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Sample records for des mutations contemporaines

  1. Le risque de détresse morale dans la pratique contemporaine des soins de santé.

    PubMed

    Austin, Wendy

    2016-05-01

    Les professionnels de la santé sont des agents moraux dont la relation fiduciaire avec le public est animée par la responsabilité et la promesse de puiser dans leurs connaissances et leurs habiletés pour aider les personnes sous leurs soins. Lorsque leur capacité à tenir cette promesse est freinée ou compromise, ils risquent de souffrir de détresse morale. Le concept de détresse morale est défini et mis en contexte dans le milieu de la santé. Les contraintes et les facteurs qui en sont à l'origine sont présentés, de même que les moyens utilisés par les professionnels de la santé et les organisations de santé pour la soulager. Un changement transformateur s'impose pour vaincre la culture du silence et maintenir un système de santé où il est possible de vivre avec sa conscience. PMID:27068874

  2. Le risque de détresse morale dans la pratique contemporaine des soins de santé.

    PubMed

    Austin, Wendy

    2016-05-01

    Les professionnels de la santé sont des agents moraux dont la relation fiduciaire avec le public est animée par la responsabilité et la promesse de puiser dans leurs connaissances et leurs habiletés pour aider les personnes sous leurs soins. Lorsque leur capacité à tenir cette promesse est freinée ou compromise, ils risquent de souffrir de détresse morale. Le concept de détresse morale est défini et mis en contexte dans le milieu de la santé. Les contraintes et les facteurs qui en sont à l'origine sont présentés, de même que les moyens utilisés par les professionnels de la santé et les organisations de santé pour la soulager. Un changement transformateur s'impose pour vaincre la culture du silence et maintenir un système de santé où il est possible de vivre avec sa conscience.

  3. Major mutation events in structural genes of peste des petits ruminants virus through serial passages in vitro.

    PubMed

    Wu, Xiaodong; Liu, Fuxiao; Li, Lin; Zou, Yanli; Liu, Shan; Wang, Zhiliang

    2016-06-01

    Peste des petits ruminants (PPR) is an highly contagious disease of small ruminants, and caused by peste des petits ruminants virus (PPRV), a member of the genus Morbillivirus in the family Paramyxoviridae. The first outbreak of PPR in China was officially reported in July 2007, when a PPRV strain was successfully isolated from a sick goat in Tibet, followed by sequencing at a full-genome level (China/Tibet/Geg/07-30, GenBank: FJ905304.1). To date, this isolate has been virulently attenuated by more than 90 serial passages in Vero-Dog-SLAM cells at our laboratory. In this study, a total of nine strains by serial passages (namely the 10th, 20th, 30th, 40th, 50th, 60th, 70th, 80th, and 90th passages) were chosen for sequencing of six structural genes in PPRV. The sequence analysis showed that mutation rates in all viral genes were relatively low, and only a few identical mutations within certain genes were stably maintained after an earlier passage, perhaps indicating a predominance of mutants after such a passage. PMID:26995222

  4. Einstein à l'épreuve des faits

    NASA Astrophysics Data System (ADS)

    Bonnet-Bidaud, J. M.

    1998-02-01

    Apres plus de 80 ans d'existence, la theorie d'Einstein cherche encore des preuves, bien que plusieurs de ses predictions aient ete deja verifiees avec une incroyable precision et certains de ses effets les plus spectaculaires reconnus de facon indeniable. Plusieurs missions parmi les plus complexes jamais envisagees sont en projet ou en cours de construction dans le but unique de verifier la relativite. Pourquoi cet enjeu est-il capital pour la physique contemporaine ?

  5. Les reseaux de politique publique comme facteur d'influence du choix des instruments de politique energetique canadienne a des fins environnementales de 1993 a nos jours

    NASA Astrophysics Data System (ADS)

    Fathy El Dessouky, Naglaa

    Au cours de la derniere decennie, les modes de la gouvernance ont pris place dans un contexte totalement different de celui qu'ils avaient auparavant. Les gouvernements modernes se rendent compte qu'ils perdent de plus en plus leur capacite a elaborer et a gerer les changements d'une maniere autonome. Ainsi, les fonctions et les activites traditionnellement accomplies exclusivement par le gouvernement engagent de nos jours une gamme d'acteurs etatiques et non etatiques. A l'encontre du concept traditionnel de l'Etat controleur, la gouvernance contemporaine est ainsi devenue moins une question d'offre de service et davantage une gestion indirecte des reseaux de politique publique. Dans cette entreprise, les gouvernements contemporains, cherchant plus d'information, de soutien et de legitimite en matiere de formulation des decisions, ont besoin d'etablir des relations avec les divers groupes d'interet qui, a leur tour, voulaient plus de promotion et de protection en faveur de leurs interets a travers leur implication au processus de l'elaboration et de la mise en oeuvre des politiques publiques. Ainsi, l'approche des reseaux de politique publique represente aujourd'hui un courant considerable au sein du champ d'analyse des politiques publiques. Toutefois, les preoccupations des chercheurs pour cette approche, dans le domaine des politiques energetiques a des fins environnementales, semblent recentes, et les etudes realisees sont encore trop peu nombreuses. Au Canada, au debut des annees 1990, le gouvernement ainsi que plusieurs groupes d'interets, des differents secteurs energetique, industriel et environnemental, ont commence a intensifier leurs efforts pour s'attaquer au probleme du changement climatique d'origine energetique, genere surtout par le secteur de l'industrie. Au cours de la derniere decennie, la question touchant plutot le sujet du developpement energetique durable represente le plus important domaine des politiques publiques ayant surgi recemment dans

  6. Des Moines.

    ERIC Educational Resources Information Center

    Gore, Deborah, Ed.

    1988-01-01

    This document, intended for elementary students, contains articles and activities designed to acquaint young people with the history of Des Moines, Iowa. The articles are short, and new or difficult words are highlighted and defined for young readers. "The Raccoon River Indian Agency" discusses the archeological exploration of the indian…

  7. Effets perturbateurs endocriniens des pesticides organochlores.

    PubMed

    Charlier, C; Plomteux, G

    2002-01-01

    Xenoestrogens such organochlorine pesticides are known to induce changes in reproductive development, function or behaviour in wildlife. Because these compounds are able to modify the estrogens metabolism, or to compete with estradiol for binding to the estrogen receptor, it may be possible that these products affect the risk of developing impaired fertility, precocious puberty or some kinds of cancer in man. Le plus ancien récit de lutte contre la pollution remonte à une légende indienne racontant que la divinité Sing-bonga était incommodée par les émanations des fours dans lesquels les Asuras fondaient leurs métaux (1). Evidemment depuis, la problématique n-a cessé de s-accroître et la contamination de la Terre par de nombreux polluants est devenue aujourd-hui un problème majeur de notre Société. La protection de notre environnement est une question capitale qui doit être respectée malgré la pression économique actuelle et qui ne cessera de croître au cours des prochaines années même si l-identification objective et indiscutable de ce qui est essentiel - donc devant être prioritairement garanti sur la planète - est difficile à cerner (2). « Un oiseau en mauvais état ne pond pas de bons oeufs » disait un proverbe grec. Mais ce n-est qu-à partir de la seconde moitié du XXème siècle que les toxicologues ont commencé à identifier les effets qu-avaient entraînés à l-échelle mondiale les pollutions émises aux XIXème siècle sur la faune sauvage et sur le cheptel (3). L-histoire contemporaine des pesticides industriels commence vers 1874 (synthèse des organochlorés) et se poursuit tout au long de ces 2 siècles en passant par la synthèse des organophosphorés (1950), des carbamates (1970) et des pyréthroïdes (1975) (4). Le dichlorodiphényltrichloroéthane (DDT) a été synthétisé pour la première fois par un étudiant en cours de préparation de sa thèse de doctorat : Othmer Zeidler. La production, reprise par les

  8. Do mutator mutations fuel tumorigenesis?

    PubMed

    Fox, Edward J; Prindle, Marc J; Loeb, Lawrence A

    2013-12-01

    The mutator phenotype hypothesis proposes that the mutation rate of normal cells is insufficient to account for the large number of mutations found in human cancers. Consequently, human tumors exhibit an elevated mutation rate that increases the likelihood of a tumor acquiring advantageous mutations. The hypothesis predicts that tumors are composed of cells harboring hundreds of thousands of mutations, as opposed to a small number of specific driver mutations, and that malignant cells within a tumor therefore constitute a highly heterogeneous population. As a result, drugs targeting specific mutated driver genes or even pathways of mutated driver genes will have only limited anticancer potential. In addition, because the tumor is composed of such a diverse cell population, tumor cells harboring drug-resistant mutations will exist prior to the administration of any chemotherapeutic agent. We present recent evidence in support of the mutator phenotype hypothesis, major arguments against this concept, and discuss the clinical consequences of tumor evolution fueled by an elevated mutation rate. We also consider the therapeutic possibility of altering the rate of mutation accumulation. Most significantly, we contend that there is a need to fundamentally reconsider current approaches to personalized cancer therapy. We propose that targeting cellular pathways that alter the rate of mutation accumulation in tumors will ultimately prove more effective than attempting to identify and target mutant driver genes or driver pathways.

  9. Traitement intra-artériel des métastases hépatiques de cancer colorectal

    PubMed Central

    Pellerin, O.; Geschwind, J.-F.

    2015-01-01

    Le cancer colorectal représente un problème majeur de santé publique. Son incidence annuelle mondiale est d’environ un million de cas et la mortalité annuelle est de plus de 500 000 cas par an. Le foie est l’organe le plus fréquemment touché par les métastases. Leur survenue est observée dans 40 à 60% des cas (contemporaines dans 25% des cas). Bien que la résection chirurgicale soit le seul traitement curatif, nombre de patients ne peuvent en bénéficier en raison de l’importante diffusion des métastases hépatiques. Chimiothérapies et biothérapies systémiques sont les options conventionnelles de la prise en charge des métastases hépatiques multiples. C’est dans ces situations cliniques que les thérapies intra-artérielles peuvent jouer un rôle important. Dans cet article, nous présenterons les différentes thérapies endovasculaires applicables aux métastases hépatiques de cancers colorectaux, avec leurs indications, résultats et complications éventuelles. PMID:21944243

  10. Abnormal desmin protein in myofibrillar myopathies caused by desmin gene mutations.

    PubMed

    Li, M; Dalakas, M C

    2001-04-01

    Muscle proteins were extracted in various sodium dodecyl sulfate buffers from 6 patients with myofibrillar myopathy (MFM) and previously identified with mutations in the desmin gene (desmin myopathy; DesM), 6 with MFM without mutations, and 14 disease controls to search for alterations in biochemistry and solubility of mutated desmin filaments. In the 1% posthigh-speed pellet fraction, desmin was detected with immunoblots only in DesM and not the other MFM. We conclude that mutant desmin forms insoluble aggregates that are specific for the DesM and can be detected with Western blots.

  11. Identification et prise en charge des femmes ayant des antécédents familiaux de cancer du sein

    PubMed Central

    Heisey, Ruth; Carroll, June C.

    2016-01-01

    Résumé Objectif Résumer les meilleures données portant sur les stratégies d’identification et de prise en charge des femmes qui présentent des antécédents familiaux de cancer du sein. Sources d’information Une recherche a été effectuée sur PubMed à l’aide des mots-clés anglais suivants : breast cancer, guidelines, risk, family history, management et magnetic resonance imaging screening, entre 2000 et 2016. La plupart des données sont de niveau II. Message principal Une bonne anamnèse familiale est essentielle lors de l’évaluation du risque de cancer du sein afin d’identifier les femmes qui sont candidates à une recommandation en counseling génétique pour un éventuel test génétique. On peut sauver des vies en offrant aux femmes porteuses d’une mutation au gène BRCA des interventions chirurgicales de réduction des risques (mastectomie bilatérale prophylactique, salpingo-ovariectomie bilatérale). Il faut encourager toutes les femmes qui présentent des antécédents familiaux de cancer du sein à demeurer actives et à limiter leur consommation d’alcool à moins de 1 verre par jour; certaines femmes sont admissibles à la chimioprévention. Il faut offrir aux femmes dont le risque à vie de cancer du sein est de 20 à 25 % ou plus un dépistage poussé par imagerie par résonance magnétique en plus d’une mammographie. Conclusion Une vie saine et la chimioprévention (chez les candidates) pourraient réduire l’incidence du cancer du sein; le dépistage poussé pourrait entraîner une détection plus précoce. Le fait d’aiguiller des femmes porteuses d’une mutation au BRCA vers la chirurgie de réduction des risques sauve des vies. PMID:27737991

  12. Des ballons pour demain

    NASA Astrophysics Data System (ADS)

    Régipa, R.

    A partir d'une théorie sur la détermination des formes et des contraintes globales d'un ballon de révolution, ou s'en rapprochant, une nouvelle famille de ballons a été définie. Les ballons actuels, dits de ``forme naturelle'', sont calculés en général pour une tension circonférencielle nulle. Ainsi, pour une mission donnée, la tension longitudinale et la forme de l'enveloppe sont strictement imposées. Les ballons de la nouvelle génération sont globalement cylindriques et leurs pôles sont réunis par un câble axial, chargé de transmettre une partie des efforts depuis le crochet (pôle inférieur), directement au pôle supérieur. De plus, la zone latérale cylindrique est soumise à un faible champ de tensions circonférencielles. Ainsi, deux paramètres permettent de faire évoluer la distribution des tensions et la forme de l'enveloppe: - la tension du câble de liaison entre pôles (ou la longueur de ce câble) - la tension circonférencielle moyenne désirée (ou le rayon du ballon). On peut donc calculer et réaliser: - soit des ballons de forme adaptée, comme les ballons à fond plat pour le bon fonctionnement des montgolfières infrarouge (projet MIR); - soit des ballons optimisés pour une bonne répartition des contraintes et une meilleure utilisation des matériaux d'enveloppe, pour l'ensemble des programmes stratosphériques. Il s'ensuit une économie sensible des coûts de fabrication, une fiabilité accrue du fonctionnement de ces ballons et une rendement opérationnel bien supérieur, permettant entre autres, d'envisager des vols à très haute altitude en matériaux très légers.

  13. Des Vents et des Jets Astrophysiques

    NASA Astrophysics Data System (ADS)

    Sauty, C.

    well expected result from the theory. Although, collimation may be conical, paraboloidal or cylindrical (Part 4), cylindrical collimation is the more likely to occur. The shape of outflows may then be used as a tool to predict physical conditions on the flows or on their source. L'éjection continue de plasma autour d'objets massifs est un phénomène largement répandu en astrophysique, que ce soit sous la forme du vent solaire, de vents stellaires, de jets d'étoiles en formation, de jets stellaires autour d'objets compacts ou de jets extra-galactiques. Cette zoologie diversifiée fait pourtant l'objet d'un commun effort de modélisation. Le but de cette revue est d'abord de présenter qualitativement le développement, depuis leur origine, des diverses théories de vents (Partie 1) et l'inter disciplinarité dans ce domaine. Il s'agit d'une énumération, plus ou moins exhaustive, des idées proposées pour expliquer l'accélération et la morphologie des vents et des jets, accompagnée d'une présentation sommaire des aspects observationnels. Cette partie s'abstient de tout aspect faisant appel au formalisme mathématique. Ces écoulements peuvent être décrits, au moins partiellement, en résolvant les équations magnétohydrodynamiques, axisymétriques et stationnaires. Ce formalisme, à la base de la plupart des théories, est exposé dans la Partie 2. Il permet d'introduire quantitativement les intégrales premières qu'un tel système possède. Ces dernières sont amenées à jouer un rôle important dans la compréhension des phénomènes d'accélération ou de collimation, en particulier le taux de perte de masse, le taux de perte de moment angulaire ou l'énergie du rotateur magnétique. La difficulté de modélisation réside dans l'existence de points critiques, propres aux équations non linéaires, qu'il faut franchir. La nature physique et la localisation de ces points critiques fait l'objet d'un débat important car ils sont la clef de voute de la r

  14. Injectabilite des coulis de ciment dans des milieux fissures

    NASA Astrophysics Data System (ADS)

    Mnif, Thameur

    Le travail presente ici est un bilan du travaux de recherche effectues sur l'injectabilite des coulis de ciment dans lu milieux fissures. Un certain nombre de coulis a base de ciment Portland et microfin ont ete selectionnes afin de caracteriser leur capacite a penetrer des milieux fissures. Une partie des essais a ete menee en laboratoire. L'etude rheologique des differents melanges a permis de tester l'influence de l'ajout de superplastifiant et/ou de fumee de silice sur la distribution granulometrique des coulis et par consequent sur leur capacite a injecter des colonnes de sable simulant un milieu fissure donne. La classe granulometrique d'un coulis, sa stabilite et sa fluidite sont apparus comme les trois facteurs principaux pour la reussite d'une injection. Un facteur de finesse a ete defini au cours de cette etude: base sur la classe granulometrique du ciment et sa stabilite, il peut entrer dans la formulation theorique du debit d'injection avant application sur chantier. La deuxieme et derniere partie de l'etude presente les resultats de deux projets de recherche sur l'injection realises sur chantier. L'injection de dalles de beton fissurees a permis le suivi de l'evolution des pressions avec la distance au point d'injection. L'injection de murs de maconnerie a caractere historique a montre l'importance de la definition de criteres de performance des coulis a utiliser pour traiter un milieu donne et pour un objectif donne. Plusieurs melanges peuvent ainsi etre predefinis et mis a disposition sur le chantier. La complementarite des ciments traditionnels et des ciments microfins devient alors un atout important. Le choix d'utilisation de ces melanges est fonction du terrain rencontre. En conclusion, cette recherche etablit une methodologie pour la selection des coulis a base de ciment et des pressions d'injection en fonction de l'ouverture des fissures ou joints de construction.

  15. Grundlagen des Tissue Engineering

    NASA Astrophysics Data System (ADS)

    Mayer, Jörg; Blum, Janaki; Wintermantel, Erich

    Die Organtransplantation stellt eine verbreitete Therapie dar, um bei krankheitsoder unfallbedingter Schädigung eines Organs die Gesamtheit seiner Funktionen wieder herzustellen, indem es durch ein Spenderorgan ersetzt wird. Organtransplantationen werden für die Leber, die Niere, die Lunge, das Herz oder bei schweren grossflächigen Verbrennungen der Haut vorgenommen. Der grosse apparative, personelle und logistische Aufwand und die Risiken der Transplantationschirurgie (Abstossungsreaktionen) sowie die mangelnde Verfügbarkeit von immunologisch kompatiblen Spenderorganen führen jedoch dazu, dass der Bedarf an Organtransplantaten nur zu einem sehr geringen Teil gedeckt werden kann. Sind Spenderorgane nicht verfügbar, können in einzelnen Fällen lebenswichtige Teilfunktionen, wie beispielsweise die Filtrationsfunktion der Niere durch die Blutreinigung mittels Dialyse ersetzt oder, bei mangelnder Funktion der Bauchspeicheldrüse (Diabetes), durch die Verabreichung von Insulin ein normaler Zustand des Gesamtorganismus auch über Jahre hinweg erhalten werden. Bei der notwendigen lebenslangen Anwendung apparativer oder medikamentöser Therapie können für den Patienten jedoch häufig schwerwiegende, möglicherweise lebensverkürzende Nebenwirkungen entstehen. Daher werden in der Forschung Alternativen gesucht, um die Funktionen des ausgefallenen Organs durch die Implantation von Zellen oder in vitro gezüchteten Geweben möglichst umfassend wieder herzustellen. Dies erfordert biologisch aktive Implantate, welche die für den Stoffwechsel des Organs wichtigen Zellen enthalten und einen organtypischen Stoffwechsel entfalten.

  16. De L'Economie des moyens linguistiques en francais et en anglais dans l'usage standard contemporain (On the Economy of Linguistic Means in French and English Standard Contemporary Usage).

    ERIC Educational Resources Information Center

    Calve, Pierre

    1989-01-01

    The conciseness and "ease of use" often attributed to North American English relative to French in standard contemporary usage is explained in terms of English morpho-syntactic structure and of the values of the classical norm and rhetoric affecting French. (Author/MSE)

  17. Reticulation des fibres lignocellulosiques

    NASA Astrophysics Data System (ADS)

    Landrevy, Christel

    Pour faire face à la crise économique la conception de papier à valeur ajoutée est développée par les industries papetières. Le but de se projet est l'amélioration des techniques actuelles de réticulation des fibres lignocellulosiques de la pâte à papier visant à produire un papier plus résistant. En effet, lors des réactions de réticulation traditionnelles, de nombreuses liaisons intra-fibres se forment ce qui affecte négativement l'amélioration anticipée des propriétés physiques du papier ou du matériau produit. Pour éviter la formation de ces liaisons intra-fibres, un greffage sur les fibres de groupements ne pouvant pas réagir entre eux est nécessaire. La réticulation des fibres par une réaction de « click chemistry » appelée cycloaddition de Huisgen entre un azide et un alcyne vrai, catalysée par du cuivre (CuAAC) a été l'une des solutions trouvée pour remédier à ce problème. De plus, une adaptation de cette réaction en milieux aqueux pourrait favoriser son utilisation en milieu industriel. L'étude que nous désirons entreprendre lors de ce projet vise à optimiser la réaction de CuAAC et les réactions intermédiaires (propargylation, tosylation et azidation) sur la pâte kraft, en milieu aqueux. Pour cela, les réactions ont été adaptées en milieu aqueux sur la cellulose microcristalline afin de vérifier sa faisabilité, puis transférée à la pâte kraft et l'influence de différents paramètres comme le temps de réaction ou la quantité de réactifs utilisée a été étudiée. Dans un second temps, une étude des différentes propriétés conférées au papier par les réactions a été réalisée à partir d'une série de tests papetiers optiques et physiques. Mots Clés Click chemistry, Huisgen, CuAAC, propargylation, tosylation, azidation, cellulose, pâte kraft, milieu aqueux, papier.

  18. Education relative a l'environnement (ERE): Une etude des representations sociales et des pratiques educatives d'enseignants de science et technologie du secondaire en contexte de formation continue

    NASA Astrophysics Data System (ADS)

    Collard-Fortin, Ugo

    Le developpement des sciences/technologie a tres clairement contribue a ce que ce dernier domaine de savoirs jouisse d'une place de choix au sein de notre societe. Au-dela des progres de notre civilisation inherents a ce dernier developpement, cette croissance amena avec elle un lot d'ineluctables dommages collateraux, contribuant en corollaire a l'emergence de diverses problematiques environnementales inquietantes pour lesquelles les valeurs ainsi que le mode de fonctionnement de la societe occidentale contemporaine sont largement tributaires. C'est entre autres en reponse a cet etat de fait que la recente vague de reforme de l'Education conduisit a l'integration, dans les curricula de sciences/technologie, de contenus relavant d'education relative a l'environnement (ERE). Face au changement, les enseignants de sciences ont du s'approprier ce nouveau programme afm de l'enseigner a leurs eleves. Toutefois, l'analyse de la situation montre que les prescriptions du programme en matiere d'ERE ne se sont pas toujours traduites en de reelles actions dans la pratique. Le contexte de notre etude s'est interesse aux pratiques educatives de l'ERE ainsi qu'a la representation sociale qui en decoule. Notre recherche aborde plus specifiquement la problematique de la modification de ces derniers objets chez les enseignants de sciences et technologie du deuxieme cycle du secondaire. Pour y arriver, nous avons propose a un groupe de trois praticiens de participer a une activite, en communaute de pratique, de formation continue orientee autour de thematiques ERE. Cette recherche developpement, s'inscrivant dans un paradigme qualitatif/interpretatif, s'est appuyee sur une cueillette de donnees effectuee a partir d'entrevues semi-dirigees, d'observations en situation et d'un groupe de discussion, au debut et a la fm de la formation continue. Les donnees brutes ont ete soumises a une demarche d'analyse inductive et ont genere diverses categories etayant nos objets de recherche

  19. La dysplasie fibreuse: état des lieux

    PubMed Central

    Akasbi, Nessrine; Abourazzak, Fatima Ezzahra; Talbi, Sofia; Tahiri, Latifa; Harzy, Taoufik

    2015-01-01

    La dysplasie fibreuse des os est une affection osseuse bénigne congénitale mais non héréditaire, où l'os normal est remplacé par un tissu fibreux renfermant une ostéogenèse immature. Elle est due à une mutation du gène GNAS 1sur le chromosome 20q13, une mutation activatrice de la sous-unité α de la protéine G. C'est une pathologie qui est le plus souvent silencieuse, de découverte fortuite sur une radiographie standard ou révélée par une douleur osseuse ou une fracture pathologique. L'imagerie et l'histologie, quand elle est nécessaire, permettent d’établir le diagnostic. Bien qu'il ne s'agisse pas d'une tumeur, elle est souvent classée dans la catégorie des tumeurs osseuses bénignes pour des raisons de diagnostic différentiel radiographique et anatomopathologique. Elle peut être monostotique ou polyostotique. L'approche thérapeutique est essentiellement symptomatique. Quelques publications récentes ont suggéré l'intérêt majeur d'un bisphosphonate, en particulier le pamidronate, qui diminuerait les douleurs et stimulerait une reminéralisation progressive des zones ostéolytiques chez les patients traités. D'autres traitements tels que la thérapie ciblée sont en cours d’évaluation. PMID:26401215

  20. Excrétion rénale des ions divalents après homotransplantation rénale

    PubMed Central

    Cartier, F.; Popovtzer, M. M.; Robinette, J.; Pinggera, W. F.; Halgrimson, C. G.; Starzl, T. E.

    2010-01-01

    RÉSUMÉ L’élimination rénale des ions divalents, celle du Na et du K, ont été étudiées de façon comparative dans les suites immédiates de l’homotransplantation rénale chez 6 patients. Durant la période initiale polyurique (> 3ml/mn), le taux d’excrétion du Ca filtré (Cca/Ccr), du Mg, du P, du Na et du K, est élevé et il existe une corrélation étroite et quasi constante entre l’élimination du Ca, du Mg et du Na ; la corrélation n’est pas constante entre l’élimination du Na et du K, du Mg et du K. Pendant les deux jours suivants, le taux d’excrétion diminue, sauf pour le P ; il existe encore une corrélation entre l’excrétion du Ca, du Mg et du Na, non entre celle du Na et du K, du Mg et du K. L’excrétion du Ca l’emporte sur celle du Na au cours de la première période, non au cours de la seconde. A la lumière de ces données, on envisage l’intervention possible de divers facteurs, tels l’inflation hydrosique et l’hyperazotémie préalables, l’ischémie rénale contemporaine de la transplantation, les effets de la dénervation rénale, du traitement cortisonique, de l’hyperparathyroïdie et ceux des modifications circulatoires rénales. PMID:4574592

  1. Mutational landscape of yeast mutator strains.

    PubMed

    Serero, Alexandre; Jubin, Claire; Loeillet, Sophie; Legoix-Né, Patricia; Nicolas, Alain G

    2014-02-01

    The acquisition of mutations is relevant to every aspect of genetics, including cancer and evolution of species on Darwinian selection. Genome variations arise from rare stochastic imperfections of cellular metabolism and deficiencies in maintenance genes. Here, we established the genome-wide spectrum of mutations that accumulate in a WT and in nine Saccharomyces cerevisiae mutator strains deficient for distinct genome maintenance processes: pol32Δ and rad27Δ (replication), msh2Δ (mismatch repair), tsa1Δ (oxidative stress), mre11Δ (recombination), mec1Δ tel1Δ (DNA damage/S-phase checkpoints), pif1Δ (maintenance of mitochondrial genome and telomere length), cac1Δ cac3Δ (nucleosome deposition), and clb5Δ (cell cycle progression). This study reveals the diversity, complexity, and ultimate unique nature of each mutational spectrum, composed of punctual mutations, chromosomal structural variations, and/or aneuploidies. The mutations produced in clb5Δ/CCNB1, mec1Δ/ATR, tel1Δ/ATM, and rad27Δ/FEN1 strains extensively reshape the genome, following a trajectory dependent on previous events. It comprises the transmission of unstable genomes that lead to colony mosaicisms. This comprehensive analytical approach of mutator defects provides a model to understand how genome variations might accumulate during clonal evolution of somatic cell populations, including tumor cells.

  2. La biogenèse des mélanosomes

    PubMed Central

    Delevoye, Cédric; Giordano, Francesca; van Niel, Guillaume; Raposo, Graça

    2012-01-01

    Les mélanocytes situés à la base de l’épiderme produisent des mélanosomes qui sont transférés aux kératinocytes pour assurer la pigmentation de l’épiderme et sa photoprotection contre les rayons ultraviolets. Les mélanosomes, organites apparentés aux lysosomes, sont le lieu de synthèse et de stockage d’un pigment, la mélanine. Leur formation dépend de protéines mélanosomales qui transitent par les voies de biosynthèse et d’endocytose et exploitent les mécanismes moléculaires du trafic intracellulaire. Les acteurs moléculaires impliqués dans le transport des protéines mélanosomales et la biogenèse des mélanosomes sont la cible de mutations dans des maladies génétiques accompagnées d’hypopigmentation comme l’albinisme et les maladies lysosomales. Les études menées sur les mélanocytes issus de souris modèles de ces maladies permettent de comprendre certaines des étapes-clés de la mélanogenèse ainsi que les dysfonctionnements associés à ces pathologies. De plus, décrypter la mélanogenèse facilite également la compréhension d’autres processus physiologiques, comme l’illustrent les similitudes inattendues avec l’amyloïdogenèse dans les maladies neurodégénératives. PMID:21382323

  3. Mutation accumulation and fitness in mutator subpopulations of Escherichia coli.

    PubMed

    Maharjan, Ram P; Liu, Bin; Li, Yang; Reeves, Peter R; Wang, Lei; Ferenci, Thomas

    2013-02-23

    Bacterial populations in clinical and laboratory settings contain a significant proportion of mutants with elevated mutation rates (mutators). Mutators have a particular advantage when multiple beneficial mutations are needed for fitness, as in antibiotic resistance. Nevertheless, high mutation rates potentially lead to increasing numbers of deleterious mutations and subsequently to the decreased fitness of mutators. To test how fitness changed with mutation accumulation, genome sequencing and fitness assays of nine Escherichia coli mutY mutators were undertaken in an evolving chemostat population at three time points. Unexpectedly, the fitness in members of the mutator subpopulation became constant despite a growing number of mutations over time. To test if the accumulated mutations affected fitness, we replaced each of the known beneficial mutations with wild-type alleles in a mutator isolate. We found that the other 25 accumulated mutations were not deleterious. Our results suggest that isolates with deleterious mutations are eliminated by competition in a continuous culture, leaving mutators with mostly neutral mutations. Interestingly, the mutator-non-mutator balance in the population reversed after the fitness plateau of mutators was reached, suggesting that the mutator-non-mutator ratio in populations has more to do with competition between members of the population than the accumulation of deleterious mutations.

  4. [Prediction of the onset of voice mutation in singers of professional Boys' choirs: investigation of members of the Thomaner choir, Leipzig].

    PubMed

    Fuchs, M; Behrendt, W; Keller, E; Kratzsch, J

    1999-01-01

    Die phoniatrische Betreuung der kindlichen Singstimme während des Stimmwechsels erscheint gerade bei Sängern in Knabenchören mit hoher stimmlicher Belastung wichtig. Die vorliegende Studie sucht nach Methoden, den Eintrittszeitpunkt der Mutation vorherzusagen und das Vorliegen einer Mutation differentialdiagnostisch von hyperfunktionellen Stimmstörungen oder entzündlichen Erkrankungen des Stimmorganes zu trennen. Dazu wurden 36 Knaben des Leipziger Thomanerchores im Sinne einer Longitudinalstudie alle 3 Monate über 3,5 Jahre bis zum hörbaren Einsetzen der Mutation untersucht. Es erfolgte die Bestimmung von zehn stimmlichen und acht stimmunabhängigen Parametern, die erstmals in solch umfassender Form auf ihre prädiktive Aussagekraft geprüft wurden. Die statistische Auswertung wies besonders den Serumtestosteronspiegel und die Wachstumsrate als Grössen aus, die mit dem Prämutationsverlauf korrelieren und eine konkrete Vorhersage ermöglichen. Das Vorliegen einer Mutation kann ausserdem durch den Verlauf der mittleren ungespannten Sprechstimmlage und unter Hinzuziehung des Genitalstatus bestätigt werden. Durch die exakte und prädiktive Bestimmung des Mutationsbeginnes können Erkrankungen des Stimmapparates vermieden werden, die aus dem intensiven Singen in der Mutation resultieren. Weiterhin geben die Ergebnisse dem Chorleiter wertvolle Informationen für die Planung der Besetzung seiner Knabenstimmen.

  5. Médecine des voyages

    PubMed Central

    Aw, Brian; Boraston, Suni; Botten, David; Cherniwchan, Darin; Fazal, Hyder; Kelton, Timothy; Libman, Michael; Saldanha, Colin; Scappatura, Philip; Stowe, Brian

    2014-01-01

    Résumé Objectif Définir la pratique de la médecine des voyages, présenter les éléments fondamentaux d’une consultation complète préalable aux voyages à des voyageurs internationaux et aider à identifier les patients qu’il vaudrait mieux envoyer en consultation auprès de professionnels de la médecine des voyages. Sources des données Les lignes directrices et les recommandations sur la médecine des voyages et les maladies liées aux voyages publiées par les autorités sanitaires nationales et internationales ont fait l’objet d’un examen. Une recension des ouvrages connexes dans MEDLINE et EMBASE a aussi été effectuée. Message principal La médecine des voyages est une spécialité très dynamique qui se concentre sur les soins préventifs avant un voyage. Une évaluation exhaustive du risque pour chaque voyageur est essentielle pour mesurer avec exactitude les risques particuliers au voyageur, à son itinéraire et à sa destination et pour offrir des conseils sur les interventions les plus appropriées en gestion du risque afin de promouvoir la santé et prévenir les problèmes médicaux indésirables durant le voyage. Des vaccins peuvent aussi être nécessaires et doivent être personnalisés en fonction des antécédents d’immunisation du voyageur, de son itinéraire et du temps qu’il reste avant son départ. Conclusion La santé et la sécurité d’un voyageur dépendent du degré d’expertise du médecin qui offre le counseling préalable à son voyage et les vaccins, au besoin. On recommande à ceux qui donnent des conseils aux voyageurs d’être conscients de l’ampleur de cette responsabilité et de demander si possible une consultation auprès de professionnels de la médecine des voyages pour tous les voyageurs à risque élevé.

  6. UV Signature Mutations

    PubMed Central

    2014-01-01

    Sequencing complete tumor genomes and exomes has sparked the cancer field's interest in mutation signatures for identifying the tumor's carcinogen. This review and meta-analysis discusses signatures and their proper use. We first distinguish between a mutagen's canonical mutations – deviations from a random distribution of base changes to create a pattern typical of that mutagen – and the subset of signature mutations, which are unique to that mutagen and permit inference backward from mutations to mutagen. To verify UV signature mutations, we assembled literature datasets on cells exposed to UVC, UVB, UVA, or solar simulator light (SSL) and tested canonical UV mutation features as criteria for clustering datasets. A confirmed UV signature was: ≥60% of mutations are C→T at a dipyrimidine site, with ≥5% CC→TT. Other canonical features such as a bias for mutations on the non-transcribed strand or at the 3' pyrimidine had limited application. The most robust classifier combined these features with criteria for the rarity of non-UV canonical mutations. In addition, several signatures proposed for specific UV wavelengths were limited to specific genes or species; non-signature mutations induced by UV may cause melanoma BRAF mutations; and the mutagen for sunlight-related skin neoplasms may vary between continents. PMID:25354245

  7. Peste des petits ruminants.

    PubMed

    Parida, S; Muniraju, M; Mahapatra, M; Muthuchelvan, D; Buczkowski, H; Banyard, A C

    2015-12-14

    Peste des petits ruminants virus causes a highly infectious disease of small ruminants that is endemic across Africa, the Middle East and large regions of Asia. The virus is considered to be a major obstacle to the development of sustainable agriculture across the developing world and has recently been targeted by the World Organisation for Animal Health (OIE) and the Food and Agriculture Organisation (FAO) for eradication with the aim of global elimination of the disease by 2030. Fundamentally, the vaccines required to successfully achieve this goal are currently available, but the availability of novel vaccine preparations to also fulfill the requisite for differentiation between infected and vaccinated animals (DIVA) may reduce the time taken and the financial costs of serological surveillance in the later stages of any eradication campaign. Here, we overview what is currently known about the virus, with reference to its origin, updated global circulation, molecular evolution, diagnostic tools and vaccines currently available to combat the disease. Further, we comment on recent developments in our knowledge of various recombinant vaccines and on the potential for the development of novel multivalent vaccines for small ruminants.

  8. Peste des petits ruminants.

    PubMed

    Parida, S; Muniraju, M; Mahapatra, M; Muthuchelvan, D; Buczkowski, H; Banyard, A C

    2015-12-14

    Peste des petits ruminants virus causes a highly infectious disease of small ruminants that is endemic across Africa, the Middle East and large regions of Asia. The virus is considered to be a major obstacle to the development of sustainable agriculture across the developing world and has recently been targeted by the World Organisation for Animal Health (OIE) and the Food and Agriculture Organisation (FAO) for eradication with the aim of global elimination of the disease by 2030. Fundamentally, the vaccines required to successfully achieve this goal are currently available, but the availability of novel vaccine preparations to also fulfill the requisite for differentiation between infected and vaccinated animals (DIVA) may reduce the time taken and the financial costs of serological surveillance in the later stages of any eradication campaign. Here, we overview what is currently known about the virus, with reference to its origin, updated global circulation, molecular evolution, diagnostic tools and vaccines currently available to combat the disease. Further, we comment on recent developments in our knowledge of various recombinant vaccines and on the potential for the development of novel multivalent vaccines for small ruminants. PMID:26443889

  9. Peste des petits ruminants

    PubMed Central

    Parida, S.; Muniraju, M.; Mahapatra, M.; Muthuchelvan, D.; Buczkowski, H.; Banyard, A.C.

    2015-01-01

    Peste des petits ruminants virus causes a highly infectious disease of small ruminants that is endemic across Africa, the Middle East and large regions of Asia. The virus is considered to be a major obstacle to the development of sustainable agriculture across the developing world and has recently been targeted by the World Organisation for Animal Health (OIE) and the Food and Agriculture Organisation (FAO) for eradication with the aim of global elimination of the disease by 2030. Fundamentally, the vaccines required to successfully achieve this goal are currently available, but the availability of novel vaccine preparations to also fulfill the requisite for differentiation between infected and vaccinated animals (DIVA) may reduce the time taken and the financial costs of serological surveillance in the later stages of any eradication campaign. Here, we overview what is currently known about the virus, with reference to its origin, updated global circulation, molecular evolution, diagnostic tools and vaccines currently available to combat the disease. Further, we comment on recent developments in our knowledge of various recombinant vaccines and on the potential for the development of novel multivalent vaccines for small ruminants. PMID:26443889

  10. Gestational mutations in radiation carcinogenesis

    NASA Astrophysics Data System (ADS)

    Meza, R.; Luebeck, G.; Moolgavkar, S.

    Mutations in critical genes during gestation could increase substantially the risk of cancer. We examine the consequences of such mutations using the Luebeck-Moolgavkar model for colorectal cancer and the Lea-Coulson modification of the Luria-Delbruck model for the accumulation of mutations during gestation. When gestational mutation rates are high, such mutations make a significant contribution to cancer risk even for adult tumors. Furthermore, gestational mutations ocurring at distinct times during emryonic developmemt lead to substantially different numbers of mutated cells at birth, with early mutations leading to a large number (jackpots) of mutated cells at birth and mutation occurring late leading to only a few mutated cells. Thus gestational mutations could confer considerable heterogeneity of the risk of cancer. If the fetus is exposed to an environmental mutagen, such as ionizing radiation, the gestational mutation rate would be expected to increase. We examine the consequences of such exposures during gestation on the subsequent development of cancer.

  11. Mutation rates as adaptations.

    PubMed

    Maley, C

    1997-06-01

    In order to better understand life, it is helpful to look beyond the envelop of life as we know it. A simple model of coevolution was implemented with the addition of a gene for the mutation rate of the individual. This allowed the mutation rate itself to evolve in a lineage. The model shows that when the individuals interact in a sort of zero-sum game, the lineages maintain relatively high mutation rates. However, when individuals engage in interactions that have greater consequences for one individual in the interaction than the other, lineages tend to evolve relatively low mutation rates. This model suggests that one possible cause for differential mutation rates across genes may be the coevolutionary pressure of the various forms of interactions with other genes. PMID:9219670

  12. Mutation and premating isolation.

    PubMed

    Woodruff, R C; Thompson, J N

    2002-11-01

    While premating isolation might be traceable to different genetic mechanisms in different species, evidence supports the idea that as few as one or two genes may often be sufficient to initiate isolation. Thus, new mutation can theoretically play a key role in the process. But it has long been thought that a new isolation mutation would fail, because there would be no other individuals for the isolation-mutation-carrier to mate with. We now realize that premeiotic mutations are very common and will yield a cluster of progeny carrying the same new mutant allele. In this paper, we discuss the evidence for genetically simple premating isolation barriers and the role that clusters of an isolation mutation may play in initiating allopatric, and even sympatric, species divisions.

  13. Multiplex detection of mutations.

    PubMed

    Perlin, David S; Balashov, Sergey; Park, Steven

    2008-01-01

    Rapid and reliable detection of mutations at the genetic level is an integral part of modern molecular diagnostics. These mutations can range from dominant single nucleotide polymorphisms within specific loci to codominant heterozygotic insertions and they present considerable challenges to investigators in developing rapid nucleic acid-based amplification assays that can distinguish wild-type from mutant alleles. The recent improvements of real-time polymerase chain reaction (PCR) using self-reporting fluorescence probes have given researchers a powerful tool in developing assays for mutation detection that can be multiplexed for high-throughput screening of multiple mutations and cost effectiveness. Here we describe an application of a multiplexed real-time PCR assay using Molecular Beacon probes for the detection of mutations in codon 54 of the CYP51A gene in Aspergillus fumigatus conferring triazole resistance.

  14. Mutation and premating isolation

    NASA Technical Reports Server (NTRS)

    Woodruff, R. C.; Thompson, J. N. Jr

    2002-01-01

    While premating isolation might be traceable to different genetic mechanisms in different species, evidence supports the idea that as few as one or two genes may often be sufficient to initiate isolation. Thus, new mutation can theoretically play a key role in the process. But it has long been thought that a new isolation mutation would fail, because there would be no other individuals for the isolation-mutation-carrier to mate with. We now realize that premeiotic mutations are very common and will yield a cluster of progeny carrying the same new mutant allele. In this paper, we discuss the evidence for genetically simple premating isolation barriers and the role that clusters of an isolation mutation may play in initiating allopatric, and even sympatric, species divisions.

  15. Etude des Abondances de MG et de fe dans la Composante Stellaire des Disques des Galaxies Spirales

    NASA Astrophysics Data System (ADS)

    Beauchamp, Dominique

    Je presente ici une technique d'observation par imagerie des disques stellaires des galaxies spirales. Je tente, a l'aide d'un modele evolutif multiphase, de determiner les abondances de fer et de magnesium dans les disques. Dans ce but, je mesure les indices Mg2 et Fe5270 du systeme de Lick. Ces elements representent un choix judicieux d'indicateurs car ils sont formes par des supernovae de deux types differents ayant des durees de vie differentes. Le rapport d'abondances de ces deux elements est un indicateur du taux de formation des populations stellaires. Je decris, en premier lieu, les observations, la technique de mesure, ainsi que son application. J'analyse ensuite les indices mesures. A partir du modele multiphase, j'explore differents parametres physiques des spirales comme le taux de formation stellaire, l'evolution des abondances, les effets possibles de la presence de la barre, etc.

  16. Classification of 20 DES Supernova with OzDES

    NASA Astrophysics Data System (ADS)

    Davis, T. M.; Kim, A. G.; Macualay, E.; Lidman, C.; Sharp, R.; Tucker, B. E.; Yuan, F.; Zhang, B.; Lewis, G. F.; Sommer, N. E.; Martini, P.; Mould, J.; Ahn, E.; Finley, D. A.; Frieman, J.; Marriner, J.; Wester, W.; Aldering, G.; Thomas, R. C.; Barbary, K.; Bloom, J. S.; Goldstein, D.; Nugent, P.; Perlmutter, S.; Foley, R. J.; Pan, Y.-C.; Casas, R.; Castander, F. J.; Desai, S.; Paech, K.; Smith, R. C.; Schubnell, M.; Kessler, R.; Lasker, J.; Scolnic, D.; Brout, D. J.; Gladney, L.; Sako, M.; Wolf, R. C.; Brown, P. J.; Krisciunas, K.; Suntzeff, N.; Nichol, R.; Papadopoulos, A.; Childress, M.; D'Andrea, C.; Smith, M.; Sullivan, M.; Maartens, R.; Gupta, R.; Kovacs, E.; Kuhlmann, S.; Spinka, H.

    2015-12-01

    We report new spectroscopic classifications by OzDES of supernovae discovered by the Dark Energy Survey (ATEL #4668). The spectra (370-885nm) were obtained with the AAOmega Spectrograph (Saunders et al. 2004, SPIE, 5492, 389) and the 2dF fibre positioner at the Anglo-Australian Telescope (AAT).

  17. Classification of 8 DES Supernova with OzDES

    NASA Astrophysics Data System (ADS)

    King, A.; Moller, A.; Sommer, N. E.; Tucker, B. E.; Childress, M. J.; Lewis, G. F.; Lidman, C.; OâNeill, C.; Casas, R.; Castander, F. J.; Desai, S.; Paech, K.; Smith, R. C.; Schubnell, M.; Kessler, R.; Lasker, J.; Scolnic, D.; Brout, D. J.; Gladney, L.; Sako, M.; Wolf, R. C.; Brown, P. J.; Krisciunas, K.; Suntzeff, N.; Nichol, R.; Papadopoulos, A.; D'Andrea, C.; Prajs, S.; Smith, M.; Sullivan, M.; Maartens, R.; Gupta, R.; Kovacs, E.; Kuhlmann, S.; Spinka, H.; Ahn, E.; Finley, D. A.; Frieman, J.; Marriner, J.; Wester, W.; Aldering, G.; Kim, A. G.; Thomas, R. C.; Barbary, K.; Bloom, J. S.; Goldstein, D.; Nugent, P.; Perlmutter, S.; Foley, R. J.; Pan, Y.-C.

    2016-09-01

    We report new spectroscopic classifications by OzDES of supernovae discovered by the Dark Energy Survey (ATEL #4668). The spectra (370-885nm) were obtained with the AAOmega Spectrograph (Saunders et al. 2004, SPIE, 5492, 389) and the 2dF fibre positioner at the Anglo-Australian Telescope (AAT).

  18. Classification of 13 DES supernova with OzDES

    NASA Astrophysics Data System (ADS)

    Sommer, N.; Tucker, B. E.; Moller, A.; Zhang, B.; Macualay, E.; Lidman, C.; Gshwend, J.; Martini, P.; Foley, R. J.; Pan, Y.-C.; Casas, R.; Castander, F. J.; Desai, S.; Paech, K.; Smith, R. C.; Schubnell, M.; Kessler, R.; Lasker, J.; Scolnic, D.; Brout, D. J.; Gladney, L.; Sako, M.; Wolf, R. C.; Brown, P. J.; Krisciunas, K.; Suntzeff, N.; Nichol, R.; Papadopoulos, A.; Childress, M.; D'Andrea, C.; Prajs, S.; Smith, M.; Sullivan, M.; Maartens, R.; Gupta, R.; Kovacs, E.; Kuhlmann, S.; Spinka, H.; Ahn, E.; Finley, D. A.; Frieman, J.; Marriner, J.; Wester, W.; Aldering, G.; Kim, A. G.; Thomas, R. C.; Barbary, K.; Bloom, J. S.; Goldstein, D.; Nugent, P.; Perlmutter, S.

    2016-09-01

    We report new spectroscopic classifications by OzDES of supernovae discovered by the Dark Energy Survey (ATEL #4668). The spectra (370-885nm) were obtained with the AAOmega Spectrograph (Saunders et al. 2004, SPIE, 5492, 389) and the 2dF fibre positioner at the Anglo-Australian Telescope (AAT).

  19. Classification of 3 DES Supernovae with OzDES

    NASA Astrophysics Data System (ADS)

    Moller, A.; Tucker, B. E.; Yuan, F.; Lewis, G.; Lidman, C.; Macaulay, E.; Nichol, R.; Papadopoulos, A.; Childress, M.; D'Andrea, C.; Smith, M.; Sullivan, M.; Maartens, R.; Gupta, R.; Kovacs, E.; Kuhlmann, S.; Spinka, H.; Ahn, E.; Finley, D. A.; Frieman, J.; Marriner, J.; Wester, W.; Aldering, G.; Kim, A. G.; Thomas, R. C.; Barbary, K.; Bloom, J. S.; Goldstein, D.; Nugent, P.; Perlmutter, S.; Foley, R. J.; Pan, Y.-C.; Casas, R.; Castander, F. J.; Desai, S.; Paech, K.; Smith, R. C.; Schubnell, M.; Kessler, R.; Lasker, J.; Scolnic, D.; Brout, D. J.; Gladney, L.; Sako, M.; Wolf, R. C.; Brown, P. J.; Krisciunas, K.; Suntzeff, N.

    2016-02-01

    We report new spectroscopic classifications by OzDES of supernovae discovered by the Dark Energy Survey (ATEL #4668). The spectra (370-885nm) were obtained with the AAOmega Spectrograph (Saunders et al. 2004, SPIE, 5492, 389) and the 2dF fibre positioner at the Anglo-Australian Telescope (AAT).

  20. Classification of 2 DES supernova with OzDES

    NASA Astrophysics Data System (ADS)

    O'Neill, C. R.; Moller, A.; Sommer, N. E.; Tucker, B. E.; Childress, M. J.; Lewis, G. F.; Lidman, C.; Desai, S.; Paech, K.; Smith, R. C.; Schubnell, M.; Kessler, R.; Lasker, J.; Scolnic, D.; Brout, D. J.; D'Andrea, C.; Gladney, L.; March, M.; Sako, M.; Wolf, R. C.; Brown, P. J.; Krisciunas, K.; Suntzeff, N.; Macaulay, E.; Nichol, R.; Prajs, S.; Smith, M.; Sullivan, M.; Maartens, R.; Kovacs, E.; Kuhlmann, S.; Spinka, H.; Ahn, E.; Finley, D. A.; Frieman, J.; Marriner, J.; Wester, W.; Aldering, G.; Kim, A. G.; Thomas, R. C.; Barbary, K.; Bloom, J. S.; Goldstein, D.; Gupta, R.; Nugent, P.; Perlmutter, S.; Foley, R. J.; Pan, Y.-C.; Casas, R.; Castander, F. J.; Papadopoulos, A.; Morganson, E.

    2016-10-01

    We report new spectroscopic classifications by OzDES of supernovae discovered by the Dark Energy Survey (ATEL #4668). The spectra (370-885nm) were obtained with the AAOmega Spectrograph (Saunders et al. 2004, SPIE, 5492, 389) and the 2dF fibre positioner at the Anglo-Australian Telescope (AAT).

  1. Mutations in man

    SciTech Connect

    Obe, G.

    1984-01-01

    This book contains 13 selections that cover some of the following topics: DNA repair, gene or point mutations, aspects of nondisjunction, origin and significance of chromosomal alterations, structure and organization of the human genome, and mutagenic activity of cigarette smoke.

  2. L'astronomie des Anciens

    NASA Astrophysics Data System (ADS)

    Nazé, Yaël

    2009-04-01

    Quelle que soit la civilisation à laquelle il appartient, l'être humain cherche dans le ciel des réponses aux questions qu'il se pose sur son origine, son avenir et sa finalité. Le premier mérite de ce livre est de nous rappeler que l'astronomie a commencé ainsi à travers les mythes célestes imaginés par les Anciens pour expliquer l'ordre du monde et la place qu'ils y occupaient. Mais les savoirs astronomiques passés étaient loin d'être négligeables et certainement pas limités aux seuls travaux des Grecs : c'est ce que l'auteur montre à travers une passionnante enquête, de Stonehenge à Gizeh en passant par Pékin et Mexico, fondée sur l'étude des monuments anciens et des sources écrites encore accessibles. Les tablettes mésopotamiennes, les annales chinoises, les chroniques médiévales, etc. sont en outre d'une singulière utilité pour les astronomes modernes : comment sinon remonter aux variations de la durée du jour au cours des siècles, ou percer la nature de l'explosion qui a frappé tant d'observateurs en 1054 ? Ce livre offre un voyage magnifiquement illustré à travers les âges, entre astronomie et archéologie.

  3. Comparing Mutational Variabilities

    PubMed Central

    Houle, D.; Morikawa, B.; Lynch, M.

    1996-01-01

    We have reviewed the available data on V(M), the amount of genetic variation in phenotypic traits produced each generation by mutation. We use these data to make several qualitative tests of the mutation-selection balance hypothesis for the maintenance of genetic variance (MSB). To compare V(M) values, we use three dimensionless quantities: mutational heritability, V(M)/V(E); the mutational coefficient of variation, CV(M); and the ratio of the standing genetic variance to V(M), V(G)/V(M). Since genetic coefficients of variation for life history traits are larger than those for morphological traits, we predict that under MSB, life history traits should also have larger CV(M). This is confirmed; life history traits have a median CV(M) value more than six times higher than that for morphological traits. V(G)/V(M) approximates the persistence time of mutations under MSB in an infinite population. In order for MSB to hold, V(G)/V(M) must be small, substantially less than 1000, and life history traits should have smaller values than morphological traits. V(G)/V(M) averages about 50 generations for life history traits and 100 generations for morphological traits. These observations are all consistent with the predictions of a mutation-selection balance model. PMID:8807316

  4. Mutational spectrum drives the rise of mutator bacteria.

    PubMed

    Couce, Alejandro; Guelfo, Javier R; Blázquez, Jesús

    2013-01-01

    Understanding how mutator strains emerge in bacterial populations is relevant both to evolutionary theory and to reduce the threat they pose in clinical settings. The rise of mutator alleles is understood as a result of their hitchhiking with linked beneficial mutations, although the factors that govern this process remain unclear. A prominent but underappreciated fact is that each mutator allele increases only a specific spectrum of mutational changes. This spectrum has been speculated to alter the distribution of fitness effects of beneficial mutations, potentially affecting hitchhiking. To study this possibility, we analyzed the fitness distribution of beneficial mutations generated from different mutator and wild-type Escherichia coli strains. Using antibiotic resistance as a model system, we show that mutational spectra can alter these distributions substantially, ultimately determining the competitive ability of each strain across environments. Computer simulation showed that the effect of mutational spectrum on hitchhiking dynamics follows a non-linear function, implying that even slight spectrum-dependent fitness differences are sufficient to alter mutator success frequency by several orders of magnitude. These results indicate an unanticipated central role for the mutational spectrum in the evolution of bacterial mutation rates. At a practical level, this study indicates that knowledge of the molecular details of resistance determinants is crucial for minimizing mutator evolution during antibiotic therapy.

  5. Mutations in Lettuce Improvement

    PubMed Central

    Mou, Beiquan

    2011-01-01

    Lettuce is a major vegetable in western countries. Mutations generated genetic variations and played an important role in the domestication of the crop. Many traits derived from natural and induced mutations, such as dwarfing, early flowering, male sterility, and chlorophyll deficiency, are useful in physiological and genetic studies. Mutants were also used to develop new lettuce products including miniature and herbicide-tolerant cultivars. Mutant analysis was critical in lettuce genomic studies including identification and cloning of disease-resistance genes. Mutagenesis combined with genomic technology may provide powerful tools for the discovery of novel gene alleles. In addition to radiation and chemical mutagens, unconventional approaches such as tissue or protoplast culture, transposable elements, and space flights have been utilized to generate mutants in lettuce. Since mutation breeding is considered nontransgenic, it is more acceptable to consumers and will be explored more in the future for lettuce improvement. PMID:22287955

  6. Variable pathogenic potentials of mutations located in the desmin alpha-helical domain.

    PubMed

    Goudeau, Bertrand; Rodrigues-Lima, Fernando; Fischer, Dirk; Casteras-Simon, Monique; Sambuughin, Nyamkhishig; de Visser, Marianne; Laforet, Pascal; Ferrer, Xavier; Chapon, Françoise; Sjöberg, Gunnar; Kostareva, Anna; Sejersen, Thomas; Dalakas, Marinos C; Goldfarb, Lev G; Vicart, Patrick

    2006-09-01

    Mutations in the desmin gene have been recognized as a cause of desminopathy, a familial or sporadic disorder characterized by skeletal muscle weakness, often associated with cardiomyopathy or respiratory insufficiency. Distinctive histopathologic features include aberrant intracytoplasmic accumulation of desmin (DES). We present here comparative phenotypic, molecular, and functional characteristics of four novel and three previously reported, but not fully characterized, desmin mutations localized in desmin alpha-helical domain. The results indicate that the c.638C>T (p.A213V), c.1178A>T (p.N393I), and to some extent the c.1078G>C (p.A360P) mutations exhibit pathogenic potentials only if combined with other mutations in desmin or other genes and should therefore be considered conditionally pathogenic. The c.1009G>C (p.A337P), c.1013T>G (p.L338R), c.1195G>T (p.D399Y), and c.1201G>A (p.E401K) mutations make desmin filaments dysfunctional and are capable of causing disease. The pathogenic potentials of desmin mutations correlate with the type and location of the disease-associated mutations in the relatively large and structurally and functionally complex desmin molecule. Mutations within the highly conserved alpha-helical structures are especially damaging since the integrity of the alpha-helix is critical for desmin filament assembly and stability.

  7. Transport quantique dans des nanostructures

    NASA Astrophysics Data System (ADS)

    Naud, C.

    2002-09-01

    structure des oscillations de conductance en fonction du flux du champ magnétique de période h/e dont l'amplitude est beaucoup plus importante que celle mesurée sur un réseau carré de même dimension. Cette différence constitue une signature d'un effet de localisation induit par le champ magnétique sur la topologie mathcal{T}3. Pour des valeurs spécifiques du champ magnétique, du fait des interférences destructives Aharonov-Bohm, la propagation des fonctions d'ondes est limitée à un ensemble fini de cellule du réseau appelé cage. De la dépendance en température des oscillations de période h/e mesurées sur le réseau mathcal{T}3 nous avons tiré une longueur caractéristique qui peut être rattachée au périmètre des cages. Un phénomène inattendu fut l'observation, pour des champs magnétiques plus importants, d'un doublement de fréquence des oscillations. Ces oscillations de période h/2e pouvant avoir une amplitude supérieure aux oscillations de période h/e, une interprétation en terme d'harmonique n'est pas possible. Enfin, l'influence de la largeur électrique des fils constituant le réseau et donc celle du nombre de canaux par brin a été étudiée en réalisant des grilles électrostatique. Les variations de l'amplitude des signaux en h/e et h/2e en fonction de la tension de grille ont été mesurés.

  8. Impact de la preparation des anodes crues et des conditions de cuisson sur la fissuration dans des anodes denses

    NASA Astrophysics Data System (ADS)

    Amrani, Salah

    La fabrication de l'aluminium est realisee dans une cellule d'electrolyse, et cette operation utilise des anodes en carbone. L'evaluation de la qualite de ces anodes reste indispensable avant leur utilisation. La presence des fissures dans les anodes provoque une perturbation du procede l'electrolyse et une diminution de sa performance. Ce projet a ete entrepris pour determiner l'impact des differents parametres de procedes de fabrication des anodes sur la fissuration des anodes denses. Ces parametres incluent ceux de la fabrication des anodes crues, des proprietes des matieres premieres et de la cuisson. Une recherche bibliographique a ete effectuee sur tous les aspects de la fissuration des anodes en carbone pour compiler les travaux anterieurs. Une methodologie detaillee a ete mise au point pour faciliter le deroulement des travaux et atteindre les objectifs vises. La majorite de ce document est reservee pour la discussion des resultats obtenus au laboratoire de l'UQAC et au niveau industriel. Concernant les etudes realisees a l'UQAC, une partie des travaux experimentaux est reservee a la recherche des differents mecanismes de fissuration dans les anodes denses utilisees dans l'industrie d'aluminium. L'approche etait d'abord basee sur la caracterisation qualitative du mecanisme de la fissuration en surface et en profondeur. Puis, une caracterisation quantitative a ete realisee pour la determination de la distribution de la largeur de la fissure sur toute sa longueur, ainsi que le pourcentage de sa surface par rapport a la surface totale de l'echantillon. Cette etude a ete realisee par le biais de la technique d'analyse d'image utilisee pour caracteriser la fissuration d'un echantillon d'anode cuite. L'analyse surfacique et en profondeur de cet echantillon a permis de voir clairement la formation des fissures sur une grande partie de la surface analysee. L'autre partie des travaux est basee sur la caracterisation des defauts dans des echantillons d'anodes crues

  9. Sex and deleterious mutations.

    PubMed

    Gordo, Isabel; Campos, Paulo R A

    2008-05-01

    The evolutionary advantage of sexual reproduction has been considered as one of the most pressing questions in evolutionary biology. While a pluralistic view of the evolution of sex and recombination has been suggested by some, here we take a simpler view and try to quantify the conditions under which sex can evolve given a set of minimal assumptions. Since real populations are finite and also subject to recurrent deleterious mutations, this minimal model should apply generally to all populations. We show that the maximum advantage of recombination occurs for an intermediate value of the deleterious effect of mutations. Furthermore we show that the conditions under which the biggest advantage of sex is achieved are those that produce the fastest fitness decline in the corresponding asexual population and are therefore the conditions for which Muller's ratchet has the strongest effect. We also show that the selective advantage of a modifier of the recombination rate depends on its strength. The quantification of the range of selective effects that favors recombination then leads us to suggest that, if in stressful environments the effect of deleterious mutations is enhanced, a connection between sex and stress could be expected, as it is found in several species.

  10. Mutator and MULE Transposons.

    PubMed

    Lisch, Damon

    2015-04-01

    The Mutator system of transposable elements (TEs) is a highly mutagenic family of transposons in maize. Because they transpose at high rates and target genic regions, these transposons can rapidly generate large numbers of new mutants, which has made the Mutator system a favored tool for both forward and reverse mutagenesis in maize. Low copy number versions of this system have also proved to be excellent models for understanding the regulation and behavior of Class II transposons in plants. Notably, the availability of a naturally occurring locus that can heritably silence autonomous Mutator elements has provided insights into the means by which otherwise active transposons are recognized and silenced. This chapter will provide a review of the biology, regulation, evolution and uses of this remarkable transposon system, with an emphasis on recent developments in our understanding of the ways in which this TE system is recognized and epigenetically silenced as well as recent evidence that Mu-like elements (MULEs) have had a significant impact on the evolution of plant genomes.

  11. OXPHOS mutations and neurodegeneration

    PubMed Central

    Koopman, Werner J H; Distelmaier, Felix; Smeitink, Jan AM; Willems, Peter HGM

    2013-01-01

    Mitochondrial oxidative phosphorylation (OXPHOS) sustains organelle function and plays a central role in cellular energy metabolism. The OXPHOS system consists of 5 multisubunit complexes (CI–CV) that are built up of 92 different structural proteins encoded by the nuclear (nDNA) and mitochondrial DNA (mtDNA). Biogenesis of a functional OXPHOS system further requires the assistance of nDNA-encoded OXPHOS assembly factors, of which 35 are currently identified. In humans, mutations in both structural and assembly genes and in genes involved in mtDNA maintenance, replication, transcription, and translation induce ‘primary' OXPHOS disorders that are associated with neurodegenerative diseases including Leigh syndrome (LS), which is probably the most classical OXPHOS disease during early childhood. Here, we present the current insights regarding function, biogenesis, regulation, and supramolecular architecture of the OXPHOS system, as well as its genetic origin. Next, we provide an inventory of OXPHOS structural and assembly genes which, when mutated, induce human neurodegenerative disorders. Finally, we discuss the consequences of mutations in OXPHOS structural and assembly genes at the single cell level and how this information has advanced our understanding of the role of OXPHOS dysfunction in neurodegeneration. PMID:23149385

  12. Etude des effets du martelage repetitif sur les contraintes residuelles

    NASA Astrophysics Data System (ADS)

    Hacini, Lyes

    L'assemblage par soudage peut engendrer des contraintes residuelles. Ces contraintes provoquent des fissurations prematurees et un raccourcissement de la duree de vie des composants. Dans ce contexte, le martelage robotise est utilise pour relaxer ces contraintes residuelles. Trois volets sont presentes: le premier est l'evaluation des effets des impacts unitaires repetes sur le champ de contraintes developpe dans des plaques d'acier inoxydable austenitique 304L vierges ou contenant des contraintes residuelles initiales. Dans la deuxieme partie de ce projet, le martelage est applique grace au robot SCOMPI. Les contraintes residuelles induites et relaxees par martelage sont ensuite mesurees par la methode des contours, qui a ete adaptee a cet effet. Dans la troisieme partie, le martelage est modelise par la methode des elements finis. Un modele axisymetrique developpe grace au logiciel ANSYS permet de simuler des impacts repetes d'un marteau elastique sur une plaque ayant un comportement elastoplastique.

  13. Mucopolysaccharidosis IVA mutations in Chinese patients: 16 novel mutations.

    PubMed

    Wang, Zheng; Zhang, Weimin; Wang, Yun; Meng, Yan; Su, Liang; Shi, Huiping; Huang, Shangzhi

    2010-08-01

    Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is a lysosomal storage disease caused by deficiency of N-acetylgalactosamine-6-sulfatase (GALNS) and transmitted as an autosomal recessive trait. This is the first systematic mutation screen in Chinese MPS IVA patients. Mutation detections in 24 unrelated Chinese MPS IVA patients were performed by PCR and direct sequencing of exons or the mRNA of GALNS. A total of 42 mutant alleles were identified, belonging to 27 different mutations. Out of the 27 mutations, 16 were novel, including 2 splicing mutations (c.567-1G>T and c.634-1G>A), 2 nonsense mutations (p.W325X and p.Q422X) and 12 missense mutations (p.T88I, p.H142R, p.P163H, p.G168L, p.H236D, p.N289S, p.T312A, p.G316V, p.A324E, p.L366P, p.Q422K and p.F452L). p.G340D was found to be a common mutation in the Chinese MPS IVA patients, accounting for 16.7% of the total number of mutant alleles. The results show that the mutations in Chinese MPS IVA patients are also family specific but have a different mutation spectrum as compared to those of other populations.

  14. Calreticulin Mutations in Myeloproliferative Neoplasms

    PubMed Central

    Lavi, Noa

    2014-01-01

    With the discovery of the JAK2V617F mutation in patients with Philadelphia chromosome-negative (Ph−) myeloproliferative neoplasms (MPNs) in 2005, major advances have been made in the diagnosis of MPNs, in understanding of their pathogenesis involving the JAK/STAT pathway, and finally in the development of novel therapies targeting this pathway. Nevertheless, it remains unknown which mutations exist in approximately one-third of patients with non-mutated JAK2 or MPL essential thrombocythemia (ET) and primary myelofibrosis (PMF). At the end of 2013, two studies identified recurrent mutations in the gene encoding calreticulin (CALR) using whole-exome sequencing. These mutations were revealed in the majority of ET and PMF patients with non-mutated JAK2 or MPL but not in polycythemia vera patients. Somatic 52-bp deletions (type 1 mutations) and recurrent 5-bp insertions (type 2 mutations) in exon 9 of the CALR gene (the last exon encoding the C-terminal amino acids of the protein calreticulin) were detected and found always to generate frameshift mutations. All detected mutant calreticulin proteins shared a novel amino acid sequence at the C-terminal. Mutations in CALR are acquired early in the clonal history of the disease, and they cause activation of JAK/STAT signaling. The CALR mutations are the second most frequent mutations in Ph− MPN patients after the JAK2V617F mutation, and their detection has significantly improved the diagnostic approach for ET and PMF. The characteristics of the CALR mutations as well as their diagnostic, clinical, and pathogenesis implications are discussed in this review. PMID:25386351

  15. Ostéosynthèse des fractures des métacarpiens et des phalanges de la main par mini plaque: à propos de 12 cas

    PubMed Central

    Moncef, Erraji; Abdelhafid, Derfoufi; Abdessamad, Kharraji; Omar, Agoumi; Najib, Abdeljaouad; Abdelkrim, Daoudi; Hicham, Yacoubi

    2016-01-01

    Le traitement des fractures instables des métacarpes et des phalanges reste un objet de controverse. Peu de séries ont été rapportées dans la littérature, rendant leur analyse difficile. Nous rapportons une étude rétrospective comportant 12 patients, opérés par cette technique, ayant eu des fractures déplacées des métacarpes ou des phalanges, sur une période de deux ans. Les résultats globaux ont été bons dans 75% des cas, moyenne dans 16,5% des cas et mauvais dans 8,5% des cas. La stabilité du montage par mini plaques des fractures instables des métacarpiens et des phalanges ont permis une mobilisation précoce des articulations de la main, évitant ainsi la raideur. PMID:27800079

  16. Peste des Petits Ruminants Virus.

    PubMed

    Baron, M D; Diallo, A; Lancelot, R; Libeau, G

    2016-01-01

    Peste des petits ruminants virus (PPRV) causes a severe contagious disease of sheep and goats and has spread extensively through the developing world. Because of its disproportionately large impact on the livelihoods of low-income livestock keepers, and the availability of effective vaccines and good diagnostics, the virus is being targeted for global control and eventual eradication. In this review we examine the origin of the virus and its current distribution, and the factors that have led international organizations to conclude that it is eradicable. We also review recent progress in the molecular and cellular biology of the virus and consider areas where further research is required to support the efforts being made by national, regional, and international bodies to tackle this growing threat. PMID:27112279

  17. Filaggrin mutations and the skin.

    PubMed

    De, Dipankar; Handa, Sanjeev

    2012-01-01

    Filaggrin is very important in the terminal differentiation of the skin and the formation of cornified envelope in the stratum corneum. Several mutations in the filaggrin gene have been identified in the last decade, mostly from the European countries. Loss of function mutations in the filaggrin gene results in reduced production of filaggrin, depending on the type and site of mutation. Such mutations in the filaggrin gene have been shown to be the most significant genetic risk factor for development of atopic dermatitis and undoubtedly has a role in the pathogenesis of ichthyosis vulgaris. Though there is theoretical possibility of association with hand eczema and allergic contact dermatitis; in clinical studies, the strength of these associations was not significantly strong. In this review, we have discussed the structure and function of filaggrin, basic genetics, type of mutations in filaggrin gene, and association of such mutations with different dermatoses.

  18. Missense mutations in desmin associated with familial cardiac and skeletal myopathy.

    PubMed

    Goldfarb, L G; Park, K Y; Cervenáková, L; Gorokhova, S; Lee, H S; Vasconcelos, O; Nagle, J W; Semino-Mora, C; Sivakumar, K; Dalakas, M C

    1998-08-01

    Desmin-related myopathy (OMIM 601419) is a familial disorder characterized by skeletal muscle weakness associated with cardiac conduction blocks, arrhythmias and restrictive heart failure, and by intracytoplasmic accumulation of desmin-reactive deposits in cardiac and skeletal muscle cells. The underlying molecular mechanisms are unknown. Involvement of the desmin gene (DES) has been excluded in three families diagnosed with desmin-related myopathy. We report two new families with desmin-related cardioskeletal myopathy associated with mutations in the highly conserved carboxy-terminal end of the desmin rod domain. A heterozygous A337P mutation was identified in a family with an adult-onset skeletal myopathy and mild cardiac involvement. Compound heterozygosity for two other mutations, A360P and N393I, was detected in a second family characterized by childhood-onset aggressive course of cardiac and skeletal myopathy.

  19. Cancer risk in DES daughters

    PubMed Central

    Verloop, Janneke; van Leeuwen, Flora E.; Helmerhorst, Theo J. M.; van Boven, Hester H.

    2010-01-01

    Objective We examined long-term risk of cancer in women exposed to diethylstilbestrol (DES) in utero. Methods A total of 12,091 DES-exposed women in the Netherlands were followed prospectively from December 1992 till June 2008. Cancer incidence was assessed through linkage with the Dutch pathology database (PALGA) and the Netherlands Cancer Registry and compared with the Dutch female population. Results A total of 348 medically verified cancers occurred; median age at end of follow-up was 44.0 years. No overall increased risk of cancer was found (standardized incidence ratio [SIR] = 1.01; 95% confidence interval [CI] = 0.91, 1.13). The risk of clear cell adenocarcinoma of the vagina and cervix (CCA) was statistically significantly increased (SIR = 24.23; 95% CI = 8.89, 52.74); the elevated risk persisted above 40 years of age. The risk of melanoma diagnosed before age 40 was increased (SIR = 1.59; 95% CI = 1.08, 2.26). No excess risks were found for other sites, including breast cancer. Conclusions Except for an elevated risk of CCA, persisting at older ages, and an increased risk of melanoma at young ages, we found no increased risk of cancer. Longer follow-up is warranted to examine cancer risk at ages when cancer occurs more frequently. Electronic supplementary material The online version of this article (doi:10.1007/s10552-010-9526-5) contains supplementary material, which is available to authorized users. PMID:20204493

  20. The enhancement of existing DES Maplet interface

    NASA Astrophysics Data System (ADS)

    Abdullah, Nur Lina; Mutalip, Rasidah Abdull; Abdullah, Kamilah

    2014-07-01

    This study pertains to the process of Data Encryption Standard, DES. DES consists of encryption and decryption processes linked with mathematical elements such as algebra and number theory. Preliminary, studies revealed that most of mathematics students face a problem in understanding the complicated process of DES. In modern learning methods, learning environment becomes more interesting with the use of computer and a variety of mathematical software packages. Several mathematical softwares such as Maple, Mathematica, Mathlab and Sage were developed in order to fulfill the specific calculation requirements. Correspondingly, motivated from that, this study incorporated with Maple to enhance the existing DES Maplet interface to be more interactive and user-friendly compared to the original version.

  1. Évolution de leucémies myéloïdes chroniques sous nilotinib après échec a l'imatinib

    PubMed Central

    Sawadogo, Salifo; Hien, Francis Michel; Ouédraogo, Macaire Sampawendé; Drabo, Youssouf Joseph

    2014-01-01

    C'est une étude observationnelle prospective ouverte: quatre leucémies myéloïdes chroniques résistant ou intolérant à l'Imatinib ont été traitées par le Nilotinib. Elles ont été incluses dans le programme GIPAP et suivies selon les recommandations de “European LeukemiaNet”. Trois ont un score de Sokal de haut risque et une de bas risque. Deux étaient hypertendues. Mises sous Nilotinib, il y a eu deux rémissions cytogénétiques complètes et deux échecs. Le traitement a été interrompu chez les deux rémissions complètes, l'un pour effet secondaire du Nilotinib et l'autre pour changement de pays. Les deux échecs sont dus à des résistances. Le Nilotinib réduisant la fréquence des mutations des leucémies myéloïdes chroniques à haut risque et risque intermédiaire, il serait judicieux d'utiliser ce produit en première intention dans ces cas - ci pour réduire la charge des examens complémentaires. Les pays à bas revenu confrontés à des problèmes de survie ont besoin de la solidarité mondiale pour prendre en charge les leucémies myéloïdes chroniques. PMID:25419280

  2. Ramifications of four concurrent thrombophilic mutations and one hypofibrinolytic mutation.

    PubMed

    Glueck, Charles J; Goldenberg, Naila; Wang, Ping; Aregawi, Dawit

    2004-10-01

    A kindred was examined in which the 48-year-old white female proband with three deep venous thrombosis-pulmonary emboli events had four thrombophilic and one hypofibrinolytic mutations, and in which her 14-year-old asymptomatic daughter had four thrombophilic mutations. The proband was heterozygous for the G1691A factor V Leiden, G20210A prothrombin, and platelet glycoprotein IIIa PL A1/A2 mutations, had high factor VIII (221%), and was homozygous for the 4G4G plasminogen activator inhibitor-1 gene mutation, with high plasminogen activator inhibitor activity (23.7 U/mL). Her 14-year-old daughter was homozygous for the G1691A factor V Leiden and platelet glycoprotein IIb-IIIa PL A2/A2 mutations, compound heterozygous for the C677T and A1298C methylenetetrahydrofolate reductase (MTHFR) mutations, and heterozygous for the G20210A prothrombin mutation, a combination with an estimated likelihood of 1.6 x 10(-7). In 247 white healthy controls, there was no V Leiden homozygosity and no V Leiden-prothrombin gene compound heterozygosity. Heterozygosity for the V Leiden and prothrombin gene mutations was 3.2% and 4.1%, respectively. Homozygosity for the platelet glycoprotein IIb-IIIa PL A2A2, PAI-1 gene 4G4G, and C677T MTHFR mutations was 3.2%, 22.7%, and 12%, respectively. The proband will receive anticoagulation therapy for life. Beyond aspirin, avoidance of exogenous estrogens, and enoxaparin prophylaxis during pregnancy, it is not known whether the proband's daughter should have lifelong anticoagulation therapy, or only after her first thrombotic event. PMID:15497023

  3. Parkinsonism Associated with Glucocerebrosidase Mutation

    PubMed Central

    Sunwoo, Mun-Kyung; Kim, Seung-Min; Lee, Sarah

    2011-01-01

    Background Gaucher's disease is an autosomal recessive, lysosomal storage disease caused by mutations of the β-glucocerebrosidase gene (GBA). There is increasing evidence that GBA mutations are a genetic risk factor for the development of Parkinson's disease (PD). We report herein a family of Koreans exhibiting parkinsonism-associated GBA mutations. Case Report A 44-year-old woman suffering from slowness and paresthesia of the left arm for the previous 1.5years, visited our hospital to manage known invasive ductal carcinoma. During a preoperative evaluation, she was diagnosed with Gaucher's disease and double mutations of S271G and R359X in GBA. Parkinsonian features including low amplitude postural tremors, rigidity, bradykinesia and shuffling gait were observed. Genetic analysis also revealed that her older sister, who had also been diagnosed with PD and had been taking dopaminergic drugs for 8-years, also possessed a heterozygote R359X mutation in GBA. 18F-fluoropropylcarbomethoxyiodophenylnortropane positron-emission tomography in these patients revealed decreased uptake of dopamine transporter in the posterior portion of the bilateral putamen. Conclusions This case study demonstrates Korean familial cases of PD with heterozygote mutation of GBA, further supporting the association between PD and GBA mutation. PMID:21779299

  4. 33 CFR 117.439 - Des Allemands Bayou.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 33 Navigation and Navigable Waters 1 2011-07-01 2011-07-01 false Des Allemands Bayou. 117.439... DRAWBRIDGE OPERATION REGULATIONS Specific Requirements Louisiana § 117.439 Des Allemands Bayou. (a) The draw of the S631 bridge, mile 13.9 at Des Allemands, shall open on signal if at least four hours notice...

  5. 33 CFR 117.439 - Des Allemands Bayou.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Des Allemands Bayou. 117.439... DRAWBRIDGE OPERATION REGULATIONS Specific Requirements Louisiana § 117.439 Des Allemands Bayou. (a) The draw of the S631 bridge, mile 13.9 at Des Allemands, shall open on signal if at least four hours notice...

  6. 75 FR 63714 - Drawbridge Operation Regulation; Des Allemands Bayou, LA

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-18

    ... SECURITY Coast Guard 33 CFR Part 117 Drawbridge Operation Regulation; Des Allemands Bayou, LA AGENCY: Coast... Burlington Northern Santa Fe Railway swing bridge across Des Allemands Bayou, mile 14.0, in St. Charles and... INFORMATION: The Burlington Northern Santa Fe Railway swing span drawbridge across Bayou Des Allemands,...

