1H-",
"1,2,4-triazoles,",
"see:",
"Voronkov",
"et",
"al.",
"(1976).",
"For",
"the",
"1H",
"and",
"13C",
"NMR",
"spectra",
"of",
"3-pyridyl-substituted",
"5-amino-1,2,4-triazoles,",
"see:",
"Dolzhenko",
"et",
"al.",
"(2009a).",
"For",
"typical",
"NMR",
"chemical",
"shifts",
"of",
"3-substituted",
"5-amino-1,2,4-triazoles",
"and",
"their",
"salts,",
"see:",
"Chernyshev",
"et",
"al.",
"(2010).",
"For",
"the",
"crystal",
"structures",
"of",
"3-",
"substituted",
"5-amino-1H-1,2,4-triazoles,",
"see:",
"Rusinov",
"et",
"al.",
"(1991);",
"Daro",
"et",
"al.",
"(2000);",
"Boechat",
"et",
"al.",
"(2004);",
"Dolzhenko",
"et",
"al.",
"(2009b,c).",
"For",
"the",
"crystal",
"structures",
"of",
"3(5)-pyridyl-substi-",
"tuted",
"1,2,4-triazoles",
"protonated",
"at",
"the",
"pyridine",
"ring,",
"see:",
"Ren",
"&",
"Jian",
"(2008);",
"Xie",
"et",
"al.",
"(2009);",
"Du",
"et",
"al.",
"(2009).",
"For",
"values",
"of",
"bond",
"lengths",
"in",
"organic",
"compounds,",
"see:",
"Allen",
"et",
"al.",
"(1987).",
"For",
"the",
"correlation",
"of",
"bond",
"lengths",
"with",
"bond",
"orders",
"between",
"sp2-hybridized",
"C",
"and",
"N",
"atoms,",
"see:",
"Burke-Laing",
"&",
"Laing",
"(1976).",
"Experimental",
"Crystal",
"data",
"C7H8N5+",
"Cl",
"H2O",
"Mr",
"=",
"215.65",
"Monoclinic,",
"P21=c",
"a",
"=",
"5.3411",
"(5)",
"A˚",
"b",
"=",
"24.656",
"(3)",
"A˚",
"c",
"=",
"7.3488",
"(7)",
"A˚",
"=",
"97.62",
"(2)",
"Data",
"collection",
"Enraf–Nonius",
"CAD-4",
"diffractometer",
"Absorption",
"correction:",
"refined",
"from",
"F",
"(Walker",
"&",
"Stuart,",
"1983)",
"Tmin",
"=",
"0.314,",
"Tmax",
"=",
"0.961",
"2389",
"measured",
"reflections",
"Refinement",
"R[F",
"2",
">",
"2",
"(F",
"2)]",
"=",
"0.042",
"wR(F",
"2)",
"=",
"0.109",
"S",
"=",
"0.93",
"2389",
"reflections",
"151",
"parameters",
"Table",
"1",
"Hydrogen-bond",
"geometry",
"(A˚",
",",
").",
"D—H",
"A",
"N1—H1",
"N16—H16",
"N51—H51A",
"N51—H51B",
"O1—H1A",
"O1—H1B",
"O1i",
"Cl1",
"Cl1ii",
"N4iii",
"Cl1iv",
"Cl1v",
"D—H",
"0.876",
"(19)",
"0.85",
"(2)",
"0.82",
"(2)",
"0.82",
"(2)",
"0.89",
"(3)",
"0.88",
"(3)",
"V",
"=",
"959.22",
"(18)",
"A˚",
"3",
"Z",
"=",
"4",
"Ag",
"K",
"radiation",
"=",
"0.56085",
"A˚",
"=",
"0.20",
"mm",
"1",
"T",
"=",
"295",
"K",
"0.20",
"0.20",
"0.20",
"mm",
"2389",
"independent",
"reflections",
"1518",
"reflections",
"with",
"I",
">",
"2",
"(I)",
"Rint",
"=",
"0.000",
"1",
"standard",
"reflections",
"every",
"60",
"min",
"intensity",
"decay:",
"2%",
"H",
"atoms",
"treated",
"by",
"a",
"mixture",
"of",
"independent",
"and",
"constrained",
"refinement",
"max",
"=",
"0.26",
"e",
"A˚",
"3",
"min",
"=",
"0.24",
"e",
"A˚",
"3",
"H",
"A",
"1.97",
"(2)",
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"(2)",
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"(2)",
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"(3)",
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"A",
"2.842",
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"(18)",
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"(18)",
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"(2)",
"3.159",
"(2)",
"3.187",
"(2)",
"D—H",
"A",
"175.0",
"(18)",
"169",
"(2)",
"160.5",
"(19)",
"174",
"(2)",
"167",
"(3)",
"168",
"(2)",
"Symmetry",
"codes:",
"(i)",
"x;",
"y",
"þ",
"21;",
"z",
"þ",
"21;",
"(ii)",
"x",
"þ",
"1;",
"y",
"12;",
"z",
"þ",
"32;",
"(iii)",
"x",
"þ",
"2;",
"y;",
"z",
"þ",
"2;",
"(iv)",
"x;",
"y",
"þ",
"1;",
"z",
"þ",
"1;",
"(v)",
"x",
"þ",
"1;",
"y",
"þ",
"1;",
"z",
"þ",
"1.",
"Data",
"collection:",
"CAD-4",
"EXPRESS",
"(Enraf–Nonius,",
"1994);",
"cell",
"refinement:",
"CAD-4",
"EXPRESS;",
"data",
"reduction:",
"XCAD4",
"(Harms",
"&",
"Wocadlo,",
"1995);",
"program(s)",
"used",
"to",
"solve",
"structure:",
"SHELXS97",
"(Sheldrick,",
"2008);",
"program(s)",
"used",
"to",
"refine",
"structure:",
"SHELXL97",
"(Sheldrick,",
"2008);",
"molecular",
"graphics:",
"ORTEP-3",
"(Farrugia,",
"1997);",
"software",
"used",
"to",
"prepare",
"material",
"for",
"publication:",
"WinGX",
"(Farrugia,",
"1999).",
"This",
"work",
"was",
"supported",
"by",
"the",
"Ministry",
"of",
"Education",
"and",
"Science",
"of",
"the",
"Russian",
"Federation",
"through",
"the",
"Federal",
"Target",
"Program",
"‘Research",
"and",
"Educational",
"Personnel",
"of",
"Innovative",
"Russia",
"at",
"2009–2013",
"Years’,",
"State",
"contract",
"P1472,",
"project",
"NK-",
"186P/3.",
"The",
"authors",
"are",
"indebted",
"to",
"the",
"Russian",
"Foundation",
"for",
"Basic",
"Research",
"for",
"covering",
"the",
"licence",
"fee",
"for",
"use",
"of",
"the",
"Cambridge",
"Structural",
"Database",
"(Allen,",
"2002).",
"o466",
"Chernyshev",
"et",
"al.",
"doi:10.1107/S1600536811002406",
"Acta",
"Cryst.",
"(2011).",
"E67,",
"o466–o467"
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] | [
"Upsala",
"Journal",
"of",
"Medical",
"Sciences.",
"2012;",
"117:",
"99–112",
"REVIEW",
"ARTICLE",
"PDGF",
"and",
"PDGF",
"receptors",
"in",
"glioma",
"INGA",
"NAZARENKO1,",
"SANNA-MARIA",
"HEDE1,3,",
"XIAOBING",
"HE",
"1",
",",
"ANNA",
"HEDRÉN1,",
"JAMES",
"THOMPSON1,2,",
"MIKAEL",
"S.",
"LINDSTRÖM1",
"&",
"MONICA",
"NISTÉR1,2",
"1Department",
"of",
"Oncology-Pathology,",
"Karolinska",
"Institutet,",
"CCK",
"R8:04,",
"Karolinska",
"University",
"Hospital",
"Solna,",
"SE-17176",
"Stockholm,",
"Sweden,",
"2Karolinska",
"Healthcare",
"Research",
"Biobank",
"(KHRBB),",
"Clinical",
"Pathology/Cytology,",
"Karolinska",
"University",
"Hospital,",
"SE-17176",
"Stockholm,",
"Sweden,",
"and",
"3(currently)",
"Uppsala",
"University,",
"Rudbeck",
"Laboratory,",
"Department",
"of",
"Immunology,",
"Genetics",
"and",
"Pathology,",
"SE-751",
"85",
"Uppsala,",
"Sweden",
"Abstract",
"The",
"family",
"of",
"platelet-derived",
"growth",
"factors",
"(PDGFs)",
"plays",
"a",
"number",
"of",
"critical",
"roles",
"in",
"normal",
"embryonic",
"development,",
"cellular",
"differentiation,",
"and",
"response",
"to",
"tissue",
"damage.",
"Not",
"surprisingly,",
"as",
"it",
"is",
"a",
"multi-faceted",
"regulatory",
"system,",
"numerous",
"pathological",
"conditions",
"are",
"associated",
"with",
"aberrant",
"activity",
"of",
"the",
"PDGFs",
"and",
"their",
"receptors.",
"As",
"we",
"and",
"others",
"have",
"shown,",
"human",
"gliomas,",
"especially",
"glioblastoma,",
"express",
"all",
"PDGF",
"ligands",
"and",
"both",
"the",
"two",
"cell",
"surface",
"receptors,",
"PDGFR-a",
"and",
"-b.",
"The",
"cellular",
"distribution",
"of",
"these",
"proteins",
"in",
"tumors",
"indicates",
"that",
"glial",
"tumor",
"cells",
"are",
"stimulated",
"via",
"PDGF/PDGFR-a",
"autocrine",
"and",
"paracrine",
"loops,",
"while",
"tumor",
"vessels",
"are",
"stimulated",
"via",
"the",
"PDGFR-b.",
"Here",
"we",
"summarize",
"the",
"initial",
"discoveries",
"on",
"the",
"role",
"of",
"PDGF",
"and",
"PDGF",
"receptors",
"in",
"gliomas",
"and",
"provide",
"a",
"brief",
"overview",
"of",
"what",
"is",
"known",
"in",
"this",
"field.",
"Key",
"words:",
"Animal",
"tumor",
"model,",
"brain",
"tumor,",
"cancer",
"stem",
"cell,",
"glioma,",
"neural",
"stem",
"cell,",
"platelet-derived",
"growth",
"factor",
"(PDGF),",
"PDGF",
"receptor",
"Introduction",
"Gliomas",
"are",
"the",
"most",
"common",
"form",
"of",
"primary",
"malignancies",
"of",
"the",
"central",
"nervous",
"system",
"(CNS)",
"mainly",
"affecting",
"adults.",
"These",
"tumors",
"have",
"a",
"histo-",
"logical",
"resemblance",
"to",
"different",
"types",
"of",
"glial",
"cells",
"and",
"are",
"categorized",
"into",
"astrocytomas,",
"oligodendroglio-",
"mas,",
"oligoastrocytomas,",
"and",
"ependymomas,",
"based",
"on",
"the",
"predominant",
"cell",
"type(s)",
"in",
"the",
"respective",
"tumor",
"(1).",
"Initial",
"discovery",
"and",
"extensive",
"studies",
"of",
"the",
"epi-",
"dermal",
"growth",
"factor",
"(EGF)",
"and",
"transforming",
"growth",
"factor",
"alpha",
"(TGF-a),",
"as",
"well",
"as",
"the",
"platelet-",
"derived",
"growth",
"factor",
"(PDGF)",
"family,",
"revealed",
"their",
"presence",
"in",
"glioblastoma",
"cell",
"cultures",
"and",
"tissues.",
"These",
"growth",
"factors,",
"by",
"signaling",
"via",
"their",
"cell",
"sur-",
"face",
"tyrosine",
"kinase",
"receptors,",
"EGFR",
"and",
"PDGFR-a",
"and",
"-b,",
"were",
"able",
"not",
"only",
"to",
"induce",
"normal",
"mitogenic",
"and",
"migratory",
"responses,",
"but",
"when",
"aberrantly",
"activated",
"they",
"were",
"also",
"able",
"to",
"transform",
"cells.",
"Knowledge",
"gained",
"from",
"in",
"vitro",
"experiments",
"was",
"transferred",
"to",
"in",
"vivo",
"systems,",
"and",
"several",
"mouse",
"models",
"were",
"created",
"showing",
"that",
"gliomas",
"can",
"be",
"induced",
"by",
"forced",
"expression",
"of",
"PDGF-B",
"in",
"the",
"brain.",
"However,",
"treatment",
"with",
"single",
"tyrosine",
"kinase",
"inhibitors",
"(TKIs)",
"given",
"to",
"glioma",
"patients",
"has",
"gener-",
"ally",
"not",
"been",
"successful.",
"Ever",
"since",
"the",
"initial",
"discoveries,",
"investigations",
"on",
"the",
"molecular",
"mechanisms",
"and",
"signaling",
"pathways",
"involved",
"in",
"glioma",
"have",
"provided",
"a",
"more",
"detailed",
"insight",
"into",
"the",
"key",
"events",
"behind",
"brain",
"tumor",
"initi-",
"ation,",
"maintenance,",
"and",
"progression",
"and",
"have",
"resulted",
"in",
"significantly",
"improved",
"cancer",
"drug",
"discov-",
"eries.",
"However,",
"the",
"prognosis",
"for",
"patients",
"with",
"aggres-",
"sive",
"brain",
"tumors",
"is",
"still",
"very",
"poor.",
"One",
"intriguing",
"hypothesis",
"is",
"that",
"glioblastoma",
"resistance",
"to",
"therapy",
"and",
"its",
"rapid",
"recurrence",
"is",
"due",
"to",
"the",
"presence",
"of",
"a",
"subpopulation",
"of",
"tumor",
"cells",
"displaying",
"stem",
"cell",
"Correspondence:",
"Monica",
"Nistér",
"MD",
"PhD,",
"Department",
"of",
"Oncology-Pathology,",
"Karolinska",
"Institutet,",
"CCK",
"R8:04,",
"Karolinska",
"University",
"Hospital",
"Solna,",
"SE-17176",
"Stockholm,",
"Sweden.",
"E-mail:",
"Monica.Nister@ki.se",
"(Received",
"24",
"January",
"2012;",
"accepted",
"6",
"February",
"2012)",
"ISSN",
"0300-9734",
"print/ISSN",
"2000-1967",
"online",
"2012",
"Informa",
"Healthcare",
"DOI:",
"10.3109/03009734.2012.665097"
] | [
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] | [
"R",
"E",
"V",
"I",
"E",
"W",
"Treatment",
"of",
"Lennox-Gastaut",
"syndrome:",
"overview",
"and",
"recent",
"f",
"indings",
"Kenou",
"van",
"Rijckevorsel",
"Reference",
"Centre",
"of",
"Refractory",
"Epilepsy,",
"Cliniques",
"Universitaires",
"St",
"Luc,",
"Université",
"Catholique",
"de",
"Louvain,",
"Brussels,",
"Belgium",
"Correspondence:",
"Kenou",
"van",
"Rijckevorsel",
"Reference",
"Centre",
"for",
"Refractory",
"Epilepsy,",
"Cliniques",
"Universitaires",
"St",
"Luc,Avenue",
"Hippocrate,",
"10,",
"B-1200",
"Brussels,",
"Belgium",
"Tel",
"+32",
"2",
"7643308",
"Fax",
"+32",
"2",
"7642142",
"Email",
"vanrijckevorsel@nops.ucl.ac.be",
"Abstract:",
"Lennox-Gastaut",
"syndrome",
"(LGS)",
"is",
"a",
"rare,",
"age-related",
"syndrome,",
"characterized",
"by",
"multiple",
"seizure",
"types,",
"a",
"specific",
"electro-encephalographic",
"pattern,",
"and",
"mental",
"regression.",
"However,",
"published",
"data",
"on",
"the",
"etiology,",
"evolution,",
"and",
"therapeutic",
"approach",
"of",
"LGS",
"are",
"contradictory,",
"partly",
"because",
"the",
"precise",
"definition",
"of",
"LGS",
"used",
"in",
"the",
"literature",
"varies.",
"In",
"the",
"most",
"recent",
"classification,",
"LGS",
"belongs",
"to",
"the",
"epileptic",
"encephalopathies",
"and",
"is",
"highly",
"refractory",
"to",
"all",
"antiepileptic",
"drugs.",
"Numerous",
"treatments,",
"medical",
"and",
"non-medical,",
"have",
"been",
"proposed",
"and",
"results",
"mostly",
"from",
"open",
"studies",
"or",
"case",
"series",
"have",
"been",
"published.",
"Sometimes,",
"patients",
"with",
"LGS",
"are",
"included",
"in",
"a",
"more",
"global",
"group",
"of",
"patients",
"with",
"refractory",
"epilepsy.",
"Only",
"6",
"randomized",
"double-blind",
"controlled",
"trials",
"of",
"medical",
"treatments,",
"which",
"included",
"patients",
"with",
"LGS,",
"have",
"been",
"published.",
"Overall,",
"treatment",
"is",
"rarely",
"effective",
"and",
"the",
"final",
"prognosis",
"remains",
"poor",
"in",
"spite",
"of",
"new",
"therapeutic",
"strategies.",
"Co-morbidities",
"need",
"specific",
"treatment.",
"This",
"paper",
"summarizes",
"the",
"definition,",
"diagnosis",
"and",
"therapeutic",
"approach",
"to",
"LGS,",
"including",
"not",
"only",
"recognized",
"antiepileptic",
"drugs,",
"but",
"also",
"“off",
"label”",
"medications,",
"immune",
"therapy,",
"diet,",
"surgery",
"and",
"some",
"perspectives",
"for",
"the",
"future.",
"Keywords:",
"Lennox-Gastaut",
"syndrome,",
"treatment,",
"VNS,",
"surgery,",
"epileptic",
"encephalopathies,",
"LGS,",
"refractory",
"Introduction",
"The",
"term",
"Lennox-Gastaut",
"syndrome",
"(LGS)",
"appeared",
"in",
"the",
"literature",
"for",
"the",
"first",
"time",
"in",
"1969",
"(Niedermeyer",
"1969),",
"but",
"this",
"syndrome",
"was",
"actually",
"first",
"described",
"by",
"Lennox",
"and",
"Davis",
"in",
"1950",
"and",
"by",
"Gastaut",
"et",
"al",
"in",
"1966.",
"The",
"International",
"League",
"Against",
"Epilepsy",
"(ILAE)",
"Commission",
"(Classification",
"Epilepsia",
"1989)",
"classified",
"LGS",
"among",
"the",
"cryptogenic",
"or",
"symptomatic",
"generalized",
"epilepsies,",
"but,",
"more",
"recently,",
"the",
"ILAE",
"Task",
"Force",
"classified",
"it",
"among",
"the",
"age-related",
"epileptic",
"encephalopathies",
"(Engel",
"2001).",
"LGS",
"comprises",
"atypical",
"absences",
"with",
"slow",
"spike-and-wave",
"(SW)",
"complexes,",
"tonic",
"seizures",
"that",
"are",
"mostly",
"sleep-related,",
"and",
"cognitive",
"deterioration",
"(ILAE).",
"However,",
"LGS",
"has",
"also",
"been",
"defined",
"as",
"diffuse",
"SW",
"pattern",
"on",
"electroencephalogram",
"(EEG),",
"mental",
"retardation,",
"and",
"multiple",
"types",
"of",
"seizures",
"without",
"reference",
"to",
"age",
"or",
"to",
"nocturnal",
"tonic",
"seizures",
"(French",
"et",
"al",
"2004).",
"This",
"broader",
"definition,",
"mostly",
"used",
"in",
"the",
"US,",
"may",
"include",
"for",
"example,",
"Dravet",
"syndrome,",
"Doose",
"syndrome,",
"or",
"focal",
"cryptogenic",
"epilepsies,",
"especially",
"of",
"frontal",
"lobe",
"origin.",
"According",
"to",
"Genton",
"et",
"al",
"(2000),",
"EEG",
"criteria",
"should",
"include",
"not",
"only",
"bilateral",
"slow",
"SW",
"but",
"also",
"10–20",
"Hz",
"epileptic",
"fast",
"rhythms,",
"predominantly",
"in",
"sleep.",
"Furthermore,",
"this",
"syndrome",
"belongs",
"to",
"the",
"age-related",
"epileptic",
"encephalopathies",
"and",
"starts",
"during",
"childhood.",
"When",
"using",
"these",
"full",
"criteria,",
"LGS",
"appears",
"to",
"be",
"rare.",
"Largely",
"as",
"a",
"result",
"of",
"the",
"different",
"definitions,",
"the",
"literature",
"presents,",
"or",
"seems",
"to",
"present,",
"contradictory",
"data",
"about",
"the",
"frequency",
"of",
"seizure",
"types,",
"epidemiology,",
"treatment",
"options,",
"prognosis,",
"and",
"long",
"term",
"evolution",
"of",
"LGS.",
"Furthermore,",
"results",
"of",
"clinical",
"studies",
"are",
"difficult",
"to",
"compare",
"in",
"terms",
"of",
"efficacy",
"and",
"most",
"of",
"them,",
"especially",
"randomized",
"studies,",
"do",
"not",
"cover",
"more",
"than",
"a",
"few",
"weeks",
"(Hancock",
"and",
"Cross",
"2003).",
"Neuropsychiatric",
"Disease",
"and",
"Treatment",
"2008:4(6)",
"1001–1019",
"©",
"2008",
"Dove",
"Medical",
"Press",
"Limited.",
"All",
"rights",
"reserved",
"1001"
] | [
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] | [
"Endothelial",
"Cells",
"Modify",
"the",
"Costimulatory",
"Capacity",
"of",
"Transmigrating",
"Leukocytes",
"and",
"Promote",
"CD28-mediated",
"CD41",
"T",
"Cell",
"Alloactivation",
"By",
"Mark",
"D.",
"Denton,*‡",
"Christopher",
"S.",
"Geehan,*",
"Steve",
"I.",
"Alexander,*",
"Mohamed",
"H.",
"Sayegh,‡",
"and",
"David",
"M.",
"Briscoe*",
"From",
"the",
"*Division",
"of",
"Nephrology,",
"Department",
"of",
"Medicine,",
"Children’s",
"Hospital,",
"and",
"the",
"‡Laboratory",
"of",
"Immunogenetics",
"and",
"Transplantation,",
"Renal",
"Division,",
"Department",
"of",
"Medicine,",
"Brigham",
"and",
"Women’s",
"Hospital,",
"and",
"Harvard",
"Medical",
"School,",
"Boston,",
"Massachusetts",
"02115",
"Summary",
"Activated",
"vascular",
"endothelial",
"cells",
"(ECs)",
"express",
"major",
"histocompatibility",
"complex",
"(MHC)",
"class",
"II",
"molecules",
"in",
"vitro",
"and",
"in",
"vivo",
"in",
"acute",
"and",
"chronic",
"allograft",
"rejection.",
"However,",
"hu-",
"man",
"ECs",
"may",
"be",
"limited",
"in",
"their",
"ability",
"to",
"effectively",
"activate",
"CD41",
"T",
"cells,",
"because",
"they",
"do",
"not",
"express",
"members",
"of",
"the",
"B7",
"family",
"(CD80",
"and",
"CD86)",
"of",
"costimulatory",
"molecules.",
"In",
"this",
"study,",
"we",
"show",
"that",
"ECs",
"promote",
"the",
"full",
"activation",
"of",
"CD41",
"T",
"cells",
"via",
"trans-costimulatory",
"interactions.",
"By",
"reverse",
"transcriptase",
"polymerase",
"chain",
"reaction,",
"Western",
"blot,",
"and",
"FACS®",
"analysis,",
"we",
"could",
"not",
"detect",
"the",
"expression",
"of",
"CD80",
"and",
"CD86",
"on",
"activated",
"ECs",
"and",
"found",
"minimal",
"expression",
"on",
"purified",
"CD41",
"T",
"cells.",
"In",
"contrast,",
"both",
"CD80",
"and",
"CD86",
"were",
"ex-",
"pressed",
"in",
"allogeneic",
"CD41",
"T",
"cell–EC",
"cocultures.",
"Expression",
"of",
"CD86",
"peaked",
"at",
"early",
"times",
"between",
"12",
"and",
"24",
"h",
"after",
"coculture,",
"whereas",
"CD80",
"was",
"not",
"expressed",
"until",
"72",
"h.",
"Addition",
"of",
"anti-CD86",
"but",
"not",
"anti-CD80",
"monoclonal",
"antibodies",
"to",
"cocultures",
"inhibited",
"IL-2",
"production",
"and",
"the",
"proliferation",
"of",
"CD41",
"T",
"cells",
"to",
"allogeneic",
"donor",
"human",
"umbilical",
"vein",
"ECs",
"(HU-",
"VECs),",
"as",
"well",
"as",
"to",
"skin",
"and",
"lung",
"microvascular",
"ECs.",
"Furthermore,",
"we",
"found",
"that",
"interferon",
"g–activated",
"ECs",
"but",
"not",
"untreated",
"ECs",
"induced",
"mRNA",
"and",
"cell",
"surface",
"expression",
"of",
"CD80",
"and",
"CD86",
"on",
"CD41",
"T",
"cells,",
"and",
"these",
"T",
"cells",
"were",
"functional",
"to",
"provide",
"a",
"trans-costimulatory",
"signal",
"to",
"autologous",
"CD41",
"T",
"cells.",
"Blockade",
"of",
"MHC",
"class",
"II",
"and",
"lymphocyte",
"function–associ-",
"ated",
"antigen",
"3",
"but",
"not",
"other",
"EC",
"cell",
"surface",
"molecules",
"on",
"IFN-g–activated",
"ECs",
"inhibited",
"the",
"induction",
"of",
"CD86",
"on",
"CD41",
"T",
"cells.",
"Transmigration",
"of",
"purified",
"populations",
"of",
"monocytes",
"across",
"EC",
"monolayers",
"similarly",
"resulted",
"in",
"the",
"induction",
"of",
"functional",
"CD86,",
"but",
"also",
"induced",
"the",
"de",
"novo",
"expression",
"of",
"the",
"cytokines",
"interleukin",
"(IL)-1a",
"and",
"IL-12.",
"In",
"addition,",
"EC-modi-",
"fied",
"monocytes",
"supported",
"enhanced",
"proliferation",
"of",
"allogeneic",
"and",
"autologous",
"CD41",
"T",
"cells.",
"Taken",
"together,",
"these",
"data",
"define",
"the",
"ability",
"of",
"the",
"endothelium",
"to",
"modify",
"CD41",
"T",
"cells",
"and",
"monocytes",
"for",
"trans-costimulatory",
"events.",
"This",
"unique",
"function",
"of",
"the",
"endothelium",
"in",
"alloim-",
"mune",
"T",
"cell",
"activation",
"has",
"functional",
"consequences",
"for",
"the",
"direct",
"and",
"the",
"indirect",
"pathways",
"of",
"allorecognition.",
"Key",
"words:",
"endothelium",
"•",
"T",
"lymphocyte",
"•",
"monocyte",
"•",
"allorecognition",
"•",
"transplantation",
"Rtocompatibility",
"antigens)",
"by",
"CD41",
"T",
"cells",
"is",
"the",
"ini-",
"ecognition",
"of",
"alloantigen",
"(donor",
"major",
"or",
"minor",
"his-",
"tiating",
"event",
"that",
"ultimately",
"leads",
"to",
"graft",
"rejection.",
"Recip-",
"ient",
"CD41",
"T",
"cells",
"may",
"recognize",
"either",
"intact",
"allo-MHC",
"class",
"II",
"molecules",
"on",
"donor",
"cells",
"(known",
"as",
"direct",
"allorec-",
"ognition)",
"or",
"peptides",
"derived",
"from",
"allo-MHC",
"molecules,",
"shed",
"from",
"the",
"allograft",
"and",
"subsequently",
"processed",
"and",
"pre-",
"sented",
"bound",
"to",
"MHC",
"class",
"II",
"on",
"recipient",
"APCs",
"(known",
"as",
"indirect",
"allorecognition)",
"(1).",
"Irrespective",
"of",
"the",
"pathway",
"of",
"allorecognition,",
"full",
"activation",
"of",
"naive",
"or",
"previously",
"ac-",
"tivated",
"CD41",
"T",
"cells",
"requires",
"a",
"second",
"signal",
"that",
"may",
"be",
"provided",
"by",
"soluble",
"factors",
"such",
"as",
"cytokines,",
"but",
"more",
"of-",
"ten",
"is",
"provided",
"by",
"cell",
"surface",
"costimulatory",
"molecules",
"such",
"as",
"B7-1",
"(CD80)",
"and",
"B7-2",
"(CD86)",
"(2,",
"3).",
"These",
"molecules",
"are",
"expressed",
"by",
"professional",
"APCs",
"and",
"bind",
"the",
"counter-",
"receptors",
"CD28",
"and",
"cytolytic",
"T",
"lymphocyte–associated",
"an-",
"tigen",
"(CTLA)41",
"expressed",
"by",
"CD41",
"T",
"cells.",
"Ligation",
"of",
"1Abbreviations",
"used",
"in",
"this",
"paper:",
"CHO,",
"Chinese",
"hamster",
"ovary;",
"CTLA4,",
"cytolytic",
"T",
"lymphocyte–associated",
"antigen",
"4;",
"EC,",
"endothelial",
"cell;",
"HU-",
"VEC,",
"human",
"umbilical",
"vein",
"EC;",
"ICAM-1,",
"intercellular",
"adhesion",
"mole-",
"cule",
"1;",
"LFA-3,",
"lymphocyte",
"function–associated",
"antigen",
"3;",
"U,",
"abbitor",
"units.",
"555",
"J.",
"Exp.",
"Med.",
"The",
"Rockefeller",
"University",
"Press",
"•",
"0022-1007/99/08/555/12",
"$5.00",
"Volume",
"190,",
"Number",
"4,",
"August",
"16,",
"1999",
"555–566",
"http://www.jem.org"
] | [
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] | [
"Annals",
"of",
"Clinical",
"Microbiology",
"and",
"Antimicrobials",
"BioMed",
"Central",
"Research",
"Open",
"Access",
"Minor",
"contribution",
"of",
"mutations",
"at",
"iniA",
"codon",
"501",
"and",
"embC-embA",
"intergenic",
"region",
"in",
"ethambutol-resistant",
"clinical",
"Mycobacterium",
"tuberculosis",
"isolates",
"in",
"Kuwait",
"Al-Anoud",
"Jaber,",
"Suhail",
"Ahmad*",
"and",
"Eiman",
"Mokaddas",
"Address:",
"Department",
"of",
"Microbiology,",
"Faculty",
"of",
"Medicine,",
"Kuwait",
"University,",
"Kuwait",
"City,",
"Kuwait",
"Email:",
"Al-Anoud",
"Jaber",
"-",
"Gad1978@hotmail.com;",
"Suhail",
"Ahmad*",
"-",
"suhail_ah@hsc.edu.kw;",
"Eiman",
"Mokaddas",
"-",
"e.mokaddas@hsc.edu.kw",
"*",
"Corresponding",
"author",
"Published:",
"15",
"January",
"2009",
"Annals",
"of",
"Clinical",
"Microbiology",
"and",
"Antimicrobials",
"2009,",
"8:2",
"doi:10.1186/1476-0711-8-2",
"This",
"article",
"is",
"available",
"from:",
"http://www.ann-clinmicrob.com/content/8/1/2",
"Received:",
"2",
"November",
"2008",
"Accepted:",
"15",
"January",
"2009",
"©",
"2009",
"Jaber",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Abstract",
"Background:",
"Ethambutol",