  7. Statutes of limitations: the special problem of DES suits.

    PubMed

    Feigin, C A

    1981-01-01

    In 1971, medical studies determined that DES causes a rare type of vaginal cancer in a small number of daughters of mothers who took DES during pregnancy. Subsequently, medical studies determined that exposure to DES can cause other vaginal abnormalities in the daughters, some of which may be precancerous. As a result of these discoveries, many lawsuits have been filed by these daughters against DES manufacturers. Many DES suits may be barred by statutes of limitations, both because the number of years between the daughters' exposure to DES in utero and the discovery that DES can cause injuries exceeds the statutory period, and because the cancer or other injuries caused by DES may not develop for many additional years. This Note discusses two methods that DES plaintiffs may be able to use to overcome the potential statutes of limitations bar: the discovery rule, and state provisions which toll the statute of limitations for minors. The Note contends that courts should apply an expanded discovery rule to DES suits to avoid the unfair result of barring a claim before the plaintiff could have known that she had a cause of action. In addition, the Note argues that the injury which causes the statute of limitations to begin to run in DES suits should not be rigidly defined. Finally, the Note urges that courts allow eligible DES plaintiffs to take advantage of applicable state provisions that toll the statute of limitations for minors.

  8. Bladder Cancer and Genetic Mutations.

    PubMed

    Zhang, Xiaoying; Zhang, Yangde

    2015-09-01

    The most common type of urinary bladder cancer is called as transitional cell carcinoma. The major risk factors for bladder cancer are environmental, tobacco smoking, exposure to toxic industrial chemicals and gases, bladder inflammation due to microbial and parasitic infections, as well as some adverse side-effects of medications. The genetic mutations in some chromosomal genes, such as FGFR3, RB1, HRAS, TP53, TSC1, and others, occur which form tumors in the urinary bladder. These genes play an important role in the regulation of cell division which prevents cells from dividing too quickly. The changes in the genes of human chromosome 9 are usually responsible for tumor in bladder cancer, but the genetic mutation of chromosome 22 can also result in bladder cancer. The identification of p53 gene mutation has been studied at NIH, Washington, DC, USA, in urine samples of bladder cancer patients. The invasive bladder cancers were determined for the presence of gene mutations on p53 suppressor gene. The 18 different bladder tumors were evaluated, and 11 (61 %) had genetic mutations of p53 gene. The bladder cancer studies have suggested that 70 % of bladder cancers involve a specific mutation in a particular gene, namely telomerase reverse transcriptase (TERT) gene. The TERT gene is involved in DNA protection, cellular aging processes, and cancer. The Urothelial carcinomas of the bladder have been described in Atlas of genetics and cytogenetics in oncology and hematology. HRAS is a proto-oncogene and has potential to cause cancer in several organs including the bladder. The TSC1 c. 1907 1908 del (E636fs) mutation in bladder cancer suggests that the location of the mutation is Exon 15 with frequency of TSC1 mutation of 11.7 %. The recent findings of BAP1 mutations have shown that it contributes to BRCA pathway alterations in bladder cancer. The discoveries of more gene mutations and new biomarkers and polymerase chain reaction bioassays for gene mutations in bladder

  9. Mutational landscape and underlying mutational processes in chronic lymphocytic leukemia.

    PubMed

    Kasar, S; Brown, J R

    2016-07-01

    Sequencing studies have been instrumental in understanding the genetic basis of chronic lymphocytic leukemia (CLL). Our recent whole-genome sequencing study focusing on lower cytogenetic risk CLL demonstrated that CLL mutations can be attributed to 3 key mutational processes-2 types of activation induced-cytidine deaminase (AID) signatures and an aging signature-that operate at different times throughout CLL evolution. PMID:27652313

  10. PPARγ mutations, lipodystrophy and diabetes.

    PubMed

    Astapova, Olga; Leff, Todd

    2014-11-01

    The focus of this review is the lipodystrophy syndrome caused by mutation in the PPARγ nuclear receptor - partial familial lipodystrophy FPLD3. To provide a broader context for how these mutations act to generate the clinical features of partial lipodystrophy we will review the basic biology of PPARγ and also survey the set PPARγ genetic variants that do not cause lipodystrophy, but are nonetheless associated with clinically related syndromes, specifically type 2 diabetes.

  11. Mutations in cardiovascular connexin genes.

    PubMed

    Molica, Filippo; Meens, Merlijn J P; Morel, Sandrine; Kwak, Brenda R

    2014-09-01

    Connexins (Cxs) form a family of transmembrane proteins comprising 21 members in humans. Cxs differ in their expression patterns, biophysical properties and ability to combine into homomeric or heteromeric gap junction channels between neighbouring cells. The permeation of ions and small metabolites through gap junction channels or hemichannels confers a crucial role to these proteins in intercellular communication and in maintaining tissue homeostasis. Among others, Cx37, Cx40, Cx43, Cx45 and Cx47 are found in heart, blood and lymphatic vessels. Mutations or polymorphisms in the genes coding for these Cxs have not only been implicated in cardiovascular pathologies but also in a variety of other disorders. While mutations in Cx43 are mostly linked to oculodentodigital dysplasia, Cx47 mutations are associated with Pelizaeus-Merzbacher-like disease and lymphoedema. Cx40 mutations are principally linked to atrial fibrillation. Mutations in Cx37 have not yet been described, but polymorphisms in the Cx37 gene have been implicated in the development of arterial disease. This review addresses current knowledge on gene mutations in cardiovascular Cxs systematically and links them to alterations in channel properties and disease.

  12. Note des Éditeurs scientifiques

    NASA Astrophysics Data System (ADS)

    Averbuch, P.

    Cette série d'articles est une revue de résultats expérimentaux sur différents "fluides" moléculaires, dans lesquels la cohésion est due à des forces de Van der Waals et à des liaisons hydrogène, l'eau étant un de ces fluides. Ces résultats sont présentés de façon à justifier expérimentalement un modèle original, non extensif, des propriétés de ces fluides, et l'ensemble se présente sous la forme de trois articles décrivant le modèle, suivis chacun par un article le comparant aux résultats expérimentaux publiés par de nombreux auteurs. Le caractère non extensif des propriétés physiques des fluides est choquant, contraire à beaucoup d'idées établies, il semble n'avoir en sa faveur qu'un argument, la comparaison avec un nombre de résultats expérimentaux assez grand pour que l'effet du hasard soit difficilement soupçonnable. En particulier, les écarts entre des résultats de mesures faits par des auteurs différents dans des conditions différentes sont expliqués, le sérieux et la compétence des différents expérimentateurs ne sont plus mis en doute : mais l'interprétation de ces résultats avec un modèle extensif non adapté est seule mise en cause. Les modèles extensifs étant utilisés systématiquement, au delà des expériences de physiciens, dans les calculs d'ingénieurs, et dans la modélisation d'appareils qui fonctionnent et de phénomènes naturels observés par tout le monde, il fallait expliquer pourquoi on pouvait renoncer à l'extensivité. Les raisons du succès pratique des modèles extensifs sont données, d'abord dans le cas des nématiques, puis dans celui des liquides ordinaires, et c'est ce qui rend l'ensemble cohérent, tant avec les mesures physiques fines qu'avec les observations quotidiennes. Il n'en reste pas moins que si l'interprétation donnée dans cette série d'articles est généralisable, une justification théorique du modèle utilisé devient nécessaire. Pour ce qui est des propriétés d

  13. Genome destabilizing mutator alleles drive specific mutational trajectories in Saccharomyces cerevisiae.

    PubMed

    Stirling, Peter C; Shen, Yaoqing; Corbett, Richard; Jones, Steven J M; Hieter, Philip

    2014-02-01

    In addition to environmental factors and intrinsic variations in base substitution rates, specific genome-destabilizing mutations can shape the mutational trajectory of genomes. How specific alleles influence the nature and position of accumulated mutations in a genomic context is largely unknown. Understanding the impact of genome-destabilizing alleles is particularly relevant to cancer genomes where biased mutational signatures are identifiable. We first created a more complete picture of cellular pathways that impact mutation rate using a primary screen to identify essential Saccharomyces cerevisiae gene mutations that cause mutator phenotypes. Drawing primarily on new alleles identified in this resource, we measure the impact of diverse mutator alleles on mutation patterns directly by whole-genome sequencing of 68 mutation-accumulation strains derived from wild-type and 11 parental mutator genotypes. The accumulated mutations differ across mutator strains, displaying base-substitution biases, allele-specific mutation hotspots, and break-associated mutation clustering. For example, in mutants of POLα and the Cdc13-Stn1-Ten1 complex, we find a distinct subtelomeric bias for mutations that we show is independent of the target sequence. Together our data suggest that specific genome-instability mutations are sufficient to drive discrete mutational signatures, some of which share properties with mutation patterns seen in tumors. Thus, in a population of cells, genome-instability mutations could influence clonal evolution by establishing discrete mutational trajectories for genomes.

  14. Genome Destabilizing Mutator Alleles Drive Specific Mutational Trajectories in Saccharomyces cerevisiae

    PubMed Central

    Stirling, Peter C.; Shen, Yaoqing; Corbett, Richard; Jones, Steven J. M.; Hieter, Philip

    2014-01-01

    In addition to environmental factors and intrinsic variations in base substitution rates, specific genome-destabilizing mutations can shape the mutational trajectory of genomes. How specific alleles influence the nature and position of accumulated mutations in a genomic context is largely unknown. Understanding the impact of genome-destabilizing alleles is particularly relevant to cancer genomes where biased mutational signatures are identifiable. We first created a more complete picture of cellular pathways that impact mutation rate using a primary screen to identify essential Saccharomyces cerevisiae gene mutations that cause mutator phenotypes. Drawing primarily on new alleles identified in this resource, we measure the impact of diverse mutator alleles on mutation patterns directly by whole-genome sequencing of 68 mutation-accumulation strains derived from wild-type and 11 parental mutator genotypes. The accumulated mutations differ across mutator strains, displaying base-substitution biases, allele-specific mutation hotspots, and break-associated mutation clustering. For example, in mutants of POLα and the Cdc13–Stn1–Ten1 complex, we find a distinct subtelomeric bias for mutations that we show is independent of the target sequence. Together our data suggest that specific genome-instability mutations are sufficient to drive discrete mutational signatures, some of which share properties with mutation patterns seen in tumors. Thus, in a population of cells, genome-instability mutations could influence clonal evolution by establishing discrete mutational trajectories for genomes. PMID:24336748

  15. Developpement des betons semi autoplacants a rheologie adaptee pour des infrastructures

    NASA Astrophysics Data System (ADS)

    Sotomayor Cruz, Cristian Daniel

    Au cours des dernières décennies, les infrastructures canadiennes et québécoises comportent plusieurs structures en béton armé présentant des problèmes de durabilité dus aux conditions climatiques sévères, à la mauvaise conception des structures, à la qualité des matériaux, aux types des bétons choisis, aux systèmes de construction ou à l'existence d'événements incontrôlables. En ce qui concerne le choix du béton pour la construction des infrastructures, une vaste gamme de béton divisée en deux principaux types peut être utilisée: le béton conventionnel vibré (BCV) et le béton autoplaçant (BAP). Dans le cas d'un BCV, la consolidation inadéquate par vibration a été un problème récurrent, occasionnant des dommages structuraux. Ceci a conduit à une réduction de la durabilité et à une augmentation du coût d'entretien et de réparation des infrastructures. Rien que l'utilisation d'un BAP a des avantages tels que l'élimination de la vibration, la réduction des coûts de main d'oeuvre et l'amélioration de la qualité des structures, néanmoins, le coût initial d'un BAP par rapport à un BCV ne permet pas encore de généraliser son utilisation dans l'industrie de la construction. Ce mémoire présente la conception d'une nouvelle gamme de béton semi-autoplaçant pour la construction des infrastructures (BSAP-I) exigeant une vibration minimale. Il s'agit de trouver un équilibre optimal entre la rhéologie et le coût initial du nouveau béton pour conférer une bonne performance structurale et économique aux structures. Le programme expérimental établi a premièrement permis d'évaluer la faisabilité d'utilisation des BSAP-I pour la mise en place des piliers d'une infrastructure de pont à Sherbrooke. En plus, l'utilisation d'un plan d'expériences a permis l'évaluation de trois paramètres de formulation sur les propriétés des mélanges de BSAP-I à l'état frais et durci. Finalement, l'évaluation de la performance des

  16. Etude theorique et experimentale des evaporateurs de dioxyde de carbone operant dans des conditions de givrage

    NASA Astrophysics Data System (ADS)

    Bendaoud, Adlane Larbi

    Les evaporateurs de refrigeration sont surtout du type tube a ailettes, appeles serpentins, et fonctionnent dans l'une des conditions suivantes: seche, humide ou avec formation de givre. Il a ete demontre que la formation du givre sur la paroi exterieure de l'echangeur engendre une surconsommation energetique a cause des operations de degivrage puisque 15 a 20% seulement de la chaleur produite sert au degivrage tandis que le reste est dissipee dans l'environnement [1]. Avec l'avenement des nouveaux refrigerants, moins nocifs envers l'environnement, l'industrie du froid se trouve penalisee du fait que peu ou pas de composantes mecaniques (compresseur, pompe, echangeur...etc.) adaptees sont disponibles [3]. Il s'agit pour la communaute des frigoristes de combler ce retard technologique en redeveloppant ces composantes mecaniques afin qu'elles soient adaptees aux nouveaux refrigerants. Dans cette optique, et afin de mieux comprendre le comportement thermique des evaporateurs au CO2 fonctionnant dans des conditions seches, qu'un groupe de chercheurs du CanmetENERGIE avaient lance, en 2000, un programme de R & D. Dans le cadre de programme un outil de simulation des evaporateurs au CO2 a ete developpe et un banc d'essai contenant une boucle secondaire de refrigeration utilisant le CO2 comme refrigerant a ete construit. Comme continuite de ce travail de recherche, en 2006 ce meme groupe de recherche a lance un nouveau projet qui consiste a faire une etude theorique et experimentale des evaporateurs au CO2 operants dans des conditions de givrage. Et, c'est exactement dans le cadre de ce projet que se positionne ce travail de these. Ce travail de recherche a ete entrepris pour mieux comprendre le comportement thermique et hydrodynamique des serpentins fonctionnant dans des conditions de givrage, l'effet des circuits de refrigerant ainsi que celui des parametres geometriques et d'operation. Pour cela, un travail theorique supporte par une etude experimentale a ete effectue

  17. The androgen receptor gene mutations database.

    PubMed

    Patterson, M N; Hughes, I A; Gottlieb, B; Pinsky, L

    1994-09-01

    The androgen receptor gene mutations database is a comprehensive listing of mutations published in journals and meetings proceedings. The majority of mutations are point mutations identified in patients with androgen insensitivity syndrome. Information is included regarding the phenotype, the nature and location of the mutations, as well as the effects of the mutations on the androgen binding activity of the receptor. The current version of the database contains 149 entries, of which 114 are unique mutations. The database is available from EMBL (NetServ@EMBL-Heidelberg.DE) or as a Macintosh Filemaker file (mc33001@musica.mcgill.ca).

  18. Mutator Dynamics on a Smooth Evolutionary Landscape

    NASA Astrophysics Data System (ADS)

    Kessler, David A.; Levine, Herbert

    1998-03-01

    We investigate a model of evolutionary dynamics on a smooth landscape which features a ``mutator'' allele which increases the mutation rate. We show that when the fitness is far from its equilibrium value the expected proportion of mutators approaches a value governed solely by the transition rates into and out of the mutator state, resulting in a much faster fitness increase than would be the case without the mutator allele. Near the fitness equilibrium, the mutators are severely suppressed, due to the detrimental effects of a large mutation rate near the fitness maximum. We discuss the results of a recent experiment on natural selection of E. coli in the light of our model.

  19. Effets des electrons secondaires sur l'ADN

    NASA Astrophysics Data System (ADS)

    Boudaiffa, Badia

    Les interactions des electrons de basse energie (EBE) representent un element important en sciences des radiations, particulierement, les sequences se produisant immediatement apres l'interaction de la radiation ionisante avec le milieu biologique. Il est bien connu que lorsque ces radiations deposent leur energie dans la cellule, elles produisent un grand nombre d'electrons secondaires (4 x 104/MeV), qui sont crees le long de la trace avec des energies cinetiques initiales bien inferieures a 20 eV. Cependant, il n'y a jamais eu de mesures directes demontrant l'interaction de ces electrons de tres basse energie avec l'ADN, du principalement aux difficultes experimentales imposees par la complexite du milieu biologique. Dans notre laboratoire, les dernieres annees ont ete consacrees a l'etude des phenomenes fondamentaux induits par impact des EBE sur differentes molecules simples (e.g., N2, CO, O2, H2O, NO, C2H 4, C6H6, C2H12) et quelques molecules complexes dans leur phase solide. D'autres travaux effectues recemment sur des bases de l'ADN et des oligonucleotides ont montre que les EBE produisent des bris moleculaires sur les biomolecules. Ces travaux nous ont permis d'elaborer des techniques pour mettre en evidence et comprendre les interactions fondamentales des EBE avec des molecules d'interet biologique, afin d'atteindre notre objectif majeur d'etudier l'effet direct de ces particules sur la molecule d'ADN. Les techniques de sciences des surfaces developpees et utilisees dans les etudes precitees peuvent etre etendues et combinees avec des methodes classiques de biologie pour etudier les dommages de l'ADN induits par l'impact des EBE. Nos experiences ont montre l'efficacite des electrons de 3--20 eV a induire des coupures simple et double brins dans l'ADN. Pour des energies inferieures a 15 eV, ces coupures sont induites par la localisation temporaire d'un electron sur une unite moleculaire de l'ADN, ce qui engendre la formation d'un ion negatif transitoire

  20. The "Conservatoire National des Arts et Metiers"

    ERIC Educational Resources Information Center

    Kuhn, Gerard

    2004-01-01

    The overall mission of the Conservatoire national des arts et metiers--(CNAM) [National Conservatory of Industrial Arts and Trades] is outlined. One of its centers, the "Centre national de l'entrepreneuriat"--(CNE) [National Center for Entrepreneurship] is described in greater detail. In particular, this center offers various services, notably…

  1. Fiabilité des structures mécaniques adaptatives: effet de la panne des actionneurs ou des capteurs sur la stabilité

    NASA Astrophysics Data System (ADS)

    Fall, H.; Charon, W.; Kouta, R.

    2002-12-01

    Ces dernières décennies, des activités significatives dans le monde étaient dirigées autour du contrôle actif. Le but de ces recherches était essentiellement d'améliorer les performances, la fiabilité et la sécurité des systèmes. Notamment dans le cas des structures soumises à des vibrations aléatoires. D'importants travaux ont été consacré à l'utilisation des “matériaux intelligents” comme capteurs et actionneurs. Cette article propose l'analyse de la fiabilité des systèmes mécaniques en étudiant les pannes des actionneurs ou des capteurs. L'effet de ces pannes sur la stabilité et la performance du système y est démontré. Les méthodologies de conception y sont rappelées. Des exemples numériques sont fournis à travers le contrôle d'un panneau sous chargement dynamique pour illustrer la méthode proposée.

  2. HFE mutations in the elderly.

    PubMed

    Willis, Gavin; Wimperis, Jennie Z; Smith, Katy; Fellows, Ian W; Jennings, Barbara A

    2003-01-01

    Most individuals diagnosed with hereditary hemochromatosis have mutations in both copies of the HFE gene, with such mutations being common in populations of north European origin. The number of individuals currently diagnosed and treated for hemochromatosis is small relative to the number carrying two HFE mutations. Studies searching for undiagnosed hemochromatosis cases among disease cohorts have generally failed to find the number of cases that would be expected if disease were the commonest outcome for individuals with two C282Y HFE mutations. Our aim was to test the hypothesis that individuals with two HFE mutations would be under-represented in an elderly population because many would have died from disease caused by hemochromatosis before they reached old age. This is a cross-sectional study of elderly patients referred for full blood counts at the Norfolk and Norwich University Hospital. We screened blood samples from 1,000 elderly men (aged 85 and over) and women (aged 89 and over) for the C282Y, H63D, and S65C mutations of the HFE gene. We also analyzed any recent laboratory data relevant to signs of hemochromatosis. None of the ten possible genotypes was significantly under- or over-represented compared to the expected frequency calculated from the Hardy-Weinberg equation. Four C282Y homozygotes were found. There were few significant differences in the laboratory findings between the genotypes. Our data suggest that most people with HFE mutations survive to old age and do not suffer from signs of iron overload and hemochromatosis. PMID:12972032

  3. [Founder mutation in Lynch syndrome].

    PubMed

    Cajal, Andrea R; Piñero, Tamara A; Verzura, Alicia; Santino, Juan Pablo; Solano, Angela R; Kalfayan, Pablo G; Ferro, Alejandra; Vaccaro, Carlos

    2016-01-01

    Lynch syndrome is the most frequent syndrome in hereditary colorectal cancer, a family-specific deleterious mutations in genes encoding DNA reparation proteins: MLH1 (mutL homolog 1), MSH2, MSH6 (mutS homolog 2 y 6, respectively), PMS2 (PMS1 homolog 2, mismatch repair system component) y MUTYH (mutY DNA glycosylase). The c.2252_2253delAA, p.Lys751Serfs*3 mutation in MLH1 gene segregates with a haplotype reported in the northern region of Italy and whose origin was attributed to a founder effect. This mutation co-segregates with typical characteristics of Lynch syndrome, including early age at onset and multiple primary tumors in the same individual, a high frequency of pancreatic cancer, high microsatellite instability and lack of PMS2 expression. This report describes a mutation in an Argentinian patient with endometrioid adenocarcinoma of uterus. Her first-degree relatives had a history of colon cancer diagnosed before 50 years, fulfilling the Amsterdam Criteria I and Lynch syndrome II. The high pathogenicity associated to this mutation makes necessary the study of all members from families with hereditary cancer, allowing pre-symptomatic genetic diagnosis, early assessment and the instauration of preventive treatments.

  4. Accelerating Mutational Load Is Not Due to Synergistic Epistasis or Mutator Alleles in Mutation Accumulation Lines of Yeast.

    PubMed

    Jasmin, Jean-Nicolas; Lenormand, Thomas

    2016-02-01

    Much of our knowledge about the fitness effects of new mutations has been gained from mutation accumulation (MA) experiments. Yet the fitness effect of single mutations is rarely measured in MA experiments. This raises several issues, notably for inferring epistasis for fitness. The acceleration of fitness decline in MA lines has been taken as evidence for synergistic epistasis, but establishing the role of epistasis requires measuring the fitness of genotypes carrying known numbers of mutations. Otherwise, accelerating fitness loss could be explained by increased genetic mutation rates. Here we segregated mutations accumulated over 4800 generations in haploid and diploid MA lines of the yeast Saccharomyces cerevisiae. We found no correspondence between an accelerated fitness decline and synergistic epistasis among deleterious mutations in haploid lines. Pairs of mutations showed no overall epistasis. Furthermore, several lines of evidence indicate that genetic mutation rates did not increase in the MA lines. Crucially, segregant fitness analyses revealed that MA accelerated in both haploid and diploid lines, even though the fitness of diploid lines was nearly constant during the MA experiment. This suggests that the accelerated fitness decline in haploids was caused by cryptic environmental factors that increased mutation rates in all lines during the last third of the lines' transfers. In addition, we provide new estimates of deleterious mutation rates, including lethal mutations, and highlight that nearly all the mutational load we observed was due to one or two mutations having a large effect on fitness.

  5. Gene mutations in Cushing's disease

    PubMed Central

    Xiong, Qi; Ge, Wei

    2016-01-01

    Cushing's disease (CD) is a severe (and potentially fatal) disease caused by adrenocorticotropic hormone (ACTH)-secreting adenomas of the pituitary gland (often termed pituitary adenomas). The majority of ACTH-secreting corticotroph tumors are sporadic and CD rarely appears as a familial disorder, thus, the genetic mechanisms underlying CD are poorly understood. Studies have reported that various mutated genes are associated with CD, such as those in menin 1, aryl hydrocarbon receptor-interacting protein and the nuclear receptor subfamily 3 group C member 1. Recently it was identified that ubiquitin-specific protease 8 mutations contribute to CD, which was significant towards elucidating the genetic mechanisms of CD. The present study reviews the associated gene mutations in CD patients. PMID:27588171

  6. Etude du processus de changement vecu par des familles ayant decide d'adopter volontairement des comportements d'attenuation des changements climatiques

    NASA Astrophysics Data System (ADS)

    Leger, Michel T.

    Les activites humaines energivores telles l'utilisation intensive de l'automobile, la surconsommation de biens et l'usage excessif d'electricite contribuent aux changements climatiques et autres problemes environnementaux. Bien que plusieurs recherches rapportent que l'etre humain est de plus en plus conscient de ses impacts sur le climat de la planete, ces memes recherches indiquent qu'en general, les gens continuent a se comporter de facon non ecologique. Que ce soit a l'ecole ou dans la communaute, plusieurs chercheurs en education relative a l'environnement estiment qu'une personne bien intentionnee est capable d'adopter des comportements plus respectueux de l'environnement. Le but de cette these etait de comprendre le processus d'integration de comportements d'attenuation des changements climatiques dans des familles. A cette fin, nous nous sommes fixe deux objectifs : 1) decrire les competences et les procedes qui favorisent l'adoption de comportements d'attenuation des changements climatiques dans des familles et 2) decrire les facteurs et les dynamiques familiales qui facilitent et limitent l'adoption de comportements d'attenuation des changements climatiques dans des familles. Des familles ont ete invitees a essayer des comportements personnels et collectifs d'attenuation des changements climatiques de sorte a integrer des modes de vie plus ecologiques. Sur une periode de huit mois, nous avons suivi leur experience de changement afin de mieux comprendre comment se produit le processus de changement dans des familles qui decident volontairement d'adopter des comportements d'attenuation des changements climatiques. Apres leur avoir fourni quelques connaissances de base sur les changements climatiques, nous avons observe le vecu de changement des familles durant huit mois d'essais a l'aide de journaux reflexifs, d'entretiens d'explicitation et du journal du chercheur. La these comporte trois articles scientifiques. Dans le premier article, nous presentons une

  7. Phenotypic clustering in MPZ mutations.

    PubMed

    Shy, Michael E; Jáni, Agnes; Krajewski, Karen; Grandis, Marina; Lewis, Richard A; Li, Jun; Shy, Rosemary R; Balsamo, Janne; Lilien, Jack; Garbern, James Y; Kamholz, John

    2004-02-01

    Myelin protein zero (MPZ) is a member of the immunoglobulin gene superfamily with single extracellular, transmembrane and cytoplasmic domains. Homotypic interactions between extracellular domains of MPZ adhere adjacent myelin wraps to each other. MPZ is also necessary for myelin compaction since mice which lack MPZ develop severe dysmyelinating neuropathies in which compaction is dramatically disrupted. MPZ mutations in humans cause the inherited demyelinating neuropathy CMT1B. Some mutations cause the severe neuropathies of infancy designated as Dejerine-Sottas disease, while others cause a 'classical' Charcot-Marie-Tooth (CMT) disease Type 1B (CMT1B) phenotype with normal early milestones but development of disability during the first two decades of life. Still other mutations cause a neuropathy that presents in adults, with normal nerve conduction velocities, designated as a 'CMT2' form of CMT1B. To correlate the phenotype of patients with MPZ mutations with their genotype, we identified and evaluated 13 patients from 12 different families with eight different MPZ mutations. In addition, we re-analysed the clinical data from 64 cases of CMT1B from the literature. Contrary to our expectations, we found that most patients presented with either an early onset neuropathy with signs and symptoms prior to the onset of walking or a late onset neuropathy with signs and symptoms at around age 40 years. Only occasional patients presented with a 'classical' CMT phenotype. Correlation of specific MPZ mutations with their phenotypes demonstrated that addition of either a charged amino acid or altering a cysteine residue in the extracellular domain caused a severe early onset neuropathy. Severe neuropathy was also caused by truncation of the cytoplasmic domain or alteration of an evolutionarily conserved amino acid. Taken together, these data suggest that early onset neuropathy is caused by MPZ mutations that significantly disrupt the tertiary structure of MPZ and thus

  8. La microscopie ionique analytique des tissus biologiques

    NASA Astrophysics Data System (ADS)

    Galle, P.

    Proposed in 1960 by R. Castaing and G. Slodzian, secondary ion emission microanalysis is a microanalytical method which is now largely used for the study of inert material. The instrument called the analytical ion microscope can also be used for the study of biological spécimens ; images representing the distribution of a given stable or radioactive isotope in a tissue section are obtained with a resolution of 0.5 μm. Among the characteristics of this method, two are of particular interest in biological research : its capacity for isotopic analysis and its very high sensitivity which makes possible for the first time a chemical analysis of element at a very low or even at a trace concentration in a microvolume. Proposé en 1960 par R. Castaing et G. Slodzian, la microanalyse par émission ionique secondaire est une méthode qui permet, entre autre, d'obtenir des images représentant la distribution des isotopes présents à la surface d'un échantillon solide avec une résolution de 0,5 μm. D'intérêt très général, cette méthode a été d'abord largement utilisée pour l'étude des matériaux inertes. Elle offre en outre des possibilités entièrement nouvelles dans le domaine de la recherche biomédicale. L'instrument réalisé, le microscope ionique analytique présente deux caractéristiques particulièrement intéressantes pour la biologie : la possibilité d'analyse isotopique, et l'extrême sensibilité permettant de détecter et de localiser dans une coupe histologique des éléments à des concentrations très faibles voire à l'état de trace.

  9. Elaboration de nouvelles approches micromecaniques pour l'optimisation des performances mecaniques des materiaux heterogenes

    NASA Astrophysics Data System (ADS)

    Aboutajeddine, Ahmed

    Les modeles micromecaniques de transition d'echelles qui permettent de determiner les proprietes effectives des materiaux heterogenes a partir de la microstructure sont consideres dans ce travail. L'objectif est la prise en compte de la presence d'une interphase entre la matrice et le renforcement dans les modeles micromecaniques classiques, de meme que la reconsideration des approximations de base de ces modeles, afin de traiter les materiaux multiphasiques. Un nouveau modele micromecanique est alors propose pour tenir compte de la presence d'une interphase elastique mince lors de la determination des proprietes effectives. Ce modele a ete construit grace a l'apport de l'equation integrale, des operateurs interfaciaux de Hill et de la methode de Mori-Tanaka. Les expressions obtenues pour les modules globaux et les champs dans l'enrobage sont de nature analytique. L'approximation de base de ce modele est amelioree par la suite dans un nouveau modele qui s'interesse aux inclusions enrobees avec un enrobage mince ou epais. La resolution utilisee s'appuie sur une double homogeneisation realisee au niveau de l'inclusion enrobee et du materiau. Cette nouvelle demarche, permettra d'apprehender completement les implications des approximations de la modelisation. Les resultats obtenus sont exploites par la suite dans la solution de l'assemblage de Hashin. Ainsi, plusieurs modeles micromecaniques classiques d'origines differentes se voient unifier et rattacher, dans ce travail, a la representation geometrique de Hashin. En plus de pouvoir apprecier completement la pertinence de l'approximation de chaque modele dans cette vision unique, l'extension correcte de ces modeles aux materiaux multiphasiques est rendue possible. Plusieurs modeles analytiques et explicites sont alors proposee suivant des solutions de differents ordres de l'assemblage de Hashin. L'un des modeles explicite apparait comme une correction directe du modele de Mori-Tanaka, dans les cas ou celui ci echoue a

  10. Étude des déplacements induits par des précipités dans des alliages à base de cuivre

    NASA Astrophysics Data System (ADS)

    Guillon, I.; Servant, C.; Lyon, O.

    2004-11-01

    Cette étude a pour but de mieux comprendre les premières étapes des phénomènes se produisant lors de la formation de nanoprécipités. En effet, la microstructure des alliages conditionne leurs propriétés mécaniques, et donc l'emploi de ces matériaux. Alors que l'anisotropie des déformations élastiques permet d'expliquer la morphologie des précipités formés lors des traitements thermiques de revenu, peu d'études se sont attachées à les déterminer expérimentalement. Mots clés : transformations de phases, diffusion/diffraction, synchrotron, alliages à base Cu, déplacements

  11. TRANSPLANTATION EN MASSE DES ORGANES ABDOMINAUX

    PubMed Central

    STARZL, T.

    2010-01-01

    Les transplantations multi-organes, comprenant les blocs foie-duodénum-pancréas, foie-estomac-duodénum-pancréas, et foie-intestin sont réalisées avec un succés croissant Ces techniques et leurs combinaisons variées de transplantation monobloc ne sont pas de pratique courante. Les techniques de prélévement, de conservation et de soins post-opératoires sont décrites pour la transplantation multi-organes compléte ainsi que pour les variantes incomplétes. Le probléme particulier à ce type de transplantation est celui de la transplantation intestinale, c’est-à-dire la transplantation d’un organe à composante lymphoréticulaire complexe ce qui peut provoquer un syndrome greffon contre hôte. Par erreur de conception, et un peu par esprit de systéme, les efforts par le passé étaient dirigés sur la modification et la destruction des systémes lymphoréticulaires grâce au traitement préalable du donneur ou des organes transplantés, par médicaments, radiation ou autres moyens. Actuellement, I’idée directrice est de garder intacte les systémes lymphoréticulaires qui deviennent alors le site d’une circulation à double sens aprés transplantation. Avec la puissante immunodépression que fournit le FK 506, les cellules lymphoréticulaires du donneur peuvent circuler chez le receveur sans créer de syndrome du greffon contre hôte clinique et les cellules de la greffe s’assimilent à celles du receveur (chimérisme local) sans provoquer de rejet. Même si I’on évite le rejet ou le syndrome greffon contre hôte, il existe, à côté de ces entités, des relations métaboliques entre les organes greffés ainsi qu’entre les organes greffés et les viscéres du receveur laissés en place, qui peuvent influencer I’avenir soit des organes greffés, soit des organes laissés en place. Parmi les échanges métaboliques les mieux connus actuellement, il y a les facteurs splanchniques hépatotrophes endogénes, dont I’insuline est la mieux

  12. A Magellanic origin of the DES dwarfs

    NASA Astrophysics Data System (ADS)

    Jethwa, P.; Erkal, D.; Belokurov, V.

    2016-09-01

    We establish the connection between the Magellanic Clouds (MCs) and the dwarf galaxy candidates discovered in the Dark Energy Survey (DES) by building a dynamical model of the MC satellite populations, based on an extensive suite of tailor-made numerical simulations. Our model takes into account the response of the Galaxy to the MCs infall, the dynamical friction experienced by the MCs and the disruption of the MC satellites by their hosts. The simulation suite samples over the uncertainties in the MC's proper motions, the masses of the MW and the Clouds themselves, and allows for flexibility in the intrinsic volume density distribution of the MC satellites. As a result, we can accurately reproduce the DES satellites' observed positions and kinematics. Assuming that Milky Way (MW) dwarfs follow the distribution of sub-haloes in Λ cold dark matter, we further demonstrate that, of 14 observed satellites, the MW halo contributes fewer than 4(8) of these with 68(95) per cent confidence and that 7(12) DES dwarfs have probabilities greater than 0.7(0.5) of belonging to the Large Magellanic Cloud (LMC). Marginalizing over the entire suite, we constrain the number of Magellanic satellites in the range -7 < MV < -1 which exceed the DES surface brightness threshold at ˜70, and the mass of the LMC around 1011 M⊙. The data also strongly support a first-infall scenario for the LMC. Finally, we give predictions for the line-of-sight velocities and the proper motions of the satellites discovered in the vicinity of the LMC.

  13. Peste des petits ruminants in Arabian wildlife.

    PubMed

    Kinne, J; Kreutzer, R; Kreutzer, M; Wernery, U; Wohlsein, P

    2010-08-01

    Recurrence of peste des petits ruminants (PPR) was diagnosed in the United Arabian Emirates in several wild ruminants confirmed by morphological, immunohistochemical, serological and molecular findings. Phylogenetic analysis revealed that the virus strain belongs to lineage IV, which is different to some previously isolated PPR strains from the Arabian Peninsula. This study shows that wild ruminants may play an important epidemiological role as virus source for domestic small ruminants.

  14. Inhomogeneites dans le Vent des Etoiles Wolf-Rayet

    NASA Astrophysics Data System (ADS)

    Robert, Carmelle

    1992-01-01

    Des mesures spectroscopiques effectuees avec un haut rapport signal sur bruit et une bonne resolution ont demontre l'existence de regions perturbees en mouvement dans le vent d'etoiles Wolf-Rayet (WR). L'echantillon d'objets etudies ici comprend 9 etoiles WR couvrant differents sous-types WN et WC. De nombreuses petites structures variables superposees au profil des raies d'emission formees dans le vent stellaire signalent la presence des perturbations. L'etude des variations globales des raies et l'examen des micro-structures individuelles ont permis de decrire plusieurs caracteristiques des perturbations. Entre autres, on observe des correlations significatives entre le niveau de variabilite des raies et certains parametres des etoiles qui confirment que le phenomene de variabilite est intrinseque au vent stellaire. En comparant les changements des vitesses radiales et des largeurs equivalentes des differentes raies d'une meme etoile, on conclut que les regions perturbees ont une etendue finie par rapport a l'enveloppe des etoiles. On peut facilement suivre les structures individuelles sur une periode de temps couvrant ~eq8 heures (et peut etre meme 24 heures) avant qu'elles ne disparaissent. Durant ce temps les structures se deplacent en s'eloignant du centre de la raie. A partir des differents comportements notes lors de l'analyse des variations globales et lors de l'examen des structures individuelles, on propose de representer les perturbations par un modele d'inhomogeneites discretes en expansion dans le vent. On suppose simplement que les inhomogeneites emettent comme le vent global (et absorbent aussi si le vent global montre un profil P Cyg). La superposition du graphique de l'acceleration radiale moyenne des inhomogeneites de WR140 en fonction de leur vitesse radiale et du modele theorique d'inhomogeneites qui suivent la loi generale de vitesse donne un taux d'acceleration lent, avec beta >= 3 pour les inhomogeneites de cette etoile. On obtient, entre

  15. Dermatomyosite et panniculite: place des immunoglobulines

    PubMed Central

    Abdelhafidh, Nadia Ben; Toujeni, Sana; Kefi, Asma; Bousetta, Najeh; Sayhi, Sameh; Gharsallah, Imen; Othmani, Salah

    2016-01-01

    La panniculite est une maladie inflammatoire du tissu adipeux sous-cutané rarement associée à la dermatomyosite. Elle peut survenir avant, après ou en même temps que l'atteinte musculaire. Dans la plupart des cas, l’évolution de la panniculite et des autres atteintes de la dermatomyosite est favorable sous traitement corticoïde et/ou immunosuppresseur. Nous rapportons le cas d'une patiente âgée de 48 ans ayant présenté des lésions de panniculite précédant de 2 mois les signes musculaires. L'atteinte cutanée était résistante au traitement corticoïde associés aux immunosuppresseurs ce qui a nécessité le recours au traitement par Immunoglobulines polyvalentes permettant ainsi une amélioration à la fois de l'atteinte cutanée et musculaire. PMID:27516827

  16. Profil anthropometrique des enfants scolarises tananariviens

    PubMed Central

    Razafimanantsoa, Fetralinjiva; Razafindramaro, Notahiana; Raherimandimby, Hasina; Robinson, Annick; RakotoAlson, Olivat; Rasamindrakotroka, Andry

    2013-01-01

    Les enfants tananariviens sont en état de malnutrition chronique. Notre objectif est d’évaluer l'indice de masse corporelle (IMC) pour estimer les enfants apparemment "sains". Une enquête et une mesure de la taille et du poids des enfants scolarisés tananariviens de 6 à 11 ans ont été réalisées. Après leur accord, la taille et l'indice de masse corporelle des 442 enfants tirés au hasard ont été ainsi obtenus. L'analyse de la moyenne de la taille a révélé une différence significative à 8 ans, une différence non évidente sur l'indice de masse corporelle. La comparaison avec les valeurs de référence (OMS 2006) a montré un retard statural de 34% avec une tendance globale à la hausse et un déficit pondéral égal à 5,5% selon le z score. Ainsi, au sein d'une population malnutrie, l'indice de masse corporelle pourrait être utilisé comme un des paramètres à considérer dans l’évaluation de l’état de santé pour classer ces enfants en bonne santé apparente. PMID:24711862

  17. Newtons Universum. Materialien zur Geschichte des Kraftbegriffes.

    NASA Astrophysics Data System (ADS)

    Mit einem Vorwort von E. Seibold und einer Einführung von W. Neuser. This book is a selection of 15 articles published in the journal "Spektrum der Wissenschaft". The original English versions of the papers were first published in "Scientific American". Contents: 1. Impetustheorie und Intuition in der Physik (M. McCloskey). 2. Mittelalterliche Ursprünge der industriellen Revolution (T. S. Reynolds). 3. Leonardo da Vincis Beiträge zur theoretischen Mechanik (V. Foley, W. Soedel). 4. Nikolaus Kopernikus und Tycho Brahe (O. Gingerich). 5. Keplers Entdeckung der ersten beiden Planetengesetze (C. Wilson). 6. Galileis Entdeckung des Fallgesetzes (S. Drake). 7. Galileis Beobachtung des Neptun (S. Drake, C. T. Kowal). 8. Galileo Galilei und der Schatten des Giordano Bruno (L. S. Lerner, E. A. Gosselin). 9. Der Fall Galilei (O. Gingerich). 10. Newtons Apfel und Galileis "Dialog" (S. Drake). 11. Newtons Gravitationsgesetz - aus Formeln wird eine Idee (I. B. Cohen). 12. Christopher Wren: Astronom und Architekt (H. Dorn, R. Mark). 13. Atomismus und Kräfte in der Geschichte (L. Holliday). 14. Ein Elitezirkel vor 200 Jahren: Die Lunar Society von Birmingham (L. Ritchie-Calder). 15. Sadi Carnot: Technik und Theorie der Dampfmaschine (S. S. Wilson).

  18. Sécurité au-delà des mythes et des croyances

    SciTech Connect

    2010-06-24

    Présentation orale en français, support visuel en français et en anglais. La pire des failles de sécurité est l'impression de sécurité. Le décalage entre la compréhension que l’on a des technologies utilisées, et leurs potentiels réels, ainsi que l'impact potentiellement négatif qu'elles peuvent avoir sur nos vies, n'est pas toujours compris, ou pris en compte par la plupart d'entre-nous. On se contente de nos perceptions pour ne pas avoir à se confronter à la réalité... Alors qu'en est-il vraiment ? En matière de sécurité qui de l'humain ou des technologies a le contrôle ?

  19. Paternité des articles et intérêts concurrents : une analyse des recommandations aux auteurs des journaux traitant de pratique pharmaceutique

    PubMed Central

    Courbon, Ève; Tanguay, Cynthia; Lebel, Denis; Bussières, Jean-François

    2014-01-01

    RÉSUMÉ Contexte : La présence d’auteurs honorifiques et fantômes ainsi que les intérêts concurrents représentent des difficultés bien documentées, liées à la publication d’articles scientifiques. Il existe des lignes directrices encadrant la rédaction et la publication de manuscrits scientifiques, notamment celles de l’International Committee of Medical Journal Editors (ICMJE). Objectifs : L’objectif principal de cette étude descriptive et transversale visait à recenser les instructions portant sur la paternité des articles et les intérêts concurrents provenant des recommandations aux auteurs des journaux traitant de pratique pharmaceutique. L’objectif secondaire visait à déterminer des mesures correctrices pour une paternité des articles plus transparente. Méthode : La recherche a débuté par l’identification des journaux traitant de pratique pharmaceutique. La consultation des instructions aux auteurs des journaux a permis ensuite de recenser les recommandations destinées à éviter les problèmes de paternité des articles et d’intérêts concurrents. Finalement, les membres de l’équipe de recherche se sont consultés afin de définir des mesures correctrices possibles à l’intention des chercheurs. Résultats : Des 232 journaux traitant de pharmacie, 33 ont été définis comme traitant de pratique pharmaceutique. Un total de 24 (73 %) journaux mentionnaient suivre la politique de l’ICMJE, 14 (42 %) demandaient aux auteurs de remplir un formulaire de déclaration d’intérêts concurrents au moment de la soumission de l’article, 17 (52 %) présentaient une définition de la qualité d’auteur et 5 (15 %) demandaient de détailler les contributions de chaque auteur. Une grille de 40 critères a été élaborée pour définir l’attribution du statut d’auteur. Conclusion : Moins de la moitié des journaux demandait aux auteurs de transmettre un formulaire de déclaration des intérêts concurrents au moment de la

  20. Radiation-induced mutation at minisatellite loci

    SciTech Connect

    Dubrova, Y.E. |; Nesterov, V.N.; Krouchinsky, N.G.

    1997-10-01

    We are studying the radiation-induced increase of mutation rate in minisatellite loci in mice and humans. Minisatellite mutations were scored by multilocus DNA fingerprint analysis in the progeny of {gamma}-irradiated and non-irradiated mice. The frequency of mutation in offspring of irradiated males was 1.7 higher that in the control group. Germline mutation at human minisatellite loci was studied among children born in heavily polluted areas of the Mogilev district of Belarus after the Chernobyl accident and in a control population. The frequency of mutation assayed both by DNA fingerprinting and by eight single locus probes was found to be two times higher in the exposed families than in the control group. Furthermore, mutation rate was correlated with the parental radiation dose for chronic exposure {sup 137}Cs, consistent with radiation-induction of germline mutation. The potential use of minisatellites in monitoring germline mutation in humans will be discussed.

  1. Signatures of mutational processes in human cancer

    PubMed Central

    Alexandrov, Ludmil B.; Nik-Zainal, Serena; Wedge, David C.; Aparicio, Samuel A.J.R.; Behjati, Sam; Biankin, Andrew V.; Bignell, Graham R.; Bolli, Niccolo; Borg, Ake; Børresen-Dale, Anne-Lise; Boyault, Sandrine; Burkhardt, Birgit; Butler, Adam P.; Caldas, Carlos; Davies, Helen R.; Desmedt, Christine; Eils, Roland; Eyfjörd, Jórunn Erla; Foekens, John A.; Greaves, Mel; Hosoda, Fumie; Hutter, Barbara; Ilicic, Tomislav; Imbeaud, Sandrine; Imielinsk, Marcin; Jäger, Natalie; Jones, David T.W.; Jones, David; Knappskog, Stian; Kool, Marcel; Lakhani, Sunil R.; López-Otín, Carlos; Martin, Sancha; Munshi, Nikhil C.; Nakamura, Hiromi; Northcott, Paul A.; Pajic, Marina; Papaemmanuil, Elli; Paradiso, Angelo; Pearson, John V.; Puente, Xose S.; Raine, Keiran; Ramakrishna, Manasa; Richardson, Andrea L.; Richter, Julia; Rosenstiel, Philip; Schlesner, Matthias; Schumacher, Ton N.; Span, Paul N.; Teague, Jon W.; Totoki, Yasushi; Tutt, Andrew N.J.; Valdés-Mas, Rafael; van Buuren, Marit M.; van ’t Veer, Laura; Vincent-Salomon, Anne; Waddell, Nicola; Yates, Lucy R.; Zucman-Rossi, Jessica; Futreal, P. Andrew; McDermott, Ultan; Lichter, Peter; Meyerson, Matthew; Grimmond, Sean M.; Siebert, Reiner; Campo, Elías; Shibata, Tatsuhiro; Pfister, Stefan M.; Campbell, Peter J.; Stratton, Michael R.

    2013-01-01

    All cancers are caused by somatic mutations. However, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here, we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, kataegis, is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer with potential implications for understanding of cancer etiology, prevention and therapy. PMID:23945592

  2. Signatures of mutational processes in human cancer.

    PubMed

    Alexandrov, Ludmil B; Nik-Zainal, Serena; Wedge, David C; Aparicio, Samuel A J R; Behjati, Sam; Biankin, Andrew V; Bignell, Graham R; Bolli, Niccolò; Borg, Ake; Børresen-Dale, Anne-Lise; Boyault, Sandrine; Burkhardt, Birgit; Butler, Adam P; Caldas, Carlos; Davies, Helen R; Desmedt, Christine; Eils, Roland; Eyfjörd, Jórunn Erla; Foekens, John A; Greaves, Mel; Hosoda, Fumie; Hutter, Barbara; Ilicic, Tomislav; Imbeaud, Sandrine; Imielinski, Marcin; Imielinsk, Marcin; Jäger, Natalie; Jones, David T W; Jones, David; Knappskog, Stian; Kool, Marcel; Lakhani, Sunil R; López-Otín, Carlos; Martin, Sancha; Munshi, Nikhil C; Nakamura, Hiromi; Northcott, Paul A; Pajic, Marina; Papaemmanuil, Elli; Paradiso, Angelo; Pearson, John V; Puente, Xose S; Raine, Keiran; Ramakrishna, Manasa; Richardson, Andrea L; Richter, Julia; Rosenstiel, Philip; Schlesner, Matthias; Schumacher, Ton N; Span, Paul N; Teague, Jon W; Totoki, Yasushi; Tutt, Andrew N J; Valdés-Mas, Rafael; van Buuren, Marit M; van 't Veer, Laura; Vincent-Salomon, Anne; Waddell, Nicola; Yates, Lucy R; Zucman-Rossi, Jessica; Futreal, P Andrew; McDermott, Ultan; Lichter, Peter; Meyerson, Matthew; Grimmond, Sean M; Siebert, Reiner; Campo, Elías; Shibata, Tatsuhiro; Pfister, Stefan M; Campbell, Peter J; Stratton, Michael R

    2013-08-22

    All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.

  3. Les effets du travail en equipe dans l'apprentissage par projets sur la motivation des etudiantes et des etudiants en formation des ingenieurs

    NASA Astrophysics Data System (ADS)

    Fernandez, Nicolas

    Les representants des secteurs industriels et les, milieux professionnels en Amerique du Nord reprochaient aux universites de former des ingenieurs avec peu d'experience pratique en resolution de problemes et en conception. Quelques programmes de genie ont alors mis en place le travail en equipe dans l'apprentissage par projets. Beaucoup d'ecrits font valoir les benefices de l'apprentissage par projets sur la motivation des etudiants. Or, ces benefices commencent a peine a faire l'objet de recherches visant a produire des donnees probantes a ce sujet. Les travaux sur la motivation en contexte d'apprentissage et les modeles theoriques developpes sont issus d'environnements d'apprentissage marques par l'enseignement magistral. Le modele de la valeur attendue de la tache (Eccles et Wigfield, 1995; Neuville, 2004) et le modele du systeme-groupe (St-Arnaud, 2008) ont ete retenus pour mesurer les effets du travail en equipe dans l'apprentissage par projets sur la motivation. La recherche visait aussi a approfondir et a nuancer la comprehension de la motivation des etudiants universitaires apprenant en contexte innovant. Les sujets constituent des etudiants (n=100) travaillant sur des projets d'integration au cours des trois sessions initiales du programme de genie mecanique d'une universite canadienne. L'analyse de regression multiple revele que les construits de la motivation expliquent un tiers de la variance de l'engagement academique dans la realisation du projet d'integration. Les perceptions de l' "expectancy", de la valeur intrinseque et utilitaire sont les determinants principaux de l'engagement des etudiants. L'analyse de variance multivariee a mesures repetees indique que la motivation des etudiants pour le travail sur les projets d'integration a augmente au cours des trois sessions initiales du parcours de formation. Finalement, malgre l'absence d'interaction significative entre les variables de motivation et de l'equipe, les reponses des sujets indiquent une

  4. Etude des phenomenes dynamiques ultrarapides et des caracteristiques impulsionnelles d'emission terahertz du supraconducteur YBCO

    NASA Astrophysics Data System (ADS)

    Savard, Stephane

    Les premieres etudes d'antennes a base de supraconducteurs a haute temperature critique emettant une impulsion electromagnetique dont le contenu en frequence se situe dans le domaine terahertz remontent a 1996. Une antenne supraconductrice est formee d'un micro-pont d'une couche mince supraconductrice sur lequel un courant continu est applique. Un faisceau laser dans le visible est focalise sur le micro-pont et place le supraconducteur dans un etat hors-equilibre ou des paires sont brisees. Grace a la relaxation des quasiparticules en surplus et eventuellement de la reformation des paires supraconductrices, nous pouvons etudier la nature de la supraconductivite. L'analyse de la cinetique temporelle du champ electromagnetique emis par une telle antenne terahertz supraconductrice s'est averee utile pour decrire qualitativement les caracteristiques de celle-ci en fonction des parametres d'operation tels que le courant applique, la temperature et la puissance d'excitation. La comprehension de l'etat hors-equilibre est la cle pour comprendre le fonctionnement des antennes terahertz supraconductrices a haute temperature critique. Dans le but de comprendre ultimement cet etat hors-equilibre, nous avions besoin d'une methode et d'un modele pour extraire de facon plus systematique les proprietes intrinseques du materiau qui compose l'antenne terahertz a partir des caracteristiques d'emission de celle-ci. Nous avons developpe une procedure pour calibrer le spectrometre dans le domaine temporel en utilisant des antennes terahertz de GaAs bombarde aux protons H+ comme emetteur et detecteur. Une fois le montage calibre, nous y avons insere une antenne emettrice dipolaire de YBa 2Cu3O7-delta . Un modele avec des fonctions exponentielles de montee et de descente du signal est utilise pour lisser le spectre du champ electromagnetique de l'antenne de YBa 2Cu3O7-delta, ce qui nous permet d'extraire les proprietes intrinseques de ce dernier. Pour confirmer la validite du modele

  5. MECHANISMS OF STATIONARY PHASE MUTATION: A Decade of Adaptive Mutation

    PubMed Central

    Foster, P. L.

    2010-01-01

    A decade of research on adaptive mutation has revealed a plethora of mutagenic mechanisms that may be important in evolution. The DNA synthesis associated with recombination could be an important source of spontaneous mutation in cells that are not proliferating. The movement of insertion elements can be responsive to environmental conditions. Insertion elements not only activate and inactivate genes, they also provide sequence homology that allows large-scale genomic rearrangements. Some conjugative plasmids can recombine with their host’s chromosome, and may acquire chromosomal genes that could then spread through the population and even to other species. Finally, a subpopulation of transient hypermutators could be a source of multiple variant alleles, providing a mechanism for rapid evolution under adverse conditions. PMID:10690404

  6. Tracking Down Mutations Cell by Cell.

    PubMed

    Kosik, Kenneth S

    2016-03-16

    Using somatic cell nuclear transfer, Hazen et al. (2016) examined clonally expanded single neurons for mutations and found ∼100 mutations from a variety of classes. Post-mitotic mutations in individual neurons represent an exploratory direction for finding fundamental origins of neurodegeneration. PMID:26985720

  7. Mutation rate evolution in replicator dynamics.

    PubMed

    Allen, Benjamin; Rosenbloom, Daniel I Scholes

    2012-11-01

    The mutation rate of an organism is itself evolvable. In stable environments, if faithful replication is costless, theory predicts that mutation rates will evolve to zero. However, positive mutation rates can evolve in novel or fluctuating environments, as analytical and empirical studies have shown. Previous work on this question has focused on environments that fluctuate independently of the evolving population. Here we consider fluctuations that arise from frequency-dependent selection in the evolving population itself. We investigate how the dynamics of competing traits can induce selective pressure on the rates of mutation between these traits. To address this question, we introduce a theoretical framework combining replicator dynamics and adaptive dynamics. We suppose that changes in mutation rates are rare, compared to changes in the traits under direct selection, so that the expected evolutionary trajectories of mutation rates can be obtained from analysis of pairwise competition between strains of different rates. Depending on the nature of frequency-dependent trait dynamics, we demonstrate three possible outcomes of this competition. First, if trait frequencies are at a mutation-selection equilibrium, lower mutation rates can displace higher ones. Second, if trait dynamics converge to a heteroclinic cycle-arising, for example, from "rock-paper-scissors" interactions-mutator strains succeed against non-mutators. Third, in cases where selection alone maintains all traits at positive frequencies, zero and nonzero mutation rates can coexist indefinitely. Our second result suggests that relatively high mutation rates may be observed for traits subject to cyclical frequency-dependent dynamics.

  8. Mutation analysis in patients with Wilson disease: identification of 4 novel mutations. Mutation in brief no. 250. Online.

    PubMed

    Haas, R; Gutierrez-Rivero, B; Knoche, J; Böker, K; Manns, M P; Schmidt, H H

    1999-01-01

    In order to obtain novel mutations in the recently discovered Wilson disease gene, we screened 5 unrelated German individuals for mutations in the 21 exons and their flanking intronic sequences. We detected 9 mutations affecting the Wilson disease gene. Four of those, designated 802-808delTGTAAGT, 2008-2013delTATATG, Cys985Thr, and Ile1148Thr have not yet been reported. One patient had a homozygous mutation whereas the remaining four subjects were compound heterozygous. Therefore these data confirm, that mutations causing Wilson disease are frequently found in affected subjects and they are very heterogenous. PMID:10447265

  9. Plastome Mutations and Recombination Events in Barley Chloroplast Mutator Seedlings.

    PubMed

    Landau, Alejandra; Lencina, Franco; Pacheco, María G; Prina, Alberto R

    2016-05-01

    The barley chloroplast mutator (cpm) is an allele of a nuclear gene that when homozygous induces several types of cytoplasmically inherited chlorophyll deficiencies. In this work, a plastome Targeting Induced Local Lesions in Genomes (TILLING) strategy based on mismatch digestion was used on families that carried the cpm genotype through many generations. Extensive scanning of 33 plastome genes and a few intergenic regions was conducted. Numerous polymorphisms were detected on both genic and intergenic regions. The detected polymorphisms can be accounted for by at least 61 independent mutational events. The vast majority of the polymorphisms originated in substitutions and small indels (insertions/deletions) in microsatellites. The rpl23 and the rps16 genes were the most polymorphic. Interestingly, the variation observed in the rpl23 gene consisted of several combinations of 5 different one nucleotide polymorphisms. Besides, 4 large indels that have direct repeats at both ends were also observed, which appear to be originated from recombinational events. The cpm mutation spectrum suggests that the CPM gene product is probably involved in plastome mismatch repair. The numerous subtle molecular changes that were localized in a wide range of plastome sites show the cpm as a valuable source of plastome variability for plant research and/or plant breeding. Moreover, the cpm mutant appears to be an interesting experimental material for investigating the mechanisms responsible for maintaining the stability of plant organelle DNA.

  10. Interplay of mutation and disassortativity

    NASA Astrophysics Data System (ADS)

    Dwivedi, Sanjiv K.; Jalan, Sarika

    2015-08-01

    Despite disassortativity being commonly observed in many biological networks, our current understanding of its evolutionary origin is inadequate. Motivated by the occurrence of mutations during an evolutionary time span that results in changes in the behavior of interactions, we demonstrate that if we maximize the stability of the underlying system, the genetic algorithm leads to the evolution of a disassortative structure. The mutation probability governs the degree of saturation of the disassortativity coefficient, and this reveals the origin of the wide range of disassortativity values found in real systems. We analytically verify these results for star networks, and by considering various values for the antisymmetric couplings, we find a regime in which scale-free networks are more stable than the corresponding random networks.

  11. Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype.

    PubMed

    Worgan, Lisa C; Niles, Kirsten; Tirone, Jamie C; Hofmann, Adam; Verner, Andrei; Sammak, Alya'a; Kucic, Terrence; Lepage, Pierre; Rosenblatt, David S

    2006-01-01

    Cobalamin nonresponsive methylmalonic acidemia (MMA, mut complementation class) results from mutations in the nuclear gene MUT, which codes for the mitochondrial enzyme methylmalonyl CoA mutase (MCM). To better elucidate the spectrum of mutations that cause MMA, the MUT gene was sequenced in 160 patients with mut MMA. Sequence analysis identified mutations in 96% of disease alleles. Mutations were found in all coding exons, but predominantly in exons 2, 3, 6, and 11. A total of 116 different mutations, 68 of which were novel, were identified. Of the 116 different mutations, 53% were missense mutations, 22% were deletions, duplications or insertions, 16% were nonsense mutations, and 9% were splice-site mutations. Sixty-one of the mutations have only been identified in one family. A novel mutation in exon 2, c.322C>T (p.R108C), was identified in 16 of 27 Hispanic patients. SNP genotyping data demonstrated that Hispanic patients with this mutation share a common haplotype. Three other mutations were seen exclusively in Hispanic patients: c.280G>A (p.G94R), c.1022dupA, and c.970G>A (p.A324T). Seven mutations were seen almost exclusively in black patients, including the previously reported c.2150G>T (p.G717V) mutation, which was identified in 12 of 29 black patients. Two mutations were seen only in Asian patients. Some frequently identified mutations were not population-specific and were identified in patients of various ethnic backgrounds. Some of these mutations were found in mutation clusters in exons 2, 3, 6, and 11, suggesting a recurrent mutation.

  12. Tailoring the metabolism against mutations

    NASA Astrophysics Data System (ADS)

    Gulbahce, Natali; Motter, Adilson E.; Almaas, Eivind; Barabasi, Albert Laszlo

    2008-03-01

    In the post-genomic era, organisms can be modelled at the whole-cell level in silico via steady state methods to describe their metabolic capabilities. We use two such methods, Flux Balance Analysis and Minimization of Metabolic Adjustment to explore the behavior of cells (of E. coli and S. cerevisiae) after severe mutations. We propose experimentally feasible ways of modifying the underlying biochemical reaction network of a mutant cell such that cell functionality, in particular growth rate, is significantly improved.

  13. [Pathologic manifestations of hormonal receptor mutations].

    PubMed

    Milgrom, E

    2000-01-01

    Mutations of receptor genes are involved in various aspects of thyroid and gonadal pathology. Activating mutations of TSH and LH receptors are associated with hyperthyroidism and premature puberty. These mutations are dominant and lead to the synthesis of a constitutive receptor, i.e. a receptor active even in the absence of hormone. Inactivating mutations of TSH, gonadotropin and GnRH receptors are recessive. They determine either a hypothyroidism or a hypogonadism. In the case of alterations of gonadotropin receptors the hypogonadism is hypergonadotrophic. It is hypogonadotrophic in the case of mutations of the GnRH receptor. PMID:10989556

  14. Somatic mutation, genomic variation, and neurological disease.

    PubMed

    Poduri, Annapurna; Evrony, Gilad D; Cai, Xuyu; Walsh, Christopher A

    2013-07-01

    Genetic mutations causing human disease are conventionally thought to be inherited through the germ line from one's parents and present in all somatic (body) cells, except for most cancer mutations, which arise somatically. Increasingly, somatic mutations are being identified in diseases other than cancer, including neurodevelopmental diseases. Somatic mutations can arise during the course of prenatal brain development and cause neurological disease-even when present at low levels of mosaicism, for example-resulting in brain malformations associated with epilepsy and intellectual disability. Novel, highly sensitive technologies will allow more accurate evaluation of somatic mutations in neurodevelopmental disorders and during normal brain development.

  15. Somatic Mutation, Genomic Variation, and Neurological Disease

    PubMed Central

    Poduri, Annapurna; Evrony, Gilad D.; Cai, Xuyu; Walsh, Christopher A.

    2014-01-01

    Genetic mutations causing human disease are conventionally thought to be inherited through the germ line from one’s parents and present in all somatic (body) cells, except for most cancer mutations, which arise somatically. Increasingly, somatic mutations are being identified in diseases other than cancer, including neurodevelopmental diseases. Somatic mutations can arise during the course of prenatal brain development and cause neurological disease—even when present at low levels of mosaicism, for example—resulting in brain malformations associated with epilepsy and intellectual disability. Novel, highly sensitive technologies will allow more accurate evaluation of somatic mutations in neurodevelopmental disorders and during normal brain development. PMID:23828942

  16. Etude des defauts microscopiques et des proprietes optiques, electroniques et magnetiques du compose neodyme cerium oxyde de cuivre

    NASA Astrophysics Data System (ADS)

    Richard, Pierre

    La presente these, qui combine des mesures de diffusion Raman, de transmission infrarouge, de conductivite hyperfrequence et d'interferometrie ultrasonore sur les composes Nd 2-xCexCuO 4, traite des defauts d'oxygene, ainsi que des proprietes optiques, electroniques et magnetiques de ces materiaux. Les resultats experimentaux obtenus sont correles avec plusieurs donnees experimentales disponibles dans la litterature. D'abord, la caracterisation des modes Raman et des niveaux d'energie de champ cristallin de l'ion Nd3+ au moyen de techniques optiques, en fonction du dopage en cerium et du contenu en oxygene, permettent de conclure a la presence de defauts lies a une non-stoechiometrie en oxygene dans ces composes. En effet, des excitations de champ cristallin assignees a des ions Nd3+ en sites irreguliers sont observees, en plus des bandes d'absorption associees aux ions Nd3+ en site regulier, dans les spectres correspondant aux multiplets 4I11/2, 4I13/2 et 4I 15/2 de l'ion Nd3+. Les resultats experimentaux indiquent que, contrairement a la croyance largement repandue, les oxygenes apicaux, bien que presents dans les echantillons dopes, ne sont pas enleves lors du processus de reduction des echantillons necessaire pour faire apparaitre la supraconductivite dans cette famille de cuprates. Au contraire, des lacunes d'oxygene, dont le type varie en fonction du dopage, sont creees lors de ce processus. En particulier, il est montre dans ce travail que la reduction des echantillons dopes de maniere optimale conduit a la creation de lacunes d'oxygene dans les plans CuO2. Les consequences de telles lacunes sont largement discutees. En outre, il est suggere que de telles lacunes sont responsables de la perte de l'ordre antiferromagnetique a longue portee des ions Cu2+. Finalement, l'interaction d'echange anisotrope Nd3+-Cu 2+ dans le compose nondope est caracterisee au moyen de la transmission infrarouge sous champ magnetique. L'eclatement des doublets de Kramers mesure

  17. LHON: Mitochondrial Mutations and More.

    PubMed

    Kirches, E

    2011-03-01

    Leber's hereditary optic neuropathy (LHON) is a mitochondrial disorder leading to severe visual impairment or even blindness by death of retinal ganglion cells (RGCs). The primary cause of the disease is usually a mutation of the mitochondrial genome (mtDNA) causing a single amino acid exchange in one of the mtDNA-encoded subunits of NADH:ubiquinone oxidoreductase, the first complex of the electron transport chain. It was thus obvious to accuse neuronal energy depletion as the most probable mediator of neuronal death. The group of Valerio Carelli and other authors have nicely shown that energy depletion shapes the cell fate in a LHON cybrid cell model. However, the cybrids used were osteosarcoma cells, which do not fully model neuronal energy metabolism. Although complex I mutations may cause oxidative stress, a potential pathogenetic role of the latter was less taken into focus. The hypothesis of bioenergetic failure does not provide a simple explanation for the relatively late disease onset and for the incomplete penetrance, which differs remarkably between genders. It is assumed that other genetic and environmental factors are needed in addition to the 'primary LHON mutations' to elicit RGC death. Relevant nuclear modifier genes have not been identified so far. The review discusses the unresolved problems of a pathogenetic hypothesis based on ATP decline and/or ROS-induced apoptosis in RGCs.

  18. Les neuropeptides gastro-intestinaux cibles des effets des rayonnements ionisants : altérations fonctionnelles

    NASA Astrophysics Data System (ADS)

    Linard, C.; Esposito, V.; Wysocki, J.; Griffiths, N. M.

    1998-04-01

    The symptoms associated with exposure to ionizing radiation are nausea, vomiting, diarrhoea. The response of the gut is complex involving modifications of motility and fluid and electrolyte transport. Gastrointestinal regulatory peptides have an important role in these functions. This study showed that radiation-induced tissue variations of neuropeptides have some repercussions on intestinal biological activity of these peptides soon after irradiation. In addition such modifications are also seen a few years after irradiation. Les symptômes associés à l'exposition aux rayonnements ionisants sont des nausées, vomissements et diarrhées. La réponse du système digestif est complexe, impliquant des modifications de la motilité et du transport d'eau et d'électrolytes. les neuropeptides gastro-intestinaux ont un rôle important dans ces fonctions. Cette étude montre que les variations tissulaires de ces neuropeptides induites par l'irradiation ont des répercussions sur l'activité biologique intestinale pour des temps précoces mais que ces perturbations sont encore visibles quelques années après l'irradiation.

  19. Comparaison des effets des irradiations γ, X et UV dans les fibres optiques

    NASA Astrophysics Data System (ADS)

    Girard, S.; Ouerdane, Y.; Baggio, J.; Boukenter, A.; Meunier, J.-P.; Leray, J.-L.

    2005-06-01

    Les fibres optiques présentent de nombreux avantages incitant à les intégrer dans des applications devant résister aux environnements radiatifs associés aux domaines civil, spatial ou militaire. Cependant, leur exposition à un rayonnement entraîne la création de défauts ponctuels dans la silice amorphe pure ou dopée qui constitue les différentes parties de la fibre optique. Ces défauts causent, en particulier, une augmentation transitoire de l'atténuation linéique des fibres optiques responsable de la dégradation voire de la perte du signal propagé dans celles-ci. Dans cet article, nous comparons les effets de deux types d'irradiation: une impulsion X et une dose γ cumulée. Les effets de ces irradiations sont ensuite comparés avec ceux induits par une insolation ultraviolette (244 nm) sur les propriétés d'absorption des fibres optiques. Nous montrons qu'il existe des similitudes entre ces différentes excitations et qu'il est possible, sous certaines conditions, d'utiliser celles-ci afin d'évaluer la capacité de certaines fibres optiques à fonctionner dans un environnement nucléaire donné.

  20. 1. ORIGINAL STONE ARCH BRIDGE OVER THE DES PLAINES RIVER ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    1. ORIGINAL STONE ARCH BRIDGE OVER THE DES PLAINES RIVER AT NINTH STREET IN LOCKPORT. THE BRIDGE WAS BUILT ABOUT 1865. NOTE METAL CLAMP ON THE NEAR PIER AND THE 20TH CENTURY REINFORCED CONCRETE ADDITION. - Lockport Historic District, Stone Arch Bridge, Spanning Des Plaines River at Ninth Street, Lockport, Will County, IL

  1. Vers des boites quantiques a base de graphene

    NASA Astrophysics Data System (ADS)

    Branchaud, Simon

    Le graphene est un materiau a base de carbone qui est etudie largement depuis 2004. De tres nombreux articles ont ete publies tant sur les proprietes electroniques, qu'optiques ou mecaniques de ce materiel. Cet ouvrage porte sur l'etude des fluctuations de conductance dans le graphene, et sur la fabrication et la caracterisation de nanostructures gravees dans des feuilles de ce cristal 2D. Des mesures de magnetoresistance a basse temperature ont ete faites pres du point de neutralite de charge (PNC) ainsi qu'a haute densite electronique. On trouve deux origines aux fluctuations de conductance pres du PNC, soit des oscillations mesoscopiques provenant de l'interference quantique, et des fluctuations dites Hall quantique apparaissant a plus haut champ (>0.5T), semblant suivre les facteurs de remplissage associes aux monocouches de graphene. Ces dernieres fluctuations sont attribuees a la charge d'etats localises, et revelent un precurseur a l'effet Hall quantique, qui lui, ne se manifeste pas avant 2T. On arrive a extraire les parametres caracterisant l'echantillon a partir de ces donnees. A la fin de cet ouvrage, on effectue des mesures de transport dans des constrictions et ilots de graphene, ou des boites quantiques sont formees. A partir de ces mesures, on extrait les parametres importants de ces boites quantiques, comme leur taille et leur energie de charge.

  2. Peste des petits ruminants virus in Heilongjiang province, China, 2014.

    PubMed

    Wang, Jingfei; Wang, Miao; Wang, Shida; Liu, Zaisi; Shen, Nan; Si, Wei; Sun, Gang; Drewe, Julian A; Cai, Xuehui

    2015-04-01

    During March 25-May 5, 2014, we investigated 11 outbreaks of peste des petits ruminants in Heilongjiang Province, China. We found that the most likely source of the outbreaks was animals from livestock markets in Shandong. Peste des petits ruminants viruses belonging to lineages II and IV were detected in sick animals. PMID:25811935

  3. Peste des petits ruminants virus in Heilongjiang province, China, 2014.

    PubMed

    Wang, Jingfei; Wang, Miao; Wang, Shida; Liu, Zaisi; Shen, Nan; Si, Wei; Sun, Gang; Drewe, Julian A; Cai, Xuehui

    2015-04-01

    During March 25-May 5, 2014, we investigated 11 outbreaks of peste des petits ruminants in Heilongjiang Province, China. We found that the most likely source of the outbreaks was animals from livestock markets in Shandong. Peste des petits ruminants viruses belonging to lineages II and IV were detected in sick animals.

  4. The evolution of low mutation rates in experimental mutator populations of Saccharomyces cerevisiae.

    PubMed

    McDonald, Michael J; Hsieh, Yu-Ying; Yu, Yen-Hsin; Chang, Shang-Lin; Leu, Jun-Yi

    2012-07-10

    Mutation is the source of both beneficial adaptive variation and deleterious genetic load, fueling the opposing selective forces than shape mutation rate evolution. This dichotomy is well illustrated by the evolution of the mutator phenotype, a genome-wide 10- to 100-fold increase in mutation rate. This phenotype has often been observed in clonally expanding populations exposed to novel or frequently changing conditions. Although studies of both experimental and natural populations have shed light on the evolutionary forces that lead to the spread of the mutator allele through a population, significant gaps in our understanding of mutator evolution remain. Here we use an experimental evolution approach to investigate the conditions required for the evolution of a reduction in mutation rate and the mechanisms by which populations tolerate the accumulation of deleterious mutations. We find that after ∼6,700 generations, four out of eight experimental mutator lines had evolved a decreased mutation rate. We provide evidence that the accumulation of deleterious mutations leads to selection for reduced mutation rate clones in populations of mutators. Finally, we test the long-term consequences of the mutator phenotype, finding that mutator lines follow different evolutionary trajectories, some of which lead to drug resistance.

  5. Myopathies associated with β-tropomyosin mutations.

    PubMed

    Tajsharghi, H; Ohlsson, M; Palm, L; Oldfors, A

    2012-11-01

    Mutations in TPM2, encoding β-tropomyosin, have recently been found to cause a range of muscle disorders. We review the clinical and morphological expression of the previously reported mutations illustrating the heterogeneity of β-tropomyosin-associated diseases and describe an additional case with a novel mutation. The manifestations of mutations in TPM2 include non-specific congenital myopathy with type 1 fibre predominance, nemaline myopathy, cap disease and distal arthrogryposis. In addition, Escobar syndrome with nemaline myopathy is a manifestation of homozygous truncating β-tropomyosin mutation. Cap disease appears to be the most common morphological manifestation. A coarse intermyofibrillar network and jagged Z lines are additional frequent changes. The dominant β-tropomyosin mutations manifest either as congenital myopathy or distal arthrogryposis. The various congenital myopathies are usually associated with moderate muscle weakness and no congenital joint contractures. The distal arthrogryposis syndromes associated with TPM2 mutations include the less severe forms, with congenital contractures mainly of the hands and feet and mild or no muscle weakness. The dominant TPM2 mutations include amino acid deletions/insertions and missense mutations. There is no clear relation between the type of mutations or the localisation of the mutated residue in the β-tropomyosin molecule and the clinical and morphological phenotype. PMID:22749895

  6. Mechanisms of Mutation in Nondividing Cells

    PubMed Central

    Foster, Patricia L.; Rosche, William A.

    2010-01-01

    When populations of cells are subjected to nonlethal selection, mutations arise in the absence of cell division, a phenomenon that has been called “adaptive mutation.” In a strain of Escherichia coli that cannot metabolize lactose (Lac−) but that reverts to lactose utilization (Lac+) when lactose is its sole energy and carbon source, the mutational process consists of two components. (1) A highly efficient, recombination-dependent mechanism giving rise to mutations on the F′ episome that carries the Lac− allele; and (2) a less efficient, unknown mechanism giving rise to mutations elsewhere in the genome. Both selected and nonselected mutations arise in the Lac− population, but nonselected mutations are enriched in Lac+ mutants, suggesting that some Lac+ cells have passed though a transient period of increased mutation. These results have several evolutionary implications. (1) DNA synthesis initiated by recombination could be an important source of spontaneous mutation, particularly in cells that are not undergoing genomic replication. (2) The highly active mutational mechanism on the episome could be important in the horizontal transfer of variant alleles among species that carry and exchange conjugal plasmids. (3) A subpopulation of cells in a state of transient mutation could be a source of multiple variant alleles and could provide a mechanism for rapid adaptive evolution under adverse conditions. PMID:10415479

  7. KRAS mutation testing in clinical practice.

    PubMed

    Perincheri, Sudhir; Hui, Pei

    2015-03-01

    Activating mutation of KRAS plays a significant role in the pathogenesis of common human malignancies and molecular testing of KRAS mutation has emerged as an essential biomarker in the current practice of clinical oncology. The presence of KRAS mutation is generally associated with clinical aggressiveness of the cancer and reduced survival of the patient. Therapeutically, KRAS mutation testing has maximum utility in stratifying metastatic colorectal carcinoma and lung cancer patients for treatment with targeted therapy. Diagnostically, KRAS mutation testing is useful in the workup of pancreaticobiliary and thyroid cancers, particularly using cytological specimens. In the era of precision medicine, the role of KRAS mutation testing is poised to expand, likely in a setting of combinatorial therapeutic strategy and requiring additional mutation testing of its upstream and/or downstream effectors.

  8. Androgen receptor gene mutation, rearrangement, polymorphism.

    PubMed

    Eisermann, Kurtis; Wang, Dan; Jing, Yifeng; Pascal, Laura E; Wang, Zhou

    2013-09-01

    Genetic aberrations of the androgen receptor (AR) caused by mutations, rearrangements, and polymorphisms result in a mutant receptor that has varied functions compared to wild type AR. To date, over 1,000 mutations have been reported in the AR with most of these being associated with androgen insensitivity syndrome (AIS). While mutations of AR associated with prostate cancer occur less often in early stage localized disease, mutations in castration-resistant prostate cancer (CRPC) patients treated with anti-androgens occur more frequently with 10-30% of these patients having some form of mutation in the AR. Resistance to anti-androgen therapy usually results from gain-of-function mutations in the LBD such as is seen with bicalutamide and more recently with enzalutamide (MDV3100). Thus, it is crucial to investigate these new AR mutations arising from drug resistance to anti-androgens and other small molecule pharmacological agents.

  9. Etude du processus de changement vecu par des familles ayant decide d'adopter volontairement des comportements d'attenuation des changements climatiques

    NASA Astrophysics Data System (ADS)

    Leger, Michel T.

    Les activites humaines energivores telles l'utilisation intensive de l'automobile, la surconsommation de biens et l'usage excessif d'electricite contribuent aux changements climatiques et autres problemes environnementaux. Bien que plusieurs recherches rapportent que l'etre humain est de plus en plus conscient de ses impacts sur le climat de la planete, ces memes recherches indiquent qu'en general, les gens continuent a se comporter de facon non ecologique. Que ce soit a l'ecole ou dans la communaute, plusieurs chercheurs en education relative a l'environnement estiment qu'une personne bien intentionnee est capable d'adopter des comportements plus respectueux de l'environnement. Le but de cette these etait de comprendre le processus d'integration de comportements d'attenuation des changements climatiques dans des familles. A cette fin, nous nous sommes fixe deux objectifs : 1) decrire les competences et les procedes qui favorisent l'adoption de comportements d'attenuation des changements climatiques dans des familles et 2) decrire les facteurs et les dynamiques familiales qui facilitent et limitent l'adoption de comportements d'attenuation des changements climatiques dans des familles. Des familles ont ete invitees a essayer des comportements personnels et collectifs d'attenuation des changements climatiques de sorte a integrer des modes de vie plus ecologiques. Sur une periode de huit mois, nous avons suivi leur experience de changement afin de mieux comprendre comment se produit le processus de changement dans des familles qui decident volontairement d'adopter des comportements d'attenuation des changements climatiques. Apres leur avoir fourni quelques connaissances de base sur les changements climatiques, nous avons observe le vecu de changement des familles durant huit mois d'essais a l'aide de journaux reflexifs, d'entretiens d'explicitation et du journal du chercheur. La these comporte trois articles scientifiques. Dans le premier article, nous presentons une

  10. Etude des systèmes protoplanétaires

    NASA Astrophysics Data System (ADS)

    Augereau, Jean-Charles

    2000-11-01

    Les disques de poussières et de gaz autour des étoiles rejoignant la Séquence Principale sont les sites de formation des planètes extra-solaires dont l'existence s'est vu confirmée récemment. Cette thèse aborde l'étude de la poussière des environnements circumstellaires. Elle associe des observations spatiales à haute résolution angulaire, la modélisation des propriétés physico-chimiques des poussières et leur comportement optique, la modélisation des disques optiquement fins et la dynamique des planétésimaux à l'origine des grains observés autour des étoiles âgées. Les images obtenues avec le Télescope Spatial Hubble révèlent deux nouveaux disques circumstellaires autour des étoiles HD 141569 et HD 100546, parfois classées dans la catégorie des étoiles de Herbig. Bien que les systèmes présentent des âges proches (~10 millions d'années), les morphologies très différentes des disques mettent en évidence la difficulté pour élaborer un scénario unique d'évolution des systèmes protoplanétaires. L'anneau fin de poussières autour de HR 4796A, une étoile d'âge similaire aux précédentes, est marginalement résolu depuis le sol. La modélisation complète de ce disque permet de reproduire l'ensemble des observations disponibles. Ces résultats impliquent la présence de planétésimaux, à un âge aussi peu avancé, pour repeupler le disque en poussières poreuses et essentiellement amorphes qui sont soufflées par la pression de radiation. Une modélisation dynamique du prototypique disque autour de β Pictoris est proposée. Associée à une description réaliste du comportement optique des grains, cette approche reproduit les caractéristiques générales du disque ainsi que des asymétries plus fines en supposant la présence d'une planète dans un disque de planétésimaux et en tenant compte des effets différentiels de la pression de radiation sur les grains. Enfin, le modèle de disques que j'ai développé est exploit

  11. Etude de la dynamique des porteurs dans des nanofils de silicium par spectroscopie terahertz

    NASA Astrophysics Data System (ADS)

    Beaudoin, Alexandre

    Ce memoire presente une etude des proprietes de conduction electrique et de la dynamique temporelle des porteurs de charges dans des nanofils de silicium sondes par rayonnement terahertz. Les cas de nanofils de silicium non intentionnellement dopes et dopes type n sont compares pour differentes configurations du montage experimental. Les mesures de spectroscopie terahertz en transmission montre qu'il est possible de detecter la presence de dopants dans les nanofils via leur absorption du rayonnement terahertz (˜ 1--12 meV). Les difficultes de modelisation de la transmission d'une impulsion electromagnetique dans un systeme de nanofils sont egalement discutees. La detection differentielle, une modification au systeme de spectroscopie terahertz, est testee et ses performances sont comparees au montage de caracterisation standard. Les instructions et des recommendations pour la mise en place de ce type de mesure sont incluses. Les resultats d'une experience de pompe optique-sonde terahertz sont egalement presentes. Dans cette experience, les porteurs de charge temporairement crees suite a l'absorption de la pompe optique (lambda ˜ 800 nm) dans les nanofils (les photoporteurs) s'ajoutent aux porteurs initialement presents et augmentent done l'absorption du rayonnement terahertz. Premierement, l'anisotropie de l'absorption terahertz et de la pompe optique par les nanofils est demontree. Deuxiemement, le temps de recombinaison des photoporteurs est etudie en fonction du nombre de photoporteurs injectes. Une hypothese expliquant les comportements observes pour les nanofils non-dopes et dopes-n est presentee. Troisiemement, la photoconductivite est extraite pour les nanofils non-dopes et dopes-n sur une plage de 0.5 a 2 THz. Un lissage sur la photoconductivite permet d'estimer le nombre de dopants dans les nanofils dopes-n. Mots-cles: nanofil, silicium, terahertz, conductivite, spectroscopie, photoconductivite.

  12. Anisotropie des coefficients de diffusion dans des cristaux liquides discotiques hexagonaux

    NASA Astrophysics Data System (ADS)

    Daoud, M.; Gharbia, M.; Gharbi, A.

    1994-06-01

    The diffusion constants of dyes in several hexagonal discotic liquid crystals are measured and discussed. For all the liquid crystals studied, these constants are anisotropic : the diffusion in the direction parallel to the columns is faster than that in the perpendicular plane (frac{D_allel}{D_perp}>1). The effects of the length and shape of the chains bound to the triphenylene discs are shown. The effect of the dye molecular size is also described. The study of the diffusion coefficients of hexapentoxytriphenylene (C5HET) as a function of temperature has shown that the activation energies along the columns and perpendicular to the columns are comparable. The main features of dye diffusion in the hexagonal columnar liquid crystals studied are similar to those reported in nematic phases. Les mesures des constantes de diffusion de colorants dans plusieurs cristaux liquides discotiques hexagonaux sont présentées et discutées. Pour tous les cristaux liquides étudiés, ces constantes présentent une anisotropie, avec une diffusion plus rapide parallèlement aux colonnes que perpendiculairement à celles-ci (frac{D_allel}{D_perp}>1). Des effets de longueur et de forme des chaînes branchées sur les disques de triphénylène sont mis en évidence. Il en est de même pour la taille des molécules de colorants. L'étude en fonction de la température a montré que dans le cas de l'hexapentoxytriphénylène (C5HET), les énergies d'activation dans les directions parallèle et perpendiculaire aux colonnes sont comparables. Les caractéristiques de la diffusion de colorants dans les cristaux liquides colonnaires hexagonaux étudiés sont semblables à celles des nématiques.

  13. Hans Bethe : Des etoiles a la bombe

    NASA Astrophysics Data System (ADS)

    Bonnet-Bidaud, J. M.

    1996-06-01

    Il comprit le premier comment brillent les etoiles. Il fut aussi de cette poignee de scientifiques qui, dans le secret de Los Alamos, mirent au point la tristement celebre bombe atomique. Hans Bethe est l'un des derniers geants qui auront marque la physique de ce siecle d'une empreinte indelebile. C'est dans le bureau 01 du prestigieux laboratoire Kellog de l'institut Caltech qu'il a bien voulu retracer pour nous son impressionnante carriere, et revenir sur les motivations qui ont guide ses pas.

  14. A limited spectrum of mutations causes constitutive activation of the yeast alpha-factor receptor.

    PubMed

    Sommers, C M; Martin, N P; Akal-Strader, A; Becker, J M; Naider, F; Dumont, M E

    2000-06-13

    Activation of G protein coupled receptors (GPCRs) by binding of ligand is the initial event in diverse cellular signaling pathways. To examine the frequency and diversity of mutations that cause constitutive activation of one particular GPCR, the yeast alpha-factor receptor, we screened libraries of random mutations for constitutive alleles. In initial screens for mutant receptor alleles that exhibit signaling in the absence of added ligand, 14 different point mutations were isolated. All of these 14 mutants could be further activated by alpha-factor. Ten of the mutants also acquired the ability to signal in response to binding of desTrp(1)¿Ala(3)ălpha-factor, a peptide that acts as an antagonist toward normal alpha-factor receptors. Of these 10 mutants, at least eight alleles residing in the third, fifth, sixth, and seventh transmembrane segments exhibit bona fide constitutive signaling. The remaining alleles are hypersensitive to alpha-factor rather than constitutive. They can be activated by low concentrations of endogenous alpha-factor present in MATa cells. The strongest constitutively active receptor alleles were recovered multiple times from the mutational libraries, and extensive mutagenesis of certain regions of the alpha-factor receptor did not lead to recovery of any additional constitutive alleles. Thus, only a limited number of mutations is capable of causing constitutive activation of this receptor. Constitutive and hypersensitive signaling by the mutant receptors is partially suppressed by coexpression of normal receptors, consistent with preferential association of the G protein with unactivated receptors. PMID:10841771

  15. Too Many Mutants with Multiple Mutations

    PubMed Central

    Drake, John W.

    2007-01-01

    It has recently become clear that the classical notion of the random nature of mutation does not hold for the distribution of mutations among genes: most collections of mutants contain more isolates with two or more mutations than predicted by the mutant frequency on the assumption of a random distribution of mutations. Excesses of multiples are seen in a wide range of organisms, including riboviruses, DNA viruses, prokaryotes, yeasts, and higher eukaryotic cell lines and tissues. In addition, such excesses are produced by DNA polymerases in vitro. These “multiples” appear to be generated by transient, localized hypermutation rather than by heritable mutator mutations. The components of multiples are sometimes scattered at random and sometimes display an excess of smaller distances between mutations. As yet, almost nothing is known about the mechanisms that generate multiples, but such mutations have the capacity to accelerate those evolutionary pathways that require multiple mutations where the individual mutations are neutral or deleterious. Examples that impinge on human health may include carcinogenesis and the adaptation of microbial pathogens as they move between individual hosts. PMID:17687667

  16. Mutations affecting enzymatic activity in liver arginase

    SciTech Connect

    Vockley, J.G.; Tabor, D.E.; Goodman, B.K.

    1994-09-01

    The hydrolysis of arginine to ornithine and urea is catalyzed by arginase in the last step of the urea cycle. We examined a group of arginase deficient patients by PCR-SSCP analysis to characterize the molecular basis of this disorder. A heterogeneous population of nonsense mutations, microdeletions, and missense mutations has been identified in our cohort. Microdeletions which introduce premature stop codons downstream of the deletion and nonsense mutations result in no arginase activity. These mutations occur randomly along the gene. The majority of missense mutations identified appear to occur in regions of high cross-species homology. To test the effect of these missense mutations on arginase activity, site-directed mutagenesis was used to re-create the patient mutations for in vivo expression studies in a prokaryotic fusion-protein expression system. Of 4 different missense mutations identified in 6 individuals, only one was located outside of a conserved region. The three substitution mutations within the conserved regions had a significant effect on enzymatic activity (0-3.1 nmole/30min, normal is 1300-1400 nmoles/30min, as determined by in vitro arginase assay), while the fourth mutation, a T to S substitution, did not. In addition, site-directed mutagenesis was utilized to create mutations not in residues postulated to play a significant role in the enzymatic function or active site formation in manganese-binding proteins such as arginase. We have determined that the substitution of glycine for a histidine residue, located in a very highly conserved region of exon 3, and the substitution of a histidine and an aspartic acid residue within a similarly conserved region in exon 4, totally abolishes enzymatic activity. Mutations substituting glycine for an additional histidine and aspartic acid residue in exon 4 and two aspartic acid residues in exon 7 have also been created. We are currently in the process of characterizing these mutations.

  17. How mutation affects evolutionary games on graphs.

    PubMed

    Allen, Benjamin; Traulsen, Arne; Tarnita, Corina E; Nowak, Martin A

    2012-04-21

    Evolutionary dynamics are affected by population structure, mutation rates and update rules. Spatial or network structure facilitates the clustering of strategies, which represents a mechanism for the evolution of cooperation. Mutation dilutes this effect. Here we analyze how mutation influences evolutionary clustering on graphs. We introduce new mathematical methods to evolutionary game theory, specifically the analysis of coalescing random walks via generating functions. These techniques allow us to derive exact identity-by-descent (IBD) probabilities, which characterize spatial assortment on lattices and Cayley trees. From these IBD probabilities we obtain exact conditions for the evolution of cooperation and other game strategies, showing the dual effects of graph topology and mutation rate. High mutation rates diminish the clustering of cooperators, hindering their evolutionary success. Our model can represent either genetic evolution with mutation, or social imitation processes with random strategy exploration.

  18. DCDC2 Mutations Cause Neonatal Sclerosing Cholangitis.

    PubMed

    Girard, Muriel; Bizet, Albane A; Lachaux, Alain; Gonzales, Emmanuel; Filhol, Emilie; Collardeau-Frachon, Sophie; Jeanpierre, Cécile; Henry, Charline; Fabre, Monique; Viremouneix, Loic; Galmiche, Louise; Debray, Dominique; Bole-Feysot, Christine; Nitschke, Patrick; Pariente, Danièle; Guettier, Catherine; Lyonnet, Stanislas; Heidet, Laurence; Bertholet, Aurelia; Jacquemin, Emmanuel; Henrion-Caude, Alexandra; Saunier, Sophie

    2016-10-01

    Neonatal sclerosing cholangitis (NSC) is a rare biliary disease leading to liver transplantation in childhood. Patients with NSC and ichtyosis have already been identified with a CLDN1 mutation, encoding a tight-junction protein. However, for the majority of patients, the molecular basis of NSC remains unknown. We identified biallelic missense mutations or in-frame deletion in DCDC2 in four affected children. Mutations involve highly conserved amino acids in the doublecortin domains of the protein. In cholangiocytes, DCDC2 protein is normally located in the cytoplasm and cilia, whereas in patients the mutated protein is accumulated in the cytoplasm, absent from cilia, and associated with ciliogenesis defect. This is the first report of DCDC2 mutations in NSC. This data expands the molecular spectrum of NSC, that can be considered as a ciliopathy and also expands the clinical spectrum of the DCDC2 mutations, previously reported in dyslexia, deafness, and nephronophtisis. PMID:27319779

  19. DCDC2 Mutations Cause Neonatal Sclerosing Cholangitis.

    PubMed

    Girard, Muriel; Bizet, Albane A; Lachaux, Alain; Gonzales, Emmanuel; Filhol, Emilie; Collardeau-Frachon, Sophie; Jeanpierre, Cécile; Henry, Charline; Fabre, Monique; Viremouneix, Loic; Galmiche, Louise; Debray, Dominique; Bole-Feysot, Christine; Nitschke, Patrick; Pariente, Danièle; Guettier, Catherine; Lyonnet, Stanislas; Heidet, Laurence; Bertholet, Aurelia; Jacquemin, Emmanuel; Henrion-Caude, Alexandra; Saunier, Sophie

    2016-10-01

    Neonatal sclerosing cholangitis (NSC) is a rare biliary disease leading to liver transplantation in childhood. Patients with NSC and ichtyosis have already been identified with a CLDN1 mutation, encoding a tight-junction protein. However, for the majority of patients, the molecular basis of NSC remains unknown. We identified biallelic missense mutations or in-frame deletion in DCDC2 in four affected children. Mutations involve highly conserved amino acids in the doublecortin domains of the protein. In cholangiocytes, DCDC2 protein is normally located in the cytoplasm and cilia, whereas in patients the mutated protein is accumulated in the cytoplasm, absent from cilia, and associated with ciliogenesis defect. This is the first report of DCDC2 mutations in NSC. This data expands the molecular spectrum of NSC, that can be considered as a ciliopathy and also expands the clinical spectrum of the DCDC2 mutations, previously reported in dyslexia, deafness, and nephronophtisis.

  20. Spliceosome mutations exhibit specific associations with epigenetic modifiers and proto-oncogenes mutated in myelodysplastic syndrome.

    PubMed

    Mian, Syed A; Smith, Alexander E; Kulasekararaj, Austin G; Kizilors, Aytug; Mohamedali, Azim M; Lea, Nicholas C; Mitsopoulos, Konstantinos; Ford, Kevin; Nasser, Erick; Seidl, Thomas; Mufti, Ghulam J

    2013-07-01

    The recent identification of acquired mutations in key components of the spliceosome machinery strongly implicates abnormalities of mRNA splicing in the pathogenesis of myelodysplastic syndromes. However, questions remain as to how these aberrations functionally combine with the growing list of mutations in genes involved in epigenetic modification and cell signaling/transcription regulation identified in these diseases. In this study, amplicon sequencing was used to perform a mutation screen in 154 myelodysplastic syndrome patients using a 22-gene panel, including commonly mutated spliceosome components (SF3B1, SRSF2, U2AF1, ZRSR2), and a further 18 genes known to be mutated in myeloid cancers. Sequencing of the 22-gene panel revealed that 76% (n=117) of the patients had mutations in at least one of the genes, with 38% (n=59) having splicing gene mutations and 49% (n=75) patients harboring more than one gene mutation. Interestingly, single and specific epigenetic modifier mutations tended to coexist with SF3B1 and SRSF2 mutations (P<0.03). Furthermore, mutations in SF3B1 and SRSF2 were mutually exclusive to TP53 mutations both at diagnosis and at the time of disease transformation. Moreover, mutations in FLT3, NRAS, RUNX1, CCBL and C-KIT were more likely to co-occur with splicing factor mutations generally (P<0.02), and SRSF2 mutants in particular (P<0.003) and were significantly associated with disease transformation (P<0.02). SF3B1 and TP53 mutations had varying impacts on overall survival with hazard ratios of 0.2 (P<0.03, 95% CI, 0.1-0.8) and 2.1 (P<0.04, 95% CI, 1.1-4.4), respectively. Moreover, patients with splicing factor mutations alone had a better overall survival than those with epigenetic modifier mutations, or cell signaling/transcription regulator mutations with and without coexisting mutations of splicing factor genes, with worsening prognosis (P<0.001). These findings suggest that splicing factor mutations are maintained throughout disease

  1. The Mutational Robustness of Influenza A Virus.

    PubMed

    Visher, Elisa; Whitefield, Shawn E; McCrone, John T; Fitzsimmons, William; Lauring, Adam S

    2016-08-01

    A virus' mutational robustness is described in terms of the strength and distribution of the mutational fitness effects, or MFE. The distribution of MFE is central to many questions in evolutionary theory and is a key parameter in models of molecular evolution. Here we define the mutational fitness effects in influenza A virus by generating 128 viruses, each with a single nucleotide mutation. In contrast to mutational scanning approaches, this strategy allowed us to unambiguously assign fitness values to individual mutations. The presence of each desired mutation and the absence of additional mutations were verified by next generation sequencing of each stock. A mutation was considered lethal only after we failed to rescue virus in three independent transfections. We measured the fitness of each viable mutant relative to the wild type by quantitative RT-PCR following direct competition on A549 cells. We found that 31.6% of the mutations in the genome-wide dataset were lethal and that the lethal fraction did not differ appreciably between the HA- and NA-encoding segments and the rest of the genome. Of the viable mutants, the fitness mean and standard deviation were 0.80 and 0.22 in the genome-wide dataset and best modeled as a beta distribution. The fitness impact of mutation was marginally lower in the segments coding for HA and NA (0.88 ± 0.16) than in the other 6 segments (0.78 ± 0.24), and their respective beta distributions had slightly different shape parameters. The results for influenza A virus are remarkably similar to our own analysis of CirSeq-derived fitness values from poliovirus and previously published data from other small, single stranded DNA and RNA viruses. These data suggest that genome size, and not nucleic acid type or mode of replication, is the main determinant of viral mutational fitness effects. PMID:27571422

  2. The Mutational Robustness of Influenza A Virus

    PubMed Central

    McCrone, John T.; Lauring, Adam S.

    2016-01-01

    A virus’ mutational robustness is described in terms of the strength and distribution of the mutational fitness effects, or MFE. The distribution of MFE is central to many questions in evolutionary theory and is a key parameter in models of molecular evolution. Here we define the mutational fitness effects in influenza A virus by generating 128 viruses, each with a single nucleotide mutation. In contrast to mutational scanning approaches, this strategy allowed us to unambiguously assign fitness values to individual mutations. The presence of each desired mutation and the absence of additional mutations were verified by next generation sequencing of each stock. A mutation was considered lethal only after we failed to rescue virus in three independent transfections. We measured the fitness of each viable mutant relative to the wild type by quantitative RT-PCR following direct competition on A549 cells. We found that 31.6% of the mutations in the genome-wide dataset were lethal and that the lethal fraction did not differ appreciably between the HA- and NA-encoding segments and the rest of the genome. Of the viable mutants, the fitness mean and standard deviation were 0.80 and 0.22 in the genome-wide dataset and best modeled as a beta distribution. The fitness impact of mutation was marginally lower in the segments coding for HA and NA (0.88 ± 0.16) than in the other 6 segments (0.78 ± 0.24), and their respective beta distributions had slightly different shape parameters. The results for influenza A virus are remarkably similar to our own analysis of CirSeq-derived fitness values from poliovirus and previously published data from other small, single stranded DNA and RNA viruses. These data suggest that genome size, and not nucleic acid type or mode of replication, is the main determinant of viral mutational fitness effects. PMID:27571422

  3. LHON: Mitochondrial Mutations and More

    PubMed Central

    Kirches, E

    2011-01-01

    Leber’s hereditary optic neuropathy (LHON) is a mitochondrial disorder leading to severe visual impairment or even blindness by death of retinal ganglion cells (RGCs). The primary cause of the disease is usually a mutation of the mitochondrial genome (mtDNA) causing a single amino acid exchange in one of the mtDNA-encoded subunits of NADH:ubiquinone oxidoreductase, the first complex of the electron transport chain. It was thus obvious to accuse neuronal energy depletion as the most probable mediator of neuronal death. The group of Valerio Carelli and other authors have nicely shown that energy depletion shapes the cell fate in a LHON cybrid cell model. However, the cybrids used were osteosarcoma cells, which do not fully model neuronal energy metabolism. Although complex I mutations may cause oxidative stress, a potential pathogenetic role of the latter was less taken into focus. The hypothesis of bioenergetic failure does not provide a simple explanation for the relatively late disease onset and for the incomplete penetrance, which differs remarkably between genders. It is assumed that other genetic and environmental factors are needed in addition to the ‘primary LHON mutations’ to elicit RGC death. Relevant nuclear modifier genes have not been identified so far. The review discusses the unresolved problems of a pathogenetic hypothesis based on ATP decline and/or ROS-induced apoptosis in RGCs. PMID:21886454

  4. Copy number variation and mutation

    NASA Astrophysics Data System (ADS)

    Clark, Brian; Weidner, Jacob; Wabick, Kevin

    2009-11-01

    Until very recently, the standard model of DNA included two genes for each trait. This dated model has given way to a model that includes copies of some genes well in excess of the canonical two. Copy number variations in the human genome play critical roles in causing or aggravating a number of syndromes and diseases while providing increased resistance to others. We explore the role of mutation, crossover, inversion, and reproduction in determining copy number variations in a numerical simulation of a population. The numerical model consists of a population of individuals, where each individual is represented by a single strand of DNA with the same number of genes. Each gene is initially assigned to one of two traits. Fitness of the individual is determined by the two most fit genes for trait one, and trait two genetic material is treated as a reservoir of junk DNA. After a sufficient number of generations, during which the genetic distribution is allowed to reach a steady-state, the mean numberof genes per trait and the copy number variation are recorded. Here, we focus on the role of mutation and compare simulation results to theory.

  5. Determination of a mutational spectrum

    DOEpatents

    Thilly, William G.; Keohavong, Phouthone

    1991-01-01

    A method of resolving (physically separating) mutant DNA from nonmutant DNA and a method of defining or establishing a mutational spectrum or profile of alterations present in nucleic acid sequences from a sample to be analyzed, such as a tissue or body fluid. The present method is based on the fact that it is possible, through the use of DGGE, to separate nucleic acid sequences which differ by only a single base change and on the ability to detect the separate mutant molecules. The present invention, in another aspect, relates to a method for determining a mutational spectrum in a DNA sequence of interest present in a population of cells. The method of the present invention is useful as a diagnostic or analytical tool in forensic science in assessing environmental and/or occupational exposures to potentially genetically toxic materials (also referred to as potential mutagens); in biotechnology, particularly in the study of the relationship between the amino acid sequence of enzymes and other biologically-active proteins or protein-containing substances and their respective functions; and in determining the effects of drugs, cosmetics and other chemicals for which toxicity data must be obtained.

  6. Point mutation instability (PIN) mutator phenotype as model for true back mutations seen in hereditary tyrosinemia type 1 - a hypothesis.

    PubMed

    van Dyk, Etresia; Pretorius, Pieter J

    2012-05-01

    Hereditary tyrosinemia type 1 (HT1) is an autosomal recessive disorder affecting fumarylacetoacetate hydrolase (FAH), the last enzyme in the tyrosine catabolism pathway. The liver mosaicism observed in HT1 patients is due to the reversion to the wild type of one allele of the original point mutation in fah. It is generally accepted that these reversions are true back mutations; however, the mechanism is still unresolved. Previous reports excluded intragenic recombination, mitotic recombination, or homologous recombination with a pseudogene as possible mechanisms of mutation reversion in HT1. Sequence analysis did not reveal DNA motifs, tandem repeats or other sequence peculiarities that may be involved in mutation reversion. We propose the hypothesis that a point mutation instability mutator (PIN) phenotype brought about by the sustained stress environment created by the accumulating metabolites in the cell is the driver of the true back mutations in HT1. The metabolites accumulating in HT1 create a sustained stress environment by activating the extracellular signal-regulated kinase (ERK) and AKT survival pathways, inducing aberrant mitosis and development of death resistant cells, depleting glutathione, and impairing DNA ligase IV and possibly DNA polymerases δ and ε. This continual production of proliferative and stress-related survival signals in the cellular environment coupled with the mutagenicity of FAA, may instigate a mutator phenotype and could end in tumorigenesis and/or mutation reversion. The establishment of a PIN-mutator phenotype therefore not only seems to be a possible mechanism underlying the true back mutations, but also contributes to explaining the clinical heterogeneity seen in hereditary tyrosinemia type 1.

  7. Methods for detection of ataxia telangiectasia mutations

    DOEpatents

    Gatti, Richard A.

    2005-10-04

    The present invention is directed to a method of screening large, complex, polyexonic eukaryotic genes such as the ATM gene for mutations and polymorphisms by an improved version of single strand conformation polymorphism (SSCP) electrophoresis that allows electrophoresis of two or three amplified segments in a single lane. The present invention also is directed to new mutations and polymorphisms in the ATM gene that are useful in performing more accurate screening of human DNA samples for mutations and in distinguishing mutations from polymorphisms, thereby improving the efficiency of automated screening methods.

  8. Novel PORCN mutations in focal dermal hypoplasia.

    PubMed

    Froyen, G; Govaerts, K; Van Esch, H; Verbeeck, J; Tuomi, M-L; Heikkilä, H; Torniainen, S; Devriendt, K; Fryns, J-P; Marynen, P; Järvelä, I; Ala-Mello, S

    2009-12-01

    Focal dermal hypoplasia (FDH), Goltz or Goltz-Gorlin syndrome, is an X-linked dominant multisystem disorder characterized primarily by involvement of the skin, skeletal system and eyes. We screened for mutations in the PORCN gene in eight patients of Belgian and Finnish origin with firm clinical suspicion of FDH. First, we performed quantitative PCR (qPCR) analysis to define the copy number at this locus. Next, we sequenced the coding regions and flanking intronic sequences of the PORCN gene. Three de novo mutations were identified in our patients with FDH: a 150-kb deletion removing six genes including PORCN, as defined by qPCR and X-array-CGH, and two heterozygous missense mutations; c.992T>G (p.L331R) in exon 11 and c.1094G>A (p.R365Q) in exon 13 of the gene. Both point mutations changed highly conserved amino acids and were not found in 300 control X chromosomes. The three patients in whom mutations were identified all present with characteristic dermal findings together with limb manifestations, which were not seen in our mutation-negative patients. The clinical characteristics of our patients with PORCN mutations were compared with the previously reported mutation-positive cases. In this report, we summarize the literature on PORCN mutations and associated phenotypes.

  9. Repair-Resistant Mutation in Neurospora

    PubMed Central

    Stadler, David; Macleod, Helen; Loo, Melanie

    1987-01-01

    Chronic UV treatment produces severalfold fewer mutations in Neurospora conidia than does the same total dose of acute UV. Experiments were designed to determine the conditions required for chronic UV mutagenesis. Measurement of the coincidence frequency for two independent mutations revealed the existence of a subset of cells which are mutable by chronic UV. Analysis of forward mutation at the mtr locus showed that the genetic alterations produced by chronic UV were virtually all point mutants, even though the assay system could detect alterations or deletions extending into neighboring genes. A significant fraction of the mutants produced by acute UV were multigenic deletions. The size of the dose-rate effect (acute UV mutation frequency divided by chronic UV mutation frequency) was compared for several different mutation assay systems. Forward mutations (recessive lethals and mtr) gave values ranging from four to nine. For events which were restricted to specific molecular sites (specific reversions and nonsense suppressor mutations), there was a wider range of dose-rate ratios. This suggests that chronic UV mutation may be restricted to certain molecular sequences or configurations. PMID:3609724

  10. Calreticulin Exon 9 Mutations in Myeloproliferative Neoplasms

    PubMed Central

    Kim, Yu-Kyung

    2015-01-01

    Background Calreticulin (CALR) mutations were recently discovered in patients with myeloproliferative neoplasms (MPNs). We studied the frequency and type of CALR mutations and their hematological characteristics. Methods A total of 168 MPN patients (36 polycythemia vera [PV], 114 essential thrombocythemia [ET], and 18 primary myelofibrosis [PMF] cases) were included in the study. CALR mutation was analyzed by the direct sequencing method. Results CALR mutations were detected in 21.9% of ET and 16.7% of PMF patients, which accounted for 58.5% and 33.3% of ET and PMF patients without Janus kinase 2 (JAK2) or myeloproliferative leukemia virus oncogenes (MPL) mutations, respectively. A total of five types of mutation were detected, among which, L367fs*46 (53.6%) and K385fs*47 (35.7%) were found to be the most common. ET patients with CALR mutation had lower leukocyte counts and ages compared with JAK2-mutated ET patients. Conclusion Genotyping for CALR could be a useful diagnostic tool for JAK2-or MPL-negative ET or PMF patients. CALR mutation may be a distinct disease group, with different hematological characteristics than that of JAK2-positive patients. PMID:25553276

  11. Gene mutations in chronic lymphocytic leukemia.

    PubMed

    Amin, Nisar A; Malek, Sami N

    2016-04-01

    The recent discovery of genes mutated in chronic lymphocytic leukemia (CLL) has stimulated new research into the role of these genes in CLL pathogenesis. CLL cases carry approximately 5-20 mutated genes per exome, a lower number than detected in many human tumors. Of the recurrently mutated genes in CLL, all are mutated in 10% or less of patients when assayed in unselected CLL cohorts at diagnosis. Mutations in TP53 are of major clinical relevance, are often associated with del17p and gain in frequency over time. TP53 mutated and associated del17p states substantially lower response rates, remission duration, and survival in CLL. Mutations in NOTCH1 and SF3B1 are recurrent, often associated with progressive CLL that is also IgVH unmutated and ZAP70-positive and are under investigation as targets for novel therapies and as factors influencing CLL outcome. There are an estimated 20-50 additional mutated genes with frequencies of 1%-5% in CLL; more work is needed to identify these and to study their significance. Finally, of the major biological aberration categories influencing CLL as a disease, gene mutations will need to be placed into context with regard to their ultimate role and importance. Such calibrated appreciation necessitates studies incorporating multiple CLL driver aberrations into biological and clinical analyses. PMID:27040699

  12. Compensating the Fitness Costs of Synonymous Mutations

    PubMed Central

    Knöppel, Anna; Näsvall, Joakim; Andersson, Dan I.

    2016-01-01

    Synonymous mutations do not change the sequence of the polypeptide but they may still influence fitness. We investigated in Salmonella enterica how four synonymous mutations in the rpsT gene (encoding ribosomal protein S20) reduce fitness (i.e., growth rate) and the mechanisms by which this cost can be genetically compensated. The reduced growth rates of the synonymous mutants were correlated with reduced levels of the rpsT transcript and S20 protein. In an adaptive evolution experiment, these fitness impairments could be compensated by mutations that either caused up-regulation of S20 through increased gene dosage (due to duplications), increased transcription of the rpsT gene (due to an rpoD mutation or mutations in rpsT), or increased translation from the rpsT transcript (due to rpsT mutations). We suggest that the reduced levels of S20 in the synonymous mutants result in production of a defective subpopulation of 30S subunits lacking S20 that reduce protein synthesis and bacterial growth and that the compensatory mutations restore S20 levels and the number of functional ribosomes. Our results demonstrate how specific synonymous mutations can cause substantial fitness reductions and that many different types of intra- and extragenic compensatory mutations can efficiently restore fitness. Furthermore, this study highlights that also synonymous sites can be under strong selection, which may have implications for the use of dN/dS ratios as signature for selection. PMID:26882986

  13. A Landscape of Driver Mutations in Melanoma

    PubMed Central

    Hodis, Eran; Watson, Ian R.; Kryukov, Gregory V.; Arold, Stefan T.; Imielinski, Marcin; Theurillat, Jean-Philippe; Nickerson, Elizabeth; Auclair, Daniel; Li, Liren; Place, Chelsea; DiCara, Daniel; Ramos, Alex H.; Lawrence, Michael S.; Cibulskis, Kristian; Sivachenko, Andrey; Voet, Douglas; Saksena, Gordon; Stransky, Nicolas; Onofrio, Robert C.; Winckler, Wendy; Ardlie, Kristin; Wagle, Nikhil; Wargo, Jennifer; Chong, Kelly; Morton, Donald L.; Stemke-Hale, Katherine; Chen, Guo; Noble, Michael; Meyerson, Matthew; Ladbury, John E.; Davies, Michael A.; Gershenwald, Jeffrey E.; Wagner, Stephan N.; Hoon, Dave S.B.; Schadendorf, Dirk; Lander, Eric S.; Gabriel, Stacey B.; Getz, Gad; Garraway, Levi A.; Chin, Lynda

    2012-01-01

    SUMMARY Despite recent insights into melanoma genetics, systematic surveys for driver mutations are challenged by an abundance of passenger mutations caused by carcinogenic ultraviolet (UV) light exposure. We developed a permutation-based framework to address this challenge, employing mutation data from intronic sequences to control for passenger mutational load on a per gene basis. Analysis of large-scale melanoma exome data by this approach discovered six novel melanoma genes (PPP6C, RAC1, SNX31, TACC1, STK19 and ARID2), three of which - RAC1, PPP6C and STK19 - harbored recurrent and potentially targetable mutations. Integration with chromosomal copy number data contextualized the landscape of driver mutations, providing oncogenic insights in BRAF- and NRAS-driven melanoma as well as those without known NRAS/BRAF mutations. The landscape also clarified a mutational basis for RB and p53 pathway deregulation in this malignancy. Finally, the spectrum of driver mutations provided unequivocal genomic evidence for a direct mutagenic role of UV light in melanoma pathogenesis. PMID:22817889

  14. Regular systems of inbreeding with mutation.

    PubMed

    Campbell, R B

    1988-08-01

    Probability of identity by type is studied for regular systems of inbreeding in the presence of mutation. Analytic results are presented for half-sib mating, first cousin mating, and half nth cousin mating under both infinite allele and two allele (back mutation) models. Reasonable rates of mutation do not provide significantly different results from probability of identity by descent in the absence of mutation. Homozygosity is higher under half-sib mating than under first cousin mating, but the expected number of copies of a gene in the population is higher under first cousin mating than under half-sib mating.

  15. Evolution of Mutation Rate in Asexual Populations

    NASA Astrophysics Data System (ADS)

    Wylie, Scott; Levine, Herbert; Kessler, David

    2007-03-01

    Several evolution experiments with E. coli document the spontaneous emergence and eventual fixation of so called ``mutator'' alleles that increase the genomic mutation rate by the order of 100-fold. Variations in mutation rates are due to polymorphisms in the molecular machinery that copies and checks the genome for errors. These polymorphisms are coded in the genome and thus heritable. Like any heritable trait, elevated mutation rates are subject to natural selection and evolution. However, unlike other traits, mutation rate does not directly affect the rate at which an organism reproduces, i.e. its fitness. Rather, it affects the statistical distribution of the offspring's fitness. This fitness distribution, in turn, leads via ``hitchhiking'' to a change in the frequency of the mutator allele, i.e. evolution of the mutation rate itself. In our work we simulate a birth-death process that approximates simple asexual populations and we measure the fixation probability of rare mutators. We then develop an approximate analytic model of the population dynamics, the results of which agree reasonably well with simulation. In particular, we are able to analytically predict the ``effective fitness'' of mutators and the conditions under which they are expected to emerge.

  16. WRN mutations in Werner syndrome patients: genomic rearrangements, unusual intronic mutations and ethnic-specific alterations

    PubMed Central

    Friedrich, Katrin; Lee, Lin; Leistritz, Dru F.; Nürnberg, Gudrun; Saha, Bidisha; Hisama, Fuki M.; Eyman, Daniel K.; Lessel, Davor; Nürnberg, Peter; Li, Chumei; Garcia-F-Villalta, María J.; Kets, Carolien M.; Schmidtke, Joerg; Cruz, Vítor Tedim; Van den Akker, Peter C.; Boak, Joseph; Peter, Dincy; Compoginis, Goli; Cefle, Kivanc; Ozturk, Sukru; López, Norberto; Wessel, Theda; Poot, Martin; Ippel, P. F.; Groff-Kellermann, Birgit; Hoehn, Holger; Martin, George M.; Kubisch, Christian; Oshima, Junko

    2015-01-01

    Werner syndrome (WS) is an autosomal recessive segmental progeroid syndrome caused by null mutations at the WRN locus, which codes for a member of the RecQ family of DNA helicases. Since 1988, the International Registry of Werner syndrome had enrolled 130 molecularly confirmed WS cases from among 110 worldwide pedigrees. We now report 18 new mutations, including two genomic rearrangements, a deep intronic mutation resulting in a novel exon, a splice consensus mutation leading to utilization of the nearby splice site, and two rare missense mutations. We also review evidence for founder mutations among various ethnic/geographic groups. Founder WRN mutations had been previously reported in Japan and Northern Sardinia. Our Registry now suggests characteristic mutations originated in Morocco, Turkey, The Netherlands and elsewhere. PMID:20443122

  17. Sécurité au-delà des mythes et des croyances

    ScienceCinema

    None

    2016-07-12

    Présentation orale en français, support visuel en français et en anglais. La pire des failles de sécurité est l'impression de sécurité. Le décalage entre la compréhension que l’on a des technologies utilisées, et leurs potentiels réels, ainsi que l'impact potentiellement négatif qu'elles peuvent avoir sur nos vies, n'est pas toujours compris, ou pris en compte par la plupart d'entre-nous. On se contente de nos perceptions pour ne pas avoir à se confronter à la réalité... Alors qu'en est-il vraiment ? En matière de sécurité qui de l'humain ou des technologies a le contrôle ?

  18. Evaluation des connaissances des parents sur les bronchiolites aiguës

    PubMed Central

    Gueddari, Widad; Tazi, Abderrahmane; Ouardi, Amine; Nani, Samira; Zineddine, Abdelhadi

    2014-01-01

    Les infections respiratoires (IR) constituent la deuxième cause de mortalité infantile au Maroc, dû en partie à l'absence d'information et de sensibilisation. Le but de ce travail était d’évaluer les connaissances des parents sur la bronchiolite aiguë, infection respiratoire très fréquente. Nous avons réalisé une enquête basée sur un questionnaire, auprès de parents de nourrissons consultants pour toux, avec ou sans gêne respiratoire. 180 parents ont été inclus dans l’étude. Les parents pensaient que l'infection respiratoire était secondaire au climat froid (96%); seuls 4% ont évoqué une origine infectieuse. Aucun des parents ne savait que le lavage des mains était un moyen de prévention de la transmission. Les parents ont majoritairement répondu que la kinésithérapie respiratoire ne servait à rien (65%), et qu'elle était nocive (24.5%). Ce manque de connaissances fondamentales en matière d'IR et de bronchiolite en particulier, devrait inciter à entreprendre un programme de sensibilisation PMID:25328606

  19. Mutations, mutation rates, and evolution at the hypervariable VNTR loci of Yersinia pestis.

    PubMed

    Vogler, Amy J; Keys, Christine E; Allender, Christopher; Bailey, Ira; Girard, Jessica; Pearson, Talima; Smith, Kimothy L; Wagner, David M; Keim, Paul

    2007-03-01

    VNTRs are able to discriminate among closely related isolates of recently emerged clonal pathogens, including Yersinia pestis the etiologic agent of plague, because of their great diversity. Diversity is driven largely by mutation but little is known about VNTR mutation rates, factors affecting mutation rates, or the mutational mechanisms. The molecular epidemiological utility of VNTRs will be greatly enhanced when this foundational knowledge is available. Here, we measure mutation rates for 43 VNTR loci in Y. pestis using an in vitro generated population encompassing approximately 96,000 generations. We estimate the combined 43-locus rate and individual rates for 14 loci. A comparison of Y. pestis and Escherichia coli O157:H7 VNTR mutation rates and products revealed a similar relationship between diversity and mutation rate in these two species. Likewise, the relationship between repeat copy number and mutation rate is nearly identical between these species, suggesting a generalized relationship that may be applicable to other species. The single- versus multiple-repeat mutation ratios and the insertion versus deletion mutation ratios were also similar, providing support for a general model for the mutations associated with VNTRs. Finally, we use two small sets of Y. pestis isolates to show how this general model and our estimated mutation rates can be used to compare alternate phylogenies, and to evaluate the significance of genotype matches, near-matches, and mismatches found in empirical comparisons with a reference database. PMID:17161849

  20. Clock-like mutational processes in human somatic cells

    PubMed Central

    Alexandrov, Ludmil B.; Jones, Philip H.; Wedge, David C.; Sale, Julian E.; Campbell, Peter J.; Nik-Zainal, Serena; Stratton, Michael R.

    2016-01-01

    During the course of a lifetime somatic cells acquire mutations. Different mutational processes may contribute to the mutations accumulated in a cell, with each imprinting a mutational signature on the cell’s genome. Some processes generate mutations throughout life at a constant rate in all individuals and the number of mutations in a cell attributable to these processes will be proportional to the chronological age of the person. Using mutations from 10,250 cancer genomes across 36 cancer types, we investigated clock-like mutational processes that have been operating in normal human cells. Two mutational signatures show clock-like properties. Both exhibit different mutation rates in different tissues. However, their mutation rates are not correlated indicating that the underlying processes are subject to different biological influences. For one signature, the rate of cell division may influence its mutation rate. This study provides the first survey of clock-like mutational processes operative in human somatic cells. PMID:26551669

  1. Clock-like mutational processes in human somatic cells

    SciTech Connect

    Alexandrov, Ludmil B.; Jones, Philip H.; Wedge, David C.; Sale, Julian E.; Campbell, Peter J.; Nik-Zainal, Serena; Stratton, Michael R.

    2015-11-09

    During the course of a lifetime, somatic cells acquire mutations. Different mutational processes may contribute to the mutations accumulated in a cell, with each imprinting a mutational signature on the cell's genome. Some processes generate mutations throughout life at a constant rate in all individuals, and the number of mutations in a cell attributable to these processes will be proportional to the chronological age of the person. Using mutations from 10,250 cancer genomes across 36 cancer types, we investigated clock-like mutational processes that have been operating in normal human cells. Two mutational signatures show clock-like properties. Both exhibit different mutation rates in different tissues. However, their mutation rates are not correlated, indicating that the underlying processes are subject to different biological influences. For one signature, the rate of cell division may influence its mutation rate. This paper provides the first survey of clock-like mutational processes operating in human somatic cells.

  2. DES the year in review: controversies.

    PubMed

    Garg, S; Bourantas, C; Serruys, P W

    2013-04-01

    Drug-eluting stents (DES) have transformed interventional cardiology over the past decade. Whilst their efficacy has rarely been called into question, there have been concerns over the safety of the early devices, which has prompted the development of new coronary stents. Many of these new devices have entered clinical practice, however questions remain as to whether they offer the improvements in clinical outcomes that were originally anticipated. In addition, there is a debate whether the reported high efficacy of these devices enables percutaneous coronary intervention (PCI) to be performed in patient and lesion sub-groups previous entirely the domain of the cardiac surgeon. This review paper addresses these outstanding questions. PMID:23492595

  3. Formation et Evolution des Quasars et Contraintes cosmologiques

    NASA Astrophysics Data System (ADS)

    Hatziminaoglou, Evanthia

    2000-06-01

    Cette thèse porte sur l'étude de l'évolution des quasars. Elle en aborde certains aspects théoriques et observationnels, ainsi que la construction des grands échantillons de quasars dans le but à long terme de combiner le tout dans un test cosmologique géométrique pour déterminer les valeurs des paramètres cosmologiques Omega et Lambda. Les paramètres cosmologiques Omegaspan>et Lambdaspan>décrivent la géométrie globale de l'Univers. En faisant des hypothèses raisonnables sur la distribution spatiale et l'évolution des objets astrophysiques (galaxies, amas des galaxies, quasars), on peut déterminer les valeurs de ces paramètres qui sont cohérentes avec ces hypothèses. Les tests cosmologiques traditionnels ont besoin de ''chandelles standards'', objets dont les propriétés intrinsèques sont indépendantes des distances. De tels objets sont probablement fictifs. Néanmoins, certains de ces tests cosmologiques peuvent être adaptés si l'évolution individuelle, ou au moins l'évolution statistique d'une population d'objets est connue. La question de la nature de l'évolution des quasars a très vite été posée et des réponses ''phénoménologiques'' ont d'abord été données. Ces réponses ne faisaient que donner une forme mathématique à l'évolution mais n'expliquaient rien de la physique duphénomène. Les premières tentatives de construction d'un modèle physique, liées au processus d'accrétion sur un trou noir et à la théorie de la formation de l'Univers ont commencé à la fin des années 80. Depuis, des dizaines de modèles tentent d'expliquer les observations, qui sont les résultats de l'étude d'objets de plus en plus nombreux. Au cours de cette thèse, le test V/Vmax a été appliqué sur l'échantillon du Large Bright Quasar Survey en montrant 1) que l'échantillon était biaisé à cause des critères de sélection et 2) que la (simple) loi de Pure Evolution en Luminosité n'était pas une bonne approximation à tout

  4. Le syndrome des enfants battus: aspects cliniques et radiologiques

    PubMed Central

    Jlalia, Zied; Znaigui, Talel; Smida, Mahmoud

    2016-01-01

    La maltraitance physique des enfants ou le syndrome des enfants battus est responsable de plus de 75.000 décès par an en France. Ce problème de santé publique reste sous diagnostiqué en Tunisie et dans le monde. Le chemin a été laborieux pour la reconnaissance du syndrome des enfants battus dans certaines sociétés même occidentales. Nous avons voulus exposer ce problème aux praticiens afin qu'il soit mieux diagnostiqué et pris en charge. La maltraitance physique des enfants est appelée à tort syndrome de Silverman qui ne regroupe en fait que les lésions squelettiques chez ces enfants tels que les fractures. Mots clés: Fracture, maltraitance, enfant, neuro-radiologie PMID:27642408

  5. Discovery and Classification of DES15S2kqw

    NASA Astrophysics Data System (ADS)

    Kasai, E.; Bassett, B.; Crawford, S.; Kniazev, A.; Childress, M.; D'Andrea, C.; Smith, M.; Sullivan, M.; Maartens, R.; Gupta, R.; Kovacs, E.; Kuhlmann, S.; Spinka, H.; Ahn, E.; Finley, D. A.; Frieman, J.; Marriner, J.; Wester, W.; Aldering, G.; Kim, A. G.; Thomas, R. C.; Barbary, K.; Bloom, J. S.; Goldstein, D.; Nugent, P.; Perlmutter, S.; Foley, R. J.; Casas, R.; Castander, F. J.; Desai, S.; Paech, K.; Smith, R. C.; Schubnell, M.; Kessler, R.; Lasker, J.; Scolnic, D.; Brout, D. J.; Gladney, L.; Sako, M.; Wolf, R. C.; Brown, P. J.; Krisciunas, K.; Suntzeff, N.; Nichol, R.; Papadopoulos, A.

    2015-10-01

    We report optical spectroscopy of DES15S2kqw discovered by the Dark Energy Survey. The spectrum (380-820nm) was obtained using the Robert Stobie Spectrograph (RSS) on the South African Large Telescope (SALT).

  6. 2. Photocopied 1972 from Ecole imperiale des ponts et chaussees, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    2. Photocopied 1972 from Ecole imperiale des ponts et chaussees, Collection de Dessins Distribues aus eleves, (n.d. and no place), ORIGINAL FINK TRUSS BRIDGE, 1852. - Baltimore & Ohio Railroad, Fairmont Bridge, Spanning Monongahela River, Fairmont, Marion County, WV

  7. Efficiency of carcinogenesis: is the mutator phenotype inevitable?

    PubMed

    Beckman, Robert A

    2010-10-01

    Cancer development requires multiple oncogenic mutations. Pathogenic mechanisms which accelerate this process may be favored carcinogenic pathways. Mutator mutations are mutations in genetic stability genes, and increase the mutation rate, speeding up the accumulation of oncogenic mutations. The mutator hypothesis states that mutator mutations play a critical role in carcinogenesis. Alternatively, tumors might arise by mutations occurring at the normal rate followed by selection and expansion of various premalignant lineages on the path to cancer. This alternative pathway is a significant argument against the mutator hypothesis. Mutator mutations may also lead to accumulation of deleterious mutations, which could lead to extinction of premalignant lineages before they become cancerous, another argument against the mutator hypothesis. Finally, the need for acquisition of a mutator mutation imposes an additional step on the carcinogenic process. Accordingly, the mutator hypothesis has been a seminal but controversial idea for several decades despite considerable experimental and theoretical work. To resolve this debate, the concept of efficiency has been introduced as a metric for comparing carcinogenic mechanisms, and a new theoretical approach of focused quantitative modeling has been applied. The results demonstrate that, given what is already known, the predominance of mutator mechanisms is likely inevitable, as they overwhelm less efficient non-mutator pathways to cancer.

  8. Efficiency of carcinogenesis: is the mutator phenotype inevitable?

    PubMed

    Beckman, Robert A

    2010-10-01

    Cancer development requires multiple oncogenic mutations. Pathogenic mechanisms which accelerate this process may be favored carcinogenic pathways. Mutator mutations are mutations in genetic stability genes, and increase the mutation rate, speeding up the accumulation of oncogenic mutations. The mutator hypothesis states that mutator mutations play a critical role in carcinogenesis. Alternatively, tumors might arise by mutations occurring at the normal rate followed by selection and expansion of various premalignant lineages on the path to cancer. This alternative pathway is a significant argument against the mutator hypothesis. Mutator mutations may also lead to accumulation of deleterious mutations, which could lead to extinction of premalignant lineages before they become cancerous, another argument against the mutator hypothesis. Finally, the need for acquisition of a mutator mutation imposes an additional step on the carcinogenic process. Accordingly, the mutator hypothesis has been a seminal but controversial idea for several decades despite considerable experimental and theoretical work. To resolve this debate, the concept of efficiency has been introduced as a metric for comparing carcinogenic mechanisms, and a new theoretical approach of focused quantitative modeling has been applied. The results demonstrate that, given what is already known, the predominance of mutator mechanisms is likely inevitable, as they overwhelm less efficient non-mutator pathways to cancer. PMID:20934514

  9. Studies of human mutation rates

    SciTech Connect

    Neel, J.V.

    1990-01-01

    November 1989, marked the beginning of a new three-year cycle of DOE grant support, in connection with which the program underwent a major reorganization. This document presents the progress on the three objectives of the present program which are: to isolate by the technique of two-dimensional polyacrylamide gel electrophoresis (2-D PAGE), proteins of special interest because of the relative mutability of the corresponding gene, establish the identity of the protein, and, for selected proteins, move to a characterization of the corresponding gene; to develop a more efficient approach, based on 2-D PAGE, for the detection of variants in DNA, with special reference to the identification of mutations in the parents of the individual whose DNA is being examined; and, to continue an effective interface with the genetic studies on the children of atomic bomb survivors in Japan, with reference to both the planning and implementation of new studies at the molecular level.

  10. Die Evolution des Universums. Eine Geschichte der Kosmologie.

    NASA Astrophysics Data System (ADS)

    Hiller, H.

    This volume covers in an elementary course a historical overview on cosmology ranging from the ancient aspects up to big bang theory and the concepts of inflationary universe and grand unified theories. Contents: 1. Auf dem Wege zur Wissenschaft. 2. Die neue Kosmologie. 3. Die Struktur des Weltalls. 4. Dramatik im Weltall. 5. Die endliche Welt. 6. Die Evolution des frühen Universums. 7. Die Zukunft. 8. Die neue Teleologie. 9. Das Leben.

  11. De novo mutations in epileptic encephalopathies.

    PubMed

    Allen, Andrew S; Berkovic, Samuel F; Cossette, Patrick; Delanty, Norman; Dlugos, Dennis; Eichler, Evan E; Epstein, Michael P; Glauser, Tracy; Goldstein, David B; Han, Yujun; Heinzen, Erin L; Hitomi, Yuki; Howell, Katherine B; Johnson, Michael R; Kuzniecky, Ruben; Lowenstein, Daniel H; Lu, Yi-Fan; Madou, Maura R Z; Marson, Anthony G; Mefford, Heather C; Esmaeeli Nieh, Sahar; O'Brien, Terence J; Ottman, Ruth; Petrovski, Slavé; Poduri, Annapurna; Ruzzo, Elizabeth K; Scheffer, Ingrid E; Sherr, Elliott H; Yuskaitis, Christopher J; Abou-Khalil, Bassel; Alldredge, Brian K; Bautista, Jocelyn F; Berkovic, Samuel F; Boro, Alex; Cascino, Gregory D; Consalvo, Damian; Crumrine, Patricia; Devinsky, Orrin; Dlugos, Dennis; Epstein, Michael P; Fiol, Miguel; Fountain, Nathan B; French, Jacqueline; Friedman, Daniel; Geller, Eric B; Glauser, Tracy; Glynn, Simon; Haut, Sheryl R; Hayward, Jean; Helmers, Sandra L; Joshi, Sucheta; Kanner, Andres; Kirsch, Heidi E; Knowlton, Robert C; Kossoff, Eric H; Kuperman, Rachel; Kuzniecky, Ruben; Lowenstein, Daniel H; McGuire, Shannon M; Motika, Paul V; Novotny, Edward J; Ottman, Ruth; Paolicchi, Juliann M; Parent, Jack M; Park, Kristen; Poduri, Annapurna; Scheffer, Ingrid E; Shellhaas, Renée A; Sherr, Elliott H; Shih, Jerry J; Singh, Rani; Sirven, Joseph; Smith, Michael C; Sullivan, Joseph; Lin Thio, Liu; Venkat, Anu; Vining, Eileen P G; Von Allmen, Gretchen K; Weisenberg, Judith L; Widdess-Walsh, Peter; Winawer, Melodie R

    2013-09-12

    Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10(-3)). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10(-10) and P = 7.8 × 10(-12), respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10(-8)), as has been reported previously for autism spectrum disorders.

  12. Quantifying the mutational meltdown in diploid populations.

    PubMed

    Coron, Camille; Méléard, Sylvie; Porcher, Emmanuelle; Robert, Alexandre

    2013-05-01

    Mutational meltdown, in which demographic and genetic processes mutually reinforce one another to accelerate the extinction of small populations, has been poorly quantified despite its potential importance in conservation biology. Here we present a model-based framework to study and quantify the mutational meltdown in a finite diploid population that is evolving continuously in time and subject to resource competition. We model slightly deleterious mutations affecting the population demographic parameters and study how the rate of mutation fixation increases as the genetic load increases, a process that we investigate at two timescales: an ecological scale and a mutational scale. Unlike most previous studies, we treat population size as a random process in continuous time. We show that as deleterious mutations accumulate, the decrease in mean population size accelerates with time relative to a null model with a constant mean fixation time. We quantify this mutational meltdown via the change in the mean fixation time after each new mutation fixation, and we show that the meltdown appears less severe than predicted by earlier theoretical work. We also emphasize that mean population size alone can be a misleading index of the risk of population extinction, which could be better evaluated with additional information on demographic parameters.

  13. Mitochondrial DNA mutations in human cancer.

    PubMed

    Chatterjee, A; Mambo, E; Sidransky, D

    2006-08-01

    Somatic mitochondrial DNA (mtDNA) mutations have been increasingly observed in primary human cancers. As each cell contains many mitochondria with multiple copies of mtDNA, it is possible that wild-type and mutant mtDNA can co-exist in a state called heteroplasmy. During cell division, mitochondria are randomly distributed to daughter cells. Over time, the proportion of the mutant mtDNA within the cell can vary and may drift toward predominantly mutant or wild type to achieve homoplasmy. Thus, the biological impact of a given mutation may vary, depending on the proportion of mutant mtDNAs carried by the cell. This effect contributes to the various phenotypes observed among family members carrying the same pathogenic mtDNA mutation. Most mutations occur in the coding sequences but few result in substantial amino acid changes raising questions as to their biological consequence. Studies reveal that mtDNA play a crucial role in the development of cancer but further work is required to establish the functional significance of specific mitochondrial mutations in cancer and disease progression. The origin of somatic mtDNA mutations in human cancer and their potential diagnostic and therapeutic implications in cancer are discussed. This review article provides a detailed summary of mtDNA mutations that have been reported in various types of cancer. Furthermore, this review offers some perspective as to the origin of these of mutations, their functional consequences in cancer development, and possible therapeutic implications.

  14. Stress-directed adaptive mutations and evolution.

    PubMed

    Wright, Barbara E

    2004-05-01

    Comparative biochemistry demonstrates that the metabolites, complex biochemical networks, enzymes and regulatory mechanisms essential to all living cells are conserved in amazing detail throughout evolution. Thus, in order to evolve, an organism must overcome new adverse conditions without creating different but equally dangerous alterations in its ongoing successful metabolic relationship with its environment. Evidence suggests that stable long-term acquisitive evolution results from minor increases in mutation rates of genes related to a particular stress, with minimal disturbance to the balanced and resilient metabolism critical for responding to an unpredictable environment. Microorganisms have evolved specific biochemical feedback mechanisms that direct mutations to genes derepressed by starvation or other stressors in their environment. Transcription of the activated genes creates localized supercoiling and DNA secondary structures with unpaired bases vulnerable to mutation. The resulting mutants provide appropriate variants for selection by the stress involved, thus accelerating evolution with minimal random damage to the genome. This model has successfully predicted mutation frequencies in genes of E. coli and humans. Stressed cells observed in the laboratory over hundreds of generations accumulate mutations that also arise by this mechanism. When this occurs in repair-deficient mutator strains with high rates of random mutation, the specific stress-directed mutations are also enhanced.

  15. Analyzing Effects of Naturally Occurring Missense Mutations

    PubMed Central

    Zhang, Zhe; Miteva, Maria A.; Wang, Lin; Alexov, Emil

    2012-01-01

    Single-point mutation in genome, for example, single-nucleotide polymorphism (SNP) or rare genetic mutation, is the change of a single nucleotide for another in the genome sequence. Some of them will produce an amino acid substitution in the corresponding protein sequence (missense mutations); others will not. This paper focuses on genetic mutations resulting in a change in the amino acid sequence of the corresponding protein and how to assess their effects on protein wild-type characteristics. The existing methods and approaches for predicting the effects of mutation on protein stability, structure, and dynamics are outlined and discussed with respect to their underlying principles. Available resources, either as stand-alone applications or webservers, are pointed out as well. It is emphasized that understanding the molecular mechanisms behind these effects due to these missense mutations is of critical importance for detecting disease-causing mutations. The paper provides several examples of the application of 3D structure-based methods to model the effects of protein stability and protein-protein interactions caused by missense mutations as well. PMID:22577471

  16. Validation of Deleterious Mutations in Vorderwald Cattle

    PubMed Central

    Reinartz, Sina; Distl, Ottmar

    2016-01-01

    In Montbéliarde cattle two candidate mutations on bovine chromosomes 19 and 29 responsible for embryonic lethality have been detected. Montbéliarde bulls have been introduced into Vorderwald cattle to improve milk and fattening performance. Due to the small population size of Vorderwald cattle and the wide use of a few Montbéliarde bulls through artificial insemination, inbreeding on Montbéliarde bulls in later generations was increasing. Therefore, we genotyped an aborted fetus which was inbred on Montbéliarde as well as Vorderwald x Montbéliarde crossbred bulls for both deleterious mutations. The abortion was observed in an experimental herd of Vorderwald cattle. The objectives of the present study were to prove if one or both lethal mutations may be assumed to have caused this abortion and to show whether these deleterious mutations have been introduced into the Vorderwald cattle population through Montbéliarde bulls. The aborted fetus was homozygous for the SLC37A2:g.28879810C>T mutation (ss2019324563) on BTA29 and both parents as well as the paternal and maternal grandsire were heterozygous for this mutation. In addition, the parents and the paternal grandsire were carriers of the MH2-haplotype linked with the T-allele of the SLC37A2:g.28879810C>T mutation. For the SHBG:g.27956790C>T mutation (rs38377500) on BTA19 (MH1), the aborted fetus and its sire were heterozygous. Among all further 341 Vorderwald cattle genotyped we found 27 SLC37A2:g.28879810C>T heterozygous animals resulting in an allele frequency of 0.0396. Among the 120 male Vorderwald cattle, there were 12 heterozygous with an allele frequency of 0.05. The SLC37A2:g.28879810C>T mutation could not be found in further nine cattle breeds nor in Vorderwald cattle with contributions from Ayrshire bulls. In 69 Vorderwald cattle without genes from Montbéliarde bulls the mutated allele of SLC37A2:g.28879810C>T could not be detected. The SHBG:g.27956790C>T mutation appeared unlikely to be responsible

  17. Validation of Deleterious Mutations in Vorderwald Cattle.

    PubMed

    Reinartz, Sina; Distl, Ottmar

    2016-01-01

    In Montbéliarde cattle two candidate mutations on bovine chromosomes 19 and 29 responsible for embryonic lethality have been detected. Montbéliarde bulls have been introduced into Vorderwald cattle to improve milk and fattening performance. Due to the small population size of Vorderwald cattle and the wide use of a few Montbéliarde bulls through artificial insemination, inbreeding on Montbéliarde bulls in later generations was increasing. Therefore, we genotyped an aborted fetus which was inbred on Montbéliarde as well as Vorderwald x Montbéliarde crossbred bulls for both deleterious mutations. The abortion was observed in an experimental herd of Vorderwald cattle. The objectives of the present study were to prove if one or both lethal mutations may be assumed to have caused this abortion and to show whether these deleterious mutations have been introduced into the Vorderwald cattle population through Montbéliarde bulls. The aborted fetus was homozygous for the SLC37A2:g.28879810C>T mutation (ss2019324563) on BTA29 and both parents as well as the paternal and maternal grandsire were heterozygous for this mutation. In addition, the parents and the paternal grandsire were carriers of the MH2-haplotype linked with the T-allele of the SLC37A2:g.28879810C>T mutation. For the SHBG:g.27956790C>T mutation (rs38377500) on BTA19 (MH1), the aborted fetus and its sire were heterozygous. Among all further 341 Vorderwald cattle genotyped we found 27 SLC37A2:g.28879810C>T heterozygous animals resulting in an allele frequency of 0.0396. Among the 120 male Vorderwald cattle, there were 12 heterozygous with an allele frequency of 0.05. The SLC37A2:g.28879810C>T mutation could not be found in further nine cattle breeds nor in Vorderwald cattle with contributions from Ayrshire bulls. In 69 Vorderwald cattle without genes from Montbéliarde bulls the mutated allele of SLC37A2:g.28879810C>T could not be detected. The SHBG:g.27956790C>T mutation appeared unlikely to be responsible

  18. The androgen receptor gene mutations database.

    PubMed

    Gottlieb, B; Trifiro, M; Lumbroso, R; Vasiliou, D M; Pinsky, L

    1996-01-01

    The current version of the androgen receptor (AR) gene mutations database is described. We have added (if available) data on the androgen binding phenotype of the mutant AR, the clinical phenotype of the affected persons, the family history and whether the pathogenicity of a mutation has been proven. Exonic mutations are now listed in 5'-->3' sequence regardless of type and single base pair changes are presented in codon context. Splice site and intronic mutations are listed separately. The database has allowed us to substantiate and amplify the observation of mutational hot spots within exons encoding the AR androgen binding domain. The database is available from EML (ftp://www.ebi.ac.uk/pub/databases/androgen) or as a Macintosh Filemaker file (MC33@musica.mcgill.ca).

  19. The fitness costs of antibiotic resistance mutations

    PubMed Central

    Melnyk, Anita H; Wong, Alex; Kassen, Rees

    2015-01-01

    Antibiotic resistance is increasing in pathogenic microbial populations and is thus a major threat to public health. The fate of a resistance mutation in pathogen populations is determined in part by its fitness. Mutations that suffer little or no fitness cost are more likely to persist in the absence of antibiotic treatment. In this review, we performed a meta-analysis to investigate the fitness costs associated with single mutational events that confer resistance. Generally, these mutations were costly, although several drug classes and species of bacteria on average did not show a cost. Further investigations into the rate and fitness values of compensatory mutations that alleviate the costs of resistance will help us to better understand both the emergence and management of antibiotic resistance in clinical settings. PMID:25861385

  20. Elevated germline mutation rate in teenage fathers

    PubMed Central

    Forster, Peter; Hohoff, Carsten; Dunkelmann, Bettina; Schürenkamp, Marianne; Pfeiffer, Heidi; Neuhuber, Franz; Brinkmann, Bernd

    2015-01-01

    Men age and die, while cells in their germline are programmed to be immortal. To elucidate how germ cells maintain viable DNA despite increasing parental age, we analysed DNA from 24 097 parents and their children, from Europe, the Middle East and Africa. We chose repetitive microsatellite DNA that mutates (unlike point mutations) only as a result of cellular replication, providing us with a natural ‘cell-cycle counter’. We observe, as expected, that the overall mutation rate for fathers is seven times higher than for mothers. Also as expected, mothers have a low and lifelong constant DNA mutation rate. Surprisingly, however, we discover that (i) teenage fathers already set out from a much higher mutation rate than teenage mothers (potentially equivalent to 77–196 male germline cell divisions by puberty); and (ii) ageing men maintain sperm DNA quality similar to that of teenagers, presumably by using fresh batches of stem cells known as ‘A-dark spermatogonia’. PMID:25694621

  1. The Human PAX6 Mutation Database.

    PubMed

    Brown, A; McKie, M; van Heyningen, V; Prosser, J

    1998-01-01

    The Human PAX6 Mutation Database contains details of 94 mutations of the PAX6 gene. A Microsoft Access program is used by the Curator to store, update and search the database entries. Mutations can be entered directly by the Curator, or imported from submissions made via the World Wide Web. The PAX6 Mutation Database web page at URL http://www.hgu.mrc.ac.uk/Softdata/PAX6/ provides information about PAX6, as well as a fill-in form through which new mutations can be submitted to the Curator. A search facility allows remote users to query the database. A plain text format file of the data can be downloaded via the World Wide Web. The Curation program contains prior knowledge of the genetic code and of the PAX6 gene including cDNA sequence, location of intron/exon boundaries, and protein domains, so that the minimum of information need be provided by the submitter or Curator.

  2. Quantification of Colonic Stem Cell Mutations.

    PubMed

    Whetstone, Ryan D; Gold, Barry

    2015-01-01

    The ability to measure stem cell mutations is a powerful tool to quantify in a critical cell population if, and to what extent, a chemical can induce mutations that potentially lead to cancer. The use of an enzymatic assay to quantify stem cell mutations in the X-linked glucose-6-phosphate dehydrogenase gene has been previously reported.(1) This method requires the preparation of frozen sections and incubation of the sectioned tissue with a reaction mixture that yields a blue color if the cells produce functional glucose-6-phosphate dehydrogenase (G6PD) enzyme. If not, the cells appear whitish. We have modified the reaction mixture using Optimal Cutting Temperature Compound (OCT) medium in place of polyvinyl alcohol. This facilitates pH measurement, increases solubilization of the G6PD staining components and restricts diffusion of the G6PD enzyme. To demonstrate that a mutation occurred in a stem cell, the entire crypt must lack G6PD enzymatic activity. Only if a stem cell harbors a phenotypic G6PD mutation will all of the progeny in the crypt lack G6PD enzymatic activity. To identify crypts with a stem cell mutation, four consecutive adjacent frozen sections (a level) were cut at 7 µm thicknesses. This approach of making adjacent cuts provides conformation that a crypt was fully mutated since the same mutated crypt will be observed in adjacent sections. Slides with tissue samples that were more than 50 µm apart were prepared to assess a total of >10(4) crypts per mouse. The mutation frequency is the number of observed mutated (white) crypts÷by the number of wild type (blue) crypts in a treatment group. PMID:26436534

  3. MED12 mutation in patients with hysteromyoma

    PubMed Central

    YE, JUN; WANG, HUA; CHEN, YA-BAO; YUAN, DONG-LAN; ZHANG, LI-XIN; LIU, LIN

    2015-01-01

    Mediator Complex Subunit 12 (MED12) is a subunit of the mediator complex, which is believed to regulate global, as well as gene-specific, transcription. It has been reported that MED12 is mutated at high frequency in hysteromyoma. Recent studies have also shown that MED12 presents with different mutation frequencies in hysteromyoma patients of different populations. However, there are few studies with regard to the MED12 gene mutation in hysteromyoma patients in the Chinese Han population. In the present study, the MED12 mutations of 171 patients with hysteromyoma were analyzed; the results showed that 93 patients exhibited different MED12 mutations, including 131G→T, 131G→A, 130G→A, 146C→T, 130G→A, 130G→C, 128A→C, 130G→T, 127Ins27, 118_132Del15, 117_134Del18, 131_148Del18 and 141_165Del15. The mutation frequency was similar to that found in individuals of African descent or individuals of other non-Caucasian ethnicities, and lower than that in the Finnish or North American populations. Further analysis of 141 patients whose hysteromyoma was measured showed that the mutation frequency of MED12 in patients with large hysteromyomas was significantly lower than that in those with small hysteromyomas. These results suggested that MED12 mutation was important in the development of hysteromyomas in the Chinese Han population and that the size of the hysteromyoma may negatively correlate with the mutation frequency of MED12. This study supplemented current information on MED12 mutations in different races and may aid in developing personalized diagnoses for patients with hysteromyoma in the future. PMID:26137144

  4. HPMV: human protein mutation viewer - relating sequence mutations to protein sequence architecture and function changes.

    PubMed

    Sherman, Westley Arthur; Kuchibhatla, Durga Bhavani; Limviphuvadh, Vachiranee; Maurer-Stroh, Sebastian; Eisenhaber, Birgit; Eisenhaber, Frank

    2015-10-01

    Next-generation sequencing advances are rapidly expanding the number of human mutations to be analyzed for causative roles in genetic disorders. Our Human Protein Mutation Viewer (HPMV) is intended to explore the biomolecular mechanistic significance of non-synonymous human mutations in protein-coding genomic regions. The tool helps to assess whether protein mutations affect the occurrence of sequence-architectural features (globular domains, targeting signals, post-translational modification sites, etc.). As input, HPMV accepts protein mutations - as UniProt accessions with mutations (e.g. HGVS nomenclature), genome coordinates, or FASTA sequences. As output, HPMV provides an interactive cartoon showing the mutations in relation to elements of the sequence architecture. A large variety of protein sequence architectural features were selected for their particular relevance to mutation interpretation. Clicking a sequence feature in the cartoon expands a tree view of additional information including multiple sequence alignments of conserved domains and a simple 3D viewer mapping the mutation to known PDB structures, if available. The cartoon is also correlated with a multiple sequence alignment of similar sequences from other organisms. In cases where a mutation is likely to have a straightforward interpretation (e.g. a point mutation disrupting a well-understood targeting signal), this interpretation is suggested. The interactive cartoon can be downloaded as standalone viewer in Java jar format to be saved and viewed later with only a standard Java runtime environment. The HPMV website is: http://hpmv.bii.a-star.edu.sg/ .

  5. Why Are Phenotypic Mutation Rates Much Higher Than Genotypic Mutation Rates?

    PubMed Central

    Bürger, Reinhard; Willensdorfer, Martin; Nowak, Martin A.

    2006-01-01

    The evolution of genotypic mutation rates has been investigated in numerous theoretical and experimental studies. Mutations, however, occur not only when copying DNA, but also when building the phenotype, especially when translating and transcribing DNA to RNA and protein. Here we study the effect of such phenotypic mutations. We find a maximum phenotypic mutation rate, umax, that is compatible with maintaining a certain function of the organism. This may be called a phenotypic error threshold. In particular, we find a minimum phenotypic mutation rate, umin, with the property that there is (nearly) no selection pressure to reduce the rate of phenotypic mutations below this value. If there is a cost for lowering the phenotypic mutation rate, then umin is close to the optimum phenotypic mutation rate that maximizes the fitness of the organism. In our model, there is selective pressure to decrease the rate of genotypic mutations to zero, but to decrease the rate of phenotypic mutations only to a positive value. Despite its simplicity, our model can explain part of the huge difference between genotypic and phenotypic mutation rates that is observed in nature. The relevant data are summarized. PMID:16143614

  6. Profil épidémiologique des tumeurs malignes primitives des glandes salivaires : à propos de 154 cas

    PubMed Central

    Setti, Khadija; Mouanis, Mohamed; Moumni, Abdelmounim; Maher, Mostafa; Harmouch, Amal

    2014-01-01

    Introduction Les tumeurs des glandes salivaires sont des tumeurs rares représentant 3à 5% des tumeurs de la tête et du cou. La classification de l'OMS 2005 distingue les tumeurs épithéliales, les tumeurs mésenchymateuses, les tumeurs hématologiques et les tumeurs secondaires. Méthodes Notre travail consiste en une étude rétrospective réalisée sur une période de 10 ans allant de janvier 2002 à janvier 2012. Les critères d'inclusion étaient: l'âge, le sexe, le siège de la tumeur et le type histologique. Résultats L'incidence annuelle des tumeurs malignes primitives des glandes salivaires dans notre série était de 15 cas par an. Cent cinquante quatre cas de tumeurs malignes primitives des glandes salivaires ont été colligés sans prédominance de sexe (78 femmes (50,6%) et 76 hommes (49,4%)). La moyenne d'âge était de 60 ans avec des extrêmes de 4 et 83 ans et un pic de fréquence entre 51et 70 ans. Deux tiers des cas (65%) avaient une localisation au niveau des glandes principales avec 66 cas au niveau de la parotide (43%) et 34 cas au niveau de la glande sous maxillaire (22%). Cinquante quatre patients avaient une tumeur maligne des glandes salivaires accessoires (35%) dont 61% au niveau du palais. Aucun cas de tumeur maligne de la glande sublinguale n'a été recensé dans notre étude. Le type histologique prédominant dans notre série était le carcinome adénoïde kystique et retrouvé chez 43 patients (27,9%), suivi de l'adénocarcinome sans autre indication chez 37 patients (24%) puis du carcinome mucoépidermoïde chez 16 patients (10,4%) et de l'adénocarcinome polymorphe de bas grade également chez 16 patients (10. 4%). Conclusion Les tumeurs malignes des glandes salivaires représentent un ensemble hétérogène de maladies de caractérisation complexe et de fréquence variable. PMID:25120861

  7. Desmin common mutation is associated with multi-systemic disease manifestations and depletion of mitochondria and mitochondrial DNA

    PubMed Central

    McCormick, Elizabeth M.; Kenyon, Lawrence; Falk, Marni J.

    2015-01-01

    Desmin (DES) is a major muscle scaffolding protein that also functions to anchor mitochondria. Pathogenic DES mutations, however, have not previously been recognized as a cause of multi-systemic mitochondrial disease. Here, we describe a 45-year-old man who presented to The Children's Hospital of Philadelphia Mitochondrial-Genetics Diagnostic Clinic for evaluation of progressive cardiac, neuromuscular, gastrointestinal, and mood disorders. Muscle biopsy at age 45 was remarkable for cytoplasmic bodies, as well as ragged red fibers and SDH positive/COX negative fibers that were suggestive of a mitochondrial myopathy. Muscle also showed significant reductions in mitochondrial content (16% of control mean for citrate synthase activity) and mitochondrial DNA (35% of control mean). His family history was significant for cardiac conduction defects and myopathy in multiple maternal relatives. Multiple single gene and panel-based sequencing studies were unrevealing. Whole exome sequencing identified a known pathogenic p.S13F mutation in DES that had previously been associated with desmin-related myopathy. Desmin-related myopathy is an autosomal dominant disorder characterized by right ventricular hypertrophic cardiomyopathy, myopathy, and arrhythmias. However, neuropathy, gastrointestinal dysfunction, and depletion of both mitochondria and mitochondrial DNA have not previously been widely recognized in this disorder. Recognition that mitochondrial dysfunction occurs in desmin-related myopathy clarifies the basis for the multi-systemic manifestations, as are typical of primary mitochondrial disorders. Understanding the mitochondrial pathophysiology of desmin-related myopathy highlights the possibility of new therapies for this otherwise untreatable and often fatal class of disease. We postulate that drug treatments aimed at improving mitochondrial biogenesis or reducing oxidative stress may be effective therapies to ameliorate the effects of desmin-related disease. PMID

  8. Physical characteristics of stream subbasins in the Des Moines River, Upper Des Moines River, and East Fork Des Moines River basins, southern Minnesota and northern Iowa

    USGS Publications Warehouse

    Sanocki, Christopher A.

    2000-01-01

    Data that describe the physical characteristics of stream subbasins upstream from selected sites on streams in the Des Moines River, Upper Des Moines River, and East Fork Des Moines River Basins, located in southwestern Minnesota, and northwestern Iowa, are presented in this report. The physical characteristics are the drainage area of the subbasin, the percentage area of the subbasin covered only by lakes, the percentage area of the subbasin covered by both lakes and wetlands, the main-channel length, and the main-channel slope. Stream sites include outlets of subbasins of at least 5 square miles, and locations of U.S. Geological Survey high-flow, and continuous-record gaging stations.

  9. [Le leadership en santé et l'éthique de la gestion des attentes des soignants et des patients].

    PubMed

    Browne, Alister

    2016-03-01

    Les dispensateurs de soins et les patients sont souvent déçus du niveau de soins que les hôpitaux publics peuvent prodiguer. La solution consiste à réduire les attentes. Les dispensateurs devraient être amenés à considérer que leur obligation consiste à prodiguer les meilleurs soins en fonction des ressources. Le public devrait être bien informé des services que les hôpitaux de soins actifs peuvent ou non lui offrir et participer aux prises de décision. Les leaders en santé peuvent jouer des rôles novateurs à cet égard.

  10. Mecanique et mecanisme de la dechirure des materiaux textiles

    NASA Astrophysics Data System (ADS)

    Triki, Ennouri

    Cette thèse vise à apporter une contribution à l’étude et à la modélisation de la déchirure des textiles et des textiles enduits. Notons que la résistance à la déchirure est l’une des caractéristiques mesurées pour les équipements de protection contre les agresseurs mécaniques en milieu de travail. Jusqu'à présent, ce comportement en déchirure a été étudié en mesurant la force de déchirure et le travail de déchirure. De fait, aucun critère de rupture en déchirure n’existe actuellement. Par conséquent, en s’inspirant de la théorie du Griffith et de la mécanique de la rupture, une formulation d’un nouveau critère de rupture des structures textiles a été proposée. Cette approche offre la possibilité de déterminer d’une manière plus précise l’énergie nécessaire pour la création d’une nouvelle surface de rupture. Ce critère nous permet d’analyser l’effet des caractéristiques des tissus sur la variation de l’énergie de rupture. Cette étude montre que la résistance au glissement des fils dans la structure est le principal facteur qui contrôle la propagation de la fissure. En se basant sur la théorie de la mécanique de la rupture, un modèle de calcul de l’énergie de rupture par déchirure a été aussi élaboré. Ce modèle de déchirure relie l’énergie aux paramètres caractérisant les phénomènes affectant la déchirure des tissus, notamment la force de glissement et la force à la rupture des fils. Cette modélisation a tenu compte de certaines caractéristiques des tissus tels que l’épaisseur du matériau, la densité des fils, etc. Par l’étude de la variation de l’énergie de rupture par déchirure en fonction du rapport établi entre la force à la rupture et la force de glissement d’un fil ( FYB/FS), l’effet des mécanismes de la propagation de la fissure dans les tissus sur leur comportement en déchirure a été aussi observé. Les résultats obtenus

  11. Bureau for International Language Coordination (BILC) Bulletin No. 2.

    ERIC Educational Resources Information Center

    Waters, J., Ed.