"(EMB)",
"is",
"a",
"first-line",
"drug",
"for",
"the",
"treatment",
"of",
"tuberculosis",
"(TB).",
"Resistance",
"to",
"EMB",
"in",
"Mycobacterium",
"tuberculosis",
"isolates",
"is",
"mediated",
"by",
"mutations",
"in",
"several",
"genes",
"involved",
"in",
"arabinan",
"synthesis",
"notably",
"three",
"emb",
"(arabinosyl",
"transferase)",
"and",
"iniA",
"(isoniazid-",
"inducible)",
"genes.",
"Most",
"epidemiologically",
"unrelated",
"EMB-resistant",
"M.",
"tuberculosis",
"strains",
"contain",
"mutations",
"at",
"embB",
"codons",
"306,",
"406",
"and",
"497,",
"embC-embA",
"intergenic",
"region",
"(IGR)",
"and",
"iniA",
"codon",
"501",
"(iniA501).",
"Objective:",
"To",
"develop",
"a",
"more",
"comprehensive",
"molecular",
"screen",
"for",
"EMB-resistance",
"detectioamong",
"epidemiologically",
"unrelated",
"EMB-resistant",
"M.",
"tuberculosis",
"strains",
"previously",
"analyzed",
"for",
"embB",
"codon",
"306,",
"406",
"and",
"497",
"mutations",
"by",
"including",
"analysis",
"of",
"mutations",
"at",
"iniA501",
"and",
"in",
"embC-embA",
"IGR.",
"Methods:",
"Fifty",
"consecutive",
"and",
"phenotypically",
"documented",
"EMB-resistant",
"and",
"25",
"pansusceptible",
"M.",
"tuberculosis",
"strains",
"isolated",
"from",
"75",
"different",
"TB",
"patients",
"over",
"a",
"four-year",
"period",
"in",
"Kuwait",
"were",
"analyzed.",
"Mutations",
"at",
"iniA501",
"were",
"detected",
"by",
"PCR",
"amplification",
"followed",
"by",
"restriction",
"fragment",
"length",
"polymorphism",
"(RFLP)",
"patterns",
"generated",
"with",
"Hpy",
"99",
"I.",
"Direct",
"DNA",
"sequencing",
"was",
"used",
"to",
"confirm",
"RFLP",
"results",
"and",
"for",
"detecting",
"mutations",
"in",
"embC-embA",
"IGR.",
"Results:",
"Nearly",
"same",
"number",
"of",
"EMB-resistant",
"M.",
"tuberculosis",
"strains",
"were",
"resistant",
"to",
"EMB",
"alone",
"and",
"EMB",
"together",
"with",
"additional",
"resistance",
"to",
"rifampicin",
"and",
"isoniazid",
"(9",
"of",
"50,",
"18%",
"and",
"11",
"of",
"50,",
"22%,",
"respectively).",
"All",
"the",
"25",
"pansusceptible",
"strains",
"contained",
"wild-type",
"sequences",
"at",
"iniA501",
"and",
"in",
"embC-embA",
"IGR.",
"The",
"analysis",
"of",
"50",
"EMB-resistant",
"M.",
"tuberculosis",
"isolates",
"showed",
"that",
"only",
"one",
"strain",
"contained",
"a",
"mutated",
"iniA501",
"while",
"no",
"mutation",
"was",
"detected",
"in",
"embC-embA",
"IGR",
"in",
"any",
"of",
"the",
"isolate.",
"Conclusion:",
"Analysis",
"of",
"iniA501",
"and",
"embC-embA",
"IGR",
"in",
"epidemiologically",
"unrelated",
"EMB-resistant",
"M.",
"tuberculosis",
"isolates",
"in",
"Kuwait",
"indicate",
"that",
"mutations",
"at",
"these",
"locations",
"occur",
"very",
"infrequently",
"and",
"their",
"inclusion",
"for",
"the",
"development",
"of",
"a",
"comprehensive",
"molecular",
"screen",
"will",
"make",
"only",
"minor",
"contribution",
"towards",
"rapid",
"EMB",
"resistance",
"detection.",
"Page",
"1",
"of",
"9",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
] | [
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] | [
"DATABASES",
"Human",
"Mutation",
"dbNSFP:",
"A",
"Lightweight",
"Database",
"of",
"Human",
"Nonsynonymous",
"SNPs",
"and",
"Their",
"Functional",
"Predictions",
"Xiaoming",
"Liu,",
"Xueqiu",
"Jian,",
"and",
"Eric",
"Boerwinkle",
"Human",
"Genetics",
"Center,",
"School",
"of",
"Public",
"Health,",
"The",
"University",
"of",
"Texas",
"Health",
"Science",
"Center",
"at",
"Houston,",
"Houston,",
"Texas",
"Communicated",
"by",
"George",
"Patrinos",
"Received",
"23",
"February",
"2011;",
"accepted",
"revised",
"manuscript",
"13",
"April",
"2011.",
"Published",
"online",
"21",
"April",
"2011",
"in",
"Wiley",
"Online",
"Library",
"(www.wiley.com/humanmutation).",
"DOI",
"10.1002/humu.21517",
"OFFICIAL",
"JOURNAL",
"www.hgvs.org",
"ABSTRACT:",
"With",
"the",
"advance",
"of",
"sequencing",
"technologies,",
"whole",
"exome",
"sequencing",
"has",
"increasingly",
"been",
"used",
"to",
"identify",
"mutations",
"that",
"cause",
"human",
"diseases,",
"especially",
"rare",
"Mendelian",
"diseases.",
"Among",
"the",
"analysis",
"steps,",
"functional",
"prediction",
"(of",
"being",
"deleterious)",
"plays",
"an",
"important",
"role",
"in",
"filtering",
"or",
"prioritizing",
"nonsynonymous",
"SNP",
"(NS)",
"for",
"further",
"analysis.",
"Unfortunately,",
"different",
"prediction",
"algorithms",
"use",
"different",
"information",
"and",
"each",
"has",
"its",
"own",
"strength",
"and",
"weakness.",
"It",
"has",
"been",
"suggested",
"that",
"investigators",
"should",
"use",
"predictions",
"from",
"multiple",
"algorithms",
"instead",
"of",
"relying",
"on",
"a",
"single",
"one.",
"However,",
"querying",
"predictions",
"from",
"different",
"databases/Web-servers",
"for",
"different",
"algorithms",
"is",
"both",
"tedious",
"and",
"time",
"consum-",
"ing,",
"especially",
"when",
"dealing",
"with",
"a",
"huge",
"number",
"of",
"NSs",
"identified",
"by",
"exome",
"sequencing.",
"To",
"facilitate",
"the",
"process,",
"we",
"developed",
"dbNSFP",
"(database",
"for",
"nonsynonymous",
"SNPs’",
"functional",
"predictions).",
"It",
"compiles",
"prediction",
"scores",
"from",
"four",
"new",
"and",
"popular",
"algorithms",
"(SIFT,",
"Polyphen2,",
"LRT,",
"and",
"MutationTaster),",
"along",
"with",
"a",
"conservation",
"score",
"(PhyloP)",
"and",
"other",
"related",
"information,",
"for",
"every",
"potential",
"NS",
"in",
"the",
"human",
"genome",
"(a",
"total",
"of",
"75,931,005).",
"It",
"is",
"the",
"first",
"integrated",
"database",
"of",
"functional",
"predictions",
"from",
"multiple",
"algorithms",
"for",
"the",
"comprehensive",
"collection",
"of",
"human",
"NSs.",
"dbNSFP",
"is",
"freely",
"available",
"for",
"download",
"at",
"http://sites.google.com/site/jpopgen/dbNSFP.",
"Hum",
"Mutat",
"32:894–899,",
"2011.",
"&",
"2011",
"Wiley-Liss,",
"Inc.",
"KEY",
"WORDS:",
"dbNSFP;",
"functional",
"prediction;",
"database;",
"SIFT;",
"Polyphen2;",
"LRT;",
"MutationTaster;",
"PhyloP",
"Introduction",
"A",
"nonsynonymous",
"SNP",
"(NS)",
"is",
"a",
"single",
"nucleotide",
"variant",
"that",
"causes",
"an",
"amino",
"acid",
"change",
"of",
"its",
"corresponding",
"protein.",
"Because",
"of",
"their",
"direct",
"link",
"to",
"protein",
"changes,",
"NSs",
"are",
"believed",
"to",
"be",
"the",
"major",
"contributor",
"to",
"heritable",
"human",
"diseases",
"among",
"all",
"types",
"of",
"variants",
"in",
"the",
"human",
"genome.",
"As",
"evidence,",
"NSs",
"constitute",
"more",
"than",
"half",
"of",
"the",
"entries",
"of",
"disease-causing",
"genetic",
"changes",
"in",
"the",
"Human",
"Gene",
"Mutation",
"Database",
"(HGMD)",
"[Stenson",
"et",
"al.,",
"2009].",
"Additional",
"Supporting",
"Information",
"may",
"be",
"found",
"in",
"the",
"online",
"version",
"of",
"this",
"article.",
"Correspondence",
"to:",
"Xiaoming",
"Liu,",
"Human",
"Genetics",
"Center,",
"School",
"of",
"Public",
"Health,",
"The",
"University",
"of",
"Texas",
"Health",
"Science",
"Center",
"at",
"Houston,",
"1200",
"Herman",
"Pressler",
"Drive,",
"E529,",
"Houston,",
"Texas",
"77030.",
"E-mail:",
"xiaoming.liu@uth.tmc.edu",
"Contract",
"grant",
"sponsor:",
"The",
"National",
"Institutes",
"of",
"Health;",
"Contract",
"grant",
"numbers:",
"RC2-HL02419-01;",
"RC2",
"HL103010-01;",
"1U01HG005728-01.",
"Based",
"on",
"current",
"technologies,",
"it",
"is",
"too",
"costly",
"and",
"time-",
"consuming",
"to",
"investigate",
"the",
"functional",
"effect",
"of",
"every",
"NS",
"experimentally.",
"Fortunately,",
"there",
"are",
"algorithms",
"available",
"to",
"help",
"to",
"predict",
"the",
"potential",
"of",
"a",
"NS",
"being",
"functional",
"or",
"deleterious.",
"Functional",
"prediction",
"algorithms",
"for",
"NS",
"have",
"been",
"developed",
"in",
"recent",
"years",
"with",
"the",
"advance",
"of",
"phylogenetics,",
"structure",
"biology,",
"bioinformatics",
"and",
"population",
"genetics",
"(see",
"reviews",
"by",
"[Horner",
"et",
"al.,",
"2010;",
"Karchin,",
"2009;",
"Ng",
"and",
"Henikoff,",
"2006;",
"Thusberg",
"and",
"Vihinen,",
"2009]).",
"Usually,",
"the",
"algorithms",
"output",
"a",
"score",
"measuring",
"how",
"likely",
"an",
"NS",
"is",
"deleterious,",
"along",
"with",
"its",
"binary",
"prediction.",
"Functional",
"predictions",
"play",
"an",
"important",
"role",
"in",
"sequencing",
"based",
"genotype–phenotype",
"association",
"analyses.",
"Prediction",
"scores",
"have",
"been",
"used",
"to",
"weight",
"different",
"NSs",
"in",
"order",
"to",
"increase",
"the",
"power",
"of",
"detecting",
"genes",
"influencing",
"a",
"trait",
"[Price",
"et",
"al.,",
"2010].",
"More",
"importantly,",
"functional",
"prediction",
"has",
"become",
"an",
"indispensable",
"step",
"in",
"identifying",
"genes",
"causing",
"rare",
"Mendelian",
"diseases",
"using",
"an",
"exome-sequencing",
"approach",
"[Cooper",
"et",
"al.,",
"2010;",
"Ng",
"et",
"al.,",
"2010a,b,c].",
"Functional",
"predictions",
"or",
"conservation",
"information",
"are",
"used",
"to",
"filter",
"or",
"prioritize",
"the",
"novel",
"NSs",
"for",
"further",
"analysis",
"or",
"confirmation",
"[Ng",
"et",
"al.,",
"2010].",
"Because",
"different",
"algorithms",
"use",
"different",
"information",
"and",
"are",
"based",
"on",
"different",
"training",
"data,",
"each",
"has",
"its",
"own",
"strength",
"and",
"weakness.",
"It",
"has",
"been",
"suggested",
"to",
"use",
"the",
"outputs",
"from",
"multiple",
"algorithms",
"to",
"make",
"a",
"more",
"reliable",
"prediction",
"for",
"a",
"NS",
"(e.g.,",
"by",
"using",
"consensus",
"prediction",
"or",
"majority",
"vote)",
"[Chun",
"and",
"Fay,",
"2009].",
"Because",
"querying",
"predictions",
"from",
"different",
"databases/Web-",
"servers",
"for",
"different",
"algorithms",
"is",
"both",
"tedious",
"and",
"time",
"consuming,",
"we",
"developed",
"dbNSFP",
"(database",
"for",
"nonsynonymous",
"SNPs’",
"functional",
"predictions)",
"to",
"facilitate",
"the",
"process.",
"We",
"first",
"compiled",
"a",
"collection",
"of",
"all",
"possible",
"NSs",
"in",
"the",
"human",
"genome",
"(a",
"total",
"of",
"75,931,005)",
"based",
"on",
"the",
"annotation",
"of",
"the",
"Consensus",
"Coding",
"Sequence",
"(CCDS)",
"project",
"[Pruitt",
"et",
"al.,",
"2009].",
"We",
"next",
"collected",
"their",
"corresponding",
"prediction",
"scores",
"from",
"four",
"new",
"and",
"popular",
"prediction",
"algorithms",
"(SIFT",
"[Kumar",
"et",
"al.,",
"2009],",
"Polyphen2",
"[Adzhubei",
"et",
"al.,",
"2010],",
"LRT",
"[Chun",
"and",
"Fay,",
"2009],",
"and",
"MutationTaster",
"[Schwarz",
"et",
"al.,",
"2010]).",
"We",
"also",
"added",
"other",
"related",
"information",
"including",
"a",
"conservation",
"score",
"(PhyloP)",
"[Siepel",
"et",
"al.,",
"2006],",
"degenerate",
"type,",
"and",
"corresponding",
"codons",
"and",
"genes.",
"The",
"dbNSFP",
"is",
"the",
"first",
"known",
"integrated",
"database",
"of",
"functional",
"predictions",
"from",
"multiple",
"algorithms",
"for",
"the",
"compre-",
"hensive",
"collection",
"of",
"human",
"NSs.",
"Data",
"Sources",
"and",
"Processing",
"The",
"genes",
"and",
"their",
"corresponding",
"codons",
"were",
"determined",
"based",
"on",
"CCDS",
"version",
"20090327.",
"This",
"is",
"the",
"latest",
"version",
"based",
"on",
"the",
"human",
"reference",
"sequence",
"build",
"hg18.",
"Although",
"the",
"current",
"human",
"reference",
"sequence",
"is",
"build",
"hg19,",
"many",
"important",
"human",
"sequence",
"resources",
"are",
"based",
"on",
"hg18,",
"including",
"current",
"&",
"2011",
"WILEY-LISS,",
"INC."