    This is the second bulletin in a series dealing with international issues in language instruction in the military. Articles include: (1) "L'Enseignement des langues (etrangeres) dans les Forces Armees Belges," (2) "La Morphologic de la Conjugaison ecrite simple en francais contemporain: evantail des cas et rendement des categories," (3) "Data…

  12. Les sarcomes des tissus mous: à propos de 33 cas

    PubMed Central

    Abdou, Jiddou; Elkabous, Mustapha; M'rabti, Hind; Errihani, Hassan

    2015-01-01

    L'objectif de cette étude est de rapporter les particularités épidémiologiques, cliniques, histologiques, thérapeutiques et évolutives des sarcomes des tissus mous à l'Institut National d'Oncologie et de définir les facteurs influençant la survie des patients. C'est une étude rétrospective de 33 cas de sarcome des tissus mous, colligés entre janvier 2008 et décembre 2010. Les critères d’éligibilité étaient un âge supérieur à 16 ans, une épreuve histologique d'un sarcome des tissus mous à l'exclusion des tumeurs stromales gastro-intestinales (GIST). Les items recueillis étaient: épidémiologiques, cliniques, histologiques, Radiologiques, et thérapeutiques. Des analyses univariées puis multivariées ont été réalisées à la recherche de facteurs influençant la survie à 2 ans. Il s'agit de 33 cas, 17 Hommes et 16 Femmes, l’âge moyen était de 43,21 ans (Extrêmes= 18-76 ans). La tumeur était localisée aux extrémités dans 24 cas (72,72%). Le type histologique prédominant était le Liposarcome dans 9 cas (27,27%). Le stade tumoral était localisé dans 25 cas (75,8%), métastatique dans 8 cas (24,2%). Vingt-cinq tumeurs ont été traitées chirurgicalement dont 21 cas (84%) de chirurgie conservatrice et 4 cas (16%) de chirurgie radicale. La radiothérapie a été réalisée chez 10 patients (30,3%). La chimiothérapie a été faite chez 20 patients. En analyse univariée les facteurs pronostiques étaient l’âge (p=0,03) et le stade tumoral (p=0,09). L’âge et le stade tumoral sont des facteurs pronostiques influençant la survie des sarcomes des tissus mous. PMID:27022434

  13. WT1 mutations in T-ALL.

    PubMed

    Tosello, Valeria; Mansour, Marc R; Barnes, Kelly; Paganin, Maddalena; Sulis, Maria Luisa; Jenkinson, Sarah; Allen, Christopher G; Gale, Rosemary E; Linch, David C; Palomero, Teresa; Real, Pedro; Murty, Vundavalli; Yao, Xiaopan; Richards, Susan M; Goldstone, Anthony; Rowe, Jacob; Basso, Giuseppe; Wiernik, Peter H; Paietta, Elisabeth; Pieters, Rob; Horstmann, Martin; Meijerink, Jules P P; Ferrando, Adolfo A

    2009-07-30

    The molecular mechanisms involved in disease progression and relapse in T-cell acute lymphoblastic leukemia (T-ALL) are poorly understood. We used single nucleotide polymorphism array analysis to analyze paired diagnostic and relapsed T-ALL samples to identify recurrent genetic alterations in T-ALL. This analysis showed that diagnosis and relapsed cases have common genetic alterations, but also that relapsed samples frequently lose chromosomal markers present at diagnosis, suggesting that relapsed T-ALL emerges from an ancestral clone different from the major leukemic population at diagnosis. In addition, we identified deletions and associated mutations in the WT1 tumor suppressor gene in 2 of 9 samples. Subsequent analysis showed WT1 mutations in 28 of 211 (13.2%) of pediatric and 10 of 85 (11.7%) of adult T-ALL cases. WT1 mutations present in T-ALL are predominantly heterozygous frameshift mutations resulting in truncation of the C-terminal zinc finger domains of this transcription factor. WT1 mutations are most prominently found in T-ALL cases with aberrant rearrangements of the oncogenic TLX1, TLX3, and HOXA transcription factor oncogenes. Survival analysis demonstrated that WT1 mutations do not confer adverse prognosis in pediatric and adult T-ALL. Overall, these results identify the presence of WT1 mutations as a recurrent genetic alteration in T-ALL. PMID:19494353

  14. SOX10 mutations mimic isolated hearing loss.

    PubMed

    Pingault, V; Faubert, E; Baral, V; Gherbi, S; Loundon, N; Couloigner, V; Denoyelle, F; Noël-Pétroff, N; Ducou Le Pointe, H; Elmaleh-Bergès, M; Bondurand, N; Marlin, S

    2015-10-01

    Ninety genes have been identified to date that are involved in non-syndromic hearing loss, and more than 300 different forms of syndromic hearing impairment have been described. Mutations in SOX10, one of the genes contributing to syndromic hearing loss, induce a large range of phenotypes, including several subtypes of Waardenburg syndrome and Kallmann syndrome with deafness. In addition, rare mutations have been identified in patients with isolated signs of these diseases. We used the recent characterization of temporal bone imaging aspects in patients with SOX10 mutations to identify possible patients with isolated hearing loss due to SOX10 mutation. We selected 21 patients with isolated deafness and temporal bone morphological defects for mutational screening. We identified two SOX10 mutations and found that both resulted in a non-functional protein in vitro. Re-evaluation of the two affected patients showed that both had previously undiagnosed olfactory defects. Diagnosis of anosmia or hyposmia in young children is challenging, and particularly in the absence of magnetic resonance imaging (MRI), SOX10 mutations can mimic non-syndromic hearing impairment. MRI should complete temporal bones computed tomographic scan in the management of congenital deafness as it can detect brain anomalies, cochlear nerve defects, and olfactory bulb malformation in addition to inner ear malformations.

  15. RUNX2 mutations in cleidocranial dysplasia.

    PubMed

    Lee, K-E; Seymen, F; Ko, J; Yildirim, M; Tuna, E B; Gencay, K; Kim, J-W

    2013-01-01

    The runt-related transcription factor 2 gene (RUNX2), which is also known as CBFA1, is a master regulatory gene in bone formation. Mutations in RUNX2 have been identified in cleidocranial dysplasia (CCD) patients. CCD is a rare autosomal dominant skeletal dysplasia that is characterized by delayed closure of cranial sutures, aplastic or hypoplastic clavicle formation, short stature, and dental anomalies, including malocclusion, supernumerary teeth, and delayed eruption of permanent teeth. In this study, we recruited three de novo CCD families and performed mutational analysis of the RUNX2 gene as a candidate gene approach. The mutational study revealed three disease-causing mutations: a missense mutation (c.674G>A, p.Arg225Gln), a frameshift mutation (c.1119delC, p.Arg374Glyfs*), and a nonsense mutation (c.1171C>T, p.Arg391*). Clinical examination revealed a unique dental phenotype (no typical supernumerary teeth, but duplication of anterior teeth) in one patient. We believe that this finding will broaden the understanding of the mechanism of supernumerary teeth formation and CCD-related phenotypes. PMID:24222232

  16. New mutations affecting induced mutagenesis in yeast.

    PubMed

    Lawrence, C W; Krauss, B R; Christensen, R B

    1985-01-01

    Previously isolated mutations in baker's yeast, Saccharomyces cerevisiae, that impair induced mutagenesis were all identified with the aid of tests that either exclusively or predominantly detect base-pair substitutions. To avoid this bias, we have screened 11 366 potentially mutant clones for UV-induced reversion of the frameshift allele, his4-38, and have identified 10 mutants that give much reduced yields of revertants. Complementation and recombination tests show that 6 of these carry mutations at the previously known REV1, REV1 and REV3 loci, while the remaining 4 define 3 new genes, REV4 (2 mutations), REV5 and REV6. The rev4 mutations are readily suppressed in many genetic backgrounds and, like the rev5 mutation, impart only a limited deficiency for induced mutagenesis: it is likely, therefore that the REV4+ and REV5+ gene functions are only remotely concerned with this process. The rev6 mutants have a more general deficiency, however, as well as marked sensitivity to UV and an increased spontaneous mutation rate, properties that suggest the REV6 gene is directly involved in mutation induction. The REV5 gene is located about 1 cM proximal to CYC1 on chromosome X.

  17. Muller's ratchet, epistasis and mutation effects.

    PubMed

    Butcher, D

    1995-09-01

    In this study, computer simulation is used to show that despite synergistic epistasis for fitness, Muller's ratchet can lead to lethal fitness loss in a population of asexuals through the accumulation of deleterious mutations. This result contradicts previous work that indicated that epistasis will halt the ratchet. The present results show that epistasis will not halt the ratchet provided that rather than a single deleterious mutation effect, there is a distribution of deleterious mutation effects with sufficient density near zero. In addition to epistasis and mutation distribution, the ability of Muller's ratchet to lead to the extinction of an asexual population under epistasis for fitness depends strongly on the expected number of offspring that survive to reproductive age. This strong dependence is not present in the nonepistatic model and suggests that interpreting the population growth parameter as fecundity is inadequate. Because a continuous distribution of mutation effects is used in this model, an emphasis is placed on the dynamics of the mutation effect distribution rather than on the dynamics of the number of least mutation loaded individuals. This perspective suggests that current models of gene interaction are too simple to apply directly to long-term prediction for populations undergoing the ratchet.

  18. New mutations in CMT 1 and HNPP

    SciTech Connect

    Vandenberghe, A.; Boucherat, M.; Bonnebouche, C.

    1994-09-01

    The majority of mutations in CMT 1 (Charcot-Marie-Tooth disease type 1) are due to a duplication of a 1.5 Mb fragment from chromosome 17 containing the PMP22 myelin gene. In addition, micromutations are found in the genes for PMP22 and myelin Po. We collected data from over one hundred families with a duplication in 17p11.2. In about 10% of these families, a de novo mutation was observed. All parents were clinically examined as normal and correct paternity was confirmed. Some families were informative for polymorphic probes located in the duplicated region, and we could deduce a majority of new mutations to be from paternal origin. HNPP (hereditary neuropathy with liability to pressure palsies) is believed to be the reciprocal product of an unequal crossing over underlying the CMT 1 mutation and is due to a deletion of the 1.5 Mb fragment. One new HNPP mutation was found among 7 deleted HNPP families. This mutation is of paternal origin. Clinically assigned CMT 1 patients without a duplication are screened for micromutations applying the SSCP technique. In one family, a de novo mutation was found in the gene for Po.

  19. Significance of duon mutations in cancer genomes

    NASA Astrophysics Data System (ADS)

    Yadav, Vinod Kumar; Smith, Kyle S.; Flinders, Colin; Mumenthaler, Shannon M.; de, Subhajyoti

    2016-06-01

    Functional mutations in coding regions not only affect the structure and function of the protein products, but may also modulate their expression in some cases. This class of mutations, recently dubbed “duon mutations” due to their dual roles, can potentially have major impacts on downstream pathways. However their significance in diseases such as cancer remain unclear. In a survey covering 4606 samples from 19 cancer types, and integrating allelic expression, overall mRNA expression, regulatory motif perturbation, and chromatin signatures in one composite index called REDACT score, we identified potential duon mutations. Several such mutations are detected in known cancer genes in multiple cancer types. For instance a potential duon mutation in TP53 is associated with increased expression of the mutant allelic gene copy, thereby possibly amplifying the functional effects on the downstream pathways. Another potential duon mutation in SF3B1 is associated with abnormal splicing and changes in angiogenesis and matrix degradation related pathways. Our findings emphasize the need to interrogate the mutations in coding regions beyond their obvious effects on protein structures.

  20. Predicting Resistance Mutations Using Protein Design Algorithms

    SciTech Connect

    Frey, K.; Georgiev, I; Donald, B; Anderson, A

    2010-01-01

    Drug resistance resulting from mutations to the target is an unfortunate common phenomenon that limits the lifetime of many of the most successful drugs. In contrast to the investigation of mutations after clinical exposure, it would be powerful to be able to incorporate strategies early in the development process to predict and overcome the effects of possible resistance mutations. Here we present a unique prospective application of an ensemble-based protein design algorithm, K*, to predict potential resistance mutations in dihydrofolate reductase from Staphylococcus aureus using positive design to maintain catalytic function and negative design to interfere with binding of a lead inhibitor. Enzyme inhibition assays show that three of the four highly-ranked predicted mutants are active yet display lower affinity (18-, 9-, and 13-fold) for the inhibitor. A crystal structure of the top-ranked mutant enzyme validates the predicted conformations of the mutated residues and the structural basis of the loss of potency. The use of protein design algorithms to predict resistance mutations could be incorporated in a lead design strategy against any target that is susceptible to mutational resistance.

  1. RET mutations in MEN 2 associated diseases

    SciTech Connect

    Hofstra, R.M.W.; Stelwagen, T.; Stulp, R.P.

    1994-09-01

    Multiple endocrine neoplasia type 2 (MEN 2) comprises three clinically distinct dominantly inherited cancer syndromes namely MEN 2A, MEN 2B and familial medullary thyroid carcinoma (FMTC). Germline (point) mutations of the RET proto-oncogene have been reported to occur in all these syndromes. In MEN 2A and FMTC patients the mutations occurred within codons specifying cysteine residues in the transition of the RET extracellular and transmembrane domains, while in MEN 2B patients we could detect a single RET mutation in the tyrosine kinase domain in all patients. Also in patients suffering from Hirschsprung`s disease (HSCR), mutations in the RET gene have been found. These mutations are spread all over the gene. Several families have been described in which MEN 2 and HSCR are associated. MEN 2A is also found associated with cutaneous lichen amyloidosis (CLA). It might be that specific RET mutations correlate with these disease associations. We therefore scanned DNA from patients from a family with MEN 2A and HSCR, MEN 2A and CLA and CLA only for RET mutations. Results obtained thus far do not support the existence of specific correlations.

  2. Significance of duon mutations in cancer genomes

    PubMed Central

    Yadav, Vinod Kumar; Smith, Kyle S.; Flinders, Colin; Mumenthaler, Shannon M.; De, Subhajyoti

    2016-01-01

    Functional mutations in coding regions not only affect the structure and function of the protein products, but may also modulate their expression in some cases. This class of mutations, recently dubbed “duon mutations” due to their dual roles, can potentially have major impacts on downstream pathways. However their significance in diseases such as cancer remain unclear. In a survey covering 4606 samples from 19 cancer types, and integrating allelic expression, overall mRNA expression, regulatory motif perturbation, and chromatin signatures in one composite index called REDACT score, we identified potential duon mutations. Several such mutations are detected in known cancer genes in multiple cancer types. For instance a potential duon mutation in TP53 is associated with increased expression of the mutant allelic gene copy, thereby possibly amplifying the functional effects on the downstream pathways. Another potential duon mutation in SF3B1 is associated with abnormal splicing and changes in angiogenesis and matrix degradation related pathways. Our findings emphasize the need to interrogate the mutations in coding regions beyond their obvious effects on protein structures. PMID:27272679

  3. Proliferation of mutators in A cell population.

    PubMed Central

    Mao, E F; Lane, L; Lee, J; Miller, J H

    1997-01-01

    A Lac- strain of Escherichia coli that reverts by the addition of a G to a G-G-G-G-G-G sequence was used to study the proliferation of mutators in a bacterial culture. Selection for the Lac+ phenotype, which is greatly stimulated in mismatch repair-deficient strains, results in an increase in the percentage of mutators in the selected population from less than 1 per 100,000 cells to 1 per 200 cells. All the mutators detected were deficient in the mismatch repair system. Mutagenesis results in a similar increase in the percentage of mutators. Mutagenesis combined with a single selection can result in a population of more than 50% mutators when a sample of several thousand cells is grown out and selected. Mutagenesis combined with two or more successive selections can generate a population that is 100% mutator. These experiments are discussed in relation to ideas that an early step in carcinogenesis is the creation of a mutator phenotype. PMID:8990293

  4. BRCA1 mutations in southern England.

    PubMed Central

    Eccles, D. M.; Englefield, P.; Soulby, M. A.; Campbell, I. G.

    1998-01-01

    If genetic testing for breast and ovarian cancer predisposition is to become available within a public health care system there needs to be a rational and cost-effective approach to mutation analysis. We have screened for BRCA1 mutations in 230 women with breast cancer, all from the Wessex region of southern England, in order to establish the parameters on which to base a cost-effective regional mutation analysis strategy. Truncating mutations were detected in 10/155 (6.5%) consecutive cases selected only for diagnosis under the age of 40 (nine of these ten women had a strong family history of breast or ovarian cancer), 3/61 (4.9%) bilateral-breast cancer cases (all three mutations occurring among women for whom the first cancer was diagnosed under 40 years) and 8/30 (26.6%) breast cancer cases presenting to the genetics clinic (for whom a strong family history of breast and/or ovarian cancer was present). Ten different mutations were detected in 17 families, but three of these accounted for 10/17 (59%) of the families. The cost of screening the population for mutations in the entire BRCA1 gene is unacceptably high. However, the cost of screening a carefully selected patient cohort is low, the risk of misinterpretation much less and the potential clinical benefits clearer. PMID:9649133

  5. Genetic Characterization of a Novel Mutant of Peste Des Petits Ruminants Virus Isolated from Capra ibex in China during 2015

    PubMed Central

    Zhu, Zixiang; Zhang, Xiaocui; Adili, Gulizhati; Huang, Jiong; Du, Xiaoli; Zhang, Xiangle; Li, Pengfei; Zheng, Xueguang; Liu, Xiangtao; Zheng, Haixue; Xue, Qinghong

    2016-01-01

    Peste des petits ruminants virus (PPRV) is the causative agent of peste des petits ruminants (PPR). The spread of PPR often causes severe economic losses. Therefore, special attention should be paid to the surveillance of PPR emergence, spread, and geographic distribution. Here we describe a novel mutant of PPRV China/XJBZ/2015 that was isolated from Capra ibex in Xinjiang province in China 2015. The sequence analysis and phylogenetic assessment indicate that China/XJBZ/2015 belongs to lineage IV, being closely related to China/XJYL/2013 strain. Interestingly, the V protein sequence of China/XJBZ/2015 showed lower homology with other Chinese PPRVs isolated during 2013 to 2014 (94%~95%), whereas it shared 100% identity with three Tibet strains isolated in China 2007. The 3′ UTR, V gene, and C gene were determined to be highly variable. Besides, 29 PPR genomic sequences available in GenBank were analyzed in this study. It is the first time to use PPRV genomic sequences to classify the different lineages which confirmed the lineage clustering of PPRVs using N gene 255 bp fragments and F gene 322 bp fragments. In conclusion, our findings indicate that the PPRVs continue to evolve in China, and some new mutations have emerged. PMID:26998489

  6. Genetic Characterization of a Novel Mutant of Peste Des Petits Ruminants Virus Isolated from Capra ibex in China during 2015.

    PubMed

    Zhu, Zixiang; Zhang, Xiaocui; Adili, Gulizhati; Huang, Jiong; Du, Xiaoli; Zhang, Xiangle; Li, Pengfei; Zheng, Xueguang; Liu, Xiangtao; Zheng, Haixue; Xue, Qinghong

    2016-01-01

    Peste des petits ruminants virus (PPRV) is the causative agent of peste des petits ruminants (PPR). The spread of PPR often causes severe economic losses. Therefore, special attention should be paid to the surveillance of PPR emergence, spread, and geographic distribution. Here we describe a novel mutant of PPRV China/XJBZ/2015 that was isolated from Capra ibex in Xinjiang province in China 2015. The sequence analysis and phylogenetic assessment indicate that China/XJBZ/2015 belongs to lineage IV, being closely related to China/XJYL/2013 strain. Interestingly, the V protein sequence of China/XJBZ/2015 showed lower homology with other Chinese PPRVs isolated during 2013 to 2014 (94%~95%), whereas it shared 100% identity with three Tibet strains isolated in China 2007. The 3' UTR, V gene, and C gene were determined to be highly variable. Besides, 29 PPR genomic sequences available in GenBank were analyzed in this study. It is the first time to use PPRV genomic sequences to classify the different lineages which confirmed the lineage clustering of PPRVs using N gene 255 bp fragments and F gene 322 bp fragments. In conclusion, our findings indicate that the PPRVs continue to evolve in China, and some new mutations have emerged. PMID:26998489

  7. La planification préalable des soins pour les patients en pédiatrie

    PubMed Central

    2008-01-01

    RÉSUMÉ Les progrès médicaux et technologiques ont permis d’ac-croître les taux de survie et d’améliorer la qualité de vie des nourrissons, des enfants et des adolescents ayant des maladies chroniques mettant la vie en danger. La planifi-cation préalable des soins inclut le processus relié aux discussions sur les traitements essentiels au maintien de la survie et la détermination des objectifs des soins de longue durée. Les dispensateurs de soins pédiatriques ont l’obligation éthique d’assimiler cet aspect des soins médicaux. Le présent document de principes vise à aider les dispensateurs de soins à discuter de la planification préalable des soins des patients pédiatriques dans diverses situations. La planification préalable des soins exige des communications efficaces afin de clarifier les objectifs des soins et de s’entendre sur les traitements pertinents ou non pour réaliser ces objectifs, y compris les mesures de réanimation et les mesures palliatives.

  8. Reverse mutations in fragile X syndrome

    SciTech Connect

    Brown, W.T.; Nolin, S.; Houck, G.E.

    1994-09-01

    The fragile X syndrome is the most common inherited form of mental retardation. Yet new mutations have not been described and no affected child has been born to a carrier mother having less than 60 FMR-1 CGG triplet repeats. Reverse mutations also appear to be very rare. We have previously identified the daughter of a premutation mother (95 CGGs) who inherited a normal repeat size of 35 as a reverse mutation. In the process of carrier testing by PCR, we have now identified two additional females with reverse mutations. All three of these reverse mutation women were previously tested by linkage as part of known fragile X families (subsequently confirmed by direct analysis), and assigned a > 99% risk as a carrier. In the second family, the mother carries a premutation allele of 95 repeats and the daughter inherited a 43 repeat allele. Prior to direct DNA testing, she had a positive prenatal diagnosis by linkage (> 99% risk) and cytogenetics with 3/450 cells apparently positive. Subsequent retesting of the products of conception by PCR now reveals a 43 repeat allele from her carrier mother with an 82 repeat allele. Testing with close CA markers (FRAXAC1 and DXS548) confirmed that these women inherited the same chromosome and their full mutation brothers. Further analysis is pending. These examples of reverse mutations are the only ones we have identified in our study of offspring of more than 200 carriers (400+ meioses) examined to date. Therefore, we conclude the frequency of fragile X back mutations is likely to be less than 1%. Retesting of linkage positive carriers is recommended to detect reverse mutations and assure accurate genetic counseling.

  9. Comprehensive mutation profiling of mucinous gastric carcinoma.

    PubMed

    Rokutan, Hirofumi; Hosoda, Fumie; Hama, Natsuko; Nakamura, Hiromi; Totoki, Yasushi; Furukawa, Eisaku; Arakawa, Erika; Ohashi, Shoko; Urushidate, Tomoko; Satoh, Hironori; Shimizu, Hiroko; Igarashi, Keiko; Yachida, Shinichi; Katai, Hitoshi; Taniguchi, Hirokazu; Fukayama, Masashi; Shibata, Tatsuhiro

    2016-10-01

    Mucinous gastric carcinoma (MGC) is a unique subtype of gastric cancer with a poor survival outcome. Comprehensive molecular profiles and putative therapeutic targets of MGC remain undetermined. We subjected 16 tumour-normal tissue pairs to whole-exome sequencing (WES) and an expanded set of 52 tumour-normal tissue pairs to subsequent targeted sequencing. The latter focused on 114 genes identified by WES. Twenty-two histologically differentiated MGCs (D-MGCs) and 46 undifferentiated MGCs (U-MGCs) were analysed. Chromatin modifier genes, including ARID1A (21%), MLL2 (19%), MLL3 (15%), and KDM6A (7%), were frequently mutated (47%) in MGC. We also identified mutations in potential therapeutic target genes, including MTOR (9%), BRCA2 (9%), BRCA1 (7%), and ERBB3 (6%). RHOA mutation was detected only in 4% of U-MGCs and in no D-MGCs. MYH9 was recurrently (13%) mutated in MGC, with all these being of the U-MGC subtype (p = 0.023). Three U-MGCs harboured MYH9 nonsense mutations. MYH9 knockdown enhanced cell migration and induced intracytoplasmic mucin and cellular elongation. BCOR mutation was associated with improved survival. In U-MGCs, the MLH1 expression status and combined mutation status (TP53/BCL11B or TP53/MLL2) were prognostic factors. A comparative analysis of driver genes revealed that the mutation profile of D-MGC was similar to that of intestinal-type gastric cancer, whereas U-MGC was a distinct entity, harbouring a different mutational profile to intestinal- and diffuse-type gastric cancers. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:27313181

  10. BRCC3 mutations in myeloid neoplasms

    PubMed Central

    Huang, Dayong; Nagata, Yasunobu; Grossmann, Vera; Radivoyevitch, Tomas; Okuno, Yusuke; Nagae, Genta; Hosono, Naoko; Schnittger, Susanne; Sanada, Masashi; Przychodzen, Bartlomiej; Kon, Ayana; Polprasert, Chantana; Shen, Wenyi; Clemente, Michael J.; Phillips, James G.; Alpermann, Tamara; Yoshida, Kenichi; Nadarajah, Niroshan; Sekeres, Mikkael A.; Oakley, Kevin; Nguyen, Nhu; Shiraishi, Yuichi; Shiozawa, Yusuke; Chiba, Kenichi; Tanaka, Hiroko; Koeffler, H. Phillip; Klein, Hans-Ulrich; Dugas, Martin; Aburatani, Hiroyuki; Miyano, Satoru; Haferlach, Claudia; Kern, Wolfgang; Haferlach, Torsten; Du, Yang; Ogawa, Seishi; Makishima, Hideki

    2015-01-01

    Next generation sequencing technologies have provided insights into the molecular heterogeneity of various myeloid neoplasms, revealing previously unknown somatic genetic events. In our cohort of 1444 cases analyzed by next generation sequencing, somatic mutations in the gene BRCA1-BRCA2-containing complex 3 (BRCC3) were identified in 28 cases (1.9%). BRCC3 is a member of the JAMM/MPN+ family of zinc metalloproteases capable of cleaving Lys-63 linked polyubiquitin chains, and is implicated in DNA repair. The mutations were located throughout its coding region. The average variant allelic frequency of BRCC3 mutations was 30.1%, and by a serial sample analysis at two different time points a BRCC3 mutation was already identified in the initial stage of a myelodysplastic syndrome. BRCC3 mutations commonly occurred in nonsense (n=12), frameshift (n=4), and splice site (n=5) configurations. Due to the marginal male dominance (odds ratio; 2.00, 0.84–4.73) of BRCC3 mutations, the majority of mutations (n=23; 82%) were hemizygous. Phenotypically, BRCC3 mutations were frequently observed in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms and associated with -Y abnormality (odds ratio; 3.70, 1.25–11.0). Clinically, BRCC3 mutations were also related to higher age (P=0.01), although prognosis was not affected. Knockdown of Brcc3 gene expression in murine bone marrow lineage negative, Sca1 positive, c-kit positive cells resulted in 2-fold more colony formation and modest differentiation defect. Thus, BRCC3 likely plays a role as tumor-associated gene in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms. PMID:26001790

  11. BRCC3 mutations in myeloid neoplasms.

    PubMed

    Huang, Dayong; Nagata, Yasunobu; Grossmann, Vera; Radivoyevitch, Tomas; Okuno, Yusuke; Nagae, Genta; Hosono, Naoko; Schnittger, Susanne; Sanada, Masashi; Przychodzen, Bartlomiej; Kon, Ayana; Polprasert, Chantana; Shen, Wenyi; Clemente, Michael J; Phillips, James G; Alpermann, Tamara; Yoshida, Kenichi; Nadarajah, Niroshan; Sekeres, Mikkael A; Oakley, Kevin; Nguyen, Nhu; Shiraishi, Yuichi; Shiozawa, Yusuke; Chiba, Kenichi; Tanaka, Hiroko; Koeffler, H Phillip; Klein, Hans-Ulrich; Dugas, Martin; Aburatani, Hiroyuki; Miyano, Satoru; Haferlach, Claudia; Kern, Wolfgang; Haferlach, Torsten; Du, Yang; Ogawa, Seishi; Makishima, Hideki

    2015-08-01

    Next generation sequencing technologies have provided insights into the molecular heterogeneity of various myeloid neoplasms, revealing previously unknown somatic genetic events. In our cohort of 1444 cases analyzed by next generation sequencing, somatic mutations in the gene BRCA1-BRCA2-containing complex 3 (BRCC3) were identified in 28 cases (1.9%). BRCC3 is a member of the JAMM/MPN+ family of zinc metalloproteases capable of cleaving Lys-63 linked polyubiquitin chains, and is implicated in DNA repair. The mutations were located throughout its coding region. The average variant allelic frequency of BRCC3 mutations was 30.1%, and by a serial sample analysis at two different time points a BRCC3 mutation was already identified in the initial stage of a myelodysplastic syndrome. BRCC3 mutations commonly occurred in nonsense (n=12), frameshift (n=4), and splice site (n=5) configurations. Due to the marginal male dominance (odds ratio; 2.00, 0.84-4.73) of BRCC3 mutations, the majority of mutations (n=23; 82%) were hemizygous. Phenotypically, BRCC3 mutations were frequently observed in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms and associated with -Y abnormality (odds ratio; 3.70, 1.25-11.0). Clinically, BRCC3 mutations were also related to higher age (P=0.01), although prognosis was not affected. Knockdown of Brcc3 gene expression in murine bone marrow lineage negative, Sca1 positive, c-kit positive cells resulted in 2-fold more colony formation and modest differentiation defect. Thus, BRCC3 likely plays a role as tumor-associated gene in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms. PMID:26001790

  12. FLG mutations in ichthyosis vulgaris and atopic eczema: spectrum of mutations and population genetics.

    PubMed

    Akiyama, M

    2010-03-01

    Filaggrin is a key protein involved in skin barrier function. Mutations in the gene encoding filaggrin (FLG) have been identified as the cause of ichthyosis vulgaris and have been shown to be major predisposing factors for atopic eczema (AE), initially in European populations. Subsequently, FLG mutations were identified in Japanese, Chinese, Taiwanese and Korean populations. It was demonstrated that FLG mutations are closely associated with AE in the Japanese population. Notably, the same FLG mutations identified in the European population were rarely found in Asians. These results exemplify differences in filaggrin population genetics between Europe and Asia. For mutation screening, background information needs to be obtained on prevalent FLG mutations for each geographical population. It is therefore important to establish the global population genetics maps for FLG mutations. Mutations at any site within FLG, even mutations in C-terminal imperfect filaggrin repeats, cause significant reductions in amounts of profilaggrin/filaggrin peptide in patient epidermis as the C-terminal region is essential for proper processing of profilaggrin into filaggrin. Thus, no genotype-phenotype correlation has been observed in patients with FLG mutations. A restoration of the barrier function seems a feasible and promising strategy for treatment and prevention in individuals with filaggrin deficiency.

  13. MutationAligner: a resource of recurrent mutation hotspots in protein domains in cancer

    PubMed Central

    Gauthier, Nicholas Paul; Reznik, Ed; Gao, Jianjiong; Sumer, Selcuk Onur; Schultz, Nikolaus; Sander, Chris; Miller, Martin L.

    2016-01-01

    The MutationAligner web resource, available at http://www.mutationaligner.org, enables discovery and exploration of somatic mutation hotspots identified in protein domains in currently (mid-2015) more than 5000 cancer patient samples across 22 different tumor types. Using multiple sequence alignments of protein domains in the human genome, we extend the principle of recurrence analysis by aggregating mutations in homologous positions across sets of paralogous genes. Protein domain analysis enhances the statistical power to detect cancer-relevant mutations and links mutations to the specific biological functions encoded in domains. We illustrate how the MutationAligner database and interactive web tool can be used to explore, visualize and analyze mutation hotspots in protein domains across genes and tumor types. We believe that MutationAligner will be an important resource for the cancer research community by providing detailed clues for the functional importance of particular mutations, as well as for the design of functional genomics experiments and for decision support in precision medicine. MutationAligner is slated to be periodically updated to incorporate additional analyses and new data from cancer genomics projects. PMID:26590264

  14. Mutational screening of the RB1 gene in Italian patients with retinoblastoma reveals 11 novel mutations.

    PubMed

    Sampieri, Katia; Hadjistilianou, Theodora; Mari, Francesca; Speciale, Caterina; Mencarelli, Maria Antonietta; Cetta, Francesco; Manoukian, Siranoush; Peissel, Bernard; Giachino, Daniela; Pasini, Barbara; Acquaviva, Antonio; Caporossi, Aldo; Frezzotti, Renato; Renieri, Alessandra; Bruttini, Mirella

    2006-01-01

    Retinoblastoma (RB, OMIM#180200) is the most common intraocular tumour in infancy and early childhood. Constituent mutations in the RB1 gene predispose individuals to RB development. We performed a mutational screening of the RB1 gene in Italian patients affected by RB referred to the Medical Genetics of the University of Siena. In 35 unrelated patients, we identified germline RB1 mutations in 6 out of 9 familial cases (66%) and in 7 out of 26 with no family history of RB (27%). Using the single-strand conformational polymorphism (SSCP) technique, 11 novel mutations were detected, including 3 nonsense, 5 frameshift and 4 splice-site mutations. Only two of these mutations (1 splice site and 1 missense) were previously reported. The mutation spectrum reflects the published literature, encompassing predominately nonsense or frameshift and splicing mutations. RB1 germline mutation was detected in 37% of our cases. Gross rearrangements outside the investigated region, altered DNA methylation, or mutations in non-coding regions, may be the cause of disease in the remainder of the patients. Some cases, e.g. a case of incomplete penetrance, or variable expressivity ranging from retinoma to multiple tumours, are discussed in detail. In addition, a case of pre-conception genetic counselling resolved by rescue of banked cordonal blood of the affected deceased child is described.

  15. La France contemporaine: bibliographie (Contemporary France: A Bibliography)

    ERIC Educational Resources Information Center

    Santoni, Georges V.

    1976-01-01

    A selective bibliography of relatively recent titles useful for incorporating cultural instruction in a French language or civilization course. It is divided into the following headings: reference; contemporary history; general works; the family; woman; teaching and youth; social groups; economics; urbanism and ecology; religion; information;…

  16. Studies of human mutation rates

    SciTech Connect

    Neel, J.V.

    1991-07-15

    The three objectives of the program are: To isolate by the technique of two-dimensional polyacrylamide gel electrophoresis (2-D PAGE), proteins of special interest because of the relative mutability of the corresponding gene, establish the identity of the protein, and, for selected proteins, move to a characterization of the corresponding gene; To develop a more efficient approach, based on 2-D PAGE, for the detection of variants in DNA, with special reference to the identification of a variant in a child not present in either parent of the child (i.e., a mutation); and, To continue an effective interface with the genetic studies on the children of atomic bomb survivors in Japan, with reference to both the planning and implementation of new studies at the molecular level. For administrative purposes, the program is subdivided into four sections, each under the direction of one of the four co-PIs; the progress during the past year will be summarized in accordance with this sectional structure. 1 tab.

  17. Melanoma: from mutations to medicine

    PubMed Central

    Tsao, Hensin; Chin, Lynda; Garraway, Levi A.; Fisher, David E.

    2012-01-01

    Melanoma is often considered one of the most aggressive and treatment-resistant human cancers. It is a disease that, due to the presence of melanin pigment, was accurately diagnosed earlier than most other malignancies and that has been subjected to countless therapeutic strategies. Aside from early surgical resection, no therapeutic modality has been found to afford a high likelihood of curative outcome. However, discoveries reported in recent years have revealed a near avalanche of breakthroughs in the melanoma field—breakthroughs that span fundamental understanding of the molecular basis of the disease all the way to new therapeutic strategies that produce unquestionable clinical benefit. These discoveries have been born from the successful fruits of numerous researchers working in many—sometimes-related, although also distinct—biomedical disciplines. Discoveries of frequent mutations involving BRAF(V600E), developmental and oncogenic roles for the microphthalmia-associated transcription factor (MITF) pathway, clinical efficacy of BRAF-targeted small molecules, and emerging mechanisms underlying resistance to targeted therapeutics represent just a sample of the findings that have created a striking inflection in the quest for clinically meaningful progress in the melanoma field. PMID:22661227

  18. De l'importance des orbites periodiques: Detection et applications

    NASA Astrophysics Data System (ADS)

    Doyon, Bernard

    L'ensemble des Orbites Periodiques Instables (OPIs) d'un systeme chaotique est intimement relie a ses proprietes dynamiques. A partir de l'ensemble (en principe infini) d'OPIs cachees dans l'espace des phases, on peut obtenir des quantites dynamiques importantes telles les exposants de Lyapunov, la mesure invariante, l'entropie topologique et la dimension fractale. En chaos quantique (i.e. l'etude de systemes quantiques qui ont un equivalent chaotique dans la limite classique), ces memes OPIs permettent de faire le pont entre le comportement classique et quantique de systemes non-integrables. La localisation de ces cycles fondamentaux est un probleme complexe. Cette these aborde dans un premier temps le probleme de la detection des OPIs dans les systemes chaotiques. Une etude comparative de deux algorithmes recents est presentee. Nous approfondissons ces deux methodes afin de les utiliser sur differents systemes dont des flots continus dissipatifs et conservatifs. Une analyse du taux de convergence des algorithmes est aussi realisee afin de degager les forces et les limites de ces schemes numeriques. Les methodes de detection que nous utilisons reposent sur une transformation particuliere de la dynamique initiale. Cette astuce nous a inspire une methode alternative pour cibler et stabiliser une orbite periodique quelconque dans un systeme chaotique. Le ciblage est en general combine aux methodes de controle pour stabiliser rapidement un cycle donne. En general, il faut connaitre la position et la stabilite du cycle en question. La nouvelle methode de ciblage que nous presentons ne demande pas de connaitre a priori la position et la stabilite des orbites periodiques. Elle pourrait etre un outil complementaire aux methodes de ciblage et de controle actuelles.

  19. Catalog Production for the DES Blind Cosmology Challenge

    NASA Astrophysics Data System (ADS)

    Busha, Michael T.; Wechsler, R. H.; Becker, M. R.; Erickson, B.; Evrard, A. E.

    2013-01-01

    The Blind Cosmology Challenge (BCC) is an effort by the Dark Energy Survey (DES) to test analysis tools for extracting cosmological information using a set of detailed synthetic galaxy catalogs. Here, we describe the creation of these synthetic sky catalogs based on requirements of the optical (DES) and the near-IR VISTA Hemisphere Survey, producing catalogs covering a quarter of the sky to z ˜ 2, with sources complete to r ˜ 25. Starting with a nested set of lightcone outputs of large, N-body simulation, galaxies are assigned to the dark matter distribution using an empirical algorithm that is tunable to match observed evolution of low-order galaxy population properties (counts and spatial clustering) in luminosity-color-density space. Galaxies are lensed by matter along the line of sight (including magnification, shape distortion, and multiple images), using a new algorithm that calculates shear with 3.22 arcsec resolution at galaxy positions in the full catalog. The catalog is well suited to support DES+VISTA joint studies of galaxy clustering, groups and clusters of galaxies, and gravitational lensing, and we highlight their application to the ongoing DES BBCC. Catalogs include ˜320 million galaxies and ˜150 million stars, with realistic colors, shapes and photometric errors. Using the expected DES photometric errors, three independent photometric redshift codes are run on the catalog, two of which produce full probability distributions. The synthetic observable catalog includes object position, magnitudes in the DES and VISTA bands, photometric errors, photometric redshifts, size, ellipticity, for each of ˜ 500 million objects. The galaxy distribution is additionally masked appropriately for the 5000 square degree DES footprint, including the impact of bright stars. In addition, we offer separate catalogs with magnitudes for additional existing and planned surveys, including SDSS, CFHTLS, HSC, LSST, and Euclid.

  20. Spectrum of mutations and genotype-phenotype analysis in Noonan syndrome patients with RIT1 mutations.

    PubMed

    Yaoita, Masako; Niihori, Tetsuya; Mizuno, Seiji; Okamoto, Nobuhiko; Hayashi, Shion; Watanabe, Atsushi; Yokozawa, Masato; Suzumura, Hiroshi; Nakahara, Akihiko; Nakano, Yusuke; Hokosaki, Tatsunori; Ohmori, Ayumi; Sawada, Hirofumi; Migita, Ohsuke; Mima, Aya; Lapunzina, Pablo; Santos-Simarro, Fernando; García-Miñaúr, Sixto; Ogata, Tsutomu; Kawame, Hiroshi; Kurosawa, Kenji; Ohashi, Hirofumi; Inoue, Shin-Ichi; Matsubara, Yoichi; Kure, Shigeo; Aoki, Yoko

    2016-02-01

    RASopathies are autosomal dominant disorders caused by mutations in more than 10 known genes that regulate the RAS/MAPK pathway. Noonan syndrome (NS) is a RASopathy characterized by a distinctive facial appearance, musculoskeletal abnormalities, and congenital heart defects. We have recently identified mutations in RIT1 in patients with NS. To delineate the clinical manifestations in RIT1 mutation-positive patients, we further performed a RIT1 analysis in RASopathy patients and identified 7 RIT1 mutations, including two novel mutations, p.A77S and p.A77T, in 14 of 186 patients. Perinatal abnormalities, including nuchal translucency, fetal hydrops, pleural effusion, or chylothorax and congenital heart defects, are observed in all RIT1 mutation-positive patients. Luciferase assays in NIH 3T3 cells demonstrated that the newly identified RIT1 mutants, including p.A77S and p.A77T, and the previously identified p.F82V, p.T83P, p.Y89H, and p.M90I, enhanced Elk1 transactivation. Genotype-phenotype correlation analyses of previously reported NS patients harboring RIT1, PTPN11, SOS1, RAF1, and KRAS revealed that hypertrophic cardiomyopathy (56 %) was more frequent in patients harboring a RIT1 mutation than in patients harboring PTPN11 (9 %) and SOS1 mutations (10 %). The rates of hypertrophic cardiomyopathy were similar between patients harboring RIT1 mutations and patients harboring RAF1 mutations (75 %). Short stature (52 %) was less prevalent in patients harboring RIT1 mutations than in patients harboring PTPN11 (71 %) and RAF1 (83 %) mutations. These results delineate the clinical manifestations of RIT1 mutation-positive NS patients: high frequencies of hypertrophic cardiomyopathy, atrial septal defects, and pulmonary stenosis; and lower frequencies of ptosis and short stature. PMID:26714497

  1. Novel pathogenic mutations in the glucocerebrosidase locus.

    PubMed

    Duran, Raquel; McNeill, Alisdair; Mehta, Atul; Hughes, Derralyn; Cox, Timothy; Deegan, Patrick; Schapira, Anthony H V; Hardy, John

    2012-08-01

    To determine the frequency of mutations responsible for Gaucher's disease, we systematically sequenced the GBA1 gene as part of a molecular characterization of 73 adult patients in the United Kingdom. Five hitherto unknown pathogenic variants were identified, one of which is a splice site change; the others are novel missense mutations. Given that GBA1 gene mutations are an important risk factor for the development of Parkinson's disease, we contend that a complete analysis and molecular characterization of both the known and novel GBA1 variants will be needed before the biochemical processes underlying this genetic association can be fully understood. PMID:22658918

  2. Novel mutations in the human HPRT gene.

    PubMed

    Nguyen, Khue Vu; Naviaux, Robert K; Paik, Kacie K; Nyhan, William L

    2011-06-01

    Inherited mutation of a purine salvage enzyme, hypoxanthine guanine phosphoribosyltransferase (HPRT), gives rise to Lesch-Nyhan Syndrome (LNS) or HPRT-related gout. Here, we report five novel independent mutations in the coding region of the HPRT gene from five unrelated male patients manifesting different clinical phenotypes associated with LNS: exon 2: c.133A > G, p.45R > G; c.35A > C, p.12D > A; c.88delG; exon 7: c.530A > T, p.177D > V; and c.318 + 1G > C: IVS3 + 1G > C splice site mutation.

  3. 75 FR 25319 - Agency Information Collection (Survey of Satisfaction With the Disability Evaluation System (DES...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-07

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF VETERANS AFFAIRS Agency Information Collection (Survey of Satisfaction With the Disability Evaluation System (DES... Control No. 2900-New (DES).'' SUPPLEMENTARY INFORMATION: Title: Survey of Satisfaction with the...

  4. Multiple mutations and mutation combinations in the sodium channel of permethrin resistant mosquitoes, Culex quinquefasciatus

    NASA Astrophysics Data System (ADS)

    Li, Ting; Zhang, Lee; Reid, William R.; Xu, Qiang; Dong, Ke; Liu, Nannan

    2012-10-01

    A previous study identified 3 nonsynonymous and 6 synonymous mutations in the entire mosquito sodium channel of Culex quinquefasciatus, the prevalence of which were strongly correlated with levels of resistance and increased dramatically following insecticide selection. However, it is unclear whether this is unique to this specific resistant population or is a common mechanism in field mosquito populations in response to insecticide pressure. The current study therefore further characterized these mutations and their combinations in other field and permethrin selected Culex mosquitoes, finding that the co-existence of all 9 mutations was indeed correlated with the high levels of permethrin resistance in mosquitoes. Comparison of mutation combinations revealed several common mutation combinations presented across different field and permethrin selected populations in response to high levels of insecticide resistance, demonstrating that the co-existence of multiple mutations is a common event in response to insecticide resistance across different Cx. quinquefasciatus mosquito populations.

  5. The androgen receptor gene mutations database.

    PubMed

    Gottlieb, B; Trifiro, M; Lumbroso, R; Pinsky, L

    1997-01-01

    The current version of the androgen receptor (AR) gene mutations database is described. The total number of reported mutations has risen from 212 to 272. We have expanded the database: (i) by adding a large amount of new data on somatic mutations in prostatic cancer tissue; (ii) by defining a new constitutional phenotype, mild androgen insensitivity (MAI); (iii) by placing additional relevant information on an internet site (http://www.mcgill.ca/androgendb/ ). The database has allowed us to examine the contribution of CpG sites to the multiplicity of reports of the same mutation in different families. The database is also available from EMBL (ftp.ebi.ac.uk/pub/databases/androgen) or as a Macintosh Filemaker Pro or Word file (MC33@musica,mcgill.ca)

  6. BRAF mutation in papillary thyroid carcinoma.

    PubMed

    Cohen, Yoram; Xing, Mingzhao; Mambo, Elizabeth; Guo, Zhongmin; Wu, Guogun; Trink, Barry; Beller, Uziel; Westra, William H; Ladenson, Paul W; Sidransky, David

    2003-04-16

    The BRAF gene has been found to be activated by mutation in human cancers, predominantly in malignant melanoma. We tested 476 primary tumors, including 214 lung, 126 head and neck, 54 thyroid, 27 bladder, 38 cervical, and 17 prostate cancers, for the BRAF T1796A mutation by polymerase chain reaction (PCR)-restriction enzyme analysis of BRAF exon 15. In 24 (69%) of the 35 papillary thyroid carcinomas examined, we found a missense thymine (T)-->adenine (A) transversion at nucleotide 1796 in the BRAF gene (T1796A). The T1796A mutation was detected in four lung cancers and in six head and neck cancers but not in bladder, cervical, or prostate cancers. Our data suggest that activating BRAF mutations may be an important event in the development of papillary thyroid cancer.

  7. Mutations affecting gonadotropin secretion and action.

    PubMed

    Huhtaniemi, Ilpo

    2003-01-01

    A number of mutations are known to disturb the development and function of the hypothalamic-pituitary-gonadal axis. They affect hypothalamic-pituitary-gonadal function at multiple levels, from the migration of gonadotropin releasing hormone neurons to the hypothalamus right through to gonadotropin action in the ovary and testis. Most of the mutations are inactivating, causing various forms of hypogonadism. Exceptions are the activating mutations of the luteinizing hormone receptor, causing male-limited gonadotropin-independent precocious puberty. The human mutations and genetically modified animal models have clarified the molecular pathogenesis of hypogonadism and such disorders can now be diagnosed using molecular biological techniques, enabling selection of specific treatments and appropriate counselling of patients and their families.

  8. BRCA1 and BRCA2 Mutations

    MedlinePlus

    ... testing may be offered. Genetic testing requires a DNA sample from blood or saliva. There are several ... specific BRCA mutation is present. This is called DNA sequencing. Your DNA then can be tested to ...

  9. Mutations in GNAL cause primary torsion dystonia

    PubMed Central

    Fuchs, Tania; Saunders-Pullman, Rachel; Masuho, Ikuo; Luciano, Marta San; Raymond, Deborah; Factor, Stewart; Lang, Anthony E.; Liang, Tsao-Wei; Trosch, Richard M.; White, Sierra; Ainehsazan, Edmond; Herve, Denis; Sharma, Nutan; Ehrlich, Michelle E.; Martemyanov, Kirill A.; Bressman, Susan B.; Ozelius, Laurie J.

    2012-01-01

    Dystonia is a movement disorder characterized by repetitive twisting muscle contractions and postures1,2. Its molecular pathophysiology is poorly understood, in part due to limited knowledge of the genetic basis of the disorder. Only three genes for primary torsion dystonia (PTD), TOR1A (DYT1)3, THAP1 (DYT6)4, and CIZ15 have been identified. Using exome sequencing in two PTD families we identified a novel causative gene, GNAL, with a nonsense p.S293X mutation resulting in premature stop codon in one family and a missense p.V137M mutation in the other. Screening of GNAL in 39 PTD families, revealed six additional novel mutations in this gene. Impaired function of several of the mutations was shown by bioluminescence resonance energy transfer (BRET) assays. PMID:23222958

  10. Emerging patterns of somatic mutations in cancer

    PubMed Central

    Watson, Ian R.; Takahashi, Koichi; Futreal, P. Andrew; Chin, Lynda

    2014-01-01

    The advance in technological tools for massively parallel, high-throughput sequencing of DNA has enabled the comprehensive characterization of somatic mutations in large number of tumor samples. Here, we review recent cancer genomic studies that have assembled emerging views of the landscapes of somatic mutations through deep sequencing analyses of the coding exomes and whole genomes in various cancer types. We discuss the comparative genomics of different cancers, including mutation rates, spectrums, and roles of environmental insults that influence these processes. We highlight the developing statistical approaches used to identify significantly mutated genes, and discuss the emerging biological and clinical insights from such analyses as well as the challenges ahead translating these genomic data into clinical impacts. PMID:24022702

  11. De novo mutations in human genetic disease.

    PubMed

    Veltman, Joris A; Brunner, Han G

    2012-08-01

    New mutations have long been known to cause genetic disease, but their true contribution to the disease burden can only now be determined using family-based whole-genome or whole-exome sequencing approaches. In this Review we discuss recent findings suggesting that de novo mutations play a prominent part in rare and common forms of neurodevelopmental diseases, including intellectual disability, autism and schizophrenia. De novo mutations provide a mechanism by which early-onset reproductively lethal diseases remain frequent in the population. These mutations, although individually rare, may capture a significant part of the heritability for complex genetic diseases that is not detectable by genome-wide association studies. PMID:22805709

  12. ATM Mutations in Cancer: Therapeutic Implications.

    PubMed

    Choi, Michael; Kipps, Thomas; Kurzrock, Razelle

    2016-08-01

    Activation of checkpoint arrest and homologous DNA repair are necessary for maintenance of genomic integrity during DNA replication. Germ-line mutations of the ataxia telangiectasia mutated (ATM) gene result in the well-characterized ataxia telangiectasia syndrome, which manifests with an increased cancer predisposition, including a 20% to 30% lifetime risk of lymphoid, gastric, breast, central nervous system, skin, and other cancers. Somatic ATM mutations or deletions are commonly found in lymphoid malignancies, as well as a variety of solid tumors. Such mutations may result in chemotherapy resistance and adverse prognosis, but may also be exploited by existing or emerging targeted therapies that produce synthetic lethal states. Mol Cancer Ther; 15(8); 1781-91. ©2016 AACR. PMID:27413114

  13. Emerging patterns of somatic mutations in cancer.

    PubMed

    Watson, Ian R; Takahashi, Koichi; Futreal, P Andrew; Chin, Lynda

    2013-10-01

    Recent advances in technological tools for massively parallel, high-throughput sequencing of DNA have enabled the comprehensive characterization of somatic mutations in a large number of tumour samples. In this Review, we describe recent cancer genomic studies that have assembled emerging views of the landscapes of somatic mutations through deep-sequencing analyses of the coding exomes and whole genomes in various cancer types. We discuss the comparative genomics of different cancers, including mutation rates and spectra, as well as the roles of environmental insults that influence these processes. We highlight the developing statistical approaches that are used to identify significantly mutated genes, and discuss the emerging biological and clinical insights from such analyses, as well as the future challenges of translating these genomic data into clinical impacts.

  14. Modelisation des emissions de particules microniques et nanometriques en usinage

    NASA Astrophysics Data System (ADS)

    Khettabi, Riad

    La mise en forme des pieces par usinage emet des particules, de tailles microscopiques et nanometriques, qui peuvent etre dangereuses pour la sante. Le but de ce travail est d'etudier les emissions de ces particules pour fins de prevention et reduction a la source. L'approche retenue est experimentale et theorique, aux deux echelles microscopique et macroscopique. Le travail commence par des essais permettant de determiner les influences du materiau, de l'outil et des parametres d'usinage sur les emissions de particules. E nsuite un nouveau parametre caracterisant les emissions, nomme Dust unit , est developpe et un modele predictif est propose. Ce modele est base sur une nouvelle theorie hybride qui integre les approches energetiques, tribologiques et deformation plastique, et inclut la geometrie de l'outil, les proprietes du materiau, les conditions de coupe et la segmentation des copeaux. Il ete valide au tournage sur quatre materiaux: A16061-T6, AISI1018, AISI4140 et fonte grise.

  15. A temperature-sensitive mutation affecting cilia regeneration, nuclear development, and the cell cycle of Tetrahymena thermophila is rescued by cytoplasmic exchange

    SciTech Connect

    Pennock, D.G.; Thatcher, T.; Gorovsky, M.A. )

    1988-07-01

    A temperature-sensitive mutation was isolated that blocks cilia regeneration and arrests growth in Tetrahymena thermophila. Protein and RNA synthesis and ATP production appeared to be largely unaffected at the restrictive temperature, suggesting that the mutation is specific for cilia regeneration and growth. At the restrictive temperature, mutant cells arrested at a specific point in the cell cycle, after macronuclear S phase and shortly before micronuclear mitosis. Arrested cels did not undergo nuclear divisions, DNA replication, or cytokinesis, so the mutation appears to cause true cell cycle arrest. Surprisingly, the mutation des not appear to affect micronuclear mitosis directly but rather some event(s) prior to micronuclear mitosis that must be completed before cells can complete the cell cycle. The cell cycle arrest was transiently complemented by wild-type cytoplasm exchanged during conjugation with a wild-type cell. Each starved, wild-type cell apparently contained enough rescuing factor to support an average of six cell divisions. Thus, this mutation affects assembly and/or function of at least one but not al of the microtubule-based structures in T. thermophila.

  16. Mutations of myelodysplastic syndromes (MDS): An update.

    PubMed

    Ganguly, Bani Bandana; Kadam, N N

    2016-01-01

    The plethora of knowledge gained on myelodysplastic syndromes (MDS), a heterogeneous pre-malignant disorder of hematopoietic stem cells, through sequencing of several pathway genes has unveiled molecular pathogenesis and its progression to AML. Evolution of phenotypic classification and risk-stratification based on peripheral cytopenias and blast count has moved to five-tier risk-groups solely concerning chromosomal aberrations. Increased frequency of complex abnormalities, which is associated with genetic instability, defines the subgroup of worst prognosis in MDS. However, the independent effect of monosomal karyotype remains controversial. Recent discoveries on mutations in RNA-splicing machinery (SF3B1, SRSF2, ZRSR2, U2AF1, U2AF2); DNA methylation (TET2, DNMT3A, IDH1/2); chromatin modification (ASXL1, EZH2); transcription factor (TP53, RUNX1); signal transduction/kinases (FLT3, JAK2); RAS pathway (KRAS, NRAS, CBL, NF1, PTPN11); cohesin complex (STAG2, CTCF, SMC1A, RAD21); DNA repair (ATM, BRCC3, DLRE1C, FANCL); and other pathway genes have given insights into the independent effects and interaction of co-occurrence of mutations on disease-phenotype. RNA-splicing and DNA methylation mutations appeared to occur early and are reported as 'founder' mutations in over 50% MDS patients. TET2 mutation, through altered DNA methylation, has been found to have independent prognostic response to hypomethylating agents. Moreover, presence of DNMT3A, TET2 and ASXL1 mutations in normal elderly individuals forms the basis of understanding that accumulation of somatic mutations may not cause direct disease-development; however, cooperation with other mutations in the genes that are frequently mutated in myeloid and other hematopoietic cancers might result in clonal expansion through self-renewal and/or proliferation of hematopoietic stem cells. Identification of small molecules as inhibitors of epigenetic mutations has opened avenues for tailoring targeted drug development. The

  17. Effect of Mutation Order on Myeloproliferative Neoplasms

    PubMed Central

    Nangalia, Jyoti; Silber, Yvonne; Wedge, David C.; Grinfeld, Jacob; Baxter, E. Joanna; Massie, Charles E.; Papaemmanuil, Elli; Menon, Suraj; Godfrey, Anna L.; Dimitropoulou, Danai; Guglielmelli, Paola; Bellosillo, Beatriz; Besses, Carles; Döhner, Konstanze; Harrison, Claire N.; Vassiliou, George S.; Vannucchi, Alessandro; Campbell, Peter J.; Green, Anthony R.

    2015-01-01

    BACKGROUND Cancers result from the accumulation of somatic mutations, and their properties are thought to reflect the sum of these mutations. However, little is known about the effect of the order in which mutations are acquired. METHODS We determined mutation order in patients with myeloproliferative neoplasms by genotyping hematopoietic colonies or by means of next-generation sequencing. Stem cells and progenitor cells were isolated to study the effect of mutation order on mature and immature hematopoietic cells. RESULTS The age at which a patient presented with a myeloproliferative neoplasm, acquisition of JAK2 V617F homozygosity, and the balance of immature progenitors were all influenced by mutation order. As compared with patients in whom the TET2 mutation was acquired first (hereafter referred to as “TET2-first patients”), patients in whom the Janus kinase 2 (JAK2) mutation was acquired first (“JAK2-first patients”) had a greater likelihood of presenting with polycythemia vera than with essential thrombocythemia, an increased risk of thrombosis, and an increased sensitivity of JAK2-mutant progenitors to ruxolitinib in vitro. Mutation order influenced the proliferative response to JAK2 V617F and the capacity of double-mutant hematopoietic cells and progenitor cells to generate colony-forming cells. Moreover, the hematopoietic stem-and-progenitor-cell compartment was dominated by TET2 single-mutant cells in TET2-first patients but by JAK2–TET2 double-mutant cells in JAK2-first patients. Prior mutation of TET2 altered the transcriptional consequences of JAK2 V617F in a cell-intrinsic manner and prevented JAK2 V617F from up-regulating genes associated with proliferation. CONCLUSIONS The order in which JAK2 and TET2 mutations were acquired influenced clinical features, the response to targeted therapy, the biology of stem and progenitor cells, and clonal evolution in patients with myeloproliferative neoplasms. (Funded by Leukemia and Lymphoma Research

  18. The stability of mutator (MR)-induced X-chromosomal recessive visible mutations in Drosophila melanogaster.

    PubMed

    Eeken, J C

    1982-10-01

    In Drosophila, MR (male recombination) second chromosomes are known to act as mutators and recombination inducers in males. The induction of visible mutations by MR is observed at only a limited number of genes, such as singed bristle (sn), raspberry eye colour (ras), yellow body colour (y) and a carmine eye colour (car). Furthermore, sn mutations induced by MR are highly unstable, changing from a strong to a weak expression or reverting to the wild-type. It has been hypothesized by analogy with IS mutations in microorganisms, that MR-induced mutations also represent mutations of the insertion type. In this investigation the stability of two MR-h12-induced X-linked visible mutations was tested, one singed (snMR) and one raspberry (rasMR). The reversion frequency of both MR-induced mutations was low in the base population as well as upon outcrossing to C(1)DX, yw f females. The data reported here show that the MR-induced mutations become highly unstable when MR is re-introduced. The change of expression of an MR-induced mutation to a weaker phenotype or to the wild-type occurred at a frequency of 3.3 X 10(-3) (ras) to 20.4 X 10(-3) (sn). Recessive lethal mutations induced by MR in the X-chromosomes carrying the MR-induced singed or raspberry mutation were isolated and analysed. Among 11 independently MR-induced lethals in the rasMR-carrying X-chromosome, 4 were found to be allelic to a small deficiency that included the raspberry gene. 13 lethals were induced by MR in the snMR-carrying X-chromosome. Of these, 3 were located near the sn locus but none was allelic to a deficiency including the singed gene. PMID:6815525

  19. [Afatinib as first-line therapy in mutation-positive EGFR. Results by type of mutation].

    PubMed

    Vidal, Óscar Juan

    2016-04-01

    The discovery of endothelial growth factor receptor (EGFR) mutations has laid the foundations for personalized medicine in non-small cell lung carcinoma (NSCLC). In phase III trials, the first-generation tyrosine kinase inhibitors (TKI), gefitinib and erlotinib, demonstrated greater efficacy compared with chemotherapy in patients with EGFR mutations, achieving progression-free survival of 8-13.5 months. Afatinib, a second-generation irreversible pan-ErbB inhibitor, is the first TKI that has shown a benefit in overall survival (OS) compared with chemotherapy in EGFR mutation-positive NSCLC when used as first-line treatment. Exon 19 deletion (Del19) and the single-point substitution mutation (L858R) in exon 21, called activating mutations due to their ability to confer sensitivity to TKI, represent approximately 90% of the EGFR mutations in NSCLC. Distinct sensitivity to TKI has been observed depending on the type of mutation, with greater progression-free survival in patients with the Del19 mutation. The analysis of OS in the LUX-Lung 3 and LUX-Lung 6 trials showed a statistically significant increase in survival in afatinib-treated patients with the Del 19 mutation, but no significant increase in that of patients with the L858R mutation. Direct comparison of afatinib and gefitinib as first-line therapy (LUX-Lung 7 trial) showed a statistically-significant increase in progression-free survival (hazard ratio: 0.73; 95% confidence interval, 0.57-0.95; p=0.0165) with afatinib. In the analysis by type of mutation, this benefit was observed for both the Del19 and the L858R mutations. PMID:27426243

  20. Normal mutation rate variants arise in a Mutator (Mut S) Escherichia coli population.

    PubMed

    Turrientes, María-Carmen; Baquero, Fernando; Levin, Bruce R; Martínez, José-Luis; Ripoll, Aida; González-Alba, José-María; Tobes, Raquel; Manrique, Marina; Baquero, Maria-Rosario; Rodríguez-Domínguez, Mario-José; Cantón, Rafael; Galán, Juan-Carlos

    2013-01-01

    The rate at which mutations are generated is central to the pace of evolution. Although this rate is remarkably similar amongst all cellular organisms, bacterial strains with mutation rates 100 fold greater than the modal rates of their species are commonly isolated from natural sources and emerge in experimental populations. Theoretical studies postulate and empirical studies teort the hypotheses that these "mutator" strains evolved in response to selection for elevated rates of generation of inherited variation that enable bacteria to adapt to novel and/or rapidly changing environments. Less clear are the conditions under which selection will favor reductions in mutation rates. Declines in rates of mutation for established populations of mutator bacteria are not anticipated if such changes are attributed to the costs of augmented rates of generation of deleterious mutations. Here we report experimental evidence of evolution towards reduced mutation rates in a clinical isolate of Escherichia coli with an hyper-mutable phenotype due a deletion in a mismatch repair gene, (ΔmutS). The emergence in a ΔmutS background of variants with mutation rates approaching those of the normal rates of strains carrying wild-type MutS was associated with increase in fitness with respect to ancestral strain. We postulate that such an increase in fitness could be attributed to the emergence of mechanisms driving a permanent "aerobic style of life", the negative consequence of this behavior being regulated by the evolution of mechanisms protecting the cell against increased endogenous oxidative radicals involved in DNA damage, and thus reducing mutation rate. Gene expression assays and full sequencing of evolved mutator and normo-mutable variants supports the hypothesis. In conclusion, we postulate that the observed reductions in mutation rate are coincidental to, rather than, the selective force responsible for this evolution.

  1. [Afatinib as first-line therapy in mutation-positive EGFR. Results by type of mutation].

    PubMed

    Vidal, Óscar Juan

    2016-04-01

    The discovery of endothelial growth factor receptor (EGFR) mutations has laid the foundations for personalized medicine in non-small cell lung carcinoma (NSCLC). In phase III trials, the first-generation tyrosine kinase inhibitors (TKI), gefitinib and erlotinib, demonstrated greater efficacy compared with chemotherapy in patients with EGFR mutations, achieving progression-free survival of 8-13.5 months. Afatinib, a second-generation irreversible pan-ErbB inhibitor, is the first TKI that has shown a benefit in overall survival (OS) compared with chemotherapy in EGFR mutation-positive NSCLC when used as first-line treatment. Exon 19 deletion (Del19) and the single-point substitution mutation (L858R) in exon 21, called activating mutations due to their ability to confer sensitivity to TKI, represent approximately 90% of the EGFR mutations in NSCLC. Distinct sensitivity to TKI has been observed depending on the type of mutation, with greater progression-free survival in patients with the Del19 mutation. The analysis of OS in the LUX-Lung 3 and LUX-Lung 6 trials showed a statistically significant increase in survival in afatinib-treated patients with the Del 19 mutation, but no significant increase in that of patients with the L858R mutation. Direct comparison of afatinib and gefitinib as first-line therapy (LUX-Lung 7 trial) showed a statistically-significant increase in progression-free survival (hazard ratio: 0.73; 95% confidence interval, 0.57-0.95; p=0.0165) with afatinib. In the analysis by type of mutation, this benefit was observed for both the Del19 and the L858R mutations.

  2. Recurrent inactivating RASA2 mutations in melanoma

    PubMed Central

    Arafeh, Rand; Qutob, Nouar; Emmanuel, Rafi; Keren-Paz, Alona; Madore, Jason; Elkahloun, Abdel; Wilmott, James S.; Gartner, Jared J.; Di Pizio, Antonella; Winograd-Katz, Sabina; Sindiri, Sivasish; Rotkopf, Ron; Dutton-Regester, Ken; Johansson, Peter; Pritchard, Antonia; Waddell, Nicola; Hill, Victoria K.; Lin, Jimmy C.; Hevroni, Yael; Rosenberg, Steven A.; Khan, Javed; Ben-Dor, Shifra; Niv, Masha Y.; Ulitsky, Igor; Mann, Graham J; Scolyer, Richard A.; Hayward, Nicholas K.; Samuels, Yardena

    2016-01-01

    Analysis of 501 melanoma exomes revealed RASA2, encoding a RasGAP, as a tumor-suppressor gene mutated in 5% of melanomas. Recurrent loss-of-function mutations in RASA2 were found to increase RAS activation, melanoma cell growth and migration. RASA2 expression was lost in ≥30% of human melanomas and was associated with reduced patient survival. These findings reveal RASA2 inactivation as a melanoma driver and highlight the importance of Ras GAPs in cancer. PMID:26502337

  3. Calreticulin (CALR) mutation in myeloproliferative neoplasms (MPNs)

    PubMed Central

    Luo, Wenyi

    2015-01-01

    As a heterogeneous group of disease, myeloproliferative neoplasms (MPNs) have confused hematologists and hematopathologists with their protean clinical presentations and myriads of morphologies. A thought of classifying MPNs based on molecular alterations has gained popularity because there is increasing evidence that molecular or chromosomal alterations have a better correlation with clinical presentation, response to therapies, and prognosis than conventional morphological classification. This type of efforts has been facilitated by the advancement of molecular technologies. A significant number of gene mutations have been identified in MPNs with JAK2 and MPL being the major ones. However, a significant gap is present in that many cases of MPNs do not harbor any of these mutations. This gap is recently filled by the discovery of Calreticulin (CALR) mutation in MPNs without JAK2 or MPL mutation and since then, the clinical and molecular correlation in MPNs has become a hot research topic. There seems to be a fairly consistent correlation between CALR mutation and certain hematological parameters such as a high platelet count and a better prognosis in MPNs with CALR mutation. However, controversies are present regarding the risks of thrombosis, interactions of CALR with other gene mutation, the role of CALR in the pathogenesis, and the optimal treatment strategies. In addition, there are many questions remain to be answered, which all boiled down to the molecular mechanisms by which CALR causes or contributes to MPNs. Here, we summarized current published literatures on CALR mutations in MPNs with an emphasis on the clinical-molecular correlation. We also discussed the controversies and questions remain to be answered. PMID:27358884

  4. (Somatic mutations in nuclear and mitochondrial DNA)

    SciTech Connect

    Not Available

    1992-01-01

    The study is concerned the design of new assays that may detect rare somatic mutations in nuclear and mitochondrial DNA, which may increase upon exposure to mutagens, and thus become a marker of human exposure to such mutagens. Two assays for somatic mutation were presented, one for mitochondrial DNA deletions which was developed by the author, and one for deletions of the ADA gene which resides in the nucleus.

  5. Simulated coevolution in a mutating ecology

    NASA Astrophysics Data System (ADS)

    Sá Martins, J. S.

    2000-03-01

    The bit-string Penna model is used to simulate the competition between an asexual parthenogenetic and a sexual population sharing the same environment. A newborn of either population can mutate and become a part of the other with some probability. In a stable environment the sexual population soon dies out. When an infestation by rapidly mutating genetically coupled parasites is introduced, however, sexual reproduction prevails, as predicted by the so-called Red Queen hypothesis for the evolution of sex.

  6. Comparative mutational analyses of influenza A viruses

    PubMed Central

    Cheung, Peter Pak-Hang; Rogozin, Igor B.; Choy, Ka-Tim; Ng, Hoi Yee

    2015-01-01

    The error-prone RNA-dependent RNA polymerase (RdRP) and external selective pressures are the driving forces for RNA viral diversity. When confounded by selective pressures, it is difficult to assess if influenza A viruses (IAV) that have a wide host range possess comparable or distinct spontaneous mutational frequency in their RdRPs. We used in-depth bioinformatics analyses to assess the spontaneous mutational frequencies of two RdRPs derived from human seasonal (A/Wuhan/359/95; Wuhan) and H5N1 (A/Vietnam/1203/04; VN1203) viruses using the mini-genome system with a common firefly luciferase reporter serving as the template. High-fidelity reverse transcriptase was applied to generate high-quality mutational spectra which allowed us to assess and compare the mutational frequencies and mutable motifs along a target sequence of the two RdRPs of two different subtypes. We observed correlated mutational spectra (τ correlation P < 0.0001), comparable mutational frequencies (H3N2:5.8 ± 0.9; H5N1:6.0 ± 0.5), and discovered a highly mutable motif “(A)AAG” for both Wuhan and VN1203 RdRPs. Results were then confirmed with two recombinant A/Puerto Rico/8/34 (PR8) viruses that possess RdRP derived from Wuhan or VN1203 (RG-PR8×WuhanPB2, PB1, PA, NP and RG-PR8×VN1203PB2, PB1, PA, NP). Applying novel bioinformatics analysis on influenza mutational spectra, we provide a platform for a comprehensive analysis of the spontaneous mutation spectra for an RNA virus. PMID:25404565

  7. Mutational spectrum of adult T-ALL.

    PubMed

    Neumann, Martin; Vosberg, Sebastian; Schlee, Cornelia; Heesch, Sandra; Schwartz, Stefan; Gökbuget, Nicola; Hoelzer, Dieter; Graf, Alexander; Krebs, Stefan; Bartram, Isabelle; Blum, Helmut; Brüggemann, Monika; Hecht, Jochen; Bohlander, Stefan K; Greif, Philipp A; Baldus, Claudia D

    2015-02-20

    Novel target discovery is warranted to improve treatment in adult T-cell acute lymphoblastic leukemia (T-ALL) patients. We provide a comprehensive study on mutations to enhance the understanding of therapeutic targets and studied 81 adult T-ALL patients. NOTCH1 exhibitedthe highest mutation rate (53%). Mutation frequencies of FBXW7 (10%), WT1 (10%), JAK3 (12%), PHF6 (11%), and BCL11B (10%) were in line with previous reports. We identified recurrent alterations in transcription factors DNM2, and RELN, the WNT pathway associated cadherin FAT1, and in epigenetic regulators (MLL2, EZH2). Interestingly, we discovered novel recurrent mutations in the DNA repair complex member HERC1, in NOTCH2, and in the splicing factor ZRSR2. A frequently affected pathway was the JAK/STAT pathway (18%) and a significant proportion of T-ALL patients harboured mutations in epigenetic regulators (33%), both predominantly found in the unfavourable subgroup of early T-ALL. Importantly, adult T-ALL patients not only showed a highly heterogeneous mutational spectrum, but also variable subclonal allele frequencies implicated in therapy resistance and evolution of relapse. In conclusion, we provide novel insights in genetic alterations of signalling pathways (e.g. druggable by γ-secretase inhibitors, JAK inhibitors or EZH2 inhibitors), present in over 80% of all adult T-ALL patients, that could guide novel therapeutic approaches.

  8. Mutational spectrum of adult T-ALL.

    PubMed

    Neumann, Martin; Vosberg, Sebastian; Schlee, Cornelia; Heesch, Sandra; Schwartz, Stefan; Gökbuget, Nicola; Hoelzer, Dieter; Graf, Alexander; Krebs, Stefan; Bartram, Isabelle; Blum, Helmut; Brüggemann, Monika; Hecht, Jochen; Bohlander, Stefan K; Greif, Philipp A; Baldus, Claudia D

    2015-02-20

    Novel target discovery is warranted to improve treatment in adult T-cell acute lymphoblastic leukemia (T-ALL) patients. We provide a comprehensive study on mutations to enhance the understanding of therapeutic targets and studied 81 adult T-ALL patients. NOTCH1 exhibitedthe highest mutation rate (53%). Mutation frequencies of FBXW7 (10%), WT1 (10%), JAK3 (12%), PHF6 (11%), and BCL11B (10%) were in line with previous reports. We identified recurrent alterations in transcription factors DNM2, and RELN, the WNT pathway associated cadherin FAT1, and in epigenetic regulators (MLL2, EZH2). Interestingly, we discovered novel recurrent mutations in the DNA repair complex member HERC1, in NOTCH2, and in the splicing factor ZRSR2. A frequently affected pathway was the JAK/STAT pathway (18%) and a significant proportion of T-ALL patients harboured mutations in epigenetic regulators (33%), both predominantly found in the unfavourable subgroup of early T-ALL. Importantly, adult T-ALL patients not only showed a highly heterogeneous mutational spectrum, but also variable subclonal allele frequencies implicated in therapy resistance and evolution of relapse. In conclusion, we provide novel insights in genetic alterations of signalling pathways (e.g. druggable by γ-secretase inhibitors, JAK inhibitors or EZH2 inhibitors), present in over 80% of all adult T-ALL patients, that could guide novel therapeutic approaches. PMID:25595890

  9. RELN Mutations in Autism Spectrum Disorder

    PubMed Central

    Lammert, Dawn B.; Howell, Brian W.

    2016-01-01

    RELN encodes a large, secreted glycoprotein integral to proper neuronal positioning during development and regulation of synaptic function postnatally. Rare, homozygous, null mutations lead to lissencephaly with cerebellar hypoplasia (LCH), accompanied by developmental delay and epilepsy. Until recently, little was known about the frequency or consequences of heterozygous mutations. Several lines of evidence from multiple studies now implicate heterozygous mutations in RELN in autism spectrum disorders (ASD). RELN maps to the AUTS1 locus on 7q22, and at this time over 40 distinct mutations have been identified that would alter the protein sequence, four of which are de novo. The RELN mutations that are most clearly consequential are those that are predicted to inactivate the signaling function of the encoded protein and those that fall in a highly conserved RXR motif found at the core of the 16 Reelin subrepeats. Despite the growing evidence of RELN dysfunction in ASD, it appears that these mutations in isolation are insufficient and that secondary genetic or environmental factors are likely required for a diagnosis. PMID:27064498

  10. Diploid yeast cells yield homozygous spontaneous mutations

    NASA Technical Reports Server (NTRS)

    Esposito, M. S.; Bruschi, C. V.; Brushi, C. V. (Principal Investigator)

    1993-01-01

    A leucine-requiring hybrid of Saccharomyces cerevisiae, homoallelic at the LEU1 locus (leu1-12/leu1-12) and heterozygous for three chromosome-VII genetic markers distal to the LEU1 locus, was employed to inquire: (1) whether spontaneous gene mutation and mitotic segregation of heterozygous markers occur in positive nonrandom association and (2) whether homozygous LEU1/LEU1 mutant diploids are generated. The results demonstrate that gene mutation of leu1-12 to LEU1 and mitotic segregation of heterozygous chromosome-VII markers occur in strong positive nonrandom association, suggesting that the stimulatory DNA lesion is both mutagenic and recombinogenic. In addition, genetic analysis of diploid Leu+ revertants revealed that approximately 3% of mutations of leu1-12 to LEU1 result in LEU1/LEU1 homozygotes. Red-white sectored Leu+ colonies exhibit genotypes that implicate post-replicational chromatid breakage and exchange near the site of leu1-12 reversion, chromosome loss, and subsequent restitution of diploidy, in the sequence of events leading to mutational homozygosis. By analogy, diploid cell populations can yield variants homozygous for novel recessive gene mutations at biologically significant rates. Mutational homozygosis may be relevant to both carcinogenesis and the evolution of asexual diploid organisms.

  11. A DSPP mutation causing dentinogenesis imperfecta and characterization of the mutational effect.

    PubMed

    Lee, Sook-Kyung; Lee, Kyung-Eun; Song, Su Jeong; Hyun, Hong-Keun; Lee, Sang-Hoon; Kim, Jung-Wook

    2013-01-01

    Mutations in the DSPP gene have been identified in nonsyndromic hereditary dentin defects, but the genotype-phenotype correlations are not fully understood. Recently, it has been demonstrated that the mutations of DSPP affecting the IPV leader sequence result in mutant DSPP retention in rough endoplasmic reticulum (ER). In this study, we identified a Korean family with dentinogenesis imperfecta type III. To identify the disease causing mutation in this family, we performed mutational analysis based on candidate gene sequencing. Exons and exon-intron boundaries of DSPP gene were sequenced, and the effects of the identified mutation on the pre-mRNA splicing and protein secretion were investigated. Candidate gene sequencing revealed a mutation (c.50C > T, p.P17L) in exon 2 of the DSPP gene. The splicing assay showed that the mutation did not influence pre-mRNA splicing. However, the mutation interfered with protein secretion and resulted in the mutant protein remaining largely in the ER. These results suggest that the mutation affects ER-to-Golgi apparatus export and results in the reduction of secreted DSPP and ER overload. This may induce cell stress and damage processing and/or transport of dentin matrix proteins or other critical proteins.