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] | [
"Available",
"online",
"http://respiratory-research.com/content/3/1/12",
"Meeting",
"report",
"First",
"Siena",
"International",
"Conference",
"on",
"Animal",
"Models",
"of",
"Chronic",
"Obstructive",
"Pulmonary",
"Disease,",
"Certosa",
"di",
"Pontignano,",
"University",
"of",
"Siena,",
"Italy,",
"September",
"30–October",
"2,",
"2001",
"David",
"Hele",
"Respiratory",
"Pharmacology",
"Group,",
"Cardiothoracic",
"Surgery,",
"Faculty",
"of",
"Medicine,",
"Imperial",
"College,",
"National",
"Heart",
"and",
"Lung",
"Institute,",
"London,",
"UK",
"Correspondence:",
"David",
"Hele,",
"Respiratory",
"Pharmacology",
"Group,",
"Cardiothoracic",
"Surgery,",
"Faculty",
"of",
"Medicine,",
"Imperial",
"College,",
"National",
"Heart",
"and",
"Lung",
"Institute,",
"Dovehouse",
"Street,",
"London",
"SW3",
"6LY,",
"UK.",
"Tel:",
"+44",
"0207",
"352",
"8121",
"ext.",
"3042;",
"fax:",
"+44",
"0207",
"351",
"8126;",
"e-mail:",
"d.hele@ic.ac.uk",
"Received:",
"9",
"October",
"2001",
"Accepted:",
"25",
"October",
"2001",
"Published:",
"28",
"November",
"2001",
"Respir",
"Res",
"2002,",
"3:12",
"©",
"2002",
"BioMed",
"Central",
"Ltd",
"(Print",
"ISSN",
"1465-9921;",
"Online",
"ISSN",
"1465-993X)",
"Abstract",
"The",
"meeting",
"proved",
"of",
"great",
"interest",
"to",
"those",
"developing",
"an",
"animal",
"model",
"of",
"chronic",
"obstructive",
"pulmonary",
"disease",
"(COPD).",
"COPD",
"is",
"caused",
"by",
"cigarette",
"smoking,",
"evidenced",
"by",
"deterioration",
"in",
"lung",
"function.",
"Lung",
"function",
"is",
"only",
"rarely",
"assessed",
"in",
"animal",
"models.",
"A",
"cigarette",
"smoke",
"driven",
"pathology",
"should",
"provide",
"the",
"best",
"in",
"vivo",
"model",
"for",
"COPD.",
"However,",
"as",
"lesions",
"produced",
"this",
"way",
"take",
"8–12",
"months",
"to",
"develop",
"other",
"strategies",
"have",
"to",
"be",
"employed.",
"Emphysematous",
"lesions",
"were",
"also",
"achieved",
"by",
"treatment",
"with",
"elastase,",
"lipopolysaccharide,",
"ozone",
"and",
"other",
"inducers.",
"Several",
"studies",
"described",
"treatments",
"that",
"have",
"shown",
"activity",
"in",
"these",
"models.",
"Transgenic",
"models",
"were",
"discussed,",
"as",
"was",
"the",
"importance",
"of",
"species",
"and",
"strain",
"selection.",
"Keywords:",
"animal",
"models,",
"COPD,",
"cigarette",
"smoke,",
"elastase,",
"lung",
"function",
"Introduction",
"The",
"meeting",
"was",
"attended",
"by",
"approximately",
"80",
"people",
"and",
"was",
"designed",
"to",
"bring",
"together",
"an",
"international",
"group",
"of",
"academic",
"investigators",
"and",
"industrial",
"scientists",
"in",
"a",
"forum",
"that",
"would",
"foster",
"discussion",
"and",
"exchange",
"of",
"ideas.",
"The",
"purpose",
"of",
"the",
"meeting",
"was",
"to",
"assess",
"current",
"animal",
"models",
"of",
"emphysema",
"and",
"COPD,",
"and",
"to",
"promote",
"the",
"use",
"of",
"new",
"technologies.",
"The",
"immediate",
"goal",
"was",
"to",
"accelerate",
"the",
"translation",
"of",
"information",
"gained",
"from",
"the",
"development",
"of",
"animal",
"models",
"to",
"improvements",
"in",
"patient",
"care.",
"Specifically,",
"the",
"formal",
"presentations",
"and",
"informal",
"discussions",
"held",
"during",
"the",
"conference",
"addressed",
"aetiological",
"factors",
"in",
"COPD,",
"and",
"emphasized",
"transgenic",
"technologies",
"and",
"naturally",
"occur-",
"ring",
"genetic",
"variants.",
"The",
"objectives",
"of",
"the",
"programme",
"were",
"to",
"consolidate",
"our",
"present",
"understanding",
"of",
"lung",
"and",
"airway",
"inflammation,",
"and",
"its",
"involvement",
"in",
"the",
"COPD=chronic",
"obstructive",
"pulmonary",
"disease.",
"pathogenesis",
"of",
"COPD",
"caused",
"by",
"cigarette",
"smoking,",
"ageing",
"and",
"genetic",
"predisposition;",
"and",
"to",
"promote",
"further",
"imaginative",
"investigations.",
"Lung",
"physiology",
"and",
"lung",
"function",
"Dr",
"A.",
"Ten",
"Have-Opbroek",
"(Leiden",
"University,",
"Leiden,",
"The",
"Netherlands)",
"presented",
"an",
"overview",
"of",
"lung",
"development,",
"stating",
"that",
"animal",
"models",
"may",
"contribute",
"to",
"our",
"insight",
"into",
"the",
"pathogenesis",
"of",
"human",
"COPD",
"because",
"there",
"are",
"major",
"similarities",
"in",
"lung",
"development",
"and",
"lung",
"structure",
"between",
"mammals.",
"Many",
"attendees",
"presented",
"data",
"at",
"the",
"meeting",
"on",
"the",
"pathogenesis",
"of",
"emphysema/COPD,",
"whereas",
"little",
"was",
"presented",
"regarding",
"function",
"of",
"the",
"lungs.",
"The",
"use",
"of",
"pathology",
"to",
"establish",
"the",
"presence",
"of",
"disease",
"allied",
"to",
"an",
"assessment",
"of",
"lung",
"mechanics",
"may",
"provide",
"a",
"more",
"meaningful",
"assessment",
"in",
"the",
"animal",
"model",
"of",
"choice.",
"Page",
"1",
"of",
"3",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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] | [
"HUMAN",
"NEUROSCIENCE",
"Differential",
"maturation",
"of",
"brain",
"signal",
"complexity",
"in",
"the",
"human",
"auditory",
"and",
"visual",
"system",
"Sarah",
"Lippé1*,",
"Natasa",
"Kovacevic",
"2",
"and",
"Anthony",
"Randal",
"McIntosh",
"2",
"1",
"Centre",
"de",
"Recherche",
"CHU",
"Ste-Justine,",
"University",
"of",
"Montreal,",
"Montreal,",
"Quebec,",
"Canada",
"2",
"The",
"Rotman",
"Research",
"Institute,",
"University",
"ofToronto,Toronto,",
"Ontario,",
"Canada",
"REVIEW",
"ARTICLE",
"published:",
"16",
"November",
"2009",
"doi:",
"10.3389/neuro.09.048.2009",
"Edited",
"by:",
"Silvia",
"A.",
"Bunge,",
"University",
"of",
"California,",
"USA",
"Reviewed",
"by:",
"Rick",
"O.",
"Gilmore,The",
"Pennyslvania",
"State",
"University,",
"USA",
"*Correspondence:",
"Sarah",
"Lippé,",
"Département",
"de",
"Psychologie",
"Université",
"de",
"Montréal,",
"C.P.",
"6128,",
"succursale",
"Centre-Ville",
"Montréal,",
"Québec,",
"H3C",
"3J7,",
"Canada.",
"e-mail:",
"sarah.lippe@umontreal.ca",
"Brain",
"development",
"carries",
"with",
"it",
"a",
"large",
"number",
"of",
"structural",
"changes",
"at",
"the",
"local",
"level",
"which",
"impact",
"on",
"the",
"functional",
"interactions",
"of",
"distributed",
"neuronal",
"networks",
"for",
"perceptual",
"processing.",
"Such",
"changes",
"enhance",
"information",
"processing",
"capacity,",
"which",
"can",
"be",
"indexed",
"by",
"estimation",
"of",
"neural",
"signal",
"complexity.",
"Here,",
"we",
"show",
"that",
"during",
"development,",
"EEG",
"signal",
"complexity",
"increases",
"from",
"one",
"month",
"to",
"5",
"years",
"of",
"age",
"in",
"response",
"to",
"auditory",
"and",
"visual",
"stimulation.",
"However,",
"the",
"rates",
"of",
"change",
"in",
"complexity",
"were",
"not",
"equivalent",
"for",
"the",
"two",
"responses.",
"Infants’",
"signal",
"complexity",
"for",
"the",
"visual",
"condition",
"was",
"greater",
"than",
"auditory",
"signal",
"complexity,",
"whereas",
"adults",
"showed",
"the",
"same",
"level",
"of",
"complexity",
"to",
"both",
"types",
"of",
"stimuli.",
"The",
"differential",
"rates",
"of",
"complexity",
"change",
"may",
"reflect",
"a",
"combination",
"of",
"innate",
"and",
"experiential",
"factors",
"on",
"the",
"structure",
"and",
"function",
"of",
"the",
"two",
"sensory",
"systems.",
"Keywords:",
"development,",
"EEG,",
"signal,",
"entropy,",
"complexity,",
"vision,",
"audition,",
"infant",
"INTRODUCTION",
"Infancy",
"is",
"a",
"time",
"of",
"enormous",
"changes",
"in",
"brain",
"structure",
"and",
"function.",
"For",
"example,",
"glucose",
"metabolism",
"rises",
"(Chugani,",
"1998)",
"and",
"brain",
"volume",
"shows",
"a",
"4-fold",
"increase",
"during",
"the",
"first",
"4",
"years",
"of",
"life",
"(Courchesne",
"et",
"al.,",
"2000).",
"Increases",
"in",
"synaptic",
"density",
"are",
"followed",
"by",
"a",
"declining",
"slope",
"within",
"this",
"period",
"(Huttenlocher",
"and",
"Dabholkar,",
"1997),",
"whereas",
"myelination",
"continues",
"well",
"into",
"adolescence",
"(Paus",
"et",
"al.,",
"1999).",
"The",
"functional",
"consequence",
"of",
"these",
"changes",
"should",
"be",
"reflected",
"in",
"the",
"increasing",
"processing",
"capacities",
"of",
"the",
"developing",
"child.",
"More",
"precisely,",
"the",
"changes",
"in",
"functional",
"responses",
"are",
"thought",
"to",
"represent",
"an",
"increase",
"in",
"the",
"integration",
"within",
"local",
"neural",
"ensembles",
"together",
"with",
"more",
"precise",
"re-entrant",
"interactions",
"between",
"distal",
"ensembles",
"(Thatcher",
"et",
"al.,",
"2007;",
"Fair",
"et",
"al.,",
"2009).",
"The",
"balance",
"between",
"local",
"integration",
"and",
"distal",
"segregation",
"is",
"a",
"characteristic",
"architecture",
"for",
"a",
"complex",
"system",
"that",
"has",
"an",
"optimal",
"capacity",
"for",
"information",
"inte-",
"gration",
"(Tononi",
"et",
"al.,",
"1994).",
"Thus,",
"development",
"can",
"be",
"conceived",
"of",
"as",
"the",
"movement",
"of",
"the",
"brain",
"towards",
"a",
"complex",
"system.",
"Measures",
"of",
"complexity",
"may",
"be",
"a",
"sensitive",
"index",
"of",
"maturational",
"changes",
"in",
"brain",
"function.",
"For",
"example,",
"a",
"marked",
"increase",
"with",
"age",
"in",
"complex-",
"ity",
"of",
"the",
"brain’s",
"electrical",
"resting",
"state",
"activity",
"has",
"been",
"shown",
"by",
"(Meyer-Lindenberg,",
"1996)",
"using",
"two",
"measures",
"of",
"complexity,",
"cor-",
"relation",
"dimensions",
"and",
"the",
"Lyapunov",
"coefficient.",
"A",
"recent",
"study",
"by",
"McIntosh",
"et",
"al.",
"(2008)",
"showed",
"an",
"increase",
"in",
"EEG",
"signal",
"complexity",
"with",
"maturation",
"in",
"pre-adolescent",
"children.",
"Critically,",
"they",
"showed",
"that",
"this",
"increase",
"in",
"complexity",
"was",
"strongly",
"correlated",
"with",
"more",
"stable",
"and",
"accurate",
"behavioural",
"performance.",
"There",
"does",
"appear",
"to",
"be",
"a",
"general",
"increase",
"in",
"brain",
"signal",
"com-",
"plexity",
"with",
"maturation.",
"However,",
"the",
"maturational",
"rates",
"of",
"different",
"neural",
"systems",
"are",
"not",
"uniform.",
"For",
"example,",
"rates",
"of",
"neuroana-",
"tomical",
"and",
"functional",
"development",
"for",
"the",
"visual",
"and",
"the",
"auditory",
"systems",
"are",
"distinct.",
"The",
"subcortical",
"auditory",
"pathways",
"seem",
"to",
"mature",
"earlier",
"compared",
"to",
"the",
"visual",
"subcortical",
"system.",
"Brainstem",
"auditory",
"evoked",
"potential",
"of",
"a",
"few",
"milliseconds",
"post",
"stimulus",
"can",
"be",
"measured",
"from",
"birth",
"(Jiang",
"et",
"al.,",
"2001).",
"Conversely,",
"at",
"the",
"thalamocortical",
"level,",
"the",
"tendency",
"may",
"be",
"reversed.",
"The",
"genicu-",
"localcarine",
"tract",
"(visual",
"thalamocortical",
"pathway)",
"shows",
"relative",
"maturity",
"at",
"5",
"months",
"of",
"age,",
"whereas",
"the",
"maturation",
"of",
"the",
"tha-",
"lamic",
"projections",
"to",
"the",
"auditory",
"cortex",
"continues",
"until",
"6",
"years",
"of",
"age",
"(Yakovlev",
"and",
"Lecours,",
"1967;",
"Moore",
"and",
"Linthicum,",
"2007).",
"In",
"addition,",
"myelination",
"begins",
"earlier",
"in",
"the",
"occipital",
"lobe",
"than",
"in",
"the",
"temporal",
"lobe",
"(Yakovlev",
"and",
"Lecours,",
"1967).",
"Synapse",
"density",
"shows",
"a",
"rapid",
"increase",
"in",
"the",
"occipital",
"cortex",
"until",
"about",
"8",
"months",
"of",
"age",
"that",
"is",
"followed",
"by",
"a",
"decline",
"(Huttenlocher",
"and",
"Dabholkar,",
"1997),",
"whereas",
"the",
"synaptic",
"density",
"of",
"the",
"auditory",
"cortex",
"increases",
"until",
"50",
"months",
"before",
"connections",
"are",
"pruned",
"(Huttenlocher",
"and",
"Dabholkar,",
"1997).",
"Even",
"at",
"later",
"ages",
"of",
"childhood,",
"the",
"time",
"course",
"of",
"grey",
"matter",
"thickness",
"change",
"differs",
"across",
"brain",
"regions",
"(Giedd",
"et",
"al.,",
"2006).",
"The",
"differences",
"in",
"prenatal",
"exposure",
"of",
"the",
"sensory",
"sys-",
"tem",
"to",
"environmental",
"stimulation",
"may",
"have",
"an",
"impact",
"on",
"the",
"func-",
"tional",
"state.",
"Human",
"foetuses",
"and",
"newborns",
"detect",
"sound",
"changes",
"in",
"frequencies",
"(Draganova",
"et",
"al.,",
"2005).",
"Auditory",
"abilities",
"in",
"the",
"early",
"post-natal",
"months",
"include",
"discrimination",
"of",
"musical",
"features",
"(Leppanen",
"and",
"Lyytinen,",
"1997;",
"Ceponiene",
"et",
"al.,",
"2002;",
"Morr",
"et",
"al.,",
"2002),",
"phonemic",
"identity",
"(Cheour",
"et",
"al.,",
"1998),",
"and",
"gap",
"detection",
"(Trehub",
"et",
"al.,",
"1995).",
"By",
"8",
"months",
"of",
"age,",
"infants",
"already",
"discrimi-",
"nate",
"their",
"native",
"language",
"better",
"than",
"any",
"other",
"languages",
"(Kuhl,",
"2000).",
"On",
"the",
"contrary,",
"intrauterine",
"visual",
"competences",
"of",
"the",
"infant",
"have",
"not",
"been",
"well",
"explored.",
"Prematurely",
"born",
"infants",
"show",
"a",
"visual",
"evoked",
"potential",
"response",
"that",
"is",
"not",
"advanced",
"after",
"term",
"compared",
"to",
"infants",
"born",
"at",
"term",
"(Roy",
"et",
"al.,",
"1995).",
"The",
"development",
"of",
"visual",
"capacities",
"is",
"rapid",
"in",
"the",
"first",
"post-natal",
"months.",
"By",
"4",
"months",
"of",
"age,",
"infants",
"born",
"at",
"term",
"show",
"fixation/orientation",
"abilities,",
"saccades,",
"binocular",
"vision,",
"and",
"the",
"visual",
"fields",
"are",
"enlarged",
"(Speeg-Schatz,",
"2007).",
"Infants",
"of",
"4–6",
"months",
"of",
"age",
"and",
"on",
"can",
"segment",
"objects",
"from",
"texture",
"orientations",
"(Atkinson",
"and",
"Braddick,",
"1992;",
"Burkhalter,",
"1993;",
"Norcia",
"et",
"al.,",
"2005),",
"resulting",
"in",
"visuomotor",
"behaviours",
"devel-",
"opment",
"such",
"as",
"reaching",
"and",
"grasping",
"capacities.",
"Frontiers",
"in",
"Human",
"Neuroscience",
"www.frontiersin.org",
"November",
"2009",
"|",
"Volume",
"3",
"|",
"Article",
"48",
"|",
"1"
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] | [
"Perspectives",
"Computational",
"Biology",
"in",
"Brazil",
"Goran",
"Neshich",
"Introduction",
"At",
"the",
"request",
"of",
"the",
"PLoS",
"Computational",
"Biology",
"Editor-in-",
"Chief,",
"I",
"agreed",
"to",
"write",
"about",
"computational",
"biology",
"in",
"Brazil",
"(see",
"author",
"information",
"in",
"Box",
"1).",
"That",
"meant",
"describing:",
"a)",
"the",
"history",
"of",
"the",
"field",
"in",
"our",
"country",
"(short",
"as",
"the",
"history",
"of",
"the",
"field",
"itself",
"is",
"short);",
"b)",
"the",
"current",
"state",
"of",
"the",
"field",
"in",
"Brazil;",
"c)",
"the",
"influence",
"of",
"computational",
"biology–related",
"technologies",
"on",
"the",
"development",
"of",
"the",
"national",
"economy;",
"d)",
"the",
"entrepreneurship",
"that",
"is",
"rising",
"from",
"already-established",
"academic",
"activities;",
"and",
"e)",
"educational",
"activities",
"ongoing",
"or",
"planned",
"which",
"are",
"deemed",
"necessary",
"to",
"establish",
"the",
"required",
"critical",
"mass",
"of",
"well-trained",
"specialists.",
"Why",
"is",
"an",
"article",
"like",
"this",
"important",
"now?",
"It",
"is",
"estimated",
"that",
"Brazil",
"combined",
"with",
"China,",
"Russia,",
"and",
"India",
"will",
"have",
"a",
"larger",
"gross",
"national",
"product",
"(GNP)",
"than",
"the",
"US,",
"Japan,",
"Germany,",
"and",
"the",
"UK",
"combined",
"by",
"2020.",
"In",
"short,",
"we",
"can",
"expect",
"Brazil",
"to",
"have",
"significant",
"impact",
"on",
"the",
"field",
"of",
"computational",
"biology",
"in",
"the",
"years",
"to",
"come,",
"and",
"now",
"is",
"the",
"time",
"to",
"explore",
"that",
"promise.",
"Increased",
"Economic",
"Activity",
"Boosted",
"Research",
"Investment",
"Brazil",
"is",
"a",
"country",
"with",
"almost",
"190",
"million",
"inhabitants",
"that",
"occupies",
"an",
"area",
"equal",
"to",
"81%",
"of",
"the",
"area",
"of",
"Europe",
"and",
"115%",
"of",
"the",
"area",
"of",
"the",
"US,",
"excluding",
"Alaska",
"and",
"Hawaii.",
"In",
"the",
"late",
"1980s,",
"Brazil",
"left",
"behind",
"its",
"mantle",
"as",
"a",
"simple",
"coffee",
"producer",
"with",
"an",
"agricultural",
"boom,",
"offering",
"the",
"world",
"market",
"major",
"commodities",
"such",
"as",
"soybeans,",
"meat,",
"poultry,",
"and,",
"more",
"recently,",
"fruit",
"and",
"flour.",
"The",
"rise",
"in",
"agricultural",
"production",
"came",
"via",
"a",
"well-constructed",
"socioeconomic",
"plan",
"put",
"together",
"by",
"the",
"Brazilian",
"government,",
"including",
"targeted",
"investment",
"in",
"supporting",
"science",
"and",
"technology.",
"As",
"a",
"consequence,",
"Brazil",
"became,",
"for",
"example,",
"one",
"of",
"the",
"major",
"exporters",
"of",
"medium-sized",
"aircraft.",
"Further,",
"the",
"Brazilian",
"petroleum",
"company,",
"Petrobras,",
"provides",
"Brazil",
"self-",
"sufficiency",
"in",
"oil,",
"and",
"is",
"a",
"major",
"catalyst",
"for",
"the",
"widespread",
"use",
"of",
"ethanol",
"in",
"automobiles.",
"The",
"increasing",
"economic",
"activity",
"enabled",
"the",
"country",
"to",
"invest",
"proportionally",
"in",
"its",
"scientific",
"research.",
"Government",
"Policies",
"for",
"Research",
"and",
"Development",
"As",
"part",
"of",
"this",
"investment,",
"the",
"Brazilian",
"government",
"showed",
"specific",
"interest",
"in",
"biotechnology,",
"and",
"I",
"would",
"argue",
"that",
"the",
"current",
"favorable",
"situation,",
"in",
"which",
"computational",
"biologists",
"find",
"themselves,",
"has",
"deep",
"roots",
"in",
"the",
"long-term",
"dedication",
"of",
"policymakers",
"to",
"biotechnology.",
"In",
"the",
"1920s",
"and",
"1930s",
"the",
"first",
"Brazilian",
"universities",
"were",
"established.",
"The",
"largest",
"of",
"them",
"all,",
"USP",
"(University",
"of",
"Sa˜",
"o",
"Paulo),",
"was",
"started",
"in",
"1934.",
"Today,",
"USP",
"is",
"responsible",
"for",
"more",
"than",
"a",
"quarter",
"of",
"the",
"total",
"publications",
"in",
"Brazil",
"in",
"almost",
"every",
"scientific",
"area,",
"even",
"though",
"there",
"are",
"more",
"than",
"100",
"universities",
"in",
"Brazil",
"now.",
"In",
"terms",
"of",
"productivity,",
"three",
"other",
"universities",
"closely",
"follow:",
"UNICAMP",
"in",
"Campinas,",
"in",
"the",
"state",
"of",
"Sa˜",
"o",
"Paulo,",
"UFRJ",
"in",
"Rio",
"de",
"Janeiro,",
"and",
"UFMG",
"in",
"Belo",
"Horizonte.",
"Notably,",
"these",
"four",
"universities",
"together",
"with",
"EMBRAPA",
"(Brazilian",
"enterprise",
"for",
"research",
"in",
"agriculture,",
"a",
"close",
"equivalent",
"to",
"the",
"US",
"Department",
"of",
"Agriculture),",
"Fiocruz,",
"and",
"Ludwig",
"Institute,",
"both",
"of",
"which",
"are",
"involved",
"in",
"human",
"health",
"related",
"research,",
"and",
"the",
"National",
"Laboratory",
"for",
"Scientific",
"Computation",
"(LNCC),",
"are",
"responsible",
"for",
"most",
"of",
"the",
"scientific",
"publications",
"in",
"computational",
"biology.",
"To",
"consolidate",
"its",
"efforts",
"in",
"building",
"consistent",
"policies",
"for",
"scientific",
"growth",
"and",
"to",
"create",
"a",
"critical",
"mass",
"of",
"specialists",
"in",
"various",
"areas",
"of",
"science,",
"in",
"1951",
"the",
"Brazilian",
"government",
"established",
"the",
"National",
"Research",
"Council",
"(CNPq),",
"and",
"the",
"National",
"Agency",
"for",
"Scholarly",
"Advancement",
"in",
"Scientific",
"Research",
"(CAPES).",
"The",
"former",
"agency",
"was",
"focused",
"on",
"guiding",
"national",
"scientific",
"advancement",
"through",
"financing",
"research",
"projects",
"and",
"collaborations,",
"while",
"the",
"latter",
"provided",
"scholarships",
"to",
"anyone",
"who",
"wanted",
"to",
"obtain",
"higher",
"degrees",
"(Master’s,",
"Ph.D.)",
"and",
"to",
"undertake",
"postdoctoral",
"training,",
"either",
"here",
"in",
"Brazil",
"or",
"abroad.",
"In",
"parallel,",
"Brazilian",
"states",
"initiated",
"their",
"own",
"Scientific",
"Research",
"Agencies",
"(FAP)",
"and",
"Sa˜",
"o",
"Paulo",
"started",
"with",
"its",
"own,",
"FAPESP,",
"in",
"1958.",
"As",
"Sa˜",
"o",
"Paulo",
"is",
"the",
"richest",
"state",
"in",
"the",
"Brazilian",
"federation,",
"the",
"impact",
"of",
"FAPESP",
"investments",
"on",
"science",
"and",
"technology",
"in",
"that",
"particular",
"region",
"were,",
"and",
"are,",
"substantial.",
"The",
"positive",
"impact",
"of",
"FAPESP",
"can",
"be",
"attributed",
"to",
"at",
"least",
"two",
"factors.",
"First,",
"Sa˜",
"o",
"Paulo",
"has",
"a",
"law",
"stating",
"that",
"1%",
"of",
"the",
"tax",
"revenue",
"collected",
"by",
"the",
"state",
"has",
"to",
"be",
"given",
"to",
"FAPESP,",
"and,",
"second,",
"the",
"administrative",
"costs",
"of",
"FAPESP",
"are",
"limited",
"to",
"not",
"more",
"than",
"5%",
"of",
"its",
"total",
"budget.",
"On",
"the",
"national",
"level,",
"in",
"1981",
"the",
"Brazilian",
"government",
"initiated",
"a",
"broad",
"program",
"(PRONAB)",
"for",
"supporting",
"scientific",
"research",
"in",
"biotechnology.",
"A",
"further",
"government",
"program,",
"PADCT,",
"was",
"initiated",
"in",
"1984.",
"As",
"a",
"consequence",
"of",
"these",
"national",
"programs,",
"Brazil",
"has",
"established",
"a",
"critical",
"mass",
"of",
"well-trained",
"specialists",
"and",
"equipped",
"many",
"laboratories,",
"which",
"were",
"fully",
"functional",
"by",
"the",
"early",
"1990s.",
"These",
"programs",
"notwithstanding,",
"Brazil",
"remains",
"below",
"many",
"countries",
"with",
"only",
"12%",
"of",
"17-",
"to",
"25-year-olds",
"studying",
"at",
"universities",
"compared",
"with",
"approximately",
"50%",
"in",
"the",
"United",
"States.",
"Genomics",
"and",
"Bioinformatics",
"In",
"1997",
"FAPESP",
"began",
"to",
"invest",
"both",
"financial",
"and",
"human",
"resources",
"in",
"genome",
"sequencing.",
"No",
"central",
"sequencing",
"Editor:",
"Philip",
"E.",
"Bourne,",
"University",
"of",
"California",
"San",
"Diego,",
"United",
"States",
"of",
"America",
"Citation:",
"Neshich",
"G",
"(2007)",
"Computational",
"Biology",
"in",
"Brazil.",
"PLoS",
"Comput",
"Biol",
"3(10):",
"e185.",
"doi:10.1371/journal.pcbi.0030185",
"Copyright:",
"2007",
"Goran",
"Neshich.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Goran",
"Neshich",
"is",
"with",
"the",
"Embrapa",
"Informa´tica",
"Agropecua´ria,",
"Campinas,",
"Brazil.",
"E-",
"mail:",
"neshich@cbi.cnptia.embrapa.br",
"PLoS",
"Computational",
"Biology",
"|",
"www.ploscompbiol.org",
"1845",
"October",
"2007",
"|",
"Volume",
"3",
"|",
"Issue",
"10",
"|",
"e185"
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] | [
"Bisgin",
"et",
"al.",
"BMC",
"Cancer",
"2012,",
"12:58",
"http://www.biomedcentral.com/1471-2407/12/58",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"Increased",
"serum",
"sTRAIL",
"levels",
"were",
"correlated",
"with",
"survival",
"in",
"bevacizumab-treated",
"metastatic",
"colon",
"cancer",
"Atil",
"Bisgin1*,",
"Aysegul",
"Kargi2,",
"Arzu",
"D",
"Yalcin3,",
"Cigdem",
"Aydin1,",
"Deniz",
"Ekinci2,",
"Burhan",
"Savas2",
"and",
"Salih",
"Sanlioglu1",
"Abstract",
"Background:",
"Colorectal",
"cancer",
"is",
"the",
"third",
"most",
"common",
"cancer",
"and",
"the",
"third",
"leading",
"cause",
"of",
"cancer-related",
"death.",
"Bevacizumab",