  12. Exploring the common molecular basis for the universal DNA mutation bias: Revival of Loewdin mutation model

    SciTech Connect

    Fu, Liang-Yu; Wang, Guang-Zhong; Ma, Bin-Guang; Zhang, Hong-Yu

    2011-06-10

    Highlights: {yields} There exists a universal G:C {yields} A:T mutation bias in three domains of life. {yields} This universal mutation bias has not been sufficiently explained. {yields} A DNA mutation model proposed by Loewdin 40 years ago offers a common explanation. -- Abstract: Recently, numerous genome analyses revealed the existence of a universal G:C {yields} A:T mutation bias in bacteria, fungi, plants and animals. To explore the molecular basis for this mutation bias, we examined the three well-known DNA mutation models, i.e., oxidative damage model, UV-radiation damage model and CpG hypermutation model. It was revealed that these models cannot provide a sufficient explanation to the universal mutation bias. Therefore, we resorted to a DNA mutation model proposed by Loewdin 40 years ago, which was based on inter-base double proton transfers (DPT). Since DPT is a fundamental and spontaneous chemical process and occurs much more frequently within GC pairs than AT pairs, Loewdin model offers a common explanation for the observed universal mutation bias and thus has broad biological implications.

  13. An Alpha Tubulin Mutation Suppresses Nuclear Migration Mutations in Aspergillus Nidulans

    PubMed Central

    Willins, D. A.; Xiang, X.; Morris, N. R.

    1995-01-01

    Microtubules and cytoplasmic dynein, a microtubule-dependent motor, are required for nuclei to move along the hyphae of filamentous fungi. Nuclear migration in Aspergillus nidulans is blocked by heat-sensitive (hs(-)) mutations in the nudA gene, which encodes dynein heavy chain, and the nudF gene, which encodes a G protein β-subunit-like protein. Hs(-) mutations in the nudC and nudG genes also prevent nuclear migration. We have isolated extragenic suppressor mutations that reverse the hs(-) phenotypes caused by these mutations. Here we show that one nudF suppressor also suppresses hs(-) mutations in nudA, nudC, and nudG and deletions in nudA and nudF. This suppressor mutation is in the tubA alpha tubulin gene, and its characteristics suggest that it destabilizes microtubules. The mutation alters microtubule staining and confers sensitivity to cold and benomyl, two treatments that destabilize microtubules. Treatment with low concentrations of benomyl also suppresses the hs(-) nudA, nudC, nudF, and nudG mutations and the nudA and nudF deletions. Suppression of the hs(-) nudA mutation and the nudA deletion is especially interesting because these strains lack active dynein heavy chain. Together, these results suggest that microtubule destabilization allows nuclei to migrate even in the absence of cytoplasmic dynein motor function. PMID:8601474

  14. Problemes en enseignement fonctionnel des langues (Problems in the Functional Teaching of Languages). Publication B-103.

    ERIC Educational Resources Information Center

    Alvarez, Gerardo, Ed.; Huot, Diane, Ed.

    Articles include: (1) "L'elaboration du materiel pedagogique pour des publics adultes" (The Elaboration of Teaching Materials for the Adult Public) by G. Painchaud-Leblanc, (2) "L'elaboration d'un programme d'etudes en francais langue seconde a partir des donnees recentes en didactique des langues" (The Elaboration of a Program of Study in French…

  15. [And Sarah Félix created "L 'Eau des Fées" and "La Parfumerie des Fées"].

    PubMed

    Raynal, Cécile

    2015-12-01

    century, the parisian perfumery of Sarah Felix was famous especially for her cosmetic "L'Eau des Fées" ("Water of the Fairies"), a dyeing supposed to give back to the old hair the color of their youth. Sarah Felix, sister of the famous actress Rachel, exercised several jobs before becoming perfumer. At first, she was actress, then she tried ... oyster culture in Normandy ! Abandoning these activities, Sarah Felix became really a businesswoman in Paris. She dedicated herself to perfumery, in particular to "L'Eau des Fées", from 1866. To launch its product, she was associated to competency characters (engineer, pharmacist, physician) and benefited from the protection of the imperial family. A lawsuit between the associates and the 1870 war hindered the company's early days, but "L'Eau des Fées" provided with quality pledges, imposed itself definitely. The "Parfumerie des Fées" completed the range of its cosmetics with creams, powders, etc. Sarah Félix paid attention to present "L'Eau des Fées" as a dye devoid of toxicity. Was it really the case and could il be sold nowadays? These two issues are discussed in the last part. PMID:26827551

  16. [And Sarah Félix created "L 'Eau des Fées" and "La Parfumerie des Fées"].

    PubMed

    Raynal, Cécile

    2015-12-01

    century, the parisian perfumery of Sarah Felix was famous especially for her cosmetic "L'Eau des Fées" ("Water of the Fairies"), a dyeing supposed to give back to the old hair the color of their youth. Sarah Felix, sister of the famous actress Rachel, exercised several jobs before becoming perfumer. At first, she was actress, then she tried ... oyster culture in Normandy ! Abandoning these activities, Sarah Felix became really a businesswoman in Paris. She dedicated herself to perfumery, in particular to "L'Eau des Fées", from 1866. To launch its product, she was associated to competency characters (engineer, pharmacist, physician) and benefited from the protection of the imperial family. A lawsuit between the associates and the 1870 war hindered the company's early days, but "L'Eau des Fées" provided with quality pledges, imposed itself definitely. The "Parfumerie des Fées" completed the range of its cosmetics with creams, powders, etc. Sarah Félix paid attention to present "L'Eau des Fées" as a dye devoid of toxicity. Was it really the case and could il be sold nowadays? These two issues are discussed in the last part.

  17. Restauration adaptative des contours par une approche inspiree de la prediction des performances

    NASA Astrophysics Data System (ADS)

    Rousseau, Kami

    En teledetection, les cartes de contours peuvent servir, entre autres choses, a la restitution geometrique, a la recherche d'elements lineaires, ainsi qu'a la segmentation. La creation de ces cartes est faite relativement tot dans la chaine de traitements d'une image. Pour assurer la qualite des operations subsequentes, il faut veiller a obtenir une carte de contours precise. Notre problematique est de savoir s'il est possible de diminuer la perte de temps liee au choix d'algorithme et de parametre en corrigeant automatiquement la carte de contours. Nous concentrerons donc nos efforts sur le developpement d'une methode de detection/restauration de contours adaptative. Notre methode s'inspire d'une technique de prediction des performances d'algorithmes de bas niveau. Elle consiste a integrer un traitement par reseau de neurones a une methode " classique " de detection de contours. Plus precisement, nous proposons de combiner la carte de performances avec la carte de gradient pour permettre des decisions plus exactes. La presente etude a permis de developper un logiciel comprenant un reseau de neurones entraine pour predire la presence de contours. Ce reseau de neurones permet d'ameliorer les decisions de detecteurs de contours, en reduisant le nombre de pixels de fausses alarmes et de contours manques. La premiere etape de ce travail consiste en une methode d'evaluation de performance pour les cartes de contours. Une fois ce choix effectue, il devient possible de comparer les cartes entre elles. Il est donc plus aise de determiner, pour chaque image, la meilleure detection de contours. La revue de la litterature realisee simultanement a permis de faire un choix d'un groupe d'indicateurs prometteurs pour la restauration de contours. Ces derniers ont servi a la calibration et a l'entrainement d'un reseau de neurones pour modeliser les contours. Par la suite, l'information fournie par ce reseau a ete combinee par multiplication arithmetique avec les cartes d

  18. 394delTT: a Nordic cystic fibrosis mutation.

    PubMed

    Schwartz, M; Anvret, M; Claustres, M; Eiken, H G; Eiklid, K; Schaedel, C; Stolpe, L; Tranebjaerg, L

    1994-02-01

    In a systematic screening for mutations in the gene encoding the cystic fibrosis transmembrane regulator among Danish cystic fibrosis (CF) patients, we identified a mutation in exon 3 (394delTT); this mutation was found to be relatively common in Denmark. We therefore screened for 394delTT in Sweden and Norway, where it turned out to be the second most frequent mutation, accounting for 4% of all CF mutations. It also occurs with a high frequency in Finland, but has not been found in larger surveys of mutations in the CFTR gene. Thus, 394delTT seems to be a specific Nordic CF mutation.

  19. Novel recurrently mutated genes and a prognostic mutation signature in colorectal cancer

    PubMed Central

    Yu, Jun; Wu, William K K; Li, Xiangchun; He, Jun; Li, Xiao-Xing; Ng, Simon S M; Yu, Chang; Gao, Zhibo; Yang, Jie; Li, Miao; Wang, Qiaoxiu; Liang, Qiaoyi; Pan, Yi; Tong, Joanna H; To, Ka F; Wong, Nathalie; Zhang, Ning; Chen, Jie; Lu, Youyong; Lai, Paul B S; Chan, Francis K L; Li, Yingrui; Kung, Hsiang-Fu; Yang, Huanming; Wang, Jun; Sung, Joseph J Y

    2015-01-01

    Background Characterisation of colorectal cancer (CRC) genomes by next-generation sequencing has led to the discovery of novel recurrently mutated genes. Nevertheless, genomic data has not yet been used for CRC prognostication. Objective To identify recurrent somatic mutations with prognostic significance in patients with CRC. Method Exome sequencing was performed to identify somatic mutations in tumour tissues of 22 patients with CRC, followed by validation of 187 recurrent and pathway-related genes using targeted capture sequencing in additional 160 cases. Results Seven significantly mutated genes, including four reported (APC, TP53, KRAS and SMAD4) and three novel recurrently mutated genes (CDH10, FAT4 and DOCK2), exhibited high mutation prevalence (6–14% for novel cancer genes) and higher-than-expected number of non-silent mutations in our CRC cohort. For prognostication, a five-gene-signature (CDH10, COL6A3, SMAD4, TMEM132D, VCAN) was devised, in which mutation(s) in one or more of these genes was significantly associated with better overall survival independent of tumor-node-metastasis (TNM) staging. The median survival time was 80.4 months in the mutant group versus 42.4 months in the wild type group (p=0.0051). The prognostic significance of this signature was successfully verified using the data set from the Cancer Genome Atlas study. Conclusions The application of next-generation sequencing has led to the identification of three novel significantly mutated genes in CRC and a mutation signature that predicts survival outcomes for stratifying patients with CRC independent of TNM staging. PMID:24951259

  20. Frequent PIK3CA Mutations in Colorectal and Endometrial Cancer with Double Somatic Mismatch Repair Mutations

    PubMed Central

    Cohen, Stacey A.; Turner, Emily H.; Beightol, Mallory B.; Jacobson, Angela; Gooley, Ted A.; Salipante, Stephen J.; Haraldsdottir, Sigurdis; Smith, Christina; Scroggins, Sheena; Tait, Jonathan F.; Grady, William M.; Lin, Edward H.; Cohn, David E.; Goodfellow, Paul J.; Arnold, Mark W.; de la Chapelle, Albert; Pearlman, Rachel; Hampel, Heather; Pritchard, Colin C.

    2016-01-01

    Background & Aims Double somatic mutations in mismatch repair (MMR) genes have recently been described in colorectal and endometrial cancers with microsatellite instability (MSI) not attributable to MLH1 hypermethylation or germline mutation. We sought to define the molecular phenotype of this newly recognized tumor subtype. Methods From two prospective Lynch syndrome screening studies, we identified patients with colorectal and endometrial tumors harboring ≥2 somatic MMR mutations, but normal germline MMR testing (“double somatic”). We determined the frequencies of tumor PIK3CA, BRAF, KRAS, NRAS, and PTEN mutations by targeted next-generation sequencing and used logistic-regression models to compare them to: Lynch syndrome, MLH1 hypermethylated, and microsatellite stable (MSS) tumors. We validated our findings using independent datasets from The Cancer Genome Atlas (TCGA). Results Among colorectal cancer cases, we found that 14/21 (67%) of double somatic cases had PIK3CA mutations vs. 4/18 (22%) Lynch syndrome, 2/10 (20%) MLH1 hypermethylated, and 12/78 (15%) MSS tumors; p<0.0001. PIK3CA mutations were detected in 100% of 13 double somatic endometrial cancers (p=0.04). BRAF mutations were absent in double somatic and Lynch syndrome colorectal tumors. We found highly similar results in a validation cohort from TCGA (113 colorectal, 178 endometrial cancer), with 100% of double somatic cases harboring a PIK3CA mutation (p<0.0001). Conclusions PIK3CA mutations are present in double somatic mutated colorectal and endometrial cancers at substantially higher frequencies than other MSI subgroups. PIK3CA mutation status may better define an emerging molecular entity in colorectal and endometrial cancers, with the potential to inform screening and therapeutic decision making. PMID:27302833

  1. Heparin enhances the catalytic activity of des-ETW-thrombin.

    PubMed

    Goodwin, C A; Deadman, J J; Le Bonniec, B F; Elgendy, S; Kakkar, V V; Scully, M F

    1996-04-01

    The thrombin mutant, des-ETW-thrombin, lacking Glu(146), Thr(147), and Trp(148) within a unique insertion loop located at the extreme end of the primary specificity pocket, has been shown previously to exhibit reduced catalytic activity with respect to macromolecular and synthetic thrombin substrates and reduced or enhanced susceptibility to inhibition. Investigation of the hydrolysis of peptidyl p-nitroanilide substrates by des-ETW-thrombin showed increased activity in the presence of heparin and other sulphated glycosaminoglycans. No effect was observed upon the activity of wild-type thrombin. Heparin was found to decrease the K(m) for cleavage of four thrombin-specific substrates by des-ETW-thrombin by 3-4-fold. Similarly, pentosan polysulphate (PPS) decreased the K(m) with these substrates by 8-10-fold. Heparin also increased the rate of inhibition of des-ETW-thrombin by antithrombin III and D-phenylalanyl-prolyl-arginylchloromethane (PPACK). The inhibition of des-ETW-thrombin by a number of thrombin-specific peptide boronic acids also showed significant reduction in the final K(i) in the presence of heparin, due to reduction in the off-rate. A peptide analogue of a sequence of hirudin which binds thrombin tightly to exosite I (fibrinogen recognition site) potentiated the activity of des-ETW-thrombin against peptide p-nitroanilide substrates in a manner similar to heparin. The K(i) for the inhibition of des-ETW-thrombin by p-aminobenzamidine was decreased by these ligands from 9.7 mM to 7.5 mM, 5.1 mM, and 2.5 mM in the presence of heparin, hirudin peptide and PPS respectively, suggesting the increased catalytic activity is due to enhanced access to the primary specificity pocket. The positive influence of these ligands on des-ETW-thrombin was reversed in the presence of ATP or ADP; the latter has previously been shown to inhibit thrombin activity by blocking initial interaction with fibrinogen at exosite 1. Because the effect of heparin and PPS is similar to

  2. Mediastinal paragangliomas related to SDHx gene mutations

    PubMed Central

    Ćwikła, Jarosław; Prejbisz, Aleksander; Kwiatek, Paweł; Szperl, Małgorzata; Michalski, Wojciech; Wyrwicz, Lucjan; Kuśmierczyk, Mariusz; Januszewicz, Andrzej; Maciejczyk, Anna; Roszczynko, Marta; Pęczkowska, Mariola

    2016-01-01

    Introduction Paragangliomas (PGLs) related to hereditary syndromes are rare mediastinal tumors. Paragangliomas are caused by mutations in genes encoding subunits of succinate dehydrogenase enzyme (SDH). Aim To evaluate clinical, anatomical and functional characteristics of mediastinal paragangliomas related to SDHx gene mutations. Material and methods Retrospective analysis of 75 patients with confirmed SDHx gene mutations (24 patients with SDHB, 5 SDHC, 46 with SDHD mutations) was performed. Patients underwent evaluation using computed tomography (CT), somatostatin receptor scintigraphy (SRS) (99mTc-[HYNIC,Tyr3]-octreotide), 123I mIBG scintigraphy and urinary excretion of total methoxycatecholamines. Results Out of 75 patients, 16 (21%) patients (1 SDHB, 15 SDHD mutations) had 17 PGLs localized in the mediastinum. Fourteen PGLs were localized in the middle mediastinum (intrapericardial) and 3 PGLs in the posterior mediastinum. The median diameter of paragangliomas measured on the axial slice was 24.3 mm (interquartile range (IQR): 14.7–36.6), and the median volume was 2.78 ml (IQR: 0.87–16.16). Twelve out of 16 patients (75%) underwent SRS, and 11 of them (92.3%) had pathological uptake of the radiotracer. Eleven (68.75%) out of 16 patients underwent 123 I mIBG, with only 3 positive results. Symptoms of catecholamine excretion were observed in 3 patients with PGLs localized in the posterior mediastinum. All PGLs were benign except in 1 patient with the SDHB mutation and PGL detected in the posterior mediastinum, who had a metastatic disease. Conclusions Most mediastinal paragangliomas were related to SDHD gene mutations. They were asymptomatic, localized in the medial mediastinum, intrapericardially. PMID:27785149

  3. MUTATIONS INDUCED BY URBAN AIR AND DRINKING WATER: DO THEY LEAVE A MUTATIONAL SIGNATURE IN HUMAN TUMORS?

    EPA Science Inventory

    Mutations Induced by Urban Air and Drinking Water: Do They Leave a Mutational Signature in Human Tumors?

    Mutation spectra of complex environmental mixtures have been determined thus far only in Salmonella. We have determined mutation spectra for the particulate organics ...

  4. Directed evolution of mutator adenoviruses resistant to antibody neutralization.

    PubMed

    Myers, Nicolle D; Skorohodova, Ksenia V; Gounder, Anshu P; Smith, Jason G

    2013-05-01

    We incorporated a previously identified mutation that reduces the fidelity of the DNA polymerase into a human adenovirus vector. Using this mutator vector, we demonstrate rapid selection of resistance to a neutralizing anti-hexon monoclonal antibody due to a G434D mutation in hexon that precludes antibody binding. Since mutator adenoviruses can accumulate compound mutations that are unattainable using traditional random mutagenesis techniques, this approach will be valuable to the study of antivirals and host factor interactions.

  5. Comparison des donnees simulees des capteurs de SPOT et landsat-D: Application a une region agricole

    NASA Astrophysics Data System (ADS)

    Saint, Gilbert; Podaire, Alain

    La modélisation de la luminance spectrale des objets observés en télédétection permet d'effectuer des simulations de différents capteurs à partir de données obtenues au moyen d'un scanneur DAEDALUS aéroporté : les qualités radiométrique et géométrique ont pu être évaluées par une comparaison avec des données Landsat réelles. L'analyse sur une zone agricole met surtout en évidence le rôle important de l'accroissement de la résolution.

  6. Analyse des facteurs prédictifs de malignité des goitres nodulaires : à propos de 500 cas

    PubMed Central

    Bouaity, Brahim; Darouassi, Youssef; Chihani, Mehdi; Touati, Mohamed Mliha; Ammar, Haddou

    2016-01-01

    Les nodules thyroïdiens sont très fréquents et moins de 10% d'entre eux sont malin. Ils posent un véritable problème diagnostique et thérapeutique surtout par rapport à leur nature bénigne ou maligne. L’étude de certains facteurs cliniques et paracliniques de présomption de malignité permet de bien codifier la stratégie thérapeutique. Le but de ce travail est d’étudier les facteurs prédictifs de malignité des goitres nodulaires et comparer nos résultats à ceux de la littérature. Il s'agit d'une étude rétrospective à propos de 500 cas de goitres nodulaires opérés au service d'Oto-rhino-laryngologie (ORL) et Chirurgie cervico-faciale (CCF) de l'hôpital militaire Avicenne de Marrakech entre 2006 et 2012. Le pourcentage de cancers a été de 6,8%. L’âge moyen de nos patients était de 46 ans, avec une sex-ratio de 5 (F/H). A la palpation cervicale; le caractère dure du nodule a été constaté dans 94,4% des cas de cancer, avec des limites irrégulières dans 64,70% des cas de cancer. Trois nodules étaient fixes et ils étaient tous malins. Les adénopathies cervicales ont été constatées chez 8 malades dont 7 présentaient des cancers. A l’échographie, 61,8% des nodules malins présentaient un aspect hypoéchogène, avec des contours flous dans 88,24% des cas. La vascularisation intra nodulaire était présente dans 35,3% de ces cas des cancers avec des microcalcifications chez 55,9% d'entre eux. Le halo hypoéchogene périnodulaire était incomplet dans 73,5% des cas de cancer. Nos patients étaient en euthyroïdie dans 84,6% des cas. Les facteurs prédictifs de malignité d'un goitre nodulaire, étaient donc dans notre étude d'abord cliniques: l’âge supérieur à 60 ans, la consistance dure du nodule, sa fixité, son caractère irrégulier et mal limité à la palpation, ainsi que la présence d'adénopathie(s) cervicale(s) à l'examen; et échographiques: le caractère hypoéchogène, les limites floues, la présence de

  7. Classification of DES16C2nm as a SLSN at z=1.998

    NASA Astrophysics Data System (ADS)

    Galbany, L.; D'Andrea, C.; Prajs, S.; Smith, M.; Sullivan, M.; Ponder, K.; Gonzalez-Gaitan, S.; Forster, F.; Hamuy, M.; Prieto, Jose Luis; Schubnell, M.; Kessler, R.; Lasker, J.; Scolnic, D.; Brout, D. J.; Gladney, L.; March, M.; Sako, M.; Wolf, R. C.; Brown, P. J.; Krisciunas, K.; Suntzeff, N.; Macaulay, E.; Nichol, R.; Childress, M.; Maartens, R.; Kovacs, E.; Kuhlmann, S.; Spinka, H.; Ahn, E.; Finley, D. A.; Frieman, J.; Marriner, J.; Wester, W.; Aldering, G.; Gupta, R.; Kim, A. G.; Thomas, R. C.; Barbary, K.; Bloom, J. S.; Goldstein, D.; Nugent, P.; Perlmutter, S.; Foley, R. J.; Pan, Y.-C.; Casas, R.; Castander, F. J.; Papadopoulos, A.; Morganson, E.; Desai, S.; Paech, K.; Smith, R. C.

    2016-11-01

    We report the spectroscopic classification of DES16C2nm as a superluminous supernova (SLSN) discovered by the Dark Energy Survey (ATEL #4668). DES16C2nm was discovered in the first epoch of DES Y4, on 22 August 2016 at R.A. = 03:40:14.83, Decl = -29:05:53.5 with i = 23.2 mag. DES16C2nm has a non-detection in the final epoch of DES Y3 on 08 February 2016.

  8. Integrative analysis of mutational and transcriptional profiles reveals driver mutations of metastatic breast cancers.

    PubMed

    Lee, Ji-Hyun; Zhao, Xing-Ming; Yoon, Ina; Lee, Jin Young; Kwon, Nam Hoon; Wang, Yin-Ying; Lee, Kyung-Min; Lee, Min-Joo; Kim, Jisun; Moon, Hyeong-Gon; In, Yongho; Hao, Jin-Kao; Park, Kyung-Mii; Noh, Dong-Young; Han, Wonshik; Kim, Sunghoon

    2016-01-01

    Despite the explosion in the numbers of cancer genomic studies, metastasis is still the major cause of cancer mortality. In breast cancer, approximately one-fifth of metastatic patients survive 5 years. Therefore, detecting the patients at a high risk of developing distant metastasis at first diagnosis is critical for effective treatment strategy. We hereby present a novel systems biology approach to identify driver mutations escalating the risk of metastasis based on both exome and RNA sequencing of our collected 78 normal-paired breast cancers. Unlike driver mutations occurring commonly in cancers as reported in the literature, the mutations detected here are relatively rare mutations occurring in less than half metastatic samples. By supposing that the driver mutations should affect the metastasis gene signatures, we develop a novel computational pipeline to identify the driver mutations that affect transcription factors regulating metastasis gene signatures. We identify driver mutations in ADPGK, NUP93, PCGF6, PKP2 and SLC22A5, which are verified to enhance cancer cell migration and prompt metastasis with in vitro experiments. The discovered somatic mutations may be helpful for identifying patients who are likely to develop distant metastasis. PMID:27625789

  9. Integrative analysis of mutational and transcriptional profiles reveals driver mutations of metastatic breast cancers

    PubMed Central

    Lee, Ji-Hyun; Zhao, Xing-Ming; Yoon, Ina; Lee, Jin Young; Kwon, Nam Hoon; Wang, Yin-Ying; Lee, Kyung-Min; Lee, Min-Joo; Kim, Jisun; Moon, Hyeong-Gon; In, Yongho; Hao, Jin-Kao; Park, Kyung-Mii; Noh, Dong-Young; Han, Wonshik; Kim, Sunghoon

    2016-01-01

    Despite the explosion in the numbers of cancer genomic studies, metastasis is still the major cause of cancer mortality. In breast cancer, approximately one-fifth of metastatic patients survive 5 years. Therefore, detecting the patients at a high risk of developing distant metastasis at first diagnosis is critical for effective treatment strategy. We hereby present a novel systems biology approach to identify driver mutations escalating the risk of metastasis based on both exome and RNA sequencing of our collected 78 normal-paired breast cancers. Unlike driver mutations occurring commonly in cancers as reported in the literature, the mutations detected here are relatively rare mutations occurring in less than half metastatic samples. By supposing that the driver mutations should affect the metastasis gene signatures, we develop a novel computational pipeline to identify the driver mutations that affect transcription factors regulating metastasis gene signatures. We identify driver mutations in ADPGK, NUP93, PCGF6, PKP2 and SLC22A5, which are verified to enhance cancer cell migration and prompt metastasis with in vitro experiments. The discovered somatic mutations may be helpful for identifying patients who are likely to develop distant metastasis.

  10. Nonadaptive mutations occur on the F' episome during adaptive mutation conditions in Escherichia coli.

    PubMed Central

    Foster, P L

    1997-01-01

    One of the most studied examples of adaptive mutation is a strain of Escherichia coli, FC40, that cannot utilize lactose (Lac-) but that readily reverts to lactose utilization (Lac+) when lactose is its sole carbon source. Adaptive reversion to Lac+ occurs at a high rate when the Lac- allele is on an F' episome and conjugal functions are expressed. It was previously shown that nonselected mutations on the chromosome did not appear in the Lac- population while episomal Lac+ mutations accumulated, but it remained possible that nonselected mutations might occur on the episome. To investigate this possibility, a second mutational target was created on the Lac- episome by mutation of a Tn1O element, which encodes tetracycline resistance (Tetr), to tetracycline sensitivity (Tets). Reversion rates to Tetr during normal growth and during lactose selection were measured. The results show that nonselected Tetr mutations do accumulate in Lac- cells when those cells are under selection to become Lac+. Thus, reversion to Lac+ in FC40 does not appear to be adaptive in the narrow sense of the word. In addition, the results suggest that during lactose selection, both Lac+ and Tetr mutations are created or preserved by the same recombination-dependent mechanism. PMID:9045812

  11. Integrative analysis of mutational and transcriptional profiles reveals driver mutations of metastatic breast cancers

    PubMed Central

    Lee, Ji-Hyun; Zhao, Xing-Ming; Yoon, Ina; Lee, Jin Young; Kwon, Nam Hoon; Wang, Yin-Ying; Lee, Kyung-Min; Lee, Min-Joo; Kim, Jisun; Moon, Hyeong-Gon; In, Yongho; Hao, Jin-Kao; Park, Kyung-Mii; Noh, Dong-Young; Han, Wonshik; Kim, Sunghoon

    2016-01-01

    Despite the explosion in the numbers of cancer genomic studies, metastasis is still the major cause of cancer mortality. In breast cancer, approximately one-fifth of metastatic patients survive 5 years. Therefore, detecting the patients at a high risk of developing distant metastasis at first diagnosis is critical for effective treatment strategy. We hereby present a novel systems biology approach to identify driver mutations escalating the risk of metastasis based on both exome and RNA sequencing of our collected 78 normal-paired breast cancers. Unlike driver mutations occurring commonly in cancers as reported in the literature, the mutations detected here are relatively rare mutations occurring in less than half metastatic samples. By supposing that the driver mutations should affect the metastasis gene signatures, we develop a novel computational pipeline to identify the driver mutations that affect transcription factors regulating metastasis gene signatures. We identify driver mutations in ADPGK, NUP93, PCGF6, PKP2 and SLC22A5, which are verified to enhance cancer cell migration and prompt metastasis with in vitro experiments. The discovered somatic mutations may be helpful for identifying patients who are likely to develop distant metastasis. PMID:27625789

  12. Volatility of Mutator Phenotypes at Single Cell Resolution.

    PubMed

    Kennedy, Scott R; Schultz, Eric M; Chappell, Thomas M; Kohrn, Brendan; Knowels, Gary M; Herr, Alan J

    2015-04-01

    Mutator phenotypes accelerate the evolutionary process of neoplastic transformation. Historically, the measurement of mutation rates has relied on scoring the occurrence of rare mutations in target genes in large populations of cells. Averaging mutation rates over large cell populations assumes that new mutations arise at a constant rate during each cell division. If the mutation rate is not constant, an expanding mutator population may contain subclones with widely divergent rates of evolution. Here, we report mutation rate measurements of individual cell divisions of mutator yeast deficient in DNA polymerase ε proofreading and base-base mismatch repair. Our data are best fit by a model in which cells can assume one of two distinct mutator states, with mutation rates that differ by an order of magnitude. In error-prone cell divisions, mutations occurred on the same chromosome more frequently than expected by chance, often in DNA with similar predicted replication timing, consistent with a spatiotemporal dimension to the hypermutator state. Mapping of mutations onto predicted replicons revealed that mutations were enriched in the first half of the replicon as well as near termination zones. Taken together, our findings show that individual genome replication events exhibit an unexpected volatility that may deepen our understanding of the evolution of mutator-driven malignancies.

  13. Transport de paires EPR dans des structures mesoscopiques

    NASA Astrophysics Data System (ADS)

    Dupont, Emilie

    Dans cette these, nous nous sommes particulierement interesses a la propagation de paires EPR1 delocalisees et localisees, et a l'influence d'un supraconducteur sur le transport de ces paires. Apres une introduction de cette etude, ainsi que du cadre scientifique qu'est l'informatique quantique dans lequel elle s'inscrit, nous allons dans le chapitre 1 faire un rappel sur le systeme constitue de deux points quantiques normaux entoures de deux fils supraconducteurs. Cela nous permettra d'introduire une methode de calcul qui sera reutilisee par la suite, et de trouver egalement le courant Josephson produit par ce systeme transforme en SQUID-dc par l'ajout d'une jonction auxiliaire. Le SQUID permet de mesurer l'etat de spin (singulet ou triplet), et peut etre forme a partir d'autres systemes que nous etudierons ensuite. Dans le chapitre 2, nous rappellerons l'etude detaillee d'un intricateur d'Andreev faite par un groupe de Bale. La matrice T, permettant d'obtenir le courant dans les cas ou les electrons sont separes spatialement ou non, sera etudiee en detail afin d'en faire usage au chapitre suivant. Le chapitre 3 est consacre a l'etude de l'influence du bruit sur le fonctionnement de l'intricateur d'Andreev. Ce bruit modifie la forme du courant jusqu'a aboutir a d'autres conditions de fonctionnement de l'intricateur. En effet, le bruit present sur les points quantiques peut perturber le transport des paires EPR par l'intermediaire des degres de liberte. Nous montrerons que, du fait de l'"intrication" entre la charge de la paire et le bruit, la paire est detruite pour des temps longs. Cependant, le resultat le plus important sera que le bruit perturbe plus le transport des paires delocalisees, qui implique une resonance de Breit-Wigner a deux particules. Le transport parasite n'implique pour sa part qu'une resonance de Breit-Wigner a une particule. Dans le chapitre 4, nous reviendrons au systeme constitue de deux points quantiques entoures de deux fils

  14. Mutations des roles techniques et formation. Etude documentaire (Changes in the Roles and Education of Technicians. Documentary Study).

    ERIC Educational Resources Information Center

    Pinard, Helene

    Drawing from research conducted in 1990-91, this report examines trends affecting the future work of technicians in Quebec, their pre-employment education, and the link between college and work. Part 1 focuses on aspects of the economic, technological, and social environment that will influence the future role of technicians. Economic concerns…

  15. Measurements of mutation rates in B lymphocytes.

    PubMed

    Wabl, M; Jäck, H M; Meyer, J; Beck-Engeser, G; von Borstel, R C; Steinberg, C M

    1987-04-01

    It is established that somatic mutation is an important source of antibody diversity in vivo. It is also established that Igh-V gene segments are hypermutable in vitro. This is not a completely satisfactory situation. While there is no reason to believe that Igh-V genes are not hypermutable in vivo as well, direct experimental evidence is lacking. Perhaps experiments with transgenic mice will soon fill this gap. It is not so clear how much higher than normal the rate of hypermutation is. As far as we are aware, there are no direct measurements of mutation rates per base pair per cell generation in mammals, certainly not for lymphocyte cell lines. For a variety of reasons, it is difficult to measure very low mutation rates. The general consensus is that the normal rate should be somewhere between 10(-10) and 10(-12) mutations per base pair per cell generation. Therefore, an experiment designed to directly determine a rate using the compartmentalization test would involve hundreds of cultures, each containing at least 10(9) cells. It is not a trivial problem to find one or a few mutants among so many cells. It is simple to study mutation to resistance to a drug, for example, ouabain or azaguanine, but, as we discussed, there are technical and conceptual pitfalls. The vast excess of dead cells influences the growth of a few mutant cells, particularly in lymphocyte cell lines. Even if this problem could be solved, the mutation rate so obtained would be "per gene(s)" and not "per base pair". The problems associated with cytotoxic agents can be avoided by immunofluorescence methods in conjunction with selective cloning or cell sorting. Using these techniques, we have carried out extensive experiments to determine whether the immunoglobulin mutator system acts, at least partially, on genetic elements other than those in or near the heavy chain variable region gene segment. For an opal termination codon in a heavy chain constant region gene segment, the rate of reversion

  16. Ontogeny of the barley plant as related to mutation expression and detection of pollen mutations

    SciTech Connect

    Hodgdon, A.L.; Marcus, A.H.; Arenaz, P.; Rosichan, J.L.; Bogyo, T.P.; Nilan, R.A.

    1980-05-29

    Clustering of mutant pollen grains in a population of normal pollen due to premeiotic mutational events complicates translating mutation frequencies into rates. Embryo ontogeny in barley will be described and used to illustrate the formation of such mutant clusters. The nature of the statistics for mutation frequency will be described from a study of the reversion frequencies of various waxy mutants in barley. Computer analysis by a jackknife method of the reversion frequencies of a waxy mutant treated with the mutagen sodium azide showed a significantly higher reversion frequency than untreated material. Problems of the computer analysis suggest a better experimental design for pollen mutation experiments. Preliminary work on computer modeling for pollen development and mutation will be described.

  17. Ontogeny of the barley plant as related to mutation expression and detection of pollen mutations

    SciTech Connect

    Hodgdon, A.L.; Marcus, A.H.; Arenaz, P.; Rosichan, J.L.; Bogyo, T.P.; Nilan, R.A.

    1981-01-01

    Clustering of mutant pollen grains in a population of normal pollen due to premeiotic mutational events complicates translating mutation frequencies into rates. Embryo ontogeny in barley will be described and used to illustrate the formation of such mutant clusters. The nature of the statistics for mutation frequency will be described from a study of the reversion frequencies of various waxy mutants in barley. Computer analysis by a ''jackknife'' method of the reversion of a waxy mutant treated with the mutagen sodium azide showed a significantly higher reversion frequency than untreated material. Problems of the computer analysis suggest a better experimental design for pollen mutation experiments. Preliminary work on computer modeling for pollen development and mutation will be described.

  18. Opération multimode transverse des OPOs: des structures classiques aux corrélations quantiques

    NASA Astrophysics Data System (ADS)

    Martinelli, M.; Ducci, S.; Gigan, S.; Treps, N.; Maître, A.; Fabre, C.

    2002-06-01

    Nous démontrons la formation de structures transverses sur les faisceaux émis par un oscillateur paramétrique optique (OPO) de type II en configuration confocale. D'un point de vue classique nous mettons en évidence le caractère multimode transverse de telles structures. A travers l'étude des corrélations spatiales des faisceaux générés nous montrons que ces structures sont également multimodes d'un point de vue quantique.

  19. Apport des moyens endoscopiques dans la dilatation des sténoses caustiques de l’œsophage

    PubMed Central

    Seydou, Togo; Abdoulaye, Ouattara Moussa; xing, Li; Zi, Sanogo Zimogo; sekou, Koumaré; Wen, Yang Shang; Ibrahim, Sankare; Sekou, Toure Cheik Ahmed; Boubacar, Maiga Ibrahim; Saye, Jacque; Jerome, Dakouo Dodino; Dantoumé, Toure Ousmane; Sadio, Yena

    2016-01-01

    Introduction Toutes les sténoses symptomatiques de l’œsophage peuvent être dilatées par voie endoscopique. Nous évaluons l'apport des moyens endoscopiques dans la prise en charge de la dilatation œsophagienne pour sténose caustique de l’œsophage (SCO) au Mali. Méthodes IL s'agissait d'une étude descriptive et prospective réalisée dans le service de chirurgie thoracique à l'hôpital du Mali. Au total 46 dossiers cliniques de patients on été enregistrés et subdivisés en 4 groupes en fonction de la topographie des lésions cicatricielles. Le nombre de cas d'assistance endoscopique réalisé a été déterminé afin de comprendre l'apport des moyens endoscopiques dans le succès de la dilatation des SCO. Pour les 2 différentes méthodes de dilatation utilisées, le résultat du traitement et le coût ont comparés. Résultats La FOGD a été utilisée dans 19 cas (41.30%) de dilatation avec la bougie de Savary Guillard et dans 47.82% des cas dans la dilatation de Lerut. La vidéo-laryngoscopie a été utilisé 58.69% des cas de dilatation à la bougie de Lerut. Le passage de guide métallique et / ou de fil-guide a été réalisée dans 39.13% avec la vidéo laryngoscopie et dans 58.68% avec la FOGD. Dans la comparaison des deux méthodes, il existe une différence significative dans la survenue des complications (p=0.04075), l'anesthésie générale (p=0.02287), l'accessibilité à la méthode (p=0.04805) et la mortalité (p=0.00402). Conclusion La SCO est une pathologie grave et sous évaluée au Mali. Les moyens endoscopiques contribuent considérablement au succès de la dilatation œsophagienne pour sténose caustique dans les différentes méthodes utilisées. PMID:27200129

  20. Urinary Tract Effects of HPSE2 Mutations

    PubMed Central

    Stuart, Helen M.; Roberts, Neil A.; Hilton, Emma N.; McKenzie, Edward A.; Daly, Sarah B.; Hadfield, Kristen D.; Rahal, Jeffery S.; Gardiner, Natalie J.; Tanley, Simon W.; Lewis, Malcolm A.; Sites, Emily; Angle, Brad; Alves, Cláudia; Lourenço, Teresa; Rodrigues, Márcia; Calado, Angelina; Amado, Marta; Guerreiro, Nancy; Serras, Inês; Beetz, Christian; Varga, Rita-Eva; Silay, Mesrur Selcuk; Darlow, John M.; Dobson, Mark G.; Barton, David E.; Hunziker, Manuela; Puri, Prem; Feather, Sally A.; Goodship, Judith A.; Goodship, Timothy H.J.; Lambert, Heather J.; Cordell, Heather J.; Saggar, Anand; Kinali, Maria; Lorenz, Christian; Moeller, Kristina; Schaefer, Franz; Bayazit, Aysun K.; Weber, Stefanie; Newman, William G.

    2015-01-01

    Urofacial syndrome (UFS) is an autosomal recessive congenital disease featuring grimacing and incomplete bladder emptying. Mutations of HPSE2, encoding heparanase 2, a heparanase 1 inhibitor, occur in UFS, but knowledge about the HPSE2 mutation spectrum is limited. Here, seven UFS kindreds with HPSE2 mutations are presented, including one with deleted asparagine 254, suggesting a role for this amino acid, which is conserved in vertebrate orthologs. HPSE2 mutations were absent in 23 non-neurogenic neurogenic bladder probands and, of 439 families with nonsyndromic vesicoureteric reflux, only one carried a putative pathogenic HPSE2 variant. Homozygous Hpse2 mutant mouse bladders contained urine more often than did wild-type organs, phenocopying human UFS. Pelvic ganglia neural cell bodies contained heparanase 1, heparanase 2, and leucine-rich repeats and immunoglobulin-like domains-2 (LRIG2), which is mutated in certain UFS families. In conclusion, heparanase 2 is an autonomic neural protein implicated in bladder emptying, but HPSE2 variants are uncommon in urinary diseases resembling UFS. PMID:25145936

  1. GREMLIN 2 Mutations and Dental Anomalies.

    PubMed

    Kantaputra, P N; Kaewgahya, M; Hatsadaloi, A; Vogel, P; Kawasaki, K; Ohazama, A; Ketudat Cairns, J R

    2015-12-01

    Isolated or nonsyndromic tooth agenesis or hypodontia is the most common human malformation. It has been associated with mutations in MSX1, PAX9, EDA, AXIN2, EDAR, EDARADD, and WNT10A. GREMLIN 2 (GREM2) is a strong bone morphogenetic protein (BMP) antagonist that is known to regulate BMPs in embryogenesis and tissue development. Bmp4 has been shown to have a role in tooth development. Grem2(-/-) mice have small, malformed maxillary and mandibular incisors, indicating that Grem2 has important roles in normal tooth development. Here, we demonstrate for the first time that GREM2 mutations are associated with human malformations, which include isolated tooth agenesis, microdontia, short tooth roots, taurodontism, sparse and slow-growing hair, and dry and itchy skin. We sequenced WNT10A, WNT10B, MSX1, EDA, EDAR, EDARADD, AXIN2, and PAX9 in all 7 patients to rule out the effects of other ectodermal dysplasias and other tooth-related genes and did not find mutations in any of them. GREM2 mutations exhibit variable expressivity even within the same families. The inheritance is autosomal dominant with incomplete penetrance. The expression of Grem2 during the early development of mouse teeth and hair follicles and the evaluation of the likely effects of the mutations on the protein structure substantiate these new findings.

  2. Mutations in ANTXR1 Cause GAPO Syndrome

    PubMed Central

    Stránecký, Viktor; Hoischen, Alexander; Hartmannová, Hana; Zaki, Maha S.; Chaudhary, Amit; Zudaire, Enrique; Nosková, Lenka; Barešová, Veronika; Přistoupilová, Anna; Hodaňová, Kateřina; Sovová, Jana; Hůlková, Helena; Piherová, Lenka; Hehir-Kwa, Jayne Y.; de Silva, Deepthi; Senanayake, Manouri P.; Farrag, Sameh; Zeman, Jiří; Martásek, Pavel; Baxová, Alice; Afifi, Hanan H.; St. Croix, Brad; Brunner, Han G.; Temtamy, Samia; Kmoch, Stanislav

    2013-01-01

    The genetic cause of GAPO syndrome, a condition characterized by growth retardation, alopecia, pseudoanodontia, and progressive visual impairment, has not previously been identified. We studied four ethnically unrelated affected individuals and identified homozygous nonsense mutations (c.262C>T [p.Arg88*] and c.505C>T [p.Arg169*]) or splicing mutations (c.1435–12A>G [p.Gly479Phefs*119]) in ANTXR1, which encodes anthrax toxin receptor 1. The nonsense mutations predictably trigger nonsense-mediated mRNA decay, resulting in the loss of ANTXR1. The transcript with the splicing mutation theoretically encodes a truncated ANTXR1 containing a neopeptide composed of 118 unique amino acids in its C terminus. GAPO syndrome’s major phenotypic features, which include dental abnormalities and the accumulation of extracellular matrix, recapitulate those found in Antxr1-mutant mice and point toward an underlying defect in extracellular-matrix regulation. Thus, we propose that mutations affecting ANTXR1 function are responsible for this disease’s characteristic generalized defect in extracellular-matrix homeostasis. PMID:23602711

  3. Somatic mutation of PTEN in bladder carcinoma

    PubMed Central

    Aveyard, J S; Skilleter, A; Habuchi, T; Knowles, M A

    1999-01-01

    The tumour suppressor gene PTEN/MMAC1, which is mutated or homozygously deleted in glioma, breast and prostate cancer, is mapped to a region of 10q which shows loss of heterozygosity (LOH) in bladder cancer. We screened 123 bladder tumours for LOH in the region of PTEN. In 53 informative muscle invasive tumours (≥ pT2), allele loss was detected in 13 (24.5%) and allelic imbalance in four tumours (overall frequency 32%). LOH was found in four of 60 (6.6%) informative, non-invasive tumours (pTa/pT1). We screened 63 muscle invasive tumours for PTEN mutations by single-strand conformation polymorphism (SSCP) analysis and for homozygous deletion by duplex quantitative polymerase chain reaction (PCR). Two homozygous deletions were identified but no mutations. Of 15 bladder tumour cell lines analysed, three showed homozygous deletion of all or part of the PTEN gene, but none had mutations detectable by SSCP analysis. Our results indicate that PTEN is involved in the development of some bladder tumours. The low frequency of mutation of the retained allele in tumours with 10q23 LOH suggests that there may be another predominant mechanism of inactivation of the second allele, for example small intragenic deletions, that hemizygosity may be sufficient for phenotypic effect, or that there is another target gene at 10q23. © 1999 Cancer Research Campaign PMID:10360673

  4. Genotype-Phenotype Correlations by Ethnicity and Mutation Location in BRCA Mutation Carriers.

    PubMed

    Bayraktar, Soley; Jackson, Michelle; Gutierrez-Barrera, Angelica M; Liu, Diane; Meric-Bernstam, Funda; Brandt, Amanda; Woodson, Ashley; Litton, Jennifer; Lu, Karen H; Valero, Vicente; Arun, Banu K

    2015-01-01

    The genotype-phenotype correlations of the specific BRCA1 and BRCA2 mutations in multi-ethnic populations in USA have not yet been fully investigated. This study was designed to evaluate the effects of ethnicity at specific mutation locations and breast/ovarian cancer phenotypes. Our cohort included 445 women with different ethnic backgrounds who underwent BRCA genetic testing between 1997 and 2010. Known clinical and pathologic characteristics were compared with Chi-Square Analysis or Fisher's Exact test as appropriate. The three most common mutation locations in BRCA1 (exons 2, 11, and 20) and BRCA2 (exons 10, 11, and 25) genes were chosen. Prevalence of BRCA1 exon 2 mutations were significantly higher in Ashkenazi Jewish (AJ) women compared to Caucasians (41% versus 15%; p = 0.001). Similarly, AJ women with breast cancer were more likely to have BRCA1 exon 2 mutation (47% positivity in AJ women versus 0-12.5% positivity in other ethnicities; p = 0.004). Women carrying the exon 20 BRCA1 mutation had the highest probability of having combined breast and ovarian cancers compared to women carrying other exon mutations (p = 0.05). The median age at initial cancer diagnosis, phenotypic features of breast cancer tumors, and overall survival did not vary significantly by ethnicity or mutation location. Our data suggest that ethnicity does not affect age of onset, overall survival or confer different risks of breast and ovarian cancer development in BRCA carriers. These results also suggest that women carrying the exon 20 BRCA1 mutation may warrant mutation-specific counseling and be more aggressively managed for risk reduction.

  5. Mutation rates, spectra, and genome-wide distribution of spontaneous mutations in mismatch repair deficient yeast.

    PubMed

    Lang, Gregory I; Parsons, Lance; Gammie, Alison E

    2013-09-01

    DNA mismatch repair is a highly conserved DNA repair pathway. In humans, germline mutations in hMSH2 or hMLH1, key components of mismatch repair, have been associated with Lynch syndrome, a leading cause of inherited cancer mortality. Current estimates of the mutation rate and the mutational spectra in mismatch repair defective cells are primarily limited to a small number of individual reporter loci. Here we use the yeast Saccharomyces cerevisiae to generate a genome-wide view of the rates, spectra, and distribution of mutation in the absence of mismatch repair. We performed mutation accumulation assays and next generation sequencing on 19 strains, including 16 msh2 missense variants implicated in Lynch cancer syndrome. The mutation rate for DNA mismatch repair null strains was approximately 1 mutation per genome per generation, 225-fold greater than the wild-type rate. The mutations were distributed randomly throughout the genome, independent of replication timing. The mutation spectra included insertions/deletions at homopolymeric runs (87.7%) and at larger microsatellites (5.9%), as well as transitions (4.5%) and transversions (1.9%). Additionally, repeat regions with proximal repeats are more likely to be mutated. A bias toward deletions at homopolymers and insertions at (AT)n microsatellites suggests a different mechanism for mismatch generation at these sites. Interestingly, 5% of the single base pair substitutions might represent double-slippage events that occurred at the junction of immediately adjacent repeats, resulting in a shift in the repeat boundary. These data suggest a closer scrutiny of tumor suppressors with homopolymeric runs with proximal repeats as the potential drivers of oncogenesis in mismatch repair defective cells. PMID:23821616

  6. Germline mutation rates and the long-term phenotypic effects of mutation accumulation in wild-type laboratory mice and mutator mice.

    PubMed

    Uchimura, Arikuni; Higuchi, Mayumi; Minakuchi, Yohei; Ohno, Mizuki; Toyoda, Atsushi; Fujiyama, Asao; Miura, Ikuo; Wakana, Shigeharu; Nishino, Jo; Yagi, Takeshi

    2015-08-01

    The germline mutation rate is an important parameter that affects the amount of genetic variation and the rate of evolution. However, neither the rate of germline mutations in laboratory mice nor the biological significance of the mutation rate in mammalian populations is clear. Here we studied genome-wide mutation rates and the long-term effects of mutation accumulation on phenotype in more than 20 generations of wild-type C57BL/6 mice and mutator mice, which have high DNA replication error rates. We estimated the base-substitution mutation rate to be 5.4 × 10(-9) (95% confidence interval = 4.6 × 10(-9)-6.5 × 10(-9)) per nucleotide per generation in C57BL/6 laboratory mice, about half the rate reported in humans. The mutation rate in mutator mice was 17 times that in wild-type mice. Abnormal phenotypes were 4.1-fold more frequent in the mutator lines than in the wild-type lines. After several generations, the mutator mice reproduced at substantially lower rates than the controls, exhibiting low pregnancy rates, lower survival rates, and smaller litter sizes, and many of the breeding lines died out. These results provide fundamental information about mouse genetics and reveal the impact of germline mutation rates on phenotypes in a mammalian population.

  7. Germline mutation rates and the long-term phenotypic effects of mutation accumulation in wild-type laboratory mice and mutator mice

    PubMed Central

    Uchimura, Arikuni; Higuchi, Mayumi; Minakuchi, Yohei; Ohno, Mizuki; Toyoda, Atsushi; Fujiyama, Asao; Miura, Ikuo; Wakana, Shigeharu; Nishino, Jo; Yagi, Takeshi

    2015-01-01

    The germline mutation rate is an important parameter that affects the amount of genetic variation and the rate of evolution. However, neither the rate of germline mutations in laboratory mice nor the biological significance of the mutation rate in mammalian populations is clear. Here we studied genome-wide mutation rates and the long-term effects of mutation accumulation on phenotype in more than 20 generations of wild-type C57BL/6 mice and mutator mice, which have high DNA replication error rates. We estimated the base-substitution mutation rate to be 5.4 × 10−9 (95% confidence interval = 4.6 × 10−9–6.5 × 10−9) per nucleotide per generation in C57BL/6 laboratory mice, about half the rate reported in humans. The mutation rate in mutator mice was 17 times that in wild-type mice. Abnormal phenotypes were 4.1-fold more frequent in the mutator lines than in the wild-type lines. After several generations, the mutator mice reproduced at substantially lower rates than the controls, exhibiting low pregnancy rates, lower survival rates, and smaller litter sizes, and many of the breeding lines died out. These results provide fundamental information about mouse genetics and reveal the impact of germline mutation rates on phenotypes in a mammalian population. PMID:26129709

  8. Contribution aux Methodes Analytiques des Substances a L'aide de Faisceaux de Particules Chargees

    NASA Astrophysics Data System (ADS)

    Saidi, Abdelmajid

    Nous avons vu les possibilites d'analyse par particules chargees des aerosols recueillis sur des filtres de type MILLIPORE. La meme technique a ete utilisee pour des filtres ayant servi a la filtration de l'eau du fleuve Saint-laurent. Deux techniques ont ete utilisees: (1) FAST (Forward Alpha Scattering Technique): pour analyser l'hydrogene, le carbone, l'oxygene et puis l'azote. Des alpha de 12 MeV ont ete utilises. (2) PIXE (Particle Induced X-ray Emission): pour analyser les elements moyens et lourds, dans ce cas des protons de 3 MeV ainsi que des ions d'argon de 1 et 1.6 MeV ont ete utilises. Les etudes ont montre que sous vide, la majorite des problemes proviennent des dommages causes par l'echauffement du a l'impact du faisceau sur le filtre. L'analyse quantitative par l'intermediaire du faisceau extrait peut presenter des difficultes en ce qui concerne les elements legers pour lesquels l'absorption des rayonnements caracteristiques dans l'atmosphere externe est importante. Les ions lourds se pretent mal aux analyses des aerosols du fait de leur limite de sensibilite. L'analyse directe de liquides par des protons est particulierement interessante puisqu'elle ne necessite aucune preparation prealable des echantillons. A cet effet, un programme de calcul de concentration des elements dans la solution a analyser a ete mis au point. Nous avons determine la limite de sensibilite de la methode PIXE pour les cibles minces (filtre) et pour le cas ou la matrice est de l'eau. Enfin, la technique FAST peut etre un complement de la technique PIXE.

  9. Inherited thrombocytopenia due to GATA-1 mutations.

    PubMed

    Millikan, Patrick D; Balamohan, Sanjeev M; Raskind, Wendy H; Kacena, Melissa A

    2011-09-01

    The GATA family of transcription factors, including the founding member, GATA-1, have an important role in gene regulation. GATA-1 is integral to successful hematopoiesis. A wide variety of mutations in GATA-1 affect its function, as well as its interaction with its cofactors (especially Friend of GATA) and the genes upon which GATA-1 acts. Here we review the known mutations, focusing on the specific alterations within the amino acid sequence, the resulting effect on hematopoietic development, and the clinical manifestations that result. Attention is also paid to the relationship between Trisomy 21, also known as Down syndrome, and the phenomenon of a truncated GATA-1, named GATA-1s. The evidence for specific interaction between GATA-1 and chromosome 21, which may explain the correlation between these two mutations, is briefly reviewed.

  10. BRAF Mutation in Colorectal Cancer: An Update

    PubMed Central

    Barras, David

    2015-01-01

    Colorectal cancer (CRC) is still one of the deadliest cancer-related diseases. About 10% of CRC patients are characterized by a mutation in the B-Raf proto-oncogene serine/threonine kinase (BRAF) gene resulting in a valine-to-glutamate change at the residue 600 (V600E). This mutation is also present in more than 60% of melanoma patients. BRAF inhibitors were developed and found to improve patient survival; however, most patients at the end of the track ultimately develop resistance to these inhibitors. Melanoma patients benefit from the combination of BRAF inhibitors with mitogen/extracellular signal-regulated kinase (MEK) inhibitors, among others. Unfortunately, colorectal patients do not respond much efficiently, which suggests different resistance mechanisms between the two cancer types. This review aims at shedding light on recent discoveries that improve our understanding of the BRAF mutation biology in CRC. PMID:26396549

  11. LRRK2 mutations and neurotoxicant susceptibility

    PubMed Central

    Lee, Jang-Won

    2015-01-01

    Interactions between genetic and environmental factors are thought to contribute to the pathogenesis of the majority of Parkinson’s disease (PD) cases. However, our understanding of these interactions is at an early stage. Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of hereditary PD. Penetrance of LRRK2 mutations is incomplete and variable, suggesting that other environmental or genetic factors may contribute to the development of the disorder. Recently, using animal models, several attempts have been made to understand if LRRK2 may mediate sensitivity to environmental neurotoxicants. Here, we critically review the most current data on how LRRK2 mutations influence neurotoxicity in PD models. PMID:25888648

  12. Effect of Mutations on HP Lattice Proteins

    NASA Astrophysics Data System (ADS)

    Shi, Guangjie; Vogel, Thomas; Landau, David; Li, Ying; Wüst, Thomas

    2013-03-01

    Using Wang-Landau sampling with approriate trial moves[2], we investigate the effect of different types of mutations on lattice proteins in the HP model. While exact studies have been carried out for short HP proteins[3], the systems we investigate are of much larger size and hence not accessible for exact enumerations. Based on the estimated density of states, we systematically analyse the changes in structure and degeneracy of ground states of particular proteins and measure thermodynamic quantities like the stability of ground states and the specific heat, for example. Both, neutral mutations, which do not change the structure and stability of ground states, as well as critical mutations, which do change the thermodynamic behavior qualitatively, have been observed. Research supported by NSF

  13. Radiation-induced mutations and plant breeding

    SciTech Connect

    Naqvi, S.H.M.

    1985-01-01

    Ionizing radiation could cause genetic changes in an organism and could modify gene linkages. The induction of mutation through radiation is random and the probability of getting the desired genetic change is low but can be increased by manipulating different parameters such as dose rate, physical conditions under which the material has been irradiated, etc. Induced mutations have been used as a supplement to conventional plant breeding, particularly for creating genetic variability for specific characters such as improved plant structure, pest and disease resistance, and desired changes in maturity period; more than 200 varieties of crop plants have been developed by this technique. The Pakistan Atomic Energy Commission has used this technique fruitfully to evolve better germplasm in cotton, rice, chickpea, wheat and mungbean; some of the mutants have become popular commercial varieties. This paper describes some uses of radiation induced mutations and the results achieved in Pakistan so far.

  14. The Importance of Mutational Drivers in GBM.

    PubMed

    Kalkan, Rasime

    2016-01-01

    Glioblastoma (GBM) is the most aggressive primary brain tumor, providing few effective therapeutic options, given the tumor heterogeneity and the accumulation of different genetic abnormalities that cause treatment failure. The many different genetic and epigenetic alterations present in GBM lead to modification of several major signaling pathways resulting in brain tumor growth, progression, and therapeutic resistance. Many functionally important mutations have been discovered, known as neutral passengers. IDH1/2, EZH2, and DNMT3A are the best known epigenetic modifiers in cancer. These mutations are important in determining disease prognosis such that the status of the MGMT gene is a direct target of chemotherapy. For these reasons, newly developed technologies are necessary to determine new candidate targets for targeted-therapy development in GBM. The determination of mutations will aid in this and in the discovery of combinations of targeted and conventional therapies to improve GBM treatment. PMID:27278882

  15. Association of mutations in FLNA with craniosynostosis

    PubMed Central

    Fennell, Nathalie; Foulds, Nicola; Johnson, Diana S; Wilson, Louise C; Wyatt, Michelle; Robertson, Stephen P; Johnson, David; Wall, Steven A; Wilkie, Andrew O M

    2015-01-01

    Mutations of FLNA, an X-linked gene that encodes the cytoskeletal protein filamin A, cause diverse and distinct phenotypes including periventricular nodular heterotopia and otopalatodigital spectrum disorders (OPDS). Craniofacial abnormalities associated with OPDS include supraorbital hyperostosis, down-slanting palpebral fissures and micrognathia; craniosynostosis was previously described in association with FLNA mutations in two individual case reports. Here we present four further OPDS subjects who have pathological FLNA variants and craniosynostosis, supporting a causal link. Together with the previously reported patients, frontometaphyseal dysplasia was the most common clinical diagnosis (4 of 6 cases overall); 5 patients had multiple suture synostosis with the sagittal suture being the most frequently involved (also 5 patients). No genotype-phenotype correlation was evident in the distribution of FLNA mutations. This report highlights the need to consider a filaminopathy in the differential diagnosis of craniosynostosis, especially in the presence of atypical cranial or skeletal features. PMID:25873011

  16. Simulations of the OzDES AGN reverberation mapping project

    SciTech Connect

    King, Anthea L.; Martini, Paul; Davis, Tamara M.; Denney, K. D.; Kochanek, C. S.; Peterson, Bradley M.; Skielboe, Andreas; Vestergaard, Marianne; Huff, Eric; Watson, Darach; Banerji, Manda; McMahon, Richard; Sharp, Rob; Lidman, C.

    2015-08-26

    As part of the Australian spectroscopic dark energy survey (OzDES) we are carrying out a large-scale reverberation mapping study of ~500 quasars over five years in the 30 deg2 area of the Dark Energy Survey (DES) supernova fields. These quasars have redshifts ranging up to 4 and have apparent AB magnitudes between 16.8 mag < r < 22.5 mag. The aim of the survey is to measure time lags between fluctuations in the quasar continuum and broad emission-line fluxes of individual objects in order to measure black hole masses for a broad range of active galactic nuclei (AGN) and constrain the radius–luminosity (R–L) relationship. Here we investigate the expected efficiency of the OzDES reverberation mapping campaign and its possible extensions. We expect to recover lags for ~35–45 % of the quasars. AGN with shorter lags and greater variability are more likely to yield a lag measurement, and objects with lags ≲6 months or ~1 yr are expected to be recovered the most accurately. The baseline OzDES reverberation mapping campaign is predicted to produce an unbiased measurement of the R–L relationship parameters for Hβ, MgIIλ2798, and C IVλ1549. As a result, extending the baseline survey by either increasing the spectroscopic cadence, extending the survey season, or improving the emission-line flux measurement accuracy will significantly improve the R–L parameter constraints for all broad emission lines.

  17. Recognition of Langue des Signes Quebecoise in Eastern Canada

    ERIC Educational Resources Information Center

    Parisot, Anne-Marie; Rinfret, Julie

    2012-01-01

    This article presents a portrait of two community-level and legal efforts in Canada to obtain official recognition of ASL and LSQ (Langue des signes quebecoise), both of which are recognized as official languages by the Canadian Association of the Deaf (CAD). In order to situate this issue in the Canadian linguistic context, the authors first…

  18. Mechanistic Enzymology of the Radical SAM Enzyme DesII

    PubMed Central

    2016-01-01

    DesII is a member of the radical SAM family of enzymes that catalyzes radical-mediated transformations of TDP-4-amino-4,6-didexoy-D-glucose as well as other sugar nucleotide diphosphates. Like nearly all radical SAM enzymes, the reactions begin with the reductive homolysis of SAM to produce a 5′-deoxyadenosyl radical which is followed by regiospecific hydrogen atom abstraction from the substrate. What happens next, however, depends on the nature of the substrate radical so produced. In the case of the biosynthetically relevant substrate, a radical-mediated deamination ensues; however, when this amino group is replaced with a hydroxyl, one instead observes dehydrogenation. The factors that govern the fate of the initially generated substrate radical as well as the mechanistic details underlying these transformations have been a key focus of research into the chemistry of DesII. This review will discuss recent discoveries pertaining to the enzymology of DesII, how it may relate to understanding other radical-mediated lyases and dehydrogenases and the working hypotheses currently being investigated regarding the mechanism of DesII catalysis.

  19. Rescue of a vaccine strain of peste des petits ruminants virus: In vivo evaluation and comparison with standard vaccine

    PubMed Central

    Muniraju, Murali; Mahapatra, Mana; Buczkowski, Hubert; Batten, Carrie; Banyard, Ashley C.; Parida, Satya

    2015-01-01

    Across the developing world peste des petits ruminants virus places a huge disease burden on agriculture, primarily affecting the production of small ruminant. The disease is most effectively controlled by vaccinating sheep and goats with live attenuated vaccines that provide lifelong immunity. However, the current vaccines and serological tests are unable to enable Differentiation between naturally Infected and Vaccinated Animals (DIVA). This factor precludes meaningful assessment of vaccine coverage and epidemiological surveillance based on serology, in turn reducing the efficiency of control programmes. The availability of a recombinant PPRV vaccine with a proven functionality is a prerequisite for the development of novel vaccines that may enable the development of DIVA tools for PPRV diagnostics. In this study, we have established an efficient reverse genetics system for PPRV Nigeria 75/1 vaccine strain and, further rescued a version of PPRV Nigeria 75/1 vaccine strain that expresses eGFP as a novel transcription cassette and a version of PPRV Nigeria 75/1 vaccine strain with mutations in the haemagglutinin (H) gene to enable DIVA through disruption of binding to H by the C77 monoclonal antibody used in the competitive (c) H-ELISA. All three rescued viruses showed similar growth characteristics in vitro in comparison to parent vaccine strain and, following in vivo assessment the H mutant provided full protection in goats. Although the C77 monoclonal antibody used in the cH-ELISA was unable to bind to the mutated form of H in vitro, the mutation was not sufficient to enable DIVA in vivo. PMID:25444790

  20. Rescue of a vaccine strain of peste des petits ruminants virus: In vivo evaluation and comparison with standard vaccine.

    PubMed

    Muniraju, Murali; Mahapatra, Mana; Buczkowski, Hubert; Batten, Carrie; Banyard, Ashley C; Parida, Satya

    2015-01-01

    Across the developing world peste des petits ruminants virus places a huge disease burden on agriculture, primarily affecting the production of small ruminant. The disease is most effectively controlled by vaccinating sheep and goats with live attenuated vaccines that provide lifelong immunity. However, the current vaccines and serological tests are unable to enable Differentiation between naturally Infected and Vaccinated Animals (DIVA). This factor precludes meaningful assessment of vaccine coverage and epidemiological surveillance based on serology, in turn reducing the efficiency of control programmes. The availability of a recombinant PPRV vaccine with a proven functionality is a prerequisite for the development of novel vaccines that may enable the development of DIVA tools for PPRV diagnostics. In this study, we have established an efficient reverse genetics system for PPRV Nigeria 75/1 vaccine strain and, further rescued a version of PPRV Nigeria 75/1 vaccine strain that expresses eGFP as a novel transcription cassette and a version of PPRV Nigeria 75/1 vaccine strain with mutations in the haemagglutinin (H) gene to enable DIVA through disruption of binding to H by the C77 monoclonal antibody used in the competitive (c) H-ELISA. All three rescued viruses showed similar growth characteristics in vitro in comparison to parent vaccine strain and, following in vivo assessment the H mutant provided full protection in goats. Although the C77 monoclonal antibody used in the cH-ELISA was unable to bind to the mutated form of H in vitro, the mutation was not sufficient to enable DIVA in vivo. PMID:25444790

  1. Understanding mutagenesis through delineation of mutational signatures in human cancer.

    PubMed

    Petljak, Mia; Alexandrov, Ludmil B

    2016-06-01

    Each individual cell within a human body acquires a certain number of somatic mutations during a course of its lifetime. These mutations originate from a wide spectra of both endogenous and exogenous mutational processes that leave distinct patterns of mutations, termed mutational signatures, embedded within the genomes of all cells. In recent years, the vast amount of data produced by sequencing of cancer genomes was coupled with novel mathematical models and computational tools to generate the first comprehensive map of mutational signatures in human cancer. Up to date, >30 distinct mutational signatures have been identified, and etiologies have been proposed for many of them. This review provides a brief historical background on examination of mutational patterns in human cancer, summarizes the knowledge accumulated since introducing the concept of mutational signatures and discusses their future potential applications and perspectives within the field.

  2. The spectrum of mutation produced by low dose radiation

    SciTech Connect

    Morley,Alexander,A; Turner, David,R

    2004-10-31

    Inherited mutations are the basis of evolution and acquired mutations in humans are important in ageing, cancer and possibly various forms of tissue degeneration. Mutations are responsible for many of the long-term effects of radiation. However, sensitive direct detection of mutations in humans has been difficult. The aims of the project were to develop methods for the sensitive enumeration of mutations in DNA, to measure mutation frequencies in a wide variety of tissue types and to quantify the mutational effect of direct oxidative damage produced by radiation, at both high and low doses. The project was successful in developing a sensitive method which could detect mutations directly in the genetic material, DNA at a sensitivity of 1 mutated molecule in 1000000000 unmutated molecules. However a number of methodological problems had to be overcome and lack of ongoing funding made it impossible to fulfill all of the aims of the project

  3. Understanding mutagenesis through delineation of mutational signatures in human cancer

    DOE PAGES

    Petljak, Mia; Alexandrov, Ludmil B.

    2016-05-04

    Each individual cell within a human body acquires a certain number of somatic mutations during a course of its lifetime. These mutations originate from a wide spectra of both endogenous and exogenous mutational processes that leave distinct patterns of mutations, termed mutational signatures, embedded within the genomes of all cells. In recent years, the vast amount of data produced by sequencing of cancer genomes was coupled with novel mathematical models and computational tools to generate the first comprehensive map of mutational signatures in human cancer. Up to date, >30 distinct mutational signatures have been identified, and etiologies have been proposedmore » for many of them. This paper provides a brief historical background on examination of mutational patterns in human cancer, summarizes the knowledge accumulated since introducing the concept of mutational signatures and discusses their future potential applications and perspectives within the field.« less

  4. Driver Missense Mutation Identification Using Feature Selection and Model Fusion.

    PubMed

    Soliman, Ahmed T; Meng, Tao; Chen, Shu-Ching; Iyengar, S S; Iyengar, Puneeth; Yordy, John; Shyu, Mei-Ling

    2015-12-01

    Driver mutations propel oncogenesis and occur much less frequently than passenger mutations. The need for automatic and accurate identification of driver mutations has increased dramatically with the exponential growth of mutation data. Current computational solutions to identify driver mutations rely on sequence homology. Here we construct a machine learning-based framework that does not rely on sequence homology or domain knowledge to predict driver missense mutations. A windowing approach to represent the local environment of the sequence around the mutation point as a mutation sample is applied, followed by extraction of three sequence-level features from each sample. After selecting the most significant features, the support vector machine and multimodal fusion strategies are employed to give final predictions. The proposed framework achieves relatively high performance and outperforms current state-of-the-art algorithms. The ease of deploying the proposed framework and the relatively accurate performance make this solution applicable to large-scale mutation data analyses. PMID:26402258

  5. Cystic fibrosis mutations in Costa Rica.

    PubMed

    Venegas, Patricia B; Novak, Jessica M; Oscar, Castro A; Sánchez, Félix L; Gutiérrez, Inés G; Rivera, Julio M; Salas, Jorge P; Montero, Jenny F; Grody, Wayne W

    2003-04-01

    Using polymerase chain reaction amplification of DNA in dried blood spots and a nonisotopic reverse dot blot hybridization method, we performed molecular genetic analysis for 6 and for 16 of the most common mutations of the cystic fibrosis transmembrane conductance regulator gene (CFTR) in 24 unrelated Costa Rican individuals with cystic fibrosis (CF). While many countries and ethnic groups have been surveyed for CF mutations since the cloning of CFTR, Costa Rica has not heretofore been studied. Moreover, Costa Rica represents an especially intriguing population because of its mixed European-African-Amerindian origins and the existence of a detailed historical record of the founding Spanish families. Thus, such a study may reveal not only the population frequencies of various mutant alleles in this country, but also something about their geographic migrations and ethnic founder effects. The most common CF mutation in Caucasians, deltaF508, was found in only 11 (23%) of the CF chromosomes studied, while the G542X mutation, relatively rare in the general population but more common in southern Europe, was observed in 12 (25%). None of the other mutations tested was found in any of the subjects. We failed to detect the second mutant allele in 17 subjects and could not detect either allele in 4 subjects. The high prevalence of the G542X mutation in our cohort, which exceeds that of both the general Caucasian population and the American Hispanic population, reflects the strong genetic influence of the original Spanish founding families of Costa Rica. These results highlight important differences in Costa Rican CF genotypes as compared both to other North American and European populations and to American Hispanics, raising important implications about isolated founder effects and strategies for population screening in that country.

  6. DNAJC13 mutations in Parkinson disease

    PubMed Central

    Vilariño-Güell, Carles; Rajput, Alex; Milnerwood, Austen J.; Shah, Brinda; Szu-Tu, Chelsea; Trinh, Joanne; Yu, Irene; Encarnacion, Mary; Munsie, Lise N.; Tapia, Lucia; Gustavsson, Emil K.; Chou, Patrick; Tatarnikov, Igor; Evans, Daniel M.; Pishotta, Frederick T.; Volta, Mattia; Beccano-Kelly, Dayne; Thompson, Christina; Lin, Michelle K.; Sherman, Holly E.; Han, Heather J.; Guenther, Bruce L.; Wasserman, Wyeth W.; Bernard, Virginie; Ross, Colin J.; Appel-Cresswell, Silke; Stoessl, A. Jon; Robinson, Christopher A.; Dickson, Dennis W.; Ross, Owen A.; Wszolek, Zbigniew K.; Aasly, Jan O.; Wu, Ruey-Meei; Hentati, Faycal; Gibson, Rachel A.; McPherson, Peter S.; Girard, Martine; Rajput, Michele; Rajput, Ali H.; Farrer, Matthew J.

    2014-01-01

    A Saskatchewan multi-incident family was clinically characterized with Parkinson disease (PD) and Lewy body pathology. PD segregates as an autosomal-dominant trait, which could not be ascribed to any known mutation. DNA from three affected members was subjected to exome sequencing. Genome alignment, variant annotation and comparative analyses were used to identify shared coding mutations. Sanger sequencing was performed within the extended family and ethnically matched controls. Subsequent genotyping was performed in a multi-ethnic case–control series consisting of 2928 patients and 2676 control subjects from Canada, Norway, Taiwan, Tunisia, and the USA. A novel mutation in receptor-mediated endocytosis 8/RME-8 (DNAJC13 p.Asn855Ser) was found to segregate with disease. Screening of cases and controls identified four additional patients with the mutation, of which two had familial parkinsonism. All carriers shared an ancestral DNAJC13 p.Asn855Ser haplotype and claimed Dutch–German–Russian Mennonite heritage. DNAJC13 regulates the dynamics of clathrin coats on early endosomes. Cellular analysis shows that the mutation confers a toxic gain-of-function and impairs endosomal transport. DNAJC13 immunoreactivity was also noted within Lewy body inclusions. In late-onset disease which is most reminiscent of idiopathic PD subtle deficits in endosomal receptor-sorting/recycling are highlighted by the discovery of pathogenic mutations VPS35, LRRK2 and now DNAJC13. With this latest discovery, and from a neuronal perspective, a temporal and functional ecology is emerging that connects synaptic exo- and endocytosis, vesicular trafficking, endosomal recycling and the endo-lysosomal degradative pathway. Molecular deficits in these processes are genetically linked to the phenotypic spectrum of parkinsonism associated with Lewy body pathology. PMID:24218364

  7. L'Infection Nosocomiale en Reanimation des Brules

    PubMed Central

    Siah, S.; Belefqih, R.; Elouennass, M.; Fouadi, F.E.; Ihrai, I.

    2009-01-01

    Summary L'infection nosocomiale bactérienne étant l'une des principales causes de morbidité et de mortalité chez le brûlé, nous avons réalisé une étude rétrospective portant sur 84 patients hospitalisés au sein du service de réanimation des brûlés de l'Hôpital Militaire d'Instruction Mohammed V de Rabat, sur une période de 3 ans, du premier janvier 2001 au 31 décembre 2003. Les critères d'infection nosocomiale étaient ceux du Center for Disease Control d'Atlanta de 1988. Les taux d'incidence ont été calculés. La population infectée a été comparée à celle non infectée. L'écologie bactérienne du service a été décrite comme aussi l'antibiotype. Il ressort de cette étude la survenue de 87 infections nosocomiales chez 27 patients. L'incidence cumulative était de 103 infections pour 1000 jours de traitement. Pour ce qui est des caractéristiques des infections bactériennes, les sites infectés étaient la peau (77%), le sang (13,8%), les voies urinaires (8%) et les poumons (1,1%). Les principaux germes étaient: Staphylococcus sp. (33,3%), Pseudomonas aeruginosa (23%), Enterococcus faecalis et Acinetobacter (8%). Les staphylocoques étaient méticillo-résistants dans 22,2% des cas. Le Pseudomonas et l'Acinetobacter étaient multirésistants (60%). Dans notre étude les facteurs prédictifs de survenue des infections nosocomiales que nous avons retenus après l'étude comparative des populations infectées et non infectées ont été l'âge, le body mass index, l'abbreviated burn severity index et le remplissage initial. En isolant ces paramètres, nous avons pu établir une équation à valeur prédictive de survenue d'infection nosocomiale chez le patient brûlé. PMID:21991158

  8. Confidence-based somatic mutation evaluation and prioritization.

    PubMed

    Löwer, Martin; Renard, Bernhard Y; de Graaf, Jos; Wagner, Meike; Paret, Claudia; Kneip, Christoph; Türeci, Ozlem; Diken, Mustafa; Britten, Cedrik; Kreiter, Sebastian; Koslowski, Michael; Castle, John C; Sahin, Ugur

    2012-01-01

    Next generation sequencing (NGS) has enabled high throughput discovery of somatic mutations. Detection depends on experimental design, lab platforms, parameters and analysis algorithms. However, NGS-based somatic mutation detection is prone to erroneous calls, with reported validation rates near 54% and congruence between algorithms less than 50%. Here, we developed an algorithm to assign a single statistic, a false discovery rate (FDR), to each somatic mutation identified by NGS. This FDR confidence value accurately discriminates true mutations from erroneous calls. Using sequencing data generated from triplicate exome profiling of C57BL/6 mice and B16-F10 melanoma cells, we used the existing algorithms GATK, SAMtools and SomaticSNiPer to identify somatic mutations. For each identified mutation, our algorithm assigned an FDR. We selected 139 mutations for validation, including 50 somatic mutations assigned a low FDR (high confidence) and 44 mutations assigned a high FDR (low confidence). All of the high confidence somatic mutations validated (50 of 50), none of the 44 low confidence somatic mutations validated, and 15 of 45 mutations with an intermediate FDR validated. Furthermore, the assignment of a single FDR to individual mutations enables statistical comparisons of lab and computation methodologies, including ROC curves and AUC metrics. Using the HiSeq 2000, single end 50 nt reads from replicates generate the highest confidence somatic mutation call set.

  9. Recurrent inactivating RASA2 mutations in melanoma.

    PubMed

    Arafeh, Rand; Qutob, Nouar; Emmanuel, Rafi; Keren-Paz, Alona; Madore, Jason; Elkahloun, Abdel; Wilmott, James S; Gartner, Jared J; Di Pizio, Antonella; Winograd-Katz, Sabina; Sindiri, Sivasish; Rotkopf, Ron; Dutton-Regester, Ken; Johansson, Peter; Pritchard, Antonia L; Waddell, Nicola; Hill, Victoria K; Lin, Jimmy C; Hevroni, Yael; Rosenberg, Steven A; Khan, Javed; Ben-Dor, Shifra; Niv, Masha Y; Ulitsky, Igor; Mann, Graham J; Scolyer, Richard A; Hayward, Nicholas K; Samuels, Yardena

    2015-12-01

    Analysis of 501 melanoma exomes identified RASA2, encoding a RasGAP, as a tumor-suppressor gene mutated in 5% of melanomas. Recurrent loss-of-function mutations in RASA2 were found to increase RAS activation, melanoma cell growth and migration. RASA2 expression was lost in ≥30% of human melanomas and was associated with reduced patient survival. These findings identify RASA2 inactivation as a melanoma driver and highlight the importance of RasGAPs in cancer. PMID:26502337

  10. On spatial mutation-selection models

    SciTech Connect

    Kondratiev, Yuri; Kutoviy, Oleksandr E-mail: kutovyi@mit.edu; Minlos, Robert Pirogov, Sergey

    2013-11-15

    We discuss the selection procedure in the framework of mutation models. We study the regulation for stochastically developing systems based on a transformation of the initial Markov process which includes a cost functional. The transformation of initial Markov process by cost functional has an analytic realization in terms of a Kimura-Maruyama type equation for the time evolution of states or in terms of the corresponding Feynman-Kac formula on the path space. The state evolution of the system including the limiting behavior is studied for two types of mutation-selection models.