"is",
"a",
"humanized",
"monoclonal",
"antibody",
"developed",
"against",
"vascular",
"endothelial",
"growth",
"factor",
"(VEGF)",
"for",
"the",
"treatment",
"of",
"metastatic",
"cancer.",
"The",
"parameters",
"of",
"RECIST",
"(Response",
"Evaluation",
"Criteria",
"for",
"Solid",
"Tumors)",
"are",
"not",
"adequate",
"to",
"detect",
"important",
"treatment",
"effects",
"and",
"response.",
"Our",
"goal",
"was",
"to",
"evaluate",
"the",
"possibility",
"of",
"using",
"sTRAIL",
"(serum-soluble",
"TNF-related",
"apoptosis-inducing",
"ligand)",
"and",
"VEGF",
"as",
"markers",
"of",
"treatment",
"efficacy",
"and",
"prognosis",
"in",
"patients",
"with",
"metastatic",
"colon",
"cancer.",
"Methods:",
"sTRAIL",
"and",
"VEGF",
"levels",
"were",
"measured",
"by",
"ELISA",
"in",
"the",
"sera",
"of",
"16",
"bevacizumab-treated",
"metastatic",
"colon",
"cancer",
"patients",
"and",
"10",
"presumably",
"healthy",
"age-matched",
"controls.",
"The",
"measurements",
"were",
"taken",
"before",
"and",
"after",
"treatment",
"for",
"comparison",
"purposes.",
"Results:",
"Elevated",
"levels",
"of",
"sTRAIL",
"were",
"found",
"in",
"seven",
"out",
"of",
"16",
"patients",
"after",
"bevacizumab",
"treatment.",
"Although",
"these",
"patients",
"had",
"a",
"median",
"survival",
"time",
"of",
"20.6",
"months,",
"the",
"remaining",
"bevacizumab-treated",
"patients",
"who",
"did",
"not",
"show",
"an",
"increase",
"in",
"sTRAIL",
"had",
"a",
"median",
"survival",
"time",
"of",
"9.4",
"months.",
"As",
"expected,",
"serum",
"VEGF",
"levels",
"were",
"decreased",
"in",
"all",
"patients",
"who",
"received",
"bevacizumab",
"therapy",
"and",
"showed",
"no",
"correlation",
"between",
"serum",
"VEGF",
"levels",
"and",
"patient",
"survival",
"(data",
"not",
"shown).",
"Conclusions:",
"Serum",
"sTRAIL",
"levels",
"might",
"be",
"a",
"useful",
"predictor",
"of",
"prognosis",
"in",
"metastatic",
"colon",
"cancer,",
"in",
"the",
"early",
"evaluation",
"stages",
"following",
"bevacizumab",
"treatment.",
"Background",
"Colorectal",
"cancer",
"is",
"the",
"third",
"most",
"common",
"cancer",
"and",
"the",
"second",
"leading",
"cause",
"of",
"cancer-related",
"death",
"[1].",
"Overall,",
"the",
"5-year",
"survival",
"rate",
"is",
"<10%",
"for",
"stage",
"IV",
"cancer",
"[2].",
"The",
"cure",
"rate",
"with",
"surgery",
"alone",
"is",
"very",
"low",
"and",
"chemotherapy",
"and",
"radiotherapy",
"are",
"usually",
"needed",
"in",
"patients",
"with",
"untreated",
"metastatic",
"colon",
"cancer.",
"The",
"development",
"of",
"colorectal",
"cancer",
"is",
"characterized",
"by",
"a",
"sequence",
"of",
"events",
"during",
"which",
"normal",
"colonic",
"epithe-",
"lium",
"gradually",
"transforms",
"to",
"carcinoma",
"tissue,",
"in",
"most",
"cases,",
"via",
"the",
"development",
"of",
"colorectal",
"adenomas",
"[3].",
"This",
"sequence",
"of",
"events",
"is",
"driven",
"by",
"an",
"accumulation",
"of",
"molecular",
"(epi)genetic",
"alterations",
"causing",
"progressive",
"disorders",
"in",
"cell",
"growth,",
"differentiation",
"and",
"apoptosis",
"*",
"Correspondence:",
"atilbisgin@yahoo.co.uk",
"1Human",
"Gene",
"and",
"Cell",
"Therapy",
"Center",
"of",
"Akdeniz",
"University",
"Hospitals",
"and",
"Clinics,",
"Department",
"of",
"Medical",
"Genetics,",
"Antalya,",
"Turkey",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"[4,5].",
"Apoptosis,",
"or",
"programmed",
"cell",
"death,",
"plays",
"an",
"important",
"role",
"in",
"the",
"development",
"and",
"maintenance",
"of",
"tissue",
"homeostasis",
"but",
"also",
"represents",
"an",
"effective",
"mechanism",
"by",
"which",
"abnormal",
"cells,",
"such",
"as",
"tumor",
"cells,",
"can",
"be",
"eliminated",
"[6-8].",
"Abnormalities",
"in",
"apoptotic",
"function",
"or",
"resistance",
"to",
"apoptosis",
"have",
"been",
"identified",
"as",
"important",
"events",
"in",
"the",
"pathogenesis",
"of",
"colorectal",
"cancer",
"and",
"its",
"resistance",
"to",
"chemotherapeutic",
"drugs",
"and",
"radiotherapy",
"[9,10].",
"In",
"recent",
"years,",
"bevacizumab,",
"a",
"novel",
"humanized",
"monoclonal",
"antibody",
"directed",
"against",
"vascular",
"endothe-",
"lial",
"growth",
"factor",
"(VEGF)",
"has",
"found",
"widespread",
"clinical",
"use",
"as",
"an",
"angiogenesis",
"inhibitor",
"for",
"certain",
"types",
"of",
"metastatic",
"cancers",
"[11].",
"Treatment",
"with",
"bevacizumab",
"with/without",
"the",
"combination",
"of",
"other",
"chemotherapeu-",
"tic",
"agents",
"inhibits",
"VEGF",
"receptor",
"activation",
"and",
"vascular",
"permeability,",
"which",
"eventually",
"lead",
"to",
"tumor",
"cell",
"apop-",
"tosis",
"[12,13].",
"Apoptosis",
"can",
"be",
"induced",
"passively,",
"©",
"2012",
"Bisgin",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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] | [
"Available",
"online",
"http://ccforum.com/content/10/6/169",
"Commentary",
"Live",
"and",
"let",
"die:",
"asymmetric",
"dimethylarginine",
"and",
"septic",
"shock",
"Rainer",
"H",
"Böger",
"Clinical",
"Pharmacology",
"Unit,",
"Institute",
"of",
"Experimental",
"and",
"Clinical",
"Pharmacology,",
"University",
"Hospital",
"Hamburg-Eppendorf,",
"Germany",
"Corresponding",
"author:",
"Rainer",
"H",
"Böger,",
"boeger@uke.uni-hamburg.de",
"Published:",
"3",
"November",
"2006",
"This",
"article",
"is",
"online",
"at",
"http://ccforum.com/content/10/6/169",
"©",
"2006",
"BioMed",
"Central",
"Ltd",
"See",
"related",
"research",
"by",
"O’Dwyer",
"et",
"al.,",
"http://ccforum.com/content/10/5/R139",
"Critical",
"Care",
"2006,",
"10:169",
"(doi:10.1186/cc5076)",
"Abstract",
"Nitric",
"oxide",
"(NO)",
"is",
"an",
"important",
"mediator",
"of",
"host",
"defence",
"and",
"of",
"vascular",
"tone.",
"In",
"septic",
"shock,",
"upregulation",
"of",
"inducible",
"NO",
"synthase",
"leads",
"to",
"the",
"production",
"of",
"vast",
"amounts",
"of",
"NO,",
"which",
"contribute",
"to",
"pathogen",
"elimination",
"but",
"also",
"to",
"inappropriate",
"vaso-",
"dilation",
"and",
"to",
"loss",
"of",
"vascular",
"resistance.",
"Asymmetric",
"dimethyl-",
"arginine",
"(ADMA)",
"is",
"an",
"endogenous",
"inhibitor",
"of",
"NO",
"synthases",
"shown",
"to",
"contribute",
"to",
"the",
"regulation",
"of",
"vascular",
"tone.",
"ADMA",
"was",
"recently",
"identified",
"as",
"a",
"marker",
"of",
"organ",
"dysfunction",
"and",
"mortality",
"in",
"intensive",
"care",
"patients",
"and",
"as",
"a",
"novel",
"cardiovascular",
"risk",
"factor.",
"In",
"the",
"present",
"issue",
"of",
"Critical",
"Care,",
"a",
"study",
"by",
"O’Dwyer",
"and",
"colleagues",
"identifies",
"ADMA",
"as",
"a",
"potential",
"regulator",
"of",
"NO",
"production",
"in",
"septic",
"shock.",
"Being",
"an",
"inhibitor",
"of",
"NO",
"production,",
"ADMA",
"may",
"at",
"least",
"partly",
"counteract",
"pathological",
"hypotension,",
"but",
"at",
"the",
"same",
"time",
"may",
"impair",
"the",
"NO-dependent",
"host",
"defence.",
"A",
"mechanism",
"is",
"proposed",
"by",
"which",
"the",
"interplay",
"between",
"ADMA",
"and",
"inducible",
"NO",
"synthase",
"activity",
"is",
"mediated.",
"ADMA",
"levels",
"should",
"be",
"determined",
"in",
"future",
"studies",
"evaluating",
"the",
"regulation",
"of",
"NO",
"in",
"the",
"intensive",
"care",
"setting.",
"In",
"the",
"present",
"issue",
"of",
"Critical",
"Care,",
"O’Dwyer",
"and",
"colleagues",
"[1]",
"report",
"the",
"results",
"of",
"a",
"study",
"in",
"47",
"patients",
"with",
"septic",
"shock.",
"Asymmetric",
"dimethylarginine",
"(ADMA)",
"levels",
"were",
"elevated",
"in",
"these",
"patients",
"at",
"the",
"time",
"of",
"admission",
"to",
"the",
"intensive",
"care",
"unit",
"(ICU)",
"as",
"compared",
"with",
"a",
"group",
"of",
"10",
"healthy",
"controls.",
"ADMA",
"levels",
"in",
"septic",
"patients",
"directly",
"correlated",
"with",
"the",
"Sequential",
"Organ",
"Failure",
"Assessment",
"scores,",
"with",
"the",
"degree",
"of",
"acidaemia",
"and",
"lactaemia,",
"and",
"with",
"vasopressor",
"requirements.",
"Interestingly",
"enough,",
"ADMA",
"levels",
"were",
"higher",
"in",
"patients",
"requiring",
"vasoactive",
"infusions",
"than",
"in",
"those",
"not",
"requiring",
"vasoactive",
"infusions.",
"ADMA",
"levels",
"further",
"increased",
"during",
"the",
"subsequent",
"7",
"days",
"of",
"ICU",
"treatment.",
"Nonsurvivors",
"tended",
"to",
"have",
"higher",
"ADMA",
"plasma",
"levels",
"on",
"days",
"1",
"and",
"7",
"of",
"ICU",
"treatment",
"as",
"compared",
"with",
"survivors,",
"although",
"this",
"trend",
"was",
"insignificant",
"in",
"the",
"small",
"patient",
"group.",
"The",
"authors",
"also",
"demonstrated",
"that",
"a",
"genetic",
"polymorphism",
"in",
"the",
"promoter",
"region",
"of",
"the",
"dimethylarginine",
"dimethylaminohydrolase",
"(DDAH)",
"II",
"gene",
"was",
"significantly",
"associated",
"with",
"ADMA",
"levels",
"in",
"these",
"patients,",
"suggesting",
"that",
"the",
"genetically",
"anchored",
"dysfunction",
"of",
"the",
"enzyme",
"that",
"metabolises",
"ADMA",
"may",
"importantly",
"regulate",
"ADMA",
"levels.",
"Standard",
"therapy",
"for",
"patients",
"with",
"sepsis",
"includes",
"ICU",
"admission,",
"careful",
"selection",
"of",
"antibiotic",
"therapy,",
"and,",
"if",
"needed,",
"haemodynamic",
"and",
"ventilatory",
"support",
"[2].",
"Despite",
"the",
"use",
"of",
"these",
"intensive",
"therapies,",
"however,",
"mortality",
"from",
"sepsis",
"has",
"remained",
"at",
"levels",
"between",
"35%",
"and",
"50%",
"[2].",
"Nitric",
"oxide",
"(NO)",
"is",
"referred",
"to",
"as",
"a",
"key",
"mediator",
"of",
"vasodilatation",
"and",
"catecholamine",
"resistance",
"in",
"septic",
"shock",
"[3,4].",
"Whereas",
"in",
"physiological",
"conditions",
"NO",
"is",
"mainly",
"formed",
"in",
"the",
"endothelium",
"at",
"low",
"rates",
"by",
"the",
"activity",
"of",
"the",
"constitutive,",
"endothelial",
"isoform",
"of",
"the",
"enzyme",
"NO",
"synthase,",
"inflammatory",
"stimuli",
"such",
"as",
"bacterial",
"lipopolysaccharides",
"and",
"cytokines",
"released",
"during",
"sepsis",
"result",
"in",
"a",
"strong",
"upregulation",
"of",
"an",
"inducible",
"isofom",
"of",
"NO",
"synthase",
"(iNOS).",
"This",
"isoform,",
"once",
"upregulated,",
"releases",
"huge",
"amounts",
"of",
"NO",
"during",
"prolonged",
"time",
"intervals.",
"The",
"iNOS-derived",
"NO",
"contributes",
"to",
"pathogen",
"elimination.",
"NO-induced",
"vaso-",
"dilatation,",
"however,",
"also",
"contributes",
"to",
"widespread",
"vascular",
"loss",
"of",
"tone",
"and",
"has",
"been",
"implicated",
"in",
"the",
"cardiovascular",
"failure",
"in",
"septic",
"shock",
"[5].",
"There",
"has",
"been",
"controversy",
"about",
"the",
"pathophysiological",
"roles",
"of",
"iNOS",
"and",
"NO",
"in",
"the",
"development",
"of",
"septic",
"shock",
"after",
"a",
"phase",
"III",
"trial",
"with",
"NG-",
"monomethyl-L-arginine,",
"a",
"nonselective",
"NO",
"synthase",
"inhibitor,",
"resulted",
"in",
"excess",
"mortality",
"[6].",
"Indeed,",
"experimental",
"studies",
"have",
"suggested",
"that",
"iNOS-derived",
"NO",
"plays",
"an",
"important",
"role",
"in",
"host",
"defence",
"and",
"organ",
"protection",
"[7].",
"During",
"the",
"past",
"decade",
"knowledge",
"has",
"accumulated",
"of",
"endogenous",
"compounds",
"that",
"inhibit",
"NO",
"synthase",
"activity,",
"and",
"thereby",
"regulate",
"NO-dependent",
"vascular",
"function.",
"The",
"major",
"molecule",
"endogenously",
"present",
"in",
"the",
"circulation",
"at",
"concentrations",
"sufficiently",
"high",
"to",
"exert",
"inhibitory",
"effects",
"on",
"ADMA",
"=",
"asymmetric",
"dimethylarginine;",
"DDAH",
"=",
"dimethylarginine",
"dimethylaminohydrolase;",
"ICU",
"=",