  11. p16 Mutations in hereditary melanomas

    SciTech Connect

    Hussussian, C.J.; Struewing, J.P.; Goldstein, A.M.

    1994-09-01

    The p16 gene (CDK4 inhibitor) is located in chromosome 9p21, a region that shows linkage to hereditary melanoma and is deleted in many different tumors. p16 was analyzed in 19 families with hereditary melanoma by amplifying the entire coding region in 5 short segments and screening by SSCP under several conditions that should resolve >95% of polymorphisms. A total of 10 variants were detected in 15 families. The mutations detected included 7 missense, 1 silent, 1 nonsense, and one that destroyed a consensus splice donor site. One of the missense mutations was present in 5/21 spouses in these families, giving an estimated allele frequency of 0.12. Therefore the {triangle}436 [G{yields}A] variant is a common polymorphism and is not involved in the development of melanoma. However, there was strong evidence for the involvement of the other p16 mutations in five 9p21 linked families. In these families, a total of 17/19 individuals with melanoma inherited the mutant allele, while only 2/26 unaffected family members (1 with dysplastic nevi) and 0/13 spouses had the mutant alleles. In two additional 9p21 linked families, one segregated a silent mutation in 3/4 of the affected individuals, and the second only contained the common {triangle}436 [G{yields}A] mutation. In the two families with strong evidence of linkage to chromosome 1p36 and exclusion of linkage to 9p21, no SSCP variants were detected at p16 among 11 melanoma cases, except for a single affected individual who inherited the variant from an unaffected parent. These data confirm the existence of genetic heterogeneity in families with hereditary melanoma. Most (5/7) of the families with strong linkage to 9p21 had p16 missense mutations that segregated with the disease, while 2 families with strong linkage to chromosome 1p36 did not have any detectable p16 mutations that segregated with the disease. Further functional analyses of these mutations will clarify which are causally related to hereditary melanoma.

  12. The study of human mutation rates

    SciTech Connect

    Neel, J.V.

    1992-01-01

    We will describe recent developments regarding the question of induced mutations in the survivors of the atomic bombings of Hiroshima and Nagasaki. As part of that work we, describe some developments with respect to the Amerindian blood samples collected under DoE sponsorship between 1964 and 1982. Then developments regarding the application of two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) to the study of genetic variation and mutation affecting protein characteristics. In particular, we will report on the identification and isolation of genes of especial interest as reflected in the behavior of the proteins which they encode.

  13. Mutational dynamics of aroid chloroplast genomes.

    PubMed

    Ahmed, Ibrar; Biggs, Patrick J; Matthews, Peter J; Collins, Lesley J; Hendy, Michael D; Lockhart, Peter J

    2012-01-01

    A characteristic feature of eukaryote and prokaryote genomes is the co-occurrence of nucleotide substitution and insertion/deletion (indel) mutations. Although similar observations have also been made for chloroplast DNA, genome-wide associations have not been reported. We determined the chloroplast genome sequences for two morphotypes of taro (Colocasia esculenta; family Araceae) and compared these with four publicly available aroid chloroplast genomes. Here, we report the extent of genome-wide association between direct and inverted repeats, indels, and substitutions in these aroid chloroplast genomes. We suggest that alternative but not mutually exclusive hypotheses explain the mutational dynamics of chloroplast genome evolution. PMID:23204304

  14. Lignes directrices canadiennes sur l’utilisation sécuritaire et efficace des opioïdes pour la douleur chronique non cancéreuse

    PubMed Central

    Kahan, Meldon; Wilson, Lynn; Mailis-Gagnon, Angela; Srivastava, Anita

    2011-01-01

    Résumé Objectif Présenter aux médecins de famille un résumé clinique pratique sur la prescription d’opioïdes à des populations particulières en se fondant sur les recommandations faites dans les lignes directrices canadiennes sur l’utilisation sécuritaire et efficace des opioïdes pour la douleur chronique non cancéreuse. Qualité des données Pour produire les lignes directrices, les chercheurs ont effectué une synthèse critique de la littérature médicale en insistant plus précisément sur les études de l’efficacité et de la sécurité des opioïdes dans des populations particulières. Message principal Les médecins de famille peuvent atténuer les risques de surdose, de sédation, d’usage abusif et de dépendance grâce à des stratégies adaptées à l’âge et à l’état de santé des patients. Dans le cas de patients à risque de dépendance, on devrait réserver les opioïdes aux douleurs nociceptives ou neuropathiques bien définies qui n’ont pas répondu aux traitements de première intention. Il faut procéder lentement au titrage des opioïdes, avec des dispensations fréquentes et une étroite surveillance pour dépister tout signe d’usage abusif. Une dépendance aux opioïdes suspectée est prise en charge au moyen d’une thérapie structurée aux opioïdes, d’un traitement à la méthadone ou à la buprénorphine ou encore d’un traitement fondé sur l’abstinence. Les patients souffrant de troubles de l’humeur ou d’anxiété ont tendance à avoir une réponse analgésique atténuée aux opioïdes, sont à risque plus élevé d’usage abusif et prennent souvent des sédatifs qui interagissent défavorablement avec les opioïdes. Il faut prendre des précautions semblables à celles utilisées avec d’autres patients à risque élevé. Il faut faire un sevrage progressif si la douleur du patient demeure sévère même avec un essai adéquat de thérapie aux opioïdes. Chez les personnes âgées, la s

  15. Molecular evaluation of a novel missense mutation & an insertional truncating mutation in SUMF1 gene

    PubMed Central

    Kotecha, Udhaya H.; Movva, Sireesha; Sharma, Deepak; Verma, Jyotsna; Puri, Ratna Dua; Verma, Ishwar Chander

    2014-01-01

    Background & objectives: Multiple suphphatase deficiency (MSD) is an autosomal recessive disorder affecting the post translational activation of all enzymes of the sulphatase family. To date, approximately 30 different mutations have been identified in the causative gene, sulfatase modifying factor 1 (SUMF1). We describe here the mutation analysis of a case of MSD. Methods: The proband was a four year old boy with developmental delay followed by neuroregression. He had coarse facies, appendicular hypertonia, truncal ataxia and ichthyosis limited to both lower limbs. Radiographs showed dysostosis multiplex. Clinical suspicion of MSD was confirmed by enzyme analysis of four enzymes of the sulphatase group. Results: The patient was compound heterozygote for a c.451A>G (p.K151E) substitution in exon 3 and a single base insertion mutation (c.690_691 InsT) in exon 5 in the SUMF1 gene. The bioinformatic analysis of the missense mutation revealed no apparent effect on the overall structure. However, the mutated 151-amino acid residue was found to be adjacent to the substrate binding and the active site residues, thereby affecting the substrate binding and/or catalytic activity, resulting in almost complete loss of enzyme function. Conclusions: The two mutations identified in the present case were novel. This is perhaps the first report of an insertion mutation in SUMF1 causing premature truncation of the protein. PMID:25222778

  16. PAH Mutation Analysis Consortium Database: 1997. Prototype for relational locus-specific mutation databases.

    PubMed Central

    Nowacki, P M; Byck, S; Prevost, L; Scriver, C R

    1998-01-01

    PAHdb (http://www.mcgill.ca/pahdb ) is a curated relational database (Fig. 1) of nucleotide variation in the human PAH cDNA (GenBank U49897). Among 328 different mutations by state (Fig. 2) the majority are rare mutations causing hyperphenylalaninemia (HPA) (OMIM 261600), the remainder are polymorphic variants without apparent effect on phenotype. PAHdb modules contain mutations, polymorphic haplotypes, genotype-phenotype correlations, expression analysis, sources of information and the reference sequence; the database also contains pages of clinical information and data on three ENU mouse orthologues of human HPA. Only six different mutations account for 60% of human HPA chromosomes worldwide, mutations stratify by population and geographic region, and the Oriental and Caucasian mutation sets are different (Fig. 3). PAHdb provides curated electronic publication and one third of its incoming reports are direct submissions. Each different mutation receives a systematic (nucleotide) name and a unique identifier (UID). Data are accessed both by a Newsletter and a search engine on the website; integrity of the database is ensured by keeping the curated template offline. There have been >6500 online interrogations of the website. PMID:9399840

  17. Variable expressivity and mutation databases: The androgen receptor gene mutations database.

    PubMed

    Gottlieb, B; Beitel, L K; Trifiro, M A

    2001-05-01

    For over 50 years genetics has presumed that variations in phenotypic expression have, for the most part, been the result of alterations in genotype. The importance and value of mutation databases has been based on the premise that the same gene or allelic variation in a specific gene that has been proven to determine a specific phenotype, will always produce the same phenotype. However, recent evidence has shown that so called "simple" Mendelian disorders or monogenic traits are often far from simple, exhibiting phenotypic variation (variable expressivity) that cannot be explained solely by a gene or allelic alteration. The AR gene mutations database now lists 25 cases where different degrees of androgen insensitivity are caused by identical mutations in the androgen receptor gene. In five of these cases the phenotypic variability is due to somatic mosaicism, that is, somatic mutations that occur in only certain cells of androgen-sensitive tissue. Recently, a number of other cases of variable expressivity have also been linked to somatic mosaicism. The impact of variable expressivity due to somatic mutations and mosaicism on mutation databases is discussed. In particular, the effect of an organism exhibiting genetic heterogeneity within its tissues, and the possibility of an organism's genotype changing over its lifetime, are considered to have important implications for mutation databases in the future. PMID:11317353

  18. Target gene mutational pattern in Lynch syndrome colorectal carcinomas according to tumour location and germline mutation

    PubMed Central

    Pinheiro, Manuela; Pinto, Carla; Peixoto, Ana; Veiga, Isabel; Lopes, Paula; Henrique, Rui; Baldaia, Helena; Carneiro, Fátima; Seruca, Raquel; Tomlinson, Ian; Kovac, Michal; Heinimann, Karl; Teixeira, Manuel R

    2015-01-01

    Background: We previously reported that the target genes in sporadic mismatch repair (MMR)-deficient colorectal carcinomas (CRCs) in the distal colon differ from those occurring elsewhere in the colon. This study aimed to compare the target gene mutational pattern in microsatellite instability (MSI) CRC from Lynch syndrome patients stratified by tumour location and germline mutation, as well as with that of sporadic disease. Methods: A series of CRC from Lynch syndrome patients was analysed for MSI in genes predicted to be selective MSI targets and known to be involved in several pathways of colorectal carcinogenesis. Results: The most frequently mutated genes belong to the TGF-β superfamily pathway, namely ACVR2A and TGFBR2. A significantly higher frequency of target gene mutations was observed in CRC from patients with germline mutations in MLH1 or MSH2 when compared with MSH6. Mutations in microsatellite sequences (A)7 of BMPR2 and (A)8 of MSH3 were significantly more frequent in the distal CRC. Additionally, we observed differences in MSH3 and TGFBR2 mutational frequency between Lynch syndrome and sporadic MSI CRC regarding tumour location. Conclusions: Our results indicate that the pattern of genetic changes differs in CRC depending on tumour location and between Lynch syndrome and sporadic MSI CRC, suggesting that carcinogenesis can occur by different pathways even if driven by generalised MSI. PMID:26247575

  19. Confirmation of the mitochondrial ND1 gene mutation G3635A as a primary LHON mutation.

    PubMed

    Yang, Juhua; Zhu, Yihua; Tong, Yi; Chen, Lu; Liu, Lijuan; Zhang, Zhiqiang; Wang, Xiaoyan; Huang, Dinggou; Qiu, Wentong; Zhuang, Shuliu; Ma, Xu

    2009-08-14

    We report the clinical and genetic characterization of two Chinese LHON families who do not carry the primary LHON-mutations. Mitochondrial genome sequence analysis revealed the presence of a homoplasmic ND1 G3635A mutation in both families. In Family LHON-001, 31 other variants belonging to the East Asian haplogroup R11a were identified and in Family LHON-019, 37 other variants belonging to the East Asian haplogroup D4g were determined. The ND1 G3635A mutation changes the conversed serine110 residue to asparagine. This mutation has been previously described in a single Russian LHON family and has been suggested to contribute to increased LHON expressivity. In addition, a mutation in cytochrome c oxidase subunit II at C7868T (COII/L95F) may act in synergy with G3635A, increasing LHON expressivity in Family LHON-001, which had a higher level of LHON penetrance than Family LHON-019. In summary, the G3635A mutation is confirmed as a rare primary pathogenic mutation for LHON.

  20. Relation entre les caractéristiques des table-bancs et les mesures anthropométriques des écoliers au Benin

    PubMed Central

    Falola, Stève Marjelin; Gouthon, Polycarpe; Falola, Jean-Marie; Fiogbe, Michel Armand; Nigan, Issiako Bio

    2014-01-01

    Introduction Le mobilier scolaire et la posture assise en classe sont souvent impliqués dans l'apparition des douleurs rachidiennes, influant de fait sur la qualité des tâches réalisées par les apprenants. Aucune étude n'a encore vérifié le degré d'adéquation entre les caractéristiques du mobilier et celles des écoliers au Bénin. L'objectif de cette étude transversale est donc de déterminer la relation entre les dimensions des table-bancs utilisées en classe et les mesures anthropométriques des écoliers au Bénin. Methods Elle a été réalisée avec un échantillon probabiliste de 678 écoliers, âgés de 4 à 17 ans. Les mesures anthropométriques des écoliers et les mensurations relatives aux longueurs, largeurs et hauteurs des table-bancs ont été mesurées, puis intégrées aux équations proposées dans la littérature. Les pourcentages des valeurs situées hors des limitesacceptables, dérivées de l'application des équations ont été calculés. Results La largeur et la hauteur des table-bancs utilisées par les écoliers étaient plus élevées (p < 0,05) que les valeurs de référence recommandées par les structures officielles de contrôle et de production des mobiliers scolaires au Bénin. Quel que soit le sexe, il y avait une inadéquation entre la largeur du banc et la longueur fesse-poplité, puis entre la hauteur de la table et la distance coude-bancdes écoliers. Conclusion Les résultats suggèrent de prendre en compte l’évolution des mesures anthropométriques des écoliers dans la confection des table-bancs, afin de promouvoir de bonnes postures assises en classe et de réduire le risque de troubles du rachis. PMID:25317232

  1. The Alternative Splicing Mutation Database: a hub for investigations of alternative splicing using mutational evidence

    PubMed Central

    Bechtel, Jason M; Rajesh, Preeti; Ilikchyan, Irina; Deng, Ying; Mishra, Pankaj K; Wang, Qi; Wu, Xiaochun; Afonin, Kirill A; Grose, William E; Wang, Ye; Khuder, Sadik; Fedorov, Alexei

    2008-01-01

    Background Some mutations in the internal regions of exons occur within splicing enhancers and silencers, influencing the pattern of alternative splicing in the corresponding genes. To understand how these sequence changes affect splicing, we created a database of these mutations. Findings The Alternative Splicing Mutation Database (ASMD) serves as a repository for all exonic mutations not associated with splicing junctions that measurably change the pattern of alternative splicing. In this initial published release (version 1.2), only human sequences are present, but the ASMD will grow to include other organisms, (see Availability and requirements section for the ASMD web address). This relational database allows users to investigate connections between mutations and features of the surrounding sequences, including flanking sequences, RNA secondary structures and strengths of splice junctions. Splicing effects of the mutations are quantified by the relative presence of alternative mRNA isoforms with and without a given mutation. This measure is further categorized by the accuracy of the experimental methods employed. The database currently contains 170 mutations in 66 exons, yet these numbers increase regularly. We developed an algorithm to derive a table of oligonucleotide Splicing Potential (SP) values from the ASMD dataset. We present the SP concept and tools in detail in our corresponding article. Conclusion The current data set demonstrates that mutations affecting splicing are located throughout exons and might be enriched within local RNA secondary structures. Exons from the ASMD have below average splicing junction strength scores, but the difference is small and is judged not to be significant. PMID:18611286

  2. Biallelic BRCA2 Mutations Shape the Somatic Mutational Landscape of Aggressive Prostate Tumors.

    PubMed

    Decker, Brennan; Karyadi, Danielle M; Davis, Brian W; Karlins, Eric; Tillmans, Lori S; Stanford, Janet L; Thibodeau, Stephen N; Ostrander, Elaine A

    2016-05-01

    To identify clinically important molecular subtypes of prostate cancer (PCa), we characterized the somatic landscape of aggressive tumors via deep, whole-genome sequencing. In our discovery set of ten tumor/normal subject pairs with Gleason scores of 8-10 at diagnosis, coordinated analysis of germline and somatic variants, including single-nucleotide variants, indels, and structural variants, revealed biallelic BRCA2 disruptions in a subset of samples. Compared to the other samples, the PCa BRCA2-deficient tumors exhibited a complex and highly specific mutation signature, featuring a 2.88-fold increased somatic mutation rate, depletion of context-specific C>T substitutions, and an enrichment for deletions, especially those longer than 10 bp. We next performed a BRCA2 deficiency-targeted reanalysis of 150 metastatic PCa tumors, and each of the 18 BRCA2-mutated samples recapitulated the BRCA2 deficiency-associated mutation signature, underscoring the potent influence of these lesions on somatic mutagenesis and tumor evolution. Among all 21 individuals with BRCA2-deficient tumors, only about half carried deleterious germline alleles. Importantly, the somatic mutation signature in tumors with one germline and one somatic risk allele was indistinguishable from those with purely somatic mutations. Our observations clearly demonstrate that BRCA2-disrupted tumors represent a unique and clinically relevant molecular subtype of aggressive PCa, highlighting both the promise and utility of this mutation signature as a prognostic and treatment-selection biomarker. Further, any test designed to leverage BRCA2 status as a biomarker for PCa must consider both germline and somatic mutations and all types of deleterious mutations.

  3. Optimisation des proprietes fonctionnelles des alliages a memoire de forme suite a l'application de traitements thermomecaniques

    NASA Astrophysics Data System (ADS)

    Demers, Vincent

    L'objectif de ce projet est de determiner les conditions de laminage et la temperature de traitement thermique maximisant les proprietes fonctionnelles de l'alliage a memoire de forme Ti-Ni. Les specimens sont caracterises par des mesures de calorimetrie, de microscopie optique, de gene ration de contrainte, de deformation recuperable et des essais mecaniques. Pour un cycle unique, l'utilisation d'un taux d'ecrouissage e=1.5 obtenu avec l'application d'une force de tension FT = 0.1sigma y et d'une huile minerale resulte en un echantillon droit, sans microfissure et qui apres un recuit a 400°C, produit un materiau nanostructure manifestant des proprietes fonctionnelles deux fois plus grandes que le meme materiau ayant une structure polygonisee. Pour des cycles repetes, les memes conditions de laminage sont valables mais le niveau de deformation optimal est situe entre e=0.75-2, et depend particulierement du mode de sollicitation, du niveau de stabilisation et du nombre de cycles a la rupture requis par l'application.

  4. Mutations in Escherichia coli that relieve catabolite repression of tryptophanase synthesis. Tryptophanase promoter-like mutations.

    PubMed

    Ward, D F; Yudkin, M D

    1976-01-01

    From a strain lacking adenyl cyclase and the catabolite-sensitive gene activator protein, two mutants were isolated that can synthesize tryptophanase. Each mutation is extremely closely linked to the tryptophanase structural gene. The mutations differ from one another in the rate of synthesis of tryptophanase that they permit in the genetic background in which they were isolated; they differ from one another and also from the wild type in the maximum rate of synthesis of tryptophanase that they permit in a genetic background with intact adenyl cyclase and catabolite-sensitive gene activator protein. Both mutations appear to lie in the tryptophanase promoter.

  5. Somatic mitochondrial DNA mutations do not increase neuronal vulnerability to MPTP in young POLG mutator mice.

    PubMed

    Dai, Ying; Clark, Joanne; Zheng, Kangni; Kujoth, Gregory C; Prolla, Tomas A; Simon, David K

    2014-01-01

    Mitochondrial DNA (mtDNA) mutations are hypothesized to play a pathogenic role in aging and age-related neurodegenerative diseases such as Parkinson's disease (PD). In support of this, high levels of somatic mtDNA mutations in “POLG mutator” mice carrying a proofreading-deficient form of mtDNA polymerase ã (Polg(D257A)) lead to a premature aging phenotype. However, the relevance of this finding to the normal aging process has been questioned as the number of mutations is greater even in young POLG mutator mice, which shows no overt phenotype, than levels achieved during normal aging in mice. Vulnerability of dopaminergic neurons to 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) increases with age, and we hypothesized that this may result in part from the accumulation with age of somatic mtDNA mutations. If correct, then levels of mutations in young (2–3 month old) POLG mutator mice should be sufficient to increase vulnerability to MPTP. In contrast, we find that susceptibility to MPTP in both heterozygous and homozygous POLG mutator mice at this young age is not different from that of wild type littermate controls as measured by levels of tyrosine hydroxylase positive (TH+) striatal terminals, striatal dopamine and its metabolites, a marker of oxidative damage, or stereological counts of TH+ and total substantia nigra neurons. These unexpected results do not support the hypothesis that somatic mtDNA mutations contribute to the age-related vulnerability of dopaminergic neurons to MPTP. It remains possible that somatic mtDNA mutations influence vulnerability to other stressors, or require additional time for the deleterious consequences to manifest. Furthermore, the impact of the higher levels of mutations present at older ages in these mice was not assessed in our study, although a prior study also failed to detect an increase in vulnerability to MPTP in older mice. With these caveats, the current data do not provide evidence for a role of somatic mt

  6. Positive mutations and mutation-dependent Verhulst factor in Penna ageing model

    NASA Astrophysics Data System (ADS)

    Moss de Oliveira, S.; Stauffer, D.; de Oliveira, P. M. C.; Sá Martins, J. S.

    2004-02-01

    We modify twice the Penna model for biological ageing. First, we introduce back (good) mutations and a memory for them into the model. It allows us to observe an improvement of the species fitness over long-time scales as well as punctuated equilibrium. Second, we adopt a food/space competition factor that depends on the number of accumulated mutations in the individuals genomes, and get rid of the fixed limiting number of allowed mutations. Besides reproducing the main results of the standard model, we also observe a mortality maximum for the oldest old.

  7. Microscopie interférentielle X-UV : un outil pour l'étude des endommagements des surfaces optiques

    NASA Astrophysics Data System (ADS)

    Jamelot, G.; Ros, D.; Cassou, K.; Kazamias, S.; Klisnick, A.; Kozlová, M.; Mocek, T.; Homer, P.; Polan, J.; Stupka, M.

    2006-12-01

    Nous présentons des résultats récents concernant des premières investigations de microscopie interférentielle par laser X-UV d'endommagement optique. Le laser X-UV utilisé est un laser collisionnel en régime quasi-stationnaire émettant à 21.2 nm, développé au Prague Asterix Laser System (PALS, Prague, République Tchèque). Des échantillons de silice fondue de haute qualité, avec ou sans rayure, étaient irradiées en face avant par un laser bleu, correspondant au 3selectfontfontsize{7{9}{textrm{ème}}} harmonique du laser à iode du PALS (1.315 μ m), servant également à réaliser le laser X-UV à 21.2 nm. Celui-ci était utilisé, 5 ns après l'irradiation pour réaliser une imagerie microscopique et interférentielle de la face arrière de l'échantillon. Les résultats font apparaître des déformations locales transitoires. Des premières analyses mettent en évidence une probable variation de la rugosité de la surface. Cette démonstration expérimentale encourageante ouvre la voie à de futures investigations, notamment sur notre prochaine installation laser : LASERIX.

  8. Methodes iteratives paralleles: Applications en neutronique et en mecanique des fluides

    NASA Astrophysics Data System (ADS)

    Qaddouri, Abdessamad

    Dans cette these, le calcul parallele est applique successivement a la neutronique et a la mecanique des fluides. Dans chacune de ces deux applications, des methodes iteratives sont utilisees pour resoudre le systeme d'equations algebriques resultant de la discretisation des equations du probleme physique. Dans le probleme de neutronique, le calcul des matrices des probabilites de collision (PC) ainsi qu'un schema iteratif multigroupe utilisant une methode inverse de puissance sont parallelises. Dans le probleme de mecanique des fluides, un code d'elements finis utilisant un algorithme iteratif du type GMRES preconditionne est parallelise. Cette these est presentee sous forme de six articles suivis d'une conclusion. Les cinq premiers articles traitent des applications en neutronique, articles qui representent l'evolution de notre travail dans ce domaine. Cette evolution passe par un calcul parallele des matrices des PC et un algorithme multigroupe parallele teste sur un probleme unidimensionnel (article 1), puis par deux algorithmes paralleles l'un mutiregion l'autre multigroupe, testes sur des problemes bidimensionnels (articles 2--3). Ces deux premieres etapes sont suivies par l'application de deux techniques d'acceleration, le rebalancement neutronique et la minimisation du residu aux deux algorithmes paralleles (article 4). Finalement, on a mis en oeuvre l'algorithme multigroupe et le calcul parallele des matrices des PC sur un code de production DRAGON ou les tests sont plus realistes et peuvent etre tridimensionnels (article 5). Le sixieme article (article 6), consacre a l'application a la mecanique des fluides, traite la parallelisation d'un code d'elements finis FES ou le partitionneur de graphe METIS et la librairie PSPARSLIB sont utilises.

  9. De Novo Discovery of Mutated Driver Pathways in Cancer

    NASA Astrophysics Data System (ADS)

    Vandin, Fabio; Upfal, Eli; Raphael, Benjamin J.

    Next-generation DNA sequencing technologies are enabling genome-wide measurements of somatic mutations in large numbers of cancer patients. A major challenge in interpretation of this data is to distinguish functional driver mutations that are important for cancer development from random, passenger mutations. A common approach to identify driver mutations is to find genes that are mutated at significant frequency in a large cohort of cancer genomes. This approach is confounded by the observation that driver mutations target multiple cellular signaling and regulatory pathways. Thus, each cancer patient may exhibit a different combination of mutations that are sufficient to perturb the necessary pathways. However, the current understanding of the somatic mutational process of cancer [3,5,6] places two additional constraints on the expected patterns of somatic mutations in a cancer pathway. First, an important cancer pathway should be perturbed in a large number of patients. Thus we expect that with genome-wide measurements of somatic mutations a driver pathway will exhibit high coverage, where most patients will have a mutation in some gene in the pathway. Second, since driver mutations are relatively rare and typically a single driver mutation is sufficient to perturb a pathway, a reasonable assumption is that most patients have a single driver mutation in a pathway. Thus, the genes in a driver pathway exhibit a pattern of mutually exclusive driver mutations, where driver mutations are observed in exactly one gene in the pathway in each patient. There are numerous examples of sets of mutually exclusive mutations [5,6].

  10. From Gene Mutation to Protein Characterization

    ERIC Educational Resources Information Center

    Moffet, David A.

    2009-01-01

    A seven-week "gene to protein" laboratory sequence is described for an undergraduate biochemistry laboratory course. Student pairs were given the task of introducing a point mutation of their choosing into the well studied protein, enhanced green fluorescent protein (EGFP). After conducting literature searches, each student group chose the…

  11. Air pollution induces heritable DNA mutations

    PubMed Central

    Somers, Christopher M.; Yauk, Carole L.; White, Paul A.; Parfett, Craig L. J.; Quinn, James S.

    2002-01-01

    Hundreds of thousands of people worldwide live or work in close proximity to steel mills. Integrated steel production generates chemical pollution containing compounds that can induce genetic damage (1, 2). Previous investigations of herring gulls in the Great Lakes demonstrated elevated DNA mutation rates near steel mills (3, 4) but could not determine the importance of airborne or aquatic routes of contaminant exposure, or eliminate possible confounding factors such as nutritional status and disease burden. To address these issues experimentally, we exposed laboratory mice in situ to ambient air in a polluted industrial area near steel mills. Heritable mutation frequency at tandem-repeat DNA loci in mice exposed 1 km downwind from two integrated steel mills was 1.5- to 2.0-fold elevated compared with those at a reference site 30 km away. This statistically significant elevation was due primarily to an increase in mutations inherited through the paternal germline. Our results indicate that human and wildlife populations in proximity to integrated steel mills may be at risk of developing germline mutations more frequently because of the inhalation of airborne chemical mutagens. PMID:12473746

  12. Novel ATM mutations with ataxia-telangiectasia.

    PubMed

    Liu, Xiao-Li; Wang, Tian; Huang, Xiao-Jun; Zhou, Hai-Yan; Luan, Xing-Hua; Shen, Jun-Yi; Chen, Sheng-Di; Cao, Li

    2016-01-12

    Ataxia telangiectasia is an autosomal recessive multisystem disorder characterized by progressive cerebellar ataxia with onset in childhood, oculocutaneous telangiectasia, increased serum alpha-fetoprotein, immunodeficiency, chromosomal instability, and radiation hypersensitivity. Ataxia-telangiectasia mutated gene (ATM) is one of the known genes to be associated with ataxia telangiectasia. We reported the clinical and genetic findings of three early-onset Chinese patients who demonstrated ataxia, oculomotor apraxia, choreoathetosis, myoclonus and telangiectasia of eyes. Sequence analysis of ATM revealed two known nonsense mutations c.8287C>T and c.9139C>T in the siblings. Though the siblings carried the same mutations, they showed different clinical features involving strephenopodia, exotropia, torsion dystonia, myoclonus and extrapyramidal impairments. The other patient was compound heterozygotes for ATM: c.8911C>T and c.7141_7151delAATGGAAAAAT, both of which were not reported previously and not found in 200 control chromosomes. This study widens the spectrum of mutations and phenotypes in ataxia telangiectasia.

  13. PMS2 mutations in childhood cancer.

    PubMed

    De Vos, Michel; Hayward, Bruce E; Charlton, Ruth; Taylor, Graham R; Glaser, Adam W; Picton, Susan; Cole, Trevor R; Maher, Eamonn R; McKeown, Carole M E; Mann, Jill R; Yates, John R; Baralle, Diana; Rankin, Julia; Bonthron, David T; Sheridan, Eamonn

    2006-03-01

    Until recently, the PMS2 DNA mismatch repair gene has only rarely been implicated as a cancer susceptibility locus. New studies have shown, however, that earlier analyses of this gene have had technical limitations and also that the genetic behavior of mutant PMS2 alleles is unusual, in that, unlike MLH1 or MSH2 mutations, PMS2 mutations show low heterozygote penetrance. As a result, a dominantly inherited cancer predisposition has not been a feature reported in families with PMS2 mutations. Such families have instead been ascertained through childhood-onset cancers in homozygotes or through apparently sporadic colorectal cancer in heterozygotes. We present further information on the phenotype associated with homozygous PMS2 deficiency in 13 patients from six families of Pakistani origin living in the United Kingdom. This syndrome is characterized by café-au-lait skin pigmentation and a characteristic tumor spectrum, including leukemias, lymphomas, cerebral malignancies (such as supratentorial primitive neuroectodermal tumors, astrocytomas, and glioblastomas), and colorectal neoplasia with an onset in early adult life. We present evidence for a founder effect in five families, all of which carried the same R802-->X mutation (i.e., arginine-802 to stop) in PMS2. This cancer syndrome can be mistaken for neurofibromatosis type 1, with important management implications including the risk of the disorder occurring in siblings and the likelihood of tumor development in affected individuals.

  14. Mutational Analysis of Merkel Cell Carcinoma

    PubMed Central

    Erstad, Derek J.; Cusack, James C.

    2014-01-01

    Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine malignancy that is associated with a poor prognosis. The pathogenesis of MCC is not well understood, and despite a recent plethora of mutational analyses, we have yet to find a set of signature mutations implicated in the majority of cases. Mutations, including TP53, Retinoblastoma and PIK3CA, have been documented in subsets of patients. Other mechanisms are also likely at play, including infection with the Merkel cell polyomavirus in a subset of patients, dysregulated immune surveillance, epigenetic alterations, aberrant protein expression, posttranslational modifications and microRNAs. In this review, we summarize what is known about MCC genetic mutations and chromosomal abnormalities, and their clinical significance. We also examine aberrant protein function and microRNA expression, and discuss the therapeutic and prognostic implications of these findings. Multiple clinical trials designed to selectively target overexpressed oncogenes in MCC are currently underway, though most are still in early phases. As we accumulate more molecular data on MCC, we will be better able to understand its pathogenic mechanisms, develop libraries of targeted therapies, and define molecular prognostic signatures to enhance our clinicopathologic knowledge. PMID:25329450

  15. Novel ATM mutations with ataxia-telangiectasia.

    PubMed

    Liu, Xiao-Li; Wang, Tian; Huang, Xiao-Jun; Zhou, Hai-Yan; Luan, Xing-Hua; Shen, Jun-Yi; Chen, Sheng-Di; Cao, Li

    2016-01-12

    Ataxia telangiectasia is an autosomal recessive multisystem disorder characterized by progressive cerebellar ataxia with onset in childhood, oculocutaneous telangiectasia, increased serum alpha-fetoprotein, immunodeficiency, chromosomal instability, and radiation hypersensitivity. Ataxia-telangiectasia mutated gene (ATM) is one of the known genes to be associated with ataxia telangiectasia. We reported the clinical and genetic findings of three early-onset Chinese patients who demonstrated ataxia, oculomotor apraxia, choreoathetosis, myoclonus and telangiectasia of eyes. Sequence analysis of ATM revealed two known nonsense mutations c.8287C>T and c.9139C>T in the siblings. Though the siblings carried the same mutations, they showed different clinical features involving strephenopodia, exotropia, torsion dystonia, myoclonus and extrapyramidal impairments. The other patient was compound heterozygotes for ATM: c.8911C>T and c.7141_7151delAATGGAAAAAT, both of which were not reported previously and not found in 200 control chromosomes. This study widens the spectrum of mutations and phenotypes in ataxia telangiectasia. PMID:26628246

  16. Integrative visual analysis of protein sequence mutations

    PubMed Central

    2014-01-01

    Background An important aspect of studying the relationship between protein sequence, structure and function is the molecular characterization of the effect of protein mutations. To understand the functional impact of amino acid changes, the multiple biological properties of protein residues have to be considered together. Results Here, we present a novel visual approach for analyzing residue mutations. It combines different biological visualizations and integrates them with molecular data derived from external resources. To show various aspects of the biological information on different scales, our approach includes one-dimensional sequence views, three-dimensional protein structure views and two-dimensional views of residue interaction networks as well as aggregated views. The views are linked tightly and synchronized to reduce the cognitive load of the user when switching between them. In particular, the protein mutations are mapped onto the views together with further functional and structural information. We also assess the impact of individual amino acid changes by the detailed analysis and visualization of the involved residue interactions. We demonstrate the effectiveness of our approach and the developed software on the data provided for the BioVis 2013 data contest. Conclusions Our visual approach and software greatly facilitate the integrative and interactive analysis of protein mutations based on complementary visualizations. The different data views offered to the user are enriched with information about molecular properties of amino acid residues and further biological knowledge. PMID:25237389

  17. LEOPARD Syndrome: Clinical Features and Gene Mutations

    PubMed Central

    Martínez-Quintana, E.; Rodríguez-González, F.

    2012-01-01

    The RAS/MAPK pathway proteins with germline mutations in their respective genes are associated with some disorders such as Noonan, LEOPARD (LS), neurofibromatosis type 1, Costello and cardio-facio-cutaneous syndromes. LEOPARD is an acronym, mnemonic for the major manifestations of this disorder, characterized by multiple lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness. Though it is not included in the acronym, hypertrophic cardiomyopathy is the most frequent cardiac anomaly observed, representing a potentially life-threatening problem in these patients. PTPN11, RAF1 and BRAF are the genes known to be associated with LS, identifying molecular genetic testing of the 3 gene mutations in about 95% of affected individuals. PTPN11 mutations are the most frequently found. Eleven different missense PTPN11 mutations (Tyr279Cys/Ser, Ala461Thr, Gly464Ala, Thr468Met/Pro, Arg498Trp/Leu, Gln506Pro, and Gln510Glu/Pro) have been reported so far in LS, 2 of which (Tyr279Cys and Thr468Met) occur in about 65% of the cases. Here, we provide an overview of clinical aspects of this disorder, the molecular mechanisms underlying pathogenesis and major genotype-phenotype correlations. PMID:23239957

  18. RPGR mutation analysis and disease: an update.

    PubMed

    Shu, Xinhua; Black, Graeme C; Rice, Jacqueline M; Hart-Holden, Niki; Jones, Alison; O'Grady, Anna; Ramsden, Simon; Wright, Alan F

    2007-04-01

    Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene are the most common single cause of retinitis pigmentosa, accounting for up to 15 to 20% of cases in Caucasians. A total of 240 different RPGR mutations have been reported, including 24 novel ones in this work, which are associated with X-linked retinitis pigmentosa (XLRP) (95%), cone, cone-rod dystrophy, or atrophic macular atrophy (3%), and syndromal retinal dystrophies with ciliary dyskinesia and hearing loss (2%). All disease-causing mutations occur in one or more RPGR isoforms containing the carboxyl-terminal exon open reading frame 15 (ORF15), which are widely expressed but show their highest expression in the connecting cilia of rod and cone photoreceptors. Of reported RPGR mutations, 55% occur in a glutamic acid-rich domain within exon ORF15, which accounts for only 31% of the protein. RPGR forms complexes with a variety of other proteins and appears to have a role in microtubular organization and transport between photoreceptor inner and outer segments.

  19. Prostaglandin transporter mutations cause pachydermoperiostosis with myelofibrosis.

    PubMed

    Diggle, Christine P; Parry, David A; Logan, Clare V; Laissue, Paul; Rivera, Carolina; Restrepo, Carlos Martín; Fonseca, Dora J; Morgan, Joanne E; Allanore, Yannick; Fontenay, Michaela; Wipff, Julien; Varret, Mathilde; Gibault, Laure; Dalantaeva, Nadezhda; Korbonits, Márta; Zhou, Bowen; Yuan, Gang; Harifi, Ghita; Cefle, Kivanc; Palanduz, Sukru; Akoglu, Hadim; Zwijnenburg, Petra J; Lichtenbelt, Klaske D; Aubry-Rozier, Bérengère; Superti-Furga, Andrea; Dallapiccola, Bruno; Accadia, Maria; Brancati, Francesco; Sheridan, Eamonn G; Taylor, Graham R; Carr, Ian M; Johnson, Colin A; Markham, Alexander F; Bonthron, David T

    2012-08-01

    Pachydermoperiostosis, or primary hypertrophic osteoarthropathy (PHO), is an inherited multisystem disorder, whose features closely mimic the reactive osteoarthropathy that commonly accompanies neoplastic and inflammatory pathologies. We previously described deficiency of the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (HPGD) as a cause of this condition, implicating elevated circulating prostaglandin E(2) (PGE(2)) as causative of PHO, and perhaps also as the principal mediator of secondary HO. However, PHO is genetically heterogeneous. Here, we use whole-exome sequencing to identify recessive mutations of the prostaglandin transporter SLCO2A1, in individuals lacking HPGD mutations. We performed exome sequencing of four probands with severe PHO, followed by conventional mutation analysis of SLCO2A1 in nine others. Biallelic SLCO2A1 mutations were identified in 12 of the 13 families. Affected individuals had elevated urinary PGE(2), but unlike HPGD-deficient patients, also excreted considerable quantities of the PGE(2) metabolite, PGE-M. Clinical differences between the two groups were also identified, notably that SLCO2A1-deficient individuals have a high frequency of severe anemia due to myelofibrosis. These findings reinforce the key role of systemic or local prostaglandin excess as the stimulus to HO. They also suggest that the induction or maintenance of hematopoietic stem cells by prostaglandin may depend upon transporter activity. PMID:22553128

  20. Timing, rates and spectra of human germline mutation

    PubMed Central

    Lindsay, Sarah J.; Hardwick, Robert J.; Alexandrov, Ludmil B.; Turki, Saeed Al; Dominiczak, Anna; Morris, Andrew; Porteous, David; Smith, Blair; Stratton, Michael R.; Hurles, Matthew E.

    2015-01-01

    Germline mutations are a driving force behind genome evolution and genetic disease. We investigated genome-wide mutation rates and spectra in multi-sibling families. Mutation rate increased with paternal age in all families, but the number of additional mutations per year differed more than two-fold between families. Meta-analysis of 6,570 mutations showed that germline methylation influences mutation rates. In contrast to somatic mutations, we found remarkable consistency of germline mutation spectra between the sexes and at different paternal ages. 3.8% of mutations were mosaic in the parental germline, resulting in 1.3% of mutations being shared between siblings. The number of these shared mutations varied significantly between families. Our data suggest that the mutation rate per cell division is higher during both early embryogenesis and differentiation of primordial germ cells, but is reduced substantially during post-pubertal spermatogenesis. These findings have important consequences for the recurrence risks of disorders caused by de novo mutations. PMID:26656846

  1. Detection of mutations in the ALD gene (ABCD1) in seven Italian families: description of four novel mutations.

    PubMed

    Lira, M G; Mottes, M; Pignatti, P F; Medica, I; Uziel, G; Cappa, M; Bertini, E; Rizzuto, N; Salviati, A

    2000-09-01

    The study describes the mutations causing adrenoleukodystrophy in seven Italian families. Four missense mutations leading to amino acid substitutions, two frameshift mutations leading to a premature termination signal, and a splicing mutation were identified. Mutations 2014C>T (P543L), 2053A>G (Q556A), 673-674insCC, and 1874+1G>A are described for the first time in this report. Mutations 1638C>T (R418W), 1588G>A(R401Q), and 1801-1802delAG are already known to be link to ALD.

  2. Genetic mutations associated with status epilepticus.

    PubMed

    Bhatnagar, M; Shorvon, S

    2015-08-01

    This paper reports the results of a preliminary search of the literature aimed at identifying the genetic mutations reported to be strongly associated with status epilepticus. Genetic mutations were selected for inclusion if status epilepticus was specifically mentioned as a consequence of the mutation in standard genetic databases or in a case report or review article. Mutations in 122 genes were identified. The genetic mutations identified were found in only rare conditions (sometimes vanishingly rare) and mostly in infants and young children with multiple other handicaps. Most of the genetic mutations can be subdivided into those associated with cortical dysplasias, inborn errors of metabolism, mitochondrial disease, or epileptic encephalopathies and childhood syndromes. There are no identified 'pure status epilepticus genes'. The range of genes underpinning status epilepticus differs in many ways from the range of genes underpinning epilepsy, which suggests that the processes underpinning status epilepticus differ from those underpinning epilepsy. It has been frequently postulated that status epilepticus is the result of a failure of 'seizure termination mechanisms', but the wide variety of genes affecting very diverse biochemical pathways identified in this survey makes any unitary cause unlikely. The genetic influences in status epilepticus are likely to involve a wide range of mechanisms, some related to development, some to cerebral energy production, some to diverse altered biochemical pathways, some to transmitter and membrane function, and some to defects in networks or systems. The fact that many of the identified genes are involved with cerebral development suggests that status epilepticus might often be a system or network phenomenon. To date, there are very few genes identified which are associated with adult-onset status epilepticus (except in those with preexisting neurological damage), and this is disappointing as the cause of many adult

  3. Mesure des stades de developpement du sapin baumier (Abies balsamea [L.] Mill.) par teledetection des maxima locaux sur images a tres haute resolution

    NASA Astrophysics Data System (ADS)

    Demers, Alain

    L'objectif principal de cette these est d'identifier les parametres cles pour lier le developpement morphologique de la cime du sapin baumier (Abies balsamea [L.] Mill.) aux patrons de reflectance qu'elle genere sur une image aerienne a haute resolution. La quantite et la distribution spatiale des aiguilles dans le sapin dependent de la structure des branches. Un mecanisme de ramification particulier (la reiteration) ressort comme le parametre cle pour lier l'augmentation de la biomasse foliaire et la forme de la branche. Les reiterats forment des agglomerats de feuillage qui engendrent des inegalites dans les patrons de reflectance de la cime. La reflectance est plus elevee ou il y a une forte concentration de reiterats (maximum local). On demontre que le developpement du sapin baumier se mesure au moyen de l'analyse des maxima locaux de la cime sur une image. La biomasse de l'arbre se mesure par la teledetection et l'analyse des patrons de reflectance de la cime, c'est-a-dire la mesure du niveau de reiteration par le decompte des maxima locaux de la cime. Cette etude demontre qu'il est possible de proceder a l'inventaire du volume de bois d'un peuplement par la teledetection de l'architecture des arbres.

  4. Reverse mutation in fragile X syndrome

    SciTech Connect

    Antinolo, G.; Borrego, S.; Cabeza, J.C.

    1996-01-01

    The fragile X syndrome is the most common cause of familial mental retardation, with an incidence of {approximately}1/1,500 in males and 1/2,500 in females. The clinical expression includes moderate to severe mental retardation, macroorchidism, dysmorphic facial features and behavior disturbances. In 1991, the FMR-1 gene was isolated from the region of the fragile X site. The fragile X phenotype has been found, in most cases, to be characterized at the molecular level by expansion of a (CGG){sub n} repeat and hypermethylation of a CpG island identified in the 5{prime}-UTR of the FMR-1 gene. It has been proposed, and some evidence has been shown, that germ cells carry only premutation alleles and that expansion occurs at a postzygotic stage. A few cases of reduction of the (CGG){sub n} repeat in fragile X syndrome have been reported. These reductions were from a larger premutation to a smaller premutation, in female-to-male transmission, from full mutation to a mosaic pattern, reduction from mosaic full-mutation/premutation females or regression from premutation to normal. We present here the novel observation of a phenotypically normal female carrying a nonmosaic full-mutation allele in somatic cells who transmits a premutation allele to her daughter. This daughter has three mosaic offspring with the full mutation and the premutation. Two of them are monozygotic (MZ) twins sharing a concordant mutation pattern. They are monoamniotic monochorionic, which indicates a late form of twinning. 20 refs., 1 fig.

  5. Mitochondrial mutations in subjects with psychiatric disorders.

    PubMed

    Sequeira, Adolfo; Rollins, Brandi; Magnan, Christophe; van Oven, Mannis; Baldi, Pierre; Myers, Richard M; Barchas, Jack D; Schatzberg, Alan F; Watson, Stanley J; Akil, Huda; Bunney, William E; Vawter, Marquis P

    2015-01-01

    A considerable body of evidence supports the role of mitochondrial dysfunction in psychiatric disorders and mitochondrial DNA (mtDNA) mutations are known to alter brain energy metabolism, neurotransmission, and cause neurodegenerative disorders. Genetic studies focusing on common nuclear genome variants associated with these disorders have produced genome wide significant results but those studies have not directly studied mtDNA variants. The purpose of this study is to investigate, using next generation sequencing, the involvement of mtDNA variation in bipolar disorder, schizophrenia, major depressive disorder, and methamphetamine use. MtDNA extracted from multiple brain regions and blood were sequenced (121 mtDNA samples with an average of 8,800x coverage) and compared to an electronic database containing 26,850 mtDNA genomes. We confirmed novel and rare variants, and confirmed next generation sequencing error hotspots by traditional sequencing and genotyping methods. We observed a significant increase of non-synonymous mutations found in individuals with schizophrenia. Novel and rare non-synonymous mutations were found in psychiatric cases in mtDNA genes: ND6, ATP6, CYTB, and ND2. We also observed mtDNA heteroplasmy in brain at a locus previously associated with schizophrenia (T16519C). Large differences in heteroplasmy levels across brain regions within subjects suggest that somatic mutations accumulate differentially in brain regions. Finally, multiplasmy, a heteroplasmic measure of repeat length, was observed in brain from selective cases at a higher frequency than controls. These results offer support for increased rates of mtDNA substitutions in schizophrenia shown in our prior results. The variable levels of heteroplasmic/multiplasmic somatic mutations that occur in brain may be indicators of genetic instability in mtDNA.

  6. The Wilson disease gene: Haplotypes and mutations

    SciTech Connect

    Thomas, G.R.; Roberts, E.A.; Cox, D.W.; Walshe, J.M.

    1994-09-01

    Wilson disease (WND) is an autosomal recessive defect of copper transport. The gene involved in WND, located on chromosome 13, has recently been shown to be a putative copper transporting P-type ATPase, designated ATP7B. The gene is highly similar to ATP7A, located on the X chromosome, which is defective in Menkes disease, another disorder of copper transport. We have available for study WND families from Canada (34 families), the United Kingdom (32 families), Japan (4 families), Iceland (3 families) and Hong Kong (2 families). We have utilized four highly polymorphic CA repeat markers (D13S296, D13S301, D13S314 and D13S316) surrounding the ATP7B locus to construct haplotypes in these families. Analysis indicates that there are many unique WND haplotypes not present on normal chromosomes and that there may be a large number of different WND mutations. We have screened the WND patients for mutations in the ATP7B gene. Fifty six patients, representing all of the identified haplotypes, have been screened using single strand conformational polymorphism (SSCP), followed by selective sequencing. To date, 19 mutations and 12 polymorphisms have been identified. All of the changes are nucleotide substitutions or small insertions/deletions and there is no evidence for larger deletions as seen in the similar gene on the X chromosome, ATP7A. Haplotypes of close markers and the ability to detect some of the mutations present in the gene allow for more reliable molecular diagnosis of presymptomatic sibs of WND patients. A reassessment of individuals previously diagnosed in the presymptomatic phase is now required, as we have have identified some heterozygotes who are biochemically indistinguishable from affected homozygotes. The identification of specific mutations will soon allow direct diagnosis of WND patients with a high level of certainty.

  7. Coherent Somatic Mutation in Autoimmune Disease

    PubMed Central

    Ross, Kenneth Andrew

    2014-01-01

    Background Many aspects of autoimmune disease are not well understood, including the specificities of autoimmune targets, and patterns of co-morbidity and cross-heritability across diseases. Prior work has provided evidence that somatic mutation caused by gene conversion and deletion at segmentally duplicated loci is relevant to several diseases. Simple tandem repeat (STR) sequence is highly mutable, both somatically and in the germ-line, and somatic STR mutations are observed under inflammation. Results Protein-coding genes spanning STRs having markers of mutability, including germ-line variability, high total length, repeat count and/or repeat similarity, are evaluated in the context of autoimmunity. For the initiation of autoimmune disease, antigens whose autoantibodies are the first observed in a disease, termed primary autoantigens, are informative. Three primary autoantigens, thyroid peroxidase (TPO), phogrin (PTPRN2) and filaggrin (FLG), include STRs that are among the eleven longest STRs spanned by protein-coding genes. This association of primary autoantigens with long STR sequence is highly significant (). Long STRs occur within twenty genes that are associated with sixteen common autoimmune diseases and atherosclerosis. The repeat within the TTC34 gene is an outlier in terms of length and a link with systemic lupus erythematosus is proposed. Conclusions The results support the hypothesis that many autoimmune diseases are triggered by immune responses to proteins whose DNA sequence mutates somatically in a coherent, consistent fashion. Other autoimmune diseases may be caused by coherent somatic mutations in immune cells. The coherent somatic mutation hypothesis has the potential to be a comprehensive explanation for the initiation of many autoimmune diseases. PMID:24988487

  8. Preaxial polydactyly associated with a MSX1 mutation and report of two novel mutations.

    PubMed

    Wattanarat, Onnida; Kantaputra, Piranit Nik

    2016-01-01

    We report two novel heterozygous missense MSX1 mutations in two Thai families (c.739C>T; p.Pro247Ser and c.607G>A; p.Ala203Thr). The p.Ala203Thr mutation was found in a female patient, her sister, and their father and is associated with unilateral cleft lip and palate, hypodontia, and microdontia. The p.Pro247Ser mutation was found in a three-generation Thai family and was associated with bilateral cleft lip and palate, hypodontia, microdontia, and dens invaginatus. The proband also had preaxial polydactyly of the left hand. The role of Msx1 in limb development in mice is discussed. Intrafamilial variability of the phenotypes is clearly evident. This is the first time that a limb anomaly has been reported to be associated with a mutation in MSX1.

  9. GATA2 mutations in sporadic and familial acute myeloid leukaemia patients with CEBPA mutations.

    PubMed

    Green, Claire L; Tawana, Kiran; Hills, Robert K; Bödör, Csaba; Fitzgibbon, Jude; Inglott, Sarah; Ancliff, Phil; Burnett, Alan K; Linch, David C; Gale, Rosemary E

    2013-06-01

    GATA2 mutations have recently been reported in acute myeloid leukaemia (AML) patients with CEBPA-double mutations. To explore their impact on this favourable-risk disease, we determined GATA2 status in 153 sporadic AML patients and three members of a germ-line CEBPA-mutant family at AML presentation. Overall, 27% (15/55) CEBPA-double, 16% (7/43) CEBPA-single and 0% (0/55) normal karyotype/CEBPA-wild-type patients were GATA2-mutant. All familial AML patients acquired both a second CEBPA and a GATA2 mutation. CEBPA and GATA2 mutant levels indicated that both mutations were likely to be early events in leukaemogenesis. GATA2 status did not impact on the favourable outcome of CEBPA-double/FLT3-inernal tandem duplication-negative patients.

  10. Mutation--The Engine of Evolution: Studying Mutation and Its Role in the Evolution of Bacteria.

    PubMed

    Hershberg, Ruth

    2015-09-01

    Mutation is the engine of evolution in that it generates the genetic variation on which the evolutionary process depends. To understand the evolutionary process we must therefore characterize the rates and patterns of mutation. Starting with the seminal Luria and Delbruck fluctuation experiments in 1943, studies utilizing a variety of approaches have revealed much about mutation rates and patterns and about how these may vary between different bacterial strains and species along the chromosome and between different growth conditions. This work provides a critical overview of the results and conclusions drawn from these studies, of the debate surrounding some of these conclusions, and of the challenges faced when studying mutation and its role in bacterial evolution. PMID:26330518

  11. Mitochondrial DNA mutations in mutator mice confer respiration defects and B-cell lymphoma development.

    PubMed

    Mito, Takayuki; Kikkawa, Yoshiaki; Shimizu, Akinori; Hashizume, Osamu; Katada, Shun; Imanishi, Hirotake; Ota, Azusa; Kato, Yukina; Nakada, Kazuto; Hayashi, Jun-Ichi

    2013-01-01

    Mitochondrial DNA (mtDNA) mutator mice are proposed to express premature aging phenotypes including kyphosis and hair loss (alopecia) due to their carrying a nuclear-encoded mtDNA polymerase with a defective proofreading function, which causes accelerated accumulation of random mutations in mtDNA, resulting in expression of respiration defects. On the contrary, transmitochondrial mito-miceΔ carrying mtDNA with a large-scale deletion mutation (ΔmtDNA) also express respiration defects, but not express premature aging phenotypes. Here, we resolved this discrepancy by generating mtDNA mutator mice sharing the same C57BL/6J (B6J) nuclear background with that of mito-miceΔ. Expression patterns of premature aging phenotypes are very close, when we compared between homozygous mtDNA mutator mice carrying a B6J nuclear background and selected mito-miceΔ only carrying predominant amounts of ΔmtDNA, in their expression of significant respiration defects, kyphosis, and a short lifespan, but not the alopecia. Therefore, the apparent discrepancy in the presence and absence of premature aging phenotypes in mtDNA mutator mice and mito-miceΔ, respectively, is partly the result of differences in the nuclear background of mtDNA mutator mice and of the broad range of ΔmtDNA proportions of mito-miceΔ used in previous studies. We also provided direct evidence that mtDNA abnormalities in homozygous mtDNA mutator mice are responsible for respiration defects by demonstrating the co-transfer of mtDNA and respiration defects from mtDNA mutator mice into mtDNA-less (ρ(0)) mouse cells. Moreover, heterozygous mtDNA mutator mice had a normal lifespan, but frequently developed B-cell lymphoma, suggesting that the mtDNA abnormalities in heterozygous mutator mice are not sufficient to induce a short lifespan and aging phenotypes, but are able to contribute to the B-cell lymphoma development during their prolonged lifespan.

  12. The topography of mutational processes in breast cancer genomes

    PubMed Central

    Morganella, Sandro; Alexandrov, Ludmil B.; Glodzik, Dominik; Zou, Xueqing; Davies, Helen; Staaf, Johan; Sieuwerts, Anieta M.; Brinkman, Arie B.; Martin, Sancha; Ramakrishna, Manasa; Butler, Adam; Kim, Hyung-Yong; Borg, Åke; Sotiriou, Christos; Futreal, P. Andrew; Campbell, Peter J.; Span, Paul N.; Van Laere, Steven; Lakhani, Sunil R.; Eyfjord, Jorunn E.; Thompson, Alastair M.; Stunnenberg, Hendrik G.; van de Vijver, Marc J.; Martens, John W. M.; Børresen-Dale, Anne-Lise; Richardson, Andrea L.; Kong, Gu; Thomas, Gilles; Sale, Julian; Rada, Cristina; Stratton, Michael R.; Birney, Ewan; Nik-Zainal, Serena

    2016-01-01

    Somatic mutations in human cancers show unevenness in genomic distribution that correlate with aspects of genome structure and function. These mutations are, however, generated by multiple mutational processes operating through the cellular lineage between the fertilized egg and the cancer cell, each composed of specific DNA damage and repair components and leaving its own characteristic mutational signature on the genome. Using somatic mutation catalogues from 560 breast cancer whole-genome sequences, here we show that each of 12 base substitution, 2 insertion/deletion (indel) and 6 rearrangement mutational signatures present in breast tissue, exhibit distinct relationships with genomic features relating to transcription, DNA replication and chromatin organization. This signature-based approach permits visualization of the genomic distribution of mutational processes associated with APOBEC enzymes, mismatch repair deficiency and homologous recombinational repair deficiency, as well as mutational processes of unknown aetiology. Furthermore, it highlights mechanistic insights including a putative replication-dependent mechanism of APOBEC-related mutagenesis. PMID:27136393

  13. Modelling mutational landscapes of human cancers in vitro

    NASA Astrophysics Data System (ADS)

    Olivier, Magali; Weninger, Annette; Ardin, Maude; Huskova, Hana; Castells, Xavier; Vallée, Maxime P.; McKay, James; Nedelko, Tatiana; Muehlbauer, Karl-Rudolf; Marusawa, Hiroyuki; Alexander, John; Hazelwood, Lee; Byrnes, Graham; Hollstein, Monica; Zavadil, Jiri

    2014-03-01

    Experimental models that recapitulate mutational landscapes of human cancers are needed to decipher the rapidly expanding data on human somatic mutations. We demonstrate that mutation patterns in immortalised cell lines derived from primary murine embryonic fibroblasts (MEFs) exposed in vitro to carcinogens recapitulate key features of mutational signatures observed in human cancers. In experiments with several cancer-causing agents we obtained high genome-wide concordance between human tumour mutation data and in vitro data with respect to predominant substitution types, strand bias and sequence context. Moreover, we found signature mutations in well-studied human cancer driver genes. To explore endogenous mutagenesis, we used MEFs ectopically expressing activation-induced cytidine deaminase (AID) and observed an excess of AID signature mutations in immortalised cell lines compared to their non-transgenic counterparts. MEF immortalisation is thus a simple and powerful strategy for modelling cancer mutation landscapes that facilitates the interpretation of human tumour genome-wide sequencing data.

  14. Mutated Genes in Schizophrenia Map to Brain Networks

    MedlinePlus

    ... 2013 Mutated Genes in Schizophrenia Map to Brain Networks Schizophrenia networks in the prefrontal cortex area of the brain. ... of spontaneous mutations in genes that form a network in the front region of the brain. The ...

  15. Recurrent Somatic Mutations in Regulatory Regions of Human Cancer Genomes

    PubMed Central

    Melton, Collin; Reuter, Jason A.; Spacek, Damek V.; Snyder, Michael

    2015-01-01

    Aberrant regulation of gene expression in cancer can promote survival and proliferation of cancer cells. Here we integrate TCGA whole genome sequencing data of 436 patients from eight cancer subtypes with ENCODE and other regulatory annotations to identify point mutations in regulatory regions. We find evidence for positive selection of mutations in transcription factor binding sites, consistent with these sites regulating important cancer cell functions. Using a novel method that adjusts for sample- and genomic locus-specific mutation rate, we identify recurrently mutated sites across cancer patients. Mutated regulatory sites include known sites in the TERT promoter and many novel sites, including a subset in proximity to cancer genes. In reporter assays, two novel sites display decreased enhancer activity upon mutation. These data demonstrate that many regulatory regions contain mutations under selective pressure and suggest a larger role for regulatory mutations in cancer than previously appreciated. PMID:26053494

  16. Alström Syndrome: Mutation Spectrum of ALMS1.

    PubMed

    Marshall, Jan D; Muller, Jean; Collin, Gayle B; Milan, Gabriella; Kingsmore, Stephen F; Dinwiddie, Darrell; Farrow, Emily G; Miller, Neil A; Favaretto, Francesca; Maffei, Pietro; Dollfus, Hélène; Vettor, Roberto; Naggert, Jürgen K

    2015-07-01

    Alström Syndrome (ALMS), a recessive, monogenic ciliopathy caused by mutations in ALMS1, is typically characterized by multisystem involvement including early cone-rod retinal dystrophy and blindness, hearing loss, childhood obesity, type 2 diabetes mellitus, cardiomyopathy, fibrosis, and multiple organ failure. The precise function of ALMS1 remains elusive, but roles in endosomal and ciliary transport and cell cycle regulation have been shown. The aim of our study was to further define the spectrum of ALMS1 mutations in patients with clinical features of ALMS. Mutational analysis in a world-wide cohort of 204 families identified 109 novel mutations, extending the number of known ALMS1 mutations to 239 and highlighting the allelic heterogeneity of this disorder. This study represents the most comprehensive mutation analysis in patients with ALMS, identifying the largest number of novel mutations in a single study worldwide. Here, we also provide an overview of all ALMS1 mutations identified to date.

  17. Genetics Home Reference: familial acute myeloid leukemia with mutated CEBPA

    MedlinePlus

    ... N. A family harboring a germ-line N-terminal C/EBPalpha mutation and development of acute myeloid leukemia with an additional somatic C-terminal C/EBPalpha mutation. Genes Chromosomes Cancer. 2010 Mar; ...

  18. Alström Syndrome: Mutation Spectrum of ALMS1.

    PubMed

    Marshall, Jan D; Muller, Jean; Collin, Gayle B; Milan, Gabriella; Kingsmore, Stephen F; Dinwiddie, Darrell; Farrow, Emily G; Miller, Neil A; Favaretto, Francesca; Maffei, Pietro; Dollfus, Hélène; Vettor, Roberto; Naggert, Jürgen K

    2015-07-01

    Alström Syndrome (ALMS), a recessive, monogenic ciliopathy caused by mutations in ALMS1, is typically characterized by multisystem involvement including early cone-rod retinal dystrophy and blindness, hearing loss, childhood obesity, type 2 diabetes mellitus, cardiomyopathy, fibrosis, and multiple organ failure. The precise function of ALMS1 remains elusive, but roles in endosomal and ciliary transport and cell cycle regulation have been shown. The aim of our study was to further define the spectrum of ALMS1 mutations in patients with clinical features of ALMS. Mutational analysis in a world-wide cohort of 204 families identified 109 novel mutations, extending the number of known ALMS1 mutations to 239 and highlighting the allelic heterogeneity of this disorder. This study represents the most comprehensive mutation analysis in patients with ALMS, identifying the largest number of novel mutations in a single study worldwide. Here, we also provide an overview of all ALMS1 mutations identified to date. PMID:25846608

  19. The topography of mutational processes in breast cancer genomes

    SciTech Connect

    Morganella, Sandro; Alexandrov, Ludmil B.; Glodzik, Dominik; Zou, Xueqing; Davies, Helen; Staaf, Johan; Sieuwerts, Anieta M.; Brinkman, Arie B.; Martin, Sancha; Ramakrishna, Manasa; Butler, Adam; Kim, Hyung -Yong; Borg, Ake; Sotiriou, Christos; Futreal, P. Andrew; Campbell, Peter J.; Span, Paul N.; Van Laere, Steven; Lakhani, Sunil R.; Eyfjord, Jorunn E.; Thompson, Alastair M.; Stunnenberg, Hendrik G.; van de Vijver, Marc J.; Martens, John W. M.; Borresen-Dale, Anne -Lise; Richardson, Andrea L.; Kong, Gu; Thomas, Gilles; Sale, Julian; Rada, Cristina; Stratton, Michael R.; Birney, Ewan; Nik-Zainal, Serena

    2016-01-01

    Somatic mutations in human cancers show unevenness in genomic distribution that correlate with aspects of genome structure and function. These mutations are, however, generated by multiple mutational processes operating through the cellular lineage between the fertilized egg and the cancer cell, each composed of specific DNA damage and repair components and leaving its own characteristic mutational signature on the genome. Using somatic mutation catalogues from 560 breast cancer whole-genome sequences, here we show that each of 12 base substitution, 2 insertion/deletion (indel) and 6 rearrangement mutational signatures present in breast tissue, exhibit distinct relationships with genomic features relating to transcription, DNA replication and chromatin organization. This signature-based approach permits visualization of the genomic distribution of mutational processes associated with APOBEC enzymes, mismatch repair deficiency and homologous recombinational repair deficiency, as well as mutational processes of unknown aetiology. Lastly, it highlights mechanistic insights including a putative replication-dependent mechanism of APOBEC-related mutagenesis.

  20. An MRPS12 mutation modifies aminoglycoside sensitivity caused by 12S rRNA mutations

    PubMed Central

    Emperador, Sonia; Pacheu-Grau, David; Bayona-Bafaluy, M. Pilar; Garrido-Pérez, Nuria; Martín-Navarro, Antonio; López-Pérez, Manuel J.; Montoya, Julio; Ruiz-Pesini, Eduardo

    2015-01-01

    Several homoplasmic pathologic mutations in mitochondrial DNA, such as those causing Leber hereditary optic neuropathy or non-syndromic hearing loss, show incomplete penetrance. Therefore, other elements must modify their pathogenicity. Discovery of these modifying factors is not an easy task because in multifactorial diseases conventional genetic approaches may not always be informative. Here, we have taken an evolutionary approach to unmask putative modifying factors for a particular homoplasmic pathologic mutation causing aminoglycoside-induced and non-syndromic hearing loss, the m.1494C>T transition in the mitochondrial DNA. The mutation is located in the decoding site of the mitochondrial ribosomal RNA. We first looked at mammalian species that had fixed the human pathologic mutation. These mutations are called compensated pathogenic deviations because an organism carrying one must also have another that suppresses the deleterious effect of the first. We found that species from the primate family Cercopithecidae (old world monkeys) harbor the m.1494T allele even if their auditory function is normal. In humans the m.1494T allele increases the susceptibility to aminoglycosides. However, in primary fibroblasts from a Cercopithecidae species, aminoglycosides do not impair cell growth, respiratory complex IV activity and quantity or the mitochondrial protein synthesis. Interestingly, this species also carries a fixed mutation in the mitochondrial ribosomal protein S12. We show that the expression of this variant in a human m.1494T cell line reduces its susceptibility to aminoglycosides. Because several mutations in this human protein have been described, they may possibly explain the absence of pathologic phenotype in some pedigree members with the most frequent pathologic mutations in mitochondrial ribosomal RNA. PMID:25642242

  1. Exonuclease mutations in DNA polymerase epsilon reveal replication strand specific mutation patterns and human origins of replication.

    PubMed

    Shinbrot, Eve; Henninger, Erin E; Weinhold, Nils; Covington, Kyle R; Göksenin, A Yasemin; Schultz, Nikolaus; Chao, Hsu; Doddapaneni, HarshaVardhan; Muzny, Donna M; Gibbs, Richard A; Sander, Chris; Pursell, Zachary F; Wheeler, David A

    2014-11-01

    Tumors with somatic mutations in the proofreading exonuclease domain of DNA polymerase epsilon (POLE-exo*) exhibit a novel mutator phenotype, with markedly elevated TCT→TAT and TCG→TTG mutations and overall mutation frequencies often exceeding 100 mutations/Mb. Here, we identify POLE-exo* tumors in numerous cancers and classify them into two groups, A and B, according to their mutational properties. Group A mutants are found only in POLE, whereas Group B mutants are found in POLE and POLD1 and appear to be nonfunctional. In Group A, cell-free polymerase assays confirm that mutations in the exonuclease domain result in high mutation frequencies with a preference for C→A mutation. We describe the patterns of amino acid substitutions caused by POLE-exo* and compare them to other tumor types. The nucleotide preference of POLE-exo* leads to increased frequencies of recurrent nonsense mutations in key tumor suppressors such as TP53, ATM, and PIK3R1. We further demonstrate that strand-specific mutation patterns arise from some of these POLE-exo* mutants during genome duplication. This is the first direct proof of leading strand-specific replication by human POLE, which has only been demonstrated in yeast so far. Taken together, the extremely high mutation frequency and strand specificity of mutations provide a unique identifier of eukaryotic origins of replication.

  2. Frameshift mutations in dentin phosphoprotein and dependence of dentin disease phenotype on mutation location.

    PubMed

    Nieminen, Pekka; Papagiannoulis-Lascarides, Lisa; Waltimo-Siren, Janna; Ollila, Päivi; Karjalainen, Sara; Arte, Sirpa; Veerkamp, Jaap; Tallon Walton, Victoria; Chimenos Küstner, Eduard; Siltanen, Tarja; Holappa, Heidi; Lukinmaa, Pirjo-Liisa; Alaluusua, Satu

    2011-04-01

    We describe results from a mutational analysis of the region of the dentin sialophosphoprotein (DSPP) gene encoding dentin phosphoprotein (DPP) in 12 families with dominantly inherited dentin diseases. In eight families (five mutations in the N-terminal third of DPP), the clinical and radiologic features were uniform and compatible with dentin dysplasia type II (DD-II) with major clinical signs in the deciduous dentition. In the other families (four mutations in the more C-terminal part), the permanent teeth also were affected, and the diseases could be classified as variants of dentinogenesis imperfecta. Attrition was not prominent, but periapical infections were common. Discoloring with varying intensity was evident, and pulps and root canals were obliterated in the permanent dentition. All mutations caused a frameshift that replaced the Ser-Ser-Asx repeat by a code for a hydrophobic downstream sequence of approximately original length. We conclude that frameshift mutations in DSPP explain a significant part of dentin diseases. Furthermore, we propose that the location of the mutation is reflected in the phenotypic features as a gradient from DD-II to more severe disease that does not conform to the classic definitions of DI-II. PMID:20949630

  3. Repository of mutations from Oman: The entry point to a national mutation database

    PubMed Central

    Rajab, Anna; Hamza, Nishath; Al Harasi, Salma; Al Lawati, Fatma; Gibbons, Una; Al Alawi, Intesar; Kobus, Karoline; Hassan, Suha; Mahir, Ghariba; Al Salmi, Qasim; Mons, Barend; Robinson, Peter

    2015-01-01

    The Sultanate of Oman is a rapidly developing Muslim country with well-organized government-funded health care services, and expanding medical genetic facilities. The preservation of tribal structures within the Omani population coupled with geographical isolation has produced unique patterns of rare mutations. In order to provide diagnosticians and researchers with access to an up-to-date resource that will assist them in their daily practice we collated and analyzed all of the Mendelian disease-associated mutations identified in the Omani population. By the 1 st of August 2015, the dataset contained 300 mutations detected in over 150 different genes. More than half of the data collected reflect novel genetic variations that were first described in the Omani population, and most disorders with known mutations are inherited in an autosomal recessive fashion. A number of novel Mendelian disease genes have been discovered in Omani nationals, and the corresponding mutations are included here. The current study provides a comprehensive resource of the mutations in the Omani population published in scientific literature or reported through service provision that will be useful for genetic care in Oman and will be a starting point for variation databases as next-generation sequencing technologies are introduced into genetic medicine in Oman. PMID:26594346

  4. Was the C282Y mutation an Irish Gaelic mutation that the Vikings help disseminate?

    PubMed

    Whittington, C A

    2006-01-01

    The C282Y mutation is held to have arisen in either a Celtic or a Viking ancestor some 60 generations ago. While the Scandinavians have a high frequency of C282Y, the Irish have the highest frequency of the C282Y mutation in the world. However testing of the Irish people for C282Y has been patchy. The true frequency of the C282Y mutation in Ireland and specifically in the relatively isolated western province of Connaught is unknown. Establishment of the C282Y frequency in the Irish male population of Connaught with traditional Irish surnames, a group which has a virtual fixation for Y chromosome R1b3, could help establish C282Y as an Irish mutation. Elucidation of greater C282Y haplotype diversity for the Irish as opposed to the Scandinavians would indicate the Irish as the likely source population for C282Y. Taken together, linking of C282Y to the Irish Gaelic male population of Connaught and establishment of an Irish origin of the C282Y mutation would point to dissemination of the C282Y mutation by Viking raiders and colonizers.

  5. Repository of mutations from Oman: The entry point to a national mutation database.

    PubMed

    Rajab, Anna; Hamza, Nishath; Al Harasi, Salma; Al Lawati, Fatma; Gibbons, Una; Al Alawi, Intesar; Kobus, Karoline; Hassan, Suha; Mahir, Ghariba; Al Salmi, Qasim; Mons, Barend; Robinson, Peter

    2015-01-01

    The Sultanate of Oman is a rapidly developing Muslim country with well-organized government-funded health care services, and expanding medical genetic facilities. The preservation of tribal structures within the Omani population coupled with geographical isolation has produced unique patterns of rare mutations. In order to provide diagnosticians and researchers with access to an up-to-date resource that will assist them in their daily practice we collated and analyzed all of the Mendelian disease-associated mutations identified in the Omani population. By the 1 (st) of August 2015, the dataset contained 300 mutations detected in over 150 different genes. More than half of the data collected reflect novel genetic variations that were first described in the Omani population, and most disorders with known mutations are inherited in an autosomal recessive fashion. A number of novel Mendelian disease genes have been discovered in Omani nationals, and the corresponding mutations are included here. The current study provides a comprehensive resource of the mutations in the Omani population published in scientific literature or reported through service provision that will be useful for genetic care in Oman and will be a starting point for variation databases as next-generation sequencing technologies are introduced into genetic medicine in Oman. PMID:26594346

  6. Estimation of the RNU2 macrosatellite mutation rate by BRCA1 mutation tracing

    PubMed Central

    Tessereau, Chloé; Lesecque, Yann; Monnet, Nastasia; Buisson, Monique; Barjhoux, Laure; Léoné, Mélanie; Feng, Bingjian; Goldgar, David E.; Sinilnikova, Olga M.; Mousset, Sylvain; Duret, Laurent; Mazoyer, Sylvie

    2014-01-01

    Large tandem repeat sequences have been poorly investigated as severe technical limitations and their frequent absence from the genome reference hinder their analysis. Extensive allelotyping of this class of variation has not been possible until now and their mutational dynamics are still poorly known. In order to estimate the mutation rate of a macrosatellite, we analysed in detail the RNU2 locus, which displays at least 50 different alleles containing 5-82 copies of a 6.1 kb repeat unit. Mining data from the 1000 Genomes Project allowed us to precisely estimate copy numbers of the RNU2 repeat unit using read depth of coverage. This further revealed significantly different mean values in various recent modern human populations, favoring a scenario of fast evolution of this locus. Its proximity to a disease gene with numerous founder mutations, BRCA1, within the same linkage disequilibrium block, offered the unique opportunity to trace RNU2 arrays over a large timescale. Analysis of the transmission of RNU2 arrays associated with one ‘private’ mutation in an extended kindred and four founder mutations in multiple kindreds gave an estimation by maximum likelihood of 5 × 10−3 mutations per generation, which is close to that of microsatellites. PMID:25034697

  7. Frameshift mutations in dentin phosphoprotein and dependence of dentin disease phenotype on mutation location.

    PubMed

    Nieminen, Pekka; Papagiannoulis-Lascarides, Lisa; Waltimo-Siren, Janna; Ollila, Päivi; Karjalainen, Sara; Arte, Sirpa; Veerkamp, Jaap; Tallon Walton, Victoria; Chimenos Küstner, Eduard; Siltanen, Tarja; Holappa, Heidi; Lukinmaa, Pirjo-Liisa; Alaluusua, Satu

    2011-04-01

    We describe results from a mutational analysis of the region of the dentin sialophosphoprotein (DSPP) gene encoding dentin phosphoprotein (DPP) in 12 families with dominantly inherited dentin diseases. In eight families (five mutations in the N-terminal third of DPP), the clinical and radiologic features were uniform and compatible with dentin dysplasia type II (DD-II) with major clinical signs in the deciduous dentition. In the other families (four mutations in the more C-terminal part), the permanent teeth also were affected, and the diseases could be classified as variants of dentinogenesis imperfecta. Attrition was not prominent, but periapical infections were common. Discoloring with varying intensity was evident, and pulps and root canals were obliterated in the permanent dentition. All mutations caused a frameshift that replaced the Ser-Ser-Asx repeat by a code for a hydrophobic downstream sequence of approximately original length. We conclude that frameshift mutations in DSPP explain a significant part of dentin diseases. Furthermore, we propose that the location of the mutation is reflected in the phenotypic features as a gradient from DD-II to more severe disease that does not conform to the classic definitions of DI-II.

  8. The spectrum of β-thalassemia mutations in Hatay, Turkey: reporting three new mutations.

    PubMed

    Aldemir, Ozgur; Izmirli, Muzeyyen; Kaya, Hasan

    2014-01-01

    β-Thalassemia (β-thal) is an important health problem in Hatay, Southern Turkey, because of its high carrier frequency and the frequency of consanguinity. The aim of this study was to reveal the spectrum of β-thal mutations and to provide a foundation for prenatal genetic testing that will be a part of an effective prevention program for β-thal disease in Hatay. We determined the spectrum of β-thal mutations in 93 unrelated affected patients. Using a direct sequencing method, we identified a large number of β-thal mutations. We found different results from other parts of Turkey. A total of 16 different β-thal mutations were characterized in the parents. The most common mutations were: IVS-I-110 (G>A), IVS-I-6 (T>C), IVS-I-1 (G>A), frameshift codon (FSC) 8 (-AA), codon 39 (C>T) and IVS-II-745 (C>G). Since our region has seen many Syrian and Iraqi immigrants, we report that the prevalence of the thalassemia traits are different from other regions of Turkey. Our study demonstrates the spectrum of β-thal mutations in the Hatay region, and that there was great molecular heterogeneity.