"intensive",
"care",
"unit;",
"iNOS",
"=",
"inducible",
"NO",
"synthase;",
"NO",
"=",
"nitric",
"oxide.",
"Page",
"1",
"of",
"3",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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] | [
"PDHK-2",
"Deficiency",
"Is",
"Associated",
"with",
"Attenuation",
"of",
"Lipase-Mediated",
"Fat",
"Consumption",
"for",
"the",
"Increased",
"Survival",
"of",
"Caenorhabditis",
"elegans",
"Dauers",
"Sunhee",
"Kim,",
"E-Jin",
"Shin,",
"Jeong-Hoon",
"Hahm,",
"Pil-Jong",
"Park,",
"Ji-Eun",
"Hwang,",
"Young-Ki",
"Paik*",
"Department",
"of",
"Biochemistry",
"and",
"Integrated",
"Omics",
"for",
"Biomedical",
"Science,",
"World",
"Class",
"University",
"Program,",
"College",
"of",
"Life",
"Science",
"and",
"Biotechnology,",
"Yonsei",
"Proteome",
"Research",
"Center,",
"Yonsei",
"University,",
"Seoul,",
"Korea",
"Abstract",
"In",
"Caenorhabditis",
"elegans,",
"slow",
"fat",
"consumption",
"has",
"been",
"suggested",
"to",
"contribute",
"to",
"the",
"extension",
"of",
"the",
"survival",
"rate",
"during",
"nutritionally",
"adverse",
"conditions.",
"Here,",
"we",
"investigated",
"the",
"potential",
"role",
"of",
"pyruvate",
"dehydrogenase",
"kinase",
"(PDHK)-",
"2,",
"the",
"C.",
"elegans",
"homolog",
"of",
"mammalian",
"PDK,",
"effects",
"on",
"fat",
"metabolism",
"under",
"nutritional",
"conditions.",
"PDHK-2",
"was",
"expressed",
"at",
"low",
"levels",
"under",
"well-fed",
"conditions",
"but",
"was",
"highly",
"induced",
"during",
"long-term",
"starvation",
"and",
"in",
"the",
"dauer",
"state.",
"This",
"increase",
"in",
"pdhk-2",
"expression",
"was",
"regulated",
"by",
"both",
"DAF-16",
"and",
"NHR-49.",
"Dauer-specific",
"induction",
"of",
"PDHK-2",
"was",
"abolished",
"upon",
"entry",
"into",
"the",
"post-dauer",
"stage.",
"Interestingly,",
"in",
"the",
"long-term",
"dauer",
"state,",
"stored",
"fat",
"levels",
"were",
"higher",
"in",
"daf-2(e1370);pdhk-2",
"double",
"mutants",
"than",
"in",
"daf-2(e1370),",
"suggesting",
"a",
"positive",
"relationship",
"between",
"PDHK-2",
"activity",
"and",
"fat",
"consumption.",
"PDHK-2",
"deficiency",
"has",
"been",
"shown",
"to",
"lead",
"to",
"greater",
"preservation",
"of",
"residual",
"fats,",
"which",
"would",
"be",
"predicted",
"to",
"contribute",
"to",
"survival",
"during",
"the",
"dauer",
"state.",
"A",
"test",
"of",
"this",
"prediction",
"showed",
"that",
"the",
"survival",
"rates",
"of",
"daf-2(e1370);pdhk-",
"2(tm3075)",
"and",
"daf-2(e1370);pdhk-2(tm3086)",
"double",
"mutants",
"were",
"higher",
"than",
"that",
"of",
"daf-2(e1370),",
"suggesting",
"that",
"loss",
"of",
"either",
"the",
"ATP-binding",
"domain",
"(tm3075)",
"or",
"branched",
"chain",
"keto-acid",
"dehydrogenase",
"kinase",
"domain",
"(tm3086)",
"of",
"PDHK-2",
"leads",
"to",
"reduced",
"fat",
"consumption",
"and",
"thus",
"favors",
"increased",
"dauer",
"survival.",
"This",
"attenuated",
"fat",
"consumption",
"in",
"the",
"long-",
"term",
"dauer",
"state",
"of",
"C.",
"elegans",
"daf-2",
"(e1370);pdhk-2",
"mutants",
"was",
"associated",
"with",
"concomitant",
"down-regulation",
"of",
"the",
"lipases",
"ATGL",
"(adipose",
"triglyceride",
"lipase),",
"HSL",
"(hormone-sensitive",
"lipase),",
"and",
"C07E3.9",
"(phospholipase).",
"In",
"contrast,",
"PDHK-2",
"overexpression",
"in",
"wild-type",
"starved",
"worms",
"induced",
"lipase",
"expression",
"and",
"promoted",
"abnormal",
"dauer",
"formation.",
"Thus,",
"we",
"propose",
"that",
"PDHK-2",
"serves",
"as",
"a",
"molecular",
"bridge,",
"connecting",
"fat",
"metabolism",
"and",
"survival",
"under",
"nutritionally",
"adverse",
"conditions",
"in",
"C.",
"elegans.",
"Citation:",
"Kim",
"S,",
"Shin",
"E-J,",
"Hahm",
"J-H,",
"Park",
"P-J,",
"Hwang",
"J-E,",
"et",
"al.",
"(2012)",
"PDHK-2",
"Deficiency",
"Is",
"Associated",
"with",
"Attenuation",
"of",
"Lipase-Mediated",
"Fat",
"Consumption",
"for",
"the",
"Increased",
"Survival",
"of",
"Caenorhabditis",
"elegans",
"Dauers.",
"PLoS",
"ONE",
"7(7):",
"e41755.",
"doi:10.1371/journal.pone.0041755",
"Editor:",
"Howard",
"Riezman,",
"University",
"of",
"Geneva,",
"Switzerland",
"Received",
"June",
"18,",
"2012;",
"Accepted",
"June",
"25,",
"2012;",
"Published",
"July",
"27,",
"2012",
"Copyright:",
"2012",
"Kim",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"This",
"study",
"was",
"supported",
"by",
"the",
"National",
"Research",
"Foundation",
"of",
"Korea",
"(NRF)",
"grant",
"(No.",
"2011-0028112",
"to",
"YKP)",
"and",
"WCU",
"Program",
"(R31-2008-000-",
"10086-0)",
"funded",
"by",
"the",
"Korean",
"government",
"(MEST),",
"and",
"the",
"National",
"Project",
"for",
"Personalized",
"Genomic",
"Medicine",
"(A111218-11-CP01",
"to",
"YKP).",
"The",
"funders",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript.",
"Competing",
"Interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"*",
"E-mail:",
"paikyk@yonsei.ac.kr",
"Introduction",
"It",
"has",
"been",
"well",
"documented",
"that",
"a",
"close",
"relationship",
"exists",
"between",
"energy",
"metabolism",
"and",
"aging",
"processes",
"in",
"animals,",
"including",
"the",
"nematode",
"Caenorhabditis",
"elegans",
"[1,2].",
"In",
"C.",
"elegans,",
"in",
"particular,",
"the",
"critical",
"role",
"of",
"insulin/insulin-like",
"growth",
"factor-1",
"(IGF-1)",
"signaling",
"(IIS)",
"in",
"metabolism",
"and",
"the",
"control",
"of",
"aging",
"has",
"been",
"well",
"established.",
"For",
"example,",
"suppression",
"of",
"the",
"IIS",
"pathway",
"has",
"been",
"shown",
"to",
"cause",
"a",
"substantial",
"increase",
"in",
"both",
"mean",
"lifespan",
"(MLS)",
"and",
"fat",
"accumulation",
"[1–3].",
"This",
"pathway",
"also",
"controls",
"the",
"dauer",
"state,",
"a",
"non-aging",
"condition",
"that",
"is",
"important",
"in",
"determining",
"the",
"relationship",
"between",
"metabolism",
"and",
"aging",
"[4,5].",
"When",
"C.",
"elegans",
"encounters",
"unfavorable",
"growth",
"conditions",
"(e.g.,",
"lack",
"of",
"food",
"or",
"high",
"temperatures)",
"or",
"high",
"concentrations",
"of",
"dauer",
"pheromones",
"(daumones",
"or",
"ascarosides),",
"it",
"can",
"enter",
"the",
"dauer",
"state",
"[5–10].",
"Studies",
"on",
"dauer",
"entry",
"in",
"C.",
"elegans",
"have",
"suggested",
"that",
"this",
"process",
"is",
"compartmentalized",
"according",
"to",
"metabolic",
"phase",
"and",
"growth",
"time",
"[11].",
"When",
"L2",
"larvae",
"prepare",
"for",
"dauer",
"entry,",
"nutritional",
"adaptation",
"accompanies",
"intestinal",
"and",
"hypodermal",
"fat",
"accumulation,",
"enabling",
"C.",
"elegans",
"to",
"survive",
"an",
"extended",
"dormant",
"period",
"[12].",
"The",
"dauer",
"state",
"is",
"controlled",
"by",
"an",
"IIS",
"mechanism",
"in",
"which",
"DAF-16",
"serves",
"as",
"a",
"downstream",
"effector",
"[11–13].",
"The",
"dauer",
"state",
"is",
"resistant",
"to",
"environmental",
"stresses,",
"such",
"as",
"heat",
"and",
"cold,",
"as",
"well",
"as",
"oxidative",
"stress,",
"and",
"the",
"metabolic",
"activity",
"of",
"dauer",
"larvae",
"is",
"generally",
"reduced",
"[12].",
"Because",
"dauer",
"larvae",
"do",
"not",
"feed,",
"they",
"use",
"mostly",
"stored",
"triglycerides",
"(TGs)",
"as",
"an",
"energy",
"source",
"[12,13];",
"TGs,",
"in",
"turn,",
"are",
"hydrolyzed",
"to",
"fatty",
"acids",
"by",
"lipases",
"[14].",
"Additional",
"macronutrients",
"that",
"are",
"stored",
"and",
"metabolized",
"in",
"dauer",
"larvae",
"include",
"glycogen",
"and",
"trehalose",
"[15].",
"Because",
"their",
"supply",
"of",
"stored",
"nutrients",
"is",
"limited,",
"dauers",
"must",
"suppress",
"energy-consuming",
"metabolic",
"activities",
"to",
"survive",
"[16].",
"Microarray",
"and",
"SAGE",
"(serial",
"analysis",
"of",
"gene",
"expression)",
"assays",
"of",
"dauer",
"larvae,",
"recovered",
"dauers,",
"and",
"mixed-stage",
"populations",
"have",
"suggested",
"that",
"the",
"expression",
"of",
"enzymes",
"involved",
"in",
"b-oxidation",
"of",
"fatty",
"acids,",
"glycolysis,",
"glyoxylate,",
"and",
"gluconeogenesis",
"pathways",
"are",
"enhanced",
"under",
"nutritionally",
"adverse",
"conditions,",
"indicating",
"that",
"TGs",
"are",
"degraded",
"by",
"lipases",
"and",
"converted",
"into",
"sugars",
"that",
"are",
"used",
"for",
"survival",
"[17–21].",
"Slow",
"energy",
"release",
"and",
"tightly",
"controlled",
"energy",
"consumption",
"may",
"be",
"critical",
"to",
"long-term",
"survival",
"through",
"diapause,",
"hibernation,",
"or",
"long-term",
"fasting",
"in",
"a",
"PLoS",
"ONE",
"|",
"www.plosone.org",
"1",
"July",
"2012",
"|",
"Volume",
"7",
"|",
"Issue",
"7",
"|",
"e41755"
] | [
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] | [
"Rasul",
"et",
"al.",
"Cardiovascular",
"Diabetology",
"2011,",
"10:55",
"http://www.cardiab.com/content/10/1/55",
"O",
"R",
"I",
"G",
"I",
"N",
"A",
"L",
"I",
"N",
"V",
"E",
"S",
"T",
"I",
"G",
"A",
"T",
"I",
"O",
"N",
"CARDIO",
"VASCULAR",
"DIABETOLOGY",
"Open",
"Access",
"Circulating",
"angiopoietin-2",
"and",
"soluble",
"Tie-2",
"in",
"type",
"2",
"diabetes",
"mellitus:",
"a",
"cross-sectional",
"study",
"Sazan",
"Rasul1,",
"Marie",
"Helene",
"Reiter2,",
"Aysegul",
"Ilhan3,",
"Katharina",
"Lampichler2,",
"Ludwig",
"Wagner3",
"and",
"Alexandra",
"Kautzky-Willer1*",
"Abstract",
"Background:",
"Type",
"2",
"diabetes",
"is",
"associated",
"with",
"increased",
"levels",
"of",
"Angiopoietin-2",
"(Ang-2)",
"and",
"soluble",
"Tie-2",
"(sTie-",
"2),",
"but",
"its",
"impact",
"on",
"vascular",
"disease",
"is",
"still",
"unknown.",
"This",
"study",
"aimed",
"to",
"further",
"explore",
"the",
"associations",
"of",
"Ang-2",
"and",
"sTie-2",
"with",
"metabolic",
"control",
"and",
"diabetic",
"complications.",
"Methods:",
"In",
"a",
"cross-sectional",
"designed",
"study,",
"levels",
"of",
"Ang-2",
"and",
"sTie-2",
"as",
"well",
"as",
"their",
"relationships",
"to",
"cardiometabolic",
"parameters",
"were",
"determined",
"in",
"80",
"type",
"2",
"diabetic",
"subjects",
"(age",
"65",
"±",
"7",
"years,",
"female",
"47.4%).",
"Results:",
"After",
"controlling",
"for",
"age",
"and",
"BMI,",
"Ang-2",
"levels",
"were",
"associated",
"with",
"levels",
"of",
"sTie-2,",
"diastolic",
"blood",
"pressure,",
"plasma",
"insulin,",
"homeostasis",
"model",
"assessment",
"of",
"insulin",
"resistance",
"(HOMA-IR),",
"creatinine,",
"glomerular",
"filtration",
"rate",
"(GFR),",
"and",
"gamma-glutamyl",
"transferase",
"(GGT)",
"(all",
"p",
"<",
"0.02).",
"Presence",
"of",
"diabetic",
"macrovascular",
"complications,",
"polyneuropathy",
"and",
"insulin",
"therapy",
"were",
"associated",
"with",
"higher",
"Ang-2",
"levels",
"(p",
"<",
"0.05).",
"Conversely,",
"sTie-2",
"levels",
"were",
"associated",
"with",
"glycated",
"hemoglobin",
"(HbA1c),",
"fasting",
"plasma",
"glucose",
"and",
"insulin,",
"HOMA-IR,",
"triglyceride,",
"and",
"liver",
"function",
"parameters",
"(all",
"p",
"<",
"0.03).",
"Multiple",
"linear",
"regression",
"analysis",
"showed",
"that",
"Ang-2",
"remained",
"significantly",
"associated",
"only",
"with",
"levels",
"of",
"GGT",
"(p",
"<",
"0.04),",
"whereas",
"sTie-2",
"remained",
"significantly",
"associated",
"with",
"HbA1c,",
"insulin",
"levels,",
"and",
"HOMA-IR",
"(p",
"<",
"0.03).",
"No",
"differences",
"in",
"Ang-2",
"and",
"sTie-2",
"levels",
"were",
"observed",
"with",
"regard",
"to",
"gender",
"of",
"participants.",
"Conclusions:",
"Ang-2",
"is",
"independently",
"associated",
"with",
"levels",
"of",
"GGT",
"while",
"sTie-2",
"is",
"independently",
"associated",
"with",
"levels",
"of",
"HbA1c,",
"plasma",
"insulin",
"and",
"HOMA-IR",
"in",
"type",
"2",
"diabetic",
"subjects.",
"Therefore",
"we",
"suggest",
"that",
"the",
"associations",
"of",
"Ang-2",
"and",
"sTie-2",
"with",
"type",
"2",
"diabetes",
"are",
"based",
"on",
"different",
"patho-physiological",
"mechanisms.",
"Background",
"Angiopoietins",
"are",
"growth",
"factors",
"that",
"promote",
"angiogen-",
"esis",
"together",
"with",
"vascular",
"endothelial",
"growth",
"factor",
"(VEGF).",
"Among",
"the",
"four",
"identified",
"angiopoietins",
"(1-4),",
"Angiopoietin",
"(Ang)-1",
"and",
"Ang-2",
"are",
"reported",
"to",
"be",
"required",
"for",
"the",
"formation",
"of",
"mature",
"blood",
"vessels,",
"as",
"demonstrated",
"by",
"mouse",
"knock",
"out",
"studies",
"[1,2].",
"Ang-2",
"is",
"expressed",
"primarily",
"in",
"the",
"vascular",
"endothelium",
"at",
"sites",
"of",
"vascular",
"remodeling",
"[3].",
"Both",
"Ang-1",
"and",
"Ang-2",
"act",
"by",
"binding",
"to",
"the",
"endothelium-specific",
"receptor",
"tyrosine",
"kinase",
"2",
"(Tie-2).",
"A",
"soluble",
"form",
"of",
"the",
"Tie-2",
"receptor",
"can",
"be",
"detected",
"in",
"human",
"biological",
"fluids",
"[4].",
"The",
"Ang/Tie",
"system",
"tightly",
"controls",
"the",
"endothelial",
"phenotype",
"during",
"*",
"Correspondence:",
"Alexandra.kautzky-willer@meduniwien.ac.at",
"1Department",
"of",
"Internal",
"Medicine",
"III,",
"Division",
"of",
"Endocrinology",
"and",
"Metabolism,",
"Unit",
"of",
"Gender",
"Medicine,",
"Medical",
"University",
"of",
"Vienna,",
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"[12].",
"©",
"2011",
"Rasul",
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] | [
"Huo",
"et",
"al.",
"BMC",
"Neuroscience",
"2011,",
"12:49",
"http://www.biomedcentral.com/1471-2202/12/49",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"Dexamethasone",
"inhibits",
"the",
"Nox-dependent",
"ROS",
"production",
"via",
"suppression",
"of",
"MKP-1-dependent",
"MAPK",
"pathways",
"in",
"activated",
"microglia",
"Yingqian",
"Huo,",
"Parakalan",
"Rangarajan,",
"Eng-Ang",
"Ling",
"and",
"S",
"Thameem",
"Dheen*",
"Abstract",
"Background:",
"Nox-2",
"(also",
"known",
"as",
"gp91phox),",
"a",
"subunit",
"component",
"of",
"NADPH",
"oxidases,",
"generates",
"reactive",
"oxygen",
"species",
"(ROS).",
"Nox-dependent",
"ROS",
"generation",
"and",
"nitric",
"oxide",
"(NO)",
"release",
"by",
"microglia",
"have",
"been",
"implicated",
"in",
"a",
"variety",
"of",
"diseases",
"in",
"the",
"central",
"nervous",
"system.",
"Dexamethasone",
"(Dex)",
"has",
"been",
"shown",
"to",
"suppress",
"the",
"ROS",
"production,",
"NO",
"release",
"and",
"inflammatory",
"reaction",
"of",
"activated",
"microglial",
"cells.",
"However,",
"the",
"underlying",
"mechanisms",
"remain",
"unclear.",
"Results:",
"The",
"present",
"study",
"showed",
"that",
"the",
"increased",
"ROS",
"production",
"and",
"NO",
"release",
"in",
"activated",
"BV-2",
"microglial",
"cells",
"by",
"LPS",
"were",
"associated",
"with",
"increased",
"expression",
"of",
"Nox-2",
"and",
"iNOS.",
"Dex",
"suppressed",
"the",
"upregulation",
"of",
"Nox-2",
"and",
"iNOS,",
"as",
"well",
"as",
"the",
"subsequent",
"ROS",
"production",
"and",
"NO",
"synthesis",
"in",
"activated",
"BV-2",
"cells.",
"This",
"inhibition",
"caused",
"by",
"Dex",
"appeared",
"to",
"be",
"mediated",
"by",
"upregulation",
"of",
"MAPK",
"phosphatase-1",
"(MKP-1),",
"which",
"antagonizes",
"the",
"activity",
"of",
"mitogen-activated",
"protein",
"kinases",
"(MAPKs).",
"Dex",
"induced-suppression",
"of",
"Nox-2",
"and",
"-upregulation",
"of",
"MKP-",
"1",
"was",
"also",
"evident",
"in",
"the",
"activated",
"microglia",
"from",
"corpus",
"callosum",
"of",
"postnatal",
"rat",
"brains.",
"The",
"overexpression",
"of",
"MKP-1",
"or",
"inhibition",
"of",
"MAPKs",
"(by",
"specific",
"inhibitors",
"of",
"JNK",
"and",
"p38",
"MAPKs),",
"were",
"found",
"to",
"downregulate",
"the",
"expression",
"of",
"Nox-2",
"and",
"iNOS",
"and",
"thereby",
"inhibit",
"the",
"synthesis",
"of",
"ROS",
"and",
"NO",
"in",
"activated",
"BV-2",
"cells.",
"Moreover,",
"Dex",
"was",
"unable",
"to",
"suppress",
"the",
"LPS-induced",
"synthesis",
"of",
"ROS",
"and",
"NO",
"in",
"BV-2",
"cells",
"transfected",
"with",
"MKP-1",
"siRNA.",
"On",
"the",
"other",
"hand,",
"knockdown",
"of",
"Nox-2",
"in",
"BV-2",
"cells",
"suppressed",
"the",
"LPS-induced",
"ROS",
"production",
"and",
"NO",
"release.",
"Conclusion:",
"In",
"conclusion,",
"it",
"is",
"suggested",
"that",
"downregulation",
"of",
"Nox-2",
"and",
"overexpression",
"of",
"MKP-1",
"that",
"regulate",
"ROS",
"and",
"NO",
"may",
"form",
"the",
"potential",
"therapeutic",
"strategy",
"for",
"the",
"treatment",
"of",
"neuroinflammation",
"in",
"neurodegenerative",
"diseases.",
"Keywords:",
"microglia,",
"Nox-2,",
"MAPKs,",
"ROS,",
"dexamethasone",
"Background",
"An",
"inflammatory",
"process",
"in",
"the",
"central",
"nervous",
"system",
"(CNS)",
"is",
"considered",
"to",
"be",
"a",
"prominent",
"feature",
"in",
"a",
"num-",
"ber",
"of",
"neurodegenerative",
"diseases",
"and",
"is",
"mediated",
"by",
"the",
"activated",
"microglia,",
"the",
"resident",
"immune",
"cells",
"of",
"the",
"CNS.",
"The",
"microglia",
"normally",
"respond",
"to",
"neuronal",
"damage",
"and",
"remove",
"the",
"damaged",
"cells",
"by",
"phagocytosis",
"[1].",
"The",
"chronic",
"activation",
"of",
"these",
"cells",
"appears",
"to",
"cause",
"neuronal",
"damage",
"through",
"enhanced",
"release",
"of",
"potentially",
"cytotoxic",
"molecules",
"such",
"as",
"proinflammatory",
"cytokines",
"including",
"tumor",
"necrosis",
"factor-a",
"(TNF-a)",
"and",
"*",
"Correspondence:",
"antstd@nus.edu.sg",
"Department",
"of",
"Anatomy",
"Yong",
"Loo",
"Lin",
"school",
"of",
"Medicine",
"National",
"University",
"of",
"Singapore,",
"117597,",
"Singapore",
"interleukin-1b",
"(IL-1b),",
"nitric",
"oxide",
"(NO),",
"reactive",
"oxygen",
"intermediates,",
"proteinases",
"and",
"complement",
"proteins",
"[2-5].",
"Moreover,",
"microglia-derived",
"free",
"radicals",
"as",
"well",
"as",
"the",
"reactive",
"reaction",
"products,",
"hydrogen",
"peroxide",
"and",
"peroxynitrite,",
"have",
"the",
"potential",
"to",
"harm",
"cells",
"and",
"have",
"been",
"implicated",
"in",
"contributing",
"to",
"oxidative",
"damage",
"and",
"neurodegeneration",
"in",
"neurological",
"diseases",
"[6,7].",
"There-",
"fore,",
"suppression",
"of",
"microglia-mediated",
"inflammation",
"has",
"been",
"considered",
"as",
"an",
"important",
"strategy",
"in",
"neurode-",
"generative",
"disease",
"therapy.",
"Nicotinamide",
"adenine",
"dinuceotide",
"phosphate",
"(NADPH)",
"oxidase,",
"a",
"multi-component",
"enzyme",
"complex",
"is",
"an",
"impor-",
"tant",
"source",
"of",
"reactive",
"oxygen",
"species",
"(ROS)",
"in",
"respiratory",
"oxidative",
"stress",
"and",
"intracellular",
"signaling",
"pathways",
"[8,9].",
"©",
"2011",
"Huo",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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] | [
"Available",
"online",
"at",
"http://www.biij.org/2009/3/e25",
"doi:",
"10.2349/biij.5.3.e25",
"biij",
"Biomedical",
"Imaging",
"and",
"Intervention",
"Journal",
"TECHNICAL",
"REPORT",
"Third",
"party",
"EPID",
"with",
"IGRT",
"capability",
"retrofitted",
"onto",
"an",
"existing",
"medical",
"linear",
"accelerator",
"DO",
"Odero*,1,2,",
"PhD,",
"DS",
"Shimm1,",
"MD",
"1",
"Radiation",
"Therapy,",
"Raleigh",
"Regional",
"Cancer",
"Center,",
"Beckley,",
"West",
"Virginia,",
"United",
"States",
"2",
"Radiologic",
"Technology,",
"Mountain",
"State",
"University,",
"Beckley,",
"West",
"Virginia",
"United",
"States",
"Received",
"30",
"October",
"2008;",
"received",
"in",
"revised",
"form",
"4",
"June",
"2009,",
"accepted",
"23",
"June",
"2009",
"ABSTRACT",
"Radiation",
"therapy",
"requires",
"precision",
"to",
"avoid",
"unintended",
"irradiation",
"of",
"normal",
"organs.",
"Electronic",
"Portal",
"Imaging",
"Devices",
"(EPIDs),",
"can",
"help",
"with",
"precise",
"patient",
"positioning",
"for",
"accurate",
"treatment.",
"EPIDs",
"are",
"now",
"bundled",
"with",
"new",
"linear",
"accelerators,",
"or",
"they",
"can",
"be",
"purchased",
"from",
"the",
"Linac",
"manufacturer",
"for",
"retrofit.",
"Retrofitting",
"a",
"third",
"party",
"EPID",
"to",
"a",
"linear",
"accelerator",
"can",
"pose",
"challenges.",
"The",
"authors",
"describe",
"a",
"relatively",
"inexpensive",
"third",
"party",
"CCD",
"camera-based",
"EPID",
"manufactured",
"by",
"TheraView",
"(Cablon",
"Medical",
"B.V.),",
"installed",
"onto",
"a",
"Siemens",
"Primus",
"linear",
"accelerator,",
"and",
"integrated",
"with",
"a",
"Lantis",
"record",
"and",
"verify",
"system,",
"an",
"Oldelft",
"simulator",
"with",
"Digital",
"Therapy",
"Imaging",
"(DTI)",
"unit,",
"and",
"a",
"Philips",
"ADAC",
"Pinnacle",
"treatment",
"planning",
"system",
"(TPS).",
"This",
"system",
"integrates",
"well",
"with",
"existing",
"equipment",
"and",
"its",
"software",
"can",
"process",
"DICOM",
"images",
"from",
"other",
"sources.",
"The",
"system",
"provides",
"a",
"complete",
"imaging",
"system",
"that",
"eliminates",
"the",
"need",
"for",
"separate",
"software",
"for",
"portal",
"image",
"viewing,",
"interpretation,",
"analysis,",
"archiving,",
"image",
"guided",
"radiation",
"therapy",
"and",
"other",
"image",
"management",
"applications.",
"It",
"can",
"also",
"be",
"accessed",
"remotely",
"via",
"safe",
"VPN",
"tunnels.",
"TheraView",
"EPID",
"retrofit",
"therefore",
"presents",
"an",
"example",
"of",
"a",
"less",
"expensive",
"alternative",
"to",
"linear",
"accelerator",
"manufacturers’",
"proprietary",
"EPIDs",
"suitable",
"for",
"implementation",
"in",
"third",
"world",
"countries",
"radiation",
"therapy",
"departments",
"which",
"are",
"often",
"faced",
"with",
"limited",
"financial",
"resources.",
"©",
"2009",
"Biomedical",
"Imaging",
"and",
"Intervention",
"Journal.",
"All",
"rights",
"reserved.",
"Keywords:",
"Portal",
"Imaging;",
"Simulation;",
"EPID;",
"IMRT;",
"IGRT",
"INTRODUCTION",
"The",
"aim",
"of",
"external",
"beam",
"radiotherapy",
"is",
"to",
"deliver",
"a",
"tumoricidal",
"radiation",
"dose",
"while",
"minimizing",
"dose",
"to",
"the",
"surrounding",
"normal",
"tissues,",
"which",
"requires",
"accurate",
"and",
"reproducible",
"field",
"placement.",
"Verifying",
"patient",
"position",
"and",
"fields",
"historically",
"has",
"been",
"accomplished",
"*",
"Corresponding",
"author.",
"Present",
"address:",
"Raleigh",
"Regional",
"Cancer",
"Center",
"and",
"Mountain",
"State",
"University,",
"275",
"Dry",
"Hill",
"Road,",
"Beckley",
"WV",
"25801",
"USA.",
"E-mail:",
"oderodan@netscape.net",
"(Dan",
"Odero).",
"via",
"exit",
"radiation",
"portal",
"films.",
"Ideally,",
"films",
"should",
"be",
"performed",
"every",
"day",
"before",
"the",
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"[1-4],",
"but",
"this",
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"ties",
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"personnel,",
"the",
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"the",
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"machine",
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"while",
"the",
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"must",
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"on",
"the",
"treatment",
"table.",
"The",
"electronic",
"portal",
"imaging",
"device",
"(EPID)",
"[5]",
"is",
"a",
"relatively",
"new",
"development",
"in",
"portal",
"imaging.",
"Boyer",
"et",
"al",
"[6]",
"and",
"Munro",
"[7]",
"have",
"written",
"comprehensive",
"reviews",
"of",
"EPIDs,",
"and,",
"briefly,",
"they",
"consist",
"of",
"an",
"image",
"acquisition",
"unit",
"fitted",
"to",
"the",
"linear",
"accelerator",
"(Linac),"
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