  9. The molecular landscape of ASPM mutations in primary microcephaly

    PubMed Central

    Nicholas, A K; Swanson, E A; Cox, J J; Karbani, G; Malik, S; Springell, K; Hampshire, D; Ahmed, M; Bond, J; Di Benedetto, D; Fichera, M; Romano, C; Dobyns, W B; Woods, C G

    2009-01-01

    Background: Autosomal recessive primary microcephaly (MCPH) is a model disease to study human neurogenesis. In affected individuals the brain grows at a reduced rate during fetal life resulting in a small but structurally normal brain and mental retardation. The condition is genetically heterogeneous with mutations in ASPM being most commonly reported. Methods and results: We have examined this further by studying three cohorts of microcephalic children to extend both the phenotype and the mutation spectrum. Firstly, in 99 consecutively ascertained consanguineous families with a strict diagnosis of MCPH, 41 (41%) were homozygous at the MCPH5 locus and all but two families had mutations. Thus, 39% of consanguineous MCPH families had homozygous ASPM mutations. Secondly, in 27 non-consanguineous, predominantly Caucasian families with a strict diagnosis of MCPH, 11 (40%) had ASPM mutations. Thirdly, in 45 families with a less restricted phenotype including microcephaly and mental retardation, but regardless of other neurological features, only 3 (7%) had an ASPM mutation. This report contains 27 novel mutations and almost doubles the number of MCPH associated ASPM mutations known to 57. All but one of the mutations lead to the use of a premature termination codon, 23 were nonsense mutations, 28 deletions or insertions, 5 splicing, and 1 was a translocation. Seventeen of the 57 mutations were recurrent. There were no definitive missense mutations found nor was there any mutation/phenotype correlation. ASPM mutations were found in all ethnic groups studied. Conclusion: This study confirms that mutations in ASPM are the most common cause of MCPH, that ASPM mutations are restricted to individuals with an MCPH phenotype, and that ASPM testing in primary microcephaly is clinically useful. PMID:19028728

  10. Inactivation of Cancer Mutations Utilizing CRISPR/Cas9.

    PubMed

    Gebler, Christina; Lohoff, Tim; Paszkowski-Rogacz, Maciej; Mircetic, Jovan; Chakraborty, Debojyoti; Camgoz, Aylin; Hamann, Martin V; Theis, Mirko; Thiede, Christian; Buchholz, Frank

    2017-01-01

    Although whole-genome sequencing has uncovered a large number of mutations that drive tumorigenesis, functional ratification for most mutations remains sparse. Here, we present an approach to test functional relevance of tumor mutations employing CRISPR/Cas9. Combining comprehensive sgRNA design and an efficient reporter assay to nominate efficient and selective sgRNAs, we establish a pipeline to dissect roles of cancer mutations with potential applicability to personalized medicine and future therapeutic use. PMID:27576906

  11. RNF43 is frequently mutated in colorectal and endometrial cancers

    PubMed Central

    Giannakis, Marios; Hodis, Eran; Mu, Xinmeng Jasmine; Yamauchi, Mai; Rosenbluh, Joseph; Cibulskis, Kristian; Saksena, Gordon; Lawrence, Michael S.; Qian, ZhiRong; Nishihara, Reiko; Van Allen, Eliezer M.; Hahn, William C.; Gabriel, Stacey B.; Lander, Eric S.; Getz, Gad; Ogino, Shuji; Fuchs, Charles S.; Garraway, Levi A.

    2014-01-01

    We report somatic mutations of RNF43 in over 18% of colorectal adenocarcinomas and endometrial carcinomas. RNF43 encodes an E3 ubiquitin ligase that negatively regulates Wnt signaling. Truncating mutations of RNF43 are more prevalent in microsatellite-unstable tumors and show mutual exclusivity with inactivating APC mutations in colorectal adenocarcinomas. These results indicate that RNF43 is one of the most commonly mutated genes in colorectal and endometrial cancers. PMID:25344691

  12. Markov chain for estimating human mitochondrial DNA mutation pattern

    NASA Astrophysics Data System (ADS)

    Vantika, Sandy; Pasaribu, Udjianna S.

    2015-12-01

    The Markov chain was proposed to estimate the human mitochondrial DNA mutation pattern. One DNA sequence was taken randomly from 100 sequences in Genbank. The nucleotide transition matrix and mutation transition matrix were estimated from this sequence. We determined whether the states (mutation/normal) are recurrent or transient. The results showed that both of them are recurrent.

  13. Spectrum of small mutations in the dystrophin coding region

    SciTech Connect

    Prior, T.W.; Bartolo, C.; Pearl, D.K.

    1995-07-01

    Duchenne and Becker muscular dystrophies (DMD and BMD) are caused by defects in the dystrophin gene. About two-thirds of the affected patients have large deletions or duplications, which occur in the 5` and central portion of the gene. The nondeletion/duplication cases are most likely the result of smaller mutations that cannot be identified by current diagnostic screening strategies. We screened {approximately} 80% of the dystrophin coding sequence for small mutations in 158 patients without deletions or duplications and identified 29 mutations. The study indicates that many of the DMD and the majority of the BMD small mutations lie in noncoding regions of the gene. All of the mutations identified were unique to single patients, and most of the mutations resulted in protein truncation. We did not find a clustering of small mutations similar to the deletion distribution but found > 40% of the small mutations 3` of exon 55. The extent of protein truncation caused by the 3` mutations did not determine the phenotype, since even the exon 76 nonsense mutation resulted in the severe DMD phenotype. Our study confirms that the dystrophin gene is subject to a high rate of mutation in CpG sequences. As a consequence of not finding any hotspots or prevalent small mutations, we conclude that it is presently not possible to perform direct carrier and prenatal diagnostics for many families without deletions or duplications. 71 refs., 2 figs., 2 tabs.

  14. More Frequent than Desired: Midgut Stem Cell Somatic Mutations.

    PubMed

    Li, Qi; Ip, Y Tony

    2015-12-01

    The accumulation of somatic mutations in adult stem cells contributes to the decline of tissue functions and cancer initiation. In this issue of Cell Stem Cell, Siudeja et al. (2015) investigate the rate and mechanism of naturally occurring mutations in Drosophila midgut intestinal stem cells during aging and find high-frequency mutations arising from multiple mechanisms. PMID:26637937

  15. Mitochondrial DNA exhibits resistance to induced point and deletion mutations

    PubMed Central

    Valente, William J.; Ericson, Nolan G.; Long, Alexandra S.; White, Paul A.; Marchetti, Francesco; Bielas, Jason H.

    2016-01-01

    The accumulation of somatic mitochondrial DNA (mtDNA) mutations contributes to the pathogenesis of human disease. Currently, mitochondrial mutations are largely considered results of inaccurate processing of its heavily damaged genome. However, mainly from a lack of methods to monitor mtDNA mutations with sufficient sensitivity and accuracy, a link between mtDNA damage and mutation has not been established. To test the hypothesis that mtDNA-damaging agents induce mtDNA mutations, we exposed MutaTMMouse mice to benzo[a]pyrene (B[a]P) or N-ethyl-N-nitrosourea (ENU), daily for 28 consecutive days, and quantified mtDNA point and deletion mutations in bone marrow and liver using our newly developed Digital Random Mutation Capture (dRMC) and Digital Deletion Detection (3D) assays. Surprisingly, our results demonstrate mutagen treatment did not increase mitochondrial point or deletion mutation frequencies, despite evidence both compounds increase nuclear DNA mutations and demonstrated B[a]P adduct formation in mtDNA. These findings contradict models of mtDNA mutagenesis that assert the elevated rate of mtDNA mutation stems from damage sensitivity and abridged repair capacity. Rather, our results demonstrate induced mtDNA damage does not readily convert into mutation. These findings suggest robust mitochondrial damage responses repress induced mutations after mutagen exposure. PMID:27550180

  16. Tobacco Induced Mutations: A Fun, Visually Impressive Experiment

    ERIC Educational Resources Information Center

    Milholland, Rebecca B. R.; Hines, Stefani D.

    2004-01-01

    A modified version "Tobacco Induced Mutations" of Ames assay experiment provides a meaningful context for students to learn about the concept of mutations by using a known carcinogen that is tobacco. This experiment shows toxicological concept of the dose/response relationship and visually demonstrates when a mutation have occurred in bacteria…

  17. A Haplotype Framework for Cystic Fibrosis Mutations in Iran

    PubMed Central

    Elahi, Elahe; Khodadad, Ahmad; Kupershmidt, Ilya; Ghasemi, Fereshteh; Alinasab, Babak; Naghizadeh, Ramin; Eason, Robert G.; Amini, Mahshid; Esmaili, Mehran; Esmaeili Dooki, Mohammad R.; Sanati, Mohammad H.; Davis, Ronald W.; Ronaghi, Mostafa; Thorstenson, Yvonne R.

    2006-01-01

    This is the first comprehensive profile of cystic fibrosis transmembrane conductance regulator (CFTR) mutations and their corresponding haplotypes in the Iranian population. All of the 27 CFTR exons of 60 unrelated Iranian CF patients were sequenced to identify disease-causing mutations. Eleven core haplotypes of CFTR were identified by genotyping six high-frequency simple nucleotide polymorphisms. The carrier frequency of 2.5 in 100 (1 in 40) was estimated from the frequency of heterozygous patients and suggests that contrary to popular belief, cystic fibrosis may be a common, under-diagnosed disease in Iran. A heterogeneous mutation spectrum was observed at the CFTR locus in 60 cystic fibrosis (CF) patients from Iran. Twenty putative disease-causing mutations were identified on 64 (53%) of the 120 chromosomes. The five most common Iranian mutations together represented 37% of the expected mutated alleles. The most frequent mutation, ΔF508 (p.F508del), represented only 16% of the expected mutated alleles. The next most frequent mutations were c.1677del2 (p.515fs) at 7.5%, c.4041C>G (p.N1303K) at 5.6%, c.2183AA>G (p.684fs) at 5%, and c.3661A>T (p.K1177X) at 2.5%. Three of the five most frequent Iranian mutations are not included in a commonly used panel of CF mutations, underscoring the importance of identifying geographic-specific mutations in this population. PMID:16436643

  18. Clock-like mutational processes in human somatic cells

    DOE PAGES

    Alexandrov, Ludmil B.; Jones, Philip H.; Wedge, David C.; Sale, Julian E.; Campbell, Peter J.; Nik-Zainal, Serena; Stratton, Michael R.

    2015-11-09

    During the course of a lifetime, somatic cells acquire mutations. Different mutational processes may contribute to the mutations accumulated in a cell, with each imprinting a mutational signature on the cell's genome. Some processes generate mutations throughout life at a constant rate in all individuals, and the number of mutations in a cell attributable to these processes will be proportional to the chronological age of the person. Using mutations from 10,250 cancer genomes across 36 cancer types, we investigated clock-like mutational processes that have been operating in normal human cells. Two mutational signatures show clock-like properties. Both exhibit different mutationmore » rates in different tissues. However, their mutation rates are not correlated, indicating that the underlying processes are subject to different biological influences. For one signature, the rate of cell division may influence its mutation rate. This paper provides the first survey of clock-like mutational processes operating in human somatic cells.« less

  19. Exploration des mécanismes de repliement des protéines par dynamique moléculaire

    NASA Astrophysics Data System (ADS)

    Gilquin, B.

    2005-11-01

    Comment se replient les protéines? Cette question est ancienne. En introduction nous rappellerons ce qu'est le paradoxe de Levinthal et comment on est passé de la notion de chemin de repliement à la notion de paysage énergétique. Les simulations de dynamique moléculaire ont permis d'aborder la compréhension du processus de repliement au niveau atomique. Cependant l'échelle de temps des processus de repliement (de l'ordre de la milliseconde) n'est pas accessible aux simulations numériques (de l'ordre de la nanoseconde). Plusieurs auteurs ont donc proposé de simuler le dépliement des protéines par dynamique moléculaire. En admettant le principe de micro-réversibilité l'étude du processus de dépliement renseigne sur celui de repliement. Cependant, il est nécessaire d'accélérer le dépliement en introduisant un biais afin que les états dépliées soient accessibles aux échelles de temps des simulations. Nous présenterons un exemple de ce qui a été réalise dans le cas de l'étude de protéines de petite taille suivant un repliement simple, globalement à deux états. Nous présenterons ensuite ce que nous avons réalisé dans le cas d'une protéine de taille plus importante et pour laquelle le processus de repliement est plus complexe car il existe un intermédiaire transitoire de repliement. C'est le cas du lysozyme pour lequel les simulations de dépliement permettent d'accéder au mécanisme atomique de repliement et de comprendre pourquoi des mutants de cette protéine se replient plus lentement et forment des fibres amyloïdiques. Ainsi les intermédiaires de repliement seraient à l'origine de formes pathogènes des protéines observées dans les maladies neuro-dégéneratives. Enfin nous montrerons comment à partir de plusieurs simulations longues de dynamique moléculaire, le paysage énergétique pour de petites protéines peut être calculé.

  20. The DES Science Verification weak lensing shear catalogues

    NASA Astrophysics Data System (ADS)

    Jarvis, M.; Sheldon, E.; Zuntz, J.; Kacprzak, T.; Bridle, S. L.; Amara, A.; Armstrong, R.; Becker, M. R.; Bernstein, G. M.; Bonnett, C.; Chang, C.; Das, R.; Dietrich, J. P.; Drlica-Wagner, A.; Eifler, T. F.; Gangkofner, C.; Gruen, D.; Hirsch, M.; Huff, E. M.; Jain, B.; Kent, S.; Kirk, D.; MacCrann, N.; Melchior, P.; Plazas, A. A.; Refregier, A.; Rowe, B.; Rykoff, E. S.; Samuroff, S.; Sánchez, C.; Suchyta, E.; Troxel, M. A.; Vikram, V.; Abbott, T.; Abdalla, F. B.; Allam, S.; Annis, J.; Benoit-Lévy, A.; Bertin, E.; Brooks, D.; Buckley-Geer, E.; Burke, D. L.; Capozzi, D.; Carnero Rosell, A.; Carrasco Kind, M.; Carretero, J.; Castander, F. J.; Clampitt, J.; Crocce, M.; Cunha, C. E.; D'Andrea, C. B.; da Costa, L. N.; DePoy, D. L.; Desai, S.; Diehl, H. T.; Doel, P.; Fausti Neto, A.; Flaugher, B.; Fosalba, P.; Frieman, J.; Gaztanaga, E.; Gerdes, D. W.; Gruendl, R. A.; Gutierrez, G.; Honscheid, K.; James, D. J.; Kuehn, K.; Kuropatkin, N.; Lahav, O.; Li, T. S.; Lima, M.; March, M.; Martini, P.; Miquel, R.; Mohr, J. J.; Neilsen, E.; Nord, B.; Ogando, R.; Reil, K.; Romer, A. K.; Roodman, A.; Sako, M.; Sanchez, E.; Scarpine, V.; Schubnell, M.; Sevilla-Noarbe, I.; Smith, R. C.; Soares-Santos, M.; Sobreira, F.; Swanson, M. E. C.; Tarle, G.; Thaler, J.; Thomas, D.; Walker, A. R.; Wechsler, R. H.

    2016-08-01

    We present weak lensing shear catalogues for 139 square degrees of data taken during the Science Verification (SV) time for the new Dark Energy Camera (DECam) being used for the Dark Energy Survey (DES). We describe our object selection, point spread function estimation and shear measurement procedures using two independent shear pipelines, IM3SHAPE and NGMIX, which produce catalogues of 2.12 million and 3.44 million galaxies, respectively. We detail a set of null tests for the shear measurements and find that they pass the requirements for systematic errors at the level necessary for weak lensing science applications using the SV data. We also discuss some of the planned algorithmic improvements that will be necessary to produce sufficiently accurate shear catalogues for the full 5-yr DES, which is expected to cover 5000 square degrees.

  1. Peste des petits ruminants outbreaks in White Nile State, Sudan.

    PubMed

    Ishag, Osama M; Saeed, Intisar K; Ali, Yahia H

    2015-01-01

    Eight outbreaks of peste des petits ruminants in sheep and goats were reported in White Nile State, Sudan, between 2008 and 2009. A mortality rate of 4.2% was reported across the different outbreaks. Clinically the disease was characterised by high fever, ocular and nasal discharge, pneumonia, ulceration of the mucous membranes, diarrhoea and death. The postmortem findings included necrotic lesions in the mouth and gastrointestinal tract, and swollen, oedematous lymph nodes associated with the lungs and intestine. Of the 209 serum samples tested by competitive enzyme-linked immunosorbent assay, 113 (54%) were found positive. Peste des petits ruminants virus was confirmed in tissues, nasal swabs and blood samples by immunocapture enzyme-linked immunosorbent assay, reverse-transcription polymerase chain reaction and isolation of the virus in culture of lamb testicle cells. PMID:26304168

  2. Zweistufige Segmentierung des Tracheobronchialbaums mittels iterativen adaptiven Bereichswachstumsverfahren

    NASA Astrophysics Data System (ADS)

    Gergel, Ingmar; Wegner, Ingmar; Tetzlaff, Ralf; Meinzer, Hans-Peter

    Die Segmentierung des Tracheobronchialbaums aus medizinischen Bilddaten ist essentiell für unterschiedliche Anwendungen, beispielsweise der navigierten Bronchoskopie. Hierbei liegt das Hauptaugenmerk auf einer möglichst detaillierten Segmentierung der Bronchien bei möglichst geringer Laufzeit des Algorithmus. Dieser Beitrag beschreibt ein Verfahren, welches in zwei Schritten den Tracheobronchi-albaum anhand eines adaptiven Bereichswachstumsverfahrens aus CT-Aufnahmen segmentiert. Im ersten Schritt werden die großen Atemwege und im zweiten Schritt die kleinen Atemwege getrennt segmentiert. Insgesamt wird dadurch die Anzahl der Voxel, die von rechenaufwändigeren Algorithmen (bspw. Gefäß-Tracking) verarbeitet werden müssen, verringert. Die Ergebnisse zeigen bei minimaler Laufzeiterhöhung eine deutliche Steigerung der Anzahl sowie Tiefe der segmentierten Bronchien.

  3. Peste des petits ruminants outbreaks in White Nile State, Sudan.

    PubMed

    Ishag, Osama M; Saeed, Intisar K; Ali, Yahia H

    2015-08-21

    Eight outbreaks of peste des petits ruminants in sheep and goats were reported in White Nile State, Sudan, between 2008 and 2009. A mortality rate of 4.2% was reported across the different outbreaks. Clinically the disease was characterised by high fever, ocular and nasal discharge, pneumonia, ulceration of the mucous membranes, diarrhoea and death. The postmortem findings included necrotic lesions in the mouth and gastrointestinal tract, and swollen, oedematous lymph nodes associated with the lungs and intestine. Of the 209 serum samples tested by competitive enzyme-linked immunosorbent assay, 113 (54%) were found positive. Peste des petits ruminants virus was confirmed in tissues, nasal swabs and blood samples by immunocapture enzyme-linked immunosorbent assay, reverse-transcription polymerase chain reaction and isolation of the virus in culture of lamb testicle cells.

  4. The DES Science Verification Weak Lensing Shear Catalogs

    DOE PAGES

    Jarvis, M.

    2016-05-01

    We present weak lensing shear catalogs for 139 square degrees of data taken during the Science Verification (SV) time for the new Dark Energy Camera (DECam) being used for the Dark Energy Survey (DES). We describe our object selection, point spread function estimation and shear measurement procedures using two independent shear pipelines, IM3SHAPE and NGMIX, which produce catalogs of 2.12 million and 3.44 million galaxies respectively. We also detail a set of null tests for the shear measurements and find that they pass the requirements for systematic errors at the level necessary for weak lensing science applications using the SVmore » data. Furthermore, we discuss some of the planned algorithmic improvements that will be necessary to produce sufficiently accurate shear catalogs for the full 5-year DES, which is expected to cover 5000 square degrees.« less

  5. Partager : des technologies de pointe au service de la société

    SciTech Connect

    2011-02-14

    Médecine, climatologie, métrologie et informatique, les techniques utilisées par le LHC trouvent déjà des répercussions dans d’autres domaines scientifiques. Utilisant des techniques inédites, la physique des particules en fait bénéficier la société toute entière.

  6. Partager : des technologies de pointe au service de la société

    ScienceCinema

    None

    2016-07-12

    Médecine, climatologie, métrologie et informatique, les techniques utilisées par le LHC trouvent déjà des répercussions dans d’autres domaines scientifiques. Utilisant des techniques inédites, la physique des particules en fait bénéficier la société toute entière.

  7. Modelisations des effets de surface sur les jets horizontaux subsoniques d'hydrogene et de methane

    NASA Astrophysics Data System (ADS)

    Gomez, Luis Fernando

    Le developpement des codes et de normes bases sur une methodologie scientifique requiert la capacite de predire l'etendue inflammable de deversements gazeux d'hydrogene sous differentes conditions. Des etudes anterieures ont deja etabli des modeles bases sur les lois de conservation de la mecanique des fluides basees sur des correlations experimentales qui permettent de predire la decroissance de la concentration et de la vitesse d'un gaz le long de l'axe d'un jet libre vertical. Cette etude s'interesse aux effets de proximite a une surface horizontale parallele sur un jet turbulent. Nous nous interessons a son impact sur l'etendue du champ de la concentration et sur l'enveloppe inflammable en particulier. Cette etude est comparative : l'hydrogene est compare au methane. Ceci permet de degager l'influence des effets de difference de la densite sur le comportement du jet, et de comparer le comportement de l'hydrogene aux correlations experimentales, qui ont ete essentiellement etablies pour le methane. Un modele decrivant l'evolution spatio-temporelle du champ de concentration du gaz dilue est propose, base sur la mecanique des fluides computationnelle. Cette approche permet de varier systematiquement les conditions aux frontieres (proximite du jet a la surface, par exemple) et de connaitre en detail les proprietes de l'ecoulement. Le modele est implemente dans le code de simulations par volumes finis de FLUENT. Les resultats des simulations sont compares avec les lois de similitudes decoulant de la theorie des jets d'ecoulements turbulents libres ainsi qu'avec les resultats experimentaux disponibles. L'effet de la difference des masses molaires des constituantes du jet et des constituantes du milieu de dispersion est egalement etudie dans le contexte du comportement d'echelle de la region developpee du jet.

  8. Des recommandations probantes pour surveiller l’innocuité des antipsychotiques de deuxième génération chez les enfants et les adolescents

    PubMed Central

    Pringsheim, Tamara; Panagiotopoulos, Constadina; Davidson, Jana; Ho, Josephine

    2012-01-01

    HISTORIQUE : Au Canada, l’utilisation d’antipsychotiques, notamment les antipsychotiques de deuxième génération (ADG), a augmenté de façon considérable depuis cinq ans chez les enfants ayant des troubles de santé mentale. Ces médicaments ont le potentiel de causer de graves complications métaboliques et neurologiques lorsqu’on les utilise de manière chronique. OBJECTIF : Synthétiser les données probantes relatives aux effets secondaires métaboliques et neurologiques précis associés à l’usage d’ADG chez les enfants et fournir des recommandations probantes sur la surveillance de ces effets secondaires. MÉTHODOLOGIE : Les auteurs ont procédé à une analyse systématique des essais cliniques contrôlés des ADG auprès d’enfants. Ils ont fait des recommandations à l’égard de la surveillance de l’innocuité des ADG d’après un modèle de classification fondé sur le système GRADE (système de notation de l’évaluation et de l’élaboration des recommandations). Lorsque les données probantes n’étaient pas suffisantes, ils fondaient leurs recommandations sur le consensus et l’avis d’experts. Un groupe consensuel multidisciplinaire a analysé toutes les données probantes pertinentes et est parvenu à un consensus à l’égard des recommandations. RÉSULTATS : Les recommandations probantes portant sur la surveillance de l’innocuité des ADG figurent dans les présentes lignes directrices. Les auteurs indiquent la qualité des recommandations relatives à des examens physiques et tests de laboratoire précis à l’égard de chaque ADG à des moments déterminés. CONCLUSION : De multiples essais aléatoires et contrôlés ont permis d’évaluer l’efficacité de bon nombre des ADG utilisés pour traiter les troubles de santé mentale en pédiatrie. Toutefois, leurs avantages ne sont pas sans risques : on observe à la fois des effets secondaires métaboliques et neurologiques chez les enfants traités au moyen d

  9. Targeted next-generation sequencing extends the phenotypic and mutational spectrums for EYS mutations

    PubMed Central

    Gu, Shun; Tian, Yuanyuan; Chen, Xue

    2016-01-01

    Purpose We aim to determine genetic lesions with a phenotypic correlation in four Chinese families with autosomal recessive retinitis pigmentosa (RP). Methods Medical histories were carefully reviewed. All patients received comprehensive ophthalmic evaluations. The next-generation sequencing (NGS) approach targeting a panel of 205 retinal disease–relevant genes and 15 candidate genes was selectively performed on probands from the four recruited families for mutation detection. Online predictive software and crystal structure modeling were also applied to test the potential pathogenic effects of identified mutations. Results Of the four families, two were diagnosed with RP sino pigmento (RPSP). Patients with RPSP claimed to have earlier RP age of onset but slower disease progression. Five mutations in the eyes shut homolog (EYS) gene, involving two novel (c.7228+1G>A and c.9248G>A) and three recurrent mutations (c.4957dupA, c.6416G>A and c.6557G>A), were found as RP causative in the four families. The missense variant c.5093T>C was determined to be a variant of unknown significance (VUS) due to the variant’s colocalization in the same allele with the reported pathogenic mutation c.6416G>A. The two novel variants were further confirmed absent in 100 unrelated healthy controls. Online predictive software indicated potential pathogenicity of the three missense mutations. Further, crystal structural modeling suggested generation of two abnormal hydrogen bonds by the missense mutation p.G2186E (c.6557G>A) and elongation of its neighboring β-sheet induced by p.G3083D (c.9248G>A), which could alter the tertiary structure of the eys protein and thus interrupt its physicochemical properties. Conclusions Taken together, with the targeted NGS approach, we reveal novel EYS mutations and prove the efficiency of targeted NGS in the genetic diagnoses of RP. We also first report the correlation between EYS mutations and RPSP. The genotypic-phenotypic relationship in all

  10. Les mémoires de la dynastie Tang

    NASA Astrophysics Data System (ADS)

    Bonnet-Bidaud, J. M.

    1996-07-01

    Dans la nuit des temps, les astronomes chinois ont ete d'incomparables observateurs de cometes. Ces savants, dont les notations raffinees ponctuaient l'histoire officielle des empereurs, relevaient chaque passage d'astre errant avec une precision inestimable. Un veritable tresor ou puise encore la science contemporaine.

  11. Simulations of the OzDES AGN reverberation mapping project

    DOE PAGES

    King, Anthea L.; Martini, Paul; Davis, Tamara M.; Denney, K. D.; Kochanek, C. S.; Peterson, Bradley M.; Skielboe, Andreas; Vestergaard, Marianne; Huff, Eric; Watson, Darach; et al

    2015-08-26

    As part of the Australian spectroscopic dark energy survey (OzDES) we are carrying out a large-scale reverberation mapping study of ~500 quasars over five years in the 30 deg2 area of the Dark Energy Survey (DES) supernova fields. These quasars have redshifts ranging up to 4 and have apparent AB magnitudes between 16.8 mag < r < 22.5 mag. The aim of the survey is to measure time lags between fluctuations in the quasar continuum and broad emission-line fluxes of individual objects in order to measure black hole masses for a broad range of active galactic nuclei (AGN) and constrainmore » the radius–luminosity (R–L) relationship. Here we investigate the expected efficiency of the OzDES reverberation mapping campaign and its possible extensions. We expect to recover lags for ~35–45 % of the quasars. AGN with shorter lags and greater variability are more likely to yield a lag measurement, and objects with lags ≲6 months or ~1 yr are expected to be recovered the most accurately. The baseline OzDES reverberation mapping campaign is predicted to produce an unbiased measurement of the R–L relationship parameters for Hβ, MgIIλ2798, and C IVλ1549. As a result, extending the baseline survey by either increasing the spectroscopic cadence, extending the survey season, or improving the emission-line flux measurement accuracy will significantly improve the R–L parameter constraints for all broad emission lines.« less

  12. Landform Variability in the Chaine Des Puys Tracing Multiple Processes

    NASA Astrophysics Data System (ADS)

    van Wyk de Vries, B.; Grosse, P.

    2014-12-01

    The Chaîne des Puys is a highly varied, type monogenetic field, and was acknowledged by 38th WH UNESCO Committee to contain Outstanding Universal Value. The Chaîne des Puys - Limagne Fault should be presented in 2016 for World Heritage Status. The 30 km long Chaîne des Puys contains ranges from simple basaltic scoria cones to complex, multicrater cones, and small simple domes to complicated trachytic edifices. There is also a range of phreatomagmatic landforms from tuff rings to maars and vulcanian to sub plinian deposits. There is a wide range of pahoehoe and aa lava types, that have flowed over different topographies. Here we take morphometrical data to analyse the variability of the edifices using a 10 m regional topographic DTM. The volcanoes form a broad continuum of morphological features, and height/widths of domes and cones overlap. Some edifices, are smooth and elliptical, even though they have erupted complex lava sequences, while others complex shapes, but are related to simple lava flows. There seems to be no easy correlation between cone morphology and eruption histories derived from lava fields and distal tephras. In the few cones where the interior is visible, the shape of the cone is seen to vary with changing eruption events. The final shape is a combination of changing activity, with the last events having the strongest morphometic signature. The broad variations in edifice, lava field, and deposit morphology are described and quantified, however it becomes clear from the few individual eruptions already studied, that to fully appreciate the range of monogenetic eruption scenarios presented by the Chaîne des Puys, much more detailed work is required. This is being made possible by new acquisitions of LiDAR imagery, new geophysical work, and the combination of excellent preservation and extensive outcrop that is partly the result the original geology and long term responsible land management by the local populace, regional park and local

  13. Gestion des plaines inondables: Hauteur ou débit

    NASA Astrophysics Data System (ADS)

    El-Jabi, Nassir; Rousselle, Jean

    1983-07-01

    A stochastic model based on the recent developments in the theory of extreme values is presented to describe the flood occurrence. This model is applied to the "Rivière des Prairies", assuming that the exceedances (flood peak and/or stage above a given base flow and/or base stage) are independent and identically distributed in the time interval for a given year and season.

  14. Discovery and Classification of DES15S2lam

    NASA Astrophysics Data System (ADS)

    Pan, Y.-C.; Foley, R. J.; Nichol, R.; Papadopoulos, A.; Childress, M.; D'Andrea, C.; Smith, M.; Sullivan, M.; Maartens, R.; Gupta, R.; Kovacs, E.; Kuhlmann, S.; Spinka, H.; Ahn, E.; Finley, D. A.; Frieman, J.; Marriner, J.; Wester, W.; Aldering, G.; Kim, A. G.; Thomas, R. C.; Barbary, K.; Bloom, J. S.; Goldstein, D.; Nugent, P.; Perlmutter, S.; Casas, R.; Castander, F. J.; Desai, S.; Paech, K.; Smith, R. C.; Schubnell, M.; Kessler, R.; Lasker, J.; Scolnic, D.; Brout, D. J.; Gladney, L.; Sako, M.; Wolf, R. C.; Brown, P. J.; Krisciunas, K.; Suntzeff, N.

    2015-10-01

    We report optical spectroscopy of DES15S2lam discovered by the Dark Energy Survey. The spectrum (540-965nm) was obtained using GMOS on Gemini-North. Object classification was performed using superfit (Howell et al, 2005, ApJ, 634, 1190) and SNID (Blondin & Tonry, 2007, ApJ, 666, 1024), the details of which are reported in the table below.

  15. Evolution of Bacillus subtilis to enhanced growth at low pressure: up-regulated transcription of des-desKR, encoding the fatty acid desaturase system.

    PubMed

    Fajardo-Cavazos, Patricia; Waters, Samantha M; Schuerger, Andrew C; George, Sheeja; Marois, James J; Nicholson, Wayne L

    2012-03-01

    The atmospheric pressure on Mars ranges from 1-10 mbar, about 1% of Earth pressure (∼1013 mbar). Low pressure is a growth-inhibitory factor for terrestrial microorganisms on Mars, and a putative low-pressure barrier for growth of Earth bacteria of ∼25 mbar has been postulated. In a previous communication, we described the isolation of a strain of Bacillus subtilis that had evolved enhanced growth ability at the near-inhibitory low pressure of 50 mbar. To explore mechanisms that enabled growth of the low-pressure-adapted strain, numerous genes differentially transcribed between the ancestor strain WN624 and low-pressure-evolved strain WN1106 at 50 mbar were identified by microarray analysis. Among these was a cluster of three candidate genes (des, desK, and desR), whose mRNA levels in WN1106 were higher than the ancestor on the microarrays. Up-regulation of these genes was confirmed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis. The des, desK, and desR genes encode the Des membrane fatty acid (FA) desaturase, the DesK sensor kinase, and the DesR response regulator, respectively, which function to maintain membrane fluidity in acute response to temperature downshift. Pressure downshift caused an up-regulation of des mRNA levels only in WN1106, but expression of a des-lacZ transcriptional fusion was unaffected, which suggests that des regulation was different in response to temperature versus pressure downshift. Competition experiments showed that inactivation of the des gene caused a slight, but statistically significant, loss of fitness of strain WN1106 at 50 mbar. Further, analysis of membrane FA composition of cells grown at 1013 versus 50 mbar revealed a decrease in the ratio of unsaturated to saturated FAs but an increase in the ratio of anteiso- to iso-FAs. The present study represents a first step toward identification of molecular mechanisms by which B. subtilis could sense and respond to the novel environmental stress

  16. Approche à l’endroit des blessures traumatiques à la main en soins primaires

    PubMed Central

    Cheung, Kevin; Hatchell, Alexandra; Thoma, Achilleas

    2013-01-01

    Résumé Objectif Passer en revue la prise en charge initiale des blessures traumatiques communes à la main que voient les médecins de soins primaires. Sources des données Nous avons examiné les données cliniques probantes et les ouvrages spécialisés récents cernés par des recherches dans la base de données électronique MEDLINE. Nous avons utilisé l’opinion d’experts pour compléter les recommandations dans les domaines où les données scientifiques étaient rares. Message principal Les médecins de soins primaires sont couramment appelés à prendre en charge des patients victimes de blessures traumatiques à la main. Dans le contexte d’un cas clinique, nous examinons l’évaluation, le diagnostic et la prise en charge initiale des traumatismes communs à la main. La présentation et la prise en charge des blessures au lit de l’ongle, des amputations de l’extrémité du doigt, des doigts en maillet, des fractures à la main, des lacérations de tendons, des morsures et de la ténosynovite infectieuse seront aussi discutées. Les principes de la prise en charge des blessures traumatiques à la main comportent la réduction et l’immobilisation des fractures, la prescription d’imagerie radiographique post-réduction, l’obtention d’un recouvrement par les tissus mous, la prévention et le traitement des infections et l’assurance d’une prophylaxie antitétanique. Conclusion Il est essentiel d’assurer une évaluation et une prise en charge appropriées des blessures traumatiques à la main pour prévenir une morbidité considérable à long terme dans une population autrement en santé. La reconnaissance sans délai des blessures qui nécessitent une demande de consultation urgente ou rapide auprès d’un chirurgien spécialiste de la main est également critique.

  17. [Influence of diethyl sulfate (DES) mutagenesis on growth properties and pigment secondary metabolites of Phellinus igniarius].

    PubMed

    Wang, Jing; Wu, Xin-yuan; Ma, Wei; Chen, Jing; Liu, Cheng; Wu, Xiu-li

    2015-06-01

    The diethyl sulfate (DES) mutagenesis was chosen for the mutagenic treatment to Phellinus igniarius, and the relationship of mutagenesis time and death rate was investigated with 0.5% DES. The differences of mycelial growth speed, liquid fermentation mycelia biomass, morphology and pigment classes of secondary metabolites production speed and antioxidant activities of metabolite products were discussed. The study displayed that DES mutagenesis could change mycelial morphology without obvious effect on mycelium growth, and the DES mutagenesis improved antioxidant activities of the active ingredients of P. igniarius and had more antioxidant activity of hypoxia/sugar PC12 nerve cells than that of P. igniarius. PMID:26591512

  18. Mutations in ARSB in MPS VI patients in India.

    PubMed

    Mathew, Juby; Jagadeesh, Sujatha M; Bhat, Meenakshi; Udhaya Kumar, S; Thiyagarajan, Saravanamuthu; Srinivasan, Sudha

    2015-09-01

    Mucopolysaccharidosis VI (MPS VI) is an autosomal recessive inborn error of metabolism caused by mutations in the arylsulfatase B gene (ARSB) and consequent deficient activity of ARSB, a lysosomal enzyme. We present here the results of a study undertaken to identify the mutations in ARSB in MPS VI patients in India. Around 160 ARSB mutations, of which just 4 are from India, have been reported in the literature. Our study covered nine MPS VI patients from eight families. Both familial mutations were found in seven families, and only one mutation was found in one family. Seven mutations were found - four novel (p.G38_G40del3, p.C91R, p.L98R and p.R315P), two previously reported from India (p.D53N and p.W450C), and one reported from outside India (p.R160Q). One mutation, p.W450C, was present in two families, and the other six mutations were present in one family each. Analysis of the molecular structure of the enzyme revealed that most of these mutations either cause loss of an active site residue or destabilize the structure of the enzyme. The only previous study on mutations in ARSB in Indian MPS VI patients, by Kantaputra et al. 2014 [1], reported four novel mutations of which two (p.D53N and p.W450C) were found in our study as well. Till date, nine mutations have been reported from India, through our study and the Kantaputra study. Eight out of these nine mutations have been found only in India. This suggests that the population studied by us might have its own typical set of mutations, with other populations equally likely to have their own set of mutations. PMID:26937411

  19. C and D comes curbside in Des Moines

    SciTech Connect

    Cox, C.

    1997-07-01

    Until last October, virtually all the commingled construction and demolition (C and D) waste in Des Moines, Iowa, was being landfilled. But thanks to a $483,000 grant from the state and the financial commitment of two local solid waste businesses, overall diversion rates of C and D waste have gone from 20% to 50%, and are still climbing as the construction season shifts into high gear. It is a demonstration project initiated by Iowa`s Department of Natural Resources (DNR). In the late 1980s, the state passed legislation that called for a goal of 50% of all solid waste to be diverted from landfills by 2000. Last October, the grant was awarded to the Corell Team, a joint effort comprising Central Recycling, a unit of Corell Contractor (Des Moines, Iowa), Corell itself, and Artistic Waste Services, Inc. (Des Moines, Iowa). The uniqueness of the project is its degree of vertical integration, from the collection and transport of C and D waste to its recycling, marketing, and disposal. Artistic collects, presorts recoverable commodities, and hauls them to its own markets or to Central Recycling for further sorting and recycling. Central, using a Re-Tech (Myerstown, Pa.) trommel and a 12-man picking crew, further sorts and recycles materials.

  20. CMB lensing tomography with the DES Science Verification galaxies

    NASA Astrophysics Data System (ADS)

    Giannantonio, T.; Fosalba, P.; Cawthon, R.; Omori, Y.; Crocce, M.; Elsner, F.; Leistedt, B.; Dodelson, S.; Benoit-Lévy, A.; Gaztañaga, E.; Holder, G.; Peiris, H. V.; Percival, W. J.; Kirk, D.; Bauer, A. H.; Benson, B. A.; Bernstein, G. M.; Carretero, J.; Crawford, T. M.; Crittenden, R.; Huterer, D.; Jain, B.; Krause, E.; Reichardt, C. L.; Ross, A. J.; Simard, G.; Soergel, B.; Stark, A.; Story, K. T.; Vieira, J. D.; Weller, J.; Abbott, T.; Abdalla, F. B.; Allam, S.; Armstrong, R.; Banerji, M.; Bernstein, R. A.; Bertin, E.; Brooks, D.; Buckley-Geer, E.; Burke, D. L.; Capozzi, D.; Carlstrom, J. E.; Carnero Rosell, A.; Carrasco Kind, M.; Castander, F. J.; Chang, C. L.; Cunha, C. E.; da Costa, L. N.; D'Andrea, C. B.; DePoy, D. L.; Desai, S.; Diehl, H. T.; Dietrich, J. P.; Doel, P.; Eifler, T. F.; Evrard, A. E.; Neto, A. Fausti; Fernandez, E.; Finley, D. A.; Flaugher, B.; Frieman, J.; Gerdes, D.; Gruen, D.; Gruendl, R. A.; Gutierrez, G.; Holzapfel, W. L.; Honscheid, K.; James, D. J.; Kuehn, K.; Kuropatkin, N.; Lahav, O.; Li, T. S.; Lima, M.; March, M.; Marshall, J. L.; Martini, P.; Melchior, P.; Miquel, R.; Mohr, J. J.; Nichol, R. C.; Nord, B.; Ogando, R.; Plazas, A. A.; Romer, A. K.; Roodman, A.; Rykoff, E. S.; Sako, M.; Saliwanchik, B. R.; Sanchez, E.; Schubnell, M.; Sevilla-Noarbe, I.; Smith, R. C.; Soares-Santos, M.; Sobreira, F.; Suchyta, E.; Swanson, M. E. C.; Tarle, G.; Thaler, J.; Thomas, D.; Vikram, V.; Walker, A. R.; Wechsler, R. H.; Zuntz, J.

    2016-03-01

    We measure the cross-correlation between the galaxy density in the Dark Energy Survey (DES) Science Verification data and the lensing of the cosmic microwave background (CMB) as reconstructed with the Planck satellite and the South Pole Telescope (SPT). When using the DES main galaxy sample over the full redshift range 0.2 < zphot < 1.2, a cross-correlation signal is detected at 6σ and 4σ with SPT and Planck , respectively. We then divide the DES galaxies into five photometric redshift bins, finding significant (>2σ) detections in all bins. Comparing to the fiducial Planck cosmology, we find the redshift evolution of the signal matches expectations, although the amplitude is consistently lower than predicted across redshift bins. We test for possible systematics that could affect our result and find no evidence for significant contamination. Finally, we demonstrate how these measurements can be used to constrain the growth of structure across cosmic time. We find the data are fit by a model in which the amplitude of structure in the z < 1.2 universe is 0.73 ± 0.16 times as large as predicted in the Λ cold dark matter Planck cosmology, a 1.7σ deviation.

  1. CMB lensing tomography with the DES Science Verification galaxies

    DOE PAGES

    Giannantonio, T.

    2016-01-07

    We measure the cross-correlation between the galaxy density in the Dark Energy Survey (DES) Science Verification data and the lensing of the cosmic microwave background (CMB) as reconstructed with the Planck satellite and the South Pole Telescope (SPT). When using the DES main galaxy sample over the full redshift range 0.2 < zphot < 1.2, a cross-correlation signal is detected at 6σ and 4σ with SPT and Planck respectively. We then divide the DES galaxies into five photometric redshift bins, finding significant (>2σ) detections in all bins. Comparing to the fiducial Planck cosmology, we find the redshift evolution of themore » signal matches expectations, although the amplitude is consistently lower than predicted across redshift bins. We test for possible systematics that could affect our result and find no evidence for significant contamination. Finally, we demonstrate how these measurements can be used to constrain the growth of structure across cosmic time. We find the data are fit by a model in which the amplitude of structure in the z < 1.2 universe is 0.73 ± 0.16 times as large as predicted in the LCDM Planck cosmology, a 1.7σ deviation.« less

  2. Infections fongiques des brûlé : revue

    PubMed Central

    Arnould, JF.; Le Floch, R.

    2015-01-01

    Summary Les infections fongiques locales ou générales sont souvent d’une extrême gravité chez les brûlés. Les brûlés combinent de nombreux facteurs de risque à une immunodépression induite par la brûlure. Les infections de plaies sont le fait des genres Candida, Aspergillus et des agents de mucormycoses. Ces deux derniers cas sont à l’origine de lésions particulièrement sévères. Leur diagnostic repose sur la biopsie cutanée avec examens mycologique et anatomopathologique. Le traitement est essentiellement chirurgical, associé à une antibiothérapie adaptée. Les septicémies sont le fait de levures, essentiellement du genre Candida. Le diagnostic en est difficile dans le contexte des brûlés et repose souvent sur une forte suspicion clinique. Leur traitement repose sur les échinocandines et plus secondairement sur le fluconazole. PMID:26668558

  3. The Androgen Receptor Gene Mutations Database.

    PubMed

    Gottlieb, B; Lehvaslaiho, H; Beitel, L K; Lumbroso, R; Pinsky, L; Trifiro, M

    1998-01-01

    The current version of the androgen receptor (AR) gene mutations database is described. The total number of reported mutations has risen from 272 to 309 in the past year. We have expanded the database: (i) by giving each entry an accession number; (ii) by adding information on the length of polymorphic polyglutamine (polyGln) and polyglycine (polyGly) tracts in exon 1; (iii) by adding information on large gene deletions; (iv) by providing a direct link with a completely searchable database (courtesy EMBL-European Bioinformatics Institute). The addition of the exon 1 polymorphisms is discussed in light of their possible relevance as markers for predisposition to prostate or breast cancer. The database is also available on the internet (http://www.mcgill. ca/androgendb/ ), from EMBL-European Bioinformatics Institute (ftp. ebi.ac.uk/pub/databases/androgen ), or as a Macintosh FilemakerPro or Word file (MC33@musica.mcgill.ca).

  4. Big Blue Transgenic Mouse lacl mutation analysis

    SciTech Connect

    Stiegler, G.L.; Stillwell, L.C. )

    1993-01-01

    In this report the authors describe a rapid general method for mutant blue plaque molecular analysis. The mutant analysis discussed here resulted from radon inhalation exposure. The described method circumvents Stratagene's plasmid isolation and ensuing sequence analysis of the entire lac1 gene. The authors have adapted the polymerase chain reaction (PCR) method and single-strand conformation polymorphism (SSCP) analysis for localizing mutations within the lac1 coding region. Three overlapping PCR products of approximately 450 bp representing the entire lac1 coding region are used for SSCP analysis. Those PCR products with an altered SSCP electrophoretic migration focus the mutation to a smaller region of the lac1 gene that is analyzed by direct cycle sequencing. 5 refs., 1 fig.

  5. Ghrelin Receptor Mutations and Human Obesity.

    PubMed

    Wang, W; Tao, Y-X

    2016-01-01

    Growth hormone secretagogue receptor (GHSR) was originally identified as an orphan receptor in porcine and rat anterior pituitary membranes. In 1999, GHSR was deorphanized and shown to be a receptor for ghrelin, a peptide hormone secreted from the stomach. Therefore, GHSR is also called ghrelin receptor. In addition to regulating growth hormone secretion, ghrelin receptor regulates various physiological processes, including food intake and energy expenditure, glucose metabolism, cardiovascular functions, gastric acid secretion and motility, and immune function. Several human genetic studies conducted in populations originated from Europe, Africa, South America, and East Asia identified rare mutations and single nucleotide polymorphisms that might be associated with human obesity and short stature. Functional analyses of mutant GHSRs reveal multiple defects, including cell surface expression, ligand binding, and basal and stimulated signaling. With growing understanding in the functionality of naturally occurring GHSR mutations, potential therapeutic strategies including pharmacological chaperones and novel ligands could be used to correct the GHSR mutants. PMID:27288828

  6. ELOVL5 mutations cause spinocerebellar ataxia 38.

    PubMed

    Di Gregorio, Eleonora; Borroni, Barbara; Giorgio, Elisa; Lacerenza, Daniela; Ferrero, Marta; Lo Buono, Nicola; Ragusa, Neftj; Mancini, Cecilia; Gaussen, Marion; Calcia, Alessandro; Mitro, Nico; Hoxha, Eriola; Mura, Isabella; Coviello, Domenico A; Moon, Young-Ah; Tesson, Christelle; Vaula, Giovanna; Couarch, Philippe; Orsi, Laura; Duregon, Eleonora; Papotti, Mauro Giulio; Deleuze, Jean-François; Imbert, Jean; Costanzi, Chiara; Padovani, Alessandro; Giunti, Paola; Maillet-Vioud, Marcel; Durr, Alexandra; Brice, Alexis; Tempia, Filippo; Funaro, Ada; Boccone, Loredana; Caruso, Donatella; Stevanin, Giovanni; Brusco, Alfredo

    2014-08-01

    Spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal-dominant neurodegenerative disorders involving the cerebellum and 23 different genes. We mapped SCA38 to a 56 Mb region on chromosome 6p in a SCA-affected Italian family by whole-genome linkage analysis. Targeted resequencing identified a single missense mutation (c.689G>T [p.Gly230Val]) in ELOVL5. Mutation screening of 456 independent SCA-affected individuals identified the same mutation in two further unrelated Italian families. Haplotyping showed that at least two of the three families shared a common ancestor. One further missense variant (c.214C>G [p.Leu72Val]) was found in a French family. Both missense changes affect conserved amino acids, are predicted to be damaging by multiple bioinformatics tools, and were not identified in ethnically matched controls or within variant databases. ELOVL5 encodes an elongase involved in the synthesis of polyunsaturated fatty acids of the ω3 and ω6 series. Arachidonic acid and docosahexaenoic acid, two final products of the enzyme, were reduced in the serum of affected individuals. Immunohistochemistry on control mice and human brain demonstrated high levels in Purkinje cells. In transfection experiments, subcellular localization of altered ELOVL5 showed a perinuclear distribution with a signal increase in the Golgi compartment, whereas the wild-type showed a widespread signal in the endoplasmic reticulum. SCA38 and SCA34 are examples of SCAs due to mutations in elongase-encoding genes, emphasizing the importance of fatty-acid metabolism in neurological diseases.

  7. Better living with hyper-mutation.

    PubMed

    Goodman, Myron F

    2016-07-01

    The simplest forms of mutations, base substitutions, typically have negative consequences, aside from their existential role in evolution and fitness. Hypermutations, mutations on steroids, occurring at frequencies of 10(-2) -10(-4) per base pair, straddle a domain between fitness and death, depending on the presence or absence of regulatory constraints. Two facets of hypermutation, one in Escherichia coli involving DNA polymerase V (pol V), the other in humans, involving activation-induced deoxycytidine deaminase (AID) are portrayed. Pol V is induced as part of the DNA-damage-induced SOS regulon, and is responsible for generating the lion's share of mutations when catalyzing translesion DNA synthesis (TLS). Four regulatory mechanisms, temporal, internal, conformational, and spatial, activate pol V to copy damaged DNA and then deactivate it. On the flip side of the coin, SOS-induced pols V, IV, and II mutate undamaged DNA, thus providing genetic diversity heightening long-term survival and evolutionary fitness. Fitness in humans is principally the domain of a remarkably versatile immune system marked by somatic hypermutations (SHM) in immunoglobulin variable (IgV) regions that ensure antibody (Ab) diversity. AID initiates SHM by deaminating C → U, favoring hot WRC (W = A/T, R = A/G) motifs. Since there are large numbers of trinucleotide motif targets throughout IgV, AID must exercise considerable catalytic restraint to avoid attacking such sites repeatedly, which would otherwise compromise diversity. Processive, random, and inefficient AID-catalyzed dC deamination simulates salient features of SHM, yet generates B-cell lymphomas when working at the wrong time in the wrong place. Environ. Mol. Mutagen. 57:421-434, 2016. © 2016 Wiley Periodicals, Inc.

  8. Selection-mutation process of RNA viruses

    NASA Astrophysics Data System (ADS)

    Aafif, Amal; Lin, Juan

    1998-02-01

    RNA viruses mutate at a rate 105-106 times faster than their DNA counterparts. This process can be simulated by a continuous stochastic model on a smooth one-dimensional fitness landscape where selection forces the viral quasispecies to climb uphill to higher fitness values. Theoretical results of the model with drift velocity proportional to fitness are fitted to the experimental observations made by Novella et al. [Proc. Natl. Acad. Sci. U.S.A. 92, 5841 (1995)].

  9. Genetic mutations in Gorlin-Goltz syndrome

    PubMed Central

    Daneswari, Muthumula; Reddy, Mutjumula Swamy Ranga

    2013-01-01

    Gorlin-Goltz syndrome is a rare multisystemic disease inherited in a dominant autosomal at a high level of penetrance and variable expressiveness. It is mainly characterized by basal cell carcinoma, odontogenic keratocyst and skeletal anomalies. Diagnosis is based upon established major and minor clinical and radiographic criteria and gene mutation analysis. This article presents a case of Gorlin-Goltz syndrome, its genetic predisposition, diagnosis and management. PMID:24339558

  10. Activating STAT6 mutations in follicular lymphoma

    PubMed Central

    Yildiz, Mehmet; Li, Hongxiu; Bernard, Denzil; Amin, Nisar A.; Ouillette, Peter; Jones, Siân; Saiya-Cork, Kamlai; Parkin, Brian; Jacobi, Kathryn; Shedden, Kerby; Wang, Shaomeng; Chang, Alfred E.; Kaminski, Mark S.

    2015-01-01

    Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma in the Western world. FL cell-intrinsic and cell-extrinsic factors influence FL biology and clinical outcome. To further our understanding of the genetic basis of FL, we performed whole-exome sequencing of 23 highly purified FL cases and 1 transformed FL case and expanded findings to a combined total of 114 FLs. We report recurrent mutations in the transcription factor STAT6 in 11% of FLs and identified the STAT6 amino acid residue 419 as a novel STAT6 mutation hotspot (p.419D/G, p.419D/A, and p.419D/H). FL-associated STAT6 mutations were activating, as evidenced by increased transactivation in HEK293T cell–based transfection/luciferase reporter assays, heightened interleukin-4 (IL-4) –induced activation of target genes in stable STAT6 transfected lymphoma cell lines, and elevated baseline expression levels of STAT6 target genes in primary FL B cells harboring mutant STAT6. Mechanistically, FL-associated STAT6 mutations facilitated nuclear residency of STAT6, independent of IL-4–induced STAT6-Y641 phosphorylation. Structural modeling of STAT6 based on the structure of the STAT1-DNA complex revealed that most FL-associated STAT6 mutants locate to the STAT6-DNA interface, potentially facilitating heightened interactions. The genetic and functional data combined strengthen the recognition of the IL-4/JAK/STAT6 axis as a driver of FL pathogenesis. PMID:25428220

  11. The point mutation process in proteins

    NASA Technical Reports Server (NTRS)

    Schwartz, R. M.; Dayhoff, M. O.

    1978-01-01

    An optimized scoring matrix for residue-by-residue comparisons of distantly related protein sequences has been developed. The scoring matrix is based on observed exchanges and mutabilities of amino acids in 1572 closely related sequences derived from a cross-section of protein groups. Very few superimposed or parallel mutations are included in the data. The scoring matrix is most useful for demonstrating the relatedness of proteins between 65 and 85% different.

  12. Parton branching in the color mutation model

    NASA Astrophysics Data System (ADS)

    Hwa, Rudolph C.; Wu, Yuanfang

    1999-11-01

    The soft production problem in hadronic collisions as described in the eikonal color mutation branching model is improved in the way that the initial parton distribution is treated. Furry branching of the partons is considered as a means of describing the nonperturbative process of parton reproduction in the soft interaction. The values of all the moments, and Cq, for q=2,...,5, as well as their energy dependences, can be correctly determined by the use of only two parameters.

  13. The directed mutation controversy and neo-Darwinism.

    PubMed

    Lenski, R E; Mittler, J E

    1993-01-01

    According to neo-Darwinian theory, random mutation produces genetic differences among organisms whereas natural selection tends to increase the frequency of advantageous alleles. However, several recent papers claim that certain mutations in bacteria and yeast occur at much higher rates specifically when the mutant phenotypes are advantageous. Various molecular models have been proposed that might explain these directed mutations, but the models have not been confirmed. Critics contend that studies purporting to demonstrate directed mutation lack certain controls and fail to account adequately for population dynamics. Further experiments that address these criticisms do not support the existence of directed mutations.

  14. Clinical relevance between CALR mutation and myeloproliferative neoplasms

    PubMed Central

    Wu, Zhiyuan; Zhang, Chen; Ma, Xiaochao

    2015-01-01

    In late 2013, somatic mutations in calreticulin (CALR), mainly those involving insertions and deletions in exon 9, attracted the great attention of hematologists and researchers. These JAK2- and MPL- mutual exclusive mutations enjoy a favorable specificity and prevalence (20-30%) in patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF), suggesting promise for these mutations in disease management. Moreover, these genetic variations are now also considered as a group of independent risk factors for disease prognosis. In this mini-review, we will document the value of CALR mutations in disease diagnosis, prognosis, and therapeutic strategy selection, and we will discuss current advances in methods to detect these mutations. PMID:27358872

  15. Novel recurrently mutated genes in African American colon cancers

    PubMed Central

    Guda, Kishore; Veigl, Martina L.; Varadan, Vinay; Nosrati, Arman; Ravi, Lakshmeswari; Lutterbaugh, James; Beard, Lydia; Willson, James K. V.; Sedwick, W. David; Wang, Zhenghe John; Molyneaux, Neil; Miron, Alexander; Adams, Mark D.; Elston, Robert C.; Markowitz, Sanford D.; Willis, Joseph E.

    2015-01-01

    We used whole-exome and targeted sequencing to characterize somatic mutations in 103 colorectal cancers (CRC) from African Americans, identifying 20 new genes as significantly mutated in CRC. Resequencing 129 Caucasian derived CRCs confirmed a 15-gene set as a preferential target for mutations in African American CRCs. Two predominant genes, ephrin type A receptor 6 (EPHA6) and folliculin (FLCN), with mutations exclusive to African American CRCs, are by genetic and biological criteria highly likely African American CRC driver genes. These previously unsuspected differences in the mutational landscapes of CRCs arising among individuals of different ethnicities have potential to impact on broader disparities in cancer behaviors. PMID:25583493

  16. Novel recurrently mutated genes in African American colon cancers.

    PubMed

    Guda, Kishore; Veigl, Martina L; Varadan, Vinay; Nosrati, Arman; Ravi, Lakshmeswari; Lutterbaugh, James; Beard, Lydia; Willson, James K V; Sedwick, W David; Wang, Zhenghe John; Molyneaux, Neil; Miron, Alexander; Adams, Mark D; Elston, Robert C; Markowitz, Sanford D; Willis, Joseph E

    2015-01-27

    We used whole-exome and targeted sequencing to characterize somatic mutations in 103 colorectal cancers (CRC) from African Americans, identifying 20 new genes as significantly mutated in CRC. Resequencing 129 Caucasian derived CRCs confirmed a 15-gene set as a preferential target for mutations in African American CRCs. Two predominant genes, ephrin type A receptor 6 (EPHA6) and folliculin (FLCN), with mutations exclusive to African American CRCs, are by genetic and biological criteria highly likely African American CRC driver genes. These previously unsuspected differences in the mutational landscapes of CRCs arising among individuals of different ethnicities have potential to impact on broader disparities in cancer behaviors. PMID:25583493

  17. Persistence of HIV-1 transmitted drug resistance mutations.

    PubMed

    Castro, Hannah; Pillay, Deenan; Cane, Patricia; Asboe, David; Cambiano, Valentina; Phillips, Andrew; Dunn, David T

    2013-11-01

    There are few data on the persistence of individual human immunodeficiency virus type 1 (HIV-1) transmitted drug resistance (TDR) mutations in the absence of selective drug pressure. We studied 313 patients in whom TDR mutations were detected at their first resistance test and who had a subsequent test performed while ART-naive. The rate at which mutations became undetectable was estimated using exponential regression accounting for interval censoring. Most thymidine analogue mutations (TAMs) and T215 revertants (but not T215F/Y) were found to be highly stable, with NNRTI and PI mutations being relatively less persistent. Our estimates are important for informing HIV transmission models.

  18. Prospects for cellular mutational assays in human populations

    SciTech Connect

    Mendelsohn, M.L.

    1984-06-29

    Practical, sensitive, and effective human cellular assays for detecting somatic and germinal mutations would have great value in environmental mutagenesis and carcinogenesis studies. Such assays would fill the void between human mutagenicity and the data that exist from short-term tests and from mutagenicity in other species. This paper discusses the following possible human cellular assays: (1) HPRT (hypoxanthine phosphoribosyltransferase) somatic cell mutation based on 6-thioguanine resistance; (2) hemoglobin somatic cell mutation assay; (3) glycophorin somatic cell mutation assay; and (4) LDH-X sperm cell mutation assay. 18 references.

  19. Superfund Record of Decision (EPA Region 7): Des Moines TCE, Des Moines, Polk County, Iowa, July 1986. Final report

    SciTech Connect

    Not Available

    1986-07-21

    The Des Moines TCE site includes the underground infiltration gallery used by the Des Moines Water Works (DMWW) as a source of the public water supply. The site was discovered in 1984 after trichloroethylene (TCE) was detected in the city's public water supply. The Dico Company disposed of an unknown quantity of oily waste sludge containing TCE onto their parking lot for dust control and into a drainage ditch on their property. The primary contaminants of concern include: TCE, PCE, 1,2-dichloroethane, vinyl chloride. The selected remedial action for this site includes: extraction wells to collect the contaminated ground water; isolation of the northern-most section of the north gallery; treatment of the ground water through air stripping to remove 96% of the TCE; discharge of the treated water to the Raccoon River; operation of the west extraction wells until established effluent levels are achieved for four consecutive months.

  20. Que peut-on voir avec des neutrons? Une introduction pour des non spécialistes

    NASA Astrophysics Data System (ADS)

    Schweizer, J.

    2005-11-01

    Le neutron est une particule élémentaire qui a été découverte en 1932 par James Chadwick. Ses caractéristiques principales sont résumées dans le tableau I. Il a été utilisé pour la première fois par Clifford Shull en 1946 comme outil pour des expériences de diffusion. Cette technique s'est depuis constamment développée pour concerner tous les aspects de la matière condensée: physique, chimie, matériaux, biologie. Il s'agit d'un outil tout à fait exceptionnel car le neutron possède des propriétés uniques et particulièrement adaptées pour ces études.

  1. Mutation detection in X-linked hydrocephalus

    SciTech Connect

    Forrest, S.M.; Balnaves, M.E.; Rosenthal, A.

    1994-09-01

    X-linked hydrocephalus (XLH), which maps to Xq28, affects about 1 in 30,000 male births. A candidate gene, L1-CAM, which codes for a neural adhesion molecule, mapped to the same region of the X chromosome. Rosenthal et al. (1992) identified a patient with XLH that had aberrant splicing of L1-CAM. A mutation at a potential branch point signal in an intron was identified. The gene has a number of exons and encodes a 4.2 kb mRNA. We isolated RNA from lymphocytes or fibroblasts from five XLH patients. cDNA was synthesized and the gene was amplified in two overlapping fragments, 2.2 kb and 1.7 kb respectively. A nested PCR approach with two rounds of PCR amplification was employed. Patient 900124 did not have a full length 5{prime} fragment and 880022 did not have a full length 3{prime} product. Restriction digestions defined the region of the alteration in the messenger RNA and sequencing in this region showed the loss of exons 10 and 21, respectively. All 5{prime} and 3{prime} products were also digested with several restriction enzymes (e.g., Msp I, Taq I), which have CG in their recognition sites, in the hope that point mutations that alter these restriction enzyme sites might be identified. A point mutation creating an Msp I site was found in patient 930067.

  2. ACTN1 mutations cause congenital macrothrombocytopenia.

    PubMed

    Kunishima, Shinji; Okuno, Yusuke; Yoshida, Kenichi; Shiraishi, Yuichi; Sanada, Masashi; Muramatsu, Hideki; Chiba, Kenichi; Tanaka, Hiroko; Miyazaki, Koji; Sakai, Michio; Ohtake, Masatoshi; Kobayashi, Ryoji; Iguchi, Akihiro; Niimi, Gen; Otsu, Makoto; Takahashi, Yoshiyuki; Miyano, Satoru; Saito, Hidehiko; Kojima, Seiji; Ogawa, Seishi

    2013-03-01

    Congenital macrothrombocytopenia (CMTP) is a heterogeneous group of rare platelet disorders characterized by a congenital reduction of platelet counts and abnormally large platelets, for which CMTP-causing mutations are only found in approximately half the cases. We herein performed whole-exome sequencing and targeted Sanger sequencing to identify mutations that cause CMTP, in which a dominant mode of transmission had been suspected but for which no known responsible mutations have been documented. In 13 Japanese CMTP-affected pedigrees, we identified six (46%) affected by ACTN1 variants cosegregating with CMTP. In the entire cohort, ACNT1 variants accounted for 5.5% of the dominant forms of CMTP cases and represented the fourth most common cause in Japanese individuals. Individuals with ACTN1 variants presented with moderate macrothrombocytopenia with anisocytosis but were either asymptomatic or had only a modest bleeding tendency. ACTN1 encodes α-actinin-1, a member of the actin-crosslinking protein superfamily that participates in the organization of the cytoskeleton. In vitro transfection experiments in Chinese hamster ovary cells demonstrated that altered α-actinin-1 disrupted the normal actin-based cytoskeletal structure. Moreover, transduction of mouse fetal liver-derived megakaryocytes with disease-associated ACTN1 variants caused a disorganized actin-based cytoskeleton in megakaryocytes, resulting in the production of abnormally large proplatelet tips, which were reduced in number. Our findings provide an insight into the pathogenesis of CMTP.

  3. Cis-regulatory mutations in human disease

    PubMed Central

    2009-01-01

    Cis-acting regulatory sequences are required for the proper temporal and spatial control of gene expression. Variation in gene expression is highly heritable and a significant determinant of human disease susceptibility. The diversity of human genetic diseases attributed, in whole or in part, to mutations in non-coding regulatory sequences is on the rise. Improvements in genome-wide methods of associating genetic variation with human disease and predicting DNA with cis-regulatory potential are two of the major reasons for these recent advances. This review will highlight select examples from the literature that have successfully integrated genetic and genomic approaches to uncover the molecular basis by which cis-regulatory mutations alter gene expression and contribute to human disease. The fine mapping of disease-causing variants has led to the discovery of novel cis-acting regulatory elements that, in some instances, are located as far away as 1.5 Mb from the target gene. In other cases, the prior knowledge of the regulatory landscape surrounding the gene of interest aided in the selection of enhancers for mutation screening. The success of these studies should provide a framework for following up on the large number of genome-wide association studies that have identified common variants in non-coding regions of the genome that associate with increased risk of human diseases including, diabetes, autism, Crohn's, colorectal cancer, and asthma, to name a few. PMID:19641089

  4. Ichthyosis vulgaris: the filaggrin mutation disease.

    PubMed

    Thyssen, J P; Godoy-Gijon, E; Elias, P M

    2013-06-01

    Ichthyosis vulgaris is caused by loss-of-function mutations in the filaggrin gene (FLG) and is characterized clinically by xerosis, scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. According to the published studies presented in this review article, FLG mutations are observed in approximately 7·7% of Europeans and 3·0% of Asians, but appear to be infrequent in darker-skinned populations. This clinical review article provides an overview of ichthyosis vulgaris epidemiology, related disorders and pathomechanisms. Not only does ichthyosis vulgaris possess a wide clinical spectrum, recent studies suggest that carriers of FLG mutations may have a generally altered risk of developing common diseases, even beyond atopic disorders. Mechanistic studies have shown increased penetration of allergens and chemicals in filaggrin-deficient skin, and epidemiological studies have found higher levels of hand eczema, irritant contact dermatitis, nickel sensitization and serum vitamin D levels. When relevant, individuals should be informed about an increased risk of developing dermatitis when repeatedly or continuously exposed to nickel or irritants. Moreover, with our current knowledge, individuals with ichthyosis vulgaris should be protected against neonatal exposure to cats to prevent atopic dermatitis and should abstain from smoking to prevent asthma. Finally, they should be advised against excessive exposure to factors that decrease skin barrier functions and increase the risk of atopic dermatitis.

  5. Painful peripheral neuropathy and sodium channel mutations.

    PubMed

    Hoeijmakers, Janneke G J; Faber, Catharina G; Merkies, Ingemar S J; Waxman, Stephen G

    2015-06-01

    Peripheral neuropathy can lead to neuropathic pain in a subset of patients. Painful peripheral neuropathy is a debilitating disorder, reflected by a reduced quality of life. Therapeutic strategies are limited and often disappointing, as in most cases targeted treatment is not available. Elucidating pathogenetic factors for pain might provide a target for optimal treatment. Voltage-gated sodium channels NaV1.7-NaV1.9 are expressed in the small-diameter dorsal root ganglion neurons and their axons. By a targeted gene approach, missense gain-of-function mutations of NaV1.7-NaV1.9 have been demonstrated in painful peripheral neuropathy. Functional analyses have shown that these mutations produce a spectrum of pro-excitatory changes in channel biophysics, with the shared outcome at the cellular level of dorsal root ganglion hyperexcitability. Reduced neurite outgrowth may be another consequence of sodium channel mutations, and possible therapeutic strategies include blockade of sodium channels or block of reverse operation of the sodium-calcium exchanger. Increased understanding of the pathophysiology of painful peripheral neuropathy offers new targets that may provide a basis for more effective treatment.

  6. Bypass of genetic constraints during mutator evolution to antibiotic resistance

    PubMed Central

    Couce, Alejandro; Rodríguez-Rojas, Alexandro; Blázquez, Jesús

    2015-01-01

    Genetic constraints can block many mutational pathways to optimal genotypes in real fitness landscapes, yet the extent to which this can limit evolution remains to be determined. Interestingly, mutator bacteria elevate only specific types of mutations, and therefore could be very sensitive to genetic constraints. Testing this possibility is not only clinically relevant, but can also inform about the general impact of genetic constraints in adaptation. Here, we evolved 576 populations of two mutator and one wild-type Escherichia coli to doubling concentrations of the antibiotic cefotaxime. All strains carried TEM-1, a β-lactamase enzyme well known by its low availability of mutational pathways. Crucially, one of the mutators does not elevate any of the relevant first-step mutations known to improve cefatoximase activity. Despite this, both mutators displayed a similar ability to evolve more than 1000-fold resistance. Initial adaptation proceeded in parallel through general multi-drug resistance mechanisms. High-level resistance, in contrast, was achieved through divergent paths; with the a priori inferior mutator exploiting alternative mutational pathways in PBP3, the target of the antibiotic. These results have implications for mutator management in clinical infections and, more generally, illustrate that limits to natural selection in real organisms are alleviated by the existence of multiple loci contributing to fitness. PMID:25716795

  7. Pan-Cancer Analysis of Mutation Hotspots in Protein Domains.

    PubMed

    Miller, Martin L; Reznik, Ed; Gauthier, Nicholas P; Aksoy, Bülent Arman; Korkut, Anil; Gao, Jianjiong; Ciriello, Giovanni; Schultz, Nikolaus; Sander, Chris

    2015-09-23

    In cancer genomics, recurrence of mutations in independent tumor samples is a strong indicator of functional impact. However, rare functional mutations can escape detection by recurrence analysis owing to lack of statistical power. We enhance statistical power by extending the notion of recurrence of mutations from single genes to gene families that share homologous protein domains. Domain mutation analysis also sharpens the functional interpretation of the impact of mutations, as domains more succinctly embody function than entire genes. By mapping mutations in 22 different tumor types to equivalent positions in multiple sequence alignments of domains, we confirm well-known functional mutation hotspots, identify uncharacterized rare variants in one gene that are equivalent to well-characterized mutations in another gene, detect previously unknown mutation hotspots, and provide hypotheses about molecular mechanisms and downstream effects of domain mutations. With the rapid expansion of cancer genomics projects, protein domain hotspot analysis will likely provide many more leads linking mutations in proteins to the cancer phenotype. PMID:27135912

  8. Bypass of genetic constraints during mutator evolution to antibiotic resistance.

    PubMed

    Couce, Alejandro; Rodríguez-Rojas, Alexandro; Blázquez, Jesús

    2015-04-01

    Genetic constraints can block many mutational pathways to optimal genotypes in real fitness landscapes, yet the extent to which this can limit evolution remains to be determined. Interestingly, mutator bacteria elevate only specific types of mutations, and therefore could be very sensitive to genetic constraints. Testing this possibility is not only clinically relevant, but can also inform about the general impact of genetic constraints in adaptation. Here, we evolved 576 populations of two mutator and one wild-type Escherichia coli to doubling concentrations of the antibiotic cefotaxime. All strains carried TEM-1, a β-lactamase enzyme well known by its low availability of mutational pathways. Crucially, one of the mutators does not elevate any of the relevant first-step mutations known to improve cefatoximase activity. Despite this, both mutators displayed a similar ability to evolve more than 1000-fold resistance. Initial adaptation proceeded in parallel through general multi-drug resistance mechanisms. High-level resistance, in contrast, was achieved through divergent paths; with the a priori inferior mutator exploiting alternative mutational pathways in PBP3, the target of the antibiotic. These results have implications for mutator management in clinical infections and, more generally, illustrate that limits to natural selection in real organisms are alleviated by the existence of multiple loci contributing to fitness.

  9. Mutated tumor alleles are expressed according to their DNA frequency.

    PubMed

    Castle, John C; Loewer, Martin; Boegel, Sebastian; Tadmor, Arbel D; Boisguerin, Valesca; de Graaf, Jos; Paret, Claudia; Diken, Mustafa; Kreiter, Sebastian; Türeci, Özlem; Sahin, Ugur

    2014-04-22

    The transcription of tumor mutations from DNA into RNA has implications for biology, epigenetics and clinical practice. It is not clear if mutations are in general transcribed and, if so, at what proportion to the wild-type allele. Here, we examined the correlation between DNA mutation allele frequency and RNA mutation allele frequency. We sequenced the exome and transcriptome of tumor cell lines with large copy number variations, identified heterozygous single nucleotide mutations and absolute DNA copy number, and determined the corresponding DNA and RNA mutation allele fraction. We found that 99% of the DNA mutations in expressed genes are expressed as RNA. Moreover, we found a high correlation between the DNA and RNA mutation allele frequency. Exceptions are mutations that cause premature termination codons and therefore activate nonsense-mediated decay. Beyond this, we did not find evidence of any wide-scale mechanism, such as allele-specific epigenetic silencing, preferentially promoting mutated or wild-type alleles. In conclusion, our data strongly suggest that genes are equally transcribed from all alleles, mutated and wild-type, and thus transcribed in proportion to their DNA allele frequency.

  10. Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype.

    PubMed

    Tatton-Brown, Katrina; Murray, Anne; Hanks, Sandra; Douglas, Jenny; Armstrong, Ruth; Banka, Siddharth; Bird, Lynne M; Clericuzio, Carol L; Cormier-Daire, Valerie; Cushing, Tom; Flinter, Frances; Jacquemont, Marie-Line; Joss, Shelagh; Kinning, Esther; Lynch, Sally Ann; Magee, Alex; McConnell, Vivienne; Medeira, Ana; Ozono, Keiichi; Patton, Michael; Rankin, Julia; Shears, Debbie; Simon, Marleen; Splitt, Miranda; Strenger, Volker; Stuurman, Kyra; Taylor, Clare; Titheradge, Hannah; Van Maldergem, Lionel; Temple, I Karen; Cole, Trevor; Seal, Sheila; Rahman, Nazneen

    2013-12-01

    Weaver syndrome, first described in 1974, is characterized by tall stature, a typical facial appearance, and variable intellectual disability. In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome. To date, we have identified 48 individuals with EZH2 mutations. The mutations were primarily missense mutations occurring throughout the gene, with some clustering in the SET domain (12/48). Truncating mutations were uncommon (4/48) and only identified in the final exon, after the SET domain. Through analyses of clinical data and facial photographs of EZH2 mutation-positive individuals, we have shown that the facial features can be subtle and the clinical diagnosis of Weaver syndrome is thus challenging, especially in older individuals. However, tall stature is very common, reported in >90% of affected individuals. Intellectual disability is also common, present in ~80%, but is highly variable and frequently mild. Additional clinical features which may help in stratifying individuals to EZH2 mutation testing include camptodactyly, soft, doughy skin, umbilical hernia, and a low, hoarse cry. Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes. As mutation testing becomes increasingly accessible and larger numbers of EZH2 mutation-positive individuals are identified, knowledge of the clinical spectrum and prognostic implications of EZH2 mutations should improve.

  11. Mutation analysis of 28 gaucher disease patients: The Australasian experience

    SciTech Connect

    Lewis, B.D.; Nelson, P.V.; Robertson, E.F.; Morris, C.P.

    1994-01-15

    Gaucher disease is the most common lysomal storage disease. It is an autosomal recessive disorder that results from a deficiency of {beta}-glucocerrebrosidase. Three clinical phenotypes have been described: non-neuronopathic, acute neuronopathic, and subacuteneuronopathic. Genomic DNA from 28 Australasian patients of diverse ethnic origin with Gaucher disease was screened for 3 common mutations (1226G, 1448C and 84GG) using the amplification refractory mutation system (ARMS), and one uncommon mutation (1504T) by restriction enzyme digestion. Thirty-eight of the 56 independent alleles in these patients were characterized, with 1448C present in 42% and 1226G in 28% of the alleles. The 1226G mutation was associated only with the nonneuronopathic phenotype and 7 of the 15 patients who carried the 1448C mutation developed neuronopathic disease. Three infants who died in the neonatal period following a rapidly progressive neurodegenerative course carried no identifiable mutations. The 84GG mutation was carried by 2 Jewish patients and 1504T was present in one patient. It is now possible to rapidly identify the common Gaucher mutations using ARMS and restriction enzyme digestion, and our findings confirm the heterogeneity of mutations in Gaucher disease. It is also possible to predict in part the phenotypic outcome when screening patients for these mutations. The authors consider mutation analysis to be of most use in prenatal diagnosis and for carrier detection within affected families. 27 refs., 2 figs., 2 tabs.

  12. Mitochondrial Mutations in Adenoid Cystic Carcinoma of the Salivary Glands

    PubMed Central

    Tan, Marietta; Smith, Ian M.; Califano, Joseph A.; El-Naggar, Adel K.; Ha, Patrick K.

    2009-01-01

    Background The MitoChip v2.0 resequencing array is an array-based technique allowing for accurate and complete sequencing of the mitochondrial genome. No studies have investigated mitochondrial mutation in salivary gland adenoid cystic carcinomas. Methodology The entire mitochondrial genome of 22 salivary gland adenoid cystic carcinomas (ACC) of salivary glands and matched leukocyte DNA was sequenced to determine the frequency and distribution of mitochondrial mutations in ACC tumors. Principal Findings Seventeen of 22 ACCs (77%) carried mitochondrial mutations, ranging in number from 1 to 37 mutations. A disproportionate number of mutations occurred in the D-loop. Twelve of 17 tumors (70.6%) carried mutations resulting in amino acid changes of translated proteins. Nine of 17 tumors (52.9%) with a mutation carried an amino acid changing mutation in the nicotinamide adenine dinucleotide dehydrogenase (NADH) complex. Conclusions/Significance Mitochondrial mutation is frequent in salivary ACCs. The high incidence of amino acid changing mutations implicates alterations in aerobic respiration in ACC carcinogenesis. D-loop mutations are of unclear significance, but may be associated with alterations in transcription or replication. PMID:20041111

  13. Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype.

    PubMed

    Tatton-Brown, Katrina; Murray, Anne; Hanks, Sandra; Douglas, Jenny; Armstrong, Ruth; Banka, Siddharth; Bird, Lynne M; Clericuzio, Carol L; Cormier-Daire, Valerie; Cushing, Tom; Flinter, Frances; Jacquemont, Marie-Line; Joss, Shelagh; Kinning, Esther; Lynch, Sally Ann; Magee, Alex; McConnell, Vivienne; Medeira, Ana; Ozono, Keiichi; Patton, Michael; Rankin, Julia; Shears, Debbie; Simon, Marleen; Splitt, Miranda; Strenger, Volker; Stuurman, Kyra; Taylor, Clare; Titheradge, Hannah; Van Maldergem, Lionel; Temple, I Karen; Cole, Trevor; Seal, Sheila; Rahman, Nazneen

    2013-12-01

    Weaver syndrome, first described in 1974, is characterized by tall stature, a typical facial appearance, and variable intellectual disability. In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome. To date, we have identified 48 individuals with EZH2 mutations. The mutations were primarily missense mutations occurring throughout the gene, with some clustering in the SET domain (12/48). Truncating mutations were uncommon (4/48) and only identified in the final exon, after the SET domain. Through analyses of clinical data and facial photographs of EZH2 mutation-positive individuals, we have shown that the facial features can be subtle and the clinical diagnosis of Weaver syndrome is thus challenging, especially in older individuals. However, tall stature is very common, reported in >90% of affected individuals. Intellectual disability is also common, present in ~80%, but is highly variable and frequently mild. Additional clinical features which may help in stratifying individuals to EZH2 mutation testing include camptodactyly, soft, doughy skin, umbilical hernia, and a low, hoarse cry. Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes. As mutation testing becomes increasingly accessible and larger numbers of EZH2 mutation-positive individuals are identified, knowledge of the clinical spectrum and prognostic implications of EZH2 mutations should improve. PMID:24214728

  14. Mutation Update and Review of Severe Methylenetetrahydrofolate Reductase Deficiency.

    PubMed

    Froese, D Sean; Huemer, Martina; Suormala, Terttu; Burda, Patricie; Coelho, David; Guéant, Jean-Louis; Landolt, Markus A; Kožich, Viktor; Fowler, Brian; Baumgartner, Matthias R

    2016-05-01

    Severe 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency is caused by mutations in the MTHFR gene and results in hyperhomocysteinemia and varying severity of disease, ranging from neonatal lethal to adult onset. Including those described here, 109 MTHFR mutations have been reported in 171 families, consisting of 70 missense mutations, 17 that primarily affect splicing, 11 nonsense mutations, seven small deletions, two no-stop mutations, one small duplication, and one large duplication. Only 36% of mutations recur in unrelated families, indicating that most are "private." The most common mutation is c.1530A>G (numbered from NM_005957.4, p.Lys510 = ) causing a splicing defect, found in 13 families; the most common missense mutation is c.1129C>T (p.Arg377Cys) identified in 10 families. To increase disease understanding, we report enzymatic activity, detected mutations, and clinical onset information (early, <1 year; or late, >1 year) for all published patients available, demonstrating that patients with early onset have less residual enzyme activity than those presenting later. We also review animal models, diagnostic approaches, clinical presentations, and treatment options. This is the first large review of mutations in MTHFR, highlighting the wide spectrum of disease-causing mutations. PMID:26872964

  15. Screening of sarcomere gene mutations in young athletes with abnormal findings in electrocardiography: identification of a MYH7 mutation and MYBPC3 mutations.

    PubMed

    Kadota, Chika; Arimura, Takuro; Hayashi, Takeharu; Naruse, Taeko K; Kawai, Sachio; Kimura, Akinori

    2015-10-01

    There is an overlap between the physiological cardiac remodeling associated with training in athletes, the so-called athlete's heart, and mild forms of hypertrophic cardiomyopathy (HCM), the most common hereditary cardiac disease. HCM is often accompanied by unfavorable outcomes including a sudden cardiac death in the adolescents. Because one of the initial signs of HCM is abnormality in electrocardiogram (ECG), athletes may need to monitor for ECG findings to prevent any unfavorable outcomes. HCM is caused by mutations in genes for sarcomere proteins, but there is no report on the systematic screening of gene mutations in athletes. One hundred and two genetically unrelated young Japanese athletes with abnormal ECG findings were the subjects for the analysis of four sarcomere genes, MYH7, MYBPC3, TNNT2 and TNNI3. We found that 5 out of 102 (4.9%) athletes carried mutations: a heterozygous MYH7 Glu935Lys mutation, a heterozygous MYBPC3 Arg160Trp mutation and another heterozygous MYBPC3 Thr1046Met mutation, all of which had been reported as HCM-associated mutations, in 1, 2 and 2 subjects, respectively. This is the first study of systematic screening of sarcomere gene mutations in a cohort of athletes with abnormal ECG, demonstrating the presence of sarcomere gene mutations in the athlete's heart.

  16. Costs and benefits of mutational robustness in RNA viruses.

    PubMed

    Stern, Adi; Bianco, Simone; Yeh, Ming Te; Wright, Caroline; Butcher, Kristin; Tang, Chao; Nielsen, Rasmus; Andino, Raul

    2014-08-21

    The accumulation of mutations in RNA viruses is thought to facilitate rapid adaptation to changes in the environment. However, most mutations have deleterious effects on fitness, especially for viruses. Thus, tolerance to mutations should determine the nature and extent of genetic diversity that can be maintained in the population. Here, we combine population genetics theory, computer simulation, and experimental evolution to examine the advantages and disadvantages of tolerance to mutations, also known as mutational robustness. We find that mutational robustness increases neutral diversity and, as expected, can facilitate adaptation to a new environment. Surprisingly, under certain conditions, robustness may also be an impediment for viral adaptation, if a highly diverse population contains a large proportion of previously neutral mutations that are deleterious in the new environment. These findings may inform therapeutic strategies that cause extinction of otherwise robust viral populations.

  17. Rare nonconservative LRP6 mutations are associated with metabolic syndrome.

    PubMed

    Singh, Rajvir; Smith, Emily; Fathzadeh, Mohsen; Liu, Wenzhong; Go, Gwang-Woong; Subrahmanyan, Lakshman; Faramarzi, Saeed; McKenna, William; Mani, Arya

    2013-09-01

    A rare mutation in LRP6 has been shown to underlie autosomal dominant coronary artery disease (CAD) and metabolic syndrome in an Iranian kindred. The prevalence and spectrum of LRP6 mutations in the disease population of the United States is not known. Two hundred white Americans with early onset familial CAD and metabolic syndrome and 2,000 healthy Northern European controls were screened for nonconservative mutations in LRP6. Three novel mutations were identified, which cosegregated with the metabolic traits in the kindreds of the affected subjects and none in the controls. All three mutations reside in the second propeller domain, which plays a critical role in ligand binding. Two of the mutations substituted highly conserved arginines in the second YWTD domain and the third substituted a conserved glycosylation site. The functional characterization of one of the variants showed that it impairs Wnt signaling and acts as a loss of function mutation.

  18. Hepatitis C virus induces a mutator phenotype: enhanced mutations of immunoglobulin and protooncogenes.

    PubMed

    Machida, Keigo; Cheng, Kevin T-N; Sung, Vicky M-H; Shimodaira, Shigetaka; Lindsay, Karen L; Levine, Alexandra M; Lai, Ming-Yang; Lai, Michael M C

    2004-03-23

    Hepatitis C virus (HCV) is a nonretroviral oncogenic RNA virus, which is frequently associated with hepatocellular carcinoma (HCC) and B cell lymphoma. We demonstrated here that acute and chronic HCV infection caused a 5- to 10-fold increase in mutation frequency in Ig heavy chain, BCL-6, p53, and beta-catenin genes of in vitro HCV-infected B cell lines and HCV-associated peripheral blood mononuclear cells, lymphomas, and HCCs. The nucleotide-substitution pattern of p53 and beta-catenin was different from that of Ig heavy chain in HCV-infected cells, suggesting two different mechanisms of mutation. In addition, the mutated protooncogenes were amplified in HCV-associated lymphomas and HCCs, but not in lymphomas of nonviral origin or HBV-associated HCC. HCV induced error-prone DNA polymerase zeta, polymerase iota, and activation-induced cytidine deaminase, which together, contributed to the enhancement of mutation frequency, as demonstrated by the RNA interference experiments. These results indicate that HCV induces a mutator phenotype and may transform cells by a hit-and-run mechanism. This finding provides a mechanism of oncogenesis for an RNA virus.

  19. Novel IFT122 mutations in three Argentinian patients with cranioectodermal dysplasia: Expanding the mutational spectrum.

    PubMed

    Moosa, Shahida; Obregon, Maria Gabriela; Altmüller, Janine; Thiele, Holger; Nürnberg, Peter; Fano, Virginia; Wollnik, Bernd

    2016-05-01

    Cranioectodermal dysplasia (CED), also known as Sensenbrenner syndrome, is an autosomal recessive ciliary chondrodysplasia characterized by a recognizable craniofacial gestalt, skeletal abnormalities, and ectodermal features. To date, four genes have been shown to underlie the syndrome, namely, IFT122 (WDR10), WDR35 (IFT121), IFT43 (C14orf179), and WDR19 (IFT144). Clinical characterization of a larger cohort of patients with CED has been undertaken previously. Nevertheless, there are too few molecularly confirmed patients reported in the literature to determine precise genotype-phenotype correlations. To date, biallelic IFT122 mutations have been described in only five families. We therefore studied three unrelated Argentinian patients with typical features of CED using a 4813 next-generation sequencing (NGS) gene panel, which we call the "Mendeliome." The three patients had different, novel, compound heterozygous mutations in IFT122. Consequently, we compared these three patients to those previously described with IFT122 mutations. Thus, our report serves to add 6 novel mutations to the IFT122 mutation spectrum and to contribute to the IFT122-related clinical characterization. PMID:26792575

  20. Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer.

    PubMed

    Fujimoto, Akihiro; Furuta, Mayuko; Totoki, Yasushi; Tsunoda, Tatsuhiko; Kato, Mamoru; Shiraishi, Yuichi; Tanaka, Hiroko; Taniguchi, Hiroaki; Kawakami, Yoshiiku; Ueno, Masaki; Gotoh, Kunihito; Ariizumi, Shun-Ichi; Wardell, Christopher P; Hayami, Shinya; Nakamura, Toru; Aikata, Hiroshi; Arihiro, Koji; Boroevich, Keith A; Abe, Tetsuo; Nakano, Kaoru; Maejima, Kazuhiro; Sasaki-Oku, Aya; Ohsawa, Ayako; Shibuya, Tetsuo; Nakamura, Hiromi; Hama, Natsuko; Hosoda, Fumie; Arai, Yasuhito; Ohashi, Shoko; Urushidate, Tomoko; Nagae, Genta; Yamamoto, Shogo; Ueda, Hiroki; Tatsuno, Kenji; Ojima, Hidenori; Hiraoka, Nobuyoshi; Okusaka, Takuji; Kubo, Michiaki; Marubashi, Shigeru; Yamada, Terumasa; Hirano, Satoshi; Yamamoto, Masakazu; Ohdan, Hideki; Shimada, Kazuaki; Ishikawa, Osamu; Yamaue, Hiroki; Chayama, Kazuki; Miyano, Satoru; Aburatani, Hiroyuki; Shibata, Tatsuhiro; Nakagawa, Hidewaki

    2016-05-01

    Liver cancer, which is most often associated with virus infection, is prevalent worldwide, and its underlying etiology and genomic structure are heterogeneous. Here we provide a whole-genome landscape of somatic alterations in 300 liver cancers from Japanese individuals. Our comprehensive analysis identified point mutations, structural variations (STVs), and virus integrations, in noncoding and coding regions. We discovered mutational signatures related to liver carcinogenesis and recurrently mutated coding and noncoding regions, such as long intergenic noncoding RNA genes (NEAT1 and MALAT1), promoters, CTCF-binding sites, and regulatory regions. STV analysis found a significant association with replication timing and identified known (CDKN2A, CCND1, APC, and TERT) and new (ASH1L, NCOR1, and MACROD2) cancer-related genes that were recurrently affected by STVs, leading to altered expression. These results emphasize the value of whole-genome sequencing analysis in discovering cancer driver mutations and understanding comprehensive molecular profiles of liver cancer, especially with regard to STVs and noncoding mutations. PMID:27064257

  1. RAS Mutations and Oncogenesis: Not all RAS Mutations are Created Equally

    PubMed Central

    Miller, Mark Steven; Miller, Lance D.

    2012-01-01

    Mutation in RAS proteins is one of the most common genetic alterations observed in human and experimentally induced rodent cancers. In vivo, oncogenic mutations have been shown to occur at exons 12, 13, and 61, resulting in any 1 of 19 possible point mutations in a given tumor for a specific RAS isoform. While some studies have suggested a possible role of different mutant alleles in determining tumor severity and phenotype, no general consensus has emerged on the oncogenicity of different mutant alleles in tumor formation and progression. Part of this may be due to a lack of a single, signature pathway that shows significant alterations between different mutations. Rather, it is likely that subtle differences in the activation, or lack thereof, of downstream effectors by different RAS mutant alleles may determine the eventual outcome in terms of tumor phenotype. This paper reviews our current understanding of the potential role of different RAS mutations on tumorigenesis, highlights studies in model cell culture and in vivo systems, and discusses the potential of expression array and computational network modeling to dissect out differences in activated RAS genes in conferring a transforming phenotype. PMID:22303394

  2. Characteristics of Frontotemporal Dementia Patients with a Progranulin Mutation

    PubMed Central

    Huey, Edward D.; Grafman, Jordan; Wassermann, Eric M.; Pietrini, Pietro; Tierney, Michael C.; Ghetti, Bernardino; Spina, Salvatore; Baker, Matt; Hutton, Mike; Elder, Joshua W.; Berger, Stephen L.; Heflin, Kyle A.; Hardy, John; Momeni, Parastoo

    2010-01-01

    Objective Mutations in the Progranulin gene (PGRN) recently have been discovered to be associated with frontotemporal dementia (FTD) linked to 17q21 without identified MAPT mutations. The range of mutations of PGRN that can result in the FTD phenotype and the clinical presentation of patients with PGRN mutations have yet to be determined. Methods In this study, we examined 84 FTD patients from families not known previously to have illness linked to chromosome 17 for identified PGRN and MAPT mutations and sequenced the coding exons and the flanking intronic regions of PGRN. We compared the prevalence, clinical characteristics, magnetic resonance imaging and 18-fluoro-deoxyglucose positron emission tomography results, and neuropsychological testing of patients with the PGRN R493X mutation with those patients without identified PGRN mutations. Results We discovered a new PGRN mutation (R493X) resulting in a stop codon in two patients. This was the only PGRN mutation identified in our sample. The patients with the PGRN R493X mutation had a rapid illness course and had predominant right-sided atrophy and hypometabolism on magnetic resonance imaging and 18-fluoro-deoxyglucose positron emission tomography. The affected father of one of the patients with the PGRN R493X mutation showed frontal and temporal atrophy without neurofibrillary tangles on neuropathological examination. Interpretation Known PGRN and MAPT mutations were rare and of similar prevalence in our sample (2 compared with 1/84). The patients with the PGRN R493X mutation had a clinical presentation comparable with other behavior-predominant FTD patients. The neuropathology of an affected family member of a patient with the PGRN R493X mutation appears not to be Alzheimer’s disease. PMID:16983677

  3. Distinct clinical characteristics of myeloproliferative neoplasms with calreticulin mutations

    PubMed Central

    Andrikovics, Hajnalka; Krahling, Tunde; Balassa, Katalin; Halm, Gabriella; Bors, Andras; Koszarska, Magdalena; Batai, Arpad; Dolgos, Janos; Csomor, Judit; Egyed, Miklos; Sipos, Andrea; Remenyi, Peter; Tordai, Attila; Masszi, Tamas

    2014-01-01

    Somatic insertions/deletions in the calreticulin gene have recently been discovered to be causative alterations in myeloproliferative neoplasms. A combination of qualitative and quantitative allele-specific polymerase chain reaction, fragment-sizing, high resolution melting and Sanger-sequencing was applied for the detection of three driver mutations (in Janus kinase 2, calreticulin and myeloproliferative leukemia virus oncogene genes) in 289 cases of essential thrombocythemia and 99 cases of primary myelofibrosis. In essential thrombocythemia, 154 (53%) Janus kinase 2 V617F, 96 (33%) calreticulin, 9 (3%) myeloproliferative leukemia virus oncogene gene mutation-positive and 30 triple-negative (11%) cases were identified, while in primary myelofibrosis 56 (57%) Janus kinase 2 V617F, 25 (25%) calreticulin, 7 (7%) myeloproliferative leukemia virus oncogene gene mutation-positive and 11 (11%) triple-negative cases were identified. Patients positive for the calreticulin mutation were younger and had higher platelet counts compared to Janus kinase 2 mutation-positive counterparts. Calreticulin mutation-positive patients with essential thrombocythemia showed a lower risk of developing venous thrombosis, but no difference in overall survival. Calreticulin mutation-positive patients with primary myelofibrosis had a better overall survival compared to that of the Janus kinase 2 mutation-positive (P=0.04) or triple-negative cases (P=0.01). Type 2 calreticulin mutation occurred more frequently in essential thrombocythemia than in primary myelofibrosis (P=0.049). In essential thrombocythemia, the calreticulin mutational load was higher than the Janus kinase 2 mutational load (P<0.001), and increased gradually in advanced stages. Calreticulin mutational load influenced blood counts even at the time point of diagnosis in essential thrombocythemia. We confirm that calreticulin mutation is associated with distinct clinical characteristics and explored relationships between mutation

  4. Differential Persistence of Transmitted HIV-1 Drug Resistance Mutation Classes

    PubMed Central

    Jain, Vivek; Sucupira, Maria C.; Bacchetti, Peter; Hartogensis, Wendy; Diaz, Ricardo S.; Kallas, Esper G.; Janini, Luiz M.; Liegler, Teri; Pilcher, Christopher D.; Grant, Robert M.; Cortes, Rodrigo; Deeks, Steven G.

    2011-01-01

    Background. Transmitted human immunodeficiency virus type 1 (HIV-1) drug resistance (TDR) mutations can become replaced over time by emerging wild-type viral variants with improved fitness. The impact of class-specific mutations on this rate of mutation replacement is uncertain. Methods. We studied participants with acute and/or early HIV infection and TDR in 2 cohorts (San Francisco, California, and São Paulo, Brazil). We followed baseline mutations longitudinally and compared replacement rates between mutation classes with use of a parametric proportional hazards model. Results. Among 75 individuals with 195 TDR mutations, M184V/I became undetectable markedly faster than did nonnucleoside reverse-transcriptase inhibitor (NNRTI) mutations (hazard ratio, 77.5; 95% confidence interval [CI], 14.7–408.2; P < .0001), while protease inhibitor and NNRTI replacement rates were similar. Higher plasma HIV-1 RNA level predicted faster mutation replacement, but this was not statistically significant (hazard ratio, 1.71 log10 copies/mL; 95% CI, .90–3.25 log10 copies/mL; P = .11). We found substantial person-to-person variability in mutation replacement rates not accounted for by viral load or mutation class (P < .0001). Conclusions. The rapid replacement of M184V/I mutations is consistent with known fitness costs. The long-term persistence of NNRTI and protease inhibitor mutations suggests a risk for person-to-person propagation. Host and/or viral factors not accounted for by viral load or mutation class are likely influencing mutation replacement and warrant further study. PMID:21451005

  5. Etudes physiques des mélanges eau-cryoprotecteurs

    NASA Astrophysics Data System (ADS)

    Vassoille, R.; Perez, J.

    The aim of the following review is to present the most important studies concerning the physical properties of water-solutes mixtures used in cryobiology. Cryobiology is a branch of biology which deals with the very low temperature behaviour of cells. This technique is developed today in several directions. The creation of banks of cells and perhaps in a short time of small organs, is the purpose of much research in this domain. Before freezing, living cells are generally put in a solution containing one or more solutes. The role of these solutes is to protect the cells against damage due to crystallization of water (cryoprotectors). The mechanisms of cryoprotection are not well known ; nevertheless the vitreous state formation during cooling is often invoked. So, it is possible to avoid crystallization damage such as mechanical strain (due to an increase of volume of about 10 %) and salt effects (due to osmotic pressure). The conditions in which the vitreous state is obtained, maintained during cooling, storage at low temperature and rewarming can be defined by physical studies presented in the following review. Le présent travail est essentiellement une revue bibliographique des principales études physiques qui ont été réalisées avec des solutions de composés habituellement employés en cryobiologie. La cryobiologie est une branche de la biologie qui s'intéresse au comportement des cellules à basse température. Cette discipline est actuellement en plein développement dans des domaines très divers. Son principal but est la création de banques de cellules de plus en plus complexes avec comme perspective la conservation des organes. Les cellules vivantes sont généralement placées avant congélation dans une solution contenant divers composés dont le rôle est de protéger les cellules contre les effets de la cristallisation de l'eau. L'action protectrice de ces cryoprotecteurs est encore mal connue; cependant, la formation d'un état vitreux lors du

  6. Superfund Record of Decision (EPA Region 7): Des Moines TCE Site, Operable Unit 3, Des Moines, IA. (Second remedial action), September 1992. Final report

    SciTech Connect

    Not Available

    1992-09-18

    The Des Moines TCE site is located southwest of downtown Des Moines, Polk County, Iowa. Land use in the area is predominantly industrial and commercial, and part of the site lies within the floodplain of the Raccoon River. Water from the Des Moines Water Works north infiltration gallery was found to be contaminated with trichloroethylene (TCE), dichloroethylene (DCE), and vinyl chloride at levels above accepted drinking water standards. The ROD addresses OU3, which encompasses potential sources of ground water contamination in an area north of the Raccoon River. The selected remedial action for OU3 includes no action with periodic groundwater monitoring.

  7. Profil épidemio-clinique et radiologique des atteintes ostéo-articulaires des hémophiles à Madagascar

    PubMed Central

    Narindra, Lova Hasina Rajaonarison Ny Ony; Rabemanorintsoa, Feno Hasina; Randrianantenaina, Faralahy Ravelonarivo; Rakoto, Olivat Alson Aimée; Ahmad, Ahmad

    2014-01-01

    Introduction Déterminer le profil épidémio-clinique et radiologique des atteintes ostéo-articulaires des hémophiles malagasy. Méthodes Une étude prospective, descriptive portant sur 25 patients hémophiles venant de tout Madagascar a été réalisée. Des radiographies numérisées des genoux, des chevilles et des coudes en incidence de face et de profil ainsi qu'une échographie des hanches, des genoux, des chevilles et des coudes ont été réalisées chez ces patients. Le type et la sévérité de la maladie ainsi que l'aspect de la cavité articulaire, la synoviale, les noyaux épiphysaires et les surfaces articulaires ont été analysés. Résultats Soixante-huit pourcent des patients étaient hémophiles de type A et 32 % de type B. Quarante pourcent étaient classés sévères, 28 % modérés et 32 % mineurs. Les atteintes ostéo-articulaires ont été retrouvées chez 56 % des patients. Il n'existait pas de prédominance d'atteinte selon le type ni la sévérité de la maladie. Les plus jeunes étaient les plus atteints et l'articulation du genou et de la cheville étaient les plus touchées. Conclusion Les complications ostéo-articulaire de l'hémophilie sont graves et ne dépendent pas du type ni de la sévérité de l'affection. Elles touchent surtout les enfants d'âge scolaire. Le couple radiographie-échographie permet de diagnostiquer et de surveiller ces lésions. PMID:25870742

  8. A germ-line-selective advantage rather than an increased mutation rate can explain some unexpectedly common human disease mutations.

    PubMed

    Choi, Soo-Kyung; Yoon, Song-Ro; Calabrese, Peter; Arnheim, Norman

    2008-07-22

    Two nucleotide substitutions in the human FGFR2 gene (C755G or C758G) are responsible for virtually all sporadic cases of Apert syndrome. This condition is 100-1,000 times more common than genomic mutation frequency data predict. Here, we report on the C758G de novo Apert syndrome mutation. Using data on older donors, we show that spontaneous mutations are not uniformly distributed throughout normal testes. Instead, we find foci where C758G mutation frequencies are 3-4 orders of magnitude greater than the remaining tissue. We conclude this nucleotide site is not a mutation hot spot even after accounting for possible Luria-Delbruck "mutation jackpots." An alternative explanation for such foci involving positive selection acting on adult self-renewing Ap spermatogonia experiencing the rare mutation could not be rejected. Further, the two youngest individuals studied (19 and 23 years old) had lower mutation frequencies and smaller foci at both mutation sites compared with the older individuals. This implies that the mutation frequency of foci increases as adults age, and thus selection could explain the paternal age effect for Apert syndrome and other genetic conditions. Our results, now including the analysis of two mutations in the same set of testes, suggest that positive selection can increase the relative frequency of premeiotic germ cells carrying such mutations, although individuals who inherit them have reduced fitness. In addition, we compared the anatomical distribution of C758G mutation foci with both new and old data on the C755G mutation in the same testis and found their positions were not correlated with one another. PMID:18632557

  9. Clinical and Genetic Characterization of Manifesting Carriers of DMD Mutations

    PubMed Central

    Soltanzadeh, Payam; Friez, Michael J.; Dunn, Diane; von Niederhausern, Andrew; Gurvich, Olga L.; Swoboda, Kathryn J.; Sampson, Jacinda B.; Pestronk, Alan; Connolly, Anne M.; Florence, Julaine M.; Finkel, Richard S.; Bönnemann, Carsten G.; Medne, Livija; Mendell, Jerry R.; Mathews, Katherine D.; Wong, Brenda L.; Sussman, Michael D.; Zonana, Jonathan; Kovak, Karen; Gospe, Sidney M.; Gappmaier, Eduard; Taylor, Laura E.; Howard, Michael T.; Weiss, Robert B.; Flanigan, Kevin M.

    2010-01-01

    Manifesting carriers of DMD gene mutations may present diagnostic challenges, particularly in the absence of a family history of dystrophinopathy. We review the clinical and genetic features in fifteen manifesting carriers identified among 860 subjects within the United Dystrophinopathy Project, a large clinical dystrophinopathy cohort whose members undergo comprehensive DMD mutation analysis. We defined manifesting carriers as females with significant weakness, excluding those with only myalgias/cramps. DNA extracted from peripheral blood was used to study X chromosome inactivation patterns. Among these manifesting carriers, age at symptom onset ranged from 2 to 47 years. Seven had no family history and eight had male relatives with Duchene muscular dystrophy (DMD). Clinical severity among the manifesting carriers varied from a DMD-like progression to a very mild Becker muscular dystrophy-like phenotype. Eight had exonic deletions or duplications and six had point mutations. One patient had two mutations (an exonic deletion and a splice site mutation), consistent with a heterozygous compound state. The X chromosome inactivation pattern was skewed toward nonrandom in four out of seven informative deletions or duplications but was random in all cases with nonsense mutations. We present the results of DMD mutation analysis in this manifesting carrier cohort, including the first example of a presumably compound heterozygous DMD mutation. Our results demonstrate that improved molecular diagnostic methods facilitate the identification of DMD mutations in manifesting carriers, and confirm the heterogeneity of mutational mechanisms as well as the wide spectrum of phenotypes. PMID:20630757

  10. Phenylketonuria mutation analysis in Northern Ireland: A rapid stepwise approach

    SciTech Connect

    Zschocke, J.; Graham, C.A.; Nevin, N.C.

    1995-12-01

    We present a multistep approach for the rapid analysis of phenylketonuria (PKU) mutations. In the first step, three common mutations and a polymorphic short tandem repeat (STR) system are rapidly analyzed with a fluorescent multiplex assay. In the second step, minihaplotypes combining STR and VNTR data are used to determine rare mutations likely to be present in an investigated patient, which are then confirmed by restriction enzyme analysis. The remaining mutations are analyzed with denaturant gradient-gel electrophoresis and sequencing. The first two steps together identify both mutations in 90%-95% of PKU patients, and results can be obtained within 2 d. We have investigated 121 Northern Irish families with hyperphenylalaninemia, including virtually all patients born since 1972, and have found 34 different mutations on 241 of the 242 mutant alleles. Three mutations (R408W, 165T, and F39L) account for 57.5% of mutations, while 14 mutations occur with a frequency of 1%-6%. The present analysis system is efficient and inexpensive and is particularly well suited to routine mutation analysis in a diagnostic setting. 19 refs., 5 tabs.

  11. The Origin of Spontaneous Mutation in SACCHAROMYCES CEREVISIAE

    PubMed Central

    Quah, Siew-Keen; von Borstel, R. C.; Hastings, P. J.

    1980-01-01

    Characterization of two antimutator loci in yeast shows that both are members of the same mutagenic repair system known to be responsible for almost all induced mutation (Lawrence and Christensen 1976, 1979a,b; Prakash 1976). One of the these newly isolated antimutator mutations is an allele of rev3 (Lemontt 1971b). Two other alleles of rev3 were tested and were also found to be antimutators. Double mutants carrying rev3 and mutator mutations of rad3, rad51 or rad18 are like rev3 single mutants with respect to spontaneous mutation rate, supporting the hypothesis (Hastings, Quah and von Borstel 1976) that many mutators in yeast act by channelling spontaneous lesions from accurate to mutagenic repair. However, the enhanced mutation rate seen in a radiation-resistant mutator mutant mut1 is not dependent on REV3, but is dependent on another gene designated ANT1. An additive effect on the reduction in spontaneous mutation, seen in the ant1 rev3 double-mutant strain, leads to the conclusion that at least 90% of spontaneous mutations seen in the wild type are caused by mutagenic repair of spontaneous lesions. PMID:7021317

  12. CALR mutation profile in Irish patients with myeloproliferative neoplasms.

    PubMed

    Haslam, Karl; Conneally, Eibhlin; Flynn, Catherine M; Cahill, Mary R; Gilligan, Oonagh; O'Shea, Derville; Langabeer, Stephen E

    2016-09-01

    Insertion and/or deletion mutations of the CALR gene have recently been demonstrated to be the second most common driver mutations in the myeloproliferative neoplasms (MPNs) of essential thrombocythemia (ET) and primary myelofibrosis (PMF). Given the diagnostic and emerging prognostic significance of these mutations, in addition to the geographical heterogeneity reported, the incidence of CALR mutations was determined in an Irish cohort of patients with MPNs with a view to incorporate this analysis into a prospective screening program. A series of 202 patients with known or suspected ET and PMF were screened for the presence of CALR mutations. CALR mutations were detected in 58 patients. Type 1 and Type 1-like deletion mutations were the most common (n=40) followed by Type 2 and Type 2-like insertion mutations (n=17). The CALR mutation profile in Irish ET and PMF patients appears similar to that in other European populations. Establishment of this mutational profile allows the introduction of a rational, molecular diagnostic algorithm in cases of suspected ET and PMF that will improve clinical management. PMID:27352261

  13. The rich phase structure of a mutator model

    PubMed Central

    Saakian, David B.; Yakushkina, Tatiana; Hu, Chin-Kun

    2016-01-01

    We propose a modification of the Crow-Kimura and Eigen models of biological molecular evolution to include a mutator gene that causes both an increase in the mutation rate and a change in the fitness landscape. This mutator effect relates to a wide range of biomedical problems. There are three possible phases: mutator phase, mixed phase and non-selective phase. We calculate the phase structure, the mean fitness and the fraction of the mutator allele in the population, which can be applied to describe cancer development and RNA viruses. We find that depending on the genome length, either the normal or the mutator allele dominates in the mixed phase. We analytically solve the model for a general fitness function. We conclude that the random fitness landscape is an appropriate choice for describing the observed mutator phenomenon in the case of a small fraction of mutators. It is shown that the increase in the mutation rates in the regular and the mutator parts of the genome should be set independently; only some combinations of these increases can push the complex biomedical system to the non-selective phase, potentially related to the eradication of tumors. PMID:27721395

  14. Mutation Profile of Well-Differentiated Thyroid Cancer in Asians

    PubMed Central

    Song, Young Shin; Lim, Jung Ah

    2015-01-01

    Recent advances in molecular diagnostics have led to significant insights into the genetic basis of thyroid tumorigenesis. Among the mutations commonly seen in thyroid cancers, the vast majority are associated with the mitogen-activated protein kinase pathway. B-Raf proto-oncogene (BRAF) mutations are the most common mutations observed in papillary thyroid cancers (PTCs), followed by RET/PTC rearrangements and RAS mutations, while follicular thyroid cancers are more likely to harbor RAS mutations or PAX8/peroxisome proliferator-activated receptor γ (PPARγ) rearrangements. Beyond these more common mutations, alterations in the telomerase reverse transcriptase (TERT) promoter have recently been associated with clinicopathologic features, disease prognosis, and tumorigenesis in thyroid cancer. While the mutations underlying thyroid tumorigenesis are well known, the frequency of these mutations is strongly associated with geography, with clear differences reported between Asian and Western countries. Of particular interest is the prevalence of BRAF mutations, with Korean patients exhibiting the highest rate of BRAF-associated thyroid cancers in the world. Here, we review the prevalence of each of the most common mutations in Asian and Western countries, and identify the characteristics of well-differentiated thyroid cancer in Asians. PMID:26435130

  15. Genomic mutation rates that neutralize adaptive evolution and natural selection.

    PubMed

    Gerrish, Philip J; Colato, Alexandre; Sniegowski, Paul D

    2013-08-01

    When mutation rates are low, natural selection remains effective, and increasing the mutation rate can give rise to an increase in adaptation rate. When mutation rates are high to begin with, however, increasing the mutation rate may have a detrimental effect because of the overwhelming presence of deleterious mutations. Indeed, if mutation rates are high enough: (i) adaptive evolution may be neutralized, resulting in a zero (or negative) adaptation rate despite the continued availability of adaptive and/or compensatory mutations, or (ii) natural selection may be neutralized, because the fitness of lineages bearing adaptive and/or compensatory mutations--whether established or newly arising--is eroded by excessive mutation, causing such lineages to decline in frequency. We apply these two criteria to a standard model of asexual adaptive evolution and derive mathematical expressions--some new, some old in new guise--delineating the mutation rates under which either adaptive evolution or natural selection is neutralized. The expressions are simple and require no a priori knowledge of organism- and/or environment-specific parameters. Our discussion connects these results to each other and to previous theory, showing convergence or equivalence of the different results in most cases.

  16. Genomic mutation rates that neutralize adaptive evolution and natural selection.

    PubMed

    Gerrish, Philip J; Colato, Alexandre; Sniegowski, Paul D

    2013-08-01

    When mutation rates are low, natural selection remains effective, and increasing the mutation rate can give rise to an increase in adaptation rate. When mutation rates are high to begin with, however, increasing the mutation rate may have a detrimental effect because of the overwhelming presence of deleterious mutations. Indeed, if mutation rates are high enough: (i) adaptive evolution may be neutralized, resulting in a zero (or negative) adaptation rate despite the continued availability of adaptive and/or compensatory mutations, or (ii) natural selection may be neutralized, because the fitness of lineages bearing adaptive and/or compensatory mutations--whether established or newly arising--is eroded by excessive mutation, causing such lineages to decline in frequency. We apply these two criteria to a standard model of asexual adaptive evolution and derive mathematical expressions--some new, some old in new guise--delineating the mutation rates under which either adaptive evolution or natural selection is neutralized. The expressions are simple and require no a priori knowledge of organism- and/or environment-specific parameters. Our discussion connects these results to each other and to previous theory, showing convergence or equivalence of the different results in most cases. PMID:23720539

  17. Analysis of Dominant Mutations Affecting Muscle Excitation in Caenorhabditis Elegans

    PubMed Central

    Reiner, D. J.; Weinshenker, D.; Thomas, J. H.

    1995-01-01

    We examined mutations that disrupt muscle activation in Caenorhabditis elegans. Fifteen of 17 of these genes were identified previously and we describe new mutations in three of them. We also describe mutations in two new genes, exp-3 and exp-4. We assessed the degree of defect in pharyngeal, body-wall, egg-laying, and enteric muscle activation in animals mutant for each gene. Mutations in all 17 genes are semidominant and, in cases that could be tested, appear to be gain-of-function. Based on their phenotypes, the genes fall into three broad categories: mutations in 11 genes cause defective muscle activation, mutations in four genes cause hyperactivated muscle, and mutations in two genes cause defective activation in some muscle types and hyperactivation in others. In all testable cases, the mutations blocked response to pharmacological activators of egg laying, but did not block muscle activation by irradiation with a laser microbeam. The data suggest that these mutations affect muscle excitation, but not the capacity of the muscle fibers to contract. For most of the genes, apparent loss-of-function mutants have a grossly wild-type phenotype. These observations suggest that there is a large group of genes that function in muscle excitation that can be identified primarily by dominant mutations. PMID:8582640

  18. MoKCa database—mutations of kinases in cancer

    PubMed Central

    Richardson, Christopher J.; Gao, Qiong; Mitsopoulous, Costas; Zvelebil, Marketa; Pearl, Laurence H.; Pearl, Frances M. G.

    2009-01-01

    Members of the protein kinase family are amongst the most commonly mutated genes in human cancer, and both mutated and activated protein kinases have proved to be tractable targets for the development of new anticancer therapies The MoKCa database (Mutations of Kinases in Cancer, http://strubiol.icr.ac.uk/extra/mokca) has been developed to structurally and functionally annotate, and where possible predict, the phenotypic consequences of mutations in protein kinases implicated in cancer. Somatic mutation data from tumours and tumour cell lines have been mapped onto the crystal structures of the affected protein domains. Positions of the mutated amino-acids are highlighted on a sequence-based domain pictogram, as well as a 3D-image of the protein structure, and in a molecular graphics package, integrated for interactive viewing. The data associated with each mutation is presented in the Web interface, along with expert annotation of the detailed molecular functional implications of the mutation. Proteins are linked to functional annotation resources and are annotated with structural and functional features such as domains and phosphorylation sites. MoKCa aims to provide assessments available from multiple sources and algorithms for each potential cancer-associated mutation, and present these together in a consistent and coherent fashion to facilitate authoritative annotation by cancer biologists and structural biologists, directly involved in the generation and analysis of new mutational data. PMID:18986996

  19. Inference of directional selection and mutation parameters assuming equilibrium.

    PubMed

    Vogl, Claus; Bergman, Juraj

    2015-12-01

    In a classical study, Wright (1931) proposed a model for the evolution of a biallelic locus under the influence of mutation, directional selection and drift. He derived the equilibrium distribution of the allelic proportion conditional on the scaled mutation rate, the mutation bias and the scaled strength of directional selection. The equilibrium distribution can be used for inference of these parameters with genome-wide datasets of "site frequency spectra" (SFS). Assuming that the scaled mutation rate is low, Wright's model can be approximated by a boundary-mutation model, where mutations are introduced into the population exclusively from sites fixed for the preferred or unpreferred allelic states. With the boundary-mutation model, inference can be partitioned: (i) the shape of the SFS distribution within the polymorphic region is determined by random drift and directional selection, but not by the mutation parameters, such that inference of the selection parameter relies exclusively on the polymorphic sites in the SFS; (ii) the mutation parameters can be inferred from the amount of polymorphic and monomorphic preferred and unpreferred alleles, conditional on the selection parameter. Herein, we derive maximum likelihood estimators for the mutation and selection parameters in equilibrium and apply the method to simulated SFS data as well as empirical data from a Madagascar population of Drosophila simulans.

  20. Novel CDKN2A mutations in Austrian melanoma patients.

    PubMed

    Burgstaller-Muehlbacher, Sebastian; Marko, Martha; Müller, Christoph; Wendt, Judith; Pehamberger, Hubert; Okamoto, Ichiro

    2015-10-01

    CDKN2A is the most prominent familial melanoma gene, with mutations occurring in up to 40% of the families. Numerous mutations in the gene are known, several of them representing regional founder mutations. We sought to determine, for the first time, germline mutations in CDKN2A in Austria to identify novel mutations. In total, 700 individuals (136 patients with a positive family history and 164 with at least two primary melanomas as the high-risk groups; 200 with single primary melanomas; and 200 healthy individuals as the control groups) were Sanger sequenced for CDKN2A exon 1α, 1β, and 2. The 136 patients with affected relatives were also sequenced for CDK4 exon 2. We found the disease-associated mutations p.R24P (8×), p.N71T (1×), p.G101W (1×), and p.V126D (1×) in the group with affected relatives and p.R24P (2×) in the group with several primary melanomas. Furthermore, we discovered four mutations of unknown significance, two of which were novel: p.A34V and c.151-4 G>C, respectively. Computational effect prediction suggested p.A34V as conferring a high risk for melanoma, whereas c.151-4 G>C, although being predicted as a splice site mutation by MutationTaster, could not functionally be confirmed to alter splicing. Moreover, computational effect prediction confirmed accumulation of high-penetrance mutations in high-risk groups, whereas mutations of unknown significance were distributed across all groups. p.R24P is the most common high-risk mutation in Austria. In addition, we discovered two new mutations in Austrian melanoma patients, p.A34V and c.151-4 G>C, respectively.

  1. Novel CDKN2A mutations in Austrian melanoma patients.

    PubMed

    Burgstaller-Muehlbacher, Sebastian; Marko, Martha; Müller, Christoph; Wendt, Judith; Pehamberger, Hubert; Okamoto, Ichiro

    2015-10-01

    CDKN2A is the most prominent familial melanoma gene, with mutations occurring in up to 40% of the families. Numerous mutations in the gene are known, several of them representing regional founder mutations. We sought to determine, for the first time, germline mutations in CDKN2A in Austria to identify novel mutations. In total, 700 individuals (136 patients with a positive family history and 164 with at least two primary melanomas as the high-risk groups; 200 with single primary melanomas; and 200 healthy individuals as the control groups) were Sanger sequenced for CDKN2A exon 1α, 1β, and 2. The 136 patients with affected relatives were also sequenced for CDK4 exon 2. We found the disease-associated mutations p.R24P (8×), p.N71T (1×), p.G101W (1×), and p.V126D (1×) in the group with affected relatives and p.R24P (2×) in the group with several primary melanomas. Furthermore, we discovered four mutations of unknown significance, two of which were novel: p.A34V and c.151-4 G>C, respectively. Computational effect prediction suggested p.A34V as conferring a high risk for melanoma, whereas c.151-4 G>C, although being predicted as a splice site mutation by MutationTaster, could not functionally be confirmed to alter splicing. Moreover, computational effect prediction confirmed accumulation of high-penetrance mutations in high-risk groups, whereas mutations of unknown significance were distributed across all groups. p.R24P is the most common high-risk mutation in Austria. In addition, we discovered two new mutations in Austrian melanoma patients, p.A34V and c.151-4 G>C, respectively. PMID:26225579

  2. Parkinson disease (PARK) genes are somatically mutated in cutaneous melanoma

    PubMed Central

    Samuels, Yardena; Azizi, Esther; Qutob, Nouar; Inzelberg, Lilah; Domany, Eytan; Schechtman, Edna; Friedman, Eitan

    2016-01-01

    Objective: To assess whether Parkinson disease (PD) genes are somatically mutated in cutaneous melanoma (CM) tissue, because CM occurs in patients with PD at higher rates than in the general population and PD is more common than expected in CM cohorts. Methods: We cross-referenced somatic mutations in metastatic CM detected by whole-exome sequencing with the 15 known PD (PARK) genes. We computed the empirical distribution of the sum of mutations in each gene (Smut) and of the number of tissue samples in which a given gene was mutated at least once (SSampl) for each of the analyzable genes, determined the 90th and 95th percentiles of the empirical distributions of these sums, and verified the location of PARK genes in these distributions. Identical analyses were applied to adenocarcinoma of lung (ADENOCA-LUNG) and squamous cell carcinoma of lung (SQUAMCA-LUNG). We also analyzed the distribution of the number of mutated PARK genes in CM samples vs the 2 lung cancers. Results: Somatic CM mutation analysis (n = 246) detected 315,914 mutations in 18,758 genes. Somatic CM mutations were found in 14 of 15 PARK genes. Forty-eight percent of CM samples carried ≥1 PARK mutation and 25% carried multiple PARK mutations. PARK8 mutations occurred above the 95th percentile of the empirical distribution for SMut and SSampl. Significantly more CM samples harbored multiple PARK gene mutations compared with SQUAMCA-LUNG (p = 0.0026) and with ADENOCA-LUNG (p < 0.0001). Conclusions: The overrepresentation of somatic PARK mutations in CM suggests shared dysregulated pathways for CM and PD. PMID:27123489

  3. Novel pathogenic mutations and skin biopsy analysis in Knobloch syndrome

    PubMed Central

    Suzuki, Oscar; Kague, Erika; Bagatini, Kelly; Tu, Hongmin; Heljasvaara, Ritva; Carvalhaes, Lorenza; Gava, Elisandra; de Oliveira, Gisele; Godoi, Paulo; Oliva, Glaucius; Kitten, Gregory; Pihlajaniemi, Taina; Passos-Bueno, Maria-Rita

    2009-01-01

    Purpose To facilitate future diagnosis of Knobloch syndrome (KS) and better understand its etiology, we sought to identify not yet described COL18A1 mutations in KS patients. In addition, we tested whether mutations in this gene lead to absence of the COL18A1 gene product and attempted to better characterize the functional effect of a previously reported missense mutation. Methods Direct sequencing of COL18A1 exons was performed in KS patients from four unrelated pedigrees. We used immunofluorescent histochemistry in skin biopsies to evaluate the presence of type XVIII collagen in four KS patients carrying two already described mutations: c.3277C>T, a nonsense mutation, and c.3601G>A, a missense mutation. Furthermore, we determined the binding properties of the mutated endostatin domain p.A1381T (c.3601G>A) to extracellular matrix proteins using ELISA and surface plasmon resonance assays. Results We identified four novel mutations in COL18A1, including a large deletion involving exon 41. Skin biopsies from KS patients revealed lack of type XVIII collagen in epithelial basement membranes and blood vessels. We also found a reduced affinity of p.A1381T endostatin to some extracellular matrix components. Conclusions COL18A1 mutations involved in Knobloch syndrome have a distribution bias toward the coding exons of the C-terminal end. Large deletions must also be considered when point mutations are not identified in patients with characteristic KS phenotype. We report, for the first time, lack of type XVIII collagen in KS patients by immunofluorescent histochemistry in skin biopsy samples. As a final point, we suggest the employment of this technique as a preliminary and complementary test for diagnosis of KS in cases when mutation screening either does not detect mutations or reveals mutations of uncertain effect, such as the p.A1381T change. PMID:19390655

  4. Somatic CALR Mutations in Myeloproliferative Neoplasms with Nonmutated JAK2

    PubMed Central

    Baxter, E.J.; Nice, F.L.; Gundem, G.; Wedge, D.C.; Avezov, E.; Li, J.; Kollmann, K.; Kent, D.G.; Aziz, A.; Godfrey, A.L.; Hinton, J.; Martincorena, I.; Van Loo, P.; Jones, A.V.; Guglielmelli, P.; Tarpey, P.; Harding, H.P.; Fitzpatrick, J.D.; Goudie, C.T.; Ortmann, C.A.; Loughran, S.J.; Raine, K.; Jones, D.R.; Butler, A.P.; Teague, J.W.; O’Meara, S.; McLaren, S.; Bianchi, M.; Silber, Y.; Dimitropoulou, D.; Bloxham, D.; Mudie, L.; Maddison, M.; Robinson, B.; Keohane, C.; Maclean, C.; Hill, K.; Orchard, K.; Tauro, S.; Du, M.-Q.; Greaves, M.; Bowen, D.; Huntly, B.J.P.; Harrison, C.N.; Cross, N.C.P.; Ron, D.; Vannucchi, A.M.; Papaemmanuil, E.; Campbell, P.J.; Green, A.R.

    2014-01-01

    BACKGROUND Somatic mutations in the Janus kinase 2 gene (JAK2) occur in many myeloproliferative neoplasms, but the molecular pathogenesis of myeloproliferative neoplasms with nonmutated JAK2 is obscure, and the diagnosis of these neoplasms remains a challenge. METHODS We performed exome sequencing of samples obtained from 151 patients with myeloproliferative neoplasms. The mutation status of the gene encoding calreticulin (CALR) was assessed in an additional 1345 hematologic cancers, 1517 other cancers, and 550 controls. We established phylogenetic trees using hematopoietic colonies. We assessed calreticulin subcellular localization using immunofluorescence and flow cytometry. RESULTS Exome sequencing identified 1498 mutations in 151 patients, with medians of 6.5, 6.5, and 13.0 mutations per patient in samples of polycythemia vera, essential thrombocythemia, and myelofibrosis, respectively. Somatic CALR mutations were found in 70 to 84% of samples of myeloproliferative neoplasms with nonmutated JAK2, in 8% of myelodysplasia samples, in occasional samples of other myeloid cancers, and in none of the other cancers. A total of 148 CALR mutations were identified with 19 distinct variants. Mutations were located in exon 9 and generated a +1 base-pair frameshift, which would result in a mutant protein with a novel C-terminal. Mutant calreticulin was observed in the endoplasmic reticulum without increased cell-surface or Golgi accumulation. Patients with myeloproliferative neoplasms carrying CALR mutations presented with higher platelet counts and lower hemoglobin levels than patients with mutated JAK2. Mutation of CALR was detected in hematopoietic stem and progenitor cells. Clonal analyses showed CALR mutations in the earliest phylogenetic node, a finding consistent with its role as an initiating mutation in some patients. CONCLUSIONS Somatic mutations in the endoplasmic reticulum chaperone CALR were found in a majority of patients with myeloproliferative neoplasms with

  5. Le contrôle des infections au cabinet du pédiatre

    PubMed Central

    2008-01-01

    RÉSUMÉ La transmission des infections au cabinet du pédiatre est de plus en plus préoccupante. Le présent document expose les voies de transmission des infections et les principes sous-jacents aux mesures actuelles pour contrôler les infections. Pour prévenir les infections, il faut bien concevoir le cabinet et adopter des politiques administratives et de triage convenables, de même que des pratiques de base pour les soins de tous les patients (p. ex., hygiène des mains, port de gants, de masques, de lunettes de protection et d’une blouse d’hôpital pour des interventions précises; nettoyage, désinfection et stérilisation convenables des surfaces et du matériel, y compris les jouets, et techniques d’asepsie en cas d’interventions effractives) et des précautions additionnelles en cas d’infections précises. Le personnel doit avoir reçu les vaccins pertinents, et les personnes infectées doivent respecter les politiques de restriction au travail.

  6. Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene (SLC26A2): 22 novel mutations, mutation review, associated skeletal phenotypes, and diagnostic relevance.

    PubMed

    Rossi, A; Superti-Furga, A

    2001-03-01

    Mutations in the DTDST gene can result in a family of skeletal dysplasia conditions which comprise two lethal disorders, achondrogenesis type 1B (ACG1B) and atelosteogenesis type 2 (AO2); and two non-lethal disorders, diastrophic dysplasia (DTD) and recessive multiple epiphyseal dysplasia (rMED). The gene product is a sulfate-chloride exchanger of the cell membrane. Inactivation of the sulfate exchanger leads to intracellular sulfate depletion and to the synthesis of undersulfated proteoglycans in susceptible cells such as chondrocytes and fibroblasts. Genotype-phenotype correlations are recognizable, with mutations predicting a truncated protein or a non-conservative amino acid substitution in a transmembrane domain giving the severe phenotypes, and non-transmembrane amino acid substitutions and splice site mutations giving the milder phenotypes. The clinical phenotype is modulated strictly by the degree of residual activity. Over 30 mutations have been observed, including 22 novel mutations reported here. The most frequent mutation, 862C>T (R279W), is a mild mutation giving the rMED phenotype when homozygous and mostly DTD when compounded; occurrence at a CpG dinucleotide and its panethnic distribution suggest independent recurrence. Mutation IVS1+2T>C is the second most common mutation, but is very frequent in Finland. It produces low levels of correctly spliced mRNA, and results in DTD when homozygous. Two other mutations, 1045-1047delGTT (V340del) and 558C>T (R178X), are associated with severe phenotypes and have been observed in multiple patients. Most other mutations are rare. Heterozygotes are clinically unaffected. When clinical samples are screened for radiologic and histologic features compatible with the ACG1B/AO2/DTD/rMED spectrum prior to analysis, the mutation detection rate is high (over 90% of alleles), and appropriate genetic counseling can be given. The sulfate uptake or sulfate incorporation assays in cultured fibroblasts have largely been

  7. Lignes directrices canadiennes sur l’utilisation sécuritaire et efficace des opioïdes pour la douleur chronique non cancéreuse

    PubMed Central

    Kahan, Meldon; Mailis-Gagnon, Angela; Wilson, Lynn; Srivastava, Anita

    2011-01-01

    Résumé Objectif Présenter aux médecins de famille un résumé clinique pratique des lignes directrices canadiennes sur l’utilisation sécuritaire et efficace des opioïdes pour la douleur chronique non cancéreuse, produites par le National Opioid Use Guideline Group. Qualité des données Pour produire les lignes directrices, les chercheurs ont effectué une synthèse critique de la littérature médicale sur l’efficacité et l’innocuité des opioïdes pour la douleur chronique non cancéreuse et ont rédigé une série de recommandations. Un panel de 49 cliniciens experts de toutes les régions du Canada ont passé en revue l’ébauche et ont atteint un consensus sur 24 recommandations. Message principal Il est recommandé de faire un dépistage du risque de dépendance avant de prescrire des opioïdes. On recommande des opioïdes faibles (codéine et tramadol) pour une douleur de légère à modérée qui n’a pas répondu aux traitements de première intention. On peut essayer l’oxycodone, l’hydromorphone et la morphine chez les patients qui n’ont pas eu de soulagement avec des opioïdes plus faibles. Une faible dose initiale et une lente hausse du titrage sont recommandées, ainsi qu’une étroite surveillance du patient qu’on a d’abord renseigné. Les médecins doivent surveiller l’apparition de complications comme l’apnée du sommeil. La dose optimale est celle qui améliore le fonctionnement ou atténue les cotes d’évaluation de la douleur d’au moins 30 %. Pour la grande majorité des patients, la dose optimale sera bien en deçà de l’équivalent de 200 mg de morphine par jour. On recommande le sevrage progressif pour les patients qui n’ont pas répondu à un essai d’opioïdes adéquat. Conclusion Les opioïdes jouent un rôle important dans la prise en charge de la douleur chronique non cancéreuse, mais il faut en prescrire avec prudence pour limiter les dommages potentiels. Les nouvelles lignes directrices

  8. Comprendre la maltraitance des aînés en pratique familiale

    PubMed Central

    Yaffe, Mark J.; Tazkarji, Bachir

    2012-01-01

    Résumé Objectif Présenter ce qui constitue la maltraitance des aînés, ce dont les médecins de famille devraient être au courant, les signes et les symptômes laissant présager de mauvais traitements chez des adultes plus âgés, comment l’outil Elder Abuse Suspicion Index peut aider à détecter la maltraitance et les options qui existent pour réagir en cas de soupçons de maltraitance. Sources des données On a fait une recension dans MEDLINE, PsycINFO et Social Work Abstracts pour trouver des publications en français ou en anglais, de 1970 à 2011, à l’aide des expressions elder abuse, elder neglect, elder mistreatment, seniors, older adults, violence, identification, detection tools et signs and symptoms. Les publications pertinentes ont fait l’objet d’un examen. Message principal La maltraitance des aînés est une cause importante de morbidité et de mortalité chez les adultes plus âgés. Si les médecins de famille sont bien placés pour détecter des mauvais traitements infligés aux aînés, leurs taux réels de signalement de cas de maltraitance sont plus faibles que dans d’autres professions. Cette situation pourrait s’améliorer s’ils comprenaient mieux les genres d’agissements qui constituent de la maltraitance des aînés, ainsi que les signes et les symptômes observés au bureau qui pourraient pointer vers des cas de mauvais traitements. La détection de tels cas pourrait être facilitée par le recours à un court outil validé, comme l’Elder Abuse Suspicion Index. Conclusion Les médecins de famille peuvent jouer un rôle plus important dans la détection d’une éventuelle maltraitance des aînés. Une fois qu’on soupçonne de mauvais traitements, il existe dans la plupart des communautés des services sociaux ou des forces de l’ordre accessibles pour effectuer des évaluations plus approfondies et intervenir.

  9. [Treatment of BRAF-mutated metastatic melanoma].

    PubMed

    Boyles, Tessa Bystrup; Svane, Inge Marie; Bastholt, Lars; Schmidt, Henrik

    2016-08-29

    Melanoma is an aggressive form of skin cancer which is the cause of a great number of skin cancer-related deaths worldwide and about 300 deaths in Denmark. After several years of failure of treatment of metastatic melanoma, the development of BRAF- and later MEK inhibitors was considered revolutionary. Treatment with BRAF inhibitors alone and especially in combination with a MEK inhibitor improves outcome for patients with BRAF V600-mutated metastatic melanoma. However, even when treated with the combination of the inhibitors, many patients develop acquired resistance within a year. PMID:27592869

  10. Equine diseases caused by known genetic mutations.

    PubMed

    Finno, Carrie J; Spier, Sharon J; Valberg, Stephanie J

    2009-03-01

    The recent development of equine genome maps by the equine genome community and the complete sequencing of the horse genome performed at the Broad Institute have accelerated the pace of genetic discovery. This review focuses on genetic diseases in the horse for which a mutation is currently known, including hyperkalemic periodic paralysis, severe combined immunodeficiency, overo lethal white syndrome, junctional epidermolysis bullosa, glycogen branching enzyme deficiency, malignant hyperthermia, hereditary equine regional dermal asthenia, and polysaccharide storage myopathy. Emphasis is placed on the prevalence, clinical signs, etiology, diagnosis, treatment and prognosis for each disease.

  11. Novel MPZ mutations and congenital hypomyelinating neuropathy

    PubMed Central

    McMillan, Hugh J.; Santagata, Sandro; Shapiro, Frederic; Batish, Sat Dev; Couchon, Libby; Donnelly, Stephen; Kang, Peter B.

    2010-01-01

    We report two new MPZ mutations causing congenital hypomyelinating neuropathies; c.368_382delGCACGTTCACTTGTG (in-frame deletion of five amino acids) and c.392A>G, Asn131Ser. Each child had clinical and electrodiagnostic features consistent with an inherited neuropathy, confirmed by sural nerve biopsy. The cases illustrate the clinically heterogeneity that exists even within early-onset forms of this disease. They also lend additional support to the emerging clinical and laboratory evidence that impaired intracellular protein trafficking may represent the cause of some congenital hypomyelinating neuropathies. PMID:20621479

  12. A novel mutation in type II methemoglobinemia.

    PubMed

    Hudspeth, Michelle P; Joseph, Sumy; Holden, Kenton R

    2010-01-01

    Type II methemoglobinemia is a somatic deficiency of cytochrome b5 reductase with severe global neurologic impairment. We report a novel mutation in exon 3 of the CYB5R3 gene on chromosome 22 consisting of homozygous 1-base pair (bp) deletion noted as c.215delG; p.Gly72AlafsX100. The patient had improvement of gross motor skills, chewing, and swallowing that may be due to the initiation of daily ascorbic acid therapy. We hypothesize that a possible response to ascorbic acid may be related to the effect of making additional ferrous iron available for its role as a cofactor in carnitine synthesis. PMID:19471045

  13. Defining actionable mutations for oncology therapeutic development.

    PubMed

    Carr, T Hedley; McEwen, Robert; Dougherty, Brian; Johnson, Justin H; Dry, Jonathan R; Lai, Zhongwu; Ghazoui, Zara; Laing, Naomi M; Hodgson, Darren R; Cruzalegui, Francisco; Hollingsworth, Simon J; Barrett, J Carl

    2016-04-26

    Genomic profiling of tumours in patients in clinical trials enables rapid testing of multiple hypotheses to confirm which genomic events determine likely responder groups for targeted agents. A key challenge of this new capability is defining which specific genomic events should be classified as 'actionable' (that is, potentially responsive to a targeted therapy), especially when looking for early indications of patient subgroups likely to be responsive to new drugs. This Opinion article discusses some of the different approaches being taken in early clinical development to define actionable mutations, and describes our strategy to address this challenge in early-stage exploratory clinical trials. PMID:27112209

  14. Mutations in ZBTB20 cause Primrose syndrome.

    PubMed

    Cordeddu, Viviana; Redeker, Bert; Stellacci, Emilia; Jongejan, Aldo; Fragale, Alessandra; Bradley, Ted E J; Anselmi, Massimiliano; Ciolfi, Andrea; Cecchetti, Serena; Muto, Valentina; Bernardini, Laura; Azage, Meron; Carvalho, Daniel R; Espay, Alberto J; Male, Alison; Molin, Anna-Maja; Posmyk, Renata; Battisti, Carla; Casertano, Alberto; Melis, Daniela; van Kampen, Antoine; Baas, Frank; Mannens, Marcel M; Bocchinfuso, Gianfranco; Stella, Lorenzo; Tartaglia, Marco; Hennekam, Raoul C

    2014-08-01

    Primrose syndrome and 3q13.31 microdeletion syndrome are clinically related disorders characterized by tall stature, macrocephaly, intellectual disability, disturbed behavior and unusual facial features, with diabetes, deafness, progressive muscle wasting and ectopic calcifications specifically occurring in the former. We report that missense mutations in ZBTB20, residing within the 3q13.31 microdeletion syndrome critical region, underlie Primrose syndrome. This finding establishes a genetic link between these disorders and delineates the impact of ZBTB20 dysregulation on development, growth and metabolism.

  15. Emerging pathogens: Dynamics, mutation and drug resistance

    SciTech Connect

    Perelson, A.S.; Goldstein, B.; Korber, B.T.

    1997-10-01

    This is the final report of a one-year, Laboratory Directed Research and Development (LDRD) project at Los Alamos National Laboratory (LANL). The objectives of this project were to develop models of the spread of pathogens, such as HIV-1 and influenza, in humans, and then to use the models to address the possibility of designing appropriate drug therapies that may limit the ability of the pathogen to escape treatment by mutating into a drug resistant form. We have developed a model of drug-resistance to amantidine and rimantadine, the two major antiviral drugs used to treat influenza, and have used the model to suggest treatment strategies during an epidemic.

  16. What We Did Last Summer: Depicting DES Data to Enhance Simulation Utility and Use

    NASA Technical Reports Server (NTRS)

    Elfrey, Priscilla; Conroy, Mike; Lagares, Jose G.; Mann, David; Fahmi, Mona

    2009-01-01

    At Kennedy Space Center (KSC), an important use of Discrete Event Simulation (DES) addresses ground operations .of missions to space. DES allows managers, scientists and engineers to assess the number of missions KSC can complete on a given schedule within different facilities, the effects of various configurations of resources and detect possible problems or unwanted situations. For fifteen years, DES has supported KSC efficiency, cost savings and improved safety and performance. The dense and abstract DES data, however, proves difficult to comprehend and, NASA managers realized, is subject to misinterpretation, misunderstanding and even, misuse. In summer 2008, KSC developed and implemented a NASA Exploration Systems Mission Directorate (ESMD) project based on the premise that visualization could enhance NASA's understanding and use of DES.

  17. Approche à l’égard des nouveaux anticoagulants oraux en pratique familiale

    PubMed Central

    Douketis, James; Bell, Alan David; Eikelboom, John; Liew, Aaron

    2014-01-01

    Résumé Objectif Comparer les caractéristiques principales des nouveaux anticoagulants oraux (NACO), soit le dabigatran, le rivaroxaban et l’apixaban, et répondre aux questions qui font surface lors de la comparaison de ces agents. Qualité des données Une recherche dans PubMed a été effectuée afin de relever les études cliniques récentes (de janvier 2008 à la semaine 32 de 2013) portant sur l’emploi des NACO pour la prévention des AVC dans les cas de fibrillation auriculaire (FA) et pour le traitement de la thromboembolie veineuse aiguë. Message principal Selon 3 essais d’envergure, tous les NACO sont au moins aussi efficaces que la warfarine dans la prévention des AVC chez les patients atteints d’une FA non valvulaire, et au moins aussi sûrs pour ce qui est du risque de saignement. Des méta-analyses de ces essais ont montré que, comparativement au traitement par la warfarine, les NACO avaient réduit la mortalité totale, la mortalité d’origine cardiovasculaire et les saignements intracrâniens, et était aussi ressortie une tendance vers la réduction des saignements généraux. Du côté pratique, les avantages des NACO par rapport à la warfarine sont : posologie orale fixe uniquotidienne ou biquotidienne sans devoir surveiller la coagulation et peu d’interactions connues ou définies avec d’autres médicaments ou des aliments. Les désavantages potentiels des NACO sont notamment un risque de saignement qui serait accru chez les patients de plus de 75 ans, une hausse des saignements gastro-intestinaux majeurs avec des doses élevées de dabigatran, une hausse des cas de dyspepsie avec le dabigatran, l’absence d’un test de laboratoire de routine visant à mesurer de façon fiable l’effet anticoagulant et l’absence d’antidote pour renverser l’effet anticoagulant. Aucun essai randomisé contrôlé n’a effectué de comparaison directe des NACO, et le choix d’un NACO est influencé par les caract

  18. Influence des défauts de la structure du verre sur la résistance mécanique des fibres optiques

    NASA Astrophysics Data System (ADS)

    Chmel, A.; Baptizmanski, V. V.; Kharshak, A. A.

    1992-12-01

    For silica (pure and doped) optical fibers prepared from preforms irradiated by thermal neutrons and Ar^+ ions, the measurements of lifetime under transverse stress were carried out. It is found that the neutron bombardment leads to decrease of the lifetime and the strength of fiber while the ion implantation results in increasing of these parameters. The influence of particle irradiation on the glass strength is explained by the generation of structural defects which were observed by the infrared an Raman spectroscopy methods. The direction of the change of mechanical properties of fibers is determined by the type of defects and their distribution in the cross-section of fiber. Des préformes de fibres optiques de silice ont été exposées à un bombardement par des faisceaux de neutrons thermiques et d'ions Ar^+ à énergie de 40 keV afin d'engendrer des défauts de la structure respectivement dans le volume ou dans la couche superficielle des échantillons. Les fibres obtenues des préformes irradiées et non irradiées ont été mises en charge de flexion. On a déterminé leur temps de rupture sous diverses contraintes de traction sur la surface extérieure de la fibre en flexion. On a observé une diminution du temps de rupture des fibres après le bombardement neutronique et une augmentation après l'implantation ionique. L'analyse de la nature des défauts en faisant appel à la spectroscopie infrarouge et Raman a fait ressortir que l'irradiation aux ions entraînait essentiellement des liaisons chimiques dans une fine couche superficielle de l'échantillon alors que l'irradiation aux neutrons occasionnait une déformation des zones du réseau silicique dans toute la section de la préforme et de la fibre. L'amélioration de la résistance mécanique s'explique par une augmentation de la mobilité des éléments structuraux de la matrice de verre par suite d'une rupture partielle des liaisons chimiques et sa diminution par l'apparition de concentrateurs

  19. Prévalence des cervicalgies et douleurs des membres supérieures chez les utilisateurs d'ordinateur en milieu professionnel à Casablanca (Maroc)

    PubMed Central

    Seknaji, Nawal; Rachidi, Wafaa; Hassoune, Samira; Janani, Saadia; Nani, Samira; Maaroufi, Abderrahmane; Mkinsi, Ouafaa

    2013-01-01

    Introduction Les cervicalgies et douleurs du membre supérieur (CDMS) affectent des millions d'utilisateurs d'ordinateurs dans les pays développés. L'objectif de ce travail était de déterminer la prévalence des cervicalgies et douleurs du membre supérieur (CDMS) à Casablanca et identifier les différents facteurs de risque qui y sont impliqués, afin de définir les sous-groupes à haut risque, et d’établir des plans d'intervention efficaces. Méthodes Il s'agit d'une étude transversale, menée chez 118 employés de bureau francophones et utilisant l'ordinateur, à Casablanca. Les données ont été collectées de Décembre 2011 à Juin 2012, en utilisant la version française d'un questionnaire validé: Maastricht-Upper-extremity-Questionnaire. Résultats 118 utilisateurs d'ordinateur en milieu professionnel ont été recrutés. Parmi les employés enquêtés, 93% ont rapporté des CDMS localisées au moins à un site. Les plaintes les plus fréquemment rapportées étaient les douleurs des épaules et les cervicalgies (48,3% et 46,6% respectivement). Nous n'avons pas remarqué de différence significative des fréquences des douleurs selon le genre. Nos résultats concordent avec les données de la littérature où il existe un certain consensus quant à l'impact des mauvaises conditions ergonomiques sur les troubles musculo-squelettiques du membre supérieur en milieu professionnel. De même, les études récentes examinant les effets combinés et/ou interactifs tant des facteurs biomécaniques/physiques que de facteurs psychosociaux professionnels vont de pair avec nos résultats. Conclusion Il en ressort que les stratégies d'intervention visant à réduire les CDMS doivent agir essentiellement sur 3 volets, le premier correspond à l'amélioration et la sensibilisation quant au respect des conditions ergonomiques, le second concerne l'amélioration des conditions psychosociales. Enfin le troisième volet vise la rationalisant de la demande de

  20. Glucose-6-phosphate dehydrogenase (G6PD) mutations database: review of the "old" and update of the new mutations.

    PubMed

    Minucci, Angelo; Moradkhani, Kamran; Hwang, Ming Jing; Zuppi, Cecilia; Giardina, Bruno; Capoluongo, Ettore

    2012-03-15

    In the present paper we have updated the G6PD mutations database, including all the last discovered G6PD genetic variants. We underline that the last database has been published by Vulliamy et al. [1] who analytically reported 140 G6PD mutations: along with Vulliamy's database, there are two main sites, such as http://202.120.189.88/mutdb/ and www.LOVD.nl/MR, where almost all G6PD mutations can be found. Compared to the previous mutation reports, in our paper we have included for each mutation some additional information, such as: the secondary structure and the enzyme 3D position involving by mutation, the creation or abolition of a restriction site (with the enzyme involved) and the conservation score associated with each amino acid position. The mutations reported in the present tab have been divided according to the gene's region involved (coding and non-coding) and mutations affecting the coding region in: single, multiple (at least with two bases involved) and deletion. We underline that for the listed mutations, reported in italic, literature doesn't provide all the biochemical or bio-molecular information or the research data. Finally, for the "old" mutations, we tried to verify features previously reported and, when subsequently modified, we updated the specific information using the latest literature data. PMID:22293322

  1. Somatic CTNNB1 mutation in hepatoblastoma from a patient with Simpson-Golabi-Behmel syndrome and germline GPC3 mutation.

    PubMed

    Kosaki, Rika; Takenouchi, Toshiki; Takeda, Noriko; Kagami, Masayo; Nakabayashi, Kazuhiko; Hata, Kenichiro; Kosaki, Kenjiro

    2014-04-01

    Simpson-Golabi-Behmel syndrome is a rare overgrowth syndrome caused by the GPC3 mutation at Xq26 and is clinically characterized by multiple congenital abnormalities, intellectual disability, pre/postnatal overgrowth, distinctive craniofacial features, macrocephaly, and organomegaly. Although this syndrome is known to be associated with a risk for embryonal tumors, similar to other overgrowth syndromes, the pathogenetic basis of this mode of tumorigenesis remains largely unknown. Here, we report a boy with Simpson-Golabi-Behmel syndrome who had a germline loss-of function mutation in GPC3. At 9 months of age, he developed hepatoblastoma. A comparison of exome analysis results for the germline genome and for the tumor genome revealed a somatic mutation, p.Ile35Ser, within the degradation targeting box of β-catenin. The same somatic mutation in CTNNB1 has been repeatedly reported in hepatoblastoma and other cancers. This finding suggested that the CTNNB1 mutation in the tumor tissue represents a driver mutation and that both the GPC3 and the CTNNB1 mutations contributed to tumorigenesis in a clearly defined sequential manner in the propositus. The current observation of a somatic CTNNB1 mutation in a hepatoblastoma from a patient with a germline GPC3 mutation supports the notion that the mutation in GPC3 may influence one of the initial steps in tumorigenesis and the progression to hepatoblastoma. PMID:24459012

  2. Somatic CTNNB1 mutation in hepatoblastoma from a patient with Simpson-Golabi-Behmel syndrome and germline GPC3 mutation.

    PubMed

    Kosaki, Rika; Takenouchi, Toshiki; Takeda, Noriko; Kagami, Masayo; Nakabayashi, Kazuhiko; Hata, Kenichiro; Kosaki, Kenjiro

    2014-04-01

    Simpson-Golabi-Behmel syndrome is a rare overgrowth syndrome caused by the GPC3 mutation at Xq26 and is clinically characterized by multiple congenital abnormalities, intellectual disability, pre/postnatal overgrowth, distinctive craniofacial features, macrocephaly, and organomegaly. Although this syndrome is known to be associated with a risk for embryonal tumors, similar to other overgrowth syndromes, the pathogenetic basis of this mode of tumorigenesis remains largely unknown. Here, we report a boy with Simpson-Golabi-Behmel syndrome who had a germline loss-of function mutation in GPC3. At 9 months of age, he developed hepatoblastoma. A comparison of exome analysis results for the germline genome and for the tumor genome revealed a somatic mutation, p.Ile35Ser, within the degradation targeting box of β-catenin. The same somatic mutation in CTNNB1 has been repeatedly reported in hepatoblastoma and other cancers. This finding suggested that the CTNNB1 mutation in the tumor tissue represents a driver mutation and that both the GPC3 and the CTNNB1 mutations contributed to tumorigenesis in a clearly defined sequential manner in the propositus. The current observation of a somatic CTNNB1 mutation in a hepatoblastoma from a patient with a germline GPC3 mutation supports the notion that the mutation in GPC3 may influence one of the initial steps in tumorigenesis and the progression to hepatoblastoma.

  3. Systematic Mapping of Protein Mutational Space by Prolonged Drift Reveals the Deleterious Effects of Seemingly Neutral Mutations.

    PubMed

    Rockah-Shmuel, Liat; Tóth-Petróczy, Ágnes; Tawfik, Dan S

    2015-08-01

    Systematic mappings of the effects of protein mutations are becoming increasingly popular. Unexpectedly, these experiments often find that proteins are tolerant to most amino acid substitutions, including substitutions in positions that are highly conserved in nature. To obtain a more realistic distribution of the effects of protein mutations, we applied a laboratory drift comprising 17 rounds of random mutagenesis and selection of M.HaeIII, a DNA methyltransferase. During this drift, multiple mutations gradually accumulated. Deep sequencing of the drifted gene ensembles allowed determination of the relative effects of all possible single nucleotide mutations. Despite being averaged across many different genetic backgrounds, about 67% of all nonsynonymous, missense mutations were evidently deleterious, and an additional 16% were likely to be deleterious. In the early generations, the frequency of most deleterious mutations remained high. However, by the 17th generation, their frequency was consistently reduced, and those remaining were accepted alongside compensatory mutations. The tolerance to mutations measured in this laboratory drift correlated with sequence exchanges seen in M.HaeIII's natural orthologs. The biophysical constraints dictating purging in nature and in this laboratory drift also seemed to overlap. Our experiment therefore provides an improved method for measuring the effects of protein mutations that more closely replicates the natural evolutionary forces, and thereby a more realistic view of the mutational space of proteins.

  4. Isolation and Characterization of Dominant Female Sterile Mutations of Drosophila Melanogaster. I. Mutations on the Third Chromosome

    PubMed Central

    Erdelyi, M.; Szabad, J.

    1989-01-01

    Fifty-one dominant female sterile (Fs) mutations linked to the third chromosome of Drosophila melanogaster are described. EMS induced Fs mutations arise with the frequency of one Fs per about 2500 recessive lethals. Complementation analysis of the revertants showed that these Fs mutations represent 27-34 loci, about 60% of the third chromosome units mutable to dominant female sterility by EMS. The Fs mutations were mapped on the basis of mitotic recombination induced in the female (in 16 cases also in the male) germ-line. Behavior of the revertants and the Fs(+) germ-line clones demonstrate the gain-of-function nature of the Fs alleles. With two exceptions, the Fs(3) mutations are germ-line dependent. Novel phenotypes appeared in most of the Fs mutations. With eight exceptions, the Fs(3) mutations are fully penetrant, in some cases with variable expressivity. One of the Fs(3) mutations is a non-ovary-dependent egg retention mutation, two others alter egg shape, and 27 bring about arrest in development at about the time of fertilization. In 21 of the Fs(3) mutations embryos develop to the larval stage of differentiation; this group includes 5 new alleles of Toll and 4 of easter. PMID:2499514

  5. Systematic Mapping of Protein Mutational Space by Prolonged Drift Reveals the Deleterious Effects of Seemingly Neutral Mutations

    PubMed Central

    Rockah-Shmuel, Liat; Tóth-Petróczy, Ágnes; Tawfik, Dan S.

    2015-01-01

    Systematic mappings of the effects of protein mutations are becoming increasingly popular. Unexpectedly, these experiments often find that proteins are tolerant to most amino acid substitutions, including substitutions in positions that are highly conserved in nature. To obtain a more realistic distribution of the effects of protein mutations, we applied a laboratory drift comprising 17 rounds of random mutagenesis and selection of M.HaeIII, a DNA methyltransferase. During this drift, multiple mutations gradually accumulated. Deep sequencing of the drifted gene ensembles allowed determination of the relative effects of all possible single nucleotide mutations. Despite being averaged across many different genetic backgrounds, about 67% of all nonsynonymous, missense mutations were evidently deleterious, and an additional 16% were likely to be deleterious. In the early generations, the frequency of most deleterious mutations remained high. However, by the 17th generation, their frequency was consistently reduced, and those remaining were accepted alongside compensatory mutations. The tolerance to mutations measured in this laboratory drift correlated with sequence exchanges seen in M.HaeIII’s natural orthologs. The biophysical constraints dictating purging in nature and in this laboratory drift also seemed to overlap. Our experiment therefore provides an improved method for measuring the effects of protein mutations that more closely replicates the natural evolutionary forces, and thereby a more realistic view of the mutational space of proteins. PMID:26274323

  6. Mutations affecting the chemosensory neurons of Caenorhabditis elegans

    SciTech Connect

    Starich, T.A.; Herman, R.K.; Kari, C.K.

    1995-01-01

    We have identified and characterized 95 mutations that reduce or abolish dye filling of amphid and phasmid neurons and that have little effect on viability, fertility or movement. Twenty-seven mutations occurred spontaneously in strains with a high frequency of transposon insertion. Sixty-eight were isolated after treatment with EMS. All of the mutations result in defects in one or more chemosensory responses, such as chemotaxis to ammonium chloride or formation of dauer larvae under conditions of starvation and overcrowding. Seventy-five of the mutations are alleles of 12 previously defined genes, mutations which were previously shown to lead to defects in amphid ultrastructure. We have assigned 20 mutations to 13 new genes, called dyf-1 through dyf-13. We expect that the genes represented by dye-filling defective mutants are important for the differentiation of amphid and phasmid chemosensilla. 58 refs., 3 figs., 6 tabs.

  7. PHF6 mutations in adult acute myeloid leukemia.

    PubMed

    Van Vlierberghe, P; Patel, J; Abdel-Wahab, O; Lobry, C; Hedvat, C V; Balbin, M; Nicolas, C; Payer, A R; Fernandez, H F; Tallman, M S; Paietta, E; Melnick, A; Vandenberghe, P; Speleman, F; Aifantis, I; Cools, J; Levine, R; Ferrando, A

    2011-01-01

    Loss of function mutations and deletions encompassing the plant homeodomain finger 6 (PHF6) gene are present in about 20% of T-cell acute lymphoblastic leukemias (ALLs). Here, we report the identification of recurrent mutations in PHF6 in 10/353 adult acute myeloid leukemias (AMLs). Genetic lesions in PHF6 found in AMLs are frameshift and nonsense mutations distributed through the gene or point mutations involving the second plant homeodomain (PHD)-like domain of the protein. As in the case of T-ALL, where PHF6 alterations are found almost exclusively in males, mutations in PHF6 were seven times more prevalent in males than in females with AML. Overall, these results identify PHF6 as a tumor suppressor gene mutated in AML and extend the role of this X-linked tumor suppressor gene in the pathogenesis of hematologic tumors.

  8. The origins, determinants, and consequences of human mutations.

    PubMed

    Shendure, Jay; Akey, Joshua M

    2015-09-25

    Germline mutations are the principal cause of heritable disease and the ultimate source of evolutionary change. Similarly, somatic mutations are the primary cause of cancer and may contribute to the burden of human disease more broadly than previously appreciated. Here, we review recent insights into the rates, spectrum, and determinants of genomic mutations and how these parameters inform our understanding of both Mendelian and complex human diseases. We also consider models for conceptualizing mutational consequences and outline several key areas for future research, including the development of new technologies to access and quantify the full spectrum of mutations, as well as to better interpret the consequences of mutations with respect to molecular functionality, evolutionary fitness, and disease pathogenicity.

  9. Update of the androgen receptor gene mutations database.

    PubMed

    Gottlieb, B; Beitel, L K; Lumbroso, R; Pinsky, L; Trifiro, M

    1999-01-01

    The current version of the androgen receptor (AR) gene mutations database is described. The total number of reported mutations has risen from 309 to 374 during the past year. We have expanded the database by adding information on AR-interacting proteins; and we have improved the database by identifying those mutation entries that have been updated. Mutations of unknown significance have now been reported in both the 5' and 3' untranslated regions of the AR gene, and in individuals who are somatic mosaics constitutionally. In addition, single nucleotide polymorphisms, including silent mutations, have been discovered in normal individuals and in individuals with male infertility. A mutation hotspot associated with prostatic cancer has been identified in exon 5. The database is available on the internet (http://www.mcgill.ca/androgendb/), from EMBL-European Bioinformatics Institute (ftp.ebi.ac.uk/pub/databases/androgen), or as a Macint